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The reactivity of some N-linked substituted-methyl groups attached to azole rings

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Title:
The reactivity of some N-linked substituted-methyl groups attached to azole rings
Creator:
Lam, Jamshed Noshir, 1957-
Publication Date:
Language:
English
Physical Description:
ix, 184 leaves : ill. ; 28 cm.

Subjects

Subjects / Keywords:
Anions ( jstor )
Atoms ( jstor )
Azoles ( jstor )
Benzimidazoles ( jstor )
Chlorides ( jstor )
Chromatography ( jstor )
Iodides ( jstor )
Nitrogen ( jstor )
Protons ( jstor )
Solvents ( jstor )
Benzimidazoles ( lcsh )
Benzotriazole ( lcsh )
Chemistry thesis Ph.D
Dissertations, Academic -- Chemistry -- UF
Pyrazoles ( lcsh )

Notes

Thesis:
Thesis (Ph. D.)--University of Florida, 1988
Bibliography:
Includes bibliographical references.
General Note:
Typescript.
General Note:
Vita
Statement of Responsibility:
by Jamshed Noshir Lam.

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University of Florida
Holding Location:
University of Florida
Rights Management:
Copyright [name of dissertation author]. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Resource Identifier:
024469555 ( ALEPH )
19915134 ( OCLC )
AFK9828 ( NOTIS )

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THE REACTIVITY


SOME N-LINKED SUBSTITUTED-METHYL
ATTACHED TO AZOLE RINGS


GROUPS


JAMSHED


A DISSERTATION PRESENT
OF THE UNIVERSITY OF FLOOR
OF THE REQUIREMENTS
DOCTOR OF


UNIVERSITY


NOSHIR


D TO THE GRADUATE SCHOOL
IDA IN PARTIAL FULFILLMENT
FOR THE DEGREE OF
PHILOSOPHY


FLORIDA
































To My


Parents


with


Love

















ACKNOWLEDGEMENTS



I am deeply indebted to my advisor Prof. Alan R.


Katritzky FRS,


for his invaluable guidance,


patience and


faith over the years.


It has been a pleasure working with


him.


would also like to take this opportunity to thank


the Chemistry faculty for giving me the opportunity to


work in thi


department,


especially Dr


Battiste,


Deyrup,


Jones,


and Schulman for the time they have spent as


members of my committee.


wish to thank Dr.


Steve Cato,


whose friendship,


time,


help and patience has been invaluable to me,


especially during the preparation of thi

I am extremely indebted to Dr. Saumi


s manuscript.


tra Sengupta for


all his suggestions and help and especially his


"interesting evenings of chemistry"


during those otherwise


late,


lonely nights.


thank also Dr.


Wojtek


Kuzmierkiewicz,


whose company in the lab was a blessing


and made those long hours of column chromatography

tolerable.











Special


thanks also go out to Dina Yannakopoulou,


Drs. Ramiah Murugan,


Rick Offerman and Jos6 Aurrecoechea


for their help/suggestions and discussions.


Dawn Sullivan


also deserves a special mention for all her help in the

office.


, Prem,


Sunil, Maria and Lucy have been my closest


friends in America.


I really appreciate all


the times they


went out of their way to take care of me and cheer me up:

The good times together will always be remembered.


Special


thanks are due to all


the waitresses at Cafe


Gardens for their excellent service during many ale-


shifting evenings during the last

Last but not the least, I wou

parents for all that they have do


seven years.


ld like to thank my


ne for me.


















TABLE OF CONTENTS



ACKNOWLEDGEMENTS.. .. .. ... iii

ABSTRACT.. .. .. .. ....... ..... .. .. .... .. .. v111

CHAPTERS

I. INTRODUCTION .. ...... .. .. .......... ...... 1

1 .1 Carbanions .. ................... ... 1
1 .2 Azoles ..... ........... ... ... .............. 3
1.3 General Outlook ... ....... .. 7

II. GENERATION OF a-CARBANIONS FROM 1-(PHENYLTHIO-
METHYL)BENZIMIDAZOLE AND RELATED COMPOUNDS .... 9

2.1 Introduction .. .. .. ... .. ... .. 9
2.1.1 Lithiation of Imidazole Systems ........ 10
2.1.2 Metallation of Other N-Alkylheterocycles 10
2.1.3 Aims of the Work . .. .. 14
2.2 Results and Discussion ... .. .. .. .. ..... 22
2.2.1 Preparation of 1-(Phenylthiomethyl)-
benzimidazole ...... ...... ..... ...... 22
2.2.2 Lithiation of 1-(Phenylthiomethyl)-
benzimidazole . 23
2.2.3 Lithiation of 1-(Phenylsulfinylmethyl)-
and l-(Phenylsulfonylmethyl)-
benzimidazole .. .. .. 32
2.2.3.1 Preparation of 1-(phenylsulfinyl-
methyl)- and 1-(phenylsulfonyl-
methyl)-benzimidazole .............. 32
2.2.3.2 Reaction of 1-(phenylsulfinyl-
methyl)benzimidazole with LDA and
electrophiles .. .. 33
2.2.3.3 Reaction of 1-(phenylsulfonyl-
methyl)benzimidazole with LDA and
electrophiles .. .. 35
2.2.4 Studies on 2-Phenyl-l-(phenylthio-
methyl)benzimidazole and Related
a a. a- -. .3 ^"











2.2.4.2 Condensation studies with quaternary
salts of 2-phenyl-N-(substituted-
methyl)benzimidazoles ...... .. ....
Conclusions . ...
Experimental .. .. .... .... .......


III. SYNTHESIS AND REACTIONS OF SOME BENZOTRIAZOLE
DERIVATIVES ... .. .. ... ... .. .. ....


3.1 Introduction .. .. .. ......
3.1.1 Selection of a Novel Activating/
Protecting Group .
3.1.2 Previous Work on (Trimethylsilylmethyl)-
azoles ...... .. ...... ... .
3.1.3 Aims of the Work .. .. .
3.2 Results and Discussion .. ... ...
3.2.1 Preparation of 1-(Trimethylsilyl)methyl-
benzotriazole . .
3.2.2 Lithiation of 1-(Trimethylsilyl)methyl-
benzotriazole and its Derivatives ....
3.2.2.1 Reactions of 1-(trimethylsilyl-
methyl)benzotriazole with n-butyl-
lithium and subsequently with
electrophiles ...
3.2.2.2 Anion formation from 1-(a-trimethyl-
silylalkyl)benzotriazole and
subsequent reactions with
electrophiles .. .. ... .
3.2.2.3 Anion formation from 1-alkenyl-
benzotriazoles .. .
3.2.3 Fluoride Catalyzed Desilylations .......
3.2.4 Acylative Desilylation .. .
3.2.5 Removal of Benzotriazole Moieties .
3.2.5.1 Reductive elimination of
benzotriazole ..... ... .... .
3.2.5.2 Attempted hydrolysis of
benzotriazolylalkenes ....... ...
3.3 Conclusions .. .. ......... .. .. .. ..
3. 4 Experimental .. .. .. ...


IV. STUDIES ON N-(SUBSTITUTED-METHYL)-3,5-DIMETHYL-
PYRAZOLES .. .. .. ... .

4 .1 Introduction ...............................
4.1.1 The Chemistry of N-Chloromethyl
Compounds . ... .
4.1.2 Synthetic Utility ... .. .. .....
4.1.2.1 Generation of N-(substituted-
_~~----------------^ _












4.1.3 Aims of the Work
4.2 Results and Discussiol


n .. ..


4.2.1 Reactions of 3,5-Dimethyl-1-(phenylthio-
methyl)pyrazole .. .. ...
4.2.2 Reaction of l-Chloromethyl-3,5-dimethyl-


pyrazolium Chloride with
Nucleophiles .. .... ...


N-. and 0-


4.2.2.1 Reaction with sulfur nucleophiles
4.2.2.2 Reaction with nitrogen and oxygen
nucleophiles .. .. ......
4.2.3 Attempted Carbanionic Rearrangements via
Three-Membered Cyclic Intermediates ....
4.2.3.1 The a-2-mercaptobenzothiazole


adducts


S. 150


4.2.3.2 The a-N,N-diethyldithiocarbamate


adducts


4.2.3.3 The a-2-pyridone adducts


......... 152
. 156


4.3 Conclusions
4.4 Experimental


............
* a S S S
S S S" S


........


............


V. SUMMARY

REFERENCES


BIOGRAPHICAL SKETCH















Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy


THE REACTIVITY OF SOME N-LINKED SUBSTITUTED-METHYL GROUPS
ATTACHED TO AZOLE RINGS



By

JAMSHED NOSHIR LAM


April 1988


Chairman: Alan R.
Major Department:


Katritzky,
Chemistry


FRS


Carbanionic species derived from N-(substituted-


methyl)azoles were studied


intermediates in synthetic


transformations at the C-a position.

1-(Phenylthiomethyl)benzimidazole underwent lithiation

initially at the 2-position. At low temperatures the

2-lithio derivative reacted with active electrophiles to


form 2-substituted products


. At higher temperatures,


rearrangement occurred to give the C-a lithiated isomer


which was trapped by benzyl bromide


However,


lithiation


was directed exclusively to the methylene group by using

the corresponding sulfoxide or sulfone derivatives.

Blocking the 2-position of the benzimidazole ring with a











The use of silicon to stabilize an


"alpha"


carbanion


was investigated in the lithiation studies of


1-(trimethylsilyl)methylbenzotriazole.


The anion was


readily alkylated and acylated and underwent Peterson


olefination with carbonyl compound


1-(Cyclohexylidene-


methyl)benzotriazole was lithiated


exc


lusively at the


a-carbon atom and the anion cleanly alkylated.

derivatives underwent fluoride catalyzed desil


carbonyl compounds.


The silyl


.ylation with


l-(a-Acylalkyl)benzotriazoles were


reduced to ketones with zinc and acid.

The synthetic utility of N-chloromethylheterocycles


was investigated with pyrazol


e as


the heterocycle.


chloride ion in l-chloromethyl-3,5-dimethylpyrazole was


readily displaced by N,


0, and


nucleophiles.


3,5-Dimethyl-1-(phenylthiomethyl)pyrazole formed a


carbanion at the

electrophiles. T


C-ao


position and reacted with


he phenylsulfenyl


group was selectively


removed by Raney-Nickel desulfurization


. The effect of an


electrophilic site


"beta"


to the carbanion generated


was


also studied in other pyrazol


promote rearrangements


e systems in attempts to


three-membered intermediates.

















CHAPTER I

INTRODUCTION



This dissertation consists of three main chapters

dealing with three different azole systems:


benzimidazole,


(ii) benzotriazole, and (iii)


pyrazole.


The work discussed here is concerned with the reactivity

at the N-substituent in these three ring systems.



1.1 Carbanions


Carbanions are synthetically u


[79MI1].


seful intermediates


One of the most common methods utilized to


generate a carbanion i


to abstract a proton.


variety of the


s the use of organometallic reagents


commercial availability of a


organometallic reagents has led to the


discovery of new functional


groups that promote


metallation and to the elaboration of novel heterocyclic

and olefinic species that can undergo metallation.


Consequently,


heteroatom-facilitated lithiation [790R1]


has been widely used not only in the elaboration of


S I I S 1


r *I 1 *I 1 1







2



Systems have been used where the negative charge is

stabilized by the inductive effect of an c-heteroatom such

as nitrogen or oxygen. In certain heterocyclic systems

(such as pyridones), stabilization of the carbanion can


also occur by co-ordination effects


83T1975].


The fact that sulfur is a strong activator was


explained by the


inductive effect of the more

nitrogen atoms [64JOM(2)304]


60JA2505,


d-a) overlap which outweighed the


electronegative oxygen and

Early theorists (56JCS4895,


74CRV157] suggested overlap of the lone pair


orbital on the carbanion with the empty d-orbitals on


sulfur provided the

arguments [60CRV147


stabilization. While there were

, 69MI1] that the empty sulfur


3d-orbitals were too high in energy to interact, Wolfe

[83TL4071] suggested that the d-orbitals were important in


lowering the energy by n-a


work [78JA1604, 83JA3789, 86JA1397


interaction. However, recent


is beginning to show


that the sulfur d-orbitals have no substantial bonding

interactions with e-carbanions. Instead it is possible

that simple coulombic interactions play a dominant role

with significant charge polarization.

While this debate lingers on, the fact remains that

the stabilization of a-carbanions by sulfur has several

consequences. As a result this property has been utilized
f l C r r 1 I n r %4- a F i n / ^si-^-^n s-I n I A.rr n. 1 4 4 J- a n











[85JOC1351,


87J(PI)781]


for stabilizing the C-a carbanion


when previously the anion was either unstable or could not

be generated.

Lithiating agents can be divided into two broad


categories.


Those that belong to the first class are the


alkyl and aryl lithiums.


nucleophili


These reagents are more


c than those of the second category which are


the n-butyllithium/amine complexes and lithium


dialkylamides. In som

may not be important.


ie cases,


the choice of the reagent


On the other hand,


there are many


instances where the nucleophilicity or


strength of the


base plays an important part in determining the outcome of

the final product.


Azoles


Azole


s are readily available heterocyclic systems.


Those azoles that contain more than one nitrogen atom


display dual property


since


e the two nitrogen atoms are


not identical.


One of the nitrogen


while


e although being


bonded to three atoms is


pair of


hybridized


electrons reside in a p-orbital


involved in the n-system.


This nitrogen


since the lone

since they are

is commonly


referred to as a pyrrole-like nitrogen atom.


The other











(the triazoles and the tetrazoles)


have their other


nitrogens pyridine like.


The additional nitrogen atoms have an inducti


electron-withdrawing effect and can provide stabilization


to negatively charged reaction intermediates.


of the additional nitrogen atoms to a


The presence


ssist in the


reactivity is demonstrated in the following two examples


which occur in these azol


e systems but


rarely observed


in pyrrole or furan or thiophene.


The nucleophilic


addition-elimination reaction (Figu


1.la)


occurs readily


in imidazol


e systems


85MI1].


Stabilization of the


intermediate anion by the additional nitrogen atom also


assi


sts in the deprotonation of substituent methyl


groups


(Figure l.lb).


a- N


a- N
//z
< ^


a--- N

b z/
^^^ 1^


a- N
b//z


a- N

--
__. N// \


a--N
b// z
< ^


2-1 I 1


._ t 1 .. 1 _- -







5



The lone pairs on nitrogen provide sites for

protonation and most azoles are stronger bases than


pyrrole.


stability of azolyl anions makes azol


containing NH groups


stronger acid


s than pyrrole


.The pK


value


s for


some


azoles are listed in Figure 1.2


[76MI1,


79MI1]


. The base


strength of th


e azoles decrease


s as


number of nitrogen atoms increa


ses.


s factor is


attributed to the inducti


electron-withdrawing effect of


the additional nitrogen atoms.


-N

N
NA


N- N


N
H


14.52


N
H


Figure 1.2


values of some azoles.


Whil


a lot of research has been carri


out on


ni C a 9 A a a I I a r











halogenation at the para position.


undergo


1-Phenylpyrazole


metallation at the ortho position of the


N-phenyl group.


1-Arylbenzotriazoles upon pyrolysis give


carbazol


[81AHC(28)2311].


Similarly,


1,5-diphenyl-


tetrazol


e undergoes thermolysis to form


2-phenylbenzimidazole


The N-alkyl


group in azolium salt


nucleophilic SN2 reaction


. However,


s can be removed by

there is competition;


example,


both N-methyl


- and N-ethyl-imidazol


are


formed in the reaction of the N-ethyl-N'-methylimidazolium

salt with iodide [80AHC(27)241].


In neutral N-alkyl azoles,


especially in


pyrazol


deprotonation occurs at the


treated with n-butyllithium.


On the


C-ao


contrary,


ition when


the more


acidic


proton is removed in l-methylbenzimidazole.


The presence of extra nitrogen atoms mak


e azol


stronger bases than pyrrole.


The stability


of azolyl


anions makes azole rings good leaving groups.

N-acylazoles are readily hydrolyzed.


Except for a few other examples,


a result,


there has been no


systematic work carried out on the generation of

carbanions at the C-a position for various N-alkyl azoles.











General Outlook


The aim of the overall project is briefly mentioned in


this section.


The specific details are discussed more


thoroughly in the corresponding chapters.


As mentioned previously, only N-alkylpyrazoles have

been lithiated at the C-a position. For benzimidazoles,


the kinetic acidity of the ring proton is greater.


Furthermore, even with a methyl or a benzyl substituent at

the 2-position, lithiation occurs at the C-2 methyl or the


methylene carbon rather than at the N-methyl site.


Thus


the aim was to find a substituent which would generate and


stabilize the carbanion at the C-a site.


Sulfur,


being a


strong a-activator was selected as the heteroatom.


phenylsulfenyl moeity would be the substituent to use.


need be,


the acidity of the adjacent methylene protons


could be further increased by oxidizing the sulfide to the

sulfoxide or to the sulfone.


In benzotriazoles, there is no competition as observed

in benzimidazole. However, the anion of 1-methyl-


benzotriazole being unstable requires the presence of a

group that can stabilize a-carbanions. Nitrogen and oxygen

while being more electronegative do not generally


stabilize a-carbanions.


This is due to the repulsion


t.1.-- I 1 1 1_ n


I^ _- L \-- 1 .. __ 1. r .S\


^ .











and is a suitable candidate in this case.


Furthermore,


silicon atom can be readily removed under moderately mild

conditions.


In pyrazoles,


since the C-a carbanion is


stable,


need of an external functionality i


not required.


Consequently,the


C-a carbanion


can be generated for a


variety of N-(substituted-methyl)pyrazoles.


derivative


These


s are in turn formed from the N-chloromethyl-


pyrazole which due to the large difference in reactivity

between the heterocycle and the chlorine atom make them

interesting synthetic intermediates.


















CHAPTER


GENERATION


a-CARBANIONS


FROM


1-(PHENYLTHIOMETHYL)-


BENZIMIDAZOLE AND


RELATED


COMPOUNDS


Introduction


An azole


ring


can


render


acidic


hydrogen


atoms


attached


carbon


least


four


distinct


environments:


ring


:CH'


a to


ring


sulfur


nitrogen;


substituent


*CHXY


attached


to a ring


carbon


a or


pyridine-like


ring


nitrogen;


substituent


*CHXY


attached


to a pyrrole-like


ring


nitrogen


atom;


ortho


:CH'


a phenyl


group


a to a pyridine-


like


ring


nitrogen.


= H,


order


kinetic


acidity


imidazole


s (as


found


hydrog


en/deuterium


exchange


or in


metallati


reactions


790R1


Figure


.1).


CHXY


I
CHXY


I I











2.1.1


Lithiation of Imidazole Systems


Kinetic acidity of the type discussed above


was


observed when 1-methyl- (2.1) and 1-benzyl-benzimidazole


(2.2) were shown to undergo lithiation at


74JOC1374). 2-Methyl- (2.3) and


[58JOC1791,


2-benzyl-benzimidazole


(2.4) when metallated with an


excess


of butyllithium react


with various electrophiles at the


methylene group [73JOC4379


Sullivan


methyl or


(Figure 2.2). Furthermore,


70JMC784] demonstrated the weakly acidic


character of the methyl protons of 2-methylbenzimidazole

(2.3) by condensing it with aromatic aldehydes in the

presence of either an acidic or a basic catalyst to form

2-styrylbenzimidazoles.


-phenylbenzimidazole (2.5) the ortho position of


the phenyl substituent


disubstituted compounds such


lithiated [78CI(L)582]


In


1,2-dimethylbenzimidazole


2.6) [76KGS1699] or 1,2-dimethylimidazole (2.7)


[83J(PI)271], metallation occurs exclusively at the C-2

methyl group. At higher temperatures, dimerizations are


observed in some


cases


[5830C1791]


2.1.2


Metallation of Other N-Alkylheterocycles











reaction with electrophiles


[790R1,


855302]


. Some of these


systems are shown in Figure


.3 and include 1-benzyl-


4,6-diphenyl-2-pyridone


(2.8)


[80J(PI)2851]


, 3-benzyl-


2-phenylquinazolin-4(3H)-one (2.9) and related compounds


[82JCR(S)26],


and N-alkylpyrazoles


(2.10)


[83T2023].


N


N
I
CH2R


CH2R


R=H


R= H


R = Ph


R = Ph


N

N

I
H


Figure


Lithiation


sites


in benzimidazole and imidazole


systems.


In all


cases


the metallations can occur at a ring


position and


in some


cases


exceptionally at


of the


alkyl radical


The carbanionic species generated from





















NhPh


Ph


2.10


Figure 2.3


Metallation studies on some other N-alkyl-
heterocycles.


A systematic study


N-benzyl- (2.10a) and N-methyl-


pyrazol


(2.10b) [83T2023] reported that


whereas the


N-substituted metallation product


2.11


was


kinetically


favored, at higher temperatures, the metal atom


observed to have

more stable 5-is


was


migrated to yield the thermodynamically


omer 2.12 (Scheme 2.1).


By contrast,


carbazol


are relatively inert to


C-lithiation [41JA1758, 43JA1729]. However, 9-ethyl-


carbazole has been


shown t


lithiate at C-i rather than











n-BuLi
-780C


LN
Li F


2.10


2.11


2.12


- Ph

- H


Scheme 2.1


The order of kinetic acidity i


s expected to change if


for the substituent


*CHXY


, X or Y i


s a heteroatom.


Katritzky et al.


[83T4133


suggested that metallation of


gem-bi


pyrazol-1-yl)methane (


2.13)


would occur at the


N-alkyl site,


due t


o the fact that the double activation


of the C-H bonds would facilitate both the


preparation and the


ease


stability of these compound


Treatment with n-butyllithium at


followed by reaction


with methyl iodide or benzyl chloride gave the expected


1-substituted derivati


2.14 (Scheme


Surprisingly,


reaction with carbonyl electrophiles under the same

conditions gave the products 2.15 which arose from ring


lithiation.


However,


with lithium diisopropylamide


(LDA)


at 0C,


exclusive a-addition occurred to give the
























n-BuLi


2.13


N

I
CH- E
I
N.


2.14


N'
NN

CH2


2.15


Scheme


2.1.3


Aims of the Work


It was


seen earlier


(Section 2.1.2)


that


C-a


metallation can compete with ring metallation.


Sulfur,


although 1


ess


electronegative than nitrogen (but similar


to carbon),


has been known to


stabili


an a-carbanion.







15



consequently able to compete with deprotonation at ring

positions ortho to the ring sulfur or nitrogen.


The presence of a phenylthi


effective in achieving N-


group did prove to be


metalation on some azol


systems in our


laboratory


Katritzky


. [87J(PI)781]


successfully lithiated 1-(phenylthiomethyl)benzotriazole


(2.16a) at the


"alpha" position to gi


corresponding


N-C,


substituted adduct 2.17


Scheme


2.3)


Thi


was in


contrast to the lithiation of 1-methylbenzotriazole


(2.16b)


[86UP1] where


either


starting material and


uncharacterizable products were obtained rather than

1-(substituted-methyl)benzotriazoles 2.18.


N
/


2.16


R = SPh


IN
"N
/


2.17


R=H


R = SPh


R =H


9 1a












A similar result


was


also achieved [85JOC1351]


in the


oc-lithiation of 9-(phenylthiomethyl)carbazol


generating N-[(phenylthio)alkyl]carbazoles


(2.19a)


2.20)


yield (Scheme 2.4


. This


was


an improvement over the


result


of Gilman and Dirby (36JOC146]


Seebach


[72CB487] where lithiation of 9


-ethylcarbazole


(2.19b)


was


shown to occur on the ring to give the C-i substituted

product 2.21.


2.19


= SPh


2.20


R =CH3


R = SPh


R= CH


2.21


Scheme 2.4


Based upon the above


success


was


decided


I 1 I I I I


11 I


* *


Y







17



was felt that the presence of a phenylthio group at the

C-a position would be more preferable than blocking the


position with an alkyl or aryl


group


. Thi


s was


attributed to the results discussed previously (


Section


2.1.1) where lithiation occurred on the

itself in the substituted benzimidazole


C-2

s 2.


substituent

3-2.6 shown in


Figure


2.2.


Success in thi


s system would help to develop a


general procedure for the synthesis and transformations of

N-substituted azoles.


NO


N
Ia
C H2SPh


RLi / E+


2.22


2.23


Scheme


The alkylation of the benzimida


phenylthiomethyl chloride


e anion with


as described by Russian authors


[69KGS934]


and in a patent


[79MIP469492]


gave low yields


crude products which necessitated chromatographi


purification. An alternative procedure for the synthesis


of 2.22 would be a nucleophi

1-(chloromethyl)benzimidazol


c substitution on


e (2.24) by thiophenol in the


N


N
N















PhSH / Base


2.24


2.22


Scheme 2.6


Successive treatment of 2.22


with base and


electrophiles should give the C-a disubstituted derivative


2.25 which


, depending on the leaving group ability of


either the heterocycle or the sulfur functionality,


could


provide the sulfide 2.26 or the 1-substituted


benzimidazole 2.27,


respectively (Scheme


however,


the ring carbon did compete


e in


metallation with the


position,


it would be ne


ces


sary


to find alternate


ves in


order to achieve


regioselect


metallation.


One alternative would be to further increase


the kinetic acidity of the N-methylene group.


s should


be possible by oxidizing the sulfur moiety in


1-(phenylthiomethyl)benzimidazole


sulfoxide 2.28 or the sulfone 2.29


2.22)


either the


Scheme


Under


conditions,


lithiation should be expected to occur


i a a I .i -^ -S


N


"-N


* I 1























2.22


N

N


2.25


2.26


N

N


2.27


Scheme


Sulfoxides which contain a 0-hydrogen undergo


elimination on pyrolysis at about 800


mechanism with syn elimination


via


60JA1810


a five-membered

, 64JOC2699,


67JOC1631]


If the derivative 2.30 contained a 3-hydrogen,


heating it would give rise to alkylidenebenzimidazoles

2.32 which would be a novel method for the preparation of
--- *- 1- ^ / n" 1- -l r















S(O), Ph


2.22


2.28
2.29


Base / E+


S(O)nPh


2.30
2.31


Scheme


SOPh


2.30


2.32







21



Previous routes to alkylidenebenzimidazoles 2.32 have

included the reaction of alkynes with benzimidazole under


high pressure


[82MI1] or the use of catalysts and high


temperature [78JHC1543,


78MI1]. Amongst the more specific


uses of these derivatives


were their use


in the synthesis


of anion exchangers [82MI1] and of their


co-


ordination


with metals in the study


of antitumor activity [83MI1].


If the above increase in acidity


was


still


sufficient


to achi


eve


regioselective lithiation


an alternative would


be to find a good blocking group for the


position.


This


would leave the


site


the only


active


site


Treatment


of such a 2-substituted-l-(phenylthiomethyl)-


benzimidazole


(2.33) with b


ase


electrophiles should


enable electrophili


c addition to be carried out at the


site to afford the required derivatives 2.34

(Scheme 2.10)


2.22


2.33


Base / E+


C-a


0 -^


I|











Alternatively,


forming the quaternary salt of the


benzimidazole derivative


2.22


was


expected to


increase the acidity of the S-methylene protons.


Treatment


of the quaternary


salt


.35 with aldehydes would thu


generate the alkylidene derivatives


in Scheme 2.11.


CH3X


depicted below


2.22


2.35


CH3




sN


2.35


RCHO


Base


X ~





CHR


Scheme 2.11


2.36


Results and Discussion


2.2.1


Preparation of i-(Phenylthiomethyl)benzimidazoie


N











(Scheme


[430SC65]


.12).


Treatment of 2.37 with formic acid at 100C


readily generated benzimidazole (2.38)


(80%


solution of 2.38 and of 37


aqueous formaldehyde in


methanol


[50JCS1600]


afforded the


corresponding


1-(hydroxymethyl)benzotriazol


(2.39


in a greater than


yield.


The chloroderivative 2.40 was obtained by


treatment with thionyl chloride (50JCS1600] and was


isolated as the hydrochloride salt


. The formation of


chloromethylazoles as the hydrochloride salts is quite

common in the case of the more basic azoles.


1-(Chloromethyl)benzotriazole i


s one of the few


such


azoles which is stable as the free base


[87J(PI)781]


Treating the hydrochloride salt 2.40 with two


equivalents


of sodium ethoxide and thiophenol afforded


1-(phenylthiomethyl)benzimidazole


(2.22


as colorless


plates in 8


2.2.2


yield.


Lithiation of 1-(Phenylthiomethyl)benzimidazole


The lithiation of 1-(phenylthiomethyl)benzimidazole


(2.22) was carried out with lithium diisopropylamide


in dry tetrahydrofuran (THF


(LDA)


at -780C and the


corresponding anion quenched with benzyl chloride.


Work up


- A I ri r rI 1 r I`









NH2


V NhM,


HCOOH


1000C


2.37


2.38


SOCI,2


CH20
MeOH


2.39


N


PhSH / NaOEt


EtOH


2.40


2.22


cheme


PhCH


2.22







25



The use of the more reactive benzyl bromide proved
*


futile,


since starting material was still observed


(ca.


30%,


estimated from the integrated 1H-NMR). Attempts to


purify the mixture


via


Kugelrohr distillation failed since


the compound decomposed at high temperatures to give

benzimidazole (2.38) and 0-phenylthiostyrene (2.42),


latter isolated in a 67% yield (Scheme


2.14).


Compound


2.41 was finally obtained in a pure


reaction temperature to


state by raising the


-200C after addition of benzyl


bromide.


Katritzky


(87J(PI)7753 al


observed


analogous behavior with


ethyl iodid


e and isopropyl iodide


electrophiles under similar conditions.


2.22


2.41


PhSCH=CHPh


2.42


2.38


Scheme


2.14


When the anion generated from 2.22 was treated with


the more reactive


electrophile methyl iodid


substituted product 2.43a


was


obtained


Thi


s was


evident


by the fact that the


1H-NMR


spectrum


of the product


*' rr I r


I


I


1 ~1I











were utilized as the electrophile


, a similar phenomenon


was observed to give the alcohols 2.43b,c in yields of


over


(Scheme 2.15).


LDA / E


2.22


2.43


E = Me

E = 4-MeCGH4CH(OH)

E = PhC(OH)


Scheme 2.15


As discussed earlier


Section 2.1.2)


, competition


between chain and ring lithiation in azole


s is quite


common.


It might be po


ble that in this system at


-78C,


both the anion


s could be formed with the ring metallated


carbanion 2.44 predominating.


The nature of the


2-lithio


derivative was such that it precipitated out of solution.


At higher temperatures (


-400C to


-200C


rearrangement


of 2.44 occurred via a transmetallation to generate the

isomeric C-a carbanion 2.45 (Scheme 2 16) which was

soluble in the solvent system employed. The fact that


4 liar av; 0 4 1 rI-c 4- t-Tr- A 4 n P ra i4 nb ,,Tv- 4 r, s 4r


r" E ^ C I h f- rt ?* 1^ nf


r. 4











with certain electrophiles to give the


substituted


derivative 2.43


On the other hand,


the isomeric carbanion


2.45 reacted with electrophiles that did not react with

the C-2 lithio derivative.


addition of 1-(phenylthiomethyl)benzimidazole


(2.22) to an LDA solution at


precipitate after


lh.


-780C afforded a yellow


When the various electrophiles


were added at


-78C,


the precipitate


either dissolved


rapidly (to give 2.43)


-400C to -20C


, or di


giving 2.41).


ssolved on slow warming at


In the former case,


products always displayed a


singlet at about 65.3


(and


integrated for two protons


, indicating no attack at the


C-a position but attack at


instead.


Hence,


in the


reactions with methyl iodide,


4-methylbenzaldehyde and


benzophenone,


the precipitate dissolved at


-780C and the


substituted product


s 2.43 were obtained.


The reaction of benzyl iodide and 2.22 at -78C


provided a mixture which,


after purification,


showed it to


be approximately a 1:1 mixture of starting material 2.22


and the complex


substituted product


ethyl)-l-(phenylthiomethyl)benzimidazol


2.17)


2-diphenyl-


(2.46)


Compound 2.46 was characterized by it


(Scheme


H-NMR


spectrum


300 MHz) which displayed a narrow AB system at


65.1


J 14.4 H
-AB


for the S-methylene group and an


fl, .. .. r',


'h MV n e, L1 i* A *- n I^t ^ "> nI -












this assignment with sp


signals at 48.6 (CH SPh),
-2


46.1


(CHPh), and 41.6 (CH Ph).
- 2


-780C


2.22


^/ -400C
to -20C


2.44


2.43


2.45


2.41


Scheme 2.16


This dibenzylation probably


ses


by the


transformation of an initial


lithiated intermediate


a reactive


benzylated intermedi


ate


which has


a more













LDA / PhCH2I


N 'Ph


2.22


2.46


Scheme 2.17


Attempts to obtain select


increasing the temperature


+

2.22


lithiation at


e of the reaction mixture before


addition of the


electrophile failed on numerous o


occasions.


Warming to


followed by addition of methyl iodide or


4-methylbenzaldehyde afforded either mixtures of


starting


material


s and


substituted products


(in yields of less


than 40%


or no reaction at all.


similar behavior


was


observed when the anion 2.44


was


allowed to warm to -400C


few hours and then


addition of the electrophile.


cooled back to -780C before


When a mixture of


n-butyllithium and N,N,N',N'-tetramethylethylenediamine


(TMEDA) was added to 2.22 in ether at


0C a dark


solution


was


obtained. Quenching with methyl iodide showed


some


-a


alkylation but only to an extent


about


30%.


t, -, -t -- -- -- I.I.2,


i, ,, i_, '1, _" 1



















































^/ r-1
IO
rI N
(a
4-4 '0
O *r



W
5
*e-4

SC



-4-)

-H O
U ..


to >t
0l-c
0 4-



cC
N )
EO

o C

S 0L

o --
m f
3>

ff; (1
S :C
2: a

t i
r-< r


-^i











In a separate experiment


, 1-(phenylthiomethyl)-


benzimidazole (2.22) was metallated with phenyllithium in


diethyl ether at -780C to gi


a pale yellow solution.


Trapping the carbanion with deuterium oxide gave


solely


the C-2 deuteriated product 2.47


Scheme


2.18)


which was


confirmed by the disappearance of the singlet at 88.06 in


1
H-NMR (DMSO-d6


spectrum of the product.


PhLi / DO20


Et2O
2


2.22


N


N


-D




SPh


2.47


Scheme 2.18


These observations wer


e quite similar to


that obtained


by Katritzky et al.


[83T4133]


see


Section


) where


lithiation of bis(pyrazol-l-yl)methane


(2.13) afforded the


1-substituted derivative 2.14 with benzyl bromid


Alternatively


, the ring substituted product 2.15 was


obtained with deuterium oxide and carbonyl compounds


electrophil


es.


By contrast,


exclusive


C-a


substitution


could be achieved by changing the base and reaction


temperature for the pyrazol


2.13,


while no change


in the


- 1- .. .-- -. -.. .-.- .- --- -


N


N


*I l-. 1 i, _1 i ~ ~1 \-- J I .















2.2.3


Lithiation of 1-(Phenylsulfinylmethyl)- and
1-(Phenylsulfonyimethyl)-benzimidazole


2.2.3.1


Preparation of 1-(phenylsulfinylmethyl)- and
1-(phenylsulfonylmethy l)-benzimidazo e


In an attempt to solve the problems of competitive


attack encountered in the metallated derivat


ives


1-(phenylthiomethyl)benzimid


azole (2.22),


was


decided


to investigate


e the


corresponding sulf


oxide


.28 and


sulfone 2.29 derivat


ives


2.22 which should display


more


kinetically


acidic N-methylene group.


Phenyl-


sulfinylmethyl)


(2.28) and 1-(phenylsulfonylmethyl)-


benzimidazole (2.29) were readily obtained


via


oxidation


of 2.22 with one and two


equivalents of m-chloroperbenzoic


acid in methylene chloride respectively


cheme


2.19).


mCPBA
CH2CI2


S(O)nPh


2.22


2.28


2.29


n=2


Crhmo ? 10Q


-ax


n = 1







33



Compounds 2.28 and 2.29 were characterized by their


elemental analyses,


IR and IH-NMR data


. The IR spectrum


for 2.28 showed the characteristic sulfoxide absorption at


1030 cm-1
1030 cm


, while the asymmetric and symmetric ab


sorptions


for the sulfone 2.29 were observed at 1320 and 1130 cm

respectively.


H-NMR spectra of the sulfoxide 2.28 were


interesting in that in DMSO-d6, the

as an AB pattern with the resonance


protons appeared


s centered at


.66 and


5.86 and having a coupling constant of J 14 Hz.


the AB pattern wa


observed upfield at


85.2


In CDCl3,

3 with the


resonances only 0.04 ppm apart


. The N-methylene protons


for the sulfone 2.29 resonated


a singlet at 6


5.46 in


CDC13 which was 0.8 ppm upfield from the resonance


observed in DMSO-d6


However,


irrespective


of the solvent


used,


the N-methylene signals for the sulfoxide


2.28


were


upfield to that


of the sulfide 2.22 while those for the


sulfone 2.29 were downfield.


2.2.3.2


Reaction of 1-(phenylsulfinylmethyl)benzimidazole
(2.28) with LDA and electrophiles


(Phenylsulfinylmethyl)benzimidazole


(2.28) underwent


lithiation with LDA at


[2-phenyl-l


-780C to give the


crude product


phenylsulfinyl)ethyl]benzimidazole


(2.30a)


. 1 A 1


r- -L ,-


A \


- -- a


I I nC1 r 1 TIIl A I I r f41 i Aj.1I ,, i


*


I~1 TE ^ *l- T I -J If


a^lQm- c t- r\ rmnt r- t h \7 ;













LDA / E*


SOPh


SOPh


2.28


2.30


E = PhCH2

E = 4-MeC6H4CH(OH)


2.30a


CHPh


2.32


Scheme 2.20


The benzylated derivative (2.30a)


was


obtained in a


reasonably pure state by triturating the crude mixture


with cyclohexanone.


On heating 2.30a in toluene,


a white


solid


was


obtained.


1H-NMR spectrum


of the solid


displayed no aliphatic resonance


s indicating the expected


elimination of the phenylsulfinyl group to give


1-styrylbenzimidazole (2.32)


Thi


s was


confirmed by


+" h 0 TPR c r* rnni r I Q -ho rkrQ rinI-o r 1-4 t -N i f Ao


N
N


r <-l F11 F ; in











generated from 2.28


was


trapped with 4-methylbenzaldehyde,


the corresponding alcohol l-(2-hydroxy

l-(phenylsulfinyl)ethyl]benzimidazole


(4-methylphenyl)-


(2.30b) was obtained


70% yield.


As can be seen,


this system seemed promising since


regi


ose


lective lithiation could be achieved here


However,


the low stability of the sulfinyl adducts 2.30a,b,


problems during purification which


caused


as a result led to the


search for a more stable system.


2.2.3.3


Reaction of 1-(phenylsulfonylmethyl)benzimidazole
(2.29) with LDA and electrophiles


Sulfones containing a 3-hydrogen are more stable than

their sulfoxide counterparts since they do not undergo


elimination


on pyrol


Thus,


the adduct


s 2.31 obtained


from the lithiation of 1-(phenylsulfonylmethyl)-


benzimidazole (2.29


should be more stable than the


sulfinyl derivati


ves


Treatment


of 2.29 with LDA


followed by addition of benzyl bromide afforded

1-[2-phenyl-l-(phenylsulfonyl)ethyl]benzimidazole (2.31a)


tan needles in


yield


Scheme


2.21).


The benzylated


sulfone 2.31a


was


stable and did not decompose even upon


heating to 2000C.


The sulfone 2.31a


was


characterized by its


1
H-NMR











at 65.47.


Each of the methylene protons also displayed


double doublet centered at 64.08 and 3.80 with a geminal


coupling constant of J 14 Hz.


This ABX system ari


ses


from


the fact that the N-C


carbon atom


asymmetric and th


renders the adjacent methylene protons diastereotropi


a result,


the two methylene protons


1
H-NMR spectrum of compound


.31a


are


was


nonequivalent


identical


The


to that of


the product obtained upon


oxidation of the benzylated


sulfide 2.41 with an


excess


of m-chloroperbenzoic acid.


LDA/ E


SO2 Ph


2.29


'mCPBA
(xs)


2.31

E = PhCH2

E = 4-MeC6H4CH(OH)


2.41


Cr rbhnn 9 31


SO2Ph







37



When 4-methylbenzaldehyde was used as the


electrophile,


-(4-methylphenyl


the corresponding alcohol 1-[2-hydroxy-


-1-(phenylsulfonyl)ethyl]benzimidazole


(2.31b) was obtained in 55


yield.


The sulfonylphenyl moeity thus


seemed to be a better


activating group enabling regioselective metallation at

the C-a position to give adducts 2.31 which were more

stable than their sulfinyl analogs 2.30.


However,


when the reaction was carried out with methyl


4-methylbenzoate or benzonitrile,


only starting material


was recovered.


2.2.4


Studies on 2-Phenyl-l-(phenylthiomethyl)-
benzimidazole and Related Compounds


2.2.4.1


Lithiation of 2-phenyl-l-(phenylthiomethyl)-
benzimidazole and related compounds


In the previous section


(Section 2.2.2)


it wa


s seen


that with the phenylthio moeity regioselective metallation

at the C-a position was only partially successful.


Increasing the kinetic acidity of the


introduction of phenylsulfinyl


C-a


(Section


proton


2.2.


s by the

and


phenylsulfonyl


Section


2.2.3.


moeities did aid in


achieving regioselective addition.


Hovever,


there were


problems


ass


ociated with these systems


(instability of the


-4 -


I *












Although 2-phenylbenzimidazole


(2.5)


s known to


undergo lithiation at the ortho position of the phenyl


substituent [78CI(L)582]


it wa


s believed that with the


presence of the thiophenol moeity attached to the


carbon it would be possible


e to selectively metallate at


"alpha" position.


2-Phenyl-l-(phenylthiomethyl)benzimidazole


(2.49) was


prepared from 1,2-phenylenediamine (2.37)


via


a two


step


procedure.


The reaction of 1,


-phenylenediamine (2.37)


with benzoic acid in phosphori


c acid at 180C


57JA427]


afforded 2-phenylbenzimidazol


prisms in


yield (Scheme


Treatment


phenylthiomethyl chloride


(2.48)


of 2.5 with


in the presence of sodium


hydride in dry dimethylformamide


1-(phenylthiomethyl)benzimidazole


DMF)


2.49)


produced 2-phenyl-


in over 80


yield.

The lithiation of 2-phenyl-l-(phenylthiomethyl)-


benzimidazole


(2.49)


was


carried


out using a mixture of


n-butyllithium-TMEDA in


ether and trapping the anion with


benzyl bromide and methyl iodide to afford


2-phenyl-


1-[2-phenyl-l-(phenylthio


ethyl]benzimidazole


(2.50a


2-phenyl-l-[1


phenylthio


ethyl]benzimidazole


(2.50b),


respectively (Scheme


In both


cases,


however,


reactions went to about 70%
1--1-.


completion (estimated from the


m 1 -. V r -. r nf l


L
















N


NH2



NH2


PhCOOH


2.37


PhSCH2CI


DMF


2.48


2.49


Scheme


Base / E+


SPh E


2.49


2.50


= PhCH2

= Me


1.-


-^ r\_











Katritzky et al.


[87J(PI)775]


also examined the


reaction of 2.49 with 4-methylbenzaldehyde to give the


corresponding alcohol


With all electrophil


employed,


only the


C-a


alkylated products were formed. No products


arising from lithiation at the ortho position of the


2-phenyl substituent wer


e identified.


In an attempt to get the reaction to go to completion,


it was again necessary to increa


protons.


the kinetic acidity of


Utilizing conditions described earlier


(Section


.2.3.1),


the sulfide 2.49


was


readily oxidized


with m-chloroperbenzoi


c acid giving 2-phenyl-l-(phenyl-


sulfinylmethyl)-


(2.51) and


2-phenyl-l-(phenylsulfonyl-


methyl)-benzimidazole (2.52)


in yields of 77


and 81%,


respectively (Scheme


H-NMR spectrum (CDC13) of


the sulfoxide 2.51 displayed an AB pattern centered at


65.35


mCPBA
CH2C1,


S(O)nPh


2.49


2.51


n = 1


2.52


n=2












The sulfoxide 2.51


was


treated with LDA and the anion


reacted with benzyl bromide to afford the benzylated

adduct 2-phenyl-l- 2-phenyl-l-(phenylsulfinyl)ethyl]-


benzimidazole


(2.53)


in 60% yield


(Scheme


addition to the abov


product,


2-phenyl-l-styryl-


benzimidazole (2.54)


10%)


was


also obtained.


LDA / PhCH2Br


SOPh


SOPh


2.51


2.53


---Ph -




CHPh


2.54


Scheme


2.25


The above behavior


observed earlier


was


(Scheme


in accordance with that


where the benzylated


S_ __ __ I 1_


. In


-1 -** ,I t l 1- ._ ^ -_ *l .c ^ <


1 1











always obtained in 10-15% yields.


The latter was also


readily obtained when the benzylated derivative 2.53 was

heated under reflux in toluene to afford 2.54 as colorless


needles which wa


s characterized by its


IH-NMR spectrum and


microanalysis data. T

absorption at 1050 cm


he absence of the sulfoxide


further confirmed the elimination


of the phenylsulfinyl moiety.

In an attempt to determine if the C-a methine proton


in 2.53 is capable

displacement, 2.5


of further undergoing electrophilic


3 was treated with a second equivalent of


LDA at -78C and deuterium oxide added to trap the anion


formed.


However,


the only product i


isolated in this


case


was the styryl derivative 2.54,


instead of the deuteriated


sulfoxide 2.55 (Scheme


.26)


. It is possible that the


"beta" hydrogen is acidic enough to

deprotonation of the methine proton


compete with the


causing elimination to


occur


rather than electrophili


c substitution.


Sulfoxides


having a


"beta" hydrogen are known to undergo elimination


in the presence of base


63CI(L)1243]


When 2-phenyl-l-(phenylsulfonylmethyl)benzimidazole


(2.52) was allowed to react with LE

of benzyl bromide or methyl iodide,

was recovered in both cases. The us


)A followed by addition

only starting material


;e of n-butyllithium


base or increasing the reaction time or temperature before

addition of the electirnnhile did not aid in aPneratina the












LDA / D20


SOPh


SOPh


2.53


2.55


CHPh


2.54


Scheme


2.2.4.2


2.26


Condensation studies with quaternary salts of
2-phenyl-N-(substituted-methyl)benzimidazoles


As discussed earlier,


(Section 2.1


the quaternary


salt of benzimidazole derivatives could increase the

acidity of the S-methylene protons enabling condensations


with aldehydes at that


site.


Since the sulfinyl


derivati


ves


2.30a and


were


generally unstable,


it was


1 __ --- .. L ... ... -- ... LL -- 1 .. I







44



Heating the sulfide 2.49 or sulfone 2.52 with methyl


iodide under reflux afforded the


corresponding quaternary


salts 2.56 and 2.57


(Scheme


.27)


in yields above


70%.


methylene protons displayed a downfield shift of ca


0.3 ppm due to the presence


of a positive


charge on the


benzimidazole ring.


S(O)nPh


S(O)nPh


2.49
2.52


2.56
2.57


Scheme


2.27


The acidities of the methylene protons of 2.56 -and


2.57,

studied


were determined by hydrogen/deuterium


s.


When the corresponding


exc


salts were di


change


ssolved in


deuterium oxide and deuteriated acetonitrile


exchange was observed (as monitored by


1H-NMR),


in either


case at room temperature or at -70


The presence


of a weak base such


triethylamine did


not aid in achieving any exchange


orotons of 1(3)-methvl-2-Dhenv


However the methylene


1-3(1)-(ohenvlsulfonvl-


, no











bisdeuterated derivative 2.58 (Scheme


2.28). A stronger


base was required in the


case


of the sulfide 2.56 where


complete exchange occurred in the presence of piperidine


after heating the mixture for


days at 800C giving the


deuterio compound 2.59.


CH3

4.1


Pyridine
= 2


D S(O)nPh


2.58


Piperidine
n == 0


S(0))nPh


CH3

4.


2.56
2.57


0D<
D


SPh


2.59


2.28


The condensations on 2.56 and


.57


I r I


were attempted with
I


CH3
4.lI
+N


Scheme


I 1 I











2.60 (Scheme 2.29).


However,


only starting materials were


recovered.


The use of longer reaction times


excess


base,


higher reaction temperatures


(heating under reflux in


butanol) did not a


assist in any way.


While


steric reasons


could be a possibility,


the same result was obtained when


primary aliphatic


aldehydes


were


employed.


RCHO


Base


S(O)nPh


S(O)nPh


2.56
2.57


2.60


Scheme


2.29


The use of an inorganic base such

led to decomposition products. Since


sodium hydroxide


this scheme did not


appear promising,


further investigations


were


attempted.


Conclusions


CHs

N


N










attack was observed at both the


as well as the C-a


positions with the former being the more reactive site.

The C-a anion formed at higher temperatures reacted with


electrophil


that did not react with the isomeric


carbanion


. The use of slightly elevated temperatures


(-40


to -20C)


in an attempt to achieve exclusive C-a


lithiation failed,


since uncharacterizable mixtures or


starting materials were generally obtained.

Regioselective metallation was carried out by

increasing the kinetic acidity of the methylene protons

which was achieved by oxidizing the sulfur moeity to the


sulfoxide 2.28 and sulfone 2.29,


respectively.


Problems


were encountered with the sulfoxide 2.28 during

purification of the products 2.30 since the presence of an


acidic proton at the


"beta" position led to cis-pyrolytic


elimination to give the styryl derivative 2.32.


sulfone adducts 2.31 were more stable and as a result,


regioselective metallation could be achieved her


The other alternative was the use


of a blocking group


at the


position.


Katritzky et al.


[87J(PI)775]


showed


that a methyl


group at the


towards metallation.


However,


[87J(PI)775] or a phenyl group


the C-a position.


position was succeptible


the presence of a t-butyl

. directed metallation to


The 2-phenyl derivative 2.49 underwent


metallation and electronhillic attack but the reactions











other hand,


in the case of the sulfoxide 2.50 the


reaction


did go to completion but


in the earlier case (Section


the product was not stable and tended to undergo


elimination of the phenysulfinyl moeity even at low

temperatures.

Forming the quaternary salts of the 2-phenyl-

benzimidazole derivatives 2.49 and 2.52 did increase the


acidity of the


C-a


methylene protons


as demonstrated by


the hydrogen/deuterium exchange reactions.


However,


when


attempt


s were made to react them with aliphati


aromatic aldehydes,


the condensations failed.


did not look promising at all,


Since this


further investigation


was


discontinued.


Experimental


2.4.1


Apparatus and Experimental Procedures


Melting points were determined on a Kofler hot-stage


microscope and are uncorrec

the following instruments:


ted. Spectra were recorded with

1H-NMR spectrawith a Varian


Model EM


Me Si
4


60 L or a Varian Model


internal standard;


Mnl ,l JNM-F3 1I


11Il -


VXR 300 spectrometer with


13C-NMR spectra with a JEOL


r forr inr r n cin n- Ql n rr


nf nmn


.3.2)











spectra were obtained at


70 eV on an AEI MS 30


spectrometer operating with a DS-55 data system.


analyse


Elemental


were performed under the supervision of Dr.


King of the department of chemistry.

Diethyl ether and tetrahydrofuran (THF) were distilled


from sodium-benzophenone ketyl,


refluxed over CaH2, distilled and


diisopropylamine and TMEDA


stored over


molecular


sieves,


N,N-dimethylformamide


DMF) dried by


azeotropi


distillation with benzene followed by


distillation under reduced pressure and


molecular


stored over


sieves.


All moisture sensitive reactions


were


carried out in


oven-dried (120C overnight)


apparatus under a slight


positive pressure of dry argon and transferring operations


done using syringe techniques.


Flash chromatography


[78JOC2923] was carried out with MCB silica gel


(230-400


mesh).


.4.2


The following compounds wer


e prepared by known


literature pro


cedures


: benzimid


azole (2.38), m.p.


169-


1710C,


(lit. ,


[430SC6


. 170-17


1-(hydroxymethyl)benzimidazol


e (2.39), m.p.


139-141C


(lit.,


[50JCS1600] m.p.


141-1430


chloromethyl)-


benzimidazolium chloride (2.40),


m.p.


168-1710C(dec.),


t 14 -


r nirc1cnn1


1_I AOPI~ p 1.











2-phenylbenzimidazole (2.5)


57JA427] m.p


, m.p. 293-2950C, (lit.,


94.5-295.5C); phenylthiomethyl chloride


2.48), b.p. 660


mmHg,


lit., [55JA572] b.p. 10


104C/12 mmHg).


2.4.3


1-(Phenylthiomethyl)benzimidazol


e (2.22)


To a solution of sodium ethoxide (1 M in ethanol,

90 ml, 90 mmol) was added a solution of thiophenol (5.4 g,


49 mmol


in ethanol (10 ml) and the mixture stirred at


ambient temperature for 0.5h. 1


Chloromethyl)-


benzimidazolium chloride


2.40


9.0 g


, 44 mmol) was then


added slowly


. The reaction was


stirred for a further 2h


after which the solvent was removed in


vacuo


to leave a


pale yellow gum. Water (40 ml) was added, the organic


material extracted with chloroform (3


0 ml), the


combined organic layers washed with water (2


0 ml),


dried (Na2SO4), and the


solvent removed in


vacuo


to afford


a colorless oil. Crystallization from benzene/petroleum


ether gave (2.22)


color


ess


prisms


, 9.0 g, 85%, m.p.


86-880C


, (lit


, [69KGS934] 89-900C); H (CDC13


8.1-7.8


, m)


7.56


7.5-7


, m)


, and


.40 (2H, s);


6H([ H6


-DMSO


8.06 (1H,


2H, m),


7.36


and 5.93 (2H,


2.4.4


2-Phenvl-l-(ohenvlthiomethvl)benzimidazole (2.49)


7H, m),











suspension in mineral oil;


1.33 g,


33 mmol) was added


slowly and the reaction stirred at ambient temperature for

lh. After addition of phenylthiomethyl chloride (2.48)


(4.2 ml,


500C for


31.5 mmol),


the reaction mixture was


2h, cooled and poured into water


stirred at


600 ml)


. The


crude material was extracted with ether


dried


(3 x 150 ml),


MgS04), and the solvent removed in vacuo to give a


yellow oil which


solidified on trituration with n-pentane.


Crystallization from benzene-hexanes afforded 2.49 as


colorle


ss prisms,


8.05 g,


84%, m.p.


66-670C,


lit. ,


[87J(PI)775] m.p.


2.4.5


67-690C).


General Procedure for the Oxidation of Sulfides
with m-Chloroperbenzoic Acid


To a solution of the corresponding sulfide


(10 mmol)


in methylene chloride


(100 ml


was added m-chloro-


perbenzoic acid:


10 mmol


(ii)


(80%,


mmol)


in portions at


The reaction mixture was


stirred at


-200C for


extracted with saturated aqueous sodium


bicarbonate (2


x 30 ml)


and water


x 20ml)


and dried


(MgSO4).


The solvent wa


s removed in vacuo and the crude


material crystallized from benzene unle


indicated.


otherwise


The following were prepared in this manner.


2.4.5.1


1-(Phenylsulfinylmethyl)benzimidazole


2.28)











(Found


: C, 65.30; H, 4


.75; N, 10.80.


C14H 2N20S requires


.59; H


.72; N, 10.93%); 6H(CDC13) 7.8-7.6 (2H, m),


.5-7.0 (8H


.20 (1H


AB, JAB 14.6 Hz), and
-AB


(1H,


AB, JAB 14.6 Hz); 6H
ABJ H


, 7.4-7.15 (2H


H6]-DMSO


8.10 (1H,


.86 (1H, AB, J 14H
-AB


, and


(1H, AB, J 14Hz).


2.4.


1-(Phenylsulfonylmethyl)benzimidazole (2.29)


The sulfide 2.22 and (ii) afforded the sulfone 2.29


tan needles (


, m.p. 148-150


(Found:


C, 6


.10;


.35; N, 10.15


C14H12N20


require


61.7


4; H


, 4.44;


10.29%); 6H(CDC1


-DMSO


.9-7.0


8.06


, m)


.9-7.1


.46 (2H


9H, m), and 6


(2H, s)


2.4.5.3


1-[2-Phenyl-1-(phenylsulfonyl)ethyl)benzimidazole
(2.31a)


1-(2-Phenyl-l-(phenylthio)ethyl]benzimidazole (2.41)


and (ii) gave the sulfone


2.31a


e yellow needles


(60%), m.p. 213-2160C, identical in all respects to the


sulfone prepared by the lithiation of


.29 described


ow.


2.4.5.4


2-Phenyl-l-(phenylsulfinylmethyl)benzimidazole
(2.51)


The sulfide 2.49 and


i) gave the 2-phenyl derivative


, s);


, m)


, m),











H, 4.85; N, 8.43%); 6H(CDC13


8.0-7.3 (14H, m), 5.35 (1H,


AB, J 14Hz), and 5.16 (1H, AB, J 14Hz).
-AB -AB


2.4.5.5


2-Phenyl-l-(phenylsulfonylmethyl)benzimidazole
(2.52)


2-Phenyl-l-(phenylthiomethyl)benzimidazole (2.49) and

(ii) gave after work up the corresponding sulfone 2.52 as


a brown gum

requires M+


88%); (Found M+


, m/z


, m/z 348.0932); 6 (CDC13


48.0928.


.3-7.


0 16N202S


, m) and


5. 63(2H, s).


2.4.6


General Procedure for the Lithiation of
1-(Phenylthiomethyl)benzimidazole (2.22) in LDA-THF
and Reaction with Electrophiles


The benzimidazole 2.22 (1

(50 ml) was added to a soluti


mmol) in dry THF


on of LDA [prepared from


diisopropylamine


0.78 ml


mmol) and n-butyllithium


(2.5 M in hexane


.1 ml


in dry THF (30 ml)] at


-780C and


stirred for 3h to form a pale yellow precipitate. The


electrophile (5.


mmol) dissolved in dry THF (5 ml


was


then added and the reaction mixture stirred at the


appropriate temperature. Water (30 ml)


was


then added and


the organic materials extracted with diethyl ether [or


CHCl3 as in the case of 2.43b3 (3


x 30 ml), and the


combined organic extracts washed with brine (1


x 25


ml),


dried (MgSOQ), and the solvents removed in vacuo to give











2.4.6.1


1-[2-Phenyl-l-(phenylthio)ethyl]benzimidazole
(2.41)


After addition of benzyl bromide, the reaction mixture


was


stirred at -78


for 3h and warmed gradually to -200C


whereupon the pr


ipitate dissolved to


need


es from


benzene-hexane


), m.p


. 102-1030C;


lit., [87J(PI)775]


. 103-1040C); 6H (CDC13


7.8-6


.60 (1H, t,


J 7 Hz), and 3


2.4.6.2


1H, d, J 7 Hz)


2-Methyl-l-(phenylthiomethyl)benzimidazole
(2.43a)


With methyl iodide


the electrophile, the yellow


precipitate dissolved at


2-substituted deri


benzene-hexanes


-78C


vative 2.43a


), m.p


within ih t

as nale vel


L S


116-119


o give the

low needles from


(lit., [87J(PI)775]


m.p. 118-1200C);


H(CDCl3)


-7.6


1H, m),


.5-7


.20 (2H, s), and


2.4.6.3


(3H,


2-[Hydroxy-(4-meth lphenyl)methyl]-l-(phenylthio-
methyl)benzimidazole (2.43b)


Addition of 4-methylbenzaldehyde caused the yellow


precipitate to di


sso


lye almost instantaneously


Work up


gave the alcohol 2.43b


colorl


ess


needles from ethyl


acetate


90%), m.p


179-1900C


(Found:


.90; H,


5.70;


7.40.


6H(CDC13
H3j


C22H20N2OS requires


2H6]-DMSO) 7.9-7.6 (1H, m),


, 73.30; H


7.6-7.


5%);


12H, m),


, m),











2.4.6.4


2-[Hydroxy(diphenyl)methyl]-1-(phenylthiomethyl)-
benzimidazole (2. 3c)


Benzophenone


was


used


the carbonyl compound causing


the yellow precipitate to dissolve in 3h at -780C

Crystallization from benzene afforded the alcQhol


colorle


needles (


), m.p


131-1330


lit. ,


[87J(PI)77


m.p.


(CDC13)


8.0-7.7


(1H, m),


7.6-


18H, m),


5.45


, s)


, and


2.4.6.5


2-(1,2-Diphenylethyl)-l-(phenylthiomethyl)-
benzimidazole (2.46)


With benzyl iodide,


the precipitate dissolved after


at -780C and the crude product purified by


column


chromatography (ethyl a


cetate:hexanes,


to give


2-(1,


-diphenylethyl)-1-( phenylthiomethyl)benzimidazole


(2.46) a


s color


ess need


es (35%),


m.p.


103-105


(Found:


9.90


.90; N,


6.60


require


9.96;


, 6.66


H (CDC13,


00MHz)


, J 8


Hz),


1H, m


-7.0


13H, m


, 6.91-6


5-6.8


1H, AB


, J 14.4 Hz),
-AB


4.99


(1H,


J 14.4 Hz),


1H, AMX


' JAM
AM


.6 Hz


' JAX 9.6 Hz),
-AX


(1H, AMX,


.6 Hz,


J 13.4 H


AMX


SJAX 9.6 Hz,


JM 1
-MX


.4 Hz)


(CDC13)


, 142


139.7,


139.0


, 134.4,


, 129


, 129


, 128.4,


127.0,


, 122.4,


109.8


, 48


, 46.1,


AC i


SC28H24N2


, m),












2.4.7


1-(Phenylthiomethyl)-2-[ H ]benzimidazole


(2.47)


To a suspension of l-(phenylthiomethyl)benzimidazole


(2.22)


5 mmol)


in dry diethyl ether


(50 ml)


-78C wa


s added phenyllithium (2 M in cyclohexane-ether;


2.6 ml)


to give a yellow


cloudy


solution


. The solution was


stirred at -780C for ih and then D20 (0.3 ml) was added.


After 0.5h water


(20 ml


was added and the organic


material extracted with ether


x 30 ml),


dried


Mgso4),


and the solvent removed in vacuo to give a yellow solid

which was recrystallized from benzene-petroleum ether to


give pale yellow need


(0.91 g


6%), m.p.


83-840C;


(Found


69.31;


, 69.68;


01; N,


.08; N,


11.46


11.61%)


SC14H 11DN

2H ]-DMSO)


require


7.9-7.6


7.5-7.2


2.4.8


and 5.93


, s)


General Procedure for the Lithiation of l-(Phenyl-
sulfinyl methyl)- (2,8) and 1-(Phenylsulfonylmethyl)-
benzimi dazoe (2.29) in LDA-THF and Reaction with
Electrophiles


The sulfoxide 2.28


8 g,


mmol)


(ii)


sulfone 2.29


1.36 g


mmol)


in dry THF (50 ml) was added


to a


solution


of LDA


prepared from diisopropylamine


(0.78 ml,


5.5 mmol


and n-butyllithium (


2.5 M in hexane


.1 ml


in dry THF


30 ml)


80C and


stirred for


lh to


give a


clear yellow


solution.


The carbanion


was quenched


(2H,


: C,











case


of benzyl bromide and 15 min for


4-methyl-


benzaldehyde.


Water


(50 ml)


and diethyl ether


(75 ml) were


added,


the layers separated and the aqueous layer washed


with diethyl ether (2


x 25


ml).


combined organic


extracts were washed with brine


x 25


ml), dried


(MgSO4), and the solvents removed in vacuo to gi


crude products which were then purified.


The following


compounds were prepared in this manner.


2.4.8.1


1-[2-Phenyl-l-(phenylsulfinyl)ethyljbenzimidazole
(2.30a)


From benzyl bromide following (i)


to give


a fine


powder


(after triturating with


lohexanone:


recrystallization led to decomposition


(83%),


. 132


1330C;


.9-6


S6(CDCl3


14H,


(1H,


ABX,


JAX
-AX


4.7 H


, J 8.3 Hz)
-BX


, 3.9


(1H, ABX,


J
-AX


4.7 Hz,


J 16.0 H


and 3.64


ABX,


JBX 8.
BX


J 16.0 Hz).


2.4.8.2


1-[2-Hydroxy-(4-methylphenyl)-1-(phenylsulfinyl)-
ethyl]benzimidazole (2.30b)


4-Methylbenzaldehyde and


gave needles from


benzene-ethyl acetate (70%)


, m.p


. 210


120C;


87J(PI)775] m.p.


210-214


6H(CDCl3-( H6]-DMSO)


8.7-8.3


1H, m)


8.0-6.6


(13H, m),


.6-5.2


(2H, m),











2.4.8.3


1-[2-Phenyl-l-(phenylsulfonyl)ethyl)benzimidazole
(2.31a)


The sulfone 2.29 and benzyl bromide gave the


benzylated adduct 2.31a


colorle


ss need


from benzene


(68%), m.p


215-2170C;


Found:


, 69


.03; N,


7.60.


C21H18N20

6 H(CDC13)


requi


res


69.59


.9 (1H, m),


, 5.01; N,


7.8-6.9


.73%)


, m), 5.47


ABX, J 4.5 Hz
-AX


', J X 11.0 Hz), 4.0
-BX


1H, ABX, J 4
-AX


J 14.5 Hz), and 3.78
~~ABD


1H, ABX, J 11.0 Hz, J 14
-BX -AB


Hz).


2.4.8.4


1-[2-Hydroxy-2-(4-methylphenyl)-1-(phenylsulfonyl)-
ethyl]benzimidazole (2.31b)


From (ii) and 4-methylbenzaldehyde


, the alcohol 2.31b


was


obtained


colorle


need


es from


ethyl a


cetate


(55%), m.p.


22H20N20


H(CDCl


201-204C;


requi


-TFA) 8.0


Found


67.31


14H, m), 6


, 67.17; H,


, 5.14; N,


.5-6


N, 6.99.


.14%);


.0 (2H, m), and 2.20


(3H,



2.4.9


s).



2-Phenyl-l-[2-phenyl-l-(phenylthio)ethyl]-
benzimidazole (2.50a)


To a solution of 2-phenyl-l-(phenylthiomethyl)-


benzimidazole 2.49 (0.95 g


mmol) in dry diethyl ether


(50 ml


at -78C


was


added


a mixture


e of n-butyllithium-


TMEDA


prepared by adding n-butyllithium (2.4 M in hexane;







59



and then benzyl bromide (0.4 ml, 3.3 mmol) in dry diethyl


ether


5 ml) was added. The reaction


was


stirred at -78C


for 3h and warmed slowly to ambient temperature. Water


(30 ml


was then added, the layer


s separated and the


aqueous layer washed with diethyl ether


x 20 ml), the


combined ethereal extracts dried


MgSO4


and the


solvent


removed in vacuo to give the crude product. Purification

by column chromatography (hexanes:methylene chloride, 1:3)


gave a colorle


oil (0.73 g, 60%);


lit., [87J(PI)775


colorless oil 62%).


2.4.10


2-Phenyl-l-[1-(phenylthio)ethyl]benzimidazole
(2.50b)


Utilizing the conditions described above and methyl


iodide (0.21 ml, 3.3 mmol) a


s the


electrophile, the


corresponding methyl derivative 2.50b was obtained


color


ess


prisms from n-pentane


5%), m.p


89-


90C; (Found


, 76.53; H,


require


es C


2; H, 5.49; N, 8.48%)


-7.8


H(CDCl


7.6-6.8 (12H, m),


1H, q, J 7 H


, and 2.00


3H, t, J 7 Hz


2.4.11


2-Phenyl-1-[2-phenyl-l-(phenylsulfinyl)ethyl]-
benzimidazole (2.53)


Utilizing the conditions described in Section 2.4.8,
1l ti rl r 1 I C c i j3l In rT l- i r v f"l m A\ nJ A c i r 1


2H, m),


C2


118N







60



crystallization led to decomposition (60%), 8H(CDCl3) 8.4-

7.0 (15H, m), 6.9-6.5 (4H, m), 5.4-5.1 (1H, m), and 4.2-


3.0 (2H, m).



2.4.12 1-Styrylbenzimidazole (2.32)


-Phenyl-l-(phenylsulfinyl)ethyl]benzimidazole


(2.30a) (1.04 g


, 3 mmol) was dissolved in toluene (20 ml)


and the mixture heated under reflux for 4h. The solvent

was then removed in vacuo and the crude material


crystallized from


ethanol


colorless needles (0.46 g,


70%), m.p. 121-124C; (lit. 78JHC1543] m.p. 1220C)


2.4.13


2-Phenyl-l-styrylbenzimidazole (2.54)


Under the conditions described above,


-phenyl-


1-[2-phenyl-l-(phenylsulfinyl)ethyl]benzimidazole (2.53)


afforded 2-phenyl-l-styrylbenzimidazole (2.54)


colorless need


(Found:


from


3; H,


ethanol (6


.51; N, 9


5%), m.p. 165-1660C;


3. C21H6N2 requires


C, 85.10; H,


.44; N, 9.45%); 6H(CDC13) 8.2-6.9


16H, m).


2.4.14


1(3)-Methyl-2-phenyl-3(1) (phenylthiomethyl)-
benzimidazolium iodide (2. 56)


The sulfide 2.49


1.58 g,


mmol)


was


dissolved in


methyl iodide (20 ml


and the mixture heated under reflux


for ih. The


excess


methyl iodide


was


removed in


vacuo











prisms (2.1 g, 95%), m.p. 173-1750C; (Found


: C, 55.37;


.29; N


, 5.88.


1H9 IN2S requires C,


H, 4.18;


, 6.11%); 8H(CDC13) 8.2-7.0 (14H, m),


.96 (3H


2.4.15


2H, s), and


, s).



1(3)-Methyl-2-phenyl-3(1)-(phenylsulfonylmethyl)-
benzimidazolium 1odide (2.57)


The sulfone 2.52 (1.74 g,


methyl iodide (20 ml


mmol) was dissolved in


and the mixture heated under reflux


for 3h. Work up


above gave th


e quaternary salt 2.57


brown microcrystals from ethanol


2.08 g, 85%), m.p.


2380C; (Found:


51.38; H, 3.93; N,


.46.


21H 9IN202


requires C, 51.44; H,


3.91; N,


.71%); 6H(CDC13) 7.9-7.4


(14H, m), 5.90 (2H, s), and 4.00 (3H,

















CHAPTER III

SYNTHESIS AND REACTIONS OF SOME BENZOTRIAZOLE DERIVATIVES



3.1 Introduction


Functional


group transformations have always played a


major role in organic synthesis.


Hence,


routes to carbon-


carbon


single bond or carbon-carbon double bond formations


are under constant investigation.


Carbon-carbon bonds can


be formed via a variety of radical processes or by the

combination of a nucleophile with an electrophile in an


addition or substitution reaction.


Very often the


conditions employed for these transformations are not


mild,


requiring high temperatures or pressure and the use


of very specific reagents.


Consequently,


the presence of


an activating moiety should promote much more facil


transformations. As a result a substituent Het which could

be a heteroatom or a heterocyclic group could be initially

placed as an anchor and an activator to facilitate

electrophilic addition and then removed under various

conditions depending on the type of intermediate


synthesized.


Thus compounds of tvoe Het-CH, could be











1. Base


(El)


Base
(E2)+


Het-CH3


Het-CH E
2


1 2Het-CHE
Het-CHE E


Base
E3)+
(E)


Het-CE E2E


CEIE2E3Nu


Scheme


Benzotriazole has recently been shown to be a good

leaving group when one of the substituents introduced on


Het-CH3 is nitrogen.


Thus


, aminomethylbenzotriazole


s 3.2


can be reduced with sodium borohydride


87J(PI)805]


afford the methyl derivati


methylene derivative

benzotriazole can al


(3.3


be display


3.3, R1


= H) or the


Similarly


ced by alkyl lithiums


[84TL1635] or by Grignard reagents


87J(PI)805]


to afford


the methylene derivati


3.4,


= H) or the methine


compound


(3.4, R1


(Scheme


.2).


s good leaving group ability has been extensively


exploited in the monoalkylation of amines


R.Ar


187J(PI)8051


alkvlation of amides


= H.


J J


f


J











[87UP1], hydroxylamines (X


= OH


= CH2R)
2


[87UP2] and


sulfonamides


= H,


= SO2R


[87UP4]


N
N

N


\y


R1/

3.2


NaBH4


or R2MgX


R1 CH2- N


R2CH(R')- N


Scheme


an extension of this reasoning,


if 1-methyl-


benzotriazole


(3.6)


were


used


, then it might be possible


to promote


carbon-carbon bond formations


For


example


treatment


of 3.6 with base and


esters,


alkyl halide


ketones would give ri


to ketomethyl- (3.5)


, alkyl


- (3.7)


or hydroxyethyl-benzotriazole


(3.9


res


pectively.


Elimination of benzotriazol


would then gi


rise


to a


number of different compounds such


the ketones 3.8 or


alcohols 3.10, all originating from one intermediate


(Scheme














/ N RCO2R2

N
SN, / ,


CH2COR'


BuLi
RR 2CO
9


N


/N
N


3.10


Scheme


However,


Katritzky and Kuzmierkiewicz have shown


[86UP1]


that the


carbanion generated from 1-methyl-


benzotriazole (3.6)


s unstable


When lithiation of 3.6


was attempted with lithium diisopropylamide (LDA)


n-butyllithium,


starting material and uncharacterizable


products were obtained


t might,


however,


be feasible


attach another arouo


to the methvl


arouD which,


C


f










3.1.1


Selection of a Novel Activating/Protecting Group


The presence of an electronegative atom such


nitrogen or oxygen adjacent to carbon induces a

polarization in the carbon-nitrogen or carbon-oxygen bond

due to its inductive electron withdrawal effect. As a


result,


the a-carbon bears a small positive charge.


Consequently this should enhance the generation of an

a-aminocarbanion or an a-hydroxycarbanion respectively,

leading to the possibility of electrophilic substitution

at the a-carbon atom.


In practice,


however,


such a-heterocarbanions are


difficult to generate for two reasons.


Firstly,


the more


acidic amino or hydroxy protons need to be suitably


protected.


experlen


Secondly,


ces


such a carbanion once generated,


strong repulsion between the nitrogen (or


oxygen)


lone pair and the


- lone pair thu


destabilizing


Sulfur,


while not being a


s electronegative as nitrogen


or oxygen,


is a strong activating group


, sin


the lone


pair of the carbanion


can be


stabilized due to the


presence of empty d-orbitals


enhanced stability has been shown to have


synthetic utility by Katritzky et al.


transformations utilizing 1


[87J(PI)781]


phenylthiomethyl


benzotriazole (3.11)


(Scheme


3.4).


However,


the yields










utility was further


limited by the fact that the


thiophenyl group could only be removed


Raney nickel


desulfurization to afford 1-alkylbenzotriazoles


N
N


(3.12).


N
N


3.11


Raney Ni


/ N
N


3.12


Scheme 3.4



Another element that has empty d-orbitals is silicon.


In recent years,


great


strides have been mad


e in the


utilization of silicon in organic synthesis


[79MI3,


82MI2]


While the silicon atom favors,


by a


hyperconjugation mechanism,


a posit


charge


"beta"


itself,


silicon can al


stabile


an a-carbanion,


in both


r. n ,^ tn A at 4e l T 1 : T r- n F : r FV 1 u 4- : i 1 1 r -I


n- r r r











silicon.


This property has been fully exploited by Magnus


[80MI1].


Silicon thus seems to be an ideal


"masked proton"


and worthy of further investigation with the benzotriazole

group.


3.1.2


Previous Work on (Trimethylsilylmethyl)azoles


Reactions of a-heterosubstituted silyl derivatives


with aldehydes to yield alcohol


s have been explored in


recent nucleophili


c amino-


and hydroxy- methylations of


carbonyl compound


s [84CL1803,


85BCJ1991,


86H237]


Recently


Katritzky et al.


[87JOC844] have shown


thio)(trimethylsilyl)methane


synthon for HSCH


R Br


(3.13a)


which enable


R CH(SH)SiMe3 and R2R3CO


benzothiazol-2-yl-


to be a convenient


he general conversions

--> R2R3C(OH)CH(SH)R1


These transformations were accomplished by (i)

deprotonation of the silyl derivative 3.13a with LDA and


reaction with


electrophiles,


(ii)


fluoride


catalyzed


desilylation with carbonyl


nucleophilic displacement


compounds,


of benzothiazole by


alkyllithium.

trimethylsilyl


Furthermore,


the presence of the


group in 3.13a stabilizes the


carbanion


generated as


evidenced by the fact that carbanions


analogous to 3.13 could not be prepared by deprotonation


of 2-(ethyvlthio)benzothiazole


(3.13b) or of higher











SCH2X


LDA/ R'Br

X = SiMe3


SiMes


3.13


X = SiMe3

X= CH3


R2COR3


TBAF


tBuLi


SiMe3


tBuLi




SH




Scheme



Katritzky and Kuzmierkiewi


[86UP1] also showed that


reaction of the lithio derivat


of 3.13a with


esters


gave ri


to a mixture


e of the ketone 3.14 and the enol


ether (3.15) (Scheme


search


h in the iiteratu


N-(trimethyisilyl


- a 4. LL 1 1 n *- 1 ..-, ..S L 3%*3


- -- ,..- ,- -


I*1 L1 IrI *1 Y~. IWfC










azol-1-ylethanols


(3.17)


(Scheme 3.7) which have received


considerable attention recently due to the importance of

their general structure in orally-active antifungal azole

moieties [83JMC768].


SCH2COR


3.14


RCO2Et


SiMe3


3.13a


SCH=C(OEt)R


3.15


Scheme 3.6


X N!


YX-
II
X. N


SiMe3


3.16


3.17


Scheme







71


Additionally, bis(trimethylsilyl)methyl-1,2,4-triazole

(3.18) was shown to be a novel precursor [87JO0C2314]

towards the synthesis of 1-vinyl-l,2,4-triazoles (3.19)

(Scheme 3.8).


N

X N


Me3Si


/ R'R2CO


SiMe3


Z



I
CH=R' R2


3.18


3.19


Scheme 3.8


Katritzky and Kuzmierkiewi


[86UP1


first attempted


the synthesis of 1-(trimethylsilyl)methylbenzotriazole

(3.22) utilizing conditions similar to those used for


benzothiazol-2-ylthio)(trimethylsilyl)methane (3.13a)


[87J(PI)7691. However alkylation of the lithio derivative

of 1-methylbenzotriazole (3.20) with chlorotrimethylsilane

(3.21) afforded 1-bis(trimethylsilyl)methylbenzotriazole

(3.24) in addition to starting material.

It seemed that the monosilyl derivative 3.22 underwent

a transmetallation with the 1-lithiomethylbenzotriazole


(3.20) initially formed


, to g


the more stable


1 1 : +-c 4 ; n _. 1 _.. / 4- v ; lm~4l^~ r" ^ 1 F ^Tlr \ fl^^^t^^" 1^^r*-/^ C- Cty^^ rr f "2 -< 1 n r;ar1 ^^ ?3










reacted


with


a seco


nd equival


ent


chlorotrimethylsilane


3.21)


to give


N
^N
N
I
CH3


Scheme.


N
^N


CISiMe3


3.21


3.20


N


N


SiMe3


3.20


SiMe3


3.22 3.23


3.23


3.21


Me3Si


SiMea


3.24


Scheme


N
I


N

/







73



chloromethyltrimethylsilane in the presence of bases such


as potassium carbonate


(86JOC3897,


87JOC844],


butyllithium


73USP3692798], or in the presence of potassium

68USP3346588].


3.1.3


Aims of the Work


As discussed above,


both benzotriazole and silicon


functionality could hopefully be employed in the


activation


of a methylene group


. The first step dealt with


finding an alternate approach for the synthesi


s of


1-(trimethylsilyl)methylben


zotriazole


(3.22).


Once


prepared it


was


hoped that 3.22 could be readily


lithiated


and the


stable carbanion trapped with specific


electrophiles to


(3.25)


afford the corresponding derivatives


(Scheme 3.10).


N


BuLi / E+


SiMe3


SiMe3


3.22


3.25


Scheme 3.10


Fmrnlrt I-ho rkrr kir rC rrnr~ t rf t i m ; i Q T C- T n i r


N
^N

N






74



difficult to synthesize since the a-carbanion generated

from 1-alkylbenzotriazole has been known to be unstable


[86UP1]. As mentioned previously (Section


3.1.2),


azol-1-ylethanols (3.17) hold promise in orally-active

antifungal azole moieties [83JMC768], but there has been

no mention of benzotriazole in these systems.


F / R1R2CO


SiMe3


3.25


Scheme 3.11


3.26


Silicon elimination of a 8-silylethanol generally


requires an


equivalent of base


84S384]. However, if the


anion of 3.22 (3.23) were to be treated with a


carbonyl


compound


, the Peterson olefination product (3.27)


should


be formed (Scheme


.12). This would afford an alternate


synthetic route to 1-alkylidenebenzotriazol


have been previously prepared by the treatment


1-chlorobenzotriazol


3.27 which

of


e with olefins [69JCS(C)1478],


base-induced isomerization of allylbenzotriazoles

[79HCA2129] and most recently [87UP3] by the reaction

l-bis(trimethylsilyl)methylbenzotriazole (3.24) with







75



Vinylbenzotriazoles and their analogs have numerous


synthetic utilities.


Some more


specific


c uses are their


biological activity


84IJC(B)844] and the antitumor


activity of some platinum and palladium complexes with


1-vinylbenzotriazole


[83MI1,


85JGU923].


They have also


found use in photographic hardening agents


[73GEP2309525],


for organic lubricating


composition


s [77USP4048082


for electroplating baths [84JAP59182986].


Alkylidenebenzotriazoles have al


been employed in the


study of their electron-donor properties


[76KGS828 ]


and in


the synthesis


s of 3-substituted indoles


via


flash vacuum


pyrolysis


[87J(PII)IP1]


Earlier,


Section


.1.2)


it was mentioned that


lithiation of the (trimethylsilyl)methylazole 3.13a gave


the enol ether


3.15 in addition to the ketone


3.14


Treatment of 3.23 with esters followed by hydrolysis of


the reaction mixture


should generate the ketone


3.28


exclusively


Scheme


.12).


Once the required functionality has been introduced,

the next step dealt with removal of the activating


moietie


discussed earlier


Section


benzotriazole has been shown to be display


ced by sodium


borohydride or Grignard reagent


s [87J(PI)80


] or by


alkyllithiums [84TL1635].















R1 R2CO


N


/


SiMe3


CH=CR1R2

3.27


R'CO2Et


3.23


CH2COR1


3.28


Scheme 3.12


It ha


s been known from the work


of Sidel'korskaya


[54BAU589


and Zelenskaya


52BAU627 i


that N-vinyl


compounds could be decomposed quantitatively in the


presence


of water to form acetaldehyd


Similarly,


1-vinylindole also underwent hydrolys


4% sulfuri


in the presence of


c acid [65MI1].


NMR studies have indicated that in the reaction of


benzotriazol


e with carbonyl compounds,


there


existed an


equilibrium between the starting materials and the


benzotri


azo


l-1-ylalkanols 3.29 in solution


[87J(PI)7911


n faI-, 1 -


1


_- *


I


-


mr... L.













N

N/


Cs


3.29


v


N

/
N
I)


N

/\


+O=CHR


O=CHR +


,N

- N


Scheme


1-Alkylidenebenzotriazoles


(3.30)


would


thus


expected


to hydroly


presence


an acid


form


carbonyl


compounds


3.32


via


a-hydroxy


intermediate


cheme


.14)


Elimination


good


leaving


groups


"alpha


carbonyl


carbon


have


been


indu


ced with


zinc


in acetic


acid


66JA5498,


0HCA2197


ammonium


format


nroaeanr


nl I ia4 un m In


zr'I-4 irn 4-n


k nrrn*n


H
NI

N

I


" to


Q -7^r t.I;


B ---H


E ^


n


T~














CR' R2


3.30



Hr


N
N


3.31


3.32


Scheme


3.14


N
N
N


3.28


3.33






79



Since the fluoride ion has been used to remove the


trimethylsilyl group,


treatment of 1-(trimethylsilyl)-


alkylbenzotriazoles (3.22, R3


tetrabutylammonium fluoride


; 3.25, R3


(TBAF)


? H) with


in the presence


water should generate 1-alkylbenzotriazoles 3.35.


would be an interesting route


since the mor


e general


method,


which involved treatment of benzotriazole with an


alkyl halide in the presence of base,


usually gave a


mixture of the 1- and 2-alkylbenzotriazoles.


This would be where the difference


could lie over the


2-mercaptobenzothiazol


e route (Scheme


.5),


in that,


while


the latter was restricted to the formation of mercaptans,

various functionalized compounds could be obtained from

this system (Scheme 3.16).


Results and Discussion


3.2.1


Preparation of 1-(Trimethylsilyl)methylbenzotriazole


At the start of thi


s investigation benzotriazole was


treated with chloromethyltrimethylsilane in dry


dimethylformamide (DMF)


in the presence of pota


carbonate but the major product isolated in


yield


was


1-methylbenzotriazole


(3.6). Thi


s could be


due t


o the


= H


*












N


N


R' HO


3.26


3.34


N


N


N
\N


N
N


CR'R2


SiMe3


3.30


3.22;


3.25


3.28


N
'N
N

LR3


3.32


3_35


3_33











benzotriazole


anion


that


reaction


could


carried


in a neutral


medium.


This


was


easi


done


adding


benzotriazole


to a solution


sodium hyd


rox


ethanol


. Removal


solvent


behind


sodium


salt


.36)


as a white


solid.


a result,


multigram quantiti


3.22


were


readily


epared


ating


sodium


salt


of ben


zotr


iazole


.36)


with


chloromethyltrimethyl


silane


(3.37)


in dry


Scheme


3.17)


. Some


corresponding


-(trimethyl


silyl)methylben


zotriazole


ca.


was


also


formed


but,


being


an oil,


remained


solution.


N

1


NaOH
EtOH


N
N


3.36


3.36


CICH2SiMe3


3.37


SiMe3


3.22


N
N
N











3.2.2


Lithiation of 1-(Trimethylsilyl)methylbenzotriazole
and its Derivatives


3.2.2.1


Reactions of 1-( t r i methylsilylmethyl )benzotri.azole
with n-but 1 ithium and subsequent y with
electrophil es


1-(Trimethylsilyl)methylbenzotriazol


e (3.22)


was


readily


lithiated with equimolar n-butyllithium in dry THF


at -780C and the dark blue lithium


salt


(3.23) effectively


trapped with benzyl bromide to give l-(benzotriazol-1-yl)-


2-phenyl-l-(trimethylsilyl)


ethane


(3.25a)


color


ess


need


in a yield of 81%


Scheme


.18).


Other alkyl and


silyl halide


s reach


ted in


a similar fashion.


The results


are summarized in Tabl


THF
-78oC


SiMe3


SiMe3


3.23


3.25


Scheme 3.18











Table 3.1


Treatment of 1-(Trimethylsilyl )methyl-
benzotriazole (3.22) with n-Butyllithium and
Electrophiles.


Product Electrophile Reaction Yield M.p. a
No. Time(h) (%) (C)



3.25a PhCH2Br 4 81 108-108.5

3.25b Mel 4 86 71-72

3.25c Hxl 6 82 50-51

3.25d Me3SiC1 2 83 147-147.5b

3.25e Me3SiCH2Cl 2 83 86-88c


Needl


- I-


from hexanes,
c -


. From methanol.


. ro


unless otherwise stated.


m methanol-water.


The phenyl analog 3.39 was prepared by the treatment


of the lithium


salt of 1-benzylbenzotriazole


chlorotrimethylsilane (3.21)


(Scheme


(3.38) with


3.19).


CISiMe3


N
N

N


SiMe3


""rar







84



The addition of aldehydes and ketones to 3.23 gives


the Peterson olefination product


s 3.27a-d (Scheme 3.20)


although in the preparation of 3.27c from acetophenone,


some unreacted starting material


(ca.


was also


recovered. The results are summarized in Table


structures were confirmed by their


3.2.


H- and 13C-NMR


spectra, in particular by the absence of the


trimethylsilyl resonances in all


cases.


THF
-78C


SiMe3


CR'R2


3.23


3.27


Scheme 3.20


Table


Formation of Peterson Olefination Products


(3.22


- 3.27).


Product Electrophile Reaction Yield M.p.
No. Time(h) (%) (C)



3.27a C6H100 2 83 100-102

3.27b CH3COCH3 6 80 68-70a

3.27c PhCOCH3 6 38 65-67






85



With cyclohexenone (3.40) and the lithio deivative


3.23,


the Michael addition product


3-[(benzotriazol-1-yl)-


(trimethylsilyl)methyl]cyclohexanone


3.41) was obtained


70% yield


. When ethyl


4-methylbenzoate


(3.42) wa


s used


as the

IN HC1


electrophile and the reaction mixture


, the ketone 2-(benzotriazol-l-yl


treated with


-1-(4-methyl-


phenyl)ethanone (3.28a) was obtained in 51%


. Furthermore,


none of the enol ether observed by Katritzky and

Kuzmierkiewicz [86UP1] (Section 3.1.3) was isolated in


this ca


se.


By contrast


, when the a,0-unsaturated


ester


ethyl 3,3-dimethylacrylate


(3.43) was used


, the ketone


1-(benzotriazol-1-yl)-4-methyl-3-pentenone


only product obtained with no


adduct being formed (Scheme


(3.44) was the


evidence of the Michael


This could be


attributed to the fact that that there is steric hindrance


at the


"beta" position,


more reactive


. The


thus causing the ester


structure of the ketone


site to be


(3.44) was


confirmed by the


H-NMR spectrum which still displayed the


vinyl proton at 66.08 and al


by the absence


trimethylsilyl and ethoxy resonance


. The


of the


C-NMR


displayed the carbonyl resonance slightly upfield at 190.3

ppm indicating unsaturation at the "alpha" position.


























N
^N


SiMes


3.23


3.40


N
N
N


3.41


/ \CO2Et


3.42


CO2Et


3.43


N
/,


3.28a


N
N


3.44











3.2.2.2


Anion formation from 1-(a-trimethylsilylalkyl)-
benzotriazole and subsequent reactions with
electrophiles


The 1-(trimethylsilyl)alkylbenzotriazoles (3.25)

prepared above can be treated with another equivalent of


n-butyllithium and a


s in the


case


of 3.25b the anion was


trapped with hexyl iodide and benzyl bromide to furnish


3.45a,b in yields of 80 and 71


3.22).


respectively (Scheme


1H-NMR spectrum of 3.45b is interesting in that


the presence of the chiral center,


renders the benzylic


protons diastereotopic with one proton resonating 0.4


ppm.


upfield from the other.


N



BuL / E*


SN
"N
/,


SiMe3


SiMe3


3.25b


3.45


= Hx


= PhCh2


Scheme


3.22


The treatment of lithio derivative


with


ester


s and


acid chlorides generally gives low yields due to the


possibility of the product


(a ketone adduct)


behaving











were treated with ethyl


4-methylbenzoate or


4-methyl-


benzoyl chloride,


low yields and a large number of side


product


s were obtained.


In the previous section


Section


3.2.2.1)


was


mentioned that the Peterson olefination


product 3.27 was formed readily when 3.23 wa


carbonyl compounds. However,


s treated with


when the anions derived from


3.25a,b were treated with cyclohexanone,


the reactions


went to only 80


completion


The phenyl derivative


((benzotriazol-l-yl)(phenyl)methylene]cyclohexane (3.46)


was


however prepared by the reaction of the lithio


derivative of 1-( a-trimethylsilyl)benzylbenzotriazole


(3.39) with cyclohexanone (


N

N


Scheme 3.23).


N
/N
N


Me3Si


3.39


3.46


Scheme


3.2.2.3


3.23


Anion formation from 1-alkenylbenzotriazoles


It was mentioned above


(Section


3.2.2


that the


rPartin nf Mh a nnn nf 2 K h wi -h


InhoYvnnnn Hid


I \ i











1-(cyclohexylidenemethyl)benzotriazole (3.27a)


with methyl iodide and hexyl iodide respectively


reacted


. As


result, when equimolar n-butyllithium was added to 3.27a

at -780C, a green precipitate was formed within 0.5h which


readily dissolved when deuterium oxide was added affording


the mono deuterio derivative (3.30a)


(Scheme 3


.24)


With


methyl iodide,


hexyl iodide and 4-methylbenzaldehyde,


corresponding alkyl and hydroxy derivatives 3.30b-d were


formed in moderate to high yields


shown in Table 3.3.


In all cases, metallation of 1-(cyclohexylidenemethyl)-


benzotriazole


(3.27a) with n-butyllithium occurred readily


and exclusively at the


position rather than at the


allylic position in the cyclohexane ring.


The structures


of the products were confirmed by elemental analysis and


by their NMR spectra,


of the


in particular by the disappearance


vinyl proton at 86.81 and of the carbon signal at


113.7 ppm in the


N
N


1H- and 13C-NMR spectra,



BuU / E+


respectively.


INN
N9"


3.27a


E'


3.30


iN
"^\












Table 3.3


Treatment of 1-( Cyclohexylidenemethyl)-
benzotriazole with n-Butyllithium and
Electrophiles.


Product Electrophile Reaction Yield M.p.
No. Time(h) (%) (C)


3.30a


99-101

Oil


3.30b


3.30c

3.30d


4-MeC6gHCHO


151-1


3.2.3


Fluoride Catalyzed Desilylations


Shimizu and Ogata


86JOC3897]


showed that silyl


compounds reacted smoothly with carbonyl compounds in the

presence of a catalytic amount of TBAF. Applying these


conditions to the benzotriazol


e system,


2-(benzotriazol-


l-yl)ethanol


s (3.47)


(Scheme


.25) wer


e obtained in good


yields when 3.22 or its derivative


s 3.25 and 3.45 were


treated with aromati


c and aliphati


c carbonyl compounds in


the presence of a catalytic amount of TBAF in THF.














R3R4CO


TBAF


SN

N


SiMe3


3.47


Scheme


3.25


Table 3.4


Fluoride Induced Reaction of 1


a-Trimethyl-


silyl)alkylbenzotriazoles with Carbonyl
Compounds


Substrate Carbonyl Product Yield
No. Compound No. (%)


3.22


3.22


3.25a

3.25a

3.25b

3.45a


C6 100


4-MeC6H4CHO

C3H70
4-MeC6 HCHO

4-MeC6gHCHO

4-MeC6 4CHO


3.45b


C6 100


3.47a

3.47b

3.47c

3.47d

3.47e

3.47f

3.47g




Full Text
mmi

THE REACTIVITY OF SOME N-LINKED SUBSTITUTED-METHYL GROUPS
ATTACHED TO AZOLE RINGS
By
JAMSHED NOSHIR LAN
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1988

To My Parents with Love

ACKNOWLEDGEMENTS
I am deeply indebted to my advisor Prof. Alan R.
Katritzky FRS, for his invaluable guidance, patience and
faith over the years. It has been a pleasure working with
him.
I would also like to take this opportunity to thank
the Chemistry faculty for giving me the opportunity to
work in this department, especially Drs. Battiste, Deyrup,
Jones, and Schulman for the time they have spent as
members of my committee.
I wish to thank Dr. Steve Cato, whose friendship,
time, help and patience has been invaluable to me,
especially during the preparation of this manuscript.
I am extremely indebted to Dr. Saumitra Sengupta for
all his suggestions and help and especially his
"interesting evenings of chemistry" during those otherwise
late, lonely nights. I thank also Dr. Wojtek
Kuzmierkiewicz, whose company in the lab was a blessing
and made those long hours of column chromatography
ni
tolerable.

Special thanks also go out to Dina Yannakopoulou, and
Drs. Ramiah Murugan, Rick Offerman and José Aurrecoechea
for their help/suggestions and discussions. Dawn Sullivan
also deserves a special mention for all her help in the
office.
Avi, Prem, Sunil, Maria and Lucy have been my closest
friends in America. I really appreciate all the times they
went out of their way to take care of me and cheer me up:
The good times together will always be remembered.
Special thanks are due to all the waitresses at Café
Gardens for their excellent service during many ale-
shifting evenings during the last seven years.
Last but not the least, I would like to thank my
parents for all that they have done for me.
IV

TABLE OF CONTENTS
ACKNOWLEDGEMENTS iii
ABSTRACT viii
CHAPTERS
I. INTRODUCTION 1
1.1 Carbanions 1
1 . 2 Azoles
1.3 General Outlook 7
II. GENERATION OF a-CARBANIONS FROM 1-(PHENYLTHI0-
METHYL)BENZIMIDAZOLE AND RELATED COMPOUNDS .... 9
2.1 Introduction 9
2.1.1 Lithiation of Imidazole Systems 10
2.1.2 Metallation of Other N-Alkylheterocycles 10
2.1.3 Aims of the Work 14
2.2 Results and Discussion 22
2.2.1 Preparation of l-(Phenylthiomethyl)-
benzimidazole 22
2.2.2 Lithiation of 1-(Phenylthiomethyl)-
benzimidazole 23
2.2.3 Lithiation of 1-(Phenylsulfinylmethyl)-
and 1-(Phenylsulfonylmethyl)-
benzimidazole 32
2.2.3.1 Preparation of 1-(phenylsulfinyl-
methyl)- and 1-(phenylsulfonyl-
methyl)-benzimidazole 32
2.2.3.2 Reaction of l-(phenylsulfinyl-
methyl)benzimidazole with LDA and
electrophiles 33
2.2.3.3 Reaction of 1-(phenylsulfonyl-
methyl)benzimidazole with LDA and
electrophiles 35
2.2.4 Studies on 2-Phenyl-l-(phenylthio¬
methyl )benzimidazole and Related
Compounds 37
2.2.4.1Lithiation of 2-phenyl-l-(phenyl¬
thiomethyl ) benzimidazole and related
compounds 37
v

2.2.4.2Condensation studies with quaternary
salts of 2-phenyl-N-(substituted-
methyl)benzimidazoles 43
2.3 Conclusions 46
2.4 Experimental 48
III. SYNTHESIS AND REACTIONS OF SOME BENZOTRIAZOLE
DERIVATIVES 62
3.1 Introduction 62
3.1.1 Selection of a Novel Activating/
Protecting Group 66
3.1.2 Previous Work on (TrimethylsilyImethyl)-
azoles 68
3.1.3 Aims of the Work 73
3.2 Results and Discussion 79
3.2.1 Preparation of 1-(Trimethylsilyl)me thy1-
benzotriazole 79
3.2.2 Lithiation of 1-(Trimethy1silyl)methyl-
benzotriazole and its Derivatives 82
3.2.2.1 Reactions of 1-(trimethylsilyl-
methyl)benzotriazole with n-butyl-
lithium and subsequently with
electrophiles 82
3.2.2.2 Anion formation from 1-(a-trimethyl-
si lylalkyl ) benzot r i azole and
subsequent reactions with
electrophiles 87
3.2.2.3 Anion formation from 1-alkenyl-
benzotriazoles 88
3.2.3 Fluoride Catalyzed Desily1 ations 90
3.2.4 Acylative Desilylation 92
3.2.5 Removal of Benzotriazole Moieties 94
3.2.5.1 Reductive elimination of
benzotriazole 95
3.2.5.2 Attempted hydrolysis of
benzotriazolylalkenes 95
3.3 Conclusions 97
3.4 Experimental 101
IV. STUDIES ON N-(SUBSTITUTED-METHYL)-3,5-DIMETHYL-
PYRAZOLES 121
4.1Introduction 121
4.1.1 The Chemistry of N-Chloromethyl
Compounds 121
4.1.2 Synthetic Utility 123
4.1.2.1 Generation of N-(substituted-
methyl)heterocycles 123
4.2.2.2 Generation of C-a carbanions 124
4.2.2.3 Carbanionic Rearrangements via
Cyclic Intermediates 125
vi

4.1.3Aims of the Work 130
4.2 Results and Discussion 140
4.2.1 Reactions of 3,5-Dimethyl-l-(phenylthio-
methyl)pyrazole 140
4.2.2 Reaction of l-Chloromethyl-3,5-dimethyl-
pyrazolium Chloride with S-, N-, and 0-
Nucleophiles 145
4.2.2.1 Reaction with sulfur nucleophiles .. 145
4.2.2.2 Reaction with nitrogen and oxygen
nucleophiles 145
4.2.3 Attempted Carbanionic Rearrangements via
Three-Membered Cyclic Intermediates .... 150
4.2.3.1 The a-2-mercaptobenzothiazole
adducts 150
4.2.3.2 The a-N,N-diethyldithiocarbamate
adducts 152
4.2.3.3 The cx-2-pyridone adducts 156
4.3 Conclusions 158
4.4 Experimental 160
V. SUMMARY 170
REFERENCES 173
BIOGRAPHICAL SKETCH 184
vi i

Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
THE REACTIVITY OF SOME N-LINKED SUBSTITUTED-METHYL GROUPS
ATTACHED TO AZOLE RINGS
By
JAMSHED NOSHIR LAM
April 1988
Chairman: Alan R. Katritzky, FRS
Major Department: Chemistry
Carbanionic species derived from N-(substituted-
methyl)azoles were studied as intermediates in synthetic
transformations at the C-a position.
1-(Phenylthiomethyl)benzimidazole underwent lithiation
initially at the 2-position. At low temperatures the
2-lithio derivative reacted with active electrophiles to
form 2-substituted products. At higher temperatures,
rearrangement occurred to give the C-a lithiated isomer
which was trapped by benzyl bromide. However, lithiation
was directed exclusively to the methylene group by using
the corresponding sulfoxide or sulfone derivatives.
Blocking the 2-position of the benzimidazole ring with a
phenyl substituent also enabled regiospecific metallation
vi i i
at the C-a site.

The use of silicon to stabilize an "alpha" carbanion
was investigated in the lithiation studies of
1-(trimethy1silyl)methylbenzotriazole. The anion was
readily alkylated and acylated and underwent Peterson
olefination with carbonyl compounds. 1-(Cyclohexylidene-
methyl)benzotriazole was lithiated exclusively at the
a-carbon atom and the anion cleanly alkylated. The silyl
derivatives underwent fluoride catalyzed desilylation with
carbonyl compounds. 1-(a-Acylalkyl)benzotriazoles were
reduced to ketones with zinc and acid.
The synthetic utility of N-chloromethylheterocycles
was investigated with pyrazole as the heterocycle. The
chloride ion in l-chloromethyl-3,5-dimethylpyrazole was
readily displaced by N, 0, and S nucleophiles.
3,5-Dimethyl-1-(phenylthiomethyl)pyrazole formed a
carbanion at the C-a position and reacted with
electrophiles. The phenylsulfenyl group was selectively
removed by Raney-Nickel desulfurization. The effect of an
electrophilic site "beta" to the carbanion generated was
also studied in other pyrazole systems in attempts to
promote rearrangements via three-membered intermediates.
i x

CHAPTER I
INTRODUCTION
This dissertation consists of three main chapters
dealing with three different azole systems:
(i) benzimidazole, (ii) benzotriazole, and (iii) pyrazole.
The work discussed here is concerned with the reactivity
at the N-substituent in these three ring systems.
1.1 Carbanions
Carbanions are synthetically useful intermediates
[79MI1]. One of the most common methods utilized to
generate a carbanion is the use of organometallic reagents
to abstract a proton. The commercial availability of a
variety of these organometallic reagents has led to the
discovery of new functional groups that promote
metallation and to the elaboration of novel heterocyclic
and olefinic species that can undergo metallation.
Consequently, heteroatom-faci1itated lithiation [790R1]
has been widely used not only in the elaboration of
aromatic and heteroaromatic systems, but also in synthetic
aliphatic chemistry.
1

2
Systems have been used where the negative charge is
stabilized by the inductive effect of an a-heteroatom such
as nitrogen or oxygen. In certain heterocyclic systems
(such as pyridones), stabilization of the carbanion can
also occur by co-ordination effects [83T1975].
The fact that sulfur is a strong activator was
explained by the (d-a) overlap which outweighed the
inductive effect of the more electronegative oxygen and
nitrogen atoms [64JOM(2)304]. Early theorists [56JCS4895,
60JA2505, 74CRV157] suggested overlap of the lone pair
orbital on the carbanion with the empty d-orbitals on
sulfur provided the stabilization. While there were
arguments [60CRV147, 69MI1] that the empty sulfur
3d-orbitals were too high in energy to interact, Wolfe
[83TL4071] suggested that the d-orbitals were important in
★
lowering the energy by n-cr interaction. However, recent
work [78JA1604, 83JA3789, 86JA1397] is beginning to show
that the sulfur d-orbitals have no substantial bonding
interactions with a-carbanions. Instead it is possible
that simple coulombic interactions play a dominant role
with significant charge polarization.
While this debate lingers on, the fact remains that
the stabilization of a-carbanions by sulfur has several
consequences. As a result this property has been utilized
in the elaboration of certain heterocyclic systems

3
[85JOC1351, 87J(PI)781] for stabilizing the C-a carbanion
when previously the anion was either unstable or could not
be generated.
Lithiating agents can be divided into two broad
categories. Those that belong to the first class are the
alkyl and aryl lithiums. These reagents are more
nucleophilic than those of the second category which are
the n-butyllithium/amine complexes and lithium
dialkylamides. In some cases, the choice of the reagent
may not be important. On the other hand, there are many
instances where the nucleophi1icity or strength of the
base plays an important part in determining the outcome of
the final product.
1.2 Azoles
Azoles are readily available heterocyclic systems.
Those azoles that contain more than one nitrogen atom
display dual properties since the two nitrogen atoms are
not identical. One of the nitrogens while although being
2
bonded to three atoms is sp hybridized since the lone
pair of electrons reside in a p-orbital since they are
involved in the n-system. This nitrogen is commonly
referred to as a pyrrole-like nitrogen atom. The other
nitrogen is said to be pyridine-like since it has its lone
pair of electrons in the plane of the ring and are not
involved in the n-electron system. The subsequent analogs

4
(the triazoles and the tetrazoles) have their other
nitrogens pyridine like.
The additional nitrogen atoms have an inductive
electron-withdrawing effect and can provide stabilization
to negatively charged reaction intermediates. The presence
of the additional nitrogen atoms to assist in the
reactivity is demonstrated in the following two examples
which occur in these azole systems but is rarely observed
in pyrrole or furan or thiophene. The nucleophilic
addition-elimination reaction (Figure 1.1a) occurs readily
in imidazole systems [85MI1]. Stabilization of the
intermediate anion by the additional nitrogen atom also
assists in the deprotonation of substituent methyl groups
(Figure 1.1b).
Figure 1.1 Azole reactions involving negatively charged
intermediates.

5
The lone pairs on nitrogen provide sites for
protonation and most azoles are stronger bases than
pyrrole. The stability of azolyl anions makes azoles
containing NH groups stronger acids than pyrrole. The pK
values for some azoles are listed in Figure 1.2 [76MI1,
79MI1]. The base strength of the azoles decreases as the
number of nitrogen atoms increases. This factor is
attributed to the inductive electron-withdrawing effect of
the additional nitrogen atoms.
Figure 1.2 pKQ values of some azoles.
While a lot of research has been carried our on
C-substituted azole derivatives, the chemistry of
N-substituted azoles is less common. The aryl group in
1-phenyl-pyrazóles and -imidazoles undergoes nitration and

6
halogenation at the para position. 1-Phenylpyrazole
undergoes metallation at the ortho position of the
N-phenyl group. 1-Arylbenzotriazoles upon pyrolysis give
carbazoles [81AHC(28)231]. Similarly, 1,5-diphenyl-
tetrazole undergoes thermolysis to form
2-phenylbenzimidazoles.
The N-alkyl group in azolium salts can be removed by
nucleophilic S^2 reactions. However, there is competition;
for example, both N-methyl- and N-ethyl-imidazoles are
formed in the reaction of the N-ethyl-N'-methylimidazolium
salt with iodide [8OAHC(27)241].
In neutral N-alkyl azoles, and especially in
pyrazoles, deprotonation occurs at the C-a position when
treated with n-butyllithium. On the contrary, the more
acidic C-2 proton is removed in 1-methylbenzimidazole.
The presence of extra nitrogen atoms make azoles
stronger bases than pyrrole. The stability of azolyl
anions makes azole rings good leaving groups. As a result,
N-acylazoles are readily hydrolyzed.
Except for a few other examples, there has been no
systematic work carried out on the generation of
carbanions at the C-a position for various N-alkyl azoles.

7
1.3 General Outlook
The aim of the overall project is briefly mentioned in
this section. The specific details are discussed more
thoroughly in the corresponding chapters.
As mentioned previously, only N-alkylpyrazoles have
been lithiated at the C-a position. For benzimidazoles,
the kinetic acidity of the ring proton is greater.
Furthermore, even with a methyl or a benzyl substituent at
the 2-position, lithiation occurs at the C-2 methyl or the
methylene carbon rather than at the N-methyl site. Thus
the aim was to find a substituent which would generate and
stabilize the carbanion at the C-a site. Sulfur, being a
strong a-activator was selected as the heteroatom. The
phenylsulfenyl moeity would be the substituent to use. If
need be, the acidity of the adjacent methylene protons
could be further increased by oxidizing the sulfide to the
sulfoxide or to the sulfone.
In benzotriazoles, there is no competition as observed
in benzimidazole. However, the anion of 1-methyl-
benzotriazole being unstable requires the presence of a
group that can stabilize a-carbanions. Nitrogen and oxygen
while being more electronegative do not generally
stabilize a-carbanions. This is due to the repulsion
between the nitrogen (or oxygen) lone pair and the C lone
pair. However, silicon is known to stabilize a-carbanions

8
and is a suitable candidate in this case. Furthermore, the
silicon atom can be readily removed under moderately mild
conditions.
In pyrazoles, since the C-a carbanion is stable, the
need of an external functionality is not required.
Consequently,the C-a carbanion can be generated for a
variety of N-(substituted-methyl)pyrazoles. These
derivatives are in turn formed from the N-chloromethyl-
pyrazole which due to the large difference in reactivity
between the heterocycle and the chlorine atom make them
interesting synthetic intermediates.

CHAPTER II
GENERATION OF a-CARBANIONS FROM 1-(PHENYLTHIOMETHYL ) -
BENZIMIDAZOLE AND RELATED COMPOUNDS
2.1 Introduction
An azole ring can render acidic hydrogen atoms
attached to carbon in at least four distinct environments:
(a) ring : CH • a to ring sulfur or nitrogen;
(b) substituent •CHXY attached to a ring carbon a or
Y to a pyridine-like ring nitrogen;
(c) substituent •CHXY attached to a pyrrole-like ring
nitrogen atom;
(d) the ortho :CH• of a phenyl group a to a pyridine¬
like ring nitrogen.
For X = Y = H, the order of kinetic acidity in
imidazoles (as found by hydrogen/deuterium exchange or in
metallation reactions [790R1]) is a,b > c (Figure 2.1).
a
Figure 2.1 Order of kinetic acidity in imidazoles.
9

10
2.1.1 Lithiation of Imidazole Systems
Kinetic acidity of the type discussed above was
observed when 1-methyl- (2.1) and 1-benzyl-benzimidazole
(2.2) were shown to undergo lithiation at C-2 [58JOC1791,
74JOC1374]. 2-Methyl- (2.3) and 2-benzyl-benzimidazole
(2.4) when metallated with an excess of butyllithium react
with various electrophiles at the C-2 methyl or C-2
methylene group [73JOC4379] (Figure 2.2). Furthermore,
Sullivan [70JMC784] demonstrated the weakly acidic
character of the methyl protons of 2-methylbenzimidazole
(2.3) by condensing it with aromatic aldehydes in the
presence of either an acidic or a basic catalyst to form
2-styrylbenzimidazoles.
In 2-phenylbenzimidazole (2.5) the ortho position of
the phenyl substituent is lithiated [78CI(L)582 ] . In
disubstituted compounds such as 1,2-dimethylbenzimidazole
(2.6) [76KGS1699] or 1,2-dimethylimidazole (2.7)
[83J(PI)271], metallation occurs exclusively at the C-2
methyl group. At higher temperatures, dimerizations are
observed in some cases [58JOC1791].
2.1.2 Metallation of Other N-Alkylheterocycles
Renewed attention has also recently been paid to the
metallation of other N-alkylheterocycles followed by

11
reaction with electrophiles [790R1, 85S302]. Some of these
systems are shown in Figure 2.3 and include 1-benzyl-
4,6-diphenyl-2-pyridone (2.8) [80J(PI)2851], 3-benzyl-
2-phenylquinazolin-4(3H)-one (2.9) and related compounds
[82JCR(S)26], and N-alkylpyrazoles (2.10) [83T2023].
Figure 2.2 Lithiation sites in benzimidazole and imidazole
systems.
In all cases the metallations can occur at a ring
position and in some cases exceptionally at C-a of the
alkyl radical. The carbanionic species generated from
metallation at the C-a site can be categorized as a dipole
stabilized carbanion [78CRV275].

12
2.8
2.9
2.10
Figure 2.3 Metallation studies on some other N-alkyl-
hete rocycles.
A systematic study of N-benzyl- (2.10a) and N-methyl-
pyrazoles (2.10b) [83T2023] reported that whereas the
N-substituted metallation product 2.11 was kinetically
favored, at higher temperatures, the metal atom was
observed to have migrated to yield the thermodynamically
more stable 5-isomer 2.12 (Scheme 2.1).
By contrast, carbazoles are relatively inert to
C-lithiation [41JA1758, 43JA1729]. However, 9-ethyl-
carbazole has been shown to lithiate at C-l rather than at
N-Ca [36JOC146 , 72CB487].

13
2.10 2.11 2.12
(a) r = Ph
(b) r = H
Scheme 2.1
The order of kinetic acidity is expected to change if
for the substituent -CHXY, X or Y is a heteroatom.
Katritzky et al. [83T4133] suggested that metallation of
cjem-bi s ( pyrazol-l-yl) methane (2.13) would occur at the
N-alkyl site, due to the fact that the double activation
of the C-H bonds would facilitate both the ease of
preparation and the stability of these compounds.
Treatment with n-butyllithium at 25°C followed by reaction
with methyl iodide or benzyl chloride gave the expected
1-substituted derivative 2.14 (Scheme 2.2). Surprisingly,
reaction with carbonyl electrophiles under the same
conditions gave the products 2.15 which arose from ring
lithiation. However, with lithium diisopropylami de (LDA)
at 0°C, exclusive a-addition occurred to give the
1-substituted compounds 2.14.

14
2.13
E+
2.14
Scheme 2.2
2.15
2.1.3 Aims of the Work
It was seen earlier (Section 2.1.2) that C-a
metallation can compete with ring metallation. Sulfur,
although less electronegative than nitrogen (but similar
to carbon), has been known to stabilize an a-carbanion. As
a result the anion generated from an N-CH-,-SR system
should be considerably more stable than that from N-Me and

15
consequently able to compete with deprotonation at ring
positions ortho to the ring sulfur or nitrogen.
The presence of a phenylthio group did prove to be
effective in achieving N-C^ metalation on some azole
systems in our laboratory. Katritzky et al. [87J(PI)781]
successfully lithiated 1-(phenylthiomethyl)benzotriazole
(2.16a) at the "alpha" position to give the cor responding
N-C substituted adduct 2.17 (Scheme 2.3). This was in
OC
contrast to the lithiation of 1-methylbenzotriazole
(2.16b) [86UP1] where either starting material and
uncharáeterizable products were obtained rather than
l-(substituted-methyl)benzotriazoles 2.18.
2.16
(a) r = sPh
(b) r = h
2.18
Scheme 2.3

16
A similar result was also achieved [85JOC1351] in the
a-lithiation of 9-(phenylthiomethyl)carbazole (2.19a)
generating N-[(phenylthio)alkyl]carbazoles (2.20) in 70^
yield (Scheme 2.4). This was an improvement over the
results of Gilman and Dirby [36JOC146] and Seebach
[72CB487] where lithiation of 9-ethylcarbazole (2.19b) was
shown to occur on the ring to give the C-l substituted
product 2.21.
Scheme 2.4
Based upon the above successes, it was decided tc
attempt similar reqioselective lithiation at the C-a
position in 1-(phenylthiomethyl)benzimidazole (2.22) to
give the C-a substituted derivative 2.23 (Scheme 2.5). It

17
was felt that the presence of a phenylthio group at the
C-a position would be more preferable than blocking the
C-2 position with an alkyl or aryl group. This was
attributed to the results discussed previously (Section
2.1.1) where lithiation occurred on the C-2 substituent
itself in the substituted benzimidazoles 2.3-2.6 shown in
Figure 2.2. Success in this system would help to develop a
general procedure for the synthesis and transformations of
N-substituted azoles.
Scheme 2.5
The alkylation of the benzimidazole anion with
phenylthiomethyl chloride as described by Russian authors
[69KGS934] and in a patent [79MIP469492] gave low yields
or crude products which necessitated chromatographic
purification. An alternative procedure for the synthesis
of 2.22 would be a nucleophilic substitution on
1-(chloromethyl)benzimidazole (2.24) by thiophenol in the
presence of base (Scheme 2.6) under conditions similar to
that described for the synthesis of 1-(phenylthiomethyl)-
benzotriazole (2.16a) [87J(PI)781].

18
2.24 2.22
Scheme 2.6
Successive treatment of 2.22 with base and
electrophiles should give the C-a disubstituted derivative
2.25 which, depending on the leaving group ability of
either the heterocycle or the sulfur functionality, could
provide the sulfide 2.26 or the 1-substituted
benzimidazole 2.27, respectively (Scheme 2.7).
If, however, the ring carbon did compete in
metallation with the C-a position, it would be necessary
to find alternatives in order to achieve regioselective
metallation. One alternative would be to further increase
the kinetic acidity of the N-methylene group. This should
be possible by oxidizing the sulfur moiety in
1-(phenylthiomethy1)benzimidazole (2.22) to either the
sulfoxide 2.28 or the sulfone 2.29 (Scheme 2.8). Under
these conditions, lithiation should be expected to occur
at the C-a site to give the corresponding adducts 2.30 and
2.31, respectively.

19
E1
2.26
Scheme 2.7
Sulfoxides which contain a 6-hydrogen undergo
elimination on pyrolysis at about 80°C via a five-membered
E^ mechanism with syn elimination [60JA1810, 64JOC2699,
67JOC1631]. If the derivative 2.30 contained a 6-hydrogen,
heating it would give rise to alkylidenebenzimidazoles
2.32 which would be a novel method for the preparation of
such compounds (Scheme 2.9).

20
Base / E+
9
2.30 n
2.31 n
S(0)nPh
= 1
= 2
Scheme 2.8
2.30
2.32
Scheme 2.9

21
Previous routes to alkylidenebenzimidazoles 2.32 have
included the reaction of alkynes with benzimidazole under
high pressure [82M11] or the use of catalysts and high
temperature [78JHC1543, 78MI1). Amongst the more specific
uses of these derivatives were their use in the synthesis
of anion exchangers [82MI1] and of their co-ordination
with metals in the study of antitumor activity [83MI1].
If the above increase in acidity was still sufficient
to achieve regioselective lithiation, an alternative would
be to find a good blocking group for the C-2 position.
This would leave the C-a site as the only active site.
Treatment of such a 2-substituted-1-(phenylthiomethyl ) -
benzimidazole (2.33) with base and electrophiles should
enable electrophilic addition to be carried out at the C-a
site to afford the required derivatives 2.34
(Scheme 2.10) .
Scheme 2.10
2.34

22
Alternatively, forming the quaternary salt of the
benzimidazole derivative 2.22 was also expected to
increase the acidity of the S-methylene protons. Treatment
of the quaternary salt 2.35 with aldehydes would thus
generate the alkylidene derivatives 2.36 as depicted below
in Scheme 2.11.
CH3
+
CH.X
SPh
2.22
SPh
2.2 Results and Discussion
2.2.1 Preparation of 1-(Phenylthiomethy1)benzimidazole
l-(Phenylthiomethyl)benzimidazole (2.22) was prepared
in four steps starting from 1,2-phenylenediamine (2.37)

23
(Scheme 2.12). Treatment of 2.37 with formic acid at 100°C
[430SC65] readily generated benzimidazole (2.38) (80%). A
solution of 2.38 and of 37% aqueous formaldehyde in
methanol [50JCS1600] afforded the corresponding
1-(hydroxymethyl)benzotriazole (2.39) in a greater than
90% yield. The chloroderivative 2.40 was obtained by
treatment with thionyl chloride [50JCS1600] and was
isolated as the hydrochloride salt. The formation of
chloromethylazoles as the hydrochloride salts is quite
common in the case of the more basic azoles.
1-(Chloromethy1)benzotriazole is one of the few such
azoles which is stable as the free base [87J(PI ) 781 ] .
Treating the hydrochloride salt 2.40 with two equivalents
of sodium ethoxide and thiophenol afforded
1-(phenylthiomethyl)benzimidazole (2.22) as colorless
plates in 85% yield.
2.2.2 Lithiation of 1-(Phenylthiomethy1)benzimidazole
The lithiation of 1-(phenylthiomethyl)benzimidazole
(2.22) was carried out with lithium diisopropylamide (LDA)
in dry tetrahydrofuran (THF) at -78°C and the
corresponding anion quenched with benzyl chloride. Work up
of the reaction mixture afforded 1-[2-phenyl-l-(phenyl-
thio)ethyl]benzimidazole (2.41) in addition to some
unreacted starting material (Scheme 2.13).

24
2.39
2.40
2.22
Scheme 2.12
2.22
Scheme 2.13
2.41

25
The use of the more reactive benzyl bromide proved
futile, since starting material was still observed (ca.
30%, estimated from the integrated ^H-NMR). Attempts to
purify the mixture via Kugelrohr distillation failed since
the compound decomposed at high temperatures to give
benzimidazole (2.38) and g-phenylthiostyrene (2.42), the
latter isolated in a 67% yield (Scheme 2.14). Compound
2.41 was finally obtained in a pure state by raising the
reaction temperature to -20°C after addition of benzyl
bromide. Katritzky et al_. [87J(PI)775] also observed
analogous behavior with ethyl iodide and isopropyl iodide
as electrophiles under similar conditions.
2.22 + 2.41
2.38
Scheme 2.14
When the anion generated from 2.22 was treated with
the more reactive electrophile methyl iodide, the C-2
substituted product 2.43a was obtained. This was evident
by the fact that the H-NMR spectrum of the product
displayed two singlets at S5.3 and 2.1 instead of a
quartet and a doublet as would have been expected for the
C-a attack. When 4-methylbenzaldehyde and benzophenone

26
were utilized as the electrophile, a similar phenomenon
was observed to give the alcohols 2.43b,c in yields of
over 75% (Scheme 2.15).
E
SPh
2.43
(a) e = Me
(b) E = 4-MeCgH4CH(OH)
(c) E = Ph2C(OH)
Scheme 2.15
As discussed earlier (Section 2.1.2), competition
between chain and ring lithiation in azoles is quite
common. It might be possible that in this system at -78°C,
both the anions could be formed with the ring metallated
carbanion 2.44 predominating. The nature of the 2-lithio
derivative was such that it precipitated out of solution.
At higher temperatures (c£. -40°C to -20°C) rearrangement
of 2.44 occurred via a transmetallation to generate the
isomeric C-a carbanion 2.45 (Scheme 2.16) which was
soluble in the solvent system employed. The fact that
there exists two different physical states makes it
difficult to compare the stability of the individual
anions. Consequently, the insoluble 2-anion 2.44 reacted

27
with certain electrophiles to give the C-2 substituted
derivative 2.43. On the other hand, the isomeric carbanion
2.45 reacted with electrophiles that did not react with
the C-2 lithio derivative.
Thus addition of l-(phenylthiomethyl)benzimidazole
(2.22) to an LDA solution at -78°C afforded a yellow
precipitate after ca. Ih. When the various electrophiles
were added at -78°C, the precipitate either dissolved
rapidly (to give 2.43), or dissolved on slow warming at
-40°C to -20°C (giving 2.41). In the former case, the
products always displayed a singlet at about 65.3 (and
integrated for two protons), indicating no attack at the
C-a position but attack at C-2 instead. Hence, in the
reactions with methyl iodide, 4-methylbenzaldehyde and
benzophenone, the precipitate dissolved at -78°C and the
C-2 substituted products 2.43 were obtained.
The reaction of benzyl iodide and 2.22 at -78°C
provided a mixture which, after purification, showed it to
be approximately a 1:1 mixture of starting material 2.22
and the complex C-2 substituted product 2-(1,2-diphenyl-
ethyl)-1-( phenyl thi ome thyl) benz imidazole (2.46) (Scheme
2.17). Compound 2.46 was characterized by its ^H-NMR
spectrum (300 MHz) which displayed a narrow AB system at
ca. 65.1 (£ab 14.4 Hz) for the S-methylene group and an
AMX pattern between 3.9 and 3.2 ppm due to the C-2
substituent (Figure 2.4). The ^C-NMR spectrum confirmed

28
this assignment with sp -C signals at 48.6 (CH-,SPh), 46.1
(CHPh ) , and 41.6 (CH0Ph).
2.43
2.45
E+
2.41
Scheme 2.16
This dibenzylation probably arises by the
transformation of an initial C-2 lithiated intermediate to
a reactive C-2 benzylated intermediate which has a more
acidic CH^ group. 2-Benzylbenzimidazole (2.4) is known to
undergo lithiation at the C-2 methylene group [73JOC4379 ] .

29
2.22 2.46
+
2.22
Scheme 2.17
Attempts to obtain selective lithiation at C-a by
increasing the temperature of the reaction mixture before
addition of the electrophile failed on numerous occasions.
Warming to -40°C followed by addition of methyl iodide or
4-methylbenzaldehyde afforded either mixtures of starting
materials and C-2 substituted products (in yields of less
than 40%) or no reaction at all. A similar behavior was
observed when the anion 2.44 was allowed to warm to -40°C
for a few hours and then cooled back to -78°C before
addition of the electrophile. When a mixture of
n-buty11ithium and N,N,NN'-tetramethylethylenediamine
(TMEDA) was added to 2.22 in ether at -20°C a dark red
solution was obtained. Quenching with methyl iodide showed
some C-a alkylation but only to an extent of about 30%.
Lower reaction temperatures or longer reaction times did
not improve the situation.

Figure 2.4 ^H-NMR (300 MHz ) spectrum of 2-(l,2-diphenylethyl)-
l-(phenylthiomethyl)benzimidazole (2.46)

31
In a separate experiment, 1-(phenylthiomethyl)-
benzimidazole (2.22) was metallated with phenyl1ithium in
diethyl ether at -78°C to give a pale yellow solution.
Trapping the carbanion with deuterium oxide gave solely
the C-2 deuteriated product 2.47 (Scheme 2.18) which was
confirmed by the disappearance of the singlet at S8.06 in
the ^H-NMR (DMSO-dg) spectrum of the product.
PhLi / D20
Ét¡o
^SPh
2.22 2.47
Scheme 2.18
These observations were quite similar to that obtained
by Katritzky et. ad.. [ 8 3 T 41 3 3 ] (see Section 2.1.2) where
lithiation of bis(pyrazol-1-yl)methane (2.13) afforded the
1-substituted derivative 2.14 with benzyl bromide.
Alternatively, the ring substituted product 2.15 was
obtained with deuterium oxide and carbonyl compounds as
electrophiles. By contrast, exclusive C-a substitution
could be achieved by changing the base and reaction
temperature for the pyrazole 2.13, while no change in the
outcome was observed for 1-(phenylthiomethyl)benzimidazole
(2.22) .

32
2.2.3 Lithiation of 1-(Phenylsulfinylmethyl)- and
1-(Phenylsulfonyimethyl)-benzimidazole
2.2.3.1 Preparation of 1-(phenylsulfinylmethyl)- and
1-(phenylsulfonyimethyl)-benzimidazole
In an attempt to solve the problems of competitive C-a
vs C-2 attack encountered in the metallated derivatives of
1-(phenylthiomethyl)benzimidazole (2.22), it was decided
to investigate the corresponding sulfoxide 2.28 and
sulfone 2.29 derivatives of 2.22 which should display a
more kinetically acidic N-methylene group. l-(Phenyl-
sulfinylmethyl)- (2.28) and 1-(phenylsulfonylmethy1)-
benzimidazole (2.29) were readily obtained via oxidation
of 2.22 with one and two equivalents of m-chloroperbenzoic
acid in methylene chloride respectively (Scheme 2.19).
2.22
2.28 n = 1
2.29 n = 2
Scheme 2.19

33
Compounds 2.28 and 2.29 were characterized by their
elemental analyses, IR and ^ H-NMR data. The IR spectrum
for 2.28 showed the characteristic sulfoxide absorption at
1030 cm ^ , while the asymmetric and symmetric absorptions
for the sulfone 2.29 were observed at 1320 and 1130 cm ^
respectively.
The ^H-NMR spectra of the sulfoxide 2.28 were
interesting in that in DMSO-dg, the C-a protons appeared
as an AB pattern with the resonances centered at 65.66 and
5.86 and having a coupling constant of J 14 Hz. In CDCl^,
the AB pattern was observed upfield at ca. 65.23 with the
resonances only 0.04 ppm apart. The N-methylene protons
for the sulfone 2.29 resonated as a singlet at 55.46 in
CDC1^ which was 0.8 ppm upfield from the resonance
observed in DMSO-dg. However, irrespective of the solvent
used, the N-methylene signals for the sulfoxide 2.28 were
upfield to that of the sulfide 2.22 while those for the
sulfone 2.29 were downfield.
2.2.3.2 Reaction of l-(phenylsulfinylmethyl)benzimidazole
(2.28) with LDA and electrophiles
1-(Phenylsulfinylmethyl)benzimidazole (2.28) underwent
lithiation with LDA at -78°C to give the crude product
l-[2-phenyl-l-(phenylsulfinyl)ethyl]benzimidazole (2.30a)
in a 95% yield (Scheme 2.20). However, attempts to purify
the product via crystallization failed since the compound
tended to decompose.

34
2.28
2.30
(a) E = PhCH2
(b) E = 4-MeC6H4CH(OH)
2.30a
Scheme 2.20
2.32
The benzylated derivative (2.30a) was obtained in a
reasonably pure state by triturating the crude mixture
with cyclohexanone. On heating 2.30a in toluene, a white
solid was obtained. The ^H-NMR spectrum of the solid
displayed no aliphatic resonances indicating the expected
elimination of the phenylsulfinyl group to give
1-styrylbenzimidazole (2.32). This was also confirmed by
the IR spectrum where the characteristic sulfoxide
absorption at 1030 cm ^ was not observed. When the anion

35
generated from 2.28 was trapped with 4-methylbenzaldehyde,
the corresponding alcohol 1-[2-hydroxy-2-(4-methylphenyl)-
1-(phenylsulfinyl)ethyl]benzimidazole (2.30b) was obtained
in 70% yield.
As can be seen, this system seemed promising since
regioselective lithiation could be achieved here. However,
the low stability of the sulfinyl adducts 2.30a,b, caused
problems during purification which as a result led to the
search for a more stable system.
2.2.3.3 Reaction of 1-(phenylsulfonylmethyl)benzimidazole
T2 :~29 ) with LDA and electrophiles
Sulfones containing a 8-hydrogen are more stable than
their sulfoxide counterparts since they do not undergo
elimination on pyrolysis. Thus, the adducts 2.31 obtained
from the lithiation of 1-(phenylsulfonylmethyl)-
benzimidazole (2.29) should be more stable than the
sulfinyl derivatives 2.30. Treatment of 2.29 with LDA
followed by addition of benzyl bromide afforded
l-[2-phenyl-l-(phenylsulfonyl)ethylJbenzimidazole (2.31a)
as tan needles in 67% yield (Scheme 2.21). The benzylated
sulfone 2.31a was stable and did not decompose even upon
heating to 200°C.
The sulfone 2.31a was characterized by its ^H-NMR
spectrum and elemental analysis. In the “H-NMR spectrum,
the methine proton resonated as a double doublet centered

36
at 65.47. Each of the methylene protons also displayed a
double doublet centered at 64.08 and 3.80 with a geminal
coupling constant of J 14 Hz. This ABX system arises from
the fact that the N-C^ carbon atom is asymmetric and this
renders the adjacent methylene protons diastereotropic. As
a result, the two methylene protons are nonequivalent. The
^H-NMR spectrum of compound 2.31a was identical to that of
the product obtained upon oxidation of the benzylated
sulfide 2.41 with an excess of m-chloroperbenzoic acid.
(b) E = 4-MeC6H4CHfOH)
Scheme 2.21

37
When 4-methylbenzaldehyde was used as the
electrophile, the corresponding alcohol 1-[2-hydroxy-
2-(4-methylphenyl)-l-(phenylsulfonyl)ethyl]benzimidazole
(2.31b) was obtained in 55% yield.
The sulfonylphenyl moeity thus seemed to be a better
activating group enabling regioselective metallation at
the C-a position to give adducts 2.31 which were more
stable than their sulfinyl analogs 2.30.
However, when the reaction was carried out with methyl
4-methylbenzoate or benzonitrile, only starting material
was recovered.
2.2.4 Studies on 2-Phenyl-l-(phenylthiomethyl)-
benzimidazole and Related Compounds
2.2.4 .1 Lithiation of 2-pheny1-1-(phenylthiomethy1)-
benzimidazole and related compounds
In the previous section (Section 2.2.2) it was seen
that with the phenylthio moeity regioselective metallation
at the C-a position was only partially successful.
Increasing the kinetic acidity of the C-a protons by the
introduction of phenylsulfinyl (Section 2.2.3.2) and
phenylsulfonyl (Section 2.2.3.3) moeities did aid in
achieving regioselective addition. Hovever, there were
problems associated with these systems (instability of the
sulfoxide adducts and low selectivity of electrophiles for
the sulfone). The other alternative (Section 2.1.3) was to
block the C-2 position.

38
Although 2-phenylbenzimidazole (2.5) is known to
undergo lithiation at the ortho position of the phenyl
substituent [78CI(L)582] it was believed that with the
presence of the thiophenol moeity attached to the C-a
carbon it would be possible to selectively metallate at
the "alpha" position.
2-Phenyl-l-(phenylthiomethyl)benzimidazole (2.49) was
prepared from 1,2-phenylenediamine (2.37) via a two step
procedure. The reaction of 1,2-phenylenediamine (2.37)
with benzoic acid in phosphoric acid at 180°C [57JA427]
afforded 2-phenylbenzimidazole (2.5) as prisms in 70%
yield (Scheme 2.22). Treatment of 2.5 with
phenylthiomethyl chloride (2.48) in the presence of sodium
hydride in dry dimethylformamide (DMF) produced 2-phenyl-
1-(phenylthiomethyl)benzimidazole (2.49) in over 80%
yield.
The lithiation of 2-phenyl-l-(phenylthiomethyl)-
benzimidazole (2.49) was carried out using a mixture of
n-butyllithium-TMEDA in ether and trapping the anion with
benzyl bromide and methyl iodide to afford 2-phenyl-
1-[2-phenyl-l-(phenylthio)ethyl]benzimidazole (2.50a) and
2-phenyl-l-[l-(phenylthio)ethylJbenzimidazole (2.50b),
respectively (Scheme 2.23). In both cases, however, the
reactions went to about 70% completion (estimated from the
integrated ^H-NMR spectrum). The use of LDA in THF or
ether and longer reaction times did not alter the outcome.

39
Scheme 2.22
2-49 2.50
Scheme 2.23
(a) E = PhCH2
(b) E = Me

40
Katritzky e_t a_l. [87J(PI)775] also examined the
reaction of 2.49 with 4-methylbenzaldehyde to give the
corresponding alcohol. With all electrophiles employed,
only the C-a alkylated products were formed. No products
arising from lithiation at the ortho position of the
2-phenyl substituent were identified.
In an attempt to get the reaction to go to completion,
it was again necessary to increase the kinetic acidity of
the C-a protons. Utilizing conditions described earlier
(Section 2.2.3.1), the sulfide 2.49 was readily oxidized
with m-chloroperbenzoic acid giving 2-phenyl-l-(phenyl-
sulfinylmethyl)- (2.51) and 2-phenyl-l-(phenylsulfonyl-
methyl)-benzimidazole (2.52) in yields of 77 and 81%,
respectively (Scheme 2.24). The ^ H-NMR spectrum (CDCl^) of
the sulfoxide 2.51 displayed an AB pattern centered at
55.35 and 5.16.
2.49
2.51 n = 1
2.52 n = 2
Scheme 2.24

41
The sulfoxide 2.51 was treated with LDA and the anion
reacted with benzyl bromide to afford the benzylated
adduct 2-phenyl-l-[2-phenyl-l-(phenylsulfinyl)ethyl]-
benzimidazole (2.53) in 60% yield (Scheme 2.25). In
addition to the above product, 2-phenyl-l-styryl-
benzimidazole (2.54) (ca. 10%) was also obtained.
2.54
Scheme 2.25
The above behavior was in accordance with that
observed earlier (Scheme 2.2.3.2) where the benzylated
derivative (2.30a) readily eliminated the phenylsulfinyl
group on heating. However, irrespective of how carefully
the reaction was worked up, the styryl derivative 2.54 was

42
always obtained in 10-15% yields. The latter was also
readily obtained when the benzyiated derivative 2.53 was
heated under reflux in toluene to afford 2.54 as colorless
needles which was characterized by its ^ H-NMR spectrum and
microanalysis data. The absence of the sulfoxide
absorption at 1050 cm ^ further confirmed the elimination
of the phenylsulfinyl moiety.
In an attempt to determine if the C-a methine proton
in 2.53 is capable of further undergoing electrophilic
displacement, 2.53 was treated with a second equivalent of
LDA at -78°C and deuterium oxide added to trap the anion
formed. However, the only product isolated in this case
was the styryl derivative 2.54, instead of the deuteriated
sulfoxide 2.55 (Scheme 2.26). It is possible that the
"beta" hydrogen is acidic enough to compete with the
deprotonation of the methine proton causing elimination to
occur rather than electrophilic substitution. Sulfoxides
having a "beta" hydrogen are known to undergo elimination
in the presence of base [63CI(L)1243].
When 2-pheny1-1-(phenylsulfonylmethyl)benzimidazole
(2.52) was allowed to react with LDA followed by addition
of benzyl bromide or methyl iodide, only starting material
was recovered in both cases. The use of n-butyl1ithium as
base or increasing the reaction time or temperature before
addition of the electrophile did not aid in generating the
expected products.

43
2.54
Scheme 2.26
2.2 . 4 . 2 Condensation studies with quaternary salts of
2-phenyl-N-( substituted-methy 1 )benzimidazole~s
As discussed earlier, (Section 2.1.3) the quaternary
salt of benzimidazole derivatives could increase the
acidity of the S-methylene protons enabling condensations
with aldehydes at that site. Since the sulfinyl
derivatives 2.30a and 2.53 were generally unstable, it was
decided to attempt these condensations on 2-phenyl-
1-(phenylthiomethyl)- (2.49) and 2-phenyl-l-(phenyl-
sulfonylmethyl)-benzimidazole (2.52).

44
Heating the sulfide 2.49 or sulfone 2.52 with methyl
iodide under reflux afforded the corresponding quaternary
salts 2.56 and 2.57 (Scheme 2.27) in yields above 70%. The
methylene protons displayed a downfield shift of ca.
0.3 ppm due to the presence of a positive charge on the
benzimidazole ring.
2.49 n = 0
2.52 n = 2
2.56 n = 0
2.57 n = 2
Scheme 2.27
The acidities of the methylene protons of 2.56 and
2.57, were determined by hydrogen/deuterium exchange
studies. When the correspondiing salts were dissolved in
deuterium oxide and deuteriated acetonitrile (1:2), no
exchange was observed (as monitered by ^H-NMR), in either
case at room temperature or at -70°C.
The presence of a weak base such as triethylamine did
not aid in achieving any exchange. However the methylene
protons of 1(3)-methyl-2-phenyl-3(1)-(phenylsulfony1-
methyl)benzimidazolium iodide (2.57) exchanged
instantaneously in the presence of pyridine to afford the

45
bisdeuterated derivative 2.58 (Scheme 2.28). A stronger
base was required in the case of the sulfide 2.56 where
complete exchange occurred in the pesence of piperidine
after heating the mixture for six days at 80°C giving the
D
2.59
Scheme 2.28
The condensations on 2.56 and 2.57 were attempted with a
catalytic amount of the respective bases in ethanol and
aromatic aldehydes such as 4-methyl- or 4-nitro-
benzaldehyde, in order to obtain the alkylidene derivatives

46
2.60 (Scheme 2.29). However, only starting materials were
recovered. The use of longer reaction times, excess base, or
higher reaction temperatures (heating under reflux in
butanol) did not assist in any way. While steric reasons
could be a possibility, the same result was obtained when
primary aliphatic aldehydes were employed.
2.56 n = 0 2.60
2.57 n = 2
Scheme 2.29
The use of an inorganic base such as sodium hydroxide
led to decomposition products. Since this scheme did not
appear promising, further investigations were not
attempted.
2.3 Conclusions
The lithiation of 1-( phenyl t.hi omethyl ) benz imida zole
(2.22) was interesting due to the fact that electrophilic

47
attack was observed at both the C-2 as well as the C-a
positions with the former being the more reactive site.
The C-a anion formed at higher temperatures reacted with
electrophiles that did not react with the isomeric
carbanion. The use of slightly elevated temperatures (-40
to -20°C) in an attempt to achieve exclusive C-a
lithiation failed, since uncharacterizable mixtures or
starting materials were generally obtained.
Regioselective metallation was carried out by
increasing the kinetic acidity of the methylene protons
which was achieved by oxidizing the sulfur moeity to the
sulfoxide 2.28 and sulfone 2.29, respectively. Problems
were encountered with the sulfoxide 2.28 during
purification of the products 2.30 since the presence of an
acidic proton at the "beta" position led to cis-pyrolytic
elimination to give the styryl derivative 2.32. The
sulfone adducts 2.31 were more stable and as a result,
regioselective metallation could be achieved here.
The other alternative was the use of a blocking group
at the C-2 position. Katritzky et al. [87J(PI)775] showed
that a methyl group at the C-2 position was succeptible
towards metallation. However, the presence of a t_-butyl
[87J(PI)775] or a phenyl group, directed metallation to
the C-a position. The 2-phenyl derivative 2.49 underwent
metallation and electrophi11ic attack but the reactions
went to about 70% completion. When the sulfone 2.52 was
employed only starting materials were recovered. On the

48
other hand, in the case of the sulfoxide 2.50 the reaction
did go to completion but as in the earlier case (Section
2.2.3.2) the product was not stable and tended to undergo
elimination of the phenysulfinyl moeity even at low
temperatures.
Forming the quaternary salts of the 2-phenyl-
benzimidazole derivatives 2.49 and 2.52 did increase the
acidity of the C-a methylene protons as demonstrated by
the hydrogen/deuterium exchange reactions. However, when
attempts were made to react them with aliphatic or
aromatic aldehydes, the condensations failed. Since this
did not look promising at all, further investigation was
discontinued.
2.4 Expe rimental
2.4.1 Apparatus and Experimental Procedures
Melting points were determined on a Kofler hot-stage
microscope and are uncorrected. Spectra were recorded with
the following instruments: J‘H-NMR spectrawith a Varian
Model EM 360 L or a Varian Model VXR 300 spectrometer with
Me^Si as internal standard; ^C-NMR spectra with a JEOL
Model JNM-FX 100, referring to the center signal of CDCl^
(77.0) and of [^Hg]-DMSO (39.5), respectively; mass

49
spectra were obtained at 70 eV on an AEI MS 30
spectrometer operating with a DS-55 data system. Elemental
analyses were performed under the supervision of Dr. R. W.
King of the department of chemistry.
Diethyl ether and tetrahydrofuran (THF) were distilled
from sodium-benzophenone ketyl, diisopropylamine and TMEDA
refluxed over CaH_, , distilled and stored over 4 Á
molecular sieves, N,N-dimethy1formamide (DMF) dried by
azeotropic distillation with benzene followed by
distillation under reduced pressure and stored over 3 A
molecular sieves.
All moisture sensitive reactions were carried out in
oven-dried (120°C overnight) apparatus under a slight
positive pressure of dry argon and transferring operations
done using syringe techniques. Flash chromatography
[78JOC2923] was carried out with MCB silica gel (230-400
mesh).
2.4.2 The following compounds were prepared by known
literature procedures: benzimidazole (2.38), m.p. 169-
1710 C, (lit., [430SC65] m.p. 170-172°C);
1-(hydroxymethyl)benzimidazole (2.39), m.p. 139-141°C
(lit., [50JCS1600] m.p. 141-143°C); 1-(chloromethyl)-
benzimidazolium chloride (2.40), m.p. 168-1710C(dec.),
(lit., [50JCS1600] m.p. 173-174°C(dec.));

50
2-phenylbenzimidazole (2.5), m.p. 293-295°C, (lit.,
[57JA427] m.p. 294.5-295 . 5 0C); phenylthiomethy1 chloride
(2.48), b.p. 66°C/2 mmHg, (lit., [55JA572] b.p. 103-
104 °C/12 mmHg) .
2.4.3 l-(Phenylthiomethyl)benzimidazole (2.22)
To a solution of sodium ethoxide (1 M in ethanol,
90 ml, 90 mmol) was added a solution of thiophenol (5.4 g,
49 mmol) in ethanol (10 ml) and the mixture stirred at
ambient temperature for 0.5h. 1-(Chloromethyl)-
benzimidazolium chloride (2.40) (9.0 g, 44 mmol) was then
added slowly. The reaction was stirred for a further 2h
after which the solvent was removed _in vacuo to leave a
pale yellow gum. Water (40 ml) was added, the organic
material extracted with chloroform (3 x 50 ml), the
combined organic layers washed with water (2 x 20 ml),
dried (Na^SO^), and the solvent removed _in vacuo to afford
a colorless oil. Crystallization from benzene/petroleum
ether gave (2.22) as colorless prisms, 9.0 g, 85%, m.p.
86-88 °C, (lit., [69KGS934] 89-90°C); &H(CDCl3) 8.1-7.8
(1H, m), 7.56 (1H, s), 7.5-7.2 (8H, m), and 5.40 (2H, s);
SH([2H6l-DMSO) 8.06 (1H, s), 7.77 (2H, m), 7.36 (7H, m),
and 5.93 (2H, s).
2.4.4 2-Phenyl-l-(phgnylthiomethyl)benzimidazole (2.49)
2-Phenylbenzimidazole (2.5) (5.85 g, 30 mmol) was
dissolved in dry DMF (30 ml) and sodium hydride (60%

51
suspension in mineral oil; 1.33 g, 33 mmol) was added
slowly and the reaction stirred at ambient temperature for
lh. After addition of phenylthiomethyl chloride (2.48)
(4.2 ml, 31.5 mmol), the reaction mixture was stirred at
50°C for 2h, cooled and poured into water (600 ml). The
crude material was extracted with ether (3 x 150 ml),
dried (MgSO^), and the solvent removed i_n vacuo to give a
yellow oil which solidified on trituration with n-pentane .
Crystallization from benzene-hexanes afforded 2.49 as
colorless prisms, 8.05 g, 84%, m.p. 66-67°C, (lit.,
[87J(PI)775] m.p. 67-69°C).
2.4.5 General Procedure for the Oxidation of Sulfides
with m-Chloroperbenzoic Acid
To a solution of the corresponding sulfide (10 mmol)
in methylene chloride (100 ml) was added m-chloro-
perbenzoic acid: (i) (80%, 10 mmol) or (ii) (80%, 22 mmol)
in portions at -20°C. The reaction mixture was stirred at
-20°C for 3h, extracted with saturated aqueous sodium
bicarbonate (2 x 30 ml), and water (1 x 20ml) and dried
(MgSO^). The solvent was removed i_n vacuo and the crude
material crystallized from benzene unless otherwise
indicated. The following were prepared in this manner.
2.4 . 5.1 l-(Phenylsulfinylmethyl)benzimidazole (2.28)
1-(Phenylthiomethyl)benzimidazole 2.22 and (i)
afforded 2.28 as colorless prisms (82%), m.p. 138-139°C;

52
(Found: C, 65.30 ; H, 4.75; N, 10.80. requires
C, 65.59; H, 4.72; N, 10.93%); 5„(CDC1,) 7.8-7.6 (2H, m),
7.5-7.0 (8H, m), 5.20 (1H, AB, J 14.6 Hz), and 5.15 (1H,
í\ D
AB, J._ 14.6 Hz); 5„([2H,]-DMSO) 8.10 (1H, s), 7.63 (7H,
—A.d ri D
m), 7.4-7.15 (2H, m), 5.86 (1H, AB, JAB 14Hz), and 5.66
(1H, AB, JAB 14Hz ) .
2.4.5.2 l-(Phenylsulfonylmethyl)benzimidazole (2.29)
The sulfide 2.22 and (ii) afforded the sulfone 2.29 as
tan needles (72%), m.p. 148-150°C; (Found: C, 62.10;
H, 4.35; N, 10.15. ci4Hi2N2°2S requires C, 61.74; H, 4.44;
N, 10.29%); 6„(CDCl,) 7.9-7.0 (10H, m) and 5.46 (2H, s);
ri j
8R( [ 2fi6 ]~DMS°) 8*06 (1H' s)' 7-9-7.1 ( 9H, m), and 6.26
(2H, s ) .
2.4.5 . 3 1-[2-Phenyl-l-(phenylsulfonyl)ethy1(benzimidazole
(2.31a)
l-[2-Phenyl-l-(phenylthio)ethyl]benzimidazole (2.41)
and (ii) gave the sulfone 2.31a as pale yellow needles
(60%), m.p. 213-216°C, identical in all respects to the
sulfone prepared by the lithiation of 2.29 described
below.
2.4.5.4 2-Phenyl-l-(phenylsulfinylmethyl)benzimidazole
(¿.51)
The sulfide 2.49 and (i) gave the 2-phenyl derivative
2.51 as colorless prisms (78%), m.p. 149-151°C; (Found:
C, 72.37 ; H, 4.95; N, 8.42. C-,QH^gN0OS requires C, 72.26 ;

53
H, 4.85; N, 8.43%); SH(CDCl3) 8.0-7 . 3 (14 H, m), 5.35 (1H,
AB, J._ 14Hz ) , and 5.16 (1H, AB, J _ _ 14Hz).
—Ad —Ad
2.4.5.5 2-Phenyl-l-( phenylsulfonylmethyl)benzimidazole
(2.52)
2-Phenyl-l-(phenylthiomethyl)benzimidazole (2.49) and
(ii) gave after work up the corresponding sulfone 2.52 as
a brown gum (88%); (Found M+, m/z 348.0928. ^gH^g^O^S
requires M+, m/z 348.0932); SH(CDCl3) 8.3-7.2 (14H, m) and
5.6 3(2H, s ) .
2.4.6 General Procedure for the Lithiation of
1-(Phenylthiomethy1)benzimidazole ( 2.2~2 ) in LDA-THF
and Reaction with Electrophiles
The benzimidazole 2.22 (1.2 g, 5 mmol) in dry THF
(50 ml) was added to a solution of LDA [prepared from
diisopropylamine (0.78 ml, 5.5 mmol) and n-butyl1ithium
(2.5 M in hexane; 2.1 ml) in dry THF (30 ml)] at -78°C and
stirred for 3h to form a pale yellow precipitate. The
electrophile (5.2 mmol) dissolved in dry THF (5 ml) was
then added and the reaction mixture stirred at the
appropriate temperature. Water (30 ml) was then added and
the organic materials extracted with diethyl ether [or
CHCl^ as in the case of 2.43b] (3 x 30 ml), and the
combined organic extracts washed with brine (1 x 25 ml),
dried (MgSO^), and the solvents removed iri vacuo to give
the crude products which were then purified. The following
compounds were prepared in this manner.

54
2.4.6.1 l-[2-Phenyl-l-(phenylthio)ethyl]benzimidazole
(2.41)
After addition of benzyl bromide, the reaction mixture
was stirred at -78°C for 3h and warmed gradually to -20°C
whereupon the precipitate dissolved to give needles from
benzene-hexanes (82%), m.p. 102-103°C; (lit., [87J(PI)775]
m.p. 103-104°C); 5„(CDC1,) 7.8-6.7 (15H, m), 5.60 (1H, t,
n j
J 7 Hz), and 3.50 (1H, d, J 7 Hz).
2.4.6.2 2-Methyl-l-(phenylthiomethyl)benzimidazole
(2.43a")
With methyl iodide as the electrophile, the yellow
precipitate dissolved at -78°C within lh to give the
2-substituted derivative 2.43a as pale yellow needles from
benzene-hexanes (76%), m.p. 116-119°C; (lit., [87J(PI)775]
m.p. 118-120 °C); ¿H(CDCl3) 7.9-7.6 (1H, m), 7.5-7.1 (8H,
m), 5.20 (2H, s), and 2.05 (3H, s).
2.4.6.3 2-[Hydroxy-(4-methylphenyl)methy!]-!-(phenylthio-
methyl)benzimidazole (2.43b)~
Addition of 4-methylbenzaldehyde caused the yellow
precipitate to dissolve almost instantaneously. Work up
gave the alcohol 2.43b as colorless needles from ethyl
acetate (90% ) ,
m.p. 179-190°C;
(Found:
C, 72.90; H,
5.70;
N, 7.40.
C22H20
^OS requires C,
73.30;
H, 5.59; N,
7.75%) ;
VCDC13-
[2h61-
DMSO) 7.9-7.6 (1H, m) ,
7.6-7.0 (12H,
m) ,
6.35 (1H,
d, J
4 Hz, exchanges
with D
¿j
0) , 5.95 (1H,
d, J 4
Hz), 5.80
( 1H,
AB, JAD 12.6 Hz)
—AB
, 5.58
UH, AB, JAB
12.6
Hz), and 2.35 (3H, s ) .

55
2.4.6.4 2-[Hydroxy(diphenyl)methyl]-l-(phenylthiomethyl)-
benzimidazole (2.43c)
Benzophenone was used as the carbonyl compound causing
the yellow precipitate to dissolve in 3h at -78°C.
Crystallization from benzene afforded the alcqhol as
colorless needles (75%), m.p. 131-133°C; (lit.,
[87J(PI)775] m.p. 132°C); 6 (CDC13) 8.0-7.7 (1H, m), 7.6-
6.9 (18H, m), 5.45 (2H, s), and 3.9 (1H, br s).
2.4.6.5 2-(l,2-Diphenylethyl)-l-(phenylthiomethyl)-
benzimidazole (2.46)
With benzyl iodide, the precipitate dissolved after 2h
at -78°C and the crude product purified by column
chromatography (ethyl acetate:hexanes, 2:1) to give
2-(1,2-diphenylethyl)-1-(phenylthiomethyl(benzimidazole
(2.46) as colorless needles (35%), m.p. 103-105°C; (Found:
C, 79.90 ; H, 5.90; N, 6.60. C ? QH4 FU S requires C, 79.96;
H, 5.75; N, 6.66%); 6„(CDC1,, 300MHz) 7.85 (1H, d, J 8
Hz), 7.4 7.3 (1H, m), 7.3-7.0 (13H, m), 6.91-6.88 (2H, m),
6.85-6.8 (2H, m), 5.06 (1H, AB, JAB 14.4 Hz), 4.99 (1H,
AB, Jno 14.4 Hz), 3.85 (1H, AMX, J... 5.6 Hz, J.v 9.6 Hz),
3.58 (1H, AMX, JAM 5.6 Hz, Jflx 13.4 Hz), and 3.30 (1H,
AMX, JAX 9.6 Hz, JMX 13.4 Hz); &c(CDCl3) 155.5, 142.2,
139.7, 139.0, 134.4, 131.7, 129.3, 129.2, 128.4, 127.8,
127.0, 125.9, 122.4, 122.1, 119.5, 109.8, 48.6, 46.1, and
46.1.

56
2.4.7 l-(Phenylthiomethyl)-2-[‘'H^]benzimidazole (2.47)
To a suspension of 1-(phenylthiomethyl)benzimidazole
(2.22) (1.2 g, 5 mmol) in dry diethyl ether (50 ml) at
-78°C was added pheny11ithium (2 M in cyclohexane-ether;
2.6 ml) to give a yellow cloudy solution. The solution was
stirred at -78°C for lh and then D^O (0.3 ml) was added.
After 0.5h water (20 ml) was added and the organic
material extracted with ether (3 x 30 ml), dried (MgSO^),
and the solvent removed _in vacuo to give a yellow solid
which was recrystallized from benzene-petroleum ether to
give pale yellow needles (0.91 g, 76%), m.p. 83-84°C;
(Found: C, 69.31; H, 5.08; N, 11.46. c ]_ 4 H ]_ ]_DN s requires
C, 69.68; H, 5.01; N, 11.61%); 6H([2Hg]-DMSO) 7.9-7.6 (2H,
m), 7.5-7.2 (7H, m), and 5.93 (2H, s).
2.4.8 General Procedure for the Lithiation of l-(Phenyl-
sulfinylmethyl)- (2.26) and 1-(Phenylsulfonylmethyl)-
benzimidazole (2.29) in LDA-THF and Reaction with-
Electrophi le~s
(i) The sulfoxide 2.28 (1.28 g, 5 mmol) or (ii) the
sulfone 2.29 (1.36 g, 5 mmol) in dry THF (50 ml) was added
to a solution of LDA [prepared from diisopropylamine
(0.78 ml, 5.5 mmol) and n-butyl1ithium (2.5 M in hexane;
2.1 ml) in dry THF (30 ml)] at -78°C and stirred for lh to
give a clear yellow solution. The carbanion was quenched
with the corresponding electrophile (5.2 mmol) dissolved
in dry THF (5 ml). The solution was kept for lh in the

57
case of benzyl bromide and 15 min for 4-methyl-
benzaldehyde. Water (50 ml) and diethyl ether (75 ml) were
added, the layers separated and the aqueous layer washed
with diethyl ether (2 x 25 ml). The combined organic
extracts were washed with brine (1 x 25 ml), dried
(MgSO^), and the solvents removed rn vacuo to give the
crude products which were then purified. The following
compounds were prepared in this manner.
2.4.8.1 l-[2-Phenyl-l-(phenylsulfinyl)ethyl]benzimidazole
(2.30a)
From benzyl bromide following (i) to give a fine
powder (after triturating with cyclohexanone:
recrystallization led to decomposition) (83%), m.p. 132-
1 3 3 0 C; SH
(CDC13) 8.30
(1H, s), 7.9-6.6
( 14H,
m) ,
5 .
30 (1H,
ABX' —AX
4.7 Hz, JBX 8
.3 Hz), 3.95 (1H,
ABX,
—AX
4 .
7 Hz ,
—AB 16-°
Hz), and 3.64
(1H, ABX, JBX 8.
3 Hz ,
-AB
16
.0 Hz ) .
2.4 . 8.2 1-[2-Hydroxy-(4-methylphenyl)-!-(phenvlsulfinyl)-
ethyl ] benzimidazole (2.30b")
4-Methylbenzaldehyde and (i) gave needles from
benzene-ethyl acetate (70%), m.p. 210-212°C; (lit.,
[87J(PI)775] m.p. 210-214°C; ¿H(CDCl3~[2Hg]-DMSO) 8.7-8.3
(1H, m), 8.0-6.6 (13H, m), 5.6-5.2 (2H, m), and 2.35
(3H, s ) .

58
2.4.8.3 l-[2-Phenyl-l-(phenylsulfonyl)ethyl)benzimidazole
(2.31a)
The sulfone 2.29 and benzyl bromide gave the
benzylated adduct 2.31a as colorless needles from benzene
(68% ) , m.
p. 215-217°C; (Found:
C, 69.57;
H, 5.03;
N, 7.60
C21H18N2°
3S requires C, 69.59;
H, 5.01;
N, 7.73%);
sh(cdci3)
8.2-7.9 (1H, m), 7.8
-6.9 (14 H,
m), 5.47
( 1H,
ASX, JAX
4.5 Hz, Jn„ 11.0 Hz),
— DA
4.07 (1H,
ABX, JAX
4.5 Hz,
J.n 14.5 Hz), and 3.78 (1H, ABX, Jnv 11.0 Hz, J.n 14.5
—Ad —da —Ad
Hz ) .
2.4 . 8.4 l-[2-Hydroxy-2-(4-methylphenyl)-l-(phenylsulfonyl)-
ethyl]benzimidazole (2.31b)
From (ii) and 4-methylbenzaldehyde, the alcohol 2.31b
was obtained as colorless needles from ethyl acetate
(55%), m.p. 201-204°C; (Found: C, 67.17; H, 5.24; N, 6.99.
C22H20N',O3S requires C, 67.31; H, 5.14; N, 7.14%);
SH(CDC13-TFA) 8.0-6.9 (14H, m), 6.5-6.0 (2H, m), and 2.20
(3H, s).
2.4.9 2-Phenyl-l-[2-phenyl-l-(phenylthio)ethyl ] -
benzimidazole (2.50aT
To a solution of 2-phenyl-l-(phenylthiomethyl)-
benzimidazole 2.49 (0.95 g, 3 mmol) in dry diethyl ether
(50 ml) at -78°C was added a mixture of n-butyllithium-
TMEDA [prepared by adding n-butyl1ithium (2.4 M in hexane;
1.3 ml) to TMEDA (0.5 ml, 3.3 mmol) in dry diethyl ether
(5 ml)]. The yellow suspension was stirred at -78°C for Ih

59
and then benzyl bromide (0.4 ml, 3.3 mmol) in dry diethyl
ether (5 ml) was added. The reaction was stirred at -78°C
for 3h and warmed slowly to ambient temperature. Water
(30 ml) was then added, the layers separated and the
aqueous layer washed with diethyl ether (2 x 20 ml), the
combined ethereal extracts dried (MgSO^) and the solvent
removed ini vacuo to give the crude product. Purification
by column chromatography (hexanes:methylene chloride, 1:3)
gave a colorless oil (0.73 g, 60%); (lit., [87J(PI)775]
colorless oil 62%).
2.4.10 ^-Phenyl-l-tl^phenylthicQethyllbenzimidazole
Utilizing the conditions described above and methyl
iodide (0.21 ml, 3.3 mmol) as the electrophile, the
corresponding methyl derivative 2.50b was obtained as
colorless prisms from n-pentane (0.55 g, 55%), m.p. 89-
9 0 0 C; (Found: C, 76.53 ; H, 5.63; N, 8.36. C?1H18N^S
requires C, 76.32; H, 5.49; N, 8.48%); ¿H(CDCl3) 8.2-7.8
(2H, m), 7.6-6.8 (12H, m), 5.86 (1H, q, J 7 Hz), and 2.00
(3 H, t, J 7 Hz) .
2.4.11 2-Phenyl-l-[2-phenyl-l-(phenylsulfinyl)ethyl]~
benzimidazole (2.53)
Utilizing the conditions described in Section 2.4.8,
the sulfoxide 2.51 and benzyl bromide afforded the crude
product as an oil. Purification by column chromatography
(ethyl acetate: hexanes, 1:2) gave a colorless wax:

60
crystallization led to decomposition (60%), ¿^(CDCl^) 8.4-
7.0 (15H, m), 6.9-6.5 (4H, m), 5.4-5.1 (1H, m), and 4.2-
3.0 (2H, m).
2.4.12 1-Styrylbenzimidazole (2.32)
l-[2-Phenyl-l-(phenylsulfinyljethyljbenzimidazole
(2.30a) (1.04 g, 3 mmol) was dissolved in toluene (20 ml)
and the mixture heated under reflux for 4h. The solvent
was then removed i^n vacuo and the crude material
crystallized from ethanol as colorless needles (0.46 g,
70%), m.p. 121-124°C; (lit., [78JHC1543] m.p. 122°C).
2.4.13 2-Phenyl-l-styrylbenzimidazole (2.54)
Under the conditions described above, 2-phenyl-
l-[2-phenyl-l-(phenylsulfinyl)ethyl]benzimidazole (2.53)
afforded 2-phenyl-l-styrylbenzimidazole (2.54) as
colorless needles from ethanol (65%), m.p. 165-166°C;
(Found: C, 85.23; H, 5.51; N, 9.23. C21H16N^ rec!uires
C, 85.10; H, 5.44; N, 9.45%); 5„(CDC1,) 8.2-6.9 (16H, m).
ri j
2.4.14 1(3)-Methyl-2-phenyl-3(1)-(phenylthiomethyl)-
benzimidazolium iodide (2.56)
The sulfide 2.49 (1.58 g, 5 mmol) was dissolved in
methyl iodide (20 ml) and the mixture heated under reflux
for lh. The excess methyl iodide was removed in vacuo and
the crude salt crystallized from ethanol to afford yellow

61
prisms (2.1 g, 95%), m.p. 173-175°C; (Found: C, 55.37;
H, 4.29; N, 5.88. ^i^gl^S requires C, 55.02; H, 4.18;
N, 6.11%); 6„(CDCl,) 8.2-7.0 (14H, m), 5.83 (2H, s), and
n o
3.96 (3H, s ) .
2.4.15 1(3)-Methyl-2-phenyl-3(1)-(phenylsulfonylmethy1)-
benzimidazolium iodide (2.57) —
The sulfone 2.52 (1.74 g, 5 mmol) was dissolved in
methyl iodide (20 ml) and the mixture heated under reflux
for 3h. Work up as above gave the quaternary salt 2.57 as
brown microcrystals from ethanol (2.08 g, 85%), m.p. 237-
2 38 °C; (Found: C, 51.38; H, 3.93; N, 5.46. C2lHl9IN2°°S
requires C, 51.44; H, 3.91; N, 5.71%); Su(CDCl-.) 7.9-7.4
(14H, m), 5.90 (2H, s), and 4.00 (3H, s).

CHAPTER III
SYNTHESIS AND REACTIONS OF SOME BENZOTRIAZOLE DERIVATIVES
3 .1 Introduction
Functional group transformations have always played a
major role in organic synthesis. Hence, routes to carbon-
carbon single bond or carbon-carbon double bond formations
are under constant investigation. Carbon-carbon bonds can
be formed via a variety of radical processes or by the
combination of a nucleophile with an electrophile in an
addition or substitution reaction. Very often the
conditions employed for these transformations are not
mild, requiring high temperatures or pressure and the use
of very specific reagents. Consequently, the presence of
an activating moiety should promote much more facile
transformations. As a result a substituent Het which could
be a heteroatom or a heterocyclic group could be initially
placed as an anchor and an activator to facilitate
electrophilic addition and then removed under various
conditions depending on the type of intermediate
synthesized. Thus compounds of type Het-CH^ could be
transformed into the tetrasubstituted methane 3.1 as
depicted in Scheme 3.1 below.
62

63
He t-CH 3
1. Base
2. (E1)+
>
Het-CH-.E1
z
1. Base
2. (E2)+
>
Het-CHE
1
EZ
1 . Base
2. (E3)+ Nu~
12 3 12 3
> Het-CE E E > CE E E Nu
3.1
Scheme 3.1
Benzotriazole has recently been shown to be a good
leaving group when one of the substituents introduced on
Het-CH^ is nitrogen. Thus, aminomethylbenzotriazoles 3.2
can be reduced with sodium borohydride [87J(PI)805] to
afford the methyl derivative (3.3, = H) or the
methylene derivative (3.3, t H). Similarly
benzotriazole can also be displaced by alkyl lithiums
[84TL1635] or by Grignard reagents [87J(PI)805] to afford
the methylene derivative (3.4, R^ = H) or the methine
compound (3.4, R^ t H) (Scheme 3.2).
This good leaving group ability has been extensively
exploited in the monoalkylation of amines (X = H, Y =
R,Ar) [87J(PI ) 805], alkylation of amides (X = H, Y =
C(=0)R) [87J(PI)IPl] and thioamides (X = H, Y = C(=S)R)
[87TLIP1], synthesis of tertiary amines (X,Y = R,Ar)

64
[87UP1], hydroxylamines (X = OH, Y = CH-.R) [87UP2] and
sulfonamides (X = H, Y = S0oR) [87UP4].
Rl/
3.2
NaBH,
R2Li
or R2MgX
R1
CH2 N
/
\
X
Y
3.3
R2CH(R1) N
3.4
\
Y
Scheme 3.2
As an extension of this reasoning, if 1-methyl-
benzotriazole (3.6) were used, then it might be possible
to promote carbon-carbon bond formations. For example
treatment of 3.6 with base and esters, alkyl halides, or
ketones would give rise to ketomethyl- (3.5), alkyl- (3.7)
or hydroxyethyl-benzotriazole (3.9) respectively.
Elimination of benzotriazole would then give rise to a
number of different compounds such as the ketones 3.8 or
alcohols 3.10, all originating from one intermediate
(Scheme 3.3).

65
3.8
However, Katritzky and Kuzmierkiewicz have shown
[86UP1] that the carbanion generated from 1-methyl-
benzotriazole (3.6) is unstable. When lithiation of 3.6
was attempted with lithium di isopropylamide (LDA) or
n-butyllithium, starting material and uncharacterizable
products were obtained. It might, however, be feasible to
attach another group Z to the methyl group which, in
addition to enhancing the acidity of the methyl protons,
could stabilize the carbanion formed and then be easily
removed with concomitant introduction of functionality.

66
3.1.1 Selection of a Novel Activatinq/Protecting Group
The presence of an electronegative atom such as
nitrogen or oxygen adjacent to carbon induces a
polarization in the carbon-nitrogen or carbon-oxygen bond
due to its inductive electron withdrawal effect. As a
result, the a-carbon bears a small positive charge.
Consequently this should enhance the generation of an
a-aminocarbanion or an a-hydroxycarbanion respectively,
leading to the possibility of electrophilic substitution
at the a-carbon atom.
In practice, however, such a-hete rocarbanions are
difficult to generate for two reasons. Firstly, the more
acidic amino or hydroxy protons need to be suitably
protected. Secondly, such a carbanion once generated,
experiences strong repulsion between the nitrogen (or
oxygen) lone pair and the C— lone pair thus destabilizing
it. Sulfur, while not being as electronegative as nitrogen
or oxygen, is a strong activating group, since the lone
pair of the carbanion can be stabilized due to the
presence of empty d-orbitals.
This enhanced stability has been shown to have
synthetic utility by Katritzky e_t al. [87J(PI)781] in
transformations utilizing 1-(phenylthiomethyl)-
benzotriazole (3.11) (Scheme 3.4). However, the yields
obtained from the above reactions were moderate. The

67
utility was further limited by the fact that the
thiophenyl group could only be removed via Raney nickel
desulfurization to afford 1-alkylbenzotriazoles (3.12).
3.11
Raney Ni
Scheme 3.4
Another element that has empty d-orbitals is silicon.
In recent years, great strides have been made in the
utilization of silicon in organic synthesis [79MI3,
82MI2]. While the silicon atom favors, by a
hyperconjugation mechanism, a positive charge "beta" to
itself, silicon can also stabilize an a-carbanion, in both
cases due to the availability of its d-orbitals. As a
result, the negative charge on the carbon atom can be
effectively delocalized into the vacant d-obitals of

68
Silicon. This property has been fully exploited by Magnus
[80MI1]. Silicon thus seems to be an ideal "masked proton"
and worthy of further investigation with the benzotriazole
group.
3.1.2 Previous Work on (Trimethylsilylmethyl)azoles
Reactions of a-he terosubstituted silyl derivatives
with aldehydes to yield alcohols have been explored in
recent nucleophilic amino- and hydroxy- methylations of
carbonyl compounds [84CL1803, 85BCJ1991, 86H237]. Recently
Katritzky e_t a_l. [87JOC844 ] have shown (benzothiazol-2-yl-
thio)(trimethylsilyl)me thane (3.13a) to be a convenient
synthon for HSCH which enables the general conversions
R1Br > R1CH(SH)SiMe3 and R2R3CO > R2R3C(OH)CH(SH)R1 .
These transformations were accomplished by (i)
deprotonation of the silyl derivative 3.13a with LDA and
reaction with electrophiles, (ii) fluoride catalyzed
desilylation with carbonyl compounds, and (iii)
nucleophilic displacement of benzothiazole by
alkyl1ithium. Furthermore, the presence of the
trimethylsilyl group in 3.13a stabilizes the carbanion
generated as evidenced by the fact that carbanions
analogous to 3.13 could not be prepared by deprotonation
of 2-(ethylthio)benzothiazole (3.13b) or of higher
homologs (Scheme 3.5).

69
Scheme 3.5
Katritzky and Kuzmierkiewicz [86UP1] also showed that
reaction of the lithio derivative of 3.13a with esters
gave rise to a mixture of the ketone 3.14 and the enol
ether (3.15) (Scheme 3.6).
A search in the literature for N-(trimethylsilyl)-
methylazoles afforded few references to such compounds.
Shimizu and Ogata [86JOC3897] utilized compounds of this
type (3.16) as precursors in synthetic routes to

70
azol-l-ylethanols (3.17) (Scheme 3.7) which have received
considerable attention recently due to the importance of
their general structure in orally-active antifungal azole
moieties [83JMC768].
.N
>
7
SiMe-:
3.13a
LDA
RC02Et
SCH2COR
+
SCH=C(OEt)R
Scheme 3.6
Scheme 3.7

71
Additionally, bis(t rime thylsilyl)methyl-1,2,4-triazole
(3.18) was shown to be a novel precursor [87JOC2314]
towards the synthesis of 1-vinyl-l,2,4-triazoles (3.19)
(Scheme 3.8).
3-18 3.19
Scheme 3.8
Katritzky and Kuzmierkiewicz (86UP1] first attempted
the synthesis of 1-(trimethylsilyl)methylbenzotriazole
(3.22) utilizing conditions similar to those used for
(benzothiazol-2-ylthio)(trimethylsilyl)methane (3.13a)
[87J(PI ) 769 ] . However alkylation of the lithio derivative
of 1-methylbenzotriazole (3.20) with chiorotrimethy1si1ane
(3.21) afforded 1-bis(trimethylsilyl)methylbenzotriazole
(3.24) in addition to starting material.
It seemed that the monosilyl derivative 3.22 underwent
a transmetallation with the 1-1ithiomethylbenzotriazole
(3.20) initially formed, to give the more stable
1-1ithio-l-(trimethylsilyl)methylbenzotriazole (3.23) and
1-methylbenzotriazole (3.6). Intermediate 3.23 then

72
reacted with a second equivalent of chiorotriraethylsi1ane
(3.21) to give 3.24 (Scheme 3.9).
/^"SiMe3
Me3Si
3.24
Scheme 3 . 9
1-(Trimethylsilyl)methylazoles are also prepared by
other routes, in particular, treatment of the azole with

73
chloromethyltrimethylsilane in the presence of bases such
as potassium carbonate [86JOC3897, 87JOC844], butyllithium
[73USP3692798], or in the presence of potassium
[68USP3346588 ] .
3.1.3 Aims of the Work
As discussed above, both benzotriazole and silicon
functionality could hopefully be employed in the
activation of a methylene group. The first step dealt with
finding an alternate approach for the synthesis of
1-(trimethy1silyl)methylbenzotriazole (3.22). Once
prepared it was hoped that 3.22 could be readily lithiated
and the stable carbanion trapped with specific
electrophiles to afford the corresponding derivatives
(3.25) (Scheme 3.10).
3.25
3.22
Scheme 3.10
Employing the conditions utilized by Shimizu and Ogata
[86JOC3897], one could generate a variety of benzotriazol-
1-ethanols (3.26) (Scheme 3.11) which were otherwise

difficult to synthesize since the a-carbanion generated
from 1-alkylbenzotriazole has been known to be unstable
[86UP1]. As mentioned previously (Section 3.1.2),
azol-l-ylethanols (3.17) hold promise in orally-active
antifungal azole moieties [83JMC768], but there has been
no mention of benzotriazole in these systems.
3.25
Scheme 3.11
Silicon elimination of a 6-silylethanol generally
requires an equivalent of base [8 4 S 3 8 4 ] . However, if the
anion of 3.22 (3.23) were to be treated with a carbonyl
compound, the Peterson olefination product (3.27) should
be formed (Scheme 3.12). This would afford an alternate
synthetic route to 1-alkylidenebenzotriazoles 3.27 which
have been previously prepared by the treatment of
1-chlorobenzotriazole with olefins [69JCS(C ) 1478 ] , via
base-induced isomerization of allylbenzotriazoles
[79HCA2129] and most recently [87UP3] by the reaction of
1-bis(trimethylsilyl)methylbenzotriazole (3.24) with
carbonyl compounds in the presence of fluoride ion.

75
Vinylbenzotriazoles and their analogs have numerous
synthetic utilities. Some more specific uses are their
biological activity [84 IJC(B)844] and the antitumor
activity of some platinium and palladium complexes with
1-vinylbenzotriazole [83MI1, 85JGU923). They have also
found use in photographic hardening agents [7 3GEP2309525 ] ,
for organic lubricating compositions [77USP4048082] and
for electroplating baths [84JAP59182986].
Alkylidenebenzotriazoles have also been employed in the
study of their electron-donor properties [76KGS828] and in
the synthesis of 3-substituted indoles via flash vacuum
pyrolysis [87J(PII ) I Pi ] .
Earlier, (Section 3.1.2) it was mentioned that
lithiation of the (trimethylsilyl)methylazole 3.13a gave
the enol ether 3.15 in addition to the ketone 3.14.
Treatment of 3.23 with esters followed by hydrolysis of
the reaction mixture should generate the ketone 3.28
exclusively (Scheme 3.12).
Once the required functionality has been introduced,
the next step dealt with removal of the activating
moieties. As discussed earlier (Section 3.1),
benzotriazole has been shown to be displaced by sodium
borohydride or Grignard reagents [87J(PI)805] or by
alkyl1ithiums [84TL1635].

76
R1R2CO
3.23
CH=CR1 R2
3.27
3.23
Scheme 3.12
It has been known from the work of Side 1'korskaya
[54BAU589] and Zelenskaya [52BAU627] that N-vinyl
compounds could be decomposed quantitatively in the
presence of water to form acetaldehyde. Similarly,
1-vinylindole also underwent hydrolysis in the presence of
4% sulfuric acid [65H11].
NMR studies have indicated that in the reaction of
benzotriazole with carbonyl compounds, there existed an
equilibrium between the starting materials and the
benzotriazol-l-ylalkanols 3.29 in solution [87J(PI)791]
Thus bases (e.g. trimethyiamine> or acids (e.g.
trifluoroacetic acid) shift the equilibrium strongly
towards the starting materials (Scheme 3.13).

77
Scheme 3.13
1-Alkylidenebenzotriazoles (3.30) would thus be
expected to hydrolyse in the presence of an acid to form
carbonyl compounds 3.32 via the a-hydroxy intermediate
3.31 (Scheme 3.14) .
Elimination of good leaving groups "alpha" to the
carbonyl carbon have been induced with zinc in acetic acid
[66JA5498, 70HCA2197] or by ammonium formate in the
presence of activated palladium on charcoal [87TL515].
Thus under these conditions, ketones of type 3.33 should
be formed from 3.28 (Scheme 3.15).

78
3.30
3.31
hr
Scheme 3.14
3.28
3.33
Scheme 3.15

79
Since the fluoride ion has been used to remove the
trimethylsilyl group, treatment of l-(trimethylsilyl)-
alkylbenzotriazoles (3.22, R3 = H; 3.25, t H) with
tetrabutylammonium fluoride (TBAF) in the presence of
water should generate 1-alkylbenzotriazoles 3.35. This
would be an interesting route since the more general
method, which involved treatment of benzotriazole with an
alkyl halide in the presence of base, usually gave a
mixture of the 1- and 2-alkylbenzotriazoles.
This would be where the difference could lie over the
2-mercaptobenzothiazole route (Scheme 3.5), in that, while
the latter was restricted to the formation of mercaptans,
various functionalized compounds could be obtained from
this system (Scheme 3.16).
3.2 Results and Discussion
3.2.1 Preparation of 1-(Trimethylsilyl)me thylbenzotriazole
At the start of this investigation benzotriazole was
treated with chloromethyltrimethylsilane in dry
dimethylformamide (DMF) in the presence of potassium
carbonate but the major product isolated in 55% yield was
1-methylbenzotriazole (3.6). This could be due to the
presence of base hydrolyzing the trimethylsilyl derivative
3.22 during work up. The alternative was to isolate the

80
3.32 3.35 3.33
Scheme 3.16

81
benzotriazole anion so that the reaction could be carried
out in a neutral medium. This was easily done by adding
benzotriazole to a solution of sodium hydroxide in
ethanol. Removal of the solvent left behind the sodium
salt (3.36) as a white solid.
As a result, multigram quantities of 3.22 were readily
prepared by treating the sodium salt of benzotriazole
(3.36) with chloromethyltrimethylsilane (3.37) in dry DMF
(Scheme 3.17). Some of the corresponding
2-(trimethylsilyl)methylbenzotriazole (ca. 15%) was also
formed but, being an oil, it remained in solution.
3.36
3.22
Scheme 3.17

82
3.2.2 Lithiation of 1-(Trimethylsilyl)methylbenzotriazole
and its Derivatives
3.2.2.1 Reactions of 1- ( t rime thyls ilyIme thy1 )benzotri. azole
with n-butylllthium and subsequently with
electrophile's
1-(Trimethylsilyl)methylbenzotriazole (3.22) was
readily lithiated with equimolar n-butyl1ithium in dry THF
at -78°C and the dark blue lithium salt (3.23) effectively
trapped with benzyl bromide to give l-(benzotriazol-l-yl)-
2-phenyl-l-(trimethylsilyl)ethane (3.25a) as colorless
needles in a yield of 81% (Scheme 3.18). Other alkyl and
silyl halides reacted in a similar fashion. The results
are summarized in Table 3.1.
Scheme 3.18

83
Table 3.1
Treatment of 1
-(Trimethylsi
lyl)methyl-
benzotriazole
(3.22) with n
-Butyl1ithiurn and
Electrophiles.
Product
No.
Electrophile
Reaction
Time(h)
Yield
(%>
a
M. p.
( °C)
3.25a
PhCH2Br
4
81
108-108.5
3.25b
Mel
4
86
71-72
3.25c
Hxl
6
82
50-51
3.25d
Me 3SiCl
2
83
147-147.5b
3.25e
Me3SiCH-,Cl
2
83
00
(Tv
1
CO
CO
o
Needles from hexanes, unless otherwise stated.
. From methanol. '. From methanol-water.
The phenyl analog 3.39 was prepared by the treatment
of the lithium salt of 1-benzylbenzotriazole (3.38) with
chlorotrimethylsilane (3.21) (Scheme 3.19).
3.38
Scheme 3.19
3.39

84
The addition of aldehydes and ketones to 3.23 gives
the Peterson olefination products 3.27a-d (Scheme 3.20)
although in the preparation of 3.27c from acetophenone,
some unreacted starting material (£a. 6%) was also
recovered. The results are summarized in Table 3.2. The
structures were confirmed by their ^H- and b^C-NMR
spectra, in particular by the absence of the
trimethylsilyl resonances in all cases.
3.23
Scheme 3.20
3.27
Table 3.2 Formation of Peterson Olefination Products
(3.22 -» 3.27) .
Product
No .
Electrophile
Reaction
Time(h)
Yield
( % )
M.p.
( °C)
3.27a
C6H10°
2
83
100-102
3.27b
ch3coch3
6
80
68-70a
3.27c
PhCOCH 3
6
38
65-67
3.27d
PhCOPh
6/12b
45
76-79C
a. Lit [79HCA21^9] m.p. 70-71°C. b. 12h at ambient
temperature. ". Lit [87UP3] m.p. 78-80°C.

85
With cyclohexenone (3.40) and the lithio deivative
3.23, the Michael addition product 3-[(benzotriazol-l-yl)-
(trimethylsilyl)methyl]cyclohexanone (3.41) was obtained
in 70% yield. When ethyl 4-methylbenzoate (3.42) was used
as the electrophile and the reaction mixture treated with
IN HCl, the ketone 2-(benzotriazol-l-yl)-1-(4-methyl-
phenyl ) e thanone (3.28a) was obtained in 51%. Furthermore,
none of the enol ether observed by Katritzky and
Kuzmierkiewicz (86UP1] (Section 3.1.3) was isolated in
this case. By contrast, when the a,g-unsaturated ester
ethyl 3,3-dimethylacrylate (3.43) was used, the ketone
1-(benzotriazol-l-yl)-4-methyl-3-pentenone (3.44) was the
only product obtained with no evidence of the Michael
adduct being formed (Scheme 3.21). This could be
attributed to the fact that that there is steric hindrance
at the "beta" position, thus causing the ester site to be
more reactive. The structure of the ketone (3.44) was
confirmed by the ^H-NMR spectrum which still displayed the
vinyl proton at 66.08 and also by the absence of the
trimethylsilyl and ethoxy resonances. The ^C-NMR
displayed the carbonyl resonance slightly upfield at 190.3
ppm indicating unsaturation at the "alpha" position.

86
3.41
3.44
Scheme 3.21

87
3.2.2.2 Anion formation from 1-(g-trimethylsilylalkyl)-
benzotriazole and subsequent reactions with
electrophiles
The 1-(trimethylsilyl)alkylbenzotriazoles (3.25)
prepared above can be treated with another equivalent of
n-butyl1ithium and as in the case of 3.25b the anion was
trapped with hexyl iodide and benzyl bromide to furnish
3.45a,b in yields of 80 and 71% respectively (Scheme
3.22). The â– '"H-NMR spectrum of 3.45b is interesting in that
the presence of the chiral center, renders the benzylic
protons diastereotopic with one proton resonating 0.45
ppm. upfield from the other.
Scheme 3.22
The treatment of lithio derivatives with esters and
acid chlorides generally gives low yields due to the
possibility of the product (a ketone adduct) behaving as
an electrophile and thus competing with the ester or acid
chloride. As a result when the anions derived from 3.25b,c

88
were treated with ethyl 4-methylbenzoate or 4-methyl-
benzoyl chloride, low yields and a large number of side
products were obtained. In the previous section (Section
3.2.2.1) it was mentioned that the Peterson olefination
product 3.27 was formed readily when 3.23 was treated with
carbonyl compounds. However, when the anions derived from
3.25a,b were treated with cyclohexanone, the reactions
went to only 80% completion. The phenyl derivative
[(benzotriazol-l-yl)(phenyl)methylenejcyclohexane (3.46)
was however prepared by the reaction of the lithio
derivative of 1-(a-trimethylsilyl)benzylbenzotriazole
(3.39) with cyclohexanone (Scheme 3.23).
Scheme 3.23
3.2.2.3 Anion formation from 1-alkenylbenzotriazoles
It was mentioned above (Section 3.2.2.2) that the
reaction of the anion of 3.25b,c with cyclohexanone did
not go to completion. However, the same products should
also be formed if the lithio derivative of

89
l-(cyclohexylidenemethyl)benzotriazole (3.27a) is reacted
with methyl iodide and hexyl iodide respectively. As a
result, when equimolar n-buty11ithium was added to 3.27a
at -78°C, a green precipitate was formed within 0.5h which
readily dissolved when deuterium oxide was added affording
the mono deuterio derivative (3.30a) (Scheme 3.24). With
methyl iodide, hexyl iodide and 4-methylbenzaldehyde, the
corresponding alkyl and hydroxy derivatives 3.30b-d were
formed in moderate to high yields as shown in Table 3.3.
In all cases, metallation of 1-(cyclohexylidenemethy1)-
benzotriazole (3.27a) with n-butyl1ithium occurred readily
and exclusively at the C-a position rather than at the
allylic position in the cyclohexane ring. The structures
of the products were confirmed by elemental analysis and
by their NMR spectra, in particular by the disappearance
of the vinyl proton at 86.81 and of the carbon signal at
113.7 ppm in the ^H- and ^C-NMR spectra, respectively.
Scheme 3.24

90
Table 3.3 Treatment of 1-(Cyclohexylidenemethyl)-
benzotriazole with n-Butyl1ithium and
Electrophiles"!
Product
No.
Electrophile
Reaction
Time(h)
Yield
(%)
M . p .
( °C)
3.30a
d2o
LD
O
94
99-101
3.30b
Mel
2
90
Oil
3.30c
Hxl
6
76
Oil
3.30d
4-MeC6H4CHO
2
74
151-152
3.2.3 Fluoride Catalyzed Desilylations
Shimizu and Ogata [86JOC3897] showed that silyl
compounds reacted smoothly with carbonyl compounds in the
presence of a catalytic amount of TBAF. Applying these
conditions to the benzotriazole system, 2-(benzotriazol-
1-yl)ethanols (3.47) (Scheme 3.25) were obtained in good
yields when 3.22 or its derivatives 3.25 and 3.45 were
treated with aromatic and aliphatic carbonyl compounds in
the presence of a catalytic amount of TBAF in THF. The
results are summarized in Table 3.4.

91
Scheme 3.25
3.47
Table 3.4 Fluoride Induced Reaction of 1-(a-Trimethyl-
silyl)alkylbenzotrlazóles with Carbonyl
Compounds
Substrate
No.
Carbonyl
Compound
Product
No.
Yield
(%)
3.22
C6H10°
3.47a
39
3.22
4-MeCgH4CHO
3.47b
76
3.25a
c3h?o
3.47c
63
3.25a
4-MeCgH^CHO
3.47d
57
3.25b
4-MeCgH4CHO
3.47e
72
3.45a
4-MeCgH4CHO
3.4 7 f
65
3.45b
C6H10°
3.47g
44

92
In all the cases discussed above, the hydrolysis
product (i.e. displacement of the trimethylsilyl group
with hydrogen) (ca. 10%) was also obtained. A similar
behavior was also observed when Katritzky et al.
[87JOC844] treated derivatives of (benzothiazol-2-
ylthio)(trimethylsilyl)me thane (3.13a) with carbonyl
compounds. In the case of enolizable carbonyl compounds
such as cyclohexanone the yields are much lower. The
amount of 1-methylbenzotriazole (3.6) formed is greater in
these cases than when aldehydes were used.
Based upon the previous observation that the
hydrolysis product is also obtained during the fluoride
catalyzed des ilylation, it was established that treatment
of the silyl derivatives with TBAF in refluxing wet THF
for 12h afforded the corresponding 1-alkylbenzotriazoles
(3.48) in yields of greater than 70% (Table 3.5).
3.2.4 Acylative Desilylation
Desilylations could also be effected by treatment of
the corresponding compounds with acyl halides in the
absence of F . The aliphatic acyl halides were generally
more reactive than those of the aryl series to afford the
ketones (3.28) in yields of about 70% (Scheme 3.26). The
products were characterized by their elemental analysis

93
and ^H-NMR spectra which displayed the C-a protons 1.5 - 2
ppm downfield for the ketones as compared to their silyl
precursors. However, steric hindrance plays an important
factor with the hydrolysis product being formed when the
more substituted derivatives 3.25 were used. Sulfonyl
halides failed to react in a similar manner, even in the
presence of F .
Table 3.5 Fluoride Induced Desilylations. Formation of
1-Alkylbenzotriazoles (3.46).
Substrate
No.
R1
R2
Product
No .
Yield
(%)
3.25a
H
PhCH2
3.48a
79
3.25c
H
Hx
3.48b
7 3
3.45a
Me
Hx
3.48c
84
3.45b
Me
PhCH2
3.48d
82

94
(a) R1 = H, R2 = 4-MeC6H4
(b) R1 = H, R2 = Me
(C) R1 = H, R2 = Ph
(d) R1 = Me, R2 = 4-MeC6H4
Scheme 3.26
3.2.5 Removal of Benzotriazole Moieties
As was discussed earlier (Section 3.1), aminomethyl-
benzotriazoles readily eliminate benzotriazole when
treated with sodium borohydride or Grignard reagents
[87J(PI)805]. It was thus decided to attempt removal of
benzotriazole from these systems also.

95
3.2.5.1. Reductive elimination of benzotriazole
As was mentioned above (Section 3.1.3), elimination of
good leaving groups "alpha" to the carbonyl carbon can be
induced with zinc in acetic acid [66JA5498, 70HCA2197] or
by ammonium formate in the presence of activated palladium
on charcoal [87TL515]. When compounds of type 3.28 were
treated with zinc in the presence of acetic acid,
benzotriazole was readily eliminated, generating the
ketones 3.33 in moderate yields (Scheme 3.27). Loss of
benzotriazole was evidenced by the absence of the
benzotriazole resonances in the ^H-NMR spectra of the
isolated products. On the contrary, when reduction was
attempted with ammonium formate and activated palladium on
carbon, in dry methanol the keto group was simply reduced
to the alcohol. Thus 3.28a afforded 3.47b in over 80%.
3.2.5.2 Attempted hydrolysis of benzotriazolylalkenes
It was mentioned earlier (Section 3.1.3) that N-vinyl
compounds could be hydrolyzed in the presence of acid.
Under similar conditions, compounds 3.27a and 3.30b were
unreactive. In concentrated sulfuric acid, the solutions
turned dark within a few minutes. Work up of the reaction
mixtures afforded oils, the ^H- and ^C-NMR spectra of
which still contained peaks attributable to 1-substituted
benzotriazole in addition to a large number of aliphatics.

96
While the spectra did show evidence of attack on the
double bond, the presence of the large number of
aliphatics probably indicates over-oxidation or
polymerization. A similar behavior was observed when
trifluoromethanesulfonic acid was used. Under milder
conditions (c_a. 10% acid in methanol), no reaction was
observed. Treatment of the above compounds with IN - ION
hydrochloric acid had no effect on the double bond with
starting material being recovered in all cases. Refluxing
hydrobromic acid solutions afforded dark uncharáeterizable
gums.
AcOH
EtOH
3.33
o
o
3.28
(a) R1 = H, R2 = 4-MeC6H4
(b) R1 = Me, R2 = 4-MeC6H4
HC02NH4
Pd / C
OH
3.47
Scheme 3.27

97
The double bond is, however, reactive towards
electrophilic addition. Bromination of 1-(cyclohexylidene-
methyl)benzotriazole (3.27a) in carbon tetrachloride at
-5°C readily afforded the dibromo derivative (3.49) in 81%
yield (Scheme 3.28). The compound was characterized by its
elemental analysis and ^C-NMR spectrum which displayed an
upfield shift of 38 ppm for the C-a carbon, indicating
2
loss of sp character.
Br,
CCI4
-5°C
Scheme 3.28
It thus seems that alkylidenebenzotriazoles are
moderately unreactive towards hydrolysis. However, under
harsher conditions, the reaction may occur but the
reaction conditions are too strong to enable subsequent
isolation of the aldehyde or ketone.
3.3 Conclusions
Although removal of the benzotriazole moiety was not
as straightfoward as expected, the silicon-containing

98
N-substituent in 1-(trimethylsi1ylmethy1)benzotriazole
stabilized the C-a carbanion. As a result a successive
introduction of alkyl, alkylidene, and acyl groups at the
a-position to the ring was facilitated via treatment with
alkyl or silyl halides, with carbonyl compounds, and with
esters respectively. With a,8-unsaturated ketones the
Michael type addition product was formed while with
hindered a,6-unsaturated esters, the ketone was obtained.
The yields of these reactions were good especially in the
alkylations where relatively high yields were obtained.
Treatment of the silyl compounds with aldehydes and
ketones in the presence of fluoride ion afforded the
benzotriazol-l-ylethanols under mild conditions while the
corresponding reaction with acid chlorides (in the absence
of F ) provided the ketones. As in the previous case,
anhydrous conditions were essential since water causes
protiodesilylation generating the alkylbenzotriazole
rather than the expected alcohol. This observation was
exploited in an alternate route to synthesize
1-alkylbenzotriazoles.
Benzotriazole was removed cleanly in the presence of
zinc and acetic acid. The difficulty in the hydrolysis of
the alkylidenebenzotriazoles was a little disappointing.
There might be ways around this problem such as formation
of the epoxide (3.50) followed by nucleophilic attack at
the C-a position to give the diol (3.51) (Scheme 3.29)

99
which could then lose benzotriazole more easily
(Section 3.1.3).
Scheme 3.29
However we have observed the synthesis of a wide range
of functionally substituted benzotriazoles (Figure 3.1),
suggesting that similar methodology would be useful in the
elaboration of N-substituents in other heterocyclic ring
systems.

100
Pd/NH,CO,H
4 2
ch2cor
R COCI
CH 2 SiMe ^
R^ COR5
Bt
I 4 5
CHjCR R
(3.28)
Zn
HOAc
h3cor
(3.41)
r2chcor1
(3.22)
BuLi
4 5
R COR
Li-CHSiMe.
(3.23)
r2x
TBAF
4 5
Bt
I
CH = C R * R
(3.27)
OH
(3.47)
W >
Li-CR SiMe.
4 _ 5
O
4 5
HCCHR P.
(3.32)
R CH C(OH)R R
1 4 5
Li-C = CP. R
(3.28)
Zn
HOAc
r2ch2cor1
(3.33)
r2r3c-cor1
r3x
Bt
R2R3CSiMe.
(3.30)
RJCOR5
OH
2 3 1 4 5
CR (R )CR R
(3.32)
(3.48)
(3.47)
Where Bt = Benzotriazol-l-y1
Figure 3.1 Transformations of 1-(trimethylsilylmethy1)-
benzotriazle

101
3.4 Expe rimental
3.4.1 Apparatus and Experimental Procedures
The apparatus and general procedures used in this
Chapter are identical to those described in Chapter 2 with
the addition that 200 MHz ^H- and 50 MHz ^C-NMR spectra
were run using a Varian XL-200 (FT mode) spectrometer.
The following compound was prepared by the known
literature procedure:
1-Benzylbenzotriazole (3.38); (65%), m.p. 116-118°C;
(lit., [79HCA2129] 116-117°C).
3.4.2 Preparation of Starting Materials
3 . 4.2.1 1-(Trimethylsilylmethyl)benzotriazole (3.22)
Benzotriazole (11.9 g, 100 mmol) was dissolved in
sodium ethoxide solution (1 M in ethanol, 100 ml,
100 mmol). The solvent was then removed in vacuo and the
resulting solid dried overnight in a vacuum oven at 50°C.
The solid was dissolved in DMF (100 ml), chloromethyl-
trimethylsilane (13.9 ml, 100 mmol) added slowly and the
mixture stirred at ambient temperature for 24h. Water
(75 ml) was then added and the mixture extracted with Et^O
(7 x 50 ml), dried (Na^SO^) and the solvent removed in
vacuo to give a yellow oil. Crystallization from hexanes

102
afforded colorless needles (13.75 g , 67%), m.p. 55-56°C;
(Found: C , 58.28 ; H, 7.58; N, 20.36. C^H^N^Si requires
58.49 ;
H, 7.36;
N,
20.46%); Su 7.8-7.6 (1H, m),
rl
7.2-6.8
, m) ,
4.00 (2H,
s )
, and 0.20 (9H, s); Sr 145.4,
133.6,
126.5, 123.4, 119.5, 109.4, 38.7, and -2.1.
3.4.3 General Procedure for Lithiation with n-Butyl-
lithium and Reaction with Electrophiles
To a solution of the corresponding precursor (10 mmol)
in dry THF (100 ml) at -78°C was added dropwise
n-butyl1ithium (2.5 M in hexanes, 4.4 ml, 11 mmol) and the
resulting colored solution or precipitate (as in the case
of 3.23a) was stirred at that temperature for lh. To the
solution of the corresponding lithio derivative was added
a solution of the electrophile (10.5 mmol) and the
resulting solution stirred at -78°C for the appropriate
time (see Tables 3.1-3.3). The reaction mixture was then
poured into saturated aqueous ammonium chloride (75 ml)
and the layers separated (it was sometimes necessary to
add a little water to dissolve any inorganic precipitate).
The aqueous layer was extracted with Et2 combined organic extracts washed with water and dried
(MgSO^). The solvent was then evaporated to give the crude
product, which was purified by crystallization unless
otherwise stated. The following compounds were prepared in
this manne r:

103
3 . 4 . 3.1 l-(Benzotriazol-l-yl)-2-phenyl-l-(trimethyl-
silyl)ethane (3.25a)
See Table 3.1; (Found: C, 69.10; H, 7.41; N, 14.11.
C17H21N3SÍ requires C, 69.11; H, 7.16; N, 14.22%); SH 8.0-
7.9 (1H, m), 7.3-7.1 (2H, m), 7.05-7.0 (3H, m), 6.9-6.8
(3H, m) , 4.23 (1H, dd, J 4, 10 Hz), 3.4-3.2 (2H, m), and
0.18 (9H, s); &c 145.1, 139.3, 134.1, 128.4, 128.3, 126.4,
126.3, 123.2, 119.4, 109.2, 53.7, 37.9, and -2.7.
3 . 4.3.2 l-( Benzotriazol-l-yl)-1-(trimethylsilyl)ethane
(3.25b)
See Table 3.1; (Found: C, 60.34; H, 8.08; N, 19.15.
C11H17N3SÍ requires C, 60.23; H, 7.81; N, 19.16%);
SH 8.05-8.0 (1H, m), 7.6-7.3 (3H, m), 4.24 (1H, q,
J 8 Hz), 1.67 (3H, d, J 8 Hz), and 0.16 (9H, s); 5C 145.6,
133.1, 126.4, 123.4, 119.7, 109.5, 45.6, 16.3, and -3.0.
3.4.3.3 l-(Benzotriazol-l-yl)-l-(trimethylsilyl)heptane
(3.25b)
See Table 3.1; (Found: C, 66.49; H, 9.39; N, 14.47.
C16H27N3SÍ requires C, 66.38; H, 9.40; N, 14.51%);
SH 8.15-8.1 (1H, m), 7.6-7.4 (3H, m), 4.19 (1H, dd, J 3.4,
11.3 Hz), 3.5-1.8 (2H, m), 1.23 (8H, m), 0.87 (3H, m),
0.16 (9 H, s); &c 145.4, 134.0, 126.5, 123.3, 119.8, 109.5,
51.6, 31.4, 31.0, 28.7, 27.8, 22.4, 13.9, and -2.8.

104
3.4.3.4 1—[Bis(trimethylsilyl)methyl]benzotriazole (3.25d)
See Table 3.1; (Found: C, 56.31; H, 8.36. 3N3S i ?
requires C, 56.26; H, 8.35%); 8„ 8.22 (1H, d, J 8 Hz),
7.5-7.3 (3H, m), 3.69 (1H, s), and 0.10 (18H, s);
§c 145.1, 133.8, 126.2, 123.3, 119.7, 109.7, 43.3, and
-0.8.
3.4.3.5 l-(Benzotriazol-l-yl)-l,2-bis(trimethylsilyl)-
ethane (3.25e)
See Table 3.1; (Found: C, 57.76; H, 8.71; N, 14.40.
C14H25N3S*2 rec3uires c' 57.68; H, 8.64; N, 14.41%);
SH 7.90 (1H, d, J 8 Hz), 7.4-7.15 (3H, m), 4.20 (1H, dd,
J 2.6, 13.6 Hz), 1.74 (1H, dd, J 13.6, 15.2 Hz), 0.97
(1H, dd, J 2.6, 15.2 Hz), 0.11 (9H, s), and -0.45 (9H, s);
Sc 145.5, 133.2, 126.5, 123.4, 119.9, 109.6, 47.8, 17.3,
-2.0, and -3.4 .
3.4.3.6 l-(g-Trimethylsilyl)benzylbenzotriazole (3.39)
1-Benzylbenzotriazole (3.38) [79HCA2129] was treated
with n-butyl1ithium and chlorotrimethylsilane (3.21) to
afford 3.39 as colorless needles from hexanes (91%),
m.p. 127-128°C; (Found: C, 67.99; H, 7.02; N, 14.87.
C16H19N3Si‘ requires C, 68.28; H, 6.80; N, 14.93%); ¿H 8.1-
8.0 (1H, m), 7.3-7.15 (6H, m), 7.05-7.0 (2H, m), 5.20
(1H, s), and 0.26 (9H, s); 5C 145.9, 138.4, 133.7, 128.5,
126.8, 126.6, 126.2, 123.7, 119.6, 110.2, 56.6, and -2.1.

105
3.4.3 . 7 l-(Cyclohexylidenemethyl)benzotriazole (3.27a) .
See Table 3.2; (Found: C, 72.82; H, 7.36; N, 19.67.
C"13H15N3 requires C, 73.21; H, 7.09; N, 19.70%); 8.1-
8.0 (1H, m), 7.5-7.3 (3H, m), 6.81 (1H, s), 2.40 (2H, t,
J 5 Hz), 2.17 (2H, t, J 5 Hz), and 1.85-1.5 (6H, m);
&c 145.4, 145.1, 133.3, 127.3, 123.7, 119.6, 113.7, 109.8,
33.4, 28.7, 27.9, 27.1, and 25.9.
3 . 4 . 3 . 8 l-(Benzotriazol-l-yl)-2-methylpropene (3.27b)
See Table 3.2; 6U 8.06 (1H, d, J 8 Hz), 7.5-7.3
(3H, m), 6.85 (1H, s), 2.03 (3H, s), and 1.77 (3H, s).
3.4.3.9 l-(Benzotriazol-l-yl)-2-phenylpropene (3.27c)
See Table 3.2; purified by column chromatography
(ethyl acetate:hexanes, 1:9) to give 3.27c as colorless
microcrystals; (Found: C, 76.55; H, 5.72; N, 17.61.
C"15H13N3 requires C, 76.57 ; H, 5.57; N, 17.86%); 6H 8.0-
7.9 (1H, m), 7.25-6.9 (8H, m), and 2.36 (3H, s); 145.2,
138.7, 137.6, 132.2, 128.3, 128.0, 127.2, 127.0, 123.6,
119.4, 118.3, 110.2, and 22.3.
3.4.3.10 l-(Benzotriazol-l-yl)-2,2-diphenylethene (3.27d)
See Table 3.2; colorless microcrystals after column
chromatography (chloroform:hexanes, 1:2); 8.0-7.9
(1H, m), 7.63 (1H, s), 7.4 (5H, s), and 7.3-7.0 (8H, m).

106
3.4.3.11 3-[(Benzotriazol-l-yl)(trimethylsilyl)methyl]-
cyclohexanone (3.41)
The reaction of 3.23 with 2-cyclohexen-l-one (3.40)
gave after 4h and column chromatography (chloroform:-
hexanes, 1:2) the Michael addition product 3.41 as a
colorless oil which slowly solidifided into colorless
plates (70%), m.p. 126-128°C; (Found: C, 63.74; H, 7.73.
C16H23N3OS^ rec3u^res C, 63.75 ; H, 7.69%); 8.1-8.0
(1H, m), 7.5-7.35 (3H, m), 4.12 (1H, d, J 7 Hz), 2.7-2.5
(1H, m), 2.3-1.2 (8H, m), and 0.13 (9H, s); 6r 209.8,
145.2, 134.3, 127.1, 123.7, 119.9, 109.3, 56.0, 45.8,
41.5, 40.7, 30.6, 24.8, and -1.7.
3.4.3.12 2-(Benzotriazol-l-yl)-l-(4-methylphenyl)ethanone
(3.28a)
Ethyl 4-methylbenzoate (3.42) and 3.23 gave after 6h
at -78°C and the general work up a mixture which was
purified by column chromatography (chloroform:hexanes,
1:3) and the resulting white solid stirred overnight in
hexanes to furnish 3.28a as colorless needles (51%), m.p.
134-135°C; (Found: C, 71.82; H, 5.20; N, 16.78. C15H13N3°
requires C, 71.70; H, 5.21; N, 16.72%); 5„ 8.03 (1H, d,
H
J 8 Hz), 7.9 (2H, d, J 7 Hz) 7.5-7.2 (5H, m), 6.03
(2H, s), and 2.40 (3H, s); 5 189.9, 145.8, 145.4, 133.7,
1341.3, 129.6, 128.2, 127.5, 123.8, 119.7, 109.5, 53.6,
and 21.6.

107
3.4.3.13 l-(Benzotriazol-l-yl)-4-methyl-3-penten-2-one
(T.44)
Ethyl 3,3-dimethylacrylate (3.43) and 3.23 gave after
6h and the general work up a mixture purified by column
chromatography (chloroform:hexanes, 1:1) to afford 3.44 as
colorless plates (45%), m.p. 78-80°C; (Found: C, 66.64?
H, 5.99; N, 19.63. C]_2H13N3^ requires C, 66.96 ; H, 6.09?
N, 19.52%); 6„ 8.1-8.0 (1H, m), 7.5-7.3 (3H, m), 6.08
H
(1H, s), 5.42 (2H, s), 2.15 (3H, s), and 1.90 (3H, s);
Sc 190.3, 161.5, 145.7, 133.4, 127.5, 123.7, 119.7, 119.0,
109.3, 56.8, 27.8, and 21.2.
3.4.3.14 2-(Benzotriazol-l-yl)-2-(trimethylsilyl)octane
(3.45a)
l-(Benzotriazol-l-yl)-1-(trimethylsilyl(ethane (3.25b)
and hexyl iodide as electrophile gave after work up a
brown oil purified by column chromatography (chloroform:-
hexanes, 1:2) to give a pale yellow oil (80%); (Found: M ,
m/z 303.2130. C^-;H~,gN^Si requires M+, m/z 303.2130);
5h 8.1-8.0 (1H, m), 7.8-7.7 (1H, m), 7.4-7.25 (2H, m),
2.5-2.0 (2H, m), 1.85 (3H, m), 1.16 (8H, m), 0.80 (3H, t,
J 6 Hz), and 0.18 (9H, s); 146.5, 133.0, 126.1, 123.2,
120.1, 112.2, 57.3, 37.4, 31.4, 29.5, 23.6, 22.4, 22.1,
13.9, and -2.0.

108
3.4.3.15 2-(Benzotriazol-l-yl)-l-phenyl-2-(trimethyl-
silyl)propane (3.45b)
The reaction of the lithio salt of 3.25b and benzyl
bromide gave colorless needles from hexanes (71%), m.p.
8 7 - 8 90 C; (Found: C, 69.43; H, 7.91; N, 13.70. C18H->3N3Si
requires C, 69.86 ; H, 7.49; N, 13.58%); S„ 8.1-8.0
n
(1H, m), 7.3-6.95 (6 H, m), 6.6-6.5 (2H, m), 3.64 (1H, d,
J 14 Hz), 3.17 (1H, d, J 14 Hz), 1.84 (3H, s), and 0.19
(9H, s); Sc 146.2, 136.2, 133.9, 130.0, 127.9, 126.6,
126.0, 123.1, 119.9, 112.4, 57.7, 43.3, 20.1, and -2.2.
3.4.3.16 [(Benzotriazol-l-yl)(phenyl)me thylene]-
cyclohexane (3.46)
l-(a-Trimethylsilyl)benzylbenzotriazole (3.38)
cyclohexanone as the electrophile (reaction time 6h at
-78°C, 12h at ambient temperature) gave an oil which was
purified by column chromatography (chloroform:hexanes,
1:2) to yield 3.46 as an oil which slowly solidified
(70%), m.p. 108-110°C; (Found: C, 78.92; H, 6.84;
N, 14.63. C]_9H]_gN3 requires C, 78.86; H, 6.62; N, 14.52%)
6 8.06 (1H, d, J 8 Hz), 7.4-7.2 (8H, m), 2.54 (2H, t,
J 5 Hz), and 2.0-1.2 (8H, m); & 145.4, 144.0, 135.8,
133.6, 128.9, 128.3, 128.1, 127.5, 126.7, 123.7, 119.7,
110.2, 31.4, 30.9, 28.1, 28.0, and 26.2.

109
3.4.3.17 [ (Benzotriazol-l-yl)(deuterio)methylene ] -
cyclohexane (3.30a)
See Table 3.3; (Found: H+, m/z 214.1331. 3H]_ 4DN3
requires 214.1328); 6„ 8.05 (1H, m), 7.6-7.3 (3H, m), 2.41
ri
(2H, t, J 5 Hz), 2.18 (2H, t, J 5 Hz), 1.8-1.5 (6H, m);
&c 145.3, 145.1, 133.4, 127.4, 123.8, 119.7, 109.9, 33.4,
28.7, 27.9, 27.1, and 26.0 (the deuterated carbon signal
was not observed).
3.4.3.18 [l-(Benzotriazol-l-yl)ethylidene]cyclohexane
(3.30b)
See Table 3.3; a brown oil purified by column
chromatography (chloroform:hexanes, 1:1) to afford 3.30b
as a pale yellow oil; (Found: M+, m/z 227.1412. C^H^N^
requires 227.1422); 6U 8.07 (1H, d, J 8 Hz), 7.5-7.3
(3H, m), 2.46 (2H, t, J 6 Hz), 2.20 (3H, s), and 1.8-1.3
(8H, m); 6C 145.1, 140.7, 132.9, 127.2, 123.6, 121.8,
119.6, 109.8, 30.3, 29.8, 27.5, 27.4, 26.0, and 17.8.
3 . 4 . 3.19 [l-(Benzotriazol-l-yl)hepthylidene¡cyclohexane
(3.30c)
See Table 3.3; a brown oil after purification by
column chromatography (chloroform:hexanes, 2:3); (Found:
M+, m/z 297.2204. ('i9H27t^3 rec3uires , m/z 297.2222);
6„ 8.08 (1H, d, J 8 Hz), 7.5-7.3 (3H, m), 2.61 (2H, m),
ri —
2.48 (2H, m), 1.8-1.4 (8H, m), 1.3-1.1 (8H, m), and 0.82
(3H, t, J 6 Hz); 6C 145.1, 141.0, 133.8, 127.3, 126.8,
123.6, 119.8, 110.0, 32.0, 31.4, 30.3, 30.0, 28.6, 27.8,
27.7, 27.6, 26.2, 22.4, and 13.9.

110
3.4.3.20 [(4-Methyl-a-hydroxybenzyl)(benzotriazol-l-yl)-
methyl1 cyclohexane (3.30d)~
See Table 3.3; the crude mixture was purified by
column chromatography (chloroform:hexanes, 1:1) to give
3.30d as microcrystals; (Found: C, 75.02; H, 7.20;
N, 11.92. requires C, 75.65 ; H, 6.95;
N, 12.60%); 6„ 7.9 (1H, m), 7.5-6.5 (7H, m), 6.18 (1H, d,
n
J 5 Hz), 3.8 (1H, bs, OH), 2.75 (2H, bs), 2.15 (2H, bs ) ,
and 1.9-1.3 (8H, m); 6r 144.7, 144.4, 137.8, 136.7, 134.5,
128.6, 127.2, 124.9, 123.6, 119.2, 109.9, 69.7, 30.4,
27.8, 27.6, 26.0, and 20.8.
3.4.4 General Procedure for the F Catalyzed Reaction
of 3.22, 3.25, and 3.45 with Carbonyl Compounds
AIM solution of TBAF in THF (0.1 ml, 0.1 mmol) was
added at ambient temperature to a solution of the carbonyl
compound (10 mmol) and 3.22, 3.25, or 3.45 (5 mmol) in dry
THF (15 ml). After ca. 6h, a further portion of TBAF (1 M
in THF, 0.1 ml, 0.1 mmol) was added and the mixture
stirred for another 18h. Water (10 ml) and HCl (1 M,
10 ml) were then added and the mixture stirred until
hydrolysis of the silyl ether was complete (monitorred by
TLC). The layers were separated, the aqueous layer
extracted with Et^O (3 x 20 ml), and the combined organic
extracts washed with water and dried (MgSOd). Evaporation
of the solvent gave the crude product which was then
purified to afford the alcohols 3.47a-g respectively. The
following compounds we re prepared in this fashion:

Ill
3 . 4 . 4 .1 l-(Benzotriazol-l-ylmethyl)cyclohexanol (3.47a)
See Table 3.4; the crude mixture was purified by
column chromatography (chloroform:hexanes, 1:1) to give
colorless microcrystals, m.p. 132-134°C; (Found C, 67.60;
H, 7.69; N, 17.48. requires C, 67.51; H, 7.41;
N, 18.17%); SH 7.93 (1H, d, J 8 Hz), 7.68 (1H, d, J 8 Hz),
7.45-7.25 (2H, m), 4.60 (2H, s), 2.97 (1H, s), and 1.7-1.2
(10H, m); Sc 145.2, 134.1, 127.1, 123.7, 119.3, 110.7,
72.0, 57.9, 35.1, 25.3, and 21.5.
3.4.4.2 2-(Benzotriazol-l-yl)-l-(4-methylphenyl)ethanol
Tl"T7b)
See Table 3.4; the crude product was purified by
column chromatography (chloroform:hexanes, 1:2) to afford
3.47b as colorless microcrystals, m.p. 143-145°C; (Found
C, 71.15; H, 6.20; N, 16.26. C^H^N-^O requires C, 71.13;
H, 5.97; N, 16.59%); 7.8-7.5 (1H, m), 7.4-6.9 (7H, m),
5.4-5.2 (1H, m), 4.8-4.65 (2H, m), 3.9-3.6 (1H, bs, OH),
and 2.40 (3H, m); 145.2, 138.0, 137.5, 133.7, 129.3,
127.2, 125.8, 123.8, 119.2, 110.0, 73.0, 55.6, and 21.0.
3 . 4 . 4 . 3 2-Benzotriazol-yl-l-phenylhexan-3-ol (3.47c)
See Table 3.4; column chromatography (chloroform) gave
the alcohol (3.47c) as a 3:1 mixture of diaste reome rs;
(Found: M+, m/z 295.1659. C]_8^21^3° re(7ui>:es M+ > m/z
295.1684); 6„ 8.0-7.9 (1H, m), 7.4-6.9 (8H, m), 5.1-4.7
H

112
(1H, m), 4.4-4.1 (1H, m, OH), 4.0-3.5 (3H, m), 1.7-1.2
(4 H, m), and 1.0-0.8 (3H, m); Sc 144.8, 137.4, 137.0,
134.0, 133.8, 128.7, 128.6, 128.3, 128.2, 127.2, 127.0,
126.6, 126.4, 123.8, 123.7, 119.5, 119.4, 109.6, 109.4,
73.4, 72.6, 66.4, 65.9, 38.4, 36.6, 36.4, 35.6, 18.9, and
13.8.
3 . 4 . 4 . 4 2-(Benzotriazol-l-yl)-l-(4-methylphenyl)-3-
phenylpropan-l-ol (3.47d)
See Table 3.4; the oil was purified by column
chromatography (chloroform:hexanes, 1:3) to afford (as a
5:3 mixture of diastereomers). Further separation of the
mixture by column chromatography (chloroform) afforded the
individual diasteromers A and B.
Compound A: (= 0.36), colorless prisms, m.p. 137-
13 8 0 C; (Found: C, 76.45 ; H, 6.16; N, 12.02. C2^H21N3°
requires C, 76.94; H, 6.16; N, 12.24%); Su 7.9-7.75
ri
(1H, m), 7.3-6.7 (12H, m), 5.38 (1H, d, J 5.5 Hz), 5.0-4.9
(1H, m), 4.18 (1H, bs, OH), 3.60 (2H, d, J 6.5 Hz), and
2.21 (3H, s); &c 144.8, 137.7, 137.4, 137.2, 133.7, 129.0,
128.7, 128.2, 126.8, 126.4, 125.9, 123.5, 119.2, 109.3,
75.8, 67.8, 35.9, and 20.9.
Compound B: (R^ = 0.24), colorless gum; (Found:
C, 77.28 ; H, 6.02. C^H-^N^O requires C, 76.94 ; H, 6.16%);
§H 7.69 (1H, d, J 8 Hz), 7.3-6.8 (12H, m), 5.40 (1H, t,
J 5.5 Hz), 4.98 (1H, m), 4.2-4.1 (1H, m, OH), 3.44
(1H, dd, J 10.9, 13.7 Hz), 3.16 (1H, dd, J 4.5, 13.7 Hz),

113
and 2.28 (3H, s); Sc 144.8, 137.9, 137.7, 137.0, 134.4,
129.3, 128.5, 128.3, 126.8, 126.5, 126.1, 123.6, 119.1,
109.5, 75.6, 67.9, 38.0, and 21.0.
3.4.4.5 2-(Benzotriazol-l-yl)-l-(4-methylphenyl)propan-
r-oT~1TT~47?T
See Table 3.4; column chromatography of the crude
mixture (chloroform:hexanes, 1:2) furnished the alcohol
3.47e as a colorless oil (5:3 mixture of diastereomers).
The diastereomers were separated by column chromatography
(chloroform:hexanes, 1:9) to give two products A and B.
Compound A: (R^ = 0.31), colorless oil; (Found
C, 71.70; H, 6.45. C^H^N^O requires C, 71.88; H, 6.41%);
8h 7.80 (1H, d, J 8 Hz), 7.4-7.15 (3H, m), 7.08 (2H, AB,
JAB 7.8 Hz), 6.96 (2H, AB, JAB 7.8 Hz), 5.25-5.15 (1H, m),
4.97 (1H, m), 4.6-4.3 (1H, bs, OH), 2.20 (3H, s), and 1.73
(3H, d, j 7 Hz); 145.2, 137.3, 132.7, 128.7, 126.8,
125.8, 123.6, 119.3, 110.0, 76.0, 61.2, 20.8, and 14.8.
Compound B: (= 0.22), colorless prisms, m.p. 122-
12 3 0 C; (Found C, 72.20 ; H, 6.19; N, 15.31. C16H17N3°
requires C, 71.88; H, 6.41; N, 15.72%); 5H 7.7-7.5
(2H, m), 7.4-7.0 (6H, m), 5.3-5.15 (1H, m), 4.93 (1H, m),
4.5-4.3 (1H, bs, OH), 2.30 (3H, s), and 1.48 (3H, d,
J 7 Hz); 8C 145.0, 137.7, 133.5, 129.1, 126.7, 126.4,
123.6, 119.0, 110.1, 77.0, 61.3, 21.0, and 17.2.

114
3.4.4.6 2-(Benzotriazol-l-yl)-l-(4-methylphenyl)octan-l-ol
(3.47f)
See Table 3.4? the alcohol 3.47f was obtained as a
colorless gum (7:5 ratio of diastereomers) after
purification by column chromatography (chloroform:hexanes
1:2). Further chromatography (ethyl acetate:hexanes, 1:6)
of the diastereomers afforded the following two compounds
A and B.
Compound A: (= 0.42), colorless microcrystals m.p.
86-88°C; (Found C, 75.24; H, 8.35. ('22H':,9N3(") requires
C, 75.17; H, 8.32%); 7.85 (lH, d, J 8 Hz), 7.40 (1H, d,
H —
J 8 Hz), 7.21 (2H, m), 6.83 (2H, AB, J 8.1 Hz), 6.68
(2H, AB, J... 8.1 Hz), 5.07 (1H, s), 3.35 (lH, bs, OH),
D
2.8-2.6 (1H, m), 2.14 (3H, s), 2.1-1.9 (lH, m), 1.78
(3H, s), 1.08 (8H, m), and 0.72 (3H, t, J 6 Hz); 6 c 146.1,
137.6, 136.4, 133.8, 128.4, 127.0, 126.6, 123.2, 119.8,
112.7, 80.1, 70.3, 35.9, 31.5, 29.4, 23.1, 22.4, 20.9,
20.2, and 13.9.
Compound B: (= 0.33) colorless oil; (Found
C, 74.96 ; H, 8.39. C^2H29N3^ re<3uires C, 75.17; H, 8.32%);
SH 7.6 (2H, t, J 8 Hz), 7.25-7.0 (2H, m), 6.86 (2H, AB,
JAB 8.6 Hz), 6.83 (2H, AB, JAB 8.6 Hz), 5.10 (lH, d,
J 3.7 Hz), 3.70 (1H, d, J 3.7 Hz, OH), 2.5-2.3 (1H, m),
2.13 (3H,s), 1.71 (3H, s), 1.7-1.5 (lH, m), 0.95 (8H, m),
and 0.61 (3H, t, J 7 Hz); Sr 146.0, 137.5, 136.4, 133.6,
128.4, 127.5, 126.6, 123.3, 119.6, 112.7, 79.5, 70.7,
37.1, 31.3, 29.2, 22.8, 22.3, 20.9, 19.7, and 13.8.

115
3.4.4.7 1-[(2-benzotriazol-l-yl)-lf-phenylpropyl]-
cyclohexanol (3.47g)
See Table 3.4; column chromatography (chloroform:
hexanes, 1:1) of the crude brown oil afforded
l-[(2-benzotriazol-l-yl)-l'-phenylpropyl]cyclohexanol
(3.47g) m.p. 128-130°C; (Found C, 73.92; H, 7.97;
N, 11
.99.
C21
H2 5
n3°
requires
c,
75.19;
H,
7 . 51
N, 12
. 53% )
; 6
H 8
. 1-8
. 0
( 1H,
m) ,
7.65-7.
55
( 1H,
m)
, 7.
4-
7.25
( 2H,
m) ,
7 .
05-6
.9
( 3H,
m) ,
6.7-6.6
( 2H, m
) ,
4 .46
( 1H,
d, J
14
Hz )
, 3.
39
( 1H,
bs ,
OH), 3 .
06
( 1H,
d,
J 14
Hz ) ,
1.85 (
3H,
s )
, and
2.1
-1.0 (10H,
m) ;
SC
145 .
9,
136.5
, 135
.0,
130.1,
127.8 ,
127
.2, 126.
3,
123 .
4,
120 .
1,
113.1
, 77.
7,
74 .
8, 40.
8 , 32 .
4,
31.6, 25
• 6 ,
21 .
5,
and
21
3.4.5 General Procedure for the F Induced Desilylations
To a solution of the corresponding silyl derivative
(5 mmol) in THF (10 ml) was added TBAF (1 M in THF,
5.5 ml, 5.5 mmol). The solution was heated under reflux
for 12h. Water (15 ml) was then added and the organic
material extracted with chloroform (3 x 10 ml), dried
(MgSO^) and the solvent removed in vacuo. The crude oil
was then purified by column chromatography (chloroform:-
hexanes, 2:3) to give pale yellow oils. The following
compounds were prepared in this manner:

116
3.4.5.1 1-(2-Phenylethyl)benzotriazole (3.48a)
[67J(PI)781].
See Table 3.5; 6„ 8.1-7.9 (1H, m), 7.4-7.0 (8H, m),
4.82 (2H, t, J 7 Hz), and 3.27 (2H, t, J 7 Hz).
3.4.5.2 1-Heptylbenzotriazole (3.48b)
See Table 3.5; S„ 8.06 (1H, d, J 8 Hz), 7.6-7.3
rl —
(3H, m), 4.63 (2H, t, J 7 Hz), 2.05-1.95 (2H, m), 1.4-1.2
(8H, m), and 0.86 (3H, t, J 7 Hz); &c 145.8, 132.8, 127.0,
123.6, 119.8, 109.2, 48.1, 31.4, 29.5, 28.5, 26.5, 22.4,
and 13.9.
3 . 4 . 5 . 3 2-(Benzotriazol-l-yl)octane (3.48c)
See Table 3.5; (Found H+, m/z 231.1724. C]_4H2iN3
requires M+, m/z 231.1735); 6U 8.06 (1H, d, J 8 Hz), 7.6-
7.3 (3H, m), 4.92 (1H, m), 1.70 (3H, d, J 7 Hz), 2.3-1.2
(10H, m), and 0.81 (3H, t, J 6 Hz); 6C 145.9, 132.2,
126.6, 123.5, 119.8, 109.5, 55.9, 36.1, 31.3, 28.6, 26.0,
22.2, 20.6, and 13.8.
3.4.5.4 2-(Benzotriazol-l-yl)-l-phenylpropane (3.48d)
See Table 3.5; 7.99 (1H, d, J 8 Hz), 7.5-6.9
(8H, m), 5.05 (1H, m), 3.40 (1H, dd, J 8.2, 13.7 Hz), 3.22
(1H, dd, J 6.4, 13.7 Hz), and 1.75 (3H, d, J 6 Hz);
6C 145.6, 137.1, 132.5, 128.6, 128.2, 126.58, 126.53,
123.4, 119.5, 109.2, 57.1, 42.8, and 20.1.

117
3.4.6 General Procedure for Desilylation with Acid
Chlorides ~
Method A. The trimethylsilyl derivative 3.22
(10 mmol) and the acid chlorides (12 mmol) were dissolved
in dry THF (10 ml) and the mixture heated under reflux. On
cooling the colorless needles were filtered and dried.
Method B. The corresponding trimethylsilyl
derivative (10 mmol) and 4-methylbenzoyl chloride was
dissolved in dry carbon tetrachloride (10 ml) and the
mixture heated under reflux. 2N HCl (5 ml) was then added
and the mixture washed with methylene chloride (3 x 15 ml)
and the combined organic fractions washed with 5% aqueous
^2^^ (2 x 10 ml), water (1 x 10 ml), and dried (Na2SO^).
Evaporation of the solvent gave the crude product which
was then purified by column chromatography. The following
compounds were prepared in this manner:
3.4.6.1 2-(Benzotriazol-l-yl)-l-(4-methylphenyl)ethanone
(3.¿8a)
4-Methylbenzoyl chloride and 1-(trimethylsilylmethyl)-
benzotriazole (3.22) afforded the ketone 3.28a after
heating under reflux for 72h (72%); m.p. 133-135°C;
Identical in all respects to the ketone prepared earlier.
3.4.6.2 l-(Benzotriazol-l-yl)propan-2-one (3.28b)
Acetyl chloride and 3.22 afforded after heating under
reflux for 6h 3.28b (73%); m.p. 126-127°C; (Found:
C, 61.87; H, 5.18; N, 23.88. C^H^N^O requires C, 61.70;

118
H, 5.18; N 23.99%); 8.1-8.05 (1H, m), 7.6-7.3 (3H, m),
5.44 (2H, s), and 2.21 (3H, s); &r 199.8, 145.9, 133.4,
127.9, 124.1, 120.0, 109.0, 56.7, and 27.0.
3 . 4.6 . 3 2-(Benzotriazol-l-yl)-l-phenylethanone (3.28c)
1-(Trimethylsilylmethyl)benzotriazole (3.22) and
benzoyl chloride gave after 24h 3.28c (72%); m.p. 113—
1140C; 8.1-8.0 (3H, m), 7.7-7.25 (5H, m), and 6.09
rl
(2H, s); 6C 190.3, 146.0, 134.5, 133.9, 133.8, 129.1,
128.2, 127.8, 124.0, 120.0, 109.5, and 53.8.
3.4.6.4 2-(Benzotriazol-l-yl)-l-(4-methylphenyl)propanone
(3.28d)
l-(Benzotriazol-l-yl)-1-(trimethylsilyl)ethane (3.25b)
and 4-methylbenzoyl chloride gave after 72h an oil which
was purified by chromatography (chloroform:hexanes, 1:1)
to give 3.28d as a colorless oil (77%); (Found Mr, m/z
265.1187. ^i6H15N3^ rec3u:*-res 1 m/z 265.1215); 6^ 8.02
(1H, d, J 8 Hz), 7.91 (2H, d, J 8 Hz), 7.55-7.25 (3H, m),
7.19 (2H, d, J 8 Hz), 6.69 (1H, q, J 7 Hz), 2.33 (3H, s),
and 1.96 (3H, d, J 7 Hz); &c 193.3, 146.5, 145.1, 132.0,
131.6, 129.5, 128.8, 127.6, 123.9, 120.1, 110.4, 59.3,
21.6, and 16.2.

119
3.4.7 General Procedure for the Formation of Ketones
3.33.
To a mixture of 3.28 (2 mmol) in acetic acid (2 ml)
and dry ethanol (6 ml) was added zinc metal (granular, 20
mesh) (0.65 g, 10 mmol) and the mixture stirred at ambient
temperature. Ethanol (10 ml) was then added. The insoluble
materials were filtered off and the solvent evaporated.
The residue was then purified by column chromatography
(chloroform:hexanes 1:2). The following were prepared in
this manner:
3.4.7.1 4'-Methylacetophenone (3.33a)
Colorless liquid (60%); b.p. 221-223°C; (lit.,
[24JA1893] b.p. 225°C); 6U 7.73 (2H, d, J 8 Hz), 7.13
(2H, d, J 8 Hz), 2.50 (3H, s), and 2.33 (3H, s).
3 . 4.7.2 4'-Methylpropiophenone (3.33b)
Colorless liquid (71%); b.p. 236-239°C; (lit.,
[24JA1893] b.p. 2 3 9 0 C); 7.96 (2H, d, J 8 Hz), 7.33
(2H, d, J 8 Hz), 3.00 (2H, q, J 7 Hz), 2.40 (3H, s), and
1.20 (3H, t, J 7 Hz) .
3.4.8 Palladium Catalyzed Reduction
3.4.8.1 2-(Benzotriazol-l-yl)-l-(4-methylphenyl)ethanol
(3.47b)
To a solution of 2-(benzotriazol-l-yl)-1-(4-methyl-
phenyl ) ethanone (3.28a) (0.50 g, 2 mmol) and ammonium

120
formate (0.65 g, 10 mmol) in dry methanol (15 ml) was
added palladium on carbon (palladium content 10%, 0.5 g).
The mixture was then heated under reflux for 3h. The
catalyst was filtered off through a celite pad and to the
filtrate was added chloroform (40 ml). The mixture was
washed with water (3 x 15 ml), dried (MgSO^), and the
solvent removed in vacuo to give a white solid (0.45 g,
90%), the physical and spectral properties of which were
similar to the alcohol prepared earlier.
3.4.9 l-Bromo-l-[(benzotriazol-l-yl)(bromo)methyl]-
cyclohexane (3.49)
To a solution of 1-(cyclohexylidenemethyl)-
benzotriazole (0.5 g, 2.35 mmol) in carbon tetrachloride
(CCl^) (25 ml) at -5°C was added a solution of bromine
(0.5 g, 3.12 mmol) in CCl^ (15 ml) in 1 ml portions. After
addition was complete, the mixture was heated to 50°C to
remove the excess bromine. The solution was then
concentrated to ca. 15 ml. On cooling, pale yellow needles
crystallized out which were filtered and dried. Yield
0.71 g, 81%; m.p. 152-153°C; (Found C, 42.20; H, 3.78;
N, 10.90. requires C, 41.85; H, 4.05;
N, 11.26%); 6 8.15-8.05 (1H, m), 7.95-7.85 (1H, m), 7.6-
ri
7.4 (2H, m), 7.01 (1H, s), 2.6-2.4 (1H, m), 2.3-1.7
(8H, m), and 1.4-1.2 (1H, m); 6r 145.6, 132.8, 128.0,
124.6, 120.1, 112.0, 75.3, 68.6, 38.4, 36.4, 24.6, 22.9,
and 22.4.

121
CHAPTER IV
STUDIES ON N-(SUBSTITUTED-METHYL)-3,5-DIMETHYLPYRAZOLES
4 .1 Introduction
4.1.1 The Chemistry of N-Chloromethyl Compounds
N-Halomethyl compounds of the type Het-CH2~Cl (where
Het = heteroaromatic ring) could belong to a general class
of synthons of the formaldehyde anion equivalent
X-CH2-Y > X-CH-Y, where X and Y are two functions
which may be displaced subsequently to generate a carbonyl
group.
In this laboratory we recently made a substructure
search in the Chemical Abstracts Online system for ClCH^-
attached to a five- or six-membered ring and this revealed
over eight hundred entries covering more than forty
different heterocyclic systems. However, very few of these
systems have been systematically investigated, and the
majority of the references were to the patent literature.
These N-halomethyl compounds, have a much greater
synthetic potential than most analogous synthons, since

122
the two substituent groups have different reactivity and
as a result can be displaced independently under different
conditions.
The chlorine atom can be replaced by nucleophiles and
the literature search mentioned above also indicated that
this has already been demonstrated for many of the
systems. N-Alkyl groups in certain azole systems have the
ability to undergo lithiation at the C-tx site [790R1,
80J(PI ) 2851, 83T2023, 85S302, 87J(PI)781]. Furthermore,
some heterocycles are synthetically good leaving groups
[80T679, 8 4AG(E)4 2 0, 84TL1635, 87J(PI)805]. The above
features make H-chloromethylheterocycles an important
class of industrial intermediates.
Consequently, these classes of compounds might be
used:
a) as synthons for C++ and thus as precursors for
the preparation of tetrasubstituted methanes of
the type E"E"CNu'*'Nu“ by reaction with (Nu"*-) ,
(E ^ )+, (E“)+ (via carbanions), and then removal
2 -
of the heterocycle by (Nu ) ;
b) for the preparation of a number of interestng
compounds through a variety of novel carbanionic
rearrangements followed by loss of the
heterocycle.

123
4.1.2 Synthetic Utility
4 .1.2.1 Generation of N-(substituted-methyl)heterocycles
In the previous section (Section 4.1.1) the difference
in the reactivity as leaving groups of the heterocycle and
of the chlorine atom was mentioned. Hence it is possible
to replace the chlorine atom of a N-chloromethyl-
heterocycle (4.1) by a suitable nucleophile to give the
substituted derivative 4.2 (Scheme 4.1). A wide variety of
these types of displacements have been reported in the
literature. Some of the more general ones are the
displacements using alcohols and phenols [1898CB1225 ] ,
mercaptans and thiophenols [61JOC3591, 63AP54, 73AP684],
sulfinates [73AP684], thiocarbonates [67AP64],
dithiocarbamates [73AP684], pyridine [27JCS528], and
triphenylphosphine [72JGU942],
Het-CH2-CI + Nu “ — Het-CH,-Nu
4.1 4.2
Scheme 4.1

124
4.2.2.2 Generation of C-a carbanions
Once the required nucleophile has been introduced,
derivative 4.2 should be succeptible to metallation
forming a carbanion at the C-a site. Depending upon the
heterocyclic system employed this carbanion could be
stabilized inductively as in the lithio derivative 4.3 or
by co-ordination to another heteroatom in the ring
[78CRV275, 790R1] as in 4.4 (Scheme 4.2).
Scheme 4.2
Treatment of the lithium salt of 4.2 with
electrophiles should form the substituted derivative 4.5
which upon treatment with another equivalent of
organolithium and another electrophile should give the
disubstituted compound 4.6. If the heterocycle is a good
leaving group, nucleophilic displacement of the
heterocycle should afford the tetrasubstituted methane 4.7
(Scheme 4.3). Of course, this sequence may be stopped at
any stage.

125
1) RLi
2) (E1)+
E1
1) RLi
2) (E2)+
E1
(Nu2)
E1
I
Nu2—C—Nu1
I
E2
4.7
Scheme 4.3
4.2.2.3 Carbanionic Rearrangements via Cyclic
Intermediates
If the nucleophile Nu selected in 4.2 is such that
there exists an electrophilic site "beta" to the carbanion
generated in 4.3 or 4.4, it might be possible to form the
three-membered ring intermediate 4.8 which would be
stabilized by the electron withdrawing ability of Z.
Fission of the ring with rearrangement (Route A) would
give the heterocyclic derivative 4.9. If the heterocycle
were a good leaving group, then ring opening with
concomitant loss of the heterocycle (Route 3) would give
the corresponding imine (or aldehyde or thioaldehyde) 4.10
(for X = N, 0, or S respectively) (Scheme 4.4).

126
4.9
X-*
4.8
I
l
Route B
I
t
• ?
I
I
I
\
4.10
X = N, O, or S
Scheme 4.4
If the heteroatom X is -S- or -SO-,-, then extrusion of
X from 4.8 could be possible forming the heterocyclic
compound 4.11 via the mechanism depicted below
(Scheme 4.5).
-X
\
A
Scheme 4.5

127
For X = S, Hayashi and Baba [75JA1608] observed
rearrangement when the dithiocarbamate 4.12 was treated
with LDA in the presence of hexamethylphosphoramide (HMPA)
to give the sulfide 4.13 (Scheme 4.6).
4.13
Scheme 4.6
The closest analogy to the extrusion of sulfur in such
a system was in work by Eschenmoser [70QR366, 71HCA710]
and by Bridges and Whitman [75J(PI)1603]. In the presence
of base, the dithiocarbonate 4.14 was found to lose sulfur
to give the thioester 4.15 (Scheme 4.7).
Katritzky e_t al. [ 80J ( PI ) 2851 ] observed a
rearrangement when 1-(a-methylbenzvl)-4,6-diphenyi-
2-pyridone (4.16) was reacted with LDA in THF at -78°C. At
ambient temperature, the anion 4.17 was found to have

128
rearranged to 2-methyl-2,5,7-triphenylazepin-3-one (4.19)
presumably via the three-membered aziridine intermediate
4.18. (Scheme 4.8).
4.15
Scheme 4.7
For rearrangements via an oxirane ring (i.e. when
oxygen is the nucleophilic atom), Crooks e_t al.
[76CI(L)693] showed that benzoin (4.22) was formed during
the rearrangement of benzyl benzoate (4.20) via the
oxirane intermediate (4.21) (Scheme 4.9).

129
4.16
4.17
4.18
4.19
Scheme 4.8
4.20
4.21
4.22
Scheme 4.9

130
4.1.3 Aims of the Work
The first step was the selection of a suitable
heterocycle, the choice of which depended upon the
following criteria:
a) the ring must sufficiently activate the proton on
the o-carbon atom;
b) the ring should not itself be metallated or
attacked under the reaction conditions employed;
c) the ring should be a relatively good leaving
group;
d) the heterocyclic system should be readily
available or capable of being synthesized from
easily accessible materials;
e) the heterocycle should have a pyrrole-like ring
nitrogen atom rather than or in addition to a
pyridine-like ring nitrogen atom.
Earlier (Section 2.1.1), it was mentioned that
1-methyl- and 1-benzyl-benzimidazole undergo lithiation at
C-2 [58JOC1791, 74JOC1374]. A similar behavior was also
observed for 1,2-dimethylbenzimidazole [76KGS1699] and
1,2-dimethylimidazole [83J(PI ) 271 ] , where metallation
occurred exclusively at the C-2 methyl group. On the other
hand, pyrroles and indoles are difficult to lithiate even
at the C-2 ring carbon.
N-Alkylbenzotriazoles [86UP1] and N-alkylcarbazoles
[36JOC146, 72CB487] do not lithiate at the C-a position

131
and require the presence of an activating group in order
to undergo C-a metallation [85JOC1351, 87J(PI)781]. This
severely restricted the choice of nucleophiles that could
be used. The excellent leaving group ability of
benzotriazole in aminomethylbenzotrizoles [84TL1635,
87J(PI)805] made it less interesting since cleavage might
have been the preferred route instead of the required
rear rangement.
For N-alkylpyrazoles (4.23), powerful nucleophiles
abstract the C-3 proton with a concomitant ring opening of
the anion to give nitriles 4.24 [76MI1]. With
n-butyllithium, the N-substituted pyrazoles 4.23 are known
to be metallated at C-5 [76MI1, 79RCR289, 83T4133] to give
the 5-lithio derivative 4.25 (Scheme 4.10).
R
4.25
Scheme 4.10

132
When the 3- and 5-positions were blocked by methyl
groups, as in 1,3,5-trimethylpyrazóle (4.26), lithiation
occurred at the N-methyl group to afford derivatives of
type 4.28 [70CJC2006, 83T2023]. This finding was
significant since the N-(a-1ithioalkyl)pyrazole 4.27 could
be reacted with a variety of electrophiles to form
products 4.28 often not easily accessible by other routes
(Scheme 4.11) .
4.26 4.27 4.28
Scheme 4.11
The above result led us to expect that a wide variety
of nucleophiles could be reacted with the corresponding
N-chloromethylpyrazole, since it would not be necessary
for the group introduced as the nucleophile to activate
the C-a site or to stabilize the carbanion formed.
Consequently, the various pyrazole-CH^-Nu systems would be
capable of undergoing the transformations mentioned in
Scheme 4.3. If the nucleophile were such that there was an
electrophilic site "beta" to the carbanion generated, it

133
was hoped that the system would undergo the rearrangements
discussed in Section 4.2.2.3. 3,5-Dimethylpyrazole thus
seemed to be a suitable heterocycle to be investigated.
Hiittel and Jochum [52CB820] showed that a variety of
C-substituted-N-unsubstituted pyrazoles reacted with
formaldehyde to give the corresponding N-hydroxymethyl
derivatives, including 3,5-dimethyl-l-hydroxymethyl-
pyrazole (4.30), the preparation of which was also
reported by Dvoretzky and Richter [50JOC1285] starting
from 3,5-dimethylpyrazole (4.29). The conversion of 4.30
to the chloromethyl derivative (isolated as the
hydrochloride salt) 4.31 (Scheme 4.12) was first reported
in the patent literature [63FRPl331721] and later utilized
by Rüfenacht [73HCA2186] as a precursor to various
thiophosphates for use as insectides. Similar work has
been done on other chloromethylpyrazole derivatives
[82EUP51784, 82GEP3122174]. However, there have been no
apparent attempt to use l^chloromethylpyrazoles as general
intermediates for more complex N-substituted pyrazoles.
Once synthesized, the chloromethylpyrazole 4.31 was
expected to react with nucleophiles under conditions
described in the literature for 1-chloromethyl-
benzotriazole [87J(PI)781] or those used for the synthesis
of 1-(phenylthiomethyl)benzimidazole described in Section
2.2.1. The phenylthio group has shown promise in a number
of azole systems where otherwise lithiations have been

134
difficult to achieve (see Section 2.1.3). The
phenylsulfenyl group being stable towards lithiation
should be a good nucleophile to use for attempting the
transformations 4.31 > 4.34 as depicted in
Scheme 4.13.
4.31
Scheme 4.12
For simplicity, the selection of suitable nucleophiles
was based on two aspects. In addition to having variety
(so as to demonstrate the usefulness of the
1-chloromethylpyrazoles 4.31 as general intermediates),

135
the nucleophile should also be of the type —X-C(=Z)- so
that the carbanionic rearrangements could be attempted on
these same systems.
4.31
ch3
4.32
NaOEt / PhSH
BOH
1) Base
2) (EV
4.33
4.34
Scheme 4.13
Based upon the systems utilized in the literature, one
of the sulfur nucleophiles selected was N,N-diethyl-
dithiocarbamate. The availability of 2-mercaptobenzo-
thiazole in our laboratory prompted its use as the other
sulfur nucleophile. Treatment of the corresponding
pyrazole derivatives 4.35 or 4.36 with LDA was expected to
give the thiirane ring intermediates 4.37 and 4.38. Ring

136
opening as depicted in Schemes 4.4 or 4.5 would then give
the corresponding products 4.39 or 4.40 (Scheme 4.14).
Scheme
4.4 or 4.5
?
Products
4.39
Scheme
4.4 or 4.5
?
Products
4.40
Scheme 4.14

137
Treatment of l-chloromethyl-3,5-dimethylpyrazolium
chloride (4.31) with 4,6-diphenyl-2-pyridone (4.41) in the
presence of base should give the N-substituted adduct
4.42. Treatment of derivative 4.42 with organolithium
would generate the C-a carbanion which could attack the
carbonyl group to give the three-membered aziridine
intermediate 4.43. Depending upon the leaving group
ability of the pyrazole, rearrangement of the bicyclic
intermediate 4.43 was expected to form the azepin-3-one
4.44 or the derivative 4.45 which still contained the
heterocycle (Scheme 4.15).
Consequently, if it was also possible to promote
O-alkylation from the pyridone nucleophile to afford 4.46,
then rearrangement of the carbanion would possibly give
pyridine carboxaldehyde 4.48 (Scheme 4.4; Route A) or the
corresponding alcohol 4.49 (Scheme 4.4; Route B) via the
oxirane intermediate 4.47 (Scheme 4.16). However, it would
be necessary to use LDA as the base here since it has been
shown [85TH1] that the anion generated from 2-(phenylthio-
methoxy)-4,6-diphenyl-2-pyridone with n-butyl1ithium
decomposes at higher temperatures to form 4,6-diphenyl-
2-pyridone and possibly phenylthiomethane carbene.
In all the rearrangements discussed above, the
presence of a heterocyclic moiety has the added advantage
that it could also be a good leaving group. Consequently,

138
4.44
Scheme 4.15
4.45

139
in addition to the products obtained via the
rearrangements discussed in the literature, loss of the
heterocycle was expected to give rise to a different class
of products from those obtained in the literature. Thus
these rearrangements were expected to be a good method for
the insertion of a carbon atom into an X-Y bond in systems
of type -X—Y=Z.
CH3
ch3
h3c
LDA
H3C
Ph
Ph
OHC
Ph
Scheme 4.16

140
Depending upon the successes of these systems, it
would be interesting to investigate reactions where the
electrophilic site Y would be at the "delta" position as
in 4.50 rather than at the "beta" position. Rearrangement
would then give the corresponding derivatives 4.52 similar
to that observed above but via the five-membered ring
intermediate 4.51 (Scheme 4.17).
M= X
Scheme 4.17
4.52
4.2 Results and Discussion
4.2.1 Reactions of 3,5-Dimethyl-1-(phenylthiomethy1)-
pyrazóle
l-Chloromethyl-3,5-dimethylpyrazolium chloride (4.31)
was prepared in three easy steps starting from

141
2,4-pentanedione (4.53). Treatment of the diketone 4.53
with hydrazine hydrate (4.54) under conditions employed by
Rothenberg [1894CB1097] afforded 3,5-dimethylpyrazole
(4.29) as large flakes from petroleum ether in a yield of
95%. Heating the pyrazole 4.29 with paraformaldehyde at
110°C [50JOC1285] afforded the corresponding hydroxymethyl
derivative 4.30 which was then treated with thionyl
chloride in dry chloroform at -20 to -10°C [73HCA2186] to
give the chloromethylpyrazole 4.31 isolated as the
hydrochloride salt in almost quantitative yield. The
reaction of the chloride 4.31 with thiophenol utilizing
the conditions employed for the benzimidazole analog (see
Section 2.2.1) gave 3,5-dimethyl-l-(phenylthiomethyl)-
pyrazole (4.32) as a yellow oil in 72% yield
(Scheme 4.18) .
Treatment of the sulfide 4.32 with LDA at -78°C
generated the carbanion which was then trapped with methyl
iodide, with benzyl bromide, or with 4-methylbenzaldehyde
to give the corresponding methyl, benzyl and
hydroxythioether derivatives 4.33a-c, respectively, in
yields of 50-55% (Scheme 4.19).

+ n2h4h2o
EtOH
H30Y"r0H3
o o
4.53
(CH20)n
110°C
4.54
4.29
SOCI2
4.30
NaOEt / PhSH
BOH
4.31
4.32
Scheme 4.18
The use of n-butyl1ithium as base and leaving the
reaction mixture overnight at ambient temperature (after
addition of the electrophile) increased the yields to
about 70%. The methyl derivative 1-{3,5-dimethylpyrazol-
1-yl)-l-(phenylthio)ethane 4.33a when reacted with anothe
equivalent of n-butyllithium and benzyl bromide afforded

143
the benzylated adduct 4.34 as plates in 72% yield
(Scheme 4.20). Compound 4.34 was characterized by its
^H-NMR spectrum which showed the loss of the methine
quartet at 65.4. However, since a chiral center exists,
the adjacent methylene protons are not equivalent with
each appearing as a doublet 0.8 ppm apart.
4.32
4.33
Scheme 4.19
4.33a
4.34
Scheme 4.20

144
The benzylated derivatives 4.33b and 4.34 and the
hydroxyethylpyrazole 4.33c were subjected to Raney-Nickel
desulfurization to give the corresponding alkyl- and
hydroxyalkyl-pyrazoles 4.55 in about 70% yields
(Scheme 4.21) .
4.55
(a) R1 = H, R2 = PhCH2
(b) R1 = CH3, R2 = PhCH2
(C) R1 = H, R2 = 4-MeC6H4CH(OH)
Scheme 4.21
The ABX pattern in the 1H-NMR spectrum of 4.33b
simplified into two sets of triplets due to the loss of
the chiral center at the C-a position in 3,5-dimethyl-
1-(2-phenylethyl)pyrazole (4.55a). For the disubstituted
derivative 4.55b, the change from a quaternary to a
tertiary carbon caused the adjacent methylene protons to
each resonate as double doublets. However, the resonances
were only 0.27 ppm apart.
In all cases, no decompositions, ring lithiations, or
ring openings were observed. These results were

145
encouraging in that it seemed the pyrazole was
sufficiently stable and would be a good heterocycle with
which to attempt the rearrangements.
4.2.2 Reaction of l-Chloromethyl-3,5-dimethylpyrazolium
Chloride with S-, N-, and O-Nucleophiles
4.2.2.1 Reaction with sulfur nucleophiles
The reaction of l-chloromethyl-3,5-dimethylpyrazolium
chloride (4.31) with 2-mercaptobenzothiazole (4.56) was
carried out in the presence of two equivalents of sodium
ethoxide under conditions similar to that for the
phenylthio derivative 4.32 prepared earlier. Work up of
the reaction mixture gave a red solid which was
recrystallized from ethanol/water to afford
l-(benzothiazol-2-ylthio)me thy1-3,5-dimethylpyrazole
(4.35) as tan plates in 71% (Scheme 4.22). On the other
hand, the sodium salt of N,N-diethyldithiocarbamic acid
(4.57) was treated with 4.31 to give the corresponding
adduct 4.36 as a yellow oil in 90%.
4.2.2.2 Reaction with nitrogen and oxygen nucleophiles
In a preliminary experiment, 2-pyridone (4.59) was
treated with the chloride 4.31 under conditions similar to
those for the sulfur nucleophiles. The ^H-NHR spectrum of

146
the crude material showed it to be a mixture of two
compounds one of which was 3,5-dimethyl-l-ethoxymethyl-
pyrazole (4.58). It seemed that in the case of nitrogen
nucleophiles, the ethoxide ion also competes as a
nucleophile. This behavior was not observed with the
stronger sulfur nucleophiles. Hence it was necessary to
use a non-nucleophi1ic base for the 2-pyridone systems.
Consequently, the ethoxy derivative 4.58 was obtained in a
pure state by heating a solution of the chloromethyl-
pyrazole 4.31 with two equivalents of sodium ethoxide
under reflux in ethanol (Scheme 4.23).
CH3
4.57 4.36
Scheme 4.22

147
4.31
4.58
Scheme 4.23
With sodium hydride as the base and THF as the
solvent, 2-pyridone (4.59) was reacted with the chloride
to give the corresponding N-alkylated derivative 4.60
(Scheme 4.24). The pyrazolylmethylpyridone 4.60 was
characterized by its ^C-NMR spectrum which displayed the
methylene resonance at 57.5 ppm indicating an N-Cf^-N
linkage, while the carbonyl resonance was observed at
161.5 ppm.
CH3
4.31 4.59 4.60
Scheme 4.24

148
Compound 4.60 had the required skeletal system for the
carbanionic rearrangement. However, the 4- and 6-
positions of the pyridone ring are succeptible to
metallation and thus needed to be blocked.
3-Cyano-4,6-diphenyl-2-pyridone (4.61a) (which is an
intermediate in the preparation of 4,6-diphenyl-
2-pyridone), was treated with the pyrazole 4.31 under
conditions similar to those for the 2-pyridone case.
Surprisingly, the O-alkylated derivative 4.63a was also
obtained in addition to the N-substituted pyridone 4.62a
(Scheme 4.25). The formation of the O-alkylated product
was attributed to the steric hindrance at the nitrogen
atom by the 6-phenyl group.
Compounds 4.62a and 4.63a were characterized by their
^H— and l^C-NMR spectra. In the proton spectra, the
methylene resonance for the N-alkylated product 4.62a was
observed at 66.00 which was about 0.6 ppm upfield from the
O-substituted adduct 4.63a. Furthermore, the C-5 proton in
the pyridone ring was observed at 66.40 while that for the
pyridine ring in 4.63a resonated downfield with the other
aromatics. The ^C-NMR spectrum of 4.62a displayed the C-a
resonance at 56.2 ppm which was similar to that observed
for 4.60. For compound 4.63a, the C-a signal resonated at
73.5 ppm indicating attachment to a more electronegative
atom. This further strengthened the suggestion that
O-alkylation had occurred.

149
4.61
(a) x = cn
(b) x = H
+
4.62
(a) x=cn
(b) x = H
4.63
(a) x = cn
(b) x = H
Scheme 4.25
A similar result was obtained when the chloride 4.31
was treated with 4 ,6-diphenyl-2-pyridone (4.61b). In
addition to the N-alkylated derivative 4.62b, the
O-alkylated product 4.63b was also formed (Scheme 4.25).
The two isomers were characterized by their ~H- and
13
C-NMR spectra which displayed a pattern similar to their
corresponding cyano analogs 4.62a and 4.63a.

150
4.2.3 Attempted Carbanionic Rearrangements via Three-
Membered Cyclic Intermediates
4.2.3.1 The g-2-mercaptobenzothiazole adducts
In a preliminary experiment, (benzothiazol-2-ylthio)-
methyl-3,5-dimethylpyrazole (4.35) was treated with LDA at
-78°C and to the dark brown solution was added benzyl
bromide. Work up of the reaction afforded a mixture.
Attempts to separate the mixture by chromatography proved
futile since the products decomposed or possibly
polymerized to give uncharáeterizable gums. The use of
longer reaction times did not alter the outcome. The
â– '"H-NMR of the crude mixture did reveal attack at the C-oc
site (as estimated by the integrated "'‘H-NMR). However, the
presence of singlets at 63.91 and 5.1 and the absence of
an ABX pattern indicated no formation of a benzylated
product. When the more reactive electrophile methyl iodide
was used, again a mixture was obtained which also
decomposed during attempted separation.
In an attempt to see if any rearrangement would occur,
the anions were generated at -78°C and warmed to -40°C,
-20°C and 0°C before being quenched with water. In all
cases, in the ^H-NMR spectra of the crude mixtures, a
decrease in the intensity of the methylene resonance was
observed. The decrease in the intensity was greater for
the higher temperatures indicating that some reaction was
occurring. However, in all cases, the products isolated

151
were either uncharacterizable gums or products that
decomposed or polymerized during column chromatography.
None of the expected rearranged products 4.64-4.66 were
obtained (Scheme 4.26).
4.65
4.66
Scheme 4.26
In one isolated instance, the
1
H-NMR spectrum of one
of the fractions isolated did hint at the possibility of

152
the thiol 4.64 being formed. Unfortunately, this product
was unstable and thus further characterization was not
possible. Furthermore, the above result was not
reproducible. Consequently, further investigation in this
direction was not attempted.
4.2.3.2 The «-N,N-diethyldithiocarbamate adducts
In a preliminary experiment, the dithiocarbamate 4.36
was treated with LDA at -78°C and the reaction mixture
quenched with D2°- Work up gave a mixture. The major
fraction which accounted for about 50% of the mixture was
the mono-deuteriated product 4.67 whose presence implied
that at -78°C, no rearrangement occurred (Scheme 4.27).
Another fraction isolated was a colorless, smelly liquid.
Its ^H-NMR spectrum only displayed the N-ethyl signals
indicating cleavage of the carbon-sulfur bond. Since this
seemed to be just a minor byproduct, it was not fully
characterized.
4.36 4.67
Scheme 4.27

153
It seemed that higher temperatures were necessary for
the rearrangement to occur. The dithiocarbamate 4.36 was
thus treated with LDA at -78°C and the reaction mixture
stirred overnight at ambient temperature. Work up with
water gave a mixture of three products. The first fraction
which amounted to about 5% by weight of the total mixture
again displayed only the N-ethyl resonances and thus
seemed similar to the byproduct obtained in the previous
reaction.
The ^H-NMR spectrum of the second fraction (a yellow
smelly oil) showed presence of both the pyrazole group as
well as the N,N-diethyldithiocarbamate system. However,
the high integration ratio of the ethyl groups as compared
to the rest of the molecule, hinted at the possibility of
two such groups being present in the molecule. The methine
proton resonated downfield at 67.79.
This assumption was further strengthened by the
â– ^C-NMR spectrum of the oil which displayed two resonances
at 191 and 192.8 ppm implying the molecule had two
thiocarbonyl groups. A methine resonance was observed at
74.4 ppm. In the aliphatic region, four resonances each
for the methylene and for the methyl carbons of the
N-ethyl group were observed. It is known that allyl
carbanions of N,N-diethyldithiocarbamates (4.68) undergo
thiocarbomylsulfenylation at the a-carbon [75S727] with
tetraethylthiuram disulfide (4.69) to give the

154
intermediate 4.70 which undergoes a [3,3]-sigmatropic
rearrangement to form bis[N,N-diethylthiocarbamoylthio]-
1-alkenes (4.71) (Scheme 4.28).
4.70
Et2N
S R2
NEt2
Scheme 4.28
It was mentioned earlier, that the first fraction
isolated only displayed the N-ethyl resonances. Hence it
could be possible that the disulfide 4.69 might be a
byproduct which reacted with the carbanion to give an
intermediate of type 4.70. However, due to the absence of
an allyl group, further rearrangement could not occur and
the reaction stopped at compound 4.72 (Scheme 4.29).

155
Scheme 4.29
4.72
Since higher temperature appeared to be the cause of
this product being formed, it was decided to try slightly
milder conditions and methyl iodide as the electrophile.
In a trial run, the anion was kept at temperatures of
-40°C, -25°C and -5°C before being quenched with methyl
iodide. Thin layer chromatography of the three mixtures
showed that while for the reaction at -40°C some starting
material was still present, the reaction went to near
completion at -5°C.
The anion was thus formed at -78°C, kept at -78°C for
lh and then stirred at -5°C for 4h before being quenched
with methyl iodide. Purification by chromatography gave a
smelly colorless liquid as the first fraction. The ^H- and
â– ^C-NMR spectra showed it to be methyl N,N-diethyl-
dithiocarbamate (4.73) which was isolated in a 22% yield
(Scheme 4.30) .

156
CH3
4.36
-5°C
LDA
NEt2
(?)
S
4.73
4.74
Scheme 4.30
The next major fraction displayed (together with the
signals corresponding to the pyrazole ring and the -NEt-,
unit) a methine singlet at 56.48 and another singlet at
1
52.44 in the
H-NMR spectrum. This strongly hinted at a
rearrangement to give (4.74). However, the low stability
prevented complete characterization of this compound.
Although the dithiocarbamate system seemed more
promising, the instability and unpleasant odors arising
from the reaction products did not make this system as
attractive as it was hoped.
4.2.3 . 3 The a-2-pyridone adducts
The lithiation of 2-[(3,5-dimethylpyrazol-l-yl)-
methoxy]-4,6-diphenylpyridine (4.63b) was carried out with
LDA and the anion quenched with water at -78°C. However,
the only product isolated was the starting material. When

157
the anion was kept at ambient temperature for 12h before
being treated with water, no reaction was observed.
These observations displayed no hint of any type of
rearrangement occuring, indicating that formation of the
oxirane ring was unlikely. This was in contrast to the
dithiocarbamate derivative 4.36 where while there was some
hint of a thiirane ring as an intermediate, the products
were not stable enough to be characterized.
Based upon the successful results by Katritzky e_t al .
[80J(PI)2851 ] for 1-(a-methylbenzyl)-4,6-diphenyl-
2-pyridone (4.16) (Section 4.2.2.3), a similar reaction
was attempted on the corresponding pyrazole analog 4.62b.
Treatment of 4.62b with LDA at -78°C afforded a pale
yellow solution which stirred at ambient temperature for
lh (as for the 1-benzyl analog 4.16) before being quenched
with water. Work up afforded mixtures which gave
decomposition products and uncharacterizable gums upon
attempting purification.
This result was very discouraging since even the
closest analogy failed. Furthermore, since the entire
rearrangement scheme showed very little promise, further
investigations on these systems or the search for
different systems were not attempted.

158
4 . 3 Conclusions
At the onset of this project, the selection of
3.5-dimethylpyrazole as the heterocyclic system seemed
promising since it was one of the few azoles that
underwent lithiation at the C-a site.
It was even more encouraging when 3,5-dimethyl-
1-(phenylthiomethyl)pyrazole underwent lithiation quite
readily with both LDA as well as butyl1ithium. Raney-
Nickel desulfurization afforded the corresponding 1-alkyl-
and 1-(hydroxyalkyl)-pyrazoles in good yields.
In Section 4.2.2, the ability of 1-chloromethyl-
3.5-dimethylpyrazolium chloride to react with various
nucleophiles was aptly demonstrated.
Unfortunately, there was a complete lack of success in
the attempted rearrangements for any of the systems. The
most promising was the dithiocarbamate adduct. However,
the low stability and unpleasant odors of the products,
decreased the attractiveness of this system.
On the other hand, this failure does not eliminate the
synthetic utility of N-chloromethylheterocycles as
precursors since we have observed a wide range of
reactivity in the pyrazole analog (Scheme 4.31).
Furthermore, the results obtained here should encourage
attempts to use 1-chloromethylheterocycles as general
intermediated for more complex 1-substituted-methyl
heterocycles.

159
PyrH
PyrCH2OH
PyrCH2-NR9
4.29
PyrCH2-SR
4.30
4.60
4.62
PyrCH2CI.HCI
PyrCH2-OR
4.35
4.36
4.31
4.58
4.63
PyrCH2-SPh
4.32
PyrC(R1)(R2)SPh — PyrCH(R1)R2
4.33 4.55
4.34
ch3
Scheme 4.31

160
4.4 ExDerimental
4.4.1 Apparatus and Experimental Procedures
The apparatus and general procedures used in this
Chapter are identical to those described in the previous
two chapte rs.
4.4.2 Preparation of Known Compounds
The following compounds were prepared by known
literature methods: 3,5-dimethylpyrazóle (4.29), m.p. 106-
10 8 0 C; (lit., [1894CB1097] m.p. 105-108°C);
l-hydroxymethyl-3,5-dimethylpyrazole (4.30), m.p. 105-
107°C; (lit., [50JOC1285] m.p. 108-109°C); 1-chloromethyl-
3,5-dimethylpyrazolium chloride (4.31) [73HCA2186];
Su 16.13 (1H, s), 6.50 (3H, bs), 2.66 (3H, s), and 2.59
n
(3H, s); 3-cyano-4,6-diphenyl-2-pyridone (4.61a), m.p.
318-319°C; (lit., [30JIC490] m.p. 318-320°C).
4.4.3 4,6-Diphenyl-2-pyridone (4.61b)
4,6-Diphenyl-2-pyrone [25CB2318] (10 g, 40 mmol) and
ammonium acetate (31 g, 400 mmol) were heated at 150°C for
60h. On cooling, chloroform (100 ml) was added and the
organic layer washed with saturated sodium bicarbonate
(2 x 25 ml), water (2 x 25 ml), dried (MgSO, ), and the
solvent removed to afford tan microcrystals (8.11 g, 8 2%) ,
m.p. 205-207°C; (lit., [30JIC490] m.p. 207-208°C).

161
4.4.4 l-Ethoxymethyl-3,5-dimethylpyrazóle (4.58)
To a solution of sodium ethoxide (1 M in ethanol,
60 ml, 60 mmol) was added slowly 1-chloromethyl-
3,5-dimethylpyrazolium chloride (4.31) (5.0 g, 27 mmol).
The reaction mixture was then heated under reflux for 12h.
The solvent was removed in. vacuo and chloroform (50 ml)
added to the residue. The mixture was washed with water
(3 x 20 ml), dried (MgSO^), and the solvent removed to
leave behind a pale yellow oil. Distillation under vacuum
gave 4.58 as a colorless liquid (2.96 g, 70%), b.p./mm
98 0 C/31mm; 6U 6.03 (1H, s), 5.50 (2H, s), 3.61 (2H, q, J =
7 Hz), 2.36 (3H, s), 2.28 (3H, s), and 1.16 (3H, t, J = 7
Hz); Sc 147.4, 139.4, 106.0, 77.3, 63.5, 14.3, 13.0, and
10.1.
4.4.5 General Procedure for the Reaction of 1-Chloromethyl-
3,5-dimethylpyrazolium Chloride with Sulfur
Nucleophiles
To a solution of sodium ethoxide (1 M in ethanol,
150 ml, 150 mmol) at 0°C was added the corresponding
sulfur nucleophile (75 mmol). After 0.5h, 1-chloromethyl-
3,5-dimethylpyrazolium chloride (4.31) (70 mmol) was added
slowly and the mixture stirred at ambient temperature for
3h. The solvent was then removed _in vacuo and the residue
treated with water (75 ml). The organic material was
extracted with chloroform (3 x 50 ml), dried (MgSO^), and
the solvent removed to give the crude product.
The following compounds were prepared in this manner:

162
4 . 4 . 5.1 l-(Phenylthio)methyl-3,5-dimethylpyrazole (4.32)
Thiophenol and (4.31) gave a pink oil which was
purified by distillation to give a pale yellow oil (72%),
b.p./mm 138-140°C/0.85; 7.7-7.3 (5H, m), 5.93 (1H, s),
5.43 (2H, s), 2.26 (3H, s), and 1.93 (3H, s); 148.2,
139.4, 133.5, 132.8, 128.8, 128.0, 105.8, 53.4, 13.3, and
10.4.
4 . 4.5.2 l-(Benzothiazol-2-ylthio)methyl-3,5-dimethyl-
pyrazole (4.35)
From 2-mercaptobenzothiazole (4.56) and (4.31) a red
solid was obtained which was crystallized from ethanol/-
water to give tan plates (71%), m.p. 96-98°C; (Found:
C, 56.62 ; H, 4.70; N, 15.02. re(3uii:es C' 56.69;
H, 4.76; N, 15.26%); S0 8.1-7.6 (2H, m), 7.6-7.3 (2 H, m),
rl
6.10 (2H, s), 5.90 (1H, s), 2.36 (3H, s), and 2.26
(3H, s).
4.4.6 l-(N,N-Diethyldithiocarbamy1)methyl-3,5-dimethyl-
pyrazole (4.36)
To a solution of sodium diethyldithiocarbamate
trihydrate (4.57) (9.75 g, 43.5 mmol) in ethanol (150 ml)
was added l-chloromethyl-3,5-dimethylpyrazolium chloride
(4.31) (3.75 g, 20.7 mmol), and the mixture stirred
overnight at ambient temperature. The solvent was then
removed .iri vacuo and the residue treated with water
(100 ml). The organic material was extracted with
chloroform (3x25 ml), dried (MgSO^), and the solvent

163
removed to afford the crude mixture as an oil.
Purification by chromatography (chloroform/hexanes 2:1)
gave (4.36) as a yellow oil (4.62 g, 87%); 6^ 5.95
(2H, s),
5.
81
( 1H,
s) ,
4.01
( 2H,
q*
J 7 Hz), 3.70
(2H, q,
J 7 Hz ) ,
2 .
34
( 3H,
s ) ,
2.21
( 3H,
s )
, and 1.26 (6H,
t, J 7
Hz); 5C
192
.3,
149
.1,
140.2,
106
.1,
55.2, 49.2, 46
.7,
13.4, 12
.4,
11
• 3,
and
11.2.
4.4.7 General Procedure for Lithiation with n-Butyllithium
and Subsequent Treatment with Electrophiles
To a solution of the corresponding precursor (10 mmol)
in dry THF (100 ml) at -78°C was added dropwise
n-butyl1ithium (2.5M in hexanes, 4.4 ml, 11 mmol) and the
resulting solution stirred at that temperature for 2h. To
this solution of the corresponding lithio derivative was
added a solution of the electrophile (10.5 mmol) in dry
THF (10 ml) and the resulting solution stirred at -78°C
for 6h and at ambient temperature for 12h. The reaction
mixture was then poured into saturated aqueous ammonium
chloride (75 ml) and the layers separated. The aqueous
layer was washed with Et-,0 ( 3 x 25 ml), the combined
organic extracts washed with water, dried (MgSO^), and the
solvent evaporated to give the crude product, which was
then purified.
The following compounds were prepared in this manner:

164
4.4.7.1 l-(3,5-Dimethylpyrazol-l-yl)-l-(phenylthio)ethane
(4.33a)
Obtained from 4.32 and methyl iodide as a colorless
oil purified by column chromatography (chloroform/hexanes
2:
1);
( 66
% )
; SH 7.20 (
5H, m), 5.65 (1H,
s) ,
5.
40
(1H, q, J
7
Hz )
, 2.
25
(3H, s ) , 1
.91 (3H, d,
J 7 Hz),
and
1.
70
( 3H ,
s ) ;
6C
148.2, 139
. 5 , 135.1,
132.3,
128
• 6,
105.0 ,
61
.4,
21.
2,
13.6, and
10.3.
4 .
4.7
.2
1-
( 3,5-Dimethylpyrazol-l
-yl)-2
-phe
nyl
-1-
(phenyl-
x — \ j , j-uimc my i a
thio)ethane (4.33b)
Benzyl bromide and 4.32 gave 4.33b as colorless
needles from n-pentane (74%), m.p. 69-70°C; (Found
C, 74.06; H, 6.78; N, 8.94. CigH7C)N2S requires C, 73.98 ;
H, 6.54; N, 9.08%); 6U 7.3-7.1 (8H, m), 7.0-6.9 (2H, m),
ri
5.52 (1H, s), 5.28 (1H, dd, J 4.5 Hz, 9.8 Hz), 3.71
(1H, dd, J 9.8 Hz, 13.6 Hz), 3.36 (1H, dd, J 4.5 Hz, 13.6
Hz), 2.30 (3H, s), and 1.36 (3H, s).
4 . 4 . 7 . 3 2-(3,5-Dimethylpyrazol-l-yl)-!-(4-methylphenyl-
2-(phenylthio)ethanol(4.33c)
4-Methylbenzaldehyde and 4.32 afforded the alcohol as
colorless microcrystals from n-pentane (63%), m.p. 123-
12 4 0 C; (Found C, 70.90 ; H, 6.81; N, 8.12. C^H^N^S
requires C, 70.97; H, 6.55; N, 8.28%); &0 7.57 (5H, s),
H
7.26 (4 H, s), 6.3-6.0 (1H, m, OH), 5.73 (1H, s), 5.6-5.4
(2H, m), 2.33 (6H, s), and 1.30 (3H, s).

165
4.4 . 7 . 4 2- (3,5-Dime thylpyrazol-l-yl)-1-phenyl-2-(phenyl-
thio)propane (4.34)
Compound 4.33a and benzyl bromide gave the product as
a colorless oil which slowly solidified. Crystallization
from n-pentane gave colorless plates (72%), m.p. 64-66°C;
(Found C, 74.51; H, 7.12; N, 8.33. C2qH-,2N-,s requires
C, 74.49 ; H, 6.88; N, 8.69%); Su 7.3-7.1 (6H, m), 7.05-
6.95 (2H, m), 6.95-6.85 (2H, m), 5.83 (1H, s), 4.03
(1H, d, J 14 Hz), 3.21 (1H, d, J 14 Hz), 2.36 (3H, s),
2.15 (3H, s), and 1.73 (3H, s).
4.4.8 General Procedure for the Raney-Nickel
Desulfurization
To a solution of the corresponding sulfide (2 mmol) in
ethanol (20 ml) was added Raney-Nickel (ca. 3 g). The
mixture was heated under reflux for 12h. The Raney-Nickel
was then filtered off and the solvent removed iji vacuo to
give the crude product. Purification by column
chromatography (chloroform:hexanes, 1:1) afforded the pure
products. The following compounds were prepared in this
manne r :
4.4.8.1 l-(3,5-Dimethylpyrazol-l-yl)-2-phenylethane (4.55a)
A yellow liquid (68%); S„ 7.4-7.0 (5H, m), 5.73
ri
( 1H,
s ) ,
4.16 (2H,
t , J 7 Hz), 3.06 (2H, t, J 7 Hz ) ,
r 2.30
( 3H ,
S ) ,
and 1.86
(3H, s).

166
4.4.8.2 2-(3,5-Dimethylpyrazol-l-yl)-l-phenylpropane
(4.55b)
A yellow oil (70%); S„ 7.2-7.1 (3H, m), 6.9-6.8
(2H, m), 5.61 (1H, s), 4.3-4.1 (1H, m), 3.18 (1H, dd, J 9,
13.2 Hz), 2.92 (1H, dd, J 5.3, 13.2 Hz), 2.26 (3H, s),
1.72 (3H, s), and 1.54 (3H, d, J 7 Hz); 146.9, 138.7,
138.6, 128.8, 128.0, 126.1, 103.9, 55.2, 43.4, 20.7, 13.5,
and 10.6.
4 . 4.8.3 1-(4-Methylphenyl)-2-(3,5-Dimethylpyrazol-l-yl)-
ethan-l-ol (4.55c)
Colorless microcrystals (68%), m.p. 125-126°C; (Found:
C, 73.10; H, 7.89. C^^H^gN^O requires C, 73.01; H, 7.88%);
S„ 7.18 (2H, AB, 8.4 Hz) , 7.11 (2H, AB, J._ 8.4 Hz) ,
5.74 (1H, s), 5.01 (1H, m), 2.32 (3H, s), 2.19 (3H, s),
and 1.98 (3H, s ) .
4.4.9 General Procedure for the Reaction of 1-Chloromethyl-
3,5-dimethylpyrazolium Chloride with Pyridones
To a suspension of NaH (60% in mineral oil; 55 mmol)
in THF (150 ml) was added the corresponding pyridone
(27.5 mmol). After stirring at ambient temperature for
0.5h, l-chloromethyl-3,5-dimethylpyrazolium chloride
(4.31) (25 mmol) was added slowly, and the mixture allowed
to react further. The solvent was then removed in vacuo
and the residue treated with water (75 ml). The organic
material was extracted with chloroform (3 x 50 ml), dried

167
(MgSO^), and the solvent removed to give the crude
product.
The following reactions were thus carried out:
4.4.9.1 Reaction with 2-Pyridone
The reaction mixture was heated under reflux for 48h,
followed by the general work up to give the crude product
as a brown wax. Crystallization from ethyl acetate
afforded l-(3,5-dimethylpyrazol-l-yl)methylpyrid-2-one
(4.60) as brown needles (32%), m.p. 131-132°C; (Found:
C, 65.21; H, 6.59; N, 20.35. cnH]^3N30 requires C, 65.01;
H, 6.45; N, 20.68%); 6U 7.9-7.3 (2H, m), 6.8-6.1 (4H, m),
ri
6.00 (1H, s), 2.43 (3H, s), and 2.23 (3H, s); 6C 161.5,
149.2, 140.5, 139.9, 138.7, 136.3, 120.6, 106.3, 105.9,
102.7, 57.5, 13.2, and 10.5.
4.4.9.2 Reaction with 3-Cyano-4,6-diphenyl-2-pyridone
3-Cyano-4,6-diphenyl-2-pyridone (4.61a) and (4.31)
gave after work up a mixture of two products which were
separated by column chromatography (chloroform/hexanes
3:1) ;
The first product isolated (R^ = 0.41) was characterized
as 3-cyano-2-(3,5-dimethylpyrazol-l-yl)methoxy-
4,6-diphenylpyridine (4.63a), colorless needles (35%),
m.p. 153-154 °C; (Found: C, 75.98 ; H, 5.45; N, 14.50.

168
C24H20N4° requires C, 75.76 ; H, 5.30; N, 14.73%); 8.4-
8.1 (2H, m), 7.8-7.3 (9H, m), 6.57 (2H, s), 6.00 (1H, s),
2.43 (3H, s), and 2.27 (3H, s); Sc 162.9, 157.9, 157.0,
149.3, 140.9, 136.9, 136.0, 130.6, 130.0, 128.9, 128.8,
128.3, 127.4, 114.6, 114.4, 107.1, 93.6, 73.5, 13.4, and
10.8.
Fraction 2 (R^ = 0.14), 3-cyano-l-(3,5-dimethylpyrazol-
l-yl)methyl-4,6-diphenylpyrid-2-one (4.62a), colorless
microcrystals (20%), m.p. 198-200°C; (Found: C, 75.55;
H, 5.
28 ;
N,
14
.42.
C2 4
H20N4°
requires
C, 7 5.76 ? H,
N, 14
.73
%) ;
SH
7.9
-7.4
( 10H,
m) ,
6.40
(1H, s), 6.00
(2H,
s ) ,
5.
80
( 1H,
s ) ,
2.33
( 3H,
s ) ,
and 2.13 (3H,
6C 161.0, 159.0, 154.1, 148.9, 141.3, 135.3, 133.6, 130.7,
130.1, 129.2, 128.8, 128.6, 128.1, 115.7, 110.0, 105.3,
101.0, 56.2, 13.7, and 10.7.
4.4.9.3 Reaction with 4,6-Diphenyl-2-pyridone
The reaction mixture gave, after 18h at ambient
temperature and the general work up, a mixture of two
compounds separated by column chromatography (chloroform/-
hexanes 3:1):
Fraction 1 (R^ = 0.53), isolated as a colorless oil and
characterized as 2-(3,5-dimethylpyrazol-l-yl)methoxy-
4,6-diphenylpyridine (4.63b) (44%); (Found: M+, m/z
355.1685. requires 355.1676 ; 6^ 8.3-8.1 (2H, m),
7.8-7.2 (9H, m), 7.06 (1H, s), 6.50 (2 H, s), 6.00 (1H, s),
2.36 (3H, s), and 2.30 (3H, s), 6C 162.5, 155.0, 152.4,

169
149.4, 140.6, 138.8, 138.3, 129.0, 128.6, 126.9, 126.8,
112.7, 107.4, 106.6, 72.4, 13.5, and 10.8.
Fraction 2 (R^ = 0.21), characterized as 1-(3,5-dimethyl-
pyrazol-l-yl)methyl-4,6-diphenylpyrid-2-one (4.62b),
colorless needles (21%), m.p. 160-161°C; (Found: C, 77.68;
H, 6 .
01;
N,
11
.68.
C2 3
H21N3
0
requires
c,
77 .
72;
H , 5 .
N, 11
.82
%) ;
SH
7.6-
-7.5
( 4H,
in
) ,
7.5-7
. 3
( 6H,
m) ,
6.76
( 1H,
d,
J 2
Hz
) , 6,
. 37
( 1H,
d,
J
2 Hz )
, 5
.95
( 2H,
s ) ,
( 1H,
s ) ,
2 .
22
( 3H,
s ) ,
and
2 .
10
( 3H,
s ) .

CHAPTER V
SUMMARY
Nitrogen heterocycles or more specifically, azoles were
used to promote carbanionic reactions at the C-a position
in N-(substituted methyl)azoles.
In Chapter II, the lithiation of benzimidazole
derivatives was discussed. The 2-position of the
benzimidazole ring is prone to lithiation and consequently,
a lot of 2-substituted benzimidazoles are known. On the
other hand, alkylation at the N-methyl site is less common.
The use of a strong activating group to stabilize the
carbanion at the C-a site was required.
Consequently, lithiation of 1-(phenylthiomethyl)-
benzimidazole was attempted. Moderate success was achieved
when the less reactive electrophile benzyl bromide reacted
at the C-a site. However, aldehydes, ketones, and methyl
iodide afforded the 2-substituted products. Increasing the
kinetic acidity by oxidizing the sulfide to the sulfoxide
or sulfone helped in achieving regioselective metallation.
The other alternative of blocking the C-2 position also
gave positive results. For 2-phenyl-l-(phenylthiomethyl ) -
benzimidazole, regioselective metallation. was observed in

171
all cases. However, the reactions did not go to completion.
With the sulfoxide, the reaction went to completion but the
adducts were unstable. Forming the quaternary salts also
increased the acidity of the C-a methylene protons as
demonstrated in the hydrogen/deuterium exchange studies.
Unfortunately, attempted condensations with aldehydes gave
back starting materials.
The good leaving group ability of benzotriazole made it
an azole worth investigating. Previous work has shown that
the anion of 1-methylbenzotriazole is unstable but can be
stabilized by a heteroatom having d-orbitals. As a result,
the silicon-containing N-substituent in l-(trimethylsilyl-
methyl)benzotriazole stabilized the C-a carbanion, enabling
the generation of more complex N-alkyl, N-alkylidene, and
N-acyl derivatives. The silyl group was readily removed by
the fluoride ion. Thus the presence of carbonyl compounds
in the above reaction mixture afforded benzotriazol-
1-ylethanols. The absence of a heteroatom at the 6-position
caused problems in attempted removal of benzotriazole from
the 6-hydroxy and the alkylidene derivatives. However, with
a carbonyl group at the 6-position, benzotriazole was
removed with zinc and acetic acid.
In Chapter IV, the synthetic utility of N-chloromethyl-
pyrazole was investigated. The difference in reactivity of
the two functionalities attached to the methylene group was
demonstrated by the selective displacement of the chlorine

172
atom by a variety of nucleophiles. The formation of some
more complex N-substituted pyrazoles was observed in the
treatment of the carbanion of 3,5-dimethyl-l-(phenylthio-
methyl)pyrazole with electrophiles. Furthermore, the
phenylsulfenyl moeity was also selectively removed.

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Skvortsova, and M. G. Voronkov, J. Gen.
Chem. USSR (Engl. Transí)., 1985, 55,
923 .
8 5J0C13 51
A. R. Katritzky, F. Saczewski, and C. M.
Marson, J. Org. Chem., 1985, 50, 1351.
85MI1
T. L. Gilchrist, Heterocyclic Chemistry,
Pitman Publishing Ltd., UK, 1985, 354.
85MI2
A. R. Katritzky, Handbook of Hetrocyclic
Chemistry, Pergamon Press, Oxford, 1985,
293 .
8BS302
M. R. Cuberos, M. Moreno-Manos, and A.
Trius, Synthesis, 1985, 302.
85TH1
J. M. Aurrecoechea, Ph. D. Thesis, 1985.
86H237
S. Shimizu and M. Ogata, Heterocycles,
1986, 2_4, 237.
86JAI 397
D. A. Bors and A. Streitwieser, Jr., J.
Am. Chem. Soc., 1986, 108, 1397.
86JOC3897
S. Shimizu and M. Ogata, J. Org. Chem.,
1986, 51, 3897.
86UP1
A. R. Katritzky and W. Kuzmierkiewicz,
unpublished results, 1987.
87JOC844
A. R. Katritzky, W. Kuzmierkiewicz, and
J. M. Aurrecoechea, J. Org. Chem., 1987,
52, 844.
87JOC2314
S. Shimizu and M. Ogata, J. Orq. Chem.,
1987, 52, 2314.
87J(PI)769
A. R. Katritzky, J. M. Aurrecoechea, and
L. M. Vazquez de Miguel, J. Chem. Soc.,
Perkin Trans. 1, 1987, 769.
87J(PI ) 775
A. R. Katritzky, W. H. Ramer, and J. N.
Lam, J. Chem. Soc., Perkin Trans. 1,
1987, 775.

183
8 7 J(PI)7 8 1
A. R. Katritzky, S. Rachwal, K. C.
Caster, and (in part) F. Mahni, K. W.
Law, and 0. Rubio, J. Chem. Soc., Perkin
Trans. 1, 1987, 781.
87J(PI ) 791
A. R. Katritzky, S. Rachwal, and B.
Rachwal, J. Chem. Soc., Perkin Trans. 1,
1987, 791.
87J(PI)805
A. R. Katritzky, S. Rachwal, and B.
Rachwal, J. Chem. Soc., Perkin Trans. 1,
1987, 805.
87J(PI ) 819
A.. R. Katritzky and W. Kuzmie r k i ewi cz , J.
Chem. Soc., Perkin Trans. 1, 1987, 819.
8 7 J(PI)IP1
A. R. Katritzky and M. Drewniak, J. Chem.
Soc., Perkin Trans. 1, 1987, accepted.
8 7 J(PII)IP1
A. Maquestiau, D. Beugnies, R. Flammang,
A. R. Katritzky, ri. Solemain, T. Davis,
and J. N. Lam, J. Chem. Soc., Perkin
Trans. 2, 1987, in press.
87TL515
S. Ram and D. Spicer, Tetrahedron Lett.,
1987, 28, 515.
87TLIP1
A. R. Katritzky and M. Drewniak,
Tetrahedron Lett., 1987, accepted.
87UP1
A. R. Katritzky and K. Yannakopoulou,
unpublished work, 1987.
87UP2
A. R. Katritzky, P. Lue, D. Rasala, and
L. Urogdi, unpublished work, 1987.
87UP3
A. R. Katritzky, R. J. Offerman, P.
Cabildo, and M. Solemain, unpublished
work, 1987.
87UP4
A. R. Katritky and C. V. Hughes,
unpublished work, 1987.

BIOGRAPHICAL SKETCH
Jamshed N. Lam was born on May 9, 1957, in Bombay,
India. He received his undergraduate degree majoring in
chemistry, from the Indian Institute of Technology,
Bombay, India, in June 1980.
He then enrolled in the Graduate School at the
University of Florida in September 1980.
Jamshed Lam is the only son of Noshir and Villoo Lam.
He has one sister, Feroza.
As of this date and time, he is still single and
available.
181

I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
/
Z
Alan R. Katritzky, Chavfman
Kenan Professor of Chemistry
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
Merle A. Battiste
Professor of Chemistry
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
James A. Deyrup •
Professor of Chemistry
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
William M. Jones
Professor of Chemistry

I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor
Stephen G. S'chulman
Professor of Pharmaceutics
This dissertation was submitted to the Graduate
Faculty of the Department of Chemistry in the College of
Liberal Arts and Sciences and to the Graduate School and
was accepted as partial fulfilment of the requirements for
the degree of Doctor of Philosophy.
April, 1988
Dean, Graduate School




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