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

MISSING IMAGE

Material Information

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

Subjects

Subjects / Keywords:
Benzimidazoles   ( lcsh )
Benzotriazole   ( lcsh )
Pyrazoles   ( lcsh )
Chemistry thesis Ph.D
Dissertations, Academic -- Chemistry -- UF
Genre:
bibliography   ( marcgt )
non-fiction   ( marcgt )

Notes

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

Record Information

Source Institution:
University of Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 001113208
oclc - 19915134
notis - AFK9828
System ID:
AA00002142:00001

Full Text














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