Benzotriazole mediated heteroalkylation and arylalkylation in organic synthesis

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Title:
Benzotriazole mediated heteroalkylation and arylalkylation in organic synthesis
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vii, 94 leaves : ill. ; 29 cm.
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English
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Xie, Linghong, 1963-
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Subjects / Keywords:
Heterocyclic compounds -- Synthesis   ( lcsh )
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Thesis:
Thesis (Ph. D.)--University of Florida, 1994.
Bibliography:
Includes bibliographical references (leaves 86-93).
General Note:
Typescript.
General Note:
Vita.
Statement of Responsibility:
by Linghong Xie.

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University of Florida
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BENZOTRIAZOLE MEDIATED HETEROALKYLATION
AND ARYLALKYLATION IN ORGANIC SYNTHESIS









BY

LINGHONG XIE


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

1994
























To my daughter, Stephanie, with love












ACKNOWLEDGEMENTS



I am deeply indebted to my supervisor, Professor Alan R. Katritzky, for his

invaluable guidance, encouragement and trust over the years. It has been a rewarding

experience and a pleasure to work with him.


I would like to express my sincere gratitude to Dr.


William Dolbier, Dr. Eric


Enholm, Dr. Richard Yost and Dr. Dinesh Shah, for their help, suggestions and time

as my supervisory committee members.


I would like to give my special thanks to Dr.


Wei-Qiang Fan and Dr. Darren


Cundy for their help and cooperation during these years.

The people in the Katritzky Group are like a big family and have always been

very supportive. Thanks also go to them for their help and friendship.

I am deeply grateful to my parents and my parents-in-law, for their love and

support, for taking very good care of my little baby.

Last but not the least, I am greatly indebted to my husband, Jianqing, for his

constant understanding, encouragement and support, for everything he has done for

me.












TABLE OF CONTENTS


ACKNOWLEDGEMENTS


ABSTRACT


CHAPTERS


GENERAL INTRODUCTION


AMIDOALKYLATION OF AMINES AND THIOLS
WITH 1-[(a-FORMYLAMINO)ALKYL]BENZOTRIAZOLES:
SYNTHESIS OF a-AMINO ISONITRILES AND
-ALKYLTHIO ISONTRILES .............................. ..........


Introduction ............. .............................................. ......
Results and Discussion .................................... .... ........
Experimental ............. ........... ............... ..... .. ....... ..... .....


THIOALKYLATION OF REACTIVE AROMATIC
COMPOUNDS WITH a-(BENZOTRIAZOL-1-YL)BENZYL
PHENYL SULFIDE ............... ....... .... ..... ...................... ......


3.1 Introduction ....................... ....... .......................... ........
3.2 Results and Discussion ....................................................
3.3 Experim mental .............. ................... .............................

HETEROARYLALKYLATION OF ELECTRON-RICH HETERO-
AROMATIC COMPOUNDS: CONVENIENT NOVEL SYNTHESIS
OF 1, 1 BIS (HETEROARYL)ALKANES ..................... .... ...........


Introduction ....... .................. ................... ..... .............
Results and Discussion ... .......................... .................
Experimental ...... .... ............ ...... ............ ............ .... ......


INDOLYLALKLATION. PART I: A
OF 3-SUBSTITUTED INDOLES


VERSATILE SYNTHESIS


Introduction ............................ .......................... ........











INDOLYLALKYLATION. PART II: A GENERAL
AND FACILE SYNTHESIS OF HETEROCYCLO[B]-
FUSED CARBAZOLES ............................................................


Introduction .....................................................................
Results and Discussion ......................................................
Experimental ........................ ....................................... ...


CONCLUSION


BIBLIOGRAPHY

BIOGRAPHICAL SKET(


................ ...ec. ......... mce. .... a. a. -. emeem

* .............. W.............. .. ..eec







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

BENZOTRIAZOLE MEDIATED HETEROALKYLATION
AND ARYLALKYLATION IN ORGANIC SYNTHESIS

By

Linghong Xie


December, 1994

Chairman: Alan R. Katritzky, FRS
Major Department: Chemistry

a-(Benzotriazol-1-yl)alkyl groups are incorporated into amides, sulfides and


electron-rich


heteroaromatic


systems.


These


benzotriazole


derivatives


undergo


amidoalkylation, thioalkylation and heteroarylalkylation with the displacement of the


benzotriazolyl group by various nucleophiles to furnish a


wide spectrum


of useful


organic compounds.


a-Amino


isonitriles


a-alkylthio


isonitriles


synthesized


dehydrations of N-(a-aminoalkyl)formamides and N-[a-(alkylthio)alkyl]formamides,


themselves


prepared


from


amidoalkylation


amines


thiols


with


1 [(a-formylamino)alkyl]benzotriazoles.


a-(Benzotriazol- l1-yl)alkyl


phenyl


sulfides,


readily


available


from


benzotriazole,


an aldehyde


thiophenol,


react


smoothly


with


active


aromatic


compounds to afford a variety of thioalkylated products.


a-(Benzotriazol-l-yl)alkyl groups are incorporated into thiophene,


indole systems via the reaction of N-[(a-benzotriazol-1-yl)alkyl]carbamates,


furan and


which


are easily


prepared


from


condensation


benzotriazole,


an aldehyde


carbamate,


with 2-methylthiophene, 2-methylfuran and 1-methylindole, respectively.







derivatives


provides


a wide


range


symmetrical


unsymmetrical


1,1 -bis(heteroaryl)alkanes.

Following a similar protocol, a variety of 3-substituted indoles are prepared


from


indolylalkylation


various


nucleophiles


with


1-methyl-3-[(a-benzo-


triazol- 1-yl)alkyl]indole,


which


obtained


either


condensation


3-methylindole with N-[(a-benzotriazol-l-yl)alkyl]carbamates or via the reactions of

lithiated 1-methyl-3-[(benzotriazol- 1-yl)methyl]indole with electrophiles.


Indolylalkylation


been


successfully


extended


synthesis


thieno[b]carbazoles,


furo[b]carbazoles


indolo[b]carbazoles.


Thus,


1-methyl-2-


bromo-3-[(benzotriazol-l-yl)methyl]indole,

1-methyl-3-[(benzotriazol-l-yl)methyl]indole,


available f

undergoes


rom


bromination


halogen-lithium


exchange


with t-butyllithium and the resulting carbanion reacts with thiophenecarboxaldehydes,


furancarboxaldehydes


indolecarboxaldehyde.


subsequently


quenching


methyl iodide, the corresponding methyl ether intermediate products are obtained in

excellent yields. Intramolecular indolylalkylation of these intermediates is effected by


refluxing


in 1,2,4-trichlorobenzene


or 1,2-dichlorobenzene,


which


followed


simultaneous


aromatization


provides


these


important


novel


polycyclic


compounds.











CHAPTER I
GENERAL INTRODUCTION


Work in our laboratory has demonstrated benzotriazole as a useful synthetic


auxiliary


[91T2683].


One of the


special


features


attributing


to the


usefulness


benzotriazole


is its


strong


acidity


'FIx2-


which endows


it with


important


properties.


it readily


undergoes


Mannich-type


condensation


with


aldehyde and a compound containing an active hydrogen atom to form a variety of


benzotriazolyl


derivatives, and


the other is that its anion is a good leaving group


which can be displaced by various types of nucleophiles in its derivatives of type


Bt-C-heteroatom


or O)


Bt-C-Ar


= electron


aromatics).


combination


of -these


properties


allows


a wide


spectrum


useful


organic


compounds to be readily accessible.



BENZOTRIAZOLE MEDIATED HETEROALKYLATION


R/X


-N,


conversion


a benzotriazolyl


derivative


Bt-C-heteroatom


with


displacement of benzotriazole by nucleophile

benzotriazole. Conceptually similar, benzotri


is called heteroalkylation mediated by


\azole mediated arylalkylation indicates







2



the displacement of type Bt-C-Ar 1.3 and 1.5 by nucleophiles. In these processes, the

dissociation of the C-Bt bond is assisted by the lone electron pair on the heteroatom X

to form reactive intermediates, cations 1.2, 1.4 and 1.6 [87JCS(P1)2673, 89H1121],

which subsequently react with nucleophiles to fulfil the transformations.



BENZOTRIAZOLE MEDIATED ARYLALKYLATION


=N,


parc


or ortho position


Since benzotriazolyl derivatives are usually more stable and/or more readily


accessible


their


chloro


bromo


analogues,


benzotriazole-mediated


methodology


proves


to be a highly


advantageous one


and in many


cases even a


necessity.







3



The objective of this project is to investigate the applications of benzotriazole

mediated heteroalkylation and arylalkylation in the synthesis of a variety of useful


organic compounds,


results


reported in


five chapters.


Chapter


describes the synthesis of a-amino isocyanides and a-alkylthio isocyanides via the


amidoalkylation


amines


thiols


with


1-(1 -formylaminoalkyl)benzotriazole,


followed by the dehydration of formed intermediate products. Chapter III discusses

the thioalkylation of reactive aromatic compounds with a-(benzotriazol-l-yl)benzyl


phenyl


sulfide.


Chapters


with


synthetic


applications


benzotriazole


mediated heteroarylalkylation in


the synthesis of


1,1-bis(heteroaryl)-


alkanes and 3-substituted indoles.


The work in Chapter VI extends the benzotriazole


mediated


heteroarylalkylation


synthesis


thieno[b]carbazoles,


furo[b]-


carbazoles and indolo[b]carbazoles.










CHAPTER II
AMIDOALKYLATION OF AMINES AND THIOLS WITH
1-(1 -FORMYLAMINOALKYL)BENZOTRIAZOLE:
SYNTHESIS OF a-AMINO ISONITRILES AND a-ALKYLTHIO ISONITRILES


2.1 Introduction



The chemistry of isonitriles in general is well documented [71MI1], but far

less work has been reported on functionalized, specifically a-substituted isonitriles

2.1. Bohme and Fuchs reported the three-step synthesis of (isocyanomethyl)phenyl


sulfone (2.1, Y


= PhSO2, R


= H) and of N-(isocyanomethyl)phthalimide starting from


corresponding


(formamidomethyl)dialkylamine,


failed


obtain


(alkylthio)methyl isocyanides (2.1,


= RS) [70CB2775].


Diethyl isocyanomethyl-


phosphonate (2.1,


phosphite


= (EtO)2P(O), R =


H) was prepared from the reaction of triethyl


N-(formylaminomethyl)trimethylammonium


followed


treatment


with


POC13


presence


triethylamine


[73TL633].


Other


isocyanomethyl substituted phosphorus compounds have also been reported [74LA44,


81LA99,


81LA709].


Treatment


O2NNPrCH2CI


with


NaCN-ZnC12


gave


N-(isocyanomethyl)-N-nitropropylamine (2.1, Y


= O2NNPr, R


= H) which rearranged


to its corresponding nitrile form [81AP459]. 1-Isocyanomethylazoles RCH2NC (R =


1 -imidazolyl,


1,2,4-triazol-2-yl,


1-benzimidazolyl and


benzotriazolyl) were synthe-


sized by the reaction of RH with HCONHCH2N+Me3I- followed by dehydration of


RCH2NHCHO


using


POC13


or PPh3/CCl4


[83CPB723].


Preparations


a few


a-(arylthio)methyl isonitriles (2.1,


= ArS, R


= H) [88TL1435] and


1-(arylthio)-












NHCHO


alkenyl isonitriles [85RTC177] have also been reported.


these


previously


reported


a-substituted


isonitriles


are isocyanomethyl


derivatives (2.1,


=H).


Our own group recently disclosed the synthesis of a-(benzo-


triazolyl)alkyl


isonitriles


(2.1,


= benzotriazolyl,


= alkyl)


dehydration


1-(1-formylaminoalkyl)benzotriazoles (2.3) which were prepared by the condensation


benzotriazole, an aldehyde and formamide [90JCS(P1)1847].


(Benzotriazol-1 -yl)-


ailcyl


isocyanides


have


been


used


as versatile


synthons


preparation


unsymmetrical formamidines. In


this chapter,


we now report for the first time the


synthesis


an a-aminoisonitrile


(2.1,


= R


= alkyl)


elaborated


a-alkylthioisonitriles


(2.1,


alkyl)


from


1-(1-formylaminoalkyl)-


benzotriazoles.


Results and Discussion


a-Aminoisonitriles


a-alkylthioisonitriles


were


prepared


as shown


Scheme


1-[a-(Formylamino)benzyl]benzotriazole (2.3a) and 1-[1-(formylamino)-


-2-methylpropyl]benzotriazole (2.3b) were prepared from


benzotriazole, formamide


and the appropriate aldehyde as previously described [90JCS(P1)1847].


Reaction of













RCHO / H2NCHO


N
N
N


2.3a
2.3b


=Ph
= i-Pr


NHCHO


R'SH / EtOH / Na


NHCHO


(R = Ph)
morpholine
K2C03 / MeOH
20C, 12h


0


N


NHCHO


POCL / CH2CI2


oC,


Na2C03


20C


2.5, 2.7 R R'

a i- Pr Ph

b Ph 3 -MeC6H4

c Ph i Pr


.POC13 / CH2C12


ooC,


Na2CO3
200C, 12h


0


N


Scheme


presence


potassium


carbonate


gave N- (a-morpholinobenzyl)formamide


(2.4)










alkyl]formamides 2.5a


- 2.5e in good yields.


The byproduct sodium or potassium


benzotriazolate,


produced


during


these


reactions,


was


easily


removed


during


aqueous


workup.


Dehydration


N-(a-aminoalkyl)-


(2.4)


and N-(a-alkylthio-


alkyl)-formamides (2.5a


- 2.5c) with POC13 in the presence of i-Pr2NH


gave the


corresponding


a-aminoisonitrile


2.6 and


a-alkylthioisonitriles 2.7a


- 2.7c in


good


yields.


believed


amidoalkylations


morpholine


thiols


with


compounds 2.3a and 2.3b involve electrophilic attack by the carbocation of type 1.2


= NHCHO)


which


stabilized


nitrogen


atom


as mentioned


introduction.

The dehydration of formamide derivatives with POC13 in the presence of an


amine and other dehydrating reagents, such as tosyl chloride [65CA 1441],


thionyl


chloride and base [72JOC187] or triphenylphosphine in CC14 [71AG143] are well


known.


Therefore,


preparations


N-(a-aminoalkyl)-


(2.2,


= R2N)


N-(a-alkylthioalkyl)-formamides (2.2,


= RS) are the key to the synthesis of the


corresponding


a-substituted


isonitriles


(Formamidomethyl)dialkylamines


have


usually been synthesized by the condensation of formamide with formaldehyde and

secondary amines, but the condensation is, in general, not applicable to either other


aliphatic


aromatic


aldehydes


[70CB2775,


81CB3421].


Synthetic


access


formamidomethyl alkyl sulfides (2.2,


=RS, R


= H), the precursors for (alkylthio)-


methyl


isonitriles,


available


from


reactions


thiols


hydroxymethyl-


formamide


[85JCS(P1)75],


p-tosylmethylformamide


[87RTC159,


87T5073],


quarternary


ammonium


cations


[70CB2775,


88TL1435]


with


chloromethyl-











However,


none


these


methods


been


used


preparation


[a-(alkylthio)alkyl]formamides (2.2,


= RS, R


= alkyl).


The novel aspect of


work is that using


1-(1-formylaminoalkyl)benzotriazoles now provides a convenient


route to the preparation of both a-(formamidoalkyl)dialkylamines and a-(formamido-

alkyl)alkyl sulfides in good yield. This method works particularly well with aromatic

and aliphatic aldehydes under mild conditions.


N-(a-Morpholinobenzyl)formamide


(2.4)


N-[(a-alkylthio)alkyl]-


formamides (2.5a-2.5c) were characterized by elemental analyses and by their 1H and

13C NMR spectra. In the 1H NMR spectra of 2.4 and 2.5, the NH protons appear as


doublets at 8.64 to 9.1


ppm with coupling constants ranging from 9.3


10.0 Hz, and


the formyl CH protons at 8.28-7.78 ppm with small coupling constants (0.9 Hz). In


the 13C NMR spectra, formyl carbonyl carbons appear at 160.0


carbons at 68.9


161.2 ppm and CH


- 52.9 ppm. All of the a-substituted isocyanides are new compounds.


The isocyanide structure is confirmed by the strong IR abortion band at 2250 cm-1

for the compound 2.6 and 2120 cm"1 for compounds 2.7, and by the 13C signals of


the isocyanato carbons at 159.7


- 160.4 ppm.


The structures of the isonitrile 2.6 is


further


confirmed


elemental


analysis


compounds


2.7a


- 2.7c


high


resolution mass spectra.


2.3 Experimental


Melting


points


were


determined


with


a hot


stage


apparatus


were


uncorrected.


1H (300 MHZ) NMR and 1"C (75 MHz) NMR spectra were recorded on


'7- 2<- -A -- A '-


. flr-.


Il 1


r


"~'


I '


1


1










Model


283B


grating


spectrometer.


1-[1-(Formylamino)benzyl]benzotriazole


(2.3a)


1-[1-(formylamino)-2-methylpropyl]benzotriazole


(2.3b)


were


prepared


previously described [90JCS(P1)1847].


2.3.1 N-(a-Morpholinobenzyl)formamide (2.4)


A mixture of 1-(1-formylamidobenzyl)benzotriazole (2.3) (1.89 g, 7.5 mmol),

morpholine (0.86 g, 10 mmol) and potassium carbonate (2.25 g) in methanol (20 ml)


was stirred at 200C overnight.


The solvent was evaporated, the residue dissolved in


ethyl acetate (100 ml),


washed with aqueous sodium hydroxide (3 x 20 ml,


10%),


water (2 x 10 ml) and dried (MgSO4).


Evaporation of the solvent gave a white solid


which was recrystallized from ethyl acetate/hexane (3/1) to give 2.4 as white needles


(1 g, 62


mp. 141-1420C.


1H-NMR (DMSO-d6):


= 8.74 (d, 1H, J


= 9.3 Hz, NH),


8.28 (d, 1H, J


= 0.9 Hz, CHO), 7.47-7.30 (m,


5H, ArH), 5.71-5.68 (d, 1H,


= 9.6 Hz,


CH), 3.57 (t,


4H, J


= 4.2 Hz), 2.38 (t,


4H, J


13C-NMR: 8


= 161


(CO),


138.6, 128.3, 128.


127.6, 127.2, 68.9 (CH), 66.2 (CH20),


48.3 (CH2N).


Analysis


for C12H16N202 (220.3): calc.


C 65.43


H 7.32


found C 65.20


H 7.36


2.3.2 N-(1-Phenylthio-2-methylpropyl)formamide (2.5a)


Typical Procedure


A solution of thiophenol (3.3 g, 30 mmol) and sodium (0.7


g, 30 mmol) in


absolute ethanol


(60 ml)


was added


a suspension


of 1-(1-formylaminobenzyl)-






10



was removed under reduced pressure and the residue dissolved in ethyl acetate (100

ml), washed with aqueous NaOH (3 x 20 ml, 10%) and water (2 x 10 ml) and dried


(MgSO4).


Evaporation of the solvent and recrystallization from ethyl acetate/hexane


(3/1) gave 2.5a as white needles (2.32 g, 74%),


mp. 65-66"C.


1H-NMR (CDC13):


1H, J


= 10.0 Hz, NH),


7.98 (d,


1H, J


= 0.9 Hz, CHO),


7.44-7


(m, 5H,


ArH),


5.31 (dd,


1H. J


.4 Hz, CH),


1.98 (m,


1H, CH),


1.00 (m, 6H,


13C-NMR:


= 160.4


(CO),


133.8,


131.1


, 126.9,


60.9,


19.4,


Analysis for C11H15NOS (209.2):


calc.


C 63.1


N 6.69


found C 62.99


N 6.66.


N-[a-(3-Methylphenylthio)benzyll form amide


(2.5b):


White


needles


from


AcOEt/hexane


, mp 132-1330C.


1H-NMR (CDC13):


= 9.05 (d,


1H, J = 9.6 Hz,


NW[,


7.78 (s, 1H,


CHO), 7.36-6.86 (m,


ArH), 6.32 (d,


IH, J


= 9.6 Hz, 1H),


3H, CH3)


13C-NMR


160.0 (CO),


138.9


138.3


, 133.2,


131.9,


128.8


128.4


128.1


126.8


20.8.


Analysis


for C15Hs1NOS (


57.9):


calc.


C 70.1


H 5.88


N 5.44; found C 69.57


H 5.78


N 5.34.


N-[(a-IsoDropylthio)benzvllformamide (2.5c): Needles


(AcOEt/hexane),


80%


mp. 62-630C.


1H-NMR (DMSO-d6):


= 9.15 (d, 1H,


= 9.6 Hz, NH),


8.13 (d,


1H, J


= 0.6


, CHO),


7.49-7.26 (m,


5H, ArH),


6.26 (d,


= 9.6 Hz, CH),


3.03 (m,


CH), 1


(d, 3H, J


= 6.6 Hz, CH3); 1.19 (d,


3H, J


= 6.6 Hz, CH3)


13C-NMR: 8


160.1


139.7


, 128.4,


127.7,


126.6, 52.9, 34.6,


22.5.


Analysis for C1iH1sNOS


(209.2): calc. C 63.1


N 6.69; found C 63.34


H 7.19


N 6.65.


2 x CH3);












2.3.3 a-Morpholinobenzyl isocyanide (2.6)


Typical Procedure for the Preparation of


2.6, 2.7a, 2.7b, 2.7c


Diisopropylamine (0.303 g, 3 mmol) was added to N-(a-morpholinobenzyl)-


formamide (2.4) (0.


g, 1 mmol) in CH2C12 (40 ml).


Phosphorous oxychloride (0.20


g, 1.3 mmol) in CH2C12 was added dropwise at 0C with stirring.


The solution was


stirred for 4h at 0C and aqueous sodium carbonate (8 ml, 20%) was added slowly.


After stirring at 200C for


, CH2C12 (20 ml) and water (20 ml) were added.


organic layer was washed with water (3 x 15 ml),


dried (MgSO4) and evaporated. The


crude product was purified by column chromatography (silica,


CH2C12) to give a


yellowish solid (0.19 g, 96%),


mp. 66-670C.


1H-NMR (CDCl3):


7.52


2H, ArH),


7.43-7.37


ArH),


CH),


3.74 (m,


x CH20),


60-2.57 (m,


2 x CH2N)


13C-NMR: 8


= 132.3


, 129.0, 128.8, 127.9, 115.1,


66.6,


, 49.9; IR


(KBr):


= 2250.0 (-NC). Analysis for C12H14N20 (202.2): calc.


71.26


H 6.96


N 13.85:


found C 71.00


H 7.12


N 13.73.


1 -Phenylthio-2-methylpropyl isocyanide (2.7a):


This compound was prepared


as an oil


from 2.5a by the same procedure as 2.6.


1H-NMR (CDC13): 8


7.57-7.54 (m,


2H),


32-7.32


(m, 3H,


ArH),


4.50 (d,


1H, J


=4.8 H


z, CH),


12 (m,


1H, CH),


1.13 (d, 3H,


=5.1


, CH3),


1.11 (d, 3H,


1 Hz, CH3)


13C-NMR: 8


158.8


131.5


128.8


,32.9, 19.2,


IR (KBr):


= 2120 (-NC).


HRMS:


Cl1H13NS, calc. 191.0752


found 191.0752.


a-(3-Methylphenylthio)benzvl


isocyanide


(2.7b):


This


compound


was










160.4, 139.1, 135.4, 133.9, 131.8,


131.7


,131.6, 130.2,


129.1, 128.7


126.3


,62.8 (CH),


IR (KBr):


120.1


(-NC).


HRMS: C15H13NS,


calc.


239.0769


found


239.0769.


a-(Isopropylthio)benzyl isocyanide (2.7c):


This compound was prepared as an


oil (74%) from 2.5c by the same procedure as 2.6.


'H-NMR (CDC13)


7.49-7.34


5H, ArH),


74 (s,


1H, CH), 3.27 (m, 1H, CH),


1.43 (d, 3H, J


= 6.6 Hz, CH3),


1.29 (d,


3H, J


= 6.6


Hz, CH3);


13C-NMR: 8


= 159.7


128.9,


128.1


, 36.3,


IR (KBr):


= 2120.1


(-NC).


HRMS:


CiHi3NS,


calc.


191.0772; found 191.0770.











CHAPTER III
THIOALKYLATION OF REACTIVE AROMATIC COMPOUNDS
WITH a-(BENZOTRIAZOL-1-YL)BENZYL PHENYL SULFIDE


3.1 Introduction


concept


"amidoalkylation"


replacement


"active"


hydrogen atom in OH, SH, NH or CH compounds by a group CRR"NHCOR' is well


recognized


been


reviewed


[73S703,


70S49,


84S85,


84S181].


have


successfully


employed


benzotriazole


mediated amidoalkylation


the synthesis of


a-ammo


isocyanides


a-alkylthio


isocyanides


discussed


Chapter


However, the analogous concept of "thioalkylation", i.e.


the replacement of H in XH


by the group CRR"SR' is less familiar, but has previously been accomplished in a


variety


ways,


using


following


reagents


actually


or potentially


RR"CSR'Y where Y is a leaving group:


= Halogen:


phenyl sulfides (3.1)


Lewis


generate


acid-catalyzed


the corresponding


dehalogenations

carbocation wh


a-chloroalkyl


ich participates in


electrophilic substitution of aromatic compounds to give the thioalkylation products

3.2 (Scheme 3.1). However, application of this method appears to be limited to cases

where at least one of the alkyl groups in RR"C is strongly electron-withdrawing, i.e.


structures


91CPB 1148].


where


= CF3


a-Chloroalkyl


[89TL2265],


alkyl


sulfides


CO2Et,

(3.1)


COR

were


or CN

prepared


[80TL2547


from


corresponding sulfides with N-chlorosuccinimide [77MI51].













Lewis Acid / ArH


nR nCF


CO2Et


COMe


COPh


Scheme


(b) Y


= OR: Treatment of trimethylstyrylsilanes with 1-ethoxy-1-(phenylthio)-


ethane (3.3) or 2-ethoxy-l,3-dithiolane (3.4) in the presence of Lewis acids gives allyl

sulfides 3.5 and 3.6, respectively (Scheme 3.2) [83BCJ1569], but the yields were low


- 42%).


The reaction of enol silyl ethers with 2-ethoxy-1,3-dithiolane (3.4) in the


presence


(Scheme


chloride


[8 1TL3243].


affords


However,


half-protected


these reactions


1,3-dicarbonyl


were reported


compounds


only for some


unsaturated


silicon


compounds,


not for


thioalkylation


aromatic


or active


methylene compound


RR"CSR'OEt.


Lewis


treatment


of 2,2,2-trifluoro-1-


methoxyethyl phenyl sulfide (3.8) does not generate the corresponding carbocation

[87BCJ3823, 87JOC5489], and no thioalkylation was observed.


= SR:


Benzaldehyde diethylmercaptal


(3.12),


benzophenone diethyl-


mercaptal and ethyl orthotrithioformate (3.9) react with copper(II) chelates 3.13 of

1,3-dicarbonyl compounds, or with anisole in the presence of cupric chloride, to give


condensation


or substitution


products


(3.14


or 3.16)


[70BCJ2549].


However,


requirement for copper(II) salts for this thioalkylation has restricted its use. Moreover,













MoC15 or


OEt2


SiMe3


MoC15 or


SiMe3


RR'C


3 OEt2


= CR"(OSiMe3)


ZnC1


COR"


EtS-(


SePh


3.10


Scheme


S

S












Cu/2
/


Ph SEt


3.12


3.13


3.14


3.15


OMe


OMe


PhOMe


OMe


3.16


3.17


Scheme


the case of anisole, the alkylthio group is often replaced by another anisole residue,


forming


a mixture


anisylphenylmethyl


ethyl


sulfide


(3.16)


dianisylphenylmethane


(3.17)


(Scheme


3.3).


Ethyl


orthotrithioformate


(3.9)


yields


three products [69JA4315].


(d) Y


= SeR:


The sulfo-selenoacetals 3.10 are cleaved by butyllithium in THF


(-78 C) to give a-sulfo-carbanions,


which add to a variety of carbonyl compounds


enolisable


ketones,


producing


P-hydroxysulfides


[75TL1617].


preparation


sulfo-selenoacetals


generally


required


treatment










Carbanions from deprotonation of a-(phenylthio)alkaneboronic esters 3.11 can


be acylated with methyl esters to form a-(phenylthio)ketones [78JA1325].


However,


deprotonation


boronic


ester


requires


lithium


diisopropylamide


phenylthioalkylboronic esters themselves have to be made


from


(phenylthio)alkyl-


lithiums.


Acid


catalyzed


reactions


phenols


with


dicyclohexylcarbodiimide


dimethyl sulfoxide can be used for the (methylthio)methylation of phenols but gives


low yields (3


) [66JA5855].


now


report


chapter


results


reaction


a-(benzotriazol-l-yl)alkyl phenyl sulfides, a new useful thioalkylation reagent,


with


various electron-rich aromatic compounds.



3.2 Results and Discussion


Thioalkylation


reagents,


a- (benzotriazol-1 -yl)benzyl


phenyl


sulfide


(3.18a)


[a-(benzotriazol-1-yl)-a-(4-methylphenyl)]methyl


phenyl


sulfide


(3.18b)


were


prepared


from


thiophenol,


aldehyde


benzotriazole


good


yields


[91HCA1931].


The thioalkylation reactions were carried out in dry ether at reflux in


presence


equimolar


amounts


bromide


under


argon.


Thus,


a-(benzotriazolyl)alkyl phenyl sulfides 3.18a and


3.18b


reacted


with a


variety


active aromatic compounds


desired


thioalkylation


products 3.19a-i


moderate to good yields.


Table 3.1


These reactions and results are listed in Scheme 3.4 and


The active aromatic compounds used include anisole, dimethoxybenzene


nn A n, ni-i, nw. rn nfhti, ol anac' nhanalc nnA\C lI nnnbttrtc* or T~.,ana n.r*4ohn1 .k04..


nn~ m n)~ nvr m nnl\~l\ nlonno







18



N,N-dimethylaniline no sulfur containing product was isolated but a product similar to


leucomalachite


green


was


obtained.


Presumably


phenylthio


group


was


replaced by N,N-dimethylaniline. Similar reactions have been reported [69JA4315].


PhSH / RCHO
benzene / p-TsOH


reflux


3.18a


=Ph


ArH / ZnBr


/ Et2O


- MeC6H4 64


reflux


Ar-(
SPh

3.19


3.19 R Ar 3.19 R Ar

a Ph 4-MeOC6H4 f Ph 4-HOC6H4

b Ph 4-MeOCioH6 g Ph 2-Me-4-HOC6H3

c Ph 1-MeOC1oH6 h Ph 4-HOCloH6

d Ph 2-MeOC1oH6 i 4-MeC6H4 3,4-(MeO)2C6H3

e Ph 3,4-(MeO)2C6H3


Scheme


analogy


amidoalkylation


discussed


Chapter


thioalkvlation


aromatics


comnounds


l 1Rh


'., A WV I L IU '-- 'l I tI *S*


nresumablv


rOeS


Ill~a


w lL I


. I










these


reactions


since


coordination


of lone


electrons


on the


nitrogen


benzotriazolyl group with ZnClz greatly enhances its leaving ability, thus facilitating

the reactions.

For monosubstituted benzenes (anisole and phenol) the thioalkylation occurred

at the para-position as clearly shown by the typical signals for the para disubstituted

benzene in the 1H NMR spectra of the thioalkylation products (3.19a and 3.19f). The

thioalkylation of 2-substituted naphthalenes occurred at the 1-position as we compared


NMR


spectrum


isolated


product


(3.19d)


starting


material. However,


1-methoxynaphthalene reacted to give mainly the 4-substituted


product


(3.19b)


a small


amount


2-substituted


isomer


(3.19c).


These


isomers were separated by column chromatography and assigned by their 1H NMR

spectra. For the 4-substituted product 3.19b, the doublet of C4 proton at 7.60 ppm

[88MI1] disappeared and the doublet of C2 proton at 6.50 remained. By contrast, the


C4 proton was seen and C2 proton was replaced in the


1H NMR of the compound


3.19c.


thioalkylation


products


are all


new


except


3.19a


[68CA39258,


67MI105].


The structures were characterized


by their elemental analyses or high


resolution mass spectra (Table 3.2) and by their 1H and 13C NMR spectral data. The

1H and 13C NMR chemical shifts and their assignments are listed in the experimental

section. In the 1H NMR spectra, typical singlets were observed at 5.38-6.72 ppm for


group.


Generally,


protons


three


1-hydroxy-


1-methoxynaphthalenes


(3.19b,


3.19c


and 3.19g)


appeared


at relatively


downfield


(6.23


- 6.72 ppm), while those of other thioalkylation products occurred at higher field


- ~1 2-- -.an-.


-rf rf~











conclusion,


hydroxy


or methoxy


substituted


benzenes


naphthalenes


react


under


mild


conditions


with


a-(benzotriazol- 1-yl)alkyl


phenyl


sulfides


(themselves easily available from benzotriazole, an aldehyde and thiophenol) to form

the thioalkylation products. Although the yields are moderate, the products are easily


purified.


benzotriazole


methodology


companson


other


thioalkylation reagents is advantageous in that our method gives similar yields under


significantly


milder


conditions.


Moreover,


reagents


a-(benzotriazol- 1-yl)benzyl


phenyl


sulfide


offer


advantages


over


previous


reagents in being more easily prepared and/or more stable.



3.3 Experimental



Melting points were determined on a hot stage apparatus and are uncorrected.


(300 MHz) NMR and


13C (75 MHz) NMR spectra were recorded on a


Varian


VXR


spectrometer


CDC13


TMS


as the


internal


standard.


Mass


spectra


were


obtained from a Finnigan Mat 95. Column chromatography was performed with MCB

silica gel (230-400 mesh).


3.3.1 a-(Benzotriazol-1-yl)benzyl phenyl sulfide (3.18a)


Typical procedure


A mixture of benzotriazole (3.6 g, 30 mmol), thiophenol (3.3 g, 30 mmol) and

benzaldehyde (3,2 g, 30 mmol) was refluxed in benzene (200 mL) in the presence of

p-toluenesulfonic acid (0.5 g) under a Dean-Stark head. After the collection of water










and thiol. Diethyl ether (300 ml) was added to the mixture and the organic


layer


separated, washed with water, dried (MgSO4) and the solvent removed to give an oily


residue


which


was recrystallized from Et20,


g (47%),


- 82C


[91HCA1931] mp. 80


- 81C).


[(benzotriazol-1 -vl)(4-methylphenvl)1 methyl


phenyl


sulfide


(3.18b):


Yield


64%


, mp. 97-980C; 1H NMR(CDC13) 8 8.05 (d, J


= 8.0 Hz, 1H),


7.95 (d, J


= 8.0 Hz,


1H), 7.57 (m, 3H), 7.40 (t, J= 7


Hz, 1H),


7.35-7.10 (m, 8H),


.29 (3H, CH3); 13C


NMR


5 138.7


132.1, 130.6, 129.4, 129.1, 128.9, 128.4,


127.7, 127.6, 127


124.3, 119.4, 111.3, 66.9, 20.7 (CH3). Analysis for C2oH17N3S (331.4): calc. C 72.48


H 5.17


found C 72.14


H 5.05


2.27.


3.3.2 1 -(4-Methoxyphenyl)-1 -phenyl-1-phenylthiomethane (3.19a); Typical procedure
for thioalkylation


Anisole (0.54 g,


mmol) in dry ether (20 mL) was added to a solution of


a-(benzotriazol-l-yl)benzyl phenyl sulfide (3.18a, 1.59 g,


5 mmol) and zinc bromide


(1.4 g, 5 mmol) in dry ether (50 mL). The mixture was refluxed under argon for 10 hr,

cooled, filtered and the solvent removed under reduced pressure. The oily residue was


chromatographed


with


hexane-chloroform


(2:1)


as eluent


recrystallized


from


ether-petroleum ether to give colorless prisms.


IH NMR 8 7.40 (d,


= 7.5


Hz, 2H),


7.35-7.13 (m, 10H), 6.80 (d, J =


Hz, 2H),


.51 (s,


3.72 (s, 3H)


13C NMR 8


158.6


, 141.2, 136.6, 133.0, 130.3,


129.4, 128.6, 12


127.1


,126.4, 113.8,


55.1.


Other thioalkylation products were prepared similarly


from


the appropriate


aromatics and compounds 3.18a or 3.18b.


1- (A-MPthnrv- 1 -nnnhthvll- 1 -nhpnvl- 1 -fnhp.nvlthinimp.th an.(3_1 9h


1H NMR










2H), 7.30 (m, 1H), 7.29-7.04 (m, 9H),


6.73 (d, J


= 8.1 Hz, 1H), 6.24 (s, 1H, CH),


(s, 3H);


13C NMR 8


155.1


, 132.4, 129


129.0,


128.7


, 128.6,


, 126.8, 126.6, 126.9, 124.9, 124.0, 123.3, 122.7, 103


55.4


1-(1-Methoxv-2-naphthyl)-phenvl-1-(phenvlthio)methane (3.19c):


1H NMR 8


8.31 (d,


3H), 6.77 (d, J


= 8.7 Hz, 1H), 7.88 (d, J


= 8.1 Hz, 1H),


= 7.8 Hz, 1H), 7.45-7


6.72 (s, 1H, CH), 6.59 (d, J


2H),


= 8.1 Hz, 1H),


7.30-7.12 (m,


3.91 (s,


OCH3);


13C NMR 8


154.4,


144.0,


132.6,


131.9,


129.8


, 128.4,


127.7


126.6


, 126.5,


126.3


,126.0, 124.8, 124.0, 122


103.0,


48.7.


1-(2-Methoxxy-1-naphthyl)- 1-phenyl-1-phenylthiomethane (3.19d):


1H NMR 8


7.67 (m,


3H), 7.39-7.26 (m, 5H), 7.24-7.06 (m, 8H),


NMR 8 157.6, 139.6, 134.4, 132.4,


129.2, 128.7


5.42 (s, 1H), 3.79 (s,


128.6,


3H);


, 127.6,


.4, 126.6, 126.2, 123.4, 118


60.4, 55.0.


4-[Phenvl(phenvlthio)methyll- 1,2-dimethoxybenzene (3.19e):


1H NMR 8 7.31


= 7.8 Hz


,2H), 7.20-7.00 (m, 8H),


(s, 1H),


6.80 (d, J


= 8.4 Hz, 1H),


6.63 (d,


= 8.1


1H, CH),


3.69 (s,


3H),


3.68 (s, 3H)


; 13C NMR


148.7


148.0,


140.9


, 136.0,


133.3


130.3


128.4,


128.1


127.1


, 126.4,


120.5


lilA4,


110.8, 56.9, 56.8,


4- rPhenyl(phenylthio)methyllphenol (3.19f):


1H NMR 8 7.40 (d, J


= 8.6 Hz


2H),


7.30-7.10 (m, 9H),


6.82 (d, J


4 Hz, 1H),


.49 (s,


CH),


.37 (br, 1H, OH);


13C NMR 8 154.6


141.1


136.1


133.4


,130.4, 129.7


, 127.1, 126.5, 120.7


115.3, 56.7.


3-Methyl-4-[phenyl(phenylthio)methyllphenol (3.19g):


1H NMR 8 7.40-7.36


(m, 3H),


7.28-


7.10 (m, 8H),


6.63 (m, 2H),


.65 (s, 1H, CH),


.30 (br, 1H, OH),


31- CH&~


13 NMR 8


140 6


137 6


1367


111 1


1 1() 01


170 R


I i-


._


,,










4-fPhenyl(phenylthio)methyll -1 -naphthol


(3.19h):


1H NMR


8 8.21


8.05 (d, 1H), 7.54 (d, 1H),


7.40 (m,


3H),


7.35-7.02 (m, 9H),


6.62 (d, 1H), 6.


23 (s, 1H,


CH),


5.94 (br, 1H, OH); 13C NMR


140.8


, 137.0, 132.1,


,128.8, 1


8.6, 1


, 127.9, 127.1,


127.0, 126.8,


126.1


,124.9, 123.4, 122.


107.9


(CH).


4- (4-Methyvlphenvl)(phenylthio)methyl-l1,2-dimethoxy


benzene


(3.19i):


NMR 8 7.20 (d, J


=7.6 Hz, 2H),


7.13 (d, J


=7.8 Hz, 2H),


7.05-6.95 (m, 5H), 6.86 (s,


6.80 (d, J


=7.5


Hz, 1H),


6.61 (d, J


= 8.4 Hz,


5.38 (s,


1H, CH), 3.66 (s, 6H,


2 x OCH3),


16 (s, 3H, CH3)


13C NMR:


8 148.7


, 147.9, 137.9,


136.7


, 136.3, 133


130.1


129.1


,128.0, 126.


,120.4, 111.4, 110.8, 56.6,


, 55.6, 20.9 (CH3).







24








Table 3.1 Thioalkylation of Active Aromatic Compounds


Thio-


Prod-
uct


alkylation
position


Yield


mp (oC)


3.19a


3.19b


3.19c


3.19d


3.19e


3.19f


3.19g


3.19h


3.19i


PhOMe


1-MeOCo1H7


1-MeOCIoH7


2-MeOCIoH7


o-(MeO)2C6H4


PhOH


96-98


119-121


116-117


123-125


92-93


99-100


m-MeC6H4OH


1-CloH7OH


o-(MeO)2C6H4





















Table 3


.2 Microanalyses / HRMS data of Thioalkylated Products 3.19a-i


Compd


Molecular
Formula


Analysis / HRM


required


found


3.19a


3.19b


3.19c

3.19d

3.19e

3.19f

3.19g


C2oH18OS


C24H2oOS


C24H20OS

C24H2oOS

C21H2oOS

C19H16OS


78.40


80.86


80.62


80.86


80.94


80.86


81.27


74.97


74.90


78.05


77.65


306.1087


3.19h


343.1157


306.1087


343.1171


3.19i


C22H22OS


350.3333


350.1333


5.90


C20H18










CHAPTER IV
HETEROARYLALKYLATION OF HETEROAROMATIC COMPOUNDS:
CONVENIENT NOVEL SYNTHESES OF 1,1-BIS(HETEROARYL)ALKANES


4.1 Introduction


Bis-heterocyclylmethanes


are of


interest


to the


food


industry


as they


present


natural


compounds


food


beverage


items


such


licorice


[77MI1


For example, difuryl-


and dithienyl- alkanes are flavor agents in coffee


[90MI802,


67HCA628].


Many


bisheterocyclylmethanes


are also


importance


dyestuff


chemistry as they are readily oxidized to the corresponding cyanine dyes


[63MI540,


63CA573861a].


Furthermore,


1,1-bis(heterocyclyl)alkanes are important


intermediates


synthesis


various


heterocyclic


macromolecules


[77MI47


78CA90046p],


for example


dipyrromethanes


have


been


widely


used


as synthetic


intermediates in total syntheses of porphyrins [78MI1]. The action of dichloromethyl


alkyl


ether


tin(IV)


chloride


on diheteroarylmethanes


a useful


route


polycyclic heteroaromatic systems [73JCS(P 1)1099].


Het


Het'


4.1


Several synthetic routes to bis-heteroarylmethanes 4.1 are known, but none is


both


general


convenient.


Many


are only


applicable


to the


preparation






27



symmetrical bis(heterocyclyl)methanes. Di-2-furylmethane has been prepared by the


reduction


di-2-furyl


ketone


[32HCA1066]


interaction


2-chloromercurifuran

corresponding dil


furfuryl


chloride


heteroarylmethanols


[33JA3302].

gives


Reduction


diheteroarylmethanes


[73JCS(P1)1099].


However, most of these methods are limited to the preparation of


compounds in which an unsubstituted methylene group links the two heteroaromatic


rings


(4.1,


- Het'


= H),


their


utility


further


restricted


inaccessibility


heteroaryl-lithium


suitable


with


diheteroaryl


ketones


a heteroarylmethyl


methanols.


chloride


reaction


[73JCS(P 1)1099]


gives


diheteroaryl


methane,


requires


severe


conditions.


Thiophenes,


furans


pyrroles with free a-positions are susceptible to electrophilic attack by aldehydes or


ketones


known


route


(diheteroaryl)methane


derivatives


[63AHC1]. However, this type of condensation generally requires a strong inorganic


catalyst, such as


75% H2S04 [51JA1377] or hydrochloric acid [56CJC1147].


These


experimental


conditions


present


drawback


causing


resinification


[51JA1270] and degradation [72ACS1018] of the heterocyclic rings of substrates and


products.


improvement


this condensation


using


macroporous


ion-exchange


resins


as catalyst


[89SC3169]


satisfactory


preparation


difuryl


dithienyl derivatives.

Unsymmetrical bis(heterocyclyl)methanes are far less explored, in fact some


structurally


simple


bis(heterocyclyl)methanes,


especially


different


heterocyclic ring systems, are not known.


synthetic


procedures available


have only


to a limited number of


compounds of this class.


Perhaps the most


*


- -- .- ~ ~-L-- .L1.


Lu-,


cv-. a: -~


,,,,,,,,,1~,,


,l,,tl,










diheteroarylmethanes in 32-76%


yield [910PP403], however,


use of this reduction


method has been confined to the methylene derivatives (4.1, R = H). Moreover, the


preparation


diheteroarylmethanols


usually


requires


lithiation


under


severe


conditions.


Alkyl


a-methoxy-


a-hydroxy-pyrrylacetates


interact


with


N-methylindole in the presence of Lewis acids to give diarylacetic esters [92SL745],


but the starting materials are not easily available and


this method is not


general.


Condensation of an a-acetoxymethylpyrrole with an appropriately substituted pyrrole


with


a free


a-position


in acetic


[70AJC2443],


presence


toluene


p-sulphonic


[72TL2203]


Montmorillonite


[85TL793]


produces


unsymmetrical dipyrrolylmethanes. However, the isolation of the product from tarry

reaction by products is tedious. Symmetrical pyrrolylmethanes are often formed as


by-products


self-condensation


acetoxymethylpyrrole


[74JCS(P1)1188,


75CC570], and the method is useful only for the fully substituted dipyrrolylmethanes

in order to avoid polymerization. Unsymmetrical difurylmethanes are obtained from


reaction


5-methylfurylphosphinyl


carbinol


furan


followed


Wittig-Horner reaction


[85TL6399],


but this method is not general.


Alkylation


furan, thiophene, and pyrrole with furfuryl alcohol in


the presence of the strongly


acidic


Amberlyst


cation


-exchange


resin


affords


respective


2-furylhetarylmethanes [89KGS746], however,


the yields are low and


purification is


difficult


(preparative


GLC)


because


formation


difurylmethyl


ether


resinous by-products.


now


report


in this chapter


a general


convenient


method


preparation of both symmetrical and unsymmetrical bis-heterocyclic alkanes via the


heternarvlalkvlation


L.II


heternarom atic


comnounds


with


nr-henzotriazolvlalkvl






29





4.2 Results and Discussion



4.2.1 Condensation of Benzotriazole, Aldehydes and Carbamates


Mannich condensation of benzotriazole, an aldehyde, and a carbamate is


known


N-(1-benzotriazol-l-ylalkyl)carbamate


good


yield


[90JOC2206].


Thus the benzotriazole derivatives 4.2a,


4.2b,


4.2c and 4.2d were prepared by the


literature procedures in 84%, 78%, 74% and 69


yields respectively (see


Table 4.1)


(Scheme 4.1 ). The 1H and 13C NMR spectra of these benzotriazolylalkyl carbamates


(Table 4.2


and 4.3) indicated that they were all benzotriazol-1-yl isomers, furthermore


no isomerization


to the


2-isomer


was


observed


dimethyl


sulfoxide


room


temperature.


This


behaviour


similar


found


N-( 1-amidoalkyl)benzotriazoles [90JOC2206].


H2NCO2R'


RCHO


TsOH / Benzene


reflux


4.2a:
4.2b:
4.2c:
4.2d:


= i-Pr
= Ph.


=Me


=Me
=Me


84%
78%
74%


NHCO2R


=Ph


Scheme 4.1







30



4.2.2 Preparation of Symmetrical Bis-heteroarvlalkanes


methyl


N-(ac-benzotriazol- 1-ylalkyl)carbamates


4.2a,


4.2b


reacted smoothly with an excess amount of 2-methylthiophene or


2-methylfuran in


CH2C12


presence


chloride


room


temperature


corresponding


symmetrical


1,1 -bis(heteroaryl)alkanes.


reaction,


ZnC12


CH2C12


excess


4.3a:
4.3b:
4.3c:


= i-Pr
=Ph
=H


ZnC12


CH2C12,


excess


4.4a:
4.4b:


= i-Pr
= Ph


Scheme 4.2



benzotriazole and methoxycarbamoyl acted as leaving groups and each was replaced


a heterocycle.


1,1 -Di(5-methylthiophen-2-yl)alkanes


4.3a,


4.3b










occurred at the free a-positions of furan and thiophene as shown by the

spectra of the products.


1H NMR


Similarly,


phenyl


N- (a-benzotriazol- 1-ylbenzyl)carbamate


4.2d


gave


a,a-di(5-methylfur-2-yl)toluene 4.4b in 65%


2-methylfuran in CH2Cl2


yield on


with zinc bromide as the ca


treatment with an excess of

italyst. However, the methyl


carbamate is a better reagent in light of the yield and the ease of product purification.

The five symmetrical 1,1-bis(heterocyclyl)methanes (4.3a-c, 4.4a-b) were all

previously unknown and were characterized by elemental analyses or high resolution

mass spectrometry and by 1H and 13C NMR spectra (Table 4.5 and 4.6).



4.2.3 Preparation of Unsymmetrical Bis-heteroarylalkanes


It is clear that the


reactions shown


Scheme


proceed


stepwise.


departure of either benzotriazole or the alkoxyamido group with the assistance of the


Lewis


to the


formation


a carbocation


which


was


stabilized


remaining carbamate or benzotriazolyl group (via the iminium ion).


This carbocation


then attacks the electron-rich heterocycle ring to give a monosubstituted intermediate.


This process is repeated if


excess of the heterocycle is present in the solution to


produce


only


the symmetrical


one equivalent


bis-heteroaromatic methane.


a heterocycle


Based on


added,


this hypothesis,


monosubstituted


intermediate should be formed. If it could be isolated, it should react further with a

different heterocyclic molecule, and provide a useful synthetic route to unsymmetrical

bis-heteroarylmethanes.


Indeed,


when methyl N-(a-benzotriazol-l-ylalkyl)carbamate 4.2a was treated







32



(thiophen-2-yl)-2-methylpropyl]carbamate 4.6, and the bis(thiophen-2-yl)alkane 4.3a


(Scheme

could be


4.3).


2-Methyl-5-[ 1-(benzotriazol-1 -yl)-2-methylpropyl]thiophene


; separated either by


column chromatography


(4.5)


or by recrystallization from


CHCl3/hexane.


CH2C12


It reacted

; presence


readily

of zil


with


2-methylfuran


chloride


room


or with


1-methylpyrrole


temperature


unsymmetrical bis-heteroaryl alkanes 4.7 and 4.8 in 92% and


52%


yields (Table 4.7),


respectively


(Scheme


4.4).


reaction,


benzotriazole


activated


CH2Cl2

ZnCl2,


NHCO2CH3


Scheme 4.3


Lr-f2.


Jll_... ~ ~. l_~.lt_~ ~1.~..1_ _C I r Pr"






33



methoxycarbamoyl group is also a suitable leaving group and can also be substituted


a heterocycle,


mixture


compounds 4.5


4.6 on


treatment with


2-methylfuran under the same conditions gave the expected product 4.7 in 95%

and with 2-methylpyrrole afforded the compound 4.8 in 65% yield (Scheme 4.5).


yield,


ZnC12


CH2C12, r.t.


ZnC12


CH2Cl2


Scheme


- methylfuran


(mixture)


- methylpyrrole


95%


65%










Similarly,


when


carbamate


4.2a


was


treated


with


equivalent


2-methylfuran,


a mixture


benzotriazole derivative


methyl N-[l-(fur-2-


yl)-2-methylpropyl]carbamate 4.10 and


bis-(fur-2-yl)alkane 4.4a


was afforded.


ZnC12


, CH2CI2


N
N
/
N


NHCOOCH3


4.4a


4.10


ZnCI2


CH2CI2
r.t.


Scheme 4.6


Treatment of the mixture of compounds 4.9 and 4.10 with 1-methylpyrrole in CH2C12


in the presence of zinc chloride at room temperature gave


1-(1 -methylpyrrol-2-yl)-










The carbamate 4.2a reacted with


1-methylindole in a


ratio in CH2C12


under the


same conditions


give,


after recrystallization


from


CHCl3/hexane,


[(a-benzotriazol- 1-yl)alkyl]indole 4.12


70%


yield


as the


only isolated


product.


Intermediate


was


treated


further


with


2-methylthiophene


with


2-methylfuran


room


temperature


afford


3-(a-fur-2-yl)alkyl-


(4.13)


3-(a-thiophen-2-yl)alkylindole (4.14) respectively in excellent yields (Scheme 4.7).


CH2Cl2


4.2a


ZnC12
0C to r.t.


CH2C12


ZnC12


Scheme 4.7


practice,


however,


is not


necessary


to isolate


intermediates






36



reacting 4.2a with successive molar equivalents of 1- methylindole and 2-methylfuran

as illustrated in Scheme 4.8.


NHCOOCH3


4.2a


1-methylindole
2 -methylfuran


, ZnCl2
, ZnCl2


, CH2C12
, CHzCl2


Scheme 4.8



The proposed structures of the new unsymmetrical bis-heteroaryl alkanes 4.5,

4.7, 4.8, 4.11-4.14 were confirmed by NMR spectroscopy, elemental analyses or high

resolution mass spectrometry.


each


these


compounds


a-CH


group


showed


a large


coupling


(J=8.3-10.4


to the


P-CH


spectra.


Similarly


a-carbons


characteristic


resonance


between


8=43.8-66.1


NMR spectra.


features of the NMR spectra of the benzotriazolyl substituted intermediates 4.5 and

4.12 indicated that they were the benzotriazol-1-yl regioisomers. For those products

containing either the 2-methylthiophene or 2-methylfuran moieties the two doublets (J


= 3.5


two ortho-heteroaromatic


protons


were


strong


evidence






37



4.13 and 4.14 was indicative of substitution of the 3-position. Detailed assignments of

the NMR spectra are listed in Table 4.8, 4.9 and in the experimental section.

We believe that the reaction of a-benzotriazolylalkyl substituted heterocycles

with thiophene, furan or indole involved electrophilic attack by the carbocation of


1.4 which was stabilized by the heteroatom as illustrated in the introduction.


Similar


to the


thioalkylation


discussed


Chapter


Lewis


acids


assisted


ionization of these benzotriazole derivatives.


The ease


with


which


these


carbocations


can be


formed


their


smooth


reactions with a variety of heteroaromatics has provided a new and significantly more

convenient route to the corresponding bis-heteroarylalkanes. In addition to affording


good to excellent yields,


this novel methodology also incorporates the advantage of


simple removal of the benzotriazole auxiliary from the product mixture by extraction

with dilute base.


4.3 Experimental


Melting points were determined


with a Kofler hot stage apparatus without


correction.


1H and


13C NMR spectra were taken at 300 and 75 MHz, respectively.


Tetramethylsilane was used as the internal standard for the 1H NMR spectra, and the


central line of CDC13 (5


= 77.0) or DMSO-d6 (5


= 39.5) was referenced in 13C NMR


spectra.



4.3.1 N-(a-Benzotriazolvlalkyl)carbamates 4.2a, 4.2b, 4.2c and 4.2d






38



4.3.2 General Procedure for the Preparation of Symmetrical 1,1-Bis(heteroaryl)-
alkanes 4.3a, 4.3b, 4.3c, 4.4a and 4.4b


mixture


N- (a-benzotriazolylalkyl)carbamate


mmol),


heterocycle (


mmol) and zinc chloride (20 mmol) in dry methylene chloride (50


mmol) was stirred at room temperature overnight and poured into ice-water (50 ml).


The water layer was extracted with chloroform (2 x 20 ml).


layer was washed with NaOH solution (30 ml,


MgSO4 (10 mg).


The combined organic


and water (30 ml) and dried over


The solvent was evaporated and the residue was purified by column


chromatography (silica gel, CH2C12) to give the pure product (Table 4.4).



4.3.3 2-Methyl-5- 1l-(benzotriazol- 1-yl)-2-methylpropyllthiophene (4.5)


was


prepared


procedure


described


above


symmetrical


1,1-bis(heteroaryl)alkanes


from


methyl


N-[ 1 -(benzotriazol- 1 -yl)-2-methylpropyl]-


carbamate


(2.5g,


10 Ommol),


2-methylthiophene


(0.98g,


l0mmol)


zinc chloride


(1.36g,


10mmol).


was


purified


recrystallization


from


CHCl3/hexane


(yield


56%). mp. 90-91C.


IH NMR (CDC13) 6 7.94 (d, J


= 8.3 Hz, 1H),


7.50 (d, J


= 8.3 Hz,


7.34 (t, J


= 8.1 Hz, 1H), 7


= 8.2 Hz, 1H), 6.85 (d, J


= 3.4 Hz, 1H), 6.45 (d,


= 3.4 Hz, 1H), 5.50 (d, J


1.01 (d, J


= 10.4 Hz


,1H, CH),


6.6 Hz, 3H, CH3),


(d, J


.96 (m, 1H, CHMe2),


= 6.5


z, 3H, CH3)


2.28 (s, 3H,

13C NMR 8


145.8


140.3


138.3


, 132.4, 126.9, 126.6, 124.4, 123.6, 119.9,


109.7


, 66.1 (CH), 33.7


20.6, 20.5, 19.9.


Anal.Calcd for C15H17N3S: C,


66.39; H,


6.31; N, 15.48.


Found: C,


66.47


15.77.


crude


mixture


was


separated


column


chromatograpy (silica gel, CH2C12), it gave 4.3a (10%) and a mixture of 4.5 and 4.6

(59% and 16% respectively based on the 'H NMR).


CH[3),






39



4.4.4 1-Methyl-3-[1-(Benzotriazol-1 -vl)-2-methvlpropyl]indole (4.12)


1-Methylindole (10 mmol) was added to a mixture of


4.2a (10 mmol) and


ZnCl2 (15 mmole) in dry CH2C12 (40 ml) at 0C. The solution was stirred at 0C for

2h then allowed to warm to room temperature and stirring continued overnight. After

work-up as above, the product was purified by column chromatography (silica gel,


CH2C12). (yield 70%). mp.147-1480C,


1H NMR (CDC13) 8 8.00 (d, J


.2 Hz, 1H),


7.69 (d, J


= 8.0 Hz, 1H), 7.55 (d, J


= 8.4 Hz, 1H), 7.38-


(m, 3H), 7.18 (t, J = 6.7


Hz, 1H),


7.08 (t, J


= 7.9 Hz


,1H),


5.80 (d, J = 10.2 Hz, 1H, CH), 3.72 (s, 3H, CH3),


3.23 (m, 1H, CHMe2), 1.12 (d, J


= 6.6 Hz, 3H, CH3), 0.85 (d, J


6.6 Hz, 3H, CH3)


13C NMR 8


145.8,


136.6,


132.8,


127.6,


127.5,


126.9,


121.9


, 119.8,


119.6,


118.9


, 111.9, 109.9, 109.3, 62.9,


32.9, 32.8,


20.9, 20.1. Anal.Calcd for C19H20N4: C,


74.97


H, 6.62


N, 18.41.


Found:


C, 75.03; H,


N, 18.40.


4.4.5 1-(5-Methylfur-2-yl)-1-(5-methylthiophen-2-yl)-2-meth ylpropane (4.7); Typical
procedure for Unsymmetrical 1,1-Bis(heteroaryl)alkanes 4.7, 4.8, 4.11, 4.13 and
4.14.

To a solution of either compound 4.5 (2.6g, 10mmol) or a mixture of 4.5 + 4.6

(10mmol) in dry methylene chloride was added 2-methylfuran (0.82g, 10mmol) and


zinc chloride (1.4g, 10mmol).


The mixture was stirred at room temperature overnight


and worked-up as for the symmetrical derivatives. Similarly, 4.8 was prepared from


1-methylpyrrole and either 4.5 or the mixture of


4.5 + 4.6


compound 4.11


from


2-methylfuran


+ 4.10;


compound


4.13


from


2-methylfuran


4.12;


compound 4.14 from 2-methylthiophene and 4.12 (Table 4.7).






40


4.4.6 One-pot Preparation of 1-(5-Methylfur-2-yl)-1-(1-methylindol-3-vyl)-2-methyl-
propane (4.13)

A mixture of 4.2a (10 mmol), 1-methylindole (10 mmol) and zinc chloride (10


mmol)


methylene


chloride


was


stirred


room


temperature


overnight.


2-Methylfuran (10 mmol) and zinc chloride (10 mmol) were added and the solution


stirred at the same temperature for an additional lOh.


The work-up procedure was as


described above.



















Table 4.1


Preparation of N-(1-benzotriazolylalkyl)carbamates


compd R R' mp(C) yield(%) molecular found (required)
formula C H N


4.2a iPr Me 118-120 84 C12HI6N402 58.05 6.53 22.44
(58.05) (6.50) (22.57)


4.2b Ph Me 123-124 78 C15H14N402 63.87 5.03 19.90
(63.82) (5.00) (19.85)


4.2c H Me 155-156 74 C9H1oN402 52.38 4.86 27.45
(52.42) (4.89) (27.17)

69.59 4.73 16.27
4.2d Ph Ph 162-164 69 C2oH6N402 69.59
(69.76) (4.68) (16.27)

















Table 4.2


1H NMR Data of N-(1-Benzotriazolylalkyl)carbamates 4.2


Cpd Benzotriazole


(each


J, Hz)


OMe


Other Signals


JHz)


(J Hz)


4.2a


8.10


7.59


6.15(t, J=9.0, 1H),


(d, J=9,0) (t, J=


=7.6)


.4) (d, J


=8.7)


.71(m, 1H),


(d, J=6.6,


3H), 0.57


(d, J=6.6, 3H)


4.2b


(m)a


(t, J=


4) (d,


7.86(d, J
7.41(m,


=8.5)


.6, 1H),


6.06(d, J=6.8,


(d, J=8.3)


(t, J=


(t, J=6.9)


4.2d


7.44

(m)a


86(m,


(m)"


=8.5)


7.44(m,
7.18(m,


2H),
7H),


7.18(m, 1H)


a Overlapped with Ph-H


(m)a








43











-
v U


Ca rr -) en
*^ -
Uv 'a _'a
N '-00 N1
-~~o Go, 00 CMtf

a1 -cC
'a en; 'a';Inc
'- ON( In ''vn0 I


I In tA v

o~ ON n en I

-4 en 001 C M
-q 0

FI.


SU 4-4 -


I ~

Cuv- In ~.Otf
od C) '-4 -4


C() -l *


ON -4 -I -4


en U -

o~ cl 'ci" ON
N Nu N


















Table 4.4


Preparation of Symmestry 1,1-Bis(heteroaryl)alkanes 4.3, 4.4


HR MS / Analysis
Cpd Heteroaryl R mp Molecular found required Yield
(C) Formula C H C H (%)

4.3a 5-methyl- i-Pr 45 -46 C14H18S2 67.07 7.26 67.15 7.25 90
thiophen-2-yl


4.3b 5-methyl- Ph oil C17H16S2 284.0717 284.0694 94
thiophen-2-yl


4.3c 5-methyl- H oil C11H12S2 208.0380 208.0380 86
thiophen-2-yl


4.4a 5-methyl- i-Pr oil C14H1802 218.1304 218.1307 88
fur-2-yl


4.4b 5-methyl- Ph oil C17H1602 252.1167 252.1150 90
fur-2-yl (65)*


from


phenyl N-(1-benzotrazol-l-yl) carbamates 4.2d



















Table 4.5


1H NMR Data of Symmetrical 1,1-Bis(heteroaryl)alkanes 4.3, 4.4


Cpd heteroaryl 5-methyl CH R
(S, 611H)


4.3a 6.56(d,J=3.3Hz,2H), 2.38 3.89(d,J=9.0Hz) 2.17(m,1H,CHMe2),
6.50(d,J=3.6Hz,2H) 0.94(d,J=6.7Hz,6H)


4.3b 6.56(d,J=3.4Hz,2H), 2.39 5.66(s) 7.29(d,J=4.2Hz,2H)
6.54(d,J=3.3Hz,2H) 7.25(m,3H)


4.3c 6.62(d,J=3.4Hz,2H), 2.40 4.16(s,2H,CH2)
6.54(d,J=3.3Hz,2H)


4.4a 5.96(s,2H), 2.24 3.68(d,J=8.0Hz) 2.29(m,lH,CHMe2),
5.85(s,2H) 0.88(d,J=6.8Hz,6H)


4.4b 5.80(s,2H), 2.02 5.28(s) 7.20-7.08(m,5H,Ph)
5.77(s,2H)





















Table 4.6


"C NMR Data of Symmetrical 1,1-Bis(heteroaryl)alkanes 4.3, 4.4


Cpd heteroaryl 5-methyl CH R


4.3a 145.5,137.7, 15.2 50.5 35.4(CH),21.3(CH3)
124.2,124.1

4.3b 145.1,138.9, 15.4 47.8 143.6,128.3,128.2,126.8
125.5,124.4

4.3c 141.1,138.4, 15.3 30.5 -

124.7,124.6

4.4a 153.2,150.2, 13.6 46.3 31.2(CH),20.7(CH3)

106.7,105.8

4.4b 152.7,151.2, 13.7 45.1 139.8,128.3,128.2,126.8
108.1,105.9






















Table


Preparation of Unsymmestrical 1,1-Bis(Heteroaryl)alkanes


4.7-8, 4.11,


4.13-14


Yield


cursor


Form


(%)


Molecular
Formula


HR -MS / Analysis
found required


C14H18OS


234.1071


234.1078


4.5 + 4.6


C14Hi9NS


233.1221


233.1238


5+ 4.6


4.11



4.13


4.9 + 4.10


CI4H19NO



CisH21NO


4.12


217.147


217.1467


267.1624


267.1623


- Pot


4.14


4.12


C18H21NS


75.95


4.86


76.28


4.94















Table 4.8


H NMR Data of Unsymmetrical l,l-Bis(Heteroaryl)alkanes


4.7-8, 4.11, 4.13-14

Cpd Het1 Het2 CH iPr


5-methylthiophen-2-yl

6.64(d,J=3.4Hz, H),
6.53(d,J=3.3Hz, H),


2.40(s,3H,CH3)


5-methylfur-2-yl

5.95(d,J=3.1Hz, 1H),
5.83(d,J=3.0Hz, 1H),


3.75(d,


J=8.8Hz)


2.24(s,3H,CH3)


m,IH,CHMe2),


0.91(d,J=6.6Hz,3H,CH3),
0.89(d,J=6.6Hz,3H,CH3)


5-methylthiophen-2-yl
6.45(d,J=3.3Hz,1lH),
6.41(d,J=3.0Hz,1H),


2.32(s,3H,CH3)


5-methylfur-2-yl


5.81(s,2H)


.23(s,3H,CH3)


1-methylpyrrol-2-yl


6.40(m,lH),


6.01(d,J=2.1Hz,2H),
3.38(s,3H,NCH3)


1 -methylpyrrol-2-yl
6.49(t,J=2.3Hz,1H),
6.07(d,J=2.3Hz,2H),
3.48(s,3H,NCH3)


3.60(d,


J=9.0Hz)


3.60(d.
J=8.5Hz)


.20(m,lH,CHMe2),


0.97(d,J=6.7Hz,3H,CH3),
0.86(d,J=6.7Hz,3H,CH3)


2.33(m,lH,CHMe2),
0.94(d,J=6.6Hz,3H,CH3),
0.89(d,J=6.8Hz,3H,CH3)


5-methylfur-2-yl
5.95(d,J=2.9Hz, H),
5.81(d,J=3.0Hz, IH),


2.24(s,3H,CH3)


5-methylthiophen-2-yl

6.67(d,J=2.9Hz,1H),
6.49(d,J=2.7Hz,lH),


2.37(s,3H,CH3)


1-methylindol-3-yl
7.64(d,J=7.8Hz,lH),
7.24(d,J=7.5Hz,1H),
7.18(d,J=8.0Hz,1H),
7.07(t,J=8.0Hz,lH),
6.96(s,lH,H-2),
3.71(s,3H,NCH3)


1-methylindol-3-yl

7.62(d,J=7.8Hz,lH),
7.23(d,J=8.0Hz, 1H),
7.18(t,J=7.8Hz,lH),
7.07(t,J=8.0Hz,lH),
6.93(s, 1H,H-2),
a 'IIm -U NrOT-I


3.90(d,


J=8.3Hz)


4.09(d,
J=8.5Hz)


2.44(m


,1H,CHMe2),


0.93(d,J=6.6Hz,3H,CH3),
0.89(d,J=6.SHz,3H,CH3)


2.43(m,lH,CHMe2),
0.98(d,J=6.7Hz,3H,CH3),
0.95(d,J=6.8Hz,3H,CH3)

















Table 4.9


13C NMR Data of Unsymmetrical 1,1-Bis(Heteroaryl)alkanes


4.7-8, 4.11,


4.13-4.14


Cpd Het1 Het2 CH iPr


5-methylthiophen-
143.0,137.7,124.5,


124.3,1


4.13


(CH3)


5-methylthiophen-2-yl
145.3,137.9,124.0,
123.9,15.3(CH3)

5-methylfur-2-yl
154.4,150.1,106.5,
105.7,13.7(CH3)

5-methylfur-2-yl
155.9,149.8,106.0,


5-methylfur-2-yl
154.8,150.4,106.4,


33.6,
21.0,
20.9


105.8,13.6(CH3)


1-methylpyrrol-2-yl


135.2,1


1.0,106.4,


46.3


105.2,22.1(CH3) 2

1-methylpyrrol-2-yl


132.9,120.9,106.4,
106.3,21.6(CH3)

1-metheylindol-3-yl
136.7,127.7,126.7,1:


1.1.119


105.6,13.8(CH3,)


118.4,115


108.9,21.4(CH3) 21.3


4.14


5-methylthiophen-2-yl
146.9,136.9,124.0,


1 -methylindol-3-yl


136.7,127.6,126.2,121.3,119


123.8,15.4(CH3)


118.5.117


,109.0,


1.7(CH3) 21.6












CHAPTER V
INDOLYLALKYLATION. PART I:
VERSATILE SYNTHESIS OF 3-SUBSTITUTED INDOLES


5.1 Introduction


3-Substituted


indoles


are potential


intermediates


many


alkaloids


pharmacologically


important substances [91JMC 140,


89JMC890]. Accordingly, the


synthetic elaboration of the indole side chain at the 3-position has been employed as a

key step in the synthesis of related alkaloids.


Numerous synthetic


approaches


to 3-substituted


indoles are


known, among


which,


the methods


via 3-


(dimethylaminomethyl)indole [53JA1967


54CB692]


3-bromomethylindole


[92JHC953]


most


important


introducing


extending functionalized carbon chains at C-3. However, both of these methods are


limited to the preparation of compounds


n which an unsubstituted methylene group


links the indole ring and the nucleophile.


It is


known


deprotonation


chains


it-deficient


N-heteroaromatics pyridinee and quinoline) followed by electrophile quenching is an


important


synthetic


route


chain


functionalization


[85HHC1,


84CHC1].


However,


methods


metallation


chains


n-electron


heteroaromatics


such


as indole


are much


advanced.


Previous


work


laboratory has succeeded in introducing functionality to the 2-alkyl side chain with

carbon dioxide [86JA6808], but few other methods are known for the metallation of


an alkyl group on C-2 [90JCS(P1)179].


We are aware of only two reports dealing with










the analogous


3-alkylindole metallation,


both methods are confined


to cyano


derivatives.


Deprotonation


of 3-cyanomethylindole


sodium


amide in liquid


ammonia [62BSF290] and (ii) sodium hydride [74KGS1502] gave a cyano stabilized

carbanion which was subsequently quenched by electrophiles.

Work in our laboratory has demonstrated that benzotriazole can sufficiently


stabilize

Chapter


an a-carbanion


we have


to its electron-withdrawing


described


versatility


ability


[91JOC6917].


of benzotriazolylalkyl


substituted


heterocycles in the synthesis of 1,1-bis-(heteroaryl)alkanes (also


[93JOC4376]).


see Katritzky et al


Of these derivatives the utility of 3-(benzotriazolylalkyl)indoles has


now been further extended to provide new routes to a wide range of 3-substituted

indoles.


Results and Discussion


Our previous work has shown that


1-methyl-3-(benzotriazol-l-ylalkyl)indole


5.1a was readily available from the corresponding methyl N-(benzotriazol-l-ylalkyl)-


carbamate and


1-methylindole (see Chapter


Compound 5.1b was prepared in


58%


yield by the same procedure (Scheme


1 and Table


1). However, this method


was limited to the preparation of compounds in which R was an alkyl group.

In order to explore the generality of this methodology, attention was turned to


synthesis


1-methyl-3-(benzotriazol-1-ylmethyl)indole


(5.2),


which


was


expected


to undergo


deprotonation


subsequent


reaction


electrophiles


functionalize the side chain at the 3-position.


We were unable to access 5.2 by the


nn.- .min,,r I, A oln.r4.aA nkr,, FCr C 1, lo qn n C lh nr1,cilm!hlxv hptr-aiie it i; rnnr rtiffkillt tn













BtCH20H


Toluene


reflux


BtCHRNHCOOMe
ZnC12, r.t.


N
Me


5.2

In-BuLi


N
Me


Mel
Me3SiC1
Ph2CO
PhNCO


i-Pr
Et
Me
SiMe3
C(Ph)20H
C(=O)NHPh


Scheme


N-(benzotriazol- 1-ylmethyl)carbamate


compound 5.2 was prepared


[Chapter


Mannich


93JOC4376].


reaction of


However,


1-(hydroxymethyl)-


benzotriazole and 1-methvlindole in 40% vield As we expected denrntnnntinn nf 5.2










corresponding


anion,


which


treatment


with


methyl


iodide


chlorotrimethylsilane gave the corresponding alkylated and silylated products 5.1c

and 5.1d in yields of 95% and 93%, respectively (Scheme 5.1 and Table 5.1). Using


benzophenone


phenyl


isocyanate


electrophiles


gave,


respectively,


corresponding alcohol 5.1e and amide 5.1f in excellent yields (Scheme 5.1 and Table

5.1).


1-Methyl-3-(benzotriazol-1 -ylalkyl)indoles


5.1b-f


were


previously


unknown


were


characterized


elemental


analyses


or high


resolution


mass


spectrometry and by 1H and 13C NMR spectroscopy (Tables


5.3 and 5.4).


chemical shift of the methine carbon of 5.id was upfield of those of the alkylated


derivatives 5.1a-c and 5.1le-f, due to the shielding effect of silicon.


The presence of


the chiral center of 5.1e rendered the two phenyl groups non-equivalent as illustrated

by its 13C NMR spectrum, similar to the two methyl groups in 5.1la.


benzotriazole


moiety


1 -methyl-3-(benzotriazol-1 -ylalkyl)indoles


can be displaced by a variety of nucleophiles. As exemplified by the reactions of 5.1a,


a variety


3-substituted


indoles


were


prepared


(Scheme


Table


5.5).


Accordingly,


treatment


S.la


with


sodium


thiophenol


refluxing


n-butanol


afforded


1-methyl-3-(1-phenylthio-2-methylpropyl)indole


(5.3a)


73%


yield,


whereas reaction


with


ethylmagnesium


iodide in


boiling


toluene


gave 5.3b


(47%).


Compounds 5.3c (74%) and 5.3d (53%) were obtained by heating 5.la with


N,N-dimethylaniline or N-methylaniline respectively at


1500C. Noteworthy was the


fact that, in each case, the substitution occurred exclusively at the para-position of the

aniline moiety as shown by the AB pattern in the iH NMR spectra of the products.























N
N-N


R


5.3a-d








- CN 5.4







5.5


NaCN


1500C


NaSPh
EtMgBr

PhNMe2

PhNHMe


NMe2

NHMe


Scheme


This


regiospecificity


was


observed


3-(dimethylaminomethyl)indoles


[72CHE179].


5.3







55


singlet at ca 6.9 ppm for the 2-proton of the indole ring. An analogous result was

observed in the displacement of trimethylamine from 3-indolylmethylammonium salt

by cyanide ion [72CHE179].


3-Vinylindoles are important intermediates


for the synthesis of


substituted


carbazoles,


carbolines


DNA intercalating


agents


[92JHC953]


and are readily


available from 3-(benzotriazol-l-ylalkyl)indoles.


When compound


la was heated at


1500C for two days, the product isolated displayed no benzotriazole resonances in the


NMR spectra. Furthermore,


the presence of a vinylic proton signal illustrated that


elimination


benzotriazole


occurred


to afford


3-vinylindole


(50%)


(Scheme 5


.2 and Table 5.5).


Its formation is likely to occur by El elimination via the


carbocation of type 1.4.

(Trimethylsilylmethyl)arenes have been recognized as versatile intermediates


in organic


synthesis


[82TL5079],


until


recently


literature


contained


example of the synthesis of (trimethylsilylmethyl)indoles.


While Ishibashi et al have


reported


a two-step


synthetic


sequence


using


a-chloro-a-silylsulfide,


overall


yields are low (highest 34%) [93SC2381]).


We now report a readily accessible and


high-yielding


alternative


approach.


Heating


1-methyl-3-[(1-trimethylsilyl-


1-benzotriazol-l-yl)methyl]indole (5.1d) with an excess of methylmagnesium iodide

in toluene at 80C for 5 h gave (1-trimethylsilylalkyl)indole (5.6) in excellent yield


(Scheme


5.3 and Table 5.5).


It is worthwhile to mention


that our attempts to replace the benzotriazolyl


group from 5.1e and 5. f were unsuccessful. Upon treatment with thiophenolate 5.1e


reverted back to its starting materials, 5.2 and benzophenone,


while the reaction of














SiMe3


Me3Si


I N
N-N


MeMgI
Toluene


80 C


N
CH,


5.1d


Scheme


On the other hand, treatment of 5.1f either with thiophenolate in refluxing ethanol or

with 2-methylfuran under Lewis acid conditions always led to the total recovery of

the starting materials. This result indicated that compound 5.1f is not reactive towards

nucleophilic substitution due to the existence of the electron-withdrawing group, the

amide group, which is in agreement with the carbocation mechanism discussed above.


Results


shown


Chapter


have


demonstrated


ZnBr2


enhance


leaving ability


of benzotriazolyl


group.


Following a similar protocol,


interestingly,


a-indol-3-yl ketones, 5.7 and 5.8, were readily prepared in good yields


in one-pot by the subsequent addition of ZnBr2 to the reaction mixture of lithiated


1-methyl-3-(benzotriazol-l-ylmethyl)indole


p-chlorobenzaldehyde


cyclohexanone (Scheme 5.4, Table 5.5).

These results might be explained in terms of the formation of the carbocations

5.7b and 5.8b with the assistance of ZnBr2, and their subsequent rearrangements. In














n-BuLi / THF


2. p-C1C6H4CHO


Bt

1. n-BuLi / THF
2. cyclohexanone


CH3


5.8a


CH3


ZnBr2


ZnBr2


Bt


5.7b











5.7


CH3


CH3


5.8b











5.8


N
CH3


N
CH3


-C4


5.7a











The structures of indole derivatives 5.3a-d, 5.4, 5.5, 5.6, 5.7


and 5.8 were


confirmed by the 'H and 13C NMR data and by CHN microanalyses or high resolution

mass spectrometry. For 5.3a-d, the chiral center induced magnetic non-equivalence of

the two methyl groups in the adjacent iso-propyl group, as indicated by their 'H NMR

and / or 1C NMR spectra. Detailed assignments of the NMR data are given in Tables

5.6 and 5.7.


5.3 Experimental


Melting points


were determined with a


Kofler hot stage apparatus without


correction.


'H and 13C NMR spectra were recorded at 300 and 75 MHz, respectively.


Tetramethylsilane was used as the internal standard for the 'H NMR spectra, and the


central line of CDCl3 (6 =


77.0) or DMSO-d6 (6 =


) was referenced in the '"C


NMR spectra.



5.3.1 1-Methyvl-3-(benzotriazol-1-vlalkyl)indoles 5.1a and 5.1b

They were prepared by the literature procedure [Chapter IV and 93JOC4376].



5.3.2 General Procedure for the Preparation of 1-Methvl-3-(benzotriazol-1-ylalkyl)-
indoles 5.1c-f


a solution


mmol)


THF


was


added


n-butyllithium (2.5 M in hexanes


.0 ml,


.0 mmol) at


- 780C.


The solution was


stirred at


78"C for 1 h, and a solution of the corresponding electrophile (5.0 mmol)


* r..- in 1' t .


rr..


-,rnn/ tFr'


I1 I


* *s t. U l 't *~ -*~ .n n nn au)n n a nfl e~vg -nr a r.a km .t *I~ ao -U nl~o -


nrij-






59



30 ml). The organic layer was then washed with H20 and dried (MgSO4). The solvent


was


removed


afford


crude


product,


which


was


purified


column


chromatography (silica gel,


CH2C12) to give pure product.


5.3.3 1-Methvl-3-(benzotriazol-l-vlmethyl)indole 5.2


mixture


1-methylindole


(3.93


mmol)


1-(hydroxymethyl)-


benzotriazole (6.7 g,


45 mmol) in toluene (150 ml) was refluxed for 40 h. After the


solvent was evaporated, the residue was purified by column chromatography (silica


gel, CH2C12) to give the pure product (40%),


mp 153-1540C.


.3.4 1-Methyl-3-(1-phenvlthio-2-methvlpropyl)indole 5.3a


To a solution of thiophenol (0.55


g, 5 mmol) and sodium metal (0.12 g, 5


mmol) in n-butanol (50 ml) 5.1a (0.91 g, 3 mmol) was added and the mixture refluxed

for 50 h. n-Butanol was removed under reduced pressure and the residue dissolved in


CH2C12 (30 ml), washed with water (2


x 10 ml) and dried (MgSO4).


The solvent was


evaporated


residue


purified


column


chromatography


(silica


CH2C12


hexanes


: 1) to give the pure product (73%).


1-Methyl-3-( -ethyl-2-methvlropyvl)indole 5.3b


To a solution of 5.la (0.91 g, 3 mmol) in toluene (50 ml) was added a solution










with Et20 (3


x 30 ml).


The organic


layer was dried over MgSO4 and the solvent


evaporated.


The residue was purified by column chromatography (silica gel, hexanes)


to give a colorless oil (47%).



5.3.6 1-Methvl-3-[1-(4-N,N-dimethvlamino)phenvl-2-methyll proDvlindole 5.3c


To a small vial 5.la (0.4 g,


1.3 mmol) and N,N-dimethylaniline (0.24 g, 2


mmol) were added.


The mixture was heated in an oil bath at 1500C for


2 days and


then separated by column chromatography (silica gel, hexanes : ethyl acetate = 1 :1)

to give the pure product (74%).



5.3.7 1-Methvl-3-fl-(4-N-methvlamino)phenvl-2-methv lpropylindole 5.3d


To a small


vial 5.la (0.25


g, 0.8


mmol) and N-methylaniline (0.13


mmol) were added.


The mixture was heated in an oil bath at 150C for


then separated by column chromatography (silica gel,


hexanes


days and


ethyl acetate = 3


to give the pure product (53%).



5.3.8 1-Methyl-2-cvano-3-(2-methylpropvl)indole 5.4


To a solution of 5.1a (0.6 g,


cyanide (0.


mmol) in DMF (40 ml) was added sodium


4 mmol). The mixture was stirred at 1300C for 50 h. Ethyl acetate (60


ml) was added and the mixture washed with water (4


x 40 ml).


The organic layer was


dried


(M eSOfl


solvent evanorated.


residue


was


nurified


column










chromatography (silica gel, CH2Cl2


hexanes = 1 :1 ) to yield the pure product (60%)


as a colorless oil.


5.3.9 1-Methvl-3-(2-methvlpropen- 1-vl)indole 5.5


A solution of 5.1a (0.91 g, 3 mmol) in DMF (20 ml) was heated at 1500C for


days. Ethyl acetate (30 ml) was added and the mixture washed with water (3


x 30 ml).


The organic


layer was dried


(MgSO4) and the solvent removed.


The residue was


separated by column chromatography (silica gel, CH2C12


hexanes


: 1) to afford


the pure product (50%) as a colorless oil.


5.3.10 1-Methyl-3-( 1-trimethylsilvlethyl)indole 5.6


To a solution of 5.1d (1.0 g, 3 mmol) in toluene (50 ml) was added a solution


of methylmagnesium iodide (8 mmol) in Et20O (10 ml).


800C for


The mixture was heated at


hours. The reaction mixture was then poured into saturated aqueous NH4C1


(40 ml), and the aqueous layer extracted with Et20 (3 x 30 ml). The organic layer was


dried over MgSO4.


The solvent was evaporated and the residue purified by column


chromatography (silica gel, hexanes) to give a white solid (90%).


5.3.11 f1-Methvl-3-(4-chlorobenzoyl)methyllindole 5.7 and [1-methyl-3-(2-oxocarbo-
heptvl)lindole 5.8; General procedure


solution


mmol)


THF


was


added










THF (10 ml) was added.


The reaction mixture was stirred at this temperature for


further 2 h and a solution of ZnBr2 (0.95g,


4.2 mmol) in THF (10 ml) was added. The


mixture was


allowed


warm


to r.t. overnight and


refluxed


for 6


After


aqueous work-up, the crude product was purified by column (silica gel, hexanes


ethyl acetate


: 1) to yield the pure product.






63













Table 5.1 Preparation of Adducts 5.1a-f and 5.2


Compd Yield Method mp
(%) (oC)

5.la d 70 b 147-148

5.lb 58 b 131-132

5.1c 95 c oil

5.1d 93 c 176-177

5.1e 91 c 214-215

5.1f 90 c 233-234

5.2 40 a 153-154

aCondensation of 3-methylindole with BtCH2OH.
b Condensation of 3-methylindole with N-(benzotriazol- l-yl)-
carbamates.
c Lithiation / eletrophile-quenching of 5.2
d Previously obtained and characterized (Chapter IV)







64















In~
en -l~
o\N 0d eno

Vd V t 'n V
10 Cl
'C ci 0 en 0
a- CC


SI; 1,

cU


zcC; cd i ad
o- -



-C -r 'C

4) ~ \ VO V V it t)V

vN en cicc
~f'oc oorci c;
CU


cnO
Vt t V
C ~~ c UZ Z
Z rJurZ Z Z
ci Vt 0' Vt3:31

U U UU U


Ha


CUca
o -d -1 -b -) -
C)r ()( r








65










o -l

00 9 en 6 &
ci (1 '-a

vrII Ca '-I- II c
CM e Nn *

n r--
enI II N
+- o II- 14
clm 00 tii '- -4I
S"
en Nn N
r--N, -. In
O 4J *J/?

>1 N m -4S1-
E 'a'1 Ca '~ e
t-:~~I U II3 m3
in~I cI N-c~

ci -r-" Bj t
U' S.. U.m\do
C.) -N 'a uN en *,,,
-' 5- en'. QON;=dF

-I II 3,N 4 c
001 -c.l F'II ci d
-.~c -


en oE rr
o ~ I _
N ~-b I
00v -
O1
r, -4
0I a' 1
Z Ci -ci 3 5

-A -. U' ci5'
-4i '- 'S-- Ca O \\



C- en NI 00 CM 00
U' '0r ccaar
a ~ re 5
en en eni en e;vi




























r4 r


- S4


1p- -I


--


oR \6
-CI


ct d
-4O
- -


- -rl


-( -


v-.. J-,,


r-


I- l


Sd 00
0
- -


-~ -II


YIntn
c; ca
TCflN


r4 -


0000Q

odoRl


rl rl







67









zo 0




N o o n o
vi t~cc; en ent
N N\ -l -Q 0
'1CJ 0~ C( N
eND % 0
& NZ h~
-aI:o
U)"




en 0% cM y O
y;~.4 CMl CM 'C N N
(%4 c -i -I -1
tfl N enC tl-
o~\ ci enC -
CI 'C cih
*
-V UJ N1 -




en N\ c d r 5
*-- ci4 -




en


-S Inoo rLo o~ d
C) \

-c-




t n n 4 en 0 0 0 0 '
ON Njvi In; 'C In 0% Nj N




















































































-4 cJ










































\q rj













CHAPTER VI

INDOLYLALKYLATION. PART II: A GENERAL AND FACILE
SYNTHESIS OF HETEROCYCLO[B]-FUSED CARBAZOLES


6.1 Introduction


Heterocyclo[b]-fused carbazole systems


are of


great importance as they


present in many natural products [88MI3, 85MI1]. Moreover, many heterocycle-fused


carbazoles,


such as pyridocarbazoles


indolocarbazoles


have


proven


possess


very interesting biological activities [88MI3, 86MI1673, 85MI1].


Although


several


synthetic


routes


indolo[b]carbazoles


reported


[92JHC1237


89AP451, 70T3353,


63JCS3097


JOC1509], they usually used either


some


inconvenient


reagents


or tedious


procedures.


Furthermore,


only


confined to indolocarbazole systems.


There are no general methods available in the


literature


synthesis


of heterocyclo[b]-fused


carbazoles.


thieno[b]-


carbazole and furo[b]carbazole systems remain unknown previously.


Their supposed


inaccessibility is a possible explanation.


Herein


we delineate


a general


facile approach


for the construction


heterocyclo[b]-fused carbazoles: indolo[b]carbazole, thieno[b]carbazole, and furo[b]-


carbazole


systems


using


readily


available


1 -methyl-3-[(benzotriazol- -yl)-


methyl]indole


(5.2)


as the


precursor.


Work


Chapter


demonstrated


versatility of benzotriazolylalkyl substituted heterocycles in the synthesis of 1,1-bis-


(heteroaryl)alkanes


[93JOC4376].


these


derivatives


utility


1-methyl-3-






71



[(benzotriazol-1-yl)methyl]indole (5.2) has been especially extended to the synthesis


of a wide range of 3-substituted indoles as described in Chapter V


. Compound 5.2 has


now been further developed to provide an efficient route to various heterocyclo[b]-

fused carbazoles.



6.2 Results and Discussion



The requisite 1-methyl-3-[(benzotriazol-l-yl)methyl]indole (5.2) was prepared

in 40% yield from 1-methyl indole as described in Chapter V.

One of the key steps to heterocyclo[b]-fused carbazoles 6.7 is the generation


2-lithio


derivative


as shown


Scheme


Although


2-lithiation


directly from indoles has been well documented [53JA375, 73JOC3324, 89H745], the


lithiation


1-methyl-3-[(benzotriazol-l-yl)methyl]indole


(5.2)


always


occurs


regiospecifically


at the side chain


to the electron


withdrawing


nature


benzotriazolyl group as demonstrated by our previous observations (see Chapter V).


Thus,


regiospecific


2-bromoindole


generation


was


chosen


2-lithioindole


target


since


molecule


halogen-metal


exchange


methodology


been


efficiently


used


formation


reactive


carbanions


[92H2095, 83JOC2690].


Regioselective bromination of 5.2 was readily accomplished


using


bromine


as the


reagent


in CH2Cl2.


Accordingly,


2-bromoindole


was


obtained in 81% yield. That this bromination is regioselective in the desired sense was

indicated by the disappearance of the 1H singlet (2-proton of indole) at ca 7.0 ppm in

the 'H NMR spectrum of 6.1.












Bt

Br2


BtCH2OH


CH2C12


N

Me


tert-BuLi


CHO


N

Me


HetCHO
Mel / HMPA


~-Bt


thien-3-yl
furan-3-yl
thien-2-yl
furan-2-yl
indol-3-yl


N

Me


Het


OMe
OMe


Scheme 6.1


accord


with


expectations,


lithiation


occurred


exclusively


--~~~-~~-~ ~~










without any


detectable side chain


lithiation.


Thus,


treating


with


1.2 equiv


tert-butyllithium (-780C, THF) resulted in the immediate formation of a deep brown

color due to the anion 6.2. After 5 min this solution was treated with thiophene-3-


carboxaldehyde,


furan-3-carboxaldehyde,


thiophene-2-carboxaldehyde,


furan-2-


carboxaldehyde and indole-3-carboxaldehyde respectively, followed by the protection

of the oxygen anion formed with methyl iodide and HMPA to give the intermediate

products 6.4a-e in excellent yields (Table 6.1). The structures of 6.4a-e are confirmed

by elemental analyses and NMR spectra data. In these compounds, the chiral center

induces magnetic non-equivalence of the two protons of the methylene group adjacent

to the benzotriazole and indole rings, as indicated by the two doublets at ca 6.0 ppm


their


NMR


spectra.


Detailed


assignments


NMR


are given


experimental section.


As discussed in previous chapters,


various types of benzotriazole derivatives


reversibly ionize to yield the benzotriazolyl anion and the corresponding carbocations


ionization


can be


efficiently


facilitated


Lewis


acids.


to such


ionization,


nucleophiles.


benzotriazole


analogy


auxiliary


other


group


benzotriazole


displaced


derivatives,


different


compounds


presumably exist in equilibrium with ion pairs 6.5 under certain reaction conditions


(Scheme 6.2),


which should react intramolecularly to furnish the cyclized products.


Accordingly,


we first


employed


Lewis


conditions


to effect


cyclization.


Unfortunately,


compounds 6.4 were very unstable in the presence of Lewis acid such


as zinc bromide even at low temperature (-100C) and immediately led to oligomers.

This result however is not very surprising as the existence of the Lewis acid greatly










After the unsuccessful attempts to cyclize under Lewis acid conditions,


examined high temperature methodology as a means with which to effect the desired


ionization and ring closure and we found that it was very successful.


Thus, refluxing


N
Me


OMe


'N
+ \
Me


Het


OMe


- MeOH


I OMe


Scheme 6.2


the solution of compounds 6.4a-d respectively in


1,2,4-trichlorobenzene (ca 2160C)


2 days


furnished


the corresponding


expected


products


5-methylthieno[3,2-b]-


carbazole


(6.7a),


5-methylfuro[3,2-b]carbazole


(6.7b),


5-methylthieno[


carbazole (6.7c) and 5-methylfuro[2,3-b]carbazole (6.7d) in good yields (Table 6.2).

Compound 6.4e is less stable and more reactive than 6.4a-d and its cyclization was


,3-bl-










envisioned to proceed via intramolecular cyclization to form intermediates 6.6,


which


undergo aromatization in situ by losing a molecule of methanol to afford the desired


products 6.7. Fused carbazoles 6.7a-d are new and thieno[3,2-b]carbazole,


thieno-


[2,3-b]carbazole,


furo[3,2-b]carbazole


furo[2,3-b]carbazole


previously


unknown tetracyclic condensed systems.


Their structures (see Scheme 6.3) are fully


supported by elemental analyses and NMR spectra data (see experimental section).


The two


1H singlets (4,10-protons) in


the region of 7.4-8


ppm in the


1H NMR


spectra


characteristics


fused


carbazole


systems


6.7a-d.


5,11-Dimethylindolo[3,2-b]carbazole (6.7e) is known previously [76LA1090] and its

structure is also confirmed by CHN analysis and NMR spectra data (see experimental


section).


A 2H


singlet


at 7.93


(6,12-protons)


NMR


spectrum


indicative of the symmetrical structure of the indolo[3,2-b]carbazole 6.7e.

It is worthwhile to mention that our attempted cyclization from compound 6.3,


which


was


prepared


in 91%


yield in


similar way


as 6.4


without subsequent


protection of the oxygen anion as shown in Scheme 6.1, was unsuccessful and no pure

compound 6.7a was isolated although trace of the product was detected by 1H NMR


spectroscopy.


The existence of the labile hydroxy group might be responsible for the


complexities.


In conclusion, a general,


facile route to heterocyclo[b]-fused carbazoles has


been developed, simply starting from 1-methylindole. One obvious attractive feature

of this synthetic approach is that by appropriate choice of the heteroaryl aldehydes a


wide


variety


of heterocyclo[b]-fused carbazoles can


readily


accessible.


work,


heterocyclo[b]-fused


carbazoles


6.7a-e


have


been


synthesized.


Among


- a- .- a a r rr ~



















r 5a "N 4a N
6 5| 4
Me

6.7a


5a N 4a
6 5| 4
Me

6.7b


9
S9a

5a"
6 5


10


I 4


S.; a-sN- 4a v 3a C
6 5I 4 3


6.7d


s 4a'N a ( "a 6hb N
4 i5 6 7
Me


6.7e


Scheme 6.3





6.3 Experimental










standard


(300


MHz)


or solvent


as internal


standard


MHz).


Assignments


NMR


spectra


m necessary


cases


were


confirmed


APT


experiments.


Tetrahydrofuran


was distilled under nitrogen immediately


before


from sodium / benzophenone. All reactions with air-sensitive compounds were carried


out in argon atmospheres.


Column chromatography was conducted


with silica gel


grade


230-400


mesh.


1 -Hydroxymethylbenzotriazole


compound


were


prepared according to previous procedure (see Chapter V).



6.3.1 1 -Methvl-2-bromo-3-r(benzotriazol-1 -vl)methvllindole(6.1):


a solution


1-methyl-3-[(benzotriazol-l-yl)methyl]indole


(5.2)


mmol,


methylene chloride (100 ml)


was


added


dropwise


a solution


bromine (8


mmol, 1.3 g) in methylene chloride (30 ml) at 0C. After addition was


finished, the reaction mixture was further stirred at 0C


for 45 mm. Cold sodium


bicarbonate solution (5%,


70 ml) was added.


The organic layer was further washed


with sodium bicarbonate solution (5%,


70 ml), then water. After drying over MgSO4,


the solvent was evaporated. The crude product was purified by washing with hot ethyl

acetate (20 ml) to give the pure compound in 80% yield. mp 145-146 C; 1H NMR 8


3.71 (s, 3H,


CH3), 5.96 (s, 2H, CH2), 7.04-7.07 (m,


1H, In), 7.15-7.27 (m, 3H, Bt and


In, overlapped), 7.30-7.35 (m, 1H,


Bt), 7


= 8.0 Hz, 1H, In), 7.63 (d, J


= 8.0


Hz, Bt),


(d, J = 8.0 Hz, Bt);


1"C NMR 8 31.5 (CH4),


44.3 (CH2), 107.9 (In),


109.4 (Bt), 110.0 (In),


115.0 (In), 118.5 (In), 119.7 (In), 120.6 (Bt), 122.5 (In), 123.6


(Bt),


126.2


127.0


(Bt),


132.4


(Bt),


136.8


146.1


(Bt).


Anal.


Calcd










.3.2 1-Methyl-2- r(1-hydroxy- 1-thien-3-yl)methvll-3-r(benzotriazol- 1-yl)methyll-
indole 6.3:


To a solution of


1-methyl-2-bromo-3-[(benzotriazol-l-yl)methyl]indole


(6.1)


(3.5 mmol, 1


g) in THF (40 ml) was added tert-BuLi (4.2


mmol


.5 ml, 1.7 M in


petane) at -780C under argon.


After


mm, thiophene-3-carboxaldehyde (4.2 mmol,


0.47 g) in THF (8 ml) was added dropwise. The reaction mixture was stirred at -780C


2 h and quenched with water.


The organic layer was washed with water and dried


(MgSO4).


solvent


was


evaporated


residue


subjected


column


chromatography (hexanes


: ethyl acetate


: 1) to afford pure product (91


78-79C


H NMR 8 3.34 (s,


, NCH3),


5.32 (d, J


= 4.7 Hz, 1H,


CH),


.63 (d, J


15.4 Hz,


, CHBt),


70 (d, J


.4 Hz,


, CHBt),


= 3.6


thiophene),


6.60 (d,


= 4.7 Hz, 1H, OH), 6.87-7.08 (m,


, Bt, In, and thiophene),


7.29 (d, J


.2 Hz, 1H,


7.42 (d, J


= 7.9 Hz, 1H, In),


7.60 (d, J


Hz, 1H,


13C NMR 8 30.5 (NCH3),


(In), 119


42.3 (CH2), 64.8 (CH),


119.9 (Bt),


105.9 (In), 109.3 (In),


(thiophene),


109.9 (Bt),


123.7 (Bt), 126.0 (2C,


thiophene),


126.4


127.0


(Bt),


132.4


(Bt),


137.(


142.8


(thiophene),


145.4 (Bt)


Anal. Calcd for C


21HgN40S:


67.36


14.96.


Found:


67.68


14.93.


6.3.3 General Procedure for the Preparation of Intermediate Products 6.4a-e:


To the solution of 1-methyl-2-bromo-3-[(benzotriazol-l-yl)methyl]indole (6.1)


(3.5 mmol, 1


g) in


THF (40 ml) was added tert-BuLi (4.2 mmol,


5 ml, 1.7 M in


-,norq a._. Arx rt .. r IA fl -l !--I,..11 I


r\






79



Methyl iodide (1.7 ml) and HMPA (30 ml) were then added. The mixture was allowed


to warm to room temperature and stirred overnight.


After aqueous work-up,


product was subjected to column chromatography (hexanes


the crude


: ethyl acetate


: 1)to


give pure compound.

1-Methvl-2-r(1-methoxy-1-thien-3-vl)methyl-3-(benzotriazol-1-)methvll-


indole 6.4a: 1H NMR 8 3.18 (s,


3H, NCH4),


3.54 (s, 3H, OCH3),


5.98 (s,


CH),


6.05 (d, J




6.14 (d, J


= 15


Hz, 1H, CHBt),


6.69 (d, J


= 5.0 Hz,


1H, thiophene), 6.90 (d, J


= 4.3 Hz,


, thiophene),


7.14-7.36 (m,


, Bt, In, and


thiophene, overlapped),


7.76 (d,


= 7.7 Hz, In, 1H),


7.94-7.98 (m,


Bt, 1 H)


1C NMR


8 30.7


(NCH3),


42.6 (CH2), 56.5 (OCH3),


73.9 (CH),


107.9 (In),


109.4 (In),


109.9


(Bt), 118.3 (In),


119.7 (In), 120.3 (Bt), 121.5 (thiophene),


5 (In),


123.6 (Bt), 125.9


(thiophene),


126.0 (thiophene),


126.5 (In),


127.0 (Bt),


4 (Bt),


137.3


140.7 (thiophene),


146.1 (Bt).


1-Methyl-2-I(1-methoxv-l-furan-3-vl)methvll-3-r(benzotriazol-l-vl)methyll-


indole 6.4b: 1H NMR 8 3.61 (s,


3H, NCH3),


3.62 (s,


3H, OCH3),


.91 (d, J


=2.2


1H, furan), 6.03 (s,


1H, CH),


6.04 (d, J


5.4 Hz, 1H, CHBt),


6.11 (d, J


= 15.4 Hz,


,CHBt),


7.06 (d, J


1H, furan),


7.18-7.29 (m, 6H,


Bt, In, and furan),


7.36-7.39 (m, 1H, Bt),


7.76 (d, J


=7.0 Hz


1H, In),


7.94-7.98 (m,


1H, Bt); 13C NMR 8


30.7 (NCH3),


42.5 (CH2), 56.3 (OCH3), 70.8 (CH),


107.7 (In), 108.9 (furan),


109.4


109.9


(Bt),


118.2


119.6


(Bt),


122.5


123.5


(Bt),


124.9


(furan),


126.5 (In),


126.9 (Bt),


132.4 (Bt),


135.7 (In),


137.3 (In),


139.5 (furan), 143.2


(furan),


146.0 (Bt).


1-Methyl-2-[ (1-methoxvy-l-thien-2-vl)methvll-3-r(benzaztriazol-l-yl)methyll-


IUA ,A 1 tn *r%, C. f4 n TrrlTr % r-


rr rn


Arl hFltf


I' nr rl t


1 1A tt


/r










1H, thiophene), 6.76 (m,


1H, thiophene),


7.15-7.37 (m,


7H), 7.74 (d, J


= 7.6 Hz, 1H,


In), 7.93-7.96 (m, 1H, Bt);


(CH),


13C NMR 8 30.9 (NCH3),


(In), 109.4 (In), 109.9 (Bt), 118.4 (In),


42.5 (CH2),


119.6 (In),


56.6 (OCH3),


120.3 (Bt), 122.6 (In),


123.5 (Bt), 124.4 (thiophene), 1


(thiophene),


126.4 (thiophene),


126.5 (In),


126.8


(Bt),


132.4 (Bt),


135.5 (In), 137.3 (In), 143.1 (thiophene),


146.0(Bt).


1-Methvl-2-[(1-methoxy-1-furan-2-vl)methyl]-3-r(benzotriazol-l-vl)methvll-


indole 6.4d:


'H NMR 6 3.26 (s,


3H, NCH3),


3.75 (s, 3H, OCH3),


.96 (s,


1H, CH),


6.01-6.06 (m,


2H, CHBt and thiophene, overlapped), 6.14 (d, J


.5 Hz, 1H,


CHBt),


21-6.23 (m, 1H, thiophene),


7.14-7.31


7H, Bt, In,


and thiophene,


overlapped),


7.67 (d, J

(NCH3),


= 7.9 Hz, 1

42.8 (CH2),


7.95 (dd,


56.7 (OCH3),


= 6.9 and


71.6 (CH),


107.6 (In),


,Bt)


"13C NMR 8 30.9


108.4 (furan),


109.4 (In),


110.0 (furan),


126.5 (In),


110.1


126.7


(Bt),


(Bt),


118.4 (In),


132.4 (Bt),


119.4 (In),


134.0 (In),


(Bt),


142.6 (furan),


123.4 (Bt),

146.0 (Bt),


(furan).


1-Methyl-


[1-methoxvy- 1-(1-methylindol-3-vl)1methyl}-3- (benzotriazol-


1-vl)methvllindole 6.4e:


1H NMR 8 3.23 (s,


3H, NCH3),


3.41 (s,


3H, OCH3),


3.59 (s,


3H, OCHR),


.99 (d, J


Hz, 1H,


CHBt),


6.14 (d, J


,CHBt),


6.15 (s,


CH),


1H, In),


6.98-7.02


7.07-7.23


Bt and


overlapped),


7.43 (d, J


= 8.1 Hz, 1H,


Bt), 7.72 (d, J


= 7.7 Hz, 1H,


7.83 (d,


= 8.1


Hz, 1H, Bt)


13C NMR 8 31.0 (NCH3), 3


.5 (NCH3),


42.9 (CH2), 56.5 (OCH3),


(CH),


107.4 (In),


109.3 (In),


109.4 (In),


110.3 (Bt),


113.4 (In),


118.8 (In),


119.5 (In),


119.6 (In),


119.7 (In), 120.3 (Bt),


0 (In),


122.3 (In),


123.4 (Bt),


126.5 (In, 2C),


127.0 (In),


127.5 (Bt), 132.6 (Bt), 136.7 (In),


137.3 (In, 2C), 146.0 (Bt).










6.3.4


General


Procedure


Preparation


Heterocyclolbl-fused


Carbazoles


6.7a-e:


solution


the corresponding


intermediate


products


mmol)


1,2,4-trichlorobenzene (40 ml) (for 6.4a-d) or in

6.4e) was refluxed under argon for 48 h. The solvi


dichlorobenzene (40 ml) (for


ent was evaporated and the residue


was subjected to column chromatography (hexanes


: methylene chloride


1) to


give pure product.


5-Methvlthienor3,2-blcarbazole 6.7a:


H NMR 8 3.80 (s, 3H, CH3), 7.18-7.23


= 7.7 Hz, 1H, 8-H),


7.38-7.51 (m,


4H),


(s, 1H,


4-H),


8.08 (d, J


=7.7 H


9-H),


8.48 (s,


1H, 10-H)


C NMR 8 28


(CH3), 100.8,


107.3


, 112.4, 117.8, 119.3,


120.8


,121.5, 1


22.7,


125.4


,130.4, 137.4, 139.1,


141.3.


5-Methvlfuror3,2-blcarbazole 6.7b: 1H NMR 8 3.79 (s,


3H, NCH,),


7.86 (d, J


=2.2


Hz, 1H,


3-H),


7.21 (t, J


= 7.7 Hz, 1H,


8-H),


7.33 (d,


= 7.7 Hz, 1H,


6-H),


7.42


4-H),


7.47 (t, J


= 7.7 Hz, 1H, 7-H), 7.69 (d,


Hz, 1H, 2-H), 8.10 (d, J


7.7 Hz


, 9-H), 8.15 (s,


1H, 10-H); I


C NMR 8 29.


(NCH3),


98.4, 101.8,


106.7


108.1


118.3


120.1


, 121.4, 1


.8, 126.7


138.8


142.1


145.7


150.2.


5-Methvlthienof2,3-b1carbazole 6.7c: 'H NMR 8 3.79 (s,


3H, CH3),


7.21-7.37


3H),


7.43 (d, J


= 5.5 Hz, 1H,


2-H), 7.49 (t, J


= 7.5 Hz, 1H, 7-H), 7.76 (s, 1H,


4-H),


8.13 (d,


= 7.5 Hz,


1H, 9-H),


8.45 (s,


, 10-H)


"13C NMR 8 29


(CH3),


100.7


, 114.4,


118.7


120.3


123.8


126.1


, 133.0,


138.6,


140.3


5-Methvlfuror2,3-b1carbazole 6.7d:


'H NMR 8 3.8


, 3H, CH3),


6.88 (d, J










106.7


, 108.1,


111.5


118.7


, 119.9,


120.5,


120.9,


122.9,


125.3,


141.9,


143.9,


148.4,


154.8.


11-Dimethylindolor3,2-b1carbazole 6.7e:


NMR


, 2CH3),


7.14-7.19 (m,


2H, H


7.33 (d,


= 8.0 Hz, 2H, H-4,10),


7.40-7.43 (m,


2H, H-3,9),


7.93 (s,


2H, H-6,12),


(d, J


= 7.8 Hz, 2H, H-1,7)


"3C NMR 8 29.4 (2CH3), 98.6


(C-4,


C-10),


108.1


(C-l,


118.1


(C-3,


120.1


(C-2,


(C-6b,


C-12b),


122.9 (C-6a, C12a),


(C-6,


C-12),


136.8 (C-4a,


C-lOa),


142.2 (C-5a,


C-11a).


C-7),


C-9),


C-8),








83










ci 'n c: 'n; 0


z a; Ini v;vi
"0-
C)~F~ft\




ci i I vi
Ur ~ I 5 6


at a


Cd c: -4 N

U ON ON ON '

U &- 6 ad 6
'-4 V N V N


C.)~tf c 0I


OO


r 00 N M
N CM cM CM CM




oL U
00 t6 Z fl O


N I

C.)f
0. -- 4 -
-E I I I I
en ci ci en
I Ij Id Id Id







84














'n 'n oR 0



V1 Cz V~ C



Cl CM Crl Cl


U~r vi n


I -n en C- V
C)r 00j Cl 00- C'f
r'A '.6 oRoo
N



"0

Ua N nCN0

N 00 NO 0 00

C)o U) 0 ( 0
-- zc z\ z
Ui
ol II\
N-
Sd 00\



o *
'. ClN-0
ON Cl 00 Nr c
I Ii \l ON \












CHAPTER VII
CONCLUSION


wide spectrum of useful organic compounds, a-functionalized isonitriles,


substituted


benzyl


phenyl


sulfides,


both


symmetrical


unsymmetrical


l,l-bis(heteroaryl)alkanes, 3-substituted indoles and heterocyclo[b]-fused carbazoles,

have been synthesized via benzotriazole mediated heteroalkylation and arylalkylation

methodology.


ease


with


which


various


types


benzotriazole


derivatives


can be


prepared and the benzotriazolyl group can be displaced subsequently by a wide range

of nucleophiles proves this methodology to be general and facile.










BIBLIOGRAPHY





The reference system used here is that from the book series "Comprehensive


Heterocyclic


Chemistry"


edited


Alan


Katritzky


Charles


Rees,


Pergamon


Press,


Oxford,


1984.


Throughout


dissertation,


references


designated a number-letter coding of which the first two numbers denote tens and

units of the year of publication, the next one to three letters denote the journal, and the


final numbers denote the page.


This code appears in the text each time a reference is


quoted.



Some commonly used additional notes are given below:


The list of reference is arranged in order of (a) year, (b) journal in alphabetical


order of journal code, (c) part letter or number if relevant, (d) volume number

if relevant, (e) page number.


In the reference list the code is followed by the complete literature citation in


the conventional manner.


For journals which are published in separate parts, the part letter of number is


given


(when


necessary)


in parentheses


immediately


after the


journal


code


letters.


Journal


volumn numbers are not included in the code numbers unless more


than one volume was published in the year in question, in which case the











volume number is included in parentheses immediately after the journal code

letters.

Patents are assigned appropriate three letter codes.

Frequently cited books are assigned codes, but the whole code is now prefixed


by the letter "B-"


Less common journals and books are given the code "MI" for miscellaneous.

Where journals have changed names, the same code is used throughout.


[32HCA1066]


Reichstein,
Acta 1932, 1


Grussner


Zschokke,


1066.


[33JA3302]


Gilman,
3302.


Wright,


F. J. Am.


Chem.


1933,


1JA1


270]


Cairns,


McKusick,


Chem. Soc. 1951


Weinmayr,


1270.


1JA1377]


Schick, J.
1377.


Crowley,


D.J.


J. Am. Chem. Soc. 1951


,73,


[53JA375]


Shirley, D. A.


Roussel, P


.A. J.


Am. Chem. Soc. 1953,


[53JA1967]


Kissman, H.
75, 1967.


., Witkop, B.


J. Amer.


Chem. Soc.


1953,


[54CB692]


Thesing, J.


Chem.Ber. 1954, 87,


[56CJC 1147]


[61JOC1509]


Brown,
1147.


Grotta, H. M.;
1961, 26, 1509.


Sawatzky


Riggle,


Can.


Bearse


J. Chem.


A. E.


1956, 34,


Chem.


[62BSF290]


Meier, J.


Bull. Soc. Chim. Fr. 1960, 290.


[63AHC1]


Gronowitz, S. Adv.


Heterocycl. Chem.


1963, 1,


[63CA573861a]


Gol'dfarb,


Danyushevskii


Chem.


Abstr.


Helv.


C/tim.


. J. Am.










[63MI540]


Gol'dfarb, Ya. L.; Danyushevskii Ya. L. IZV. AkacL Nauk
SSSR, Ser. Khim. 1963, 3, 540.


[65CA11441C]


Steiger, N. USP 1965, 3
11441C.


182 053; Chem. Abstr. 1965, 63,


[66JA5855]


Burdon, M. G.; Moffatt, J. G. J. Am. Chem. Soc. 1966, 88,
5855.


[67HCA628]


Stoll, M.; Winter, M.; Gautschi, F.; Flamment,
Willhalm, B. Helv. Chim. Acta 1967, 50, 628.


[67MI105]


Lapkin, I. I.
Org. Sin.,
1967, 105.


; Bogoslavskii, N.
Akad. Nauk. SSR.


V. Probl. Paluch. Poluprod.
OtcL Obshch, Tekh. Khim.


[68CA39258]


Lapkin, I. I.; Bogoslavskii, N.
39258.


Chem. Abstr.


1968, 68,


[69JA4315]


Mukaiyama, T.; Narasaka, K.; Hokonoki, H. J. Am. Chem.


1969, 91,


4315.


[70AJC2443]


Clezy, P.


Liepa, A. J. Aust. J. Chem. 1970,


2443.


[70BCJ2549]


Mukaiyama, T.; Narasaka, K.; Maekawa, K.; Hokonoki, H.
Bull. Chem. Soc. Jpn. 1970, 43, 2549.


[70CB2775]


Bohme


Fuchs, G. Chem. Ber. 1970, 103,


2775.


[70S49]


Zaugg, H. E. Synthesis 1970, 49.


[70T3353]


Bergman, J. Tetrahedron 1970,


26, 3353.


[71AG143]


Appel, R.; Kleinstuck, R.; Ziehn, K. -D. Agnew. Chem.
1971, 83, 143; Agnew. Chem. Int. Ed. Engl. 1971, 10, 132.


[71MI1]


Ugi, I.
1971.


"Isonitrile Chemistry,"


Academic Press, New York,


[72ACS 1018]


Pennanen,
1018.


Nyman,


G. Acta.


Chem.


Scand.


1972, 26,


[72CHE179]


[72JOC187]


Troxler, F. Chem. Heterocycl. Compd. 1972,


25-2,


Walborsky, H. M.; Niznik, G. E. J. Org. Chem.
187.


1972,










[73JCS(P1)1099]


Ahmed, M.; Ashby, J.; Ayad, M.; Meth-Cohn, O. J. Chem.
Soc., Perkin Trans.I 1973, 1, 1099.


[73JOC3324]


[73S703]


Sundberg, R. J.
3324.


Tramontini, M. Synthesis


1973,703.


[73TL633]


Schollkopf, U.;


Schroder, R. Tetrahedron Lett. 1973, 633.


[74AJC 1579]


Chamberlain, K.; Summers, L. A. Aust. J. Chem. 1974,
1579.


[74JCS(P1)1188]


Cavaleiro, J. A. S.; Kenner, G. W.; Smith, K. M.
Soc., Perkin Trans. 1 1974, 1188.


J. Chem.


[74KGS1502]


Rozhkov, V. S.; Smushkevich, Yu. I.; K
Savorow, N. N. Khim. Geterotsikl. Soedin.
(Chem. Abstr. 1975, 82, 139887f).


7ozik,
1974,


T. A.;
1502.


[74LA44]


Schollkopf, U.;
Chem. 1974, 44.


Schroder,


Stafforst,


Liebigs Ann.


[75CC570]


Engel, J.; Gossauer, A. J.
1975, 570.


Chem.


Soc.,


Chem.


Commun.


[75TL1617]


Anciaux, A.; Eman, A.;
Tetrahedron Lett. 1975, 1617.


Dumont,


Krief,


[75TL1613]


Anciaux, A.; Eman, A.; Dumont,
A. Tetrahedron Lett. 1975, 1613.


W.; Van Ende, D.; Krief,


[76LA1090]


Hunig, S.
1976, 1090.


Steinmetzer,


Liebigs


Ann.


Chem.


[77MI47]


Gandini, A. Adv. Polym. Sci. 1977,


[77MI51]


Bohme, H.; Krack, W. Ann. Chem. 1977, 51.


[77MI1238]


Frattini, C.; Bicchi, C.; Barettini, C.; Nano, G. M. J. Agric.
Food Chem. 1977, 25, 1238.


[78CA8890046p]


Gandini, A. Chem. Abstr. 1978, 88,90046p.


[78JA1 325]


Matteson, D.
1325.


Arne, K. J. Am.


Chem. Soc.


1978, 100,


Russell, H. F. J. Am. Chem. Soc. 1973, 38,










[80TL2547]


Tamura, Y.; Shindo, H.; Uenishi,
Tetrahedron Lett. 1980, 21, 2547.


Ishibashi,


[81AP459]


Unterhalt, B.; Leiblein, F. Arch. Pharm. 1981,


314, 459.


[81CB3421]


Bohme, H.; Raude, E. Chem. Ber. 1981,


114, 3421.


[81LA99]


Rachon, J.; Schollkopf, U


Liebigs Ann. Chem. 1981, 99.


[81LA709]


Rachon, J.; Schollkopf, U.
1981, 709.


Wintel, Th. Liebigs Ann. Chem.


[81TL3243]


Hatanaka, K.; Tanimoto, S.; Sugimoto,
Tetrahedron Lett. 1981, 22, 3243.


Okano,


[82TL5079]


Ricci, A.; Fiorenza, M.; Grifagni,
Seconi, G. Tetrahedron Lett. 1982,1


Bartolini,


5079.


[83BCJ1569]


Hirao, T.; Kohno, S.; Ohshiro,
Soc. Jpn. 1983, 56, 1569.


.; Agawa,


T. Bull.


Chem.


[83CPB723]


Saikachi, H.; Sasaki, H.; Kitagawa, T. Chem. Pharm. Bull.
1983, 31, 723.


[83JOC2690]


Saulnier, M. G.; Gribble, G.
2690.


Org.


Chem.


1983,


[84CHC 1]


Katritzky, A. R., Rees, C. W. "Comprehensive
Heterocyclic Chemistry," Pergamon: Oxford, 1984; vols.
1-8.


[84S85]


Zaugg, H. E. Synthesis 1984,


[84S181]


Zaugg, H. E. Synthesis 1984, 181


[85HHC1]


Katritzky, A. R. "Handbook of Heterocyclic Chemistry,"
Pergamon: Oxford, 1985.


[85MI1]


Suffness, M.; Cardell, G. A. "The Alkaloids," Brossi, A.,
Ed.; Academic: New York, 1985; Vol. XXV, p 1.


[85JCS(P1)75]


Addison, S. J.; Cunningham,
P. Z.; Threadgill, M. D. J.
1985, 75.


B. D. M.; Gate, E. N.; Shah,
Chem. Soc., Perkin Trans. 1


[85RTC177]


van Leusen, A. M.; Wildeman, J.; Moskal, J.; van Hemert,
A fl T rI i Ci fl fl -fl 1~ r v^ i^











[85TL6933]


Castagnino, E. Tetrahedron Lett. 1985, 6399.


[86JA6808]


Katritzky, A. R., Akutagawa, K. J. Amer. Chem. Soc. 1986,
108, 6808.


[86MI1673]


Gillner, M.; Fernstrom, B.; Gustafsson, J.-A. Chemosphere
1986, 15, 1673.


[87BCJ3823]


Umemoto,
3823.


T.; Gotoh,


Bull.


Chem. Soc. Jpn.


1987, 60,


[87JCS(P1)2673]


Katritzky, A, R.; Yannakopoulou, K.; Ki
W.; Aurrecoechea, J. M; Palenik, G. J.; i
Szczesniak, M.; Skarjune, R. J. Chem. Soc.,
1 1987, 2673.


uzmierkiewicz,
Koziol, A. E.;
Perkin Trans.


[87JOC5489]


Fuchgami, T.; Nakagawa,
1987, 52, 5489.


Y.; Nonaka,


T. J.


Org.


Chem.


[87RTC159]


Hundscheid, F. J. A/
M.; Van Leusen, A.
106, 159.


; Tandon, V.
M. Recl. Tray


K.; Rouwette, P. H. F.
. Chim. Pays-Bas 1987,


[87T5073]


Hundscheid, F. J. A.; Tandon, V. K.; Rouwette, P. H. F.
M.; Van Leusen, A. M. Tetrahedron, 1987, 43, 5073.


[88MI1]


"The Sadtler Standard
Laboratories: Philadelphia.


Spectra,"


Sadder


Research


[88MI3]


Bergman, J. "Studies in Natural Produc
Atta-ur-Rahman, ed.; Elsevier: Amsterdam,
Stereoselective Synthesis (Part A), p 3.


:t Chemistry,"
1988; Vol. 1,


[88TL1435]


Ranganathan,
1435.


Singh,


W. P. Tetrahedron Lett. 1988, 29,


[89AP451]


Lehmann, J.; Hartmann, U. Arch. Pharm. 1989,


[89H745]


Bennasar, M.-L.;
Heterocycles 1989


Torrens,
29, 745.


Rubiralta,


Bosch,


[89H1121]


Katritzky, A.
28. 1121.


Yannakopoulou, K. Heterocycles


1989,


D. R.,


[89JMC890]


Martinez, G. R., Walker,


K. A. M., Hirschfeld,










[89KGS746]


Iovel, I. G.; Goldberg, Yu. Sh.; Shimanskaya, M.
Geterotsikl. Soedin. 1989, 746.


V. Khim.


[89SC3169]


Riad, A.; Mouloungui, Z.; Delmas, M.; Gaset, A. Synthetic
Commun. 1989, 19, 3169.


[89TL2265]


Uneyama,
2265.


Momota,


Tetrahedron


1989, 30,


[90JCS(P1)179]


Inagaki, S., Nishizawa, Y., Sugiura,
Chem. Soc., Perkin Trans. 1 1990, 179.


Ishihara,


[90JCS(P1)1847]


Katritzky, A. R.; Sutharchanadevi, M.; Urogdi, L. J. Chem.
Soc., Perkin Trans. 1 1990, 1847.


[90JOC2206]


[90MI802]


Katritzky, A. R.;
1990, 55, 2206.


Urogdi, L.; Mayence A. J.


Shimoda, M.; Shibamoto,
38, 802.


Chem.


1990,


[91CPB 1148]


Ishibashi, N.; Mino, M.; Sakats, M.; Inada, A.; Ikeda, M.
Chem. Pharm. Bull. 1991, 39, 1148.


[91HCA1931]


Katritzky, A. R.; Afridi, A.
Chim. Acta 1991, 74, 1931.


Kuzmierkiewicz,


W. Helv.


[91JMC140]


Swain, C. J., Baker, R., Kneen, C., M
J., Seward, E. M., Stevenson, G., Beer
Watling, K. J. Med. Chem., 1991, 34,


loseley, J., Saunder,
, M., Stanton, J., and
140.


[91JOC6917]


Katritzky, A. R.,
56, 6917.


Yang


Lam, J.


N. J. Org. Chem. 1991,


[910PP403]


Nutaitis, C. F.; Patragnoni,
B.; Obaza-Nutaitis, J. Org.


R.; Goodkin,
Prep. Proce.


Neighbour,
1991, 23,


[91T2683]


Katritzky, A. R.; Rachwal,
1991, 47, 2683.


Hitchings, G. J. Tetrahedron


[92H2095]


Conway,
2095.


Gribble,


Heterocycles


1992,


[92JHC953]


Nagarathnam, D.


J. Heterocyclic Chem., 1992,


ro9 T TI-1- 1 9


Kicanmmachfr A


Mill n K 1 -Ifotprnrvrlir (horm


100


T. J. Agric. Food Chem.











[92T4971]


Katritzky, A. I
1992, 48, 4971.


Yang,


Lam


Tetrahedron,


[93JOC4376]


Katritzky, A. R.
58, 4376.


W.-Q. J. Org. Chem. 1993,


[93S45]


Katritzky, A. R.


Xie, L.


Fan, W


Synthesis, 1993, 45.