1-propargylbenzotriazole--a useful building block in the synthesis of heterocycles

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Title:
1-propargylbenzotriazole--a useful building block in the synthesis of heterocycles
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viii, 105 leaves : ill. ; 29 cm.
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Li, Jianqing, 1962-
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Thesis:
Thesis (Ph. D.)--University of Florida, 1995.
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Includes bibliographical references (leaves 98-104).
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Typescript.
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Vita.
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by Jianqing Li.

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1-PROPARGYLBENZOTRIAZOLE -- A USEFUL BUILDING
BLOCK IN THE SYNTHESES OF HETEROCYCLES









BY

JIANQING LI


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

1995

























To my wife, Linghong, and 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 also like to take this opportunity to express my sincere gratitude to

Drs. Eric J. Enholm, John R. Reynolds, David E. Richardson and Nicholas S. Bodor

for their help, suggestions and time they have spent as my supervisory committee

members.

I would like to give my special thanks to Dr. Nageshwar Malhotra and Dr.

Mikhail F. Gordeev for their valuable help and cooperation during these years. My

thanks also go to all ARK group members and my friends outside who are too many

to mention individually, for their support and friendship.

I am deeply indebted to my parents and my parents in-law, for their support

and encouragement, without which I could not have become a doctor.

Last but not the least, I am extremely grateful to my wife, Linghong, for her


constant understanding, support and criticizing,


and for everything she has done for










TABLE OF CONTENTS


ACKNOWLEDGEMENTS


ABSTRACT


CHAPTERS


GENERAL INTRODUCTION


1-PROPARGYLBENZOTRIAZOLE:
REACTIONS OF ITS LITHIUM DERIVATIVES.............................


EIpexrrient~i1 ............ ..a...... ne... secr .a.


NEW SYNTHETIC ROUTE TO FURANS AND DIHYDRO-
FURANS FROM 1-PROPARGYLBENZOTRIAZOLE ....................


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


NEW SYNTHESIS OF 2-ARYL- AND 2-HETARYL-PYRROLES
FROM 1-PROPARGYLBENZOTRIAZOLE. ....................................


InxtI..cuction. .. .......S S .......... ........*m ..S

Experimental ...e ....... ........ .. ...........


A NOVEL FURAN RING CONSTRUCTION
AND SYNTHESES OF 4- AND 4,5-SUBSTITUTED
2- (a-HETEROCYCLO) ALKYLFURANS ........................ ...... ..........


5.1 Introduction m..... ... ................. .... ............ .. ............
5.2 Results and Discussion ...............................................
5.3 Experimental ....... ................. ..... .............. ... .............. .

FACILE SYNTHESIS OF 2-SUBSTITUTED INDOLES
AND INDOLO[3,2-b]CARBAZOLES FROM
I, /I'r~kT'7f'lrmDT A 'rl 1VT 7ACT1 1 UT \U'n T KTT'flT f?








Results and Discussion
Experimental ...


4-SUBSTITUTED AND 4,5-DISUBSTITUTED
2-(BENZOTRIAZOL- 1-YL)METHYLPYRROLES
AS VERSATILE SYNTHETIC INTERMEDIATES


1Restilts arid IIiscubssjofl.....................*m*m m...
Experirrenta.1


CONCLUSION


BIBLIOGRAPHY

BIOGRAPHICAL SKETCH












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

1-PROPARGYLBENZOTRIAZOLE -- A USEFUL BUILDING
BLOCK IN THE SYNTHESES OF HETEROCYCLES

By

JIANQING LI


August, 1995

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

1-Propargylbenzotriazole, readily prepared from benzotriazole and propargyl

bromide, has been used as a synthetic building block in [3 + 2] annulations either as a


two-carbon


or a three-carbon


unit for


synthesis


various


5-membered


heterocycles.


benzotriazolylmethyl


chains


attached


to heterocycles


produced and further elaborated by alkylation and substitution.

1-Propargylbenzotriazole undergoes lithiation first at the acetylenic CH and


CH2


group.


dilithiated


species,


generated


treatment


1 -propargylbenzotriazole


with


equivalents


butyllithium,


reacts


with


electrophile first at the carbon atom adjacent to the nitrogen, and then at the terminal

carbon. Hence lithiation of 1-propargylbenzotriazole and subsequent reactions with

electrophiles afford mono- and di-alkylated products depending upon the amounts of

butyllithium and of the electrophiles used.


Base-assisted


cyclizations


1-[3-hydroxy(substituted-methyl)propargyl]-


benzotriazoles,


derived


from


lithiated


1-propargylbenzotriazole


aromatic







aldehydes or ketones, give 2-arylfurans or 1-(5,5-diaryl-2,5-dihydrofuran-2-yl)benzo-


triazoles,


respectively.


reactions


1-(5,5-diaryl-2,5-dihydrofuran-2-yl)-


benzotriazoles with Grignard reagents yield trisubstituted 2,5-dihydrofurans.


Reactions


1-(3-lithiopropargyl)benzotriazole


with N-tosylarylimines


adducts which undergo cycloelimination on treatment with ethanolic alkali to afford


2-aryl-


2-hetaryl-pyrroles.


Treatment


1-(1,3-dilithiopropargyl)benzotriazole


successively with one equivalent of an alkyl halide followed by N-tosyl-(1-naphthyl)-


imine


ethanolic


alkali


gives


corresponding


5-alkyl-2-(1-naphthyl)-


pyrroles.


4-Substituted


4,5-disubstituted


2-(benzotriazol-1 -yl)methylfurans


have been prepared from


1-propargylbenzotriazole and a-bromoketones via one-pot


processes.


2-(benzotriazol- 1-yl)methyl


chains


are alkylated


lithiation


followed


quenching


with


electrophiles


afford


4,5-substituted


2-(a-benzotriazol-l-yl)alkylfurans. Substitutions of benzotriazolyl groups with other


heterocycles


presence


ZnCI2


a variety


4,5-substituted


(a-heterocyclo)alkylfurans.


Replacement of the benzotriazole moiety


N-alkyl-2-(1-benzotriazol- 1-yl-


alkyl)indoles, prepared from 1-propargylbenzotriazole and o-iodoaniline followed by


alkylation,


with


Grignard


reagents


gives


corresponding


2-substituted


indoles.


Treatment of N-alkyl-2-(1-benzotriazol-l-ylalkyl)indoles with zinc chloride afforded


6,12-disubstituted-6,12-dihydroindolo[3,2-b]carbazoles.


5,11-dihydroindolo[3,2-b]carbazoles are prepared readily from


6,12-Disubstituted-


2-(benzotriazol-1 -yl-


alkyl)indoles


dimerization


presence


chloride


followed


dehydrogenation on exposure to air.







4-Substituted-


4,5-disubstituted-2-(benzotriazol-1 -yl)methylpyrroles


are easily prepared


from


the reaction


of 5-(benzotriazol- 1-yl)-l 1,2-epoxy-3-pentyne


derivatives


pnmary


amines


i-PrOH.


2-(benzotriazol- 1-yl)methyl


chains


are elaborated


nucleophilic


substitution


initial


alkylation


followed by replacement or elimination of benzotriazolyl moiety to afford a variety of

2,4-di- and 2,3,5-trisubstituted-pyrroles.












CHAPTER I
GENERAL INTRODUCTION


The propargyl moiety is one of the most important carbon functional groups in

synthetic organic chemistry because of its availability and the great versatility of its

transformations. Much of the interest in the use of propargyl units involves (i) inter-

and intra-molecular additions to the triple bond, which frequently result in specifically

substituted acyclic and cyclic alkenes; (ii) base-assisted rearrangement of propargyl to


allenyl,


which is also a versatile species; (iii) metalations due to the acidity of the


alkynyl and methylene protons and subsequent alkylations or coupling reactions of


alkynyl


methylene


carbons


a wide


range


electrophiles,


which


especially


attractive


have


been


widely


employed


carbon


chain


extension


reactions recently. The great value of the propargyl group in organic synthesis and the


synthetic


applications


propargyl


derivatives


have


been


frequently


documented [78MI199, 91MI81, 94MI1 and 950PP127].

Over the last several years, the use of benzotriazole as synthetic auxiliary in

the preparation of many useful organic compounds has been intensively investigated


Katritzky research


laboratory


[91T2683,


94S445


and 94MI31].


to the


electron-withdrawing


nature


nitrogen-nitrogen


double


bond,


benzotriazole


possesses two important features: (i) the ability to act as an activating group towards

a-proton loss and (ii) good leaving ability in the nucleophilic substitutions.


Combination


propargyl


benzotriazolyl


moieties


generates


interesting synthetic precursor,


1-propargylbenzotriazole (1.1),


with


which


a variety






2



of synthetic transformations can be realized.


First,


both


the sp3-CH2 and


the sp-CH


can be lithiated,


regioselective


reactions of the corresponding mono- and di-anions can be directed to occur with


electrophiles on either the sp-


or sp3-hybridized carbon


atom


or at both of these


centers.


1-PROPARGYLBENZOTRIAZOLE


1.1


Secondly, and most importantly, 1-propargylbenzotriazole (1.1) can serve as a


synthetic


building


block in


+ 2]


annulations


for the syntheses of


5-membered


heterocycles. As shown in the following schemes, 1-propargylbenzotriazole (1.1) can

behave as the 1,3-dipolar species 1.2 which can form rings with carbonyl groups or

imines 1.3 to afford furans or pyrroles 1.4. On the other hand, the triple bond of 1.1

can also act as a two carbon unit in [3 + 2] annulation with other 1,3-dipolar species

1.5 to provide the benzotriazolylmethyl attached heterocycles of type 1.6.

Furthemore, since benzotriazole is both an electron-withdrawing and a leaving


group,


benzotriazolylmethyl


chain


can


elaborated


lithiation/alkylation


subsequent


replacement


benzotriazole


group


with


nucleophiles.







3




[3 + 2] ANNULATIONS


Bt


XXB
Bt


=O, NR


ELABORATION OF BENZOTRIAZOLYLMETHYL SIDE CHAIN


1. BuLi


---,










results


reported


following


chapters:


Chapter


describes


preparation


1-propargylbenzotriazole


(1.1)


reactions


lithium


derivatives.


Chapters


with


synthetic


applications of


1-propargyl-


benzotriazole (1.1) in the synthesis of substituted furans, dihydrofurans and pyrroles.


Chapters


through


VII cover the


synthesis of 2-(benzotriazol- l-yl)methyl-furans,


-indoles and -pyrroles, and the elaborations of their benzotriazolylmethyl side chains.













CHAPTER II
1-PROPARGYLBENZOTRIAZOLE: REACTIONS OF ITS LITHIUM
DERIVATIVES


1.1 Introduction


Recently, a large number of benzotriazole derivatives have been prepared in

our laboratory and have been used as synthetic precursors for the synthesis of a wide


spectrum


useful


organic


compounds


[91T2683,


94S445


94MI31].


1 -Propargylbenzotriazole


(2.1)


containing


two functional


groups,


propargyl


benzotriazol-1-yl,


should


show


interesting


reactivities,


however,


it had


not been


synthesized previously.

In this chapter, we report the preparation of 1-propargylbenzotriazole (2.1) and

the reactions of its lithium derivatives.


Results and Discussion


Since


benzotriazole is an electron-withdrawing


group,


proton


a to


benzotriazole group is relatively acidic and can be deprotonated. However, the acidity


an sp-CH


usually


stronger than


that of


an sp3-CH,


therefore


benzotriazoles


carrying


acetylene


groups


could


show


interesting


behavior


lithiation.


1-Propargylbenzotriazole (2.1) was prepared in 60%


yield from


benzotriazole and


propargyl bromide in the presence of sodium hydroxide at room temperature (Scheme


2.1).


When the 'H- and 13C-NMR spectra of


the crude product were examined










Experimental),


the presence of about 30%


2-allenylbenzotriazole besides the


major


product


1 -propargylbenzotriazole


(2.1)


was


demonstrated.


Presumably


2-propargylbenzotriazole initially formed is easily isomerized into the allenyl isomer.

The 1-propargylbenzotriazole (2.1) was purified by crystallization twice from diethyl

ether/hexane.


BrCH2C=CH


NaOH
EtOH


-5 oC to rt


Bt=


Scheme 2.1


1 -Propargylbenzotriazole


(2.1)


lithiation


equivalent


butyllithium in THF followed by reaction with benzophenone gave compound 2.2a in


60%


yield.


Likewise,


compounds


2.2b-d


were


obtained


60-70%


yields


from


cyclohexanone, benzaldehyde and furfural respectively (Scheme 2.2).


The 1H-NMR


spectra


compounds


2.2b-d


show


clearly


mono-lithiation


occurs


at the


acetylenic hydrogen, the CH2 protons adjacent to the benzotriazole nitrogen (singlets

at 8 = 5.42-5.92) remain unchanged compared with the starting material whereas the


acetylenic


proton


= 2.


16-2.70)


disappears


in the


NMR


spectra.


These


deductions were confirmed by the attached proton test (APT) in the 13C NMR spectra.

The structures of comnounds 2.2a-d were also sunnorted by their elemental analyses











2.3a: R
2.3b: R
2.3c: R


2.3d:


= Ph2C(OH)
= (CH2)5C(OH)


= PhCH


= n-C6E13


i) BuLi (2
ii) E+


i) BuLi
ii) E+


i) BuLi (2 eq


ii) E+ (2


2.2a: R
2.2b: R
2.2c: R
2.2d: R


= Ph2C(OH)
= (CH2)5C(OH)
= PhCH(OH)
= C4H3OCH(OH)


i)BuLi (
ii) E+
iii) Mel


2.4a: R


2.4b


= Ph2C(OH)
= (CH2)5C(OH)


Bt
Bt


OCH3


OCH3


2.5a


Bt


CH2Ph


2.5b


Scheme


On the other hand, when 1-propargylbenzotriazole (2.1) was lithiated with two


equivalents of butyllithium and quenched with one equivalent of benzophenone,


monosubstituted compound 2.3a was formed in 67


yield. Similar procedures with


cyclohexanone,


benzyl


bromide


hexyl


iodide


produced


compounds


2.3b-d


respectively


67-81


yields


(Table


these


cases,


electrophilic











easily deduced from their analyses, and 1H and 13C NMR spectra (Tables


These results demonstrate that if one equivalent of butyllthium is used, the

more acidic acetylenic proton is removed and the subsequent alkylation occurs at the


acetylenic position to form compounds 2.2.


When two equivalents of butyllithium are


used,


a 1,3-dilithiated


derivative


obviously


produced


only


equivalent of electrophile is added, the more basic carbanion adjacent to benzotriazole

nitrogen reacts to form compounds 2.3.

If the above reasoning is correct, using two equivalents of butyllithium and


equivalents


electrophile


should


form


dialkylated


products.


When


was


lithiated


with


equivalents


butyllithium


resulting


1.3-dilithiated


derivative was treated with two equivalents of benzophenone, the dialkylated product

2.4a was indeed obtained in 54% yield. Similar treatment with cyclohexanone gave


compound


2.4b


79%


yield.


bisalkylated


products


2.4a


2.4b


were


characterized


their elemental


analyses


NMR


spectral


data.


acetylenic


proton signal was seen in the 1H NMR spectra and the one-proton singlet at 8


= 6.68


(2.4a) and 5.76 (2.4b) was assigned to the CH group adjacent to the benzotriazole

nitrogen.


According


these


results,


quenching


di-lithiated


intermediate


successively


with


one equivalent


one electrophile


followed


a different


electrophile should result in the corresponding unsymmetrically disubstituted product.

Thus, 2.1 was treated with two equivalents of butyllithium followed by one equivalent

of benzophenone and then an excess of methyl iodode to give the product 2.5a in 69%

yield. Similar initial reaction with cyclohexanone followed by methyl iodide gave











methoxy signals in the 'H NMR (8


= 3.18 for 2.5a and 8


= 3.26 for 2.5b) and the 13C


NMR spectra (8 = 51.7 for 1.5a and 8 = 49.3 for 2.5b).


When benzyl bromide was


used as the first electrophile in a similar procedure, the mixed bisalkylated product

2.5c was formed in 51% yield. As previously discussed, the first electrophile would

attack the more nucleophilic carbanion position adjacent to the benzotriazole, and

methyl iodide would then react with the acetylenic carbanion to form the bisalkylated


product 2.5 as shown in scheme


triplet at 8


= 5.92 and a doublet at 8


This was supported by the AX2-spin pattern (a

= 3.46) assigned for CHCH2Ph in the 'H NMR


spectrum of 2.5c.


2.3 Experimental


Melting


points


were


determined


with


a Thomas-Hoover


capillary


melting


point apparatus and are uncorrected.


Varian


'H- and '"C-NMR spectra were recorded with a


VXR 300 FT mode NMR spectrometer, operating at 300 MHz for 1H and 75


MHz for '3C NMR. The chemical shifts of the proton-NMR spectra are reported in 8

values downfield from tetramethylsilane (TMS) as internal standard and the chemical

shifts of '3C NMRs are reported in 8 values using a deuterated solvent (CDC13 or


[D6]DMSO as the internal standard).


-Abbreviation: Bt


= benzotriazole.


-Thin-layer


chromatography (TLC) was performed on precoated silica gel 60 F254 plastic sheets


Merck Co.).


Column chromatography was conducted over silica gel


(200-400


mesh).


-Tetrahydrofuran was predried over 4-A molecular sieves and distilled from


sodium/benzophenone


under


nitrogen.


Electrophiles


were


purified


standard







10



3.1 Preparation of 1-Propargylbenzotriazole (2.1)


A solution of sodium hydroxide (10.0 g,


0.25 mol) in water (25 ml) was added


slowly,


with vigorous stirring,


to an ice-cold solution of benzotriazole (29.7


mol) in absolute ethanol (150 ml).


After 10 min, propargyl bromide (35.9 g, 0.27


mol,


80%


in hexane)


was


added,


mixture


was


allowed


warm


room


temperature. Et2O (200 ml) and H20 were added and the organic phase was separated,


washed with H20 and dried (MgSO4).


Removal of the solvent gave an oil which was


recrystallized


from


60%); m.p. 57-580C.


Et20/hexane

-H NMR: 8


to afford


1 -propargylbenzotriazole


= 8.06 (1H, d, J


= 8.4 Hz, Ar-H),


(2.1)


7.36-7.7


(23.6


(3H, m,


Ar-H),


44 (2H,


s, CH2),


(1H,


s, CH).


-13C NMR: 5


= 109.7


120.0


, 124.0,


27.6,


146.1


(Ar-C),


(-C-),


.0 (=CH), 37.9 (CH2).


C9H7N


Calcd. C, 68.78,


4.49, N,


26,73. Found. C,


68.98


The second component, 2-allenylbenzotriazole, could not be isolated in pure

form but the 1H NMR spectra of the mixture show signals for 2-allenylbenzotriazole


7.82-7.85


H-Bt),


7.33-7.38


(2H,


H-Bt,


overlapped


1-propargylbenzotriazole signals),


and the '3C NMR spectra showed signals at 8


117.6. 126.8


,144.7 (C-Bt),


203.9 (=C=


103.1


(CH2) and 88.9 (CH).


The chemical


shift of allene carbon fall within the range of 8


= 211.4 [72JA5084].


These spectral


data confirmed the presence of 2-allenylbenzotriazole.


3.2 General Procedure for Lithiation of 1-Propargylbenzotriazole (2.1)











for 2.3a-d, 2.4a-b and 2.5a-c), dropwise, at -780C.


The mixture was stirred at this


temperature for 45 min. A solution of the alkyl halide or ketone (5 mmol for 2.2a-d

and 2.3a-d, 10 mmol for 2.4a-b) in THF (5 ml) was added (for 2.5a-c first 5 mmol of

ketone or halide was added followed by 10 mmol of iodide). The mixture was allowed


to warm to room temperature and then stirred for 2h.


The reaction was quenched with


water, the product extracted with diethyl ether (3 x 100 ml), dried (MgSO4) and the


solvent removed under reduced pressure to give yellow oil.


This was purified by


column chromatography or recrystallization (Table 2.1).




















Table 2.1


Alkylation of 1-Propargylbenzotriazole (2.1)


analysis / HR-MS
compd. yield m.p. Crystal molecular found (%) required (%)
No. (%) (oC) form fomula
C H N C H N


198-9

150-1

97-8


powder

cubes

cubes


C22H17N30

C15H17N30

C16H13N30


C14H 1N302


253.0843


253.0851


179-80


powder


2H17N30


77.64


12.23


77.86


12.38


cubes


C15H17H30


71.66


14.83


77.06


14.83


247.1114

241.1574


247.1109

241.1579


186-7


powder


N302


80.27


80.44


C21H27N302

C24H21N30


353.2090

367.1678


353.2103

367.1685


113-4


powder


C17H21N30


70.97


16.43


70.56


16.41


261.1265


261.1266


C16H13N3

C15H19N3


C35H27


C17H15N3



























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CHAPTER III
NEW SYNTHETIC ROUTES TO FURANS AND DIHYDROFURANS FROM
1 -PROPARGYLBENZOTRIAZOLE


3.1 Introduction


Furans


constitute


one of


most


important


classes


heteroaromatic


compounds. The furan ring is common to many naturally occurring compounds, such


as terpenoids, lipids, steroids, ionophores, and aflatoxines [84MI705, 81MI263].


role of furans and their hydrogenated derivatives is also significant because of the


presence


important


furan


nucleus


pharmaceuticals,


structures


flavor


a variety


fragrance


commercially


compounds


[84MI705,


84JA440],


as well


as in


diverse


synthetic


intermediates


[86CR785].


Numerous


synthetic approaches to furans and dihydrofurans are known


(for recently reported


procedures


84JA4407


84JCS(C)804,


85JA7233,


90JA8985


, 90JA8995,


91JA8995, 91JOC2955, 91JOC4598, 91TL4687 and references therein),


but the most


important methods all involve C-O bond formation at the key step of the heterocyclic

ring construction.

Recently, efficient [3+2] annulations of allenylsilanes with aldehydes in the


presence of TiC14 [85JA7233],


of allenylsilanes with acylium ions [84JA4407], and of


the dienolate anion


ethyl


2-bromo-4-[(tert-butyldimethylsilyl)oxy]crotonate with


aldehydes [91JOC4598] have been described for the synthesis of substituted furans


[84JA4407]


2,3-dihydrofurans


[85JA7233


91JOC4598].


These


methods,


however, are


limited


by the


relatively


low availability


the starting compounds:











thus,


2-bromo-4-[(tert-butyldimethylsilyl)oxy]crotonate has been synthesized in three


steps from ethyl


4-hydroxycrotonate,


tert-butyldimethysilyl chloride and imidazole


with


an overall


38%


yield


[89JA6691].


An improved


four-step


preparation


from


bromomagnesio(trimethylsilyl)acetylide


[3-(trimethylsilyl)-2-propynilidene]-


-4-methylbenzenesulfonyl


hydrazide


gave


a 40%


yield


(trimethylsilyl)allene


[83T935].


Moreover, attempted annulations of allenylsilanes employing ketones did


not give satisfactory results


[85JA7233],


no analogous


transformations


using


aromatic aldehydes have been reported.

We now report a new and simple synthetic route to substituted furans and

dihydrofurans using readily available 1-propargylbenzotriazole 3.1 as a three-carbon


annulation


unit.


chapter


described


preparation


1-propargylbenzotriazole and some regioselective reactions of its mono- and dianions


with electrophiles,


which reactions can be directed to occur on either the sp- or the


sp3-hybridized carbon atom


or at both these centers [92LA843].


The reactions of


1-(3-lithiopropargyl)benzotriazole (generated in situ from 3.1 and BuLi in THF) with


aromatic


aldehydes


or ketones


yielded


addition


products


high


yields


[92LA843].


These transformations have now been further developed to provide new


routes to furans and to 2,5-dihydrofurans (Schemes 3.1 and 3.2).



3.2 Results and Discussion


Compounds


derived


from


1 -propargylbenzotriazole


aromatic


aldehydes


upon


heating


with


ethanolic


NaOH


cyclized


with


elimination







17



preparations of furans from 4-[(tetrahydropyran-2-yl)oxy]-2-butynolates [79AC875]

or allenylaluminium reagents [82CL1029] with aldehydes. Evidently, the mechanism


presently


described


process


(Scheme


includes


an intermediate


formation of a-allenyl alkoxides 3.3 (derived from the isomerization of the acetylenes


3.2) followed by their intramolecular cyclization into


,5-dihydrofurans 3.4. The latter


are readily


aromatized


under


reaction


conditions


elimination


benzotriazolyl


anion


to yield


furans


3.5).


Significantly,


cycloeliminations


compounds


furans


require


treatment


intermediate


2,5-dihydrofurans 3.4 with acids,


82CL1029].


which is essential for prior procedures [79AC875,


Interestingly, in contrast to our reaction, 3.1 to 3.5, (Scheme 3.1), [3+2]


annulation


lithio


derivative


methoxyallene


ketones


aldehydes


occurred via an attack of C-1 of the reagent on the carbonyl group of substrates and


yielded 3-methoxy-2,5-dihydrofurans or, depending on steric factors,


[84JCS(C)804].


vinyl epoxides


The feasibility of the acetylene allene isomerization of 3.2 into 3.3


demonstrated


easy


transformation


1 -propargylbenzotriazole


1-allenylbenzotriazole 3.6 under the reaction conditions (Scheme 3.1).

An analogous [3+2] annulation of 3.1 with aromatic ketones resulted in the


formation of 1-(5,5-diaryl-2,5-dihydrofuran-2-yl)benzotriazoles 3.7 in 68-90%


yield


(Scheme


3.2).


2,5-Dihydrofurans


3.7b,c


have


been


isolated


as mixtures


diastereomers in ratios of


1:1.3 and


1:1.5, respectively (by


'H and


NMR


spectra).


contrast


to the


analogous


intermediates


derived


from


aldehydes, compounds 3.7 were found to be relatively stable under basic conditions.

Previous papers from this laboratory demonstrated that benzotriazole-derived












NaOH / EtOH


Bt


3.6


BuLi
R1COR2


NaOH / EtOH


Bt


C-


3.2a: R1
3.2b: R1
3.2c: R1


=Ph, R2


= 2-furanyl, R


= 4-CIC6H4, R2


= H
= H


=H)


3.5a: R1
3.5b: R1
3.5c: R1


=Ph


Scheme 3.1


= 4-CiPh
= 2-furanyl


the conductivity of these compounds in solutions (for a review


see 91T2683).


Due to


such ionization, aminals of this type were able to undergo the replacement of the

benzotriazole auxiliary group by Grignard and other organometallic reagents resulting


in the introduction of various carbon substituents [91T2683, 91JCS(P1)2199].


In view


of the similar reactivity of benzotriazole-derived N,O- and N,S-acetals, an analogous


-. 4 4 a U rU U .


( F I rn











BuLi


R1COR2


3.2d: R1 =Ph, R


=Ph


3.2e: R1
3.2f: R1


=Ph, R
= Ph. R:


= 4-CIC6H4
= 3,4-C12C6H4


NaOH / EtOH
heat


Bt
V-


3.7a: R1
3.7b: R1
3.7c: R1


=Ph, R
=Ph, R
= Ph. R'


=Ph


= 4-C1C6H4
= 3,4-C12C6H4


R3MgX
- BtMgX


3.9a: R1
3.9b: R1
3.9c: R1
3.9d: R1
3.9e: R1
3.9f: R1


=Ph, R'
= Ph, R2
= Ph, R2
= Ph, R2
= Ph, R2
= Ph, R2


=Ph, R3
= Ph, R3
= Ph, R3


=Et
=Ph


= i-Pr


= 4-C1C6H4, R0
= 4-C1C6H4, R3
= 2.4-CloC-Ho.


=Me
= i-Pr
R3 = Et


I


(R3MgX)
heat


3.10


2.11a: R1
2.11b: R1


= Ph, Rt
= Ph, R2


= Ph, R3


=Me


= 3,4-C12C6H4,


L~V-J'






20



Grignard reagent increases in a parallel with the degree of a substitution at the acetal

carbon atom, in agreement with SN1 but not with the alternative SN2 mechanism (cf.

91HCA1924: the displacement of benzotriazolate anion in [(a-alkylthio)tert-alkyl]-


benzotriazoles


occurs


smoothly,


sec-alkyl


N,S-acetals


91HCA1924.).


have


now


found


2,5-dihydrofurans


bearing


benzotriazol-1-yl substituent in the 2-position of the heterocyclic ring can also serve

as substrates in transformations of this type. Thus, compounds 3.7 upon heating with


Grignard


reagents


in toluene


yielded


2,5,5-trisubstituted


2,5-dihydrofurans


82-95% yields (Scheme 3.2).


Analogously to the previously reported transformations


benzotriazole-derived


aminals,


N,O-


N,S-acetals


[91T2683,


91HCA1924,


91S69],


our new


reaction


to 3.9


probably


occurs


SN 1-mechanism involving ionization of the N-C bond of the N,O-acetal fragment of

the 2,5-dihydrofurans 3.7 to generate cationic species 3.8, which then couples with the

Grignard reagent to yield the product 3.9 (Scheme 3.2).


Interestingly


prolonged heating of compounds 3.7 with an excess of Grignard


reagent in toluene resulted in the formation of p,y-unsaturated ketones 3.11 (Scheme


3.2).


formation


compounds


probably


involved


a base-assisted


isomerisation of initially formed 2,5-dihydrofurans 3.9 to 2,3-dihydrofuran derivatives


3.10, followed by the ring cleavage in dihydrofurans 3.10 to give ketones 3.11.


latter


process


probably


occurred


a deprotonation


allylic


position


compounds


3.10.


Previously,


conversion


2,5-dihydrofurans


their


thermodynamically more stable 2,3-dihydro isomers was achieved by heating then


S n ~rr n art m nnw~rafl~* I


CCI I TCnlln~rlnl











In conclusion,


1-propargylbenzotriazole 3.1 has been shown to be a useful


reagent


new


potentially


quite


general


synthetic


routes


furan


2,5-dihydrofuran derivatives.


The presence of the benzotriazol-1-yl substituent in the


compounds


enables


additional


functionalizations


these


2,5-dihydrofurans (cf. with 91T2683).



3.3 Experimental


Melting


points


were


determined


with


a Thomas-Hoover


capillary


melting


point


apparatus


are uncorrected.


spectra


were


recorded


CHCl3.


NMR


spectra


were


taken in


CDC13 except for compounds 3.7


which


were recorded


(CD3)2SO, with tetramethylsilane as internal standard for 1H (300 MHz) or solvent for


13C (75MHz).


Tetrahydrofuran was distilled


under nitrogen immediately before use


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

out in atmospheres of argon or nitrogen. Column chromatography was conducted with

silica gel grade 60-200 mesh. Compounds 3.1, 3.2a-f were prepared analogously to


literature


procedures


[92LA843].


Analytical


for new


compounds 3.2c,e,f


given below.

1-Hvdroxv-4-(benzotriazol-l-yl)-l-(4-chlorophenyl)but-2-yne (3.2c): Needles,


yield 75%:


mp 164-5 oC (from ethanol). IR 3370 cm-1 (OH)


1H NMR 8


5.41 (s, 1 H,


CH), 5.59 (s,


2 H, CH2),


7.29 (d, J


= 8.5 Hz,


H, Ar), 7.39-7.44 (m, 3 H,


Bt and Ar,


overlapped), 7


(dd, J


= 8.3 and 6.9 Hz, 1 H, Bt),


7.75 (d, J


= 8.3 Hz, 1 H, Bt)


NMR 8 37.2 (CH2), 61.5 (CHOH),


76.4 (CH2C=C), 86.2 (C=C),


109.2 (Bt),


118.6


--










Found: C


64.63


H, 4.14; N,


14.21.


1-Hvdroxvy-4-(benzotriazol- 1-vl)-1 -(4-chlorophenvl)-1-phenvlbut-2-vne


(3.2e): Needles,


yield 80%:


130-1


OC (from ethanol).


IR 3331


cm-1


(OH);


NMR8


2 H, CH2), 7


1-7.50 (m, 11 H, Bt and Ar overlapped), 7.56 (d, J


8.4 Hz, 1 H, Bt),


7.93 (d, J


8.4 Hz 1 H, Bt); '3C NMR 8 38.4 (CH2),


73.7 (COH),


78.8 (CH2CMC), 89.2 (C-C),


(2 C, Ar), 127.5 (Bt), 128.0 (2


109.7 (Bt),


119.7 (Bt), 124.2 (Bt), 125.9 (C,


, Ar), 128.3 (4 C,


Ar), 132.2 (Bt),


127.4


133.6 (Ar), 143.0


(Ar),


143.9 (Ar),


145.7 (Bt).


Anal. Calcd. for C22H16C1N30: C,


70.68


11.24. Found: C. 70.63


H, 4.26


11.17.


1-Hvdroxy-4-(benzotriazol-1-vl)-1-(3,4-dichlorophenvyl)- 1-phenvlbut-2-yne


(3.2f):


Needles,


yield 78%:


137-8 C (from ethanol). IR 3373 cm-1 (OH)


NMR 8 5.95 (s,


2 H, CH2),


7.16 (s,


,OH), 7


7.64 (m,


9 H, Bt and Ar),


8.00 (d,


= 8.5 Hz, 1 H, Bt), 8.10 (d, J


= 8.3 Hz, 1H,


Bt); 13C NMR 8 37.7


(CH2),


(COH), 80.1 (CH2C=C), 87.9 (C-C), 110.7 (Bt),


119.3 (Bt), 124.3 (Bt),


(2 C,


Ar), 126.0 (Ar), 127.3 (Bt),


7.6 (2 C, Ar),


Ar),


130.0 (Ar),


130.4 (Ar),


130.8


(Ar),


(Bt),


144.7


(Ar),


145.3


(Bt),


146.9


(Ar);


Anal.


Calcd.


C22H15C12N30: C,


64.72


H, 3.70; N,


10.29. Found: C, 64.94; H, 3.68


10.27


3.3.1 General Procedure for the Preparation of 2-Substituted Furans (3.5a-b)


A mixture of the appropriate alcohol 3.2a-c (


(0.4 g, 10 mmol) in ethanol (50 ml) was refluxed for 12


mmol) and sodium hydroxide


Water (30 ml) and ethyl


ether (50 ml) were added. The organic phase was separated, washed with water (3 x











2-Phenylfuran (3.5a):


Purified by column chromatography (chloroform).


NMR (CDC13) 5 6.41 (dd, J =

1 H, H-3 of furan), 7.23 (d, J


land 1


Hz, 1 H,


= 7.8 Hz, 1 H,


H-4 of furan),


7.34 (dd, J


6.60 (d, J


= 3.6 Hz,


=8.1 and 7


Ph), 7.42 (d, J


1.8 Hz, 1 H, H-5 of furan), 7.65 (d, J


(CDC13) 8 104.9 (C-4 of furan),


111.6 (C-3 of furan),


= 8.1 Hz,


2 H, Ph)


123.7 (2 C,


"1C NMR

27.3 (Ph),


128.6 (2 C,


130.8 (Ph), 142.0 (C-5 of furan), 153.9 (C


of furan).


2-(4-Chlorophenvl)furan (3.5b):


Purified by recrystallization from ethanol.


NMR (CDCl3) 8 6.46 (dd, J


= 3.3 and 1.8 Hz, 1 H, H-4 of furan), 6.63 (d, J


= 3.4 Hz,


, H-3 of furan),


7.34 (d,


= 9.0 Hz,


7.45 (d,


= 1.8 Hz, 1 H, H


-5 of


furan), 7.58 (d, J


= 8.8 Hz,


,Ar)


NMR 6 105.4 (C-4 of furan),


111.7 (C-3 of


furan),


.0 (2 C,


Ar), 1


8.8 (2


, Ar), 129.3 (Ar), 132.9 (Ar), 142.3 (C


of furan),


.9 (C-2 of furan).


-Bifurvl (3.5c)


Purified by column chromatography (chloroform


- hexane


H NMR (CDCI3) 8 6.44 (dd, J


= 3.4 and 1.8 Hz,


2 H, H-4 of furan), 6.54 (d, J


, H-3 of furan),


7.40 (d,


= 1.8 Hz,


of furan)


13C NMR 6 105.0


(C-4),


111.3 (C-3), 141.7 (5-C),


146.6 (C-2).


1-Allenvlbenzotriazole (3.6):


A mixture of 1-propargylbenzotriazole 3.1 (0.1


mol, 1


7 g) and sodium hydroxide (0.1mol,


4.0 g) in ethanol (50 ml) was stirred at


OC for 10 h.


Water (100 ml) was added and the mixture was extracted with diethyl


ether (100 ml),


washed with water (3


x 50 ml) and dried (MgSO4).


Solvent was


evaporated


vacuo


a crude


product


which


was


purified


recrystallization from cold diethyl ether.


Needles, yield 9.42 g (60%):


mp 45-46 C


H NMR (CDC,) 8 5.79 (d, J


= 6.6 Hz,


2 H, CH2), 7.34-7.47 (m,


2 H, Bt),


7.78 (m,


Ar),


--











Anal. Calcd. for C9H7N3: C, 68.78; H,


26.73.


Found: C


68.71


4.47; N,


3.3.2


General


Procedure


Preparation


2-(Benzotriazol- 1-vl)-5,5-diarvl-


dihvdrofurans (3.7a-c)


A mixture of the appropriate alcohol 3.2d-f (10 mmol) and sodium hydroxide


(0.40 g, 10 mmol) in ethanol (50 ml) was stirred at 60-800C for 12


Water (50 ml)


and ethyl ether (100 ml) were added.


The organic phase was separated,


washed with


water (80 ml x 3) and dried (MgSO4). Solvent was evaporated in vacuo, and the crude

product recrystallized from ethanol.


2-(Benzotriazol- 1-vl)-5,5-diphenyl-2,5-dihydrofuran (3.7a):


'H NMR 8 6.30


(dd, J


= 5.9 and 1.4 Hz, 1 H, H-2 of furan), 7.02 (dd, J


= 5.9 and


1 Hz


,1 H, H-3 of


furan), 7.17-7.42 (m,


of furan), 8.02 (d, J


furan),


13 H, Bt and Ph, overlapped), 7


= 8.3 Hz, 1 H, Bt)


(dd, J


13C NMR 8 92.9 (C-2 of furan),


110.9 (Bt), 119.8 (Bt), 123.4 (C-3 of furan),


124.0 (Bt),


1 and 1.4 Hz, H-4


98.2 (C-5 of


126.2 (4 C,


(Bt),


127.6 (Ph), 127.8 (Ph),


128.2 (2 C,


Ph), 128.4 (2 C, Ph), 1


0 (Bt),


139.1 (C-4


of furan),


142.5 (Ph), 143.6 (Ph), 146.7 (Bt).


2-(Benzotriazo- 1-vl)-5-(4-chlorophenvl)-5-phenvl-2,5-dihvdrofuran


(3.7b):


mixture of two diastereomers in a ratio of 1:1.3.


H NMR 8 6.35 (m,


1 H, H-2


furan), 6.98 (m, 1 H, H-3 of furan), 7.16-7.38 (m, 1 H, Bt and Ar, overlapped),


(d, J


= 7.3 Hz, 1 H, H-4 of furan),


furan), 92.5 (0.4 C,


of furan),


8.05 (m, 1 H, Bt)


13C NMR 8 92.3 (0.6 C, C-2 of


95.4 (C-5 of furan), 110.3 (0.6 C,


110.5 (0.4 C,


119.3 (0.6 C, Bt), 119.4 (0.4 C, Bt),


123.4 (C-3 of furan),


123.8 (Bt), 127.0 (Bt),


a -nas4 fs A 4 rk Ji 41 ik n 4 nl 4l4 4


I \ (nr s


4 A D


k


I AA


,n


r A D R


I111*( IACI A


4 An f-










furan),


141.0 (0.6 C, Ar),


141.8 (0.4 C, Ar),


142.0 (0.4 C, Ar),


142.8 (0.6 C, Ar),


146.1(0.6 C, Bt), 146.2 (0.4 C, Bt).

2-(Benzotriazol-l-yl)-5-(3,4-dichlorophenyl)-5-phenyl-2,5-dihydrofuran


(3.7c): A mixture of two diastereomers in a ratio of 1:1.5.


1H NMR 5 6.25 (m, 1 H,


H-2 of furan), 6.85 (m. 1 H, H-3 of furan), 6.92-7.42 (m, 1 H, H-4 of furan), 6.92-7.42

(m, 12 H, Ar), 7.92 (m, 1H, Bt); 13C NMR (CDC13) 8 92.4 (0.6 C, C-2 of furan), 92.7


(0.4 C, C-2 of furan), 95.1 (0.6 C, C-5 of furan), 95.2 (0.4 C, C-5 of furan), 110.3 (0.6


C, Bt), 110.6 (0.4 C, Bt),


119.8 (0.4 C, Bt), 119.9 (0.6 C, Bt),


124.1 (0.4 C, Bt), 124.2


(0.6 C,


Bt), 125.9 (C-3 of furan), 127.4 (0.4 C, Bt), 127.6 (0.6 C,


Bt), 1


125.7


125.8


126.1


, 127.9, 128


128.3


, 128.4, 128.5, 128.6 (6 C,


Ar), 130.2


(0.6 C,


132.3 (0.6 C, Ar),


132.5 (0.4 C, Ar), 138.1 (C-4 of furan ), 141.5 (0.4 C, Ar), 142.4


(0.6 C, Ar),


142.9 (0.6 C,


143.9 (0.4 C,


Ar), 146.5 (Bt).


3.3.3 General Procedure for the Preparation of 2,2,5-Trisubstituted-2,5-dihydrofurans
(3.9)


1.0 M Grignard reagent in diethyl ether (4 mmol) was added dropwise at


with stirring to a solution of the appropriate compound 7a-c (2 mmol) in toluene (20


The mixture was refluxed for


2 h and cooled to


Water (50 ml) was added,


followed by extraction with diethyl ether (40 ml). The organic phase was washed with


water (3 x 30 ml) and dried (MgSO4).


The solvent was evaporated in vacuo and the


residue subjected to column chromatography (chloroform) to afford pure product.

2,2-Diphenvl-5-ethyl-2,5-dihvdrofuran (3.9a): 'H NMR (CDCl3) 8 0.82 (t, J =


7.4 Hz, 3 H, CH3), 1.55 (dq, J


13.5 and 7.4 Hz,


2 H, CH3),


4.82 (m,


1 H, H-5 of


- ~ ~ ~ I -I -L -I -1 -I nI C -r - ---


II -111 I -










(CH2),


(C-5 of furan),


94.0 (C-2 of furan), 126.2, 126.5, 126.9


128.0 (10 C, Ph),


129.5 (C-3 of furan), 132.8 (C-4 of furan),


145.6 (Ph), 145.8 (Ph).


2,2,5-Triphenvl-2,5-dihydrofuran (3.9b): 'H NMR (CDC13) 8 5.94 (dd, J


=2.4


and 1.5 Hz, 1 H, H-5 of furan), 6.00 (dd, J


= 5.9 and 1


Hz, 1 H, H-4 of furan),


(dd. J


= 5.9 and


2.4 Hz,


H, H-3 of furan),


7.17-7.44 (m,


15 H, Ph);


13C NMR


(CDCI3) 8 87.9 (C-5 of furan),


95.0 (C-2 of furan), 126.


126.8


127.1


,127.9,


128.1


8.4, 128.7 (15 C, Ph),


130.2 (C-4 of furan),


132.8 (C-3 of furan),


140.8


(Ph), 145


.2 (Ph),


145.3 (Ph).


Diphenvl-5-isoproDvl-2,5-dihvdrofuran


(3.9c):


H NMR


(CDC13) 8 0.77


(d, J


= 6.8 Hz, 3 H, CH3),


0.87 (d,


= 6.8 Hz, 3 H, CH3),


1.73 (dq,


= 6.8 and 13.4


Hz, 1 H, CH), 4.5

furan, 6.23 (dd, J


16 (m, 1 H, H-5 of furan),


= 6.0 and


86 (dd, J


= 6.0 and 1.4 Hz, 1 H, H-4 of


1 Hz, 1 H, H-3 of furan), 7.07-7.29 (m,


10 H, Ph)


NMR (CDC13) 8 18.3 (CH3), 18.9 (CH3), 33


(CH),


91.4 (C-5 of furan),


93.9 (C


furan), 126.


(2 C, Ph),


126.9 (2 C, Ph), 127.9 (C-4 of furan), 1


8.0 (2


Ph),


128.3


,Ph),


133.3 (C-3 of furan),


145.7 (Ph), 145.8 (Ph).


2-(4-Chlorophenvl)-2-phenyl-5-methyll2,5-dihydrofuran (3.9d):


A mixture of


two diastereomers in a ratio of 1:1


1H NMR (CDC13) 8 1.33 (dd, J


= 6.4 and 6.5 Hz, 3


H, CH3),


5.05 (m,


1 H, H-5 of furan),


6.18 (dd, J


= 5.9 and


3Hz, 1H,


H-3 of furan),


7.15-7.33 (m,


9H, Ar); 3C NMR (CDC13) 8


1.7 (CH3), 81.9 (0.5 C, C-5 of furan),


82.0 (0.


C,C


Of furan),


93.8 (0.5 C, C-


2 of furan),


93.9 (0.5 C,


C-2 of furan),


126.2


,126.4 (2 C, Ar),


127.1 (0.5 C, Ph), 127


(0.5 C,


Ph), 127.8,


127.9, 1


8.0, 1


(6 C,


Ar), 131 .4 (C-4 of furan), 131.9 (C-3 of furan),


132.8 (Ph),


144.0 (0.


C, Ar),


144.6 (0.5 C, Ar), 144.8 (0.5 C,


Ar), 145.4 (0.5 C, Ar).


-. -1 d I *I -\ .A .- I i- f


IA n










0.84 (dd, J


= 6.8 and 6.8 Hz, 3 H, CH3),


1.68 (m,


CH),


4.63 (m,


1 H, H-5


of furan),


.84 (m, 1 H, H-4 of furan), 6.16 (m,


3"C NMR (CDC13) 8


1 H, 3-H of furan),


18.3 (0.5 C,


CH4),


7.04-7.24 (m, 9 H,


18.8 (CH3),


(CH),


(C-5 of furan), 93.4 (0.


, C-2 of furan),


of furan),


126.0


(Ar),


2 (Ar),


126.5 (2 C, Ar),


127.6 (Ar),


27.8 (Ar), 1


8.0 (Ar),


28.1 (2


C, Ar),


128.7 (C-4 Of furan),


132.7 (Ph), 132.8 (C-3 of furan),


144.3 (0.5 C, Ar),


, Ar), 145.3 (0.5 C,


2-(3,4-Dichlorophenyl)


-Dhenvl-5-ethvl-2


dihydrofuran


(3.9f):


A mixture


of diastereomers in a ratio of 1:1.


1H NMR (CDCl3) 8 0.


3 H, CH3),


H, CH2),


4.81 (m, 1 H, H-


of furan),


5.86 (dd, J


= 6.0 and 1


.2 Hz, H-4 of furan),


(dd, J


= 6.0 and


2 Hz, 1 H, H-3 of furan),


7.00-7.30 (m,


,Ar),


7.38 (s,


1 H, Ar);


13 C NMR (CDCI3) 8 9.7 (0


9.8 (0.5 C,


28.7 (CH2),


furan),


(C-2 of furan),


126.0,


126.1


, 126.2,


126.3


128.1


128.3


, 128.4, 128.6,


129.9 (8 C, Ar),


30.4 (C-4 of furan),


130.8 (Ph),


131.7 (C-3 of furan),


132.0 (0.


C, Ar),


(0.5 C,


144.4 (0.


Ar),


144.6


(0.5 C,


146.0 (0.5 C,


Ar), 146.3 (0.5 C,


3.3.4 General Procedure for the Preparation of 3B,-Unsaturated Ketones


(3.11a,b)


1.0 M Grignard reagent in diethyl ether (4 mmol) was added dropwise at 25


OC with stirring to a solution of the appropriate compound 7a,c (


mmol) in toluene


(20 ml).


The mixture was refluxed for 48 h and cooled to


Water (50 ml) was


added, followed by extraction


with diethyl ether (40 ml).


The organic phase


was


p.. .n nfl 1' 1 1' I as nr' r rr .I


CH3),


CH,),


GH,),


CH,),


mi






28


1:1) to afford pure product as the major fraction.


5,5-Diphenvlpent-4-ene-2-one (3.11a):


IR 1712 cm-' (OH); 'H NMR 8 2.09 (s,


, CH3), 3


(d, J


= 7.3 Hz, 2 H, CH2), 6.28 (t, J


= 7.3 Hz, 1 H, CH=),


7.11-7.40


(m, 10 H, Ph).


13C NMR 8 29.7 (CH3),


44.5 (CH2), 120.4 (CH=),


(2 C,


128.0 (2 C,


128.2 (2 C,


128.3 (2 C,


129.5 (2 C,


139.3 (Ph),


141.7


(Ph), 144.6 (>C


=), 206.4 (CO).


6-(3,4-Dichlorophenyl)-6-Dhenylhex-5-ene-3-one (3.11b):


A mixture of two


geometric isomers in a ratio of ca. 1.5:1.


IR 1708 cm-' (CO); 1H NMR 8 0.95 (dd, J


7.3 and 7.2 Hz, 3H,


CH3),


31 (m,


2H, CH2CO), 3.14 (m, 2 H, CH2), 6.23 (m, 1 H,


=), 6.92-7.39(m, 8H,


13C NMR 6


17.8 (CH3),


(CH,),


(CH2CO),


122.0 (0.4 C,


CH=


, minor isomer), 122.5 (0.6 C, CH=,


major isomer), 126.5,


127.6,


127.7


, 128.2,


128.5


, 129.0,


129.1


129.4


129.5


, 129.9,


130.3


131.1


, 131.4,


131.5


132.2


132.5


138.2


,139.4, 140.8,


141.9 (12 C,


142.3 (0.4 C,


minor


isomer),


142.4 (0.6 C, >C=, major isomer),


208.6 (CO).


* Assignments for 13C NMR spectra in necessary cases were confirmed by


APT


experiments.








29











In 00 00 .


enO nf 0 C N? 0 N,

C N In V -



ae c a I
C') I CC 0
CWJ: C M
C's CM -O e
rr~~0 C- C.) U



aO Z -
ci)- -o -, t o ~v r
0 C
-% -NA-' C

eq %% 0p

U n QU
00 '. N N o

0 '0 C nI

o -; :
~In


0 ;
- r

0 e 'a l -O NI 0
H s .r. .n 0%'

00 33 .004


VV S -C
04.r 0 Ue 0 0C)4 -
Sn~~~ SI tr 1i0 O
r, d ~ r-: U
O cF\ \ U












CHAPTER IV
NEW SYNTHESIS OF 2-ARYL- AND 2-HETARYL-PYRROLES FROM
1 -PROPARGYLBENZOTRIAZOLE


4.1 Introduction


Pyrrole


derivatives


are of


enormous


importance


m organic


bio-chemistry, and found many applications in medicine and technology, as covered


in numerous monographs and reviews (see 90MI177 and refs. cited therein).


Various


aryl-


hetaryl-substituted


pyrroles


are of


pharmaceutical


interest


[84MI313,


84ZOR60] and as potential monomers for conducting polymers and nonlinear optics


materials [84MI313,


92H2003].


In chapter II, we described the preparation of 1-propargylbenzotriazole 4.1 and

some regioselective reactions of its mono- and dianions with electrophiles which can

be directed to occur either at the sp- or at the sp3-hybridized carbon atom or at both


these centres [92LA843].


The reactions of 1-(3-lithiopropargyl)benzotriazole 4.2 with


carbonyl compounds enabled novel preparations of furans and of 2,5-dihydrofurans


[93JOC3038,


see chapter II].


We have now extended these studies to provide a


new


simple


synthetic


route


to 2-aryl-


2-hetaryl-pyrroles


using


readily


available 1-propargylbenzotriazole 4.1 as a three-carbon annulation unit.



4.2 Results and Discussion


1-(3-Lithiopropargyl)benzotriazole 4.2 (generated in situ from 4.1 and BuLi in

THF) reacted readily with N-tosvlarvlimines to give the corresDondine adducts 4.4a-e











in high yields (Scheme 4.1 and Table 4.1

by analytical and spectral data, thus the


). The structures of 4.4a-e were supported

13C NMR spectra displayed characteristic


resonances


for the


acetylenic


carbons


region


of 78-89 ppm.


None


isomeric


allene derivatives 4.5 or


4.6 could


be isolated from,


or detected


reaction mixtures.


Compounds 4.4 upon heating with ethanolic sodium


hydroxide


afforded 2-aryl- or 2-hetaryl-pyrroles 4.8a-e in 40-60% yields. The mechanism of this

novel transformation is probably closely related to that previously suggested for the


base-assisted


cycloeliminations


1-hydroxy-4-benzotriazolyl-l-arylbut-2-ynes


[93JOC3038],


and involves an acetylene-allene isomerization of compounds 4.4a-e to


intermediates 4.5a-e which further cyclize to 2,5-dihydropyrroles 4.7a-e.


This is then


followed


heteroaromatization


N-deprotection


elimination


benzotriazole and of p-toluenesulfonic acid, respectively, to yield the pyrroles 4.8a-e

(Scheme 4.1 and Table 4.2).


we demonstrated


chapter


[92LA843],


1-(1 ,3-dilithiopropargyl)-


benzotriazole 4.3 can react with electrophilic reagents selectively in position 1 of the

propargyl fragment to afford the corresponding mono-anions of the type 4.9 (Scheme


4.1).


Analogous to the transformation of 1-(3-lithiopropargyl)benzotriazole 4.2 just


described, intermediates 4.9a,b (generated in situ from 4.2 and one


equivalent of


methyl or ethyl iodide) reacted with N-tosylarylimines to give compounds 4.10a-d in

high yields. Compounds 4.10a,b were then cyclized by heating with ethanolic alkali

to afford the corresponding 5-alkyl-2-(1-naphthyl)pyrroles 4.11a,b in 46 and 58%

yields, respectively.

















60-90%


NUTI


4.4 a-e


=c-K
NHTs
4.6 a-e


NHT


4.5 a-e


4.9 a,b


50-87
r


C
(for Ar = 1-naphthyl)


NHT


4.10 a-d


46-58
r


40-60%k


4.7 a-e


4.4-4.8 Ar
a Ph
b 2-thienyl
c p-Tol
d 1-naphthyl
e p-C1C6H4


4.9, 4.11 R
a Me
b Et


4.8 a-e


4.11 a,b


4.10 Ar R
a 1-naphthyl Me
b 1-naphthyl Et
c p-Tol Me
d p-C1C6H4 Et


Scheme 4.1


Reagents and conditions: a. BuLi/hexane/THF


-78 OC:


Bt


H


Napht


+--


.











should


noted


however,


attempted


preparations


5-alkyl-2-arylpyrroles


from


acetylenes


4.10c-d


were


not successful


no pure


compounds were isolated although traces of the expected products were detected by


'H NMR.


Although the exact reason remains unclear, in part,


it can probably be


accounted for by a concurrent isomerization of compounds 4.10c-d into allenes of


rather


to intermediates


required


pyrrole


formation. This probably results from a decreased acidity of the methyne(alkyl) group

a to the benzotriazol-1-yl substituent, as compared to that of a methylene group in

intermediates 4.4a-e (Scheme 4.1). Indeed, our previous studies demonstrated an easy


isomenzation


1 -propargylbenzotriazole


1 -allenylbenzotriazole,


whereas


a-alkyl


substituted


derivatives


were


relatively


stable


under


basic


conditions


[92LA843, 93JOC3038].

Among the previously reported routes to 2-aryl- and 2-hetaryl-pyrroles, the


Trofimov reaction


of ketoximes


acetylenes


(or their precursors)


the most


important (for a review


see 90MI177).


However,


application of this procedure to


2-naphthylpyrroles


was


accompanied


considerable


resinification


gave


yields, e.g. 2-(1-naphthyl)pyrrole 4.8d in


15% yield [82KGS1351].


Other reported


preparations of 2-arylpyrroles include thermal rearrangement of 1-phenylpyrrole to


2-phenylpyrrole


[41JA1563],


a 4-step


route


Hemetsberger


reaction


3-arylacroleins


with


methyl


azidoacetate


[79TL1717],


synthesis


,4-diphenylpyrrole


a rhodium-catalyzed


hydroformylation


(1,3-diphenyl-


propargyl)amine


[91TL1093],


2-phenylpyrrole


from


1 -trimethylsilyl-NN-


-bis(trimethylsilyl)propargylamine


from


1-phenyl- 1-trimethylsiloxy-4-[N,N-







34



constructions of the pyrrole ring also involving a formation of N-C(2) and C(4)-C(5)

bonds via condensations of a-amino acids and their derivatives with j-dicarbonyl or

a,j-unsaturated carbonyl compounds (see a review 84MI313 and refs. cited therein).


In conclusion,


1-propargylbenzotriazole 4.1 has been shown to be a useful


reagent for new and convenient synthetic route to 2-aryl-


and 2-hetaryl-pyrroles. The


method


generally restricted


to the


preparation


of 2-substituted


pyrroles,


but in


certain cases enables also the synthesis of 5-alkyl-2-arylpyrroles.



4.3 Experimental


Melting


points


were


determined


with


stage


apparatus


uncorrected.


1H and


13C NMR spectra were recorded on a


Varian


VXR-300 (300


MHz) spectrometer using


TMS as an internal standard. HRMS were obtained on a


Finnigan


spectrometer.


Elemental


analyses


were


determined


Department. Column chromatography was conducted over silica gel (


30-400 mesh).


N-Tosylarylimines were prepared by the literature procedure [81JCS(P1)2435].



4.3.1 1-Benzotriazol-1-yl-4-(N-tosyl)amido-4-arylbut-2-ynes 4.4


A solution of n-butyllithium in hexane (4.4 mL,


11 mmol,


5 M) is added


dropwise with stirring to a solution of 1-propargylbenzotriazole 4.1 (1.57 g, 10 mmol)


in THF (50 mL) at


-780 C. The mixture is stirred at this temperature for 45 min, and


an appropriate N-tosylarylimine ( 10 mmol) in THF (20 mL) is added dropwise.







35


solvent is removed under reduced pressure to give crude products which are purified

by crystallization from EtOH.


4.3.2 1-Benzotriazol- 1-yl-4-(N-tosyl)amido-4-aryl-1-alkvlbut-2-vnes 4.10


M Butyllithium


in hexane (8.8 mL,


mmol) is added dropwise with


stirring to a solution of 1-propargylbenzotriazole 4.1 (1.57


10 mmol) in


THF (80


mL) at


-780 C.


The mixture is stirred at this temperature for 1 hr and an alkyl iodide


(11 mmol) is added slowly. The

color of the reaction disappeared.


added slowly at


mixture is stirred for several hours

N-Tosylarylimine (10 mmol) in T


-78 C and the mixture is stirred for 4 hr.


until the blue


-HF (30 mL) is


Water (150 mL) and diethyl


ether (200 mL) are added. The organic phase is washed with water (3 x 50 mL) and


dried (MgS04).


The solvent is removed under reduced pressure to give the crude


products which are purified by recrystallization from EtOH.


4.3.3 2-Arvylpyrroles 4.8 and 2-(1-Naphthyl)-5-alkylpvrroles 4.11



A mixture of the appropriate compound 4.4 or 4.10 (5 mmol) and sodium


hydroxide (0.8 g, 20 mmol) is refluxed in ethanol (50 mL) for 1


and ethyl ether (100 mL) are added.

mL) and dried (MgSO4). The solv<


Water (50 mL)


The organic phase is washed with water (3 x 30

ent is removed under reduced pressure, and the


products are separated by column chromatography using eluents indicated in

4.2.


Table











Table 4.1


Products 4.4 and 4.10 from Lithiated 1-Propargylbenzotriazole 4.1


Product Yielda (%) mp (oC)b Crystal Formc Molcular Formulad


4.4a 81 155-156 Needles C23H20N42S (416.5)

4.4b 82 142-143 Plates C21H19N402S2 (423.5)

4.4c 72 168-170 Plates C24H22N402S (430.6)

4.4d 92 197-198 Prisms C27H22N402S (466.6)

4.4e 76 154-155 Needles C23H 19N4C102S (450.9)

4.10a 77 192 Plates C28H24N402S (480.6)

4.10b 72 177 Plates C29H26N402S (494.6)

4.10c 81 121 Needles C25H24N402S (444.6)

4.10d 76 135 Plates C25H23N4CIO2S (479.0)


a Yields


are of purified products based on 1-propargylbenzotriazole 4.1.


b Melting points are uncorrected.
c All products were recrystallized from EtOH.
d Satisfactory microanalysis obtained: C 0.40, H 0.17, N 0.26.


Table 4.2 2-Arylpyrroles 4.8 and


(1-Naphthyl)


-alkylpyrroles 4.11


Product Yielda (%) mp (oC)b Lit. mp (oC) or Eluent (bexane/CH3Cl)
Molecular Formulaa
4.8a 51 129 129-130 [41JA1563] 1: 1

4.8b 60 154 154 [79TL1717] 1 :2

4.8c 45 153 153 [1904CB2796] 1: 1

4.8d 58 176-178 174-180 [82KGS1351] 1 :2

4.8e 47 139 140 [85KGS1501] 1 :2

4.11a 56 oil C15H13N (207.3) 1:2































00
In



-J J


'- '-




- v%


rjl













'ct


M4ni


b v
r- b,


%oc
I',.


0;ct


oJ fl





ocd


-c
In-






II



cc1









38










'0 U-i N '6c U. t 9
N1 en 00 00 --~ Nen 0% m
..C CN1CI ei J
-~~r -n n --
ad cc c.~ *e

N N UN r od enj N enr
Nr mn' Cl en
rI' FI '

Nmo Nm Nr N0 ct n
l -J -3 -l -( -( 4N
i a' .5- --
0\ 9 Ni .. .. V)V -
u~c'o -P.
ear c-I UcV U n
Oct *n a. .. cc ~ r


9? N d 'Cj 00r-N-
0 ~ I1 tel en Nj N4e
00N 00 0 0 0 0e


o N N mN N N~ 00 -
uJ 00F \ 0 1 I r
00 0% cc 'n oqr oN -c en C
ccs 4r iN \a N\ 'cm i-c
od e n ~a a a

Cu t2 en; an ode

tU~~~ en en ene n
en 0XNNO 0 0--

u N N rN NJ N N-N Ncira-N v

Z Cj 9i 0 N C. N
en en en enr en en e, en en
-l - --
-4C



m t t to tt 45 4
0 - -; -; -
0I l Fl lr E
cU N In e ne 0I 5e
HU -~ -

N o V) r CC N 0 0) 0

(NI N r
CM 0% 0% 0% 0V enc C'
&; cc cc cc 0% 0% 0i 0%
U -I -r -" -l -l -N
II Ct .0 ~r
U U C 6 0X 0
4 4 4 4 Wg























































('Ia










40













0 N -

-c r4 -

C) U UJ m U
ci ci v-- e ci cvi
i~* '-I a ai -r
t~~ ~ 0I 00r J I

- Ud ar a arc
'0 ci rae duen r r
aC ci ci -------
CA 0 -d a
o~~r U vc
-~~ cc cc-

C1 N '00
en en N ccI1 rr
ci ci icii @4c
-- --
4-hC o or



ul r I Il I- II l ci

I
en-ia
e e
g ca -

00









-' 00 fJIl 0% ci e e


CU 04 C
4-.
Cu00 0 enc 0'
-

z1
S ci 0% -
-Ir 0d cc 0 0
-~ ~ ~ en en ci ene i





rrJ -l ~ FI r

-c I~ d 3b
Cu 04 'V dmd
H~













CHAPTER V
A NOVEL FURAN RING CONSTRUCTION AND SYNTHESES OF 4- AND
4,5-SUBSTITUTED 2-(a-HETEROCYCLO)ALKYLFURANS


5.1 Introduction


The synthesis of furans is of importance since the furan ring is present in


numerous


natural


compounds


which


exhibit


interesting


biological


activities


[93JOC21].


The ring system is also found in industrially significant substances and in


many


useful


synthetic


building


blocks


[84MI657


86CR795].


A variety


approaches


leading


to the


generation


furan


have


been


documented


[84MI657


66MI377


, 93JOC3038 and 93SL905]


and among them, several


general


methods utilize an


intramolecular cycloaddition


alkoxides


to double and


triple


bonds as the key reaction. Recently, many acyclic precursors have been employed for


synthesis


a wide


range


substituted


furans


[94H223].


example,


alkynyloxiranes,


prepared


coupling


vinylic


halides


or triflates


with


terminal


alkynes followed by epoxidation with m-CPBA, are isomerized under strongly basic


conditions


or reduced


with


samarium


diiodide


afford


2,4-,


2,3,5-substituted furans [94H223, 91JOC1683, 92JACS1450 and 93JOC3435], in a

reaction pathway involving 5-endo-dig cyclization of the corresponding cumulenyl

alkoxides.


In chapter II, III, IV


and VI,


we demonstrated that 1-propargylbenzotriazole


(5.1), readily available from the reaction of benzotriazole with propargyl bromide in

the presence of sodium hydroxide [92LA843], is a useful reagent for the synthesis of






42



furans, dihydrofurans [93JOC3038], pyrroles [94S93] and indoles [95UP1]. Thus, the


reactions of 1-(3-lithiopropargyl)benzotriazole (5.4) with aromatic aldehydes


1- [(3-hydroxyarylmethyl)propargyl] benzotriazoles


which


undergo


base-assisted


rearrangement to


form


a-hydroxyallenes.


Subsequent intramolecular cyclization


(benzotriazol-1 -yl)-5-aryldihydrofurans


elimination


of benzotriazole


affords


2-arylfurans [93JOC3038].

We now report a novel one-pot procedure for furan ring construction from


1-propargylbenzotriazole


(5.1)


a-bromoketones.


resulting


4,5-substituted


2-(benzotriazol- 1-yl)methylfurans


can


undergo,


either


directly


following alkylation, displacement of the benzotriazole groups by other heterocycles


to give


the corresponding


4- and


4,5-substituted 2-(a-heterocyclo)alkylfurans 5.10


and 5.12. Compounds of types 5.10 and 5.12 play important roles in the food industry


as intermediates for the synthesis of


other organic compounds and


polymers


[93JOC4376].


Few previous methods are reported for the synthesis of 5.10 and 5.12.


particular,


such


systems


with


different


simple


heterocyclic


rings


were


unknown until our previous work [93JOC4376].



5.2 Results and Discussion


5.2.1 Furan ring construction
triazol- 1-vl)methvlfurans 5.3


- Preparation


4,5-substituted


2-(benzo-


an extension


our investigation


concerning the reactivity


of lithiated


1-propargylbenzotriazole (5.4) towards ketones for the preparation of dihydrofurans







43



equivalent of a-bromoketone at -78 oC and subsequent warming to room temperature

gave the corresponding alkynyloxirane 5.2 as the major product with smaller amounts


substituted


furan


structures


of both


derivative


were


supported by 'H and APT NMR spectra.


When the reaction was carried out at


-78 C


without warming, the alkynyloxirane 5.2 could be isolated exclusively (as was done

for 5.2d, RI=R2=CH3, see experimental). Assuming that product 5.3 was formed via


isomerization


of intermediate


presence


a trace


of base,


we treated


alkynyloxirane 5.2 with KOBu


in HOBu


at 50 oC for several hours.


The expected


product 5.3 was afforded in


good


yield.


Similar base-catalyzed transformations of


alkynyloxiranes into furans are found in the literature,

alkynyloxiranes are prepared by multi-step methods and


however, the corresponding

S18-crown-6 is required for


the ring formation [92JACS1450].


(i) n-BuLi / THF


- Bt


3b: R1
3c: R1
3d: R1



Bt=


= Ph, R" = H
= 2-naphthyl, R2


=Ph, R


KOBut
HOBut
50 C


=CH3


= CH3


(51-61


5.2 R











practice, it is not necessary to isolate


the alkynyloxiranes


Thus


one-pot synthesis of


4- and 4,5-substituted 2-(benzotriazol-l-yl)methylfurans 5.3 is


available


(Scheme


5.1).


1 -Propargylbenzotriazole


(5.1)


was


treated


with


equivalent


n-butyllithium


at -78


followed


treatment


with


a-bromoketones for 4 h at the same temperature.


A solution of KOBu


in HOBu


was


added and the reaction mixtures were warmed to 50 oC overnight to give the products


5.3 in 51-61


yields (Table 5.1).


The products 5.3 were characterized by 1H and 13C


NMR spectra and elemental analyses (Table


and 5.3).


Mechanism of furan fine construction


The following mechanism is proposed based on experimental and literature

evidence (Scheme 5.2). 1-Propargylbenzotriazole (5.1) was deprotonated on treatment


with


n-BuLi


to generate


anion


which


attacks


carbonyl


group


a-bromoketone


to yield


adduct


oxygen


anion


intramolecularly


displaced


bromide


to form


epoxide


which


isolable.


Since


benzotriazole


electron withdrawing,


the propargyl triple bond can readily rearrange to an allene


under


basic


conditions


[93JOC3038].


Therefore,


KOBut


efficiently


promoted


1,4-elimination


alkynyloxirane


form


cumulenyl


alkoxide


which


underwent


1,5-endo-dig


cyclization


to afford


vinyl


anion


followed


rapid


protonation to give compound 5.8. Intermediate 5.8, (which could be isolated at room


temperature as demonstrated for 5.8c, RI=Ph, R2--CH3,


see experimental), rearranged


upon


heating


with


KOBut


to form


which


was


protonated


one















n-BuLi


0*


46


r


ButO-


1,4-elim


=C -


1,5-endo-dig


HOBut


KOBut


HOBut


50 C


Scheme







46



5.2.3 Alkylation of 4- and 4,5-substituted 2-(benzotriazol-l-vl)methvlfurans 5.3 and
formation of 4- and 4,5-substituted 2-(a-heterocvclo)alkylfurans 5.10 and 5.12


Benzotriazole


been


extensively


used


our laboratory


as a synthetic


auxiliary


its electron


withdrawing


good


leaving


group


properties


[93JOC4376].


Therefore,


benzotriazol- 1-ylmethyl


chain


can be


elaborated by alkylation and substitution (Scheme 5.3).


Compound 5.3 was treated


with one equivalent of n-BuLi at -78 C to generate anion 5.9 which then reacted with


electrophiles


such


as benzyl


bromide, n-butyl iodide,


i-propyl


iodide


methyl


iodide to give the alkylated products 5.11 in 65-87% yields.

Compounds 5.3 and 5.11, upon treatment with ZnC12 in CH2C12, underwent


Friedel-Crafts


type


reactions


with


other


heterocycles


such


2-methylfuran,


2-methylthiophene


N-methylindole


afford


4,5-substituted


2-(ac-heterocyclo)alkylfurans 5.10 and 5.12 in good to excellent yields.


The function


of ZnCl2 is to coordinate the nitrogen lone pair electrons of the benzotriazolyl group


assist


benzotriazolyl


group


removal


to generate


carbocation.


Since


reaction involved


the formation


carbocation 5.13 (Scheme 5.4),


the R3


and R2


groups are essential for the reactivity of compounds 5.3 and 5.11. Accordingly, the

reactions of alkylated products 5.11 were carried out at room temperature. However,


reactions of


compounds


5.3c,d


must


be carried


out under reflux


CH2C12.


Compounds 5.3a,b (R3=R2=H) did not undergo the reaction under reflux either in

CH2C12 or in CHCl3 and were recovered unchanged after such treatment. The mixture


of 5.3a and


2-methylthiophene,


when heated


under reflux


in CHCl1CHC12


presence of ZnC12, gave a complicated mixture.













n-BuLi


heterocycles
ZnC12 / CH2C12
reflux


R3X


(65-87%)


R3


Bt


(57-86%)


heterocycles
ZnC12 / CH2C12


(57-95%)


compd


Ph
Ph
CH3
CH3
Ph
2-naphthyl
Ph
CH3
Ph
Ph
2-naphthyl
Ph


CH3
CH3
CH3
CHa
H
H
CH3
CH3
H
H
H
CH3
flr rr


PhCH2
i-Pr
n-Bu
CH3
PhCH2
PhCH2
i-Pr
n-Bu
flr."I


5-methylfuran-2-yl
5-methylthiophen-2-yl
5-methylthiophen-2-yl
N-methylindol-3-yl
a

-

5-methylthiophen-2-yl
N-methylindol-3-yl
5-methylfuran-2-yl
5-methylfuran-2-yl
IT -1 .< '- I^


















Scheme


attached


proton


(APT)


spectra


clearly


showed


quaternary


carbon


signals


(8=149.6-153.7) indicating C-


of the 5-methylfuran-2-yl groups of compounds


5.12c and 5.12d. Similarly, the C


signals of the 5-methylthiophen-2


-yl groups of


products


5.10b,


5.10c


5.12a


appeared


at 8=


142.5.


singlets


8=6.65-6.87


, which are characteristic resonances of the a-H in 3-substituted indoles,


and the quaternary carbon signals at


111.3-117.7 in the 'H and APT NMR spectra


compounds


Sl10d,


5.12b


5.12e,


are strong


evidence


for the


3-substituted


N-methylindole.


Interestingly, the 'H NMR spectra of compounds 5.12a and 5.12b


clearly showed two sets of doublet of doublets between


and 3.47 ppm with


large


couplings


(J=13.4-13.5


7.1-8.1


indicating


CH2


diastereotopic


signals are attached to chiral centers. Detailed assignments of the NMR spectra are


listed in Tables


.5 and 5.6.


All products are novel and are characterized by


'3C and APT NMR spectra


combustion


analyses


(Tables


Excess


2-methylfuran


2-methylthiophene was used to minimize polymerization of compounds 5.3 and 5.11


was


removed


distillation


at the


completion


reactions.


ZnC12


was


removed by washing with


N HC1 solution and benzotriazole was extracted into the


aqueous phase with


NaOH.


The products were readily isolated by short column


,t. ,,,t. .. --.. -, I. 1 T -, -.- aZ-- -.a-


,r, Cln,,l rr











conclusion,


we have


described


a simple


one-pot


synthesis of 2,4-


2,4,5-substituted


furans


from


readily


commercially


available


starting


materials


1 -propargylbenzotriazole


(5.1)


a-bromoketones.


benzotriazolyl


group assisted the base-catalyzed isomerization of the intermediate alkynyloxiranes


5.2, and therefore, 18-crown-6 was not required.


In addition, since the benzotriazolyl


group acts as either an electron withdrawing substituent or as a good leaving group,


benzotriazol- 1-ylmethyl


group


compounds


readily


elaborated


alkylation


substitution.


variety


4,5-substituted


2-(a-heterocyclo)alkylfurans 5.10 and 5.12 were prepared in this manner.



5.3 Experimental


Melting points were determined on a bristoline hot-stage microscope and are

uncorrected. NMR spectra were taken in CDC13 with TMS as an internal standard for

'H (300 MHz) or CDC13 as an internal standard for 13C (75 MHz). Assignments for


13C NMR spectra in necessary cases were confirmed by APT experiments.


analyses (C, H,


Elemental


N) were carried out within the department. Column chromatography


was conducted over silica gel (230-400 mesh).


All a-bromoketones and ZnC12 were


used as purchased.


1-Propargylbenzotriazole (5.1) was prepared


by the previously


reported method [92LA843].



5.3.1 6-(Benzotriazol- 1-vl)-2,3-epoxy-3-methyl-4-hexyne (5.2d)











cyclohexane,


mmol).


The mixture was stirred at this temperature


h and


3-bromo-2-butanone (1.66


mmol) in


THF


(5 mL) was added slowly.


After


stirring at -78 oC for 4 h, ether (100 mL) was added and the reaction mixture was


washed with saturated NH4Cl solution (3 x 100 mL) and dried (MgS04).


Evaporation


of the solvent gave a crude product which was purified by column chromatography

using EtOAc/hexane (1:4) as the eluent to afford pure 5.2d (1.82 g, 80%) as a white


solid: mp 83-84 C

Bt), 7.50-7.55 (m,


; H NMR 8 8.05 (d, J

1 H, Bt), 7.36-7.42 (m,


= 8.4 Hz, 1 H,


1 H, Bt),


5.48 (s,


7.69 (d, J

H, CH2),


= 8.3 Hz

3.21 (q, J


,1H,

= 5.5


Hz, 1 H, CH), 1.45 (s, 3 H, CH3), 1.27 (d, J


= 5.5


Hz, 3 H, CH3)


13C NMR 6 145.9


(Bt),


132.2


(Bt),


127.4 (Bt),


123.8 (Bt),


119.7


(Bt),


109.5


(Bt),


(C-C),


(CH2CeC),


60.0 (CH), 50.1


(OCCH3), 37.9 (CH2),


(CH3),


(CH3).


Anal.


Calcd for C13H13N30: C,


68.69


18.50. Found:


68.74


18.49.


Preparation


4,5-Substituted


2-(a-benzotriazol- 1-vl)methylfurans


5.3a-d


A solution of n-BuLi (10.


dropwise with stirring


.0 M in cyclohexane, 21 mmol) was added


to a solution of 1-propargylbenzotriazole (5.1) (3.14 g,


mmol) in THF (100 mL) at


-78 oC.


The mixture was stirred at this temperature for 1 h


and a-bromoketone (21 mmol) in THF (10 mL) was added slowly. The mixture was


stirred for 4 h and KOBu


t (2.24 g, 20 mmol) in HOBut (20 mL) was added.


reaction solution was allowed to warm to room temperature and then heated at 50 C


overnight. H20 (100 mL) and EtOAc (100 mL) were added.


The organic phase was







51


recrystallization or column chromatography to afford the product 3 (Table 5.1).


5.3.3 2-(Benzotriazol-l-vl)methylene-4-phenvl-5-methyl-2,5-dihvdrofuran (5.8c)


To a stirred solution of 1-propargylbenzotriazole (5.1) in THF (30 mL) at -78

oC was addd a solution of n-BuLi (5.5 mL, 2.0 M in cyclohexane, 11 mmol). After 1


h, 2-bromopropiophenone (2.60 g,


90%, 11 mmol) in THF (5 mL) was added and the


reaction mixture was stirred for 4 h. KOBut (1.12 g, 10 mmol) in HOBut (10 mL) was

added at -78 oC and the reaction solution was allowed to warm to room temperature


overnight.


The reaction mixture was quenched with saturated NH4C1 solution (100


mL), extracted with EtOAc, washed with saturated NH4CI solution (3 x 100 mL) and

dried (MgSO4). Removal of the solvent under reduced pressure gave an oil which was


subjected to column chromatography to afford pure Sc (1.50 g,


) as a yellow oil:


1H NMR 8 8.05 (d, J


= 8.4 Hz, 1 H, Bt),


7.67 (d,


= 8.3 Hz, 1 H, Bt), 7.32-7.50 (m, 7


H, Bt and Ph overlapped), 6.64 (s,


1 H, CH),


1 H, C=--CH), 6.58 (s,


(d, J = 6.5 Hz, 3 H, CH3);


1 H, C=CH),


13C NMR 8


(q, J


= 6.5


151.5


(C=CH), 145.3 (Bt), 132.8 (Bt), 131.0 (Ph), 129.5 (Ph),


128.8 (2C,


Ph), 126.8 (Bt),


126.4 (2C, Ph), 123.6 (Bt), 119.5 (Bt), 117.0 (C=CH), 111.7 (Bt), 93.9 (C=CH), 85.7


(CH), 20.4 (CH3).


Anal. Calcd for C18H15N30: C, 74.71


H, 5.23


N, 14.53.


Found: C,


75.09; H, 5.32;


N, 14.40.


5.3.4 Alkylation of 4- and 4,5-Substituted 2-(a-benzotriazol-1-yl)methylfurans 5.3


156.2 (C=CH),











at -78 OC.


The mixture was stirred for


1 h and


alkyl halide (5


mmol) was added.


The mixture was stirred at


-78 oC for


5 h and was then allowed to warm to room


temperature. H20 (100 mL) and Et20 (100 mL) were added and the organic phase


was


washed


with


NaCI


solution


dried


(MgSO4).


Et20O


was


evaporated


under reduced


pressure


give an


which


was purified


column


chromatography to yield the product 5.11 (Table


Formation of 4- and 4,5-Substituted


(a-heterocvclo)alkylfurans


10 and


A mixture of


4- or 4,5-substituted 2-(a-benzotriazol-l-yl)alkylfuran 5.3 or


(2 mmol),


ZnC12 (2 mmol) and heterocycle (20 mmol for


2-methylfuran and


2-methylthiophene and


2 mmol for N-methylindole) in CH2C12 (50 mL) was stirred at


room


temperature (for 5.3c and 5.3d under reflux) under nitrogen


overnight.


reaction was washed with HC1 solution (2 N,


50 mL), NaOH solution (5


mL) and dried


(MgS04).


CH2Cl2


was removed


under reduced


pressure to


give a


residue.


product


5.10


or 5.12


was


separated


from


residue


column


chromatography (Table 5.4).










53











ri 0 0 N C Cl



Cl 0% Zn n U, -S

in do &,m~Ft
Cl 4. 00 C




U*~ e\


z N; ri ri 0% cc


1- N N N V r N N No C
-: 00 -O 4.(r
r ii 4. 00 -i -i ('4



cc C

- Va 4. it, It in V V r



4. 00 0 0% 0% N .

10


Cl Z
en 'n in, en a' -, e




CtI

tcr I- 4

4) 4) 4) 8) 4) C


CI a
itt
V-,



ori en 0S N5 P
Cai -! Cl0I Qr Q
o ('4 Zn 00 ('1 Vj *i V t9































t--
\0%
In '-~

r16O


- ..
,-% -a

*v cE


*cr'd
(-4-'-


'I-

0:



S:











55














N

a en0C


00 2 V
^ o

rN C e
w~Cr M ,-^ ^ o



N Nq N- oo w' N- Nt ('4
&~~ ~ vS 06uiF i oti ^


j~ S.
'0 4 4s ent 6 enO ci
*; c oo aor d o& Nor
en - -*
Q en mo to i vi -~ 3'
Q Cr i od vs r^ oo od M t
00 (' Nh 000 '4N0


o N en
(' NC i' en N N
c___ - -~ ^
y^ c^l rl csi w r M ^


to N &r a t OO CSr Ml
- .4 en en Nn \n N0 enju

- en en N en en oo N en 2
* - n -


*0 "1w In cc N en 0
UoU.' 00 I? V 0 00 t
c ;r;0;r lii c, n; 02




-1-^ -~ ^- -^ -< -1 -
rl (l en N 0% 00 N ^
U* -. -^
c ^f t^ r rl *-* *^* ro r^r-
C -



0 00

0 -S S c oo -
(a) N 9 iC< i-0 02 0 en
o U t 0 to In It

00 N Ifl '0 einn*<
5 N No N N p
N1 en e en en en en





Z c- -
?_;~~~~r rjrlWW








Q ( 0 0%^ 00 NM^:-
f^3 W vO dO V1 \O W 0O r0
en 'a '.6 to '. vi v C






en U 'It 's *^

CQ '^^ 0 o oo 'a en n en
N^ oR 6 6 6 i
U 00 0 -^ -

S3 O o oo 3
C en en en en e

-I -
~Moq od N 00
-TO~r *l rl T* WWW











U A U at U ^M ^
l2v U "






en en en ei n r-- -p
SU vi v .4 .4 '4 .
rjI ,-< t ^r^ll M '^'

ii "g o u; o:S5
3 o
g ~ I r fl n F I itu









56















N --



0 0 00 -0 Ng 00I
so 'a Nd I-dr: i \ \
I'a 'a '6 Sr '6 'a

Ca S

0r '0 0' 0\ 0o Cfl -
-udu ;dv '.rd N- -
ccI 0% % I e
aa 'q a r
cUU 00 N N 0 0 C 00 C 0
C) C

o~~ 0r 0 0! z
'0 '0 t N V N t 0
-N N -
o a'c '
--~~c N N NC '0e Ne Ni
r- -O eq c-a e, e -y e
SU U U U U U U U U
*0-
U
L(U
(N 0d~ I Qt




a a uY au aq v PU
Ur Ce r C- Cr Nr Nl Cl q
CC ; vi c;
ttn f4 I




(U o a 'V s3(
5.4 -5 00'
t


03 St I It
cUF eq eq eq eq eq eq

C4t
or


Sf3 (UI 91 -r -l -l -la
0" 0

F-e b P
El- c- en It an) CI NO 00 0%




































I t'
:00

r4-a


lcr-



U) f
-
N'-~


D~
hV100
tiT;F:
.rl
rl
VsB
cn
FI~I
rr~crn
rc~
V
r:%S
~"~d
rthF.1
tr~Ov
rr
d~lr;

pJC30Q
vV~
On~f
P~B


r-


1 vli


I;


*


-S -
000
*




tU)


erln


9.
U
c-ct
*SO






Er)i



~e4~


us Ui


In







en

r4

crl












n
c~ 9.

g-: c


r 4

0




4)


4)










58













C

NO
en\ ci d eq


Nd d q


enn 0% 0

-J 0' 0'a
'C -r ` CI O
o;~~ N;r; b
N e
- N' Nc
-C -4
U


eqi ad d 6d N
-~ ~ NJ N .4c e



'0 04P N CI m
cc 00 ci N en


en) -r 0% tr enN



o U J Nr ` en en n
oC


F I n *I 0% ~

-4 -lr l~ 4 -l -4 -l -4rl
_~r en 9 l N N
N~~~~~~r In InN-'0CI CCI

er r -J Cc -
81 *J UU Id\ i
FIt en en N1 -( en Nl i
-t -4 -41 -4 -4 -4 -4 -4 -
Z C) C5 4r I, U. U. U.
VI *l 9l *l %0 N



0%) CC Cr In N Cl N 6) In
IA U en en envir


-I -J It C CQ 3
Nd Nj -1 N e' Nz

ot 0

o In C, CC t It 'n n
N -; d en '4
On i n In n vI InI nI



-i I-i -i -j -i -iv













CHAPTER VI
FACILE SYNTHESIS OF 2-SUBSTITUTED INDOLES AND
INDOLO[3,2-b]CARB AZOLES FROM
2-(BENZOTRIAZOL- 1-YLMETHYL)INDOLE


6.1 Introduction


2-Substituted


indoles


are pharmacologically


important


substances


precursors for a wide variety of


alkaloids [83MI1] such as vindoline,


vindorosine


[87JOC347],


ellipticine


[89JOC3084],


etc. Perhaps,


the most


general


approach


2-substituted indoles involves 2-lithiation of indoles, promoted by directing groups


such


1-benzenesulfonyl


[73JOC3324],


1-lithiocarboxylate


[85TL5935],


1-(dimethylamino)methyl


[89H849],


1-tert-butylcarbamoyl


[91S1079]


1-(2-oxazolinyl) [92H173],


followed by reaction with a wide range of electrophiles.


Recently, several methods for the preparation of 2-substituted indoles were developed

which involve elaboration of 2-methylindole, eg. a-bromination [82S926, 85S 188 and

92S743] followed by substitution of the bromine atom or a-deprotonation followed by


alkylation of protected indoles [89TL2509 and 92S648].


However, protection of the


indole 3-position is a problem associated with many of these methods. In our previous

work, we described a useful methodology in which a variety of 2-substituted indoles

were afforded by 2-alkyl lithiation of 2-alkylindoles activated by carbon dioxide and

subsequent electrophilic substitution [86JA6808].

Indolo[3,2-b]carbazoles have gained significant importance pharmacologically


since they inhibit the specific


binding


toxic


dioxins


which


rise to thymic











atrophy,


hyperkeratosis


chloracne in


liver


cytosol


[86MI1673].


A number of


synthetic methods


for the preparation of


5,11-dihydroindolo[3,2-b]carbazoles


have


been


described:


vapor


phase


catalytic


cyclodehydrogenation


N,N'-di-


phenyl-p-phenylenediamine


[61JOC1509];


Fischer


indolization


cyclo-


hexane-1,4-dione bisphenylhydrazone [63JCS3097]


(iii) condensation of indole and


formaldehyde in the presence of air and sensitizers [70T3353]; (iv) polymerization of


indole


p-toluenesulfonic


Dowtherm


[88JCS(P1)2387];


transformation


4,9-dihydropyrano[3,4-b]indol-1 (3H)-ones


presence


mineral acids [89AP451].


However, all of these methods suffer from low yields and


require


vigorous


reaction


conditions.


general


method


conversion


2-substituted indoles to indolo[3,2-b]carbazoles has been reported previously.

We now present a convenient method for the synthesis of 2-substituted indoles

from 1-propargylbenzotriazole and o-iodoaniline involving alkylation and subsequent

displacement of the benzotriazole moiety and a general method for the preparation of


6,12-dihydroindolo[3,2-b]carbazoles and 5,11-dihydroindolo[3


b]carbazoles.


6.2 Results and Discussion


6.2.1 Preparation of 2-(benzotriazol-1-vlmethvl)indole (6.3)


Castro and coworkers


[66JOC4071]


developed an efficient method for the


formation


of 2-alkyl- and 2-aryl-


indoles from


a variety


cupric acetylides and


o-iodoaniline derivatives. However, the possibility of employing this method for the







61



which contains a side chain methylene group that can be further elaborated as the

benzotriazolyl group acts as both an activator for deprotonation and a good leaving

group, as has been demonstrated extensively in our laboratory [91T2683].


CuSO4-5H20, NH-3H20


NH20H.HC1, EtOH


OOCto rt


DMF


lo0OC


NH2


60%


= benzotriazol-1-yl


Scheme 6.1


6.2.2


Deprotonation


of 2-(benzotriazol-1 -ylmethyl)indole


(6.3)


and reaction of


lithiated derivatives with electrophiles


Compound 6.3 was treated with


1 equivalents of n-butyllithium in


THF at


-30 oC for 30 mm or at


-78 OC for 5 h to generate the dianion 6.5 which was then


reacted with 1.1 equivalents of alkyl halide to form anions 6.7.


These anions 6.7 were


n..n~nnknA ..*k .nndn. t- nFtn..A e-,- nlnln~ nll~ t~n 0: :n k:k


I


NH2














H
6.3

I BuLi (2.1 eq) / THF


-30 C


30 mm


-78 oC,


Li

Bt
Bt


HMPA
R1X (3 eq)
-78 0C to rt


R'X (1.1 eq)
-78 C


Li
6.7


6.6a: R1
6.6b: R1
6.6c: R1


= PhCHg
= n-Bu


H20


HMPA


6.8a: R
6.8b: R
6.8c: R


R2X (2 eq)


6.9a: R1


6.9b


6.9c: R1


= n-Bu, R
= i-Pr, R2
= PhCH2,


1 = n-Bu
1 = n-C5H11
1 = n-C6H13

=PhCH2


=CH3


= n-Bu


6.9d:
6.9e:


= CH3, R2


=Et, R


=CH3


CH3











The N-alkylation of indole has


been


well studied


[67TL3771,


72S566 and


73JCS(P 1)499].


The general method involves N-metalation followed by substitution


with alkyl halides. The reaction solvents are especially important and the site-specific


N-alkylation


favored


dipolar


aprotic


solvents


such


as HMPA


DMSO


[72S566 and 73JCS(P1)499].


When anions 6.7


were quenched with


excess


halide


(PhCH2Br or n-Bul) in THF at room temperature for 24 hours, only trace amounts of

N-alkylated products were detected by 'H NMR. Presumably, the nucleophilicities of


indole


lithium


salts


are weaker


those


indole


sodium


salts


[67TL3771].


However, when HMPA was added to comprise 50% of the total solvent, high yields


of N-alkylated products were obtained.


Thus, after the generation of dianion 6.5 in


THF, an equal amount of HMPA as solvent and three equivalents of alkyl halide were


added to the reaction mixture at -30 oC.


The solution was allowed to warm to room


temperature overnight to give the dialkylated products 6.6 in good yield.

Alternatively, the dianion 6.5 was first reacted with 1.1 equivalents of alkyl


halide at


-78 oC in THF for several hours.


Two equivalents of a second alkyl halide


and an amount of HMPA equal to that of THF were added at -30 oC.


The reaction


mixture was allowed to warm to room temperature and stirred overnight to form the


regiospecifically


1,2-dialkylated products 6.9.


variety


mono-


dialkylated


compounds were prepared similarly (Scheme 6.2).


and 6.9 were confirmed by 'H,


The structures of products 6.6, 6.8


'3C, and APT NMR spectra (Tables 6.4 and 6.5) and


elemental analyses (Table 6.1).







64



6.2.3 Substitution of 2-(1-benzotriazol-l-ylalkvl)indoles 6.6 and 6.9 with Grignard


reagents


It is well-known that the benzotriazole moiety acts as a good leaving group in


reactions with Grignard reagents [91T2683].


Therefore, reaction of compounds 6.6


and 6.9 with aryl or alkyl magnesium halides in refluxing toluene for 3 hours gave the


corresponding products 6.10 in good yield (Scheme 6.3).


wide range of


Following this procedure, a


2-alkylindoles 6.10 was obtained (Table 6.2).


R3MgX


toluene
reflux
3h


6.6, 6.9


6.10


Scheme 6.3


The structures of compounds 6.10 were elucidated by 1H,

spectra (Tables 6.6 and 6.7) and combustion analyses (Table 6.:


13C and APT NMR


Interestingly


H NMR spectra of compounds 6.10b and 6.10f showed typical diastereotopic CH2


patterns.


The presence of two doublet of doublet signals at 8 3.06-3.48 ppm in each


compound indicated that the CH2 protons were attached to the chiral centers. The two


doublets (8 4.90, 5.12) with larger coupling constants (J


= 17.1 Hz) in the 1H NMR


spectrum of compound 6.10b showed strong through space interaction between the

N-CH2Ph and the chiral center. Moreover, the second CH2 protons in the N-butyl


chain of compound 6.10f resonated at greatly different fields (5


1.26-1.41


ppm and


1 rv;


r.amcnrtl7rlu\


;nd;r ~ti n


Qbhnrt


distance


between


* l ft -lll *l~V UI "U** N U*t kILI JA --Lrat ----











6.2.4 Dimerization and dehydrogenation


It has been previously reported that Lewis acids readily assist the formation of


benzotriazolyl


anion


corresponding


carbocations


from


benzotriazole


adducts.


Such


carbocations


available


reaction


with


nucleophiles


[91S868].


Therefore, compounds 6.6, 6.8 and 6.9 can act not only as nucleophiles due


ZnC12
CH2C12


reflux


N
R2
R


,3h
= alkyl)


6.6, 6.8, 6.9


6.11a: R1


ZnC12 / CH2C1
reflux. 3 h


6.11b:
6.11c:


=H)


=CH3


= CH3, R = Et
=Et, R2=CH3


air
------- l


6.13


6.12


6.13a: R1
6.13b: R1
6.13c: R1


Scheme 6.4


= n-Bu
= n-C5H11
= n-C6H13


to the unoccupied 3-position of the indole ring, but also as carbocations with the











6,12-dihydroindolo[3,2-b]carbazoles


which


were


relatively


stable


in air. No


dehydrogenated product was detected by 'H NMR spectroscopy.


When compounds


6.8 were


refluxed with


zinc chloride in methylene chloride


hours,


dimeric


intermediates 6.12 were formed which rapidly dehydrogenated in air to give 6,12-di-

(n-alkyl)-5,11-dihydroindolo[3,2-b]carbazoles 6.13 (Scheme 6.4). Surprisingly, under

similar reaction conditions, 2-(benzotriazol-l-ylmethyl)indole (6.3) did not undergo


dimerization in either CH2Cl2 or CHCl3.


This indicates that the alkyl group of 6.8


efficiently stabilizes the cation and lowers the activation energy of


the carbocation


formation.


summary,


2-(benzotriazol- l1-ylmethyl)indole


(6.3),


derived


from


1 -propargylbenzotriazole


cupnc


(6.2)


o-iodoaniline


(Scheme


[66JOC4071],


treated


with


n-butyllithium


to generate


anion


which


was


subsequently trapped by electrophiles to give 2-(1-benzotriazol-l-ylalkyl)indoles 6.8


in high yield (Scheme 6.2).


Compounds 6.8 underwent dimerization under the action


Lewis


acid,


followed


dehydrogenation


afford


6,12-dialkyl-5,11-dihydroindolo[3,2-b]carbazoles 6.13 in


good


yield


(Scheme 6.4).


The treatment of 6.3 with two equivalents of n-butyllithium followed by quenching


with


three


equivalents


alkyl


halide


using


HMPA


solvent


gave


N-alkyl-2-(1-benzotriazol-l-ylalkyl)indoles 6.6. Reaction of dianion 6.5 sequentially


with two different halides afforded compounds of type 6.9.


Under similar reaction


conditions


,6.6 and 6.9 were converted to 6,12-dihydroindolo[3


-b]carbazoles 6.11.


The benzotriazolyl group of compounds 6.6 and 6.9 was conveniently displaced by


Grignard reagents to give 2-alkylindoles 6.10 in good yield.


The reaction of N-alkyl-







67



6.3 Experimental


Melting


points


were


determined


a hot-stage


microscope


uncorrected.


'H NMR spectra were recorded on a 300 MHz spectrometer using TMS


as the internal standard.


13C NMR spectra were recorded at 75 MHz on the same


instrument with the solvent peak as the reference. Elemental analyses (C, H, N) were

carried out within the Department.


o-Iodoaniline


was


purchased


neat


used


without


further


purification


(Aldrich,


$67.15/25g).


1 -Propargylbenzotriazole


(6.1)


was


prepared


from


benzotriazole and propargyl bromide (80% in toluene) in ethanolic sodium hydroxide


[92LA843].


cupnc


1-propargylbenzotriazole


was


prepared


quantitatively according to the literature procedure [66JOC4071].



6.3.1 Preparation of 2-(Benzotriazol-1-ylmethyl)indole (6.3)



A mixture of the cupric salt 6.2 of 1-propargylbenzotriazole (3.64 g, 20 mmol)

and o-iodoaniline (4.38, 20 mmol) in absolute DMF (100 mL) was heated at 110 C

under nitrogen for 22 h. The dark reaction mixture was filtered and the DMF distilled


off under reduced pressure.


The residue was dissolved in ethyl acetate (100 mL),


washed with water (3 x 100 mL), and dried (MgSO4).


The solvent was removed under


reduced pressure to afford the crude product, which was purified by recrystallization


from chloroform (2.98 g,


60%) (Table 6.1):


'H NMR (CDClI) 8 10.84 (s,


1 H),


(d, J


=8.1 Hz, 1 H), 7.56 (d, J


= 8.3 Hz, 1 H),


7.51 (d, J


= 7.8 Hz, 1 H),


7.41-7.29 (m,











110.7


,109.4, 101.4, 45.1.


6.3.2


General


Procedure


for the


Lithiation


Subsequent Reaction


with


Electrophiles


To a stirred solution of 2-(benzotriazol-l-ylmethyl)indole (6.3) (1 eq) in THF


was added dropwise a solution of n-butyllithium (2.1 eq, 2.0 M in hexane) at

under nitrogen. The mixture was warmed to -30 oC for 30 min (or stirred at -7{


-78 C


8 C for


5 h) and then cooled to


-78 oC. The appropriate alkyl halide (1.1 eq,


see Table 1)


was


added to the mixture and the solution was stirred for an additional 3 h at -78 OC. The


reaction


mixture


was quenched with


water and


extracted


with ethyl


acetate.


organic phase was separated, washed with water, and dried (MgSO4). The solvent was

removed under reduced pressure to give the corresponding crude products 6.8, which


were purified either by recrystallization or column chromatography (Tables 6.1,


and 6.5).

Compounds 6.6 were obtained by quenching the dilithium salt 6.5 with three


equivalents of alkyl halide together with HMPA (equal amount to


THF) at


-30 OC.


The solution was allowed to warm to room temperature and stirred overnight.


isolation and purification procedure was as described above (Tables 6.1,


6.4 and 6.5).


Compounds 6.9 were obtained by the treatment of dilithium salt 6.5 with 1.1


equivalents


alkyl


halide


followed


addition


equivalents of a second alkyl halide together with HMPA (equal amount to


THF) at


-30 OC. The reaction mixture was stirred at room temperature overnight. The isolation


and purification procedure was the same as described above (Tables 6.1


6.4 and 6.5).










6.9 with


6.3.3 Substitution of N-Alkvl-2-(1-benzotriazol--yvlalkvl)indoles
Grinnard Reagents


a solution


N-alkyl-2-(1-benzotriazol- l-ylalkyl)indole


mmol) in toluene was added a Grignard reagent


(5 mmol in


or 6.9


diethyl ether) under


nitrogen. The mixture was refluxed for 3 h. After cooling, the solvent was distilled off


under reduced


pressure


residue


was dissolved


diethyl


ether


mL),


washed with water (3 x 30 mL), and dried (MgSO4).


The solvent was removed and


the crude products purified by column chromatography to afford the pure products


6.10 (Tables 6


6.6 and 6.7).


6.3.4 Preparation of 6,12-Dihydroindolo[3,2-blcarbazoles
indolor3,2-blcarbazoles 6.13


5,11-Dihvdro-


A solution of compound 6.6 or 6.8 or 6.9 (2 mmol) and ZnClz (4 mmol) in

CH2C12 (100 mL) was refluxed for 3 h. After cooling, hydrochloric acid (2 N, 100


mL) was added and the organic phase was separated,

hydroxide (5%, 3 x 100 mL) and dried (MgSO4). The


washed with aqueous sodium


solvent was removed and the


residue was subjected to column chromatography on silica gel using CH2C12 / hexane

(1:4) as the eluent to afford the pure products 6.11. Alternatively, the residue was

washed with a small amount of CH2Cl2 to give the pure compounds 6.13 (Tables 6.3,

6.8 and 6.9).














































In




FI

N4
s-s
Ur
Ni


z



In
-4
C-,







r4








r4





















I








I0I
\0









71













00 mt C enS r
0% C -: CC CC"
'ii '6; en d


e n -I N e
r ~ vi -0 n N
020 en N 0%oi

0% CC d &; ; ren

o~o CC CC C C CC CC~
U Zn n en~
U 0 N- vlOCC
NO 0% '0 en 00
CC 00 0 0 00 CC 00


- Zn Zn 0% 0 N

Vlc
00 N % 0
N-
a .) UU )
en

a 'a
C4 ar
a 0 0
0
0 ~
CU 0 C 00 ( C


I- U
Nr



.0 ..M .0

N" (
en en
(N U



NN

-~ en



cli 0
I~ C-










72





















cc ad &: 'S

-o '0 '0 ~
*S '0 S 0 '0 '
-- -~ '0 '

CU U en 'a1~0
-~ 0I t 0


N0 N '0 '0 D
00 v

Cu~F C 0
-I 0% 0'
ZN & d c



00 0 0 00 0


o N 4. 4. 0 a

S% U U U U U U
N N N ('

C. '0 00 N-
L t a N N N
Qua


0o -O cc en N 4

Cu 0
01 .0U0 .0c
I- -l r
'C 'C 'C 'C '
0





























00


doo



S00
"d 3-
*~z~




NO
Nd
er)~X


0
St


en

ICr)

Cs'



v;N





'~a
'0'-


Icc







-i -
.'"
N.


'I,
'ON
ri









74











ci en cie
00. t nrjt:


en1 ci 'o eic a.
cic a '6c 6 '
In 00 -v -~
UO 02 I rci l cc- lv
-) eneq. en c
*v 52 -c -r '
eq~ ~~ en, en -n en n

-i ci It en en Ni It
('U I g cc en 00 d cc
It S -S r CI C
-r -i c~i Ci
-9 o o 0 0 0 o 0 0 0 0



g 0' 0% 0% 0 % 0
S. S. S. -r S.S.
C -z 6 o v o a 00 -' 0d
C. *l *I S.rlE
4- a i a'ctC I 0'0C f
o \0 ci cici c
N~~0 Nc N N i c

eq ci ci ci c~i C. e ci Cj i ('4 ('
SN -
S. S. S. S. S. r ( .S.S
C4saU,



'S '1ci

en en en en e, en n n n en en
- -
4d -r -h -D *e a # r
oq ~~~ ~ r 0'0 c c'c
*j S S
N ~ ~ I Nl Nl Vl V NNN
en e ne n n e n e
-4~~~~d 4- 4- 4-- 4-



It ccI Cr 0% 0 it In N


zl e -~ N~ en en 'St In N


V) N N Ni N N N cN N N1 N
ci ci cie i e iC. qc '

4O eq ci ci -i r l I


*r -, S
6 -J OR o o -t
u ci eq -d ci eqc i c














































































'6 '6










76












00


'.0e 9

^- d

4.

c'4
-J -daI;co

*r c\ l.
-a 0
o 4.

o~~ 'V eq 'a
0? od 9 F



e~n 'a c e

00 0' en eq
4. N In c '
*j en eq In eq
* eq vi 0%:




04 In -n-



V
u 0' N 0


o S Io v ~

1-4 -' an c
cr; a;o; '4
4.. -~ 9
0% 0' 0% 0% 0% 0

-j -C -


4t
Uc !m m o
cro r r



'V en 4. en~ en n
Pc- Cc --
cU ., S 4
4. n
F-1 Nr vi vi 'S d
4. 4. 4.
-l -l -l -1
0 .0 U P S...r









77









en

S S ti
u -u


NI U -j -, C

Ii *i *0
en N I0
e c~n 0~Or
'1) U o F
Up 00 U' -0 ,2
en Ct C c3 en cc C C
CUc -4 'n'qUcc
'a 05 *i iU* U -
0% Nc ccc

('4J C. N NIN (N
C) N C) '. C C

o: c-a: ZJ cc enU~ ;ar


(4a &i N~ N c
.4 .2 .2 .2


*t -

cc cc S 9 ~
*~ n en cc Nc N c

N o nn -\P d(


VI~~~ ti zc c c Y 8 c 0

N

z N c
-u cc Cu ac
N, N0 0 Ne N ( 00

No -Y *0 N
In~ C C c goe
*, Sn erudd
(N A: -; 4.
S S
N N N) Nt N C
Ir I "a









78

















-: -a
-U U
en eq
-O 'd l

S U

o~ w a
Cu U tj 02 Ff pj

C)~~ 0. I.4.3


O~~~e ent; ;r;y
o 3 9 e

-~ 0% 00 en -r -
"o eq en en n e



N e nn en ccr

0.. --- r- -e

S N t' 00lctC

'net~~ --

S~ -jS 'aN '0 '
cU~ Ne 00 00 0% 0'


I- 00 0 00 -I Cl
S-: r- -J -

eq Ir eq l eq Cl
U.l U. 3. 3. 3


U & CUP$
enI en t1nr
-~ -t -I -~ -
z U U -d Ud d














CHAPTER VII
4-SUBSTITUTED AND 4,5-DISUBSTITUTED
2-(BENZOTRIAZOL-1-YL)METHYLPYRROLES AS VERSATILE SYNTHETIC
INTERMEDIATES


7.1 Introduction


2-(Functionalized-methyl)pyrroles 7.1 and 2-alkenylpyrroles 7.2 are important


intermediates


in organic


synthesis,


especially


natural


products


[84MI270


85JA2485].


Owing


to their


great


synthetic


importance,


a wide


range


pyrrole


intermediates containing 2-CH2X groups have been studied [84MI270 and 77MI355],

in which X is halogen, hydroxy, alkoxy, alkylthio, amino, cyano, etc. as shown in


Block


Among


these,


halogenomethyl


groups


have


been


most


frequently


employed


inter


preparation


other


-CH2X


groups


nucleophilic


substitutions. However, the use of CH2-halogen groups is limited to pyrroles in which


all the ring carbons are substituted,


otherwise difficulties arise from instability and the


sensitivity to intermolecular nucleophilic attack to form polymers rapidly [84MI270,


63CR511, 78LA2024, 80JA1377 and 80JOC1786].


Quaternary ammonium groups of


type -CH2N+R3 can also be displaced by nucleophiles [77MI355].


Other functional


groups X mentioned are less susceptible to nucleophilic substitution. In most


cases,


base-assisted


alkylation


can not be


achieved,


except


2-cyanomethyl-


2-alkoxycarbonylmethyl-pyrroles


[84MI270].


Furthermore,


alkylation


subsequent nucleophilic substitution of CH2X to give CHRNu or the elimination


form


2-alkenylpyrroles


another class


of important compounds,


have not been










previously reported.


= halogen, OH, OR, SR, NH2, NR2


CN, carboxylate,


+PPh3, N3


Block 7.1


now


report


a convenient


method


synthesis


4-mono-


4,5-di-substituted-2-(benzotriazol-1 -yl)methylpyrroles


7.15


elaborations of


their side chain


2-(benzotriazol- 1-yl)methyl


group


nucleophilic


substitution


or first


alkylation


followed


replacement


or elimination


benzotriazolyl


group


which


allows


preparation


elaborated


pyrroles


unsubstituted at the 3- and 5-positions and at the 3-positions.



7.2 Results and Discussion


7.2.1 Preparation of 4-mono-
methylpyrroles 7.7 and 7.15


5-di-substituted-2-(benzotriazol- 1-yl)-


chapter


described


synthesis


substituted


furans


base-catalyzed


cyclization


alkynyloxiranes


7.14


which


were


easily


prepared from


the reaction of 1-propargylbenzotriazole (7.3) with a-bromoketones


+NR3,











i-PrOH gave 4-mono- (7.7,


Scheme 7.1) and 4, 5-di-substituted-2-(benzotriazol-l-yl)-


methylpyrroles (7.15, Scheme 7.3) in good yields. A similar reaction was previously


reported for other alkynyloxiranes without using solvents [58ZOK2360].


However,


our alkynyloxiranes 7.4 or 7.14 with amines under these reaction conditions


gave


furans as major products [95JOC638],


presumably


1,4-elimination of 7.4 and 7.14


was predominated instead of nucleophilic attack at epoxide ring under these reaction


conditions.

better with


Therefore, in the present cases, solvent is essential and the yields were

i-PrOH than with DMF.


7.2.2 Elaboration of the


(Benzotriazol-1-yl)methyl Side Chain


Work in our laboratory has demonstrated that benzotriazole is a good synthetic


auxiliary [95UP2].


The good leaving ability and the anion-stabilizing capability are


two of its advantageous features which have been well recognized. Thus, compounds

7.7a readily underwent nucleophilic substitution with methylmagnesium iodide and

sodium thiophenolate to give the corresponding products 7.6 and 7.8 respectively in


good yields (Scheme 7.1).


The electron-rich pyrrole nucleus assisted the reaction by


stabilizing the transient carbocations.

It is well-known that pyrroles smoothly undergo 2-lithiation, however, in the


case of compounds 7.7,


lithiation occurred regiospecifically at the carbon attached to


benzotriazolyl


group due to the electron


withdrawing ability of the benzotriazolyl


moiety.


Accordingly,


3,5-unsubstituted-


(benzotriazol-1 -yl)methylpyrroles


7.7a-b were easily alkylated by lithiation and subsequent quenches with electrophiles





















&1

7"
IN


-I


-I


JCD-
r r
II "I
P: [I


I4P
I.-,.
1r;


N
Nu


CoZT


II fl0


H ~IIj


H II II
rrm
i.cisi
0002
r r r
rI Ir,


-cc

"c

H, II


0.


0.4
-J3


-I


Irl

Cg+
w






83


benzotriazolyl group in the substituted intermediates 7.10a with sodium thiophenolate
was much faster than that of compounds 7.7a due to the stabilization of intermediate
carbocation by the directly attached methyl group and the reaction gave the product


higher


yield


(Table


7.1).


Compounds


7.10b


7.10c


readily


underwent reductive elimination of benzotriazole when they were treated with zinc in


presence


acidic


generate


pyrrol-2-yl-acetanilide


-thioacetanilide 7.13 respectively.


Interestingly, the reaction of 7.10a with sodium cyanide in DMF gave SN


of "abnormal"


product


52%


yield,


this result strongly


supported


pathway as described by Maryanoff and her coworkers [77JOC1096].


mechanism is illustrated in scheme


The proposed


We were unable to isolate other possible


isomers by column chromatography.


N

KPh
7.10a


N +
L-p


SPh


1,5-H-shift


N

KPh


KPh


,, -, 7.9







84


Preparation and Subsequent Elaboration of 4,5-Disubstituted


2-(Benzotriazol- 1-vl)methyvlvrroles


n-BuLi


7.14


7.14a: R1


7.14b:


=CH3
=Ph


SBt


R2NH2
r


"N


7.15


7.15a: R1
7.15b: R1


= CH3a, R


=Ph, R


= n-Bu


=CH3OCH2CH2


7.16


n-BuLi
.n-BuI
Ph


7.17


K2C03


PhMgBr


7.18


NaCH(COOEt)2


n-BuLi
PhCHO


3. CH3I, HMPA

Bt


i OCH3
7h 1


7.19


NaCN


CN


" Ph


0%,


0,











Similarly,


benzotriazolyl


group


3-unsubstituted


2-(benzo-


triazol-1-yl)methylpyrroles 15a was readily replaced by phenylmagnesium bromide to


give compound 7.18 (Scheme


7.3). Compound 7.15b was treated with 1.1 equiv of


n-BuLi at -78 OC for 1 h and followed by reaction with n-butyl iodide to yield product

7.17. Upon treatment with potassium carbonate in DMF under reflux, compound 7.17

underwent base-catalyzed elimination of benzotriazole to form alkenylpyrrole 7.20


which is stable and can be isolated by column chromatography.


7.17


When the compound


was refluxed with sodium malonate in DMF for 12 h, the substituted product of


type 7.21 was obtained in 76% yield.


Treatment of compound 7.15 with 1.1 equiv of


n-butyllithium followed quench with benzaldehyde to generate the alkylated anion

which was trapped by addition of methyl iodide and HMPA to give the intermediate


7.19.


7.19 was


treated


with


sodium


cyanide


without


purification


to undergo


nucleophilic substitution of benzotriazolyl group with cyanide and then elimination of

methanol to afford vinylpyrrole 7.22.


All products are novel and were characterized by


1H and


13C NMR spectra


and elemental analyses (see experimental and Table 7.1)


conclusion,


4-mono-


4,5-di-substituted-2-(benzotriazol- l-yl)-


methylpyrroles 7.7


and 7.15, derived from the reaction of alkynyloxiranes 7.4 and


7.14


with


a-bromoketones,


readily


underwent


nucleophilic


replacements


their


benzotriazolyl group with Grignard reagents and


sodium thiophenolate. Compounds


7.7 and 7.15 were alkylated via lithiation and subsequent quenches with electrophiles


to give intermediates 7.10,


7.17 and 7.19 in which benzotriazolyl group could either


be replaced by a variety of nucleophiles or eliminated in the presence of a base.







86


find the general use in synthesis including natural products.


7.3 Experimental


Melting


points


were


determined


hot-stage


microscope


uncorrected.


1H NMR spectra were recorded on a 300 MHz spectrometer using TMS


as the internal standard and CDC13 as the solvent.

75 MHz on the same instrument with the solve


13C NMR spectra were recorded at


:nt peak (CDCl3) as the reference.


Elemental analyses (C. H. N) were carried out within the department.


1-Propargylbenzotriazole


(7.3)


was


prepared


according


to the


procedure


described in chapter II. All a-bromoketones were purchased neat and used without


further purification.


The preparation of compound 7.14a was reported in chapter V


[95JOC638].



7.3.1 Preparation of Epoxides 7.4a,b and 7.14b


To a stirred solution of 1-propargylbenzotriazole (7.3) (1.57


g, 10 mmol) in


THF (50 mL) was added at


-78 oC a solution of n-BuLi (5.5 mL,


11 mmol, 2.0 M in


cyclohexane). The mixture was stirred at this temperature for 1 h and a-bromoketone

(indicated in schemes 7.1 and 7.3) (10 mmol) in THF (5 mL) was added slowly. After


stirring at


-78 OC for 5 to 8 h, diethyl ether (100 mL) and water (100 mL) were added


and the organic phase was separated, washed with saturated NH4CI solution (100 mL

x 3) and dried (MgSO4). Evaporation of the solvent gave the crude product which was










5-(Benzotriazol-1 -vl)-1,2-epoxvy


-phenyl-3-pentyne (7.4a): oil, yield 76%:


NMR 8 8.05 (d,


= 8.4 Hz, 1 H),


7.69 (d, J


= 8.3 Hz,


1 H),


7.46-7


1 H),


7.28-7.41 (m, 6 H),


13C NMR 8 145.9


3.35 (d, J


,135.9, 132.


= 6.0 Hz, 1 H),


128.3


2.97 (d, J


4.0, 119.8,


= 6.0 Hz, 1 H);


109.5


75.9, 58.6, 50.


,38.0. Anal. calcd for C17H13N30: C, 74.15


H, 4.76


Found:


C. 74.03


H, 4.77


15.37.


(Benzotriazol- 1-yl)- 1,2-epoxy


-(t-butvl)-3-Dentvne


7.4b: solid,


yield 76


mp 49-50 C


H NMR 8 8.09 (d,


= 8.4 H


= 8.4 Hz


7.51-7.57 (m, 1 H), 7.30-7.44 (m,


1 H),


2 H), 2.93 (d, J


.2 Hz, 1 H),


(d, J


.2 Hz, 1 H),


0.97 (s, 9 H)


13C NMR 8


132.4,


124.1


120.1


109.6, 85.4, 74.5,


.4. Anal. calcd for C15Hi7N30: C,


70.55


H, 6.72:


16.47


. Found: C, 70.


H, 6.69; N,


16.77


(Benzotriazol- 1-vl)-1,2-epoxy- 1 -methyl-2-Dhenvl-3-pentvne


(7.14b):


yield 67


'H NMR 8 8.05 (d, J


= 8.3 Hz


7.66 (d, J


= 8.3 Hz, 1 H),


7.46-7


(m, 1 H),


7.30-7.42 (m, 6 H), 5.51 (s,


2 H), 3.53 (q,


= 5.4 Hz, 1 H), 1.01 (d, J


=5.4


Hz, 3 H);


3C NMR 8 146.0, 134.3, 132.3,


128.1


, 128.0, 1


126.7


, 124.0, 119.9,


109.6


, 74.5, 62.7,


Anal. calcd for C18H15N30: C,


74.71


14.53.


Found:


C. 74.37


H, 5.24; N,


14.73.


7.3.2 Preparation ot
Dyrroles 7.7 and 7.15


4-Mono-


4,5-Di-substituted-2-(benzotriazol- 1-yl)methyl-


A solution of epoxide 7.4 or 7.14 and appropriate primary amine (see schemes

7.1 and 7.3) in i-PrOH was refluxed for 24 to 48 h. After cooling, the solvent was
i" '11 S ^/* 1Pi 1 5 "1 i S I"* I 1


1











product.


N-Benzvl-2- (benzotriazol-1-vl)methyl-4-phenvlpvrrole


(7.7a):


needles,


yield


mp 157-158 oC:


'H NMR 8 7.97 (d, J


= 8.0 Hz


,1 H), 7.51 (d,J


=7.2


2H),


7.16-7.44 (m, 9 H), 7.02 (d, J


= 1.9 Hz, 1 H), 6.90-6.92 (m,


H), 6.76 (d, J


= 1.9 Hz,


1 H),


5.74 (s,


2 H), 5.08 (s,


13C NMR 8 146.3


136.8


,135.0, 1


128.7


127.6


125.6,


124.9,


124.0,


123.9


120.9


, 119.9,


110.1


, 109.8,


50.9, 44.9. Anal. calcd for C24H2oN4:


C, 79.08


H, 5.53


15.38. Found


C. 78.81


5.46


15.35.


N-(n-Butvl)-2


-(benzotriazol- 1-yl)methvl-4-(t-butvl)ovrrole (7.7b):


solid


,yield


mp 69-70 oC;


1H NMR 8 8.01 (d, J


Hz, 1 H),


7.26-7.37 (m, 3 H),


6.44 (d, J


= 2.0 Hz, 1 H),


(d, J


= 2.0 Hz, 1 H),


5.79 (s,


2 H), 3.73 (t, J


= 7.4 Hz,


2 H),


1.02-1.40 (m,


4H), 1


9 H), 0.79 (t, J


= 7.3 Hz, 3 H)


"3C NMR 8 146.


134.5,


132.7


, 127.0,


3.6, 123.2,


119.6


117.7


108.8


46.3


,31.6, 30.3,


Anal. calcd for C19H26N4:


C, 73.50; H, 8.45


18.06.


Found: C, 73.86; H,


18.16.


N-(n-Butyl)


-2-(benzotriazol- 1-vl)methvl-4,5-dimethvlpvrrole


(15a):


solid,


yield 62


mp 86-87 C


1H NMR 8 7.99 (d,


Hz, 1 H),


7.47 (d,


7.24-7.37 (m, 2 H), 6.17 (s,


1 H), 5.76 (s,


2 H), 3.74 (t, J


= 7.8 Hz,


2 H),


.04 (s, 3


2.01 (s,


3 H),


1.10-1.28 (m,


4H),


0.81 (t, J


= 7.1 Hz, 3 H)


13C NMR 8 146.1


132.5


126.9


, 126.6, 123.5, 121.3,


119.4, 113.8,


111.5


, 110.3,


43.7


,32.9, 19.7,


, 10.9, 10.5. Anal. calcd for C17H22N4:


72.29; H,


7.86; N,


19.85. Found:


72.60; H, 7.88


19.92.


N-(2-Methoxv)ethvl-2-(benzotriazol- 1-vl)methyl-4-phenvl-5-


methylpyvrrole











2 H), 3.33 (t, J


= 5.4 Hz,


3.21 (s, 3 H),


2.27 (s, 3 H)


13C NMR 8 146.


136.7,


132.7


127.9


127.1


127.0


123.9


123.7


, 121.4,


119.6


,45.0,


, 10.9. Anal. calcd for C21H22N40: C,


72.79


H, 6.40; N,


16.18.


Found:


7.3.3


C. 73.12


Alkvlation


H, 6.57


16.11.


4-Mono-


4,5-Di-substituted-2-(benzotriazol- 1-vl)methvl-


ovrroles 7.7 and 7.15


To a solution of compound 7.7 or 7.15 (


mmol) in


THF (80 mL) at


-78 C


was added a solution of n-BuLi (5


reaction mixture was stirred at


mmol


-78 oC for


.0 M in cyclohexane).


1 h and then a solution of an appropriate


electrophile (5


mmol)


THF


mL) such


as methyl iodide,


phenyl


isocyanate,


phenyl isothiocyanate and butyl iodide was added. After the reaction solution was


stirred for another hour, water (100 mL) was poured into the solution


and the mixture


was extracted with ethyl acetate (100 mL), washed with water (100 mL x 3) and dried


(MgSO4).


The solvent


was distilled off under reduced


pressure to


give the crude


product which was purified either by recrystallization or column chromatography to

afford the corresponding product in pure state.


N-Benzvl-2-( 1 -benzotriazol-1 -vl)ethvl-4-Dhenvlpvrrole


(7.10a):


recrystallized


from EtOAc/hexane (1:3), cubes, yield 98


142-143 C


1H NMR 5 7.91-7.95


(m, 1 H),


7.58 (d, J


= 8.0 Hz,


2 H),


7.35-7.40 (m,


2 H),


7.18-7


4 H),


7.08-7.13


(m, 3 H), 7.02 (d, J


= 1.6 Hz


,1H),


6.93 (d, J


= 1.6 Hz, 1 H), 6.76-6.80 (m,


(q, J


=7.1 Hz


4.83 (d, J


Hz, 1 H), 4.69 (d, J


= 16.2


Hz, 1 H),


.01 (d, J


Hz, 3


13C NMR 8


138.1


, 136.7,


133.1


, 131.4,


130.4,


130.1


, 129.1,


1 H),










a-(N-Benzvl-4-ohenvl)Dvrrol-2-vl-a-(benzotnazol- 1-vl)acetanilide


(7.10b):


recrystallized from


EtOAc/hexane


(1:3),


powder,


yield 87%:


104-105 C


NMR 8 9.70 (s,


1 H), 7.56 (d, J


= 8.4 Hz, 1 H), 7.34-7.44 (m, 5 H), 6.9


.7.24 (m, 10


6.58-6.74 (m,


4 H), 6.33 (d, J


= 7.2


2 H), 4.68 (d, J


= 16.2 Hz, 1 H), 4.54 (d, J


= 16.2 Hz, 1 H); '3C NMR 8 164.5,


145.8, 137.4,


135.8


134.5


128.9, 128.1,


127.8, 12


,125.9, 1


124.7


,124.2, 121.5,


119.9, 119.0, 112


109.9


60.6


50.4.


Anal. calcd for C31H25NsO: C, 77.00; H,


14.49. Found:


C, 77.29


H, 5.24


14.43.


a- IN-(n-Butvl)-4-(t-butvl)l vrrol-2-vl-a-(benzotriazol- 1-vl)thioacetanilide


(7.10c): recrystallized from Et20O, powder,


yield 94%:


147-148 C


1H NMR 8


10.00 (s, 1 H),


8.01 (d, J


= 8.3 Hz


(d, J


= 7.7 Hz,


2 H), 7.33-7.48 (m,


5 H),


7.22-7.27 (m,


2 H), 6.54 (d, J


2 H), 1.42-1.54 (m, 1 H),


.0 Hz, 1 H), 6.48 (d, J


1.03-1.36 (m, 12


= 2.0 Hz, 1 H), 3.59-3.73 (m,

1 = 7.3 Hz, 3 H); 13C NMR 8


192.8


145.7


135.3,


133.4,


128.9,


128.0,


127.0,


124.3


, 123.4,


119.9,


119.0,


110.5


108.5


68.4,


Anal.


calcd


C26H31N5S:


C, 70.08


H, 7.01


72. Found:


C. 70.


H, 7.08


N-(2-Methoxv)ethvl-2-(a-benzotriazol- 1-vl)pentvl-4-phenvl-5-methvlpvrrole


(7.17)


purified by column chromatography using EtOAc/hexane (1:4),


oil, yield 77


'H NMR 8 8.00-8.04 (m, 1 H), 7.50-7


5 (m,


1 H),


7.19-7.44 (m, 7 H), 6.67 (s, 1 H),


6.41 (t, J


= 7.6 Hz, 1 H),


3.94-4.04 (m, 1 H), 3.80-3.89 (m,


1 H),


3.15-3.20(m,


2 H),


3.17 (s, 3 H), 2.45-2.53 (m,


2 H),


2.26 (s,


3 H), 1.26-1.47 (m,


3 H),


1.08-1.18 (m, 1


0.86 (t, J


= 7.1 Hz, 3 H)


13C NMR 8


146.7


, 136.9, 131.6, 128


128.0, 127.4,


126.9,


126.7


123.7


108.4,


,58.9, 56.9,


32.6,


1


119.8, 111.1,







91



7.3.4 Nucleophilic substitution of 7.7a and 7.15a with Grignard reagents


To a solution of compound 7.7a or 7.15a (2 mmol) in toluene (30 mL) was


added a freshly prepared solution of CH3MgI


(5 mmol) in Et20O (5 mL) at room


temperature and the solution was then refluxed for the time indicated in


Table


After cooling, the solvent was removed under reduced pressure and the residue was


extracted with Et20 (50 mL),


washed with water (50 mL x 3) and dried (MgSO4).


After


removal


solvent,


crude


product


was


purified


column


chromatography using CH2C12/hexane (1:4) as the eluent to afford the product 7.6 or

7.18.


N-Benzvl-2-ethyl-4-phenvlovrroles 7.6:


see Table


H NMR 8 7.47-7.50


2 H),


7.19-7.29 (m,


5 H), 7.06-7.11 (m,


1 H), 6.98 (d,


= 7.0 Hz,


2 H), 6.87 (d, J


.0 Hz, 1 H), 6.28 (d,


.0 Hz, 1 H), 4.93 (s,


2 H),


43 (q,


z, 2 H), 1.19


(t, J


= 7.5 Hz, 3 H)


'3C NMR 8


138.1


136.1


, 136.0,


128.6,


128.5,


126.3,


.0, 124.7


,103.4, 50.2,


12.8.


N-(n-Butvl)


benzvl-4,5-dimethvlpvrrole


7.18:


see Table


NMR


7.11-7


8 (m,


5 H),


5.61 (s, 1 H), 3.87 (s,


2 H),


3.59 (t, J


= 7.9 Hz,


2.09 (s, 3 H),


1-1.30 (m,


0.85 (t, J


= 7.4 Hz


,3 H)


NMR 8 140.0, 128.9, 128.6, 128.3, 126.0, 123.9,


113.2, 108.3,


,20.1,


Nucleophilic Substitution of 7.7a and 7.10a with Sodium thiophenolate


1.98 (


3 H),


1.34-1.44 (m,











indicated in Table 7.1.


After cooling, water (100 mL) and Et20 (100 mL) were added.


The organic phase was separated and washed with saturated NaCI solution (100 mL x

3) and dried (MgSO4). After removal of the solvent, the residue was subjected to

column chromatography using CH2Cl2/hexane (1:4) as the eluent to afford the product

7.8 or 7.11.


N-Benzvl-2-(phenvlthiomethvl)-4-DhenvlDvrrole 7.8:


see Table


1H NMR


8 7.50 (d, J


2 H),


7.06-7.34 (m,


13 H),


6.95 (d, J


= 1.7 Hz, 1 H), 6.36 (d, J


1.7 Hz, 1 H),


5.17 (


4.00 (


,2H)


13C NMR 8 137.7


135.8


130.6,


128.8


128.7


128.5


128.3


, 127.6,


126.7


, 126.6,


125.3


124.8


123.7


, 119.5,


108.0,


31.1.


N-Benzvl-2-(1-Dhenvlthio)ethvl-4-DhenvlDvrrole 7.11


see Table 7.1.


1H NMR


8 7.38 (d, J


= 7.1 Hz,


2 H), 7.10-7.26 (m, 10 H), 6.97-7.07 (m,


3 H),


6.86 (d, J


= 1.7


Hz, 1 H), 6.31 (d, J


= 1.7 Hz, 1 H),


.27 (d, J


Hz, 1 H),


.03 (d, J


= 16.


2Hz, 1


4.06 (q,


= 6.9 Hz, 1 H),


1.49 (d, J


= 6.9 Hz, 3 H)


13C NMR 8 138.0, 135.6,


133.8


, 133.4,


128.8


128.7


, 127.6,


27.5,


125.2,


124.7


119.1


,105.8, 50.5, 39.5,


20.7.


7.3.6 Formation of N-Benzvl-2-cyano-3-phenyl-5-ethylpvrrole (7.9)


A solution of compound 7.10a (0.76 g,


DMF (


mmol) and NaCN (0.49, 10 mmol) in


mL) was refluxed for 12 h. After cooling, water (100 mL) and diethyl ether


(100 mL) were added and the organic phase was separated,


NaCi solution (100 mL x 3) and dried (MgSO4).


washed with saturated


The solvent was removed to give an