Nucleophilic additions to acceptor-substituted 2-vinylindoles

0040.#39/91 $3.00 + .oo Pergamon Press plc

Tew&.dron Letters, Vo1.32, No.49, pp 7237-7240,1991 hinted in Great Britain

Nucleophilic Additions to Acceptor-Substituted

2-Vinylindoles

Siegfried Blechert* and Thomas Wirth Technische

Universitiit

Berlin,

Strak

des 17. Juni 135, D-1000

Berlin

12, Germany

Abstract : 1,2-Additions, I,4-additions and 1,4-additions with subsequent cyclisation to

cu-ethylidene-@)-lH-indole-2-acetonitrile 3a yield finctionalized 2-substituted indoles, which are attractive intermediates for the synthesis of heteroqcles and alkaloids.

H

Acceptor-substituted

Ace

2-vinylindoles

3 are easily

prepared

acceptor-substituted process

and

functionalized

allenes 2. 1 Using this domino reaction, allowing a vast variability of substituents, 2-vinylindoles

in gram-amounts.

that have been used in the synthesis alkaloids,

we have examinated

various

nucleophiles.

indoles.

Addition

N-phenylnitrones

Compounds

of type 3 are important

of some alkaloids. 2 provides

functionalized

easy access nucleophiles

7237

1 and

that has been optimized to a one-pot we are able to prepare various During

synthetic

to a great

intermediates

studies of indole

the reaction of c?i-ethylidene-(Z)-lH-indole-2-acetonitrile

This method

of suitably

from

3a with

number

of 2-substituted

to acceptor-substituted

2-vinylindoles

7238

followed

by an eleetrophilic

attack on the indole leads to ring anellation.

used to build up tricyclic

indole heterocycles.

cyclisation

or indole-3-position.

in the indole-l-

1.4-Additions

to cr-ethvlidene-(Z)-lH-indole-2-acetonitrile

organocerium

or organoytterbium

3a in dry THF with Grignard reagents,

compounds

yields, after aqueous work-up,

addition products 4. The influence of the metal ion on the reaction was investigated. that with organolithium only poor

turnovers

compounds could

and Grignard

be reached.

Better

can be

allows a directed

3a

Reaction of a-ethylidene-(Z)-lH-indole-2-acetonitrile organolithium,

This reaction

The choice of the nucleophile

reagents yields

in combination

could

be obtained

the

It was shown

with copper(I)sa with organocerium

compounds

3 and in some cases a nearly quantitative reaction is observed with organoytterbium compounds.4 After transmetallation of the organolithium reagent with anhydrous ytterbium(III)chloride and subsequent addition of 3a, one can isolate the Michael-addition products in very good yields.5

In Table 1 a survey of the applied nucleophiles

and the isolated yields (mixture of

synianti isomers) is given. Table 1: 1.4-Additions

to cr-ethylidene-(Z)-lH-indole-2-acetonitrile

3a

d

3@

3@

M&CUI

Li

Ce

Yb

*CH,

4a

46%

36%

84%

92%

“4

4b

7%

10%

68%

59%

4c

27%

27%

74%

91%

4d

__

35%

72%

69%

eCH2

e

i\ c) 0

Michael-addition the preparation

products

4 could not yet be obtained by the vinylindole

of the corresponding

nitrones

is problematic.

interesting structures for the synthesis of natural product method can be the basis of new synthetic strategies.

skeletons

1.2-Additions

3a

to cr-ethvlidene-(ZI-lH-indole-2-acetonitrile

Using modified

reaction conditions

synthesis,

Since compounds

because

of type 4 are

and other heterocycles,

one can achieve an addition to the nitrile moiety of 3a. In

this way it is possible to introduce a carbonyl group into the molecule (after acid hydrolysis resulting

imine) with maintenance

manipulations

this

of the vinylic double bond,

in the course of the synthesis of alkaloids.

of the

which can be used for further

While the reaction of acetylallene

with

7239

nitrones

gave the corresponding

group could be achieved lH-indole-2-acetonitrile

2-vinylindoles

only in poor yields,

3a with organolithium

gives, after aqueous work-up,

1,2-addition

to the cyano

Thus, the reaction of cr-ethylidene-(Z)-

under other solvent conditions.

compounds

in an unpolar

solvent

like hexane

addition products of type 5.

Nu 5

3a

Table 2: 1,2-Additions

to o-ethylidene-(Z)-1H-indole-2-acetonitrile

3a

Li-CH,

sa

14%

Ring anellation bv 1.4-addition After

1,4-addition

5c 64%

5b 50%

with subseauent

of suitably

indoles one can achieve a subsequent

I

cyclisation

functionalized

nucleophiles

ring anellation.

to acceptor-substituted

The cyclisation

can be directed

into the indole-l- or indole-3-position by the choice of the nucleophile. The reaction of cy-ethylidene-(Z)-lHindole-2-acetonitrile 3a with lithiated gives the enol ether 6 in 84% yield. After liberation HCl, the cyclisation gave compound

3a

to the indole-l-position

occurs,

of the ketone by treatment subsequent

2-vinylselectively

ethylvinyl

ether

of 6 with diluted

water elimination

and H-shift

7 in good yield.

6

(86%)

7

(63%)

“Soft” anions like deprotonated malonic ester or ethyl acetoacetate can be added to cr-ethylidene-(Z)-lH-indole-2-acetonitrile 3a. Under the basic reaction conditions the primary adduct with malonic ester cyclizes onto the indole-l-position to form the tricyclic molecule 8.

7240

a

3a

Reaction of 3a with deprotonated cyclisation

ethyl acetoacetate

occurs onto the indole-3-position.

CO,Et

(74%)

also gives l,Caddition,

Here, after water elimination

but in this case

and aromatisation,

the

carbazole 9 was isolated with 14% yield.

3

3a

References

1.

(14%)

and Notes :

Blechert,

S. Liebigs

Ann.

Chem. 1985,

673. Wilkens,

J.; Kiihling,

A.;

Blechert,

S.

Tetrahedron 1987, 43, 3237. 2.

Schroers,

3.

Imamoto,

H. Ph.D. thesis, Universitat

Bonn 1990.

T.;

Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.; M. J. Org. Chem. 1984, 49, 3904. Imamoto, T.; Sugiura, Y.; Takiyama, N.

Yokoyama,

Tetrahedron Lett. 1984, 25, 4233. Imamoto, T.;

Kamiya,

Y. J. Am. Chem.

Sot.

1989,

T.; Takiyama, III,

4392.

N.; Nakamura,

N.; Hatajima,

L.A. ; Learn,

Paquette,

KS.;

Romine, J.L.; Lin, H. J. Am. Chem. Sot. 1988, 110, 879. 4.

Utimoto,‘K.;

5.

General procedure

Nakamura,

To 3.5 mmol organolithium (140 mg) anhydrous

S. J. Am.

A.; Matsubara,

for preparation

Sot.

1990,

112,

8189.

in 10 ml of dry THF at -78 “C was given 0.5 mmol

compound

YbCI,.

Chem.

of 4 :

The reaction

mixture

was allowed

to warm

up to room

temperature

and, after cooling to -50 “C, 0.5 mmol (91 mg) cY-ethylidene-(Z)-lH-indole-2-

acetonitrile

3a, dissolved

in 2 ml dry THF, was added. After lo-30 minutes (TLC control)

of stirring it was hydrolyzed

by adding water. After extraction

product was purified by chromatography

with methyl t-butyl ether the

on silica gel (methyl t-butyl ether:petroleum

ether

1:3). 4a : (addition of trimethylytterbium) (CH,OH):

1.12; 1.13 (d, J=6.5 lH), 6.49

IR (CHC13): 3470, 2980, 2260, 1625, 1460 cm-l. UV

XmX = 228, 268, 278 (shoulder), (s, lH), 7.15 (dd, J=8

7.32 (d, J=8

288 nm (shoulder).

Hz, 6H), 2.28 (dsept, J=6.5

Hz, lH), 7.60 (d, J=8

Hz, J=8

tH-NMR

(CD(&):

6=

Hz, 5=6 Hz lH), 3.91 (d, 5=6 Hz,

Hz, lH), 7.22 (dd, d=8

Hz, 3=8 Hz, lH),

Hz, lH), 8.36 (s, 1H). 13C-NMR (CDCls):

19.2 (q),

20.6 (q), 32.8 (d), 39.2 (d), 102.5 (d), 111.0 (d), 118.6 (s), 120.4 (d), 120.6 (d), 122.6 (d), 128.1 (s), 130.9 (s), 136.2 (s). MS: 198 (34%, M+),

(Received in Germany 26 August 1991)

156 (84), 155 (lOO), 128 (16).