Methodology for indole synthesis

22, NO. 16, pp 1475 -

Tetrahedron Letters, Vol. Printed in Great Britain

METHODOLOGY

1478rI981

0040-4039/81/161475-04p(O2.00/0 01981 Pergamon Press Ltd.

FOR INDDLE SYNTHESIS

1* Paul A. Wender and Alan W. White of Chemistry, Harvard University, Cambridge,

Department

MA

Abstract: An efficient synthesis of indole derivatives in one operation organodilithium reagents with vicinal dication equivalents is described. The indole general

ring system is one of the medicinally

ortho-alkylaniline

problem

(eq l), which was developed and designed

reagents4

is described

in organic

in connection

to deliver

important

synthesis.

the target

by reaction

expressions2

A methodology

with our continuing

02138

studies

system in one operation

Of

of the more

for indole synthesis3 on organodimetallic

with complete

regiocontro 1,

herein.

1

k

EQUIVALENT 2

al X=H,M=Li,R=COtBu bl X= OCH,,M

=Li,R=COCF,

c) X=H,M=Li,R=COCF3

The organodimetallic bromoaniline

derivatives

reagents

required

via bromine-lithium -

site-specific

lithiation.

Thus, reaction

methyllithium

at -78OC followed

in this strategy exchange,

were readily prepared

a process

which

allows

for efficient,

of 2'-bromo-2,2_dimethylpropionanilide

by addition

of t-butyllithium

provided

from 2-

(4a) with

the organodilithium

derivative

la5 in a minimum of 89% as determined by the efficiency of its reaction with - 6 benzaldehyde. When 2-chlorocyclohexanone (5), a differentiated biselectrophile equivalent (cf 2), was used in place of benzaldehyde saturated

NH4C1,

the indole precursor

and the reaction

6a was obtained

was subsequently

in 92% yield

formation mediacy

of both of the bonds required for the indole system is consistent 8 of a -cis-chloroalkoxide. The effect of variations in the nitrogen

and reaction

temperature

As required

on this process

for synthetic

be formed from intermediate CH2C12

at room temperature

6a.

are shown in entries

versatility,

provided

l-4 in Table

either an N-protected

Thus, its dehydration the N-protected 1475

quenched

with 7

(Table I, entry 2).

The

with the interprotecting

group

I.

or unprotected

indole

can

induced by a trace of CF CO H in 3 2 product, P-(2',2'dimethylpropionyl)-1,2,

1476

TABLE

ENTRY/ANILINE DERIVATIVE

1

BISELECTROPHILE/ ________.__..__, WORE-UP

PREPARATION OF= ORGAXODIMETALLIC

b PRODUCI'S(YIELD)

0

1)

0

A ia

" (-78'C)/ B hOR

(R=tBu)

ka

(77%)

fa (13%)

La ( 7%)

2)

4a

A

2

(-lO'C)/ B

$a (92%)

3)

4b (R=OtBu)

A

2

(-lO’C)/

Lb (67%)

A

5 (-lO'C)/B

A

2 (-10°C); KOtBu; H20/ C

4) Lc (R=cF3)

4a

5)

B

SC (58%) zc ( 15%) s (18%)

qo s (77%)

i (-30'C)~ 10%

2

KOH/MeOH

/

C

(lO°C)t KOtBu; H20/ C

s (75%)

s (74%)

7c(45%)

A

8) AC

(52%) 0

9)

A=

Br

10)

A

&

A

2 (-30°C)# 10% KOH/MeOY

c, (-30 0;

/C

CHP

NHCOCF,

10% KOR/MeOB /C

cl (67%)

c%om

(69%)

lo a) Method A - CH3Lii ZtBuLi b) Method B - saturated NH4Cli Method C - 5% HCl c) If the chloroalkoxide is not quenched at -7R°C, the predominant pathway for reaction is apparently epoxide formation. d) This aminoalcohol can be quantitatively dehydrated to the corresponding indole with triflouroaceticacid in methylene chloride.

1477

3,4-tetrahydrocarbazole,

in 94% yield.

anhydrous

hydroxide

procedure'

carbazole

8 in 93% yield.

Importantly,

in 77% yield when the addition and H20

Similarly,

(entry 5).

cyclohexanone

(entry 6).

tetrahydrocarbazole

Finally,

produced

commercially

(2 equiv.)

available

in this way was then used directly

directly

by the addition

from 4a of KOtBu

of 4c was reacted with 2-chloro-

mixture,

8 was obtained

directly

2-bromoaniline

@)can be converted to I For this purpose, 9 was _ chloride (1 equiv.) and the resulting

(entry 7).

and pivaloyl

exchange

8 was obtained

derivative

in one operation

to halogen-lithium

of 6a according to Gassman's 10 (5% HCl) tetrahydro-

workup

was followed

was added to the resulting

8 in 74% yield,

submitted

tetrahydrocarbazole

when the dilithium

first treated with methyllithium intermediate

hydrolysis

extractive

of chlorocyclohexanone

and 10% KOH/MeOH

in 75% yield

Alternatively,

gave, after standard

with t-butyllithium.

in the aforementioned

The dianion

la

condensation/hydrolysis

sequence. The regiocontrol preparation process

corresponding

1; however,

by this methodology

of 7-methoxy-1,2,3,4-tetrahydrocarbazole

provided

Variations

provided

the 2-lithio-5-methoxy

3-methoxy

tion and reaction

10 (entry 10).

In this case, the exchange

lb whereas deprotonation of the _ to give the 2-lithio-3-methoxy anilide.

do not change

enolization

to the

generally

the regiochemistry occurs

depending

of the addition on substrate

of

substitu-

temperature.

Biselectrophile the production

substrate

induced

in its application

intermediate

anilide would be expected

in the chloroketone some reagent

anilide

is reflected

equivalents

of indoles.

well in this connection after acidic workup

other than cr-chlorocarbonyl

The enolate

(eq 2).

Thus, treatment

12 in 59% yield.

CO&H,

of cyclohexenone

Treatment

compounds can also be used for __ (ll),ll for example, served

epoxide

of this enolate with dianion lc provided . of this compound with O.lN NaOH/MeOH at room

1478

temperature as another expected methyl

for 12h gave 13 in greater type of biselectrophile.

alcohol

15 in 77% yield.

ester of indole-2-acetic

Acknowledgement.

than 603 yield.

For example,

Enediones

reaction

also serve effectively

of dianion

lc with

14 gave the

Hydrolysis

acid

(16).

This work was supported

of 15 followed by dehydration afforded Further studies are in progress.

by a grant from the National

Science

the

Foundation

(CHE-7821463). References

and Notes

1.

Fellow of the Alfred P. Sloan Foundation, Scholar Award Recipient, 1980-1985.

2.

R.T. Brown, J.A. Joule, and P.G. Sammes, in "Comprehensive Organic Chemistry", D.H.R. Barton and W.D. Ollis, eds., Vol. 4, Pergamon Press, Oxford, 1979 p. 411; J.P. Kutney in "Total Synthesis of Natural Products", J. ApSimon, ed., Vol. 3, Wiley-Interscience, New York, 1977; L.R. Smith in "Hetercyclic Compounds", W.J. Houlihan, ed., Vol. 25, Wiley-Interscience, New York, 1972, p.65.

3.

For recent indole syntheses, see R. Odle, B. Blevins, M. Ratcliff, and L.S. Hegedus, 2. Org. Chem. 45, 2709 (1980); R.R. Bard and J.F. Bunnett, J. Org. Chem. 45, 1546 (1980); L.S. Hegedus, G.F. Allen, and D.J. Olsen, J. Amer. Chem. Sot. 102, 3583 (1980); R. Beugelmans and G. Roussi, J. Chem. Sot. Chem. Corenun. 950 (1979); T. Sugasawa, M. Adachi and K. Sasakura, J. Org. Chem. 44, 578 (1979); and Ref. 2.

4.

P.A. Wender

5.

For an alternative preparation of 5 and a related dilithium reagent, see W. Fuhrer and H.W. Gschwend, J. Org.-Chem. 44, 1133 (1979); J.M. Muchowski and M.C. Venuti, J. Org. Chem. 45, 4798 (1980).

6.

All new compounds reported were homogeneous exact mass or combustion analysis.

7.

CH3Li (1.00 mmole) &a (1.00 mmole) was dissolved in 20 mL of THF and cooled to -78°C. t-BuLi (2.00 mmole) was added, and the resulting clear solution was stirred for 10 min. After lh at -78OC, the yellow solution was warmed slowly was then added over 5 min. 2-chlorocyclohexanone (1.20 mmole) was added (neat) over 10 min, (20 min) to -1OOC. and the now colorless solution was stirred for 30 min at -1O'C and 30 min at r-t. After a standard workup with saturated NH4C1, the majority of the product could be crystallized The remainder can be obtained by from crude reaction mixture with 25% EtzO/hexanes. 1.40 (s, 9H), IR (KBr) 3350, 1620, 1585 cm-l; NMR (CDC13) silica gel chromatography. 0.75-2.65 (m, 9H), 4.30-4.55 (m, lH), 7.00-7.50 (m, 3H), 8.05-8.30 (m, 1H); mP 115.5116.5OC (d).

8.

For other examples of lithium and Grignard reagent additions to cyclic a-chloroketones, see A.J. Sisti and A.C. Vitale, J. Org. Chem. 37, 4090 (1972); A.S. Hussey and R.R. Herr, J. Org. Chem. 24, 843 (1959); A. Marcou, W. Chodkiewicz, and P. Cadiot, Bull. Sot. Chim. France, 2429 (1967).

9.

P.G. Gassman and W.N. Schenk, J. Org. Chem. 42, 918 (1977); P.G. Gassman, and R.J. Balchunis, J. Am. Chem. Sot. 98, 1275 (1976).

and S.L. Eck, Tetrahedron

1979-1981;

Letters,

1245

Camille

by TLC and gave satisfactory

to the corresponding

TLC indicates that the hydroxyamide which dehydrates on workup.

11.

A study of the reaction of this and other epoxyenolates submitted for publication. in

USA 5 January 1981)

ga is hydrolyzed

Teacher-

(1977).

10.

(Received

and Henry Dreyfus

IR, NMR,

P.K.G.

MS

and

Hodgson,

amino alcohol

with organometallics

has been