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A CONVENIENT N-ACETYLATION OFINDOLESGordon W. Gribble a , Laurence W. Reilly Jr. a & Jerry L. Johnson aa Department of Chemistry, Dartmouth College, Hanover, NewHampshire, 03755

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To cite this article: Gordon W. Gribble, Laurence W. Reilly Jr. & Jerry L. Johnson (1977): ACONVENIENT N-ACETYLATION OF INDOLES, Organic Preparations and Procedures International: TheNew Journal for Organic Synthesis, 9:6, 271-276

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ORGANIC PREPARATIONS AND PROCEDURES INT. 9(6), 271-276 (1977)

A CONVENIENT N-ACETYLATION OF INDOLES

tt Gordon W. Gribble,* Laurence W . Re i l l y , Jr.,+ Je r ry L. Johnson

Department o f Chemistry, Dartmouth College Hanover, New Hampshire 03755

We now repor t a rap id and e f f i c i e n t method f o r the se lec t i ve N-acety-

l a t i o n o f indoles under m i l d condi t ions. Thus, treatment o f I w i t h

powdered potassium hydroxide i n dimethyl su l fox ide a t room temperature

generates the i n d o l y l potassium anion which on add i t i on o f ace t i c

anhydride a f fo rds the N-acetyl indole (11) i n good y i e l d .

sumnarized i n the Table.

1

Our r e s u l t s are

R3 1. KOH/DMSO QT 1: 2. (CH3 C0)20 >

R4 .. I I 1 CH3

This method provides a very a t t r a c t i v e a l t e r n a t i v e t o e a r l i e r indo le

acy la t i on methodsY2 some o f which give a mixture o f N- and C-acylat ion

product, and t o the more recent method^^-^ f o r se lec t i ve N-acylat ion

t h a t requ i re elevated temperatures and/or extended reac t ion times.

method seems t o be app l icab le t o any i ndo le capable o f forming the

corresponding i n d o l y l anion under these condi t ions and c lean ly a f fo rds

N-acylat ion product (11).

reac t ion product i s unchanged indo le which can be removed by c rys ta l -

l i z a t i o n o r chromatography. Attempts t o d r i v e the reac t ion t o com-

p l e t i o n by using a l a rge excess o f reagents were no t successful and the

Our

The on ly o ther mater ia l present i n the

271 @ 1977 by Organic Preparations and Procedures, Inc.

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GRIBBLE, REILLY AND JOHNSON

Tab1 e

N-Acetylat ion o f Indoles w i t h Potassium Hydroxide/Acetic Anhydride i n Dimethyl Su l fox ide

Substratea

No. R1 R2 R3 R4 Y ie ldb mp. o r bp . / to r r ( % I

I a H H H H 65 97.5-101"/0.15 (Ref.' 152-153'/14)

I b CH3 H H H 36' 42-42.5'

I c H CH3 H H 54d 60-62.5" (Ref. l1 66-67")

I d CH3 CH3 H H 43 68-70°(Ref.4 68-70")

I e H

If1' -CH2CH2CH2CH2- H H 61 75-75.5O(Ref. l3 77-78O)

I g C6H5 C6H5 H H 61f 139-140°(Ref.14 138O)

I h H H B r H 80 109-109.5°(Ref.5 101-102°)

Ii H H N02 H 80 178.5-180°(Ref.3 178-180")

Ik16 H C H 2 C O N 3 H H 62 132.5-1340h

a) Commercial mater ia ls unless otherwise noted. b ) Yields r e f e r t o re- c r y s t a l l i z e d (95% ethanol) o r d i s t i l l e d product. I n some cases add i t iona l product and recovered I was obtained by dry column chromatography o r pre- pa ra t i ve T.L.C. o f the r e c r y s t a l l i z a t i o n mother l i q u o r s . A l l products exh ib i t ed s a t i s f a c t o r y I.R., U.V., and H-N.M.R. spectra. c ) The prod- u c t decomposes a t room temperature; 38% o f 2-methyl indole was recovered a f t e r a reac t i on t ime o f 5 min. v ious l y bu t physical p roper t ies were n o t recorded." d) methyl indole: 15%. e) Recovered 7-methyl indole: 10%; Calcd. f o r CllHllNO (173.1): C,76.28; H,6.40; N,8.09; 'found: 76.05; 6.32; 8.26. f) Recovered 2,3-diphenylindole: 12%. g) calcd. f o r C14H13N04 (259.1): C,64.86; H,5.05; N,5.40; found: 64.96; 5.10; 5.44. h) Calcd. f o r C17H20N202 (284.1): C,71.81; H,7.09; N,9.85; found: 71.92; 6.87; 9.99.

51e 75-75.5O H H CH3

1 j15 H C O C O ~ C ~ H ~ H H 54 94-9509

1

This compound has been prepared pre- Recovered 3- D

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A CONVENIENT N-ACETYLATION OF INDOLES

1.009 (0.005 mol) of 5-bromoindole ( I h ) i n one por t ion .

s t i r r e d an add i t i ona l 5 min and then 1.0 m l (0.011 mol) o f ace t i c

anhydride was added i n one por t ion . The r e s u l t i n g viscous s o l u t i o n

was s t i r r e d f o r an add i t i ona l 30 min a t room temperature. The reac t ion

was worked up by pour ing onto ice-water, e x t r a c t i n g w i t h e ther (3x),

washing the e ther e x t r a c t w i t h water (5x) and b r i n e ( l x ) , dry ing over

sodium su l fa te , and concentrat ing i n vacuo t o a f f o r d the crude product.

C r y s t a l l i z a t i o n from 95% ethanol gave, i n several crops, 0.979 (80%) o f

N-acetyl-5-bromoindole ( I I h ) as co lo r less needles, m.p. 109-109.5O, lit.

101-1020.

'H-N.M.R. (CDC13): 6=2.54 (S,3H), 6.43 (d,lH,J=4 Hz),

The mix tu re was

5

7.22-7.44 (m,2H), 7.58 (d,lH,J=2HZ) and 8.17 (d,lH,J=9HZ) ppm.

I .R . (CHC13) v max: 1710 cm", no N-H.

U.V. (95% EtOH) X max: 244,286,295,304 nm.

N-Acetyl i ndo le (I I a ) . - The above procedure was followed using 40 m l o f dimethyl su l fox ide ,

1.919 (0.034 mol) o f potassium hydroxide, 2.009 (0.017 mol) o f i ndo le

( Ia ) , and 3.3 m l (0.035 ml) o f ace t i c anhydride t o a f fo rd , a f t e r

workup, a golden o i l .

( I I a ) and l a as a co lo r less o i l ; y i e l d : 1.949; bp. 97.5-101°/0.15 t o r r .

Analysis by G.L.C. showed 1Ia:Ia i n the r a t i o 79:21 (1.5% OV-101 on

100-120 chromosorb 6; 5'X1/8"; 110O).

column chromatography o r p repara t ive T.L.C. The po t residue was sub-

j ec ted t o p repara t ive T.L.C. ( s i l i c a gel , benzene) t o a f f o r d an add i t ion-

a l 0.239 o f pure I I a . Total y i e l d o f I I a : 1.779 (65%). The product

was i d e n t i c a l w i t h a commercial sample o f I I a ( K & K Laboratories).

D i s t i l l a t i o n gave a mixture o f N-acetyl indole

These could be separated by dry

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GRIBBLE, REILLY AND JOHNSON

gen was added 0.579 (0.010 mol) of powdered potassium hydroxide. The

mixture was mechanically stirred for 5 m i n and to i t was then added

Acknowledgement.- T h i s invest igation was supported by Grant

CA-14968, awarded by the national Cancer Ins t i tu te , DHEW, and

by the Petroleum Research Fund, administered by the American

Chemical Society. W e a l s o wish to thank Merck Sharp and Dohme

Research Laboratories and E l i L i l l y for the ir support of our

research program.

RFFERENCES

t.

tt.

1.

2.

3.

4.

5.

6.

7.

8.

Goodyear Predoctoral Fellow, 1977-1978.

Goodyear Predoctoral Fellow, 1975-1976.

These conditions have been used previously to generate and N- alkylate the indolyl anion: H . Heaney and S. V. Ley, J. Chem. SOC. Perkin Trans. I , 499 (1973); see also R. Garner, P . J . Albisser, M. A. Penswick and M. J. Whitehead, Chem. and Ind., 110 (1974).

For reviews, see R. J. Sundberg, "The Chemistry o f Indoles," pp. 33- 39, Academic Press, New York, N . Y . , 1970; and W . A. Remers, Indoles, Part I , i n W. J . Houlihan, "The Chemistry of Heterocyclic Compounds," Vol. 25, pp . 111-121, Wiley-Interscience, New York, N.Y. , 1972.

Acetic anhydride/potassium acetate: A. E. Hydorn, J . Org. Chem., - 32, 4100 (1967).

Acetic anhydride/camphor-10-sulfonic acid: V . Dave and E. W . Warnhoff, Can. 3. Chem, 2, 1911 (1971).

Acetyl imi dazol e/dimethyl sul fox! de: J . Bergman , R. Carl sson and S. Misztal , Acta Chem. Scand. B. , 30, 853 (1976).

B. G. Cox, G. R. Hedwig, A. J. Parker and D. W. Watts, Aust. J . Chem., 27, 477 (1974), and references cited therein.

S. A . Heininger and J. Dazzi, Chem. Eng. News, 2, [91, 87 (1957).

E. H . A-Neizer, S. K. R a y , R. A. Shaw and B. C. Smi th , J. Chem. SOC. , 6250 (1965).

9. S. Horie, Mem. Inst . Sci. Ind. Research Osaka Univ., 7, 143 (1950); C. A. , 45, 9030e (1951).

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A CONVENIENT N-ACETYLATION OF I N W L E S

optimum conditions appear t o involve -using two equivalents each of

potassium hydroxide and acet ic anhydride. Presumably, the equal excess

of each reagent resul ts i n self-neutralization dur ing workup and pre-

cludes the possibi l i ty of base-catalyzed hydrolysis of the lab i le 11.

For example, Bergman and his group have reported t h a t N-acetylindole i s

hydrolyzed to indole by treatment w i t h 0.1 M sodium hydroxide i n aqueous

ethanol a t 2 5 O for 30 minute^.^ However, control experiments demonstrate

that recovered I does not a r i se from I1 by hydrolysis d u r i n g workup.

As seen by examples i n the Table, our N-acetylation method i s

general for a variety of alkyl- and aryl-substituted indoles and leaves

untouched the es te r function i n Ij and the amide function i n I k . The

method should be applicable to the synthesis of other N-acylindoles,

and we have prepared N-propionylindole and N-benzoylindole i n yields of

42% (34% recovered I ) and 22% (75% recovered I ) , respectively, under

these same reaction conditions.

The absence of C-acetylation product ( i . e . , I , R2 = COCH3) i s n o t

surprising’ since i t i s well established that dimethyl sulfoxide

strongly solvates potassium cation,6 elevating the react ivi ty of the

indolyl anion and giving exclusive N-acetylation (the s i t e of highest

charge density) . We have avoided using carboyylic acid chlorides in th i s reaction

( a p a r t from one spectacularly unsuccessful attempt) because of the

reported violence of the i r reaction with dimethyl s ~ l f o x i d e . ~ ’ ~

EXPERIMENTAL

General Procedure.

dimethyl sul foxide ( d i s t i l led from CaH2) a t room temperature under nitro-

N-Acet~l-5-bromindole~IIh).- To 20 ml of dry

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10. T. Toth and A. Borsodi Magy. Kem. Foly. 77, 576 (1971); C. A. , - 77, 966352 (1972).

11. A. Borsodi and T. Toth, Magy. Kem. Foly. 75, 251 (1969); C. A., - 71, 49691f (1969).

12. W. H. Perkin and S. G. P . P lant , J . Chem. SOC., 1825 (1921).

13. H. Yamamoto, J. Org. Chem., 32, 3693 (1967).

14. R. C. 6. Fennel1 and S. G. P . P lant , J. Chem. SOC., 2872 (1932).

15. T. Nogrady and T. W . Doyle, Can. J. Chem., 42, 485 (1964).

16. E. Wenkert and B. Wickberg, J. Amer. Chem. SOC., 84, 4914 (1962).

(Received August 1, 1977; in revised form October 5, 1977)

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