Current Organic Chemistry, 2009, 13, 0000-0000 1

1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

3-Acetylindoles: Synthesis, Reactions and Biological Activities

Mohamed A. Metwally,a Saad Shaaban,

a Bakr F. Abdel-Wahab

b and Gamal A. El-Hiti*

c

a Department of Chemistry, Faculty of Science, University of Mansoura, P.O. Box 23, Mansoura, Egypt

b Applied Organic Chemistry Department, National Research Center, Dokki, Giza, Egypt

c School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK

Abstract: This review deals with synthesis and reactions of 3-acetylindoles as well as their biological activities. The data

published over the last few years on the methods of synthesis and chemical properties of 3-acetylindoles are reviewed

here for the first time.

1. INTRODUCTION

3-Acetylindole derivatives have been in the centre of at-tention of researchers over many years due to the high prac-tical value of these compounds, in the first place, the unusu-ally broad spectrum of biological activities. For example, 4-(1H-indol-3-yl)-2-hydroxy-4-oxobut-2-enoic acid was useful as anti-HIV agent, other compounds derived from 3-acetylindoles used in the treatment of gastrointestinal, car-diovascular and CNS disorders, and also used as HIV-1 inte-

grase inhibitors. Despite this importance, 3-acetylindoles have not been previously reviewed. The main purpose of this review is to present a survey of the literature on 3-acetylindole's chemistry and provides useful and up-to-date

data for medicinal chemists.

2. METHODS OF SYNTHESIS

2.1. Friedel-Crafts Acetylation

3-Acetylindoles (2) were prepared by Friedel-Crafts ace-tylation of indoles (1) with acetyl chloride (AcCl) or acetic anhydride (Ac2O) in the presence of a catalyst (Scheme 1). Various catalysts were used in acetylation of indoles, such as diethyl aluminium chloride [1,3], PPh3-HClO4 (TPP) [4], Indium trichloride and indium triflate [5], tin tetrachloride [6], AlCl3 [7], zinc chloride [8], vinyl acetate or styrene [9],

*Address correspondence to this author at the School of Chemistry, Cardiff

University, Main Building, Park Place, Cardiff CF10 3AT, UK; Tel: ---------

-; Fax: ------------; E-mail:

perchloric acid [10,11], silicon tetrachloride and tin tetra-chloride [12].

NH

R NH

R

Ac

2

AcCl or Ac2O

1, R = H, Cl, OMe

Scheme 1.

Treatment of 1-acylindoles (3) with acetyl chloride in the presence of AlCl3 as a catalyst gave the corresponding 1-acyl-3-acetylindoles 4 (Scheme 2) in 76-97% yields. Hy-drolysis of 4 (R = Me) with KOH in aqueous MeOH pro-

duced 3-acetylindole (2a; Scheme 2) [13].

Ethyl indole-2-carboxylates (5) were reacted with acetic acid in the presence of trifluoroacetic anhydride (TFAA) and phosphoric or polyphosphoric acid (PPA) to produce ethyl 3-acetylindole-2-carboxylates 6 (Scheme 3) [14].

Friedel-Crafts acetylation of 1-(phenylsulfonyl)indoles (7) with acetic anhydride or acetyl chloride in the presence of aluminium chloride gave 3-acyl-1-(phenylsulfonyl)indoles 8 (Scheme 4). Base hydrolysis converted 8 to 3-acylindoles 9

(Scheme 4) in 79-96% yields [15].

Heating N-acetoacetylindole (10) with acetic anhydride afforded 1-acetoacetyl-3-acetylindole (11; Scheme 5) which

on hydrolysis with 5% NaOH gave 2a in ca. 13% yield [16].

Treatment of methyl N-alkyl-2-indole carboxylates 12 with a mixture of trifluoroacetic anhydride, glacial acetic acid and 85% H3PO4 in acetonitrile gave the corresponding methyl N-alkyl-3-acetyl-2-indole carboxylates 13 (Scheme

R = Me, CH2Cl, Ph

N

O

R

N

OR

Ac

KOH

MeOH/H2ONH

Ac

3 4

2a

AcCl

AlCl3

Scheme 2.

2 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

6) which on alkaline hydrolysis gave the corresponding N-

alkyl-3-acetyl-2-indole carboxylic acids 14 (Scheme 6) [17].

Treatment of indole (1a) with acetic anhydride in the presence of formic acid afforded 3-(1-acetyl-1-hydroxyethyl) indole (15; Scheme 7). Photolysis of 15 at room temperature

under nitrogen for 48 h gave 2a in 77% yield [18].

NH

1a

Ac2O/HCO2H

NH

15

Me

OH

Ac

Scheme 7.

Reaction of an equimolar mixture of 2,4,4,5,5-pentamethyldioxolanium perchlorate and indole (1a) in ace-tic acid followed by hydrolysis with 5% HCl gave 2a in 51%

yield [19].

2.2. Grignard Reactions

Addition of 2-(benzyloxy)acetyl chloride (17) to (1H-indol-3-yl)magnesium iodide (16) in diethyl ether afforded 3-benzyloxyacetylindole (18; Scheme 8). Reduction of 18 with Raney Ni in absolute ethanol gave 2-hydroxy-1-(1H-

indol-3-yl)ethanone (19; Scheme 8) in 68% yield [20].

Reaction of indole (1a) with ethylmagnesium iodide in

dry ether followed by reaction with acetyl chloride produced

a mixture of 2a and 1,3-diacetylindole (20; Scheme 9) [21].

NH

1a

+1, EtMgI

2, AcClNH

2a

Ac

N

Ac

Ac

20

Scheme 9.

R = H, PhCH2, R1 = H, Cl, OMe

N

R

CO2Et

R1

N

R

CO2Et

R1

5 6

Ac

AcOH

TFAA/H3PO4

Scheme 3.

R = H, 6-OMe, 5-OMe, 5-F

N

SO

O

Ph

RAc2O or AcCl

AlCl3

base

7

N

SO

O

Ph

R

8

Ac

NH

R

9

Ac

Scheme 4.

R = Me, Et

O

O N

R

CO2Me

O

O N

R

CO2Me

Ac

KOHO

O N

R

CO2H

Ac

12 13 14

TFAA/AcOH

H3PO4/MeCN

Scheme 6.

O

OClN

H

MgI

+Et2O Raney Ni

EtOH

16 17 18

NH

O

O

19

NH

O

OH

Scheme 8.

10 11

N

O

Ac

N

O

Ac

Ac

Ac2O

Scheme 5.

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 3

2.3. Hydrolysis of diacyl-4,5-dihydroimidazole or 3-acetoacetylindole

Hydrolysis of both N,N'-diacyl-4,5-dihydroimidazole (21; Fig. 1) or 3-acetoacetylindole (22; Fig. 1) gave 2a

[22,23].

22

NH

N

N

Me

21

Ac

Ac

NH

O

Me

O

Fig. (1).

2.4. Rearrangement of 2-acetylindole

2-Acetylindole (23) was rearranged to produce 2a, but in very low yield, when treated with polyphosphoric acid at 100

°C (Scheme 10) [24].

23

NH

Ac

2a

NH

PPA

100 °C

Ac

Scheme 10.

2.5. Reduction of 1-hydroxymethyl-3-acetylindole

Hydrogenation of 1-hydroxymethyl-3-acetylindole (24) over Raney Ni in EtOH gave 2a in 82% yield (Scheme 11)

[25].

2a

NH

Raney Ni

N

Ac

OH

24

Ac

Scheme 11.

2.6. Fisher Indole Synthesis

Heating 3-(2-phenylhydrazono)butan-2-one (25), which could be obtained from diacetyl and PhNHNH2.HCl, in polyphosphoric acid afforded 2a in 52% yield (Scheme 12)

[26].

2a

NH

PPA

25

Ac

NH

N

AcMe

Scheme 12.

2.7. From Dichlorocarbene

Addition of monochlorocarbene to indole (1a) followed by rearrangement and hydrolysis produced 2a (Scheme 13)

[27].

2.8. From Halobenzene Derivatives

Palladium catalyzed cross-coupling reaction of 3-methyl-4-(tributylstannyl)isoxazole with 2-iodonitrobenzene fol-lowed by reductive cyclization gave 2a [28]. Treatment of 2-bromoanilines (26) with but-3-en-2-one (27) in the pres-ence of palladium(II) chloride afforded 28 (Scheme 14). A

NH

Cl

H

NH

H

Cl

NH

CHClH

- HCl N

Cl

H

N

H

Cl

NH

Cl

H2O

NH

Ac

2a

1a

Scheme 13.

R = H, 3-CO2Me, 4-CO2Me, 5-CO2Me, 5-OMe

O

Me

Br

NH2

R +

PdCl2 Pd

NH

Ac

R

26 28

Br

NH

R

27

Ac

2

Scheme 14.

4 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

palladium (0)-assisted cyclization of 28 led to the formation

of 3-acetylindoles 2 [29].

2.9. From 1,1,1-triethoxyethane

Acylation of 2-substituted indoles 29 with 1,1,1-triethoxyethane or 1-(trimethoxymethyl)benzene and in presence of HBF4 proceeded with high regioselectivity to give acylindole tetrafluoroborates 30 (Scheme 15) in 45-95% yields. Base catalyzed hydrolysis of 30 gave 3-acetylindoles 31 in the yields of 95-98% [30,31].

2.10. From (2-isocyanobenzyl)lithium

Treatment of (2-isocyanobenzyl)lithium (32) with methyl but-3-enoate afforded 1-(2-isocyanophenyl)propan-2-one (33), which on treatment with cuprous oxide gave

3-acetylindole (2a; Scheme 16) [32].

2.11. From Thioketals

Treatment of thioketals 34 with an acidic catalyst such as Dowex 50W in the presence of paraformaldehyde under mild conditions afforded 3-acetylindoles 35 (Scheme 17) in rea-

sonable yields [33].

N

R

S

S

Dowex 50W, acetone

paraformaldehydeN

Ac

R

34 35R = H, Ac Scheme 17.

2.12. Debenzylation or Desulfonylation

Debenzylation of 1-benzyl-3-acetylindole (36) using aluminium chloride in benzene or anisole gives 2a (Scheme

18) [34].

Desulfonylation of 1-[1-(methylsulfonyl)-1H-indol-3-yl]ethanone (37) proceeded using KF/Al2O3 or TBAF in THF under reflux conditions to produce 2a (Scheme 19)

[35,36].

NH

Ac

2a

N

36

Ac

AlCl3

Scheme 18.

NH

Ac

2a

N

SO2CH3

37

Ac

KF/Al2O3

or TBAF

Scheme 19.

2.13. From Amide Derivatives

3-Acetylindole (2a) was synthesized from reaction of in-dole with acetamide in the presence of phosphorus oxychlo-ride [37]. 6-Benzyloxy-3-acetylindole (38) was obtained from reaction of 5-benzyloxyindole with a mixture of N,N-dimethylacetamide and phosphorus oxychloride (Scheme 20)

[38].

2.14. From Diketone Diazonium Salts

The Rh(II) acetate catalyzed reaction of 3-diazo-1-(indol-3-yl)propane-1,2-dione (39) produces 2a in 70% yield (Scheme 21). The reaction involves a Wolff rearrangement

[39].

3. PROPERTIES

The melting point of 3-acetylindole (2a) is 189-90 °C [40], the spectrophotometrical determination of pKa value of 3-acetylindole was 13.79 in 50% aq. MeOH, while, the pKb values of 2a and 3-acetyl-N-methylindole were -1.74 and -1.53, respectively. Protonation of acylindoles took place on the carbonyl group [41]. IR, UV, and NMR spectral data and dipole moments indicated that 3-acetylindole exist as an equilibrium mixture of s-cis and s-trans conformers with the

latter predominant [42,43].

N

R1

R

MeC(OEt)3

PhC(OMe)3 N

R1

R

R2OMe

BF4

N

R1

R

29 30 31R, R1 = H, Me, Ph; R2 = Me, Et

OMe

Scheme 15.

O

MeOLi

NC

+

COMe

NCNH

Cu2O

32 33 2a

Ac

Scheme 16.

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 5

Rh(CH3COO)2

NH

2a

NH

39

OO

NN

OMe

Scheme 21.

4. REACTIONS

4.1. Reactions of Acetyl Group

4.1.1. Reduction

Reaction of 3-acetylindole (2a) with propanol and NADPH in phosphate buffer and MgCl2 (pH 7.1) afforded (R)-1-(1H-indol-3-yl)ethanol (40; Scheme 22) [44]. The al-cohol dehydrogenase from Lactobacillw kefir simultaneously catalyzed carbonyl reduction of 2a into (R)-1-(1H-indol-3-

yl)ethanol (40) [45].

Me

NH

HO

NH

2a 40

propanol

NADPH

OMe

Scheme 22.

Treatment of 2a with lithium borohydride gave 1-(1H-indol-3-yl)ethanol (41) along with starting material being recovered (Scheme 23).

NH

2a 41

NH

Me

HO

LiBH4

O

Me

Scheme 23.

While, treatment of 2a with lithium borohydride in THF under reflux conditions gave 3-ethylindole (42; Scheme 24) [46]. Also, reduction of 2a with diborane gave 3-ethylindole

(42; Scheme 24) [47].

NH

2a 42

NH

Et

LiBH4

or B2H6

O

Me

Scheme 24.

Reduction of 1-[1-(phenylsulfonyl)-1H-indol-3-yl]etha-none (43) with sodium borohydride in trifluoroacetic acid under nitrogen gave 3-ethyl-1-(phenylsulfonyl)-1H-indole

(44; Scheme 25) [15].

N

SO

O

Ph

N

Et

SO

O

Ph

43 44

NaBH4

CF3CO2H

OMe

Scheme 25.

4.1.2. Oxidation

Oxidation of 3-acetylindole (2a) with selenium dioxide in pyridine or potassium permanganate gave 2-(1H-indol-3-yl)-

2-oxoacetic acid (45; Scheme 26) [48].

NH

2a

SeO2

or KMnO4 NH

OO

OH

45

O

Me

Scheme 26.

O

MeN

Me

Me+P

O

Cl

Cl

Cl N C

Me

Me

Me

O POCl2

Cl

NH

OPh

N

OPh

O

Cl2OP

MeN

H

N

OPh

Me

N

Me

Me

NH

OPh

Me

N

Me

Me

NaOH

NH

OPh

Ac

38 Scheme 20.

6 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

4.1.3. Halogenation

Topsentin-A (48) was prepared according to Scheme 27. Treatment of 2-bromo-1-(1H-indol-3-yl)ethanone (46), pre-pared from bromination of 2a, with 1,1-dimethyl hydrazine gave 2-(2,2-dimethylhydrazinyl)-1-(1H-indol-3-yl)ethanone

(47) which rearranged to produce 48 (Scheme 27) [49].

1-(1H-Indol-3-yl)-2-iodoethanone (49) was prepared by reaction of 2a with elemental iodine in methanol as a solvent and in the presence of 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) as iodina-

tion mediator (Scheme 28) [50].

4.1.4. Claisen Condensation

3-Acetylindole (2a) condensed with diethyl oxalate in sodium methoxide at room temperature to give ethyl 4-(1H-

indol-3-yl)-2,4-dioxobutanoate (50). Cyclization of 50 with hydrazines gave the corresponding ethyl 3-(1H-indol-3-yl)-1H-pyrazole-5-carboxylates 51 (Scheme 29). Hydrolysis of 50 with aqueous sodium hydroxide afforded 4-(1H-indol-3-

yl)-2,4-dioxobutanoic acid (52; Scheme 29) [51,52].

3-Acetylindoles 2 were coupled with ethyl 1-(4-methoxybenzyl)-1H-tetrazole-5-carboxylate (53) in the pres-ence of LHMDS to provide the corresponding 1-(1H-indol-3-yl)-3-hydroxy-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)prop-2-en-1-ones 54 (Scheme 30) [53].

4.1.5. Mannich Reaction

Reaction of 2a with treptamine hydrochloride and para-formaldehyde gave 1-(1H-indol-3-yl)-3-(phenethylamino) propan-1-one hydrochloride (55; Fig. 2) as Mannich adduct. Also its reaction with N-phenyl piperazines gave 1-(1H-

NH

OBr

N

Me

Me

NH2

NH

OHN

N

Me

Me

NH

O

NH

484746

N

HN

Scheme 27.

NH

NH

OI

N+N+F

Cl . (BF4)22-

492a

I2

OMe

Scheme 28.

NH

O

O

O

OEt RNHNH2

NH

N

N

R

aq. NaOH

NH

O

O

O

OH

51 R = H, Ph52 50

O

OEt

Scheme 29.

NH

X

+N

N N

N

OMe

O

EtO

HN

O

X

LHMDS

THF

OH

N N

N

N

OMe

2 53 54X = H, Cl, F

OMe

Scheme 30.

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 7

indol-3-yl)-3-(4-arylpiperazin-1-yl)propan-1-ones 56 (Fig.

2) [54,55].

Mannich reaction of 1-(4-fluorobenzoyl)-3-acetylindole (57) with 1-arylpiperazine and paraformaldehyde in ethanol as a solvent gave the corresponding Mannich bases identified as 1-[1-(4-fluorobenzoyl)-1H-indol-3-yl]-3-(piperazin-1-yl) propan-1-ones 58 (Scheme 31) [56].

Mannich reaction of 2a, paraformaldehyde and l-nore-phedrine in 2-propanol as a solvent afforded 3-(1-hydroxy-1-phenylpropan-2-ylamino)-1-(1H-indol-3-yl)propan-1-one (59; Fig. 3) [57]. Also, Mannich reaction of 2a with formal-dehyde and alicyclic amines in ethanol as a solvent afforded the corresponding 3-substituted amino-1-(1H-indol-3-yl) propan-1-one 60 (Fig. 3: R

2 = 1-pyrrolidonyl, 1-piperidinyl,

4-morpholinyl, etc) [58].

4.1.6. Knoevenagel Reaction

Base-catalyzed ring closure reaction of 2a with malononitrile in the presence of high concentration of di-methylamine afforded 2-[1-(1H-indol-3-yl)ethylidene] malononitrile (61; Fig. 4) [59]. While, the solid state con-densation of 2a with 5-methyl-2-phenylpyrazolidin-3-one afforded 4-[1-(1H-indol-3-yl)ethylidene]-3-methyl-1-phenyl-

1H-pyrazol-5(4H)-one (62; Fig. 4) [60].

NH

MeCN

CN

61

NH

Me

N

N

O

Me

Ph

62

Fig. (4).

4.1.7. Reformatsky Reaction

3-Acetyl-1-methylindole (63) was treated with ethyl bromoacetate and Zn to give ethyl 3-(1-methyl-3-

indolyl)crotonate (64) as the only product (Scheme 32) [61].

Me

O

EtO

N

Me

N

Me

63 64

Zn

BrCH2CO2Et

Me

O

Scheme 32.

NH

OHN

. HCl

NH

O

NN

R

55 56 R = OMe, Cl

Fig. (2).

NAc

O

F

CH2O

NH

N

Ar

N

O

O

F

N

N

Ar

57 58 Scheme 31.

NH

O

NH

MeOH

59

NH

O

NR2

60

Fig. (3).

8 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

4.1.8. Vilsmeier Reaction

Treatment of 2a with the Vilsmeier complex, phosphorus pentachloride and DMF, gave 3-chloro-3-(1H-indol-3-yl)acrylaldehyde (65) which on treatment with 40% NaOH and PhCH2NMe3Cl in dioxane as a solvent afforded 3-

ethynyl-1H-indole (66; Scheme 33) [62].

4.1.9. Decarbonylation

Treatment of 2a with sodium methoxide in methanol for 13 h at 210 °C gave 3-methylindole, skatole (67) by cleavage

and realkylation (Scheme 34) [63].

1-(2-Methyl-1H-indol-3-yl)ethanone (68) was trans-formed into 2,3-dimethylindole (69) by action of sodium metal in methanol (Scheme 35) [64].

NH

Me

68

NH

Me

69

Me

Na/MeOH

O

Me

Scheme 35.

4.1.10. Grignard Reaction

2-(1H-Indol-3-yl)propan-2-ols 71 were synthesized from N-protected 3-acetylindoles (70) by reaction with methyl

magnesium bromide in THF as a solvent (Scheme 36) [65].

N

R

MeMgBr/THF

N

HO

Me

R

Me

70 71

OMe

Scheme 36.

4.1.11. Reaction with Hydroxylamine

1-(1H-Indol-3-yl)ethanone oximes 72 were synthesized from reactions of 3-acetylindoles 70 with hydroxylamine

hydrochloride under alkaline conditions (Scheme 37)

[66,67].

NH

2a

NH

O

Ar

73

ArCHO+

O

Me

Scheme 37.

4.1.12. Reaction with Aldehydes

3-Acetylindole (2a) condensed with various aromatic al-dehydes to afford the corresponding chalcones 73 (Scheme 38) [58,68-71].

NH

2a

NH

O

Ar

73

ArCHO+

O

Me

Scheme 38.

Aldol condensation of 2a and polymer supported 75 in THF in the presence of potassium carbonate for 48 h under reflux conditions produced 76 (Scheme 39). Compound 75 was first obtained from reaction of 5-(3-formyl-4-nitrophenoxy)pentanoic acid (74) and hydroxyethyl polysty-rene in the presence of DIPC and DMAP in DCM at room temperature for 22 h (Scheme 39). Reduction of 76 followed by cyclization in the presence of hydrated SnCl2 in a mixture of DCM and EtOH under reflux conditions for 4 h afforded the corresponding quinoline-N-oxide 77 (Scheme 39). Treat-ment of 77 with TiCl3 at room temperature afforded quino-line derivative 78. Reaction of 78 with amines in the pres-ence of AlMe3 at room temperature afforded the correspond-ing 5-(2-(1H-indol-3-yl)quinolin-6-yloxy)pentanamides (79)

(Scheme 39) [72].

NH

Cl

NH

65 66

40% NaOH/dioxane

PhCH2NMe3ClNH

2a

PCl5/DMF

Me

O

O

Scheme 33.

NH

2a

N

O

Me

H

Me

NH

NH

Me

67

MeONa

MeOH

O

Me

Scheme 34.

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 9

Reaction of 3-acetylindole (2a) and oxazole-4-carbaldehyde (80) in the presence of LDA in dry THF pro-duced 3-hydroxy-1-(1H-indol-3-yl)-3-(oxazol-4-yl)propan-1-one (81) which on sequential treatment with MsCl/Et3N and aq. NaOH gave 5-(1H-indol-3-yl)-1H-pyrrole-2-carbalde-hyde (82; Scheme 40) [73].

ondensation of 6-amino-2-ethoxy-5-formyl-4-phenyl-nicotinonitrile (83) with 3-acetylindole (2a) under catalytic alkaline conditions gave 2-ethoxy-7-(1H-indol-3-yl)-4-phenyl-1,8-naphthyridine-3-carbonitrile (84), the expected

Friedlaender product (Scheme 41) [74].

4.1.13. Reaction with DMF/DMA

Treatment of 2a with dimethylformamide/dimethylacetal

(DMF/DMA) gave the corresponding N-methylated product

85 (Fig. 5; R = H) in 85% yield. While, 85 (Fig. 5; R = Me)

was obtained in 71% yield when 2a was treated with

DMF/dimethylformamide-di-tert-butylacetal. Treatment of

85 with guanidine in 2-propanol and in the presence of so-

dium methoxide gave 86 (Fig. 5) in 74% yield when R = H

and 44% yield when R = Me [75,76].

HN

2a

CHO

NO2

O

O

OH

HN

N

74 76

77

O

NO2

O

O

O

O

O

O

OH

-O

+

CHO

NO2

O

O

O

75

P P

P

HN

N

78

O

O

O P

HN

N

79

O

O

NHR

Scheme 39.

NH

O

HO

O

N

NH

O

N CHO

LDA, THF

NH

NH

CHO

81 822a

1, MsCl, Et3N, THF

2, NaOH, H2O

OMe

80

+

Scheme 40.

N

NC

EtO

Ph

CHO

NH2

+

NH

N

N Ph

CN

OEt

HN

83 2a 84

KOH

EtOH

O

Me

Scheme 41.

10 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

N

O N

Me

Me

R

N

N

N

H2N

R

8685 Fig. (5).

4.1.14. Reaction with Isatins

Condensation of 5-bromoisatin and 2a gave 3-[2-(1H-indol-3-yl)-2-oxoethyl]-5-bromo-3-hydroxyindolin-2-one

(87; Fig. 6) [77].

NH

HO

O

Br

ONH

87 Fig. (6).

Treatment of isatins with 3-acetylindole (2a) afforded the corresponding indolylcinchoninic acids 88 (Scheme 42) [78-

80].

4.1.15. Reaction with 1,2-ethanthiol

3-(2-methyl-1,3-dithiolan-2-yl)-1H-indole (89; Fig. 7)

was prepared from reaction of 2a with 1,2-ethanthiol [81].

NH

Me

S

S

89 Fig. (7).

4.1.16. Reaction with Hexamethylenetetramine

One-step condensation of hexamethylenetetramine with 2a in acetic acid gave 7-(3-indolyl)-1,3,5-triazaadamantane

(90; Fig. 8) [82].

N

N

N

O

HN

90

Fig. (8).

4.1.17. Reaction with Hydrazines, Thiosemicarbazides, Am-

ides and Hydrazides

Thiosemicarbazone derivatives 91 were obtained from

direct condensation of 2a with substituted semi and/or

thiosemicarbazides in refluxing ethanol (Scheme 43). Also,

91 can be obtained from reaction of 2a with hydrazine hy-

drate to produce 92 followed by reaction with iso and/or

thiocyanates (Scheme 43) [83].

Reaction of 2a with hydrazine gave 4-(2-aminophenyl)

pyrazole (93; Fig. 9) [84-87]. It was found that condensation

of 2a with thiosemicarbazides in ethanol afforded the corre-

sponding products 94 (Fig. 9) [88].

(6-tert-Butyl-3-pyridazinyl)hydrazine reacted with 2a in

toluene and in the presence of a catalytic amount of

4-methylbenzenesulfonic acid to afford 3-[1-[2-(6-tert-

butylpyridazin-3-yl)hydrazono]ethyl]-1H-indole (95; Fig. 9)

[89].

3-Dimethylamino-1-(1H-indol-3-yl)propenone (96), pre-

pared from reaction of 3-acetylindole (2a) with di-

methoxymethyl/dimethylamine, undergoes cyclocondensa-

tion with guanidine carbonate to produce 4-(1H-indol-3-yl)-

pyrimidin-2-ylamine (97; Scheme 44) [90].

Treatment of acid hydrazides 98 with 2a gave the corre-

sponding hydrazones 99 (Scheme 45) [91].

4.1.18. Reaction with Heterocycles

The iodination-alkylation between 2a and 4-tert-

butylpyridine afforded the corresponding pyridinium iodide

100. Reductive cyclization of 100 with lithium aluminum

hydride in THF followed by acidification gave 101 (Scheme

46). Hydrogenation of 101 in ethanol over palla-

dium/charcoal gave cis-2-tert-butyl-1,2,3,4,6,7,12,12b-

octahydroindolo[2,3-a]quinolizine (102; Scheme 46) along

with traces of its trans-isomer [92].

NH

R1+

NH

O

O

R2

N

R2

NH

R1

R1 = H, Me, Ph; R2 = H, Me, Br 882a

OOH

OMe

Scheme 42.

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 11

Reaction of 2a with isoquinoline gave 2-[2-(3-indolyl)-2-oxoethyl]isoquinolinium iodide (103; Fig. 10) [93]. While, treatment of isoquinoline with 2a and benzoyl chloride gave the corresponding isoquinoline derivative (104; Fig. 10)

[94].

4.1.19. Reaction with Organophosphorous Compounds

Treatment of 3-acetylindole (2a) with diethyl phosphoro-cyanidate and lithium cyanide gave the corresponding 3-(1-

cyanoethyl)-1H-indole-2-carbonitrile (105; Scheme 47) [95].

NH

O

Me

NH

NC

Me

CN

O

PEtO CN

OEt

LiCN

1052a

Scheme 47.

NNH

NH2

93

NH

MeN

NH

S

NH

(CH2)n X

94 X = NMe2, NEt2, 1-pyrrolidinyl…etc; n = 2, 3

NH

Me

N

HN

NN

But

95

Fig. (9).

HN

N

Me

Me

O

H2NNH2

NH H2N

N

N

NH

96 97

. H2CO3

Scheme 44.

N Ph

R

O NHNH2

+

NH

OMe

N Ph

R

OHN

N

Me

NH

992a98 R = H, Me

Scheme 45.

NH

O

N+

I-

NH

N

NH

N

H

H

100

1, LiAlH4/THF

2, H+

101

H2

Pd/C

102

Scheme 46.

N+

O

HNI-

103

N Ph

OO

NH

104

Fig. (10).

12 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

Treatment of 2-cyano-3-indoleacetonitrile (106) with acetylene carboxylates afforded the corresponding 1-amino-

4-cyanocarbazoles 107 (Scheme 48) [95].

Also, it was found that reaction of 2a with diethyl cyano-phosphonate in the presence of lithium cyanide can produce diethyl 2-cyano-3-(1-cyanoethyl)-1H-indol-1-yl-1-phospho-

nate (108; Fig. 11) [95,96].

N

Me

CN

PO

EtO

OEt

CN

108 Fig. (11).

4.1.20. Allylation

Allylation of 2a with allylboronic acid under standard conditions gave homoallylic amine (109; Fig. 12) which can easily isolated in high yield through simple acid–base extrac-

tion [97].

NH

H2N

Me

109 Fig. (12).

4.1.21. Reaction with Lawesson’s Reagent

Reaction of 2a with Lawesson’s reagent gave 1-(1H-

indol-3-yl)ethanethione (110; Fig. 13) [98].

NH

S

Me

110 Fig. (13).

Treatment of 3-[(benzylthio)vinyl]indole (111), synthe-sized from 3-thioacetylindole (110) on treatment with NaH and benzyl chloride in THF, with dimethyl but-2-ynedioate gave dimethyl 4-(benzylthio)-9H-carbazole-1,2-dicarboxy-

late (112; Scheme 49) [98].

4.1.22. Miscellaneous Reactions

The N-protected diazoacetylindole 114 was readily syn-

thesized from 113 using the modified diazo transfer proce-

dure (Scheme 50). Rhodium(II) acetate catalysed decomposi-

tion of 114 in boiling acetonitrile gave tert-butyl 3-(2-

methyloxazol-5-yl)-1H-indole-1-carboxylate (115), which on

treatment with sodium methoxide in methanol/THF gave 5-

(1H-indol-3-yl)-2-methyloxazole (116; Scheme 50) [99,100].

(S)-1-[5-(1H-Indol-3-yl)oxazol-2-yl]-N,N-dimethyl-2-

phenylethanamine (117; Fig. 14) was synthesized by aza-

Wittig reaction of (S)-N-phthaloylphenylalanyl chloride and

iminophosphorane derived from -azidoacetylindole [101].

Two-step reaction of 3-acetylindole (2a) and 3-(1,1-ethylenedioxyethyl)pyridine gave 1-((12bS)-1,2,3,4,6,7,12, 12b-octahydroindolo[2,3-a]quinolizin-3-yl)ethanone (118;

Fig. 14) [102].

Rhodanine derivative, (E)-2-[5-[1-(1H-indol-3-yl)ethyl-

idene]-4-oxo-2-thioxothiazolidin-3-yl]acetic acid (119; Fig.

14), was prepared from condensation of rhodanine-3-acetic

acid with 2a in the presence of 1,8-diazabicyclo[5.4.0]undec-

7-ene [103].

Treatment of the dianion of 3-acetylindole 120 with ben-

zophenone and diethylmalonic dichloride resulted in the

production of 4-(diphenylmethylene)-6,6-diethylcyclo-

oct[cd]indole-3,5,7(1H,4H,6H)-trione (121; Scheme 51)

[104].

4.2. N-Substitution

4.2.1. N-Alkylation

Alkylation of 2a with alkyl halides (MeI, EtI,

H2C=CHCH2Br, PhCH2Br) in the presence of lithium cya-

nide in THF as a solvent afforded the corresponding N-alkyl

indoles 122 (Fig. 15) [105,106].

CO2MeR

N

Me NH2

CO2Me

R

CN

107 R = Me, CO2Me

NaHCNN

Me

CN

106

Scheme 48.

MeO2C CO2Me

HN

S

S Ph

NH

CO2Me

CO2Me111 112

Scheme 49.

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 13

N

R

Ac

122 R = Me, Et, H2C=CHCH2, PhCH2 Fig. (15).

Acylation of 3-acetyl-1-methylindole (63) with ethyl cyanoformate followed by diazo transfer reaction, in the

presence of 4-acetamidobenzenesulfonyl azide, gave ethyl 2-diazo-3-(1-methyl-1H-indol-3-yl)-3-oxopropanoate (123; Scheme 52) [107,108].

N-Alkylation of 2a with the appropriate 2-bromoalkyl

chloride (n = 1, 2) gave the corresponding chloro derivatives

124, which gave the corresponding azides 125 on reaction

with sodium azide in DMSO (Scheme 53). Heating 125 in

bromobenzene at 180 °C, in a sealed metal reactor, afforded

126 (Scheme 53) [109,110].

N

OMe

Boc

LiHMDS, THF, -78°C

CF3CO2CH2CF3, MsN3, Et3N N

O

Boc

N2

N

Boc

NO

Me

NH

NO

Me

114

115 116

113

Rh(OAc)2

MeCN

MeONa

THF/MeOH

Scheme 50.

SS

N

O

O

OH

Me

NH

119118

NH

N O

MeH

NH

O

N

NMe2

117

Fig. (14).

N

O

N

O

PhPh

O-

Ph Ph

-O

O

O

Cl

Cl

Me

Me

NH

O

O

O Ph

Ph

Et

Et

121

Ph2CO

N

HO

2 Li+

120

+ H+

- H+

Scheme 51.

N

Me

N

O

Me

1, LHMDS, THF, DMPU, EtO2CCN

2, ArSO2N3, Et3N, MeCN

CO2Et

N2

12363

OMe

Scheme 52.

14 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

The synthesis of ribofuranosylindole (129; Scheme 54) involved alkylation of the sodium salt of 3-acetylindole 127, obtained from 2a on treatment with NaH in MeCN, with 1-chloro-2,3,5-tri-O-acetyl-D-ribose (128). Removal of pro-tecting group was easily achieved on treatment with sodium

alkoxide [111].

Treatment of 2a with formalin in the presence of Na-HCO3 afforded 1-hydroxymethyl-3-acetylindole (24; Fig.

16) [25].

N

OH

24

Ac

Fig. (16).

Hydrolysis of 2-[(3-acetyl-1H-indol-1-yl)methoxy]ethyl acetate (130), prepared from condensation of 2a with (2-acetoxyethoxy)methyl bromide, gave 1-{1-[(2-hydroxy-ethoxy)methyl]-1H-indol-3-yl}ethanone (131; Scheme 55)

[112].

N-Alkylation of 3-acetylindoles 2 with benzyl bromides gave the corresponding N-benzyl indoles 132 (Scheme 56). Reaction of 132 with diethyl oxalate in THF or dry sodium ethoxide afforded ethyl 4-(1-benzyl-1H-indol-3-yl)-2-hydroxy-4-oxobut-2-enoate (133) which on hydrolysis with NaOH/MeOH furnished the corresponding acids 134

(Scheme 56) [1].

Condensation of 2a with bromobenzene under the Ull-mann conditions (copper (II) oxide catalyst and DMF as the solvent) gave 1-(1-phenyl-1H-indol-3-yl)ethanone (135; Fig. 17) [113]. Also, N-(4-fluorophenyl)-3-acetylindole (136; Fig. 17) was synthesized from 2a and 1-fluoro-4-iodobenzene by

NH

+ BrCH2(CH2)nCl

NaH/DMF

N

Ac

Cl

NaN3, DMSO

NN3

PhBr

NNH

2a 124 125 126

Ac AcAc

( )n( )n

( )n

Scheme 53.

N

Ac

O

AcO OAc

Cl

AcORONa/ROH N

Ac

O

HO

OH

OH

127 128 129

+

Scheme 54.

N

Ac

O

O

O

MeN

Ac

O

OH

130 131

MeONa

MeOH

Scheme 55.

NH

R

Br

R'

NR

Ac

R'

EtO2C

O

OEt

NR

O

R'

HOCO2Et

NaH or EtONa

NR

O

R'

HOCO2H

NaOH/MeOH

2 132

133 134

Ac

R = H, OMe, Cl; R' = H, F

NaH/THF

Scheme 56.

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 15

an analogous Ullmann condensation procedure using copper

metal powder as the catalyst [114].

Reaction of 2a with bis(dimethylamino)methane in the presence of succinic anhydride and potassium carbonate af-forded 1-{1-[(dimethylamino)methyl]-1H-indol-3-yl}etha-none (137; Fig. 17) [115]. While, N-vinyl-3-acetylindole (138; Fig. 17) was prepared from reaction of 2a with 1-bromo-2-chloroethane in the presence of 18-crown-6 and

powdered potassium hydroxide in toluene [116].

4.2.2. N-Acylation

Acylation of 2a with acyl halides in the presence of lith-ium cyanide in THF afforded the corresponding N-acyl in-

doles 4 (Fig. 18) [105].

N

Ac

OR

4 R = Me, Et, Ph Fig. (18).

N-Acylation of 2a with pent-4-ynoic acid generates 1-(3-acetyl-1H-indol-1-yl)but-3-yn-1-one (139). Compound 139 was readily converted to methoxime derivative 140, which cyclized to give 1-methyl-4H-indolo[3,2,1-ij][1,6]naphthy-ridin-6(5H)-one (141; Scheme 57). Compound 141 was de-hydrogenated to give 1-methyl-6H-indolo[3,2,1-ij][1,6]

naphthyridin-6-one (142; Scheme 57) [117].

N-Acetylation of 2a with hex-4-enoyl chloride afforded the corresponding amide which was converted to tetracyclic silyl enol ether 143 that readily hydrolyzed to give the corre-

sponding ketone 144 (Scheme 58) [99].

4.2.3. N-Amination

3-Acetylindole (2a) was converted to 1-amino-3-acetylindole (145) via N-amination with NH2Cl in the pres-ence of sodium hydride [118]. Also, amination of 2a with H2NOSO3H in anhydrous DMF containing KOH gave 145

(Fig. 19) [119].

N

Ac

NH2145

Fig. (19).

4.24. N-Silylation

Silylation of 2a with tert-butylchlorodimethylsilane gives

N-silylated derivative 146 (Fig. 20) [120].

N

SiMe

Me

But

146

Ac

Fig. (20).

N

Ac

138

N

Ac

N

Me

Me

137

N

F

136

Ac

N

Ac

135

Fig. (17).

N

Ac

O

MeONH2.HCl

C5H5N

95% EtOH

N

NMe

O

OMe

tolueneN

N

Me

O

30% Pd/C

sulfolane

N

N

Me

O

139 140 141 142

Scheme 57.

NH

AcCl

O

Et3N

2, TMSOTf

3, 270 °C

N

TMSO

O

H

N

O

O

H

143144

2a

1,

Scheme 58.

16 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

4.3. Ring Reactions

4.3.1. Halogenation

3,5-Dihydro-3-methyl-2H-thiopyrano[4,3,2-cd]indole-2-carboxamide (150) was prepared starting from 2a through intermediates 147, 148 and 149 via multi-steps reaction

(Scheme 59) [121].

4.3.2. Nitration

3-Acetylindole (2a) reacted regioselectively with NO2BF4 in the presence of SnCl4 to produce 3-acetyl-5-nitroindole (151; Fig. 21) or 3-acetyl-6-nitroindole (152; Fig. 21), depending on the temperature of the reaction [122]. Nitration of 2a in the presence of acetonitrile solvates of

Cu2+

, Al3+

, and Fe2+

salts yielded 3-nitroindole (153; Fig. 21), 3-acetyl-4-nitroindole (154; Fig. 21) and 3-acetyl-6-

nitroindole (152; Fig. 21), respectively [123].

Catalytic reduction of 3-acetyl-4-nitroindole (154) with TiCl3 in methanol gave 4-amino-3-acetylindole (155) which gave the corresponding diazonium salt 156 on treatment with nitrous acid at low temperature (Scheme 60) [124]. Treat-ment of 156 with KI gave the corresponding 4-iodo deriva-tive 157 (Scheme 60) [123]. Compound 158 was produced from 157 via displacement of iodine at position 4 with thio-acetate. Treatment of 158 with ammonium acetate in acetic acid afforded dehydrochuangxinmycin (159), the dehydrate derivative of the antibiotic alkaloid chuangxinmycin, in ex-

cellent yield (Scheme 60) [123].

NH

Tl(CF3CO2)3

CuI/I2 NH

I

NH

S Me

CO2Me

NH

NMeS

NHTsCO2Me

NaH NH3/MeOH

NH

S Me

CONH2

150

2a

1, Me3SnSCH2CO2Me

2, TsNHNH2, 97%

147 148

149

OMe

OMe

Scheme 59.

NH

O2N

NH

O2N

151 152

Ac Ac

NH

NH

153 154

AcNO2

NO2

Fig. (21).

NH

NO2

NH

NH2

HCl

NaNO2 NH

N2Cl

NH

I

HS

O

OMe

Pyridine-MeOH NH

S

O OMe

NH

SMe

O OMe

154 155

157 158 159

156

Ac Ac Ac

Ac Ac

TiCl3

MeOH

KI

NH4OAc

MeOH

Scheme 60.

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 17

4.3.4. Acetylation

Acetylation of 2a with AcCl/AlCl3 in PhNO2/CH2Cl2 gave mainly 3,5-diacetylindole (160) together with some 3,6-diacetylindole (161) and 3,7-diacetylindole (162), re-

spectively (Fig. 22) [124].

NH

NH

NH

Ac

160 161 162

Ac

Ac

Ac

Ac Ac

Fig. (22).

4.3.5. Thallation

Thallation of 2a gave 163, which on treatment with KI gave 1-(4-iodo-1H-indol-3-yl)ethanone (164; Scheme 61)

[125].

NH

AcTl

F3COC COCF3

KI

NH

AcI

163 164 Scheme 61.

4.4. Photolysis

Irradiation of 2a in ethanol gives a mixture of 4-acetylindoles (165), 6-acetyl indoles (166) and 2-acetylindoles (23), respectively (Fig. 23) by Fries type

rearrangement [126].

NH

NH

Ac

NH

Ac

165 166 23

Ac

Fig. (23).

5. MEDICINAL APPLICATIONS

4-(5-Chloro-1H-indol-3-yl)-2-hydroxy-4-oxobut-2-enoic acid (167; Fig. 24) is useful as anti-HIV agent [127-129], while indole derivative 168 (Fig. 24) is used as modulators

of ghrelin receptor [130].

4-[5-Chloro-1-(2,6-difluorobenzyl)-1H-indole-3-carbonyl]-3-hydroxyfuran-2(5H)-one (169; Fig. 25) is useful as HIV-1 integrase inhibitor [131]. 3-bromo-4-(4-oxo-3,4-dihydro-1H-carbazol-9(2H)-yl)benzamide (170; Fig. 25) is

useful as antiproliferative agent [55,132].

O

OHO

O

N

F

FCl

169

N

O

O

NH2

Br

170

Fig. (25).

1-[3-(1H-Indol-3-yl)-5-aryl-4-(phenyldiazenyl)-4,5-dihydro-1H-pyrazol-1-yl]ethanones 171 (Fig. 26) showed

anti-inflammatory activity [69].

HNN

NAc

ArNN

Ph

171 Ar = Ph, 4-HOC6H4, 4-Me2NC6H4, 3-MeOC6H4

Fig. (26).

4-(1H-Indol-3-yl)-2-(4-methoxyphenyl)-2,3-dihydro-

benzo[b][1,4]thiazepine (172; Fig. 27), N-{[(4-(1H-indol-3-

yl)-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]thiazepin-

3-yl]methyl}aniline (173; Fig. 27) and 3-[(3-chlorophenyl)

diazenyl]-4-(1H-indol-3-yl)-2-(4-methoxyphenyl)-2,3-dihy-

drobenzo[b][1,4]oxazepine (174; Fig. 27) are useful as an-

tipsychotic agents [133].

1-(1H-Indol-3-yl)-3-hydroxy-3-(1-(4-methoxybenzyl)-

1H-tetrazol-5-yl)prop-2-en-1-ones (175; Fig. 28) are useful

as HIV-1 Integrase Inhibitors [53].

Ribofuranosylindole 128 (Scheme 54) was found to be

useful as potential antiviral agents [111]. 1-(1-Methyl-1H-

indol-3-yl)-3-(4-arylpiperazin-1-yl)propan-1-ones 176 (Fig.

28) showed moderate antagonism at the 5-HT3 receptor [55].

1-(1-(4-Fluorobenzoyl)-1H-indol-3-yl)-3-(piperazin-1-

NH

O

OH

Cl

167

N

OMe

N

O

F

168

Ac

OOH

Fig. (24).

18 Current Organic Chemistry, 2009, Vol. 13, No. 14 Metwally et al.

yl)propan-1-ones 58 (Scheme 31) were found to be useful as 5-hydroxytryptamine and dopamine receptor modulators in mice [56]. 3-(1H-indol-3-yl)butanoic acid (177; Fig. 29) or its salts are useful for control of bacterial wilt (caused by Pseudomonas solanacearum) [134]. While, the oxalate salt of 3-(1-butylpiperidin-4-yl)-1-(3,4-dihydro-2H-[1,3]oxazino [3,2-a]indol-10-yl)propan-1-one (178; Fig. 29) was found to be useful as 5-HT4 receptor antagonists in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS

disorders [135].

The mineral acid salts of 3-pyridazinylhydrazone 95 (Fig. 9) was found to be active as antiviral agents and agrochemi-cal fungicides [90]. Indolmycin derivatives 179 (Fig. 29)

showed antibacterial activity [136].

Rhodanine derivative 119 (Fig. 14) was found to be use-ful as blood platelet aggregation inhibitors [103]. 3-(1-hydroxy-1-phenylpropan-2-ylamino)-1-(1H-indol-3-yl)pro-pan-1-one (180; Fig. 30) was found to be useful for treat-

ment of heart disease at 0.1-500 mg oral doses [57].

HN

S

N

MeO

HN

S

N

MeO

NH

HN

O

N

MeO

N

N

Cl

172 173 174

Fig. (27).

NH

OX HO

N N

NN

OMe

175 X = H, Cl, F

N

O

N N Ar

Me

176

Fig. (28).

Me

O

HO

NH

177

O

NBu

N

O

178

NH

Me

N

O

N

R2

R1O

H

179 R1 = H, Me; R2 = cycloalkyl, substituted alkyl,

alkanoyl, substituted alkanoyl Fig. (29).

NH

O

NH

Me

OH

180

NH

O

NH

O

181

N

Me

HO

182

HN

O

Pr

Fig. (30).

3-Acetylindoles: Synthesis, Reactions and Biological Current Organic Chemistry, 2009, Vol. 13, No. 14 19

3-[2-(1H-Indol-3-yl)-2-oxoethyl]-5,6-dihydropyridin-2(1H)-one (181; Fig. 30) was isolated from the marine sponge Halichondria melanodocia with some applications [137]. While, N-[2-hydroxy-2-(1-methyl-1H-indol-3-yl)ethyl]butyramide (182; Fig. 30) was found to be a potent inhibitors of lipid peroxidation in rat liver microsomes [138].

CONCLUSION

The chemistry of 3-acetylindol has exhibited promise on a number of fronts; the full evaluation of its utility in hetero-cycles synthesis was not sufficiently investigated. The aim of this review was to demonstrate the wide synthetic applica-

tion of 3-acetylindole in organic synthesis.

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