Novel and simple methodology for the synthesis of 3-acetylindoles and their N-alkyl derivatives using TBAB as phase transfer catalyst

Article abstract of DOI:10.2174/157017811799304395

Using 5% aq. NaOH, a simple method for the transformation of 3-cyanoacetylindoles 2(a-e) into 3-acetylindoles 3 (a-e), in good yields, is reported. Tetrabutylammoniumbromide (TBAB) is found to be an efficient phase transfer catalyst for the synthesis of N-alkyl derivatives 5(a-t) of 3-acetylindoles 3(a-e) giving products in excellent yields. 2 (a-e) were themselves obtained from simple indoles 1 (a-e) by reaction with cyano acetic acid in the presence of propionic anhydride at 100 °C for 5-10 min. Partial hydrolysis of 2 (a-e) under hot acidic conditions yielded the corresponding carboxamides α-(3-indolecarboxoyl)acetamides 4(a-e). Which could be readily transformed into the respective 3(a-e) by refluxing with 5% aq. NaOH for 2-2.5 h.

Full text of DOI:10.2174/157017811799304395

656
Letters in Organic Chemistry, 2011, 8, 656-662
Novel and Simple Methodology for the Synthesis of 3-Acetylindoles and
their N-Alkyl Derivatives Using TBAB as Phase Transfer Catalyst
M. Venkatanarayana* and Pramod K. Dubey
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, College of Engineering, Kukatpally,
Hyderabad (A.P), 500 085, India
Received January 27, 2011: Revised March 01, 2011: Accepted August 09, 2011
Abstract: Using 5% aq. NaOH, a simple method for the transformation of 3-cyanoacetylindoles 2(a-e) into 3-
acetylindoles 3 (a-e), in good yields, is reported. Tetrabutylammoniumbromide (TBAB) is found to be an efficient phase
transfer catalyst for the synthesis of N-alkyl derivatives 5(a-t) of 3-acetylindoles 3(a-e) giving products in excellent
yields. 2 (a-e) were themselves obtained from simple indoles 1 (a-e) by reaction with cyano acetic acid in the presence of
propionic anhydride at 100 ˚C for 5-10 min. Partial hydrolysis of 2 (a-e) under hot acidic conditions yielded the
corresponding carboxamides ꢀ-(3-indolecarboxoyl)acetamides 4(a-e). Which could be readily transformed into the
respective 3(a-e) by refluxing with 5% aq. NaOH for 2-2.5 h.
Keywords: 3-cyanoacetylindole, 5% aq. NaOH, 3-acetylindole, alkylating agent, phase transfer catalyst (TBAB).
INTRODUCTION
Although the 3-position is the most reactive site for
electrophilic attack, [11] low yields encountered in this
reaction are usually attributed to the competitive formation
of 1-acylated and or 1, 3 diacylated products due to the
ambident character of the indole system. Other side
reactions, often observed in acidic conditions, are the self-
polymerization of indole and the less common formation of
di-indolylmethanes [20]. The use of N-protecting groups is
generally the chosen strategy to overcome the concurrent
formation of 1-acyl derivatives and to limit polymerization,
which has not been observed when the indole system is
deactivated by the presence of electron-withdrawing groups
on the ring. Nevertheless, troublesome protection-
deprotection steps are necessary in such situations [21, 22].
Additionally, the Vilsmeier-Haack reaction, involving
amides and POCl3, is not always effective, [12, 23, 24]
providing only moderate yields and requiring the preparation
of the amide if it is not commercially available.
Indole and its derivatives possess a wide range of
biological activities and the chemistry of indoles has been
reviewed by Gribble [1]. Acetylindoles are used as starting
materials for the synthesis of carbazole [2], pyridocarbazole
[3], carbolines [4] etc. several catalysts like Si(O2C-CH2-
CH2-COOCH3)4 / SnCl2 [5] , HClO4 [6], SiCl4 [7] and ZnCl2
[8] have been used for the acetylation of indoles. Okauchi et
al. [9] reported that the indoles were converted into a metal
derivative with Et2AlCl or Me2AlCl followed by treatment
with acid chlorides to give acetyl indoles.
The synthesis of 3-acylindoles has been the subject of
considerable interest not only because they are used as
intermediates in alkaloid synthesis but also because they
have useful biological activities [10]. Three major synthetic
methods have been employed to prepare this class of
compounds using indole as the starting material: (1)
Acylation of the indole using Grignard reagents [11-14] (i.e.
treatment of indole with EtMgI in dry ether followed by
reaction with acetyl chloride producing 3-acetylindole) (2)
acylation of N-protected indoles [15] and (3) the Vilsmeier-
Haack reaction [11] (on simple and substituted indoles).
There are also other methods based on acyl cation
equivalents, such as nitrilium salts [16] and on dialkyl
carbenium ions [17, 18]. Another method, using N-(R-
haloacyl)pyridinium salts, gives predominantly 3-acylindoles
under controlled conditions, but it seems to be restricted to
some very reactive R-haloacyl halides [19]. Each of these
methodologies has merits and shortcomings that limit their
scope and yield.
RESULTS AND DISCUSSION
Herein we describe a novel and simple methodology for
the synthesis of 3-acetylindoles
3
(a-e) from 3-
cyanoacetylindoles 2 (a-e) in the presence of 5% aq. NaOH,
through a very easy method that gives 3-acetylindoles in
high yields without laborious work ups. Earlier it was
reported from our lab [28] that the reaction of differently
substituted indoles 1 (a-e) with cyanoacetic acid in the
presence of propionic anhydride under heating at 60-70˚C
within 5-10 min gave different 3-cyanoacetylindoles 2(a-e)
in high yields (90-96 %) (Scheme 1). Treatment of 2 (a-e)
with 5% aq. NaOH under reflux for 3-4 h, gave 3-
acetylindoles 3(a-e) in excellent yields (90-96 %) (Table 1)
(Scheme 1).
*Address correspondence to this author at the Department of Chemistry,
Jawaharlal Nehru Technological University Hyderabad, College of
Engineering, Kukatpally, Hyderabad (A.P), 500 085, India; Tel: 91-
990800580; E-mail: venkatphdm@gmail.com
In all cases, the reaction proceeds smoothly with 5 % aq.
NaOH only. This method is very facile and convenient for
the preparation of large amount of differently substituted 3-
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

Novel and Simple Methodology for the Synthesis of 3-Acetylindoles
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
657
CN
O
O
CH3
R
R
R
Propionic anhydride
5% aq. NaOH
3- 4 h / Reflux
R1
N
Cyanoacetic acid / 5-10 min / 100 ˚C
N
H
R1
N
R1
H
H
(2)
(1)
(3)
PPA / 100 ˚C / 1 h
R2-X / K2CO3 / TBAB/
O
CH3CN / RT / 20-30 min
NH2
O
5% aq. NaOH
2- 2.
R
5 h / Re
flu
x
O
N
R1
CH3
H
R
(4)
N
R1
R2
(5)
(R2= Me, Et, PhCH2, PhSO2)
Scheme 1. Synthesis of 3-acetylindoles and N-Substituted 3-acetylindoles.
Table 1. Synthesis of 3 from 2 by Heating with 5% aq. NaOH
S.NO.
Substrate used
Time (hrs.)
Product obtained
Yield (%)
M.P (˚C)
1.
2.
3.
4.
5.
2a(R=H, R1=H)
2b(R=OMe,R1=H)
2c(R=H, R1=OMe)
2d(R=Br, R1=H)
2e(R=NO2, R1=H)
3.5 (Lit 26: 10)
3a(R=H, R1=H)
3b(R=OMe,R1=H)
3c(R=H,R1=OMe)
3d(R=Br, R1=H)
3e(R=NO2, R1=H)
96 (Lit [26]: 78%)
186 (Lit [26]: 187)
4
4
90
92
94
95
210
214-15
248
3.5
3.5
>280
acetylindoles. The above reaction was attempted in the
presence of various bases and acids like, 5%alc. NaOH,
5%alc. KOH, dil. HCl, dil. H2SO4 etc. but there was not
much progress in this reaction. The rates of reactions in
different basic and acidic media are described in Table 2.
In the reaction mechanism shown in Scheme 2, the HO-
ions attack the nitrile carbon yielding a nitrile anion which
abstracts a proton from water giving the iminol intermediate
(2l). The latter then tautomerises to form the amide 4 which
undergoes hydrolysis by the common mechanism (shown
above) giving the unstable ketoacid 4l that loses CO2 to give
3, a behavior typical of ꢀ-ketoacids.
100˚C for 1h, yielding the amide 4(a-e) (Table 3), followed
by hydrolysis with 5% aq NaOH for 2-2.5 h giving 3(a-e) in
yields of 80-85% (Table 4).
The reaction of 3(a-e) with dimethylsulphate (DMS)),
diethylsulphate (DES), benzyl chloride and benzenesulfonyl
chloride in the presence of a weak base K2CO3 and catalytic
amount of tetrabutylammonium bromide (TBAB) as phase
transfer catalyst in a suitable solvent at room temperature for
15-30 min gave 5(a-t) in high yields (Scheme 1) (Table 5).
Acetonitrile seems to be the best choice among the solvents
used for alkylation. The details of reactions done in different
solvents are described in Table 6.
Alternatively, 3-acetylindoles 3(a-e) could also be
prepared from 4(a-e) by the reaction of 2 (a-e) with PPA at
In summary, the advantage of the procedure described
herein over that of others is that N-alkylation and N-
Table 2. The Rates of the Reactions Carried Out in Different Basic and Acidic Media for Conversion of 2a to 3a
S. NO.
Substrate used
Reagent
Time (hrs.)
Temp (˚C)
Product obtained
Yield (%)
1
2
3
4
5
2a(R=R1=H)
2a(R=R1=H)
2a(R=R1=H)
2a(R=R1=H)
2a(R=R1=H)
5% aq. NaOH
5% alc. NaOH
5% alc. KOH
dil.HCl
3.5-4
48
3.5-4
48
3a(R=R1=H)
3a(R=R1=H)
3a(R=R1=H)
3a(R=R1=H)
3a(R=R1=H)
96
Nil
Nil
Nil
Nil
48
48
48
48
dil. H2SO4
24
24

658 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Venkatanarayana and Dubey
O
NH2
O
H2O
O
OH
NH
N
C
O
OH
C
H
C
Hr
N
O
Hr
Hr
C
O
OH
Hr
-OH
(4)
(2)
(2l)
H
H
O
O
O
C
O
O
C
O
O
O
H
NH2
H
C
Hr
CH3
Hr
O
Hr
NH3
Hr
-NH3
O
-CO2
(3)
H2O
(4l)
R
Hr=
N
R1
H
Scheme 2. A plausible mechanism for the formation of 3 from 2.
Table 3. Synthesis of 4 from 2 by Using PPA at 100 ˚C for 1 h
S. No.
Substrate used
Reaction Time (hrs.)
Product obtained
Yield (%)
1.
2
2a(R=H, R1=H)
2b(R=OMe,R1=H)
2c(R=H, R1=OMe)
2d(R=Br, R1=H)
2e(R=NO2, R1=H)
1
1
1
1
1
4a(R=H, R1=H)
4b(R=OMe,R1=H)
4c(R=H, R1=OMe)
4d(R=Br, R1=H)
4e(R=NO2, R1=H)
91
94
89
92
95
3.
4.
5.
Table 4. Alternative Synthesis of 3 from 4 by Using 5% aq. NaOH Reflux for 2-2.5 h
S. No.
Substrate used
Reaction Time (hrs.)
Product obtained
Yield (%)
1.
2.
3.
4.
5.
4a(R=H, R1=H)
4b(R=OMe,R1=H)
4c(R=H, R1=OMe)
4d(R=Br, R1=H)
4e(R=NO2, R1=H)
2
2
3a(R=H, R1=H)
3b(R=OMe,R1=H)
3c(R=H, R1=OMe)
3d(R=Br, R1=H)
3e(R=NO2, R1=H)
82
81
80
83
85
2
2
2.5
sufonylation of 3-acetylindole proceeds by a simple
procedure without having tedious workup and high purity of
the products under phase transfer catalytic conditions.
EXPERIMENTAL SECTION
Melting points were determined using a Buchi melting
point B-545 apparatus and are uncorrected. TLC checking
was done on glass plates coated with Silica Gel –G and
spotting was done using iodine or UV lamp. IR spectra were
recorded using Perkin Elmer model-446 FTIR in KBr.1H-
NMR spectra were recorded on a Gemini AV-400
instruments operating at 400 MHz.
CONCLUSION
We have developed a simple and general method for the
synthesis of 3-acetylindoles from 3-cyanoacetylindoles in the
presence of 5% aq. NaOH. This reaction proceeds under
mild conditions and is applicable to indoles bearing various
functional groups without NH protection. Furthermore, the
3-acetylindoles could be smoothly alkylated to obtain 1-
alky-3-acetylindoles using alkylating agents (DMS, DES,
C6H5CH2Cl and benzenesulfonyl chloride) in acetonitrile
using K2CO3 as a base and TBAB as phase transfer catalyst.
General Procedure for the Preparation of 3 from 2
A mixture of aq. NaOH (5%, 20 ml) and 2 (10 mM) was
refluxed for 3.5- 4 h. At the end of this period, the reaction
mixture was cooled to rt. The separated solid was filtered,

Novel and Simple Methodology for the Synthesis of 3-Acetylindoles
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
659
Table 5. Synthesis of 5 from 3 by Using K2CO3/TBAB/CH3CN/ RT/ Alkylating Agent
S.NO.
Substrate used
Reaction Time (min)
Product obtained
Yield (%)
M.P (˚C)
1.
2.
3a(R=H, R1=H)
3b(R=OMe,R1=H)
3c(R=H, R1=OMe)
3d(R=Br, R1=H)
3e(R=NO2, R1=H)
3a(R=H, R1=H)
20(Lit [27]: 180)
5a(R=H, R1=H, R2=Me)
5b(R=OMe,R1=H, R2=Me)
5c(R=H,R1=OMe, R2=Me)
5d(R=Br, R1=H, R2=Me)
5e(R=NO2, R1=H, R2=Me)
5f(R=H, R1=H, R2=Et)
94(Lit [27]: 85)
96 (Lit [25]: 95)
158-160
162-163
170-172
224
30
25
28
30
28
30
27
31
30
30
30
30
30
30
18
20
20
19
15
91
90
91
95
92
90
92
94
96
92
90
91
95
96
98
94
92
94
90
3.
4.
5.
6.
88 (Lit [25]: 89)
95
7.
3b(R=OMe,R1=H)
3c(R=H, R1=OMe)
3d(R=Br, R1=H)
3e(R=NO2, R1=H)
3a(R=H, R1=H)
5g(R=OMe,R1=H, R2=Et)
5h(R=H,R1=OMe, R2=Et)
5i(R=Br, R1=H, R2=Et)
8
125-126
133
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19
20.
5j(R=NO2, R1=H, R2=Et)
5k(R=H, R1=H, R2=PhCH2)
5l(R=OMe,R1=H, R2=PhCH2)
5m(R=H,R1=OMe, R2=PhCH2)
5n(R=Br, R1=H, R2=PhCH2)
5o(R=NO2, R1=H, R2=PhCH2)
5p(R=H, R1=H, R2=PhSO2)
5q(R=OMe,R1=H, R2=PhSO2)
5r(R=H,R1=OMe, R2=PhSO2)
5s(R=Br, R1=H, R2=PhSO2)
5t(R=NO2, R1=H, R2=PhSO2)
217-218
80
3b(R=OMe,R1=H)
3c(R=H, R1=OMe)
3d(R=Br, R1=H)
3e(R=NO2, R1=H)
3a(R=H, R1=H)
123
142
118
180-182
245
3b(R=OMe,R1=H)
3c(R=H, R1=OMe)
3d(R=Br, R1=H)
3e(R=NO2, R1=H)
>280
199-200
>280
212
Table 6. The Alkylation of 3a to 5a in Different Solvents
Entry
Reagent
Time (min)
Temp
Yield (%)
1
2
3
4
5
6
K2CO3 / TBAB/ CH3CN
K2CO3 / TBAB/ CHCl3
K2CO3 / TBAB/ DMF
K2CO3 / TBAB/ MeOH
K2CO3 / TBAB/ Ethylacetate
TBAB/ CH3CN
15-30
120
60
RT
RT
RT
RT
RT
RT
90-96
75-80
63-68
NIL
240
180
300
45-50
NIL
washed with water and dried to obtain crude 3 which on
recrystallization from hot ethyl acetate gave pure 3.
indole ring), 7.45-7.47 (m, 1H, aryl proton of the indole
ring), 8.17-8.30 (m, 2H, one is aryl proton of the indole ring
and one is ꢀ-proton of the indole ring), 11.93 (br s, 1H, D2O
exchangeable -NH); C13- NMR (DMSO-d6 /TMS): ꢀ 27.6,
112.5, 117.3, 121.8, 122.1, 123.1, 125.7, 134.7 and 137.1
and 193.1; MS m/z = 160 (M+. +1); Anal. Calcd. for
C10H9NO (159.06): C, 75.45 %; H, 5.70 %. Found: C, 75.47
%; H, 5.71 %.
Alternative General Method for the Preparation of 3
from 4
A mixture of 5% aq. NaOH (20 ml) and 4 (10 mM) was
refluxed for 2-2.5h. At the end of this period, the solid was
separated from the reaction mixture. The separated solid was
filtered, washed with water and dried to obtain the crude 3
which on recrystallization from hot ethyl acetate obtained
pure 3.
3b: Colourless solid; Yield = 1.70 (90%); m.p. 210 ˚C;
IR(KBr): 3172 cm-1 (broad, medium, –NH ) and 1640 cm-1
1
(strong, sharp –CO); H- NMR (DMSO-d6/TMS): ꢀ 2.41 (s,
3H, -CH3), 3.75 (s, 3H, -OCH3), 6.82 (q, J = 2.5 Hz, 1H),
7.34 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 8.23 (s,
1H, ꢀ-proton of the indole ring), 11.79 (br, 1H, D2O-
exchangeable -NH); MS m/z = 190(M+. +1); Anal. Calcd. for
3a: Colorless solid; Yield = 1.52 gms (96%); m.p. 186-
189 ˚C; IR (KBr): 3162 cm-1 (broad, medium, –NH) and
1
1631 cm-1 (strong, sharp, –CO); H- NMR (DMSO-d6/TMS)
ꢀ 2.48 (s, 3H, -CH3), 7.14-7.21(m, 2H aryl protons of the

660 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Venkatanarayana and Dubey
C11H11NO2 (189.21): C, 69.83 %; H, 5.86 %. Found: 69.79
%; H, 5.84 %.
1H), ꢀ 7.5-7.54 (m, 1H), 7.99-8.01 (m, 1H), 8.20-8.23 (m,
1H), 11.79 (br s, 1H, D2O-exchangeable -NH ); MS m/z =
233 (M+. +1); Anal. Calcd. for C12H12N2O3 (232.01): C,
62.06 %; H, 5.21 %. Found: C, 62.09 %; H, 5.24 %.
3c: Colourless solid; Yield = 1.73 gms (92%); m.p. 214-
215˚C; IR(KBr): 3162 cm-1 (broad, medium, –NH ) and 1629
1
cm-1 (sharp, strong –CO); H- NMR (DMSO-d6/TMS): ꢀ
4d: Brick red solid; Yield = 2.57 gms (92%); m.p. 208-
210 ˚C; IR(KBr): 3226 cm-1 (broad, medium, –NH), 1603cm-
2.42 (s, 3H, -CH3), 3.78 (s, 3H, -OCH3), 6.81- (q, J = 2 Hz,
1H), 6.94 (d, J = 2 Hz, 1H), 8.01-8.03 (d, J = 8.8 Hz, 1H),
8.17 (s, 1H, ꢀ-proton of the indole ring), 11.71 (br, 1H, D2O-
exchangeable -NH); MS m/z = 190(M+. +1); Anal. Calcd. for
C11H11NO2 (189.21): C, 69.83 %; H, 5.86 %. Found: 69.79
%; H, 5.84 %.
(sharp, strong, -CO) and 1522cm-1 (sharp, strong, -
1
1
CONH2); H- NMR (DMSO-d6/TMS): ꢀ 3.68 (s, 2H, -CH2),
7.35 (b r s, 1H), 7.42 (br s, 1H), 7.44 (m, 1H), 7.46-7.54 (m,
1H), 8.29-8.35-8 (m, 1H), 8.35 (m, 1H), 12.19 (br s, 1H,
D2O-exchangeable -NH); MS m/z = 281 (M+. +1); Anal.
Calcd. for C11H9BrN2O2 (280.01): C, 47.00 %; H, 3.23 %.
Found: C, 47.02 %; H, 3.24 %.
3d: Colourless solid; Yield = 2.37 gms (94%); m.p.
248˚C; IR(KBr): 3212 cm-1 (broad, medium, –NH ) and 1636
1
cm-1 (sharp, strong, –CO); H- NMR (DMSO-d6/TMS): ꢀ
4e: light yellow solid; 2.34 (95%); m.p. 240-42 ˚C;
IR(KBr): 3276 cm-1 (broad, medium, –NH), 1661 cm-1
(sharp, strong, -CO) and 1601 cm-1 (sharp, strong, –CONH2);
1H- NMR (DMSO-d6/TMS): ꢀ 3.60-3.64 (s, 2H, -CH2), 7.18-
7.21 (br, s, 1H), 7.34 (br, s, 1H), 7.48-7.50 (m, 2H), 7.52-
7.56 (m, 1H), 8.20-8.22 (m, 1H), (m, 1H), ꢀ 12.29 (br, s, 1H,
D2O-exchangeable -NH); MS m/z = 248 (M+. +1); Anal.
Calcd. for C11H9N3O4 (247.02): C, 53.44 %; H, 3.67 %.
Found: C, 53.42 %; H, 3.69 %.
2.47 (s, 3H, -CH3), 7.14-7.21 (m, 2H), 7.46 (d, J = 7.1 Hz,
1H), 8.18-8.29 (m 2H), 11.92 (br, 1H, D2O-exchangeable -
NH); MS m/z = 238(M+. +1); Anal. Calcd. for C10H8BrNO
(236.99): C, 50.45 %; H, 3.39 %. Found: C, 50.47 %; H,
3.41 %.
3e: Light yellow solid; Yield = 1.93 gms (95%); m.p.
>260˚C; IR(KBr): 3231 cm-1 (broad, medium, –NH ) and
1641 cm-1 (sharp, strong, –CO); 1H- NMR (DMSO-d6/TMS):
ꢀ 2.48 (s, 3H, -CH3), 7.63 (d, J = 8.9, 1H), 8.07 (m, J = 2.0
Hz, 1H), 8.55 (s, 1H), 8.99 (s, 1H, ꢀ-Proton of the indole
ring) 12.4 (br, 1H, D2O-exchangeable -NH); MS m/z =
205(M+. +1); Anal. Calcd. for C10H8N2O3 (204.04): C,
58.82%; H, 3.95 %. Found: C, 58.79 %; H, 3.98 %.
General Procedure for the Preparation of 5 from 3
A mixture of CH3CN (20 ml), K2CO3 (2.07 gms, 15
mM), catalytic amount of TBAB (ꢁ40 mg), 3 (10 mM) and
alkylating agent (12 mM) was stirred at room temperature
for 20-30 min. At the end of this period, the mixture was
poured into water (ꢁ 100 ml). The separated solid was
filtered, washed with water and dried to obtain the crude
product which on recrystallization from hot ethyl acetate
gave pure desired N-substituted-3-acetylindoles.
General Procedure for the Preparation of 4 from 2
2 (10mM) was added to PPA (15mL), and the resulting
mixture was heated at 100 ˚C for 1 h, and then poured on to
ice (ꢁ100 gms). The precipitate formed was collected by
filtration and washed with water to afford 4. The crude
product obtained above was recrystallized from methanol to
give pure 4 as a solid.
5a: Colourless solid; Yield = 1.62 gms (94%); m.p. 96˚C;
IR(KBr): 1639cm-1 (sharp, strong, –CO); 1H- NMR (DMSO-
d6/TMS): ꢀ 2.23-2.45 (s, 3H, -CH3), 3.86 (s, 3H, N-CH3),
7.18-26 (m, 2H), 7.47-7.49 (m, 1H), 8.14-8.16 (m, 1H),
8.24-8.25 (s, 1H, ꢀ-proton of the indole ring); MS m/z =
174(M+. +1); Anal. Calcd. for C11H11NO (173.08); C, 76.28
%; H, 6.40 %. Found: C, 76.26 %; H, 6.38 %.
4a: Light brown colour solid; Yield = 1.83 gms (91%);
m.p. 207 ˚C; IR(KBr): 3192 cm-1 (broad, medium, –NH),
1645 cm-1 (sharp, strong, –CO) and 1606 cm-1 (strong, sharp,
–CONH2); 1H- NMR (DMSO-d6/TMS): ꢀ 3.64-3.67 (s, 2H, -
CH2), ꢀ 7.04 (b r s, 1H), ꢀ 7.17-7.22 (m, 2H), ꢀ 7.45-7.47 (m,
1H), ꢀ 7.53 (br s, 1H), ꢀ 8.14-8.16 (m, 1H), ꢀ 8.33 (m, 1H), ꢀ
12.02 (br s, 1H, D2O-exchangeable -NH); MS m/z 203 (M+.
+1) Anal. Calcd. for C11H10N2O2 (202.05): C, 65.34 %; H,
4.98 %. Found. C, 65.32 %; H, 4.99 %.
5b: Colourless solid; Yield = 1.84 gms (91%); m.p. 158-
1
160 ˚C; IR(KBr): 1633 cm-1 (sharp, strong, –CO); H- NMR
(DMSO-d6/TMS): ꢀ 2.44 (s, 3H, -CH3), 3.73 (s, 3H, -OCH3),
3.91 (s, 3H, -N-CH3), 6.81 (q, J = 2.5 Hz, 1H), 7.34 (d, J =
8.6 Hz, 1H), 7.66-7.67 (d, J = 2.5 Hz, 1H), 8.24 (s, 1H, ꢀ-
proton of the indole ring); MS m/z = 204(M+. +1); Anal.
Calcd. for C12H13NO2 (203.06): C, 70.92 %; H, 6.45 %.
Found: C, 70.98 %; H, 6.47 %.
4b: Grey coloured solid; Yield = 2.18 gms (94%); m.p.
139 ˚C; IR(KBr): 3194cm-1 (broad, medium, –NH), 1619cm-
(sharp, strong, –CO) and 1519cm-1 (strong, –CONH2); H-
1
1
NMR (DMSO-d6/TMS): ꢀ 3.65 (s, 2H, -CH2 ), 3.78 (s, 3H, -
OCH3 ), 7.01 (br s, 1H), 7.21 (br s, 1H), 7.45 (m, 1H), 7.5-
7.57 (m, 1H), 7.99-8.06 (m, 1H), ꢀ 8.22-8.24 (m, 1H), 11.89
(br s, 1H, D2O-exchangeable -NH ); MS m/z = 233 (M+. +1);
Anal. Calcd. for C12H12N2O3 (232.01): C, 62.06 %; H, 5.21
%. Found: C, 62.09 %; H, 5.24 %.
5c: Colourless solid; Yield = 1.82 gms (90%); m.p. 162-
163 ˚C; IR(KBr): 1631 cm-1 ( sharp, strong, –CO); 1H- NMR
(DMSO-d6/TMS): ꢀ 2.41 (s, 3H, -CH3), 3.71 (s, 3H, -OCH3),
3.94 (s, 1H, -N-CH3), 6.8 (q, J = 2.1 Hz, 1H), 6.93 (d, J = 2.1
Hz, 1H), 8.01-8.02 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H, ꢀ-proton
of the indole ring); MS m/z = 204 (M+. +1); Anal. Calcd. for
C12H13NO2 (203.06): C, 70.92 %; H, 6.45 %. Found: C,
70.98 %; H, 6.47 %.
4c: Off white solid; Yield = 2.06 gms (89%); m.p. 230-
232 ˚C; IR(KBr): 3120 cm-1 (broad, medium, –NH), 1601cm-
1
(sharp, strong, –CO) and 1516 cm-1 (sharp, strong, –
5d: Colourless solid; Yield = 2.29 gms (91%); m.p. 170-
CONH2); 1H- NMR (DMSO-d6/TMS): ꢀ 3.64 (s, 2H, -CH2 ),
3.9 (s, 3H, -OCH3), 6.81 (b r s, 1H), 6.94 (br s, 1H), 7.01 (m,
172˚C; IR(KBr): 1634 cm-1 (sharp, strong, –CO); H- NMR
1
(DMSO-d6/TMS): ꢀ 2.48 (s, 3H, -CH3), 7.13-7.21 (m, 2H),

Novel and Simple Methodology for the Synthesis of 3-Acetylindoles
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
661
7.46-7.47 (d, J = 7.3 Hz, 1H), 8.18-8.23 (m 2H); MS m/z =
253(M+. +1); Anal. Calcd. for C11H10BrNO (252.01): C,
52.41 %; H, 4.00 %. Found: C, 52.40 %; H, 4.02 %.
5l: Colourless solid; Yield = 2.51 gms (90%); m.p.
123˚C; IR(KBr): 1614 cm-1 (sharp, strong, -CO); 1H- NMR
(DMSO-d6/TMS): ꢀ 2.44 (s, 3H, -CH3), 3.72 (s, 3H, O-CH3),
5.40 (s, 2H, N-CH2), 7.23-8.23 (m, 9H, four aryl protons of
the indole ring + five aromatic protons), 8.51 (s, 1H, ꢀ-
proton of the indole ring); MS m/z = 280 (M+. +1); Anal.
Calcd. for C18H17NO2 (279.10): C, 77.40 %; H, 6.13 %.
Found: C, 77.42 %; H, 6.14 %.
5e: Yellow solid; Yield = 2.08 gms (95%); m.p. 224˚C;
IR(KBr): 1644 cm-1 (sharp, strong, –CO); 1H- NMR
(DMSO-d6/TMS): ꢀ 2.49 (s, 3H, -CH3), 4.01 (s, 3H, -N-
CH3) 7.62 (d, J = 8.7, 1H), 8.06 (m, J = 2.0 Hz, 1H), 8.52 (s,
1H), 8.94 (s, 1H, ꢀ-Proton of the indole ring); MS m/z =
220(M+. +1); Anal. Calcd. for C11H10N2O3 (219.14): C, 60.55
%; H, 4.62 %. Found: C, 60.48 %; H, 4.64 %.
5m: Colourless solid; Yield = 2.53 gms (91%); m.p. 142
1
˚C; IR(KBr): 1625 cm-1 ( sharp, strong, –CO); H- NMR
(DMSO-d6/TMS): ꢀ 2.47 (s, 3H, -CH3), 3.64 (s, 3H, -OCH3),
5.10 (s, 2H, N-CH2), 7.23-8.12 (m, 9H, four aryl protons of
the indole ring + five aromatic protons) 8.49 (s, 1H, ꢀ-proton
of the indole ring); MS m/z = 280 (M+. +1); Anal. Calcd. for
C18H17NO2 (279.10): C, 77.40; H, 6.13. Found: C, 77.42 %;
H, 6.14 %.
5f: Colourless solid; Yield = 1.72 gms (92%); m.p. 80˚C;
IR(KBr): 1634 cm-1 (Sharp, strong, –CO); 1H- NMR
(DMSO-d6/TMS): ꢀ 1.41 (t, J = 7.22, 3H, -CH3), 4.26 (q, J =
7.2, 2H, -CH2), 7.18-8.19 (m, 4H, aryl protons of the indole
ring), 8.81 (s, 1H, ꢀ-proton of the indole ring); MS m/z =
186(M-1); Anal. Calcd. for C12H13NO (187.21): C, 76.98 %;
H, 7.00 %. Found: C, 76.96 %; H, 6.99 %.
5n: Colourless solid; Yield = 3.09 gms (95%); m.p.
118˚C; IR(KBr): 1646 cm-1 ( sharp, strong, –CO); 1H- NMR
(DMSO-d6/TMS): ꢀ 2.37 (s, 3H, -CH3), 5.43 (s, 2H, N-CH2),
7.33-8.31 (m, 9H, four aryl protons of the indole ring + five
aromatic protons) 8.53 (s, 1H, ꢀ-proton of the indole ring);
MS m/z = 328 (M+. +1); Anal. Calcd. for C17H14BrNO
(327.01): C, 62.21 %; H, 4.30 %. Found: C, 62.19 %; H,
4.32 %.
5g: Colourless solid; Yield = 1.97 gms (90%); m.p. 80
1
˚C; IR(KBr): 1633 cm-1 ( sharp, strong, –CO); H- NMR
(DMSO-d6/TMS): ꢀ 1.42 (t, J = 7.1 Hz, 3H), 2.44 (s, 3H, -
CH3), 3.71 (s, 3H, -OCH3), 3.91 (s, 3H, -N-CH3), 4.3 (q, J =
7.1 Hz, 2H), 6.82 (q, J = 2.5 Hz, 1H), 7.36 (d, J = 8.6 Hz,
1H), 7.67-7.68 (d, J = 2.5 Hz, 1H), 8.26 (s, 1H, ꢀ-proton of
the indole ring); MS m/z = 218 (M+. +1); Anal. Calcd. for
C13H15NO2 (217.10): C, 71.87 %; H, 6.96 %. Found: C,
71.90 %; H, 6.99 %.
5o: Light yellow solid; Yield = 2.82 gms (96%); m.p.
1
180-182˚C; IR(KBr): 1643 cm-1 (sharp, strong, –CO); H-
NMR (DMSO-d6/TMS): ꢀ 2.67 (s, 3H, -CH3), 5.56 (s, 2H,
N-CH2), 7.31-8.36 (m, 9H, four aryl protons of the indole
ring + five aromatic protons) 8.61 (s, 1H, ꢀ-proton of the
indole ring); MS m/z = 295 (M+. +1); Anal. Calcd. for
C17H14N2O (294): C, 69.38 %; H, 4.79 %. Found: C, 69.44
%; H, 4.81 %.
5h: Colourless solid; Yield = 1.99 gms (92%); m.p. 125-
1
126˚C; IR(KBr): 1630 cm-1 (sharp, strong, –CO); H- NMR
(DMSO-d6/TMS): ꢀ 1.30 (t, J = 7.0 Hz, 3H), 2.42 (s, 3H, -
CH3), 3.61 (s, 3H, -OCH3), 3.94 (s, 1H, -N-CH3), 4.2 (q, J =
7.0 Hz, 2H), 6.6 (q, J = 2.2 Hz, 1H), 6.94 (d, J = 2.2 Hz, 1H),
8.04 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H, ꢀ-proton of the indole
ring); MS m/z = 218 (M+. +1); Anal. Calcd. for C13H15NO2
(217.10): C, 71.87 %; H, 6.96 %. Found: C, 71.90 %; H,
6.99 %.
5p: Colourless solid; Yield = 2.93 gms (98%); m.p: >
245 ˚C; IR(KBr) 1688 cm-1 (sharp, strong, –CO), and a
strong unequal doublet at 1170 and 1140 cm-1 (due to –SO2);
1H- NMR (DMSO-d6/TMS): ꢀ 2.4-2.5(s, 3H, -CH3), 7.31-
8.17(m, 9H, five phenyl an+ four aryl protons of the indole
ring), 8.8 (s, 1H, ꢀ-proton of the indole ring); MS m/z: 300
(M+. +1); Anal. Calcd. for C16H13NO3S (299.02): C, 64.20
%; H, 4.38 %. Found: C, 64.18 %; H, 4.37 %.
5i: Grey coloured solid; Yield = 2.49 gms (94%); m.p.
1
126˚C; IR(KBr): 1633 cm-1 (sharp, strong, –CO); H- NMR
(DMSO-d6/TMS): ꢀ 1.27 (t, J = 7.1 Hz, 3H), 2.46 (s, 3H, -
CH3), 4.31 (q, j = 7.1 Hz, 2H), 7.12-7.19 (m, 2H), 7.45-7.47
(m 1H), 8.19-8.24 (m, 2H, one is ꢀ-proton of the indole ring
+ one is aryl proton of the indole ring); MS m/z = 266 (M+.
+1) Anal. Calcd. for C12H12BrNO (265.00): C, 54.16 %; H,
4.54 %. Found: C, 54.13 %; H, 4.56 %.
5q: Grey coloured solid; Yield = 3.09 games (94%); m.p.
> 280 ˚C; IR (KBr) 1691 cm-1 (sharp, strong, –CO), and a
strong unequal doublet at 1169 and 1114 cm-1 (due to –SO2);
1H- NMR (DMSO-d6/TMS): ꢀ 2.62 (s, 3H, -CH3), 3.76 (s,
3H, -OCH3), 7.36-8.21 (m, 8H, five phenyl + three aryl
protons of the indole ring), 8.73 (s, 1H, ꢀ-proton of the
indole ring); MS m/z: 330 (M+. +1); Anal. Calcd. For
C17H15NO4S (329.02): C, 61.99 %; H, 4.59 %. Found: C,
62.01 %; H, 5.00 %.
5j: Light yellow solid; Yield = 2.22 gms (96%); m.p.
1
217-218˚C; IR(KBr): 1641 cm-1 ( sharp, strong, –CO); H-
NMR (DMSO-d6/TMS): ꢀ 1.30 (t, J = 7.1 Hz, 3H), 2.47 (s,
3H, -CH3), 4.43 (q, J = 7.1 Hz, 2H), 7.62 (m, 1H), 8.07 (m,
1H), 8.32 (s, 1H), 8.99 (s, 1H, ꢀ-Proton of the indole ring);
MS m/z = 233 (M+. +1); Anal. Calcd. for C12H12N2O3
(232.08): C, 62.06 %; H, 5.21 %. Found: C, 62.04 %; H,
5.19 %.
5r: Colourless solid; Yield = 3.02 gms (92%); m.p. 199-
200 ˚C; IR (KBr) 1696 cm-1 (sharp, strong, –CO), and a
strong unequal doublet at 1170 and 1116 cm-1 (due to –SO2);
1H- NMR (DMSO-d6/TMS): ꢀ 2.62 (s, 3H, -CH3), 3.74 (s,
3H, -OCH3), 7.30-8.19 (m, 8H, five phenyl + three aryl
protons of the indole ring), 8.70 (s, 1H, ꢀ-proton of the
indole ring); MS m/z: 330 (M+. +1); Anal. Calcd. for
C17H15NO4S (329.02): C, 61.99 %; H, 4.59 %. Found: C,
62.01 %; H, 5.00 %.
5k: Colourless solid; Yield = 2.29 gms (92%); m.p. 80
˚C; IR(KBr): 1614 cm-1 (sharp, strong, –CO); 1H- NMR
(DMSO-d6/TMS): ꢀ 2.45 (s, 3H, -CH3), 5.42-5.46 (s, 2H, N-
CH2), 7.2-8.2 (m, 9H, four aryl protons of the indole ring +
five aromatic protons), 8.58-8.60 (s, 1H, ꢀ-proton of the
indole ring); MS m/z= 250(M+. +1); Anal. Calcd. for
C17H15NO (249.11): C, 81.90 %; H, 6.06 %. Found: C, 81.93
%; H, 6.05 %.

662 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Venkatanarayana and Dubey
[9]
Okauchi, T.; Honaga, M.;Minami, T.; Owa, T.; Kiloh, K.; Yoshino,
H. A general method for acylation of indoles at the 3-position with
acyl chlorides in the presence of dialkylaluminum chloride. Org.
Lett., 2000, 2(10)1485-1487.
Keasling, H. H.; Willette, R. E.; Szmuszkovicz, J. The
anticonvulsant activity of 3-acetylindoes compared with
Phenobarbital. J. Med. Chem., 1964, 7, 94-96.
Sundberg, R. J. The Chemistry of Indoles; Academic Press:
NewYork, 1970. 18, 1-489.
Bergman, J.; Venemalm, L. Acylation of the zinc salt of Indole.
Tetrahedron., 1990, 46(17), 6061-6066.
Yang, C.; Patel, H. H.; Ku, Y.; Shah R.; Sawick, D. The use of
Lewis acid in the reaction of zinc salts of indoles and acyl
chlorides. Synth. Commun., 1997, 27(12), 2125-2132.
Ketcha, D. M.; Gribble, G. W. . A Convenient synthesis of 3-
acylindoles via Friedel-Crafts acylation of 1-(Phenylsulfonyl)-
5s: Ash Coloured solid; Yield = 3.40 gms (94%); m.p. >
280 ˚C; IR (KBr) 1699 cm-1 (sharp, strong, –CO), and a
strong unequal doublet at 1174 and 1117 cm-1 (due to –SO2);
1H- NMR (DMSO-d6/TMS): ꢀ 2.60 (s, 3H, -CH3), 7.28-8.12
(m, 8H, five phenyl an+ three aryl protons of the indole
ring), 8.53 (s, 1H, ꢀ-proton of the indole ring); MS m/z: 378
(M+. +1); Anal. Calcd. for C16H12BrNO3S (376.98): C, 50.81
%; H, 3.20 %. Found: C, 50.79 %; H, 3.22 %.
[10]
[11]
[12]
[13]
5t: Light yellow solid; Yield = 3.09 gms (90%); m.p. 212
˚C; IR (KBr) 1695 cm-1 (sharp, strong, –CO), and a strong
1
unequal doublet at 1170 and 1114 cm-1 (due to –SO2); H-
[14]
NMR (DMSO-d6/TMS): ꢀ 2.63 (s, 3H, -CH3), 7.19-8.19 (m,
8H, five phenyl an+ three aryl protons of the indole ring),
8.60 (s, 1H, ꢀ-proton of the indole ring); MS m/z: 345 (M+.
+1); Anal. Calcd. for C16H12N2O5S (344.01): C, 55.81 %; H,
3.51 %; C, 55.83 %; H, 3.53 %.
indole.
A new route to pyridocarbazole-5, 11-quinones and
ellipticine. J. Org. Chem., 1985, 50(26), 5451-5457.
[15]
[16]
[17]
Eyley, S. C.; Giles, R. G.; Heaney, H. The formation of acylimino-
derivatives of indoles and pyrroles by reactions with nitrilium salts.
Tetrahedron Lett., 1985, 26(38), 4649-4652.
Pfeuffer, L.; Sody, E.; Pindur, U. Preparation of 3-acylindoles.
Triethyl orthoacetate and trimethyl orthobenzoate as effective
acylating agents . Chem,. Zeitung. 1987, 11(2), 84.
Pindur, U.; Flo, C.; Akgun, E.; Tunali, M. Reactions of electron-
rich heterocycles with ortho carboxylic acid derivatives. Acylation
of indole and methylindoles with dialkoxycarbenium
tetrafluoroborates Liebigs Ann. Chem., 1986, 9, 1621-1627.
Bergman, J.; Ba¨ckvall, J. E.; Lindstro¨n, J. O. Synthesis and
reactions of some 3-(2-haloacyl)indoles. Tetrahedron,. 1973, 29(7),
971-976.
Kamal, A.; Qureshi, A. A. Syntheses of substituted
diindolylmethanes in aqueous medium at room temperature.
Tetrahedron., 1963, 19. 513-520.
Shner, V. F.; Sladkova, T. N.; Turchin, K. F.; Suvorov, N. N.
Syntheses of substituted diindolylmethanes in aqueous medium at
room temperature. Geterotsikl. Soedin., 1989, 3, 328-330.
Watanabe T.; Kobayashi A.; Nishiura, M.; Takahashi, H.; Usui, T.;
Kamiyama, I.; Mochizukin, N.; Noritake, K.; Yokoama, Y.;
Murakami, Y. Synthetic studies on indoles and related compounds.
XXVI. The debenzylation of protected indole nitrogen with
aluminum chloride. Chem. Pharm. Bull., 1991, 39(5), 1152-1156.
Degraw, J. I.; Kennedy, J. G.; Skinner, W. A. preparation and
reduction of 5-cyano-3-indolyl ketones. Synthesis of 5-
cyanotryptamines. J. Heterocycl. Chem., 1966, 3(1), 9-13.
Murakami, Y.; Tani, M.; Suzuki, M.; Sudoh, K.; Uesato, M.;
Tanaka, K.; Yokoyama, Y. Synthetic studies on indoles and related
compounds. XII. A simple general method for the C-3 acylation of
ethyl indole-2-carboxylates. Chem. Pharm. Bull., 1985, 33(11),
4707-4716.
Takushi, K.; Toshiro, F.; Shinya, H.; Ryuuji, Y. Simple N-
alkylation and N-acylation of 3-acetylindole and 3-
Indolecarboxaldehyde. Synthesis. 1987, 4, 396-397.
Nickisch, K.; Klosee, W.; Bohlmann, F. N-Acctylation of
substituted pyrroles. Chem. Ber., 1980, 113, 2038-2039.
Olivia, O.; Amarilis de, V. F.; Neder, Ana K. B. Dias.; Rosimeire,
P. A.; Cruz, Ligia B. Acylation of Indole under FriedelꢁCrafts
Conditions an improved method to obtain 3-acylindoles
regioselectively. Org. Lett., 2001, 3(7), 1005-1007.
ACKNOWLEDGEMENTS
The authors are indebted to the authorities of Jawaharlal
Nehru Technological University Hyderabad for providing
laboratory facilities. They are also thankful to the authorities
of University Grants Commission, Govt. of India, New
Delhi, for providing financial support.
[18]
[19]
[20]
[21]
REFERENCES
[1]
[2]
[3]
Gribble, G.W. Recent developments in indole ring Synthesis-
methodology and applications. J. Chem. Soc. Perkin Trans 1,.
2000, 1045-1047.
Jeevanandam, A.; Srinivasan, P.C. Synthesis and cycloaddition of
2,4-dihydropyrrolo[3,4-b]indoles. J. Chem. Soc. Perkin Trans 1.,
1995, 20, 2663-2665.
(a) Gribble, G.W.; Keavy, D.J.; Davis, D.A.; Saulnier, M.G.;
Pelcman, B.; Barden, T.C.; Sibi, M.P.; Olson, E.R.; Belbruno, J.J.
Syntheses and Diels-Alder cycloaddition reactions of 4H-furo[3,4-
b]indoles. A regiospecific Diels-Alder synthesis of ellipticine. J.
Org. Chem., 1992, 57(22), 5878-5891. (b) Gribble, G.W.; Saulnier,
M.G.; Sibi, M.P.; Obaza-Nutiatits, J.A. Synthesis and Diels-Alder
reactions of 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole.
A new annulation strategy for the construction of ellipticine and
isoellipticine. J. Org Chem., 1984, 49(23), 4518-4523.
[22]
[23]
[4]
[5]
Markgraf, J.H.; Synder, S.A.; Vosburg, D.A. Intramolecular Hetero
Diels-Alder Routes to -Carboline Alkaloids. Tetrahedron., 2000,
56(30), 5329-5335.
[24]
Kost, A.N.; Mitropal’skaya, V.N.; Pornova, S.L.; Krasnova, V.A.
InCl3 and In(OTf)3 catalyzed reactions: synthesis of 3-acetyl
indoles, bis-indolylmethane and indolylquinoline derivatives. J.
Gen. Chem. USSR (English Transl)., 1964, 34, 3025-3028.
Dorofeenko, G.N.; Zh- Veses, K.;. Obshehestvaim, D.I. Simple
method for the preparation of some aromatic and heterocyclic
ketone .1960, 5, 354-355; Chem. Abstr., 1960, 54, 22563.
Yur’er, Y.K.; Elyakov, G.B.; Zh-Obshch, K. Tetraacyl hydroxy
silanes in organic synthesis.VI.Silicoanhydrides of monobasic
organic acids in synthesis of ketones of indole and pyrrole series.
1956, 26, 2350-2355. Chem. Abst., 1957, 51, 5042.
[25]
[26]
[6]
[7]
[27]
[28]
Tatsuo, Okauchi.; Masaaki, I.; Toru, M.; Takashi, O.; Kyosuke, K.;
Hiroshi, Y. Regiospecific C-acylation of pyrroles and indoles using
N-acylbenzotriazoles. Org. Lett., 2000, 9(2), 1485-1487.
Venkatanarayana, M.; Dubey, P.K. A facile cyanoacetylation of
indoles with cyanocetic acid and propionic anhydride. India J.of.
Chem. Sec-B., (Communicated).
[8]
Douglas, B.; Krikpatrick, J.L.; Moore, B.P.; Weisbach, J.A.
Alkaloids of Ochrosia poweri. II. The 2-acylindole stem-bark
bases. Aust. J. Chem., 1964, 17(2), 246-255.