A facile method for the synthesis of acetylcarbazoles and carbazole aldehydes

Article abstract of DOI:10.1081/SCC-120038488

Acetylation of 9-alkylcarbazoles with acetic anhydride catalyzed by PPh₃. HClO₄ was reported to give acetylcarbazoles. Carbazole aldehydes were easily synthesized by the Vilsmeier reaction of 9-alkylcarbazoles under microwave condition in good yields.

Full text of DOI:10.1081/SCC-120038488

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A Facile Method for the Synthesis of
Acetylcarbazoles and Carbazole Aldehydes
a
a
Rajagopal Nagarajan & Paramasivan T. Perumal
a
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai, 600
20, India
0
Published online: 17 Aug 2006.
To cite this article: Rajagopal Nagarajan & Paramasivan T. Perumal (2004) A Facile Method for the Synthesis of
Acetylcarbazoles and Carbazole Aldehydes, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 34:12, 2127-2133, DOI: 10.1081/SCC-120038488
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 12, pp. 2127–2133, 2004
A Facile Method for the Synthesis of
Acetylcarbazoles and Carbazole Aldehydes
*
Rajagopal Nagarajan and Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute,
Adyar, Chennai, India
ABSTRACT
Acetylation of 9-alkylcarbazoles with acetic anhydride catalyzed by
.
PPh3 HClO was reported to give acetylcarbazoles. Carbazole aldehydes
4
were easily synthesized by the Vilsmeier reaction of 9-alkylcarbazoles
under microwave condition in good yields.
Key Words: Carbazoles; Acetylation; Acetylcarbazoles; Vilsmeier
reagent; Carbazole aldehydes.
[1]
The synthesis of substituted carbazoles has attracted considerable atten-
tion in recent years as this class of compounds constitutes structural frame-
works of several naturally occurring alkaloids which display a wide range
*
Correspondence: Paramasivan T. Perumal, Organic Chemistry Division, Central
Leather Research Institute, Adyar, Chennai 600 020, India; Fax: 91-44-24911589;
E-mail: ptperumal@hotmail.com.
2
127
DOI: 10.1081/SCC-120038488
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
2
128
Nagarajan and Perumal
of biological activities. Acetylcarbazoles were used as the useful synthon for
the synthesis of condensed carbazole heterocyles.
The acetylation of 9-ethylcarbazole with acetyl chloride catalyzed
by AlCl had been reported to give the mixture of 3- and 3,6-diacetyl
3
[
2]
derivatives
acidity of AlCl . In continuation of our research on triphenyl phosphonium
and large amount of tarry products due to high Lewis
3
[
perchlorate, it was of our interest to carry out the acetylation of carbazoles
3]
.
catalyzed by PPh3 HClO , since PPh HClO4 is known to be efficient
.
4
3
catalyst for organic reactions.
The reaction was performed by addition of 20 mol% of PPh3 HClO to
.
4
a stirred solution of 9-ethylcarbazole in excess acetic anhydride for 2 hr.
Examination of the TLC shows only 3-acetylated product and there is no
diacetylated carbazole formed during the acetylation. There is not much
.
tarry products formed when PPh3 HClO was used as a catalyst. PPh HClO4
.
4
3
is found to be better over other catalysts because it is mild, inexpensive,
requires shorter reaction times, and 3-acetylated carbazole was only the
product. The results of acetylation of other substituted carbazoles catalyzed
.
by PPh3 HClO were given in Sch. 1 and Table 1.
4
.
To prove the generality of PPh3 HClO , the acylation was carried out
4
with other anhydrides such as benzoic anhydride and propionic anhydride.
The reaction of 9-ethylcarbazole with benzoic anhydride in CH Cl catalyzed
2
2
.
by PPh3 HClO (20 mol%) for 3 hr yielded the 3-benzoylcarbazole in 34%
4
yield. However, the reaction of 9-ethylcarbazole with propionic anhydride
proceeded for 1.5 hr and gave mainly 3,6-propionyl-9-ethylcarbazole (49%)
as the major product together with 3-propionylcarbazole (22%). The acylation
of carbazoles with acid chlorides results in the formation of large amount of
tarry products and lesser yields of the 3-acylcarbazoles due to the formation
of HCl as the side product.
Carbazole aldehydes occur in nature as alkaloids, namely, Mukonal,
Murrayanine, Heptaphylline, Murrayacine, which exhibit wide range of bio-
[
1]
logical activities. They also serve as a synthon for the synthesis of pyrido-
carbazole alkaloids, such as ellipticine, 9-methoxy ellipticine and olivacine,
Scheme 1.

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Synthesis of Acetylcarbazoles and Carbazole Aldehydes
2129
.
Table 1. Synthesis of acetylcarbazoles with PPh
(
3
HClO
4
a
20 mol%).
Substituents
Time
(hr)
Yield
(%)
1
R
2
R
Carbazole
1a
1b
1c
CH3
H
H
2.0
2.0
2.5
56
61
59
C
C
2
H
H
5
2
5
CH
3
a
The yield is based on isolation by column chromatography and
the products were characterized by IR, NMR, and mass spectra.
which exhibit pronounced anti-cancer activity in several animal and human
[
4a]
tumor systems,
cancer, and other solid tumors.
in treatment of myleoblastic leukemia, advanced breast
[4]
[5]
In continuation of our research on Vilsmeier reaction, we herein report
the synthesis of carbazole aldehydes through Vilsmeier reaction under micro-
wave irradiation. The procedure offers advantages such as better yields and
easier reaction conditions. The reaction is complete within a few minutes.
To a stirred solution of 9-ethylcarbazole in DMF under ice-cold condi-
tion, POCl was added. When the addition is over, the reaction is brought
3
to room temperature and irradiated in microwave oven with low power
(
30%) for 1.5 min (with a time intervals of 30 sec). After work up, the crude
product is purified by column chromatography and eluted with ethyl acetate–
petroleum ether to give 9-ethylcarbazole-3-aldehyde in 89% yield (Sch. 2).
The results with other substituted carbazoles are given in Table 2.
In conventional method, N-methylformanilide was used instead of DMF
and o-dichlorobenzene as the solvent in water bath temperature for longer
reaction time. Steam distillation is necessary to remove the side product
N-methylaniline as well as solvent o-dichlorobenzene and the product was
purified through vacuum distillation. However, the microwave accelerated
Scheme 2.

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2
130
Nagarajan and Perumal
Table 2. Synthesis of carbazoles aldehydes.
Substituents
Time of
irradiation
(min)
1
2
Carbazole
R
R
Yield (%)
a [6]
a [6]
1
1
1
1
a
b
c
CH
C H
3
H
1.5 (360)
1.5 (240)
2.0
82 (61)
89
a [7]
H
2
5
5
5
a [7]
C
C
2
H
H
CH
Br
3
90 (60)
87
a [7]
1.8 (240)
d
2
a
Yield reported in the literature.
formylation of 9-alkylcarbazoles with DMF and POCl proceeds nearly giving
3
higher yields of the products in few minutes and pure product was obtained
by recrystallization from the crude product (ethyl acetate : petroleum ether
mixture).
In conclusion we have shown the efficient method for the synthesis of
acetylcarbazoles by acetylation of carbazoles with acetic anhydride catalyzed
.
by PPh3 HClO . Carbazole aldehydes were easily synthesized by the reaction
of 9-alkylcarbazoles with Vilsmeier reagent in good yields.
4
PROCEDURE FOR ACETYLATION
To a stirred mixture of carbazoles (0.5 g, 1 eq.) and acetic anhydride
.
3 eq.) in CH Cl (10 mL), PPh HClO (20 mol%) was added and stirred
2 2 3 4
(
for appropriate time. Water (50 mL) was added to the reaction mixture,
extracted with CH Cl (3 ꢀ 10 mL), and dried with anhydrous Na SO . The
2
2
2
4
solvent was distilled off and the residue was chromatographed over silica
gel, eluted with ethyl acetate : petroleum ether mixture (1 : 9) to give the acetyl
carbazoles.
3
-Acetyl-9-ethylcarbazole (2b). Colorless needles of 0.371 g (61%);
[
2]
m.p. 115–1168C (Lit. 115); IR: 3046, 2921, 1667, 1593, 1495, 1351,
2
1 1
1
8
1
1
1
5
170, 838 cm ; H NMR (300 MHz, CDCl ): d 8.75 (d, 1H, J ¼ 1.2 Hz),
3
.18 (m, 2H), 7.50 (t, 1H), 7.46–7.26 (m, 3H), 4.42 (q, 2H); 2.73 (s, 3H),
1
.46 (t, 3H); C NMR (75 MHz, CDCl ): d 197.2, 142.2, 140.2, 128.3,
3
3
26.0, 122.8, 122.2, 121.4, 120.2, 119.5, 108.5, 107.6, 107.4, 37.3, 26.1,
þ
3.3; Mass m/z 237 (M ); Anal. calcd for C H NO: C, 80.98; H, 6.37; N,
1
6 15
.90; Found: C, 81.22; H, 6.48; N, 6.76.
-Methyl-6-acetyl-9-ethylcarbazole (2c). Colorless crystals of 0.354 g
59%); m.p. 90–918C; IR: 3049, 2976, 2922, 1629, 1667, 1596, 1448,
3
(
2
1
1
1
353, 1302, 1244, 1161, 804 cm ; H NMR (300 MHz, CDCl ): d 8.70
3

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Synthesis of Acetylcarbazoles and Carbazole Aldehydes
2131
(
(
(
d, 1H, J ¼ 1.2 Hz), 8.11 (dd, 1H, J ¼ 1.5 Hz, J ¼ 8.4 Hz), 7.95 (s, 1H), 7.37
1
2
1
m, 3H), 4.37 (q, 2H), 2.71 (s, 3H), 2.55 (s, 3H), 1.42 (t, 3H); C NMR
3
75 MHz, CDCl ): d 198.1, 143.3, 139.3, 129.8, 128.9, 128.1, 126.6, 123.8,
3
1
22.9, 122.3, 121.1, 109.1, 108.3, 38.2, 27.1, 21.8, 14.2; Mass m/z 251
þ
(
M ); Anal. calcd for C H NO: C, 81.24; H, 6.82; N, 5.57; Found: C,
1
7 17
81.54; H, 6.79; N, 5.36.
GENERAL PROCEDURE FOR THE VILSMEIER
REACTION
To a stirred mixture of 9-alkyl carbazole (0.5 g, 1 eq.) in DMF (7 mL)
under ice-cold condition, POCl (3 eq.) was added and then brought to room
3
temperature. The reaction mixture was then irradiated in MW oven (30%
power) for appropriate time. The reaction mixture was then poured onto
crushed ice, neutralized with Na CO solution (saturated), and extracted
2
3
with CHCl (3 ꢀ 10 mL). The organic layer is separated, dried with anhydrous
3
Na SO , and distilled under reduced pressure. The residue was recrystallized
4
2
from ethyl acetate : petroleum ether mixture (2 : 8).
-Ethylcarbazole-3-aldehyde (3b). Colorless crystalline solid of
9
[7]
0
.526 g (89%); m.p. 94–958C (Lit. 94); IR: 3051, 2970, 2820, 1674,
21 1
384, 769 cm ; H NMR (300 MHz, CDCl ): d 10.07 (s, 1H, CHO), 8.56
1
3
(
s, 1H), 8.14 (d, 1H, J ¼ 7.8 Hz), 8.00 (dd, 1H, J ¼ 1.5 Hz, J ¼ 8.6 Hz),
1
2
1
.56–7.29 (m, 4H), 4.38 (q, 2H), 1.44 (t, 3H); C NMR (75 MHz, CDCl ):
3
7
d 191.7, 143.4, 140.5, 128.3, 127.0, 126.6, 123.9, 122.9, 122.8, 120.6,
120.2, 109.0, 108.5, 37.8, 13.7; Mass m/z 223 (M ); Anal. calcd for
C H NO: C, 80.69; H, 5.87; N, 6.27; Found: C, 80.86; H, 5.79; N, 6.36.
3
þ
1
5 13
3
-Methyl-9-ethylcarbazole-6-aldehyde (3c). Colorless crystalline solid
[
7]
of 0.510 g (90%); m.p. 92–938C (Lit. 91); IR: 3018, 2973, 1681, 1597,
21 1
484, 1331, 811 cm ; H NMR (300 MHz, CDCl ): d 10.06 (s, 1H, CHO),
1
3
8
.56 (s, 1H), 7.99 (dd, 1H, J ¼ 1.5 Hz, J ¼ 8.6 Hz), 7.94 (s, 1H), 7.44
1
2
(
d, 1H, J ¼ 8.5 Hz), 7.34 (s, 2H), 4.39 (q, 2H), 2.55 (s, 3H), 1.44 (t, 3H);
1
3
C NMR (75 MHz, CDCl ): d 191.8, 143.6, 138.8, 129.7, 128.2, 127.9,
3
1
2
8
26.9, 124.0, 123.1, 122.9, 120.7, 108.8, 108.5, 38.9, 21.4, 13.8; Mass m/z
þ
37 (M ); Anal. calcd for C H NO: C, 80.98; H, 6.37; N, 5.90; Found: C,
1
6 15
0.76; H, 6.42; N, 5.76.
ACKNOWLEDGMENT
We thank the Council of Scientific and Industrial Research, New Delhi,
India for financial support.

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Nagarajan and Perumal
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Synthesis of Acetylcarbazoles and Carbazole Aldehydes
2133
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Received in India May 28, 2003

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