Microwave-assisted one-pot synthesis of 1,2,3,4-tetrahydrocarbazoles

Article abstract of DOI:10.1080/00397910600588330

A series of 1,2,3,4-tetrahydrocarbazoles 3a-m were synthesized by the reaction of substituted 2-bromocyclohexanones 2a-c with appropriate anilines 1a-i under microwave irradiation without any other catalysts. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600588330

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Microwave‐Assisted One‐Pot Synthesis of
1
,2,3,4‐Tetrahydrocarbazoles
a a
Jing Chen & Yongzhou Hu
a
Department of Medicinal Chemistry, School of Pharmaceutical Science, Zhejiang University,
Hangzhou, China
Published online: 21 Aug 2006.
To cite this article: Jing Chen & Yongzhou Hu (2006) Microwave‐Assisted One‐Pot Synthesis of 1,2,3,4‐Tetrahydrocarbazoles,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:11,
1485-1494
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Synthetic Communications , 36: 1485–1494, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600588330
Microwave-Assisted One-Pot Synthesis
of 1,2,3,4-Tetrahydrocarbazoles
Jing Chen and Yongzhou Hu
Department of Medicinal Chemistry, School of Pharmaceutical Science,
Zhejiang University, Hangzhou, China
Abstract: A series of 1,2,3,4-tetrahydrocarbazoles 3a–m were synthesized by the
reaction of substituted 2-bromocyclohexanones 2a–c with appropriate anilines 1a–i
under microwave irradiation without any other catalysts.
Keywords: Anilines, 2-bromocyclohexanones, microwave, 1,2,3,4-tetrahydrocarbazoles
Substituted 1,2,3,4-tetrahydrocarbazoles have been reported to possess many
[1]
biological properties, such as central nervous system activity, antihista-
[4]
[2]
[3]
mine, antidiabetic, and anti-inflammatory properties. Also, they are
important as intermediates for the production of pharmaceutically active
[
5,6]
compounds.
of this ring system, including the acid-induced Fischer indole synthesis from
There are a number of methods available for the construction
[
7]
arylhydrazines and cyclohexanones,
palladium-catalyzed coupling of
the Bartoli indole synthesis from
ortho-substituted nitro-aromatic compounds with vinylmagnesium
[
8]
o-haloanilines with cyclohexanone,
[
9]
bromide, Ruthenium complex–catalyzed synthesis from aminoarenes and
[
,2-cyclohexanediol,
hexanones and anilines.
10]
1
and the Bischler synthesis from a-halocyclo-
11]
Nevertheless, all of them have shortcomings,
[
such as trouble with operation, harsh conditions, difficulty in preparation of
Received in Japan September 13, 2005
Address correspondence to Yongzhou Hu, Department of Medicinal Chemistry,
School of Pharmaceutical Science, Zhejiang University, Hangzhou, China. E-mail:
huyz@zjuem.zju.edu.cn
1
485

1
486
J. Chen and Y. Hu
starting materials (arylhydrazines, which are sensitive to air), the need for
excess reagents (metal catalysts, acidic catalysts), and longer reaction times.
Among these methodologies, the Bischler synthesis applied to the preparation
[12]
of tetrahydrocarbazoles was a potentially attractive method for us. Ott
first
mentioned in 1923 that a-halocyclohexanones could be condensed with
aromatic amines to give arylaminocyclohexanones and then these could be
cyclized to the desired tetrahydrocarbazoles. Although the two-step
operation and lower yields limited its use in preparation of tetrahydrocarba-
zoles, the readily available starting materials made us interested in finding
new ways to improve this methodology.
In recent years, the application of microwave (MW) irradiation in organic
synthesis has been the focus of considerable attention and is becoming an
[13]
increasingly popular technology.
The prominent features of the
microwave approach are rapid reaction, clean reaction conditions, and ease
of manipulation. We report herein a microwave-assisted direct coupling of a
variety of anilines 1 with 2-bromocyclohexanones 2, leading to the
synthesis of 1,2,3,4-tetrahydrocarbazoles 3 without any other catalysts
(
Scheme 1).
RESULTS AND DISCUSSION
To study the microwave-assisted synthesis of 1,2,3,4-tetrahydrocarbazoles,
we investigated the reaction by choosing different solvents, such as toluene,
1,4-dioxane, ethanol, tert-butanol, and 2-ethoxyethanol. The object products
cannot be obtained in the case of toluene. The reactions proceeded slowly,
and the yields were very low with a lot of uncyclized intermediates in
ethanol or tert-butanol. The yields also cannot be improved in 1,4-dioxane.
When the higher boiling solvent, 2-ethoxyethanol, was used the yields were
improved greatly.
Thus, 2-bromocyclohexanone 2a was treated with varying amounts of
aniline 1a in 2-ethoxyethanol under different conditions in a microwave
oven (Table 1). The results demonstrated that a microwave power of 325 W
was most appropriate. A higher microwave power increased the rate of
reaction, but the yields were decreased (entries 9–11). The yields were
markedly affected by the molar ratio of 1a to 2a. By increasing 1a from 1
Scheme 1.

Microwave-Assisted One-Pot Synthesis of 1,2,3,4-Tetrahydrocarbazoles
1487
Table 1. Microwave-assisted direct coupling 1a with 2a under various conditions
a
b
Entry
1a:2a
Power (W)
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
1:1
1:1
325
325
325
325
325
325
325
325
325
455
650
Toluene
1,4-Dioxane
10
10
10
10
10
10
10
10
10
8
—
25
20
11
34
44
51
66
84
81
62
1:1
1:1
Ethanol
tert-Butanol
1:1
2-Ethoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
1.5:1
2:1
2.5:1
3:1
1
1
0
1
3:1
3:1
5
a
b
Molar ratio of 1a to 2a.
Isolated yields.
equiv to 3 equiv, the yields would be corresponding improved (entries 5–9).
Therefore, the best condition was treating 1a (3 equiv) with 2a for
1
0 min using a microwave power of 325 W in 2-ethoxyethanol. The results
of the experiment are summarized in Table 2. Clearly, introducing
microwave irradiation to the Bischler synthesis would be of significant
benefit for the yields and reaction time. The reaction would also proceed
when 2-bromocyclohexanone was replaced with 2-bromocyclopentanone
2
d, but the yield was lower (entry 14). However, the reaction of aniline
with 4-tert-butyl-2-bromocyclohexanone 2b or 4-phenyl-2-bromocyclohexa-
none 2c led to a mixture of 2- and 3-substituted-1,2,3,4-tetrahydrocarbazoles
(
entries 10–13). The plausible mechanism of the reaction is showed in
Scheme 2.
In summary, we have explored an efficient one-pot route to synthesize a
series of 1,2,3,4-tetrahydrocarbazoles from easily available 2-bromocyclohex-
anones and substituted anilines under microwave-irradiation conditions
without any other catalysts. The simple procedure, mild reaction conditions,
and shorter reaction times render this method a valuable addition to tetrahy-
drocarbazole chemistry.
EXPERIMENTAL
Melting points were obtained on a B-540 B u´´ chi melting-point apparatus and
1
are uncorrected. H NMR spectra were recorded on a Brucker AM 400-
MHz spectrometer with SiMe as the internal standard in CDCl . Element
3
4
analyses were performed on a EA-1110 instrument. Infrared spectra were
recorded on a Bruck Vector 200 spectrophotometer.

1
488
J. Chen and Y. Hu
Table 2. Synthesis of 1,2,3,4-tetrahydrocarbazoles under microwave irradiation
a
2
b
Yield (%)
Entry
1
1
3
8
8
4
3
2
3
4
5
7
4
4
9
7
1
6
7
8
9
7
7
4
6
1
1
0
1
1
0
34
2
8
(
continued)

Microwave-Assisted One-Pot Synthesis of 1,2,3,4-Tetrahydrocarbazoles
1489
Table 2. Continued
a
2
b
Yield (%)
Entry
11
1
3
34
2
4
12
36
1
7
13
35
2
0
14
2
6
a
The requisite bromides were prepared from the appropriate cyclohexanone
14]
[
following the method described in the literature.
b
Isolated yields.
General Procedure for the Preparation of
,2,3,4-Tetrahydrocarbazoles (3)
1
A mixture of aniline 1 (0.9 mmol), 2-bromocyclohexanone 2 (0.3 mmol), and
.5 mL 2-ethoxyethanol were mixed in a round-bottom flask (25 mL). The
0
mixture was irradiated with microwaves (325 W) under nitrogen for 10 min.
After completion of the reaction, the solvent was evaporated and the crude
residue was extracted with ethyl acetate (3 mL Â 2). The extracts were

1
490
J. Chen and Y. Hu
Scheme 2. Plausible reaction mechanism for the synthesis of 1,2,3,4-
tetrahydrocarbazoles.
dried over anhydrous sodium sulfate and concentrated under vacuum. All the
products were purified by column chromatography over silica gel, using a
different ratio of ethyl acetate and petroleum ether as eluent according to
different products.
Data
[
15]
1
(
,2,3,4-Tetrahydrocarbazole (3a): mp 113–1148C (lit.
115–1168C); IR
21 1
KBr): n 3400 (NH), 3050 (ArH), 2927, 2849, 1589, 1469, 738 cm ; H
NMR (CDCl ): d 7.69 (br, NH), 7.50 (d, J ¼ 7.6 Hz, 1H), 7.31
3
(
d, J ¼ 8.0 Hz, 1H), 7.17–7.09 (m, 2H), 2.78–2.74 (m, 4H), 1.96–1.91
(
m, 4H); anal. calcd. for C H N: C, 84.17; H, 7.65; N, 8.18. Found C,
2 13
1
84.57; H, 7.34; N, 7.97.
[
16]
6
-Methyl-1,2,3,4-tetrahydrocarbazole (3b): mp 138–1408C (li2t. 1388C);
1
IR (KBr): n 3393 (NH), 3022 (ArH), 2925, 2846, 1589, 796 cm ; H NMR
1
(
(
CDCl ): d 7.57 (br, NH), 7.24 (s, 1H), 7.16 (d, J ¼ 8.0 Hz, 1H), 6.93
3
d, J ¼ 8.0 Hz, 1H), 2.72–2.66 (m, 4H), 2.17 (s, 3H), 1.92–1.84 (m, 4H);
anal. calcd. for C H N: C, 84.28; H, 8.16; N, 7.56. Found C, 84.12; H,
1
3 15
8
.37; N, 7.19
,7-Dimethoxyl-1,2,3,4-tetrahydrocarbazole (3c): mp 100–1028C (lit.
01–1038C); IR (KBr): n 3390 (NH), 3075 (ArH), 2923, 2834, 1596, 1487,
[17]
6
1

Microwave-Assisted One-Pot Synthesis of 1,2,3,4-Tetrahydrocarbazoles
1491
21 1
32 cm ; H NMR (CDCl ): d 7.51 (br, NH), 6.92 (s, 1H), 6.84 (s, 1H), 3.93
8
3
(s, 3H), 3.90 (s, 3H), 2.70–2.67 (m, 4H), 1.89–1.88 (m, 4H); anal. calcd. for
C H NO : C, 72.70; H, 7.41; N, 6.06. Found C, 72.51; H, 7.05; N, 5.89.
1
4
17
2
[
11]
6
1
-Methoxyl-1,2,3,4-tetrahydrocarbazole (3d): mp 91–928C (Lit.
92–
1
2
1
038C); IR (KBr): n 3388 (NH), 2951, 2850, 1592, 1485, 801 cm ; H
NMR (CDCl ): d 7.56 (br, NH), 7.16 (d, J ¼ 8.0 Hz, 1H), 6.93 (s, 1H), 6.77
3
(
d, J ¼ 8.0 Hz, 1H), 3.86 (s, 3H), 2.72–2.67 (m, 4H), 1.92–1.87 (m, 4H);
anal. calcd. for C H NO: C, 77.58; H, 7.51; N, 6.96. Found C, 77.94; H,
13 15
7
.82; N, 6.82.
8-Methoxyl-1,2,3,4-tetrahydrocarbazole (3e): compound 3e was obtained
as an oil; IR (KBr): n 3404 (NH), 3062 (ArH), 2926, 2850, 1572, 1467,
2
1 1
7
74 cm ; H NMR (CDCl ): d 7.99 (br, NH), 7.15 (d, J ¼ 8.0 Hz, 1H),
3
7
.05 (t, J ¼ 8.0 Hz, 1H), 6.66 (d, J ¼ 8.0 Hz, 1H), 3.99 (s, 3H), 2.76–2.70
(m, 4H), 1.97–1.91 (m, 4H); anal. calcd. for C H NO: C, 77.58; H, 7.51;
N, 6.96. Found C, 77.35; H, 7.84; N, 6.78.
13 15
[
16]
6
-Chloro-1,2,3,4-tetrahydrocarbazole (3f): mp 140–1418C (lit.
21
1
1
38–1408C); IR (KBr): n 3404 (NH), 2937, 2846, 1580, 1467, 800 cm
;
H NMR (CDCl ): d 7.71 (br, NH), 7.43 (d, J ¼ 2.0 Hz, 1H), 7.19
3
(
d, J ¼ 8.0 Hz, 1H), 7.07 (dd, J ¼ 8.0, 2.0 Hz, 1H), 2.75–2.66 (m, 4H),
1
Found C, 69.80; H, 5.99; N, 6.68.
.96–1.85 (m, 4H); anal. calcd. for C H ClN: C, 70.07; H, 5.88; N, 6.81.
12 12
[
18]
7
-Chloro-1,2,3,4-tetrahydrocarbazole (3g): mp 178–1808C (lit.
21
1
1
28–1308C); IR (KBr): n 3392 (NH), 2941, 2853, 1539, 1469, 801 cm
;
H NMR (CDCl ): d 7.66 (br, NH), 7.34 (d, J ¼ 8.0 Hz, 1H), 7.24
3
(
d, J ¼ 1.6 Hz, 1H), 7.03 (dd, J ¼ 8.0, 1.6 Hz, 1H), 2.72–2.66 (m, 4H),
1
Found C, 70.24; H, 6.01; N, 6.54.
.94–1.83 (m, 4H); anal. calcd. for C H ClN: C, 70.07; H, 5.88; N, 6.81.
12 12
[
18]
8
-Chloro-1,2,3,4-tetrahydrocarbazole (3 h): mp 136–1398C (lit.
21
1
1
38–1408C); IR (KBr): n 3443 (NH), 2927, 2853, 1588, 1464, 773 cm
;
HNMR (CDCl ): d 7.94 (br, NH), 7.36 (d, J ¼ 8.0 Hz, 1H), 7.11
3
(
d, J ¼ 8.0 Hz, 1H), 7.01 (t, J ¼ 8.0 Hz, 1H), 2.78–2.69 (m, 4H), 1.96–1.80
(
m, 4H); anal. calcd. for C H ClN: C, 70.07; H, 5.88; N, 6.81. Found C,
1
2 12
6
9.75; H, 6.05; N, 6.72.
[
19]
6
1
-Fluoro-1,2,3,4-tetrahydrocarbazole (3i): mp 106–1088C (lit.
103–
1
2
1
048C); IR (KBr): n 3407 (NH), 2930, 2852, 1583, 1482, 795 cm ; H
NMR (CDCl ): d 7.65 (br, NH), 7.17 (m, 1H), 7.10 (dd, J ¼ 9.2, 2.8 Hz,
3
1H), 6.86–6.81 (m, 1H), 2.73–2.64 (m, 4H), 1.94–1.84 (m, 4H); anal.
calcd. for C H FN: C, 76.17; H, 6.39; N, 7.40. Found C, 76.54; H, 6.02;
N, 7.76.
1
2 12
[20]
3
-tert-Butyl-1,2,3,4-tetrahydrocarbazole (3j ): mp 126–1278C (lit.
1
1
29–1318C); IR (KBr): n 3409 (NH), 3022 (ArH), 2959, 2920, 2862, 2842,

1
492
J. Chen and Y. Hu
2
1 1
1
468, 742 cm ; H NMR (CDCl ): d 7.66 (br, NH), 7.48 (d, J ¼ 8.0 Hz, 1H),
3
7
.27 (d, J ¼ 8.0 Hz, 1H), 7.14–7.08 (m, 2H), 2.85–2.75 (m, 3H), 2.45–2.38
(m, 1H), 2.13–2.10 (m, 1H), 1.55–1.53 (m, 2H), 0.99 (s, 9H); anal. calcd.
for C H N: C, 84.53; H, 9.31; N, 6.16. Found C, 84.59; H, 9.01; N, 6.18.
1
6 21
2
3
-tert-Butyl-1,2,3,4-tetrahydrocarbazole (3j ): mp 129–1318C; IR (KBr): n
2
21 1
407 (NH), 3048 (ArH), 2956, 2920, 2867, 1591, 1469, 738 cm ; H NMR
(
CDCl ): d 7.63 (br, NH), 7.46 (d, J ¼ 8.0 Hz, 1H), 7.27 (d, J ¼ 8.0 Hz,
3
1
H), 7.13–7.05 (m, 2H), 2.89–2.84 (m, 1H), 2.77–2.72 (m, 1H), 2.60–2.53
(
m, 2H), 2.14–2.10 (m, 1H), 1.66–1.64 (m, 1H), 1.44–1.40 (m, 1H), 1.00
s, 9H); anal. calcd. for C H N: C, 84.53; H, 9.31; N, 6.16. Found C,
(
1
6 21
84.49; H, 9.58; N, 6.34.
3
-tert-Butyl-6-methyl-1,2,3,4-tetrahydrocarbazole (3 k ): mp 122–1238C;
1
IR (KBr): n 3401 (NH), 3009 (ArH), 2960, 2920, 2855, 1595, 1474,
2
1
1
793 cm
;
H NMR (CDCl ): d 7.51 (br, NH), 7.22 (s, 1H), 7.12
3
(
d, J ¼ 8.0 Hz, 1H), 6.90 (d, J ¼ 8.0 Hz, 1H), 2.79–2.74 (m, 3H), 2.40
s, 3H), 2.38–2.31 (m, 1H), 2.08–2.04 (m, 1H), 1.51–1.45 (m, 2H), 0.97
s, 9H); anal. calcd. for C H N: C, 84.59; H, 9.60; N, 5.80. Found C,
(
(
1
7 23
84.67; H, 9.52; N, 6.07.
2
-tert-Butyl-6-methyl-1,2,3,4-tetrahydrocarbazole (3 k ): mp 167–1688C;
2
IR (KBr): n 3398 (NH), 3018 (ArH), 2961, 2919, 2867, 2842, 1596, 1467,
2
1
1
7
98 cm
;
H NMR (CDCl ): d 7.53 (br, NH), 7.23 (s, 1H), 7.15
3
(
d, J ¼ 8.0 Hz, 1H), 6.92 (d, J ¼ 8.0 Hz, 1H), 2.84–2.79 (m, 1H), 2.73–
2
1
8
.68 (m, 1H), 2.59–2.46 (m, 2H), 2.43 (s, 3H), 2.12–2.08 (m, 1H), 1.68–
.58 (m, 1H), 1.45–1.34 (m, 1H), 0.97 (s, 9H); anal. calcd. for C H N: C,
1
7 23
4.59; H, 9.60; N, 5.80. Found C, 84.46; H, 9.79; N, 6.10.
3
3
-Phenyl-1,2,3,4-tetrahydrocarbazole (3l ): mp 121–1238C; IR (KBr): n
391 (NH), 3026 (ArH), 2915, 1493, 1468, 743, 700 cm
1
2
1
1
; H NMR
(
CDCl ): d 7.73 (br, NH), 7.44 (d, J ¼ 8.0 Hz, 1H), 7.34–7.32 (m, 4H),
3
7
.30 (d, J ¼ 8.0 Hz, 1H), 7.26–7.22 (m, 1H), 7.15–7.06 (m, 2H), 3.10–
3.06 (m, 2H), 2.92–2.88 (m, 1H), 2.85–2.78 (m, 2H), 2.24–2.10 (m, 2H);
anal. calcd. for C H N: C, 87.41; H, 6.93; N, 5.66. Found C, 87.71; H,
1
8 17
7.15; N, 5.43.
2
3
-Phenyl-1,2,3,4-tetrahydrocarbazole (3l ): mp 159–1618C; IR (KBr): n
2
2
396 (NH), 3028 (ArH), 2912, 2842, 1492, 1470, 741, 698 cm ; H NMR
1 1
(
CDCl ): d 7.69 (br, NH), 7.50 (d, J ¼ 8.0 Hz, 1H), 7.37–7.29 (m, 5H),
3
7
.27–7.24 (m, 1H), 7.17–7.09 (m, 2H), 3.19–3.11 (m, 1H), 3.01–2.77
(m, 4H), 2.23–2.19 (m, 1H), 2.08–2.00 (m, 1H); anal. calcd. for C H N:
18 17
C, 87.41; H, 6.93; N, 5.66. Found C, 87.63; H, 7.23; N, 5.93.
3
-Phenyl-6-methyl-1,2,3,4-tetrahydrocarbazole (3 m ): mp 68–708C; IR
1
21
(
1
KBr): n 3403 (NH), 3025 (ArH), 2915, 2848, 1593, 1453, 793, 700 cm
H NMR (CDCl ): d 7.63 (br, NH), 7.30–7.16 (m, 6H), 7.14 (d, J ¼ 8.0 Hz,
;
3
1H), 7.05 (d, J ¼ 8.0 Hz, 1H), 3.13–3.08 (m, 2H), 2.95–2.85 (m, 3H), 2.44

Microwave-Assisted One-Pot Synthesis of 1,2,3,4-Tetrahydrocarbazoles
1493
(
s, 3H), 2.25–2.02 (m, 2H); anal. calcd. for C H N: C, 87.31; H, 7.33; N,
1
9 19
5
.36. Found C, 87.00; H, 7.65; N, 5.72.
2
-Phenyl-6methyl-1,2,3,4-tetrahydrocarbazole (3 m ): mp 146–1498C; IR
2
2
1
(
KBr): n 3403 (NH), 3025 (ArH), 2915, 2848, 1592, 1451, 792, 699 cm
;
1
H NMR (CDCl ): d 7.59 (br, NH), 7.36–7.22 (m, 6H), 7.17 (d, J ¼ 8.0 Hz,
3
1
H), 6.95 (d, J ¼ 8.0 Hz, 1H), 3.17–3.09 (m, 1H), 2.98–2.76 (m, 4H), 2.44
(s, 3H), 2.21–2.17 (m, 1H), 2.05–1.98 (m, 1H); anal. calcd. for C H N:
C, 87.31; H, 7.33; N, 5.36. Found C, 87.53; H, 7.18; N, 5.01.
1
9
19
[
15]
1
1
7
1
,2,3,4-Tetrahydrocyclopenta[b]indole (3n): mp 102–1048C (lit.
02–1048C); IR (KBr): n 3405 (NH), 3050 (ArH), 2930, 2867, 1460,
2
1 1
45 cm ; H NMR (CDCl ): d 7.83 (br, NH), 7.46 (dd, J ¼ 6.0, 4.0 Hz,
3
H), 7.33–7.30 (m, 1H), 7.13–7.08 (m, 2H), 2.91–2.83 (m, 4H), 2.60–2.53
(m, 2H); anal. calcd. for C H N: C, 84.04; H, 7.05; N, 8.91. Found C,
11 11
8
4.31; H, 7.35; N, 9.03.
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1
2
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