Synthesis of indoles: Sulfur-assisted reaction of 2-nitrostilbenes with carbon monoxide

Article abstract of DOI:10.3987/COM-13-12708

When 2-nitrostilbenes were treated with carbon monoxide in the presence of elemental sulfur, the reductive N-heterocyclization of the 2-nitrostilbenes smoothly proceeded to give the corresponding indoles in moderate to good yields.

Full text of DOI:10.3987/COM-13-12708

HETEROCYCLES, Vol. 87, No. 6, 2013, pp. . © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 16th March, 2013, Accepted, 26th April, 2013, Published online, 13th May, 2013
DOI: 10.3987/COM-13-12708
SYNTHESIS OF INDOLES: SULFUR-ASSISTED REACTION OF
2-NITROSTILBENES WITH CARBON MONOXIDE
Rui Umeda, Yuuta Nishimoto, Tsukasa Mashino, and Yutaka Nishiyama*
Department of Chemistry and Materials Engineering, Faculty of Chemistry,
Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
E-mail: nishiya@kansai-u.ac.jp
Abstract – When 2-nitrostilbenes were treated with carbon monoxide in the
presence of elemental sulfur, the reductive N-heterocyclization of the 2-nitro-
stilbenes smoothly proceeded to give the corresponding indoles in moderate to
good yields.
1
The indole ring system is one of the most ubiquitous heterocyclics in nature, and the development of a
synthetic method of the indole system has received considerable attention in the industrial, agricultural,
2
and pharmaceutical chemistries. For well over a hundred years, numerous synthetic methods of indoles
3
4
5
6
including the well-established methods such as the Fischer, Madelung, Leimgruber-Batcho, Bartoli,
7
8
9
10
11
12
Bischler-Mohlan, Hametsberger-Knittel, Larock, Reissert, Gassman, and Sundberg indol syntheses
have been disclosed. As the other attractive applications on the synthesis of indoles, there are some
13
reports on the metal-catalyzed cyclization of 2-amino substituted arenes. Alternatively, transition
metal-catalyzed reductive N-heterocyclization of 2-nitrostyrenes with carbon monoxide as a reducing
1
4,15
agent has been developed for the synthesis of indoles.
As another approach for the method using
reductive N-heterocyclization, we have recently shown that selenium, non transition metal, was an
efficient catalyst for the synthesis of indoles by the reductive cyclization of 2-nitro substituted styrenes
1
6
with carbon monoxide. However, for these methods using carbon monoxide as a reducing agent, there
are some disadvantages such as the use of expensive metals, unstable catalysts in air or moisture, and
their toxicity. To solve these disadvantages, we examined the use of sulfur for the reaction of 2-nitro
substituted stilbenes with carbon monoxide and found that the reductive N-heterocyclization of these
compounds proceeded to give the corresponding indoles in moderate to good yields.
To determine the optimized reaction conditions, 2-nitrostilbene (1a) was allowed to react with carbon
monoxide in the presence of sulfur under various reaction conditions, and these results are shown in Table
1
. When 1a was treated with carbon monoxide (30 atm) in the presence of sulfur and excess amounts of

triethylamine in DMF solvent at 120 °C for 24 h, the reductive N-heterocyclization of 1a efficiently
occurred to give 2-phenylindole (2a) in 59% yield along with the formation of 2-aminostilbene (3a)
(
(
17%) (entry 1). In the cases of DMA and acetonitrile, 2a was formed in 56 and 39% yields, respectively
entries 2 and 3). The use of other solvents, such as THF and benzene, caused a distinct decrease in the
yield of 2a (entries 4 and 5). For the reaction using N-methylpyrrolidine, DBN and DBU instead of
triethylamine as a base, the yield of 2a was decreased (entries 6-8). At a lower reaction temperature
(80 °C), the yield of 2a was low (entry 10). The yield of 2a was improved by elevating the reaction
temperature (150 °C) (entry 9). In order to determine the possible catalytic use of sulfur, 1a was treated
with carbon monoxide in the presence of a catalytic amount of sulfur (20 mol%). 2-Phenylindole (2a) was
formed in 200% yield based on sulfur.
Table 1. The Sulfur-Assisted Reaction of 2-Nitrostilbene with Carbon Monoxide under Various
a)
Reaction Conditions
S
amine
+
CO
+
solvent
N
H
NO2
NH2
(
E : Z = 44 : 56)
1a
2a
3a
Yield / %b)
o
Entry
Amine
Solvent
Temp. / C
Time / h
2
a
3a
1
Et N
DMF
DMA
120
24
59
17
13
5
3
2
3
4
Et N
120
120
120
24
24
24
56
39
0
3
Et N
CH CN
3
3
Et N
THF
0
3
5
6
Et N
benzene
120
120
24
24
0
7
0
3
NMe
DMF
1
7
8
9
DBN
DBU
DMF
DMF
DMF
DMF
120
120
150
80
24
24
24
24
7
35
42
11
Et N
83 (68) 13
3
10
Et N
7
1
3
a) Reaction conditions: 2-nitrostilbene (0.5 mmol), sulfur (0.5 mmol), amine (10 mmol) and solvent (5 mL)
under CO (30 atm). b) GLC yields. The number in parenthesis shows the isolated yield.
To determine the applicability of the sulfur-assisted reductive N-heterocyclization of 2-nitrostilbene

derivatives with carbon monoxide, a variety of 2-nitro substituted stilbenes was allowed to react with
carbon monoxide in the presence of a stoichiometric amount of sulfur using triethylamine as the base and
1
7
DMF as the solvent. These results are shown in Table 2. In the case of 1-(2-nitrostyryl)-4-methyl-
benzene, 1-(2-nitrostyryl)-3-methylbenzene, and 1-(2-nitrostyryl)-3-methoxybenzene having electron
donating groups, the reductive N-heterocyclization efficiently proceeded to form the corresponding
indoles, 2b-c and 2e, in 86, 82 and 85%, respectively (entries 1, 2, and 4). Similarly,
1
-(2-nitrostyryl)-4-chlorobenzene and 1-(2-nitrostyryl)-4-trifluoromethylbenzene, in which electron
withdrawing groups were substituted on the aromatic ring, were reductive N-heterocyclized to give the
corresponding 2-aryl substituted indoles 2f-g in good yields (entries 5 and 6). In the case of
1
-(2-nitrostyryl)-2-methylbenzene, which has a sterically hindered group, the yield of 2d slightly
decreased (entry 3). The reductive N-heterocyclization of 1-(4-methoxy-2-nitrostyryl)benzene with
carbon monoxide also occurred to produce 2h in 43% yield (entry 7). 2-Methylindole (2i) was also
prepared by the sulfur-assisted reductive N-heterocyclization with carbon monoxide (entry 8).
Although the reaction pathway for the preparation of the indoles by the reaction of 2-nitrostilbenes with
carbon monoxide in the presence of sulfur has not been fully clarified, one of the plausible reaction
pathways is shown in Scheme 1. Miyata and Sonoda et al. reported the sulfur-assisted synthesis of
benzimidazolones, benzoxazolones, and benzothiazolones by the reaction of o-substituted nitrobenzenes
1
8
with carbon monoxide in the presence of water. They proposed that the generation of carbonyl sulfide
by the reaction of sulfur and carbon monoxide in the presence of a tertiary amine was the initial step of
the reaction. Thus, we propose that the reaction starts with the deoxygenation of the nitro group with SCO,
which was generated by the elemental sulfur and carbon monoxide in the presence of the tertiary amine,
forming the corresponding short-lived nitrene or nitrenoid species. The intramolecular insertion of the
nitrene or nitrenoid species into the vinylic C-H bond efficiently proceeded to produce the indoles.
R
R
+
SCO
R
N
NO2
N
H
Et N
3
SCO
CO2
R
S + CO
-
S
SeCO CO2
R
R
-
S
N O
N O
N S
S
Scheme 1. A Plausible Reaction Path

a)
Table 2. Synthesis of Various Indoles
S
R1
Et N
3
R1
+
CO
DMF
R2
N
R2
NO2
H
2
Entry
1
Substrate
Product
Yield / %b)
Me
Me
86
N
H
NO2
(2b)
(
(
E : Z = 50 : 50)
2
82
Me
N
H
Me
NO2
(
2c
)
E : Z = 50 : 50)
Me
3
60
85
90
82
N
H
Me
2d)
NO2
(
(
(
E : Z = 50 : 50)
OMe
OMe
4
N
H
NO2
(
2e)
E : Z = 53 : 47)
Cl
Cl
5
N
H
NO2
(
2f)
(
E : Z = 63 : 37)
CF3
CF3
6
7
N
H
NO2
(2g)
(
(
E : Z = 75 : 25)
(43)
(38)
N
H
MeO
MeO
NO
2
(2h)
E : Z = 47 : 53)
8
N
NO2
H
(
E : Z = 28 : 72)
(2i)
3
a) Reaction conditions: 2-nitrostyrenes (0.5 mmol), sulfur (0.5 mmol), Et N (10 mmol) and DMF (5 mL) under CO (30
atm) at 150 C for 24 h. b) GLC yields. The numbers in parentheses show the isolated yields.

In summary, we have succeeded in the synthesis of indoles via the sulfur-assisted reductive
N-heterocyclization of 2-nitrostilbenes with carbon monoxide using sulfur.
ACKNOWLEDGMENT
This work was financially supported in part by a Grant-in-Aid for Science Research on Priority Area and
Strategic Project to Support the Formation of Research Bases at Private University from the Ministry of
Education, Culture Sports, and Science and Technology of Japan.
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6
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2
4
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1
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7. Experimental Procedure
General
1
The FT-IR spectra were recorded by a JASCO FT/IR-4100 instrument. The H-NMR spectra were
1
3
recorded at 270 or 400 MHz and the C-NMR spectra at 67.5 or 100 MHz by a JEOL,
JNM-EX-270 or JEOL JNM-AL400. Chemical shifts were reported in ppm relative to
tetramethylsilane or residual solvent as the internal standard. The GLC mass spectral analyses were
performed by a Shimadozu GCMS-QP5050A with CBP-M25-025. The mass spectral analyses were
performed by a JEOL JMS-700 spectrometer for the EI and FAB ionization. Preparative HPLC
separation was undertaken using a JAI LC-908 chromatograph equipped 600 mm x 20 mm
JAIGEL-1H and 2H GPC columns and CHCl as the eluent.
3
Reagents
The sulfur and carbon monoxide were commercially available and were used without further
purification. The 2-nitrostilbenes were synthesized by the Wittig reaction. All other chemical agents
were commercially obtained and purified by distillation.
General Procedure for Sulfur-Assisted Reaction of 2-Nitrostilbens with Carbon Monoxide
To an autoclave, 2-nitrostilbene (0.5 mmol), sulfur (16 mg, 0.5 mmol), and triethylamine (101 mg,
1
0 mmol), was added to DMF (5 mL). The apparatus was then flushed several times with carbon

monoxide and fully charged with carbon monoxide (30 atm) at room temperature. The reaction was
carried out at 150 °C for 24 h. The reaction apparatus was then cooled to room temperature. After
the evacuation of the excess carbon monoxide, the deposited sulfur and salt were filtered off and the
4
solution was then extracted with diisopropyl ether. The organic layer was dried over MgSO . The
resulting mixture was filtered, and the filtrate was concentrated. Purification of the residue by silica
gel column chromatography afforded the indoles. The structures of the products were assigned by
1
13
their H and C-NMR, and mass spectra. The product was characterized by comparing its spectral
1
9
20
20
data with those of an authentic sample or previous reports on 2a-h, 2i, and 3a.
1
8. (a) T. Miyata, N. Kambe, S. Murai, N. Sonoda, O. Nishiguchi, and T. Hirashima, Nippon
Kagakukaishi, 1987, 1332; (b) T. Miyata, T. Mizuno, Y. Nagahama, O. Nishiguchi, T. Hirashima, N.
Sonoda, Heteroatom Chem., 1991, 2, 473.
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473.
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0. M. Shen, B. E. Leslie, and T. G. Driver, Angew. Chem. Int. Ed., 2007, 47, 5056.