An efficient method for the N-bromosuccinimide catalyzed synthesis of indolyl-nitroalkanes

Article abstract of DOI:10.3390/molecules14103952

An efficient and practical method for the synthesis of indolyl-nitroalkane derivatives catalyzed by N-bromosuccinimide is described. The generality of this method was demonstrated by synthesizing an array of diverse 3-substituted indole derivatives by the reaction of different β-nitrostyrenes with various substituted indoles. Simple reaction conditions accompanied by good yields of indolyl-nitroalkanes are the merits of this methodology.

Full text of DOI:10.3390/molecules14103952

Molecules 2009, 14, 3952-3963; doi:10.3390/molecules14103952
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
An Efficient Method for the N-Bromosuccinimide Catalyzed
Synthesis of Indolyl-Nitroalkanes
Chun-Wei Kuo, Chun-Chao Wang, Hu-Lin Fang, B. Rama Raju, Veerababurao Kavala,
Pateliya Mujjamil Habib and Ching-Fa Yao *
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei
116, Taiwan
* Author to whom correspondence should be addressed; E-Mail: cheyaocf@ntnu.edu.tw;
Tel.: +886-2-2930-9092; Fax: +886-2-2932-4249.
Received: 25 August 2009; in revised form: 25 September 2009 / Accepted: 27 September 2009 /
Published: 9 October 2009
Abstract: An efficient and practical method for the synthesis of indolyl-nitroalkane
derivatives catalyzed by N-bromosuccinimide is described. The generality of this method
was demonstrated by synthesizing an array of diverse 3-substituted indole derivatives by
the reaction of different β-nitrostyrenes with various substituted indoles. Simple reaction
conditions accompanied by good yields of indolyl-nitroalkanes are the merits of this
methodology.
Keywords: indolyl-nitroalkane; N-bromosuccinimide; nitroalkenes; Friedel-Crafts
alkylation
Introduction
The indole nucleus is one of the most ubiquitous scaffolds found in natural products,
pharmaceuticals, functional materials, and agrochemicals [1-3]. Several indole derivatives that occur
in nature possess pharmacological activity. These include the hapalindole alkaloids, which exhibit
significant antibacterial and antimycotic activity. Other indole alkaloids are uleine, aspidospermidine,
the ibophyllidine alkaloids, brevicolline and numerous tryptamine derivatives which exhibit important
biological activities (Figure 1) [4-6].

Molecules 2009, 14
3953
Figure 1. Indole alkaloids.
Cl
Me
Me
N
N
N
Me
N
H
H
Me
Me
NC
H
N
H
N
N
H
H
H
CO2Me
N
H
Me
Brevicolline
Hapalindole G
Deethylibophyllidine
Uleine
Owing to the importance of the indole framework-containing compounds, the development of new
strategies to synthesize indole derivatives remain a subject of interest in the present days. During the
past several years, Michael addition was the most frequently employed tool for the synthesis of 3-
substituted indole derivatives [7]. This is due to the fact that nitroalkenes are very good Michael
acceptors and further the Michael adduct of the nitroalkenes are amenable to transformation into a
wide range of different functionalized species. Similarly, Friedel-Crafts alkylation of indoles with
nitroolefins in the presence of acidic catalysts is well documented in the literature [8-22]. Neverthless,
most of the procedures reported suffer from several shortcomings such as the use of hazardous
catalysts, tedious workup procedures and difficulties in product isolation. The most important
drawback is the tendency of electron-rich heteroaromatic rings to undergo polymerization under acid
catalyzed conditions. Hence the development of an effective method for the synthesis of 3-substituted
indoles has still remained a problem far from resolution. In addition, recent progress in the
stereoselective synthesis of these compounds was reported [23,24].
N-Bromosuccinimide (NBS), a mild source of bromine, is widely used in the presence of a catalytic
amount of free-radical initiators for benzylic and allylic brominations with high regioselectivity [25].
In many instances, NBS have been used as an activator in stereoselective glycosidation [26],
protection [27] and deprotection of ketals [28] or THP ethers [29] and in the synthesis of
diindolylalkanes [30]. It is also widely employed as a mild oxidant [31] as well as for oxidative
cyclizations [32,33]. Recently, we have reported synthesis of 1,5-benzodiazepine derivatives catalyzed
by NBS under mild conditions [34]. In continuation of our research work on nitroolefins [35-43], we
have developed a new route for the synthesis of 3-alkylated indoles via Friedel-Crafts alkylation of
indole with β-nitrostyrene, catalyzed by N-bromosuccinimide.
Results and Discussion
Initially, we examined the reaction between β-nitrostyrene and indole with 10 mol% of N-bromo-
succinimide in dichloromethane at room temperature (Scheme 1). We were able to obtain only 67% of
the corresponding alkylated adduct. Further, we examined the fate of the reaction at elevated
o
temperatures. Conducting the reaction at 40 C afforded the product in 94% yield, after 5 h (entry 3,
Table 1). With 20 mol% of N-bromosuccinimide, the product yield remained the same, along with the
same reaction time as when 10 mol% of NBS was utilized. Our optimization studies showed that

Molecules 2009, 14
3954
10 mol% of N-bromosuccinimide could be the best choice for this transformation, which is evident
from Table 1.
Scheme 1. Alkylation of indole with β-nitrostyrene.
HN
NO2
NO2
NBS
solvent
N
H
Table 1. Optimization studies of the alkylation reaction of indole and β-nitrostyrene.
Yield (%)a
Entry NBS (mol %)
Solvent
CHCl3
Condition Time (h)
1
2
3
10
10
10
rt
rt
16
12
5
60
67
94
CH2Cl2
CH2Cl2
40 oC
40 oC
40 oC
20
-
CH2Cl2
CH2Cl2
5
5
95
13
4
5
a Yields were determined from 1H-NMR with toluene as internal standard.
When 1 mmol of β-nitrostyrene 1 was reacted with 1.3 mmol of indole in the presence of 10 mole%
of N-bromosuccinimide using dichloromethane as solvent at 40 °C, the reaction afforded exclusively
the corresponding indolyl-nitroalkane in good to excellent yields. To further explore the scope and
limitations of this methodology, we tested the alkylation reaction of indole with a wide array of
structurally diverse nitroalkenes (Scheme 2). As seen from Table 2, the alkylation of indoles proceeds
with various nitroolefins. The rate of the reaction is controlled by both electronic and steric factors of
the substituent attached to the benzene ring of the β-nitrostyrene. For example, the nitroolefins
containing electron-withdrawing groups (chloro and nitro, entries 2 and 4, Table 2) react well to afford
the 3-alkylated indoles in excellent yields. However, nitroalkenes equipped with strong electron-
donating groups such as methyl or methoxy (entries 1 and 3) required relatively longer reaction times.
Moreover, sterically hindered substrates (entries 5-8) reacted smoothly under the present reaction
conditions. Acid sensitive heterocyclic moieties substrates such as thienyl (entry 9) and furoyl (entry
10) and less reactive aliphatic nitroalkenes (entries 11 and 12) also reacted with equal ease to furnish
the Friedel-Crafts products in high yields. 1-Nitrocyclohex-1-ene (entry 13), upon reaction with indole
resulted in a mixture of two diastereomers in 7:3 ratio.

Molecules 2009, 14
Scheme 2. Reaction of indole with various nitroalkenes catalyzed by NBS.
3955
HN
NO2
NO2
NBS (10 mol %)
CH2Cl2, 40 oC
R
N
H
R
2a-n
1
Table 2. Synthesis of indolyl-nitroalkane derivatives from various nitroalkenes.
Entrya
Nitroalkene
Product
Time (h) Yield(%)b
NO2
H3C
NH
NH
1
2b
2c
10
8
89
84
H3C
Cl
O2N
NO2
Cl
2
3
O2N
O2N
O2N
NO2
NO2
H3CO
O2N
NH
NH
2d
16
87
H3CO
O2N
2e
2f
85
90
4
5
4
NO2
NH
18
O2N
HN
NH
NO2
2g
2h
6
7
24
6
87
85
86
HN
O2N
Br
NO2
NH
Br
O2N
NO2
NO2
NH
8
2i
23
NO2
O2N

Molecules 2009, 14
3956
Table 2. Cont.
Entrya
9
Yield(%)b
79
Nitroalkene
S
Product
Time (h)
18
NO2
NH
NH
S
2j
O2N
O
NO2
10
2k 16
95
70
O
O2N
NH
2l
6
7
NO2
11
12
O2N
NH
2m
85
NO2
O2N
NH
NO2
2n 10
67c
13
NO2
a
All reactions were performed by using 1 equiv. of nitroalkene and 1.3 equiv. of indole in the
presence of 10 mol% of NBS;b Isolated yields; c A mixture of two diastereomers in 7:3 ratio.
Furthermore, to study the effect of the substituents on the heterocyclic substrate, the reaction of β-
nitrostyrene with various substituted indole and other heterocyclic derivatives was examined (Scheme
3). 2-Methylindole was reacted with β-nitrostyrene to furnish the product 4b in high yield. Similarly,
5-methoxyindole bearing an electron-donating group (entry 5, Table 3) was alkylated with β-
nitrostyrene in a shorter time to give the desired product 4e in excellent yield. Moreover, increasing
the size of the substituent on the indole nucleus, such as in the case of 2-phenylindole, gave only 47%
yield. Generally, alkylation of hydroxyindoles with nitroalkenes often results in various side products,
thereby decreasing the yields of alkylated product which may be due to the interaction of the hydroxyl
group with the Lewis acid catalyst [44]. Indole containing free or protected hydroxyl group (entries 6,
8 and 9) reacted with the nitroolefin without any interference of the functional group. It is interesting
to note that fused heteroarenes such as 7-azaindole (entry 10, Table 3) reacted with β-nitrostyrene to
afford the corresponding adduct in moderate yield after prolonged reaction time. This method was
found to be quite successful with the highly nucleophilic substrate pyrrole (entry 11) and the acid
sensitive substrate 2-methoxyfuran (entry 12), producing the expected products in better yields
compared to the earlier reported methods [45].

Molecules 2009, 14
Scheme 3. Reaction of β-nitrostyrene with various indoles and other heterocyclic
3957
compounds catalyzed by NBS.
NO2
NH
R
NBS (10 mol%)
CH2Cl2, 40 oC
N
X
H
X= C or N
R
O2N
3
4a-l
Table 3. Synthesis of aryl-nitroalkane derivatives from various indoles and other
heterocyclic derivatives.
Entrya
Reactant
Yield (%)b
79
Product
Time (h)
5.5
N
1
4a
N
O2N
NH
NH
2
4b
4
86
N
H
O2N
O2N
Ph
Ph
3
4
4c
14
24
47
10
N
H
4d
N
H
N
H
O2N
O2N
H3CO
NH
5
4e
3.5
85
N
H
OCH3
HO
Br
NH
NH
NH
6
7
N
H
4f
4g
4h
5
89
90
70
O2N
O2N
OH
Br
5.5
8.5
N
H
OH
8
N
H
O2N
HO

Molecules 2009, 14
3958
Table 3. Cont.
Entrya
9
Yield (%)b
55
Product
NH
Reactant
OAc
Time (h)
24
4i
N
H
O2N
AcO
NH
N
4j
4k
4l
36
4
68
85
79
10
11
N
H
N
O2N
N
H
N
H
O2N
10
OCH3
12
O
H3CO
O
O2N
a
All reactions were carried out by using 1 equiv. of nitroalkene and 1.3 equiv. of indole in the
presence of 10 mol% of NBS; b isolated yields.
Scheme 4. Synthesis of the key precursor of (S)-brevicolline.
H
N
Boc
NBS (10 mol %)
CH2Cl2, 40 oC
N
N
N
NO2
H
Boc
5
3
O2N
6
An interesting application of this methodology involves the synthesis of the compound 6, which is
the key precursor for the synthesis of the natural product (S)-brevicolline. The nitroalkene 5 was
prepared by the condensation of Boc-S-pyrrolidine-2-carboxyaldehyde with nitromethane according to
the reported procedure [46]. Compound 6 was obtained as a mixture of two diastereomers in the ratio
of 9:1 (HPLC) in 80% yield by the reaction of indole with nitroalkene 5 under the present reaction
conditions in 16 h. The aforementioned example demonstrates the usefulness and versatility of this
synthetic methodology.
Conclusion
In conclusion, we have developed a simple and efficient method for the synthesis of indolyl-
nitroalkanes in good yields under catalytic conditions. This method is applicable to a wide range of
nitroalkenes and various indoles. Low cost of the reagents and convenient isolation process of this
reaction makes this method an attractive alternative to existing methods.

Molecules 2009, 14
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Experimental
General
All reagents and chemicals were purchased from Sigma-Aldrich Chemical Company, Acros
Organics, Alfa Aesar or Merck and were used as received. Analytical thin layer chromatography was
performed with E. Merck silica gel 60F glass plates and flash chromatography with E. Merck silica gel
60 (230-400 mesh). Melting points were determined with a microscope hot-stage apparatus and
1
uncorrected. H- and 13C-NMR spectra were recorded on a Bruker Avance 400 instrument.
Chloroform-d was used as the solvent and TMS (δ = 0.00 ppm) as an internal standard. Chemical shift
values are reported in ppm relative to TMS in delta (δ) units. Chemical shifts are recorded in parts per
million (ppm). For 1H-NMR spectra the residual solvent peak was used as an internal reference (CHCl3
13
7.26). For C-NMR spectra the central peak of the CDCl3 triplet was used as the internal reference
(77.26). Multiplicities are recorded as s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet;
br broadened; m, multiplet. Coupling constants (J) are expressed in Hertz. MS and HRMS were
measured on JEOL JMS-D300 and JEOL JMS-HX110 spectrometers, respectively.
General procedure for the synthesis of aryl-nitroalkanes
To a stirred solution of nitroalkene derivative (1 mmol) and indole (1.3 mmol) in CH2Cl2 (2 mL)
was added NBS (0.1 mmol). The reaction mixture was then warmed to 40 °C with continuous stirring
until the completion of the reaction as monitored by TLC. Upon completion, the reaction mixture was
diluted with water and extracted with CH2Cl2 (3 x 15 mL), washed with brine, and then dried over
MgSO4. The solvent was removed under reduced pressure and the crude residue was purified by flash
chromatography on silica gel to afford pure product. The references of the known compounds are: 2a
[14,15,17,19], 2b [36], 2c [15,22], 2d [13,15,17], 2e [36], 2f [36], 2g [22], 2j [15,22], 2k [15,36], cis-
2n [14], trans-2n [14], 4a [15,17,19], 4b [15,17], 4c [12,36], 4d [15], 4e [14,17], 4f [14], 4g [17,19],
4k [15,35], 4l [45], 5 [46].
1
3-(1-(2-Bromophenyl)-2-nitroethyl)-1H-indole (2h): Colorless solid. mp 117-118 °C. H-NMR
(400 MHz, CDCl3): δ 8.07 (brs, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.2
Hz, 1H), 7.20-7.18 (m, 3H), 7.12-7.05 (m, 3H), 5.72 (t, J = 8.0 Hz, 2H), 4.99-4.90 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 138.3 (C), 136.7 (C), 133.7 (C), 129.4(CH), 129.3 (CH), 128.1 (CH), 126.4
(CH), 124.7 (CH), 123.0 (CH), 122.1 (C), 120.2 (CH), 119.2 (CH), 113.6 (C), 111.6 (CH), 78.0 (CH2),
40.8 (CH); MS (EI) m/z (relative intensity): 346 (14) [M+2]+, 344 (13) [M]+, 297 (28), 218 (100), 204
(27), 108 (20); HRMS-EI: m/z [M]+ calcd. for C16H13BrN2O2: 344.0160; found: 344.0155.
1
3-(2-Nitro-1-(2-nitrophenyl)ethyl)-1H-indole (2i): Yellow solid. mp 117-119 °C. H-NMR (400 MHz,
CDCl3): δ 8.20 (brs,1H), 7.89 (d, J = 7.8 Hz, 1H), 7.48-7.37 (m, 3H), 7.32 (dd, J = 12.7 and 8.4 Hz,
2H), 7.18 (t, J = 7.6 Hz, 1H), 7.13 (s, 1H), 7.03 (t, J = 7.3 Hz, 1H), 5.87 (t, J = 7.7 Hz, 1H), 5.09 (m,
13
2H). C-NMR (100 MHz, CDCl3): δ 149.8 (C), 136.7 (C), 133.9 (C), 133.4 (C), 130.1 (CH), 128.8
(CH), 126.1 (CH), 125.3 (CH), 123.2 (CH), 122.3 (CH), 120.4 (CH), 118.8 (CH), 113.0 (C), 111.7

Molecules 2009, 14
3960
(CH), 78.3 (CH2), 36.6 (CH); MS (EI) m/z (relative intensity): 311 (19) [M]+, 264 (29), 247 (33), 219
(100), 204 (39), 130 (57); HRMS-EI: m/z [M]+ calcd for C16H13N3O4: 311.0906; found: 311.0901.
1
3-(1-Nitromethylpentyl)-1H-indole (2l): H-NMR (400 MHz, CDCl3): δ 8.06 (brs, 1H), 7.61 (d,
J = 7.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.23-7.18 (m, 1H), 7.15-7.11 (m, 1H), 6.98 (d, J = 2.0 Hz,
1H), 4.59 (m, 2H), 3.86 (m, 1H), 1.89 (m, 1H), 1.52 (m, 2H), 0.89 (d, J = 6.0 Hz, 3H), 0.87 (d,
J = 6.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 136.5 (C), 126.1 (C), 122.4 (CH), 122.1 (CH), 119.7
(CH), 118.7 (CH), 114.1 (C), 111.5 (CH), 81.0 (CH2), 41.4 (CH), 34.4 (CH2), 25.4 (CH2), 23.3 (CH2),
21.5 (CH3); MS (EI) m/z (relative intensity): 246 (19) [M]+, 178 (11), 157 (30), 144 (18), 143 (61), 130
(100), 115 (22), 77 (10); HRMS-EI: m/z [M]+ calcd for C14H18O2N2: 246.1368; found: 246.1370.
1
3-(3-Methyl-1-nitromethylbutyl)-1H-indole (2m): H-NMR (400 MHz, CDCl3): δ 8.07 (brs, 1H), 7.62
(d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.20 (m, 1H), 7.13 (m, 1H), 6.99 (d, J = 2.2 Hz, 1H), 4.59
(m, 2H), 3.87 (m, 1H), 1.89 (m, 1H), 1.51 (m, 2H), 0.88 (dd, J = 6.0 and 5.7 Hz, 6H); 13C-NMR (100
MHz, CDCl3): δ 136.5 (C), 126.1 (C), 122.3 (CH), 119.7 (CH), 118.7 (CH), 113.9 (C), 111.5 (CH),
80.9 (CH2), 41.4 (CH2), 34.4 (CH), 25.4 (CH), 23.3 (CH), 21.5 (CH3); MS (EI) m/z (relative intensity):
246 (24) [M]+, 157 (26), 144 (36), 143 (71), 130 (100), 115 (24), 84 (19), 57 (31), 55 (25); HRMS-EI:
m/z [M]+ calcd for C14H18O2N2: 246.1368; found: 246.1365.
1
3-(2-Nitro-1-phenylethyl)-1H-indol-4-ol (4h): H-NMR (400 MHz, CDCl3): δ 7.94 (brs, 1H), 7.31-
7.24 (m, 4H), 7.18 (d, J = 9.4 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.64 (s, 1H),
6.32 (d, J = 7.5 Hz, 1H), 5.43 (t, J = 8.1 Hz, 1H), 5.23 (dd, J = 12.7 and 6.6 Hz, 1H), 5.11 (brs, 1H),
4.87 (t, J = 11.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 149.7 (C), 139.7 (C), 138.9 (C), 128.8 (CH),
127.8 (CH), 127.4 (CH), 123.4 (CH), 121.8 (C), 115.5 (CH), 114.7 (C), 104.8 (CH), 104.5 (CH), 79.8
(CH2), 42.1 (CH); MS (EI) m/z (relative intensity): 282 (54) [M]+, 236 (47), 235 (100), 234 (32), 222
(70), 220 (45), 117 (14), 103 (17), 77 (12); HRMS-EI: m/z [M]+ calcd for C16H14O3N2: 282.1004;
found: 282.1000.
1
3-(2-Nitro-1-phenylethyl)-1H-indol-4-yl acetate (4i): H-NMR (400 MHz, CDCl3): δ 8.16 (brs, 1H),
7.27-7.06 (m, 7H), 6.79 (d, J = 6.8 Hz, 1H), 6.65 (s, 1H), 5.19 (m, 1H), 5.01 (dd, J = 12.8 and 6.5 Hz,
1H), 4.85 (dd, J = 11.8 and 9.9 Hz, 1H), 2.21 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 170.3 (C), 143.8
(C), 139.0 (C), 138.9 (C), 129.0 (CH), 127.8 (CH), 127.7 (CH), 124.0 (CH), 122.8 (CH), 118.5 (CH),
113.2 (C), 112.6 (CH), 109.7 (CH), 79.9 (CH2), 42.0 (CH), 21.3 (CH3); MS (EI) m/z (relative
intensity): 324 (16) [M]+ , 282 (68), 236 (55), 235 (100), 222 (49); HRMS-EI: m/z [M]+ calcd for
C18H16N2O4: 324.1110; found: 324.1111.
1
3-(2-Nitro-1-phenylethyl)-1H-pyrrolo[2,3-b]pyridine (4j): H-NMR (400 MHz, CDCl3): δ 8.31
(d, J = 3.5 Hz, 1H), 7.87 (dd, J = 7.7 and 1.1 Hz, 1H), 7.33-7.30 (m, 5H), 7.20 (d, J = 3.5 Hz, 1H),
7.07 (dd, J = 7.7 and 4.7 Hz, 1H), 6.71 (dd, J = 9.2 and 6.1 Hz, 1H), 6.47 (d, J = 3.6 Hz, 1H), 5.37 (dd,
13
J = 13.4 and 9.2 Hz, 1H), 5.16 (dd, J = 13.4 and 6.1 Hz, 1H). C-NMR (100 MHz, CDCl3): δ 147.6
(C), 143.2 (CH), 135.9 (C), 129.3 (CH), 129.1 (CH), 129.0 (CH), 128.8 (CH), 127.0 (CH), 126.0 (CH),
121.0 (C), 116.6 (CH), 101.4 (C), 56.7 (CH2); MS (EI) m/z (relative intensity): 267 (5) [M]+, 221 (21),

Molecules 2009, 14
3961
149 (11), 118 (100), 102 (18), 91 (70), 84 (25), 77 (45), 63 (21), 51 (28); HRMS-EI: m/z [M]+ calcd
for C15H13O2N3: 267.1008; found: 267.1005.
Acknowledgements
Financial support of this work by the National Science Council of the Republic of China is
gratefully acknowledged.
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Sample Availability: Samples of the compounds are available from the authors.
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