An efficient and clean Michael addition of indoles to electron-deficient olefins under solvent- and catalyst-free condition

Article abstract of DOI:10.1002/jhet.569

An efficient Michael addition of indoles to electron-deficient olefins under solvent- and catalyst-free condition afforded biologically important 3-substituted indole derivatives in good to excellent yields was reported. The acidic N-H proton of indole pl

Full text of DOI:10.1002/jhet.569

March 2011
An Efficient and Clean Michael Addition of Indoles to Electron-
Deficient Olefins Under Solvent- and Catalyst-Free Condition
489
Xiong-Li Liu, Dong Xue,* and Zun-Ting Zhang
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of
Chemistry and Materials Science, Shaanxi Normal University, Xi’an 710062,
People’s Republic of China
*E-mail: xuedong_welcome@snnu.edu.cn
Received March 26, 2010
DOI 10.1002/jhet.569
Published online 16 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
An efficient Michael addition of indoles to electron-deficient olefins under solvent- and catalyst-free
condition afforded biologically important 3-substituted indole derivatives in good to excellent yields
was reported. The acidic NAH proton of indole plays a key role in Michael addition of indoles to
electron-deficient olefins. This very simple procedure provides an efficient and clean process for the
synthesis of indole derivatives.
J. Heterocyclic Chem., 48, 489 (2011).
INTRODUCTION
NAH proton and hydrogen bonding can play a key role
in organcatalysts, we supposed indole itself as catalyst
in Michael addition of indoles to electron-deficient ole-
fins. This very simple procedure provides an efficient
and clean process for the synthesis of indole derivatives.
The development of new environmentally friendly reac-
tion is a challenging goal for organic chemist [1–3]. Due to
its low cost, reduced pollution, simplicity in process, and
handling, the reaction under the solvent-free conditions has
been extensively explored recently [4,5]. Indole and many
of its derivatives are present in many compounds with
pharmacological and biological activities [6,7]. Therefore,
the development of green strategies to synthesize indole
derivatives has attracted much attention in recent years.
Michael addition is one of the most important tools for the
synthesis of 3-substituted indole derivatives [8–10]. Elec-
tron-deficient olefins are strong Michael acceptors, and
Michael adducts of electron-deficient olefins can be readily
transformed into different functionalities [8–10].
RESULTS AND DISCUSSION
In our initial study, we observed the reaction of
b-nitrostyrene with 2-methylindole at 50ꢀC without any
catalyst in different solvents. Conducting the reaction in
CH2ClCH2Cl or toluene did not get the desired product
after 12 h. Only 6% of adduct was obtained after 12 h
when CH3CN was used as solvent (Table 1, entry 3).
During the period, an interesting phenomenon attract
our attention, after mixing the two starting materials to-
gether, a thick yellow oil was formed quickly without
the addition of solvent. Considering that indole has an
acidic NAH proton, we hypothesize indole itself can act
as catalyst in Michael addition of indoles to electron-de-
ficient olefins. When the oil was heated at 50ꢀC without
any solvent, the desired product was obtained in excel-
lent yield within 1.5 h (Table 1, entry 4). When the
reaction was carried out under argon with identical ex-
perimental conditions, the desired Michael addition
product was obtained with the excellent yield (95%)
(Table 1, entry 5), which showed the procedure did not
require any inert atmospheric condition. The addition
also occurs at room temperature but extensive reaction
time (4 h) is required and isolated yield of product is
lower (81%; Table 1, entry 6).
Owing to the importance of this transformation, sev-
eral procedures have been reported in literature. A wide
variety of acid catalysts [11,12], Lewis acids [13–19], or
other catalysts [20–30] were used for this reaction.
However, these catalysts still appeared to have several
shortcomings, for example, toxicity of metal salts.
Recently, catalyst-free Michael addition of nitrostyrene
with indole was developed [31,32]. However, the reac-
tion required higher temperature and use benzene or
water as the solvent [31,32]. The development of more
efficient and environmentally accessible method is still
required. Here, we would like to report for the first time
a clean Michael addition of indoles to electron-deficient
olefins under solvent- and catalyst-free condition. The
reaction avoids both an organic solvent and the need for
a catalyst. Considering that the indole has an acidic
C
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490
X.-L. Liu, D. Xue, and Z.-T. Zhang
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Table 1
b-nitrostyrenes, vinyl ethyl cyanoacetates, and vinyl
malononitriles (Scheme 1) could react with indoles
under the best reaction conditions to give the corre-
sponding 3-substituted indole derivatives in good to
excellent yields. First, indole 1a was used as a standard
substrate to study the reactivity of different nitroalkenes
in this reaction. A wide range of nitroalkenes bearing
electron-donating (3d–3g), electron- withdrawing (3b,
3c) group substituted at aromatic ring, and heteroaro-
matic (3h) groups could react with indole 1a and the
Michael addition products 3 were obtained with excel-
lent yields (Table 2, entries 1–8). The results suggest
that nitroalkenes with an electron-withdrawing group
substituted at aromatic ring react much faster than nitro-
alkenes with an electron-donating substituent (Table 2,
entries 1–7). The generality of the reaction was further
demonstrated by using substituted indoles such as 5-meth-
ylindole, 5-methoxyindole, and 2-methylindole; good to
excellent yields were obtained. As seen in Table 2, the
indole bearing Br group resulted in a lower yield and
required a longer reaction time (Table 2, entry 9). When
we introduced a 5-methoxy group or methyl group to
The Reaction of b-nitrostyrene with 2-methylindole.
Entrya
T (ꢀC)
Solvent
Time (h)
Yieldb (%)
1
2
50
50
50
50
50
r.t.
CH2ClCH2Cl
Toluene
CH3CN
Neat
12
12
12
1.5
1.5
4
Trace
Trace
6
3
4
95
95
5c
6
Neat
Neat
81
a Unless noted, reactions were carried out with 0.5 mmol of 2-methyl-
indoles, 0.4 mmol of b-nitrostyrene.
b Isolated yield after flash chromatography.
c The reaction was carried out in Ar.
With the best reaction conditions in hand, we next
turned our interest to the reaction scope, and the results
are summarized in Table 2. It clearly indicates that
Table 2
The Michael addition of indoles to electron-deficient olefins under solvent-free and catalyst-free condition.
Entrya
Indoles
Olefins
Product
Time (h)
Yieldb (%)
1
2
3
1a
1a
1a
1a
1a
1a
1a
1a
1c
1d
1b
1b
1b
1b
1b
1b
1b
1b
2a
2b
2c
2d
2e
2f
2g
2h
2a
2a
2a
2d
2g
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
20
10
10
24
24
24
20
20
50
5
95 (85)f
99
98
4
5
94 (76)f
95
6
7
96
95 (81)f
90 (68)f
76 (73)f
93 (83)f
94 (80)f
96
8
9
10
11
12
13
14
15
16
17
18
1.5
3
2
98
90c
24
24
20
28
20
2j
2k
2l
61d
85e
70
2m
96
a Unless noted, reactions were carried out with 0.4 mmol of electron-deficient olefins, 0.5 mmol of indoles.
bIsolated yield after flash chromatography.
cdr ¼ 3.8:1.
ddr ¼ 1.3:1.
edr ¼ 1.1:1.
f Data of H2O as catalyst in parentheses refers to the results in literature [32].
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March 2011
An Efficient and Clean Michael Addition of Indoles to Electron-Deficient Olefins
Under Solvent- and Catalyst-Free Condition
491
Scheme 1. The structure of olefins.
5-position of indole or 2-position of indole, to our
delight, the reaction proceeded very well, giving the cor-
responding products in excellent yield even with shorter
reaction time (Table 2, entries 10–13). A possible expla-
nation may be due to the presence of 5-methoxy group
in 5-position of indole or the methyl group in 2-position
of indole, which increased the electron density of the ar-
omatic ring to accelerate the reaction. Moreover, with
a,b-disubstituted nitroalkene, we observed low diaster-
eoselectivity, the 1H-NMR spectra of 3n revealed the
presence of diastereomer in the ratio of 3.8:1 for 3n
(Table 2, entry 14). Furthermore, to the best of our
knowledge, few reports about conjugate addition of
indoles with vinyl ethyl cyanoacetates and vinyl malo-
nonitriles have been reported in the literature. The
results (Table 2, entries 15–18) showed that our present
synthetic methodology can get these conjugate addition
enhancement of the rates and the yields of the products
are observed (Scheme 4). Further application of the cata-
lytic activity of acidic NAH proton of indole and a
detailed study of the catalytic mechanism are in progress.
CONCLUSIONS
In summary, we have developed a rare example of an
efficient Michael addition of indoles to electron-deficient
olefins that avoids both an organic solvent and the need
for a catalyst. The reaction is a green method for the
synthesis of important 3-substituted indole derivatives
with the advantages such as mild condition and high
yields. Furthermore, this reaction is the first example of
electron-deficient olefins activation catalyzed by an
acidic NAH proton of indoles and its application to
other addition reactions are underway.
1
products with high yields. The H-NMR spectra of 3o,
3p revealed the presence of diastereomers in the ratio of
1.3:1 for 3o and 1.1:1 for 3p.
EXPERIMENTAL
To demonstrate the synthetic utility of the present
system, we carried out the reaction in large scale. The
mixture of 40 mmol of (E)-1-(2-nitrovinyl)benzene and
60 mmol of 2-methylindole was stirred at 50ꢀC without
solvent and catalyst for 1.5 h. The corresponding adduct
3k was obtained in 96% yield (Scheme 2).
Indoles were purchased from Alfa Aesar Company. Elec-
tron-deficient olefins were prepared according to the literature
procedures and spectral data were consistent with the literature
report. All solvent were purchased from commercial sources
and used without further purification. Reactions were moni-
tored by thin layer chromatography (TLC) using silica gel
GF254 plates. Column chromatography was performed on silica
To gain insight into the reaction mechanism, we
examined N-methylindole as a substrate under solvent-
and catalyst-free condition at 50ꢀC (Scheme 3). As
expected, it was found that the target Michael adducts
was obtained only in a trace amount even with pro-
longed reaction time (10 h). In any event, the presence
of the acidic NAH proton seems mandatory as every
attempt to use N-methylindole for these reactions failed to
get the product. Therefore, we assume that an acidic NAH
proton of indole activates the nitro moiety, a drastic
Scheme 2. Large-scale reaction of (E)-1-(2-nitrovinyl) benzene with 2-
methylindole.
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492
X.-L. Liu, D. Xue, and Z.-T. Zhang
Vol 48
Scheme 3. The reaction of b-nitrostyrenes with N-methylindole.
gel (300–400 mesh). NMR spectra were recorded on a 300-
1
MHz instrument. H-NMR chemical shifts are reported in ppm
3-(1-(2-Chlorophenyl)-2-nitroethyl)-1H-indole [33] (3b). White
solid. yield: 99%. mp 144.1–145.3ꢀC. IR (KBr), m (cmꢁ1):
3438, 2958, 2913, 1547, 1436, 1411, 1379, 1334, 1096, 742.
1H-NMR (300 MHz, CDCl3), d 4.91–5.01 (m, 2H), 5.72 (t, J
¼ 7.8 Hz, 1H), 7.03–7.21 (m, 6H), 7.30 (d, J ¼ 7.8 Hz, 1H),
7.41 (t, J ¼ 5.7 Hz, 2H), 8.05 (br, 1H); 13C-NMR (75 MHz,
CDCl3), d 136.5, 133.8, 130.1, 129.0, 128.8, 127.33, 126.2,
122.8, 122.0, 120.0, 118.9, 113.2, 111.4, 77.7, 38.0.
3-(1-(4-Bromophenyl)-2-nitroethyl)-1H-indole [34] (3c). Pale
pink solid. yield: 98%. mp 122.7–123.9ꢀC. IR (KBr), m
(cmꢁ1): 3396, 2946, 2915, 1535, 1484, 1427, 1380, 1337, 744.
1H-NMR (300 MHz, CDCl3), d 4.84 (dd, J ¼ 8.7, 8.4, 12.5
Hz, 1H), 4.98 (dd, J ¼ 7.5, 7.5, 12.3 Hz, 1H), 5.10 (t, J ¼ 7.8
Hz, 1H), 6.92 (s, 1H), 7.06 (t, J ¼ 7.5 Hz, 1H), 7.14–7.21 (m,
3H), 7.30 (d, J ¼ 7.8 Hz, 1H), 7.38 (t, J ¼ 7.5 Hz, 3H), 8.04
(br, 1H); 13C-NMR (75 MHz, CDCl3), d 138.3, 136.5, 132.0,
129.5, 125.9, 122.9, 121.6, 121.5, 120.1, 118.8, 113.8, 111.5,
79.2, 41.0.
(d) relative to tetramethylsilane (TMS) with the solvent reso-
nance used as the internal standard (CDCl3, d 7.26 ppm). Data
are reported as follows: chemical shift, multiplicity (s ¼ sin-
glet, d ¼ doublet, t ¼ triplet, m ¼ multiplet), coupling con-
stants (Hz), and integration. 13C-NMR chemical shifts are
reported in ppm from TMS with the solvent resonance as the
internal standard (CDCl3, d 77.0 ppm). IR data were obtained
from FT spectrometer and recorded as cmꢁ1
.
The optimization of reaction conditions of b-nitrostyrene
with 2-methylindole. In a tube equipped with a magnetic stir-
ring bar, 0.5 mmol of 2-methylindoles, 0.4 mmol of b-nitro-
styrene was added. Thick yellow oil was formed quickly, and
then the mixture was stirred with the time and temperature
shown in Table 1. After the completion of the reaction, the
raw product was purified by silica gel column chromatography
(EtOAc/petroleum ether) to give light yellow oil with the yield
shown in Table 1.
3-(1-(4-Methoxyphenyl)-2-nitroethyl)-1H-indole
[32]
(3d). White solid. yield: 94%. mp 152.5–153.6ꢀC. IR (KBr), m
(cmꢁ1): 3379, 2986, 1547, 1509, 1243, 746. 1H-NMR (300
MHz, CDCl3), d 3.77 (s, 3H), 4.89 (dd, J ¼ 8.4, 8.4, 12.1 Hz,
1H), 5.04 (dd, J ¼ 7.6, 7.4, 12.0 Hz, 1H), 5.13 (t, J ¼ 7.8 Hz,
1H), 6.84 (d, J ¼ 8.4 Hz, 7.01–7.09 (m, 2H), 7.16–7.25 (m,
3H), 7.35 (d, J ¼ 8.1 Hz, 1H), 7.43 (d, J ¼ 7.8 Hz, 1H), 8.07
(br, 1H); 13C-NMR (75 MHz, CDCl3), d 158.9, 136.5, 131.2,
128.8, 126.1, 122.6, 121.4, 119.9, 119.0, 114.8, 114.3, 111.3,
79.7, 55.2, 40.8.
General experimental procedure for the synthesis of
3a–3u. In a tube equipped with a magnetic stirring bar, elec-
tron-deficient olefin (0.4 mmol) and indole (0.6 mmol) was
added. Then the tube was closed with a rubber stopper, the
reaction mixture was stirred for the appropriate time at 50ꢀC.
After completion of the reaction, as indicated by TLC, the
reaction mixture was directly purified by flash chromatography
to yield the desired product. The compounds 3a–3l and 3r are
known compounds; their identities were proven by means of
1
melting points, H-NMR, 13C-NMR, and IR. All the analytical
3-(1-(3-Methoxyphenyl)-2-nitroethyl)-1H-indole [35] (3e). Pale
yellow viscous oil. yield: 95%. IR (KBr), m (cmꢁ1): 3414,
2910, 2834, 1548, 1487, 1456, 1376, 1261, 743. H-NMR (300
data were in accord with the spectra reported in the literature.
The compounds 3m–3q are new compounds; their identities
1
1
were proven by means of HRMS, H-NMR, 13C–NMR, and IR.
MHz, CDCl3), d 3.69 (s, 3H), 4.86 (dd, J ¼ 8.4, 8.4, 12.6 Hz,
1H), 4.97 (dd, J ¼ 7.8, 7.5, 12.5 Hz, 1H), 5.11 (t, J ¼ 15.9
Hz, 1H), 6.76 (d, J ¼ 8.1 Hz, 1H), 6.87 (t, J ¼ 17.4 Hz, 3H),
7.04 (t, J ¼ 14.7 Hz, 1H), 7.12–7.26 (m, 3H), 7.43 (d, J ¼ 7.8
Hz, 1H), 8.01 (br, 1H); 13C-NMR (75 MHz, CDCl3), d 159.9,
141.0, 136.5, 129.9, 126.1, 122.6, 121.7, 120.1, 119.9, 118.9,
114.1, 114.1, 112.5, 111.5, 79.5, 55.2, 41.5.
3-(2-Nitro-1-phenylethyl)-1H-indole [33] (3a). Pale yellow
viscous oil. yield: 95%. IR (KBr), m (cmꢁ1): 3411, 2898, 1547,
1453, 1420, 1374, 1336, 742, 700. 1H-NMR (300 MHz,
CDCl3), d 4.89 (dd, J ¼ 8.7, 8.4, 12.5 Hz, 1H), 5.01 (dd, J ¼
7.5, 7.5, 12.3 Hz, 1H), 5.15 (t, J ¼ 7.8 Hz, 1H), 6.93 (s, 1H),
7.05 (t, J ¼ 7.5 Hz, 1H), 7.14–7.30 (m, 7H), 7.42 (d, J ¼ 7.8
Hz, 1H), 7.99 (br, 1H); 13C-NMR (75 MHz, CDCl3), d 138.8,
136.0, 128.4, 127.3, 127.2, 127.1, 125.6, 122.2, 121.1, 119.4,
118.4, 113.9, 110.9, 79.09, 41.1.
3-(1-(2-Methoxyphenyl)-2-nitroethyl)-1H-indole [33] (3f). Pale
yellow viscous oil. yield: 96%. IR (KBr), m (cmꢁ1): 3415,
2898, 2836, 1548, 1489, 1457, 1373, 1244, 745. H-NMR (300
1
MHz, CDCl3), d 3.85 (s, 3H), 4.89–5.03 (m, 2H), 5.58 (t, J ¼
7.8 Hz, 1H), 6.80 (t, J ¼ 7.4 Hz, 1H), 6.88 (d, J ¼ 8.1 Hz,
1H), 7.01–7.27 (m, 6H), 7.45 (d, J ¼ 7.8 Hz, 1H), 7.97 (br,
1H); 13C-NMR (75 MHz, CDCl3), d 156.9, 136.4, 128.9,
128.7, 127.3, 126.5, 122.4, 122.0, 120.8, 119.7, 119.1, 113.9,
111.3, 110.9, 78.2, 55.5, 35.5.
Scheme 4. The two proposed reaction mechanism.
3-(2-Nitro-1-p-tolylethyl)-1H-indole [32] (3g). Pale yellow
viscous oil. yield: 95%. IR (KBr), m (cmꢁ1): 3415, 2916, 1548,
1
1512, 1455, 1422, 1376, 743. H-NMR (300 MHz, CDCl3), d
2.28 (s, 3H), 4.88 (dd, J ¼ 8.4, 8.7, 12.2 Hz, 1H), 5.01 (dd,
J ¼ 7.8, 7.5, 12.2 Hz, 1H), 5.12 (t, J ¼ 7.8 Hz, 1H), 6.94 (s,
1H), 7.02–7.20 (m, 6H), 7.29 (d, J ¼ 8.1 Hz, 1H), 7.43 (d,
J ¼ 7.8 Hz, 1H), 8.00 (br, 1H); 13C-NMR (75 MHz, CDCl3),
Journal of Heterocyclic Chemistry
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March 2011
An Efficient and Clean Michael Addition of Indoles to Electron-Deficient Olefins
Under Solvent- and Catalyst-Free Condition
493
d 136.7, 136.0, 135.7, 129.1, 127.1, 125.6, 122.1, 121.1, 119.4,
118.5, 114.1, 110.9, 79.1, 40.7, 20.5.
3-(1-(Furan-2-yl)-2-nitroethyl)-1H-indole [33] (3h). Pale
46.5, 12.1. HRMS (ESI-TOF) (M þ Hþ):357.1603, found:
320.1601.
Ethyl 2-cyano-3-(2-methyl-1H-indol-3-yl)decanoate (3o). Pale
yellow viscous oil. yield: 61%. dr ¼ 1.3:1. IR (KBr), m
(cmꢁ1): 3394, 2931, 2855, 2360, 2336, 1741, 1459, 1369,
yellow viscous oil. yield: 90%. IR (KBr), m (cmꢁ1) 3403,
1
2915, 1543, 1505, 1455, 1421, 1371, 1340, 734. H-NMR (300
1
1302, 1245, 1024, 741. H-NMR (300 MHz, CDCl3), d 0.80–
MHz, CDCl3), d 4.87 (dd, J ¼ 7.5, 7.5, 12.6 Hz, 1H), 5.01 (dd,
J ¼ 8.1, 8.1, 12.3 Hz, 1H), 5.22 (t, J ¼ 7.7 Hz, 1H), 6.13 (d, J
¼ 3 Hz, 1H), 6.28 (s, 1H), 7.02 (s, 1H), 7.08–7.21 (m, 2H),
7.32 (t, J ¼ 18.0 Hz, 2H), 7.53 (d, J ¼ 7.8 Hz, 1H), 8.05 (br,
1H); 13C-NMR (75 MHz, CDCl3), d 152.3, 142.2, 136.3, 125.7,
122.8, 122.6, 120.1, 118.7, 111.6, 110.5, 107.4, 77.9, 35.7.
5-Bromo-3-(2-nitro-1-phenylethyl)-1H-indole [32] (3i). Pale
pink solid. yield: 76%. mp 116.6–117.5ꢀC. IR (KBr), m
(cmꢁ1): 3427, 2907, 1548, 1456, 1373, 1104, 799. 1H-NMR
(300 MHz, CDCl3), d 4.89 (dd, J ¼ 8.1, 8.1, 12.3 Hz, 1H), 4.99
(dd, J ¼ 8.4, 8.1, 12.2 Hz, 1H), 5.10 (t, J ¼ 7.8 Hz, 1H), 7.02
(s, 1H), 7.15–7.29 (m, 7H), 7.53 (s, 1H), 8.13 (br, 1H); 13C-
NMR (75 MHz, CDCl3), d 138.7, 135.1, 129.0, 127.9, 127.7,
127.6, 125.6, 122.7, 121.4, 114.0, 113.2, 112.8, 79.4, 41.3.
0.90 (m, 5H), 1.20 (t, J ¼ 14.7 Hz, 13H), 2.37 (s, 1.7H), 2.43
(s, 1.3H), 3.52–3.60 (m, 1H), 3.93 (t, J ¼ 17.1 Hz, 2H), 4.19
(t, J ¼ 11.1 Hz, 1H), 7.03–7.13 (m, 2H), 7.25 (s, 1H), 7.51 (d,
J ¼ 7.2 Hz, 0.5H), 7.59 (d, J ¼ 7.5 Hz, 0.5H), 7.88 (br,
0.5H), 7.95 (br, 0.5H); 13C-NMR (75 MHz, CDCl3), d 166.1,
165.8, 135.5, 135.4, 133.5, 132.9, 126.8, 121.2, 121.1, 119.5,
119.4, 118.7, 118.5, 116.9, 116.6, 110.5, 108.4, 108.3, 62.5,
62.1, 43.7, 43.4, 39.0, 38.9, 31.8, 31.7, 29.2, 29.1, 29.0, 29.0,
27.5, 27.4, 22.55, 14.0, 13.8, 13.4, 12.3, 12.1. HRMS (ESI-
TOF) (M þ Hþ):355.2386, found: 355.2388.
Ethyl 2-cyano-3-(2-methyl-1H-indol-3-yl)-3-phenylpropa-
noate (3p). Pale yellow viscous oil. yield: 85%. dr ¼ 1.1:1. IR
(KBr), m (cmꢁ1): 3401, 2981, 2922, 2245, 1740, 1457, 1305,
1
1244, 1030, 742, 694. H-NMR (300 MHz, CDCl3), d 0.88 (t,
5-Methoxy-3-(2-nitro-1-phenylethyl)-1H-indole [33] (3j). Pale
yellow viscous oil. yield: 93%. IR (KBr), m (cmꢁ1): 3415,
2951, 1549, 1484, 1453, 1375, 798, 701. H-NMR (300 MHz,
J ¼ 14.4 Hz, 1.5H), 1.06 (t, J ¼ 14.4 Hz, 1.5H), 2.24 (s,
1.5H), 2.34 (s, 1.5H), 3.91–3.99 (m, 1H), 4.05–4.12 (m, 1H),
4.46 (d, J ¼ 9.9 Hz, 0.5H), 4.60 (d, J ¼ 9.9 Hz, 0.5H), 5.01
(t, J ¼ 17.7 Hz, 1H), 7.00–7.08 (m, 2H), 7.17–7.36 (m, 5H),
7.48 (t, J ¼ 18.0 Hz, 2H), 7.91 (br, 0.5H), 7.97 (br, 0.5H);
13C-NMR (75 MHz, CDCl3), d 165.7, 165.4, 139.6, 139.2,
135.4, 135.1, 133.2, 133.0, 128.8, 128.7, 128.6, 127.7, 127.6,
127.4, 127.3, 127.2, 127.0, 121.4, 121.3, 119.8, 119.7, 118.7,
118.4, 116.6, 116.4, 110.7, 110.6, 109.5, 109.4, 62.8, 62.5,
43.4, 43.2, 42.4, 42.0, 13.6, 13.4, 12.4, 12.2. HRMS (ESI-
TOF) (M þ Hþ): 333.1603, found: 320.1604.
1
CDCl3), d 3.74 (s, 3H), 4.89 (dd, J ¼ 8.4, 8.4, 12.3 Hz, 1H),
5.00 (dd, J ¼ 7.5, 7.5, 12.3 Hz, 1H), 5.10 (t, J ¼ 8.0 Hz, 1H),
6.83 (d, J ¼ 5.4 Hz, 2H), 6.92 (s, 1H), 7.15–7.30 (m, 6H),
7.98 (br, 1H); 13C-NMR (75 MHz, CDCl3), d 153.7, 138.7,
131.1, 128.4, 127.2, 127.0, 126.1, 121.8, 113.5, 112.2, 111.6,
100.4, 79.0, 55.4, 41.0.
2-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole [33] (3k). Pale
pink solid. yield: 94%. mp 94.5–95.7ꢀC. IR (KBr), m (cmꢁ1):
3413, 2919, 1545, 1457, 1431, 1384, 1299, 741, 704. H-NMR
1
2-((2-Methyl-1H-indol-3-yl)(phenyl)methyl)malononitrile
(3q). White solid. yield: 70%. mp 164.4–166.1ꢀC. IR (KBr), m
(cmꢁ1): 3405, 2895, 2712, 2650, 2252, 1952, 1458, 1419,
1348, 1307, 1245, 1040, 762, 728. 1H-NMR (300 MHz,
CDCl3), d 2.39 (s, 3H), 4.66 (d, J ¼ 9.4 Hz, 1H), 4.94 (d, J ¼
9.4 Hz, 1H), 7.03–7.15 (m, 2H), 7.25–7.43 (m, 7H), 8.02 (br,
1H); 13C-NMR (75 MHz, CDCl3), d 136.7, 134.9, 133.4,
128.5, 127.5, 126.9, 125.7, 121.3, 119.6, 117.7, 112.2, 112.0,
110.5, 107.4, 43.7, 27.2, 11.8. HRMS (ESI-TOF) (M þ
Hþ):286.1344, found: 286.1338.
2-((3-Chlorophenyl)(2-methyl-1H-indol-3-yl)methyl)malono-
nitrile (3r). White solid. yield: 96%. mp 190.4–192.1ꢀC. IR
(KBr), m (cmꢁ1): 3376, 2920, 2255, 1592, 1569, 1456, 1427,
1307, 1244, 1193, 746. 1H-NMR (300 MHz, CDCl3), d 2.43
(s, 3H), 4.63 (d, J ¼ 9.6 Hz, 1H), 4.90 (d, J ¼ 9.6 Hz, 1H),
7.02–7.17 (m, 2H), 7.25–7.37 (m, 6H), 8.08 (br, 1H); 13C-
NMR (75 MHz, CDCl3), d 139.1, 135.4, 135.0, 134.0, 130.2,
128.3, 127.9, 125.2, 122.0, 120.3, 118.0, 112.4, 112.1, 111.1,
111.0, 107.2, 43.9, 27.6, 12.4. HRMS (ESI-TOF) (M þ Hþ):
320.0955, found: 320.0949.
(300 MHz, CDCl3), d 2.31 (s, 3H), 5.08–5.23 (m, 3H), 6.98–
7.11 (m, 2H), 7.20–7.36 (m, 7H), 7.82 (br, 1H); 13C-NMR (75
MHz, CDCl3), d 139.1, 134.9, 132.4, 128.3, 126.8, 126.6,
126.4, 120.8, 119.2, 118.1, 110.2, 108.3, 78.1, 40.0, 11.4.
3-(1-(4-Methoxyphenyl)-2-nitroethyl)-2-methyl-1H-indole [12]
(3l). Pale pink solid. yield: 96%. mp 155.5–156.4ꢀC. IR (KBr),
m (cmꢁ1): 3425, 2921, 1612, 1546, 1510, 1460, 1381, 1244,
1
1183, 1031, 745. H-NMR (300 MHz, CDCl3), d 2.28 (s, 3H),
3.71 (s, 3H), 5.01–5.17 (m, 3H), 6.79 (d, J ¼ 8.7 Hz, 2H),
6.98–7.10 (m, 2H), 7.19 (d, J ¼ 8.4 Hz, 3H), 7.35 (d, J ¼ 7.8
Hz, 1H), 7.83 (br, 1H); 13C-NMR (75 MHz, CDCl3), d 158.0,
135.0, 132.3, 131.13, 127.9, 126.4, 120.8, 119.2, 118.1, 113.7,
110.2, 108.5, 78.4, 54.7, 39.4, 11.4.
2-Methyl-3-(2-nitro-1-p-tolylethyl)-1H-indole [36] (3m). Pale
pink solid. yield: 98%. mp 152.7–153.9ꢀC. IR (KBr), m
(cmꢁ1): 3413, 2917, 1619, 1544, 1456, 1429, 1384, 1204, 739.
1H-NMR (300 MHz, CDCl3), d 2.28 (s, 3H), 2.34 (s, 3H),
5.04–5.22 (m, 3H), 6.99–7.09 (m, 4H), 7.17–7.24 (m, 3H),
7.36 (d, J ¼ 7.8 Hz, 1H), 7.82 (br, 1H); 13C-NMR (75 MHz,
CDCl3), d 136.2, 135.9, 134.9, 132.2, 128.9, 126.7, 126.6,
126.4, 120.8, 119.2, 118.1, 110.1, 108.5, 78.2, 39.6, 20.4, 11.4.
2-Methyl-3-(2-nitro-1,2-diphenylethyl)-1H-indole (3n). Pale
pink solid. yield: 90%. dr ¼ 3.8:1. mp 158.5–161.4ꢀC. IR
(KBr), m (cmꢁ1): 3420, 2921, 1549, 1490, 1454, 1358, 1303,
739. 1H-NMR (300 MHz, CDCl3), d 2.17 (s, 0.6 H), 2.40 (s,
2.4H), 5.36 (d, J ¼ 12.0 Hz, 1H), 6.68 (d, J ¼ 12.3 Hz, 1H),
6.97–7.39 (m, 11H), 7.49–7.77 (m, 4H); 13C-NMR (75 MHz,
CDCl3), d 139.0, 135.4, 133.6, 132.6, 129.8, 129.5, 128.9,
128.8, 128.5, 128.4, 128.3, 127.6, 127.3, 127.1, 126.5, 121.1,
121.0, 119.7, 119.6, 118.7, 110.8, 110.6, 93.7, 93.2, 46.92,
Acknowledgments. This research was supported by the National
Natural Science Foundation of China (No.: 20602024).
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