Catalyst-free aqueous-mediated conjugative addition of indoles to β-nitrostyrenes

Article abstract of DOI:10.1016/j.tetlet.2008.09.109

A catalyst free aqueous-mediated alkylation of indoles with various β-nitrostyrenes was performed at elevated temperature. No catalyst, clean reaction conditions, simple workup procedure, easy isolation, viability for large scale preparation, and environm

Full text of DOI:10.1016/j.tetlet.2008.09.109

Tetrahedron Letters 49 (2008) 7005–7007
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalyst-free aqueous-mediated conjugative
addition of indoles to b-nitrostyrenes
*
Pateliya Mujjamil Habib, Veerababurao Kavala, Chun-Wei Kuo, Ching-Fa Yao
Department of Chemistry, National Taiwan Normal University, 88, Section 4, Tingchow Road, Taipei 116, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2008
Revised 17 September 2008
Accepted 19 September 2008
Available online 23 September 2008
A catalyst free aqueous-mediated alkylation of indoles with various b-nitrostyrenes was performed at
elevated temperature. No catalyst, clean reaction conditions, simple workup procedure, easy isolation,
viability for large scale preparation, and environmentally acceptable medium are the best features in this
process.
Ó 2008 Elsevier Ltd. All rights reserved.
The use of water as a green media for organic synthesis has be-
come an important research area. Other than the economical and
environmental benefits, water also exhibits unique physical and
chemical properties which lead to unique reactivity and selectivity
in comparison with organic solvents. Thus, the development of
organic reaction in water medium is necessitating in the present
days.1 Indole and many of its derivatives are widely distributed
in the nature, which possesses biological and pharmacological
activity.2 For instance, the hapalindole alkaloids, which exhibit sig-
nificant antibacterial and antimycotic activity, and several indole
alkaloids such as uleine, aspidospermidine, ibophyllidine alkaloids,
and numerous tryptamine derivatives are also associated with
important biological activity.3 Therefore, the development of new
strategies to synthesize indole derivatives has been the subject of
interest in the present days. Michael addition is one of the most
important tools for the synthesis of 3-substituted indole deriva-
tives.4 Nitroalkenes are strong Michael acceptors, and Michael
adducts of nitroalkenes can be readily transformed into different
functionalities.4
and toxicity of metal salts makes methods less attractive. The
drawbacks associated with some of the procedures reported in lit-
erature are the use of hazardous catalysts, tedious workup proce-
dures, and difficulties in product isolation. The most important
drawback is the tendency of electron-rich hetero aromatics to un-
dergo polymerization in the presence of acid catalyst. In this con-
text, the search for achieving
a general and environmental
accessible method for conjugative addition of indoles to b-nitrosty-
rene remains in great demand. Hence, we reveal a new, mild, and
easy procedure for conjugative addition of indole to b-nitrosty-
renes in aqueous medium without any catalyst.
Conjugative addition of indoles to b-nitroalkenes in presence of
acid catalyst in aqueous medium has been reported in litera-
ture.6c,6h,6i,6k It was observed that the reaction of b-nitrostyrene
with indole under catalyst-free conditions, in aqueous medium, re-
sulted in 28% of product formation. However, upon addition of the
surfactant (SDS) did not show any improvement in the reaction.6h
Recently, Kusurkar group have described catalyst-free Michael
addition of b-nitrostyrene with indole at 120–140 °C in benzene
in 48 h.8 It has been proven that water acts as an acid at elevated
temperature in different reactions.9 Recently, many of the acid-cat-
alyzed reactions were carried out successfully without any catalyst
in aqueous medium.10 Based on the above reports, we assume that
the reaction of b-nitrostyrene with indole could work in water
without any catalyst under thermal conditions.
In our initial efforts, we observed that the reaction of b-nitrosty-
rene 1 (2 mmol) with indole (2.4 mmol) in water (5 ml) without
any catalyst, ca. 30% of the product was formed after 24 h at room
temperature. When the reaction was conducted at 50–60 °C, the
reaction proceeded to near completion in 20 h. However, upon fur-
ther increasing the temperature to 100 °C, the reaction was com-
pleted in 6 h. With this preliminary success, further we focused
our attention to extend the scope of the reaction by choosing wide
varieties of indoles and b-nitrostyrenes. This synthetic approach
allows the facile introduction of 2-nitroethyl-functionalized
Owing to the importance of this transformation, several proce-
dures have been reported in literature using acid catalysts.5 A wide
variety of Lewis acids such as Yb(OTf)3,6a InCl3,6b InBr3,6c Yb(OTf)3
6d
in ScCO2, SmI3,6e CeCl3Á7H2O–NaI–SiO2,6f and iodine6g were used
for this purpose. Other catalysts such as [Al(DS)3]Á3H2O,6h hetero-
polyacids,6i and basic alumina6j were also used for this reaction.
Very recently, sulfamic acid6k and carbohydrate-based tolylsulfo-
nyl hydrazines6l were reported as catalysts for this transformation.
Chiral version of this reaction was also reported using various
chiral catalysts.7
Although metal salts, triflates, and other acidic catalysts are
effective for the Friedel–Crafts alkylation reaction, their use is lim-
ited. The strong acidic character of triflates results in side reactions
* Corresponding author. Tel./fax: +886 2 29309092.
E-mail address: cheyaocf@yahoo.com.tw (C.-F. Yao).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.109

7006
P. M. Habib et al. / Tetrahedron Letters 49 (2008) 7005–7007
substituents into the 3-position of indole nucleus, possibly serving
as a source for the corresponding amino-based building blocks for
the construction of biomolecules.11
The reaction time varied according to the nature of the substi-
tuent on the b-nitrostyrene. For example, b-nitrostyrene possess-
ing strong electron-releasing group (OMe) such as 4-methoxy-(b-
nitrostyrene) (3) and 3,4-methyleneoxy-(b-nitrostyrene) (4)
underwent slow reaction (12 h and 10 h) to obtain their corre-
sponding adducts (3a and 4a), respectively. Similar trend was
observed in case of 4-methyl-(b-nitrostyrene) (5). Whereas
b-nitrostyrenes bearing electron-withdrawing groups (Cl, NO2),
such as 4-chloro (b-nitrostyrene) (6) and 4-nitro-(b-nitrostyrene)
(7), proceed smoothly in short reaction times (6 h and 4 h) to their
corresponding indole adducts. Moreover, sterically hindered naph-
thyl nitroalkene (8) reacted with indole to afford the product (8a)
in good yield. It’s important to note that the acid-sensitive moieties
such as furan (9) and thiophene (10) survived under the present
reaction conditions (Table 1).
The electronic density of the indole ring would also play an
important role in this reaction. The electron-rich indole such as
5-methoxy indole alkylated with b-nitrostyrene in shorter time
to obtained (1e) in high yield. The reaction of N-methylindole with
b-nitrostyrene underwent smoothly to furnish the product (1c) in
high yield. This may be due to the presence of electron-releasing
methyl group which activates the indole ring towards the nucleo-
philic attack. It was observed that increasing the size of the substi-
tuent close to the reaction center, as in case of 2-methyl indole and
2-phenyl indole, also added to b-nitrostyrene without any diffi-
culty, which cannot be attained in basic conditions.6j However,
electron-withdrawing group (Br) bearing indole such as 5-bromo
indole took longer reaction period to obtain good yield of product
(1f). The results are summarized in Table 2.
Table 1
Reaction of various b-nitrostyrenes with indoles in water12
HN
NO2
+
Water
NO2
R
100 o
C
N
R
H
Substratea
Productb
Time
(h)
Yieldc
(%)
NH
NH
NO2
1
1a
2a
5
6
85
O2N
OH
NO2
2
69
76
64
81
80
78
70
68
65
OH
O2N
O
The most important feature of this method is dialkylation of
1,4-bis-(2-nitrovinyl)benzene with substituted indoles. Under the
NH
NH
NO2
3a
4a
12
10
8
3
O
Table 2
O2N
Reaction of b-nitrostyrene with various indoles in water12
O
R'
HN
NO2
O
O
O
4
NO2
+
Water
NO2
O2N
R'
100 oC
N
H
NH
Substratea
Productb
Time (h)
6
Yieldc (%)
NO2
5a
5
NH
N
O2N
1b
1c
80
82
b
N
H
Cl
NH
NO2
O2N
O2N
6a
6
6
Cl
O2N
6
8
c
N
O2N
NH
NO2
4
7a
7
O2N
O2N
NH
NH
Ph
d
78
N
H
NH
1d
NO2
10
5
O2N
O2N
8a
8
O2N
O
NH
NH
1e
5
83
73
O
e
N
H
O
O2N
NO2
O
9a
9
NH
Br
S
1f
15
f
S
NO2
10
9
N
H
O2N
10a
Br
O2N
a
a
All reactions were performed at 2 mmol scale.
All reactions were performed at 2 mmol scale.
b
All products were well characterized by 1H NMR, 13C NMR, and mass
b
All products were well characterized by 1H NMR, 13C NMR, and mass
spectroscopy.13
spectroscopy.13
c
c
Isolated yields.
Isolated yields.

P. M. Habib et al. / Tetrahedron Letters 49 (2008) 7005–7007
7007
Melloni, A.; Umani-Ronchi, A. Synthesis 2002, 1110; (d) Komoto, I.; Kobayashi,
S. J. Org. Chem. 2004, 69, 680; (e) Zhan, Z.-P.; Yang, R.-F.; Lang, K. Tetrahedron
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Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2005, 70, 1941; (g) Lin, C.;
Hsu, J.; Sastry, M. N. V.; Fang, H.; Tu, Z.; Liu, J.-T.; Yao, C.-F. Tetrahedron 2005,
61, 11751; (h) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F. Chem. Commun. 2005,
789; (i) Azizi, N.; Arynasab, F.; Saidi, M. R. Org. Biomol. Chem. 2006, 4275; (j)
Ballini, R.; Clemente, R. R.; Palmieri, A.; Petrini, M. Adv. Synth. Catal. 2006, 348,
191; (k) An, L.-T.; Zou, J.-P.; Zhang, L. L.; Zhang, Y. Tetrahedron Lett. 2007, 48,
4297; (l) Wu, P.; Wan, Y.; Cai, J. Synlett 2008, 1193.
O2N
NO2
R
R
NH
HN
11
O2N
Water
100 o
+
C
NO2
R
R
H
CH3
Time(h)
Yield %
70
N
11a
11b
7
12
R = H, CH3
H
60
7. (a) Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006, 71, 75; (b)
Bandini, M.; Garelli, A.; Rovinetti, M.; Tommasi, S.; Umani-Ronchi, A. Chirality
2005, 17, 522; (c) Zhan, Z.-P.; Lang, K. Synlett 2005, 1551; (d) Dessolé, G.;
Herrera, R. P.; Ricci, A. Synlett 2004, 2374; (e) Herrera, R. P.; Sgarzani, V.;
Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576; (f) Zhuang, W.;
Hazell, R. G.; Jorgensen, K. A. Org. Biomol. Chem. 2005, 2566.
Scheme 1. Reaction of 1,4-bis-(2-nitrovinyl)benzene with various indoles.
HN
8. Kusurkar, R. S.; Alkobati, N. A.; Gokule, A. S.; Chaudhari, P. M.; Waghchaure, P.
B. Synth. Commun. 2006, 36, 1075.
9. (a) Kavala, V.; Samal, A. K.; Patel, B. K. Arkivoc 2005, i, 20; (b) Nagai, Y.;
Matubayasi, N.; Nakahara, M. Bull. Chem. Soc. Jpn. 2004, 77, 691 references cited
therein.
10. (a) Maggi, R.; Bigi, F.; Carloni, S.; Mazzacani, A.; Sartori, G. Green Chem. 2001,
173; (b) Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649; (c) Chankeshwara, S. V.;
Chakraborti, A. K. Org. Lett. 2006, 8, 3259; (d) Khatik, G. L.; Kumar, R.;
Chakraborti, A. K. Org. Lett. 2006, 8, 2433.
25 mL
100 oC
NO2
NO2
+
N
H
30 mmol
36 mmol
87 %
Scheme 2. Large-scale reaction of b-nitrostyrenes with indole.
11. (a) McNulty, J.; Mo, R. Chem. Commun. 1998, 933; (b) Weller, T.; Seebach, D.
Tetrahedron Lett. 1982, 23, 935.
present reaction conditions, various indoles reacted with 1,4-bis-
(2-nitrovinyl)benzene to give moderate yields of bis-indolyl
adducts (Scheme 1).
In order to extend the scope of the methodology, we carried out
the reaction in large scale by taking 30 mmol of nitrostyrene and
36 mmol of indole in 25 ml water at 100 °C. The reaction pro-
ceeded without any difficulty to obtain high yield of product
(Scheme 2).
12. Typical experimental procedure:
A mixture of indole (1.2 mmol) and
b-nitrostyrene (1 mmol) was suspended in 2 mL of water, and the reaction
mixturewas heatedat 100 °C. Theprogress ofthe reactionwas monitored byTLC.
After completion of the reaction, the reaction mixture was extracted with ethyl
acetate (2 Â 10 mL). The organic layer was separated, dried over anhydrous
sodium sulfate, and concentrated to obtain crude product. Further purification
was achieved by column chromatography using EA/hexane as eluent.
13. Spectral data: 1a,6f,6g,6i,6k 3a,6e,6g,6i 4a,6g 6a,6g,8 9a,6g,6k,8 10a,6g,8 1b,6g,6i
,
1c,6g,6i,6k 1e,6f,6i 1f,6k and 11a6k are known compounds. 2-(1-(1H-Indol-3-yl)-
2-nitroethyl) phenol (2a): colorless solid, mp 72–74 °C. 1H NMR (CDCl3,
400 MHz): d 8.10 (br s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H),
7.18–7.06 (m, 5H), 6.84 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.48 (t,
J = 7.8 Hz, 1H), 5.34 (br s, 1H), 5.12–5.00 (m, 2H). 13C NMR (CDCl3, 100 MHz): d
154.3, 136.6, 129.3, 128.7, 126.6, 125.7, 122.6, 122.3, 120.6, 119.8, 119.2, 116.2,
113.8, 111.5, 78.2, 36.3. Ms (m/z) (relative intensity) 282(M+, 30), 235(12),
234(18), 220(100), 204(12), 165(12), 143(12), 130(12), 117(24), 91(12),
77.1(10). HRMS: calcd for C16H14N2O3: calcd 282.0999 found 282.1000. 3-(2-
Nitro-1-p-tolylethyl)-1H-indole (5a): viscous liquid 1H NMR (CDCl3, 400 MHz): d
8.06 (br s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.16–7.25 (m,
3H), 7.11 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 1.8 Hz,1H), 5.14
(t, J = 8.0 Hz, 1H), 5.01–5.07 (m, 1H), 4.88–4.93 (m, 1H), 2.3 (s, 3H). 13C NMR
(CDCl3, 100 MHz): d 137.4, 136.7, 136.4, 129.8, 127.8, 126.3, 122.8, 121.7,
120.1, 119.2, 114.8, 111.5, 79.8, 41.4, 21.2. MS m/z (relative intensity) 280(M+,
63), 233(100), 235(12), 220(80), 218(48), 204(15), 132(18), 115(20), 108(24),
89(9). HRMS: calcd for C17H16N2O2: calcd 280.1206 found 280.1210. 3-(1-(4-
Nitrophenyl)-2-nitroethyl)-1H-indole (7a): colorless solid; mp 145–147 °C. 1H
NMR (CDCl3, 400 MHz): d 8.22 (br s, 1H), 8.18 (d, J = 8.8 Hz, 2H), 7.52 (d,
J = 8.4 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz,
1H), 7.05 (s, 1H), 5.30 (t, J = 8.0 Hz, 1H), 5.08–5.13 (m, 1H), 4.95–5.02 (m, 1H).
13C NMR (CDCl3, 100 MHz): d 147.6, 146.9, 136.7, 128.9, 125.8, 124.4, 123.3,
121.8, 120.5, 118.7, 113.2, 111.8, 78.9, 41.4. MS m/z (relative intensity):
311(M+, 44), 264(100), 218(28), 204(16), 143(4), 108(12). HRMS: calcd for
C16H13N3O4: calcd 311.0901 found 311.0896. 3-(1-(Naphthalen-2-yl)-2-
nitroethyl)-1H-indole (8a): colorless solid; mp 140–142 °C. 1H NMR (CDCl3,
400 MHz): d 8.27 (d, J = 8.4 Hz, 1H), 8.04 (br s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.78
(t, J = 4.8 Hz, 1H), 7.57–7.50 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.38–7.33 (m, 3H),
7.19 (t, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.07 (t,
J = 7.8 Hz, 1H), 5.06–5.11 (m, 2H). 13C NMR (CDCl3, 100 MHz): d 136.6, 134.6,
134.2, 131.1, 129.2, 128.3, 126.8, 126.1, 125.9, 125.3, 124.6, 122.7, 122.6, 122.5,
120.0, 118.8, 114.3, 111.4, 78.5, 36.9. MS m/z (relative intensity): 316(M+,40),
269(76), 268(100), 254(57), 241(18), 226(9), 153.1(78), 115(28), 89.(9). HRMS:
calcd for C20H16N2O2: calcd 316.1206 found 316.1213. 3-(2-Nitro-1-
phenylethyl)-2-phenyl-1H-indole (1d): colorless solid; mp 143–145 °C. 1H
NMR (CDCl3, 400 MHz): d 8.14 (br s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.43 (br s,
5H), 7.38–7.26 (m, 5H), 7.28–7.17 (m, 2H), 7.1 (t, J = 7.4 Hz, 1H), 5.31 (t,
J = 8.0 Hz, 1H), 5.09–5.20 (m, 2H). 13C NMR (CDCl3, 100 MHz): d 140.1, 137.1,
136.3, 132.4, 129.1, 129.0, 128.9, 128.8, 127.7, 127.4, 122.7, 120.5, 120.1, 111.6,
109.8, 79.3, 40.9. MS m/z (relative intensity): 342(M+, 96), 296(18), 294(90),
282(50), 280(18), 218(60), 207(100), 165 (16), 139(14), 103(12), 77(18).
HRMS: calcd for C22H18N2O2: calcd 342.1363 found 342.1366. 1,4-Bis(1-(2-
methyl-1H-indol-3-yl)-2-nitroethyl) benzene (11b): colorless solid mp 238–
240 °C. 1H NMR (DMSO-d6, 400 MHz): d 10.9 (br s, 2H), 7.44 (d, J = 8.0 Hz, 2H),
7.30 (s, 4H), 7.22 (d, J = 8. Hz, 2H), 6.95 (t, J = 7.6 Hz, 2H), 6.84 (t, J = 7.6 Hz 2H),
5.47–5.42 (m, 2H) 5.25–5.31 (m, 2H), 4.97–5.10 (m, 2H), 2.39 (s, 6H). 13C NMR
(DMSO-d6, 100 MHz): d 138.9, 135.5, 133.2, 127.6, 126.5, 120.3, 118.7, 118.5,
110.9, 108.2, 78.2, 11.7. MS m/z (relative intensity): 482(M+, 12), 422(9),
374(16), 216(6), 187(6), 143(100), 129(30). HRMS: calcd for C28H26N4O4: calcd
482.1954. found 482.1949.
In conclusion, we have achieved an un-catalyzed Friedel–Craft’s
alkylation of indole with b-nitrostyrenes in water. The procedure is
entirely green, and applied for structurally diverse indoles as well
as for b-nitrostyrenes to obtained good yields. Simple reaction con-
ditions, easy isolation of the products, use of green solvent and via-
bility for the large-scale preparation are the advantages of the
present method over the reported procedures. Hence, this method
is not only representing green alternatives to the literature proce-
dures but also would find practical use in the construction of
3-substituted indole derivatives.
Acknowledgments
Financial support of this work by the National Science Council
of the Republic of China and National Taiwan Normal University
(TOP001) is gratefully acknowledged.
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