Boric acid-mediated mild and efficient friedel-crafts alkylation of indoles with nitro styrenes

Article abstract of DOI:10.1080/00397910903457316

An efficient method has been developed for the synthesis of indole 3-derivatives by the Friedel-Crafts alkylation of indole with nitro olefins in presence of boric acid in aqueous medium. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903457316

This article was downloaded by: [University of Wyoming Libraries]
On: 04 September 2013, At: 21:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Boric Acid–Mediated Mild and Efficient
Friedel–Crafts Alkylation of Indoles with
Nitro Styrenes
H. M. Meshram a , N. Nageswara Rao a & G. Santosh Kumar a
a Organic Chemistry Division – I, Indian Institute of Chemical
Technology, Hyderabad, India
Published online: 05 Nov 2010.
To cite this article: H. M. Meshram , N. Nageswara Rao & G. Santosh Kumar (2010) Boric
Acid–Mediated Mild and Efficient Friedel–Crafts Alkylation of Indoles with Nitro Styrenes, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:23, 3496-3500, DOI: 10.1080/00397910903457316
To link to this article: http://dx.doi.org/10.1080/00397910903457316
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 40: 3496–3500, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457316
BORIC ACID–MEDIATED MILD AND EFFICIENT
FRIEDEL–CRAFTS ALKYLATION OF INDOLES
WITH NITRO STYRENES
H. M. Meshram, N. Nageswara Rao, and G. Santosh Kumar
Organic Chemistry Division – I, Indian Institute of Chemical Technology,
Hyderabad, India
An efficient method has been developed for the synthesis of indole 3-derivatives by the
Friedel–Crafts alkylation of indole with nitro olefins in presence of boric acid in aqueous
medium.
Keywords: Boric acid; indole; N-methyl indole; nitro styrene; water
INTRODUCTION
Indole and its derivatives constitute a core structure of many biologically active
natural products some of the indole derivatives are also known to possess important
biological[1] and pharmacological[2] activity. For example, hapalindole alkaloids
exhibit antibacterial and antimycotic activity, and there is continuous interest in
the synthesis of indole derivatives. Commonly indole 3-derivatives are prepared by
the Michael addition of indoles with b-nitrostyrenes in the presence of protic[3] or
Lewis acid[4] such as SmI3, ScCO2, CeCl3. 7H2O–NaI-SiO2, Yb(OTf)3, InCl3, InBr3,
and I2 have been reported for this reaction. Sulfamic acid[5] also reported to catalyze
the Michael addition of indole in solvent free condition. Recently catalyst-free
conjugate addition of indole to b-nitro styrene was reported in aqueous medium[6]
at higher temperature with extended reaction time.
Prospectus of water as a media in organic synthesis is an area of great interest
because of economical and environmental benefits. Recently boric acid[7] has been
employed for various transformations because it is mild and readily available. In
addition, boric acid is an environmentally safe reagent. In fact, some pharmaceutical
and agricultural products contain boric acid. We envisioned to accelerate the
efficiency of the reaction by the addition of boric acid. In our work on the develop-
ment of green and clean methodologies, we describe the boric acid-promoted
efficient and mild Friedel–Crafts alkylation of indole with b-nitro styrene.
Thus the reaction of indole (1 eq.) with b-nitrostyrene (1 eq.) in the presence
of boric acid (1 eq.) in water (Scheme 1) leads to high yield of expected product in
Received August 7, 2009.
Address correspondence to H. M. Meshram, Organic Division I, Indian Institute of chemical
Technology, Hyderabad 500 007, India. E-mail: hmmeshram@yahoo.com
3496

ALKYLATION OF INDOLES WITH NITRO STYRENES
3497
Scheme 1. Friedel–Crafts alkylation of indole with nitro olefins.
10 min. This reaction enhancement may be attributed to the presence boric acid.
Next we optimize the ratio of boric acid to catalyze this transformation. It was grati-
fying to note that 20 mol% of boric acid was found suitable for optimum yield (85%)
of product. The same reaction with 10 mol% of boric acid afforded the expected
product in 40% in 45 min. We have not observed any substantial increase in the yield
of product after addition of more boric acid (30 mol %).
To study the effect of substituent on the reactivity of styrene, we examined
the substituted b-nitrostyrene having electron withdrawal and electron donation and
observed that nitrostyrene with m-nitro substituted (entries 1c and 2c) reacted very rap-
idly with indole to yield the desired product in high yield. In the electron donating
(entry-1a, 1b, 2a and 2b) however, substituent on nitrosryrene suppress the reaction
of indole. Further the reaction of N-methyl indole with nitrosyrene gives high yield
of product within a short time (entry-2c). This fact suggests that the presence of methyl
in nitrogen increases the electron density at third position of indole. Though the reac-
tion is reported only in aqueous medium, the present study showed remarkably great
enhancement in the reaction using boric acid which may save the time and energy.
In conclusion we have demonstrated a very rapid Friedel–Crafts alkylation
of indole with nitro styrene in the presence of boric acid. The high yield, shortest
reaction time, mild reaction condition and aqueous medium are the important
features of the present protocol.
EXPERIMENTAL
General Procedure: Synthesis of 3-(2-Nitro-1-(3-nitrophenyl)
ethyl)-1H-Indole
To a mixture of indole (1 eq.) and Nitrostyrene (1 eq.) in water was added
boric acid (20 mol %) the mixture was stirred at room temperature for appropriate time
(see Table 1). After completion of the reaction as indicated by TLC, the mixture was
diluted with water. It was extracted with ethyl acetate, combine organic layer washed
with water dried over sodium sulphate and solvent removed under reduced pressure.
The crude product was purified by column chromatography using ethyl acetate-hexane
(9:1) as an eluent. All the compounds were characterized by spectral data.
I
Compound 1a: HNMR (CDCl3, 300 MHz) d (ppm) 3.77 (s, 3H), 4.88–5.02
(m, 2H), 5.12 (t, 1H, J ¼ 7.6 Hz), 6.20–6.85 (m, 2H), 7.01–7.10 (m, 2H), 7.17–7.35

3498
H. M. MESHRAM, N. N. RAO, AND G. SANTOSH KUMAR
Table 1. Friedel–Crafts alkyation of indoles with nitrostyrene
(m, 4H), 7.45 (d, 1H), 8.06 (s, 1H). IR (KBr) n ¼ 700, 753, 906, 1120, 1280, 1338,
1378, 1430, 1510, 1550, 1598, 2853, 3010, 3358 cmꢀ1. EIMS: m=z 296 (Mþ).
Compound 1b: IHNMR (CDCl3, 300 MHz) d (ppm) 3.78 (s,3H), 3.84 (s, 3H)
4.80–5.04 (m, 2H), 5.10 (t, 1H, J ¼ 7.8 Hz), 6.75–6.86 (m, 3H), 6.96 (d, 1H,

ALKYLATION OF INDOLES WITH NITRO STYRENES
3499
J ¼ 2.0 Hz), 7.03 (t, 1H, J ¼ 7.5 Hz), 7.15 (t, 1H, J ¼ 7.4 Hz), 7.30 (d, 1H, J ¼ 8.1 Hz),
7.40 (d, 1H, J ¼ 7.9 Hz), 8.05 (br, s, 1H). IR (KBr) n ¼ 662, 694, 753, 862, 904,
1024, 1102, 1143, 1260, 1339, 1377, 1424, 1459, 1514, 1550, 1595, 2853, 2927,
I
3011, 3367 cmꢀ1. EIMS: m=z 326(Mþ). Compound 1c: HNMR (CDCl3, 300 MHz)
d (ppm) 4.90–5.10 (m, 2H), 5.28 (t, 1H, J ¼ 7.9 Hz), 7.02–7.04 (d, 1H, J ¼ 2.4 Hz),
7.04–7.08 (d, 1H, J ¼ 7.3 Hz), 7.15–7.21 (m, 1H), 7.31–7.36 (d, 2H, J ¼ 8.6 Hz),
7.52 (t, 1H, J ¼ 7.9 Hz), 7.66–7.72 (d, 1H, J ¼ 7.7 Hz), 8.11–8.15 (m, 2H), 8.20 (br,
s, 1H). IR (KBr) n ¼ 742, 807, 1098, 1348, 1461, 1527, 1553, 1616, 1645, 2853,
2923, 3416 cmꢀ1. EIMS: m=z 334 (MþNa). Compound 1d: 1HNMR (CDCl3,
300 MHz) d (ppm) 4.80–5.00 (m, 2H), 5.62 (t, 1H, J ¼ 7.7 Hz), 7.00–7.08 (m, 3H),
7.12–7.19 (m, 2H), 7.30 (d, 2H, J ¼ 7.9 Hz), 7.46(d, 1H, J ¼ 1.5 Hz), 8.08(br, s,
1H). IR (KBr) n ¼ 752, 1101, 1375, 1461, 1552, 1636, 2855, 2922, 3419 cmꢀ1. EIMS:
I
m=z 358(MþNa). Compound 1e: HNMR (CDCl3, 300 MHz) d (ppm) 4.80–5.04 (m,
2H), 5.12 (t, 1H), 6.96–6.99 (m, 1H), 7.06 (t, 1H, J ¼ 7.5 Hz), 7.13–7.21 (m, 2H),
7.28–7.37 (m, 3H), 7.40 (br, s, NH). IR (KBr) n ¼ 674, 746, 1029, 1130, 1195,
1376, 1422, 1464, 1551, 1627, 2854, 2923, 3421 cmꢀ1. EIMS: m=z 358 (Mþ Na).
I
Compound 1f: HNMR (CDCl3, 300 MHz) d (ppm) 5.02–5.10 (m, 2H), 5.54 (t, 1H,
J ¼ 7.9 Hz), 7.08–7.12 (m, 1H), 7.13–7.16 (t, 1H, J ¼ 2.2 Hz), 7.18–7.24 (m, 1H),
7.26 (s, 1H), 7.28–7.38 (m, 2H), 7.42 (d, 1H, J ¼ 7.9 Hz), 8.14–8.18 (m, 1H),
8.21(br, s, 1H). IR (KBr) n ¼ 703, 744, 832, 906, 1103, 1248, 1346, 1420, 1461,
I
1554, 1628, 2853, 2922, 3418 cmꢀ1. EIMS: m=z 329(Mþ). Compound 2a: HNMR
(CDCl3, 300 MHz) d (ppm) 3.78 (s, 3H), 3.82 (s, 3H), 4.81–5.01 (m, 2H), 5.07 (t,
1H, J ¼ 7.7 Hz), 6.21–6.81 (m, 2H), 7.02–7.12 (m, 2H), 7.15–7.38 (m, 2H), 7.42 (m,
2H), 7.54 (m, 1H). IR (KBr) n ¼ 707, 763, 1112, 1280, 1336, 1410, 1520, 1599,
I
2873, 3011, 3354 cmꢀ1. EIMS: m=z 333 (MþNa). Compound 2b: HNMR (CDCl3,
300 MHz) d (ppm) 3.74 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 4.79–4.98 (m, 2H), 5.05
(t, 1H, J ¼ 7.8 Hz), 6.74 (d, 3H, J ¼ 7.8 Hz), 6.82 (m, 1H), 7.01 (t, 1H, J ¼ 7.8 Hz),
7.16 (t, 1H, J ¼ 7.8 Hz), 7.21 (s, 1H), 7.38 (d, 1H, J ¼ 7.8 Hz). IR (KBr) n ¼ 677,
734, 761, 803, 840, 861, 905, 1020, 1089, 1133, 1155, 1240, 1264, 1303, 1332, 1374,
1428, 1462, 1511, 1550, 1608, 2925, 3003, 3047, 3119 cmꢀ1. EIMS: m=z 363(MþNa).
Compound 2c: IHNMR (CDCl3, 300 MHz) d (ppm) 3.80 (s, 3H), 4.91–5.07 (m, 2H),
5.25 (t, 1H, J ¼ 8.2 Hz), 6.88 (s, 1H), 7.04 (t, 1H, J ¼ 7.8z), 7.18–7.22 (t, 1H,
J¼ 6.8 Hz, J ¼ 7.8 Hz), 7.25 (m, 2H), 7.33 (d, 1H, J ¼ 7.8 Hz), 7.51 (t, 1H, J ¼ 7.8 Hz),
7.67 (d, 1H, J ¼ 7.8 Hz), 8.13 (d, 1H, J ¼ 7.8 Hz), 8.19 (br, s, 1H). IR (KBr)
n ¼ 690, 740, 769, 898, 1089, 1218, 1347, 1375, 1432, 1473, 1528, 1617, 2854, 2924,
I
3040 cmꢀ1. EIMS: m=z 326 (Mþ þ 1). Compound 2d: HNMR (CDCl3, 300 MHz) d
(ppm) 3.79 (s, 3H), 4.85–4.93 (m, 2H), 5.61 (t, 1H, J ¼ 7.5 Hz), 6.90 (s, 1H), 7.03
(m, 1H), 7.13–7.28 (m, 2H), 7.30–7.38 (m, 1H), 7.40 (d, 1H, J ¼ 1.5 Hz), 7.45 (s,
1H), 7.62 (d, 1H, J ¼ 8.3 Hz). IR (KBr) n ¼ 700, 742, 810, 870, 1020, 1230, 1333,
1370, 1420, 1520, 1616, 2923, 3040 cmꢀ1. EIMS: m=z 372(MþNa). Compound 2e:
IHNMR (CDCl3, 300 MHz) d (ppm) 3.78 (s, 3H), 4.78–5.02 (m, 2H), 5.11 (t, 1H,
J ¼ 7.7 Hz), 6.80 (s, 1H), 7.05 (t, 1H, J ¼ 7.9 Hz), 7.14–7.25 (m, 3H), 7.33 (d, 1H,
J ¼ 7.9 Hz), 7.35–7.42 (d, 2H, J ¼ 7.9 Hz). IR (KBr) n ¼ 707, 743, 818, 868, 1030,
1077, 1132, 1245, 1334, 1375, 1403, 1471, 1552, 1616, 2923, 3056 cmꢀ1. EIMS: m=z
349 (Mþ). Compound 2f: IHNMR (CDCl3, 300 MHz) d(ppm) 3.80 (s, 3H), 4.97–5.06
(m, 2H), 5.49 (t, 1H, J ¼ 8.2 Hz), 6.93 (s, 1H), 7.08 (t, 1H, J ¼ 7.8 Hz), 7.19–7.28 (m,
3H), 7.43 (d, 1H, J ¼ 7.8 Hz), 8.14–8.20 (m, 2H). IR (KBr) n ¼ 743, 833, 905, 1014,

3500
H. M. MESHRAM, N. N. RAO, AND G. SANTOSH KUMAR
1085, 1122, 1247, 1247, 1345, 1375, 1474, 1527, 1552, 1586, 1623, 2853, 2923,
3044 cmꢀ1. EIMS: m=z 343 (Mþ1).
ACKNOWLEDGMENTS
The authors thank CSIR-UGC for the award of a fellowship and Dr. J. S.
Yadav, Director IICT, for his support and encouragement.
REFERENCES
1. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970.
2. (a) Kalir, A.; Szara, S. Synthesis and pharmacological activity of fluorinated tryptamine
derivatives. J. Med. Chem. 1963, 6, 716–719; (b) Moore, R. E.; Cheuk, C.; Yang, X. Q.;
Patterson, G. M. L.; Bonjouklian, R.; Smita, T. A.; Myderse, J.; Foster, R. S.; Jones, N.
D.; Skiatzendrtuber, J. K.; Deeter, J. B. Hapalindoles, antibacterial and antimycotic
alkaloids from the cyanophyte hapalosiphon fontinalis. J. Org. Chem. 1987, 52, 1036–
1043; (c) Noland, W. E.; Christensen, G. M.; Sauer, G. L.; Dutton, G. G. S. The reaction
of nitroolefins with indole. J. Am. Chem. Soc. 1955, 77, 456–457.
3. (a) Bandini, M.; Fagioli, M.; Uma-Ronchi, A. Solid acid–catalysed Michael type conjugate
=
addition of indoles to electron-poor C C bonds: Towards high atom economical semi-
continuous processes. Adv. Synth. Catal. 2004, 346, 545–548; (b) Szmuskovicz, J. The
reaction of substituted indoles with methyl vinyl ketone: New synthesis of 2-methylcarbazole.
J. Am. Chem. Soc. 1957, 79, 2819–2821.
4. (a) Zhang-Ping, Z.; Kai, L. Microwave-accelerated samarium triiodide catalyzed conjugate
addition of indoles with electron-deficient olefins. Synlett 2005, 10, 1551–1554; (b) Komoto,
I.; Kobayashi, S. Lewis acid catalysis in supercritical carbon dioxide. Use of poly(ethylene
glycol) derivatives and perfluoroalkylbenzenes as surfactant molecules which enable
efficient catalysis in ScCO2. J. Org. Chem. 2004, 69, 680–688; (c) Bartoli, G.; Bosco, M.;
Giuli, S.; Giuliani, A.; Lucarelli, L.; Marcantoni, E.; Sambri, L.; Torregiani, E. Efficient
preparation of 2-indolyl-1-nitroalkane derivatives employing nitroalkenes as versatile
Michael acceptors: New practical linear approach to alkyl 9H-b-carboline-4-carboxylate.
J. Org. Chem. 2005, 70, 1941–1944; (d) Harrington, P. E.; Kerr, M. A. Reaction of indoles
with electron deficient olefins catalyzed by Yb(OTf)3 ꢁ 3H2O. Synlett 1996, 1047–1048; (e)
Yadav, J. S.; Abraham, S.; Reddy, B. V. S.; Sabitha, G. InCl3-catalysed conjugate addition
of indoles with electron-deficient olefines. Synthesis 2001, 2165–2169; (f) Bandini, M.;
Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. A practical indium tribromide catalysed
addition of indoles to nitro alkenes in aqueous media. Synthesis 2002, 1110–1114; (g)
Chunch, L.; Jianming, H.; Sastry, M. N. V.; Hulin, F.; Zhijay, T.; Ju-Tsung, L.; Ching-Fa,
Y. I2-catalysed Michael addition of indole and pyrrole to nitroolefins. Tetrahedron 2005,
61, 11751–11757.
5. Li-Tao, A.; Jian-Ping Z.; Li-Li, Z.; Yong, Z. Sulfamic acid catalysed Michael addition
of indoles and pyrrole to electron-deficient nitroolefins under solvent-free condition.
Tetrahedron Lett. 2007, 48, 4297–4300.
6. Pateliya, M. H.; Veerababurao, K.; Chun-Wei, K.; Ching-Fa, Y. Catalyst-free aqueous-
mediated conjugative addition of indoles to b-nitrostyrenes. Tetrahedron Lett. 2008, 49,
7005–7007.
7. (a) Todd, A. H.; Brendan, L. W.; Joanne, T. B. Boric acid catalyzed chemoselective
esterfication of a-hydroxycarboxylic acids. Org. Lett. 2004, 6, 679–681; (b) Pingwah, T.
Boric acid catalyzed amide formation from carboxylic acids and amines: N-Benzyl-
4-phenylbutyramide. Org. Synth. 2005, 81, 262–268.