Mild and efficient Michael addition of activated olefins to indoles using TBAB as a catalyst: Synthesis of 3-substituted indoles

Article abstract of DOI:10.1080/00397910801989600

A mild and efficient method for the synthesis of 3-substituted indoles by treatment of activated olefins with indoles using TBAB as a catalyst afforded the corresponding products in excellent yields. The method is general for the preparation of a wide var

Full text of DOI:10.1080/00397910801989600

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Mild and Efficient Michael Addition of
Activated Olefins to Indoles using TBAB as a
Catalyst: Synthesis of 3‐Substituted Indoles
K. Suresh Babu a , V. Rama Subba Rao a , P. Sunitha a , S. Sivaram Babu a & J.
Madhusudana Rao a
a Organic Chemistry Division I, Natural Products Laboratory, Indian Institute
of Chemical Technology, Hyderabad, India
Published online: 09 May 2008.
To cite this article: K. Suresh Babu , V. Rama Subba Rao , P. Sunitha , S. Sivaram Babu & J. Madhusudana Rao
(2008) Mild and Efficient Michael Addition of Activated Olefins to Indoles using TBAB as a Catalyst: Synthesis
of 3‐Substituted Indoles, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:11, 1784-1791, DOI: 10.1080/00397910801989600
To link to this article: http://dx.doi.org/10.1080/00397910801989600
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Synthetic Communicationsw, 38: 1784–1791, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801989600
Mild and Efficient Michael Addition
of Activated Olefins to Indoles using TBAB
as a Catalyst: Synthesis of 3-Substituted
Indoles
K. Suresh Babu, V. Rama Subba Rao, P. Sunitha, S. Sivaram
Babu, and J. Madhusudana Rao
Organic Chemistry Division I, Natural Products Laboratory, Indian
Institute of Chemical Technology, Hyderabad, India
Abstract: A mild and efficient method for the synthesis of 3-substituted indoles by
treatment of activated olefins with indoles using TBAB as a catalyst afforded the cor-
responding products in excellent yields. The method is general for the preparation of a
wide variety of 3-substituted indoles.
INTRODUCTION
The synthesis of 3-substituted indoles has received attention from organic
chemists because they are very important building blocks for biologically
active compounds.[1] Indole-3-acetic acid is mostly known as one of the
auxins, which, in cooperation with other plant hormones, coordinate plant
growth and development.[2] Recently, indole-3-acetic acid (IAA) and its ring-
substituted derivatives[3] also attracted attention as experimental prodrugs for
use in cancer therapy because oxidants, such as horseradish peroxidase,
convert these compounds to products toxic to human tumor cells.[4] Addition
of activated olefins to indoles fulfills the role of synthesis of 3-substituted
indoles. Traditionally these compounds have been synthesized by Michael
addition[5] of a,b-unsaturated carbonyl compounds to indoles with strong
Received in India September 9, 2007
Address correspondence to J. Madhusudana Rao, Organic Chemistry Division I,
Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad,
India. E-mail: sivarambabu_anu@yahoo.co.in
1784

3-Substituted Indoles
1785
bases, such as alkali metal alkoxides, hydroxides, amines, and Brønsted acids.[6]
In recent years, it has been noted that these reactions can also be promoted by
Lewis acids.[7,8] However, the use of either strongly acidic or basic conditions
frequently leads to the formation of undesirable side products, such as polymer-
ization, self-condensation, and rearrangements, which in turn decrease the purity
and yields of the desired products.[9] In view of current interest in catalytic
processes, there is a merit in developing 1,4-addition of activated olefins to
indoles using an inexpensive, mild, and nonpolluting reagent.
Organic reactions using a mild water-tolerant catalyst have received
much attention in recent years as they can conveniently be handled and
removed from the reaction mixture, making the experimental procedure
simple and ecofriendly.[10] Tetra-alkylammonium bromides, (NR4)þBr2,
have a molecular structure similar to that of the cationic surfactants previously
employed,[11] with the main difference being the absence of the long hydro-
phobic tail, which prevents the formation of any organized structure
(micelle) and thereby the partition of the substrate. These salts are
promising additives as different alkyl residues in the (R4N)þ ammonium
cation lead to different charge density and hydrophobicity. In continuation
of our work to develop new organic transformations, we have observed
Michael addition of activated olefins to indoles using tetra butyl ammonium
bromide (TBAB) as a mild and efficient catalyst (Scheme 1).
RESULTS AND DISCUSSION
In the present method, we have described a mild, efficient, and high-yielding
protocol for the 3-substituted indoles. In general, all the reactions were
carried out by the addition of a,b-unsaturated compounds (1 mmol) to
indole (1 mmol) in the presence of TBAB (10 mol%) in acetonitrile at
refluxing temperature to give the corresponding 3-substituted indoles in
excellent yields (90–95%, Table 1) after purification by silica-gel column
chromatography. The times required for derivatization were comparatively
very short (10–20 min). Further, we carried out the reaction with
activated olefins like vinyl nitro compounds; they are also efficiently
converted into corresponding 3-substituted indoles in excellent yields
(Table 1, entries 6–15).
Scheme 1.

1786
K. S. Babu et al.
Table 1. Synthesis of 3-substituted indoles using TBAB as a catalyst
Activated
olefins
Time Yield
(min)
Entry
1
Indole
Product
(%)
10
95
2
3
4
10
15
20
95
94
95
5
6
20
10
96
90
7
8
9
10
10
15
90
90
90
(continued)

3-Substituted Indoles
1787
Table 1. Continued
Activated
olefins
Time Yield
(min)
Entry
10
Indole
Product
(%)
15
90
11
12
15
10
90
92
13
14
10
15
93
91
15
15
95
1
The structure of the product was assigned based on H NMR, mass, and
IR spectral data. To examine the generality of the reaction, several a,b-unsa-
turated carbonyl compounds, activated olefins, and differently substituted
indoles were subjected to the same conditions, and the results are summarized
in Table 1. All the substrates afforded products arising from a formal
Michael addition of a,b-unsaturated carbonyl compounds and activated
olefins to indoles.

1788
K. S. Babu et al.
CONCLUSIONS
In conclusion, we have demonstrated an efficient and novel method for the
synthesis of 3-substituted indoles using TBAB as a catalyst. The present
method has the advantage of improved yields and simple experimental
procedure in comparatively less reaction time with excellent yields using a
less toxic and inexpensive reagent.
EXPERIMENTAL SECTION
Typical Experimental Procedure for the Synthesis of 3-Substituted
Indoles:
To a mixture of a,b-unsaturated carbonyl compounds/activated olefins
(1 mmol) and indoles (1 mmol), TBAB (10 mol%) was added. The contents
were refluxed in acetonitrile (10 mL) for an appropriate time. The reaction
was monitored by thin-layer chromatography (TLC). After complete conversion,
the solvent was evaporated, and the product was extracted into ethyl acetate
(3 ꢀ 20 mL). The combined organic layer was dried over anhydrous sodium
sulphate and evaporated under reduced pressure, purified by silica-gel column
chromatography to afford pure product.
Spectral Data for Selected Compounds
Entry 6: 1H NMR (300 MHz, CDCl3): d ¼ 4.88 (dd, 1H, J ¼ 12.05 &
2.00 Hz), 5.01 (dd, 1H, J ¼ 12.05 & 2.50 Hz), 5.15 (t, 1H J ¼ 7.20 Hz),
6.95 (d, 1H, J ¼ 7.80 Hz), 7.05 (t, 1H, J ¼ 8.15 Hz), 7.18 (t, 1H,
J ¼ 8.50 Hz), 7.20–7.31 (m, 6H), 7.38 (d, 1H, J ¼ 8.20 Hz), 8.05 (bs, 1H);
EIMS: Mþ1, m/z 267. IR (neat): 3422, 1549, 1456, 1377, 744, 702 cm21
.
Entry 8: 1H NMR (300 MHz, CDCl3): d ¼ 2.25 (s, 3H), 5.08–5.19 (m, 3H), 6.91–
7.10 (m, 2H), 7.12 (dd, 1H, J ¼ 8.20 Hz), 7.15–7.30 (m, 6H), 7.78 (bs, 1H);
EIMS: Mþ1, m/z 281. IR (neat): 3408, 3057, 1550, 1458, 1377, 744, 700 cm21
.
Entry 9: 1H NMR (300 MHz, CDCl3): d ¼ 2.38 (s, 3H), 4.91 (dd, 1H, J ¼ 6.01
& 3.00 Hz), 5.12–5.21 (m, 2H), 6.09 (d, 1H, J ¼ 4.00 Hz), 6.30 (d, 1H,
J ¼ 4.50 Hz), 7.01–7.15 (m, 2H), 7.27 (dd, 1H, J ¼ 4.50 & 2.00 Hz), 7.38
(dd, 1H, J ¼ 8.20 & 3.00 Hz) 7.90 (bs, 1H); EIMS: Mþ1, m/z 271; I.R
(neat): 1552, 1460, 1378, 1013, 742 cm21
.
1
Entry 10: H NMR (300 MHz, CDCl3): d ¼ 5.08–5.15 (m, 2H), 5.30 (t, 1H,
J ¼ 7.20 Hz), 7.05 (t, 1H, J ¼ 8.6 Hz), 7.15–7.32 (m, 7H), 7.40–7.50
(m, 6H), 8.10 (bs, 1H); EIMS: Mþ1, m/z 343; IR (KBr): 3411, 3027, 2923,
1560, 1455, 1377, 768, 751, 697, 526 cm21
.

3-Substituted Indoles
1789
Entry 11: 1H NMR (200 MHz, CDCl3): d ¼ 4.92 (dd, 1H, J ¼ 12.22 &
2.50 Hz), 5.22 (dd, 1H, J ¼ 12.20 & 2.00 Hz), 5.35 (t, 1H, J ¼ 7.51 Hz),
6.12 (d, 1H, J ¼ 4.51 Hz), 6.30 (d, 1H, J ¼ 4.70 Hz), 7.10 (t, 1H,
J ¼ 7.91 Hz), 7.21 (t, 1H, J ¼ 8.20 Hz), 7.31–7.40 (m, 2H), 7.40–7.58
(m, 6H), 8.12 (bs, 1H); EIMS: Mþ1, m/z 333; IR (KBr): 3429, 3390, 3057,
2924, 2853, 1746, 1560, 1456, 1449, 1382, 1309, 1198, 1138, 1009, 772,
729, 571, 513 cm21
.
1
Entry 12: H NMR (300 MHz, CDCl3): d ¼ 1.38 (t, 3H, J ¼ 7.8 Hz), 2.80
(q, 2H, J ¼ 8.00 & 3.20 Hz), 4.81–5.20 (m, 3H), 7.00 (m, 3H), 7.20–7.35
(m, 6H), 7.95 (bs, 1H); EIMS: Mþ1, m/z 295; IR (KBr): 3422, 2965, 2928,
1550, 1433, 1377, 1097, 748, 702 cm21
.
1
Entry 13: H NMR (200 MHz, CDCl3): d ¼ 1.35 (t, 3H, J ¼ 7.50 Hz), 2.81
(q, 2H, J ¼ 7.52 & 3.20 Hz), 4.81–4.90 (m, 1H), 4.95–5.05 (m, 1H), 5.20
(t, 1H, J ¼ 7.01 Hz), 6.11 (d, 1H, J ¼ 3.91 Hz), 6.28 (d, 1H, J ¼ 3.70 Hz),
6.95–7.05 (m, 3H), 7.36–7.40 (m, 2H), 8.00 (bs, 1H); EIMS: Mþ1, m/z
284; IR (KBr): 3795, 3729, 3642, 3417, 2929, 2355, 1552, 1368, 1217,
1013, 757, 669, 527 cm21
.
Entry 14: 1H NMR (300 MHz, CDCl3): d ¼ 4.80 (dd, 1H, J ¼ 12.02 &
2.50 Hz), 4.91 (dd, 1H, J ¼ 12.02 & 2.00 Hz), 5.09–5.11 (m, 1H), 5.20
(s, 2H), 6.85 (s, 1H), 6.98 (dd, 3H, J ¼ 8.20 Hz), 7.05–7.31 (m, 10H), 7.45
(d, 1H, J ¼ 8.25 Hz); EIMS: Mþ1, m/z 357; IR (KBr): 3030, 2922, 1550,
1462, 1375, 739, 699 cm21
.
Entry 15: 1H NMR (300 MHz, CDCl3): d ¼ 4.85 (dd, 1H, J ¼ 12.20 &
2.50 Hz), 5.00 (dd, 1H, J ¼ 12.00 & 2.00 Hz), 5.14–5.15 (m, 1H), 5.25
(s, 2H), 6.11 (d, 1H, J ¼ 4.30 Hz), 6.28 (d, 1H, J ¼ 4.20 Hz), 7.00 (s, 1H),
7.03–7.30 (m, 5H), 7.35–7.48 (m, 4H), 7.51 (d, 1H, J ¼ 7.90 Hz); EIMS:
M
þ1, m/z 347; IR (KBr): 2924, 2855, 2361, 1461, 1375, 736, 531 cm21
.
ACKNOWLEDGMENT
The authors thank University Grants Commission (UGC), New Delhi, India,
for the financial support and the director, Indian Institute of Chemical Tech-
nology (IICT), for his encouragement.
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