Efficient conjugate addition of 1H-indoles to electron-deficient olefins catalyzed by silica-supported sodium hydrogen sulfate (NaHSO4· SiO2)

Article abstract of DOI:10.1002/hlca.200790040

A simple, mild, rapid, and highly efficient method for the conjugate addition of 1H-indoles to electron-deficient olefins has been developed using NaHSO₄·SiO₂ as heterogeneous catalyst. The conversion proceeds at room temperature, and the corresponding Michael adducts are formed in good-to-excellent yields.

Full text of DOI:10.1002/hlca.200790040

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Helvetica Chimica Acta – Vol. 90 (2007)
Efficient Conjugate Addition of 1H-Indoles to Electron-Deficient Olefins
Catalyzed by Silica-Supported Sodium Hydrogen Sulfate (NaHSO4 ·SiO2)1)
by Biswanath Das*, Nikhil Chowdhury, K. Damodar, and K. Ravinder Reddy
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(phone: +91-40-7193434; fax: +91-40-7160512; e-mail: biswanathdas@yahoo.com)
A simple, mild, rapid, and highly efficient method for the conjugate addition of 1H-indoles to elec-
tron-deficient olefins has been developed using NaHSO4 ·SiO2 as heterogeneous catalyst. The conversion
proceeds at room temperature, and the corresponding Michael adducts are formed in good-to-excellent
yields.
Introduction. – Indole moieties are frequently found in pharmaceuticals and biolog-
ically active compounds [1], and 3-substituted congeners are important building blocks
for the synthesis of different therapeutic agents and natural products [2]. The general
method for the synthesis of 3-alkylated indoles involves conjugate addition to electron-
deficient olefins in the presence of H+ [3] or Lewis acids [4]. However, acid-catalyzed
reactions of indoles require precise control of acidity to avoid side reactions such as
dimerization or polymerization. Moreover, harsh reaction conditions, expensive
reagents, long reaction times, low yields, and tedious experimental procedures are dis-
advantages of many reported methods.
Results and Discussion. – In continuation of our work on the development of useful
synthetic methodologies [5], we recently observed that silica-supported sodium hydro-
gen sulfate (NaHSO4 ·SiO2) efficiently catalyzes the conjugate addition of 1H-indoles
to electron-deficient olefins to form the corresponding Michael adducts at room tem-
perature (Scheme). A variety of indoles and activated olefins were, thus, tested to elu-
cidate the scope of the reaction.
Scheme
1
)
Part 120 in the series ꢀStudies on Novel Synthetic Methodologiesꢁ; IICT Communication No. 070108.
ꢂ 2007 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 90 (2007)
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As can be seen from the Table, good-to-excellent yields were obtained for the con-
densation of various 1H-indoles and olefinic substrates. Both unsubstituted 1H-indoles
as well as indoles carrying a substituent at C(2) or at the benzene ring readily under-
went the reaction, giving rise to 3-substituted Michael adducts in yields of 79–98%.
In the case of 3-methyl-1H-indole (Entries 3 and 6), 2- instead of 3-substituted indole
adducts were obtained, and the yields were somewhat lower (67–69%). As activated
olefins, a series of a,b-unsaturated ketones and nitro compounds were used. With ali-
phatic enones (acyclic or cyclic) and a,b-unsaturated nitro compounds, the reactions
were complete within 2–15 min. In the case of a,b-unsaturated carbonyl compounds
carrying a conjugated aromatic ring, the reaction time was 30–35 min (Entries 8–12).
Most of the earlier reported methods for the preparation of 3-substituted 1H-
indoles by conjugate addition require much longer reaction times [3][4]. Also, our syn-
thetic protocol is very simple, and inert atmospheric conditions are not needed. As a
further advantage, the indole N-atom does not have to be protected, since no N-alky-
lation [6] takes place under the reaction conditions.
The catalyst, NaHSO4 ·SiO2, works under heterogeneous conditions. In recent
years, heterogeneous catalysts have gained importance in various organic transforma-
tions due to their reactivity as well as for economic and environmental reasons.
NaHSO4 ·SiO2 has been found to be highly efficient in the present conversion. It can
easily be prepared [7] from inexpensive, readily available, and non-toxic NaHSO4
and silica gel (SiO2), and it can conveniently be removed from the reaction mixture
by simple filtration. In the present reaction, no product was formed in the absence of
catalyst.
In conclusion, we have developed a method for the conjugate addition of 1H-
indoles to electron-deficient olefins in the presence of NaHSO4 ·SiO2. Our protocol
has the advantages of being mild, fast, simple, inexpensive, and high-yielding.
We wish to thank CSIR and UGC, New Delhi, for financial assistance.
Experimental Part
General. 1H-NMR Chemical shifts d and coupling constants J are given in ppm (rel. to Me4Si) and in
Hz, resp. Mass-spectrometric (MS) data are reported in m/z. Elemental-analyses data are reported in %.
General Procedure. To a mixture of an 1H-indole (1 mmol) and an electron-deficient olefin (1 mmol)
in MeCN (1 ml) is added NaHSO4 ·SiO2 (30 mg) [7], prepared by addition of silica gel (200–400 mesh, 10
g) to a soln. of NaHSO4 ·H2O (4.14 g) in H2O (20ml) followed by gently heating on a hot plate for 0.5 h to
make a free-flowing white solid, which was further dried in an oven at 1208 for 48 h prior to use. The mix-
ture is stirred at r.t., the progress of the reaction being monitored by TLC. After completion, the catalyst
is separated by filtration, the solvent is removed under reduced pressure, and the residue is subjected to
column chromatography (SiO2; hexane/AcOEt) to afford the pure Michael adduct. The anal. data of
some representative products are given below.
1-(1H-Indol-3-yl)pentan-3-one (Table, Entry 5). Solid. 1H-NMR (CDCl3, 200 MHz): 7.89 (br. s, 1 H);
7.52 (d, J=8.0, 1 H); 7.28 (d, J=8.0, 1 H); 7.16–7.04 (m, 2 H); 6.91 (d, J=1.5, 1 H); 3.02 (t, J=7.0, 2 H);
2.78 (t, J=7.0, 2 H); 2.36 (q, J=7.0, 2 H); 1.01 (t, J=7.0, 3 H). FAB-MS: 201 ([M+H]+). Anal. calc. for
C13H15NO: C 77.61, H 7.46, N 6.96; found: C 77.56, H 7.41, N 6.90.

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Helvetica Chimica Acta – Vol. 90 (2007)
Table. Conjugate Addition of 1H-Indoles to Activated Olefins in the Presence of NaHSO4 ·SiO2 as Catalyst
in MeCN at Ambient Temperature
Entry Indole
Olefin
Product
Time [min] Yield [%]a)
1
5
98
2
3
4
5
15
5
94
69
89
5
6
7
5
15
5
88
67
85
8
9
3084
3082

Helvetica Chimica Acta – Vol. 90 (2007)
343
Table (cont.)
Entry Indole
Olefin
Product
Time [min] Yield [%]a)
10
11
12
35
79
35
76
3081
13
14
5
5
82b)
80b)
15
16
2
2
92
90

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Helvetica Chimica Acta – Vol. 90 (2007)
Table (cont.)
Entry Indole
Olefin
Product
Time [min] Yield [%]a)
17
18
2
5
88
91
a) After column-chromatographic purification. b) Some 10% of the corresponding higher adduct was also
obtained.
1
1-(5-Bromo-1H-indol-3-yl)pentan-3-one (Table, Entry 7). Solid. H-NMR (CDCl3, 200 MHz): 8.04
(br. s, 1 H); 7.70( s, 1 H); 7.31–7.22 (m, 2 H); 7.00 (d, J=1.5, 1 H); 3.02 (t, J=7.0, 2 H); 2.81 (d,
J=7.0, 2 H); 2.42 (q, J=7.0, 2 H); 1.08 (t, J=7.0, 3 H). FAB-MS: 282/280 ([M+H]+). Anal. calc. for
C13H14BrNO: C 55.17, H 5.00, N 5.00; found: C 55.22, H 5.08, N 5.12.
3-(4-Chlorophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (Table, Entry 10). Solid. 1H-NMR
(CDCl3, 200 MHz): 7.98 (br. s, 1 H); 7.90( d, J=8.0, 1 H); 7.59–7.05 (m, 11 H); 7.03–6.90 (m, 2 H);
5.01 (dd, J=7.0, 5.5, 1 H); 3.78 (dd, J=12.5, 5.5, 1 H); 3.62 (dd, J=12.5, 7.0, 1 H). FAB-MS: 362/360
([M+H]+). Anal. calc. for C23H18ClNO: C 76.77, H 5.01, N 3.89; found: C 76.63, H 5.12, N 3.91.
3-(5-Bromo-1H-indol-3-yl)-3-(4-chlorophenyl)-1-phenylpropan-1-one (Table, Entry 11). Solid. 1H-
NMR (CDCl3, 200 MHz): 7.99 (br. s, 1 H); 7.89 (d, J=8.0, 1 H); 7.56–7.40 (m, 4 H); 7.26–7.13 (m, 7
H); 6.92 (d, J=1.5, 1 H); 4.97 (dd, J=7.0, 5.5, 1 H); 3.71 (dd, J=12.0, 5.5 1 H); 3.61 (dd, J=12.0, 7.0,
1 H). FAB-MS: 442/440/438 ([M+H]+). Anal. calc. for C23H17BrClNO: C 62.97, H 3.88, N 3.19;
found: C 62.91, H 3.82, N 3.23.
5-Bromo-3-(2-nitro-1-phenylethyl)-1H-indole (Table, Entry 17). Solid. 1H-NMR (CDCl3, 200 MHz):
8.28 (br. s, 1 H); 7.50( d, J=1.5, 1 H); 7.45–7.18 (m, 7 H); 7.03 (d, J=1.5, 1 H); 5.11 (dd, J=7.0, 5.5, 1 H);
5.01–4.79 (m, 2 H). FAB-MS: 347/345 ([M+H]+). Anal. calc. for C16H13BrN2O2: C 55.65, H 3.76, N 8.11;
found: C 55.58, H 3.81, N 8.17.
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Received October 31, 2006