Bismuth nitrate-catalyzed michael reactions of indoles in water

Article abstract of DOI:10.3987/com-06-10957

A remarkable and simple bismuth nitrate-catalyzed Michael reaction of indoles with 1,2-unsaturated ketones in water has been developed to reduce the complications that characterize the current standard conditions.

Full text of DOI:10.3987/com-06-10957

HETEROCYCLES, Vol. 71, No. 4, 2007
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HETEROCYCLES, Vol. 71, No. 4, 2007, pp. 919 - 924. © The Japan Institute of Heterocyclic Chemistry
Received, 24th November, 2006, Accepted, 23rd February, 2007, Published online, 27th February, 2007. COM-06-10957
BISMUTH NITRATE-CATALYZED MICHAEL REACTIONS OF
INDOLES IN WATER
Bimal K. Banik,* Isabella Garcia, and Frances R. Morales
Department of Chemistry, The University of Texas-Pan American, 1201 West
University Drive, Edinburg, Texas, U.S.A. 78541; Phone: 956-380-8741; Fax:
9
56-384-5006; E-mail: banik@panam.edu
Abstract – A remarkable and simple bismuth nitrate-catalyzed Michael reaction of
indoles with 1,2-unsaturated ketones in water has been developed to reduce the
complications that characterize the current standard conditions.
INTRODUCTION
1
In general, Michael reaction of nucleophiles to unsaturated carbonyl compounds requires basic or acidic
2
conditions. Methods classified as Michael reactions require stoichiometric amounts or excess acids and
3
bases in organic solvents, and side reactions can occur if the reactive partners are sensitive. The main
4
improvement of these reagents is the ability to limit the catalysts used to catalytic amounts. Despite their
tremendous success, however, the literature reveals that the success depends on the choice of the catalyst
5
and organic solvent. For example, indium salts are very effective for Michael reactions with indoles and
6
7
pyrroles, but they are not good promoters in catalyzing a similar reaction with carbamates. In contrast,
7
platinum salts are very effective for this purpose. These reactions were performed in organic solvents. An
alternative attractive method using an effective catalyst in aqueous medium would be highly desirable,
timely and challenging. This paper describes the development of a simple and environmentally friendly
bismuth nitrate pentahydrate-catalyzed Michael reaction of indoles with unsaturated ketones in water.
We have been studying reactions mediated by metals or their salts with the aim of developing several
8
9
biologically active compounds, including anticancer agents and β-lactams. The use of bismuth-derived
1
0
reagents in several organic transformations has been demonstrated by our group.
RESULTS AND DISCUSSION
1
1
Several addition reactions of enones to indoles using Lewis and Bronsted acids have been published.
Acid-induced reaction of indoles requires careful control of the acidity to prevent unwanted side reactions,

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HETEROCYCLES, Vol. 71, No. 4, 2007
1
2
including dimerization and polymerization. Our bismuth nitrate-catalyzed reaction in water has been
tested with several indoles and ketones, the results of which have been very encouraging (Table 1). The
reactions are efficient, and the products are isolated in high yield. In general, the reactions took place at the
3
-position of the indole ring. The reaction produced 2-substituted products when the 3 position is occupied.
Table 1. Bi(NO)3. 5H O- catalyzed Michael
2
reaction of enones with Indoles in water
Entries
Enones
Indoles
Products
% yield
78
O
O
NC
1
NC
N
H
N
H
O
O
2
50
85
N
H
N
H
NC
O
O
O
NC
O
3
4
5
N
H
N
H
BnO
BnO
O
80
50
N
N
H
H
O
N
H
N
H
O
O
8
5
5
5
6
7
8
9
H
3
C
N
H
H
3
C
N
H
O
O
N
H
N
H
O
O
NC
NC
85
50
50
N
H
N
H
O
O
N
O
N
H
H
O
1
0
N
N
CH
3
CH
3
Catalytic amounts of bismuth nitrate in water were necessary for a complete reaction. The reaction did not
proceed at all in the absence of bismuth nitrate. A number of reactions were investigated with bismuth
nitrate in varying proportions in water. For example, reaction of indole (1 mmol) with methyl vinyl ketone
(
1 mmol) was performed with 50 mg, 25 mg, and 5 mg of bismuth nitrate in 1 mL of water for 2 h. It was
found that all proportions of bismuth nitrate produced product in excellent yield. Bismuth chloride,
scandium triflate, ytterbium triflate and borontrifluoride dietherate proved to be partially effective under
identical conditions and did not yield product in good yield. Interestingly, the reaction produced products
in the absence of water, when the reaction was conducted in more than 2 g scale. However, for very small

HETEROCYCLES, Vol. 71, No. 4, 2007
921
scale reactions it was difficult to isolate the product in good yield. Mixing of the reactants in a small scale
was not adequate and, therefore, bismuth nitrate was not exposed properly to the reactants. This was not
the case with gram quantities of the reagents when bismuth nitrate could go into the reactants much more
easily.
This method suggests that it is not necessary to use large excess of corrosive acid in Michael reaction of
indoles with unsaturated ketones. Bismuth nitrate is an inexpensive, commercially available, water soluble
and non-toxic solid and therefore, an ideal catalyst for this reaction.
In conclusion, Michael reactions of various indoles have been successfully carried out in the presence of
13
aqueous bismuth nitrate solution with products in excellent yield.
EXPERIMENTAL
Bismuth nitrate (25 mg) in water (1 mL) was added to a mixture of indole (1.00 mmol) and ketone (1.00
mmol). The reaction mixture was then stirred at rt for 2 h. It was then extracted with CH Cl (2 x 5 mL),
2
2
washed with saturated aqueous NaHCO
The extracts were then concentrated and the crude product was purified using flash chromatography
silica gel, 30% EtOAc-70% hexane) to afford pure compound (50-85%).
The compound characterization data is given below: 3-(5-Cyano-3-indolyl)cyclohexan-1-one (entry
3 2 4
(2 x 10 mL), brine solution (10 mL) and dried over Na SO .
(
1
0f
-1 1
1
): yield 78%; IR (neat): 3324, 2940, 2218, 1698, 1617, 1472, 1429,1344, 1224, 1344, 1224 cm ; H
NMR (300 MHz, CDCl ) δ: 1.92-2.05 (m, 3 H), 2.23-2.30 (m, 1 H), 2.43-2.48 (m, 2 H,CH ), 2.64-2.68
m, 1 H, CH), 2.76-2.77 (m, 1 H) 3.43-3.48 (m, 1 H, CH), 7.03 (q, 1 H, ArH), 7.44 (d, 2 H, J ) 1.2 Hz,
3
2
(
1
3
ArH), 7.98 (brs, 1 H, ArH), 8.51 (brs, 1 H, NH); C NMR (75MHz) δ: 25.0, 32.1, 35.9, 41.8, 48.1, 102.9,
1
5
3
12.6, 120.8, 123.1,125.1, 125.5, 126.4, 138.5, 211.6; Anal. Calcd for C15
.92; N, 11.76. Found: C, 75.47; H, 5.58; N, 11.71.
14 2
H N O (238.290): C, 75.61; H,
1
0f
-(3-Methyl-2-indolyl)cyclohexan-1-one (entry 2): yield 50%; IR (neat): 3407, 2940, 1702, 1463, 1344
-1 1
cm ; H NMR (300 MHz, CDCl
3
2 2 3
) δ 1.89-1.96 (m, 2 H, CH ), 2.13-2.18 (m, 2H, CH ), 2.25 (s, 3 H, CH ),
2
7
1
7
4
1
.50-2.66 (m, 4 H, 2 x CH
2
), 3.38-3.37 (m, 1 H, CH), 6.91-7.16 (m, 2 H, ArH), 7.29-7.32 (m, 1H, ArH),
1
3
.51 (d, J ) 6 Hz, 1 H, ArH), 7.80 (brs, 1 H, NH); CNMR (75 MHz) δ 8.8, 25.8, 31.9, 36.8, 41.7, 47.6,
07.1, 110.8,118.7, 119.7, 121.9, 129.5, 135.5, 136.3, 210.8; Anal. Calcd for C15
9.26; H, 7.54; N, 6.16. Found: C, 79.19; H, 7.58; N, 6.01.
H17NO (227.307): C,
10f
-(5-Cyano-3-indolyl)butan-2-one (entry 3): yield 85%; mp 108-112 °C; IR (neat) 3338, 2919, 2218,
-1 1
706, 1619,1473, 1434, 1359, 1230 cm ; H NMR (300 MHz, CDCl
), 3.02 (t, J) 6 Hz, 2 H, CH ), 7.11-7.12 (m, 1 H, ArH), 7.41-7.42 (m, 2H, ArH), 7.90
brs, 1 H, ArH), 8.29 (brs, 1 H, NH); C NMR(75 MHz) δ: 102.8, 112.4, 116.6, 121.1, 124.1, 124.8,
3 3
) δ: 2.16 (s, 3 H, COCH ), 2.84 (t,
J ) 6 Hz, 2 H, CH
2
2
1
3
(
1
12 2
25.3,127.5, 127.5, 129.2, 131.3, 138.2; Anal. Calcd for C13H N O (212.252): C, 73.56; H, 5.70; N,

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HETEROCYCLES, Vol. 71, No. 4, 2007
1
4
1
3.20. Found: C, 73.29; H, 5.48; N, 13.11.
10f
-(5-Benzyloxy-3-indolyl)butan-2-one (entry 4): yield 80%; IR (neat): 3407, 3032, 2915, 1705, 1624,
-1 1
582, 1482,1374, 1292, 1197 cm ; H NMR (300 MHz, CDCl
3
) δ: 2.13 (s,3 H, CH
3
), 2.78-2.83 (t, J ) 9
Hz, 2 H, CH
2
), 2.97-3.02 (t, J) 6 Hz, 2 H, CH ) 5.12 (s, 2 H, OCH
2
2
), 6.91-6.94 (m, 2 H, ArH), 7.10 (d, J )
1
3
2
.4, 1 H, ArH), 7.22-7.41 (m, 6 H, ArH), 7.48 (m, 2 H, ArH), 7.80 (brs, 1 H, NH); C NMR (75 MHz) δ:
1
9.7, 30.4, 44.3, 71.4, 102.8, 112.2, 113.28, 115.3, 122.7, 127.9,128.0, 128.1, 128.9, 131.2, 138.0, 153.5,
2
09.1; Anal. Calcd for C19
.61.
2
H19NO (293.366): C, 77.79; H, 6.53; N, 4.77. Found: C, 77.39; H, 6.34; N,
4
10f
4
-(3-Methyl-2-indolyl)butan-2-one (entry 5): yield 50%; IR (neat): 3407, 2400, 1714, 1605, 1455, 1360,
-1 1
1
166 cm ; H NMR (300 MHz, CDCl ) δ: 2.16 (s, 3 H, CH ), 2.23 (s, 3 H,CH ), 2.82 (t, J ) 6.6 Hz, 2 H,
3 3 3
2 2
CH ), 2.98 (t, J ) 6.6 Hz, 2 H,CH ), 7.05-7.11 (m, 2 H, ArH), 7.25-7.27 (m, 1 H, ArH), 7.45-7.48 (d, J ) 9
1
3
Hz, 1 H, ArH), 8.29 (brs, 1 H, NH); C NMR (75 MHz) δ 8.7, 19.7, 30.4, 44.0, 107.0, 110.7, 118.4,
19.2,121.5, 129.3, 134.6, 135.5, 209.7; Anal. Calcd for C13 15NO (201.269): C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.39; H, 7.59; N, 6.71.
1
H
-1
3
-(6-Methyl-3-indolyl)cyclohexan-1-one (entry 6): yield 55%; IR (neat): 3325, 2940, 1695, 1610 cm ;
1
3
H NMR (300 MHz, CDCl ) δ: 1.42-1.98 (m, 4 H), 2.20 (s, 3 H), 2.19-2.60 (m, 5 H), 6.82 (d, J= 6 Hz, 1
H), 7.01 (s, 1 H), 7.2 (s, 1 H), 7.35 (d, J= 6 Hz, 1 H), 7.85 (s, 1 H); Anal. Calcd for C15
H17NO (227): C,
7
3
9.29; H, 7.48; N, 6.16. Found: C, 79.01; H, 7.15; N, 5.98.
-1
1
-Indolylpent-3-one (entry 7): yield 85%; IR (neat): 3330, 2920, 1710, 1615, 1475 cm ; H NMR (300
MHz, CDCl
m, 5 H, ArH), 8.00 (s, 1 H, NH); Anal. Calcd for C13
Found: C, 77.41; H, 7.28; N, 7.01.
3
) δ: 0.95 (t, 3 H, CH
3
), 2.32 (q, 2 H, CH
2
), 2.85 (q, 2 H, CH
2 2
), 3.15 (q, 2 H, CH ), 7.12-7.65
(
H15ON (201.13): C, 77.62; H, 7.45; N, 6.96.
-
1 1
(
(
(
5-Cyano-3-indolyl)pentan-3-one (entry 8): yield 85%; IR (neat): 3400, 2950, 1705, 1620 cm ; H NMR
300 MHz, CDCl ) δ: 0.95 (t, 3 H, CH ), 2.40 (q, 2 H, CH ), 2.80 (t, 2 H, CH ), 3.12 (t, 2 H, CH ), 7.10
s, 1 H, ArH), 7.25-7.45 (m, 2 H, ArH), 7.80 (s, 1 H, ArH), 9.20 (s, 1 H, NH); Anal. Calcd for
O (226.14): C, 74.35; H, 6.19; N, 12.38. Found: C, 74.11; H, 6.30; N, 12.00.
-Indolylcyclohexan-1-one (entry 9): yield 50%; IR (neat): 3330, 2950, 1698, 1470 cm ; H NMR (300
3
3
2
2
2
14 14 2
C H N
-1 1
3
MHz, CDCl
3
) δ: 1.30-1.55 (m, 4 H, CH
.95-7.45 (m, 5 H, ArH), 7.70 (d, 1 H, ArH), 7.85 (s, 1 H, NH); Anal. Calcd for C14
2.74; H, 6.48; N, 6.05. Found: C, 72.51; H, 6.30; N, 5.89.
2
), 1.60-1.70 (m, 1 H, CH), 2.30 (t, 2 H, CH
2
), 2.60 (t, 2 H, CH
2
),
6
7
H15NO (231.14): C,
-1
(
N-Methyl-3-indolyl)cyclohexan-1-one (entry 10): yield 50%; IR (neat): 3320, 2945, 1700, 1615 cm ;
1
H NMR (300 MHz, CDCl
3 2 2
) δ: 1.75-1.80 (m, 4 H, CH ), 1.81-1.85 (m, 1 H, CH) 2.20 (t, 2 H, CH ), 2.50
(
t, 2 H, CH ), 3.82 (s, 3 H, N-CH ), 6.90 (s, 3 H, ArH), 6.92 (d, ArH, 1 H), 7.22 (d, 1 H, ArH), 7.38 (d,
2
3
ArH, 1 H), 7.38 (d, 1 H, ArH); Anal. Calcd for C15H17NO (227.15): C, 79.15; H, 7.48; N, 6.16. Found: C,

HETEROCYCLES, Vol. 71, No. 4, 2007
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7
9.15; H, 7.43; N, 6.01.
ACKNOWLEDGEMENTS
We gratefully acknowledge the partial funding support received for this research project from Robert
Welch Foundation departmental grant (BG 0017) and Hispanic Health Research Center; supported by
NIH NCMHD P20 MD000170-04 located at Brownsville Regional Campus of the University of Texas
School of Public Health.
Isabella Garcia and Frances Rachel Morales are undergraduate research participants.
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