Efficient michael addition of indoles using bismuthyl perchlorate as catalyst

Article abstract of DOI:10.3987/COM-06-10697

An efficient method for Michael addition of indoles hasbeen developed using bismuthyl perchlorate (BiOClO₄·xH₂O) as catalyst. The reaction proceeds to give 3-substituted indoles excellently stirring indoles and Michael acceptors in acetonitrile in the presence of the catalyst at room temperature or in much shorter reaction times under sonication at ambient temperature.{A figure is presented}.

Full text of DOI:10.3987/COM-06-10697

HETEROCYCLES, Vol. 68, No. 9, 2006
1837
HETEROCYCLES, Vol. 68, No. 9, 2006, pp. 1837 - 1843. © The Japan Institute of Heterocyclic Chemistry
Received, 9th February, 2006, Accepted, 27th June, 2006, Published online, 29th June, 2006. COM-06-10697
EFFICIENT MICHAEL ADDITION OF INDOLES USING BISMUTHYL
PERCHLORATE AS CATALYST
Iraj Mohammadpoor-Baltork,* Hamid Reza Memarian,* Ahmad Reza
Khosropour, and Kobra Nikoofar
Department of Chemistry, Isfahan University, Isfahan 81746-73441, Iran; E-mail:
imbaltork@sci.ui.ac.ir; E-mail: memarian@sci.ui.ac.ir
Abstract- An efficient method for Michael addition of
indoles
has
been
developed using bismuthyl perchlorate (BiOClO ·xH O) as catalyst. The reaction
4
2
proceeds to give 3-substituted indoles excellently stirring indoles and Michael
acceptors in acetonitrile in the presence of the catalyst at room temperature or in
much shorter reaction times under sonication at ambient temperature.
In recent years attentions have been focused particularly on 3-substituted indoles due to their various
1
pharmacological or biological activities. They have emerged as integral backbones of several
2
antibacterial, antialgal and antimycotic agents. This is an impressive profile that bodies well for the
interaction of this heterocyclic building block with a variety of biological targets of interest in medicinal
chemistry. Moreover, some alkaloids containing indole unit have been isolated from marine sources like
3
Hapalosiphon fontinalis (a blue-green algae). The scope of this has been further increased by the
4
identification of the tri- or tetracyclic skeleton derivatives called hapalindole, as a biogenetic precursor.
5
Michael reaction of indoles with ꢀ,ꢁ-unsaturated compounds using acid catalysts has been reported.
Acid induced reaction of indoles requires precise control of the acidity to prevent side reactions, including
dimerization and polymerization. Recently, a number of methods and reagents have been developed to
6
-13
overcome the problem. However, the application of these methods suffer from some disadvantages
such as the use of hazardous or expensive and or less easily available catalysts, vigorous reaction
conditions, prolonged reaction times, low yields and formation of side products. Furthermore, some of
these methods require strictly anhydrous conditions. Consequently, there is a need for the development of
protocols using readily available and safe reagents which lead to high yields of 3-substituted indole
derivatives. Recently, bismuth compounds have become attractive candidates for use as reagents in
organic synthesis due to their low toxicity, ease of handling and relatively insensitivity to air and
1
4
moisture. Bismuth has been heralded as a green element, and the low toxicity of many bismuth

1838
HETEROCYCLES, Vol. 68, No. 9, 2006
1
5
compounds is evident from their LD50
.
Bismuthyl perchlorate (BiOClO ·xH O) is a commercially available reagent and requires no special
4
2
1
6
handling. Several organic transformations using this reagent have been reported in the literature. We
now report a rapid and efficient method for the Michael addition of indoles (1a~d) in the presence of
4 2
catalytic amount of BiOClO ·xH O under two conditions: at room temperature (method A) and sonication
atambient room temperature (method B) (Scheme 1).
R3
R4
.
BiOClO xH O (0.09 mmol)
4
2
R2
(1.1 mmol)
+ R CH=CHR4
3
(1 mmol)
R2
MeCN, rt or sonication
N
N
2
a-g
1a-d
3a-p
R1
3
4
R1
a: R = H, R = MeCO
3
4
b: R = C H , R = NO
6
5
2
3
4
c: R = C H , R = MeCO
1
2
6
5
a: R = R = H
3
4
d: R = C H , R = C H CO
1
2
6
5
6
5
b: R = H, R = CO Et
2
3
4
e: R = C H , R = C H CH= CHCO
6
5
6
5
1
2
c: R = H, R = CH
3
4
3
f: R = H, R = CN
1
2
3
4
d: R = Me, R = H
g: R = H, R = CO Et
2
Scheme 1
First, in order to investigate the influence of solvents on the catalyst, the addition reaction of indole (1a)
with methyl vinyl ketone (2a) was carried out in hexane, chloroform, dichloromethane,
1
,2-dichloroethane, dimethylformamide, methanol, and acetonitrile at room temperature. As shown in
Table 1, the best result was obtained after 50 min in acetonitrile in the presence of 9 mol% of the catalyst
Entry 7). It was found that BiOClO ·xH O is soluble in acetonitrile, methanol and dimethylformamide,
(
4
2
while it is slightly soluble in chloroform, dichloromethane, and 1,2-dichloroethane, while insoluble in
hexane. The results indicate that the solubility of the catalyst is not an important factor for the addition
4 2
reaction. It is possible that solvation of Bi atom in BiOClO ·xH O by the lone pairs of oxygen atom of
dimethylformamide decreases the Lewis acidity of the catalyst so that the reaction does not proceed in
this solvent as supported by the data in Table 1 (Entry 5). In methanol, although it is a good solvent for
the catalyst, the solvation may decrease the nucleophilicity of indole and therefore results in longer
reaction time and lower yield compared to acetonitrile (Entry 6). Long reaction time and low yield in
hexane may be related to low solubility of substrates and possibly insolubility of the catalyst (Entry 1).
On the other hand, chloroform, dichloromethane, and 1,2-dichloroethane are much better solvents for the
substrates. Although, the catalyst is slightly soluble in these solvents, the reaction times and the yields
indicate that the reaction may proceed via heterogeneous catalysis (Entries 2-4). We also found that the
presence of water in the reaction media has no influence on the yield (Entry 8) and therefore, in contrast
5
,6a
to some of the previous methods, anhydrous solvent is not necessary. The generality of this addition

HETEROCYCLES, Vol. 68, No. 9, 2006
1839
reaction proceeded effectively in the reaction of indoles with a wide range of Michael acceptors in
acetonitrile at room temperature without ultrasonic irradiation (Table 2, method A).
Table 1. Solvent effect on the reaction of indole (1a) with
a,b
methyl vinyl ketone (2a) in the presence of BiOClO ·xH O
4
2
c
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
Hexane
180
90
10
89
90
82
3
CHCl
3
CH Cl2
75
2
ClCH CH Cl
90
2
2
DMF
240
120
50
MeOH
MeCN
MeCN
75
97
97
d
8
50
a
b
Without ultrasonic irradiation at room temperature. In the presence of 9
c
d
mol% catalyst and 10 ml solvent. Isolated yields. In the presence of 2%
H O.
2
However, improvement in yields and reaction times was observed under ultrasonic irradiation (Method B)
(
Table 2). The procedure for this reaction is remarkably simple. In a model reaction, indole (1a) and
methyl vinyl ketone (2a) in acetonitrile were stirred in a container under irradiation using a laboratory
sonication bath. This method allows a shorter reaction time at ambient temperature in contrast to Method
A. To evaluate the use of this procedure, a variety of substituted indoles (1b~d) are reacted with Michael
acceptors (2a~g). The reaction proceeds very cleanly and no undesirable side reactions were observed.
4 2
On the other hand, in the absence of BiOClO ·xH O the reaction did not proceed even after 2 h.
According to our examination, we found that treatment of indoles (1), carrying either carboethoxy as an
electron-withdrawing group or methyl as an electron-donating group, afforded Michael adducts (3) in
high to excellent yields in short reaction times (Table 2). It is important to note that the protection of NH
group of indole is not necessary and, under these conditions, 3-substituted indoles (3) were obtained
without formation of any N-alkylation products (Entries 1-13). Another important aspect of this method is
found in Entry 8. Very recently Bartoli et al. reported that presence of electron-withdrawing group in
pyrrole ring of indole does not produce the corresponding product using cerlum (III) chloride as
6
c
catalyst. However, we observed that by utilizing of our procedure, synthesis of the corresponding
Michael adducts has been performed successfully (Table 2, Entry 8).
Furthermore, unlike some of the previous methods, the present protocol dose not require either strong
acids or high temperatures to afford indole derivatives. Thus, this method provides an easy access to the
preparation of 3-substituted indoles (3) without any side reactions such as dimerization, polymerization

1840
HETEROCYCLES, Vol. 68, No. 9, 2006
4 2
Table 2. Reactions of indoles with Michael acceptors in the presence of BiOClO ·xH O under
Two conditions
a
a
Entry
Indole
Michael
acceptor
Product
Method A
Time
min)
50
Method B
References
for known
compounds
10b
Yield
(%)
Time
(min)
15
Yield
(%)
b
b
(
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
1d
1d
1d
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
97
88
90
92
80
87
90
96
96
90
89
90
85
95
84
88
99
89
92
94
82
92
91
99
99
98
93
92
87
98
86
91
90
120
105
120
60
60
45
60
60
30
45
15
20
30
45
45
60
25
60
45
6c
10a
5d
6b
13b
10c
-
2g
2a
2a
2b
2c
2d
2e
2a
2b
2c
3g
3h
3i
90
45
60
5b
1
1
1
1
1
1
1
0
1
2
3
4
5
6
3j
120
120
120
135
75
11
3k
3l
6b
10b
-
3m
3n
3o
3p
10a
11
135
135
10a
a
Method A: without ultrasonic irradiation at room temperature, Method B: under ultrasonic irradiation.
b
Isolated yields.
and N-alkylation and offers several advantages such as higher yields, shorter reaction times, cleaner
reaction profiles with simple experimental and workup procedures.
In addition, the chemoselectivity of the present method is also demonstrated. It is interesting to note that
some acid-sensitive groups such as TMS-ethers were stable under these reaction conditions. For example,
when a mixture of methyl vinyl ketone and 4-methylbenzyl trimethylsilyl ether was allowed to react with
indole in the presence of 9 mol% BiOClO ·xH O for 50 min at room temperature or 15 min under
4
2
ultrasonic irradiation, the Michael acceptor was chemoselectively converted to the corresponding product
but the TMS-ether remained intact (Scheme 2). It is noteworthy that deprotection of silyl ethers has been
1
6c
reported using this catalyst previously.
In conclusion, we have described a mild, efficient and selective procedure for the synthesis of
-substituted indoles. No side products were observed. As this reaction is not sensitive to moisture, the
3
solvent used and reaction conditions need not be absolutely anhydrous. Moreover, the catalyst is an
inexpensive, relatively non-toxic and commercially available chemical that is commonly found in most
organic laboratories.

HETEROCYCLES, Vol. 68, No. 9, 2006
1841
CH OTMS
2
+
CH =CHCOMe
+
2
N
H
Me
1
a (1.1 mmol)
2a (1 mmol)
(1 mmol)
.
BiOClO xH O (0.09 mmol)
4
2
CH CN
3
COMe
CH OTMS
2
+
N
H
Me
Method A (50 min):3a (95 %)
Method B (15 min):3a (98 %)
100 %
100 %
Scheme 2
EXPERIMENTAL
All products were identified by comparison of their physical and spectral data with those of authentic
samples. Melting points were determined using a Stuart Scientific apparatus and are uncorrected. IR
1
spectra were run on a Shimadzu IR-435 spectrophotometer. H NMR spectra were recorded in CDCl
3
solvent on a Bruker 500 MHz spectrometer. Yields refer to isolated products. The Bi and water contents
of the catalyst were determined by atomic absorption spectrometry and Karl Fischer method respectively,
which indicated the water content was about 1.7 mole per mole of the catalyst.
General procedure (Method A): To a stirred solution of indole (1) (1.1 mmol) in MeCN (10 ml),
α,β-unsaturated compound (2) (1 mmol) and BiOClO
of the reaction monitored by TLC (Table 2), the solvent was evaporated. The residue was diluted with
water (10 ml), extracted with ethyl acetate (3×10 ml) and then dried over MgSO · Column
using hexane/ethyl acetate (9/1) as eluent gave the pure
4 2
·xH O (0.09 mmol) were added. After completion
4
chromatography of the crude residue on SiO
2
products (3) in 80-97% yields.
General procedure (Method B): A mixture of indole (1) (1.1 mmol), α,β-unsaturated compound (2) (1
mmol) and BiOClO ·xH O (0.09 mmol) in MeCN (10 ml) was irradiated for 15-60 min in a laboratory
4
2
ultrasonic bath. After completion of the reaction (monitored by TLC), the solvent was evaporated, diluted
with water (10 ml) and then extracted with ethyl acetate (3×10 ml). The combined organic layer was dried
with MgSO
4
and after removing the solvent under vaccum, the crude product was purified by
using hexane/ethyl acetate (9/1) as eluent to afford pure products (3) in 82-99%
chromatography on SiO
2

1842
HETEROCYCLES, Vol. 68, No. 9, 2006
yields. Compound (3h) (Entry 8), mp 116-117 °C. IR (KBr): 3291, 2979, 1689, 1544, 1254, 1023, 738
-1 1
cm . H NMR (500 MHz, CDCl
3
): 1.39 (t, J = 7.12 Hz, 3H), 2.13 (s, 3H), 2.79 (t, J = 7.86 Hz, 2H), 3.34
(
t, J = 7.83 Hz, 2H), 4.40 (q, J = 7.01 Hz, 2H), 7.13 (t, J = 7.47 Hz, 1H), 7.30 (t, J = 7.07 Hz, 1H), 7.35 (d,
+
J = 8.26 Hz, 1H), 7.68 (d, J = 8.26 Hz, 1H), 8.81 (s, 1H). EIMS: m/z 259 (M ), 216, 202, 189, 170, 156,
1
7
1
43. Compound (3m) (Entry 13), mp 104-105 °C. IR (KBr): 3409, 3022, 2902, 1606, 1461, 1300, 1093,
-1 1
33 cm . H NMR (500 MHz, CDCl
3
): 2.45 (s, 3H), 3.56 (dd, J = 15.35, 6.05 Hz, 1H), 3.75 (dd, J =
5.35, 8.70 Hz, 1H), 5.01 (t, J = 7.34 Hz, 1H), 6.61 (d, J = 16.19 Hz, 1H), 7.06 (t, J = 7.48 Hz, 1H), 7.13
(
t, J = 7.51 Hz, 1H), 7.21 (t, J = 7.28 Hz, 2H), 7.28 (d, J = 11.32 Hz, 1H), 7.31-7.44 (m, 8H), 7.52 (d, J =
+
7
.83 Hz, 2H), 7.87 (br s, 1H). EIMS: m/z 365(M ), 234, 220, 204, 145, 131.
ACKNOWLEDGEMENT
We are thankful to the Isfahan University Research Council for partial support of this work.
REFERENCES
1
.
(a) R. J. Sundberg, ‘The Chemistry of Indoles’, Academic, New York, 1970. (b) T. Fukuyama and X.
Chen, J. Am. Chem. Soc., 1994, 116, 3125.
2
.
(a) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045. (b) J. A. Joule, ‘Science of Synthesis’,
Vol. 10, ed. by E. J. Thomas, Thieme, Stuttgart, 2000, p. 361.
3
.
.
R. E. Moore, C. Cheuk, and G. M. L. Patterson, J. Am. Chem. Soc., 1984, 106, 6456.
R. E. Moore, C. Cheuk, X.-Q. Yang, G. M. L. Patterson, R. Bonjouklian, T. A. Smitka, J. Mynderse,
R. S. Foster, N. D. Jones, J. K. Swartzendruber, and J. B. Deeter, J. Org. Chem., 1987, 52, 1036.
(a) W. E. Noland, G. M. Christensen, G. L. Sauer, and G. G. S. Dutton, J. Am. Chem. Soc., 1955, 77,
4
5
.
4
56. (b) Z. Iqbal, A. H. Jackson, and K. R. N. Rao, Tetrahedron Lett., 1988, 29, 2577. (c) W. J.
Houlihan, ‘Indoles’, Vol. 1, John Wiley & Sons, New York, 1972, p. 71. (d) S.-J. Ji and S.-Y. Wang,
Ultrason. Sonochem., 2005, 12, 339.
6
.
(a) M. Bandini, P. G. Cozzi, M. Giacomini, P. Melchiorre, S. Selva, and A. Umani-Ronchi, J. Org.
Chem., 2002, 67, 3700. (b) Z.-P. Zhan, R.-F. Yang, and K. Lang, Tetrahedron Lett., 2005, 46, 3859.
(
c) G. Bartoli, M. Bosco, S. Giuli, A. Giuliani, L. Lucarelli, E. Marcantoni, L. Sambri, and E.
Torregiani, J. Org. Chem., 2005, 70, 1941.
7
8
.
.
S.-J. Ji and S.-Y. Wang, Synlett, 2003, 2074.
M. Bandini, M. Fagioli, P. Melchiorre, A. Melloni, and A. Umani-Ronchi, Tetrahedron Lett., 2003,
4
4, 5843.
9
1
.
A. Arcadi, G. Bianchi, M. Chiarini, G. D’Anniballe, and F. Marinelli, Synlett, 2004, 944.
0. (a) P. E. Harrington and M. A. Kerr, Synlett, 1996, 1047. (b) A. V. Reddy, K. Ravinder, T. V. Goud,
P. Krishnaiah, T. V. Raju, and Y. Venkateswarlu, Tetrahedron Lett., 2003, 44, 6257. (c) D. A.

HETEROCYCLES, Vol. 68, No. 9, 2006
1843
Benson, I. Karsch-Mizrachi, D. J. Lipman, J. Ostell, B. A. Rapp, and D. L. G. Wheeler, Nucl. Acids
Res., 2000, 28, 15. (d) M. Kawatsura, S. Aburatani, and J. Uenishi, Synlett, 2005, 2492.
1. G. Dessole, R. P. Herrera, and A. Ricci, Synlett, 2004, 2374.
1
1
1
2. B. K. Banik, M. Fernandez, and C. Alvarez, Tetrahedron Lett., 2005, 46, 2479.
3. (a) N. Srivastava and B. K. Banik, J. Org. Chem., 2003, 68, 2109. (b) M. M. Alam, R. Varala, and S.
R. Adapa, Tetrahedron Lett., 2003, 44, 5115.
1
4. (a) H. Suzuki, T. Ikegami, and Y. Matano, Synthesis, 1997, 249. (b) N. M. Leonard, L. C. Wieland,
and R. S. Mohan, Tetrahedron, 2002, 58, 8373. (c) J. V. Yadav, B. V. S. Reddy, P. N. Reddy, and M.
S. Rao, Synthesis, 2003, 1387. (d) I. Mohammadpoor-Baltork, H. Aliyan, and A. R. Khosropour,
Tetrahedron, 2001, 57, 5851. (e) I. Mohammadpoor-Baltork, M. M. Khodaei, and K. Nikoofar,
Tetrahedron Lett., 2003, 44, 591. (f) G. Sabitha, E. V. Reddy, R. Swapna, N. A. Reddy, and J. S.
Yadav, Synlett, 2004, 1276. (g) J. S. Yadav, B. V. S. Reddy, and K. Premalatha, Synlett, 2004, 963.
(
h) I. Mohammadpoor-Baltork, A. R. Khosropour, and S. F. Hojati, Synlett, 2005, 2747. (i) B. A.
Nattier, K. J. Eash, and R. S. Mohan, Synthesis, 2001, 1010. (j) R. Ghosh, S. Maiti, and A.
Chakraborty, Synlett, 2005, 115. (k) A. R. Khosropour, M. M. Khodaei, M. Beygzadeh, and M.
Jokar, Heterocycles, 2005, 65, 767.
1
5. (a) N. Irwing-Sax and R. J. Bewis, ‘Dangerous Properties of Industrial Materials’, Van Nostrand
Reinhold, New York, 1989, p. 522. (b) U. Wormser and I. Nir, ‘The Chemistry of Organic Arsenic,
Antimony and Bismuth Compounds’, ed. by S. Patai, Wiley, New York, 1994, p. 715.
6. (a) A. M. Anderson, J. M. Blazek, P. Garg, B. J. Payne, and R. S. Mohan, Tetrahedron Lett., 2000,
1
4
1, 1527. (b) A. K. Chakraborti and R. G. Shivani, Synlett, 2003, 1805. (c) R. D. Grouch, C. A.
Romany, A. C. Kreshock, K. A. Menconi, and J. L. Zile, Tetrahedron Lett., 2004, 45, 1279.