The Michael Addition of Indole to α,β-Unsaturated Ketones Catalyzed by Iodine at Room Temperature

Article abstract of DOI:10.1055/s-2003-42105

Indole undergoes conjugate addition with α,β-unsaturated ketones by means of alkylation of indole in the presence of a catalytic amount of molecular I₂ at room temperature to afford the corresponding adduct in excellent yields (up to 96%). The

Full text of DOI:10.1055/s-2003-42105

LETTER
2377
The Michael Addition of Indole to a,b-Unsaturated Ketones Catalyzed by
Iodine at Room Temperature
M
a
ichael
Addit
h
ion of Indole
u
to
a
,
b
-Unsa
n
turatedKeto
-
nes Yi Wang,a Shun-Jun Ji,*a Teck-Peng Loh*a,b
College of Chemistry and Chemical Engineering of Suzhou University, Suzhou, 215006 China
b
Department of Chemistry, 3 Science Drive 3, National University of Singapore, 117543 Singapore
Fax +86(512)65224873; E-mail: shunjun@suda.edu.cn
Received 13 September 2003
Abstract: Indole undergoes conjugate addition with a,b-unsaturat-
ed ketones by means of alkylation of indole in the presence of a
catalytic amount of molecular I2 at room temperature to afford the
corresponding adduct in excellent yields (up to 96%). The substitu-
tion on the indole nucleus occurred exclusively at the 3-position.
N-alkylation products have not been observed.
HN
O
O
I2/C2H5OH
r.t.
+
R2
N
H
R1
R1
R2
1
2
3
Key words: molecular iodine, indoles, Michael reaction
Scheme 1
The investigation of the chemistry of indoles has been,
and continues to be, one of the most active areas of hetero-
cyclic chemistry.1 Among the derivatives of indoles, b-in-
dolylketones are important building blocks for the
synthesis of many natural products such as hapalindole D
1.2 Therefore, many methods have been developed for the
synthesis of this class of compounds. In the last few years,
several Lewis acid-mediated Friedel–Crafts-type addi-
tions of indoles to a,b-unsaturated ketones exclusively at
the 3-position, have been reported.2–4 However, many of
these procedures involved strong acidic conditions, ex-
pensive reagents, longer reaction times, low yields of
products and complex handling. More recently, we have
reported that ceric ammonium nitrate (CAN) efficiently
catalyzes the Michael addition of indole to a,b-unsaturat-
ed carbonyl ketones under sonic waves.5 In continuation
of our ongoing interest in green chemistry, we are interest-
Table 1 The Solvent Effect of Michael Addition of Indole 1 with
a,b-Unsaturated Compounds 2aa
Entry
Solvent
Time/h.
4 (3)d
3 (3)
8 (3)
8
Yield (%)b
86 (70)
90 (81)
75 (31)
80
1
2
3
4
5
6
anhyd EtOH
anhyd MeOH
CH3CN
C2H5OH–H2O = 95:5
C2H5OH–H2O = 1:1
H2O (PTCc)
12
50
12
0
a All reaction were carried out using cat. amount of I2 (10% mol) at
ambient temperature.
b Isolated yields.
c Bu4NBr (10% mol).
ed in using I2, which has received considerable attention d The results in parentheses have been reported using cat. amount of
CAN (10% mol) under ultrasonic irradiation.5
as an inexpensive and easily available catalyst for effi-
cient various organic transformations,6,7 to catalyze this
reaction.
vents. The results are listed in Table 1. The reaction of in-
dole (1) with 2a in the presence of I2 (10 mmol) and
anhydrous EtOH (2 mL) proceeded smoothly at room
temperature, giving the 3-oxoalkylation adduct 3a in 86%
The I2–EtOH system offers some advantages over exist-
ing methods with InCl3,8 CeCl3·7H2O–NaI.4a As shown in
Table 1 (entries 1–4), it is found that this system is more
desirable than CAN–MeOH system under ultrasonic irra-
yield, while 90% yield was found in anhydrous MeOH (2
diation in terms of yields and reaction times using differ-
mL) (Table 1, entries 1 and 2). Especially noteworthy is
ent solvents. Herein, we describe a remarkable catalytic
that this reaction can also work in aqueous media (entry
4). However, increasing the amount of water resulted in a
decrease in yield (entries 5 and 6) under identical condi-
tions, even in the presence of PTC. Considering the toxic
activity of I2 in conjugate addition of indole 1 with a,b-un-
saturated carbonyl compounds 2 which provide an effi-
cient route to the synthesis of b-indolyketones
(Scheme 1).
nature of the MeOH, study continued to be done using
First we carried out the reaction of indole (1) with 2a in
I2–EtOH system.
the presence of I2 at room temperature using different sol-
I2 was found to be an efficient catalyst in terms of price,
handling, temperature, yields and reaction times in com-
parison to the reported methods. This is because of the
mild Lewis acidity of I2 and a small quantity of the solvent
needed. As shown in Table 2, this method works with a
SYNLETT 2003, No. 15, pp 2377–2379
0
1
.1
2
.2
0
0
3
Advanced online publication: 22.10.2003
DOI: 10.1055/s-2003-42105; Art ID: U18103ST
© Georg Thieme Verlag Stuttgart · New York

2378
S.-Y. Wang et al.
LETTER
Table 2 Michael Addition of Indole 1 with a,b-Unsaturated Compounds 2a–la,11,12,
Entry
1
Chalone
Product
Time (h)
4
Yield (%)b
863b (85)c
2a
3a
O
O
O
2
3
2b
2c
3b
3c
5
5
86
969
O
4
2d
3d
5
92
O
O
Cl
5
6
2e
2f
3e
3f
5
5
86
96
S
O
Cl
7
8
2g
2h
2i
3g
3h
3i
5
8
5
5
9210
O
O
60
O
O
O
O
Cl
9
90
S
10
2j
3j
9610
O
O
11
12
2k
2l
3k
3l
10
12
929
O
703b
O
a All reactions were carried out in anhyd EtOH at r.t., employing 10 mol% I2.
b All products are determined by IR, 1H NMR, HRMS and mp etc. The superscripts are the citation for the known compounds.
c The result for large-scale synthesis (50 mmol level) under identical condition is listed in parentheses.
Synlett 2003, No. 15, 2377–2379 © Thieme Stuttgart · New York

LETTER
Michael Addition of Indole to a,b-Unsaturated Ketones
2379
(7) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S. Synlett 2003, 11,
1722.
(8) Babu, L. R.; Perumal, P. T. Aldrichim. Acta 2000, 33, 16.
(9) Merchant, J. Indian Chem. Soc. 1971, 48, 613.
(10) Kuchkova, K. I. Chem. Heterocycl. Compd. (Engl. Transl.)
1970, 6, 182.
wide variety of substrates. In most cases, the reactions
proceeded smoothly to produce the corresponding 3-(3-
oxoalkyl)indole 3 in good yields. The treatment of indole
1 with 2c afforded 3c in 96% yield under identical condi-
tion. Michael acceptors such as 2l also reacted well under
our condition. The reactions were clean and the products
were obtained in excellent yields without the formation of
any side products such as N-alkylation products. And
these reactions work with an open vessel with stirring,
which makes the upscaling of the reactions to larger scale
possible without decreasing yields (Table 2, entry 1, foot-
note c). The I2–EtOH reaction system is easier to handle
and is easy for large-scale reaction as compared to the re-
action using CAN under sonication.
(11) Typical Experimental Procedure: A mixture of indole
(0.117 g, 1 mmol), 2c (0.355 g, 1 mmol), I2 (0.025 g, 0.1
mmol) and anhyd EtOH (2 mL) was stirred in an open vessel
at r.t. until the disappearance of the starting indole (5 h,
checked by TLC). After standing for 2 h, the reaction
mixture was washed by cold water (2 ´ 25 mL) and cold
EtOH (2 ´ 0.5 mL). The crude mixture recrystallized from
hot EtOH to afford the pure product 3c (0.453 g, yield: 96%).
3-(1H-Indol-3-yl)-3-(4-methoxy-phenyl)-1-phenyl-propan-
1-one (3c): solid; mp 161–162 °C (Lit.9 162 °C). IR (KBr):
1669 (CO), 3420 (NH) cm–1. 1H NMR (400 MHz, CDCl3):
d = 3.69–3.83 (m, 5 H, CH2, CH3), 5.02 (t, J = 7.2 Hz, 1 H,
CH), 6.79–7.63 (m, 12 H), 7.98–8.03 (m, 3 H). HRMS: m/z
[M] calcd for C24H21NO2: 355.1572; found: 355.1555 [M+].
(12) Selected Characterization Data of New Compounds.
3-(1H-Indol-3-yl)-1-phenyl-3-p-tolyl-propan-1-one (3b):
solid; mp 140 °C. IR (KBr): 1672 (CO), 3428 (NH) cm–1. 1H
NMR (400 MHz, CDCl3): d = 2.28 (s, 3 H, CH3), 3.68–3.84
(m, 2 H, CH2), 5.04 (t, J = 7.2 Hz, 1 H, CH), 6.97–7.53 (m,
12 H), 7.91–7.96 (m, 3 H). HRMS: m/z [M] calcd for
C24H21NO: 339.1623; found: 339.1634 [M+].
In conclusion, we have developed a simple, convenient
and efficient protocol for 3 using catalytic amount of I2
under mild conditions at room temperature. The ability for
this reaction to work in protic solvents (e.g. alcohol, wa-
ter, etc) make this method one of the most efficient meth-
ods for the synthesis of this class of compounds. In
addition, the mechanism is still ongoing in our laboratory.
Acknowledgement
3-(4-Chloro-phenyl)-3-(1H-indol-3-yl)-1-phenyl-propan-1-
one (3d): solid; mp 127–129 °C. IR (KBr): 1677 (CO), 3401
(NH) cm–1. 1H NMR (400 MHz, CDCl3): d = 3.66–3.83 (m,
2 H, CH2), 5.04 (t, J = 7.2 Hz, 1 H, CH), 6.70–7.60 (m, 12
H), 7.92–8.00(m, 3 H). HRMS: m/z [M] calcd for
C23H18ClNO: 359.0891; found: 359.0855 [M+].
3-(1H-Indol-3-yl)-1-phenyl-3-thiophen-2-yl-propan-1-one
(3e): solid; mp 151–153 °C. IR (KBr): 1683 (CO),
3401(NH) cm–1. 1H NMR (400 MHz, CDCl3): d = 3.83 (d, J
= 7.2 Hz, 2 H, CH2), 5.36 (t, J = 7.2 Hz, 1 H, CH), 6.87–7.55
(m, 12 H), 7.92–8.00 (m, 3 H). HRMS: m/z [M] calcd for
C21H17NOS: 331.1031; found: 331.0977 [M+].
1-(4-Chloro-phenyl)-3-(1H-indol-3-yl)-3-phenyl-propan-1-
one (3f): solid; mp 158–160 °C. IR (KBr): 1680 (CO), 3445
(NH) cm–1. 1H NMR (400 MHz, CDCl3): d = 3.65–3.80 (m,
2 H, CH2), 5.03 (t, J = 7.2 Hz, 1 H, CH), 6.99–7.43 (m, 12
H), 7.84–7.98 (m, 3 H). HRMS: m/z [M] calcd for
C23H18ClNO: 359.0891; found: 359.0891 [M+].
3-(4-Chloro-phenyl)-3-(1H-indol-3-yl)-1-(4-methoxy-
phenyl)-propan-1-one (3h): solid; mp 123–125 °C. IR
(KBr): 1658 (CO), 3461(NH) cm–1. 1H NMR (400 MHz,
CDCl3):
This work was supported by the National Natural Science Founda-
tion of China (No.20172039) and grants from the National Univer-
sity of Singapore.
References
(1) Gilchrist, T. L. Heterocyclic Chemistry; Academic Press:
London, 1997.
(2) Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047.
(3) (a) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.;
Selva, S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67, 3700.
(b) Harrington, P. E.; Kerr, M. A. Can. J. Chem. 1998, 76,
1256. (c) Yadav, J. S.; Abraham, S.; Subba Reddy, B. V.;
Sabitha, G. Synthesis 2001, 2165. (d) Manabe, K.; Aoyama,
N.; Kobayashi, S. Adv. Synth. Catal. 2001, 174. (e) Yadav,
J. S.; Subba Reddy, B. V.; Murthy, V. S. R.; Mahesh Kumar,
G.; Madan, C. Synthesis 2001, 783. (f) Iqbal, Z.; Jackson,
A. H.; Rao, K. R. N. Tetrahedron Lett. 1988, 29, 2577.
(g) BF3·OEt2: Dujardin, G.; Poirier, J.-M. Bull. Soc. Chim.
Fr. 1994, 131, 900. (h) Komoto, I.; Kobayashi, S. Org. Lett.
2002, 4, 1115.
d = 3.22–3.35 (m, 2 H, CH2), 3.89 (s, 3 H, CH3), 5.30 (t, J =
7.2 Hz, 1 H, CH), 6.93–7.60 (m, 11 H), 7.74–7.95(m, 3 H).
HRMS: m/z [M] calcd for C24H20ClNO2: 389.1183; found:
389.1194 [M+].
(4) (a) Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.;
Giuliani, A.; Marcantoni, E.; Sambri, L.; Torregiani, E. J.
Org. Chem. 2003, 68, 4594. (b) Alam, M. M.; Varala, R.;
Adapa, S. Tetrahedron Lett. 2003, 44, 5115.
3-(1H-Indol-3-yl)-1-(4-methoxy-phenyl)-3-thiophen-2-yl-
propan-1-one (3i): solid; mp 149–151 °C. IR (KBr): 1670
(CO), 3430 (NH) cm–1. 1H NMR (400 MHz, CDCl3): d =
3.78 (d, J = 7.2 Hz, 2 H, CH2), 3.86 (s, 3 H, CH3), 5.37 (t,
J = 7.2 Hz, 1 H, CH), 6.87–7.56 (m, 10 H), 7.92–8.00 (m, 3
H). HRMS: m/z [M] calcd for C22H19NO2S: 361.1136;
found: 361.1066 [M+].
(5) Ji, S.-J.; Wang, S.-Y. Synlett 2003, 2074.
(6) (a) Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.; Reddy, G. S.
K. K. Synthesis 2000, 1532. (b) Basu, M. K.; Samajdar, M.
K.; Becker, F. F.; Banik, B. K. Synlett 2002, 2, 319.
(c) Yadav, J. S.; Reddy, B. V. S.; Rao, C. V.; Reddy, S. G.
Synlett 2003, 2, 247.
Synlett 2003, No. 15, 2377–2379 © Thieme Stuttgart · New York