Indium(III) chloride catalyzed conjugate addition of 1,3-dicarbonyl compounds to α,β-unsaturated ketones

Article abstract of DOI:10.1081/SCC-120014790

Indium trichloride catalyzes efficiently the Michael reactions of 1,3-dicarbonyl compounds with α,β-unsaturated ketones to afford the corresponding Michael adducts in high yields with high selectivity.

Full text of DOI:10.1081/SCC-120014790

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INDIUM(III) CHLORIDE CATALYZED CONJUGATE ADDITION
OF 1,3-DICARBONYL COMPOUNDS TO α,β-UNSATURATED
KETONES*
J. S. Yadav a , V. Geetha a & B. V. Subba Reddy a
a Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad, 500 007,
India
Version of record first published: 22 May 2009.
To cite this article: J. S. Yadav, V. Geetha & B. V. Subba Reddy (2002): INDIUM(III) CHLORIDE CATALYZED CONJUGATE ADDITION
OF 1,3-DICARBONYL COMPOUNDS TO α,β-UNSATURATED KETONES*, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:22, 3519-3524
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 22, pp. 3519–3524, 2002
INDIUM(III) CHLORIDE CATALYZED
CONJUGATE ADDITION OF
1,3-DICARBONYL COMPOUNDS TO
a,b-UNSATURATED KETONES*
J. S. Yadav,y V. Geetha, and B. V. Subba Reddy
Organic Chemistry Division-I, Indian Institute of
Chemical Technology, Hyderabad-500 007, India
ABSTRACT
Indium trichloride catalyzes efficiently the Michael reactions
of 1,3-dicarbonyl compounds with a,b-unsaturated ketones to
afford the corresponding Michael adducts in high yields with
high selectivity.
Lewis acid promoted carbon–carbon bond forming reactions are of
great interest because of their unique reactivity and selectivity. Among vari-
ous Lewis acid catalyzed C–C bond forming reactions, Michael reaction is
one of the most important transformations[1] in organic synthesis.
Traditionally, the Michael reactions are performed, under the influence of
strong bases[2] such as alkali metal alkoxides or hydroxides. However, the
*IICT Communication No. 4700.
yCorresponding author. E-mail: yadav@iict.ap.nic.in
3519
DOI: 10.1081/SCC-120014790
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3520
YADAV, GEETHA, AND REDDY
strongly basic conditions often lead to a number of undesirable side reac-
tions such as aldol cyclizations, ester solvolysis, rearrangements such as
retro-Claisen or retro-Michael reactions and polymerization reactions.
Alternatively, several Lewis acids have been developed[3–7] to carry out
the Michael reactions under mild conditions with high efficiency.
However, most Michael reactions reported so far are performed in organic
solvents, today’s environmental concerns demands organic reactions in sol-
vent free conditions or in water. Although metal triflates are found to cat-
alyze Michael reactions in water, the reactions proceeded very slowly and
required a period of three to five days for completion and also metal triflates
are highly expensive. Recently, FeCl3ꢀ6H2O has also proved to be the most
effective catalyst[8] for Michael reactions. However, the catalyst cannot be
recovered and reused because it decomposes under quenching conditions.
The presence of even a small amount of water causes lower yields, probably
due to the rapid decomposition or deactivation of the catalyst and also the
solvolysis of ester.
Recently, indium trichloride has emerged as potential Lewis acid
catalyst[9] imparting high regio- and chemoselectivity in various chemical
transformations in both aqueous and non-aqueous media. The reactions
can be performed under mild conditions either neat or in water and the
catalyst can be recovered and reused after the completion of the reactions.
The unique features of indium(III) chloride prompted us to investigate the
use of this catalyst for Michael reactions. Even though InCl3 has been used
in the conjugate addition reactions of amines to a,b-unsaturated com-
pounds,[10] it has not been used in the Michael reaction of 1,3-dicarbonyl
compounds and enones.
In this report, we describe a mild and efficient protocol for conjugate
addition of 1,3-dicarbonyl compounds to a,b-unsaturated ketones using
catalytic amount of indium trichloride in solvent free conditions (Sch. 1).
In all the cases the reaction proceeded smoothly at room temperature
and the products (Michael adducts) were obtained in high yields. In the
Scheme 1.

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DICARBONYL COMPOUNDS AND UNSATURATED KETONES
3521
absence of catalyst, the reactions did not yield any product even after a
long reaction time at room temperature. It should be noted that no bis-
Michael adduct was obtained in the reaction of cyclic b-ketoesters with
enones. The Michael acceptors such as ethyl acrylate and acrylonitrile
failed to react with enones under the similar reaction conditions. The
reaction of ethyl 2-oxo-cyclopentanecarboxylate with methyl vinyl ketone
in the presence of 10 mol% indium chloride under neat conditions resulted
in the formation of corresponding Michael adduct in 90% yield. Similarly
various b-keto esters were reacted with enones to afford respective Michael
adducts in high yields. The best results were obtained by carrying out the
reactions at room temperature in the presence of 10 mol% InCl3 without
any solvent. Reactions in dry media or under solvent free conditions are
especially appealing, as they provide an opportunity to work with an open
vessel, thus avoiding the risk of high internal pressure development and
with the possibility of upscaling the reactions to large scale. Several
examples illustrating this novel procedure for the conjugate addition of
b-keto esters to a,b-unsaturated compounds are summarized in Table 1.
Among various Lewis acids such as YCl3, BiCl3 and YbCl3 used for this
transformation InCl3 was found to be effective in terms of yields and
reaction times.
In conclusion, we have demonstrated that indium trichloride is a
superior and water-tolerant Lewis acid in the conjugate addition of b-keto
esters to a,b-unsaturated ketones under neat conditions. In addition to its
simplicity and milder reaction conditions, this method works well even with
acid sensitive substrates such as methyl vinyl ketone. Improved yields,
greater selectivity, experimental simplicity, stability and recoverability of
the catalyst are the notable features of this procedure.
EXPERIMENTAL
General Procedure for the Conjugate Addition of
b-Keto Esters to a,b-Unsaturated Ketones
A mixture of b-keto ester (5 mmol), a,b-unsaturated ketone (5 mmol)
and indium trichloride (10 mol%) was stirred at room temperature under
neat conditions for an appropriate time (Table 1). After completion of the
reaction as indicated by TLC, the reaction mixture was quenched by
water (10 mL) and extracted with ether (2 ꢁ 20 mL). The combined organic
layers were dried over anhydrous Na2SO4, concentrated in vacuo and
purified by column chromatography on silica gel (Merck, 100–200 mesh,

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3522
YADAV, GEETHA, AND REDDY
Table 1. InCl3 Catalyzed Conjugate Addition of 1,3-Diketones to Enones
b-Keto Ester
Enone
2
Producta
Reaction Time
(h)
Yieldb
(%)
Entry
a)
1
3
6.0
90
b)
8.0
87
c)
d)
e)
7.0
8.5
6.0
82
89
87
f)
8.5
9.0
90
88
g)
h)
i)
7.0
6.5
85
81
j)
7.0
8.5
78
84
k)
l)
9.0
7.5
80
85
m)
n)
8.0
80
1
aAll products were characterized by H NMR, IR and Mass spectra.
bIsolated and unoptimized yields.

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DICARBONYL COMPOUNDS AND UNSATURATED KETONES
3523
ethyl acetate : hexane, 1 : 9) to afford Michael adduct in pure form. The
aqueous layer was concentrated in vacuo to recover the catalyst.
Spectral data of compounds:
3a: 1H NMR (CDCl3, 200 MHz) ꢀ: 1.80–2.05 (m, 4H), 2.05–2.15
(m, 1H), 2.20 (s, 3H), 2.25–2.52 (m, 4H), 2.72 (ddd, J ¼ 17.5, 9.5 and
5.6 Hz, 1H), 3.75 (s, 3H). 13C NMR (CDCl3, 200 MHz, proton decoupled):
19.42, 27.01, 29.58, 33.81, 37.62, 39.21, 58.79, 61.41, 172.42, 208.47, 215.31.
IR (cmꢂ1): 2959, 1714, 1436, 1368, 1260, 1165, 1022, 817. EI MS: m/z 212.
1
3b: H NMR (CDCl3, 200 MHz) ꢀ: 1.25 (t, J ¼ 7.8 Hz, 3H), 1.36–1.46
(m, 1H), 1.55–1.66 (m, 2H), 1.68–1.75 (m, 1H), 1.85 (ddd, J ¼ 13.5, 9.8 and
5.4 Hz, 1H), 1.90–2.0 (m, 1H), 2.05 (ddd, J ¼ 13.5, 9.8 and 5.2, 1H), 2.12
(s, 3H), 2.35 (m, 1H), 2.42–2.55 (m, 3H), 2.60 (m, 1H), 4.10–4.25 (q,
J ¼ 7.8 Hz, 2H). 13C NMR (CDCl3, 200 MHz, proton decoupled): 14.52,
22.57, 28.01, 29.42, 31.30, 35.86, 39.01, 41.05, 61.21, 62.72, 173.41, 208.71,
209.12. IR (cmꢂ1): 2989, 2871, 2357, 1736, 1514, 1195, 1135, 1092, 1020,
861. EI MS: m/z 240, 212, 194, 170, 151, 124.
1
3c: H NMR (CDCl3, 200 MHz) ꢀ: 1.25 (t, J ¼ 7.8 Hz, 3H), 2.15 (s,
3H), 2.18–2.30 (m, 2H), 2.55–2.70 (m, 2H), 4.12–4.25 (q, J ¼ 7.8 Hz, 2H),
4.50 (m, 1H), 7.50–7.55 (m, 2H), 7.62–7.73 (m, 1H), 8.0 (m, 2H). 13C NMR
(CDCl3, 200 MHz, proton decoupled): 14.01, 23.14, 30.22, 41.71, 52.51,
61.07, 128.37, 129.12, 134.17, 135.89, 170.41, 194.94, 207.76. IR (cmꢂ1):
3063, 2982, 2940, 2905, 1735, 1715, 1685, 1597, 1448, 1369, 1286, 1246,
1180, 1157, 1025, 691. EI MS: m/z 262, 105, 77, 43.
1
3d: H NMR (CDCl3, 200 MHz) ꢀ: 1.24 (t, J ¼ 7.8 Hz, 3H), 1.96–2.12
(m, 2H), 2.12 (s, 3H), 2.21 (s, 3H), 2.45–2.50 (m, 2H), 3.15 (t, J ¼ 7.8 Hz,
1H), 4.15–4.22 (q, J ¼ 7.8 Hz, 2H). IR (cmꢂ1): 2983, 2940, 1738, 1713,
1445, 1419, 1359, 1244, 1217, 1151, 1097, 1023, 957, 858. EI MS: m/z
200, 158, 112.
1
3e: H NMR (CDCl3, 200 MHz) ꢀ: 2.05 (m, 2H), 2.18 (s, 9H), 2.50
(dd, J ¼ 11.0 and 6.0 Hz, 2H), 3.6 (t, J ¼ 6.8 Hz, 1H). IR (cmꢂ1): 2970, 2941,
1699, 1569, 1420, 1358, 1154. EI MS: m/z 170, 102, 92, 71, 55.
1
3g: H NMR (CDCl3, 200 MHz) ꢀ: 1.30 (t, J ¼ 6.8 Hz, 3H), 1.60–1.80
(m, 6H), 2.0–2.30 (m, 2H), 2.45–2.60 (m, 2H), 2.80–3.0 (m, 1H), 3.05–3.25
(m, 1H), 4.25 (q, J ¼ 6.8 Hz, 2H), 7.45–7.50 (m, 3H), 8.0 (d, J ¼ 8.0 Hz, 2H).
EI MS: m/z 302.
3h: 1H NMR (CDCl3, 200 MHz) ꢀ: 1.20 (t, J ¼ 7.0 Hz, 3H), 2.40
(m, 2H), 3.05–3.20 (m, 2H), 4.20 (q, J ¼ 7.0 Hz, 2H), 4.58 (t, J ¼ 6.8 Hz,
1H), 7.45–7.60 (m, 6H), 7.95 (d, J ¼ 8.0 Hz, 2H), 8.10 (d, J¼ 8.0 Hz, 2H).
EI MS: m/z 324.
3n: 1H NMR (CDCl3, 200 MHz) ꢀ: 0.85 (t, J ¼ 6.8 Hz, 3H), 2.01 (s, 3H),
2.81–2.84 (m, 2H), 3.75–3.85 (m, 2H), 4.15–4.24 (m, 1H), 8.05–8.07 (m, 2H).
EI MS: m/z 338, 292, 247, 233, 187, 147, 105, 77.

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3524
YADAV, GEETHA, AND REDDY
ACKNOWLEDGMENTS
VG and BVS thank CSIR New Delhi, for the award of fellowships.
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Received in the UK July 30, 2001