Eco-friendly polyethylene glycol promoted Michael addition reactions of α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2008.09.116

Intra- and inter-nucleophilic addition reactions of different α,β-unsaturated carbonyl compounds were found to be highly effective without any additives in PEG-400 as a recyclable reaction medium under neutral conditions.

Full text of DOI:10.1016/j.tetlet.2008.09.116

Tetrahedron Letters 49 (2008) 6974–6976
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Tetrahedron Letters
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Eco-friendly polyethylene glycol promoted Michael addition reactions of
a,b-unsaturated carbonyl compounds
a
a
b,
*
Dalip Kumar a, , Gautam Patel , Braja G. Mishra , Rajender S. Varma
*
a Chemistry Group, Birla Institute of Technology and Science, Pilani 333031, India
b Sustainable Technology Division, National Risk Management Research Laboratory, US EPA, 26W. Martin Luther King Drive, MS 443, Cincinnati, OH 45268, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2008
Revised 16 September 2008
Accepted 17 September 2008
Available online 23 September 2008
Intra- and inter-nucleophilic addition reactions of different
found to be highly effective without any additives in PEG-400 as a recyclable reaction medium under
neutral conditions.
a,b-unsaturated carbonyl compounds were
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Polyethylene glycol
Michael addition
20-Hydroxychalcone
20-Aminochalcones
a,b-Unsaturated carbonyl compounds
There has been an increasing emphasis among researchers from
tive solvent in organic synthesis. Many organic transformations
such as substitution reactions,9 oxidation and reduction reac-
tions,10 Heck reaction,11 asymmetric dihydroxylation,12 Suzuki
cross-coupling reaction,13 Wacker reaction,14 and partial reduc-
tions of alkynes15 are accomplished using PEG as a solvent or co-
solvent. Herein, we report catalysis-free Michael addition reactions
both academia and industry to design synthetic strategies keeping
in view the principles of ‘Green Chemistry’.1a Adopting the
principles of green chemistry means to reduce or eliminate the
generation and use of hazardous substances. In recent years,
replacement of hazardous solvents with environmentally benign
solvents1b,c or development of solvent-free syntheses2 is one of
the major focus areas of Green Chemistry. The utility of alternative
reaction solvents such as water,3 ionic liquid,4 fluorous,5 super-
critical media,6 and polyethylene glycol (PEG)7 is rapidly growing.
The Michael addition reaction is the one of the important meth-
ods, which is widely used in organic synthesis to make carbon–car-
bon and carbon–heteroatom bonds.8 Several Lewis acid catalysts
are reported to be highly effective in Michael addition of nucleo-
of a,b-unsaturated carbonyl compounds in PEG-400 as a recyclable
and recoverable medium.
In our efforts to study Michael addition reactions of a,b-unsat-
urated compounds, at first, we investigated intramolecular cycliza-
tion of 20-hydroxychalcones 1 and 20-aminochalcones 3, which are
reported to afford flavanones and quinolones, respectively, in low
to moderate yields.16–20 Generally, cyclization of 1 and 3 are car-
ried out using different acids,16 bases,17and other reagents18–20 in
combination with highly volatile organic solvents and under harsh
reaction conditions. Flavanones and quinolones are rudimentary
structures for synthesis of many biologically active potent mole-
cules. Our initial attempts to cyclize 20-hydroxychalcones 1 and
20-aminochalcones 3 under conventional heating without any sol-
vent afforded only trace amounts of products 2 and 4, respectively,
along with largely unchanged starting materials. Cyclization of 1
and 3 in polar solvents DMSO and DMF also remained incomplete
under conventional heating at various temperatures.
philes on a
,b-unsaturated carbonyl compounds.8
Recently, PEG and its solutions have been introduced as inter-
esting green solvent systems.7 These have replaced many other
‘neoteric solvents’ such as ionic liquids, super-critical carbon diox-
ide, and micellar systems whose toxicological properties, short and
long-term hazardous nature, and biodegradability have not been
established completely. Low cost, reduced flammability, reduced
toxicity, recyclability, completely nonhalogenated composition,
easily degradable, and miscibility with wide variety of organic sol-
vents are some of the properties that render PEG a benign alterna-
With our recent success in the synthesis of 2-aminochromenes
in aqueous PEG-400,21 we explored cyclizations of 1 and 3 in PEG-
400, and gratifyingly found that reactions were completed without
any additives (Schemes 1 and 2). In order to optimize reaction tem-
perature, a series of experiments of 1 and 3 in PEG-400 at various
* Corresponding authors. Tel.: +1 513 487 2701; fax: +1 513 569 7677.
E-mail addresses: dalipk@bits-pilani.ac.in (D. Kumar), varma.rajender@epa.gov
(R. S. Varma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.116

D. Kumar et al. / Tetrahedron Letters 49 (2008) 6974–6976
6975
Table 3
Reactions of
O
O
a,b-unsaturated carbonyl compounds in PEG-400
Acceptor
Nucleophile
Producta
Time
(h)
Yieldb
(%)
PEG-400
130 °
C
O
Ar
OH Ar
O
O
2
1
C6H5NH2
5.0
92
6a
Scheme 1.
NHC6H5
5a
H
N
O
O
C6H5
CO2Me
C6H5CH2NH2
4.5
5.5
5.5
6.5
89
84
87
89
CO2Me
5b
6b
PEG-400
130 °C
N
H
4
Ar
Ar
NH2
n
-BuHN
CO2Me
5b
n-BuNH2
3
6c
Scheme 2.
H
N
6d
5b
5b
N
CO2Me
CO2Me
Table 1
Cyclization of 20-hydroxychalcones 1a–g in PEG-400
N
HN
N
N
Producta
Ar
Time (h)
Yieldb (%)
6e
2a
2b
2c
2d
2e
2f
C6H5
p-FC6H4
1.0
3.0
2.5
2.5
2.5
2.5
2.5
63
65
62
74
64
65
67
Products were characterized by their 1H, 13C NMR, and HRMS spectral data.
Yields refer to isolated pure products.
a
b
p-MeC6H4
p-ClC6H4
p-MeOC6H4
2,6-Cl2C6H3
2-Furyl
compounds generally involve relatively expensive and hazardous
reagents under various reaction conditions. Reactions of amines
2g
Products were characterized by their 1H, 13C NMR, and HRMS spectral data.
Yields refer to isolated pure products.
a
and imidazole with
a,b-unsaturated carbonyl compounds (5a,b)
b
in PEG-400 proceeded smoothly to afford products in good yields
(Table 3, 6a–e).23–25 Recovered PEG-400 was recycled for the reac-
tion of cyclohex-2-enone 5a with aniline successively for three
times without loosing product yield. Probably, weak interaction
of PEG-400 via hydrogen bonding with the oxygen of enone in-
duces electrophilic character at the b-carbon, which is attacked
by the nucleophile.
In summary, we have accomplished nucleophilic addition reac-
a,b-unsaturated compounds in PEG-400, an
easily recyclable and highly effective reaction medium, under neu-
Table 2
Cyclization of 20-aminochalcones 3a–f in PEG-400
Producta
Ar
Time (h)
Yieldb (%)
4a
4b
4c
4d
4e
4f
C6H5
12.0
14.5
11.0
11.5
12.0
10.5
91
89
87
88
85
82
p-MeC6H4
p-ClC6H4
p-BnOC6H4
2,6-Cl2C6H3
2-Furyl
tions of a variety of
tral conditions.
a
Products were characterized by their 1H, 13C NMR, and HRMS spectral data.
Yields refer to isolated pure products.
Acknowledgment
b
Authors are grateful for the financial support received from
DRDO, New Delhi (Project No. ERIP/ER/0505034/M/01/902).
temperatures were performed, and it was found that 130 °C is the
optimum temperature to get satisfactory results.22 Attempts to
expedite cyclizations of 1 and 3 under microwave irradiation were
unsuccessful. Cyclizations of 20-amino-chalcones 3 were conver-
gent to completion, whereas in the case of 20-hydroxychalcones 1
minor amounts of unreacted starting materials were recovered.
The results of cyclizations of 1 and 3 are summarized in Tables 1
and 2.
References and notes
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Chakraborti, A. K.; Rudrawar, S.; Jadhav, K. B.; Kaur, G.; Chankeshwara, S. V.
Green Chem. 2007, 9, 1335; (e) Sharma, G.; Kumar, R.; Chakraborti, A. K.
Tetrahedron Lett. 2008, 49, 4269; (f) Khatik, G. L.; Kumar, R.; Chakraborti, A. K.
Org. Lett. 2006, 8, 2433; (g) Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett.
2006, 8, 3259.
Finally, intermolecular nucleophilic addition reactions of vari-
ous
a,b-unsaturated compounds (5a,b) under similar conditions
were also investigated (Scheme 3). The literature reports on inter-
molecular Michael addition reactions of a,b-unsaturated carbonyl
4. Sheldon, R. A. Chem. Commun. 2001, 2399.
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NuH
PEG-400
RT
Nu
Scheme 3.

6976
D. Kumar et al. / Tetrahedron Letters 49 (2008) 6974–6976
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(0.2 g) yield. Mp 74–75 °C; IR (KBr) 1680 cmꢁ1 (C@O); 1H NMR (400 MHz,
CDCl3) d 7.90 (d, 1H, J = 8.0 Hz), 7.49 (m, 3H), 7.03 (dd, 1H, J = 14.0, 7.6 Hz), 6.42
(dd, 1H, J = 21.6, 3.2 Hz), 5.54 (dd, 1H, J = 11.60, 3.2 Hz), 3.2 (dd, 1H, J = 16.8,
8.0 Hz), 2.97 (dd, 1H, J = 17.20, 3.2 Hz); 13C NMR (100 MHz, CDCl3) d 192.24,
160.74, 150.89, 143.43, 136.24, 126.95, 121.73, 120.93, 118.12, 110.51, 109.34,
72.27, 40.80.
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Compound 4f: IR (KBr) 3325 (NH), 1690 (C@O) cmꢁ1 1H NMR (400 MHz,
;
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22. Synthesis of 2-(furan-2-yl)-2,3-dihydrochromen-4-one (2g): A mixture of 1g
(0.3 g, 1.40 mmol) and PEG-400 (0.5 mL) was stirred vigorously for 2.5 h at
130 °C. After completion of the reaction, as indicated by TLC, the reaction
mixture was extracted with diethyl ether (3 ꢀ 3 mL). The combined organic
phase was washed with saturated brine solution, dried over anhydrous Na2SO4,
and diethyl ether was removed by distillation. The crude product was
percolated over a bed of silica gel to afford pure flavanone 2g26 in 67%
CDCl3) d 7.85 (d, 1H, J = 8.0 Hz), 7.37–7.26 (m, 2H), 6.78–6.69 (m, 2H), 6.32 (d,
1H, J = 1.2 Hz), 6.25 (d, 1H, J = 1.53 Hz), 4.82 (dd, 1H, J = 9.6, 5.1 Hz), 4.77 (br s,
1H, NH), 3.07–2.92 (m, 2H); 13C NMR (100 MHz, CDCl3) d 192.72, 153.48,
150.61, 142.48, 135.54, 127.56, 119.34, 118.69, 117.17, 116.14, 110.21, 50.79,
42.07.
23. Representative procedure for Michael addition reaction of cyclohex-2-enone
5a: A mixture of 5a (0.50 g, 5.2 mmol) and aniline (0.48 g, 5.2 mmol) was
placed in a round-bottomed flask containing 0.5 mL of PEG-400. The reaction
mixture was allowed to stir for 5 h at room temperature. After completion of
the reaction as indicated by TLC, the reaction mixture was extracted with
diethyl ether (3 ꢀ 3 mL). The combined organic layer was washed with
saturated brine solution, dried over anhydrous Na2SO4, and distilled. The
crude product was purified by percolation over a bed of silica gel to afford pure
product 6a25 in 92% yield (0.90 g). Compound 6a; IR (Neat) 3360 (NH), 1705
(C@O) cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.19–7.13 (m, 2H), 6.77–6.58 (m, 3H),
;
3.8 (m, 1H), 2.82 (m, 1H), 2.40–2.25 (m, 4H), 2.04 (m, 2H), 1.73–1.68 (m, 2H);
13C NMR (100 MHz, CDCl3) d 209.73, 146.31, 129.37, 118.64, 113.37, 52.36,
48.65, 41.23, 31.15, 22.22. Similarly, compounds 6b–e were prepared and
analyzed.
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