The Michael addition of 1,2-cyclohexanedione to β-nitrostyrenes (I): The synthesis of 3-aryl-5,6-dihydrobenzofuran-7(4H)-ones

Article abstract of DOI:10.1016/j.tetlet.2013.04.053

The reaction of β-nitrostyrenes with 1,2-cyclohexanedione using K ₂CO₃ as a base results in the formation of 3-aryl-5,6-dihydrobenzofuran-7(4H)-ones in good yields. A putative reaction mechanism involves an initial Michael addition of the dione C-enolate to the β-nitro-styrene, followed by intramolecular cyclization of the resulting O-enolate anion, elimination of nitrite ion, and air oxidation. Product formation is highly dependent on base stoichiometry.

Full text of DOI:10.1016/j.tetlet.2013.04.053

Tetrahedron Letters 54 (2013) 3371–3373
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Tetrahedron Letters
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The Michael addition of 1,2-cyclohexanedione to b-nitrostyrenes (I):
the synthesis of 3-aryl-5,6-dihydrobenzofuran-7(4H)-ones
⇑
Chad M. Simpkins, David A. Hunt
Department of Chemistry, The College of New Jersey, 2000 Pennington Road, Ewing, NJ 08628, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of b-nitrostyrenes with 1,2-cyclohexanedione using K2CO3 as a base results in the formation
of 3-aryl-5,6-dihydrobenzofuran-7(4H)-ones in good yields. A putative reaction mechanism involves an
initial Michael addition of the dione C-enolate to the b-nitro-styrene, followed by intramolecular cycliza-
tion of the resulting O-enolate anion, elimination of nitrite ion, and air oxidation. Product formation is
highly dependent on base stoichiometry.
Received 26 March 2013
Revised 12 April 2013
Accepted 15 April 2013
Available online 24 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
1,2-Cyclohexanedione
b-Nitrostyrenes
Michael addition
3-Aryl-5,6-dihydrobenzofuran-7(4H)-ones
The use of cyclohexanediones in organic synthesis has been
firmly established.1,2 While the 1,3-cyclohexanedione system has
been widely studied, the chemistry of the 1,2-cyclohexanedione
system by comparison has only recently been investigated. The
first thorough study of the Michael reaction of 1,2-cyclohexanedi-
one, which focused on the development of optimal conditions for
conjugate addition chemistry with simple Michael acceptors, was
reported in 1985.3 During the course of this study, it was found
that intramolecular cyclizations could occur through carbonyl
trapping of the intermediate anion from the addition of the enolate
to the Michael acceptor to afford bicyclo[3,2,1]octan-8-one ring
systems (Scheme 1).
In a related study, Ding and co-workers have utilized the
Michael reaction properties of 1,2-cyclohexanedione to prepare
2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles
(5).4 More recently, Ding et al. have shown that bicy-
cle[3,2,1]octan-8-ones (7a and b) may be prepared with a high de-
gree of enantioselectivity by using catalytic quantities of chiral
bases and b-nitrostyrenes as the Michael acceptor system
(Scheme 2).5
reaction afforded 3-aryl-5,6-dihydrobenzofuran-7(4H)-ones in
good yields (Scheme 3).8 While 2-aryl substituted 4,5-dihydro-
7(6H)-benzofuranone derivatives have been prepared through
the reaction of 1,2-cyclohexanedione with electron rich olefins un-
der free-radical conditions,9 preparation of the corresponding 3-
aryl systems is unknown.
Reactions using a K2CO3:substrate stoichiometry ratio of 10:1
provided the desired product cleanly by GC/mass spectrometry
(Table 1). Preliminary studies indicate that fewer than 10 equiv
of K2CO3 resulted in significantly lower yields of product with con-
comitant impurity formation. Studies regarding this observation
and the determination of the identity of the impurities are contin-
uing and will be described in due course. A possible reaction mech-
anism involves an initial Michael addition of the dione C-enolate to
the b-nitrostyrene, followed by intramolecular cyclization of the
resulting O-enolate anion, elimination of nitrite ion, and air oxida-
tion (Scheme 4). The primary difference in product outcome ob-
served between Ding’s work5 and this work can be attributed to
Based on our long-standing interest in the Michael chemistry of
b-nitrostyrenes6 and the chemistry of 1,2-cyclohexanedione,7 we
initiated a study of the reaction between these substrates with a
variety of base systems. We found that the use of greater than stoi-
chiometric quantities of a relatively strong base (K2CO3) in the
O
O
O
O
base
+
O
R
R
HO
1
2
3
⇑
Corresponding author.
E-mail address: hunt@tcnj.edu (D.A. Hunt).
Scheme 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.053

3372
C. M. Simpkins, D. A. Hunt / Tetrahedron Letters 54 (2013) 3371–3373
O
O
R
base
O
O
NH2
CN
CN
CN
+
R
1
4
5
O
O
chiral basic
catalyst
NO2
HO
O2N
H
HO
O2N
H
+
1
+
R
R = H
X
X
X
6
7a
7b
Scheme 2.
Table 1
O
O
O
O
NO2
K2CO3
DMF
R
R
X
1
+
R
X
X
6
8
8
Compound
R
X
Yield (%)
Scheme 3. Synthesis of 8.
8a
8b
8c
8d
8e
8f
–H
–H
–H
4–Cl
–H
4–Br
4–OCH3
–H
4–CN
3–OCH3
61
40
63
67
84
60
73
79
–CH3
–CH3
–CH3
–CH2CH3
–CH2CH3
–CH2CH3
the strength of the base system employed. Maintaining a high con-
centration of relatively strong base in the system insures the for-
mation of a high concentration of enolate relative to the catalytic
method described by Deng.
8g
8h
O
O
O
O
O
O
H
R
R
B:
BH
NO2
NO2
NO2
X
X
X
R
Y
Y
Y
O
O
O
O
OH
O
1)
2)
-NO2
[O]
R
R
R
B:
NO2
NO2
X
X
X
Y
Y
Y
8
Scheme 4. Proposed mechanism for the formation of 8.

C. M. Simpkins, D. A. Hunt / Tetrahedron Letters 54 (2013) 3371–3373
3373
3. Utaka, M.; Fujii, Y.; Takeda, A. Chem. Lett. 1985, 1123–1126.
4. Ding, D.; Zhao, C.-G. Tetrahedron Lett. 2010, 51, 1322–1325.
Acknowledgments
5. Ding, D.; Zhao, C.-G.; Guo, Q.; Arman, H. Tetrahedron 2010, 66, 4423–4427.
6. Clarke, A. J.; Hunt, D. A. Tetrahedron Lett. 2009, 50, 2949–2951.
7. Hunt, D. A. U.S. Patent 4,463,184, July 31, 1984.
8. General procedure for synthesis of 3-aryl-5,6-dihydrobenzofuran-7(4H)-ones. 2-
Methyl-3-phenyl-5,6-dihydrobenzofuran-7(4H)-one (8c).
The authors wish to thank The College of New Jersey for their
support of this work through the auspices of a MUSE Grant to
C.S. We also wish to thank The University of California, Riverside
High Resolution Mass Spectrometry Facility for high resolution
mass spectral data and Dr. Benny Chan of TCNJ for the x-ray crystal
structure determination.
To a 100 mL round bottomed flask equipped with a magnetic stirrer and reflux
condenser was added 1,2-cyclohexanedione (1.00 g; 8.92 mmol), b-methyl b-
nitrostyrene10 (1.46 g; 8.92 mmol), DMF (30 mL), and K2CO3 (12.33 g;
89.21 mmol). The reaction was heated to 80 °C using an oil bath for a period
of 4 h during which time the reaction mixture changed in color from water
white/pale yellow to brown. The mixture was then allowed to cool to room
temperature. Dichloromethane (30 mL) and deionized H2O (100 mL) were
added to the reaction mixture and the solution was brought to neutral pH with
10% HCl. The resulting mixture was transferred to a separatory addition funnel
and the organic layer removed. After dichloromethane washes (2 Â 30 mL), the
organic layers were combined and washed with H2O (3 Â 100 mL). The organic
layer was dried over anhydrous MgSO4 and the dichloromethane was removed
in vacuo to provide the crude product which was purified by flash
chromatography on silica gel eluting with hexanes/EtOAc to afford 9c as a
white crystalline solid, mp 105–108 °C (1.28 g, 63.2% yield). The structure was
supported by X-ray crystallography. 1H NMR d 7.29À7.06 (m, 5H), 2.55 (t,
J = 6.0 Hz, 2H), 2.40 (t, J = 6.0 Hz, 2H), 2.26 (s, 3H), 1.95 (p, J = 6.0 Hz, 2H). 13C
NMR d 185.9, 155.2, 146.0, 140.5, 131.7, 128.8, 127.5, 122.8, 38.1, 24.5, 22.6,
13.1. IR 167, 1424, 1252 cmÀ1. HRMS: Calcd for (C15H15O2)H+ 227.1067; found
227.1075.
References and notes
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Acta 1950, 33, 2215–2228; (c) Sondheimer, F.; Elad, D. J. Am. Chem. Soc. 1957,
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purification or prepared in accordance to literature procedures: (a) Gairaud,
C. B.; Lappin, G. R. J. Org. Chem. 1953, 18, 1–3; (b) Campbell, N.; Anderson, W.;
Gilmore, J. J. Chem. Soc. 1940, 446–451; (c) Hass, H. B.; Susie, A. G.; Heider, R. L.
J. Org. Chem. 1950, 15, 8–14.