β-nitroacrylates as key starting materials for the uncatalysed one-pot synthesis of polyfunctionalized dihydroquinoxalinone derivatives, via an anti-Michael reaction

Article abstract of DOI:10.1055/s-0028-1088197

The reaction of o-phenylenediamine with β-nitroacrylates allows the in situ preparation of dihydroquinoxalinones, via an anti-Michael reaction, under uncatalysed reaction conditions.

Full text of DOI:10.1055/s-0028-1088197

LETTER
965
b-Nitroacrylates as Key Starting Materials for the Uncatalysed One-Pot
Synthesis of Polyfunctionalized Dihydroquinoxalinone Derivatives, via an
anti-Michael Reaction
O
ne-Pot Synthesi
o
s
of Polyfun
b
ctionalized D
e
ihydroquin
r
oxalinon
t
es o Ballini,* Serena Gabrielli, Alessandro Palmieri
‘Green Chemistry Group’, Dipartimento di Scienze Chimiche dell’Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy
Fax +39(0737)402297; E-mail: roberto.ballini@unicam.it
Received 16 December 2008
During our studies devoted to explore the chemical poten-
tial of b-nitroacrylates we discovered an innovative
procedure for the synthesis of polyfunctionalised dihydro-
quinoxalinone derivatives in one-pot under uncatalysed
reaction conditions. Thus, the reaction of o-phenylenedi-
amine (1) with b-nitroacrylates 2 allows the anti-Michael
adducts 3 that, in situ, convert to the target dihydroqui-
noxalinones 4 (Scheme 1).
Abstract: The reaction of o-phenylenediamine with b-nitroacry-
lates allows the in situ preparation of dihydroquinoxalinones, via an
anti-Michael reaction, under uncatalysed reaction conditions.
Key words: b-nitroacrylates, anti-Michael reaction, uncatalysed,
quinoxalinones
Quinoxalinone derivatives represent an important class of
nitrogen-containing heterocycles as they are useful inter-
mediates in organic synthesis.1 They have received con-
siderable interest from the pharmaceutical industry
because they are useful templates for drug development
due to their structural relationship to benzodiazepines.2 In
addition, quinoxalinones exhibit a wide variety of biolog-
ical activity, including antidiabetic3 and antiviral effects,
in particular against retroviruses such as HIV.4 They also
are inhibitors of aldose reductase,5 partial agonists of the
g-aminobutyric acid (GASBA)–benzodiazepine receptor
complex,6 and antagonists of the AMPA and angiotensis
II receptors.7 Related 3,4-dihydroquinoxalines also pos-
sess biological activity, for example, as inhibitors of cho-
lesteryl ester transfer proteins.8 Quinoxalinones have been
identified as desirable scaffolds for diversity-oriented
synthesis as they may be assembled in a modular fashion
on solid-phase media.9
NO2
O
NH2
NH2
NO2
O
solvent
R
OEt
+
NH
R
OEt
1
2a–j
NH2
3a–j
– EtOH
H
N
O
R
N
H
NO2
4a–j
Scheme 1
Despite the importance of these heterocycles, their syn-
thetic routes are limited, and the main strategies are based
on nucleophilic aromatic substitution of o-halonitroben-
zene, followed by cyclization of the obtained o-nitro-
amine,10 or the reaction of o-phenylenediamines with
different substrates such as acetylenedicraboxylates,11 a-
bromoesters,12 anisylidine pyruvic acid,13 and 2,3-epoxy-
aldehydes.14
In order to optimize the reaction conditions, we first ex-
amined, as a representative conversion, the preparation of
compound 4c starting from the o-phenylenediamine with
the b-nitroacrylate 2c. As reported in Table 1, the best
yield was obtained after two hours at room temperature,
using 1.25 equivalents of diamine and ethyl acetate as sol-
vent.
Use of an excess of diamine reduces the formation of
byproducts. Use of one equivalent of diamine results in
formation of the target dihydroquinoxalinone 4c accom-
panied by a moderate amount of the bisadduct 5
(Figure 1). Thus, the formation of 5 can be minimized by
employing a slight excess of diamine.
b-Nitroacrylates are an emerging class of functionalized
electron-poor alkenes since they can be converted into
other important intermediates15 or employed as Michael
acceptors with indoles,16 amines,17 and b-dicarbonyl de-
rivatives.18
The synthetic utility of b-nitroacrylates is due to the si-
multaneous presence of two different electron-withdraw-
ing groups, in a- and b-positions on a double bond.
Finally, with the intent to test the generality of our meth-
od, we examined a variety of b-nitroacrylates obtaining
good to excellent yields (70–90%) of 4 (Table 2).
A particular behaviour was observed with b-nitroacrylate
2k (R = Ph), since the crude product 4k (obtained after 1
h, Scheme 2) was unstable during the purification step
(chromatography), giving the quinoxalin-2(1H)-one 7
SYNLETT 2009, No. 6, pp 0965–0967
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088197; Art ID: D41508ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9

966
R. Ballini et al.
LETTER
(confirmed by NMR spectroscopy). The probable mecha-
nism (Scheme 2) consists of an intramolecular deprotona-
tion of 4k and simultaneous cleavage of C–C bond in 4-
and 3-positions, respectively, affording 6 and the nitronic
acid 7 (stabilized by the high conjugation with the aromat-
ic system), that tautomerises into the more stable phenyl-
nitromethane 8 (detected by GC and TLC).
Table 1 Optimization of the Reaction
H
N
O
NH2
NO2
O
solvent
r.t., 2 h
+
Pr
NO2
Pr
OEt
N
H
4c
NH2
1
2c
1 (equiv)
1.0
Solvent
EtOAc
EtOAc
EtOAc
CH2Cl2
toluene
Yield of 4c (%)a
H
59
84
78
68
60
NH3
NH2
N
O
N
NO2
O
EtOAc
+
1.25
1.5
Ph
O
Ph
OEt
N
H
1
2k
O
1.25
1.25
4k
a Yield of pure isolated product.
H
N
O
OH
NO2
O
N
+
Ph
NO2
O
Ph
N
8
7
6
Pr
Pr
OEt
NH
Scheme 2
NH
In conclusion, we have discovered an novel procedure for
the synthesis compounds 4, that can be considered as a
new important class of dihydroquinoxalinone derivative
due to the presence of other important functionalities,
such as ether, nitrile, ketal, and nitro, that can be preserved
under the mild reaction conditions. Of particular interest
is the presence of a valuable functionality such as the sec-
ondary nitro group that can be converted into an array of
other functionalities,19 or can be employed to stabilise a
carbanion for the generation of new C–C bonds.19c,20
OEt
NO2
O
5
Figure 1
Table 2 Preparation of Dihydroquinoxalinones 4a–j
H
N
O
NH2
NH2
NO2
O
EtOAc
r.t., 2 h
+
R
R
OEt
N
H
4a–j
Acknowledgment
NO2
1
2a–j
The authors thank the University of Camerino and MIUR-Italy
(National Project ‘Sintesi organiche ecosostenibili da nuovi sistemi
catalitici‘) for financial support.
Entry
R
Yield of 4 (%)a
drb
1
2
Me
Et
Pr
83
79
84
80
82
85
70
90
71
82
65:35
73:27
70:30
50:50
65:35
75:25
50:50
70:30
65:35
60:40
References and Notes
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Chemistry, Vol 3; Katritzky, A. R.; Rees, C. W., Eds.;
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A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon:
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J.-P.; Meichsner, C.; Riess, G.; Winkler, I. US 5,723,461,
1998.
3
4
MeO(O)C(CH2)4
BnCH2
5
6
Me(OCH2CH2O)CCH2
CH2=CH(CH2)8
N≡C(CH2)4
7
8
9
Me(CH2)6
10
Me2CHCH2CH2
a Yield of pure isolated product.
b The dr was evaluated by 1H NMR spectroscopy.
(5) (a) Sarges, R.; Lyga, J. W. J. Heterocycl. Chem. 1988, 25,
1475. (b) Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc.
1992, 114, 10997.
Synlett 2009, No. 6, 965–967 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Polyfunctionalized Dihydroquinoxalinones
967
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Spectroscopic Data for Representative Compounds
Compound 4b (diastereomeric mixture): yellow solid. IR
(KBr): n = 1362, 1546, 1686, 3049, 3414 cm–1. 1H NMR
(400 MHz, acetone): d = 0.95 (t, 3 H, J = 7.3 Hz), 1.88–2.02
(m, 1 H), 2.07–2.25 (m, 1 H), 4.39 (dd, 0.27 H, J = 3.4, 6.8
Hz), 4.62 (dd, 0.73 H, J = 2.6, 4.3 Hz), 4.76–4.84 (m, 0.27
H), 4.88–4.97 (m, 0.73 H), 5.68 (br s, 0.73 H), 5.81 (br s,
0.27 H), 6.66–6.76 (m, 1 H), 6.79–6.92 (m, 3 H), 9.65 (br s,
1 H). 13C NMR (100 MHz, acetone): d = 10.6, 10.8, 23.1,
24.1, 59.4, 59.8, 90.3, 91.5, 114.9, 115.6, 116.0, 116.1,
119.8, 119.9, 124.4, 124.5, 126.0, 126.3, 132.7, 133.4,
163.6, 164.2. API-ES: m/z = 258.2 [M + Na+]. Anal. Calcd
for C11H13N3O3 (235.24): C, 56.16; H, 5.57; N, 17.86.
Found: C, 56.44; H, 5.71; N, 17.71.
Compound 4d (diastereomeric mixture): yellow solid. IR
(KBr): n = 1363, 1544, 1677, 1735, 3067, 3397 cm–1. 1H
NMR (400 MHz, acetone): d = 1.26–1.48 (m, 2 H), 1.51–
1.70 (m, 2 H), 1.86–2.02 (m, 1 H), 2.07–2.25 (m, 1 H), 2.26–
2.35 (m, 2 H), 3.58 (s, 1.5 H), 3.59 (s, 1.5 H), 4.41 (dd, 0.5
H, J = 3.0, 6.8 Hz), 4.64 (dd, 0.5 H, J = 2.6, 4.3 Hz), 4.85–
4.93 (m, 0.5 H), 4.99–5.06 (m, 0.5 H), 5.67 (br s, 0.5 H), 5.82
(br s, 0.5 H), 6.67–6.74 (m, 1 H), 6.78–6.91 (m, 3 H), 9.64
(br s, 1 H). 13C NMR (100 MHz, acetone): d = 24.9, 25.0,
26.0, 26.1, 29.4, 30.3, 33.8, 33.9, 51.6, 59.4, 59.9, 88.7, 89.7,
114.9, 115.5, 116.0, 116.1, 119.8, 119.9, 124.3, 124.4,
126.0, 126.2, 132.6, 133.4, 163.7, 164.1, 173.8, 173.9.
API-ES: m/z = 344.4 [M + Na+]. Anal. Calcd for C15H19N3O5
(321.33): C, 56.07; H, 5.96; N, 13.08. Found: C, 56.38; H,
6.18; N, 12.81.
Compound 4e (diastereomeric mixture): yellow solid. IR
(KBr): n = 1361, 1544, 1679, 3059, 3397 cm–1. 1H NMR
(400 MHz, acetone): d = 2.18–2.32 (m, 1 H), 2.40–2.55 (m,
1 H), 2.59–2.74 (m, 2 H), 4.49 (dd, 0.35 H, J = 3.0, 6.8 Hz),
4.66 (dd, 0.65 H, J = 2.6, 4.3 Hz), 4.91–4.98 (m, 0.35 H),
4.99–5.05 (m, 0.65 H), 5.74 (br s, 0.65 H), 5.86 (br s, 0.35
H), 6.65–6.73 (m, 1 H), 6.78–6.90 (m, 3 H), 7.11–7.32 (m, 5
H), 9.67 (br s, 1 H). 13C NMR (100 MHz, acetone): d = 31.6,
32.5, 32.6, 32.7, 59.6, 60.0, 88.1, 89.5, 114.9, 115.4, 116.0,
116.1, 119.8, 119.9, 124.4, 124.5, 125.9, 126.1, 127.1,
129.2, 129.3, 129.4, 129.5, 132.6, 133.2, 141.1, 141.3,
163.7, 164.0. API-ES: m/z = 334.4 [M + Na+]. Anal. Calcd
for C17H17N3O3 (311.34): C, 65.58; H, 5.50; N, 13.50.
Found: C, 65.84; H, 5.73; N, 13.23.
Compound 4f (diastereomeric mixture): yellow solid. IR
(KBr): n = 1040, 1376, 1553, 1683, 3051, 3389 cm–1. 1H
NMR (400 MHz, acetone): d = 1.21–1.26 (m, 3 H), 2.21 (dd,
0.75 H, J = 1.7, 15.4 Hz), 2.38 (dd, 0.25 H, J = 2.6, 15.4 Hz),
2.64–2.79 (m, 1 H), 3.71–3.96 (m, 4 H), 4.33 (dd, 0.25 H,
J = 3.0, 7.3 Hz), 4.50 (dd, 0.75 H, J = 2.6, 4.3 Hz), 4.89–4.96
(m, 0.25 H), 5.06–5.13 (m, 0.75 H), 5.66 (br s, 0.75 H), 5.82
(br s, 0.25 H), 6.67–6.76 (m, 1 H), 6.79–6.91 (m, 3 H), 9.67
(br s, 1 H). 13C NMR (100 MHz, acetone): d = 24.3, 24.4,
38.4, 39.0, 60.1, 60.3, 65.4, 65.5, 84.1, 85.7, 108.5, 114.9,
115.7, 115.9, 116.0, 116.1, 119.8, 119.9, 124.4, 124.5,
125.9, 126.0, 132.4, 132.9, 163.4, 163.5. API-ES: m/z =
330.4 [M + Na+ ]. Anal. Calcd for C14H17N3O5 (307.30): C,
54.72; H, 5.58; N, 13.67. Found: C, 54.36; H, 5.31; N, 13.83.
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(21) Typical Procedure for the Conjugate Addition of Active
Methylene 5 to b-Nitroacrylates 1
b-Nitroacrylate 2 (1 mmol) and o-phenylenediamine 1 (1.25
mmol) were dissolved in EtOAc (2 mL) and mixed at r.t.,
with magnetic stirring, for 2 h. Then, acetone (2 mL, in order
to increase the solubility of 4) and 0.8 g of SiO2 (Silica Gel
60, 0,040–0,063 mm, 230–400 mesh ASTM, Merck), were
added and the mixture was stirred for 5 min. Finally, the
solvent was removed under vacuum and the crude product
(adsorbed on SiO2) was charged onto a chromatography
column (cyclohexane–EtOAc) allowing the pure products 4.
Synlett 2009, No. 6, 965–967 © Thieme Stuttgart · New York