Ugi-smiles access to quinoxaline derivatives

Article abstract of DOI:10.3987/COM-07-S(U)26

Two different Ugi-Smiles post-condensations strategies have been used for new three and four-component formation of quinoxaline scaffolds. In the first approach, a one-pot hydrogenation-cyclization affords the heterocycle with loss of the initial isocyani

Full text of DOI:10.3987/COM-07-S(U)26

HETEROCYCLES, Vol. 73, 2007
503
HETEROCYCLES, Vol. 73, 2007, pp. 503 - 517. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd June, 2007, Accepted, 9th August, 2007, Published online, 10th August, 2007. COM-07-S(U)26
UGI-SMILES ACCESS TO QUINOXALINE DERIVATIVES
Julie Oble, Laurent El Kaïm,* Marion Gizzi, and Laurence Grimaud*
Laboratoire Chimie et Procédés, UMR 7652, Ecole Nationale Supérieure de
Techniques Avancées, 32 Bd Victor, Paris 75015, France.
laurent.elkaim@ensta.fr; laurence.grimaud@ensta.fr
E-mail :
Abstract – Two different Ugi-Smiles post-condensations strategies have been
used for new three and four-component formation of quinoxaline scaffolds. In the
first approach, a one-pot hydrogenation-cyclization affords the heterocycle with
loss of the initial isocyanide moiety. In the second one, the use of
o-iodonitrophenol as starting phenol, coupled with copper catalyzed cyclization
gave us similar quinoxaline derivatives resulting from a four coupling.
INTRODUCTION
Quinoxaline derivatives represent an important class of biologically active compounds.1 Their broad
spectrum of activity is evidenced by their use as anti HIV agents,2 angiotensin receptor antagonists,3
antiviral,4 antitumoral and antibacterial5 agents. Being considered as privileged structures in drug discovery,
numerous synthesis approaches have been reported6 and more recently adapted to combinatorial formation
of quinoxaline libraries.7 When combinatorial accesses to heterocycles are needed, one of the most efficient
strategies involves the use of Ugi couplings8 with di-functional components. The desired heterocyclic
scaffold is then obtained through post-condensation modifications of the initial Ugi adduct.9 This strategy
has been applied successfully to the formation of quinoxaline derivatives using Ugi/Pd N-arylation,10
Ugi/SNAr,11 or Hulme UDC strategy.12
We recently reported a new Ugi type coupling using electron-deficient phenols in place of the traditional
carboxylic acids. This reaction introduces a Smiles rearrangement as the key step of the conversion
(Scheme 1).13 First observed with o- and p-nitrophenols, this study was further extended to the use of
salicylates and hydroxy-heterocycles such as pyridine or pyrimidine.14

504
HETEROCYCLES, Vol. 73, 2007
R1CHO
R2NH2
R3NC
O
R2 NO2
N
MeOH
OH
+
R3HN
60°C
NO2
R1
R4
O2N
O2N
O
R5
O
Smiles
H
R2
R3
H
R2
N
R3
N
N
N
R1
R1
Scheme 1: Ugi/Smiles coupling
In the light of the general structure of the Ugi/Smiles adducts obtained, it seems obvious that
post-condensation strategies may bring efficient 4-component formation of various benzofused
heterocycles. This was demonstrated on a single example by a hydrogenation/cyclization sequence to give
quinoxaline (Scheme 2).13 We now wish to give a full report on the use of Ugi-Smiles reaction to reach
dihydroquinoxaline scaffolds by a three and four component approach.
OMe
NO2
O
CyNC
EtCHO
MeO
Et
O
NH
OH
NO2
MeOH
1. H2, Pd/C, MeOH
2. PTSA, MeOH
+
N
N
CyHN
MeO
NH2
Et
71%
80%
Scheme 2: dehydroquinoxalinone formation
RESULTS AND DISCUSSION
Different dehydroquinoxalines were prepared according to this procedure, varying the aldehyde, the
primary amine and the isocyanide partners. The reduction of the intermediate Ugi-Smiles adducts was
performed in methanol under hydrogen atmosphere with a catalytic amount of Pd/C (10 mol%). The crude
resulting mixture was then submitted to acidic conditions to provide the desired quinoxaline derivatives in
good yields (Table 1, entries 1-4). The final step seems to be sensitive to steric hindrance as no cyclized
product could be detected with tert-butylamide 2e (Table 1, entry 5). The synthesis of these benzofused
heterocycles has been optimized in a three step one-pot procedure for dehydroquinoxaline 3a. Under these
conditions, the desired adduct was obtained in 47% yield, compared to 60% when the Ugi-Smiles
intermediate was purified (Table 1, entry 1). This tandem process has been successfully extended to the
synthesis of pyridopiperazinone derivatives (Table 1, entries 6-7).

HETEROCYCLES, Vol. 73, 2007
505
Table 1
R1CHO
R1
R1
H
R2NH2
OH
R2
X
O
N
R2
1- H2 Pd/C
MeOH, rt, 24 h
N
R3
N
MeOH, 60°C
1 M
+
NH
O
NO2
X
2- PTSA
MeOH, rt, 24 h
+
R3NH2
NO2
R3NC
X
X = CH or N
Ugi-Smiles Product (time,
Cyclization Product
(yield) 3
Entry
1
R1CHO
R2NH2
R3NC
Phenol 1
yield) 2
MeO
O
O
N
MeO
NHCy
NO2
NO2
OH
N
NH
H2N
CyNC
CHO
CHO
CHO
OMe
1a
3a
2a
2b
2c
85%a
4 h, 71%
MeO
OMe
O
O
MeO
MeO
NHCy
NO2
N
NO2
OH
N
OMe
OMe
NH
CyNC
2
3
H2N
1a
3b
3c
60%
16 h, 64%
O
CO2Et
ClBn
p-
O
ClBn
p-
N
HN
NO2
OH
N
H2N
NH
NO2
Cl
CN
COOEt
1a
1a
1a
67%
16 h, 60%
Cl
Cl
O
NO2
OH
H2N
ClBn
p-
ClBn
p-
O
NHCy
NO 2
N
OHC
Cl
CyNC
N
Cl
4
NH
2d
3d
20 h, 80%
61%
O
O
5
5
ClBn
p-
p- Cl Bn
NH Bu
t-
NO2
OH
NHt -Bu
N
N
H2N
H2N
H2N
NO2
NH2
Cl
Cl
Cl
5
6
7
CHO
t-BuNc
5
2e
68%
4 h, 79%
O
ClBn
p-
O
ClBn
p-
OH
N
NHCy
N
NO2
NH
N
NO2
CyNC
CHO
N
N
1b
1b
3f
2f
53%
16 h, 68%
O
ClBn
p-
O
ClBn
p-
OH
N
NHCy
NO2
N
O
NO2
NH
N
CyNC
N
N
3g
2g
55%
10 d, 25%
a This compound was obtained in 47% yield in one-pot procedure without isolation of the Ugi-Smiles intermediate.
Although this method constitutes an easy and rapid access to those heterocycles, the elimination of the
isocyanide moiety during the heterocyclization reduces the diversity of the process from a 4-component to
a 3-component coupling. In order to maintain the initial diversity of the Ugi-Smiles reaction, we envisioned

506
HETEROCYCLES, Vol. 73, 2007
the formation of quinoxalines by a cyclization of the amide onto a properly substituted phenyl core.
N-Arylation of amides has been thoroughly reported under palladium15or copper16 catalysis by substitution
on a chloro, bromo or iodo benzene. We have already reported the successful coupling of
2-chloro-4-nitrophenol with an isocyanide, a primary amine and an aldehyde. Unfortunately, the adduct did
not give any cyclization (Scheme 3). We then focused our efforts on iodinated compounds easily prepared
from iodine treatment of nitrophenol.
O
p-ClBn
CuI (10% mol)
L-proline (20% mol)
N
NHCy
Cl
X
K3PO4
MeCN, 80°C
NO2
Scheme 3: N-arylation of amides for chlorinated Ugi-Smiles adduct
The MCR coupling using 2-iodo-4-nitrophenol turned out to be quite inefficient under the classical
conditions: when performed in methanol, no adduct could be isolated from the resulting complex mixture.
In toluene, the desired adduct was obtained as the major compound but with feeble reproducibility. Adding
one equivalent of NH4Cl as reported by Zhu and coworkers in various Ugi processes17 slightly improved the
yield of the reaction. Finally the best yields resulted in the use of a 10:1 mixture of toluene: water at 100°C
with 1 equiv. of NH4Cl. Under these optimized conditions, the 2-iodo-4-nitrophenol was coupled with
allylamine, benzylisocyanide and isovaleraldehyde to afford the desired adduct in a 95% isolated yields
(Scheme 4).
i-Bu
O
OH
I
N
NHBn
i-BuCHO
BnNC
+
+
+
H2N
I
NO2
NO2
Conditions
Isolated Yield
MeOH, 60°C
-
freshly distilled toluene, 110°C
freshly distilled toluene, NH4Cl (1 equiv.), 110°C
toluene, 110°C
35%
49%
55%
47%
95%
toluene: H2O (10:1), 100°C
toluene: H2O (10:1), NH4Cl (1 equiv.), 110°C
Scheme 4: Ugi-Smiles conditions for iodinated phenols
We thus prepared various iodinated N-aryl amino amides 2h-2k (Table 2). These latter were then heated in
acetonitrile at 80°C in the presence of a catalytic amount of Cu(I) using proline as ligand and K3PO418 to
give the desired quinoxaline derivatives 3h-3k in moderate to good yields. The commercially available
2,6-diiodo-4-nitrophenol gives the 4-component adduct 2l in very low yield and this latter gave complex

HETEROCYCLES, Vol. 73, 2007
507
mixture under cyclization conditions (Table 2, entry 5). When performed under microwaves conditions, the
cyclization occurred more rapidly in similar yields (Table 2, entry 1).18
Table 2
R3
R1
HN
O
N
R2
O
R1CHO
R3NC
R2NH2
OH
N
toluene / H2O (9/1)
NH4Cl (1equiv.), 100°C
CuI 10% mol
R2
L-proline 20%mol
Y
N
R1
Y
R3
+
I
1 M
K3PO4
Y
I
MeCN, 80°C
NO2
NO2
NO2
Y = H, Cl
Ugi-Smiles Product
Cyclization Product
Entry
R1CHO
R2NH2
R3NC
Phenol 1
(time, yield) 2
(time, yield) 3
OH
O
O
N
N
I
NC
NHp-ClBn
N
I
p-ClBn
NH2
1
O
Cl
NO2
1c
NO2
NO2
2h
3h
13 h, 64%
18 h, 65%a
OH
O
NHCy
O
N
N
I
I
NCy
NH2
2
CyNC
O
NO2
1c
NO2
NO2
2i
3i
20 h, 24%
16 h, 61%
OH
p-ClBn
O
NHp-ClBn
p-ClBn
O
N
N
Cl
I
Cl
NC
NC
NC
N
Cl
I
Cl
p-ClBn
3
O
H2N
Cl
Cl
Cl
NO2
1d
NO2
NO2
2j
3j
20 h, 80%
OMe
18 h, 55%
OMe
OH
Cl
I
O
p-ClBn
O
N
OMe
N
NH2
4
NHp-ClBn
Cl
I
N
Cl
OHC
NO2
1d
NO2
NO2
2k
3k
3 d, 74%
2 d, 45%
OH
O
N
I
I
NHp-ClBn
I
I
NH2
5
-
O
NO2
1e
NO2
2l
20 h, 18%
a This compound was obtained in 62% yield under microwave conditions (180°C, 80W, 80 min).

508
HETEROCYCLES, Vol. 73, 2007
Moreover the use of microwave conditions for each step allows an optimization of the whole process: the
reaction was performed without purification of the Ugi-Smiles intermediate in a couple of hours to give the
desired quinoxaline derivative in a 39% isolated yield (Scheme 5).
NH2
CHO
CuI/L-proline
K3PO4, MeCN, 80°C
toluene / H2O (9/1)
NH4Cl (1equiv.)
O
O
N
N
NC
+
OH
NHp-ClBn
I
N
MW (180°C, 80W, 80 min)
MW (100°C, 50W, 30 min)
p-ClBn
I
NO2
NO2
NO2
Cl
cr ude
Scheme 5: optimization of the whole process using microwaves
In conclusion, we have prepared new quinoxaline derivatives using Ugi-Smiles couplings. The most
important feature of these reactions is the involvement of a new rearrangement step in an Ugi type process
coupled with easy formation of N-arylated derivatives. This reaction is perfectly suited for the formation of
fused bicyclic heterocycles. Indeed, different Ugi-Smiles post-condensations can give both three and
four-component entries to such heterocyclic scaffolds. Most noteworthy is the successful formation of
Ugi-Smiles adduct with o-iodophenols which opens the way to a rich variety of organometallic
post-condensations.
EXPERIMENTAL
General procedure for ortho-nitrophenol and 2-hydroxy-3-nitropyridine induced Ugi-4CR
To a 1 M solution of the aldehyde (0.8 mmol) in methanol were added successively 1.0 equiv. of amine,
1.0 equiv. of isocyanide and 1.0 equiv. of phenol 1 under inert atmosphere. The resulting mixture was
stirred at 60°C or 40°C until completion (TLC). It was then concentrated in vacuo and the crude product 2
was purified by flash chromatography on silica gel.
N-Cyclohexyl-2-[N-(2-methoxyethyl)-N-(2-nitrophenyl)amino]butyramide 2a
The typical procedure was followed employing the ortho-nitrophenol 1a (110 mg, 0.8 mmol) to afford the
compound 2a (205 mg, 71%, 4 h, 40°C) as an yellow oil by flash chromatography on silica gel (petroleum
ether/Et2O: 60/40). 1H NMR (CDCl3, 400 MHz) δ 7.70 (dd, 1H, J = 8.1, 1.5 Hz), 7.50 (td, 1H, J = 7.6, 1.5
Hz), 7.43 (br s, 1H), 7.31 (dd, 1H, J = 7.6, 1.0 Hz), 7.17 (ddd, 1H, J = 8.1, 7.6, 1.0 Hz), 3.81-3.72 (m, 1H),
3.69 (t, 1H, J = 6.8 Hz), 3.40-3.28 (m, 4H), 3.22 (s, 3H), 2.06-1.96 (m, 2H), 1.93-1.79 (m, 2H), 1.77-1.65

HETEROCYCLES, Vol. 73, 2007
509
(m, 4H), 1.42-1.06 (m, 4H), 0.93 (t, 3H, J = 7.3 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 172.2, 146.9, 142.9,
133.1, 125.9, 125.5, 124.1, 70.1, 69.6, 59.1, 49.9, 48.4, 33.2, 33.1, 26.0, 25.3, 24.0, 11.7. IR (thin film)
3332, 2936, 1654, 1522, 1359, 1119 cm-1. MS (DI, CI NH3) m/z 364. Anal. Calcd. for C19H29N3O4: C,
62.79 ; H, 8.04. Found: C, 62.61 ; H, 8.42.
N-Cyclohexyl-2-[N-(2,2-dimethoxyethyl)-N-(2-nitrophenyl)amino]butyramide 2b
The typical procedure was followed employing the ortho-nitrophenol 1a (110 mg, 0.8 mmol) to afford the
compound 2b (206 mg, 64%, 16 hours, 60°C) as an yellow oil by flash chromatography on silica gel
1
(petroleum ether/Et2O: 60/40). H NMR (CDCl3, 400 MHz) δ 7.70 (dd, 1H, J = 8.1, 1.5 Hz), 7.52 (td, 1H,
J = 7.6, 1.5 Hz), 7.39 (dd, 1H, J = 7.6, 1.0 Hz), 7.33 (br s, 1H), 7.21 (ddd, 1H, J = 8.1, 7.6, 1.0 Hz), 4.24 (dd,
1H, J = 6.6, 4.3 Hz), 3.80-3.70 (m, 1H), 3.64 (t, 1H, J = 6.6 Hz), 3.36 (dd, 1H, J = 13.9, 6.6 Hz), 3.30 (s, 3H),
3.24 (s, 3H), 3.10 (dd, 1H, J = 13.9, 4.3 Hz), 2.01-1.81 (m, 2H), 1.78-1.57 (m, 4H), 1.46-1.04 (m, 6H), 0.92
(t, 3H, J = 7.6 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 170.9, 147.1, 143.4, 133.1, 125.8, 125.5, 124.6, 102.6,
70.5, 55.1, 54.3, 52.1, 48.4, 33.4, 33.1, 26.0, 25.3, 23.9, 11.8. IR (thin film) 3366, 2931, 2852, 1528, 1450,
1128 cm-1. MS (DI, CI NH3) m/z 393. HRMS Calcd. for C20H31N3O5 393.2264, Found 393.2267.
Ethyl 2-[2-(N-(4-chlorobenzyl)-N-(2-nitrophenyl)amino)butyramido]acetate 2c
The typical procedure was followed employing the ortho-nitrophenol 1a (110 mg, 0.8 mmol) to afford the
compound 2c (208 mg, 60%, 16 hours, 60°C) as a brown solid by flash chromatography on silica gel
1
(petroleum ether/ Et2O: 70/30). H NMR (CDCl3, 400 MHz) δ 7.66 (dd, 1H, J = 8.1, 1.5 Hz), 7.44 (td, 1H,
J = 7.6, 1.3 Hz), 7.30-7.08 (m, 7H), 4.35 (d, 1H, J = 14.4 Hz), 4.22 (q, 2H, J = 7.3 Hz), 4.20 (d, 1H, J = 14.4
Hz), 4.11 (d, 2H, J = 5.6 Hz), 3.67 (dd, 1H, J = 9.3, 4.8 Hz), 2.01-1.89 (m, 1H), 1.73-1.62 (m, 1H), 1.28 (t,
3H, J = 7.3 Hz), 0.91 (t, 3H, J = 7.3 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 172.9, 169.9, 147.5, 142.2, 135.2,
133.6, 133.08, 130.5, 128.9, 126.9, 125.6, 125.2, 70.0, 61.9, 54.4, 41.7, 23.3, 14.6, 11.6. IR (thin film) 3404,
3054, 2985, 1743, 1679, 1424 cm-1. MS (DI, CI NH3) m/z 435. HRMS Calcd. for C21H24ClN3O5 433.1404,
Found 433.1409. mp 79°C.
[N-(4-Chlorobenzyl)-N-(2-nitrophenyl)amino]-2-(4-chlorophenyl)-N-cyclohexylacetamide 2d
The typical procedure was followed employing the ortho-nitrophenol 1a (110 mg, 0.8 mmol) to afford the
compound 2d (328 mg, 80%, 20 hours, 60°C) as an yellow solid by flash chromatography on silica gel
1
(petroleum ether/ Et2O: 80/20). H NMR (CDCl3, 400 MHz) δ 7.67 (dd, 1H, J = 8.1, 1.5 Hz), 7.47-7.33 (m,
4H), 7.28-7.22 (m, 2H), 7.18-7.12 (m, 3H), 6.96 (d, 1H, J = 7.1 Hz), 6.65 (d, 2H, J = 8.1 Hz), 4.80 (s, 1H),
4.01 (d, 1H, J = 14.1 Hz), 3.95 (d, 1H, J = 14.1 Hz), 3.53-3.46 (m, 1H), 1.72-1.50 (m, 4H), 1.45-1.25 (m,
4H), 1.15-1.04 (m, 2H). 13C NMR (CDCl3, 100.6 MHz) δ 169.8, 147.8, 141.9, 135.0, 134.8, 134.4, 132.9,
133.0, 131.2, 130.3, 129.3, 128.9, 127.3, 126.1, 124.9, 71.2, 57.0, 48.2, 32.8, 25.7, 24.9, 22.7. IR (thin film)
3332, 2929, 2854, 1662, 1522, 1364, 1090, 1015 cm-1. MS (DI, CI NH3) m/z 513 (M+2). Anal. Calcd for
C27H27Cl2N3O3: C, 63.28 ; H, 5.31. Found: C, 63.24 ; H, 5.56. mp 156°C.

510
HETEROCYCLES, Vol. 73, 2007
2-[N-(4-chlorobenzyl)-N-(3-nitropyridin-2-yl)amino]-N-Cyclohexylbutyramide 2f
The typical procedure was followed employing the ortho-nitrophenol 1b (110 mg, 0.8 mmol) to afford the
compound 2f (234 mg, 68%, 16 hours, 60°C) as an yellow oil by flash chromatography on silica gel
(petroleum ether/ Et2O: 90/10). 1H NMR (CDCl3, 400 MHz) δ 8.39 (dd, 1H, J = 4.5, 1.7 Hz), 8.00 (dd,
1H, J = 8.1, 1.7 Hz), 7.32 (br s, 1H), 7.11 (d, 2H, J = 8.3 Hz), 6.91 (d, 2H, J = 8.3 Hz), 6.81 (dd, 1H, J = 8.1,
4.5 Hz), 4.79 (dd, 1H, J = 8.8, 6.3 Hz), 4.67 (d, 1H, J = 15.8 Hz), 4.55 (d, 1H, J = 15.8 Hz), 3.90-3.77 (m,
1H), 2.18-2.00 (m, 1H), 2.06-1.96 (m, 3H), 1.88-1.56 (m, 6H), 1.46-1.14 (m, 2H), 1.00 (t, 3H, J = 7.3 Hz).
13C NMR (CDCl3, 100.6 MHz) δ 170.0, 152.4, 151.8, 135.8, 135.1, 134.8, 133.6, 129.9, 128.9, 115.2, 66.1,
49.7, 48.4, 33.5, 33.4, 25.9, 25.0, 22.9, 11.3. IR (thin film) 3323, 2935, 2861, 1667, 1515, 1335, 1256, 1092
cm-1. MS (DI, CI NH3) m/z 431. HRMS Calcd. for C22H27ClN4O3 430.1772, Found 430.1782.
2-[N-(4-chloro-benzyl)-N-(3-nitro-pyridin-2-yl)amino]-N-Cyclohexyl-2-methylbutyramide 2g
The typical procedure was followed employing the ortho-nitrophenol 1b (110 mg, 0.8 mmol) to afford the
compound 2g (180 mg, 25%, 10 days, 60°C) as a yellow oil by flash chromatography on silica gel
(petroleum ether/ Et2O: 80/20). 1H NMR (CDCl3, 400 MHz) δ 8.58 (dd, 1H, J = 4.6, 1.8 Hz), 7.92 (dd,
1H, J = 8.1, 1.8 Hz), 7.44 (br s, 1H), 7.12-7.06 (m, 3H), 6.86 (d, 2H, J = 8.4 Hz), 4.29 (d, 1H, J = 13.8 Hz),
4.20 (d, 1H, J = 13.8 Hz), 3.88-3.77 (m, 1H), 1.98-1.91 (m, 1H), 1.90-1.80 (m, 2H), 1.79-1.69 (m, 2H), 1.73
13
(s, 3H), 1.66-1.60 (m, 2H), 1.44-1.37 (m, 2H), 1.31-1.20 (m, 3H), 0.88 (t, 3H, J = 7.4 Hz). C NMR
(CDCl3, 100.6 MHz) δ 173.5, 153.5, 152.0, 135.6, 134.2, 133.8, 130.7, 129.7, 128.9, 119.9, 70.3, 53.8,
48.4, 33.6, 33.4, 32.3, 25.9, 25.2, 19.0, 9.0. IR (thin film) 3387, 2931, 2856, 1668, 1593, 1522, 1451, 1263
cm-1. MS (DI, CI NH3) m/z 445. HRMS Calcd. for C23H29ClN4O3 444.1928, Found 444.1950.
General procedure for synthesis of dehydroquinoxalines 3
A catalytic amount of Pd/C (10%) was added to a solution of the resulting arylamide in MeOH (0.5 M), the
mixture was stirred at rt under hydrogen atmosphere for 24 h. Hydrogen was then replaced by argon and a
catalytic amount of p-toluenesulfonic acid was added. The resulting mixture was stirred at rt for 24 h. After
addition of a saturated aqueous solution of NaHCO3, filtration, and extraction with Et2O, the combined
organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo.
The crude product 3 was purified by flash chromatography on silica gel.
3-Ethyl-3,4-dihydro-4-(2-methoxyethyl)quinoxalin-2(1H)-one 3a
The typical procedure was followed employing the arylamide 2a (73 mg, 0.2 mmol) to afford the
compound 3a (40 mg, 85%) as an yellow oil by flash chromatography on silica gel (petroleum ether/ Et2O:
70/30). 1H NMR (CDCl3, 400 MHz) δ 8.62 (br s, 1H), 7.02-6.96 (m, 1H), 6.80-6.70 (m, 3H), 3.86 (t, 1H, J
= 6.8 Hz), 3.73-3.63 (m, 1H), 3.57 (t, 2H, J = 6.8 Hz), 3.37 (s, 3H), 3.41-3.31 (m, 1H), 1.72-1.60 (m, 2H),
0.95 (t, 3H, J = 7.3 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 168.9, 134.2, 126.7, 124.5, 119.1, 115.9, 113.5,

HETEROCYCLES, Vol. 73, 2007
511
70.5, 64.6, 59.4, 50.1, 24.1, 10.4. IR (thin film) 3200, 2925, 1675, 1117 cm-1. MS (DI, CI NH3) m/z 235.
HRMS Calcd. for C13H18N2O2 234.1368, found 234.1363.
Furthermore, this compound 3a was obtained in 47% yield in one-pot procedure without isolation of the
Ugi-Smiles intermediate 2a.
3,4-Dihydro-4-(2,2-dimethoxyethyl)-3-ethylquinoxalin-2(1H)-one 3b
The typical procedure was followed employing the arylamide 2b (195 mg, 0.5 mmol) to afford the
compound 3b (80 mg, 61%) as a yellow oil by flash chromatography on silica gel (petroleum ether/ Et2O:
70/30). 1H NMR (CDCl3, 400 MHz) δ 9.06 (br s, 1H), 7.01-6.96 (m, 1H), 6.80-6.73 (m, 3H), 4.47 (dd, 1H,
J = 6.6, 3.5 Hz), 3.92 (t, 1H, J = 6.6 Hz), 3.70 (dd, 1H, J = 14.6, 3.5 Hz), 3.41 (s, 3H), 3.39 (s, 3H), 3.23 (dd,
1H, J = 14.6, 6.6 Hz), 1.70-1.61 (m, 2H), 0.95 (t, 3H, J = 7.8 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 168.9,
134.2, 126.7, 124.5, 119.3, 115.9, 113.8, 103.2, 65.0, 55.5, 54.4, 53.1, 24.3, 10.5. I.R. (thin film) 3208,
3057, 2930, 1681, 1440, 1303, 1125 cm-1. MS (DI, CI NH3) m/z 265. HRMS Calcd. for C14H20N2O3
264.1474, Found 264.1484.
4-(4-Chlorobenzyl)-3,4-dihydro-3-ethylquinoxalin-2(1H)-one 3c
The typical procedure was followed employing the arylamide 2c (82 mg, 0.19 mmol) to afford the
compound 3c (38 mg, 67%) as a brown oil by flash chromatography on silica gel (petroleum ether/ Et2O:
80/20). 1H NMR (CDCl3, 400 MHz) δ 9.52 (br s, 1H), 7.36-7.24 (m, 4H), 6.96-6.89 (m, 1H), 6.85 (d, 1H,
J = 7.5 Hz), 6.82-6.76 (m, 1H), 6.65 (d, 1H, J = 8.0 Hz), 4.66 (d, 1H, J = 15.4 Hz), 4.28 (d, 1H, J = 15.4 Hz),
3.83 (dd, 1H, J = 6.8, 6.5 Hz), 1.78-1.61 (m, 2H), 0.96 (t, 3H, J = 7.5 Hz). 13C NMR (CDCl3, 100.6 MHz)
δ 169.2, 139.9, 134.3, 133.6, 129.3, 129.2, 127.9, 126.7, 124.5, 115.9, 112.9, 63.9, 52.9, 23.0, 10.7. I.R.
(thin film) 3307, 3055, 2977, 1684, 1503, 1431, 1162 cm-1. MS (DI, CI NH3) m/z 300. HRMS Calcd. for
C17H17ClN2O 300.1029, Found 300.1022.
4-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3,4-dihydroquinoxalin-2(1H)-one 3d
The typical procedure was followed employing the arylamide 2d (170 mg, 0.35 mmol) to afford the
compound 3d (80 mg, 61%) as a brown oil by flash chromatography on silica gel (petroleum ether/ Et2O:
1
80/20). H NMR (CDCl3, 400 MHz) δ 8.81 (br s, 1H), 7.34-7.19 (m, 6H), 7.13 (d, 2H, J = 8.3
Hz), 7.02-6.96 (m, 1H), 6.85-6.80 (m, 2H), 6.71 (d, 1H, J = 8.3 Hz), 4.93 (s, 1H), 4.65 (d, 1H, J = 15.6
Hz), 4.06 (d, 1H, J = 15.6 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 166.6, 135.6, 135.0, 134.9, 134.1, 133.9,
129.5, 129.4, 125.6, 125.6, 119.8, 116.1, 112.9, 64.9, 51.7. I.R. (thin film) 3417, 3053, 2985, 1687, 1424,
1158, 1098 cm-1. MS (DI, CI NH3) m/z 384 (M+2). HRMS Calcd. for C21H16Cl2N2O 382.0640, Found
382.0631.
4-(4-Chlorobenzyl)-3-ethyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one 3f
The typical procedure was followed employing the arylamide 2f (110 mg, 0.25 mmol) to afford the
compound 3f (40 mg, 53%) as an yellow oil by flash chromatography on silica gel (petroleum ether/ Et2O:

512
HETEROCYCLES, Vol. 73, 2007
70/30). 1H NMR (CDCl3, 400 MHz) δ 8.65 (br s, 1H), 7.88 (dd, 1H, J = 5.3, 1.3 Hz), 7.33-7.26 (m, 4H),
6.92 (dd, 1H, J = 7.3, 1.3 Hz), 6.65 (dd, 1H, J = 7.3, 5.3 Hz), 5.52 (d, 1H, J = 15.4 Hz), 4.18 (d, 1H, J = 15.4
Hz), 4.00 (dd, 1H, J = 7.1, 4.3 Hz), 1.91-1.69 (m, 2H), 0.91 (t, 3H, J = 7.3 Hz). 13C NMR (CDCl3, 100.6
MHz) δ 167.1, 146.3, 142.7, 136.4, 133.6, 129.8, 129.2, 121.0, 120.5, 120.5, 61.5, 48.1, 24.2, 9.7. IR (thin
film) 3388, 2927, 1686, 1612, 1488, 1159, 1098 cm-1. MS (DI, CI NH3) m/z 302. HRMS Calcd. for
C16H16ClN3O 301.0982, Found 301.0972.
4-(4-Chlorobenzyl)-3-ethyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one 3g
The typical procedure was followed employing the arylamide 2g (180 mg, 0.4 mmol) to afford the
compound 3f (70 mg, 55%) as an yellow oil by flash chromatography on silica gel (petroleum ether/ Et2O:
80/20). 1H NMR (CDCl3, 400 MHz)δ 7.83 (dd, 1H, J = 4.2 Hz), 7.40 (br s, 1H), 7.27-7.19 (m, 4H), 6.73 (s,
1H), 5.19 (d, 1H, J = 16.1 Hz), 4.27 (d, 1H, J = 16.1 Hz), 2.07-1.94 (m, 1H), 1.91-1.81 (m, 1H), 1.57 (s, 3H),
0.81 (t, 3H, J = 7.1 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 163.5, 145.8, 143.0, 138.6, 132.7, 128.8, 128.6,
120.3, 118.6, 114.7, 66.8, 45.0, 31.8, 24.7, 9.3. IR (thin film) 3412, 2924, 1665, 1473, 1117 cm-1. MS (DI,
+
CI NH3) m/z 333 (M+NH4 ). HRMS Calcd. for C17H18ClN3O 315.1138, Found 315.1152.
General procedure for iodinated phenol Ugi-4CR
To a 1 M solution of the aldehyde (0.8 mmol) in a 9:1 mixture of toluene and water were added
successively 1.0 equiv. of amine, 1.0 equiv. of isocyanide, 1.0 equiv. of phenol 1c-d and 1.0 equiv. of
ammonium chloride. The resulting mixture was stirred at 100°C until completion (TLC). It was then
concentrated in vacuo and the crude products 2h-k were purified by flash chromatography on silica gel.
2-[N-Allyl-N-(2-iodo-4-nitrophenyl)amino]-N-(4-chlorobenzyl)-4-methylpentanamide 2h
The typical procedure was followed employing the 2-iodo-4-nitrophenol 1c (205 mg, 0.8 mmol) to afford
the compound 2h (270 mg, 64%, 13 h) as an yellow oil by flash chromatography on silica gel (petroleum
1
ether/ Et2O: 90/10). H NMR (CDCl3, 400 MHz) δ 8.68 (d, 1H, J = 2.6 Hz), 8.17 (dd, 1H, J = 8.9, 2.6
Hz), 7.29-7.28 (m, 2H), 7.19-7.15 (m, 3H), 7.07 (br s, 1H), 5.63 (dddd, 1H, J = 17.1, 10.3, 6.0, 5.6 Hz), 5.09
(dd, 1H, J = 10.3, 1.2 Hz), 5.03 (dd, 1H, J = 17.1, 1.2 Hz), 4.45 (dd, 1H, J = 14.7, 6.1 Hz), 4.41 (dd, 1H, J =
14.7, 5.9 Hz), 4.03 (dd, 1H, J = 8.7, 5.1 Hz), 3.91 (dd, 1H, J = 15.9, 6.0 Hz), 3.60 (dd, 1H, J = 15.9, 5.6 Hz),
1.93-1.85 (m, 1H), 1.66-1.54 (m, 1H), 1.49-1.40 (m, 1H), 0.81 (d, 3H, J = 6.5 Hz), 0.80 (d, 3H, J = 6.5 Hz).
13C NMR (CDCl3, 100.6 MHz) δ 171.7, 156.0, 144.4, 136.9, 136.3, 133.8, 132.7, 129.7, 129.2, 124.9,
124.3, 119.5, 97.9, 69.3, 52.3, 43.3, 38.5, 25.9, 23.9, 22.4. IR (thin film) 3386, 3083, 1662, 1578, 1515,
1339, 1163 cm-1. MS (DI, CI NH3) m/z 542. HRMS Calcd. for C22H25ClN3O3 541.0629, Found 541.0612.
2-[N-Allyl-N-(2-iodo-4-nitrophenyl)amino]-N-cyclohexyl-4-methylpentanamide 2i
The typical procedure was followed employing the 2-iodo-4-nitrophenol 1c (205 mg, 0.8 mmol) to afford
the compound 2i (95 mg, 24%, 20 h) as an yellow oil by flash chromatography on silica gel (petroleum

HETEROCYCLES, Vol. 73, 2007
513
1
ether/ Et2O: 80/20). H NMR (CDCl3, 400 MHz) δ 8.75 (d, 1H, J = 2.7 Hz), 8.19 (dd, 1H, J = 8.9, 2.7
Hz), 7.19 (d, 1H, J = 8.9 Hz), 6.74 (d, 1H, J = 8.6 Hz), 5.70 (ddt, 1H, J = 17.2, 10.6, 5.7 Hz), 5.13 (dd, 1H,
J = 10.6, 1.7 Hz), 5.09 (dd, 1H, J = 17.1, 1.3 Hz), 3.97 (dd, 1H, J = 8.4, 5.3 Hz), 3.95-3.89 (m, 1H),
3.86-3.76 (m, 1H), 3.63 (dd, 1H, J = 16.2, 5.7 Hz), 1.91-1.83 (m, 2H), 1.75-1.55 (m, 5H), 1.45-1.32 (m, 2H),
1.23-1.09 (m, 4H), 0.79 (d, 3H, J = 6.5 Hz), 0.77 (d, 3H, J = 6.5 Hz). 13C NMR (CDCl3, 100.6 MHz) δ
170.5, 156.4, 144.3, 136.3, 133.0, 124.9, 124.3, 119.3, 97.7, 65.4, 52.1, 48.5, 38.6, 33.6, 33.3, 26.0, 25.8,
25.1, 25.0, 23.3, 22.5. IR (thin film) 3392, 2931, 2858, 1664, 1595, 1517, 1463, 1340, 1160 cm-1. MS (DI,
CI NH3) m/z 499. HRMS Calcd. for C21H30IN3O3 499.1332 , Found 499.1323.
N-(4-Chlorobenzyl)-2-[N-(4-chlorobenzyl)-N-(6-chloro-2-iodo-4-nitrophenyl)amino]-4-methylpentan-
amide 2j
The typical procedure was followed employing the 2-chloro-6-iodo-4-nitrophenol 1d (240 mg, 0.8 mmol)
to afford a 2:1 mixture of atropomers A:B of the compound 2j (400 mg, 82%, 24 h) as an yellow oil by flash
chromatography on silica gel (petroleum ether/ Et2O: 95/5). 1H NMR (CDCl3, 400 MHz) δ 8.05 (d, 1HA, J
= 2.4 Hz), 7.92 (d, 1HB, J = 2.5 Hz), 7.85 (t, 1HB, J = 5.4 Hz), 7.61 (d, 1HB, J = 2.5 Hz), 7.38-7.29 (m, 11HA,
6HB), 7.07 (d, 2HB, J = 8.5 Hz), 7.04 (d, 4HA, J = 8.3 Hz), 6.80 (d, 2HB, J = 8.5 Hz), 6.46 (d, 4HA, J = 8.3
Hz), 4.66-4.57 (m, 4HA, 1HB), 4.50-4.39 (m, 4HA, 1HB), 4.05 (dd, 1HB, J = 12.0, 4.1 Hz), 3.96 (d, 1HB, J =
13.3 Hz), 3.77 (d, 1HB, J = 13.3 Hz), 3.66 (d, 1HA, J = 12.6 Hz), 1.72-1.62 (m, 1HB, 2HA), 1.57-1.49 (m,
1HB, 2HA), 1.09 (d, 6HA, J = 6.4 Hz), 1.04 (d, 3HB, J = 6.4 Hz), 1.02-095 (m, 1HB, 2HA), 0.84 (d, 3HB, J =
6.4 Hz), 0.82 (d, 6HA, J = 6.4 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 173.5 (CA), 173.0 (CB), 154.7 (CA),
151.1 (CB), 144.4 (CA), 143.0 (CB), 139.0 (CA), 138.7 (CB), 137.6 (CA), 137.7 (CB), 134.5, 134.3, 134.2,
134.0, 133.8 (CA and CB), 131.6 (CB), 131.4 (CA), 129.9, 129.4 (CA, CB), 129.1 (CA), 128.7, 126.2, 124.4
(CB), 112.3 (CB), 98.2 (CA), 69.9 (CB), 66.0 (CA), 57.0 (CB), 55.8 (CA), 43.1 (CB), 42.9 (CA), 40.9(CB), 40.8
(CA), 25.6 (CB), 25.5 (CA), 24.7 (CA), 24.6 (CB), 21.7 (CA), 21.5 (CB). IR (thin film) 3389, 3055, 2959, 1671,
1532, 1437, 1356, 1094 cm-1. HRMS Calcd. for C26H25ICl3N3O3 659.0006, Found 658.9992.
2-[N-Allyl-N-(2-chloro-6-iodo-4-nitrophenyl)amino]-N-(4-chlorobenzyl)-2-(4-methoxyphenyl)acetamide
2k
The typical procedure was followed employing the 2-chloro-6-iodo-4-nitrophenol 1d (240 mg, 0.8 mmol)
to afford a 2.5:1 mixture of atropomers A:B of the compound 2k (360 mg, 74%, 3 days) as an yellow oil by
flash chromatography on silica gel (petroleum ether/ Et2O: 80/20). 1H NMR (CDCl3, 400 MHz) δ 8.01 (d,
2.5HA, J = 2.5 Hz), 7.97 (t, 2.5HA, J = 5.7 Hz), 7.82 (d, 1HB, J = 2.5 Hz), 7.57 (d, 2.5HA, J = 2.5 Hz), 7.54
(d, 1HB, J = 2.5 Hz), 7.48 (d, 2HB, J = 8.7 Hz), 7.33-7.26 (m, 5HA, 3HB), 7.21 (d, 5HA, J = 8.4 Hz), 7.13 (d,
2HB, J = 8.3 Hz), 6.98 (d, 5HA, J = 8.7 Hz), 6.73 (d, 2HB, J = 8.7 Hz), 6.64 (d, 5HA, J = 8.7 Hz), 5.97 (ddt,
2.5HA, J = 17.2, 9.9, 7.4 Hz), 5.72 (ddt, 1HB, J = 16.7, 9.8, 6.6 Hz), 5.23 (s, 1HA), 5.29 (dd, 2.5HA, J = 17.2,
1.2 Hz), 5.07 (dd, 2.5HA, J = 9.8, 1.2 Hz), 5.00 (d, 1HB, J = 16.7 Hz), 4.98 (d, 1HB, J = 9.8 Hz), 4.87 (s,

514
HETEROCYCLES, Vol. 73, 2007
2.5HA), 4.48 (dd, 2.5HA, J = 14.7, 5.8 Hz), 4.44 (dd, 2.5HA, J = 14.7, 5.6 Hz), 4.37 (d, 2HB, J = 6.1 Hz),
4.00-3.91 (m, 2.5HA, 1HB), 3.87-3.79 (m, 2.5HA), 3.77 (s, 3HB), 3.74 (s, 7.5HA), 3.57-3.49 (m, 1HB). 13C
NMR (CDCl3, 100.6 MHz) δ 171.4 (CA), 171.3 (CB), 160.0 (CA), 159.9 (CB), 152.5 (CB), 149.3 (CA), 144.3
(CA), 143.7 (CB), 141.7 (CA, CB), 136.9 (CA, CB), 133.8, 133.3 (CA, CB), 132.7 (CA, CB), 130.7, 129.9, 129.6,
129.2, 129.1 (CB, CA), 127.7, 126.9 (CA, CB), 126.7, 125.0 (CB, CA), 121.2 (CA ), 120.8 (CB), 114.3 (CA),
114.1 (CB), 110.7 (CA), 72.5 (CΑ), 72.0 (CΒ), 59.4 (CΑ, CB), 55.6 (CA, CB), 43.3 (CΑ), 43.1 (CΒ). IR (thin
film) 3368, 2927, 1668, 1526, 1458, 1349, 1176, 1093 cm-1. HRMS Calcd. for C25H22ICl2N3O4 625.0032,
Found 625.0020.
General procedure for the synthesis of benzopyrazinone by Cu-catalyzed intramolecular amidation
To a solution of arylamide 2h-k in acetonitrile were added 10% mol of copper iodide, 20% mol of L-proline
and 1 equiv. of K3PO4. The resulting mixture was stirred at 80°C under inert atmosphere until completion
(TLC). It was then concentrated in vacuo and the crude products 3h-k were purified with preparative
chromatography.
4-Allyl-1-(4-chlorobenzyl)-3-isobutyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one 3h
The typical procedure was followed employing the arylamide 2h (40 mg, 0.074 mmol) to afford the
compound 3h (20 mg, 65%, 18 hours) as an yellow oil with preparative chromatography (petroleum ether/
Et2O: 50/50). This compound was also obtained in 62% yield under microwave conditions (180°C, 80W,
80 min). 1H NMR (CDCl3, 400 MHz)δ 7.93 (dd, 1H, J = 9.0, 2.4 Hz), 7.78 (d, 1H, J = 2.4 Hz), 7.34 (d, 2H,
J = 8.5 Hz), 7.23 (d, 2H, J = 8.5 Hz), 6.72 (d, 1H, J = 9.0 Hz), 5.88 (dddd, 1H, J = 16.1, 10.1, 6.1, 5.4 Hz),
5.41 (dd, 1H, J = 16.1, 1.2 Hz), 5.36 (dd, 1H, J = 10.1, 1.2 Hz), 4.98 (d, 2H, J = 16.1 Hz), 4.24 (dd, 1H, J =
9.5, 5.0 Hz), 4.21 (dd, 1H, J = 15.5, 5.4 Hz), 3.88 (dd, 1H, J = 15.5, 6.1 Hz), 1.76-1.66 (m, 1H), 1.54-1.46
(m, 1H), 1.45-1.36 (m, 1H), 1.00 (d, 3H, J = 6.4 Hz), 0.93 (d, 3H, J = 6.7 Hz). 13C NMR (CDCl3, 100.6
MHz) δ 166.1, 141.5, 139.6, 134.7, 134.0, 132.3, 129.6, 128.6, 128.1, 121.2, 119.9, 112.3, 111.3, 60.6, 52.6,
45.6, 39.1, 25.2, 23.6, 22.3. IR (thin film) 3380, 2959, 1681, 1592, 1518, 1447, 1333, 1116 cm-1. MS (DI,
CI NH3) m/z 414. HRMS Calcd. for C22H24ClN3O2 415.1506, Found 413.1515.
4-Allyl-1-cyclohexyl-3-isobutyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one 3i
The typical procedure was followed employing the arylamide 2i (40 mg, 0.08 mmol) to afford the
compound 3i (18 mg, 61%, 16 h) as an yellow oil with preparative chromatography (petroleum ether/ Et2O:
50/50). 1H NMR (CDCl3, 400 MHz) δ 8.04 (d, 1H, J = 2.4 Hz), 7.94 (dd, 1H, J = 9.0, 2.4 Hz), 6.69 (d, 1H,
J = 9.0 Hz), 5.88 (dddd, 1H, J = 16.3, 10.2, 6.2, 5.5 Hz), 5.33 (dd, 1H, J = 16.1, 1.3 Hz), 5.32 (dd, 1H, J =
10.2, 1.3 Hz), 4.35-4.25 (m, 1H), 4.12 (dd, 1H, J = 15.4, 6.2 Hz), 4.00 (dd, 1H, J = 9.3, 5.6 Hz), 3.79 (dd, 1H,
J = 15.4, 5.5 Hz), 2.54-2.41 (m, 1H), 2.50-2.37 (m, 1H), 1.94-1.67 (m, 3H), 1.50-1.17 (m, 8H), 0.93 (d, 3H,
J = 6.5 Hz), 0.85 (d, 3H, J = 6.5 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 167.4, 143.0, 139.5, 132.6, 128.9,

HETEROCYCLES, Vol. 73, 2007
515
120.8, 119.7, 112.5, 112.1, 61.5, 58.0, 52.3, 37.9, 30.7, 28.9, 27.0, 26.6, 25.7, 25.2, 23.7, 23.4. IR (thin
film) 3401, 3054, 2985, 1677, 1587, 1509, 1422, 1161 cm-1. MS (DI, CI NH3) m/z 372. HRMS Calcd. for
C21H29N3O3 371.2209, Found 371.2194.
5-Chloro-1,4-bis-(4-chlorobenzyl)-3-isobutyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one 3j
The typical procedure was followed employing the arylamide 2j (85 mg, 0.14 mmol) to afford the
compound 3j (41 mg, 55%, 18 h) as an yellow oil with preparative chromatography (petroleum
ether/EtOAc: 80/20). 1H NMR (CDCl3, 400 MHz) δ 7.50 (s, 1H), 7.36 (d, 2H, J = 8.0 Hz), 7.31 (d, 2H, J =
7.9 Hz), 7.17 (d, 2H, J = 8.0 Hz), 7.09 (d, 2H, J = 7.9 Hz), 7.00 (s, 1H), 5.25 (d, 2H, J = 16.1 Hz), 4.81 (d,
1H, J = 16.1 Hz), 4.31 (d, 1H, J = 14.7 Hz), 4.31 (d, 1H, J = 14.7 Hz), 4.03 (d, 1H, J = 14.7 Hz), 3.80 (dd,
1H, J = 9.8, 5.0 Hz), 1.88-1.77 (m, 1H), 1.47-1.22 (m, 2H), 0.86 (d, 3H, J = 6.5 Hz), 0.77 (d, 3H, J = 6.5 Hz).
13C NMR (CDCl3, 100.6 MHz) δ 168.8, 145.7, 137.3, 134.7, 134.2, 131.3, 130.7, 129.8, 129.6, 129.4,
128.2, 128.2, 119.7, 119.2, 59.1, 59.0, 53.9, 45.7, 39.9, 24.3, 23.5, 21.7. IR (thin film) 3410, 2927, 2857,
1688, 1599, 1533, 1462, 1371, 1095 cm-1. MS (DI, CI NH3) m/z 532, 534. HRMS Calcd. for
C26H24Cl3N3O3 531.0883, Found 531.0864.
1-Allyl-5-chloro-4-(4-chlorobenzyl)-3-(4-methoxyphenyl)-7-nitro-3,4-dihydroquinoxalin-2(1H)-one 3k
The typical procedure was followed employing the arylamide 2k (50 mg, 0.08 mmol) to afford the
compound 3k (20 mg, 45%, 2 days) as an yellow oil with preparative chromatography (petroleum ether/
Et2O: 50/50). 1H NMR (CDCl3, 400 MHz) δ 7.54 (d, 1H, J = 2.2 Hz), 7.37 (d, 2H, J = 8.7 Hz), 7.28 (d, 2H,
J = 8.5 Hz), 7.05 (d, 2H, J = 8.5 Hz), 6.90 (d, 1H, J = 2.2 Hz), 6.83 (d, 2H, J = 8.7 Hz), 5.90 (dddd, 1H, J =
17.1, 10.0, 7.2, 5.9 Hz), 5.45 (d, 1H, J = 16.4 Hz), 5.34 (dd, 1H, J = 17.1, 1.1 Hz), 5.30 (dd, 1H, J = 10.0, 1.1
Hz), 5.21 (s, 1H), 4.93 (d, 1H, J = 16.4 Hz), 3.93 (dd, 1H, J = 14.7, 5.9 Hz), 3.78 (s, 3H), 3.77 (dd, 1H, J =
14.7, 7.2 Hz).13C NMR (CDCl3, 100.6 MHz) δ 168.6, 159.4, 144.9, 139.6, 134.4, 132.9, 132.6, 129.9,
129.6, 129.4, 128.4, 127.6, 127.0, 121.4, 120.4, 115.5, 62.8, 58.9, 55.6, 46.1. IR (thin film) 3394, 3053,
2928, 1660, 1603, 1464, 1382, 1161, 1096 cm-1. MS (DI, CI NH3) m/z 497, 499. HRMS Calcd. for
C25H21Cl2N3O4 497.0909, Found 497.0922.
ACKNOWLEDGEMENTS
J.O. thanks the MENR for a fellowship. Financial support was provided by the ENSTA.
REFERENCES
1. Reviews: A. E. Porter, “Comprehensive Heterocyclic Chemistry,” ed. by A. R. Katritzky and C. W.
Rees, Pergamon: Oxford, 1984, Vol. 3, part 2B, 157; N. Sato, “Comprehensive Heterocyclic
Chemistry II,” ed. by A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Pergamon: Oxford, 1996; Vol.
6, 233; G. Sakata, K. Makino, and Y. Kurasama, Heterocycles, 1988, 27, 2481; G. W. H. Cheeseman

516
HETEROCYCLES, Vol. 73, 2007
and E. S. G. Werstiuk, Adv. Heterocycl. Chem., 1978, 22, 367.
2. M. Patel, R. J. Jr. Mc Hugh, B. C. Cordova, R. M. Klabe, S. Erickson-Vitanen, G. L. Trainor, and J. D.
Rodgers, Bioorg. Med. Chem. Lett., 2000, 10, 1729.
3. K. S. Kim, L. Qian, J. E. Bird, K. E. J. Dickinson, S. Moreland, T. R. Schaeffer, T. L. Waldron, C. L.
Delaney, H. N. Weller, and A. V. Miller, J. Med. Chem., 1993, 36, 2335.
4. J. Harmenberg, A. Akesson-Johansson, A.Gräslund, T. Malmfors, J. Bergman, B. Wahren, S.
Akerfeldt, L. Lundblad, and S. Cox, Antiviral Res., 1991, 15, 193.
5. M. A. Naylor, M. A. Stephen, J. Nolan, B. Sutton, J. H. Tocher, E. M. Fielden, G. E. Adams, and I. J.
Strafford, Anticancer Drug Des., 1993, 8, 439; P. Sanna, A. Carta, M. Loriga, S. Zanetti, and L. Sechi,
Farmaco, 1999, 54, 169; L. Yan, F. Liu, G. Dai, and H. Liu, Bioorg. Med. Chem. Lett., 2007, 17, 609.
6. For some recent examples see: S. Antoniotti and E. Dunach, Tetrahedron Lett., 2002, 43, 3971; S. A.
Raw, C. D. Wilfred, and R. J. K. Taylor, Chem. Commun., 2003, 2286 ; G. Kaupp and M. R.
Naimi-Jamal, Eur. J. Org. Chem., 2002, 1368; P. Chen, J. C. Barrish, E. Iwanowicz, J. Lin, M. S.
Bednarz, and B.-C. Chen, Tetrahedron Lett., 2001, 42, 4293; B. C. G. Soderberg, J. M. Wallace, and J.
Tamariz, Org. Lett., 2002, 4, 1339; M. Suginome, S. Collet, and Y. Ito, Org. Lett., 2002, 4, 351; R.
Mukhopadhyay and N. G. Kundu, Tetrahedron Lett., 2000, 41, 9927; R. A. Bunce, D. M. Herron, and
M. L. Ackerman, J. Org. Chem., 2000, 65, 2847; B. K. Banik, I. Banik, L. Hackfeld, and F. F. Becker,
Heterocycles, 2002, 56, 467; S. Goswami and A. K. Adak, Chem. Lett., 2003, 32, 678; O. A. Attanasi,
L. De Crescentini, P. Fillippone, F. Mantellini, and S. Santeusanio, Synlett, 2003, 1183 ; K. H. Popat,
K. S. Nimavat, K. M. Thaker, and H. S. Joshi, J. Indian Chem. Soc., 2003, 80, 709; K. V. Subba Rao
and M. Subrahmanyam, Chem. Lett., 2002, 234; V. Nair, R. Dhanya, C. Rajesh, M. M. Bhadbhade,
and K. Manoj, Org. Lett., 2004, 6, 4743; B. Chen, R. Zhao, M. S. Bednarz, B. Wang, J. E. Sundeen,
and Joel C. Barrish, J. Org. Chem., 2004, 69, 977; C. Venkatesh, B. Singh, P. K. Mahata, H. Ila, and H.
Junjappa, Org. Lett., 2005, 7, 2169; D. Aparicio, O. A. Attanasi, P. Filippone, R. Ignacio, S. Lillini, F.
Mantellini, F. Palacios, and J. M. Santos, J. Org. Chem., 2006, 71, 5897.
7. J. Zhang, L. Zhang, S. Zhang, Y. Wang, and G. Liu, J. Comb. Chem., 2005, 7, 657; J. A. Kowalski, S.
F. Leonard, and G. E. Lee, J. Comb. Chem., 2006, 8, 774; J. Azizian, A. R. Karimi, Z. Kazemizadeh, A.
A. Mohammadi, and M. R. Mohammadizadeh, Tetrahedron Lett., 2005, 46, 6155; A. Staszewska, P.
Stefanowicz, and Zbigniew Szewczuk, Tetrahedron Lett., 2005, 46, 5525.
8. For reviews see: R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown, and T. A. Keating, Acc.
Chem. Res., 1996, 29, 123; H. Bienaymé, C. Hulme, G. Oddon, and P. Schmitt, Chem. Eur. J., 2000, 6,
3321. (c) A. Dömling and I. Ugi, Angew. Chem. Int. Ed., 2000, 39, 3168; A. Dömling, Curr. Opin.
Chem. Bio., 2002, 6, 306. J. Zhu, Eur. J. Org. Chem., 2003, 68, 1133; I. Ugi, B. Werner, and A.
Dömling, Molecules, 2003, 8, 53; C. Hulme and V. Gore, Curr. Med. Chem., 2003, 10, 51; A.

HETEROCYCLES, Vol. 73, 2007
517
Dömling, Chem. Rev., 2006, 106, 17.
9. For heterocycles formation using Ugi post-condensations see: S. Marcaccini and T. Torroba, in
“Multicomponent Reactions”, ed. by J. Zhu and H. Bienaymé, Wiley-VCH: Weinheim, 2005, pp.
33-75.
10. C. Kalinski, M. Umkehrer, G. Ross, J. Kolb, C. Burdack, and W. Hiller, Tetrahedron Lett., 2006, 47,
3423.
11. C. Kalinski, M. Umkehrer, S. Gonnard, N. Jäger, G. Ross, and W. Hiller, Tetrahedron Lett., 2006, 47,
2041.
12. C. Hulme, J. Peng, B. Louridas, P. Menard, P. Krolikowski, and N. V. Kumar, Tetrahedron Lett., 1998,
39, 8047; C. Hulme, J. Peng, G. Morton, M. J. Salvino, T. Herpin, and R. Labaudiniere, Tetrahedron
Lett., 1998, 39, 7227; C. Hulme and M. Cherrier, Tetrahedron Lett., 1999, 40, 5295; P. Tempest, V.
Ma, S. Thomas, Z. Hua, M. G. Kelly, and C. Hulme, Tetrahedron Lett., 2001, 42, 4959.
13. L. El Kaim, L. Grimaud, and J. Oble, Angew. Chem. Int. Ed., 2005, 44, 7961.
14. L. El Kaim, M. Gizolme, L. Grimaud, and J. Oble, Org. Lett., 2006, 8, 4019; L. El Kaim, M. Gizolme,
L. Grimaud, and J. Oble, J. Org. Chem., 2007, 72, 465.
15. J. Yin and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 6043; R. R. Poondra and N. J. Tumer, Org.
Lett., 2005, 7, 863; T. Furuta, Y. Kitamura, A. Hashimoto, S. Fujii, K. Tanaka, and T. Kan, Org. Lett.,
2007, 9, 183; M. Carril, R. San Martin, E. Dominguez, and I. Tellitu, Tetrahedron, 2007, 63, 690; X. J.
Xu and Y. X. Zong, Tetrahedron Lett., 2007, 48, 129.
16. B. Sreedhar, K. B. Shiva Kumar, P. Srinivas, V. Balasubrahmanyam, and G. T. Venkanna, J. Mol. Cat.
A: Chemical, 2006, 265, 183; K. Okano, H. Tokuyama, and T. Fukuyama, J. Am. Chem. Soc., 2006,
128, 7136; A. Shafir, A. A. Lichtor, and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129, 3490.
17. P. Cristau, J.-P. Vors, and J. Zhu, Org. Lett., 2001, 3, 4079; P. Janvier, X. Sun, H. Bienaymé, and J.
Zhu, J. Am. Chem. Soc., 2002, 124, 2560.
18. G. Feng, J. Wu, and W. M. Daï, Tetrahedron Lett., 2007, 48, 401.