Unique substituted 3-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole-1- carboxamides generated by Ugi 3CC using bifunctional starting material

Article abstract of DOI:10.1016/j.tet.2010.08.057

2-(2-Formyl-1H-benzimidazol-1-yl)acetic acid, as a bifunctional formyl-acid was prepared in four steps. This compound underwent one-pot reaction with primary amines, and alkyl isocyanides under Ugi conditions. A series of novel 3-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole-1-carboxamides were obtained in moderate to excellent yields.

Full text of DOI:10.1016/j.tet.2010.08.057

Tetrahedron 66 (2010) 8231e8237
Contents lists available at ScienceDirect
Tetrahedron
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Unique substituted 3-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole-
1-carboxamides generated by Ugi 3CC using bifunctional starting material
*
Mehdi Ghandi , Nahid Zarezadeh, Abuzar Taheri
School of Chemistry, College of Science, University of Tehran, Tehran, PO Box 14155 6455, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2010
Received in revised form 31 July 2010
Accepted 23 August 2010
Available online 27 August 2010
2-(2-Formyl-1H-benzimidazol-1-yl)acetic acid, as a bifunctional formyl-acid was prepared in four steps.
This compound underwent one-pot reaction with primary amines, and alkyl isocyanides under Ugi
conditions.
A series of novel 3-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole-1-carboxamides
were obtained in moderate to excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ugi reaction
6-Oxo-pyrazine-2-carboxamides
Multicomponent reactions
1. Introduction
privileged structures in medicinal chemistry, and benzimidazoles
with the known extensive biochemical and pharmacological prop-
erties,12 we envisioned that fusion of these moieties could rapidly
identify new novel compounds. We have carried out the synthesis of
2-(2-formyl-1H-benzoimidazol-1-yl)acetic acid 4 in four steps
(Scheme 1) in order to use it as a formyl-acid bifunctional starting
material with isocyanides and primary amines in Ugi three-com-
ponent reaction. We expected to obtain the novel pyrazino[1,2-a]
benzimidazole-3-one (structure A) heterocycles (Fig. 1).
Multicomponent reactions (MCRs)1 in general and isocyanide-
based multicomponent reactions (IMCRs)2 in particular have
attracted the chemist attentions during the past years. These re-
actions are well defined and suited for combinational library syn-
thesis due to the fact that products are formed in one-pot reactions.3
The most popular IMCR is probably the Ugi reaction in which
a carboxylic acid, a primary amine, an aldehyde, and an isocyanide
react in a one-pot manner to afford N-substituted acyl aminoamide
containing four independently varying groups in one reaction.4
Piperazines, and their keto analogs are among the most impor-
tant backbones in today’s drug discovery.5 Piperazines are the
unique class of compounds with the privileged structures in mole-
cules involved in the regulation of a wide variety of biological pro-
cesses.6 A privileged structure is a molecular scaffold that is able to
provide potent and selective ligands for a range of different bi-
ological targets through modification of functional groups, and
usually exhibits good drug-like properties that lead to more drug-
like compound libraries and leads.7 Heteroaryl-fused pyrazin-3-one
fragments are present in a number of natural and synthetic physi-
ologically active agents.8 Among them are antineoplastic and anti-
bacterial alkaloids longamide, longamide B (structures Ia,b), and
phakellstatins (IIa,b) isolated from marine organisms Agelas genus,
Homaxinella sp., and Phakellia mauritiana,9 antitromboticagent III10
and potential antiprotozoal drug IV11 (Fig. 1). Given the success of
2. Results and discussion
2.1. Preparation of 2-(2-formyl-1H-benzoimidazol-1-yl)acetic
acid (4)
The 2-(2-formyl-1H-benzoimidazol-1-yl)acetic acid 4 chosen
for this study was synthesized according to the procedure pre-
sented in Scheme 1. 2-(Diethoxymethyl)-1H-benzimidazole 1 was
prepared on the basis of the previously reported method. The
spectral data of 1 were similar to that of the authentic sample.13
Subsequent treatment of 1 with methyl chloroacetate in the
presence of K2CO3 in refluxing CH3CN for 6 h afforded the methyl
2-(2-(diethoxymethyl)-1H-benzoimidazol-1-yl)acetate 2 in 91%.
Transformation of 2 to 2-(2-(diethoxymethyl)-1H-benzoimidazol-
1-yl)acetic acid 3 was then to carried out in a mixture of methanolic
NaOH at rt for 4 h in 95%. Reaction of 3 with HCl in THF/H2O under
reflux for 24 h finally afforded the desired bifunctional compound 4
in 92%. The structure of compounds 2 and 3 was confirmed by their
analytical and spectral data.
* Corresponding author. Tel.: þ98 21 61112250; fax: þ98 21 66495291; e-mail
address: ghandi@khayam.ut.ac.ir (M. Ghandi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.057

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M. Ghandi et al. / Tetrahedron 66 (2010) 8231e8237
Figure 1. Some natural and synthetic physiologically active heteroaryl-fused pyrazin-3-ones.
H
N
CH3OCOCH2Cl
K2CO3, CH3CN
reflux, 6 h
O
NH2
NH2
Na, EtOH
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
reflux, 24 h
H3CH2CO
N
82%
91%
1
OCH3
OH
O
OH
O
O
HCl, THF, H2O
reflux, 24 h
NaOH, MeOH
rt, 4 h
OCH2CH3
OCH2CH3
N
N
OCH2CH3
OCH2CH3
N
O
N
95%
N
92%
H
N
2
3
4
Scheme 1. Synthesis of formyl acid 4.
OH
O
R1
O
MeOH
O
N
40 °C, 4-18 h
R1-NH2
+
R2-NC
O
+
N
N
N
62-92%
N
HN
R2
H
R2 = (Me)3C-CH2-C(Me)2-
or C6H11
-
4
5a-h
6a-p
Scheme 2. Synthesis of benzimidazoketopiprazines 6aep.
2.2. Preparation of substituted 3-oxo-1,2,3,4-
tetrahydropyrazino[1,2-a]benzimidazole-1-carboxamide
(6aep)
40 ꢀC in 4 h to afford 6d in 90% yield (entry 4, Table 1). These reactions
demonstrated that ketopiperazine annulated benzimidazoles can be
prepared through 3CC Ugi reactions.
The structure of compounds 6aep was confirmed by their an-
alytical and spectral data. The mass spectra of 6a displayed the
molecular ion peak at 419 for Mþþ1 consistent with the molecular
structure. The IR spectrum of 6a displayed characteristic absorption
bands at 3399 and 1672 cmꢁ1 due to NeH and C]O stretching
vibrations, respectively. The 1H NMR spectrum of 6a consisted
Formyl-acid acid 4 reacted with commercially available primary
amines 5aeh and isocyanides to give the 3-oxo-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamides 6aep (Scheme 2).
Various amines and the commercial 1,1,3,3- tetramethylbutyl or
cyclohexyl isocyanides were incorporated into this structure in
moderate to high yields (Table 1). For example, 2-formyl-acid reacted
with 3,4-dimethylaniline and 1,1,3,3-tetramethylbutyl isocyanide at
characteristic singlets at
d 0.73 (9H, 3Me), 1.16 (3H, Me) and 1.27
(3H, Me), two doublets at 1.45 (1H, J 14.8 Hz, CCHC), 1.76 (1H, J

M. Ghandi et al. / Tetrahedron 66 (2010) 8231e8237
Table 1 (continued )
8233
Table 1
Structure and yields of compounds 6aep obtained from 4, amines 5aeh, and 1,1,3,3-
tetramethylbutyl or cyclohexyl isocyanides
Entry
R1
Product
Time (h) Yielda (%)
O
N
OMe
Cl
Entry
1
R1
Product
Time (h) Yielda (%)
N
N
13
7
5
76
85
62
MeO
Cl
NH2
NH2
H
N
O
N
O
6m
N
N
6
4
5
76
92
72
NH2
H
N
O
O
6a
6b
6c
N
O
N
N
14
15
H
N
O
N
6n
N
N
2
3
NH2
H
N
O
O
N
N
NH2
18
H
N
N
O
O
N
6o
NH2
N
N
H
N
O
N
O
NH2
N
N
16
8
82
H
N
O
6p
O
N
a
NH2
N
N
4
4
90
Based on isolated products.
H
N
O
6d
14.8 Hz, CCHC) together with two doublets and a singlet at 5.05
(1H, J 16.6 Hz, NCHCO), 5.22 (1H, J 16.6 Hz, NCHCO), 6.07 (1H,
NCOCHN) and a broad singlet at 7.12 (1H, NH). The presence of two
C]O groups was further confirmed by the appearance of two sig-
O
OMe
Cl
N
H
N
N
N
5
6
7
6
5
67
82
68
MeO
Cl
NH2
nals at
d
165.1 and 165.3 in the 13C NMR spectrum of 6a. The 1H
NMR and 13C NMR spectra of 6bep were similar to that of 6a.
As has been rationalized in Scheme 3, it is conceivable that the
initial event is the formation of iminium ion I from the amine, and
aldehyde 4 followed by activation of the imine by carboxylic acid.
Subsequent addition of the nucleophilic isocyanide to the activated
iminium followed by trapping of the nitrilium intermediate by
carboxylate affords the iminolactone II. The irreversible acyl
transfer step (Mumm rearrangement)5 associated with Ugi reaction
finally gives the desired 3-oxo-1,2,3,4- tetrahydropyrazino[1,2-a]
benzimidazole-1-carboxamides 6aep.
O
6e
O
N
H
N
N
N
NH2
O
6f
O
N
H
N
N
N
NH2
15
O
6g
O
N
3. Conclusions
NH2
N
N
8
8
88
H
N
In conclusion, by using a bifunctional starting material con-
taining an aldehyde and carboxylic acid functional group in a 3CC
reaction, novel heteroaryl-fused pyrazinones 6aep were prepared.
The method offers several advantages including moderate to high
yields of products and an easy experimental work-up procedure.
These new structures broaden the scaffolds that are accessible
through Ugi reactions, and many of them may represent interesting
pharmacophores.
O
O
6h
N
N
N
9
6
4
80
90
NH2
H
N
O
6i
O
N
N
N
10
NH2
H
N
O
4. Experimental section
4.1. General information
6j
O
N
NH2
N
N
11
12
6
4
77
91
H
N
All commercially available chemicals and reagents were used
without further purification. Melting points were determined with
an Electrothermal model 9100 apparatus and are uncorrected. IR
spectra were recorded on a Shimadzu 4300 spectrophotometer, in
cmꢁ1. 1H and 13C NMR spectra were recorded on a Bruker DRX-500-
AVANCE spectrometer at 500 (1H) and 125 MHz (13C) using CDCl3 as
solvent and with the residual solvent signal as internal reference
(CDCl3, 7.24 and 77.0 ppm). Mass spectra of the products were
obtained with a HP (Agilent technologies) 5937 Mass Selective
O
6k
O
N
NH2
N
N
H
N
O
6l

8234
M. Ghandi et al. / Tetrahedron 66 (2010) 8231e8237
OH
O
O
O
O
O
R1
O
R2
N
2
N
N
1
NH-R1
H
O
H
N
N
R
NC
-
N
N
R -NH2
N
N
R1
H
N
N
R2
HN
O
4
I
II
6a-p
Scheme 3. Mechanism evoked for the formation of 6aep.
Detector. Elemental analyses were carried out by a CHN-Rapid
Heraeus elemental analyzer (Wellesley, MA).
mixture and recrystallization of the solid from ethanol afforded
compound 3.
4.4.1. 2-(2-(Diethoxymethyl)-1H-benzoimidazol-1-yl)acetic
acid
(3). White solid (5.30 g, 95%), mp 173e175 ꢀC. Found: C, 60.06; H,
6.28; N, 10.12. C14H18N2O4 requires C, 60.42; H, 6.52; N, 10.07%. nmax
4.2. Preparation of 2-(diethoxymethyl)-1H-benzoimidazole
(KBr) 2800e3300, 1707 cmꢁ1
; dH (500 MHz, DMSO-d6) 1.14 (6H, t, J
To a solution of sodium ethoxide (1.20 g, 52.2 mmol Na in 30 mL
dry ethanol) were added o-phenylenediamine (2.73 g, 25.3 mmol)
and ethyl diethoxyacetate (5.35 g, 30.3 mmol), and the mixture was
heated to reflux for 24 h. After evaporation of solvent under re-
duced pressure, the residue was dissolved in water and neutralized
with acetic acid. Filteration of the solid followed by recrystallization
from ethyl acetate/hexane (1:1) afforded compound 1.
7.0 Hz, 2OCH2CH3), 3.48e3.54 (2H, m, OCH2CH3), 3.68e3.75 (2H, m,
OCH2CH3), 5.16 (2H, s, NCH2CO2H), 5.66 (1H, s, CH(OC2H5)2), 7.22
(1H, t, J 7.2 Hz, Ar), 7.27 (1H, t, J 7.2 Hz, Ar), 7.55 (1H, d, J 7.9 Hz, Ar),
7.64 (1H, d, J 7.9 Hz, Ar),13.03 (1H, br s, OH); dc (125 MHz, DMSO-d6)
15.7 (2OCH2CH3), 45.9 (NCH2CO2H), 63.7 (2OCH2CH3), 99.2 (CH
(OC2H5)2), 111.5, 120.2, 122.7, 123.8, 137.0, 142.1, 151.1 (CeAr), 170.2
(C]O); m/z (EI, 70 eV) 278 (4, Mþ), 234 (68), 205 (100), 177 (27),
159 (24), 131 (59), 104 (16), 77 (31), 47 (19%).
4.2.1. 2-(Diethoxymethyl)-1H-benzoimidazole (1). White solid (4.55 g,
82%), mp 174e176 ꢀC. Found: C, 65.40; H, 7.33; N, 12.72. C12H16N2O2
requires C, 65.43; H, 7.32; N, 12.72%. nmax (KBr) 3327, 1070 cmꢁ1
; dH
4.5. Preparation of 2-(2-formyl-1H-benzoimidazol-1-yl)acetic
(500 MHz, CDCl3) 1.20 (6H, t, J 7.2 Hz, 2OCH2CH3), 3.62e3.75 (4H, m,
2OCH2CH3), 5.71 (1H, s, CH(OC2H5)2), 7.25e7.78 (4H, m, Ar), 9.89
(1H, s, NH); dc (125 MHz, CDCl3) 15.3 (2OCH2CH3), 62.5 (2OCH2CH3),
99.6 (CH(OC2H5)2), 111.3, 120.4, 122.5, 123.6, 133.0, 143.3, 151.4 (CeAr);
m/z (EI, 70 eV) 221 (100, Mþþ1), 176 (65), 117 (20), 77 (6%).
acid 4
Water (15 mL) and 37% hydrochloride acid (13 mL) were added
to a THF (60 mL) solution of the crude 2-(2-(diethoxymethyl)-1H-
benzoimidazol-1-yl)acetic acid 3 (5.57 g, 20 mmol), and the mix-
ture was heated to reflux for 24 h. After evaporation of the volatiles,
the mixture was diluted with water (10 mL) and the pH of the re-
action mixture was then adjusted to about 3e4 with saturated
potassium carbonate solution. Filteration of the mixture and re-
crystallization of the solid from ethanol afforded compound 4.
4.3. Preparation of methyl 2-(2-(diethoxymethyl)-1H-
benzoimidazol-1-yl)acetate 2
To a solution of 1 (4.40 g, 20 mmol) in CH3CN (40 mL) were
added methyl chloroacetate (2.19 g, 20.2 mmol) and K2CO3 (2.76 g,
20 mmol) and the mixture was heated to reflux for 6 h. The solid
was filtered, and the filtrate was concentrated under reduced
pressure to afford compound 2 as a brown oil.
4.5.1. 2-(2-Formyl-1H-benzoimidazol-1-yl)acetic acid (4). White solid
(3.76 g, 92%), mp 230e232 ꢀC. Found: C, 58.80; H, 3.90; N, 13.57.
C10H8N2O3 requires C, 58.82; H, 3.95; N, 13.72%. nmax (KBr)
2900e3381, 1699 cmꢁ1
; dH (500 MHz, DMSO-d6) 5.38 (2H, s,
NCH2CO2H),7.40(1H, t,J7.6 Hz, Ar), 7.50 (1H, t, J7.6 Hz,Ar),7.83(1H, d,
J 8.2 Hz, Ar), 7.90 (1H, d, J 8.2 Hz, Ar), 10.01 (1H, s, COH); dc (125 MHz,
DMSO-d6) 46.7 (NCH2CO2H), 112.6, 122.5, 124.8, 127.5, 137.2, 142.7,
147.0 (CeAr),170.1 (C]O),186.3 (C]O); m/z (EI, 70 eV) 204 (Mþ, 83),
159 (33), 131 (100), 104 (33), 77 (51), 69 (20), 51 (20), 43 (15%).
4.3.1. Methyl 2-(2-(diethoxymethyl)-1H-benzoimidazol-1-yl)acetate
(2). Brown oil (5.32 g, 91%). Found: C, 61.23; H, 6.59; N, 9.63.
C15H20N2O4 requires C, 61.63; H, 6.90; N, 9.58%. nmax (KBr)
1752 cmꢁ1
; dH (500 MHz, CDCl3) 1.18 (6H, t, J 7.0 Hz, 2OCH2CH3),
3.50e3.56 (2H, m, OCH2CH3), 3.69 (3H, s, OCH3), 3.72e3.78 (2H, m,
OCH2CH3), 5.14 (2H, s, NCH2CO2), 5.63 (1H, s, CH(OC2H5)2),
7.23e7.28 (3H, m, Ar), 7.75 (1H, d, J 7.6 Hz, Ar); dc (125 MHz, CDCl3)
15.3 (2OCH2CH3), 45.6 (NCH2CO2), 52.7 (OCH3), 64.1 (2OCH2CH3),
99.8 (CH(OC2H5)2), 109.6, 120.7, 122.8, 124.1, 136.4, 142.1, 150.7
(CeAr),168.7 (C]O); m/z (EI, 70 eV) 293 (100, Mþþ1), 248 (68), 219
(80), 191 (9), 131 (16), 77 (6), 47 (8%).
4.6. Representative procedure for the synthesis of 3-oxo-
1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole-1-
carboxamides 6aep
A solution of 2-(2-formyl-1H-benzoimidazol-1-yl)acetic acid 4
(0.20 g, 1.0 mmol), amine (1.0 mmol), and isocyanide (1.0 mmol) in
methanol (3 mL) was stirred at 40 ꢀC for the appropriate time (see
Table 1). The progress of the reaction was monitored by TLC. On
completion, the reaction mixture was cooled to rt, the crude solid
was filtered and recrystallized from ethanol to afford compounds
6aep.
4.4. Preparation of 2-(2-(diethoxymethyl)-1H-benzoimidazol-
1-yl)acetic acid 3
To a stirred solution of methyl 2-(2-(diethoxymethyl)-1H-ben-
zoimidazol-1-yl)acetate 2 (5.85 g, 20 mmol) in methanol (20 mL),
a solution of NaOH (0.96 g, 24 mmol) in water (10 mL) was added
dropwise. The reaction mixture was stirred for 4 h at rt (TLC
monitoring). After evaporation of the volatiles, the mixture was
diluted with water (5 mL), and the pH of the reaction mixture was
then adjusted to about pH 3e4 with HCl solution. Filteration of the
4.6.1. 3-Oxo-2-phenyl-N-(1,1,3,3-tetramethylbutyl)-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamide (6a). White solid
(0.32 g, 76%), mp 225e227 ꢀC. Found: C, 71.38; H, 7.62; N, 13.25.
C25H30N4O2 requires C, 71.74; H, 7.22; N, 13.39%. nmax (KBr) 3399,
1672 cmꢁ1
; dH (500 MHz, CDCl3) 0.73 (9H, s, CMe3), 1.16 (3H, s,

M. Ghandi et al. / Tetrahedron 66 (2010) 8231e8237
8235
CMe2), 1.27 (3H, s, CMe2), 1.45 (1H, d, J 14.8 Hz, CCHC), 1.76 (1H, d, J
14.8 Hz, CCHC), 5.05 (1H, d, J 16.6 Hz, NCHCO), 5.22 (1H, d, J 16.6 Hz,
NCHCO), 6.07 (1H, s, NCOCHN), 7.29e7.50 (9H, m, Ar), 7.12 (1H, br s,
NH); dc (125 MHz, CDCl3) 28.9 (CMe2), 29.4 (CMe2), 31.5 (CMe3), 31.7
(CMe3), 47.4 (NCH2CO), 51.6 (CCH2C), 56.8 (CMe2), 64.2 (NCOCHN),
110.0, 119.9, 123.8, 124.1, 127.7, 128.8, 130.1, 134.0, 140.8, 142.9, 145.5
(CeAr), 165.1 (C]O), 165.3 (C]O); m/z (EI, 70 eV) 419 (9, Mþþ1),
297 (43), 263 (100), 234 (83), 219 (9), 158 (16), 131 (51), 104 (23), 77
(29), 57 (64), 41 (24%).
(1H, d, J 14.7 Hz, CCHC), 3.86 (3H, s, OMe), 5.04 (1H, d, J 16.6 Hz,
NCHCO), 5.22 (1H, d, J 16.6 Hz, NCHCO), 6.13 (1H, s, NCOCHN), 6.97
(2H, d, J 8.8 Hz, Ar), 7.30e7.34 (5H, m, NH, Ar), 7.38 (1H, t, J 6.9 Hz,
Ar), 7.44 (1H, d, J 7.9 Hz, Ar); dc (125 MHz, CDCl3) 28.8 (CMe2), 29.3
(CMe2), 31.5 (CMe3), 31.7 (CMe3), 47.3 (NCH2CO), 51.6 (CCH2C), 56.0
(OMe), 56.8 (CMe2), 64.4 (NCOCHN), 110.0, 115.3, 119.9, 123.7, 124.0,
129.0, 133.5, 134.1, 143.1, 145.7, 159.8 (CeAr), 165.4 (C]O), 165.6
(C]O); m/z (EI, 70 eV) 448 (5, Mþ), 293 (100), 264 (23), 219 (24),
205 (13), 131 (19), 77 (7), 57 (12%).
4.6.2. 3-Oxo-2-p-tolyl-N-(1,1,3,3-tetramethylbutyl)-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamide (6b). White solid
(0.40 g, 92%), mp 256e258 ꢀC. Found: C, 72.50; H, 7.75; N, 12.73.
C26H32N4O2 requires C, 72.19; H, 7.46; N, 12.95%. nmax (KBr) 3397,
4.6.6. 2-(4-Chlorophenyl)-3-oxo-N-(1,1,3,3-tetramethylbutyl)-
1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole-1-carboxamide
(6f). White solid (0.37 g, 82%), mp 256e257 ꢀC. Found: C, 66.45; H,
6.39; N, 12.30. C25H29ClN4O2 requires C, 66.29; H, 6.45; N, 12.37%.
1656 cmꢁ1
;
dH (500 MHz, CDCl3) 0.73 (9H, s, CMe3), 1.12 (3H, s,
nmax (KBr) 3415, 1669 cmꢁ1
; dH (500 MHz, CDCl3) 0.76 (9H, s, CMe3),
CMe2), 1.25 (3H, s, CMe2), 1.43 (1H, d, J 14.7 Hz, CCHC), 1.78 (1H, d, J
14.7 Hz, CCHC), 2.44 (3H, s, Me), 5.05 (1H, d, J 16.6 Hz, NCHCO), 5.24
(1H, d, J 16.6 Hz, NCHCO), 6.18 (1H, s, NCOCHN), 7.24e7.32 (6H, m,
Ar), 7.36 (1H, br s, NH), 7.40 (1H, t, J 7.7 Hz, Ar), 7.44 (1H, d, J 8.0 Hz,
Ar); dc (125 MHz, CDCl3) 21.6 (Me), 28.8 (CMe2), 29.3 (CMe2), 31.5
(CMe3), 31.7 (CMe3), 47.4 (NCH2CO), 51.6 (CCH2C), 56.8 (CMe2), 64.2
(NCOCHN), 110.0, 119.9, 123.6, 124.0, 127.4, 130.7, 134.1, 138.2, 138.8,
143.0, 145.7 (CeAr), 165.2 (C]O), 165.6 (C]O); m/z (EI, 70 eV) 433
(7, Mþþ1), 277 (100), 248 (62), 131 (35), 91 (16), 77 (5), 57 (41), 41
(15%).
1.23 (3H, s, CMe2), 1.31 (3H, s, CMe2), 1.51 (1H, d, J 14.8 Hz, CCHC),
1.77 (1H, d, J 14.8 Hz, CCHC), 5.04 (1H, d, J 16.7 Hz, NCHCO), 5.16
(1H, d, J 16.7 Hz, NCHCO), 5.86 (1H, s, NCOCHN), 6.86 (1H, br s, NH),
7.28e7.48 (8H, m, Ar); dc (125 MHz, CDCl3) 29.0 (CMe2), 29.4
(CMe2), 31.5 (CMe3), 31.7 (CMe3), 47.3 (NCH2CO), 51.6 (CCH2C), 57.0
(CMe2), 64.2 (NCOCHN), 109.9, 120.0, 123.9, 124.2, 129.2, 130.2,
134.0, 134.7, 139.2, 143.1, 145.0 (CeAr), 164.9 (C]O), 165.2 (C]O);
m/z (EI, 70 eV) 453 (2, Mþþ1), 297 (100), 269 (53), 53 (12), 158 (14),
131 (48), 111 (12), 77 (11), 57 (59), 41 (22%).
4.6.7. 3-Oxo-2-propyl-N-(1,1,3,3-tetramethylbutyl)-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamide (6g). White solid
(0.26 g, 68%), mp 185e188 ꢀC. Found: C, 67.73; H, 8.80; N, 14.57.
C22H32N4O2 requires C, 68.72; H, 8.39; N, 14.57%. nmax (KBr) 3292,
4.6.3. 3-Oxo-2-m-tolyl-N-(1,1,3,3-tetramethylbutyl)-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamide (6c). White solid
(0.31 g, 72%), mp 231e233 ꢀC. Found: C, 72.05; H, 7.49; N, 12.92.
C26H32N4O2 requires C, 72.19; H, 7.46; N, 12.95%. nmax (KBr) 3335,
1688 cmꢁ1
; dH (500 MHz, CDCl3) 0.80 (9H, s, CMe3), 0.95 (3H, t, J
1686 cmꢁ1
;
dH (500 MHz, CDCl3) 0.73 (9H, s, CMe3), 1.11 (3H, s,
7.3 Hz, CH2CH2CH3), 1.22 (3H, s, CMe2), 1.29 (3H, s, CMe2), 1.56 (1H,
d, J 14.8 Hz, CCHC), 1.63e1.76 (2H, m, CH2CH2CH3), 1.77 (1H, d, J
14.8 Hz, CCHC), 3.11e3.17 (1H, m, CH2CH2CH3), 4.04e4.10 (1H, m,
CH2CH2CH3), 4.93 (1H, d, J 16.5 Hz, NCHCO), 5.00 (1H, d, J 16.5 Hz,
NCHCO), 5.81 (1H, s, NCOCHN), 7.38e7.41 (3H, m, NH, Ar), 7.43 (1H,
d, J 6.5 Hz, Ar), 7.73 (1H, d, J 6.1 Hz, Ar); dc (125 MHz, CDCl3) 11.7
(CH2CH2CH3), 21.0 (CH2CH2CH3), 29.1 (CMe2), 29.4 (CMe2), 31.5
(CMe3), 31.8 (CMe3), 46.9 (NCH2CO), 49.0 (CH2CH2CH3), 50.6
(CCH2C), 56.8 (CMe2), 60.4 (NCOCHN), 110.1, 119.6, 123.9, 124.0,
134.1, 143.1, 145.8 (CeAr), 164.9 (C]O),165.3 (C]O); m/z (EI, 70 eV)
385 (9, Mþþ1), 384 (Mþ, 2), 229 (100), 200 (64), 186 (6), 158 (14),
131 (15), 57 (14), 41 (7%).
CMe2), 1.25 (3H, s, CMe2), 1.45 (1H, d, J 14.8 Hz, CCHC), 1.79 (1H, d, J
14.8 Hz, CCHC), 2.36 (3H, s, Me), 5.05 (1H, d, J 16.6 Hz, NCHCO), 5.24
(1H, d, J 16.6 Hz, NCHCO), 6.17 (1H, s, NCOCHN), 7.21e7.40 (8H, m,
NH, Ar), 7.44 (1H, d, J 8.0 Hz, Ar); dc (125 MHz, CDCl3) 21.7 (Me), 28.8
(CMe2), 29.4 (CMe2), 31.5 (CMe3), 31.7 (CMe3), 47.4 (NCH2CO), 51.5
(CCH2C), 56.8 (CMe2), 64.2 (NCOCHN), 110.0, 119.8, 123.7, 124.0,
124.6, 128.2, 129.6, 130.0, 134.1, 140.2, 140.7, 143.1, 145.7 (CeAr),
165.2 (C]O), 165.6 (C]O); m/z (EI, 70 eV) 430 (2, Mþꢁ2), 277
(100), 248 (45), 219 (79), 178 (38), 131 (39), 97 (29), 81 (38), 69 (75),
57 (71), 43 (65%).
4.6.4. 2-(3,4-Dimethylphenyl)-3-oxo-N-(1,1,3,3-tetramethylbutyl)-
1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole-1-carboxamide
(6d). White solid (0.40 g, 90%), mp 238e241 ꢀC. Found: C, 72.51; H,
7.86; N, 12.51. C27H34N4O2 requires C, 72.62; H, 7.67; N, 12.55%. nmax
4.6.8. 2-Benzyl-3-oxo-N-(1,1,3,3-tetramethylbutyl)-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamide (6h). White solid
(0.38 g, 88%), mp 210e212 ꢀC. Found: C, 72.03; H, 7.60; N, 12.41.
C26H32N4O2 requires C, 72.19; H, 7.46; N, 12.95%. nmax (KBr) 3287,
(KBr) 3410, 1663 cmꢁ1
; dH (500 MHz, CDCl3) 0.75 (9H, s, CMe3), 1.17
(3H, s, CMe2), 1.28 (3H, s, CMe2), 1.48 (1H, d, J 14.8 Hz, CCHC), 1.79
(1H, d, J 14.8 Hz, CCHC), 2.25 (3H, s, Me), 2.33 (3H, s, Me), 5.03 (1H, d,
J 16.6 Hz, NCHCO), 5.21 (1H, d, J 16.6 Hz, NCHCO), 5.98 (1H, s,
NCOCHN), 7.13 (1H, d, J 7.9 Hz, Ar), 7.17 (1H, s, Ar), 7.23 (1H, d, J
8.0 Hz, Ar), 7.32 (1H, d, J 6.9 Hz, Ar), 7.35 (1H, t, J 7.1 Hz, Ar), 7.39
(1H, t, J 7.4 Hz, Ar), 7.44 (1H, d, J 8.0 Hz, Ar), 7.04 (1H, br s, NH); dc
(125 MHz, CDCl3) 19.9 (Me), 20.2 (Me), 28.8 (CMe2), 29.4 (CMe2),
31.5 (CMe3), 31.7 (CMe3), 47.4 (NCH2CO), 51.6 (CCH2C), 56.8 (CMe2),
64.4 (NCOCHN), 109.9, 119.9, 123.6, 124.0, 124.9, 128.6, 131.2, 134.1,
137.6, 138.4, 138.6, 143.1, 145.6 (CeAr), 165.2 (C]O), 165.6 (C]O);
m/z (EI, 70 eV) 447 (8, Mþþ1), 446 (Mþ, 2), 291 (100), 262 (30), 247
(7), 235 (4), 158 (4), 131 (16), 105 (8), 77 (5), 57 (20), 41 (6%).
1684 cmꢁ1
; dH (500 MHz, CDCl3) 0.86 (9H, s, CMe3), 1.33 (3H, s,
CMe2), 1.35 (3H, s, CMe2), 1.63 (1H, d, J 14.9 Hz, CCHC), 1.79 (1H, d, J
14.9 Hz, CCHC), 4.09 (1H, d, J 15.0 Hz, NCHCO), 4.97 (2H, s, CH2Ph),
5.28 (1H, s, NCOCHN), 5.53 (1H, d, J 15.0 Hz, NCHCO), 6.78 (1H, br s,
NH), 7.18e7.26 (5H, m, Ar), 7.36e7.37 (2H, m, Ar), 7.40 (1H, d, J
7.6 Hz, Ar), 7.71 (1H, d, J 7.1 Hz, Ar); dc (125 MHz, CDCl3) 29.2
(CMe2), 29.5 (CMe2), 31.6 (CMe3), 31.9 (CMe3), 46.6 (NCH2CO), 49.8
(CH2Ph), 51.8 (CCH2C), 56.8 (CMe2), 59.2 (NCOCHN), 109.9, 120.0,
123.8, 123.9, 128.5, 129.0, 129.2, 134.0, 135.4, 143.2, 145.0 (CeAr),
164.5 (C]O), 165.0 (C]O); m/z (EI, 70 eV) 433 (5, Mþþ1), 277
(100), 186 (61), 158 (5), 131 (10), 91 (30), 57 (15), 41 (6%).
4.6.9. N-Cyclohexyl-3-oxo-2-phenyl-1,2,3,4-tetrahydropyrazino[1,2-
a]benzimidazole-1-carboxamide (6i). White solid (0.31 g, 80%), mp
280e281 ꢀC. Found: C, 71.39; H, 6.52; N, 14.43. C23H24N4O2 requires
4.6.5. 2-(4-Methoxyphenyl)-3-oxo-N-(1,1,3,3-tetramethylbutyl)-
1,2,3,4-tetrahydropyrazino[1,2-a]benzimidazole-1-carboxamide
(6e). White solid (0.30 g, 67%), mp 230e233 ꢀC Found: C, 69.74; H,
7.49; N, 12.49. C26H32N4O3 requires C, 69.62; H, 7.19; N, 12.49%. nmax
C, 71.11; H, 6.23; N, 14.42%. nmax (KBr) 3217, 1672 cmꢁ1
; dH
(500 MHz, CDCl3) 0.86e1.88 (m, 10H, 5CH2 of cyclohexyl),
3.50e3.55 (1H, m, CHNH of cyclohexyl), 5.00 (1H, d, J 16.6 Hz,
NCHCO), 5.17 (1H, d, J 16.6 Hz, NCHCO), 6.03 (1H, s, NCOCHN),
(KBr) 3272, 1679 cmꢁ1
;
dH (500 MHz, CDCl3) 0.75 (9H, s, CMe3), 1.14
(3H, s, CMe2), 1.26 (3H, s, CMe2), 1.45 (1H, d, J 14.7 Hz, CCHC), 1.77

8236
M. Ghandi et al. / Tetrahedron 66 (2010) 8231e8237
7.26e7.41 (9H, m, Ar), 8.14 (1H, d, J 6.2 Hz, NH); dc (125 MHz, CDCl3)
25.0 (2CH2), 25.6 (CH2), 32.3 (CH2), 33.1 (CH2), 47.2 (NCH2CO), 50.1
(CHNH of cyclohexyl), 63.3 (NCOCHN), 100.4, 110.0, 119.6, 123.8,
124.1, 127.6, 128.8, 130.1, 133.9, 140.6, 145.4 (CeAr), 165.0 (C]O),
166.2 (C]O); m/z (EI, 70 eV) 388 (2, Mþ), 263 (100), 234 (98), 219
(16), 158 (17), 131 (64), 104 (35), 77 (51), 55 (22), 41 (16%).
Ar), 8.44 (1H, d, J 6.5 Hz, NH); dc (125 MHz, CDCl3) 25.0 (2CH2), 25.6
(CH2), 32.3 (CH2), 33.1 (CH2), 47.1 (NCH2CO), 50.0 (CHNH of cyclo-
hexyl), 55.9 (OMe), 63.6 (NCOCHN), 110.0, 115.2, 119.6, 123.4, 123.8,
128.8, 133.2, 133.9, 143.0, 145.6, 159.6 (CeAr), 165.1 (C]O), 166.5
(C]O); m/z (EI, 70 eV) 418 (9, Mþ), 293 (96), 264 (32), 248 (23), 219
(100), 205 (26), 131 (44), 69 (30), 57 (44), 43 (40%).
4.6.10. N-Cyclohexyl-3-oxo-2-p-tolyl-1,2,3,4-tetrahydropyrazino[1,2-
a]benzimidazole-1-carboxamide (6j). White solid (0.37 g, 90%), mp
252e254 ꢀC. Found: C, 71.49; H, 6.20; N, 13.73. C24H26N4O2 requires
4.6.14. 2-(4-Chlorophenyl)-N-cyclohexyl-3-oxo-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamide (6n). White solid
(0.36 g, 85%), mp 270e271 ꢀC. Found: C, 65.10; H, 6.08; N, 12.85.
C23H23ClN4O2 requires C, 65.32; H, 5.48; N, 13.25%. nmax (KBr)
C, 71.62; H, 6.51; N, 13.92%. nmax (KBr) 3208, 1672 cmꢁ1
; dH
(500 MHz, CDCl3) 0.84e2.00 (10H, m, 5CH2 of cyclohexyl), 2.44 (3H,
s, Me), 3.56e3.62 (1H, m, CHNH of cyclohexyl), 5.05 (1H, d, J 16.6 Hz,
NCHCO), 5.23 (1H, d, J 16.6 Hz, NCHCO), 6.09 (1H, s, NCOCHN), 7.20
(1H, d, J 8.0 Hz, Ar), 7.25 (4H, br s, Ar), 7.30 (1H, t, J 7.6 Hz, Ar), 7.39
(1H, t, J 7.6 Hz, Ar), 7.44 (1H, d, J 8.0 Hz, Ar), 8.03 (1H, d, J 6.4 Hz,
NH); dc (125 MHz, CDCl3) 21.6 (Me), 25.1 (2CH2), 25.6 (CH2), 32.4
(CH2), 33.3 (CH2), 47.2 (NCH2CO), 50.2 (CHNH of cyclohexyl), 63.7
(NCOCHN), 110.0, 119.7, 123.6, 124.0, 127.5, 130.8, 134.0, 138.0, 138.9,
142.9, 145.6 (CeAr), 165.0 (C]O), 166.3 (C]O); m/z (EI, 70 eV) 401
(5, Mþꢁ1), 355 (46), 236 (20), 268 (23), 149 (19), 236 (100), 91 (85),
77 (9), 59 (16%).
3212, 1675 cmꢁ1
; dH (500 MHz, CDCl3) 0.91e1.98 (10H, m, 5CH2 of
cyclohexyl), 3.59e3.62 (1H, m, CHNH of cyclohexyl), 5.06 (1H, d, J
16.7 Hz, NCHCO), 5.21 (1H, d, J 16.7 Hz, NCHCO), 6.04 (1H, s,
NCOCHN), 7.28e7.48 (8H, m, Ar), 7.83 (1H, br s, NH); dc (125 MHz,
CDCl3) 25.0 (CH2), 25.6 (CH2), 31.3 (CH2), 32.4 (CH2), 33.2 (CH2),
47.1 (NCH2CO), 50.4 (CHNH of cyclohexyl), 63.3 (NCOCHN), 110.2,
119.4, 124.4, 124.6, 129.2, 130.4, 133.7, 134.3, 138.9, 142.6, 145.6
(CeAr), 164.8 (C]O), 165.3 (C]O); m/z (EI, 70 eV) 423 (2, Mþþ1),
297 (100), 268 (57), 186 (31), 158 (17), 131 (66), 111 (18), 91 (21), 77
(16), 55 (33), 41 (25%).
4.6.15. N-Cyclohexyl-3-oxo-2-propyl-1,2,3,4-tetrahydropyrazino[1,2-
a]benzimidazole-1-carboxamide (6o). White solid (0.22 g, 62%), mp
207e208 ꢀC. Found: C, 67.34; H, 7.84; N, 14.71. C20H26N4O2 requires
4.6.11. N-Cyclohexyl-3-oxo-2-m-tolyl-1,2,3,4-tetrahydropyrazino
[1,2-a]benzimidazole-1-carboxamide (6k). White solid (0.31 g, 77%),
mp 250e252 ꢀC. Found: C, 71.50; H, 6.59; N, 14.02. C24H26N4O2
C, 67.77; H, 7.39; N, 15.81%. nmax (KBr) 1685, 3218 cmꢁ1
; dH
requires C, 71.62; H, 6.51; N, 13.92%. nmax (KBr) 1678, 3210 cmꢁ1
;
dH
(500 MHz, CDCl3) 0.90 (3H, t, J 7.3 Hz, CH2CH2CH3), 0.96e2.11 (12H,
m, 5CH2 of cyclohexyl, CH2CH2CH3), 3.20e3.26 (1H, m,
CH2CH2CH3), 3.62e3.67 (1H, m, CHNH of cyclohexyl), 3.90e3.96
(1H, m, CH2CH2CH3), 4.94 (1H, d, J 16.5 Hz, NCHCO), 5.07 (1H, d, J
16.5 Hz, NCHCO), 5.88 (1H, s, NCOCHN), 7.40e7.43 (2H, m, Ar), 7.46
(1H, d, J 7.5 Hz, Ar), 7.73 (1H, d, J 7.2 Hz, Ar), 8.36 (1H, d, J 6.1 Hz,
NH); dc (125 MHz, CDCl3) 11.6 (CH2CH2CH3), 21.0 (CH2CH2CH3), 25.1
(CH2), 25.2 (CH2), 25.7 (CH2), 32.7 (CH2), 33.4 (CH2), 46.8 (NCH2CO),
48.9 (CH2CH2CH3), 50.3 (CHNH of cyclohexyl), 60.0 (NCOCHN),
110.2, 119.3, 124.0, 124.1, 134.1, 142.9, 145.8 (CeAr), 164.7 (C]O),
166.3 (C]O); m/z (EI, 70 eV) 353 (2, Mþꢁ1), 229 (100), 200 (10),186
(9), 158 (14), 131 (14), 55 (10), 43 (10%).
(500 MHz, CDCl3) 0.83e2.01 (10H, m, 5CH2 of cyclohexyl), 2.32 (3H,
s, Me), 3.56e3.62 (1H, m, CHNH of cyclohexyl), 5.06 (1H, d, J
16.6 Hz, NCHCO), 5.25 (1H, d, J 16.6 Hz, NCHCO), 6.20 (1H, s,
NCOCHN), 7.16e7.19 (3H, m, Ar), 7.26 (1H, d, J 7.6 Hz, Ar), 7.32 (1H, d,
J 7.8 Hz, Ar), 7.36 (1H, t, J 8.1 Hz, Ar), 7.40 (1H, t, J 7.6 Hz, Ar), 7.46
(1H, d, J 8.0 Hz, Ar). 8.22 (1H, br s, NH); dc (125 MHz, CDCl3) 21.7
(Me), 25.0 (2CH2), 25.6 (CH2), 32.3 (CH2), 33.3 (CH2), 47.2 (NCH2CO),
50.2 (CHNH of cyclohexyl), 63.5 (NCOCHN), 110.0, 119.5, 123.9,
124.2, 124.7, 128.3, 129.8, 130.0, 133.9, 140.3, 140.4, 142.6, 145.6
(CeAr); 164.8 (C]O), 166.3 (C]O); m/z (EI, 70 eV) 416 (4, Mþ), 293
(23), 277 (100), 248 (56), 219 (27), 177 (4), 131 (42), 97 (26), 81 (42),
69 (83), 57 (63), 43 (50%).
4.6.16. 2-Benzyl-N-cyclohexyl-3-oxo-1,2,3,4-tetrahydropyrazino[1,2-
a]benzimidazole-1-carboxamide (6p). White solid (0.33 g, 82%), mp
284e286 ꢀC. Found: C, 71.75; H, 6.84; N, 13.60. C24H26N4O2 requires
4.6.12. N-Cyclohexyl-2-(3,4-dimethylphenyl)-3-oxo-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamide (6l). White solid
(0.38 g, 91%), mp 262e265 ꢀC. Found: C, 72.00; H, 6.82; N, 13.15.
C25H28N4O2 requires C, 72.09; H, 6.78; N, 13.45%. nmax (KBr) 3381,
C, 71.62; H, 6.51; N, 13.92%. nmax (KBr) 3217, 1676 cmꢁ1
; dH
(500 MHz, CDCl3) 1.00e1.81 (10H, m, 5CH2 of cyclohexyl),
3.45e3.52 (1H, m, CHNH of cyclohexyl), 4.00 (1H, d, J 14.9 Hz,
CH2Ph), 4.86 (1H, d, J 16.6 Hz, NCHCO), 4.96 (1H, d, J 16.6 Hz,
NCHCO), 5.30 (1H, d, J 14.9 Hz, CH2Ph), 5.31 (1H, s, NCOCHN), 7.15
(5H, br s, Ar), 7.23e7.28 (2H, m, Ar), 7.32 (1H, d, J 7.9 Hz, Ar), 7.60
(1H, d, J 7.6 Hz, Ar), 7.64 (1H, d, J 6.9 Hz, NH); dc (125 MHz, CDCl3)
25.0 (CH2), 25.1 (CH2), 25.7 (CH2), 32.6 (CH2), 33.2 (CH2), 46.7
(NCH2CO), 49.6 (CH2Ph), 50.0 (CHNH of cyclohexyl), 58.8
(NCOCHN), 110.0, 119.7, 123.8, 124.0, 128.3, 128.9, 129.1, 133.8, 135.5,
143.2, 145.1 (CeAr), 165.0 (C]O), 135.4 (C]O); m/z (EI, 70 eV) 402
(2, Mþ), 277 (100), 186 (85), 158 (7), 131 (15), 91 (52), 55 (10), 41
(9%).
1654 cmꢁ1
; dH (500 MHz, CDCl3) 0.78e1.93 (10H, m, 5CH2 of
cyclohexyl), 2.11 (3H, s, Me), 2.25 (3H, s, Me), 3.46e3.53 (1H, m,
CHNH of cyclohexyl), 4.97 (1H, d, J 16.6 Hz, NCHCO), 5.16 (1H, d, J
16.6 Hz, NCHCO), 6.11 (1H, s, NCOCHN), 6.99 (1H, d, J 7.9 Hz, Ar), 7.02
(1H, s, Ar), 7.04 (1H, d, J 8.1 Hz, Ar), 7.12 (1H, d, J 7.8 Hz, Ar), 7.21 (1H,
t, J 7.3 Hz, Ar), 7.30 (1H, t, J 7.8 Hz, Ar), 7.37 (1H, d, J 8.0 Hz, Ar), 8.46
(1H, d, J 6.3 Hz, NH); dc (125 MHz, CDCl3) 19.8 (Me), 20.1 (Me), 25.0
(2CH2), 25.6 (CH2), 32.2 (CH2), 33.2 (CH2), 47.1 (NCH2CO), 50.0
(CHNH of cyclohexyl), 63.4 (NCOCHN), 110.0, 119.4, 123.4, 123.8,
124.9,128.5,131.1,133.9,137.4,138.1,138.5,142.8,145.7 (CeAr),164.9
(C]O),166.6 (C]O); m/z (EI, 70 eV) 416 (2, Mþ), 291 (100), 262 (30),
247 (6), 235 (4), 158 (4), 131 (19), 105 (10), 77 (8), 55 (12), 41 (7%).
Acknowledgements
4.6.13. N-Cyclohexyl-2-(4-methoxyphenyl)-3-oxo-1,2,3,4-tetrahy-
dropyrazino[1,2-a]benzimidazole-1-carboxamide (6m). White solid
(0.32 g, 76%), mp 257e260 ꢀC. Found: C, 68.96; H, 6.40; N, 13.58.
C24H26N4O3 requires C, 68.88; H, 6.26; N, 13.39%. nmax (KBr) 3365,
The authors acknowledge the University of Tehran for financial
support of this research.
1658 cmꢁ1
; dH (500 MHz, CDCl3) 0.77e1.86 (10H, m, 5CH2 of
cyclohexyl), 3.42e3.49 (1H, m, CHNH of cyclohexyl), 2.74 (3H, s,
OMe), 4.93 (1H, d, J 16.6 Hz, NCHCO), 5.11 (1H, d, J 16.6 Hz, NCHCO),
6.02 (1H, s, NCOCHN), 6.82 (2H, d, J 8.9 Hz, Ar), 7.12e7.16 (3H, m, Ar),
7.18 (1H, t, J 7.6 Hz, Ar), 7.26 (1H, t, J 10.6 Hz, Ar), 7.34 (1H, d, J 8.0 Hz,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.08.057.

M. Ghandi et al. / Tetrahedron 66 (2010) 8231e8237
8237
2003, 103, 893e930; (g) Viso, A.; Fernandez de la Pradilla, R.; Flores, A.; Garcıa,
A. Tetrahedron 2007, 63, 8017e8026.
References and notes
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M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. J. Med. Chem. 1988, 31, 2235e2246; (c) Muller, G.
Drug Discov. Today 2003, 8, 681e691.
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