Multicomponent synthesis of fused benzimidazolopiperazines

Article abstract of DOI:10.1021/jo200397m

We present a novel protocol for the efficient synthesis of fused benzimidazolo piperazines starting from a four-component Ugi-Smiles reaction and a subsequent three-step cascade involving an acid-catalyzed cyclization, an intramolecular reductive cyclizat

Full text of DOI:10.1021/jo200397m

NOTE
pubs.acs.org/joc
Multicomponent Synthesis of Fused Benzimidazolopiperazines
Laurent El Kaïm,* Laurence Grimaud,* and Srinivas Reddy Purumandla
Laboratoire Chimie et procꢀedꢀes, UMR 7652-DCSO-Ecole Polytechnique-ENSTA, Ecole Nationale Supꢀerieure de Techniques Avancꢀees,
32 Bd Victor, Paris 75015, France
S Supporting Information
b
ABSTRACT: We present a novel protocol for the efficient
synthesis of fused benzimidazolo piperazines starting from a
four-component UgiꢀSmiles reaction and a subsequent three-
step cascade involving an acid-catalyzed cyclization, an intra-
molecular reductive cyclization, and an oxidation.
n times where a premium is put on speed, diversity, and effi-
Scheme 1. Strategies for Heterocyclic Syntheses
I
ciency in the drug discovery process, multicomponent reac-
tions (MCRs)1 have become an essential tool in organic and
medicinal chemistry. The potential of MCRs coupled with
postcondensation transformations to generate highly diverse scaf-
folds within a few steps was mainly highlighted by the synthetic
developments made around the Ugi reaction.2 Recently, our
research group reported an extension of this four-component
coupling by replacing carboxylic acids with electron-deficient
phenols as acidic inputs.3 In this reaction, a final irreversible
Smiles rearrangement leads to the formation of N-arylcarbox-
amide (Scheme 1).
The potential of UgiꢀSmiles couplings was highlighted by
several syntheses of various fused heterocyclic systems.4 All these
studies involved cyclization between the aryl moiety and func-
tionalities present on the nitrogen substituents of the aniline Ugi
framework (paths a, b, or c, Scheme 1).
Scheme 2. Piperazinones from UgiꢀSmiles Couplings
Searching for more complex cyclizations involving the aro-
matic moiety, we considered the use of aminoacetaldehyde acetal
as amine input in the UgiꢀSmiles reaction. The latter has been
already used in the Ugi reaction to afford piperazine derivatives
under acidic treatment of the intermediate Ugi adducts.5 Apply-
ing a similar strategy with UgiꢀSmiles couplings, we surmised
that the newly created double bond could give us some oppor-
tunies to observe further cyclization between the aromatic
subsituents and the intermediate enamine (Scheme 2). Herein,
we report the preparation of various fused polycyclic piperazi-
nones using UgiꢀSmiles reaction of 2-nitrophenol with aminoa-
cetaldehyde dimethyl acetal.
Using aminoacetaldehyde dimethyl acetal with 2-nitrophenol
in the UgiꢀSmiles reaction, we decided to study the direct four-
component formation of ketopiperazinones 1 under a one-pot
procedure. Thus, after completion of the UgiꢀSmiles reaction
(performed under standard conditions in methanol), trifluoroa-
cetic acid was added and the mixture heated for few hours.
Following this procedure, we could obtain the ketopiperazinones
1aꢀk in moderate to good yields with a set of various nitrophe-
nols, isocyanides, and carbonyl (Table 1, entries 1ꢀ11). Similar
conditions applied to 2-hydroxypyridine (or 2-hydroxy-3-nitropyrid-
ine), cyclohexyl isocyanide, and isovaleraldehyde failed to give any
piperazine because of the inefficiency of the second step.
The N-arylpiperazinones prepared according to this sequence
are related to the N-acyl analogues obtained from traditional Ugi
reaction of aminoacetaldehyde dimethyl acetal followed by acid-
triggered cyclization.5 These intermediates have been trapped
further in PictetꢀSpengler reactions.6
In order to increase the synthetic potential of the new N-aryl
analogues, we envisioned similar formation of complex polycyclic
piperazines. Therefore, cyclizations involving the nitro and en-
amines moieties were next considered. We postulated that a
reduction of the nitro, acid-triggered addition of the resulting
amine on the enamine followed by oxidation could afford some
Received: March 4, 2011
Published: April 12, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200397m J. Org. Chem. 2011, 76, 4728–4733
|

The Journal of Organic Chemistry
NOTE
Table 1. UgiꢀSmiles/Acidic Cyclization Cascade
Table 2. Scope of Fused System Synthesis
reaction
time
yield
product (%)
1
entry
R1
i-Bu
R0
R2
R3
(h)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
Cy
Cy
Cy
Cy
Cy
Cy
H
H
32
32
32
34
24
22
34
32
32
32
30
1a
1b
1c
1d
1e
1f
54
66
55
58
51
54
62
57
41
47
60
Ph
i-Bu
Cl
(CH2)4
i-Bu
H
CH3
OCH3
Cl
(CH2)4
(CH2)4
(CH2)4
4-ClPh
4-ClBn
4-ClBn
4-ClBn
4-ClBn
1g
1h
1i
CH3
H
H
H
10 Et
11 Et
H
1j
Et CH2CO2Me Cl
1k
Scheme 3. Reductive Cyclization of Piperazinones
stable fused benzimidazole systems. Related formation of fused
piperazinobenzimidazoles from thermal degradation of naphtho-
quinone azide gives positive indications on aniline addition on the
enamine moiety.7
Hydrogenolysis of piperazine 1a under flow chemistry gave
the aniline 2a efficiently. Although the latter could be converted
into benzimidazole 3a under heating in acetic acid with palladium
on charcoal (Scheme 3), we preferred conditions that might
allow the two steps in the same pot. Still working with palladium
in the presence of ammonium formate, we thought that the
acidity of the medium could allow the reductionꢀcyclization
cascade. Indeed, the reduction of the nitro was observed at room
temperature, and the oxidative cyclization proceeded smoothly
when the temperature of the medium was raised to 60 °C to
afford 3a (Scheme 3). However, under these conditions, the
over-reduced piperazine 4a was obtained as a byproduct due to
partial reduction of the piperazine before its cyclization. Acetic
acid was then added before the mixture was heated. This more
acidic medium ensured a faster cyclization and a better selectivity.
Various piperazines 1 were converted into benzimidazoles 3
under this set of conditions (Table 2).
In conclusion, a new synthesis of complex fused benzimidazo
piperazines based on a UgiꢀSmiles four-component strategy is
reported.8 Piperazines and benzimidazoles are considered as
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The Journal of Organic Chemistry
NOTE
privilege scaffolds in medicinal chemistry.9 Indeed, these rings
may be found in a number of biologically active compounds,
including several marketed drugs. The UgiꢀSmiles reaction
with nitrophenols allows the coupling of both scaffolds in fused
systems and in a multicomponent fashion.
141.4, 137.4, 133.3, 126.5, 126.0, 122.0, 112.0, 111.0, 61.6, 52.2, 37.6,
31.5, 30.5, 25.6, 25.4, 24.7, 23.5, 22.2; IR (ATR) 2928, 2861, 1671,
1609, 1527, 1488, 1433, 1351, 1261, 1214, 1119 cmꢀ1; HRMS calcd for
C20H26ClN3O3 391.1663, found 391.1658.
9-Cyclohexyl-6-(2-nitrophenyl)-6,9-diazaspiro[4.5]dec-7-en-10-one
(1d). The typical procedure performed on a 1.0 mmol scale afforded 1d
as a reddish oil (petroleum ether/diethyl ether 90/10): yield 56% (200
mg); Rf 0.1 (90:10 petroleum ether/diethyl ether); 1H NMR (CDCl3,
400 MHz) δ 7.69 (d, 1H, J = 8.1 Hz), 7.48 (t, 1H, J = 7.8 Hz), 7.33 (t, 1H,
J = 7.8 Hz), 7.20 (d, 1H, J = 8.1 Hz), 5.73 (d, 1H, J = 5.3 Hz), 5.71(d, 1H,
J = 5.3 Hz), 4.45ꢀ4.36 (m, 1H), 2.16ꢀ2.03 (m, 2H), 1.87ꢀ1.77 (m,
4H), 1.76ꢀ1.62 (m, 7H), 1.49ꢀ1.34 (m, 4H), 1.17ꢀ1.05 (m, 1H); 13C
NMR (CDCl3, 100.6 MHz) δ 165.9, 149.5, 138.0, 132.5, 131.5, 127.0,
124.2, 118.0, 109.2, 70.8, 52.6, 34.6, 31.0, 25.7, 25.4, 24.7; IR (ATR)
’ EXPERIMENTAL SECTION
1H NMR spectra were recorded on a 400 MHz spectrometer, using
CDCl3 solvent as reference and/or internal deuterium lock. 13C NMR
spectra were recorded on a 100.6 MHz spectrometer. Two-dimensional
1
1
13
NMR spectroscopy [1Hꢀ H COSY spectra, Hꢀ C COSY spectra
(HSQC), and long-range 1Hꢀ C COSY spectra (HMBC)] was carried
13
out to determine the correlation between H and 13C. The chemical
1
2930, 2857, 1665, 1603, 1530, 1405, 1357, 1252, 1211, 1193 cmꢀ1
HRMS calcd for C20H25N3O3 355.1896, found 355.1845.
;
shifts for all NMR spectra are expressed in parts per million to high
frequency of TMS reference. Coupling constants (J) are quoted in hertz
and are recorded to the nearest 0.1 Hz. The IR spectra were obtained
using ATR accessories. High-resolution (HR) mass spectra were
performed on a GC/MS system spectrometer. TLC was carried out
using precoated plates of silica gel 60F254.
1-Cyclohexyl-3-isobutyl-4-(4-methyl-2-nitrophenyl)-3,4-dihydropyrazin-
2(1H)-one (1e). The typical procedure performed on a 1.0 mmol scale
afforded 1e as a brown oil (petroleum ether/diethyl ether 80/20): yield
51% (190 mg); Rf 0.2 (80:20 petroleum ether/diethyl ether); 1H NMR
(CDCl3, 400 MHz) δ 7.54 (s, 1H), 7.27 (d, 1H, J = 8.1 Hz), 7.02 (d, 1H,
J = 8.6 Hz), 5.77 (d, 1H, J = 5.3 Hz), 5.35 (d, 1H, J = 5.3 Hz), 4.41ꢀ4.32
(m, 2H), 2.33 (s, 3H), 1.91ꢀ1.77 (m, 3H), 1.76ꢀ1.64 (m, 4H),
1.52ꢀ1.34 (m, 5H), 1.17ꢀ1.09 (m, 1H), 1.06 (d, 3H, J = 6.3 Hz),
0.93 (d, 3H, J = 6.3 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 162.6, 141.8,
136.6, 134.0, 132.3, 126.1, 121.6, 112.9, 109.6, 61.7, 52.0, 37.7, 31.5, 30.5,
25.6, 25.4, 24.6, 23.4, 22.2, 20.3; IR (ATR) 2933, 2857, 1668, 1620,
1526, 1498, 1432, 1404, 1347, 1263, 1206 cmꢀ1; HRMS calcd for
C21H29N3O3 371.2209, found 371.2202.
9-Cyclohexyl-6-(4-methoxy-2-nitrophenyl)-6,9-diazaspiro[4.5]dec-
7-en-10-one (1f). The typical procedure performed on a 1.0 mmol scale
afforded 1f as a yellow oil (petroleum ether/diethyl ether 80/20): yield
54% (208 mg); Rf 0.2 (80:20 petroleum ether/diethyl ether); 1H NMR
(CDCl3, 400 MHz) δ 7.18 (d, 1H, J = 2.8 Hz), 7.11(d, 1H, J = 8.8 Hz),
7.01 (dd, 1H, J = 3.0, 9.1 Hz), 5.70 (d, 1H, J = 5.3 Hz), 5.66 (d, 1H, J =
5.3 Hz), 4.46ꢀ4.35 (m, 1H), 3.83 (s, 3H), 2.19ꢀ2.07 (m, 1H), 2.05ꢀ
1.93 (m, 1H), 1.88ꢀ1.77 (m, 4H), 1.73ꢀ1.61 (m, 7H), 1.49ꢀ1.37 (m,
4H), 1.17ꢀ1.05 (m, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 165.8,
158.0, 150.2, 132.9, 130.5, 118.9, 118.5, 108.5, 108.3, 70.9, 55.9, 52.6,
35.1, 34.0, 31.0, 25.7, 25.5, 24.7; IR (ATR) 2933, 2857, 1658, 1531, 1498,
1399, 1225, 1037 cmꢀ1; HRMS calcd for C21H27N3O4 385.2002, found
385.2007.
6-(4-Chloro-2-nitrophenyl)-9-(4-chlorobenzyl)-6,9-diazaspiro[4.5]dec-
7-en-10-one (1g). The typical procedure performed on a 1.0 mmol scale
afforded 1g as a yellow oil (petroleum ether/diethyl ether 80/20): yield
62% (267 mg); Rf 0.2 (80:20 petroleum ether/diethyl ether); 1H NMR
(CDCl3, 400 MHz) δ 7.71 (br s, 1H), 7.45 (dd, 1H, J = 2.5, 8.6 Hz), 7.31
(d, 2H, J = 8.3 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.13 (d, 1H, J = 8.6 Hz), 5.67
(d, 1H, J = 5.3 Hz), 5.57 (d, 1H, J = 5.3 Hz), 4.70 (br s, 2H), 2.27ꢀ2.05
(br s, 2H), 1.79ꢀ1.61 (m, 6H); 13C NMR (CDCl3, 100.6 MHz) δ
166.3, 149.5, 136.1, 135.4, 133.3, 132.8, 132.6, 129.0, 128.8, 124.5, 118.0,
112.4, 71.0, 49.0, 35.1, 33.9, 24.6; IR (ATR) 2957, 2874, 1666, 1600,
1534, 1481, 1398, 1556, 1259, 1176, 1110, 1013 cmꢀ1; HRMS calcd for
C21H19Cl2N3O3 431.0803, found 431.0812.
9-(4-Chlorobenzyl)-6-(4-methyl-2-nitrophenyl)-6,9-diazaspiro[4.5]dec-
7-en-10-one (1h). The typical procedure performed on a 1.0 mmol scale
afforded 1h as a brown oil (petroleum ether/diethyl ether 80/20): yield
45% (183 mg); Rf 0.2 (80:20 petroleum ether/diethyl ether); 1H NMR
(CDCl3, 400 MHz) δ 7.52 (s, 1H), 7.32 (d, 2H, J = 8.3 Hz), 7.29 (dd,
1H, J = 1.8, 8.1 Hz), 7.23 (d, 2H, J = 8.3 Hz) 7.07 (d, 1H, J = 8.1 Hz), 5.72
(d, 1H, J = 5.0 Hz), 5.51 (d, 1H, J = 5.0 Hz), 4.71 (br s, 2H), 2.40 (s, 3H),
2.29ꢀ2.00 (m, 2H), 1,80ꢀ1.58 (m, 6H); 13C NMR (CDCl3, 100.6
MHz) δ 166.5, 149.4, 138.3, 135.6, 134.9, 133.4, 133.3, 131.6, 129.1,
128.8, 124.5, 119.0, 111.2, 71.0, 49.0, 35.3, 33.7, 24.6, 20.8; IR (ATR)
General Procedure for the Synthesis of 3,4-Dihydropyr-
azin-2(1H)-ones (1aꢀk). To a 1 M solution of carbonyl derivative
(1.0 equiv) in methanol were added successively 2,2-dimethoxyethyla-
mine (1.0 equiv), isocyanide (1.0 equiv) and o-nitrophenol (1 equiv).
The reaction mixture was stirred at 60 °C until completion of the
UgiꢀSmiles coupling and then cooled to room temperature. TFA (15 equiv)
was added and the mixture heated at 60 °C. After completion of the reaction,
the mixture was evaporated and purified by flash chromatography on silica gel.
1-Cyclohexyl-3-isobutyl-4-(2-nitrophenyl)-3,4-dihydropyrazin-2(1H)-
one (1a). The typical procedure performed on a 1.0 mmol scale afforded
1a as a brown oil (petroleum ether/diethyl ether 80/20): yield 54% (193
mg); Rf 0.2 (80:20 petroleum ether/diethyl ether); 1H NMR (CDCl3,
400 MHz) δ 7.74 (d, 1H, J = 8.3 Hz), 7.47 (t, 1H, J = 7.8 Hz), 7.12 (d,
1H, J = 8.3 Hz), 7.04 (t, 1H, J = 7.8 Hz), 5.82 (d, 1H, J = 5.3 Hz), 5.35
(d, 1H, J = 5.3 Hz), 4.46ꢀ4.33 (m, 2H), 1.91ꢀ1.76 (m, 4H), 1.75ꢀ1.65
(m, 3H), 1.54ꢀ1.36 (m, 5H), 1.19ꢀ1.13 (m, 1H), 1.09 (d, 3H, J = 6.3 Hz),
0.95 (d, 3H, J = 6.3 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 162.7, 141.7,
138.7, 133.2, 126.3, 121.7, 120.9, 112.6, 110.3, 61.5, 52.1, 37.6, 31.5, 30.5,
25.6, 25.4, 24.7, 23.5, 22.2; IR (ATR) 2931, 2861, 1672, 1605, 1523, 1488,
1456, 1425, 1351, 1257, 1210 cmꢀ1; HRMS calcd for C20H27N3O3
357.2052, found 357.2050.
1-Cyclohexyl-4-(2-nitrophenyl)-3-phenyl-3,4-dihydropyrazin-2(1H)-
one (1b). The typical procedure performed on a 1.0 mmol scale afforded
compound 1b as a yellow oil (petroleum ether/diethyl ether 60/40):
yield 66% (250 mg); Rf 0.4 (60:40 petroleum ether/diethyl ether); 1H
NMR (CDCl3, 400 MHz) δ 7.80 (d, 1H, J = 8.3 Hz), 7.44 (d, 2H, J = 7.3
Hz), 7.41ꢀ7.32 (m, 4H), 7.07 (t, 1H, J = 7.8 Hz), 6.97 (d, 1H, J = 8.3
Hz), 5.71 (d, 1H, J = 5.0 Hz), 5.59ꢀ5.56 (m, 2H), 4.43ꢀ4.34 (m, 1H),
1.93 (br d, 1H, J = 11.1 Hz), 1.86ꢀ1.75 (m, 2H), 1.66 (br d, 1H,
J = 13.4 Hz), 1.57ꢀ1.52 (m, 1H), 1.45ꢀ1.40 (m, 1H), 1.39ꢀ1.30 (m,
3H), 1.15ꢀ1.04 (m, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 161.9,
141.3, 138.5, 135.4, 133.3, 128.8, 128.3, 126.2, 126.0, 122.0, 120.9, 113.7,
109.2, 66.0, 52.6, 31.4, 30.1, 25.6, 25.5, 25.4; IR (ATR) 2931, 2857, 1668,
1609, 1523, 1491, 1452, 1429, 1347, 1261, 1214 cmꢀ1; HRMS calcd for
C22H23N3O3 377.1739, found 377.1730.
4-(4-Chloro-2-nitrophenyl)-1-cyclohexyl-3-isobutyl-3,4-dihydropyr-
azin-2(1H)-one (1c). The typical procedure performed on a 1.0 mmol
scale afforded 1c as a reddish oil (petroleum ether/diethyl ether 90/10):
yield 55% (215 mg); Rf 0.1 (90:10 petroleum ether/diethyl ether); 1HNMR
(CDCl3, 400 MHz) δ 7.75 (d, 1H, J = 2.5 Hz), 7.43 (dd, 1H, J = 2.5, 8.8
Hz), 7.06 (d, 1H, J = 8.8 Hz), 5.85 (d, 1H, J = 5.6 Hz), 5.29 (dd, 1H,
J = 2.0, 5.6 Hz), 4.42ꢀ4.32 (m, 2H), 1.90ꢀ1.79 (m, 3H), 1.77ꢀ1.74
(m, 1H), 1.73ꢀ1.66 (m, 3H), 1.52ꢀ1.37 (m, 6H), 1.08 (d, 3H, J = 6.6
Hz), 0.95 (d, 3H, J = 6.6 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 162.6,
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NOTE
2959, 2873, 1668, 1652, 1531, 1495, 1401, 1359, 1261, 1178, 1096,
1022 cmꢀ1; HRMS calcd for C22H22ClN3O3 411.1350, found 411.1352.
1-(4-Chlorobenzyl)-3-(4-chlorophenyl)-4-(2-nitrophenyl)-3,4-dihy-
dropyrazin-2(1H)-one (1i). The typical procedure performed on a
1.0 mmol scale afforded 1i as a colorless oil (petroleum ether/diethyl
ether 80/20): yield 41% (185 mg); Rf 0.2 (80:20 petroleum ether/
diethyl ether); 1H NMR (CDCl3, 400 MHz) δ 7.68 (d, 1H, J = 8.3 Hz),
7.30ꢀ7.25 (m, 3H), 7.21 (d, 2H, J = 8.3 Hz), 7.13 (d, 2H, J = 8.3 Hz),
7.01ꢀ6.94 (m, 3H), 6.79 (d, 1H, J = 8.3 Hz), 5.48 (dd, 1H, J = 1.8, 5.3 Hz),
5.45 (s, 1H), 5.41 (d, 1H, J = 5.3 Hz), 4.64 (d, 1H, J = 15.4 Hz), 4.45
(d, 1H, J = 15.4 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 162.1, 141.5,
138.1, 134.6, 134.4, 133.5, 133.4, 129.1, 128.8, 128.6, 127.5, 126.3,
122.8, 121.0, 114.1, 112.2, 65.3, 48.7; IR (ATR) 2928, 2857, 1679, 1644,
1613, 1495, 1413, 1351, 1280, 1175, 1096, 1018 cmꢀ1; HRMS calcd for
C23H17Cl2N3O3 453.0647, found 453.0661.
2-Cyclohexyl)-4-phenyl-1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine
(3b). The typical procedure was with 1b (100 mg, 0.26 mmol). Purification
by flash chromatography (petroleum ether/diethyl ether 50:50) afforded
3b> as a white solid: mp = 181ꢀ183 °C; yield 69% (63 mg); Rf 0.5 (50:50
petroleum ether/diethyl ether); 1H NMR (CDCl3, 400 MHz) δ 7.79 (d,
1H, J = 8.1 Hz), 7.33ꢀ7.28 (m, 4H) 7.20 (t, 1H, J = 7.8 Hz), 7.16ꢀ7.11 (m,
3H), 6.05 (s, 1H), 4.82 (d, 1H, J = 16.9 Hz), 4.67 (d, 1H, J = 16.9 Hz),
4.54ꢀ4.45 (m, 1H), 1.91ꢀ1.79 (m, 2H), 1.75ꢀ1.65 (m, 3H), 1.58ꢀ1.31
(m, 4H), 1.19ꢀ1.08 (m, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 164.1,
145.7, 143.6, 135.1, 133.0, 129.1, 128.8, 126.0, 123.1, 123.0, 119.6, 109.9,
60.8, 53.6, 39.9, 29.6, 29.1, 25.5, 25.4, 25.3; IR (ATR) 2926, 2857, 1655,
1569, 1456, 1373, 1292, 1256, 1234 cmꢀ1; HRMS calcd for C22H23N3O
345.1841, found 345.1843.
2-Cyclohexyl-4-isobutyl-1,2-dihydro-4-chlorobenzo[4,5]imidazo[1,2-a]
pyrazin-3-one (3c). The typical procedure was followed with 1c (100
mg, 0.26 mmol. Purification by flash chromatography (petroleum ether/
diethyl ether 25:75) afforded 3c as a white solid: mp = 115ꢀ116°C; yield
53% (48 mg); Rf 0.75 (25:75 petroleum ether/diethyl ether); 1H NMR
(CDCl3, 400 MHz) δ 7.77ꢀ7.73 (m, 1H), 7.38ꢀ7.34 (m, 1H), 7.31ꢀ
7.28 (m, 1H), 5.03 (t, 1H, J = 6.3 Hz), 4.75 (d, 1H, J = 16.7 Hz), 4.60 (d,
1H, J = 16.7 Hz), 4.57ꢀ4.49 (m, 1H), 1.99ꢀ1.79 (m, 6H), 1.75ꢀ1.62 (m,
3H), 1.56ꢀ1.45 (m, 3H), 1.21ꢀ1.11 (m, 1H), 0.97 (d, 3H, J = 6.6 Hz),
0.92 (d, 3H, J = 6.6 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 166.1, 145.6,
143.5, 133.3, 125.5, 122.8, 119.7, 109.3, 56.4, 53.2, 42.3, 39.8, 30.3, 29.7,
29.2, 25.6, 25.4, 25.3, 24.5, 22.8, 22.6; IR (ATR) 2928, 2856, 1652, 1539,
1465, 1439, 1297, 1232, 1183 cmꢀ1; HRMS calcd for C20H26ClN3O
359.1764, found 359.1772.
1-(4-Chlorobenzyl)-3-ethyl-4-(2-nitrophenyl)-3,4-dihydropyrazin-2(1H)-
one (1j). The typical procedure performed on a 1.0 mmol scale afforded
1j as a brown syrup (petroleum ether/diethyl ether 65/35): yield 47%
1
(174 mg); Rf 0.35 (65:35 petroleum ether/diethyl ether); H NMR-
(CDCl3, 400 MHz) δ 7.76 (d, 1H, J = 8.3 Hz), 7.50 (t, 1H, J = 7.8 Hz),
7.33 (d, 2H, J = 8.3 Hz), 7.23 (d, 2H, J = 8.3 Hz), 7.15 (d, 1H, J = 8.3 Hz),
7.08 (t, 1H, J = 7.8 Hz), 5.63 (d, 1H, J = 5.3 Hz), 5.40 (dd, 1H, J = 1.8, 5.3
Hz), 4.76 (d, 1H, J = 15.2 Hz), 4.69 (d, 1H, J = 15.2 Hz), 4.37 (t, 1H, J =
7.3 Hz), 1.98ꢀ1.79 (m, 2H), 1.07 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3,
100.6 MHz) δ 163.4, 141.9, 138.5, 134.9, 133.5, 133.3, 129.0, 128.9,
126.4, 122.2, 121.3, 113.4, 112.8, 64.0, 48.2, 22.5, 10.3; IR (ATR) 2971,
2931, 2857, 1675, 1620, 1523, 1488, 1456, 1401, 1351, 1272, 1096,
1018 cmꢀ1; HRMS calcd for C19H18ClN3O3 371.1037, found 371.1011.
Methyl 2-(4-(4-Chloro-2-nitrophenyl)-3,3-diethyl-2-oxo-3,4-dihy-
dropyrazin-1(2H)-yl)acetate (1k). The typical procedure performed
on a 1.0 mmol scale afforded 1l as a pale yellow oil (petroleum ether/
diethyl ether 70/30): yield 60% (230 mg); Rf 0.3 (70:30 petroleum
ether/diethyl ether); 1H NMR (CDCl3, 400 MHz) δ 7.77 (s, 1H), 7.45
(dd, 1H, J = 2.5, 8.8 Hz), 7.38 (d, 1H, J = 8.8 Hz), 5.47 (d, 1H, J = 5.3
Hz), 5.30 (d, 1H, J = 5.3 Hz), 4.57ꢀ3.97 (m, 2H), 3.77 (s, 3H),
2.25ꢀ2.06 (m, 1H), 2.02ꢀ1.88 (m, 2H), 1.33ꢀ1.20 (m, 1H),
1.00ꢀ0.68 (m, 6H); 13C NMR (CDCl3, 100.6 MHz) δ 168.8, 165.7,
146.1, 136.3, 132.2, 129.9, 128.7, 125.7, 115.5, 70.0, 52.3, 47.8, 8.6; IR
(ATR) 2942, 2886, 1747, 1667, 1531, 1484, 1437, 1394, 1277, 1211,
1178, 1112 cmꢀ1; HRMS calcd for C17H20ClN3O5 381.1091, found
381.1097.
General Procedure for the Synthesis of Fused Benzimida-
zolopiperazines (3aꢀl). To a 0.5 M solution of dihydroketopiper-
azine (1aꢀl) (1.0 equiv) in methanol were added ammonium formate
(5.0 equiv) and PdꢀC (10% PdꢀC, 2.0 equiv) under argon. The
reaction mixture was stirred at room temperature for 30 min, and then it
was acidified by addition of 6.0 equiv of CH3COOH and stirred at 60 °C
until completion of the reaction. The residue was filtered through a
Celite pad, and the solvent was evaporated. The crude mixture was
purified by flash chromatography on silica gel to get the required product.
2-Cyclohexyl-4-isobutyl-1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-
3-one (3a). The typical procedure was followed with 1a (100 mg,
0.28 mmol). Purification by flash chromatography (petroleum etherꢀ
diethyl ether, 40:60) afforded 3a as a colorless oil: yield 72% (65 mg); Rf
0.6 (40:60 petroleum ether/diethyl ether); 1H NMR (CDCl3, 400
MHz) δ 7.77ꢀ7.71 (m, 1H), 7.38ꢀ7.33 (m, 1H), 7.32ꢀ7.27 (m, 2H),
5.03 (t, 1H, J = 6.6 Hz), 4.75 (d, 1H, J = 16.7 Hz), 4.59 (d, 1H, J = 16.7
Hz), 4.57ꢀ4.49 (m, 1H), 1.99ꢀ1.79 (m, 5H), 1.74ꢀ1.61 (m, 3H),
1.56ꢀ1.41 (m, 4H), 1.21ꢀ1.11 (m, 1H), 0.96 (d, 3H, J = 6.6 Hz), 0.91
(d, 3H, J = 6.6 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 166.0, 145.6,
143.5, 133.3, 122.8, 119.7, 109.3, 56.4, 53.1, 42.3, 39.8, 29.7, 29.2, 25.6,
25.4, 25.3, 24.5, 22.7, 22.6; IR (ATR) 2929, 2856, 1653, 1539, 1466,
1443, 1368, 1297, 1283, 1256, 1233, 1183, 1169 cmꢀ1; HRMS calcd for
C20H27N3O 325.2154, found 325.2141.
2-Cyclohexyl-4-cyclopentyl-1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine
(3d). The typical procedure was followed with 1d (100 mg, 0.28 mmol).
Purification by flash chromatography (petroleum ether/diethyl ether
40:60) afforded 3d as a white solid: mp = 133ꢀ134 °C; yield 81% (73 mg);
1
Rf 0.6 (40:60 petroleum ether/diethyl ether); H NMR (CDCl3, 400
MHz) δ 7.72 (d, 1H, J = 7.8 Hz), 7.49 (d, 1H, J = 7.8 Hz), 7.28 (t, 1H, J =
7.3 Hz), 7.23 (t, 1H, J = 7.3 Hz), 4.71 (s, 2H), 4.57ꢀ4.49 (m, 1H),
2.57ꢀ2.48 (m, 2H), 2.46ꢀ2.37 (m, 2H), 2.22ꢀ2.10 (m, 4H), 1.90ꢀ
1.83 (m, 2H), 1.80ꢀ1.68 (m, 3H), 1.58ꢀ1.8 (m, 4H), 1.22ꢀ1.10 (m,
1H); 13C NMR (CDCl3, 100.6 MHz) δ 170.2, 145.5, 143.9, 132.1,
122.6, 122.3, 119.7, 111.5, 69.5, 53.7, 40.1, 38.1, 29.3, 27.1, 25.6, 25.3; IR
(ATR) 2931, 2856, 1644, 1544, 1472, 1452, 1427, 1332, 1297, 1180,
764, 702 cmꢀ1; HRMS calcd for C20H25N3O 323.1998, found 323.2001.
2-Cyclohexyl-4-isobutyl-1,2-dihydro-4-methylbenzo[4,5]imidazo[1,2-a]-
pyrazin-3-one (3e). The typical procedure was followed with 1c (100
mg, 0.27 mmol). Purification by flash chromatography (petroleum
etherꢀdiethyl ether 40:60) afforded 3e as a colorless oil: yield 52%
(47 mg); Rf 0.6 (40:60 petroleum ether/diethyl ether); 1H NMR
(CDCl3, 400 MHz) δ 7.52 (s, 1H), 7.23 (d, 1H, J = 8.3 Hz), 7.11 (d,
1H, J = 8.3 Hz), 4.99 (t, 1H, J = 6.6 Hz), 4.73 (d, 1H, J = 16.7 Hz), 4.58
(d, 1H, J = 16.7 Hz), 4.57ꢀ4.49 (m, 1H), 2.48 (s, 3H), 1.97ꢀ1.79 (m,
5H), 1.74ꢀ1.62 (m, 3H), 1.55ꢀ1.41 (m, 4H), 1.21ꢀ1.09 (m, 1H), 0.95
(d, 3H, J = 6.6 Hz), 0.90 (d, 3H, J = 6.6 Hz); 13C NMR (CDCl3, 100.6
MHz) δ 166.1, 145.5, 143.9, 132.6, 131.4, 124.2, 119.5, 108.8, 56.4, 53.2,
42.3, 39.9, 29.7, 29.2, 25.6, 25.4, 25.3, 24.5, 22.8, 22.6, 21.5; IR (ATR)
2930, 2857, 1656, 1537, 1464, 1450, 1294, 1186 cmꢀ1; HRMS calcd for
C21H29N3O 339.2311, found 339.2313.
1-Cyclohexyl-3-cyclopentyl-5,6-dihydrobenzo-4-methoxy[4,5]imidazo
[1,2-a]pyrazin-2-one (3f). The typical procedure was followed with 1f
(200 mg, 0.52 mmol). Purification by flash chromatography (petroleum
ether/diethyl ether 20:80) afforded 3f as a colorless oil: yield 65%
1
(119 mg); Rf 0.8 (20:80 petroleum ether/diethyl ether); H NMR
(CDCl3, 400 MHz) δ 7.35 (d, 1H, J = 8.8 Hz), 7.18 (s, 1H), 6.87 (dd,
1H, J = 8.8 Hz), 4.68 (s, 2H), 4.57ꢀ4.48 (m, 1H), 3.85 (s, 3H), 2.56ꢀ
2.47 (m, 2H), 2.41ꢀ2. 32 (m, 2H), 2.22ꢀ2.06 (m, 4H), 1.91ꢀ1.83
(m, 2H), 1.79ꢀ1.67 (m, 3H), 1.58ꢀ1.37 (m, 4H), 1.22ꢀ1.09 (m,
1H); 13C NMR (CDCl3, 100.6 MHz) δ 170.2, 156.2, 145.6, 144.9,
4731
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The Journal of Organic Chemistry
NOTE
126.5, 112.1, 111.8, 101.8, 69.4, 55.7, 53.6, 40.1, 38.2, 29.3, 27.1, 25.6,
25.3; IR (ATR) 2937, 2857, 1648, 1540, 1479, 1446, 1277, 1197,
1183, 1154, 1121, 1037 cmꢀ1; HRMS calcd for C21H27N3O2
353.2103, found 353.2104.
(m, 4H), 0.63 (t, 6H, J = 7.3 Hz); 13C NMR (CDCl3, 100.6 MHz) δ
169.1, 168.4, 144.8, 131.9, 122.9, 122.5, 119.9, 112.1, 70.2, 52.5, 48.9,
46.8, 31.3, 8.2; IR (ATR) 2928, 2857, 1752, 1658, 1437, 1333, 1281,
1206, 1173, 1018, 957 cmꢀ1; HRMS calcd for C17H20ClN3O3 349.1193,
found 349.1194.
2-(4-Chlorobenzyl)-4-cyclopentyl-1,2-dihydro-4-chlorobenzo[4,5]imidazo-
[1,2-a]pyrazin-2-one (3g). The typical procedure was followed with 1g
(100 mg, 0.23 mmol). Purification by flash chromatography (petroleum
ether/diethyl ether 20:80) afforded 3g as a white solid: mp = 139ꢀ
141 °C; yield 66% (61 mg); Rf 0.8 (20:80 petroleum ether/diethyl
4-(2-Aminophenyl)-1-cyclohexyl-3-isobutylpiperazin-2-one (4a).
To a 0.5 M solution of 1a (100 mg, 0.28 mmol) in methanol were
added ammonium formate (90 mg, 1.40 mmol) and 10% PdꢀC
(60 mg, 0.56 mmol) under argon. The reaction mixture was stirred
at room temperature for 30 min, and then it was stirred at 60 °C for
12 h. The residue was filtered through a Celite pad, and the solvent was
evaporated. The crude mixture was purified by flash chromatography
on silica gel; the products were 4a (18 mg, 20%) and 3a (31 mg, 34%):
Rf for 4a 0.2 (80:20 petroleum ether/diethyl ether); Rf for 3a 0.6
(40:60 petroleum ether/diethyl ether); 1H NMR (CDCl3, 400 MHz)
δ 6.95 (t, 1H, J = 7.6 Hz), 6.89 (d, 1H, J = 7.8 Hz), 6.74 (d, 1H, J = 7.8
Hz), 6.69 (t, 1H, J = 7.6 Hz), 4.56ꢀ4.48 (m, 1H), 3.97 (br s, 2H), 3.75
(dd, 1H, J = 5.6, 7.6 Hz), 3.35ꢀ3.27 (m, 1H), 3.23ꢀ3.15 (m, 1H),
3.12ꢀ3.05 (m, 2H), 1.84ꢀ1.76 (m, 3H), 1.75ꢀ1.62 (m, 5H),
1.48ꢀ1.31 (m, 4H), 1.11ꢀ0.99 (m, 1H), 0.88 (d, 3H, J = 6.3 Hz),
0.78 (d, 3H, J = 6.3 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 170.8,
141.8, 136.0, 125.2, 122.4, 118.4, 115.3, 61.2, 52.2, 43.4, 40.3, 38.5,
29.4, 29.3, 25.6, 25.5, 25.3, 22.9, 21.8; IR (ATR) 2933, 2862, 1620, 1503,
1
ether); H NMR (CDCl3, 400 MHz) δ 7.61 (d, 1H, J = 7.6 Hz),
7.41 (d, 1H, J = 7.6 Hz), 7.27ꢀ7.21 (m, 4H), 7.20ꢀ7.15 (m, 1H), 4.69
(s, 2H), 4.61 (s, 2H), 2.53ꢀ2.45 (m, 2H), 2.42ꢀ2.34 (m, 2H), 2.20ꢀ
2.06 (m, 4H); 13C NMR (CDCl3, 100.6 MHz) δ 170.8, 144.6, 143.9,
135.4, 131.9, 128.9, 128.2, 128.0, 122.7, 122.3, 119.8, 111.4, 69.4, 50.6,
44.7, 38.3, 27.1; IR (ATR) 2954, 1652, 1454, 1426, 1332, 1266, 1186,
735, 700 cmꢀ1; HRMS calcd for C21H19Cl2N3O 399.0905, found
399.0886.
1-(4-chlorobenzyl)-3-cyclopentyl-5,6-dihydrobenzo-4-methyl[4,5]imidazo
[1,2-a]-pyrazin-2-one (3h). The typical procedure was followed with 1h
(150 mg, 0.36 mmol). Purification by flash chromatography (petroleum
ether/diethyl ether 50:50) afforded 3h as a colorless oil: yield 67% (92
mg); Rf 0.5 (50:50 petroleum ether/diethyl ether); 1H NMR (CDCl3,
400 MHz) δ 7.47 (s, 1H), 7.37 (d, 2H, J = 8.3 Hz), 7.34ꢀ7.31 (m, 3H),
7.06 (d, 1H, J = 8.3 Hz), 4.78 (s, 2H), 4.67 (s, 2H), 2.60ꢀ2.52 (m, 2H),
2.46 (s, 3H), 2.48ꢀ2.40 (m, 2H), 2.27ꢀ2.18 (m, 3H), 1.94ꢀ1.82 (m,
1H); 13C NMR (CDCl3, 100.6 MHz) δ 171.0, 144.5, 144.4, 135.4, 132.5,
130.0, 129.0, 128.3, 128.1, 123.8, 119.6, 110.9, 69.4, 50.7, 44.8, 38.4, 27.2,
21.4; IR (ATR) 2955, 1652, 1543, 1480, 1439, 1327, 1266, 1185, 791,
733, 699 cmꢀ1; HRMS calcd for C22H22ClN3O 379.1451, found
379.1460.
1451, 1272, 1183, 1051, 900 cmꢀ1
.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures with
b
characterization data and copies of C13 and H1 NMR spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
2-(4-Chlorobenzyl)-4-(4-chlorophenyl)-1,2-dihydrobenzo[4,5]imidazo-
[1,2-a]pyrazin-3-one (3i). The typical procedure was followed with 1i
(100 mg, 0.22 mmol). Purification by flash chromatography (petroleum
ether/diethyl ether 50:50) afforded 3i as a pale yellow oil: yield 46% (43
mg); Rf 0.5 (50:50 petroleumether/diethylether);1H NMR(CDCl3, 400
MHz) δ 7.75 (d, 1H, J = 8.1 Hz), 7.35ꢀ7.28 (m, 6H), 7.24ꢀ7.21 (m,
2H), 7.19ꢀ7.15 (m, 2H), 7.10 (d, 1H, J = 7.8 Hz), 6.12 and its rotamer
6.08 (s, 1H), 4.86 (dd, 1H, J = 6.1, 14.6 Hz), 4.77 (s, 2H), 4.64 (d, 1H, J =
14.6 Hz); 13C NMR (CDCl3, 100.6 MHz, rotamers observed) δ 164.6
(164.1), 143.5 (144.9), 135.1, 135.0 (134.8), 133.6, 129.4 (129.2), 129.0
(128.9), 128.3, 128.2 (128.1), 127.6, 126.2 (125.5), 123.2 (123.4), 123.2
(123.1), 119.7 (119.6), 110.0 (109.9), 60.7 (60.1), 50.7 (50.6), 30.3
(29.7); IR (ATR) 2923, 2853, 1659, 1541, 1454, 1440, 1324, 1295,
1261 cmꢀ1; HRMS calcd for C23H17Cl2N3O 421.0749, found 421.0756.
2-(4-Chlorobenzyl)-4-ethyl-1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-
2-one (3j). The typical procedure was followed with 1j (100 mg, 0.27
mmol). Purification by flash chromatography (petroleum ether/diethyl
ether 10:90) afforded 3j as a colorless oil: yield 59% (54 mg); Rf 0.9
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: laurent.elkaim@ensta-paristech.fr; grimaud@dcso.
polytechnique.fr.
’ ACKNOWLEDGMENT
We thank the ENSTA and ANR-CP2D (Muse project) for
financial support.
’ REFERENCES
(1) Multicomponent Reactions; Zhu, J., Bienaymꢀe, H., Eds.; Wiley-
VCH: Weinheim, 2005.
(2) For some reviews, see: (a) Armstrong, R. W.; Combs, A. P.;
Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
29, 123–131. (b) D€omling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168–3210. (c) Bienaymꢀe, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem.—Eur. J. 2000, 6, 3321–3329. (d) Ugi, I.; Werner, B.; D€omling, A.
Molecules 2003, 8, 53–66. (e) D€omling, A. Chem. Rev. 2006, 106, 17–89.
(f) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 50, 1741–1743.
(3) (a) El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005,
117, 7961–7164. (b) El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J.
J. Org. Chem. 2007, 72, 4169–4180. (c) Barthelon, A.; El Kaim, L.;
Gizolme, M. Eur. J. Org. Chem. 2008, 5974–5987.
1
(10:90 petroleum ether/diethyl ether); H NMR (CDCl3, 400 MHz)
δ 7.76ꢀ7.71 (m, 1H), 7.41ꢀ7.29 (m, 7H), 5.15 (t, 1H, J = 4.8 Hz), 4.87
(d, 1H, J = 14.4 Hz), 4.76 (d, 1H, J = 14.4 Hz), 4.70 (d, 1H, J = 16.9 Hz),
4.64 (d, 1H, J = 17.9 Hz), 2.38ꢀ2.25 (m, 2H), 0.77 (t, 3H,
J = 7.6 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 166.0, 144.8, 143.6,
135.2, 132.8, 129.0, 128.5, 128.2, 123.0, 122.8, 119.7, 109.7, 58.0, 50.5,
44.7, 26.6, 8.4; IR (ATR) 2964, 2929, 1670, 1507, 1494, 1454, 1376,
1304, 1276, 1177, 1077 cmꢀ1; HRMS calcd for C19H18ClN3O
339.1138, found 339.1138.
1-(Carbomethoxymethyl)-3,3-diethyl-5,6-dihydrobenzo-4-chloro[4,5]-
imidazo[1,2-a]pyrazin-2-one (3k). The typical procedure was followed
with 1k (100 mg, 0.27 mmol). Purification by flash chromatography
(petroleum ether/diethyl ether 10:90) afforded 3l as a colorless oil: yield
80% (280 mg); Rf 0.7 (30:70 petroleum ether/diethyl ether); 1H NMR
(CDCl3, 400 MHz) δ 7.77 (br s, 1H), 7.56 (d, 1H, J = 8.1 Hz), 7.32
(t, 1H, J = 7.9 Hz), 4.92 (s, 2H), 4.32 (s, 2H), 3.80 (s, 3H), 2.52ꢀ2.35
(4) (a) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem.
2007, 72, 5835–5838. (b) Oble, J.; El Kaim, L.; Gizzi, M.; Grimaud, L.
Heterocycles 2007, 73, 503–517. (c) El Kaim, L.; Grimaud, L.; Gizzi, M.
Org. Lett. 2008, 10, 3417–3419. (d) Coffinier, D.; El Kaim, L.; Grimaud,
L. Org. Lett. 2009, 11, 995–997. (e) Barthelon, A.; Legoff, X.-F.; El Kaim,
L.; Grimaud, L. Synlett 2010, 153–157. (f) El Kaïm, L.; Grimaud, L. Mol.
Div. 2010, 14, 855–867. (g) El Kaim, L.; Grimaud, L.; Wagschal, S. J. Org.
4732
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The Journal of Organic Chemistry
NOTE
Chem. 2010, 75, 5343–5346. (h) El Kaim, L.; Grimaud, L.; Legoff, X.-F.;
Schiltz, A. Org. Lett. 2011, 13, 534–536. (i) El Kaim, L.; Grimaud, L.;
Wagschal, S. Chem. Commun. 2011, 47, 1887–1889.
(5) Cheng, J.-F.; Chen, M.; Arrhenius, T.; Nadzan, A. Tetrahedron
Lett. 2002, 43, 6293–6295.
(6) (a) Liu, H. X.; Domling, A. J. Org. Chem. 2009, 74, 6895–6898.
(b) Wang, W.; Olliot, S.; Herdtweck, E.; Domling, A. Chem. Commun.
2010, 46, 770–772. Wang, W.; Olliot, S.; Herdtweck, E.; Domling, A.
J. Org. Chem. 2011, 76, 637–644.
(7) Berezhnaya, V.N.;Shishkina, R.P.;Fokin, E. P.Izv. Akad. Nauk SSSR,
Ser. Khim. 1988, 12, 2822–2826. For related benzimidazole formation, see:
Schmutz, J.; K€unzle, F. Helv. Chim. Acta 1956, 39, 1144–1154.
(8) For reviews on piperazine and ketopiperazine formation, see:
(a) Dinsmore, C. J.; Beshore, D. C. Tetrahedron Lett. 2002, 58, 3297–3312.
For isocyanide-based preparation of piperazines, see: (b) Domling, A.;
Huang, Y. Synthesis 2010, 2859–2883. For a review on the synthesis of
fused benzimidazole hetrocycles, see: (c) Dawood, K. M.; Abdel-Wahab, B. F.
ARKIVOC 2010, 333–389.
(9) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893–930.
4733
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