Novel heterocyclic β-nitroenamines-based on a one-pot three-component reaction: A facile synthesis of fully substituted 1H-pyrrolo[1,2-a]-fused-1,3- diazaheterocycles

Article abstract of DOI:10.1016/j.tet.2010.10.052

A one-pot multicomponent synthesis of a novel class of 2,3-dihydro-1H- pyrrolo[1,2-a]imidazoles, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidines, and 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepines, starting from simple and readily available inputs includ

Full text of DOI:10.1016/j.tet.2010.10.052

Tetrahedron 66 (2010) 9933e9937
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel heterocyclic
b-nitroenamines-based on a one-pot three-component
reaction: a facile synthesis of fully substituted
1H-pyrrolo[1,2-a]-fused-1,3-diazaheterocycles
,
a
b
Abdolali Alizadeh a , Atieh Rezvanian , Yuan Deng
*
a Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran 14115, Iran
b Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2010
Received in revised form 27 September 2010
Accepted 18 October 2010
Available online 17 November 2010
A one-pot multicomponent synthesis of a novel class of 2,3-dihydro-1H-pyrrolo[1,2-a]imidazoles, 1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrimidines, and 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepines, starting
from simple and readily available inputs including diveres diamines, l,l-bis(methylthio)-2-nitroethen and
diaroylacetylene, in excellent yields is described.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,n-Diamines
l,l-Bis(methylthio)-2-nitroethen
Diaroylacetylene
1H-Pyrrolo[1,2-a]-fused-1,3-
diazaheterocycles
Multicomponent reaction
1. Introduction
2-deoxycadeguomycin10,11 also posses a pyrrolo[2,3-a]pyrimidine
moiety. A number of pyrrolopyrimidine derivatives structurally
Heterocyclic compounds are important natural and synthetic
materials. The remarkable ability of heterocyclic cores to serve both
as biomimetics and active pharmacophores has largely contributed
to their unique value as traditional key elements of numerous drugs
and designed medicinal agents in medicinal chemistry.1 In parti-
cular, nitrogen containing heterocycles are prevalent in many
drugs,2 thus synthetic chemists are increasingly motivated to dis-
cover new methods for rapid construction of pharmacologically
important drug-like compounds.3 Amongst them, the pyrroloimi-
dazole, pyrrolopyrimidine, and pyrrolodiazepine scaffolds have
been used for both synthetic and clinical studies. Pyrroloimidazoles
are useful in the treatment of hypoalkemia, hypertension, and
congestive heart failure.4 Compounds containing the imidazole
moiety have many pharmacological properties and play important
roles in biochemical processes.5 Pyrrolopyrimidine nucleoside de-
rivatives are reported to have various biological activities, such as
anti-HCV, anti-HIV type 1, and anti-HSV as well as being adenosine
kinase, aurora-A kinase, and cAMP phosphodiesterase inhib-
itors.6e9 Naturally occurring mycalisine A, cadeguomycin, and
related to toyocamycin, sangivamycin, and the seco nucleosides of
tubercidin have antiviral activity.12,13 The diazepine nucleus is
a pharmacophoric scaffold and many diazepines have recently
received great attention, because of their wide range of therapeutic
and pharmacological properties. Many members of the diazepine
family are widely used as antianxiety, antidepressant, sedative,
hypnotic, tranquilizing, anticonvulsant, antihistaminic, analgesic,
and anti-inflammatory agents.14,15
The development of new approaches for the efficient con-
struction of these heterocycles continues to be essential for
accessing natural products and their structural analogues.
Accordingly, and because of their scarce occurrence in exotic or-
ganisms, novel strategies for the synthesis of these N-heterocycles
have received considerable attention in the past decades.16 Het-
erocyclic enamines are versatile building blocks for the synthesis of
various bicyclic and tricyclic structures bearing a bridgehead ni-
trogen atom. Among them, cyclic b-nitroenamines, which consist of
pushepull ethylene systems with two donors (amine) at the two
ends and an acceptor (nitro) at the other end of the ethylene,
manifest themselves as common enamines in electrophilic re-
actions and could react with a variety of electrophiles, with elec-
trophilic attack proceeding at either or both of two nucleophilic
centers.17e21 The high solubility of the nitroenamines in general
* Corresponding author. Tel.: þ98 21 8800663; fax: þ98 21 88006544; e-mail
address: aalizadeh@modares.ac.ir (A. Alizadeh).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.052

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A. Alizadeh et al. / Tetrahedron 66 (2010) 9933e9937
organic solvents enables chemists to conduct reactions in the or-
ganic media accompanied by easy experimental manipulations and
considerable safety. Although several nitroenamines have been
known for a long time, apart from a few reactions,22e24 they have
not been used in organic synthesis. In the course of our research
program into design of new routes for the synthesis of a variety of
active biologically nitrogen heterocycles in our laboratory via one-
pot synthesis and reactions of enamines,25 we become interested in
the application of l,l-bis(methylthio)-2-nitroethen for preparation
Absorption bands at 1653 and 1603 cmꢀ1 are due to the C]O
and NC]C groups. The 1H NMR spectrum of 5b showed five
multiplets for CH2 groups because these protons are diastereo-
topic
3.51e3.56 ppm), two sharp singlets for the two methyl groups
¼2.27 and 2.36 ppm), four doublets for the aromatic moieties in
the aromatic region of the spectrum (
¼7.07e7.79 ppm) and three
singlets for CH, NH and OH groups (
(d
¼1.87e1.90, 2.05e2.09, 2.83e2.88, 3.42e3.46, and
(
d
d
d
¼8.13, 8.55 and 8.92 ppm). The
most important difference between 1H NMR spectrum of com-
pounds 3, 5, and 6 is due to the chemical shift of their OH group. For
example, compound 3a can not orient for an intramolecular hy-
drogen bonding and thus OH appears as a broad bond at 1.59 ppm
of cyclic
b-nitroenamines and their behavior in one-pot multi-
component reaction. Our strategy to reach this goal is outlined in
Scheme 1.
R
NH2
H2N
R'
H
H
N
R'
N
H2N
NO2
NO2
NH2
2
R
O
R'
R'
4
MeS
MeS
NO2 Ar
+
O
N
Ar
N
Ar
EtOH, 6 h
O
Ar
EtOH, 6 h
OH
Ar
Ar
1
O
O
H
H2N
EtOH, 6 h
3
5
NH2
Yield %
78
Yield %
87
Ar
C6H5
5
a
3
Ar
C6H5
R'
NH
R
H
NO2
a
H
H
N
p-Me-C6H4
p-Me-C6H4
b
c
d
b
c
d
80
78
84
H
83
74
70
Ar
Ar
O
C6H5
C6H5
Me
Me
Me
Me
O
H
p-Me-C6H4
p-Me-C6H4
6
6
a
Yield %
86
Ar
C6H5
b
p-Me-C6H4
82
Scheme 1. The reaction of diamine, l,l-bis(methylthio)-2-nitroethen and diaroylacetylene.
2. Results and discussion
while for 5b, intramolecular hydrogen bond causes that OH group
resonances at down field (8.92 ppm). The 1H decoupled 13C NMR
spectrum of 5b showed 19 distinct resonances in agreement with
the suggested structure.
Finally, the structures of 5b and 6b were further confirmed by
X-ray crystallographic analysis (Fig. 1).
Although we have not established the mechanism of reaction
experimentally, a possible explanation is proposed in Scheme 2.
Two isomers Z and E for all products were expected, but when
the different 1,n-diamines were applied in the reaction, only one of
the two possible isomers (E or Z) was obtained stereospecifically for
each of them. The 1H and 13C NMR, and IR spectral data of the crude
product clearly indicated the structures of all these products.
The reaction between diamines (1,2-ethanediamine 2, 1,3-pro-
panediamine 4, 1,4-butanediamine), l,l-bis(methylthio)-2-nitro-
ethene, and diaroylacetylene in aqueous EtOH leads to the
formation of pyrrolo[1,2-a]-fused-1,3-diazaheterocycles in excel-
lent yields (Scheme 1).
The structures of compounds 3aed, 5aed, and 6aeb (Fig.1) were
deduced from their elemental analysis, IR, and high-field 1H, 13C
NMR spectra. The mass spectrum of 5b displayed the molecular ion
peak at m/z 405, which is in agreement with the proposed structure.
The IR spectrum of this compound showed absorption bands due to
the OH and NH stretching frequency at 3338 and 3040 cmꢀ1
.
Fig. 1. The molecular structure of compound 5b and 6b.

A. Alizadeh et al. / Tetrahedron 66 (2010) 9933e9937
9935
H
N
H
N
NH2
NH2
MeS
MeS
NO2
-2 MeSH
NO2
H
NO2
H
n( )
n( )
n( )
ArOC
COAr
+
N
H
N
H
7
8
H
N
H
N
H
N
NO2
O
NO2
NO2
H
N
n( )
n( )
NO2
n( )
COAr
COAr
O
n( )
N
H
,
N
H
N
N
Ar
Ar
Ar
Ar
Ar
O
O
Ar
OH
O
H
if n = 1 : 3
9
10
:
:
if n = 2
if n = 3
5
6
Scheme 2. A plausible mechanism for the formation of products 3aed, 5aed and 6a,b.
3. Conclusion
11.56%. Found: C, 66.17; H, 4.63; N, 11.32%. MS (EI, 70 eV): m/z (%)¼
357 (4), 343 (58), 331 (12), 313 (72), 297 (50), 284 (138), 226 (10),
105 (137), 77 (96), 51 (27). dH (500.1 MHz, CDCl3): 1.59 (1H, s, OH),
In summary, we have discovered a novel, mild, and straight-
forward procedure for the synthesis of a new class of substituted
N-heterocyclic derivatives from the three-component reaction be-
tween nitroenamines, derived from the addition of various di-
amines to l,l-bis(methylthio)-2-nitroethen, and diaroylacetylene, in
aqueous media. Depending on the ring size of the cyclic nitroen-
amines, various new pyrrolo[1,2-a]imidazoles, pyrrolo[1,2-a]py-
rimidines, and pyrrolo[1,2-a][1,3]diazepines have been prepared.
Good yields of the products, the ready availability of the starting
materials and the reaction’s simplicity of the process recommend
this as a useful method.
3
2
3.04 (1H, q, JHH¼10.2 Hz, CH2), 3.79 (1H, td, JHH¼10.2 Hz,
2
3
3JHH¼4.7 Hz, CH2), 4.04 (1H, td, JHH¼10.2 Hz, JHH¼4.7 Hz, CH2),
3
4.18 (1H, q, JHH¼10.2 Hz, CH2), 7.28e7.35 (2H, m, 2CH of Ph), 7.39
(2H, t, 3J¼7.9 Hz, 2CH of Ph), 7.49 (2H, d, 3J¼7.1 Hz, 2CH of Ph), 7.54
(2H, d, 3J¼7.2 Hz, 2CH of Ph), 7.90 (2H, d, 3J¼7.9 Hz, 2CH of Ph), 8.06
(1H, s, C]CH), 8.37 (1H, s, NH). dC (125.7 MHz, CDCl3): 41.4
(CH2NH), 48.4 (CH2N), 91.3 (COH), 108.4 (C]CH), 110.1 (CeNO2),
125.3 (2CH of Ph), 128.4 (2CH of Ph), 128.5 (2CH of Ph), 128.6 (2CH
of Ph), 129.0 (CH of Ph), 132.9 (CH of Ph), 137.71 (CipsoeCOH), 138.6
(CipsoeCO), 159.0 (C]CH), 163.5 (NHCN), 191.8 (CO).
4. Experimental
4.1. General
4.2.2. 2-[5-Hydroxy-5-(4-methylphenyl)-7-nitro-2,3-dihydro-1H-
pyrrolo[1,2-a]imidazol-6(5H)-yliden]-1-(4-methylphenyl)-1-etha-
none (3b). Yellow powder, mp¼100e105 ꢁC (decomp.), 0.332 g,
yield: 85%. IR (KBr) (nmax, cmꢀ1): 3353 (OH), 3065 (NH),1650 (NC]C),
1602 (C]O), 1610, 1567 and 1515 (Ar), 1539 and 1389 (CeNO2), 1275
(CeN), 1176 (CeO). Anal. calcd for C22H21N3O4 (391.42): C, 67.51; H,
5.41; N,10.74%. Found: C, 67.48; H, 5.47; N,10.68%. MS (EI, 70 eV): m/z
(%)¼391 (Mþ, 4), 387 (27), 328 (41), 312 (73), 234 (59), 178 (63), 149
(58), 91 (74), 69 (100), 43 (93). dH (500.1 MHz, CDCl3): 1.59 (1H, s, OH),
2.28(3H, s, CH3), 2.37(3H, s, CH3), 3.05(1H, q, 3JHH¼10.1 Hz, CH2), 3.79
(1H, td, 2JHH¼10.2 Hz, 3JHH¼4.7 Hz, CH2), 4.04 (1H, td, 2JHH¼10.2 Hz,
The diamines, and l,l-bis(methylthio)-2-nitroethene were
obtained from Merck (Germany) and Fluka (Switzerland) and were
used without further purification. Diaroylacetylene was prepared
according to published procedures.26,27 Melting points were mea-
sured on an Electrothermal 9100 apparatus. Elemental analyses for
C, H, and N were performed using a Heraeus CHNeOeRapid
analyzer. Mass spectra were recorded on a FINNIGAN-MATT 8430
mass spectrometer operating at an ionization potential of 70 eV. 1H
and 13C NMR spectra were measured (CDCl3 solution) with a Bruker
DRX-500 AVANCE spectrometer at 500.13 and 125.8 MHz,
respectively. IR spectra were recorded on a Shimadzu IR-460
3
3JHH¼4.6 Hz, CH2), 3.79 (1H, q, JHH¼10.1 Hz, CH2), 7.11 (2H, d,
3JHH¼8.0 Hz, 2CH of Ar), 7.19 (2H, d, 3JHH¼8.1 Hz, 2CH of Ar), 7.39 (2H,
d,3JHH¼8.1 Hz,2CHofAr),7.82(2H,d,3JHH¼8.0 Hz,CHofAr), 8.04(1H,
s, C]CH), 8.42 (1H, s, NH). dC (125.7 MHz, CDCl3): 21.0 (CH3), 21.5
(CH3), 41.3 (CH2NH), 48.3 (CH2N), 91.4 (COH), 108.6 (C]CH), 110.8
(CeNO2),125.3 (2CH of Ar),128.9 (2CH of Ar),129.1 (2CH of Ar),129.1
(2CH of Ar), 134.8 (CipsoeCOH), 136.0 (CipsoeMe), 138.8 (CipsoeCO),
143.7 (CipsoeMe), 158.6 (C]CH), 163.4 (NHCN), 191.9 (CO).
spectrometer, absorbencies are reported in cmꢀ1
.
4.2. General synthesis procedure: (for example 5b)
A solution of l,l-bis(methylthio)-2-nitroethene (0.162 g, 1 mmol)
and 1,3-propanediamine (0.074 g, 1 mmol) in ethanol (5 mL) was
magnetically stirred for 4 h at reflux. Then a solution of 1,4-bis(4-
methylphenyl)-2-butyne-1,4-dione (0.26 g, 1 mmol) in ethanol
(3 mL) was added dropwise at rt and the mixture was stirred for
2 h. The solvent was removed under reduced pressure, and the
residue was purified by silica gel (Merck 230e240 mesh) column
chromatography using hexaneeEtOAc (5:1).
4.2.3. 2-[5-Hydroxy-2-methyl-7-nitro-5-phenyl-7-nitro-2,3-dihy-
dro-1H-pyrrolo[1,2-a]imidazol-6(5H)-yliden]-1-phenyl-1-ethanone
(3c). Yellow powder, mp¼110e114 ꢁC (decomp.), 0.347 g, yield:
92%. IR (KBr) (nmax, cmꢀ1): 3271 (OH), 3062 (NH),1657 (NC]C),1619
(C]O), 1595, 1576 and 1522 (Ph), 1545 and 1382 (CeNO2), 1266
(CeN), 1176 (CeO). Anal. calcd for C21H19N3O4 (377.40): C, 66.83; H,
5.07; N,11.13%. Found: C, 66.75; H, 5.11; N,11.17%. MS (EI, 70 eV): m/z
(%)¼377 (Mþ, 6), 344 (22), 297 (7), 234 (6),105 (31), 91 (24), 77 (31),
57 (35), 43 (100). dH (500.1 MHz, CDCl3): 1.59 (1H,s, OH),1.45 (3H, d,
3JHH¼6.1 Hz, CH3), 3.44e3.52 (1H, m, CH), 3.71 (1H, t, 3JHH¼10.4 Hz,
CH2), 4.08 (1H, t, 3JHH¼9.7 Hz, CH2), 7.26e7.53(10H, m, 10CH of Ph),
8.03 (1H, s, C]CH), 8.46 (1H, s, NH). dC (125.7 MHz, CDCl3): 18.8
(CH3), 48.0 (CH), 52.4 (CH2N), 92.2 (COH), 108.3 (C]CH), 111.5
(CeNO2), 125.3 (2CH of Ph), 128.4 (2CH of Ph), 128.5 (2CH of Ph),
4.2.1. 2-[5-Hydroxy-7-nitro-5-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]
imidazol-6(5H)-yliden]-1-phenyl-1-ethanone (3a). Yellow powder,
mp¼120e124 ꢁC (decomp.), 0.327 g, yield: 90%. IR (KBr) (nmax
,
cmꢀ1): 3345 (OH), 3048 (NH), 1649 (NC]C), 1623 (C]O), 1600,
1577 and 1525 (Ph), 1553 and 1394 (CeNO2), 1263 (CeN), 1171
(CeO). Anal. calcd for C20H17N3O4 (363.37): C, 66.11; H, 4.72; N,

9936
A. Alizadeh et al. / Tetrahedron 66 (2010) 9933e9937
128.6 (2CH of Ph), 128.9 (1CH of Ph), 132.7 (1CH of Ph), 137.4 (Cip-
soeCOH), 138.5 (CipsoeCO), 159.5 (C]CH), 163.5 (NHCN), 191.7 (CO).
at 295(2) K with a Bruker APEX area-detector diffractometer, and
employing /2
ꢀ12ꢃkꢃ12, ꢀ20ꢃlꢃ20; the structure was solved by a direct method,
all non-hydrogen atoms were positioned and anisotropic thermal
parameters refined from 2635 observed reflections with R (into)¼
0.0768 by a full-matrix least-squares technique converged to
u
q
scanning technique, in the range of ꢀ6ꢃhꢃ7,
4.2.4. 2-[5-Hydroxy-2-methyl-5-(4-methylphenyl)-7-nitro-2,3-dihy-
dro-1H-pyrrolo[1,2-a]imidazol-6(5H)-yliden]-1-(4-methylphenyl)-1-
ethanone (3d). Yellow powder, mp¼100e105 ꢁC (decomp.), 0.352 g,
yield: 87%. IR (KBr) (nmax, cmꢀ1): 3340 (OH), 3053 (NH),1653 (NC]C),
1604 (C]O),1590,1566 and 1520 (Ar), 1563 and 1348 (CeNO2),1285
(CeN), 1177 (CeO). Anal. calcd for C23H23N3O4 (405.45): C, 68.13; H,
5.72; N,10.36%. Found: C, 68.22; H, 5.59; N,10.34%. MS (EI, 70 eV): m/z
(%)¼405 (Mþ, 9), 387 (8), 359 (32), 286 (13), 257 (17), 178 (31), 149
(55), 119 (32), 69 (100), 57 (89), 43 (84). dH (500.1 MHz, CDCl3): 1.45
(3H, d, 3JHH¼6.1 Hz, CH3),1.53 (1H, s, OH), 2.29(3H, s, CH3), 2.36 (3H, s,
CH3), 3.47e3.52 (1H, m, CH), 3.70 (1H, t, 3JHH¼10.4 Hz, CH2), 4.06 (1H,
t, 3JHH¼9.7 Hz, CH2), 7.12 (2H, d, 3JHH¼8.2 Hz, 2CH of Ar), 7.18 (2H, d,
3JHH¼8.1 Hz, 2CH of Ar), 7.41 (2H, d, 3JHH¼7.9 Hz, 2CH of Ar), 7.81 (2H,
R¼0.0509 and Raw¼0.1524 [I>2
s(I)]. Complete crystallographic data
(excluding structural factors) have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
number CCDC 778304. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: þ44(0) 1223 336033 or e-mail: deposit@ccdc.com.ac.uk].
4.2.7. 2-[6-Hydroxy-3,3-dimethyl-8-nitro-6-phenyl-1,2,3,4,-tetrahy-
dropyrrolo[1,2-a]pyrimidin-7(6H)-yliden]-1-phenyl-1-ethanone
(5c). Yellow powder, mp¼220e225 ꢁC (decomp.), 0.364 g, yield:
90%. IR (KBr) (nmax, cmꢀ1): 3315 (OH), 3056 (NH),1667 (NC]C),1615
(C]O), 1600, 1577 and 1523 (Ph), 1553 and 1391 (CeNO2), 1288
(CeN),1177 (CeO). Anal. calcd for C23H23N3O4 (405.451): C, 68.13; H,
5.72; N,10.36%. Found: C, 68.17; H, 5.69; N,10.43%. MS (EI, 70 eV): m/
z (%)¼405 (Mþ, 6), 387 (8), 362 (67), 344 (65), 330 (24), 270 (18),161
(17), 91 (100), 57 (21), 43 (25). dH (500.1 MHz, CDCl3): 0.82 (3H, s,
CH3),1.09 (3H, s, CH3), 2.54 (1H, d, 3JHH¼12.3 Hz, CH2), 3.14 (2H, ABq,
3JHH¼12.4 Hz, CH2), 3.20 (1H, d, 3JHH¼12.3 Hz, CH2), 7.26e7.31 (2H,
m, 2CH of Ph), 7.37 (2H, t, 3J¼7.8 Hz, 2CH of Ph), 7.47 (2H, d, 3J¼7.5 Hz,
2CH of Ph), 7.52 (2H, d, 3J¼7.5 Hz, 2CH of Ph), 7.86 (2H, d, 3J¼7.8 Hz,
2CH of Ph), 8.15 (1H, s, C]CH), 8.40 (1H, s, NH), 8.87 (1H, s, OH). dC
(125.7 MHz, CDCl3): 24.0 (CH3), 24.3 (CH3), 27.6 (Me2C), 47.6
(CH2NH), 50.0 (CH2N), 92.9 (COH), 107.8 (C]CH), 111.7 (CeNO2),
125.7 (2CH of Ph),128.0 (2CH of Ph),128.3 (2CH of Ph),128.6 (2CH of
Ph), 128.8 (CH of Ph), 132.6 (CH of Ph), 138.5 (CipsoeCOH), 138.7
(CipsoeCO), 153.6 (C]CH), 154.9 (NHCN), 192.1 (CO).
3
d, JHH¼8.1 Hz, CH of Ar), 8.01 (1H, s, C]CH), 8.50 (1H, s, NH). dC
(125.7 MHz, CDCl3): 18.7 (CH3), 21.0 (CH3), 21.6 (CH3), 52.4 (CH), 55.6
(CH2N), 92.3 (COH), 108.0 (C]CH), 114.0 (CeNO2), 125.3 (2CH of Ar),
128.9 (2CH of Ar), 129.0 (2CH of Ar), 129.1 (2CH of Ar), 134.5 (Cip-
soeCOH), 136.0 (CipsoeMe), 138.8 (CipsoeCO), 143.6 (CipsoeMe), 159.1
(C]CH), 163.5 (NHCN), 191.2 (CO).
4.2.5. 2-[6-Hydroxy-8-nitro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrimidin-7(6H)-yliden]-1-phenyl-1-ethanone (5a). Yellow pow-
der, mp¼130e134 ꢁC (decomp.), 0.332 g, yield: 88%. IR (KBr) (nmax
,
cmꢀ1): 3301 (OH), 3085 (NH), 1665 (NC]C), 1615 (C]O), 1595, 1586
and 1521 (Ph),1565 and 1391 (CeNO2),1286 (CeN),1192 (CeO). Anal.
calcd for C21H19N3O4 (377.40): C, 66.83; H, 5.07; N, 11.13%. Found: C,
66.76; H, 5.00; N, 11.15%. MS (EI, 70 eV): m/z (%)¼377 (Mþ, 37), 331
(100), 286 (9), 256 (21), 105 (69), 91 (9), 77 (57), 57 (17), 43 (14). dH
(500.1 MHz, CDCl3): 1.87e1.90 (1H, m, CH2), 2.06e2.09 (1H, m, CH2),
2.81e2.86 (1H, m, CH2), 3.43e3.45 (1H, m, CH2), 3.53e3.56 (2H, m,
CH2), 7.24e7.31 (2H, m, 2CH of Ph), 7.36 (2H, t, 3J¼7.6 Hz, 2CH of Ph),
7.46 (2H, d, 3J¼7.5 Hz, 2CH of Ph), 7.51 (2H, d, 3J¼7.5 Hz, 2CH of Ph),
7.86 (2H, d, 3J¼7.6 Hz, 2CH of Ph), 8.14 (1H, s, C]CH), 8.51 (1H, s, NH),
8.93 (1H, s, OH). dC (125.7 MHz, CDCl3): 19.6 (CH2), 36.2 (CH2NH), 38.3
(CH2N), 93.1 (COH), 107.6 (C]CH), 111.8 (CeNO2), 125.6 (2CH of Ph),
128.1 (2CH of Ph), 128.3 (2CH of Ph), 128.6 (2CH of Ph), 128.9 (1CH of
Ph), 132.6 (1CH of Ph), 138.3 (CipsoeCOH), 138.68 (CipsoeCO), 154.4
(C]CH), 154.7 (NHCN), 192.2 (CO).
4.2.8. 2-[6-Hydroxy-3,3-dimethyl-6-(4-methylphenyl)-8-nitro-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrimidin-7(6H)-yliden]-1-(4-methylphenyl)-
1-ethanone (5d). Yellow powder, mp¼180e184 ꢁC (decomp.),
0.364 g, yield: 84%. IR (KBr) (nmax, cmꢀ1): 3296 (OH), 3028 (NH),1658
(NC]C), 1606 (C]O), 1594, 1579 and 1534 (Ph), 1563 and 1344
(CeNO2), 1276 (CeN), 1176 (CeO). Anal. calcd for C25H27N3O4
(433.50): C, 69.27; H, 6.28; N, 9.69%. Found: C, 69.33; H, 6.21; N,
9.62%. MS (EI, 70 eV): m/z (%)¼433 (Mþ, 9), 387 (28), 293 (9), 236 (5),
119 (27), 99 (17), 85 (46), 71 (67), 57 (100), 43 (66). dH (500.1 MHz,
CDCl3): 0.82 (3H, s, CH3), 1.08 (3H, s, CH3), 2.26 (3H, s, CH3), 2.35 (3H,
4.2.6. 2-[6-Hydroxy-6-(4-methylphenyl)-8-nitro-1,2,3,4-tetrahy-
dropyrrolo[1,2-a]pyrimidin-7(6H)-yliden]-1-(4-methylphenyl)-1-
ethanone (5b). Yellow powder, mp¼120e124 ꢁC (decomp.), 0.385 g,
yield: 90%. IR (KBr) (nmax, cmꢀ1): 3338 (OH), 3040 (NH),1653 (NC]C),
1603 (C]O), 1593,1575 and 1519 (Ph), 1561 and 1383 (CeNO2),1285
(CeN), 1178 (CeO). Anal. calcd for C23H23N3O4 (405.45): C, 68.13; H,
5.72; N,10.36%. Found: C, 68.02; H, 5.74; N,10.33%. MS (EI, 70 eV): m/z
(%)¼405 (Mþ, 28), 359 (83), 286 (6), 270 (17),194 (6),149 (8),119 (53),
84 (89), 69 (18), 49 (100). dH (500.1 MHz, CDCl3): 1.87e1.90 (1H, m,
CH2), 2.05e2.09 (1H, m, CH2), 2.27 (3H, s, CH3), 2.36 (3H, s, CH3),
2.83e2.88 (1H, m, CH2), 3.42e3.46 (1H, m, CH2), 3.51e3.56 (2H, m,
CH2), 7.07 (2H, d, 3JHH¼8.05 Hz, 2CH of Ar), 7.17 (2H, d, 3JHH¼8.1 Hz,
3
s, CH3), 2.54 (1H, d, 3JHH¼12.7 Hz, CH2), 3.08 (1H, d, JHH¼13.30 Hz,
CH2), 3.18 (2H, d, 3JHH¼12.6 Hz, CH2), 7.07 (2H, d, 3JHH¼8.0 Hz, 2CH of
Ar), 7.16 (2H, d, 3JHH¼8.1 Hz, 2CH of Ar), 7.39 (2H, d, 3JHH¼8.1 Hz, 2CH
3
of Ar), 7.78 (2H, d, JHH¼8.0 Hz, CH of Ar), 8.14 (1H, s, C]CH), 8.45
(1H, s, NH), 8.89 (1H, s, OH). dC (125.7 MHz, CDCl3): 21.0 (CH3), 21.6
(CH3), 24.0 (CH3), 24.3 (CH3), 27.6 (Me2C), 47.6 (CH2NH), 50.0 (CH2N),
93.0 (COH), 108.0 (C]CH), 111.6 (CeNO2), 125.6 (2CH of Ar), 128.7
(2CH of Ar), 128.8 (2CH of Ar), 129.0 (2CH of Ar), 135.6 (CipsoeCOH),
136.1 (CipsoeMe), 138.6 (CipsoeCO), 143.5 (CipsoeMe), 153.5 (C]CH),
154.6 (NHCN), 191.7 (CO).
3
2CH of Ar), 7.38 (2H, d, JHH¼8.1 Hz, 2CH of Ar), 7.79 (2H, d,
4.2.9. 2-[7-Hydroxy-9-nitro-7-phenyl-2,3,4,5-tetrahydropyrrolo[1,2-
3JHH¼8.2 Hz, CH of Ar), 8.13 (1H, s, C]CH), 8.55 (1H, s, NH), 8.92 (1H,
s, OH). dC (125.7 MHz, CDCl3): 19.7 (CH2), 21.0 (CH3), 21.6 (CH3), 36.1
(CH2NH), 38.2 (CH2N), 93.1 (COH), 107.8 (C]CH), 112.2 (CeNO2),
125.5 (2CH of Ar),128.8 (2CH of Ar),128 (2CH of Ar),129.0 (2CH of Ar),
135.5 (CipsoeCOH), 136.1 (CipsoeMe), 138.6 (CipsoeCO), 143.5
(CipsoeMe), 154.3 (C]CH), 154.4 (NHCN), 191.8 (CO). Crystal data for
5b C23H23N3O4 (CCDC 778304): MW¼405.5, triclinic, space group
a][1,3]diazepin-8-(7H)-yliden]-1-phenyl-1-ethanone
(6a). Yellow
powder, mp¼200e205 ꢁC (decomp.), 0.352 g, yield: 90%. IR (KBr)
(
nmax, cmꢀ1): 3263 (OH), 3051 (NH), 1645 (NC]C), 1612 (C]O),
1604,1572 and 1515 (Ph), 1564 and 1360 (CeNO2), 1286 (CeN),1197
(CeO). Anal. calcd for C22H21N3O4 (391.42): C, 67.51; H, 5.41; N,
10.74%. Found: C, 67.36; H, 5.44; N, 10.62%. MS (EI, 70 eV): m/z (%)¼
391 (Mþ, 55), 345 (100), 286 (23), 268 (35), 119 (22), 105 (99), 91
(16), 77 (30), 55 (24), 41 (9). dH (500.1 MHz, CDCl3): 1.62e1.72 (1H,
m, CH2), 1.82e1.94 (2H, m, CH2), 1.98e2.o9 (1H, m, CH2), 3.11e3.15
(1H, m, CH2), 3.58e3.65 (3H, m, CH2), 7.27e7.31 (2H, m, 2CH of Ph),
7.36 (2H, t, 3J¼7.7 Hz, 2CH of Ph), 7.47 (2H, d, 3J¼7.7 Hz, 2CH of Ph),
ꢀ
ꢀ
ꢀ
a
Pꢀ1, a¼5.9788(4) A, b¼10.8688(7) A, c¼17.1068(12) A, ¼77.991(1)
3
ꢀ
b
¼88.607(1),
g
¼78.278(1), V¼1064.57(12) A, Z¼2, Dc¼1.265 mg/
m3, F (000)¼273, crystal dimension 0.12ꢂ0.20ꢂ0.48 mm, radiation,
ꢀ
Mo K
a
(l
¼0.71073 A), 1.96ꢃ2
q
ꢃ25.20, intensity data were collected

A. Alizadeh et al. / Tetrahedron 66 (2010) 9933e9937
9937
7.52 (2H, d, 3J¼7.3 Hz, 2CH of Ph), 7.84 (2H, d, 3J¼7.3 Hz, 2CH of Ph),
References and notes
8.13 (1H, s, C]CH), 8.71 (1H, s, NH), 9.98 (1H, s, OH). dC (125.7 MHz,
CDCl3): 26.0 (CH2), 27.0 (CH2), 43.0 (CH2NH), 44.2 (CH2N), 93.6
(COH), 107.7 (C]CH), 111.5 (CeNO2), 125.8 (2CH of Ph), 128.0 (2CH
of Ph), 128.3 (2CH of Ph), 128.6 (2CH of Ph), 128.8 (CH of Ph), 132.6
(CH of Ph), 138.7 (CipsoeCOH), 138.9 (CipsoeCO), 154.7 (C]CH), 160.0
(NHCN), 192.3 (CO).
1. (a) Hansch, C.; Sammes, P. G.; Taylor, J. B. Comprehensive Medicinal Chemistry;
Pergamon: Oxford, 1990; Vol. 2, Chapter 7.1; (b) Erlanson, D. A.; Mc Dowell, R. S.;
O’Brien, T. J. Med. Chem. 2004, 47, 3463.
2. Butler, M. S. J. Nat. Prod. 2004, 67, 2141.
3. Padwa, A. Prog. Heterocycl. Chem. 1994, 6, 36.
4. (a) Ksander, G.M.; Meredith, E.; Monovich, L.H.; Papillon, J.; Firooznia, F.; Hu, Q.
WO 024945, 2007. (b) Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E. J. Med.
Chem. 1991, 34, 725.
5. Lambardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17, 1182.
6. Varaprasad, C. V. N. S.; Ramasamy, S. K.; Girardet, J. L.; Gunic, E.; Lai, V.; Zhong,
Z.; An, H.; Hong, Z. Bioorg. Chem. 2007, 35, 25.
7. Srikanth, K.; Debnath, B.; Jha, T. Bioorg. Med. Chem. Lett. 2002, 12, 899.
8. Moriarty, K. J.; Koblish, H. K.; Garrabrant, T.; Maisuria, J.; Khalil, E.; Ali, F.;
Petrounia, L. P.; Crysler, C. S.; Maroney, A. C.; Johnson, D. L.; Galemmo, R. A.
Bioorg. Med. Chem. Lett. 2006, 16, 5778.
9. Klump, S.; Frey, M.; Kleefeld, G.; Sauer, A.; Eger, K. Biochem. Pharmacol. 1989, 38,
949.
10. Wade, A. E.; Krawczyk, S. H.; Townsend, B. L. Tetrahedron Lett. 1988, 29, 4073.
11. Edstrom, E. D.; Wei, Y. Tetrahedron Lett. 1994, 35, 8989.
12. Gupta, P. K.; Daunert, S.; Nassiri, M. R.; Wotring, L. L.; Drach, J. C.; Townsend, L.
B. J. Med. Chem. 1989, 32, 402.
4.2.10. 2-[7-Hydroxy-7-(4-methylphenyl)-9-nitro-2,3,4,5-tetrahy-
dropyrrolo[1,2-a][1,3]diazepin-8-(7H)-yliden]-1-(4-methylphenyl)-1-
ethanone (6b). Yellow powder, mp¼200e205 ꢁC (decomp.), 0.398 g,
yield: 95%. IR (KBr) (nmax, cmꢀ1): 3335 (OH), 3052 (NH),1648 (NC]C),
1602 (C]O), 1600, 1564 and 1515 (Ph), 1558 and 1381 (CeNO2),1286
(CeN), 1179 (CeO). Anal. calcd for C24H25N3O4 (419.48): C, 68.72; H,
6.01; N,10.02%. Found: C, 68.53; H, 5.99; N,10.08%. MS (EI, 70 eV): m/z
(%)¼419 (Mþ, 22), 387 (28), 373 (39), 310 (46), 236 (29), 91 (71), 57
(96), 43 (100). dH (500.1 MHz, CDCl3): 1.63e1.72 (1H, m, CH2),
1.85e1.94 (2H, m, CH2), 2.01e2.07 (1H, m, CH2), 2.26 (3H, s, CH3), 2.35
(3H, s, CH3), 3.10e3.14 (1H, m, CH2), 3.56e3.62 (3H, m, CH2), 7.06 (2H,
d, 3JHH¼7.7 Hz, 2CH of Ar), 7.16 (2H, d, 3JHH¼7.7 Hz, 2CH of Ar), 7.39
(2H, d, 3JHH¼7.8 Hz, 2CH of Ar), 7.77 (2H, d, 3JHH¼7.8 Hz, CH of Ar), 8.12
(1H, s,C]CH), 8.75(1H, s,NH),9.98(1H, s,OH).dC (125.7 MHz,CDCl3):
21.0 (CH3), 21.56 (CH3), 26.0 (CH2), 27.0 (CH2), 43.0 (CH2NH), 44.1
(CH2N), 93.6 (COH), 107.8 (C]CH), 112.9 (CeNO2), 125.7 (2CH of Ar),
128.7 (2CH of Ar), 128.8 (2CH of Ar), 129.0 (2CH of Ar), 136.0 (Cip-
soeCOH), 136.1 (CipsoeMe), 138.5 (CipsoeCO), 143.5 (CipsoeMe), 154.5
(C]CH), 159.8 (NHCN), 191.9 (CO). Crystal data for 6b C24H25N3O4
(CCDC 778303): MW¼419.44, triclinic, space group Pꢀ1, a¼6.4600
13. Gupta, P. K.; Nassiri, M. R.; Coleman, L. A.; Wotring, L. L.; Drach, J. C.; Townsend,
L. B. J. Med. Chem. 1989, 32, 1420.
14. (a) Schutz, H. Benzodiazepines; Springer: Heidelberg, 1982; (b) Smalley, R. K. In
Comprehensive Organic Chemistry; Barton, D., Ollis, W. D., Eds.; Pergamon:
Oxford, 1979; Vol. 4, p 600; (c) Landquist, J. K. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 1,
p 166; (d) De Baun, J.R.; Pallos, F.M.; Baker, D.R. U.S. Patent 3,978,227, 1976;
Chem. Abstr. 1977, 86, 5498d; (e) Archer, G. A.; Sternbach, L. H. Chem. Rev. 1968,
68, 747.
15. (a) Zellou, A.; Cherrah, Y.; Hassar, M.; Essassi, E.-M. Ann. Pharm. Fr. 1998, 56, 169;
(b) Savelli, F.; Boido, A.; Mule, A.; Piu, L.; Alamanni, M. C.; Pirisino, G.; Satta, M.;
Peana, A. Farmaco 1989, 44, 125; (c) Srivastava, V. K.; Satsangi, R. K.; Kishore, K.
Arzneim. Forsch. 1982, 32, 1512; (d) Parker, K. A.; Dermatakis, A. J. Org. Chem.
1997, 62, 4164; (e) Failli, A. A.; Shumsky, J. S.; Steffan, R. J.; Caggiano, T. J.;
Williams, D. K.; Trybulski, E. J.; Ning, X.; Lock, Y.; Tanikella, T.; Hartmann, D.;
Chan, P. S.; Park, C. H. Bioorg. Med. Chem. Lett. 2006, 16, 954; (f) Hadac, E. M.;
Dawson, E. S.; Darrow, J. W.; Sugg, E. E.; Lybrand, T. P.; Miller, L. J. J. Med. Chem.
2006, 49, 850.
ꢀ
ꢀ
ꢀ
a
(3) A, b¼10.4517(4) A, c¼15.7074(7) A,
¼90.0550(10),
¼90.9930(10), V¼1056.06(8) A , Z¼2, Dc¼1.306 mg/m , F
(000)¼436, crystal dimension 0.28ꢂ0.23ꢂ0.15 mm, radiation, Mo K
b
¼95.1650
3
ꢀ
3
(10),
g
a
ꢀ
(l
¼0.71073 A), 1.30ꢃ2
(2) K with a Bruker APEX area-detector diffractometer, and employ-
ing /2
q
ꢃ25.20, intensity data were collected at 295
16. Tehrani, K. A.; D’hooghe, M.; De Kimpe, N. Tetrahedron 2003, 59, 3099.
17. Kagabu, S.; Moriya, K.; Shibuya, K.; Hattori, Y.; Tsuboi, S.; Shiokawa, K. Biosci.
Biotechnol. Biochem. 1992, 56, 362.
u
q
scanning technique, in the range of ꢀ7ꢃhꢃ7, ꢀ12ꢃkꢃ12,
18. Rajappa, S. Tetrahedron 1999, 55, 7065.
ꢀ18ꢃlꢃ18; the structure was solved by a direct method, all non-hy-
drogen atoms were positioned and anisotropic thermal parameters
refined from 3055observedreflectionswithR (into)¼0.0705bya full-
matrix least-squares technique converged to R¼0.0574 and
19. Komoto, I.; Seko, S. J. Chem. Soc., Perkin Trans. 1 1998, 2957.
20. Nazarenko, K. G.; Shvidenko, K. V.; Pinchuk, A. M.; Tolmachev, A. A. Monatsh.
Chem. 2005, 136, 211.
21. Aoki, I.; Tabuchi, T.; Minamida, I. U.S. Patent 5,122,527, 1992.
22. (a) Rajappa, S. Tetrahedron 1981, 37, 1453; (b) Efremov, D. A.; Perekalin, V. V.;
Lipina, E. S.; Berestovitskaya, V. M. Nitroalkenes; John Wiley: New York, NY,
1994.
23. Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.; Efremov, D. Nitroalkenes,
Conjugated Nitro Compounds; Wiley: New York, NY, 1994; p 210.
24. Nishiwaki, N.; Mizukawa, Y.; Terai, R.; Tohda, Y.; Ariga, M. ARKIVOC 2000, 1, 115.
25. (a) Alizadeh, A.; Rezvanian, A.; Zhu, L. G. Tetrahedron 2010, 66, 6924; (b) Ali-
zadeh, A.; Rezvanian, A.; Zhu, L. G. Tetrahedron 2008, 64, 351; (c) Alizadeh, A.;
Rezvanian, A. Synthesis 2008, 11, 1747; (d) Alizadeh, A.; Rezvanian, A.; Bi-
janzadeh, H. R. Synthesis 2008, 5, 725; (e) Alizadeh, A.; Babaki, M.; Zohreh, N.;
Rezvanian, A. Synthesis 2008, 23, 3793; (f) Alizadeh, A.; Rezvanian, A.; Zhu, L. G.
Helv. Chim. Acta 2007, 90, 2414.
Raw¼0.1648 [I>2
s(I)]. Complete crystallographic data (excluding
structural factors) have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication number CCDC
778303. Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: þ44(0)
1223 336033 or e-mail: deposit@ccdc.com.ac.uk].
Supplementary data
26. Skattebol, L.; Jones, E. R. H.; Whiting, M. C. Organic Syntheses Collective, IV;
Wiley: New York, NY, 1963; p 792.
27. Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. J. Chem. Soc. 1946, 39.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.10.052.