Synthesis of polyfunctionalized 1,4-dihydropyridine-fused-1,3- diazaheterocycles: One-pot reaction of 1,1-bis(methylthio)-2-nitroethylene, 1,n-diamine, arylaldehyde, and malononitrile

Article abstract of DOI:10.1002/jhet.1028

An efficient, one-pot synthetic protocol for polyfunctionalized 1,4-dihydropyridine-fused-1,3-diazaheterocycles, a class of biologically active compounds, starting from 1,1-bis(methylthio)-2-nitroethylene, 1,n-diamine, arylaldehyde, and malononitrile is described. The reactions are completed within 12-15 h under refluxing conditions and in the presence of 10 mol % of piperidine as a basic catalyst to produce the title compounds in 60-75% yields.

Full text of DOI:10.1002/jhet.1028

Month 2013
Synthesis of Polyfunctionalized 1,4-Dihydropyridine-Fused-1,3-
Diazaheterocycles: One-Pot Reaction of 1,1-Bis(methylthio)-2-
nitroethylene, 1,n-Diamine, Arylaldehyde, and Malononitrile
*
Abdolali Alizadeh, Tahereh Firuzyar, and Azadeh Mikaeili
Department of Chemistry, Tarbiat Modares University, Tehran, Iran
*
E-mail: abdol_alizad@yahoo.com, aalizadeh@modares.ac.ir
Received April 11, 2011
DOI 10.1002/jhet.1028
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
An efficient, one-pot synthetic protocol for polyfunctionalized 1,4-dihydropyridine-fused-1,3-diazahe-
terocycles, a class of biologically active compounds, starting from 1,1-bis(methylthio)-2-nitroethylene,
1,n-diamine, arylaldehyde, and malononitrile is described. The reactions are completed within 12–15
h under refluxing conditions and in the presence of 10 mol % of piperidine as a basic catalyst to produce
the title compounds in 60–75% yields.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
aminals is their bisnucleophilicity via the α-carbon and
the secondary amino nitrogen toward biselectrophilic
reagents and this has been successfully and frequently
applied in the preparation of a wide range of fused-ring
polycyclic heterocycles. These fused heterocyclic frame-
works are frequently found in pharmacophores and play
important roles in the drug industry [6–8]. Considering
the above reports, the development of new and simple
synthetic methods for the efficient preparation of the
1,4-dihydropyridine-fused-1,3-diazaheterocycles will be
a beneficial and interesting challenge.
Six-membered nitrogen-containing heterocycles, such as
pyridines, quinoline, and isoquinoline, are important
constituents that often exist in biologically active natural
products and synthetic compounds of medicinal interest.
Among them, 1,4-dihydropyridines (1,4-DHPs) have
received much attention because of their wide range of
pharmaceutical and biological properties such as bron-
chodilator, antiviral, antibacterial, antihypertensive, and
anticancer effects [1]. They serve as key intermediates in
biogenesis of indol alkaloids [2]. 1,4-Dihydropyridine-
containing drugs, such as nifedipine 1, nicardipine 2, and
others have been found to be useful as calcium channel
blockers, and are used most frequently as cardiovascular
agents for the treatment of hypertension (Fig. 1) [3]. The
classical synthesis of a 1,4-dihydropyridine (1,4-DHP) is
a three-component condensation reaction of aldehyde,
alkylacetoacetate, and ammonia under acidic condition or
in refluxing alcohol that was reported by Hantzsch. This
method suffers from disadvantages, such as high tempera-
tures, long reaction times, harsh reaction conditions, and
incomplete conversion of reactants [4]. Thus, the develop-
ment of new and simple synthetic methods for the prepara-
tion of 1,4-dihydropyridine derivatives has become an
interesting challenge.
RESULTS AND DISCUSSION
As a part of our ongoing investigations aimed at expand-
ing libraries of the aforementioned bioactive compounds
[9] and in continuing of our previous research on the
one-pot synthesis of spirooxindole derivatives containing
1,4-dihydropyridine-fused-1,3-diazaheterocycle fragments
[10], we described here a four-component reaction of 1,1-
bis(methylthio)-2-nitroethylene, 1,n-diamine 3, arylaldehyde
4, and malononitrile in ethanol as solvent and in the presence
of 10 mol% piperidine as a basic catalyst under reflux to afford
a series of 1,4-dihydropyridine-fused-1,3-diazaheterocycle
derivatives in 60–75% yields (Table 1).
Heterocyclic ketene aminals (HKAs) have been signifi-
cantly used as powerful and versatile synthons for the
construction of a wide variety of heterocycles [5]. One of
the most conspicuous features of heterocyclic ketene
Compounds 5a–j are stable solids and their structures
1
were elucidated from their mass, IR and high field H
and 13C-NMR spectra as described for 5a. The IR spec-
trum of 5a showed absorption bands due to the NH2 and
© 2013 HeteroCorporation

A. Alizadeh, T. Firuzyar, and A. Mikaeili
Vol 000
Scheme 1. Plausible mechanism for the formation of compound 5.
Figure 1. 1,4-Dihydropyridine-containing drugs.
Table 1
The reaction of 1,1‐bis(methylthio)‐2‐nitroethylene, 1,n‐diamine 3,
arylaldehyde 4, and malononitrile in EtOH under reflux conditions.
nitroethylene and 1,n-diamine 3 produces heterocyclic
ketene aminal 6 that is effective aza-ene component. In
the next step the addition of arylaldehyde 4, malononitrile,
and piperidine as a basic catalyst to the reaction pot lead to
the formation of arylidenemalononitrile 7, which in situ is
formed from Knoevenagel condensation of malononitrile
and arylaldehyde 4. The aza-ene reaction between hetero-
cyclic ketene aminal 6 and arylidenemalononitrile 7 gives
the intermediate 8, which undergoes successive imine-
enamine tautomerization, followed by nucleophilic addi-
tion of the secondary amino group to the cyano group,
resulting in the formation of intermediate 9. Finally 1,3-H
migration or imine-enamine tautomerization gives the title
compound 5.
Yield
(%)
Product
3
Ar
5a
5b
5c
5d
5e
5f
1,2‐Ethanediamine
1,2‐Ethanediamine
1,2‐Ethanediamine
1,3‐Propanediamine
1,3‐Propanediamine
1,4‐Butanediamine
1,4‐Butanediamine
2,2‐Dimethyl‐1,3‐
propanediamine
2,2‐Dimethyl‐1,3‐
propanediamine
2,2‐Dimethyl‐1,3‐
propanediamine
C6H5
4‐ClC6H4
4‐O2NC6H4
C6H5
4‐ClC6H4
C6H5
75
68
70
71
68
73
60
70
5g
5h
4‐O2NC6H4
C6H5
5i
5j
4‐ClC6H4
65
68
4‐O2NC6H4
CONCLUSION
In summary, we have reported a one-pot method for the
construction of 1,4-dihydropyridine-fused-1,3-diazahetero-
cycle derivatives from simple and commercially available
starting material under mild condition. The advantages of
the present procedure are simplicity of the operation. In
addition, workup and purification of products are simple.
Furthermore, the number of functional groups that exist
in these types of heterocycles lead to the biological activi-
ties of the title compounds.
NH groups at 3446, 3352, and 3219 cm−1. Stretching
frequencies related to CN, and C═C functional groups
appeared at 2186, and 1650 cm−1, respectively. Three
sharp singlet signals recognized as arising from a CH
group (δ = 4.59), NH2 group (δ = 6.47), and NH group
1
(δ = 9.48) appeared in the H-NMR spectrum of 5a. The
phenyl moiety gave rise to characteristic signals in the
1
aromatic region of the spectrum. H-decoupled 13C-NMR
spectrum of 5a showed 12 distinct signals in agreement
with the proposed structures. Resonances due to C-CN,
C-NO2, CN, and Cipso-CH, appearing at δ = 59.27,
105.67, 120.86, and 144.95 ppm, respectively. However,
no molecular ion peak was exhibited in the mass spectrum
of 5a but two fragmentations that related to C6H5 and
C8H9N5O2 molecular formulas appeared at m/z 77 and 206.
A plausible reaction mechanism is suggested in the
Scheme 1. At first, the reaction of 1,1-bis(methylthio)-2-
EXPERIMENTAL
All chemicals were purchased from Merck or Aldrich and were
used without further purification. Melting points measured on an
Electrothermal 9100 apparatus. IR spectra were recorded as
1
KBr pellets on FT-IR spectrometer. H-NMR (500.13 MHz) and
13C-NMR (125.75 MHz) spectra were obtained using a Bruker
DRX-500 AVANCE spectrometer. All NMR spectra were
determined in DMSO-d6. Chemical shifts are reported in parts per
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of Polyfunctionalized 1,4-Dihydropyridine-Fused-1,3-Diazaheterocycles
million (δ) downfield from an internal tetramethylsilane reference.
Coupling constants (J values) are reported in hertz (Hz), and spin
multiplicities are indicated by the following symbols: s (singlet),
d (doublet), t (triplet), m (multiplet). Mass spectra were recorded
on a FINNIGAN-MATT 8430 mass spectrometer operating at an
ionization potential of 20 or 70 eV.
179 (16), 165 (18), 152 (22), 140 (14), 127 (14), 69 (21), 57 (14).
Anal. Calcd for C14H12N6O4 (328.28): C, 51.22; H, 3.68; N,
25.60. Found: C, 51.34; H, 3.70; N, 25.55.
6-Amino-9-nitro-8-phenyl-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]
pyrimidine-7-carbonitrile (5d). Yield: 0.21 g (71%); yellow
crystals; mp = 247 °C (dec). IR (KBr): 3337 and 3229 (NH2 and
NH), 2181 (CN), 1647 (C═C), 1454 and 1425 (CH2), 1337
(NO2) cm−1. 1H-NMR (500.13 MHz, DMSO-d6): δH = 1.83–
1.95 (1 H, m, NCH2CH2CH2NH), 2.10–2.34 (1 H, m,
NCH2CH2CH2NH), 3.32–3.36 (1 H, m, NCH2CH2CH2NH),
3.45–3.59 (1 H, m, NCH2CH2CH2NH), 3.73–3.80 (2 H, m,
NCH2CH2CH2NH), 4.66 (1 H, s, CH), 6.39 (2 H, s, NH2), 7.13
General procedure for the synthesis of 5-amino-8-nitro-7-
phenyl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile
(5a). To a magnetically stirred solution of 1,1-bis(methylthio)-2-
nitroethylene (0.16 g, 1 mmol) in EtOH (3 mL), 1,2-ethanediamine
(0.06 g, 1 mmol) was added. The reaction mixture was then stirred
for 7 h. After that, benzaldehyde (0.10 g, 1 mmol), malononitrile
(0.06 g, 1 mmol), and piperidine (10 mol %) were added
simultaneously. The reaction mixture was stirred for 7 h under
refluxing condition and the progress of the reaction was followed
by thin layer chromatography. After completion, the reaction
mixture was filtered and the precipitate was washed with cool
EtOH (4 mL) and CH2Cl2 (5 mL) to afford the pure product 5a
(0.21 g, 75%), as yellow powder; mp = 180°C. IR (KBr): 3446,
3352, and 3219 (NH2 and NH), 2186 (CN), 1650 (C═C), 1468
(CH2), 1360 (NO2) cm−1. 1H-NMR (500.13 MHz, DMSO-d6):
δH = 3.78–3.82 (2 H, m, CH2NH), 3.94–4.04 (2 H, m, CH2N),
4.59 (1 H, s, CH), 6.47 (2 H, s, NH2), 7.15–7.18 (3 H, m, Ph),
7.24–7.27 (2 H, m, Ph), 9.48 (1 H, s, NH). 13C-NMR (125.75
MHz, DMSO-d6): δC = 40.78 (CH), 43.23 (CH2), 44.62 (CH2),
59.27 (C-CN), 105.67 (C-NO2), 120.86 (CN), 126.37 (CHpara
of Ph), 126.89 (2 CHmeta of Ph), 128.06 (2 CHortho of Ph), 144.95
(Cipso-CH), 149.31 (NH2CN), 151.60 (NCNH). MS: m/z (%) =
275 (2), 261 (3), 248 (32), 234 (100), 219 (23), 206 (15), 175 (6),
158 (4), 114 (9), 103 (4), 77 (9). Anal. Calcd for C14H13N5O2
(283.29): C, 59.36; H, 4.63; N, 24.72. Found: C, 59.47; H, 4.65;
N, 24.33.
3
3
(2 H, d, JH,H = 7.5 Hz, Ph), 7.18 (1 H, t, JH,H = 7.2 Hz,
3
Ph), 7.26 (2 H, t, JH,H = 7.5 Hz, Ph), 11.50 (1 H, s, NH).
13C-NMR (125.75 MHz, DMSO-d6): δC
= 19.66 (CH),
38.37 (NCH2CH2CH2NH), 40.09 (NCH2CH2CH2NH), 43.02
(NCH2CH2CH2NH), 61.19 (C-CN), 107.88 (C-NO2), 120.72
(CN), 124.20 (CHpara of Ph), 126.51 (2 CHmeta of Ph), 128.29
(2 CHortho of Ph), 144.19 (Cipso-CH), 150.40 (NH2CN), 150.81
(NCNH). MS: m/z (%) = 297 (M+, 13), 279 (6), 264 (8), 251
(100), 236 (7), 220 (37), 207 (5), 194 (18), 174 (10), 164 (4), 154
(8), 140 (21), 128 (17), 118 (9), 93 (24), 77 (27), 69 (14), 57 (16).
Anal. Calcd for C15H15N5O2 (297.31): C, 60.60; H, 5.09; N,
23.56. Found: C, 60.75; H, 5.12; N, 23.60.
6-Amino-8-(4-chlorophenyl)-9-nitro-1,3,4,8-tetrahydro-2H-
pyrido[1,2-a]pyrimidine-7-carbonitrile (5e). Yield: 0.21 g (68%);
yellow crystals; mp = 267°C (dec). IR (KBr): 3386, 3344, and 3227
(NH2 and NH), 2187 (CN), 1661 and 1630 (C═C), 1488 and 1428
(CH2), 1350 (NO2) cm−1. 1H-NMR (500.13 MHz, DMSO-d6): δH =
2.10–2.49 (2 H, m, NCH2CH2CH2NH), 3.30–3.35 (2 H, m,
NCH2CH2CH2NH), 3.73–3.78 (2 H, m, NCH2CH2CH2NH),
3
4.68 (1 H, s, CH), 6.41 (2 H, s, NH2), 7.17 (2 H, d, JH,H
=
3
5-Amino-7-(4-chlorophenyl)-8-nitro-1,2,3,7-tetrahydroimidazo
[1,2-a]pyridine-6-carbonitrile (5b). Yield: 0.21 g (68%); yellow
crystals; mp = 270°C (dec). IR (KBr): 3400, 3342, and 3218
(NH2 and NH), 2176 (CN), 1660 (C═C), 1467 (CH2), 1372
6.7 Hz, Ar), 7.31 (2 H, d, JH,H = 6.7 Hz, Ar), 11.50 (1 H, s,
NH). 13C-NMR (125.75 MHz, DMSO-d6): δC = 19.57 (CH),
38.37 (NCH2CH2CH2NH), 38.84 (NCH2CH2CH2NH), 43.04
(NCH2CH2CH2NH), 60.67 (C-CN), 107.63 (C-NO2), 120.55
(CN), 128.21 (2 CH of Ar), 128.48 (2 CH of Ar), 131.06
(Cipso-Cl), 143.14 (Cipso-CH), 150.30 (NCNH), 150.92 (NH2CN).
MS: m/z (%) = 299 (5), 279 (3), 267 (5), 248 (14), 220 (10),
176 (6), 167 (9), 149 (18), 125 (25), 111 (27), 97 (43), 83 (45),
69 (69), 57 (100). Anal. Calcd for C15H14ClN5O2 (331.76):
C, 54.31; H, 4.25; N, 21.11. Found: C, 54.35; H, 4.33; N, 21.15.
7-Amino-10-nitro-9-phenyl-1,2,3,4,5,9-hexahydropyrido[1,2-a]
[1,3]diazepine-8-carbonitrile (5f). Yield: 0.23 g (73%); yellow
crystals; mp = 275°C (dec). IR (KBr): 3455 and 3364 (NH2 and
NH), 2183 (CN), 1650 and 1603 (C═C), 1450 and 1418 (CH2),
1
(NO2) cm−1. H-NMR (500.13 MHz, DMSO-d6): δH = 3.80–3.83
(2 H, m, CH2NH), 3.99–4.00 (2 H, m, CH2N), 4.61 (1 H, s,
3
CH), 6.51 (2 H, s, NH2), 7.20 (2 H, d, JH,H = 7.6 Hz, 2 CH of
3
Ar), 7.31 (2 H, d, JH,H = 7.6 Hz, 2 CH of Ar), 9.39 (1 H, s,
NH). 13C NMR (125.75 MHz, DMSO-d6): δC = 40.36 (CH),
43.26 (CH2), 44.63 (CH2), 58.67 (C-CN), 105.37 (C-NO2),
120.77 (CN), 128.00 (2 CH of Ar), 128.87 (2 CH of Ar),
130.87 (Cipso-Cl), 143.96 (Cipso-CH), 149.35 (NCNH), 151.47
(NH2CN). MS: m/z (%) = 296 (8), 282 (8), 248 (12), 234 (12),
219 (7), 194 (4), 149 (10), 137 (10), 123 (14), 109 (15), 97 (38), 81
(45), 69 (100), 57 (70). Anal. Calcd for C14H12ClN5O2 (317.73): C,
52.92; H, 3.81; N, 22.04. Found: C, 52.85; H, 3.72; N, 22.10.
5-Amino-8-nitro-7-(4-nitrophenyl)-1,2,3,7-tetrahydroimidazo
[1,2-a]pyridine-6-carbonitrile (5c). Yield: 0.23 g (70%); yellow
crystals; mp = 244°C (dec). IR (KBr): 3425, 3336, and 3237
(NH2 and NH), 2182 (CN), 1661 (C═C), 1513 and 1349 (NO2),
1352 (NO2) cm−1. 1H-NMR (500.13 MHz, DMSO-d6): δH
=
1.48–1.50 (1 H, m, CH2), 1.77–1.79 (2 H, m, CH2), 1.94–2.00
(1 H, m, CH2), 3.25–3.26 (2 H, m, CH2), 3.76–3.80 (1 H, m,
CH2), 4.01–4.08 (1 H, m, CH2), 4.77 (1 H, s, CH), 6.37 (2 H,
3
s, NH2), 7.11 (2 H, d, JH,H = 7.4 Hz, 2 CH of Ph), 7.21 (1 H, t,
3
3JH,H = 7.2 Hz, CH of Ph), 7.29 (2 H, t, JH,H = 7.4 Hz, 2 CH
1465 (CH2) cm−1. 1H-NMR (500.13 MHz, DMSO-d6): δH
=
of Ph), 10.52 (1 H, s, NH). 13C-NMR (125.75 MHz, DMSO-d6):
δC = 25.08 (2 CH2), 26.35 (CH), 45.06 (CH2NH), 52.77 (CH2N),
64.69 (C-CN), 112.77 (C-NO2), 120.28 (CN), 126.20 (2 CHmeta
of Ph), 126.73 (CHpara of Ph), 128.60 (2 CHortho of Ph), 143.43
(Cipso-CH), 154.26 (NH2CN), 157.03 (NCNH). MS: m/z (%) =
313 (M++2, 7), 311 (M+, 5), 293 (6), 279 (5), 265 (53), 248 (23),
234 (22), 219 (17), 206 (9), 194 (8), 170 (7), 157 (53), 140 (14),
127 (20), 111 (21), 97 (37), 83 (44), 69 (59), 55 (100). Anal.
Calcd for C16H17N5O2 (311.34): C, 61.73; H, 5.50; N, 22.49.
Found: C, 61.78; H, 5.62; N, 22.52.
3.77–3.86 (2 H, m, CH2NH), 3.95–4.05 (2 H, m, CH2N), 4.76
3
(1 H, s, CH), 6.64 (2 H, s, NH2), 7.46 (2 H, d, JH,H = 8.4 Hz,
3
2 CH of Ar), 8.14 (2 H, d, JH,H = 8.4 Hz, 2 CH of Ar), 9.59
(1 H, s, NH). 13C-NMR (125.75 MHz, DMSO-d6): δC = 40.95
(CH), 43.39 (CH2), 44.69 (CH2), 57.81 (C-CN), 104.87 (C-NO2),
120.56 (CN), 123.48 (2 CH of Ar), 128.26 (2 CH of Ar),
146.18 (Cipso-NO2), 149.65 (NCNH), 151.52 (NH2CN), 152.64
(Cipso-CH). MS: m/z (%) = 328 (M+, 5), 326 (100), 310 (21), 296
(31), 281 (48), 263 (7), 248 (26), 234 (67), 221 (10), 206 (43),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Alizadeh, T. Firuzyar, and A. Mikaeili
Vol 000
7-Amino-10-nitro-9-(4-nitrophenyl)-1,2,3,4,5,9-hexahydropyrido
[1,2-a][1,3]diazepine-8-carbonitrile (5g). Yield: 0.21 g (60%);
yellow crystals; mp = 235°C (dec). IR (KBr): 3388, 3330, and
3217 (NH2 and NH), 2191 (CN), 1653 and 1624 (C═C), 1525
and 1335 (NO2), 1425 (CH2) cm−1. 1H-NMR (500.13 MHz,
DMSO-d6): δH = 1.50–1.53 (1 H, m, CH2), 1.79–1.81 (2 H,
m, CH2), 1.98–2.00 (1 H, m, CH2), 3.35–3.39 (2 H, m, CH2),
3.75–3.78 (1 H, m, CH2), 4.04–4.06 (1 H, m, CH2), 4.93 (1 H,
236 (9), 219 (7), 206 (3), 147 (10), 129 (12), 111 (20), 85 (25), 83
(100), 57 (53). Anal. Calcd for C17H18ClN5O2 (359.81): C, 56.75;
H, 5.04; N, 19.46. Found: C, 56.80; H, 5.00; N, 19.50.
6-Amino-3,3-dimethyl-9-nitro-8-(4-nitrophenyl)-1,3,4,8-
tetrahydro-2H-pyrido[1,2-a]pyrimidine-7-carbonitrile (5j).
Yield: 0.25 g (68%); yellow crystals; mp = 236°C (dec). IR
(KBr): 3342 and 3223 (NH2 and NH), 2186 (CN), 1658
3
and 1625 (C═C), 1517 and 1348 (NO2), 1426 (CH2) cm−1
.
s, CH), 6.49 (2 H, s, NH2), 7.40 (2 H, d, JH,H = 7.6 Hz, 2 CH
3
1H-NMR (500.13 MHz, DMSO-d6): δH = 0.99 (3 H, s, Me), 1.05
of Ar), 8.16 (2 H, d, JH,H = 7.6 Hz, 2 CH of Ar), 10.56 (1 H,
s, NH). 13C-NMR (125.75 MHz, DMSO-d6): δC = 24.94 (2 CH2),
26.24 (CH), 45.10 (CH2NH), 52.78 (CH2N), 62.81 (C-CN),
111.80 (C-NO2), 119.97 (CN), 123.99 (2 CH of Ar), 127.52
(2 CH of Ar), 146.37 (Cipso-NO2), 150.99 (NCNH), 154.68
(NH2CN), 157.00 (Cipso-CH). MS: m/z (%) = 340 (7), 310 (5),
285 (6), 265 (10), 248 (15), 219 (17), 199 (27), 169 (13), 146
(30), 126 (25), 104 (18), 84 (100), 57 (80). Anal. Calcd for
C16H16N6O4 (356.34): C, 53.93; H, 4.53; N, 23.58. Found: C,
53.97; H, 4.58; N, 23.66.
2
(3 H, s, Me), 3.25 (2 H, AB system, JH,H = 12.3 Hz, CH2NH),
2
3.51 (2 H, AB system, JH,H = 11.0 Hz, CH2N), 4.85 (1 H, s,
3
CH), 6.57 (2 H, s, NH2), 7.39 (2 H, d, JH,H = 5.9 Hz, 2 CH of
3
Ar), 8.16 (2 H, d, JH,H = 5.9 Hz, 2 CH of Ar), 11.47 (1 H, s,
NH). 13C-NMR (125.75 MHz, DMSO-d6): δC = 22.59 (CH3),
23.68 (CH3), 26.97 (CH), 38.20 (C3), 49.17 (CH2N), 53.07
(CH2NH), 59.58 (C-CN), 106.84 (C-NO2), 120.32 (CN), 123.75
(2 CH of Ar), 127.64 (2 CH of Ar), 146.28 (Cipso-NO2), 149.39
(NCNH), 151.29 (NH2CN), 151.70 (Cipso-CH). MS: m/z (%) =
368 (6), 321 (4), 278 (7), 264 (5), 247 (55), 236 (12), 219 (37),
206 (3), 194 (4), 175 (8), 148 (14), 139 (8), 128 (21), 111 (21), 97
(42), 83 (51), 69 (78), 55 (100). Anal. Calcd for C17H18N6O4
(370.36): C, 55.13; H, 4.90; N, 22.69. Found: C, 55.18; H, 4.92;
N, 22.72.
6-Amino-3,3-dimethyl-9-nitro-8-phenyl-1,3,4,8-tetrahydro-
2H-pyrido[1,2-a]pyrimidine-7-carbonitrile (5h). Yield: 0.23 g
(70%); yellow crystals; mp = 277°C (dec). IR (KBr): 3382, 3340,
and 3227 (NH2 and NH), 2187 (CN), 1661 and 1627 (C═C),
1502 and 1340 (NO2), 1422 (CH2) cm−1. 1H-NMR (500.13 MHz,
DMSO-d6): δH = 0.98 (3 H, s, Me), 1.06 (3 H, s, Me), 3.24 (2 H,
2
AB system, JH,H = 13.2 Hz, CH2NH), 3.49 (2 H, AB system,
2JH,H = 13.0 Hz, CH2N), 4.70 (1 H, s, CH), 6.41 (2 H, s, NH2),
REFERENCES AND NOTES
3
3
7.12 (2 H, d, JH,H = 7.1 Hz, 2 CH of Ph), 7.18 (1 H, t, JH,H
=
3
[1] Kappe, C. O. Tetrahedron 1993, 49, 6937.
7.3 Hz, CH of Ph), 7.27 (2 H, t, JH,H = 7.4 Hz, 2 CH of Ph),
11.47 (1 H, s, NH). 13C-NMR (125.75 MHz, DMSO-d6): δC
=
[2] (a) Godfraind, T.; Miller, R.; Wibo, M. Pharmacol Rev 1986,
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Zhong, R. G. J Org Chem 2009, 74, 6386; (b) Ram, V. J.; Goel, A.; Sarkhel,
S.; Maulik, P. R. Bioorg Med Chem 2002, 10, 1275.
22.38 (CH3), 23.78 (CH3), 27.02 (CH), 38.68 (C3), 49.12 (CH2N),
53.11 (CH2NH), 61.13 (C-CN), 107.67 (C-NO2), 120.67 (CN),
126.35 (2 CHortho of Ph), 126.60 (CHpara of Ph), 128.32 (2 CHmeta
of Ph), 144.10 (Cipso-CH), 149.52 (NCNH), 150.94 (NH2CN).
MS: m/z (%) =326 (M++1, 85), 325 (M+, 10), 310 (23), 294 (55),
279 (90), 263 (14), 248 (100), 234 (78), 219 (55), 206 (98), 194
(17), 178 (18), 164 (28), 151 (32), 139 (22), 127 (23), 114 (22),
69 (55), 55 (50). Anal. Calcd for C17H19N5O2 (325.37): C, 62.76;
H, 5.89; N, 21.52. Found: C, 62.85; H, 5.90; N, 21.60.
6-Amino-8-(4-chlorophenyl)-3,3-dimethyl-9-nitro-1,3,4,8-
tetrahydro-2H-pyrido[1,2-a]pyrimidine-7-carbonitrile (5i).
Yield: 0.23 g (65%); yellow crystals; mp = 270°C (dec). IR
(KBr): 3345 and 3230 (NH2 and NH), 2187 (CN), 1663 (C═C),
1440 (CH2), 1348 (NO2) cm−1. 1H-NMR (500.13 MHz,
DMSO-d6): δH = 0.97 (3 H, s, Me), 1.05 (3 H, s, Me), 3.23 (2 H,
[7] Jordan, A. D.; Vaidya, A. H.; Rosenthal, D. I.; Dubinsky, B.;
Kordik, C. P.; Sanfilippo, P. J.; Wub, W. N.; Reitza, A. B. Biomed Chem
Lett 2002, 12, 2381.
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Gupta, S. Eur J Med Chem 2007, 511; (b) Abdelhalima, M. M.; El-Saidib,
M. M. T.; Rabieb, S. T.; Elmegeedag, A. Steroids 2007, 72, 459.
[9] (a) Zohreh, N.; Alizadeh, A.; Bijanzadeh, H. R.; Zhu, L. G. J
Comb Chem 2010, 12, 497; (b) Alizadeh, A.; Rezvanian, A. Tetrahedron
2010, 66, 6924; (c) Rostamnia, S.; Alizadeh, A.; Zhu, L. G. J Comb Chem
2009, 11, 143; (d) Alizadeh, A.; Noaparast, Z.; Sabahnoo, H.; Zohreh, N.
Synlett 2010, 10, 1496; (e) Alizadeh, A.; Rostamnia, S.; Zhu, L. G.
Tetrahedron Lett 2010, 51, 4750; (f) Alizadeh, A.; Sabahnoo, H.;
Noaparast, Z.; Zohreh, N.; Mikaeili, A. Synlett 2010, 1854.
2
AB system, JH,H = 13.1 Hz, CH2NH), 3.49 (2 H, AB system,
2JH,H = 11.9 Hz, CH2N), 4.71 (1 H, s, CH), 6.47 (2 H, s, NH2),
3
3
7.14 (2 H, d, JH,H = 7.6 Hz, 2 CH of Ar), 7.34 (2 H, d, JH,H
=
7.6 Hz, 2 CH of Ar), 11.46 (1 H, s, NH). 13C-NMR (125.75
MHz, DMSO-d6): δC = 22.46 (CH3), 23.72 (CH3), 26.98 (CH),
38.67 (C3), 49.15 (CH2N), 53.07 (CH2NH), 60.53 (C-CN),
107.40 (C- NO2), 120.52 (CN), 128.27 (2 CH of Ar), 128.29
(2 CH of Ar), 131.14 (Cipso-Cl), 143.04 (NCNH), 149.41
(NH2CN), 151.06 (Cipso-CH). MS: m/z (%) = 313 (3), 248 (7),
[10] Alizadeh, A.; Firuzyar, T.; Mikaeili, A. Synthesis 2010, 3913.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet