Synthesis of 2-oxopyridine-fused 1,3-diazaheterocyclic compounds via a three-component reaction

Article abstract of DOI:10.1002/hlca.201000453

An efficient and simple route for the preparation of 2-oxopyridine-fused 1,3-diazaheterocyclic compounds via a three component reaction is described. It involves the reaction between alkylenediamines 1, 1,1-bis(methylsulfanyl)-2- nitroethene, and alkyl pr

Full text of DOI:10.1002/hlca.201000453

Helvetica Chimica Acta – Vol. 94 (2011)
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Synthesis of 2-Oxopyridine-Fused 1,3-Diazaheterocyclic Compounds via a
Three-Component Reaction
by Abdolali Alizadeh*, Azadeh Mikaeili, Tahereh Firuzyar, and Mahdi Ahmadi
Department of Chemistry, Tarbiat Modares University, P. O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: abdol_alizad@yahoo.com,
aalizadeh@Modares.ac.ir)
An efficient and simple route for the preparation of 2-oxopyridine-fused 1,3-diazaheterocyclic
compounds via a three component reaction is described. It involves the reaction between alkylenedi-
amines 1, 1,1-bis(methylsulfanyl)-2-nitroethene, and alkyl prop-2-ynoates 2 in refluxing THF (Table).
1
The structures were corroborated by spectroscopic (IR, H- and 13C-NMR, and EI-MS) and elemental
analyses. A plausible mechanism for this type of cyclization is proposed (Scheme).
Introduction. – The development of new and simple methods for the efficient
preparation of compounds containing 2-oxopyridine-fused 1,3-diazaheterocycle moi-
eties is a beneficial and interesting challenge [1 – 6]. As a part of our research program,
which is aimed at developing libraries of bioactive compounds, and in continuation of
our interest in one-pot and multicomponent reactions (MCRs), a three-component
reaction toward fused heterocycles is described herein.
Results and Discussion. – In this article, we report a simple method for the synthesis
of 2-oxopyridine-fused 1,3-diazaheterocycles via a three-component reaction of
alkylenediamines 1, 1,1-bis(methylsulfanyl)-2-nitroethene, and alkyl prop-2-ynoates 2
(cf. the Table). The reactions were performed under one-pot condition in refluxing
THF and led to compounds 3a – 3g in yields of 65 – 75%.
The structures of compounds 3a – 3g were deduced from their elemental analyses,
1
and IR, H- and 13C-NMR, and mass spectra. The mass spectrum of 3a displays the
molecular-ion peak at m/z 195, which is in agreement with the proposed structure. The
IR spectrum of 3a shows four stretching frequencies at 3216, 1673, and 1579 and
ꢀ1
~
~
1339 cm , which correspond to an NH group, the CO group of an amide, and nas and ns
1
of a NO2 group, respectively. The H-NMR spectra of 3a exhibited a singlet at d(H)
10.26 for NH, two triplets for CH2NH and CH2N (d(H) 3.63 (J ¼ 6.0) and 4.07 (J ¼
6.0)), one multiplet for CH2 (d(H) 2.15 – 2.19), and two doublets for a (Z)-configured
CH¼CH moiety (d(H) 5.90 (3J ¼ 10.1), and 8.16 (3J ¼ 10.1)). The 1H-decoupled
13C-NMR spectrum of 3a showed eight distinct resonances in agreement with the
suggested structure. Partial assignments of these signals are given in the Exper. Part.
The proposed mechanism of the reaction is depicted in the Scheme and includes the
nucleophilic attack of 1 at C(1) of 1,1-bis(methylsulfanyl)-2-nitroethene to yield
intermediate 4 which cyclizes by a second nucleophilic attack to ketene aminal 5. In the
next step, the aza-ene reaction [7][8] between cyclic ene-1,1-diamine 5 and alkyl prop-
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Table. Reaction of Alkylenediamines 1, 1,1-Bis(methylsulfanyl)-2-nitroethene, and Alkyl Prop-2-ynoates
2 in Refluxing THF
Entry
1
R
R’
Product
Catalyst
Yield [%]
1
2
3
4
5
6
7
Propane-1,3-diamine
Propane-1,3-diamine
2,2-Dimethylpropane-1,3-diamine
2,2-Dimethylpropane-1,3-diamine
Butane-1,4-diamine
Me
Et
Me
Et
Me
Et
Me
H
Ph
H
Ph
H
Ph
H
3a
3b
3c
3d
3e
3f
3g
–
75
65
70
70
65
70
70
TsOH
–
TsOH
–
TsOH
–
Butane-1,4-diamine
Cyclohexane-1,2-diamine
2-ynoates 2 gives the intermediate 6, which undergoes nucleophilic attack of the
secondary amino group at the CO group of the ester function leading to adduct 3. It
should be mentioned that we applied TsOH for activating the CO group, when ethyl 3-
phenylprop-2-ynoate was used as reagent 2.
Scheme. Proposed Mechanism for the Formation of 2-Oxopyridine-Fused 1,3-Diazaheterocycles 3
In conclusion, we have developed a convenient one-pot procedure for the synthesis
of 2-oxopyridine-fused 1,3-diazaheterocycles, which represent a class of potentially
bioactive compounds. The starting materials are readily available.
Experimental Part
General. Reagents and solvents were obtained from Fluka (CH-Buchs) and used without further
purification. M.p.: Electrothermal 9100 apparatus. IR Spectra: in KBr, Shimadzu IR-460 spectrometer.
1H- and 13C-NMR spectra: at 500 and 125 MHz, resp., Bruker DRX 500-Avance FT-NMR instrument, in
CDCl3 if not otherwise stated. MS: Finnigan-MAT 8430 mass spectrometer operating at an ionization
potential of 70 eV. Elemental analyses for C, H, and N: Heraeus CHN-O-Rapid analyzer.

Helvetica Chimica Acta – Vol. 94 (2011)
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General Procedure (exemplified for 3a). To a magnetically stirred soln. of 1,1-bis(methylsulfanyl)-2-
nitroethene (0.166 g, 1 mmol) and propane-1,3-diamine (1a; 0.074 g, 1 mmol) in THF (5 ml) under reflux
was slowly added methyl prop-2-ynoate (0.142 g, 1 mmol), and stiring was continued for 2 – 3 h. After
completion of the reaction, the crude product was purified by CC (SiO2; Merck, 230 – 240 mesh; hexane/
AcOEt 5 :1).
1,2,3,4-Tetrahydro-9-nitro-6H-pyrido[1,2-a]pyrimidin-6-one (3a). Yield: 150 mg (75%). Yellow
crystals. M.p. 222 – 2268. IR: 3216 (NH), 1673 (CON), 1579, 1339 (NO2). 1H-NMR: 2.15 – 2.19 (m,
2 H); 3.63 (t, J ¼ 6.0, 2 H); 4.07 (t, J ¼ 6.0, 2 H); 5.90 (d, J ¼ 10.1, 1 H); 8.16 (d, J ¼ 10.1, 1 H); 10.26 (s,
1 H). 13C-NMR: 19.0; 39.0; 39.9; 106.6; 114.3; 135.7; 150.4; 161.2. EI-MS: 195 (100, Mþ), 165 (81), 149
(13), 137 (35), 121 (89), 109 (17), 93 (26), 81 (22), 69 (37), 64 (40), 55 (39), 41 (50). Anal. calc. for
C8H9N3O3 (195.18): C 49.23, H 4.65, N 21.53; found: C 49.20, H 4.69, N 21.57.
1,2,3,4-Tetrahydro-9-nitro-8-phenyl-6H-pyrido[1,2-a]pyrimidin-6-one (3b). Yield: 190 mg (65%).
1
Yellow crystals. M.p. 2108. IR: 3211 (NH), 1683 (CON), 1587, 1368 (NO2). H-NMR: 2.13 – 2.18 (m,
2 H); 3.60 – 3.63 (m, 2 H); 4.12 (t, J ¼ 5.9, 2 H); 5.83 (s, 1 H); 7.21 – 7.23 (m, 2 H); 7.36 – 7.40 (m, 3 H);
10.21 (s, 1 H). 13C-NMR: 18.8; 39.1; 39.8; 109.5; 114.0; 125.9; 127.9; 128.1; 138.7; 150.1; 150.2; 159.7. EI-
MS: 271 (100, Mþ), 234 (57), 209 (26), 192 (26), 169 (17), 156 (16), 140 (23), 128 (30), 115 (28), 103 (57),
77 (74), 57 (63). Anal. calc. for C14H13N3O3 (271.27): C 61.99, H 4.83, N 15.49; found: C 61.94, H 4.87, N
15.53.
1,2,3,4-Tetrahydro-3,3-dimethyl-9-nitro-6H-pyrido[1,2-a]pyrimidin-6-one (3c). Yield: 160 mg
1
(70%). Yellow crystals. M.p. 2028 (dec.). IR: 3229 (NH), 1675 (CON), 1601, 1347 (NO2). H-NMR:
1.14 (s, 6 H); 3.28 (s, 2 H); 3.75 (s, 2 H); 5.91 (d, J ¼ 10.2, 1 H); 8.17 (d, J ¼ 10.2, 1 H); 10.25 (s, 1 H).
13C-NMR: 24.0; 26.4; 50.3; 50.6; 106.6; 106.7; 135.7; 149.5; 161.5. EI-MS: 223 (32, Mþ), 211 (17), 149 (12),
117 (100), 112 (59), 100 (63), 91 (35), 83 (34), 71 (72), 57 (93), 41 (45). Anal. calc. for C10H13N3O3
(223.23): C 53.81, H 5.87, N 18.82; found: C 53.83, H 5.89, N 18.80.
1,2,3,4-Tetrahydro-3,3-dimethyl-9-nitro-8-phenyl-6H-pyrido[1,2-a]pyrimidin-6-one (3d). Yield:
210 mg (70%). Yellow crystals. M.p. 244 – 2478. IR: 3200 (NH), 1682 (CON), 1582, 1361 (NO2).
1H-NMR ((D6)DMSO): 1.03 (s, 6 H); 3.31 (s, 2 H); 3.68 (s, 2 H); 5.61 (s, 1 H); 7.22 (d, J ¼ 6.4, 2 H); 7.33 –
7.38 (m, 3 H); 10.08 (s, 1 H). 13C-NMR ((D6)DMSO): 23.6; 25.8; 50.2; 50.5; 108.5; 113.4; 126.3; 128.0;
128.4; 139.5; 149.4; 149.5; 159.7. EI-MS: 299 (100, Mþ), 269 (43), 253 (8), 225 (7), 209 (5), 197 (6), 185
(6), 169 (9), 157 (6), 140 (15), 128 (11), 115 (15), 102 (10), 77 (9), 69 (7), 55 (11). Anal. calc. for
C16H17N3O3 (299.33): C 64.20, H 5.72, N 14.04; found: C 64.24, H 5.75, N 14.08.
2,3,4,5-Tetrahydro-10-nitropyrido[1,2-a][1,3]diazepin-7(1H)-one (3e). Yield: 140 mg (65%). Yellow
crystals. M.p. 157 – 1608. IR: 3229 (NH), 1688 (CON), 1579, 1371 (NO2). 1H-NMR: 2.01 – 2.10 (m, 4 H);
3.75 (t, J ¼ 7.9, 2 H); 4.35 (t, J ¼ 6.1, 2 H); 5.93 (d, J ¼ 10.2, 1 H); 8.11 (d, J ¼ 10.2, 1 H); 10.04 (s, 1 H).
13C-NMR: 23.4; 24.2; 44.5; 44.9; 108.0; 116.5; 135.4; 155.0; 161.8. EI-MS: 209 (100, Mþ), 192 (99), 179
(12), 162 (57), 134 (25), 106 (14), 80 (13), 55 (27). Anal. calc. for C9H11N3O3 (209.20): C 51.67, H 5.30, N
20.09; found: C 51.70, H 5.32, N 20.07.
2,3,4,5-Tetrahydro-10-nitro-9-phenylpyrido[1,2-a][1,3]diazepin-7(1H)-one (3f). Yield: 200 mg
(70%). Yellow crystals. M.p. 202 – 2068. IR: 3303 (NH), 1665 (CON), 1549, 1333 (NO2). 1H-NMR:
1.98 – 2.10 (m, 4 H); 3.61 (t, J ¼ 7.2, 2 H); 4.35 (t, J ¼ 7.3, 2 H); 6.01 (s, 1 H); 7.23 – 7.27 (m, 2 H); 7.35 – 7.39
(m, 3 H); 9.11 (s, 1 H). 13C-NMR: 23.6; 24.4; 45.4; 45.7; 112.3; 118.6; 125.7; 127.9; 128.0; 137.4; 149.1;
154.2; 160.8. EI-MS: 285 (100, Mþ), 268 (34), 238 (30), 169 (16), 140 (20), 115 (21), 97 (27), 83 (27), 69
(39), 55 (67). Anal. calc. for C15H15N3O3 (285.30): C 63.15, H 5.30, N 14.73; found: C 63.18, H 5.33, N
14.74.
5a,6,7,8,9,9a-Hexahydro-4-nitropyrido[1,2-a]benzimidazol-1(5H)-one (3g). Yield: 160 mg (70%).
Yellow crystals. M.p. 194 – 1968 (dec.). IR: 3331 (NH), 1680 (CON), 1570, 1345 (NO2). 1H-NMR: 1.36 –
2.34 (m, 8 H); 3.49 – 3.55 (m, 1 H); 3.68 – 3.74 (m, 1 H); 5.85 (d, J ¼ 10.1, 1 H); 7.96 (d, J ¼ 10.1, 1 H); 8.07
(s, 1 H). 13C-NMR: 23.2; 23.7; 28.7; 29.2; 63.3; 65.6; 109.7; 113.8; 134.5; 153.2; 162.0. EI-MS: 235 (100,
Mþ), 190 (21), 161 (21), 125 (12), 81 (34), 55 (11). Anal. calc. for C11H13N3O3 (235.24): C 56.16, H 5.57, N
17.86; found: C 56.13, H 5.60, N 17.83.

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Received December 9, 2010