Efficient synthesis of chromenopyridines containing intramolecular hydrogen bonds through a sequential three-component reaction

Article abstract of DOI:10.1007/s11164-015-2414-6

A one-pot sequential reaction of 1,1-bis(methylsulfanyl)-2-nitroethene, diamines, and 3‐formylchromones in EtOH has been developed to afford chromenopyridines. The method is operationally simple and the products are obtained in good yields.

Full text of DOI:10.1007/s11164-015-2414-6

Res Chem Intermed
DOI 10.1007/s11164-015-2414-6
Efficient synthesis of chromenopyridines containing
intramolecular hydrogen bonds through a sequential
three-component reaction
Abdolali Alizadeh1 Fahimeh Bayat1 Zhe Zhu2
•
•
Received: 29 August 2015 / Accepted: 28 December 2015
Ó Springer Science+Business Media Dordrecht 2016
Abstract A one-pot sequential reaction of 1,1-bis(methylsulfanyl)-2-nitroethene,
diamines, and 3-formylchromones in EtOH has been developed to afford
chromenopyridines. The method is operationally simple and the products are
obtained in good yields.
Keywords 1,1-Bis(methylsulfanyl)-2-nitroethene Á Diamine Á
3-Formylchromone Á Chromenopyridine Á Intramolecular hydrogen bond
Introduction
Chromones are key building blocks for natural products, bioactive compounds, and
drugs [1]. Among them, chromenopyridines are a significant class of heterocyclic
compounds with extensive applications in medicinal chemistry. For example, some
chromenopyridines show a broad spectrum of biological activities such as
antibacterial [2], antimyopic [3], antiasthmatic [4], and hypotensive activities [5,
6]. They act as an inhibitor of potent BACE1 [7] and mitogen-activated protein
kinase [8] and as a fluorescent probe for (Zn2?) [9]. Moreover, they are key building
blocks for amlexanox and pranoprofen that are valuable therapeutic agents for
treatment of recurrent aphthous ulcers [10] and inflammation [11], respectively
(Fig. 1).
As a result, their importance has drawn considerable attention from organic
chemists to construct chromenopyridines. The most popular one-pot methods for
&
Abdolali Alizadeh
aalizadeh@modares.ac.ir; abdol_alizad@yahoo.com
1
2
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027,
China
123

A. Alizadeh et al.
Fig. 1 Examples of biologically active chromenopyridines
these kinds of compounds are based on the reaction of two equivalents of
malononitrile with salicylic aldehydes and different nucleophiles like thiols [12],
secondary amines [13], and anions of malononitriles [8]. Some chromenopyridines
were also synthesized by different approaches, such as refluxing o-quinonemethides,
excess malononitrile and quaternary ammonium salts in ethanol in the presence of
NaOH as a catalyst [14]. In addition, multicomponent reaction of chromone-3-
benzoylhydrazones with isocyanides and acetylenedicarboxylates has been used for
the preparation of chromenopyridines [15]; Yaqub et al. [16] synthesized
chromenopyridines from ketene aminals and 3-formylchromones.
The structural features of 3-formylchromones, having three electron-deficient
centers, may render them as useful synthons for the construction of a variety of
novel heterocycles possessing diverse biological activities [17].
Experimental
Elemental analyses for C, H and N were performed using an Heraeus CHN–O–
Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MATT 8430 mass
spectrometer operating at an ionization potential of 70 eV. Proton nuclear magnetic
resonance (1H-NMR, 300 MHz) and carbon-13 NMR (13C-NMR, 75 MHz) spectra
were obtained usinga Bruker DRX-400 AVANCE. Infrared (IR) spectra were
recorded as KBr pellets on a NICOLET FT-IR 100 spectrometer; absorbencies are
reported in cm-1. Melting points were measured on an Electrothermal 9100.
General procedure for preparation of 3a
A mixture of 1,1-bis(methylsulfanyl)-2-nitroethene (1 mmol) and diamine 1a
(1 mmol) in EtOH (3 mL) was heated at reflux temperature for 2 h. Then 3-
formylchromone 2a (1 mmol) was added to the reaction mixture at room
temperature. Upon completion (3 h), monitored by thin layer chromatography
(TLC), the mixture was filtered and the precipitate was washed with distilled water
(2 mL) and EtOH (5 mL) to afford the pure product 3a.
4-Nitro-1,2,3,11a-tetrahydro-6H-chromeno[3,2-e]imidazo[1,2-a]pyridine-6-one
(Table 2, entry a) Yellow powder, mp = 238 °C dec, 0.21 g, yield: 75 %. IR
(KBr) (mmax, cm-1): 3402 (NH), 1656 (C=O), 1597 (Ar), 1530 and 1393 (NO2),
123

Efficient synthesis of chromenopyridines containing…
1299 (C–N), 1235 and 1181 (C–O). Anal. calc. for C14H11N3O4 (285.26): C, 58.95;
H, 3.89; N, 14.73 %. Found C, 59.01; H, 3.94; N, 14.65 %. MS (EI, 70 eV): m/z
(%) = 285 (M?, 21), 283 (100), 253 (93), 237 (42), 210 (32), 181 (50), 153 (22),
121 (21). dH (300.1 MHz, DMSO-d6): 3.73-3.92 (3H, m, CH2), 4.10–4.15 (1H, m,
3
CH2), 6.37 (1H, s, CH), 7.07 (1H, d, JHH = 8.1 Hz, CH of Ar), 7.15 (1H, t,
3
3JHH = 7.3 Hz, CH of Ar), 7.59 (1H, t, JHH = 7.4 Hz, CH of Ar), 7.81 (1H, d,
3JHH = 7.4 Hz, CH of Ar), 7.82 (1H, s, = CH), 9.58 (1H, s, NH). dC (75 MHz,
DMSO-d6): 43.4 (CH2), 46.3 (CH2), 85.0 (CH), 108.4 (C–NO2), 111.9 (CH of Ar),
118.1 (CH of Ar), 122.7 (C–CO), 123.1 (Cipso–CO), 126.9 (CH of Ar), 127.4 (CH of
Ar), 136.0 (=CH), 153.8 (Cipso–O), 156.1 (NCNH), 179.1 (C=O).
1-Methyl-4-nitro-1,2,3,11a-tetrahydro-6H-chromeno[3,2-e]imidazo[1,2-a]pyridine-
6-one (Table 2, entry b) Yellow powder, mp = 212–215 °C, 0.21 g, yield: 70 %.
IR (KBr) (mmax, cm-1): 3281 (NH), 1660 (C=O), 1581 and 1527 (Ar), 1519 and
1390 (NO2), 1326 and 1290 (C–N), 1239 and 1181 (C–O). Anal. calc. for
C15H13N3O4 (299.28): C, 60.20; H, 4.38; N, 14.04 %. Found C, 60.12; H, 4.43; N,
13.95 %. MS (EI, 70 eV): m/z (%) = 299 (M?, 90), 282 (81), 267 (62), 252 (100),
236 (55), 210 (27), 121 (33). dH (300.1 MHz, DMSO-d6): 1.36 (3H, d,
3JHH = 5.7 Hz, CH3), 3.91–4.07 (1H, m, CH2), 4.21–4.27 (1H, m, CH2),
3
4.29–4.31 (1H, m, CH), 6.32 (1H, s, CH), 7.05 (1H, d, JHH = 7.9 Hz, CH of
Ar), 7.14 (1H, t, 3JHH = 7.4 Hz, CH of Ar), 7.58 (1H, t, 3JHH = 7.4 Hz, CH of Ar),
3
7.79 (1H, d, JHH = 7.4 Hz, CH of Ar), 7.81 (1H, s, =CH), 9.73 (1H, s, NH). dC
(75 MHz, DMSO-d6): 20.0 (CH3), 51.5 (CH), 52.6 (CH2), 85.0 (CH), 108.2
(C–NO2), 111.7 (CH of Ar), 118.3 (CH of Ar), 122.7 (CH of Ar), 123.0 (C–CO),
123.1 (Cipso–CO), 126.9 (CH of Ar), 135.9 (=CH), 153.0 (Cipso–O), 156.4 (NCNH),
179.0 (C=O).
5-Nitro-2,3,4,12a-tetrahydro-1H,7H-chromeno[30,20:5,6]pyrido[1,2-a]pyrimidine-
7-one (Table 2, entry c) Yellow powder, mp = 230 °C dec, 0.25 g, yield: 85 %.
IR (KBr) (mmax, cm-1): 3320 (NH), 1672 (C=O), 1614 (Ar), 1549 and 1373 (NO2),
1296 (C–N), 1240 and 1199 (C–O). Anal. calc. for C15H13N3O4 (299.28): C, 60.20;
H, 4.38; N, 14.04 %. Found C, 60.14; H, 4.31; N, 14.13 %. MS (EI, 70 eV): m/z
(%) = 299 (M?, 2), 297 (7), 267 (100), 252 (33), 238 (99), 211 (11), 197 (26), 184
(12), 121 (6). dH (300.1 MHz, DMSO-d6): 1.98-2.06 (2H, m, CH2), 3.43–3.56 (1H,
m, CH2), 3.57–3.78 (2H, m, CH2), 3.80–3.98 (1H, m, CH2), 6.32 (1H, s, CH),
6.90–7.30 (2H, m, CH of Ar), 7.50–7.90 (2H, m, CH of Ar), 7.92 (1H, s, =CH),
10.65 (1H, s, NH). dC (75 MHz, DMSO-d6): 18.4 (CH2), 38.4 (CH2–N), 45.0
(CH2–N), 87.3 (CH), 109.9 (C–NO2), 111.7 (C–CO), 118.2 (CH of Ar), 122.6 (CH
of Ar), 123.1 (Cipso–CO), 126.8 (CH of Ar), 127.1 (CH of Ar), 136.0 (=CH), 150.1
(Cipso–O), 156.3 (NCNH), 179.6 (C=O). Crystal data for 3c C15H13N3O4
˚
˚
3
(CCDC 1041247): MW = 299.28, a = 19.2939(17) A, b = 12.4436(11) A,
˚
˚
c = 14.2947(13) A, a = 90.00, b = 129.6610(10), c = 90.00, V = 2642.0(4) A ,
Z = 8, (000) = 1248, crystal dimension
Dc = 1.505 mg/m3,
F
˚
0.4 9 0.3 9 0.2 mm, radiation, Mo Ka (k = 0.71073 A), 2.14 B 2h B 25.10,
intensity data were collected at 295(2) K with a Bruker APEX area detector
diffractometer, and employing a x/2h scanning technique, in the range of
123

A. Alizadeh et al.
-22 B h B 16, -14 B k B 13, -17 B l B 17; the structure was solved by a direct
method, all non-hydrogen atoms were positioned and anisotropic thermal param-
eters were refined from 2337 observed reflections with R (into) = 0.0780 by a full-
matrix least-squares technique converged to R = 0.0559 and Raw = 0.1732
[I [ 2sigma(I)].
9-Chloro-5-nitro-2,3,4,12a-tetrahydro-1H,7H-chromeno[30,20:5,6]pyrido[1,2-a]
pyrimidine-7-one (Table 2, entry d) Yellow powder, mp = 238 °C, 0.27 g,
yield: 82 %. IR (KBr) (mmax, cm-1): 3138 (NH), 1669 (C=O), 1612 (Ar), 1543 and
1371 (NO2), 1320 (C–N), 1239 and 1195 (C–O). Anal. calc. for C15H12ClN3O4
(333.73): C, 53.99; H, 3.62; N, 12.59 %. Found C, 54.04; H, 3.70; N, 12.54 %. MS
(EI, 70 eV): m/z (%) = 333 (M?, 1), 331 (7), 301 (73), 272 (100), 231 (11), 195
(19), 154 (17), 126 (11). dH (300.1 MHz, DMSO-d6): 1.56–2.19 (2H, m, CH2),
3.52–3.62 (2H, m, CH2), 3.54–4.20 (2H, m, CH2), 6.35 (1H, s, CH), 7.12 (1H, s, CH
of Ar), 7.43–7.87 (2H, m, CH of Ar), 7.94 (1H, s, =CH), 10.61 (1H, s, NH). dC
(75 MHz, DMSO-d6): 18.3 (CH2), 38.4 (CH2–N), 45.1 (CH2–N), 87.6 (CH), 105.6
(C–NO2), 110.5 (C–CO), 120.5 (CH of Ar), 125.8 (CH of Ar), 126.7 (Cipso–CO),
127.4 (Cipso–Cl), 127.9 (CH of Ar), 135.4 (=CH), 150.0 (Cipso–O), 152.3 (NCNH),
178.5 (C=O).
2,2-Dimethyl-5-nitro-2,3,4,12a-tetrahydro-1H,7H-chromeno[30,20:5,6]pyrido[1,2-
a]pyrimidine-7-one (Table 2, entry e) Yellow powder, mp = 235 °C dec, 0.28 g,
yield: 87 %. IR (KBr) (mmax, cm-1): 3180 (NH), 1672 (C=O), 1610 (Ar), 1554 and
1370 (NO2), 1292 (C–N), 1243 and 1161 (C–O). Anal. calc. for C17H17N3O4
(327.33): C, 62.38; H, 5.23; N, 12.84 %. Found C, 62.34; H, 5.16; N, 12.90 %. MS
(EI, 70 eV): m/z (%) = 327 (M?, 100), 298 (51), 280 (59), 253 (32), 238 (27), 223
(20), 197 (36), 169 (31), 121 (14). dH (300.1 MHz, DMSO-d6): 1.02 (3H, s, CH3),
2
1.09 (3H, s, CH3), 3.31 (3H, d, JHH = 12.2 Hz, 3 CH of 2 9 CH2), 3.59 (1H, d,
3
2JHH = 12.2 Hz, CH2), 6.33 (1H, s, CH), 7.08 (1H, d, JHH = 8.2 Hz, CH of Ar),
7.15 (1H, t, 3JHH = 7.4 Hz, CH of Ar), 7.59 (1H, t, 3JHH = 7.4 Hz, CH of Ar), 7.79
3
(1H, d, JHH = 7.5 Hz, CH of Ar), 7.93 (1H, s, =CH), 10.66 (1H, s, NH). dC
(75 MHz, DMSO-d6): 23.0 (CH3), 23.7 (CH3), 25.9 (CMe2), 49.6 (CH2–N), 55.2
(CH2–N), 87.1 (CH), 109.7 (C–NO2), 111.8 (C–CO), 118.2 (CH of Ar), 122.7 (CH
of Ar), 123.1 (CH of Ar), 126.8 (CH of Ar), 127.1 (Cipso–CO), 136.0 (=CH), 149.3
(Cipso–O), 156.3 (NCNH), 179.7 (C=O).
9-Chloro-2,2-dimethyl-5-nitro-2,3,4,12a-tetrahydro-1H,7H-chromeno[30,20:5,6]
pyrido[1,2-a]pyrimidine-7-one (Table 2, entry f) Yellow powder, mp = 237–
239 °C, 0.30 g, yield: 82 %. IR (KBr) (mmax, cm-1): 3160 (NH), 1660 (C=O), 1597
(Ar), 1544 and 1379 (NO2), 1360 (C–N), 1249 and 1170 (C–O). Anal. calc. for
C17H16ClN3O4 (361.78): C, 56.44; H, 4.46; N, 11.61 %. Found C, 56.49; H, 4.42; N,
11.67 %. MS (EI, 70 eV): m/z (%) = 361 (M?, 12), 329 (61), 314 (47), 299 (12),
272 (100), 259 (18), 231 (48) 155 (10). dH (300.1 MHz, DMSO-d6): 1.02 (3H, s,
2
CH3), 1.08 (3H, s, CH3), 3.30 (3H, d, JHH = 12.2 Hz, 3 CH of 2 9 CH2), 3.55
(1H, d, 2JHH = 12.2 Hz, CH2), 6.33 (1H, s, CH‘), 7.11 (1H, s, CH of Ar), 7.61-7.67
(2H, m, CH of Ar), 7.93 (1H, s, =CH), 10.63 (1H, s, NH). dC (75 MHz, DMSO-d6):
23.0 (CH3), 23.6 (CH3), 25.9 (CMe2), 49.7 (CH2–N), 55.2 (CH2–N), 87.4 (CH),
123

Efficient synthesis of chromenopyridines containing…
109.9 (C–NO2), 110.6 (C–CO), 120.5 (CH of Ar), 124.2 (CH of Ar), 125.7 (CH of
Ar), 126.7 (Cipso–CO), 127.9 (Cipso–Cl), 135.4 (=CH), 149.2 (Cipso–O), 154.9
(NCNH), 178.4 (C=O).
6-Nitro-1,2,3,4,5,13a-hexahydro-8H-chromeno[30,20:5,6]pyrido[1,2-a][1, 3]di-
azepin-8-one (Table 2, entry g) Yellow powder, mp = 212–215 °C, 0.25 g,
yield: 80 %. IR (KBr) (mmax, cm-1): 3200 (NH), 1667 (C=O), 1593 (Ar), 1530 and
1373 (NO2), 1283 (C–N), 1209 (C–O). Anal. calc. for C16H15N3O4 (313.31): C,
61.34; H, 4.83; N, 13.41 %. Found C, 61.41; H, 4.77; N, 13.47 %. MS (EI, 70 eV):
m/z (%) = 313 (M?, 100), 294 (58), 281 (25), 266 (21), 237 (27), 209 (17), 196
(47), 157 (20) 121 (12). dH (300.1 MHz, DMSO-d6): 1.95-2.14 (4H, m, CH2), 3.66-
3.90 (3H, m, CH2), 4.23 (1H, t, 3JHH = 12.5 Hz, CH2), 6.39 (1H, s, CH), 7.07 (1H,
3
3
d, JHH = 8.2 Hz, CH of Ar), 7.13 (1H, t, JHH = 7.4 Hz, CH of Ar), 7.59 (1H, t,
3
3JHH = 7.5 Hz, CH of Ar), 7.79 (1H, d, JHH = 7.6 Hz, CH of Ar), 7.88 (1H,
s, = CH), 10.72 (1H, s, NH). dC (75 MHz, DMSO-d6): 24.3 (CH2), 25.2 CH2), 44.4
(CH2–N), 53.7 (CH2–N), 89.7 (CH), 112.2 (C–NO2), 113.2 (C–CO), 118.4 (CH of
Ar), 122.5 (CH of Ar), 123.0 (CH of Ar), 126.5 (Cipso–CO), 126.8 (CH of Ar), 136.0
(=CH), 156.0 (Cipso–O), 156.5 (NCNH), 179.5 (C=O).
10-Chloro-6-nitro-1,2,3,4,5,13a-hexahydro-8H-chromeno[30,20:5,6]pyrido[1,2-a]
[1, 3]diazepin-8-one (Table 2, entry h) Yellow powder, mp = 239 °C dec,
0.26 g, yield: 74 %. IR (KBr) (mmax, cm-1): 3129 (NH), 1668 (C=O), 1592 (Ar),
1560 and 1383 (NO2), 1340 (C–N), 1262 and 1191 (C–O). Anal. calc. for
C16H14ClN3O4 (347. 76): C, 55.26; H, 4.06; N, 12.08 %. Found C, 55.19; H, 4.15;
N, 12.13 %. MS (EI, 70 eV): m/z (%) = 347 (M?, 34), 300 (41), 271 (95), 259 (57),
244 (74), 230 (100), 217 (50), 155 (66), 126 (48). dH (300.1 MHz, DMSO-d6):
1.99–2.12 (4H, m, CH2), 3.71–3.76 (2H, m, CH2), 3.83–3.86 (1H, m, CH2),
4.20–4.24 (1H, m, CH2), 6.41 (1H, s, CH), 7.11 (1H, d, 3JHH = 7.9 Hz, CH of Ar),
7.61 (1H, d, 3JHH = 7.9 Hz, CH of Ar), 7.70 (1H, s, CH of Ar), 7.91 (1H, s, =CH),
10.68 (1H, s, NH). dC (75 MHz, DMSO-d6): 24.2 (CH2), 25.1 CH2), 44.3 (CH2–N),
53.8 (CH2–N), 90.0 (CH), 112.1 (C–NO2), 112.2 (C–CO), 120.8 (CH of Ar), 124.2
(Cipso–CO), 125.8 (CH of Ar), 126.5 (CH of Ar), 127.4 (Cipso–Cl), 135.5 (=CH),
155.2 (Cipso–O), 156.0 (NCNH), 178.0 (C=O).
2-Nitro-1,9a,10a,11,12,13,14,14a-octahydro-4H-chromeno[30,20:5,6]pyrido[1,2-a]
benzimidazol-4-one (Table 2, entry i) Yellow powder, mp = 274 °C, dec, 0.25 g,
yield: 73 %. IR (KBr) (mmax, cm-1): 3314 (NH), 1654 (C=O), 1612 and 1554 (Ar),
1520 and 1364 (NO2), 1298 (C–N), 1220 and 1199 (C–O). Anal. calc. for
C18H17N3O4 (339.35): C, 63.71; H, 5.05; N, 12.38 %. Found C, 63.76; H, 4.97; N,
12.31 %. MS (EI, 70 eV): m/z (%) = 339 (M?, 100), 310 (68), 294 (55), 264 (75),
238 (27), 184 (17), 121 (15). dH (300.1 MHz, DMSO-d6): 1.20–1.60 (4H, m, CH2),
1.66–2.00 (4H, m,CH2), 3.35–3.50 (2H, m, CH), 6.43 (1H, s, CH), 7.03 (1H, d,
3
3JHH = 8.0 Hz, CH of Ar), 7.15 (1H, t, JHH = 7.3 Hz, CH of Ar), 7.58 (1H, t,
3
3JHH = 7.0 Hz, CH of Ar), 7.78 (1H, d, JHH = 7.0 Hz, CH of Ar), 7.83 (1H,
s, = CH), 9.98 (1H, s, NH). dC (75 MHz, DMSO-d6): 23.3 (CH2), 23.5 (CH2), 28.5
(CH2), 29.5 (CH2), 61.8 (CH–N), 67.8 (CH–N), 86.2 (CH), 109.0 (C–NO2), 112.3
123

A. Alizadeh et al.
(C–CO), 118.2 (CH of Ar), 122.7 (CH of Ar), 123.0 (CH of Ar), 126.8 (CH of Ar),
127.4 (Cipso–CO), 136.0 (=CH), 155.7 (Cipso–O), 156.3 (NCNH), 178.8 (C=O).
Results and discussion
As a follow up to our interest in one-pot synthesis of heterocycles, [18–22] we
considered the synthesis of chromenopyridine from the reaction of 1,1-bis(methyl-
sulfanyl)-2-nitroethene, diamines 1, and 3-formylchromones 2. As 3-formylchro-
mone 2 behaves as unknown (2-hydroxyphenyl)malonicdialdehyde [17], depending
on regioselectivity of the reaction and also recyclization or ring annulation paths,
different products are possible. First we investigated the reaction of ethylenedi-
amine 1a with 1,1-bis(methylsulfanyl)-2-nitroethene (1 mmol), and 3-formylchro-
mone 2a (1 mmol) in ethanol. Interestingly, the reaction yielded regioselectively the
chromenopyridines 3a.
To optimize the reaction conditions for the synthesis of chromenopyridines 3a,
different solvents and temperatures were investigated. The yield reached up to 70 %
if the reaction was performed in EtOH (entry 2, Table 1). It is noticeable that
although for the formation of 2-(nitromethylene)imidazolidine 4a the reflux
temperature is necessary, the second step of the reaction was performed best at
room temperature (entry 2 and 8, Table 1).
With the optimized reaction conditions in hand, we studied the scope and
limitations of this transformation with a wide range of amines and 3-formylchro-
mones (Table 2). When o-phenylenediamine or two equivalents of amines like
Table 1 Optimization of the reaction condition
Entry
Solvent
Temp °C (1)/temp °C (2)
Yield of 3a (%)
1
2
3
4
5
6
7
8
H2O
100/rt
78/rt
64/rt
153/rt
82/rt
61/rt
66/rt
78/78
63
70
68
65
60
50
54
60
EtOH
MeOH
DMF
CH3CN
CHCl3
THF
EtOH
123

Efficient synthesis of chromenopyridines containing…
Table 2 Synthesis results of chromenopyridines 3a-i via one-pot reaction
Entry
a
Diamine
R
H
Yield (%)
75
b
H
70
c
d
e
f
H
Cl
H
85
82
87
82
80
74
Cl
H
g
h
Cl
i
H
73
propylamine, allylamine, and benzylamine were applied, the enamines were formed,
but the regioselectivity of the second step of the reaction decreased and the reaction
yielded many products, but the yields of all of them were low and were not
separable. 2-Aminothiophenol or 2-aminophenol did not react with 1,1-bis(methyl-
sulfanyl)-2-nitroethene in ethanol at reflux temperature. Using NaOH in refluxing
dimethylformamide (DMF) yield the enamine in low yield. Subsequent addition of
3-formylchromone 2a yielded the products in very low yield, according to TLC
plates.
The newly synthesized products 3a–i were fully characterized by their IR, mass,
1H-NMR, and 13C-NMR spectra and the structure was unambiguously confirmed by
X-ray crystal structure analysis of 3c (Fig. 2).
The mass spectrum of 3a displayed the molecular ion peak at m/z = 285, which
is in agreement with the proposed structure. In the IR spectrum of 3a, absorption
bands at 3402 (NH), 1656 (C=O), 1530 and 1393 (NO2) cm-1 are the most
significant stretching frequencies. In 1H-NMR spectrum of 3a, two multiplet signals
123

A. Alizadeh et al.
Fig. 2 Oak Ridge thermal ellipsoid plot (ORTEP) diagram of 3c
at d 3.73–3.92 and 4.10–4.15 and three singlet signals at d 6.37, 7.82, and 9.58 are
related to two CH2, one aliphatic CH, =CH and NH groups, respectively. The four
aromatic H atoms gave rise to characteristic resonances in the aromatic region of the
spectrum. Observation of 14 distinct signals in the 1H-decoupled 13C-NMR
spectrum of 3a is in agreement with the proposed structure.
In pharmaceutical chemistry, the presence of an intramolecular hydrogen bond
(IMHB) is important due to the effect of it on the different properties of molecules,
like solubility and permeability. In a lipophilic environment, a conformer with an
intramolecular hydrogen bond is formed and displays a higher membrane
permeability, while in aqueous medium, the polar functional groups enhance
solubility by formation of intermolecular hydrogen bonds with water [23–25].
˚
Based on the single crystal analysis, the length of the N1–H1 (0.859 A), H1–O2
˚
˚
(1.915 A), and N1–O2 (2.592 A), the structure of product 3c shows a hydrogen bond
between the N–H group and the oxygen atom of the nitro group.
On the basis of the results obtained above, a plausible reaction scenario for this
one-pot reaction is outlined in Scheme 1. Formation of chromenopyridine can be
explained by the initial addition of the nitro ketene aminal 4, resulted from the
coupling of nitro ketene dithioacetal and diamine 1 at the formyl group of 2 as an
electrophilic center followed by attack of the NH at the double bond and loss of
H2O. The regioselectivity of the reaction is probably due to the formation of
intermolecular hydrogen bonding between the amino group and carbonyl groups of
the 3-formylchromone.
Conclusion
In conclusion, we have developed a concise and efficient one-pot process which
provided a facile access to chromenopyridines from 1,1-bis(methylsulfanyl)-2-
nitroethene, diamines, and 3-formylchromones under mild reaction conditions. In
123

Efficient synthesis of chromenopyridines containing…
Scheme1 Mechanistic rationalization for the formation of 3
addition, the method has the advantages of regioselectivity, easy accessibility of
reactants and workup procedure, good yields, absence of any bases or catalysts, and
no need for column chromatography.
Acknowledgments Financial support of this research from Tarbiat Modares University, Iran is
gratefully acknowledged.
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