JOURNAL OF CHEMICAL RESEARCH 2013 113
4-(4-Chlorophenyl)-7-methoxy-2-oxo-2H-chromene-3-carbonitrile
(4a): Yield 83%; m.p. 207–208 °C. IR (KBr): 3096 (CH arom.), 2990
(CH aliph.), 2219 (C≡N), 1727 (C=O) cm−1; 1H NMR (CDCl3): δ 3.94
(s, 3H, OCH3); 6.85 (s, 1H, ArH); 6.90 (d, J = 9 Hz,1H, ArH); 7.24 (d,
J = 9 Hz, 1H, ArH); 7.43 (d, J = 8.4 Hz, 2H, ArH); 7.60 (d, J = 8.4 Hz,
2H, ArH); 13C NMR (CDCl3): δ 56.24, 97.92, 101.27, 111.49, 113.79,
114.11, 129.53, 129.86, 130.44, 137.41, 156.43, 157.29, 162.58,
Experimental
Reactions were routinely monitored by TLC on silica gel sheets that
precoated with UV fluorescent silica (MERCK 60 F 254) and spots
were developed using I2 vapour/UV light as visualising agents. Sol-
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vent system was chloroform: methanol (in different ratio). H NMR
spectra were determined in CDCl3, or DMSO-d6 solvent with Varian
Gemini 300 MHz Spectrometer. Peak positions were given in parts
per million (δ) downfield the tetramethylsilane as internal standard.
13C NMR spectra were carried out on Gemini 75 MHz Spectrometer.
IR spectra were recorded on a Shimadzu 435 Spectrometer, using KBr
discs and values were represented in cm−1. GC Mass spectra were run
on Shimadzu QP-2010 spectrometer and Mass spectra were run on
Hewlett Packard 5988 spectrometer at the Microanalytical Center,
Cairo University, Egypt. Melting points were determined on a Griffin
instrument and are uncorrected. All reported products showed 1H
NMR spectra in agreement with the assigned structures. Elemental
analyses were performed at the Micro-analytical Center, Cairo Uni-
versity, Egypt. Compound 1a and 1b was prepared adopting a reported
procedure.13,14
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165.72; GCMS: m/z 313 (M+2 | , 35.63), 311 (M | , 100), 283
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(M-CO | , 46.37). Anal. Calcd for C17H10ClNO3 (311.73): C, 65.50;
H, 3.23; N, 4.49. Found: C, 65.30; H, 3.52; N, 4.39%.
4-(4-Chlorophenyl)-7-ethoxy-2-oxo-2H-chromene-3-carbonitrile
(4b): Yield 78%; m.p. 171–172 °C. IR (KBr): 3095 (CH arom.), 2944
(CH aliph.), 2224 (C≡N), 1730 (C=O) cm−1; 1H NMR (CDCl3): δ 1.48
(t, J = 7.2 Hz, 3H, CH3); 4.15 (q, J = 7.2 Hz, 2H, CH2); 6.83 (s, 1H,
ArH); 6.88 (d, J = 9 Hz, 1H, ArH); 7.24 (d, J = 9 Hz, 1H, ArH); 7.41
(d, J = 8.7 Hz, 2H, ArH); 7.59 (d, J = 8.7 Hz, 2H, ArH). Anal. Calcd
for C18H12ClNO3 (325.75): C, 66.37; H, 3.71; N, 4.30. Found: C,
66.14; H, 3.84; N, 3.99%.
Synthesis of compounds (RS)-N-(EZ)-7-alkoxy-4-(4-chlorophenyl)-3-
cyano-4H-chromen-2-ylformimidates (5a and 5b); general procedure
A mixture of compound 2a or 2b (0.01 mol) and triethyl orthoformate
(20 mL) was heated under reflux for 4 h. The reaction mixture was
evaporated under reduced pressure, and then the residue was washed
with ethanol and crystallised from the appropriate solvent to give 5a
or 5b respectively.
Synthesis of compounds (RS) 8-alkoxy-5-(4-chlorophenyl)-5H-
chromeno[2,3-d]pyrimidin-4-amines (2a and 2b); general procedure
A solution of 1a or 1b (0.01 mol) in formamide (20 mL) was heated
under reflux for 3 hnd was then cooled and poured into ice-cold
water (20 mL). The precipitated solid was filtered, washed with
water and crystallised from the appropriate solvent to afford 2a or 2b
respectively.
Ethyl
(RS)-N-[(EZ)-4-(4-chorophenyl)-3-cyano-7-methoxy-4H-
(RS)-5-(4-Chlorophenyl)-8-methoxy-5H-chromeno[2,3-d]pyr-
imidin-4-amine (2a): Crystallised from benzene: acetone (1: 1) mix-
ture.Yield 96%; m.p. 226–227 °C. IR (KBr): 3206 (NH2), 1626 (C=N)
cm−1; 1H NMR (DMSO-d6): δ 3.80 (s, 3H, OCH3); 5.30 (s, 1H, C5H);
6.72–7.42 (m, 7H, ArH + 2H, NH2, D2O exchangeable); 8.18 (s, 1H,
C2H) ppm. Anal. Calcd for C18H14ClN3O2 (339.78): C, 63.63; H, 4.15;
N, 12.37. Found: C, 63.92; H, 4.29; N, 12.08%.
chromen-2-yl]formimidate (5a): Crystallised from absolute ethanol.
Yield 88%; m.p. 130–132 °C. IR (KBr): 3068 (CH arom.), 2965
(CH aliph.), 2200 (C≡N), 1644 (C=N) cm−1; 1H NMR (CDCl3): δ 1.39
(t, J = 7.6 Hz, 3H, CH2CH3); 3.80 (s, 3H, OCH3); 4.43 (q, J = 7.6 Hz,
2H, CH2); 4.80 (s, 1H, C4H); 6.60 (s, 1H, ArH); 6.65 (d, J = 8.7 Hz,
1H, ArH); 6.84 (d, J = 8.7 Hz, 1H, ArH); 7.15 (d, J = 8.7 Hz, 2H,
ArH); 7.30 (d, J = 8.7 Hz, 2H, ArH); 8.38 (s, 1H, N=CH). Anal. Calcd
for C20H17ClN2O3 (368.82): C, 65.13; H, 4.65; N, 7.60. Found: C,
65.28; H, 4.66; N, 7.80%.
(RS)-5-(4-Chlorophenyl)-8-ethoxy-5H-chromeno[2,3-d]pyrimidin-4-
amine (2b): Crystallised from benzene. Yield 92%; m.p. 209–210 °C.
IR (KBr): 3385, 3335 (NH2), 3165 (CH arom.), 2979 (CH aliph.),
Ethyl (RS)-N-(EZ)-4-(4-chlorophenyl)-3-cyano-7-ethoxy-4H-chro-
men-2-ylformimidate (5b): Crystallised from methanol. Yield 61%;
m.p. 134–136 °C. IR (KBr): 3067 (CH arom.), 2981 (CH aliph.), 2208
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1653 (C=N)cm−1; H NMR (DMSO-d6) δ 1.38 (t, J = 7.2 Hz, 3H,
CH3); 3.98 (q, J = 7.2 Hz, 2H, CH2); 4.85 (s, 2H, NH2, D2O exchange-
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(C≡N), 1619 (C=N) cm−1; H NMR (CDCl3): δ 1.28–1.36 (m, 6H,
able); 4.89 (s, 1H, C5H); 6.57–7.27 (m, 7H, ArH), 8.09 (s, 1H, C2H)
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ppm; MS: m/z 355 (M+2 | , 7.93), 353 (M | , 24.88), 242
2CH2CH3); 3.94 (q, J = 7.2 Hz, 2H, OCH2CH3); 4.35 (q, J = 7.6 Hz,
2H, N=CHOCH2CH3); 4.71 (s, 1H, C4H); 6.49 (s, 1H, ArH); 6.54
(d, J = 8.4 Hz, 1H, ArH); 6.74 (d, J = 8.4 Hz, 1H, ArH); 7.07 (d,
J = 8.4 Hz, 2H, ArH); 7.21 (d, J = 8.4 Hz, 2H, ArH); 8.30 (s, 1H,
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(M-C6H4Cl | ,100). Anal. Calcd for C19H16ClN3O2 (353.81): C,
64.50; H, 4.56; N, 11.88. Found: C, 64.80; H, 4.69; N, 11.98%.
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Synthesis of compounds (RS) N-acetyl-N-[7-alkoxy-4-(4-chloro-phenyl)-
3-cyano-4H-chromen-2-yl]acetamides (3a and 3b); general procedure
A mixture of 1a or 1b (0.01 mol) and acetic anhydride (20 mL)
was heated under reflux for 5 h. The precipitated crystals formed
after cooling were filtered and recrystallised from ethanol to give
compounds 3a or 3b respectively.
(RS)-N-Acetyl-N-[4-(4-chlorophenyl)-3-cyano-7-methoxy-4H-
chromen-2-yl]acetamide (3a):Yield 78%; m.p. 134–135 °C. IR (KBr):
3069 (CH arom.), 2949 (CH aliph.), 2220 (C≡N), 1744 (2 acetyl C=O)
cm−1; 1H NMR (CDCl3): δ 2.46 (s, 6H, 2COCH3); 3.79 (s, 3H, OCH3);
4.90 (s, 1H, C4H); 6.60 (s, 1H, ArH); 6.70 (d, J = 8.7 Hz, 1H, ArH);
6.87 (d, J = 8.7 Hz, 1H, ArH); 7.22 (d, J = 8.4 Hz, 2H, ArH); 7.35 (d,
J = 8.4 Hz, 2H, ArH). Anal. Calcd for C21H17ClN2O4 (396.83): C,
63.56; H, 4.32; N, 7.06. Found: C, 63.81; H, 4.24; N, 7.05%.
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N=CH); MS: m/z 384 (M+2 | , 7.31), 382 (M | , 20.40), 271
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(M-C6H4Cl | , 100). Anal. Calcd for C21H19ClN2O3 (382.85): C,
65.88; H, 5.00; N, 7.32. Found: C, 66.09; H, 4.80; N, 7.12%.
Synthesis of compounds (RS)-N′-(EZ)-(7-alkoxy-4-(4-chloro-phenyl)-
3-cyano-4H-chromen-2-yl)-N-carbamothioylformimidamides (6a and
6b); general procedure
Sodium ethoxide (0.01 mol) [sodium metal (0.23 g, 0.01 mol) and
absolute ethanol (5 mL)] was added to a mixture of the iminoether 5a
or 5b (0.01 mol) and thiourea (0.76 g, 0.01 mol) in absolute ethanol
(30 mL),. The reaction mixture was heated under reflux for 2 h then
cooled and poured into ice-cold water. The precipitated solid was
filtered, washed with water, dried and crystallised from benzene to
afford 6a or 6b respectively.
(RS)-N-Acetyl-N-[4-(4-chlorophenyl)-3-cyano-7-ethoxy-4H-chromen-
2-yl]acetamide (3b): Yield 74%; m.p. 164–165 °C. IR (KBr): 3106
(CH arom.), 2982 (CH aliph.), 2219 (C≡N), 1744 (2 acetyl C=O) cm−1;
1H NMR (CDCl3): δ 1.40 (t, J = 7.2 Hz, 3H, CH3); 2.46 (s, 6H,
2COCH3); 4.01 (q, J = 7.2 Hz 2H, CH2); 4.90 (s, 1H, C4H); 6.58
(s, 1H, ArH); 6.69 (d, J = 8.7 Hz, 1H, ArH); 6.86 (d, J = 8.7 Hz, 1H,
ArH); 7.25 (d, J = 8.1 Hz, 2H, ArH); 7.34 (d, J = 8.1 Hz, 2H, ArH);
(RS)-N′-(EZ)-(4-(4-Chlorophenyl)-3-cyano-7-methoxy-4H-chro-
men-2-yl)-N-carbamothioyl formimidamide (6a): Yield 95%; m.p.
229–230 °C. IR (KBr): 3481, 3376, 3340 (NH, NH2), 3186 (CH
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arom.), 2939 (CH aliph.), 2193 (C≡N), 1629 (C=N) cm−1; H NMR
(CDCl3): δ 2.34 (br. s, 1H, NH, D2O exchangeable); 3.78 (s, 3H,
OCH3); 4.95 (s, 1H, C4H); 5.02 (s, 2H, NH2, D2O exchangeable);
6.59–7.36 (m, 7H, ArH); 8.31 (s, 1H, N=CH). Anal. Calcd for
C19H15ClN4O2S (398.87): C, 57.21; H, 3.79; N, 14.05. Found: C,
57.30; H, 4.10; N, 13.83%.
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GCMS: m/z 412 (M+2 | , 1.54), 410 (M | , 4.71), 215
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(M-C10H8ClO2 | , 100). Anal. Calcd for C22H19ClN2O4 (410.86): C,
64.32; H, 4.66; N, 6.82. Found: C, 64.20; H, 4.80; N, 6.80%.
(RS)-N′-(EZ)-(4-(4-Chlorophenyl)-3-cyano-7-ethoxy-4H-chromen-
2-yl)-N-carbamothioyl formimidamide (6b): Yield 84%; m.p. 235–
236 °C. IR (KBr): 3381, 3336 (NH, NH2), 3180 (CH arom.), 2979
(CH aliph.), 2194 (C≡N), 1621 (C=N) cm−1; 1H NMR (CDCl3): δ 1.38
(t, J = 7.2 Hz, 3H, CH3); 2.60 (br. s, 1H, NH, D2O exchangeable); 4.00
(q, J = 7.2 Hz, 2H, CH2); 4.96 (s, 1H, C4H); 5.26 (br. s, 2H, NH2, D2O
exchangeable); 6.59–7.34 (m, 7H, ArH); 8.32 (s, 1H, N=CH); MS:
Synthesis of compounds 7-alkoxy-4-(4-chlorophenyl)-2-oxo-2H-
chromene-3-carbonitriles (4a and 4b); general procedure
A mixture of 1a or 1b (0.01mol), the appropriate acid chloride
(0.01 mol) and anhydrous potassium carbonate (2.07 g, 0.015 mol) in
tetrahydrofuran (30 mL) was heated under reflux for 2 h. The solid
that separated after cooling was collected by filtration, washed with
water, dried and crystallised from ethanol to afford compounds 4a or
4b respectively.
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m/z 414 (M+2 | , 30.86), 412 (M | , 37.88), 411 (M-1 | , 42.01),
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55 (M-C18H14ClN2O2S | , 100). Anal. Calcd for C20H17ClN4O2S