org/joc
mssinghbhu@yahoo.co.in
Received August 13, 2010
An efficient and highly convergent route to dihydropyrimidinones (DHPMs) and hitherto unre-
ported dihydropyridopyrimidinones has been developed by one-pot, three-component cyclocon-
densation of aromatic aldehydes, β-oxodithioesters, and urea/6-amino-1,3-dimethyluracil in the
presence of recyclable SiO2-H2SO4. On the other hand, salicylaldehyde, β-oxodithioester, and urea
reacted under similar conditions to afford the 3-aroyl/heteroaroyl-2H-chromen-2-thiones in high
yields instead of Biginelli product. The attractive feature of this approach is the synthesis of three
important bioactive heterocyclic frameworks from the same β-oxodithioester under the similar
reaction conditions, making this new strategy highly useful in diversity-oriented synthesis (DOS).
DOI: 10.1021/jo101572c Published on Web 10/27/2010 J. Org. Chem. 2010, 75, 7785–7795 7785
r 2010 American Chemical Society
JOC Article Nandi et al.
CHART 1. Examples of Biologically Active Heterocyclic Fra- mitotic kinesin Eg5 inhibitor (monastrol, 4), and anticancer
meworks (5, MAL3-101).9 Furthermore, apart from synthetic DHPM
derivatives, several marine natural products containing DHPM
skeleton such as batzelladine B (6), ptilomycalines, and
crambescidines with interesting biological activities4d,5e,f
have recently been isolated. Similarly, thiocoumarins display
a remarkable array of biochemical and pharmacological
actions10 such as 7 is used as blocker10e of the lymphocyte
potassium channel Kv1.3. Another heterocyclic core unit
dihydropyridopyrimidinones, which is structurally similar
with the DHPM also display the promising pharmacological
activity such as adenosine kinase inhibitor,11a AbI kinase
inhibitor,11b tyrosine phosphatase inhibitor,11c antiviral,11d
in treatment of diarrhea,11e and as a Ca2þ channel modu-
lator. The diverse range of biological activities of these
moieties has stimulated considerable interest to synthesize
these units via a new and efficient route.
In the 1970s and 1980s, interest slowly increased, and the
scope of the original cyclocondensation reaction shown in
Scheme 1 was gradually extended by variation of all the three
building blocks allowing access to a large number of attrac-
tive multifunctionalized DHPMs. A plethora of useful meth-
odologies involving various types of homogeneous and
heterogeneous catalysts12,13 have been elaborated in order
to keep the simplicity and to improve the efficiency of the
classical Biginelli protocol and to simultaneously overcome
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Muchmore, S.; Yu, H.; Kohlhaas, K.; Alexander, K. M.; McGaraughty,
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TABLE 4. Scope Exploration for the Synthesis of 14a SCHEME 6. Plausible Mechanism for the Synthesis of
entry Ar1 R product timeb (h) yieldc (%) 2H-Chromene-2-thiones 14
1 Ph H 14a 3.5 76
2 Ph 3-OMe 14b 2.5 85
3 4-MeO 3 C6H4 5-Br 14c 3 82
4 4-MeO 3 C6H4 5-NO2 14d 3.5 73
5 2-thienyl 3-OMe 14e 2.5 83
6 2-thienyl 5-Br 14f 3 82
7 2-furyl 3-OEt 14g 2.5 87
8 2-furyl 5-Br 14h 3 83
a
Reaction of β-oxodithioester (1 mmol), salicylaldehyde (1 mmol),
and urea (1 mmol). bTime required. cIsolated yields.
Conclusion
In summary, β-oxodithioesters as 1,3-dicarbonyl compo-
nents for the Biginelli reaction have been identified, and a
diverse set of 5-methylmercaptothiocarbonyl-substituted
3,4-dihydropyrimidin-2(1H)-ones has been synthesized in
high yields at ambient temperature. Our literature survey
shows that this is the first example promoted by silica-
sulfuric acid in which β-oxodithioesters as an activated
β-dicarbonyl synthon is used in a Biginelli reaction. The
DHPM formation is accomplished through the ability of
silica-sulfuric acid to function dually as a Lewis acid and
dehydrating agent in the same transformation. The metho-
dology has been further elaborated to the corresponding
6-amino-1,3-dimethyluracil, the cyclic analogue of urea leading
to pyridopyrimidinones, thus providing a further point of
diversity in the newly synthesized heterocyclic framework.
The synthesis commenced with commercially available Further, the facile access to 3-aroyl/heteroaroyl-2H-chromen-
6-amino-1,3-dimethyluracil 16, which upon treatment with 2-thiones demonstrates the versatility of the annulation proto-
9 and 10 resulted in dihydropyridopyrimidinones 17 in col via β-oxodithioesters in generating novel biologically
55-66% yields (Scheme 7). In this case, the reaction of important thiocoumarins, as some of them cannot be synthe-
3-nitrobenzaldehyde, 6-amino-1,3-dimethyluracil 16, and sized easily by traditional classical methods. The tolerance to
β-oxodithioester 9a was taken as a model reaction and per- acid-sensitive reactants such as thienyl and furyl carbaldehydes,
formed in the presence of SiO2-H2SO4 in refluxing ethanol to applicability to sterically hindered β-oxodithioesters, and sim-
afford 17a in 66% yield (Table 5, entry 1). To check the real ple recyclability without losing catalytic activity make this
effect of the catalyst, the reaction was performed without cata- catalyst a good alternative to literature methods.
lyst, which gave the expected product 17a in low yield (25%). To
increase the yield of the desired product, catalysts such as Experimental Section
BF3 3 OEt2 and InCl3 were also tried that furnished the desired General Methods. All starting materials were commercially
products but in lower yields (40-45%). Further, we carried out available and used as received without further purification.
the above reaction under solvent-free condition also, which Silica-sulfuric acid was prepared according to the protocol
shows several close spots on TLC, and the desired product could described in literature.33b β-Oxodithioesters 9a-e were pre-
not be isolated. In order to find the optimum solvent, the pared following the known procedure36 displayed in Scheme 2.
reaction was performed in various solvents, such as EtOH, Thin-layer chromatography (TLC) was performed using silica
MeOH, acetonitrile, THF, DMF, and CCl4 at 80 °C, and it gel 60 F254 precoated plates. Infrared (IR) spectra are measured
was found that EtOH provided the best result. To evaluate the in KBr, and wavelengths (ν) are reported in cm-1. 1H and 13C
scope of the reaction, various substituted aldehydes 10 and NMR spectra were recorded on NMR spectrometers operating
structurally varied β-oxodithioesters 9 were used, and in all at 300 and 75.5 MHz, respectively. Chemical shifts (δ) are given
in parts per million (ppm) using the residue solvent peaks as
cases, moderate yields were obtained (Table 5). However, when reference relative to TMS. J values are given in Hz. Mass spectra
some aliphatic aldehydes such as acetaldehyde, propionalde- were recorded using electrospray ionization (ESI) mass spectro-
hyde, and isobutyraldehyde were used, it led to a number of very metry. The C, H, and N analyses were performed from micro-
close spots on TLC, which could not be isolated. The structures analytical laboratory. The melting points are uncorrected.
General Procedure for Synthesis of Dihydropyrimidin-2(1H)-
(41) (a) Crystallographic data for compound 12t have been deposited ones (12a-v). The β-oxodithioester (1.0 mmol), aldehyde (1.1
with the Cambridge Crystallographic Data Centre as supplementary pub- mmol), and urea (1.2 mmol) were mixed in a minimum amount
lication no. CCDC 784530. These data can be obtained free of charge at of dry ethanol to get a paste like mixture. SiO2-H2SO4 (60 mg)
www.ccdc.cam.ac.uk; (b) Crystallographic data for compound 17a have
been deposited with the Cambridge Crystallographic Data Centre as supple-
was added to the pasty mixture, which was then heated at 80 °C
mentary publication no. CCDC 783933. These data can be obtained free of for the stipulated period of time. After completion of the
charge at www.ccdc.cam.ac.uk. reaction (monitored by TLC), EtOAc (10 mL) was added to
the reaction mixture and the catalyst was filtered off. Then water 134.6, 133.9, 129.8, 128.7, 128.4, 128.1, 119.6, 113.9, 60.4, 55.2,
(20 mL) was added to the reaction mixture to remove any 20.4; IR (KBr, νmax, cm-1): 3214, 3078, 1695, 1457; MS m/z =
unreacted urea and the mixture extracted with ethyl acetate 370 (Mþ). Anal. Calcd for C19H18N2O2S2: C, 61.60; H, 4.90; N,
(2 10 mL). The combined organic layers were dried over 7.56. Found: C, 61.42; H, 5.26; N, 7.76.
anhyd Na2SO4 and then evaporated in vacuo. The crude residue 5-Methylmercaptothiocarbonyl-4-(4-chlorophenyl)-6-phenyl-
was purified by column chromatography over silica gel using 3,4-dihydropyrimidin-2(1H)-one (12e): bright yellow powder;
acetone/dichloromethane (1:99) as eluent to afford pure dihy- mp 250-251 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 7.45-
dropyrimidin-2(1H)-ones. 7.25 (m, 9H), 6.38 (s, 1H), 5.94 (d, J = 2.4 Hz, 1H), 5.38 (s, 1H),
General Procedure for the Synthesis of 2H-Chromene-2- 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6, δ ppm)
thiones (14a-h). The β-oxodithioester (1.0 mmol), salicylalde- 224.3, 151.4, 140.5, 140.2, 133.3, 131.5, 128.6, 127.7, 127.4,
hyde (1.2 mmol), urea (1.0 mmol), and SiO2-H2SO4 (60 mg) 127.2, 127.1, 117.3, 57.6, 19.3; IR (KBr, νmax, cm-1) 3196, 3080,
were mixed and heated at 85 °C for the stipulated period of time. 1696, 1457; MS m/z = 374 (Mþ). Anal. Calcd for C18H15ClN2-
After completion of the reaction (monitored by TLC), ethyl OS2: C, 56.67; H, 4.03; N, 7.47. Found: C, 56.82; H, 4.30; N,
acetate (10 mL) was added to the reaction mixture, and the 7.28.
catalyst was filtered off. Water (20 mL) was then added to the 5-Methylmercaptothiocarbonyl-4-thienyl-6-phenyl-3,4-dihy-
reaction mixture and the mixture extracted with ethyl acetate dropyrimidin-2(1H)-one (12f): bright yellow powder; mp 201-
(2 10 mL). The combined organic layers were dried over 202 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 7.44-7.41 (m,
anhyd Na2SO4 and then evaporated in vacuo. The crude residue 5H), 7.03-6.91 (m, 3H), 6.34 (s, 1H), 6.24 (d, J=2.7 Hz, 1H),
was purified by column chromatography over silica gel using 5.45 (s, 1H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm)
increasing amounts of ethyl acetate in n-hexane as eluent to 225.1, 152.4, 145.6, 138.1, 134.5, 130.2, 128.9, 128.4, 126.7,
afford 2H-chromene-2-thiones. 125.5, 125.2, 119.6, 56.0, 20.7; IR (KBr, νmax, cm-1) 3196,
General Procedure for the Synthesis of Pyridopyrimidinones 3085, 1695, 1523; MS m/z=346 (Mþ). Anal. Calcd for C16H14-
(17a-h). To an ethanolic solution of β-oxodithioester (1.0 mmol), N2OS3: C, 55.46; H, 4.07; N, 8.08. Found: C, 55.23; H, 4.26; N,
aldehyde (1.0 mmol), and 6-amino-1,3-dimethyluracil (1.2 mmol) 8.30.
was added SiO2-H2SO4 (60 mg) and the mixture refluxed for the 5-Methylmercaptothiocarbonyl-4-(4-bromophenyl)-6-(4-meth-
stipulated period of time. After completion of the reaction oxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (12g): bright yellow
(monitored by TLC), the catalyst was filtered out. Ethanol was powder; mp 194-195 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
evaporated; water (20 mL) was added and the mixture extracted 7.44-7.34 (m, 4H), 7.26-7.23 (m, 2H), 7.11 (s, 1H), 6.89 (d, J =
by ethyl acetate (2 10 mL). The combined organic layers were 8.7 Hz, 2H), 6.03 (s, 1H), 5.85 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H),
dried over anhyd Na2SO4 and then evaporated in vacuo. The 2.32 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 226.7, 160.9,
crude residue was purified by column chromatography over silica 152.8, 140.9, 137.6, 131.7, 129.8, 128.8, 126.4, 122.0, 118.3,
gel using increasing amounts of ethyl acetate in n-hexane as eluent 114.1, 60.1, 55.3, 20.5; IR (KBr, νmax, cm-1) 3212, 3091, 1697,
to afford pyridopyrimidinones. 1454; MS m/z = 448 (Mþ). Anal. Calcd for C19H17BrN2O2S2: C,
Characterization Data of the Isolated Compounds. 5-Methyl- 50.78; H, 3.81; N, 6.23. Found: C, 50.54; H, 3.67; N, 6.41.
mercaptothiocarbonyl-4-(4-nitrophenyl)-6-phenyl-3,4-dihydro- 5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-6-(4-meth-
pyrimidin-2(1H)-one (12a): bright yellow powder; mp 214- oxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (12h): bright yellow
215 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 8.20 (d, J = 8.7 powder; mp 203-204 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
Hz, 2H), 7.57-7.41 (m, 7H), 7.16 (s, 1H), 6.33 (s, 1H), 6.04 (d, J = 7.39-7.36 (m, 2H), 7.30-7.25 (m, 2H), 6.89-6.82 (m, 4H), 6.32 (s,
2.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 1H), 5.86 (d, J = 2.1 Hz, 1H), 5.29 (s, 1H), 3.82 (s, 3H), 3.78 (s,
226.1, 153.1, 148.5, 147.5, 137.9, 133.9, 130.2, 128.8, 128.2, 128.0, 3H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6, δ
123.9, 118.0, 59.8, 20.5; IR (KBr, νmax, cm-1) 3215, 3076, 1697, ppm) 227.3, 160.8, 159.3, 152.4, 136.3, 134.0, 129.6, 128.4, 126.8,
1530; MS m/z = 385 (Mþ). Anal. Calcd for C18H15N3O3S2: C, 119.2, 114.1, 113.9, 60.5, 55.3, 55.2, 20.4; IR (KBr, νmax, cm-1)
56.09; H, 3.92; N, 10.90. Found: C, 56.18; H, 3.78; N, 11.01. 3196, 3096, 1699, 1639; MS m/z = 400 (Mþ). Anal. Calcd for
5-Methylmercaptothiocarbonyl-4-(4-bromophenyl)-6-phenyl- C20H20N2O3S2: C, 59.98; H, 5.03; N, 6.99. Found: C, 60.18; H,
3,4-dihydropyrimidin-2(1H)-one (12b): bright yellow powder; 5.29; N, 7.26.
mp 239-240 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 7.46- 5-Methylmercaptothiocarbonyl-4-(2-chlorophenyl)-6-(4-meth-
7.37 (m, 8H), 7.27-7.24 (m, 1H), 6.46 (s, 1H), 5.93 (d, J = 2.7 oxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (12i): bright yellow
Hz, 1H), 5.45 (s, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3þ powder; mp 239-241 °C; 1H NMR (300 MHz, CDCl3, δ ppm)
DMSO-d6, δ ppm) 224.3, 151.5, 141.0, 140.2, 133.3, 130.1, 7.48-7.38 (m, 4H), 7.26-7.23 (m, 2H), 6.95-6.88 (m, 3H), 6.18
128.7, 127.8, 127.3, 119.9, 117.3, 57.8, 19.3; IR (KBr, νmax, (d, J = 3.0 Hz, 1H), 5.74 (s, 1H), 3.86 (s, 3H), 2.36 (s, 3H); 13C
cm-1) 3197, 3081, 1697, 1636; MS m/z=418 (Mþ). Anal. Calcd NMR (75 MHz, CDCl3 þ DMSO-d6, δ ppm) 224.7, 160.3,
for C18H15BrN2OS2: C, 51.55; H, 3.61; N, 6.68. Found: C, 151.9, 141.2, 138.2, 132.1, 129.7, 129.1, 128.4, 127.8, 126.5,
51.36; H, 3.77; N, 6.41. 125.6, 115.6, 113.3, 56.3, 54.5, 19.6; IR (KBr, νmax, cm-1)
5-Methylmercaptothiocarbonyl-4,6-diphenyl-3,4-dihydropyri- 3205, 3067, 1703, 1635; MS m/z = 404 (Mþ). Anal. Calcd for
midin-2(1H)-one (12c): bright yellow powder; mp 196-198 °C; C19H17ClN2O2S2: C, 56.36; H, 4.23; N, 6.92. Found: C, 56.13;
1
H NMR (300 MHz, CDCl3, δ ppm) 7.45-7.29 (m, 10H), 6.97 H, 4.19; N, 7.25.
(s, 1H), 5.91 (s, 1H), 5.81 (s, 1H), 2.28 (s, 3H); 13C NMR (75 5-Methylmercaptothiocarbonyl-4-phenyl-6-(4-methoxyphenyl)-
MHz, CDCl3, δ ppm) 227.0, 152.5, 141.6, 136.3, 134.5, 129.8, 3,4-dihydropyrimidin-2(1H)-one (12j): bright yellow powder; Mp
128.7, 128.6, 128.1, 127.1, 119.3, 60.9, 20.4; IR (KBr, νmax, 199-200 °C; 1H NMR (300 MHz, CDCl3, δ ppm): 7.39-7.25 (m,
cm-1) 3214, 3085, 1698, 1637; MS m/z = 340 (Mþ). Anal. Calcd 7H), 6.89 (d, J = 8.7 Hz, 2H), 6.77 (s, 1H), 5.90 (d, J=1.8 Hz,
for C18H16N2OS2: C, 63.50; H, 4.74; N, 8.23. Found: C, 63.33; 1H), 5.63 (s, 1H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3, δ
H, 4.93; N, 8.39. ppm) 227.0, 160.8, 141.9, 137.4, 129.8, 129.3, 128.6, 127.9, 127.1,
5-Methylmercaptothiocarbonyl-4-(4-methoxyphenyl)-6-phenyl- 126.7, 126.5, 118.7, 114.0, 60.6, 55.2, 20.4; IR (KBr, νmax, cm-1)
3,4-dihydropyrimidin-2(1H)-one (12d): bright yellow powder; mp 3206, 3088, 2193, 1695; MS m/z = 370 (Mþ). Anal. Calcd for
188-190 °C; 1H NMR (75 MHz, CDCl3, δ ppm) 7.46-7.37 (m, C19H18N2O2S2: C, 61.60; H, 4.90; N, 7.56. Found: C, 61.88; H,
5H), 7.31-7.26 (m, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.32 (s, 1H), 5.18; N, 7.32.
5.89 (d, J = 1.5 Hz, 1H), 5.29 (s, 1H), 3.78 (s, 3H), 2.28 (s, 3H); 5-Methylmercaptothiocarbonyl-4-thienyl-6-(4-methoxyphenyl)-
13
C NMR (300 MHz, CDCl3, δ ppm) 227.2, 159.3, 152.5, 136.1, 3,4-dihydropyrimidin-2(1H)-one (12k): bright yellow powder; mp
3-(4-Methoxybenzoyl)-6-bromo-2H-chromene-2-thione (14c): 146.3, 143.1, 135.1, 134.1, 133.0, 129.9, 129.4, 129.0, 128.2, 127.9,
yellow solid; mp 206-207 °C; 1H NMR (300 MHz, CDCl3, δ 127.0, 126.5, 124.1, 89.9, 44.3, 28.7, 28.1, 20.5; IR (KBr, νmax,
ppm) 7.91 (d, J = 9.0 Hz, 2H), 7.74-7.69 (m, 2H), 7.45 (s, 1H), cm-1) 3447, 2954, 1709, 1499; MS m/z = 469 (Mþ). Anal. Calcd
7.40 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H); for C23H20ClN3O2S2: C, 58.77; H, 4.29; N, 8.94. Found: C, 58.52;
13
C NMR (75 MHz, CDCl3, δ ppm) 192.9, 190.2, 164.4, 155.6, H, 4.43; N, 8.72.
140.3, 135.6, 132.1, 131.2, 130.5, 128.3, 121.5, 118.4, 118.2, 6-Methylmercaptothiocarbonyl-5-(4-bromophenyl)-7-(4-methoxy-
114.1, 55.5; IR (KBr, νmax, cm-1) 3076, 3031, 1656, 1607, phenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-
1235; MS m/z = 374 (Mþ). Anal. Calcd for C17H11BrO3S: C, d]pyrimidine (17c): reddish powder; mp 205-206 °C; 1H NMR
54.41; H, 2.95. Found: C, 54.22; H, 3.15. (300 MHz, CDCl3, δ ppm) 7.42-7.36 (m, 4H), 7.30-7.25 (m,
3-(4-Methoxybenzoyl)-6-nitro-2H-chromene-2-thione (14d): yel- 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.86 (s, 1H), 5.36 (s, 1H), 3.83 (s,
low solid; mp 208-209 °C; 1H NMR (300 MHz, CDCl3, δ ppm) 3H), 3.48 (s, 3H), 3.28 (s, 3H), 2.33 (s, 3H); 13C NMR (75 MHz,
8.46 (m, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.63-7.58 (m, 2H), 6.95 (d, CDCl3, δ ppm) 229.9, 160.9, 160.8, 150.9, 143.5, 143.0, 133.3,
J = 8.7 Hz, 2H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 131.3, 129.7, 129.6, 127.2, 123.6, 120.7, 114.4, 90.2, 55.3, 44.0,
192.2, 189.6, 164.6, 159.3, 132.1, 130.7, 127.9, 127.3, 123.9, 120.1, 28.7, 28.1, 20.5; IR (KBr, νmax, cm-1) 3451, 2934, 1707, 1506;
117.6, 114.2, 55.6; IR (KBr, νmax, cm-1) 3051, 1643, 1593, 1236; MS m/z = 543 (Mþ). Anal. Calcd for C24H22BrN3O3S2: C,
MS m/z = 341 (Mþ). Anal. Calcd for C17H11NO5S: C, 59.82; H, 52.94; H, 4.07; N, 7.72. Found: C, 52.68; H, 4.23; N, 7.50.
3.25; N, 4.10. Found: C, 59.98; H, 3.06; N, 4.38. 6-Methylmercaptothiocarbonyl-7-(4-methoxyphenyl)-1,3-dimeth-
3-(2-Acetylthiophene)-8-methoxy-2H-chromene-2-thione (14e): yl-5-(3-nitrophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]-
yellow solid; mp 174-175 °C; 1H NMR (300 MHz, CDCl3, δ pyrimidine (17d): reddish powder; mp 240-241 °C; 1H NMR (300
ppm) 7.75 (d, J = 4.2 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.57 (s, MHz, CDCl3, δ ppm) 8.24 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.79
1H), 7.32-7.26 (m, 1H), 7.18-7.11 (m, 3H), 4.01 (s, 3H); 13C (d, J = 7.5 Hz, 1H), 7.45-7.41 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H),
NMR (75 MHz, CDCl3, δ ppm) 192.2, 184.3, 146.7, 142.8, 139.0, 5.99 (s, 1H), 5.51 (s, 1H), 3.84 (s, 3H), 3.51 (s, 3H), 3.28 (s, 3H),
135.5, 135.0, 133.0, 128.3, 125.7, 120.4, 119.5, 114.6, 56.3; IR 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 229.2, 161.0,
(KBr, νmax, cm-1) 3059, 2985, 1671, 1602, 1230; MS m/z = 302 150.8, 148.4, 146.7, 143.2, 134.8, 134.4, 129.7, 128.9, 126.9, 122.5,
(Mþ). Anal. Calcd for C15H10O3S2: C, 59.58; H, 3.33. Found: C, 121.8, 114.5, 89.7, 55.4, 44.2, 28.8, 28.1, 20.5; IR (KBr, νmax,
59.73; H, 3.52. cm-1) 3449, 2934, 1701, 1512; MS m/z = 510 (Mþ). Anal. Calcd
3-(2-Acetylthiophene)-6-bromo-2H-chromene-2-thione (14f): for C24H22N4O5S2: C, 56.46; H, 4.34; N, 10.97. Found: C, 56.67;
yellow solid; mp 166-167 °C; 1H NMR (300 MHz, CDCl3, δ H, 4.59; N, 10.71.
ppm) 7.78-7.64 (m, 4H), 7.50 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6-Methylmercaptothiocarbonyl-1,3-dimethyl-5-(3-nitrophenyl)-
7.15-7.11 (t, J = 4.2 Hz, 1H); 13C NMR (75 MHz, CDCl3, δ 2,4-dioxo-7-thiophen-2-yl-1,2,3,4,5,8-hexahydropyrido[2,3-d]-
ppm) 192.4, 183.7, 155.7, 142.5, 139.6, 135.9, 135.1, 131.2, 130.6, pyrimidine (17e): reddish powder; mp 235-236 °C; 1H NMR
128.4, 121.2, 118.5, 118.2; IR (KBr, νmax, cm-1) 3054, 1676, 1610; (300 MHz, CDCl3, δ ppm) 8.23 (s, 1H), 8.06 (d, J = 8.1 Hz,
MS m/z = 350 (Mþ). Anal. Calcd for C14H7BrO2S2: C, 47.87; H, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.45-7.39 (m, 2H), 7.29-7.28
2.01. Found: C, 47.66; H, 2.21. (m, 1H), 7.06-7.03 (m, 1H), 6.07 (s, 1H), 5.39 (s, 1H), 3.57 (s,
3-(2-Acetylfuran)-8-ethoxy-2H-chromene-2-thione (14g): yel- 3H), 3.27 (s, 3H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3, δ
low solid; mp 175-176 °C; 1H NMR (300 MHz, CDCl3, δ ppm) ppm) 222.8, 160.9, 146.2, 143.1, 134.8, 129.3, 128.9, 128.4,
7.61-7.58 (m, 2H), 7.29-7.23 (m, 2H), 7.17-7.10 (m, 2H), 6.57 127.8, 123.0, 122.7, 122.0, 112.8, 112.6, 89.4, 44.4, 28.7, 28.2,
(d, J = 1.8 Hz, 1H), 4.28 (q, J = 6.9 Hz, 2H), 1.55-1.53 (m, 3H); 20.5; IR (KBr, νmax, cm-1) 3441, 2945, 1700, 1503; MS m/z =
C NMR (75 MHz, CDCl3, δ ppm) 192.7, 179.6, 151.7, 147.4, 486 (Mþ). Anal. Calcd for C21H18N4O4S2: C, 51.84; 3.73; N,
13
146.0, 138.2, 133.8, 125.7, 120.5, 120.1, 119.6, 116.0, 112.7, 65.1, 11.51. Found: C, 51.99; H, 3.98; N, 11.27.
14.6; IR (KBr, νmax, cm-1) 3085, 3033, 1677, 1600, 1225; MS 6-Methylmercaptothiocarbonyl-7-(4-chlorophenyl)-1,3-dimeth-
m/z = 300 (Mþ). Anal. Calcd for C16H12O4S: C, 63.99; H, 4.03. yl-5-(3-nitrophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]-
Found: C, 64.05; 4.32. pyrimidine (17f): reddish powder; mp 257-258 °C; 1H NMR (300
3-(2-Acetylfuran)-6-bromo-2H-chromene-2-thione (14h): yel- MHz, CDCl3, δ ppm) 8.23 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.76
low solid; mp 198-199 °C; 1H NMR (300 MHz, CDCl3, δ ppm) (d, J = 7.5 Hz, 1H), 7.46-7.37 (m, 5H), 5.89 (s, 1H), 5.51 (s, 1H),
7.74-7.62 (m, 2H), 7.51 (s, 1H), 7.39-7.25 (m, 3H), 6.59 (s, 1H); 3.51 (s, 3H), 3.27 (s, 3H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3 þ
13
C NMR (75 MHz, CDCl3, δ ppm) 192.5, 179.0, 155.7, 147.6, DMSO-d6, δ ppm) 228.1, 160.6, 150.5, 147.7, 147.1, 143.7, 136.5,
138.9, 136.0, 131.7, 130.7, 121.3, 120.2, 118.5, 118.2, 112.9; IR 135.2, 134.1, 132.9, 130.5, 128.5, 128.1, 121.7, 121.5, 121.0, 90.0, 42.9,
(KBr, νmax, cm-1) 3076, 3023, 1667, 1606, 1223; MS m/z = 334 29.7, 27.5, 19.9; IR (KBr, νmax, cm-1) 3451, 2961, 1703, 1509; MS m/
(Mþ). Anal. Calcd for C14H7BrO3S: C, 50.17; H, 2.11. Found: z = 514 (Mþ). Anal. Calcd for C23H19ClN4O4S2: C, 53.64; H, 3.72;
C, 50.01; H, 2.28. N, 10.88. Found: C, 53.89; H, 3.91, N, 10.68.
6-Methylmercaptothiocarbonyl-1,3-dimethyl-5-(3-nitrophenyl)- 6-Methylmercaptothiocarbonyl-7-furan-2-yl-1,3-dimethyl-5-(3-
2,4-dioxo-7-phenyl-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine nitrophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine
(17a): red crystals; mp 222-223 °C; 1H NMR (300 MHz, CDCl3, (17g): reddish powder; mp 238-239 °C; 1H NMR (300 MHz,
δ ppm) 8.26 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 6.9 Hz, CDCl3, δ ppm) 8.20 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.72 (d, J = 7.5
1H), 7.50-7.43 (m, 6H), 5.99 (s, 1H), 5.54 (s, 1H), 3.51 (s, 3H), Hz, 1H), 7.51-7.38 (m, 2H), 6.73 (s, 1H), 6.57 (d, J = 3.3 Hz,
3.28 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 1H), 6.46 (s, 1H), 5.20 (s, 1H), 3.61 (s, 3H), 3.27 (s, 3H), 2.51 (s,
229.0, 160.9, 150.8, 148.4, 146.5, 143.3, 134.8, 134.0, 130.1, 129.0, 3H); 13C NMR (75 MHz, CDCl3, δ ppm) 230.2, 160.9, 150.8,
128.9, 128.3, 123.2, 122.6, 121.9, 89.4, 44.3, 28.9, 28.1, 20.4; IR 148.4, 146.1, 144.5, 143.3, 142.8, 134.7, 128.9, 122.9, 122.6, 122.1,
(KBr, νmax, cm-1) 3453, 2961, 1705, 1510; MS m/z=480 (Mþ). 112.7, 112.6, 88.6, 44.5, 28.6, 28.1, 20.5; IR (KBr, νmax, cm-1) 3447,
Anal. Calcd for C23H20N4O4S2: C, 57.48; H, 4.19; N, 11.66. 2953, 1705, 1505; MS m/z = 470 (Mþ). Anal. Calcd for C21H18-
Found: C, 57.61; H, 4.35; N, 11.42. N4O5S2: C, 53.61; H, 3.86; N, 11.91. Found: C, 53.46; H, 3.98; N,
6-Methylmercaptothiocarbonyl-5-(3-chlorophenyl)-1,3-dimeth- 11.72.
yl-2,4-dioxo-7-phenyl-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine 6-Methylmercaptothiocarbonyl-7-furan-2-yl-1,3-dimethyl-5-(4-
(17b). Reddish powder; Mp 233-234 °C; 1H NMR (300 MHz, nitrophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyri-
CDCl3, δ ppm) 7.50-7.37 (m, 6H), 7.32-7.29 (m, 1H), 7.18-7.16 midine (17h): reddish powder; mp 235-236 °C; 1H NMR (300
(m, 2H), 5.91 (s, 1H), 5.40 (s, 1H), 3.49 (s, 3H), 3.29 (s, 3H), 2.31 (s, MHz, CDCl3, δ ppm) 8.12 (d, J = 8.4 Hz, 2H), 7.55-7.51 (m,
3H). 13C NMR (75 MHz, CDCl3, δ ppm) 229.6, 160.9, 150.9, 3H), 6.71 (s, 1H), 6.57 (d, J = 3.3 Hz, 1H), 6.48 (t, J = 1.5 Hz,