A convenient synthesis and biological activity of novel pyrido[4,3-d]pyrimidin-4(3H)-ones

Article abstract of DOI:10.1002/jhet.2119

Fifteen novel 2-alkylamino-3-aryl-8-cyano-5-methyl-7-(methylthio)-pyrido[4,3-d]pyrimidin-4(3H)-ones 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j, 6k, 6l, 6m, 6n, 6o were designed and have been successfully synthesized via tandem aza-Wittig and annulation reacti

Full text of DOI:10.1002/jhet.2119

Month 2014
A Convenient Synthesis and Biological Activity of Novel Pyrido[4,3-d]
pyrimidin-4(3H)-ones
a
b
c,a
b
a
*
*
Qingyun Ren, ShiYan Xia, Yucheng Gu, Baoju Li, and Hongwu He
aKey Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal
University, 152 Luoyu Road, Wuhan, 430079, China
bInstitute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
cSyngenta Jealott’s Hill International Research Centre, Bracknell,, Berkshire RG42 6EY, United Kingdom
*
E-mail: ren0227@gmail.com; he1208@ccnu.edu.cn
Received April 30, 2013
DOI 10.1002/jhet.2119
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Fifteen novel 2-alkylamino-3-aryl-8-cyano-5-methyl-7-(methylthio)-pyrido[4,3-d]pyrimidin-4(3H)-ones
6a–6o were designed and have been successfully synthesized via tandem aza-Wittig and annulation reactions
with the corresponding iminophosphoranes 4, aryl isocyanate, and amines in good yields. Their structures
1
were clearly verified by IR spectroscopy, H-NMR spectroscopy, EI-MS, and elemental analysis, and in
the case of compound 6i, further analyzed by single-crystal X-ray diffraction. The preliminary results of
an in vivo bioassay showed that some compounds display moderate antifungal activity.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
increasing attention in view of their utility in the synthesis
of N-heterocyclic compounds [17]. Previously, we had
designed and synthesized fused pyrimidine derivatives such
as thiazolopyrimidinones [18], thienopyrimidinones [19],
and triazolopyrimidinones [20] prepared from various
iminophosphoranes, and it was found that these novel fused
pyrimidines compounds displayed good antifungal activity
against Rhizoctonia solani. As a continuation of our ongoing
project related to the discovery and optimization of pesticide
leads, we would like to describe a facile synthesis of novel
pyrido[4,3-d]pyrimidine derivatives via the tandem aza-
Wittig and cyclization reaction. The preliminary results of
an in vivo bioassay indicated that some of these compounds
display moderate antifungal activity.
Derivatives of pyridopyrimidines have been the focus of
great interest over many years. This is due to the wide range
of biological activities associated with heterocyclic scaffold.
Some of these compounds have shown remarkable biological
properties such as antitumor, antiviral, antibacterial,
antihypertensive, antibronchitis, antiallergic, antiarthritic, and
anti-HIV activities [1–7], whereas others exhibited good
insecticidal, growth regulatory, herbicidal, and fungicidal ac-
tivities [8–10]. For example, some related 4-(phenylamino)
pyrido[d]pyrimidines have been reported as selective
inhibitors of tyrosine phosphorylation by the epidermal
growth-factor receptor and have become an important class
of potential anticancer drugs [1,2].
The pyrido[2,3-d]pyrimidine system has been studied in
more detail, because examples have medicinal applications as
inhibitors of tyrosine kinase [11] or dihydrofolate reductase
[11,12]. However, few reports [1,13] are available so far to
the preparation of pyrido[4,3-d]pyrimidine derivatives, which
are of considerable interest as potential biologically active
compounds or pharmaceuticals. The methods described so
far for the preparation of some representative derivatives of this
ring system involve two general routes [1–16]: (a) formation of
the pyridine ring by cyclization of suitable substituents of a
pyrimidine and (b) formation of the pyrimidine ring by cycli-
zation of a suitable pyridine derivative. However, these
methods often require forcing conditions, long reaction times,
and complex synthetic pathways.
RESULTS AND DISCUSSION
The intermediate 1 was prepared by the reaction of
malononitrile and carbon bisulfide in the presence of KOH as
base in acetonitrile and then treated with ammonium hydroxide
in ethanol [21]. It was reported that 4-aminonicotinonitrile 3
was prepared from reaction of ketene N,S-acetal 1 with ethyl
acetoacetate 2 in moderate yield (48%) by using anhydrous
stannic chloride as catalyst [22]. Herein, we investigated the
effects of a variety of catalysts such as zinc chloride, ferric
chloride, zinc nitrate, and zinc acetate instead of anhydrous
stannic chloride on the reaction. Zinc nitrate was finally
selected as catalyst, and much higher yield (95%) was achieved
(Scheme 1). Optimization of the reaction conditions and the
detailed mechanism using zinc nitrate as catalyst were further
elucidated in our published paper [23].
For the reason given earlier, the synthesis of pyrido[4,3-d]
pyrimidine derivatives is challenging. The aza-Wittig
reactions of iminophosphoranes have recently received
© 2014 HeteroCorporation

Q. Ren, S. Xia, Y. Gu, B. Li, and H. He
Vol 000
Scheme 1. Synthesis of 4-aminonicotinonitrile 3.
Compound 3 was further converted to iminophosphorane 4
via reaction with triphenylphosphine, hexachloroethane, and
triethylamine in good yield. Iminophosphorane 4 reacted
with aromatic isocyanates and gave carbodiimides 5. In
refluxing toluene, the direct reaction of carbodiimides 5 with
alkylamines did not react to give the target compounds 6.
However, when the solvent was changed to CH2Cl2 and in the
presence of a catalytic amount of EtONa/EtOH, compound 5
was converted smoothly to the 2-alkylamino-pyrido[4,3-d]
pyrimidin-4(3H)-ones 6 in satisfactory yields at room
temperature (Scheme 2, Table 1).
alkylamino-pyrido[4,3-d]pyrimidin-4(3H)-ones 6, and an-
other kind of cyclization compound 2-arylamino-pyrido
[4,3-d]pyrimidin-4(3H)-ones 8 were not found (Scheme 3).
This might be due to the geometry of the guanidine inter-
mediate and the conjugative effect of compounds 6. As
the amines were reacted with 5, intermediates 7a were
formed because the amines would attack 5 mainly from
the opposite direction of the CO2Et group because of the
group’s steric hindrance. At the same time, the compounds
6 are more stable than compounds 8 because of the
conjugative effect between the pyridopyrimidine ring and
the phenyl ring. Therefore, only compounds 6 were
obtained regioselectively.
It is worth noting that the reaction between
carbodiimides 5 and primary amines obtained mainly 2-
Scheme 2. Synthesis of 2-alkylamino-pyrido[4,3-d]pyrimidin-4(3H)-ones 6.
Table 1
Synthesis of compound 6.
Compounds
RNH
PrNH
BuNH
i-BuNH
Ar
Yield (%)a
Compounds
RNH
Ar
Yield (%)a
6a
6b
6c
6d
6e
6f
4-FPh
4-FPh
4-FPh
4-FPh
4-FPh
4-FPh
4-FPh
4-ClPh
76
86
88
91
85
78
87
83
6i
6j
6k
6l
6m
6n
6o
BuNH
4-ClPh
4-ClPh
Ph
Ph
Ph
82
91
85
81
87
83
79
Cyclohexylamino
2-ClPhCH2NH
4-FPhCH2NH
3-MePhCH2NH
4-FPh CH2CH2NH
4-MeOPh CH2CH2NH
t-BuNH
CH3(CH2)4NH
CH3(CH2)5NH
Allylamino
PrNH
Ph
Ph
6g
6h
aYields of isolated products based on iminophosphorane 4.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Convenient Synthesis and Biological Activity of Novel Pyrido[4,3-d]pyrimidin-4
(3H)-ones
Scheme 3. Possible mechanism of the formation of compounds 6.
All the compounds of the 6 series were obtained as white
solids after recrystallization from ethanol. Their structures
were fully characterized by IR spectroscopy, 1H-NMR
spectroscopy, EIMS, and elemental analysis. In the case
of 6o, the structure was additionally solved by single-
crystal X-ray diffraction [24] (Figure 1). All structures
were supported spectroscopically. For example, the IR
spectra of 6l revealed CN and C═O absorption bands at
2216 and 1684 cmÀ1, respectively; the signals attributable
to NH are found at 3390 cmÀ1. The corresponding
1H-NMR spectrum showed the 5-Me group at δ(H) 2.90
(s), and the CH3 signals of the SMe appeared at δ(H)
2.69. The other signals resonated at δ(H) 6.97–7.65
(m, 9 arom. H), 4.63 (d, J = 5.6 Hz, CH2), and 4.89
(s, NH). The mass spectrum of 6l showed the molecular
ion peak at m/z 431 as the base peak (100%). The
structures of 6l and the other analogs were further
confirmed on the basis of elemental analysis.
Figure 1. Perspective view of the X-ray crystal structure of 6o.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Q. Ren, S. Xia, Y. Gu, B. Li, and H. He
Vol 000
were recorded in CDCl3 on a Mercury Plus 400 MHz (Varian,
Palo Alto, CA, USA), and resonances were given in parts per
million (d) relative to TMS (d 0.00 ppm). 13C-NMR spectra were
recorded using CDCl3 as the solvent on a Unity Inova 600 MHz
(Varian), and resonances were given in parts per million (d)
relative to CDCl3 (d 77.00 ppm). The elementary analysis was
performed on a Vario EL III elementary analysis instrument
(Elementar Analysensysteme GmbH, Germany). The X-ray sin-
gle crystal diffractometer is Bruker Smart Apex CCD X-ray crys-
tal (Elementar Analysensysteme GmbH). All of the solvents and
materials were reagent grade and purified as required.
The preliminary antifungal activity of compounds 6
series was measured at a concentration of 500 mg/L using
a reported procedure [25], and the in vivo inhibition rates
are listed in Table 2. Fungicidal activities of commercial
fungicides chlorothalonil, dimethomorph, and thiophanate
methyl as a control against the five fungi mentioned in
Table 2 were evaluated at the same condition. It was found
that most of the compounds exhibited inhibitory activity
against Cladosporium cucumerinum and Phytophthora
capsici. They did have any obvious influence on the
growth of Corynespora cassiicola, R. solani, and Fusarium
oxysporum. Although the antifungal activity of these
compounds are lower than that of commercial fungicides,
the inhibitory activity of title compounds could be further
improved by incorporating appropriate functional groups.
In summary, we have developed an efficient and conve-
nient synthetic method for the preparation of pyrido[4,3-d]
pyrimidin-4(3H)-ones in good yield via tandem aza-Wittig
reaction and annulation reactions. The preliminary results
of an in vivo bioassay showed that some compounds display
moderate antifungal activities, and further bioassay,
optimization, and structure–activity relationships of the title
compounds are underway.
Synthesis of 6-methylsulfanyl-4-amino-5-cyano-2-methyl-
nicotinic acid ethyl esters 3. A mixture of 2-(methylsulfanyl-
amino-methylene)-malononitrile 1 (10mmol) and Zn(NO2)2.6H2O
(20 mmol) were added to a stirred solution of ethyl acetoacetate 2
(20 mmol) in ethanol (30mL). The solution was refluxed for 6–8 h
and then cooled to room temperature. The crude precipitated
product was collected by filtration. Further purification was
accomplished by recrystallization from ethanol to give pure
products of 3 in 95% yield. White solid, mp 136.0–138.0°C;
1H-NMR (CDCl3) δ 1.41 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.62
(s, 3H, SCH3), 2.70 (s, 3H, py-CH3), 4.39 (q, J = 7.2 Hz, 2H,
OCH2), 6.68ppm (s, 2H, NH2). MS: m/z 252 (M+ + 1, 23), 251
(M+, 100), 250 (M+ À 1, 41), 223 (47), 205 (31), 177(30); Anal.
Calcd for C11H13N3O2S: C, 52.57; H, 5.21; N, 16.72; S, 12.76.
Found: C, 52.75; H, 4.80; N, 16.89; S, 12.72.
Synthesis of 6-methylsulfanyl-5-cyano-2-methyl-4-[(triphen-
xylphosphanylidene)amino]-nicotinic acid ethyl esters 4. To a
solution of 3 (2.51 g, 10 mmol) in MeCN (40mL) were added
Ph3P (7.86 g, 30mmol), C2Cl6 (7.12g, 30mmol), and Et3N
(8.0mL), in this order. The mixture was stirred for 6–7 h at rt.
Then, the solution was concentrated, and the residue was
recrystallized from EtOH to give 4 in 90% yield. mp 153–155°C.
1H-NMR (CDCl3) δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 2.37 (s, 3H,
SCH3), 2.51 (s, 3H, py-CH3), 3.95 (q, J = 7.2 Hz, 2H, OCH2),
7.44–7.71ppm (m, 15H, Ph-H).
EXPERIMENTAL
Melting points were measured on an electrothermal melting
point apparatus X-4(Beijing Tektronix Instrument Icn., Beijing,
China) and uncorrected. Mass spectra were measured on a
Finnigan Trace MS 2000 spectrometer (Thermo Finnigan, Silicon
Valley, CA, USA). IR spectra were recorded on a NicoletAvatar
360 FT-IR spectrometer (Thermo Electron Inc., San Jose, CA,
USA) as KBr pellets with absorption in cmÀ1. H-NMR spectra
1
Table 2
Antifungal activity (relative inhibition (%), in vivo, 500 mg/L) of compound 6.
Cladosporium
cucumerinum
Corynespora
cassiicola
Rhizoctonia
solani
Phytophthora
capsici
Fusarium
oxysporum
Compounds
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
44
51
21
72
58
7
65
0
69
9
37
18
25
70
40
94
50
47
19
21
46
39
3
25
46
58
0
17
38
47
29
95
54
0
0
0
0
3
63
54
44
49
23
68
24
46
36
58
68
71
55
39
0
0
0
0
0
0
6
37
77
0
0
0
50
31
0
0
77
28
11
0
6
17
0
6
11
6
Chlorothalonil
Dimethomorph
Thiophanatemethyl
98
90
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
A Convenient Synthesis and Biological Activity of Novel Pyrido[4,3-d]pyrimidin-4
(3H)-ones
General procedure for the preparation of 2-alkylamino-3-
aryl-8-cyano-5-methyl-7-(methylthio)-pyrido[4,3-d]pyrimidin-4
(3H)-ones (6a–6o). To a solution of iminophosphorane 4 (0.51 g,
1 mmol) in dry methylene chloride (10 mL), aryl isocyanate
(1.1 mmol) was added under nitrogen at room temperature. After
the reaction mixture was left unstirred for 6–12 h, the solvent was
removed under vacuum, and Et2O/petroleum ether (1:2, 20 mL)
was added to precipitate triphenylphosphine oxide. Removal of the
solvent gave carbodiimides 5, which were used directly without
further purification.
8-Cyano-3-(4-fluorophenyl)-5-methyl-7-(methylthio)-2-(pent-
ylamino)-pyrido[4,3-d]pyrimidin-4(3H)-one (6e). This compound
was obtained as a white solid, mp 263.0–264.0°C, yield 0.35 g,
85%; IR (KBr): 3356, 2857, 2220 (CN), 1682 (C═O), 1558,
1508 cmÀ1 1H-NMR (CDCl3) δ 0.87 (t, J = 7.2 Hz, 3H, CH3),
;
1.23–1.32 (m, 4H, 2*CH2CH2), 1.52–1.55 (m, 2H, CH2), 2.67 (s,
3H, SCH3), 2.88 (s, 3H, py-CH3), 3.50–3.53 (m, 2H, NCH2), 4.48
(s, 1H, NH), 7.30–7.33 ppm (m, 4H, Ar-H). Anal. Calcd for
C21H22FN5OS: C, 61.29; H, 5.39; N, 17.02. Found: C, 61.20; H,
5.11; N, 16.76.
8-Cyano-3-(4-fluorophenyl)-2-(hexylamino)-5-methyl-7-(meth-
Alkylamine (1.1 mmol) was added into the solution of 5 prepared
earlier in CH2Cl2 (10 mL). After the reaction mixture was stirred
continuously for an additional 6 h, the solvent was removed, and
10mL of anhydrous ethanol with several drops of sodium ethoxide
in ethanol (3M) was added. After stirring for another 0.5–1 h, the
solution was condensed, and the residue was recrystallized
from dichloromethane/petroleum ether to give pure 2-alkylamino-
3-aryl-8-cyano-5-methyl-7-(methylthio)-pyrido[4,3-d]pyrimidin-4
(3H)-ones (6a–6o).
ylthio)-pyrido[4,3-d]pyrimidin-4(3H)-one (6f).
This compound
was obtained as a white solid, mp 162.0–164.0°C; yield 0.33 g,
78%; IR (KBr): 3366, 2929, 2220 (CN), 1683 (C═O), 1558,
1532 cmÀ1 1H-NMR (CDCl3) δ 0.86 (t, J= 6.4 Hz, 3H, CH3),
;
1.26–1.53 (m, 8H, 4*CH2), 2.68 (s, 3H, SCH3), 2.89 (s, 3H, py-
CH3), 3.50–3.53 (m, 2H, NCH2), 4.42 (s, 1H, NH), 7.29–7.35 ppm
(m, 4H, Ar-H). Anal. Calcd for C22H24FN5OS: C, 62.10; H, 5.68;
N, 16.46. Found: C, 62.38; H, 5.35; N, 16.19.
2-Allylamino-8-cyano-3-(4-fluorophenyl)-5-methyl-7-(meth-
ylthio)-pyrido[4,3-d]pyrimidin-4(3H)-one (6g). This compound
was obtained as a white solid, mp 285.0–286.0°C; yield
0.33 g, 87%; 1H-NMR (CDCl3) δ 2.63 (s, 3H, SCH3), 2.78
(s, 3H, CH3), 3.93–3.96 (m, 2H, NCH2), 5.07 (d, J = 10 Hz,
1H, CH), 5.17 (d, J = 16.8 Hz, 1H, CH), 5.81–5.85 (m, 1H,
CH), 7.07 (s, 1H, NH), 7.41–7.49 ppm (m, 4H, Ar-H). MS: m/z 382
(M+ +1, 6), 381 (M+, 19), 380 (M+ À 1, 19), 366 (100), 348 (19),
340 (10), 204 (4), 190 (6), 135 (14); Anal. Calcd for
C19H16FN5OS: C, 59.83; H, 4.23; N, 18.36. Found: C, 60.10; H,
4.22; N, 17.91.
8-Cyano-3-(4-fluorophenyl)-5-methyl-7-(methylthio)-2-prop-
ylamino-pyrido[4,3-d]pyrimidin-4(3H)-one (6a). This compound
was obtained as a white solid, mp 270.5–272.0°C, yield 0.29 g,
76%; IR (KBr): 3357, 2963, 2221 (CN), 1682 (C═O), 1584, 1559,
1508 cmÀ1 1H-NMR (CDCl3) δ 0.88 (t, J=7.2Hz, 3H, CH3),
;
1.55–1.60 (m, 2H, CH2), 2.67 (s, 3H, SCH3), 2.87 (s, 3H, py-CH3),
3.50–3.52 (m, 2H, NCH2), 4.46 (s, 1H, NH), 7.26–7.33 ppm
(m, 4H, Ar-H). MS: m/z 385 (M+ + 2, 11), 384 (M+ + 1, 38), 383
(M+, 100), 382 (M+ À 1, 24), 355 (13), 340 (75), 325 (8), 95 (33),
75 (15), 41 (76); Anal. Calcd for C19H18FN5OS: C, 59.51; H, 4.73;
N, 18.26. Found: C, 59.75; H, 4.54; N, 18.60.
3-(4-Chlorophenyl)-8-cyano-5-methyl-7-(methylthio)-2-prop-
2-Butylamino-8-cyano-3-(4-fluorophenyl)-5-methyl-7-(meth-
ylamino-pyrido[4,3-d]pyrimidin-4(3H)-one (6h).
This compound
ylthio)-pyrido[4,3-d]pyrimidin-4(3H)-one (6b).
This compound
was obtained as a white solid, mp 235.0–238.0°C, yield 0.33 g,
83%; 1H-NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H, CH3), 1.55–
1.61 (m, 2H, CH2), 2.68 (s, 3H, SCH3), 2.89 (s, 3H, py-CH3),
3.51–3.53 (m, 2H, NCH2), 4.46 (s, 1H, NH), 7.25–7.63ppm (m,
4H, Ar-H). MS: m/z 401 (M+ + 2, 37), 400 (M+ + 1, 26), 399 (M+,
96), 356 (100), 341 (9), 246 (7), 231 (8), 204 (10), 152 (21);
Anal. Calcd for C19H18ClN5OS: C, 57.07; H, 4.54; N, 17.51.
Found: C, 57.25; H, 4.56; N, 16.94.
3-(4-Chlorophenyl)-8-cyano-2-butylamino-5-methyl-7-(meth-
ylthio)-pyrido[4,3-d]pyrimidin-4(3H)-one (6i). This compound
was obtained as a white solid, mp 233.0–234.0°C, yield 0.34 g,
82%; 1H-NMR (CDCl3) δ 0.91 (t, J = 7.2 Hz, 3H, CH3), 1.24–
1.32 (m, 2H, CH2), 1.49–1.56 (m, 2H, CH2), 2.68 (s, 3H, SCH3),
2.88 (s, 3H, py-CH3), 3.53–3.55 (m, 2H, NCH2), 4.44 (s, 1H,
NH), 7.25–7.63 ppm (m, 4H, Ar-H). MS: m/z 415 (M+ + 2, 8),
414 (M+ + 1, 26), 413 (M+, 100), 322 (34), 204 (52), 182 (55),
167 (67), 106 (31), 91 (65), 77(20); Anal. Calcd for
C20H20ClN5OS: C, 58.03; H, 4.87; N, 16.92. Found: C, 58.12; H,
4.41; N, 16.61.
3-(4-Chlorophenyl)-2-cyclohexylamino-8-cyano-5-methyl-7-
(methylthio)-pyrido[4,3-d]pyrimidin-4(3H)-one (6j). This compound
was obtained as a white solid, mp >280°C, yield 0.40 g, 91%;
1H-NMR (CDCl3) δ 1.06–1.36 (m, 4H, 2*CH2), 1.38–1.47
(m, 2H, CH2), 1.59–1.62 (m, 2H, CH2), 1.97–1.99 (m, 2H, CH2),
2.68 (s, 3H, SCH3), 2.87 (s, 3H, CH3), 4.10–4.14 (m, 1H, CH),
4.26 (d, J = 7.2 Hz, 1H, NH), 7.24–7.63 ppm (m, 4H, Ar-H). MS:
m/z 441 (M+ + 2, 32), 440 (M+ + 1, 18), 439 (M+, 83), 358 (93),
356 (100), 341 (15), 247 (8), 192 (19), 177(6), 152(7); Anal.
Calcd for C22H22ClN5OS: C, 60.06; H, 5.04; N, 15.92. Found:
C, 59.84; H, 4.44; N, 15.47.
was obtained as a white solid, mp >280°C, yield 0.34 g, 86%; IR
(KBr): 3344, 2951, 2222 (CN), 1682 (C═O), 1584, 1559,
1510 cmÀ1 1H-NMR (DMSO) δ 0.88 (t, J= 7.2 Hz, 3H, CH3),
;
1.23–1.26 (m, 2H, CH2), 1.50–1.53 (m, 2H, CH2), 2.63 (s, 3H,
SCH3), 2.78 (s, 3H, py-CH3), 3.32–3.36 (m, 2H, NCH2), 6.84 (s,
1H, NH), 7.41–7.44 ppm (m, 4H, Ar-H). MS: m/z 399 (M+ +2, 4),
398 (M+ + 1, 38), 397 (M+, 30), 396 (M+ À 1, 14), 382 (31), 368
(14), 340 (50), 325 (9), 43 (100); Anal. Calcd for C20H20FN5OS: C,
60.44; H, 5.07; N, 17.62. Found: C, 60.95; H, 4.65; N, 18.00.
8-Cyano-3-(4-fluorophenyl)-2-(iso-butylamino)-5-methyl-7-
(methylthio)-pyrido[4,3-d]pyrimidin-4(3H)-one (6c).
This
compound was obtained as a white solid, mp >280°C, yield
0.35 g, 88%; IR (KBr): 3374, 2930, 2220 (CN), 1682 (C═O),
1
1559, 1531 cmÀ1; H-NMR (CDCl3) δ 0.86 (d, J = 6.8 Hz, 6H,
2*CH3), 1.85–1.89 (m, 1H, CH), 2.68 (s, 3H, SCH3), 2.89 (s,
3H, py-CH3), 3.34–3.38 (m, 2H, NCH2), 4.48 (s, 1H, NH),
7.26–7.34 ppm (m, 4H, Ar-H). Anal. Calcd for C20H20FN5OS:
C, 60.44; H, 5.07; N, 17.62. Found: C, 60.58; H, 4.63; N, 17.31.
8-Cyano-3-(4-fluorophenyl)-5-methyl-7-(methylthio)-2-(tert-
butylamino)-pyrido[4,3-d]pyrimidin-4(3H)-one (6d).
This
compound was obtained as a white solid, mp 278.0–278.9°C,
yield 0.36 g, 91%; IR (KBr): 3416, 2928, 2213 (CN), 1685
(C═O), 1564 cmÀ1 1H-NMR (CDCl3) δ 1.45 (s, 9H, 3*CH3),
;
2.68 (s, 3H, SCH3), 2.87 (s, 3H, py-CH3), 4.30 (s, 1H, NH),
7.29–7.32 ppm (m, 4H, Ar-H). 13C-NMR (CDCl3) δ 13.1, 26.4,
28.8, 53.9, 98.5, 108.0, 114.9, 117.9, 118.2, 129.6, 130.7,
151.8, 157.7, 161.6, 164.6, 167.2 ppm; Anal. Calcd for
C20H20FN5OS: C, 60.44; H, 5.07; N, 17.62. Found: C, 60.72;
H, 4.61; N, 17.30.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Q. Ren, S. Xia, Y. Gu, B. Li, and H. He
Vol 000
2-(2-Chlorobenzylamino)-8-cyano-5-methyl-7-(methylthio)-
3-phenyl-pyrido[4,3-d]pyrimidin-4(3H)-one (6k). This compound
Acknowledgments. The present work was supported by the National
Basic Research Program of China (no. 2010CB126100) and the
National Natural Science Foundation of China (no. 20772042,
21002037). The research was supported in part by the PCSIRT
(no. IRT0953) and a studentship awarded to Qingyun Ren by
Syngenta Ltd.
was obtained as a white solid, mp 202.9–204.9°C, yield 0.38 g,
85%; IR (KBr): 3352, 2919, 2224 (CN), 1688 (C═O), 1557,
1532cmÀ1 1H-NMR (CDCl3) δ 2.68 (s, 3H, SCH3), 2.87
;
(s, 3H, py-CH3), 4.68 (d, J = 6.4 Hz, 2H, NCH2), 5.31
(s, 1H, NH), 7.17–7.80ppm (m, 9H, Ar-H). MS: m/z 450 (M+ + 3,
11), 449 (M+ + 2, 41), 448 (M+ + 1, 34), 447 (M+, 100), 446
(M+ À 1, 17), 412 (78), 322 (33), 140 (14); Anal. Calcd for
C23H18ClN5OS: C, 61.67; H, 4.05; N, 15.63. Found: C, 61.84;
H, 3.88; N, 15.24.
REFERENCES AND NOTES
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8-Cyano-2-(4-fluorobenzylamino)-5-methyl-7-(methylthio)-3-
phenyl-pyrido[4,3-d]pyrimidin-4(3H)-one (6l). This compound
was obtained as a white solid, mp 230.0–232.0°C, yield 0.35 g,
81%; IR (KBr): 3390, 2925, 2216 (CN), 1684 (C═O), 1556,
1
1529cmÀ1; H-NMR (CDCl3) δ 2.69 (s, 3H, SCH3), 2.90 (s, 3H,
[4] Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S. J Med Chem
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py-CH3), 4.63 (d, J = 5.6 Hz, 2H, NCH2), 4.89 (s, 1H, NH),
6.97–7.65 ppm (m, 9H, Ar-H). MS: m/z 433 (M+ + 2, 10), 432
(M+ + 1, 28), 431 (M+, 100), 430 (M+ À 1, 17), 322 (12), 185
(13); Anal. Calcd for C23H18FN5OS: C, 64.02; H, 4.20; N, 16.23.
Found: C, 64.79; H, 3.98; N, 15.92.
[5] Huryn, D. M.; Okabe, M. Chem Rev 1992, 92, 1745.
[6] Kuyper, L. F.; Garvey, J. M.; Baccanari, D. P.; Champness, J. N.;
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[8] Heckler, R. E.; Jourdan, G. P. Eur. Patent 414386, February
27, 1991.
8-Cyano-5-methyl-2-(3-methylbenzylamino)-7-(methylthio)-
3-phenyl-pyrido[4,3-d]pyrimidin-4(3H)-one (6m).
This compound
[9] Rouchaud, J.; Neus, O.; Eelen, H. Weed Res 2002, 42, 14.
[10] Yamada, H. Eur. Patent 665224, June 13, 1995.
[11] (a) Boschelli, D.; Wu, Z.-P.; Klutchko, S. R.; Showalter, H. D. J
Med Chem 1998, 41, 4365; (b) Jérôme A. Tetrahedron 2004, 60(18), 4107.
[12] (a) Rosowsky, A.; Chen, H. J Org Chem 2001, 66, 7522; (b)
DeGraw, J. I.; Christie, P. H.; Colwell, W. T.; Sirotnak, F. M. J Med
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[13] Ren, Q. Y.; Cui, Z. P.; He, H. W.; Gu, Y. C. J Fluorine Chem
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[14] Bhuyan, P.; Boruah, R. C.; Sandhu, J. S. J Org Chem 1990, 55, 568.
[15] Kajino, M.; Meguro, K. Heterocycles 1990, 31, 2153.
[16] Hosmane, R. S.; Lim, B. B.; Summers, M. F.; Hosmane, N. S.
J Org Chem 1988, 53, 5309.
was obtained as a white solid, mp 190.3–192.9°C, yield 0.37 g,
87%; IR (KBr): 3429, 2922, 2215 (CN), 1698 (C═O), 1581,
1
1540cmÀ1; H-NMR (CDCl3) δ 2.33 (s, 3H, CH3), 2.68 (s, 3H,
SCH3), 2.89 (s, 3H, py-CH3), 4.65 (d, J = 5.6Hz, 2H, CH2),
4.86 (s, 1H, NH), 7.07–7.64 ppm (m, 9H, Ar-H). MS: m/z 429
(M+ + 2, 9), 428 (M+ + 1, 29), 427 (M+, 100), 426 (M+ À 1, 16),
322 (14), 196 (33), 120 (32); Anal. Calcd for C24H21N5OS:
C, 67.43; H, 4.95; N, 16.38. Found: C, 67.89; H, 4.77; N, 16.18.
8-cyano-2-(4-fluorophenethylamino)-5-methyl-7-(methylthio)-
3-phenyl-pyrido[4,3-d]pyrimidin-4(3H)-one (6n).
This compound
was obtained as a white solid, mp 207.0–208.7°C, yield 0.37 g,
83%; IR (KBr): 3429, 2928, 2222 (CN), 1693 (C═O), 1557,
[17] Bonini, C.; Auria, M. D.; Funicello, M.; Romaniello, G. Tetra-
hedron 2002, 58, 3507.
;
1535cmÀ1 1H-NMR (CDCl3) δ 2.69(s, 3H, SCH3), 2.86
[18] Liang, Y.; Fan, S.; Mo, W. Y.; He, H. W. J Fluorine Chem
2007, 128(7), 879.
[19] Ren, Q. Y.; Liang, Y. J.; He, H. W.; Fu, L. W.; Gu, Y. C.
Bioorg Med Chem Lett 2009, 19, 6713.
[20] Zhao, J. F.; Xie, C.; Ding, M. W.; He, H. W. Chem Lett 2005,
34, 1022.
[21] Ren, Q. Y.; Mo, W. Y.; Gao, L.; He, H. W.; Gu, Y. C.
J Heteroc Chem 2010, 47, 171.
(t, J = 7.2 Hz, 2H, CH2 ), 2.89 (s, 3H, py-CH3), 3.70–3.72 (m, 2H,
NCH2), 4.46 (s, 1H, NH), 6.91–7.58ppm (m, 9H, Ar-H). MS: m/z
447 (M+ + 2, 5), 446 (M+ + 1, 14), 445 (M+, 63), 425 (20), 322
(100), 307 (7), 122 (50); Anal. Calcd for C24H20FN5OS: C, 64.70;
H, 4.52; N, 15.72. Found: C, 64.67; H, 4.17; N, 15.30.
8-cyano-2-(3-methoxyphenethylamino)-5-methyl-7-(methylthio)-
3-phenyl-pyrido[4,3-d]pyrimidin-4(3H)-one (6o).
This compound
was obtained as a white solid, mp 185.5–188.5°C, yield 0.36 g, 79%; IR
(KBr): 3412, 2931, 2219 (CN), 1689 (C═O), 1556, 1535 cmÀ1; 1H-NMR
(CDCl3) δ 2.69 (s, 3H, SCH3), 2.85 (t, J= 6.4 Hz, 2H, CH2), 2.90 (s, 3H,
py-CH3), 3.72–3.75 (m, 2H, NCH2), 3.79 (s, 3H, OCH3), 4.47 (s, 1H,
NH), 6.61–7.54 ppm (m, 9H, Ar-H). MS: m/z 459 (M++2, 4), 458
(M++1, 13), 457 (M+, 41), 322 (35), 307 (10), 134 (100), 91 (23), 77(23);
Anal. Calcd for C25H23N5O2S: C, 65.63; H, 5.07; N, 15.31. Found:
C, 65.48; H, 4.97; N, 15.07.
[22] Zhao, W. G.; Liu, Z. X.; Li, Z. M.; Wang, B. L. Syn Commun
2003, 33, 4229.
[23] Ren, Q. Y.; Mo, W. Y.; Yao, Y. Y.; He, H. W.; Gu, Y. C. Syn
Commun 2010, 40, 303.
[24] The crystallographic data have been deposited at the Camdridge
Crystallographic Data Center (E-mail: deposit@ccdc.cam.ac.uk).
The deposition number is CCDC-759540.
[25] Shi, Y. X..; Yuan, L. P.; Zhang, Y. B.; Li, B. J. Chin J Pest Sci
2007, 9, 126.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet