Synthesis and biological activity of 4-methylene-pyrido[4,3-d]pyrimidines

Article abstract of DOI:10.1002/jhet.124

(Chemical Equation Presented) Fifteen novel 3-substituted-5-methyl-4- methylene-7-alkylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitriles 5a-o, were synthesized via a facile annulation process in which formation of the pyrimidine ring proceeded

Full text of DOI:10.1002/jhet.124

July 2009
Synthesis and Biological Activity of
4-Methylene-pyrido[4,3-d]pyrimidines
579
Wenyan Mo,a Yongyan Yao,a Yunli Shen,a Hongwu He,a* and Yucheng Gua,b
aKey Laboratory of Pesticide & Chemical Biology, Ministry of Education, Institute of Pesticide
Chemistry, Central China Normal University, Wuhan, People’s Republic of China
bSyngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, United Kingdom
*E-mail: he1208@mail.ccnu.edu.cn
Received January 8, 2009
DOI 10.1002/jhet.124
Published online 25 June 2009 in Wiley InterScience (www.interscience.wiley.com).
Fifteen novel 3-substituted-5-methyl-4-methylene-7-alkylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimi-
dine-8-carbonitriles 5a–o, were synthesized via a facile annulation process in which formation of the
pyrimidine ring proceeded smoothly by the regioselective attack of a formamidate group on a neighbor-
ing carbonyl group instead of a cyano group. Bioassay results indicated that these compounds showed
significant herbicidal activity at a dose of 100 lg/mL on the roots of oil rape and barnyard grass. In
addition, some of these compounds displayed fungicidal activity.
J. Heterocyclic Chem., 46, 579 (2009).
INTRODUCTION
noted that the synthesis of the substituted pyridines, or
the pyrimidine ring closure, always suffered from cer-
tain drawbacks, such as low yield, long reaction time, or
difficulty in isolating or purifying the products [3,4]. In
the protocol described here, formation of the pyrimidine
ring proceeded regioselectively and with high efficiency
(see Scheme 1).
Reports in the literature on the biological activity of
pyrido[4,3-d]pyrimidines relate mainly to their pharma-
ceutical activity as EGFR-TK and DHFR inhibitors [1].
Very little has been reported about their biological activ-
ities relating to agriculture [2].
Generally, pyrido[d]pyrimidines have been prepared
by routes in which the pyrimidine ring is formed by cy-
clization of suitable substituents on a pyridine [3]. For
example, it has been reported that formamidate reacts
with a cyano group in the neighboring position to afford
a pyrimidine ring [4]. However, there are no reports
about formamidate regioselectively attacking a neighbor-
ing carbonyl group instead of a cyano group.
The intermediates 1 and 2 can be prepared according
to a published method [6]. It was reported that 4-amino
nicotinonitrile 3 was prepared in moderate yield (48%)
by using anhydrous stannic chloride as catalyst [7]. We
improved the conditions by using zinc nitrate as catalyst
to achieve much higher yield than the reported method
(over 83%) [8]. By optimizing the reaction conditions,
formamidate 4a was obtained with the yield of 87%
yield in the presence of p-toluene sulfonic acid. By
comparison, only 32% yield was obtained when no cata-
lyst was used, and formamidate 4b was obtained with
82% yield in the presence of acetic anhydride as the
catalyst.
In our previous work, we have synthesized various
pyrido[4,3–d]pyrimidine derivatives possessing fungici-
dal and herbicidal activity [5]. As a progression to this
research, we herein describe a highly efficient regiose-
lective cyclization reaction leading to the synthesis of
pyrido[4,3–d]pyrimidines under mild conditions and in
short reaction times. A preliminary in vitro bioassay
indicated that these 4-methylene-pyrido[4,3–d]pyrimi-
dines have strong herbicidal activity and that some have
fungicidal activity as well.
The formamidate 4 reacted with primary amines
smoothly and regioselectively in acetonitrile at 40ꢀ
50ꢁC to give the title compounds 5a–o in moderate to
excellent yields. The products were easily isolated by
filtration. The structures of compounds 5a–o were fully
elucidated by a comprehensive analysis of their IR, MS,
1
and H NMR spectra and by elemental analysis.
RESULTS AND DISCUSSION
The compounds 5a–o were screened for activity
against six fungi, namely Fusarium oxysporium, Rhizo-
ctonia solani, Botrytis cinerea, Gibberella zeae,
Dothiorella gregaria, and Colletotrichum gossypii, at a
The conventional synthetic route to pyrido[4,3–d]pyri-
midines involves formation of the pyrimidine ring by
closure of suitable substituents on a pyridine. It was
C
V
2009 HeteroCorporation

580
W. Mo, Y. Yao, Y. Shen, H. He, and Y. Gu
Vol 46
Scheme 1
(2-chloropyridin-4-yl)methyl moiety in position 3 of the
pyrimidine ring showed much better activity than the
rest of the series with over 85% inhibition even at
the lower concentration of 10 lg/mL. Switching the sub-
stituent R from methyl to ethyl has no obvious effect on
the inhibition rates. In terms of R1, the substituents with
electron-donating groups on the phenyl rings seem to
have somewhat higher herbicidal activity. For example,
compounds 5d and 5e showed better activity than
compound 5c, and compounds 5l–o were better than
compound 5k.
EXPERIMENTAL
concentration of 50 lg/mL according to a reported
method [5]. As the results in Table 1 show, most of the
compounds have weak fungicidal activity. Among these
compounds, only compound 5a, in which R1 is (2-
chloropyridin-4-yl)methyl group, exhibited moderate
inhibitory activity against each of the six fungi. This
might imply that the introduction of pyridine ring to the
position 3 of pyrimidines was important for its fungici-
dal activity. All the remaining compounds, in which the
substituent R1 is alkyl or substituted benzyl, showed
only weak antifungal activity.
All chemicals were of reagent grade and were commercially
available. Solvents were either used directly or were purified
as required. Fusarium oxysporium, Rhizoctonia solani, Botrytis
cinerea, Gibberella zeae, Dothiorella gregaria, Colletotrichum
gossypii, and seeds of oil rape and barnyard grass were pro-
vided through the courtesy of the Bioassay Center, Central
China Normal University.
Melting points were measured on a WRS-1B Digital melting
point apparatus. 1H NMR spectra were recorded at 400 MHz
in CDCl3 solution on a Varian VNMR-400 Spectrometer,
whereas IR spectra were recorded on a Nicolet AVATAR-360
Infrared Spectrometer. The MS spectra were determined using
a Finnigan Trace MS Spectrometer, and the signals were given
in m/z. Elementary analysis was carried out on a Vario EL III
CHNSO elemental analyzer.
The herbicidal activity of compounds 5a–o was also
evaluated, against two representative targets, oil rape
and barnyard grass, at concentrations of 100 and 10 lg/
mL, according to a literature method [9]. The results are
listed in Table 2 and show that these compounds have
moderate to good herbicidal activity against the roots of
these two species at the rate of 100 lg/mL, especially
against the root of barnyard grass. Compound 5a with
Intermediates 1 and 2 were prepared according to the
literature [6].
5-Acetyl-4-amino-6-methyl-2-alkylsulfanyl-nicotinonitrile
(3). Acetylacetone (1.0 g, 10 mmol) and 2 (10 mmol) were
added to a stirred solution of zinc nitrate in 30 mL alcohol.
The mixture was stirred and refluxed for 12 h. The precipitate
Table 1
Antifungal activity of compounds 5a–o (% inhiblition).
50 lg/mL
Compounds
R
R1
F. oxysporium
R. solani
B. cinerea
G. zeae
D. gregaria
C. gossypii
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
Me
Me
Me
Me
Me
Et
2-Chloropyridin-4-yl-methyl
a-Phenyl ethyl
2AClAC6H4ACH2A
2ACH3AC6H4ACH2A
3ACH3AC6H4ACH2A
Ethyl
36
42
12
8
52
33
3
81
48
12
19
19
17
14
9
43
56
9
60
14
20
26
26
21
21
10
7
54
26
14
14
11
31
27
23
27
15
19
15
4
0
0
3
11
6
0
50
35
15
19
15
4
32
9
7
Et
Et
Propyl
Butyl
19
19
16
9
Et
Et
Amyl
Hexyl
0
4
23
20
11
23
17
0
10
0
0
Et
Et
2AClAC6H4ACH2A
2ACH3AC6H4ACH2A
3ACH3AC6H4ACH2A
4ACH3AC6H4ACH2A
4AOCH3AC6H4ACH2A
7
2
6
9
4
Et
Et
Et
4
0
3
3
15
19
0
4
9
3
0
0
19
19
0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Synthesis and Biological Activity of 4-Methylene-pyrido[4,3-d]pyrimidines
581
Table 2
Herbicidal activity of compounds 5a-o (% inhibition).
Oil rape (root/stalk)
Barnyard grass (root/stalk)
Compds
R
R1
100 lg/mL
10 lg/mL
100 lg/mL
10 lg/mL
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
Me
Me
Me
Me
Me
Et
2-Chloropyridin-4-yl-methyl
a-Phenylethyl
96/63
68/26
62/5
91/37
37/21
13/0
97/81
72/56
77/67
89/77
87/50
69/59
42/41
53/48
92/76
89/72
77/59
78/62
94/72
92/76
88/66
87/69
67/50
62/56
64/56
64/60
8/0
2AClAC6H4ACH2A
2ACH3AC6H4ACH2
3ACH3AC6H4ACH2
Ethyl
68/16
82/21
45/35
46/41
63/29
43/35
71/29
51/35
64/35
81/47
61/35
86/41
18/11
26/16
54/18
17/6
Et
Et
Propyl
Butyl
28/41
0/0
25/18
32/24
45/24
17/24
32/29
26/29
39/18
36/35
Et
Et
Amyl
Hexyl
19/17
39/35
58/52
67/59
64/55
68/57
64/48
Et
Et
2AClAC6H4ACH2A
2ACH3AC6H4ACH2A
3ACH3AC6H4ACH2A
4ACH3AC6H4ACH2A
4AOCH3AC6H4ACH2A
Et
Et
Et
was filtered off, washed with water (10 mL ꢂ 3), and recrys-
talized from alcohol to give 3.
5-acetyl-4-amino-6-methyl-2-methylsulfanyl-nicotinonitrile
(3a). White solid, m.p. 163.5–164.5ꢁC, yield 83%. 1H NMR
(CDCl3): d 2.58 (s, 3H, CH3), 2.61 (s, 3H, SCH3), 2.68 (s, 3H,
COCH3), 6.60 ppm (br, 2H, NH2).
5-acetyl-4-amino-6-methyl-2-ethylsulfanyl-nicotinonitrile
(3b). Yellowish solid, m.p. 139.0–140.0ꢁC, yield 89%. 1H
NMR (CDCl3): d 1.38 (t, 3H, SCH2CH3, J ¼ 7.4 Hz), 2.59 (s,
3H, CH3), 2.70 (s, 3H, COCH3), 3.15 (q, 2H, SCH2CH3, J ¼
7.4 Hz), 6.68 ppm (br, 2H, NH2).
3-[(2-Chloropyridin-4-yl)methyl]-5-methyl-4-methylene-7-
methylsulfanyl-3,4-dihydropyrido[4,3–d]pyrimidine-8-carbon-
itrile (5a). This compound was obtained as a pale yellow
solid, m.p. 167.9–168.2ꢁC, yield 59%. IR (KBr): m 3036,
2931, 2218, 1610, 1550, 1523, 1390, 1278 cmꢃ1 1H NMR
;
(CDCl3): d 2.61 (s, 3H, CH3), 2.64 (s, 3H, SCH3), 4.67 (d,
2H, ¼¼CH2), 4.83 (s, 2H, CH2), 7.20-7.64 (m, 3H, pyridine-H),
7.86 ppm (s, 1H, pyrimidine-H); ms: m/z 357 (Mþþ1 20).
Anal. Calcd. for C17H14ClN5S (356): C, 57.38; H, 3.97; N,
19.68. Found C, 57.82; H, 3.44; N, 19.71.
3-(ꢀ-Phenylethyl)-5-methyl-4-methylene-7-methylsulfanyl-
3,4-dihydropyrido[4,3–d]pyrimidine-8-carbonitrile (5b). This
compound was obtained as a white solid, m.p. 147.4–148.5ꢁC,
yield 62%. IR (KBr): m 3170, 2978, 2925, 2211, 1621, 1563,
N-(3-Acetyl-5-cyano-2-methyl-6-alkylsulfanyl-pyridin-4-yl)-
formimidic acid ethyl ester (4). To a solution of 4-aminopyri-
dine 3 (10 mmol) in triethyl orthoformate (5.92 g, 40 mmol)
was added acetic anhydride or p-toluene sulfonic acid as cata-
lyst. The mixture was heated and monitored by TLC. The
triethyl orthoformate was removed at reduced pressure, and the
residue was purified by silica gel chromatography (ether:petro-
leum ether¼1:10) to afford formamidate 4.
1514, 1399, 1294 cmꢃ1 1H NMR (CDCl3): d 1.63 (d, 3H,
;
PhACH3, J ¼ 4.0 Hz), 2.45 (s, 3H, CH3), 2.60 (s, 3H, SCH3),
4.65 (d, 2H, ¼¼CH2), 6.41 (d, 1H, PhACH, J ¼ 4.0 Hz), 6.27-
7.43 (m, 5H, ArH), 7.75 ppm (s, 1H, pyrimidine-H); ms: m/z
334 (Mþ 8). Anal. Calcd. for C19H18N4S (334): C, 68.23; H,
5.42; N, 16.75. Found C, 68.29; H, 5.44;, N, 16.51.
N-(3-acetyl-5-cyano-2-methyl-6-methylsulfanyl-pyridin-4-yl)-
formimidic acid ethyl ester (4a). White solid, m.p. 78.5–
3-(2-Chlorophenyl)-5-methyl-4-methylene-7-methyl sulfanyl-
3,4-dihydropyrido[4,3–d]pyrimidine-8-carbonitrile (5c). This
compound was obtained as a white solid, m.p. 143.2–144.5ꢁC,
yield 63%. IR (KBr): m 3148, 2927, 2215, 1601, 1548, 1524,
1
79.9ꢁC, yield 95%. H NMR: d 1.40 (t, 3H, CH2CH3, J ¼ 8.0
Hz), 2.46 (s, 3 H, CH3), 2.56 (s, 3H, SCH3), 2.62 (s, 3H,
COCH3), 4.39 (q, 2H, CH2CH3, J ¼ 8.0 Hz), 8.06 ppm (s, 1H,
¼¼CH). ms (70 Ev): m/z 277 (Mþ, 63).
1396, 1280 cmꢃ1 1H NMR (CDCl3): d 2.61 (s, 3H, CH3),
;
N-(3-acetyl-5-cyano-2-methyl-6-ethylsulfanyl-pyridin-4-yl)-
formimidic acid ethyl ester (4b). Yellowish liquid, yield 82%.
1H NMR: d 1.38 (t, 3H, SCH2CH3, J ¼ 3.8 Hz), 1.40 (t, 3H,
CH2CH3, J ¼ 3.8 Hz), 2.45 (s, 3H, CH3), 2.46 (s, 3H,
COCH3), 3.27 (q, 2H, SCH2CH3, J ¼ 3.6 Hz), 4.27 (q, 2H,
CH2CH3, J ¼ 3.6 Hz), 7.65 ppm (s, 1H, N¼¼CH).
2.66 (s, 3H, SCH3), 4.46 (d, 1H, ¼¼CHa, J ¼ 2.0 Hz), 4.64 (d,
1H, ¼¼CHb, J ¼ 2.0 Hz), 4.86 (s, 2H, CH2), 7.21-7.47 (m, 4H,
ArH), 7.55 ppm (s, 1H, pyrimidine-H); ms: m/z 357 (Mþþ2
7), 355(Mþ 24). Anal. Calcd. for C18H15ClN4S (355): C,
60.92; H, 4.26; N, 15.79. Found C, 60.72; H, 4.44; N, 15.71.
3-(2-Methylphenyl)-5-methyl-4-methylene-7-methyl sulfanyl-
3,4-dihydro-pyrido[4,3–d]pyrimidine-8-carbonitrile (5d). This
compound was obtained as a white solid, m.p. 184.2–184.8ꢁC,
yield 75%. IR (KBr): m 3001, 2926, 2218, 1604, 1553, 1521,
General procedure for the preparation of compounds
(5a–m). To a solution of formamidate 4 (10 mmol) in anhy-
drous acetonitrile (10 mL) was added the appropriate amine
(15 mmol), and the mixture was stirred and heated at 40–50ꢁC
for 30 min. The precipitate was isolated by filtration, then
recrystalized from acetone/petroleum ether to give pure
products 5.
1
1399, 1278 cmꢃ1; H NMR (CDCl3): d 2.32 (s, 3H, PhACH3),
2.62 (s, 3H, CH3), 2.69 (s, 3H, SCH3), 4.50 (d, 1H, ¼¼CHa,
J ¼ 2.0 Hz), 4.65 (d, 1H, ¼¼CHb, J ¼ 2.0 Hz), 4.69 (s, 2H,
ACH2A), 7.16-7.28 (m, 4H, ArH), 7.44 ppm (s, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

582
W. Mo, Y. Yao, Y. Shen, H. He, and Y. Gu
Vol 46
pyrimidine-H); ms: m/z 335(Mþþ1 9), 334(Mþ 20). Anal.
Calcd. for C19H18N4S (334): C, 68.23; H, 5.42; N, 16.75.
Found C, 68.72; H, 5.44; N, 16.71.
1H, pyrimidine-H); ms: m/z 315(Mþþ1 13), 314(Mþ 47),
313(MþꢃH 14). Anal. Calcd. for C17H22N4S (314): C, 64.93;
H, 7.05; N, 17.82. Found C, 64.59; H, 7.28; N, 17.66.
3-(3-Methylphenyl)-5-methyl-4-methylene-7-methyl sulfanyl-
3,4-dihydro-pyrido[4,3–d]pyrimidine-8-carbonitrile (5e). This
compound was obtained as a white solid, m.p. 162.1–163.6ꢁC,
yield 90%. IR (KBr): m 3074, 2926, 2219, 1607, 1555, 1522,
3-Hexyl-5-methyl-4-methylene-7-ethylsulfanyl-3,4-dihydro
pyrido[4,3–d]pyrimidine-8-carbonitrile (5j). This compound
was obtained as a white solid, m.p. 131.5–132.4ꢁC, yield 79%.
IR (KBr): m 3174, 2950, 2865, 2222, 1615, 1547, 1523,
1
1401, 1262 cmꢃ1; H NMR (CDCl3): d 2.34 (s, 3H, PhACH3),
1397cmꢃ1 1H NMR (CDCl3): d 0.88–0.91 (t, 3H, ACH2CH2
;
2.62 (s, 3H, CH3), 2.64 (s, H, SCH3), 4.54 (d, 1H, ¼¼CHa, J ¼
2.0 Hz), 4.62 (d, 1H, ¼¼CHb, J ¼ 2.0 Hz), 4.74(s,2H,
ACH2A), 7.06–7.28 (m, 4H, ArH), 7.58 ppm (s, 1H, pyrimi-
dine-H); ms: m/z 334(Mþ 43). Anal. Calcd. for C19H18N4S
(334): C, 68.23; H, 5.42; N, 16.75. Found C, 68.39; H, 5.44;
N, 16.73.
CH2CH2CH2CH3, J ¼ 6.8 Hz), 1.33–1.40 (m, 9H, ACH2CH2
CH2CH2CH2CH3 and ASCH2CH3), 1.72ꢃ1.77 (m, 2H,
ACH2CH2CH2CH2CH2CH3), 2.69 (s, 3H, ACH3), 3.25 (q, 2H,
ASCH2CH3, J ¼ 7.3 Hz), 3.61 (t, 2H, ACH2CH2CH2CH2CH3,
J ¼ 7.2 Hz), 4.63 (d, 1H, ¼¼CHa, J ¼ 3.2 Hz), 4.65 (d, 1H,
¼¼CHb, J ¼ 3.2 Hz), 7.47 ppm (s, 1H, pyrimidine-H); ms: m/z
328(Mþ 41). Anal. Calcd. for C18H24N4S (328): C, 65.82; H,
7.36; N, 17.06. Found C, 65.53; H, 7.41; N, 16.99.
3-Ethyl-5-methyl-4-methylene-7-ethylsulfanyl-3,4-dihydro-
pyrido[4,3–d]pyrimidine-8-carbonitrile (5f). This compound
was obtained as a white solid, m.p. 144.1–145.0ꢁC, yield 63%.
IR (KBr): m 3170, 2975, 2931, 2221, 1615, 1547, 1523, 1399
3-(2-Chlorobenzyl)-5-methyl-4-methylene-7-ethylsulfanyl-
3,4-dihydropyrido[4,3–d]pyrimidine-8-carbonitrile (5k). This
compound was obtained as a white solid, m.p. 148.5–149.5ꢁC,
yield 61%. IR (KBr): m 3066, 2928, 2216, 1599, 1548, 1525,
cmꢃ1
;
1H NMR (CDCl3): d 1.36–1.41 (m, 6H, CH3 in
ACH2CH3 and ASCH2CH3), 2.69 (s, 3H, ACH3), 3.24 (q, 2H,
ASCH2CH3, J ¼ 7.3 Hz), 3.69 (q, 2H, ACH2CH3, J ¼ 7.2
Hz), 4.64 (d, 1H, ¼¼CHa, J ¼ 3.2 Hz), 4.65 (d, 1H, ¼¼CHb,
J ¼ 3.2 Hz), 7.52 ppm (s, 1H, pyrimidine-H); ms: m/z
273(Mþþ1 3), 272(Mþ 3). Anal. Calcd. for C14H16N4S (272) :
C, 61.74; H, 5.92; N, 20.57. Found C, 61.72; H, 5.72; N,
20.30.
1393 cmꢃ1
; d 1.37–1.41 (t, 3H,
1H NMR (CDCl3):
ASCH2CH3, J ¼ 7.4 Hz), 2.66 (s, 3H, ACH3), 3.25 (q, 2H,
ASCH2CH3, J ¼ 7.3 Hz), 4.45 (d, 1H, ¼¼CHa, J ¼ 3.6 Hz),
4.63 (d, 1H, ¼¼CHb, J ¼ 3.2 Hz), 4.86 (s, 2H, ACH2A), 7.21–
7.47 (m, 4H, ArH), 7.55 ppm (s, 1H, pyrimidine-H); ms: m/z
370(Mþþ2 7), 368(Mþ 23). Anal. Calcd. for C19H17ClN4S
(368): C, 61.86; H, 4.65; N, 15.19. Found C, 61.62; H, 4.74;
N, 14.93.
3-Propyl-5-methyl-4-methylene-7-ethylsulfanyl-3,4-dihydro-
pyrido[4,3–d]pyrimidine-8-carbonitrile (5g). This compound
was obtained as a white solid, m.p. 148.8–150.4ꢁC, yield 61%.
IR (KBr): m 3180, 2966, 2875, 2221, 1613, 1548, 1521,
3-(2-Methylbenzyl)-5-methyl-4-methylene-7-ethylsulfanyl-
3,4-dihydro-pyrido[4,3–d]pyrimidine-8-carbonitrile (5l). This
compound was obtained as a white solid, m.p. 153.9–154.9ꢁC,
yield 68%. IR (KBr): m 3066, 2966, 2218, 1607, 1554, 1523,
1
1388 cmꢃ1; H NMR (CDCl3): d 0.99 (t, 3H, ACH2CH2CH3,
J ¼ 7.4 Hz), 1.38 (t, 3H, ASCH2CH3, J ¼ 8.0 Hz), 1.75ꢃ1.81
(m, 2H, ACH2CH2CH3), 2.69 (s, 3H, ACH3), 3.25 (q, 2H,
ASCH2CH3, J ¼ 7.3 Hz), 3.58 (t, 2H, ACH2CH2CH3, J ¼ 7.2
Hz), 4.63 (d, 1H, ¼¼CHa, J ¼ 3.2 Hz), 4.65 (d, 1H, ¼¼CHb,
J ¼ 3.2 Hz), 7.47 ppm (s, 1H, pyrimidine-H); ms: m/z
286(Mþ 64). Anal. Calcd. for C15H18N4S (286) : C, 62.91; H,
6.33; N, 19.56. Found C, 62.88; H, 6.40; N, 19.61.
1400 cmꢃ1 1H NMR (CDCl3): d 1.39 (t, 3H, ASCH2CH3,
;
J ¼ 7.6 Hz), 2.33 (s, 3H, PhACH3), 2.68 (s, 3H, ACH3), 3.24
(q, 2H, ASCH2CH3, J ¼ 7.3 Hz), 4.49 (d, 1H, ¼¼CHa, J ¼ 3.6
Hz), 4.65 (d, 1H, ¼¼CHb, J ¼ 3.6 Hz), 4.69 (s, 2H, ACH2A),
7.16–7.27 (m, 4H, ArH), 7.43 ppm (s, 1H, pyrimidine-H); ms:
m/z 348(Mþ 32). Anal. Calcd. for C20H20N4S (348): C, 68.93;
H, 5.79; N, 16.08. Found C, 69.06; H, 5.88; N, 15.94.
3-Butyl-5-methyl-4-methylene-7-ethylsulfanyl-3,4-dihydro
pyrido[4,3–d]pyrimidine-8-carbonitrile (5h). This compound was
obtained as a white solid, m.p. 144.6–145.1ꢁC, yield 59%. IR
3-(3-Methylbenzyl)-5-methyl-4-methylene-7-ethylsulfanyl-
3,4-dihydro-pyrido[4,3–d]pyrimidine-8-carbonitrile (5m). This
compound was obtained as a white solid, m.p. 145.2–146.0ꢁC,
yield 80%. IR (KBr): m 3001, 2967, 2926, 2217, 1606, 1550,
(KBr): m 3047, 2959, 2871, 2218, 1597, 1550, 1517, 1388 cmꢃ1
;
1H NMR (CDCl3): d 0.96ꢃ1.00 (t, 3H, ACH2CH2CH2CH3, J ¼
7.2 Hz), 1.36–1.44 (m, 5H, ACH2CH2CH2CH3 and
ASCH2CH3), 1.69–1.76 (m, 2H, ACH2CH2CH2CH3), 2.69 (s,
3H, ACH3), 3.25 (q, 2H, ASCH2CH3, J ¼ 4.9 Hz), 3.62 (t, 2H,
ACH2CH2CH2CH3, J ¼ 7.0 Hz), 4.62 (d, 1H, ¼¼CHa, J ¼ 3.2
Hz), 4.64 (d, 1H, ¼¼CHb, J ¼ 3.2 Hz), 7.47 ppm (s, 1H, pyrimi-
dine-H); ms: m/z 301(MþþH 31), 300(Mþ 67). Anal. Calcd. for
C16H20N4S (300): C, 63.97; H, 6.71; N, 18.65. Found C, 64.02;
H, 6.84; N, 18.43.
; d 1.38 (t, 3H,
1524, 1401 cmꢃ1 1H NMR (CDCl3):
ASCH2CH3, J ¼ 7.4 Hz), 2.35 (s, 3H, PhACH3), 2.64 (s, 3H,
ACH3), 3.25 (q, 2H, ASCH2CH3, J ¼ 7.3 Hz), 4.52 (d, 1H,
¼¼CHa, J ¼ 3.6 Hz), 4.62 (d, 1H, ¼¼CHb, J ¼ 3.6 Hz), 4.74 (s,
2H, ACH2Ph), 7.06–7.27 (m, 4H, ArH), 7.57 ppm (s, 1H, py-
rimidine-H); ms: m/z 348(Mþ 16). Anal. Calcd. for C20H20N4S
(348): C, 68.93; H, 5.79; N, 16.08. Found C, 68.81; H, 5.86;
N, 15.91.
3-Amyl-5-methyl-4-methylene-7-ethylsulfanyl-3,4-dihydro
pyrido[4,3–d]pyrimidine-8-carbonitrile (5i). This compound was
obtained as a white solid, m.p. 134.8–135.4ꢁC, yield 56%. IR
3-(4-Methylbenzyl)-5-methyl-4-methylene-7-ethylsulfanyl-
3,4-dihydro-pyrido[4,3–d]pyrimidine-8-carbonitrile (5n). This
compound was obtained as a white solid, m.p. 163.5–164.5ꢁC,
yield 63%. IR (KBr): m 3030, 2974, 2927, 2218, 1606, 1554,
(KBr): m 3163, 2957, 2868, 2211, 1613, 1548, 1522, 1395cmꢃ1
;
1H NMR (CDCl3): d 0.93 (t, 3H, ACH2CH2CH2CH2CH3, J ¼
6.8 Hz), 1.33–1.40 (m, 7H, ACH2CH2CH2CH2CH3 and
ASCH2CH3), 1.73–1.78 (m, 2H, ACH2CH2CH2CH2CH3), 2.694
(s, 3H, ACH3), 3.25 (q, 2H, ASCH2CH3, J ¼ 7.4 Hz), 3.61 (t,
2H, ACH2CH2CH2CH2CH3, J ¼ 7.0 Hz), 4.62 (d, 1H, ¼¼CHa,
J ¼ 3.2 Hz), 4.65 (d, 1H, ¼¼CHb, J ¼ 3.2 Hz), 7.47 ppm (s,
1521, 1399 cmꢃ1 1H NMR (CDCl3): d 1.36–1.40 (t, 3H,
;
ASCH2CH3, J ¼ 7.2 Hz), 2.36 (s, 3H, PhACH3), 2.63 (s, 3H,
ACH3), 3.25 (q, 2H, ASCH2CH3, J ¼ 7.3 Hz), 4.53 (d, 1H,
¼¼CHa, J ¼ 3.6 Hz), 4.60 (d, 1H, ¼¼CHb, J ¼ 3.2 Hz), 4.74 (s,
2H, ACH2Ph), 7.14-7.20 (m, 4H, ArH), 7.57 ppm (s, 1H, py-
rimidine-H); ms: m/z 348(Mþ 5). Anal. Calcd. for C20H20N4S
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Synthesis and Biological Activity of 4-Methylene-pyrido[4,3-d]pyrimidines
583
Slintak, V.; Elliot, W. L.; Roberts, B. J.; Vincent, P. W.; Patmore, S.
J. J Med Chem 1999, 42, 1803; (d) Elselarge, E. F.; Clarke, J.; Jacob,
P. J. Heterocyclic Chem 1972, 9, 1113; (e) Rosowsky, A.; Bader, H.;
Moran, R. G. J Heterocycl Chem 1989, 26, 509; (f) Rosowsky, A.;
Mota, C. E.; Queener, S. F. J Heterocycl Chem 1995, 32, 335; (g)
Hussein, E. S.; Suhair, M. A. Z.; Mona, A. M. J Med Chem 2000, 43,
2915.
(348): C, 68.93; H, 5.79; N, 16.08. Found C, 68.84; H, 5.63;
N, 15.90.
3-(4-Methoxybenzyl)-5-methyl-4-methylene-7-ethyl sulfanyl-
3,4-dihydro-pyrido[4,3–d]pyrimidine-8-carbonitrile (5o). This
compound was obtained as a white solid, m.p. 156.1–156.9ꢁC,
yield 82%. IR (KBr): m 2934, 2220, 1612, 1547, 1515, 1404
1
cmꢃ1; H NMR (CDCl3): d 1.38 (t, 3H, ASCH2CH3, J ¼ 7.2
[2] (a) Brighty, K. E.; Lowe, J. A. US Pat. 50378341, 1991; (b)
Hacker, R. E.; Jourdan, G. P. Eur. Pat. 0414386, 1991; (c) Yamada, H.
Eur. Pat. 0665224, 1994; (d) Mo, W.-Y.; He, H.-W. Chin J Struct
Chem 2007, 26, 172.
Hz), 2.63 (s, 3H, ACH3), 3.24 (q, 2H, ASCH2CH3, J ¼ 7.5
Hz), 3.81 (s, 3H, AOCH3), 4.57 (d, 1H, ¼¼CHa, J ¼ 3.2 Hz),
4.61 (d, 1H, ¼¼CHb, J ¼ 3.2 Hz), 4.71 (s, 2H, ACH2Ph), 6.90–
7.20 (m, 4H, ArH) 7.54 ppm (s, 1H, pyrimidine-H); ms: m/z
364(Mþ 12). Anal. Calcd. for C20H20N4OS (364): C, 65.91; H,
5.53; N, 15.37. Found C, 65.84; H, 5.63; N, 15.21.
[3] (a) Rewcastle, W. G.; Palmer, D. B.; Thompson, A. M.;
Bridges, A. J.; Cody, D. R.; Zhou, H. R.; Fry, D. W.; McMichael, A.;
Denny, W. A. J Med Chem 1996, 39, 1823; (b) T. B. Brown and
M. F. Stevens. J Chem Soc Perkin Trans I 1975, 11, 1023. (c) Thomp-
son, A. M.; Bridges, A. J.; Fry, D. W.; Kraker, A. J.; Denny, W. A.
J Heterocycl Chem 1995, 38, 3780; (d) Liu, J.-C.; He, H.-W.; Ding,
M.-W. Helv Chim Acta 2007, 90, 1337.
Acknowledgments. This work was supported by the National
Basic Research Program of China (No. 2003CB114400),
National Natural Science Foundation of China (No.20372023,
20772042) and Syngenta Ltd. We thank Dr. John Clough of Syn-
gfenta Jealott’s Hill International Research Centre for proof
reading.
[4] Hosmane, R. S.; Lim, B. B.; Summers, M. F. J Org Chem
1988, 53, 5309.
[5] Ren, Q.-Y.; Cui, Z.-P.; He, H.-W.; Gu, Y.-C. J Fluorine
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet