Facile synthesis and biological activities of novel fluorine-containing pyrido[4,3-d]pyrimidines

Article abstract of DOI:10.1016/j.jfluchem.2008.03.011

Fourteen novel 3-substituted-5-methyl-4-methylene-7-alkylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitriles, compounds 4a-n, were designed and synthesized via a facile regioselective cyclization process. The intermediate 2 reacted with triethyl orthoformate (molar ratio is 1:4) in the presence of acetic anhydride to give formamidate 3, which was cycled to 4 regioselectively upon addition of different amines at mild condition. The structures of compounds 4a-n were confirmed by IR, ¹H NMR, MS and elemental analysis. The preliminary bioassay indicated that some compounds possess significant herbicidal activity against the roots of rape and barnyard grass, especially when the fluorine atom was introduced to the para position of the substitutents on pyrimidine ring; some compounds showed fungicidal activities against Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Dothiorella gregaria, Colletotrichum gossypii as well, and the introduction of fluorine has negative effect on the antifungal activities.

Full text of DOI:10.1016/j.jfluchem.2008.03.011

Journal of Fluorine Chemistry 129 (2008) 519–523
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Facile synthesis and biological activities of novel fluorine-containing
pyrido[4,3-d]pyrimidines
*
Wenyan Mo, Guihong Liao, Tao Wang, Hongwu He
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, Institute of Pesticide Chemistry, Central China Normal University, Wuhan, Hubei 430079, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
Fourteen novel 3-substituted-5-methyl-4-methylene-7-alkylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimi-
dine-8-carbonitriles, compounds 4a–n, were designed and synthesized via a facile regioselective
cyclization process. The intermediate 2 reacted with triethyl orthoformate (molar ratio is 1:4) in the
presence of acetic anhydride to give formamidate 3, which was cycled to 4 regioselectively upon addition
of different amines at mild condition. The structures of compounds 4a–n were confirmed by IR, 1H NMR,
MS and elemental analysis. The preliminary bioassay indicated that some compounds possess significant
herbicidal activity against the roots of rape and barnyard grass, especially when the fluorine atom was
introduced to the para position of the substitutents on pyrimidine ring; some compounds showed
fungicidal activities against Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Dothiorella gregaria,
Colletotrichum gossypii as well, and the introduction of fluorine has negative effect on the antifungal
activities.
Received 1 March 2008
Received in revised form 25 March 2008
Accepted 25 March 2008
Available online 30 March 2008
Keywords:
Pyrido[4,3-d]pyrimidines
Regioselective cyclization
Synthesis
Herbicidal activity
Fungicidal activity
ß 2008 Elsevier B.V. All rights reserved.
1. Introduction
2. Results and discussion
Pyrido[4,3-d]pyrimidines possess various biological activities,
especially pharmaceutical activities in terms of EGFR-TK (epider-
mal growth factor receptor-tyrosine kinase) and DHFR (dihydro-
folate reductase) inhibitors. These compounds display antitumor,
antiviral, anti-inflammatory and antimicrobial properties [1]. And
some of pyrido[4,3-d]pyrimidines have been reported as agricul-
tural lead compounds, possessing herbicidal and fungicidal
activities [2], which attracted our interest intensely.
The methods described so far on preparation of pyrido[d]pyr-
imidines mainly involve the formation of the pyridine or
pyrimidine ring by cyclization of suitable substitutents of another
ring [3]. It has been reported that formamidate cyclized with cyano
group in the neighboring position to afford pyrimidine ring [4].
As a part of our extensive research program to rapidly synthesize
novel bioactive heterocycles, we developed herein a facile regiose-
lective annulation process for a highly efficient assembly of
pyrido[4,3-d]pyrimidines at mild condition. The formamidate’
attacking neighboring carbonyl instead of cyano group regioselec-
tively afford pyrido[4,3-d]pyrimidines. The preliminary results in
vitro bioassay indicated that some title compounds displayed
favorable herbicidal activity and moderate fungicidal activity.
2.1. Synthesis
The intermediates of 1 were 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
methanol [5]. And the 4-aminopyridines 2, which were easily
obtained from compounds 1 in the presence of zinc nitrate, were
converted to the formamidates 3 in good yield via reaction with
triethyl orthofromate, using acetic anhydride as catalyst. Treated
with amines, the formamidates 3 were cyclized easily and
regioselectively to afford 4 in good yields (Table 1). This process
can be rationalized in Scheme 1.
In previous report, compound 2 was synthesized with moderate
yield (58%), using anhydrous stannic chloride as the catalyst [6].
Herein, we use Lewis acid Zn(NO3)2Á6H2O as catalyst instead of
anhydrous stannic chloride to obtain higher yield (83%). Further-
more, we found that formamidates 3 can react with primary
amines to afford pyrido[4,3-d]pyrimidines, the cyclization pro-
ceeded very smoothly and regioselectively by attacking neighbor-
ing carbonyl instead of cyano group.
All products 4 were obtained as white crystal after filtration and
recrystallization from acetone/petroleum ether. The structures
were fully confirmed by IR, 1H NMR, MS and elemental analysis and
all structures were supported spectroscopically. For example, the
1H NMR spectrum of 4d revealed that the two hydrogen of
* Corresponding author. Tel.: +86 27 67867960.
E-mail address: he1208@mail.ccnu.edu.cn (H. He).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.03.011

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W. Mo et al. / Journal of Fluorine Chemistry 129 (2008) 519–523
Table 1
Table 2
Yields of compounds 4
The herbicidal activity of compounds 4
Compounds
R1
R2
Yields
Compounds
Relative inhibition (root/stalk, %a)
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Me
Me
Me
Et
PhCH2–
67
60
71
80
78
54
79
70
63
59
61
49
61
84
Rape
Barnyard grass
100 mg/L
PhCH2CH2–
PhCH2CH2CH2–
2-FPhCH2–
3-FPhCH2–
4-FPhCH2–
4-FPhCH2CH2–
PhCH2–
100 mg/L
10 mg/L
10 mg/L
4a
4b
4c
4d
4e
4f
90/67
88/80
82/60
56/21
71/5
37/na
74/40
30/16
30/na
49/11
68/40
80/46
36/35
26/24
31/29
29/29
36/24
56/35
34/12
91/40
96/59
91/na
64/61
54/61
98/70
96/64
78/62
75/62
72/55
67/62
61/55
89/72
83/66
51/13
62/na
62/16
59/53
41/22
84/41
67/18
14/21
25/na
14/7
4g
4h
4i
Et
PhCH2CH2–
PhCH2CH2CH2–
2-FPhCH2–
3-FPhCH2–
4-FPhCH2–
4-FPhCH2CH2–
99/79
88/57
40/35
34/29
33/41
36/35
51/35
70/41
41/29
4j
Et
4g
4h
4i
4k
4l
Et
Et
4m
4n
Et
4j
Et
4k
4l
50/45
17/17
69/52
47/31
4m
4n
a
4-methylene group in pyrimidine was nuclear isoequivalent,
appears at (H) 4.63–
(H) 4.58–4.59 (d, J = 4.0 Hz, =CHa) and
4.64 (d, J = 4.0 Hz, =CHb), and 7-SMe group at
(H) 2.65(s), 5-Me
group at (H) 2.61(s). In IR spectra, the relatively strong absorption
of phenyl ring appeared at 1601–1523 cmÀ1. The stretching
resonance of CBB N showed strong absorption at about
2219 cmÀ1. The mass spectra showed strong molecular ion peaks.
na-inactive.
d
d
d
d
(R1 = Et), the fluorine introduced to the para position of the
substitutent R2 was also favorable. For example, compounds 4m
(R2 = 4-FPhCH2–), 4n (R2 = 4-FPhCH2CH2–) showed higher inhibi-
tion rate against the roots of rape and barnyard grass than
compounds 4h (R2 = PhCH2–), 4i (R2 = PhCH2CH2–), respectively.
Comparatively, introduction of fluorine to other position (o-, m-) of
the substitutent R2 has no obvious effect on the inhibition activity.
When the substituents R2 remain the same, the increment of
methylene in the substituents R1, respectively decreased the
herbicidal activity obviously. For example, compounds 4a
(R1 = Me, R2 = PhCH2–), 4b (R1 = Me, R2 = PhCH2CH2–), 4c
(R1 = Me, R2 = PhCH2CH2CH2–) showed higher inhibition rates
than 4h (R1 = Et, R2 = PhCH2–), 4i (R1 = Et, R2 = PhCH2CH2–), 4j
(R1 = Et, R2 = PhCH2CH2CH2–), respectively. However, when the
substituents R1 remain the same, the increment of methylene in
the substituent R2 has no obvious influence on the activity.
The fungicidal activity of compounds 4 was screened against six
fungi, Fusarium oxysporium, Rhizoctonia solani, Botrytis cinereapers,
Gibberella zeae, Dothiorella gregaria and Colletotrichum gossypii
according to the reported method [8] at a dosage of 50 mg/L.
As listed in Table 3, among the compounds 4, the most active is
4a, where R1 was methyl and R2 was an unsubstituted benzyl.
Compound 4a exhibited significant broad spectrum fungicidal
activity, with nearly complete inhibition against F. oxysporium, B.
2.2. Biological activities
The herbicidal activity of all compounds 4 against Brassica
napus (rape) and Echinochloa crus-galli (barnyard grass) has been
investigated at the dosage of 100 mg/L and 10 mg/L using known
procedure [7] compared with distilled water. The results of
bioassay showed that some of them exhibited pronounced
herbicidal activity against the roots of rape and barnyard grass
when fluorine atom is introduced to the para position of the
substitutent R2. See Table 2.
Comparing activities among compounds (R1 = Me), the position
of fluorine on the substituent R2 greatly affected herbicidal activity.
For example, compounds 4f (R2 = 4-FPhCH2À), 4g (R2 = 4-
FPhCH2CH2–) showed higher inhibition rate against the growth
of rape and barnyard grass than compounds 4a (R2 = PhCH2–), 4b
(R2 = PhCH2CH2–), respectively. It showed that fluorine introduced
to the para position of the substitutent R2 was useful for the
improvement of herbicidal activity. However, the introduction of
fluorine to other position (o-, m-) of the substitutent R2 decreased
the inhibition activity. For example, compounds 4d (R2 = 2-
FPhCH2–), 4e (R2 = 3-FPhCH2–) showed lower activity against
the roots of rape and barnyard grass than compound 4a
(R2 = PhCH2–) at dosage of 100 mg/L. Among compounds
cinereapers and G. zeae at dosage of 50
mg/mL. Among compounds
(R1 = Me), most of them showed significant activities. When
fluorine was introduced to the compounds, the inhibition rates
decreased obviously. It showed that the introduction of fluorine
Scheme 1. Synthesis of the title compounds 4.

W. Mo et al. / Journal of Fluorine Chemistry 129 (2008) 519–523
521
Table 3
The fungicidal activity of compounds 4
Compounds
Inhibition rate (%a, 50 mg/L)
Fusarium oxysporium
Rhizoctonia solani
Botrytis cinereapers
Gibberella zeae
Dothiorella gregaria
Colletotrichum gossypii
4a
4b
4c
4d
4e
4f
98
50
41
4
87
67
74
15
21
84
80
0
100
65
57
na
12
91
61
9
99
63
41
na
6
89
75
56
6
86
80
67
11
18
67
67
12
23
12
8
na
59
41
23
12
19
12
27
23
19
26
81
56
24
3
74
37
9
4g
4h
4i
na
0
na
23
na
20
17
0
9
4j
9
21
na
3
4k
4l
2
6
na
4
6
19
27
27
4m
4n
a
22
13
21
7
5
na-inactive.
has negative effect on the fungicidal activity, especially the
introduction to the o-, m-position of substituent R2. For example,
compounds 4d, 4e, 4f showed lower inhibition rates than
compound 4a against all six fungi; and 4g was lower than 4b
with R. solani as exception. When the substituents R1 remain the
same, the increment of methylene in the substituents R2 decreased
the fungicidal activity. Comparatively, all compounds where R1 is
Et exhibited very low fungicidal activities. It indicated that the
increment of substituent R1 induced obvious decrease of fungicidal
activity.
4.2. Synthesis of 5-acetyl-4-amino-6-methyl-2-alkylsulfanyl-
nicotinonitrile (2a–b)
Acetylacetone (1.0 g, 10 mmol) and 1 (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 was filtered and
washed with water (10 mL Â 3) and purified from alcohol to afford
2.
5-acetyl-4-amino-6-methyl-2-methylsulfanyl-nicotinonitrile
(2a): Colorless crystal, mp 163.5–164.5 8C, yield 83%. 1H NMR
(400 MHz, CDCl3): d 2.58 (s, 3H, CH3), 2.61 (s, 3H, SCH3), 2.68 (s, 3H,
COCH3), 6.60 (s, 2H, NH2).
3. Conclusion
5-acetyl-4-amino-6-methyl-2-ethylsulfanyl-nicotinonitrile (2b):
Yellowish crystal, mp 139.0–140.0 8C, yield 89%. 1H NMR
The title compounds 4 were designed, synthesized by a novel
regioselective cyclization process. Some of these compounds had
significant herbicidal activity against the roots of rape and
barnyard grass, the introduction of fluorine to the para position
of the substitutent R2 was useful for the improvement of herbicidal
activity. Compound 4a showed potent broad-spectrum fungicidal
activity, and it can be developed as lead compound for further
study.
(400 MHz, CDCl3):
d 1.36–1.40 (t, 3H, J = 7.4 Hz, SCH2CH3), 2.59
(s, 3H, CH3), 2.70 (s, 3H, COCH3), 3.12–3.18 (q, 2H, J = 7.4 Hz,
SCH2CH3), 6.68(s, 2H, NH2).
4.3. Synthesis of N-(3-acetyl-5-cyano-2-methyl-6-alkylsulfanyl-
pyridin-4-yl)-formimidic acid ethyl ester (3a–b)
To a solution of 2 (10 mmol) in triethyl orthoformate (5.92 g,
40 mmol) was added catalyzed amount acetic anhydride. The
mixture was heated to 130–140 8C for 8–0 h. The extensive triethyl
orthoformate was removed at reduced pressure, and the residue
was purified by chromatography (ether:petroleum ether = 1:10) to
afford formamidate 3.
4. Experimental
Melting points were measured on an electrothermal melting
point apparatus and are uncorrected. IR spectra were recorded on a
Nicolet Avatar360 FTIR spectrometer in KBr pellets. 1H NMR
spectra was performed on Mercury 400 (Varian, 400 MHz)
spectrometer with CDCl3 as solvent and TMS as internal standard.
Mass spectra were determined on a Finnigan Trace MS 2000
spectrometer. Elemental analysis was taken on Elementar Vario EL
III elementary analyzer. All the solvent and materials are reagent
grades and purified before use.
N-(3-acetyl-5-cyano-2-methyl-6-methylsulfanyl-pyridin-4-yl)-
formimidic acid ethyl ester (3a): Colorless crystal, mp 78.5–79.9 8C,
yield 95%. 1H NMR (400 MHz, CDCl3):
d 1.38–1.42 (t, 3H, J = 8.0 Hz,
CH2CH3), 2.46 (s, 3H, CH3), 2.56 (s, 3H, SCH3), 2.62 (s, 3H, COCH3),
4.36–4.42 (q, 2H, J = 8.0 Hz, CH2CH3), 8.06 (s, 1H, N = CH). EI-MS
(70 eV, m/z): 277 (M+, 63), 199 (31), 183 (22), 152 (28), 77 (100).
N-(3-acetyl-5-cyano-2-methyl-6-ethylsulfanyl-pyridin-4-yl)-for-
mimidic acid ethyl ester (3b): Yellowish oil, yield 82%. 1H NMR
4.1. Synthesis of 2-(amino-alkylsulfanyl-methylene)-malononitrile
(1a–b)
(400 MHz, CDCl3): d 1.37–1.39 (t, 3H, J = 3.8 Hz, SCH2CH3), 1.39–
1.41 (t, 3H, J = 3.8 Hz, CH2CH3), 2.45 (s, 3H, CH3), 2.46 (s, 3H,
COCH3), 3.24–3.29 (q, 2H, J = 3.6 Hz, SCH2CH3), 4.24–4.29 (q, 2H,
J = 3.6 Hz, CH2CH3), 7.65 (s, 1H, N = CH).
Intermediates 1 were synthesized according to the literature
[5].
2-(amino-methylsulfanyl-methylene)-malononitrile (1a): Yel-
lowish crystal, mp 218.0–220.0 8C, yield 82%. 1H NMR (400 MHz,
4.4. General procedure for the preparation of 3,4-dihydro-3-
substituted-5-methyl-4-methylene-7-alkylsulfanyl-pyrido[4,3-
d]pyrimidine-8-carbonitrile (4a–m)
CDCl3):
d 1.26 (s, 3H, SCH3), 8.75 (s, 2H, NH2).
2-(amino-methylsulfanyl-methylene)-malononitrile (1b): Color-
less crystal, mp 187.1–187.4 8C, yield 85%. 1H NMR (400 MHz,
CDCl3):
d
1.21–1.25 (t, 3H, J = 7.4 Hz, SCH2CH3), 3.12–3.18 (q, 2H,
To a solution of formamidate 3 (10 mmol) in acetonitrile
J = 7.4 Hz, SCH2CH3), 8.72 (s, 2H, NH2).
(10 mL) was added the appropriate amine (15 mmol), and the

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W. Mo et al. / Journal of Fluorine Chemistry 129 (2008) 519–523
mixture was stirred at room temperature for 0.5–1 h. The
precipitate was isolated by filtration, recrystallized from acet-
one/petroleum ether to give pure products 4.
4.4.7. 3,4-Dihydro-3-(4-fluorophenethyl)-5-methyl-4-methylene-7-
methylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4g)
Colorless crystal, yield 79%, mp 205.9–206.2 8C; IR (KBr):
y
3170, 2919, 2850, 2217, 1607, 1547, 1524, 1389, 1280, 916 cmÀ1
;
1H NMR (400 MHz, CDCl3):
d 2.61 (s, 3H, CH3), 2.73 (s, 3H, SCH3),
4.4.1. 3,4-Dihydro-3-benzyl-5-methyl-4-methylene-7-
methylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4a)
3.00–3.04 (t, 2H, J = 8.0 Hz, CH2CH2Ph), 3.82–3.86 (t, 2H, J = 8.0 Hz,
CH2CH2Ph), 4.73 (d, 2H, =CH2), 6.98–7.14 (m, 4H, Ph–H), 7.18 (s,
1H, pyrimidine–H); EI-MS (70 eV): m/z 352 (M+). Elemental anal.
calcd. for C19H17FN4S: C 64.77, H 4.83, N 15.91; found C 64.63, H
4.76, N 15.23.
Colorless crystal, yield 67%, mp 173.0–174.0 8C; IR (KBr):
3034, 2970, 2929, 2219, 1610, 1544, 1522, 1402, 1277, 916 cmÀ1
1H NMR (400 MHz, CDCl3):
2.57 (s, 3H, CH3), 2.68 (s, 3H, SCH3),
y
;
d
4.65 (s, 2H, CH2Ph), 4.99 (d, 2H, =CH2), 7.29–7.41 (m, 5H, Ph–H),
8.06 (s, 1H, pyrimidine–H); EI-MS (70 eV): m/z 320 (M+). Elemental
anal. calcd. for C18H16N4S: C 67.47, H 5.03, N 17.49; found C 66.99,
H 5.17, N 17.52.
4.4.8. 3,4-Dihydro-3-benzyl-5-methyl-4-methylene-7-ethylsulfanyl-
pyrido[4,3-d]pyrimidine-8-carbonitrile (4h)
Colorless crystal, yield 70%, mp 146.6–147.6 8C; IR (KBr):
3034, 2961, 2869, 2218, 1607, 1546, 1520, 1400, 916 cmÀ1
NMR (400 MHz, CDCl3):
y
4.4.2. 3,4-Dihydro -3-phenethyl-5-methyl-4-methylene-7-
;
1H
methylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4b)
d
1.36–1.40 (t, 3H, J = 7.4 Hz, SCH2CH3),
Colorless crystal, yield 60%, mp 131.7–131.9 8C; IR (KBr):
3132, 3023, 2925, 2219, 1629, 1600, 1579, 1396, 1265, 852 cmÀ1
1H NMR (400 MHz, CDCl3):
2.54 (s, 3H, CH3), 2.74 (s, 3H, SCH3),
2.54–2.74 (m, 2H, CH2CH2Ph), 3.16 (t, 2H, J = 13.6 Hz, CH2CH2Ph),
4.30 (d, 2H, =CH2), 6.89–7.33 (m, 6H, Ph–H and pyrimidine–H).
Elemental anal. calcd. for C19H18N4S: C 68.23, H 5.42, N 16.75;
found C 67.90, H 5.47, N 16.63.
y
;
2.63 (s, 3H, CH3), 3.22–3.27 (q, 2H, J = 7.3 Hz, SCH2CH3), 4.52–4.53
(d, 1H, J = 3.6 Hz, =CHa), 4.61–4.62 (d, 1H, J = 3.2 Hz, =CHb), 4.79 (s,
2H, CH2Ph), 7.25–7.40 (m, 5H, Ph–H), 7.59 (s, 1H, pyrimidine–H);
EI-MS (70 eV): m/z 334 (M+). Elemental anal. calcd. for C19H18N4S:
C 68.23, H 5.42, N 16.75; found C 68.39, H 5.65, N 16.69.
d
4.4.9. 3,4-Dihydro-3-phenethyl-5-methyl-4-methylene-7-
ethylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4i)
4.4.3. 3,4-Dihydro-3-(3-phenylpropyl)-5-methyl-4-methylene-7-
Colorless crystal, yield 63%, mp 131.3–132.3 8C; IR (KBr):
3029, 2956, 2931, 2216, 1605, 1548, 1521, 1389, 954 cmÀ1
NMR (400 MHz, CDCl3):
2.72 (s, 3H, CH3), 3.01–3.05 (t, 2H, J = 7.0 Hz, CH2CH2Ph), 3.22–3.28
(q, 2H, J = 7.3 Hz, SCH2CH3), 3.84–3.87 (t, 2H, J = 7.2 Hz, CH2CH2Ph),
4.72–4.73 (d, 1H, J = 3.6 Hz, =CHa), 4.74–4.75 (d, 1H, J = 3.2 Hz,
=CHb), 7.15–7.31 (m, 6H, Ph–H and pyrimidine–H); EI-MS (70 eV):
m/z 348 (M+). Elemental anal. calcd. for C20H20N4S: C 68.93, H 5.79,
N 16.08; found C 68.56, H 5.85, N 16.27.
y
methylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4c)
;
1H
Colorless crystal, yield 71%, mp 152.1–152.9 8C; IR (KBr):
3187, 3029, 2943, 2221, 1609, 1550, 1524, 1395, 1280, 918 cmÀ1
1H NMR (400 MHz, CDCl3):
2.60 (s, 3H, CH3), 2.71 (s, 3H, SCH3),
y
;
d
1.37–1.40 (t, 3H, J = 7.4 Hz, SCH2CH3),
d
2.09–2.13 (m, 4 H, CH2CH2CH2Ph), 3.62 (t, 2H, J = 14.0 Hz,
CH2CH2CH2Ph), 4.53 (d, 1H, J = 3.6 Hz, =CHa), 4.61 (d, 1 Hb,
J = 3.6Hz, =CHb), 7.17–7.30 (m, 5H, Ph–H), 7.43 (s, 1 H, pyrimi-
dine–H); EI-MS (70 eV): m/z 348 (M+). Elemental anal. calcd. for
C
20H20N4S: C 68.93, H 5.79, N 16.08; found C 68.65, H 5.95, N 16.17.
4.4.10. 3,4-Dihydro-3-(3-phenylpropyl)-5-methyl-4-methylene-7-
4.4.4. 3,4-Dihydro-3-(2-fluorobenzyl)-5-methyl-4-methylene-7-
methylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4d)
Colorless crystal, yield 80%, mp 151.9–152.3 8C; IR (KBr):
ethylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4j)
Colorless crystal, yield 59%, mp 152.0–152.9 8C; IR (KBr):
3024, 2927, 2222, 1608, 1554, 1524, 1392, 921 cmÀ1 1H NMR
(400 MHz, CDCl3): 1.36–1.40 (t, 3H, J = 7.4 Hz, SCH2CH3), 2.09–
y
y
;
3149, 3036, 2929, 2219, 1395, 1278, 915 cmÀ1; 1H NMR (400 MHz,
d
CDCl3):
d
2.61 (s, 3H, CH3), 2.65 (s, 3H, SCH3), 4.58–4.59 (d, 1H,
2.41 (m, 2H, CH2CH2CH2Ph), 2.64–2.77 (m, 5H, CH2CH2CH2Ph and
CH3), 3.22–3.27 (q, 2H, J = 7.3 Hz, SCH2CH3), 3.60–3.64 (t, 2H,
J = 7.2 Hz, CH2CH2CH2Ph), 4.52–4.53 (d, 1H, J = 3.2 Hz, =CHa), 4.60–
4.61 (d, 1H, J = 3.2 Hz, =CHb), 7.16–7.31 (m, 5H, Ph–H), 7.43 (s, 1H,
pyrimidine–H); EI-MS (70 eV): m/z 360 (M+). Elemental anal. calcd.
for C21H22N4S: C 69.58, H 6.12, N 15.46; found C 69.49, H 6.35, N
15.65.
J = 4.0 Hz, =CHa), 4.63–4.64 (d, 1H, J = 4.0 Hz, =CHb), 4.83 (s, 2H,
CH2Ph), 7.11–7.36 (m, 4H, Ph–H), 7.60 (s, 1H, pyrimidine–H); EI-
MS (70 eV): m/z 340 (M++2), 338 (M+). Elemental anal. calcd. for
C
18H15FN4S: C 63.89, H 4.47, N 16.56; found C 64.02, H 4.82, N
16.35.
4.4.5. 3,4-Dihydro-3-(3-fluorobenzyl)-5-methyl-4-methylene-7-
methylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4e)
Colorless crystal, yield 78%, mp 164.1–165.7 8C; IR (KBr):
4.4.11. 3,4-Dihydro-3-(2-fluorobenzyl)-5-methyl-4-methylene-7-
y
1H
ethylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4k)
3178, 2928, 2218, 1607, 1554, 1522, 1396, 1277, 915 cmÀ1
;
Colorless crystal, yield 61%, mp 145.1–146.1 8C; IR (KBr):
3041, 2967, 2928, 2217, 1599, 1547, 1524, 1393, 918 cmÀ1
NMR (400 MHz, CDCl3):
y
1H
NMR (400 MHz, CDCl3):
d
2.62 (s, 3H, CH3), 2.65 (s, 3H, SCH3), 4.47–
;
4.48 (d, 1H, J = 4.0 Hz, =CHa), 4.63–4.64 (d, 1H, J = 4.0 Hz, =CHb)
4.79 (s, 2H, CH2Ph), 6.96–7.38 (m, 4H, Ph–H), 7.59 (s, 1H,
pyrimidine–H); EI-MS (70 eV): m/z 340 (M+ + 2), 338 (M+).
Elemental anal. calcd. for C18H15FN4S: C 63.89, H 4.47, N 16.56;
found C 63.62, H 4.72, N 16.45.
d
1.37–1.38 (t, 3H, J = 2.2 Hz, SCH2CH3),
2.64 (s, 3H, –CH3), 3.24–3.26 (q, 2H, J = 2.4 Hz, SCH2CH3), 4.57–4.58
(d, 1H, J = 4.0 Hz, =CHa), 4.63–4.64 (d, 1H, J = 3.6 Hz, =CHb), 4.83 (s,
2H, CH2Ph), 7.11–7.36 (m, 4H, Ph–H), 7.61 (s, 1H, pyrimidine–H);
EI-MS (70 eV): m/z 352 (M+). Elemental anal. calcd. for C19H17FN4S:
C 64.75, H 4.86, N 15.90; found C 64.50, H 5.05, N 16.17.
4.4.6. 3,4-Dihydro-3-(4-fluorobenzyl)-5-methyl-4-methylene-7-
methylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4f)
4.4.12. 3,4-Dihydro-3-(3-fluorobenzyl)-5-methyl-4-methylene-7-
Colorless crystal, yield 54%, mp 136.6–136.9 8C; IR (KBr):
3148, 2932, 2222, 1627, 1563, 1510, 1397, 1285, 900 cmÀ1
NMR (400 MHz, CDCl3):
(s, 2H, CH2Ph), 4.64 (d, 2H, =CH2), 7.02–7.37 (m, 4H, Ph–H), 7.82 (s,
1H, pyrimidine–H); EI-MS (70 eV): m/z 365 (M++1). Elemental anal.
calcd. for C18H15FN4S: C 63.91, H 4.44, N 16.57; found C 64.02, H
4.82, N 16.35.
y
ethylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4l)
;
1H
Colorless crystal, yield 49%, mp 145.3–145.8 8C; IR (KBr):
3041, 2965, 2872, 2218, 1608, 1551, 1521, 1401, 917 cmÀ1
NMR (400 MHz, CDCl3):
y
1H
d
2.47 (s, 3H, CH3), 2.61 (s, 3H, SCH3), 2.69
;
d
1.36–1.40 (t, 3H, J = 7.4 Hz, SCH2CH3),
2.64 (s, 3H, CH3), 3.22–3.28 (q, 2H, J = 7.2 Hz, SCH2CH3), 4.47 (d, 1H,
J = 3.6 Hz, =CHa), 4.62–4.63 (d, 1H, J = 3.2 Hz, =CHb), 4.80 (s, 2H,
CH2Ph), 6.96–7.38 (m, 4H, Ph–H), 7.60 (s, 1H, pyrimidine–H); EI-

W. Mo et al. / Journal of Fluorine Chemistry 129 (2008) 519–523
523
MS (70 eV): m/z 352 (M+). Elemental anal. calcd. for C19H17FN4S: C
64.75, H 4.86, N 15.90; found C 64.54, H 5.10, N 16.07.
2003CB114400) and National Natural Science Foundation of China
(Nos. 20372023, 20772042).
4.4.13. 3,4-Dihydro-3-(4-fluorobenzyl)-5-methyl-4-methylene-7-
ethylsulfanyl-pyrido[4,3-d]pyrimidine-8-carbonitrile (4m)
References
Colorless crystal, yield 61%, mp 128.6–129.2 8C; IR (KBr):
2965, 2928, 2220, 1611, 1553, 1524, 1403 cmÀ1 1H NMR
(400 MHz, CDCl3): 1.36–1.40 (t, 3H, J = 7.2 Hz, –SCH2CH3), 2.63
(s, 3H, –CH3), 3.22–3.28 (q, 2H, J = 7.4 Hz, –SCH2CH3), 4.48–4.49 (d,
1H, J = 3.2 Hz, =CHa), 4.62 (d, 1H, J = 3.2 Hz, =CHb), 4.77 (s, 2H, –
CH2Ph), 7.07–7.10 (t, 2H, J = 7.0 Hz, Ph–H), 7.23–7.26 (t, 2H,
J = 7.0 Hz, Ph–H), 7.59 (s, 1H, pyrimidine–H); EI-MS (70 eV): m/z
352 (M+). Elemental anal. calcd. for C19H17FN4S (352.1): C 64.75, H
4.86, N 15.90; found C 64.49, H 4.95, N 15.67.
y
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3032, 2979, 2933, 2218,1607, 1545, 1518, 1390, 915 cmÀ1
NMR (400 MHz, CDCl3):
y
;
1H
d
1.37–1.41(t, 3H, J = 7.4 Hz, SCH2CH3),
2.72 (s, 3H, CH3), 3.00–3.03 (t, 2H, J = 6.8 Hz, CH2CH2Ph), 3.22–3.28
(q, 2H, J = 7.4 Hz, SCH2CH3), 2.82–3.86 (t, 2H, J = 7.2 Hz, CH2CH2Ph),
4.72 (d, 2H, =CH2), 6.98–7.14 (m, 4H, Ph–H), 7.19 (s, 1H,
pyrimidine–H); EI-MS (70 eV): m/z 366 (M+). Elemental anal.
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5.35, N 14.97.
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Acknowledgements
We gratefully acknowledge financial support of this work by
National Key Basic Research Development Program of China (No.