A facile synthesis and fungicidal activities of novel fluorine-containing pyrido[4,3-d]pyrimidin-4(3H)-ones

Article abstract of DOI:10.1016/j.jfluchem.2007.06.007

Sixteen novel 2-substituted-5,8,9-trimethyl-3-(4-fluoro-substituted)phenyl-thieno [3′,2′-5,6] pyrido[4,3-d]pyrimidin-4(3H)-ones 5a-5p were designed and have been successfully synthesized via tandem aza-Wittig and annulation reactions of the corresponding

Full text of DOI:10.1016/j.jfluchem.2007.06.007

Journal of Fluorine Chemistry 128 (2007) 1369–1375
www.elsevier.com/locate/fluor
A facile synthesis and fungicidal activities of novel fluorine-containing
pyrido[4,3-d]pyrimidin-4(3H)-ones
b
Qingyun Ren a, Zeping Cui a, Hongwu He a, , Yucheng Gu
*
a The Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, PR China
b Jealott’s Hill International Research Centre, Syngenta, Bracknell, Berkshire RG42 6EY, United Kingdom
Received 8 May 2007; received in revised form 13 June 2007; accepted 19 June 2007
Available online 28 June 2007
Abstract
Sixteen novel 2-substituted-5,8,9-trimethyl-3-(4-fluoro-substituted)phenyl-thieno[30,20-5,6] pyrido[4,3-d]pyrimidin-4(3H)-ones 5a–5p were
designed and have been successfully synthesized via tandem aza-Wittig and annulation reactions of the corresponding iminophosphorances 1,
para-fluoro phenyl isocyanate, and substituted phenols or amines in 73–90% isolated yields. Their structures were clearly verified by IR, 1H NMR,
EI-MS spectroscopy and elemental analysis, and in the case of compound 5a, analyzed by single-crystal X-ray diffraction further. The results of
preliminary bioassay indicated that some compounds possess inhibition activities against Rhizoctonia solani and Botrytis cinereapers at a dosage
of 50 mg/L.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Pyrido[4,3-d]pyrimidin-4(3H)-one; aza-Wittig reaction; Synthesis; Fungicidal activity
1. Introduction
fluorine atoms or fluorinated substituents into certain com-
pounds influences the herbicidal activity [5,6], fungicidal
activity [7,8] and insecticidal activity [9–11].
The 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 this heterocyclic scaffold.
For example, some related 4-(phenylamino) pyrido [4,3-
d]pyrimidines have been reported as selective inhibitors of
tyrosine phosphorylation by the epidermal growth-factor
receptor (EGFR), and have become an important class of
potential anticancer drugs [1,2]. However, few reports so far are
available on the pesticidal activities of pyrido[4,3-d]pyrimidine
derivatives.
The aza-Wittig reactions of iminophosphoranes have
received increasing attention in view of their utility in the
synthesis of N-heterocyclic compounds [12]. Recently, we have
become interested in the synthesis of new bioactive hetero-
cycles such as pyrazolopyrimidinones [13], thienopyrimidi-
nones [14], and triazolopyrimidinones [15] from various
iminophosphoranes, with the aim of evaluating their biological
activities. Herein, we would like to describe a facile synthesis of
2-substituted-5,8,9-trimethyl-3-(4-fluoro-substituted)phenyl-
thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones (5) via the
tandem aza-Wittig and cyclization reaction. The preliminary
bioassay showed that some of them have fungicidal activities.
It is well known that fluorine can affect the biological
activity of compounds in a number of important ways because
of the highest electronegativity, high thermal stability and
lipophilicity. Therefore, fluorinated compounds in general and
fluorinated heterocycles are the focus of many researches [3]. In
the area of modern crop protection, fluoro agrochemicals are
widely employed as herbicides, insecticides and fungicides [4].
Some examples also demonstrate that the incorporation of
2. Result and discussion
2.1. Synthesis
The 2-amino-3-cyano-4, 5-dimethylthieno [16] (3) was
converted to thienopyridine derivative 2 via reaction with
acetoacetic ester and tin tetrachloride under heating. The
* Corresponding author.
E-mail address: he1208@mail.ccnu.edu.cn (H. He).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.06.007

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Q. Ren et al. / Journal of Fluorine Chemistry 128 (2007) 1369–1375
Table 1
rationalized in terms of an initial nucleophilic addition of
Yields of compounds 5
phenoxides to the carbodiimides 4 to give the intermediate 6
which cyclize to give 5a–j (Scheme 1). Irrespective of the fact
whether the substituents on the phenols were electronwith-
drawing or electronreleasing groups, the cyclization was
completed smoothly.
Compounds
RO or R1R2N
Yield (%)a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
4-MePhO
88
90
82
90
84
82
84
86
85
82
83
83
83
73
74
79
1,2,3,4,5-Cl5PhO
2-NO2PhO
2-ClPhO
In refluxing toluene, 4 did not react with alkylamines to the
target compounds. However, in CH2Cl2 and in the presence of a
catalytic amount of EtONa, compounds 4 were converted
smoothly into the 2-(alkylamino)-thieno[30,20:5,6]pyrido[4,3-
d]pyrimidin-4(3H)-ones 5k–p in satisfactory yields at room
temperature for 0.5–1 h whether primary or secondary amines
were used (Scheme 2). Worth noting the reaction between
carbodiimides 4 and primary amines gives mainly 2-(alkyla-
mino)-thieno [30,20:5,6]pyrido[4,3-d] pyrimidin-4(3H)-ones (5)
and another kind of cyclization compounds 2-(arylamino)-
thieno[30,20:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones(7)werenot
founded (Scheme 3), this might be due to the geometry of the
guanidine intermediate and conjugative effect of compounds 5.
As the amines were reacted with 4, intermediates 6awere formed
since the amines would attack 4 mainly from the opposite
direction of CO2Et group due to the steric hindrance of CO2Et
group. At the same time, the compounds 5 are more stable
than compounds 7 because of the conjugative effect between
the pyridopyrimidine ring and phenyl ring. Therefore, only
compounds 5 were obtained regioselectively.
3-MePhO
2-MePhO
PhO
4-ClPhO
2,4-Cl2PhO
2-Cl-4-FPhO
NCH2CH3
NH(CH2)2CH3
NHCH(CH3)2
NH(CH2)3CH3
NHC(CH3)3
N(C4H9)2
a
Yields of isolated products based on iminophosphorane 1.
iminophosphorane 1 was subsequently obtained in a satisfac-
tory yield when 2 was treated with triphenylphosphine,
hexachloroethane and Et3N. Iminophosphorane 1 reacted with
para-fluorophenyl isocyanate to give carbodiimide 4. The
direct reaction of carbodiimide 4 with phenols did not produce
2-aryloxyl-thieno[30,20:5,6]pyrido[4,3-d]pyrimidin-4(3H)-one
(5). However, the reaction took place to give 5a–j in good yields
under the condition of heating for 1–2 h in the presence of
catalytic amount of K2CO3 (Table 1). The formation of 5 can be
All products of type 5 were obtained as white solid after
recrystallization from CH2Cl2/petroleum ether, and were
Scheme 1. Synthesis of the title compounds 5a–j.
Scheme 2. Synthesis of the title compounds 5k–p.

Q. Ren et al. / Journal of Fluorine Chemistry 128 (2007) 1369–1375
1371
Scheme 3. Formation of compounds 5.
characterized by IR, 1H NMR and elemental analysis, and some
of them were confirmed by EI-MS. For example, the 1H NMR
spectrum of 5 m showed the signal of NH at d 4.37 as singlet,
which was not the same as the proton of PhNH, of which the
chemical shift is greater than d 7.0 [17]. In IR spectrum, the
relatively strong absorption of C O appeared at 1674–
1704 cmꢀ1. The MS spectrum displayed strong molecule ion
peaks. All the fragmentation ions are consistent with their
structures and can be clearly assigned. In the case of 5a, the
structure was additionally solved by single-crystal X-ray
diffraction (Fig. 1). In the crystal structure, the C–S bond
˚
lengths are 1.730(2) A and 1.744(2) A, respectively, which are
˚
˚
greater than those observed in free thiophene [1.714(2) A] [18].
The C5–S1–C6 angle of 91.29(10)8 in (I) is slightly less than
Fig. 1. View and atom labeling of 5a.

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Q. Ren et al. / Journal of Fluorine Chemistry 128 (2007) 1369–1375
Table 2
Fungicidal comparison with unfluorinated compounds
Compounds
R1
R2
Relative inhibition (%), 50 mg/L
F. oxyporium
R. solani
B. cinereapers
G. zeae
D. gregaria
5q
5r
5g
5s
5t
PhO
H
Cl
F
40.00
72.00
86.36
37.50
72.73
59.09
75.00
98.33
99.43
77.76
96.47
91.95
83.33
100.00
98.91
72.41
98.15
97.83
55.56
88.89
93.55
62.55
96.30
67.74
66.67
85.71
96.15
58.82
97.06
84.62
PhO
PhO
NH(CH2)3CH3
NH(CH2)3CH3
NH(CH2)3CH3
H
Cl
F
5n
that observed in free thiophene [92.2(2)8]. As expected for a
nonprotonated ring system, the C1–N1–C9 angle of 117.17(16)8
is smaller than 1208[19]. The torsion angles C4–C3–C9–N1 and
C9–C8–C5–S1 are 179.41(17)8 and 179.89(13)8, respectively,
showing the essential planarity of the tricyclic system. There is
no intermolecular non-bonded interaction with fluorine or sulfur
atom from the data. And the crystal packing is stabilized by P–P
stacking interactions and van der Waals forces.
spectra were recorded on a PE-983 infrared spectrometer as
KBr pellets with absorption in cmꢀ1. 1H NMR were recorded in
CDCl3 as solvent on a Varian Mercury 400 spectrometer and
resonances are given in ppm (d) relative to TMS. Elementary
analyses were taken on a Vario EL III elementary analysis
instrument. All of the solvents and materials were reagent grade
and purified as required.
3.1. Synthesis of 4-amino-2,5,6-trimethyl-thieno[2,3-
b]pyridine-3-carboxylate (2) [22]
2.2. Fungicidal activity
The preliminary fungicidal activities of compounds 5 were
measured in a concentration of 50 mg/L using a reported
procedure[20]andtheinhibitionratesarelistedinTables2and3.
It was found that most of the compounds induce a good inhibition
effect against Rhizoctonia solani and Botrytis cinereapers when
fluorine atom is introduced but has not obvious influence on
Gibberella zeae, Fusarium oxyporium and Dothiorella gregaria.
For example, the inhibitory rate of compounds 5b, 5i and 5l to B.
cinereapers were 100, 100 and 100%, compounds 5g and 5l to R.
solani were 99 and 98%. As the results listed in Table 2, fluorine-
containing compounds 5g and 5n displayed much better
fungicidal activities than non-substituted phenyl compounds
5q and 5s but showed the same effect with para-chlorosub-
stituted phenyl compounds 5r and 5t, respectively [21].
In summary, we have developed a novel approach of
synthesizing 2-substituted-5,8,9-trimethyl-3-(4-fluoro-substi-
tuted)phenyl-thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-
ones (5) via tandem aza-Wittig and annulation reactions. The
biological evaluation showed that these compounds have
fungicidal activities and could be further developed as lead
compounds.
2-Amino-4,5-dimethyl-thiophene-3-carbonitrile (3; 2.4 g,
16 mmol) and SnCl4 (3.7 mL, 32 mmol) were added to a
stirred solution of ethyl acetoacetate (2.08 mL, 16 mmol) in
anhydrous toluene (20 mL). The mixture was stirred at r.t. for
1 h, and then heated at reflux for 5 h. The mixture was added to
sat.aq. Na2CO3 solution (60 mL, pH 10), and the resulting
suspension was extracted with AcOEt (3ꢁ 50 mL). The
Table 3
The fungicidal activity of compound 5
Compounds Relative inhibition (%), 50 mg/L
F. oxyporium R. solani B. cinereapers G. zeae D. gregaria
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
59.09
54.17
39.13
65.22
52.17
54.55
86.36
81.82
59.09
50.00
54.55
66.67
45.45
59.09
54.17
45.45
86.21
90.20
80.00
83.81
90.48
85.06
99.43
95.40
91.95
85.06
83.91
98.04
80.46
91.95
89.22
80.46
91.30
100.00
90.48
88.10
95.24
82.61
98.91
97.83
100.00
84.78
86.96
100.00
80.43
97.83
97.44
93.48
67.74
62.16
52.94
50.00
79.41
58.06
93.55
83.87
70.97
70.97
51.61
75.68
51.61
67.74
59.46
51.61
76.92
55.00
56.52
65.22
82.61
69.23
96.15
84.62
84.62
61.54
61.54
85.00
53.85
84.62
60.00
92.31
3. Experimental
Melting points were measured on an electrothermal melting
point apparatus and are uncorrected. Mass spectra were
measured on a Finnigan Trace MS 2000 spectrometer. IR

Q. Ren et al. / Journal of Fluorine Chemistry 128 (2007) 1369–1375
1373
combined extracts were dried (Na2SO4) and concentrated under
reduced pressure to afford 2 in 67% yield. Colorless crystals.
m.p. 132–133 8C; H NMR (400 MHz, CDCl3) d 1.20 (t, 3H,
J = 7.2 Hz, CH3), 2.39 (s, 3H, CH3), 2.57 (s, 3H, CH3), 2.77 (s,
3H, CH3), 4.40 (q, 2H, J = 7.2 Hz, OCH2CH3), 6.65–6.73 (s,
2H, NH2); Elemental Anal. Calcd. for C13H16N2O2S: C, 59.07;
H, 6.10; N, 10.60. Found: C, 59.47; H, 6.03; N, 10.05.
1.90 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.98 (s, 3H, CH3), 7.32–
7.50 (m, 4H, Ar-H); EI-MS (70 eV, m/z): 605 (M+ + 2, 78), 603
(M+, 100), 601 (M+ ꢀ 2, 65), 338 (52), 75 (23); Elemental Anal.
Calcd. for C24H13Cl5FN3O2S: C, 47.72; H, 2.17; N, 6.96.
Found: C, 47.23; H, 2.25; N, 6.90.
1
3.3.3. 3-(4-Fluorophenyl)-2-[(2-nitrophenyl)oxy]-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]pyrim-idin-4(3H)-
one (5c)
3.2. Synthesis of iminophosphorane 1
White solid, yield 82%, m.p. 242.7–244 8C; IR (KBr): y
3193, 1610 (C O), 1540 cmꢀ1; 1H NMR (400 MHz, CDCl3) d
1.86 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.97 (s, 3H, CH3), 7.28–
7.77 (m, 8H, Ar-H); EI-MS (70 eV, m/z): 476 (M+, 100), 460
(41), 338 (38), 277 (59); Elemental Anal. Calcd. for
C24H17FN4O4S: C, 60.50; H, 3.57; N, 11.76; S, 6.73. Found:
C, 60.12; H, 3.52; N, 11.45; S, 7.06.
To a solution of 2 (1.56 g, 6 mmol) in MeCN (20 mL) was
added Ph3P (3.2 g, 12 mmol), C2Cl6 (2.8 g, 12 mmol) and, in
this order, Et3N (5.0 ml). The mixture was stirred for 6–7 h at
r.t. Then, the solution was concentrated, and the residue was
recrystallized from EtOH to give 1 in 90.2% yield. m.p. 217–
218 8C. 1H NMR (400 MHz, CDCl3) d 1.02 (t, 3H, J = 7.2 Hz,
CH3), 2.11 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.46 (s, 3H, CH3),
3.16 (q, 2H, J = 7.2 Hz, CH2CO), 7.42–7.63 (m, 18H, Ar-H);
Elemental Anal. Calcd. for C31H29N2O2PS: C, 70.97; H, 5.57;
N, 5.34. Found: C, 71.43; H, 5.39; N, 5.80.
3.3.4. 2-[(2-Chlorophenyl)oxy]-3-(4-fluorophenyl)-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (5d)
White solid, yield 90%, m.p. 270.9–271.4 8C; IR (KBr): y
1
3.3. General procedure for the preparation of 2-aryloxy-
5,8,9-trimethyl-3-(4-fluoro-substituted) phenyl-thieno[30,20-
5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones (5a–j)
2936, 1692 (C O), 1656, 1561 cmꢀ1; H NMR (400 MHz,
CDCl3) d 1.89 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.98 (s, 3H,
CH3), 7.16–7.51 (m, 8H, Ar-H); EI-MS (70 eV, m/z): 467
(M+ + 2, 32), 465 (M+, 100), 431 (96), 338 (74); Elemental
Anal. Calcd. for C24H17ClFN3O2S: C, 61.87; H, 3.68; N, 9.02;
S, 6.88. Found: C, 61.90; H, 3.67; N, 8.94; S, 7.18.
To a solution of iminophosphorane 1 (1.1 g, 2 mmol) in dry
methylene chloride (10 mL), para-fluorophenyl isocyanate
(0.21 g, 2 mmol) was added under nitrogen at room tempera-
ture. 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 4, which
were used directly without further purification.
3.3.5. 3-(4-Fluorophenyl)-2-[(3-methylphenyl)oxy]-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (5e)
White solid, yield 84%, m.p. 259.1–260.1 8C; IR (KBr): y
2930, 2857, 1688 (C O), 1656, 1561 cmꢀ1
;
1H NMR
To the solution of 4 prepared above in CH3CN (15 mL) was
added substituted phenol (2 mmol) and cat solid K2CO3
(0.024 g, 0.2 mmol). The mixture was stirred for 1–2 h at 75 8C
and filtered, the filtrate was condensed and the residue was
recrystallized from dichloromethane/petroleum ether to give
pure 2-aryloxy-5,8,9-trimethyl-3-(4-fluoro-substituted)phenyl-
thieno[30,20-5,6]pyrido[4,3-d] pyrimidin-4(3H)-ones 5a–j [23].
(400 MHz, CDCl3) d 2.02 (s, 3H, CH3), 2.39 (s, 6H,
2*CH3), 3.04 (s, 3H, CH3), 6.95–7.45 (m, 8H, Ar-H); EI-MS
(70 eV, m/z): 445 (M+, 100), 338 (43); Elemental Anal. Calcd.
for C25H20FN3O2S: C, 67.40; H, 4.52; N, 9.43; S, 7.19. Found:
C, 67.43; H, 4.22; N, 9.33; S, 7.45.
3.3.6. 3-(4-Fluorophenyl)-2-[(2-methylphenyl)oxy]-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]-pyrimidin-4(3H)-
one (5f)
3.3.1. 3-(4-Fluorophenyl)-2-[(4-methylphenyl)oxy]-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (5a)
White solid, yield 82%, m.p. 280.1–281.2 8C; IR (KBr): y
1
2927, 1718, 1688 (C O), 1654, 1620, 1580, 1543 cmꢀ1; H
White solid, yield 88%, m.p. 254.7–255.3 8C; IR (KBr): y
NMR (400 MHz, CDCl3) d 1.90 (s, 3H, CH3), 2.17 (s, 3H, CH3),
2.37 (s, 3H, CH3), 3.03 (s, 3H, CH3), 7.07–7.44 (m, 8H, Ar-H);
Elemental Anal. Calcd. for C25H20FN3O2S: C, 67.40; H, 4.52; N,
9.43; S, 7.19. Found: C, 67.81; H, 4.17; N, 9.53; S, 7.29.
2929, 2852, 1693 (C O), 1620, 1562 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 2.02 (s, 3H, CH3), 2.39 (s, 3H, CH3),
3.05 (s, 6H, 2*CH3), 7.21–7.41 (m, 8H, Ar-H); EI-MS (70 eV,
m/z): 445 (M+, 100), 308 (98), 188 (85); Elemental Anal. Calcd.
for C25H20FN3O2S: C, 67.40; H, 4.52; N, 9.43. Found: C, 67.25;
H, 4.59; N, 9.59.
3.3.7. 3-(4-Fluorophenyl)-2-phenoxy-5,8,9-trimethyl-
thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-one (5g)
White solid, yield 84%, m.p. 266.9–267.5 8C; IR (KBr): y
1
3.3.2. 3-(4-Fluorophenyl)-2-[(1,2,3,4,5-
pentachlorophenyl)oxy]-5,8,9-trimethyl-thieno[30,20-
5,6]pyri-do[4,3-d]pyrimidin-4(3H)-one (5b)
White solid, yield 90%, m.p. >280 8C; IR (KBr): y 2919,
1704 (C O), 1626, 1563 cmꢀ1; 1H NMR (400 MHz, CDCl3) d
2933, 2853, 1735, 1680 (C O), 1616, 1561 cmꢀ1; H NMR
(400 MHz, CDCl3) d 1.98 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.03
(s, 3H, CH3), 7.13–7.44 (m, 9H, Ar-H); Elemental Anal. Calcd.
for C24H18FN3O2S: C, 66.81; H, 4.20; N, 9.74; S, 7.43. Found:
C, 66.46; H, 4.42; N, 9.39; S, 7.37.

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Q. Ren et al. / Journal of Fluorine Chemistry 128 (2007) 1369–1375
3.3.8. 2-[(4-Chlorophenyl)oxy]-3-(4-fluorophenyl)-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (5h)
3.4.2. 3-(4-Fluorophenyl)-2-n-propylamino-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4 (3H)-
one (5l)
White solid, yield 86%, m.p. 270.2–270.9 8C; IR (KBr): y
White solid, yield 83%, m.p. >280 8C; IR (KBr): y 3443
1
1
3076, 2935, 2852, 1733, 1680 (C O), 1615,1551 cmꢀ1; H
(N–H), 2963, 2930, 2874, 1686 (C O), 1581, 1561 cmꢀ1; H
NMR (400 MHz, CDCl3) d 2.03 (s, 3H, CH3), 2.40 (s, 3H,
CH3), 3.02 (s, 3H, CH3), 7.09–7.42 (m, 8H, Ar-H); Elemental
Anal. Calcd. for C24H17ClFN3O2S: C, 61.87; H, 3.68;
N, 9.02; S, 6.88. Found: C, 61.53; H, 3.49; N, 8.97; S,
7.04.
NMR (400 MHz, CDCl3) d 0.90 (t, 3H, J = 7.4 Hz, CH2CH3),
1.62 (q, 2H, J = 7.4 Hz, CH2CH3), 2.48 (s, 3H, CH3), 2.71 (s,
3H, CH3), 2.94 (s, 3H, CH3), 3.45 (q, 2H, J = 6.8 Hz,
NHCH2CH2), 4.37 (s, 1H, N–H), 7.26–7.33 (m, 4H, Ar-H);
EI-MS (70 eV, m/z): 396 (M+, 100), 354 (86), 338 (20);
Elemental Anal. Calcd. for C21H21FN4OS: C, 63.62; H, 5.34;
N, 14.13. Found: C, 63.45; H, 5.51; N, 14.11.
3.3.9. 3-(4-Fluorophenyl)-2-[(2,4-dichlorophenyl)oxy]-
5,8,9-trimethyl-thieno[30,20-5,6]pyrido[4,3-d] pyrimidin-
4(3H)-one (5i)
3.4.3. 3-(4-Fluorophenyl)-2-iso-propylamino-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-
one (5m)
White solid, yield 85%, m.p. 277.7–279.1 8C; IR (KBr): y
1
3040, 2919, 2840, 1688 (C O), 1621, 1562 cmꢀ1; H NMR
(400 MHz, CDCl3) d 1.95 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.02
(s, 3H, CH3), 7.17–7.51 (m, 7H, Ar-H); Elemental Anal. Calcd.
for C24H17Cl2FN3O2S: C, 57.61; H, 3.22; N, 8.40; S, 6.41.
Found: C, 58.04; H, 3.40; N, 8.34; S, 6.72.
White solid, yield 83%, m.p. >280 8C; IR (KBr): y 3437
(N–H), 2966, 2924, 2868, 1674 (C O), 1581, 1561 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d 1.23 (d, 6H, J = 6.8, 2*CH3), 2.48
(s, 3H, CH3), 2.69 (s, 3H, CH3), 2.94 (s, 3H, CH3), 4.04 (d, 1H,
J = 6.8 Hz, CH), 4.33 (d, 1H, J = 6.8 Hz, N–H), 7.26–7.33
(m, 4H, Ar-H); Elemental Anal. Calcd. for C21H21FN4OS:
C, 63.62; H, 5.34; N, 14.13. Found: C, 63.40; H, 5.44; N,
13.71.
3.3.10. 3-(4-Fluorophenyl)-2-[(2-chloro-4-
fluorophenyl)oxy]-5,8,9-trimethyl-thieno[30,20-5,6]pyrido
[4,3-d]pyrimidin-4(3H)-one (5j)
White solid, yield 82%, m.p. 260.1–261.9 8C; IR (KBr): y
1
2988, 2935, 2852, 1687 (C O), 1664, 1621, 1580 cmꢀ1; H
3.4.4. 2-n-Butylamino-3-(4-fluorophenyl)-5,8,9-trimethyl-
thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4 (3H)-one (5n)
White solid, yield 73%, m.p. >280 8C; IR (KBr): y 3443
NMR (400 MHz, CDCl3) d 1.96 (s, 3H, CH3), 2.40 (s, 3H,
CH3), 3.03 (s, 3H, CH3), 7.06–7.68 (m, 7H, Ar-H); Elemental
Anal. Calcd. for C24H16ClF2N3O2S: C, 59.57; H, 3.33;
N, 8.68; S, 6.61. Found: C, 59.86; H, 3.76; N, 8.44; S,
6.64.
(N–H), 2930, 2863, 1682 (C O), 1580 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 0.92 (t, 3H, J = 7.2 Hz, CH3), 1.25–
1.34 (m, 2H, CH2), 1.54–1.61 (m, 2H, CH2), 2.48 (s, 3H, CH3),
2.71 (s, 3H, CH3), 2.95 (s, 3H, CH3), 3.49 (q, 2H, J = 4.2 Hz,
CH2), 4.35 (s, 1H, N–H), 7.26–7.33 (m, 4H, Ar-H); Elemental
Anal. Calcd. for C22H23FN4OS: C, 64.37; H, 5.65; N, 13.65.
Found: C, 64.67; H, 5.45; N, 13.47.
3.4. General procedure for the preparation of 2-
alkylamino-5,8,9-trimethyl-3-(4-fluoro-substituted) phenyl-
thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones (5k–p)
Alkylamine (2 mmol) was added into the solution of 4
prepared above in CH2Cl2 (10 mL). After the reaction mixture
was stirred continuously for an addition 6 h, the solvent was
removed and 10 mL of anhydrous ethanol with several drops of
sodium ethoxide in ethanol (3 M) were 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-5,8,9-trimethyl-3-(4-fluoro-substi-
tuted) phenyl-thieno[30,20-5,6]pyrido [4,3-d]pyrimidin-4(3H)-
ones 5k–p.
3.4.5. 2-tert-Butylamino-3-(4-fluorophenyl)-5,8,9-
trimethyl-thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4 (3H)-
one (5o)
White solid, yield 74%, m.p. >280 8C; IR (KBr): y 3430
(N–H), 3054 (Ph-H), 2964, 2924, 1677 (C O), 1579,
1559 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H,
;
3*CH3), 2.49 (s, 3H, CH3), 2.74 (s, 3H, CH3), 2.96 (s, 3H, CH3),
4.21 (s, 1H, N–H), 7.26–7.33 (m, 4H, Ar-H); Elemental Anal.
Calcd. for C22H23FN4OS: C, 66.92; H, 6.70; N, 12.01. Found:
C, 66.90; H, 6.99; N, 11.68.
3.4.1. 2-Ethylamino-3-(4-fluorophenyl)-5,8,9-trimethyl-
thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4(3H)-one (5k)
White solid, yield 83%, m.p. 275.7–276.1 8C; IR (KBr): y
3.4.6. 2-Di-butylamino-3-(4-fluorophenyl)-5,8,9-trimethyl-
thieno[30,20-5,6]pyrido[4,3-d]pyrimidin-4 (3H)-one (5p)
White solid, yield 78%, m.p. >280 8C; IR (KBr): y 2956,
1
3425 (N–H), 2929, 2852, 1693 (C O), 1620, 1562 cmꢀ1; H
2928, 2868, 1680 (C O), 1604, 1556 cmꢀ1 1H NMR
;
NMR (400 MHz, CDCl3)
d
1.22 (t, 3H, J = 7.0 Hz,
(400 MHz, CDCl3) d 0.85 (q, 6H, J = 7.6 Hz, 2*CH3),
1.14–1.45 (m, 8H, 4*CH2), 2.49 (s, 3H, CH3), 2.69 (s, 3H,
CH3), 2.96(s, 3H, CH3), 3.12 (q, 4H, J = 2.4 Hz, 2*CH2),
7.19–7.40 (m, 4H, Ar-H); Elemental Anal. Calcd. for
C26H31FN4OS: C, 66.92; H, 6.70; N, 12.01. Found: C,
66.78; H, 6.79; N, 11.92.
CH2CH3), 2.48 (s, 3H, CH3), 2.70 (s, 3H, CH3), 2.97 (s,
3H, CH3), 3.52–3.58 (m, 2H, CH2), 4.36 (s, 1H, NH),
7.15–7.33 (m, 4H, Ar-H); Elemental Anal. Calcd. for
C20H19FN4OS: C, 62.81; H, 5.01; N, 14.65. Found: C,
62.75; H, 5.37; N, 14.66.

Q. Ren et al. / Journal of Fluorine Chemistry 128 (2007) 1369–1375
1375
3.5. Fungicidal testing
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