Synthesis, characterization, and fungicidal activity of new thienopyridopyrimidine derivatives

Article abstract of DOI:10.1080/00397911.2011.552154

Iminophosphorane 3 is a important intermediate in organic synthesis. A series of new 2-substituted tetrahydrobenzo[4′,5′]thieno[3′, 2′:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones 5 have been designed and synthesized via the tandem aza-Wittig reaction in 58-92%

Full text of DOI:10.1080/00397911.2011.552154

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Synthesis, Characterization,
and Fungicidal Activity of New
Thienopyridopyrimidine Derivatives
Jian-Chao Liu a & Hong-Wu He a
a College of Chemistry, Central China Normal University, Wuhan,
China
Available online: 27 Oct 2011
To cite this article: Jian-Chao Liu & Hong-Wu He (2012): Synthesis, Characterization, and Fungicidal
Activity of New Thienopyridopyrimidine Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:14, 2075-2082
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Synthetic Communications1, 42: 2075–2082, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.552154
SYNTHESIS, CHARACTERIZATION, AND FUNGICIDAL
ACTIVITY OF NEW THIENOPYRIDOPYRIMIDINE
DERIVATIVES
Jian-Chao Liu and Hong-Wu He
College of Chemistry, Central China Normal University, Wuhan, China
GRAPHICAL ABSTRACT
Abstract Iminophosphorane 3 is a important intermediate in organic synthesis. A series of
new 2-substituted tetrahydrobenzo[40,50]thieno[30,20:5,6]pyrido[4,3-d]pyrimidin-4(3H)-
ones 5 have been designed and synthesized via the tandem aza-Wittig reaction in 58–92%
yields. Iminophosphorane 3 reacted with phenyl isocyanate (or 4-chlorophenyl isocyanate,
4-fluorophenyl isocyanate) to give carbodiimide 4, which was further treated with amines to
cyclize in the presence of a catalytic amount of EtONa. The structures of compounds 5 have
been confirmed by 1H NMR, electron-impact mass spectrometry, infrared spectroscopy,
and elemental analyses. 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.
Keywords Aza-Wittig reaction; carbodiimide; fungicidal activity; iminophosphorane;
pyrido[4,3-d]pyrimidin-4(3H)-ones
INTRODUCTION
The derivatives of pyrido[4,3-d]pyrimidine have attracted the interest of
pharmaceutical companies recently. Many pyrido[4,3-d]pyrimidines have been
synthesized as EGFR-TK (epidermal growth factor receptor–tyrosine kinase) and
DHFR (dihydrofolate reductase) inhibitors. Some reports have showed that these
compounds exhibited a wide range of biological activities such as antitumor,
Received October 31, 2010.
Address correspondence to Hong-Wu He, College of Chemistry, Central China Normal University,
Wuhan 430079, China. E-mail: liujc@mail.ccnu.edu.cn
2075

2076
J.-C. LIU AND H.-W. HE
antiviral, anti-inflammatory, and antimicrobial properties.[1,2] However, few reports
so far are available on the pesticidal activities of pyrido[4,3-d]pyrimidine derivatives.
The methods described so far to prepare pyrido[4,3-d]pyrimidines mainly
involve the formation of pyrimidine ring by cyclization of suitable substitutents of
pyridine ring, but the yields are very poor in most cases. For example, pyrido[4,3-d]-
pyrimidine was constructed by condensing 4-amino- 2,6-dichloronicotinamide with
triethylorthoacetate, but pyrido[4,3-d]pyrimidine derivative could be isolated in only
a 38% yield.[3]
The aza-Wittig reactions of iminophosphoranes have received increasing
attention in view of their utility in the synthesis of N-heterocyclic compounds.[4,5]
Recently, we focused our attention on the synthesis of pyrazolopyrimidinones,
thienopyrimidinones, and pyridopyrimidinones from various iminophosphoranes,
with the aim of evaluating their biological activities.[6,7] Here we report a facile
synthesis of pyrido[4,3-d]pyrimidine derivatives from the easily accessible iminopho-
sphorane 3 in good yields. The structures of the prepared compounds, 2-substituted
tetrahydrobenzo[40,50]thieno[30,20:5,6] pyrido[4,3-d]pyrimidin-4(3H)-ones 5, have
been comfirmed by 1H NMR, electron-impact mass spectrometry (EI-MS), infrared
(IR) spectroscopy, and elemental analyses. The preliminary bioassay showed that
some of them have fungicidal activities.
RESULTS AND DISCUSSION
The tetrahydrobenzo[4,5]thieno[2,3-b]pyridine 2, easily obtained from tetrahy-
drobenzo[b] thiophene-3-carbonitrile 1 and methyl acetoacetate in the presence of
SnCl4, was converted to iminophosphorane 3 via reaction with Ph3P in CH2Cl2,
Br2, and Et3N (Scheme 1).
The iminophosphorane 3 reacted with phenyl isocyanate (or 4-chlorophenyl
isocyanate,4-fluorophenyl isocyanate) to give carbodiimide 4. Even in refluxing
toluene, 4 did not react with alkylamines to give the target compounds. However,
in CH2Cl2 in the presence of a catalytic amount of NaOEt, compounds 4 were con-
verted smoothly to 2-alkylamino-8,9,10,11-tetrahydrobenzo[40,50]thieno[30,20:5,6]-
pyrido[4, 3-d]pyrimidin-4(3H)-ones 5a–5r in satisfactory yields at room temperature.
Irrespective of the fact of whether primary or secondary alkylamines were used, the
cyclization was completed in good yields (Table 1).
Scheme 1. Reaction pathway to 2-substituted tetrahydrobenzo[40,50]thieno[30,20:5,6] pyrido[4,3-d]-
pyrimidin-4(3H)-ones.

2077

2078

NEW THIENOPYRIDOPYRIMIDINE DERIVATIVES
2079
All products of type 5 were purified by recrystallization from CH2Cl2 and
petroleum ether. The results are listed in Table 1. All target compounds are white
crystals and their melting points are high. The structures were confirmed by their
spectroscopic data (Tables 2–4). For example, ꢁt1he IR spectra of 5a revealed
absorption bands at 1710 cmꢁ1 (C O), 3178 cm (Ph-H), and 2985, 2924 cmꢁ1
=
1
(C-H). The H NMR spectra of 5a showed the singlet of Me at the pyridine ring
Table 3. 1H NMR spectral data of compounds 5
Compound
1H NMR (ppm, CDCl3, TMS, 400 MHz)
5a
1.89–1.97 (m, 4H, 2CH2), 2.81–3.27 (m, 4H, 2CH2), 2.98 (s, 3H, CH3), 3.30–3.41 (m, 4H,
2CH2), 3.68–3.74 (m, 4H, 2CH2), 6.94–7.26 (m, 5H, Ar-H).
=
1.92–1.99 (m, 4H, 2CH2), 2.93–3.26 (m, 4H, 2CH2), 3.07 (s, 3H, CH3), 6.87 (s, 1H, C CH),
5b
5c
5d
=
=
6.92 (s, 1H, C CH), 7.26–7.57 (m, 5H, Ar-H), 7.83 (s, 1H, C CH).
1.91–1.98 (m, 4H, 2CH2), 2.89–3.37 (m, 4H, 2CH2), 2.97 (s, 3H, CH3), 4.37 (s, 1H, NH),
2.90–2.94 (m, 2H, CH2), 3.67–3.86 (m, 2H, CH2), 7.04–7.55 (m, 5H, Ar-H).
0.87–0.91 (m, 6H, 2CH3), 1.89–1.96 (m, 4H, 2CH2), 2.88–3.29 (m, 4H, 2CH2), 2.95 (s, 3H,
CH3), 1.97–2.04 (m, 1H, CH), 1.56–1.63 (m, 2H, CH2), 4.43 (s, 1H, NH), 7.26–7.62 (m, 4H,
Ar-H).
5e
5f
1.43 (s, 9H, 3CH3), 1.90–1.97 (m, 4H, 2CH2), 2.89–3.28 (m, 4H, 2CH2), 2.95 (s, 3H, CH3),
4.19 (s, 1H, NH), 7.27–7.62 (m, 4H, Ar-H).
0.93 (t, 6H, J ¼ 7.2 Hz, 2CH3), 1.91–1.96 (m, 4H, 2CH2), 2.89–3.27 (m, 4H, 2CH2), 2.97
(s, 3H, CH3), 3.25 (q, 4H, J ¼ 7.2 Hz, 2CH2), 7.27–7.53 (m, 4H, Ar-H).
1.80 (s, 1H, NH), 1.86–1.93 (m, 4H, 2CH2), 2.89–3.29 (m, 4H, 2CH2), 2.99 (s, 3H, CH3),
5g
=
4.70–4.77 (m, 2H, CH2), 6.21 (s, 1H, C CH), 6.32(s, 1H, C CH), 6.62 (s, 1H, C CH),
=
=
7.28–7.58 (m, 4H, Ar-H).
5h
5i
5j
1.38 (s, 4H, 2CH2 of pyridyl), 1.51 (s, 2H, CH2 of pyridyl), 1.90–1.96 (m, 4H, 2CH2),
2.88–3.27 (m, 4H, 2CH2), 2.97 (s, 3H, CH3), 3.18–3.29 (m, 4H, 2CH2N), 7.27–7.50 (m, 4H,
Ar-H).
0.76 (t, 3H, J ¼ 7.2 Hz, CH3), 1.38 (s, 6H, 2CH3), 1.81 (q, 2H, J ¼ 7.2 Hz, CH2), 1.90–1.98
(m, 4H, 2CH2), 2.89–3.26 (m, 4H, 2CH2), 2.96 (s, 3H, CH3), 4.11 (s, 1H, NH), 7.27–7.62
(m, 4H, Ar-H).
0.86 (t, 6H, J ¼ 7.2 Hz, 2CH3), 1.12–1.20 (m, 4H, 2CH2), 1.25–1.28 (m, 4H, 2CH2), 1.90–1.96
(m, 4H, 2CH2), 2.89–3.28 (m, 4H, 2CH2), 2.97 (s, 3H, CH3), 3.10–3.22 (m, 4H, 2CH2N),
7.27–7.50 (m, 4H, Ar-H).
5k
5l
0.78 (d, 6H, J ¼ 7.2 Hz, 2CH3), 1.34–1.46 (m, 4H, 2CH2), 1.90–1.97 (m, 4H, 2CH2), 2.88–3.27
(m, 4H, 2CH2), 2.96 (s, 3H, CH3), 3.02–3.17 (m, 4H, 2CH2N), 7.27–7.50 (m, 4H, Ar-H).
1.90–1.98 (m, 4H, 2CH2), 2.89–3.27 (m, 4H, 2CH2), 2.99 (s, 3H, CH3), 3.23–3.36 (m, 4H,
2CH2), 3.51–3.59 (m, 4H, 2CH2), 7.26–7.52 (m, 4H, Ar-H).
=
1.91–1.97 (m, 4H, 2CH2), 2.92–3.23 (m, 4H, 2CH2), 3.06 (s, 3H, CH3), 6.89 (s, 1H, C CH),
5m
5n
5o
5p
5q
=
=
6.98 (s, 1H, C CH), 7.24–7.53 (m, 4H, Ar-H), 7.86 (s, 1H, C CH).
1.88–1.96 (m, 4H, 2CH2), 2.88–3.35 (m, 4H, 2CH2), 2.96 (s, 3H, CH3), 4.29 (s, 1H, NH),
2.91–2.93 (m, 2H, CH2), 3.72–3.78 (m, 2H, CH2), 7.04–7.49 (m, 4H, Ar-H).
1.90–1.97 (m, 4H, 2CH2), 2.89–3.36 (m, 4H, 2CH2), 2.95 (s, 3H, CH3), 4.31 (s, 1H, NH),
2.90–2.93 (m, 2H, CH2), 3.71–3.79 (m, 2H, CH2), 7.05–7.30 (m, 4H, Ar-H).
1.89–1.95 (m, 4H, 2CH2), 2.89–3.24 (m, 4H, 2CH2), 2.98 (s, 3H, CH3), 3.23–3.28 (m, 4H,
2CH2N), 3.54ꢂ3.59 (m, 4H,2CH2O), 7.21–7.41 (m, 4H, Ar-H).
0.90 (t, J ¼ 7.6 Hz, 3H, CH3), 1.62 (q, J ¼ 7.6 Hz, 2H, CH2), 1.88–1.96 (m, 4H, 2CH2),
2.87–3.29 (m, 4H, 2CH2), 2.94 (s, 3H, CH3 of pyridyl), 3.41–3.49 (m, 2H, NCH2), 3.75
(s, 1H, NH), 7.26–7.32 (m, 4H, Ar-H).
5r
0.93 (t, J ¼ 7.2 Hz, 3H, CH3), 1.32 (q, J ¼ 7.2 Hz, 2H, CH2), 1.54–1.61 (m, 2H, CH2),
1.90–1.94 (m, 4H, 2CH2), 2.87–3.30 (m, 4H, 2CH2), 2.95 (s, 3H, CH3 of pyridyl), 3.46–3.50
(m, 2H, NCH2), 4.35 (s, 1H, NH), 7.26–7.33 (m, 4H, Ar-H).

2080
J.-C. LIU AND H.-W. HE
Table 4. EI–mass spectra of compounds 5
MS (EI, m=z, %)
Compound
5a
5b
5c
434 (36), 432 (Mþ, 100), 406 (59), 393 (18), 387 (56), 346 (29).
413 (Mþ, 100), 399 (32), 386 (39), 346 (6), 76 (23.70).
468 (12), 467 (Mþ þ 1, 42), 466 (Mþ, 90), 375 (25), 362 (100), 361 (39), 347 (26), 334 (19),
90 (18).
5d
5e
455 (49), 452 (Mþ, 100), 437 (13), 398 (18), 396 (21), 395 (31), 56 (38), 43 (37).
454 (34), 453 (Mþ þ 1, 11), 452 (Mþ, 100), 398 (48), 396 (75), 395 (99), 391 (48), 367 (29),
56 (25).
5f
454 (20), 453 (Mþ, 78), 426 (34), 424 (100), 380 (16), 314 (15), 313 (34).
479 (23), 477(Mþ, 25), 476 (100), 447 (21), 419 (14), 395 (19), 80 (40), 52 (18).
466 (35), 465 (Mþ þ 1, 28), 464 (Mþ, 100), 438 (11), 436 (31), 380 (12), 326 (12), 216 (12),
194 (34).
5g
5h
5i
5j
468 (14), 467 (15), 466 (Mþ, 46), 399 (25), 398 (28), 396 (100), 381 (15), 367 (17).
511 (34), 510 (Mþ þ 1, 30), 509 (Mþ, 100), 480 (33), 466 (13), 452 (83), 409 (50), 341 (38),
299 (43).
5k
482 (Mþ þ 1, 28), 481 (Mþ, 100), 440 (31), 437 (97), 409 (30), 380 (27), 329 (15), 327 (37),
298 (15).
469 (31), 468 (Mþ þ 1, 26), 467 (Mþ, 100), 435 (8), 421 (16), 410 (19).
450 (30), 448 (Mþ, 100), 433 (17), 420 (10), 419 (13).
5l
5m
5n
503 (13), 502 (Mþ þ 1, 14), 501 (Mþ, 56), 485 (30), 396 (100), 380 (63), 368 (17), 365 (13),
102 (11).
5o
5p
5q
5r
486 (Mþ þ 1, 20), 485 (Mþ, 74), 393 (17), 381 (100), 377 (23), 366 (29), 352 (22), 351 (11).
451 (Mþ, 100), 422 (9), 419 (9), 406 (25), 394 (25), 364 (9).
423 ((Mþ, 100), 408 (15), 394 (8), 380 (43), 365 (16), 352 (10), 95 (13).
437 (Mþ, 100), 394 (10), 381 (11), 379 (11), 365 (11), 95 (19), 57 (13).
at 2.98 ppm and signals of the cyclohexenyl CH2 at 1.89–1.97 and 2.81–3.27 ppm.
The signals of the morpholin CH2 were at 3.30–3.41 and 3.68–3.74 ppm. The other
signals appeared at 6.94–7.26 (m, 5H, Ar-H). The MS spectrum of 5a shows the
molecule ion peak at m=z 432 with 100% abundance. All the fragmentation ions were
consistent with their structures and can be clearly assigned. The structure of 5a was
also established on the basis of elemental analysis data (Table 2), and the errors
between found values and calculated values are no more than 0.5%.
The preliminary fungicidal activities of compounds 5 were measured in a con-
centration of 50 mg=L using a reported procedure.[8] Six fungi, Fusarium oxysporium,
Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Dothiorella gregaria, and
Bipolaris maydis, were tested, and the data of inhibition rates are listed in Table 5.
It was found that some of the target compounds induce a good inhibition effect
against Rhizoctonia solani and Botrytis cinereaper. For example, the inhibition rates
of compound 5l against Rhizoctonia solani was 98.05% and against Botrytis cinerea-
pers was 100%. It is worth noting that the chloro-containing compound 5l displayed
much better fungicidal activity than nonsubstituted phenyl compound 5a. The
biological evaluation showed that some 2-substituted tetrahydrobenzo[40,50]thieno-
[30,20:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones have fungicidal activities and could be
further developed as lead compounds.
In conclusion, we have developed a facile and efficient regioselective method
for the preparation of pyrido[4,3-d]pyrimidine derivatives. The thienopyridine

NEW THIENOPYRIDOPYRIMIDINE DERIVATIVES
2081
Table 5. Fungicidal activity of some compounds 5 (50 ppm)
Inhibition rate (%)
Fusarium
oxysporium
Rhizoctonia
solani
Botrytis
cinereapers
Gibberella
zeae
Dothiorella
gregaria
Bipolaris
maydis
Compound
5a
5c
5d
5h
5i
49.35
39.63
58.06
48.39
51.61
83.55
61.29
50.75
66.66
63.46
56.06
84.54
80.41
85.57
98.05
82.47
73.79
86.05
70.91
67.91
88.10
73.81
95.24
100.00
93.33
82.36
91.23
44.23
34.50
62.16
45.95
62.16
71.89
56.76
54.85
68.43
56.08
38.29
60.00
52.00
68.00
67.43
60.00
55.94
62.79
51.20
42.22
77.27
63.64
68.18
80.76
72.73
64.38
74.57
5l
5n
5o
5p
derivative 2 reacts with Ph3P and Br2 to give iminophosphorane 3 in excellent yield.
Iminophosphorane 3 is an important intermediate in organic synthesis. The results
of preliminary bioassay indicated that some compounds posses inhibition activities
against Rhizoctonia solani and Botrytis cinereapers at a dosage of 50 mg=L.
EXPERIMENTAL
Melting points were measured on a WRS-1B digital apparatus and are
uncorrected. MS were measured on a Finnigan Trace MS spectrometer. IR spectra
were recorded on a PE-983 IR spectrometer as KBr pellets, in cmꢁ1. 1H NMR spectra
were recorded in CDCl3 on a Varian Mercury 400 spectrometer and resonances are
given in parts per million (ppm) relative to tetramethyl silane (TMS). Elemental
analyses were taken on a Vario EL III instrument. All of the solvents and materials
were reagent grade and purified as required.
Preparation of Thienopyridine Derivatives 2[9]
The thienopyridine derivative 2 was prepared according to literature[9]
procedures.
Preparation of Iminophosphorane 3[10]
A solution of triphenylphosphine (2.6 g, 10 mmol) in dichloromethane (50 mL)
at 0 ꢀC was treated with bromine (1.60 g, 10 mmol). The resulting reaction mixture
was stirred at 0 ꢀC for 30 min and then treated with triethylamine (2.1 g, 20 mmol),
followed immediately by the addition of the thienopyridine derivative 2 (2.77 g,
10 mmol). After 2 was added, the cooling bath was removed and the reaction mixture
was allowed to stir at 25 ꢀC for 20 h.The reaction mixture was washed with water and
then dried. After removal of the solvent, residue was recrystallized from EtOH to
give 3 in 93% yield.

2082
J.-C. LIU AND H.-W. HE
Preparation of Carbodiimides 4 and Compounds 5a–5n[10]
The aryl isocyanate (1.1 mmol) to a solution of 3 (0.525 g, 1 mmol) in dry
CH2Cl2 (20 ml) was added under N2 at room temperature. After the reaction mixture
was stirred for 1.5 h, alkylamine (1.1 mmol) was added to the reaction solution and
stirred for an addition 30 min. Then the solvent was removed under reduced pressure,
and 20 ml of anhydrous EtOH with several drops of EtONa in EtOH were added. The
mixture was stirred for 5–10 h at room temperature. The mixture was filtered, furnish-
ing a white solid, which was either recrystallized from CH2Cl2=petroleum ether or
purified on silica gel to give 2-alkylamino-3-aryl-5-methyl-8,9,10,11-tetrahydrobenzo
[40,50]thieno[30,20:5,6]pyrido[4,3-d]pyrimidin-4(3H)-ones 5a–5n.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the National
Natural Science Foundation of China (No. 20372023) and Hunan S&T Project
(No. 2009RS3029).
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