Efficient synthesis of 2-substituted thieno[2,3-d]pyrimidin-4(3H)-ones via an iminophosphorane

Article abstract of DOI:10.1002/hc.20424

The carbodiimides 4, obtained from reactions of iminophosphorane 3 with aromatic isocyanates, were reacted with secondary amines to give 2-dialkylamino-5-ethyl-6-methyl-thieno[2,3-d]pyrimidin-4(3H)-ones 6 in the presence of catalytic amount of EtONa. Reac

Full text of DOI:10.1002/hc.20424

Heteroatom Chemistry
Volume 19, Number 3, 2008
Efficient Synthesis of 2-Substituted
Thieno[2,3-d]pyrimidin-4(3H)-ones
via an Iminophosphorane
Zheng-Dong Fang,1,2 Yang-Gen Hu,1 and Ming-Wu Ding1
1Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal
University, Wuhan 430079, People’s Republic of China
2Department of Chemistry, Hubei Normal University, Huangshi 435002, People’s Republic of China
Received 2 November 2006; revised 9 November 2007
2-alkyl-substituted thienopyrimidinones show sig-
ABSTRACT: The carbodiimides 4, obtained from
nificant antifungal and antibacterial activities [1–7],
reactions of iminophosphorane 3 with aromatic
whereas others exhibited good anticonvulsant and
isocyanates, were reacted with secondary amines
angiotensin or H1 receptor antagonistic activities
to give 2-dialkylamino-5-ethyl-6-methyl-thieno[2,3-
[8–12]. The chemistry of thienopyrimidinones
d]pyrimidin-4(3H)-ones 6 in the presence of catalytic
has also received attention because their starting
amount of EtONa. Reactions of 4 with phenols or
materials, 2-amino-3-carboxythiophenes, can be
ROH in the presence of the catalytic amount of K2CO3
conveniently synthesized by the Gewald reaction
or RONa gave 2-aryloxy- or 2-alkoxy-5-ethyl-6-methyl-
[13]. Synthetically useful approaches to thienopy-
thieno[2,3-d]pyrimidin-4(3H)-ones 6 in satisfactory
rimidinones starting from easily accessible 2-
yields. The effects of the nucleophiles on cyclization
amino-3-carboxythiophenes are, therefore, of great
ꢀ
C
have been investigated.
2008 Wiley Periodicals, Inc.
importance. Recently, we have become interested in
the preparation of N-heteroaryliminophosphoranes
because these species are promising building
blocks for the synthesis of nitrogen heterocycles
[14–18]. Herein, we report an efficient synthesis of
various 2-substituted 5-ethyl-6-methyl-thieno[2,3-
d]pyrimidin-4(3H)-ones via iminophosphorane
3.
Heteroatom Chem 19:266–270, 2008; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20424
INTRODUCTION
The derivatives of heterocycles containing thienopy-
rimidine system are of great importance because
of their remarkable biological activity for use as
potential drugs. For example, some 2-alkoxy- or
RESULTS AND DISCUSSION
Ethyl-2-amino-5-ethyl-6-methyl-thiophene-3-carbo-
xylate 2, easily obtained by the Gewald method
from 3-pentanone 1, ethyl cyanoacetate, and
sulfur in the presence of morpholine, was con-
verted to iminophosphorane 3 by the treatment
with triphenylphosphine, hexachloroethane, and
Correspondence to: Ming-Wu Ding; e-mail: ding5229@yahoo.
com.cn.
Contract grant sponsor: Natural Science Foundation of Hubei
Province and China, the Key Project of Chinese Ministry of
Education.
Contract grant number: 2006ABB016, 20772041, and 107082.
2008 Wiley Periodicals, Inc.
c
ꢀ
266

Efficient Synthesis of 2-Substituted Thieno[2,3-d]pyrimidin-4(3H)-ones via an Iminophosphorane 267
triethylamine in dry acetonitrile (Eq. (1)).
group (6e, 6g in Table 1).
(2)
(1)
Iminophosphorane 3 reacted with an equimolec-
ular quantity of the aromatic isocyanates to give the
carbodiimides 4, which were allowed to react with
secondary amines to provide guanidine intermedi-
ates 5 (Y = NR1R2). Even in refluxing toluene, the in-
termediates 5 did not cyclize. However, by treatment
with sodium ethoxide in ethanol at room tempera-
ture, the intermediates 5 underwent intramolecular
heterocyclization to give the expected pyrimidinones
6 in satisfactory yields (Eq. (2)). The results are listed
in Table 1. The yields of products 6 are related to the
substituents R1 and R2 of the secondary amines. Bet-
ter yields are obtained as R1 and R2 are small alkyl or
cyclic alkyl group (6a, 6d, 6f, 6h, 6j in Table 1); how-
ever, lower yields are obtained when R1 and R2 are
a long-chain alkyl group or one of them is a phenyl
The direct reaction of carbodiimide 4 with
phenols did not produce 2-aryloxy-thieno[2,3-
d]pyrimidin-4(3H)-ones 6. However, when carried
out in the presence of catalytic amount of potas-
sium carbonate, the reaction gave 6 (Y = OAr) in
good yields (Table 1). The formation of 6 can be
rationalized in terms of an initial nucleophilic ad-
dition of phenoxides to the carbodiimides 4 to give
the intermediates 5 that cyclize to give 6. The yields
of products 6 are also related to the substituents
of phenols. Better yields are obtained as electron-
donating substituents are present in the phenol ring
(6o, 6p in Table 1). The direct reaction of car-
bodiimide 4 with ROH gave a complex mixture;
however, when the reaction was carried out in the
presence of catalytic amount of RO−Na+, the re-
action took place smoothly and 2-alkoxy-thieno[2,
TABLE 1 Preparation of 2-Substituted Thieno[2,3-d]pyrimidin-4(3H)-ones 6
No.
Ar
Y
Formula
Conditions
Yield (%)a
MP ( ◦C)
6a
6b
6c
Ph
Ph
Ph
NEt2
N(i-Bu)2
N(n-C5H11 2
C19H23N3OS
C23H31N3OS
C25H35N3OS
r.t./6 h
r.t./6 h
r.t./6 h
93
81
85
144–145
123–124
73–74
)
6d
Ph
C20H23N3OS
r.t./6 h
92
128–129
6e
6f
6g
6h
6i
Ph
NMePh
NEt2
N(n-C5H11 2
NEt2
N(n-Bu)2
C22H21N3OS
C20H25N3OS
C26H37N3OS
C20H25N3OS
C24H33N3OS
r.t./6 h
r.t./6 h
r.t./6 h
r.t./6 h
r.t./6 h
64
88
64
86
73
153–154
96–97
70–71
103–104
65–66
4-MeC6H4
4-MeC6H4
3-MeC6H4
3-MeC6H4
)
.
6j
3-MeC6H4
C21H25N3OS
r.t./6 h
87
157–158
6k
4-ClC6H4
C19H20ClN3O2S
r.t./8 h
78
205–206
6l
4-MeC6H4
4-MeC6H4
4-ClC6H4
Ph
Ph
Ph
MeO
EtO
MeO
4-MeC6H4O
4-MeOC6H4O
4-ClC6H4O
C17H18N2O2S
C18H20N2O2S
C16H15ClN2O2S
C22H20N2O2S
C22H20N2O3S
C21H17ClN2O2S
r.t./6 h
r.t./6 h
r.t./8 h
r.t./6 h
r.t./6 h
r.t./6 h
82
84
77
83
76
74
153–154
158–159
184–185
203–204
88–89
6m
6n
6o
6p
6q
138–139
r.t. = Room temperature.
aIsolated yields are based on iminophosphorane 3.
Heteroatom Chemistry DOI 10.1002/hc

268 Fang et al.
TABLE 2 The Elemental Analysis and IR Data of Thieno[2,3-d]pyrimidin-4(3H)-ones 6
Anal. (Calcd) (%)
IR (cm−1
)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
C, 66.95 (66.83); H, 6.50 (6.79); N, 12.20 (12.31)
C, 69.52 (69.48); H, 8.06 (7.86); N, 10.54 (10.57)
C, 70.75 (70.55); H, 8.41 (8.29); N, 9.80 (9.87)
C, 67.96 (67.96); H, 6.54 (6.56); N, 11.74 (11.89)
C, 70.10 (70.37); H, 5.85 (5.64); N, 10.92 (11.19)
C, 67.43 (67.57); H, 7.00 (7.09); N, 11.64 (11.82)
C, 71.03 (71.03); H, 8.28 (8.48); N, 9.31 (9.56)
C, 67.28 (67.57); H, 7.23 (7.09); N, 11.79 (11.82)
C, 69.82 (70.03); H, 8.19 (8.08); N, 10.35 (10.21)
C, 68.60 (68.63); H, 7.03 (6.86); N, 11.24 (11.43)
C, 58.35 (58.53); H, 5.44 (5.17); N, 10.62 (10.78)
C, 64.87 (64.94); H, 5.67 (5.77); N, 8.98 (8.91)
C, 65.94 (65.83); H, 5.97 (6.14); N, 8.80 (8.53)
C, 57.44 (57.40); H, 4.78 (4.52); N, 8.58 (8.37)
C, 70.04 (70.19); H, 5.46 (5.35); N, 7.51 (7.44)
C, 67.44 (67.33); H, 5.31 (5.14); N, 6.92 (7.14)
C, 63.46 (63.55); H, 4.43 (4.32); N, 6.97 (7.06)
1681, 1592, 1540, 1497, 1469
1678, 1591, 1525, 1464, 1434
1692, 1589, 1541, 1497, 1469
1682, 1591, 1522, 1439, 1364
1682, 1594, 1529, 1488, 1439
1681, 1540, 1510, 1467, 1493
1686, 1587, 1537, 1498, 1469
1678, 1607, 1541, 1500, 1471
1686, 1606, 1540, 1493, 1452
1687, 1532, 1510, 1444, 1365
1681, 1593, 1584, 1540, 1491
1684, 1605, 1569, 1552, 1500
1693, 1551, 1500, 1474, 1439
1693, 1597, 1574, 1492, 1461
1693, 1599, 1570, 1549, 1506
1689, 1570, 1505, 1349, 1304
1693, 1602, 1572, 1545, 1485
3-d]pyrimidin-4(3H)-ones 6 (Y = OR) were obtained
in satisfactory yields (Table 1).
trometer (Hewlett-Packard Company, Palo Alto,
California). 1H NMR spectra were recorded in CDCl3
on a Varian Mercury Plus 400 (400 Hz) spectrometer
(Varian Company, Palo Alto, California), and chem-
ical shifts (δ) are given in ppm using (CH3)4Si as an
internal reference (δ = 0). Elementary analyses were
taken on a Perkin-Elmer CHN2400 elemental anal-
ysis instrument (PerkinElmer Company, Waltham,
Massachusetts).
The structure of the synthesized compound 6
was confirmed by their spectral data and elemental
analyses (Tables 2 and 3). For example, the IR spec-
tra of 6a revealed C O absorption bands at 1681
cm−1. The 1H NMR spectral data show the signals of
NCH2 at 3.04 ppm as quartets and signals of CH3 at
2.36, 1.13, and 0.80 ppm as singlets or triplets. The
phenyl signals appeared at 7.26–7.50 (m, 5H, Ar-H).
The MS spectrum of 6a shows molecule ion peak
(M+ + 1) at m/z 342.
Preparation of Ethyl-3-ethyl-4-methyl-2-amino-
thiophene-3-carboxylate (2)
In conclusion, we have developed an effi-
cient method for the synthesis of 2-substituted
To a stirred mixture of 0.42 g (0.005 mol) of 3-
pentanone (1), 0.16 g (0.005 mol) of sulfur, and
0.57 g (0.005 mol) of ethyl cyanoacetate in 10 mL
of ethanol, 1.2 mL of morpholine was added. After
the mixture was stirred at 45◦C for 5 h, the solid
was filtered and the filtrate was poured into water.
The formed yellow solid was separated and recrystal-
lized from methanol to give 2 as light yellow needles,
thieno[2,3-d]pyrimidin-4(3H)-ones via
a
base-
catalyzed reaction of functionalized carbodiimides
with various secondary amines, phenols, or alcohols.
The synthetic approach shows that the aza-Wittig
reaction of iminophosphorane affords a general
route to the heterocyclic system, containing various
substituents in the pyrimidine ring. Owing to the
easily accessible and versatile starting material,
this method has the potential in the synthesis of
many biologically and pharmaceutically active
thienopyrimidinone derivatives.
1
0.65 g (61%), mp 40–41◦C. H NMR (CDCl3): δ 1.02
(t, 3H, J = 7.2 Hz, CH3), 1.33 (t, 3H, J = 7.2 Hz, CH3),
2.03 (s, 3H, CH3), 2.66 (q, 2H, J = 7.2 Hz, CH2), 4.32
(q, 2H, J = 7.2 Hz, OCH2), 5.84 (s, 2H, NH2); MS: m/z
(%) 213 (M+, 53%), 183 (47), 107 (100). Anal. Calcd
for C10H15NO2S: C, 56.31; H, 7.09; N, 6.57. Found: C,
56.22; H, 7.35; N, 6.71.
EXPERIMENTAL
Melting points were determined using a X-4 model
apparatus (Beijing Taike Company, Beijing, People’s
Republic of China) and were uncorrected. IR spec-
tra were recorded on a Nicolet 7500 NXR infrared
spectrometer (Thermonicolet Company, Waltham,
Massachusetts) as KBr pellets with absorption given
in cm−1. MS were measured on a HP5988A spec-
Preparation of Ethyl-3-ethyl-4-methyl-2-[(triphe-
nylphosphanylidene)amino]thiophene-3-
carboxylate (3)
To
a
mixture
of
ethyl-3-ethyl-4-methyl-2-
aminothiophene-3-carboxylate (2; 0.64 g, 3 mmol),
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of 2-Substituted Thieno[2,3-d]pyrimidin-4(3H)-ones via an Iminophosphorane 269
TABLE 3 The MS and 1H-NMR Data of Thieno[2,3-d]pyrimidin-4(3H)-ones 6
FAB-MS
1H-NMR (CDCl3, δ)
6a
6b
6c
342 (M+ + 1)
398 (M+ + 1)
425 (M+)
0.80 (t, 6H, J = 7.0 Hz, 2CH3); 1.13 (t, 3H, J = 6.8 Hz, CH3); 2.36 (s, 3H, CH3); 2.85 (q, 2H,
J = 7.2 Hz, CH2); 3.04 (q, 4H, J = 7.2 Hz, 2NCH2); 7.26–7.50 (m, 5H, Ar-H)
0.77 (d, 12H, J = 6.8 Hz, 4CH3); 1.13 (t, 3H, J = 7.2 Hz, CH3); 1.75–1.81 (m, 2H, 2CH); 2.36
(s, 3H, CH3); 2.79–2.86 (m, 6H, 3CH2); 7.27–7.51 (m, 5H, Ar-H)
0.84 (t, 6H, J = 7.2 Hz, 2CH3); 1.13 (t, 3H, J = 7.2 Hz, CH3); 1.17–1.24 (m, 6H,
2CH2CH2CH2); 2.36 (s, 3H, CH3); 2.85 (q, 2H, J = 7.2 Hz, CH2); 2.94 (t, 4H, J = 7.2 Hz,
2NCH2); 7.26–7.47 (m, 5H, Ar-H)
1.12 (t, 3H, J = 7.2 Hz, CH3); 1.22–1.40 (m, 6H, 3CH2); 2.37 (s, 3H, CH3); 2.86 (q, 2H,
J = 7.2 Hz, CH2); 3.06 (t, 4H, J = 5.4 Hz, 2CH2); 7.27–7.49 (m, 5H, Ar-H)
1.13 (t, 3H, J = 7.2 Hz, CH3); 2.41 (s, 3H, CH3); 2.86 (q, 2H, J = 7.2 Hz, CH2); 3.25 (s, 3H,
NCH3); 6.58–7.26 (m, 10H, Ar-H)
6d
6e
6f
353 (M+)
376 (M+ + 1)
356 (M+ + 1)
0.82 (t, 6H, J = 7.2 Hz, 2CH3); 1.12 (t, 3H, J = 6.4 Hz, CH3); 2.36 (s, 3H, CH3); 2.40 (s, 3H,
CH3); 2.85 (q, 2H, J = 6.8 Hz, CH2); 3.05 (t, 4H, J = 7.2 Hz, 2NCH2); 7.15–7.28 (m, 4H,
Ar-H)
6g
6h
6i
440 (M+ + 1)
356 (M+ + 1)
411 (M+)
0.84 (t, 6H, J = 7.2 Hz, 2CH3); 1.12 (t, 3H, J = 7.2 Hz, CH3); 1.16–1.24 (m, 12H,
2CH2CH2CH2); 2.36 (s, 3H, CH3); 2.39 (s, 3H, CH3); 2.84 (q, 2H, J = 7.2 Hz, CH2); 2.95
(t, 4H, J = 7.2 Hz, 2CH2); 7.28–7.13 (m, 4H, Ar-H)
0.81 (t, 6H, J = 7.2 Hz, 2CH3); 1.13 (t, 3H, J = 7.2 Hz, CH3); 2.36 (s, 3H, CH3); 2.39 (s, 3H,
CH3); 2.86 (q, 2H, J = 7.2 Hz, CH2); 3.05 (q, 4H, J = 7.2 Hz, 2NCH2); 7.07–7.38 (m, 4H,
Ar-H)
0.82 (t, 6H, J = 6.8 Hz, 2CH3); 1.10–1.22 (m, 11H, 2CH2CH2, and CH3); 2.36 (s, 3H, CH3);
2.39 (s, 3H, CH3); 2.85 (q, 2H, J = 7.2 Hz, CH2); 2.96 (t, 4H, J = 7.2 Hz, 2NCH2);
7.06–7.38 (m, 4H, Ar-H)
6j
368 (M+ + 1)
390 (M+ + 1)
315 (M+ + 1)
329 (M+ + 1)
1.12 (t, 3H, J = 6.8 Hz, CH3); 1.23–1.41 (m, 6H, 3CH2); 2.36 (s, 3H, CH3); 2.40 (s, 3H, CH3);
2.85 (q, 2H, J = 6.8 Hz, CH2); 3.07 (t, 4H, J = 4.8 Hz, 2NCH2); 7.19–7.28 (m, 4H, Ar-H)
1.12 (t, 3H, J = 7.2 Hz, CH3); 2.38 (s, 3H, CH3); 2.84 (q, 2H, J = 7.2 Hz, CH2); 3.08 (t, 4H,
J = 4.8 Hz, 2NCH2); 3.46 (t, 4H, J = 4.8 Hz, 2OCH2); 7.27–7.49 (m, 4H, Ar-H)
1.12 (t, 3H, J = 7.2 Hz, CH3); 2.37 (s, 3H, CH3); 2.41 (s, 3H, CH3); 2.86 (q, 2H, J = 7.2 Hz,
CH2); 3.91 (s, 3H, OCH3); 7.10–7.31 (m, 4H, Ar-H)
1.12 (t, 3H, J = 7.2 Hz, CH3); 1.24 (t, 3H, J = 7.2 Hz, CH3); 2.37 (s, 3H, CH3); 2.41 (s, 3H,
CH3); 2.86 (q, 2H, J = 7.2 Hz, CH2); 4.41 (q, 2H, J = 7.2 Hz, OCH2); 7.08–7.30 (m, 4H,
Ar-H)
6k
6l
6m
6n
6o
6p
6q
334 (M+)
1.12 (t, 3H, J = 7.2 Hz, CH3); 2.38 (s, 3H, CH3); 2.85 (q, 2H, J =7.2 Hz, CH2); 3.92 (s, 3H,
OCH3); 7.16–7.48 (m, 4H, Ar-H)
377 (M+ + 1)
393 (M+ + 1)
396 (M+)
1.14 (t, 3H, J = 7.2 Hz, CH3); 2.35 (s, 3H, CH3); 2.36 (s, 3H, CH3); 2.88 (q, 2H, J = 7.2 Hz,
CH2); 6.98–7.56 (m, 9H, Ar-H)
1.14 (t, 3H, J = 7.2 Hz, CH3); 2.36 (s, 3H, CH3); 2.88 (q, 2H, J = 7.2 Hz, CH2); 3.80 (s, 3H,
OCH3); 6.87–7.56 (m, 9H, Ar-H)
1.14 (t, 3H, J = 7.2 Hz, CH3); 2.37 (s, 3H, CH3); 2.88 (q, 2H, J = 7.2 Hz, CH2); 7.05–7.57 (m,
9H, Ar-H)
triphenylphosphine (2.36 g, 9 mmol), and hex-
achloroethane (2.13 g, 9 mmol) in dry acetonitrile
(10 mL), triethylamine (1.84 g, 18 mmol) was added
dropwise in a nitrogen atmosphere. The mixture
was stirred for 3 h at room temperature. After the
reaction mixture was poured into cold water (200
mL), the precipitate obtained was recrystallized
from ethanol to give the desired iminophosphorane
3 in 88% yield with mp 106–107◦C. 1H NMR (CDCl3):
δ 1.04 (t, 3H, J = 7.2 Hz, CH3); 1.35 (t, 3H, J = 7.2
Hz, CH3), 2.04 (s, 3H, CH3), 2.66 (q, 2H, J = 7.2 Hz,
CH2), 4.29 (q, 2H, J = 7.2 Hz, OCH2), 7.84–7.47 (m,
15H, Ar-H); MS: m/z (%) 473 (M+, 100%), 262 (78),
183 (74), 107 (63). IR (KBr, cm−1): 1664, 1470, 1437,
1398, 1329. Anal. Calcd for C28H28NO2PS: C, 71.02;
H, 5.96; N, 2.96. Found: C, 70.24; H, 6.19; N, 2.93.
General Preparation of 2-Dialkylamino-5-ethyl-
6-methyl-thieno[2,3-d]pyrimidin-4(3H)-ones
(6a–6k)
To a solution of iminophosphorane 3 (0.95 g,
2 mmol) in anhydrous CH2Cl2 (10 mL), aromatic
isocyanate (2 mmol) was added under nitrogen at-
mosphere at room temperature. After the reaction
mixture was left unstirred for 6–12 h at 0–5◦C, the
iminophosphorane 3 had disappeared (TLC mon-
itored). The solvent was removed under reduced
Heteroatom Chemistry DOI 10.1002/hc

270 Fang et al.
pressure, and Et2O/petroleum ether (1:2, 20 mL) was
added to precipitate triphenylphosphine oxide. Re-
moval of the solvent gave carbodiimides 4, which
were used directly without further purification. To
the solution of 4 in dichloromethane (10 mL), di-
alkylamine (2 mmol) was added. After the reaction
mixture was left unstirred for 5–6 h, the solvent was
removed and anhydrous EtOH (10 mL) with several
drops of EtONa in EtOH was added. The mixture
was stirred for 6–12 h at room temperature. The so-
lution was condensed, and the residue was recrys-
tallized from EtOH to give the expected cyclic com-
pounds 6a–6k in good yields.
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General Preparation of 2-Aryloxy-5-ethyl-6-methyl-
thieno[2,3-d]pyrimidin-4(3H)-ones (6o–6q)
To the solution of 4 prepared as mentioned
above in dry acetonitrile (10 mL), substituted
phenol (2 mmol) and cat. solid K2CO3 (0.14 g,
10 mmol) were added. The mixture was stirred
for
6
h
at room temperature and filtered.
The filtrate was condensed, and the residue
was recrystallized from dichloromethane–petroleum
ether to give 2-arlyoxy-5-ethyl-6-methyl-thieno[2,3-
d ]pyrimidin-4(3H)-ones 6o–6q.
Heteroatom Chemistry DOI 10.1002/hc