New efficient synthesis of 2-substituted benzothieno[3,2-d]pyrimidin-4(3H)- ones via a tandem aza-Wittig reaction

Article abstract of DOI:10.1055/s-2006-950364

1-Aryl-3-[2-(ethoxycarbonyl)benzothien-3-yl]carbodiimides 4, obtained from aza-Wittig reactions of iminophosphorane 3 with aryl isocyanates, reacted with secondary amines, phenols, or alkanols in the presence of a catalytic amount of potassium carbonate o

Full text of DOI:10.1055/s-2006-950364

4180
PAPER
New Efficient Synthesis of 2-Substituted Benzothieno[3,2-d]pyrimidin-4(3H)-
ones via a Tandem Aza-Wittig Reaction
2
-Substituted B
h
enzothieno[
e
3, 2-
d
]pyrim
n
idin-4(3
H
)-
g
ones via
a
T
a
-
ndem
A
Z
za-Wittig Reac
h
tion en Xu, Yang-Gen Hu, Ming-Wu Ding*
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, P. R. of China
Fax 86(27)67862041; E-mail: mwding@mail.ccnu.edu.cn
Received 5 July 2006; revised 28 August 2006
interested in the synthesis of quinazolinones, thieno-
Abstract: 1-Aryl-3-[2-(ethoxycarbonyl)benzothien-3-yl]carbodi-
pyrimidinones, and imidazolinones via the aza-Wittig
reaction of a- or b-ethoxycarbonyl-substituted imino-
phosphorane derivatives with aryl isocyanates and subse-
imides 4, obtained from aza-Wittig reactions of iminophosphorane
3 with aryl isocyanates, reacted with secondary amines, phenols, or
alkanols in the presence of a catalytic amount of potassium carbon-
ate or sodium alkoxide to give 2-substituted benzothieno[3,2-d]py- quent reaction with various nucleophiles under mild
conditions.18–21 Herein we wish to report a new efficient
synthesis of benzothieno[3,2-d]pyrimidin-4(3H)-ones.
rimidin-4(3H)-ones 6 in good yields. The reaction of carbodiimides
4 with primary amines RNH2 (R ≠ H, Me) in the presence of sodium
ethoxide selectively produced one regioisomer 8 via a base-cata-
Ethyl 3-aminobenzothiophene-2-carboxylate (2), readily
obtained by cyclization of 2-chlorobenzonitrile (1) with
ethyl 2-sulfanylacetate under basic conditions
(Scheme 1),22 was converted into iminophosphorane 3 via
reaction with triphenylphosphine, hexachloroethane, and
triethylamine.
lyzed cyclization mechanism. However, a different regioisomer 9
was obtained when primary amines RNH2 (R = H, Me) were used
in the absence of sodium ethoxide via a direct cyclization mecha-
nism.
Key words: benzothieno[3,2-d]pyrimidin-4(3H)-one, iminophos-
phorane, carbodiimide, aza-Wittig reaction, synthesis
S
Cl
COOEt
HSCH2COOEt
EtONa
The derivatives of fused pyrimidinones have been the fo-
cus of great interest for many years. This is probably due
to the fact that many compounds containing a fused pyri-
midinone ring play an important part in the biochemistry
of the living cell.1 Thienopyrimidines are of great impor-
tance because of their significant antifungal and antibac-
terial activities, as well as their good anticonvulsant and
angiotensin or H1 receptor antagonistic activities.2–6 Al-
though some derivatives of benzothienopyrimidines have
shown good antithrombotic, cardiotonic, and a adrenergic
antagonistical activities,7–10 there are few reports on the
synthesis of benzothieno[3,2-d]pyrimidin-4(3H)-ones,
which are of considerable interest as potential biologically
active compounds or pharmaceuticals. The methods de-
scribed for the preparation of some representative deriva-
tives of this ring system involve the cyclization of ethyl 3-
aminobenzothiophene-2-carboxylate with an orthofor-
mate and an amine, or with formamide.11–13 However, 2-
substituted benzothieno[3,2-d]pyrimidin-4(3H)-ones are
not easily accessible by current routes.
CN
NH2
1
2
S
COOEt
Ph3P, C2Cl6
Et3N
N=PPh3
3
Scheme 1
Iminophosphorane 3 reacted with aryl isocyanates to give
carbodiimides 4, which were allowed to react with sec-
ondary amines to provide guanidine intermediates 5
(Scheme 2). Even in refluxing toluene, guanidines 5 did
not cyclize, however, in the presence of a catalytic amount
of sodium ethoxide guanidines 5 were readily converted
into 3-aryl-2-(dialkylamino)benzothieno[3,2-d]pyrimi-
din-4(3H)-ones 6 in satisfactory yields at room tempera-
ture. The results are listed in Table 1.
The aza-Wittig reactions of iminophosphoranes have re-
ceived increased attention in view of their utility in the
synthesis of nitrogen-containing heterocyclic com-
pounds.14–17 Annulation of ring systems containing nitro-
gen heterocycles by means of an aza-Wittig reaction has
been widely utilized because of the availability of
functionalized iminophosphoranes. We are currently
The direct reaction of carbodiimides 4 with phenols also
did not produce 3-aryl-2-(aryloxy)benzothieno[3,2-d]py-
rimidin-4(3H)-ones 6. However, when carried our in the
presence of a catalytic amount of potassium carbonate, the
reaction took place to give 6 in good yields. The formation
of 6 can be rationalized in terms of initial nucleophilic ad-
dition of phenoxide to the carbodiimide derivatives 4 to
give the intermediates 5 that cyclize to give 6. Regardless
of whether the substituents on the phenols are electron-
withdrawing (Table 1, entries 13, 14, and 17) or electron-
donating (Table 1, entries 15 and 16), the cyclization can
SYNTHESIS 2006, No. 24, pp 4180–4186
x
x.
x
x
.
2
0
0
6
Advanced online publication: 13.11.2006
DOI: 10.1055/s-2006-950364; Art ID: F10306SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
2-Substituted Benzothieno[3,2-d]pyrimidin-4(3H)-ones via a Tandem Aza-Wittig Reaction
4181
The reaction of carbodiimides 4 with primary amines
RNH2 (R ≠ H, Me) in the presence of sodium ethoxide
provided only 2-(alkylamino)-3-arylbenzothieno[3,2-
d]pyrimidin-4(3H)-ones 8, one of the possible regioiso-
mers. We obtained only 8 from the reaction mixture after
S
S
COOEt
COOEt
HY
ArNCO
N=C=NAr
N=PPh3
3
4
1
recrystallization; the other isomer was not found by H
O
NMR analysis of the reaction mixture. The structures of
derivatives 8 were deduced from their 1H NMR data. For
example, the 1H NMR spectrum of 8b (R = Pr) shows the
N–H signal at d = 4.19 as a broad absorption and N–CH2
at d = 3.50–3.45 as multiple absorption, which strongly
suggest the existence of NHCH2CH2CH3 group in 8b.
Whenever the primary amine used was small (R = Pr) or
bulky (R = t-Bu), the cyclizations were all achieved in
good yields with similar selectivity. The results are also
listed in Table 2 (entries 1–6). The sole formation of de-
rivatives 8 can be rationalized in terms of a base-catalyzed
cyclization of the guanidine intermediates 7 to give 8
across the arylamino group rather than the alkylamino
group. This is probably due to the preferential generation
of -N–Ar from the more acidic -NHAr group. On the other
hand, the reaction of phenylcarbodiimide 4 with ammonia
S
S
COOEt
NHAr
N
Ar
N
N
Y
Y
5
6
Scheme 2
be completed smoothly under mild conditions. The direct
reaction of carbodiimides 4 with alkanols gave a complex
mixture; however, when the reaction was carried out in
the presence of a catalytic amount of sodium alkoxide the
reaction took place smoothly and 2-alkoxybenzo-
thieno[3,2-d]pyrimidin-4(3H)-ones 6 were obtained in
satisfactory yields.
Table 1 Preparation of 2-Substituted 3-Arylbenzothieno[3,2-d]pyrimidin-4(3H)-ones
Entry
1
Product
6a
6b
6c
Ar
Y
Conditions
r.t., 5 h
Yielda (%)
84
Ph
NEt2
2
Ph
NPr2
r.t., 6 h
75
3
Ph
N(i-Bu)2
N(n-C5H11)2
N(Me)Ph
morpholin-4-yl
piperidin-1-yl
morpholin-4-yl
piperidin-1-yl
NEt2
r.t., 6 h
70
4
6d
6e
Ph
r.t., 6 h
66
5
Ph
r.t., 6 h
78
6
6f
Ph
r.t., 5 h
90
7
6g
6h
6i
Ph
r.t., 5 h
87
8
4-MeC6H4
r.t., 5 h
92
9
4-ClC6H4
r.t., 5 h
88
10
11
12
13
14
15
16
17
18
19
20
6j
4-MeC6H4
r.t., 6 h
81
6k
6l
4-ClC6H4
NEt2
r.t., 6 h
80
Ph
OPh
60 °C, 5 h
60 °C, 8 h
60 °C, 8 h
60 °C, 5 h
60 °C, 6 h
60 °C, 10 h
r.t., 4 h
75
6m
6n
6o
6p
6q
6r
Ph
4-ClC6H4O
4-BrC6H4O
4-MeOC6H4O
4-MeSC6H4O
3-O2NC6H4O
OMe
66
Ph
73
Ph
87
Ph
86
Ph
63
Ph
82
6s
Ph
OEt
r.t., 6 h
76
6t
4-ClC6H4
OMe
r.t., 5 h
87
a Isolated yields based on iminophosphorane 3.
Synthesis 2006, No. 24, 4180–4186 © Thieme Stuttgart · New York

4182
S.-Z. Xu et al.
PAPER
ternal reference. Elemental analyses were taken on a Vario EL III
elementary analysis instrument.
or methylamine (R = H, Me) gave directly 2-(phenylami-
no)benzothieno[3,2-d]pyrimidin-4(3H)-ones 9, another of
the possible regioisomers, as the sole product in the ab-
sence of sodium ethoxide (Table 2, entries 7 and 8). The
reversed, selective formation of 9 can be rationalized in
terms of direct cyclization of the guanidine intermediates
7 to give 9 across the sterically smaller amino or methyl-
amino group rather than the arylamino group. The same
selectivity has been observed in similar cases.23
Ethyl 3-[(Triphenylphosphoranylidene)amino]benzo-
thieno[3,2-d]pyrimidine-2-carboxylate (3)
To a mixture of ethyl 3-aminobenzothieno[3,2-d]pyrimidine-2-car-
boxylate (2)22 (1.77 g, 8 mmol), Ph3P (3.14 g, 12 mmol), and C2Cl6
(2.84 g, 12 mmol) in anhyd MeCN (40 mL), was added dropwise
Et3N (2.42 g, 24 mmol) at r.t.; the mixture rapidly became yellow in
color. The mixture was stirred for 4–6 h and then the solvent was
removed under reduced pressure and the residue was recrystallized
(EtOH) to give iminophosphorane 3 as white crystals; yield: 3.27 g
(85%); mp 153–154 °C.
1H NMR (400 MHz, CDCl3): d = 7.90–7.16 (m, 19 H, Ar-H), 3.82
(q, J = 7.2 Hz, 2 H, OCH2), 0.99 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 163.5 (C=O), 150.5, 140.0,
139.8, 138.7, 133.0, 132.4, 132.3, 132.0, 131.2, 128.2, 128.1, 126.9,
124.7, 123.0, 122.3, 108.5, 59.3, 14.3.
S
COOEt
NHPh
S
COOEt
RNH2
N
N=C=NPh
NHR
4
7
EtONa
O
MS: m/z (%) = 481 (100) [M+], 452 (17), 408 (61), 183 (57), 77
(55).
O
S
S
Anal. Calcd for C29H24NO2PS: C, 72.33; H, 5.02; N, 2.91. Found:
C, 72.58; H, 5.17; N, 2.84.
N
Ph
N
R
N
N
NHR
NHPh
3-Aryl-2-(dialkylamino)- and 3-Aryl-2-(diarylamino)benzo-
thieno[3,2-d]pyrimidin-4(3H)-ones 6a–k; General Procedure
To a soln of iminophosphorane 3 (1.44g, 3 mmol) in anhyd CH2Cl2
(10 mL) was added the aryl isocyanate (3 mmol) under N2 at 0–
5 °C; the mixture was left to stand unstirred at 0–5 °C for 8–12 h.
The solvent was then removed under reduced pressure and Et2O–
petroleum ether (1:2, 12 mL) was added to precipitate Ph3PO. Re-
moval of the solvent gave carbodiimides 4, which were used direct-
ly without further purification.
9
8
(R = H, Me)
(R = Et, Pr, Bu, etc.)
Scheme 3
Table 2 Reaction of Carbodiimides with Amines
Entry
Product
8a
R
Conditions Yielda (%)
To a soln of 4 in CH2Cl2 (10 mL) was added dialkylamine (3 mmol);
the mixture was left to stand unstirred for 2–3 h. The solvent was
then removed and anhyd EtOH (8 mL) and EtONa (0.3 mmol, 10%
equiv) in EtOH were added. The mixture was stirred at r.t. for 4–6
h. The soln was condensed and the residue was recrystallized
(EtOH) to give 6a–k.
1
2
3
4
5
6
7
8
Et
r.t., 4 h
r.t., 4 h
r.t., 6 h
r.t., 4 h
r.t., 8 h
r.t., 5 h
r.t., 1 h
r.t., 1 h
79
88
81
84
85
80
87
82
8b
Pr
8c
i-Pr
Bu
t-Bu
Bn
H
8d
2-(Diethylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-4(3H)-
one (6a)
White crystals; mp 128–129 °C.
IR (KBr): 1670 (C=O), 1541, 1341, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.27–7.34 (m, 9 H, Ar-H), 3.15 (q,
J = 6.9 Hz, 4 H, 2 × NCH2), 0.90 (t, J = 7.0 Hz, 6 H, 2 × CH3).
13C NMR (100 MHz, CDCl3): d = 160.0 (C=O), 157.1, 152.4,
142.1, 137.8, 134.6, 129.0, 128.9, 128.6, 128.1, 124.5, 123.6, 123.3,
115.8, 45.3, 12.4.
8e
8f
9a
9b
Me
a Isolated yields based on iminophosphorane 3.
MS: m/z (%) = 349 (100) [M+], 277 (22), 200 (6), 146 (42), 77 (34).
In conclusion, we have developed a new efficient and se-
lective synthesis of 2-substituted benzothieno[3,2-d]pyri-
Anal. Calcd for C20H19N3OS: C, 68.74; H, 5.48; N, 12.02. Found:
midin-4(3H)-ones via reaction of functionalized C, 68.88; H, 5.54; N, 11.97.
carbodiimides with various amines, phenols, or alcohols.
2-(Dipropylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (6b)
White crystals; mp 108–110 °C.
IR (KBr): 1688 (C=O), 1534, 1320, 656 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.27–7.34 (m, 9 H, Ar-H), 3.05 (q,
J = 6.9 Hz, 4 H, 2 × NCH2), 1.34–1.28 (m, 4 H, 2 × CH2), 0.74 (t,
J = 7.0 Hz, 6 H, 2 × CH3).
13C NMR (100 MHz, CDCl3): d = 160.0 (C=O), 157.2, 152.5,
142.1, 137.8, 134.6, 129.0, 128.8, 128.6, 128.2, 124.5, 123.6, 123.3,
115.5, 53.1, 20.7, 11.4.
Due to the easily accessible and versatile starting material,
this method can potentially be used for the synthesis of
many biologically and pharmaceutically active benzo-
thienopyrimidinone derivatives.
Melting points are uncorrected. MS were measured on a Finnigan
Trace MS spectrometer. IR spectra were recorded on a PE-983
spectrophotometer as KBr pellets. NMR spectra were recorded in
CDCl3 on a Varian Mercury 400 spectrometer with TMS as the in-
Synthesis 2006, No. 24, 4180–4186 © Thieme Stuttgart · New York

PAPER
2-Substituted Benzothieno[3,2-d]pyrimidin-4(3H)-ones via a Tandem Aza-Wittig Reaction
4183
MS: m/z (%) = 377 (63) [M+], 277 (72), 201 (20), 146 (100), 77
(58).
1H NMR (400 MHz, CDCl3): d = 8.28–7.39 (m, 9 H, Ar-H), 3.18 (q,
J = 5.2 Hz, 4 H, 2 × NCH2), 1.45–1.28 (m, 6 H, 3 × CH2).
Anal. Calcd for C22H23N3OS: C, 70.00; H, 6.14; N, 11.13. Found:
C, 70.18; H, 6.25; N, 11.08.
13C NMR (100 MHz, CDCl3): d = 159.7 (C=O), 157.8, 152.3,
142.0, 137.6, 134.5, 128.8, 128.7, 128.6, 128.0, 124.5, 123.6, 123.3,
116.6, 50.2, 24.9, 24.1.
2-(Diisobutylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (6c)
White crystals; mp 154–155 °C.
IR (KBr): 1687 (C=O), 1531, 1357, 702 cm–1.
MS: m/z (%) = 361 (19) [M+], 277 (24), 146 (100), 77 (92).
Anal. Calcd for C21H19N3OS: C, 69.78; H, 5.30; N, 11.62. Found:
C, 69.92; H, 5.14; N, 11.78.
1H NMR (400 MHz, CDCl3): d = 8.25–7.35 (m, 9 H, Ar-H), 2.92 (q,
J = 6.9 Hz, 4 H, 2 × NCH2), 1.95–1.81 (m, 2 H, 2 × CH), 0.80 (d,
J = 7.0 Hz, 12 H, 4 × CH3).
13C NMR (100 MHz, CDCl3): d = 160.0 (C=O), 156.9, 152.8,
142.2, 137.7, 134.7, 129.0, 128.6, 128.3, 124.5, 123.7, 123.3, 114.8,
59.3, 27.4, 20.4.
2-(Morpholin-4-yl)-3-(4-tolyl)benzothieno[3,2-d]pyrimidin-
4(3H)-one (6h)
White crystals; mp 195–197 °C.
IR (KBr): 1678 (C=O), 1539, 1364, 755 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.25–7.28 (m, 8 H, Ar-H), 3.48 (t,
J = 4.8 Hz, 4 H, 2 × NCH2), 3.21 (t, J = 4.8 Hz, 4 H, 2 × OCH2),
2.42 (s, 3 H, CH3).
MS: m/z (%) = 405 (54) [M+], 277 (83), 200 (14), 146 (80), 77 (33).
Anal. Calcd for C24H27N3OS: C, 71.08; H, 6.71; N, 10.36. Found:
C, 71.12; H, 6.79; N, 10.32.
13C NMR (100 MHz, CDCl3): d = 159.5 (C=O), 156.8, 151.9,
142.0, 138.5, 134.5, 134.2, 129.7, 128.7, 128.2, 124.7, 123.6, 123.4,
117.3, 66.0, 49.3, 21.2.
2-(Dipentylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (6d)
White crystals; mp 85–87 °C.
IR (KBr): 1680 (C=O), 1533, 1381, 654 cm–1.
MS: m/z (%) = 377 (100) [M+], 291 (34), 146 (40), 91 (32).
Anal. Calcd for C21H19N3O2S: C, 66.82; H, 5.07; N, 11.13. Found:
C, 67.07; H, 5.04; N, 10.98.
1H NMR (400 MHz, CDCl3): d = 8.25–7.33 (m, 9 H, Ar-H), 3.10 (q,
J = 6.9 Hz, 4 H, 2 × NCH2), 1.32–1.09 (m, 12 H, 6 × CH2), 0.84 (t,
J = 7.0 Hz, 6 H, 2 × CH3).
3-(4-Chlorophenyl)-2-(piperidin-1-yl)benzothieno[3,2-d]pyrim-
idin-4(3H)-one (6i)
White crystals; mp 202–204 °C.
IR (KBr): 1681 (C=O), 1533, 1369, 754 cm–1.
MS: m/z (%) = 433 (67) [M+], 277 (100), 200 (16), 146 (90), 77
(25).
1H NMR (400 MHz, CDCl3): d = 8.26–7.34 (m, 8 H, Ar-H), 3.17 (q,
J = 5.2 Hz, 4 H, 2 × NCH2), 1.60–1.34 (m, 6 H, 3 × CH2).
MS: m/z (%) = 395 (100) [M+], 311 (10), 146 (39), 111 (15).
Anal. Calcd for C26H31N3OS: C, 72.02; H, 7.21; N, 9.69. Found: C,
72.26; H, 7.28; N, 9.67.
Anal. Calcd for C21H18ClN3OS: C, 63.71; H, 4.58; N, 10.61. Found:
C, 63.95; H, 4.74; N, 10.48.
2-[Methyl(phenyl)amino]-3-phenylbenzothieno[3,2-d]pyrim-
idin-4(3H)-one (6e)
White crystals; mp 223–225 °C.
IR (KBr): 1677 (C=O), 1539, 1334, 696 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.36–6.60 (m, 14 H, Ar-H), 3.40
(s, 3 H, CH3).
MS: m/z (%) = 383 (100) [M+], 277 (97), 201 (25), 146 (98), 76
(96).
2-(Diethylamino)-3-(4-tolyl)benzothieno[3,2-d]pyrimidin-
4(3H)-one (6j)
White crystals; mp 143–145 °C.
IR (KBr): 1670 (C=O), 1542, 1340, 754 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.27–7.21 (m, 8 H, Ar-H), 3.17 (q,
J = 6.9 Hz, 4 H, 2 × NCH2), 2.41 (s, 3 H, CH3), 0.90 (t, J = 7.0 Hz,
6 H, 2 × CH3).
Anal. Calcd for C23H17N3OS: C, 72.04; H, 4.47; N, 10.96. Found:
C, 72.05; H, 4.54; N, 10.80.
MS: m/z (%) = 363 (78) [M+], 291 (49), 200 (13), 146 (64), 91 (24).
Anal. Calcd for C21H21N3OS: C, 69.39; H, 5.82; N, 11.56. Found:
C, 69.28; H, 6.04; N, 11.57.
2-(Morpholin-4-yl)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (6f)
White crystals; mp 166–168 °C.
IR (KBr): 1674 (C=O), 1530, 1381, 695 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.28–7.41 (m, 9 H, Ar-H), 3.48 (t,
J = 4.8 Hz, 4 H, 2 × NCH2), 3.21 (t, J = 4.8 Hz, 4 H, 2 × OCH2).
13C NMR (100 MHz, CDCl3): d = 159.4 (C=O), 156.7, 151.9,
142.0, 136.9, 134.4, 129.0, 128.7, 128.6, 128.5, 124.7, 123.6, 123.4,
117.4, 65.9, 49.4.
3-(4-Chlorophenyl)-2-(diethylamino)benzothieno[3,2-d]pyrim-
idin-4(3H)-one (6k)
White crystals; mp 176–178 °C.
IR (KBr): 1670 (C=O), 1542, 1341, 729 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.27–7.30 (m, 8 H, Ar-H), 3.16 (q,
J = 6.9 Hz, 4 H, 2 × NCH2), 0.93 (t, J = 7.0 Hz, 6 H, 2 × CH3).
MS: m/z (%) = 383 (71) [M+], 310 (41), 200 (26), 146 (100), 111
(9).
MS: m/z (%) = 363 (48) [M+], 306 (31), 277 (49), 146 (100), 103
(38).
Anal. Calcd for C20H18ClN3OS: C, 62.57; H, 4.73; N, 10.95. Found:
C, 62.75; H, 4.64; N, 11.07.
Anal. Calcd for C20H17N3O2S: C, 66.10; H, 4.71; N, 11.56. Found:
C, 66.02; H, 4.94; N, 11.47.
2-(Aryloxy)benzothieno[3,2-d]pyrimidin-4(3H)-ones 6l–q;
General Procedure
To the soln of carbodiimide 4 (ca. 3 mmol) in MeCN (15 mL) was
added ArOH (3 mmol) and K2CO3 (0.3 mmol) in anhyd MeCN (10
3-Phenyl-2-(piperidin-1-yl)benzothieno[3,2-d]pyrimidin-4(3H)-
one (6g)
White crystals; mp 177–178 °C.
IR (KBr): 1673 (C=O), 1540, 1374, 700 cm–1.
Synthesis 2006, No. 24, 4180–4186 © Thieme Stuttgart · New York

4184
S.-Z. Xu et al.
PAPER
mL). The mixture was stirred at 50–60 °C for 6–8 h. The soln was
MS: m/z (%) = 416 (71) [M+], 277 (62), 200 (11), 146 (92), 139
condensed and the residue was recrystallized (EtOH) to give 6l–q.
(100), 77 (71).
Anal. Calcd for C23H16N2O2S2: C, 66.32; H, 3.87; N, 6.73. Found:
C, 66.60; H, 3.94; N, 6.67.
2-Phenoxy-3-phenylbenzothieno[3,2-d]pyrimidin-4(3H)-one
(6l)
White crystals; mp 220–222 °C.
IR (KBr): 1694 (C=O), 1551, 1356, 685 cm–1.
2-(3-Nitrophenoxy)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (6q)
White crystals; mp 226–227 °C.
IR (KBr): 1684 (C=O), 1532, 1348, 694 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.99 (d, J = 7.6 Hz, 1 H, Ar-H),
7.87 (d, J = 8.0 Hz, 1 H, Ar-H), 7.59–7.20 (m, 12 H, Ar-H).
13C NMR (100 MHz, CDCl3): d = 158.8 (C=O), 154.8, 151.9,
150.8, 141.8, 134.8, 133.9, 129.4, 129.3, 129.1, 128.8, 128.1, 125.9,
124.7, 123.7, 123.2, 121.4, 118.0.
1H NMR (400 MHz, CDCl3): d = 8.19–7.41 (m, 13 H, Ar-H).
MS: m/z (%) = 415 (5) [M+], 277 (9), 200 (11), 146 (37), 77 (100).
Anal. Calcd for C22H13N3O4S: C, 63.61; H, 3.15; N, 10.11. Found:
C, 63.65; H, 3.04; N, 10.07.
MS: m/z (%) = 370 (100) [M+], 277 (52), 146 (67), 77 (54).
Anal. Calcd for C22H14N2O2S: C, 71.33; H, 3. 81; N, 7.56. Found:
C, 71.27; H, 3.94; N, 7.60.
2-Alkoxy-3-arylbenzothieno[3,2-d]pyrimidin-4(3H)-ones 6r–t;
General Procedure
2-(4-Chlorophenoxy)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (6m)
White crystals; mp 215–216 °C.
IR (KBr): 1668 (C=O), 1488, 1348, 704 cm–1.
To the soln of 4 (ca. 3 mmol) in anhyd alkanol ROH (8 mL) was
added EtONa (0.3 mmol, 10% equiv) in EtOH. The mixture was
stirred for at r.t 4–6 h. The soln was condensed and the residue was
recrystallized (ROH) to give 6r–t.
1H NMR (400 MHz, CDCl3): d = 8.01 (d, J = 8.0 Hz, 1 H, Ar-H),
7.88 (d, J = 8.0 Hz, 1 H, Ar-H), 7.60–7.15 (m, 11 H, Ar-H).
MS: m/z (%) = 404 (24) [M+], 277 (29), 200 (6), 146 (58), 77 (59).
2-Methoxy-3-phenylbenzothieno[3,2-d]pyrimidin-4(3H)-one
(6r)
White crystals; mp 212–214 °C.
IR (KBr): 1676 (C=O), 1520, 1346, 695 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.28–7.28 (m, 9 H, Ar-H), 4.05 (s,
3 H, OCH3).
MS: m/z (%) = 308 (100) [M+], 277 (51), 200 (11), 146 (93), 77
(58).
Anal. Calcd for C22H13ClN2O2S: C, 65.27; H, 3.24; N, 6.92. Found:
C, 65.50; H, 3.19; N, 6.97.
2-(4-Bromophenoxy)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (6n)
White crystals; mp 221–222 °C.
Anal. Calcd for C17H12N2O2S: C, 66.22; H, 3.92; N, 9.08. Found: C,
66.48; H, 4.04; N, 9.01.
IR (KBr): 1688 (C=O), 1485, 1348, 703 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.01 (d, J = 8.0 Hz, 1 H, Ar-H),
7.88 (d, J = 8.0 Hz, 1 H, Ar-H), 7.59–7.10 (m, 11 H, Ar-H).
2-Ethoxy-3-phenylbenzothieno[3,2-d]pyrimidin-4(3H)-one (6s)
13C NMR (100 MHz, CDCl3): d = 158.7 (C=O), 154.5, 150.9,
150.6, 141.8, 134.6, 133.9, 132.4, 129.5, 129.3, 128.9, 128.0, 124.8,
123.7, 123.3, 119.0, 118.3.
White crystals; mp 190–192 °C.
IR (KBr): 1673 (C=O), 1522, 1334, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.26–7.28 (m, 9 H, Ar-H), 4.58 (q,
J = 6.9 Hz, 2 H, OCH2), 1.31 (t, J = 7.0 Hz, 3 H, CH3).
MS: m/z (%) = 448 (2) [M+], 277 (36), 200 (8), 145 (96), 77 (100).
13C NMR (100 MHz, CDCl3): d = 159.0 (C=O), 155.3, 151.3,
141.9, 134.9, 134.2, 129.2, 128.8, 128.7, 128.6, 128.1, 124.6, 123.5,
123.4, 117.0, 65.1, 14.0.
MS: m/z (%) = 322 (4) [M+], 293 (6), 200 (9), 145 (100), 102 (32),
77 (50).
Anal. Calcd for C22H13BrN2O2S: C, 58.81; H, 2.92; N, 6.23. Found:
C, 59.03; H, 2.84; N, 6.17.
2-(4-Methoxyphenoxy)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (6o)
White crystals; mp 202–204 °C.
Anal. Calcd for C18H14N2O2S: C, 67.06; H, 4.38; N, 8.69. Found: C,
67.20; H, 4.29; N, 8.77.
IR (KBr): 1688 (C=O), 1500, 1349, 693 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.01–6.90 (m, 13 H, Ar-H), 3.83
(s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 158.8 (C=O), 157.2, 155.2,
150.9, 145.4, 141.7, 134.8, 134.0, 129.4, 129.0, 128.8, 128.1, 124.6,
123.7, 123.2, 122.2, 117.8, 114.2.
3-(4-Chlorophenyl)-2-methoxybenzothieno[3,2-d]pyrimidin-
4(3H)-one (6t)
White crystals; mp 240–242 °C.
IR (KBr): 1675 (C=O), 1538, 1346, 694 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.28–7.22 (m, 8 H, Ar-H), 4.06 (s,
3 H, CH3).
MS: m/z (%) = 342 (100) [M+], 311 (12), 200 (13), 145 (92), 102
MS: m/z (%) = 400 (61) [M+], 277 (86), 146 (100), 77 (52).
Anal. Calcd for C23H16N2O3S: C, 68.98; H, 4.03; N, 7.00. Found: C,
68.93; H, 4.14; N, 6.97.
(46), 102 (46), 76 (36).
2-[4-(Methylsulfanyl)phenoxy]-3-phenylbenzothieno[3,2-d]py-
rimidin-4(3H)-one (6p)
White crystals; mp 211–212 °C.
Anal. Calcd for C17H11ClN2O2S: C, 59.56; H, 3.23; N, 8.17. Found:
C, 59.67; H, 3.47; N, 8.02.
IR (KBr): 1700 (C=O), 1556, 1346, 691 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.02–7.12 (m, 13 H, Ar-H), 2.50
(s, 3 H, SCH3).
2-(Alkylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-4(3H)-
ones 8a–f; General Procedure
To the soln of 4 (ca. 3 mmol) in CH2Cl2 (10 mL) was added alkyl-
amine (3 mmol) and the mixture was allowed to stand unstirred for
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2-Substituted Benzothieno[3,2-d]pyrimidin-4(3H)-ones via a Tandem Aza-Wittig Reaction
4185
several minutes. The solvent was removed and anhyd EtOH (8 mL)
with EtONa (0.3 mmol, 10% equiv) in EtOH was added. The mix-
ture was stirred at r.t. for 4–6 h. The soln was condensed and the res-
idue was recrystallized (EtOH) to give 8a–f.
13C NMR (100 MHz, CDCl3): d = 159.0 (C=O), 153.5, 151.5,
142.0, 134.9, 134.8, 130.6, 129.8, 128.8, 128.5, 124.3, 123.7, 123.3,
112.5, 52.8, 28.8.
MS: m/z (%) = 349 (44) [M+], 277 (12), 200 (6), 146 (52), 77 (56).
Anal. Calcd for C20H19N3OS: C, 68.74; H, 5.48; N, 12.02. Found:
C, 68.90; H, 5.64; N, 11.97.
2-(Ethylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-4(3H)-
one (8a)
White crystals; mp 191–193 °C.
IR (KBr): 1673 (C=O), 1544, 1321, 756 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.27–7.34 (m, 9 H, Ar-H), 4.17 (s,
1 H, NH), 3.56–3.51 (m, J = 7.0 Hz, 2 H, CH2), 1.18 (t, J = 7.0 Hz,
3 H, CH3).
2-(Benzylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-4(3H)-
one (8f)
White crystals; mp 205–207 °C.
IR (KBr): 1677 (C=O), 1549, 1328, 756 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.26–7.27 (m, 14 H, Ar-H), 4.74
(d, J = 5.6 Hz, 2 H, NCH2), 4.59 (s, 1 H, NH).
MS: m/z (%) = 321 (55) [M+], 277 (32), 200 (9), 146 (62), 77 (24).
Anal. Calcd for C18H15N3OS: C, 67.27; H, 4.70; N, 13.07. Found:
C, 67.38; H, 4.54; N, 13.28.
13C NMR (100 MHz, CDCl3): d = 158.8 (C=O), 153.5, 152.5,
141.9, 138.3, 134.5, 134.3, 130.6, 129.9, 128.7, 128.5, 127.4, 124.3,
123.6, 123.2, 112.9, 45.7.
MS: m/z (%) = 383 (100) [M+], 277 (37), 200 (12), 146 (49), 77
(36).
3-Phenyl-2-(propylamino)benzothieno[3,2-d]pyrimidin-4(3H)-
one (8b)
White crystals; mp 147–149 °C.
IR (KBr): 1673 (C=O), 1544, 1319, 757 cm–1.
Anal. Calcd for C23H17N3OS: C, 72.04; H, 4.47; N, 10.96. Found:
C, 72.19; H, 4.34; N, 10.77.
1H NMR (400 MHz, CDCl3): d = 8.27–7.34 (m, 9 H, Ar-H), 4.19 (s,
1 H, NH), 3.50–3.45 (m, 2 H, NCH2), 1.62–1.56 (q, J = 7.0 Hz, 2 H,
CH2), 0.90 (t, J = 7.0 Hz, 3 H, CH3).
2-(Phenylamino)benzothieno[3,2-d]pyrimidin-4(3H)-ones 9a,b;
General Procedure
To the soln of 4 (ca. 3 mmol) in MeCN (10 mL) was added NH3 or
MeNH2 (3 mmol) and the mixture was stirred for 0.5 h. The soln
was condensed and the residue was recrystallized (EtOH) to give
9a,b.
MS: m/z (%) = 335 (58) [M+], 277 (22), 200 (8), 146 (56), 77 (26).
Anal. Calcd for C19H17N3OS: C, 68.03; H, 5.11; N, 12.53. Found:
C, 68.18; H, 5.04; N, 12.50.
2-(Isopropylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (8c)
White crystals; mp 167–169 °C.
IR (KBr): 1675 (C=O), 1546, 1324, 756 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.27–7.33 (m, 9 H, Ar-H), 4.37
(m, 1 H, NCH), 3.94 (d, J = 7.2 Hz, 1 H, NH), 1.19 (d, J = 6.4 Hz,
6 H, 2 × CH3).
2-(Phenylamino)benzothieno[3,2-d]pyrimidin-4(3H)-one (9a)
White crystals; mp >300 °C.
IR (KBr): 1679 (C=O), 1545, 1346, 759 cm–1.
1H NMR (400 MHz, DMSO): d = 11.14 (s, 1 H, NHCO), 8.89 (s, 1
H, NHPh), 8.21–7.09 (m, 9 H, Ar-H).
MS: m/z (%) = 293 (100) [M+], 201 (32), 146 (92), 77 (44).
13C NMR (100 MHz, CDCl3): d = 158.9 (C=O), 153.8, 152.0,
142.0, 134.6, 134.5, 130.6, 129.9, 128.8, 128.5, 124.3, 123.6, 123.3,
112.4, 44.0, 22.5.
Anal. Calcd for C16H11N3OS: C, 65.51; H, 3.78; N, 14.32. Found:
C, 65.38; H, 3.94; N, 14.07.
3-Methyl-2-(phenylamino)benzothieno[3,2-d]pyrimidin-4(3H)-
one (9b)
White crystals; mp 297–299 °C.
IR (KBr): 1683 (C=O), 1544, 1343, 757 cm–1.
MS: m/z (%) = 335 (74) [M+], 277 (25), 200 (6), 146 (93), 77 (68).
Anal. Calcd for C19H17N3OS: C, 68.03; H, 5.11; N, 12.53. Found:
C, 68.21; H, 5.14; N, 12.37.
2-(Butylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-4(3H)-
one (8d)
1H NMR (400 MHz, DMSO): d = 8.87 (s, 1 H, NHPh), 8.05–7.14
(m, 9 H, Ar-H), 3.64 (s, 3 H, NCH3).
White crystals; mp 98–100 °C.
IR (KBr): 1675 (C=O), 1546, 1324, 756 cm–1.
MS: m/z (%) = 307 (100) [M+], 215 (25), 200 (21), 146 (90), 77
(36).
1H NMR (400 MHz, CDCl3): d = 8.27–7.34 (m, 9 H, Ar-H), 4.17 (s,
1 H, NH), 3.56–3.45 (m, 2 H, NCH2), 1.34–1.28 (m, 4 H, 2 × CH2),
0.90 (t, J = 7.0 Hz, 3 H, CH3).
Anal. Calcd for C17H13N3OS: C, 66.43; H, 4.26; N, 13.67. Found:
C, 66.58; H, 4.34; N, 13.35.
MS: m/z (%) = 349 (46) [M+], 277 (34), 200 (8), 146 (73), 77 (60).
Acknowledgment
Anal. Calcd for C20H19N3OS: C, 68.74; H, 5.48; N, 12.02. Found:
C, 68.60; H, 5.34; N, 12.26.
We gratefully acknowledge financial support of this work by the
Natural Science Foundation of Hubei Province (Project No.
2006ABB016).
2-(tert-Butylamino)-3-phenylbenzothieno[3,2-d]pyrimidin-
4(3H)-one (8e)
White crystals; mp 237–239 °C.
IR (KBr): 1673 (C=O), 1551, 1323, 757 cm–1.
References
(1) Purines in Cellular Signaling: Targets for New Drugs;
Jacobson, K. A.; Daly, J. W.; Manganiello, V., Eds.;
Springer Verlag: New York, 1990.
1H NMR (400 MHz, CDCl3): d = 8.25–7.33 (m, 9 H, Ar-H), 4.07 (s,
1 H, NH), 1.45 (s, 9 H, 3 × CH3).
(2) Walter, H. WO 9914202, 1999; Chem. Abstr. 1999, 130,
252368.
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4186
S.-Z. Xu et al.
PAPER
(3) Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.; Bahekar, R.
H. Eur. J. Med. Chem. 2003, 38, 89.
(4) Taguchi, M.; Ota, T.; Hatayama, K. WO 9303040, 1993;
Chem. Abstr., 1993, 119, 160309.
(5) Shishoo, C. J.; Shirsath, V. S.; Rathod, I. S.; Yande, V. D.
Eur. J. Med. Chem. 2000, 35, 351.
(13) Robba, M.; Touzot, P.; El-Kashef, H. J. Heterocycl. Chem.
1980, 17, 923.
(14) Blackburn, C.; Achab, A.; Elder, A.; Ghosh, S.; Guo, J.;
Harriman, G.; Jones, M. J. Org. Chem. 2005, 70, 10206.
(15) Izquierdo, I.; Plaza, M. T.; Rodríguez, M.; Franco, F.;
Martos, A. Tetrahedron 2005, 61, 11697.
(6) De Laszlo, S. E.; Patchett, A. A.; Allen, E. E.; Greenlee, W.
J. EP 0502725, 1992; Chem. Abstr. 1992, 118, 22249.
(7) Eggenweiler, H. M.; Eiermann, V. WO 2002049649, 2002;
Chem. Abstr. 2002, 137, 47217.
(16) Palacios, F.; Alonso, C.; Rodríguez, M.; Martinez de
Marigorta, E.; Rubiales, G. Eur. J. Org. Chem. 2005, 1795.
(17) Braese, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem. Int. Ed. 2005, 44, 5188.
(8) Nomoto, Y.; Takai, H.; Ohno, T.; Kubo, K. Chem. Pharm.
(18) Ding, M. W.; Xu, S. Z.; Zhao, J. F. J. Org. Chem. 2004, 69,
Bull. 1991, 39, 352.
8366.
(9) Meyer, M. D.; Altenbach, R. J.; Basha, F. Z.; Carroll, W. A.;
Drizin, I.; Elmore, S. W.; Kerwin, J. F. Jr.; Lebold, S. A.;
Lee, E. L.; Sippy, K. B.; Tietje, K. R.; Wendt, M. D. US
5597823, 1997; Chem. Abstr. 1997, 126, 199575.
(10) Ehrlich, P. P.; Ralston, J. W.; Daanen, J. F.; Meyer, M. D.
WO 9957122, 1999; Chem. Abstr. 1999, 131, 337029.
(11) Bridges, A. J.; Zhou, H. J. Heterocycl. Chem. 1997, 34,
1163.
(19) Ding, M. W.; Chen, Y. F.; Huang, N. Y. Eur. J. Org. Chem.
2004, 3872.
(20) Zhao, J. F.; Xie, C.; Xu, S. Z.; Ding, M. W.; Xiao, W. J. Org.
Biomol. Chem. 2006, 4, 130.
(21) Ding, M. W.; Fu, B. Q.; Cheng, L. Synthesis 2004, 1067.
(22) De Angelis, G. G.; Hess, H.-J. E. US 3706747, 1972; Chem.
Abstr. 1973, 78, 72187z.
(23) Zhao, J. F.; Xie, C.; Ding, M. W.; He, H. W. Chem. Lett.
2005, 34, 1022.
(12) El-Telbany, F.; Hutchins, R. O. J. Heterocycl. Chem. 1985,
22, 401.
Synthesis 2006, No. 24, 4180–4186 © Thieme Stuttgart · New York