Efficient synthesis of benzothieno[3,2-d]-imidazo[1,2-a] pyrimidine-2,5-(1H, 3H)-diones via a tandem aza-Wittig/heterocumulene-mediated annulation

Article abstract of DOI:10.1002/jhet.258

(Chemical Equation Presented) Carbodiimide 2, obtained from aza-Wittig reaction of iminophosphorane 1 with aromaic isocyanate, reacted with α-amino ester in the presence of catalytic amount of sodium ethoxide to give selectively new tetracyclic benzothieno[3,2-d]-imidazo[1,2-a]pyrimidine-2, 5-(1H, 3H)-diones 5 in good yields. X-Ray structure analysis of 5b verified the proposed structure and the reaction selectivity.

Full text of DOI:10.1002/jhet.258

68
Efficient Synthesis of Benzothieno[3,2-d]-imidazo[1,2-a]
pyrimidine-2,5-(1H, 3H)-diones via a Tandem aza-Wittig/
Heterocumulene-Mediated Annulation
Vol 47
Sheng-Zhen Xu,a,b Jing Wu,a Min-Hui Cao,b and Ming-Wu Dinga*
aKey Laboratory of Pesticide and Chemical Biology of Ministry of Education, Central China
Normal University, Wuhan 430079, People’s Republic of China
bCollege of Basic Science, HuaZhong Agricultural University, Wuhan 430070,
People’s Republic of China
*E-mail: ding5229@yahoo.com.cn
Received June 24, 2009
DOI 10.1002/jhet.258
Published online 29 December 2009 in Wiley InterScience (www.interscience.wiley.com).
Carbodiimide 2, obtained from aza-Wittig reaction of iminophosphorane 1 with aromaic isocyanate,
reacted with a-amino ester in the presence of catalytic amount of sodium ethoxide to give selectively
new tetracyclic benzothieno[3,2-d]-imidazo[1,2-a]pyrimidine-2,5-(1H, 3H)-diones 5 in good yields. X-
Ray structure analysis of 5b verified the proposed structure and the reaction selectivity.
J. Heterocyclic Chem., 47, 68 (2010).
INTRODUCTION
thesis of pyrimidinones and imidazolones via aza-Wittig
reaction, with the aim of evaluating their fungicidal
activities [24–32]. We also reported an efficient synthe-
sis of benzothieno[3,2-d]pyrimidin-4(3H)-ones via aza-
Wittig reaction of b ethoxycarbonyl iminophosphorane 1
with isocyanate and subsequent reaction with various
nucleophiles under mild conditions [29]. However, the
reaction of a-amino ester with b ethoxycarbonyl carbo-
diimde was not investigated. Here, we wish to report
further a selective synthesis of the previously unreported
benzothieno[3,2-d]imidazo[1,2-a]pyrimidine-2,5-(1H, 3H)-
diones via a tandem aza-Wittig/heterocumulene-mediated
annulation.
Thienopyrimidines are of great importance because of
their significant antifungal and antibacterial activities, as
well as their good anticonvulsant and angiotensin or H1
receptor antagonistic activities [1,2]. Although some
derivatives of benzothienopyrimidines have shown good
antithrombotic, cardiotonic, and a adrenergic antagonis-
tical activities [3,4], there are few reports on synthesis
of benzothieno[3,2-d]pyrimidin-4(3H)-ones, which are
of considerable interest as potential biological active
compounds or pharmaceuticals. On the other hand, het-
erocycles containing imidazolones nucleus also exhibit
various biological activities. Several of them have
shown good antibacterial, antifungal activities or being
used as leukotriene B4 receptor antagonist and potas-
sium channel openers [5,6]. The introduction of an imi-
dazolone ring to the benzothieno[3,2-d]pyrimidin-4(3H)-
one system is expected to influence the biological activ-
ities significantly. However, this tetracyclic system has
been much less investigated and there is no report on
synthesis of benzothieno[3,2-d]-imidazo[1,2-a]pyrimi-
dine-2,5-(1H, 3H)-diones, probably due to the fact that
the tetracyclic system is not easily accessible by routine
synthetic methods.
RESULTS AND DISCUSSION
Iminophosphorane 1 reacted with isocyanates to give
carbodiimides 2, which were allowed to react with a-
amino ester at room temperature in the presence of cata-
lytic amount of sodium ethoxide to give benzo-
thieno[3,2-d]imidazo[1,2-a]pyrimidine-2,5-(1H, 3H)-dio-
nes 5 selectively (Scheme 1). A variety of a-amino ester
and isocyanate could be used for this synthetic strategy
and the products 5 were obtained in good yields (Table
1). Presumably, the reaction of carbodiimides 2 with a-
amino ester should afford primarily guanidine intermedi-
ates of type 3. From these intermediates 3, the formation
of two cyclized products imidazolone 4 (via path a),
benzothieno[3,2-d]pyrimidin-4(3H)-one 6 (via path b)
could in principle take place. The formation of 5 might
The aza-Wittig reactions of iminophosphoranes have
received increased attention in view of their utility in
the synthesis of nitrogen heterocyclic compounds [7–
23]. Annelation of ring systems with N-heterocycles by
means of an aza-Wittig reaction has been widely utilized
because of the availability of functionalized iminophos-
phoranes. Recently, we have been interested in the syn-
probably due to
a tandem cyclization of 3 to
C
V
2009 HeteroCorporation

January 2010 Efficient Synthesis of Benzothieno[3,2-d]-imidazo[1,2-a]pyrimidine-2,5-(1H, 3H)-diones
via a Tandem aza-Wittig/Heterocumulene-Mediated Annulation
69
Scheme 1
illustrated that the imidazolone 4 is more easily produced
from intermediate 3 than benzothieno[3,2-d]pyrimidin-
4(3H)-one 6, and the cyclization of 4 to product 5 should
be carried out in strong basic condition.
When chiral a-amino ester was used, recemization of
the product 5 took place completely under the reaction
condition. This is probably due to the easy recemization
of C-3 of the benzothieno[3,2-d]imidazo[1,2-a] pyrimi-
dine-2,5-(1H, 3H)-dione ring under the strong basic
condition.
The structure of benzothieno[3,2-d]imidazo[1,2-a]py-
rimidine-2,5-(1H, 3H)-diones 5 was confirmed by their
1
spectrum data. For example, the H NMR spectrum of
5b shows two singlets at 4.98 ppm as quarterlets and
1.95 ppm as doublet due to the CH and CH3, respec-
tively. The signals attributable to the ArAHs are found
at 8.12 ppm–7.44 ppm as mutiplets. The IR spectra of
5b revealed two C¼¼O absorption bands at 1761 and
1683 cmꢀ1 due to the imidazolone and pyrimidinone
carbonyl group, respectively. The MS spectrum of 5b
shows strong molecular ion peak at m/z 347 with 100%
abundance. Furthermore, a single crystal of 5b was
obtained from a CH2Cl2 solution of 5b. X-ray structure
analysis verified again the proposed structure (Fig. 1).
The pyrimidine ring has a flattened-boat conformation
and a pseudo-mirror plane running through the bridge-
head N atom and the opposite C atom. The dihedral
angles between the planar fused benzene (A), thienyl
(B), imidazole (D), and substituent phenyl (E) rings are
imidazolone intermediate 4 and further base catalytic cy-
clization between the imidazolone ring’s NH and ethoxy-
late. An imidazolone intermediate 4d had been success-
fully isolated before the reaction mixture was treated with
sodium ethoxide. Further treatment of 4d with sodium
ethoxide also gave the cyclized product 5d. The result
Table 1
Physical and analytical data of compounds 5.
Analysis % calcd./found
Molecular
formula
Comp.
R1
R2
Time (hours)
4
Mp (ꢁC)
246–247
Yield %a
81
C
H
N
5a
Ph
sec-Bu
C22H19N3O2S
C19H13N3O2S
C21H17N3O2S
C25H17N3O2S
C25H16ClN3O2S
C21H16ClN3O2S
C16H15N3O2S
C22H19N3O2S
C23H21N3O2S
C17H17N3O2S
67.84
67.97
65.69
65.73
67.18
67.46
70.90
70.99
65.57
65.70
61.53
61.70
61.32
61.44
67.84
67.95
68.46
68.52
62.36
62.50
4.92
5.04
3.77
3.89
4.56
4.75
4.05
4.15
3.52
3.66
3.93
4.08
4.82
4.97
4.92
5.01
5.25
5.34
5.23
5.37
10.79
10.69
12.10
12.01
11.19
11.03
9.92
5b
5c
5d
5e
5f
Ph
Ph
Me
i-Pr
2
5
3
4
3
2
3
3
3
268–269
263–265
225–227
223–224
219–220
189–190
189–191
202–203
175–176
87
88
89
83
87
76
84
76
80
Ph
PhCH2
PhCH2
i-Pr
9.88
9.18
4-ClC6H4
4-ClC6H4
i-Pr
9.01
10.25
9.79
5g
5h
5i
Me
13.41
13.33
10.79
10.69
10.41
10.29
12.83
12.74
i-Pr
PhCH2
PhCH2
Me
Bu
5j
Bu
a Yields based on iminophosphorane 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

70
S.-Z. Xu, J. Wu, M.-H. Cao, and M.-W. Ding
Vol 47
eral drops of EtONa in EtOH was added. The mixture was
stirred for 4–6 h at room temperature The solution was con-
centrated under reduced pressure and the residual was recrys-
tallized from methylene dichloride/petroleum ether to give
benzothieno [3,2-d]-imidazo[1,2-a]pyrimidine-2,5-(1H, 3H)-
diones 5.
3-(Sec-butyl)-1-phenylbenzothieno[3,2-d]imidazo[1,2-a]pyrim-
idine-2,5-(1H, 3H)-dione (5a). White solid. 1H NMR (400
MHz, CDCl3) d (ppm): 8.13 (d, J ¼ 7.6 Hz, 1H, ArAH), 7.89
(d, J ¼ 8.4 Hz, 1H, ArAH), 7.61–7.43 (m, 7H, ArAH), 5.02
(d, J ¼ 3.6 Hz, 1H, NCH), 3.01–2.96 (m, 1H, CH), 1.93–1.71
(m, 2H, CH2), 1.11 (t, J ¼ 7.2 Hz, 3H, CH3), 0.92 (d, J ¼ 6.8
Hz, 3H, CH3). IR (KBr): 1756 (C¼¼O), 1686 (C¼¼O), 1599,
1500, 1366, 750 cmꢀ1. MS: m/z (%) 389 (55, Mþ), 313 (43),
201 (24), 146 (100), 77 (75).
3-Methyl-1-phenylbenzothieno[3,2-d]imidazo[1,2-a]pyrimidine-
2,5-(1H, 3H)-dione (5b). White solid. 1H NMR (400 MHz,
CDCl3) d (ppm): 8.12 (d, J ¼ 8.0 Hz, 1H, ArAH), 7.88 (d,
J ¼ 8.4 Hz, 1H, ArAH), 7.63–7.44 (m, 7H, ArAH), 4.98 (q,
J ¼ 7.2 Hz, 1H, NCH), 1.95 (d, J ¼ 6.4 Hz, 3H, CH3). IR
(KBr): 1761 (C¼¼O), 1683 (C¼¼O), 1603, 1498, 1396, 752
cmꢀ1. MS: m/z (%) 347 (36, Mþ), 271 (46), 201 (33), 146
(100), 77 (65).
Figure 1. ORTEP diagram of the crystal structure of tricyclic com-
pound 5b (Drawn at the 50% thermal ellipsoids). [Color figure can be
viewed in the online issue, which is available at www.interscience.
wiley.com.]
1-Phenyl-3-(i-propyl)benzothieno[3,2-d]imidazo[1,2-a]pyrimi-
1
dine-2,5-(1H, 3H)-dione (5c). White solid. H NMR (400 MHz,
A/B ¼ 1.63 (3)ꢁ, A/D ¼ 5.80 (2)ꢁ, B/D ¼ 5.49 (3)ꢁ, and
D/E ¼ 39.73 (3)ꢁ.
CDCl3) d (ppm): 8.13 (d, J ¼ 8.0 Hz, 1H, ArAH), 7.89 (d, J ¼
8.0 Hz, 1H, ArAH), 7.61–7.43 (m, 7H, ArAH), 4.93 (d, J ¼ 2.8
Hz, 1H, NCH), 3.28–3.16 (m, 1H, CH), 1.38 (d, J ¼ 6.8 Hz,
3H, CH3), 0.97 (d, J ¼ 7.2 Hz, 3H, CH3). IR (KBr): 1756
(C¼¼O), 1687 (C¼¼O), 1603, 1501, 1364, 751 cmꢀ1. MS: m/z
(%) 375 (48, Mþ), 299 (26), 201 (41), 146 (100), 77 (73).
3-Benzyl-1-phenylbenzothieno[3,2-d]imidazo[1,2-a]pyrimidine-
2,5-(1H, 3H)-dione (5d). White solid. 1H NMR (400 MHz,
CDCl3) d (ppm): 8.00 (d, J ¼ 7.6 Hz, 1H, ArAH), 7.89 (d,
J ¼ 8.0 Hz, 1H, ArAH), 7.56–7.08 (m, 12H, ArAH), 5.26 (dd,
J1 ¼ 4.8 Hz, J2 ¼ 2.8 Hz, 1H, NCH), 4.11 (dd, J1 ¼ 14.0 Hz,
J2 ¼ 4.8 Hz, 1H, CH2), 3.53 (dd, J1 ¼ 14.0 Hz, J2 ¼ 2.8 Hz,
1H, CH2). IR (KBr): 1761 (C¼¼O), 1684 (C¼¼O), 1584, 1497,
1357, 749 cmꢀ1. MS: m/z (%) 423 (59, Mþ), 347 (39), 201
(37), 146 (100), 91 (57), 77 (54).
3-Benzyl-1-(4-chlorophenyl)benzothieno[3,2-d]imidazo[1,2-
a]pyrimidine-2,5-(1H, 3H)-dione (5e). White solid. 1H NMR
(400 MHz, CDCl3) d (ppm): 8.01 (d, J ¼ 8.0 Hz, 1H, ArAH),
7.90 (d, J ¼ 8.0 Hz, 1H, ArAH), 7.58–7.04 (m, 11H, ArAH),
5.26 (dd, J1 ¼ 2.8 Hz, J2 ¼ 4.8 Hz, 1H, NCH), 4.11 (dd, J1 ¼
14.0 Hz, J2 ¼ 4.8 Hz, 1H, CH2), 3.51 (dd, J1 ¼ 14.0 Hz, J2 ¼
2.8 Hz, 1H, CH2). IR (KBr): 1751 (C¼¼O), 1697 (C¼¼O),
1602, 1501, 1360, 749 cmꢀ1. MS: m/z (%) 457 (47, Mþ), 347
(45), 200 (30), 146 (100), 91 (57), 77 (60).
In summary, we have developed an efficient synthesis
of benzothieno [3,2-d]imidazo[1,2-a]pyrimidine-2,5-(1H,
3H)-diones via a cascade aza-Wittig/heterocumulene-
mediated annulation. This method utilizes easily accessi-
ble starting material and allows mild reaction conditions,
straightforward product isolation and good yields.
EXPERIMENTAL
Melting points were determined using a X-4 model appara-
tus and were uncorrected. MS were measured on a Finnigan
Trace MS spectrometer. NMR spectra were recorded in CDCl3
on a Varian Mercury Plus 400 (400 Hz) spectrometer and
chemical shifts (d) were given in ppm using (CH3)4Si as an in-
ternal reference (d ¼ 0). IR was recorded on a PE-983 infrared
spectrometer as KBr pellets with absorption in cmꢀ1. Elemen-
tary analyses were taken on a Vario EL III elementary analysis
instrument. The X-ray diffraction data were collected on a
Bruker SMART AXS CCD diffractometer.
General procedure for the preparation of benzothieno
[3,2-d]imidazo[1,2-a]pyrimidine-2,5-(1H, 3H)-diones (5). To
a solution of iminophosphorane 1 (0.96 g, 2 mmol) in dry
methylene dichloride (15 mL) was added aromatic isocyanate
(2 mmol) under nitrogen at room temperature. After the reac-
tion mixture was stood for 6–8 h at 0–5ꢁC, the solvent was
removed off under reduced pressure and ether/petroleum ether
(1:2, 20 mL) was added to precipitate triphenylphosphine ox-
ide. Filtered, the solvent was removed to give carbodiimide 2,
which was directly used without further purification. A mixture
of a-amino acid ester hydrochloride (2 mmol) and triethyl-
amine (0.61 g, 4 mmol) in acetonitrile (10 mL) was stirred for
10 min and filtered. Then, the filtrate was added to the solution
of carbodiimide 2 prepared above in dry methylene dichloride
(10 mL) at room temperature. After stirring for 0.5 h, the solu-
tion was concentrated and anhydrous EtOH (10 mL) with sev-
3-Benzyl-1-(4-chlorophenyl)benzothieno[3,2-d]imidazo[1,2-
a]pyrimidine-2,5-(1H, 3H)-dione (5f). White solid. 1H NMR
(400 MHz, CDCl3) d (ppm): 8.13 (d, J ¼ 8.0 Hz, 1H, ArAH),
7.90 (d, J ¼ 8.0 Hz, 1H, ArAH), 7.59–7.45 (m, 6H, ArAH),
4.92 (d, J ¼ 2.4 Hz, 1H, NCH), 3.23–3.18 (m, 1H, CH), 1.37
(d, J ¼ 7.2 Hz, 3H, CH3), 0.95 (d, J ¼ 6.8 Hz, 3H, CH3). IR
(KBr): 1752 (C¼¼O), 1698 (C¼¼O), 1592, 1503, 1387, 748
cmꢀ1. MS: m/z (%) 409 (44, Mþ), 299 (33), 200 (22), 146
(100), 77 (77).
3-Methyl-1-(iso-propyl)benzothieno[3,2-d]imidazo[1,2-a]py-
1
rimidine-2,5-(1H, 3H)-dione (5g). White solid. H NMR (400
MHz, CDCl3) d (ppm): 8.26 (d, J ¼ 7.6 Hz, 1H, ArAH), 7.90
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010 Efficient Synthesis of Benzothieno[3,2-d]-imidazo[1,2-a]pyrimidine-2,5-(1H, 3H)-diones
via a Tandem aza-Wittig/Heterocumulene-Mediated Annulation
71
(d, J ¼ 8.0 Hz, 1H, ArAH), 7.58–7.50 (m, 2H, ArAH), 4.82–
4.74 (m, 2H, 2CH), 1.82 (d, J ¼ 6.8 Hz, 3H, CH3), 1.64 (d,
J ¼ 6.4 Hz, 6H, 2CH3), 1.62 (d, J ¼ 6.0 Hz, 3H, CH3). IR
(KBr): 1742 (C¼¼O), 1685 (C¼¼O), 1594, 1505, 1336, 748
cmꢀ1. MS: m/z (%) 313 (66, Mþ), 271 (42), 201 (29), 146
(100), 77 (67).
Acknowledgment. The authors gratefully acknowledge financial
support of this work by the National Natural Science Foundation of
China (No. 20772041), the Key Project of Chinese Ministry of Edu-
cation (No. 107082), and the Doctors’ Research Foundation of
Huazhong Agricultural University (No. 52204-07092).
REFERENCES AND NOTES
3-Benzyl-1-(iso-propyl)benzothieno[3,2-d]imidazo[1,2-a]py-
rimidine-2,5-(1H, 3H)-dione (5h). White solid. 1H NMR
(400 MHz, CDCl3) d (ppm): 8.16 (d, J ¼ 8.0 Hz, 1H,
ArAH), 7.91 (d, J ¼ 8.4 Hz, 1H, ArAH), 7.59–7.01 (m, 7H,
ArAH), 5.01 (t, J ¼ 2.8 Hz, 1H, NCH), 4.54–4.50 (m, 1H,
NCH), 4.02 (dd, J1 ¼ 14.0 Hz, J2 ¼ 3.6 Hz, 1H, CHaPh),
3.42 (dd, J1 ¼ 13.6 Hz, J2 ¼ 2.8 Hz, 1H, CHbPh), 1.32 (d, J
¼ 6.8 Hz, 3H, CH3), 1.25 (d, J ¼ 7.2 Hz, 3H, CH3). IR
(KBr): 1750 (C¼¼O), 1683 (C¼¼O), 1592, 1503, 1387, 748
cmꢀ1. MS: m/z (%) 389 (58, Mþ), 347 (31), 201 (18), 146
(76), 91 (67), 77 (100).
3-Benzyl-1-butylbenzothieno[3,2-d]imidazo[1,2-a]pyrimidine-
2,5-(1H, 3H)-dione (5i). White solid. 1H NMR (400 MHz,
CDCl3) d (ppm): 8.17 (d, J ¼ 8.0 Hz, 1H, ArAH), 7.91 (d,
J ¼ 8.0 Hz, 1H, ArAH), 7.59–7.03 (m, 7H, ArAH), 5.05 (dd,
J1 ¼ 2.8 Hz, J2 ¼ 4.8 Hz, 1H, NCH), 4.04 (dd, J1 ¼ 14.0 Hz,
J2 ¼ 4.8 Hz, 1H, CHaPh), 3.68–3.61 (m, 2H, NCH2), 3.44 (dd,
J1 ¼ 14.0 Hz, J2 ¼ 2.8 Hz, 1H, CHbPh), 1.41–1.37 (m, 2H,
CH2), 1.10–1.02 (m, 2H, CH2), 0.86 (t, J ¼ 7.2 Hz, 3H, CH3).
IR (KBr): 1754 (C¼¼O), 1673 (C¼¼O), 1605, 1505, 1364, 750
cmꢀ1. MS: m/z (%) 403 (55, Mþ), 347 (44), 201 (34), 146
(75), 91 (66), 77 (100).
1-Butyl-3-methylbenzothieno[3,2-d]imidazo[1,2-a]pyrimidine-
2,5-(1H, 3H)-dione (5j). White solid. 1H NMR (400 MHz,
CDCl3) d (ppm): 8.28 (d, J ¼ 7.6 Hz, 1H, ArAH), 7.90 (d,
J ¼ 8.4 Hz, 1H, ArAH), 7.59–7.52 (m, 2H, ArAH), 4.81 (q,
J ¼ 6.8 Hz, 1H, NCH), 3.93–3.89 (m, 2H, NCH2), 1.85–1.79
(m, 5H, CH2 and CH3), 1.47–1.41 (m, 2H, CH2), 1.01 (t, J ¼
7.2 Hz, 3H, CH3). IR (KBr): 1747 (C¼¼O), 1680 (C¼¼O),
1605, 1504, 1353, 751 cmꢀ1. MS: m/z (%) 327 (65, Mþ), 271
(39), 201 (26), 146 (100), 77 (48).
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Isolation of the intermediate 4d. A mixture of ethyl 2-
amino-3-phenylpropanoate hydrochloride (0.46 g, 2 mmol) and
triethylamine (0.61 g, 4 mmol) in acetonitrile (10 mL) was
stirred for 10 min and filtered. Then, the filtrate was added to
the solution of carbodiimide 2 prepared above in dry methyl-
ene dichloride (10 mL) at room temperature. After stirring for
2 h, the solution was concentrated under reduced pressure and
the residual was recrystallized from methylene dichloride/pe-
troleum ether to give imidazolone 4d. White solid; mp: 191–
193ꢁC. 1H NMR (400 MHz, CDCl3) d (ppm): 7.73–7.13 (m,
14H, ArAH), 4.87 (s, 1H, NH), 4.42–4.32 (m, 3H, OCH2 and
CH), 3.25 (dd, J1 ¼ 3.6 Hz, J2 ¼ 14.0 Hz, 1H, PhCHa), 3.06
(dd, J1 ¼ 8.0 Hz, J2 ¼ 14.0 Hz, 1H, PhCHb), 1.39 (t, J ¼ 7.2
Hz, 3H, CH3). IR (KBr): 3324 (NH), 1762 (C¼¼O), 1691
(C¼¼O), 1596, 1503, 1428, 1239 cmꢀ1. MS: m/z (%) 469 (100,
Mþ), 333 (27), 277 (28), 146 (50), 91 (34). Anal. Calcd for
C27H23N3O3S: C, 69.06; H, 4.94; N, 8.95. Found: C, 69.24; H,
4.87; N, 8.73.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet