An efficient route for synthesis of 2-alkylamino benzo[b]thieno[3,2-d] pyrimidin-4(3H)-one

Article abstract of DOI:10.1016/j.cclet.2010.11.015

The carbodiimide 2, obtained from the aza-Wittig reactions of iminophosphorane 1 with alkyl isocyanates, reacted with primary amino to give 2-alkylamino benzo[b]thieno[3,2-d]pyrimidin-4(3H)-ones 4 and 5. The formation mechanism of the title compounds has

Full text of DOI:10.1016/j.cclet.2010.11.015

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 443–446
www.elsevier.com/locate/cclet
An efficient route for synthesis of 2-alkylamino
benzo[b]thieno[3,2-d]pyrimidin-4(3H)-one
*
Min Hui Cao, Sheng Zhen Xu , Chang Shui Chen
College of Basic Science, Huazhong Agricultural University, Wuhan 430070, China
Received 25 August 2010
Available online 17 January 2011
Abstract
The carbodiimide 2, obtained from the aza-Wittig reactions of iminophosphorane 1 with alkyl isocyanates, reacted with primary
amino to give 2-alkylamino benzo[b]thieno[3,2-d]pyrimidin-4(3H)-ones 4 and 5. The formation mechanism of the title compounds
has been investigated.
# 2010 Sheng Zhen Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Carbodiimides; Aza-Wittig reaction; Iminophosphorane; Isocyanates; Synthesis
Fused pyrimidines continue to attract considerable attention because of their great practical usefulness, primarily,
due to a very wide spectrum of biological activities. Along with some other pyrimidine systems containing an
annulated five-membered heteroaromatic ring [1,2], thienopyrimidines are structural analogs of biogenic purines and
can be considered as potential nucleic acid antimetabolites. Some thienopyrimidine shows significant antifungal and
antibacterial as well as their good anticonvulsant and angiotensin or A2A-receptor antagonistic activities [3–7].
The aza-Wittig reactions of iminophosphoranes have received increasing attention in view of their useful utilities in
the synthesis of nitrogen heterocyclic compounds under mild conditions [8–10]. The very reactive carbodiimides can
be used as synthetic intermediates of a wide variety of polyheterocycles by domino processes involving aza-Wittig/
intermolecular nucleophilic addition/intramolecular cyclization (AW–NA–IC). A series of thienopyrimidine have
been prepared, but 2-amino substituted thienopyrimidinones are not easily accessible by currently existing routes.
Recently we have been interested in the synthesis of triazoloquinazolinones, thienopyrimidinones and imidazolinones
via aza-Wittig reaction, with the aim of evaluating their fungicidal activities [11–15]. Reported herein is a new
efficient synthesis of 2-alkylamino benzothieno[3,2-d]pyrimidin-4(3H)-ones 4 and 5 from easily accessible
iminophosphorane 1 [16].
Iminophosphorane 1 reacted with aromatic isocyanates to give carbodiimide 2, which were allowed to react with
primary amines to provide guanidine intermediate 3. Even in refluxing toluene, 3 did not cyclize, however, in the
presence of catalytic amount of sodium ethoxide, 3 was converted easily to 2-alkylamino benzo[b]thieno[3,2-d]py-
rimidin-4(3H)-ones 4 and 5 in satisfactory yields at room temperature. The results are listed in Table 1.
* Corresponding author.
E-mail addresses: xusz@mail.hzau.edu.cn, xsz1976@yahoo.com.cn (S.Z. Xu).
1001-8417/$ – see front matter # 2010 Sheng Zhen Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.11.015

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M.H. Cao et al. / Chinese Chemical Letters 22 (2011) 443–446
Table 1
Preparation of compds. 4 and 5.
Entry
Compd.
R
R0
Condition
Yielda (%)
Mp (8C)
1
2
4a
4b
4c
4d
5a
5b
5c
5d
5e
5f
i-Pr
t-Bu
i-Pr
n-C6H11
Bn
EtOH/CH2Cl2/EtONa, 10 h, r.t.
EtOH/CH2Cl2/EtONa, 8 h, r.t.
EtOH/CH2Cl2/EtONa, 6 h, r.t.
EtOH/CH2Cl2/EtONa, 8 h, r.t.
EtOH/CH2Cl2/EtONa, 8 h, r.t.
EtOH/CH2Cl2/EtONa, 8 h, r.t.
EtOH/CH2Cl2/EtONa, 10 h, r.t.
EtOH/CH2Cl2/EtONa, 8 h, r.t.
EtOH/CH2Cl2/EtONa, 8 h, r.t.
EtOH/CH2Cl2/EtONa, 6 h, r.t.
EtOH/CH2Cl2, 0.5 h, r.t.
79
78
63
74
85
82
79
76
61
78
89
87
85
83
175–176
219–220
159–160
156–157
230–232
249–250
194–196
219–221
154–155
237–239
281–283
259–260
>300
n-Bu
n-Bu
n-Bu
i-Pr
3
4
5
Et
6
i-Pr
n-Pr
i-Pr
n-Bu
n-C6H13
Bn
7
i-Pr
8
i-Pr
9
i-Pr
10
11
12
13
14
i-Pr
5g
5h
5i
i-Pr
H
i-Pr
Me
EtOH/CH2Cl2, 0.5 h, r.t.
n-Bu
n-Bu
H
EtOH/CH2Cl2, 0.5 h, r.t.
5j
Me
EtOH/CH2Cl2, 0.5 h, r.t.
251–253
a
Isolated yield based on the iminophosphorane 1.
It is interesting to note that a differentiation between the carbodiimide 2 reacted with variable primary amine to
obtain guanidine intermediate 3. When R < R0, such as R = i-Pr, R0 = t-Bu or R = n-Bu, R0 = i-Pr, cyclohexyl or Bn,
the cyclization can be completed smoothly at room temperature through the RNH in the presence of catalytic amount
of ROꢀNa+ (Scheme 1 and Table 1, entries 1–4), provided only 2-alkylaminobenzo[b]thieno[3,2-d]pyrimidin-4(3H)-
one 4, one of the possible regioisomers. When R ꢁ R0(R0 ¼ H, Me), the guanidine intermediate 3 was treated with
ROH in the presence of catalytic ROꢀNa+, one of the possible regioisomers 5 (entries 5–10) was obtained in
satisfactory yields. When R0 = H or Me, no matter how R = n-Bu or i-Pr, we obtained only 5 (entries 11–14) from the
1
reaction mixture in the absence of sodium ethoxide after recrystallization, the other isomer 4 was not found by H
1
NMR analysis of the reaction mixture. The structure of 4 and 5 is deduced from its H NMR data (Table 2). For
1
example, the H NMR spectrum in 5j (R = Me) shows the signals of N–CH3 (s, 3H, NCH3) at 3.54 as a simple
absorption which strongly suggests the existence of NCH3 group but not NHCH3 in 5j. The results are listed in Table 3.
Reagents and chemicals were obtained from Acros, Aldrich, Shanghai or Beijing chemicals and were used without
further purification. All solvents were freshly distilled. Melting points are uncorrected. MS were measured on a
Finnigan Trace MS spectrometer. IR is recorded on a PE-983 infrared spectrometer as KBr pellets with absorption in
cmꢀ1. NMR is recorded in CDCl3 or DMSO-d6 on a Varian Mercury 400 spectrometer and resonances are given in
ppm relative to TMS. Elementary analyses were taken on a Vario EL III elementary analysis instrument.
General procedure for the synthesis of compounds 4 and 5: to a solution of iminophosphorane 1 (2 mmol) in dry
methylene chloride (15 mL) was added alkyl isocyanate (2 mmol) under nitrogen at room temperature. After the
reaction mixture was stood for 10 h at 0–5 8C, the solvent was removed off under reduced pressure and ether–
petroleum ether (1:2, 20 mL) was added to precipitate triphenylphosphine oxide. After filtration, the solvent was
removed to give carbodiimide 2, which was used directly without further purification.
To the solution of 2 prepared above in CH2Cl2 (15 mL) was added primary amine (2 mmol). After the reaction
mixture was allowed to stand for 0.5 h, the solution was condensed and anhyd. EtOH–CH2Cl2 (4:1, 10 mL) with
[()TD$FIG]
Scheme 1. (a) RNCO, CH2Cl2, 0–5 8C, 8–12 h; (b) R0NH2, CH2Cl2, 0.5–1 h; (c) EtOH/CH2Cl2/EtONa, 6–10 h; and (d) EtOH/CH2Cl2/EtONa, 6–
10 h or EtOH/CH2Cl2, 0.5 h.

M.H. Cao et al. / Chinese Chemical Letters 22 (2011) 443–446
445
Table 2
Elementary analysis, MS of compds. 4 and 5.
Elementary analysis (%, calcd.)
MS (m/z,%)
C
H
N
4a
4b
4c
4d
5a
5b
5c
5d
5e
5f
64.73 (64.87)
64.73 (64.84)
67.57 (67.67)
69.39 (69.57)
62.69 (62.77)
63.76 (63.81)
63.76 (63.82)
64.73 (64.87)
66.81 (66.94)
68.74 (68.88)
60.21 (60.17)
61.51 (61.47)
61.51 (61.47)
62.69 (62.55)
6.71 (6.89)
6.71 (6.85)
7.09 (7.17)
5.82 (5.94)
5.96 (6.14)
6.35 (6.45)
6.35 (6.47)
6.71 (6.89)
8.13 (8.25)
5.48 (5.64)
5.05 (4.94)
5.53 (5.47)
5.53 (5.47)
5.96 (5.86)
13.32 (13.20)
13.32 (13.23)
11.82 (11.69)
11.56 (11.46)
14.62 (14.49)
13.94 (13.76)
13.94 (13.72)
13.32 (13.20)
11.69 (11.54)
12.02 (11.86)
16.20 (16.37)
15.37 (15.48)
15.37 (15.48)
14.62 (14.78)
315 (44) [M+], 243 (65), 146 (90), 77 (62)
315 (38) [M+], 257 (67), 146 (100), 77 (61)
355 (32) [M+], 257 (66), 146 (87), 77 (59)
363 (36) [M+], 257 (71), 146 (89), 77 (68)
287 (89) [M+], 229 (59), 146 (100), 77 (79)
301 (37) [M+], 243 (55), 146 (95), 77 (63)
301 (49) [M+], 243 (53), 146 (89), 77 (75)
315 (46) [M+], 257 (66), 146 (80), 77 (62)
359 (29) [M+], 285 (31), 146 (93), 77 (59)
349 (75) [M+], 291 (78), 146 (100), 77 (55)
259 (100) [M+], 201 (86), 146 (100), 77 (64)
273 (93) [M+], 215 (85), 146 (88), 77 (71)
273 (76) [M+], 215 (74), 146 (88), 77 (71)
287 (88) [M+], 215 (82), 146 (87), 77 (69)
5g
5h
5i
5j
Table 3
1H NMR of compounds 4a–d, and 5a–j.
1H NMR (CDCl3, 400 MHz), d
4a
4b
8.16 (d, 1H, J = 7.6 Hz, Ar-H), 7.81 (d, 1H, J = 8.4 Hz, Ar-H), 7.50–7.40 (m, 2H, Ar-H), 5.78 (s, 1H, NH), 4.65 (m, 1H, NCH),
1.62–1.50 (m, 15H, 5CH3)
8.19 (d, 1H, J = 8.0 Hz, Ar-H), 7.82 (d, 1H, J = 7.6 Hz, Ar-H), 7.52–7.40 (m, 2H, Ar-H), 4.51–4.43 (m, 1H, NCH), 4.40
(d, 1H, J = 6.8 Hz, NH), 4.06 (t, 2H, J = 7.6 Hz, NCH2), 1.76–1.65 (m, 2H, CH2), 1.51–1.41 (m, 2H, CH2), 1.40–1.31
(m, 6H, 2CH3), 1.40–0.97 (m, 3H, CH3)
4c
8.18 (d, 1H, J = 7.6 Hz, Ar-H), 7.81 (d, 1H, J = 8.0 Hz, Ar-H), 7.51–7.39 (m, 2H, Ar-H), 4.57 (d, 1H, J = 7.2 Hz, NH), 4.20–4.13
(m, 1H, NCH), 4.06 (t, 2H, J = 7.6 Hz, NCH2), 2.19–2.15 (m, 2H, CH2), 1.81–1.66 (m, 4H, 2CH2), 1.56–1.26 (m, 8H, 4CH2), 0.98
(t, 3H, J = 7.2 Hz, CH3)
4d
8.19 (d, 1H, J = 7.6 Hz, Ar-H), 7.82 (d, 1H, J = 8.0 Hz, Ar-H), 7.52–7.40 (m, 2H, Ar-H), 7.36–7.24 (m, 5H, Ar-H), 5.31
(s, 2H, NCH2), 4.66 (s, 1H, NH), 3.47–3.40 (m, 2H, NCH2), 1.47–1.40 (m, 2H, CH2), 1.17–1.09 (m, 2H, CH2), 0.83
(t, 3H, J = 7.4 Hz, CH3)
5a
5b
8.20 (d, 1H, J = 7.6 Hz, Ar-H), 7.83 (d, 1H, J = 8.0 Hz, Ar-H), 7.51–7.40 (m, 2H, Ar-H), 4.48 (t, 1H, J = 6.4 Hz, NH), 4.47–4.35
(m, 1H, NCH), 4.15 (q, 2H, J = 6.4 Hz, NCH2), 1.62–1.30 (m, 9H, 3CH3)
8.19 (d, 1H, J = 8.0 Hz, Ar-H), 7.82 (d, 1H, J = 8.0 Hz, Ar-H), 7.53–7.40 (m, 2H, Ar-H), 4.50 (t, 1H, J = 6.8 Hz, NH), 4.48–4.43
(m, 1H, NCH), 4.04 (t, 2H, J = 7.6 Hz, NCH2), 1.84–1.72 (m, 2H, CH2), 1.36 (d, 6H, J = 6.4 Hz, 2CH3), 1.04
(t, 3H, J = 7.6 Hz, CH3)
5c
8.17 (d, 1H, J = 7.6 Hz, Ar-H), 7.81 (d, 1H, J = 8.0 Hz, Ar-H), 7.51–7.40 (m, 2H, Ar-H), 5.60 (s, 1H, NH), 4.53–4.49
(m, 1H, NCH), 4.48–4.40 (m, 1H, NCH), 1.58 (d, 6H, J = 6.8 Hz, 2CH3), 1.37 (d, 6H, J = 6.0 Hz, 2CH3)
8.19 (d, 1H, J = 7.6 Hz, Ar-H), 7.80 (d, 1H, J = 8.0 Hz, Ar-H), 7.50–7.40 (m, 2H, Ar-H), 4.64 (t, 1H, J = 6.8 Hz, NH), 4.50–4.46
(m, 1H, NCH), 4.08 (t, 2H, J = 7.6 Hz, NCH2), 1.74–1.60 (m, 2H, CH2), 1.48–1.39 (m, 2H, CH2), 1.35 (d, 6H, J = 6.4 Hz, 2CH3),
0.97 (t, 3H, J = 7.2 Hz, CH3)
5d
5e
8.20 (d, 1H, J = 7.6 Hz, Ar-H), 7.89 (d, 1H, J = 8.0 Hz, Ar-H), 7.48–7.38 (m, 2H, Ar-H), 4.75 (t, 1H, J = 6.4 Hz, NH), 4.54–4.44
(m, 1H, NCH), 4.07 (t, 2H, J = 7.6 Hz, NCH2), 1.76–1.66 (m, 2H, CH2), 1.40–1.18 (m, 8H, 4CH2), 1.31 (d, 6H, J = 8.0 Hz, 2CH3),
0.85 (t, 6H, J = 7.0 Hz, 2CH3)
5f
5g
5h
5i
8.20 (d, 1H, J = 8.0 Hz, Ar-H), 7.85 (d, 1H, J = 8.0 Hz, Ar-H), 7.55–7.28 (m, 7H, Ar-H), 5.38–5.34 (m, 2H, NCH2), 4.36
(t, 1H, J = 6.4 Hz, NH), 4.31–4.24 (m, 1H, NCH), 1.11 (d, 6H, J = 6.4 Hz, 2CH3)
11.52 (s, 1H, NHCO), 8.27 (d, 1H, J = 7.6 Hz, Ar-H), 7.85 (d, 1H, J = 8.0 Hz, Ar-H), 7.58–7.40 (m, 2H, Ar-H), 6.39
(d, 1H, J = 7.6 Hz, NH), 4.46 (q, 1H, J = 6.8 Hz, NCH), 1.44 (d, 6H, J = 6.4 Hz, 2CH3)
8.25 (d, 1H, J = 7.6 Hz, Ar-H), 7.84 (d, 1H, J = 8.0 Hz, Ar-H), 7.57–7.40 (m, 2H, Ar-H), 4.59 (s, 1H, NH), 3.56
(q, 1H, J = 6.8 Hz, NCH), 3.54 (s, 3H, NCH3), 1.44 (d, 6H, J = 6.4 Hz, 2CH3)
11.54 (s, 1H, NH), 8.26 (d, 1H, J = 7.6 Hz, Ar-H), 7.85 (d, 1H, J = 8.0 Hz, Ar-H), 7.58–7.40 (m, 2H, Ar-H), 6.34 (s, 1H, NH),
3.67–3.60 (m, 2H, NCH2), 1.83–1.72 (m, 2H, CH2), 1.58–1.48 (m, 2H, CH2), 1.02 (t, 3H, J = 7.4 Hz, CH3)
8.21 (d, 1H, J = 7.6 Hz, Ar-H), 7.83 (d, 1H, J = 7.6 Hz, Ar-H), 7.54–7.40 (m, 2H, Ar-H), 4.65 (s, 1H, NH), 3.63
(t, 2H, J = 6.4 Hz, NCH2), 3.54 (s, 3H, NCH3), 1.76–1.67 (m, 2H, CH2), 1.53–1.43 (m, 2H, CH2), 1.01 (t, 3H, J = 6.4 Hz, CH3)
5j

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M.H. Cao et al. / Chinese Chemical Letters 22 (2011) 443–446
several drops of EtONa in EtOH was added. The mixture was stirred for 6–10 h at r.t. The solution was concentrated
under reduced pressure and the residue was recrystallized from EtOH to give the 2-alkylamino benzo[b]thieno[3,2-
d]pyrimidin-4(3H)-ones 4 (entries 1–4) and 5 (entries 5–10).
To the solution of 2 prepared above in EtOH (15 mL) was added ammonia or methylamino (2 mmol). After the
reaction mixture was allowed to stand for 0.5 h, the solution was concentrated under reduced pressure and the residue
was recrystallized from EtOH to give the 2-alkylaminobenzo[b]thieno[3,2-d]pyrimidin-4(3H)-one 5 (entries 11–14).
Acknowledgments
We gratefully acknowledge financial supported by Huazhong Agricultural University Scientific & Technological
Self-innovation Foundation (Nos. 2007XRC064 and 2008XKJC005).
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