New efficient synthesis of pyrimido[1,6-c]quinazolin-4-ones by a Biginelli 3CC/Staudinger/aza-Wittig sequence

Article abstract of DOI:10.1016/j.tet.2010.08.046

Dihydropyrimidinone azides 1, obtained from trimethylsilyl chloride-catalyzed Biginelli reaction of 2-azidobenzaldehyde, ethyl acetoacetate, and urea (or thiourea) at room temperature, reacted with triphenylphosphine to give iminophosphorane 2. A tandem aza-Wittig reaction of iminophosphorane 2 with isocyanate, acyl chloride or CS₂ in the presence of K₂CO₃ or NEt₃ generated pyrimido[1,6-c]quinazolin-4-ones 4, 6 or 8 in moderate to good yield.

Full text of DOI:10.1016/j.tet.2010.08.046

Tetrahedron 66 (2010) 8151e8159
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Tetrahedron
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New efficient synthesis of pyrimido[1,6-c]quinazolin-4-ones by a Biginelli
3CC/Staudinger/aza-Wittig sequence
*
Wen-Jing Li, Shuai Liu, Ping He, Ming-Wu Ding
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2010
Received in revised form 16 August 2010
Accepted 17 August 2010
Available online 21 August 2010
Dihydropyrimidinone azides 1, obtained from trimethylsilyl chloride-catalyzed Biginelli reaction of
2-azidobenzaldehyde, ethyl acetoacetate, and urea (or thiourea) at room temperature, reacted with
triphenylphosphine to give iminophosphorane 2. A tandem aza-Wittig reaction of iminophosphorane 2
with isocyanate, acyl chloride or CS2 in the presence of K2CO3 or NEt3 generated pyrimido[1,6-c]qui-
nazolin-4-ones 4, 6 or 8 in moderate to good yield.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
The nitrogen-containing heterocyclic molecules, particularly
with fused heterocyclic structures, have demonstrated a high
The multicomponent reaction (MCR) was considered as a pow-
erful synthetic tool for preparing target molecules of biological
relevance in an efficient manner. In addition these MCRs involve
the stepwise one-pot transformation of three or more reactants
into a single product that contains portions of all the starting
components and are especially suitable in combinatorial and me-
dicinal chemistry.1 Other benefits of MCRs are the intrinsic labor
and time-saving nature and the high purity of products they gen-
erate owing to their high selectivity.2 The Biginelli reaction, one of
the most useful multicomponent reactions, offers an efficient way
to access multifunctionalized 3,4-dihydropyrimidin-2-(1H)-ones
(DHPMs). Such heterocycles have proved to be efficient calcium
channel modulators, mitotic kinesine inhibitors, adrenergic re-
ceptor antagonists, antibacterial and antiviral agents.3 Such a wide
spectrum of biological activity allows consideration of the DHPMs
structural unit as one of the most important drug-like scaffolds.4
Furthermore, most notable among these are the batzelladine al-
kaloids A and B, which inhibit the binding of HIV envelope protein
gp-120 to human CD4 cells and, therefore, are potential new leads
for AIDS therapy.5
degree of binding affinity when they serve as ligands for various
biological receptors. Some of the fused Biginelli derived heterocy-
cles have been attracted attention for medicinal chemistry in drug
discovery area. For example, the thiazolo[3,2-a]pyrimidine A is
a micromolar inhibitor of the group 2 GPCR metabotropic gluta-
mate receptor, whereas pyrido[3,4-c]quinoline B has been used in
the treatment of asthma (Fig.1).8 However, despite of the important
drug-like scaffolds of DHPMs, other fused DHPMs were less
investigated previously and there is no report on synthesis of 3,11b-
dihydro-4H-pyrimido[1,6-c]quinazolin-4-(thi)ones.
NH
Cl
Cl
EtOOC
H3C
EtOOC
H3C
N
O
S
N
N
H
CH3
B
A
Figure 1. Examples of fused Biginelli derived heterocycles having biological activities.
In the study of the Biginelli multicomponent process much
emphasis was placed on catalysts screening: various Bronsted
and Lewis acids were reported to mediate the Biginelli reaction.6
However, far less attention has been paid to the further func-
tionalization of the Biginelli adducts,7 in spite of the fact that the
structures thus obtained may present significant biological
activity.
The aza-Wittig reactions of iminophosphoranes have received
increased attention in view of their utility in the synthesis of
nitrogen heterocyclic compounds.9 Thus, it is envisioned that
combining the efficiency of the Biginelli reaction with a post-con-
densation aza-Wittig reaction would facilitate access to a series of
fused DHPMs, which are of considerable interest as potential bi-
ological active compounds or pharmaceuticals. Recently we have
been interested in the synthesis of various heterocycles via aza-
Wittig reaction, with the aim of evaluating their biological
* Corresponding author. Tel.: þ86 27 63158845; fax: þ86 27 67862041; e-mail
address: ding5229@yahoo.com.cn (M.-W. Ding).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.046

8152
W.-J. Li et al. / Tetrahedron 66 (2010) 8151e8159
activities.10 Here we wish to report a fundamentally new approach
to the synthesis of previously unreported 3,11b-dihydro-4H-pyr-
imido[1,6-c]quinazolin-4-(thi)ones by the Biginelli reaction be-
tween easily accessible 2-azidobenzaldehyde, ethyl acetoacetate,
and (thio)ureas, followed by a Staudinger/aza-Wittig cyclization of
the Biginelli products.
N3
X
N3
Me3SiCl
CH3CN/DMF
r.t.
EtOOC
H3C
CHO
+
NH
EtOOC
H3C
NH2
N
R1
1
R1HN
X
O
2. Results and discussion
Scheme 2. Preparation of compounds 1.
Although many aldehydes were utilized in the Biginelli reaction,
2-azidobenzaldehyde was not used previously in the reaction to
prepare corresponding tetrahydropyrimidine azides 1. It has been
reported that the Biginelli reaction can be efficiently promoted by
various acids such as HCl, Bi(OTf)3, BF3, H3BO3, LaX3 (X¼Cl, OTf), Yb
(OTf)3, In(OTf)3, ZrCl4, Mn(OAc)3, FeCl3$6H2O, NiCl3$6H2O, RuCl3,
etc. as catalyst, however, many of the reactions were carried out at
refluxing temperature, which is not suitable for preparing the
thermal labile azides 1. Some catalysts, such as Me3SiCl, Me3SiI,
SiCl4, were also successfully utilized in the Biginelli reaction under
room temperature condition.11 Initially, the Biginelli reaction of
2-azidobenzaldehyde, ethyl acetoacetate, and urea was chosen as
a model to optimize the reaction condition (Scheme 1). We used
a CH3CN/DMF (4:1) solution of 2-azidobenzaldehyde (3 mmol),
ethyl acetoacetate (3 mmol), and urea (3.6 mmol) in the presence of
HCl, H2SO4, or Me3SiCl that was stirred at room temperature for 4 h
(Table 1). With HCl and H2SO4 as catalysts, the desired product was
formed only in moderate yields. TMSCl proved to be a very effective
catalyst and provided high yield of the azide 1a as 0.5 equiv amount
of it was used. Further increasing the amount of TMSCl (1.0 equiv)
did not improve the product yield considerably.
Table 2
Preparation of azides 1 via Biginelli reaction
Compd
X
R1
Yielda [%]
1a
1b
1c
1d
1e
1f
O
S
H
H
91
90
77
87
88
82
O
O
O
S
Et
Me
Ph
Ph
a
Isolated yields of 1 based on 2-azidobenzaldehyde.
were treated with aromatic or aliphatic isocyanates at room or
refluxing temperature, carbodiimides 3 were isolated in moderate
to good yields. The direct cyclization of 3 to 4 through the addition
of pyrimidinone NH to the carbodiimide moiety didn’t occur under
the reaction condition. This is probably due to the low nucleo-
philicity of the NH on the pyrimidinone ring. Heating of carbo-
diimide 3 in toluene resulted in a complex mixture owning to the
unstablity of the carbodiimide 3 at high temperature. However, in
the presence of catalytic amount of potassium carbonate in CH3CN
at room temperature, carbodiimides 3 cyclized easily to give pyr-
imido[1,6-c]quinazolin-4-ones 4 in moderate to good overall yields
(Scheme 3, Table 3). It’s noteworthy that the reaction proceeds
under mild conditions to give various substituted pyrimido[1,6-c]
quinazolin-4-ones, and the overall transformation can be run in
a one-pot procedure from azides 1, or with isolation of the in-
termediate iminophosphoranes 2 or carbodiimides 3.
N3
N3
Catalyst
EtOOC
CHO
+
NH
CH3CN/DMF
EtOOC
H3C
NH2
r.t.
H3C
N
H
O
H2N
O
O
1a
Scheme 1. Preparation of compound 1a.
Table 1
Optimization of the reaction conditions
N=PPh3
N3
R2NCO
Ph3P
EtOOC
EtOOC
H3C
Entry
Catalyst
Proportion
Yielda [%]
NH
NH
1
2
3
4
5
6
7
8
9
NON
HCl
HCl
H2SO4
H2SO4
TMSCl
TMSCl
TMSCl
TMSCl
d
0
61
46
50
33
46
52
91
92
1:1
1:0.5
1:1
1:0.5
1:0.1
1:0.2
1:0.5
1:1
H3C
N
R1
2
X
N
R1
1
X
N
N=C=NR2
EtOOC
H3C
K2CO3 (s)
N
NHR2
EtOOC
a
Isolated yields of 1a based on 2-azidobenzaldehyde.
NH
N
R1
4
X
H3C
N
R1
3
X
With the optimized condition, various ureas and thioureas were
employed for the Biginelli reaction in the presence of 0.5 equiv
amount of Me3SiCl (Scheme 2). All reactions proceeded smoothly to
give the corresponding dihydropyrimidinone azides 1 (Table 2) in
good yields at room temperature.
Scheme 3. Preparation of compounds 4.
The obtained azides 1 were further reacted with triphenyl-
phosphine, and the iminophosphoranes 2 was obtained in excel-
lent isolated yields (88e94%) via Staudinger reaction (Scheme 3).
When solutions of iminophosphoranes 2 in dry CH2Cl2 or CH3CN
The reaction of iminophosphoranes 2 with CS2 in refluxing
CH3CN also gave the isothiocyanate 5. In the presence of catalytic
amount of potassium carbonate in CH3CN, 5 was easily transferred
into 6 in good yield (Scheme 4).

W.-J. Li et al. / Tetrahedron 66 (2010) 8151e8159
8153
Table 3
Preparation of compounds 4 and 6
Cl
R1
R2
Yielda [%]
N=PPh3
X
Compd
X
N
X
R2COCl
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
S
O
S
H
H
H
H
Et
H
Me
Ph
Ph
Me
H
Me
Ph
Me
Ph
Et
Ph
Ph
57
59
85
57
60
75
64
75
64
78
72
60
69
62
69
73
72
77
86
82
EtOOC
H3C
R2
EtOOC
H3C
NH
NH
i-Pr
4-CleC6H4
Ph
i-Pr
Ph
Ph
i-Pr
i-Pr
3-MeeC6H4
4-CleC6H4
4-CleC6H4
4-FeC6H4
4-FeC6H4
i-Pr
N
R1
2
N
R1
S
O
O
O
O
O
O
S
O
O
O
O
O
S
7
N
X
EtOOC
H3C
R2
NEt3
N
N
R1
8
Ph
Ph
H
Ph
i-Pr
S
S
O
Scheme 5. Preparation of compounds 8.
6a
6b
H
a
Isolated yields based on iminophosphorane 2.
initial aza-Wittig reaction between the iminophosphorane 2 and
acyl chlorideinpresence of triethylamine affording the intermediate
imidoyl chloride 7, which undergoes cyclization to give 8.
The structure of pyrimido[1,6-c]quinazolines 4, 6, and 8 was
confirmed by their spectrum data. Furthermore a single crystal of
8a was obtained from a CH2Cl2 solution of 8a. X-ray structure
analysis verified again the proposed structure (Fig. 2).
N=C=S
X
N=PPh3
CS2
EtOOC
H3C
EtOOC
H3C
NH
NH
N
R1
N
R1
2
X
5
NH
S
EtOOC
H3C
K2CO3 (s)
N
N
X
R1
6
Scheme 4. Preparation of compounds 6.
Iminophosphoranes 2 reacted with acyl chlorides in the presence
of triethylamine in CH3CN at refluxing temperature to give directly
2-substituted pyrimido[1,6-c]quinazolines
8
in good yields
(61e92%, Table 4, Scheme 5). The formation of 8 can be viewed as an
Figure 2. ORTEP diagram of the crystal structure of tricyclic compound 8a (50%
thermal ellipsoids).
Table 4
Preparation of compounds 8 from iminophosphoranes 2
Compd
X
R1
R2
Yielda [%]
3. Conclusion
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
S
S
H
H
Ph
65
61
81
84
80
81
76
79
81
81
80
63
88
90
77
74
92
3-CleC6H4
Ph
Ph
We have developed a new MCR, yielding 3,11b-dihydro-4H-
pyrimido[1,6-c]quinazolin-4-(thi)ones, by a sequence of a trime-
thylsilyl chloride-catalyzed Biginelli reaction, Staudinger reaction
and a tandem aza-Wittig ring closure. This method utilizes easily
accessible starting material and allows mild reaction conditions,
straightforward product isolation, and good yields.
O
O
O
O
O
O
O
O
O
O
S
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
4-MeeC6H4
4-MeeC6H4
2-CleC6H4
2-CleC6H4
3-CleC6H4
3-CleC6H4
2-FeC6H4
4-FeC6H4
Ph
4-NO2eC6H4
3-CleC6H4
4-MeeC6H4
2-CleC6H4
4. Experimental
4.1. General
S
S
S
S
Melting points were uncorrected. MS were measured on a Fin-
nigan Trace MS spectrometer. IR were recorded on a PE-983 in-
frared spectrometer as KBr pellets with absorption in cmꢀ1. NMR
a
Isolated yields based on iminophosphorane 2.

8154
W.-J. Li et al. / Tetrahedron 66 (2010) 8151e8159
were recorded in CDCl3 or DMSO-d6 on a Varian Mercury 400 or
600 spectrometer and resonances relative to TMS. Elementary
analyses were taken on a Vario EL III elementary analysis in-
strument. The X-ray diffraction data were collected on a Bruker
C20H19N5O3: C, 63.65; H, 5.07; N, 18.56. Found: C, 63.74; H, 5.01;
N, 18.75.
4.2.6. 4-(2-Azidophenyl)-5-ethoxycarbonyl-6-methyl-1-phenyl-3,4-
dihydropyrimidine-2(1H)-thione (1f). Operation as above with
1-phenylthiourea (0.36 g, 2.4 mmol), compound 1f (0.64 g, 82%)
was also isolated as white solid. Mp: 179e181 ꢁC. IR (KBr): 3410,
SMART AXS CCD diffractometer, Mo K
a, 2
q
¼1.86e27.50ꢁ. 2-Azido-
benzaldehyde was easily prepared from the reaction of sodium
azide with 2-nitrobenzaldehyde according to the literature
reports.12
3157, 2130, 1702, 1685 cmꢀ1. 1H NMR (CDCl3, 600 MHz):
d 7.70e7.16
(m, 9H, AreH), 7.00 (br s, 1H, NH), 5.70 (d, J¼3.2 Hz, 1H, CH),
4.13e4.06 (m, 2H, OCH2), 2.22 (s, 3H, CH3), 1.12 (t, J¼7.2 Hz, 3H,
CH3). Anal. Calcd for C20H19N5O2S: C, 61.05; H, 4.87; N,17.80. Found:
C, 61.28; H, 4.63; N, 17.95.
4.2. Synthesis of azides 1 via Biginelli reaction
4.2.1. 4-(2-Azidophenyl)-5-ethoxycarbonyl-6-methyl-3,4-dihy-
dropyrimidin-2(1H)-one
(1a). 2-Azidobenzaldehyde (0.29 g,
2.0 mmol), urea (0.14 g, 2.4 mmol), and ethyl acetoacetate (0.26 g,
2.0 mmol) were added to acetonitrile/DMF (4 mL/1 mL) sequen-
tially at room temperature. After the addition of Me3SiCl (0.11 g,
1.0 mmol), the mixture was stirred for 4 h at ambient tempera-
ture. The crude product was collected by filtration and washed
with ethanol to give 0.55 g (91%) of azide 1a as white solid. Mp:
206e208 ꢁC. IR (KBr): 3242, 3112, 2957, 2128, 1716, 1702,
4.3. Synthesis of the iminophosphoranes 2 via Staudinger
reaction
4.3.1. 5-Ethoxycarbonyl-6-methyl-4-(2-(triphenylphosphor-
anylideneamino)phenyl)-3,4-dihydropyrimidin-2(1H)-one (2a). To
a stirred solution of azide 1a (0.60 g, 2 mmol) in CH2Cl2 (10 mL)
was added dropwise triphenylphosphine (0.52 g, 2 mmol) in
CH2Cl2 (5 mL) at room temperature. After the reaction mixture was
stirred for 2 h at ambient temperature, the solvent was removed
off under reduced pressure and the residual was recrystallized
from methylene dichloride/petroleum ether to give 0.96 g (90%) of
iminophosphorane 2a as white solid. Mp: 253e255 ꢁC. IR (KBr):
3242, 3112, 2957, 1716, 1702, 1637 cmꢀ1. 1H NMR (CDCl3, 600 MHz):
1637 cmꢀ1. 1H NMR (DMSO-d6, 600 MHz):
d 9.20 (s, 1H, NH), 7.55
(s, 1H, NH), 7.36e7.16 (m, 4H, AreH), 5.44 (s, 1H, CH), 3.90 (q,
J¼7.2 Hz, 2H, OCH2), 2.29 (s, 3H, CH3), 1.00 (t, J¼7.2 Hz, 3H, CH3).
MS m/z: 272 (MþꢀN2ꢀ1, 2), 200 (11), 155 (10), 103 (14), 42 (100).
Anal. Calcd for C14H15N5O3: C, 55.81; H, 5.02; N, 23.24. Found: C,
55.63; H, 5.17; N, 23.46.
d
7.77e7.45 (m, 15H, AreH), 7.17 (s, 1H, NH), 7.04 (s, 1H, NH), 6.94
4.2.2. 4-(2-Azidophenyl)-5-ethoxycarbonyl-6-methyl-3,4-dihy-
dropyrimidine-2(1H)-thione (1b). Operation as above with thiourea
(0.18 g, 2.4 mmol), compound 1b (0.57 g, 90%) was also isolated as
white solid. Mp: 176e177 ꢁC. IR (KBr): 3402, 3198, 2984, 2124,
(d, J¼4.8 Hz, 1H, AreH), 6.78e6.75 (m, 1H, AreH), 6.57 (t, J¼7.2 Hz,
1H, AreH), 6.40 (d, J¼7.8 Hz, 1H, AreH), 6.17 (s, 1H, CH), 4.06 (q,
J¼7.2 Hz, 2H, OCH2), 2.45 (s, 3H, CH3), 1.06 (t, J¼7.2 Hz, 3H, CH3).
MS m/z: 535 (Mþ, 56), 462 (8), 277 (30), 262 (100), 183 (54). Anal.
Calcd for C32H30N3O3P: C, 71.76; H, 5.65; N, 7.85. Found: C, 71.95;
H, 5.51; N, 7.95.
1710 cmꢀ1. 1H NMR (CDCl3, 600 MHz):
d 8.03 (s, 1H, NH), 7.36e7.09
(m, 5H, AreH), 5.69 (d, J¼3.0 Hz, 1H, CH), 4.06 (q, J¼7.2 Hz, 2H,
OCH2), 2.44 (s, 3H, CH3), 1.10 (t, J¼7.2 Hz, 3H, CH3). Anal. Calcd for
C14H15N5O2S: C, 52.98; H, 4.76; N, 22.07. Found: C, 52.84; H, 4.79; N,
22.26.
4.3.2. 5-Ethoxycarbonyl-6-methyl-4-(2-(triphenylphosphor-
anylideneamino)phenyl)-3,4-dihydropyrimidine-2(1H)-thione
(2b). Operation as above with azide 1b (0.63 g, 2 mmol), com-
pound 2b (0.97 g, 88%) was also isolated as white solid. Mp:
242e244 ꢁC. IR (KBr): 3236, 3118, 2956, 1711, 1702, 1638 cmꢀ1. 1H
4.2.3. 4-(2-Azidophenyl)-5-ethoxycarbonyl-1-ethyl-6-methyl-3,4-di-
hydropyrimidin-2(1H)-one (1c). Operation as above with 1-ethyl-
urea (0.21 g, 2.4 mmol), compound 1c (0.51 g, 77%) was also
isolated as white solid. Mp: 143e145 ꢁC. IR (KBr): 3406, 3218,
NMR (CDCl3, 600 MHz): d 8.79 (s, 1H, NH), 7.79e7.38 (m, 16H, AreH
and NH), 6.90e6.38 (m, 4H, AreH), 6.19 (s, 1H, CH), 4.08 (q,
J¼7.2 Hz, 2H, OCH2), 2.43 (s, 3H, CH3), 1.08 (t, J¼7.2 Hz, 3H, CH3). MS
m/z: 551 (Mþ, 53), 478 (20), 277 (34), 262 (100), 183 (52), 108 (18).
Anal. Calcd for C32H30N3O2PS: C, 69.67; H, 5.48; N, 7.62. Found: C,
69.41; H, 5.24; N, 7.76.
.
2988, 2957, 2127, 1682 cmꢀ1 1H NMR (CDCl3, 600 MHz):
d
7.32e7.04 (m, 4H, AreH), 5.73 (s, 1H, NH), 5.57 (s, 1H, CH),
4.06e4.03 (m, 2H, OCH2), 3.92e3.66 (m, 2H, NCH2), 2.63 (s, 3H,
CH3), 1.17 (t, J¼7.2 Hz, 3H, CH3), 1.09 (t, J¼7.2 Hz, 3H, CH3). MS
m/z: 329 (Mþ, 2), 300 (20), 228 (100), 200 (48), 185 (34), 70 (52).
Anal. Calcd for C16H19N5O3: C, 58.35; H, 5.81; N, 21.26. Found: C,
58.38; H, 5.71; N, 21.51.
4.3.3. 5-Ethoxycarbonyl-1-ethyl-6-methyl-4-(2-(triphenylphosphor-
anylideneamino)phenyl)-3,4-dihydropyrimidin-2(1H)-one
(2c). Operation as above with azide 1c (0.66 g, 2 mmol), compound
2c (1.06 g, 94%) was also isolated as white solid. Mp: 195e197 ꢁC. IR
4.2.4. 4-(2-Azidophenyl)-1,6-dimethyl-5-ethoxycarbonyl-3,4-dihy-
dropyrimidin-2(1H)-one (1d). Operation as above with 1-methyl-
urea (0.18 g, 2.4 mmol), compound 1d (0.55 g, 87%) was also
isolated as white solid. Mp: 158e160 ꢁC. IR (KBr): 3422, 3239,
(KBr): 3240, 3110, 2958, 1714, 1700, 1641 cmꢀ1 1H NMR (CDCl3,
.
600 MHz):
d 7.77e6.38 (m, 20H, AreH and NH), 6.09 (s, 1H, CH),
4.08e4.03 (m, 2H, OCH2), 3.86e3.65 (m, 2H, NCH2), 2.65 (s, 3H,
CH3), 1.15 (t, J¼7.2 Hz, 3H, CH3), 1.04 (t, J¼7.2 Hz, 3H, CH3). MS m/z:
563 (Mþ, 100), 534 (21), 490 (7), 300 (14), 262 (86), 183 (23). Anal.
Calcd for C34H34N3O3P: C, 72.45; H, 6.08; N, 7.46. Found: C, 72.23; H,
6.22; N, 7.21.
2926, 2129, 1680 cmꢀ1. 1H NMR (CDCl3, 600 MHz):
d 7.32e7.05 (m,
4H, AreH), 5.76 (s, 1H, NH), 5.59 (s, 1H, CH), 4.05 (q, J¼7.2 Hz, 2H,
OCH2), 3.19 (s, 3H, NCH3), 2.62 (s, 3H, CH3), 1.10 (t, J¼7.2 Hz, 3H,
CH3). Anal. Calcd for C15H17N5O3: C, 57.13; H, 5.43; N, 22.21. Found:
C, 57.35; H, 5.21; N, 22.37.
4.3.4. 1,6-Dimethyl-5-ethoxycarbonyl-4-(2-(triphenylphosphor-
anylideneamino)phenyl)-3,4-dihydropyrimidin-2(1H)-one
(2d). Operation as above with azide 1d (0.63 g, 2 mmol), com-
pound 2d (1.00 g, 91%) was also isolated as light yellow solid. Mp:
4.2.5. 4-(2-Azidophenyl)-5-ethoxycarbonyl-6-methyl-1-phenyl-3,4-
dihydropyrimidin-2(1H)-one (1e). Operation as above with
1-phenylurea (0.33 g, 2.4 mmol), compound 1e (0.66 g, 88%) was
also isolated as white solid. Mp: 211e213 ꢁC. IR (KBr): 3351, 2979,
212e214 ꢁC. 1H NMR (CDCl3, 600 MHz):
d 7.77e7.46 (m,15H, AreH),
2130, 1685 cmꢀ1
.
1H NMR (CDCl3, 600 MHz):
d
7.44e7.14 (m, 9H,
7.05e6.38 (m, 5H, AreH and NH), 6.09 (s, 1H, CH), 4.06 (q, J¼7.2 Hz,
2H, OCH2), 3.17 (s, 3H, NCH3), 2.63 (s, 3H, CH3), 1.05 (t, J¼7.2 Hz, 3H,
CH3). MS m/z: 549 (Mþ, 20), 476 (8), 286 (13), 277 (14), 262 (100),
AreH), 5.85 (s, 1H, NH), 5.70 (s, 1H), 4.04e4.12 (m, 2H, OCH2),
2.21 (s, 3H, CH3), 1.12 (t, J¼7.2 Hz, 3H, CH3). Anal. Calcd for

W.-J. Li et al. / Tetrahedron 66 (2010) 8151e8159
8155
183 (52), 56 (44). Anal. Calcd for C33H32N3O3P: C, 72.12; H, 5.87; N,
7.65. Found: C, 72.04; H, 5.70; N, 7.91.
Anal. Calcd for C18H22N4O2S: C, 60.31; H, 6.19; N, 15.63. Found: C,
60.12; H, 6.26; N, 15.68.
4.3.5. 5-Ethoxycarbonyl-6-methyl-1-phenyl-4-(2-(triphenylphos-
phoranylideneamino)phenyl)-3,4-dihydropyrimidin-2(1H)-one
(2e). Operation as above with azide 1e (0.75 g, 2 mmol), compound
2e (1.12 g, 92%) was also isolated as light yellow solid. Mp:
4.4.4. 6-(4-Chlorophenylamino)-1-ethoxycarbonyl-2-methyl-3,11b-
dihydro-4H-pyrimido[1,6-c]quinazoline-4-thione (4d). Operation as
above with 4-chlorophenylisocyanate (0.15 g, 1 mmol) at room
temperature for 1 h, compound 4d (0.24 g, 57%) was also isolated as
white solid. Mp: 214e216 ꢁC. IR (KBr): 3434, 3336, 2992, 1692,
230e232 ꢁC. 1H NMR (CDCl3, 600 MHz):
d 7.78e6.41 (m, 25H, AreH
and NH), 6.21 (s,1H, CH), 4.13e4.05 (m, 2H, OCH2), 2.22 (s, 3H, CH3),
1.09 (t, J¼7.2 Hz, 3H, CH3). Anal. Calcd for C38H34N3O3P: C, 74.62; H,
5.60; N, 6.87. Found: C, 74.87; H, 5.63; N, 6.72.
1640 cmꢀ1. 1H NMR (CDCl3, 600 MHz):
d 7.96 (s, 1H, NH), 7.69e6.85
(m, 9H, AreH and NH), 5.63 (s, 1H, CH), 4.28e4.22 (m, 2H, OCH2),
2.42 (s, 3H, CH3), 1.23 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
100 MHz):
d 175.4, 165.2, 144.8, 143.4, 142.1, 136.7, 129.0, 128.9,
4.3.6. 5-Ethoxycarbonyl-6-methyl-1-phenyl-4-(2-(triphenylphos-
phoranylideneamino)phenyl)-3,4-dihydropyrimi dine-2(1H)-thione
(2f). Operation as above with azide 1f (0.63 g, 2 mmol), compound
2f (1.00 g, 93%) was also isolated as white solid. Mp: 229e230 ꢁC. IR
128.6, 127.3, 124.0, 123.3, 122.8, 121.1, 99.8, 60.8, 54.5, 18.0, 14.2. MS
m/z: 426 (Mþ, 29), 293 (34), 280 (16), 256 (13), 127 (100), 110 (29).
Anal. Calcd for C21H19ClN4O2S: C, 59.08; H, 4.49; N, 13.12. Found: C,
59.29; H, 4.25; N, 13.03.
(KBr): 3244, 3116, 2958, 1714, 1708, 1635 cmꢀ1 1H NMR (CDCl3,
.
600 MHz):
d
9.04 (s, 1H, NH), 7.82e6.40 (m, 24H, AreH), 6.21 (s, 1H,
4.4.5. 1-Ethoxycarbonyl-3-ethyl-6-phenylamino-2-methyl-3,11b-dihy-
dro-4H-pyrimido[1,6-c]quinazolin-4-one (4e). Operation as above
with iminophosphorane 2c (0.56 g, 1 mmol) at room temperature
for 2 h, compound 4e (0.24 g, 60%) was also isolateꢀd1 as white
CH), 4.17e4.08 (m, 2H, OCH2), 2.22 (s, 3H, CH3), 1.12 (t, J¼7.2 Hz, 3H,
CH3). Anal. Calcd for C38H34N3O2PS: C, 72.71; H, 5.46; N, 6.69.
Found: C, 72.64; H, 5.42; N, 6.88.
solid. Mp: 201e203 ꢁC. IR (KBr): 3310, 1668, 1635 cm
.
1H NMR
4.4. Synthesis of pyrimido[1,6-c]quinazolin-4-ones 4
(CDCl3, 600 MHz): d 7.74e6.87 (m, 10H, AreH and NH), 5.50 (s,
1H, CH), 4.27e4.22 (m, 2H, OCH2), 3.65e3.72 (m, 2H, NCH2),
2.63 (s, 3H, CH3), 1.19 (t, J¼6.6 Hz, 3H, CH3), 1.11 (t, J¼7.2 Hz, 3H,
4.4.1. 1-Ethoxycarbonyl-6-phenylamino-2-methyl-3,11b-dihydro-
4H-pyrimido[1,6-c]quinazoline-4-thione (4a). To a solution of imi-
nophosphorane 2b (0.55 g, 1 mmol) in CH3CN (10 mL) was added
phenylisocyanate (0.12 g, 1 mmol) under nitrogen at room tem-
perature. After stirred for 2 h at room temperature, K2CO3 (0.014 g,
0.1 mmol) was added and the mixture was stirred for 1 h. The
solvent was removed off under reduced pressure and the residue
was recrystallized from methylene dichloride and ethanol to give
0.22 g (57%) of compound 4a as light yellow solid. Mp: 160e161 ꢁC.
CH3). 13C NMR (CDCl3, 100 MHz):
d 165.9, 150.8, 149.4,
145.5, 143.1, 138.9, 128.6, 128.5, 127.3, 123.3, 122.9, 122.5, 119.6,
100.6, 60.5, 52.5, 38.8, 15.9, 14.5, 14.1. MS m/z: 404 (Mþ, 100), 374
(45), 330 (28), 286 (29), 227 (32), 92 (95). Anal. Calcd for
C23H24N4O3: C, 68.30; H, 5.98; N, 13.85. Found: C, 68.27; H, 5.84;
N, 13.96.
4.4.6. 1-Ethoxycarbonyl-6-isopropylamino-2-methyl-3,11b-dihydro-
4H-pyrimido[1,6-c]quinazolin-4-one (4f). Operation as above with
iminophosphorane 2a (0.54 g, 1 mmol) and isopropylisocyanate
(0.09 g, 1 mmol) at refluxing temperature for 4 h, compound 4f
(0.26 g, 75%) was also isolated as white solid. Mp: 280e282 ꢁC. IR
IR (KBr): 3297, 1634, 1591 cmꢀ1. 1H NMR (CDCl3, 600 MHz):
d 7.93
(s, 1H, NH), 7.75e6.85 (m, 10H, AreH and NH), 5.64 (s, 1H, CH), 4.25
(q, J¼7.2 Hz, 2H, OCH2), 2.43 (s, 3H, CH3), 1.23 (t, J¼7.2 Hz, 3H, CH3).
MS m/z: 392 (Mþ, 100), 319 (20), 300 (21), 260 (55), 181 (14). Anal.
Calcd for C21H20N4O2S: C, 64.27; H, 5.14; N, 14.28. Found: C, 64.16;
H, 5.17; N, 14.53.
(KBr): 3113, 2967, 1696, 1648 cmꢀ1 1H NMR (CDCl3, 600 MHz):
.
d
7.79 (s, 1H, NH), 7.23e6.79 (m, 4H, AreH), 5.46 (s, 1H, CH), 5.16 (d,
J¼6.0 Hz, 1H, NH), 4.28e4.17 (m, 3H, NCH and OCH2), 2.38 (s, 3H,
4.4.2. 1-Ethoxycarbonyl-6-phenylamino-2-methyl-3,11b-dihydro-
4H-pyrimido[1,6-c]quinazolin-4-one (4b). Operation as above with
iminophosphorane 2a (0.54 g, 1 mmol) at room temperature for
2 h, compound 4b (0.22 g, 59%) was also isolated as white solid.
Mp: 247e249 ꢁC. IR (KBr): 3300, 1706, 1648 cmꢀ1. 1H NMR (CDCl3,
CH3), 1.28 (d, J¼6.6 Hz, 6H, 2CH3), 1.18 (t, J¼7.2 Hz, 3H, CH3). 13C
NMR (CDCl3, 100 MHz):
d 165.6, 150.6, 147.4, 146.7, 143.9, 128.4,
127.0, 122.6, 122.4, 97.6, 60.3, 53.8, 43.7, 22.8, 22.3, 18.1, 14.1. MS
m/z: 342 (Mþ, 100), 313 (30), 271 (26), 226 (19), 210 (19), 184 (13).
Anal. Calcd for C18H22N4O3: C, 63.14; H, 6.48; N, 16.36. Found: C,
63.06; H, 6.53; N, 16.10.
600 MHz):
d
8.22 (s, 1H, NH), 7.67 (d, J¼7.8 Hz, 2H, AreH), 7.58 (s,
1H, NH), 7.30e6.83 (m, 7H, AreH), 5.54 (s, 1H, CH), 4.23e4.17 (m,
2H, OCH2), 2.31 (s, 3H, CH3), 1.21 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
4.4.7. 2,3-Dimethyl-1-ethoxycarbonyl-6-phenylamino-3,11b-dihy-
dro-4H-pyrimido[1,6-c]quinazolin-4-one (4g). Operation as above
with iminophosphorane 2d (0.55 g, 1 mmol) at room temperature
for 4 h, compound 4g (0.25 g, 64%) was also isolateꢀd1 as white
(CDCl3, 100 MHz):
d 165.5, 150.8, 147.3, 144.2, 142.7, 138.8, 128.8,
128.6, 127.3, 123.5, 123.2, 122.8, 119.6, 97.5, 60.5, 53.9, 18.3, 14.1. MS
m/z: 376 (Mþ, 100), 347 (54), 302 (46), 260 (23), 220 (27), 77 (50).
Anal. Calcd for C21H20N4O3: C, 67.01; H, 5.36; N, 14.88. Found: C,
67.17; H, 5.18; N, 14.85.
solid. Mp: 235e237 ꢁC. IR (KBr): 3331, 1679, 1634 cm
.
1H NMR
(CDCl3, 600 MHz):
d 7.76e6.87 (m, 10H, AreH and NH), 5.53 (s,
1H, CH), 4.25e4.20 (m, 2H, OCH2), 3.16 (s, 3H, CH3), 2.61 (s, 3H,
4.4.3. 1-Ethoxycarbonyl-6-isopropylamino-2-methyl-3,11b-dihydro-
4H-pyrimido[1,6-c]quinazoline-4-thione (4c). Operation as above
with isopropylisocyanate (0.09 g, 1 mmol) at refluxing temperature
for 4 h, compound 4c (0.30 g, 85%) was also isolated as light yellow
CH3), 1.20 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d
165.8, 151.2, 149.9, 145.2, 143.2, 138.8, 128.7, 128.6, 127.3, 123.4,
123.2, 123.0, 122.6, 119.6, 100.2, 60.6, 52.5, 30.9, 16.7, 14.1. MS m/z:
390 (Mþ, 25), 361 (26), 317 (13), 260 (11), 243 (18), 212 (20), 92
(100). Anal. Calcd for C22H22N4O3: C, 67.68; H, 5.68; N, 14.35.
Found: C, 67.54; H, 5.75; N, 14.21.
solid. Mp: 216e218 ꢁC. IR (KBr): 3365, 3124, 2982, 1700, 1646 cmꢀ1
.
1H NMR (CDCl3, 600 MHz):
d 7.88 (s, 1H, NH), 7.26e6.79 (m, 4H,
AreH), 5.51 (s, 1H, CH), 5.17 (s, 1H, NH), 4.28e4.19 (m, 3H, OCH2 and
NCH), 2.39 (s, 3H, CH3), 1.38 (d, J¼6.6 Hz, 3H, CH3), 1.30 (d, J¼6.6 Hz,
3H, CH3), 1.22 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
4.4.8. 1-Ethoxycarbonyl-2-methyl-3-phenyl-6-phenylamino-3,11b-
dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (4h). Operation as
above with iminophosphorane 2e (0.61 g, 1 mmol) at room tem-
perature for 3 h, compound 4h (0.34 g, 75%) was also isolated as
white solid. Mp: 206e208 ꢁC. 1H NMR (CDCl3, 400 MHz):
d
175.3, 165.4, 148.0, 143.7, 143.4, 128.8, 127.2, 122.7, 122.6, 122.5,
99.5, 60.6, 54.3, 44.0, 22.8, 21.7, 17.6, 14.1. MS m/z: 358 (Mþ, 100),
325 (21%), 301 (23%), 269 (26%), 226 (95%), 184 (53%), 169 (46%).

8156
W.-J. Li et al. / Tetrahedron 66 (2010) 8151e8159
d
7.69e6.97 (m, 15H, AreH and NH), 5.68 (s, 1H, CH), 4.24 (q,
75 (16), 56 (95). Anal. Calcd for C22H21ClN4O3:, C, 62.19; H, 4.98; N,
13.19. Found: C, 62.16; H, 4.73; N, 13.28.
J¼7.2 Hz, 2H, OCH2), 2.20 (s, 3H, CH3), 1.21 (t, J¼7.2 Hz, 3H, CH3). 13
C
NMR (CDCl3, 100 MHz):
d 165.6, 150.6, 149.5, 145.1, 143.3, 138.8,
136.6, 129.2, 129.1, 129.0, 128.6, 128.4, 127.2, 123.4, 123.0, 122.9,
122.4, 119.7, 101.1, 60.6, 53.1, 18.5, 14.1. MS m/z: 452 (Mþꢀ1, 26), 423
(13), 378 (12), 258 (10), 145 (21), 118 (66), 77 (100). Anal. Calcd for
C27H24N4O3: C, 71.67; H, 5.35; N, 12.38. Found: C, 71.72; H, 5.30;
N, 12.24.
4.4.13. 6-(4-Chlorophenylamino)-2-methyl-3-phenyl-1-ethoxy-
carbonyl-3,11b-dihydro-4H-pyrimido[1,6-c]quinazolin-4-one
(4m). Operation as above with iminophosphorane 2e (0.61 g,
1 mmol) and 4-chlorophenylisocyanate (0.15 g, 1 mmol) at room
temperature for 2 h, compound 4m (0.34 g, 69%) was also isolated
as white solid. Mp: 153e155 ꢁC. IR (KBr): 3304, 1675, 1631 cmꢀ1. 1H
4.4.9. 1-Ethoxycarbonyl-6-isopropylamino-2-methyl-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (4i). Operation
as above with iminophosphorane 2e (0.61 g, 1 mmol) and iso-
propylisocyanate (0.09 g, 1 mmol) at refluxing temperature for 4 h,
compound 4i (0.27 g, 64%) was also isolated as white solid. Mp:
200e202 ꢁC. IR (KBr): 3340, 2972, 1693, 1629 cmꢀ1. 1H NMR (CDCl3,
NMR (CDCl3, 400 MHz): d 7.64e7.00 (m, 14H), 5.66 (s, 1H), 4.26 (q,
J¼7.2 Hz, 2H), 2.21 (s, 3H), 1.23 (t, J¼7.2 Hz, 3H). MS m/z: 486 (Mþ,
100), 457 (69), 412 (31), 275 (22), 118 (59), 77 (35). Anal. Calcd for
C27H23ClN4O3: C, 66.60; H, 4.76; N, 11.51. Found: C, 66.75; H, 4.54;
N, 11.78.
400 MHz):
d
7.38e6.92 (m, 9H, AreH), 5.55 (s, 1H, CH), 5.16 (d,
4.4.14. 2,3-Dimethyl-1-ethoxycarbonyl-6-(4-fluorophenylamino)-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (4n). Operation
as above with iminophosphorane 2d (0.55 g, 1 mmol) and 4-fluo-
rophenylisocyanate (0.14 g, 1 mmol) at room temperature for 1 h,
compound 4n (0.25 g, 62%) was also isolatedꢀa1s white solid. Mp:
J¼8.0 Hz, 1H, NH), 4.30e4.19 (m, 3H, OCH2 and NCH), 2.18 (s, 3H,
CH3), 1.27 (d, J¼6.8 Hz, 6H, 2CH3), 1.20 (t, J¼7.2 Hz, 3H, CH3). 13C
NMR (CDCl3, 100 MHz):
d 165.7, 150.4, 149.2, 148.1, 144.2, 136.9,
129.2, 128.7, 128.5, 128.4, 127.0, 122.4, 122.3, 122.2, 100.7, 60.4, 53.0,
43.5, 22.5, 21.9, 18.4, 14.0. MS m/z: 418 (Mþ, 100), 389 (56), 344 (36),
304 (30), 274 (29), 118 (87). Anal. Calcd for C24H26N4O3: C, 68.88; H,
6.26; N, 13.39. Found: C, 68.63; H, 6.12; N, 13.57.
203e204 ꢁC. IR (KBr): 3309, 1676, 1634 cm
.
1H NMR (CDCl3,
400 MHz):
d 7.72e6.87 (m, 9H), 5.52 (s, 1H), 4.25e4.21 (m, 2H),
3.16 (s, 3H), 2.62 (s, 3H), 1.20 (t, J¼7.2 Hz, 3H). MS m/z: 408 (Mþ,
100), 379 (67), 334 (48), 242 (30), 213 (22), 56 (41). Anal. Calcd for
C22H21FN4O3: C, 64.70; H, 5.18; N, 13.72. Found: C, 64.78; H, 5.33;
N, 13.57.
4.4.10. 2,3-Dimethyl-1-ethoxycarbonyl-6-isopropylamino-3,11b-
dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (4j). Operation as
above with iminophosphorane 2d (0.55 g, 1 mmol) and iso-
propylisocyanate (0.09 g, 1 mmol) at refluxing temperature for
4 h, compound 4j (0.28 g, 78%) was also isolated as white solid.
4.4.15. 1-Ethoxycarbonyl-6-(4-fluorophenylamino)-2-methyl-3-phe-
nyl-3,11b-dihydro-4H-pyrimido[1,6-c]quinazolin-4-one
(4o). Operation as above with iminophosphorane 2e (0.61 g,
1 mmol) and 4-fluorophenylisocyanate (0.14 g, 1 mmol) at room
temperature for 2 h, compound 4o (0.32 g, 69%) was also isolatedꢀa1s
Mp: 154e156 ꢁC. IR (KBr): 3366, 2974, 1685, 1631 cmꢀ1
(CDCl3, 400 MHz):
.
1H NMR
7.25e6.81 (m, 4H, AreH), 5.41 (s, 1H, CH),
d
5.02 (d, J¼8.0 Hz, 1H, NH), 4.31e4.17 (m, 3H, OCH2 and NCH), 3.13
(s, 3H, NCH3), 2.59 (s, 3H, CH3), 1.33 (d, J¼6.4 Hz, 3H, CH3), 1.29 (d,
J¼6.4 Hz, 3H, CH3), 1.18 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
white solid. Mp: 126e128 ꢁC. IR (KBr): 3312, 2981, 1677, 1635 cm
.
1H NMR (CDCl3, 400 MHz):
d 6.95e7.66 (m, 14H, AreH and NH),
100 MHz):
d
165.9, 151.2, 149.8, 148.4, 144.2, 128.4, 127.0, 122.5,
5.67 (s, 1H, CH), 4.25 (q, J¼7.2 Hz, 2H, OCH2), 2.21 (s, 3H, CH3), 1.22
122.4, 122.2, 100.2, 60.4, 52.4, 43.6, 30.7, 22.7, 22.1, 16.6, 14.1. MS
m/z: 355 (Mþꢀ1, 100), 326 (27), 286 (9), 240 (11), 44 (9). Anal.
Calcd for C19H24N4O3: C, 64.03; H, 6.79; N, 15.72. Found: C, 64.27;
H, 6.78; N, 15.53.
(t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 165.6, 159.8,
157.4, 150.9, 149.5, 145.1, 143.2, 136.7, 134.9, 129.5, 128.8, 128.7,
127.2, 123.6, 123.1, 122.5, 121.3, 121.2, 115.1, 114.9, 101.4, 60.8, 53.2,
18.5, 14.2. MS m/z: 470 (Mþ, 100), 441 (64), 396 (39), 304 (18), 275
(20), 118 (43), 77 (34). Anal. Calcd for C27H23FN4O3: C, 68.93; H,
4.93; N, 11.91. Found: C, 68.68; H, 4.74; N, 11.95.
4.4.11. 1-Ethoxycarbonyl-2-methyl-6-(3-methylphenylamino)-3,11b-
dihydro-4H-pyrimido[1,6-c]quinazoline-4-thione (4k). Operation as
above with 3-methylphenylisocyanate (0.13 g, 1 mmol) at room
temperature for 4 h, compound 4k (0.29 g, 72%) was also isolatedꢀa1s
4.4.16. 1-Ethoxycarbonyl-3-ethyl-6-isopropylamino-2-methyl-3,11b-
dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (4p). Operation as
above with iminophosphorane 2c (0.56 g, 1 mmol) and iso-
propylisocyanate (0.09 g, 1 mmol) at refluxing temperature for 4 h,
compound 4p (0.27 g, 73%) was also isolated as white solid. Mp:
white solid. Mp: 136e138 ꢁC. IR (KBr): 3393, 2979, 1635, 1588 cm
.
1H NMR (CDCl3, 400 MHz):
d 8.02 (s, 1H, NH), 7.59e6.84 (m, 9H,
AreH and NH), 5.64 (s, 1H, CH), 4.26e4.23 (m, 2H, OCH2), 2.42 (s,
3H, CH3), 2.39 (s, 3H, CH3), 1.23 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
94e96 ꢁC. IR (KBr): 3350, 2977, 1685, 1630 cmꢀ1
.
1H NMR (CDCl3,
d 7.24e6.81 (m, 4H, AreH), 5.37 (s, 1H, CH), 5.01 (d,
(CDCl3, 100 MHz):
d
175.5, 165.3, 145.1, 143.8, 142.6, 138.8, 137.9,
400 MHz):
128.9, 128.8, 127.5, 124.6, 123.7, 123.4, 122.8, 120.4, 117.1, 99.7, 60.8,
54.4, 21.6, 17.8, 14.2. MS m/z: 406 (Mþ, 1), 376 (7), 275 (86), 216 (34),
170 (40), 128 (86), 76 (100). Anal. Calcd for C22H22N4O2S: C, 65.00;
H, 5.46; N, 13.78. Found: C, 65.24; H, 5.32; N, 13.85.
J¼7.6 Hz, 1H, NH), 4.31e4.16 (m, 3H, OCH2 and NCH), 3.70e3.63 (m,
2H, NCH2), 2.61 (s, 3H, CH3), 1.37e1.09 (m, 12H, 4CH3). 13C NMR
(CDCl3, 100 MHz):
d 166.0, 150.6, 149.2, 148.6, 144.1, 128.3, 127.1,
122.4, 122.3, 122.2, 100.4, 60.3, 52.4, 43.5, 38.6, 22.7, 22.1, 15.9, 14.6,
14.1. MS m/z: 370 (Mþ, 20), 341 (6), 299 (8), 227 (16), 69 (100). Anal.
Calcd for C20H26N4O3: C, 64.84; H, 7.07; N, 15.12. Found: C, 64.93; H,
7.21; N, 15.04.
4.4.12. 6-(4-Chlorophenylamino)-2,3-dimethyl-1-ethoxycarbonyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (4l). Operation
as above with iminophosphorane 2d (0.55 g, 1 mmol) and
4-chlorophenylisocyanate (0.15 g, 1 mmol) at room temperature for
1 h, compound 4l (0.25 g, 60%) was also isolateꢀd1as white solid. Mp:
4.4.17. 1-Ethoxycarbonyl-2-methyl-3-phenyl-6-phenyl amino-3,11b-
dihydro-4H-pyrimido[1,6-c]quinazoline-4-thione (4q). Operation as
above with iminophosphorane 2f (0.63 g, 1 mmol) at room tem-
perature for 2 h, compound 4q (0.34 g, 72%) was also isolated ꢀa1s
white solid. Mp: 224e225 ꢁC. IR (KBr): 3410, 2982, 1681, 1637 cm
.
204e205 ꢁC. IR (KBr): 3328, 1680, 1634 cm
.
1H NMR (CDCl3,
400 MHz):
d
7.70 (d, J¼8.8 Hz, 2H, AreH), 7.38 (s, 1H, NH),
7.30e6.87 (m, 6H, AreH), 5.52 (s, 1H, CH), 4.24e4.21 (m, 2H, OCH2),
3.16 (s, 3H, NCH3), 2.62 (s, 3H, CH3), 1.20 (t, J¼7.2 Hz, 3H, CH3). 13
C
1H NMR (CDCl3, 400 MHz):
d 7.75e6.73 (m, 15H, AreH and NH),
NMR (CDCl3, 100 MHz):
d
165.7, 151.3, 149.8, 144.9, 142.9, 137.6,
5.64 (s, 1H, CH), 4.30e4.24 (m, 2H, OCH2), 2.21 (s, 3H, CH3), 1.24 (t,
128.7, 128.6, 127.8, 127.2, 123.6, 123.1, 122.7, 120.6, 100.4, 60.7, 52.5,
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 179.8, 165.6, 147.4,
147.0,143.1,140.5,138.5,130.7,129.6,128.9,128.7,128.4,127.4,123.7,
30.9, 16.7, 14.2. MS m/z: 424 (Mþ, 100), 395 (56), 350 (48), 242 (28),

W.-J. Li et al. / Tetrahedron 66 (2010) 8151e8159
8157
123.4, 123.3, 122.4, 119.8, 104.0, 60.9, 53.6, 18.8, 14.1. MS m/z: 469
(Mþþ1, 23), 360 (11), 349 (10), 118 (23), 77 (100). Anal. Calcd for
C27H24N4O2S: C, 69.21; H, 5.16; N, 11.96. Found: C, 69.15; H, 5.28;
N, 11.73.
C21H19N3O2S: C, 66.82; H, 5.07; N, 11.13. Found: C, 66.85; H, 5.21;
N, 11.06.
4.6.2. 6-(3-Chlorophenyl)-1-ethoxycarbonyl-2-methyl-3,11b-dihy-
dro-4H-pyrimido[1,6-c]quinazoline-4-thione (8b). Operation as
above with 3-chlorobenzoyl chloride (0.18 g, 1 mmol) for 4 h, 8b
(0.25 g, 61%) was also isolated as white solid. Mp: 267e268 ꢁC.
4.4.18. 1-Ethoxycarbonyl-6-isopropylamino-2-methyl-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazoline-4-thione
(4r). Operation as above with iminophosphorane 2f (0.63 g,
1 mmol) isopropylisocyanate (0.09 g, 1 mmol) at refluxing tem-
perature for 4 h, compound 4r (0.33 g, 77%) was also isolated ꢀa1s
1H NMR (CDCl3, 600 MHz):
d 8.10e6.98 (m, 9H, AreH and NH),
5.49 (s, 1H, CH), 4.27 (q, J¼6.6 Hz, 2H, OCH2), 2.46 (s, 3H, CH3),
1.26 (t, J¼7.2 Hz, 3H, CH3). MS m/z: 411 (Mþ, 100), 382 (37), 365
(48), 337 (44), 279 (35), 215 (19), 83 (17). Anal. Calcd for
C21H18ClN3O2S: C, 61.23; H, 4.40; N, 10.20. Found: C, 61.43; H,
4.56; N, 10.14.
white solid. Mp: 170e172 ꢁC. IR (KBr): 3386, 2974, 1740, 1635 cm
.
1H NMR (CDCl3, 400 MHz):
d 7.44e6.71 (m, 9H, AreH), 5.51 (s, 1H,
CH), 4.85 (d, J¼7.6 Hz, 1H, NH), 4.29e4.22 (m, 3H, OCH2 and NCH),
2.18 (s, 3H, CH3), 1.35e1.22 (m, 9H, 3CH3). 13C NMR (CDCl3,
100 MHz):
d
180.0, 165.7, 150.0, 147.3, 144.1, 140.7, 130.7, 129.6,
4.6.3. 2,3-Dimethyl-1-ethoxycarbonyl-6-phenyl-3,11b-dihydro-4H-
pyrimido[1,6-c]quinazolin-4-one (8c). Operation as above with
iminophosphorane 2d (0.55 g, 1 mmol) for 6 h, 8c (0.30 g, 81%)
was also isolated as white solid. Mp: 156e157 ꢁC. 1H NMR (CDCl3,
128.8, 128.6, 127.2, 122.9, 122.6, 122.2, 104.0, 60.8, 53.6, 44.0, 22.9,
21.7, 18.8, 14.2. MS m/z: 434 (Mþ, 1), 220 (2), 195 (3), 135 (5), 118
(20), 77 (100), 43 (69). Anal. Calcd for C24H26N4O2S: C, 66.33; H,
6.03; N, 12.89. Found: C, 66.26; H, 6.17; N, 12.81.
400 MHz):
d 8.09e6.97 (m, 9H, AreH), 5.44 (s, 1H, CH), 4.24 (q,
J¼7.2 Hz, 2H, OCH2), 3.13 (s, 3H, NCH3), 2.67 (s, 3H, CH3), 1.21 (t,
4.5. Synthesis of pyrimido[1,6-c]quinazolin-4-ones 6
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 165.9, 154.6,
150.8, 150.4, 142.4, 134.7, 131.2, 129.0, 128.5, 128.4, 128.2, 126.9,
125.0, 122.7, 99.7, 60.5, 51.8, 30.6, 16.9, 14.1. MS m/z: 375 (Mþ,
100), 346 (99), 301 (93), 271 (23), 178 (17), 103 (14), 77 (11). Anal.
Calcd for C22H21N3O3: C, 70.38; H, 5.64; N, 11.19. Found: C, 70.14;
H, 5.87; N, 11.15.
4.5.1. 1-Ethoxycarbonyl-2-methyl-7,11b-dihydro-4H-pyrimido[1,6-c]-
quinazoline-4,6(1H)-dithione (6a). To a solution of iminophos-
phorane 2b (0.55 g, 1 mmol) in CH3CN (5 mL) was added CS2
(5.0 mL) at room temperature. After the reaction mixture was
refluxed for 12 h, K2CO3 (0.014 g, 0.1 mmol) was added and the
mixture was stirred for 2 h. The white precipitated solid was col-
lected by filtration and washed with ethanol to give 0.29 g (86%) of
6a as white solid. Mp: 195e197 ꢁC. IR (KBr): 3445, 3289, 3143,
4.6.4. 3,6-Diphenyl-1-ethoxycarbonyl-2-methyl-3,11b-dihydro-4H-
pyrimido[1,6-c]quinazolin-4-one (8d). Operation as above with
iminophosphorane 2e (0.61 g, 1 mmol) for 4 h, 8d (0.37 g, 84%)
was also isolated as white solid. Mp: 210e211 ꢁC. 1H NMR (CDCl3,
3000, 1668, 1520 cmꢀ1 1H NMR (DMSO-d6, 600 MHz):
. d 12.97 (s,
1H, NH), 11.06 (s, 1H, NH), 7.35e6.93 (m, 4H, AreH), 5.41 (s, 1H, CH),
4.17e4.13 (m, 2H, OCH2), 2.38 (s, 3H, CH3),1.15 (t, J¼7.2 Hz, 3H, CH3).
400 MHz): d 8.10e6.82 (m, 14H, AreH), 5.55 (s, 1H, CH), 4.31e4.23
(m, 2H, OCH2), 2.28 (s, 3H, CH3), 1.24 (t, J¼7.2 Hz, 3H, CH3). 13C
13C NMR (DMSO-d6, 100 MHz):
d
179.1, 175.2, 164.8, 145.9, 135.8,
NMR (CDCl3, 100 MHz): d 165.9, 154.6, 150.4, 149.9, 142.6, 136.7,
129.0, 127.5, 124.9, 123.5, 115.8, 97.6, 60.0, 52.9, 16.9, 14.1. MS m/z:
334 (Mþþ1, 14), 300 (47), 259 (100), 225 (47), 140 (48). Anal. Calcd
for C15H15N3O2S2: C, 54.03; H, 4.53; N, 12.60. Found: C, 54.16; H,
4.51; N, 12.36.
134.7, 131.3, 130.1, 129.1, 128.9, 128.8, 128.6, 128.4, 128.2, 127.2,
125.2, 122.6, 100.8, 60.7, 52.3, 18.8, 14.2. MS m/z: 437 (Mþ, 38),
408 (100), 362 (57), 271 (51), 243 (63), 180 (36), 118 (27). Anal.
Calcd for C27H23N3O3: C, 74.12; H, 5.30; N, 9.60. Found: C, 74.15; H,
5.46; N, 9.41.
4.5.2. 1-Ethoxycarbonyl-2-methyl-6-thioxo-3,6,7,11b-tetrahydro-4H-
pyrimido[1,6-c]quinazolin-4-one (6b). Operation as above with
iminophosphorane 2a (0.54 g, 1 mmol), compound 6b (0.26 g,
82%) was also isolated as white solid. Mp: 252e254 ꢁC. IR (KBr):
4.6.5. 2,3-Dimethyl-1-ethoxycarbonyl-6-(4-methylphenyl)-3,11b-di-
hydro-4H-pyrimido[1,6-c]quinazolin-4-one (8e). Operation as above
with iminophosphorane 2d (0.55 g, 1 mmol) and 4-methylbenzoyl
chloride (0.15 g, 1 mmol) for 8 h, 8e (0.31 g, 80%) was also isolated
3427, 3160, 2994, 1668, 1706, 1664 cmꢀ1 1H NMR (DMSO-d6,
.
600 MHz):
d
12.63 (s, 1H), 9.94 (s, 1H), 7.36e6.90 (m, 4H), 5.33 (s,
as white solid. Mp: 199e200 ꢁC. 1H NMR (CDCl3, 400 MHz):
d 7.96
1H), 4.15e4.10 (m, 2H), 2.34 (s, 3H), 1.12 (t, J¼7.2 Hz, 3H). 13C NMR
(d, J¼8.4 Hz, 2H, AreH), 7.47e6.96 (m, 6H, AreH), 5.42 (s, 1H, CH),
4.28e4.19 (m, 2H, OCH2), 3.12 (s, 3H, NCH3), 2.67 (s, 3H, CH3), 2.41
(s, 3H, CH3), 1.21 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
(DMSO-d6, 100 MHz):
d 178.2, 164.8, 149.1, 147.8, 136.0, 128.7,
127.1, 124.6, 123.2, 115.3, 94.9, 59.7, 53.4, 17.6, 14.1. MS m/z: 317
(Mþ, 11), 284 (19), 243 (100), 154 (66), 136 (54). Anal. Calcd for
C15H15N3O3S: C, 56.77; H, 4.76; N, 13.24. Found: C, 56.88; H, 4.72;
N, 13.28.
d
166.0, 154.6, 150.8, 150.4, 142.6, 141.7, 132.0, 129.2, 129.0, 128.4,
128.2, 126.7, 124.9, 122.7, 99.7, 60.5, 51.8, 30.6, 21.5, 16.9, 14.1. MS
m/z: 389 (Mþ, 91), 360 (97), 301 (100), 285 (18), 223 (22), 56 (65).
Anal. Calcd for C23H23N3O3: C, 70.93; H, 5.95; N, 10.79. Found: C,
70.71; H, 5.74; N, 10.81.
4.6. Synthesis of pyrimido[1,6-c]quinazolin-4-ones 8
4.6.1. 1-ethoxycarbonyl-2-methyl-6-phenyl-3,11b-dihydro-4H-pyr-
4.6.6. 1-Ethoxycarbonyl-2-methyl-6-(4-methylphenyl)-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (8f). Operation
as above with iminophosphorane 2e (0.61 g, 1 mmol) and 4-
methylbenzoyl chloride (0.15 g, 1 mmol) for 8 h, 8f (0.37 g, 81%)
was also isolated as white solid. Mp: 205e206 ꢁC. 1H NMR (CDCl3,
imido[1,6-c]quinazoline-4-thione (8a). To
a solution of imino-
phosphorane 2b (0.55 g, 1 mmol) and benzoyl chloride (0.14 g,
1 mmol) in CH3CN (10 mL) was added NEt3 (0.28 g, 2 mmol). The
mixture was stirred at reflux temperature for 6 h and then cooled
to room temperature. The white precipitated solid was collected
by filtration and recrystallized from methylene dichloride/pe-
troleum ether to give 0.25 g (65%) of 8a as yellow crystals. Mp:
400 MHz):
d
7.98 (d, J¼8.4 Hz, 2H, AreH), 7.49e6.80 (m, 11H,
AreH), 5.53 (s, 1H, CH), 4.30e4.24 (m, 2H, OCH2), 2.39 (s, 3H, CH3),
2.27 (s, 3H, CH3), 1.24 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
259e261 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
8.10e6.96 (m, 10H,
100 MHz): d 166.0, 154.7, 150.5, 150.0, 142.9, 141.8, 136.9, 132.1,
AreH and NH), 5.50 (s, 1H, CH), 4.26 (q, J¼7.2 Hz, 2H, OCH2), 2.46
(s, 3H, CH3), 1.24 (t, J¼7.2 Hz, 3H, CH3). MS m/z: 377 (Mþ, 100), 348
(61), 304 (64), 271 (22), 245 (61), 77 (56), 42 (63). Anal. Calcd for
129.4, 129.3, 129.1, 128.6, 128.5, 128.4, 128.3, 127.0, 125.2, 122.6,
100.9, 60.7, 52.4, 21.6, 18.9, 14.2. MS m/z: 452 (Mþþ1, 12), 422 (79),
375 (36), 259 (57), 220 (65), 213 (60),193 (100),118 (52). Anal. Calcd

8158
W.-J. Li et al. / Tetrahedron 66 (2010) 8151e8159
for C28H25N3O3: C, 74.48; H, 5.58; N, 9.31. Found: C, 74.37; H, 5.75;
N, 9.38.
white solid. Mp: 201e203 ꢁC. 1H NMR (CDCl3, 400 MHz):
8.10e6.97 (m, 8H, AreH), 5.42 (s, 1H, CH), 4.27e4.20 (m, 2H,
OCH2), 3.12 (s, 3H, NCH3), 2.67 (s, 3H, CH3), 1.21 (t, J¼7.2 Hz, 3H,
CH3). 13C NMR (CDCl3, 100 MHz):
166.0, 153.6, 150.8, 150.5, 142.4,
131.1, 130.5, 130.4, 129.0, 128.9, 128.6, 127.1, 125.1, 122.8, 115.7, 115.5,
100.0, 60.6, 51.9, 30.7, 17.0, 14.2. MS m/z: 393 (Mþ, 21), 364 (42), 348
(6), 262 (13), 197 (12), 56 (100). Anal. Calcd for C22H20FN3O3: C,
67.17; H, 5.12; N, 10.68. Found: C, 67.36; H, 5.02; N, 10.89.
d
4.6.7. 6-(2-Chlorophenyl)-2,3-dimethyl-1-ethoxycarbonyl-3,11b-di-
hydro-4H-pyrimido[1,6-c]quinazolin-4-one (8g). Operation as above
with iminophosphorane 2d (0.55 g, 1 mmol) and 2-chlorobenzoyl
chloride (0.18 g, 1 mmol) for 8 h, 8g (0.31 g, 76%) was also isolated
as white solid. Mp: 156e157 ꢁC. 1H NMR (CDCl3, 400 MHz):
d
d
7.90e6.98 (m, 8H, AreH), 5.65 (s, 1H, CH), 4.32e4.19 (m, 2H,
OCH2), 3.11 (s, 3H, NCH3), 2.63 (s, 3H, CH3), 1.22 (t, J¼7.2 Hz, 3H,
CH3). 13C NMR (CDCl3, 100 MHz):
165.8, 152.7, 149.8, 148.4, 141.9,
135.0, 132.0, 131.3, 130.8, 129.7, 128.8, 128.2, 127.2, 126.7, 124.6,
122.9, 98.9, 60.4, 51.7, 30.3, 16.8, 13.9. MS m/z: 409 (Mþ, 60), 378
(100), 336 (50), 301 (25), 55 (88). Anal. Calcd for C22H20ClN3O3: C,
64.47; H, 4.92; N, 10.25. Found: C, 64.68; H, 4.74; N, 10.07.
4.6.13. 3,6-diphenyl-1-ethoxycarbonyl-2-methyl-3,11b-dihydro-4H-
pyrimido[1,6-c]quinazoline-4-thione (8m). Operation as above with
iminophosphorane 2f (0.63 g, 1 mmol) for 6 h, 8m (0.40 g, 88%) was
also isolated as white solid. Mp: 230e232 ꢁC. 1H NMR (CDCl3,
d
400 MHz):
d 8.19e6.72 (m, 14H, AreH), 5.49 (s, 1H, CH), 4.30e4.22
(m, 2H, OCH2), 2.27 (s, 3H, CH3), 1.23 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
(CDCl3, 100 MHz):
d 179.0, 165.8, 155.8, 148.1, 142.5, 140.1, 134.8,
4.6.8. 6-(2-Chlorophenyl)-1-ethoxycarbonyl-2-methyl-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (8h). Operation
as above with iminophosphorane 2e (0.61 g, 1 mmol) and
2-chlorobenzoyl chloride (0.18 g, 1 mmol) for 8 h, 8h (0.37 g, 79%)
was also isolated as white solid. Mp: 207e208 ꢁC. 1H NMR (CDCl3,
131.2, 130.9, 129.5, 128.9, 128.7, 128.5, 128.2, 128.0, 127.2, 125.3,
122.5, 103.3, 60.9, 52.8, 19.0, 14.2. MS m/z: 453 (Mþ, 38), 308 (53),
188 (47),118 (100), 77 (86). Anal. Calcd for C27H23N3O2S: C, 71.50; H,
5.11; N, 9.26. Found: C, 71.67; H, 5.01; N, 9.03.
400 MHz):
d
7.88e6.94 (m, 13H, AreH), 5.76 (s, 1H, CH), 4.34e4.22
4.6.14. 1-Ethoxycarbonyl-2-methyl-6-(4-nitrophenyl)-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazoline-4-thione
(8n). Operation as above with iminophosphorane 2f (0.63 g,
1 mmol) and 4-nitrobenzoyl chloride (0.16 g, 1 mmol) for 4 h, 8n
(0.45 g, 90%) was also isolated as yellow solid. Mp: 280e282 ꢁC. 1H
(m, 2H, OCH2), 2.22 (s, 3H, CH3), 1.24 (t, J¼7.2 Hz, 3H, CH3). MS m/z:
471 (Mþ, 47), 422 (100), 397 (43), 250 (53), 215 (76), 118 (44). Anal.
Calcd for C27H22ClN3O3: C, 68.71; H, 4.70; N, 8.90. Found: C, 68.48;
H, 4.84; N, 8.75.
NMR (CDCl3, 400 MHz):
CH), 4.36e4.24 (m, 2H, OCH2), 2.28 (s, 3H, CH3),1.25 (t, J¼7.2 Hz, 3H,
CH3). 13C NMR (CDCl3, 100 MHz):
178.8, 165.6, 153.7, 148.6, 148.0,
142.0, 141.0, 139.8, 131.1, 129.6, 129.2, 128.9, 128.8, 128.7, 128.4,
125.8, 123.8, 122.8, 103.5, 61.1, 52.8, 19.1, 14.2. MS m/z: 498 (Mþ, 47),
425 (67), 390 (65), 290 (45), 244 (39), 118 (71), 77 (100). Anal. Calcd
for C27H22N4O4S: C, 65.05; H, 4.45; N, 11.24. Found: C, 65.28; H,
4.57; N, 11.18.
d 8.33e6.72 (m, 13H, AreH), 5.51 (s, 1H,
4.6.9. 6-(3-Chlorophenyl)-2,3-dimethyl-1-ethoxycarbonyl-3,11b-di-
hydro-4H-pyrimido[1,6-c]quinazolin-4-one (8i). Operation as above
with iminophosphorane 2d (0.55 g, 1 mmol) and 3-chlorobenzoyl
chloride (0.18 g,1 mmol) for 4 h, 8i (0.33 g, 81%) was also isolated as
d
white solid. Mp: 190e192 ꢁC. 1H NMR (CDCl3, 400 MHz):
d 8.05 (s,
1H, AreH), 7.95 (d, J¼7.6 Hz, 1H, AreH), 7.49e6.97 (m, 6H, AreH),
5.43 (s, 1H, CH), 4.26e4.23 (m, 2H, OCH2), 3.13 (s, 3H, NCH3), 2.68 (s,
3H, CH3), 1.22 (t, J¼7.2 Hz, 3H, CH3). MS m/z: 410 (Mþþ1, 73), 379
(100), 335 (69), 301 (25), 244 (13), 212 (12), 136 (12), 77 (13). Anal.
Calcd for C22H20ClN3O3: C, 64.47; H, 4.92; N, 10.25. Found: C, 64.63;
H, 4.76; N, 10.28.
4.6.15. 1-Ethoxycarbonyl-2-methyl-6-(4-nitrophenyl)-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazoline-4-thione
(8o). Operation as above with iminophosphorane 2f (0.63 g,
1 mmol) and 3-chlorobenzoyl chloride (0.18 g, 1 mmol) for 4 h, 8o
(0.38 g, 77%) was also isolated as white solid. Mp: 173e175 ꢁC. 1H
4.6.10. 6-(3-Chlorophenyl)-1-ethoxycarbonyl-2-methyl-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazolin-4-one (8j). Operation
as above with iminophosphorane 2e (0.61 g, 1 mmol) and
3-chlorobenzoyl chloride (0.18 g, 1 mmol) for 4 h, 8j (0.38 g, 81%)
was also isolated as white solid. Mp: 154e155 ꢁC. 1H NMR (CDCl3,
NMR (CDCl3, 400 MHz):
d
8.14 (s, 1H, AreH), 8.04 (d, J¼7.2 Hz, 1H,
AreH), 7.54e6.71 (m, 11H, AreH), 5.46 (s, 1H, CH), 4.29e4.23 (m,
2H, OCH2), 2.27 (s, 3H, CH3), 1.24 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
(CDCl3, 100 MHz):
d 179.0, 165.6, 154.5, 148.0, 142.2, 139.9, 136.8,
400 MHz):
d
8.05 (s, 1H, AreH), 7.98 (d, J¼7.6 Hz, 1H, AreH),
134.4, 131.1, 130.6, 129.7, 129.5, 129.0, 128.7, 128.0, 127.8, 127.6,
126.2, 125.4, 122.6, 103.4, 60.9, 52.8, 19.0, 14.1. MS m/z: 487 (Mþ, 12),
307 (61), 188 (22), 118 (82), 77 (100), 44 (39). Anal. Calcd for
C27H22ClN3O2S: C, 66.45; H, 4.54; N, 8.61. Found: C, 66.31; H, 4.68;
N, 8.87.
7.51e6.82 (m,11H, AreH), 5.54 (s,1H, CH), 4.31e4.26 (m, 2H, OCH2),
2.28 (s, 3H, CH3), 1.25 (t, J¼7.2 Hz, 3H, CH3). MS m/z: 471 (Mþ, 63),
441 (100), 397 (67), 280 (41), 210 (20), 118 (52). Anal. Calcd for
C27H22ClN3O3: C, 68.71; H, 4.70; N, 8.90. Found: C, 68.54; H, 4.85; N,
8.78.
4.6.16. 1-Ethoxycarbonyl-2-methyl-6-(4-methylphenyl)-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazoline-4-thione
(8p). Operation as above with iminophosphorane 2f (0.63 g,
1 mmol) and 4-methylbenzoyl chloride (0.15 g, 1 mmol) for 8 h,
8p (0.35 g, 74%) was also isolated as white solid. Mp: 172e173 ꢁC.
4.6.11. 2,3-Dimethyl-1-ethoxycarbonyl-6-(2-fluorophenyl)-3,11b-di-
hydro-4H-pyrimido[1,6-c]quinazolin-4-one (8k). Operation as above
with iminophosphorane 2d (0.55 g, 1 mmol) and 2-fluorobenzoyl
chloride (0.14 g, 1 mmol) for 4 h, 8k (0.31 g, 80%) was also isolated
as white solid. Mp: 195e196 ꢁC. 1H NMR (CDCl3, 400 MHz):
1H NMR (CDCl3, 400 MHz):
d
8.07 (d, J¼8.0 Hz, 2H, AreH),
d
8.33e6.99 (m, 8H, AreH), 5.48 (s, 1H, CH), 4.31e4.21 (m, 2H,
7.52e6.70 (m, 11H, AreH), 5.47 (s, 1H, CH), 4.28e4.23 (m, 2H,
OCH2), 2.40 (s, 3H, CH3), 2.26 (s, 3H, CH3), 1.23 (t, J¼7.2 Hz, 3H,
CH3). MS m/z: 468 (Mþþ1, 6), 118 (58), 104 (24), 92 (10), 77 (100).
Anal. Calcd for C28H25N3O2S: C, 71.92; H, 5.39; N, 8.99. Found: C,
71.84; H, 5.48; N, 8.82.
OCH2), 3.13 (s, 3H, NCH3), 2.68 (s, 3H, CH3), 1.23 (t, J¼7.2 Hz, 3H,
CH3). MS m/z: 393 (Mþ, 2), 307 (11), 184 (21), 118 (100), 77 (71).
Anal. Calcd for C22H20FN3O3: C, 67.17; H, 5.12; N, 10.68. Found: C,
67.39; H, 5.04; N, 10.41.
4.6.12. 2,3-Dimethyl-1-ethoxycarbonyl-6-(4-fluorophenyl)-3,11b-di-
hydro-4H-pyrimido[1,6-c]quinazolin-4-one (8l). Operation as above
with iminophosphorane 2d (0.55 g, 1 mmol) and 4-fluorobenzoyl
chloride (0.14 g,1 mmol) for 4 h, 8l (0.25 g, 63%) was also isolated as
4.6.17. 6-(2-chlorophenyl)-1-ethoxycarbonyl-2-methyl-3-phenyl-
3,11b-dihydro-4H-pyrimido[1,6-c]quinazoline-4-thione
(8q). Operation as above with iminophosphorane 2f (0.63 g,
1 mmol) and 2-chlorobenzoyl chloride (0.18 g, 1 mmol) for 6 h, 8q

W.-J. Li et al. / Tetrahedron 66 (2010) 8151e8159
8159
(0.38 g, 92%) was also isolated as white solid. Mp: 205e206 ꢁC. 1H
NMR (CDCl3, 400 MHz):
8.06 (d, J¼7.2 Hz,1H), 7.56e6.82 (m,12H),
5.73 (s, 1H), 4.35e4.23 (m, 2H), 2.22 (s, 3H), 1.24 (t, J¼7.2 Hz, 3H).
13C NMR (CDCl3, 100 MHz):
176.0, 165.9, 153.9, 147.3, 142.0, 140.2,
134.9, 133.0, 131.1, 130.6, 130.0, 129.3, 129.2, 128.7, 128.6, 128.2,
127.6, 126.7, 125.3, 122.5, 102.1, 60.9, 52.9, 19.2, 14.1. MS m/z: 487
(Mþ, 19), 425 (4), 384 (100), 175 (6), 137 (7), 118 (24), 89 (20), 77
(100). Anal. Calcd for C27H22ClN3O2S: C, 66.45; H, 4.54; N, 8.61.
Found: C, 66.65; H, 4.69; N, 8.57.
(62). Anal. Calcd for C15H15N3O3S: C, 56.77; H, 4.76; N, 13.24.
Found: C, 56.94; H, 4.70; N, 13.12.
d
d
5. Crystallographic material
Compound 8a: formula C21H19N3O2S, yellow crystal. The crystal is
ꢀ
of monoclinic, space group P2(1)/n with a¼9.6802(6) A, b¼19.7155
3
ꢀ
ꢀ
ꢀ
(10) A, c¼10.3032(6) A,
b
¼104.431(1)ꢁ, V¼1904.32(19) A , Z¼4,
Dc¼1.317 g/cm3, F(000)¼792,
m
¼0.191 mmꢀ1
,
R¼0.0418 and
wR¼0.0449 for 4134 observed reflections with I>2
s(I0). Crystallo-
4.7. Isolation of some of the intermediates 3 and 5
graphic data for 8a have been deposited in the Cambridge Crystal-
lographic Data Center as supplementary publication numbers CCDC
761594. Copies of the data may be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.7.1. 5-Ethoxycarbonyl-6-methyl-4-(2-((phenylimino)methyl-
eneamino)phenyl)-3,4-dihydropyrimidin-2(1H)-one (3b). To a stir-
red solution of azide 1a (0.30 g, 1 mmol) in CH2Cl2 (10 mL) was
added dropwise triphenylphosphine (0.26 g, 1 mmol) in CH2Cl2
(5 mL) at room temperature. After the reaction mixture was stirred
for 2 h at ambient temperature, phenylisocyanate (0.12 g, 1 mmol)
was added under nitrogen at room temperature. After stirred for
2 h at room temperature, the solvent was removed off under re-
duced pressure and the residue was eluted with ether/petroleum
ether through a short silica gel to give 0.26 g (68%) of carbodiimide
3b as white solid. Mp: 152e154 ꢁC. IR (KBr): 3417, 3230, 3106, 2140,
Acknowledgements
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 20772041) and
the Doctor Independent Foundation of Central China Normal Uni-
versity (No. 2009011).
1701, 1641 cmꢀ1. 1H NMR (CDCl3, 600 MHz):
d 8.02 (s,1H), 7.36e7.10
Supplementary data
(m, 9H), 5.86 (s, 1H), 5.83 (s, 1H), 4.05 (q, J¼7.2 Hz, 2H), 2.44 (s, 3H),
1.10 (t, J¼7.2 Hz, 3H). MS m/z: 376 (Mþ, 97), 347 (38), 303 (90), 284
(99), 260 (100). Anal. Calcd for C21H20N4O3: C, 67.01; H, 5.36; N,
14.88. Found: C, 67.24; H, 5.49; N, 14.81.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.08.046. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
4.7.2. 5-Ethoxycarbonyl-4-(2-((isopropylimino)methyleneamino)-
phenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (3f). Operation
as above with isopropylisocyanate (0.09 g, 1 mmol) at refluxing
temperature for 4 h, compound 3f (0.28 g, 82%) was also isolated as
white solid. Mp: 265e267 ꢁC. IR (KBr): 3227, 3103, 2124, 1692,
References and notes
1. (a) Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH: New York, NY,
2005; (b) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39, 451.
2. Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
1637 cmꢀ1. 1H NMR (CDCl3, 600 MHz):
d 8.41 (s, 1H, NH), 7.22e7.01
(m, 4H, AreH), 5.88 (s, 1H, NH), 5.78 (s, 1H, CH), 4.03 (q, J¼7.2 Hz,
2H, OCH2), 3.88e3.83 (m, 1H, NCH), 2.42 (s, 3H, CH3), 1.37 (d,
J¼6.6 Hz, 6H, CH3), 1.08 (t, J¼7.2 Hz, 3H, CH3). MS m/z: 342 (Mþ, 78),
313 (68), 277 (100), 227 (88), 226 (65), 199 (63), 183 (76). Anal.
Calcd for C18H22N4O3: C, 63.14; H, 6.48; N, 16.36. Found: C, 63.06; H,
6.62; N, 16.14.
3. (a) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043; (b) Russowsky, D.; Canto, R. F.
S.; Sanches, S. A. A.; D’Oca, M. G. M.; Fatima, A. D.; Carvalho, J. E. D. Bioorg.
Chem. 2006, 34, 173; (c) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.;
Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley, M. F. J. Med.
Chem. 1992, 35, 3254; (d) Brier, S.; Lemaire, D.; DeBonis, S.; Forest, E.; Kozielski,
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O. V.; Shivanyuk, A. N.; Tolmachev, A. A. Org. Lett. 2007, 9, 4215.
5. Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; De Brosse, C.;
Mai, S.; Truneh, A.; Faulkner, D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.;
Johnson, R. K.; Westley, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60, 1182.
6. (a) Lu, J.; Bai, Y. Synthesis 2002, 466; (b) Kumar, K. A.; Kasthuraiah, M.; Reddy, C.
S.; Reddy, C. D. Tetrahedron Lett. 2001, 42, 7873; (c) Reddy, C. V.; Mahesh, M.;
Raju, P. V. K.; Babu, T. R.; Reddy, V. V. N. Tetrahedron Lett. 2002, 43, 2657; (d)
Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270; (e) Jenner, G. Tet-
rahedron Lett. 2004, 45, 6195; (f) Ramaliga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
Synlett 2001, 863; (g) Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63,
3454.
4.7.3. 1,6-Dimethyl-5-ethoxycarbonyl-4-(2-((isopropylimino)methyl-
eneamino)phenyl)-3,4-dihydropyrimidin-2(1H)-one (3j). Operation
as above with azide 1d (0.32 g, 1 mmol) and isopropylisocyanate
(0.09 g, 1 mmol) at refluxing temperature for 4 h, compound 3j
(0.31 g, 86%) was also isolated as white solid. Mp: 124e125 ꢁC. IR
(KBr): 3417, 3244, 2978, 2137, 1679, 1629 cmꢀ1
.
1H NMR (CDCl3,
7.19e7.02 (m, 4H, AreH), 5.90 (s, 1H, NH), 5.70 (d,
400 MHz):
d
J¼3.2 Hz, 1H, CH), 4.10e4.01 (m, 2H, OCH2), 3.90e3.83 (m, 1H,
NCH), 3.18 (s, 3H, NCH3), 2.62 (s, 3H, CH3), 1.38 (d, J¼3.2 Hz, 6H,
2CH3), 1.09 (t, J¼7.2 Hz, 3H, CH3). Anal. Calcd for C19H24N4O3: C,
64.03; H, 6.79; N, 15.72. Found: C, 64.11; H, 6.67; N, 15.94.
7. Matache, M.; Dobrota, C.; Bogdan, N. D.; Dumitru, I.; Ruta, L. L.; Paraschivescu,
C. C.; Farcasanu, I. C.; Baciu, I.; Funeriu, D. P. Tetrahedron 2009, 65, 5949.
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Chem. Lett. 1999, 9, 1573; (b) Shroff, J. R.; Loev, B. U.S. Patent 4,478,834, 1984.
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44, 5188; (b) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; Santos, J. M.
Tetrahedron 2007, 63, 523; (c) Polienko, J. F.; Schanding, T.; Gatilov, Y. V.; Gri-
gor’ev, I. A.; Voinov, M. A. J. Org. Chem. 2008, 73, 502; (d) Loos, P.; Riedrich, M.;
Arndt, H.-D. Chem. Commun. 2009, 1900; (e) Marsden, S. P.; McGonagle, A. E.;
McKeever-Abbas, B. Org. Lett. 2008, 10, 2589.
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N. Y.; Liu, M. G.; Ding, M. W. J. Org. Chem. 2009, 74, 6874; (c) Ding, M. W.; Xu, S.
Z.; Zhao, J. F. J. Org. Chem. 2004, 69, 8366; (d) He, P.; Wu, J.; Nie, Y. B.; Ding, M.
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Ding, M. W. Tetrahedron 2008, 64, 9052.
4.7.4. 5-Ethoxycarbonyl-4-(2-isothiocyanatophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (5b). To a solution of iminophos-
phorane 2b (0.55 g, 1 mmol) in CH3CN (5 mL) was added CS2
(5 mL) at room temperature. After the reaction mixture was
refluxed for 12 h, the solvent was removed off under reduced
pressure and the residue was eluted with ether/petroleum ether
through a short silica gel to give 0.28 g (87%) of isothiocyanate 5b
as white solid. Mp: 247e248 ꢁC. IR (KBr): 3357, 3116, 2977, 2089,
11. (a) Sabitha, G.; Reddy, G. S. K. K.; Reddy, Ch. S.; Yadav, J. S. Synlett 2003, 858; (b)
Kantevari, S.; Bantu, R.; Nagarapu, L. ARKIVOC 2006, xvi, 136; (c) Zhu, Y.; Pan, Y.;
Huang, S. Synth. Commun. 2004, 34, 3167; (d) Ramalingan, C.; Kwak, Y.-W.
Tetrahedron 2008, 64, 5023.
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Spagnolo, P. J. Org. Chem. 1995, 60, 2254.
1698, 1635 cmꢀ1 1H NMR (CDCl3, 600 MHz):
. d 8.62 (s, 1H, NH),
7.31e7.23 (m, 4H, AreH), 5.85 (s, 1H, NH), 5.71 (s, 1H, CH), 4.03 (q,
J¼7.2 Hz, 2H, OCH2), 2.41 (s, 3H, CH3), 1.11 (t, J¼7.2 Hz, 3H, CH3).
MS m/z: 317 (Mþ, 8), 284 (82), 243 (100), 183 (86), 155 (56), 137