Synthesis, characterization and crystal structure of heterocyclic tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidinone derivatives via sequential aza-Wittig/base catalyzed cyclization

Article abstract of DOI:10.1016/j.molstruc.2018.11.091

Seventeen examples of 7-Benzyl-5,6,7,8-tetrahydropyrido [4′,3′:4,5]thieno [2,3-d]pyrimidin-4(3H) -ones were synthesized by base catalyzed reactions of nucleophilic reagents (aliphatic amines, alcohols or phenols) with carbodiimides 3, which in turn were obtained by the aza-Wittig reaction of iminophosphorane 2 with aromatic isocyanates. The compounds were fully characterized by analytical and spectroscopic techniques (FT-IR, ¹H NMR, ¹³C NMR and MS). Crystal structure determination of three tetrahydropyrido [4′,3':4,5]thieno [2,3-d]pyrimidinone derivatives has been undertaken in order to better understanding the influence of structural modifications upon overall molecular geometry and conformation. 3D supramolecular architectures are formed in the crystals by self-assembly of the molecules via stacking interactions and various hydrogen bonds. Meanwhile, crystal structure of a guanidine intermediate 4a was characterized in order to proclaim the reaction mechanism of the base catalyzed intramolecular cycloaddition.

Full text of DOI:10.1016/j.molstruc.2018.11.091

Journal of Molecular Structure 1180 (2019) 31e40
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis, characterization and crystal structure of heterocyclic
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidinone derivatives via
sequential aza-Wittig/base catalyzed cyclization
,
, *
Hong Chen a b, Ming-Guo Liu b
a Key Laboratory of Radiation Physics and Technology, Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu,
610064, China
b Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University,
Yichang, 443002, China
a r t i c l e i n f o
a b s t r a c t
Seventeen examples of 7-Benzyl-5,6,7,8-tetrahydropyrido [40,30:4,5]thieno [2,3-d]pyrimidin-4(3H) -ones
were synthesized by base catalyzed reactions of nucleophilic reagents (aliphatic amines, alcohols or
phenols) with carbodiimides 3, which in turn were obtained by the aza-Wittig reaction of iminophos-
phorane 2 with aromatic isocyanates. The compounds were fully characterized by analytical and spec-
troscopic techniques (FT-IR, 1H NMR, 13C NMR and MS). Crystal structure determination of three
tetrahydropyrido [40,3':4,5]thieno [2,3-d]pyrimidinone derivatives has been undertaken in order to
better understanding the influence of structural modifications upon overall molecular geometry and
conformation. 3D supramolecular architectures are formed in the crystals by self-assembly of the mol-
ecules via stacking interactions and various hydrogen bonds. Meanwhile, crystal structure of a guanidine
intermediate 4a was characterized in order to proclaim the reaction mechanism of the base catalyzed
intramolecular cycloaddition.
Article history:
Received 27 August 2018
Received in revised form
12 November 2018
Accepted 26 November 2018
Available online 27 November 2018
Keywords:
Crystal structure
Tetrahydropyrido[40,30:4,5]thieno[2,3-d]
pyrimidinone
Aza-Wittig reaction
Carbodiimide
Iminophosphorane
© 2018 Elsevier B.V. All rights reserved.
1. Introduction
have made synthetic studies of very attractive thienopyrimidinone
derivatives. Noteworthily, 2-amino-thieno [2,3-c]pyridine de-
The synthesis of thienopyrimidinone derivatives has attracted
considerable attention in virtue of their various important biolog-
ical activities and the unique pharmacophores of these ring systems
not only in medical chemistry but also in pesticidal chemistry area,
and much effort has been invested in the synthesis of these com-
pounds to deduce structureeactivity relationships and discover
new analogues with improved properties (Fig.1, blue). For example,
some 2-alkoxy or 2-alkyl substituted thienopyrimidinone de-
rivatives have been assigned as privileged structures in drugs
because of the remarkable pharmacological activities including
anti-plasmodial [1,2], anti-malarial [3], dual anti-inflammatory
antimicrobial [4e9], and anti-cancer [10,11]. Others exhibited
good anticonvulsant, angiotensin, or melanin-concentrating hor-
mone receptor-1 (MCH-R1) antagonistic activities [12e18]. The
widely biological activities and characteristic chemical structures
rivatives is a structural motif in numerous biological compounds
and also serves as fundamental building blocks for various appli-
cations in organic synthesis [19]. Consequently, new and direct
synthetic method to pyridothienopyrimidinones is still desirable in
synthetic organic and pharmaceutical chemistry.
The aza-Wittig reactions of vinyliminophosphoranes with
carbonyl compounds have received considerable attention due to
their efficient application in heterocyclic synthesis [20e30]. It has
provided a powerful method for the assembly of C]N double bond
under mild and neutral conditions [31e35]. Owing to its good
stability, vinyliminophosphoranes may be regarded as an equiva-
lent of the unstable enamine and it has been used in the synthesis
of various N-heterocyclic derivatives, such as dihydroquinazolines,
imidazoles, imidazolidines, and dihydropyrimidines [36e41].
Continuing our interests in multicomponent reactions and aza-
Wittig reactions of vinyliminophosphoranes [42e52], we wish to
report herein a new facile synthesis of 2-substituted derivatives of
7-benzyl-5,6,7,8-tetrahydropyrido [40,3':4,5]thieno [2,3-d]pyr-
imidin-4(3H)-ones, which were obtained by aza-Wittig reaction
* Corresponding author.
E-mail address: mgliu1966@163.com (M.-G. Liu).
https://doi.org/10.1016/j.molstruc.2018.11.091
0022-2860/© 2018 Elsevier B.V. All rights reserved.

32
H. Chen, M.-G. Liu / Journal of Molecular Structure 1180 (2019) 31e40
Fig. 1. Selected examples of biologically active thienopyrimidinones, 2-amino-thieno [2,3-c]pyridine containing compounds, and our work.
Table 1
and further reaction of the carbodiimides with nucleopilic reagents,
such as amines, alcohols or phenols. Single crystal X-ray structure
determination of three tetrahydropyrido [40,3':4,5]thieno [2,3-d]
pyrimidinone derivatives has been undertaken in order to better
understanding the influence of structural modifications upon
overall molecular geometry and conformation. Furthermore, crys-
tal structure of a guanidine intermediate was separated and char-
acterized in order to proclaim the reaction mechanism of the base
catalyzed intramolecular cycloaddition.
Preparation of thieno [2,3-d]pyrimidinone derivatives 5a-5o and 6a-6b via
sequential aza-Wittig/base catalyzed cyclization.
a
Entry
Ar
Y
Product
Yielda(%)
1
2
3
4
5
6
7
8
4-F-C6H4
4-Cl-C6H4
4-Cl-C6H4
Ph
Morpholino
NHC(CH3)3
N(CH2CH3)2
NH(Cyclohexyl)
NHC(CH3)3
NHCH2CH2CH3
Morpholino
Pyrrolidino
NH(Cyclohexyl)
EtO
(CH3)2CHCH2O
CH3(CH2)3O
2-Me-C6H4O
3-Me-C6H4O
1-Naphthyloxy
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
6a
6b
90
83
80
86
86
77
91
88
87
82
79
77
90
86
92
83
86
Ph
4-F-C6H4
4-Cl-C6H4
3-Me-C6H4
4-F-C6H4
3-Me-C6H4
4-Cl-C6H4
4-F-C6H4
3-Me-C6H4
3-Me-C6H4
3-Me-C6H4
Ph
9
2. Results and discussion
10
11
12
13
14
15
16
17
2.1. Synthesis and structure characterization
Compound 1, 2-amino-6-benzyl-3-ethoxycarbonyl-4,5,6,7-
tetrahydrothieno [2,3-c]pyridine, was synthesized by the Gewald
reaction in good yield (85%). Compound 1 was easily converted to
iminophosphorane 2 by treatment with Ph3P, C2Cl6 and Et3N in dry
CH3CN in good yield (Scheme 1). The conversion of compound 1 to
iminophosphorane 2 involves initial formation of Ph3PCl2 from the
reaction of Ph3P, C2Cl6, and further reaction with compound 1 to
give iminophosphorane 2 in the presence of Et3N [53].
Iminophosphorane 2 reacted with an equimolar quantity of the
aromatic isocyanates to give carbodiimides 3, which were allowed
to react with aliphatic amines to provide guanidine intermediates
4. Even in refluxing toluene, intermediates 4 did not cyclize.
However, by treatment with a catalytic amount of EtONa in EtOH at
room temperature, guanidine intermediates 4 undergo intra-
molecular heterocyclization to give the expected 2-alkylamino-
thieno [2,3-d] pyrimidin-4(3H)-ones (5a-5i) in 77e90% yields
(Scheme 1, Table 1). In order to better understanding the intra-
molecular cycloaddition mechanism of the guanidine
4-F-C6H4
a
Isolated yields based on iminophosphoranes 2.
intermediates, compounds 4a and 5a were separated and purified.
The crystal structure of 4a and 5a has been determined by single
crystal X-ray diffraction and was shown in Fig. 2 and Fig. 3. The X-
ray crystal analysis confirmed the structure of the corresponding
products and the (E) geometry about the imine bond of 4a. On the
basis of the results obtained, a possible mechanism for the forma-
tion of product 5a can be proposed (Scheme 2). It presumably in-
volves (i) the formation of 4a’ through the intramolecular proton
transfer of 4a, (ii) regioselective nucleophilic attack of the carbanyl
group by NH of the guanidine intermediate 4a’, (iii) elimination
reaction of 4a’ to the formation of thieno [2,3-d]pyrimidin-4(3H)-
Scheme 1. Preparation of compounds 5 via a sequential aza-Wittig/base catalyzed cyclization.

H. Chen, M.-G. Liu / Journal of Molecular Structure 1180 (2019) 31e40
33
Fig. 2. (a) The X-ray molecular structure of compound 4a with atom labeling; (b) Fragment of the 1D chain depicting the connection via the CeH/O and NeH/O hydrogen bonds;
(c) Fragment of the 3D supramolecular network in compound 4a showing intramolecular and intermolecular interactions. The green and yellow dashed lines demonstrate the
hydrogen bonds and CeH$$$
p stacking interactions, respectively (Some hydrogen atoms are omitted for clarity).
one (5a).
4.221 ppm as quartets, which strongly suggest the existence of
OCH2CH3 group in compound 4a. The 1H NMR spectral data of 5b
shows the signals of NH at 3.895 ppm as a singlet and the C(CH3)3 at
1.352 ppm as singlet. Meanwhile, the phenyl signals of 5b appeared
at 7.564e7.196 ppm. The carbon signals in 13C NMR spectra of all the
target compounds were also in accord with the characteristic peaks
in the molecular structure. For example, the 13C NMR spectrum
data in 4a and 5a showed the signals of C]O carbon at 166.37 and
163.37 ppm, respectively. Viewed from the IR spectra, the broad
absorption bands at 1670-1690 cmꢁ1 were the typical absorption of
carbonyl group (C]O) for 4a, 5a, 5b and 5c, respectively. It is
interesting to note that the HR-ESI-MS spectrum of 5b and 5c show
molecule ion peak (M þ H)þ at m/z 479.16419 and 479.16723 with
100% abundance [See S11 and S14 in Supporting Information], but
the largest m/z peak in the spectrum was (2 M þ K)þ at 995.27777
for 5b and (2 M þ Na)þ at 979.30336 for 5c, respectively.
The reaction of carbodiimides 3 with alcohols in the presence of
a catalytic amount of sodium alkoxide produces 2-alkyloxy-thieno
[2,3-d]pyrimidin-4(3H)-ones (5j-5l) in good yields at room tem-
perature. The reaction of carbodiimides 3 with phenols in the
presence of a catalytic amount of solid potassium carbonate pro-
duces 2-aryloxy-thieno [2,3-d]pyrimidin-4(3H)-ones (5m-5o) in
good yields (Table 1). Carbodiimides 3 react with hydrazine hydrate
(85%) to give, selectively, the 3-amino-2-arylamino-thieno [2,3-d]
pyrimidin-4(3H)-ones (6a-6b) in 83e86% yields (Scheme 3). It is
worth noting that the reaction between carbodiimides 3 and hy-
drazine hydrate gives mainly abnormal products 6a-6b; this might
be due to the geometry of the guanidine intermediate. The
abnormal formation of 6a-6b can be rationalized in terms of an
initial nucleophilic addition of hydrazine to give the guanidine in-
termediates 4, which cyclizes to give 6a-6b across the strong
nucleophilic hydrazine group rather than the arylamine one.
Owing to the great reactive activity of carbodiimides 3, the
preparation of carbodiimides 3 must be carried out at low tem-
perature (0e5 ꢀC) and long reaction time (12 h) under dry condi-
tion. Otherwise, hydrolysis or polymeric side reaction of
carbodiimides 3 might take place, which resulted in low yields of 5.
In the preparation of products 5, all reactions between carbodii-
mides 3 and nucleophilic reagents (aliphatic amines or alcohols)
proceeded smoothly at room temperature though the reactivities of
carbodiimides 3 varied with the substituent on the benzene ring.
This also implies the high reactivity of carbodiimides 3.
Whenever the primary amine was small (Y ¼ NHCH2CH2CH3) or
bulky (Y ¼ NHC(CH3)3), the final cyclization could be achieved in
good yields (Table 1). The solitary formation of 5 could be ratio-
nalized in terms of a base catalytic cyclization of the guanidine
intermediates 4 to give 5 through the arylamino group rather than
the alkylamino one, which might be the reason of the preferential
generation of eNeAr from more acidic eNHAr. The same selectivity
was also observed in similar cases [54,55]. The isolated yields of
compounds 5 were related to the substituents (Y) of the nucleo-
philic reagents. Better isolated yields were obtained as the sub-
stituents (Y) were aryloxy groups (5m-5o in Table 1); however, a
relatively lower yields were obtained when the substituents (Y)
were long chain groups (5f, 5k and 5l in Table 1) probably due to
their better solubility in recrystallization solvent.
The results of elemental analysis, IR, 1H NMR, 13C NMR and HR-
ESI-MS of the products (5e6) are all in good agreement with the
assumed structure. For example, the 1H NMR spectral data of 4a
shows the signals of CH3 at 1.283 ppm as a triplet and the CH2 at

34
H. Chen, M.-G. Liu / Journal of Molecular Structure 1180 (2019) 31e40
Fig. 3. (a) The X-ray molecular structure of compound 5a with atom labeling; (b) Fragment of the 3D supramolecular structure of compound 5a showing intermolecular in-
teractions; (c) The X-ray molecular structure of compound 5b with atom labeling; (d) Fragment of the crystal packing structure of compound 5b showing the supramolecular
interactions; (e) The X-ray molecular structure of compound 5c with atom labeling; (f) Fragment of the crystal packing structure of compound 5c showing intramolecular and
intermolecular interactions. The green dashed lines demonstrate the hydrogen bonds, while the yellow dashed lines demonstrate the intermolecular
interactions, respectively (Some hydrogen atoms are omitted for clarity).
pep and CeH$$$p stacking
Scheme 2. A possible mechanism for the formation of compound 5a.
2.2. Crystal structure analysis of compounds 4a, 5a, 5b and 5c
that compound 5a, 5b and 5c have thieno [2,3-d]pyrimidinone
skeleton. 3D supramolecular architectures are formed in the crys-
tals by self-assembly of the molecules via stacking interactions and
various hydrogen bonds (Table 3). Compound 4a and 5a belongs to
the monoclinic system, space group P21/n, each containing four
molecules. Compound 5b and 5c is made up of monoclinic unit
cells, space group P21/c, each containing four molecules.
The molecular structures of 4a, 5a, 5b and 5c with atomic
numbering are shown in Figs. 2 and 3. All of the compounds have a
molecular crystal structure built up by the corresponding neutral
entities as shown in Figs. 2 and 3, without any co-crystallized sol-
vent molecules. X-ray single-crystal structural analysis revealed

H. Chen, M.-G. Liu / Journal of Molecular Structure 1180 (2019) 31e40
35
Scheme 3. Preparation of compounds 6.
Table 2
Crystallographic data, details of data collection and structure refinement parameters for 4a, 5a, 5b and 5c.
Compound
4a
5a
5b
5c
Empirical formula
Formula weight/g molꢁ1
Crystal system
Space group
Morphology
Size/mm
C28H31FN4O3S
522.63
monoclinic
P21/n
C26H25FN4O2S
476.56
monoclinic
P21/n
C26H27ClN4OS
479.03
monoclinic
P21/c
C26H27ClN4OS
479.03
monoclinic
P21/c
block
block
block
block
0.22 ꢂ 0.20 ꢂ 0.18
13.907 (3)
10.227 (2)
19.287 (4)
90.00
100.708 (4)
90.00
2695.4 (11)
4
0.30 ꢂ 0.28 ꢂ 0.18
9.217 (3)
15.113 (5)
16.639 (5)
90.00
93.541 (5)
90.00
2313.4 (12)
4
0.22 ꢂ 0.20 ꢂ 0.18
15.193 (3)
6.0928 (10)
26.639 (4)
90.00
95.145 (3)
90.00
2456.0 (7)
4
0.28 ꢂ 0.26 ꢂ 0.25
20.465 (12)
7.465 (4)
16.074 (9)
90.00
99.217 (6)
90.00
2424 (2)
4
a/Å
b/Å
c/Å
o
a
/
o
b
/
o
g
/
V/Å3
Z
T/K
296 (2)
1.280
0.163
296 (2)
1.368
0.180
296 (2)
1.296
0.267
296 (2)
1.313
0.270
Dc/g cmꢁ3
m
/mmꢁ1
F (000)
1092.0
1000.0
1008.0
1008.0
Theta range for data collection
h, k, lmax
1.7ꢃ
q
ꢃ 26.4ꢀ
1.8ꢃ
q
ꢃ 26.4ꢀ
1.4ꢃ
q
ꢃ 26.4ꢀ
2.6ꢃ
q
ꢃ 27.5ꢀ
17, 12, 24
11, 18, 20
18, 7, 33
26, 9, 20
Reflections collected/unique
Data/restraints/parameters
R indices (all data)
Largest diff. peak and hole
S (GOF on F2)
30094/5509 [Rint ¼ 0.032]
26004/4722 [Rint ¼ 0.028]
26981/5032 [Rint ¼ 0.039]
24974/5544 [Rint ¼ 0.083]
5509/0/335
4722/0/307
5032/0/301
5544/7/300
R1 ¼ 0.058, wR2 ¼ 0.169
0.41 and ꢁ0.44 e Åꢁ3
1.035
R1 ¼ 0.048, wR2 ¼ 0.143
0.41 and ꢁ0.21 e Åꢁ3
1.084
R1 ¼ 0.043, wR2 ¼ 0.134
0.28 and ꢁ0.28 e Åꢁ3
1.026
R1 ¼ 0.056, wR2 ¼ 0.159
0.27 and ꢁ0.23 e Åꢁ3
1.025
Table 3
Hydrogen bond lengths (Å) and bond angles (o) of compounds 4a, 5a, 5b and 5c.
Compound
DeH$$$A
DeH(Å)
H$$$A(Å)
D$$$A(Å)
<DeH$$$A(o)
4a
N (2)eH (2)$$$O (2)
0.86
0.97
0.93
0.93
0.96
0.96
0.96
0.97
2.05
2.53
2.71
2.58
2.59
2.56
2.60
2.59
2.6896
2.8784
3.3908
3.4459
3.1703
3.1284
3.1078
2.9667
131
101
129
155
119
118
113
103
C (9)eH (9B)/O (1)
C (27)eH (27)$$$O (2)
C (23)eH (23)$$$O (2)
C (18)eH (18C)/N (3)
C (19)eH (19A)$$$N (3)
C (24)eH (24A)$$$N (2)
C (25)eH (25B)/N (3)
5a
5b
5c
Compound 4a possesses a benzyl substituent at the N (1) atom
of the thienopyridine ring and an ethyl ester group substituent at C
(13). In compound 4a, the C (18)eN (2) (1.3814 (29) Å) and C (18)eN
(4) (1.3809 (27) Å) bonds are remarkably shorter than the normal
CeN bond (1.50 Å), but close to the C]N double bond (1.38 Å).
Meanwhile, the C (18) ¼ N (3) (1.2812 (28) Å) is also shorter than
the normal C]N bond (1.38 Å) [56]. The thiophene ring system
forms diherdral angles of 79.51ꢀ and 67.38ꢀ with the adjacent 6-
membered rings C (1)eC (6) and C (23)eC (28), respectively. In
compound 5a, the C (16)eN (2) (1.3931 (25) Å) and C (16)eN (4)
(1.3851 (25) Å) bonds are shorter than the normal CeN bond
(1.50 Å), but close to the C]N double bond (1.38 Å). Meanwhile, the
C (16) ¼ N (3) (1.3061 (25) Å) is remarkably shorter than the normal
C]N bond (1.38 Å) [56]. The thieno [2,3-d]pyrimidine fused-ring
system is nearly coplanar (r.m.s deviation ¼ 0.0300 Å) with the
maximum deviations of ꢁ0.0438 and 0.0250 Å for S (1) and C (16),

36
H. Chen, M.-G. Liu / Journal of Molecular Structure 1180 (2019) 31e40
respectively. This ring system forms diherdral angles of 88.37ꢀ and
66.08ꢀ with the adjacent 6-membered rings C (1)eC (6) and C (21)e
C (26), respectively. Other selected bond lengths and bond angles of
4a and 5a are listed in Table S1 [see supplementary information].
In compound 5b, the N (3) ¼ C (16) (1.3059 (27) Å) is shorter
than the normal C]N bond (1.38 Å). The thieno [2,3-d]pyrimidine
fused-ring system is nearly coplanar (r.m.s deviation ¼ 0.0264 Å)
with the maximum deviations of ꢁ0.0578 and 0.0558 Å for C (13)
and C (11), respectively. This ring system forms dihedral angles of
85.39ꢀ and 83.86ꢀ with the adjacent 6-membered rings C (1)eC (6)
and C (21)eC (26), respectively. The CeN and C]N bonds are
shorter than the normal bond, which may be ascribed to the thieno
ray diffraction data were collected at 296 (2) K on a Bruker APEX-II
CCD diffractometer equipped with a graphite-monochromatic
MoK
a
radiation (
l
¼ 0.71073 Å). Crystal decay has not occurred
during the data collection.
3.2. Synthesis
3.2.1. Preparation of compound 1
The synthesis procedure of compound 1 was according to a
literature method [58] with some improvements (Scheme 1). A
well-stirred mixture of 1-benzylpiperidin-4-one (18.9 g, 0.1 mol),
sulfur (3.2 g, 0.1 mol), ethyl cyanoacetate (11.3 g, 0.1 mol) in EtOH
(100 mL) was cooled in an ice bath and treated dropwise with Et3N
(10.1 g, 0.1 mol). When addition was complete, the reaction mixture
was warmed to 60 ꢀC (internal) for 40 min and then stored in the
cold until crystallization occurred. The product (26.9 g, yield 85%)
was recrystallized from EtOH as light yellow needles, m.p.
113e114 ꢀC (112e113 ꢀC in literature report [58]).
[2,3-d]pyrimidine fused-ring as a big
p-conjugated system. In
compound 5c, the N (2) ¼ C (15) (1.3075 (30) Å) is shorter than the
normal C]N bond (1.38 Å). The thienopyrimidine fused-ring sys-
tem is nearly coplanar (r.m.s deviation ¼ 0.0193 Å) with the
maximum deviations of ꢁ0.0343 and 0.0506 Å for C (14) and C (15),
respectively. This ring system forms dihedral angles of 79.37ꢀ and
69.15ꢀ with the adjacent 6-membered rings C (1)eC (6) and C (17)e
C (22), respectively. Other selected bond lengths and bond angles of
5b and 5c are listed in Table S2 [see supplementary information].
The packing diagram of compound 4a in a unit cell is shown in
Fig. 2(c). Neighboring molecules packs in a parallel-bar formed by
two neighboring molecules, forming a dimer with each other in the
cell. The distance between C (22) to the thiophene ring (S (1)eC
3.2.2. Preparation of iminophosphorane 2
To a mixture of compound 1 (2.53 g, 8 mmol), PPh3 (3.14 g,
12 mmol) and C2Cl6 (2.84 g, 12 mmol) in anhydrous CH3CN (40 mL),
were added dropwise Et3N (2.42 g, 24 mmol) at room temperature.
The color of the reaction mixture quickly turned to be yellow. After
stirring for 4e6 h, the solvent was removed under reduced pressure
and the residue was recrystallized from EtOH to give iminophos-
(17)) is 3.8526 Å, suggesting the existence of weak CeH$$$
p
stacking interactions [57]. The crystal packing of compound 4a is
stabilized by classical intermolecular and intramolecular hydrogen
bond: C (27)eH (27)$$$O (2), N (2)eH (2)$$$O (2) and C (9)eH
(9B)/O (1) (Fig. 2(b)). The distances between the donors and ac-
ceptors are 3.3908 Å, 2.6896 Å and 2.8784 Å, respectively. However,
the packing mode of compound 5a is very different from that of 4a.
It packs in a big cycle through weak C (23)eH (23)$$$O (2) and
phorane
2
in light yellow crystals, 3.83 g (yield 83%),ꢁ1m.p.
115e116 ꢀC; IR (KBr) v: 1684 (C]O), 1462, 1174, 684, 524 cm
;
1H
NMR (CDCl3, 400 MHz)
d: 7.83e7.26 (m, 20H, Ar-H), 4.28 (q,
J ¼ 7.2 Hz, 2H, OCH2CH3), 3.61 (s, 2H, Ar-CH2), 3.26 (s, 2H, NCH2-
thiophene), 2.88 (t, J ¼ 5.6 Hz, 2H, NCH2CH2), 2.71 (t, J ¼ 5.6 Hz, 2H,
NCH2CH2), 1.33 (t, J ¼ 7.2 Hz, 3H, OCH2CH3); EI-MS m/z (%): 576 (Mþ,
65), 262 (63), 183 (100), 108 (41), 91 (63). Anal. calcd for
CeH$$$
p
stacking interactions (Fig. 3(b)). The distance between C
C35H33N2O2PS: C 72.89, H 5.77, N 4.86; found C 72.76, H 5.83, N 4.91.
(8) to the thiophene ring (S (1)eC (14)) is 3.8621 Å, and the distance
between C (22) to the phenyl ring (C (1)eC (6)) is 3.8101 Å. The
packing diagram of compound 5c in a unit cell is shown in Fig. 3(f).
Neighboring molecules form a one-dimensional chain structure in
3.2.3. Parallel synthesis of 2-alkylamino substituted thieno[2,3-d]
pyrimidin-4(3H)-one derivatives (5a-5i)
Aromatic isocyanate (2 mmol) under nitrogen atmosphere was
added to a solution of iminophosphorane 2 (1.15 g, 2 mmol) in
anhydrous CH2Cl2 (10 mL) at room temperature. When the reaction
mixture was left unstirred for 12 h at 0e5 ꢀC, iminophosphorane 2
was consumed (TLC monitored). The solvent was removed under
reduced pressure and ether/petroleum ether (volume ratio 1:2,
20 mL) was added to precipitate triphenylphosphine oxide.
Removal of the triphenylphosphine oxide gave carbodiimide 3,
which was used directly without further purification. Aliphatic
amine (2 mmol) was added to the solution of carbodiimide 3 in
anhydrous dichloromethane (10 mL). After the reaction mixture
was left unstirred for 5e6 h, the solvent was removed and anhy-
drous EtOH (10 mL) with several drops of EtONa (in EtOH) was
added to the mixture. The mixture was stirred for another 6e8 h at
room temperature. After that, the solution was condensed and the
residual was recrystallized from dichloromethane/EtOH to give 5a-
5i in 77e90% yields.
the c direction through weak
p-p and CeH$$$p stacking in-
teractions. The centroid-to-centroid distance between the phenyl
ring (C (1)eC (6)) to thiophene ring (S (1)eC (14)) and 6-membered
ring (N (2)eC (15)) of neighboring molecules is 4.1762 Å and
3.9827 Å, respectively.
3. Experimental section
3.1. Materials and apparatuses
All starting materials were commercial products of chemical or
analytical grade and used as received. The melting point was
determinated on a Bibby SMP3 apparatus and uncorrected. IR
spectra were recorded on a PE-983 infrared spectrometer as KBr
pellets with absorption in cmꢁ1.1H NMR and 13C NMR spectra were
recorded in CDCl3 on a Bruker vector 22FT-IR 600 MHz (or 500, 400,
300 MHz) spectrometer at 293 K. The chemical shifts are reported
(E)-Ethyl-6-benzyl-2-[(morpholino) (4-fluorophenylamino)-
methyleneamino]-4,5,6,7-tetra-hydrothieno[2,3-c]pyridine-3-
carboxylate (4a) Colorless crystals, Yield 93%, m.p.: 255e256 ꢀC. IR
(KBr) v: 3428 (N-H), 2958, 2908, 1689 (C]O), 1559, 1486, 1208, 957,
in
d value (ppm) using tetramethylsilane as an internal reference.
High-resolution ESI-mass spectra was measured on a Thermo
Exactive mass spectrometer and the data were collected in positive
ion mode. EI-MS were measured on a Finnigan Trace MS spec-
trometer (70 eV). ESI-MS were measured on a Bruker amaZon X &
ETD MS spectrometer. Elementary analysis (C, H, N) were taken on a
Vario EL III elementary analysis instrument. The reactions have
been monitored by thin layer chromatography performed on Merck
pre-coated plates (silica gel. 60 F254, 0.25 mm) and visualized by
fluorescence quenching under UV light (254 nm). Single-crystal X-
774 cmꢁ1.1H NMR (CDCl3, 500 MHz)
d(ppm): 10.09 (br, 1H, NH),
7.37e7.25 (m, 5H, Ar-H), 6.96e6.85 (m, 4H, Ar-H), 4.22 (q, J ¼ 7.0 Hz,
2H, OCH2CH3), 3.69e3.68 (m, 6H, Ar-CH2 and 2CH2), 3.47 (s, 2H,
NCH2-thiophene), 3.23 (s, 4H, 2CH2), 2.86 (t, J ¼ 5.5 Hz, 2H,
NCH2CH2), 2.75 (t, J ¼ 5.5 Hz, 2H, NCH2CH2), 1.28 (t, J ¼ 7.0 Hz, 3H,
OCH2CH3); 13C NMR (CDCl3, 125 MHz)
d: 166.37, 159.54, 157.62,
152.87, 148.36, 143.91, 137.95, 129.12, 128.29, 122.74, 115.74, 115.57,

H. Chen, M.-G. Liu / Journal of Molecular Structure 1180 (2019) 31e40
37
108.54, 66.12, 62.08, 60.13, 51.24, 50.28, 47.69, 26.92, 14.24; HR-ESI-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
MS: m/z: calcd. for [MþH]þ
¼
523.21791; found:
(5e) White solid, Yield 86%, m.p. 181e182 ꢀC; IR (KBr) v: 3457 (N-H),
[MþH]þ ¼ 523.21655. Anal. Calcd. (%) for C28H31FN4O3S: C 64.35, H
1675 (C]O), 1537, 1310, 671 cmꢁ1 1H NMR (CDCl3, 600 MHz)
; d:
5.98, N 10.72. Found (%): C 64.23, H 6.07, N 10.87.
7.59e7.25 (m,10H, Ar-H), 3.94 (br,1H, NH), 3.72 (s, 2H, Ar-CH2), 3.61
(s, 2H, NCH2-thiophene), 2.99 (t, J ¼ 5.7 Hz, 2H, NCH2CH2), 2.82 (t,
J ¼ 5.7 Hz, 2H, NCH2CH2), 1.33 (s, 9H, 3CH3); 13C NMR (CDCl3,
7-Benzyl-3-(4-fluorophenyl)-2-morpholino-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5a) Colorless crystals, Yield 90%, m.p.: 231e232 ꢀC. IR (KBr) v:
2958, 1681 (C]O), 1603, 1466, 1384, 1157, 1095, 837 cmꢁ1.1H NMR
100 MHz) d: 165.5, 158.9, 149.3, 138.3, 135.1, 130.5, 129.6, 129.5,
129.1, 128.9, 128.3, 127.2, 124.2, 114.3, 61.8, 52.7, 51.5, 49.9, 29.0,
25.5; EI-MS m/z (%): 444 (Mþ, 15), 387 (10), 325 (20), 269 (29), 91
(100). Anal. calcd for C26H28N4OS: C 70.24, H 6.35, N 12.60; found: C
70.11, H 6.12, N 12.37.
(CDCl3, 500 MHz) d(ppm): 7.69e7.17 (m, 9H, Ar-H), 3.75 (s, 2H, Ar-
CH2), 3.65 (s, 2H, NCH2-thiophene), 3.44 (t, J ¼ 4.5 Hz, 4H, 2CH2),
3.08 (t, J ¼ 4.5 Hz, 4H, 2CH2), 3.04 (t, J ¼ 5.5 Hz, 2H, NCH2CH2), 2.85
(t, J ¼ 5.5 Hz, 2H, NCH2CH2); 13C NMR (CDCl3, 125 MHz)
d
: 163.37,
7-Benzyl-3-(4-fluorophenyl)-2-propylamino-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5f) White solid, Yield 77%, m.p. 158e159 ꢀC; IR (KBr) v: 3373 (N-H),
162.95, 160.97, 159.14, 154.27, 132.09, 130.48, 129.89, 129.16, 128.39,
127.36, 117.41, 116.09, 115.91, 65.93, 61.76, 51.39, 49.74, 49.29, 25.42;
HR-ESI-MS: m/z: calcd. for [MþH]þ
¼
477.17605; found:
1673 (C]O), 1540, 1227, 696 cmꢁ1 1H NMR(CDCl3, 600 MHz)
; d:
[MþH]þ ¼ 477.16483. Anal. Calcd. (%) for C26H25FN4O2S: C 65.53, H
7.37e7.25 (m, 9H, Ar-H), 4.06 (br, 1H, NH), 3.72 (s, 2H, Ar-CH2), 3.59
(s, 2H, NCH2-thiophene), 3.31 (m, 2H, NHCH2), 2.98 (t, J ¼ 5.1 Hz,
2H, NCH2CH2), 2.82 (t, J ¼ 5.1 Hz, 2H, NCH2CH2), 1.50e1.48 (m, 2H,
CH2CH3), 0.84 (t, J ¼ 6.6 Hz, 3H, CH2CH3); EI-MS m/z (%): 448 (Mþ,
15), 357 (16), 329 (100), 287 (26), 91 (72). Anal. calcd for
5.29, N 11.76. Found (%): C 65.45, H 5.47, N 11.85.
7-Benzyl-3-(4-chlorophenyl)-2-(tert-butylamino)-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5b) Colorless crystals, Yield 83%, m.p.: 214e215 ꢀC. IR (KBr) v: 3473
(N-H), 2965, 1678 (C]O), 1613, 1467, 1378, 1293, 843 cmꢁ1.1H NMR
(CDCl3, 300 MHz) d(ppm): 7.56e7.19 (m, 9H, Ar-H), 3.89 (br,1H, NH),
3.75 (s, 2H, Ar-CH2), 3.63 (s, 2H, NCH2-thiophene), 2.99 (t,
C
25H25FN4OS: C 66.94, H 5.62, N 12.49; found: C 66.71, H 5.50, N
12.23.
7-Benzyl-3-(4-chorophenyl)-2-morpholino-5,6,7,8-
J ¼ 3.6 Hz, 2H, NCH2CH2), 2.84 (t, J ¼ 3.6 Hz, 2H, NCH2CH2), 1.35 (s,
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
9H, 3CH3); 13C NMR (CDCl3, 75 MHz)
d(ppm): 165.38,158.54,148.73,
(5g) White solid, Yield 91%, m.p. 211e212 ꢀC; IR (KBr) v: 1675 (C]
138.00, 135.63, 133.31, 130.66, 130.29, 129.29, 128.97, 128.20, 127.07,
124.24, 114.03, 61.67, 52.74, 51.33, 49.73, 28.86, 25.37. HR-ESI-MS:
m/z: calcd. for [MþH]þ ¼ 479.16723, [M þ Hþ2]þ ¼ 481.16723,
O), 1541, 1223, 691 cmꢁ1 1H NMR (CDCl3, 600 MHz)
; d: 7.48e7.14
(m, 9H, Ar-H), 3.73 (s, 2H, Ar-CH2), 3.63 (s, 2H, NCH2-thiophene),
3.45 (t, J ¼ 3.0 Hz, 4H, 2CH2), 3.09 (t, J ¼ 3.0 Hz, 4H, 2CH2), 3.02 (t,
J ¼ 5.1 Hz, 2H, NCH2CH2), 2.83 (t, J ¼ 5.1 Hz, 2H, NCH2CH2); EI-MS m/
z (%): 492 (Mþ, 12), 373 (66), 151 (20), 111 (16), 91 (100). Anal. calcd
for C26H25ClN4O2S: C 63.34, H 5.11, N 11.36; found: C 63.15, H 5.39, N
11.53.
[MþNa]þ
¼
501.14918,
[MþK]þ
¼
517.12312,
[2 M þ Na]þ ¼ 979.30859, [2 M þ K]þ ¼ 995.28253; found:
[MþH]þ
¼
479.16419, [M
501.14663,
þ
Hþ2]þ
¼
481.16096,
517.11977,
[MþNa]þ
¼
[MþK]þ
¼
[2 M þ Na]þ ¼ 979.30371, [2 M þ K]þ ¼ 995.27777. Anal. Calcd for
7-Benzyl-3-(3-methylphenyl)-2-pyrrolidino-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5h) White solid, Yield 88%, m.p. 207e208 ꢀC; IR (KBr) v: 1677 (C]
C
26H27ClN4OS: C 65.19, H 5.68, N 11.70; found: C 65.33, H 5.73, N
11.89.
7-Benzyl-3-(4-chlorophenyl)-2-diethylamino-5,6,7,8-
O), 1533, 1135, 683 cmꢁ1 1H NMR (CDCl3, 600 MHz)
; d: 7.39e7.08
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5c) Colorless crystals, Yield 80%, m.p.: 187e188 ꢀC. IR (KBr) v: 2955,
2936, 1682 (C]O), 1607, 1518, 1378, 823, 811 cmꢁ1.1H NMR (CDCl3,
(m, 9H, Ar-H), 3.74 (s, 2H, Ar-CH2), 3.62 (s, 2H, NCH2-thiophene),
3.04e3.02 (m, 6H, NCH2CH2 and 2CH2), 2.84 (t, J ¼ 5.1 Hz, 2H,
NCH2CH2), 2.39 (s, 3H, Ar-CH3), 1.70 (t, 4H, 2CH2); 13C NMR (CDCl3,
300 MHz)
d(ppm): 7.47e7.22 (m, 9H, Ar-H), 3.77 (s, 2H, Ar-CH2),
100 MHz) d: 165.6, 159.6, 152.2, 138.8, 138.1, 137.3, 129.9, 129.5,
3.66 (s, 2H, NCH2-thiophene), 3.09e3.02 (m, 6H, NCH2CH2 and
2CH2CH3), 2.87 (t, J ¼ 3.6 Hz, 2H, NCH2CH2), 0.85 (t, J ¼ 7.2 Hz, 6H,
129.0, 128.9, 128.7, 128.2, 127.1, 126.4, 124.3, 114.0, 61.8, 51.5, 50.0,
49.8, 25.5, 25.3, 21.2; EI-MS m/z (%): 456 (Mþ, 100), 365 (25), 337
(86), 187 (38), 91 (99). Anal. calcd for C27H28N4OS: C 71.02, H 6.18, N
12.27; found: C 70.85, H 6.47, N 12.51.
2CH2CH3); 13C NMR (CDCl3, 75 MHz)
d(ppm): 163.96,159.46,154.36,
137.91, 136.07, 133.85, 130.26, 129.74, 129.07, 129.01, 128.27, 127.17,
126.88, 116.43, 61.75, 51.42, 49.77, 45.03, 25.45, 12.46. HR-ESI-MS:
m/z: calcd. for [MþH]þ ¼ 479.16723, [M þ Hþ2]þ ¼ 481.16723,
[2 M þ H]þ ¼ 957.32664, [2 M þ Na]þ ¼ 979.30859; found:
7-Benzyl-3-(4-fluorophenyl)-2-piperidino-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5i) White solid, Yield 87%, m.p. 196e197 ꢀC; IR (KBr) v: 1680 (C]
[MþH]þ
¼
479.16436, [M
þ
Hþ2]þ
¼
481.16085,
O), 1531, 1139, 679 cmꢁ1 cmꢁ1 1H NMR (CDCl3, 600 MHz)
; d:
[2 M þ H]þ ¼ 957.32239, [2 M þ Na]þ ¼ 979.30336. Anal. Calcd for
7.38e7.15 (m, 9H, Ar-H), 3.73 (s, 2H, Ar-CH2), 3.62 (s, 2H, NCH2-
thiophene), 3.05e3.02 (m, 6H, NCH2CH2 and 2CH2), 2.83 (t,
C
26H27ClN4OS: C 65.19, H 5.68, N 11.70; found: C 65.45, H 5.57, N
11.63.
7-Benzyl-3-phenyl-2-cyclohexylamino-5,6,7,8-
J ¼ 5.7 Hz, 2H, NCH2CH2), 1.43 (m, 2H, CH2), 1.26 (m, 4H, 2CH2); 13
C
NMR (CDCl3, 100 MHz) d: 163.8, 163.0, 160.5, 159.4, 155.4, 138.0,
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
133.3, 130.6, 129.9, 129.0, 128.3, 127.2, 117.0, 115.8, 115.6, 61.9, 51.5,
50.2, 49.8, 25.6, 24.9, 23.9; EI-MS m/z (%): 474 (Mþ, 62), 383 (15),
355 (69), 205 (37), 91 (100). Anal. calcd for C27H27FN4OS: C 68.33, H
5.73, N 11.81; found: C 68.51, H 5.89, N 11.65.
(5d) White solid, Yield 86%, m.p. 201e202 ꢀC; IR (KBr) v: 3395 (N-
H), 3018, 1679 (C]O), 1535, 1205, 689 cmꢁ1 1H NMR (CDCl3,
;
600 MHz) d: 7.60e7.26 (m, 10H, Ar-H), 3.90e3.87 (m, 2H, NH and
CH), 3.73 (s, 2H, Ar-CH2), 3.61 (s, 2H, NCH2-thiophene), 2.99 (t,
J ¼ 5.7 Hz, 2H, NCH2CH2), 2.82 (t, J ¼ 5.7 Hz, 2H, NCH2CH2),
3.2.4. Parallel synthesis of 2-alkyloxy substituted thieno[2,3-d]
pyrimidin-4(3H)-one derivatives (5j-5l)
1.92e1.00 (m, 10H, 5CH2); 13C NMR (CDCl3, 100 MHz)
d: 166.1, 158.8,
149.8, 138.2, 134.7, 132.3, 130.6, 129.7, 129.2, 128.9, 128.3, 127.2,
124.0, 114.3, 61.9, 51.5, 50.0, 49.9, 32.8, 25.5, 25.4, 24.5; EI-MS m/z
(%): 470 (Mþ, 24), 351 (29), 269 (30), 152 (19), 91 (100). Anal. calcd
for C28H30N4OS: C 71.46, H 6.43, N 11.90; found: C 71.21, H 6.25, N
11.71.
RONa (5% w/w in ROH) was added to the solution of carbodii-
mides 4 in anhydrous dichloromethane (10 mL). The reaction
mixture was stirred for 4e7 h at room temperature. Then the so-
lution was condensed and the residual was recrystallized from
dichloromethane/EtOH to give 5j-5l in 77e82% yields.
7-Benzyl-3-(3-methylphenyl)-2-ethoxy-5,6,7,8-
7-Benzyl-3-phenyl-2-tert-butylamino-5,6,7,8-

38
H. Chen, M.-G. Liu / Journal of Molecular Structure 1180 (2019) 31e40
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5j) White solid, Yield 82%, m.p.176e177 ꢀC; IR (KBr) v: 1673 (C]O),
(5o) White solid, Yield 92%, m.p. 175e176 ꢀC; IR (KBr) v: 1687 (C]
O), 1553, 1357, 876 cmꢁ1 1H NMR (CDCl3, 600 MHz)
: 7.85e7.25
(m, 16H, Ar-H), 3.71 (s, 2H, Ar-CH2), 3.59 (s, 2H, NCH2-thiophene),
;
d
1570, 1179, 776 cmꢁ1
;
1H NMR (CDCl3, 600 MHz)
d: 7.39e6.98 (m,
9H, Ar-H), 4.39 (q, J ¼ 6.9 Hz, 2H, OCH2CH3), 3.73 (s, 2H, Ar-CH2),
3.63 (s, 2H, NCH2-thiophene), 3.05 (t, J ¼ 5.4 Hz, 2H, NCH2CH2), 2.83
(t, J ¼ 5.4 Hz, 2H, NCH2CH2), 2.39 (s, 3H, Ar-CH3), 1.23 (t, J ¼ 6.9 Hz,
3.08 (t, J ¼ 5.1 Hz, 2H, NCH2CH2), 2.84 (t, J ¼ 5.1 Hz, 2H, NCH2CH2),
2.44 (s, 3H, Ar-CH3); 13C NMR (CDCl3, 100 MHz)
d: 162.0, 158.8,
152.6, 147.5, 139.7, 138.0, 134.9, 134.6, 129.9, 129.8, 129.4, 129.0,
128.6, 128.5, 128.3, 127.9, 127.2, 126.6, 126.5, 126.4, 126.0, 125.3,
125.1, 121.0, 118.2, 117.8, 61.8, 51.4, 49.8, 25.4, 21.3; EI-MS m/z (%):
529 (Mþ, 49), 410 (69), 277 (53), 267 (58), 91 (100). Anal. calcd for
3H, OCH2CH3); 13C NMR (CDCl3, 100 MHz)
d: 162.7, 158.9, 153.1,
139.1, 138.0, 134.7, 129.8, 129.4, 129.0, 128.9, 128.6, 128.3, 127.2,
127.0, 125.1, 117.3, 64.9, 61.8, 51.4, 49.8, 25.5, 21.2, 14.0; EI-MS m/z
(%): 431 (Mþ, 13), 312 (29), 218 (14), 112 (37), 91 (100). Anal. calcd
for C25H25N3O2S: C 69.58, H 5.84, N 9.74; found: C 69.27, H 5.57, N
9.61.
C33H27N3O2S: C 74.83, H 5.14, N 7.93; found: C 74.67, H 5.49, N 7.62.
3.2.6. Parallel synthesis of 3-amino substituted thieno[2,3-d]
pyrimidin-4(3H)-one derivatives (6a-6b)
7-Benzyl-3-(4-chlorophenyl)-2-isobutoxy-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5k) White solid, Yield 79%, m.p. 148e149 ꢀC; IR (KBr) v: 1677 (C]
A solution of hydrazine hydrate (0.35 g, 6 mmol, 85%) in anhy-
drous CH3CN (5 mL) was added to the solution of carbodiimides 4
prepared above, in anhydrous CH3CN (15 mL). The mixture was
stirred for 0.5e1 h at room temperature and then filtered, the ob-
tained powder was recrystallized from dichloromethane/EtOH to
give 6a-6b in good yields.
O), 1567, 1187, 758 cmꢁ1; 1H NMR (CDCl3, 600 MHz)
d: 7.47e7.15 (m,
9H, Ar-H), 4.10 (d, J ¼ 6.0 Hz, 2H, OCH2), 3.74 (s, 2H, Ar-CH2), 3.63 (s,
2H, NCH2-thiophene), 3.04 (t, J ¼ 5.1 Hz, 2H, NCH2CH2), 2.84 (t,
J ¼ 5.1 Hz, 2H, NCH2CH2), 1.90e1.86 (m, J ¼ 6.6 Hz, 1H, CH), 0.79 (d,
J ¼ 7.2 Hz, 6H, 2CH3); EI-MS m/z (%): 479 (Mþ, 13), 360 (16), 304
(39), 151 (27), 91 (100). Anal. calcd for C26H26ClN3O2S: C 65.06, H
5.46, N 8.75; found: C 65.37, H 5.09, N 8.57.
3-Amino-2-phenylamino-7-benzyl-5,6,7,8-tetrahydropyrido
[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6a) White solid,
Yield 83%, m.p. 145e146 ꢀC; IR (KBr) v: 3463 (N-H), 3342 (N-H),
7-Benzyl-3-(4-fluorophenyl)-2-butoxy-5,6,7,8-
3307 (N-H), 1680 (C]O), 1536, 1357 cmꢁ1 1H NMR (CDCl3,
;
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
400 MHz): d 8.48 (s, 1H, NH), 7.62e7.08 (m, 10H, Ar-H), 4.75 (s, 2H,
(5l) White solid, Yield 77%, m.p. 142e143 ꢀC; IR (KBr) v: 1681 (C]
NH2), 3.71 (s, 2H, Ar-CH2), 3.52 (s, 2H, NCH2-thiophene), 3.04 (t,
O), 1577, 1173, 779 cmꢁ1; 1H NMR (CDCl3, 600 MHz)
d
: 7.39e7.17 (m,
J ¼ 5.6 Hz, 2H, NCH2CH2), 2.82 (t, J ¼ 5.6 Hz, 2H, NCH2CH2); 13C NMR
9H, Ar-H), 4.33 (t, J ¼ 6.6 Hz, 2H, OCH2), 3.74 (s, 2H, Ar-CH2), 3.63 (s,
2H, NCH2-thiophene), 3.03 (t, J ¼ 5.7 Hz, 2H, NCH2CH2), 2.84 (t,
J ¼ 5.7 Hz, 2H, NCH2CH2), 1.59e1.54 (m, J ¼ 7.5 Hz, 2H, CH2),
1.25e1.20 (m, J ¼ 7.5 Hz, 2H, CH2), 0.84 (t, J ¼ 7.5 Hz, 3H, CH3); 13C
(CDCl3, 100 MHz) d: 163.4, 157.7, 147.3, 137.6, 137.5, 129.3, 128.8,
128.7, 128.3, 127.3, 125.2, 123.3, 119.8, 114.4, 62.4, 51.3, 50.0, 25.6;
ESI-MS: [MþH]þ peak at m/z 404. Anal. calcd for C22H21N5OS: C
65.49, H 5.25, N 17.36; found: C 65.81, H 5.49, N 17.62.
NMR (CDCl3, 100 MHz)
d
: 163.7, 162.8, 161.2, 158.8, 153.1, 138.0,
3-Amino-2-[(4-fluorophenyl)amino]-7-benzyl-5,6,7,8-
132.3, 129.9, 129.1, 128.4, 127.3, 117.3, 116.3, 116.1, 69.0, 61.9, 51.5,
49.9, 30.3, 25.5, 18.9, 13.5; EI-MS m/z (%): 463 (Mþ, 30), 406 (19),
344 (31), 288 (49), 91 (100). Anal. calcd for C26H26FN3O2S: C 67.36,
H 5.65, N 9.06; found: C 67.17, H 5.51, N 8.87.
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(6b) White solid, Yield 86%, m.p.166e167 ꢀC; IR (KBr) v: 3475 (N-H),
3319 (N-H), 3276 (N-H), 1661 (C]O), 1529, 1357 cmꢁ1 1H NMR
;
(CDCl3, 400 MHz):
d 8.41 (s, 1H, NH), 7.56e7.02 (m, 9H, Ar-H), 4.78
(s, 2H, NH2), 3.71 (s, 2H, Ar-CH2), 3.52 (s, 2H, NCH2-thiophene), 3.03
3.2.5. Parallel synthesis of 2-aryloxy substituted thieno[2,3-d]
pyrimidin-4(3H)-one derivatives (5m-5o)
(t, J ¼ 5.4 Hz, 2H, NCH2CH2), 2.82 (t, J ¼ 5.4 Hz, 2H, NCH2CH2); 13C
NMR (CDCl3, 100 MHz) d: 163.3, 160.1, 157.6, 147.4, 137.5, 133.6,
Phenols were added to the solution of carbodiimides 4 in
anhydrous CH3CN (10 mL). After the mixture was stirred for 0.5e1 h
at room temperature, solid potassium carbonate was added to the
solution. The mixture was stirred for 6e8 h at 40e50 ꢀC and
filtered, the filtrate was condensed and the residual was recrys-
tallized from dichloromethane/EtOH to give 5m-5o in 85e90%
yields.
129.4, 128.4, 127.4, 125.2, 121.6, 115.5, 115.3, 114.4, 62.5, 51.3, 50.1,
25.6; ESI-MS: [MþH]þ peak at m/z 422. Anal. calcd for
C22H20FN5OS: C 62.69, H 4.78, N 16.62; found: C 62.84, H 4.49, N
16.89.
3.3. X-ray crystal structure determination of compounds 4a, 5a, 5b
and 5c
7-Benzyl-3-(3-methylphenyl)-2-(2-methylphenoxy)-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5m) White solid, Yield 90%, m.p. 155e156 ꢀC; IR (KBr) v: 1696 (C]
In order to better understanding the molecular structure of
tetrahydropyrido [40,3':4,5] thieno [2,3-d]pyrimidinone derivatives,
single crystals suitable for X-ray diffraction were prepared and
collected by slow evaporation from an ethanol/dichloromethane
(1:1) solution at room temperature. Colorless single crystals of
compounds 4a, 5a, 5b and 5c with suitable dimensions were
selected and mounted on the top of a glass fiber. The data were
collected by a Bruker APEX-II CCD diffractometer equipped with a
O), 1563, 933, 696 cmꢁ1; 1H NMR (CDCl3, 600 MHz)
d: 7.42e7.09 (m,
13H, Ar-H), 3.72 (s, 2H, Ar-CH2), 3.61 (s, 2H, NCH2-thiophene), 3.07
(t, J ¼ 5.4 Hz, 2H, NCH2CH2), 2.84 (t, J ¼ 5.4 Hz, 2H, NCH2CH2), 2.42
(s, 3H, Ar-CH3), 2.10 (s, 3H, Ar-CH3); EI-MS m/z (%): 493 (Mþ, 30),
402 (9), 374 (53), 267 (46), 91 (100). Anal. calcd for C30H27N3O2S: C
73.00, H 5.51, N 8.51; found: C 73.37, H 5.39, N 8.63.
7-Benzyl-3-(3-methylphenyl)-2-(3-methylphenoxy)-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(5n) White solid, Yield 86%, m.p. 158e159 ꢀC; IR (KBr) v: 1694 (C]
graphite-monochromatic MoK
scan mode.
Data collection and reduction along with absorption correction
a
(
l
¼ 0.71073 Å) radiation using a
j-
u
O), 1566, 937, 691 cmꢁ1; 1H NMR (CDCl3, 600 MHz)
d
: 7.42e6.91 (m,
were performed using CrysAlis software package [59]. The struc-
ture was solved by direct methods using SHELXS-97 [60], which
revealed the positions of almost all non-hydrogen atoms. The
remaining atoms were located from subsequent difference Fourier
syntheses. All H atoms were positioned geometrically [CeH ¼ 0.93,
0.96, 0.97 Å and NeH ¼ 0.86 Å] and allowed to ride on their parent
atoms, with Uiso(H) ¼ 1.2e1.5Ueq of the C or N atom. The structure
was refined using SHELXL-97 [60] with the anisotropic thermal
13H, Ar-H), 3.72 (s, 2H, Ar-CH2), 3.62 (s, 2H, NCH2-thiophene), 3.07
(t, J ¼ 5.4 Hz, 2H, NCH2CH2), 2.84 (t, J ¼ 5.4 Hz, 2H, NCH2CH2), 2.42
(s, 3H, Ar-CH3), 2.35 (s, 3H, Ar-CH3); EI-MS m/z (%): 493 (Mþ, 51),
402 (12), 374 (85), 267 (11), 91 (100). Anal. calcd for C30H27N3O2S: C
73.00, H 5.51, N 8.51; found: C 73.33, H 5.19, N 8.76.
7-Benzyl-3-(3-methylphenyl)-2-(1-naphthyloxy)-5,6,7,8-
tetrahydropyrido[4′,3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one

H. Chen, M.-G. Liu / Journal of Molecular Structure 1180 (2019) 31e40
39
S. Rault, N. Azas, Discovery of new thienopyrimidinone derivatives displaying
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collected in Table 2. CCDC-1041344 for 4a, CCDC-1041233 for 5a,
CCDC-1041236 for 5b and CCDC-846702 for 5c contain the sup-
plementary crystallographic data for this contribution. These data
can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/conts/retrieving.html or from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: þ44 1223-336-033; or e-mail: deposit@
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In conclusion, we report herein
a facile synthesis of 2-
substituted derivatives of 7-benzyl-5,6,7,8-tetrahydropyrido
[40,3':4,5]thieno [2,3-d]pyrimidin-4(3H)-ones using a sequential
aza-Wittig/base catalyzed cyclization method with good yields.
Crystal structure determination of three tetrahydropyrido
[40,3':4,5]thieno [2,3-d]pyrimidinone derivatives has been under-
taken in order to better understanding the influence of structural
modifications upon overall molecular geometry and conformation.
Meanwhile, crystal structure of a guanidine intermediate was
characterized in order to proclaim the reaction mechanism of the
base catalyzed intramolecular cycloaddition. Due to the easily
accessible and versatile starting material and the neutral ring-
closure condition, this synthetic approach discussed here has po-
tential for the synthesis of various pyridothienopyrimidinone de-
rivatives, which are of considerable interest as potential biologically
active compounds in chemical biology study or pharmaceuticals in
drug discovery.
Acknowledgement
This work was financially supported by the National Natural
Science Foundation of China (Grant Numbers 21602123, 31370373
and 21102084) and Natural Science Foundation of Hubei Province
(Grant Number 2012FKC14401). This research was also partially
supported by Scientific Foundation from graduate school of China
Three Gorges University (Grant Number SDYC2016121) and Natural
Science Foundation of China Three Gorges University (Grant
Number KJ2010B001). We would like to thank the Analytical &
Testing Center of China Three Gorges University for CCD X-ray
single crystal diffractometer work. We are grateful to Dr. Zhun Zhao
for help with the single crystal measurements.
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derivatives
for
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2018.11.091.
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