Efficient constructions of the four different thienopyrimidinone skeletons via various cyclocondensation of o-aminothienonitrile with carbonyl compounds

Article abstract of DOI:10.3987/COM-16-13427

A series of new thienopyrimidinone derivatives were synthesized via a novel, straightforward and efficient tandem cyclocondensation of o-aminothienonitrile 1 and carbonyl compounds 2 in different conditions. The synthesized four thienopyrimidinone skeleto

Full text of DOI:10.3987/COM-16-13427

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HETEROCYCLES, Vol. 92, No. 5, 2016
HETEROCYCLES, Vol. 92, No. 5, 2016, pp. 866 - 885. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 29th January, 2016, Accepted, 22nd March, 2016, Published online, 30th March, 2016
DOI: 10.3987/COM-16-13427
EFFICIENT CONSTRUCTIONS OF THE FOUR DIFFERENT
THIENOPYRIMIDINONE
SKELETONS
VIA
VARIOUS
CYCLOCONDENSATION OF o-AMINOTHIENONITRILE WITH
CARBONYL COMPOUNDS
Junjuan Yang, Daxin Shi, Kai Zhang, Zhangtao Zhao, Fadong Qiu, Yujiao
Bi, Qi Zhang, and Jiarong Li*
School of Chemical Engineering and Environment, Beijing Institute of
Technology, 100081 Beijing, China; E-mail: jrli@bit.edu.cn
Abstract – A series of new thienopyrimidinone derivatives were synthesized via a
novel, straightforward and efficient tandem cyclocondensation of
o-aminothienonitrile 1 and carbonyl compounds 2 in different conditions. The
synthesized four thienopyrimidinone skeletons were thieno[2,3-d]pyrimidinone 3,
tert-hydroxythieno[2,3-d]pyrimidinone 4, symmetrical tetracycle thienothiophene-
pyrimidone 5 and thienopyrimidine 6 respectively. Their plausible mechanisms
were proposed. The properties of compound 5 were investigated.
INTRODUCTION
Thienopyrimidinone derivatives are a highly significant class of nitrogen and sulfur heterocycles and have
received a great interest for pharmaceutical applications and their wide biological activities such as
anticancer, antimalarial, antiinflammatory, antiplasmodial, anticonvulsant and sensitizer (Figure 1).1
Therefore, much attentions have been devoted to the synthesis of thienopyrimidinones. The classical
synthetic approach toward thienopyrimidinone employed the condensation of cyclic ketones and
o-aminothiophene dicarboxamide, which are usually obtained from the hydrolysis of the corresponding
o-aminonitriles.2 And there is still a clear need for versatile methods under environmentally benign
conditions and available starting. The seeking of an efficient synthesis of the thienopyrimidinone is one of
the challenges in modern synthetic community and o-aminothienonitrile 1 seemed to be the precursor of
choice to meet this objective.3 Recently, tandem or domino reaction and multicomponent one-pot
processes are the most common approaches to meet the demand of sustainability and green chemistry.4
Based on the above considerations and following on our previous investigations on green synthetic
protocol of heterocyclic compounds,5,6 we wish to report the green method for synthesis the new

HETEROCYCLES, Vol. 92, No. 5, 2016
867
thienopyrimidinone derivatives (Figure 2, compounds 3, 4, 5, 6) with different skeletons through
controlled cyclization pathways of o-aminothienonitrile and carbonyl compounds in tandem one-pot
reaction which have not been reported.
Figure 1. Selected example of biologically active thienopyrimidinone
R2
S
O
R2
O
R2
R1
R2
S
NH2
N
R1
R2
NH
R3
R1
NH
S
HN
S
NH
R3
R1
HO S
R1
HN
NH
N
H
3
N
R4
R4
N
O
O
4
5
6
Figure 2. The synthesized thienopyrimidinone skeletons in our research
RESULTS AND DISCUSSION
As an eco- and atom-economy, efficient synthetic method of fused heterocycle, cyclocondensations of
aromatic o-aminonitriles and carbonyl compounds via PDF reaction (the Pinner to Dimroth
rearrangement in the Friedlander conversion)7 led to a lot of different nitrogen-containing heterocyclic
compounds
such
as
dihydroquinazoline,8
benzo[f]pyrimidinone,7
pyrazolopyrimidinone,9
pyrido[2,3-d]pyrimidinone10 and pyrimido[4,5-d]pyrimidinone.6 Intrigued by the important bioactivity of
thieno[2,3-d]pyrimidinone and the extension of PDF reaction, we focused our attentions on the
convenient synthesis of sulfur-containing heterocyclic compounds, and the four different
thienopyrimidinone skeleton derivatives were synthesized from the tandem one-pot condensation of
o-aminothienonitrile and carbonyl compounds in the presence of base or Lewis acid.
THIENO[2,3-d]PYRIMIDINONE DERIVATIVES (3)
The key raw substrate o-aminothienonitrile 1 used in our study was prepared from the Gewald reaction

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HETEROCYCLES, Vol. 92, No. 5, 2016
Table 1. Optimized conditions for the synthesis of thieno[2,3-d]pyrimidinone 3[a]
O
R1
R1
CN
O
Acce.
NH
+
S
1
p.
m
Te
e,
im
T
S
NH2
N
H
2
3
Entry
Accelerant
(1 equiv)
ZnCl2
Solvents
Temp.
(°C)
120
Time (h)
R1
Product
Yield[b]
1
2
3
3
3
3
3
3
3
3
3
3
1
2
4
5
3
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
trace
75.3
80.8
85.5
69.5
50.5
32.5
65.6
80.6
83.2
54.7
76.3
86.9
88.2
86.1
87.2
2
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
NaOH
MeONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
120
120
120
2
3
2
4
2
5
EtOH
reflux
reflux
120
80
6
MeCN
7
DMF
8
2
2
2
2
2
2
2
2
2
9
100
140
120
120
120
120
120
120
10
11
12
12
14
15
16
a Reactions conditions: 1 (1 mmol), 2 (1.5 mmol), Acce. (1 equiv) in solvent (3.0 mL). b Isolated yields.
Scheme 1. The synthesis of thieno[2,3-d]pyrimidinone 3
according to the literature procedure.11 The reactivity of the o-aminothienonitriles 1a toward active
ketones 2a as model substrates was investigated to optimize the conditions from the various accelerant
(ZnCl2, pyridine, NaOH, KOH, MeONa, EtONa), temperature, time and solvents, and the appreciated
results were presented in Table 1. Additionally, 120 oC was a better reaction temperature compared to the
others (entries 8-10). On the other hand, the yield of compound 3 was increased with the rasing of time,
but 3.0 h was the better selection (entries 11-14). Furthermore, treatment of compound 1 with

HETEROCYCLES, Vol. 92, No. 5, 2016
869
cyclohexanone 2 in presence of accelerant of EtONa under the optimum conditions gave the
thieno[2,3-d]pyrimidinone 3a, 3b and 3c in good yield of 85.5%, 86.1% and 87.2% respectively (entries 4,
15 and 16). The structures of 3 were established based on the spectral data.12 For example, the IR
1
spectrum of compound 3b showed absorb bands at 3247, 3208 (NH) and 1618 cm-1 (C=O). Its H NMR
(400 Hz, DMSO-d6) revealed singlet at 7.28 and 7.11 ppm assigned for two NH and its HRMS spectrum
showed the ESI peak at 319.1843. Based on the data and our previous results, the possible mechanism can
be explained as follows: Firstly, intermediate Int 1 was produced by the addition of the amino group of 1
onto the carbonyl of cyclohexanone 2 and creation of a N-C bond; Then the OH group of Int 1 attacked
the nitrile group of the o-aminothienonitriles 1 to afford oxazine Int 2 via intramolecular Pinner reaction.
Thereafter, Int 2 rearranged to the final product 3 (Dimroth rearrangement). And we named it as PDF
conversion (Scheme 1).7
TERTIARY HYDROXYL THIENO[2,3-d]PYRIMIDINONE DERIVATIVES (4)
For reducing the toxicity and increasing the biological activity, modified functional group on drug
skeleton was a conventional process and introducing a hydroxyl group has been considered as a facile
strategy
in
the
pharmaceutical
research.
It
was
worthy
to
synthesize
the
tert-hydroxythieno[2,3-d]pyrimidinone
4
which both the tertiary hydroxyl group and
thieno[2,3-d]pyrimidinone framework are combined into such a molecule. Normally, the traditional
synthesis of a tert-hydroxyl heterocyclic derivatives includes a two step process: the organic heterocyclic
skeleton was firstly constructed; and then the tertiary hydroxyl group was introduced by microbial
epoxidation,13 vivo oxidation of secondary hydroxyl series,14 alkylation of carbonyl compound,15
hydroxylation of α-furyllithium,16 asymmetric Michael addition17 and photocatalytic oxygention.18
Notably, photocatalytic reactions played important roles in both natural and artificial systems. Inspired by
the interesting works of photo-assisted synthesis and the previous results, we sought to develop a method
for the preparation of the tert-hydroxythieno[2,3-d]pyrimidinone 4 via a green one-step tandem process of
o-aminothienonitrile and carbonyl compounds.
Initially, the reaction of the o-aminothienonitrile 1a and ketone 2a afforded the fused heterocyclic
derivatives 4a containing a tert-hydroxyl substituted thieno[2,3-d]pyrimidinone in the presence of EtONa
at 120 oC with the 380 nm UV lamp irradiation (Table 2, entry 1). And a series of o-aminothienonitriles 1
and ketones
2
were employed to apply this reaction to give more corresponding
(Table 2). Interestingly, only the reaction of
tert-hydroxythieno[2,3-d]pyrimidinones
4
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile 1a and cyclohexanone 2a (m = n = 1)
provided the aimed product 4, and other designed product (m ≠ 1 or n ≠ 1) was not obtained according to
our experiment results (entries 1-9). Evidently, the substituted group on 1 and 2 significantly impacted the
preparation of 4 and only the six-membered naphthenic hydrocarbon substituted 1 and 2 (m = n = 1)

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HETEROCYCLES, Vol. 92, No. 5, 2016
could receive the corresponding derivatives 4 with good yields perhaps for the steric hindrance and ring
tension. A series of six-membered naphthenic hydrocarbon substituted substrates 1 and 2 (m = n = 1)
could be used for the synthesis of the tert-hydroxylated fused thiophene derivatives 4 (entries 10-21). The
results showed that the reactions were tolerated and afforded derivatives 4b-4m respectively when 1 and
2 bear an electron-donating group (R2 = m-, p-, Me, Et). The hydroxylated fused thiophene derivatives 4
were formed in one-pot of the different six-membered naphthenic hydrocarbon substituted on compounds
1 and 2 perhaps for the thermodynamic stability of six-membered ring and low strain of cyclohexane
collective effect.19
Table 2. The synthesis of tert-hydroxythieno[2,3-d]pyrimidinone 4[a]
Entry
1
n
1
0
0
0
1
1
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
m
1
0
1
2
0
2
0
1
2
1
1
1
1
1
1
1
1
1
1
1
1
R1
H
R2
H
R3
H
R4
H
Product Yield[b]
65.7
trace
trace
trace
trace
trace
trace
trace
trace
73.5
60.2
80.1
57.8
66.3
57.6
75.2
71.5
78.3
72.1
70.8
59.6
4a
--[c]
--
2
H
H
H
H
3
H
H
H
H
4
H
H
H
H
--
5
H
H
H
H
--
6
H
H
H
H
--
7
H
H
H
H
--
8
H
H
H
H
--
9
H
H
H
H
--
10
11
12
13
14
15
16
17
18
19
20
21
a
H
H
H
Me
Et
H
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
H
H
Me
H
Me
Me
Me
Me
H
H
H
H
Me
H
H
H
Me
Et
H
H
H
Me
Me
Me
Et
Et
H
H
Me
H
H
4j
4k
4l
H
Me
H
H
Me
H
H
Me
4m
Reactions conditions: 1a (1 mmol), EtONa (1 equiv) in corresponding ketones 2 (3.0 mL) at
120 oC for 3.0 h under irradiation with 380 nm UV lamp. b Isolated yields. c The products 4 were
not found by TLC or MS.

HETEROCYCLES, Vol. 92, No. 5, 2016
871
1
13
The chemical structures of target compounds 4 were fully characterized by IR, H NMR, C NMR, and
HRMS, while product 4a was unequivocally confirmed by X-ray diffraction analysis (Figure 3).
Figure 3. Molecular structure of compound 4a
Based on the synthesis of heterocyclic compounds 3, the mechanism can be explained as follows:
Intermediate 3 was produced by the PDF reaction, and then 3 slowly translate to the hydroxylated target
materials 4 via a tandem reaction of photo-oxygenation (Scheme 2).20
Scheme 2. The synthesis of tert-hydroxythieno[2,3-d]pyrimidinone derivatives 4
In order to prove the proposed mechanism, the intermediate 3 was tried to be separated, and fortunately,
3a was detected by TLC and isolated by thin-layer chromatography in the reaction of 1 with carbonyl
compound 2 with the 380 nm UV lamp irradiation after 1.0 h. Then 3a was induce-oxygenated in ketones
solvent in the presence of EtONa with the 380 nm UV lamp irradiation and gave the targeted product 4c
in 60.2% yield (Scheme 3).
Scheme 3. The synthesis of 4c by the oxidation of 3a under the UV lamp irradiation

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HETEROCYCLES, Vol. 92, No. 5, 2016
SYMMETRICAL TETRACYCLE THIENOTHIOPHENEPYRIMIDONE DERIVATIVES (5)
As well documented in the literature, organic compound of the 10π rich thieno[2,3-d]thiophene, a bifused
skeleton, have attracted considerable attention in the development of axially chiral systems and nonlinear
optics materials.21 In the last decades, thieno[2,3-d]thiophene derivatives have found applications as
pesticides, ligand of transition metal and clathrate crystals, dyes, etc.22 Taking into account the
importance of symmetrical thieno[2,3-d]thiophene and thienopyrimidinone cores in both biological and
chemical fields, the direct approaches to the preparation of symmetrical tetracycle thienothiophene-
pyrimidone derivatives (5) via an efficient tandem procedure was remain highly valuable additions.
SYNTHESES
3,4-Diaminothieno[2,3-d]thiophene-2,5-dicarbonitrile 7 was prepared according to the literature
methods.23 Initial attempts were made by heating a mixture of equal molar amounts of 7 and cyclic
ketones 8 under refluxing in the presence of EtONa for 4.0 h and the corresponding
tetrahydrothienothiophenepyrimidone compounds 5h was obtained in a moderate yields through PDF
conversion. The reactions with a series of ketones including aliphatic ketones and aromatic ketones or
aldehyde were all investigated and the results were summarized in Table 3.
Table 3. The synthesis of symmetric fused thienopyrimidinone derivatives 5[a]
Entry
1
R1
R2
Product
5a
Yield[b] (%)
Me
Me
Et
74
61
62
60
56
66
62
68
64
50
76
71
69
2
Me
5b
5c
3
Me
nPr
Et
4
Et
5d
5e
5
Me
iPr
iBu
6
Me
5f
7
R1+R2=(CH2)4
5g
8
R1+R2=(CH2)5
5h
5i
9
R1+R2=(CH2)6
10
11
12
13
a
R1+R2=(CH2)5Me
5j
Me
Et
Ph
5k
5l
Ph
H
nPr
5m
Reactions conditions: 7 (1 mmol), EtONa (2 equiv) in corresponding ketones 8 or ethanol (3.0
mL) refulx for 4.0 h. b Combined yield of isolated crude products.

HETEROCYCLES, Vol. 92, No. 5, 2016
873
While the cyclic ketones such as cyclopentanone, cyclohexanone, cycloheptanone and methylcyclohexa-
none were used, the reaction in ethanol had the moderate yield (Table 3, entries 1-4) perhaps for the ring
tension of cyclic ketones. Theoretically, the steric hindrance and ring tension may effect on the reaction.
As expected, the larger steric hindrance of ketones afforded the lower yields (Table 3, entries 4-13).
STRUCTURE ANALYSIS
Figure 4. Molecular structure of compound of 5a (left) and 5h (right)
Figure 5. Packing diagram of compound 5a (left) and 5h (right)
1
13
The target compounds 5 were fully characterized by IR, H NMR, C NMR, and HRMS, while product
5a and 5h were confirmed by X-ray diffraction analysis (Figure 4). Compounds 5 were symmetrical and
showed the similar structure containing a tetracyclic thienothiophenepyrimidone fused system. In these
tetracyclic fused ring system, the tetrahydrothienothiophenepyrimidone center afford the π-conjugated
interaction rigid planar structure which could lead to the large ultraviolet absorption and
photoluminescence.24 Furthermore, novel intermolecular interactions were noticed. As shown in Figure 5,
in the packing crystal of compound 5a and 5h, there were numbers of molecular pairs and they packed in
a parallel and face to face style. Each molecular pair were joined by hydrogen bonds, π-conjugation and

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HETEROCYCLES, Vol. 92, No. 5, 2016
formed a dimer.25 Based on the special structure of hydrogen bond and π-conjugated interaction, we can
conjecture that compound 5 will show better thermal stable and good optical properties.
THERMAL STABLE PROPERTIES
The thermal properties of selected 5a and 5h were gauged by thermogravimetric analysis (TGA). Both of
them exhibited high thermal stability as demonstrated by its TGA (Figure 6), with its rapid weight loss
o
o
temperature being up to 330.0 and 335.0 C. Notable, the weight loss temperature at 150 C attributed to
the loss of DMF crystallization. Additionally, 5h showed a higher melting temperature with a higher
molecular weight.
Figure 6. TG plots of 5a and 5h under N2 atmosphere
OPTICAL PROPERTIES
Figure 7. UV-vis absorption spectra (UV-vis) and fluorescence emission (FL) excited at 365 nm (right)
of compound 5h in ethanol solution at room temperature with the same concentration of 10 μM
The optical properties of compound 5h was examined by UV-vis and photoluminescence (PL) techniques
in ethanol solvent (Figure 7). As shown in Figure 7, compound 5h exhibited characteristic absorptions in
EtOH with a sharp absorption band centered at 238 nm and a broad one centered at 365 nm assigned to a

HETEROCYCLES, Vol. 92, No. 5, 2016
875
planar aromatic tetracyclic thienothiophenepyrimidone skeletons center π-conjugated interactions.
Additionally, compound 5h gave a good fluorescent emission (Φ = 0.18) at 478 nm in MeCN and a better
fluorescent emission (Φ = 0.21) at 475 nm in EtOH. These results revealed that compound 5 have
excellent thermally stable properties and good optical properties with the more potential applications in
organic semiconductor.24
THIENOPYRIMIDINES DERIVATIVES (6)
In view of the potential use of thienopyrimidines 6 as biological agents and drugs,25 in a follow up of this
investigation,26 we turned our attention on the possibility for the synthesis of heterocyclic
thienopyrimidines center via green process. The traditional synthetic approach towards thienopyrimidines
suffered from the tedious synthetic routes and time-consuming experimental procedures. Classically,
microwave irradiation has taken an important role in chemical laboratory practice for clean, fast and
convenient energy source. With respect to the valuable thienopyrimidines and in continuation of our
efforts on the green reaction of o-aminothienonitrile,9,27 an immediate, simple and straightforward
protocol for the synthesis of thienopyrimidines 6 was studied through the condensation of
o-aminothienonitrile and formamide catalyzed by ZnCl2 in DMF under microwave irradiation, and some
results were presented here (Table 4).
Table 4. The synthesis of thienopyrimidines derivatives 6[a]
Entry
Accelerant (1 equiv) Solvents
R1+R2
Product
Yield[b]
1
2
3
a
EtONa
EtONa
EtONa
DMF
DMF
DMF
R1+R2 = (CH2)3
R1+R2 = (CH2)4
R1+R2 = (CH2)5
56.9
61.2
63.1
6a
6b
6c
All reactions were carried out at variable power in a Biotage microwave reactor for 20 min using 1 (1
mmol), formamide (0.5 mL) and ZnCl2 (1.2 equiv) in DMF (1.5 mL) at reflux for 4.0 h. b Isolated yields.
CONCLUSION
In conclusion, the four new thienopyrimidinone skeletons were synthesized via a tandem one-pot
cyclocondensation reaction of o-aminothienonitrile and carbonyl compounds in different conditions. The
mild conditions, simple execution and good yields of products, made it an efficient and promising
synthetic strategy to build thienopyrimidinone skeletons with the potential applications in drugs or
semiconductor. The synthetic derivatives showed good thermal stable and optical properties.

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HETEROCYCLES, Vol. 92, No. 5, 2016
EXPERIMENTAL
General Methods: The starting materials 1 and 7 were prepared according to the literature methods.11,23
The solvents and other reagents were purchased from commercial sources and used without further
purification. Melting points were determined using XT4 microscope melting point apparatus
(uncorrected). Infrared (IR) spectra were recorded on a Perkin Elmer FT-IR spectrophotometer with KBr
1
13
pellets. H and C NMR spectra were recorded at a Bruker 400 or 500 MHz spectrometer with TMS as
the internal standard. Mass spectra were obtained with ESI ionization using a Bruker APEX IV and
ZAB-HS mass spectrometer. Ultravioletevisible (UV-vis) absorption were measured on a Hitachi
U-3900H spectropho-tometer using quartz cells of 1.0 cm path length (190-1100 nm scan range).
Fluorescence spectra measurements were performed on a Hitachi F-7000 spectrofluorimeter with quartz
cuvettes of 1.0 cm path length with a xenon lamp as the excitation source. Luminescence quantum yields
were measured using a solution of quinine sulfate in sulfuric acid (0.5M) as a standard (Φ = 0.54)28 and
were corrected for the different refraction indexes of the solvents. TGA was recorded on TGDTA 6200
LAB SYS.
General Procedure for the Synthesis of 3: To a mixture of compound 1 (1 mmol) and corresponding
ketones 2 (3 mL), 1 equiv of sodium ethoxide was added dropwise under stirring, and then the reaction
o
mixture was heated at 120 C for 3.0 h. The reaction mixture was cooled to room temperature after the
reaction finished with TLC monitoring. The resulting precipitate was collected by filtration. The crude
products were recrystallized from 95% EtOH to afford pure compounds 3.
4'-Ethyl-5,6,7,8-tetrahydro-1H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclohexan]-4(3H)-one
o
(3a): White solid; mp 278-279 C; IR (KBr, υ, cm-1) 3247, 3207, 3026, 2928, 2851, 1618, 1573, 1536,
1597, 1438; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 7.29 (s, 1H), 7.11 (s, 1H), 2.65 (q, J = 8.0 Hz, 2H),
2.45 (t, J = 8.0 Hz, 2H), 2.00 (t, J = 8.0 Hz, 2H), 1.71-1.13 (m, 13H), 0.85 (t, J = 12.0 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6) (δ, ppm): 162.1, 156.4, 132.2, 118.2, 108.8, 92.8, 77.4, 70.9, 37.8, 35.8, 28.2, 26.9,
25.9, 24.3, 23.5, 22.5, 12.1; HRMS (ESI): calcd For C17H24N2OS [M+H]+ 305.16821; found 305.16848.
4'-Ethyl-7-methyl-5,6,7,8-tetrahydro-1H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclohexan]-
o
4(3H)-one (3b): White solid; mp 259-260 C; IR (KBr, υ, cm-1) 3387, 3248, 3208, 3029, 2950, 2918,
1
2846, 2832, 1619, 1574, 1536, 1496, 1439; H NMR (400 MHz, DMSO-d6) (δ, ppm): 7.28 (s, 1H), 7.11
(s, 1H), 2.88-2.84 (m, 1H), 2.56-2.47 (m, 1H), 2.12-1.14 (m, 16H), 1.00 (d, J = 8.0 Hz, 3H), 0.87 (t, J =
13
16.0 Hz, 3H); C NMR (100 MHz, DMSO-d6) (δ, ppm): 162.2, 156.5, 131.9, 117.8, 108.7, 93.0, 77.5,
37.8, 35.8, 32.5, 30.9, 29.7, 28.4, 28.2, 26.9, 25.6, 21.9, 12.1; HRMS (ESI): calcd For C18H26N2OS
[M+H]+ 319.1839; found 319.1843.
4',7-Diethyl-5,6,7,8-tetrahydro-1H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclohexan]-4(3H)-
one (3c): White solid; mp 250-252 oC; IR (KBr, υ, cm-1) 3246, 3208, 3025, 2955, 2919, 2872, 2850, 1618,

HETEROCYCLES, Vol. 92, No. 5, 2016
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1
1575, 1537, 1497, 1437; H NMR (400 MHz, DMSO-d6) (δ, ppm): 7.29 (s, 1H), 7.15 (s, 1H), 2.89-2.85
13
(m, 1H), 2.56-2.47 (m, 1H), 2.09-2.00 (m, 3H), 1.78-1.13 (m, 16H), 0.85-0.81 (m, 6H); C NMR (100
MHz, DMSO-d6) (δ, ppm): 162.2, 156.5, 132.1, 117.9, 108.7, 70.9, 70.3, 37.8, 36.5, 35.8, 30.3, 28.9, 28.7,
28.2, 27.1, 26.9, 25.7, 12.1, 11.8; HRMS (ESI): calcd For C19H28N2OS [M+H]+ 333.19951; found
333.19909.
General Procedure for the Synthesis of 4: To a mixture of compound 1 (1 mmol) and corresponding
ketones 2 (3 mL), 1 equiv of sodium ethoxide was added dropwise under stirring with 380 nm UV lamb
irradiation, and then the reaction mixture was heated at 120 oC for 3.0 h. The reaction mixture was cooled
to room temperature after the reaction finished with TLC monitoring. The compounds 4 were obtained by
column chromatography on silica gel (200-300 mesh silica gels) with EtOAc–petroleum ether (1:3, v: v)
as eluent or by filtration.
8a-Hydroxy-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclohexan]-4-
(5H)-one (4a): White solid; mp 209-211 oC; IR (KBr, υ, cm-1) 3402, 3184, 3054, 2962, 2921, 2834, 1676,
1
1653, 1629, 1455, 1427, 1410; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.56 (s, 1H), 6.96 (s, 1H), 3.89
13
(d, J = 12Hz, 1H), 2.52 (t, J = 12.0 Hz, 1H), 2.35 (q, J = 15.0 Hz, 1H), 1.89-1.21 (m, 15 H); C NMR
(100 MHz, DMSO-d6) (δ, ppm): 166.3, 165.6, 158.6, 115.5, 92.2, 76.8, 40.4, 40.1, 39.9 26.7, 25.6, 24.8,
21.9, 21.8, 21.7; HRMS (ESI): calcd For C15H20N2O2S [M+H]+ 293.13183; found 293.13143.
8a-Hydroxy-3'-methyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclo-
o
hexan]-4(5H)-one (4b): White solid; mp 223-224 C; IR (KBr, υ, cm-1) 3398, 3182, 3058, 2942, 2933,
1
2867, 2839, 1677, 1653, 1630, 1455, 1409; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.51 (s, 1H), 6.94
(s, 1H), 3.98 (d, J = 15 Hz, 1H), 2.52 (t, J = 4.0 Hz, 1H), 2.33 (q, J = 12 Hz, 1H), 1.78-1.25 (m, 14H),
0.85 (q, J = 20 Hz,3 H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.9, 166.5, 159.4, 115.9, 92.9, 77.8,
49.3, 48.7, 33.7, 27.1, 27.0, 26.7, 26.0, 22.6, 22.2, 20.7; HRMS (ESI): calcd For C16H22N2O2S [M+H]+
307.14748; found 307.14738.
8a-Hydroxy-4'-methyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclo-
o
hexan]-4(5H)-one (4c): White solid; mp 212-213 C; IR (KBr, υ, cm-1) 3408, 3204, 3068, 2951, 2931,
1
2863, 2842, 1674, 1650, 1637, 1441, 1396; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.54 (s, 1H), 6.95
13
(s, 1H), 3.89 (d, J = 12Hz, 1H), 2.52 (t, J = 4.0 Hz, 1H), 1.89-1.29 (m, 15H), 0.931 (s, 3 H); C NMR
(100 MHz, DMSO-d6) (δ, ppm): 166.9, 166.5, 159.2, 115.9, 92.8, 77.2, 77.1, 40.4, 40.2, 31.9, 31.1, 29.9,
28.8, 28.7, 27.1, 26.0, 22.5, 22.2, 20.8; HRMS (ESI): calcd For C16H22N2O2S [M+H]+ 307.14748; found
307.14743.
4'-Ethyl-8a-hydroxy-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclohex-
an]-4(5H)-one (4d): White solid; mp 227-229 oC; IR (KBr, υ, cm-1) 3225, 2929, 2852, 1665, 1619, 1536,
1
1497, 1440; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.51 (s, 1H), 6.93 (s, 1H), 3.88 (d, J = 12.0 Hz,

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HETEROCYCLES, Vol. 92, No. 5, 2016
1H), 2.63-1.13 (m, 16H), 0.85-0.84 (m, 5H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 161.6, 161.2,
155.9, 117.7, 92.2, 76.9, 70.4, 43.2, 41.2, 38.1, 35.3 28.9, 26.6, 25.5, 23.8, 22.1, 12.0; HRMS (ESI): calcd
For C17H24N2O2S [M+H]+ 321.16313; found 321.16352.
8a-Hydroxy-6-methyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclohe-
xan]-4(5H)-one (4e): White solid; mp 214-215 oC; IR (KBr, υ, cm-1) 3400, 3187, 3058, 2954, 2927, 2871,
1677, 1654, 1631, 1455, 1428, 1407; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.53 (s, 1H), 6.91 (s, 1H),
3.87 (q, J = 12 Hz, 1H), 2.51 (t, J = 4.0 Hz, 1H), 2.26-1.21 (m, 14H), 1.00-0.98 (m, 3H), 0.84-0.82 (m,
13
1H); C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.5, 166.2, 158.8, 115.5, 92.5, 76.7, 43.4, 38.3, 31.5,
29.5, 28.5, 26.8, 25.7, 22.2, 21.8, 20.5; HRMS (ESI): calcd For C16H22N2O2S [M+H]+ 307.14748; found
307.14752.
8a-Hydroxy-3',6-dimethyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-
o
cyclohexan]-4(5H)-one (4f): White solid; mp 241-242 C; IR (KBr, υ, cm-1) 3401, 3185, 3060, 2953,
2922, 2869, 1677, 1652, 1630, 1454, 1429, 1408; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.51 (s, 1H),
6.93 (s, 1H), 3.86 (q, J = 12 Hz, 1H), 2.50 (t, J = 8.0 Hz, 1H), 2.02-1.36 (m, 14H), 0.87-0.85 (m, 3H),
0.84-0.83 (m, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.8, 166.4, 159.3, 115.8, 92.4, 77.8, 49.2,
48.7, 42.8, 34.4, 34.0, 33.7, 30.6, 26.9, 26.7, 22.6, 20.5; HRMS (ESI): calcd For C17H24N2O2S [M+H]+
321.16313; found 321.16289.
8a-Hydroxy-4',6-dimethyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-
o
cyclohexan]-4(5H)-one (4g): White solid; mp 212-213 C; IR (KBr, υ, cm-1) 3399, 3192, 3065, 2951,
2926, 2870, 2846, 1675, 1650, 1629, 1450, 1397; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.54 (s, 1H),
6.91 (s, 1H), 3.87 (q, J = 12 Hz, 1H), 2.49 (t, J = 4.0 Hz, 1H), 2.08-1.40 (m, 14H), 1.00-0.98 (m, 3H),
0.94-0.91 (m, 3H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.3, 166.2, 159.2, 116.0, 92.3, 77.2, 42.8,
41.6, 34.4, 34.0, 31.9, 31.1, 29.8, 28.8, 28.6, 22.6, 20.7; HRMS (ESI): calcd For C17H24N2O2S [M+H]+
321.16313; found 321.16355.
4'-Ethyl-8a-hydroxy-6-methyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-
o
cyclohexan]-4(5H)-one (4h): White solid; mp 232-234 C; IR (KBr, υ, cm-1) 3389, 3250, 3087, 2931,
1
2855, 2843, 1671, 1649, 1627, 1449, 1429; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.53 (s, 1H), 6.92
(s, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.31 (d, J = 12.0 Hz, 1H), 2.50-0.97 (m, 16H), 0.86-0.83 (m, 6H); 13C
NMR (100 MHz, DMSO-d6) (δ, ppm): 165.7, 165.4, 158.6, 115.5, 91.7, 76.9, 69.2, 42.3, 41.2, 38.2, 35.4,
33.5, 30.6, 30.2, 29.0, 28.3, 22.1, 11.6; HRMS (ESI): calcd For C18H26N2O2S [M+H]+ 335.17878; found
335.17880.
8a-Hydroxy-7-methyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-cyclohe-
xan]-4(5H)-one (4i): White solid; mp 220-221 oC; IR (KBr, υ, cm-1) 3401, 3184, 3058, 2948, 2916, 2868,
2862, 1678, 1655, 1629, 1456, 1411; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.52 (s, 1H), 6.91 (s, 1H),

HETEROCYCLES, Vol. 92, No. 5, 2016
879
3.87 (q, J = 20 Hz, 1H), 2.49 (t, J = 20.0 Hz, 1H), 2.36 (q, J = 15 Hz, 1H), 1.86-1.04 (m, 14H), 0.98-0.85
13
(m, 3H); C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.4, 166.1, 159.0, 116.1, 92.9, 77.3, 51.5, 40.6,
35.2, 28.4, 25.4, 25.3, 22.3, 22.2, 22.1, 21.3; HRMS (ESI): calcd For C16H22N2O2S [M+H]+ 307.14748;
found 307.14730.
8a-Hydroxy-3',7-dimethyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-
o
cyclohexan]-4(5H)-one (4j): White solid; mp 246-248 C; IR (KBr, υ, cm-1) 3402, 3185, 3060, 2948,
2926, 2867, 2838, 1678, 1655, 1627, 1456, 1411; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.51 (s, 1H),
6.95 (s, 1H), 3.87 (q, J = 12 Hz, 1H), 2.50 (t, J = 8.0 Hz, 1H), 2.37 (q, J = 8 Hz, 1H), 1.79-1.33 (m, 12H),
13
1.06-1.01 (m, 1H), 0.86-0.82 (m, 6H); C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.6, 166.5, 159.3,
116.0, 93.0, 77.9, 51.5, 49.3, 49.2, 33.7, 28.4, 27.0, 25.4, 22.6, 21.3, 20.5, 20.2; HRMS (ESI): calcd For
C17H24N2O2S [M+H]+ 321.16313; found 321.16273.
8a-Hydroxy-4',7-dimethyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-
o
cyclohexan]-4(5H)-one (4k): White solid; mp 214-215 C; IR (KBr, υ, cm-1) 3410, 3194, 3064, 2950,
1
2927, 2869, 1675, 1652, 1626, 1451, 1399; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.54 (s, 1H), 6.94
(s, 1H), 3.87 (q, J = 16 Hz, 1H), 2.50 (t, J = 12.0 Hz, 1H), 2.40 (q, J = 12 Hz, 1H), 1.86-1.06 (m, 13H),
13
0.94-0.91 (m, 3H), 0.86-0.82 (m, 3H); C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.5, 166.4, 159.2,
116.1, 93.0, 77.2, 51.5, 40.4, 38.6, 35.2, 31.9, 29.9, 28.8, 28.4, 25.4, 21.3. 20.1; HRMS (ESI): calcd For
C17H24N2O2S [M+H]+ 321.16313; found 321.16291.
8a-Hydroxy-4',7-dimethyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-
o
cyclohexan]-4(5H)-one (4l): White solid; mp 230-232 C; IR (KBr, υ, cm-1) 3407, 3182, 3059, 2948,
1
2922, 2850, 1677, 1655, 1629, 1456, 1411; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.53 (s, 1H), 6.97
(s, 1H), 3.88 (q, J = 12 Hz, 1H), 2.50-2.37 (m, 1H), 1.92-0.86 (m, 21H); 13C NMR (100 MHz, DMSO-d6)
(δ, ppm): 166.8, 159.3, 115.9, 93.1, 77.9, 49.4, 49.2, 32.9, 28.4, 25.4, 22.6, 20.5, 11.9; HRMS (ESI):
calcd For C18H26N2O2S [M+H]+ 335.17878; found 335.17828.
8a-Hydroxy-4',7-dimethyl-6,7,8,8a-tetrahydro-3H-spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,1'-
o
cyclohexan]-4(5H)-one (4m): White solid; mp 235-237 C; IR (KBr, υ, cm-1) 3400, 3194, 3064, 2949,
1
2924, 2868, 1676, 1651, 1637, 1450, 1399; H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.56 (s, 1H), 6.96
13
(s, 1H), 3.88 (q, J = 8 Hz, 1H), 2.51-0.86 (m, 23H); C NMR (100 MHz, DMSO-d6) (δ, ppm): 166.8,
159.2, 116.2, 93.1, 77.2, 49.4, 34.8, 32.9, 28.8, 28.6, 28.4, 25.4, 11.9; HRMS (ESI): calcd For
C18H26N2O2S [M+H]+ 335.17878; found 335.17834.
General Procedure for the Synthesis of 5: To a mixture of compound 7 (1 mmol) and corresponding
ketones 8 (3 mL), 2 equiv of sodium ethoxide was added dropwise under stirring, and then the reaction
mixture was heated under reflux for 4.0 h. The reaction mixture was cooled to room temperature after the
reaction finished with TLC monitoring. The resulting precipitate was collected by filtration. The target

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HETEROCYCLES, Vol. 92, No. 5, 2016
product compounds 5 were obtained through washing alternately with water and EtOH for several times
and then dried.
2,2,9,9-Tetramethyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]pyrimidi-
o
ne-4,7(1H,8H)-dione (5a): yellow solid; mp > 300 C; IR (KBr, υ, cm-1) 3264, 2977, 1638, 1592, 1545,
1399, 1181, 1116, 766, 602, 509; 1H NMR (DMSO-d6, 400 MHz) δ: 7.61 (s, 2H, NH), 7.22 (s, 2H, NH),
1.50 (s, 12H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ: 161.0, 147.6, 143.1, 126.2, 106.0, 69.0, 28.0;
HRMS (ESI): calcd For C14H16N4O2S2 [M+H]+ 337.07874; found 337.07849.
2,9-Dimethyl-2,9-diethyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]pyri-
o
midine-4,7(1H,8H)-dione (5b): Yellow solid; mp > 300 C; IR (KBr, υ, cm-1) 3263, 2969, 2929, 1631,
1607, 1554, 1403, 1117, 764, 601; 1H NMR (DMSO-d6, 400 MHz) δ: 7.61 (s, 2H, NH), 7.16 (d, J = 7.41
Hz, 2H, NH), 1.79 (dd, J = 7.78, 16.07 Hz, 4H, CH2), 1.47 (t, J = 13.77 Hz, 6H, CH3), 0.90 (dd, J = 7.14,
16.51 Hz, 6H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ: 160.9, 147.4, 143.0, 142.9, 126.2, 105.5, 105.4,
71.7, 71.6, 32.2, 26.4, 26.0, 8.4, 8.3; HRMS (ESI): calcd For C16H20N4O2S2 [M+H]+ 365.11004; found
365.10963.
2,9-Dimethyl-2,9-dipropyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]py-
rimidine-4,7(1H,8H)-dione (5c)˖˖Yellow solid; mp > 300 oC; IR (KBr, υ, cm-1) 3262, 2959, 2932, 2871,
1639, 1602, 1557, 1453, 1402, 1158, 1117, 766, 601, 513; 1H NMR (DMSO-d6, 400 MHz) δ: 7.62 (s, 2H,
NH), 7.11 (d, J = 12.72 Hz, 2H, NH), 1.70 (d, J = 38.01 Hz, 4H, CH2), 1.47 (d, J = 4.05 Hz, 6H, CH3),
1.40 (s, 4H, CH2), 0.87 (d, J = 6.14 Hz, 6H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ: 160.9, 147.4, 143.0,
142.9, 126.1, 105.6, 71.4, 71.3, 42.1, 26.8, 26.5, 16.8, 14.0; HRMS (ESI): calcd For C18H24N4O2S2
[M+H]+ 393.14134; found 393.14025.
2,2,9,9-Tetraethyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]pyrimidine-
o
4,7(1H,8H)-dione (5d): Yellow solid; mp > 300 C; IR (KBr, υ, cm-1) 3357, 3269, 3059, 2970, 2934,
1643, 1601, 1551, 1405, 1376, 1119, 767, 614; 1H NMR (DMSO-d6, 400 MHz) δ: 7.51 (s, 2H, NH), 6.97
(s, 2H, NH), 1.78 (dd, J = 13.63, 7.01 Hz, 4H, CH2), 1.68 (dd, J = 13.21, 6.86 Hz, 4H, CH2), 0.91 (d, 12H,
J = 6.34 Hz, CH3); 13C NMR (DMSO-d6, 100 MHz) δ: 161.1, 147.2, 143.1, 126.1, 104.7, 74.5, 30.8, 8.2;
HRMS (ESI): calcd For C18H24N4O2S2 [M+H]+ 393.14134; found 393.14033.
2,9-Dimethyl-2,9-diisopropyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]-
o
pyrimidine-4,7(1H,8H)-dione (5e): Yellow solid; mp > 300 C; IR (KBr, υ, cm-1) 3360, 3273, 3090,
1
2965, 2876, 1642, 1602, 1563, 1466, 1399, 1363, 1329, 1172, 1135, 765, 722, 616, 479; H NMR
(DMSO-d6, 400 MHz) δ: 7.76 (s, 2H, NH), 7.24 (s, 2H, NH), 2.31-2.22 (m, 2H, CH), 1.39 (s, 6H, CH3),
0.95-0.85 (m, 12H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ: 160.3, 147.2, 142.2, 126.1, 105.9, 73.5,
34.2, 21.0, 17.0, 16.3; HRMS (ESI): calcd For C18H24N4O2S2 [M+H]+ 393.14134; found 393.14084.

HETEROCYCLES, Vol. 92, No. 5, 2016
881
2,9-Dimethyl-2,9-diisobutyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]-
o
pyrimidine-4,7(1H,8H)-dione (5f): Yellow solid; mp > 300 C; IR (KBr, υ, cm-1) 3259, 2955, 2869,
1639, 1604, 1558, 1466, 1401, 1160, 1121, 765, 614, 508; 1H NMR (DMSO-d6, 400 MHz) δ: 7.55 (s, 2H,
13
NH), 7.13 (s, 2H, NH) 1.83-1.71 (m, 4H, CH2), 1.50 (s, 6H, CH3), 0.91-0.84 (m, 14H, CH(CH3)2); C
NMR (DMSO-d6, 100 MHz) δ: 160.8, 147.3, 142.8, 126.1, 105.3, 71.5, 47.7, 27.0, 24.2, 23.5; HRMS
(ESI): calcd For C20H28N4O2S2 [M+H]+ 421.17264; found 421.17296.
1'H,8'H-dispiro[cyclopentane-1,2'-pyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]pyrimidine-9',
o
1''-cyclopentane]-4',7'(3'H,10'H)-dione (5g):2c Yellow solid; mp 276-278 C; IR (KBr, υ, cm-1) 3252,
1
3072, 2951, 2873, 1712, 1607, 1550, 1402, 1325, 1190, 1124, 1030, 950, 767, 655, 623, 512; H NMR
(DMSO-d6, 400 MHz) δ: 7.84 (s, 2H, NH), 7.27 (s, 2H, NH), 1.93-1.68 (m, 16H, CH2); 13C NMR
(DMSO-d6, 100 MHz) δ: 161.4, 147.7, 143.7, 126.3, 107.3, 78.7, 38.3, 22.0; MS (ESI): m/z = 411.1
[M+Na]+.
1'H,8'H-dispiro[cyclohexane-1,2'-pyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]pyrimidine-9',
1''-cyclohexane]-4',7'(3'H,10'H)-dione (5h): Yellow solid; mp > 300 oC; IR (KBr, υ, cm-1) 3251, 3058,
1
2931, 2855, 1722, 1613, 1552, 1407, 1341, 1275, 1121, 1074, 765, 585, 558; H NMR (DMSO-d6, 400
MHz) δ: 7.66 (s, 2H, NH), 6.90 (s, 2H, NH), 1.95-1.26 (m, 20H, CH2); 13C NMR (DMSO-d6, 100 MHz) δ:
161.0, 147.4, 142.5, 127.7, 108.3, 69.3, 35.7, 24.8, 21.5; HRMS (ESI): calcd For C20H24N4O2S2 [M+H]+
417.14134; found 417.13992.
1'H,8'H-dispiro[cycloheptane-1,2'-pyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]pyramidine-9',
1''-cycloheptane]-4',7'(3'H,10'H)-dione (5i): Yellow solid, mp > 300 oC; IR (KBr, υ, cm-1) 3250, 2923,
1
2851, 1611, 1553, 1410, 1125, 843, 763, 616; H NMR (DMSO-d6, 400 MHz) δ: 7.75 (s, 2H, NH), 7.12
(s, 2H, NH), 2.03-1.91 (m, 8H, CH2), 1.53 (s, 16H, CH2); 13C NMR (DMSO-d6, 100 MHz) δ: 160.7,
147.3, 142.4, 126.9, 107.2, 73.8, 39.1, 28.7, 21.1; HRMS (ESI): calcd For C22H28N4O2S2 [M+H]+
445.17264; found 445.17216.
2,2''-Dimethyl-1'H,8'H-dispiro[cyclohexane-1,2'-pyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]-
pyrimidine-9',1''-cyclohexane]-4',7'(3'H,10'H)-dione (5j): Yellow solid; mp > 300 oC; IR (KBr, υ, cm-1)
3262, 2926, 2866, 1610,1555, 1408, 1342, 1255, 1123, 765, 572; 1H NMR (DMSO-d6, 400 MHz) δ: 7.64
(s, 2H, NH), 7.03 (d, J = 9.18 Hz, 2H, NH), 2.23-1.42 (m, 18H, CH2), 0.91-0.86 (m, 6H, CH3); 13C NMR
(DMSO-d6, 100 MHz) δ: 160.8, 147.8, 143.0, 126.1, 106.4, 70.7, 70.0, 44.6, 35.7, 33.7, 31.2, 28.9, 26.7,
22.1, 21.5, 20.3; HRMS (ESI): calcd For C22H28N4O2S2 [M+H]+ 445.17264; found 445.17125.
2,9-Dimethyl-2,9-diphenyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]py-
rimidine-4,7(1H,8H)-dione (5k): Yellow solid; mp > 300 oC; IR (KBr, υ, cm-1) 3373, 3249, 3078, 2990,
2936, 1641, 1606, 1547, 1444, 1392, 1218, 1152, 1083, 759, 696, 647; 1H NMR (DMSO-d6, 400 MHz) δ:
13
8.63 (s, 2H, NH), 8.31 (s, 2H, NH), 7.58-7.27 (m, 10H, ArH), 1.81(s, 6H, CH3); C NMR (DMSO-d6,

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HETEROCYCLES, Vol. 92, No. 5, 2016
100 MHz) δ: 161.4, 147.5, 147.2, 142.8, 128.0, 127.5, 126.0, 124.8, 108.6, 71.9, 30.1; HRMS (ESI):
calcd For C24H20N4O2S2 [M+H]+ 461.11004; found 461.10905.
2,9-Diethyl-2,9-diphenyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]pyri-
o
midine-4,7(1H,8H)-dione (5l): Yellow solid; mp > 300 C; IR (KBr, υ, cm-1) 3377, 3258, 3060, 2971,
1
2935, 2878, 1638, 1601, 1552, 1446, 1399, 1288, 1197, 1147, 841, 757, 697, 605; H NMR (DMSO-d6,
400 MHz) δ: 8.50 (s, 2H, NH), 8.07 (s, 2H, NH), 7.57-7.28 (m, 10H, ArH) 2.01-1.93 (m, 4H, CH2), 1.12
13
(s, 6H, CH3); C NMR (DMSO-d6, 100 MHz) δ: 161.7, 150.4, 147.3, 143.1, 128.0, 127.5, 126.4, 125.0,
108.0, 75.3, 34.5, 9.4; HRMS (ESI): calcd For C26H24N4O2S2 [M+H]+ 489.14134; found 489.14065.
2,9-Dipropyl-2,3,9,10-tetrahydropyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]pyrimidine-4,7-
(1H,8H)-dione (5m): Yellow solid; mp > 300 oC; IR (KBr, υ, cm-1) 3264, 3055, 2956, 2932, 2871, 1624,
1600, 1559, 1454, 1418, 1382, 1256, 1117, 891, 767, 605; 1H NMR (DMSO-d6, 400 MHz) δ: 7.64 (s, 2H,
NH), 7.17 (s, 2H, NH), 4.79 (s, 2H, CH), 1.74 (s, 4H, CH2), 1.47 (s, 4H, CH2), 0.93 (d, J = 6.96 Hz, 6H,
CH3); 13C NMR (DMSO-d6, 100 MHz) δ: 162.1, 148.1, 144.8, 126.1, 108.3, 65.7, 35.4, 17.1, 13.8;
HRMS (ESI): calcd For C16H20N4O2S2 [M+H]+ 365.11004; found 365.10969.
General Procedure for the Synthesis of 6: The microwave reactor "Initiator" (manufactured by Biotage,
formerly Personal Chemistry) was used in all reactions: A solution of corresponding 1 (1 mmol), 0.5 mL
methanamide, ZnCl2 (1.2 mmol) and 1.5 mL DMF were added in a 5 mL tube, sealed and heated to 160
oC for 20 min. After completion of the reaction as indicated by TLC, the mixture was cooled to room
temperature and the precipitate was isolated by filtration and then purified by crystallization from 95%
EtOH to provide the pure compounds 6.
o
6,7-Dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-amine (6a):26d White solid; mp 265-267 C;
IR (KBr, υ, cm-1) 3416, 3304, 2949, 2898, 1687, 1645, 1500, 1472; 1H NMR (400 MHz, CDCl3) (δ, ppm):
8.36 (s, 1H), 5.40 (s, 2H, NH2), 3.07-3.00 (m, 4H), 2.59-2.54 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) δ:
169.5, 156.3, 151.5, 134.8, 134.6, 110.7, 27.7, 27.3, 25.9; MS (ESI): m/z = 192.1 [M+H]+.
5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine (6b):26d White solid; mp 277-278 oC; IR
1
(KBr, υ, cm-1) 3362, 3318, 2927, 2899, 1649, 1570, 1505, 1439; H NMR (400 MHz, CDCl3) (δ, ppm):
8.35 (s, 1H), 5.37 (s, 2H, NH2), 2.93 (t, J = 8.0 Hz, 2H), 2.82 (t, J = 8.0 Hz, 2H), 1.93-1.90 (m, 4H); 13C
NMR (DMSO-d6, 100 MHz) δ: 165.9, 158.6, 153.4, 131.4, 127.4, 115.5, 25.9, 25.3, 22.7, 22.4; MS (ESI):
m/z = 206.1 [M+H]+.
6,7,8,9-Tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-amine (6c):26e White solid; mp
o
1
274-285 C; IR (KBr, υ, cm-1) 3323, 3139, 2925, 2840, 1650, 1557, 1499, 1436; H NMR (400 MHz,
CDCl3) (δ, ppm): 8.34 (s, 1H), 5.39 (s, 2H, NH2), 3.02 (t, J = 8.0 Hz, 2H), 2.90 (t, J = 8.0 Hz, 2H), 1.92
13
(quint, J = 12.0 Hz, 2H), 1.86-1.80 (m, 4H); C NMR (DMSO-d6, 100 MHz) δ: 164.7, 158.6, 152.9,
135.5, 132.6, 116.6, 31.2, 29.0, 27.3, 26.9; MS (ESI): m/z = 220.2 [M+H]+.

HETEROCYCLES, Vol. 92, No. 5, 2016
883
ACKNOWLEDGEMENTS
This work was supported by the grant of Beijing Institute of Technology. We are grateful for analytical
help of Chinese Academy of Agricultural Sciences, sciences institute of chemistry, Chinese Academy of
Sciences, Beijing University of Chemical Technology and Peking University.
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