A Convenient Synthetic Method and Spectral Characterization of New Tetrahydro[1,3]oxazinothieno[2,3-c]isoquinoline and Its Pyrimidine Derivatives

Article abstract of DOI:10.1002/jccs.201700232

Acetylation of 1-amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-phenyl carboxamide 3 afforded the corresponding tetrahydro[1,3]oxazinothieno[2,3-c]isoquinolinone compound 4. The oxazinone compound 4 underwent nucleophilic substitution reactions with various primary aliphatic and aromatic amines including some sulfa drugs such as sulfanilamide, sulfaguanidine, and sulfathiazole to afford the substituted pyrimidinone compounds 6–10. Chlorination of the pyrimidinone 10 with phosphorus oxychloride yielded the chloropyrimidine derivative 11. The latter compound was used as a versatile precursor for the synthesis of other heterocyclic rings containing the tetrahydropyrimidothienoisoquinoline moiety 12–23 through reaction with a variety of organic reagents. The newly synthesized compounds were fully characterized by elemental and spectral analyses, including melting point, TLC, and FT IR and ¹H NMR spectroscopy, as well as ¹³C NMR and mass spectroscopy for most of them. These molecules should allow to us in the future to investigate their pharmacological activities.

Full text of DOI:10.1002/jccs.201700232

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
A Convenient Synthetic Method and Spectral Characterization of New Tetrahydro[1,3]
oxazinothieno[2,3-c]isoquinoline and Its Pyrimidine Derivatives
*
Remon M. Zaki , Shaban M. Radwan and Adel M. Kamal El-Dean
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
(Received: July 1, 2017; Accepted: September 3, 2017; Published Online: October 26, 2017; DOI: 10.1002/jccs.201700232)
Acetylation of 1-amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-phenyl car-
boxamide 3 afforded the corresponding tetrahydro[1,3]oxazinothieno[2,3-c]isoquinolinone com-
pound 4. The oxazinone compound 4 underwent nucleophilic substitution reactions with various
primary aliphatic and aromatic amines including some sulfa drugs such as sulfanilamide, sulfagua-
nidine, and sulfathiazole to afford the substituted pyrimidinone compounds 6–10. Chlorination of
the pyrimidinone 10 with phosphorus oxychloride yielded the chloropyrimidine derivative 11. The
latter compound was used as a versatile precursor for the synthesis of other heterocyclic rings con-
taining the tetrahydropyrimidothienoisoquinoline moiety 12–23 through reaction with a variety of
organic reagents. The newly synthesized compounds were fully characterized by elemental and
1
spectral analyses, including melting point, TLC, and FT IR and H NMR spectroscopy, as well as
13C NMR and mass spectroscopy for most of them. These molecules should allow to us in the
future to investigate their pharmacological activities.
Keywords: Oxazinone; Pyrimidine; Pyrazole; Synthesis; Reactions.
INTRODUCTION
Tetrahydroisoquinoline derivatives constitute
6–10.13,14 The pyrimidinone compound 10 was con-
verted to the chloropyrimidine derivative 11, which was
reacted with different amines to afford the correspond-
ing substituted amines 12–14. Thionation of the chloro-
pyrimidine with thiourea in ethanol produced the
pyrimidine thione 15, which was alkylated with
α-halogenated carbonyl compounds to give the S-
alkylated products 16a–d. Finally, condensation of the
hydrazinopyrimidine 14 with compounds containing an
active methylene group such as acetyl acetone and/or
ethyl acetoacetate yielded the corresponding pyrazolyl
compounds 22 and 23, respectively. We hope that the
newly synthesized compounds have a wide variety of
biological activities.
a
major group of chemicals. Many of them exhibit impor-
tant biological activities, for example, anti-inflammatory,
antimicrobial, antibacterial, antimalarial, antileukemic,
anti-HIV, antitumor, anti-Parkinson,1,2 and others.3–6
Tetrahydropyrimidothienoisoquinolines and tetrahydro-
pyrimidothienoquinolines are useful as anti-anaphylactic
and anti-inflammatory agents and bacteriophage
inhibitors.7
Thienoquinolines are reported to exhibit a broad
spectrum of biological effects. Some of them are useful
as memory enhancers,8 antiallergics,9 anti-inflammatory
agents, immune regulators, analgesics, and antipy-
retics.10 Others are known to possess good antibacter-
ial11 and anti-anaphylactic activities.12
RESULTS AND DISCUSSION
In this paper, we report a simple and a new
method for synthesizing the tetrahydro[1,3]oxazi-
This work is a continuation of our program of syn-
thesis of novel tetrahydrothieno[2,3-c]isoquinoline
compounds.15–21 Thus, the reaction of 4-cyano-1-mor-
pholin-4-yl-5,6,7,8-tetrahydroisoquinoline-3-thione 1 with
chloroacetanilide in refluxing ethanol in presence of fused
sodium acetate afforded the cyanotetrahydroisoquinoliny
lsulfanyl-N-phenyl acetamide compound 2, which
nothieno[2,3-c]isoquinolinone
4 and its pyrimidine
derivatives by reaction of 1-aminothienotetrahydroiso-
quinoline-2-(N-phenyl) carboxamide 3 with acetic anhy-
dride to afford the corresponding oxazinone derivative
4, which was converted to the pyrimidinone compounds
*Corresponding author. Email: remon.asal2015@gmail.com; remonch2003@yahoo.com
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Zaki et al.
underwent Thorpe–Ziegler cyclization with ethanolic
sodium ethoxide solution to give the corresponding 1-
amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]is
oquinoline-2-N-(phenyl) carboxamide 3. Refluxing the
aminophenyl carboxamide 3 with acetic anhydride
afforded the unexpected 10-methyl-5-morpholin-4-yl-
1,2,3,4-tetrahydro[1,3]oxazino[40,50:4,5]thieno[2,3-c]isoqu
inolin-8-one compound 4 instead of the expected 10-
methyl-9-phenyl-5-morpholin-4-yl-1,2,3,4-tetrahydropyri-
by elimination of aniline molecule afforded the desired
oxazinone molecule 4, as shown in Scheme 2.
The oxazinone compound 4 was used as a versa-
tile precursor for the synthesis of other heterocyclic
compounds containing the tetrahydrothieno[2,3-c]iso-
quinoline moiety. Thus, the reaction with hydrazine
hydrate in refluxing ethanol afforded the N-
aminopyrimidinone compound 6. IR spectrum showed
two absorption bands at 3316 and 3250 cm−1 for the
NH2 group and at 1671 cm−1 for the CO of pyrimidine.
mido[40,50:4,5]thieno[2,3-c]isoquino-
lin-8(9H)-one
1
The H NMR spectrum showed singlet signals at 2.64
5 (Scheme 1). The chemical structure of the oxazinone
compound 4 was assigned by elemental and spectral ana-
lyses. The IR spectrum presented an absorption band at
1748 cm−1 attributed to the CO of the oxazinone ring. 1H
NMR spectrum showed a singlet signal at 2.50 ppm,
characteristic of the CH3 group. 13C NMR spectrum in
CDCl3 displayed signals at 21.46 and 162.91 for CH3 and
CO oxazinone, respectively. Also, the mass spectrum of
oxazinone compound showed the molecular ion peak at
m/z 357.22 (M+, 83%).
The mechanism of formation of compound 4 is
suggested to proceed by the acetylation of the amino
group in compound 3, which exists in tautomer with
the enol form. The nucleophilic addition of the OH
group of the enol form in the acetamido group to the
carbonyl group in the N-phenyl carboxamide followed
and 5.98 ppm for the CH3 and NH2 groups, respec-
tively. On the other hand, when the oxazinone
compound 4 was allowed to react with o- and p-
phenylenediamine in refluxing ethanol in the presence
of catalytic Et3N, the o- and p-aminophenyl pyrimidine
compounds 7a,b were obtained. Also, the reaction of
oxazinone compound 4 with 1,3-diamino propane in
ethanol afforded the aminopropyl pyrimido thienotetra-
hydroisoquinoline compound 8.
Next, we studied the reactivity of the oxazinone
ring by reaction with various primary amines. Thus,
when the oxazinone compound 4 was allowed to react
with aromatic amines and sulfa drugs such as sulfanil-
amide, sulfaguanidine, and sulfathiazole, the p-
substituted phenyl pyrimidine compounds 9a–g were
obtained. Both elemental analysis and spectral data of
Scheme 1. Synthetic approach of tetrahydro[1,3]oxazinothieno[2,3-c]isoquinolin-8-one compound 4 via acetylation of
the 1-amino-2-phenyl carboxamide derivative 3.
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Synthesis of Oxazino and Pyrimidothienoisoquinolines
O
H
N
NH2
Ac2O
CH3
H
H
N
N
N
N
S
N
N
S
3
O
O
O
O
CH3
CH3
N
O
N
OH
- PhNH2
H
O
N
N
N
S
N
N
S
O
O
O
4
Scheme 2. Suggested mechanism of formation of the oxazinone compound 4.
compounds 9a–g were consistent with the assigned
structures. The IR spectrum of compound 9c revealed
the disappearance of the characteristic absorption band
of CO of the oxazinone compound 4 at 1748 cm−1 and
the appearance of an absorption band at 1678 cm−1 for
the CO pyrimidine. The 1H NMR spectrum showed
two separate doublets at 7.32–7.38 ppm characteristic
of the p-substituted aromatic protons. The mass spec-
trum showed a molecular ion peak at m/z 446.03 (M+,
Chlorination of the pyrimidinone compound 10
with phosphorus oxychloride afforded the chloropyri-
midine compound 11, which proved its versatility for
the synthesis of other heterocyclic compounds through
various nucleophilic substitution reactions as shown in
Scheme 4.
In a similar manner, nucleophilic substitution
reactions of the chloride ion in chloropyrimidine deriva-
tive 11 with primary and secondary amines including
sulfa drugs afforded the corresponding substituted
amines 12a–f. The structure assignment of compounds
98.10%), and at m/z 445.41 as the base peak (M+
−
1, 100%). Also, the IR spectrum of compound 9g dis-
played a broad absorption band at 3157 cm−1 of the
NH group and at 1673 cm−1 characteristic of CO
pyrimidine. 1H NMR spectrum in DMSO-d6 showed
two separate doublet signals at 6.79 and 7.24 ppm for
2CH of sulfathiazole and two separate doublet signals
at 7.68 and 7.73 ppm for the p-substituted aromatic
protons (Scheme 3).
1
12a–f was carried out by IR, H NMR, 13C NMR, and
mass spectral analyses. The 13C NMR spectrum of
compound 12b showed signals at 22.30 ppm of the CH3
group and signals at 44.65, 50.15, 66.91, and 67.06 ppm
characteristic of CH2 groups of the morpholinyl ring.
The mass spectrum of compound 12b displayed a
molecular ion peak at m/z 425.50 (M+, 32%). Also, the
IR spectrum of compound 12f revealed absorption
bands at 3348 and 3382 cm−1 for two NH groups and
On fusion of the oxazinone compound 4 with
ammonium acetate in presence of a few drops of acetic
acid, the corresponding pyrimidinone derivative 10 was
obtained in good yield. The chemical structure of com-
pound 10 was established by elemental analysis as well
1
at 1350 and 1120 cm−1 for the SO2 group. H NMR
spectrum of compound 12f showed two separate dou-
blets at 6.79 and 6.80 ppm for 2CH thiazole and two
separate doublets at 7.22–7.73 ppm for p-substituted
aromatic protons. The mass spectrum displayed a
molecular ion peak at m/z 593.65 (M+, 22%).
Treatment of the chloropyrimidine compound 11
with ethanol amine, hydrazine hydrate, and thiourea in
refluxing ethanol afforded the corresponding the amino-
pyrimidinyl ethanol 13, the hydrazinopyrimidine 14,
1
as IR and H NMR spectra. The IR spectrum revealed
the disappearance of the absorption band of the CO
oxazinone and the appearance of two absorption bands
at 3310 and 1651 cm−1 due to the NH and CO groups
of pyrimidine, respectively. The 1H NMR spectrum
showed a singlet signal at 12.70 ppm characteristic of
the NH group.
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Zaki et al.
Scheme 3. Nucleophilic substitution reactions of oxazinone 4 with various aliphatic and aromatic amines affording the
pyrimidinone compounds 6–9.
and the pyrimidine thione 15, respectively. The chemi-
cal structures of the compounds 13–15 were established
by elemental analysis, IR, 1H NMR, and mass spectros-
copy. The IR spectrum of 13 showed an absorption
band at 3412 cm−1 of the NH group and a broad band
at 3400–3300 cm−1 of the OH group. The 1H NMR
spectrum of compound 13 in CDCl3 showed two trip-
lets at 3.57–3.60 and 3.71–3.75 ppm for 2CH2 groups
of ethanol amine and a singlet signal at 5.02 ppm due
to the OH group. The 13C NMR spectrum showed two
signals at 45.56 and 63.11 ppm characteristic of 2CH2
groups of ethanol amine. Also, the mass spectrum
revealed a molecular ion peak at m/z 398.82 and a base
peak at m/z 398.82 (M+ − 1, 100%). Also, the IR spec-
trum of the hydrazino compound 14 showed absorption
bands at 3330, 3270, and 3180 cm−1 corresponding to
respectively. The S-alkylated products 16a–d were
obtained by the alkylation of the pyrimidine thione
compound 15 with α-halogenated carbonyl compounds
in refluxing ethanol in the presence of fused sodium ace-
tate. The IR spectrum of compound 16a showed an
absorption band at 1741 cm−1 of the CO ester group.
The 1H NMR spectrum in DMSO-d6 showed triplet
and quartet signals at 1.21–1.25 and 3.81–3.90 ppm for
the ethyl of the ester group and a singlet signal at
4.15 ppm of the SCH2 group. 13C NMR revealed two
signals at 14.14 and 61.71 ppm for the ethyl of the ester
group in addition to a signal at 168.84 ppm due to the
CO ester group (Scheme 5).
The hydrazino compound 14 was used as a versatile
starting material for the syntheses of other heterocyclic
rings bonded or fused to the pyrimidine ring. Thus, the
reaction of the hydrazino compound 14 with diethyl oxa-
late and ethyl pyruvate in ethanol afforded the ethyl
oxoacetate 17 and ethyl propanoate 19 derivatives,
1
the NH and NH2 groups. The H NMR spectrum in
CDCl3 represented two singlet signals at 4.77 and
8.78 ppm characteristic of the NH2 and NH groups,
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JOURNAL OF THE CHINESE
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Synthesis of Oxazino and Pyrimidothienoisoquinolines
respectively. Unfortunately, all attempts to cyclize the
above compounds upon refluxing in acetic acid, ethano-
lic sodium ethoxide, ethylene glycol, or diphenyl ether to
obtain the triazino compounds 18 and 20 failed, afford-
ing the original starting materials. The formation of the
ester compounds 17 and 19 was confirmed by elemental
and spectral analysis. The IR spectrum of 17 and 19
showed absorption bands at 3400 and 3240 cm−1 of the
NH groups and at 1734 and 1701 cm−1 of the CO ester
N
O
CH
3
AcONH4/ AcOH
4
NH
N
N
S
O
10
(65%)
POCl
3
1
groups for compounds 17 and 19, respectively. The H
N
CH
3
NMR spectrum of compound 17 revealed triplet and
quartet signals at 1.53–1.56 and 4.59–4.62 ppm charac-
teristic of the ethyl group, while the H NMR spectrum
N
N
1
N
S
O
of compound 19 in CDCl3 gave rise to triplet and quartet
signals at 1.43–1.47 and 4.33–4.38 ppm of the ethyl
group. The 13C NMR spectrum of compound 17 showed
two signals at 158.44 and 161.45 ppm, distinctive for
CONH and CO of the ester groups, respectively, while
the spectrum of 19 gave a signal at 161.54 ppm for the
CO ester group (Scheme 6).
Cl
11
(83%)
Scheme 4. Converting the oxazinone 4 to the corre-
sponding pyrimidinone 10 and the chloro-
pyrimidine derivative 11.
Scheme 5. Amination and thionation of the chloropyrimidothieno-isoquinoline 11 forming compounds 12–16.
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When the hydrazinopyrimidine compound 14 was
subjected to reaction with various reagents to afford
new heterocyclic compounds by a variety of nucleo-
philic substitution reactions. We hope that these com-
pounds will show high biological activity in future
studies.
subjected to reaction with acetyl acetone in refluxing
ethanol, it afforded the corresponding dimethyl pyrazo-
lyl pyrimidothienoisoquinoline 21. On the other hand,
the reaction of the hydrazino compound with ethyl
acetoacetate in ethanol gave the corresponding ethyl
butanoate 22, which underwent ring closure with the
loss of an ethanol molecule upon refluxing in acetic acid
to give the corresponding methyl pyrazolone compound
23. The structure of compound 23 was elucidated on
the basis of elemental and spectral analyses. The IR
EXPERIMENTAL
All melting points are uncorrected and measured
on a Fisher–John apparatus. The IR spectra were
recorded in KBr. The FT IR spectra were recorded using
a Shimadzu 470 IR spectrophotometer using the KBr
spectrum showed
a
broad absorption band at
3400–3300 cm−1 for the NH group and at 1714 cm−1
1
1
wafer technique. H NMR and 13C NMR spectra were
for the CO group. The H NMR spectrum in CDCl3
represented two singlet signals at 2.34 and 2.74 ppm for
2CH3 groups and two singlet signals at 5.51 and
12.80 ppm characteristic of the CH and NH groups of
the pyrazole ring. 13C NMR showed a signal at
166.52 ppm for the CO pyrazolone (Scheme 7).
In conclusion, we have provided an easy and new
method for the syntheses of novel methyl oxazinothieno
[2,3-c]isoquinoline compounds, which were converted
to fused pyrimidine–thienoisoquinoline systems. The
methyl pyrimido thienoisoquinoline moiety was
obtained on Joel 400 MHz and Bruker 400 MHz spec-
trometers, respectively, in CDCl3 and DMSO-d6 using
Me4Si as the internal standard; the chemical shifts are
expressed as ppm. EI mass spectra were measured on a
Joel-JMS 600 (70 eV) mass spectrometer. Analytical data
were obtained on an Elemental Analyze system GmbH-
Vario EL V.3 microanalyzer in the Central Laboratory
of Assiut University. Compounds 1–3 were prepared
according to the literature procedure16 with melting
points 230–230, 233–235, and 255–257ꢀC, respectively.
O
14
H3C
(CO2Et)2
OEt
fusion/ EtOH
CH3
O
EtOH
N
N
CH3
N
N
N
S
O
O
N
N
HN
N
N
S
17
O
O
H
CH3
(48%)
19
(78%)
HN
N
OEt
O
fusion/ EtOH
EtO
N
CH3
N
N
CH3
N
O
O
N
N
S
N
N
O
O
N
N
S
O
N
18
N
20
H
CH3
Scheme 6. Condensation reactions of the hydrazinopyrimidine compound 14 with diethyl oxalate and ethyl pyruvate.
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Synthesis of Oxazino and Pyrimidothienoisoquinolines
O
O
CH3
N
OEt
14
N
EtOH
N
N
S
CH3
O
O
O
22
(50%)
HN
N
EtO
EtOH
O
AcOH
CH3
N
N
N
N
CH3
N
N
N
N
S
O
H3C
N
N
N
S
21
(86%)
O
O
CH3
NH
23
(64%)
CH3
Scheme 7. Synthesis of the dimethyl pyrazolyl (21) and methyl pyrazolone derivative (23) by condensation of hyrdrazino
(14) with acetyl acetone and ethyl acetoacetate.
10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro-[1,3]
9-Amino-10-methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro
pyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8(9H)-one (6)
A mixture of oxazinone 4 (1.00 g, 2.80 mmol) and
hydrazine 99% (1.00 mL, 0.02 mol) in absolute ethanol
(20 mL) was refluxed for 4 h. The solid product that
separated out during reflux, was filtered, dried, and
recrystallized from an ethanol:dioxane mixture (1:1) as
yellowish-white crystals in 58% (0.60 g) yield. mp
288–290ꢀC. IR (KBr, cm−1) ν: 3316, 3250 (NH2), 2955,
2848 (CH aliphatic), 1671 (CO pyrimidine), 1540
(C═N). 1H NMR (CDCl3, 400 MHz): δ = 1.70–1.85
(m, 4H, 2CH2 cyclohexeno), 2.51 (s, 3H, CH3),
2.64–2.69 (m, 4H, 2CH2 cyclohexeno), 3.06–3.52 (m,
4H, (CH2)2N morpholinyl), 3.66–3.80 (m, 4H, (CH2)2O
morpholinyl), 5.98 (s, 2H, NH2 exchangeable). Anal.
calcd. for C18H21N5O2S (371.46): C, 58.20; H, 5.70; N,
18.85; S, 8.63%. Found: C, 58.15; H, 5.62; N,
19.00; S, 8.74%.
oxazino[40,50:4,5]thieno[2,3-c]isoquinolin-8(9H)-one (4)
A
suspension of amino-N-phenylcarboxamide
3 (4.10 g, 0.01 mol) in acetic anhydride (30 mL) was
refluxed for 3 h. The solid precipitate which formed on
cooling was collected, dried, and recrystallized from an
ethanol:dioxane mixture as brilliant greenish yellow crys-
tals in 75% yield (2.40 g). mp 218–220ꢀC. IR ν (KBr,
cm−1): 2854 (CH aliphatic), 1748 (CO oxazinone), 1612
1
(C═N); H NMR (CDCl3, 400 MHz): δ = 1.715–1.925
(m, 4H, 2CH2 cyclohexeno), 2.50 (s, 3H, CH3),
2.648–2.679 (m, 4H, 2CH2 cyclohexeno), 3.297–3.319 (m,
4H, (CH2)2N morpholinyl), 3.835–3.857 (m, 4H,
(CH2)2O morpholinyl). 13C NMR (CDCl3, 100 MHz):
21.46 (CH3 pyrimidine), 22.00, (C3), 22.59 (C2), 27.05
(C4), 27.26 (C1), 49.98 (C20, C60: (CH2)2N morpholine),
66.94 (C30, C50: (CH2)2O morpholine), 120.38 (C4a),
122.92 (C7a), 127.93 (C11b), 130.01 (C11c), 147.14
(C11a), 151.85 (C5), 156.55 (C10), 160.98 (C6a), 162.91
(C8: CO). EI-MS: m/z = 357 (M+, 83%), 356 (M+ − 1,
20%), 320 (100%), 312 (31%), 300 (38%), 296 (25%), 270 -
(M+ − C4H9NO, 11%), 268 (40%), 255 (13%), 223 (10%),
163 (10%), 118 (11%), 86 (9%). Anal. calcd. for
C18H19N3O3S (357.43): C, 60.49; H, 5.36; N, 11.76; S,
8.97%. Found: C, 60.57; H, 5.50; N, 11.84; S, 9.00.
9-(o- or p-Aminophenyl)-10-methyl-5-morpholin-4-yl-
1,2,3,4-tetrahydropyrimido[40,50:4,5]thieno[2,3-c]
isoquinolin-8(9H)-one (7a,b)
General procedure. A mixture of the oxazinone
4 (1 g, 2.80 mmol) and the corresponding o- and p-phe-
nylene diamine (0.32 g, 3.00 mmol) in acetic acid
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(10 mL) was refluxed for 3 h. The solid product that
formed upon cooling and dilution with water was col-
lected, dried, and recrystallized from ethanol.
0.27 mol) was gently refluxed for 5 min, and then abso-
lute ethanol (15 mL) was added. The reaction was
allowed to continue for 2 h. The solid product that sep-
arated out during reflux, was collected, washed with
water several times, dried, and recrystallized from diox-
ane as white crystals in 71% yield (0.82 g). mp:
250–251ꢀC. IR (KBr, cm−1) ν: 3480, 3420 (NH2), 2927,
2850 (CH aliphatic), 1674 (CO pyrimidine), 1557
(C═N). 1H NMR (CDCl3, 400 MHz): δ = 1.73–1.74
(m, 4H, 2CH2 cyclohexeno), 1.87 (m, 2H, CH2: C2 pro-
pyl), 2.20–2.23 (m, 4H, 2CH2 cyclohexeno), 2.66 (s,
3H, CH3), 2.85 (t, J = 6.80 Hz, 2H, CH2NH2), 3.25 (t,
J = 6.80 Hz, 2H, CH2N propyl), 3.60–3.64 (m, 4H,
(CH2)2N morpholinyl), 3.82 (m, 4H, (CH2)2O morpho-
linyl), 7.50 (s, 2H, NH2). 13C NMR (CDCl3,
100 MHz): 22.18 (CH3 pyrimidine), 22.70 (C3), 24.35
(C2), 26.85 (C4), 27.38 (C1), 29.67 (C14: CH2 propyl),
39.50 (C13, C15: CH2N+ CH2NH2 propyl), 50.22 (C20,
C60: (CH2)2N morpholinyl), 67.00 (C30, 50: (CH2)2O
morpholiyl), 118.66 (C4a), 122.36 (C7a), 127.95 (C11b),
129.96 (C11c), 147.34 (C11a), 151.84 (C5), 155.03
(C10), 158.71 (C6a), 161.59 (CO). Anal. calcd. for
C21H27N5O2S (413.55): C, 60.99; H, 6.58; N, 16.93; S,
7.75%. Found: C, 61.10; H, 6.65; N, 17.00; S, 7.70%.
9-(o-Aminophenyl)-10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8
(9H)-one (7a)
White powder; (0.81 g, 65%) yield (EtOH); mp
190–192ꢀC; IR (KBr, cm−1) ν: 3450–3250 (br NH2),
3050 (CH aromatic), 2926, 2820 (CH aliphatic), 1674
(CO pyrimidine), 1558 (C═N). 1H NMR (CDCl3,
400 MHz): δ = 1.72–1.86 (m, 4H, 2CH2 cyclohexeno),
1.98–2.22 (m, 4H, 2CH2 cyclohexeno), 2.65 (s, 3H,
CH3), 3.06–3.52 (m, 4H, (CH2)2N morpholinyl),
3.66–3.80 (m, 4H, (CH2)2O morpholinyl), 6.67 (s, 2H,
NH2). 7.32–7.38 (m, 4H, ArH). Anal. calcd. for
C24H25N5O2S (447.56): C, 64.41; H, 5.63; N, 15.65; S,
7.16%. Found: C, 64.50; H, 5.56; N, 15.70; S, 7.26%.
9-(p-Aminophenyl)-10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8
(9H)-one (7b)
White powder, (0.85 g, 68%) yield (EtOH); mp
208–211ꢀC; IR (KBr, cm−1) ν: 3350–3300 (br NH2),
3030 (CH aromatic), 2927, 2850 (CH aliphatic), 1674
(CO pyrimidine), 1557 (C═N). 1H NMR (CDCl3,
400 MHz): δ = 1.70–1.83 (m, 4H, 2CH2 cyclohexeno),
2.10–2.35 (m, 4H, 2CH2 cyclohexeno), 2.63 (s, 3H,
CH3), 2.85–3.20 (m, 4H, (CH2)2N morpholinyl),
3.57–3.85 (m, 4H, (CH2)2-O morpholinyl), 6.80 (s, 2H,
NH2), 7.25–7.50 (2d, J = 2.50, 8.80 Hz, 4H, ArH p-
disub.). 13C NMR (CDCl3, 100 MHz): 22.18 (CH3
pyrimidine), 22.70 (C3), 24.35 (C2), 26.85 (C4), 27.38
(C1), 50.20 (C20, C60: (CH2)2N morpholinyl), 67.00
(C30, C50: (CH2)2O morpholinyl), 118.62 (C4a), 121.22,
121.49 (C300, C500: Ar), 122.36 (C7a), 127.94 (C11b),
128.31, 128.71 (C200, C600: Ar), 129.35 (C11c), 129.96
(C100: Ar), 132.41 (C400: Ar), 147.31 (C11a), 151.87
(C5), 155.02 (C10), 158.74 (C6a), 161.65 (CO). Anal.
calcd. for C24H25N5O2S (447.56): C, 64.41; H, 5.63; N,
15.65; S, 7.16%. Found: C, 64.46; H, 5.70; N,
15.72; S, 7.30%.
10-Methyl-5-morpholin-4-yl-9-(p-substitutedphenyl)-
1,2,3,4-tetrahydropyrimido[40,50:4,5]thieno[2,3-c]
isoquinolin-8(9H)-one (9a–g)
General procedure. A mixture of the oxazinone
4 (1.00 g, 2.80 mmol) and the corresponding amine
(aniline, p-chloroaniline, p-toluidine, p-anisidine, sulfa-
nilamide, sulfaguanidine, and sulfathiazole) (3 mmol)
in ethanol (20 mL) in the presence of catalytic amount
of triethyl amine (0.25 mL) was refluxed for 2 h. The
solid precipitate that formed during reflux was filtered
off, dried, and recrystallized from the proper solvent.
10-Methyl-5-morpholin-4-yl-9-phenyl-1,2,3,4-tetrahydro
pyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8(9H)-one (9a)
Orange crystals; (0.90 g, 74%) yield (EtOH); mp
214–216ꢀC; IR (KBr, cm−1) ν: 3050 (CH aromatic),
2933, 2850 (CH aliphatic), 1613 (C═N). 1H NMR
(CDCl3, 400 MHz): δ = 1.82–1.96 (m, 4H, 2CH2 cyclo-
hexeno), 2.08–2.32 (m, 4H, 2CH2 cyclohexeno), 2.75 (s,
3H, CH3), 3.20–3.34 (m, 4H, (CH2)2N morpholinyl),
3.60–3.90 (m, 4H, (CH2)2O morpholinyl), 7.29–7.61 (m,
5H, ArH). Anal. calcd. for C24H24N4O2S (432.55): C,
10-Methyl-5-morpholin-4-yl-9-aminopropyl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8
(9H)-one (8)
A mixture of the oxazinone compound 4 (1.00 g,
2.80 mmol)
and
1,3-diaminopropane
(2.00 mL,
1424
www.jccs.wiley-vch.de © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J. Chin. Chem. Soc. 2017, 64, 1417–1431

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Oxazino and Pyrimidothienoisoquinolines
66.64; H, 5.59; N, 12.95; S, 7.41%. Found: C, 66.72; H,
5.68; N, 13.10; S, 7.25%.
10-Methyl-5-morpholin-4-yl-9-(p-anisyl)-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8
(9H)-one (9d)
Buff crystals; (0.98 g, 76%) yield (EtOH); mp
258–260ꢀC. IR (KBr, cm−1) ν: 3030 (CH aromatic),
2933, 2850 (CH aliphatic), 1674 (CO pyrimidine), 1608
10-Methyl-5-morpholin-4-yl-9-(p-chlorophenyl)-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8
(9H)-one (9b)
(C═N).
1H
NMR
(DMSO-d6,
400 MHz):
White needless; (0.91 g, 70%) yield (EtOH); mp
208–210ꢀC. IR (KBr, cm−1) ν: 3050 (CH aromatic),
2929, 2851 (CH aliphatic), 1678 (CO pyrimidine), 1596
(C═N); 1H NMR (CDCl3, 400 MHz): δ = 1.73–1.86
(m, 4H, 2CH2 cyclohexeno), 2.14–2.32 (m, 4H, 2CH2
cyclohexeno), 2.60 (s, 3H, CH3), 2.90–3.05 (m, 4H,
(CH2)2N morpholinyl), 3.58–3.68 (m, 4H, (CH2)2O
morpholinyl), 7.30–7.68 (2d, J = 2.55, 8.70 Hz, 4H,
Ar-H p-disub.). Anal. calcd. for C24H23ClN4O2S
(466.99): C, 61.73; H, 4.96; Cl, 7.59; N, 12.00; S,
6.87%. Found: C, 61.80; H, 5.00; Cl, 7.46; N,
12.14; S, 6.95%.
δ = 1.69–1.84 (m, 4H, 2CH2 cyclohexeno), 2.10–2.28
(m, 4H, 2CH2 cyclohexeno), 2.40 (s, 3H, CH3 p-anisyl),
2.59 (s, 3H, CH3 pyrimidine), 3.05–3.24 (m, 4H,
(CH2)2N morpholinyl), 3.45–3.70 (m, 4H, (CH2)2O
morpholinyl), 7.28–7.46 (2d, J = 2.60, 8.95 Hz, 4H,
Ar-H p-disub.). Anal. calcd. for C25H26N4O3S
(462.57): C, 64.91; H, 5.67; N, 12.11; S, 6.93%.
Found: C, 65.00; H, 5.77; N, 12.05; S, 7.08%.
(10-Methyl-5-morpholin-4-yl-8-oxo-1,2,3,4-tetrahydro
pyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-9-yl)-p-benzene
sulfonamide (9e)
White powder; (0.83 g, 58%) yield (dioxane); mp
234–236ꢀC. IR (KBr, cm−1) ν: 3353, 3260 (NH2), 3050
(CH aromatic), 2918 (CH aliphatic), 1670
(CO pyrimidine), 1529 (C═N), 1298, 1159 (SO2NH).
1H NMR (DMSO-d6, 400 MHz): δ = 1.78–1.82 (m,
4H, 2CH2 cyclohexeno), 2.05–2.26 (m, 4H, 2CH2 cyclo-
hexeno), 2.64 (s, 3H, CH3), 3.16–3.28 (m, 4H, (CH2)2N
morpholinyl), 3.54–3.64 (m, 4H, (CH2)2O morpholinyl),
6.62 (s, 2H, NH2), 6.73–7.75 (2d, J = 2.65, 8.70 Hz,
4H, Ar-H p-disub.). Anal. calcd. for C24H25N5O4S2
(511.63): C, 56.34; H, 4.93; N, 13.69; S, 12.53%.
Found: C, 56.50; H, 4.85; N, 13.80; S, 12.64%.
10-Methyl-5-morpholin-4-yl-9-(p-tolyl)-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8
(9H)-one (9c)
White crystals; (0.93 g, 75%) yield (EtOH); mp
248–250ꢀC. IR (KBr, cm−1) ν: 3050 (CH aromatic),
2932, 2850 (CH aliphatic), 1678 (CO pyrimidine), 1557
(C═N).
1H
NMR
(DMSO-d6,
400 MHz):
δ = 1.70–1.86 (m, 4H, 2CH2 cyclohexeno), 2.15–2.19
(m, 2H, CH2 cyclohexeno), 2.39 (s, 3H, CH3 p-tolyl),
2.49 (s, 3H, CH3 pyrimidine), 2.68–2.71 (m, 2H, CH2
cyclohexeno), 3.20–3.33 (m, 4H, (CH2)2N morpholi-
nyl), 3.49–3.76 (m, 4H, (CH2)2O morpholinyl),
7.32–7.38 (2d, J = 2.55, 8.30 Hz, 4H, Ar-H p-disub.).
13C NMR (DMSO-d6, 100 MHz): 21.22 (CH3 pyrimi-
dine), 21.96 (CH3 p-tolyl), 22.62 (C3), 24.71 (C2), 26.52
(C4), 27.30 (C1), 50.30 (C20, C60: (CH2)2N morpholi-
nyl), 66.68 (C30, C50: (CH2)2O morpholinyl), 118.60
(C4a), 122.93 (C200, C600: Ar), 128.40 (C11b), 128.78
(C300, C500: Ar), 130.60 (C100: Ar), 135.37 (C11c), 139.19
(C400: Ar), 147.07 (C11a), 151.08 (C6a), 154.20 (C10),
157.60 (C7a), 159.75 (C5), 162.00 (CO). EI-MS (m/z):
446.03 (M+, 98.10%), 445.41 (M+−1, 100%), 399.70
(M+−C2H6O, 31%), 379.99 (22.6%), 340.06 (49%).
Anal. calcd. for C25H26N4O2S (446.58): C, 67.24; H,
5.87; N, 12.55; S, 7.18%. Found: C, 67.30; H, 5.78; N,
12.68; S, 7.00%.
N-Carbamimidoyl-(10-methyl-5-morpholin-4-yl-8-oxo-
1,2,3,4-tetrahydropyrimido[40,50:4,5]thieno[2,3-c]iso
quinolin-9-yl)-p-benzene sulfonamide (9f)
Yellowish white crystals; (1.00 g, 65%) yield
(EtOH: dioxane 1:1); mp 252–254ꢀC. IR (KBr, cm−1) ν:
3432, 3339, 3200 (NH, NH2), 3050 (CH aromatic),
2930, 2870 (CH aliphatic), 1678 (CO pyrimidine), 1620
(C═N), 1350, 1150 (SO2NH). 1H NMR (DMSO-d6,
400 MHz): δ = 1.76–1.82 (m, 4H, 2CH2 cyclohexeno),
2.10–2.30 (m, 4H, 2CH2 cyclohexeno), 2.61 (s, 3H,
CH3), 3.20–3.26 (m, 4H, (CH2)2N morpholinyl),
3.58–3.62 (m, 4H, (CH2)2O morpholinyl), 4.10 (s, 1H,
C═NH), 6.70 (s, 2H, NH2), 6.81–7.84 (2d, J = 2.65,
8.70 Hz, 4H, Ar-H p-disub.), 9.68 (s, 1H, SO2NH).
Anal. calcd. for C25H27N7O4S2 (553.67): C, 54.23; H,
J. Chin. Chem. Soc. 2017, 64, 1417–1431 © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.jccs.wiley-vch.de
1425

Article
Zaki et al.
4.92; N, 17.71; S, 11.58%. Found: C, 54.38; H, 5.00; N,
17.62; S, 11.70%.
400 MHz): δ = 1.72–1.89 (m, 4H, 2CH2 cyclohexeno),
2.63 (s, 3H, CH3), 2.65–2.75 (m, 4H, 2CH2 cyclohex-
eno), 3.28–3.53 (m, 4H, (CH2)2N morpholinyl),
3.80–3.82 (m, 4H, (CH2)2O morpholinyl). Anal. calcd.
for C18H19ClN4OS (374.90): C, 57.67; H, 5.11; Cl,
9.46; N, 14.94; S, 8.55%. Found: C, 57.78; H, 5.00; Cl,
9.58; N, 15.05; S, 8.46%.
4-(10-Methyl-5-morpholin-4-yl-8-oxo-1,2,3,4-tetrahydro
pyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-9-yl)-N-
(thiazol-2-yl) benzene sulfonamide (9g)
Yellow crystals; (1.10 g, 65%) yield (EtOH: diox-
ane); mp 252–254ꢀC; IR (KBr, cm−1) ν: 3157 (br NH),
3050 (CH aromatic), 2930, 2850 (CH aliphatic), 1673
(CO pyrimidine), 1595 (C═N), 1330, 1147 (SO2NH).
1H NMR (DMSO-d6, 400 MHz): δ = 1.71–1.89 (m,
4H, 2CH2 cyclohexeno), 2.03–2.21 (m, 4H, 2CH2 cyclo-
hexeno), 2.49 (s, 3H, CH3), 3.20–3.25 (m, 4H, (CH2)2N
morpholinyl), 3.40–3.45 (m, 4H, (CH2)2O morpholinyl),
6.79, 7.24 (2d, J = 3.20 Hz, 2H, 2CH thiazolyl),
7.68–7.73 (2d, J = 2.65, 8.70 Hz, 4H, Ar-H p-disub.),
12.68 (s, 1H, NH). Anal. calcd. for C27H26N6O4S3
(594.74): C, 54.53; H, 4.41; N, 14.13; S, 16.17%.
Found: C, 54.45; H, 4.60; N, 14.15; S, 16.00%.
8-Alkyl(arylamino)-10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinoline
(12a–f)
General Procedure
A mixture of the chloropyrimi-
dine 11 (1.00 g, 2.67 mmol) and the corresponding pri-
mary and secondary amines (aniline, morpholine,
piperidine, sulfanilamide, sulfaguanidine, and sulfathia-
zole) (2.80 mmol) in acetic acid (20 mL) was refluxed
for 2 h. The solid precipitate that formed during reflux
or after cooling was filtered off, dried, and recrystallized
from the proper solvent.
10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydropyrimido
[40,50:4,5]thieno[2,3-c]isoquinolin-8(9H)-one (10)
8-(Phenylamino)-10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]
A
mixture of the oxazinone
4
(4.00 g,
isoquinoline (12a)
11.20 mmol) and ammonium acetate (5.20 g, 68 mmol)
was refluxed in the presence of acetic acid (20 mL) for
2 h. The solid precipitate that formed during reflux was
filtered, dried, and recrystallized from dioxane as yel-
lowish white crystals in (2.60 g, 65%) yield, mp
>360ꢀC. IR (KBr, cm−1) ν: 3310 (NH), 2950, 2836
(CH aliphatic), 1651 (C═O pyrimidine), 1556 (C═N).
1H NMR (DMSO-d6, 400 MHz): δ = 1.70–1.91 (m,
4H, 2CH2 cyclohexeno), 2.05–2.20 (m, 4H, 2CH2 cyclo-
hexeno), 2.51 (s, 3H, CH3), 2.68–2.72 (m, 4H, (CH2)2N
morpholinyl), 3.19–3.23 (m, 4H, (CH2)2O morpholinyl),
12.70 (s, 1H, NH). Anal. calcd. for C18H20N4O2S
(356.45): C, 60.65; H, 5.66; N, 15.72; S, 9.00%.
Found: C, 60.55; H, 5.74; N, 15.90; S, 8.85%.
White crystals; (0.78 g, 68%) yield (EtOH); mp
180–182ꢀC; IR (KBr, cm−1) ν: 3303 (NH), 3050
(CH aromatic), 2933, 2850 (CH aliphatic), 1613
(C═N), 1600, 1580, 1564, 1494 (CH bending aromatic).
1H NMR (CDCl3, 400 MHz): δ = 1.23–1.92 (m, 4H,
2CH2 cyclohexeno), 2.27–2.56 (m, 4H, 2CH2 cyclohex-
eno), 2.64 (s, 3H, CH3), 3.25–3.65 (m, 4H, (CH2)2N
morpholinyl), 3.84–4.23 (m, 4H, (CH2)2O morpholinyl),
6.67–7.78 (m, 5H, Ar-H), 8.71 (s, 1H, NH). 13C NMR
(CDCl3, 100 MHz): 22.22 (CH3 pyrimidine), 22.68
(C3), 26.03 (C2), 26.82 (C4), 27.61 (C1), 50.16 (C20, 60:
(CH2)2N morpholinyl), 67.03 (C30, C50: (CH2)2O mor-
pholinyl), 109.84 (C4a), 120.74 (C7a), 122.17 (C300,
C500: Ar), 122.81 (C200, C600: Ar), 124.17 (C400: Ar),
128.98 (C11b), 138.10 (C11c), 147.78 (C100: Ar), 154.66
(C11a), 158.21 (C5), 158.86 (C10), 162.17 (C6a), 163.09
(C8). Anal. calcd. for C24H25N5OS (431.56): C,
66.80; H, 5.84; N, 16.23; S, 7.43%. Found: C, 66.94; H,
5.90; N, 16; S, 7.34%.
8-Chloro-10-methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro
pyrimido[40,50:4,5]thieno[2,3-c]isoquinoline (11)
A
solution of the pyrimidinone 10 (4 g,
11.20 mmol) in phosphorus oxychloride (20 mL) was
gently refluxed for 3 h. The solid precipitate that
formed on cooling and pouring into an ice–water mix-
ture was filtered off, dried, and recrystallized from etha-
nol as colorless crystals in (3.50 g, 83%) yield, mp:
10-Methyl-5,8-dimorpholin-4-yl-1,2,3,4-tetrahydro
pyrimido[40,50:4,5]thieno[2,3-c]isoquinoline (12b)
White needless; (0.95 g, 84%) yield (EtOH); mp
218–220ꢀC. IR (KBr, cm−1
(CH aliphatic), 1556 (C═N); 1H NMR (CDCl3,
)
ν: 2948, 2849
198–200ꢀC; IR (KBr, cm−1
)
ν: 2926, 2845
(CH aliphatic), 1556 (C═N). 1H NMR (CDCl3,
1426
www.jccs.wiley-vch.de © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J. Chin. Chem. Soc. 2017, 64, 1417–1431

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Oxazino and Pyrimidothienoisoquinolines
400 MHz): δ = 1.70–1.85 (m, 4H, 2CH2 cyclohexeno),
2.62 (s, 3H, CH3), 2.63–2.65 (m, 4H, 2CH2 cyclohex-
eno), 3.20–3.60 (m, 8H, (CH2)4N morpholine),
3.76–3.83 (m, 8H, (CH2)4-O morpholine). 13C NMR
(CDCl3, 100 MHz): 22.30 (CH3 pyrimidine), 22.66
(C3), 26.11 (C2), 26.86 (C4), 27.80 (C1), 46.65 (C20,
C60: (CH2)2N morpholinlyl of pyrimidine), 50.15 (C200,
C600 (CH2)2N morpholinlyl of isoquinoline), 66.91 (C30,
C50: (CH2)2O morpholinlyl of pyrimidine), 67.06 (C300,
C500: (CH2)2O morpholinlyl of isoquinoline), 109.67
(C7a), 120.40 (C4a), 122.11 (C11b), 130.12 (C11c);
147.70 (C11a), 158.28 (C5), 158.81 (C10), 162.19 (C6a),
162.80 (C8). EI-MS (m/z): 425.5 (M+, 32%), 424.41
(M+ − 1, 100%), 398.88 (M+ − C2H2%), 379.8 (11.2%),
367.6 (24.9%), 255.97 (13.7%). Anal. calcd. for
C22H27N5O2S (425.56): C, 62.09; H, 6.40; N, 16.46; S,
7.53%. Found: C, 62.15; H, 6.24; N, 16.55; S, 7.66%.
400 MHz): δ = 21.96 (CH3 pyrimidine), 22.57 (C3),
26.28 (C2), 26.56 (C4), 27.63 (C1), 50.30 (C20, C60:
(CH2)2N morpholinyl), 66.67 (C30, C50: (CH2)2O mor-
pholinyl), 110.72 (C4a); 121.41 (C200, C600: Ar), 122.52
(C7a); 126.80 (C11b), 127.86 (C300, C500: Ar), 138.57
(C400: Ar), 142.98 (C100: Ar), 147.32 (C11a), 154.66
(C5), 158.84 (C10), 159.59 (C11c), 162.39 (C6a), 162.74
(C8). Anal. calcd. for C24H26N6O3S2 (510.64): C,
56.45; H, 5.13; N, 16.46; S, 12.56%. Found: C,
56.40; H, 5.25; N, 16.58; S, 12.70%.
N-Carbamimidoyl-4-(10-methyl-5-morpholin-4-yl-
1,2,3,4-tetrahydropyrimido[40,50:4,5]thieno[2,3-c]
isoquinolin-8-yl amino)benzenesulfonamide (12e)
Yellowish white crystals; (0.91 g, 65%) yield (diox-
ane); mp >360ꢀC. IR (KBr, cm−1) ν: 3474, 3382, 3230,
3150 (NH, NH2), 3030 (CH aromatic), 2980, 2850
(CH aliphatic), 1643 (C═N), 1350, 1155 (SO2NH),
829 (p-disub). 1H NMR (DMSO-d6, 400 MHz):
δ = 1.70–1.92 (m, 4H, 2CH2 cyclohexeno), 2.43–2.51
(m, 4H, 2CH2 cyclohexeno), 2.61 (s, 3H, CH3),
3.19–3.29 (m, 4H, (CH2)2N morpholinyl), 3.47–3.77
(m, 4H, (CH2)2O morpholinyl), 4.06 (s, 1H, C═NH),
6.80 (s, 2H, NH2), 7.74–7.98 (2d, J = 2.65, 8.70 Hz,
4H, Ar-H p-disub.), 9.73 (s, 1H, NHPh), 12.63 (s, 1H,
SO2NH). 13C NMR (DMSO-d6, 100 MHz): 21.95
(CH3 pyrimidine), 22.57 (C3), 26.45 (C2), 27.33 (C4),
29.55 (C1), 50.31 (C20, C60: (CH2)2N morpholinyl),
66.67 (C30, C50: (CH2)2O morpholinyl), 117.16 (C4a),
121.03 (C200, C600 Ar + C7a), 121.25 (C300, C500: Ar),
122.74 (C11b), 126.66 (C400 Ar), 138.19 (C11c), 147.05
(C100 Ar), 153.68 (C11a), 156.31 (C5), 158.74 (C10),
161.92 (C6a + C═NH guanidine), 163.22 (C8). Anal.
calcd. for C25H28N8O3S2 (552.68): C, 54.33; H, 5.11; N,
20.27; S, 11.60%. Found: C, 54.50; H, 5.25; N,
20.18; S, 11.70%.
10-Methyl-5-piperidinyl-8-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]
isoquinoline (12c)
Colorless crystals, (0.92 g, 81%) yield (EtOH); mp
150–152ꢀC. IR (KBr, cm−1
)
ν: 2948, 2848
(CH aliphatic), 1556 (C═N). 1H NMR (CDCl3,
400 MHz): δ = 1.64–1.66 (m, 6H, 3CH2 piperidinyl),
1.72–1.80 (m, 4H, 2CH2 cyclohexeno), 2.64 (s, 3H,
CH3), 2.66–2.75 (m, 4H, 2CH2 cyclohexeno), 3.20–3.52
(m, 4H, (CH2)4N morpholinyl), 3.60–3.63 (m, 4H,
2CH2 piperidinyl), 3.70–3.83 (m, 4H, 2CH2 piperidi-
nyl). Anal. calcd. for C23H29N5OS (423.58): C,
65.22; H, 6.90; N, 16.53; S, 7.57%. Found: C, 65.30; H,
6.78; N, 16.60; S, 7.70%.
(10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro pyrimido
[40,50:4,5]thieno[2,3-c]isoquinolin-8-ylamino)-p-
benzenesulfonamide (12d)
Yellow crystals; (0.83 g, 61%) yield; mp
318–320ꢀC. IR (KBr, cm−1) ν: 3352, 3300, 3260 (NH,
NH2), 3050 (CH aromatic), 2922, 2850 (CH aliphatic),
1670 (C═N), 1300, 1160 (SO2NH2), 830 (p-substituted).
1H NMR (DMSO-d6, 400 MHz): δ = 1.70–1.91 (m,
4H, 2CH2 cyclohexeno), 2.41–2.51 (m, 2H, CH2 cyclo-
hexeno), 2.61 (s, 3H, CH3), 2.67–2.69 (m, 2H, CH2
cyclohexeno), 3.17–3.44 (m, 4H, (CH2)2N morpholi-
nyl), 3.53–3.77 (m, 4H, (CH2)2O morpholinyl), 5.27 (s,
2H, NH2), 7.80–8.01 (2d, J = 2.70, 8.75 Hz, 4H, Ar-H
p-disub.), 9.85 (s, 1H, NH). 13C NMR (DMSO-d6,
4-(10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro
pyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8-yl)-N-
(thiazol-2-yl) benzene sulfonamide (12f)
Yellow crystals; (1.00 g, 65%) yield (dioxane); mp
324–326ꢀC; IR (KBr, cm−1) ν: 3480, 3382 (2NH), 3050
(CH aromatic), 2980, 2850 (CH aliphatic), 1644
1
(C═N), 1350, 1120 (SO2NH), 850 (p-disub). H NMR
(DMSO-d6, 400 MHz): δ = 1.76–1.89 (m, 4H, 2CH2
cyclohexeno), 2.03–2.21 (m, 4H, 2CH2 cyclohexeno),
2.49 (s, 3H, CH3), 3.40–3.45 (m, 8H, 4CH2
J. Chin. Chem. Soc. 2017, 64, 1417–1431 © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.jccs.wiley-vch.de
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morpholine), 6.79, 6.80 (2d, J = 3.20 Hz, 2H, 2CH
thiazolyl), 7.22–7.73 (2d, J = 2.70, 8.75 Hz, 4H, Ar-H
p-disub.), 9.80 (s, 1H, NHPh), 10.27 (s, 1H, NH thiazo-
lyl). EI-MS (m/z) %: 593.65 (M+, 22%), 373.36
off, dried, and recrystallized from dioxane as pale yel-
low crystals in (2.65 g, 67%) yield, mp 294–297ꢀC. IR
(KBr, cm−1) ν: 3330, 3270, 3180 (NH, NH2), 2933,
1
2840 (CH aliphatic), 1648 (C═N). H NMR (CDCl3,
(88.10%),
316.80
(100%).
Anal.
calcd.
for
400 MHz): δ = 1.69–1.84 (m, 4H, 2CH2 cyclohexeno),
2.19 (m, 2H, CH2 cyclohexeno), 2.43 (s, 3H, CH3),
2.67–2.70 (m, 2H, CH2 cyclohexeno), 3.15–3.21 (m,
4H, (CH2)2N morpholine), 3.53–3.75 (m, 4H, (CH2)2O
morpholine), 4.77 (s, 2H, NH2), 8.78 (s, 1H, NH).
Anal. calcd. for C18H22N6OS (370.48): C, 58.36; H,
5.99; N, 22.68; S, 8.65%. Found: C, 58.46; H, 6.17; N,
22.74; S, 8.80%.
C27H27N7O3S3 (593.75): C, 54.62; H, 4.58; N, 16.51; S,
16.20%. Found: C, 54.50; H, 4.72; N, 16.58; S, 16.05%.
2-(10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro
pyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8-ylamino)
ethanol (13)
A suspension of the chloropyrimidine 11 (1.00 g,
2.67 mmol) and ethanol amine (2.00 mL, 33 mmol)
was gently refluxed for 1 h, and then absolute ethanol
(10 mL) was added. Thus, reflux was continued for an
additional 2 h. The solid precipitate that separated out
during reflux was filtered, dried, and recrystallized from
ethanol–benzene mixture as colorless crystals in (0.77 g,
72%) yield, mp 212–214ꢀC. IR (KBr, cm−1) ν: 3412
(NH), 3300 (br OH), 2922, 2850 (CH aliphatic), 1566
(C═N). 1H NMR (CDCl3, 400 MHz): δ = 1.71–1.89
(m, 4H, 2CH2 cyclohexeno), 2.58 (s, 3H, CH3), 2.65
(m, 4H, 2CH2 cyclohexeno), 3.21–3.24 (m, 4H,
(CH2)2N morpholinyl), 3.57–3.60 (t, J = 5.60 Hz, 2H,
CH2NH), 3.71–3.75 (t, J = 5.60 Hz, 2H, CH2OH), (m,
4H, (CH2)2O morpholinyl), 5.02 (s, 1H, OH), 7.19 (s,
1H, NH). EI-MS (m/z): 399.52 (M+, 15.90%), 398.82
(M+ − 1, 100%), 368.05 (M+−CH2OH, 5.30%), 354.69
(M+ − CH2CH2OH, 3.20%), 341.84 (M+ − C2H4NO,
16.30%), 314.06 (4.40%); 13C NMR (CDCl3,
400 MHz): δ = 22.11 (CH3 pyrimidine), 22.61 (C2, C3
cyclohexeno), 26.92 (C4), 27.54 (C1), 45.56 (C14:
NHCH2), 50.11 (C20, C60: (CH2)2N morpholinyl),
63.11 (C15: CH2OH), 66.98 (C30, C50: (CH2)2O mor-
pholinyl), 109.67 (C4a), 120.40 (C7a), 122.48 (C11b),
148 (C11a), 158.20 (C11c), 158.50 (C5), 158.72 (C10),
162.09 (C6a), 162.37 (C8). Anal. calcd. for
C20H25N5O2S (399.52): C, 60.13; H, 6.31; N, 17.53; S,
8.03%. Found: C, 60.25; H, 6.46; N, 17.65; S, 8.12%.
10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydropyrimido
[40,50:4,5]thieno[2,3-c]isoquinolin-8(9H)-thione (15)
A mixture of the chloropyrimidine 11 (4.00 g,
0.01 mol) and thiourea (3.00 g, 0.04 mol) in ethanol
(50 mL) was refluxed for 2 h. The solid crystals that
formed during reflux was filtered off, washed several
times with water, dried, and recrystallized from an etha-
nol:dioxane mixture as brilliant yellow needless in 80%
yield (3.20 g); mp >360ꢀC. IR (KBr, cm−1) ν: 3120
(NH), 2980, 2850 (CH aliphatic), 1631 (C═N), 1200
1
(C═S). H NMR (DMSO-d6, 400 MHz): δ = 1.72–1.88
(m, 4H, 2CH2 cyclohexeno), 2.35–2.55 (m, 4H, 2CH2
cyclohexeno), 2.62 (s, 3H, CH3), 3.25–3.33 (m, 4H,
(CH2)2-N morpholine), 3.57–3.70 (m, 4H, (CH2)2─O
morpholine), 10.35 (s, 1H, NH). Anal. calcd. for
C18H20N4OS2 (372.51): C, 58.04; H, 5.41; N, 15.04; S,
17.21%. Found: C, 58.20; H, 5.23; N, 15.20; S, 17.15%.
Alkylation of 10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]iso- quinolin-8
(9H)-thione (16a–d)
General procedure. A solution of the pyrimidine
thione 15 (1.20 g, 3.00 mmol) and α-halogenated alky-
lating agents (ethyl chloroacetate, chloroacetone, phe-
nacyl bromide, and chloroacetanilide) (3.00 mmol) in
ethanol (20 mL) in the presence of fused sodium acetate
(0.80 g, 0.01 mol) was refluxed for 3 h. The solid pre-
cipitate that formed on cooling was filtered, washed
with water several times, dried, and recrystallized from
ethanol.
8-Hydrazino-10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]
isoquinoline (14)
A suspension of the chloropyrimidine 11 (4.00 g,
0.01 mol) and hydrazine 99% (4.00 mL, 0.08 mol) in
absolute ethanol (30 mL) was refluxed for 6 h. The
solid precipitate that formed during reflux was filtered
1428
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Oxazino and Pyrimidothienoisoquinolines
Ethyl (10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8-
sulfanyl) acetate (16a)
(CH2)2-N morpholine), 3.50–3.79 (m, 4H, (CH2)2-O mor-
pholine), 4.75 (s, 2H, CH2), 7.18–8.04 (m, 5H, Ar-H). 13
C
NMR (CDCl3, 100 MHz): 22.15 (CH3 pyrimidine), 24.34
(C3), 26.93 (C2), 27.69 (C4), 29.33 (C1), 37.09 (SCH2),
50.08 (C20, C60: (CH2)2N morpholinyl), 67.00 (C30, C50:
(CH2)2O morpholinyl), 119.83 (C4a), 122.06 (C300, C500:
Ar), 123.61 (C7a), 128.67 (C11b), 129.31 (C200, C600: Ar),
133.43 (C400: Ar), 136.35 (C11c), 137.69 (C100: Ar), 148.05
(C11a), 156.34 (C5), 159.56 (C10), 162.51 (C6a), 162.62
(C8), 193.84 (CO). Anal. calcd. for C26H26N4O2S2
(490.65): C, 63.65; H, 5.34; N, 11.42; S, 13.07%.
Found: C, 63.70; H, 5.52; N, 11.35; S, 13.20%.
White crystals; (1.25 g, 85%) yield (EtOH); mp
120–122ꢀC. IR (KBr, cm−1
)
ν: 2922, 2850
(CH aliphatic), 1741 (CO ester), 1563 (C═N), 1164
(C─O). 1H NMR (DMSO-d6, 400 MHz): δ = 1.21–1.25
(t, J = 7.10 Hz, 3H, CH3), 1.72–1.85 (m, 4H, 2CH2
cyclohexeno), 2.10–2.30 (m, 4H, 2CH2 cylcohexeno),
2.64 (s, 3H, CH3), 3.32–3.40 (m, 4H, (CH2)2N morpho-
linyl), 3.58–3.66 (m, 4H, (CH2)2O morpholinyl),
3.81–3.90 (q, 2H, J = 7.10 Hz, CH2 ester), 4.15 (s, 2H,
SCH2). 13C NMR (CDCl3, 400 MHz): δ = 14.14 (CH3
ester), 22.13 (CH3 pyrimidine), 22.65 (C3), 25.94 (C2),
27.75 (C4), 29.65 (C1), 31.72 (SCH2), 50.14 (C20, C60:
(CH2)2N morpholinyl), 61.71 (CH2 ester), 66.96 (C30,
C50: (CH2)2O morpholinyl), 119.94 (C4a), 122.13
(C7a), 123.69 (C11b), 148.39 (C11a), 156.29 (C5),
159.27 (C10), 159.59 (C11c), 162.28 (C6a), 162.74 (C8),
168.84 (CO ester). Anal. calcd. for C22H26N4O3S2
(458.61): C, 57.62; H, 5.71; N, 12.22; S, 13.98%.
Found: C, 57.57; H, 5.80; N, 12.41; S, 14.15%.
(10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydropyrimido
[40,50:4,5]thieno[2,3-c]isoquinolin-8-sulfanyl)
acetanilide (16d)
Greenish white crystals; (1.43 g, 88%) yield (EtOH),
mp 192–194ꢀC. IR (KBr, cm−1) ν: 3150 (NH), 3030
(CH aromatic), 2960, 2852 (CH aliphatic), 1654
(CONH), 1599 (C═N). 1H NMR (CDCl3, 400 MHz):
δ = 1.74–1.99 (m, 4H, 2CH2 cyclohexeno), 2.32–2.74 (m,
4H, 2CH2 cyclohexeno), 2.95 (s, 3H, CH3), 3.34–3.38 (m,
4H, (CH2)2N morpholinyl), 3.60–3.65 (m, 4H, (CH2)2O
morpholinyl), 4.09 (s, 2H, CH2CO), 7.08–7.59 (m, 5H,
Ar-H), 10.0 (s, 1H, NH). Anal. calcd. for C26H27N5O2S2
(505.67): C, 61.76; H, 5.38; N, 13.85; S, 12.68%.
Found: C, 61.87; H, 5.50; N, 14.00; S, 12.77%.
(10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydropyrimido
[40,50:4,5]thieno[2,3-c]isoquinolin-8-sulfanyl)
acetone (16b)
Yellowish white crystals; (1.12 g, 81%) yield
(EtOH); mp 190–192ꢀC. IR (KBr, cm−1) ν: 2964, 2850
(CH aliphatic), 1705 (CO), 1560 (C═N). 1H NMR
(CDCl3, 400 MHz): δ = 1.27 (s, 3H, CH3 sulfanyl
acetone),1.81–1.97 (m, 4H, 2CH2 cyclohexeno), 2.43
(m, 4H, 2CH2 cyclohexeno), 2.75 (s, 3H, CH3 pyrimi-
dine), 3.35 (m, 4H, (CH2)2N morpholinyl), 3.63–3.89
(m, 4H, (CH2)2O morpholinyl), 4.18 (s, 2H, CH2CO).
Anal. calcd. for C21H24N4O2S2 (428.58): C, 58.85; H,
5.64; N, 13.07; S, 14.96%. Found: C, 59.00; H, 5.58; N,
13.20; S, 15.10%.
Ethyl 2-(2-(10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8-yl
hydrazinyl)-2-oxoacetate (17)
A solution of the hydrazino compound 14 (1.00 g,
2.70 mmol) and diethyl oxalate (2.00 mL, 0.014 mol)
was gently refluxed for 1 h, and then absolute ethanol
(20 mL) was added. Thus, reflux was continued for an
additional 2 h. The solid precipitate that separated out
during reflux was collected, dried, and recrystallized
from ethanol as orange crystals in 48% yield (0.61 g),
mp 270–273ꢀC. IR (KBr, cm−1) ν: 3400 (br NH), 2937,
2850 (CH aliphatic), 1734 (CO ester), 1631 (CONH),
1560 (C═N). 1H NMR (CDCl3, 400 MHz):
δ = 1.53–1.56 (t, J = 7.10 Hz, 3H, CH3), 1.83–1.99 (m,
8H, 4CH2 cyclohexeno), 2.76 (s, 3H, CH3 pyrimidine),
3.08–3.33 (m, 4H, 2CH2N morpholinyl), 3.61–3.90 (m,
4H, 2CH2O morpholinyl), 4.59–4.64 (q, J = 7.10 Hz,
2H, CH2 ester), 8.40, 8.85 (2 s, 2H, 2NH). 13C NMR
(CDCl3, 100 MHz): 14.28 (CH3 ethyl ester), 22.17
(10-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydropyrimido
[40,50:4,5]thieno[2,3-c]isoquinolin-8-sulfanyl)
acetophenone (16c)
Yellow crystals; (1.38 g, 87%) yield (EtOH); mp
176–178ꢀC. IR (KBr, cm−1) ν: 3050 (CH aromatic), 2937,
1
2844 (CH aliphatic), 1690 (CO), 1620 (C═N). H NMR
(CDCl3, 400 MHz): δ = 1.70–1.85 (m, 4H, 2CH2 cyclo-
hexeno), 2.21 (m, 2H, CH2 cyclohexeno), 2.51 (s, 3H,
CH3), 2.63 (m, 2H, CH2 cyclohexeno), 3.24 (m, 4H,
J. Chin. Chem. Soc. 2017, 64, 1417–1431 © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.jccs.wiley-vch.de
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(CH3 pyrimidine), 22.62 (C3), 23.93 (C2), 27.53 (C4),
29.66 (C1), 50.25 (C20, C60: (CH2)2N morpholinyl),
63.37 (CH2 ethyl ester), 66.96 (C30, C50: (CH2)2O mor-
pholinyl), 114.19 (C4a), 120.47 (C7a), 123.01 (C11b),
139.55 (C11c), 144.02 (C11a), 146.81 (C5), 147.06
(C10), 148.78 (C6a), 158.23 (C8), 158.44 (CONH),
161.45 (CO ester). EI-MS (m/z): 469.97 (M+, 4.50%),
468.78 (M+ − 1, 27.10%), 467.72 (M+ − 2, 67.80%),
ethanol (20 mL) was refluxed for 3 h. The solid product
that separated out during reflux was filtered, dried, and
recrystallized from dioxane as white crystals in 86%
yield (1.00 g), mp 228–230ꢀC. IR (KBr, cm−1) ν: 2953,
2844 (CH aliphatic), 1620(C═N). 1H NMR (CDCl3,
400 MHz): δ = 1.72–1.88 (m 4H, 2CH2 cyclohexeno),
2.28 (m, 4H, 2CH2 cyclohexeno), 2.63 (s, 3H, CH3
pyrimidine), 2.65, 2.66 (2 s, 6H, 2CH3 pyrazolyl),
3.26–3.85 (m, 8H, 4CH2 morpholinyl), 5.97 (s, 1H, CH
pyrazolyl). Anal. calcd. for C23H26N6OS (434.57): C,
63.57; H, 6.03; N, 19.34; S, 7.38%. Found: C, 63.70; H,
6.18; N, 19.45; S, 7.26%.
410.52 (M+ − C2H2O2, 10.80%), 394.83 (M+
−
HCO2C2H5, 100%), 361.77 (6.20%). Anal. calcd. for
C22H26N6O4S (470.55): C, 56.16; H, 5.57; N, 17.86; S,
6.81%. Found: C, 56.00; H, 5.68; N, 17.95; S, 6.72%.
Ethyl 2-(10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8-yl
hydrazono) propanoate (19)
Ethyl 3-(2-(10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8-yl)
hydrazono)butanoate (22)
A suspension of the hydrazino compound 14
(1.00 g, 2.70 mmol) and ethyl pyruvate (1.00 mL,
8.60 mmol) in ethanol (20 mL) was refluxed for 2 h.
The solid product that separated out during reflux was
collected, dried and recrystallized from ethanol as yel-
low needless in (0.92 g, 78%) yield, mp 250–252ꢀC. IR
(KBr, cm−1) ν: 3240 (NH), 2950, 2848 (CH aliphatic),
1701 (CO unsaturated ester), 1537 (C═N). 1H NMR
(CDCl3, 400 MHz): δ = 1.43–1.47 (t, J = 7.00 Hz, 3H,
CH3 ester), 1.71–1.89 (m, 4H, 2CH2 cyclohexeo), 2.10
(s, 3H, CH3 propanoate), 2.63–2.65 (m, 7H, 2CH2
cyclohexeno + CH3 pyrimidine), 3.25–3.27 (m, 4H,
(CH2)2N morpholinyl), 3.57–3.82 (m, 4H, (CH2)2O
morpholinyl), 4.33–4.38 (q, J = 7.00 Hz, 2H, CH2
ester), 8.56 (s, 1H, NH). 13C NMR (CDCl3, 100 MHz):
13.42 (CH3C═N), 14.25 (CH3 ethyl ester), 22.16 (CH3
pyrimidine), 22.62 (C3), 24.36 (C2), 26.86 (C4), 27.83
(C1), 50.39 (C20, C60: (CH2)2N morpholinyl), 60.66
(CH2 ethyl ester), 66.90 (C30, C50: (CH2)2O morpholi-
nyl), 118.68 (C4a), 121.70 (C7a), 123.16 (C11b), 138.34
(C11c), 145.60 (C15: NHN═C), 147.68 (C11a), 152.56
(C5), 154.42 (C10), 156.21 (C6a), 158.73 (C8), 161.54
(CO). Anal. calcd. for C23H28N6O3S (468.58): C,
58.96; H, 6.02; N, 17.94; S, 6.84%. Found: C, 59.10; H,
6.15; N, 18.05; S, 7.00%.
A mixture of the hydrazino compound 14 (1.00 g,
2.70 mmol) and ethyl acetoacetate (0.40 mL,
3.00 mmol) in ethanol (20 mL) was refluxed for 3 h.
The solid precipitate that formed on cooling was fil-
tered, dried, and recrystallized from ethanol as white
crystals in (0.65 g, 50%) yield, mp 172–174ꢀC. IR (KBr,
cm−1) ν: 3239 (NH), 2925, 2832 (CH aliphatic), 1735
1
(CO ester), 1559 (C═N). H NMR (CDCl3, 400 MHz):
δ = 1.47 (t, J = 7.10 Hz, 3H, CH3 ester), 1.71–1.89 (m,
4H, 2CH2 cyclohexeno), 2.10 (s, 3H, CH3C═N), 2.62
(s, 3H, CH3 pyrimidine), 2.63–2.66 (m, 4H, 2CH2
cyclohexeno), 3.25–3.27 (m, 4H, (CH2)2N morpholi-
nyl), 3.35 (s, 2H, CH2CO), 3.57–3.82 (m, 4H, (CH2)2O
morpholinyl), 4.33–4.38 (q, J = 7.10 Hz, 2H, CH2
ester), 8.56 (s, 1H, NH). Anal. calcd. for C24H30N6O3S
(482.61): C, 59.73; H, 6.27; N, 17.41; S, 6.64%.
Found: C, 59.81; H, 6.34; N, 17.56; S, 6.72%.
3-Methyl-1-(10-methyl-5-morpholin-4-yl-1,2,3,4-
tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8-
yl)-1H–pyrazol-5(4H)-one (23)
A solution of the butanoate ester 22 (0.50 g,
1.15 mmol) in acetic acid (10 mL) was refluxed for 3 h.
The solid precipitate that formed on cooling with dilu-
tion with water was collected, dried, and recrystallized
from acetic acid as yellow crystals in 64% yield (0.29 g),
8-(3,5-Dimethyl-1H-pyrazol-1-yl)-10-methyl-5-
morpholin-4-yl-1,2,3,4-tetrahydropyrimido[40,50:4,5]
thieno[2,3-c]isoquinoline (21)
A mixture of the hydrazino compound 14 (1.00 g,
2.70 mmol) and acetyl acetone (0.30 mL, 3.00 mmol) in
mp 250–252ꢀC. IR (KBr, cm−1
) ν: 2929, 2850
(CH aliphatic), 1630 (CONH). 1H NMR (CDCl3,
400 MHz): δ = 1.28–1.62 (m, 4H, 2CH2 cyclohexeno),
1.82–1.97 (m, 4H, 2CH2 cyclohexeno), 2.34 (s, 3H,
CH3 pyrazolyl), 2.74 (s, 3H, CH3 pyrimidine),
1430
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Oxazino and Pyrimidothienoisoquinolines
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3.39–3.65 (m, 4H, (CH2)2N morpholinyl), 3.47–3.91
(m, 4H, (CH2)2O morpholinyl), 5.51 (s, 1H, CH pyra-
zolyl), 12.80 (s, 1H, NH). 13C NMR (DMSO-d6,
100 MHz): 14.80 (CH3 pyrazole), 22.76 (CH3 pyrimi-
dine), 23.08 (C3), 24.34 (C2), 26.88 (C4), 27.41 (C1),
50.24 (C20, C60: (CH2)2N morpholinyl), 66.93 (C30, C50:
(CH2)2O morpholinyl), 97.54 (C40: CH pyrazolyl),
118.35 (C4a), 122.58 (C7a), 127.73 (C11b), 137.44
(C11c), 154.28 (C11a), 156.80 (C5), 158.93 (C10),
159.98 (C6a), 161.34 (C8), 163.30 (C300: NH─C(CH3)
pyrazole), 165.52 (CO). Anal. calcd. for C22H24N6O2S
(436.54): C, 60.53; H, 5.54; N, 19.25; S, 7.35%.
Found: C, 60.62; H, 5.63; N, 19.38; S, 7.22%.
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ACKNOWLEDGMENTS
12. E. G. Paronikyan, A. S. Noravyan, S. F. Akopyan,
F. G. Arsenyan, G. M. Stepanyan, B. T. Garibdzhanyan,
Pharm. Chem. J. 2006, 40, 293.
13. R. M. Zaki, A. M. Kamal El-Dean, A. Y. Abdulrazzaq,
J. Chin. Chem. Soc. 2015, 62, 1121.
14. A. A. Saddik, A. M. Kamal El-Dean, G. H. El-Sokary,
K. M. Hassan, M. S. Abbady, I. A. Ismail, S. H. Saberb,
J. Chin. Chem. Soc. 2017, 64, 87.
15. J. C. A. Hunt, E. Briggs, E. D. Clarke,
W. G. Whittingham, Bioorg. Med. Chem. Lett. 2007,
17, 5222.
The authors are very grateful to Prof. Dr. Kamal
I. Aly, Chairman of the Chemistry Department, for all
the facilities provided to us, and the staff members of
the Chemistry Department, Faculty of Science, Assiut
University, for their support during this work.
Supporting information
Additional supporting information is available in
the online version of this article.
16. A. M. Kamal El-Dean, S. M. Radwan, R. M. Zaki,
J. Chin. Chem. Soc. 2008, 55, 1290.
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