Synthesis of morphlinotetrahydrothieno[2,3-c]isoquinolines

Article abstract of DOI:10.1002/jccs.200800193

1-Morpholin-4-yl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (2) was synthesized from 3-amino-1-thioxo-5,6,7,8-tetrahydro-1H-isothiochromene-4- carbonitrile (1) and used as starting material to synthesize many thienotetrahydroisoquinolines (4), which in turn were used in the synthesis of many pyrimidothienotetrahydroisoquinolines.

Full text of DOI:10.1002/jccs.200800193

1290
Journal of the Chinese Chemical Society, 2008, 55, 1290-1299
Synthesis of Morphlinotetrahydrothieno[2,3-c]isoquinolines
Adel M. Kamal El-Dean,* Shaban M. Radwan and Remon M. Zaki
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
1-Morpholin-4-yl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (2) was synthesized from 3-amino-
1-thioxo-5,6,7,8-tetrahydro-1H-isothiochromene-4-carbonitrile (1) and used as starting material to syn-
thesize many thienotetrahydroisoquinolines (4), which in turn were used in the synthesis of many pyrimi-
dothienotetrahydroisoquinolines.
Keywords: Synthesis; Reactions; Tetrahydroisoquinolines; Thienotetrahydroisoquinolines;
Pyrimidothienotetrahydroisoquinolines.
INTRODUCTION
The 1,2,3,4-tetrahydroisoquinoline ring system1 is a
capto-1-morpholin-4-yl-5,6,7,8-tetrahydroisoquinoline-4-
carbonitrile (2) in the synthesis of new fused heterocycles.
When compound 2 was allowed to react with a-halo-
genated carbonyl compounds in ethanol in the presence of
sodium acetate, alkylation of the mercapto group occurred
to afford compounds 3a-j. Compounds 3d-j underwent
Thorpe-Ziegler cyclization reaction to give 2-substituted-
1-amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-
c]isoquinoline (4a-g). Compounds 4a-g also were obtained
directly from mercaptoisoquinolinecarbonitrile using a-
halogenated compounds in refluxing ethanol in the pres-
ence of anhydrous potassium carbonate (Scheme I). Cy-
clization of compounds 3d-j was confirmed using spectral
analyses. IR spectra of compounds 3d-j revealed an ab-
sorption band at 2200 cm-1 for the (CN) group, which dis-
appeared upon being cyclized into 4a-g and showing bands
characteristic of the (NH2) group at 3500-3300 cm-1. 1H-
NMR spectra of 4a-g showed the disappearance of signals
characteristic for the S-CH2-group in the starting material
and the appearance of new signals at 6-7 corresponding to
NH2.
structural component of many biologically active natural
products.2,3 Isoquinoline and its saturated derivatives have
acquired considerable significance in heterocyclic chemis-
try.4,5 Tetrahydroisoquinoline (THIQ) is a common core
structure of many alkaloids isolated from natural sources
and has shown antitumor,6 antimicrobial,7 and other bio-
logical activities.8-12 The recent success in total synthesis of
Ecteinascidin 74313-18 and its human clinical trials19,20 have
shed light on this class of natural products.
Thienopyrimidine derivatives are characterized by a
very broad spectrum of biological activities, which in-
cludes several dozen activities. Certain thienopyrimidine
derivatives exhibit antiallergic,21 antibacterial,22-26 antivi-
ral,27 antihypertensive,28 depressant,29 antihistaminic,30
antimicrobial,31,32 spasmolytic,33 analgetic, and antiinflam-
matory activities.34,36 In view of the above reported bene-
fits and in continuation of our work in synthesis of hetero-
cyclic systems containing thienopyrimidine,37-43 we aimed
to synthesize fused heterocyclic systems including a com-
bination of thienopyrimidine and tetrahydroisoquinoline,
hoping that they biologically active.
7-Morphlino-8,9,10,11-tetrahydropyrimido[4¢,5¢:4,5]-
thieno[2,3-c]isoquinoline-4(3H)-one (5) was synthesized
via two routes, either via condensation of compound 4b
with formamide or via condensation of compound 4e with
triethyl orthoformate. The products obtained from the two
routes are identical in m.p., m.m.p., and T.L.C. Also carbox-
amide derivatives 4f,g similarly reacted with triethyl ortho-
formate to afford primidothienoisoquinolines 6a,b. While
when 4e-g was allowed to react with sodium nitrite in ace-
RESULTS AND DISCUSSION
We reported previously the synthesis of 3-amino-1-
thioxo-5,6,7,8-tetrahydro-1H-isothiochromene-4-carbo-
nitrile (1)44 and its transformation into tetrahydoisoquino-
line derivative using alkali.45 Herein we report this trans-
formation using morpholine and using the produced 3-mer-
* Corresponding author. E-mail: a.eldean@aun.edu.eg

Synthesis of Morphlinotetrahydrothieno[2,3-c]isoquinolines
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1291
Scheme I
tic acid, triazinothienoisoquinolines 7a-c were produced.
When aminothienoisoquinolinecarboxamide 4e was
condensed with cycloalkanone in acetic acid followed by
cycloaddition reaction under reaction conditions to afford
spiro derivative 8a,b. Similarly, compound 4e condensed
with aromatic aldehydes in refluxed ethanol afforded the
corresponding Schiff’s base, which undergoes cycloaddi-
tion to afford tetrahydropyrimido derivative 9, while when
the reaction was carried out in acetic acid condensation oc-
curred accompanied with cycloaddition reaction followed
by elimination of a molecule of hydrogen to afford com-
pound 10 (Scheme II).
lino-8,9,10,11-tetrahydropyrimido[4¢,5¢:4,5]thieno[2,3-c]-
isoquinoline (14). Hydrazinopyrimidine derivative (14)
also was obtained from the reaction of 4-chloropyrimidine
derivative (11) with hydrazine hydrate (Scheme IV). Mass
spectrum of compound 14 showed a molecular ion peak at
355.93 in agreement with the suggested structure.
Carboxylate ester 4b was reacted with hydrazine hy-
drate in ethanol to give the corresponding 1-amino-6,7,8,9-
tetrahydrothieno[2,3-c]isoquinoline-2-carbohydrazide 15.
The carboxylate 4b was saponified with alcoholic sodium
hydroxide to give the corresponding sodium carboxylate
derivative 16, which when treated with acetic anhydride
was cyclized into oxazinothienoisoquinoline 17 (Scheme
V).
Compound 5 was converted into 4-chloro-7-morph-
lino-8,9,10,11-tetrahydropyrimido[4¢,5¢:4,5]thieno[2,3-
c]isoquinoline (11) using phosphorusoxychloride, which
in turn was converted into 7-morphlino-8,9,10,11-tetrahy-
dropyrimido[4¢,5¢:4,5]thieno[2,3-c]isoquinolin-4(3H)-
thione (12) via reaction with thiourea in refluxed ethanol
followed by treatment with sodium hydroxide solution and
then acidified with dilute HCl. Compound 12 also was ob-
tained via an alternative route by thionation of 7-morph-
lino-8,9,10,11-tetrahydropyrimido[4¢,5¢:4,5]thieno[2,3-
c]isoquinolin-4(3H)-one (5) using phosphorus pentasul-
fide in pyridine. Alkylation of compound 7 using halo-
genated compounds in ethanol in the presence of sodium
acetate afforded S-alkylated mercaptopyridothienopyrimi-
dine derivatives 13 (Scheme III).
Carbohydrazide 15 was condensed in acetyl acetone
to afford the corresponding pyrazolyl derivative 18. Also it
was condensed with triethyl orthoformate in the presence
of a catalytic amount of acetic acid to afford pyrimidothieno-
isoquinoline derivative 19. When carbohydrazide 15 was
allowed to condense with aromatic aldehyde, it afforded
the corresponding carbohydrazone 20 which cyclized us-
ing triethyl orthoformate to give pyrimidothienoisoquino-
line derivative 21. Carbohydrazide 15 was converted into
the corresponding carboazide 15 using sodium nitrite in
acetic acid. The produced compound underwent Curtius re-
arrangement when boiled in inert solvent to cyclize into
imidazothienoisoquinoline derivative 23 (Scheme VI).
Condensation of 7-morphlino-8,9,10,11-tetrahydro-
pyrimido[4¢,5¢:4,5]thieno[2,3-c]isoquinoline-4(3H)-thione
(11) with hydrazine hydrate afforded 4-hydrazino-7-morph-
EXPERIMENTAL
All melting points are uncorrected and measured on

1292 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Kamal El-Dean et al.
Scheme II
Scheme IV
Scheme III
photometer using the KBr wafer technique. NMR spectra
were recorded on a Varian EM-390 90 MHz and Joel 400
MHz spectrometers in a suitable deuterated solvent using
TMS as internal standard (chemical shifts in ppm). MS
spectra were recorded on a Jeol JMS-600 apparatus. 3-Ami-
no-1-thioxo-5,6,7,8-tetrahydro-1H-isothiochromene-4-car-
a Fisher-John apparatus. Elemental analyses were deter-
mined on an Elementar Analysensystem GmbH-VarioEL
V.3 microanalyzer in the central lab of Assiut University.
IR spectra were recorded on a Pye-Unicam Sp-100 spectro-

Synthesis of Morphlinotetrahydrothieno[2,3-c]isoquinolines
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1293
C, 60.83; H, 6.00; N, 15.04; S, 11.78%. IR: n = 2970-2850
cm-1 (SH) and 2220 cm-1 (CN). 1H-NMR (DMSO-d6): d =
1.7, 2.7, 3.7 (3m, 16H, 8CH2), 3.5 (m, 1H, SH).
3-Substituted mercapto-1-morpholin-4-yl-5,6,7,8-tetra-
hydroisoquinoline-4-carbonitrile (3a-j)
Scheme V
General procedure
A mixture of compound 2 (2.75 g, 0.01 mol), alkyl-
ating agent (0.01 mol) and fused sodium acetate (3 g, 0.034
mol) in ethanol (40 mL) was refluxed for 1 hrs. Then the re-
action mixture was allowed to cool, then poured into cold
water (100 mL). The solid precipitate was filtered off and
dried and recrystallized from ethanol. The physical con-
stants, elemental analyses and spectral data of compounds
3a-j are listed in Table 1.
bonitrile was prepared according to a literature method.44
3-Mercapto-1-morpholin-4-yl-5,6,7,8-tetrahydroiso-
quinoline-4-carbonitrile (2)
1-Amino-5-morpholino-6,7,8,9-2-substituted tetrahy-
drothieno[2,3-c]isoquinoline-2-carbonitrile (4a-g)
Method a:
4-Tetramethylene-6-amino-5-cyanothiopyrane-2(1H)-
thione (1) (22.2 g, 0.1 mol) was dissolved in morpholine
(43.5 mL, 0.5 mol); the mixture was refluxed for 100 hrs or
until H2S gas ceased. Then it was allowed to cool. The pre-
cipitated solid was filtered off, dried, and recrystallized
from ethanol as brilliant pale orange crystal to yield (17.5
g, 61%), m.p. 230-232 °C. Anal. Calcd. For C14H17N3OS
(275.380: C, 61.06; H, 6.22; N, 15.26; S, 11.64%. Found:
To a solution of the appropriate 3-substituted mer-
capto-1-morpholin-4-yl-5,6,7,8-tetrahydroisoquinoline-
4-carbonitrile (3d-j) (0.01 mol) in absolute ethanol (25
mL), a few drops of sodium ethoxide solution (prepared
from 0.5 gm of clean sodium in 20 mL ethanol) was added,
and the mixture was refluxed for 15 minutes and then left to
cool, and poured into cold water (100 mL). The solid prod-
Scheme VI

1294 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Kamal El-Dean et al.
Table 1. Physical properties, analytical and spectral data of compounds 3a-3j and 4a-g
Analytical Data (Calcd/Found)
M.P. Yield Mol. Formula
No.
Spectral Analysis
°C
(%)
(mol. Wt)
C
H
N
S
3a
3b
3c
3d
3e
118-20
72
C16H21N3OS 63.34 6.98 13.85 10.57 IR: n = 2950 cm-1 (CH-aliphatic, 2220, 2200 cm-1 (2CN). 1H-
(303.43)
63.52 7.19 14.08 10.76 NMR (CDCl3): 1.4 (t, 3H, CH3), 1.9, 2.6, 2.9, 3.4, 3.8 (5m, 18H,
9CH2).
110-12
126-28
190-2
112-4
76
71
79
83
C17H20N4OS 62.17 6.14 17.06 09.76 IR: n = 2950 cm-1 (CH-aliphatic, 2220, 22200 cm-1 (2CN). 1H-
(328.44)
61.93 5.90 16.83 10.00 NMR (CDCl3): 1.8, 2.7, 3.6 (3m, 16H, 8CH2), 3.2, 3.8 (2t, 4H,
2CH2).
C21H23N3OS 69.01 6.34 11.50 8.77 IR: n = 2950 cm-1 (CH-aliphatic), 2200 cm-1 (CN). 1H-NMR
(365.50)
68.87 6.09 11.73 9.00 (CDCl3): 1.9, 2.7, 2.95, 3.3, 3.9 (5m, 16H, 8CH2), 4.5 (s, 2H,
CH2), 7.1-7.8 (m, 5H, ArH).
C16H18N4OS 61.12 5.77 17.82 10.20 IR: n = 2920 cm-1 (CH-aliphatic), 2200 cm-1 (CN). 1H-NMR
(314.41)
60.88 6.01 18.03 09.97 (CDCl3): d = 1.9, 2.45, 2.9, 3.4, 3.8 (5m, 16H, 8CH2), 4.0 (s, 2H,
CH2).
C18H23N3O3S 59.81 6.41 11.62 8.87 IR: n = 2940 cm-1 (CH-aliphatic), 2210 cm-1 (CN), 1740 cm-1
(361.47)
60.04 6.63 11.41 9.11 (CO). 1H-NMR (CDCl3): 1.3 (t, 3H, CH3 ester), 1.8, 2.5, 2.9,
3.4, 3.8 (5m, 16H, 8CH2), 3.95 (s, 2H, CH2), 4.2 (q, 2H, CH2-
ester).
3f
130-2
152-4
78
91
C17H21N3O2S 61.61 6.39 12.68 9.67 IR: n = 2940 cm-1 (CH-aliphatic), 2200 cm-1 (CN), 1720 cm-1
(331.44)
61.84 6.60 12.91 9.88 (CO). 1H-NMR (CDCl3): 2.25 (s, 3H, CH3), 1.85, 2.6, 2.8, 3.8
(4m, 16H, 8CH2), 3.95 (s, 2H, CH2).
3g
C22H23N3O2S 67.15 5.89 10.68 8.15 IR: n = 3050 cm-1 (CH-aromatic), 2940 cm-1 (CH-aliphatic),
(393.51)
66.87 6.12 10.47 8.28 2220 cm-1 (CN), 1720 cm-1 (CO). 1H-NMR (CDCl3): 1.7, 2.5,
2.8, 3.0, 3.6 (5m, 16H, 8CH2), 4.6 (s, 2H, CH2), 7.3-7.8, 8.0 (2m,
5H, CH-aromatic).
3h
3i
186-8
233-5
75
71
C16H20N4O2S 57.81 6.06 16.85 9.65 IR: n = 3500-3350 cm-1 (NH2), 2200 cm-1 (CN), 1670 cm-1 (CO).
(332.43)
58.03 6.27 17.07 9.42 1H-NMR (DMSO-d6): 1.8, 2.6, 2.75, 3.7 (4m, 16H, 8CH2), 4.0
(s, 2H, CH2), 7.0 (s, 2H, NH2).
(C22H24N4O2S 64.68 5.92 13.71 7.85 IR: n = 3350 cm-1 (NH), 2940 cm-1 (CH-aliphatic), 2220 cm-1
(408.53)
64.87 6.13 13.92 7.74 (CN), 1680 cm-1 (CO). 1H-NMR (CDCl3): 1.8, 2.5, 2.8, 3.25,
3.65 (5m, 16H, 8CH2), 4.0 (s, 2H, CH2), 7.0-7.7 (m, 5H, CH-
aromatic), 8.5 (s, 1H, NH).
3j
218-20
246-8
202-4
192
71
84
82
80
C23H26N4O2S 65.38 6.20 13.26 7.59 1H-NMR (CDCl3): 1.8, 2.5, 2.8, 3.3, 3.65 (5m, 16H, 8CH2), 3.8
(422.55)
65.21 5.98 13.04 7.82 (s, 3H, CH3), 4.0 (s, 2H, CH2), 6.9, 7.4 (2d, 4H, CH-aromatic),
9.5 (s, 1H, NH).
4a
4b
4c
C16H18N4OS 61.12 5.77 17.82 10.20 IR: n = 3470, 3370 cm-1 (NH2), 2950 cm-1 (CH-aliphatic), 2210
(314.41)
60.88 6.00 18.05 10.01 cm-1 (CN). 1H-NMR (CDCl3): 1.8, 2.55, 2.9, 3.45, 3.8 (5m, 16H,
8CH2), 6.1 (s, 2H, NH2).
C18H23N3O3S 59.81 6.41 11.62 8.87 IR: n = 3420, 3320 cm-1, 2930 cm-1 (CH-aliphatic), 1670 cm-1
(361.47)
60.02 6.20 11.43 9.12 (CO). 1H-NMR (CDCl3): 1.3 (t, 3H, CH3 ester), 1.8, 2.6, 3.2, 3.8
(4m, 16H, 8CH2), 4.2 (q, 2H, CH2), 6.1 (s, 2H, NH2).
C17H21N3O2S 61.61 6.39 12.68 9.67 IR: n = 3450, 3350 cm-1 (NH2), 2950 cm-1 (CH-aliphatic), 1640
(331.44)
61.73 6.60 12.81 9.45 cm-1 (CO). 1H-NMR (CDCl3): 2.45 (s, 3H, CH3), 1.9, 2.65, 3.2,
3.9 (4m, 16H, 8CH2), 7.1 (s, 2H, NH2).
4d 198-200 72
C22H23N3O2S 67.15 5.89 10.68 8.15 IR: n = 3480-3380 cm-1 (NH2), 1700-1660 cm-1 (CO). 1H-NMR
(393.51)
66.87 6.92 10.90 7.91 (CDCl3): 1.7, 1.9, 2.65, 3.3, 3.8 (5m, 16H, 8CH2), 7.4-7.6 (m,
5H, Ar-H), 7.85 (s, 2H, NH2).
4e
4f
248-50
255-57
78
67
C16H20N4O2S 57.81 6.06 16.85 9.65 IR: n = 3490-3390, 3300, 3190 cm-1 (2NH2), 2920 cm-1 (CH-
(332.43)
58.03 5.84 17.07 9.85 aliphatic), 1670 cm-1 (CO). 1H-NMR (DMSO-d6): 1.8, 2.5, 2.8,
3.7 (4m, 16H, 8CH2), 6.8 (s, 2H, NH2), 8.9 (s, 1H, NH).
C22H24N4O2S 64.68 5.92 13.71 7.85 IR: n = 3430, 3330, 3250 cm-1 (NH, NH2), 2950 cm-1 (CH-
(408.53)
64.83 6.13 13.49 8.09 aliphatic), 1660 cm-1 (CO). 1H-NMR (DMSO-d6): 1.8, 2.7, 3.15,
3.3, 3.7 (5m, 16H, 8CH2), 6.9 (s, 2H, NH2), 7.2, 7.7 (2m, 5H,
ArH), 9.4 (s, 1H, NH).
4g
248-50
81
C23H26N4O2S 65.38 6.20 13.26 7.59 IR: n = 3460, 3370, 3280 cm-1 (NH, NH2), 2950 cm-1 (CH-
(422.55)
65.21 6.00 13.07 7.81 aliphatic), 1660 cm-1 (CO). 1H-NMR (DMSO-d6): 1.8, 2.7, 3.3,
3.7 (4m, 16H, 8CH2), 3.95 (s, 3H, OCH3), 6.9 (s, 2H, NH2), 7.2,
7.5 (2d, 4H, ArH), 9.6 (s, 1H, NH).

Synthesis of Morphlinotetrahydrothieno[2,3-c]isoquinolines
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1295
uct was filtered off, dried and recrystallized from ethanol.
Method b:
3-p-Toloyl-7-morphlino-8,9,10,11-tetrahydroisoquino-
lino[3¢,2¢:4,5]thieno[2,3-e]pyrimidin-4(3H)-one (6b)
Produced in 82% yield, m.p. 218-220 °C. Anal.
Calcd. For C24H24N4O2S (432.55): C, 66.64; H, 5.59; N,
12.95; S, 7.41%. Found: C, 66.85; H, 5.81; N, 13.17; S,
7.62%. IR: n = 1950 cm-1 (CH-aliphatic), 1670 cm-1 (CO).
1H-NMR (DMSO-d6): d = 1.8, 2.3, 2.8, 3.7 (4m, 16H,
8CH2), 2.1 (s, 3H, CH3), 7.1-7.3 (2d, 4H, Ar-H), 9.0 (s, 1H,
CH-pyrimidine).
A mixture of compound (2) (2.75 gm, 0.01 mol), al-
kylating agent (0.01 mol) and anhydrous potassium car-
bonate (3 gm, 0.02 mol) in ethanol (40 mL) was refluxed
for 3 hrs., then allowed to cool and poured into cold water
(100 mL). The solid precipitate was filtered off, dried and
recrystallized from ethanol. The physical constants, ele-
mental analyses and spectral data of compounds 4a-g are
listed in Table 1.
4-Aryl-7-(morpholin-4-yl)-8,9,10,11-tetrahydro[1,2,3]-
triazino[4¢,5¢:4,5]thieno[2,3-c]isoquinoline-4-one (7a-c)
General procedure
7-Morphlino-8,9,10,11-tetrahydropyrimido[4¢,5¢:4,5]-
thieno[2,3-c]isoquinoline-4(3H)-one (5)
Method a:
Sodium nitrite solution (7 g, 0.1 mol) in water (10
mL) was added dropwise to a solution of 4e-g (0.01 mol) in
acetic acid with stirring for five minutes. Then it was al-
lowed to stand for 10 h. The solid product was filtered off,
dried and recrystalized from ethanol.
A sample of compound 4b (3.6 g, 0.01 mol) in form-
amide (20 mL) was refluxed for 3 hrs. The solid precipitate
which is formed on heat was filtered off, dried and recrys-
talized from dioxan as white needles in 76% yield, m.p. >
360 °C.
7-Morphlino-3,4,8,9,10,11-hexahydroisoquinolino-
[3¢,2¢:4,5]thieno[2,3-e]-1,2,3-triazine-4-one (7a)
Produced as white crystals in 74% yield, m.p. 230 °C.
Anal. Calcd. For C16H17N5O2S (343.41): C, 55.96; H, 4.99;
N, 20.39; S, 9.34%. Found: C, 56.15; H, 5.21; N, 20.16; S,
9.15%. IR: n = 3450 cm-1 (NH), 2950 cm-1 (CH-aliphatic),
Method b:
A mixture of compound 4e (3.3 g, 0.01 mol) and tri-
ethyl orthoformate (2 mL, 0.014 mol) was refluxed in the
presence of few drops of glacial acetic acid for 30 min. The
solid precipitate which is formed on heating was filtered
off, dried and recrystalized from dioxan as white needles in
81% yield, m.p. > 360 °C. Anal. Calcd. For C17H18N4O2S
(342.42: C, 59.63; H, 5.30; N, 16.36; S, 9.36%. Found: C,
59.87; H, 5.08; N, 16.17; S, 9.55%. IR: n = 3450 cm-1 (NH),
1930 cm-1 (CH-aliphatic), and 1660 cm-1 (CO). 1H-NMR
(DMSO-d6): d = 1.7, 2.6, 3.2, 3.65 (4m, 16H, 8CH2), 8.2 (s,
1H, CH-pyrimidine), 11.5 (s, 1H, NH).
1
1660 cm-1 (CO). H-NMR (DMSO-d6): d = 1.7, 2.7, 3.7
(3m, 16H, 8CH2), 10.5 (s, 1H, NH).
3-Phenyl-7-morphlino-8,9,10,11-tetrahydroisoquinolino-
[3¢,2¢:4,5]thieno[2,3-e]-1,2,3-triazine-4-one (7b)
Produced as green crystals in 3.06 g 73% yield, m.p.
223-225 °C. Anal. Calcd. For C22H21N5O2S (419.51): C,
62.99; H, 5.05; N, 16.69; S, 7.64%. Found: C, 63.21; H,
4.85; N, 16.19; S, 7.48%. IR: n = 1950 cm-1 (CH-aliphatic),
4-Aryl-7-(morpholin-4-yl)-8,9,10,11-tetrahydropyr-
imido[4¢,5¢:4,5]thieno[2,3-c]isoquinoline-4-one (6)
General procedure
1
1685 cm-1 (CO). H-NMR (DMSO-d6): d = 1.8, 2.7, 3.7
(3m, 16H, 8CH2), 7.2-7.7 (m, 5H, Ar-H).
A mixture of compound 4f-g (0.005 mol) and triethyl
orthoformate (1 mL, 0.014 mol) was refluxed in the pres-
ence of few drops of glacial acetic acid for 30 min. The
solid precipitate which is formed on heating was filtered
off, dried and recrystalized from dioxan.
3-p-Toloyl-7-morphlino-8,9,10,11-tetrahydroisoquino-
lino[3¢,2¢:4,5]thieno[2,3-e]-1,2,3-triazine-4-one (7c)
Produced as pale yellow crystals in 78% yield, m.p.
180-182 °C. Anal. Calcd. For C23H23N5O2S (433.54): C,
63.72; H, 5.35; N, 16.15; S, 7.40%. Found: C, 63.55; H,
5.57; N, 15.93; S, 7.18%. IR: n = 1950 cm-1 (CH-aliphatic),
3-Phenyl-7-morphlino-8,9,10,11-tetrahydroisoquinolino-
[3¢,2¢:4,5]thieno[2,3-e]pyrimidin-4(3H)-one (6a)
Produced in 74% yield, m.p. 200-202 °C. Anal.
Calcd. For C23H22N4O2S (418.52): C, 66.01; H, 5.30; N,
13.39; S, 7.66%. Found: C, 65.78; H, 5.07; N, 13.54; S,
7.48%. IR: n = 1970-1930 cm-1 (CH-aliphatic), 1690-1670
cm-1 (CO). 1H-NMR (DMSO-d6): d = 1.8, 2.7, 3.2, 3.7 (4m,
16H, 8CH2), 7.0-7.4 (m, 5H, Ar-H), 8.9 (s, 1H, CH-pyrimi-
dine).
1
1680 cm-1 (CO). H-NMR (DMSO-d6): d = 1.8, 2.7, 3.7
(3m, 16H, 8CH2), 2.3 (s, 3H, CH3), 7.3, 7.8 (2d, 4H, Ar-H).
7-(Morpholin-4-yl)-2,2-tetramethylene-1,2,8,9,10,11-
hexaahydro)pyrimido[5¢,4¢:5,4]thieno[2,3-c]isoquino-
lin-4(3H)-one (8a)
A mixture of carboxamide compound 4e (0.8 g,
0.0025 mol) and cyclopentanone (0.003 mol) was fused in
the presence of a few drops of acetic acid for 30 minutes.

1296 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Kamal El-Dean et al.
The solid product which is formed on heating was filtered
off, dried and recrystalized from acetic acid into white
crystals in 78% yield, m.p. 298-300 °C. Anal. Calcd. For
C21H26N4O2S (398): C, 63.32; H, 6.53; N, 14.07; S, 8.04%.
Found: C, 63.08; H, 6.74; N, 13.86; S, 7.86%. IR: n = 3270,
3190 cm-1 (2NH), 1950 cm-1 (CH-aliphatic), 1660 cm-1
ride (10 mL) was refluxed for 3 hrs., then allowed to cool
and poured with stirring into ice cold water (100 mL). The
solid product was collected and recrystallized from ethanol
to give white crystals in 63% yield, m.p. 132 °C. Anal.
Calcd. For C17H17ClN4OS (360.87): C, 56.58; H, 4.75; Cl,
9.82; N, 15.53; S, 8.89%. Found: C, 56.79; H, 4.98; Cl,
10.07; N, 15.68; S, 9.11%. IR: n = 3050 cm-1 (CH aro-
matic), 2950 cm-1 (CH-aliphatic). 1H-NMR (DMSO-d6): d
= 1.8, 2.7, 3.7 (4m, 16H, 8CH2), and 8.9 (s, 1H, CH pyrimi-
dine).
1
(CO). H-NMR (DMSO-d6): d = 1.8, 2.1, 2.7, 3.7 (4m,
24H, 12CH2), 9.8, 10.9 (2s, 2H, 2NH).
7-(Morpholin-4-yl)-2,2-pentamethylene-1,2,8,9,10,11-
hexaahydro)pyrimido[5¢,4¢:5,4]thieno[2,3-c]isoquino-
lin-4(3H)-one (8b)
7-Morphlino-8,9,10,11-tetrahydropyrimido[4¢,5¢:4,5]-
thieno[2,3-c]isoquinoline-4(3H)-thione (12)
Prepared similarly to 8a using cyclohexanone pro-
duced white crystals in 83% yield, m.p. 310-312 °C. Anal.
Calcd. For C22H28N4O2S (412): C, 64.08; H, 6.80; N,
13.59; S, 7.77%. Found: C, 63.12; H, 7.02; N, 13.77; S,
8.00%. IR: n = 3270, 3190 cm-1 (2NH), 1950 cm-1 (CH-
aliphatic), 1660 cm-1 (CO). 1H-NMR (DMSO-d6): d = 1.5,
2.5, 3.05, 3.3, 3.6 (5m, 26H, 13CH2), 5.6, 7.8 (2s, 2H,
2NH).
A mixture of compound 11 (3.4 gm, 0.01 mol) and
thiourea (3 gm, 0.04 mol) in ethanol (50 mL) was refluxed
for 3 hrs; the solid precipitate which formed on heating was
filtered off, dissolved in NaOH solution (10%, 50 mL) and
acidified with 0.1N HCl until just acidic. The solid product
was filtered off and recrystalized from dioxan as yellow
crystals in 80% yield, m.p. > 360 °C. Anal. Calcd. For
C17H18N4OS2 (358.49): C, 56.96; H, 5.06; N, 15.63; S,
17.89%. Found: C, 57.19; H, 4.84; N, 15.80; S, 18.10%.
IR: n = 3120 cm-1 (NH), 2950 cm-1 (CH-aliphatic), 1200
2-Phenyl-1,2,3,4,8,9,10,11-octahydro-7-(morpholin-4-
yl)pyrimido[5¢,4¢:5,4]thieno[2,3-c]isoquinolin-4-one (9)
Amixture of 4e (1.66 g, 0.005 mol) and benzaldehyde
(0.6 mL, 0.0055 mol) in ethanol (20 mL) was heated under
reflux for 5 h, then allowed to cool. The solid product
which was formed on heating was filtered off, dried and
recrystalized from ethanol into pale yellow crystals in 62%
yield, m.p. 238-240 °C. Anal. Calcd. For C23H24N4O2S
(420.54): C, 65.69; H, 5.75; N, 13.32; S, 7.62%. Found: C,
65.92; H, 5.97; N, 13.08; S, 7.39%. IR: n = 3280, 3190 cm-1
(2NH), 1650 cm-1 (CO). 1H-NMR (DMSO-d6): d = 1.7, 2.7,
3.7 (3m, 16H, 8CH2), 5.5 (s, 1H, CH pyrimidine), 7.1-7.5
(m, 5H, Ar-H) and 9.0, 10.5 (2s, 2H, 2NH).
1
cm-1 (C=S). H-NMR (DMSO-d6): d = 1.8, 2.7, 3.7 (3m,
16H, 8CH2), 8.9 (s, 1H, CH pyrimidine) and 10.5 (s, 1H,
NH).
(7-Morpholin-4-yl-8,9,10,11-tetrahydropyrimido-
[5¢,4¢:2,3]thieno[5,4-c]isoquinolin-4-ylsulfanyl)acetic
acid ethyl ester (13)
To compound 12 (1 gm, 0.0028 mol) dissolved in eth-
anol (30 mL) in the presence of anhydrous potassium car-
bonate (1 gm, 0.007 mol), ethyl chloroacetate (0.4 mL,
0.003 mol) was added. The mixture was refluxed for 3 hrs,
and then allowed to cool, diluted with water (50 mL). The
solid product was filtered off, dried and recrystalized from
ethanol as white crystals in 85% yield, m.p. 158-160 °C.
Anal. Calcd. For C21H24N4O3S2 (444.58): C, 56.74; H,
5.44; N, 12.60; S, 14.42%. Found: C, 56.92; H, 5.37; N,
12.39; S, 14.18%. IR: n = 2950 cm-1 (CH-aliphatic), 1740
2-Phenyl-8,9,10,11-tetrahydro-7-(morpholin-4-yl)-pyr-
imido[5¢,4¢:5,4]thieno[2,3-c]isoquinolin-4(3H)-one (10)
Amixture of 4e (1.66 g, 0.005 mol) and benzaldehyde
(0.6 mL, 0.0055 mol) in acetic acid (20 mL) was heated un-
der reflux for 5 h, then allowed to cool. The solid formed on
heating was filtered off, dried and recrystallized from etha-
nol into white crystals in 68% yield, m.p. 308-310 °C.
Anal. Calcd. For C23H22N4O2S (418.52): C, 66.01; H,
5.30; N, 13.39; S, 7.66%. Found: C, 65.90; H, 5.08; N,
13.18; S, 7.89%. IR: n = 3480 cm-1 (NH), 1640 (CO). 1H-
NMR (DMSO-d6): d = 1.7, 2.3, 2.7, 3.7 (4m, 16H, 8CH2),
7.1-7.7 (m, 5H, Ar-H) and 10.5 (s, 1H, NH).
1
cm-1 (C=O). H-NMR (DMSO-d6): d = 1.3 (t, 3H, CH3),
1.8, 2.7, 3.7 (3m, 16H, 8CH2), 4.0 (s, 2H, CH2), 4.3 (q, 2H,
CH2), 8.9 (s, 1H, CH pyrimidine).
4-Hydrazino-7-morphlino-8,9,10,11-tetrahydropyrimi-
do[4¢,5¢:4,5]thieno[2,3-c]isoquinoline (14)
A mixture of compound 11 (3.6 gm, 0.01 mol) or
compound 12 (3.6 g, 001 mol) and hydrazine hydrate (3.5
mL, 0.07 mol) in ethanol (30 mL) was refluxed for 6 hrs.
The reaction mixture was allowed to cool. The solid prod-
4-Chloro-7-morphlino-8,9,10,11-tetrahydropyrimido-
[4¢,5¢:4,5]thieno[2,3-c]isoquinoline (11)
A sample of 5 (3.4 gm, 0.01 mol) in phosphorylchlo-

Synthesis of Morphlinotetrahydrothieno[2,3-c]isoquinolines
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1297
uct was collected and recrystallized from ethanol as white
crystals in 57% yield, m.p. 274-276 °C. Anal. Calcd. For
C17H20N6OS (356.45): C, 57.28; H, 5.66; N, 23.58; S,
9.00%. Found: C, 57.05; H, 5.66; N, 23.37; S, 8.79%. IR: n
= 3330, 3230, 3200 cm-1 (-NHNH2), 2950 cm-1 (CH-ali-
phatic), 1650 cm-1 (C=N). Mass spectrum: m/z = 355.95.
1-Amino-5-morpholino-6,7,8,9-tetrahydrothieno[2,3-c]-
isoquinoline-2-carbohydrazide (15)
and acetyl acetone (0.5 mL, 0.005 mol) was refluxed in eth-
anol (20 mL) for 4 hrs. Then the mixture is allowed to cool.
The solid product was collected and recrystalized from eth-
anol as pale yellow crystals in 85% yield, m.p. 164-167 °C.
Anal. Calcd. For C21H25N5O2S (411.53): C, 61.29; H, 6.12;
N, 17.02; S, 7.79%. Found: C, 61.07; H, 5.90; N, 16.79; S,
8.03%. IR: n = 3430, 3330 cm-1 (NH2), 2950 cm-1 (CH-ali-
phatic), 1700 cm-1 (C=O). 1H-NMR (DMSO-d6): 1.8, 2.7,
3.7 (3m, 16H, 8CH2), 2.3, 2.5 (2s, 6H, 2CH3), 6.0 (s, 1H,
CH-pyrazole), 6.9 (s, 2H, NH2).
A sample of carboxylate ester 4b (3.6 gm, 0.01 mol)
in hydrazine hydrate (80%, 5 mL, 0.1 mol) was refluxed for
2 hrs. Then absolute ethanol (20 mL) was added and reflux
was continued for an additional 5 hrs. Then it was allowed
to cool; the solid product was filtered off, dried and recrys-
talized from ethanol as white crystals in 65% yield, m.p.
268-270 °C. Anal. Calcd. For C16H21N5O2S (347.44): C,
55.31; H, 6.09; N, 20.16; S, 9.23%. Found: C, 55.09; H,
5.89; N, 19.08; S, 9.00%. IR: n = 3450, 3400, 3350, 3300
cm-1 (NH2, -NHNH2), 2950 cm-1 (CH-aliphatic), 1650 cm-1
(C=O). 1H-NMR (DMSO-d6): 1.9, 2.7, 3.3, 3.5, 3.85 (5m,
16H, 8CH2), 4.3, 6.85 (2b, 4H, 2NH2), 8.95 (s, 1H, NH).
Sodium 1-amino-5-morpholino-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-2-carboxylate (16)
3-Ethoxymetheleneamino-7-morphlino-8,9,10,11-tetra-
hydroisoquinolino[3¢,2¢:4,5]thieno[2,3-e]pyrimidin-
4(3H)-one (19)
A mixture of compound 15 (0.7 gm, 0.002 mol) and
triethyl orthoformate (3 mL) was refluxed for 3 hrs in the
presence of a few drops of glacial acetic acid (1-2 mL). The
solid precipitate that formed on cooling was collected and
recrystalized from ethanol as pale yellow crystals in 73%
yield, m.p. 120-122 °C. Anal. Calcd. For C20H23N5O3S
(413.50): C, 58.09; H, 5.61; N, 16.94; S, 7.75%. Found: C,
57.89; H, 5.39; N, 17.17; S, 8.00%. IR: n = 2950 cm-1 (CH-
aliphatic), 1700 cm-1 (C=O). 1H-NMR (CDCl3): 1.3 (t, 3H,
CH3), 4.3 (q, 2H, CH2), 1.8, 2.6, 3.2, 3.8 (4m, 16H, 8CH2),
7.9 (s, 1H, -CH=N- proton) and at 9.05 (s, 1H, CH pyrimi-
dine).
Asample of carboxylate ester 4b (5 gm, 0.014 mol) in
slightly excess ethanolic sodium hydroxide (1 gm in 30 mL
ethanol) was refluxed for 1/4 hr. The precipitated sodium
salt was filtered off, washed with alcohol and dried. The so-
dium salt obtained in (4 g, 81.5% yield). Anal. Calcd. For
C16H18N3NaO3S (355.39): C, 54.07; H, 5.11; N, 11.82; S,
9.02%. Found: C, 53.88; H, 5.00, N, 12.05, S, 8.82%. IR: n
= 3450, 3350 cm-1 (NH2), 2930 cm-1 (CH-aliphatic), 1710
cm-1 (CO).
Aryledine 1-amino-5-morpholino-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-2-carbohydrazone (20a,b)
To a mixture of carbohydrazide 15 (1 gm, 0.003 mol)
and the respective aldehyde (0.003 mol) in ethanol (20
mL), a few drops of acetic acid was added. The solid pre-
cipitate which is formed on heating was collected and re-
crystallized from dioxan to give yellow needles.
2-Methyl-7-morpholin-4-yl-8,9,10,11-tetrahydro[1,3]-
oxzazino[4¢,5¢:4,5]thieno[2,3-c]isoquinoline (17)
The sodium salt (4 g, 0.011 mol) refluxed for 3 hrs
with acetic anhydride (50 mL) was heated under reflux for
4 h. Excess acetic anhydride was recovered under vacuum.
The solid residue was collected and recrystallized from di-
oxin as white crystals in 55% yield, m.p. 230 °C. Anal.
Calcd. For C18H19N3O3S (357.43): C, 60.49; H, 5.36; N,
11.76; S, 8.97%. Found: C, 60.29; H, 5.58; N, 12.00; S,
9.16%. IR: n = 2950 cm-1 (CH-aliphatic), 1740 cm-1 (C=O).
1H-NMR (DMSO-d6): 2.5 (s, 3H, CH3), 1.8, 2.7, 3.3, 3.85
(4m, 16H, 8CH2).
Benzaylidine 1-amino-5-morpholino-6,7,8,9-tetrahy-
drothieno[2,3-c]isoquinoline-2-carbohydrazone (20a)
Produced as in the above procedure in 93% yield,
m.p. 230-232 °C. Anal. Calcd. For C23H25N5O2S (435.55):
C, 63.43; H, 5.79; N, 16.08; S, 7.36%. Found: C, 63.58; H,
6.01; N, 15.88; S, 7.52%. IR: n = 3440, 3380, 3280 cm-1
(NH, NH2), 2950 cm-1 (CH-aliphatic), 1670 cm-1 (C=O).
1H-NMR (DMSO-d6): 1.7, 2.6, 3.5, 3.8 (4m, 16H, 8CH2),
6.8 (s, 2H, NH2), 7.2-7.5, 7.7-7.9 (2m, 5h, Ar-H), 8.1 (s,
1H, -CH-N), 9.2 (s, 1H, NH).
4-Methoxybenzaylidine-1-amino-5-morpholino-6,7,8,9-
tetrahydrothieno[2,3-c]isoquinoline-2-carbohydrazone
(20b)
(1-Amino-5-morpholino-6,7,8,9-tetrahydrothieno[2,3-
c]isoquinoline-2-yl)-(3,5-dimethylpyrazol-1-yl)ketone
(18)
Produced as in the above procedure in 88% yield,
m.p. 246-248 °C. Anal. Calcd. For C24H27N5O2S (449.58):
A mixture of carbohydrazide 15 (0.7 gm, 0.002 mol)

1298 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Kamal El-Dean et al.
C, 64.12; H, 6.05; N, 15.58; S, 7.13%. Found: C, 63.88; H,
5.87; N, 15.18; S, 7.00%. IR: n = 3420, 3370, 3270 cm-1
(NH, NH2), 2950 cm-1 (CH-aliphatic), 1670 cm-1 (C=O).
1H-NMR (DMSO-d6): 1.8, 2.7, 3.4, 3.6 (4m, 16H, 8CH2),
3.9 (s, 3H, CH3), 7.1, 7.8 (2d, 4H, Ar-H), 7.3 (s, 2H, NH2),
8.1 (s, 1H, -CH-N), 9.5 (s, 1H, NH).
8.95%. Found: C, 53.84; H, 4.86; N, 23.70; S, 9.17%. IR: n
= 3350, 3250 cm-1 (NH2), 2950 cm-1 (CH aliphatic), 2100
cm-1 (N3), and at 1710 cm-1 (CO). 1H-NMR (CCl3D): d =
1.8, 2.8, 3.7 (3m, 16H, 8CH2), 6.5 (s, 2H, NH2).
6-Morpholino-2,3,6,7,8,9-hexahydroimidazo[5¢,4¢:5,4]-
thieno[2,3-c]isoquinoline-2(1H)-one (23)
3-Aryledineamino-7-morphlino-8,9,10,11-tetrahydro-
isoquinolino[3¢,2¢:4,5]thieno[2,3-e]pyrimidin-4(3H)-one
(21a,b)
1-Amino-5-morpholino-6,7,8,9-tetrahydrothieno-
[2,3-c]isoquinoline-2-carboazide (0.5 g) in dry xylene (20
mL) was refluxed for 2 hrs. The solid product that sepa-
rated on heating was filtered off, washed several times with
xylene, dried and recrystalized from xylene as dark brown
crystals in 56% yield, m.p. > 360 °C. Anal. Calcd. For
C16H18N4O2S (330.41): C, 58.16; H, 5.49; N, 16.96; S,
9.70%. Found: C, 57.93; H, 5.71; N, 17.17; S, 9.92%. IR: n
= 3450, 3280 cm-1 (2NH), 2950 cm-1 (CH aliphatic), and at
1660 cm-1 (CO). 1H-NMR (CF3CO2D): d = 2.0, 3.05, 3.5,
4.0 (4m, 16H, 8CH2).
A mixture of aryledine 1-amino-5-morpholino-6,7,8,9-
tetrahydrothieno[2,3-c]isoquinoline-2-carbohydrazone
(0.86 g, 0.002 mol) and (5 mL) triethyl orthoformate was
heated under reflux for 10 minutes in the presence of few
drops of acetic acid (1-2 mL). The solid product which
formed on heating was collected and recrystalized from di-
oxan as clear white crystals.
3-Benzylidineamino-7-morphlino-8,9,10,11-tetrahydro-
isoquinolino[3¢,2¢:4,5]thieno[2,3-e]pyrimidin-4(3H)-one
(21a)
Received May 11, 2008.
It was obtained as in the above procedure in 91%
yield, m.p. 254-256 °C. Anal. Calcd. For C24H23N5O2S
(445.55): C, 64.70; H, 5.20; N, 15.72; S, 7.20%. Found: C,
64.55; H, 4.99; N, 15.95; S, 6.98%. IR: n = 3050 cm-1 (CH
aliphatic), 2950 cm-1 (CH aliphatic), and at 1700 cm-1
(CO). 1H-NMR (DMSO-d6): d = 2.0, 3.05, 3.5, 3.95 (4m,
16H, 8CH2), 7.7, 8.0 (2m, 5H, Ar-H), 8.7, 9.4 (2s, 2H,
-CH=N-, CH pyrimidine).
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It was obtained as in the above procedure in 89%
yield, m.p. 260-262 °C. Anal. Calcd. For C25H25N5O2S
(459.57): C, 65.34; H, 5.48; N, 15.24; S, 6.98%. Found: C,
65.54; H, 5.71; N, 15.00; S, 7.18%. IR: n = 3050 cm-1 (CH
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1
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isoquinoline-2-carboazide (22)
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Sodium nitrite solution (7 mL 10%, 0.01 mol) was
added dropwise to a solution of carbohydrazide 15 (0.7 gm,
0.002 mol) in acetic acid (10 mL) at 5 °C over 5 minutes
with stirring. The solid product was filtered off, dried as
pale brown crystals in 61% yield, m.p. 140-142 °C., and
used without further purification. Anal. Calcd. For
C16H18N6O2S (358.42): C, 53.62; H, 5.06; N, 23.45; S,
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Synthesis of Morphlinotetrahydrothieno[2,3-c]isoquinolines
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1299
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