Synthesis and reactions of 1-amino-5-morpholin-4-yl-6,7,8,9- tetrahydrothieno[2,3-c]isoquinoline

Article abstract of DOI:10.1002/jccs.201190019

The pyrazolone derivative 4 was synthesized by reaction of carbohydrazide 2 with ethyl benzoylacetate in ethanol and p-toluene sulphonic acid followed by cyclization upon heating in acetic acid. Chloroacylation of amino ester and amino benzoyl compounds 1, 19 gave the chloro acetylamino derivatives 5 and 20 respectively which both of them react with different amines to afford compounds 6, 23a-d. Hydrolysis and decarboxlation of compound 1 yielded the aminothienotetrahydroisoquinoline 8 which was used as versatile material for synthesizing other heterocyclic compounds 9-18. Compound 20 react with hexamethylenetetramine and malononitrile yielded thediazepino and pyrrolo derivatives 21, 22 respectively.

Full text of DOI:10.1002/jccs.201190019

544
Journal of the Chinese Chemical Society, 2011, 58, 544-554
Synthesis and Reactions of
1-Amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline
Remon M. Zaki,* Shaban M. Radwan and Adel M. Kamal El-Dean
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Received October 23, 2010; Accepted March 7, 2011; Published Online March 29, 2011
The pyrazolone derivative 4 was synthesized by reaction of carbohydrazide 2 with ethyl benzoyl-
acetate in ethanol and p-toluene sulphonic acid followed by cyclization upon heating in acetic acid.
Chloroacylation of amino ester and amino benzoyl compounds 1, 19 gave the chloro acetylamino deriva-
tives 5 and 20 respectively which both of them react with different amines to afford compounds 6, 23a-d.
Hydrolysis and decarboxlation of compound 1 yielded the aminothienotetrahydroisoquinoline 8 which
was used as versatile material for synthesizing other heterocyclic compounds 9-18. Compound 20 react
with hexamethylenetetramine and malononitrile yielded thediazepino and pyrrolo derivatives 21, 22 re-
spectively.
Keywords: Pyridothienotetrahydroisoquinoline; Furopyridothienotetrahydroisoquinoline;
Diazepinothienotetrahydroisoquinoline; Synthesis; Reactions.
INTRODUCTION
Substituted tetrahydroisoquinolines are abundantly
dyes, pharmaceuticals, agents for chemical plant protec-
tion, surfactants, acid corrosion inhibitors, ion exchange
resins, selective sorbents, and extractants.
found in nature, especially in a variety of plants, soil, and
marine microorganisms.1 Many of tetrahydroisoquinoline
derivatives exhibit important biological activities, for ex-
ample, anti-inflammatory, anti-microbial, antibacterial,
antimalarial, anti-leukemic, anti-HIV, anti-tumor proper-
ties,2,3 cytotoxicity,4 antagonist activity to D1 and NMDA
receptors,5 analgesicactivity,6 pathogenesis of Parkinson’s
disease,7 and enzyme inhibitory activities for glucosidases8
and monoamine oxidases9 and other biological activi-
ties.10-13
E. Lukevics14 noted that compounds containing the
pyridine ring accounted for more than 10% out of 1500
medicines most regularly used at the end of the 20th cen-
tury. Among these medicines are vitamins (B3, B6, and
PP), analgetics, analeptics, antiarrhythmics, antiseptics,
antidepressants, spasmolytics, neuroleptics, tranquilizing
agents, and drugs having other pharmacological activities.
In the recent monograph on the chemistry of pyridine
bases,15 the authors stated that pyridine and its homologs
are among the most important reagents for the fine and in-
dustrial organic synthesis, which are widely used in chemi-
cal and petrochemical industry, as well as in production of
RESULTS AND DISCUSSION
1-Amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno
[2,3-c]isoquinolin-2-carbohydrazide16 (2) prepared by the
reaction of ethyl-1-amino-5-morpholin-4-yl-6,7,8,9-tetra-
hydrothieno[2,3-c]isoquinolin-2-carboxylate (1) with hy-
drazine hydrate was reacted with ethyl benzoylacetate in
refluxing ethanol in presence of p-toluene sulphonic acid to
afford the corresponding ethyl propionate ester 3 which un-
derwent ring closure when heated in acetic acid to give
2-(1-amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno-
[2,3-c]isoquinoline-2-carbonyl)-5-phenyl-2,4-dihydro-
pyrazol-3-one (4) Scheme I. The structure of the produced
compound was elucidated on the basis of 1H-NMR spectra
which revealed the disappearance of triple and quartet sig-
nals at d 1.3, 4.5 characteristic for ethyl ester group.
On the other hand, amino ester compound 1 was chlo-
roacetylated using chloroacetyl chloride in dioxan fol-
lowed by treating with sodium carbonate solution to afford
ethyl-1-chloroacetylamino-N-(2-cyano-5-morpholin-4-yl-
6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-1-yl)carbox-
* Corresponding author. E-mail: remonch2003@yahoo.com

Pyridothienotetrahydroisoquinoline
J. Chin. Chem. Soc., Vol. 58, No. 4, 2011 545
Scheme I
ylate (5). IR spectrum revealed the disappearance of ab-
sorption band at 3420, 3320 cm-1 characteristic for NH2
1
group. The H-NMR spectrum of compound 5 in CDCl3
in refluxing ethanol to afford ethyl-5-morpholin-4-yl-1-
(2-phenylaminoacetylamino)-6,7,8,9-tetrahydrothieno-
[2,3-c]isoquinoline-2-carboxylate (7) Scheme II.
showed the disappearance of signal at d 6.1 characteristic
for (NH2) group and appearance of singlet signal at d 4.3
for (CH2) which doesn’t disappear by D2O, doesn’t exist in
1H-NMR of compound 5 and showed singlet signal at 9.2
characteristic for (NH) group which disappear by D2O.
Reaction of compound 5 with potassium thiocyanate
in refluxing ethanol afforded ethyl-5-morpholin-4-yl-8-
oxo-1,2,3,4,8,9-hexahydropyrimido[4¢,5¢:4,5]thieno[2,3-
c] isoquinolin-10-ylsulfanyl acetate (6).17 The suggested
reaction mechanism for formation of compound 6 include
nucleophilic attack of NH to CN group in compound 5 to
form thiazole ring as intermediate followed by elimination
of ethanol molecule to form pyrimidinone ring then break-
ing of thiazole ring with forming ethyl sulfanylacetate was
carried out by adding ethanol molecule as shown as follows
in the following scheme (Fig. 1).
Hydrolysis of and decarboxylation of compound 1
was carried out by refluxing with alcoholic potassium hy-
droxide solution yielded the potassium salt of acid which
can’t be isolated and by acidification using HCl afforded
1-amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-
c]isoquinoline (8). IR spectrum of compound 8 revealed
the disappearance of absorption band at 1735 cm-1 charac-
teristic for (C=O) ester. 1H-NMR spectrum showed the dis-
appearance of signals at 1.3, 4.2 for ethyl ester group with
remaining the signal characteristic for NH2 at d 6.3.
IR spectrum showed of compound 6 absorption band
at 3400 characteristic for (NH) group and absorption bands
at 1670, 1650 cm-1 characteristic for two carbonyl groups.
1H-NMR spectrum of compound 6 showed triplet and quar-
tet signals at d 1.3, 4.5 characteristic for ethyl ester group
and singlet signal at d 11.5 for (NH) group. The mass spec-
trum showed a peak at 459.63 as a molecular ion peak and
as a base peak. Also, the chloro acetylamino derivative 5
underwent nucleophilic substitution reaction with aniline
Fig. 1.

546 J. Chin. Chem. Soc., Vol. 58, No. 4, 2011
Zaki et al.
Scheme II
Compound 8 was used as a versatile precursor to syn-
thesis of another heterocyclic compounds. Thus, reaction
of amino thieno tetrahydroisoquinoline derivative 8 with
2-cyano-3-ethoxyacrylic acid ethyl ester in ethanol yielded
ethyl-2-cyano-3-(5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-1-ylamino)acrylate (9). Com-
pound 9 underwent ring closure by loss of ethanol when
refluxed in acetic acid to give 5-morpholin-4-yl-8-oxo-
1,2,3,4,8,11-hexahydropyrido[2²,3²:4¢,5¢]thieno[2,3-c]-
isoquinoline-9-carbonitrile (10). IR spectrum of compound
10 revealed the disappearance of absorption band at 1680
showed absorption band at 3420, 3320 cm-1 characteristic
1
for (NH2) group and at 1710 for (C=O) ester. H-NMR
spectrum of compound 12 in CF3CO2D showed triplet and
quartet signals at d 1.35, 4.40 characteristic for (CH3, CH2)
groups of ester group and the mass spectrum of appreciable
compound showed a peak at 452.56 as a molecular ion
peak. Hydrazinolysis of compounds 11, 12 by using hydra-
zine hydrate under neat conditions followed by addition of
ethanol afforded 3-amino-10-morpholin-4-yl-6,7,8,9-tet-
rahydrofuro[2²,3²:4¢,5¢]pyrido[2¢,3¢:4,5]thieno[2,3-c]iso-
quinolin-9-carbohydrazide (13), (9-cyano-5-morpholin-4-
yl-1,2,3,4-tetrahydropyrido[2²,3²:4¢,5¢]thieno[2,3-c]iso-
quinolin-8-yloxy) acetic hydrazide (14) respectively.
Condensation of compound 14 with acetyl acetone
yielded 8-[2-(3,5-dimethylpyrazol-1-yl)-2-oxoethoxy]-5-
morpholin-4-yl-1,2,3,4-tetrahydropyrido[2¢,3¢:4,5]thieno-
[2,3-c]isoquinolin-9-carbonitrile (15) Scheme III. IR spec-
trum of compound 15 revealed disappearance of absorption
bands at 3450-3280 cm-1 characteristic for (NH, NH2)
groups. 1H-NMR spectrum in DMSO-d6 showed two sharp
singlet signals at d 2.3, 2.45 characteristic for the two pyr-
azole methyl groups and singlet signal at 6.2 characteristic
for (CH pyrazole).
1
cm-1 characteristic for C=O ester. H-NMR spectrum in
DMSO-d6 showed the disappearance of triplet and quartet
signals at d 1.3, 4.2 characteristic for (CH3 and CH2) groups
of ester group respectively. The mass spectrum of men-
tioned compound showed a peak at 366.20 as a molecular
ion peak.
When compound 10 was allowed to react with ethyl
chloroacetate in DMF on a steam bath in presence of excess
anhydrous potassium carbonate alkylation occurred to af-
ford (9-cyano-5-morpholin-4-yl-1,2,3,4,8,11-hexahydro-
pyrido[2¢,3¢:4,5]thieno[2,3-c]isoquinolin-8-yloxy)acetic-
acidethylester (11) which underwent Thorpe-Ziegler cy-
clization by refluxing in ethanol/sodium ethoxide solution
to yield the corresponding ethyl-3-amino-10-morpholin-
4-yl-6,7,8,9-tetrahydrofuro[2²,3²:4¢,5¢]pyrido[2¢,3¢:4,5]-
thieno[2,3-c]isoquinoline-2-carboxylate (12). The struc-
ture of compound 12 was confirmed on the basis of IR,
1H-NMR and mass spectrum. IR spectrum of compound 12
Heating of amino tetrahydrothienoisoquinoline de-
rivative 8 with orthophosphoric acid on a steam bath fol-
lowed by cooling and pouring on ice water mixture yielded
5-morpholin-4-yl-1-oxo-6,7,8,9-tetrahydrothieno[2,3-c]-
isoquinoline (16).18 Condensation of compound 16 with
benzaldehyde afforded the corresponding Schiff’s base 17,

Pyridothienotetrahydroisoquinoline
J. Chin. Chem. Soc., Vol. 58, No. 4, 2011 547
Scheme III
while reaction with benzyledine malononitrile yielded
10-amino-5-morpholin-4-yl-8-phenyl-1,2,3,4-tetrahydro-
8H-pyrano[2¢,3¢:4,5]thieno[2,3-c]isoquinoline-9-carbo-
nitrile (18)18 Scheme IV. 1H-NMR spectra of compound 17
in CDCl3 showed multiplet signals at d 7.45-7.80 charac-
(NH2) group and mltiplet signals at d 7.2-7.4 for aromatic
protons.
The suggested mechanism for reaction of ketone 16
with benzylidenemalononitrile to form the pyrano deriva-
tive 18 was described as follows (Fig. 2).
1
teristic for aromatic protons while H-NMR spectra of
In a similar manner, chloro acetylation of 1-amino-2-
benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]
compound 18 in CDCl3 showed singlet signal at d 4.7 for
Scheme IV

548 J. Chin. Chem. Soc., Vol. 58, No. 4, 2011
Zaki et al.
yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-1-yl)-2-al-
kyl(aryl)aminoacetamide 23 a-d Scheme V.
EXPERIMENTAL
All melting points are uncorrected and measured on a
Fisher-John apparatus. IR spectra were recorded (KBr)
1
with a Perkin-Elmer 1430 Spectrophotometer. H NMR
spectra were obtained on a Varian EM-390 MHz (90 MHz)
and Joel 400 MHz spectrometers with equal concentrations
in a suitable deutrated solvent using TMS as internal stan-
dard in CDCl3, DMSO-d6 and CF3CO2D using Me4Si as in-
ternal standard and chemical shifts are expressed as ppm.
Mass spectra were measured on a Jeol-JMS 600 spectrome-
ter. Analytical data were obtained on Elementar Analyse
system GmbH-VarioEL V.3 microanalyzer in the central
lab of Assiut University.
Fig. 2.
isoquinoline (19)28 using chloroacetyl chloride in dioxan
on a steam bath followed by treating with sodium carbonate
solution afforded N-(2-benzoyl-5-morpholin-4-yl-6,7,8,9-
tetrahydrothieno[2,3-c]isoquinolin-1-yl)-2-chloroacet-
amide (20). Also, compound 20 was used as starting mate-
rial for synthesizing compounds 21-23 a-d. Refluxing
chloro acetylamino derivative 20 with hexamethylenetet-
ramine in ethanol yielded 5-morpholin-4-yl-8-phenyl-
1,2,3,4,10-pentahydro[1,4]diazepino[5¢,6¢:4,5]thieno[2,3-
c]isoquinolin-11(12H)-one (21) through formation of hex-
aminium salt as intermediate. IR spectrum of compound 21
showed absorption bands at 3400 cm-1 characteristic for
Ethyl-1-amino-5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3,-c]isoquinoline-2-carboxylate (1), 1-amino-5-
morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquino-
line-2-carbohydrazide (2), 1-amino-2-benzoyl-5-morpho-
lin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline (19)
were prepared according to reported procedure.16 The fol-
lowing figure show the numbering of carbon atoms for
compounds 21 and 23a used in 13C-NMR analysis.
Ethyl-3-(1-amino-5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-2-carbonylhydrazono)-3-
phenylpropionate (3)
(NH) group and 1690 cm-1 for (C=O) group. H-NMR
1
Carbohydrazide derivative 2 (3.47 g, 10 mmol) and
ethyl benzoyl acetate (1.92 mL, 10 mmol) was refluxed in
ethanol (30 mL) in the presence of p-toluene sulfonic acid
(1.722 g, 10 mmol) for 1 h. The solid precipitate which
formed on hot (during reflux) was cooled, filtered off, dried
and recrystallized from chloroform to afford yellow crys-
tals in 76% yield, m.p. 194-196 oC. 1H-NMR (CDCl3): d =
1.3 (t, J = 7.5 Hz, 3H, CH3), 1.8 (m, 4H, 2CH2 cyclohex-
eno), 2.7 (m, 4H, 2CH2 cyclohexeno), 3.4 (m, 6H, (CH2)2N-
morpholine + CH2CO), 4.00 (m, 4H, (CH2)2O-morpho-
spectrum in CDCl3 showed singlet signal at d 4.5 character-
istic for (CH2) group and mass spectrum of the mentioned
compound showed a peak at 432.89 as a molecular ion
peak.
Reaction of chloro acetylamino derivative 20 with
malononitrile in refluxing ethanol in presence of anhy-
drous potassium carbonate gave 2-benzoyl-1-(2-amino-3-
cyano-5-oxopyrrol-1-yl)-5-morpholin-4-yl-6,7,8,9-tetra-
hydrothieno[2,3-c]isoquinoline (22). The structure was
confirmed on the bases of elemental and spectral analysis.
IR spectrum of compound 22 showed absorption bands at
3320, 3200 cm-1 characteristic for (NH2) and 2200 for (CN)
group. 1H-NMR spectrum CDCl3 showed singlet signal at d
2.8 for (CH2) group of pyrrole and singlet signal at d 5.3
characteristic for (NH2) group. Also, the chloro acetyl-
amino derivative 20 underwent nucleophilic substitution
reactions with various primary and secondary amines in
refluxing ethanol to afford N-(2-benzoyl-5-morpholin-4-
Fig. 3.

Pyridothienotetrahydroisoquinoline
J. Chin. Chem. Soc., Vol. 58, No. 4, 2011 549
Scheme V
line), 4.5 (q, J = 6 Hz, 2H, CH2 ester), 7.00 (s, 2H, NH2),
7.5-8.5 (m, 5H, ArH) and 9.9 (s, 1H, NH) ppm. IR: n =
3450, 3350, 3180 cm-1 (NH + NH2), 3050 cm-1 (CH aro-
matic), 1715 cm-1 (CO ester), 1620 cm-1 (CONH). Anal.
Calcd. for: C27H31N5O4S (521.64) C, 62.17; H, 5.99; N,
13.43; S, 6.15%. Found: C, 62.35; H, 6.10; N, 13.25; S,
6.00%.
was formed on hot (during reflux) was cooled, filtered off
and recrystallized from dioxan to give yellow crystals in
72% yield, m.p. 250-252 oC. 1H-NMR (DMSO-d6): d = 1.8
(m, 4H, 2CH2 cyclohexeno), 2.6 (m, 4H, 2CH2 cyclohex-
eno), 3.2 (m, 6H, (CH2)2N-morpholine + CH2 pyrazole),
3.8 (m, 4H, (CH2)2O-morpholine), 6.1 (s, 2H, NH2) and
7.5-7.9 (m, 5H, ArH) ppm. IR: n = 3400, 3350 cm-1 (NH2),
3050 cm-1 (CH aromatic), 2920, 2850 cm-1 (CH aliphatic),
1680, 1650 cm-1 (2CO). Anal. Calcd. for: C25H25N5O3S
(475.57) C, 63.14; H, 5.30; N, 14.73; S, 6.74%. Found: C,
63.00; H, 5.45; N, 15.00; S, 6.60%.
2-(1-Amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno-
[2,3-c]isoquinoline-2-carbonyl)-5-phenyl-2,4-dihydro-
pyrazol-3-one (4)
Method A
Ethylpropionate compound 3 (0.522 g, 1 mmol) was
dissolved in acetic acid (20 mL) and was refluxed for 2 h.
The solid precipitate which was formed on hot (during re-
flux) was cooled, filtered off and recrystallized from diox-
an into yellow crystals in 68% yield, m.p. 250-252 oC.
Method B
Ethyl-1-chloroacetylamino-N-(2-cyano-5-morpholin-4-
yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-1-yl)car-
boxylate (5)
A mixture of amino ester compound 1 (3.61 g, 10
mmol) and chloroacetyl chloride (1.243 mL, 11 mmol) in
dioxan (30 mL) was heated on a steam bath for 2 h. The
solid product which formed by pouring on ice water mix-
ture and neutralized with diluted sodium carbonate solu-
tion was filtered off, dried and recrystallized from ethanol
Carbohydrazide derivative 2 (1.041 g, 3 mmol) and
ethyl benzoylacetate (1.92 mL, 10 mmol) were refluxed in
ethanol and piperidine for 2 h. The solid precipitate which

550 J. Chin. Chem. Soc., Vol. 58, No. 4, 2011
Zaki et al.
o
to afford white needles in 78% yield, m.p. 160-162 C.
1H-NMR (CDCl3): d = 1.4 (t, J = 9 Hz, 3H, CH3), 1.85 (m,
4H, 2CH2), 2.8 (m, 4H, 2CH2), 3.2 (m, 4H, 2CH2), 3.9 (m,
4H, 2CH2), 4.3 (s, 2H, CH2 acetamide), 4.5 (q, J = 7.5 Hz,
2H, CH2) and 9.2 (s, 1H, NH) ppm. IR: n = 3200 cm-1 (NH),
2920, 2850 cm-1 (CH aliphatic), 1730 cm-1 (CO ester),
1670 cm-1 (CO amide). Anal. Calcd. for: C20H24ClN3O4S
(437.95) C, 54.85; H, 5.52; Cl, 8.10; N, 9.59; S, 7.32%.
Found: C, 55.00; H, 5.72; Cl, 8.00; N, 10.05; S, 7.22%.
Ethy-5-morpholin-4-yl-8-oxo-1,2,3,4,8,9-hexahydropyr-
imido[4¢,5¢:4,5]thieno[2,3-c]isoquinolin-10-yl sulfanyl
acetate (6)
1-Amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno-
[2,3-c]isoquinoline (8)
Amino ester compound 1 (1.444 g, 4 mmol) was re-
fluxed with alcoholic potassium hydroxide solution (pre-
pared by dissolving 1.00 g of potassium hydroxide in 30
mL ethanol) for 1 h. then the mixture was cooled and added
to 10% HCl solution. The solid precipitate which formed
by adding HCl solution was filtered off, dried and recrys-
tallized from dioxan to afford white crystals in 96% yield,
o
m.p. 218-220 C. 1H-NMR (DMSO-d6): d = 1.8 (m, 4H,
2CH2), 2.7 (m, 4H, 2CH2), 3.1 (m, 4H, 2CH2), 3.8 (m, 4H,
2CH2), 6.3 (s, 2H, NH2) and 7.5 (s, 1H, CH thieno) ppm.
IR: n = 3520, 3350 cm-1 (NH2), 2920, 2850 cm-1 (CH
aliphatic), 1625 cm-1 (C=N). Anal. Calcd. for: C15H19N3OS
(289.40), C, 62.25; H, 6.62; N, 14.52; S, 11.08%. Found: C,
62.40; H, 6.75; N, 14.70; S, 11.30%.
A mixture of compound 5 (1.007 g, 2.3 mmol) and
potassium thiocyanate (0.22 g, 2.3 mmol) in ethanol (30
mL) was refluxed for 4 h. The solid precipitate which
formed on cold was filtered off, dried and recrystallized
from ethanol to give white crystals in 81% yield, m.p.
140-142 oC. 1H-NMR (DMSO-d6): d = 1.3 (t, J = 7.5 Hz,
3H, CH3), 1.8 (m, 4H, 2CH2), 2.7 (m, 4H, 2CH2), 3.2 (m,
4H, 2CH2), 3.85 (m, 4H, 2CH2), 4.2 (s, 2H, CH2CO), 4.5
(q, J = 7.5 Hz, 2H, CH2 ester) and 11.5 (s, 1H, NH) ppm.
IR: n = 3290 cm-1 (NH), 2920, 2830 cm-1 (CH aliphatic),
1735 cm-1 (CO ester), 1675 cm-1 (CO amide). Mass spec-
trum m/z (%): 460 (M+, 100), 429 (31.3), 403 (42.5), 92
(49.4). Anal. Calcd. For: C21H24N4O4S2 (460.58) C, 54.76;
H, 5.25; N, 12.16; S, 13.92%. Found: C, 54.50; H, 5.43; N,
12.30; S, 14.10%.
Ethyl-2-cyano-3-(5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-1-ylamino)acrylate (9)
A mixture of amino compound 8 (2.894 g, 0.01 mol)
and ethyl 2-cyano-3-ethoxyacrylate (1.69 g, 0.01 mol) in
ethanol (30 mL) was refluxed for 2 h. The solid precipitate
which was formed on hot during reflux was cooled, filtered
off, dried and recrystallized from ethanol-benzene mixture
o
to give brown crystals in 41% yield, m.p. 270-272 C.
1H-NMR (CDCl3): d = 1.3 (t, J = 7.5 Hz, 3H, CH3), 1.9 (m,
4H, 2CH2), 2.8 (m, 4H, 2CH2), 3.3 (m, 4H, 2CH2), 3.8 (m,
4H, 2CH2), 4.2 (q, J = 6 Hz, 2H, CH2), 7.9 (s, 1H, CH
thieno), 8.6 (s, 1H, CHacrylate) and 11.5 (s, 1H, NH) ppm.
IR: n = 3380 cm-1 (NH), 2950, 2850 cm-1 (CH aliphatic),
2210 cm-1 (CN), 1680 cm-1 (CO ester), 1620 cm-1 (C=N).
Anal. Calcd. for: C21H24N4O3S (412.51) C, 61.15; H, 5.86;
N, 13.58; S, 7.77%. Found: C, 60.95; H, 6.00; N, 13.70; S,
7.54%.
Ethyl-5-morpholin-4-yl-1-(2-phenylaminoacetylamino)-
6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxy-
late (7)
Chloro acetylamino derivative 5 (0.438 g, 1 mmol)
and aniline (0.28 mL, 3.226 mmol) was gently refluxed for
10 minutes, then ethanol (10 mL) was added and reflux
continued for additional 2 h. The solid precipitate which
formed on hot during reflux was cooled, dried and recrys-
tallized from dioxan to give white needles in 80% yield,
m.p. 222-224 oC. 1H-NMR (CDCl3): d = 1.35 (t, J = 6 Hz,
3H, CH3), 1.8 (m, 4H, 2CH2), 2.7 (m, 4H, 2CH2), 3.25 (m,
4H, 2CH2), 3.9 (m, 4H, 2CH2), 4.05 (s, 2H, CH2 acet-
amide), 4.25 (q, J = 7.5 Hz, 2H, CH2), 6.6 (s, 1H, NH
phenylamino), 7.3-6.8 (m, 5H, ArH) and 9.2 (s, 1H, NH
acetamide) ppm. IR (cm-1): n = 3380, 3290 (2NH), 3030
(CH aromatic), 2920, 2850 (CH aliphatic), 1700 (CO es-
ter), 1670 (CO amide). Anal. Calcd. for: C26H30N4O4S
(494.62) C, 63.14; H, 6.11; N, 11.33; S, 6.48%. Found: C,
63.00; H, 6.23; N, 11.21; S, 6.66%.
5-Morpholin-4-yl-8-oxo-1,2,3,4,8,11-hexahydropyrido-
[2²,3²:4¢,5¢]thieno[2,3-c]isoquinoline-9-carbonitrile (10)
Ethyl acrylate compound 9 (0.578 gm, 1.4 mmol) was
refluxed in glacial acetic acid (20 mL) for 3 hrs. The solid
product which was formed on hot during reflux was cooled,
filtered off and recrystallized from DMF into green crystals
in 75% yield, m.p. 340-342 oC. 1H-NMR (DMSO-d6): d =
1.9 (m, 4H, 2CH2), 2.8 (m, 4H, 2CH2), 3.3 (m, 4H, 2CH2),
3.8 (m, 4H, 2CH2), 8.8 (s, 1H, CH pyridine), 11.4 (s, 1H,
NH pyridine) ppm. IR: n = 3220 cm-1 (NH), 2210 cm-1
(CN), 1635 cm-1 (C=O). Mass spectrum m/z (%): 366 (M+,
19.1), 365 (M+-1, 44.5), 347 (21.3), 334 (21.5), 321 (36.6),
316 (24.7), 308 (100). Anal. Calcd. for: C19H18N4O2S

Pyridothienotetrahydroisoquinoline
J. Chin. Chem. Soc., Vol. 58, No. 4, 2011 551
o
(366.44) C, 62.28; H, 4.95; N, 15.29; S, 8.75%. Found: C,
62.46; H, 5.12; N, 15.37; S, 8.88%.
300 C. IR: n = 3420, 3300, 3180 cm-1 (NH, NH2), 1630
cm-1 (CONH), 1600 cm-1 (C=N). Mass spectrum m/z (%)
437 (M+-1, 1), 402 (8), 309 (7.3), 253 (7), 197 (8), 127
(12.8), 105 (15.9), 90 (55.3), 70 (72.5), 57 (100). Anal.
Calcd. for: C21H22N6O3S (438.51) C, 57.52; H, 5.06; N,
19.16; S, 7.31%. Found: C, 57.75; H, 4.98; N, 19.00; S,
7.48%.
(9-Cyano-5-morpholin-4-yl-1,2,3,4,8,11-hexahydropyr-
ido[2²,3²:4¢,5¢]thieno[2,3-c]isoquinoline-8-yloxy)acetic
acid ethyl ester (11)
Amixture of pyrido derivative 10 (3.664 g, 0.01 mol),
ethyl chloroacetate (1.47 mL, 0.012 mol) and anhydrous
potassium carbonate (4.00 g, 0.029 mmol) in DMF (10 mL)
was heated on a steam bath for 6 h. The solid product which
was formed on hot during reflux was cooled, filtered off,
dried and recrystallized from ethanol into greenish yellow
crystals in 67.5% yield, m.p. 240-242 oC. 1H-NMR
(CF3CO2D): d = 1.3 (t, J = 6 Hz, 3H, CH3), 1.8 (m, 4H,
2CH2), 2.6 (m, 4H, 2CH2), 3.2 (m, 4H, 2CH2), 3.9 (m, 4H,
2CH2), 4.2 (q, J = 4.5 Hz, 2H, CH2), 4.8 (s, 2H, OCH2), 9.4
(s, 1H, CH pyridine) ppm. IR: n = 2920, 2850 cm-1 (CH
aliphatic), 2200 cm-1 (CN), 1735 cm-1 (CO ester). Anal.
Calcd. for: C23H24N4O4S (452.54) C, 61.05; H, 5.35; N,
12.38; S, 7.09%. Found: C, 60.86; H, 5.48; N, 12.54; S,
7.23%.
(9-Cyano-5-morpholin-4-yl-1,2,3,4-tetrahydropyrido-
[2²,3²:4¢,5¢]thieno[2,3-c]isoquinoline-8-yloxy)acetic acid
hydrazide (14)
A mixture of O-(ethoxycarbonyl)methyl derivative
11 (1 g, 2.21 mmol) and hydrazine hydrate (2 mL, 0.04
mol) was fused for 1 h. then ethanol (10 mL) was added and
reflux continued for additional 2 h. The solid precipitate
which formed on hot during reflux was cooled, filtered off
and recrystallized from dioxan to afford pale yellow crys-
tals in 45% yield, m.p. 288-290 oC. 1H-NMR (DMSO-d6): d
= 1.85 (m, 4H, 2CH2), 2.75 (m, 4H, 2CH2), 3.30 (m, 4H,
2CH2), 3.85 (m, 4H, 2CH2), 4.10 (s, 2H, NH2), 4.95 (s, 2H,
CH2), 8.7 (s, 1H, NH), 9.3 (s, 1H, CH pyridine) ppm. IR: n
= 3450, 3320, 3280 cm-1 (NH, NH2), 3050 cm-1 (CH aro-
matic), 2910, 2820 cm-1 (CH aliphatic), 2210 cm-1 (CN),
1670 cm-1 (CO amide). Anal. Calcd. for: C21H22N6O3S
(438.51) C, 57.52; H, 5.06; N, 19.16; S, 7.31%. Found: C,
57.68; H, 5.34; N, 19.00; S, 7.50%.
Ethyl-3-amino-10-morpholin-4-yl-6,7,8,9-tetrahydro-
furo[2²,3²:4¢,5¢]pyrido[2¢,3¢:4,5]thieno[2,3-c]isoquino-
line-2-carboxylate (12)
A solution of O-(ethoxycarbonyl)methyl derivative
11 (0.45 g, 1 mmol) in absolute ethanol (20 mL) was re-
fluxed in presence of few drops of sodium ethoxide solu-
tion prepared from 0.5 g clean sodium metal in absolute
ethanol (20 mL) for 1 h. The solid product which was
formed on hot during reflux was cooled, filtered off, dried
and recrystallized from ethanol in 49% yield, m.p. 296-298
oC. IR: n = 3420, 3320 cm-1 (NH2), 2920, 2850 cm-1 (CH
aliphatic), 1710 cm-1 (CO unsaturated ester), 1650 cm-1
(C=N). Mass spectrum m/z (%): 452 (M+, 1), 414 (5), 394
(16), 109 (58.8), 90 (85), 88 (63.9), 57 (100). Anal. Calcd.
for: C23H24N4O4S (452.54) C, 61.05; H, 5.35; N, 12.38; S,
7.09%. Found: C, 61.26; H, 5.50; N, 12.16; S, 7.30%.
3-Amino-10-morpholin-4-yl-6,7,8,9-tetrahydrofuro-
[2²,3²:4¢,5¢]pyrido[2¢,3¢:4,5]thieno[2,3-c]isoquinolin-9-
carbohydrazide (13)
8-[2-(3,5-Dimethylpyrazol-1-yl)-2-oxoethoxy]-5-mor-
pholin-4-yl-1,2,3,4-tetrahydropyrido[2¢,3¢:4,5]thieno-
[2,3-c]isoquinoline-9-carbonitrile (15)
The carbohydrazide compound 14 (0.482 g, 1.1
mmol) and acetylacetone (2 mL, 0.02 mol) were fused for
30 minutes then absolute ethanol (20 mL) was added and
reflux continued for additional 2 h. The solid precipitate
which formed on hot during reflux was cooled, filtered off,
dried and recrystalllized from ethanol to give yellow nee-
dles in 36% yield, m.p. 264-266 oC. 1H-NMR (DMSO-d6):
d = 1.7 (m, 4H, 2CH2), 2.3, 2.45 (2s, 6H, 2CH3 pyrazole),
2.9 (m, 4H, 2CH2), 3.2 (m, 4H, 2CH2), 3.8 (m, 4H, 2CH2),
5.7 (s, 2H, CH2), 6.2 (s, 1H, CH pyrazole), 8.8 (s, 1H, CH
pyridine) ppm. IR: n = 3050 cm-1 (CH aromatic), 2210 cm-1
(CN), 1680 cm-1 (C=O). Anal. Calcd. for: C26H26N6O3S
(502.60) C, 62.13; H, 5.21; N, 16.72; S, 6.38%. Found: C,
62.25; H, 5.05; N, 16.87; S, 6.50%.
A mixture of amino ester compound 12 (1 g, 2.21
mmol) and hydrazine hydrate (2 mL, 0.04 mol) was fused
for 1 h. then ethanol (10 mL) was added and reflux contin-
ued for additional 2 h. The solid precipitate which formed
on hot during reflux was cooled, filtered off and recrystal-
lized from dioxan in yellow crystals in 33% yield, m.p. >
5-Morpholin-4-yl-1-oxo-6,7,8,9-tetrahydrothieno[2,3-
c]isoquinoline (16)
A mixture of aminotetrahydroisoquinoline derivative

552 J. Chin. Chem. Soc., Vol. 58, No. 4, 2011
Zaki et al.
8 (1 g, 3.455 mmol) and orthophosphoric acid (3 mL) was
heated on water bath for 1 h. The solid precipitate which
formed by pouring the mixture on ice water mixture was
filtered off, dried and recrystallized from ethanol to afford
orange crystals in 71% yield, m.p. 176-178 oC. 1H-NMR
(CDCl3): d = 1.8 (m, 4H, 2CH2 cyclohexeno), 2.5 (m, 2H,
CH2 cyclohexeno), 3.15 (m, 2H, CH2N-morpholine), 3.4
(m, 4H, (CH2)2O-morpholine), 3.75 (m, 6H, (CH2)2O-mor-
pholine + CH2 thieno) ppm. IR: n = 2920, 2850 cm-1 (CH
aliphatic), 1665 cm-1 (C=O). Anal. Calcd. for: C15H18N2O2S
(290.39) C, 62.04; H, 6.25; N, 9.65; S, 11.04%. Found: C,
62.24; H, 6.06; N, 9.78; S, 11.27%.
N-(2-Benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinolin-1-yl)-2-chloroacetamide (20)
A mixture of aminobenzoyl compound 19 (3.93 g,
0.01 mol), chloro acetylchloride (1.25 mL, 0.011 mol) in
dioxan (25 mL) was heated on a steam bath for 2 h. The
solid which formed by pouring on diluted sodium carbon-
ate solution (10%) was filtered off, dried and recrystallized
from ethanol to give pale green crystals in 87% yield, m.p.
178-180 oC. 1H-NMR (DMSO-d6): d = 1.8 (m, 4H, 2CH2
cyclohexeno), 2.7 (m, 4H, 2CH2 cyclohexeno), 3.2 (m, 6H,
(CH2)2-N morpholine + CH2 acetamide), 3.8 (m, 4H, (CH2)2O
morpholine), 7.4-7.7 (m, 5H, ArH), 10.3 (s, 1H, NH) ppm.
IR: n = 3340 cm-1 (NH), 3050 cm-1 (CH aromatic), 2920,
2850 cm-1 (CH aliphatic), 1675 cm-1 (unsat C=O), 1630
cm-1 (CO amide). Anal. Calcd. for: C24H24ClN3O3S
(469.99) C, 61.33; H, 5.15; Cl, 7.54; N, 8.94; S, 6.82%.
Found: C, 61.25; H, 5.31; N, 9.14; S, 6.97%.
2-Benzylidine-5-morpholin-4-yl-1-oxo-6,7,8,9-tetrahy-
drothieno[2,3-c]isoquinoline (17)
A mixture of compound 16 (0.29 g, 1 mmol) and
benzaldehyde (0.15 mL, 1.415 mmol) were fused for 10
minutes then ethanol (20 mL) was added and reflux contin-
ued for additional 2 h. in presence of few drops of piperi-
dine. The solid precipitate which formed on hot during re-
flux was cooled, filtered off, dried and recrystallized from
ethanol-dioxan mixture to give orange crystals in 78%
yield, m.p. 220-222 oC. 1H-NMR (CDCl3): d = 1.8 (m, 4H,
2CH2), 2.5 (m, 4H, 2CH2), 3.4 (m, 4H, 2CH2), 3.8 (m, 4H,
2CH2), 7.45-7.8 (m, 5H, ArH), 7.9 (s, 1H, CH benzylidene)
ppm. IR: n = 3030 cm-1 (CH aromatic), 2920, 2850 cm-1
(CH aliphatic), 1655 cm-1 (C=O). Anal. Calcd. for:
C22H22N2O2S (378.50) C, 69.81; H, 5.86; N, 7.40; S,
8.47%. Found: C, 70.00; H, 5.74; N, 7.57; N, 7.28; S,
8.62%.
5-Morpholin-4-yl-8-phenyl-1,2,3,4,10-pentahydro[1,4]-
diazepino[5¢,6¢:4,5]thieno[2,3-c]isoquinolin-11(12H)-
one (21)
A mixture of chloro acetylamino derivative 20 (3.525
g, 7.5 mmol) and hexamethylene tetramine (1.5 g, 10.7
mmol) in ethanol (30 mL) was refluxed for 20 h. The solid
product which formed on cold was filtered off, dried and
recrystallized from ethanol in brilliant yellow crystals in
o
93% yield, m.p. 154-156 C. 1H-NMR (CDCl3): d = 1.75
(m, 4H, 2CH2), 2.6 (m, 4H, 2CH2), 3.2 (m, 4H, 2CH2), 3.75
(m, 4H, 2CH2), 4.35 (s, 2H, CH2 diazepine), 7.2-7.8 (m,
5H, ArH), 8.9 (s, 1H, NH) ppm. 13C-NMR (CDCl3): d =
162.74 (CO amide), 160.11 (CH=N diazepine), 158.83
(C-9), 154.32 (C-10), 147.83 (C-10), 137.56 (C-19 aro-
matic), 130.77 (C-3), 126.1-129 (4CH-aromatic), 122.29
(C-8), 119.14 (C-4), 93.8 (C-11), 40.0-49.96 (4CH2-mor-
pholine), 22.02-39.55 (4CH2 cyclohexeno). Mass spectrum
m/z: 433 (M++1, 1.4), 432 (M+, 100), 405 (64.2), 395
(69.9), 375 (29.7), 357 (40.9), 345 (80), 316 (35.4). IR: n =
3400 cm-1 (NH), 3050 cm-1 (CH aromatic), 2920, 2850 cm-1
(CH aliphatic), 1690 cm-1 (CO amide). Anal. calcd. for:
C24H24N4O2S (432.55) C, 66.64; H, 5.59; N, 12.95; S,
7.41%. Found: C, 66.80; H, 5.41; N, 13.11; S, 7.52%.
2-Benzoyl-1-(2-amino-3-cyano-5-oxopyrrol-1-yl)-5-
morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquin-
oline (22)
10-Amino-5-morpholin-4-yl-8-phenyl-1,2,3,4-tetrahy-
dro-8H-pyrano[2¢,3¢:4,5]thieno[2,3-c]isoquinoline-9-
carbonitrile (18)
A mixture of compound 16 (0.29 g, 1 mmol), benzyli-
dinemalononitrile (0.154 g, 1 mmol) and few drops of
piperidine as a basic catalyst was refluxed in ethanol (20
mL) for 1 h. The solid precipitate which was formed on hot
during reflux was cooled, filtered off, dried and recrystal-
lized from dioxan to afford white crystals in 86% yield,
o
1
m.p. 232-234 C. H-NMR (CDCl3): d = 1.85 (m, 4H,
2CH2), 2.7 (m, 4H, 2CH2), 3.2 (m, 4H, 2CH2), 3.8 (m, 4H,
2CH2), 4.7 (s, 2H, NH2), 4.85 (s, 1H, CH pyran), 7.2-7.4
(m, 5H, ArH) ppm. IR: n = 3350, 3200 cm-1 (NH2), 2200
cm-1 (CN), 3030 cm-1 (CH aromatic), 2950, 2850 cm-1 (CH
aliphatic), 1650 cm-1 (C=N). Anal. Calcd. for: C25H24N4O2S
(444.56) C, 67.55; H, 5.44; N, 12.60; S, 7.21%. Found: C,
67.65; H, 5.24; N, 12.77; S, 7.12%.
A mixture of chloroacetamide derivative 20 (4.70 g,
0.01 mol) and malononitrile (0.66 g, 0.01 mol) in presence
of potassium carbonate (5 g, 0.036 mol) in ethanol (30 mL)

Pyridothienotetrahydroisoquinoline
J. Chin. Chem. Soc., Vol. 58, No. 4, 2011 553
was refluxed for 3 h. The solid product which was formed
on hot during reflux was cooled, filtered off, washed with
water and recrystallized from ethanol in 72% yield, m.p.
240-242 oC. 1H-NMR (CDCl3): d = 2.00 (m, 4H, 2CH2), 2.8
(s, 2H, CH2 pyrrole), 3.4 (m, 4H, 2CH2), 3.7 (m, 4H,
2CH2), 4.0 (m, 4H, 2CH2), 5.3 (s, 2H, NH2), 7.5-7.8 (m,
5H, ArH) ppm. IR: n = 3320, 3200 cm-1 (NH2), 3050 cm-1
(CH aromatic), 2920, 2850 cm-1 (CH aliphatic), 2200 cm-1
(CN), 1680, 1640 cm-1 (2CO). Anal. Calcd. for:
C27H25N5O3S (499.60) C, 64.91; H, 5.04; N, 14.02; S,
6.42%. Found: C, 65.03; H, 4.99; N, 14.20; S, 6.53%.
N-(2-Benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-1-yl)-2-alkyl(aryl)aminoacet-
amide (23 a-d)
cyclohexeno + 4H (C-3 + C-5) piperidine), 2.5 (m, 8H, 4H
cyclohexeno + 4H (C-2 + C-4) piperidine), 2.7 (s, 2H, CH2
acetamide), 3.2 (m, 4H, (CH2)2-O morpholine), 3.8 (m, 4H,
(CH2)2-N morpholine), 7.6-8.2 (m, 5H, ArH), 10.2 (s, 1H,
NH acetamide) ppm. IR: n = 3300 cm-1 (NH), 3030 cm-1
(CH aliphatic), 2950, 2850 cm-1 (CH aliphatic), 1670 cm-1
(unsaturated CO), 1630 cm-1 (CO amide). Anal. Calcd. for:
C29H34N4O3S (518.68) C, 67.16; H, 6.61; N, 10.80; S,
6.18%. Found: C, 66.99; H, 6.74; N, 10.76; S, 6.25%.
N-(2-Benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-1-yl)-2-diethylaminoacet-
amide (23c)
Obtained by reaction with diethylamine as green
crystals when the solid product was recrystallized from eth-
anol in 78% yield, m.p. 116-118 oC. 1H-NMR (CDCl3): d =
1.1 (t, J = 7.5 Hz, 6H, 2CH3 diethylamino), 1.85 (m, 4H,
2CH2 cyclohexeno), 2.65 (m, 8H, 4H diethylamino + 4H
cyclohexeno), 3.0 (s, 2H, CH2 acetamide), 3.2 (m, 4H,
(CH2)2-N morpholine), 3.8 (m, 4H, (CH2)2-O morpholine),
7.2-7.8 (m, 5H, ArH), 10.05 (s, 1H, NH acetamide) ppm.
IR: n = 3450 cm-1 (NH), 3050 cm-1 (CH aromatic), 2920,
2850 cm-1 (CH aliphatic), 1690 cm-1 (unsaturated CO),
1630 cm-1 (CO amide). Anal. Calcd. for: C28H34N4O3S
(506.67) C, 66.38; H, 6.76; N, 11.06; S, 6.33%. Found: C,
66.23; H, 6.61; N, 11.24; S, 6.50%.
General procedure
Chloroacetamide derivative 20 (1 mmol) and the cor-
responding amine (0.01 mol) were gently refluxed for 10
minutes then ethanol (20 mL) was added and reflux contin-
ued for additional 2 h. The solid product which formed on
cold was filtered off, dried and recrystallized from ethanol.
N-(2-Benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinolin-1-yl)-2-morpholin-4-yl-acet-
amide (23a)
Obtained by reaction with morpholine as colorless
crystals when the solid product was recrystallized from eth-
anol in 87% yield, m.p. 168-170 oC. 1H-NMR (CDCl3): d =
1.8 (m, 4H, 2CH2), 2.0 (m, 4H, 2CH2), 2.8 (m, 4H, 2CH2),
3.2 (s, 2H, CH2), 3.4 (m, 6H, 3CH2), 4.0 (m, 6H, 3CH2),
7.6-8.2 (m, 5H, ArH), 10.2 (s, 1H, NH acetamide) ppm.
13C-NMR (CDCl3) d = 171.06 (COPh), 162.56 (CO amide),
157.54 (C-9), 153.04 (C-7), 145.21 (C-10), 138.97 (C-17
aromatic), 127.79-133.88 (4CH aromatic + C-3), 124.77
(C-8), 121.40 (C-4), 77.45 (C-11), 49.95-67.06 (8CH2-
Morpholine + CH2CO), 22.10-27.45 (4CH2 cyclohexeno).
IR: n = 3350 cm-1 (NH), 3050 cm-1 (CH aromatic), 2920,
2850 cm-1 (CH aliphatic), 1670 cm-1 (unsaturated CO),
1630 cm-1 (CO amide). Anal. Calcd. for: C28H32N4O4S
(520.66) C, 64.59; H, 6.20; N, 10.76; S, 6.16%. Found: C,
64.71; H, 6.35; N, 10.68; S, 6.28%.
N-(2-Benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-1-yl)-2-phenylaminoacet-
amide (23d)
Obtained by reaction with aniline as green crystals
when the solid product which was formed on cold filtered
off, dried and recrystallized from dioxan in 75% yield, m.p.
212-214 oC. 1H-NMR (CDCl3): d = 1.8 (m, 4H, 2CH2), 2.7
(m, 4H, 2CH2), 3.1 (s, 2H, CH2 acetamide), 3.2 (m, 4H,
2CH2), 3.8 (m, 4H, 2CH2), 6.8-8.0 (m, 10H, ArH), 9.8 (s,
1H, NH phenylamino), 10.2 (s, 1H, NH acetamide) ppm.
IR: n = 3450, 3350 cm-1 (2NH), 3050 cm-1 (CH aromatic),
2920, 2850 cm-1 (CH aliphatic), 1670 cm-1 (unsaturated
CO), 1625 cm-1 (CO amide), 1600 cm-1 (C=N). Anal.
Calcd. for: C30H30N4O3S (526.66) C, 68.42; H, 5.74; N,
10.64; S, 6.09%. Found: C, 68.54; H, 5.88; N, 10.51; S,
5.95%.
N-(2-Benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-1-yl)-2-piperidin-4-yl-acet-
amide (23b)
Obtained by reaction with piperidine as florescent
green crystals when the solid product was recrystallized
REFERENCES
1. Bentley, K. W. Nat. Prod. Rep. 2005, 22, 249-268.
2. Scott, J. D.; Williams, R. M., Chem. Rev. 2002, 102, 1669-
1730.
o
from ethanol in 83% yield, m.p. 154-156 C. H-NMR
1
(CDCl3): d = 1.25 (m, 2H, C-4 piperidine), 1.8 (m, 8H, 4H

554 J. Chin. Chem. Soc., Vol. 58, No. 4, 2011
Zaki et al.
3. Iwasa, K.; Moriyasu, M.; Yamori, T.; Turuo T.; Lee, D. U.;
Wiegrebe, W. J. Nat. Prod. 2001, 64, 896-898.
11. Cheng, P.; Huang, N.; Jiang, Z. Y.; Zhang, Q.; Zheng, Y. T.;
Chen, J. J.; Zhang, X. M.; Ma, Y. B. Bioorg. Med. Chem.
Lett. 2008, 18, 2475.
4. Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron. 2002,
58, 6795-6798.
12. Pham, V. C.; Ma, J.; Thomas, S. J.; Xu, Z.; Hecht, S. M. J.
Nat. Prod. 2005, 68, 1147.
5. Gao, M.; Kong, D.; Clearfield, A.; Zheng, Q. H. Bioorg.
Med. Chem. Lett. 2006, 16, 2229-2233.
13. Naito, R.; Yonetoku, Y.; Okamoto, Y.; Toyoshima, A.; Ikeda,
K.; Takeuchi, M. J. Med. Chem. 2005, 48, 6597.
14. Lukevics, E. Khim. Geterotsikl. Soedin. 1995, 72.
15. Selimov, F. A.; Dzhemilev, U. M.; and Ptashko, O. A. Metal
Complex Catalysis in Synthesis of Pyridine Bases; Khimiya:
Moscow, 2003 (In Russian).
6. Fodale, V.; Santamaria, L. B. Eur. J. Anaesthesiol. 2002,
466- 473.
7. Shinohara, T.; Takeda, A.; Toda, J.; Terasawa, N.; Sano, T.
Heterocycles 1997, 46, 555-565.
8. Takada, K.; Uehara, T.; Nakao, Y.; Matsunaga, S.; Soest, R.
W. M.; Fusetani, N. J. Am. Chem. Soc. 2004, 126, 187-193.
9. Naoi, M.; Maruyama, W.; Sasuga, S.; Deng, Y.; Dostert, P.;
Ohta, S.; Takahashi, T. Neurochem. Int. 1994, 25, 475- 481.
10. Iwasa, K.; Moriyasu, M.; Tachibana, Y.; Kim, H. S.; Wataya,
Y.; Wiegrebe, W.; Bastow, K. F.; Cosentino, L. M.; Kozuka,
M.; Lee, K. H. Bioorg. Med. Chem. 2001, 9, 2871.
16. Kamal El-Dean, A. M.; Radwan, Sh. M.; and Zaki, R. M. J.
Chin. Chem. Soc. 2008, 55(6), 1-10.
17. Gruner, M.; Rehwald, M.; Eckert, K.; Gewald, K. Hetero-
cycles 2000, 53, 2363-2377.
18. Kamal El-Dean, A. M.; Shaker, R.; Abo El-Hassan, A. A.;
Abdel Latif, F. F. J. Chin. Chem. Soc. 2004, 51, 335-345.