Synthesis and transformations of new 3-oxo(thioxo)-1-phenyl-2,3,5,6,7,8- hexahydroisoquinoline-4-carboxylic acid derivatives

Article abstract of DOI:10.1134/S1070363212040160

By condensation of 2-benzoyl-1-(morpholin-4-yl)-1-cyanohexene with cyanoacetanilides and monothiomalonodiamide the corresponding 2-substituted 3-oxo-1-phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitriles and 3-thioxo-1-phenyl-2,3,5,6,7,8-hexahydroisoq

Full text of DOI:10.1134/S1070363212040160

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 4, pp. 697–702. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © I.V. Dyachenko, M.V. Vovk, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 4, pp. 611–616.
Synthesis and Transformations
of New 3-Oxo(thioxo)-1-phenyl-2,3,5,6,7,8-
hexahydroisoquinoline-4-carboxylic Acid Derivatives
I. V. Dyachenkoa and M. V. Vovkb
a Taras Shevchenko Lugansk National University, ul. Oboronnaya 2, Lugansk, 91011 Ukraine
e-mail: ivladya87@e-mail.ua
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received February 8, 2011
Abstract—By condensation of 2-benzoyl-1-(morpholin-4-yl)-1-cyanohexene with cyanoacetanilides and
monothiomalonodiamide the corresponding 2-substituted 3-oxo-1-phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-
carbonitriles and 3-thioxo-1-phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide were obtained. The
latter was used in the synthesis of 3-alkylthio-1-phenyl-5,6,7,8-hexahydroisoquinoline-4-carboxamides and 3,3-
dimethyl-1-oxo-6-phenyl-1,2,7,8,9,10-hexahydro-3H-[1,3]thiazino[6,5-c]isoquinoline.
DOI: 10.1134/S1070363212040160
Derivatives of partially hydrogenated isoquinoline-
4-carboxylic acids are attractive objects for the
biological research. For example, among the amides
and nitriles of 3-oxo(thioxo)-2,3,5,6,7,8-hexahydro-
quinoline-4-carboxylic acid agonists have been found
with respect to the cannabinoid type 2 receptor [1, 2],
inhibitors of 11-β-hydroxysteroid dehydrogenase [3],
as well as the compounds with positive inotropic
activity [4]. However, their synthetic potential has not
been revealed completely that to some extent hinders
the rational search for substances with practically
useful properties. In particular, for the series of 3-oxo-
2,3,5,6,7,8-hexahydroquinoline-4-carbonitriles only the
transformation is known of cyano group to carboxy [1]
and amido groups [4]. For their 2-thio analogs
examples were describes of modification at the 2 posi-
tion with a pyranose fragment [5], as well as thieno-
and pyridinofusion at the 1–2 positions [6]. For this
reason, it seemed expedient to synthesize new repre-
sentatives of this heterocyclic system and explore the
possibility of their further transformations with the
participation of functional groups in positions 3 and 4.
alkyl-substituted
isoquinoline-4-carboxylic
acid
derivatives is characterized by the high selectivity. In
this report we demonstrate the possibility of using the
preparatively accessible [13] 2-benzoylcyclohexanone
enamine (I) in the condensation of this kind.
We found that 2-benzoyl-1-(morpholin-4-yl)-1-
cyclohexene I reacts at room temperature with
cyanoacetamides IIa–IIe and monothiomalonodiamide
III in anhydrous ethanol in the presence of equimolar
amount of sodium ethoxide to form earlier unknown 2-
substituted 3-oxo-1-phenyl-2,3,5,6,7,8-hexahydroiso-
quinoline-4-carbonitriles ІVa–IVe and 3-thioxo-1-
phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxamide
V in 68–82% and 69% yield respectively. The most
probable reaction scheme in the case of the cyano-
acetamides IIa–IIe seems the reaction by SNVin
mechanism that assumes the formation of inter-
mediates A and their subsequent cyclization to the
desired products ІVa–IVe. The 13C NMR spectrum of
the latter contain the characteristic signals of the
carbon atoms of pyridone ring: C1 (150–156 ppm), C3
(158–159 ppm), C4 (100–101 ppm), C5 (159–162 ppm),
and C6 (115 ppm). In the case of monothiomalo-
nodiamide III, besides the cyclization through the
intermediate B, the cyclization through the inter-
mediate C is not excluded, which would lead to the
isomeric 4-thiocarbamoyl-3-oxoisoquinoline VI. Spec-
Among the methods that have been successfully
used for the synthesis of partially hydrogenated
functionally 4-substituted isoquinolines [7–12], the
method of cyclocondensation of 2-acylcyclohexanones
with cyano(thio)acetamide [7] allowing to obtain 1-
697

698
DYACHENKO, VOVK
Covalent bond length (d) and bond angles (ω) in structure IX
Bond
d, Å
Bond
d, Å
Angle
C1S1C17
C1N1C5
C16N2C17
N1C1С2
N1C1S1
C2C1S1
C1C2C3
C1C2C16
C3C2C16
C4C3C2
C4C3C9
C2C3C9
C3C4C5
C3C4C6
C5C4C6
N1C5C4
N1C5C10
C4C5C10
C7C6C4
C8C7C6
ω, deg
Angle
C7C8C9
C8C9C3
ω, deg
S1–C1
S1–C17
O1–C16
N1–C1
N1–C5
N2–C16
N2–C17
C1–C2
C2–C3
C2–C16
C3–C4
C3–C9
C4–C5
1.7601(12)
1.8184(13)
1.2328(14)
1.3328(15)
1.3418(14)
1.3406(16)
1.4512(16)
1.3953(16)
1.4200(16)
1.4931(16)
1.4004(16)
1.5123(16)
1.4061(16)
C4–C6
C5–C10
C6–C7
C7–C8
C8–C9
C10–C15
C10–C11
C11–C12
C12–C13
C13–C14
C14–C15
C17–C18
C17–C19
1.5167(16)
1.4912(16)
1.5081(18)
1.5051(19)
1.5081(17)
1.3832(17)
1.3883(17)
1.3835(19)
1.368(2)
101.00(6)
117.81(10)
129.60(12)
124.43(11)
111.65(9)
123.83(9)
117.52(11)
120.13(10)
122.01(10)
118.49(10)
119.93(10)
121.57(11)
118.49(11)
121.54(11)
119.87(11)
123.17(11)
114.03(10)
122.75(11)
113.12(11)
109.30(12)
110.70(11)
114.67(11)
118.25(12)
119.43(11)
122.32(12)
120.61(13)
120.35(14)
119.66(14)
120.40(14)
120.72(13)
119.41(11)
121.49(11)
119.00(11)
110.77(11)
108.42(11)
111.41(11)
109.15(9)
C15C10C11
C15C10C5
C11C10C5
C12C11C10
C13C12C11
C12C13C14
C13C14C15
C14C15C10
О1C16N2
О1C16C2
N2C16C2
N2C17C18
N2C17C19
C18C17C19
N2C17S1
1.3717(19)
1.3809(18)
1.5169(19)
1.5285(18)
C18C17S1
C19C17S1
110.41(9)
106.55(10)
tral characteristics of the compound obtained, in parti-
cular, the signals of the carbon atoms in the pyridine
ring in 13C NMR spectrum, differ from those of
isoquinolines IV, but do not allow reliable determina-
tion of structure of the compound obtained.
to be different. By the example of the reactions with
allyl bromide VIІa, propargyl bromide VIІb, and α-
bromoacetophenones VIIc and VIId, which proceed
smoothly in DMF in the presence of KOH, we showed
the formation of 3-thiosubstituted isoquinolines
VIIIa–VIIId. Another important synthetic evidence of
the structure of amide V is its condensation with
acetone, which also involves carbamoyl and thio-
carbamoyl fragments of the molecule. As a result we
obtained the first representative of the heterocyclic
system of [1,3]thiazino[6,5-c]isoquinoline IX, whose
structure was reliably confirmed by X-ray diffraction
analysis (see the figure and the table), which, in turn,
allows the unambiguous attribution to the condensation
products of enamine I with monothiomalonodiamide
III of the structure of 3-thioxoisoquinoline-4-
carboxamide V.
The thiocarbamoyl fragment in the compound V is
a part of the isoquinoline ring, while in compound VI
it is exofunctionalized to the ring, therefore its
behavior with respect to alkylating agents is expectable
The cyclohexane ring conformation in compound
IX is a semichair with the C6–C4–C3–C9 planar frag-
ment [torsion angle –1.70(18)°] and atoms C7 and C8
deviating from it by –0.451(3) and 0.318 Å,
Steric structure of compound IX according to XRD data.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

SYNTHESIS AND TRANSFORMATIONS OF NEW 3-OXO(THIOXO)-...
699
CN
R
N
H
O
CN
O
CN
O
IIа_IIe
N
_H2O
Ph
N
HN
O
O
Ph
O
NH
Ph
O
R
R
A
IVа_IVe
I
O
NH2
O
NH
H2N
S
III
O
O
O
O
NH2
NH
NH2
_H2O
_H2O
Ph
N
S
Ph
N
S
H2N
O
S
Ph
H
V
B
IX
Br
X
/ KOH
VIIа_VIId
O
S
S
NH2
NH2
NH2
_H2O
Ph
N
S
X
Ph
N
H
O
H2N
O
O
Ph
C
VI
VIIIа_VIIId
II, IV, R = PhCH2 (а), cyclo-С3Н5 (b), 2-MeC6H4 (c), thiazol-2-yl (d), pyridin-2-yl (e); VII, VIII, X = Н2C=CH (а), НC≡C (b),
4-ClC6H4CO (c), 4-NO2C6H4CO (d).
respectively. The conformation of the thiazine ring is
intermediate between a sofa and a boat. The fragment
S1–C1–C2–C16 is almost planar [torsion angle –6.30(16)°],
the atoms N2 and C17 deviate from this plane by 0.260(2) Å
and 0.802 (2) Å, respectively. The repulsion between
the aromatic ring and the nearest methylene group
(short intramolecular contacts H6b···C11 and C6···C11,
the sums of the van der Waals radii 2.87 and 3.42 Å
[14], respectively) turns the phenyl substituent with
respect to the plane of the pyridine ring by the torsion
angle N1–C5–C10–C15 52.55(15)°.
amide groups N2–H2···O1 [–x, 1–y, –z] [H···O
2.063(14) Å, N–H···O 177.4(13)°]. The dimers form
stacks along the (100) direction due to the hydrogen
bond C11–H11···S1 [1 + x, y, z] (H···S 2.89 Å, C–H···S
163°), and weak C–H···π bonds C8–H8b···C16 [1 + x, y,
z] (H···C 2.81 Å, C–H···C 166°) and C7–H7b···C5 [1 – x,
–y, –z] (H···C 2.84 Å, C–H···C 159°).
EXPERIMENTAL
The crystals of compound IX are monoclinic,
C19H20N2OS, at 298 K α = 6.9586(6), b = 10.7905(9),
c = 22.433(2) Å, β = 96.931(8)°, V = 1672.1(2) Å3,
Mr = 324.43, Z = 4, space group P, Dcalc = 1.289 g cm–3,
In the crystal, the molecules form centrosymmetric
dimers connected by hydrogen bonds between the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

700
DYACHENKO, VOVK
μ(MoKα) 0.200 mm–1, F(000) 688. The unit cell para-
meters and intensities of 9713 reflections (5458 in-
dependent, Rint = 0.022) were measured on an
automatic four-circle Xcalibur-3 diffractometer (MoKα
radiation, CCD detector, graphite monochromator, ω-
scanning, 2θmax = 65.18°).
7.39–7.52 m (3H, Ph), 7.21 m (3H, Ph), 7.13 d (2H,
Ph, J 6.64 Hz), 6.81 m (2H, Ph), 4.91 s (2H, NCH2),
2.88 t (2H, CH2, J 6.0 Hz), 1.96 t (2H, CH2, J 6.4 Hz),
1.71 m (2H, CH2), 1.55 m(2H, CH2). 13C NMR spec-
trum, δ, ppm: 20.68 (CH2), 21.66 (CH2), 25.92 (CH2),
28.88 (CH2), 48.96 (CH2), 100.69 (C4), 115.06 (CN),
115.64 (C6), 126.20, 127.00, 127.92, 128.17, 128.80,
129.48, 132.38, 136.25 (Carom), 151.92 (C1), 159.15
(C3), 159.55 (C5). Mass spectrum, m/z (Irel, %): 341
(100) [M + 1]+. Found, %: C 81.01, H 5.88, N 8.19.
C23H20N2O. Calculated, %: C 81.15, H 5.92, N 8.23.
The structure was solved by the direct method
using the program package SHELX-97 [15]. The
positions of the hydrogen atoms at the carbon atoms
were calculated geometrically and refined using rider
model with Uiso = nUeq of the host atom (n = 1.5 for
methyl groups and n = 1.2 for the rest of hydrogen
atoms). The position of the hydrogen atom at the N2
was refined independently in the isotropic approxi-
mation. The structure was refined with respect to F2 in
a full-matrix anisotropic approximation for non-
hydrogen atoms to wR2 = 0.081 for 5458 reflections
[R1 = 0.041 for 2908 reflections with F > 4σ(F), S =
0.99]. The bond lengths and bond angles are listed in
the table.
3-Oxo-1-phenyl-2-cyclopropyl-2,3,5,6,7,8-hexa-
hydroisoquinoline-4-carbonitrile (IVb). Yield 2.26 g
(78%), yellow crystals, fluorescent under UV irradia-
tion, mp 142–144°C (EtOH). IR spectrum, ν, cm–1:
1
2214 (C≡N), 1646 (CO). H NMR spectrum, δ, ppm:
7.33–7.58 m (5H, Ph), 2.81 t (2H, CH2, J 6.4 Hz), 2.77
m (1H, NCH), 1.69 m (2H, CH2), 1.54 m (2H, CH2),
0.61 m (2H, CH2 cyclopropane), 0.51 m (2H, CH2
cyclopropane). 13C NMR spectrum, δ, ppm: 10.68
(2CH2), 20.70 (2CH2), 21.82 (CH2), 25.84 (CH2),
31.11 (CH), 100.86 (C4), 114.45 (CN), 115.77 (C6),
128.41, 128.58, 128.91, 133.39 (Carom), 153.44 (C1),
158.91 (C3), 160.27 (C5). Mass spectrum, m/z (Irel, %):
291 (100) [M + 1]+. Found, %: C 78.48, H 6.14, N
9.58. C19H18N2O. Calculated, %: C 78.59, H 6.25, N
9.65.
Melting points of the synthesized compounds were
determined on a Koeffler block. The IR spectra were
recorded on a SPECTRUM ONE (Perkin Elmer) FTIR
1
spectrometer from tablets with KBr. The H and 13C
NMR spectra were recorded on a Bruker DRX 500
spectrometer (500.068 and 125.7578 MHz, respectively)
from the solutions in DMSO-d6 (internal reference
TMS). GC-MS spectra were recorded on a Crommas
GC/MC Hewlett-Packard 5890/5972 instrument,
column HP-S MS, 70 eV, solutions in CH2Cl2. The
reaction progress and the purity of the compounds
obtained was monitored by TLC on Silufol UV-254
plates in the system of acetone-hexane 3:5, developers
iodine vapor and ultraviolet irradiation.
3-Oxo-2-(o-tolyl)-1-phenyl-2,3,5,6,7,8-hexahyd-
roisoquinoline-4-carbonitrile (IVc). Yield 82%, white
powder, fluorescent under UV irradiation, mp 205–
208°C (AcOH). IR spectrum, ν, cm–1: 2219 (C≡N),
1
1652 (CONH). H NMR spectrum, δ, ppm: 7.02–7.26
m (9H, Harom) 2.98 t (2H, CH2, J 6.0 Hz), 2.12 t (2H,
CH2, J 6.0 Hz), 1.81 m (2H, CH2), 1.66 m (2H, CH2).
13C NMR spectrum, δ, ppm: 17.28 (CH3), 20.71 (CH2),
21.65 (CH2), 25.89 (CH2), 29.01 (CH2), 100.97 (C4),
114.78 (CN), 115.46 (C6), 125.92, 126.65, 127.92,
128.39, 128.75, 129.26, 130.02, 132.51, 134.62,
137.04 (Carom), 151.40 (C1), 158.36 (C3), 160.15 (C5).
Mass spectrum, m/z (Irel, %): 341 (100) [M + 1]+.
Found, %: C 81.02, H 5.86, N 8.19. C23H20N2O.
Calculated, %: C 81.15, H 5.92, N 8.23.
3-Oxo-1-phenyl-2-R-2,3,5,6,7,8-hexahydroiso-
quinoline-4-carbonitriles (IVa–IVe). To a stirred
mixture of 2.71 g (10 mmol) of enaminoketone I and
10 mmol of a cyanoacetanilide IIa–IIe in 15 ml of
anhydrous ethanol at 20ºC was added a solution of
sodium ethoxide prepared from 0.23 g (10 mmol) of
sodium and 10 mmol of anhydrous ethanol. The
mixture was stirred for 1 h and left for a day. The
resulting precipitate was filtered off, washed with
ethanol, and crystallized.
3-Oxo-2-(thiazol-2-yl)-1-phenyl-2,3,5,6,7,8-hexa-
hydroisoquinoline-4-carbonitrile (IVd). Yield 2.36 g
(71%), yellow powder, fluorescent under UV irra-
diation, mp 257–259°C (BuOH). IR spectrum, ν, cm–1:
2-Benzyl-3-oxo-1-phenyl-2,3,5,6,7,8-hexahydroiso-
quinoline-4-carbonitrile (IVa). Yield 2.31 g (68%),
yellow powder, fluorescent under UV irradiation, mp
162–164°C (EtOH). IR spectrum, ν, cm–1: 2211
1
2214 (C≡N), 1665 (CONH). H NMR spectrum, δ,
ppm: 7.71 d (1H, thiazole, J 3.2 Hz), 7.54 d (1H,
thiazole, J 3.2 Hz), 7.22–7.31 m (5H, Ph), 2.96 t (2H,
1
(C≡N), 1647 (CONH). H NMR spectrum, δ, ppm:
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SYNTHESIS AND TRANSFORMATIONS OF NEW 3-OXO(THIOXO)-...
701
CH2, J 6.4 Hz), 2.11 t (2H, CH2, J 6.8 Hz), 1.74 m
(2H, CH2), 1.61 m (2H, CH2). 13C NMR spectrum, δ,
ppm: 20.58 (CH2), 21.47 (CH2), 25.63 (CH2), 29.28
(CH2), 101.44 (C4), 114.85 (CN), 115.56 (C6), 124.37,
128.03, 128.99, 129.09, 131.55, 139.92, 150.39
(Carom), 156.74 (C1), 158.89 (C3), 162.35 (C5). Mass
spectrum, m/z (Irel, %): 334 (100) [M + 1]+. Found, %:
C 68.33, H 4.48, N 12.52. C19H15N3OS. Calculated, %:
C 68.45, H 4.53, N 12.60.
3-Methylthio-1-phenyl-5,6,7,8-tetrahydroisoquino-
line-4-carboxamides (VIIIa–VIIId). To a stirred solu-
tion of 2.84 g (10 mmol) of isoquinoline-3-thione V in
15 ml of DMF was added sequentially 5.6 ml
(10 mmol) of 10% aqueous KOH and 10 mmol of an
alkylating agent VIIa–VIId. The mixture was stirred
for 1 h and left for one day. The reaction mixture was
diluted with an equal amount of water and the resulting
precipitate was filtered off, washed with water,
ethanol, and crystallized.
3-Oxo-2-(pyridin-2-yl)-1-phenyl-2,3,5,6,7,8-hexa-
hydroisoquinoline-4-carbonitrile (Ie). Yield 2.35 g
(72%), white powder, fluorescent under UV irradia-
tion, mp 235–238°C (BuOH). IR spectrum, ν, cm–1:
3-Allylthio-1-phenyl-5,6,7,8-tetrahydroisoquino-
line-4-carboxamide (VIIIa). Yield 2.56 g (79%), mp
210–212°C (EtOH). IR spectrum, ν, cm–1: 3378, 3177
1
1
2214 (C≡N), 1659 (CONH). H NMR spectrum, δ,
(NH2), 1642 (CONH). H NMR spectrum, δ, ppm:
ppm: 8.33 m (1H, pyridine), 7.76 t (1H, pyridine, J
8.0 Hz), 7.41 d (1H, pyridine, J 8.0 Hz), 7.16–7.25 m
(6H, Ph and pyridine), 2.95 m (2H, CH2), 2.08 m (2H,
7.81 br.s (1H, NH2), 7.60 br.s (1H, NH2), 7.37–7.49 m
(5H, Ph), 5.86–5.97 m (1H, =CH), 5.21 d (1H, =CH2,
Jtrans 16.8 Hz), 5.03 d (1H,=CH2, Jcis 9.6 Hz), 3.79 d
(2H, SCH2, J 6.8 Hz), 2.77 t (2H, CH2, J 5.9 Hz),
2.66 t (2H, CH2, J 5.9 Hz), 1.78 t (2H, CH2), 1.67 t
(2H, CH2). 13C NMR spectrum, δ, ppm: 21.29 (CH2),
22.11 (CH2), 25.98 (CH2), 26.90 (CH2), 32.04 (CH2),
117.12 (H2C=), 126.54 (C4), 127.90, 128.68, 131.35,
134.55 (Carom), 139.86 (=CH), 143.27 (C5), 148.91
(C3), 156.60 (C1), 167.86 [C(O)NH2]. Mass spectrum,
m/z (Irel, %): 325 (100) [M + 1]+. Found, %: C 70.28, H
6.14, N 8.58. C19H20N2OS. Calculated, %: C 70.34, H
6.21, N 8.63.
13
CH2), 1.76 m (2H, CH2), 1.61 m (2H, CH2). C NMR
spectrum, δ, ppm: 20.72 (CH2), 21.64 (CH2), 25.56
(CH2), 29.12 (CH2), 101.20 (C4), 114.54 (CN), 115.29
(C6), 123.79, 124.56, 127.95, 128.48, 128.74, 129.20,
132.05, 138.08, 148.75 (Carom), 150.76 (C1), 158.89
(C3), 161.13 (C5). Mass spectrum, m/z (Irel, %): 328
(100) [M + 1]+. Found, %: C 76.95, H 5.11, N 12.75.
C21H17N3O. Calculated, %: C 77.04, H 5.23, N 12.84.
3-Thioxo-1-phenyl-2,3,5,6,7,8-hexahydroisoquino-
line-4-carboxamide (V). To a stirred solution of
2.71 g (10 mmol) of enaminoketone I in 15 ml of an-
hydrous ethanol at 20°C was added 1.2 g (10 mmol)
monothiomalonodiamide III and a sodium ethoxide
solution prepared from 0.23 g (10 mmol) of sodium
and 10 mg of anhydrous ethanol. The mixture was
stirred for 30 min and left for 2 days. The reaction
mixture was diluted with 10% hydrochloric acid to pH
5 and left for one day. The resulting precipitate was
filtered off and crystallized from ethanol. Yield 1.96 g
(69%), yellow powder, mp 235–238°C. IR spectrum,
ν, cm–1: 3382, 3211 (NH, NH2), 1678 (C=O), 1194
3-(Prop-2-inylthio)-1-phenyl-5,6,7,8-tetrahydro-
isoquinoline-4-carboxamide (VIIIb). Yield 2.64 g
(82%), mp 157–158°C (BuOH). IR spectrum, ν, cm–1:
1
3392, 3112 (NH2), 1666 (CONH). H NMR spectrum,
δ, ppm: 7.88 br.s (1H, NH2), 7.66 br.s (1H, NH2),
7.39–7.54 m (5H, Ph), 3.93 s (2H, SCH2), 2.89 s (1H,
≡CH), 2.89 m (2H, CH2, J 6.0 Hz), 2.70 m (2H, CH2, J
6.0 Hz), 1.79 m (2H, CH2), 1.68 m (2H, CH2). Mass
spectrum, m/z (Irel, %): 323 (100) [M + 1]+. Found, %:
C 70.68, H 5.48, N 8.55. C19H18N2OS. Calculated, %:
C 70.78, H 5.63, N 8.69.
1
(C=S). H NMR spectrum, δ, ppm: 7.31–7.48 m (6H,
1-Phenyl-3-(4-chlorbenzoylmethylthio)-5,6,7,8-
tetrahydroisoquinoline-4-carboxamide (VIIIc).
Yield 3.31 g (76%), mp 225–228°C (AcOH). IR
spectrum, ν, cm–1: 3377, 3189 (NH2), 1691 (C=O),
Ph and NH2), 7.0 br.s (1H, NH2), 2.6 t (2H, CH2, J
6.0 Hz), 2.37 t (2H, CH2, J 6.0 Hz), 1.63 m (2H, CH2),
1.52 m (2H, CH2). Proton signal of N2H not observed,
apparently due to rapid deuterium exchange. 13C NMR
spectrum, δ, ppm: 21.11 (CH2), 21.62 (CH2), 25.34
(CH2), 26.66 (CH2), 120.56 (C6), 128.28, 128.71,
129.05, 129.38 ( Carom), 132.42 (C4), 138.95 (C1),
144.95 (C3), 146.93 (C5), 168.14 (C=O). Mass
spectrum, m/z (Irel, %): 285 (100) [M + 1]+. Found, %:
C 67.42, H 5.48, N 9.77. C16H16N2OS. Calculated, %:
C 67.58, H 5.67, N 9.85.
1
1636 (CONH). H NMR spectrum, δ, ppm: 8.0 br.s
(1H, NH2), 7.92 d (2H, C6H4, J 8.5 Hz), 7.77 br.s (1H,
NH2), 7.45 d (2H, C6H4, J 8.5 Hz), 7.21–7.32 m (5H,
Ph), 4.59 s (2H, SCH2), 2.74 t (2H, CH2, J 6.0 Hz),
2.58 t (2H, CH2, J 6.0 Hz), 1.71 m (2H, CH2), 1.56 m
(2H, CH2). 13C NMR spectrum, δ, ppm: 21.19 (CH2),
21.99 (CH2), 25.96 (CH2), 26.72 (CH2), 36.14 (CH2),
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DYACHENKO, VOVK
126.54 (C4), 127.49, 127.52, 128.37, 129.90, 130.45,
135.05, 137.73, 139.08 (Carom), 143.43 (C6), 148.26
(C3), 156.31 (C1), 167.66 [C(O)NH2], 193.85 (C=O).
Mass spectrum, m/z (Irel, %): 437 (100) [M + 1]+.
Found, %: C 65.80, H 4.79, N 6.35. C24H21ClN2O2S.
Calculated, %: C 65.97, H 4.84, N 6.41.
150.26 (C5), 155.24 (C3), 159.52 (C1), 164.33 (C=O) .
Mass spectrum, m/z (Irel, %): 325 (100) [M + 1]+.
Found, %: C 70.28, H 6.14, N 8.58. C19H20N2OS.
Calculated, %: C 70.34, H 6.21, N 8.63.
REFERENCES
3-(4-Nitrobenzoylmetilthio)-1-phenyl-5,6,7,8-
tetrahydroisoquinoline-4-carboxamide (VIIId).
Yield 3.13 g (70%), mp 215–217°C (BuOH). IR
spectrum, ν, cm–1: 3378, 3178, 2934 (NH2), 1698
(C=O), 1640 (NHCO), 1603 (NO2). 1H NMR
spectrum, δ, ppm: 8.09 d (2H, C6H4, J 8.0 Hz), 5.8 d
(2H, C6H4, J 8.0 Hz), 7.93 br.s (1H, NH2), 7.70 br.s
(1H, NH2), 7.15–7.33 m (5H, Ph), 4.58 s (2H, SCH2),
2.79 m (2H, CH2, J 6.0 Hz), 2.57 m (2H, CH2, J
1. Yasui, K., Morioka, Y., and Hanasaki, K., EU Patent
no. 1477186, 2004, http://espacenet/com.
2. Tada, Y., Iso, Y., and Hanasaki, K., EU Patent
no. 135711(A1), 2003, http://espacenet/com.
3. Robl J.A., Wu S.C., and Yoon D.S. WO Patent
no. 2008005910(A2), 2008, http://espacenet/com.
4. Tatsuo, K., Kunio, S., Kajiva, S., Suzuki, T., Otsuka, K.,
Ito, T., Komiya, J., and Maruyama, M., J. Med. Chem,.
1989, vol. 32, no. 2, p. 351.
13
6.0 Hz), 1.76 t (2H, CH2), 1.64 t (2H, CH2). C NMR
5. Elgemeie. G.E.H. and Attia. A.M.E., Phosphorus,
Sulfur, Silicon, Relat. Elem., 1994, vol. 92, nos. 1–4,
p. 95.
spectrum, δ, ppm: 21.12 (2CH2), 21.89 (CH2), 25.93
(CH2), 36.38 (CH2), 123.12 (C4), 126.62, 127.33,
127.42, 128.26, 129.13, 130.33, 138.88, 141.42
(Carom), 143.50 (C6), 148.06 (C5), 149.38 (C3), 156.41
(C1), 167.56 [C(O)NH2], 194.17 (C=O). Mass
spectrum, m/z (Irel, %): 448 (100) [M + 1]+. Found, %:
C 64.30, H 4.64, N 9.28. C24H21N3O4S. Calculated, %:
C 64.42, H 4.73, N 9.39.
6. Al-Omran, F., Elassar, A.-Z., and El-Khair, A.A., Tetra-
hedron, 2001, vol.57, no. 51, p. 10163.
7. Sharanin, Yu.A., Shestopalov, A.M., Promonenkov, V.K.,
and Rodinovskaya, L.A., Zh. Org. Khim., 1984, vol. 20,
no. 11, p. 2432.
8. Lozinskii, M.O., Chernega, A.N., and Shelyakin, V.V.,
Zh. Org. Khim., 2002, vol. 38, no. 11, p. 1718.
3,3-Dimethyl-1-oxo-6-phenyl-1,2,7,8.9,10-hexa-
hydro-3H-[1,3]thiazino[6,5-c]isoquinoline (IX). To a
solution of 2.84 g (10 mmol) of compound V in 10 ml
of acetone was added a drop of concentrated
hydrochloric acid. The mixture was boiled for 10 min,
filtered hot and the filtrate was left for 48 h. The
resulting yellow precipitate was filtered off, washed
with acetone, and crystallized from ethanol. Yield
2.43 g (75%), mp 195–197°C. IR spectrum, ν, cm–1:
9. Kasturi, N.R., Krishan, L., and Prasad, R.S., J. Chem.
Soc., Perkin Trans. 1, 1982, no. 1, p. 63.
10. Elgemeie, G.E.H., Elzanate, A.M., and Mansour, A.K.,
J. Chem. Soc., Perkin Trans. 1, 1992, no. 8, p. 1073.
11. Toth, G., Hazai, L., Deak, G., Duddeck, H., Kühne, H.,
and Hricovini, M., Tetrahedron, 1988, vol. 44, no. 22,
p. 6861.
12. Fadda, A.A., Indian J. Chem. B, 1991, vol. 30, no. 1,
1
p. 28.
3166 (NH), 1658 (C=O). H NMR spectrum, δ, ppm:
13. Zhang, P. and Li, L., Synt. Commun., 1986, vol. 16,
8.76 br.s (1H, NH), 7.41–7.52 m (5H, Ph), 2.65 t (2H,
CH2, J 5.9 Hz), 2.52 m (2H, CH2), 1.76 m (2H, CH2),
1.55–1.66 m (8H, CH2 and 2Me). 13C NMR spectrum,
δ, ppm: 21.13 (CH2), 21.42 (CH2), 26.95 (CH2), 27.79
(CH2), 29.54 (CH2), 58.74 [C(NH)S] , 121.27 (C4),
127.79, 128.04, 128.48, 128.70 (Carom), 139.13 (C6),
no. 8, p. 957.
14. Zefirov, Yu.V. and Zorkii, P.M., Usp. Khim., 1989,
vol. 58, no.5, p. 713.
15. Sheldrick, G., Acta Cryst., Sect. A, 2008, vol. 64, no. 1,
p. 112.
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