Ethyl 3-thioxo-1-phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxylate, new specimen of derivatives of partially hydrogenated isoquinoline-4-carboxylic acids

Full text of DOI:10.1134/S107042801305028X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 5, pp. 771−772. © Pleiades Publishing, Ltd., 2013.
Original English Text © I.V. Dyachenko, M.V. Vovk, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 5, pp. 787−788.
SHORT
COMMUNICATIONS
Ethyl 3-Thioxo-1-phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-
carboxylate, New Specimen of Derivatives
of Partially Hydrogenated Isoquinoline-4-carboxylic Acids
I. V. Dyachenkoa and M.V. Vovkb
aTaras Shevchenko Lugansk National University, Lugansk, 91011 Ukraine
e-mail: ivladya87@e-mail.ua
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev
Received August 25, 2012
DOI: 10.1134/S107042801305028X
Derivatives of partially hydrogenated 3-thioxoisoquin-
oline-4-carboxylic acids are a promising type of heterocy-
clic synthons. For instance, their nitriles easily obtained
from 2-acylcyclohexanons and cyanothioacetamide
[1] are used as semiproducts in the synthesis of HIV-1
reverse transcriptase [2], antimicrobial preparations [3],
substances with the fungicidal [4] and cardiotonic action
[5]. We recently synthesized the corresponding amides
by condensation of 1-amino-2-acylcycloalkenes with
monothiomalonodiamide [6]. The esters of these acids
were not described.
sis of ethyl 3-thioxo-1-phenyl-2,3,5,6,7,8-hexahydro-
isoquinoline-4-carboxylate (I) consisting in the reaction
of 1-benzoyl-2-(morpholin-4-yl)cyclohexene (II) [6] with
ethyl 3-amino-3-thioxopropanoate (III) in anhydrous
ethanol at 20°C in the presence of sodium ethylate.
ThealkylationofcompoundIwithN-(4-bromophenyl)-
2-chloroacetamide (IV) in DMF in the presence of alkali
resulted in the formation of the corresponding thioester
ethyl 3-[2-(4-bromophenylamino)-2-oxo-ethylsulfanyl]-
1-phenyl-5,6,7,8-tetrahydroisoquinoline-4-carboxylate
(V) in keeping with the general rules of the chemistry of
3-thioxo-2,3,5,6,7,8-hexahydroisoquinolines [7].
We describe here a convenient method of the synthe-
O
O
EtONa
_H2O
OEt
OEt
N
+
O
_
NH,
O
Ph
N
H
S
H2N
S
Ph
O
II
III
I
O
H
N
KOH_DMF
_H2O, _KCl
Cl
OEt
H
N
I +
O
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Ph
N
S
O
Br
IV
V
771

DYACHENKO, VOVK
772
Ethyl 3-thioxo-1-phenyl-2,3,5,6,7,8-hexahydroiso-
127.73, 128.35 (2C), 128.74, 129.50 (2C), 131.91 (2C),
138.97, 139.62, 145.75, 150.96, 158.50, 166.90, 167.32.
Mass spectrum, m/z (Irel, %): 527.2 (100) [M + 1]+. Found,
%: C 59.26; H 4.64; N 5.25. C26H25BrN2O3S. Calculated,
%: C 59.37; H 4.79; N 5.33. M 526.044.
quinoline-4-carboxylate (I). To a mixture of 2.71 g
(10 mmol) of enaminoketone II and 1.47 g (10 mmol) of
thioamide III in 20 ml of anhydrous ethanol was added
at 20°C while stirring a solution of sodium ethylate
prepared from 0.23 g (10 mmol) of sodium and 10 ml
of anhydrous ethanol, the mixture was stirred for 15 min
and left standing for 2 days. The reaction mixture was
diluted with 10% hydrochloric acid till pH 5, an 2 days
later the formed precipitate was filtered off and washed
in succession with water (15 ml), ethanol (15 ml), hex-
ane (15 ml), dried, and crystallized from ethanol. Yield
2.03 g (65%), yellow powder, mp 180°C (decomp.). IR
spectrum, ν, cm–1: 3431 (NH), 1726 (C=O), 1232 (C=S).
1H NMR spectrum, δ, ppm: 1.32 t (3H, CH3, J 6.2 Hz),
1.51–1.56 m (2H, CH2), 1.58–1.66 m (2H, CH2), 2.33–
2.38 m (2H, CH2), 2.45–2.49 m (2H, CH2), 4.29 q (2H,
OCH2, J 6.2 Hz), 7.39–7.56 m (5H, Ph), 13.57 br.s (NH).
13C NMR spectrum, δ, ppm: 14.39, 21.43, 22.01, 25.78,
27.04, 61.24, 121.19, 128.78 (2C), 129.60 (2C), 130.04,
132.73, 136.09, 145.88, 148.74, 166.81, 171.16. Mass
spectrum, m/z (Irel, %): 314 (100) [M + 1]+. Found, %:
C 68.86; H 5.94; N 4.35. C18H19NO2S. Calculated, %:
C 68.98; H 6.11; N 4.47. M 313.422.
IR spectra of compounds obtained were recorded on
a spectrophotometer FIR-spectrometer Spectrum One
(Perkin Elmer) from pellets with KBr. 1H NMR spectra
were registered on a spectrometer Varian Mercury-400
(400.397 MHz) from solutions in DMSO-d6, internal
reference TMS. 13C NMR spectra were taken on a spec-
trometer Varian VXR-300 (125.74 MHz) in DMSO-d6,
internal reference TMS. GC-MS analysis was carried
out on an instrument Crommas GC/MS Hewlett-Packard
5890/5972, column HP-5 MS (70 eV), eluent CH2Cl2.
Melting points were measured on a Koeffler heating
block. The reaction progress was monitored and the purity
of compounds obtained was checked by TLC on Silufol
UV-254 plates, eluent acetone–hexane, 3:5, development
in iodine vapor and under UV irradiation.
REFERENCES
1. Sharanin, Yu.A., Shestopalov, A.M., Promonenkov, V.K.,
and Rodinovskaya, L.A., Zh. Org. Khim., 1984, vol. 20,
p. 1539; Lozinskii, M.O., Chernega, A.N., and Shelya-
kin, V.V., Zh. Org. Khim., 2002, vol. 38, p. 1718.
2. Elgemeie, G.E.H.,Attia,A.M.E., and Fathy, N.M., Nucleo-
sides and Nucleotides, 1997, vol. 16, p. 485.
Ethyl 3-[2-(4-bromophenylamino)-2-oxo-
ethylsulfanyl]-1-phenyl-5,6,7,8-tetrahydroisoquino-
line-4-carboxylate (V). To a solution of 3.13 g (10 mmol)
of isoquinolinethione I in 15 ml of DMF was added at stir-
ring in succession 5.6 ml (10 mmol) of 10% water solution
of KOH and 2.5 g (10 mmol) of chloroacetamide (IV),
the mixture was stirred for 2 h and left standing for 24 h.
The reaction mixture was diluted with the same volume of
water, the formed precipitate was filtered off and washed
in succession with water (15 ml), ethanol (15 ml), hexane
(15 ml), dried, and crystallized from 1-butanol. Yield 3.9 g
(74%), colorless crystals, mp 153–155°C. IR spectrum, ν,
cm–1: 3339 (NH), 1718 (C=O), 1668 (CONH). 1H NMR
spectrum, δ, ppm: 1.34 t (3H, CH3, J 6.2 Hz), 1.52–1.66
m (2H, CH2), 1.72–1.81 m (2H, CH2), 2.53–2.61 m (2H,
CH2), 2.72–2.83 m (2H, CH2), 3.96 (2H, SCH2), 4.40 q
(2H, OCH2, J 6.2 Hz), 7.24 t (2H, Ph, J 7.1 Hz), 7.37 t
(1H, Ph, J 7.1 Hz), 7.43–7.56 m (6H, Harom), 10.30 br.s
(NH). 13C NMR spectrum, δ, ppm: 14.43, 21.66, 22.36,
27.03, 27.40, 35.51, 61.98, 115.11, 121.24 (2C), 126.33,
3. Kamal, A.M., Radwan, S.M., and Zaki, R.M., Eur. J. Med.
Chem., 2011, vol. 46, p. 567.
4. Hunt, J.C.A., Briggs, E., Clarke, E.D., and Whitting-
ham, W.G., Bioorg. Med. Chem. Lett., 2007, vol. 17,
p. 5222.
5. Mito, K., Kadziya, K., Ito, T., Kitano, T., Maruyama, M.,
and Khirayama, M., Japan Inventor’s Certificate 62-4270,
1985; Ref. Zh. Khim., 1988, 8O98P.
6. Dyachenko, I.V. and Vovk, M.V., Zh. Obshch. Khim., 2012,
vol. 82, p. 256.
7. Izbrannye metody sinteza i modifikatsii geterotsiklov. Izo-
khinoliny. Khimiya i biologicheskaya aktivnost’ (Selected
Methods of Synthesis and Modification of Heterocycles.
Isoquinolines. Chemistry and BiologicalActivity), Kartsev,
V.G., Ed., Moscow: Nauchnoe Partnerstvo, 2008.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 5 2013