Synthesis of 7-acetyl-8-aryl(hetaryl)- 6-hydroxy-1,6-dimethyl-3-selenoxo-2, 3,5,6,7,8-hexahydroiso-quinoline-4-carbonitriles by the condensation of 2,4-diacetyl-3-aryl(hetaryl)- 5-hydroxy-5-methyl-cyclohexanones with cyanoselenoacetamide

Article abstract of DOI:10.1007/s10593-011-0693-4

7-Acetyl-8-aryl(hetaryl)-6-hydroxy-1,6-dimethyl-3-selenoxo-2,3,5,6,7, 8-hexahydroisoquinoline-4-carbo- nitriles have been obtained by the condensation of 2,4-diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methyl-cyclohexanones with cyanoselenoacetamide.

Full text of DOI:10.1007/s10593-011-0693-4

Chemistry of Heterocyclic Compounds, Vol. 46, No. 12, March, 2011 (Russian Original Vol. 46, No. 12, December, 2010)
SYNTHESIS OF 7-ACETYL-8-ARYL(HETARYL)- 6-HYDROXY-
1,6-DIMETHYL-3-SELENOXO-2,3,5,6,7,8-HEXAHYDROISO-
QUINOLINE-4-CARBONITRILES BY THE CONDENSATION
OF 2,4-DIACETYL-3-ARYL(HETARYL)- 5-HYDROXY-5-METHYL-
CYCLOHEXANONES WITH CYANOSELENOACETAMIDE
V. D. Dyachenko1* and S. M. Sukach1
7-Acetyl-8-aryl(hetaryl)-6-hydroxy-1,6-dimethyl-3-selenoxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbo-
nitriles have been obtained by the condensation of 2,4-diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methyl-
cyclohexanones with cyanoselenoacetamide.
Keywords: 2,4-diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methylcyclohexanones, 7-acetyl-8-aryl(hetaryl)-
6-hydroxy-1,6-dimethyl-3-selenoxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitriles, selenoether,
alkylation, condensation.
Derivatives of partially hydrogenated isoquinolines are present in nature in the form of alkaloids [1],
which is a powerful stimulus for their detailed study.
Unlike the functionally substituted 3-oxo- and 3-thioxo-2,3,5,6,7,8-hexahydroisoquinolines synthesized
previously [2], their 3-selenoxo analogs are unknown.
It has been shown for the first time that the previously unknown 7-acetyl-8-aryl(hetaryl)-6-hydroxy-
1,6-dimethyl-3-selenoxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitriles 3a-e are formed on condensing
2,4-diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methylcyclohexanones 1a-e with cyanoselenoacetamide (2) in absolute
ethanol in the presence of triethylamine in an atmosphere of argon at 60oC. The reaction scheme probably
includes a stage of forming intermediates 4 which cyclocondense intramolecularly into compounds 3a-e.
The structure of isoquinoline 3b was confirmed by alkylation with 2-chloro-N-phenylacetamide (5), as a
result of which 2-[7-acetyl-4-cyano-8-(fur-2-yl)-6-hydroxy-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl-
selenyl]-N-phenylacetamide (6) was formed. We note that the isostructural analogs of compounds 3, the
2-selenoxo-1,2,5,6,7-hexahydroquinolines, are also alkylated by alkyl halides at the selenium atom with the
formation of selenoethers [3].
In the IR spectra of the synthesized compounds 3a-e and 6 characteristic bands were observed for the
stretching vibrations of the OH, C≡N, and C=O functional groups at 3417-3481, 2214-2224, and 1695-1721 cm-1
respectively.
_______
* To whom correspondence should be addressed, e-mail: dvd_lug@online.lg.ua.
1 Taras Shevchenko Lugansk National University, Lugansk 91011, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1795-1799, December, 2010.
Original article submitted October 15, 2010.
0009-3122/11/4612-1467©2011 Springer Science+Business Media, Inc.
1467

O
O
R
O
R
O
O
Me
CN
Se
Et3N
Me
Me
:
NH2
Me
Me
+
– H2O
H2N
Se
Me
OH
OH
CN
1a–e
2
4
NHPh
O
R
Me
O
R
Me
Cl
O
Me
Me
N
Me
NH
5
3b
NHPh
Se
Me
Se
– H2O
OH
OH
CN
O
CN
6
3a–e
1, 3 а R = 3-Py, b R = 2-Fu, c R = 5-methylfur-2-yl,
d R = Ph, e R = 4-MeС6Н4
1
In addition to the proton signals of substituents in the appropriate regions, characteristic of H NMR
spectra of partially hydrogenated functionally substituted isoquinolines 3a-e and 6, signals were present for the
protons of the methylene group of the cyclohexane fragment at 2.81-3.14 and 2.92-3.61 ppm with coupling
constant 2J = 16.0-17.8 Hz.
The mass spectra of the obtained compounds 3a-e and 6 contain low-intensity peaks for the molecular
ions and high-intensity peaks for ions of the acetyl fragment, which is characteristic for acetyl-containing
organic compounds [4].
EXPERIMENTAL
The IR spectra of the synthesized compounds were recorded on a Spectrum One (Perkin‒Elmer) FIR
1
spectrometer in KBr. The H NMR spectra were recorded on a Bruker Avance 400 (400 MHz) instrument in
DMSO-d6, internal standard was TMS. The mass spectra of compounds 3a-e and 6 were obtained on a MX-1321
(70 eV) spectrometer with direct insertion of substance into the ion source, and of compounds 1a,c on a
Crommas GC/MS Hewlett-Packard 5890/5972 instrument, HP-5 MS column (70 eV) in CH2Cl2 solution.
Melting points were determined on a Kofler block. A check on the progress of reactions and the purity of the
obtained compounds was effected by TLC on Silufol UV-254 plates, eluent was acetone–hexane, 3:5,
developing with iodine vapor and with UV light.
2,4-Diacetyl-3-aryl(hetaryl)-5-hydroxy-5-methylcyclohexanones 1a-e were obtained by the
procedure of [5].
2,4-Diacetyl-5-hydroxy-5-methyl-3-(pyrid-3-yl)cyclohexanone (1a). Yield 2.5 g (87%), white
powder, mp 175oC. IR spectrum, , cm-1: 3521 (OH), 1709 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.19 (3H,
2
s, CH3); 1.91 (3H, s, CH3); 1.92 (3H, s, CH3); 2.37, 2.92 (2H, two d, J = 10.8, AB system, CH2); 3.36 (1H, d,
J = 10.0, H-4); 4.00 (1H, t, J = 9.6, H-3); 4.30 (1H, d, J = 8.4, H-2); 5.30 (1H, br. s, OH); 7.29-7.31 (1H, m, H-5
pyridine); 7.78 (1H, d, J = 6.0, H-4 pyridine); 8.38 (1H, d, J = 7.2, H-6 pyridine); 8.50 (1H, s, H-2 pyridine).
Mass spectrum, m/z (Irel, %): 290 [M+H]+ (100). Found, %: C 66.30; H 6.57; N 4.71. C16H19NO4. Calculated, %:
C 66.42; H 6.62; N 4.84.
1468

2,4-Diacetyl-5-hydroxy-5-methyl-3-(5-methylfur-2-yl)cyclohexanone (1c). Yield 3.15 g (85%), white
1
powder, mp 125-127oC. IR spectrum, , cm-1: 3592 (OH), 1726, 1705 (C=O). H NMR spectrum, δ, ppm (J,
Hz): 1.17 (3H, s, CH3); 2.04 (3H, s, CH3); 2.07 (3H, s, CH3); 2.17 (3H, s, CH3); 2.30, 2.89 (2H, two d, 2J = 10.8,
AB system, CH2); 3.15 (1H, d, J = 9.2, H-4); 3.98 (1H, d, J = 9.6, H-2); 4.06 (1H, t, J = 9.6, H-3); 5.22 (1H, br.
s, OH); 5.90 (1H, d, J = 2.4, H-4 furan); 6.03 (1H, d, J = 2.4, H-3 furan). Mass spectrum, m/z (Irel, %): 291 [M-
H]+ (100). Found, %: C 65.65; H 6.82. C16H20O5. Calculated, %: C 65.74; H 6.90.
Cyanoselenoacetamide (2) was obtained by the procedure of [6].
7-Acetyl-6-hydroxy-1,6-dimethyl-8-(pyrid-3-yl)-3-selenoxo-2,3,5,6,7,8-hexahydroisoquinoline-
4-carbonitrile (3a). Cyanoselenoacetamide (2) (1.1 g, 7 mmol) was added to a suspension of cyclohexanone 1a
(2 g, 7 mmol) in absolute ethanol (20 ml). The reaction mixture was stirred for 15 min in an argon atmosphere,
triethylamine (1 ml, 7 mmol) was then added and the mixture heated with stirring to 60oC, and then left for 24 h.
The resulting solid was filtered off, and washed with ethanol. Yield 2 g (71%), yellow powder, mp 208-211oC. IR
spectrum, , cm-1: 3436 (OH), 3276 (NH), 2217 (C≡N), 1700 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.29 (3H,
2
s, CH3); 1.91 (3H, s, CH3); 2.16 (3H, s, CH3); 2.81, 2.92 (2H, two d, J = 17.8, AB system, CH2); 2.98 (1H, d,
J = 10.5, H-7); 4.63 (1H, d, J = 10.5, H-8); 5.00 (1H, br. s, OH); 7.28 (1H, d, J = 8.1, H-4 pyridine); 7.45 (1H,
m, H-5 pyridine); 8.35 (1H, d, J = 4.8, H-6 pyridine); 8.43 (1H, s, H-2 pyridine). The signal of the H-2 proton
was not displayed, evidently as a result of rapid deuterium exchange. Mass spectrum, m/z (Irel, %): 400 [M]+ (9),
396 (18), 318 (8), 238 (20), 160 (100), 80 (35), 43 [CH3C≡O)+ (29). Found, %: C 56.91; H 4.63; N 10.45.
C19H19N3O2Se. Calculated, %: C 57.00; H 4.78; N 10.50.
7-Acetyl-8-(fur-2-yl)-6-hydroxy-1,6-dimethyl-3-selenoxo-2,3,5,6,7,8-hexahydroisoquinoline-
4-carbonitrile (3b) was obtained analogously to compound 3a from cyclohexanone 1b. Yield 2.1 g (77%),
1
yellow powder, mp 240-242oC. IR spectrum, , cm-1: 3434 (OH), 3259 (NH), 2222 (C≡N), 1702 (C=O). H
NMR spectrum, δ, ppm (J, Hz):1.26 (3H, s, CH3); 2.10 (3H, s, CH3); 2.18 (3H, s, CH3); 2.86, 3, 09 (H, two d,
2J = 17.7, AB system, CH2); 3.03 (1H d, 7.8, H-7); 4.58 (1H, d, J = 7.8, H-8); 5.04 (1H, br. s, OH); 6.11 (1H, d,
J = 3.2, H-3 furan); 6.27 (1H, dd, J = 4.0 and J = 6.0, H-4 furan); 7.50 (1H, d, J = 1.2, H-5 furan); 14.38 (1H, br.
s, NH). Mass spectrum, m/z (Irel, %): [M]+ missing, 372 [M+H-H2O]+ (20), 371 [M-H2O]+ (11), 329 (45), 249
(14), 43 [CH3C≡O]+ (100). Found, %: C 55.49; H 4.60; N 7.08. C18H18N2O3Se. Calculated, %: C 55.53; H 4.66;
N 7.20.
7-Acetyl-6-hydroxy-1,6-dimethyl-8-(5-methylfur-2-yl)-3-selenoxo-2,3,5,6,7,8-hexahydroisoquino-
line-4-carbonitrile (3c) was obtained analogously to compound 3a from cyclohexanone 1c. Yield 1.9 g (67%),
1
yellow powder, mp 207oC. IR spectrum, , cm-1: 3429 (OH), 3272 (NH), 2222 (C≡N), 1702, 1695 (C=O). H
NMR spectrum, δ, ppm (J, Hz): 1.30 (3H, s, CH3); 2.12 (3H, s, CH3); 2.25 (3H, s, CH3); 2.34 (3H, s, CH3); 2.91
2
(1H, d, J = 7.8, H-7); 3.14, 3.61 (2H, two d, J = 16.0, AB system, CH2); 4.69 (1H, br. s, OH); 4.74 (1H, d,
J = 7.8, H-8); 5.92 (2H, d, J = 9.2, H-3 furan and H-4 furan); 7.67 (1H, br. s, NH). Mass spectrum, m/z (Irel, %):
[M]+ missing, 385 [M – H2O]+ (2), 370 [M-H2O-CH3]+ (9), 328 (25), 285 (20), 222 (17), 160 (50), 80 (74), 43
[CH3C≡O]+ (100). Found, %: C 56.52; H 4.91; N 6.80. C19H20N2O3Se. Calculated, %: C 56.58; H 5.00; N 6.95.
7-Acetyl-6-hydroxy-1,6-dimethyl-8-phenyl-3-selenoxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbo-
nitrile (3d) was obtained analogously to compound 3a from cyclohexanone 1d. Yield 2.1 g (75%), yellow
powder, mp 215oC. IR spectrum, , cm-1: 3422 (OH), 3280 (NH), 2221 (C≡N), 1700 (C=O). 1H NMR spectrum,
δ, ppm (J, Hz): 1.25 (3H, s, CH3); 1.91 (3H, s, CH3); 2.07 (3H, s, CH3); 2.82 (1H, d, J = 14.6, H-5); 2.91 (1H, d,
J = 10.8, H-7); signal of the second proton of the 5-CH2 group is masked by the signal of the water protons, 4.36
(1H, d, J = 10.8, H-8); 4.80 (1H, br. s, OH); 7.05 (2H, d, J = 7.0, C6H5); 7.22-7.28 (3H, m, C6H5); 14.22 (1H,
br. s, NH). Mass spectrum, m/z (Irel, %): 399 [M]+ (12), 381 [M-H2O]+ (26), 339 (73), 259 (20), 160 (10), 77
[C6H5]+ (8), 43 [CH3C≡O]+ (100). Found, % : C 60.00; H 4.91; N 6.95. C20H20N2O2Se. Calculated, %: C 60.15;
H 5.05; N 7.01.
1469

7-Acetyl-6-hydroxy-1,6-dimethyl-3-selenoxo-8-p-tolyl-2,3,5,6,7,8-hexahydroisoquinoline-4-carbo-
nitrile (3e) was obtained analogously to compound 3a from cyclohexanone 1e. Yield 2.2 g (76%), yellow
1
powder, mp 245-247oC. IR spectrum, , cm-1: 3417 (OH), 3263 (NH), 2224 (C≡N), 1701 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 1.26 (3H, s, CH3); 1.95 (3H, s, CH3); 2.12 (3H, s, CH3); 2.26 (3H, s, CH3); 2.85, 3.22
2
(2H, two d, J = 17.76, AB system, CH2); 2.89 (1H, d, J = 10.36, H-7); 4.32 (1H, d, J = 10.4, H-8); 4.98 (1H,
br. s, OH); 6.99 (2H, d, J = 8.0, C6H4); 7.09 (2H, d, 8.0, C6H4); 14.27 (1H, br. s, NH). Mass spectrum, m/z (Irel,
%): 413 [M]+ (10), 395 [M-H2O]+ (22), 352 [M-H2O-CH3C≡O]+ (100), 337 (19), 273 (17), 183 (8), 105 (6), 43
[CH3C≡O]+ (99). Found, %: C 60.95; H 5.31, N 6.72. C21H22N2O2Se. Calculated, %: C 61.02; H 5.36; N 6.78.
2-[7-Acetyl-4-cyano-8-(fur-2-yl)-6-hydroxy-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-ylselenyl]-
N-phenylacetamide (6). 2-Chloro-N-phenylacetamide (5) (0.24 g, 1.3 mmol) was added in a stream of argon to
a solution of compound 3b (0.5 g, 1.3 mmol) in DMF (5 ml) followed by 10% aqueous KOH solution (0.71 ml,
13 mmol). The mixture was stirred for 30 min at 50oC and then left. After 48 h the solid, which had formed was
filtered off, and washed with ethanol. Yield 0.45 g (67%), yellow powder; mp 195oC. IR spectrum, , cm-1: 3481
1
(OH), 3335 (NH), 2214 (C≡N), 1721 (C=O), 1669 (CONH). H NMR spectrum, δ, ppm (J, Hz): 1.26 (3H, s,
CH3); 2.11 (3H, s, CH3); 2.19 (3H, s, CH3); 2.83, 3.12 (2H, two d, 2J = 17.2, AB system, CH2); 3.03 (1H, d, J =
9.2, H-7); 4.13 (2H, s, SeCH2); 4.69 (1H, d, J = 9.2, H-8); 5.01 (1H, br. s, OH); 6.10 (1H, d, J = 2.8, H-3 furan);
6.34 (1H, dd, J = 2.4 and J = 1.1, H-4 furan); 7.01 (1H, t, J = 7.2, C6H5); 7.29 (2H, t, J = 7.6, C6H5); 7.49-7.54
(3H, m, H-5 furan and C6H5); 10.26 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 523 [M+H]+ (6), 413 (11),
341 (13), 327 (9), 248 (6), 207 (8), 93 [C6H5NH]+, 43 [CH3C≡O]+ (100). Found, %: C 59.60; H 4.79; N 7.98.
C26H25N3O4Se. Calculated, %: C 59.77; H 4.82; N 8.04.
REFERENCES
1.
2.
3.
4.
5.
6.
V. G. Kartsev, in: V. G. Kartsev and G. A. Tolstikov (editors), Nitrogen Heterocycles and Alkaloids, [in
Russian], Vol. 1 Interbioscreen Ltd, Moscow (2001), p. 97.
A. I. Ozols, Yu. E. Pelcher, Z. A. Kalme, Yu. Yu. Popelis, I. V. Turovskis, and G. Ya. Duburs, Khim.
Geterotsikl. Soedin., 59 (1996). [Chem. Heterocycl. Comp., 32, 52 (1996)].
V. D. Dyachenko and V. P. Litvinov, Khim. Geterotsikl. Soedin., 1384 (1997). [Chem. Heterocycl.
Comp., 33, 1203 (1997).
Yu. A. Pentin and L. V. Vilkov, Physical Methods of Investigation in Chemistry [Russian translation],
Mir, Moscow (2003), p. 46.
A. P. Kriven’ko and V. V. Sorokin, Substituted Cyclohexanolones; Training Manual [in Russian], Izd.
Sarat. Univ., Saratov (1999), p. 38.
V. P. Litvinov, V. Yu. Mortikov, Yu. A. Sharanin, and A. M. Shestopalov, Synthesis, 98 (1985).
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