Synthesis, structure, and some properties of substituted 3-carbethoxy(methoxy)-5-cyano-1,2,3,4-tetrahydrospirocyclohexane-4-pyridine-2- thiones

Article abstract of DOI:10.1023/B:COHC.0000046690.75207.9b

The condensation of cyclohexylidenemalononitrile or cyclohexylidenecyanoacetic ester with thioamidoethyl(methyl)malonate in the presence of sodium ethylate gave 6-amino-3-carbethoxy-5-cyano-4- spirocyclohexane-1,2,3,4-tetrahydropyridine-2-thione and 3-car

Full text of DOI:10.1023/B:COHC.0000046690.75207.9b

Chemistry of Heterocyclic Compounds, Vol. 40, No. 8, 2004
SYNTHESIS, STRUCTURE, AND SOME
PROPERTIES OF SUBSTITUTED 3-CARBETHOXY-
(METHOXY)-5-CYANO-1,2,3,4-TETRAHYDROSPIRO-
CYCLOHEXANE-4-PYRIDINE-2-THIONES
A. D. Dyachenko1, S. M. Desenko2, V. D. Dyachenko1, and A. N. Chernega3
The condensation of cyclohexylidenemalononitrile or cyclohexylidenecyanoacetic ester with
thioamidoethyl(methyl)malonate in the presence of sodium ethylate gave 6-amino-3-carbethoxy-5-
cyano-4-spirocyclohexane-1,2,3,4-tetrahydropyridine-2-thione and 3-carbethoxy(methoxy)-5-cyano-6-
oxo-4-spirocyclohexanepiperidine-2-thiones which were used in the synthesis of the corresponding
substituted
2-alkylthiotetrahydropyridines.
5-Carbethoxy-3-cyano-3-methyl-6-methylthio-4-spiro-
cyclohexane-3,4-dihydropyridine-2(1H)-one was studied by X-ray crystallography.
Keywords: thioamidoethyl(methyl)malonate, 4-cycloalkanespiro-substituted pyridine-2-thiones,
cyclohexylidenemalononitrile, cyclohexylidenecyanoacetic ester, alkylation, intramolecular Claisen
condensation, Michael reaction, X-ray crystallography.
We have previously prepared 3-cyano-4-cycloalkanespiro-substituted, partially hydrogenated pyridine-
2-thiones [1-3], which are promising intermediates in the search for preparations with medicinal value [4, 5]. In
extending our investigation in this direction we have discovered a route for the synthesis of
3-carbethoxy(methoxy)-substituted analogs of the class of compound mentioned above which involves the
reaction of the cyclohexylidenemalononitrile (1) with thioamidoethylmalonate (2) in ethanol in the presence of
sodium ethylate. During the reaction the formation of the 6-amino-3-carbethoxy-5-cyano-4-spirocyclohexane-
1,2,3,4-tetrahydropyridine-2-thione (3) is apparently preceded by the generation of the corresponding Michael
adduct 4 (Scheme 1).
In order to prove the structure of compound 3 (Table 1) we have used the alkylation by the halides 5 in
basic medium together with spectroscopic methods (see Experimental section and Table 2). The organic sulfides
6 obtained in this way are in accord with the general trends in the chemistry of pyridinethiones [6].
The use of the cyclohexylidenecyanoacetate ester 7 as Michael acceptor in the reaction with the
CH-acids 2 led to the preparation of 3-carbethoxy(methoxy)-5-cyano-6-oxo-4-spirocyclohexanepiperidine-2-
thiones 8. In this case, the hypothetical Michael adduct 9 could not be isolated. The use of alkylation as a
"characteristic reaction" of thiones [6] together with a series of spectroscopic methods (see Experimental section
and Table 2) readily prove the structure of compound 8 (Scheme 2).
__________________________________________________________________________________________
1
Taras Shevchenko National Pedagogical University, Lugansk 91011, Ukraine; e-mail:
2
dvd_lug@online.lg.ua.
V. N. Karazin National University, Kharkov 61070, Ukraine; e-mail:
3
desenko@univer.kharkov.ua. Organic Chemistry Institute, Ukraine National Academy of Sciences, Kiev
02094; e-mail: iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8,
pp. 1171-1178, August, 2004. Original article submitted December 18, 2001.
0009-3122/04/4008-1009©2004 Springer Science+Business Media, Inc.
1009

Scheme 1
EtO
O
S
O
S
EtONa
NC
OEt
..
N
H
C
N
H N
2
NC
CN
2
2
1
4
O
O
S
Hal
Z
NC
NC
5a,b
OEt
OEt
H N
N
Z
H N
N
H
S
2
2
6a,b
3
5 a Hal = Br, b Hal = Cl; 5, 6 a Z = 4-O2NC6H4CO; b Z = thiazol-2-ylcarbamoyl
Scheme 2
RO
O
O
EtONa
NC
OR
S
OEt
NC
H N
..
O N
H
2
EtO
S
O
7
2
9
2a,b
O
S
O
S
5 c–h
NC
O
NC
OR
OR
N
H
Z
O
N
H
10a–f
8a,b
2, 8 a R = Et, b R = Me; 5 c Hal = Cl, Z = PhNHCO, d Hal = Cl, Z = Ph, e Hal = I, Z = H,
f Hal = Cl, Z = 4-BrC6H4NHCO, g Hal = I, Z = Me, h Hal = Br, Z = PhCO; 10 a R = Et,
Z = PhNHCO, b R = Et, Z = Ph, c R = Et, Z = H, d R = Et, Z = 4-BrC6H4NHCO, e R = Me,
Z = Me, f R = Me, Z = PhCO
The sulfides 10 obtained by this means can undergo further reactions. Hence the reaction of compound
10c with MeI in basic medium occurs regioselectively via C-methylation to give 5-carbethoxy-3-cyano-3-
methyl-6-methylthio-4-spirocyclohexane-3,4-dihydropyridine-2(1H)-one (11) (method A), which can also be
synthesized in a single stage from the thione 8a and MeI (method B).
1010

TABLE 1. Parameters for Compounds 3, 6a,b, 8a,b, 10a-f, 11, 12
Found, %
Calculated, %
H
mp, °С
(crystallization
solvent)
——————
Com-
pound formula
Empirical
Yield, %
C
N
192-194
(EtOH)
3
C14H19N3O2S
57.12
57.31
57.96
57.88
52.51
52.64
56.95
57.12
55.73
55.69
61.90
61.81
65.73
65.60
58.35
58.42
52.02
52.18
58.31
58.42
63.35
63.29
59.67
59.60
6.46
6.53
5.19
5.30
5.41
5.35
5.98
6.16
5.69
5.75
5.73
5.89
6.31
6.29
6.39
6.54
4.91
4.78
6.59
6.54
5.50
5.57
6.73
6.88
14.54
14.32
12.20
12.27
16.00
16.15
9.31
9.52
9.84
10.00
9.92
9.83
7.12
7.29
8.97
9.09
8.13
8.30
8.97
9.09
6.99
7.03
8.79
8.69
7.41
7.65
83
66
76
75
61
79
71
62
57
53
55
58
68
6a
C22H24N4O5S
C19H23N5O3S2
C14H18N2O3S
C13H16N2O3S
C22H25N3O4S
C21H24N2O3S
C15H20N2O3S
C22H24BrN3O4S
C15H20N2O3S
C21H22N2O4S
C16H22N2O3S
C20H18N2O3S
180-182
(EtOH–DMF, 1:1)
6b
164-166
(EtOH)
154-156
(EtOH)
139-141
(MeOH)
153-155
(AcOH)
179-181
(EtOH)
135-137
(EtOH)
173-175
(AcOH)
156-158
(MeOH)
8a
8b
10a
10b
10c
10d
10e
10f
11
178-180
(MeOH–DMF, 1:1)
191-193
(EtOH)
268-269
(DMF)
12
65.61
65.55
5.05
4.95
O
KOH/MeI
2KOH/2MeI
NC
8a
10c
OEt
SMe
Me
O
B
A
N
H
11
Treatment of compound 10f with an aqueous solution of KOH in refluxing ethanol gives 2-benzoyl-5-
cyano-3-hydroxy-6-oxo-4,5,6,7-tetrahydrospiro(cyclohexane-4-thieno[2,3-b]pyridine) (12) as a result of an
intramolecular Claisen condensation.
OH
NC
O
O
KOH
10f
S
Ph
N
H
12
To establish the regioselectivity of the alkylation of functionally substituted tetrahydropyridines which
contain several nucleophilic centers unambiguously, we have studied compound 11 using an X-ray structural
method (Fig. 1 and Table 3).
1011

TABLE 2. IR and 1H NMR Spectra for Compounds 3, 6a,b, 8a,b, 10a-f, 11, 12
IR spectrum, ν, cm-1
Com-
pound
C≡N,
1Н NMR spectrum, δ, ppm (J, Hz)
NH
C=O
3
3430,
3330
2170,
1715
11.73 (1H, s, NH); 6.02 (2Н, br. s, NH2); 4.08 (3Н, m, OCH2
and H-3); 1.35-1.68 (10Н, m, (CH2)5); 1.23 (3H, t, J = 7.0, CH3)
6a
3510,
3390
2170,
1720,
1700
8.27 (4Н, two d, J = 9.0, Ar); 5.97 (2Н, br. s, NH2);
4.78 (2Н, q, SCH2); 4.11 (2Н, q, OCH2); 3.54 (1Н, s, H-3);
1.33-1.76 (10Н, m, (CH2)5); 1.22 (3Н, t, CH3)
6b
3420,
3300,
3150
2165,
1740,
1680
12.14 (1Н, br. s, NH); 7.38 and 7.02 (2Н, both d, J = 3.3, Het);
6.12 (2Н, br. s, NH2); 4.07 (4Н, m, SCH2 and OCH2);
3.50 (1H, s,H-3); 1.27-1.79 (10H, m, (CH2)5); 1.18 (3Н, t, CH3)
8a
3180
3210
3320
2255,
1710
13.42 (1Н, br. s, NH); 4.75 and 4.51 (2Н, both s, H-3 and H-5);
4.21 (2Н, q, OCH2); 1.39-1.73 (10H, m, (CH2)5); 1.22 (3Н, t, CH3)
8b
2245,
1710
13.39 (1Н, br. s, NH); 4.77 and 4.52 (2Н, both s, H-3 and H-5);
3.80 (3Н, s, OCH3); 1.42-1.72 (10Н, m, (CH2)5)
10a
2265,
1720,
1700,
1660
10.60 (1Н, s, NH); 10.12 (1Н, s, C6H5NHCO);
7.54 (2Н, d, J = 7.6, C6H5); 7.26 (2Н, dd, C6H5);
7.03 (1Н, dd, J = 7.3, C6H5); 4.09 (3Н, m, OCH2 and H-3);
3.67 (2Н, q, SCH2); 1.38-1.93 (10H, m, (CH2)5); 1.22 (3Н, t, CH3)
10b
10c
10d
3270,
3180
2250,
1735,
1710
10.48 (1Н, s, NH); 7.25 (5Н, m, C6H5);
4.09 (5Н, m, SCH, OCH2 and H-3); 1.35-1.72 (10H, m, (CH2)5);
1.21 (3Н, t, CH3)
3240
3350
2250,
1710,
1680
10.37 (1Н, s, NH); 4.18 (2Н, q, OCH2); 4.04 (1Н, s, H-3);
2.31 (3Н, s, SCH3); 1.39-1.84 (10H, m, (CH2)5); 1.18 (3Н, t, CH3)
2255,
1700,
1685,
1665
10.42 (1Н, s, NH); 10.17 (1H, s,4-BrC6H4NHCO);
7.53 and 7.46 (2H, both d, J = 9.0, Ar);
4.18 (3H, m, OCH2 and H-3); 3.69 (2H, q, SCH2);
1.38-1.84 (10H, m, (CH2)5); 1.21 (3H, t, CH3)
10e
10f
11
3300
3420
2250,
1720,
1700
10.36 (1H, s,NH); 4.02 (1H, s,H-3); 3.74 (3H, s,OCH3);
2.86 (2H, q, SCH2); 1.43-1.76 (10H, m, (CH2)5);
1.23 (3H, t, J = 7.2, CH3)
2270,
1710,
1670
10.41 (1H, s,NH); 7.32-7.47 (5H, m, C6H5); 4.29 (1H, s,H-3);
3.78 (3H, s,OCH3); 3.42 (2H, q, SCH2);
1.25-1.80 (10H, m, (CH2)5)
3270-
3210
2250,
1710,
1680
10.37 (1H, s,NH); 4.19 (2H, q, OCH2); 2.28 (3H, s,SCH3);
1.12-2.19 (10H, m, (CH2)5); 1.47 (3H, s,CH3);
1.30 (3H, t, OCH2CH3)
12
3430
2255,
1710,
1690
14.20 (1H, br. s, ОН); 12.01 (1Н, s, NH); 7.51-7.87 (5H, m, C6H5);
4.61 (1H, s,H-5); 2.65 (1H, m, CH); 1.93 (1H, m, CH);
1.29-1.67 (8H, m, (CH2)4)
TABLE 3. Basic Bond Lengths (d) and Valence Angles (ω) in the
Compound 11 Molecule
Bond
d, Å
Angle
ω, deg.
S(1)–C(5)
S(1)–C(16)
O(1)–C(1)
N(1)–C(1)
N(1)–C(5)
N(2)–C(7)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
1.747(5)
1.806(7)
1.220(6)
1.368(7)
1.409(6)
1.146(8)
1.519(8)
1.560(7)
1.528(7)
1.339(7)
C(5)–S(1)–C(16)
C(1)–N(1)–C(5)
N(1)–C(1)–C(2)
C(1)–C(2)–C(3)
C(2)–C(3)–C(4)
C(3)–C(4)–C(5)
S(1)–C(5)–N(1)
S(1)–C(5)–C(4)
N(1)–C(5)–C(4)
100.3(3)
123.2(5)
114.5(4)
110.8(4)
105.4(4)
120.6(4)
115.5(4)
124.2(4)
120.3(5)
1012

Fig. 1. Overall view of the compound 11 molecule with atomic numbering.
TABLE 4. Atomic Coordinates and Equivalent Isotropic Thermal
Parameters (Ueq) in the Structure 11
Atom
x
y
z
Ueq, Å2
S(1)
0.8651(3)
0.3574(7)
0.6745(8)
0.9580(7)
0.5942(7)
0.140(1)
0.54250(13)
0.4335(4)
0.3079(4)
0.2828(5)
0.4689(4)
0.1648(7)
0.4061(5)
0.3073(5)
0.2362(4)
0.3285(5)
0.4364(5)
0.3642(6)
0.2284(6)
0.1812(5)
0.0946(5)
-0.0038(6)
0.0433(6)
0.1380(5)
0.3052(5)
0.2650(12)
0.1833(13)
0.6707(6)
0.542(8)
0.36655(18)
-0.0136(4)
0.5418(4)
0.4852(4)
0.1632(4)
-0.0015(7)
0.0940(5)
0.1643(5)
0.2459(5)
0.3291(4)
0.2849(5)
0.2382(6)
0.0687(6)
0.1595(5)
0.2258(6)
0.2834(7)
0.3745(7)
0.3162(5)
0.4632(5)
0.6163(8)
0.636(1)
0.0635
0.0696
0.0713
0.0807
0.0503
0.0972
0.0491
0.0468
0.0421
0.0433
0.0476
0.0662
0.0633
0.0479
0.0626
0.0741
0.0742
0.0596
0.0555
0.1438
0.1535
0.0658
0.12(3)
O(1)
O(2)
O(3)
N(1)
N(2)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
H(1)
0.4353(8)
0.3622(8)
0.5416(8)
0.6728(8)
0.6983(8)
0.2250(9)
0.2383(9)
0.6636(8)
0.8232(9)
0.7324(12)
0.6236(12)
0.466(1)
0.7682(9)
1.0631(17)
1.205(2)
0.7037(11)
0.644(14)
0.3478(6)
0.102(9)
1013

Fig. 2. Crystal packing for compound 11
(the dotted lines show the intermolecular hydrogen bonds).
The central six-membered N(1)C(1-5) heterocycle is markedly non-planar and exists in a half-boat
conformation (the modified Kremer-Pople [7] S, θ, and ψ parameters being 0.69, 47.8°, and 25.8° respectively).
The ring torsional angles are: N(1)C(1)C(2)C(3) -43.6, C(1)C(2)C(3)C(4) 55.9, C(2)C(3)C(4)C(5) -38.0, C(3)C(4)C(5)N(1) 4.0,
C(4)C(5)N(1)C(1) 14.1, and C(5)N(1)C(1)C(2) 7.5°. The N(1) atom has a planar trigonal bond configuration with overall
valence angles at this atom of 369.3°. As a consequence of the conjugation of the unshared electron pair of the
N(1) atom with the O(1)=C(1) and C(4)=C(5) double bond π-systems, the interatomic distances for N(1)–C(1) of
1.368(7) and N(1)–C(5) 1.409(6) Å are markedly shortened when compared with the standard value of 1.45 Å for
a typical N(sp2)–C(sp2) bond [8]. The basic geometrical parameters for molecule 11 are typical [9]. In particular,
the bond lengths for S(1)–C(5) of 1.747(5) and S(1)–C(16) 1.806(7) Å are almost identical to the corresponding
parameters in the Ph–S–Me molecule (S–C(sp2) 1.749(4) and S–C(sp3) 1.803(4) Å) [10].
In the crystal of compound 11 the molecules are combined in infinite chains via O(2)···H(1)–N(1) hydrogen
bonding (Fig. 2) (O(2)···N(1) 2.973(7), O(2)···H(1) 1.90(10) Å, O(2)H(1)N(1) 164(5)°).
EXPERIMENTAL
X-ray Structural Investigation of the Monocrystal of Compound 11 with the linear parameters
0.16 × 0.19 × 0.68 mm was carried out at room temperature on an Enraf-Nonius CAD-4, automatic, four circle
diffractometer (CuKα irradiation, relative scanning rate 2θ/ω = 1.2, θmax = 70°, spherical segment 0 ≤ h ≤ 8, 0 ≤
k ≤ 13, -13 ≤ l ≤ 13). In all, 1826 reflections were gathered of which 1598 are symmetrically independent
(Rint = 0.028). Crystals of compound 11 are monoclinic with a = 6.923(1), b = 11.265(3), c = 11.117(3) Å;
β = 104.75(2)°; V = 838.4 Å3; M = 332.4; Z = 2; dcalc = 1.28 g/cm3; µ = 17.9 cm-1; F(000) = 345.5, and space
group Pc. The structure was solved using a direct method and refined using least squares analysis in a full
matrix, anisotropic approximation with the CRYSTALS program package [11]. 1365 Reflections with I > 3(I)
were used in the refinement (203 refinement parameters, number of reflections per parameter 6.7). All of the
hydrogen atoms were revealed in electron density difference synthesis and included in the calculation with fixed
positions and thermal parameters (only atom H(1) was refined isotropically). Calculation of the absorbance in the
crystal was carried out using the azimuthal scanning method [12]. The Chebyshev weighting scheme [13] was
used in the refinement with the parameters 0.96, 0.95, and -0.20. The final values of the difference factors were
R = 0.058 and Rw = 0.062, GOF = 1.103. The absolute configuration was established using the Flack method
1014

[14] (enantiopolar parameter refinement to 0.07(1) for 1486 reflections with non averaged Friedel equivalents).
The complete set of X-ray structural information has been deposited in the Cambridge structural data bank (reg.
No. CCDC176372).
IR Spectra were taken on an IRS-29 spectrometer using vaseline oil. 1H NMR spectra were recorded on
Gemini-200 (199 MHz) (compounds 6a,b, 10a,c,e, 12), Bruker AM-300 (300 MHz) (compounds 3, 8a,b), and
Bruker DRX500 (500 MHz) (compounds 10b,d,f, 11) equipment using DMSO-d6 solvent and TMS internal
standard. Mass spectra were recorded on a Kratos MS-890 (70 eV) spectrometer. Melting points were
determined on a Koffler block. Monitoring of the reaction course and the purity of the compounds obtained was
carried out using TLC (Silufol UV-254, acetone-hexane, 3: 5) and revealed using iodine vapor. The
physicochemical and spectroscopic parameters for compounds 3, 6, 8, 10, 11, 12 are given in Tables 1 and 2.
6-Amino-3-carbethoxy-5-cyano-4-spirocyclohexane-1,2,3,4-tetrahydropyridine-2-thione (3).
A
solution obtained from sodium (0.23 g, 10 mmol) in ethanol (5 ml) was added to a solution of
thioamidoethylmalonate (1.47 g, 10 mmol) in ethanol (20 ml). Cyclohexylidenemalononitrile (1.46 g, 10 mmol)
was then added with stirring. The reaction mixture was stirred for 2 h and left for 1 day after which it was
acidified with 10% aqueous HCl solution to pH 5. The precipitate formed was filtered off and washed with 40%
aqueous ethanol to give compound 3. The mass spectrum of compound 3 (EI, 70 eV), m/z (Irel, %) showed: 293
[M+] (73), 247 (29), 220 (70), 178 (100), 155 (58).
6-Amino-3-carbethoxy-5-cyano-2-(4'-nitrobenzoylmethylthio)-4-spirocyclohexane-3,4-dihydro-
pyridine (6a), 6-Amino-3-carbethoxy-5-cyano-4-spirocyclohexane-2-(thiazol-2'-ylcarbamoylmethylthio)-
3,4-dihydropyridine (6b), 5-Carbethoxy-3-cyano-2-oxo-6-phenylcarbamoylmethylthio-4-spirocyclohexane-
1,2,3,4-tetrahydropyridine (10a), 6-Benzylthio-5-carbethoxy-3-cyano-2-oxo-4-spirocyclohexane-1,2,3,4-
tetrahydropyridine (10b), 5-Carbethoxy-3-cyano-6-methylthio-2-oxo-4-spirocyclohexane-1,2,3,4-tetra-
hydropyridine (10c), 2-(4'-Bromophenylcarbamoylmethylthio)-5-carbethoxy-3-cyano-2-oxo-4-spirocyclo-
hexane-1,2,3,4-tetrahydropyridine (10d), 5-Carbomethoxy-3-cyano-6-ethylthio-2-oxo-4-spirocyclohexane-
1,2,3,4-tetrahydropyridine
(10e),
6-Benzoylmethylthio-5-carbomethoxy-3-cyano-2-oxo-4-spirocyclo-
hexane-1,2,3,4-tetrahydropyridine (10f). A mixture of the corresponding thione (10 mmol), 10% aqueous
KOH (5.6 ml, 10 mmol), and the corresponding alkyl halide (10 mmol) in DMF (20 ml) was stirred at 20°C for 4
h and left for one day. The precipitate was filtered off and washed with 40% aqueous ethanol solution and
hexane to give compounds 6a,b, 10a-f. Mass spectrum of compound 10e (EI, 70 eV), m/z (Irel, %): 308 [M+]
(55), 279 (30), 249 (100), 180 (35).
3-Carbethoxy-5-cyano-6-oxo-4-spirocyclohexanepiperidine-2-thione (8a) and 3-Carbomethoxy-5-
cyano-6-oxo-4-spirocyclohexanepiperidine-2-thione (8b). A solution obtained from sodium (0.23 g, 10 mmol)
in ethanol (5 ml) was added to a solution of the corresponding compound 2 (10 mmol) in ethanol (20 ml).
Cyclohexylidenecyanoacetic ester (1.93 g, 10 mmol) was then added with stirring. The reaction mixture was
stirred for 2 h and left for one day after which it was acidified with 10% aqueous HCl solution to pH 5. The
precipitate formed was filtered off and washed with 40% aqueous ethanol solution to give compounds 8a,b.
Mass spectrum (EI, 70 eV), m/z (Irel, %), compound 8a: 294 [M+] (90), 249 (20), 222 (100), 194 (56), 166 (30),
148 (30), 138 (52), 122 (25); compound 8b: 280 [M+] (100), 221 (45), 193 (45), 160 (42), 148 (78), 133 (27).
5-Carbethoxy-3-cyano-3-methyl-6-methylthio-4-spirocyclohexane-3,4-dihydropyridine-2(1H)-one
(11). A. A 10% aqueous solution of KOH (5.6 ml, 10 mmol) and then MeI (0.62 ml, 10 mmol) were added with
stirring to a solution of compound 10c (3.08 g, 10 mmol) in DMF (10 ml) and stirred was continued for 2 h.
After 1 day the precipitate formed was filtered off and washed with ethanol and hexane to give compound 11.
B. A 10% aqueous solution of KOH (5.6 ml, 10 mmol) and then MeI (0.62 ml, 10 mmol) were added
with stirring to a solution of compound 8a (1.47 g, 5 mmol) in DMF (10 ml) and stirring was continued for 2 h.
After 1 day the precipitate formed was filtered off and washed with ethanol and hexane to give compound 11 in
72% yield. The melting point and the chromatographic and spectroscopic date agreed with the analogous data for
compound 11 prepared as in method A. Mass spectrum of compound 11 (EI, 70 eV), m/z (Irel, %): 322 [M+] (70),
307 (100), 277 (32), 261 (69), 226 (35), 180 (55), 148 (48).
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2-Benzoyl-5-cyano-3-hydroxy-6-oxo-4,5,6,7-tetrahydrospiro(cyclohexane-4-thioeno[2,3-b]pyridine)
(12). A 10% aqueous solution of KOH (2.8 ml, 5 mmol) was added to a solution of compound 10f (1.99 g,
5 mmol) in ethanol (25 ml) and refluxed for 1 h. After 1 day the precipitate formed was filtered off and washed
with ethanol and hexane to give compound 12.
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