On the regioselectivity of the reaction of cyanothioacetamide with 2-acetylcyclo-hexanone, 2-acetylcyclopentanone, and 2-acetyl-1-(morpholin-4-yl)- 1-cycloalkenes

Article abstract of DOI:10.1007/s10593-012-0991-5

It has been established that the interaction of cyanothioacetamide with 2-acetylcyclohexanone, 2-acetylcyclopentanone, or their enamines (2-acetyl-1-(morpholin-4-yl)-1-cycloalkenes) contrary to the literature data have a non-regiospecific character and leads to the formation of mixtures of 3-cyano-4-methyl-5,6-tri(tetra)methylenepyridine-2(1H)-thiones and 3-cyano-6-methyl-4,5-tri(tetra)methylene-pyridine-2(1H)-thiones with a predominance of the latter.

Full text of DOI:10.1007/s10593-012-0991-5

Chemistry of Heterocyclic Compounds, Vol. 48, No. 2, May, 2012 (Russian Original Vol. 48, No. 2, February, 2012)
ON THE REGIOSELECTIVITY OF THE REACTION
OF CYANOTHIOACETAMIDE WITH 2-ACETYLCYCLO-
HEXANONE, 2-ACETYLCYCLOPENTANONE, AND
2-ACETYL-1-(MORPHOLIN-4-YL)-1-CYCLOALKENES
V. V. Dotsenko1**, S. G. Krivokolysko1, V. V. Polovinko2, and V. P. Litvinov3*
It has been established that the interaction of cyanothioacetamide with 2-acetylcyclohexanone,
2-acetylcyclopentanone, or their enamines (2-acetyl-1-(morpholin-4-yl)-1-cycloalkenes) contrary to the
literature data have a non-regiospecific character and leads to the formation of mixtures of 3-cyano-
4-methyl-5,6-tri(tetra)methylenepyridine-2(1H)-thiones and 3-cyano-6-methyl-4,5-tri(tetra)methylene-
pyridine-2(1H)-thiones with a predominance of the latter.
Keywords: 2-acetylcyclohexanone, 2-acetylcyclopentanone, cyanothioacetamide, Guareschi-Thorpe
reaction, regioselectivity.
One of the most convenient and efficient methods to build the pyridine ring is the interaction of
1,3-dicarbonyl compounds (β-ketoesters, β-ketoaldehydes, and 1,3-diketones) with cyanoacetic ester and
ammonia (or with derivatives of cyanoacetamide), known as the Guareschi-Thorpe reaction. This approach
enables the ready preparation of substituted pyridine derivatives by an alternative route in those cases when
direct functionalization is hindered (see reviews [1-3]). With symmetrical 1,3-diketones, the reaction proceeds
smoothly and unambiguously. However, on obtaining pyridines according to Guareschi-Thorpe protocol using
unsymmetrical diketones the problem arises in connection with the possibility of forming isomers with different
(4 or 6) positions of substituents in the pyridine nucleus (Scheme 1).
As follows from the literature data [1-3], the regioselectivity of the process and the ratio of 4-R- and
6-R-isomers are determined predominantly by the structure of the diketone substrate. Examples are known of
both low-selectivity cyclization with formation of isomeric mixtures and of regiospecific processes leading to
formation of one of the two possible isomers. The modification of the starting substrate was proposed as a
possible solution of the regiocontrol problem, as in the majority of cases 1,3-diketones or β-ketoesters may be
_______
*Deceased.
**To whom correspondence should be addressed, e-mail: Victor_Dotsenko@bigmir.net.
1"ChemEx" Laboratory, Vladimir Dal' East-Ukrainian National University, 20-A/7 Molodyozhny kv., Lugansk
91034, Ukraine.
2Enamine Ltd, 67/45 Krasnotkatskaya St., Kiev 02094, Ukraine.
3 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow
117913, Russia.
_______________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 328-338, February, 2012. Original
article submitted October 23, 2010. Revision submitted January 3, 2012.
0009-3122/12/4802-0309©2012 Springer Science+Business Media, Inc.
309

successfully replaced by the corresponding enamino ketones or enamino esters [1]. In this case the reaction may
often proceed in higher yield under milder conditions and exclusively regiospecifically (Scheme 1).
Scheme 1
CN
R
R2
R2
NC
X
R1
R2
NC
X
R1
R
O
H2N
X
+
R
O
R1
N
H
N
H
4-R-isomer
6-R-isomer
CN
X
R
NC
R1
R2
X = O, S, Se, C(CN)2
N
R2
H2N
R, R2 = alkyl, aryl
R
O
R1 = H, alkyl
X
N
R1
H
4-R-isomer
It is necessary to note specifically that literature data indicate the appreciably more selective character
of the Guareschi–Thorpe reaction in the case of 2-acylcycloalkanones compared with acyclic 1,3-diketones. It is
postulated that the interaction of 2-acylcyclopentanones and hexanones [4-10], 2,4-diacetyl-3-aryl-5-hydroxy-
5-methylcyclohexanones (β-cycloketols) [11], 2-RC(O)-5,5-dimethyltetrahydro(thio)pyran-4-ones [12, 13] with
cyanoacetamide and its S- and Se-containing analogs proceeds initially as a Knoevenagel condensation
exclusively at the endocyclic carbonyl group with subsequent ring closure involving the exocyclic acyl group.
While continuing work in the area of the 3-cyanopyridine-2(1H)-thiones chemistry we paid attention to
the reaction of 2-acetylcyclopentanone (1) and 2-acetylcyclohexanone (2) with cyanothioacetamide (3) [4, 5].
The products of the interaction, namely 1-methyl-3-thioxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbo-
nitrile (4) and 1-methyl-3-thioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (5) are promising for
subsequent transformations into polyheterocyclic systems. Compounds 4 and 5, apart from reaction of diketones
1, 2 with thioamide 3 (method a), were also obtained in reactions of thioamide 3 with 2-acetylcyclo-hexene
(method b) [4] or 2-acetyl-1-piperidyl-1-cycloalkenes (method c) [4]. In all three cases the formation of only
one regioisomer was postulated (Scheme 2).
Scheme 2
O
а
( )n
Me
N
1, 2
O
NCCH2C(S)NH2
Me
O
S
3
( )n
b
c
NH
Me
N
O
4, 5
( )n
Me
n = 0, 1
1, 4 n = 0; 2, 5 n = 1
310

On reproducing the experimental procedures from [4] we have established that the interaction of
thioamide 3 with diketones 1 and 2 in the presence of a base (triethylamine or morpholine), and also the
condensation of thioamide 3 with enamino ketones 6 and 7 are not regiospecific and lead to the formation of
mixtures of isomeric compounds 4+8 and 5+9, respectively (Scheme 3).
Scheme 3
Me
O
CN
N
O
3
3
( )n
( )n
1, 2
4, 5
+
EtOH
EtOH, B
Me
N
H
S
8, 9
6, 7
6, 8 n = 0; 7, 9 n = 1; B = Et3N, morpholine
The formation of mixtures of regioisomers 4+8 and 5+9 in the course of the reaction was confirmed by
1
13
1
1
data of H and C NMR spectroscopy, and also by the results of two-dimensional H–1H COSY and H–13C
1
HMBC experiments. In the H NMR spectrum of a sample obtained by the interaction of 2-acetylcyclo-
hexanone (2) and thioamide 3, apart from the signals of the methyl group protons and NH of isoquinolinethione
5 at 2.35 and 13.74 ppm respectively, minor peaks were detected for the regioisomeric quinolinethione 9 at 2.32
1
and 13.62 ppm (ratio of isomers 5:9 was ~3:1, Fig. 1, b). The H NMR spectrum of the product of the
interaction of 2-acetylcyclopentanone (1) and thioamide 3 disclosed a similar picture. From the ratio of the
integral intensities of the singlets of the methyl group protons (2.33 and 2.35 ppm) the ratio of the isomers 4 and
1
8 approached 1:1 (Fig. 1, a). More surprising was the fact that the same picture was observed in the H NMR
spectra of the reaction products of thioamide 3 with β-enamino ketones 6 and 7. In this case the formation of
mixtures of isomers may be explained by the partial hydrolysis of the latter to diketones 1 and 2 respectively
13
under the reaction conditions given in [4] (96% EtOH, room temperature, 3 h). In the C NMR spectra of the
obtained products, a doubling of the number of signals was also observed, indicating the formation of isomeric
products.
The results of 1H–1H COSY and 1H–13C HMBC experiments are given in Figs. 2 and 3 respectively for
the products of interaction of 2-acetylcyclohexanone (2) and cyanothioacetamide (3). Thus, peaks were
observed in Fig. 2 for the minor isomer 9: 2.32/2.32 (CH3) and 2.69/2.69 ppm (8-CH2), and the complex nature
of the multiplets at 1.71, 2.43, and 2.73 ppm was detected. Even more informative was the experiment on the
1
heteronuclear correlation by H–13C nuclei through 2-3 bonds (HMBC method with detection on protons) on a
sample of the mixture of compounds 5 and 9 (Fig. 3). It is evident that the singlet in the region of 2.32 ppm
belongs to the methyl group of the minor quinolinethione 9. Three cross-peaks were detected for the 4-CH3
protons, 2.32/114.4 (4-CH3/C-4), 2.32/121.67 (4-CH3/C-4a), and 2.32/156.5 (4-CH3/C-3), while for 1-CH3 of
the major isomer 5, two correlations were detected at 2.35/121.89 (1-CH3/C-8a) and 2.35/152.3 (1-CH3/C-1).
A series of experiments was carried out on a study of the interaction of thioamide 3 with
2-acetylcyclohexanone (2). It was established that neither the yield nor the ratio of isomeric products 5 and 9 in
the obtained mixture depend essentially on the reaction conditions (20oC or refluxing) and the choice of the base
catalyst (triethylamine, N-methylmorpholine or morpholine). Thus, the reaction of thioamide 3 with diketone 2
in 96% EtOH in the presence of triethylamine (20oC, 3 day) gave a mixture of thiones 5 and 9 in a ratio of ~5:2
in an overall yield of 74% (from the integral intensity ratio of the NH and CH3 protons peaks), while upon ten
minutes refluxing in EtOH, thiones 5 and 9 were formed in a ratio of ~7:2 in an overall yield of 70%. A high
resolution IR spectrum of the mixture of compounds 5 and 9 proved to be uninformative for clarifying the
formation of a mixture of regioisomers because of the complete overlap of the absorption bands. For example,
in place of the expected two closely located absorption bands for the stretching vibrations of the conjugated
nitrile groups of each of the isomers 5 and 9 one common absorption band was detected at 2218 cm-1 in the
spectrum.
311

Fig. 1. 1H NMR spectra of mixtures of regioisomeric compounds 4+8 (a) and 5+9 (b).
The mixtures of thiones 4+8 and 5+9 were alkylated with methyl iodide and α-chloroacetamide. In all
cases products uniform in TLC were formed, which according to 1H NMR spectroscopic data nevertheless were
mixtures of isomeric products 10+14, 11+15, 12+16, 13+17 (Scheme 4). All attempts to separate these mixtures
into individual components by column chromatography or crystallization proved to be unsuccessful. The
mixtures of compounds 11+15 and 13+17 on treatment with 10% KOH were cyclized according to Thorpe–
Ziegler and converted into mixtures of isomeric thieno[2,3-b]pyridines 18+20 and 19+21.
312

Scheme 4
R
Me
CN
MeI or ClCH2CONH2,
10% KOH, EtOH
CN
S
S
4 + 8
or
5 + 9
( )n
( )n
+
N
N
R
Me
14–17
10–13
H2N
O
H2N
Me
4
2
1
NH2
5
3
S3
NH2
O
6
11 + 15
or
13 + 17
2
( )n
10% KOH
+
1
S
( )n
N 4
7
N
5
6
20, 21
Me
18, 19
10, 12, 14, 16 R = H; 11, 13, 15, 17 R = CONH2;
10, 11, 14, 15, 18, 20 n = 0; 12, 13, 16, 17, 19, 21 n = 1
Fig. 2. 2D 1H–1H COSY spectrum of a mixture of isomers 5 and 9.
313

1
An interesting special feature of the H NMR spectra of substituted thieno[2,3-b]pyridines 18+20 and
19+21 was the low-field shift of the signals of the alkyl group protons located in position 4 of the pyridine ring
(8-CH2 for 18, 9-CH2 for 19, 4-CH3 for 20 and 21) relative to the set of signals of the protons of the remaining
alkyl fragments in the molecule. The protons of the methyl group of compounds 18 and 19 resonated at
2.44-2.48 ppm, while the protons of the methyl groups of isomers 20 and 21 were shifted to 2.60-2.65 ppm.
Fig. 3. 1H–13C HMBC (500125 MHz, DMSO-d6) NMR experiment for a mixture
of isomers 5 and 9.
It should be mentioned that the authors of the original work [4] were unable to observe the signals of the
1
regioisomeric products in the H NMR spectra obtained on an instrument with operating frequency of 90 MHz,
since the chemical shifts of the signals of the isomeric compounds 4, 5, 8, 9, and their derivatives 10-21 were
extremely close to overlapping. For example, a comparative analysis of the spectral data of the individual
compound 13 [4], a mixture of compounds 13+17 obtained by us, and individual compound 17, synthesized by
1
alternative methods [14, 15], showed that the divergence in chemical shifts in the H NMR spectra for the
separate groups of protons did not exceed 0.03-0.05 ppm on the whole. It was also interesting to compare the 1H
NMR spectra of a mixture of compounds 11+15, obtained on instruments with a frequency of 200 and 500 MHz. In
the first case (200 MHz) the signals of the SCH2 protons of compounds 11 and 15 form a single pseudosinglet at
3.84 ppm as a result of overlap, but in a spectrum obtained on an instrument with operating frequency 500 MHz,
two peaks were detected at 3.928 ppm (minor isomer 15) and 3.936 ppm (isomer 11). The signals of the methyl
groups protons of regioisomers in the spectrum at 500 MHz were detected as two singlets at 2.325 ppm (11) and
314

2.424 ppm (15), while in the spectrum obtained on a Varian Gemini 200, the singlet of the methyl protons of the
minor isomer 15 at δ 2.46 ppm was partially overlapped by the proton signals of undeuterated DMSO. The latter
may significantly hinder interpretation of the spectrum especially if it is considered that the chemical shifts of
the signals of the remaining protons at both 200 MHz and 500 MHz coincide completely.
s, 2.32
s, 3.91
O
N
m, 2.59
m, 1.78
CH3
N
br. s,
7.15,
7.58
m, 2.77
m,
1.74
s, 3.88
NH2
NH2
N
S
br. s,
7.12,
7.53
m,
N
S
m, 1.78
m, 2.81
1.74
s, 2.43
O
CH3
m, 2.56
17 (Ref. [14])
13
s, 2.42
s, 3.94
O
N
CH3
m, 2.84
m, 2.08
m, 2.96
br. s,
7.18,
7.60
m, 2.96
m, 2.08
m, 2.84
NH2
s, 3.93
N
S
br. s,
7.18,
7.60
NH2
N
N
S
s, 2.33
O
CH3
15
11
Fig. 4. Multiplicity and chemical shifts of signals (δ, ppm) in the 1H NMR spectra of compounds
13 and 17, 11 and 15.
In summary, based on the analysis of the correlation NMR spectra, we have shown that the interaction
of cyanothioacetamide with 2-acetylcyclopentanone, 2-acetylcyclohexanone, and their enamines (2-acetyl-
1-(morpholin-4-yl)-1-cycloalkenes) proceeds with a low regioselectivity and leads to the formation of mixtures
of 3-cyano-4-methyl-5,6-tri(tetra)methylenepyridine-2(1H)-thiones and 3-cyano-6-methyl-4,5-tri(tetra)-
methylenepyridine-2(1H)-thiones with a predominance of the latter. Alkylation of the products gave a mixture
of S-alkyl derivatives which was not separated successfully by crystallization or column chromatography.
EXPERIMENTAL
The IR spectra were recorded on a Thermo Nicolet Avatar 370 DTGS Fourier spectrophotometer in KBr
1
13
(compounds 5 and 9) and also on an IKS-29 spectrophotometer in nujol (remaining compounds). The H and C
1
1
NMR spectra, two-dimensional H–1H COSY, and H–13C HMBC spectra were recorded on a Bruker DRX-500
instrument in DMSO-d6 (at 500 and 125 MHz, respectively) and also on a Varian Gemini 200 (1H NMR, 200 MHz)
spectrometer in DMSO-d6, internal standard was TMS. Elemental analysis was carried out on a Perkin–Elmer
CHN Analyzer. Monitoring the homogeneity of substances was effected by TLC on Silufol UV-254 plates,
eluent was acetone–hexane, 1:1, development with iodine vapor, UV detector. Melting points of substances
were determined on a Kofler stage and are not corrected.
Diketones 1, 2 and enamines 6, 7 were obtained by the general procedure of Stork [16].
Cyanothioacetamide (3) was obtained by the procedure of Brunskill [17] modified in the following
manner. Malononitrile (100 g, 1.51 mol) and EtOH (100 ml) were placed in an Erlenmeyer flask of volume 0.5 l
and stirred at room temperature until dissolution of the malononitrile. Tertiary amine (Et3N or N-methyl-
315

morpholine, 1.0-1.5 ml) was added, the flask was closed with a rubber stopper with two glass tubes, one of
which must be immersed in the malononitrile solution, and a strong current of H2S was passed through. After a
short induction period, an exothermic reaction began accompanied by strong absorption of hydrogen sulfide by
the reaction mass. It is important to maintain the temperature within the range 15-20oC (cooling with ice or
snow), not permitting crystallization of malononitrile and heating the reaction mixture above room temperature.
After approximately 30-40 min cyanothioacetamide (3) began to crystallize. Subsequently the reaction mixture
must be stirred or periodically shaken to avoid clogging of the gas supply tube. To obtain a good yield, it was
necessary to pass hydrogen sulfide through the solution for not less than 6-8 h when cooling with ice-water. At
the end of the process the reaction mixture was strongly cooled (ice+NaCl), cyanothioacetamide (3) was filtered
off, washed many times with cold EtOH until a colorless filtrate was obtained, then with cold Et2O, and
petroleum ether. Cyanothioacetamide (3) was obtained (130-135 g, 86-89%), as sandy-yellow needle-like
crystals; mp 117-120oC (mp 121oC (EtOH) [17]). The product was suitable for further conversion without
additional purification. Cyanothioacetamide (3) must be stored in refrigerator at 0 to +4oC. IR spectrum, , cm-1:
3360, 3270, 3140 (NH2), 2258 (C≡N). 1H NMR spectrum, δ, ppm: 3.99 (2H, s, CH2); 9.49 (1H, br. s) and 9.84
(1H, br. s, C(S)NH2).
Interaction of cyanothioacetamide (3) with 1,3-diketones 1, 2 was carried out according to a
modified procedure [4]. A mixture of the corresponding freshly distilled diketone 1 or 2 (0.2 mol), cyano-
thioacetamide (3) (20 g, 0.2 mol), and base (morpholine, N-methylmorpholine, or triethylamine, 3 ml) in EtOH
(50-70 ml) was stirred with heating (40-50oC) for 5-7 h, and stored at room temperature for 24 h. Glacial acetic
acid (15 ml) was added to the mixture, the solid was filtered off, and washed with EtOH. Analytically pure
samples were obtained by refluxing in AcOH. Mixtures of thiones 4+8 (64%) and 5+9 (69%) were obtained.
1-Methyl-3-thioxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile (4) and 4-Methyl-2-
thioxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitrile (8) (ratio ~1:1). Yield 64%. Finely
crystalline powder of sandy color; sublimes >250oC, mp 293-296oC (mp 259-260oC (AcOH) [4]). IR spectrum,
1
, cm-1: 2220 (C≡N). H NMR spectrum, δ, ppm (J, Hz): 2.10 (4H, m, 6-CH2 4, 6-CH2 8); 2.35 and 2.33 (6H,
13
two s, 2CH3); 2.74 (4H, m, 7-CH2 4, 5-CH2 8); 2.94 (4H, m, 5-CH2 4, 7-CH2 8); 13.42 (2H, br. s, 2NH). C
NMR spectrum, δ, ppm: 19.2 and 17.5 (C-6 4 and 8); 22.1 and 24.1 (CH3 4 and 8); 28.7; 29.3; 31.8; 33.7 (C-5,7
4 and 8); 109.7; 113.8; 116.7; 117.1; 128.2; 129.1; 148.7; 153.9; 157.8; 164.5; 176.7 (C=S). Found, %: C 63.47;
H 5.29; N 14.80. C10H10N2S. Calculated, %: C 63.13; H 5.30; N 14.72.
1-Methyl-3-thioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (5) and 4-Methyl-2-thioxo-
1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (9) (ratio ~3:1). Yield 69%. Finely crystalline yellow powder,
chromatographically homogeneous (Rf = 0.50, acetone–hexane, 1:1), starting to decompose at T >280oC, mp
>300oC (mp 292-294oC [4], 328-330oC [5]). IR spectrum, , cm-1: 2218 (C≡N). 1H NMR spectrum, δ, ppm (J, Hz):
1.71 (8H, m, 6,7-(CH2)2 5 and 9); 2.32 and 2.35 (6H, two s, 2CH3); 2.43 (4H, m, 8-CH2 5 and 5-CH2 9); 2.73
13
(4H, m, 5-CH2 5 and 8-CH2 9); 13.65 (1H, br. s, NH 9); 13.78 (1H, br. s, NH 5). C NMR spectrum, δ, ppm:
17.3; 18.9; 20.8; 21.2; 21.7; 24.2; 27.6; 29.3 ((CH2)4 and CH3 of both isomers); 113.3 (C-4a 5); 114.4 (C-4 9);
116.6 (C≡N 5); 117.0 (C≡N 9); 121.7 (C-4a 9); 121.9 (C-8a 5); 151.2 (C-8a 9); 152.3 (C-1 5); 156.4 (C-4 5);
156.5 (C-3 9); 174.5 (C=S 5); 175.3 (C=S 9). Found, %: C 64.89; H 5.90; N 13.80. C11H12N2S. Calculated, %:
C 64.67; H 5.92; N 13.71.
Interaction of Cyanothioacetamide (3) with 2-Acetylcyclohexanone (2) at Room Temperature.
Diketone 2 (1.7 ml, 11.8 mmol), cyanothioacetamide (3) (1.0 g, 10 mmol), and Et3N (0.2 ml, 1.44 mmol) were
dissolved with stirring in 96% EtOH (15 ml) at 20oC. After 20-30 min, a solid product began to precipitate. The
reaction mixture was left for 3 days, AcOH (1-2 ml) was added, the solid was filtered off, and washed with
1
EtOH. A mixture of compounds 5+9 was obtained in 74% yield. According to the data of H NMR
spectroscopy, compounds 5 and 8 were formed in a ratio of ~5:2.
Interaction of Cyanothioacetamide (3) with 2-Acetylcyclohexanone (2) on Refluxing. A mixture of
diketone (2) (1.7 ml, 11.80 mmol), cyanothioacetamide (3) (1.0 g, 10 mmol), and Et3N (0.2 ml, 1.44 mmol) was
refluxed in 96% EtOH (20 ml). A yellow solid product formed rapidly throughout the volume of the reaction
316

mixture. The mixture was refluxed with stirring for a further 10 min, and left for 3 days at room temperature.
AcOH (1-2 ml) was added, the solid was filtered off, and washed with EtOH. A mixture of compounds 5+9 was
1
obtained in 70% yield. According to data of H NMR spectroscopy, the ratio of compounds 5 and 9 in the
mixture was ~7:2.
Interaction of cyanothioacetamide (3) with enaminо ketones 6, 7 was carried out according to a
modified procedure from [4]. A mixture of the corresponding enamino ketone 6, 7 (0.11 mol) and
cyanothioacetamide (3) (0.10 mol) in 96% EtOH (40 ml) was stirred at room temperature for 3 h, and left for 1
day. AcOH (10 ml) was added, the solid was filtered off, and washed with EtOH. For analytical purposes the
product was refluxed in AcOH. From enamino ketone 6 a mixture of thiones 4+8 was obtained (yield 58%, ratio
1
of isomers according to H NMR spectroscopy ~2:1); from enamino ketone 7 a mixture of thiones 5+9 was
formed (in a ratio of ~4:1) in 66% yield. More rigorous conditions (refluxing) did not increase the product yield
but shortened the reaction time to 0.5 h.
Alkylation of Compounds 4+8 and 5+9 with Methyl Iodide and α-Chloroacetamide. A mixture of
thiones 4+8 or 5+9 (5.00 mmol) in warm DMF (5-7 ml) was treated with 10% aqueous KOH (2.60 ml, 5.00 mmol).
A small excess of alkylating agent CH3I (0.35 ml, 5.50 mmol) or α-chloroacetamide (0.5 g, 5.35 mmol) was
added to the obtained solution and a solid was precipitated after several seconds. The reaction mass was stirred
for 2-3 h, diluted with an equal volume of water, the solid was filtered off, washed with water, then with cold
EtOH, and with petroleum ether. For analytical purposes, the substance was recrystallized from a suitable
solvent. Chromatographically homogeneous samples of S-alkylation products were obtained: 10+14, 11+15,
12+16, 13+17.
1-Methyl-3-methylsulfanyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (10) and 4-Me-
thyl-2-methylsulfanyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (14) (ratio ~3:2). Yield 89%.
Gray-beige finely crystalline powder; mp 125-127oC (EtOH). Rf = 0.75 (acetone–hexane, 1:1). IR spectrum, ,
1
cm-1: 2225 (C≡N). H NMR spectrum (200 MHz), δ, ppm; 2.10-2.22 (4H, m, 6-CH2 10 and 14); 2.39 (3H, s,
CH3 10); 2.48 (3H, s, CH3 14); 2.58 (3H, s, SCH3 10); 2.59 (3H, s, SCH3 14); 2.85-3.04 (8H, m, 5,7-(CH2)2 10
and 14). Found, %: C 64.42; H 6.00; N 13.85. C11H12N2S. Calculated, %: C 64.67; H 5.92; N 13.71.
2-[(4-Cyano-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)sulfanyl]acetamide (11) and 2-
[(3-Cyano-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)sulfanyl]acetamide (15) (ratio ~7:4). Yield
1
81%. Light-brown crystals; mp 165-170oC (EtOH). IR spectrum, , cm-1: 2219 (C≡N). H NMR spectrum, δ,
ppm: 2.08 (4H, m, 6-CH2 11 and 15); 2.33 (3H, s, CH3 11); 2.42 (3H, s, CH3 15); 2.84 (4H, m, 7-CH2 11 and
5-CH2 15); 2.96 (4H, m, 5-CH2 11 and 7-CH2 15); 3.93 (2H, s, SCH2 15); 3.94 (2H, s, SCH2 11); 7.18 (2H, br. s)
13
and 7.60 (2H, br. s, C(O)NH2 11 and 15). C NMR spectrum, δ, ppm: 17.9; 22.1; 22.8; 23.9; 28.8; 30.2; 32.7;
34.3; 35.1; 104.3; 115.5; 115.9; 133.0; 135.4; 147.9; 150.1; 157.6; 157.7; 159.2; 159.9; 168.5; 168.8; 169.4;
169.6. Found, %: C 58.49; H 5.35; N 17.10. C12H13N3OS. Calculated, %: C 58.28; H 5.30; N 16.99.
1-Methyl-3-methylsulfanyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (12) and 4-Methyl-2-methyl-
sulfanyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile (16) (ratio ~5:2). Yield 83%. White finely crystalline
powder; mp 89-91oC (EtOH–petroleum ether). Rf = 0.80, acetone–hexane, 1:1. IR spectrum, , cm-1: 2222
(C≡N). 1H NMR spectrum (200 MHz), δ, ppm: 1.81 (4H, m, 6,7-(CH2)2 12 and 16); 2.34 (3H, s, CH3 12); 2.44
(3H, s, CH3 16); 2.55 (10H, m, 8-CH2 12, 5-CH2 16, SCH3 12 and 16); 2.80 (4H, m, 5-CH2 12 and 8-CH2 16).
Found, %: C 66.26; H 6.36; N 13.05. C12H14N2S. Calculated, %: C 66.02; H 6.46; N 12.83.
2-[(4-Cyano-1-methyl-5,6,7,8-tetrahydroisoquinolin-3-yl)sulfanyl]acetamide (13) and 2-[(3-Cyano-
4-methyl-5,6,7,8-tetrahydroquinolin-2-yl)sulfanyl]acetamide (17) (ratio ~9:1). Yield 84%. Beige crystals;
mp 193-195oC (AcOH) (mp 205-206oC (EtOAc) [4], for isomer 17: mp 181-184oC (AcOH) [14], 175-177oC
[15]). IR spectrum, , cm-1: 2219 (C≡N). 1H NMR spectrum, δ, ppm: 1.74 (4H, m, 6,7-(CH2)2 13 and 17); 2.32
(3H, s, CH3 17); 2.43 (3H, s, CH3 13); 2.56 (4H, m, 8-CH2 13 and 5-CH2 17); 2.77 (4H, m, 5-CH2 13 and 8-CH2
13
17); 3.90 (2H, s, SCH2 17); 3.91 (2H, s, SCH2 13); 7.15 and 7.58 (4H, br. s, C(O)NH2 13 and 17). C NMR
spectrum, δ, ppm: 21.4; 22.1; 23.0; 25.2; 28.3; 33.9; 104.3; 115.4; 128.0; 150.7; 156.8; 161.1; 169.6. Found, %:
C 59.61; H 5.83; N 16.18. C13H15N3OS. Calculated, %: C 59.75; H 5.79; N 16.08.
317

Preparation of Thieno[2,3-b]pyridine Derivatives 18+20 and 19+21 from Thiones 4+8 and 5+9
according to Thorpe-Ziegler. A suspension of the corresponding mixture of thiones 4+8 or 5+9 (5.00 mmol)
in DMF (5-7 ml) was treated with 10% aqueous KOH (3.0 ml, 5.80 mmol). The obtained solution was treated
with α-chloroacetamide (0.5 g, 5.35 mmol), the mixture was refluxed with stirring for 2-3 min, and the reaction
mixture was stirred at room temperature for 0.5 h (solid products of S-alkylation 11+15 and 13+17 were
precipitated). Further 10% aqueous KOH (3.0 ml) was added to the mixture, which was refluxed for 3-4 min
(the solid desired product precipitated). The reaction mixture was stirred for 2-3 h, diluted with an equal volume
of EtOH, the product was filtered off, and washed sequentially with EtOH, with water, and once again with
EtOH. Analytically pure samples of mixtures of thienopyridine derivatives 18+20 and 19+21 were obtained.
1-Amino-5-methyl-7,8-dihydro-6H-cyclopenta[d]thieno[2,3-b]pyridine-2-carboxamide (18) and
3-Amino-4-methyl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxamide (20) (ratio ~4:5).
1
Yield 92%. Finely crystalline khaki-colored powder; mp 295-298oC (decomp.). H NMR spectrum, δ, ppm
(J, Hz): 2.14-2.05 (4H, m, 7-CH2 18 and 6-CH2 20); 2.46 (3H, s, CH3 18); 2.63 (3H, s, CH3 20); 2.86 (2H, t,
3
3
3
3J = 7.5, 6-CH2 18); 2.90 (2H, t, J = 7.5, 5-CH2 20); 2.97 (2H, t, J = 7.5, 7-CH2 20); 3.35 (2H, t, J = 7.2,
8-CH2 18); 6.67 (2H, br. s) and 6.82 (2H, br. s, NH2 18 and 20); 7.11 (4H, br. s, CONH2 18 and 20). Found, %:
C 58.40; H 5.33; N 17.10. C12H13N3OS. Calculated, %: C 58.28; H 5.30; N 16.99.
1-Amino-5-methyl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxamide (19) and 3-Amino-
4-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide (21) (ratio ~10:3). Yield 89%. Yellow
crystals; mp 230-235oC (mp 248-250oC (n-BuOH) [4]). IR spectrum, , cm-1 3400, 3320, 3160 (NH2), 1660
(C=O). 1H NMR spectrum, δ, ppm: 1.77 (8H, m, 7,8-(CH2)2 19, 6,7-(CH2)2 21); 2.44 (3H, s, CH3 19); 2.60 (3H,
s, CH3 21); 2.63 (2H, m, 6-CH2 19); 2.72 (2H, m, 5-CH2 21); 2.89 (2H, m, 8-CH2 20); 3.26 (2H, m, 9-CH2 19);
6.84, 6.89, and 7.09 (8H, three br. s, CONH2 and NH2 19 and 21). Found, %: C 60.13; H 5.81; N 16.17.
C13H15N3OS. Calculated, %: C 59.75; H 5.79; N 16.08.
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