Synthesis of N-methylmorpholinium 1-amino-2,4-dicyano-4-phenylcarbamoyl(ethoxycarbonyl)-1,3-butadiene-1-thiolates and their transformation into pyridine-2-thiol derivatives

Article abstract of DOI:10.1023/A:1019675425526

Condensation of ethyl 2-cyano-3-ethoxypropenoate and 2-cyano-3-ethoxy-N-phenylpropenamide with cyanothioacetamide and N-methylmorpholine gave N-methylmorpholinium 1-amino-2,4-dicyano-4-phenylcarbamoyl(ethoxycarbonyl)-1,3-butadiene-1-thiolates which were converted into pyridine-2-thiol derivatives: N-methylmorpholinium pyridine-2-thiolate, 2-alkylthiopyridines, and thieno[2,3-b]pyridine.

Full text of DOI:10.1023/A:1019675425526

Russian Journal of Organic Chemistry, Vol. 38, No. 5, 2002, pp. 731 734. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 5, 2002,
pp. 768 771.
Original Russian Text Copyright
2002 by Dyachenko, Tkachev.
Synthesis of N-Methylmorpholinium
1-Amino-2,4-dicyano-4-phenylcarbamoyl(ethoxycarbonyl)-
1,3-butadiene-1-thiolates and Their Transformation
into Pyridine-2-thiol Derivatives
V. D. Dyachenko and R. P. Tkachev
Taras Shevchenko Lugansk State Pedagogical University, ul. Oboronnaya 2, Lugansk, 91011 Ukraine
fax: (0642)530008; e-mail: dvd_lug@online.lg.ua
Received March 7, 2001
Abstract Condensation of ethyl 2-cyano-3-ethoxypropenoate and 2-cyano-3-ethoxy-N-phenylpropenamide
with cyanothioacetamide and N-methylmorpholine gave N-methylmorpholinium 1-amino-2,4-dicyano-4-
phenylcarbamoyl(ethoxycarbonyl)-1,3-butadiene-1-thiolates which were converted into pyridine-2-thiol
derivatives: N-methylmorpholinium pyridine-2-thiolate, 2-alkylthiopyridines, and thieno[2,3-b]pyridine.
Synthesis of new nicotinic acid derivatives attracts
interest primarily from the viewpoint of searching for
biologically active compounds. In particular, nicotinic
acid amides are effective in the treatment of Alz-
heimer’s disease [1], and some its esters exhibit
herbicide properties [2]. While developing new ap-
proaches to pyridine derivatives possessing amide and
ester functionalities [3], we have studied reactions of
2-cyano-3-ethoxypropenoic acid ester and amide Ia
and Ib with cyanothioacetamide (II) and N-methyl-
morpholine. These reactions resulted in formation of
N-methylmorpholinium 1-amino-2,4-dicyano-4-
phenylcarbamoyl(ethoxycarbonyl)-1,3-butadiene-1-
thiolates III which were converted into pyridine
derivatives V via alkylation with halogen derivatives
(pathway a in Scheme 1). This reaction is interesting
due to the fact that cyclization of salts III yields just
5-phenylcarbamoyl(ethoxycarbonyl)-6-aminopyridines
V rather than 5-cyano-6-oxopyridines. It is known that
ethyl 3-aryl-2-cyanopropenoates react with cyanothio-
acetamide to give 4-aryl-3,5-dicyano-6-hydroxypyri-
dine-2(1H)-thione [4]; ethyl cyano(cyclohexylidene)-
acetate and cyanothioacetamide give rise to 6-oxo-
3,5-dicyano-1,4,5,6-tetrahydropyridine-4-spirocyclo-
hexane-2-thiolate [5]; and condensation of formalde-
hyde, ethyl cyanoacetate, and cyanothioacetamide
leads to formation of 6-oxo-3,5-dicyano-1,4,5,6-tetra-
hydropyridine-2-thiolate [6]. In these cases the cyano
group was not involved in the cyclization to pyridine
ring. By contrast, salts III undergo cyclization with
participation of the cyano group. Presumably, com-
pounds I and II react following the nucleophilic vinyl
substitution mechanism (SNVin) [7] according to
which the initial configuration is often retained [8].
This means that alkene I exists as E-isomer which
endows salt III with a configuration favorable for
cyclization to aminopyridines V. By heating of salt
IIIa in ethanol we obtained pyridinethiolate VI, and
alkylation of the latter with halogen derivatives IV
gave 2-pyridyl sulfides V (pathway b in Scheme 1).
The structure of compounds V and VI was proved
by spectral data (Tables 1, 2) and chemical trans-
formations. Treatment of Va with alkali gave substi-
tuted thienopyridine VII, and diazotization of amino-
pyridine Vb afforded the corresponding hydroxy
derivative VIII.
EXPERIMENTAL
The IR spectra were recorded on an IKS-29 spec-
1
trometer in mineral oil. The H NMR spectra were
obtained on Bruker DR-500 (500.13 MHz; com-
pounds Va, Vb, Vd, Ve, and VII), Gemini-200
(199.975 MHz; compounds IIIa, Vc, Vf, Vg, Vk, VI,
and VIII), and Bruker WP-100SY spectrometers
(100 MHz; compounds IIIb, Vh, Vi, and Vj) in
DMSO-d6 using TMS as internal reference. The mass
spectra (70 eV) were run on a Kratos MS-890 mass
spectrometer. The melting points were determined
on a Koeffler device. The progress of reactions was
1070-4280/02/3805-0731$27.00 2002 MAIK Nauka/Interperiodica

732
DYACHENKO, TKACHEV
Scheme 1.
B = N-methylmorpholine; I, III, R = PhNH (a); EtO (b); IV, Hlg = Br, Z = CH CH2 (a), Et (b); Hlg = I, Z = H (c); Hlg = Cl,
Z = CONH2 (d); Hlg = Br, Z = 4-MeC6H4CO (e), 4-BrC6H4CO (f), Pr (g); V, R = PhNH, Z = 4-MeC6H4CO (a), Et (b), CH CH2
(c), H (d), CONH2 (e); R = EtO, Z = 4-BrC6H4CO (f), CH CH2 (g), Et (h), H (i), Pr (j), 4-MeC6H4CO (k).
monitored, and the pyrity of products was checked,
by TLC on Silufol UV-254 plates using acetone
hexane as eluent; development with iodine vapor.
N-Methylmorpholinium 1-amino-2,4-dicyano-
4-phenylcarbamoyl-1,3-butadiene-1-thiolate (IIIa).
N-Methylmorpholine, 2.2 ml (20 mmol), was added
at 20 C to a suspension of 1 g (10 mmol) of cyano-
thioacetamide (II) in 15 ml of ethanol. The mixture
was stirred for 5 min, and it became homogeneous.
Compound Ia, 2.16 g (10 mmol), was added, and the
mixture was stirred for 10 min. It turned dark, and
a solid precipitated. The mixture was left to stand for
24 h, and compound IIIa was filtered off and washed
with ethanol and acetone. Yield 2.6 g (71%), mp 122
1
124 C. IR spectrum, , cm : 3245, 3378, 3494
(NH2); 2190, 2205 (C N); 1678 (CONH); 1647
( NH2). 1H NMR spectrum, , ppm: 2.77 s (3H,
CH3), 3.22 m (4H, CH2NCH2), 3.70 m (4H,
CH2OCH2), 6.99 7.71 m (5H, Harom), 9.13 s (1H,
CH ), 8.33 br.s and 9.62 br.s (2H, NH2), 10.34 s
Table 1. Yields, melting points, and elemental analyses of substituted pyridines Va Vk
Found, %
Calculated, %
H
Comp.
no.
Yield,a
%
mp, C (solvent)
Formula
C
H
N
C
N
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
81 (76)
73 (65)
68 (59)
72 (63)
81 (67)
70
235 237 (EtOH)
170 172 (EtOH)
180 181 (EtOH)
210 212 (AcOH)
225 227 (EtOH)
224 226 (AcOH)
120 123 (AcOH)
120 122 (EtOH)
149 151 (AcOH)
180 182 (EtOH)
195 196 (AcOH)
65.39
61.63
62.15
58.88
54.87
48.30
54.82
54.29
50.54
56.11
60.70
4.42
4.98
4.40
4.11
3.79
3.14
5.09
5.59
4.39
5.84
5.01
14.07 C22H18N4O2S
18.12 C16H16N4OS
17.86 C16H14N4OS
19.86 C14H12N4OS
21.58 C15H13N5O2S
65.65
61.52
61.92
59.14
55.04
4.51
5.16
4.55
4.25
4.00
3.36
4.98
5.70
4.67
6.13
4.82
13.92
17.93
18.05
19.70
21.39
9.99
15.96
15.84
17.71
15.04
11.82
10.15 C17H14BrN3O3S 48.58
82
76
70
65
15.77 C12H13N3O2S
16.03 C12H15N3O2S
17.93 C10H11N3O2S
14.93 C13H17N3O2S
12.11 C18H17N3O3S
54.74
54.32
50.62
55.89
60.83
Vj
Vk
79
a
According to method b; the yields obtained by method a are given in parentheses.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 5 2002

SYNTHESIS OF N-METHYLMORPHOLINIUM 1-AMINO-2,4-DICYANO-.. .
Table 2. IR and 1H NMR spectra of compounds Va Vk
733
1
IR spectrum, , cm
1H NMR spectrum, , ppm
Comp.
no.
C N,
C O
4-H,
s
NH2,
br.s
CONH, s,
or OCH2, q
Ph or
CH3CH2, t
NH2
3300
NH2
1645
SCH2
Z
Va
Vb
Vc
2200,
1698
8.42
8.40
8.42
7.89
8.03
8.00
10.11
7.12 t (1H),
7.35 t (2H),
7.69 d (2H)
7.11 t (1H),
7.34 t (2H),
7.69 d (2H)
7.04 t (1H),
7.28 t (2H),
7.66 d (2H)
4.95 s 2.41 s (3H, CH3),
7.38 d (2H, Harom),
7.99 d (2H, Harom
)
2295
3360
1662
1655
2210,
1683
10.09
9.98
3.25 t 1.01 t (3H, CH3),
1.70 m (2H, CH2)
3303,
3368,
3484
2204,
1700
3.90 d 5.12 d (1H, CH2,
3Jcis = 9.5 Hz),
5.38 d (1H, CH2,
3Jtrans = 17.2 Hz),
5.96 m (1H, CH )
2.56 s
Vd
Ve
3315,
3360,
3472
3305,
3364,
3500
3310,
3444
3300,
3413
1650
1650
2203,
1674
8.41
8.43
8.08
8.02
7.95
10.10
10.11
7.11 t (1H),
7.32 t (2H),
7.68 d (2H)
7.12 t (1H),
7.35 t (2H),
7.69 d (2H)
1.36
2210,
1702
3.89 s 7.49 br.s and 7.18 br.s
(2H, NH2)
Vf
1620
1622
2207,
1690
2219,
1695
8.17
8.15
4.26
4.28
4.84 s 7.67 d (2H, Harom),
8.00 d (2H, Harom
)
Vg
7.98
br.d
1.35
3.88 d 5.12 d (1H, CH2,
3Jcis = 9.9 Hz),
5.37 d (1H, CH2,
3Jtrans = 16.0 Hz),
5.90 m (1H, CH )
3.21 t 0.99 t (3H, CH3),
1.68 m (2H, CH2)
Vh
Vi
3300,
3420,
3540
3248,
3355,
3450
3342,
3496
1608
1650
1645
1618
2215,
1710
8.22
8.22
8.23
8.18
8.02
br.d
4.26
4.25
4.26
4.28
1.30
1.31
1.30
1.35
2200,
1692
8.10
br.d
2.57 s
Vj
Vk
2214,
1683
8.12
br.d
3.42 t 0.90 t (3H, CH3),
1.22 1.75 m [4H,
(CH2)2]
4.87 s 2.44 s (3H, CH3),
7.35 d and 7.95 d
3302,
3426
2209,
1690
7.95
br.d
(4H, Harom
)
(1H, NH). Mass spectrum, m/z (Irel, %): 270 (13),
210 (36), 176 (100), 149 (48), 132 (35), 101 (30), 93
(35), 43 (58). Found, %: C 58.03; H 5.54; N 18.92.
C18H21N5O2S. Calculated, %: C 58.20; H 5.70;
N 18.85.
N-Methylmorpholinium 1-amino-2,4-dicyano-
4-ethoxycarbonyl-1,3-butadiene-1-thiolate (IIIb)
was synthesized as described above for salt IIIa using
ester Ib as initial compound. Yield 2.2 g (68%),
mp 113 117 C. IR spectrum, , cm : 3212, 3420
1
(NH2); 2174, 2191 (C N); 1678 (C O); 1653
( NH2). 1H NMR spectrum, , ppm: 1.19 t (3H, CH3),
2.81 s (3H, NCH3), 3.20 m (4H, CH2NCH2), 3.78 m
(4H, CH2OCH2), 4.08 q (2H, CH2), 7.52 br.s and
8.30 br.s (2H, NH2), 8.66 s (1H, CH ). Mass spec-
trum, m/z (Irel, %): 223 (36), 196 (82), 150 (100), 123
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 5 2002

734
DYACHENKO, TKACHEV
(18), 101 (14), 43 (19). Found, %: C 52.02; H 6.13;
N 17.18. C14H20N4O3S. Calculated, %: C 51.84;
H 6.21; N 17.27.
CH), 10.33 br.s (1H, CONH). Found, %: C 65.42;
H 4.33; N 14.13. C22H18N4O2S. Calculated, %:
C 65.65; H 4.51; N 13.92.
2-Amino-5-cyano-6-(Z-methylthio)nicotinic acid
anilides and esters Va Vk. a. Alkyl halide IV,
5 mmol, was added to a solution of 5 mmol of salt
IIIa or IIIb in 8 ml of DMF. The mixture sponta-
neously warmed up to 40 45 C and was stirred for
1 h. The precipitate was filtered off and washed with
ethanol and hexane. The yields, melting points, and
spectral parameters of products Va Vk are given in
Tables 1 and 2.
b. Alkyl halide IV, 10 mmol, was added to a solu-
tion of 3.71 g (10 mmol) of salt VI in 12 ml of
DMF, and the mixture was stirred for 1 h. The precip-
itate was filtered off and washed with ethanol and
hexane. Products Va Ve thus obtained were identical
(in melting points and TLC data) to those prepared
as described in a.
5-Cyano-6-hydroxy-N-phenyl-6-propylthionico-
tinamide (VIII). A solution of 0.07 g (0.96 mmol) of
NaNO2 in 1 ml of concentrated sulfuric acid was
added dropwise with stirring to a suspension of 0.2 g
(0.64 mmol) of compound Vb in 5 ml of glacial acetic
acid. The mixture was adjusted to pH 7 by adding
a saturated aqueous solution of sodium acetate, and
the precipitate was filtered off and washed with water,
ethanol, and hexane. Yield 0.15 g (75%), mp 218
1
220 C (from AcOH). IR spectrum, , cm : 3395
1
(OH), 2228 (C N), 1684 (CONH). H NMR spec-
trum, , ppm: 1.02 t (3H, CH3), 1.70 m (2H, CH2),
3.29 t (2H, SCH2), 7.06 7.63 m (5H, Harom), 8.46 s
(1H, CH), 11.03 br.s (1H, NHCO); no OH signal was
observed, presumably due to fast exchange with water
present in the solvent. Found, %: C 61.45; H 5.03;
N 14.12. C16H15N3O2S. Calculated, %: C 61.32;
H 4.82; N 13.41.
6-Allylthio-2-amino-5-cyano-N-phenylnicotin-
amide (Vc). Mass spectrum, m/z (Irel, %): 310 [M]+
(81), 295 (27), 218 (96), 177 (22), 93 (60), 65 (24),
41 (100).
REFERENCES
Ethyl 2-amino-5-cyano-6-(4-methylbenzoyl-
methylthio)nicotinate (Vk). Mass spectrum, m/z
(Irel, %): 355 [M]+ (23), 119 (100), 91 (28), 65 (9).
1. US Patent no. 5869480, 1999; Ref. Zh., Khim., 1999,
no. 23O85P.
2. US Patent no. 5877120, 1999; Ref. Zh., Khim.,
2000, no. 01 19O409P; Russian Patent Appl.
no. 96119263/04, 1998; Ref. Zh., Khim., 1999,
no. 20O345P.
N-Methylmorpholinium 6-amino-3-cyano-5-
phenylcarbamoylpyridine-2-thiolate (VI). A solu-
tion of 3.71 g (10 mmol) of salt IIIa in 20 ml of
ethanol was heated to the boiling point and was left
to stand for 24 h at room temperature. The precipitate
of salt VI was filtered off and washed with acetone.
Yield 2.5 g (67%), mp 130 132 C. IR spectrum, ,
3. Dyachenko, V.D., Krivokolysko, S.G., and Litvi-
nov, V.P., Russ. J. Org. Chem., 1998, vol. 34, no. 6,
pp. 876 881; Dyachenko, V.D., Krivokolysko, S.G.,
and Litvinov, V.P., Khim. Geterotsikl. Soedin., 1997,
no. 4, pp. 560 568; Dyachenko, V.D., Shara-
nin, Yu.A., and Krivokolysko, S.G., Russ. J. Org.
Chem., 1995, vol. 31, no. 1, pp. 136 137.
1
cm : 3180, 3303, 3397 (NH2); 2190 (C N); 1681
1
(CONH); 1647 ( NH2). H NMR spectrum, , ppm:
2.82 s (3H, CH3), 3.21 m (4H, CH2NCH2), 3.74 m
(4H, CH2OCH2), 7.02 7.55 m (5H, Harom), 8.17 br.s
(2H, NH2), 9.02 s (1H, CH), 10.18 br.s (1H, CONH).
Found, %: C 57.98; H 5.63; N 19.04. C18H21N5O2S.
Calculated, %: C 58.20; H 5.70; N 18.85.
4. Sharanin, Yu.A., Shestopalov, A.M., Mortikov, V.Yu.,
Melenchuk, S.N., Promonenkov, V.K., Zolota-
rev, B.M., and Litvinov, V.P., Izv. Akad. Nauk SSSR,
Ser. Khim., 1986, no. 1, pp. 153 159.
3,6-Diamino-2-(4-methylbenzoyl)thieno[2,3-b]-
pyridine-5-carboxanilide (VII). To a solution of 2 g
(5 mmol) of compound Va in 8 ml of DMF we added
2.8 ml (5 mmol) of 10% aqueous KOH, and the mix-
ture was stirred for 1 h. It was then diluted with 10 ml
of water, and the precipitate was filtered off and
washed with water, ethanol, and hexane. Yield 1.75 g
(87%), mp 260 262 C (from AcOH). IR spectrum, ,
5. Dyachenko, V.D., Mitroshin, A.E., and Litvinov, V.P.,
Khim. Geterotsikl. Soedin., 1996, no. 9, pp. 1235
1242.
6. Krivokolysko, S.G., Dyachenko, V.D., and Litvi-
nov, V.P., Khim. Geterotsikl. Soedin., 1998, no. 10,
pp. 1381 1383.
7. Gonter, C.E. and Petty, J.J., Anal. Chem., 1963,
1
vol. 35, no. 6, pp. 663 665.
cm : 3295, 3414 (NH2); 1720 (C O); 1700 (CONH);
1
1633 ( NH2). H NMR spectrum, , ppm: 2.89 s (3H,
8. Rappoport, Z., Acc. Chem. Res., 1992, vol. 25,
pp. 474 479; Shainyan, B.A., Izv. Sib. Otd. Akad.
Nauk SSSR, 1990, no. 4, pp. 137 144.
CH3), 7.11 7.42 m (7H, Harom, 3-NH2), 7.65 d and
7.73 d (4H, Harom), 8.28 br.s (2H, 6-NH2), 8.79 s (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 5 2002