Heterocyclization of 1,3-butadienethiolates

Article abstract of DOI:10.1007/s10593-005-0179-3

Condensation of derivatives of ethoxymethylenecyanoacetic acid with cyanothioacetamide with base catalysis gave butadienethiolates and mercaptopyridines. On interaction with alkyl halides, butadienethiolates are cyclized into alkylthiopyridines, but their reactions with phenacyl bromides give substituted thiazoles. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0179-3

Chemistry of Heterocyclic Compounds, Vol. 41, No. 4, 2005
HETEROCYCLIZATION OF 1,3-BUTADIENETHIOLATES
V. D. Dyachenko1, R. P. Tkachev1, and A. N. Chernega2
Condensation of derivatives of ethoxymethylenecyanoacetic acid with cyanothioacetamide with base
catalysis gave butadienethiolates and mercaptopyridines. On interaction with alkyl halides,
butadienethiolates are cyclized into alkylthiopyridines, but their reactions with phenacyl bromides give
substituted thiazoles.
Keywords:
1,3-butadienethiolates,
nicotinamide,
pyrido[2,3-d]pyrimidine,
derivatives
of
ethoxymethylenecyanoacetic acid, thiazole, X-ray crystallography.
We have developed a synthesis of substituted 1,3-butadienethiolates by nucleophilic vinyl substitution
(SNVin) and we have shown their use in the preparation of substituted heterocycles – pyridines and
thienopyridines [1]. The practicability of this synthetic route is based on the ability of alkyl functionalized
butadienes to undergo intramolecular cyclization with participation of the nitrile group.
In this work we have explored new synthetic possibilities for 1,3-butadienethiolates, prepared by the
interaction of derivatives of ethoxymethylenecyanoacetic acid 1a-e with cyanothioacetamide (2) in the presence
of bases. It was found that the products of the SNVin reaction (3), which could not be isolated, formed the
1,3-butadienethiolates 4a-c in the presence of N-methylmorpholine. Note that stabilization enaminocarbonyl
compounds 4a-c resulted from direct polar donor-acceptor conjugation of the functional groups [2, 3].
Increasing the basicity of the medium in this reaction facilitated intramolecular cyclization of
compounds 3 into the mercaptopyridines 5a,b. Compounds 4 reacted readily with the alkyl halides 6a-d to give
the alkylthiopyridines 7a-d (Tables 1, 2, experimental). Introduction of phenacyl bromide in this reaction gave
the thiazole 8 as a result of the Hantzsch synthesis.
Compound 8 occurs as a mixture of E- and Z-isomers according to the spectroscopic data. In the IR
spectrum there are 3 nitrile stretching bands at 2170, 2188, and 2232 cm-1. In the 1H NMR spectrum a doubling
of the signals for the protons of the ethoxycarbonyl and methyne protons was observed (Experimental). Since the
butadienethiolate 4a exists as one of the π-diastereomers [1], it may be proposed that it is possible that rotation
about the C(3)–C(4) of the butadiene occurs during the formation of the thiazole 8 to give an equal mixture of two
π-diastereomers (Scheme 1).
The pyridylthiones 5 reacted with amyl iodide to give the sulfides 9, the study of the chemical properties
of which showed they are capable of undergoing a variety of chemical transformations. In particular they were
brominated with bromine in benzene to give the derivative 10. On refluxing in acetic anhydride
2-methylpyrido[2,3-d]pyrimidine 11 was obtained, and on reaction with triethyl orthoformate (see [4])
2-unsubstituted pyrido[2,3-d]pyrimidines 12a,b were obtained.
__________________________________________________________________________________________
1
Taras Shevchenko Lugansk State Pedagogical University, Lugansk 91011, Ukraine e-mail:
dvd_lug@online.lg.ua. 2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094,
Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 589-596, April, 2005. Original article
submitted December 10, 2002.
0009-3122/05/4104-0503©2005 Springer Science+Business Media, Inc.
503

Scheme 1
EtOOC
CN
N
CN
S
Ph
BrCH2C(O)Ph
8
O
CN
S
R
Hlg
Z
O
H
+
N
Me
6a–d
CN
H2N
N
R
Z
KOH
CN
H2N
–
7a–d
S
O
4a–c
CN
O
O
C(S)NH2, B
N-methyl-
morpholine
CN
S
2
CHOEt
R
R
CN
H2N
NaOEt
CN
1a–e
3
Br
O
O
O
CN
CN
SH
CN
R
R
6d
Br2
N
H
MeO
S
H2N
N
H2N
N
5a, b
S
H2N
N
9a, b
10
Me
Me
HC(OEt)3
Ac2O
O
N
O
CN
R1
N
CN
S
N
MeO
Me
Me
N
S
Me
N
N
11
12a, b
1a R = EtO, b R = α-naphthylamino, c R = o-MeC6H4NH, d R = o-MeOC6H4NH,
e R = m-MeOC6H4NH; 4a R = EtO, b R = α-naphthylamino, c R = o-MeC6H4NH;
5, 9 a R = o-MeOC6H4NH, b R = m-MeOC6H4NH; 6 a–c Hal = Br, a Z = C(O)Ph,
b Z = CH=CH2, c Z = CH2Me; d Hal = I, Z = (CH2)3Me; 7 a,b R = EtO, a Z = C(O)Ph,
b Z = (CH2)3Me, c R = α-naphthylamino, Z = CH=CH2, d R = o-MeC6H4NH, Z = CH2Me;
12 a R1 = o-MeOC6H4, b R1 = m-MeOC6H4; B = N-methylmorpholine, NaOEt
To establish unambiguously the regioselectivity of the cyclization of olefin 3, and also by alkylation of
the thioles formed, an X-ray crystallographic investigation of 6-amino-3-cyano-5-(o-methoxyphenylcarbamoyl)-
2-pentylthiopyridine (9a) was carried out. The general shape of the molecule is shown in Fig. 1, and the basic
bond lengths and angles are shown in Table 3. Atoms N(2) and N(4) have planar trigonal arrangement of the
504

TABLE 1. Characteristics of Compounds 4b,c, 5a,b, 7a-d, and 9a,b
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, °C
C
H
N
4b
4c
5a
5b
7a
7b
7c
7d
9a
9b
C22H23N5O2S
C19H23N5O2S
C14H12N4O2S
C14H12N4O2S
C17H15N3O3S
C14H19N3O2S
C20H16N4OS
C17H18N4OS
C19H22N4O2S
C19H22N4O2S
62.34
62.69
58.98
59.20
55.51
55.98
55.69
55.98
59.99
59.81
57.63
57.31
66.57
66.64
62.69
62.55
5.65
5.50
6.12
6.01
3.89
4.03
4.25
4.03
4.29
4.43
6.74
6.53
4.39
4.48
5.55
5.56
16.88
16.62
18.09
18.17
18.42
18.66
18.91
18.66
12.27
12.31
14.89
14.32
15.47
15.55
17.23
17.17
328-330
178-180
305-307
172-174
199-201
105-107
200-202
158-160
140-142
153-155
73
82
90
68
74
85
68
70
85
81
61.49
61.60
61.45
61.60
6.11
5.99
5.88
5.99
15.34
15.12
15.02
15.12
bonds (sum of the bond angles 359.8 and 360.0°). The N(2)H2 group is practically coplanar with the ring N(1)C(1-5)
(the interfacial angle is only 3.6°), which is favorable for effective conjugation between the lone electron pair of
atom N(2) and the pyridine π-system. The conformation is also suitable for the conjugation
n(N(4))–π(C(6)=O(1)) and n(N(4))–π(C(7-12)) – the torsion angles O(1)C(6)N(4)C(7) and C(6)N(4)C(7)C(8) are 2.2 and 4.7°
respectively.
As a result of these electronic interactions the bonds N(2)–C(5) 1.338(11), N(4)–C(6) 1.360(10), and
N(4)–C(7) 1.402(11) A are considerably shorter than the standard value for a N(sp2)–C(sp2) bond of 1.45 A [5]. A
characteristic of the structure of molecule 9a is the presence of a very strong hydrogen bond (strengthened by
resonance [6]) N(2)–H(2)···O(1) (N(2)–H(2) 0.70(10), N(2)···O(1) 2.662(8), O(1)···H(2) 2.09(9) A, N(2)H(2)O(1) 133(6)°)
which closes the six-membered ring O(1)C(6)C(4)C(5)N(2)H(2). We note that the statistical average distance for N···O
in hydrogen bonds of the type N–H···O is 2.89 A [7].
Fig. 1. Overall view of compound 9a with numbering of the atoms.
505

506

507

TABLE 3. Basic Bond Lengths (Å) and Bond Angles (deg) in the Molecule 9a
Bond
d, Å
Angle
ω, deg.
S(1)–C(1)
(1)–C(15)
(1)–C(1)
N(1)–C(5)
1.763(8)
1.815(8)
1.320(8)
1.350(10)
1.338(11)
1.360(10)
1.402(11)
1.222(8)
C
(1)–S(1)–C(15)
103.0(4)
118.3(7)
130.0(8)
120.2(9)
123.0(8)
S
C(1)–N(1)–C(5)
(6)–N(4)–C(7)
O(1)–C(6)–N(4)
O(1)–C(6)–C(4)
N
C
N
(2)–C(5)
(4)–C(6)
N
N(4)–C(7)
(6)–O(1)
C
EXPERIMENTAL
Melting points were recorded on a Kofler block. IR spectra of nujol mulls were recorded with a IKS-40
1
spectrometer. H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded on a
Gemini-200 (199 MHz) spectrometer. Mass spectra were recorded with a Kratos MS-890 (70 eV) machine. The
course of reactions and the purity of products were monitored by TLC on Silufol UV-254 plates with 3:5
acetone–hexane as eluant and iodine vapor as detector.
X-ray Crystallographic Investigation of a Monocrystal of Compound 9a with linear dimensions
0.14×0.37×0.49 mm was carried out at room temperature with an Enraf-Nonius CAD-4 automatic four-circle
diffractometer (MoKα radiation, relative rate of scanning 2θ/ω = 1.2, θmax = 27°, segment of a sphere
0 ≤ h ≤ 16, 0 ≤ k ≤ 8, -29 ≤ l ≤ 29). A total of 4858 reflexions were collected, of which 4243 were symmetrically
independent (Rint = 0.018). Crystals of compound 9a are monoclinic, a = 12.962(5), b = 6.777(2),
c = 23.015(8) Å; β = 105.84(3)°; V = 1944.8(1.1) Å3; M = 370.47; Z = 4; dcalc = 1.265 g/cm3; µ = 1.78 cm-1;
F(000) = 784.56; space group P21/c. The structure was solved by direct methods and refined by least squares in
the full matric anisotropic approximation using the CRYSTALS suite of programs [8]. In the refinement 1229
reflexions with I > 3(I) (244 parameters refined, 5.0 reflexions per parameter). About half of the hydrogen
atoms were revealed in the difference syntheses of the electron density, the positions of the rest were calculated.
The hydrogen atoms on N(2) and N(4) were refined isotropically, the remaining hydrogen atoms were included in
the refinement with fixed positions and thermal parameters. Calculation of absorption in the crystal was carried
with the help azimuthal scanning [9]. The weighting scheme w = 1 / [0.01Fo2 + 12.0σ|Fo|2 + 1.0]. The final
values for the residual factors were R = 0.068 and Rw = 0.066. The residual electron densities from a Fourier
difference synthesis were 0.26 and -0.33 e/Å3. Coordinates of the non-hydrogen atoms can be obtained from the
authors.
N-Methylmorpholinium 1-Amino-2,4-dicyano-4-ethoxycarbonyl-1,3-butadiene-1-thiolate (4a) was
characterized elsewhere [1].
N-Methylmorpholinium 1-Amino-4-arylcarbamoyl-2,4-dicyano-1,3-butadiene-1-thiolates 4b,c.
N-Methylmorpholine (2.20 ml, 20 mmol) was added to a suspension of cyanothioacetamide 2 (1.00 g, 10 mmol)
in ethanol (15 ml) at 20°C and the mixture was stirred until solution occurred. Then the corresponding
ethoxymethylene derivative of cyanoacetic acid 1b,c (10 mmol) was added and stirring was continued for
10 min to give a dark solution with a precipitate. The mixture was kept for a day. The precipitate was filtered off
and washed with ethanol and hexane (Tables 1 and 2).
Nitriles of 6-Amino-5-arylcarbamoyl-2-mercaptonicotinic Acids 5a,b were obtained analogously to
salts 4 from the olefins 1d,e. Sodium ethoxide (0.68 g, 10 mmol) was used as the base (Tables 1,2).
508

Nitriles of 6-Amino-5-arylcarbamoyl(ethoxycarbonyl)-2-(Z-methylthio)nicotinic Acids 7a-d and
9a,b (General Method). A 10% aqueous solution of KOH (2.80 ml, 5 mmol) was added to a suspension of salt
4 or mercaptopyridine 5 (5 mmol) in DMF (10 ml). The corresponding alkyl halide 6 (5 mmol) was added to the
solution formed. The mixture heated spontaneously to 40-45°C and was stirred for 1 h. The precipitate which
formed was filtered off and washed ethanol and hexane (Tables 1 and 2). Mass spectrum of compound 7d, m/z
(Irel,%): 326 [M]+ (32), 220 (100), 178 (70), 107 (98).
2-(1,3-Dicyano-3-ethoxycarbonylprop-2-ene)-4-phenylthiazole (8). Phenacyl bromide (1.99 g,
10 mmol) was added to a solution of salt 4a (3.24 g, 10 mmol) in DMF (5 ml) and the mixture was stirred for
1 h. The precipitate formed was filtered off and washed with ethanol and hexane. Yield 2.55 g (79%);
1
mp 183-185°C. IR spectrum, ν, cm-1: 1684, 1698 (C=O), 2170, 2188, 2232 (C≡N). H NMR spectrum, δ, ppm
(J, Hz): 8.18 (1H, s, H(5) thiazole); 7.86 and 7.78 (1H, both d, J = 7.0, =CH–); 7.73-7.38 (5H, m, C6H5); 4.38 and
4.13 (2H, both q, J = 7.1, CH2CH3); 4.07 (1H, d, J = 7.0, CHCN); 1.40 and 1.37 (3H, both t, J = 7.1, CH3). Mass
spectrum, m/z (Irel, %): 322 [M - 1]+ (80), 276 (100), 250 (80), 134 (40), 102 (25), 82 (28), 73 (28), 44 (30).
Found, %: C 63.37; H 3.94; N 13.14. C17H13N3O2S. Calculated, %: C 63.14; H 4.05; N 12.99.
Nitrile of 6-Amino-3-(4-bromo-3-methoxyphenylcarbamoyl)-2-pentylthionicotinic Acid (10). Br2
(0.515 ml, 10 mmol) was added dropwise with stirring to a solution of pyridine 9b (3.71 g, 10 mmol) in DMF
(15 ml) and stirring was continued for 1 h. The precipitate formed was washed with ethanol and hexane.
Yield 3.99 g (89%); mp 205-207°C. IR spectrum, ν, cm-1: 1664 (C=O), 2216 (C≡N), 3178, 3326, 3384 (NH,
1
NH2). H NMR spectrum, δ, ppm (J, Hz): 10.03 (1H, s, CONH); 8.38 (1H, s, H(4)); 7.89 (2H, br. s, NH2); 7.52
(1H, s, Harom); 7.37 (1H, d, J = 8.7 , Harom); 7.21 (1H, d, J = 8.7 , Harom); 3.85 (3H, s , OCH3) , 3.20 (2H, t,
J = 7.1, SCH2); 1.68 (2H, m, SCH2CH2); 1.38 (4H, m, SCH2CH2CH2CH2); 0.90 (3H, t, J = 6.9, S(CH2)4CH3).
Found, %: C 50.93; H 4.63; N 12.31. C19H21BrN4O2S. Calculated, %: C 50.78; H 4.71; N 12.47.
6-Cyano-2-methyl-3-(3-methoyphenyl)-7-pentylthiopyrido[2,3-d]pyrimidin-4(3H)-one (11). Pyridine
(0.01 ml) was added to a solution thiol 9b (1.85 g, 5 mmol) in acetic anhydride (5 ml) and the mixture was
refluxed for 2 h. It was kept at room temperature for 1 day, the precipitate was filtered off and washed with
ethanol. Yield 1.72 g (87%); mp 260-262°C. IR spectrum, ν, cm-1: 1690 (C=O), 2230 (C≡N). 1H NMR spectrum,
δ, ppm (J, Hz): 8.59 (1H, s, H(5)); 7.44 (1H, dd, J1 = 8.1, J2 =7.6, Harom); 7.04 (1H, d, J = 8.1, Harom); 6.94 (1H, s,
Harom); 6.87 (1H, d, J = 7.6, Harom); 3.83 (3H, s, OCH3); 3.37 (2H, t, J = 7.1, SCH2); 1.78 (2H, m, SCH2CH2);
1.41 (4H, m, SCH2CH2CH2CH2); 0.93 (3H, t, J = 7.0, S(CH2)4CH3). Found, %: C 64.09; H 5.51; N 14.39. C21H
22N4O2S. Calculated, %: C 63.93; H 5.62; N 14.20.
3-Aryl-6-cyano-7-pentylthiopyrido[2,3-d]pyrimidin-4(3H)-ones (12a,b). A solution of aminopyridine
9a or 9b (1.85 g, 5 mmol) in triethyl orthoformate (1.66 ml, 10 mol) and acetic anhydride (1.42 ml, 15 mmol)
was refluxed for 1 h., then kept at room temperature for 1 day. The precipitate was filtered off and washed with
ethanol.
Compound 12a. Yield 1.37 g (72%); mp 104-106°C. IR spectrum, ν, cm-1: 1691 (C=O), 2232 (C≡N).
1H NMR spectrum, δ, ppm (J, Hz): 8.77 (1H, s, H(2)); 8.41 (1H, s, H(5)); 7.55 (1H, dd, J = 7.3,, Harom); 7.43 (1H,
d, J = 7.8, Harom,); 7.25 (1H, d, J = 7.6, Harom),7.14 (1H, dd. J1 = 7.6, J2 = 7.8, Harom) , 3.84 (3H, s, OCH3); 3.41
(2H, t, J = 7.1, SCH2); 1.81 (2H, m, SCH2CH2); 1.46 (4H, m, SCH2CH2CH2CH2); 0.96 (3H, t, J = 7.0,
S(CH2)4CH3). Found, %: C 62.91; H 5.21; N 14.92. C20H20N4O2S. Calculated,%:C 63.14; H 5.30; N 14.73.
Compound 12b. Yield 1.58 g (83%); mp 116-118°. IR spectrum, ν, cm-1: 1702 (C=O), 2230 (C≡N).
1H NMR spectrum, δ, ppm (J, Hz): 8.73 (1H, s, H(2)); 8.53 (1H, s, H(5)); 7.45 (1H, dd, J = 7.7, Harom); 7.45 (1H,
d, J = 7.7, Harom); 7.08-7.02 (3H, m, Harom); 3.85 (3H, s, OCH3); 3.38 (2H, t, J = 7.2, SCH2); 1.79 (2H, m,
SCH2CH2); 1.44 (4H, m, SCH2CH2CH2CH2); 0.94 (3H, t, J = 7.1, S(CH2)4CH3). Found, %: C 63.28; H 5.15;
N 14.51. C20H20N4O2S. Calculated,%: C 63.14; H 5.30; N 14.73.
509

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