Reaction of diketene with cyanothioacetamide: A convenient and regioselective method for the preparation of new 4(1H)-pyridone derivatives

Article abstract of DOI:10.1007/s10593-007-0094-x

The reaction of diketene with cyanothioacetamide in dry dioxane in the presence of triethylamine gives triethylammonium 3-cyano-6-methyl-4-oxo-1,4- dihydro-2-pyridinethiolate. The regioselective S-alkylation of this thiolate is a convenient method for the preparation of substituted 4(1H)-pyridones and also derivatives of thiazolo[3,2-a]pyridine and thieno[2,3-b]pyridine. The action of 2-amino-1,1,3-tricyanopropene on this thiolate leads to its transformation into a new heterocyclic system, namely, 5H-pyrido[2′,3′:4,5]thiopyrano[2, 3-b]pyridine; treatment with iodine yields the oxidation product, namely, the corresponding bis(2-pyridyl) disulfide. The structure of isopropyl (3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thioacetate was confirmed by X-ray diffraction structural analysis.

Full text of DOI:10.1007/s10593-007-0094-x

Chemistry of Heterocyclic Compounds, Vol. 43, No. 5, 2007
REACTION OF DIKETENE WITH CYANOTHIOACETAMIDE:
A CONVENIENT AND REGIOSELECTIVE METHOD FOR THE
PREPARATION OF NEW 4(1H)-PYRIDONE DERIVATIVES
V. V. Dotsenko1, S. G. Krivokolysko1, B. P. Litvinov2†, and A. N. Chernega2
The reaction of diketene with cyanothioacetamide in dry dioxane in the presence of triethylamine gives
triethylammonium
3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinethiolate.
The
regioselective
S-alkylation of this thiolate is a convenient method for the preparation of substituted 4(1H)-pyridones
and also derivatives of thiazolo[3,2-a]pyridine and thieno[2,3-b]pyridine. The action of
2-amino-1,1,3-tricyanopropene on this thiolate leads to its transformation into a new heterocyclic
system, namely, 5H-pyrido[2',3':4,5]thiopyrano[2,3-b]pyridine; treatment with iodine yields the
oxidation product, namely, the corresponding bis(2-pyridyl) disulfide. The structure of isopropyl
(3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thioacetate was confirmed by X-ray diffraction
structural analysis.
Keywords: diketene, 4(1H)-pyridones, 5H-pyrido[2',3':4,5]thiopyrano[2,3-b]pyridines, thiazolo-
[3,2-a]pyridines, thieno[2,3-b]pyridines, cyanothioacetamide, S-alkylation, X-ray diffraction structural
analysis, Thorpe-Ziegler cyclization, cyclocondensation.
As a consequence of its extremely high chemical activity, diketene 1 has found use as efficient reagent in
heterocyclic chemistry [1, 2]. In recent years, diketene has been employed to obtain derivatives of such
heterocyclic systems as cyclopropanespiro-β-lactones [3], benzofurans [4], pyrazolidines [5],
pyrido[2,3-d]pyrimidines [6], and condensed isoquinoline analogs [7]. We found special interest in the reaction
of diketene with active methylene reagents such as Meldrum’s acid [8, 9], malononitrile and ethyl cyanoacetate
[10], ethyl acetoacetate [11], diethyl 3-ketoglutarate [12], diethyl malonate [13], and 2-nitromethylimidazole
derivatives [14] since C-acetoacetylation in these cases is usually accompanied by further cyclization of the
initially formed linear intermediates [1]. Hence, such reactions may be seen as an easy preparative and
convenient general method for obtaining various functionally-substituted derivatives of pyran and pyridine.
In the past few years, we have been interested in the chemistry of cyanothioacetamide 2. Since this
reagent was first described by Howard et al. in the mid-1950's, it has attracted attention as an readily available
and convenient reagent and has found use in heterocyclic synthesis [17-20].
_______
†Deceased.
__________________________________________________________________________________________
1"ChemEx" Laboratory, Vladimir Dal East-Ukrainian National University, 91034 Lugansk, Ukraine;
e-mail: ksg@lep.lg.ua. 2N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
2
117913 Moscow, Russia; e-mail: vpl@mail.ioc.ac.ru. Institute of Organic Chemistry, National Academy of
Sciences of Ukraine, 02094 Kiev, Ukraine; e-mail: xray@bpci.kiev.ua. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 5, pp. 716-725, May, 2007. Original article submitted April 3, 2006.
0009-3122/07/4305-0599©2007 Springer Science+Business Media, Inc.
599

Cyanothioacetamide 2 has three nucleophilic sites, which may potentially undergo initial attack by the
diketene molecule: the methylene group carbon and the thioamide group nitrogen and sulfur atoms. On the
whole, under cyclocondensation or cycloaddition conditions, thioamide 2 acts as a C,N-, C,S-, or
S,N-binucleophile [17-20]. In the course of our study of the synthetic scope of cyanothioacetamide 2, we
investigated its reaction with diketene as well as the structure and transformations of the reaction products.
Scheme 1
O
O
CN
S
Et3N, dioxane
0–10 oC
O
CN
S
+
Me
..
H2N
H2N
O
1
2
+
Et3NH
4
O
O
CN
CN
S
+
HO
Me
Et3NH
– H2O
N
H
S
N
H
Me
+
Et3NH
3
5
Diketene was found to react very vigorously with thioamide 2 (in 1:1 mol ratio) in the presence of excess
triethylamine in dry dioxane with cooling to give triethylammonium 3-cyano-6-methyl-4-oxo-
1,4-dihydro-2-pyridinethiolate (3) in 46% yield. We assume that the low yield of thiolate 3 is a result of an
unavoidable side-reaction promoted by Et3N, namely, the decomposition of diketene by water eliminated during
the course of the reaction. Thus, about half of the total amount of diketene is lost as acetone and CO2 due to the
decomposition of the unstable hydrolysis product, namely, acetoacetic acid. The yield of the desired thiolate 3
can be increased to 80% by carrying out the reaction of diketene and thioamide 2 in 2:1 mol ratio. The formation
of thiolate 3 may be explained by the mechanism shown in Scheme 1. In the first step of the cascade reaction, the
attack of the diketene molecule apparently occurs highly selectively at the methylene group carbon atom as in
previous cases [1, 8-14] to give exclusively the product of C-acetoacetylation 4. Adduct 4 immediately cyclizes
to give intermediate 5, which, in turn, loses a water molecule and converts to the final thiolate 3. We should
stress that thiolate 3 is the only isolated reaction product. In light of the high yield of this reaction, it may be
considered highly regioselective.
Since it possesses both electrophilic and nucleophilic fragments, thiolate 3 holds high promise for use in
various transformations. In this regard, we studied the properties of 3 (Scheme 2). Firstly, the acidification of
thiolate 3 with dilute hydrochloric acid gave 2-mercapto-6-methyl-4-oxo-1,4-dihydro-3-pyridinecarbonitrile (6)
in virtually quantitative yield. Treatment of thiolate 3 with alkyl halides 7 under mild conditions provided
products of the regioselective S-alkylation, namely, sulfides 8 (method A). Also, sulfides 8 are formed with
somewhat higher yields starting from mercaptopyridine and halides 7 in the presence of aqueous KOH
(method B). The action of a strong base (KOH) on 8f, 8g gave a Thorpe-Ziegler cyclization and formation of
thieno[2,3-b]pyridine derivatives 9a,b in good yields. We should note that 2-{[2-(4-bromophenyl)-
2-oxoethyl]thio}-6-methyl-4-oxo-1,4-dihydro-3-pyridinecarbonitrile (8g) is spontaneously and completely
converted in the molten state into isomeric thienopyridine 9b in the absence of solvent or any catalyst. To our
knowledge, this is the first example of such a noncatalyzed synthesis of thienopyridines under Thorpe-Ziegler
reaction conditions [21]. A Hansch reaction-type cyclocondensation occurs during the reaction of
600

2-(allylthio)-6-methyl-4-oxo-1,4-dihydro-3-pyridinecarbonitrile (8b) with molecular iodine to give
thiazolo[3,2-a]pyridine derivative 10. Then, mild oxidation of thiolate 3 by iodine yields bis(3-cyano-6-methyl-
4-oxo-1,4-dihydro-2-pyridyl) disulfide (11) in 93% yield. In previous work [20, 22], we were the first to report
the unusual cascade reaction of partially hydrogenated 3-cyano-2-pyridinethiolates with malononitrile dimer
(2-amino-1,1,2-tricyanopropene (12)) leading to derivatives of 5H-pyrido[2',3':4,5]thiopyrano-[2,3-b]pyridine,
whose structures were determined by X-ray diffraction structural analysis. We have discovered that thiolate 3
reacts similarly under analogous conditions with dimer 12 to give tricyclic product 13 in 41% yield.
1
All the products were characterized by H NMR and IR spectroscopy as well as elemental analysis
(Table 1). These results indicate that all the products obtained exist exclusively in the 4(1H)-pyridone tautomeric
form and not in the 4-hydroxypyridine form both in the solid state and in solution in DMSO-d6.
Scheme 2
O
N
O
O
NH2
7
CN
CN
S
6
iv
v
8
R
5
S
Me
Me
N
H
Me
N
H
R
1
S
4
2
I
3
9 a,b
8 a-g
10
RCH2Hal (7a-g)
ii
A
iii
B
O
O
O
CN
CN
SH
CN
S
i
vi
Me
N
H
S
Me
N
H
Me
N
H
+
2
Et3NH
3
6
11
CN
CN
NC
vii
NH2
12
NH2
2
CN
1
O
N
3
9
8
10
7
4
NH2
5
Me
N
H
S
6
NH
13
i HCl, EtOH–H2O; ii EtOH–H2O, ∆; iii RCH2Hal (7a-g), 10% KOH, EtOH;
iv 10% KOH, EtOH, ∆, or melting (for 8g); v I2, EtOH–dioxane, ∆;
vi I2, EtOH–H2O, ∆; vii EtOH, boiling;
7,8 a R = H, Hal = I; b R = CH=CH2, Hal = Br; c R = COOEt, Hal = Cl; d R = COOPr-i,
Hal = Cl; e R = 3,4-Me2C6H3NHC(O), Hal = Cl; f R = 4-MeC6H4NHC(O), Hal = Cl;
g R = 4-BrC6H4C(O), Hal = Br; 9 a R = 4-MeC6H4NHC(O), b R= 4-BrC6H4C(O)
601

TABLE 1. Elemental Analysis Data of Products Obtained
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
Yield, %
(Method)
М
mp, °С
C
N
204-206 (dec.)
3
C7H6N2OS
C7H6N2OS
C8H8N2OS
267.40
166.20
180.23
57.39
58.39
49.89
50.59
52.65
53.31
8.00
7.92
3.70
3.64
4.51
4.47
15.55
15.71
16.66
16.85
15.39
15.54
80
94
6
8a
236-238
(EtOH)
170-171
40 (A)
55.5 (B)
45 (A)
58 (B)
59 (B)
8b
C10H10N2OS
206.27
57.50
58.23
4.95
4.89
13.39
13.58
8c
8d
8e
C11H12N2O3S
C12H14N2O3S
C17H17N3O2S
252.29
266.32
327.41
51.51
52.37
53.22
54.12
62.88
62.37
4.86
4.79
5.39
5.30
5.28
5.23
10.93
11.10
10.42
10.52
12.70
12.83
160-161
171-173
230-232
64 (B)
56 (A)
62 (B)
73 (B)
8f
C16H15N3O2S
313.38
62.00
61.32
49.94
49.60
61.86
61.32
49.78
49.60
36.64
36.16
51.09
50.90
51.67
52.34
4.87
4.82
3.10
3.05
4.79
4.82
3.07
3.05
2.73
2.73
3.10
3.05
3.41
3.38
13.40
13.41
7.60
7.71
13.37
13.41
7.66
7.71
8.48
8.43
16.80
16.96
27.75
28.17
227-230 (dec.)
206-208
8g
9a
9b
10
11
13
C15H11BrN2O2S 363.24
C16H15N3O2S 313.38
C15H11BrN2O2S 363.24
76 (B)
70
292-294 (dec.)
69
C10H9IN2OS
C14H10N4O2S2
C13H10N6OS
332.16
330.39
298.33
204-206 (dec.)
>350
74.5
93
41
Thus, the 1H NMR spectra of 3, 6, 8, 9, and 11 shows signals for the NH proton as very broad, partially
exchanging singlets at δ 12.90-11.12 ppm. Furthermore, the signals for C(5)H appear as narrow singlets at
δ 6.58-5.53 ppm, indicating the nonaromatic nature of these protons. The IR spectra of the products show bands
at 3240-3180 (NH) and 1640-1620 cm-1 (pyridone C=O). The structure of thiazolo[3,2-a]pyridine 10 was
supported by comparative analysis of the spectrum with the corresponding data (in particular the δ C(2)H and
1
1
C(3)H values in the H NMR spectra) for related compounds [23]. The H NMR spectrum of 10 at 200 MHz
lacks a signal for the NH group and shows a doublet at δ 3.55 (3J = 6.7 Hz) and a broad doublet at δ 3.68 ppm
(2J = 11.8 Hz) assigned to the CH2I and cis-C(2)H protons, respectively. The signal for the trans-C(2)H proton
3
appears as a doublet of doublets at δ 3.93 ppm (3J = 6.9, J = 11.8 Hz). Finally, the multiplet at δ 5.38 ppm
1
should be assigned to the C(3)H proton. The H NMR spectrum of dipyridothiopyran 13 is in good accord with
the spectra of other similar compounds [22]. Thus, the spectrum of 13 shows two broad singlets at δ 11.34 and
10.17 ppm, which should be assigned to the C(5)NH proton and one of the two protons of the C(4)NH2 amino
group, which participated in intramolecular hydrogen bonding [22]. As a consequence, its signal is shifted
downfield, while the signal of the other proton of the C(4)NH2 amino group appears at δ 7.56 Hz and partially
1
overlaps with the broad singlet of the C(2)NH2 amino group protons. Furthermore, the H NMR spectrum of
dipyridothiopyran 13 shows two singlets at δ 6.47 (C(9)H) and δ 2.32 ppm (CH3).
In order unequivocally to establish the direction of the acetoacetylation reaction and confirm the
structure of the products of the chemical transformations, the structure of isopropyl (3-cyano-6-methyl-
4-oxo-1,4-dihydro-2-pyridinyl)thioacetate (8d) was studied by X-ray diffraction structural analysis. Two
symmetrically independent molecules A and B exist in the crystal of 8d with extremely similar
602

geometry (Fig. 1). The six-membered ring N(1)C(1-5) is planar (the deviations of the atoms from the
mean-square plane in both molecules does not exceed 0.010 Å). The C(5)S(1)C(8) group is almost orthogonal to
this ring and the corresponding dihedral angle is 77.4° in molecule A and 75.1° in molecule B. The bond lengths
and angles in both independent molecules of 8d are ordinary and fall within the reported values [24].
Molecules A and B in the crystal of 8d are linked by rather strong intermolecular hydrogen bonds into infinite
chains: N(1A)-H···O(1B) (N···O, 2.707(3); N–H, 0.90(3); O···H, 1.82(3) Å, NHO, 167(2)°) and N(1B)-H···O(1A)
(N···O, 2.701(3); N–H, 0.90(3); O···H, 1.81(3) Å, NHO, 174(2)°) (Fig. 2). The corresponding crystallographic
data and the details of the structure are given in the Experimental.
Fig. 1. General view of molecule of 8d. The major bond lengths and valence angles given as the average of the
two independent molecules A and B: S(1)–C(5), 1.766(2); S(1)–C(8), 1.814(3); N(1)–C(1), 1.368(3);
N(1)–C(5), 1.350(3); N(2)–C(7), 1.142(3) Å; C(5)S(1)C(8), 100.7(1), C(1)N(1)C(5), 122.1(2)°.
Fig. 2. Crystal packing of 8d (the intermolecular N-H···O hydrogen bonds
are indicated by the dotted lines).
603

EXPERIMENTAL
1
The H NMR spectra were taken on a Varian Gemini 200 spectrometer at 200 MHz in DMSO-d6 with
TMS as the internal standard. The IR spectra were taken on an IKS-29 spectrophotometer in vaseline mull. The
elemental analyses were carried out on a Perkin–Elmer C,H,N-Analyzer. The reaction course and purity of the
products were checked by thin-layer chromatography on Silufol UV-254 plates using 1:1 acetone-heptane as the
eluent. The plates were developed with iodine vapor a UV detector. The melting points were taken on a Koefler
block and not corrected. Dioxane and triethylamine were dried over sodium.
A commercially sample of diketene supplied by Fluka was used. Samples of cyanothioacetamide [26]
and 2-amino1,1,3-tricyanopropene (12) [27] were prepared according to reported procedures.
X-Ray Diffraction Study of a spherical monocrystal of 8d (d = 0.48 Å) grown from solution in
2-propanol was carried out at room temperature on an Enraf-Nonius CAD-4 automatic four-circle diffractometer
using CuKα radiation, λ = 1.54178 Å, scanning rate ratio 2θ/ω= 1.2, θmax = 68°, sphere segment 0 ≤ h ≤ 11,
-14 ≤ k ≤ 14, -16 ≤ l ≤ 16. A total of 4349 reflections were recorded, from which 4220 were symmetrically
independent (Rint = 0.015). The unit cell data for triclinic crystals of 8d are: a = 8.571(5), b = 12.028(7),
c =13.371(11) Å, α = 87.86(7), β = 89.67(7)°, γ = 76.55(7)°, V = 1340(2) Å3, M = 266.3, Z = 4 (two independent
molecules), dcalc = 1.32g/cm3, µ = 21.36 cm-1, F(000) = 562.8, space group P (N 2). The structure was solved
1
by the direct method and refined by the method of least squares in the full-matrix anisotropic approximation
using the CRYSTALS program package [28]. A total of 3507 reflections were used in the refinement with
I > 3σ(I) (333 refinable parameters, the number of reflections per parameter was 10.5). All the hydrogen atoms
were revealed in the electron density difference map and refined with fixed positional and temperature
parameters (only H(1) and H(3) involved in hydrogen bonding were refined isotropically). The Chebyshev
weighting system [29] with three parameters: 3.55, 2.15, and 2.55 was used in the refinement. The final
R = 0.041 and Rw = 0.051, GOF = 1.040. The residual electron density from the Fourier difference map was 0.23
and -0.26 e/Å3. Absorption in the crystal was considered using an azimuthal scanning procedure [30].
The complete set of X-ray diffraction data for 8d has been deposited in the Cambridge Structural Data
Bank (CCDC 615170).
Triethylammonium 3-Cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinethiolate (3). A solution of
amide 2 (3.0 g, 30 mmol) in absolute dioxane (20 ml) was cooled to about 10°C and dry triethylamine (6.3 ml,
45 mmol) was added. Then, diketene (4.6 ml, 60 mmol) was added carefully dropwise with vigorous stirring and
ice cooling. A thick red oil remained at the end of the exothermal reaction. The reaction mixture was heated at
reflux with stirring until the reagents were completely converted, then stirred for an additional 8 h at ~20°C, and
left overnight. The oily product solidified upon adding a nucleation crystal or further stirring to give a light-
yellow fine-crystalline powder. Filtration and washing twice with acetone gave 6.4 g thiolate 3. IR
spectrum, ν, cm-1: 3180 (N–H), 2207, 2265 (shoulder) (C≡N), 1625 (C=O). 1H NMR spectrum, δ, ppm (J, Hz):
11.12 (1H, s, NH, partially exchanged); 5.53 (1H, s, C(5)H); 3.10 (2H, q, J = 7.2, CH2CH3); 2.07 (3H, s, CH3);
1.22 (3H, t, J = 7.2, CH2CH3).
2-Mercapto-6-methyl-4-oxo-1,4-dihydro-3-pyridinecarbonitrile (6). A stirred suspension of thiolate 3
(3.0 g, 11.2 mmol) in ethanol (20 ml) was treated with excess 10% hydrochloric acid (5 ml, 14.4 mmol). The
mixture was stirred for 2 h, diluted with water (5 ml), and left in a refrigerator for 12 h. The precipitate formed
was filtered off and washed with ethanol to give pyridine 6 (1.75 g) as a beige fine-crystalline powder, which
decomposed at 250-260°C. This product was used without further purification. IR spectrum, ν, cm-1: 3200 (N–H),
1
2227 (C≡N), 1635 (C=O). H NMR spectrum, δ, ppm: 12.90 (1H, br. s, NH, partially exchanged); 6.17 (1H, s,
C(5)H); 2.27 (3H, s, CH3). The signal for SH was not found, probably due to deuterium exchange.
604

Synthesis of 8a-g (General Method). A. A solution of the corresponding alkyl halide 7 (1.9 mmol) in
ethanol (5 ml) was added to a solution of thiolate 3 (0.5 g, 1.87 mmol) in hot 70% aq. ethanol (15 ml). The
mixture was heated to reflux, stirred for 8 h at ~20°C, and left stand for 72 h. The precipitate formed of the
corresponding pyridine 8a-g was filtered off and washed with ethanol.
B. A suspension of mercaptopyridine 6 (0.5 g, 3 mmol) in hot ethanol (15 ml) was treated with
10% aq. KOH (1.6 ml, 3 mmol). The potassium salt solution formed was passed through a paper filter into a
solution of the corresponding halide 7 in ethanol (5 ml). The mixture was heated to reflux and then treated as in
Procedure A.
6-Methyl-2-methylthio-4-oxo-1,4-dihydro-3-pyridinecarbonitrile (8a). Yield 0.22 g (Method A) and
1
0.30 g (Method B). IR spectrum, ν, cm-1: 3210 (N–H), 2218 (C≡N), 1635 (C=O). H NMR spectrum, δ, ppm:
12.07 (1H, br. s, NH); 6.51 (1H, s, C(5)H); 2.52 (3H, s, SCH3); 2.27 (3H, s, CH3).
2-Allylthio-6-methyl-4-oxo-1,4-dihydro-3-pyridinecarbonitrile (8b). Yield 0.28 g (Method A) and
1
0.36 g (Method B). IR spectrum, ν, cm-1: 3195 (N–H), 2223, 2258 (shoulder) (C≡N), 1628 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 6.50 (1H, s, C(5)H); 5.87 (1H, m, CH=C); 5.27 (1H, br. d, J = 17.2, trans-HC=CH2);
5.08 (1H, br. d, J = 10.2, cis-HC=CH2); 3.86 (2H, d, J = 7.0, SCH2); 2.38 (3H, s, CH3). The signal for NH was
not seen, probably due to deuterium exchange.
Ethyl (3-Cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thioacetate (8c). Yield 0.45 g (Method B).
1
IR spectrum, ν, cm-1: 3200 (N–H), 2218 (C≡N), 1725 (C=Oester), 1633 (C=Opyridone). H NMR spectrum, δ, ppm
(J, Hz): 6.58 (1H, s, C(5)H); 4.11 (2H, q, J = 7.2, CH2CH3); 3.97 (2H, s, SCH2); 2.34 (3H, s, CH3); 1.21 (3H, t,
J = 7.2, CH2CH3). The signal for NH was not seen, probably due to deuterium exchange.
Isopropyl (3-Cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thioacetate (8d). Yield 0.69 g
(Method B). IR spectrum, ν, cm-1: 3195 (N–H), 2223, 2258 (shoulder) (C≡N), 1723 (C=Oester), 1635
1
(C=Opyridone). H NMR spectrum, δ, ppm (J, Hz): 12.20 (1H, br. s, NH); 6.56 (1H, s, C(5)H); 4.94 (1H, m,
CH(CH3)2); 3.92 (2H, s, SCH2); 2.37 (3H, s, CH3); 1.23 (6H, d, J = 6.2, CH(CH3)2).
N-(3,4-Dimethylphenyl)-2-[(3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thio]acetamide (8e).
Yield 0.55 g (Method A) or 0.61 g (Method B). IR spectrum, ν, cm-1: 3510, 3390, 3210 (2N–H), 2225 (C≡N),
1665 (C=Ocarbamoyl), 1630 (C=Opyridone). 1H NMR spectrum, δ, ppm (J, Hz): 12.03 (1H, br. s, NHpyridine); 9.86 (1H,
br. s (C(O)NH); 7.30 (1H, s, C(2)Haryl); 7.23 (1H, d, J = 7.9, C(6)Haryl); 6.96 (1H, d, J = 7.9, C(5)Haryl); 6.52 (1H,
s, C(5)Hpyridine); 4.00 (2H, s, SCH2); 2.40 (3H, s, C(6)CH3 pyridine); 2.22 and 2.19 (3H each, both s, C(3)CH3 aryl and
C(4)CH3 aryl).
N-(4-Methylphenyl)-2-[3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thio]acetamide (8f). Yield
0.69 g (Method B). IR spectrum, ν, cm-1: 3460, 3330, 3240 (2N–H), 2213 (C≡N), 1650 (C=Ocarbamoyl), 1626
1
(C=Opyridone). H NMR spectrum, δ, ppm (J, Hz): 12.05 (1H, br. s, NHpyridine); 9.96 (1H, br. s, C(O)NH); 7.40
(2H, d, J = 8.2, C(2)Haryl and C(6)Haryl); 7.01 (2H, d, J = 8.2, C(3)Haryl) and C(5)Haryl); 6.51 (1H, s, C(5)Hpyridine);
4.00 (2H, s, SCH2); 2.37 (3H, s, C(6)CH3 pyridine); 2.27 (3H, s, C(4)CH3 aryl).
2-{[2-(4-Bromophenyl)-2-oxoethyl]thio}-6-methyl-4-oxo-1,4-dihydro-3-pyridinecarbonitrile (8g).
Yield 0.83 g (Procedure B); mp 206-208°C (converts to 9b). IR spectrum, ν, cm-1: 3240 (N–H), 2215 (C≡N),
1
1675 C=Ophenacyl), 1640 (C=Opyridone). H NMR spectrum, δ, ppm (J, Hz): 11.99 (1H, br. s, NH, partially
exchanged); 7.92 (2H, d, J = 8.6, C(2)Haryl and C(6)Haryl); 7.62 (2H, d, J = 8.6, C(3)Haryl and C(5)Haryl); 6.45
(1H, s, C(5)Hpyridine); 4.60 (2H, s, SCH2); 2.12 (3H, s, CH3).
Thorpe-Ziegler Cyclization of 8 Promoted by KOH (General Method). A two-fold excess of
10% aq. KOH (3.1 ml, 6 mmol) was added to a stirred suspension of corresponding pyridine 8f or 8g (3 mmol).
The mixture was heated at reflux for 5 min, cooled, stirred for 2 h at ~20°C, and then acidified by adding acetic
acid. The precipitate formed was filtered off and washed twice with ethanol to give thieno[2,3-b]pyridines 9a,b.
605

3-Amino-6-methyl-2-N-(4-methylphenyl)carbamoyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine (9a).
Yield 0.66 g. IR spectrum, ν, cm-1: 3450, 3375, 3330, 3190 (NH2, 2N–H), 1650 (C=Ocarbamoyl), 1620 (C=Opyridone).
1H NMR spectrum, δ, ppm (J, Hz): 12.10 (1H, br. s, NHpyridine, partially exchanged); 8.83 (1H, s, C(O)NH); 7.50
(4H, m, superposition of signals of NH2, C(2)Haryl and C(6)Haryl); 7.02 (2H, d, J = 8.1, C(3)Haryl and C(5)Haryl);
5.93 (1H, s, C(5)Hpyridine); 2.32 and 2.28 (each 3H, both s, C(4)CH3 aryl and C(6)CH3).
3-Amino-2-(4-bromobenzoyl)-6-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine (9b). Yield 0.75 g;
mp 330-332°C (dec., acetic acid). IR spectrum, ν, cm-1 3440, 3325 (NH2), 3230 (N–H), 1650 (C=Obenzoyl), 1625
:
1
(C=Opyridone). H NMR spectrum, δ, ppm: 12.39 (1H, br. s, NH); 8.32 (2H, br. s, NH2); 7.62 (4H, m, 4-BrC6H4);
5.86 (1H, s, C(5)H); 2.30 (3H, s, CH3).
Noncatalyzed Thermal Isomerization of Pyridine 6g to Thieno[2,3-b]pyridine 9b. A sample of 8g
(0.3 g, 0.83 mmol) was heated rapidly in an open vessel to the melting point (~210°C). The melt was converted
within a few seconds into a solid mass of thieno[2,3-b]pyridine 9b (0.3 g), mp 320-330°C (dec.), in quantitative
yield. Recrystallization from acetic acid gave 0.24 g (80%) 9b as fine yellow crystals, mp 330-332°C (dec.). The
analytical data agree with the data for a sample obtained in the cyclization promoted by KOH.
3-(Iodomethyl)-5-methyl-7-oxo-2,3-dihydro-7H-thiazolo[3,2-a]pyridine-8-carbonitrile (10). Crystalline
iodine (0.5 g, 1.97 mmol) was added in a single batch to a hot solution of pyridine 8b (0.4 g, 1.94 mmol) in
2:1 ethanol-dioxane (15 ml). The mixture was heated at reflux for 5 min and then stirred for 24 h at ~20°C. The
precipitate formed was filtered off and recrystallized from 1:1 AcOH-DMF to give 0.48 g 10, (dec.) IR spectrum,
ν, cm-1: 2224 (C≡N), 1630 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 6.09 (1H, s, C(6)H); 5.38 (1H, m, C(3)H);
3
2
2
3
3.93 (1H, dd, J = 6.9, J = 11.8, trans-C(2)H); 3.68 (1H, br. d, J = 11.8, cis-C(2)H); 3.55 (2H, d, J = 6.7,
CH2I); 2.43 (3H, s, CH3).
Bis(3-cyano-6-methyl-4-oxo--1,4-dihydro-2-pyridinyl) Disulfide (11). A solution of thiolate 3 (0.4 g,
1.5 mmol) in hot aqueous ethanol (20 ml) was treated with a hot solution of iodine (0.19 g, 0.75 mmol) in
ethanol (15 ml). The mixture was heated at reflux with vigorous stirring for 5 min and cooled. The precipitate
was filtered off and washed with ethanol to give 0.23 g disulfide 11 (dec. >250°C). IR spectrum, ν, cm-1: 3200
(2N–H), 2223 (2 C≡N), 1638 (2 C=O). 1H NMR spectrum, δ, ppm: 12.50 (2H, br. s, 2NH, partially exchanged);
6.56 (2H, s, 2C(5)H); 2.35 (6H, s, 2CH3).
2,4-Diamino-5-imino-8-methyl-10-oxo-7,10-dihydro-5H-pyrido[2',3':4,5]thiopyrano-[2,3-b]pyridine-
3-carbonitrile (13). 2-Amino-1,1,3-tricyanopropene (12) (0.48 g, 3.6 mmol) and five drops of Et3N were added
to a suspension of thiolate 3 (0.5 g, 1.8 mmol) in ethanols (20 ml). The mixture was heated at reflux for 10 h
and cooled. The precipitate was filtered off and recrystallized from 1:1 AcOH-DMF to give 0.23 g 13 as
light-brown crystals. IR spectrum, ν, cm-1: 3555, 3420, 3350-3190 (2NH2, 2N–H), 2203 (C≡N), 1640 (C=O).
1H NMR spectrum, δ, ppm: 11.34 (1H, br. s, C(4)NH2 or C(5)NH); 10.17 (1H, s, C(5)NH or C(4)NH2); 7.56
(3H, m, superposition of signals for C(4)NH2 (1H) and C(2)NH2 (2H)); 6.47 (1H,s, C(9)H), 2.32 (3H, s, CH3).
The proton for endocyclic NH was not seen, probably due to deuterium exchange.
This work was carried out with the financial support of the Russian Basic Research Fund (RFFI)
(Project 05-03-32031).
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