A simple and effective synthetic approach to pyrido[2,1-b]thiazines

Article abstract of DOI:10.1007/s10593-007-0186-7

The reaction of partially hydrogenated 2-pyridinethiols with 1,3-dibromopropane gives substituted pyrido[2,1-b][1,3]thiazines. The structure of 7,9-dicyano-6-oxo-3,4,6,7-tetrahydro-2H-spirocyclohexane-1′,8-pyrido[2, 1-b][1,3]thiazine was solved by X-ray d

Full text of DOI:10.1007/s10593-007-0186-7

Chemistry of Heterocyclic Compounds, Vol. 43, No. 9, 2007
A SIMPLE AND EFFECTIVE SYNTHETIC
APPROACH TO PYRIDO[2,1-b]THIAZINES
V. D. Dyachenko1 and A. N. Chernega2
The reaction of partially hydrogenated 2-pyridinethiols with 1,3-dibromopropane gives substituted
pyrido[2,1-b][1,3]thiazines. The structure of 7,9-dicyano-6-oxo-3,4,6,7-tetrahydro-2H-spirocyclo-
hexane-1',8-pyrido[2,1-b][1,3]thiazine was solved by X-ray diffraction structural analysis.
Keywords: 1,3-dibromopropane, pyrido[2,1-b][1,3]thiazines, partially hydrogenated 2-pyridinethiols,
alkylation, X-ray diffraction structural analysis.
The reported methods for the synthesis of substituted pyrido[2,1-b][1,3]thiazines are based on the
reaction of 2-pyridinethiol with β-bromopropionic acid [1], reaction of tetrahydro-2-pyridinethione with
benzylidenemalononitrile [2], reaction of 3,4-dihydropyridine-2(1H)-thione with epichlorhydrin [3], and
acylation of 3,4-dihydro-2(1H)-pyridinethione with cinnamyl chloride [4].
In the present work, we have found a simple and efficient method for preparing previously unreported
substituted, partially hydrogenated pyrido[2,1-b][1,3]thiazines 1-4 consisting of the regioselective alkylation of
2-pyridinethiols 5-7 and 2-pyridinethiolate 8 by 1,3-dibromopropane in DMF in the presence of aqueous KOH.
An X-ray diffraction structural analysis of 3a was carried out to establish the regioselectivity of the
alkylation of 2-pyridinethiols 5-8 by 1,3-dibromopropane. We found that there are two symmetrically
independent molecules A and B in the crystal of this compound. The major geometrical parameters of these
molecules are given in Table 1, while a general view of these molecules is given in Figs. 1 and 2. The bond
lengths and bond angles in 3a(A) and 3a(B) are virtually identical. In particular, N(1) in both molecules has
planar trigonal configuration: the sum of the bond angles at this atom is 359.0(6)° in 3a(A) and 359.9(6)° in
3a(B). In both molecules, the N(1)–C(4) and N(1)–C(8) bonds are markedly shortened relative to the standard value
for the pure N(sp2)–C(sp2) single bond (1.45 Å) [5] due to n(N(1))–π(C(4)=C(5)) and n(N(1))–π(C(8)=O(1))
conjugation. On the other hand, the conformations of these molecules differ considerably, as indicated both by
the endocyclic torsion angles (Table 2) and the modified Kramer-Pople parameters, S, θ, and Ψ [6]. Thus, while
the S(1)N(1)C(1)C(2)C(3)C(4) heterocycle in molecule A has chair conformation (S = 0.99, θ = 12.2°, ψ = 8.8°), this
heterocycle in molecule B has twist-boat conformation (S = 0.82, θ = 65.0°, Ψ = 10.0°). The central
N(1)C(4)C(5)C(6)C(7)C(8) ring in molecule A has close to half-boat conformation (S = 0.71, θ = 53.2°, Ψ = 24.2°),
while this ring in molecule B has a conformation intermediate between half-boat and half-chair (S = 0.77,
θ = 64.8°, Ψ = 15.7°). Furthermore, the arrangement of the endocyclic substituents differs significantly. Thus,
__________________________________________________________________________________________
1Taras Shevchenko Lugansk National Pedagogical University, Lugansk 91001, Ukraine; e-mail:
dvd_lug@online.lg.ua. 2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094,
Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1428-1433, September, 2007.
Original article submitted December 5, 2006.
1214
0009-3122/07/4309-1214©2007 Springer Science+Business Media, Inc.

while the C(8)=O(1) and C(7)–C(14)≡N(2) groups in molecule B have cis orientation relative to the C(7)–C(8) bond (the
O(1)–C(8)–C(7)–C(14) torsion angle is 9.1°), this torsion angle in molecule A is –104.6°. Only the cyclohexane ring
in both independent molecules has identical chair conformation though the orientation of this ring relative to the
bicyclic S(1)N(1)C(1)C(2)C(3)C(4)C(5)C(6)C(7)C(8) system in molecules A and B differs significantly: the C(10)C(11)C(12)
cyclohexane “corner” is twisted toward the C(5)–C(15)≡N(3) substituent, while it is twisted in the opposite direction
in molecule B.
S
Me
MeOOC
O
CN
SH
CN
SH
S
Me
N
O
N
H
6
MeOOC
O
CN
S
H
CN
S
5
O
N
N
2
1
Br
Br
R
Ph
O
NC
CN
NC
O
CN
SH
+
HN
–
S
N
H2N
N
Me
H
H
7
8
R
Ph
N
NC
CN
S
NC
O
CN
S
H2N
N
4
3
3, 7 a R = H, b R = Me
Thus, our X-ray diffraction structural analysis showed that two conformers exist in the crystal of 3a.
This phenomenon is not uncommon in modern crystallography.
EXPERIMENTAL
A monocrystal of 3a was rolled to give spherical form with diameter 0.38 mm. The X-ray diffraction
structural analysis was carried out at room temperature on an Enraf-Nonius CAD-4 automatic four-circle
diffractometer using MoKα radiation, λ = 0.71069 Å, relative scanning rate 2θ/ω = 1.2, θmax = 25°, sphere
segment 0 ≤ h ≤ 19, -13 ≤ k ≤ 13, -16 ≤ k 16. A total of 5152 reflections were measured, of which 4811 were
symmetrically independent (Rint = 0.020). The unit cell parameters of triclinic crystals of 3a are as follows:
a = 9.372(3), b = 11.758(3), c = 13.892(4) Å, α = 76.78(2), β = 86.06(2), γ = 74.26(2)°, V = 1434.5(7) Å3,
M = 287.38, Z = 4 (two independent molecules), dcalc = 1.33 g/cm3, µ = 2.14 cm-1, F(000) = 320.3, space group
P
(N 2). The structure was solved by the direct method and refined by the method of least squares in the
1
1215

Fig. 1. General view of molecule 3a(A) with numbering of the atoms
(the hydrogen atoms are not shown).
full-matrix anisotropic approximation using the CRYSTALS program package [7]. A total of 3142 reflections
with I > 3(I) were used in the refinement (361 refined parameters, reflections per parameter 8.7). All the
hydrogen atoms were found in the electron density map and included in the refinement with fixed positional and
temperature parameters. Absorption was taken into account using the azimuthal scanning method [8]. The
Chebisov weighting scheme [9] was used in the refinement with five parameters: 1.35, 1.53, 1.34, 0.48, and
0.28. The final R = 0.047 and Rw = 0.049, GOOF = 1.155. The coordinates of the non-hydrogen atoms may be
obtained from the authors.
Fig. 2. General view of molecule 3a(B) with numbering of the atoms
(the hydrogen atoms are not shown).
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TABLE 1. Major Bond Lengths (d) and Valence Angles (ω) in the Two
Symmetrically Independent Molecules A and B in 3a
d, Å
ω, deg
Bond
Angle
A
B
A
B
S(1)–C(1)
S(1)–C(4)
C(1)–C(2)
C(2)–C(3)
N(1)–C(3)
N(1)–C(4)
N(1)–C(8)
C(4)–C(5)
C(5)–C(6)
C(6)–C(7)
C(7)–C(8)
1.809(4)
1.759(3)
1.506(5)
1.490(5)
1.481(4)
1.406(3)
1.379(4)
1.348(4)
1.529(4)
1.556(4)
1.539(4)
1.815(4)
1.761(3)
1.507(6)
1.493(5)
1.485(4)
1.405(4)
1.371(4)
1.344(4)
1.534(4)
1.562(4)
1.526(4)
C(1)–S(1)–C(4)
C(3)–N(1)–C(4)
S(1)–C(1)–C(2)
C(1)–C(2)–C(3)
N(1)–C(3)–C(2)
S(1)–C(4)–N(1)
C(4)–N(1)–C(8)
N(1)–C(4)–C(5)
C(4)–C(5)–C(6)
C(5)–C(6)–C(7)
C(6)–C(7)–C(8)
102.6(2)
121.2(2)
112.0(2)
112.6(3)
113.8(3)
119.0(2)
120.3(2)
121.1(2)
121.0(2)
104.5(2)
109.6(2)
115.9(2)
102.9(2)
123.4(2)
112.0(3)
111.6(4)
113.7(3)
119.8(2)
120.2(2)
120.4(2)
121.2(2)
102.6(2)
109.7(2)
115.2(2)
N(1)–C(8)–C(7)
TABLE 2. Major Endocyclic Torsion Angles (τ) in the Two Symmetrically
Independent Molecules A and B in 3a
τ, deg
τ, deg
Angle
Angle
A
B
A
B
S(1)–C(1)–C(2)–C(3)
C(1)–C(2)–C(3)–N(1)
C(2)–C(3)–N(1)–C(4)
C(3)–N(1)–C(4)–S(1)
N(1)–C(4)–S(1)–C(1)
C(4)–S(1)–C(1)–C(2)
-60.1
59.9
-47.8
36.6
-32.0
43.3
64.4
-57.7
7.5
N(1)–C(4)–C(5)–C(6)
C(4)–C(5)–C(6)–C(7)
C(5)–C(6)–C(7)–C(8)
C(6)–C(7)–C(8)–N(1)
C(7)–C(8)–N(1)–C(4)
C(8)–N(1)–C(4)–C(5)
-0.9
-37.2
57.1
-44.8
5.1
-28.1
-37.7
59.5
-46.4
3.3
31.5
-20.2
-24.9
19.7
23.2
1
The IR spectra of the products were taken on an IKS-29 spectrometer in vaseline mull. The H NMR
spectra were taken on a Bruker WM-250 spectrometer at 250 MHz (for 3a), Gemini-200 spectrometer at
200 MHz (for 2 and 4), Bruker DR-500 spectrometer at 500 MHz (for 1 and 5), and Bruker WP-100 SY
spectrometer at 100 MHz (for 3b) in DMSO-d6 with TMS as the internal standard. The mass spectra were taken
on a Kratos MS-890 mass spectrometer at 70 eV. The melting points were determined on a Koefler block. The
course of the reactions was followed by thin-layer chromatography on Silufol UV-254 plates with
3:5 acetone-hexane as the eluent and development by iodine vapor or UV light.
Preparation of 1-4 (General Method). 10% Aqueous KOH (5.6 ml, 10 mmol) and
1,3-dibromopropane (1.02 ml, 10 mmol) were added to a stirred solution of corresponding pyridinethiol 5-8
(10 mmol) in DMF (10 ml) at 20°C and left for 24 h. Then, an additional 10% aqueous KOH (5.6 ml, 10 mmol)
was added and stirred for 2 h. Then, water (10 ml) was added. The precipitate formed was filtered off and
washed with 40% aqueous ethanol to give 1-4, which were recrystallized from glacial acetic acid.
9-Cyano-7-methoxycarbonyl-6-oxo-8-(2-thienyl)- 3,4,6,7-tetrahydro-2H,8H-pyrido[2,1-b][1,3]thiazine
1
(1). Yield 2.4 g (72%); mp 159-160°C. IR spectrum, ν, cm-1: 1718 (C=O), 2203 (C≡N). H NMR spectrum, δ,
ppm (J, Hz): 7.34 (1H, dd, J = 1.4 and J = 4.3, H-5 thienyl); 6.96 (2H, m, H-4 and H-3 thienyl); 4.43 (1H, d,
J = 6.2, H-7); 3.98 (1H, d, J = 6.2, H-8); 3.93 (2H, t, J = 6.2, NCH2); 3.71 (3H, s, CH3); 3.19 (2H, m, SCH2);
2.14 (2H, m, CH2). Mass spectrum, m/z (Irel, %): 334 [M]+ (9), 277 (11), 276 (18), 275 (100). Found, %: C 53.70;
H 4.01; N, 8.47. C15H14N2O3S2. Calculated, %: C, 53.87; H, 4.22; N, 8.38.
1217

9-Cyano-8-methyl-6-oxo-2,3,4,6-tetrahydropyrido[2,1-b][1,3]thiazine (2). Yield 1.73 g (84%);
mp 224-225°C. IR spectrum, ν, cm-1: 2214 (C≡N), 1675 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 6.03 (1H, s,
H-7); 3.98 (2H, t, J = 5.5, NCH2); 3.25 (2H, t, J = 6.3, SCH2); 2.20 (5H, m, CH3 and CH2). Mass spectrum, m/z
(Irel, %): 206 [M]+ (100); 205 (17), 191 (48), 178 (224), 173 (20), 150 (23). Found, %: C 58.03; H 5.12; N 13.40.
C10H10N2OS. Calculated, %: C 58.23; H 4.89; N 13.58.
7,9-Dicyano-6-oxo-3,4,6,7-tetrahydro-2H-spirocyclohexane-1',8-pyrido[2,1-b][1,3]thiazine
(3a).
Yield 1.98 g (69%); mp 144-146°C. IR spectrum, ν, cm-1: 2247 (C(7)–C≡N), 2200 (C≡N), 1680 (C=O). 1H NMR
spectrum, δ, ppm (J, Hz): 4.58 (1H, s, H-7); 3.71-3.96 (2H, m, NCH2); 2.14 (2H, t, J = 5.1, SCH2); 1.28-1.90
(12H, m, (CH2)6). Mass spectrum, m/z (Irel, %): 287 [M]+ (79), 272 (8), 258 (26), 244 (98), 231 (100), 206 (27),
179 (38), 56 (48). Found, %: C 62.50; H 6.16; N 14.52. C15H17N3OS. Calculated, %: C 62.69; H 5.96; N 14.62
7,9-Dicyano-6-oxo-3,4,6,7-tetrahydro-2H-spiro(4'-methylcyclohexane)-1',8-pyrido[2,1-b][1,3]thiazine
(3b). Yield 2.08 g (69%); mp 152-164°C. IR spectrum, ν, cm-1: 2246 (C(7)–C≡N), 2208 (C≡N), 1678 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 4.71 (1H, s, H-7); 3.94 and 3.68 (both 1H, both t, J = 6.3, NCH2); 3.13 and
3.07 (both 1H, both t, J = 6.5, SCH2); 2.11 (2H, t, J = 5.8, CH2); 1.88-1.15 (9H, m, CH and (CH2)4); 0.91 (3H, d,
J = 4.7, CH3). Found,%: C 63.60; H 6.28; N 14.07. C16H19N3OS. Calculated, %: C 63.76; H 6.35; N 13.94.
6-Amino-7,9-dicyano-8-phenyl-3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazine (4). Yield 2.21 g
1
(75%); mp 216-218°C. IR spectrum, ν, cm-1: 3182, 3308, 3455 (NH2), 2202 (C≡N), 1647 (δ NH2). H NMR
spectrum, δ, ppm (J, Hz): 7.02-7.40 (5H, m, C6H5); 6.05 (2H, br. s, NH2); 4.04 (1H, s, H-8); 3.93 and 3.49
(both 1H, both m, NCH2); 2.98 (2H, t, J = 5.0, SCH2); 2.29 and 2.10 (both 1H, both m, CH2). Found, %:
C 64.99; H 5.02; N 18.87. C16H14N4S. Calculated, %: C 65.28; H 4.79; N 19.03.
5-Cyano-6-mercapto-3-methoxycarbonyl-4-(2-thienyl)-3,4-dihydropyridin-2(1H)-one
(5)
was
obtained according to our procedure [10]. Yield 2.35 g (80% ); mp 158-160°C (ethanol). IR spectrum, ν, cm-1:
3345 (N-H), 2202 (C≡N), 1742 (C=O), 1685 (CONH). 1H NMR spectrum, δ, ppm (J, Hz): 8.70 (1H, br. s, NH);
7.34 (2H, dd, J = 1.4 and J = 4.3, H-5 thienyl); 6.93 (1H, m, H-4 thienyl); 6.87 (1H, m, H-3 thienyl); 4.20 (1H,
d, J = 6.15, H-3); 3.62 (3H, s, CH3); 3.58 (1H, br. s, SH); 3.52 (1H, d, J = 6.15, H-4). Mass spectrum, m/z
(Irel, %): 296 [M+2]+ (5), 295 [M+1]+ (9), 294 [M]+ (35), 267 (48), 235 (100), 195 (63), 137 (47), 100 (72), 58
(60). Found, %: C 49.12; H 3.15; N 9.64. C12H10N2O3S2. Calculated, %: C 48.97; H 3.42; N 9.52.
5-Cyano-6-mercapto-4-methyl-2(1H)-pyridinone (6) was characterized in our previous work [11].
3,5-Dicyano-6-mercapto-3,4-dihydrospiro(cyclohexane-1',4-pyridin)-2(1H)-one (7a) and 3,5-dicyano-
6-mercapto-3,4-dihydrospiro(4'-methylcyclohexane-1',4-pyridin)-2(1H)-one (7b) were characterized in our
previous work [12]. N-Methylmorpholinium 6-amino-3,5-dicyano-4-phenyl-1,4-dihydro-2-pyridinethiolate
(8) was characterized in our previous work [13].
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