A facile synthesis of new thieno[2,3-b][1,4]-thiazine derivatives starting from 2-acylamino-3,3-dichloroacrylonitriles

Article abstract of DOI:10.1002/hc.20232

Readily available 2-acylamino-3,3-dichloroacrylonitriles are sequentially treated with methyl mercaptoacetate in the presence of sodium methylate and with sulfuric acid to furnish the methyl ester of 7-amino-2-oxo-3H-thieno[2,3-b][1, 4]thiazine-6-carboxyl

Full text of DOI:10.1002/hc.20232

Heteroatom Chemistry
Volume 17, Number 5, 2006
A
2
Facile Synthesis of New Thieno[2,3-b][1,4]-
thiazine Derivatives Starting from
-Acylamino-3,3-dichloroacrylonitriles
1
1
Sergey V. Popil’nichenko, Vladimir S. Brovarets,
2
2
1
Alexander N. Chernega, Denis V. Poltorak, and Boris S. Drach
1
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
1
Murmanskaya Str., 02094 Kiev, Ukraine
2
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanskaya Str.,
0
2094 Kiev, Ukraine
Received 15 December 2005
thiadiazole [12] functional derivatives.
In the
ABSTRACT: Readily available 2-acylamino-3,3-
dichloroacrylonitriles are sequentially treated with
methyl mercaptoacetate in the presence of sodium
methylate and with sulfuric acid to furnish the methyl
ester of 7-amino-2-oxo-3H-thieno[2,3-b][1,4]thiazine-
present study, we have developed a new line in
the synthetic application of reagents 1a,b using
them to obtain a number of condensed heterocycles
derived from the thieno[2,3-b][1,4]thiazine-2(3H)-
one system (Table 1).
6
-carboxylic acid. Treating it first with triethyl
orthoformate and then with ammonia or primary
amines, the pyrimidine-4-one nucleus is annelated to
the thienothiazine system, which is corroborated by
spectroscopic methods and X-ray diffraction analy-
sis. ꢀC 2006 Wiley Periodicals, Inc. Heteroatom Chem
RESULTS AND DISCUSSION
On treating chloro-substituted enamidonitriles 1a,b
first with methyl mercaptoacetate in the presence
of sodium methylate and then with sulfuric acid,
the conversions 1 → 2 → 3 → 4 proceed as shown in
Scheme 1. The first stage of the process resem-
bles the reaction of compounds 1a,b with thiophe-
nols [7], and the conversion 2 → 3 is a special case
of the well-known type of heterocyclizations involv-
ing a C N bond and an active methylene group
[13,14]. The cyclocondensation 3 → 4 represents
a more original reaction that can be regarded as
an intramolecular reacylation leading to the annela-
tion of the 2-oxo-1,4-thiazine system to the thio-
phene ring. In the course of the reaction, the acyl
residue is eliminated from the nitrogen atom at the
3-position of the thiophene ring; as a result, two dif-
ferent enamidonitriles 1a,b yield the same product
17:411–415, 2006; Published online in Wiley InterScience
(
www.interscience.wiley.com). DOI 10.1002/hc.20232
INTRODUCTION
Readily available 2-acylamino-3,3-dichloroacryloni-
triles are known to be unique reagents for het-
erocyclizations, which were already employed in
the synthesis of 1,3-oxazole [1–8], 4H-imidazole
[9], pyrazole [10], 1,3,4-oxadiazole [11], and 1,3,4-
Correspondence to: Boris S. Drach; e-mail: drach@bpci.kiev.ua.
Contract grant sponsor: Science and Technology Center in
Ukraine (STCU).
4
, the methyl ester of 7-amino-2-oxo-3H-thieno[2,3-
Contract grant number: 3017R.
ꢀ
c 2006 Wiley Periodicals, Inc.
b][1,4]thiazine-6-carboxylic acid, which is evidenced
4
11

4
12 Popil’nichenko et al.
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of New Thieno[2,3-b][1,4]thiazine Derivatives Starting from 2-Acylamino-3,3-dichloroacrylonitriles 413
1
the conjugation is broken by the atom C ). A crys-
tal of compound 7i contains the molecules bound
in centrosymmetric dimers by fairly weak [16] in-
1
2
1
2
termolecular hydrogen bonds N H· · ·N (N · · ·N
˚
1
˚
2
˚
1
2
3
1
.184(3) A, N H 0.89(4) A, N · · ·H 2.36(4) A, N HN
◦
55(2) ).
In summary, it may be noted that the easily ac-
cessible key substrate 4 is appropriate for deriva-
ꢁ
ꢁ
tizing not only the pyrimido[4 ,5 :4,5]thieno[2,3-
b][1,4]thiazine system but also analogous tricyclic
N,S-containing nuclei being the subject of our
further study.
EXPERIMENTAL
1
H NMR spectra were recorded on a Varian Gemini
3
00 spectrometer at 300 MHz using TMS as an
internal standard. IR spectra were measured on a
Specord M-80 spectrometer for KBr disks. Mass
spectra were measured on a Varian MAT-311A
instrument.
SCHEME 1
Methyl 4-Acylamino-3-amino-5-(methoxycarbo-
nylmethylthio)thiophene-2-carboxylates 3a,b
by the spectral and mass spectrometric data
To a solution of 1a,b (4 mmol) obtained by the known
procedure [1,2] in absolute methanol (30 mL),
methyl mercaptoacetate (8.2 mmol) and solution of
sodium methylate (1.2 mmol) in MeOH (1.5 mL)
were added. The mixture was refluxed for 10 h, and
MeOH was removed in vacuo. For crystallization,
(
Table 2). Starting from the key substrate 4, which
contains the appropriately positioned amino and
methoxycarbonyl groups, we succeeded in conduct-
ing the steps 4 → 5 → 6 and 4 → 5 → 7 presented
in Scheme 1. Both reaction sequences end in the
annelation of the pyrimidine-4-one nucleus to the
thieno[2,3-b][1,4]thiazin-2(3H)-one system.
The cascade process 4 → 5 → 7 has proved to
be applicable rather extensively, because a variety
of aliphatic, alicyclic, and aromatic primary amines
readily enter into this condensation (Table 1). More-
over, it is conveniently conducted in one step without
isolation of intermediate compound 5.
the residue was treated with H
off and recrystallized from an appropriate solvent
Table 1).
2
O; then it was filtered
(
Methyl 7-Amino-2-oxo-3H-thieno[2,3-b][1,4]-
thiazine-6-carboxylate 4
The structures of compounds 5, 6, and 7a–m
A mixture of 3a and 3b (2 mmol) in H
2
SO (5 mL)
4
1
◦
are supported by the IR and H NMR spectral data
listed in Table 2. In addition, an unequivocal struc-
tural determination using X-ray diffraction anal-
was heated at 110–120 C under stirring for 5 min.
After pouring the solution onto ice, the precipi-
tate was filtered off and recrystallized from acetic
acid. The samples of compound 4 obtained from
2
ysis has been performed for compound 7i (R =
1
4
-ClC
6
H
4
CH
2
). As seen from Fig. 1, the molecule of
3a and 3b demonstrated identical IR and H NMR
compound 7i is essentially nonplanar, with the moi-
ety S N N C being planar accurate to 0.027 A and
the benzene ring twisted through 86.0˚ out of this
plane. The six-membered heterocycle S C N C
exhibits a strongly distorted halfbath conformation,
with the following modified Cremer–Pople parame-
ters [15]: S= 0.66, θ = 57.2 , ꢀ = 19.4 . The bond
lengths in the molecule concerned (Table 3) sug-
gest a significant delocalization of electronic density
spectra.
2
2
3
3−8
˚
Methyl 7-Etoxymethylidenamino-2-oxo-3H-
thieno[2,3-b][1,4]thiazine-6-carboxylate 5
1
1,2
1
3,8
A mixture of compound 4 (4 mmol), triethyl or-
thoformate (8 mL), and acetic anhydride (0.3 mL)
◦
◦
was refluxed for 2 h.
The precipitate formed
was filtered off and recrystallized from ethanol
(Table 1).
1
2
1−3 1−8
within the tricyclic moiety S S N
C
(except that
Heteroatom Chemistry DOI 10.1002/hc

4
14 Popil’nichenko et al.
TABLE 2 Spectroscopic Data of Compounds 3–7
IR (KBr) (cm 1
−
1
)
H NMR (DMSO-d /TMS)δ
6
a
3
a
b
1655 (NC O, OC O), 1740 (OC O),
3
2.03 (s, 3H, CH ), 3.67 (s, 3H, OCH ), 3.73 (s, 5H, CH , OCH ), 6.16
3 3 2 3
150—3340(NH)
1640 (NC O), 1675 (OC O), 1745
OC O), 3250—3400(NH)
1680 (NC O, OC O), 1620 (δ, NH2)
100—3480(NH, NH2)
1635 (C N), 1675 (NC O), 1725
OC O), 3225 (NH)
1650 (NC O), 1675 (NC O), 3100—3250
NH)
(br s, 2H, NH ), 9.26 (s, 1H, NH)
2
3
3.66 (s, 3H, OCH ), 3.75 (s, 5H, CH , OCH ), 6.28 (br s, 2H, NH ),
3
2
3
2
(
7.50—8.02(m, 5H, C H5), 9.75 (s, 1H, NH)
6
4b
5c
6
3.60 (s, 2H, CH ), 3.70 (s, 3H, OCH ), 6.45 (br s, 2H, NH ), 10.32 (s,
2 3 2
3
1H, NH)
1.34 (t, 3H, CH ), 3.52 (s, 2H, CH ), 3.70 (s, 3H, OCH ), 4.35 (q, 2H,
3
2
3
(
OCH ), 7.81 (s, 1H, CH), 10.15 (s, 1H, NH)
2
3.59 (s, 2H, CH ), 8.09 (s, 1H, CH), 10.45 (br s, 1H, NH), 12.45 (br s,
2
(
1H, NH)
a
7
7
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
1675 (NC O), 3200—3320(NH)
3.52 (s, 3H, NCH ), 3.66 (s, 2H, CH ), 8.48 (s, 1H, CH), 10.81 (br s, 1H,
3 2
NH)
a
1680 (NC O), 3170—3280(NH)
1.63 (t, 3H, CH ), 3.87 (s, 2H, CH ), 4.49 (q, 2H, CH ), 8.45 (s, 1H, CH),
3
2
2
9
.39 (s, 1H, NH)
1675 (NC O), 1700 (NC O), 3250 (NH)
1.13 (t, 3H, CH ), 2.01 (m, 2H, CH ), 3.87 (s, 2H, CH ), 4.37 (t, 2H,
3 2 2
CH ), 8.46 (s, 1H, CH), 9.37 (s, 1H, NH)
2
a
1690 (NC O), 3300 (NH)
3.70 (s, 2H, CH ), 7.00—7.55(m, 5H, C H5), 8.47 (s, 1H, CH), 10.99 (s,
2 6
1
H, NH)
a
1685 (NC O), 3295 (NH)
2.39 (s, 3H, CH ), 3.69 (s, 2H, CH ), 7.20—7.45(m, 4H, C H ), 8.43 (s,
3
2
6
4
1
H, CH), 10.98 (s, 1H, NH)
a
1690 (NC O), 3320 (NH)
3.63 (s, 2H, CH ), 3.89 (s, 3H, OCH ), 7.10 (d, 2H, 2CH), 7.45 (d, 2H,
2 3
2
CH), 8.40 (s, 1H, CH), 10.98 (s, 1H, NH)
a
g
h
i
1690 (NC O), 3300 (NH)
3.86 (s, 2H, CH ), 5.52 (s, 2H, CH ), 7.48 (s, 5H, C H5), 8.55 (s, 1H,
2
2
6
CH), 9.23 (s, 1H, NH),
a
1680 (NC O), 3200—3300(NH)
3.66 (s, 2H, CH ), 3.72 (s, 3H, OCH ), 5.14 (s, 2H, CH ), 6.92 (d, 2H,
2 3 2
2
CH), 7.34 (d, 2H, 2CH), 8.69 (s, 1H, CH), 10.65 (s, 1H, NH)
a
1685 (NC O), 3350 (NH)
3.86 (s, 2H, CH ), 5.50 (s, 2H, CH ), 7.44 (s, 4H, C H ), 8.48 (s, 1H,
2
2
6
4
CH), 9.34 (s, 1H, NH)
a
k
l
1685 (NC O), 3340 (NH)
3.86 (s, 2H, CH ), 5.54 (s, 2H, CH ), 6.47—7.50(m, 3H, 3CH), 8.42 (s,
2
2
1
H, CH), 9.42 (s, 1H, NH)
1660 (NC O), 1685 (NC O), 3300 (NH)
1655 (NC O), 1680 (NC O), 3325 (NH)
3.26 (t, 2H, CH ), 3.86 (s, 2H, CH ), 4.65 (t, 2H, CH ), 7.14—7.34(m,
2 2 2
5
H, C H5), 8.46 (s, 1H, CH), 9.32 (s, 1H, NH)
6
m
1.97 (m, 6H, 3CH ), 2.49 (m, 2H, CH ), 3.87 (s, 2H, CH ), 5.34 (m, 1H,
2 2 2
CH), 8.40 (s, 1H, CH), 9.48 (s, 1H, NH)
a
A band with a shoulder.
MS: m/z (M ) 244.
The data refer to the mainly formed geometric isomer.
b
c
+
ꢁ
ꢁ
7
H-Pyrimido[4 ,5 :4,5]thieno[2,3-b][1,4]-
ethanol, and recrystallized from the mixture
acetic acid–DMSO ∼3:1.
thiazine-4,8(3H,9H)-dione 6
(
B) A solution of compound 5 in dioxane (30 mL)
was refluxed and saturated with anhydrous am-
monia for 3 h. Methanol released was removed
in vacuo. The precipitate was recrystallized
from the mixture acetic acid–DMSO ∼3:1. The
(
A) A mixture of compound 4 (4 mmol) and for-
mamide (10 mL) was refluxed for 5 h. The pre-
cipitate formed was filtered off, washed with
1
IR and H NMR spectra for the samples of
compound 6 obtained from 4 and 5 were
identical.
7
H-3-Alkyl(aralkyl,aryl,cycloalkyl)pyrimido-
ꢁ
ꢁ
[4 ,5 :4,5]thieno[2,3-b][1,4]thiazine-
4,8(3H,9H)-diones 7a–m
A mixture of compound 4 (4 mmol), triethyl or-
thoformate (8 mL), and acetic anhydride (0.3 mL)
was refluxed for 2 h, cooled to 50 C, and treated
FIGURE 1 Perspective view and labeling scheme for the
molecule of compound 7i.
◦
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of New Thieno[2,3-b][1,4]thiazine Derivatives Starting from 2-Acylamino-3,3-dichloroacrylonitriles 415
˚
◦
located in the difference Fourier maps and included
in the final refinements with fixed positional and
TABLE 3 Selected Bond Lengths (A) and Bond Angles ( )
of Compound 7i
thermal parameters. Convergence was obtained at
S(1) C(1) 1.825(3)
S(1) C(8) 1.739(3)
S(2) C(7) 1.727(3)
S(2) C(8) 1.740(3)
N(1) C(2) 1.360(4)
N(1) C(3) 1.395(3)
N(2) C(4) 1.370(3)
N(2) C(5) 1.295(4)
N(3) C(5) 1.362(4)
N(3) C(6) 1.417(3)
C(1) C(2) 1.504(4)
C(3) C(4) 1.423(4)
C(3) C(8) 1.360(4)
C(4) C(7) 1.378(4)
C(6) C(7) 1.440(3)
C(1) S(1) C(8) 95.60(13)
C(7) S(2) C(8) 90.43(12)
C(2) N(1) C(3) 124.3(2)
C(4) N(2) C(5) 114.0(2)
C(5) N(3) C(6) 122.9(2)
S(1) C(1) C(2) 114.1(2)
N(1) C(2) C(1) 116.1(2)
N(1) C(3) C(8) 123.9(2)
C(4) C(3) C(8) 113.0(2)
N(2) C(4) C(7) 124.6(2)
C(3) C(4) C(7) 111.5(2)
N(2) C(5) N(3) 126.4(3)
N(2) C(5) N(3) 126.4(3)
N(3) C(6) C(7) 110.9(2)
S(2) C(7) C(4) 112.74(19)
C(4) C(7) C(6) 121.2(2)
S(1) C(8) C(3) 121.1(2)
S(2) C(8) C(3) 112.26(19)
N(3) C(9) C(10) 113.3(2)
2
R(F) = 0.056 and R
w
(F ) = 0.136, GOF = 0.120 (248
refined parameters; obs/variabl. = 9.5; the largest
and minimal peaks in the final difference map are
˚
−3
0
.46 and −0.40 e/A ). The Chebyshev weighting
scheme [19] with the parameters 472, 798, 530, 243,
and 74.3 was used [20].
REFERENCES
[
[
[
[
[
[
[
1] Drach, B. S.; Sviridov, E. P.; Kisilenko, A. A.; Kirsanov,
A. V. Zh Org Khim 1973, 9, 1818–1824.
2] Drach, B. S.; Sviridov, E. P.; Lavrenyuk, T. Ya. Zh Org
Khim 1974, 10, 1271–1274.
3] Matsumura, K.; Sarai, T.; Hashimoto, N. Chem
Pharm Bull 1976, 24, 924–940.
4] Matsumura, K.; Miyashita, O.; Shimadzu, H.;
Hashimoto, N. Chem Pharm Bull 1976, 24, 948–959.
5] Drach, B. S.; Mis’kevich, G. N. Zh Org Khim 1977, 13,
1
398–1404.
with an appropriate primary amine (6 mmol). The
mixture was refluxed for 2 h. The precipitate
was filtered off and recrystallized from acetic acid
6] Drach, B. S.; Mis’kevich, G. N. Zh Org Khim 1978, 14,
501–507.
7] Pilyo, S. G.; Brovarets, V. S.; Vinogradova, T. K.;
Golovchenko, A. V.; Drach, B. S. Zh Obshch Khim
(Table 1).
2
002, 72, 1818–1824.
[
[
8] Pilyo, S. G.; Brovarets, V. S.; Romanenko, Ye. A.;
Drach, B. S. Zh Obshch Khim 2002, 72, 1828–1833.
9] Vinogradova, T. K.; Mis’kevich, G. N.; Drach, B. S. Zh
Org Khim 1980, 16, 1869–1874.
X-ray Structure Determination for 7i
Crystal Data. C15
H
10ClN
3
O
2
S
2
,
M = 363.85,
[
10] Brovarets, V. S.; Pilyo, S. G.; Chernega, A. N.;
Romanenko, Ye. A.; Drach, B. S. Zh Obshch Khim
1999, 69, 1646–1651.
[11] Pilyo, S. G.; Brovarets, V. S.; Vinogradova, T. K.;
Chernega, A. N.; Drach, B. S. Zh Obshch Khim 2001,
˚
˚
triclinic, a = 6.951(1) A, b= 7.616(1) A, c= 14.698(5)
˚
◦
◦
◦
A, α = 104.31(2) , β = 92.81(2) , γ = 95.46(1) ,
˚
3
−3
V = 748.4(3) A , Z = 2, d = 1.61 g cm , space group
¯
−1
P1(N2), μ = 4.987 cm , F(0 0 0) = 372, crystal size
ca. 0.16 mm × 0.28 mm × 0.41 mm.
7
1, 310–315.
[
12] Golovchenko, O. V.; Pilyo, S. G.; Brovarets, V. S.;
Chernega, A. N.; Drach, B. S. Heteroatom Chem 2004,
15, 454–458.
[13] Rossy, Ph.; Vogel, F. C. M.; Haffmann, W.; Paust,
J.; Nurrenbach, A. Tetrahedron Lett 1981, 22,
Data Collection. All crystallographic measure-
◦
ments were performed at 20 C on a CAD-4
Enraf-Nonius diffractometer operating in the ω–2θ
scan mode (the ratio of the scanning rates
ω/2θ = 1.0). Intensity data were collected within the
3
493–3496.
[
14] Stephens, Ch. E.; Price, M. B.; Sowell, J. W. J. Hete-
rocycl Chem 1999, 36, 659–665.
◦
◦
range 3 < θ < 67 (0 ≤ h≤ 8, −9 ≤ k≤ 9, −17 ≤l ≤ 17)
[15] Zefirov, N. S.; Palyulin, V. A. Dokl Akad Nauk SSSR
980, 252, 111–115.
16] Kuleshova, L. N.; Zorkii, P. M. Acta Crystallogr Sect
B 1981, 37, 1363–1366.
17] North, A. C. T.; Phillips, D. C.; Mathews, F. S. Acta
Crystallogr Sect A 1968, 24, 351–359.
18] Watkin, D. J.; Prout, C. K.; Caruthers, J. R.;
Betteridge, P. W. CRYSTALS, Issue 10; Chemical
Crystallography Laboratory, University of Oxford:
Oxford, 1996.
1
using graphite-monochromated Cu Kꢀ radiation
[
[
[
˚
(
λ = 1.54178 A). Intensities of 2828 reflections (2343
unique reflections,
Rint = 0.020) were measured.
Data were corrected for Lorentz and polarization
effects, and an empirical absorption correction
based on azimuthal scan data was applied [17].
Structure Solution and Refinement. The struc-
ture was solved by direct methods and refined by the
full-matrix least-squares technique in the anisotropic
approximation using the CRYSTALS program pack-
age [18]. In the refinement, 2343 reflections with
I > 4σ(I) were used. All hydrogen atoms were
[19] Caruthers, J. R.; Watkin, D. J. Acta Crystallogr Sect A
979, 35, 698–699.
1
[
20] Full crystallographic details have been deposited at
Cambridge Crystallographic Data Center (CCDC).
Any request to the CCDC for this material should
quote the full literature citation and reference
number CCDC 292925.
Heteroatom Chemistry DOI 10.1002/hc