Ring Transformation and Cyclization Reactions of 1,1-Dioxo-1,2-thiazines -Syntheses of Pyridines and Benzo[c]thiazines with New Substitution Pattern

Article abstract of DOI:10.1002/(sici)1521-3897(199905)341:4<403::aid-prac403>3.0.co;2-x

In presence of ammonia/ammonium acetate the 3,5-dimethyl-2-phenyl-1,1-dioxo-1,2-thiazine-4-carbaldehyde (1) reacts with ethyl cyanoacetate to the ethyl 2-cyano-4-[1-methyl-2-methylthio-2-(N-phenylsulfamoyl)vinyl)-hexa-2,4-dienoate (3) and the Knoevenagel

Full text of DOI:10.1002/(sici)1521-3897(199905)341:4<403::aid-prac403>3.0.co;2-x

________________________________________________________________ PROCEDURES/DATA
Ring Transformation and Cyclization Reactions of 1,1-Dioxo-1,2-thiazines –
Syntheses of Pyridines and Benzo[c]thiazines with New Substitution Pattern
Hagen Bartossek and Egon Fanghänel*
Merseburg, Martin-Luther-Universität Halle-Wittenberg, Institut für Organische Chemie
Received Dezember 16th, 1998, respectively January 30th, 1999
Keywords: Aldehydes, Nitrogen heterocycles, Rearrangements, Knoevenagel condensation, Cyclisation reactions
Abstract. In presence of ammonia/ammonium acetate the
3,5-dimethyl-2-phenyl-1,1-dioxo-1,2-thiazine-4-carbalde-
hyde (1) reacts with ethyl cyanoacetate to the ethyl 2-cyano-
4-[1-methyl-2-methylthio-2-(N-phenylsulfamoyl)vinyl)-
hexa-2,4-dienoate (3) and the Knoevenagel condensation
product 4-(2-ethoxycarbonyl-2-cyanovinyl)-3,5-dimethyl-6-
methylthio-1,1-dioxo-2-phenyl-2H-1,2-thiazine (2a). The 4-
(2,2-dicyanovinyl)-3,5-dimethyl-6-methylthio-1,1-dioxo-2-
phenyl-2H-1,2-thiazine (2b) is obtained from 1 and malonon-
itril. The masked 1,5-dicarbonyl compound 2a undergoes rind
transformation to the 3-cyano-1,6-dimethyl-5-[1-methylth-
io-2-(N-phenylsulfamoyl)vinyl]pyridin-2-one (5) with meth-
ylamine. With ethanolic ethoxide the condensation products
2a,b afford the 7-amino-6-ethoxycarbonyl-4-methylthio-2,2-
dioxo-1-phenyl-benzo[c]1,2-thiazine (6a), respectively the
corresponding 6-cyano derivative 6b, while 3 cyclizises to
furnish ethyl 2-amino-6-methyl-5-[1-methyl-2-methylthio-
2-(N-phenyl-sulfamoyl)vinyl]nicotinate (4)
In the presence of ammonium acetate and ammonia the
reaction of the carbaldehyde 1 with ethyl cyanoacetate in etha-
nol a beige solid was obtained in 37% yield together with the
Knoevenagel product 2a (11%). The main product was char-
acterized by NMR as the open-chain compound 3. It should
be formed via a nucleophilic attack of ammonia on the 3-po-
sition of the thiazine ring in 1 or 2a (Scheme 2).
The substituted 2-amino nicotinate 4 is easily synthesised
from 3 by a sodium ethanolate induced ring closure reaction
at room temperature.
In former papers we described the synthesis [1] and the reac-
tions of 1,1-dioxo-1,2-thiazine-6-carbaldehydes [2]. These
compounds react as masked 1,5-dicarbonyl compounds with
ammonia or amines under ring transformation to pyridines.
The related thiazine-4-carbaldehydes – as masked 1,3-dicar-
bonyl compounds – give with nitrogen 1,2- or 1,3-dinucleo-
philes like hydrazines or amidines N-arylsulfamoylvinyl sub-
stituted pyrazoles or pyrimidines [3, 4]. In this paper we de-
scribe Knoevenagel condensations of the 1,1-dioxo-1,2-thi-
azine-4-carbaldehyde 1 with ethyl cyanoacetate and malono-
nitrile. The products contain a masked 1,5-dicarbonyl struc-
ture and should yield pyridines by ring transformation with
amines.
The 1,1-dioxo-1,2-thiazine-4-carbaldehyde 1 reacts with
ethyl cyanoacetate or malononitrile in the presence of triethyl-
amine and acetic acid at room temperature to yield the con-
densation products 2a,b. Under these reaction conditions no
reaction was observed with the less C-H-acidic acetylacetone
(Scheme 1).
COOEt
H
CN
NC-CH2-COOEt,
NH4OAc, NH3, EtOH
NH2
Me
1
2a
+
Me
SO2
3
37% (
)
MeS
NH
Ph
R1
3
H
O
N
H
R2
R1-CH2-R2, NEt3, AcOH
EtOH
Me
Me
Me
Me
NaOEt
EtOH (abs.)
41% (
)
4
69 ( ) resp. 51% (
2a
)
2b
N
MeS
S
Ph
MeS
S
Ph
Me
O
O
O O
MeS
PhHNO2S
COOEt
NH2
1
2a,b
R1
R2
Me
N
COOEt CN
a
b
4
CN
CN
Scheme 1
Scheme 2
J. Prakt. Chem. 1999, 341, No. 4
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 1436-9966/99/3410X-403 $ 17.50 + .50/0
403

H. Bartossek, E. Fanghänel
PROCEDURES/DATA _________________________________________________________________
Ring transformation of 2a with methylamine gives the
2-pyridone 5, probably by a mechanism similar to that de-
scribed for the ring transformation of the thiazine-4-carbal-
dehydes with hydrazines [3]. A 1,5-Michael addition of the
amine to the masked α,β,γ,δ-unsaturated carbonyl compound
2a (attack on the 3-position of the 1,1-dioxo-1,2-thiazine ring)
is followed by ring opening to the intermediate 3a which closes
the ring by reaction of the enamine/imine group with the es-
ter group (Scheme 3).This selective ring closure is favoured
under the used week basic reaction conditions, while a strong
basic medium induces the cyclization via the cyano group
(see 4 and 6ab).
The resulting intermediate attacks the nitrile group to yield
the benzo[c]thiazines 6a,b. This is a convenient method for
the preparation of substituted 2,2-dioxo-benzo[c]1,2-thiazines
(Scheme 4).
The structures of all new compounds were elucidated by
their NMR spectra (see Experimental).
Generous support by the Hermann-Schlosser-Foundation of
the DEGUSSA AG is gratefully acknowledged.
Experimental
NMR spectra were measured using a Varian Gemini 300 spec-
trometer (1H NMR 300 MHz; 13C NMR 75 MHz) and TMS
as internal standard. IR spectra were recorded on a Philips
PU 9426 FTIR spectrometer as KBr pellets and MS (EI) spec-
tra using an AMD 402 spectrometer. Microanalyses were
performed on a Leco CHNS-932 analyzer. Satisfactory micro-
analyses were obtained for all new substances (C, H, N, S, ±
0,4%). The 3,5-dimethyl-6-methylthio-1,1-dioxo-2-phenyl-
1,2-thiazine-4-carbaldehyde (1) was synthesized as described
in the literature [3].
CN
Ph
O2
H
COOEt
H
CH3NH2,
EtOH, H2
Me
N
O
Me
2a
- EtOH
78% (
)
5
Me
SO2
MeS
NH
Ph
3a
4-(2-Ethoxycarbonyl-2-cyanovinyl)-3,5-dimethyl-6-methyl-
thio-1,1-dioxo-2-phenyl-2H-1,2-thiazine (2a)
Me
Ph
O2
NH
S
CN
O
To a suspension of 1 (100 mg, 0.323 mmol) in EtOH (5 ml)
ethyl cyanoacetate (0.035 ml, 0.328 mmol), Et3N (0.045 ml,
0.323 mmol) and one drop of AcOH were added. After stir-
ring for 24 h 90% of the solvent was removed in vacuo. The
product 2a was separated as a yellow solid. Yield 91mg (69%);
m.p. 144 °C. – IR: ν/cm–1 = 2227 (CN), 1727 (CO) and 1596.
MeS
Me
N
Me
5
Scheme 3
1
– H NMR (DMSO-d6): δ/ppm = 1.29 (3H, t, 7 Hz, CH3),
1.99, 2.37, 2.43 (3H, s, 3CH3), 4.30 (2H, q, 7 Hz, CH2), 7.32
(2H, m, ArH), 7.56 (3H, m, ArH), 8.34 (1H, s). –
13C NMR (DMSO-d6): δ/ppm = 14.1, 19.4, 19.5, 19.6, 62.6,
110.0, 113.9, 114.9, 118.5, 128.9, 129.7, 130.2, 134.4, 146.9,
148.5, 156.5 and 161.3. – MS: m/z (%) = 404 (M+, 71), 340
(31), 325 (100).
Related 3-cyanopyridin-2-ones are of pharmaceutical in-
terest (“Milrinon”) [5, 6]. Furthermore, they are versatile start-
ing materials for syntheses of the cardiologic active imidazo-
and thiazolo[4,5-b]pyridin-2-(3H)-ones, which are presently
intensively investigated [7, 8].
We reported previously that the C-H acidic 3-methyl group
of 1,1-dioxo-1,2-thiazines is easily attacked by electrophiles
[9]. An example is the mild thiolation of 1 by sulfur in the
presence of triethylamine to give a thieno[3,4-c][1,2]thiazine
[10]. Correspondingly, the 3-methyl group of the Knoeve-
nagel products 2a,b is deprotonated with sodium ethanolate.
4-(2,2-Dicyanovinyl)-3,5-dimethyl-6-methylthio-1,1-dioxo-
2-phenyl-2H-1,2-thiazine (2b)
To a suspension of 1 (100 mg, 0.323 mmol) in EtOH (5 ml)
malononitrile (21 mg, 0.32 mmol), Et3N (5 µl, 0.0323 mmol)
and one drop of AcOH were added. After stirring for 3 h 90%
of the solvent was removed in vacuo. The product 2b was
separated as a yellow solid. Yield 59 mg (51); m.p. 186–
189 °C (EtOH). IR: ν/cm–1 = 2229 (CN). – 1H NMR (DMSO-
d6): δ/ppm = 2.03, 2.35, 2.44 (3H, s, 3CH3), 7.32 (2H, m,
ArH), 7.56 (3H, m, ArH), 8.56 (1H, s). – 13C NMR (DMSO-
d6): δ/ppm = 19.4, 19.6,87.4, 112.8, 113.5, 113.7, 123.0, 129.6,
130.1, 130.4, 133.9, 148.3, 149.1, 159.9. – MS: m/z (%) =
357 (M+), 293 (19), 278 (85), 263 (36).
R1
NH2
NaOEt
EtOH (abs.)
Me
2a,b
6a
6b
)
53 ( ) resp. 72% (
N
MeS
S
Ph
O
O
6a,b
Ethyl 2-cyano-4-[1-methyl-2-methylthio-2-(N-phenyl-
sulfamoyl)vinyl]hexa-2,4-dienoate (3)
R1
To a suspension of 1 (100 mg, 0.323 mmol) in EtOH (5 ml)
NH4OAc (38 mg, 0.493 mmol), ethyl cyanoacetate
(0.035 ml, 0.328 mmol) and ammonia liquor (22%, 0.04 ml,
a
b
COOEt
CN
Scheme 4
Scheme 4
404
J. Prakt. Chem. 1999, 341, No. 4

Ring Transformation and Cyclization Reactions of 1,1-Dioxo-1,2-thiazines
__________________________________________________________________________________ PROCEDURES/DATA
(10 ml) was added and 6a separated as a white solid by cen-
trifugation. Yield 53 mg (53%); m.p. 151–152 °C (EtOH).
IR: ν/cm–1 = 1695 (CO), 1313, 1153. – 1H NMR (DMSO-d6):
δ/ppm = 1.31 (3H, t, 6.5 Hz, CH3), 2.37, 2.63 (3H, s, 2CH3),
4.28 (2H, q, 6.6 Hz , CH2), 5.95 (1H, s, C(8)H), 7.16 (2H, s,
NH2), 7.34 (2H, m, ArH), 7.56 (3H, m, ArH), 8.15 (1H, s,
C(5)H). – 13C NMR (DMSO-d6): δ/ppm = 14.4, 18.3, 20.0,
60.5, 104.0, 106.2, 111.7, 123.7, 129.5, 129.7, 130.4, 132.4,
135.5, 145.4, 148.9, 152.9, 166.6. – MS: m/z (%) 404 (M+,
100), 325 (80).
≈ 0.5 mmol) were added. After stirring for 72 h 90 % of the
solvent was removed in vacuo. The precipitated solid was
washed with water and recrystallized from ethanol to yield 3.
From the filtrate the solvent was removed in vacuo to yield
the side product 2a. Yield 45 mg (37%); m.p. 187–188 °C
1
(EtOH). IR: ν/cm–1 = 2192 (CN), 1689 (CO). – H NMR
(DMSO-d6): δ/ppm = 1.21 (3H, t, 6.7 Hz, CH3), 2.19, 2.29,
2.35 (3H, s, 3CH3), 4.10 (2H, q, 5 Hz, CH2), 6.94 (2H, m,
ArH), 7.14 (3H, m, ArH), 7.35 (1H, br s), 7.72 (1H, br s),
8.40 (1H, br s), 9.8 (1H, br s). – 13C-NMR (DMSO-d6):
δ/ppm = 14.7, 17.5, 18.6, 26.6, 59.9, 78.2, 108.4, 118.4, 119.1,
122.5, 128.8, 138.7, 138.9, 147.4, 152.8, 164.3, 166.4. – MS:
m/z (%) = 421 (M+,71), 404 (100), 340 (34), 325 (93).
7-Amino-6-cyano-4-methyl-3-methylthio-2,2-dioxo-1-phe-
nyl-benzo[c]-1,2-thiazine (6b)
To a suspension of 2b (100 mg, 0,28 mmol) in abs. EtOH
(1 ml) a solution of sodium ethanolate (7 mg Na, 0.3 mmol,
0.2 ml abs. EtOH) was added. After stirring for 4 h 6b was
separated as a white solid. Yield 72 mg (72%); m.p. 189 –
191 °C. – IR: ν/cm–1 = 1322, 1151. – 1H NMR (DMSO-d6):
δ/ppm 2.37, 2.63 (3H, s, 2CH3), 5.94 (1H, s, C(8)H), 6.67
(2H, s, NH2), 7.3 (2H, d, 7 Hz, ArH), 7.56 (3H, m, ArH), 7.96
(1H, s, C(5)H). – 13C NMR (DMSO-d6): δ/ppm = 19.1, 20.6,
91.5, 103.5, 113.3, 118.0, 125.0, 130.8, 131.1, 131.4, 135.5,
136.1, 146.1, 149.2, 153.6. – MS: m/z (%) = 357 (M+, 98),
278 (100).
Ethyl 2-Amino-6-methyl-5-[1-methyl-2-methylthio-2-(N-phe-
nyl-sufamoyl)vinyl]nicotinate (4)
To a suspension of 3 (100 mg, 0,237 mmol) in abs. EtOH
(5 ml) a solution of sodium ethanolate (3.5 mg Na, 0.152
mmol, 2 ml abs. EtOH) was added. After stirring for 24 h the
solvent was removed in vacuo. The residue was suspended in
water to yield 4 as a light yellow solid. Yield 40 mg (41%);
m.p. 221–223 °C (EtOH). – IR: ν/cm–1 = 1685 (CO). –
1H NMR (DMSO-d6): δ/ppm = 1.31 (3H, t, 6.8 Hz, CH3),
2.09 (3H, s, CH3), 2.33 (6H, s, CH3), 4.28 (2H, q, 6.8 Hz,
CH2), 7.01 (3H, m, ArH), 7.14 (2H, s, NH2), 7.23 (3H, m,
ArH), 7.41 (1H, s, C(4)H), 10.1 (1H, s, NH). – 13C NMR
(DMSO-d6): δ/ppm = 14.4, 19.0, 22.3, 27.1, 60.6, 101.8, 119.4,
123.6, 124.2, 129.1, 134.6, 136.9, 137.9, 157.6, 158.3, 166.6.
– MS: m/z (%) = 421 (M+, 54), 265 (54), 218 (100).
References
[1] E. Fanghänel, H. A. Mohammed, A. M. Richter, R. Radeglia,
Z. Chem. 1984, 24, 403
[2] E. Fanghänel, A. Hucke, Th. Lochter, U. Baumeister, H.
Hartung, Synthesis 1996, 1375
[3] E. Fanghänel, H. Bartossek, Th. Lochter, U. Baumeister, H.
Hartung, J. Prakt. Chem. 1997, 339, 277
[4] E. Fanghänel, H. Bartossek, U. Baumeister, H. Hartung, Lie-
bigs Ann./Recueil 1997, 2617
[5] A. A. Alousi and J. Edelson, in Pharmacological and Bio-
chemical Properties of Drug Substances, American Pharma-
ceutical Association Washington DC 1982, Vol. 3, p. 120
[6] A. A. Alousi, G. P. Stankus, J. C. Stuart, L. H. Walton, J.
Cardiovasc. Pharmacol. 1983, 804
[7] B. Singh, E. R. Bacon, S. Robinson, R. K. Fritz, G. Y. Lesh-
er, V. Kumar, J. A. Dority, M. Reumann, G.-H. Kuo, M. A.
Eissenstat, E. D. Pagani, D. C. Bode, R. G. Bentley, M. J.
Connell, L. T. Hamel, P. J. Silver, J. Med. Chem. 1994, 37,
248
[8] V. Cody, A. Wojtczak, F. B. Davis, P. J. Davis, S. D. Blas, J.
Med. Chem. 1995, 38, 1990
3-Cyano-1,6-dimethyl-5-[1-methyl-2-methylthio-2-(N-
phenylsulfamoyl)vinyl]pyridin-2-one (5)
Route A: To a suspension of 2a (100 mg, 0,247 mmol) in
EtOH (5 ml) a solution of methylamine in water (0.031 ml,
0.333 mmol, 33%) was added. After stirring for 24 h 50% of
the solvent was removed in vacuo, and the precipitated pyri-
din-2-one 5 was separated. Yield 75mg, (78%); m.p. 237–
240 °C (EtOH). IR: ν/cm–1 = 2229 (CN), 1637 (CO). –
1H NMR (DMSO-d6): δ/ppm = 2.10, 2.29, 2.38 (3H, s, 3CH3),
3.47 (3H, s, NCH3), 7.00 (3H, d, 7.8 Hz, ArH), 7.08 (1H, t,
7.3 Hz, ArH), 7.28 (2H, t, 7.4 Hz, ArH), 7.35 (1H, s, C(4)H),
9.8 (1H, br s, NH). – 13C NMR (DMSO-d6): δ/ppm = 18.8,
19.0, 26.5, 32.0, 98.4, 116.8, 117.9, 120.2, 124.1, 129.3, 137.4,
137.6, 145.3, 151.0, 153.9, 159.9. – MS: m/z (%) = 389 (M+,
30), 233 (19), 186 (100).
[9] E. Fanghänel, B. Bode, K.-H. Bedemann, R. Radeglia, J.
Prakt. Chem. 1988, 330, 79
[10] E. Fanghänel, H. Bartossek, U. Baumeister, M. Biedermann,
H. Hartung, J. Heterocycl. Chem. 1998, 35, 1449
Route B: To a suspension of 1 (100 mg, 0.323 mmol) in EtOH
(5 ml) NH4OAc (38 mg, 0.493 mmol), ethyl cyanoacetate
(0.035 ml, 0.328 mmol) and a solution of methylamine in
water (33%, 0.03 ml, ≈ 0.323 mmol) were added. After stir-
ring for 72 h 50% of the solvent was removed in vacuo and 5
separated. Yield 15 mg (12%); m.p. 237–240 °C (EtOH).
Address for correspondence:
Prof. Dr. Egon Fanghänel
7-Amino-6-ethoxycarbonyl-4-methyl-3-methylthio-2,2-dioxo-
Martin-Luther-Universität Halle-Wittenberg
Institut für Organische Chemie
D-06099 Halle
Fax: Intern. code (0)3461-462081
e-mail: fanghaenel @chemie.uni-halle.de
1-phenyl-benzo[c]-1,2-thiazine (6a)
To a suspension of 2a (100 mg, 0,247 mmol) in abs. EtOH
(1 ml) a solution of sodium ethanolate (6.25 mg Na, 0.272
mmol, 1ml abs. EtOH) was added. After stirring for 24 h water
J. Prakt. Chem. 1999, 341, No. 4
405