Facile synthesis of 2-(substituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4- ones

Article abstract of DOI:10.1007/s00706-008-0920-6

Interaction between 2,5-dichlorothiophene-3-carbonyl isothiocyanate, accessible via 2,5-dichlorothiophene-3-carbonyl chloride, and model heterocyclic amines produced the respective 2,5-dichloro-N-(substituted aminocarbonothioyl) thiophene-3-carboxamides. Upon heating, the deprotonated form of the latter underwent intramolecular cyclization to deliver the corresponding 2-(substituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones. The structures of these new bicyclic derivatives and their acyclic precursors are based on microanalytical and spectral (IR, MS, and NMR) data.

Full text of DOI:10.1007/s00706-008-0920-6

Monatsh Chem 139, 1251–1255 (2008)
DOI 10.1007/s00706-008-0920-6
Printed in The Netherlands
Facile synthesis of 2-(substituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones
1
1
2
Rajab Abu-El-Halawa , Alaa Sarabi , Mustafa M. El-Abadelah
1
Chemistry Department, Faculty of Science, Al al-Bayt University, Mafraq, Jordan
Chemistry Department, Faculty of Science, The University of Jordan, Amman, Jordan
2
Received 1 March 2008; Accepted 1 March 2008; Published online 15 May 2008
Springer-Verlag 2008
#
Abstract Interaction between 2,5-dichlorothiophene-
-carbonyl isothiocyanate, accessible via 2,5-di-
chlorothiophene-3-carbonyl chloride, and model
heterocyclic amines produced the respective 2,5-di-
chloro-N-(substituted aminocarbonothioyl)thiophene-
chemical fungicide [4], and 1e that acts as broncho-
dilator, phosphordiesterase inhibitor, and is useful
for symptomatic relief in asthma and other respira-
tory diseases [5].
3
Few heteroarenes fused to the 1,3-thiazine ring,
such as pyrido[3,2-e]-1,3-thiazienes (2, Fig. 1), are
known. The latter 2 are 8-aza analogs of 1 and several
derivatives have been synthesized and claimed [6]
to possess kainic acid neuronotoxicity inhibitory ac-
tivity, useful as nervous cell protectors for prevention
and treatment of diabetes mellitus, Parkinson disease,
psychosis, epilepsy, ischemic brain diseases, multiple
scleredema, neuroallergy diseases, Huntington cho-
rea, Alzheimer diseases, drug dependence, and related
diseases.
3
-carboxamides. Upon heating, the deprotonated form
of the latter underwent intramolecular cyclization to
deliver the corresponding 2-(substituted amino)-4H-
thieno[3,2-e]-1,3-thiazin-4-ones. The structures of
these new bicyclic derivatives and their acyclic pre-
cursors are based on microanalytical and spectral (IR,
MS, and NMR) data.
Keywords 2,5-Dichlorothiophene-3-carbonyl isothiocya-
nate; sec-Cyclic amines; N-(3-thienylcarbonyl)thioureas;
Thieno[3,2-e]-1,3-thiazin-4-ones; S AE reactions.
N
From the point of isosterism, the thiophene ring
system is commonly used as replacement of the ben-
zene ring in several pharmaceutical agents. To date
the synthesis and chemistry of some thieno[3,2-d]-
[1,3]thiazin-4-ones, exemplified by 3a [7], 3b, and
3c [8] have been described in literature.
To the best of our knowledge, the isomeric 4H-
1,3-thieno[3,2-e]thiazin-4-one bicyclic system 8, a
bioisostere of 4H-1,3-benzothiazin-4-one (1), is hith-
erto undescribed. Accordingly, we thought it would
be worthwhile to synthesize a new set of 2-(sub-
stituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones
Introduction
Several 4H-1,3-benzothiazin-4-one derivatives (1,
Fig. 1) have been prepared and showed interesting
pharmacological activities, particularly those incor-
porating heterocyclic or amino appendages at the
C-2 locus [1–5]. Examples include 1a, an inhibitor
of apoptosis and cytoprotective agent [1], 1b useful
as heart muscle cell apoptosis inhibitor and remedy
for heart diseases [2], 1c that displays inhibitory
effects on xanthine oxidase [3], 1d patented as agro-
(8a–8d) utilizing the appropriate acyclic synthons
2,5-dichloro-N-(substituted aminocarbonothioyl)thio-
phene-3-carboxamides (7a–7d) as illustrated in
Scheme 1.
Correspondence: Rajab Abu-El-Halawa, Chemistry Depart-
ment, Faculty of Science, Al al-Bayt University, Mafraq, Jordan.
E-mail: halawarajab@yahoo.com or rajab@aabu.edu.jo

1
252
R. Abu-El-Halawa
Fig. 1
isothiocyanate (6). The reaction of the latter with
cyclic secondary amines (exemplified by piperidine,
morphopline, thiomorpholine, and N-methylpiperazine)
afforded the corresponding 2,5-dichloro-N-(substi-
tuted aminocarbonothioyl)thiophene-3-carboxamides
7a–7d. Upon heating, deprotonated 7a–7d under-
went intramolecular cyclization to produce the de-
sired heterocyclic compounds 8a–8g (Scheme 1).
Elemental analyses and spectral (MS and NMR)
data of the new compounds 7 and 8, given in the ex-
perimental part, are in accordance with the assigned
structures. Thus, their MS spectra display the correct
molecular ions as suggested by their molecular for-
mulae. The isotopic cluster for 7 (M, M þ 2, and
M þ 4) with relative intensities 9:6:1 is in accord
with the presence of two chlorine atoms. The molec-
ular ion region of the bicyclic compounds 8 displays
isotopic cluster (M and M þ 2) with relative inten-
sities 3:1, thus confirming the presence of only one
chlorine atom. A prominent fragmentation pattern of
7, under electron impact, involves loss of a chlorine
atom to form the cation A as the base peak which is
Scheme 1
Results and discussion
In the present work, a new selected set of 2,5-
dichloro-N-(substituted amino-carbonothioyl)thio-
phene-3-carboxamides (7a–7d) and 2-(substituted
amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones (8a–8d)
were synthesized, utilizing 2,5-dichlorothiophene-
þ
equivalent to [M] -Cl. The latter fragments further
to form the corresponding cyanamidium cation B
(Scheme 2). Another fragmentation mode of the mo-
lecular ion involves amide cleavage to produce the
corresponding cation C (m=z ¼ 179), which then
extrudes carbon monoxide to give the cation D
(m=z ¼ 151). The EI fragmentation pattern of 8 pro-
ceeds via elimination of a cyanamide molecule from
the molecular ion leading to the formation of the
respective ion E (m=z ¼ 176) as the base peak in
8a–8d (Scheme 3). The latter ion suffers extrusion
of CO to deliver ion F (m=z ¼ 148), which then elim-
inates a chlorine atom and CS with ultimate produc-
tion of ion G (m=z ¼ 69).
3
-carboxylic acid (4). The latter acid is prepared
according to a reported procedure [10] that involves
the reaction of 2,5-dichlorothiophene with acetyl
chloride in carbon disulfide in the presence of alu-
minum trichloride, followed by treatment of the re-
sulting 3-acetyl-2,5-dichlorothiophene with sodium
hypochloride solution followed by acidification. The
acid 4 was converted into 2,5-dichlorothiophene-3-
carbonyl chloride (5) upon interaction with thionyl
chloride according to Ref. [11].
Treatment of 5 with potassium thiocyanate in ace-
tonitrile yielded 2,5-dichlorothiophene-3-carbonyl

2
-(Substituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones
1253
Scheme 2
Scheme 3
1
13
H and C NMR spectroscopic data of com-
3
-Acetyl-2,5-dichlorothiophene was prepared via reac-
tion of 2,5-dichlorothiophene with acetyl chloride in carbon
disulphide in the presence of anhydrous aluminum trichlor-
ide, following Ref. [9]. 2,5-Dichlorothiophene-3-carboxylic
acid (4) was prepared by oxidation of 3-acetyl-2,5-di-
pounds 7a–7d and 8a–8d are in agreement with
the suggested structures. Signal assignments to the
various protons and carbons followed from DEPT
and 2D (COSY, HMQC, HMBC) experiments. The
thieno H-4 proton resonates as a singlet around
ꢁ
chlorothiophene using 10% aq. NaOCl solution at 55 C
according to Ref. [10]. 2,5-Dichlorothiophene-3-carbonyl
chloride (5) was prepared by interaction between 4 and
thionyl chloride in dry benzene under reflux for 6 h, follow-
ing Ref. [11].
ꢀ
¼ 7.20 and 7.49ppm for compounds 7a–7d and
a–8d, while the exchangeable C(3)-NH proton in
a–7d resonates at ca. 8.68 ppm. The IR spectra of
a–7d showed strong absorption bands, arising from
8
7
7
2
,5-Dichlorothiophene-3-carbonyl isothiocyanate
stretching vibrations, around 3180 for N–H, 1670
for C¼O, and 1240 cm for C¼S groups. On the
(
6, C H Cl NOS )
1
6
2
2
ꢀ1
Potassium thiocyanate (3.5g, 36 mmol) was added portion-
wise to a stirred solution of 2.8 g 2,5-dichlorothiophene-3-
3
carbonyl chloride (5) (13 mmol) in 25cm acetonitrile at room
temp. The reaction mixture was stirred further for 2 h, the pre-
cipitated KCl was filtered off, and the organic solvent was
evaporated from the filtrate under reduced pressure. The title
compound was obtained as a crude orange solid, which was
used in the next step without further purification. Yield 2.91 g
other hand, the IR spectra of 8a–8d showed also a
ꢀ1
strong absorption band around 1630 cm for the
C¼O group, but lacked the characteristic peaks for
the N–H and C¼S groups.
Experimental
(94%).
2
,5-Dichlorothiophene was purchased from Acros. Piperidine,
morpholine, thiomoropholine, and 1-methylpiperazine were
purchased from Fluka. Melting points were determined by
Electrothermal-9002 apparatus. IR Spectra were obtained for
KBr discs on a Nicolet Impact-400 FT-IR spectrophotometer.
2
,5-Dichloro-N-(substituted aminocarbonothioyl)thiophene-
3-carboxamides 7a–7d (General procedure)
A solution of 12mmol of the appropriate secondary amine in
1
13
3
10cm diethyl ether was added dropwise to a stirred solution
H and C NMR spectra were recorded on a Bruker DPX-300
3
of 2.86 g 6 (12 mmol) in 40cm diethyl ether. The resulting
instrument. Chemical shifts are expressed in ppm with refer-
ence to TMS as internal standard. Electron impact mass spec-
tra (EIMS) were taken with Finnigan MAT-731 at 70 eVand at
mixture was further stirred at room temp and the reaction
was completed within 7–8 h (as evidenced from TLC).
The precipitated solid product was collected by suction
filtration, washed with water, and purified by recrystalliza-
ꢁ
ion source temperature of 200 C. For analyses, all new com-
pounds were further purified on preparative TLC silica-gel
glass plates using dichloromethane as eluent. Elemental anal-
yses (C, H, N, S) were carried out at Stuttgart University=
Germany, and the results were found to be in good agreement
ꢁ
tion from dichloromethane=petroleum ether (bp 40–60 C).
For analyses, compounds 7a–7d were further purified on pre-
parative TLC silica-gel glass plates using dichloromethane as
eluent.
(
ꢂ0.3%) with the calculated values.

1
254
R. Abu-El-Halawa
ꢁ
2
,5-Dichloro-N-(piperidin-1-ylcarbonothioyl)thiophene-3-
lization from chloroform=petroleum ether (bp 40–60 C).
For analyses, compounds 8a–8d were further purified on
preparative TLC silica-gel glass plates using chloroform as
eluent.
carboxamide (7a, C H Cl N OS )
1
1
12
2
2
2
ꢁ
Yield 82%; mp 120–122 C; IR (KBr): ꢁꢀ ¼ 3184 (N–H),
078, 2887 (C–H), 1772 (C¼O), 1534 (C¼N), 1242
3
ꢀ
1
1
(
C¼S) cm
;
H NMR (300 MHz, CDCl ): ꢀ ¼ 1.71 (br
0 0 0 0
2 2 2 2
3
0
m, H -3 þ H -4 þ H -5 ), 3.61, 4.13 (2 br, H -2 þ H -6 ),
6-Chloro-2-(piperidin-1-yl)-4H-thieno[3,2-e]-1,3-thiazin-4-
2
1
3
7
.19 (s, H-4), 8.67 (br s, NH) ppm; C NMR (75 MHz,
one (8a, C H ClN OS )
1
1
11
2
2
0
0
0
ꢁ
CDCl ): ꢀ ¼ 23.1 (C-4 ), 25.2, 26.5 (C-3 , C-5 ), 52.4,
3
Yield 66%; mp 137–138 C; IR (KBr): ꢁꢀ ¼ 3082, 2876 (C–H),
ꢀ1
0
0
1
5
1
2.7 (C-2 , C-6 ), 127.3 (C-4), 127.7 (C-3), 130.2 (C-5),
32.3 (C-2), 156.3 (C¼S), 176.8 (C¼O) ppm; EIMS: m=z
1
630 (C¼O), 1540, 1514 (C¼N) cm ; H NMR (300 MHz,
0 0 0
3 2 2 2 2
CDCl ): ꢀ ¼ 1.72 (br m, H -3 þ H -4 þ H -5 ), 3.79 (br, H -
þ
13
0
0
(
8
%) ¼ 322 (M , 3), 287 (100), 179 (51), 151 (11), 111 (33),
2
ꢀ
5
(
(
þ H -6 ), 7.49 (s, H-5) ppm; C NMR (75 MHz, CDCl ):
2
3
0 0 0 0 0
4 (54).
¼ 23.4 (C-4 ), 25.5 (C-3 , C-5 ) 47.9, (C-2 , C-6 ), 125.3 (C-
), 126.0 (C-4a), 128.8 (C-6), 136.1 (C-7a), 160.2 (C-2), 164.3
þ
C-4) ppm; EIMS: m=z (%) ¼ 286 (M , 26), 176 (100), 148
2
,5-Dichloro-N-(morpholin-4-ylcarbonothioyl)thiophene-3-
17), 69 (24).
carboxamide (7b, C H Cl N O S )
0
1
10
ꢁ
2 2 2 2
Yield 83%; mp 152–153 C; IR (KBr): ꢁꢀ ¼ 3188 (N–H), 2966,
ꢀ
0
1
2
861 (C–H), 1674, C¼O), 1516 (C¼N), 1240 (C¼S) cm
;
6-Chloro-2-(morpholin-4-yl)-4H-thieno[3,2-e]-1,3-thiazin-4-
1
0
H NMR (300MHz, CDCl ): ꢀ ¼ 3.84 (br, H -3 þ H -5 ),
one (8b, C H ClN O S )
10
3
2
2
9
2 2 2
0
0
ꢁ
3
.64, 4.21 (2 br, H -2 þ H -6 ), 7.23 (s, H-4), 8.71 (br
Yield 78%; mp 190–191 C; IR (KBr): ꢁꢀ ¼ 3078, 2886 (C–
2
2
1
3
ꢀ1
1
s, NH) ppm; C NMR (75 MHz, CDCl ): ꢀ ¼ 51.5, 52.6
H), 1638 (C¼O), 1540, 1510 (C¼N) cm
;
H NMR
3
0
0
0
0
0
13
0
(
3
C-2 , C-6 ), 63.1, 66.9 (C-3 , C-5 ), 127.1 (C-4), 127.7 (C-
), 129.8 (C-5), 130.0 (C-2), 156.2 (C¼S), 177.9 (C¼O) ppm;
(300 MHz, CDCl ): ꢀ ¼ 3.81 (br, H -2 þ H -6 ), 3.83 (br,
3
2
2
0
0
H -3 þ H -5 ), 7.50 (s, H-5) ppm; C NMR (75 MHz,
2
2
þ
0
0
0
0
EIMS: m=z (%) ¼ 324 (M , 12), 289 (100), 179 (62), 151 (9),
CDCl ): ꢀ ¼ 46.6, (C-2 , C-6 ), 66.1 (C-3 , C-5 ), 125.0 (C-
3
1
13 (22), 86 (29).
5), 126.0 (C-4a), 129.3 (C-6), 135.7 (C-7a), 161.2 (C-2), 164.0
þ
(
(
C-4) ppm; EIMS: m=z (%) ¼ 288 (M , 19), 176 (100), 148
19), 69 (29).
2
3
,5-Dichloro-N-(thiomorpholin-4-ylcarbonothioyl)thiophene-
-carboxamide (7c, C H Cl N OS )
1
0
10
2
2
3
ꢁ
6-Chloro-2-(thiomorpholin-4-yl)-4H-thieno[3,2-e]-1,3-
Yield 84%; mp 154–155 C; IR (KBr): ꢁꢀ ¼ 3188 (N–H), 3100,
ꢀ
0
1
2
910 (C–H), 1662 (C¼O), 1520 (C¼N),1242 (C¼S) cm
;
thiazin-4-one (8c, C10
H
9
ClN
ꢁ
2
OS
3
)
1
0
H NMR (300MHz, CDCl ): ꢀ ¼ 2.83 (br, H -3 þ H -5 ),
Yield 82%; mp 169–170 C; IR (KBr): ꢁꢀ ¼ 3086, 2887
3
2
2
0
0
ꢀ1
1
3
.95, 4.43 (2 br, H -2 þ H -6 ), 7.20 (s, H-4), 8.68 (br s,
(C–H), 1632 (C¼O), 1532, 1512 (C¼N) cm ; H NMR
2
2
1
3
0
0
0
-5 ), 3.45 (br,
2
NH) ppm; C NMR (75 MHz, CDCl ): ꢀ ¼ 27.8, 28.4 (C-3 ,
(300 MHz, CDCl
3
): ꢀ ¼ 3.42 (br, H
2
-3 þ H
3
0
0
0
0
0
-6 ), 7.48 (s, H-5) ppm; C NMR (75 MHz,
2
13
C-5 ), 53.6, 54.2 (C-2 , C-6 ), 127.2 (C-4), 127.7 (C-3), 129.7
H
CDCl
2
-2 þ H
0
0
0
0
(
C-5), 131.0 (C-2), 156.1 (C¼S), 178.4 (C¼O), ppm; EIMS:
3
): ꢀ ¼ 29.3 (C-3 , C-5 ), 47.1, (C-2 , C-6 ), 125.0
þ
m=z (%) ¼ 340 (M , 21), 305 (100), 179 (68), 151 (11), 129
(C-5), 126.0 (C-4a), 129.1 (C-6), 135.8 (C-7a), 161.0
(C-2), 164.2 (C-4) ppm; EIMS: m=z (%) ¼ 304 (M , 46),
þ
(13), 102 (8).
1
76 (100), 148 (23), 69 (18).
2
,5-Dichloro-N-(4-methylpiperazin-1-ylcarbonothioyl)thio-
6
-Chloro-2-(4-methylpiperazin-1-yl)-4H-thieno[3,2-e]-1,3-
phene-3-carboxamide (7d, C H Cl N OS )
3
1
1
13
2
2
ꢁ
thiazin-4-one (8d, C H ClN OS )
11 12
Yield 81%; mp 151–152 C; IR (KBr): ꢁꢀ ¼ 3190 (N–H), 3097,
3
2
ꢀ
1
ꢁ
2
914 (C–H), 1632 (C¼O), 1536 (C¼N), 1242 (C¼S) cm
;
Yield 75%; mp 162–163 C; IR (KBr): ꢁꢀ ¼ 3085, 2886 (C–H),
1
ꢀ1
1
H NMR (300 MHz, CDCl ): ꢀ ¼ 2.35 (s, NCH ), 2.55 (br,
1636 (C¼O), 1538, 1515 (C¼N) cm ; H NMR (300 MHz,
3
3
0
0
0
0
0
0
-5 ), 3.85
2
H -3 þ H -5 ), 3.65, 4.22 (2 br, H -2 þ H -6 ), 7.19 (s, H-4),
CDCl
(br, H
CDCl
3
): ꢀ ¼ 2.34 (s, NCH
3
), 2.44 (br, H
2
-3 þ H
2
2
2
2
1
3
0
0
-6 ), 7.49 (s, H-5) ppm; C NMR (75 MHz,
2
13
8
.69 (br s, NH) ppm; C NMR (75 MHz, CDCl ): ꢀ ¼ 46.3
2
-2 þ H
3
0
0
0
0
0 0 0 0
), 46.1 (C-3 , C-5 ), 54.4, (C-2 , C-6 ),
3
(
(
1
NCH ), 51.1, 51.8 (C-2 , C-6 ), 54.3, 54.5 (C-3 , C-5 ), 127.2
3
3
): ꢀ ¼ 42.2 (NCH
C-4), 127.5 (C-3), 129.7 (C-5), 131.1 (C-2), 156.2 (C¼S),
125.0 (C-5), 126.0 (C-4a), 129.0 (C-6), 136.1 (C-7a), 161.9
þ
þ
77.5 (C¼O) ppm; EIMS: m=z (%) ¼ 337 (M , 15), 302
(C-2), 163.8 (C-4), ppm; EIMS: m=z (%) ¼ 301 (M , 9), 176
(
100), 179 (75), 151 (18), 126 (23), 99 (25).
(100), 148 (10), 69 (13).
2
-(Substituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones
Acknowledgements
8a–8d (General procedure)
Sodium hydride (0.48 g, 60% dispersion in mineral oil,
We thank the Deanship of Graduate Studies of Al al-Bayt
University (Mafraq, Jordan). We are also grateful for a re-
search grant from Deutsche Forschungsgemeinschaft (to
R. Abu-El-Halawa) and for the generous hospitality and dis-
cussions of Professor Volker J a¨ ger at the Institute of Organic
Chemistry, University of Stuttgart, Germany.
1
1
2 mmol) was added portionweise to a stirred solution of
3
0 mmol of the appropriate 4 in 30 cm dioxane. The reac-
tion mixture was refluxed for 16 h, the solvent was then
removed under reduced pressure, the residual solid product
was washed with 3ꢃ5 cm H O, and purified by recrystal-
3
2

2
-(Substituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones
1255
6
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