1,3- thiazin-4-one - Jordan Journal of Chemistry (JJC)

Jordan Journal of Chemistry Vol. 9 No.2, 2014, pp. 127-133
JJC
One-Pot Synthesis of 2-Alkyl/arylamino-6-chlorothieno[3,2-e]-1,3thiazin-4-one
Rajab Abu-El-Halawa
1
2
1, 2
1
1
, Imad Elddin Haj Elhussin , Mahmoud Al-Refai ,
1
Mohammad Ibrahim
Chemistry Department, Al al-Bayt University, Mafraq, Jordan
Current Address: Clinical Pharmaceutical College, Albaha University, SA
Received on March 9, 2014
Accepted on May 29, 2014
Abstract
2-Alkyl/arylamino-6-chlorothieno[3,2-e]-1,3-thiazin-3-one derivatives were prepared in
one-pot
synthesis
by
refluxing
alky/arylisothiocyanates
and
2,5-dichloro-3-thiophene-
carboxamide. Alternatively, these derivatives were prepared by the intramolecular cyclization of
the deprotonated 2,5-dichloro-N-(alkyl/arylaminocarbonothioyl)thiophene-3-carboxamides, which
were obtained by the reaction of the deprotonated 2,5-dichloro-3-thiophene-carboxamide with
alky/arylisothiocyanates. The structures of the newly synthesized bicyclic derivatives, and their
acyclic precursors, were confirmed based on microanalytical and spectral (IR, MS, and NMR)
data.
Keywords: Thieno[3,2-e]-1,3-thiazin-3-one; thiophene-3-carboxamides; isothiocyanates; intramolecular cyclization.
Introduction
Few benzo- and heteroarenes fused to 1,3-thiazine rings, such as pyrido[3,2-e]1,3-thiazines and thieno[3,2-e]-1,3-thiazines (1-3, Fig. 1), are known.
O
O
[1–8]
O
1
R
N
2
R
S
N
R
N
S
N
R
Cl
2
1
R1 = H, OMe
R2 = NR2, NH2, 2-Py,
OC6H4-Cl (p),
6-SO2Me-2-Py
S
S
R
3
R = SH, SR, NR2
R=N
Y, Y = CH2, O, S, NMe
Figure 1: Some benzo- and heteroarenes fused to 1,3-thiazine rings.
Several 1,3-benzothiazin-4-one and pyrido[3,2-e]-1,3-thiazin-4-one derivatives
(1 and 2 Fig. 1) were prepared and established to have interesting pharmacological
activities, particularly those incorporating heterocyclic or amino appendages at the C-2
locus.
[1–5]
The biological activities of these compounds included their use as inhibitor of
apoptosis and cytoprotective agent,
remedy for heart diseases,

[2]
[1]
as heart muscle cell apoptosis inhibitor and
inhibitor on xanthine oxidase,[3] agrochemical fungicide,[4]
Corresponding author: e-mail: [email protected]
127
bronchodilator, phosphordiesterase inhibitor, symptomatic relief in asthma and other
respiratory diseases.
[5]
Pyrido[3,2-e]-1,3-thiazines (2) are 8-aza analogs of 1 and several derivatives
have been synthesized and claimed to possess kainic acid neuronotoxicity inhibitory
activities.
[6,7]
They were established as nervous cell protectors for prevention and
treatment of diabetes mellitus, Parkinson disease, psychosis, epilepsy, ischemic brain
diseases, multiple scleredema, neuroallergy diseases, Huntington chorea, Alzheimer
diseases, drug dependence, and related diseases.
[6]
From the point of isosterism, the thiophene ring system is commonly used as
replacement of the benzene ring in several pharmaceutical agents. In a previous
paper,
[8]
we reported the synthesis of 6-chloro-2-(disubstituted-amino)-thieno[3,2-e]-
1,3-thiazin-4-one derivatives (3) using a reaction between 2,5-dichlorothiophene-3carbonyl-isothiocyanate and heterocyclic amines to give initially the respective 2,5dichloro-N-(disubstituted-aminocarbonothioyl)thiophene-3-carboxamides. Intramolecular cyclization to product 3 occurred upon heating the deprotonated latter intermediate,
as shown in Scheme 1.
S
O
C Cl
i
Cl
S
Cl
ii
Cl
N
N
H
iii
Cl Cl
S
O
O
C N=C=S
S
iv
N
Cl
Cl
Cl
O
Y
Cl
S
S
S
N
3
i) a) CH3COCl/AlCl3
b) NaOCl/NaOH, then H+
c) SOCl2
Y
ii) NaNCS
iii) HN(CH2CH2) 2Y
iv) NaH / reflux
Scheme 1: The synthesis of 6-chloro-2-(disubstituted-amino)-thieno[3,2-e]-1,3-thiazin4-one derivatives
In continuation of our effort in this area, we would like to report a new method for
the
synthesis
of
6-chloro-2-(alkyl/arylamino)-4H-thieno[3,2-e]-1,3-thiazin-4-one
derivatives (4a-d) by a one-pot reaction of readily available 2,5-dichlorothieno-3carboxamides (6) with the appropriate alkyl/aryl isothiocyanates (7a-d) in the presence
of sodium hydride. The reaction involved 2,5-dichloro-N-(alkyl/arylaminocarbonthioyl)thiophene-3-carboxamides (8a-d), as intermediates, which can be isolated and
characterized at room temperature. Heating compounds 8a-d, under reflux, led to the
formation of products 4a-d as shown in Scheme 2.
O
O
S
Cl
5
N
NaH
Cl
Cl
Reflux
O
NH2
Cl
S
Cl
Cl
O
6
S
N
H
Cl
S
RT
R/Ar N C S
7a-d
S
Cl
8a-d
S
N R/Ar
H
4a-d
Reflux
N R/Ar
H
4
a
b
c
d
R/Ar
Et
cyclohexyl
o-MeOC6H5
Me
Scheme 2: The synthesis of 6-chloro-2-(alkyl/arylamino)-4H-thieno[3,2-e]-1,3-thiazin4-one derivatives
128
RESULTS AND DISCUSSION
2,5-Dichlorothieno-3-carboxamide (6) was prepared in good yield from 2,5dichlorothieno-3-carbonyl chloride (5) and ammonia. The amide was transformed into
6-chloro-2-(alkyl/arylamino)-4H-thieno[3,2-e]-1,3-thiazin-4-one
derivatives
(4)
as
illustrated in Scheme 2. Thus, the carboxamide 6 was treated with sodium hydride in
THF at 0 °C, and subsequently allowed to react with the appropriate alkyl/aromatic
isothiocyanates (7). After being stirred under reflux for overnight, the aqueous workup,
followed by purification, as described in the experimental section, afforded the desired
6-chloro-2-(alkyl/arylamino)-thieno[3,2-e]-1,3-thiazin-4-one derivatives (4a-d) in fair to
good yields (35-71%). It is obvious that this transformation works well with aliphatic
and aromatic isothiocyanates to afford the respective derivatives. However, similar
treatment of the amide 6 with cyclohexyl isothiocyanate led to the formation of a
mixture of the open (8a-d) and cyclic (4a-d) products. Intermediates 8a-d were isolated
and characterized when the reaction was held at room temperature.
The cyclization of intermediate adduct 8 may take place either at the sulfur or at
the nitrogen to give the corresponding thiazine derivatives (4a-d) or the diazine
derivatives (10), respectively, as shown in Scheme 3. The product, however, was
found to be exclusively product 4 and compound 10 was not detected. The assignment
of the thiazine structure is based on 1H NMR and
13
C NMR analyses; the signal
assignable to the imino carbon appears at around 149-153 ppm and the carbonyl
carbon appears at around 162 ppm. This excludes the thioxothienopyrimidinone
structure, of which 13C NMR should reveal a signal due to the thioxo carbon at around
180-190. The open intermediate adducts (8a-d) showed the carbonyl carbon at
around 161-162 ppm and the thiocarbonyl carbon at around 178-181 ppm.
13
C
NMR spectrum shows no tautomerization between 4 and 11 as shown in Scheme 3.
O
O
N
N
Cl
O
S
Cl
X
N R/Ar
H
S
N R/Ar
H
Cl
S
S
N R/Ar
11
4
S
N
H
Cl
S
H
O
X
N
8
Cl
S
N
SH
R/Ar
10
Scheme 3: The formation of thiazine derivatives rather than the diazine derivatives
129
Experimental
Physical measurements
All analyses were performed at Al al-Bayt University. Melting point was
determined on an Electrothermal 9100 melting point apparatus. The nuclear magnetic
resonance spectra were acquired with an Ultra-shield FT-NMR Bruker spectrometer
(300 MHz). Mass spectra were obtained on GC-MS (EI) spectrometer (Shimadzu, QP5050A). Elemental analyses were recorded on EA analyzer Euro-vector EA 3000A.
High resolution mass spectra (HRMS) were measured by electrospray ionization (ESI)
technique on a Bruker APEX-2 instrument.
Preparation of 2,5-dichlorothiophene-3-carboxamide (6)
[8-10]
This compound was prepared following literature procedure
by the addition
of excess amount (35 mL) of ammonium hydroxide solution (25%) to compound 5,
m.p. = 104-106 °C, lit. m.p. = 106-108 °C; yield = 85%.
2,5-Dichloro-N-[(Alkyl/arylamino)carbonothioyl]thiophene-3-carboxamide (8a-d)
General Procedure
The desired compounds were prepared by adding sodium hydride (0.40 g, 10
mmol; suspension 60% in oil) portionwise to a solution of 2,5-dichlorothiophene-3carboxamide (6) (0.98 g, 5 mmol) dissolved in dry THF (20 mL). The reaction mixture
was stirred at room temp. for 30 min. After the evolution of H2 gas has ceased,
alkyl/aryl isothiocyanate (5.0 mmol) dissolved in dry THF was added dropwise with
intensive stirring.
After the addition was completed, the reaction mixture was stirred at room
temperature for 24 h; glacial acetic acid (5 mL) was then added. The solvent was
evaporated using rotary evaporator; the remaining solid was extracted with diethyl
ether and evaporated under vacuum. Extra purification was performed by TLC Plates
using Silica gel (UV active, 245 nm) with chloroform as a developing solvent (eluent).
The following compounds were obtained.
2,5-Dichloro-N-(ethylcarbamothioyl)thiophene-3-carboxamide (8a)
A yellowish brown precipitate; yield (1.03 g, 73%); m.p. 82–84 °C; IR (KBr):
-1 1
2959 (C–H), 1669 (C=O), 1561 (C=S) cm ; H NMR (DMSO-d6, 300 MHz) δ: 11.30 (s,
1H, NH, D2O exchangeable), 10.50 (bs, 1H, NH, D2O exchangeable), 7.47 (s, 1H, H4), 3.58 (q, J = 7.1 Hz, 2H, CH2-5'), 1.17 (t, J = 7.1 Hz, 3H, CH3-6').13C NMR (DMSOd6) δ: 179.5 (C=S), 161.6 (C=O), 132.2, 130.2, 125.6 (C -2,3,5), 127.8 (CH-4), 40.2
+
(CH2-5'), 13.7 (CH3-6'). HRMS (ESI): found 282.9528 ([M+H] ), C8H8Cl 2N2OS2 required
282.9426. Elem. Anal.: Calculated for C8H8Cl 2N2OS2, 283.18: C, 33.93; H, 2.85; N,
9.89; S, 22.65. Found: C, 34.20; H, 3.12; N, 10.10; S, 22.82.
2,5-Dichloro-N-(cyclohexylcarbamothioyl)thiophene-3-carboxamide (8b)
1
A yellowish brown precipitate; yield (1.01 g, 60%); m.p. 76–78 °C; H NMR
(DMSO-d6, 300 MHz) δ: 10.42 (s, 1H, NH, D2O exchangeable), 9.23 (s, 1H, NH, D2O
130
exchangeable), 7.21 (s, 1H, H-4), 4.29 (m, 1H, CH-5'), 1.25-2.15 (m, 10H, 5 CH2-6'13
10'). C NMR (DMSO-d6) δ: 177.6 (C=S), 159.4 (C=O), 130.3, 130.2, 128.1 (C -2,3,5),
126.9 (CH-4), 54.4 (CH-5'), 33.8-22.7 (5CH2-6'-10'). Elem. Anal.: calcd for
C12H14Cl2N2OS2, 337.27: C, 42.73; H, 4.18; N, 8.30; S, 19.01. Found: C, 42.48; H,
4.42; N, 8.59; S, 19.25.
2,5-Dichloro-N-[(2-methoxyphenyl)carbamothioyl]thiophene-3-carboxamide (8c)
1
A yellow oil; yield (0.85 g, 47%); H NMR (DMSO-d6, 300 MHz) δ: 12,65 (s, 1H,
NH, D2O exchangeable), 11.65 (s, 1H, NH, D2O exchangeable), 7.54 (s, 1H, H-4),
7.27-6.93 (m, 4H, Ar.), 3.84 (s, 3H, CH3).
13
C NMR (DMSO-d6) δ: 177.7 (C=S), 162.1
(C=O), 151.1, 132.9, 127.9 (C -2,3,5), 127.2 (CH-4), 127.3, 126.9, 123.6, 120.4, 120.3,
111.9 (Ar), 56.6 (CH3O). Elem. Anal.: Calcd for C13H10Cl 2N2O2S2, 361.25: C, 43.22; H,
2.79; N, 7.75; S, 17.75. Found: C, 43.48; H, 2.42; N, 7.89; S, 17.55.
2,5-Dichloro-N-(methylcarbamothioyl)thiophene-3-carboxamide (8d)
1
A pale yellow precipitate; yield (0.75 g, 55%); m.p. 115–117 °C; H NMR
(DMSO-d6, 300 MHz) δ: 11.30 (s, 1H, NH, H-2', D2 O exchangeable), 10.42 (s, 1H, NH,
H-4', D2O exchangeable), 7.54 (s, 1H, H-4), 3.04 (s, 3H, CH3).
13
C NMR (DMSO-d6) δ:
180.5 (C=S), 161.4 (C=O), 132.3, 130.2, 125.7 (Cq-2, 3, 5), 127.8 (CH-4), 32.6
(NCH3). Elem. Anal.: Calcd for C7H6Cl 2N2OS2, 269.16: C, 31.23; H, 2.25; N, 10.40; S,
23.82. Found: C, 31.45; H, 2.42; N, 10.27; S, 24.01.
6-Chloro-2-(Alkyl/arylamino)-thieno[3,2-e][1,3]thiazin-4-one (4a-c)
General procedure (one-pot synthesis)
The desired compounds were prepared by adding sodium hydride (0.4 g, 10
mmol, suspension 60% in oil) portionwise to a solution of 2,5-dichlorothiophene-3carboxamide (6) (0.98 g, 5 mmol) dissolved in dry THF (20 mL). The reaction mixture
was stirred at room temperature for 30 min, then after the evolution of H2 gas has
ceased, the alkyl/arylisothiocyanates (5.0 mmol) dissolved in dry DMF (20 mL) was
added dropwise with intensive stirring. After the addition was completed, the reaction
mixture was refluxed for 24 h (the progress of the reaction was followed by TLC using
chloroform as eluent, the thin layer chromatography showed that the product is a
mixture of the title compounds 4 and 8 in which the open compound 8 shows higher Rf
value as compared to the cyclic compounds 4). After the completion of the reaction,
glacial acetic acid (5 mL) was added. The solvent was evaporated by rotary
evaporator, and then the remaining solid was extracted with diethyl ether and
evaporated under vacuum. Extra purification was performed by TLC Plate using Silica
gel (UV active, 245 nm) with chloroform as an eluent. The following products were
obtained by the above general procedure:
6-Chloro-2-(ethyl amino)-thieno[3,2-e][1,3]thiazin-4-one (4a)
A yellowish brown precipitate; yield (0.73 g, 58%); m.p. 138–140 °C; IR (KBr):
1690 (C=O), 1380 (C=N) cm–1; 1H NMR (DMSO-d6, 300 MHz) δ: 10.55 (s, 1H, NH,
131
D2O exchangeable), 8.32 (br., 1H, NH, D2O exchangeable), 7.50 (s, 1H, H-5), 3.20 (q,
J = 7.1 Hz, 2H, CH2), 1.20 (t, J = 7.1 Hz, 3H, CH3).
13
C NMR (DMSO-d6) δ: 162.3
(C=O), 153.1 (C-2), 132.2, 130.8, 125.5 (C -6a, 6, 4a), 127.3, 127.5 (CH-3, CH-5), 30.4
+
(NCH2), 15.4 (CH3). HRMS (ESI): found 246.9581 ([M+H] ), C8H7ClN2OS2 requires
246.9689. Elem. Anal.: Calcd for C8H7ClN2OS2, 246.73: C, 38.94; H, 2.86; N, 11.35; S,
25.99. Found: C, 38.85; H, 3.08; N, 11.21; S, 26.18.
6-Chloro-2-(cyclohexylamino)-thieno[3,2-e][1,3]thiazin-4-one (4b)
A pale yellow precipitate; yield (0.61 g, 40%); m.p. 136–138 °C; 1H NMR
(DMSO-d6, 300 MHz) δ: 9.85 (s, 1H, NH, D2O exchangeable), 7.46 (s, 1H, H-5), 3.63
13
C NMR (DMSO-d6) δ: 161.6 (C=O), 153.2 (C-2),
(m, 1H), 1.50-1.03 (m, 10H, 5CH2).
130.2, 129.0, 127.0 (Cq-6a, 6, 4a), 127.2, 126.5 (CH-3, CH-5), 49.1 (NCH, 1'), 32.9+
22.7 (5CH2). HRMS (ESI): found 300.9291 ([M+H] ), C12H13ClN2OS2 required
301.0159. Elem. Anal.: Calcd for C12H13ClN2OS2, 300.81: C, 47.91; H, 4.36; N, 9.31; S,
21.31. Found: C, 47.72; H, 4.15; N, 9.50; S, 21.52.
6-Chloro-2-[(2-methoxyphenyl)amino]-thieno[3,2-e][1,3]thiazin-4-one (4c)
A yellow oil; yield (0.58 g, 35 %); 1H NMR (DMSO-d6, 300 MHz) δ: 8.16 (s, 1H,
NH, D2O exchangeable), 7.58 (s, 1H, H-5), 7.09 (m, 1H, CH), 6.95 (m, 1H, CH), 6.70
(m, 1H, CH), 3.88 (s, 3H, CH3).
13
C NMR (DMSO-d6) δ: 162.7 (C=O), 150.7 (C-2),
148.6, 131.8, 131.1 (C -6a, 6, 4a), 127.6, 127.3 (CH-3, CH-5), 125.6, 124.3, 121.1,
119.7, 111.4, 56.5 (CH3O). Elem. Anal.: Calcd for C13H9ClN2O2S2, 324.80: C, 48.07; H,
2.79; N, 8.62; S, 19.74. Found: C, 48.31; H, 2.64; N, 8.54; S, 20.21.
6-Chloro-2-(methylamino)-thieno[3,2-e][1,3]thiazin-4-one (4d)
A yellowish brown precipitate; yield (0.83 g, 71%); m.p. 142–143 °C; IR (KBr):
1691 (C=O), 1378 (C=N) cm–1; 1H NMR (DMSO-d6, 300 MHz) δ: 8.12 (s, 1H, NH, D2O
exchangeable), 7.52 (s, 1H, H-5), 3.25 (s, 3H, CH3).
13
C NMR (DMSO-d6) δ: 162.4
(C=0), 153.3 (C-2), 132.1, 130.7, 125.6 (C -6a, 6,4a), 127.3, 127.4 (CH-3, CH-5), 35.4
(NCH3). Elem. Anal.: Calcd. for C7H5ClN2OS2, 232.71: C, 36.13; H, 2.17; N, 12.04; S,
27.56. Found: C, 35.85; H, 2.38; N, 12.01; S, 27.32.
Synthesis of 6-chloro-2-(alkyl/arylamino)-thieno[3,2-e][1,3]thiazin-4-one (4a-d) from 2,5dichloro-N-[(alkyl/arylamino)carbonthioyl]thiophene-3-carboxamide (8a-d)
The title compounds where prepared by the dropwise addition with stirring of
sodium hydride to the respective carboxamide (1:1 mole ratio) dissolved in THF at
room temperature. The reaction mixture was stirred at room temperature for 30 min,
then after the evolution of H2 gas has ceased, the reaction mixture was refluxed for 24
h (the progress of the reaction was followed by TLC using chloroform as eluent). The
products were isolated as shown in the previous procedure.
132
Acknowledgements
Most of the work presented in this paper forms part of the second Author’s
Master Dissertation submitted to Al al-Bayt University in Jordan. This work is
supported by Al al-Bayt University. Financial support from DFG (Germany) is gratefully
acknowledged. The author is indebted to Prof. Maas (Ulm University, Germany) and
Prof. Dr. Hasan Tashtoush (Yarmouk University) for their kind encouragement,
support, advice and criticism.
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133

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