Nucleophilic Ring Enlargement of 2-Substituted-3-isothiazolones to 1,3-Thiazin-4-ones

Article abstract of DOI:10.1081/SCC-120026864

1,3-Thiazin-4-ones 9 and 10 have been prepared from the corresponding isothiazolones 7 and 8 by a clean and smooth reaction with tertiary amines at room temperature. This rearrangement is attributed to the abstraction of a methine proton from the 2-positi

Full text of DOI:10.1081/SCC-120026864

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Nucleophilic Ring Enlargement of 2-Substituted-3-
isothiazolones to 1,3-Thiazin-4-ones
Stylianos Hamilakis a & Assistant Professor Athanase Tsolomitis a
a The Laboratory of Organic Chemistry , The School of Chemical Engineering , The National
Technical University of Athens , Athens, Greece
Published online: 21 Aug 2006.
To cite this article: Stylianos Hamilakis & Assistant Professor Athanase Tsolomitis (2003) Nucleophilic Ring Enlargement
of 2-Substituted-3-isothiazolones to 1,3-Thiazin-4-ones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:24, 4339-4345, DOI: 10.1081/SCC-120026864
To link to this article: http://dx.doi.org/10.1081/SCC-120026864
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 24, pp. 4339–4345, 2003
Nucleophilic Ring Enlargement of 2-Substituted-
3-isothiazolones to 1,3-Thiazin-4-ones
*
Stylianos Hamilakis and Athanase Tsolomitis
The Laboratory of Organic Chemistry,
The School of Chemical Engineering,
The National Technical University of Athens,
Athens, Greece
ABSTRACT
1,3-Thiazin-4-ones 9 and 10 have been prepared from the corres-
ponding isothiazolones 7 and 8 by a clean and smooth reaction
with tertiary amines at room temperature. This rearrangement is
attributed to the abstraction of a methine proton from the 2-position
isothiazolone substituent, followed by ring enlargement through
cleavage of the S-N bond.
*Correspondence: Athanase Tsolomitis, Assistant Professor, The Laboratory of
Organic Chemistry, The School of Chemical Engineering, The National Technical
University of Athens, 9, Heroon Polytechniou Str., Zografou Campus, Athens
157 80, Greece; E-mail: tsolom@chemeng.ntua.gr.
4339
DOI: 10.1081/SCC-120026864
Copyright & 2003 by Marcel Dekker, Inc.
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4340
Hamilakis and Tsolomitis
Key Words: 3-Isothiazolones; 1,3-Thiazin-4-ones; Nucleophilic
ring expansion; Two phase reactions.
The 1,3-thiazin-4-one ring is found in a wide range of biologically
active molecules. Most intensive investigation has focused on the
modification of substituents in the thiazinone ring and on the synthesis
of thiazinones fused with heterocycles. A large number of articles and
patents deal with biochemical properties of these compounds, such as
analgesics,[1,2] antimicrobial agents,[3,4] psychostimulants,[5] and others.
N-Substituted-3-isothiazolones bearing a free 5-position, of the
general formula 1, have been found[6] to be dimerized readily by bases
to 2,4-bismethylene-1,3-dithietanes 3 (Sch. 1). Dithietanes of the general
formula 3 have been also obtained from N-substituted-5-aroyl-3-isothia-
zolones 4. For instance, the reaction of the N-benzyl-5-benzoylisothia-
zolone 4 (Ar ¼ -C6H5, R ¼ -CH2C6H5) with bases (e.g., EtONa/EtOH,
NaOH/H2O) has been found[7] to yield the corresponding dithietane 3
(R ¼ -CH2C6H5). The dimerization was shown to proceed through the
attack of the formed 5-anion 2 on the S-N bond of a second isothiazolone
molecule 1.
In the case of isothiazolone 4, the 5-anion 2 would result from
a nucleophilic displacement of the 5-benzoyl group. In a previous
communication,[8] the partial or the complete transformation of the
isothiazolone 4 to the corresponding dithietane 3, by treatment with
aqueous sodium hydroxide, has been examined. The reaction of a
benzene solution of the same compound with a 10% aqueous solution
of sodium hydroxide (a two phase aqueous-organic system) resulted
H
B:
S
N
R
1
O
S
S
RNHCOCH
CHCONHR
S
N
R
2
O
ArCO
3
B:
S
N
O
R
4
Scheme 1.

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1,3-Thiazin-4-one Ring
4341
C6H5 CO
(b )
C6H5 CO
O
(a )
(c)
C
6H5COCH2CH 2CO NH CH (C O2Me )2
S
C6H5
O
S
NH
O
N
6
O
5
CH (C O2Me )2
CO 2Me
Me O2
C
(a) HCl.H2NCH(CO2Me)2 and MeCO2Na in EtOH at reflux for 1hr.
(b ) Exess of SOCl2 at room temperature for 2 hours.
(c) Et3N in CHCl3 at room temperature for 10 or 30 minutes.
(d ) 10% aqueous NaOH/benzene
7
(d )
9
O
(c )
S
Me O2
NH
CO 2Me
S
O
N
C
CH (C O2Me )2
8
10
Scheme 2.
easily and quantitatively to the corresponding isothiazolone 1 (R ¼
-CH2C6H5).
Now we have prepared an isothiazolone namely 2-dimethylmalonate-
5-benzoyl-3-isothiazolone (7) from the reaction of ketoamide 6. The
synthesis sequence (Sch. 2) is an application of the general procedure[7]
for the preparation of isothiazolones of the general type 4 (Sch. 1).
When the isothiazolone 7 in a benzene solution was treated with a 10%
aqueous sodium hydroxide at room temperature, a nucleophilic displace-
ment reaction of 5-benzoyl group was occurred and isothiazolone 8 was
obtained quantitavely according to the general method.[8] The same iso-
thiazolone in a chloroform solution when treated with triethylamine at
room temperature or 1,8-bis(dimethylamino)naphthalene in refluxing
xylene, an isomeric compound was isolated in 88% yield. Structure 9
was assigned to this new compound on the basis of its 1H NMR
spectrum; besides the aromatic and aliphatic protons’ signals, one low-
field one-proton’s signal was found to be coupled to an exchangeable N-H
proton. In deuteriochloroform solution, a doublet at 6.60 ppm, J ¼ 1,2 Hz,
was assigned to the C 5 vinylic proton. The coupling between the C 5-H
and the N-H protons would be typical case of long range coupling, as
encountered in unsaturated systems incorporating a planar W-path.
Since the possibility of a nucleophilic displacement of the 5-benzoyl
group in 7 should be excluded, as anticipated, the ring enlargement of
7 into 9 can only be explained by the abstraction of a methine
proton from the dimethylmalonate group to form the anion 11 (Sch. 3).
Under the conditions used for the transformation of the isothia-
zolone 7 to the thiazinone 9, the debenzoylated isothiazolone 8 gave
also quantitatively the corresponding thiazinone 10, though it has the
easily abstracted 5-position ring’s proton (Sch. 1). In this case obviously
the dimethylmalonate anion 11 is formed faster, and is more stabilized,
from the 5-anion of the isothiazolone ring.

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4342
Hamilakis and Tsolomitis
X
X
O
X
X
R3N
[R3N+H]
S
NH
S
-
S
S
N
O
N
N
O
O
CO Me
MeO C
CH(CO Me)
C(CO Me)
C(CO Me)
-
7, X= C6H5CO-
8, X= H-
9, X= C6H5CO-
10 , X= H-
12
11
Scheme 3.
The anion 11 can then be assumed to give compounds 9 and 10
through the acylimine intermediate 12, an elimination-addition process
(E1cb mechanism). This mechanism however is favored by the labile S-N
bond[9] of the isothiazolone ring system.
In conclusion the nucleophilic displacement of the 5-benzoyl group
of isothiazolone 7 to the corresponding isothiazolone 8 was finally found
to proceed with a simple two phase reaction, though these isothiazolones
have the acidic dimethylmalonate methine proton. These isothiazolones
were converted into the corresponding 1,3-thiazin-4-ones easily in high
yields. We are currently investigating the application of the reactions
sequences (Sch. 2) to the preparation of 1,3-thiazin-4-ones and from
there to fused 1,3-thiazin-ring systems with probable interest as potential
prodrugs.
EXPERIMENTAL
Melting points were determined in capillary tubes and are
1
uncorrected. The H NMR spectra were recorded on a Varian EM-360
60 MHz spectrometer; chemical shifts are given in ppm (ꢀ) downfield
from TMS (internal standard). The IR spectra were obtained with a
Nicolet Magna 560 spectrometer; as nujol mulls and were calibrated
against the polystyrene 1601 cmꢀ1 band, and given in reciprocal
centimetres. Elemental analyses were obtained from the microanalytical
laboratory of CNRS (France).
N-Dimethylmalonate-3-benzoylpropionamide (6)
A mixture of butenolide 5,[10] 13.48 g (84.17 mmol), 15.45 g (84.15
mmol) of aminodimethylmalonate hydrochloride, 7.61 g (92.60 mmol)
of anhydrous sodium acetate in 6 mL of water and 50 mL of ethanol

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1,3-Thiazin-4-one Ring
4343
refluxed on a steam bath for 1 h. The hot mixture was filtered from the
salts and the filtrate after cooling gave a crystalline solid 19.5 g (75.4%).
M.p. 137–139ꢁ. After further recrystallization from ethanol it gave an
analytically pure sample of ketoamide 6, m.p. 140–142ꢁ. Anal. Calcd.
for C15H17NO6: C, 58.63; H, 5.58; N, 4.56. Found: C, 58.57; H, 5.48;
N, 4.42. IR (Nujol mull, cmꢀ1): 3311, 1739, 1691, 1650, 1597, 1582.
1H NMR (60 MHz, CDCl3); ꢀ 2.78 and 3.36 (two t, J ¼ 6 Hz, 4H,
-CH2CH2-), 3.81 (s, 6H, two -CH3), 5.23 (d, J ¼ 7 Hz, 1H, CH), 6.96
(br d, J ¼ 7 Hz, 1H, -NH-), 7.38–8.16 (m, 5H, aromatic protons).
2-Dimethylmalonate-5-benzoyl-3-isothiazolone (7)
Following the general method[7] a solution of the ketoamide 6, 20 g
(65.08 mmol) in 200 mL of thionyl chloride, was stirred at room tempera-
ture for 2 h. The dark green solution was concentrated under vacuum at
room temperature and the solid residue was recrystallized from methanol
to give 16 g (73.3%) of a yellow crystalline product, m.p. 96–99ꢁ. A further
recrystallization from methanol gave an analytically pure sample of
compound 7. M.p. 101–102ꢁ. Anal. Calcd. for C15H13NO6S: C, 53.73;
H, 3.90; N, 4.17; S, 9.56. Found: C, 53.58; H, 3.91; N, 4.20; S, 9.37. IR
1
(Nujol mull, cmꢀ1): 1763, 1748, 1742, 1666, 1650, and 1594. H NMR
(60 MHz, CDCl3): ꢀ 3.90 (s, 6H, two -CH3), 6.13 (s, 1H, CH), 6.75
(s,1H, vinylic proton), and 7.50–8.11 (m, 5H, aromatic protons).
2-Dimethylmalonate-3-isothiazolone (8)
To a solution of the benzoylisothiazolone 7, 1 g (2.98 mmol) in
benzene (20 mL), a 10% aqueous sodium hydroxide solution (20 mL)
was added and the mixture was stirred vigorously at room temperature
for 10 min. The water layer was then separated, acidified with a 10%
hydrochloric acid solution and saturated with NaCl, the precipitated
benzoic acid was filtered, and the filtrate was extracted some times
with chloroform. The chloroform extracts washed with a 0.1% sodium
bicarbonate solution some times and then with a 5% hydrochloric acid
solution and finally with water. The organic layer was dried (magnesium
sulfate) and concentrated under vacuum to give compound 8 as a
1
retinous mass 0.52 g (75%), as evidenced from H NMR spectrum. IR
(as retinous mass, cmꢀ1): 1754, 1647, and 1512. 1H NMR (60 MHz,
CDCl3); ꢀ 3.91 (s, 6H, two -CH3), 6.10 (s, 1H, CH), 6.31 and 8.48 (two
d, J ¼ 6.5 Hz, 2H, vinylic protons).

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4344
Hamilakis and Tsolomitis
2,2-Dimethoxycarbonyl-6-benzoyl-1,3-thiazin-4-one (9)
To a solution of the benzoylisothiazolone 7, 1 g (2.98 mmol) in 20 mL
of chloroform, 2 mL of triethylamine were added and the solution was left
at room temperature for 10 min. The solution washed with a 10%
hydrochloric acid solution and concentrated under vacuum to give
a quantitative yield of a solid residue, which was shown (1H NMR
spectrum) to be a pure sample of the corresponding thiazinone 9. A recrys-
tallization from benzene/petroleum ether gave an analytical sample 0.88 g
(88%). M.p. 119–121ꢁ. Anal. Calcd. for C15H13NO6S: C, 53.73; H, 3.90;
N, 4.17; S, 9.56. Found: C, 53.74; H, 3.90; N, 4.18; S, 9.76. IR (Nujol mull,
cmꢀ1): 3164, 1760, 1746, 1669, 1650, and 1594. 1H NMR (60 MHz,
CDCl3); ꢀ 3.95 (s, 6H, two -CH3), 6.60 (d, J ¼ 1,2 Hz,1H, vinylic
proton), 7.18 (br s, 1H, -NH-), 7.50–8.00 (m, 5H, aromatic protons).
2,2-Dimethoxycarbonyl-1,3-thiazin-4-one (10)
A solution of 0.48 g (2.07 mmol) of the isothiazolone 8, in 20 mL
chloroform and 1 mL of triethylamine was left at room temperature for
30 min. The solution washed with a 10% hydrochloric acid solution and
concentrated under vacuum to give an almost quantitative yield of a solid
residue which was shown (1H NMR spectrum) to be a pure sample of the
corresponding thiazinone 10. A recrystallization from benzene gave an
analytical sample 0.40 g (83.3%). M.p. 96–97ꢁ. Anal. Calcd. for
C8H9NO5S: C, 41.55; H, 3.92; N, 6.06; S, 13.87. Found: C, 41.55; H,
4.03; N, 6.12; S, 13.63. IR (Nujol mull, cmꢀ1): 3425, 1751, and 1677.
1H NMR (60 MHz, CDCl3); ꢀ 3.93 (s, 6H, two -CH3), 6.15, and 7.10
(two d, J ¼ 10.5 Hz, 2H, vinylic protons), 6.91 (br s, 1H, -NH-).
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1,3-Thiazin-4-one Ring
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Received in the UK June 19, 2003

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