Syntheses of 2-alkylthio-1,3-thiazine derivatives from S-alkyldithiocarbamates and α,β-unsaturated ketones

Article abstract of DOI:10.1002/hc.10055

Various 2-alkylthio-1,3-thiazine derivatives were synthesized by the reactions of S-alkylthiocarbamates with α,β-unsaturated ketones in the presence of BF₃ · Et₂O. The thiazine was converted into two isomeric dehydrated products in t

Full text of DOI:10.1002/hc.10055

Heteroatom Chemistry
Volume 13, Number 4, 2002
Syntheses of 2-Alkylthio-1,3-thiazine
Derivatives from S-Alkyldithiocarbamates
and , -Unsaturated Ketones
Mamoru Koketsu, Miki Okumura, and Hideharu Ishihara
Department of Chemistry, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
Received 20 November 2001; revised 13 December 2001
RESULTS AND DISCUSSION
ABSTRACT: Various 2-alkylthio-1,3-thiazine deriva-
tives were synthesized by the reactions of S-alkyl-
thiocarbamates with ␣,␤-unsaturated ketones in the
presence of BF3 Et2O. The thiazine was converted
into two isomeric dehydrated products in the pres-
C
Two dithiocarbamates 2 were prepared by the re-
action of thioacetic acid with thiocyanates 1, as
shown in Scheme 1. Both 2a and 2b, respectively,
were obtained in high yields. The reactions were
thought to be initiated by the nucleophilic addition
of the sulfur atom of thioacetate to the carbon atom
of the cyano group of the thiocyanate, with subse-
quent elimination of acetic acid by hydrolysis, to
give 2. Previously, syntheses of the dithiocarbamate,
such as S-methyl dithiocarbamate and S-phenyl
dithiocarbamate, were reported by the reaction of
a dithiophosphoric acid with a thiocyanate. How-
ever, the yields in these reactions were only around
40% [8]. The dithiocarbamates 2 were used for a
synthesis of 2-alkylthio-4-hydroxy-4H-5,6-dihydro-
1,3-thiazines 4 by reactions with ␣,␤-unsaturated
ketones 3.
ence of a Lewis acid.
2002 Wiley Periodicals, Inc.
Heteroatom Chem 13:377–379, 2002; Published online
in Wiley Interscience (www.interscience.wiley.com). DOI
10.1002/hc.10055
INTRODUCTION
The literature for heterocyclic pharmaceutical age-
nts includes sulfur-containing compounds [1] that
have been reported as antimalarial agents [2],
HIV-1 inhibitors [3], and antimicrobial agents [4].
Syntheses of 1,3-thiazines have been realized by
various methods [5]. For example, ␤-chlorovinyl
ketones and thioamides in the presence of per-
chloric acid give rise to intermediate S-ketovi-
nylthioimidium salts, which then cyclize to yield
1,3-thiazinium salts [6]. Recently, the selenium
analogues, 1,3-selenazines, have also been reported
[7]. In this article, we report a new synthesis of 2-
alkylthio-1,3-thiazine derivatives 4 by the reaction
of S-alkyldithiocarbamates 2 with ␣,␤-unsaturated
ketones 3 in the presence of BF3 Et2O, and the sub-
sequent conversion into two isomeric dehydrated
products from the thiazines by the reaction with
Lewis acids.
The results of the reactions of two dithiocarba-
mates 2 with various ␣,␤-unsaturated ketones 3 are
summarized in Table 1. All reactions gave 2-alkyl-
thio-4-hydroxy-5,6-dihydro-4H-1,3-thiazines
4
in
high yields. The typical procedure for the synthesis of
4 is shown in Scheme 2. Briefly, BF3 Et2O (1 equiv.)
was added to the S-benzyl dithiocarbamate 2a
(1 equiv.) in dry dichloromethane at 0 C under an
argon atmosphere. Subsequently, methyl vinyl ke-
tone (3a; 1 equiv.) was added at 0 C, and the mixture
was stirred for 2 h. After workup, 2-benzylthio-4-
hydroxy-4-methyl-5,6-dihydro-4H-1,3-thiazine (4a)
was obtained as an orange liquid in 88% yield.
Among the subsequently obtained thiazines, 4c, 4d,
4h, and 4i consist of diastereomers containing two
asymmetric centers at the C4 and C6 positions of
Correspondence to: e-mail: koketsu@cc.gifu-u.ac.jp.
2002 Wiley Periodicals, Inc.
c
377

378 Koketsu, Okumura, and Ishihara
SCHEME 2
SCHEME 1
the reflux conditions, affording the corresponding
two isomeric dehydrated products (Table 2). The
ratio of the two isomers 5a and 6a depended on
the reaction time. The amount of 5a was decreased
by applying a longer reaction time. This indicated
that 5a and 6a of a certain ratio were formed first,
and gradually isomerized to the more stable ratio
favoring 6a. In fact, when the reaction was refluxed
for 24 h, an equilibrium mixture resulted at the ratio
of 94:6 (6a:5a).
the thiazine ring. The predominant diastereomer
was confirmed to have a cis relationship between
the OH group at C4 and the substituent at C6 by
examination of the NOESY spectra.
Attempts to dehydrate the 2-benzylthio-4-
hydroxy-5,6-dihydro-4H-1,3-thiazines 4a–c were
carried out by use of a series of Lewis acids such
as BF3 Et2O, AlCl3, TiCl4, and ZnCl2. The reac-
tions of 4a with BF3 Et2O and AlCl3 at room
temperature in dichloromethane gave dehydrated
products in 53 and 26% yields, respectively, while
those with TiCl4 and ZnCl2 gave only recovered
starting materials. The products obtained from the
reaction were two isomeric dehydrated products,
viz. 4,5-dihydro-4-methylene-6H-1,3-thiazine (5a)
and 4-methyl-6H-1,3-thiazine (6a) (Scheme 3). The
optimal conditions to obtain the products of highest
yield were the reaction of 4a with BF3 Et2O under
reflux for 2 h in chloroform, affording the mixture
of 5a and 6a in the ratio of 16:84 (5a:6a) in 83%
yield. Similarly, 4b and 4c were dehydrated under
EXPERIMENTAL
Spectral Data of Representative Compounds
2-Benzylthio-4-hydroxy-4-methyl-5,6-dihydro-4H-
1,3-thiazine (4a). 1H NMR (400 MHz, CDCl3)
1.40 (s, 3H), 1.78–1.88 (m, 1H), 1.91–1.99 (m, 1H),
2.90–2.99 (m, 1H), 3.08–3.15 (m, 1H), 3.26 (br s, 1H),
4.17 (d, J = 13.6 Hz, 1H), 4.32 (d, J = 13.6 Hz, 1H),
7.17–7.33 (m, 5H); 13C NMR (100 MHz, CDCl3)
25.1, 27.7, 31.2, 34.5, 82.3, 127.0, 128.2, 128.9, 137.1,
TABLE 1 Syntheses of Various 2-Alkylthio-1,3-thiazines 4
Yield a 4 (%)
(cis/trans) b
Yield a 4 (%)
Ketone 3
Product 4
Product 4
(cis/trans) b
R = C6H5CH2, R0 = CH3.
aIsolated yield.
bCalculated by 1H NMR spectra.

Syntheses of 2-Alkylthio-1,3-thiazine Derivatives from S-Alkyldithiocarbamates and ␣,␤-Unsaturated Ketones 379
4.67 (d, J = 1.2 Hz, 1H), 5.06 (d, J = 1.2 Hz, 1H),
7.17–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3)
26.4, 27.3, 34.6, 109.1, 127.1, 128.4, 129.1, 137.2,
145.4, 157.1; MS (CI) m/z = 236 (M+ + 1).
2-Benzylthio-4-methyl-6H-1,3-thiazine (6a). 1H
NMR (400 MHz, CDCl3) 1.98 (s, 3H), 3.20 (d, J =
5.6 Hz, 2H), 4.33 (s, 2H), 4.96 (t, J = 5.6 Hz, 1H), 7.17–
SCHEME 3
7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) 22.6,
1
156.2; IR (neat) 3405, 1580 cm ; MS (CI) m/z = 254
(M+ + 1); HRMS m/z = 253.0953 for C12H15NOS2;
found, 253.0974.
25.6, 35.3, 98.4, 127.1, 128.4, 129.1, 137.2, 145.4,
158.8; MS (CI) m/z = 236 (M+ + 1); Anal. Calcd. for
C12H13NS2: C, 61.24; H, 5.57; N, 5.95. Found: C, 61.33;
H, 5.68; N, 5.92.
2-Benzylthio-4-methylene-4,5-dihydro-6H-1,3-thia-
zine (5a). 1H NMR (400 MHz, CDCl3)
2.50 (t,
J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 4.32 (s, 2H),
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TABLE 2 Dehydration of 2-Benzylthio-1,3-thiazines 4a–c
with BF3 Et2O
Products
Yield a (%)
Run Thiazine
5
6
(5/6)b
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R = C6H5CH2.
a Total Isolated yield.
b The ratio of 5 and 6 was calculated by 1H NMR spectra.