Ring transformations of 1,2,4-dithiazoles: Synthesis and biological studies of novel 5-heterocycles, and their relevant phosphono derivatives

Article abstract of DOI:10.1515/znb-2007-0113

Reactions of 5-phenyl-3(3H)-thioxo-1,2,4-dithiazole (1) with unsaturated and active phosphonium salts as well as with phosphonates, at r. t. and under the effect of basic catalysis, afforded mainly 1,3,5-dithiazines 5, 12, 17a, 17b, 23a or 23b. Substitute

Full text of DOI:10.1515/znb-2007-0113

Ring Transformations of 1,2,4-Dithiazoles: Synthesis and Biological
Studies of Novel S-Heterocycles, and Their Relevant Phosphono
Derivatives
Wafaa M. Abdou and Maha D. Khidre
Pesticide Chemistry Dept. National Research Centre, Dokki, Cairo, Egypt
Reprint requests to Dr. W. M. Abdou. E-mail: wabdou@intouch.com
Z. Naturforsch. 2007, 62b, 93 – 100; received April 18, 2006
Reactions of 5-phenyl-3(3H)-thioxo-1,2,4-dithiazole (1) with unsaturated and active phosphonium
salts as well as with phosphonates, at r. t. and under the effect of basic catalysis, afforded mainly 1,3,5-
dithiazines 5, 12, 17a, 17b, 23a or 23b. Substituted 1,3-dithiol 7 and 1,3-thiazoles 13, 19a, 19b, 22a
and 22b were isolated as by-products. 1,3,5-Dithiazine products showed pharmacological potency.
Key words: Heterocyclic Disulfides, Vinyl and Allylphosphonium Salts,
α-Alkylthiomethylphosphonates, 1,3,5-Dithiazines, 1,3-Thiazoles
Introduction
up of the product mixture yielded 4-thioxo-1,3,5-
dithiazine 5 (42 % yield), and 1,3-dithiol-2-imine 7
(18 % yield) together with unchanged substrate 1 (8 %)
(Scheme 1).
Diverse biological and pharmacological activities
have been reported for thiazoles, dithiazines and re-
lated compounds. For instance, thiazole derivatives are
in clinical use [1, 2], and many dithiazines exhibit an-
tiprotozoal, antiviral, bactericidal and fungicidal prop-
erties [3], probably by virtue of the presence of the tox-
ophoric (-N=C-S) group. Furthermore, many dithiols
and dithiazines are patented as synthetic flavor com-
pounds [4, 5] and in photographic developing by a dif-
fusion transfer process [6]. For these reasons, one of
our research programs has centered on the synthesis of
dithiols, thiazoles and phosphono-substituted S-hete-
rocycles, derived from the reactions of acyclic and
cyclic cis-disulfides with PIII and PV reagents [7]. The
work described in this article involves the reactions
of 5-phenyl-3(3H)-thioxo-1,2,4-dithiazole(1) with un-
saturated (2, 10) and active phosphonium salts 15a
and 15b as well as with α-phosphonyl carbanions 20a
and 20b. The reactions led to the synthesis of new five-
and six-membered sulfur heterocycles and their phos-
phono derivatives.
Structures 5 and 7 were assigned to the isolated
products on the basis of their elemental analyses, IR,
1H and 13C NMR, and mass spectral data. Thus, the
1H NMR spectrum of 5 exhibited the characteristic res-
onances for the 2-CHMe moiety (δ = 4.27 and 1.31)
along with resonances corresponding to the phenyl
ring. Its 13C NMR spectrum displayed the dithiazine-
carbon resonances at δ = 31.6 (C-2), 143.6 (C-6) and
204.3 (C-4), and the methyl signal at 14.6 ppm. The
mass spectrum of 5 confirmed its molecular weight.
As expected, initial fragmentation involved the loss
of CH3 and the scission of the ring. On the other
hand, the IR spectrum of 7 showed bands in the
range 1605– 1612 (C=C) and strong bands at 1485
and 1425 cm−1, which have been assigned to N-C=S
and N=C-S, respectively, in addition to several other
bands in the broad region of 1563– 700 cm−1, which
can be attributed to vibrations involving an interac-
tion between the C=S and C-N stretching [8]. In the
1H NMR spectrum of 7 the protons of the dithiol
ring appeared as two doublets (J = 5.8 Hz) at δ =
Results and Discussion
When the 1,2,4-dithiazole 1 was treated with an 7.76 and 7.82. In its 13C NMR spectrum, signals were
excess of vinyltriphenylphosphonium bromide (2) displayed at δ = 118.3, 119.7 (C–4 and C-5), 154.6
in a mixture of ethyl alcohol containing aqueous (C-2) and at 206.4 (C=S). Similar (N-thiophenacyl)-
LiOH (0.5 M) or sodium ethanolate at r. t., the re- 1,3-dithiol-2-imines were previously reported for the
action was not complete even after two days. Work- reaction product of 1 and (alkoxycarbonylmethylene)
0932–0776 / 07 / 0100–0093 $ 06.00 © 2007 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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W. M. Abdou – M. D. Khidre · Ring Transformations of 1,2,4-Dithiazoles
Scheme 1.
triphenylphosphorane [7f] and for the reaction product
of 1 with dimethyl acetylenedicarboxylate [9].
A mechanism that accounts for the formation of 5
and 7 is outlined in Scheme 1. Obviously, the strik-
ing difference between vinylphosphonium salts and
analogous ammonium salts is the ease with which the
C=C bond of the former reacts with nucleophiles [10].
Thus, the initial Michael addition of 1 to 2 leads to
the formation of both intermediates 3 and 6. Cycliza-
tion of 3 with extrusion of HBr gives the phospho-
rane 4, which by hydrolysis yields dithiazine 5 with
concomitant elimination of triphenylphosphane oxide.
The feasibility of insertion of a carbanion between two
sulfur atoms is well known [7a, 7b, 11, 12]. Neverthe-
less, intermediate 6 undergoes cyclization to yield the
dithiol 7 with elimination of hydrogen bromide and
triphenylphosphane. The latter step arises because of
the enhanced ability of the S-S linkage to be disrupted
due to the effect of the alkaline medium.
Scheme 2.
tion took place leading to the thione 9, accompanied
by elimination of HBr and Ph3PS.
When 1 was refluxed with an equimolar amount
of allyltriphenylphosphonium bromide (10) in CHCl3
containing aq. LiOH (0.5 M), dithiazine-4-thione 12
and thiazol-2-thione 13 were isolated in 44 and
21 % yield (Scheme 3). The product 13 had infrared
bands at 3358 and 1608 cm−1 attributed to the NH
1
When the reaction between the dithiol 1 and 2 was and exocyclic olefin. In the H NMR spectrum of 13
carried out in refluxing chloroform (or EtOH) contain- the exocyclic vinyl protons give signals at δ = 5.22,
ing aq. LiOH (0.5 M) for 8 h, 2-phenyl-4(4H)-thioxo- 5.64 and 6.47 ppm (AMX pattern). The presence of the
1,3-thiazine (9) was the reaction product (67 % yield) vinyl moiety was attested to the signals at δ = 109.4
(Scheme 2). Compound 9 was the only isolable adduct (CH=CH2), 125.7 (CH=CH2) and at 141.4 (C-5) in the
regardless of the ratio of the reactants employed. The 13C NMR spectrum of 13. According to Scheme 3,
identity of 9 is inferred from its analytical and spectral an initial nucleophilic addition of the carbanion cen-
properties (see Experimental Section). Following the ter in 10A at the S-S-linkage leads to the formation
initial Michael addition product 8, a substitution reac- of the zwitterion 11, which subsequently could fol-
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W. M. Abdou – M. D. Khidre · Ring Transformations of 1,2,4-Dithiazoles
95
Scheme 3.
Scheme 4.
low two different pathways: i) cyclization and addition the reaction proceeded smoothly at r. t. with stirring
of a molecule of water yields 12 and Ph3PO, as it is for 8 h. Chromatographic separation of the prod-
discussed in Scheme 1; ii) extrusion of triphenylphos- uct mixture afforded the substituted dithiazine 17a
phane sulfide from the intermediate 11 affords 13.
In a systematic study, the reaction of the thione 1
with reactive ylides 15a and 15b was studied. When 1
was treated with two molar equivalents of methyli-
denetriphenylphosphorane(15a), prepared in situ from
the corresponding phosphonium bromide 14a, in
dimethylformamide solution containing excess LiH,
(48 % yield) and the thiazole derivative 19a (23 %).
In a similar fashion, compound 1 reacted with ethyli-
denetriphenylphosphorane(15b), prepared in situ from
its bromide salt, to give 17b (42 % yield) and 19b
(25 % yield) (Scheme 4). Structures 17 and 19 were de-
rived from elemental analyses and spectroscopic data.
The IR spectrum of 19a indicates the absence of an
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96
W. M. Abdou – M. D. Khidre · Ring Transformations of 1,2,4-Dithiazoles
Scheme 5.
S-S-linkage, since a sharp and strong band assigned [9] linkage in 1 were the common major products in the
to the cis-disulfide stretching vibration at 1225 cm−1 present study (Schemes 1, 3 and 4).
in the IR spectrum of 1 was absent in the IR spectra
of 19a and 19b. On the other hand, they showed bands
in the range 1600– 1610 (C=C) and at ≈ 1420 cm−1
assigned to the N=C-S moiety. The appearance of
Next, the reaction of the 1,2-disulfide 1 with diethyl
(α-alkylthiomethyl)phosphonates 20a and 20b was in-
vestigated with regard to the synthesis of new phos-
phonate derivatives. It is conceivable that a molecu-
lar modification of thiazole or dithiazole rings by in-
troducing an organophosphorusfunctionality enhances
the potential biological activity. Treatment of 1 with a
threefold excess of 20a (or 20b) in an alcoholic sodium
ethoxide solution at r. t. yielded the phosphonates 22a
1
two signals in the H NMR spectrum of 19b at δ =
0.97 (t) and 1.54 (s), assignable to 2-CH2CH3 and
5-CH3 groups (13C NMR: δ = 12.8 and 16.4 ppm),
excludes the formation of the alternative ylidene
structure 18.
According to Scheme 4, initial nucleophilic attack (27 % yield) and 23a (40% yield), or 22b and 23b
by the carbanion center in the ylides 15a (or 15b) at in 23 % and 43% yields, respectively (Scheme 5). El-
a ring sulfur atom in 1 followed by an addition of a emental analyses and spectral data substantiated the
second phosphorane species at the thiocarbonyl carbon structures of 22 and 23. The NMR spectra of 22a (δp =
atom resulted in the formation of the intermediate 16a 18.93 ppm) showed a sharp singlet of the NH proton
(or 16b). Further thio-olefination and elimination of at δ = 9.75. The two thiomethyl groups gave one dou-
triphenylphosphanesulfide from 16 can lead to the for- blet (JHP = 4.5 Hz) at 2.16 and a singlet at 2.23 ppm.
mation of the dithiazoles 17a, 17b or of thiazoles 19a The two thiomethyl carbon signals in the 13C NMR
and 19b.
The above four reactions illustrate the dissimilarities
spectrum appeared at δ = 13.4 and 15.6 while the
C-P carbon atom gave a doublet (JCP = 184.7 Hz)
at 96.8 ppm. In the IR spectrum of 22a, the NH-
and P-O-C moieties gave rise to absorptions at 3365
and 1132 cm−1 while the exocyclic C=C gave a strong
sharp band at 1628 cm−1. The foregoing results con-
firm the vinylphosphonate structure 22 and rule out the
alternative enaminophosphonate.
between the behavior of unsaturated and active phos-
phonium salts with 1,2-dithiol 1 and the previously re-
ported [7f] behavior of resonance-stabilized ylides to-
wards the same substrate 1. In the latter case, it was
possible to isolate the symmetric dimeric form of 1
along with the thiazole or dithiol derivatives from the
reactions of 1 with ylides of the type (Ph3P=CHCORꢀ,
The mechanism outlined in Scheme 5 includes a
Rꢀ = OMe, OEt, Ph, Me). On the other hand, dithi- similar initial thiophilic addition of the phosphonyl
azines derived from an insertion reaction at the S-S- carbanions 20 to 1 leading to the intermediates 21,
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W. M. Abdou – M. D. Khidre · Ring Transformations of 1,2,4-Dithiazoles
97
which can react further on two different pathways: aqueous LiOH solution (0.5 M) (15 mL) (or NaOEt) was
added and the mixture was stirred at r. t. for 2 days (TLC).
The product mixture was concentrated, and then poured
onto H2O (50 mL), acidified with conc. HCl and then ex-
tracted with CHCl3 (2 × 100 mL). The combined organic
extracts were washed with H2O (50 mL), dried and the
solvent was removed under reduced pressure. The residue
was chromatographed on silica gel (Kieselgel 60, parti-
cle size 0.2 – 0.5 mm; E. Merck, Darmstadt) using n-hex-
ane/AcOEt as eluents. n-Hexane elution afforded colorless
i) intramolecular cyclization, as previously discussed,
affords 23; ii) further condensation [7a, 7b, 13] of 21
with a second species of 20a (or 20b) and internal
Wittig-Horner reaction gives rise to the olefin 22 with
concomitant elimination of H2S and a thiophosphonate
moiety.
Pharmacological Evaluation
◦
needles, m. p. 80 C, identified as triphenylphosphane; and
The dithiazoles 5, 12, 17a, 17b, 23a and 23b were
screened against various types of fungi including Can-
dida albicans, Asperigillus fumigatus and Cryptococ-
cus neoformans by adopting food poisoning technique.
Compounds 5 and 12 are moderately active against As.
fumigatus and Cr. neoformans at the 455 µg/mL con-
centration level, while compounds 23a, and 23b are
more active against the same fungi at the same dose
level. Compounds 23a and 5 registered 100% spore
germination inhibition in Candida albicans. Com-
pounds 12 and 23b have shown 100% inhibition in the
same fungi at 600 µg/mL. Compounds 17a and 17b
showed only feeble activity.
Compounds 5, 12, 23a and 23b exhibited also rea-
sonable activity against one or the other type of bac-
teria: B. subtilis, B. cereus and Esch. coli. Phosphory-
lated dithiazoles 23a and 23b showed the highest in-
hibitory effect against all the tested organisms.
In conclusion, compounds 23a and 23b, on the basis
of our results, could be considered as lead molecules
to be modified in order to improve the antimicrobial
activity.
n-hexane/AcOEt (up to 7 : 3, v/v) yielded colorless crystals
of triphenylphosphane oxide, m. p. 156 ◦C.
n-Hexane/AcOEt (up to 8 : 2, v/v) afforded red crystals of
unchanged substrate 1, 64 mg (8 % yield), m. p. 138 – 140 ◦C
(from EtOH) (lit. [9]: m. p. 140 ◦C).
n-Hexane/AcOEt (up to 1 : 1, v/v) gave 161 mg
(18 % yield) of colorless crystals of N-(thiophenacyl)-1,3-
dithiol-2-imine (7), m. p. 146 – 148 ◦C (from CH2Cl2). – IR:
ν = 1605 – 1612 (C=C, dithiol and aromatic), 1485 (N-C=S),
1425 (-N=C-S-) cm−1. – 1H NMR (CDCl3): δ = 7.41, 7.52
(2× d, JHH = 8.1 Hz, 2 × 2 H, H-Ph), 7.76, 7.82 (2× d, J =
5.8 Hz, 2×1 H, H-dithiol), 8.18 (m, 1 H, H-Ph). – 13C NMR
(CDCl3): δ = 118.3, 119.7 (dithiol, C-4, C-5), 126.3, 128.6,
131.2, 133.9 (C-arom.), 154.6 (C=N, exocycl.), 206.4 (C=S).
– MS: m/z (%) = 237 (29) [M+], 205 (100), 102 (77), 77
(31). – C10H7NS3 (237.37): calcd. C 50.60, H 2.97, N 5.90,
S 40.53; found C 50.64, H 2.93, N 5.85, S 40.57.
n-Hexane/AcOEt (up to 4 : 6, v/v) afforded 362 mg
(42 % yield) of straw-yellow crystals of 2-methyl-6-phenyl-
◦
4H-1,3,5-dithiazine-4-thione (5), m. p. 161 – 163 C (from
acetone). – IR: ν = 1480 (N-C=S), 1424 (N=C-S) cm−1. –
1H NMR (CDCl3): δ = 1.31 (d, J = 7.4 Hz, 3 H, 2-Me),
4.27 (q, J = 7.4 Hz, 1 H, 2-H), 7.40, 7.53 (2× d, J = 8.2 Hz,
2×2 H, H-Ph), 8.16 (m, 1 H, H-Ph). – 13C NMR (CDCl3):
δ = 14.6 (2-Me), 31.6 (C-2), 125.9, 127.3, 131.6, 133.7 (C-
arom.), 143.6 (C-6), 204.3 (C-4). – MS: m/z (%) = 239 (26)
[M+], 238 (44), 224 (16), 150 (100), 77 (21). – C10H9NS3
(239.4): calcd. C 50.17, H 3.79, N 5.85, S 40.18; found
C 50.22, H 3.76, N 5.91, S 40.12.
Experimental Section
Melting points are uncorrected. The IR spectra were
recorded on a Perkin Elmer 317 Grating IR spectrophotome-
ter, using KBr. The 1H and 13C NMR spectra were measured
on a Joel E.C.A-500 MHz instrument using SiMe4 as an in-
ternal reference. The 31P NMR spectra were recorded with
the same instrument, relative to external H3PO4 (85 %). The
mass spectra were performed on a Joel JMS-A X 500 spec-
trometer. Solvents were dried by standard techniques. The
substrate 5-phenyl-3H-1,2,4-dithiazole-3-thione (1) was pre-
pared according to the reported method [9].
Method b: In boiling chloroform; preparation of compound
9
The above reaction of 1 and 2 was repeated under reflux
for 8 h in CHCl3 (or EtOH) that contained aq. LiOH (0.5 M),
using the same amounts, whereby the procedure and the
work-up were the same. The residue was chromatographed
to give 9 along with triphenylphosphane sulfide.
Reaction of 1,2-dithiol 1 with vinyltriphenylphosphonium
bromide (2)
Method a: In ethanol at r. t.; preparation of compounds 5
and 7
2-Phenyl-4(4H)-thioxo-1,3-thiazine (9) was eluted (n-
hexane/AcOEt 8 : 2, v/v) as colorless crystals (520 mg,
To a stirred solution of 1 (0.8 g, 3.8 mmol) and 2 67 % yield), m. p. 123 – 125 ◦C (from cyclohexane). – IR: ν =
(1.55 g, 4.2 mmol) in ethanol (30 mL) a freshly prepared 1482 (N-C=S), 1422 (N=C-S) cm−1. – 1H NMR (CDCl3):
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W. M. Abdou – M. D. Khidre · Ring Transformations of 1,2,4-Dithiazoles
δ = 6.84 (d, J = 4.5 Hz, 1 H, 5-H), 7.13 (d, J = 4.5 Hz, 1 H, was introduced all at once. The reaction mixture was stirred
6-H), 7.42, 7.55 (2× d, J = 8.2 Hz, 2×2 H, H-Ph), 8.18 (m, at r. t. for further ∼ 8 h (TLC). The product mixture was con-
1 H, H-Ph). – 13C NMR (CDCl3): δ = 116.6 (C-5), 124.8 centrated to 10 mL, diluted with dist. H2O (30 mL), acid-
(C-6), 125.9, 127.6, 130.7, 133.2 (C-arom.), 153.1 (C-2), ified with conc. HCl, and then extracted with two portions
198.8 (C-4). – MS: m/z (%) = 205 (100) [M+], 179 (28), 135 (100 mL) of ethyl acetate. The AcOEt extracts were com-
(53), 77 (22). – C10H7NS2 (205.3): calcd. C 58.5, H 3.44, bined, back-washed with H2O (100 mL), dried, and the sol-
N 6.82, S 31.24; found C 58.57, H 3.45, N 6.74, S 31.29.
Reaction of 1 with allyltriphenylphosphonium bromide
(10); preparation of compounds 12 and 13: A solution of 1
(0.8 g, 3.8 mmol) and 10 (1.61 g, 4.2 mmol) in CHCl3
(40 mL) was treated with aq. LiOH solution (0.5 M) (15 mL).
The reaction mixture was heated under reflux for 5 h and
worked up as described for the reaction of 1 with 2. Column
chromatography gave compounds 12 and 13, respectively.
2-Ethyl-6-phenyl-1,3-5-dithiazine-4(4H)-thione (12) was
obtained (n-hexane/AcOEt 5 : 5, v/v) as◦pale yellow crystals
(422 mg, 44 % yield), m. p. 149 – 151 C (from MeCN). –
IR: ν = 1477 (N-C=S), 1425 (N=C-S) cm−1. – 1H NMR
(CDCl3): δ = 0.93 (t, J = 7.6 Hz, 3 H, 2-CH2Me), 2.74 (q,
J = 7.6 Hz, 2 H, 2-CH2), 4.43 (t, ill-defined, 1 H, 2-H), 7.38,
7.52 (2× d, J = 6.5 Hz, 2 × 2 H, H-Ph), 8.14 (m, 1 H, H-
Ph). – 13C NMR ([D6]DMSO): δ = 13.4 (2-CH2Me), 23.6
(2-CH2), 29.8 (C-2), 125.2, 126.8, 131.1, 133.6 (C-arom.),
148.3 (C-6), 209.2 (C-4). – MS: m/z (%) = 253 (22) [M+],
252 (41), 223 (13), 150 (100), 77 (24). – C11H11NS3 (253.4):
calcd. C 52.14, H 4.38, N 5.53, S 37.96; found C 52.21,
H 4.34, N 5.47, S 38.00.
vents were evaporated to dryness. The residue was chro-
matographed on silica gel to afford compounds 17a and 19a
or 17b and 19b.
2-Methyl-4-phenylthiazole (19a) was obtained (n-
hexane/AcOEt 8 : 2, v/v) as yellow needles (155 mg,
◦
23 % yield), m. p. 153 – 155 C (MeCN). – IR: ν = 1600 –
1610 (C=C), 1422 (N=C-S) cm−1. – 1H NMR (CDCl3): δ =
1.93 (s, 3 H, 2-Me), 7.11 (s, 1 H, 5-H), 7.38, 7.47 (2× d, J =
6.7 Hz, 2 × 2 H, H-Ph), 8.09 (m, 1 H, H-Ph). – 13C NMR
(CDCl3): δ = 18.2 (2-Me), 118.6 (C-5), 124.8, 126.4, 129.3,
130.7, 133.3 (C-arom.), 158.6 (C-2). – MS: m/z (%) = 175
(100) [M+], 116 (48), 77 (27). – C10H9NS (175.26): calcd.
C 68.53, H 5.18, N 7.99, S 18.30; found C 68.58, H 5.12,
N 7.92, S 18.36.
6-Phenyl-4H-4-methylidene-1,3,5-dithiazine (17a) was
obtained (n-hexane/AcOEt 1 : 1, v/v) as orange crystals
(376 mg, 48 % yield), m. p. 182 – 184 ◦C (EtOH). – IR:
ν = 1622 (4-C=C) cm−1. – 1H NMR ([D6]DMSO): δ =
2.72 (s, 2 H, 2-H2), 5.74 [s, 2 H, 4-(=CH2)], 7.44, 7.62
(2× d, J = 7.8 Hz, 2 × 2 H, H-Ph), 7.98 (m, 1 H, H-Ph). –
13C NMR ([D6]DMSO): δ = 29.6 (C-2), 109.4 [4-(=CH2)],
4-Phenyl-5-vinyl-2(2H)-thioxo-1,3-thiazole (13) was ob- 124.7, 126.2, 129.5, 131.8, 133.4 (C-arom.), 141.6 (C-6),
tained after chromatography (n-hexane/AcOEt 3 : 7, v/v)◦as 146.6 (C-4). – MS: m/z (%) = 207 (13) [M+], 189 (31),
yellow crystals (175 mg, 21 % yield), m. p. 168 – 170 C 135 (100, C6H5CNS+), 77 (19). – C10H9NS2 (207.3): calcd.
(from acetone). – IR: ν = 3358 (NH), 1608 (C=C, exo- C 57.93, H 4.38, N 6.76, S 30.93; found C 57.99, H 4.36,
1
cycl.) cm−1. – H NMR ([D6]DMSO): δ = 5.22 (2d, Jb,c
=
=
N 6.85, S 30.96.
16.8, Jb,a = 2.4 Hz, 1 H, Hb), 5.64 (2d, Ja,c = 10.4, Ja,b
2-Ethyl-5-methyl-4-phenylthiazole (19b) was obtained
(n-hexane/AcOEt 8 : 2, v/v) as yellow needles (192 mg,
25 % yield), m. p. 196 – 198 C (EtOH). – IR: ν = 1600 –
2.4 Hz, 1 H, Ha), 6.47 (2d, Jc,a = 16.8, Jc,b = 10.4 Hz, 1 H,
Hc), 7.40, 7.52 (2× d, J = 6.6 Hz, 2 × 2 H, H-Ph), 8.14 (m,
1 H, H-Ph), 9.76 (s, 1 H, NH). – 13C NMR ([D6]DMSO):
δ = 109.40 (5-CH=CH2), 125.7 (5-CH), 124.8, 126.4, 129.8,
131.5, 133.2, (C-arom.), 141.4 (C-5), 149.8 (C-4), 194.6
(C=S). – MS: m/z (%) = 219 (17) [M+], 218 (23), 198 (100),
122 (66), 77 (23). – C11H9NS2 (219.3): calcd. C 60.24,
H 4.14, N 6.39, S 29.24; found C 60.27, H 4.09, N 6.46,
S 29.20.
◦
1610 (C=C), 1420 (N=C-S) cm−1. – 1H NMR (CDCl3): δ =
0.97 (t, J = 6.8 Hz, 3 H, 2-CH2Me), 1.54 (s, 3 H, 5-Me),
3.67 (q, J = 6.8 Hz, 2 H, 2-CH2), 7.39, 7.49 (2× d, J =
8.1 Hz, 2 × 2 H, H-Ph), 8.12 (m, 1 H, H-Ph). – 13C NMR
(CDCl3): δ = 12.8 (2-CH2Me), 16.4 (5-Me), 124.6, 125.3,
126.8, 129.2, 133.4, 133.8 (C-Ph, and C-5), 140.2 (C-6),
148.4 (C-2). – MS: m/z (%) = 203 (100) [M+], 188 (72), 173
(76), 129 (29), 77 (24). – C12H13NS (203.3): calcd. C 70.89,
H 6.45, N 6.89, S 15.77; found C 70.83, H 6.47, N 6.96,
S 15.82.
No reaction was observed in a parallel experiment when
the reactants (1+10) were mixed at ambient temperature,
even after 48 h.
Reaction of 1 with reactive ylides 15a and 15b; prepa-
2-Methyl-6-phenyl-4(4H)-ethylidene-1,3,5-dithiazine
ration of compounds 17a, 17b, 19a and 19b: A solu- (17b) was obtained (n-hexane/AcOEt 1 : 1, v/v) as orange
◦
tion of methyltriphenylphosphonium bromide (14a) (2.7 g, prisms (374 mg, 42 % yield), m. p. 195 – 197 C (CHCl3).
1
7.7 mmol) or ethyltriphenylphosphonium bromide (14b) – IR: ν = 1628 (4- C=C) cm−1. – H NMR ([D6]DMSO):
(2.8 g, 7.7 mmol) in DMF (40 mL) was added dropwise to a δ = 1.37 (d, J = 7.6 Hz, 3 H, 2-Me), 1.86 (d, J = 6.6 Hz,
slurry of a LiH dispersion (60 % in paraffin oil) (200 mg) in 3 H, 4-(=CH)Me), 4.16 (q, J = 7.6 Hz, 1 H, 2-CH),
DMF (15 mL). The reaction mixture was stirred at r. t. until 5.86 (q, J = 6.6 Hz, 1 H, 4-CH), 7.46, 7.67 (2× d, J =
all hydrogen evolution had ceased, and 1 (0.8 g, 3.8 mmol) 8.1 Hz, 2 × 2 H, H-Ph), 7.96 (m, 1 H, H-Ph). – 13C NMR
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W. M. Abdou – M. D. Khidre · Ring Transformations of 1,2,4-Dithiazoles
99
[D6](DMSO): δ = 13.7, 16.6 (2× Me), 31.7 (C-2), 124.4, H, H-Ph), 8.09 (m, 1 H, H-Ph), 9.75 (s (br), 1 H, NH). –
125.6, 126.8, 129.3, 131.8 (C-Ph), 141.2 (C-6), 148.2 (C-4). 13C NMR (CDCl3): δ = 13.4, 15.6 (2× SCH2Me), 18.3, 18.8
– MS: m/z (%) = 235 (17) [M+], 220 (21), 207 (37), 135 (2× OCH2Me), 61.7, 62.7 (2× OCH2), 96.8 (d, J = 184.7 Hz,
(100), 77 (22). – C12H13NS2 (235.4): calcd. C 61.23, =C-P), 124.2, 124.8, 126.4, 129.1, 132.6 (C-Ph), 138.8 (C-5),
H 5.57, N 5.95, S 27.25; found C 61.31, H 5.63, N 6.01, 141.6 (C-4), 151.3 (2-C=C). – 31P NMR (CDCl3): δ = 18.93.
S 27.31.
Reaction of 1 with α-phosphonyl reagents 20a and 20b; 228 (100), 137 (36), 131 (68). – C16H22NO3PS3 (403.5):
– MS: m/z (%) = 403 (21) [M+], 402 (30), 355 (17), 308 (46),
calcd. C 47.62, H 5.49, N 3.47, P 7.68, S 23.84; found
C 47.68, H 5.46, N 3.55, P 7.73, S 23.81.
preparation of phosphonates 22a, 22b, 23a and 23b: A solu-
tion of NaOEt prepared from Na (1.0 g, 4.2 mmol) in EtOH
(15 mL) was added to a stirred solu◦tion of 20a (or 20b)
Diethyl (6-phenyl-2-ethylthio-4-thioxo-1,3,5-dithiazin-2-
(14 mmol) in EtOH (15 mL) at −10 C. Stirring was con- yl)phosphonate (23b) was obtained (n-hexane/CHCl3 2 : 8,
tinued for 20 min and a solution of 1 (0.8 g, 3.8 mmol) in v/v) as straw-yellow crystals (687 mg, 43 % yield), m. p.
EtOH (10 mL) was then added at −10 ◦C. After stirring for 133 – 135 ◦C (from cyclohexane). – IR: ν = 1484, 1428
an additional hour at 0 ◦C and for further 6 h (TLC control) (C=S) and (N=C), 1248 (P=O), 1100 (P-O-C) cm−1. –
at r. t., the solution was concentrated to half of the volume in 1H NMR (CDCl3): δ = 0.98, 1.12 (3× t (m), 3 x 3 H,
vacuo and then poured onto ice, extracted with CHCl3, dried 2× OCH2Me and SCH2Me), 3.73 (q, JHP = 4.6 Hz, 2 H,
and evaporated. The residue was purified by column chro- SCH2), 3.98, 4.07 (2q, J = 10.8 Hz, 2× OCH2), 7.47, 7.76
matography to give 22a and 23a (or 22b and 23b).
(2× d, J = 8.3 Hz, 2 × 2 H, H-Ph), 8.04 (m, 1H, H-Ph).
Diethyl (6-phenyl-2-methylthio-4-thioxo-1,3,5-dithiazin-
–
13C NMR (CDCl3): δ = 12.6 (S CH2CH3), 18.63 (O
2-yl)phosphonate (23a) was obtained as str◦aw-yellow crys- CH2CH3), 35.2 (SCH2), 38.8 (C-2), 61.73 (OCH2), 124.6,
125.7, 126.8, 129.2, 131.6 (C-Ph), 150.6 (C-6), 209.3 (C=S).
tals (617 mg, 40 % yield), m. p. 122 – 124 C (from cyclo-
hexane). – IR: ν = 1487, 1422 (N-C=S) and (N=C-S), 1256
–
31P NMR (CDCl3): δ = 18.67. – MS: m/z (%) = 421 (14)
(P=O), 1083 (P-O-C) cm−1. – 1H NMR (CDCl3): δ = 1.09, [M+], 420 (23), 359 (28), 211 (100), 196 (72), 137 (40), 135
(23). – C15H20NO3PS4), (421.6): calcd. C 42.74, H 4.78,
1.14 (2dt, JHH = 7.4, JHP = 4.8 Hz, 2×3 H, 2× OCH2Me),
2.31 (d, 3H, JHP = 4.8 Hz, SMe), 3.85, 4.02 (2× q, J = N 3.32, P 7.35, S 30.42; found C 42.62, H 4.8, N 3,45, P 7.41,
10.6 Hz, 2 × 2 H, 2× OCH2), 7.47, 7.72 (2× d, J = 8.2 Hz, S 30.25.
2 × 2 H, H-Ph), 8.04 (m, 1 H, H-Ph). – 13C NMR (CDCl3):
Diethyl 1-(4-phenyl-5-ethylthio-1,3-thiazolyl-2-ylidene)-
δ = 13.8 (SMe), 17.4, 18.6 (2× OCH2Me), 37.3 (C-2), 61.4, 1-ethylthio-methane- phosphonate (22b) was obtained (n-
62.72 (2× OCH2), 124.2, 125.6, 128.7, 129.3, 133.1 (C- hexane/CHCl3 3 : 8, v/v) as yellow needles (376 mg, 23 %
yield), m. p. 148 – 150 ◦C (CHCl3/diethylether 1 : 1, v/v).
arom.), 151.3 (C-6), 204.8 (C-4). – 31P NMR (CDCl3): δ =
19.83. – MS: m/z (%) = 407 (16) [M+], 406 (25), 359 – IR: ν = 3355 (NH) 1618 (C=C), 1258 (P=O), 1110
(17), 211 (100), 196 (68), 137 (44‘, P(O)(OEt)2, 135 (23). (P-O-C) cm−1. – 1H NMR (CDCl3): δ = 0.96 – 1.18 (4× t
(m), 4 × 3H, 2SMe and 2OCCH3), 3.88, 4.23 (4q (m),
– C14H18NO3PS4 (407.55): calcd. C 41.26, H 4.45, N 3.44,
P 7.60, S 31.47; found C 41.22, H 4.37, N 3.32, P 7.54, 4×2 H, 2× SCH2 and 2× OCH2), 7.48, 7.76 (2d, J =
S 31.51.
8.2 Hz, 2 × 2 H, H-Ph), 8.03 (m, 1 H, H-Ph), 9.62 (s (br),
1 H, NH). – 13C NMR (CDCl3): δ = 13.7, 14.6, 15.9
(2× SCH2Me and 2× OCH2Me), 28.8, 29.4 (2× SCH2),
60.6, 61.4 (2× OCH2), 101.3 (d, J = 174.6 Hz, =C-P), 124.6,
125.3, 127.4, 129.2, 133.3 (C-Ph), 138.4 (C-5), 148.5 (C-4),
153.2 (2-C=C). – 31P NMR (CDCl3): δ = 19.63. – MS: m/z
(%) = 431 (18) [M+], 430 (26), 369 (16), 308 (44), 242
(100), 145 (77), 137 (28). – C18H26NO3PS3 (431.6): calcd.
C 50.09, H 6.07, N 3.25, P 7.18, S 22.29; found C 50.15,
H 6.11, N 3.18, P 7.22, S 22.23.
Diethyl 1-(4-phenyl-5-thiomethyl-1,3-thiazolyl-2-ylidene)
-1-methylthio-methane-phosphonate (22a) was obtained
(n-hexane/CHCl3 1 : 1, v/v) as fine yellow needles (412 mg,
◦
27 % yield), m. p. 142 – 144 C (MeCN). – IR: ν = 3365
(NH), 1628 (2-C=C), 1262 (P=O), 1132 (P-O-C) cm−1. –
1H NMR (CDCl3): δ = 1.11, 1.15 (2× dt, JHH = 7.4, JHP
=
4.8 Hz, 2×3 H, 2× OCH2Me), 2.16 (d, JHP = 4.5 Hz, 3 H,
SMe), 2.23 (s, 3 H, 5-SMe), 3.88, 4.02 (2× q, J = 10.8 Hz,
2 × 2 H, 2× OCH2), 7.48, 7.75 (2× d, J = 8.2 Hz, 2 × 2
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