A qualitative comparison of the reactivities of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine and 4,5-Dichloro-1,2,3-dithiazolium Chloride

Article abstract of DOI:10.3390/molecules200814576

The high yielding transformations of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine into 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (up to 85%) and 2-(3,5-dichloro-4H-1,2,6- thiadiazin-4-ylidene)malononitrile (up to 83%) have been investigated and compared to the a

Full text of DOI:10.3390/molecules200814576

Molecules 2015, 20, 14576-14594; doi:10.3390/molecules200814576
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Qualitative Comparison of the Reactivities of
3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine and
4,5-Dichloro-1,2,3-dithiazolium Chloride
Andreas S. Kalogirou * and Panayiotis A. Koutentis
Department of Chemistry, University of Cyprus, P.O. Box 20537, Nicosia 1678, Cyprus;
E-Mail: koutenti@ucy.ac.cy
* Author to whom correspondence should be addressed; E-Mail: kalogirou.andreas@ucy.ac.cy;
Tel.: +357-892804.
Academic Editor: Derek J. McPhee
Received: 9 July 2015 / Accepted: 6 August 2015 / Published: 12 August 2015
Abstract: The high yielding transformations of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine
into 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (up to 85%) and 2-(3,5-dichloro-4H-1,2,6-
thiadiazin-4-ylidene)malononitrile (up to 83%) have been investigated and compared to the
analogous transformations of the closely-related 4,5-dichloro-1,2,3-dithiazolium chloride
(Appel’s salt) into 4-chloro-5H-1,2,3-dithiazol-5-one and 2-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)malononitrile. Furthermore, cyclocondensation of 3,4,4,5-tetrachloro-4H-1,2,6-
thiadiazine with 2-aminophenol and 1,2-benzenediamines gave fused 4H-1,2,6-thiadiazines
in 68%–85% yields.
Keywords: heterocycle; 1,2,6-thiadiazines; Appel’s salt; 1,2,3-dithiazoles
1. Introduction
3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1), which possesses a reactive geminal dichloromethylene,
is related to highly-electrophilic 4,5-dichloro-1,2,3-dithiazolium chloride (2) (Appel’s salt), in that
substitution of the S-1 sulfur by a Cl–C=N unit affords 3,4,5-trichloro-1,2,6-thiadiazinium chloride
(1′), the ionic form of 1 (Scheme 1). The late C. W. Rees recognized that the structural and electronic
similarities implied that the C-4 position of tetrachlorothiadiazine 1 and the C-5 position of Appel’s salt
2 could have similar chemical reactivities. Both of these compounds are useful and attractive heterocycles;

Molecules 2015, 20
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however, considerably more work has been reported for Appel’s salt 2, presumably owing to its more
facile synthesis.
Cl
S
Cl
S
Cl Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
N
N
N
N
N
S
Cl
Cl
1
1'
Cl
S
Cl
Cl
Cl
Cl
Cl
Cl
N
S
N
S
N
S
S
S
Cl
Cl
2'
2
Scheme 1. Comparison of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) with
4,5-dichloro-1,2,3-dithiazolium chloride (2).
Non-oxidized 4H-1,2,6-thiadiazines are rare, and accounts of their chemistry and applications are
few. Mono-5-substituted-4H-1,2,6-thiadiazines have been investigated as plant antifungals [1–5], and
to the best of our knowledge, these studies were not expanded. Furthermore, fused analogues were
studied as examples of “extreme quinoids” that have an ambiguous aromatic character [6], while others
displayed unusual liquid crystalline properties or behaved as near-infrared dyes [7,8]. Moreover, selected
4H-1,2,6-thiadiazines have been proposed as radical anion precursors for molecule-based magnetic and
conducting functional materials [9]. 4H-1,2,6-Thiadiazin-4-one containing small molecules have been
investigated as efficient electron donors in solution-processed bulk heterojunction solar cells [10], while
in an effort to understand their optical properties, key 4H-1,2,6-thiadiazines have been characterized
by resonance Raman (RR), absorption (UV-VIS) and photoluminescence (PL) spectroscopies [11].
For these potential applications to become reality, the chemistry of 4H-1,2,6-thiadiazines needs to be
further developed. To date, the most commonly used non-S-oxidized 4H-1,2,6-thiadiazine scaffold is
3,5-dichloro-4H-1,2,6-thiadiazin-4-one (3), which is a precursor to many thiadiazine derivatives, via
palladium-catalyzed C-C coupling reactions, such as Stille and Suzuki-Miyaura couplings, to give
various 3,5-di(het)aryl substituted systems [12–14] and reactions with amines to give mono-, or
3,5-diamino-substituted systems [15], or polycyclic systems [16].
Appel’s salt 2, discovered in 1985, is readily prepared from chloroacetonitrile and disulfur dichloride [17]
and has since found numerous uses as a scaffold for the synthesis of 1,2,3-dithiazole derivatives [18–21].
Dithiazolium 2 exists as a salt and not in the covalent form 2′, and it is a planar and 6π aromatic system,
although worthy of note is the 5,5-difluoro analogue, which is a non-ionic covalent bound molecule that
can be distilled and isolated as an oil [17]. The chemistry of the dithiazolium 2 is governed by the
electrophilicity of the C-5 carbon, and it readily reacts with nucleophiles to give neutral 5H-1,2,3-dithiazoles.
Bearing in mind the similarities of the two reagents thiadiazine 1 and Appel’s salt 2, we began an
investigation to compare their reactions with simple nucleophiles. Recently, the synthesis of
N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines (4) from 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) [22],
by a simple reaction with aniline was investigated. This condensation is very similar to the reaction of
anilines with Appel’s salt 2 that gives (Z)-N-aryl-4-chloro-5H-1,2,3-dithiazol-5-imines 5 (Scheme 2) [23].

Molecules 2015, 20
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We now report the reactivity of thiadiazine 1 with three different types of nucleophiles: water,
malononitrile and aromatic bisnucleophiles.
Ar
N
Cl Cl
ArNH2 (3 equiv)
MeCN, 0-20 o
Cl
Cl
Cl
Cl
C
N
N
N
N
22 examples
43-96 %
S
S
1
4
Cl
Cl
i) ArNH2 (1 equiv)
DCM, 20 oC, 1 h
N
Cl
Ar
S
N
S
N
ii) Py (2 equiv)
DCM, 20 oC, 2 h
S
S
Cl
2
5
Scheme 2. Synthesis of synthesis of N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines (4)
and (Z)-N-aryl-4-chloro-5H-1,2,3-dithiazol-5-imines (5).
2. Results and Discussion
2.1. Preparation of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1)
Two methods exist in the literature for the preparation of the tetrachlorothiadiazine 1: the reaction
of dichloromalononitrile (6) and SCl2 [15] and the reaction of N-2,2-trichloro-2-cyanoacetimidoyl
chloride (7) [24] with elemental sulfur. In our hands, both reactions worked well; however, the second
method was preferred, as it gave better yields and avoided the use of the toxic and hard to access
SCl2 (Scheme 3). Compound 7, even though it looks very reactive, was easy to prepare and isolate
and can be stored for up to six months at 0 °C. Moreover, the two reports on the isolation of
tetrachlorothiadiazine 1 gave conflicting distillation data for the product (100 °C, 8 mbar [25] vs. 90 °C,
4 mbar [26]). In our hands, the thiadiazine 1 distilled nicely at (90 °C, 30 mbar) as a pale yellow oil that
crystallized on cooling to −20 °C [mp (DSC) onset: 10.3 °C, peak max: 12.8 °C] and can be stored for
several months at −40 °C.
Cl
Cl
Cl
Cl
N
Cl
Cl
Cl
Cl
Cl
Cl
B
A
N
N
N
S
N
N
1
7
6
A: SCl2 (1 equiv), BnEt3NCl (1 mol %), neat, ca. 20 oC, 18 h, 69%
B: S8 (0.125 equiv), BnEt3NCl (1 mol %), DCM, ca. 20 oC, 18 h, 76%
Scheme 3. Synthesis of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1).
3,5-Dichloro-4H-1,2,6-thiadiazin-4-one (3) can be prepared from the reaction of glacial formic acid
with 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) [15]. In our hands, this transformation was sensitive
to the quality of the formic acid used as both a solvent and reagent. Interestingly, no other chemistry
has been reported for tetrachlorothiadiazine 1 apart from this reaction and its degradation in moist air

Molecules 2015, 20
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to give 2-chloromalonamide (8) (Scheme 4) [26]. As such, we reinvestigated the transformation of
tetrachlorothiadiazine 1 into the thiadiazinone 3 (Section 2.2.).
O
Cl
N
Cl
N
HCO2H
1 d, 20 oC
75%
moist air
2d, 20 oC
94%
H
Cl
Cl
Cl
Cl
Cl
O
O
N
N
H2N
NH2
S
S
1
8
3
Scheme 4. Known reactions of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1).
Comparing the syntheses of tetrachlorothiadiazine 1 with dithiazolium 2, it was clear that both
required similarly hazardous reagents for their preparations. The synthesis of dithiazolium 2, however,
was clearly easier, as it required only commercially-available chloroacetonitrile and disulfur dichloride
and can be isolated as a salt by simple filtration. On the other hand, the synthesis of the thiadiazine 1
required the use of chlorine gas to prepare the less readily-available dichloromalononitrile and SCl2
reagents, and the product 1 was isolated by vacuum distillation.
2.2. Preparation of the Thiadiazinone 3 and Dithiazolone 9
Both the covalent thiadiazine 1 and the ionic 1,2,3-dithiazolium 2 are hydrolytically unstable, reacting
with water or even in moist air. However, while the degradation of dithiazolium 2 in moist air gives a brown
mass from which the dithiazolone 9 can be isolated by sublimation [17], the analogous degradation of
tetrachlorothiadiazine 1 leads to ring cleavage to afford 2-chloromalonamide (8) (Scheme 4) [26].
Several improved methods are known for the transformation of Appel’s salt 2 to dithiazolone
9 [17,27], but only details of the formic acid-induced reaction have been reported for the hydrolysis
of the tetrachlorothiadiazine 1 [1,2,15]. As such, we investigated other routes to synthesize the two
ketones 3 and 9.
The hydrolytic conditions investigated included treatment with formic acid, acetic acid, sodium and
silver nitrates and DMSO (Table 1). The highest yielding (85%) and cleanest reaction conditions for
the hydrolysis of the tetrachlorothiadiazine 1 into the thiadiazinone 3 involved the use of AgNO3 in
MeCN (Table 1, Entry 6), while for the hydrolysis of Appel’s salt 2 to dithiazolone 9, the cleanest
conditions were using neat glacial formic acid (Table 1, Entry 1; 89%). While most procedures worked
equally well for both transformations, significant differences in behavior were also observed.
The reaction of tetrachlorothiadiazine 1 with glacial formic acid (98% purity) gave the thiadiazinone
3 in a reasonable 75% yield, but the use of technical-grade formic acid (85% purity), containing ca. 15%
water, led to degradation of the starting material, affording only a trace of 2-chloromalonamide (<1%).
In contrast, Appel’s salt 2 was less sensitive to the presence of water in the formic acid and with the
respective reactions gave dithiazolone 9 in 89% and 71% yields (Table 1, Entries 1 and 2).
Moreover, the classical reaction of Appel’s salt 2 with NaNO3 (1 equiv) in dichloromethane
(DCM), at ca. 20 °C, to give dithiazolone 9 in a 72% yield [17] failed to give any product with the
tetrachlorothiadiazine 1; however, when DCM was replaced by MeCN, the desired thiadiazinone 3 was
obtained in a 71%–72% yield (Table 1, Entries 4 and 5). Presumably, the more polar MeCN encouraged
the equilibrium between the covalent and ionic forms of thiadiazine 1 to shift favorably towards the latter.

Molecules 2015, 20
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Table 1. Hydrolysis of tetrachlorothiadiazine 1 and Appel’s salt 2 to thiadiazinone 3 and
dithiazolone 9, respectively.
O
Cl
Cl
Cl
Cl
O
Cl
Cl
Cl
Cl
Cl
or
or
S
N
S
N
N
N
N
N
S
S
S
S
Cl
2
3
9
1
Entry
Conditions a
Product Yields and Reaction Times
1
2
HCO2H (98%) neat
3 (75%), 24 h
3 (0%), c 18 h
3 (74%), 48 h
3 (nr), d 18 h
3 (71%), 1.5 h
3 (85%), 0.5 h
3 (77%), 4 h
3 (0%), c 20 h
3 (31%), 20 h
3 (45%), 1 h
9 (89%), 2 h
9 (72%), 1 h
9 (60%), 2 h
9 (72%), 18 h
9 (77%), 18 h
9 (72%), 1 min
9 (73%), 24 h
9 (86%), 1 h
9 (83%), 1.5 h
HCO2H (85%) b neat
AcOH neat
3
4
NaNO3 (1 equiv), DCM
NaNO3 (1 equiv), MeCN
AgNO3 (1 equiv), MeCN
Ag2SO4 (0.5 equiv), MeCN
5
6
7
8
H2O (1 equiv), DMSO (1 mol %), MeCN
DMSO (1 equiv), MeCN
DMSO neat
9
10
9 (50%), 15 min
c
a All reactions were performed at 20 °C. b Technical grade formic acid, contains 15% H2O. Degradation to
chloromalonamide 8. d nr = no reaction.
Finally, Appel’s salt 2 can react with H2O (1 equiv) in the presence of catalytic DMSO (Table 1,
Entry 8) [27]; however, under these conditions, thiadiazine 1 gave only a trace of the desired ketone 3
(Table 1, Entry 8).
This study showed that the tetrachlorothiadiazine 1 and Appel’s salt 2 have similar reactivity to
many of the investigated reagents, indicating that both compounds, despite having a different form
(covalent vs. ionic) are similarly electrophilic. However, thiadiazine 1, which is non-aromatic, is more
sensitive to the presence of water in the reaction conditions.
2.3. Preparation of Ylidenemalononitriles 10 and 11
The ylidenemalononitriles derived from tetrachlorothiadiazine 1, and Appel’s salt 2, 2-(3,5-dichloro-4H-
1,2,6-thiadiazin-4-ylidene)malononitrile (10) and 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)malononitrile
(11), respectively, are both known and are useful heterocycles. The ylidenemalononitrile 10 has been used
for the synthesis of other thiadiazine derivatives, such as furo- [28] and pyrrolo-fused thiadiazines [16,28,29]
(Scheme 5), while (1,2,6-thiadiazinylidene)malononitriles are desired as possible electron acceptors
for organic photovoltaic (OPV) devices [11,30]. Interestingly, the ylidenemalononitrile 10 could not be
prepared from the Knoevenagel condensation of the thiadiazinone 3 with malononitrile, but was
accessible from the reaction of expensive tetracyanoethene (TCNE) with SCl2. The reaction produced
several minor side products and required chromatography to isolate the desired ylidene 10 in variable
yields (30%–60%) [31]. These complications prevented scaling up the reaction and limited the supply
of this useful ylidenemalononitrile.

Molecules 2015, 20
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NC
N
CN
Cl
BnEt3NCl (1 mol %)
DCM, 25 oC, 72 h
30-60%
NC
NC
CN
CN
Cl
SCl2
+
N
S
TCNE
10
Scheme 5. Preparation of the ylidenemalononitrile 10 from tetracyanoethene (TCNE) and SCl2.
2-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)malononitrile (11) is a useful starting material for difficult
to access 3-chloroisothiazole-4,5-dicarbonitrile (12) [32,33] and 3-bromoisothiazole-4,5-dicarbonitrile
(13) (Scheme 6) [33,34]. Its preparation starting from Appel’s salt 2 has been thoroughly investigated,
and several syntheses have been reported, using malononitrile [32], tetracyanoethylene oxide
(TCNEO) [32,35], halo-substituted malononitriles [34] and dimethylsulfonium dicyano-methylide [36].
CN
Cl
Cl
Cl
NC
Hal
NC
4 routes
29-72%
S
N
S
N
N
NC
S
S
S
Cl
2
11
12 (Hal = Cl)
13 (Hal = Br)
Scheme 6. Synthesis of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)malononitrile (11) from
Appel’s salt 2. Structures of isothiazoles 12 and 13 derived from 11.
In light of the similarities between the reactivity of tetrachlorothiadiazine 1 and Appel’s salt 2,
the transformation of 1 into the ylidenemalononitrile 10 was explored: while the reaction of Appel’s
salt 2 with TCNEO (1 equiv) in PhMe heated at reflux gave the ylidene 11 in a 55% yield [32],
under these reaction conditions, the tetrachlorothiadiazine 1 gave only a complex mixture of products
containing a trace of the desired ylidenemalononitrile 10 by TLC. Similarly, while the reaction of
dimethylsulfonium dicyanomethylide 14 with Appel’s salt 2 [36] affords the ylidene 11 in medium to good
yields (29%–72%) along with other side products, the analogous reaction of tetrachlorothiadiazine 1 with
dicyanomethylide 14 was less effective, giving only a low 19% yield of ylidene 10 as the only product.
Interestingly, performing the reaction at ca. 39 °C gave surprisingly a mixture of 4,5,6-trichloropyrimidine-
2-carbonitrile (15) and the ylidene 10 in 21% and 19% yields, respectively (Scheme 7). The formation of
the pyrimidine 15 from this reaction was intriguing, as this heterocycle was first observed in the
abovementioned reaction of TCNE with SCl2 [31]. A tentative mechanism for the formation of
pyrimidine 15 is proposed below (Scheme 7).
Despite the fact that the simple pyridine-mediated condensation of malononitrile with Appel’s salt 2
gives only a low yield of ylidenemalononitrile 11 (40%) [32], when the tetrachlorothiadiazinone 1 was
treated with malononitrile (1.1 equiv) and 2,6-lutidine (2 equiv) in dry DCM, at ca. 20 °C, the starting
material was consumed quickly (TLC, 10 min) to give the ylidenemalononitrile 10 in a 78% yield (Table 2,
Entry 1). Attempts to improve the yield of this reaction involved screening the base [1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU), i-Pr2NEt (Hünig’s base), K2CO3, t-BuOK or K3PO4] and solvents (MeCN,

Molecules 2015, 20
14582
THF, PhMe), but these led to either degradation or to lower yields. Nevertheless, in DCM at ca. 20 °C
using lutidine (2 equiv) as the base, increasing the equivalents of malononitrile from 1.1–1.5 equiv
afforded the ylidenemalononitrile 10 in a slightly better yield (82%), while a further increase to 2 equiv
of malononitrile gave a similar 83% yield (Table 2, Entries 2 and 3). The reaction could be scaled up to
4 mmol, and while this led to a drop in yield (73%) (Table 2, Entry 5), it also enabled a chromatography
free work-up that involved passing the reaction mixture through a short plug of SiO2, washing the organic
phase with 2M HCl and H2O and precipitating the product from THF/pentane to give the ylidene 10 in
a preparatively useful 64% yield (Table 2, Entry 6).
NC
CN
Cl
Cl
Cl
N
Cl
N
DCM
39 oC, 20 h
Cl
Cl
NC
Me
CN
Me
Cl
Cl
Cl
+
+
N
N
S
N
N
S
S
CN
1
14
15 (21%)
10 (19%)
Cl
N
Cl
N
Cl
Cl
Cl
N
S
Cl
Cl
Cl
Cl
Cl
Cl
Cl
_
N
S
N
N
Me2S
S
S
CN
NC
CN
NC
NC
Me
NC
S
Me
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
_
15
N
N
N
S
N
_
ClCN
1/8S8
S
CN
CN
Scheme 7. Reaction of tetrachlorothiadiazine 1 with dimethylsulfonium dicyanomethylide
14 and the proposed mechanism for the formation of the pyrimidine 15.
Table 2. Transformation of the tetrachlorothiadiazine 1 into to the ylidenemalononitrile 10.
NC
CN
CH2(CN)2, solvent
2,6-lutidine (2 equiv)
0-20 oC
Cl
N
Cl
N
Cl
Cl
Cl
Cl
N
N
S
S
10
Entry 1 (mmol) CH2(CN)2 (equiv) DCM (mL) Time (min) Yield of 10 (%)
1
2
3
4
5
6
0.42
0.42
0.42
1
1.1
1.5
2
1
1
1
1
4
4
10
10
10
10
30
30
78
82
83
1.5
1.5
1.5
71
2
73
64 a
4
a Chromatography-free workup.

Molecules 2015, 20
14583
Attempts to develop a base-free protocol were less effective, as heating a PhMe solution of the
tetrachlorothiadiazine 1 with malononitrile (2 equiv) at reflux (110 °C) led to complete consumption of
the starting material only after 48 h and isolation of the desired ylidene 10 in a low 27% yield.
2.4. Cyclisation Reactions of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1)
The condensation of Appel’s salt 2 with 2-amino-4-chlorophenol or benzene-1,2-diamine affords
5-chlorobenzo[d]oxazole-2-carbonitrile (16) and 1H-benzo[d]imidazole-2-carbonitrile (17), respectively
(Scheme 8) [37].
OH
O
Cl
NH2
CN
pyridine
N
Cl
Cl
Cl
16, 62%
S
N
NH2
S
Cl
N
NH2
pyridine
2
CN
N
H
17, 70%
Scheme 8. Reactions of Appel’s salt 2 with 2-amino-4-chlorophenol or benzene-1,2-diamine.
Moreover, the condensation reactions of the thiadiazinone 3 with benzene-1,2-diamine or sodium
2-aminophenoxide to give fused systems are known (Scheme 9) [16]. Even though the thiadiazinone 3
was inert to reactions with primary amines at the C-4 position, after an initial nucleophilic addition
in the C-3 position, intramolecular cyclizations readily occur with bisnucleophiles to afford tricyclic
systems in excellent yields, e.g., 4-chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (18) and 4-chloro-
benzo[5,6][1,4]oxazino[2,3-c][1,2,6]thiadiazine (19) (Scheme 9). Worthy of note was that while an
excellent yield was reported for oxazine 19, this required an initial base activation (deprotonation) of the
hydroxy group of 2-aminophenol to direct the reaction.
O
O
S
NH2
N
S
A
Cl
Cl
Cl
B
Cl
B
+
NH2
N
N
N
N
N
N
S
3
A = NH2 or ONa
18 (B = NH, 91%)
19 (B = O, 99%)
B = NH or O
Scheme 9. Reactions of thiadiazinone 3 with benzene-1,2-diamine and sodium 2-aminophenoxide.
The dichloromethylene of the tetrachlorothiadiazine 1 was expected to be more electrophilic
and therefore more reactive than the C-3, C-4 and C-5 positions of the thiadiazinone 3. As such,
bisnucleophiles were anticipated to initially attack the geminal dichloromethylene. This reactivity
mimics that of Appel’s salt 2 (Scheme 8) with bisnucleophiles where the first nucleophilic displacement
occurs at the more electrophilic C-5 position.

Molecules 2015, 20
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Treatment of the tetrachlorothiadiazine 1 with 2-aminophenol or benzene-1,2-diamine in MeCN at
20 °C for 1 h afforded the fused heterocycles 18 (68%) and 19 (68%), respectively (Scheme 10). Tentatively,
the moderate yields (68%) can be attributed to the high reactivity of the tetrachlorothiadiazine 1 that can
presumably suffer from both halophilic and thiophilic attack, leading to its degradation.
N
Cl
N
Cl
N
MeCN,
0-20 oC, 1 h
Cl
Cl
Cl
A
NH2
AH
+
N
N
S
S
18 (A = O, 68%)
19 (A = NH, 68%)
22 (A = NPh, 85%)
A = O (4 equiv)
A = NH (3 equiv)
A = NPh (2 equiv)
1
Route a
AH
N
HN
N
A
N
Cl
Cl
Cl
Cl
Route b
N
N
S
S
21
20
Scheme 10. Reactions of the tetrachlorothiadiazine 1 with 2-aminophenol, benzene-1,2-diamine
and N′-phenylbenzene-1,2-diamine.
A proposed mechanism for this transformation involves the initial formation of imine 20, which
we know from previous studies readily forms by reaction of thiadiazine 1 with arylamines [22].
Subsequently, two routes are proposed, either a 6-exo cyclisation to give the final products (Route a) or
a 5-endo cyclisation occurs to form the spirocyclic compounds 21 that then ring-opens, assisted by
electron release from both the nitrogen’s lone pair and possibly the ring sulfur, subsequently cyclizing
at the C-3 position (route b). Interestingly, when using N′-phenylbenzene-1,2-diamine, an unsymmetrical
diamine, the less reactive secondary amine ends up cyclizing on the thiadiazine C-3 position to give
4-chloro-10-phenyl-10H-[1,2,6][3,4-b]quinoxaline (22) in an 85% yield. While this route to tricyclic
systems 18, 19 and 22 was non-quantitative, it offered two distinct advantages: firstly, it avoided the
need to access the thiadiazinone 3, thereby reducing the number of steps to the final products, and
secondly, it offered an alternative regioselectivity that avoided the need to base activate bisnucleophiles,
such as the 2-aminophenol.
2.5. Reactivity of 4-Chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (19)
Interestingly, during the synthesis and isolation of 4-chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline
(19), we observed its decomposition to 3-aminoquinoxaline-2-carbonitrile (23). Traces of this product
were initially observed during chromatography of quinoxaline 19, so we decided to investigate the
reactivity of this compound. Quinoxaline 19 was stable under basic conditions, as it was recovered
unchanged after 48 h stirring in neat Et3N, while it was unstable in acid, as heating a solution in glacial

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AcOH at reflux for 15 min led to complete consumption of the starting material and isolation of
3-aminoquinoxaline-2-carbonitrile (23) as the only product in a 38% yield. Alternatively, heating a
solution of 19 in aqueous HCl/THF at 80 °C gave the quinoxaline 23 in an 80% yield (Scheme 11).
Cl
A) MnO2 (10 equiv)
N
N
N
CN
DCM, 20 oC, 22 h, 85%
N
S
or
N
H
N
NH2
B) 2 M HCl, THF
80 oC, 1 d, 80%
19
23
Scheme 11. Conversion of 4-chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (19) to
3-aminoquinoxaline-2-carbonitrile (23).
Furthermore, quinoxaline 19 was also unstable in oxidizing and reducing conditions. Namely, stirring
a DCM solution of 19 with MnO2 (10 equiv) at ca. 20 °C led to complete consumption of the starting
material after 22 h and isolation of aminoquinazoline 23 in an 85% yield (Scheme 11). The dissolving
metal reduction with Zn (4 equiv) in AcOH led to degradation of 19 and isolation of 3-aminoquinoxaline-
2-carbonitrile (23) in only a low 6% yield.
Aminoquinoxaline 23 was previously prepared in a low yield by the reaction of 4-chloro-5-cyano-
1,2,3-dithiazolium chloride with benzene-1,2-diamine [38]. Similar degradation reactions were also
investigated for thiadiazines 18 and 22; however, these gave complex mixtures of products (by TLC)
and were not pursued further.
3. Experimental Section
3.1. General Methods and Materials
All chemicals were commercially available, except those whose synthesis is described. Anhydrous
Na2SO4 was used for drying organic extracts, and all volatiles were removed under reduced pressure.
All reaction mixtures and column eluents were monitored by TLC using commercial glass-backed thin
layer chromatography (TLC) plates (Merck Kieselgel 60 F254) [39]. The plates were observed under UV
light at 254 and 365 nm. The technique of dry flash chromatography was used throughout for all
non-TLC-scale chromatographic separations using Merck Silica Gel 60 (less than 0.063 mm, Merck
KGaA, Darmstadt, Germany). Melting points were determined using a PolyTherm-A, Wagner & Munz,
Kofler—Hotstage Microscope apparatus (Wagner & Munz, Munich, Germany) or were determined
using a TA Instruments differential scanning calorimeter (DSC) Q1000 with samples hermetically sealed
in aluminum pans under an argon atmosphere; using heating rates of 5 °C/min (DSC melting points
listed by onset and peak values). Solvents used for recrystallization are indicated after the melting point.
UV spectra were obtained using a Perkin-Elmer Lambda-25 UV-VIS spectrophotometer (Perkin-Elmer,
Waltham, MA, USA), and inflections are identified by the abbreviation “inf”. IR spectra were recorded
on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with the Pike Miracle Ge
ATR accessory (Pike Miracle, Madison, WI, USA), and strong, medium and weak peaks are represented
by s, m and w, respectively. 1H- and 13C-NMR spectra were recorded on a Bruker Avance 300 (at 300
and 75 MHz, respectively, Bruker, Billerica, MA, USA) or a 500 machine (at 500 and 125 MHz,

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respectively). Deuterated solvents were used for the homonuclear lock, and the signals are referenced to
the deuterated solvent peaks. Attached-proton-test (APT) NMR studies identified quaternary and tertiary
carbons, which are indicated by (s) and (d) notations, respectively. MALDI-TOF mass spectra were
recorded on a Bruker Autoflex III Smartbeam instrument. Low resolution (EI) mass spectra were
recorded on a Shimadzu Q2010 GC-MS with a direct inlet probe. Dichloromalononitrile (6) [24], N-2,2-
trichloro-2-cyanoacetimidoyl chloride (7) [24] and dimethylsulfonium dicyanomethylide (14) [40] were
prepared according to the reported procedures.
3.2. Preparation of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1)
3.2.1. Reaction of Dichloromalononitrile with SCl2
Performed according to the literature procedure [26]. To a stirred solution of dichloromalononitrile (6)
(100 g, 0.740 mol) was added BnEt3NCl (1.69 g, 7.40 mmol), and the mixture was cooled in an ice bath
(0 °C). Freshly distilled SCl2 (76.2 g, 0.740 mol) was then added dropwise, the cooling bath removed
and the mixture stirred overnight, protected with a CaCl2 drying tube. After 18 h, the solvent was
evaporated under vacuum and the product distilled under reduced pressure (90 °C, 30 mbar) to give
3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (121.5 g, 69%) as a pale yellow oil that crystallized on
cooling to −20 °C mp (DSC) onset: 10.3 °C, peak max: 12.8 °C; δC (125 MHz; CDCl3) 138.5 (s), 72.1 (s);
νmax/cm−1 1582m, 1566m, 1144s, 1030s, 953m, 812m, 770s; identical to an authentic sample.
3.2.2. Reaction of N-2,2-Trichloro-2-cyanoacetimidoyl Chloride (4) with S8
This was performed according to the literature procedure [26]. A stirred solution of
N-2,2-trichloro-2-cyanoacetimidoyl chloride (7) (41.2 g, 0.200 mol) in dry DCM (40 mL) was cooled in
an ice bath (0 °C), and BnEt3NCl (456 mg, 2.00 mmol) was added, followed by S8 (6.40 g, 25.0 mmol)
added in one portion. The cooling bath was then removed and the mixture stirred overnight, protected
with a CaCl2 drying tube. After 18 h, the product was distilled under reduced pressure (90 °C, 30 mbar)
to give 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (36.2 g, 76%) as a pale yellow oil that crystallized
on cooling to −20 °C mp (DSC) onset: 10.3 °C, peak max: 12.8 °C; identical to that described above.
3.3. Transformations of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) to 3,5-Dichloro-4H-1,2,6-
thiadiazin-4-one (3)
3.3.1. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with Formic Acid
This was performed according to the literature procedure [15]. 3,4,4,5-Tetrachloro-4H-1,2,6-
thiadiazine (1) (59.5 g, 0.250 mol) was added dropwise to a cold (10 °C) stirred solution of 98% HCO2H
(175 mL). The cooling bath was then removed and the solution stirred overnight, protected with a CaCl2
drying tube. After complete consumption of the starting material (TLC, 24 h), the mixture was poured
into ice water and the precipitate collected, washed with water and dried under air to yield
3,5-dichloro-4H-1,2,6-thiadiazin-4-one (3) (34.3 g, 75%) as yellowish needles, mp 81–82 °C (from
c-hexane, lit. [15] 82–83 °C); Rf 0.56 (n-hexane/DCM, 50:50); δC (125 MHz; CDCl3) 157.5 (s), 149.8

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(s); νmax/cm−1 1657s (C=O), 1501m, 1277w, 1265w, 1248m, 1227m, 1065s, 854m, 847w, 745s, identical
to an authentic sample [15].
3.3.2. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with Acetic Acid
3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) (238 mg, 1.00 mmol) was added dropwise to a stirred
solution of glacial AcOH (1 mL), and the solution was stirred at ca. 20 °C, protected with a CaCl2 drying
tube, until complete consumption of the starting material (TLC, 48 h). The mixture was then adsorbed
onto silica, and chromatography (n-hexane/DCM, 50:50) gave 3,5-dichloro-4H-1,2,6-thiadiazin-4-one
(3) (135 mg, 74%) as yellowish needles, mp 81–82 °C (from c-hexane, lit. [15] 82–83 °C), identical to
that described above.
3.3.3. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with NaNO3 in MeCN
To a solution of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (100 mg, 0.42 mmol) in dry MeCN
(1 mL) was added NaNO3 (39 mg, 0.46 mmol), and the mixture was stirred at ca. 20 °C, protected with
a CaCl2 drying tube, until consumption of the starting material (TLC, 1.5 h). The reaction mixture was
then adsorbed onto silica, and chromatography (n-hexane/DCM, 50:50) gave 3,5-dichloro-4H-1,2,6-
thiadiazin-4-one (3) (55 mg, 71%) as yellowish needles, mp 81–82 °C (from c-hexane, lit. [15] 82–83 °C),
identical to that described above.
3.3.4. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with AgNO3 in MeCN
To a solution of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (100 mg, 0.42 mmol) in dry MeCN
(1 mL) was added AgNO3 (71 mg, 0.42 mmol), and the mixture was stirred at ca. 20 °C, protected with
a CaCl2 drying tube, until consumption of the starting material (TLC, 30 min). A colorless precipitate
formed that was filtered to give AgCl (52 mg, 87%). The filtrate was then adsorbed onto silica, and
chromatography (n-hexane/DCM, 50:50) gave 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (3) (65 mg, 85%)
as yellowish needles, mp 81–82 °C (from c-hexane, lit. [15] 82–83 °C), identical to that described above.
3.3.5. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with DMSO in MeCN
To a solution of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (238 mg, 1.00 mmol) in dry MeCN
(10 mL) was added DMSO (71 μL, 1.0 mmol), and the mixture was stirred at ca. 20 °C, protected with
a CaCl2 drying tube, until consumption of the starting material (TLC, 20 h). The reaction mixture was
then adsorbed onto silica, and chromatography (n-hexane/DCM, 50:50) gave 3,5-dichloro-4H-1,2,6-
thiadiazin-4-one (3) (57 mg, 31%) as yellowish needles, mp 81–82 °C (from c-hexane, lit. [15] 82–83 °C),
identical to the one reported above.
3.3.6. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with Neat DMSO
A solution of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (238 mg, 1.00 mmol) in DMSO (2 mL)
was stirred at ca. 20 °C, protected with a CaCl2 drying tube, until consumption of the starting material
(TLC, 1 h). Water (20 mL) was then added and the mixture extracted with t-BuOMe (3 × 20 mL), the organic
phase combined, dried (Na2SO4) and evaporated to give crude 3. The crude product was then adsorbed

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onto silica, and chromatography (n-hexane/DCM, 50:50) gave 3,5-dichloro-4H-1,2,6-thiadiazin-4-one
(3) (82 mg, 45%) as yellowish needles, mp 81–82 °C (from c-hexane, lit. [15] 82–83 °C), identical to
the one reported above.
3.4. Transformations of 4,5-Dichloro-1,2,3-dithiazolium Chloride (2) into 4-Chloro-5H-1,2,3-
dithiazol-5-one (9)
3.4.1. Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride (2) with Formic Acid
Appel’s salt 2 (208 mg, 1.00 mmol) was added to a stirred solution of HCO2H (98%, 1 mL), and the
solution was stirred at ca. 20 °C, protected with a CaCl2 drying tube, until complete consumption of the
starting material (2 h). The mixture was then adsorbed onto silica, and chromatography (n-hexane/DCM,
60:40) gave 4-chloro-5H-1,2,3-dithiazol-5-one (9) (137 mg, 89%) as pale yellow plates, mp 35–36 °C
(from pentane, lit. [17] 39 °C); Rf 0.48 (n-hexane/DCM, 60:40); δC (75 MHz; CDCl3) 183.3 (s), 147.0 (s);
ν
max/cm−1 1651s (C=O), 1612m, 1501m, 1337w, 1142w, 1021m, 1080w, 847m, 837m, 806w, 785m,
identical to an authentic sample [17].
3.4.2. Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride (2) with Acetic Acid
Appel’s salt 2 (208 mg, 1.00 mmol) was added to a stirred solution of glacial AcOH (1 mL), and the
solution was stirred at ca. 20 °C, protected with a CaCl2 drying tube, until complete consumption of the
starting material (2 h). The mixture was then adsorbed onto silica, and chromatography (n-hexane/DCM,
60:40) gave 4-chloro-5H-1,2,3-dithiazol-5-one (9) (92 mg, 60%) as pale yellow plates, mp 35–36 °C
(from pentane, lit. [17] 39 °C), identical to that described above.
3.4.3. Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride (2) with NaNO3 in MeCN
To a suspension of Appel’s salt (2) (104 mg, 0.50 mmol) in dry MeCN (1 mL) was added NaNO3
(43 mg, 0.50 mmol), and the mixture was stirred at ca. 20 °C, protected with a CaCl2 drying tube,
until consumption of the starting material (18 h). The mixture was then adsorbed onto silica, and
chromatography (n-hexane/DCM, 60:40) gave 4-chloro-5H-1,2,3-dithiazol-5-one (9) (59 mg, 77%) as
pale yellow plates, mp 35–36 °C (from pentane, lit. [17] 39 °C), identical to that described above.
3.4.4. Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride (2) with AgNO3 in MeCN
To a suspension of Appel’s salt (2) (104 mg, 0.50 mmol) in dry MeCN (1 mL) was added AgNO3
(85 mg, 0.50 mmol), and the mixture was stirred at ca. 20 °C, protected with a CaCl2 drying tube, until
consumption of the starting material (1 min). A colorless precipitate formed that was filtered to give
AgCl (72 mg, 100%). The filtrate was then adsorbed onto silica and chromatography (n-hexane/DCM,
60:40) gave 4-chloro-5H-1,2,3-dithiazol-5-one (9) (55 mg, 72%) as pale yellow plates, mp 35–36 °C
(from pentane, lit. [17] 39 °C), identical to that described above.

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3.5. Transformations of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) to 2-(3,5-Dichloro-4H-1,2,6-
thiadiazin-4-ylidene)malononitrile (10)
3.5.1. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with Malononitrile
To a solution of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (100 mg, 0.42 mmol) in dry DCM
(1 mL) was added malononitrile (42 mg, 0.63 mmol), and the solution was cooled in an ice bath (0 °C).
2,6-Lutidine (98 μL, 0.84 mmol) was then added dropwise to the stirred solution. The cooling bath was
then removed and the solution stirred at ca. 20 °C until complete consumption of the starting material
(TLC, 10 min). The reaction mixture was then poured onto a silica column, and chromatography
(n-hexane/DCM, 20:80) gave 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (10) (80 mg,
82%) as yellow plates, mp 133–134 °C (from c-hexane, lit. [31] 134–135 °C); Rf 0.65 (n-hexane/DCM,
20:80); δC (125 MHz; CDCl3) 138.8 (s), 136.5 (s), 112.0 (s), 81.2 (s); νmax/cm−1 2216m (C≡N), 1522m,
1508m, 1487m, 1288s, 1273m, 1144m, 1082m, 812m, 754s; m/z (EI) 230 (M+, 100), 204 (M+-CN, 2%),
195 (M+-Cl, 55), 169 (M+-CClN, 21), 134 (M+-CCl2N, 21), identical to an authentic sample [31].
3.5.2. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with Malononitrile, Chromatography-Free
(Table 2, Entry 6)
To a solution of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (952 mg, 4.00 mmol) in dry DCM
(4 mL) was added malononitrile (396 mg, 6.00 mmol), and the solution was cooled in an ice bath (0 °C).
2,6-Lutidine (0.930 mL, 8.00 mmol) was then added dropwise to the stirred solution. The cooling bath
then removed and the solution stirred at ca. 20 °C until complete consumption of the starting material
(TLC, 30 min). The reaction mixture was then passed through a plug of silica (DCM) and washed with
2 M HCl (2 × 10 mL) and H2O (10 mL), evaporated and precipitated from THF/pentane to give 2-(3,5-
dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (10) (591 mg, 64%) as yellow plates, mp 133–134 °C
(from c-hexane, lit. [31] 134–135 °C), identical to that described above.
3.5.3. Reaction of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1) with Dimethylsulfonium
Dicyanomethylide (14)
To a solution of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) (100 mg, 0.42 mmol) in dry DCM
(1 mL) was added dimethylsulfonium dicyanomethylide (14) (58 mg, 0.46 mmol), and the mixture was
heated at ca. 39 °C, protected with a CaCl2 drying tube, until consumption of the starting material
(20 h). The reaction mixture was then adsorbed onto silica, and chromatography (n-hexane/DCM, 60:40)
gave 4,5,6-trichloropyrimidine-2-carbonitrile (15) (18 mg, 21%) as colorless needles, mp 62–63 °C
(sublimation, lit. [31] 64–65 °C); Rf 0.41 (n-hexane/DCM, 60:40); νmax/cm−1 2423w and 2363w (C≡N)
and 1530w (C=C), 1497s, 1350s, 1337m, 1315m, 1300m, 1275m, 1256m, 1209m, 1065m, 1057m,
910m, 832m, 818m, 770m; δC (125 MHz; CDCl3) 161.1 (s), 139.7 (s), 133.2 (s), 113.4 (s); m/z (EI) 207
+
(M+, 100), 172 (M+-Cl, 50%), 120 (C3Cl2N+, 28), 111 (C4ClN2 , 13), identical to an authentic sample [31].
Further elution (n-hexane/DCM, 20:80) gave 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile
(10) (18 mg, 19%) as yellow plates, mp 133–134 °C (from c-hexane, lit. [31] 134–135 °C), identical to
that described above.

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3.6. Cyclisation Reactions of 3,4,4,5-Tetrachloro-4H-1,2,6-thiadiazine (1)
3.6.1. Synthesis of 4-Chlorobenzo[5,6][1,4]oxazino[2,3-c][1,2,6]thiadiazine (18) (General Procedure)
To a cold (0 °C) stirred solution of tetrachlorothiadiazine 1 (238 mg, 1.00 mmol) in dry MeCN
(5 mL) was added in one portion 2-aminophenol (436 mg, 4.00 mmol). The cooling bath was then removed
and the solution stirred at ca. 20 °C protected with a CaCl2 drying tube until complete consumption of
the starting material (TLC, 1 h). The mixture was then adsorbed onto silica, and chromatography
(n-hexane/DCM, 50:50) gave the title compound 18 (179 mg, 76%) as orange prisms, mp 157–160 °C
(from EtOH, lit. [16] 158–163 °C); Rf 0.43 (n-hexane/DCM, 50:50); νmax/cm−1 3103w and 3048w (Ar
CH), 1614m, 1587m, 1547m, 1518m, 1456s, 1365m, 1331s, 1308m, 1294w, 1283m, 1244m, 1206m,
1184m, 1107m, 1059m, 1026m, 978m, 968m, 945m, 901s, 876s, 868m, 800s, 763s, 748s; δH (500 MHz;
DMSO-d6) 7.24 (1H, dd, J = 7.7, 1.4, Ar H), 7.18 (1H, ddd, J = 7.8, 7.8, 1.5, Ar H), 7.05 (1H, ddd,
J = 7.6, 7.6, 0.9, Ar H), 6.89 (1H, d, J = 8.1, Ar H); δC (125 MHz; DMSO-d6) 151.0 (s), 148.1 (s), 145.8 (s),
138.3 (s), 133.9 (s), 130.6 (d), 128.5 (d), 125.7 (d), 115.2 (d); m/z (EI) 237 (M+, 100%), 202 (M+-Cl, 5),
176 (M+-CClN, 9), 144 (M+-CClNS, 11), 118 (5), 93 (CClNS+, 11), 64 (6), identical to an authentic sample.
3.6.2. Synthesis of 4-Chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (19)
Similar treatment of tetrachlorothiadiazine 1 (238 mg, 1.00 mmol) with benzene-1,2-diamine
(432 mg, 3.00 mmol) gave, after the solvent was evaporated in vacuo and the crude product precipitated
from EtOH (2 mL), the title compound 19 (160 mg, 68%) as purple needles, mp 310 °C (from EtOH, lit. [16]
310 °C subl.); Rf 0.17 (n-hexane/DCM, 50:50); νmax/cm−1 3237w, 3188w, 3140w, 3069w and 3051w (Ar
CH), 1605s, 1570w, 1514m, 1470m, 1414m, 1379s, 1275m, 1221m, 1115m, 957m, 924s, 878m, 800s,
766s, 741s; δH (500 MHz; DMSO-d6) 10.19 (1H, s, NH), 6.93 (1H, ddd, J = 7.8, 7.8, 1.1, Ar H), 6.87
(1H, d, J = 8.2, Ar H), 6.66 (1H, ddd, J = 7.9, 7.9, 0.8, Ar H), 6.38 (1H, d, J = 7.9, Ar H); δC (125 MHz;
DMSO-d6) 149.9 (s), 142.2 (s), 139.7 (s), 136.4 (s), 135.8 (s), 130.5 (d), 128.3 (d), 123.1 (d), 113.5 (d);
m/z (EI) 236 (M+, 100%), 201 (M+-Cl, 32), 174 (M+-CHClN, 8), 168 (7), 162 (4), 154 (6), 149 (6), 143
(M+-CClNS, 21), 131 (6), 118 (6), 102 (5), 90 (9), 76 (C6H4+,4), 69 (11), identical to the an authentic sample.
3.6.3. Synthesis of 4-Chloro-10-phenyl-10H-[1,2,6][3,4-b]quinoxaline (22)
Similar treatment of tetrachlorothiadiazine 1 (238 mg, 1.00 mmol) with N′-phenylbenzene-1,2-diamine
(368 mg, 2.00 mmol) gave after chromatography (DCM) the title compound 22 (212 mg, 68%) as brown
needles, mp 256–258 °C (from PhMe); Rf 0.81 (DCM); (found: C, 57.26; H, 2.54; N, 17.62. C15H9ClN4S
requires C, 57.60; H, 2.90; N, 17.91%); λmax (DCM)/nm 267 (log ε 4.37), 285 inf (4.29), 296 inf (4.24),
326 (4.14), 367 (3.94), 387 (3.98), 409 (3.83), 527 (3.68), 552 (3.69), 596 inf (3.44); νmax/cm−1 3048w,
1593m, 1504m, 1497m, 1485m, 1450m, 1360s, 1317m, 1173w, 1157m, 941m, 932m, 876m, 764s, 750s,
731s, 714s; δH (500 MHz; DMSO-d6) 7.58 (2H, dd, J = 7.4, 7.4, Ar H), 7.47 (1H, dd, J = 7.3, 7.3, Ar H),
7.33 (2H, d, J = 7.4, Ar H), 7.06 (1H, d, J = 7.5, Ar H), 6.87 (1H, dd, J = 7.4, 7.4, Ar H), 6.79 (1H, dd,
J = 7.4, 7.4, Ar H), 5.66 (1H, d, J = 7.9, Ar H); δC (125 MHz; DMSO-d6) 149.6 (s), 143.3 (s), 139.3 (s),
138.4 (s), 135.7 (s), 135.2 (s), 130.6 (d), 130.3 (d), 129.0 (d), 128.8 (d), 128.7 (d), 123.7 (d), 113.5 (d);
m/z (MALDI-TOF) 314 (M++2, 47%), 312 (M+, 95), 277 (M+-Cl, 100), 245 (M+-ClS, 36).

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3.7. Reactivity of 4-Chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (19)
3.7.1. Reaction of 4-Chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (19) with MnO2
To a stirred solution of 4-chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (19) (47 mg, 0.20 mmol)
in DCM (2 mL) at ca. 20 °C was added MnO2 (174 mg, 2.0 mmol), and the mixture was protected with
a CaCl2 drying tube until complete consumption of the starting material (TLC, 22 h). The solid that formed
was removed by filtration and the filtrate adsorbed onto silica and chromatographed (n-hexane/t-BuOMe,
40:60) to give 3-aminoquinoxaline-2-carbonitrile (23) (29 mg, 85%) as yellow needles, mp 209–210 °C
(from c-hexane, lit. [38] 210 °C); Rf 0.59 (n-hexane/t-BuOMe, 40:60); νmax/cm−1 3412m, 3327m, 3132
br, 2232m (C≡N), 1661s, 1611m, 1562m, 1557m, 1489m, 1437m, 1371m, 1360m, 1323w, 1254w,
1223m, 1171w, 1144m, 1123w, 1092w, 1013w, 963w, 918m, 760s, 754s, 741m; δH (500 MHz; CDCl3)
7.94 (1H, dd, J = 8.4, 1.0, Ar H), 7.74 (1H, ddd, J = 8.4, 6.8, 1.4, Ar H), 7.69 (1H, dd, J = 8.5, 1.1, Ar
H), 7.53 (1H, ddd, J = 8.3, 6.8, 1.4, Ar H), 5.42 (2H, br s, NH2); δC (125 MHz; CDCl3) 151.8 (s), 142.5
(s), 137.5 (s), 133.8 (d), 129.7 (d), 126.8 (d), 126.4 (d), 119.2 (s), 114.9 (s); m/z (EI) 170 (M+, 100%),
+
143 (M+-CHN, 33), 118 (17), 91 (C6H5N+, 13), 84 (13), 76 (C6H4 , 6), 66 (13), identical to an authentic
sample [38].
3.7.2. Reaction of 4-Chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (19) with HCl
To a stirred solution of 4-chloro-10H-[1,2,6]thiadiazino[3,4-b]quinoxaline (19) (47 mg, 0.20 mmol)
in THF (4 mL) was added a 2 M aqueous HCl (4.0 mL, 8.0 mmol), and the mixture was stirred at ca. 80 °C
until complete consumption of the starting material (TLC, 24 h). The mixture was then cooled to ca. 20 °C,
and DCM (10 mL) was added, followed by saturated Na2CO3 until the pH reached 10. The organic phase
was separated and the mixture further extracted with DCM (2 × 10 mL), and the combined organic phase
was then dried (Na2SO4) and evaporated. The crude product was then adsorbed onto silica and
chromatographed (n-hexane/t-BuOMe, 40:60) to give 3-aminoquinoxaline-2-carbonitrile (23) (27 mg,
80%) as yellow needles, mp 209–210 °C (from c-hexane, lit. [38] 210 °C); Rf 0.59 (n-hexane/t-BuOMe,
40:60), identical to that described above.
4. Conclusions
Three modes of reactivity were investigated for the sparingly explored 3,4,4,5-tetrachloro-4H-1,2,6-
thiadiazine (1): its conversion to the useful scaffolds 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (3) and
2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile (10) in 85% and 83% yields, respectively,
and its transformation to tricyclic thiadiazines in good yields. The geminal dichloromethylene to ketone
transformation was directly compared between thiadiazine 1 and Appel’s salt 2, and similarities and
differences between the reactivity of the two reagents were identified. The reaction of thiadiazine 1
with dicyanomethylide 14 led to the isolation of an unexpected side product, 4,5,6-trichloropyrimidine-
2-carbonitrile (15), the investigation of which is now under further study. The development of the
chemistry of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (1) shows that this unexplored reagent can be a
useful scaffold in the synthesis of valuable heterocycles.

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Acknowledgments
The authors thank Nikolas Panayiotou for preliminary work on the degradation of the tricyclic
4H-1,2,6-thiadiazines and the Cyprus Research Promotion Foundation (Grant No. NEAYPODOMH/
NEKYP/0308/02), as well as the following organizations and companies in Cyprus for generous
donations of chemicals and glassware: the State General Laboratory; the Agricultural Research Institute; the
Ministry of Agriculture; MedoChemie, Ltd.; Medisell, Ltd.; and Biotronics, Ltd. Furthermore, we thank the
A. G. Leventis Foundation for helping to establish the NMR facility at the University of Cyprus.
Author Contributions
A.S.K and P.A.K. designed the research, drafted and approved the manuscript; A.S.K. performed the
synthetic work and analyzed the data.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
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