Ring transformations of 2-hydroxy-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)arenes

Article abstract of DOI:10.1016/j.tet.2014.12.046

Abstract The cyclisation reactions of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene-amino)phenol (5a), 3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol (5b) and 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)pyridin-3-ol (5c) are investigated. Thermolysis in hot PhCl (132 °C) or under solvent free conditions at ca. 200 °C gave benzo[d]oxazole-2-carbonitrile (4a), oxazolo[5,4-b]pyridine-2-carbonitrile (4b) and oxazolo[4,5-b]pyridine-2-carbonitrile (4c) in high yields, while treatment with either NaH in dry THF at 66 °C or with i-Pr₂NEt in DCM at 20 °C gave benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine (6a), [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine (6b) and oxazolo[4,5-b]pyridine (4c), respectively. The transformation of benzoxazine 6a and the pyridoxazine 6b into the corresponding oxazoles 4a and 4b was also investigated, and tentative mechanistic pathways for these transformations are proposed.

Full text of DOI:10.1016/j.tet.2014.12.046

Tetrahedron xxx (2014) 1e10
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ring transformations of 2-hydroxy-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)arenes
*
Andreas S. Kalogirou, Sophia S. Michaelidou, Maria Koyioni, Panayiotis A. Koutentis
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclisation reactions of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene-amino)phenol (5a), 3-(4-
chloro-5H-1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol (5b) and 2-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)pyridin-3-ol (5c) are investigated. Thermolysis in hot PhCl (132 ꢀC) or under solvent
free conditions at ca. 200 ꢀC gave benzo[d]oxazole-2-carbonitrile (4a), oxazolo[5,4-b]pyridine-2-
carbonitrile (4b) and oxazolo[4,5-b]pyridine-2-carbonitrile (4c) in high yields, while treatment with
either NaH in dry THF at 66 ꢀC or with i-Pr2NEt in DCM at 20 ꢀC gave benzo[b][1,2,3]dithiazolo[5,4-e][1,4]
oxazine (6a), [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine (6b) and oxazolo[4,5-b]pyridine (4c), re-
spectively. The transformation of benzoxazine 6a and the pyridoxazine 6b into the corresponding ox-
azoles 4a and 4b was also investigated, and tentative mechanistic pathways for these transformations are
proposed.
Received 23 October 2014
Received in revised form 28 November 2014
Accepted 12 December 2014
Available online xxx
Dedicated to the memory of Professor Alan
R. Katritzky who sadly passed away on the
10th Feb. 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Fused heterocycles
Ring transformations
Thermolysis
Sulfurenitrogen heterocycles
Oxazoles
Oxazines
1. Introduction
inactivation of the glutamine/amino acid transporter ASCT210 have
been demonstrated. Furthermore, benzo and heteroazine fused
(4-Chloro-1,2,3-dithiazol-5H-ylideneamino)(het)arenes 1, can
be readily prepared in good to excellent yields1e3 from the reaction
of a primary (het)arylamine with 4,5-dichloro-1,2,3-dithiazolium
chloride 2 (Appel salt)1 followed by treatment with a tertiary
amine base (2 equiv) (Scheme 1). They can also be formed from the
reaction of N-aryl-S,S-dimethylsulfimides,4 N-aryl-1,1,1-trimethyl-
N-(trimethylsilyl) silanamines,1 or tetrazoles5 with Appel salt 2.
1,2,3-dithiazoles are of interest to the material sciences.11
In addition, (4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)are-
nes are useful precursors to other heterocycles through Addition of
the Nucleophile, Ring Opening, and Ring Closure (ANRORC)12 style
ring transformations.13 For example, thiazoles,14 1,3,4-
thiadiazoles14 and heteroazine fused thiazoles15 have been pre-
pared via ANRORC type transformations,16 while the thermolysis of
(1,2,3-dithiazolylideneamino)arenes can afford (het)areno fused
thiazoles,15e17 1,2,4,-dithiazines,18 imidazoles19 oxazoles17c,20 and
oxazines.21 Moreover, 1,2,3-dithiazolylideneamines have also been
used to prepare acyclic functionalities such as isothiocyanates22
and thiocyanoformamides.2,23
Several examples of (4-chloro-5H-1,2,3-dithiazol-5-ylidene
amino)arene ring transformations involve a nucleophilic ortho
substituent on the arene. Where the ortho substituent is a primary,
secondary19,24 or even a tertiary amine,25 thermolysis affords the
analogous imidazole-2-carbonitriles 3, and when the ortho sub-
stituent is a hydroxyl group the analogous benzo[d]oxazole-2-
carbonitrile (4a) forms (Scheme 2).17a,20 Surprisingly, in the latter
case, treatment of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
phenol (5a) with NaH in dry THF gave benzo[b][1,2,3]dithiazolo
[5,4-e][1,4]oxazine (6a) (Scheme 2).17a
Scheme 1. Synthesis of (dithiazolylideneamino)arenes 1 from Appel salt 2.
Early reports on the biological activity of [(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)amino]arenes showed that some 1,2,3-
dithiazoles have antifungal6 and herbicidal7 activities, while more
recently, interesting antitumour,8 antibacterial9 activities and
* Corresponding author. E-mail address: koutenti@ucy.ac.cy (P.A. Koutentis).
http://dx.doi.org/10.1016/j.tet.2014.12.046
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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2
A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
via an ANRORC style mechanism where the amine attacks the ring
sulfur to generate a disulfide intermediate that then recyclises. Kim
et al. has reported several examples of ANRORC style indirect dis-
placement of the Cl by amines.28,29
In light of our access to 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene
amino)phenol (5a), 3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneam
ino)pyridin-2-ol (5b) and 2-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)pyridin-3-ol (5c) and our on-going interest in the
chemistry of Appel salt 2 we probed this chemistry further. Our aims
were to identify additional examples and to improve the reaction
conditions leading to the fused oxazines, to determine the influence
of additional ring nitrogens, and to propose mechanistic pathways
for the products formed.
2. Results and discussion
Scheme 2. Ring transformations of (dithiazolylideneamino)arenes bearing a nucleo-
philic ortho substituent on the arene.
2.1. Synthesis of fused oxazoles and oxazines
The latter cyclisation is analogous to the base (NaH or i-Pr2NEt in
THF or K2CO3 in MeCN) catalysed cyclisation of 2-(4-chloro-3H-1,2-
dithiol-3-ylideneamino)phenols 7, prepared from 3,4,5-trichloro-
1,2-dithiolium chloride (8) (Boberg salt)26 and 2-aminophenols, to
give 1,2-dithiolo[4,3-b][1,4]benzoxazines 9, in moderate yields
(39e45%) (Scheme 3).27
2.1.1. Synthesis of dithiazolimine starting materials. 2-(4-Chloro-
5H-1,2,3-dithiazol-5-ylideneamino)phenol (5a), 3-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol (5b) and 2-(4-chloro-
5H-1,2,3-dithiazol-5-ylideneamino)pyridin-3-ol (5c) were pre-
pared from Appel salt 2 and the corresponding ortho hydroxy
amino arenes 12 (Scheme 5).
Scheme 3. Cyclisation of 2-(4-chloro-3H-1,2-dithiol-3-ylideneamino)phenols 7.
Direct displacement of the dithiazoles C4 chlorine atom has
proved to be difficult,17a and the intramolecular cyclisation of the
(dithiazolylideneamino)phenol 5a to afford the benzoxazine 6a is
a very rare example of a cyclisation onto the dithiazole C4 position
that maintains the integrity of the dithiazole ring. The only other
known example is the reaction of 5-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10) with secondary
alkylamines to yield 6-carbamoyl-5-oxo-5H-furo[2,3-d][1,2,3]
dithiazoles (11) (Scheme 4).28 However, this cyclisation proceeds
Interestingly, the pyridin-3-ol 5c was obtained only in 11% yield,
and was accompanied by several deeply coloured side products.
Two of these were isolable and tentatively assigned as (Z)-4-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene)-2-[(Z)-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)amino]pyridin-3(4H)-one (13) (2%) and (Z)-2-
amino-6-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3(6H)-
one (14) (4%), respectively, and were a reminder that electron rich
arenes can react directly via the ring carbon in an enolic30 or
enaminic17e,18 manner.
Compound 13 was obtained as blue dust, mp 288e289 ꢀC (from
DCE). Elemental analysis and LR (EI) mass spectrometry supported
the molecular formula C9H2Cl2N4OS4; a clear two chlorine isotope
pattern was observed for the parent ion [m/z 384 (Mþþ4, 2%), 382
(Mþþ2, 4), 380 (Mþ, 8)]. UV/vis spectroscopy showed a lmax of
614 nm (log
3
3.52) that suggested the compound had extended
conjugation. 1H NMR spectroscopy showed two doublets at 9.23
and 8.08 ppm with J values of 6.0 and 5.5 Hz, respectively. The small
J
values observed in the 1H NMR data supported
a
5,6-
1
unsubstituted pyridine since JH4H5 couplings are typically larger
than JH5H6 couplings (7e9 vs 4e6 Hz).31 13C NMR spectroscopy,
1
revealed the presence of nine carbon resonances of which seven
were quaternaries and two secondaries. Based on these data a bis-
dithiazole structure was proposed for compound 13, however,
a number of geometric isomers are possible. Of these, the Z,Z iso-
mer has two favourable non-bonding interactions: the first in-
teraction between the S1 sulfur atom of the dithiazolylidene and
the oxygen atom of the carbonyl group, and the second between
the S1 sulfur atom of the other dithiazolimine and the pyridone
nitrogen atom. The non-bonding interaction between the S1 sulfur
Scheme 4. Example of intramolecular cyclisation onto the dithiazole C4 position that
maintains the integrity of the dithiazole ring, and the proposed mechanism for the
ANRORC mediated indirect displacement of the C4 chlorine by amine.
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A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
3
Scheme 5. Reaction of Appel salt 2 with ortho hydroxy amino arenes 12.
Table 1
of the dithiazole ring and the oxygen atom of the carbonyl group is
supported by the absence of a carbonyl stretch in the FTIR data.32
Tentatively, based on these data the more stable isomer was pro-
posed to be the structure shown (Scheme 5).
Differential scanning calorimetery (DSC) data for the 2-(4-chloro-5H-1,2,3-
dithiazol-5-ylideneamino)arenes 5aeca
Entry
5
Mp (ꢀC)
Onset
Decomp. (ꢀC)
Decomp. (ꢀC)
Compound 14 was obtained as lusterous bronze coloured
prisms, mp >300 ꢀC (from DCE). Elemental analysis and LR (EI)
mass spectrometry supported the molecular formula C7H4ClN3OS2;
a clear one chlorine isotope pattern was observed for the parent ion
[m/z (EI) 247 (Mþþ2, 28%), 245 (Mþ, 64)]. UV/vis spectroscopy
Peak
Onset
Peak
Onset
Peak
1
2
3
5a
5b
5c
107.9
100.1
138.4
109.0
106.4
138.9
110.1b
107.2b
139.7c
112.0b
109.3b
139.8c
d
142.5b
d
145.0b
148.7b
154.2b
a
Samples were run (1e2 mg) in hermetic aluminium pans under argon atmo-
sphere with a 5 ꢀC/min heating rate.
showed a lmax at 612 nm (log 3.35) suggesting the compound had
3
b
extended conjugation. 1H NMR spectroscopy identified one D2O
exchangeable broad doublet integrating for two Hs at 7.27 ppm,
indicating the presence of a primary amine with hindered rotation
on the NMR timescale, presumably owing to a significant contri-
bution of the resonance form 140. The amine group was additionally
Exotherm.
Endotherm.
c
order of reactivity was 5b>5a>5c (Table 2, entries 1e3). Solutions
of dithiazoles 5a and 5c in hot PhH were stable even after 24 h,
however, in hot PhMe, only the dithiazole 5c was completely stable.
In contrast, the dithiazole 5b after 24 h in hot PhMe showed con-
sumption of the starting material and only traces of both oxazole 4b
and oxazine 6b (by TLC), while the dithiazole 5a in hot PhMe was
converted slowly (48 h) into the oxazole 4a (80%) and elemental
sulfur.
supported by IR bands at n .
(NeH) 3300 and 3486 cmꢁ1 1H NMR
spectroscopy also identified two doublets, which belonged to aro-
matic hydrogens [8.50 (J 9.5 Hz) and 6.34 (J 9.0 Hz) ppm], both
integrating for 1H. The large J couplings suggested a 2,3,6-
trisubstituted pyridine.31 Tentatively, based on these data, struc-
ture 14 was proposed, however, identifying a specific geometrical
isomer proved elusive.
Under solvent free conditions the thermolysis of all three
2-hydroxy-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)arenes
5aec under an argon atmosphere at ca. 200 ꢀC for 1e5 min, gave
the corresponding fused oxazoles 4aec in 60e85% yield, together
with some S8 (60e90%) (Table 2, entries 4e6). Thermolysis of the
(dithiazolylideneamino)pyridin-2-ol 5b also gave a small quantity
of [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine (6b) (1%) (Table
2, entry 5). The reaction of the dithiazoles 5aec with NaH (1.1e2
equiv) in dry THF for 2 h heated at ca. 66 ꢀC was less predictable
(Table 2, entries 7e9): dithiazoles 5a and 5b gave the expected
oxazine products 6a and 6b in 65 and 42% yields, respectively,
while the dithiazole 5c gave only the oxazolo[4,5-b]pyridine 4c in
a relatively high yield (88%, Table 2, entry 9). The very different
behaviour of the dithiazole 5c towards NaH was also seen when the
base was replaced by tertiary amine bases: treating the dithiazoles
5a and 5b with i-Pr2NEt (1.1 equiv) in DCM at ca. 20 ꢀC for 0.5 and 7
days, respectively (Table 2, entries 10 and 11) afforded the tricyclic
oxazines 6a and 6b in 93 and 63% yields, respectively, while the
analogous treatment of the dithiazole 5c gave the oxazolo[4,5-b]
pyridine 4c in 73% yield (Table 2, entry 12).
2.1.2. Thermolysis and base mediated ring transformations. The
relative thermal stability of the 2-hydroxy(dithiazolylideneamino)
arenes 5aec was indicated during their isolation and purification:
both the (dithiazolylideneamino)phenol and pyridin-3-ol 5a and
5c, respectively, can be recrystallised as yellow cotton fibres from
warm c-hexane, however, the (dithiazolylideneamino)pyridin-2-ol
5b was unstable and partly cyclised into oxazolo[5,4-b]pyridine-2-
carbonitrile (4b) affording also traces of [1,2,3]dithiazolo[5,4-e]
pyrido[2,3-b][1,4]oxazine (6b). Purification of the (dithiazolylide-
neamino)pyridin-2-ol 5b was, therefore, carried out via pre-
cipitation in n-pentane from THF.
The instability of dithiazole 5b in hot c-hexane prompted an
examination of the thermal behaviour of all three dithiazoles by
differential scanning calorimetry (DSC) and also in a range of aro-
matic solvents: PhH (bp 80 ꢀC), PhMe (bp 110 ꢀC) and PhCl (bp
132 ꢀC). DSC of all three dithiazoles 5aec indicated that on melting
all three dithiazoles 5aec were thermally unstable (Table 1).
In hot PhCl all three dithiazoles 5aec were converted into their
respective fused 2-cyano oxazoles: benzo[d]oxazole-2-carbonitrile
(4a), oxazolo[5,4-b]pyridine-2-carbonitrile (4b) and oxazolo[4,5-b]
pyridine-2-carbonitrile (4c) and elemental sulfur. The relative
Interestingly, while the dithiazoles 5aec reacted relatively
quickly with trialkylamines such as Et3N, i-Pr2NEt or DBU, they
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A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
Table 2
Thermolysis and base reactions of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)arenes 5aec (0.20 mmol)
Entry
X
Y
Conditions
Yields (%)
S8
4
6
1
2
3
4
5
6
7
8
CH
CH
N
CH
CH
N
CH
CH
N
CH
CH
N
CH
N
CH
CH
N
CH
CH
N
CH
CH
N
PhCI, 132 ꢀC, 15 h, argon
98
100
95
60
90
4a (83)
4b (96)
4c (72)
4a (85)
4b (66)
4c (84)
4a (Trace)
4b (Trace)
4c (88)
d
PhCI, 132 ꢀC, 1 h, argon
d
PhCI, 132 ꢀC, 3 d, argon
d
200 ꢀC, 1 min, argon
d
200 ꢀC, 2 min, argon
6b (1)
d
200 ꢀC, 5 min, argon
90
55
NaH (2 equiv), THF, 66 ꢀC, 2 h
NaH (1.1 equiv), THF, 66 ꢀC, 2 h
NaH (2 equiv), THF, 66 ꢀC, 2 h
i-Pr2NEt (1.1 equiv), DCM, 20 ꢀC, 12 h
i-Pr2NEt (1.1 equiv), DCM, 20 ꢀC, 7 d
i-Pr2NEt (1.1 equiv), DCM, 20 ꢀC, 4 d
6a (65)
6b (42)
d
Traces
88
Traces
Traces
85
9
10
11
12
4a (1)
4b (Trace)
4c (73)
6a (93)
6b (63)
d
CH
were much less reactive to the weaker aromatic bases pyridine and
2,6-lutidine. In these cases, the use of only 1.1 equiv of base led to
recovered unreacted dithiazoles, although the reaction could be
brought to completion by using a large excess of base (4 equiv).
These results demonstrated that during the thermolysis, not
only oxazoles but also traces of the fused oxazines formed and that
the presence and position of an additional pyridyl nitrogen affected
the outcome of both the thermal ring contraction and the base
mediated intramolecular cyclisations. More specifically, the ther-
molysis of the pyridin-3-ol 5c took longer than the ‘parent’ phenol
5a while that of the pyridin-2-ol 5b was considerably faster. Fur-
thermore, while base treatment of both the ‘parent’ phenol 5a and
the pyridin-2-ol 5b gave the corresponding fused oxazines 6a and
6b, respectively, treatment of the pyridine-3-ol 5c gave only the
oxazole 4c.
Similar 5,5-disubstituted 1,2,3-dithiazoles to the proposed spi-
rocyclic intermediate 15 are known, such as the 5,5-difluoro-1,2,3-
dithiazole 16a,1 the dithiazole ketals 16b33 and the spirocyclic
lactams 17.32b
2.2. Mechanistic rationale
Rees also claimed that the oxazine 6a was not a precursor to the
benzoxazole 4a since a pure sample was thermally stable at
200 ꢀC.17a Nevertheless, ring contractions of 2H-benzo[b][1,4]oxa-
zin-2-ones 18a (X¼O)34 and 2H-benzo[b][1,4]oxazin-2-imines 18b
(X¼NH)35 into benzoxazoles 19a and 19b are known, and typically
initiated by either thermolysis,34i,j photolysis34a,g or by nucleo-
philes such as hydroxide,34bed,35 alcohols,34f alkylamines34e,f,k and
hydrazines34h,k (Scheme 7).
A rational mechanism for the formation of both the oxazoles 4
and the oxazines 6 must take into account that the dithiazole C5
position is more electrophilic than the C4 position. Rees17a postu-
lated that on base catalysed deprotonation the ortho hydroxyl
group cyclises onto the electrophilic C5 position to give a spirocyclic
intermediate 15 that can fragment via path A to form the oxazine or
via path B to form the oxazole (Scheme 6).
Scheme 6. Proposed mechanism for the formation of both the oxazoles and the oxazines from dithiazolimine 5a.
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A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
5
When solutions of the benzoxazine 6a or the pyridoxazine 6b in
PhCl were heated at reflux (ca. 132 ꢀC) in the presence of pyridine
(1 equiv) both oxazines were stable but in the presence of Et3N
(1 equiv) they were converted into the benzoxazole 4a (45%) and
oxazolopyridine 4b (40%), respectively, together with some ele-
mental sulfur (Table 3, entries 3 and 4). Similar products and yields
were also obtained when the trialkylamine was replaced by non-
basic but thiophilic BnEt3NCl (1 equiv), and interestingly, in these
cases (Table 3, entries 5 and 6), the reactions were notably faster
(5e12 h vs 24 h) than those involving Et3N. Moreover, in the
presence of phenol or 3-hydroxypyridine (1 equiv), which are weak
acids no reactions took place, however, when TsOH$H2O (1 equiv)
was added in either PhCl at ca. 132 ꢀC or in PhMe at ca. 110 ꢀC the
pyridoxazine 6b was converted to the oxazolopyridine 4b (Table 3,
entries 8 and 9) while the benzoxazine 6a was stable (Table 3, entry
7). Interestingly, only catalytic amounts of TsOH$H2O (5 mol %)
were needed to trigger the ring contraction of the pyridoxazine 6b
(Table 3, entry 10).
We also considered the stability of the oxazines 6a and 6b
under the conditions of the ring contraction of dithiazoles 5a and
5b in hot PhCl. As such, equimolar quantities of dithiazoles 5a
and 5b were mixed with oxazines 6a and 6b, respectively, and
heated in PhCl at 132 ꢀC until complete consumption of the imine
(TLC, 3 and 5 h, respectively). At this temperature, the pure
oxazines 6a and 6b were shown previously to be stable, however,
the reaction of dithiazole 5a gave elemental sulfur, the benzox-
azole 4a (120% based on consumed 5a) and recovered oxazine 6a
(42%), while the reaction of dithiazole 5b gave elemental sulfur,
the oxazole 4b (62% based on consumed 5b) and recovered
oxazine 6b (76%). The data indicated that the oxazines 6a and 6b,
were thermally unstable under the reaction conditions, and in
the case of the dithiazole 5a a total benzoxazole yield of 120%
supported that the oxazine 6a had contributed to formation of
the benzoxazole 4a. As such, we can conclude that while pure
samples of oxazines 6 are indeed thermally stable as reported by
Rees, in the presence of either acid or chloride and possibly other
halophiles, they are labile and can therefore also be sources of the
oxazoles isolated during the direct thermolysis of the dithiazoles
5aec.
Formally the transformation of the oxazine 6 to the oxazole 4
required the loss of diatomic sulfur (S2) and tentatively this can
occur via a stepwise mechanism that involves ring opening-ring
closing steps (mechanism A) (Scheme 8). The oxazine nitrogen
lone pair could release electron density into the dithiazole ring
leading to fragmentation via loss of S2 and formation of a highly
electrophilic nitrilium carbonitrile intermediate 20. This could
subsequently trap the phenoxide (where X¼CH) or the pyridoxide
(where X¼N) to give the observed oxazoles 4a and 4b, re-
spectively. The addition of acid could assist the ring trans-
formation by protonating the pyridyl nitrogen and thus facilitating
cleavage of the CeO bond. When Et3N or BnEt3NCl was added an
alternative mechanism (mechanism B) can be invoked that in-
volves thiophilic attack on the dithiazole ring sulfur to give in-
termediate 21, which subsequently eliminates sulfur and cyclises
to the observed oxazoles. Similar thiophilic reactions between
amines29 or tetraalkylammonium halides36 and neutral dithia-
zoles leading to ANRORC-style37 ring transformations have been
reported.
Scheme 7. Ring contractions of benzoxazinones 18a and benzoxazin-2-imines 18b to
benzoxazoles 19a and 19b.
The thermolysis of the dithiazoles 5 to give the oxazoles 4 leads
to the formation of thiophilic by-products such as HCl and ‘active’
sulfur, which could affect the stability of any oxazine 6 that may
form. As such, we reinvestigated the thermal stability of the oxa-
zines 6a and 6b.
Heating benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine (6a) or
[1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine (6b) in either
isoquinoline at 150 ꢀC or in PhCl at ca. 132 ꢀC for 24 h, led to no
decomposition indicating that under these conditions both
compounds were thermally stable. DSC studies, however,
showed that the benzoxazine 6a had an exothermic de-
composition peak at 276.1 ꢀC (onset peak at 274.6 ꢀC), while the
pyridoxazine 6b had endothermic decomposition peaks at
224.0 ꢀC (onset: 222.4 ꢀC) and 265.2 ꢀC (onset: 263.8 ꢀC), sig-
nificantly past their melting points. In light of this data, neat
samples of the oxazines 6a and 6b were thermolysed at ca. 275
and 230 ꢀC, respectively, to afford the benzoxazole 4a and the
oxazolopyridine 4b in 27 and 65% yields, respectively. These
reaction conditions were more aggressive than those required to
directly convert the 2-hydroxy(dithiazolylideneamino)arenes 5a
and 5b into the corresponding oxazoles. Nevertheless, since
trace amounts of acid, base or other nucleophiles are often
formed as by-products in these thermolyses, we reinvestigated
the oxazine to oxazole ring contractions in the presence of basic
(pyridine, Et3N), thiophilic (BnEt3NCl) and acidic (phenol,
TsOH$H2O) additives to examine if the reaction temperatures
could be lowered (Table 3).
Table 3
Ring contractions of [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine (6a) and
[1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine (6b)
Entry
Solvent
Additive (equiv)
Temp
(ꢀC)
Time
(h)
X
S8
(%)
4 (%)
1
2
3
4
5
6
7
8
9
Neat
Neat
PhCI
PhCI
PhCI
PhCI
PhCI
PhCI
PhMe
PhCI
d
275
230
132
132
132
132
132
132
110
132
7 min
10 min
24
24
12
5
24
2
3
CH 55
97
CH 85
80
CH 71
38
CH nra
4a (27)
4b (65)
4a (45)
4b (40)
4a (35)
4b (42)
nra
4b (49)
4b (47)
4b (50)
d
N
Et3N (1)
Et3N (1)
N
BnEt3NCI (1)
BnEt3NCI (1)
TsOH$H2O (1)
TsOH$H2O (1)
TsOH$H2O (1)
TsOH$H2O (0.05)
A tentative explanation for the failure to isolate the isomeric
pyridoxazine 6c in the reactions of 2-(4-chloro-5H-1,2,3-dithiazol-
5-ylideneamino)pyridin-3-ol (5c) can be that this compound,
which has two amidine like nitrogen atoms, must be more basic
and prone to protonation, and as such, if the oxazine had formed it
may have rearranged rapidly in the presence of traces of Hþ to the
N
N
N
N
83
41
86
10
20
a
nr¼No reaction.
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6
A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
Scheme 8. Possible mechanisms: the transformation of oxazine to oxazole.
oxazolo[4,5-b]pyridine (4c). This and other aspects of this chem-
istry are now under further study.
for recrystallisation are indicated after the melting point. UV
spectra were obtained using a PerkineElmer Lambda-25 UV/vis
spectrophotometer and inflections are identified by the abbre-
viation ‘inf’. IR spectra were recorded on a Shimadzu FTIR-NIR
Prestige-21 spectrometer with Pike Miracle Ge ATR accessory
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 500 machine (at 500 and 125 MHz, respectively).
Deuterated solvents were used for homonuclear lock and the
signals are referenced to the deuterated solvent peaks. CH as-
signments are made based on DEPT 135 spectroscopy. Low-res-
olution (EI) mass spectra were recorded on a Shimadzu Q2010
GCMS with direct inlet probe. MALDI TOF mass spectra were
recorded on a Bruker Autoflex III Smartbeam instrument, while
ESI-APCIþ mass spectra were recorded on a Model 6110 Quad-
rupole MSD, Agilent Technologies. 2-(4-Chloro-5H-1,2,3-
dithiazol-5-ylideneamino)phenol (5a)2 and 3-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol (5b)3 were prepared
according to literature procedures.
3. Conclusions
Thermolysis of the dithiazolylidenes 5a, 5b and 5c in hot PhCl
(132 ꢀC) or under solvent free conditions at ca. 200 ꢀC afforded
benzo[d]oxazole-2-carbonitrile (4a), oxazolo[5,4-b]pyridine-2-
carbonitrile (4b) and oxazolo[4,5-b]pyridine-2-carbonitrile (4c)
in high yields, respectively. Treatment of the dithiazolylidenes 5a,
5b and 5c with either NaH in dry THF at 66 ꢀC or with i-Pr2NEt in
DCM at 20 ꢀC afforded benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine
(6a), [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine 6b and oxa-
zolo[4,5-b]pyridine (4c), respectively, with the latter milder con-
ditions providing the higher yields. The benzoxazine 6a and the
pyridoxazine 6b can be thermolysed either neat or in PhCl solu-
tions in the presence of either Et3N (1 equiv) or BnEt3NCl (1 equiv)
to give the corresponding oxazoles in moderate yields. In the
presence of TsOH$H2O though, a solution of benzoxazine 6a in
PhCl heated to reflux was stable, while a solution of the pyr-
idoxazine 6b rapidly converted into the corresponding oxazole.
Tentative mechanistic pathways for these transformations have
been proposed.
4.2. Synthesis of 2-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)pyridin-3-ol (5c)
To a stirred solution of 4,5-dichloro-1,2,3-dithiazolium chlo-
ride 2 (956 mg, 4.59 mmol) in DCM (10 mL) at ca. 20 ꢀC and
protected with a CaCl2 drying tube was added 2-aminopyridin-3-
ol (12c). After 1 h, to the reaction mixture was added, dropwise,
4. Experimental
4.1. General procedures
pyridine (743 m
L, 9.18 mmol) and left to stir at ca. 20 ꢀC for an
All chemicals were commercially available except those whose
synthesis is described. DMF was dried by azeotropically removing
water with benzene and then distilling under vacuum over dried
additional 2 h. The reaction mixture was adsorbed onto silica and
chromatography (n-hexane) gave S8 (traces). Further elution (n-
hexane/DCM, 4:1) gave 4-chloro-5H-1,2,3-dithiazole-5-thione
(10 mg, 6%) and further elution (n-hexane/DCM, 3:7) gave the
title compound 5c as orange cotton fibres (6.5 mg, 11%), mp
142e143 ꢀC (from c-hexane/EtOH); Rf 0.84 (n-hexane/DCM, 3:7).
Found C, 34.35; H, 1.56; N, 16.95. C7H4ClN3OS2 requires C, 34.22;
ꢀ
4 A molecular sieves and then kept under an argon atmosphere in
a desiccator. Anhydrous Na2SO4 was used for drying organic ex-
tracts 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).38 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). Melting points were determined using a TA In-
struments DSC Q1000 with samples hermetically sealed in alu-
minium pans under an argon atmosphere; using heating rates of
5 ꢀC/min (DSC mp listed by onset and peak values). Solvents used
H, 1.64; N, 17.10%; lmax (DCM)/nm 247 (log
3
2.74), 265 inf (2.40),
304 (2.47), 387 inf (2.66), 407 (2.90), 428 (2.96), 454 (2.71); vmax
/
cmꢁ1 3466w and 3366w (OH), 1599w, 1572m, 1516s, 1491s,
1462m, 1433s, 1403w, 1337m, 1287m, 1271m, 1231s, 1186s, 1153s,
1105m, 1053m, 964w, 908m, 878s, 826m, 795s, 779s, 764s; dH
(500 MHz; DMSO-d6) 10.33 (1H, s, OH), 8.15 (1H, dd, J 5.0, 1.0, Py
H-4), 7.44 (1H, dd, J 8.0, 1.0, Py H-5), 7.33 (1H, dd, J 8.0, 5.0, Py H-
6); dC (75 MHz; DMSO-d6) 156.1 (s), 149.3 (s), 148.3 (s), 143.4 (s),
133.7 (d), 123.7 (d), 123.6 (d); m/z (EI) 247 (Mþþ2, 14%), 245 (Mþ,
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A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
7
34), 210 (14), 178 (4), 146 (100), 120 (9), 102 (8), 94 (41), 70 (12),
64 (38), 53 (10). Found Mþ, 244.9489. C7H4ClN3OS2 requires M,
244.9484. Further elution (DCM) gave (E)-6-(4-chloro-5H-1,2,3-
dithiazol-5-ylidene)-2-[(Z)-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)
amino]pyridin-3(6H)-one (13) as a blue dust (2.7 mg, 3%), mp
288e289 ꢀC (from DCE); Rf 0.41 (DCM). Found C, 28.51; H, 0.50;
N, 15.02. C9H2Cl2N4OS4 requires C, 28.35; H, 0.53; N, 14.69%; lmax
2.63), 327 (2.57), 418 (2.68); nmax/cmꢁ1 2257w (C^N), 1609m,
1599m, 1524m, 1476w, 1400s, 1362w, 1333s, 1279m, 1231s, 1167w,
1153m, 1117w, 1032w, 1005w, 993w, 953m, 901m, 845w, 829s,
816s, 806s, 773s; dH (300 MHz; CDCl3) 8.63 (1H, dd, J 1.5, 4.8, Py H-4
or 6), 8.26 (1H, dd, J 1.65, 7.95, Py H-6 or 4), 7.56 (1H, dd, J 4.8, 8.1, Py
H-5); dC (75 MHz; CDCl3) 158.3 (s), 149.3 (d), 137.5 (s),131.2 (s), 131.1
(d), 122.9 (d), 108.6 (s); m/z (EI) 145 (Mþ, 100%), 117 (82), 65 (35), 64
(20), 54 (8), 51 (4).
(DCM)/nm 260 (log
3
2.34), 268 (2.32), 331 (1.81), 418 (1.74), 615
(2.09); nmax/cmꢁ1 2922w, 2847w, 1570w, 1503m, 1485m, 1447m,
1424m, 1367w, 1360w, 1325s, 1288m, 1240s, 1209m, 1105w,
1047m, 941w, 914w, 883m, 851w, 824m, 808w, 789m, 779m; dH
(500 MHz; TFA-d1) 9.23 (1H, J 6.0, Py H), 8.08 (1H, J 5.5, Py H); dC
(125 MHz; TFA-d1) 164.4 (s), 162.9 (s), 155.5 (s), 146.3 (s), 141.0 (s),
129.6 (d), 129.3 (s), 119.9 (d); m/z (EI) 384 (Mþþ4, 7%), 382
(Mþþ2, 22), 380 (Mþ, 25), 347 (13), 345 (MþꢁCl, 25), 310 (4), 283
(39), 281 (100), 253 (5), 231 (14), 229 (33), 220 (4), 214 (4), 192
(3), 166 (10), 160 (7), 142 (8), 140 (14), 137 (7), 134 (11), 102 (14),
99 (11), 96 (16), 85 (11), 82 (17), 76 (18), 70 (21), 64 (80), 57 (14).
Further elution (DCM/t-BuOMe, 9:1) gave (E)-2-amino-6-(4-
chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3(6H)-one (14) as lus-
trous bronze coloured prisms (2.4 mg, 4%), mp (DSC) onset:
156.6 ꢀC peak max: 168.5 ꢀC (decomp.) (from DCE); Rf 0.53 (DCM/
t-BuOMe, 9:1). Found: C, 34.37; H, 1.72; N, 16.97. C7H4ClN3OS2
4.3.3. Thermolysis of 2-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)pyridin-3-ol (5c). Similar treatment of 2-(4-chloro-
5H-1,2,3-dithiazol-5-ylideneamino)pyridin-3-ol (5c) (49.2 mg,
0.20 mmol) gave S8 (12.2 mg, 95%) and oxazolo[4,5-b]pyridine-2-
carbonitrile (4c) (20.9 mg, 72%) as colourless needles, mp
49e50 ꢀC (from c-hexane); Rf 0.20 (n-hexane/DCM, 4:6). Found C,
57.86; H, 2.10; N, 28.88. C7H3N3O requires C, 57.94; H, 2.08; N,
28.96%; lmax (DCM)/nm 245 (log 2.63), 292 (3.09), 304 inf (2.89);
3
nmax/cmꢁ1 3043w, 2259w (C^N), 1715w, 1700w, 1684w, 1653w,
1611m, 1537m, 1506w, 1403s, 1321m, 1293w, 1260m, 1251w,
1223m, 1212w, 1171m, 1111w, 1030m, 954m, 844m, 828m, 795s,
780s; dH (300 MHz; CDCl3) 8.80 (1H, d, J 4.45, Py H-4 or 6), 8.04 (1h,
dd, J 1.4, 8.4, Py H-6 or 4), 7.59 (1H, dd, J 4.7, 8.4, Py H-5); dC
(75 MHz; CDCl3) 152.4 (s), 149.6 (d), 143.2 (s), 139.6 (s), 123.8 (d),
120.0 (d), 108.5 (s); m/z (EI) 145 (Mþ, 98%), 94 (6), 93 (100), 65 (49),
64 (23).
requires C, 34.22; H, 1.64; N, 17.10%; lmax (DCM)/nm 281 (log
3.73), 298 inf (3.66), 422 inf (3.21), 549 (4.19); nmax/cmꢁ1 3486w
and 3300m (NH2), 3215w, 1612w, 1554m, 1541s, 1511s, 1449m,
1428s, 1407s, 1365s, 1333w, 1318m, 1235s, 1206m, 1139m, 1079m,
960w, 875m, 831m, 812s, 753w; dH (500 MHz; DMSO-d6) 8.51
(1H, J 9.5, Py H), 7.49 (1H, br s, NH2), 7.06 (1H, br s, NH2), 6.34 (1H,
J 9.0, Py H); dC (125 MHz; DMSO-d6) 173.9 (s), 154.2 (s), 147.4 (s),
141.4 (s), 135.6 (s), 127.9 (d), 121.0 (d); m/z (EI) 247 (Mþþ2, 28%),
245 (Mþ, 64), 217 (4), 210 (14), 182 (13), 178 (28), 175 (35), 156 (8),
150 (5), 140 (14), 124 (9), 110 (16), 104 (35), 96 (31), 93 (31), 82
(80), 76 (84), 70 (60), 64 (100), 53 (37).
3
4.4. Solvent-free thermolysis of 2-hydroxy-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)arenes
4.4.1. Thermolysis of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
phenol (5a) (typical procedure: see Table 1). Neat 2-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)phenol
(5a)
(48.8
mg,
0.20 mmol) was heated at ca. 200 ꢀC for 1 min in argon atmo-
sphere. On cooling to ca. 20 ꢀC the reaction mixture was adsor-
bed onto silica and chromatography (n-hexane) gave S8 (4.7 mg,
60%). Further elution (n-hexane/DCM, 6:4) gave benzo[d]oxazole-
2-carbonitrile (4a) (24.7 mg, 85%) as colourless needles, mp
99e100 ꢀC (lit.39 102e104 ꢀC) (from c-hexane), identical to that
described above.
4.3. Thermolysis of 2-hydroxy-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)arenes in PhCl at reflux
4.3.1. Thermolysis of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
phenol (5a) (typical procedure: see Table 1). A stirred solution of 2-
4.4.2. Thermolysis of 3-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)pyridin-2-ol (5b). Similar treatment of 3-(4-chloro-
5H-1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol (5b) (49.2 mg,
0.20 mmol) at ca. 200 ꢀC for 2 min gave S8 (11.5 mg, 90%). Further
elution (n-hexane/DCM, 4:6) gave oxazolo[5,4-b]pyridine-2-
carbonitrile (4b) (19.1 mg, 66%) as colourless needles, mp
105e106 ꢀC (from c-hexane), identical to that described above.
Further elution (DCM) gave [1,2,3]dithiazolo[5,4-e]pyrido[3,2-b][1,4]
oxazine 6b (0.4 mg, 1%) as orange fibres, mp 217e218 ꢀC (from c-
hexane/EtOH); Rf 0.32 (DCM). Found C, 40.26; H, 1.40; N, 20.09.
C7H3N3OS2 requires C, 40.18; H,1.45; N, 20.08%; lmax (DCM)/nm 272
(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)phenol
(5a)
(48.8 mg, 0.20 mmol) in PhCl (2 mL) was heated at ca. 132 ꢀC,
until no starting materials remained (TLC, 15 h). On cooling to ca.
20 ꢀC the reaction mixture was adsorbed onto silica and chro-
matography (n-hexane) gave S8 (12.5 mg, 98%). Further elution
(n-hexane/DCM, 6:4) gave benzo[d]oxazole-2-carbonitrile (4a)
(23.9 mg, 83%) as colourless needles, mp 99e100 ꢀC (lit.39
102e104 ꢀC) (from c-hexane); Rf 0.57 (n-hexane/DCM, 6:4);
lmax (DCM)/nm 273 inf (log
3
3.19); nmax/cmꢁ1 2251m (C^N),
1794w, 1611m, 1603m, 1530m, 1476m, 1445s, 1429w, 1371w,
1341s, 1287w, 1275w, 1258m, 1233w, 1219w, 1171s, 1163w, 1136w,
1105m, 993m, 953s, 895m, 953s, 895m, 854w, 837w, 818s, 760s;
dH (300 MHz; CDCl3) 7.90e7.86 (1H, m, Ph H), 7.67e7.49 (3H, m,
Ph H); dC (75 MHz; CDCl3) 150.3 (s), 139.4 (s), 137.2 (s), 129.1 (d),
126.5 (d), 121.9 (d), 111.5 (d), 109.1 (s); m/z (EI) 144 (Mþ, 100%),
116 (8), 92 (120), 64 (35).
inf (log 2.45), 308 (2.35), 383 inf (3.02), 411 (3.17), 434 inf (3.04);
3
nmax/cmꢁ1 3044w, 3007w, 1582m, 1562s, 1501s, 1423s, 1287m,
1269w, 1234s, 1192m, 1123m, 1076m, 1045m, 982w, 932m, 856w,
806s, 756s, 727m; dH (300 MHz; DMSO-d6) 7.92 (1H, d, J 4.1, Py H),
7.52 (1H, d, J 7.3, Py H), 7.14 (1H, dd, J 5.0, 7.0, Py H); dC (75 MHz;
DMSO-d6) 166.2 (s), 152.4 (s), 150.5 (s), 144.3 (d), 133.4 (d), 127.8 (s),
122.4 (d); m/z (EI) 209 (Mþ, 100%), 135 (54), 108 (17), 103 (10), 76
(13), 70 (16), 64 (24). Found Mþ, 208.9718. C7H3N3OS2 requires M,
208.9718.
4.3.2. Thermolysis of 3-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)pyridin-2-ol (5b). Similar treatment of 3-(4-chloro-
5H-1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol (5b) (49.2 mg,
0.20 mmol) gave S8 (12.8 mg, 100%). Further elution (n-hexane/
DCM, 4:6) gave oxazolo[5,4-b]pyridine-2-carbonitrile (4b) (27.8 mg,
96%) as colourless needles, mp 105e106 ꢀC (from c-hexane); Rf 0.67
(n-hexane/DCM, 4:6). Found C, 57.86; H, 2.10; N, 28.88. C7H3N3O
4.4.3. Thermolysis of 2-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)pyridin-3-ol (5c). Similar treatment of 2-(4-chloro-
5H-1,2,3-dithiazol-5-ylideneamino)pyridin-3-ol (5c) (49.2 mg,
0.20 mmol) at ca. 200 ꢀC for 5 min gave S8 (11.5 mg, 90%) and
requires C, 57.94; H, 2.08; N, 28.96%; lmax (DCM)/nm 247 inf (log
3
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8
A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
oxazolo[4,5-b]pyridine-2-carbonitrile (4c) (24.4 mg, 84%) as colour-
less needles, mp 49e50 ꢀC (from c-hexane), identical to that de-
scribed above.
(38.7 mg, 93%) as orange fibres, mp 183e184 ꢀC (from c-hexane/
EtOH), identical that described above.
4.6.2. Reaction of 3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
pyridin-2-ol (5b) with base. Similar treatment of 3-(4-chloro-5H-
1,2,3-dithiazol-5-ylidene-amino)pyridin-2-ol (5b) (49.2 mg,
4.5. Reaction of 2-hydroxy-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)arenes with NaH
0.20 mmol) with i-Pr2NEt (37.7 mL, 0.22 mmol) gave oxazolo[5,4-b]
pyridine-2-carbonitrile (4b) (traces) as colourless needles, mp
105e106 ꢀC (from c-hexane), identical to that described above.
Further elution (DCM) gave [1,2,3]dithiazolo[5,4-e]pyrido[3,2-b]
[1,4]oxazine (6b) (26.3 mg, 63%) as orange fibres, mp 217e218 ꢀC
(from c-hexane/EtOH), identical to that described above.
4.5.1. Reaction of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
phenol (5a) with NaH (typical procedure: see Table 1). To a stirred
solution of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)phe-
nol (5a) (48.8 mg, 0.20 mmol) in dry THF (2 mL) at ca. 20 ꢀC and
protected with a CaCl2 drying tube was added NaH (9.6 mg,
0.40 mmol) and the mixture was then heated at ca. 66 ꢀC until no
more starting material remained (TLC, 2 h). The reaction mixture
was adsorbed onto silica and chromatography (n-hexane) gave S8
(7.0 mg, 55%). Further elution (n-hexane/DCM, 6:4) gave benzo[d]
oxazole-2-carbonitrile (4a) (traces) as colourless needles, mp
99e100 ꢀC (from c-hexane), identical to that described above.
Further elution (n-hexane/DCM, 3:7) gave benzo[b][1,2,3]dithia-
zolo[5,4-e][1,4]oxazine (6a) (27.0 mg, 65%) as orange fibres, mp
183e184 ꢀC (from c-hexane/EtOH). Found C, 46.24; H, 2.03; N,
13.38. C8H4N2OS2 requires C, 46.14; H, 1.94; N, 13.45%; Rf 0.67 (n-
4.6.3. Reaction of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
pyridin-3-ol (5c) with base. Similar treatment of 2-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)pyridin-3-ol
(5c)
(49.2
mg,
0.20 mmol) with i-Pr2NEt (37.7 L, 0.22 mmol) gave oxazolo[4,5-b]
m
pyridine-2-carbonitrile (4c) (21.2 mg, 73%) as colourless needles, mp
49e50 ꢀC (from c-hexane), identical to the that described above.
4.7. Thermolysis reaction of fused [1,2,3]dithiazolo[5,4-e][1,4]
oxazines
hexane/DCM, 3:7); lmax (DCM)/nm 272 inf (log 2.45), 308 (2.35),
3
4.7.1. Thermolysis reaction of benzo[b][1,2,3]dithiazolo[5,4-e][1,4]
oxazine (6a) (typical procedure: see Table 3). Neat benzo[b][1,2,3]
dithiazolo[5,4-e][1,4]oxazine 6a (41.6 mg, 0.20 mmol) in argon at-
mosphere was heated at ca. 275 ꢀC for 7 min. On cooling to ca. 20 ꢀC
the reaction mixture was adsorbed onto silica and chromatography
(n-hexane) gave S8 (7.0 mg, 55%). Further elution (n-hexane/DCM,
6:4) gave the benzo[d]oxazole-2-carbonitrile 4a (7.8 mg, 27%) as
colourless needles, mp 99e100 ꢀC (from c-hexane) identical to an
authentic sample.
383 inf (3.02), 411 (3.17), 434 inf (3.04); nmax/cmꢁ1 1584w, 1570w,
1560s, 1499w, 1491m, 1476m, 1458m, 1437w, 1371w, 1302m,
1285w, 1273w, 1236m, 1207m, 1190w, 1113m, 1049s, 974w, 939m,
926s, 856w, 841w; dH (300 MHz; DMSO-d6) 7.12e7.10 (3H, m, Ph
H), 7.01e6.99 (1H, m, Ph H); dC (75 MHz; DMSO-d6) 165.1 (s), 150.5
(s), 143.9 (s), 131.9 (s), 127.6 (d), 125.5 (d), 125.3 (d), 115.15 (d); m/z
(EI) 208 (Mþ, 100%), 144 (17), 122 (12), 104 (91), 90 (22), 78 (10), 76
(13), 70 (21), 64 (78), 51 (29).
4.5.2. Reaction of 3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
pyridin-2-ol (5b) with NaH. Similar treatment of 3-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol (5b) (49.2 mg,
0.20 mmol) with NaH (5.3 mg, 0.22 mmol) gave oxazolo[5,4-b]
pyridine-2-carbonitrile (4b) (traces) as colourless needles, mp
105e106 ꢀC (from c-hexane), identical to that described above.
Further elution (DCM) gave [1,2,3]dithiazolo[5,4-e]pyrido[3,2-b][1,4]
oxazine 6b (17.6 mg, 42%) as orange fibres, mp 217e218 ꢀC (from c-
hexane/EtOH), identical to that described above.
4.7.2. Thermolysis of [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]ox-
azine (6b). Similar treatment of [1,2,3]dithiazolo[5,4-e]pyrido[2,3-
b][1,4]oxazine (6b) (42.0 mg, 0.20 mmol) at ca. 230 ꢀC for 10 min
gave S8 (12.4 mg, 97%) and oxazolo[5,4-b]pyridine-2-carbonitrile
(4b) (19.0 mg, 65%) as colourless needles, mp 105e106 ꢀC (from
c-hexane) identical to that described previously.
4.8. Reaction of fused [1,2,3]dithiazolo[5,4-e][1,4]oxazines
with base
4.5.3. Reaction of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
pyridin-3-ol (5c) with NaH. Similar treatment of 2-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)pyridin-3-ol (5c) (49.2 mg,
0.20 mmol) with NaH (9.6 mg, 0.40 mmol) gave oxazolo[4,5-b]
pyridine-2-carbonitrile (4c) (25.5 mg, 88%) as colourless
needles, mp 49e50 ꢀC (from c-hexane), identical to that described
above.
4.8.1. Reaction of benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine (6a)
with base (typical procedure: see Table 3). To a stirred solution of
benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine
0.20 mmol) in PhCl (2 mL) at ca. 20 ꢀC and protected with a CaCl2
drying tube, was added Et3N (27.9 L, 0.20 mmol). The mixture was
(6a)
(41.6
mg,
m
then heated at ca. 132 ꢀC, until no starting materials remained (TLC,
24 h). Chromatography (n-hexane) gave S8 (10.9 mg, 85%) and
further elution gave benzo[d]oxazole-2-carbonitrile (4a) (13.0 mg,
45%) as colourless needles, mp 99e100 ꢀC (from c-hexane), iden-
tical to an authentic sample.
4.6. Reaction of 2-hydroxy-(4-chloro-5H-1,2,3-dithiazol-5-
ylideneamino)arenes with base
4.6.1. Reaction of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)
phenol (5a) with base (typical procedure: see Table 1). To a stirred
solution of 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)phenol
(5a) (48.8 mg, 0.20 mmol) in DCM (2 mL) at ca. 20 ꢀC and protected
4.8.2. Reaction of [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine
(6b) with base. Similar treatment of [1,2,3]dithiazolo[5,4-e]pyrido
[2,3-b][1,4]oxazine (6b) (42.0 mg, 0.20 mmol) with Et3N (27.9 mL,
0.20 mmol) gave S8 (10.2 mg, 80%) and further elution gave oxazolo
[5,4-b]pyridine-2-carbonitrile (4b) (11.6 mg, 40%) as colourless
needles, mp 105e106 ꢀC (from c-hexane) identical to that described
above.
with a CaCl2 drying tube, was added i-Pr2NEt (37.7 mL, 0.22 mmol)
and the mixture was left to stir until no more starting material
remained (TLC, 12 h). The reaction mixture was adsorbed onto silica
and chromatography (n-hexane) gave S8 (traces). Further elution
(n-hexane/DCM, 6:4) gave benzo[d]oxazole-2-carbonitrile (4a)
(0.3 mg, 1%) as colourless needles, mp 99e100 ꢀC (from c-hexane),
identical that described above. Further elution (n-hexane/DCM,
4.9. Reactions of oxazines 6a and 6b with BnEt3NCl
4.9.1. Reaction of benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine (6a)
with BnEt3NCl (typical procedure: see Table 3). To a stirred solution
3:7)
gave
benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine
(6a)
Please cite this article in press as: Kalogirou, A. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.12.046

A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
9
of benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine (6a) (41.6 mg,
0.20 mmol) in PhCl (2 mL) at ca. 20 ꢀC and protected with a CaCl2
drying tube was added BnEt3NCl (45.6 mg, 0.20 mmol). The mixture
was then heated at ca. 132 ꢀC, until no starting materials remained
(TLC, 12 h). Chromatography (n-hexane) gave S8 (9.1 mg, 71%) and
further elution (n-hexane/DCM, 6:4) gave benzo[d]oxazole-2-
carbonitrile (4a) (10.1 mg, 35%) as colourless needles, mp
99e100 ꢀC (from c-hexane), identical to an authentic sample.
Ltd, and Biotronics Ltd. Furthermore, we thank the A.G. Leventis
Foundation for helping to establish the NMR facility at the Uni-
versity of Cyprus.
References and notes
1. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985, 118, 1632e1643.
2. English, R. F.; Rakitin, O. A.; Rees, C. W.; Vlasova, O. G. J. Chem. Soc., Perkin Trans.
1 1997, 201e206.
3. Koutentis, P. A.; Koyioni, M.; Michaelidou, S. S. Molecules 2011, 16, 8992e9002.
4. Kalogirou, A. S.; Koutentis, P. A. Molecules 2009, 14, 2356e2362.
5. Le, V.-D.; Rees, C. W.; Sivadasan, S. J. Chem. Soc., Perkin Trans. 1 2002, 1543e1547.
6. (a) Moore, J. E. U.S. Patent 4,059,590, 1977; (b) Appel, R.; Janssen, H.; Haller, I.;
Plempel, M. DE Pat. 2848221, 1980; (c) Besson, T.; Rees, C. W.; Cottenceau, G.;
Pons, A. M. Bioorg. Med. Chem. Lett. 1996, 6, 2343e2348; (d) Benting, J.; Dahmen,
P.; Hadano, H.; Vors, J. -P.; Wachendorff-Neumann, U. WO Pat. 045726, 2012.
7. Mayer, R.; Foerster, E.; Matauschek, B. DD Pat. 212387, 1984.
4.9.2. Reaction of [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]oxazine
(6b) with BnEt3NCl. Similar treatment of [1,2,3]dithiazolo[5,4-e]
pyrido[2,3-b][1,4]oxazine (6b) (42.0 mg, 0.20 mmol) with BnEt3NCl
(45.6 mg, 0.20 mmol) gave S8 (4.9 mg, 38%) and oxazolo[5,4-b]
pyridine-2-carbonitrile (4b) (12.2 mg, 42%) as colourless needles,
mp 105e106 ꢀC (from c-hexane), identical to that described above.
8. Konstantinova, L. S.; Bol’shakov, O. I.; Obruchnikova, N. V.; Laborie, H.; Tanga,
ꢁ
ꢁ
ꢁ
A.; Sopena, V.; Lanneluc, I.; Picot, L.; Sable, S.; Thiery, V.; Rakitin, O. A. Bioorg.
4.10. Reaction of [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]ox-
azine (6b) with TsOH$H2O
Med. Chem. Lett. 2009, 19, 136e141.
9. (a) Cottenceau, G.; Besson, T.; Gautier, V.; Rees, C. W.; Pons, A. M. Bioorg. Med.
Chem. Lett. 1996, 6, 529e532; (b) Thiery, V.; Rees, C. W.; Besson, T.; Cottenceau,
G.; Pons, A. M. Eur. J. Med. Chem. 1998, 33, 149e153; (c) Joseph, R. W.; Antes, D.
L.; Osei-Gyimah, P. US Patent 5,688,744, 1997.
10. Oppedisano, F.; Catto, M.; Koutentis, P. A.; Nicolotti, O.; Pochini, L.; Koyioni, M.;
Introcaso, A.; Michaelidou, S. S.; Carotti, A.; Indiveri, C. Toxicol. Appl. Pharmacol.
2012, 265, 93e102.
11. (a) Barclay, T. M.; Beer, L.; Cordes, A. W.; Oakley, R. T.; Preuss, K. E.; Taylor, N. J.;
Reed, R. W. Chem. Commun. 1999, 531e532; (b) Beer, L.; Cordes, A. W.; Haddon,
R. C.; Itkis, M. E.; Oakley, R. T.; Reed, R. W.; Robertson, C. M. Chem. Commun.
2002, 1872e1873; (c) Constantinides, C. P.; Ioannou, T. A.; Koutentis, P. A.
Polyhedron 2013, 64, 172e180; (d) Makarov, A. Y.; Chulanova, E. A.; Semenov, N.
A.; Pushkarevsky, N. A.; Lonchakov, A. V.; Bogomyakov, A. S.; Irtegova, A. G.;
Vasilieva, N. V.; Lork, E.; Gritsan, N. P.; Konchenko, S. N.; Ovcharenko, V. I.;
Zibarev, A. V. Polyhedron 2014, 72, 43e49.
To a stirred solution of [1,2,3]dithiazolo[5,4-e]pyrido[2,3-b][1,4]
oxazine (6b) (42.0 mg, 0.20 mmol) in PhCl (2 mL) at ca. 20 ꢀC and
protected with a CaCl2 drying tube was added TsOH$H2O (1.9 mg,
0.010 mmol). The mixture was then heated at ca. 132 ꢀC, until no
starting materials remained (TLC, 20 h). Chromatography (n-hex-
ane) gave S8 (11.0 mg, 86%) and further elution gave oxazolo[5,4-b]
pyridine-2-carbonitrile (4b) (14.5 mg, 50%) as colourless needles,
mp 105e106 ꢀC (from c-hexane), identical to that described above.
4.11. Stability study of oxazines in the presence of 2-hydroxy
(dithiazolylideneamino)arenes
12. (a) Van der Plas, H. C. Adv. Heterocycl. Chem. 1999, 74, 9e86; (b) Van der Plas, H.
C. Adv. Heterocycl. Chem. 1999, 74, 87e151.
13. (a) Konstantinova, L. S.; Rakitin, O. A. Russ. Chem. Rev. 2008, 77, 521e546; (b)
Rakitin, O. A. In Comprehensive Heterocyclic Chemistry, 3rd ed.; Zhdankin, V. V.,
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
Oxford, UK, 2008; Vol. 6; Chapter 6.01, p 1; (c) Kim, K. J. Sulfur Chem. 1998, 21,
147e207; (d) Kim, K. Phosphorus Sulfur Silicon Relat. Elem. 1997, 120, 229e244.
14. Christoforou, I. C.; Kalogirou, A. S.; Koutentis, P. A. Tetrahedron 2009, 65,
9967e9972.
4.11.1. Reaction of benzo[b][1,2,3]dithiazolo[5,4-e][1,4]oxazine (6a)
and 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)phenol (5a)
(typical procedure). A stirred solution of benzo[b][1,2,3]dithiazolo
[5,4-e][1,4]oxazine (6a) (41.6 mg, 0.20 mmol) and 2-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)phenol (5a) (50.0 mg, 0.20 mmol)
in PhCl (2 mL), protected with a CaCl2 drying tube was heated at ca.
132 ꢀC until the dithiazole 5a was consumed (TLC). Chromatogra-
phy (n-hexane) gave S8 (15.8 mg, 78%) and further elution (n-
hexane/DCM, 6:4) gave benzo[d]oxazole-2-carbonitrile (4a)
(34.6 mg, 120%) as colourless needles, mp 99e100 ꢀC (from c-
hexane), identical to an authentic sample. A final elution (n-hex-
ane/DCM, 3:7) gave recovered benzo[b][1,2,3]dithiazolo[5,4-e][1,4]
oxazine (6a) (17.3 mg, 42%) as orange fibres, mp 183e184 ꢀC (from
c-hexane/EtOH), identical to an authentic sample.
15. Koutentis, P. A.; Koyioni, M.; Michaelidou, S. S. Org. Biomol. Chem. 2013, 11,
621e629.
16. Christoforou, I. C.; Koutentis, P. A.; Michaelidou, S. S. Arkivoc 2006, 7, 207e223.
17. (a) Rees, C. W. J. Heterocycl. Chem. 1992, 29, 639e651; (b) Besson, T.; Dozias, M.
J.; Guillard, J.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1998, 3925e3926; (c)
Deau, E.; Dubouilh-Benard, C.; Levacher, V.; Besson, T. Tetrahedron 2014, 70,
ꢁ
5532e5540; (d) Hedou, D.; Deau, E.; Harari, M.; Sanselme, M.; Fruit, C.; Besson,
T. Tetrahedron 2014, 70, 5541e5549; (e) Koyioni, M.; Manoli, M.; Manolis, M. J.;
Koutentis, P. A. J. Org. Chem. 2014, 79, 4025e4037.
18. Koyioni, M.; Manoli, M.; Manolis, M. J.; Koutentis, P. A. J. Org. Chem. 2014, 79,
9717e9727.
19. Rakitin, O. A.; Rees, C. W.; Vlasova, O. G. Tetrahedron Lett. 1996, 37, 4589e4592.
ꢂ
ꢁ
20. Frere, S.; Thiery, V.; Bailly, C.; Besson, T. Tetrahedron 2003, 59, 773e779.
21. Besson, T.; Guillaumet, G.; Lamazzi, C.; Rees, C. W. Synlett 1997, 704e706.
22. (a) Besson, T.; Guillard, J.; Rees, C. W.; Thiery, V. J. Chem. Soc., Perkin Trans. 1
1998, 889e892; (b) Besson, T.; Guillard, J.; Rees, C. W.; Therisod, M. Chem.
Commun. 1997, 881e882.
4.11.2. Reaction of [1,2,3]dithiazolo[5,4-e]pyrido[3,2-b][1,4]oxazine
(6b) and 3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol
(5b). Similar treatment of [1,2,3]dithiazolo[5,4-e]pyrido[3,2-b][1,4]
oxazine (6b) (42.0 mg, 0.20 mmol) and 3-(4-chloro-5H-1,2,3-
dithiazol-5-ylideneamino)pyridin-2-ol (5b) (49.2 mg, 0.20 mmol)
gave S8 (11.3 mg, 66%) and oxazolo[5,4-b]pyridine-2-carbonitrile
(4b) (18.1 mg, 62%) as colourless needles, mp 105e106 ꢀC (from c-
hexane) identical to that described previously and recovered [1,2,3]
dithiazolo[5,4-e]pyrido[3,2-b][1,4]oxazine (6b) (31.9 mg, 76%) as
orange fibres, mp 217e218 ꢀC (from c-hexane/EtOH), identical to
that described above.
23. (a) Chang, Y. G.; Kim, K. Heterocycles 1999, 51, 2653e2666; (b) Lee, H. S.; Chang,
Y. G.; Kim, K. J. Heterocycl. Chem. 1998, 35, 659e668; (c) Michaelidou, S. S.;
Koutentis, P. A. Synthesis 2009, 4167e4174.
24. Konstandinova, L. S.; Rakitin, O. A.; Rees, C. W.; Sivadasan, S.; Torrobas, T. Tet-
rahedron 1998, 54, 9639e9650.
25. (a) Besson, T.; Rees, C. W.; Roe, D. G.; Thiery, V. J. Chem. Soc., Perkin Trans. 1 2000,
555e561; (b) Rees, C. W.; Roe, D. G.; Thiery, V. Chem. Commun. 1996,
2775e2776.
26. Boberg, F. Justus Liebigs Ann. Chem. 1964, 679, 109e118.
27. Ogurtsov, V. A.; Rakitin, O. A.; Rees, C. W.; Smolentsev, A. A.; Lyssenko, K. A.
Mendeleev Commun. 2005, 15, 20e21.
28. Jeon, M.-K.; Kim, K. J. Chem. Soc., Perkin Trans. 1 2000, 3107e3112.
29. Lee, H.; Kim, K.; Whang, D.; Kim, K. J. Org. Chem. 1994, 59, 6179e6183.
30. Clarke, D.; Emayan, K.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1998, 77e82.
31. De Kowalewski, D. G.; Contreras, R. H. J. Mol. Struct. 1973, 16, 451e457.
32. (a) Jeon, M.-K.; Kim, K. Tetrahedron 1999, 55, 9651e9667; (b) Jeon, M.-K.; Kim,
K.; Ja Park, Y. Chem. Commun. 2001, 1412e1423.
Acknowledgements
The authors wish to thank the Cyprus Research Promotion
Foundation (Grants No. NEAYPODOMH/NEKYP/0308/02 and
NEAYPODOMH/STRATH/0308/06) and 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
33. Bolshakov, O. I.; Konstantinova, L. S.; Aysin, R. R.; Obruchnikova, N. V.; Lubuzha,
E. D.; Rakitin, O. A. Mendeleev Commun. 2010, 20, 212e214.
34. (a) Nonell, S.; Ferreras, L. R.; Canete, A.; Lemp, E.; Gunther, G.; Pizarro, N.;
Zanocco, A. L. J. Org. Chem. 2008, 73, 5371e5378; (b) Sobarzo-Sanchez, E.;
Jullian, C.; Cassels, B. K.; Saitz, C. Synth. Commun. 2002, 32, 3687e3693; (c)
Saitz, C.; Rodriguez, H.; Marquez, A.; Canete, A.; Jullian, C.; Zanocco, A. Synth.
Please cite this article in press as: Kalogirou, A. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.12.046

10
A.S. Kalogirou et al. / Tetrahedron xxx (2014) 1e10
Commun. 2001, 31, 135e140; (d) Sobarzo-Sanchez, E.; Cassels, B. K.; Saitz-Barria,
35. Weidinger, H.; Kranz, J. Chem. Ber. 1964, 97, 1599e1608.
36. (a) Emayan, K.; English, R. F.; Koutentis, P. A.; Rees, C. W. J. Chem. Soc., Perkin
Trans. 1 1997, 3345e3349; (b) Christoforou, I. C.; Koutentis, P. A. J. Chem. Soc.,
Perkin Trans. 1 2002, 1236e1241.
C.; Jullian, C. Magn. Reson. Chem. 2001, 39, 361e366; (e) Medaer, B. P.; Hoor-
naert, G. J. Tetrahedron 1999, 55, 3987e4002; (f) St. Georgiev, V.; Kropp, P. L.;
Carlson, R. R.; Van Inwegen, R. G.; Mack, R. A. Eur. J. Med. Chem. 1989, 24,
639e649; (g) Tauer, E.; Grellmann, K.-H. Chem. Ber. 1986, 119, 215e228; (h)
Musser, J. H.; Brown, R. E.; Love, B.; Baily, K.; Jones, H.; Kahen, R.; Huang, F.;
Khandwala, A.; Leibowitz, M. J. Med. Chem. 1984, 27, 121e125; (i) Reichen, W.
Helv. Chim. Acta 1977, 60, 186e190; (j) Rabilloud, G. C. R. Seances Acad. Sci., Ser. C
1970, 270, 2019e2021; (k) Dickore, K.; Sasse, K.; Bode, K.-D. Liebigs Ann. Chem.
1970, 733, 70e87.
37. (a) Van der Plas, H. C. Heterocycles 1978, 9, 33e78; (b) Van der Plas, H. C. Tet-
rahedron 1985, 41, 237e281.
38. Harwood, L. M. Aldrichimica Acta 1985, 18, 25.
€
39. Moller, H. Liebigs Ann. 1971, 749, 1e11.
Please cite this article in press as: Kalogirou, A. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.12.046