Effective synthesis of 6-substituted 7H-tetrazolo[5,1-b][1,3,4]thiadiazines via a one-pot condensation/nitrosation/azide-tetrazole tautomerism reaction sequence

Article abstract of DOI:10.1016/j.tetlet.2017.09.014

A new, simple, and general method for the synthesis of 6-R-7H-tetrazolo[5,1-b][1,3,4]thiadiazines (R = Ar, Het, Alk) has been developed. The described method is based on the one-pot condensation of α-haloketones with thiocarbohydrazide, nitrosation of the formed hydrazinylthiadiazine using NaNO₂/HCl, and intramolecular cyclization of the nitrosation product via azide-tetrazole tautomerism. Spectroscopic and structural investigations revealed that the azide-tetrazole equilibrium is completely shifted to the tetrazole form both in solution and the solid state.

Full text of DOI:10.1016/j.tetlet.2017.09.014

Accepted Manuscript
Effective synthesis of 6-substituted 7H-tetrazolo[5,1-b][1,3,4]thiadiazines via a
one-pot condensation/nitrosation/azide-tetrazole tautomerism reaction se-
quence
Alexander S. Kulikov, Margarita A. Epishina, Leonid L. Fershtat, Anna A.
Romanova, Nina N. Makhova
PII:
S0040-4039(17)31132-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.014
TETL 49284
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 July 2017
31 August 2017
7 September 2017
Please cite this article as: Kulikov, A.S., Epishina, M.A., Fershtat, L.L., Romanova, A.A., Makhova, N.N., Effective
synthesis of 6-substituted 7H-tetrazolo[5,1-b][1,3,4]thiadiazines via a one-pot condensation/nitrosation/azide-
tetrazole tautomerism reaction sequence, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.09.014
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Effective synthesis of 6-substituted 7H-tetrazolo[5,1-b][1,3,4]thiadiazines via a
one-pot condensation/nitrosation/azide-tetrazole tautomerism reaction
sequence
Alexander S. Kulikov,a Margarita A. Epishina,a Leonid L. Fershtat,a Anna A. Romanova,b,c Nina
N. Makhovaa*
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky
prosp., 119991, Moscow, Russian Federation. Phone: +7 (499) 1355326; Fax: +7 (499)
1355328. e-mail: mnn@ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,28
Vavilova str., 119991 Moscow, Russian Federation. Fax: +7 (499) 135 5085.
cHigher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation
Abstract
A new, simple, and general method for the synthesis of 6-R-7H-tetrazolo[5,1-
b][1,3,4]thiadiazines (R = Ar, Het, Alk) has been developed. The described method is based on
the one-pot condensation of α-haloketones with thiocarbohydrazide, nitrosation of the formed
hydrazinylthiadiazine using NaNO2/HCl, and intramolecular cyclization of the nitrosation
product via azide-tetrazole tautomerism. Spectroscopic and structural investigations revealed that
the azide-tetrazole equilibrium is completely shifted to the tetrazole form both in solution and the
solid state.
Keywords: 7H-tetrazolo[5,1-b][1,3,4]thiadiazines; furoxan; α-haloketones; nitrosation; azide-
tetrazole tautomerism.
During the last years, N-bridged fused heterocyclic systems have received significant
attention owing to their diverse pharmacological activities.1 Among them, the heterocycle-fused
1,2,4-triazole scaffold has been identified as one of the privileged structures in drug discovery.2
In particular, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines are cholinesterase and other enzyme
inhibitors, and can be used for the therapy of Alzheimer’s disease.3a Additionally, they represent
therapeutic agents, possessing antiproliferative and antileishmanial activities.3b The introduction
of the thiadiazine motif makes an appreciable contribution to their biological activity, with
applications as antibacterial,4a antifungal,4b and antidepressant4c agents.

The analogous structures containing a fused tetrazole ring, namely 6-R-7H-tetrazolo[5,1-
b][1,3,4]thiadiazines 1 (R = Ar, Alk), were previously described in only one report, along with
an examination of their free radical scavenging activity.5 Meanwhile, these structures may have
potential as pharmacologically active compounds due to the tetrazole ring being an important
pharmacophore in medicinal chemistry,6 with pharmaceutical applications which have been
widely explored and comprehensively documented in the literature.7 Tetrazole-based drug
candidates possess anticonvulsant,8 antihypertensive,9a antiallergic,9b and antibiotic activities,9c
and have also shown promising results in the treatment of various diseases, such as cancer and
AIDS.10
The key step of the single existing method for the construction of heterocyclic systems 1
is the cyclocondensation of sodium 1-amino-1H-tetrazole-5-thiolate
2
with α-
bromoacetophenones 3 in AcOH at reflux for 4 hours.5 The corresponding reaction with
chloroacetone was carried out at reflux in MeOH. Initial compounds 2 were, in turn, synthesized
by prolonged heating of methyl dithiocarbazate 4 with NaN3 in EtOH–H2O. The synthesis of
compound 4 is based on the condensation of hydrazine-hydrate, CS2, and dimethyl sulfate in the
presence of KOH (Scheme 1).
Herein, we present the development of a new, simple, and general approach for the
synthesis of 6-R-7H-tetrazolo[5,1-b][1,3,4]thiadiazines 1 (R = Ar, Het, Alk) via condensation of
the corresponding α-haloketones 3 with commercially available thiocarbohydrazide 5 at room
temperature, subsequent one-pot nitrosation of the formed hydrazinylthiadiazine 6, and
intramolecular cyclization of the nitrosation product via azide-tetrazole tautomerism to give the
desired compounds 1 in good to high yields (Scheme 1).
Scheme 1. Known and new methods for the synthesis of 6-R-7H-
tetrazolo[5,1-b][1,3,4]thiadiazines.

Our ongoing scientific interests are connected with the synthesis of pharmacologically
oriented structures comprising of the 1,2,5-oxadiazole 2-oxide (furoxan) scaffold, which is
capable of exogenous NO release in the presence of thiol cofactors,11 and other heterocycles with
known pharmacological activities. In particular, we have recently developed effective methods
for the preparation of hybrid heterocyclic structures that combine a furoxan ring with different
pharmacophoric heterocycles (1,2,3-12a-c and 1,2,4-triazole,12d 1,2,4-,12e 1,2,5-12f,g and 1,3,4-
oxadiazoles,12h tetrazole,12i pyridines,12j and others12k-o). In continuation of these investigations,
we aimed to synthesize hybrid structures containing a furoxan ring linked to the 7H-
tetrazolo[5,1-b][1,3,4]thiadiazine moiety.
Our investigation began with the development of optimal conditions for the synthesis of
(2-hydrazinyl-1,3,4-thiadiazin-5-yl)furoxans 6. We expected to nitrosate the hydrazine group in
these compounds, with formation of the corresponding azides which are prone to ring-chain
(azide-tetrazole) tautomerism, resulting in the target 6-furoxanyl-7H-tetrazolo[5,1-
b][1,3,4]thiadiazines 1. The synthesis of (α-bromoacetyl)furoxans 3a,b was previously
developed by bromination of the corresponding acetylfuroxans in concentrated HCl,13 and 4-
amino-3-(α-bromoacetyl)furoxan 3a was chosen as a model substrate. The synthesis of 5-aryl-2-
hydrazinyl-1,3,4-thiadiazines is typically based on reaction of the corresponding aromatic α-
haloketones 3 with thiocarbohydrazide 5 in AcOH14a or EtOH14b at reflux or under microwave
irradiation in the presence of K2CO3.14c Using this approach, we carried out a search for the
optimal conditions for the reaction of bromoacetylfuroxan 3a with thiocarbohydrazide 5 in order
to find milder conditions for preparation of the target thiadiazine 6a. The solvent, temperature,
and reaction time were varied (Table 1). Moderate yields were obtained in EtOH (Entries 1, 2)
and decomposition was observed in 1,4-dioxane (Entry 3), while the reactions in MeCN, DMF,
or DMSO were more successful (Entries 4-7). The optimal conditions were stirring for 1 h at 20
oC in DMSO (Entry 7). The possible intramolecular cyclization between the amino group and the
bromoacetyl functionality can be excluded since aminofuroxans are very weak nucleophiles.12n
Furoxan derivative 6b was also prepared in high yield.
Table 1. Reaction conditions screening for the synthesis of 4-amino-3-(2-hydrazino-1,3,4-
thiadiazin-5-yl)furoxan 6a.a

Entry
Solvent
EtOH
EtOH
T (oC)
20
20
Time (h)
Yield 6a (%)b
55
1
2
3
4
5
6
7
8
12
12
1
60c
d
1,4-Dioxane
MeCN
MeCN
20
-
0→20
20
20
2
84
77
85
90
95
1
DMF
DMSO
DMSO
0.5
0.5
1
20
20
a Reagents and conditions: furoxan 3a (1 mmol), thiocarbohydrazide 5 (1 mmol), solvent (2 mL)
(TLC, CHCl3:EtOAc =3:1).
b Isolated yield.
c conc. HCl used as an additive.
d Decomposition was observed.
Compounds 6a,b proved to be insufficiently stable for storage, evidently due to the high
sensitivity of the furoxan ring to strong bases15 (hydrazine group) and, hence, they were
characterized as hydrazones 7a,b. Therefore, for further transformations, solutions of hydrazine
derivatives 6a,b in DMSO were utilized in the nitrosation reaction without isolation, and the
required 6-furoxanyl-7H-tetrazolo[5,1-b][1,3,4]thiadiazines 1a,b were obtained in high yields
(Scheme 2).
H
N
N
O
N
NO2
N
N
S
H2N
N
O
7a (95%)
4-O2NC6H4CHO
N
N
N
N
NHNH2 . HBr
N
N
N
O
N
S
Br
Br
S
H2N
N
H2N
H2N
NaNO2
HCl-H2O
N
N
N
S
N
O
O
O
O
O
O
O
1a (85%)
6a
H2NHN
NHNH2
3a
5
N
DMSO, rt
N
NHNH2 . HBr
S
O
N
N
N
Me
N
N
S
Me
N
Me
NaNO2
N
N
O
HCl-H2O
N
N
O
N
O
3b
O
O
6b
4-O2NC6H4CHO
1b (78%)
H
N
N
N
NO2
N
S
Me
N
N
O
O
7b (76%)
Scheme 2. One-pot synthesis of 6-furoxanyl-7H-tetrazolo[5,1-b][1,3,4]thiadiazines 1a,b.

Diazotization of compounds 6a,b results in the initial formation of azides 8a,b. The
isolation of tetrazolo[5,1-b][1,3,4]thiadiazines 1a,b may serve as evidence for the complete shift
of the azide 8 – tetrazole 1 equilibrium towards the tetrazole in the solid state (Scheme 3). The
absence of characteristic bands for the azido group in the IR spectra (2130-2150 cm-1, KBr
pellets) and the presence of only one singlet for the methylene group protons of the 1,3,4-
thiadiazine ring in the 1H NMR spectra (DMSO-d6) indicated the existence of the tetrazole form
of compounds 1a,b. Finally, the structure of compounds 1a,b was confirmed by single-crystal X-
ray diffraction (Fig. 1).
N
N
NHNH2 . HBr
N3
N
N
N
O
N
N
N
N
N
N
S
S
H2N
N
S
H2N
H2N
NaNO2
HCl-H2O
N
N
N
O
O
O
O
O
1a
8a
6a
N
N
N3
N
NHNH2 . HBr
N
N
N
N
N
N
S
S
Me
S
Me
Me
NaNO2
HCl-H2O
N
O
N
N
N
N
N
O
O
O
O
O
8b
1b
6b
Scheme 3. Azide-tetrazole tautomerism of azide 8 and tetrazole 1 forms.
1a
1b
Figure 1. General view of compounds 1a,b. Atoms are represented by probability ellipsoids of
atomic vibrations (p=0.5).
The optimized conditions also proved suitable for the synthesis of further 6-R-7H-
tetrazolo[5,1-b][1,3,4]thiadiazines 1c-j from the corresponding α-haloketones 3c-j containing
heteroaromatic, aromatic, and aliphatic substituents (Table 2). α-Haloketones 3c,18a 3d,18b 3e-i,18c
3j18d were synthesized via halogenation of the corresponding acetyl derivatives according to
literature procedures. The intermediate hydrazine derivatives were isolated and characterized in
separate experiments, either as individual compounds (6c,h-j) or as the acetone hydrazone 7d
(see ESI). Intermediates 6e-g are known compounds.19

Table 2. Scope for the synthesis of 6-substituted 7H-tetrazolo[5,1-b][1,3,4]thiadiazines 1a-j.a
Entry α-Haloketone 3
Compound 1
Yield 1 (%)b
1
85
2
78
O
Br
Me
3
61
68
N
N
O
3c
4
5
6
7
85
82
88
8
9
80
76
O
Br
NO2
3i

10
51
a
Reagents and conditions: haloacetyl derivative 3 (2 mmol), thiocarbohydrazide 5 (2 mmol),
o
DMSO (2 mL), 20 C (TLC, CHCl3-EtOAc, 3:1), then conc. HCl (0.4 mL), NaNO2 (3 mmol), 0
→ 20 oC.
b Isolated yield.
The observed azide-tetrazole tautomerism is a well-known process, which has been
examined by both theoretical20 and experimental techniques.21 The predominance of either the
azide or tetrazole form depends on various factors; mainly the reaction conditions (temperature,
solvents) and the structure of substituents attached to the heterocyclic system. In particular, it
was found20d that the azide form predominates in non-polar solvents, while the tetrazole one is
the major tautomer in polar solvents. To estimate the possibility for the azide form of structures
1
1a-j to exist in non-polar solvents, the IR and H NMR spectra of compounds 1b, 1g, and 1j
were recorded as solutions in CHCl3 and CDCl3, respectively, because in most cases, these
solvents shift the azide-tetrazole equilibrium towards the azide form.20d However, neither the
characteristic bands of the azido group in the IR spectrum (2130-2150 cm-1) nor the double set of
1
methylene group protons of the 1,3,4-thiadiazine ring in the H NMR spectra were observed.
Therefore, the azide-tetrazole equilibrium in compounds 1a-j is completely shifted to the
tetrazole tautomer both in solution and the solid state.
In summary, a general, and highly effective method for the synthesis of diverse 6-R-7H-
tetrazolo[5,1-b][1,3,4]thiadiazines has been developed.22 This method is based on a sequence of
one-pot reactions: condensation of substituted α-haloketones 3 with commercially available
thiocarbohydrazide 5 at room temperature, nitrosation of the formed hydrazinyl-1,3,4-thiadiazine
6 using NaNO2/HCl, and intramolecular cyclization of the nitrosation product via azide-tetrazole
tautomerism to give the desired compounds 1 in good to high yields. According to IR, NMR, and
single crystal X-ray data, it was established that the synthesized 6-R-7H-tetrazolo[5,1-
b][1,3,4]thiadiazines 1 are not prone to ring-chain tautomerism either in solution or the solid
state. To the best of our knowledge, this study represents one of the rare examples of a complete
shift of the azide-tetrazole equilibrium towards the tetrazole.
Acknowledgements
This work was supported by the Russian Science Foundation (Project No 14-50-00126).

Supplementary data
Supplementary data associated with this article can be found, in the online version, at
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22.
General procedure for the synthesis of 6-substituted 7H-tetrazolo[5,1-
b][1,3,4]thiadiazines 1. Haloacetyl derivative 3 (2 mmol) was added to a magnetically stirred
solution of thiocarbohydrazide 5 (0.21 g, 2 mmol) in DMSО (2 mL). The reaction mixture was
stirred for 1 h at 20 oC until substrate 3 was consumed (TLC, CHCl3-EtOAc, 3:1), then water (10
mL) and conc. HCl (0.4 mL) were added. A solution of NaNO2 (0.21 g, 3 mmol) in water (1.5
о
mL) was added dropwise to the resulting suspension at 2-4 С over a period of 15 min. The
o
reaction mixture was stirred for 1 h at the same temperature and for 1 h at 20 C. The formed
solid was filtered off, washed with water, dried in air and recrystallized from EtOH. Compound
1j was extracted with CHCl3 (3x15 mL), dried over MgSO4, the solvent evaporated and the
residue recrystallized from EtOH.

Highlights
•
•
•
A novel method for the synthesis of tetrazolo[5,1-b]thiadiazines was developed.
The target structures were obtained in good to high yields.
A single tetrazole tautomer was found both in solution and in solid state.