Realizing the Trifunctional Potential of Alkyl 4-Chloro-2-diazo-3-oxobutanoates: Convenient Assembly of 6,7-Dihydro-4 H-[1,2,3]triazolo[5,1-c][1,4]thiazine Core

Article abstract of DOI:10.1055/s-0039-1690802

The first example of exploiting the trifunctional character of alkyl 4-chloro-2-diazo-3-oxobutanoates in the reactions with vicinal N, S-bis-nucleophiles leading to the formation of bicyclic 6,7-dihydro-4 H-[1,2,3]triazolo[5,1-c][1,4]thiazines is presente

Full text of DOI:10.1055/s-0039-1690802

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–G
paper
A
en
D. Dar’in et al.
Paper
Synthesis
Realizing the Trifunctional Potential of Alkyl 4-Chloro-2-diazo-
3-oxobutanoates: Convenient Assembly of 6,7-Dihydro-4H-
[1,2,3]triazolo[5,1-c][1,4]thiazine Core
Dmitry Dar’ina
Olesya Khoroshilovaa
Grigory Kantina
0
0
0
0-0
0
0
2-
0
4
1
3-7
4
1
3
Wolff
triazole
synthesis
SN2
N2
EtO2C
CO2Et
N
N2
NH2
S
CO2Et
HS
N
N
S
Cl
CO2Et
N
Mikhail Krasavin*a,b
0
0
0
0-0
0
0
2-
0
2
0
0-4
7
7
2
O
N
N
S
Wolff
triazole
synthesis
O
imine
formation
SN2
NH2
imine
formation
a Saint Petersburg State University, Saint Petersburg 199034,
Russian Federation
m.krasavin@spbu.ru
b Immanuel Kant Baltic Federal University, Kaliningrad 236016,
Russian Federation
92%
+ 9 other examples
Received: 16.12.2019
Accepted after revision: 03.01.2020
Published online: 27.01.2020
of 3-(chlorosulfonyl)benzoic acid and to sequester all sodi-
um azide (also used in slightly reduced amount) and pre-
vent displacement of the labile chlorine in 1 (or 2) by unre-
acted azide anion (as described for a bromo derivative6) as
was observed when the standard SAFE protocol5 was ap-
plied (Scheme 1).
DOI: 10.1055/s-0039-1690802; Art ID: ss-2019-c0684-op
Abstract The first example of exploiting the trifunctional character of
alkyl 4-chloro-2-diazo-3-oxobutanoates in the reactions with vicinal
N,S-bis-nucleophiles leading to the formation of bicyclic 6,7-dihydro-
4H-[1,2,3]triazolo[5,1-c][1,4]thiazines is presented. The key to the suc-
cessful realization of the atom-economical synthetic strategy is the ini-
tial SN2 event, which facilitates the subsequent domino 1,2,3-triazole
formation via the Wolff reaction. Equally important is the choice of so-
dium acetate as the base: acetic acid formed in the course of the initial
nucleophilic substitution acts as an efficient catalyst for the Wolff reac-
tion, which suppresses the competing, unwanted fragmentation path
(observed when other bases are used).
SAFE
diazo transfer
O
O
O
O
Cl
Cl
OEt
OEt
N2
2
1
(a)
Standard SAFE protocol5:
NaN3 (2.0 equiv.), m-HO2CC6H4SO2Cl (1.3 equiv.), K2CO3 (2.6 equiv.), H2O, r. t., 1–2 h
(b)
Modified SAFE protocol (this work):
NaN3 (1.5 equiv.), m-HO2CC6H4SO2Cl (1.5 equiv.), K2CO3 (2.6 equiv.), H2O, r. t., 1–2 h
Key words diazo transfer, multicenter reactions, nucleophilic substi-
tution, domino reactions, Wolff 1,2,3-triazole synthesis
Scheme 1 The standard (a) and modified (b) SAFE diazo transfer proto-
cols
Two-component transformations engaging multiple re-
active centers in reactants are akin to multicomponent re-
actions in terms of atom economy and rapid buildup of mo-
lecular complexity.1 Pairwise matching of reactivity of two
bifunctional reagents is commonplace: typically the first
interaction is intermolecular followed by an intramolecular,
ring-forming process.2 On the contrary, examples illustrat-
ing engagement of more than two reactive centers in at
least one of reaction partners are rather scarce.3 Such an ar-
rangement sets the ground for the formation of greater
than two new chemical bonds in an efficient, domino fash-
ion.4
Compound 1 is rather densely functionalized, contain-
ing four contiguous potentially reactive centers: a labile
chlorine, a ketone carbonyl, a diazo group, and an ester. It is
therefore quite surprising that, according to literature re-
ports, this reagent was mostly employed as a bifunctional
-diazocarbonyl compound: in the synthesis of isocouma-
rins and -pyrones7 as well as isoquinolones and pyridines8
from benzamides (involving RhIII-catalyzed carbene C–H in-
sertion), rather similar access to isoquinolines from arylim-
idates,9 divergent synthesis of chromones and benzofurans
via RhIII-catalyzed annulation of salicylaldehyde10 and a se-
ries of related annulation reactions were reported in the last
two years.11–13 Treatment of 1 as bifunctional -diazocar-
bonyl reagent is showcased in its RhII-catalyzed condensa-
tion with benzamides to give oxazoles14 and RhII-catalyzed
1,3-dipolar cycloaddition with enol ethers.15 There are rare
Recently, we became interested in synthesizing struc-
turally diverse -diazo carbonyl compounds using an aque-
ous-phase diazo transfer protocol which we dubbed ‘sulfo-
nyl-azide-free’ (SAFE).5 In particular, we prepared ethyl 4-
chloro-2-diazo-3-oxobutanoate (1) from its commercially
available active methylene precursor 2 by modifying the
SAFE procedure: namely, by slightly increasing the amount
examples of involving
1 as a monofunctional diazo
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. Dar’in et al.
Paper
Synthesis
N2
N2
S
(NH2)2CS
Br
CO2Et
(a)
N
CO2Et
H2N
O
THF, r. t., 2.5 h
36%
3
Wolff
triazole
synthesis
SN2
N2
N2
CO2Et
EtO2C
Nu
NH2
Nu
CO2Et
N
N
(b)
Cl
CO2Et
Nu
N
N
O
O
N
N
Nu
SN2
1
NH2
imine
formation
N2
i-PrNH2
H
N2
O
N
(c)
Cl
Pr-i
Cl
CO2Et
Cl
CO2Et
Pr-i
THF, 25 °C
2 h, 90%
N2
O
–
O
H2N
1
CO2Et
Figure 1 (a) Thiazole synthesis from the bromo derivative of 1 described by Padwa;6 (b) The idea of SN2-triggered tandem synthesis of 1,2,3-triazoles
investigated in this work; (c) Fragmentation of 1 by primary amines reported earlier20
compound in RhII-catalyzed carbene ylide formation16 and
carbene X–H insertion17 reactions. Padwa and co-workers
also reported reactions of 1 and its bromo derivative as -
halo ketone with various nucleophiles, including thiourea.6
The latter reaction (which resulted in the formation of a
thiazole-substituted -diazo acetate ester 3) gave us an idea
to explore a possibility for a SN2-triggered domino synthe-
sis18 of bicyclic 1,2,3-triazoles via the reaction with bifunc-
tional primary amines containing a terminal substituent
whose nucleophilicity would be higher than that of the
amino group. The initial SN2 reaction, we reasoned, will re-
quire the presence of a base (as a scavenger for HCl), how-
ever, subsequent formation of an imine will be intramolec-
ular (hence, presumably, facile) and will set the scene for
the Wolff 1,2,3-triazole synthesis.19 However, realization of
such strategy which we report herein, would require also
avoiding the potential risk of the earlier described20 frag-
mentation of 1 on addition of amine nucleophiles (Figure
1).
was achieved with methyl 4-chloro-2-diazo-3-oxopenta-
noate (6) also prepared as shown in Scheme 1b. The forma-
tion of unwanted products 4 and 5 (along with the minor
amounts of the target 1,2,3-triazoles 7 and 8, respectively,
observed in the reaction mixtures by mass spectrometry
analysis) can be justified by the significant competition of
the retro-Claisen-type acyl cleavage pathway B (with the
elimination of alkyl diazoacetate) with the desired course of
the reaction, that is, pathway A (Scheme 2).
We reasoned that the likelihood of the reaction of 1 (or
6) with -mercaptoethylamine hydrochloride to deliver the
desired bicyclic 1,2,3-triazole 7 (or 8) could be increased by
catalyzing the Wolff triazole synthesis pathway A. A litera-
ture review revealed that the involvement of -oxo--di-
azopropionate esters in the Wolff 1,2,3-triazole synthesis
with primary amines quite often required the use of acetic
acid (introduced as such or generated in situ from sodium
acetate) as the catalyst.21–26 Thus we decided to use AcONa
as the scavenger of HCl (1 equiv. from -mercaptoethyl-
amine hydrochloride and 1 equiv. – liberated in the initial
SN2 step) and, to our delight, discovered that both 1 and 6
gave exclusively the desired 1,2,3-triazole product (7 and 8,
respectively) in good to excellent yield. The structure of
compound 7 was additionally confirmed by single-crystal
X-ray crystallography27 (Scheme 3).
Indeed, as was anticipated based on the fragmentation
reaction depicted in Figure 1c, thiomorpholinone 4 was the
principal product of the reaction between 1 and -mercap-
toethylamine hydrochloride conducted in methanol in the
presence of potassium carbonate or DIPEA as the base. A
similar result (i.e., the formation of thiomorpholinone 5)
NH2
NH2
O
A
O
O
S
S
OR
Wolff
triazole
synthesis
N2
OR
O
–
– H2O
B
N2
R'
R'
O
N2
CO2R
NH2·HCl
O
HS
S
S
Cl
+
NH
N
OR
R'
R'
RO2C
N
K2CO3 or DIPEA
(2.5 equiv.)
MeOH, r. t., 16 h
R'
N2
O
N
1, R = Et, R' = H
6, R = R' = Me
4, R' = H
5, R' = Me
7 (from 1)
8 (from 6)
4:7 or 5:8 = 9:1 (K2CO3) ... 2:1 (DIPEA)
Scheme 2 Fragmentation was the predominant course of the reaction with K2CO3 or DIPEA as the base
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

C
D. Dar’in et al.
Paper
Synthesis
R'
O
OR
CO2R
N
HS
NH2.HCl
Cl
S
O
N
R'
N2
AcONa
(2.5 equiv.)
MeOH, r. t., 16 h
N
7 (R = Et, R' = H), 92%
8 (R = R' = Me), 67%
1 or 6
7
Scheme 3 SN2-triggered tandem Wolff 1,2,3-triazole synthesis using sodium acetate as the base and single-crystal X-ray structure of compound 7
Besides the advantageous choice of sodium acetate as
the base to promote the above reaction, the successful
preparation of 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]-
thiazines 7 and 8 can be primarily attributed to the intra-
molecular character of the SN2-triggered 1,2,3-triazole for-
mation. This view is supported by the following observa-
tions. Substrate 1 underwent a clean nucleophilic substitu-
tion reaction with Boc-protected cysteamine to give adduct
9 in 91% yield. The Boc group in the latter was removed by
treatment with TFA in dichloromethane. However, the for-
mation of the triazole from the intermediate trifluoroace-
tate salt was exceedingly slow (<10% conversion observed
overnight). In contrast, a rapid conversion was achieved on
addition of sodium acetate in methanol and the resulting
compound 7 was isolated in 96% yield. Thus, the combined
yield over 2 steps, 87%, was nearly the same as the yield for
the direct 1 → 7 conversion shown in Scheme 3. On the
contrary, intermolecular 1,2,3-triazole formation via the at-
tempted reaction of 1 with S-phenylcysteamine in the pres-
ence of acetic acid was completely unsuccessful as only
minute amounts of unidentified products were formed in
24 hours at room temperature (Scheme 4).
Having identified the workable set of conditions allow-
ing for an efficient formation of 6,7-dihydro-4H-[1,2,3]tri-
azolo[5,1-c][1,4]thiazines via the tandem SN2-triggered
Wolff 1,2,3-triazole synthesis, we proceeded to explore the
generality of this approach using various reagents contain-
ing the -mercaptoethylamine motif (Table 1).
Products 10–15 were formed in excellent yields; their
structures were consistent with the 1H and 13C NMR data as
well as high-resolution mass spectrometry. For compounds
12 and 13, single-crystal X-ray crystallographic information
was obtained (Figure 2).27
The one-step preparation of compound 11 (the key in-
termediate in the preparation of a potent mGluR5 receptor
antagonist patented by GlaxoSmithKline28) in 95% yield is
particularly noteworthy. The original synthesis28 of this in-
termediate from 2-amino-5-fluorobenzenethiol entailed 6
steps and delivered compound 11 in 13.7% overall yield.
We reasoned that the same approach as described above
should work for various thiosemicarbazides capable of
reacting as N,S-bis-nucleophiles. However, attempts to
involve 1 in the reaction with N-phenylsemicarbazide 16
NHBoc
CO2Et
N
O
OEt
O
OEt
HS
1) TFA (10 equiv.)
DCM, r. t., 16 h
NHBoc
S
Cl
S
O
O
N
N2
N
AcONa
(1.5 equiv.)
MeOH, r. t., 2 h
2) AcONa (2.0 equiv.)
MeOH, r. t., 4 h
N2
9, 91%
7, 96%
1
O
OEt
PhS
Cl
NH2
O
no desired product
N2
AcOH
(1.5 equiv.)
MeOH, r. t., 24 h
1
Scheme 4 Stepwise formation of 7 and the attempted intermolecular Wolff 1,2,3-triazole synthesis
Figure 2 Single-crystal X-ray crystallographic structures of compounds (a) 12, (b) 13, and (c) 19; thermal ellipsoids are shown at 50% probability.27
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
D. Dar’in et al.
Paper
Synthesis
Table 1 6,7-Dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]thiazines 10–15
Prepared
NH2
PhHN
N
O
1
NHPh
OEt
S
AcONa
(1.5 equiv.)
MeOH, r. t., 16 h
S
NHNH2
16
O
HS
NH2
O
OR
N
X
N2
N
N
17
Cl
X
(observed by 1H NMR)
O
S
CO2R
R'
N2
AcONa
R1 R2
N
R1
R'
N
(1.5 or 2.5 equiv.a)
MeOH, r. t., 16 h
1
N
N
N
N
1 or 6
10–15
R2
S
NHNH2
AcONa
(1.5 equiv.)
AcOH, r. t., 48 h
S
CO2Et
16, R1 = Ph, R2 = H
18, R1 = R2 = (CH2)4
19 (from 16), 77%
20 (from 18), 68%
O
OR
HS
NH2
Yield
(%)
Cl
1
Entry
1
Product
O
X
Scheme 5 Attempted (a) and successful (b) involvement of thiosemi-
carbazides in the reaction with 1
R'
N2
N
NH2
SH
N
N
90
95
Compounds 7,8, 10–15, and 19,20 prepared in the
course of this study contain a divalent sulfur atom, which
introduces a metabolic liability from a drug design perspec-
tive.30 This unwanted feature can be eliminated by oxidizing
these compounds to the respective sulfones as was demon-
strated for compounds 7 and 10. The latter gave excellent
yields of sulfones 21 and 22 on treatment with 2.5-fold ex-
cess m-CPBA in dichloromethane (Scheme 6).
S
CO2Et
10
F
N
NH2
SH
N
N
2
3
4
5
1
S
F
CO2Et
11
MeO2C
S
N
NH2·HCl
CO2Me
N
N
HS
1
1
1
96
83
81
CO2Et
N
N
12b
m-CPBA
N
N
N
N
S
O
S
O
DCM, r. t.
18 h
H
CO2Et
CO2Et
SH
N
7
21, 90%
N
N
NH2·HBr
H
S
CO2Et
(rac)
13b
N
N
N
N
N
N
m-CPBA
S
O
S
Me
Me
N
DCM, r. t.
18 h
O
N
CO2Et
N
CO2Et
NH2·HBr
10
22, 95%
HS
S
CO2Et
Scheme 6 Oxidation of compounds 7 and 10 to the respective sul-
14
fones
N
N
N
NH2
SH
In summary, we have presented the first example of ex-
ploiting the trifunctional character of alkyl 4-chloro-2-di-
azo-3-oxobutanoates in the reactions with vicinal N,S-
bisnucleophiles (the simplest of which is -mercaptoethyl-
amine). While the initial SN2 event is generally facile, it is
crucial for the subsequent Wolff 1,2,3-triazole synthesis
step with which it occurs in tandem. Likewise, the choice of
sodium acetate as the base to scavenge hydrochloric acid
generated in the initial SN2 step, was crucial for the success
of the subsequent 1,2,3-triazole formation as acetic acid
generated appears to be the catalyst required in the reac-
tion (the use of other bases caused alkyl diazoacetate elimi-
nation prior to the formation of 1,2,3-triazole). Acetic acid
as a solvent was also the medium of choice to promote tan-
dem SN2/Wolff 1,2,3-triazole synthesis with less reactive
thiosemicarbazides.
6
6
88
S
CO2Et
Me
15
a For entries 3–5: 2.5 equiv.
b Structure confirmed by single-crystal X-ray crystallography.
under the same conditions as were used to prepare com-
pounds 10–15, resulted only in the formation of the SN2
product 17 (observed by H NMR, not isolated). The latter,
1
however, was found to rapidly cyclize into the desired 1,2,3-
triazole in pure acetic acid. Therefore, the reaction of 1 with
semicarbazides 16 and 18 was subsequently conducted in
acetic acid and resulted in excellent yields of the anticipat-
ed 4H-[1,2,3]triazolo[1,5-d][1,3,4]thiadiazin-6-amines 19
and 20 (Scheme 5). The structure of compound 19 was con-
firmed by single-crystal X-ray crystallography (Figure 2).27
It should be noted that the 4H-[1,2,3]triazolo[1,5-
d][1,3,4]thiadiazine scaffold in compounds 19 and 20 rep-
resents a hitherto unknown heterocyclic system, according
to SciFinder® search.29
Reactions of the densely functionalized 4-chloro-2-di-
azo-3-oxobutanoate esters with other X,N-bis-nucleophiles
are currently under investigation in our laboratories and
will be reported in due course.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

E
D. Dar’in et al.
Paper
Synthesis
(2 × 5 mL). The combined organic phases were dried (anhyd Na2SO4),
and evaporated to give the desired fused triazole 7, 8 or 10–15. In
some cases, the product was additionally crystallized from MeOH.
All commercial reagents and solvents were used without further pu-
rification, unless otherwise noted. NMR spectroscopic data were re-
corded with a 400 MHz spectrometer (400.13 MHz for 1H and 100.61
MHz for 13C) in CDCl3 and in DMSO-d6 and were referenced to residual
solvent proton signals (H = 7.26 and H = 2.50, respectively) and sol-
vent carbon signals (C = 77.0 and C = 39.5, respectively). All chemical
shifts are reported in parts per million (ppm). Standard abbreviations
were used in the description of resonances. Coupling constants (J) are
quoted to the nearest 0.1 Hz. Mass spectra were recorded with a
HRMS-ESI-qTOF spectrometer (electrospray ionization mode). Melt-
ing points were determined with a melting point apparatus Stuart
SMP 50 in open capillary tubes. Analytical TLC was carried out on UV-
254 silica gel plates using appropriate eluents. Compounds were visu-
alized with short-wavelength UV light. Flash column chromatography
was performed using silica gel Merck grade 60 (0.040–0.063 mm)
230–400 mesh (isocratic or gradient elution as indicated).
Ethyl 6,7-Dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]thiazine-3-carbox-
ylate (7)
The title compound was synthesized according to GP2 from diazo
keto ester 1 and cysteamine hydrochloride; yield: 196 mg (92%); pale
beige solid; mp 126.1–127.7 °C (MeOH).
1Н NMR (400 MHz, СDCl3):  = 4.72–4.64 (m, 2 H), 4.44 (q, J = 7.1 Hz, 2
H), 4.20 (s, 2 H), 3.17–3.09 (m, 2 H), 1.43 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 161.2, 135.10, 135.09, 61.2, 48.2, 25.3,
22.8, 14.3.
HRMS (ESI +ve): m/z calcd for C8H11N3O2SNa [M + Na]+: 236.0464;
found: 236.0463.
Alkyl 4-Chloro-2-diazo-3-oxobutanoates 1 and 6; General Proce-
dure 1 (GP1)
Methyl 4-Methyl-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]thi-
azine-3-carboxylate (8)
To a stirred solution of NaN3 (572 mg, 8.8 mmol) and K2CO3 (2.21 g,
16.0 mmol) in H2O (18 mL) was added 3-(chlorosulfonyl)benzoic acid
(2.0 g, 9.0 mmol) and the mixture was stirred at r.t. for 20 min to give
a clear solution. To the obtained solution was added the substrate for
diazo transfer (6.0 mmol) under stirring at r.t. The mixture was
stirred for 2 h followed by extraction with DCM (3 × 10 mL), the com-
bined organic phases were dried (CaCl2), and evaporated to dryness to
afford pure title diazo keto esters.
The title compound was synthesized according to GP2 from diazo
keto ester 6 and cysteamine hydrochloride; yield: 143 mg (67%); col-
orless semi-solid.
1Н NMR (400 MHz, СDCl3):  = 4.80 (ddd, J = 13.6, 4.1, 3.0 Hz, 1 H),
4.57 (qd, J = 7.1, 1.2 Hz, 1 H), 4.40 (ddd, J = 13.6, 11.6, 4.4 Hz, 1 H), 3.93
(s, 3 H), 3.29 (dddd, J = 14.6, 11.6, 4.1, 0.4 Hz, 1 H), 2.99 (dddd, J = 14.6,
4.3, 3.0, 1.2 Hz, 1 H), 1.67 (d, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 161.4, 140.4, 134.0, 52.0, 48.3, 30.1,
22.6, 21.4.
Ethyl 4-Chloro-2-diazo-3-oxobutanoate (1)
HRMS (ESI +ve): m/z calcd for C8H11N3O2SNa [M + Na]+: 236.0464;
found: 236.0463.
The title compound was synthesized according to GP1 from commer-
cially available ethyl 4-chloro-3-oxobutanoate; yield 1.05 g (92%); yel-
lowish transparent oil.
1Н NMR (400 MHz, СDCl3):  = 4.61 (s, 2 H), 4.33 (q, J = 7.1 Hz, 2 H),
1.35 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 184.1, 160.8, 75.9 (C=N2), 62.0, 46.8,
14.3.
Ethyl 4-({2-[(tert-Butoxycarbonyl)amino]ethyl}thio)-2-diazo-3-
oxobutanoate (9)
The title compound was synthesized according to GP2 (reaction time,
2 h) from diazo keto ester 1 and N-Boc-cysteamine; yield: 301 mg
(91%); white solid; mp 49.2–51.6 °C.
1Н NMR (400 MHz, СDCl3):  = 4.95 (br s, 1 H), 4.32 (q, J = 7.1 Hz, 2 H),
3.73 (s, 2 H), 3.35 (br q, J = 6.1 Hz, 2 H), 2.72 (t, J = 6.4 Hz, 2 H), 1.45 (s,
9 H), 1.34 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 187.6, 161.0, 155.7, 79.4, 75.5 (C=N2),
61.7, 39.3, 37.7, 32.4, 28.4, 14.3.
HRMS (ESI +ve): m/z calcd for C13H21N3O5SNa [M + Na]+: 354.1094;
found: 354.1104.
HRMS (ESI +ve): m/z calcd for C6H7ClN2O3Na [M + Na]+: 213.0037;
found: 213.0044.
Methyl 4-Chloro-2-diazo-3-oxopentanoate (6)
The title compound was synthesized according to GP1 from methyl 4-
chloro-3-oxopentanoate;31 yield: 1.07 g (94%); yellowish transparent
oil.
1Н NMR (400 MHz, СDCl3):  = 5.43 (q, J = 6.8 Hz, 1 H), 3.87 (s, 3 H),
1.64 (d, J = 6.8 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 187.2, 160.8, 75.3 (C=N2), 53.6, 52.5,
Ethyl 4H-Benzo[b][1,2,3]triazolo[1,5-d][1,4]thiazine-3-carboxyl-
ate (10)
19.8.
The title compound was synthesized according to GP2 from diazo
keto ester 1 and 2-aminothiophenol; yield: 235 mg (90%); white sol-
id; mp 96.1–97.1 °C (MeOH).
HRMS (ESI +ve): m/z calcd for C6H7ClN2O3Na [M + Na]+: 213.0037;
found: 213.0033.
1Н NMR (400 MHz, СDCl3):  = 8.20 (dd, J = 7.9, 1.3 Hz, 1 H), 7.48 (dd,
J = 7.6, 1.5 Hz, 1 H), 7.39 (td, J = 7.7, 1.6 Hz, 1 H), 7.34 (td, J = 7.6, 1.5
Hz, 1 H), 4.49 (q, J = 7.1 Hz, 2 H), 4.45 (s, 2 H), 1.47 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 161.1, 134.2, 133.3, 132.7, 128.8,
128.3, 127.6, 124.3, 119.5, 61.5, 21.7, 14.3.
Compounds 7–15; General Procedure 2 (GP2)
To a stirred solution of the corresponding -chloro--diazo--keto es-
ter 1 or 6 (1.0 mmol) in MeOH (2 mL) were added -aminothiol hy-
drohalide salt (1.05 mmol) or o-aminothiophenol (1.05 mmol) and
AcONa (2.5 mmol or 1.5 mmol, respectively). The mixture was stirred
at r.t. for 16 h. Solvent was removed under reduced pressure, the resi-
due was diluted with sat. aq NaHCO3 (3 mL), and extracted with EtOAc
HRMS (ESI +ve): m/z calcd for C12H11N3O2SNa [M + Na]+: 284.0464;
found: 284.0463.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

F
D. Dar’in et al.
Paper
Synthesis
Ethyl 7-Fluoro-4H-benzo[b][1,2,3]triazolo[1,5-d][1,4]thiazine-3-
Methyl 4-Methyl-4H-benzo[b][1,2,3]triazolo[1,5-d][1,4]thiazine-
carboxylate (11)
3-carboxylate (15)
The title compound was synthesized according to GP2 from diazo
keto ester 1 and 2-amino-5-fluorothiophenol; yield: 265 mg (95%);
white solid; mp 130.1–130.7 °C (MeOH).
The title compound was synthesized according to GP2 from diazo
keto ester 6 and 2-aminothiophenol; yield: 231 mg (88%); white sol-
id; mp 116.8–118.7 °C (MeOH).
1Н NMR (400 MHz, СDCl3):  = 8.20 (dd, J = 9.0, 5.0 Hz, 1 H), 7.22 (dd,
J = 8.2, 2.7 Hz, 1 H), 7.11 (ddd, J = 8.9, 7.9, 2.7 Hz, 1 H), 4.49 (q, J = 7.1
Hz, 4 H), 4.47 (s, 2 H), 1.47 (t, J = 7.1 Hz, 3 H).
1Н NMR (400 MHz, СDCl3):  = 8.24 (dd, J = 7.9, 1.5 Hz, 1 H), 7.51 (dd,
J = 7.5, 1.5 Hz, 1 H), 7.48–7.32 (m, 2 H), 5.00 (q, J = 7.1 Hz, 1 H), 4.02 (s,
3 H), 1.55 (d, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 161.8 (d, J = 251.8 Hz), 161.0, 134.3,
132.8, 129.1 (d, J = 3.1 Hz), 126.7 (d, J = 9.0 Hz), 121.3 (d, J = 9.1 Hz),
115.3 (d, J = 25.5 Hz), 114.9 (d, J = 23.4 Hz), 61.8, 21.8, 14.3.
13С NMR (101 MHz, СDCl3):  = 161.5, 137.9, 132.6, 131.8, 129.2,
129.0, 127.5, 122.4, 119.2, 52.3, 30.5, 21.6.
HRMS (ESI +ve): m/z calcd for C12H11N3O2SNa [M + Na]+: 284.0464;
found: 284.0459.
HRMS (ESI +ve): m/z calcd for C12H10FN3O2SNa [M + Na]+: 302.0370;
found: 302.0364.
Compounds 19 and 20; General Procedure 3 (GP3)
3-Ethyl 7-Methyl (S)-6,7-Dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]thi-
azine-3,7-dicarboxylate (12)
To a stirred suspension of the corresponding thiosemicarbazide (1.1
mmol) in AcOH (3 mL) were added diazo keto ester 1 (1.0 mmol) and
AcONa (123 mg, 1.5 mmol). The mixture was stirred at r.t. for 48 h.
Solvent was removed under reduced pressure and the residue was di-
luted with sat. aq NaHCO3 (3 mL). Compound 19 was collected by fil-
tration, washed with H2O (2 mL) and 50% aq MeOH (2 mL), and dried
at 70 °C. Compound 20 was extracted with EtOAc (5 × 5 mL) and the
combined extracts were evaporated. The residue was purified by
chromatography on silica gel (n-hexane/acetone, from 5:1 to 3:1).
The title compound was synthesized according to GP2 from diazo
keto ester 1 and L-cysteine methyl ester hydrochloride; yield: 260 mg
(96%); white solid; mp 58.5–60.3 °C.
1Н NMR (400 MHz, СDCl3):  = 5.66 (t, J = 3.8 Hz, 1 H), 4.49–4.40 (m, 2
H), 4.25 (dd, J = 17.9, 1.0 Hz, 1 H), 4.20 (d, J = 17.9 Hz, 1 H), 3.81 (s, 3
H), 3.48 (ddd, J = 14.3, 3.5, 1.0 Hz, 1 H), 3.32 (dd, J = 14.4, 4.0 Hz, 1 H),
1.43 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 167.4, 161.1, 135.1, 134.8, 61.3, 59.2,
53.5, 28.3, 22.7, 14.3.
HRMS (ESI +ve): m/z calcd for C10H13N3O4SNa [M + Na]+: 294.0519;
found: 294.0519.
Ethyl 6-(Phenylamino)-4H-[1,2,3]triazolo[1,5-d][1,3,4]thiadia-
zine-3-carboxylate (19)
The title compound was synthesized according to GP3 from diazo
keto ester 1 and 4-phenylthiosemicarbazide; yield: 233 mg (77%);
pale yellow solid; mp 238.1–240.1 °C (dec.).
1Н NMR (400 MHz, DMSO-d6):  = 10.16 (br s, 1 H), 7.77–7.69 (m, 2
H), 7.44–7.35 (m, 2 H), 7.12 (ddt, J = 8.5, 7.2, 1.1 Hz, 2 H), 4.68 (s, 2 H),
4.34 (q, J = 7.1 Hz, 2 H), 1.34 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, DMSO-d6):  = 160.7, 154.0, 139.5, 131.5, 129.4,
124.3, 124.0, 121.1, 61.1, 21.1, 14.6.
HRMS (ESI +ve): m/z calcd for C13H13N5O2SNa [M + Na]+: 326.0682;
found: 326.0671.
Ethyl (5aR,9aS/5aS,9aR)-5a,6,7,8,9,9a-Hexahydro-4H-ben-
zo[b][1,2,3]triazolo[1,5-d][1,4]thiazine-3-carboxylate (13)
The title compound was synthesized according to GP2 from diazo
keto ester 1 and cis-2-aminocyclohexanethiol hydrobromide;32 yield:
222 mg (83%); white solid; mp 90.0–90.8 °C.
1Н NMR (400 MHz, СDCl3):  = 4.77 (dt, J = 9.9, 3.9 Hz, 1 H), 4.49–4.36
(m, 2 H), 4.26 (d, J = 17.8 Hz, 1 H), 4.13 (d, J = 17.8 Hz, 1 H), 3.54 (q, J =
4.1 Hz, 1 H), 2.47–2.35 (m, 1 H), 2.28–2.19 (m, 1 H), 2.15–1.96 (m, 2
H), 1.77–1.69 (m, 1 H), 1.63–1.48 (m, 3 H), 1.42 (t, J = 7.1 Hz, 3 H).
Ethyl 6-(Pyrrolidin-1-yl)-4H-[1,2,3]triazolo[1,5-d][1,3,4]thiadia-
zine-3-carboxylate (20)
13С NMR (101 MHz, СDCl3):  = 161.4, 134.64, 134.62, 61.1, 59.2, 40.5,
29.7, 29.3, 23.4, 22.4, 21.2, 14.4.
The title compound was synthesized according to GP3 from diazo
keto ester 1 and pyrrolidine-1-carbothiohydrazide;34 yield: 191 mg
(68%); pale yellow solid; mp 171.9–174.4 °C.
HRMS (ESI +ve): m/z calcd for C12H17N3O2SNa [M + Na]+: 290.0934;
found: 290.0929.
1Н NMR (400 MHz, DMSO-d6):  = 4.59 (s, 2 H), 4.32 (q, J = 7.1 Hz, 2
H), 3.60–3.53 (m, 1 H), 1.99–1.90 (m, 4 H), 1.33 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, DMSO-d6):  = 160.8, 155.4, 131.1, 122.9, 61.0,
48.8, 24.9, 21.0, 14.6.
HRMS (ESI +ve): m/z calcd for C11H15N5O2SNa [M + Na]+: 304.0839;
Ethyl 7,7-Dimethyl-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]thi-
azine-3-carboxylate (14)
The title compound was synthesized according to GP2 from diazo
keto ester 1 and 2-amino-2-methyl-1-propanethiol hydrobromide;33
yield 195 mg (81%); colorless viscous oil.
found: 304.0834.
1Н NMR (400 MHz, СDCl3):  = 4.42 (q, J = 7.1 Hz, 2 H), 4.13 (s, 2 H),
2.98 (s, 2 H), 1.82 (s, 6 H), 1.42 (t, J = 7.1 Hz, 3 H).
Sulfones 21 and 22; General Procedure 4 (GP4)
13С NMR (101 MHz, СDCl3):  = 161.5, 135.1, 134.6, 61.0, 59.8, 39.6,
To a solution of compound 7 or 10 (0.5 mmol) in DCM (8 mL) was
added m-CPBA (50% with H2O, 459 mg, 1.3 mmol) and the mixture
was stirred at r.t. for 18 h. To the resulting mixture was added a solu-
tion of NaHCO3 (200 mg) and Na2SO3 (200 mg) in H2O (5 mL) and
stirred vigorously for 1 h. The organic phase was separated, washed
with sat. aq NaHCO3 (5 mL), dried (Na2SO4), and evaporated to dryness
to afford the corresponding sulfone.
28.6, 23.4, 14.4.
HRMS (ESI +ve): m/z calcd for C10H15N3O2SNa [M + Na]+: 264.0777;
found: 264.0775.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

G
D. Dar’in et al.
Paper
Synthesis
Ethyl 6,7-Dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]thiazine-3-carbox-
(8) Shi, L.; Yu, K.; Wang, B. Chem. Commun. 2015, 51, 17277.
ylate 5,5-Dioxide (21)
(9) Li, X. G.; Sun, M.; Jin, Q.; Liu, K.; Liu, P. N. J. Org. Chem. 2016, 81,
3901.
(10) Sun, P.; Gao, S.; Yang, C.; Guo, S.; Lin, A.; Yao, H. Org. Lett. 2016,
18, 6464.
(11) Hou, W.; Xiong, H.; Bai, R.; Xiao, Z.; Su, L.; Ruan, B. H.; Xu, H.
Tetrahedron 2019, 75, 4005.
(12) Lade, D. M.; Aher, Y. N.; Pawar, A. B. J. Org. Chem. 2019, 84, 9188.
(13) Liu, Y.; Hu, Y.; Lv, G.; Nie, R.; Peng, Y.; Zhang, C.; Lv, S.; Hai, L.;
Wang, H.; Wu, Y. ACS Sustainable Chem. Eng. 2019, 7, 13425.
(14) Shi, B.; Blake, A. J.; Lewis, W.; Campbell, I. B.; Judkins, B. D.;
Moody, C. J. J. Org. Chem. 2010, 75, 152.
The title compound was synthesized according to GP4 from com-
pound 7; yield: 110 mg (90%); white solid; mp 148.4–150.2 °C.
1Н NMR (400 MHz, СDCl3):  = 5.13–5.05 (m, 2 H), 4.74 (s, 2 H), 4.44
(q, J = 7.1 Hz, 2 H), 3.68–3.60 (m, 2 H), 1.43 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 160.3, 137.6, 132.1, 61.8, 48.7, 47.2,
46.0, 14.3.
HRMS (ESI +ve): m/z calcd for C8H11N3O4SNa [M + Na]+: 268.0362;
found: 268.0360.
(15) Wang, Y.; Zhu, S. Tetrahedron 2001, 57, 3383.
(16) Smetanin, I. A.; Novikov, M. S.; Rostovskii, N. V.; Khlebnikov, A.
F.; Starova, G. L.; Yufit, D. S. Tetrahedron 2015, 71, 4616.
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sis 2005, 2234.
(18) Ila, H.; Acharya, A.; Peruncheralathan, S. Chapter 4 In Domino
Reactions: Concepts for Efficient Organic Synthesis, 1st ed; Tietze,
L. F., Ed.; Wiley-VCH: Weinheim, 2014, Chap. 4.
(19) Safrygin, A.; Dar’in, D.; Kantin, G.; Krasavin, M. Eur. J. Org. Chem.
2019, 4721.
Ethyl 4H-Benzo[b][1,2,3]triazolo[1,5-d][1,4]thiazine-3-carboxyl-
ate 5,5-Dioxide (22)
The title compound was synthesized according to GP4 from com-
pound 10; yield: 139 mg (95%); white solid; mp 158.3–160.1 °C.
1Н NMR (400 MHz, СDCl3):  = 8.42 (dd, J = 8.2, 0.8 Hz, 1 H), 8.11 (dd,
J = 7.9, 1.3 Hz, 1 H), 7.94–7.87 (m, 1 H), 7.71 (td, J = 7.8, 1.0 Hz, 1 H),
5.05 (s, 2 H), 4.52 (q, J = 7.1 Hz, 2 H), 1.49 (t, J = 7.1 Hz, 3 H).
13С NMR (101 MHz, СDCl3):  = 160.2, 138.5, 135.3, 132.5, 130.6,
129.7, 127.3, 124.9, 119.8, 62.1, 47.8, 14.3.
(20) Costin, T. A.; Dutra, L. G.; Bortoluzzi, A. G.; Sa, M. M. Tetrahedron
2017, 73, 4549.
HRMS (ESI +ve): m/z calcd for C12H11N3O4SNa [M + Na]+: 316.0362;
found: 316.0362.
(21) (a) Dabak, K.; Akar, A. Heterocycl. Commun. 2002, 8, 61.
(b) Dabak, K.; Akar, A. Heterocycl. Commun. 2002, 8, 385.
(22) Kawai, R.; Yamanouchi, M.; Saku, O.; Nakagawa, H.; Nakoji, M.;
Kubo, K. PCT Int. Appl WO 2013180128, 2013; Chem. Abstr.
2013, 160, 53747
(23) Foley, M. A. C.; Kuntz, K. W.; Mills, J. E. J.; Mitchell, L. H.;
Munchhof, M. J.; Harvey, D. M. PCT Int. Appl WO2016040505,
2016; Chem. Abstr. 2016, 164, 412324.
Funding Information
This research was supported by the Russian Science Foundation (proj-
ect grant 19-75-30008). The authors declare no competing financial
interest.
R
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si
a
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S
c
i
e
n
c
e
F
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n
d
ati
o
n
(19-75-3
0
0
0
8)
(24) Bischoff, A.; Subramanya, H.; Sundaresan, K.; Sammeta, S. R.;
Vaka, A. K. US Pat. Appl 20100160323, 2010; Chem. Abstr. 2010,
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Acknowledgment
(25) Dabak, K.; Sezer, O.; Akar, A.; Anac, O. Eur. J. Med. Chem. 2003,
38, 215.
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Richard-Bildstein, S.; Yuan, S. PCT Int. Appl WO 2018019929,
2018; Chem. Abstr. 2018, 168, 232762
We thank the Research Centre for Magnetic Resonance, the Center for
Chemical Analysis and Materials Research, and the Centre for X-ray
Diffraction Methods of Saint Petersburg State University Research
Park for obtaining the analytical data.
(27) CCDC 1923038 (7), 1923037 (12), 1923039 (13), and 1923040
(19) contain the supplementary crystallographic data for this
paper. The data can be obtained free of charge from The
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690802. Experimental procedures,
analytical data, copies of the 1H and 13C NMR spectra, and X-ray crys-
Cambridge
www.ccdc.cam.ac.uk/getstructures.
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Sabbatini, F. M. PCT Int. Appl WO2011151361, 2011; Chem.
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Data
Centre
via
tallographic data are included.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G