Dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide–a new cyclic ketomethylenic reagent for the Dimroth-type 1,2,3-triazole synthesis

Article abstract of DOI:10.1080/00397911.2020.1757113

A series of 1,5,6,7-tetrahydrothiopyrano[2,3-d][1,2,3]triazole 4,4-dioxides, new triazole-based bicyclic ring system, were prepared via base-mediated click reaction of organic azides with the readily available dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide. The reaction proceeded at room temperature in 5-12 h with catalysis by base-solvent system K₂CO₃/DMSO. High purity products were isolated by simple filtration and no formation of side products was observed. The key structure was confirmed by an X-ray study.

Full text of DOI:10.1080/00397911.2020.1757113

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Dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide –
a new cyclic ketomethylenic reagent for the
Dimroth-type 1,2,3-triazole synthesis
Nazariy T. Pokhodylo, Mykola A. Tupychak & Vitalii A. Palchykov
To cite this article: Nazariy T. Pokhodylo, Mykola A. Tupychak & Vitalii A. Palchykov (2020):
Dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide – a new cyclic ketomethylenic reagent for the Dimroth-
type 1,2,3-triazole synthesis, Synthetic Communications, DOI: 10.1080/00397911.2020.1757113
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1757113
Dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide – a new cyclic
ketomethylenic reagent for the Dimroth-type 1,2,3-
triazole synthesis
Nazariy T. Pokhodyloa , Mykola A. Tupychaka , and Vitalii A. Palchykovb,c
b
aDepartment of Organic Chemistry, Ivan Franko National University of Lviv, Lviv, Ukraine; Research
Institute of Chemistry and Geology, Oles Honchar Dnipro National University, Dnipro, Ukraine;
cDepartment of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA
ABSTRACT
ARTICLE HISTORY
Received 18 February 2020
A series of 1,5,6,7-tetrahydrothiopyrano[2,3-d][1,2,3]triazole 4,4-diox-
ides, new triazole-based bicyclic ring system, were prepared via
base-mediated click reaction of organic azides with the readily avail-
able dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide. The reaction pro-
ceeded at room temperature in 5-12 h with catalysis by base-solvent
system K2CO3/DMSO. High purity products were isolated by simple
filtration and no formation of side products was observed. The key
structure was confirmed by an X-ray study.
KEYWORDS
Azide; click reaction;
thiopyranone; 1,2,3-
triazoles; sulfone
GRAPHICAL ABSTRACT
Introduction
The reaction of azides with activated ketomethylenic compounds is an efficient and con-
venient method for the preparation of 1H-1,2,3-triazole derivatives and, due to the
introduction of protocols that meet the requirements of click chemistry, this type of
reactions is currently in focus.[1] A large number of organic azides, including highly
reactive electron-withdrawing azides such as unique perfluoroalkyl azides[2] or electron-
deficient aromatic azides (azidofurazans,[3] 2-azidothiazoles,[4] 2-azidothiadiazole,[5] 2-
and 4-azidopyrimidines,[6] 3-azido-1,2,4-triazine,[7] azido-1,3,5-triazines[8]), are used in
the reaction due to new modified protocols. At the same time, new ketomethylenic
compounds activated with the nitro,[2] sulfonyl,[9] phosphonate moiety[10] or electron-
deficient aromatic ring[11] were applied in the Dimroth reaction in addition to the
widely studied b-ketoesters, b-diketones and derivatives of cyanoacetic acid[12] enlarging
the scope of reaction application.
CONTACT Nazariy T. Pokhodylo
pokhodylo@gmail.com
Department of Organic Chemistry, Ivan Franko National
University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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N. T. POKHODYLO ET AL.
While the Dimroth reaction is a well-researched subject area, some of its aspects (the
recently discovered atypical attack of the azido group on the ester group instead of the
keto group in b-ketoesters,[13] the regiocontrol of the reaction in case of asymmetric
b-ketones, which is currently provided only when one of the diketone substituents is tri-
fluoromethyl,[14] competing aromatization of intermediate triazolines,[10a] or the Regitz
diazotransfer as side reaction[12]) are still studied insufficiently limiting a wide use of
this reaction. Among the aforementioned reaction limitations, the competitive diazo
transfer reaction is the most common and is always expected as a side process for cyclo-
condensation. The main reasons for the diazo transfer are: an anion asynchronous
mechanism; high acidity of the methylene proton; high basicity of the internal nitrogen
atom in intermediate triazine; low azide nucleophilicity (azides with an electron-with-
drawing group); sterically hindered or conformationally restricted keto group.
In most cases, the side diazocompounds were found in the reactions of azides with cyclic
b-diketones: dimedon, cyclohexanedione or 1,3-indandione, which had high CH-acidity and
were conformationally restricted complicating an attack of azide on the carbonyl atom.[15]
However, it was found that 6,7-dihydro-1H-benzo[d][1,2,3]triazole-4(5H)-ones could be
obtained with high yields via cyclization of azides to substituted cyclohexane-1,3-diones
using mild bases, such as triethylamine in catalytic amounts,[16] anhydrous magnesium car-
bonate in ethanol (T ¼ 20ꢀC, 8 h),[3a] 1,1,3,3-tetramethylguanidine (TMG) in ethanol at
30ꢀC[17] or DBU in PEG-400 at 80ꢀC.[18] Other cyclic ketomethylenic compounds remain
insufficiently studied. Ones of such reagents of practical interest is cyclic b-sulfoketone. It is
noteworthy that 4-(arylsulfonyl)-1-aryl-5-methyl-1H-1,2,3-triazoles, namely 4-((4-(tert-
butyl)phenyl)sulfonyl)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole, were found
recently to be highly active pregnane X receptor modulators in the treatment of a disorder
of uncontrolled cellular proliferation, such as cancer.[9d,e] Due to the concept of the lead-ori-
ented synthesis and the increasing interest to conformationally restricted structures, enno-
bling of sulfonytriazole scaffold with (CH2)n-bridge might induce the biological activity of
screening compounds. However, cyclic b-sulfoketones in the Dimroth-type reaction were
not studied. Given the fact that the sulfonyl group is much larger than the keto group, it can
create steric hindrance for the reaction to be realized as synchronous [3þ 2] cycloaddition
and, as noted above, due to the significant CH-acidity of b-sulfoketone can lead to diazo
transfer. Previously, b-sulfoketones have been commonly implemented in the Michael reac-
tion. For example, dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide has been used for creation
of small libraries of new bicyclic systems, bearing a thiopyran-S,S-dioxide motif, via the
base-catalyzed domino Knoevenagel–Michael-heterocyclization and demonstrated excellent
reactivity as CH-acid.[19] Taking into account the above facts, cyclic b-sulfoketones were
selected for the Dimroth-type 1,2,3-triazole synthesis as potential reagents for creating com-
binatorial libraries of new triazole derivatives and screening them for anticancer activity.[20]
Results and discussion
In this work, the cyclic ketones: dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide 1a,[21]
dihydrothiophen-3(2H)-one 1,1-dioxide 1b and benzo[e][1,2]oxathiin-4(3H)-one 2,2-
dioxide 1c,[22] in which the sulfone group in structural COCH2SO2 moiety served as the

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Figure 1. Selected cyclic b-sulfoketones.
Scheme 1. Previously used and proposed reagents for 4-sulfonyl-1H-1,2,3-triazoles preparation
methylene group ketomethylenic activator (Figure 1), were studied in the Dimroth-type
1,2,3-triazole synthesis.
Previously, we have found that reactions of arylsulfoacetones and arylsulfoacetoni-
triles with azides rapidly occurred in the MeONa/MeOH and led to 4-sulfonyl-1H-1,2,3-
triazoles in good or high yields at room temperature or after a brief heating and
without the formation of side products (Scheme 1).[9a] Moreover, in case of sulfoaceto-
nitrile, the reaction occurs at the time of mixing the reagents. Arylsulfoacetones reacts
slower at room temperature. The conversion of azide to triazole ended within a few
minutes at a heating or in 1 hour at room temperature depending on the substituent
in arylazide.
Based on the results of previous studies on base-mediated azides condensation reac-
tions,[10a,13] the 4-fluorophenylazide 2 was selected for optimization studies for this
cyclocondensation with dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide 1a in five base-
solvent system protocols (Table 1). All optimization experiments were performed at
room temperature (approx. 20 ꢀC) as required by click chemistry.[23] We found that the
base-solvent system sufficiently affects the yields of triazole and side diazo transfer
products formation. In MeONa/MeOH system, diazo transfer was indicated via forma-
tion of 4-flouroaniline 4 as the main reaction and no 1,2,3-triazole 3a formation was
observed. Tertiary amines, such as triethylamine in MeOH, led to the formation of
1,2,3-triazole 3a with very low yield (up to 5%) after 12 h. Pyrrolidine/THF

4
N. T. POKHODYLO ET AL.
Table 1. Optimization of the reaction conditions: effect of solvent and base.
Triazole 3
Aniline 4
Entry
Base/Solvent
MeONa/MeOH
Et3N/MeOH
Pyrrolidine/THF
DBU/THF
Time, h
yield, %a,b
yield, %a,b
1
2
3
4
5
12
12
12
1
–
5
29
48
87
56
–
–
19
–
K2CO3/DMSO
7
aIsolated yields are given.
bProducts determined by LC MS/APCI.
Scheme 2. Concurrent paths of triazole formation (A) vs. diazotransfer (B). Main factors.
demonstrated comparable catalytic activity to triethylamine providing the formation of
triazole 3a in 29% after 12 h. The 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) significantly
increase the reaction and 48% of azide 2a were converted into 1,2,3-triazole 3a after 1 h,
but more than 19% of 4-flouroaniline 4 were also found in the reaction medium. On
the contrary, in the system of K2CO3/DMSO, the reaction of dihydro-2H-thiopyran-3
(4H)-one 1,1-dioxide 1a occurs with the formation of triazole 3a in high yield after 7 h.
It is plausible to assume that K2CO3 acts not only as a base but also as a dehydrating
agent accelerates the water elimination in intermediate triazoline creating what gives an
advantage over other bases. It should be noted that the K2CO3/DMSO system was pre-
viously effective for electron-withdrawing azides[5] and sterically hindered azides.[24] On
the other hand, the cyclic dihydrothiophen-3(2H)-one 1,1-dioxide 1b and ben-
zo[e][1,2]oxathiin-4(3H)-one 2,2-dioxide 1c did not yield target triazoles under any of
the tested for dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide 1a conditions.
According to the reaction mechanism, probably, the limiting stage - the formation of
a cyclic transition state in cases of strained conformations and low reacted aromatic
ketone, becomes energetically unprofitable. The concurrent paths of the Dimroth and
Regitz reactions can be represented by the following scheme (Scheme 2).
We used a wide range of azides 2 with substituents of different nature to validate the
K2CO3/DMSO protocol. It was found that in all cases (Entry 1-7, Table 2) triazole 3

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Table 2. 1,5,6,7-Tetrahydrothiopyrano[2,3-d][1,2,3]triazole 4,4-dioxides.
Entry
R
Time, h
Yield of 3, %a
1.
2.
3.
4.
5.
6.
4-FC6H4 (a)
3-ClC6H4 (b)
3-CF3C6H4 (c)
3-NO2C6H4 (d)
4-NO2C6H4 (e)
7
7
5
5
5
87
83
92
90
91
77
10
O
O
(f)
Bn (g)
7.
12
71
aIsolated yields are given.
Figure 2. The molecular structure of 1-(3-chlorophenyl)-1,5,6,7-tetrahydrothiopyrano[2,3-d][1,2,3]tri-
azole 4,4-dioxide (3 b) with displacement ellipsoids drawn at the 50% probability level. Selected bond
distances: S1–C1 1.7439(18) Å, S1–C5 1.770(2) Å, S1–O1 1.4376(14) Å, S1–O2 1.4418(14) Å, C2–C3
1.489(3) Å, N1–C6 1.431(2) Å.
was the only product and no side products of the diazotransfer (4, 5) were observed.
Moreover, the yield of triazoles from azides 2c–e containing nitro and trifluoromethyl
was the highest. The procedure was also tolerant to the furan ring in 6-azidoisobenzo-
furan-1(3H)-one 2f,[25] but the triazole yield was slightly lower. The lowest yield was in
case of benzyl azide 2g, but no side products were isolated here.
The structure of compound 3b was also proven by a single crystal X-ray diffraction
analysis, the molecular drawing of which is shown in Figure 2. Single crystals of 1-(3-
chlorophenyl)-1,5,6,7-tetrahydrothiopyrano[2,3-d][1,2,3]triazole 4,4-dioxide (3b) were
obtained by slow dilution with water of the compound solution in DMSO. The com-
pound 3b crystallizes in the monoclinic space group P21/c with one triazole molecule in
the asymmetric unit. The 3-chlorophenyl and triazole rings are twisted relative to each
other by 45.3(2)ꢀ. The tetrahydrothiopyran ring has a synclinal conformation relative to

6
N. T. POKHODYLO ET AL.
the C3–C4 and C4–C5 bonds. The C2–C3–C4–C5 and C3–C4–C5–S1torsion angles are
ꢁ53.6(2)ꢀ and 68.17(19)ꢀ, respectively.
Conclusion
Thus, it is shown that dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide is a promising
building block for the synthesis of triazole via the Dimroth reaction. Base solvent system
K2CO3/DMSO allowed the annulation of triazole in a high yield which is an efficient
route to new bicyclic thiopyrano[2,3-d][1,2,3]triazoles in one step and this is the first
example of such a system. Results of the current study can be used both for the synthe-
sis of polycyclic triazoles and evaluation of their biological activity.
Experimental
1H and 13C NMR spectra were recorded on Varian Unity Plus 400 (400 and 101 MHz,
respectively) and Bruker 170 Avance 500 (500 and 126 MHz, respectively) spectrometers
in DMSO-d6 solutions using TMS or the deuterated solvent as internal reference. Mass
spectral analyses were performed using an Agilent 1100 series LC/MSD with API-ES/
APCI mode (200 eV). Elemental analyses were accomplished using a Carlo Erba 1106
instrument. Melting points were determined on a Boetius melting point apparatus.
Synthesis of 1-aryl-1,5,6,7-tetrahydrothiopyrano[2,3-d][1,2,3]triazole 4,4-dioxide 3
(general procedure)
Potassium carbonate 2.8 g (0.02 mol) was added with vigorous stirring to a solution of
azide 2 (0.01 mol) and dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide 1 (1.5 g, 0.01 mol)
in 5 mL of DMSO. The mixture was stirred at room temperature for 5-12 h (see Table
2) (the consumption of the starting azide was monitored by TLC) and diluted with
25 mL of water, and the precipitate was filtered off.
1-(4-Fluorophenyl)-1,5,6,7-tetrahydrothiopyrano[2,3-d][1,2,3]triazole 4,4-dioxide (3a)
1
Yield: 87% as a white solid; mp 238–239ꢀ‘; H NMR (400 MHz, DMSO-d6) d 8.02–7.67
(m, 2H), 7.65–7.24 (m, 2H), 3.78–3.44 (m, 2H), 3.15–2.76 (m, 2H), 2.53–2.18 (m, 2H).
1
13C NMR (126 MHz, DMSO-d6) d 161.06 (d, JC–F¼257.9 Hz), 143.29 (Ctriazole-4),
3
139.40 (Ctriazole-5), 131.96 (CAr-1), 127.57 (d, JC–F ¼ 9.0 Hz, 2xCHAr-2,6), 117.40 (d,
2JC–F ¼ 22.7 Hz, 2xCHAr-3,5), 52.01 (CH2), 21.45 (CH2), 20.98 (CH2); MS (m/z, APCI)
469.0 (Mþ þ 1); Anal. calcd for C11H10FN3O2S: C, 49.43; H, 3.77; N, 15.72. Found: C,
49.49; H, 3.71; N, 15.78.
Single crystal X-ray diffraction study of compound 3 b
Diffraction data for compound 3b were collected on an Agilent Gemini A four-circle
diffractometer equipped with an Atlas CCD detector with MoKa radiation
(k ¼ 0.71073 Å). The collected diffraction data were processed with the CrysAlis PRO
program.[26] The structure was solved by ShelXT and refined by least squares method

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7
on F2 by ShelXL software with the following graphical user interface of OLEX2.[27]
Atomic displacements for non-hydrogen atoms were refined using an anisotropic
model. Hydrogen atoms were situated on geometrically calculated positions and refined
as riding atoms with relative isotropic displacement parameters. The complete crystallo-
graphic dataset was deposited at the Cambridge Crystallographic Data Center (deposit
CCDC 1983912).
Acknowledgment
The authors thank Dr Evgeny Goreshnik (Department of Inorganic Chemistry and Technology,
Jozef Stefan Institute) and Dr Yuriy Slyvka (Department of Inorganic Chemistry, Ivan Franko
National University of Lviv) for X-ray crystallographic analysis.
Funding
The authors thank the Ministry of Education and Science of Ukraine for financial support of this
project [grants 0118U003610 and 0119U100724].
ORCID
Nazariy T. Pokhodylo
Mykola A. Tupychak
Vitalii A. Palchykov
http://orcid.org/0000-0001-8222-5008
http://orcid.org/0000-0002-9880-0983
http://orcid.org/0000-0003-3748-4566
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