Water/Alkali-Catalyzed Reactions of Azides with 2-Cyanothioacetamides. Eco-Friendly Synthesis of Monocyclic and Bicyclic 1,2,3-Thiadiazole-4-carbimidamides and 5-Amino-1,2,3-triazole-4-carbothioamides

Article abstract of DOI:10.1021/acs.joc.9b01599

The reactions of thioamides with azides in water were studied. It was reliably shown that the reaction of 2-cyanothioacetamides 1 with various types of azides 2 in water in the presence of alkali presents an efficient, general, one-step, atom-economic, and eco-friendly method for the synthesis of 1,2,3-thiadiazol-4-carbimidamides 5 and 1,2,3-triazole-4-carbothioamides 4. This method can be extended to the one-pot reaction of sulfonyl chlorides and 6-chloropyrimidines 2′o with sodium azide, leading to final products in higher yields, that is, avoiding the isolation of unsafe sulfonyl azides. The method was furthermore applied to the reaction of N,N′-bis-(2-cyanothiocarbonyl)pyrazine 1h with sulfonyl azides to afford bicyclic 1,2,3-thiadiazoles 8 and 1,2,3-triazoles 9 connected via a 1,1′-piperazinyl linker. 2-Cyanothioacetamides 1 were also shown to react with aromatic azides in water in the presence of alkali to afford 1-aryl-5-amino-1,2,3-triazole-4-carbothioamides 11. In contrast to aromatic azides and similarly to sulfonyl azides, 6-azidopyrimidine-2,4-diones 2o-q react with cyanothioacetamides to form N-pyrimidin-6-yl-5-dialkylamino-1,2,3-thiadiazole-4-N-l-carbimidamides 12. A mechanism was proposed to rationalize the role of water in changing the reactivity of azides toward 2-cyanothioacetamides.

Full text of DOI:10.1021/acs.joc.9b01599

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Article
Water/alkali-catalyzed reactions of azides with 2-cyanothioacetamides.
Eco-friendly synthesis of monocyclic and bicyclic 1,2,3-thiadiazole-4-
carbimidamides and 5-amino-1,2,3-triazole-4-carbothioamides
Valeriy O. Filimonov, Lidia N. Dianova, Tetyana V. Beryozkina, Dmitrii Mazur, Nikolai A. Beliaev,
Natalia N. Volkova, Vladimir G. Ilkin, Wim Dehaen, Albert T. Lebedev, and Vasiliy A. Bakulev
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01599 • Publication Date (Web): 24 Sep 2019
Downloaded from pubs.acs.org on September 28, 2019
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Water/alkali-catalyzed reactions of azides with 2-cyanothioacetamides. Eco-friendly
synthesis of monocyclic and bicyclic 1,2,3-thiadiazole-4-carbimidamides and 5-amino-1,2,3-
triazole-4-carbothioamides
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Valeriy O. Filimonov,† Lidia N. Dianova,† Tetyana V. Beryozkina,† Dmitrii Mazur,‡ Nikolai A.
Beliaev,† Natalia N. Volkova,† Vladimir G. Ilkin,† Wim Dehaen,§ Albert T. Lebedev,‡ Vasiliy A.
Bakulev†*
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†Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira st.,
Yekaterinburg 620002, Russia
‡Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia
§Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F,
B-3001 Leuven, Belgium
*E-mail: v.a.bakulev@urfu.ru
Graphical abstract
Abstract. The reactions of thioamides with azides in water were studied. It was reliably
shown that the reaction of 2-cyanothioacetamides 1 with various types of azides 2 in water in the
presence of alkali presents an efficient, general, one-step, atom economic, eco-friendly method
for the synthesis of 1,2,3-thiadiazol-4-carbimidamides 5 and 1,2,3-triazole-4-carbothioamides 4.
This method can be extended to the one pot reaction of sulfonyl chlorides and 6-
chloropyrimidines 2'o with sodium azide leading to final products in higher yields, i.e. avoiding
the isolation of unsafe sulfnyl azides. The method was furthermore applied to the reaction of
N,N'-bis-(2-cyanothiocarbonyl)pyrazine 1h with sulfonyl azides to afford bicyclic 1,2,3-
thiadiazoles 8 and 1,2,3-triazoles 9 connected via 1,1′-piperazinyl linker. 2-Cyanothioacetamides
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1 were also shown to react with aromatic azides in water in the presence of alkali to afford 1-
aryl-5-amino-1,2,3-triazole-4-carbothioamides 11. In contrast to aromatic azides and similarly to
sulfonyl azides, 6-azidopyrimidine-2,4-diones 2o-q react with cyanothioacetamides to form N-
pyrimidin-6-yl-5-dialkylamino-1,2,3-thiadiazole-4-N-l-carbimidamides 12. A mechanism was
proposed to rationalize the role of water in changing the reactivity of azides towards 2-
cyanothioacetamides.
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Introduction
Thioamides are of interest for medicinal chemistry as compounds with various biological
activities1 and for organic chemistry, as building blocks2,3 and ligands of substances used in
catalytic processes.4 Among the class of thioamides, 2-cyanothioacetamide 1, bearing several
nucleophilic and electrophilic centers, has found wide application in the synthesis of a huge
variety of sulfur- and nitrogen-containing heterocycles including monocyclic, fused and linearly
connected polycyclic compounds, as well as valuable acyclic compounds.2a To compare the
reactivity of the cyano and thioamide functions we turned our attention to reactions of 2-
cyanothioacetamide derivatives 1 with azides leading to various substituted 1,2,3-thiadiazoles5
and 1,2,3-triazoles.6 These two particular classes of heterocycles have found application in
modern organic synthesis,7 in medicinal8c,d,9 and analytical chemistry10 due to various types of
bioactivity8 as well as capacity to undergo rearrangements and transformations11 to form other
organic compounds. Earlier we have studied the reaction of 2-cyanothioacetamides 1 with
sulfonylazides 2 (Scheme 1)5b and found the appropriate conditions for the synthesis of 4-cyano-
1,2,3-thiadiazoles 3 and sodium salts of 5-sulfonamido-1,2,3-triazole-4-carbothioamides 4. The
latter were shown to rearrange to 5-cycloamino-1,2,3-thiadiazole-4-carbimidamides 5 after being
treated with dilute hydrochloric acid, representing the last stage of a two-step synthesis of
thiadiazoles 4 as a result of the reaction of 2-cyanothioacetamides with sulfonyl azides.5b It is
worth mentioning that the described above transformations of triazoles 4 and thiadiazoles 5 were
observed in electrospray ionization conditions in the gas phase as well.11c However, this method
of preparation of 1,2,3-triazoles or 1,2,3-thiadiazoles has only a narrow scope, being limited to
arylsulfonyl azides with electron-releasing groups. The method failed for the synthesis of bis-
1,2,3-triazoles and bis-1,2,3-thiadiazoles. Furthermore, the reactions of alkylsulfonyl azides with
2-cyanothioacetamides led to 5-amino-1,2,3-thiadiazole-4-carbonitriles 3 which could not be
transformed to the desired 1,2,3-thiadiazole-4-(N-sulfonyl)carbimidamides 5 (Scheme 1). The
low stability of the sodium salts of 5-sulfonamido-1,2,3-triazole-4-carbothioamides and the need
for a large excess of sodium ethoxide are additional drawbacks of this protocol. It is worth noting
that N-sulfonyl- and heteroarylamidines are of interest for medicinal chemistry since osteoclast
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differentiation inhibitors, anti-resorptive agents,12 dopamine transport inhibitors13 and inhibitors
of casein kinases14 are found among N-sulfonylamidines. Therefore, it is worthwhile to elaborate
a more general, effective and eco-friendly method for the synthesis of variously substituted
monocyclic and bicyclic N-sulfonylamidines of 1,2,3-thiadiazole-4-carboxylic acid.
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In this report reactions of azides with thioamides were studied in water and it has been shown
that application of water as a solvent and alkali as a base essentially expands the scope of
reaction of sulfonyl azides with 2-cyanothioacetamides, providing unlimited access to N-
sulfonyl- and heteroaryl 5-amino-1,2,3-thiadiazol-4-carbimidamides 5, 12 including bis-1,2,3-
thiadiazoles 8 and bis-1,2,3-triazoles 9 unavailable by reactions in other solvents (Scheme 1).
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Scheme 1. Reactions of Thioamides with Sulfonyl, Heteroaryl and Aryl Azidesa
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aERG = electron releasing group
Results and Discussion
To elaborate an efficient, general, one-step, atom economic, transition-metal-free and eco-
friendly method for the synthesis of 5-cycloalkylamino-1,2,3-thiadiazole-4-carbimidamides we
have carefully studied the reactions of thioamides 1a,b and azides 2a,b in various solvents
(Scheme 2).
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Scheme 2. The Structures of Starting Reagents Used in This Study
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Earlier it has been demonstrated that reaction of pyrrolidine-2-cyanothioacetamide 1a with mesyl
azide (2a) in various organic solvents in the presence of organic or inorganic bases in the
temperature range from -10 °C to +25 °C leads to selective formation of 5-pyrrolidino-1,2,3-
thiadiazole-4-carbonitrile 3a in good yield5b (Table 1, Entry 1). We have discovered now that
when the reaction was carried out in water at room temperature in the presence of sodium alkali,
another type of product, 5-pyrrolidino-1,2,3-thiadiazole-4-(N-sulfonyl)carbimidamide 5 is
obtained as a major product and 5-pyrrolidino-1,2,3-thiadiazole-4-carbonitrile 3 as a minor
product. Thus, we have focused our efforts on the optimization of conditions for the selective
synthesis of 1,2,3-thiadiazoles 5 using 2-cyanothioacetamide 1a and azide 2a as starting
reagents. For this purpose, we have first varied the reaction temperature and then the amount of
base. We have also checked the optimal parameters suitable for other representative starting
reagents, such as morpholine thioamide 1b and 4-nitrophenylsulfonyl azide 2c (Table 1, Entries
8‒11).
Table 1. Optimizations of the Reaction Conditions for Reaction of 1a,b with 2a-c,ja
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Entry
NR1R2
R3
Ratio
1:2
Base
(equiv)
EtONa (5) EtOH
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (1)
NaOH (2)
NaOH (1)
Solvent T, Ratio3:5 Yield of
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°C
0
23
13
0
0
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0
0
5 (%)b
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pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
morpholine
Me
Me
Me
Me
Me
Me
Me
Et
1: 1
1: 1
1: 1
1: 1
1: 2
2:1
100:0
30:70
20:80
5:95
5:95
5:95
0 (5a)
60 (5a)
66 (5a)
74 (5a)
70 (5a)
70 (5a)
68 (5a)
80 (5b)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
1:1
1:1
7:93
7:93
4-NO2C6H4
4-NO2C6H4
Me
1: 1
1: 1
1: 1
1: 1
1:1
EtONa (5) EtOH
0
no products isolated
NaOH (1)
NaOH (1)
NaOH (1)
NaOH
(1.5)
NaOH
H2O
H2O
H2O
H2O
0
0
0
0
5: 95
5:95
12:88
7:93
80 (5c)
80 (5e)
70 (5h)
79 (5h)
morpholine 2-CF3OC6H4
morpholine 2-CF3OC6H4
14
morpholine 2-CF3OC6H4
1:1
H2O
0
7:93
77 (5h)
(1.8)
a 1.0 mmol of each reagent was used in an atmosphere of air, solvent (4 mL)
b before crystallization with impurity of 3
The reaction was completed at room temperature for 3 h when the ratio of starting compounds 1a
and 2a was 1:1 to form a mixture of compounds 3a and 5a in ratio 30:70 (Table 1, Entry 2). The
decrease of the temperature to 13 °C and then to 0 °C leads to a change of the ratio of the
products in favor of compound 5 (Table 1, Entries 3, 4). The ratio of starting reagents 1:1 was
used in all further experiments because when the initial ratio of 1a and 2a was 1:2 or 2:1 the ratio
of the resulting products 3a and 5a remained unchanged while the yield of compound 5a was
lower (Table 1, Entries 5, 6). Increasing the amount of alkali decreases the yield of 1,2,3-
thiadiazole 5 (Table 1, Entries 6, 7). Reactions of azide 2b with thioamide 1a, azide 2c with 1a
and thioamide 1b with azide 2a, when carried out in water at 0 °C in the presence of sodium
hydroxide, affords compounds 5b,c,e in good yield (Entry 8, 10, 11). The pure compounds 5a-
c,e were prepared in 69‒85% yield after crystallization from ethyl acetate (Scheme 3). Thus, the
optimal conditions for the synthesis of 1,2,3-thiadiazole 5a include the use of thioamide 1a and
azide 2a in ratio 1:1, water as a solvent and 1.0 equiv. of sodium hydroxide at 0 °C. Optimal
conditions for the synthesis of 1,2,3-thiadiazole 5h involves the use of 1.5 equiv. of sodium
hydroxide (Entries 12-14). It is worth noting that in the reaction of thioamide 1a with 4-
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nitrophenylsulfonyl azide (2c) in ethanol in the presence of sodium ethoxide no product was
isolated apart from an unidentified tar (Table 1, Entry 9).
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With optimal conditions in hand we have prepared a series of 18 new 1,2,3-thiadiazoles 5 that
could not be prepared by the known methods (Scheme 3).5b
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Scheme 3. Synthesis of 1,2,3-Thiadiazoles 5 and Triazoles 4a
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a
Isolated yield. Reaction conditions for compounds 5: 1 (2.0 mmol), 2 (2.0 mmol), NaOH (2.0
mmol or 3.0 mmol (for 5d,h,i)), H2O (5 mL), 0 °C, 3 h. Reaction conditions for compounds 4: 5
(0.50 mmol), EtONa (2.5 mmol), EtOH (2 mL), 23 °C, 1 h
It is worth noting that reactions of thioamides 1 with arylsulfonyl azides with electron-releasing
substituents take place at slower rate. Thus, these experiments were carried out at 23 °C. In
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contrast to reactions of mesyl azide 2a with 2-cyanothioacetamides 1 in ethanol in the presence
of sodium ethoxide, where the formation of 5-cycloamino-1,2,3-thiadiazole-4-carbonitriles 3
took place, the reaction in water in the presence of sodium hydroxide was leading to 1,2,3-
thiadiazoles 5a,e,j in 70‒85% yields (Scheme 3). The reactions of ethylsulfonyl azide (2b) occur
similarly to furnish thiadiazoles 5b,f,k,n. Obviously, the protocol of the synthesis of 1,2,3-
thiadiazoles 5 using water and sodium hydroxide has a broad scope. Furthermore, while
reactions of 4-nitrophenylsulfonyl (2c) and 2,4-dimethylphenylsulfonyl (2e) azides with
thioamides 1a-d in ethanol/sodium ethoxide lead to a mixture of many compounds, in water they
lead exclusively to thiadiazoles 5c,g,l,m,o. In addition, we managed to carry out the same
reaction with sulfonyl azides 2d,f,g and thioamides 1e-g bearing 4-benzylpiperidine and
dialkylamino groups and reactions of thioamides 1a,b with ortho- and meta-substituted
arylsulfonyl azides 2j,k thus expanding the scope of the reaction even further. We have shown
that 1,2,3-thiadiazoles 5a-c,e-g,j,k,m,g are capable of rearranging to 5-sulfonylamido-1,2,3-
triazoles 4a-j, which were not available by any other method5b so far (Scheme 3).
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We have checked the optimal conditions in the synthesis of a series of 14 known 1,2,3-
thiadiazoles 5Sa-n (Table S1 of Supporting Information) which were prepared earlier by a two-
step protocol.5b As it is seen from Table S1 of Supporting Information, the yields of compounds
prepared by the one-step protocol are higher than those for the two-step method for all cases
except for the reactions of thioamides bearing an azepine ring (Entries 11, 12, 14).
With our knowledge that the reaction of sulfonyl azides 2 with 2-cyanothioacetamides 1 leads to
selective formation of thiadiazoles 5 and to show the practical convenience of the developed
method, we tried to synthesize thiadiazoles 5 in a one-pot manner starting from arylsulfonyl
chlorides 2'a-c, sodium azide and thioamides 1a-c,g (Table 2).
Table 2. The yields of thiadiazoles 5 according to the one-pot protocola compared to the yields
involving isolation of azides
Entry
1
ArSO2Cl
Thioamide
1
Product
Yields of 5, %
2'
5
one-pot
with isolation
of azide 2
76
synthesis
78
Ar
HNR1R2
Tolyl (2'a)
morpholine (1b)
5Sf
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Tolyl (2'a)
piperidine (1c)
5Si
5Sg
5Sj
5Sd
5r
87
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4-MeOC6H4 (2'b) morpholine (1b)
4-MeOC6H4 (2'b) piperidine (1c)
4-FC6H4 (2'c)
4-FC6H4 (2'c)
pyrrolidine (1a)
6
diethylamine (1g)
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a
1) 2' (4.84 mmol), NaN3 (9.68 mmol), H2O (20 mL), rt, 24 h. 2) 1 (4.82 mmol), NaOH (4.82
mmol), H2O (5 mL), 0 °C, 3 h.
The suspension of sulfonyl chlorides 2' in water and sodium azide were placed in the flask and
the reaction mixture was stirred at 23 oC for 24 h. Then sodium hydroxide and thioamides 1 were
o
added, followed by stirring of the reaction mixture for an additional 3 h at 0 C. After simple
filtration the pure thiadiazoles 5r,Sd,Sf,Si,Sj (Table 2) were obtained in 75‒87% yield. Table 2
demonstrates that the yields of thiadiazoles 5 using the one-pot procedure are higher compared to
the protocol involving the isolation of sulfonyl azide 1b.
Thus, a convenient effective one-pot protocol for the synthesis of thiadiazoles 5 from readily
available starting reagents was elaborated. The method also allows avoiding the isolation of
explosive sulfonyl azides, making it safer.
In order to prepare 1,2,3-thiadiazole-4-imidamides 5' bearing a tertiary-amino group instead of a
sulfonylamide function, we have studied reaction of compounds 5 with secondary cyclic amines
(Scheme 4). However, we failed to obtain the desired compounds 5': instead salts 7a-e of
triazoles with cyclic amines 6a-c were formed in very good yields. These compounds are
crystalline substances, readily soluble in organic solvents and in water and more stable than the
corresponding sodium salts 4, which slowly degrade to a variety of products during the storage
and transform to 1,2,3-thiazoles 5 very fast in water.
Scheme 4. Synthesis of Salts 7a-ea
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a Reaction conditions: 5 (1.0 mmol), 6 (1.0 mmol), EtOH (6 mL), reflux, 8‒21 h
The X-ray analysis of a monocrystal of 7d (Fig. S2 of Supporting Info) confirmed their structure.
Thus we have for the first time unambiguously obtained evidence of the structure of 5-
sulfonamido-1,2,3-triazoles salts of type 4 and 7.
To expand the scope of this approach to heterocyclic compounds bearing 1,2,3-thiadiazole or
1,2,3-triazole rings, and to increase the complexity of the final products we have prepared bis-
thioamide1h and studied its reactivity toward arylsulfonyl azides (Scheme 5). We have found
that bis-thioamide 1h reacts with tosyl azide (2d) in pyridine similar to 2-cyanothioacetamides
1a-g5b to form a novel compound 3c bearing two 1,2,3-thiadiazole rings connected via piperazine
linker (Scheme 5).
Scheme 5. Synthesis of Bis-thiadiazole 3c, Bis-amidines 8a-f and Bis-triazoles 9a-fa
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aReaction conditions for 8: 1h (100 mg, 0.4 mmol), 2 (1.0 mmol), NaOH (192 mg, 4.8 mmol),
H2O (8 mL), +5 °C→rt, overnight. Reaction conditions for 9: 8 (60‒100 mg, 0.088‒0.15 mmol),
Na (150 mg, 6.5 mmol), MeOH (5 mL), rt, 3 h
We have found that reactions of thioamide 1h with sulfonyl azides 2c,d,f-i in sodium ethoxide
were unsuccessful: no products were isolated apart of the starting compounds and a tar. It is
interesting that the reactions of the same compounds in water in the presence of 6 equivalents of
sodium hydroxide (optimization of amount of base see in Table S3 in the Supporting
Information) afford novel compounds, basically bis-amidine 8a-f and hybrid molecules
comprising two 1,2,3-thiadiazole rings 8'a-f: one bearing a cyano group and another with
attached N-sulfonyl amidine group (Scheme 5). The latter are more soluble in DMF than
compounds 8. Therefore the pure samples of 8 were obtained by treatment of the mixture with
DMF at room temperature overnight. Subsequent filtration gave pure compounds 8a-f in
57‒92% yields. From a series of compounds 8'a-f we managed to isolate pure sample of
compound 8'b only. 1H NMR spectrum of a mixture of compounds 8a and 8a' is reported in the
Supporting Information.
Compounds 8 and 8' are almost insoluble in EtOH, CH3CN and soluble in TFA (except for 8e).
The reaction of bis-thioamide 1h with azide 2c affords compound 3c (3%), apart from
thiadiazole 8d and 8'd. Reaction of azide 2i demonstrates the best conversion of the starting
materials to compound 8f, although half of the product was isolated in the triazole form 9f. It
was noticed that heating of compounds 8 in DMF or DMSO until complete dissolution resulted
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in their rearrangement into bis-1,2,3-triazoles 9a-f (Scheme 5). We could not isolate the obtained
triazoles 9 from their solution in DMF or DMSO. However, we have found that 1,2,3-
thiadiazoles 8 could be smoothly transformed to 1,2,3-triazoles 9 in methanol in the presence of
sodium methoxide. The desired compounds 9a-f were then isolated in excellent yields after
evaporation of methanol and treatment of the residue with diluted hydrochloric acid.
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The process of formation of triazoles 9 involves the rearrangement of two 1,2,3-thiadiazole rings
to 1,2,3-triazole rings,5b recently demonstrated for monocyclic compounds, where triazoles were
isolated and identified as their sodium salts.5b Here we describe the first example of isolation of
5-sulfonamido-1,2,3-triazole-4-carbothioamides.
To expand the scope for this water/base-catalyzed approach to the synthesis of 1,2,3-thiadiazole
and 1,2,3-triazole derivatives, we have studied the reactions of aromatic azides 2l,m bearing
highly electron-withdrawing nitro group in ortho- or in para positions and azide 2n with tertiary
2-cyanothioacetamides 1a-d in the optimal conditions found for the similar reactions of sulfonyl
azides. We have found that these azides react with 2-cyanothioacetamides 1a-d and 2-
cyanoacetamides 10a-d in water in the presence of sodium hydroxide at 50‒60 °C. However, the
products of that reaction were of another type, namely 5-amino-1-aryl-1,2,3-triazole-4-
carbothioamides 11a-f and amides 11g-l in 52‒90% yields (Scheme 6).
Scheme 6. Synthesis of 1-Aryl-5-amino-1,2,3-triazoles 11a-la
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a Reaction conditions: 1 or 10 (1.30 mmol), 2 (1.30 mmol), H2O (1.5 mL), 50‒60 °C, 3 h
These yields are higher than that for the method where ethanol/triethylamine was used for the
synthesis of this type of compounds (44‒80%).5c Under these conditions the triazoles are stable
and, despite of the similarity with compounds 4 do not undergo rearrangement to isomeric 1,2,3-
thiadiazole-4–carbimidamides 5. We have found that benzyl azide 2n react with 2-
cyanoacetamides 10b,d very slow to form triazoles 11k,l in low yields. The reason is that benzyl
azide 2n is less electrophylic than aryl azides 2l,m and its reactivity toward acive methylene
compounds 10 is low and concurrent reactions of degradation of starting and final compounds
also undergo at high temperature increasing the yield of the desired triazoles 11k,l.
Several years ago, we have shown the similarities in the reactivity of sulfonyl azides and 6-
azidopyrimidines toward enamines.16 This issue inspired us to check the reaction of 2-
cyanothioacetamides 1a-e with 6-azidopyrimidines 2o-q (Scheme 7).
Scheme 7. Synthesis of amidines 12a,b
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aConditions: thioamide 1 (1.0 mmol), azide 2 (1.0 mmol), NaOH (40 mg, 1.0 mmol), H2O (1.5
mL), 0 °C, 4 h
bOne-pot procedure conditions: 1) chloride 2'o (1.0 mmol), NaN3 (8.0 mmol), H2O (5 mL), rt, 48
h; 2) thioamide 1 (1.0 mmol), NaOH (1.0 mmol), H2O (2.5 mL), 0 °C, 24 h.
Our first attempt to carry out the reaction of 6-azidopyrimidines 2o-q with thioamide 1a in
ethanol in the presence of sodium ethoxide failed: the formation of a mixture of a few of
inseparable compounds occurred. Fortunately, we have discovered that azidopyrimidines 2o-q
smoothly react with 2-cyanothioacetamides 1a-e (similar to sulfonyl azides 2a-k) in water in the
presence of one equivalent of base at 0‒25 °C to form N-pyrimidyl-1,2,3-thiadiazole-4-
carbothioamides 12a-i in good yields (Scheme 7).
To show the practical convenience of the developed method for the synthesis of thiadiazoles 12,
we tried to synthesize thiadiazoles 12 in one-pot manner starting from more available 6-
chloropyrimidine 2'o, sodium azide and thioamides 1a,b,d (Scheme 7). This approach allowed
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preparing the pure thiadiazoles 12a,b,d in 70‒80% yield avoiding the use of expensive and
potentially explosive azidopyrimidines.
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The plausible mechanism for the water/alkali-catalyzed reaction of thioamides 1 with azides 2 is
partially similar to that of the reaction of sulfonyl azides with thioamides in ethanol in the
presence of sodium ethoxide.5b We surmise that triazene I1 is a common intermediate leading to
isolated products 3-5, 11 and 12 (Scheme 8).
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Scheme 8. The Plausible Mechanism for Water/Alkali-Catalyzed Reaction of Thioamides 1 with
Azides 2
Only in the reaction of the most electrophilic sulfonyl azide 2c and mesyl azide 2a, elimination
of sulfonyl amides occurs from I1 (Regitz diazo transfer15) followed by fast heteroelectrocyclic
reaction17 of diazothiocarbonyl compound I4 affording 4-cyano-1,2,3-thiadiazoles 3 as minor
products. Less electrophilic aryl azides 2l-n and pyrimidyl azides 2o-q do not undergo this type
of reaction. The competitive water/alkali-catalyzed 1,5-exo-dig-cyclization onto the cyano triple
bond via 6-membered TS leads to triazoline intermediate I2.5b We assume that the aromatization
of the latter to triazole I3 is facilitated by the presence of alkali. In the case of aromatic azides
compounds I3-11 are stable, and may be easily isolated and identified. Conversely, triazole I3
bearing strongly EWG in position 1 is unstable and is undergoing fast ring opening followed by
ring closure of diazo group onto the thioamide moiety via a Cornforth mechanism5c resulting into
thiadiazoles 5 or 12. It is worth noting that reaction of alkylsulfonyl azides 2a,b with thioamides
1 leads to compounds 3 in the case of the sodium ethoxide/ethanol system and mainly to
compounds 5 in the case of the water/alkali system. This could be explained by higher acidity of
water in comparison with ethanol which via protonation of the nitrogen atom enhances the
process of 1,5-exo-dig-cyclization onto cyano triple bond. The mechanisms of the formation of
compounds 3c and 8a-f (Scheme 5) are similar to those depictured for formation of compounds
3, 4 and 5 (Scheme 8).
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The structures of compounds 4-12 are consistent with the NMR, mass-spectra, including high
resolution mass-spectrometry and confirmed by X-ray data for single-crystals of compounds 5r,
7d and 12b (Figs. S1, S2, S3 of the Supporting Information). Signals for the thioamide carbon
atoms in compounds 5, 7-9 (DMSO-d6 solution) are displayed at 189−195 ppm, while the signals
of the amidine carbon atoms of compounds 5 and 12 in the same solvent at 169‒170 ppm.
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1
Remarkably, the H NMR spectra of bicyclic 1,2,3-triazoles 9 contain downfield signals around
15 ppm which is characteristic for the NH-proton of the 1,2,3-triazole form.5b
In conclusion, we have shown that the use of a water as a solvent and alkali as a base drastically
shifts the reaction of 2-cyanothioacetamides with sulfonyl and heteroaromatic azides in favor of
the interaction with the cyano group leading to 1,2,3-thiadiazole-4-carbimidamides 5 as the
major products. The reaction has a broad scope as bis-2-cyanothioacetamides also react with
sulfonyl azides in water/NaOH medium to form bis-1,2,3-thiadiazoles 8 and, after
rearrangements, bis-1,2,3-triazoles 9. Monocyclic and bicyclic 5-amino-1,2,3-thiadiazol-4-
carbimidamides can be transformed to 5-sulfonamido-1,2,3-triazole-4-carbothioamides thus
further expanding this series of various 1,2,3-triazoles. We have also found that 2-
cyanothioacetamides can react with aromatic azides and benzylazide in water/NaOH to form 1-
aryl/benzyl-1,2,3-triazole-4-carbothioamides. Exemplified by 6-azidopyrimidine-2,4-diones, we
have demonstrated that water/NaOH medium allows the reaction of heterocyclic azides bearing
electron-withdrawing substituents to afford N-heteroaryl-1,2,3-thiadiazole-4-carbimidamides.
Thus, we have elaborated a water/alkali-catalyzed one-step atom-economic, general, eco-friendly
and effective method for the synthesis of 1,2,3-thiadiazole-4-carbimidamides.
Experimental Section
General
Starting materials and reagents were purchased from commercial sources and used without
further purification. Ethanol and methanol were dried and distilled over CaO and magnesium
shavings correspondingly prior to use. 1,4-Dioxane and diethyl ether were dried and distilled
over Na prior to use. Pyridine, pyrrolidine, piperidine and morpholine were distilled over KOH
prior to use. Solvents used for silica gel chromatography (CHCl3/EtOH), crystallization (EtOAc),
1
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washing (EtOH) were used without purification or removal of water. H and C NMR spectra
were recorded at 400 and 100 MHz, respectively, with SiMe4 as internal reference in DMSO-d6,
DMSO-d6/CCl4, CDCl3 or CD3OD-d4; the chemical shifts (δ) were expressed in ppm, and J
values were given in Hz. Mass spectra were obtained with a mass-spectrometer using the
electron ionization (EI) technique (40–200 °C, 70 eV) with direct sample introduction into the
ion source. High-resolution mass spectra (HRMS) were obtained via electrospray ionization
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source (ESI). The compounds were analyzed in positive and negative ion detection mode. The
choice of the mode was made based on our earlier study of the structure of 1,2,3-thiadiazoles and
1,2,3-triazoles.18 The IR spectra were recorded with a FT-IR ATR (attenuated total reflection,
ZnSe) spectrometer in the 4000−500 cm-1 region. The reactions were monitored by analytical
TLC on aluminium foil plates with 0.2 mm silica gel with a fluorescent indicator visualized
under UV light. The column chromatography was performed with 60−120 mesh silica gel.
Melting points were determined on a melting point apparatus and are uncorrected.
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Preparation of thioamides. 3-(Pyrrolidin-1-yl)-3-thioxopropanenitrile19 (1a), 3-morpholino-3-
thioxopropanenitrile19 (1b), 3-(piperidin-1-yl)-3-thioxopropanenitrile19 (1c), 3-(azepan-1-yl)-3-
thioxopropanenitrile5b (1d) and 3-(4-benzylpiperidin-1-yl)-3-thioxopropanenitrile5b (1e) were
synthesized according to previously reported procedures. 2-Cyano-N,N-dimethylethanethioamide
(1f) and 2-cyano-N,N-diethylethanethioamide (1g) were commercially available.
Preparation of Azides. Sulfonyl azides 2a-i were prepared from the corresponding sulfonyl
chlorides20 and sodium azide following the literature procedures. Nitrophenyl azides 2l,m21 were
prepared from the corresponding nitroanilines following the literature procedures. Azides 2j,k,n-
q were commercially available. Warning! Azides are potentially explosive, and all reactions
should be carried out behind blast shields. We recommend the use of plastic spatulas for the
handling of solid material.
Preparation of 2-cyanoacetamides. Compounds 10a-c and 3,3'-(piperazine-1,4-diyl)bis(3-
oxopropanenitrile) were prepared from methyl cyanoacetate and the corresponding amines
following the literature procedures.21 2-Cyanoacetamide 10d was commercially available.
3,3'-(Piperazine-1,4-diyl)bis(3-thioxopropanenitrile)
(1h).
3,3'-(Piperazine-1,4-diyl)bis(3-
oxopropanenitrile) (9.97 g, 45.3 mmol) was dissolved in anhydrous 1,4-dioxane (100 mL) and
Lawesson’s reagent (20.0 g, 49.5 mmol) was added. The reaction mixture was stirred at 110 °C
(oil bath) for 8 h. Then the solvent was removed under reduced pressure and EtOH (100 mL)
was added to the residue. The suspension was stirred at room temperature for 3 h, the precipitate
was filtered off and crystallized from DMF to give thioamide 1h in 67% yield (7.60 g) as a beige
powder; mp 213‒215 °C. IR (ATR, ZnSe, cm-1): ν 2950, 2906, 2254, 1495, 1453, 1283, 1212,
1012. 1H NMR (DMSO-d6/CCl4): δ 3.97 (s, 2H), 3.99‒4.02 (m, 2H), 4.17‒4.20 (m, 2H), 4.26 (s,
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2H), 4.31‒4.32 (m, 4H). C{1H} NMR (DMSO-d6): δ 33.7, 33.8, 47.0, 47.8, 48.2, 49.3, 116.2,
116.2, 189.2, 189.4. MS (EI), m/z (%): [M]+ 252 (80). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C10H13N4S2 253.0576; Found 253.0581.
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5,5'-(Piperazine-1,4-diyl)bis(1,2,3-thiadiazole-4-carbonitrile) (3c). A mixture of azide 2d (199
mg, 1.0 mmol) and thioamide 1h (128 mg, 0.5 mmol) in anhydrous pyridine (2 mL), was stirred
at room temperature for 5 h. The reaction mixture was poured on ice, the formed precipitate was
filtered off, dried and washed with boiling EtOH to give 3c in 92% yield (142 mg) as yellow
powder; mp: 187‒190 °C (decomp.). IR (ATR, ZnSe, cm-1): ν 2217, 1535, 1440, 1286, 1262,
800. 1H NMR (DMSO-d6/CCl4): δ 3.95 (s, 8H). 13C{1H} NMR (DMSO-d6): δ 50.2, 113.8, 113.9,
171.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H9N8S2 305.0386; Found 305.0385.
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General Procedure for the Preparation of Triazoles 4a-j
The corresponding thiadiazole 5 (0.50 mmol) was added into a solution of sodium ethoxide,
freshly prepared from sodium (58.0 mg, 2.50 mmol) and anhydrous ethanol (2 mL), and the
resulting solution was stirred at +23 °С for 1 h. The formed precipitate was filtered off, washed
with diethyl ether (2 mL) and dried at 80 °C for 8 h.
Sodium (methylsulfonyl)(4-(pyrrolidine-1-carbonothioyl)-1H-1,2,3-triazol-5-yl)amide hydrate
(4a). Compound 4a was obtained in 71% (122 mg) yield according to the general procedure
(thiadiazole 5a: 138 mg, 0.50 mmol) as a colorless powder; mp > 300 °С. IR (ATR, ZnSe, cm–1):
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ν 3494, 3398, 2968, 2873, 1625, 1483, 1449, 1399, 1226, 1120, 1029, 994. H NMR (СD3OD-
d4): δ 1.92‒1.99 (m, 2H, СН2), 2.01‒2.07 (m, 2H, СН2), 2.85 (s, 3H, СН3), 3.81‒3.89 (m, 4H,
СН2), 5.00 (СD3OD-d4 + NH). 13C{1H} NMR (СD3OD-d4): δ 25.5, 27.2, 40.4, 54.1, 54.3, 138.0,
148.0, 190.9. HRMS (ESI-TOF) m/z: [M-Na]− Calcd for C8H12N5O2S2 274.0432; Found
274.0437.
Sodium (ethylsulfonyl)(4-(pyrrolidine-1-carbonothioyl)-1H-1,2,3-triazol-5-yl)amide hydrate
(4b). Сompound 4b was obtained in 77% (127 mg) yield according to the general procedure
(thiadiazole 5b: 145 mg, 0.50 mmol) as a colorless powder; mp > 300 °С. IR (ATR, ZnSe, cm–1):
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ν 3490, 3388, 2973, 2885, 1627, 1489, 1457, 1390, 1233, 1129, 1020, 984. H NMR (СD3OD-
d4): δ 1.24 (t, J = 7.4 Hz, 3H, СН3), 1.92–1.99 (m, 2H, СН2), 2.00–2.07 (m, 2H, СН2), 3.01 (k, J
= 7.4 Hz, 2H, СН2), 3.83–3.89 (m, 4H, 2СН2), 5.01 (СD3OD-d4 + NH). 13C{1H} NMR (СD3OD-
d4): δ 9.5, 25.7, 27.2, 46.9, 54.0, 54.3, 138.1, 147.8, 190.9. HRMS (ESI-TOF) m/z: [M-Na]−
Calcd for C9H14N5O2S2 288.0589; Found 288.0591.
Sodium ((4-nitrophenyl)sulfonyl)(4-(pyrrolidine-1-carbonothioyl)-1H-1,2,3-triazol-5-yl)amide
hydrate (4c). Compound 4c was obtained in 69% (146 mg) yield according to the general
procedure (thiadiazole 5c: 191 mg, 0.50 mmol) as a colorless powder; mp > 300 °С. IR (ATR,
ZnSe, cm–1): ν 3458, 3382, 2974, 2870, 1605, 1520, 1449, 1409, 1348, 1234, 1137, 1095, 983,
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949, 919, 854, 828, 739, 657, 614. H NMR (СD3OD-d4): δ 1.84‒1.89 (m, 2H, СН2), 1.93‒2.00
(m, 2H, СН2), 3.63 (t, J = 8.0 Hz, 2H, СН2), 3.71 (t, J = 8.0 Hz, 2H, СН2), 4.97 (СD3OD-d4 +
NH), 8.00 (d, J = 8.0 Hz, 2H, H-Ar), 8.15(d, J = 8.0 Hz, 2H, H-Ar). 13C{1H} NMR (СD3OD-d4):
δ 25.5, 27.1, 53.9, 54.2, 124.2, 129.1, 138.7, 146.3, 149.8, 153.7, 190.6. HRMS (ESI-TOF) m/z:
[M-Na]− Calcd for C13H13N6O4S2 381.0445; Found 381.0442.
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Sodium (methylsulfonyl)(4-(morpholine-4-carbonothioyl)-1H-1,2,3-triazol-5-yl)amide hydrate
(4d). Compound 4d was obtained in 78% (129 mg) yield according to the general procedure
(thiadiazole 5e: 147 mg, 0.50 mmol) as a colorless powder; mp > 300 °С. IR (ATR, ZnSe, cm–1):
ν 3450, 2872, 1624, 1547, 1499, 1425, 1240, 1160, 1127, 1105, 1062, 1027, 977, 899, 827, 748.
1H NMR (СD3OD-d4): δ 2.86 (s, 3H, СН3), 3.79 (br. s, 6H, СН2), 4.34 (br. s, 2H, СН2), 4.99
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(СD3OD-d4 + NH). C{1H} NMR (СD3OD-d4): δ 40.7, 50.8, 54.3, 67.5, 68.2, 136.8, 147.6,
194.6. HRMS (ESI-TOF) m/z: [M-Na]− Calcd for C8H12N5O3S2 290.0382; Found 290.0383.
Sodium (ethylsulfonyl)(4-(morpholine-4-carbonothioyl)-1H-1,2,3-triazol-5-yl)amide hydrate
(4e). Compound 4e was obtained in 71% (123 mg) yield according to the general procedure
(thiadiazole 5f: 153 mg, 0.50 mmol) as a colorless powder; mp 298‒299 °С. IR (ATR, ZnSe, cm–
1): ν 3453, 2963, 2931, 2853, 1666, 1645, 1630, 1485, 1290, 1255, 1228, 1108, 1026, 982. H
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NMR (СD3OD-d4): δ 1.26 (3H, t, СН3), 3.04 (2H, q, J = 8.0 Hz, CH3СН2), 3.77‒3.81 (6H, m,
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3CH2), 4.35 (2H, br. s, СН2), 5.14 (СD3OD-d4 + NH). C{1H} NMR (СD3OD-d4): δ 9.5, 18.4,
47.1 (2C), 58.3 (2C), 136.8, 147.7, 194.6. HRMS (ESI-TOF) m/z: [M-Na]− Calcd for
C9H14N5O3S2 304.0538; Found 304.0543.
Sodium (4-(morpholine-4-carbonothioyl)-1H-1,2,3-triazol-5-yl)((4-nitrophenyl)sulfonyl)amide
hydrate (4f). Compound 4f was obtained in 85% (186 mg) yield according to the general
procedure (thiadiazole 5g: 199 mg, 0.50 mmol) as a colorless powder; mp > 300 °С. IR (ATR,
ZnSe, cm–1): ν 3418, 3384, 3095, 2856, 1614, 1523, 1435, 1348, 1253, 1138, 1109, 1086, 1027,
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967, 921, 854, 793. H NMR (СD3OD-d4): δ 3.63 (br. s, 4H, СН2), 3.76 (br. s, 2H, СН2), 4.22
(br. s, 2H, СН2), 5.69 (СD3OD-d4 + NH), 8.00 (d, J = 8 Hz, 2H, H-Ar), 8.15 (d, J = 8 Hz, 2H, H-
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Ar). C{1Н} NMR (СD3OD-d4): δ 50.7, 54.1, 67.3, 68.1, 124.3, 129.0, 137.42, 146.1, 149.8,
153.6, 194.2. HRMS (ESI-TOF) m/z: [M-Na]− Calcd for C13H13N6O5S2 397.0389; Found
397.0394.
Sodium (methylsulfonyl)(4-(piperidine-1-carbonothioyl)-1H-1,2,3-triazol-5-yl)amide hydrate
(4g). Compound 4g was obtained in 84% (138 mg) yield according to the general procedure
(thiadiazole 5j: 145 mg, 0.50 mmol) as a colorless powder; mp 246–247 °С. IR (ATR, ZnSe, cm–
1): ν 3435, 3328, 2938, 2856, 1607, 1543, 1510, 1447, 1283, 1215, 1118, 798. 1H NMR (DMSO-
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d6:CCl4 1:1): δ 1.70‒1.71 (m, 6H, CH2), 2.96 (s, 3H, CH3), 4.20 (br. s, 4H, CH2), 11.00 (br. s,
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1H, NH). H NMR (СD3OD-d4): δ 1.62 (br. s, 2H, СН2), 1.74 (br. s, 4H, СН2), 2.84 (s, 3H,
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СН3), 3.74 (br. s, 2H, СН2), 4.30 (br. s, 2H, СН2), 5.05 (СD3OD-d4 + NH). C{1H} NMR
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(СD3OD-d4): δ 25.5, 26.7, 28.0, 40.5, 51.6, 54.8, 137.3, 147.3, 193.3. HRMS (ESI-TOF) m/z:
[M-Na]− Calcd for C9H14N5O2S2 288.0589; Found 288.0593.
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Sodium (ethylsulfonyl)(4-(piperidine-1-carbonothioyl)-1H-1,2,3-triazol-5-yl)amide hydrate (4h).
Compound 4h was obtained in 88% (151 mg) yield according to the general procedure
(thiadiazole 5k: 152 mg, 0.50 mmol) as a сolorless powder; mp: 171–173 °С. IR (ATR, ZnSe,
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cm–1): ν 2967, 2935, 1644, 1484, 1437, 1238, 1207, 1110, 1040, 1021, 881. H NMR (СD3OD-
d4): δ 1.25 (t, J = 8.0 Hz, 3H, СН3), 1.61 (br. s, 2H, СН2), 1.74 (br. s, 4H, 2СН2), 3.01 (k, J = 8.0
Hz, 2H, СН2), 3.74–3.77 (m, 2H, СН2), 4.29–4.32 (m, 2H, СН2), 4.95 (СD3OD-d4 + NH).
13C{1H} NMR (СD3OD-d4): δ 9.6, 25.5, 26.6, 28.0, 47.0, 51.6, 54.8, 137.4, 147.1, 193.3. HRMS
(ESI-TOF) m/z: [M-Na]− Calcd for C10H16N5O2S2 302.0745; Found 302.0748.
Sodium
((4-nitrophenyl)sulfonyl)(4-(piperidine-1-carbonothioyl)-1H-1,2,3-triazol-5-yl)amide
hydrate (4i). Compound 4i was obtained in 89% (194 mg) yield according to the general
procedure (thiadiazole 5m: 198 mg, 0.50 mmol) as a yellow powder; mp 255–256 °С. IR (ATR,
ZnSe, cm–1): ν 3484, 3176, 2937, 1568, 1525, 1410, 1400, 1351, 1276, 1215, 853, 815. 1H NMR
(СD3OD-d4): δ 1.48 (br. s, 2H, СН2), 1.68 (br. s, 4H, СН2), 3.55–3.58 (m, 2H, СН2), 4.14–4.18
(m, 2H, СН2), 4.94 (СD3OD-d4 + NH), 8.01 (d, J = 8.8 Hz, 2H, Н-Ar), 8.14 (2H, d, J = 8.8 Hz,
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Н-Ar). C{1H} NMR (СD3OD-d4): δ 25.4, 26.5, 27.8, 51.5, 54.6, 124.2, 129.0, 137.9, 145.8,
149.7, 154.1, 193.1. HRMS (ESI-TOF) m/z: [M-Na]− Calcd for C14H15N6O4S2 395.0596; Found
395.0597.
Sodium (4-(dimethylcarbamothioyl)-1H-1,2,3-triazol-5-yl)(tosyl)amide hydrate (4j). Compound
4j was obtained in 81% (148 mg) yield according to the general procedure (thiadiazole 5q: 163
mg, 0.50 mmol) as a сolorless powder; mp: 290–291 °С. IR (ATR, ZnSe, cm–1): ν 3458, 3150,
1723, 1687, 1455, 1368, 1221, 1129, 1091, 966. 1H NMR (СD3OD-d4): δ 2.32 (s, 3H, СН3), 3.04
(s, 3H, СН3), 3.37 (s, 3H, СН3), 4.87 (СD3OD-d4 + NH), 7.12 (d, J = 8.0 Hz, 2H, Н-Ar), 7.71 (d,
J = 8.0 Hz,2H, Н-Ar). 13C{1H} NMR (СD3OD-d4): δ 21.2, 43.2, 44.3, 128.0, 129.5, 137.8, 141.2,
144.3, 146.7, 194.8. HRMS (ESI-TOF) m/z: [M-Na]− Calcd for C12H14N5O2S2 324.0589; Found
324.0595.
General Procedure for the Preparation of 1,2,3-Thiadiazoles 5a-o
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Corresponding thioamide 1 (2.0 mmol) was added into a solution of sodium hydroxide, freshly
prepared from sodium hydroxide (2.0 or 3.0 mmol) and water (5 mL), and the resulting solution
was stirred at room temperature for 5–10 min. Then the reaction mixture was cooled till 0 °С and
the corresponding azide 2 (2.0 mmol) was added to the reaction mixture portion by portion and
the resulting mixture was stirred at 0 °С for 3 h. The formed precipitate was filtered off, washed
with cold ethanol, crystallized from ethyl acetate and dried in a desiccator over P4O10 (for 5a-c,e-
g,j-r). The reaction mixtures of thiadiazoles 5d,h,i were extracted with EtOAc (3 x 5 mL),
extracts were evaporated and the residues were purified by flash chromatography over silica gel
(CHCl3).
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(Z)-N'-(Methylsulfonyl)-5-(pyrrolidin-1-yl)-1,2,3-thiadiazole-4-carboximidamide
(5a).
Compound 5a was obtained in 70% (385 mg) yield according to the general procedure
(thioamide 1a: 308 mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2a: 242 mg, 2.0 mmol) as
colorless crystals; mp: 143–144 °С. IR (ATR, ZnSe, cm–1): ν 3409, 3303, 3223, 2961, 2830,
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1634, 1553, 1513, 1449, 1345, 1316, 1272, 1117, 958, 831. H NMR (DMSO-d6): δ 2.02–2.13
(m, 4H, СН2), 2.95 (s, 3H, СН3), 3.43–3.53 (m, 4H, СН2), 7.88 (br. s, 1H, NH2), 8.75 (br. s, 1H,
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NH2). C{1H} NMR (DMSO-d6): δ 25.8, 41.5 (2C), 55.6 (2C), 134.1, 156.8, 165.0. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C8H14N5O2S2 276.0583; Found 276.0583.
(Z)-N'-(Ethylsulfonyl)-5-(pyrrolidin-1-yl)-1,2,3-thiadiazole-4-carboximidamide (5b). Compound
5b was obtained in 69% (400 mg) yield according to the general procedure (thioamide 1a: 308
mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2b: 270 mg, 2.0 mmol) as a colorless powder;
mp: 136–137 °С. IR (ATR, ZnSe, cm–1): ν 3428, 3319, 2974, 2944, 2885, 2826, 1623, 1556,
1520, 1456, 1239, 1144, 1114, 795. 1H NMR (DMSO-d6): δ 1.30 (t, J = 7.4, 3H, СН3), 2.01–2.13
(m, 4H, СН2), 3.01 (k, J = 7.3, 2H, СН2), 3.41–3.54 (m, 4H, СН2), 7.93 (br. s, 1H, NH2), 8.72
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(br. s, 1H, NH2). C{1H} NMR (DMSO-d6): δ 7.8, 25.9, 30.6 (2С), 47.8, 55.6, 134.3, 157.3,
165.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C9H16N5O2S2 290.0740; Found 290.0741.
(Z)-N'-((4-Nitrophenyl)sulfonyl)-5-(pyrrolidin-1-yl)-1,2,3-thiadiazole-4-carboximidamide (5c).
Compound 5c was obtained in 69% (528 mg) yield according to the general procedure
(thioamide 1a: 308 mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2c: 456 mg, 2.0 mmol) as
yellow crystals; mp: 225–227 °С. IR (ATR, ZnSe, cm–1): ν 3440, 3332, 3232, 3092, 2994, 1634,
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1602, 1559, 1515, 1399, 1282, 1141, 1083, 826. H NMR (DMSO-d6): δ 1.89–1.92 (m, 4H,
СН2), 3.24–3.28 (m, 4H, СН2), 8.15 (d, J = 8.8 Hz, 2H, Н-Ar), 8.38 (d, J = 8.8 Hz, 2H, Н-Ar),
8.48 (br. s, 1H, NH2), 9.30 (br. s, 1H, NH2). 13C{1H} NMR (DMSO-d6): δ 25.8 (2C), 55.7 (2C),
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124.4, 127.8, 133.8, 147.5, 149.4, 157.8, 165.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C13H15N6O4S2 383.0591; Found 383.0591.
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(Z)-5-(Pyrrolidin-1-yl)-N'-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,3-thiadiazole-4-
carboximidamide (5d). Compound 5d was obtained in 65% (548 mg) yield according to the
general procedure (thioamide 1a: 308 mg, 2.0 mmol; NaOH: 120 mg, 3.0 mmol, azide 2k: 520
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mg, 2.0 mmol) as yellow crystals; mp: 105–107 °С. H NMR (DMSO-d6): δ 1.85–1.89 (m, 4H,
СН2), 3.19–3.22 (m, 4H, СН2), 7.68 (d, J = 7.8 Hz, 1H, Н-Ar), 7.74 (t, J = 8.1 Hz, 1H, Н-Ar),
7.87 (s, 1H, Н-Ar), 7.95 (d, J = 7.8 Hz, 1H, Н-Ar), 8.47 (br. s, 1H, NH2), 9.26 (br. s, 1H, NH2).
13C {1H} NMR (DMSO-d6): δ 25.7 (2C), 55.6 (2C), 118.9, 119.9 (q, J = 256.6 Hz), 125.1, 125.6,
131.6, 134.0, 144.2, 148.1, 157.5, 165.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H15F3N5O3S2 422.0563; Found 422.0578.
(Z)-N'-(Methylsulfonyl)-5-morpholino-1,2,3-thiadiazole-4-carboximidamide (5e). Compound 5e
was obtained in 85% (496 mg) yield according to the general procedure (thioamide 1b: 340 mg,
2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2a: 242 mg, 2.0 mmol) as colorless crystals; mp:
165–166 °С. IR (ATR, ZnSe, cm–1): ν 3406, 3294, 3233, 3165, 2918, 2842, 1624, 1549, 1503,
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1455, 1101, 1062, 1021, 795. H NMR (DMSO-d6): δ 3.00 (s, 3H, СН3), 3.41–3.43 (m, 4H,
СН2), 3.74–3.76 (m, 4H, СН2), 8.13 (br. s, 1H, NH2), 9.01 (br. s, 1H, NH2). C{1H} NMR
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(DMSO-d6): δ 41.7, 53.2 (2C), 65.1 (2C), 136.2, 156.5, 170.1. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C8H14N5O3S2 292.0533; Found 292.0532.
(Z)-N'-(Ethylsulfonyl)-5-morpholino-1,2,3-thiadiazole-4-carboximidamide (5f). Compound 5f
was obtained in 77% (470 mg) yield according to the general procedure (thioamide 1b: 340 mg,
2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2b: 270 mg, 2.0 mmol) as colorless crystals; mp:
119–120 °С. IR (ATR, ZnSe, cm–1): ν 3452, 3419, 3306, 2975, 2850, 1612, 1550, 1496, 1428,
1252, 1107, 847. 1H NMR (DMSO-d6): δ 1.34 (t, J = 7.4 Hz, 3H, СН3), 3.02 (k, J = 7.4 Hz, 2H,
СН2), 3.43–3.46 (m, 4H, СН2), 3.76–3.78 (m, 4H, СН2), 8.03 (br. s, 1H, NH2), 8.84 (br. s, 1H,
NH2). 13С{1H} NMR (DMSO-d6): δ 7.8, 30.5, 47.8, 53.1, 65.1 (2C), 136.4, 156.9, 170.1. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C9H16N5O3S2 306.0689; Found 306.0690.
(Z)-5-Morpholino-N'-((4-nitrophenyl)sulfonyl)-1,2,3-thiadiazole-4-carboximidamide
(5g).
Compound 5g was obtained in 80% (638 mg) yield according to the general procedure
(thioamide 1b: 340 mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2c: 456 mg, 2.0 mmol) as
colorless crystals; mp: 218–220 °С. IR (ATR, ZnSe, cm–1): ν 3435, 3340, 3226, 3098, 2975,
2852, 1626, 1546, 1518, 1452, 1429, 1346, 1273, 1221, 1142, 1085, 793. 1H NMR (DMSO-d6):
δ 3.32–3.35 (m, 4H, СН2), 3.62–3.65 (m, 4H, СН2), 8.15 (d, J = 8.9 Hz, 2H, Н-Ar), 8.38 (d, J =
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8.9 Hz, 2H, Н-Ar); 8.45 (br. s, 1H, NH2), 9.27 (br. s, 1H, NH2). C{1H} NMR (DMSO-d6): δ
53.1 (2C), 65.0 (2C), 124.5, 127.8, 135.8, 147.3, 149.6, 157.6, 170.4. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C13H15N6O5S2 399.0540; Found 399.0538.
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(Z)-5-Morpholino-N'-((2-(trifluoromethoxy)phenyl)sulfonyl)-1,2,3-thiadiazole-4-
carboximidamide (5h). Compound 5h was obtained in 70% (613 mg) yield according to the
general procedure (thioamide 1b: 340 mg; azide 2j: 520 mg) as colorless crystals; mp: 161–163
°С. 1H NMR (DMSO-d6): δ 3.28–3.30 (m, 4H, СН2), 3.46–3.48 (m, 4H, СН2), 7.55-7.59 (m, 2H,
Н-Ar), 7.78 (t, J = 8.0 Hz, 1H, Н-Ar); 8.05 (d, J = 8.0 Hz, 1H, Н-Ar); 8.50 (br. s, 1H, NH2), 9.35
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(br. s, 1H, NH2). C{1H} NMR (DMSO-d6): δ 53.1 (2C), 64.8 (2C), 119.9 (q, J = 259.1 Hz),
120.7, 127.4, 129.4, 134.0, 134.8, 135.8, 145.2, 157.3, 170.6. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C14H15F3N5O4S2 438.0512; Found 438.0527.
(Z)-5-Morpholino-N'-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,3-thiadiazole-4-
carboximidamide (5i). Compound 5i was obtained in 65% (569 mg) yield according to the
general procedure (thioamide 1b: 340 mg; NaOH: 120 mg, 3.0 mmol; azide 2k: 520 mg) as pink
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crystals; mp: 122–124 °С. H NMR (DMSO-d6): δ 3.23–3.25 (m, 4H, СН2), 3.52–3.53 (m, 4H,
СН2), 7.70 (d, J = 8.4 Hz, 1H, Н-Ar), 7.76 (t, J = 7.8 Hz, 1H, Н-Ar); 7.86 (s, 1H, Н-Ar), 7.93 (d,
J = 7.8 Hz, 1H, Н-Ar); 8.62 (br. s, 1H, NH2), 9.37 (br. s, 1H, NH2). 13C{1H} NMR (DMSO-d6):
δ 53.0 (2C), 64.9 (2C), 118.8, 119.9 (q, J = 256.6 Hz), 125.2, 125.5, 131.8, 136.1, 144.1, 148.1,
157.4, 170.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H15F3N5O4S2 438.0512; Found
438.0528.
(Z)-N'-(Methylsulfonyl)-5-(piperidin-1-yl)-1,2,3-thiadiazole-4-carboximidamide (5j). Compound
5j was obtained in 85% (492 mg) yield according to the general procedure (thioamide 1c: 337
mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2a: 242 mg, 2.0 mmol) as colorless crystals; mp:
142–143 °С. IR (ATR, ZnSe, cm–1): ν 3434, 3328, 3006, 2940, 2853, 1604, 1539, 1513, 1448,
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1276, 1254, 1116, 797. H NMR (DMSO-d6): δ 1.58–1.59 (m, 2H, СН2), 1.65–1.66 (m, 4H,
СН2), 3.00 (c, 3H, CH3), 3.36–3.39 (m, 4H, СН2), 8.11 (br. s, 1H, NH2), 8.97 (br. s, 1H, NH2).
13C{1H} NMR (DMSO-d6): δ 22.5, 24.7 (2C), 41.7, 54.9 (2C), 135.7, 157.1, 169.8. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C9H16N5O2S2 290.0740; Found 290.0738.
(Z)-N'-(Ethylsulfonyl)-5-(piperidin-1-yl)-1,2,3-thiadiazole-4-carboximidamide (5k). Compound
5k was obtained in 85% (516 mg) yield according to the general procedure (thioamide 1c: 339
mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2b: 270 mg, 2.0 mmol) as colorless crystals; mp:
154–156 °С. IR (ATR, ZnSe, cm–1): ν 3408, 3214, 2980, 2877, 2853, 1609, 1537, 1505, 1446,
1288, 1250, 1109, 793. 1H NMR (DMSO-d6): δ 1.31 (t, J = 7.4 Hz, 3H, СН3), 1.63–1.64 (m, 2H,
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CH2), 1.71–1.75 (m, 4H, CH2), 3.02 (k, J = 7.4 Hz, 2H, СН2), 3.39–3.42 (m, 4H, CH2), 8.00 (br.
s, 1H, NH2), 8.80 (br. s, 1H, NH2). 13C{1H} NMR (DMSO-d6): δ 7.6, 22.3, 24.5 (2C), 47.8, 54.7
(2C), 135.7, 157.4, 169.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H18N5O2S2 304.0896;
Found 304.0896.
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(Z)-N'-((2,4-Dimethylphenyl)sulfonyl)-5-(piperidin-1-yl)-1,2,3-thiadiazole-4-carboximidamide
(5l). Compound 5l was obtained in 78% (592 mg) yield according to the general procedure
(thioamide 1c: 337 mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2e: 422 mg, 2.0 mmol) as
colorless crystals; mp: 141–142 °С. IR (ATR, ZnSe, cm–1): ν 3395, 3300, 3227, 3173, 2946,
2922, 2847, 1634, 1545, 1512, 1443, 1121, 1110, 1030, 1016, 759, 712. 1H NMR (DMSO-d6): δ
1.52 (br. s, 6H, СН2), 2.35 (s, 3H, CH3), 2.57 (s, 3H, CH3), 3.29 (br. s, 4H, СН2), 7.11 (d, J = 6.0
Hz, 2H, Н-Ar), 7.83 (d, J = 8.5 Hz, 1H, Н-Ar), 8.13 (br. s, 1H, NH2), 8.91 (br. s, 1H, NH2).
13C{1H} NMR (DMSO-d6): δ 19.8, 20.6, 22.3, 24.3 (2C), 54.6 (2C), 126.2, 127.4, 132.6, 135.8,
136.4, 137.6, 142.3, 157.2, 169.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C16H22N5O2S2 380.1209; Found 380.1215.
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(Z)-N'-((4-Nitrophenyl)sulfonyl)-5-(piperidin-1-yl)-1,2,3-thiadiazole-4-carboximidamide (5m).
Compound 5m was obtained in 80% (634 mg) yield according to the general procedure
(thioamide 1c: 337 mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2c: 456 mg, 2.0 mmol) as
colorless crystals; mp: 135–136 °С. IR (ATR, ZnSe, cm–1): ν 3445, 3342, 2943, 2860, 2834,
1626, 1607, 1527, 1490, 1443, 1352, 1215, 1143, 1110, 1022, 798. 1H NMR (DMSO-d6): δ 1.58
(br. s, 6H, СН2), 3.29 (br. s, 4H, СН2), 8.14–8.17 (m, 2H, Н-Ar), 8.35–8.38 (m, 2H, Н-Ar), 8.43
(br. s, 1H, NH2), 9.21 (br. s, 1H, NH2). 13C{1H} NMR (DMSO-d6): δ 22.2, 24.4 (2C), 54.7 (2C),
124.2, 127.7, 135.1, 147.5, 149.4, 158.2, 169.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H17N6O4S2 397.0747; Found 397.0748.
(Z)-5-(Azepan-1-yl)-N'-(ethylsulfonyl)-1,2,3-thiadiazole-4-carboximidamide (5n). Compound 5n
was obtained in 71% (451 mg) yield according to the general procedure (thioamide 1d: 365 mg,
2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2b: 270 mg, 2.0 mmol) as colorless crystals; mp:
105–107 °С. IR (ATR, ZnSe, cm–1): ν 3384, 3297, 3219, 2913, 2850, 1632, 1553, 1512, 1436,
1328, 1274, 1227, 1122, 1098, 825. 1H NMR (DMSO-d6): δ 1.30 (t, J = 7.4 Hz, 3H, СН3), 1.55–
1.66 (m, 4H, СН2), 1.84 (br. s, 4H, СН2), 2.99 (k, J = 7.4 Hz, 2H, СН2), 3.58–3.60 (m, 4H, СН2),
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8.02 (br. s, 1H, NH2), 8.79 (br. s, 1H, NH2). C{1H} NMR (DMSO-d6): δ 7.7, 26.4 (2C), 26.7
(2C), 47.8, 55.8 (2C), 134.5, 158.6, 166.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C11H20N5O2S2 318.1053; Found 318.1052.
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(Z)-5-(Azepan-1-yl)-N'-((4-nitrophenyl)sulfonyl)-1,2,3-thiadiazole-4-carboximidamide
(5o).
Compound 5o was obtained in 76% (624 mg) yield according to the general procedure
(thioamide 1d: 365 mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2c: 456 mg, 2.0 mmol) as a
colorless powder; mp: 128–130 °С. IR (ATR, ZnSe, cm–1): ν 3426, 3324, 3110, 2912, 2836,
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1615, 1536, 1515, 1460, 1351, 1292, 1146, 1082, 818, 787. H NMR (DMSO-d6): δ 1.48–1.58
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(m, 4H, СН2), 1.71 (br. s, 4H, СН2), 3.44–3.47 (m, 4H, СН2), 8.12 (d, J = 8.0 Hz, 2H, Н-Ar),
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8.36 (d, J = 8.0 Hz, 2H, Н-Ar), 8.37 (br. s, 1H, NH2), 8.51 (br. s, 1H, NH2). C{1H} NMR
(DMSO-d6): δ 26.1 (2C), 26.6 (2C), 55.8 (2C), 124.2, 127.7, 133.8, 147.7, 149.4, 159.4, 166.9.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H19N6O4S2 411.0904; Found 411.0904.
(Z)-5-(4-Benzylpiperidin-1-yl)-N'-((4-methoxyphenyl)sulfonyl)-1,2,3-thiadiazole-4-
carboximidamide (5p). Compound 5p was obtained in 86% (811 mg) yield according to the
general procedure (thioamide 1e: 517 mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2f: 426 mg,
2.0 mmol) as colorless crystals; mp: 167–168 °С. IR (ATR, ZnSe, cm–1): ν 3415, 3311, 3026,
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2953, 2860, 1620, 1593, 1539, 1493, 1444, 1138, 1112, 1016, 971. H NMR (DMSO-d6): δ
1.20–1.30 (m, 2H, СН2), 1.48–1.51 (m, 2H, СН2), 1.62–1.73 (m, 1H, СН), 2.49–2.50 (m, 2H,
СН2), 2.88–2.93 (m, 2H, СН2), 3.53–3.56 (m, 2H, СН2), 3.81 (s, 3H, OCH3), 6.98 (d, J = 8.8 Hz,
2H, Н-Ar), 7.11–7.12 (m, 2H, Н-Ar), 7.15–7.18 (m, 1H, Н-Ar), 7.25–7.29 (m, 2H, Н-Ar), 7.81
(d, J = 8.8 Hz, 2H, Н-Ar), 8.20 (br. s, 1H, NH2), 8.90 (br. s, 1H, NH2). 13C{1H} NMR (DMSO-
d6): δ 30.4 (2C), 35.4, 41.5, 53.8 (2C), 55.5, 113.9, 125.7, 128.0, 128.1, 128.7, 133.9, 135.7,
139.6, 156.7, 162.1, 169.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26N5O3S2 472.1472;
Found 472.1477.
(Z)-5-(Dimethylamino)-N'-tosyl-1,2,3-thiadiazole-4-carboximidamide (5q). Compound 5q was
obtained in 70% (456 mg) yield according to the general procedure (thioamide 1f: 256 mg, 2.0
mmol; NaOH: 80 mg, 2.0 mmol; azide 2d: 394 mg, 2.0 mmol) as colorless crystals; mp: 168–
169 °С. IR (ATR, ZnSe, cm–1): ν 3463, 3301, 3223, 3120, 2927, 2840, 1598, 1425, 1200, 1124,
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1095, 969, 879. H NMR (DMSO-d6): δ 2.41 (s, 3H, СН3), 3.04 (s, 6H, СН3), 7.31 (d, J = 8.1
Hz, 2H, Н-Ar), 7.76 (d, J = 8.2 Hz, 2H, Н-Ar), 8.20 (br. s, 1H, NH2), 8.97 (br. s, 1H, NH2).
13C{1H} NMR (DMSO-d6): δ 20.9, 45.9 (2C), 126.3, 129.3, 134.8, 139.4, 142.6, 157.4, 168.9.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H16N5O2S2 326.0740; Found 326.0735.
(Z)-5-(Diethylamino)-N'-((4-fluorophenyl)sulfonyl)-1,2,3-thiadiazole-4-carboximidamide (5r).
Compound 5r was obtained in 72% (515 mg) yield according to the general procedure
(thioamide 1g: 313 mg, 2.0 mmol; NaOH: 80 mg, 2.0 mmol; azide 2g: 402 mg, 2.0 mmol) as
colorless crystals; mp: 135–136 °С. IR (ATR, ZnSe, cm–1): ν 3395, 3306, 3220, 3110, 2998,
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2933, 2859, 1631, 1547, 1519, 1487, 1448, 1277, 1231, 1083, 835. 1H NMR (DMSO-d6): δ 1.08
(t, J = 7.1 Hz, 6H, СН3), 3.42 (k, J = 7.1 Hz, 4H, СН2), 7.26–7.32 (m, 2H, Н-Ar), 7.92–7.97 (m,
2H, Н-Ar), 8.32 (br. s, 1H, NH2), 9.06 (br. s, 1H, NH2). 13C{1H} NMR (DMSO-d6): δ 11.5 (2C),
50.5 (2C), 116.1 (d, J = 30 Hz), 129.3 (d, J = 10 Hz), 134.7, 138.5 (d, J = 3 Hz), 158.4, 164.2, (d,
J = 250 Hz), 166.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H17FN5O2S2 358.0802; Found
358.0798.
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Method B. A solution of NaN3 (629 mg, 9.68 mmol) in H2O (10 mL) was added to the stirring
mixture of 4-fluorobenzenesulfonyl chloride (2'c) (942 mg, 4.84 mmol) in H2O (10 mL). The
resulting mixture was stirred at ambient temperature for 24 h and then a water-alkali solution of
thioamide 1g (753 mg, 4.82 mmol) prepared from H2O (5 mL) and NaOH (193 mg, 4.82 mmol)
was added. The reaction mixture was stirred at 0 °C for 3 h and the formed precipitate was
filtered off, crystallized from EtOAc, and dried in a desiccator over P4O10. Thiadiazole 5r was
obtained in 75% yield (1.298 g) as colorless crystals; mp: 135–136 °С.
General Procedure for the Preparation of 1,2,3-Triazol-2-ides 7a-e. A solution of corresponding
thiadiazole 5 (1.0 mmol) and amine 6 (1.0 mmol) in anhydrous ethanol (6 mL) was refluxed in
an oil bath for 8‒21 h. The reaction mixture was cooled, the formed precipitate was filtered off,
washed with ethanol and dried at 80 °C to give salts 7a-e.
1λ4-Pyrrolidin-2-ylium 4-((4-methylphenyl)sulfonamido)-5-(pyrrolidine-1-carbonothioyl)-1,2,3-
triazol-2-ide (7a). Compound 7a was obtained in 85% (359 mg) yield according to the general
procedure (thiadiazole 5s5b: 351 mg, 1.0 mmol; amine 6a: 71 mg, 82 μL, 1.0 mmol; 12 h) as
colorless powder; mp: 201‒203 °C. IR (ATR, ZnSe, cm–1): ν 2917, 2731, 2597, 2460, 1629,
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1596, 1519, 1445, 1354, 1330, 1289, 1222, 1156, 910, 708. H NMR (DMSO-d6): δ 1.79‒1.91
(m, 8H, 4CH2), 2.30 (s, 3H, CH3), 3.12 (t, J = 8.0 Hz, 4H, CH2), 3.69 (k, J = 8.0 Hz, 4H, CH2),
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7.20 (d, J = 8.0 Hz, 2H, H-Ar), 7.64 (d, J = 8.0 Hz, 2H, H-Ar). C{1H} NMR (DMSO-d6): δ
20.7, 23.5, 23.6 (2C), 25.8, 44.9 (2C), 52.9, 53.1, 126.3, 128.6, 132.8, 140.4, 140.9, 142.5, 184.1.
MS (EI), m/z (%): 351 ([M−C4H10N+H]+, 36). HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C14H16N5O2S2 350.0751. Found 350.0748.
1λ4-Piperidin-2-ylium 4-((4-methylphenyl)sulfonamido)-5-(pyrrolidine-1-carbonothioyl)-1,2,3-
triazol-2-ide (7b). Compound 7b was obtained in 74% (323 mg) yield to the general procedure
(thiadiazole 5s5b: 351 mg, 1.0 mmol; amine 6b: 85 mg, 98.6 μL, 1.0 mmol; 15 h) as colorless
powder; mp: 203‒205 °C. IR (ATR, ZnSe, cm–1): ν 3284, 2956, 2850, 2731, 2653, 2537, 2454,
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1630, 1599, 1514, 1441, 1357, 1332, 1289, 1162, 1090, 913, 657. H NMR (DMSO-d6): δ
1.54‒1.56 (m, 2H, CH2), 1.64‒1.70 (m, 4H, CH2), 1.81‒1.88 (m, 4H, CH2), 2.30 (s, 3H, CH3),
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3.01‒3.04 (m, 4H, CH2), 3.68‒3.72 (m, 4H, CH2), 7. 21 (d, J = 8.0 Hz, 2H, H-Ar), 7.64 (d, J =
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8.0 Hz, 2H, H-Ar). C{1H} NMR (DMSO-d6): δ 20.7, 21.6, 22.2, 23.7, 25.8, 43.8 (2C), 52.9,
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53.1, 59.6, 126.4, 128.6, 132.9, 140.0, 140.9, 142.2, 184.0. MS (EI), m/z (%): 351 ([M-
C5H12N+H]+, 25). HRMS (ESI-TOF) m/z: [M-H]- Calcd for C14H16N5O2S2 350.0751. Found
350.0747.
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(1R,5S)-8-Oxo-1,3,4,5,6,8-hexahydro-2H-3λ4-1,5-methanopyrido[2,1-d][1,5]diazocin-4-ylium 4-
((4-methylphenyl)sulfonamido)-5-(pyrrolidine-1-carbonothioyl)-1,2,3-triazol-2-ide
(7c).
Compound 7c was obtained in 67% (362 mg) yield to the general procedure (thiadiazole 5s5b:
351 mg, 1.0 mmol; amine 6c: 190 mg, 1.0 mmol; 21 h) as a colorless powder; mp: 188‒190 °C.
IR (ATR, ZnSe, cm–1): ν 2981, 2875, 2617, 2577, 1648, 1613, 1537, 1470, 1446, 1412, 1284,
1118, 804. 1H NMR (DMSO-d6): δ 1.90 (s, 2H, CH2), 2.00 (k, J = 4.0 Hz, 4H, CH2), 2.33 (s, 1H,
CH), 2.40 (s, 3H, CH3), 2.90‒3.00 (m, 4H, CH2), 3.03‒3.06 (m, 1H, CH), 3.72 (dd, J = 16.0 Hz,
4.0 Hz, 1H, CH), 3.81 (t, J = 6.0 Hz, 2H, CH2), 3.85‒3.91 (m, 3H, CH2+CH), 5.95 (d, J = 8.0
Hz, 1H, CH), 6.18 (d, J = 8.0 Hz, 1H, CH), 6.45 (br. s, 3H, NH2+NH), 7. 23 (k, J = 8.0 Hz, 1H,
CH), 7.29 (d, J = 8.0 Hz, 2H, H-Ar), 7.74 (d, J = 8.0 Hz, 2H, H-Ar). 13C{1H} NMR (DMSO-d6):
δ 20.9, 23.7, 24.5, 25.8, 26.0, 33.1, 48.7, 50.2, 51.2, 53.2, 53.4, 104.5, 116.0, 126.8, 129.1, 135.0,
138.5, 138.8, 141.2, 142.2, 150.2, 162.4, 182.6. MS (EI), m/z (%): 351 ([M−C5H12N+H]+, 18).
HRMS (ESI-TOF) m/z: [M-H]- Calcd for C14H16N5O2S2 350.0751. Found 350.0748.
1λ4-Pyrrolidin-2-ylium 4-(methylsulfonamido)-5-(piperidine-1-carbonothioyl)-1,2,3-triazol-2-ide
(7d). Compound 7d was obtained in 82% (294 mg) yield to the general procedure (thiadiazole
5j: 289 mg, 1.0 mmol; amine 6a: 71 mg, 82 μL, 1.0 mmol; 8 h) as a colorless powder; mp:
160‒162 °C. IR (ATR, ZnSe, cm–1): ν 2947, 2927, 2855, 2713, 2591, 2474, 1623, 1516, 1463,
1440, 1358, 1324, 1255, 1152, 1128, 1008, 958, 867. 1H NMR (DMSO-d6): δ 1.65‒1.80 (m, 6H,
CH2), 1.87‒1.94 (m, 4H, CH2), 2.98 (s, 3H, CH3), 3.15‒3.18 (m, 4H, CH2), 4.12‒4.23 (m, 4H,
CH2), 8.70 (br. s, 3H, NH2+NH). 13C{1H} NMR (DMSO-d6): δ 23.9, 24.0, 25.7, 27.0, 40.9, 45.1
(2C), 50.1, 53.4, 66.9, 132.7, 143.3, 186.7. HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C9H14N5O2S2 288.0592. Found 288.0594.
1λ4-Pyrrolidin-2-ylium 4-((4-methylphenyl)sulfonamido)-5-(piperidine-1-carbonothioyl)-1,2,3-
triazol-2-ide (7e). Compound 7e was obtained in 85% (371 mg) yield to the general procedure
(thiadiazole 5t5b: 365 mg, 1.0 mmol; amine 6a: 71 mg, 82 μL, 1.0 mmol; 15 h) as a colorless
powder; mp: 158‒160 °C. IR (ATR, ZnSe, cm–1): ν 2942, 2856, 2748, 2599, 2463, 1632, 1596,
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1518, 1444, 1363, 1336, 1293, 1230, 1159, 1089, 681. H NMR (DMSO-d6): δ 1.42 (br. s, 2H,
CH2), 1.60 (br. s, 4H, CH2), 1.82‒1.86 (m, 4H, CH2), 2.30 (s, 3H, CH3), 3.13 (t, J = 7.0 Hz, 4H,
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CH2), 3.55 (br. s, 2H, CH2), 4.14 (br. s, 2H, CH2), 7.19 (d, J = 8.0 Hz, 2H, H-Ar), 7.63 (d, J =
8.0 Hz, 2H, H-Ar). 13C{1H} NMR (DMSO-d6): δ 20.7, 23.6 (2), 25.1 (2C), 26.4, 44.5 (2C), 49.5,
52.7, 126.0 (2C), 128.5 (2C), 133.2, 140.2, 140.8, 141.8, 187.5. HRMS (ESI-TOF) m/z: [M-H]-
Calcd for C15H18N5O2S2 364.0907. Found 364.0904.
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General procedure for the synthesis of bis-thiadiazoles 8a-f. To a stirred solution of NaOH (192
mg, 4.8 mmol) in water (8 mL), thioamide 1h (100 mg, 0.4 mmol) was added and the formed
solution was cooled with an ice bath. An appropriate azide 2c,d,f-i (1.0 mmol) was added and
the reaction mixture was stirred overnight at room temperature. The precipitate was filtered off,
washed with EtOH and dried to give a mixture of 8a-f, 8'a-f (and 3c in the case of 8d, 8'd). The
mixture 8, 8' was stirred in DMF (10 mL) overnight, filtered, washed with EtOH and dried in a
desiccator to give pure product 8. When the mixture 8b, 8'b was heated at reflux in CH3CN for 1
h and the insoluble precipitate was filtered off, minor product 8'b was obtained from the filtrate
after evaporation.
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(1Z,1'Z)-1,1'-(Piperazine-1,4-diylbis(1,2,3-thiadiazole-5,4-diyl))bis(N'-tosylformimidamide)
(8a). Compound 8a was obtained in 79% yield (204 mg) from thioamide 1h (100 mg, 0.4 mmol)
and azide 2d (197 mg, 1.0 mmol) according to the general procedure as a colorless powder; mp:
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220‒222 °C (decomp.). IR (ATR, ZnSe, cm-1): ν 3321, 1630, 1597, 1262, 1143, 781. H NMR
(DMSO-d6): δ 2.36 (s, 6H, CH3), 3.18 (s, 8H, CH2), 7.38 (d, J = 7.6 Hz, 4H, H-Ar), 7.78 (d, J =
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7.6 Hz, 4H, H-Ar), 8.39 (br. s, 2H, NH2), 9.21 (br. s, 2H, NH2). C{1H} NMR (DMSO-d6): δ
20.7, 51.7, 126.0, 129.3, 136.3, 139.1, 142.6, 156.0, 169.6. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C24H27N10O4S4 647.1094; Found 647.1091.
(1Z,1'Z)-1,1'-(Piperazine-1,4-diylbis(1,2,3-thiadiazole-5,4-diyl))bis(N'-
(phenylsulfonyl)formimidamide) (8b). Compound 8b was obtained in 61% yield (150 mg) from
thioamide 1h (100 mg, 0.4 mmol) and azide 2h (183 mg, 1.0 mmol) according to the general
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procedure as a colorless powder; mp: 218‒220 °C (decomp.). H NMR (DMSO-d6): δ 3.18 (s,
8H, CH2), 7.58 (t, J = 7.4 Hz, 4H, H-Ar), 7.66 (t, J = 7.4 Hz, 2H, H-Ar), 7.9 (d, J = 7.4 Hz, 4H,
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H-Ar), 8.47 (br. s, 2H, NH2), 9.25 (br. s, 2H, NH2). C{1H} NMR (DMSO-d6): δ 51.6, 126.0,
128.9, 132.3, 136.3, 141.9, 156.4, 169.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H23N10O4S4 619.0781; Found 619.0791.
(Z)-5-(4-(4-Cyano-1,2,3-thiadiazol-5-yl)piperazin-1-yl)-N'-(phenylsulfonyl)-1,2,3-thiadiazole-4-
carboximidamide (8'b). Compound 8'b was obtained in 19% yield (34 mg) from thioamide 1h
(100 mg, 0.4 mmol) and azide 2h (183 mg, 1.0 mmol) according to the general procedure as an
orange powder; mp: 168‒170 °C. IR (ATR, ZnSe, cm-1): ν 3427, 3316, 2235, 1624, 1523, 1142,
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1085, 936, 802, 578. 1H NMR (DMSO-d6): δ 3.52‒3.55 (m, 4H, CH2), 3.65‒3.67 (m, 4H, CH2),
7.61 (t, J = 7.4 Hz, 2H, H-Ar), 7.68 (t, J = 7.4 Hz, 1H, H-Ar), 7.95 (d, J = 7.4 Hz, 2H, 1-Ar),
8.45 (br. s, 1H, NH), 9.26 (br. s, 1H, NH). 13C{1H} NMR (DMSO-d6): δ 50.8, 51.5, 113.9, 114.3,
126.3, 129.2, 132.7, 136.3, 141.8, 156.6, 169.5, 171.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C16H16N9O2S3 462.0589; Found 462.0588.
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(1Z,1'Z)-1,1'-(Piperazine-1,4-diylbis(1,2,3-thiadiazole-5,4-diyl))bis(N'-((4-
methoxyphenyl)sulfonyl)formimidamide) (8c). Compound 8c was obtained in 77% yield (207
mg) from thioamide 1h (100 mg, 0.4 mmol) and azide 2f (213 mg, 1.0 mmol) according to the
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general procedure as a colorless powder; mp: 199‒201 °C (decomp.). H NMR (DMSO-d6): δ
3.30 (s, 8H, CH2), 3.82 (s, 6H, OMe), 7.09 (d, J = 8.8 Hz, 4H, H-Ar), 7.84 (d, J = 8.8 Hz, 4H, H-
13
Ar), 8.34 (br. s, 2H, NH), 9.14 (br. s, 2H, NH). C{1H} NMR (DMSO-d6): δ 51.8, 55.5, 114.1,
128.2, 133.8, 136.4, 155.8, 162.2, 169.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C24H27N10O6S4 679.0992; Found 679.1001.
(1Z,1'Z)-1,1'-(Piperazine-1,4-diylbis(1,2,3-thiadiazole-5,4-diyl))bis(N'-((4-
nitrophenyl)sulfonyl)formimidamide) (8d). Compound 8d was obtained in 57% yield (160 mg)
from thioamide 1h (100 mg, 0.4 mmol) and azide 2c (228 mg, 1.0 mmol) according to the
general procedure as a pale yellow powder; mp: 220‒222 °C (decomp.). 1H NMR (DMSO-d6): δ
3.39 (s, 8H, CH2), 8.15 (d, J = 8.4 Hz, 4H, H-Ar), 8.39 (d, J = 8.4 Hz, 4H, H-Ar), 8.59 (br. s, 2H,
NH), 9.38 (br. s, 2H, NH). 13C{1H} NMR (DMSO-d6): δ 51.9, 124.4, 127.7, 135.9, 147.3, 149.5,
157.2, 169.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H21N12O8S4 709.0483; Found
709.0482.
(1Z,1'Z)-1,1'-(Piperazine-1,4-diylbis(1,2,3-thiadiazole-5,4-diyl))bis(N'-((4-
fluorophenyl)sulfonyl)formimidamide) (8e). Compound 8e was obtained in 59% yield (154 mg)
from thioamide 1h (100 mg, 0.4 mmol) and azide 2g (201 mg, 1.0 mmol) according to the
1
general procedure as a colorless powder; mp: 211‒213 °C (decomp.). H NMR (DMSO-d6): δ
3.34 (s, 8H, CH2), 7.40‒7.43 (m, 4H, H-Ar), 7.97‒7.99 (m, 4H, H-Ar), 8.43 (br. s, 2H, NH), 9.22
(br. s, 2H, NH). 13C{1H} NMR (DMSO-d6): δ 51.8, 116.1 (d, J = 22.7 Hz), 129.2 (d, J = 9.5 Hz),
136.2, 138.4, 156.5, 164.1 (d, J = 251.3 Hz), 169.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H21F2N10O4S4 655.0593; Found 655.0596.
N-(4-(N-((Z)-(5-(4-(4-((Z)-N'-((4-Acetamidophenyl)sulfonyl)carbamimidoyl)-1,2,3-thiadiazol-5-
yl)piperazin-1-yl)-1,2,3-thiadiazol-4-yl)(amino)methylene)sulfamoyl)phenyl)acetamide (8f) and
N-(4-(N-(4-(4-(5-((4-acetamidophenyl)sulfonamido)-1H-1,2,3-triazole-4-
carbonothioyl)piperazine-1-carbonothioyl)-1H-1,2,3-triazol-5-yl)sulfamoyl)phenyl)acetamide
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