Switchable Synthesis of 4,5-Functionalized 1,2,3-Thiadiazoles and 1,2,3-Triazoles from 2-Cyanothioacetamides under Diazo Group Transfer Conditions

Article abstract of DOI:10.1021/acs.joc.6b02736

High yield solvent-base-controlled, transition metal-free synthesis of 4,5-functionalized 1,2,3-thiadiazoles and 1,2,3-triazoles from 2-cyanothioacetamides and sulfonyl azides is described. Under diazo transfer conditions in the presence of a base in an aprotic solvent 2-cyanothioacetamides operating as C-C-S building blocks produce 5-amino-4-cyano-1,2,3-thiadiazoles exclusively. The use of alkoxide/alcohol system completely switches the reaction course due to the change of one of the reaction centers in the 2-cyanothioacetamide (C-C-N building block) resulting in the formation of 5-sulfonamido-1,2,3-triazole-4-carbothioamide sodium salts as the only products. The latter serve as good precursors for 5-amino-1,2,3-thiadiazole-4-carboximidamides, the products of Cornforth-type rearrangement occurring in neutral protic medium or under acid conditions. According to DFT calculations (B3LYP/6-311+G(d,p)) the rearrangement proceeds via intermediate formation of a diazo compound, and can be catalyzed by acids via the protonation of oxygen atom of the sulfonamide group.

Full text of DOI:10.1021/acs.joc.6b02736

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Article
Switchable Synthesis of 4,5-Functionalized 1,2,3-Thiadiazoles and 1,2,3-
Triazoles from 2-Cyanothioacetamides under Diazo Group Transfer Conditions
Valeriy O. Filimonov, Lidia N. Dianova, Kristina A. Galata, Tetyana V. Beryozkina, Mikhail Sergeevich
Novikov, Vera S. Berseneva, Oleg S. Eltsov, Albert T. Lebedev, Pavel A. Slepukhin, and Vasiliy A. Bakulev
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Mar 2017
Downloaded from http://pubs.acs.org on March 23, 2017
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Switchable Synthesis of 4,5ꢀFunctionalized 1,2,3ꢀThiadiazoles and 1,2,3ꢀ
Triazoles from 2ꢀCyanothioacetamides under Diazo Group Transfer
Conditions
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Valeriy O. Filimonov,† Lidia N. Dianova,† Kristina A. Galata,† Tetyana V. Beryozkina,† Mikhail
S. Novikov,‡ Vera S. Berseneva,† Oleg S. Eltsov,† Albert T. Lebedev§, Pavel A. Slepukhin†,│ and
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
‡St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg
199034, Russia
§Lomonosov Moscow State University, Department of Chemistry, Moscow 119991, Russia
│I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Sciences,
20 S. Kovalevskaya st., Yekaterinburg 620990, Russia
*Corresponding author. Eꢀmail: v.a.bakulev@urfu.ru
Graphical abstract
H2N
S
SO2R
X
acid
CN
N
N
X
RSO2N3
N
RSO2N3
N
N
N
N
N
N
N
N
NNaSO2R
base
aprotic solvent
strong base
protic solvent
CN
S
N
S
S
H
X
X
base
69 90%
57 93%
19 examples
75 98%
19 examples
7 examples
X = (CH2)n; OCH2; n = 1ꢀ3
Abstract
High yield solventꢀbaseꢀcontrolled, transition metalꢀfree synthesis of 4,5ꢀfunctionalized 1,2,3ꢀ
thiadiazoles and 1,2,3ꢀtriazoles from 2ꢀcyanothioacetamides and sulfonyl azides is described.
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Under diazo transfer conditions in the presence of a base in an aprotic solvent 2ꢀ
cyanothioacetamides operating as C−C−S building blocks produce 5ꢀaminoꢀ4ꢀcyanoꢀ1,2,3ꢀ
thiadiazoles exclusively. The use of alkoxide/alcohol system completely switches the reaction
course due to the change of one of the reaction centers in the 2ꢀcyanothioacetamide (C−C−N
building block) resulting in the formation of 5ꢀsulfonamidoꢀ1,2,3ꢀtriazoleꢀ4ꢀcarbothioamide
sodium salts as the only products. The latter serve as good precursors for 5ꢀaminoꢀ1,2,3ꢀ
thiadiazoleꢀ4ꢀcarboximidamides, the products of Cornforthꢀtype rearrangement occurring in
neutral protic medium or under acid conditions. According to DFT calculations (B3LYP/6ꢀ
311+G(d,p)) the rearrangement proceeds via intermediate formation of a diazo compound, and
can be catalyzed by acids via the protonation of oxygen atom of the sulfonamide group.
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Introduction
1,2,3ꢀTriazoles and 1,2,3ꢀthiadiazoles have been receiving permanent interest due to their
exciting chemical reactivity including ring rearrangements1 and transformations1aꢀd,2 to other
heterocyclic compounds and valuable organic building blocks. 1,2,3ꢀThiadizole derivatives
exhibit antibacterial, antiviral, anticancer, fungicidal, herbicidal growth regulating (plants) and
defoliating (cotton) activity.3 After the CuAAC (copperꢀcatalyzed cycloaddition of azides to
acetylenes) had been discovered4 huge variety of different series of 1,2,3ꢀtriazole derivatives
became easily available. 1,2,3ꢀTriazoles have shown many important biological properties, such
as antibacterial, including bioactivity against the Mycobacterium tuberculosis, antiviral (HIV),
antifungal, high activity against leukemia L1210, anticancer and many other types of
bioactivity.5 There are four compounds bearing 1Hꢀ1,2,3ꢀtriazole core in clinical studies which
may appear in the market of drugs in nearest future (Figure 1).5 1,2,3ꢀTriazoles can act as
bioconjugates,6 chemosensors,7 ligands,8 or anion receptors.9 In turn, 1,2,3ꢀtriazoles may be used
in materials chemistry, medicine and in analytical chemistry. Although sulfonamide group is
known as a good pharmacophore group many compounds bearing this moiety are found to
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exhibit interesting biological activities5 only a few 5ꢀsulfonylamidoꢀ1,2,3ꢀtriazoles are
published.10
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Figure 1. Medicine and agricultural preparations among 1,2,3ꢀtriazoles and 1,2,3ꢀthiadiazoles.
There are several powerful methods for the synthesis of 1,2,3ꢀtriazoles published in the
literature: thermal and metal catalyzed addition of azides to acetylenes; 1,3ꢀdipolar cycloaddition
of azides to alkynes;1b,4 reactions of azides with methylene active carbonyl compounds;11
reactions of NHꢀ1,2,3ꢀtriazoles with electrophiles; intramolecular cyclizations of αꢀdiazoimines11
and dipolar cycloaddition reactions of diazo compounds and nitriles.11b CuAAC reaction is the
most effective among them and widely used to the synthesis of various types of 1,2,3ꢀtriazole
derivatives.4 Despite of good yields this method is not applicable for the synthesis of 5ꢀaminoꢀ
1,2,3ꢀtriazole derivatives due to the poor availability of the starting compounds. Therefore the
search of new routes to functionalized 1,2,3ꢀtriazoles remains a synthetic challenge. Since few 5ꢀ
aminoꢀ1,2,3ꢀtriazoleꢀ4ꢀcarbothioamides were prepared in reactions of aryl azides with 2ꢀ
cyanothioacetamides12 we turned our attention to reaction of sulfonyl azides with
cyanothioacetamides to find an approach to 1,2,3ꢀtriazoles bearing both thioamide and
sulfonamide groups. At the same time, the reactions of primary and secondary methylene active
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thioamides with sulfonyl azides led to 5ꢀaminoꢀ1,2,3ꢀthiadiazoles (Scheme 1). Actually, the
generally accepted opinion on the single “thiadiazole direction” of the reactions of methylene
active thioamides with sulfonyl azides has been helding for long time.1a The combined
experimental and theoretical studies of reaction of tertiary cyanothioacetamides 1 with sulfonyl
azides 2 and comparison of their reactivity with that of primary and secondary 2ꢀ
cyanothioacetamides used in the present study demonstrated three directions of this reaction
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leading
to
5ꢀaminoꢀ4ꢀcyanoꢀ1,2,3ꢀthiadiazoles
3,
5ꢀsulfonamidoꢀ1,2,3ꢀtriazoleꢀ4ꢀ
carbothioamides 4 and 5ꢀcycloaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbimidamides 5 (Scheme 1).
Depending on nature of starting reagents, nature of a solvent and type and amount of a base used
a direction of the reaction can be switched of in favor of each compound as an exclusive product.
The proper conditions were found and methods were elaborated for the selective and efficient
synthesis of 4ꢀcyanoꢀ5ꢀcycloaminoꢀ1,2,3ꢀthiadiazoles 3, 5ꢀsulfonamidoꢀ1,2,3ꢀtriazoleꢀ4ꢀ
carbothioamides 4 and 5ꢀcycloaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbamidines 5.
Previous works
S
S
CN
NHR
R2
NH HN
NHR1
NHR2
NHR2
NHR1
R1
S
TsN3
TsN3
NHR
S
N
N
N
N
N
N
NC
Base
[1a]
Base
[1a]
S
S
S
S
R1, R2 = H, Alk, Ar
R = H, Alk, Ar
Present work
CN
H2N
S
SO2R
X
acid
N
N
RSO2N3
base
RSO2N3
N
X
N
N
N
N
N
H
N
N
N
CN
S
strong base
protic solvent
N
NNaSO2R
S
S
aprotic solvent
X
1
X
base
X = (CH2)n; OCH2; n = 1ꢀ3
Scheme 1. Reactions of thioamides with sulfonyl azides.
Results and discussions
In order to involve sulfonyl azides as a N=N−N building blocks in the formation of 1,2,3ꢀ
triazoles from 2ꢀcyanothioacetamides, we decided to screen the reaction conditions using 3ꢀ
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(morpholinꢀ1ꢀyl)ꢀ3ꢀthioxopropanenitrile (1a) and tosyl azide (2a) as a model precursors. Using
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5
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ethanol as a solvent we tested various bases including sodium ethoxide, pyridine, triethylamine
o
and DBU (1,8ꢀdiazabicycloundecꢀ7ꢀene) at 0 C. To our delight the reaction with EtONa
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provided triazole 4a in significant amounts along with thiadiazoles 3a,5a and tosylamide (the
ratio 3a,4a,5a,TsNH2 = 11:73:3:11) (Scheme 2).
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Scheme 2. Reaction of thioamide 1a with azide 2a.
Surprisingly, substitution of EtONa by any nitrogen base leads to the increase of
selectivity of the process and the formation of thiadiazole 3a as the only reaction product. Prior
to continue the search for optimal conditions for synthesis of triazoles 4 the generality of the
effect of a base nature to direct the reaction for various 2ꢀcyanothioacetamides was estimated.
Thus, the reaction of 2ꢀcyanothioacetamides 1a−i with azide 2b (Table 1) was thoroughly
studied. Exclusive formation of thiadiazole 3e either in pyridine or ethanol in the presence of
triethylamine or DBU or under action of EtONa in 1,4ꢀdioxane was found for reaction of
thioamide 1e with benzene sulfonyl azide (2b). Pyridine as a base and a solvent, and room
temperature (Table 1) proved to be optimal for this reaction. In this case the reaction is
completed in 1−2 h. With these conditions in hand we have prepared a series of 4ꢀcyanoꢀ5ꢀ
dialkylaminoꢀ1,2,3ꢀthiadiazoles 3a−i, including novel 5ꢀcycloaminoꢀ1,2,3ꢀthiadiazoles 3a−e, in
69−90% yields. The structures of compounds 3a−e are consistent with NMR and mass spectra
and confirmed by Xꢀray analysis data for singleꢀcrystal of compound 3a (Figure S1 of
Supporting Information).
Table 1. Synthesis of thiadiazoles 3a−i
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entry thiоamide
NRR′
thiadiaꢀ
time of
reaction,
min.a
5
yield,
%
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zole 3
1
1
2
85
86
1a
1b
3a
3b
80
3
4
10
20
90
80
1c
3c
1d
3d
5
60b
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1e
3e
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Me2N
Ph2N
H2N
NDc
NDc
20
74
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81
1f
1g
1h
1i
3f
3g
3h13
3i1l
4ꢀ
120
MeC6H4NH
aReaction times were measured for reaction of azides 2a‒e (1.0 mmol) with
appropriate thioamide 1 (2.5 mmol) in 1 mL of pyridine by IR spectroscopy.
The end of reaction was determined based on the disappearance of azide group
stretching at 2115‒2134 cm‒1 in IR spectra of a reaction mass after fast
b
evaporation of pyridine; reaction time for the reaction of thioamide 1e with
azide 2a (TsN3) is 125 min, azide 2b (PhSO2N3) ꢀ 60 min, azide 2c (4ꢀ
MeOC6H4SO2N3) ꢀ 135 min, azide 2d (4ꢀFC6H4SO2N3) ꢀ 30 min, with azide 2e
(MsN3) ꢀ 5 min; cND = not determined
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The reactions time of thioamide 1e with arylsulfonyl azides 2a‒e increases in the following
order: MsN3 (2e) >> 4ꢀFC6H4SO2N3 (2d) > PhSO2N3 (2b) > TsN3 (2a) > 4ꢀMeOC6H4SO2N3 (2c)
that coincides with their activity as diazo transfer agents.
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The tolerance of the reaction to primary, secondary, and tertiary thioacetamides 1 coupled
with the availability of these compounds provides a reason to consider the suggested protocol as
a versatile and convenient route to 5ꢀaminoꢀ4ꢀcyanoꢀ1,2,3ꢀthiadiazoles 3.
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As it was mentioned above the use of EtONa/EtOH system instead of pyridine results in
the realization of competitive reactions leading triazoles 4 and thiadiazoles 5 with the exception
of thioamide 1d which furnishes thiadiazole 3d under all used conditions.
Our further efforts were focused on the optimal conditions for the preparation of 1,2,3ꢀ
triazoles 4 using cyanothioacetamide 1b and azide 2b as precursors. In order to increase the ratio
of 4:5 we varied alcohol, temperature, type and amount of a base (Table 2).
Table 2. Optimizations of the Reaction Conditions for Reaction of 1b with 2ba
entry base (equiv) solvent
T (°C)
−10
+10
−10
+10
+20
+30
+10
total yield 4b+5b (%)
ratio 4b:5b
23:77
16:84
51:49
40:60
40:60
40:60
92:8
1
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5
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7
MeONa (1.0) MeOH
MeONa (1.0) MeOH
58
56
61
69
60
50
85
EtONa (1.0)
EtONa (1.0)
EtONa (1.0)
EtONa (1.0)
EtONa (2.0)
EtOH
EtOH
EtOH
EtOH
EtOH
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EtONa (5.0)
EtONa (5.0)
EtONa (5.0)
PrONa (1.0)
EtOH
+10
−10
+20
+10
78
83
73
82
100:0
100:0
100:0
95:5
EtOH
EtOH
PrOH
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aReaction conditions: 1b (1.0 mmol, 1.0 equiv), 2b (1.0 mmol, 1.0 equiv), base (1.0−5.0 equiv), solvent
(4 mL), −10+30°C, 1 h
Though the use of less polar alcohols and lower temperature enhances the formation of triazole
4b, more crucial is the increase of amount of sodium ethoxide. Table 2 demonstrates the
exclusive formation of triazole 4b when 5.0 equiv of sodium ethoxide are used. Thus, the
optimal conditions for the synthesis of triazoles include the use of thioamide 1b and azide 2b in
ratio 1:1, ethanol as a solvent and 5.0 equiv of sodium ethoxide at –10 °C. The desired product
4b was obtained in 83% yield (Table 2, Entry 9). As follows from Table 2, the 4b/5b ratio
depends little on temperature, but it increases significantly when changing the alcohol solvent. It
can be explained by a much larger decrease in solubility of triazole 4b than thiadiazole 5b in less
polar solvents, which leads to a shift in the equilibrium in favor of the triazole).
Inspired by this result we used the optimized reaction conditions for reactions of azides
2a−d with the tertꢀthioacetamides. Thus, we have demonstrated a method for the synthesis of
novel 5ꢀsulfonylaminoꢀ1,2,3ꢀtriazoleꢀ4ꢀcarbothioamides 4 and have prepared a series of 19
compounds bearing various tertꢀthioamide and sulfonylamino groups in good to excellent yields
(57−93%) (Table 3). The reaction tolerates various tertiary amine moieties in thioamide function
and substitutes in sulfonyl azides. However, in contrast to other reactions mesyl azide (2e) reacts
with thioаcetamide 1d to give 5ꢀ(pyrrolidinꢀ1ꢀyl)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3d) in 70%
yield (Table 3). Furthermore, the reaction of primary and secondary cyanothioacetamides 1h,i
under these conditions also affords 5ꢀaminoꢀ4ꢀcyanothiadiazoles 3h,i (Table 1).
Table 3. Synthesis of triazoles 4a−sa
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aIsolated yield. Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), EtONa (5.0 mmol), EtOH (4 mL),
‒10°C, 1h.
To gain deeper insight into the effect of the amount of base and the nature of thioamides on the
course of the process the products ratios in the reactions of tosyl azide (2a) with thioamides 1a
and 1d in the presence of sodium ethoxide at 2, 5, 10, 30 and 45 min have been examined
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(Figures 2,3). The formation of all three products 3−5 under these conditions is observed. In the
reaction of thioamide 1d with tosyl azide (2a) in the presence of 1.0 equiv of sodium ethoxide at
0 °C the constant 3d/4g+5g ratio as 5:1 was registered after 5 min (Figure 2). The use of 2 equiv
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of sodium ethoxide at 0 °C dramatically changes the ratio of these products in favor of adducts
4g/5g (ratio 3:4:5 achieved 4:65:20) (Figure S3 of Supporting Information). The NMR
monitoring of the reaction of thioamide 1a with azide 2a (1.0 equiv of EtONa, −10 °C) revealed
the sharp increase of thiadiazole 5a concentration at very early stage of the process. Further the
reduction of a share of thiadiazole 5a with the simultaneous growth of a share of triazole 4a was
observed, proving that triazole 4a originates from thiadiazole 5a.
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80.0
70.0
60.0
50.0
TsNH2
40.0
3d
30.0
20.0
4g+5g
10.0
0.0
0.0
10.0 20.0 30.0 40.0 50.0
Time (min)
Figure 2. Content of the products 3d,4g+5g in the course of the reaction of thioamide 1d with
1
tosyl azide (2a) according to H NMR spectra. Reaction conditions: 1d (1.0 equiv, 2.0 mmol,
308 mg), 2a (1.0 equiv, 2.0 mmol, 394 mg), EtONa (1.0 equiv, 2.0 mmol), EtOH (5 mL), 0 °C.
Aliquots of reaction mixture (1 mL) were taken off in 2, 5, 10, 30 and 45 min and precipitates
were filtered off.
80.0
70.0
60.0
4a
50.0
40.0
30.0
5a
20.0
10.0
0.0
3a
TsNH2
0.0
10.0
20.0
30.0
40.0
50.0
Time (min)
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Figure 3. Content of the products 3a,4a,5a in the course of the reaction of thioamide 1a with
3
4
5
1
tosyl azide (2a) according to H NMR spectra. Reaction conditions: 1a (1.0 equiv, 2.0 mmol,
6
7
8
9
340 mg), 2a (1.0 equiv, 2.0 mmol, 394 mg), EtONa (1.0 equiv, 2.0 mmol), EtOH (5 mL), 0 °C.
Aliquots of reaction mixture (1 mL) were taken off in 2, 5, 10, 30 and 45 min and precipitates
were filtered off.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Thus, the direction of the reactions of thioamides 1 with azides 2 either to 4ꢀcyanothiazoles
3 or to triazoles 4 depends whether weak or strong bases and protonic or aprotonic solvents are
used. The factors govern the directions of the reaction of thioamides 1 with azides 2 in favor of
thiadiazoles 3 or salts 4 are nature of starting reagent, type of a solvent and amount and strength
of a base (Scheme 2, Table 2). The use of either aprotonic solvents in the presence of any base or
protic solvents in the presence of a weak base leads to thiadiazoles 3 as exclusive products.
Conversely, the use of an excess of a strong base in a protic solvent favors the formation of
1,2,3ꢀtriazolꢀ4ꢀcarbothioamides 4.
The reaction of triazoles 4 formation proceeding with retention of all atoms of starting
compounds can be referred to the family of atom economic process14 and can be used for
elaboration of a new green chemistry process.15
A possible mechanism for the formation of compounds 3−5 is depicted in Scheme 3. We
assumed that triazenyl anion Zꢀ7 generated by the addition of carbanion 6 to sulfonyl azide 2 is a
common intermediate on the pathways to all products. 1,4ꢀPrototropic shift in anion Zꢀ7 leading
to carbanion 8 and cyclization across the cyano group to triazolidine 12, are those competitive
transformations that provides finally thiadiazole 3 and triazole 4, respectively. According to the
calculations performed for model triazenyl anion Zꢀ7a (Scheme 3, Fig. 4, NR2 = pyrrolidinꢀ1ꢀyl,
R′ = Me) at DFT B3LYP/6ꢀ311+G(d,p)16 level with PCM solvation model for methanol Zꢀ7a is
by 1.7 kcal/mol more stable than its E isomer and can undergo intramolecular 1,4ꢀprototropic
shift (TS1) into anion 8a (Fig. 4) even at room temperature (ꢀG≠ 21.3 kcal/mol).
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3
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7
8
‡
R
S
N
O
S
S
N
C
NH2
δ
O
H
δ'
tautoꢀ
NR2
-7-H
R
HN
H2N
NR2
NR2
NR2
S
R'SO2N
N
merism
H
NR2
S
N
NC
base
R'SO
2NH
N
R'SO2N
N
R'SO2N
H
ꢀRO
Z
NR2
1
N
S
N
N
N
5
12
R'O2S
N
H
13
N
N
ROH
H+
base
TS 7
tautoꢀ
merism
12
base
H
S
S
N
S
S
N
R'SO2N3
NH
tautoꢀ
C
C
HN
H2N
NR2
NR2
merism
NR2
NR2
R'SO2NH
NR2
NR2
2
H
N
NC
R'SO2N
N
9
R'SO2N
N
N
N
S
R'SO
2N
R'SO2N
N
N
S
N
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
14
N
-7
10
Z
11
15
S
N
S
S
N
S
S
NC
N
NR2
R'SO2N
HN
R'SO2NH
base
NR2
NR2
R'SO2NH
HN
NC
NR2
ꢀR'SO2NH
NC
NR2
NR2
S
N
N
N
HN
N
N
3
R'SO2NHN
4
N
N
N
8
17
9
16
Scheme 3. Plausible mechanism for the reaction of thioamides 1 with azides 2.
Figure 4. Relative free Gibbs energies (in kcal/mol, 298K, PCM model for the MeOH) of
compounds 3d,Zꢀ7a−11a and the transition states TS1−TS4 computed at the B3LYP/6ꢀ
311+g(d,p) level.
The latter proved to be very unstable due to the fast elimination of sulfonylamide anion (TS2,
ꢀG≠ 1.3 kcal/mol) to give diazo thioamide 9a followed by lowꢀbarrier cyclization (TS3, ꢀG≠ 4.5
kcal/mol) into thiadiazole 3 via heteroelectrocyclic (pseudopericyclic)17 mechanism. We have
also supposed that triazole 4 and thiadiazole 5 originate from triazole intermediate 13, the
tautomer of triazoline 12 (Scheme 3). The latter is the cyclization product of triazenylꢀanion Zꢀ7
across the cyano group. Intramolecular triazoline ring formation cannot occur directly in anion Zꢀ
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7 because there is no local minimum on the reaction Potential Energy Surface (PES)
corresponding to 1,5ꢀexoꢀdigꢀcyclization product (not shown in Scheme 3). An alternative
pathway to triazole 12 involves prior intermolecular tautomerization of anion Zꢀ7 to anion 10
followed by oneꢀstep cyclization/protonꢀtransfer to give thiolate 11 precursor of triazole 12.
However this transformation is unlikely to occur as the barrier for cyclization of model system
11a (TS4, Fig. 4) is much higher than for competitive proton transfer Zꢀ7a→8a (TS1). Evidently
the protonation of Zꢀ7 with protic solvent to give triazene Zꢀ7ꢀH is the sole reaction which is
capable of competing with intramolecular 1,4ꢀproton transfer leading to thiadiazole 3.
Deprotonation of triazene Zꢀ7ꢀH with a weak base, such as triethylamine, triggered the reverse
reaction sequence leading to thiadiazole 3, while in alkoxide/alcohol system 1,5ꢀexoꢀdigꢀ
cyclization onto C≡N bond via 6ꢀmemebered transition state TS7→12 with the formation
triazoline 12 as the first cyclic intermediate on the route to triazoles 4 occurs. In this case the
formation of the fiveꢀmembered ring of compound 12 is a concerted process which is facilitated
by concurrent protonation of the nitrile nitrogen by an alcohol molecule. We propose that
triazole 12 easily transforms in basic solution to aromatic triazole 13, and this is in agreement
with the isolation of stable 5ꢀaminoꢀ1ꢀarylꢀ1,2,3ꢀtriazoleꢀ4ꢀcarbothioamides in reaction of
thioamides 1a,b with aryl azides.12 Then triazole 13, bearing strong withdrawing sulfonyl group
destabilizing the ring,1b rearranges to thiadiazole 5 via transient formation of diazo compound
14. This is in good agreement with the experimentally observed high values of 5/4 ratio at an
early stage of the reaction and decrease in share of thiadiazoles 5 by the end of the reaction.
The further transformation of thiadiazole 5 to salt 4 involves baseꢀcatalyzed
tautomerization to thiadiazole 15, ring opening to diazo compound 16, cyclization to triazole 17
followed by the sodium salt formation.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The calculation results well explain the change in the reaction pathway when EtONa/EtOH
system is replaced with pyridine. In the absence of the alcohol molecules, e.g. in 1,5ꢀcyclization
of triazenylꢀanion Zꢀ7, 1,4ꢀHꢀshift leading to diazo transfer product 3 becomes the fastest process
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which, importantly, occurs irreversibly. The replacement of alkoxide/alcohol system with a
solution of weak nitrogen base in alcohol leads to the decrease of concentration of alkoxide,
which promotes cyclization of Zꢀ7ꢀH to 12. As the result, 1,4ꢀprototropic shift in anion Zꢀ7 that
is rate limited step of transformation of Zꢀ7a to thiadiazole 3 should become more preferable
than 1,5ꢀcyclization. This should inhance the formation of the latter that was observed
experimentally.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
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43
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49
50
51
52
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60
5ꢀSulfonylaminoꢀ1,2,3ꢀtriazoles 4a−s are stable as solids under storage during many days.
However they are not very stable in the presence of water and in solutions of various solvents
containing water traces. They were characterized as sodium salts hydrates. These compounds
were found to undergo rearrangement to isomeric thiadiazoles 5 when treated with water.
Reactions in water are completed within 1 h, in the presence of silica gel for 30 min and in the
presence of hydrochloric acid it takes less than 10 min. The rearrangement occurs even in solid
state (50% conversion of 4p in 1 month storage in a closed flask). The scope of the reaction is
shown in Table 4. All 5ꢀsulfonamidoꢀ1,2,3ꢀtriazoleꢀ4ꢀthiocarboxamides 4 undergo the
rearrangement to form thiadiazoles 5 in good to excellent yields. This reaction represents a new
practically useful, economic method for the synthesis of 5ꢀaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀNꢀ
sulfonylcarbamidines 5 presented in the literature by only two compounds prepared by other
method.12
Table 4. Synthesis of Thiadiazoles 5a−sa
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H2N
SO2R
S
N
N
X
H2O
N
N
N
N
N
NNaSO2R
4a s
rt, 1 h
S
N
X
H
5a s
5m
Structure of compound
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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29
30
31
32
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37
38
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41
42
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50
51
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60
O
O
O
O
O
O
O
N
O
N
H2N
H2N
S
H2N
H2N
S
S
S
N
N
N
N
N
N
Me
OMe
OMe
N
N
N
S
N
N
N
N
N
S
S
S
O
O
O
Bn
5a
, 90%
5c, 91%
5d
5b, 86%
, 89%
O
O
O
O
O
O
O
O
H2N
H2N
H2N
H2N
S
S
S
S
S
N
N
N
N
N
N
N
N
N
N
F
F
Me
N
N
N
N
N
N
S
S
S
S
O
5g
, 94%
5e
, 89%
5f, 90%
5h, 90%
H2N
O
O
O
O
O
O
O
O
H2N
H2N
H2N
S
S
S
N
N
N
N
N
N
N
N
N
F
Me
N
N
N
N
N
N
N
S
S
S
S
Bn
Bn
5i
, 87%
5k
, 98%
5j
, 94%
5l
, 75%
O
O
O
O
O
N
O
N
O
O
H2N
H2N
H2N
H2N
S
S
S
S
N
N
N
N
N
N
N
F
OMe
O
Me
N
N
N
N
N
N
N
S
S
S
S
5n
, 92%
5p
, 90%
5m
, 87%
5o
, 86%
O
O
O
O
N
O
H2N
H2N
H2N
S
S
S
N
N
N
N
N
N
Me
OMe
N
N
F
N
N
N
S
S
S
5q, 93%
5r
5s
, 85%
, 93%
aIsolated yield. Reaction conditions:
4
(1.0 mmol), H2O (4 mL), rt, 1 h.
The structures of compounds 4 and 5 are consistent with NMR and massꢀspectra,
including HRMS and confirmed by Xꢀray data for singleꢀcrystal of compound 5m. Signals of
carbon atoms of thiocarbonyl group are displayed at 194.7−194.9, atom C5 of 1,2,3ꢀtriazole ring
at 146.0−147.6 and atom C4 at 137.1−138.5 ppm. Signal of 1H in NMR spectra at 12.96−13.11 is
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characteristic of compounds 4 as 1ꢀNHꢀ1,2,3ꢀtriazole tautomeric form.18 Signals of the ring and
3
4
5
1
4ꢀsubstituents in H NMR spectra of compound 5 are slightly differed from those for triazole 4
allowing to estimate their ratio in reaction mixture. 13C NMR spectra of thiadiazoles 5 exhibit
signals of carbons: of amidino group at 156.5−157.4, of C4 at 134.1–136.3 and C5 at
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
34
35
36
37
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45
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47
48
49
50
51
52
53
54
55
56
57
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60
164.7−170.2 ppm.
All amidines 5aꢀs rearrange back to 5ꢀsulfonylaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbothioamides
4aꢀs at ambient temperature in protic solvents in the presence of 5 equiv of sodium ethoxide,
triethylamine or DBU in good yields. This novel rearrangement represents a baseꢀacid catalyzed
process between acidic (5ꢀsulfonylaminoꢀ1,2,3ꢀtriazoles 4) and basic (1,2,3ꢀthiadiazoleꢀ4ꢀ
carbamidines 5) isomeric forms. Compounds 4 are stable as sodium salts, while compounds 5
being stable in neutral and acidic mediums undergo conversion to triazoles 4 in the presence of a
sodium ethoxide. The NHꢀforms of triazoles 4 are not stable. Nevertheless 1H NMR spectrum of
NHꢀform of triazole 17 (X = CH2, R = Tos) was successfully recorded in solution of CD3OD
(Scheme 4).
Scheme 4. Reversible transformation of 1,2,3ꢀthiadiazole 5 and 1,2,3ꢀtriazole 4.
The effect of a type and amount of a base on the process of rearrangement was studied by
1H NMR spectrometry for transformation of thiadiazole 5m to triazole 17/4m in methanol in the
presence of triethylamine and sodium ethoxide (Table 5).
It was shown that the conversion of 5m achieved 10% in 24 hr after treatment with 5.0 equiv
triethylamine to form mixture of 5m and 17 (R = pꢀTolyl, X = CH2). The use of stronger base
(0.1 equiv of sodium ethoxide) increased the conversion to 97%, respectively. The complete
conversion 5m to 4m was observed when 5.0 equiv of CD3ONa was used. The halfꢀtime of the
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rearrangement of 4m in methanol in the presence of 1.0 equiv of DBU, 1.0 equiv or 5.0 equiv of
3
4
5
1
sodium ethylate was determined by H NMR spectrometry as 95, 53 and 22 min, respectively
6
7
8
9
(Figure S4 of Supporting Information). These data reveal that the time of reaction decreases with
the increase of strength and amount of the base.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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29
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32
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42
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44
45
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51
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53
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Table 5. Ratio of 17:4m:5m in 24 h after treatment of 5m with a base according to 1H NMR
spectroscopya
base
amount of base
1.0 equiv
7/0/93
0.1 equiv
8/0/92
5.0 equiv
10/0/90
0/100/0
Et3N
CD3ONa 97/0/3b
0/100/0
aReaction conditions: thiadiazole 5m (0.027 mmol), CD3OD (0.5 mL), Et3N or CD3ONa (0.1 equiv; 1.0
equiv; 5.0 equiv), 25 °C, 24 h.
The both rearrangements processes involve two atoms of 4ꢀsubstituents, opening of the ring to
form intermediate diazo compounds and concurrent cyclization of the latter by C=N or C=S
bonds to form isomeric heterocyclic compounds 4 and 5 and reffered to Cornforth type
rearrangement.1a,b,k,19 The transformation of compounds 4 to 5 represents a first example of novel
rearrangement of 1,2,3ꢀtriazoles containing C=S bond in the chain to isomeric 1,2,3ꢀthiadiazole
bearing C=N bond in the chain. The reverse rearrangement of 1,2,3ꢀthiadiazoles 5 to 1,2,3ꢀ
triazoles 4 represents first example of interchange of cyclic thioamide group by carbamidine
group of the chain. A few examples of rearrangements of 1,2,3ꢀthiadiazoles containing aldimine
group to 1,2,3ꢀtriazoles with C=S group in the chain are used to describe the mechanism of
multiꢀstep reactions. Either starting 1,2,3ꢀthiadiazoles1h or final 1,2,3ꢀtriazoles1c,i were not
isolated in these reaction and used in situ. In contrast to previously studied rearrangements in
1,2,3ꢀtriazole and 1,2,3ꢀthiadiazole series1a‒d the reversible rearrangement of 1,2,3ꢀtriazoles 4
and 1,2,3ꢀthiadiazoles 5 represent transformations where both participants are isolated and
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identified that allowed to elucidate factors govern the direction of the rearrangement. Their
directions can be switched by the change in acidity of the medium. There are any example of that
kind effect for Cornforth rearrangement between 1,2,3ꢀtriazoles and 1,2,3ꢀthiadiazoles published
in the literature.
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17
18
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To clarify the role of an acid that can operate either as a neutralizing agent or as a catalyst in
Cornforthꢀtype rearrangement of 5 to 4, quantumꢀchemical calculations of possible isomerization
routes for model triazole 18 were carried out. Calculations demonstrate (Fig. 5) that 1,2,3ꢀ
triazole ring opening in 18 with the formation of diazo compound 19 is a rate determining step
with activation barrier 23.8 kcal/mol (TS5) (Fig. 5, blue line).
Figure 5. Relative free Gibbs energies (in kcal/mol, 298K, PCM model for the MeOH) of
compounds 5t,18−21 and the transition states TS5−TS9 computed at the B3LYP/6ꢀ311+g(d,p)
level.
The subsequent steps involve rotation around single С−С bond (TS6) and cyclyzation to
thiadiazole 21 (TS7). The energies of the corresponding transition states do not exceed that for
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TS5. Thiadiazole 21 resulted from this sequence is less stable than final tautomer 5t by 11.7
kcal/mol. We also evaluated the activation barrier for ring opening of protonated triazole 18
cation 18ꢀH+ (TS8, red line) which can be generated under acidic conditions. The ring opening
of cation 18ꢀH+, resulting in the formation of Nꢀprotonated diazo compound 19ꢀH+, has much
lower barrier (TS8 16.6 kcal/mol) than that for neutral molecule (TS5 23.8 kcal/mol). Lowꢀ
barrier cyclization (TS12 11.5 kcal/mol) followed by deprotonation gives thiadiazole 5t. These
data give reasons to believe that neutral forms of thiocarbamoyltriazoles 4 kinetically are less
stable than their salts and can undergo Cornforthꢀtype rearrangement even at room temperature
via intermediate formation of the diazo compounds to give more stable in acidic medium
thiadiazoles 5. Acids catalyze this isomerization facilitating the triazole ring opening by
protonation of sulfonamide oxygen atom.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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Conclusions
A flexible and convenient method for the preparation of 4,5ꢀfunctionalized 1,2,3ꢀthiadiazoles
and 1,2,3ꢀtriazoles from cyanothioacetamides and sulfonyl azides is described. The change of the
solvent and base enables the use a 2ꢀcyanothioacetamide both as C−C−S and C−C−N building
blocks for the construction either of 1,2,3ꢀthiadiazole or 1,2,3ꢀtriazole system, respectively, from
the same precursors. The reaction of benzenesulfonyl azide with primary, secondary and tertiary
cyanothioacetamides in pyridine gives 5ꢀaminoꢀ4ꢀcyanoꢀ1,2,3ꢀthiadiazoles in good yields. The
excess of sodium alkoxide in alcohol completely switches the reaction course resulting in the
formation of 5ꢀsulfonamidoꢀ1,2,3ꢀtriazoleꢀ4ꢀcarbothioamide sodium salts as the only products.
This dramatic redirection of the reaction pathway is explained in terms of the competing
transformations of triazenideꢀanion resulting from baseꢀinduced addition of 2ꢀ
cyanothioacetamide to sulfonyl azide: intramolecular 1,4ꢀprototropic shift versus alcoholꢀ
mediated 1,5ꢀcyclization to triazoline derivative. The synthesized 1,2,3ꢀtriazoleꢀ4ꢀ
carbothioamide sodium salts serve as good precursors for 5ꢀaminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀ
carboximidamides, the products of Cornforthꢀtype rearrangement occurring in neutral protic
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medium or under acid conditions. According to DFT calculations the rearrangement proceeds via
intermediate formation of a diazo compound, and can be catalyzed by acids via the protonation
of oxygen atom of the sulfonamide group.
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General
Starting materials and reagents were purchased from commercial sources and used without
further purification. Ethanol (EtOH) was dried and distilled over CaO prior to use. Pyridine and
triethylamine (Et3N) were distilled over KOH prior to use. THF was dried over sodium
benzophenone ketyl and distilled. 1,4ꢀDioxane was dried and distilled over Na prior to use.
Solvents used for silica gel chromatography (EtOAc/petroleum ether (40–70) (PE)) and
crystallization (EtOH, Et2O) were used without purification or removal of water. H and 13C
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NMR spectra were recorded at 400 and 100 MHz, respectively, with SiMe4 as internal reference
in DMSOꢀd6, DMSOꢀd6/CHCl3, CDCl3 or CD3ODꢀd4; the chemical shifts (δ) were expressed in
ppm, and J values were given in Hz. Mass spectra were obtained with a massꢀspectrometer using
electron ionisation (EI) technique (40–200 °C, 70 eV) with direct sample introduction into the
ion source. Highꢀresolution mass spectra (HRMS) were obtained with electrospray ionization
(ESIꢀTOF). The compounds were analyzed in positive ion detection mode. The IR spectra were
recorded with a FTꢀIR ATR (attenuated total reflection, ZnSe) spectrometer in the 4000−400 cmꢀ
1 region. The reactions were monitored by analytical TLC on aluminium foil plates with 0.2 mm
silica gel with a fluorescent indicator visualed 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.
Preparation of thioamides. 3ꢀMorpholinoꢀ3ꢀthioxopropanenitrile20 (1a), 3ꢀ(piperidinꢀ1ꢀyl)ꢀ3ꢀ
thioxopropanenitrile20 (1c), 3ꢀ(pyrrolidinꢀ1ꢀyl)ꢀ3ꢀthioxopropanenitrile20 (1d), 2ꢀcyanoꢀNꢀpꢀ
tolylethanethioamide21 (1i) were synthesized according to previously reported procedures. 2ꢀ
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CyanoꢀN,Nꢀdimethylethanethioamide (1f) and cyanoethanethioamide (1h) were commercially
available. New 3ꢀ(4ꢀbenzylpiperidinꢀ1ꢀyl)ꢀ3ꢀthioxopropanenitrile (1b), 3ꢀ(azepanꢀ1ꢀyl)ꢀ3ꢀ
thioxopropanenitrile (1e) and 2ꢀcyanoꢀN,Nꢀdiphenylethanethioamide (1g) were prepared using
modified literature procedure from appropriate amides.22
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Preparation of Sulfonyl Azides. Sulfonyl azides were prepared from the corresponding sulfonyl
chlorides23 following the literature procedures. Warning! Sulfonyl 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.
3ꢀ(4ꢀBenzylpiperidinꢀ1ꢀyl)ꢀ3ꢀthioxopropanenitrile
(1b).
3ꢀ(4ꢀBenzylpiperidinꢀ1ꢀyl)ꢀ3ꢀ
oxopropanenitrile (7.27 g, 30.0 mmol) was dissolved in anhydrous 1,4ꢀdioxane (50 mL), and
Lowesson’s reagent (6.10 g, 15.0 mmol) was added. Reaction mixture was stirred at 40−50 °C
for 5 h. Then the solvent was removed under reduced pressure and EtOH (10 mL) was added to
the residue. The precipitate was formed after the reaction mixture was maintained at +8 °С for 12
h. Then it was filtered off and washed with Et2O to obtain 1b as a colorless powder (6.60 g,
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85%); mp: 115–117 °C; Rf = 0.57 (EtOAc/PE, 1:1). H NMR (DMSOꢀd6/CHCl3): δ 1.13−1.32
(m, 2H), 1.66‒1.70 (m, 2H), 1.88−1.97 (m, 1H), 2.52‒2.54 (m, 2H), 3.05‒3.06 (m, 1H),
3.23‒3.29 (m, 1H), 4.11 (d, J = 12.0 Hz, 1H), 4.36 (s, 2H), 5.22 (d, J = 12.0 Hz, 1H), 7.17−7.21
(m, 3H), 7.27−7.31 (m, 2H). 13C NMR (DMSOꢀd6): δ 30.8, 31.9, 33.7, 36.4, 41.4, 50.1, 50.3,
116.3, 125.9, 128.2, 129.0, 139.8, 187.0. IR (ATR, ZnSe, cm–1): ν 3063, 3025, 2944, 2912, 2883,
2848, 2252. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H19N2S 259.1264; Found 259.1264.
3ꢀ(Azepanꢀ1ꢀyl)ꢀ3ꢀthioxopropanenitrile (1e). 3ꢀ(Azepanꢀ1ꢀyl)ꢀ3ꢀoxopropanenitrile (2.0 g, 12.0
mmol) was dissolved in anhydrous 1,4ꢀdioxane (15 mL), and Lowesson’s reagent (2.43 g, 6.0
mmol) was added. Reaction mixture was stirred at 75 °C for 1.5 h. Then the solvent was
removed under reduced pressure and the residue was purified by flash chromatography over
silica gel (60−120) using EtOAc/PE (1:2) mixture to give 1e as pale yellow crystals (1.30 g,
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59%); mp: 58–59 °C; Rf = 0.40 (EtOAc/PE, 2:1). 1H NMR (DMSOꢀd6/CHCl3): δ 1.55−1.62 (m,
4H), 1.78−1.85 (m, 4H), 3.76−3.79 (m, 2H), 4.04−4.07 (m, 2H), 4.23 (s, 2H). 13C NMR (DMSOꢀ
d6): δ 24.6, 25.5, 26.1, 27.3, 33.7, 52.8, 53.9, 116.5, 185.6. IR (ATR, ZnSe, cm–1): ν 2984, 2941,
2920, 2856, 2252, 1512. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C9H15N2S 183.0951; Found
183.0950.
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2ꢀCyanoꢀN,Nꢀdiphenylethanethioamide (1g). 2ꢀСyanoꢀN,Nꢀdiphenylacetamide (709 mg, 3.0
mmol) was dissolved in anhydrous 1,4ꢀdioxane (20 mL), and Lowesson’s reagent (667 mg, 1.65
mmol) was added. Reaction mixture was stirred at 90 °C for 2 h. Then the solvent was removed
under reduced pressure and the residue was purified by flash chromatography over silica gel
(60−120) using EtOAc/PE mixture. To achieve better separation, a composition of the eluent was
gradually changed from 1:6 to 1:4 EtOAc/PE. Pale yellow needles (524 mg, 69%); mp: 131–133
°C; Rf = 0.40 (EtOAc/PE, 1:4). 1H NMR (DMSOꢀd6/CHCl3): δ 3.99 (s, 2H), 7.27–7.31 (m, 1H),
7.40–7.49 (m, 7H), 7.56 (d, J = 8.0 Hz, 2H). 13C NMR (DMSOꢀd6): δ 35.5, 116.1, 126.9, 127.0,
127.8, 129.0, 129.6, 130.1, 134.6, 142.2. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H13N2S
253.0794; Found 253.0790.
Experimental procedures for preliminary study of interaction of thioamide 1a with tosyl
azide 2a (Scheme 2). (A) Thioamide 1a (170 mg, 1.0 mmol) was added into cooled (+10 °С)
solution of sodium ethoxide, freshly prepared from sodium (23 mg, 1.0 mmol) and anhydrous
ethanol (4 mL), and the resulting solution was stirred at this temperature for 5–10 min. Then the
reaction mixture was cooled till 0 °С and azide 2a (197 mg, 1.0 mmol) was added to the reaction
mixture portion by portion and the resulting mixture were stirred at 0 °С for 1 h. The formed
precipitate (346 mg) was filtered off, washed with cold ethanol and diethyl ether and dried in a
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desiccator over P4O10. According to H NMR spectrum the mixture consists of 4 products:
thiadiazole 3a, triazole 4a, thiadiazole 5a and tosyl amide in ratio/yield 11/10% : 73/67% :
3/2.5% : 11/10% (1H NMR (DMSOꢀd6/CHCl3): δ 2.34 (s, 3H, Me, 4a), 2.41 (s, 3H, Me, TsNH2),
2.43 (s, 3H, Me, 5a), 3.06 (br. s, 2H, CH2, 4a), 3.27−3.30 (m, 4H, CH2, 5a), 3.55 (br. s, 2H, CH2,
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4a) + 5a (m, 4H, CH2), 3.62−3.64 (m, 4H, CH2, 3a), 3.68 (br. s, 2H, CH2, 4a), 3.78−3.81 (m, 4H,
CH2, 3a), 4.18 (br. s, 2H, CH2, 4a), 7.04 (s, 2H, NH2, TsNH2), 7.15 (d, J = 8.0 Hz, 2H, Ar, 4a),
7.29 (d, J = 8.0 Hz, 2H, Ar, TsNH2), 7.34 (d, J = 8.2 Hz, 2H, Ar, 5a), 7.65 (d, J = 8.1 Hz, 2H,
Ar, 4a), 7.71 (d, J = 8.2 Hz, 2H, Ar, TsNH2), 7.77 (d, J = 8.1 Hz, 2H, Ar, 5a), 8.24 (s, 1H, NH2,
5a), 8.97 (s, 1H, NH2, 5a), 12.96 (s, 1H, NH, 4a).
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(B) A mixture of tosyl azide 2a (170 mg, 1.0 mmol) and thioamide 1a (197 mg, 1.0 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 in desiccator over P4O10 overnight
and crystallized from EtOH−Et2O mixture to give aminonitrile 3a (157 mg, 80%) as a colorless
crystals, mp: 80–82 °C; Rf = 0.5 (EtOAc/PE, 1:2). 1H NMR (DMSOꢀd6/CHCl3): δ 3.62−3.64 (m,
4H), 3.78−3.81 (m, 4H).
General Procedure (A) for the Synthesis of 4ꢀCyanothiadiazoles 3aꢀh. A mixture of
benzenesulfonyl azide 2b (238 mg, 1.3 mmol) and corresponding thioamide 1 (1.3 mmol) in
anhydrous pyridine (2 mL) was stirred at room temperature for 1−5 h. The reaction mixture was
poured on ice, the formed precipitate was filtered off, dried in desiccator over P4O10 overnight
and crystallized from EtOH−Et2O mixture to give aminonitriles 3a,b,d,f,g. In the case of
reaction of thioamides 1c,e pyridine was removed under reduced pressure and the residue was
purified by flash chromatography over silica gel (60−120) using EtOAc/PE (2:1) mixture to give
aminonitriles 3c,e.
5ꢀMorpholinoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3a). Compound 3a was obtained in 85% yield
(217 mg) according to the general procedure A (thioamide 1a: 221 mg; 2 h) as a colorless
crystals; mp: 80–82 °C; Rf = 0.5 (EtOAc/PE, 1:2). 1H NMR (DMSOꢀd6/CHCl3): δ 3.62−3.64 (m,
4H), 3.78−3.81 (m, 4H). 13C NMR (DMSOꢀd6): δ 51.9, 64.8, 113.6, 114.4, 172.2. IR (ATR,
ZnSe, cm–1): ν 2914, 2862, 2218, 1549, 1444, 1308, 1276, 1111. HRMS (ESIꢀTOF) m/z: [M +
H]+ Calcd for C7H9N4OS 197.0492; Found 197.0488.
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5ꢀ(4ꢀBenzylpiperidinꢀ1ꢀyl)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3b). Compound 3b was obtained in
86% yield (318 mg) according to the general procedure A (thioamide 1b: 336 mg; 4 h) as a
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colorless crystals, mp: 97–99 °C; Rf = 0.2 (EtOAc/PE, 1:2). H NMR (DMSOꢀd6/CHCl3): δ
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1.36−1.46 (m, 2H), 1.77−1.81 (m, 2H), 1.85−1.91 (m, 1H), 2.57 (d, J = 8.0 Hz, 2H), 3.37−3.44
(m, 2H), 3.85 (br. s, 1H), 3.89 (br. s, 1H), 7.13−7.17 (m, 3H), 7.23−7.27 (m, 2H). 13C NMR
(DMSOꢀd6): δ 30.4, 35.4, 41.3, 53.2, 113.3, 114.3, 125.8, 128.1, 128.8, 139.5, 171.0. IR (ATR,
ZnSe, cm–1): ν 2937, 2917, 2849, 2218, 1517, 1438, 1250. HRMS (ESIꢀTOF) m/z: [M + H]+
Calcd for C15H17N4S 285.1168; Found 285.1171.
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5ꢀ(Piperidinꢀ1ꢀyl)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3c). Compound 3c was obtained in 90%
yield (228 mg) according to the general procedure A (thioamide 1c: 219 mg; 2 h) as a pale
brownish oil; Rf = 0.42 (EtOAc/PE, 1:2). 1H NMR (CDCl3): δ 1.70−1.83 (m, 6H), 3.63−3.66 (m,
4H). 13C NMR (CDCl3): δ 22.9, 25.1, 54.6, 114.2, 114.4, 171.8. IR (NPVO, ZnSe, cm–1): ν 2946,
2860, 2219, 1535, 1449, 1283. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C8H11N4S 195.0699;
Found 195.0670.
Method B. A mixture of thioamide 1c (530 mg, 3.15 mmol) and Et3N (319 mg, 0.41 mL, 3.15
mmol) in EtOH (15 mL) was stirred at ambient temperature for 0.5 h. Then the reaction mixture
was cooled down to +10 °C and tosyl azide (2a) (621 mg, 3.15 mmol) was added portion by
portion. The resulting solution was stirred at +10 °C for 1.5 h, the solvent was removed under
reduced pressure and the residue was purified by flash chromatography over silica gel (60−120)
using EtOAc/PE (1:5) mixture to give aminonitrile 3c in 75% yield (450 mg) as a pale brownish
oil; Rf = 0.2 (EtOAc/PE, 1:5).
5ꢀ(Pyrrolidinꢀ1ꢀyl)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3d). Compound 3d was obtained in 81%
yield (188 mg) according to the general procedure A (thioamide 1d: 200 mg; 1 h) as a colorless
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crystals; mp: 96–97 °C; Rf = 0.56 (EtOAc/PE, 1:1). H NMR (DMSOꢀd6/CHCl3): δ 2.10−2.18
(m, 4H), 3.61 (br. s, 4H). 13C NMR (DMSOꢀd6): δ 25.2, 53.4, 112.3, 113.9, 166.9. IR (ATR,
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ZnSe, cm–1): ν 2952, 2857, 2212. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C7H9N4S
181.0542; Found 181.0542.
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5ꢀ(Azepanꢀ1ꢀyl)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3e). Compound 3e was obtained in 69% yield
(187 mg) according to the general procedure A (thioamide 1e: 237 mg; 3.5 h) as a yellow oil; Rf
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= 0.4 (EtOAc/PE, 1:2). H NMR (DMSOꢀd6/CHCl3): δ 1.56−1.63 (m, 4H), 1.84 (br. s, 4H),
3.61−3.72 (m, 4H). 13C NMR (DMSOꢀd6): δ 26.3, 26.7, 55.6, 112.2, 114.5, 170.2. IR (ATR,
ZnSe, cm–1): ν 2934, 2859, 2218, 1540, 1449, 1305. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C9H12N4S 209.0855; Found 209.0876.
Method C. The solution of thioamide 1e (456 mg, 2.5 mmol), azide 2b (183.0 mg, 1.0 mmol)
and sodium ethoxide (68 mg, 1.0 mmol) in pyridine (1 mL) was stirred at room temperature for 5
h. The solvent was removed under reduced pressure and the residue was purified by flash
chromatography over silica gel (60−120) using EtOAc/PE (1:2) mixture to give aminonitrile 3e
in 91% yield (190 mg) as a yellow oil; Rf = 0.4 (EtOAc/PE, 1:2).
Method D. The solution of thioamide 1e (456 mg, 2.5 mmol), azide 2b (183 mg, 1.0 mmol) in
pyridine/water (1:0.4 mL) mixture was stirred at room temperature for 5 h. The solvent was
removed under reduced pressure and the residue was purified by flash chromatography over
silica gel (60−120) using EtOAc/PE (1:2) mixture to give aminonitrile 3e in 85% yield (177 mg)
as a yellow oil; Rf = 0.4 (EtOAc/PE, 1:2).
Method E. The solution of thioamide 1e (456 mg, 2.5 mmol), azide 2b (183 mg, 1.0 mmol) and
Et3N (101 mg, 1.0 mmol) in anhydrous EtOH (5 mL) was stirred at room temperature for 5 h.
The solvent was removed under reduced pressure and the residue was purified by flash
chromatography over silica gel (60−120) using EtOAc/PE (1:2) mixture to give aminonitrile 3e
in 90% yield (187 mg) as a yellow oil; Rf = 0.4 (EtOAc/PE, 1:2).
5ꢀ(Dimethylamino)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3f). Compound 3f was obtained in 74%
yield (148 mg) according to the general procedure A (thioamide 1f: 167 mg; 4 h) as a yellow
powder; mp: 62–64 °C; Rf = 0.33 (EtOAc/PE, 1:2). 1H NMR (DMSOꢀd6/CHCl3): δ 3.33 (s, 6H).
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1455, 1330. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C5H7N4S 155.0373; Found 155.0386.
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5ꢀ(Diphenylamino)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3g). Compound 3g was obtained in 81%
yield (293 mg) according to the general procedure A (thioamide 1g: 328 mg; 5 h) as a light
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yellow powder; mp: 122–124 °C; Rf = 0.72 (EtOAc/PE, 1:2). H NMR (DMSOꢀd6/CHCl3): δ
7.39−7.44 (m, 2H), 7.47−7.52 (m, 8H). 13C NMR (DMSOꢀd6): δ 111.2, 117.5, 126.0, 129.0,
130.4, 145.3, 172.1. IR (ATR, ZnSe, cm–1): ν 3057, 2227, 1587, 1484, 1454, 1374, 1289, 1267.
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H11N4S 279.0699; Found 279.0699.
5ꢀAminoꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3h). Compound 3h was obtained in 77% yield (124
mg) according to the general procedure A (thioamide 1h: 130 mg; 5 h) as a colorless crystals;
mp: 166−168 °C (lit.21 168−171 °C); Rf = 0.4 (EtOAc/PE, 1:2). H NMR (CDCl3): δ 8.33 (s,
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2H). 13C NMR (CDCl3): δ 112.8, 115.8, 170.8. IR (ATR, ZnSe, cm–1) ν 3400, 3356, 2922, 2888,
2260, 1623, 1510 1447, 1301. MS (EI), m/z (%): 126 ([M]+, 17), 98 (59), 71 (100), 45 (65), 38
(48).
5ꢀ(pꢀTolylamino)ꢀ1,2,3ꢀthiadiazoleꢀ4ꢀcarbonitrile (3i). Compound 3i was obtained in 78% yield
(219 mg) according to the general procedure A (thioamide 1i: 247 mg; 5.5 h) as a red crystals;
mp: 187–189 °C (lit.1l 185 °C); Rf = 0.8 (EtOAc/PE, 1:2). H NMR (DMSOꢀd6/CHCl3): δ 2.34
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(s, 3H), 7.19−7.24 (m, 4H), 10.99 (s, 1H). 13C NMR (DMSOꢀd6): δ 20.3, 112.5, 117.1, 119.8,
130.1, 135.3, 138.7 167.8. IR (ATR, ZnSe, cm–1): ν 3225, 2229, 1605, 1591, 1550, 1509, 1435,
1369, 1304, 1259.
General Procedure for the Synthesis of Triazoles 4aꢀs, Exemplified by Sodium (4ꢀ
(morpholineꢀ4ꢀcarbonothioyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀyl)(tosyl)amide hydrate (4a). Thioamide 1a
(170 mg, 1.0 mmol) was added into cooled to +10 °С solution of sodium ethoxide, freshly
prepared from sodium (115 mg, 5.0 mmol) and anhydrous ethanol (4 mL), and the resulting
solution was stirred at +10 °С for 5–10 min. Then the reaction mixture was cooled to –10 °С and
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azide 2a (197 mg, 1.00 mmol) was added to the reaction mixture portion by portion and the
resulting mixture were stirred at –10 °С for 1 h. The formed precipitate was filtered off, washed
with cold ethanol and diethyl ether and dried in a desiccator over P4O10. Triazole 4a was
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(СD3ODꢀd4): δ 2.31 (s, 3H), 3.52−3.62 (m, 4H), 3.74 (br. s, 2H), 4.23 (br. s, 2H), 5.12 (СD3ODꢀ
d4 + NH), 7.12 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H). 13C NMR (СD3ODꢀd4): δ 21.3, 50.6,
54.1, 67.3, 68.0, 127.8, 129.4, 137.1, 141.1, 144.7, 147.0, 194.5. IR (ATR, ZnSe, cm–1): ν 3298,
2960, 2918, 1566, 1499, 1398, 1265, 1154. MS (EI), m/z (%): 367 ([M–NaOH]+, 17), 212 (52),
184 (23), 127 (53), 91 (86), 87 (100). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C14H16N5NaO3S2 390.0665; Found 390.0668.
Sodium
(4ꢀ(4ꢀbenzylpiperidineꢀ1ꢀcarbonothioyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀyl)(phenylsulfonyl)amide
hydrate (4b). Compound 4b was obtained in 82% yield (790 mg) according to the general
procedure (sodium: 230 mg, 10.0 mmol; thioamide 1b: 517 mg, 2.0 mmol; azide 2b: 366 mg, 2.0
1
mmol; ethanol (8 mL)) as a colorless powder; mp: 225–227 °C (decomp.). H NMR (DMSOꢀ
d6:CHCl3): δ 1.16−1.32 (m, 2H), 1.38−1.40 (m, 1H), 1.70−1.73 (m, 1H), 1.81−1.84 (m, 1H),
2.50−2.52 (m, 2H), 2.90−3.01 (m, 2H), 3.55‒4.00 (m, 1H), 5.35 (d, J = 12.0 Hz, 1H), 7.12−7.17
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(m, 3H), 7.23−7.26 (m, 2H), 7.30−7.32 (m, 3H), 7.74−7.76 (m, 2H), 13.06 (br. s, 1H). H NMR
(СD3ODꢀd4): δ 1.10−1.20 (m, 1H), 1.29−1.39 (m, 2H), 1.70−1.73 (m, 1H), 1.78−1.88 (m, 1H),
2.48−2.57 (m, 2H), 2.94−3.00 (m, 2H), 3.89 (d, J = 12.0 Hz, 1H), 4.91 (СD3ODꢀd4 + NH), 5.37
(d, J = 12.0 Hz, 1H), 7.14−7.18 (m, 3H), 7.24−7.32 (m, 5H), 7.84−7.86 (m, 2H). 13C NMR
(СD3ODꢀd4): δ 32.6, 33.8, 39.2, 43.5, 50.6, 53.6, 126.9, 127.7, 128.9, 129.2, 130.1, 130.8, 137.5,
141.6, 146.6, 147.6, 193.2. IR (ATR, ZnSe, cm–1): ν 3294, 3061, 2928, 1566, 1497, 1442, 1400,
1268, 1139. MS (EI), m/z (%): 441 ([M−NaOH]+, 2), 300 (21), 272 (12), 242 (27), 174 (100),
117 (25), 91 (91). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C21H23N5NaO2S2 464.1185;
Found: 464.1187.
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Sodium (4ꢀ(morpholineꢀ4ꢀcarbonothioyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀyl)(phenylsulfonyl)amide hydrate
(4c). Compound 4c was obtained in 84% yield (330 mg) according to the general procedure
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(sodium: 115 mg, 5.0 mmol; thioamide 1a: 170 mg, 1.0 mmol; azide 2b: 183 mg, 1.0 mmol;
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ethanol (4 mL)) as a colorless powder; mp: 254–256 °C (decomp.). H NMR (СD3ODꢀd4): δ
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3.48−3.60 (m, 4H), 3.73 (br. s, 2H), 4.23 (br. s, 2H), 5.12 (СD3ODꢀd4 + NH), 7.28−7.34 (m, 3H),
7.83−7.85 (m, 2H). 13C NMR (СD3ODꢀd4): δ 50.8, 53.8, 67.3, 68.0, 127.7, 129.0, 130.9, 137.0,
146.8, 147.6, 194.5. IR (ATR, ZnSe, cm–1): ν 3337, 2971, 2945, 1597, 1124. MS (EI), m/z (%):
353 ([M−NaOH]+, 17), 212 (40), 184 (19), 127 (52), 113 (29), 86 (100), 77 (80). HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C13H15N5NaO3S2 376.0509; Found 376.0511.
Sodium
((4ꢀmethoxyphenyl)sulfonyl)(4ꢀ(morpholineꢀ4ꢀcarbonothioyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀ
yl)amide hydrate (4d). Compound 4d was obtained in 81% yield (342 mg) according to the
general procedure (sodium: 115 mg, 5.0 mmol; thioamide 1a: 170 mg, 1.0 mmol; azide 2c: 213
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mg, 1.0 mmol; ethanol (4 mL)) as a colorless powder; mp: 282–284°C (decomp.). H NMR
(СD3ODꢀd4): δ 3.52−3.59 (m, 4H), 3.75−3.78 (m, 5H), 4.25 (br. s, 2H), 5.16 (СD3ODꢀd4 + NH),
6.83 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H). 13C NMR (СD3ODꢀd4): δ 50.8, 54.1, 55.9,
67.1, 68.1, 114.2, 129.4, 137.1, 139.4, 146.7, 162.3, 194.5. IR (ATR, ZnSe, cm–1): ν 3298, 2960,
2907, 1598, 1562, 1499, 1440, 1399, 1309, 1264, 1168. MS (EI), m/z (%): 383 ([M−NaOH]+,
11), 212 (52), 189 (21), 113 (32), 107 (29), 86 (100). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C14H17N5NaO4S2 406.0614; Found 406.0611.
Sodium ((4ꢀfluorophenyl)sulfonyl)(4ꢀ(morpholineꢀ4ꢀcarbonothioyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀyl)amide
hydrate (4e). Compound 4e was obtained in 78% yield (321 mg) according to the general
procedure (sodium: 115 mg, 5.0 mmol; thioamide 1a: 170 mg, 1.0 mmol; azide 2d: 201 mg, 1.0
mmol; ethanol (4 mL)) as a colorless powder; mp: 268–270°C (decomp.). 1H NMR (СD3ODꢀd4):
δ 3.60−3.65 (m, 4H), 3.77 (br. s, 2H), 4.26 (br. s, 2H), 5.13 (СD3ODꢀd4 + NH), 6.99−7.04 (m,
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2H), 7.84−7.88 (m, 2H). C NMR (СD3ODꢀd4): δ 50.4, 53.8, 67.3, 68.1, 115.7 (d, J = 22.0 Hz),
130.3 (d, J = 8.0 Hz), 137.1, 143.8 (d, J = 3.0 Hz), 146.8, 165.0 (d, J = 267.0 Hz), 194.2. IR
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(ATR, ZnSe, cm–1): ν 3298, 2971, 2945, 1569, 1495, 1443, 1369, 1267, 1223, 1155. MS (EI),
m/z (%): 371 ([M−NaOH]+, 17), 212 (39), 184 (16), 127 (61), 95 (61), 86 (100). HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C13H14FN5NaO3S2 394.0414; Found: 394.0413.
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(phenylsulfonyl)(4ꢀ(pyrrolidineꢀ1ꢀcarbonothioyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀyl)amide
(4f).
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Compound 4f was obtained in 77% yield (292 mg) according to the general procedure (sodium:
115 mg, 5.0 mmol; thioamide 1d: 154 mg, 1.0 mmol; azide 2b: 183 mg, 1.0 mmol; ethanol (4
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mL)) as a colorless powder; mp: 272–274°C (decomp.). H NMR (СD3ODꢀd4): δ 1.76−1.82 (m,
2H), 1.90−1.97 (m, 2H), 3.45−3.48 (m, 2H), 3.71−3.75 (m, 2H), 5.09 (СD3ODꢀd4 + NH),
7.28−7.34 (m, 3H), 7.83−7.85 (m, 2H). 13C NMR (СD3ODꢀd4): δ 25.6, 27.3, 53.8, 54.1, 127.9,
128.9, 130.9, 138.4, 147.0, 147.4, 190.7. IR (ATR, ZnSe, cm–1): ν 3337, 2971, 2945, 1597, 1124.
MS (EI), m/z (%): 337 ([M−NaOH]+, 3), 176 (12), 134 (13), 117 (21), 97 (19), 70 (100). HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C13H15N5NaO2S2 360.0559; Found: 360.0558.
Sodium (4ꢀ(pyrrolidineꢀ1ꢀcarbonothioyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀyl)(tosyl)amide hydrate
(4g).
Compound 4g was obtained in 89% yield (350 mg) according to the general procedure (sodium:
115 mg, 5.0 mmol; thioamide 1d: 154 mg, 1.0 mmol; azide 2a: 197 mg, 1.0 mmol; ethanol (4
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mL)) as a colorless powder; mp: 268–270°C (decomp.). H NMR (СD3ODꢀd4): δ 1.77−1.84 (m,
2H), 1.92−1.98 (m, 2H), 2.33 (s, 3H), 3.50 (t, J = 8.0 Hz, 2H), 3.73 (t, J = 8.0 Hz, 2H), 4.90
(СD3ODꢀd4 + NH), 7.13 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H). 13C NMR (DMSOꢀd6): δ
11.8, 15.9, 17.5, 44.4, 44.6, 118.6, 120.0, 128.9, 131.9, 134.2, 137.3, 180.8. IR (ATR, ZnSe, cm–
1): ν 3301, 2968, 2870, 1572, 1517, 1430, 1350, 1322, 1229, 1150. MS (EI), m/z (%): 351
([M−NaOH]+, 21), 196 (100), 168 (22), 127 (16), 70 (64). HRMS (ESIꢀTOF) m/z: [M + H]+
Calcd for C14H17N5NaO2S2 374.0716; Found 374.0712.
Sodium
((4ꢀmethoxyphenyl)sulfonyl)(4ꢀ(pyrrolidineꢀ1ꢀcarbonothioyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀ
yl)amide hydrate (4h). Compound 4h was obtained in 82% yield (333 mg) according to the
general procedure (sodium: 115 mg, 5.0 mmol; thioamide 1d: 154 mg, 1.0 mmol; azide 2c: 213
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mg, 1.0 mmol; ethanol (4 mL)) as a colorless powder; mp: 270–272 °C (decomp.). H NMR
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