β-(Cycloalkylamino)ethanesulfonyl azides as novel water-soluble reagents for the synthesis of diazo compounds and heterocycles

Article abstract of DOI:10.1007/s10593-019-02609-z

[Figure not available: see fulltext.] Novel water-soluble sulfonyl azides were synthesized, which are basic by nature. The obtained compounds were used as donors of the diazo group in the diazo transfer reaction. Due to their good solubility in water and high polarity, the byproducts formed in this case were easily separated from the desired products by washing with water or column chromatography. It was also shown that new sulfonyl azides as a result of reactions can be incorporated in heterocyclic products, imparting them water solubility.

Full text of DOI:10.1007/s10593-019-02609-z

DOI 10.1007/s10593-019-02609-z
Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
-(Cycloalkylamino)ethanesulfonyl azides as
novel water-soluble reagents
for the synthesis of diazo compounds and heterocycles
Yuri M. Shafran1, Pavel S. Silaichev1,2, Vasiliy A. Bakulev1,3*
1 Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia; e-mail: v.a.bakulev@urfu.ru
2 Perm State National Research University,
15 Bukireva St., Perm 614990, Russia
3 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi / 20 Akademicheskaya St., Yekaterinburg 620990, Russia
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(12), 1251–1261
Submitted September 22, 2019
Accepted October 17, 2019
Novel water-soluble sulfonyl azides were synthesized, which are basic by nature. The obtained compounds were used as donors of the
diazo group in the diazo transfer reaction. Due to their good solubility in water and high polarity, the byproducts formed in this case were
easily separated from the desired products by washing with water or column chromatography. It was also shown that new sulfonyl azides
as a result of reactions can be incorporated in heterocyclic products, imparting them water solubility.
Keywords: sulfonamides, sulfonyl azides, 1,2,3-thiadiazoles, 1,2,3-triazoles, diazo transfer reaction, Regitz reaction.
The diazo transfer reaction (the Regitz reaction1) is
widely employed for the synthesis of diazo compounds, as
well as 1,2,3-thiadiazoles and 1,2,3-triazoles containing the
N=N fragment originating from the intermediate diazo
compound.2–8 In this case, the donor of the diazo group
partially transforms into a byproduct that must be separated
from the target compounds. When using benzene- and
toluenesulfonyl azides, the most popular (due to the
availability, low cost, and ease of preparation) diazo
transfer reagents, the byproducts are the corresponding
sulfonyl amides. These compounds are more or less soluble
in most organic solvents, as well as in aqueous media.
They have low UV absorption, which makes it difficult to
detect them with standard TLC by visualization under UV
light. In addition, the chromatographic mobility of benzene-
and toluenesulfonyl amides is often close to that of the
desired compounds. Sometimes the problem of separation
from diazo transfer byproducts is solved at subsequent
steps after additional transformations of the desired
compounds, but this approach cannot be acknowledged as
universal. In general, separation from sulfonyl amide
byproducts is often an intractable task.
To solve this problem, a number of alternative sulfonyl
azides have been introduced into synthetic practice in recent
decades: p-acetamidobenzenesulfonyl azide,9 p-dodecyl-
benzenesulfonyl azide,10 benzenesulfonyl azide immobi-
lized on polystyrene,11 imidazole-1-sulfonyl azide,12 p-13 and
m-carboxybenzenesulfonyl azides,14,15 mesyl azide,16 and
others. However, the use of these reagents is complicated by
safety and convenience issues, availability, environmental
concerns, and economic considerations. In addition, the elimi-
nation of certain byproducts, for example, carboxybenzene-
sulfonyl amides,13–15 requires special conditions (basic
medium). Thus, the development and implementation of sul-
fonyl azides in laboratory practice, which are converted into
sulfonyl amides as a result of diazo transfer reactions, which
would be easily separated from the desired products via
standard routines, remains an urgent task in organic synthesis.
0009-3122/19/55(12)-1251©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
Scheme 2. Synthesis of novel β-aminoethanesulfonyl azides 1c,d
and their salt forms 1e,f
In view of the foregoing, a good solution of the problem
could be the introduction of a secondary amine fragment
into the molecule of a sulfonyl azide, and consequently, the
resulting sulfonyl amide. Such a fragment could impart to
the sulfonyl amides solubility in H2O and high polarity, which
would make it possible to conveniently separate them from
the desired products by washing with H2O or simple column
chromatography. It is also known that in some reactions
sulfonyl azides are completely or partially incorporated into
the structure of the target product.17 We suggested that the
use of novel sulfonyl azides in these cases will allow the
synthesis of new water-soluble heterocyclic compounds
desired for determining their biological activity.
β-Aminoethanesulfonyl azides 1a,b were obtained from
2-chloroethanesulfonyl chloride (2) as a result of a two-step
one-pot synthesis, in the second step of which 2-chloro-
ethane-1-sulfonyl azide (3) reacts with secondary amines
4a,b.18 In turn, chloride
2 was synthesized from
commercially available isethionic acid (5)19 (Scheme 1).
Scheme 1. Synthesis of β-aminoethanesulfonyl azides 1a,b18,19
OH
Cl
Cl
PCl5
NaN3
H2O
MeCN
rt, 3 h
, 4 h
54%
O S O
O S O
O S O
cytisine fragment 6 (found, m/z: 471.2064 [M+H]+;
C24H31N4O4S; calculated, m/z: 471.2066). Morpholine
derivative 1c gradually crystallizes upon storage at room
temperature, cytisine derivative 1d is a viscous oil. In order
to obtain these compounds in a form more convenient for
laboratory use and analysis, hydrochloride 1e was
synthesized from morpholine derivative 1c, and cytisine-
containing sulfonyl azide 1d was converted to the
crystalline oxalate 1f. Salt forms 1e,f are solids that are
even more soluble in H2O while retaining good solubility
in polar organic solvents, thermally stable up to the melting
point, and convenient for purification (recrystallization
from EtOH).
Unfortunately, not all secondary amines react with
2-chloroethane-1-sulfonyl azide (3) in a manner that is
desirable for us. Thus, a reaction with 4-benzylpiperidine
(4e) under the same conditions leads to the formation of
sulfonic acid 7. The structure of compound 7 was proved
using HPLC-HRMS and NMR spectroscopy, including
1H–13C and 1H–15N HMBC 2D spectra (see Supplementary
information file). To preserve the sulfonyl azide function, a
synthesis modification may be required to exclude the
presence of H2O at the step of the reaction with 4-benzyl-
piperidine (4e) (Scheme 3).
OH
5
Cl
2
N3
3
1. K2CO3
R
2. KI (2 mol%)
3. RH 4a,b
O S O
H2O, MeCN
rt, 3 h
N3
1a (59%)
1b (57%)
S
O
O
N
a R =
, b R =
N
The reactivity of compounds 1a,b is not described in the
literature. However, sulfonyl azides 1a,b themselves can
hardly be considered as worthy candidates for the role of
reagents for the reaction with active methylene compounds,
since they are obtained using not readily available amines,
and their value as donors of a valuable fragment for the
final products is insignificant. Two novel sulfonyl azides
1c,d containing a tertiary nitrogen atom were obtained by
analogy to a described procedure18 (Scheme 2).
Morpholine derivative 1c was contemplated as an
inexpensive reagent for the diazo transfer reaction, and
cytisine derivative 1d was supposed to be used in reactions
that retain the amine fragment in the desired product. In a
crude sample of sulfonyl azide 1d, high-performance liquid
chromatography in combination with high-resolution mass
spectrometry (HPLC-HRMS) showed an impurity of the
product of further substitution of the azido group by the
Scheme 3. Alternative direction of the reaction of
2-chloroethane-1-sulfonyl azide with secondary amines
on the example of 4-benzylpiperidine (4e)
1. NaN3
2.
Cl
HN
O
HO S
O
N
4e
H2O, MeCN
rt, 2 h
60% in 2 steps
O S O
7
Cl
2
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
Scheme 5. Synthesis of 1,2,3-thiadiazole 11a
Initially, sulfonyl azide 1d was used to prepare α-diazo-
β-dicarbonyl compounds 8. Previously, the diazo transfer
reaction with acetylacetone (9a) was carried out in various
organic solvents using TsN3 (1g) in the presence of a basic
catalyst20a–e and also using p-acetamidobenzenesulfonyl
azide,20f perfluorobutanesulfonyl azide,20g mesyl azide,20h,i
2-azido-1,3-dimethylimidazolinium chloride,20j,k and ionic
liquid-supported sulfonyl azide.20l
We synthesized 3-diazopentane-2,4-dione (8a) via the
reaction of acetylacetone 9a with TsN3 (1g) and sulfonyl
azide 1c in H2O in the presence of NaOH. In the reaction of
acetylacetone 9a with TsN3 (1g), the yield of diazo
compound 8a was 54%; in order to obtain it in pure form, it
was necessary to purify the diethyl ether extract by column
chromatography (eluent CHCl3–Et3N). Replacing TsN3 (1g)
with sulfonyl azide 1c afforded compound 8a in 77% yield;
no purification of the diethyl ether extract was required.
Another diazo compound, ethyl 2-diazo-3-oxobutanoate
(8b), was previously prepared by the diazo transfer reaction
of acetoacetic ester (9b) with TsN3 (1g)21a–e and mesyl
azide.20i,21f,g We synthesized diazo compound 8b similarly
to diazoacetylacetone (8a) from the active methylene
compound 9b and sulfonyl azide 1c in the presence of Et3N
in 81% yield (Scheme 4). In this case, EtOH was chosen as
the solvent to prevent possible saponification of the ester
group in the alkaline medium. To obtain analytically pure
product 8b, it was sufficient to wash the ethereal extract
with diluted aqueous HCl.
thiadiazole 11a and TsNH2 (12g) in an approximately equal
ratio. Due to the lucky fact that thiadiazole 11a was
practically insoluble in H2O, TsNH2 (12g) was simply
washed off with boiling H2O. However, the yield of pure
thiadiazole 11a was only 22%.
Previously,17 1,2,3-thiadiazole 11b was prepared by
reacting thioamide 10b with TsN3 (1g). The yield of
desired product 11b was 90%, however, to isolate it, it was
necessary to develop a very complex procedure that was
not always reproducible. In the present study, TsN3 (1g)
was replaced by water-soluble sulfonyl azide 1c, which
made it possible to simply wash off sulfonyl amide 12c
with H2O and obtain the desired 1,2,3-thiadiazole 11b in
quantitative yield (Scheme 6).
Scheme 4. Synthesis of diazo compounds 8a,b
Scheme 6. Synthesis of 1,2,3-thiadiazole 11b
The suitability of sulfonyl azide 1c for reactions where
the intermediate diazo compound is not detected and
cyclizes to form the heterocycle even under the conditions
of its generation, was demonstrated by the example of the
interaction of sulfonyl azide 1c with methylene active
thioamides 10. Thus, 1,2,3-thiadiazole 11a was obtained in
the reaction of sulfonyl azide 1c with thioamide 10a in low
yield (Scheme 5). The final operation in the synthesis was
the purification of the product from tar-like substances
using column chromatography.
We also used a similar approach to obtain a number of
5-amino-1,2,3-triazoles 13a–k from the corresponding
amidines 14a–k (the starting compounds 14b,d, in turn,
were obtained by aminolysis of imino ethers 15b,d). For
the synthesis of triazoles 13a–k, a published method using
TsN3 (1g) as the donor of the diazo group was used as a
basis.22 However, this method does not consider separation
of the desired products from TsNH2 (12g) (synthesis of
triazoles 13a–c,k (R5 = 4-MeC6H4), Table 1). On contrary,
the substitution of TsN3 (1g) with β-morpholino-
ethanesulfonyl azide (1c) affords pure triazoles 13a–k
(Scheme 7) in good yields (Table 1). In the latter syntheses,
Et3N was added to neutralize HCl with one exception
For comparison, the reaction was carried out under
similar conditions, but using TsN3 (1g). After column
chromatography, a product was obtained which, according
1
to H NMR spectroscopy, was a mixture of the desired
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
(when preparing triazole 13h), otherwise the reactions took
an unacceptably long time. Et3N was also used to neutralize
the HCl contained in amidine 14k.
The structures of compounds 13a–k were established
using IR and NMR spectroscopy, as well as X-ray structu-
ral analysis of single crystals of compound 13d (Fig. 1)
Notably, amidines 14h–j are cyclized exclusively to
N(1)-substituted 5-amino-1,2,3-triazoles 13h–j in the
presence of an alternative reaction route. In this article, we
restrict ourselves to merely reporting this observation,
which we plan to investigate in subsequent studies.
In cases where the desired product is soluble in H2O as
well as sulfonyl azide 1c, column chromatography was
used to separate the reaction mixture. Separation is
facilitated by the significantly greater polarity of
sulfonamide 12c (compared to sulfonamide 12g), resulting
in its low chromatographic mobility in weakly polar
eluents, such as CH2Cl2, CHCl3, EtOAc. Thus, ethyl
Figure 1. Molecular structure of compound 13d with atoms
represented as thermal vibration ellipsoids of 50% probability.
Scheme 7. Synthesis of 1,2,3-triazoles 13a–k from amidines 14a–k
5-(dimethylamino)-1H-1,2,3-triazole-4-carboxylate (13k)
(obtained using TsN3 (1g)) is only partially separated from
TsNH2 (12g) by elution with CH2Cl2 on a chromatography
1
column: it was found by H NMR spectroscopy that it
contains 22% TsNH2 (12g), although it seemed to be
uniform according to TLC. In contrast, when sulfonyl azide
1e was used instead of TsN3 (1g), pure triazole 13k was
obtained in 81% yield after column chromatography under
similar conditions.
Table 1. Conditions and results of the synthesis of triazoles 13a–k from amidines 14a–k in EtOH
Addition of Temperature,
Time,
min
Amidine
R1
NR2R3
R4
R5SO2N3
Product
Yield, % Ratio of 13:12*
Et3N, equiv
°C
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
C≡N
CO2Et
CO2Et
Azepane
Azepane
H
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
70
120
15
98
91
81
95
98
93
82
91
87
85
92
84
84
89
86
60
81
62:39
100:0
100:0
70:30
100:0
61:39
100:0
100:0
100:0
100:0
100:0
60:40
100:0
100:0
100:0
78:22
100:0
14a
14a
1g
1c
1c
1g
1c
1g
1c
1c
1c
1c
1c
1g
1c
1c
1c
1g
1c
13a
13a
13a
13b
13b
13c
13c
13d
13e
13f
H
2.0
1.4
14a**
14b
Azepane
H
70
4-Benzylpiperidine
4-Benzylpiperidine
Morpholine
Morpholine
Morpholine
Pyrrolidine
Piperidine
Pyrrolidine
NH2
H
120
420
180
240
4320
4320
240
240
120
120
240
240
120
60
14b***
14c
H
1.0
H
H
1.0
1.0
1.0
1.0
1.0
14c
Ph
14d
Ph
70
14e
H
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
14f
H
14g
13g
13h
13h
13i
14h
Bn
NH2
Bn
4-MeOC6H4
4-MeC6H4
H
14h
NH2
14i
NH2
1.0
2.0
2.2
14j
14k*4
14k*4
13j
NMe2
13k
13k
NMe2
H
* Calculated from the 1H NMR spectrum of the mixture.
** The reaction was carried out in H2O.
*** 1,4-Dioxane was used instead of EtOH because of the low solubility of amidine 14b.
*4 The reaction was carried out in MeCN.
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
Scheme 8. Synthesis and the possible mechanism of formation of 1,2,3-triazoles 17d,g
Earlier, we demonstrated that the sulfonyl azide
molecule can act as a donor of the sulfonamide group3,23,24
or simultaneously a donor of the diazo group and of
sulfanilamide group in a reaction with enamines and
thioamides.17 In this work, we found that sulfonyl azides
1d,g act in the latter role when reacting with ethyl imidate
16, whereby 5-sulfonamido-1,2,3-triazoles 17d,g are
formed. The cytisine fragment in compound 17d plays
the role of a pharmacophore and also makes it soluble in
H2O. Triazole 17g was previously obtained in a different
way.25
The proposed reaction mechanism involves the
formation of triazenes 16A which then undergo
cyclocondensation into N(1)-substituted 1,2,3-triazoles
16B, followed by a 1,3-sigmatropic shift of hydrogen and
the Dimroth rearrangement into 5-substituted 1,2,3-tri-
azoles 17d,g (Scheme 8). To our knowledge, the reactions
of alkyl imidates with sulfonyl azides have not been
described in the literature to date.
To conclude, it was shown that β-R-ethanesulfonyl
azides, in which R is a secondary amine fragment, have an
advantage as reagents for diazo transfer reactions over
other donors of the diazo group, which consists in the easy
removal of sulfonyl amide byproducts, promoted by their
good solubility and high polarity. Using 2-morpholino-
ethane-1-sulfonyl azide as an example, it was shown that
water-soluble sulfonyl azides with basic groups are suitable
for the synthesis of aliphatic diazo compounds and azoles
(1,2,3-thiadiazoles, 1,2,3-triazoles, etc.) using suitable
solvents, alkaline catalysts, and, if necessary, extractants.
The techniques for these syntheses are simple and in most
cases eliminate the need for laborious preparative
chromatography. The main (or perhaps the only)
prerequisite for the diazo transfer reactions involving the
novel type of water-soluble sulfonyl azides is a low
solubility of the desired products in water or weakly acidic
aqueous media. Alternatively, they should be well
extractable from the aqueous media with organic solvents.
Thus, the possible field of application of the novel sulfonyl
azides is rather wide.
reagents for diazo transfer reactions, β-aminoethane-
sulfonyl azides are basic by nature, which significantly
expands the possibilities of using the Regitz reaction in
synthetic practice.
Experimental
IR spectra were registered on a Bruker Alpha FT-IR
spectrometer with an ATR accessory (ZnSe matrix) over
1
the 4000−400 cm−1
range. H and 13C NMR spectra were
acquired on a Bruker Avance NEO 600 spectrometer with
the broadband CryoProbe Prodigy (600 and 151 MHz,
respectively, compound 7) and a Bruker Avance II 400
spectrometer (400 and 101 MHz, respectively, the remain-
ing compounds) in DMSO-d6 or CDCl3, internal standards –
residual solvent signals: DMSO-d5 (2.50 ppm for 1H nuclei
1
and 39.5 ppm for 13C nuclei) and CHCl3 (7.26 ppm for H
nuclei and 77.2 ppm for 13C nuclei). Elemental analysis
was performed on a PerkinElmer Series II 2400 Elemental
analyzer. Mass spectra were recorded on a GCMS-QP 2010
Ultra mass spectrometer (EI ionization, 70 eV). Analysis of
products by ultra high performance liquid chromatography
with high-resolution mass spectrometric detection (UHPLC-
HRMS) was carried out using an Agilent 6540 UHD
Accurate-Mass Q-TOF LC/MS tandem quadrupole-time-of-
flight detector of exact masses. Chromatographic
separation was carried out using an Agilent 1290 Infinity
ultra high performance liquid chromatograph on a Zorbax
Extend-C18 RRHT column, 2.1 × 50 mm, 1.8 μm sorbent
particle size (Agilent 727700-902) at 50°C thermostat
temperature. Melting points were determined on a Stuart
SMP10 apparatus and are uncorrected. Monitoring of the
reaction progress and assessment of the purity of
synthesized compounds were done by TLC on Sorbfil UV-
254 plates, visualization under UV light. KSKG silica gel
(40–100 μm) was used for column chromatography.
The starting reagents were prepared or purchased from
commercial sources and used without further purification.
Amidines 14a,c,f,g were synthesized according to a
literature method,26 compound 14e was prepared according
to a patent,27 benzyl derivative 14h28 and compounds 14i,j29
were also synthesized according to published methods.
Also, β-R-ethanesulfonyl azides can be used in reactions
with retaining of the sulfonamide fragment in the final
products, which was demonstrated by us on the reaction of
cytisine sulfonyl azide with an imino ether.
The resulting reagents can be stored under normal
conditions for indefinitely long time, and their salt forms
are even more convenient for laboratory use. Unlike other
Amidine 14k was obtained following a published
procedure30 and used in the synthesis without isolation.
Solvents (PhH, PyH, EtOAc, CHCl3, CH2Cl2, petroleum
ether (40–70°C fraction), hexane, MeCN, EtOH, MeOH,
and Et2O) were used without purification and drying. All
reactions were carried out in sealed reaction vessels.
Evaporation and concentration of solutions and
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
suspensions was carried out on a rotary evaporator under
2-(Morpholin-4-yl)ethane-1-sulfonyl azide hydro-
chloride (1e). 10 N aqueous HCl (1.63 g) was added to a
solution of free base 1d (3.06 g, 13.89 mmol) in EtOH
(10 ml). Volatile components were evaporated, the residue
was re-evaporated twice with EtOH (10 ml). The residue
was crystallized from EtOH with the addition of a small
amount of Et2O to initiate crystallization. The precipitate
was separated from the liquid phase, washed with Et2O,
petroleum ether, and dried. Yield 2.84 g (80%), colorless
crystalline powder, mp 132–134°C (decomp.). IR spect-
reduced pressure. Separation of the solid phase from the
liquid was carried out by filtration or centrifugation
(3000 rpm).
2-(Morpholin-4-yl)ethane-1-sulfonyl
azide
(1c).
K2CO3 (5.41 g, 39.16 mmol), KI (55 mg, 0.34 mmol), and a
solution of morpholine (4c) (1.71 g, 19.57 mmol) in MeCN
(20 ml) were sequentially added with vigorous stirring and
cooling in ice water bath to a solution of 2-chloroethane-
1-sulfonyl azide (3), obtained from 2-chloroethanesulfonyl
chloride19 (2) (19.57 mmol); the reaction mixture gradually
discolors during the addition. The cooling was removed
and intensive stirring was continued for 3 h. The liquid
phase was decanted from the inorganics, which was
washed with PhH (2×10 ml). The organics were combined
and evaporated to dryness, the residue was re-evaporated
with PhH (2×10 ml). Another portion of PhH was added to
the residue, it was filtered off from insoluble salts, the
filtrate was evaporated to dryness, the residue was
extracted with PhH, and hot petroleum ether was gradually
added to the boiling extract. After the start of the formation
of the emulsion, it was left at room temperature until the
formation of the oily phase was complete. Yield 3.06 g
(71% over 2 steps), a viscous oil that gradually partially
solidified during storage. An analytically pure sample was
obtained by additional recrystallization from petroleum
ether, colorless needles, mp 68–69°C. IR spectrum, ν, cm–1:
1
rum, ν, cm–1: 2148 (N3). H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 3.19 (2H, dd, J = 17.2, J = 12.8, SCH2);
3.34–3.70 (4H, m, 2NCH2); 3.70–4.09 (4H, m, 2OCH2);
4.28–4.72 (2H, m, NCH2); 12.22 (1H, br. s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 48.7; 49.1; 51.1; 63.2.
Found, %: C 28.34; H 4.70; N 21.77. C6H13ClN4O3S.
Calculated, %: C 28.07; H 5.10; N 21.83.
2-(8-Oxo-1,5,6,8-tetrahydro-2H-1,5-methanopyrido-
[1,2-a][1,5]diazocin-3(4H)-yl)ethane-1-sulfonyl
azide
oxalate (1f). Oxalic acid (167 mg, 1.85 mmol) was added
with stirring in one portion to a hot solution of free base of
sulfonyl azide 1c (299 mg, 0.925 mmol) in EtOH (4 ml). A
suspension soon formed, which was stirred at room
temperature for 3 h. The residue was separated and
recrystallized from EtOH. Yield 226 mg (59%), colorless
1
needles, mp 167–168°C (decomp.). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.69 (1H, d, J = 12.0, CH2);
1.79 (1H, d, J = 12.0, CH2); 2.24 (1H, d, J = 12.0, CH);
2.23–2.42 (3H, m, CH, SCH2); 2.59–2.81 (2H, m, NCH2);
2.90–3.04 (2H, m, NCH2); 3.63–3.91 (4H, m, 2NCH2);
6.07 (1H, d, J = 6.8, H-5 pyridine); 6.19 (1H, d, J = 9.0,
H-3 pyridine); 7.31 (1H, dd, J = 8.9, J = 6.9, H-4 pyridine).
13C NMR spectrum (DMSO-d6), δ, ppm: 25.0; 27.1;
34.3; 49.3; 51.5; 52.0; 58.9; 59.7; 104.2; 115.5;
138.8; 151.6; 161.3; 162.3. Found, %: C 43.54; H 4.53;
N 17.08. C15H19N5O7S. Calculated, %: C 43.58; H 4.63;
N 16.94.
1
2138 (N3). H NMR spectrum (СDCl3), δ, ppm (J, Hz):
2.47–2.56 (4H, m, CH2 morpholine); 2.89 (2H, t, J = 6.3)
and 3.50 (2H, t, J = 6.3, CH2CH2); 3.65–3.76 (4H, m, CH2
morpholine). 13C NMR spectrum (СDCl3), δ, ppm: 52.4;
53.1; 66.6. Found, m/z: 221.0701 [M+H]+. C6H13N4O3S.
Calculated, m/z: 221.0703.
2-(8-Oxo-1,5,6,8-tetrahydro-2H-1,5-methanopyrido-
[1,2-a][1,5]diazocin-3(4H)-yl)ethane-1-sulfonyl azide (1d).
K2CO3 (3.06 g, 22.16 mmol), KI (31 mg, 0.19 mmol), and
a solution of cytisine (4d) (2.11 g, 11.078 mmol) in MeCN
(4.5 ml) were sequentially added with vigorous stirring and
cooling in ice water bath to a solution of 2-chloroethane-
1-sulfonyl azide (3), obtained from 2-chloroethanesulfonyl
chloride19 (2) (11.078 mmol). The cooling was removed
and intensive stirring was continued for 3 h. The liquid
phase was decanted from the solid inorganic precipitate,
which was washed with CH2Cl2 (15 ml). The combined
organics were evaporated to dryness. The residue was
purified by column chromatography: the mixture was
applied as a solution in CH2Cl2–Et3N, 100:1, then eluted
with the same mixture. Portions of the eluate containing
the product were pooled and evaporated to dryness.
Yield 1.85 g (52% over 2 steps), viscous oil. IR spectrum,
2-(4-Benzylpiperidin-1-yl)ethane-1-sulfonic acid (7).
A solution of 4-benzylpiperidine (4e) (1.10 g, 6.26 mmol)
in MeCN (2 ml) was gradually added to a solution of
2-chloroethane-1-sulfonyl azide (3), obtained from
2-chloroethanesulfonyl chloride19 (2) (19.57 mmol). The
suspension was stirred at room temperature for 3 h. The
solid phase was separated, the liquid phase was evaporated
to dryness. The precipitate was further washed with PhH,
the filtrate was added to the evaporation residue and again
evaporated to dryness. The residue was treated with H2O,
insoluble material was crystallized from EtOH, washed
twice with Et2O, and dried. Yield 989 mg (60% over
2 steps), colorless powder, mp 222–223°C (decomp.).
1
1
ν, cm–1: 2132 (N3). H NMR spectrum (CDCl3), δ, ppm
IR spectrum, ν, cm–1: 589, 751, 1044, 1169. H NMR
(J, Hz): 1.77 (1H, d, J = 12.0, CH2); 1.90 (1H, d, J = 12.0,
CH2); 1.95–1.99 (1H, m, NCH2); 2.43–2.48 (3H, m, CH,
SCH2); 2.79–2.98 (4H, m, NCH2, CH); 3.30 (2H, d,
J = 8.0, NCH2); 3.85–4.03 (2H, m, NCH2); 5.96 (1H, d,
J = 6.8, H-5 pyridine); 6.41 (1H, d, J = 9.0, H-3 pyridine);
7.26 (1H, dd, J = 9.1, J = 6.8, H-4 pyridine). Found, m/z:
324.1123 [M+H]+. C13H18N5O3S. Calculated, m/z:
324.1125.
spectrum (DMSO-d6), δ, ppm (J, Hz): 1.24–1.48 (2H, m,
NCH2CH2 piperidine); 1.72 (2H, d, J = 17.4, NCH2CH2
piperidine); 1.62–1.87 (1H, m, CH piperidine); 2.44–2.62
(2H, m, CH2Ph); 2.40–3.00 (4H, m, 2NCH2 piperidine);
3.29 (2H, br. s, NCH2); 3.46 (2H, br. s, CH2SO3H); 7.17
1
2
(1H, dd, J = 7.5, J = 7.5, H Ph); 7.20 (2H, d, J = 7.5,
1
2
H Ph); 7.29 (2H, dd, J = 7.5, J = 7.5, H Ph). 13C NMR
spectrum (DMSO-d6), δ, ppm: 29.0; 34.8; 41.3; 45.4; 52.0;
1256

Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
53.1; 126.1; 128.3; 129.1; 139.5. Found, m/z: 284.1324
brown powder, mp 190–192°C (decomp.). 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.97 (2H, t, J = 7.5,
NHCH2CH2); 3.57 (2H, dd, J = 14.2, J = 6.7, NHCH2CH2);
6.98 (1H, t, J = 7.3, H Ar); 7.07 (1H, t, J = 7.4, H Ar); 7.19
(1H, d, J = 1.2, H Ar); 7.34 (1H, d, J = 8.0, H Ar); 7.61
(1H, d, J = 7.8, H Ar); 8.04 (2H, s, NH2); 8.59 (1H, t,
J = 5.7, H Ar); 10.80 (1H, s, H imidazole). 13C NMR
spectrum (DMSO-d6), δ, ppm: 25.9; 40.1; 111.9; 112.3;
118.7; 118.8; 121.4; 123.1; 127.7; 134.9; 136.8; 163.0;
167.7. Mass spectrum, m/z (Irel, %): 287 [M]+ (27), 143
(81), 130 (100). Found, %: C 54.26; H 4.34; N 24.63.
C13H13N5OS. Calculated, %: C 54.34; H 4.56; N 24.37.
Method II. Sulfonyl azide 1c (186 mg, 0.85 mmol) and
Et3N (91 mg, 0.90 mmol) were added to a solution of
thioamide 10a (221 mg, 0.85 mmol) in MeOH (2 ml). The
reaction mixture was stirred at room temperature for 18 h,
and the volatiles were evaporated to dryness. The residue
was purified by column chromatography: the mixture was
applied as a solution in CH2Cl2–EtOAc, 1:1, then eluted
with the same solvent mixture. Portions of the eluate
containing the product were pooled and evaporated to
dryness. The residue was recrystallized from MeOH.
Yield 72 mg (30%), light-brown powder. Mp and
1H NMR spectra of samples obtained by methods I and II are
identical.
[M+H]+. C14H22NO3S. Calculated, m/z: 284.1315.
3-Diazopentane-2,4-dione (8a). Method I. TsN3 (1g)
(2.17 g, 11 mmol) was added in portions over 20 min to a
cooled (0°C) solution of acetylacetone (9a) (1.01 g,
10.0 mmol) in a mixture of Et2O (6 ml) and Et3N (1.13 g,
11 mmol), keeping the temperature of the mixture below 25–
30°C. The reaction mixture was kept at 0–5°C for 1 day,
then at –10°C for 4 h. The bulk of TsNH2 (12g) was
filtered off, the solid on the filter was washed with cold
Et2O (5 ml). The filtrates were combined and evaporated to
constant weight. The crude product in the form of a light-
yellow mobile liquid was purified by chromatographic
column, eluent CHCl3–Et3N, 100:1. Portions of the eluate
containing the product were pooled and evaporated to
constant weight. Yield 681 mg (54%), light-yellow mobile
1
fluid. IR spectrum, ν, cm–1: 2127 (N2). H NMR spectrum
1
(CDCl3), δ, ppm: 2.41 (6H, s, 2CH3). IR and H NMR
spectra correspond to the literature data.20l
Method II. Sulfonyl azide 1c (412 mg, 1.87 mmol) was
added with stirring in one portion to a cooled (0°C)
solution of NaOH (69 mg, 1.71 mmol) in a mixture of
acetylacetone (9a) (156 mg, 1.56 mmol) and H2O (1 ml).
The reaction mixture was stirred at 0°C for 1.5 h (sulfonyl
azide 1c completely dissolved over the first 0.5 h). A
solution of 10 N aqueous HCl (522 mg) in H2O (0.9 ml)
was added until pH 3–4 (orange homogeneous solution).
The mixture was extracted with Et2O (3×4 ml), the extract
was evaporated to constant weight. Yield 151 mg (77%),
5-(Piperidin-1-yl)-1,2,3-thiadiazole-4-carbonitrile (11b).
Sulfonyl azide 1c (512 mg, 2.33 mmol) was added to a
solution of thioamide 10b (326 mg, 1.94 mmol) in PyH
(3.17 g). The solution was kept at 55°C for 4 h. The
volatile components were evaporated to dryness, the
residue was treated with H2O (5 ml), and the heavy brown
oil was separated from the aqueous phase. The procedure
was repeated once more. The product was extracted with
Et2O (3×4 ml), and the solvent was evaporated to dryness.
The residue was extracted with a plenty of boiling
petroleum ether, which was then evaporated. Yield 373 mg
1
light-yellow mobile fluid. H NMR spectra of samples
obtained by methods I and II match to each other.
Ethyl 2-diazo-3-oxobutanoate (8b). Et3N (725 mg,
7.16 mmol) was added to a mixture of ethyl acetoacetate
(9b) (466 mg, 3.58 mmol) and sulfonyl azide 1c (1.58 g,
7.16 mmol) in EtOH (3 ml). The solution was kept at room
temperature for 70 min. The volatiles were evaporated to
constant weight. The oily residue was extracted with Et2O
(3×4 ml), the extract was treated twice with a mixture of
H2O (2.7 g) and 10 N aqueous HCl (0.24 g), then
evaporated to constant weight. Yield 452 mg (81%), light-
1
(100%), brown oil. H NMR spectrum (CDCl3), δ, ppm:
1.65–1.74 (2H, m, CH2); 1.74–1.84 (4H, m, (CH2)2); 3.57–
3.68 (4H, m, (CH2)2). Mass spectrum, m/z (Irel, %): 164
[M+ (21), 166 [M–N2]+ (40), 96 (57), 69 (59), 55 (86), 41
(100). Mass and 1H NMR spectra match published
spectra.17 Found, %: C 49.61; H 5.46; N 28.72. C8H10N4S.
Calculated, %: C 49.46; H 5.19; N 28.84.
1
yellow liquid. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
1.30 (3H, t, J = 7.1, CH2CH3); 2.45 (3H, d, J = 0.9,
CH3CO); 4.27 (2H, q, J = 7.1, CH2CH3). 1H NMR
spectrum was identical to the published one.21c,d
3-Amino-3-(4-benzylpiperidin-1-yl)acrylonitrile (14b).
A solution of imino ether 15b (5.00 g, 44.59 mmol) and
4-benzylpiperidine (7.81 g, 44.56 mmol) in absolute EtOH
(45 ml) was stirred at room temperature for 24 h. The
solution was then kept in the freezer for several hours. The
formed precipitate was filtered off and washed with
anhydrous Et2O. Yield 9.24 g (86%), colorless crystals,
mp 139‒140°C. IR spectrum, ν, cm–1: 1555, 1603, 1638,
N-[2-(1H-Indol-3-yl)ethyl]-5-amino-1,2,3-thiadiazole-
4-carboxamide (11a). Method I. Et3N (91 mg, 0.90 mmol)
and TsN3 (1g) (148 mg, 0.75 mmol) was added to a
solution of thioamide 10a (178 mg, 0.68 mmol) in MeOH
(3 ml). The reaction mixture was stirred at room
temperature for 100 min, then the volatiles were evaporated
to dryness. The residue was purified by column
chromatography: the mixture was applied as a solution in
CH2Cl2–EtOAc, 1:1, then eluted with the same solvent
mixture. Portions of the eluate containing the product were
1
2162 (C≡N), 2924, 2921, 3242, 3346, 3437. H NMR
spectrum (DMSO-d6), δ, ppm: 1.05‒1.17 (2H, m,
NCH2CH2); 1.51‒1.54 (2H, m, NCH2CH2); 1.66‒1.72 (1H,
m, CHCH2Ph); 2.50‒2.52 (2H, m, NCH2); 2.61‒2.67 (2H,
m, NCH2); 3.04 (1H, s, =CH); 3.62 (2H, d, J = 12.0,
CH2Ph); 5.75 (2H, br. s, NH2); 7.16‒7.21 (3H, m, H Ph);
7.27‒7.30 (2H, m, H Ph). 13C NMR spectrum (DMSO-d6),
δ, ppm: 31.0 (2C); 37.2; 40.4; 42.0; 46.3 (2C); 124.0;
1
pooled and evaporated to dryness. According to H NMR
spectrum, the residue was a mixture of approximately equal
parts by weight of 1,2,3-thiadiazole 11a and TsNH2 (12g).
The mixture was treated with boiling H2O (3×4 ml), and
recrystallized from EtOH–H2O. Yield 45 mg (22%), light-
1257

Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
125.8; 128.1; 129.0; 140.0; 163.1. Found, m/z: 242.1653
[M+H]+. C15H19N3. Calculated, m/z: 242.1652.
0.416 mmol). Yield 149 mg, colorless powder. Yield of
1
triazole 13b, calculated from H NMR spectrum of the
3-(Morpholin-4-yl)-3-(phenylamino)acrylonitrile (14d).
A solution of 3-ethoxy-3-(phenylamino)acrylonitrile (15d)31
(1880 mg, 10 mmol) and morpholine (1044 mg, 12 mmol)
in absolute EtOH (10 ml) was heated under reflux for
110 h. Volatile components were evaporated to dryness, the
crude product was isolated by column chromatography
(eluent petroleum ether – EtOAc, gradient from 5:1 to 3:1).
The eluate fractions containing the product were pooled,
the volatile components were evaporated to dryness, and
hexane was added to the residue. The precipitate was
filtered off, washed with hexane, and dried. The product
was used in subsequent syntheses without additional
purification. Yield 1250 mg (55%), colorless crystals,
mp 86–88°C. IR spectrum, ν, cm–1: 1116, 1370, 1582,
1598, 2187 (C≡N). Found, m/z: 230.1291 [M+H]+.
C13H16N3O. Calculated, m/z: 230.1288.
mixture, 105 mg (95%).
It was obtained according to method II from amidine
14b, 1,4-dioxane (3.3 ml), sulfonyl azide 1c (256 mg,
1.00 mmol), and Et3N (101 mg, 1.00 mmol). Yield 217 mg
(98%), colorless powder, mp 173–174°C. IR spectrum,
1
ν, cm–1: 2229 (C≡N). H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 1.58–1.69 (2H, m, CH2); 1.66–1.81 (1H, m, CH);
2.51–2.58 (2H, m, CH2); 2.90–3.03 (2H, m, CH2); 3.80
(2H, d, J = 12.7, CH2Ph); 7.14–7.22 (3H, m, H Ph); 7.24–
7.32 (2H, m, H Ph); 14.98 (1H, br. s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 30.2; 36.3; 41.7; 47.8;
102.6; 114.3; 125.6; 127.9; 128.8; 139.6; 153.5. Found,
m/z: 268.1567 [M+H]+. C15H18N5. Calculated, m/z:
268.1557.
5-(Morpholin-4-yl)-1H-1,2,3-triazole-4-carbonitrile
(13c) was obtained according to method I as a mixture with
TsNH2 (12g) from amidine 14c (100 mg, 0.654 mmol),
EtOH (2.6 ml), and sulfonyl azide 1g (129 mg,
0.655 mmol). Yield 180 mg, colorless powder. Yield of
Synthesis of 1,2,3-triazoles 13a–l (General procedure).
For yields, conditions, and product composition, see Table 1.
Method I (for compounds 13a–c,h). A mixture of TsN3
(1g) (197 mg, 1.00 mmol), amidine 14 (1.00 mmol), and
EtOH (4 ml) was stirred at room temperature. Volatiles
were evaporated to dryness, H2O (2 ml) was added to the
residue, the resulting suspension was heated under reflux
for 1 min, then cooled to room temperature. The solid
phase was separated, washed with H2O, and dried in a
vacuum desiccator over P2O5.
1
triazole 13c, calculated from H NMR spectrum of the
mixture, 109 mg (93%).
It was obtained according to method II from amidine
14c (153 mg, 1.00 mmol), EtOH (4 ml), sulfonyl azide 1c
(308 mg, 1.20 mmol), and Et3N (121 mg, 1.20 mmol).
Yield 147 mg (82%) colorless powder, mp 207–208°C.
1
IR spectrum, ν, cm–1: 2231 (C≡N). H NMR spectrum
Method II (for 1,2,3-triazoles 13a–k). A mixture of
sulfonyl azide 1c (308 mg, 1.20 mmol), Et3N, amidine 14
(1.00 mmol), and EtOH (4 ml) (for triazole 13b, the same
amount of 1,4-dioxane was used) was stirred. The volatiles
were evaporated to dryness, H2O (2 ml) was added to the
residue, the resulting suspension was heated under reflux
for 1 min, then cooled to room temperature. The solid
phase was separated, washed with H2O, and dried in a
vacuum desiccator over P2O5.
(DMSO-d6), δ, ppm: 3.30–3.39 (4H, m, 2CH2); 3.68–3.79
(4H, m, 2CH2); 15.14 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 47.5; 65.2; 103.4; 114.3; 154.6.
Found, m/z: 180.0888 [M+H]+. C7H10N5O. Calculated, m/z:
180.0880.
5-(Morpholin-4-yl)-1-phenyl-1H-1,2,3-triazole-4-carbo-
nitrile (13d) was obtained according to method II from
amidine 14d (229 mg, 1.00 mmol), EtOH (4 ml), sulfonyl
azide 1c (308 mg, 1.20 mmol), and Et3N (121 mg,
1.20 mmol). Yield 232 mg (91%), colorless powder,
mp 167–168°C. IR spectrum, ν, cm–1: 2230 (C≡N).
1H NMR spectrum (DMSO-d6), δ, ppm: 3.10–3.16 (4H, m,
2CH2); 3.57–3.64 (4H, m, 2CH2); 7.57–7.62 (1H, m,
H Ar); 7.62–7.67 (2H, m, H Ar); 7.69–7.73 (2H, m, H Ar).
13C NMR spectrum (DMSO-d6), δ, ppm: 49.1; 65.1; 106.9;
113.5; 124.3; 129.8; 130.0; 135.2; 149.9. Found, m/z:
256.1201 [M+H]+. C13H14N5O. Calculated, m/z: 256.1193.
1-Phenyl-5-(pyrrolidin-1-yl)-1H-1,2,3-triazole-4-carbo-
nitrile (13e) was obtained according to method II from
amidine 14e (213 mg, 1.00 mmol), EtOH (4 ml), sulfonyl
azide 1c (307 mg, 1.20 mmol), and Et3N (121 mg,
1.20 mmol). Yield 208 mg (87%), colorless powder,
5-(Azepan-1-yl)-1H-1,2,3-triazole-4-carbonitrile (13a)
was obtained according to method I as a mixture with
TsNH2 (12g) from amidine 14a (155 mg, 0.939 mmol),
EtOH (2 ml), and sulfonyl azide 1g (188 mg, 0.954 mmol).
Yield 236 mg, colorless powder. Yield of triazole 13a,
1
calculated from H NMR spectrum of the mixture, 176 mg
(98%).
It was obtained according to method II from amidine
14a (134 mg, 0.81 mmol), EtOH (1.8 ml), sulfonyl azide 1c
(308 mg, 1.20 mmol), and Et3N (287 mg, 2.84 mmol).
Yield 141 mg (91%), colorless powder, mp 174–175°C.
IR spectrum, ν, cm–1: 991, 1167, 1438, 1616, 2215 (C≡N).
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.50 (4H,
s, 2NCH2CH2CH2 azepane); 1.72 (4H, s, 2NCH2CH2 mp 170–171°C. IR spectrum, ν, cm–1: 2216 (C≡N).
azepane); 3.50 (4H, t, J = 5.7, 2NCH2azepane); 14.81 (1H,
br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 26.4;
27.4; 49.7; 99.6; 115.0; 151.2. Found, m/z: 192.1249
[M+H]+. C9H14N5. Calculated, m/z: 192.1244.
5-(4-Benzylpiperidin-1-yl)-1H-1,2,3-triazole-4-carbo-
nitrile (13b) was obtained according to method I as a
mixture with TsNH2 (12g) from amidine 14b (100 mg,
0.415 mmol), EtOH (4 ml), and sulfonyl azide 1g (82 mg,
1H NMR spectrum (DMSO-d6), δ, ppm: 1.76–1.83 (4H, m,
2CH2); 3.16–3.23 (4H, m, 2CH2); 7.57–7.60 (5H, m, H Ph).
13C NMR spectrum (DMSO-d6), δ, ppm: 25.1; 50.4; 101.7;
115.2; 127.2; 129.2; 130.2; 135.6; 147.5. Found, m/z:
240.1253 [M+H]+. C13H14N5. Calculated, m/z: 240.1244.
5-(Piperidin-1-yl)-1H-1,2,3-triazole-4-carbonitrile (13f)
was obtained according to method II from amidine 14f
(151 mg, 1.00 mmol), EtOH (4 ml), sulfonyl azide 1c
1258

Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
(307 mg, 1.20 mmol), and Et3N (121 mg, 1.20 mmol).
Ethyl 5-(dimethylamino)-1H-1,2,3-triazole-4-carboxy-
late (13k). Method I. TsN3 (1g) (654 mg, 3.32 mmol),
followed by Et3N (625 mg, 6.17 mmol), was added with
stirring and cooling in ice water bath to a solution of
amidine 14k (3.09 mmol) in EtOH (1.3 ml). Stirring was
continued at room temperature for 2 h. The volatiles were
evaporated to dryness, the residue was subjected to column
chromatography: the mixture was applied as a solution in
CH2Cl2, then eluted with CH2Cl2. The first portions of the
eluate containing excess amount of TsN3 (1g) (35 mg) were
collected; TsNH2 (12g) (370 mg) was found in subsequent
fraction. The last fractions of the eluate containing the
desired product were combined and evaporated to dryness.
Yield 151 mg (85%), colorless powder, mp 180–181°C.
1
IR spectrum, ν, cm–1: 2223 (C≡N). H NMR spectrum
(DMSO-d6), δ, ppm: 1.54–1.63 (6H, m, 3CH2); 3.34–3.41
(4H, m, 2CH2); 15.01 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 23.1; 24.3; 102.5; 114.6; 153.4.
Found, m/z: 178.1089 [M+H]+. C8H12N5. Calculated, m/z:
178.1087.
5-(Pyrrolidin-1-yl)-1H-1,2,3-triazole-4-carbonitrile
(13g) was obtained according to method II from amidine
14g (137 mg, 1.00 mmol), EtOH (4 ml), sulfonyl azide 1c
(307 mg, 1.20 mmol), and Et3N (121 mg, 1.20 mmol).
Yield 150 mg (92%), colorless powder, mp 219–220°C.
1
1
IR spectrum, ν, cm–1: 2216 (C≡N). H NMR spectrum
Yield 435 mg, colorless powder. According to H NMR
(DMSO-d6), δ, ppm: 1.87–2.03 (4H, m, 2CH2); 3.33–3.48
(4H, m, 2CH2); 14.80 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 25.0; 48.7; 100.0; 115.1; 149.4.
Found, m/z: 164.0932 [M+H]+. C7H10N5. Calculated, m/z:
164.0931.
spectrum, contained TsNH2 (12g) (96 mg) and 1,2,3-tri-
azole 13k (339 mg, 60%).
Method II. Sulfonyl azide 1c (190 mg, 1.32 mmol),
followed by Et3N (148 mg, 1.46 mmol), was added with
stirring and cooling in ice water bath to a solution of
amidine 14k (0.65 mmol) in EtOH (1.2 ml). Stirring was
continued at room temperature for 1 h. The volatiles were
evaporated to dryness, the residue was subjected to column
chromatography: the mixture was applied as a solution
5-Amino-1-benzyl-1H-1,2,3-triazole-4-carbonitrile
(13h) was obtained according to method I as a mixture with
TsNH2 (12g) from amidine 14h (100 mg, 0.578 mmol),
EtOH (2.3 ml), and TsN3 (1g) (114 mg, 0.579 mmol).
Yield 160 mg, colorless powder. Yield of triazole 13h,
in
CH2Cl2,
eluted
with
CH2Cl2,
and
then
1
calculated from H NMR spectrum of the mixture, 97 mg
CH2Cl2–EtOAc, 1:1. Fractions of the eluate containing
1,2,3-triazole 13k were pooled, evaporated to dryness,
and crystallized from petroleum ether. Yield 96 mg (81%),
oil that gradually crystallized upon storage under a layer of
(84%).
It was obtained according to method II from amidine
14h (173 mg, 1.00 mmol), EtOH (4 ml), sulfonyl azide 1c
(307 mg, 1.20 mmol), and Et3N (121 mg, 1.20 mmol).
Yield 150 mg (92%), colorless powder, mp 180–181°C.
1
hexane, mp 59–62°C. H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.36 (3H, t, J = 7.1, CH2CH3); 3.03 (6H, s, N(CH3)2);
4.41 (2H, q, J = 7.1, CH2CH3). 13C NMR spectrum
(CDCl3), δ, ppm: 14.3; 42.2; 61.3; 123.4; 156.1; 161.3.
Mass spectrum, m/z (Irel, %): 184 [M]+ (55), 155 (70),
139 (32), 42 (100). Found, %: C 45.86; H 6.19;
N 30.14. C7H12N4O2. Calculated, %: C 45.64; H 6.57;
N 30.42.
1
IR spectrum, ν, cm–1: 2233 (C≡N). H NMR spectrum
(DMSO-d6), δ, ppm: 5.41 (2H, s, CH2); 7.09 (2H, br. s,
NH2); 7.20–7.25 (2H, m, H Ph); 7.28–7.39 (3H, m, H Ph).
13C NMR spectrum (DMSO-d6), δ, ppm: 48.7; 101.3;
113.5; 127.4; 127.9; 128.6; 135.1; 147.9. Found, %:
C 59.92; H 4.32; N 35.08. C10H9N5. Calculated, %:
C 60.29; H 4.55; N 35.16.
Ethyl 5-{[2-(8-oxo-1,5,6,8-tetrahydro-2H-1,5-methano-
pyrido[1,2-a][1,5]diazocin-3(4H)-yl)ethyl]sulfonamido}-
1H-1,2,3-triazole-4-carboxylate (17d). Sulfonyl azide 1d
(449 mg, 1.39 mmol) was added to a suspension of imino
ether 16 (272 mg, 1.39 mmol) in MeCN (1.5 ml). The
mixture was cooled in ice water bath, and Et3N (281 mg,
2.78 mmol) was added dropwise with stirring. Cooling was
removed, and stirring was continued for another 1.5 h. The
solid phase was separated, the liquid phase was evaporated
to dryness, the residue was subjected to column
chromatography: it was applied as a solution in CH2Cl2,
eluted successively with CH2Cl2, EtOAc with AcOH
(5 drops per 10 ml), and finally EtOAc–EtOH, 7:1 with the
addition of AcOH (5 drops per 10 ml). The fractions of the
eluate containing the product were pooled, evaporated
to dryness, and the residue was recrystallized from
EtOAc–Et2O. Yield 199 mg (33%), colorless powder,
5-Amino-1-(4-methoxyphenyl)-1H-1,2,3-triazole-
4-carbonitrile (13i) was obtained according to method II
from amidine 14i (189 mg, 1.00 mmol), EtOH (4 ml),
sulfonyl azide 1c (307 mg, 1.20 mmol), and Et3N (121 mg,
1.20 mmol). Yield 192 mg (89%), light-brown powder,
mp 201–202°C. IR spectrum, ν, cm–1: 2234 (C≡N).
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.84 (3H,
s, OCH3); 7.02 (2H, br. s, NH2); 7.14 (2H, d, J = 8.7,
H Ar); 7.47 (2H, d, J = 8.7, H Ar). 13C NMR spectrum
(DMSO-d6), δ, ppm: 55.6; 101.0; 113.5; 114.9; 126.6;
126.9; 148.0; 160.1. Found, %: C 56.08; H 4.01; N 35.29.
C10H9N5O. Calculated, %: C 55.81; H 4.22; N 32.54.
5-Amino-1-(tolyl)-1H-1,2,3-triazole-4-carbonitrile
(13j) was obtained according to method II from amidine
14j (173 mg, 1.00 mmol), EtOH (4 ml), sulfonyl azide 1c
(307 mg, 1.20 mmol), and Et3N (121 mg, 1.20 mmol).
Yield 171 mg (86%), light-brown powder, mp 162–163°C.
1
mp 118–122°C (foaming). H NMR spectrum (CDCl3),
1
IR spectrum, ν, cm–1: 2244 (C≡N). H NMR spectrum
δ, ppm (J, Hz): 1.38 (3H, t, J = 8.0, CH2CH3); 1.77 (1H, d,
J = 16.0, CCH); 1.90 (1H, d, J = 16.0, CCH); 2.35–2.47
(3H, m, CCH, SCH2); 2.78–2.99 (5H, m, 2NCH2, CH);
3.35–3.55 (2H, m, 2NCH2); 3.88–4.08 (2H, m, 2NCH2);
4.48 (2H, q, J = 8.0, OCH2CH3); 6.08 (1H, d, J = 6.8,
(DMSO-d6), δ, ppm (J, Hz): 2.41 (3H, s, CH3); 7.07 (2H,
br. s, NH2); 7.41 (2H, d, J = 8.8, H Ar); 7.43 (2H, d,
J = 8.8, H Ar). 13C NMR spectrum (DMSO-d6), δ, ppm:
20.7; 101.2; 113.4; 124.8; 130.2; 131.5; 139.5; 147.8.
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Chemistry of Heterocyclic Compounds 2019, 55(12), 1251–1261
H pyridine); 6.50 (1H, d, J = 8.8, H pyridine); 7.27–7.38
References
(1H, m, H pyridine). 13C NMR spectrum (DMSO-d6),
δ, ppm: 14.4; 25.6; 27.9; 35.4; 50.3; 50.8; 51.6; 59.8; 60.6;
61.7; 106.4; 116.5; 125.1; 139.7; 145.5; 151.3; 162.2;
164.1. Found, m/z: 437.1616 [M+H]+. C18H25N6O5S.
Calculated, m/z: 437.1602.
1. Comprehensive Organic Name Reactions and Reagents;
Wang, Z., Ed.; John Wiley & Sons, Inc., 2010, p. 2322.
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Ethyl 5-[(4-methylphenyl)sulfonamido]-1H-1,2,3-tri-
azole-4-carboxylate (17g). Et3N (550 mg, 5.44 mmol) was
added dropwise with stirring and cooling in ice water bath
to a suspension of imino ether 16 (532 mg, 2.72 mmol) and
TsN3 (1g) (290 mg, 2.99 mmol) in MeCN (3 ml);
immediate precipitation occured. Cooling was removed,
and stirring was continued for another 1.5 h. The solid
phase was filtered off and washed with a small amount
of Et2O. The liquids were combined and evaporated
to dryness, the residue was subjected to column chromato-
graphy: it was applied as a solution in PhH with
the addition of Et3N (5 drops per 10 ml), successively
eluted with PhH, then PhH with the addition of AcOH
(5 drops per 10 ml). Fractions containing the desired
product were pooled and evaporated to dryness, the residue
was crystallized from EtOAc–Et2O. Yield 275 mg (33%),
colorless needles, mp 140–141°C (mp 138°C (EtOH)25).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.36 (3H, t,
J = 7.1, CH2CH3); 2.39 (3H, s, CH3); 4.39 (2H, q, J = 7.1,
CH2CH3); 7.27 (2H, d, J = 8.6, H Ar); 7.87 (2H, d, J = 8.2,
H Ar); 8.45 (1H, br. s, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 14.2; 21.6; 62.0; 125.2; 127.6; 129.8; 135.7; 144.6;
144.9; 161.8. Found, %: C 46.83; H 4.71; N 17.95.
C12H14N4O4S. Calculated, %: C 46.45; H 4.55; N 18.05.
X-ray structural analysis of compound 13d was
performed on an Xcalibur 3 single crystal diffractometer
according to the standard routine (MoKα radiation,
graphite monochromator, 295(2) K, ω-scanning with
1 deg step). The structure was solved and refined using
the SHELXTL software package.32 The structure was
solved by the direct method using the ShelXS program
and refined against F2 by the least-squares technique in the
full-matrix anisotropic approximation for non-hydrogen
atoms using the ShelXL program. Hydrogen atoms were
added to the calculated positions and included in the
refinement according to the "rider" model. X-ray structural
data: empirical formula C13H13N5O; unit cell parameters:
a 9.208(3), b 9.639(3), c 14.519(4) Å; α 90.00, β 97.25(3),
γ 90.00°; P21/n space symmetry group. The full set of
X-ray structural data was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1949437).
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1
Supplementary information file containing the H–13C
1
1
HMBC, H–13C HSQC, and H–15N HMBC spectra of
compound 7, as well as the H–13C HSQC spectrum of
1
compound 11а is available at the journal website http://
link.springer.com/journal/10593.
The authors thank the Russian Science Foundation
(Project No. 18-13-00161) for financial support.
Special thanks to Leonid Dobrolyubskii for the
illustration.
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