Some Aspects of the Azide-Alkyne 1,3-Dipolar Cycloaddition Reaction

Article abstract of DOI:10.1134/S1070428019090082

Some peculiar features of two most commonly used catalytic systems (Cul and CuSOVsodium ascorbate) controlling the regioselectivity of 1,3-dipolar cycloaddition of azides to terminal alkynes have been studied. Their potentialities, main disadvantages, and limitations have been demonstrated by a number of examples, including reactions of low-molecular-weight azides and alkynes containing heterocyclic substituents. The possibility of using novel reagents in click reactions is discussed.

Full text of DOI:10.1134/S1070428019090082

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 9, pp. 1310–1321. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 9, pp. 1393–1405.
Some Aspects of the Azide–Alkyne 1,3-Dipolar
Cycloaddition Reaction
N. T. Pokhodyloa, M. A. Tupychaka, O. Ya. Shyykaa, and M. D. Obushaka*
a Ivan Franko National University of Lviv, Lviv, Ukraine
*e-mail: mykola.obushak@lnu.edu.ua
Received February 21, 2019; revised April 6, 2019; accepted April 22, 2019
Abstract—Some peculiar features of two most commonly used catalytic systems (CuI and CuSO4/sodium
ascorbate) controlling the regioselectivity of 1,3-dipolar cycloaddition of azides to terminal alkynes have been
studied. Their potentialities, main disadvantages, and limitations have been demonstrated by a number of
examples, including reactions of low-molecular-weight azides and alkynes containing heterocyclic substituents.
The possibility of using novel reagents in click reactions is discussed.
Keywords: azides, alkynes, 1,3-dipolar cycloaddition, click reactions, catalysis, 1,2,3-triazole derivatives.
DOI: 10.1134/S1070428019090082
In recent years, azide–alkyne 1,3-dipolar cycload-
dition reactions (AAC) have been widely used for the
preparation of functional materials for different pur-
poses, as well as of polymers [1]; they provide an ef-
ficient tool for the design of new biologically active
compounds in pharmaceutical and medicinal chemistry
[2–4]. In our recent review [5], we have discussed
regioselectivity of these reactions, their mechanisms,
and application in multicomponent syntheses. Despite
numerous examples of such reactions occurring with
high yield and selectivity [6, 7], analogous reactions
with a number of accessible reagents have been poorly
studied. In the present work we studied click reactions
with such reagents.
Due to the risk of explosion, low-molecular-weight
azides have rarely been involved in copper-catalyzed
AAC reactions. We examined the reactivity of some
“small” azides 1a–1e and selectivity of their reactions
with most commonly used alkynes (Boc-protected
propargylamine 2a, propargyl alcohol 2b, and methyl
propiolate 2c) without a catalyst and in the presence of
copper catalyst (Scheme 1).
regioisomer was the major product (isomer ratio 9:1).
Here, methyl azide behaved similarly to trimethylsilyl
azide [8]. Taking into account that the regioselectivity
in the non-catalytic click reaction of methyl azide is
determined mainly by the thermodynamic factor, this
reaction can be used as a model in quantum chemical
simulation of AAC reactions.
The reactions of azides 1a–1e with alkynes 2a and
2b in the presence of copper(I) iodide were regio-
selective, and triazoles 3a–3g were generally formed
as the major products. An exception was the reaction
of 1a with 2a, which resulted in a mixture of triazole
3a and 5,5′-bitriazole 5 at a ratio of 2.4:1. Compounds
3a and 5 can readily be separated by chromatography.
In the other cases, no 5,5′-bitriazoles like 5 were
detected. Presumably, 5,5′-bitriazole 5 is formed as
a result of oxidative dimerization of intermediate A
(Scheme 2) [9, 10]. Such 5,5′-bitriazoles are consid-
ered to be undesirable by-products, and their formation
depends on both substrate structure and catalyst, base,
and reaction conditions. For example, bitriazole was
selectively obtained in the presence of 0.1 equiv of
CuBr as a catalyst and sodium ethoxide as a base at
0°C, whereas only 1,4-disubstituted triazole was
formed at 60°C in the presence of KOH as a base [11].
These data indicate that increase of the lifetime of
copper-containing intermediate A increases the prob-
ability of formation of structure 5. Intermediate A is
stabilized by copper coordination to the amide nitrogen
In the absence of a catalyst, azides 1b–1e reacted
with alkynes 2a–2c only on heating in toluene at 80–
90°C, and the products were mixtures of regioisomeric
1,2,3-triazoles 3 and 4, the former slightly prevailing
in the reactions with amine 2a. In the reaction of
methyl azide (1a) with methyl propynoate (2c) in
benzene at room temperature, the 1,4-disubstituted
1310

SOME ASPECTS OF THE AZIDE–ALKYNE 1,3-DIPOLAR CYCLOADDITION REACTION
1311
Scheme 1.
R2
R2
i or ii
R2
CH
+
+
R1
N3
R1
R1
N
N
N
N
N
N
1a–1e
2a–2c
3c–3g
4a–4e
i: R1 = H, R2 = COOMe, PhH, –20°C to room temperature, 12 h; ii: R1 ≠ H, PhMe, 80–90°C, 24 h;
3c:4a = 9:1, 3d:4b = 1.4:1, 3e:4c = 1.1:1, 3f:4d = 1:1, 3g:4e = 1.4:1.
Me
N
N
R2
NHBoc
CuI (1 mol %), Et3N
THF, room temp., 12 h
N
1a–1e
+
2a–2c
+
3a : 5 = 2.4 : 1
R1
N
N
N
BocNH
N
N
N
Me
3a–3g
5
1, R1 = H (a), CH2OH (b), CN (c), COOEt (d), CONH2 (e); 2, R2 = CH2NHBoc (a), CH2OH (b), COOMe (c); 3, R1 = H,
R2 = CH2NHBoc (a), CH2OH (b), COOMe (c); R1 = CH2OH, R2 = CH2NHBoc (d); R1 = CN, R2 = CH2NHBoc (e); R1 = COOEt,
R2 = CH2OH (f); R1 = CONH2, R2 = CH2NHBoc (g); 4, R1 = H, R2 = COOMe (a), R1 = CH2OH, R2 = CH2NHBoc (b); R1 = CN,
R2 = CH2NHBoc (c); R1 = COOEt, R2 = CH2OH (d); R1 = CONH2, R2 = CH2NHBoc (e).
atom, and the small size of the substituent (methyl
group) on the N1 nitrogen atom of the triazole ring
favors dimerization. Bulkier substituents should
hamper such transformation. It should be noted that
(1-methyl-1H-1,2,3-triazol-4-yl)methanamine (3a) is
a promising building block for combinatorial chem-
istry; however, it remains poorly explored. An alter-
native synthesis of 3a by reduction of 1-methyl-1H-
1,2,3-triazole-4-carboxamide with lithium tetrahy-
dridoborate in diethylene glycol at 155°C was
described in patent [12] related to the synthesis of anti-
inflammatory drugs.
Under similar conditions, azide with a longer ali-
phatic chain, 3-(azidomethyl)heptane (1f), reacted with
phenylacetylene (2d) at a low rate, and the yield of
triazole 3h was low. We succeeded in obtaining target
product 3h in a high yield (90%) by using copper(I)
iodide as a catalyst in combination with a catalytic
amount of benzoic acid (Scheme 3). The catalytic
system Cu(I)/BzOH was proposed for the first time in
[13] and was efficient in reactions with azides con-
taining lipophilic fragments.
The reaction of 1,3-diazidopropane (6a) with both
1 and 2 equiv of alkyne 2c in the presence of CuI gave
bis-triazole 7 in a good yield, and no by-products were
detected (Scheme 4). The reaction of diazide 6b
with excess phenylacetylene 2d in the presence of
CuSO4/sodium ascorbate also afforded bis-triazole 9;
the reaction was fast and was accompanied by appre-
ciable evolution of heat.
The acceleration effect observed in the reactions of
diazides 6a and 6b with phenylacetylene can be
rationalized by specific coordination of copper ion to
the triazole ring, which maintains a high concentration
of catalytically active copper species and thus favors
CuAAC reaction. The nature of such bonding and its
effect on the catalytic process are insufficiently clear.
It is believed that ligands affect the reaction rate by
shifting the equilibrium between copper clusters in
solution [14]. Presumably, if an azide contains a group
or a fragment capable of disrupting equilibrium proc-
esses, the reaction will be accelerated or slowed down.
Taking into account the structure of some known
co-catalysts of CuAAC reactions [15], containing a tri-
azole ring, we have synthesized new triazole deriva-
tives for this purpose. Starting from phenyl azide
We also studied CuAAC reactions of diazides ca-
pable of coordinating copper ion during the process.
Scheme 2.
Me
N
N
N
NHBoc
N
CuIL
[O]
N
N
N
Boc
N
Boc
Me
N
+
N
N
N
Cu
H
HC
N
BocNH
Me
L
N
Me
1a
2a
A
5
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

POKHODYLO et al.
Scheme 3.
1312
Me
Me
N
N
Ph
CuI, PhCOOH, i-PrOH–H2O
+
Ph
Me
N3
Me
N
HC
1f
2d
3h
(10a), we obtained intermediate (1-phenyl-1H-1,2,3-
triazol-4-yl)methanol (11) which was converted to
aldehyde 12 and acid 13. The latter is a potential co-
catalyst. Alcohol 11 was treated with phosphorus(III)
bromide in benzene, and bromomethyl derivative 14
thus formed was treated with sodium azide. The
resulting 4-(azidomethyl)-1-phenyl-1H-1,2,3-triazole
(15) proved to be quite active in the reaction with
phenylacetylene (2d) catalyzed by CuI (Scheme 5).
The reaction required a minimum amount of the
catalyst, and product 16 was formed in a high yield.
These findings indicate that triazole ring is one of the
best ligands for solving the problem of stabilization
of active copper species in the catalysis of AAC
reactions.
ring linked to the same carbon atom was difficult;
therefore, we synthesized a 1-(2-azidoethyl)benzo-
triazole derivative. Furthermore, donor methyl groups
were introduced into the benzene ring of the 1,2,3-ben-
zotriazole fragment to achieve better complexation.
Starting from 4,5-dimethyl-2-nitroaniline, we obtained
azide 17 as shown in Scheme 6. Azide 17 was reacted
with alkynes 2c and 2e. The reaction with diethyl ace-
tylenedicarboxylate (2e) in toluene afforded triazole 18
in nearly quantitative yield. The reaction of 17 with
methyl propynoate (2c) in the presence of a minimum
amount of CuI without a base gave 94% of triazole 19,
regardless of the solvent used (t-BuOH or THF), which
indicated positive effect of the benzotriazole fragment
of 17 on the concentration of catalytically active cop-
per species.
A similar pattern was observed in the reaction with
azide containing a benzotriazole fragment. The syn-
thesis of a compound with the azido group and triazole
It should be noted that the reactivity of azide 20
containing an imidazo[1,2-a]pyridine fragment was
Scheme 4.
COOMe
COOMe
N
COOMe
N
CuI (1 mol %)
Et3N, THF
COOMe
N3
N3
+
+
N
N
N
HC
N
N3
N
N
N
6a
N3
2c
N3
7, 74%
8, traces
CuSO4·5H2O, NaAsc
DMSO–H2O
N
N
Ph
Ph
Ph
+
N
N
HC
N
N
Bu-t
Bu-t
6b
2d
9, 70%
Scheme 5.
N
N
N
CuI, Et3N, t-BuOH
PhN3
+
OH
87%
HC
OH
Ph
10a
2b
CH2(COOH)2, pyridine
11
COOH
N
N
N
N
N
N
PCC, CH2Cl2
CHO
Br
Ph
Ph
Ph
12
13
NaN3, H2O
MeOH
2d, CuI (1 mol %)
N3
N
N
N
N
N
N
N
N
N
N
PBr3, PhH
THF
N
N
Ph
Ph
91%
Ph
14
15
16
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SOME ASPECTS OF THE AZIDE–ALKYNE 1,3-DIPOLAR CYCLOADDITION REACTION
1313
Scheme 6.
Me
Me
NO2
NH2
Me
Me
NH2
Me
Me
N
H2, Raney Ni, MeOH
NaNO2, AcOH, H2O
N
N
H
NH2
Me
N
Me
N
N
BrCH2COOEt
NaH, DMF
LiAlH4, THF
0°C to room temp., 12 h
N
N
N
Me
Me
OH
COOEt
Me
Me
Me
N
N
N
N
MsCl, Et3N, CH2Cl2
NaN3, DMF, 70–90°C
N
N
Me
OMs
N3
17
Me
Me
N
N
PhMe
N
N
COOEt
N
R1 = COOEt
R1
COOR2
2c, 2e
N
COOEt
18, 97%
CuI (1 mol %)
THF
Me
Me
N
N
N
COOMe
N
R1 = H
N
N
19, 94%
2c, R1 = H, R2 = Me; 2e, R1 = COOEt, R2 = Et.
triazoles in about 50% yield in the system
CuI/PEG-400/H2O.
appreciably lower. Azide 20 was synthesized from
pyridin-2-amine via a series of transformations shown
in Scheme 7, and it slowly reacted even with such
a reactive dipolarophile as acetylenecarboxylate 2c in
tert-butyl alcohol only in the presence of a basic co-
catalyst. Under the optimal conditions, the yield of
triazole 21 was 74%. Our results are very consistent
with the data of [16], according to which structurally
related azides were converted to the corresponding
Su et al. [17] recently reported the synthesis of
biologically active 1,4-disubstituted 1,2,3-triazoles
containing a 2H-1,4-benzoxazin-3(4H)-one fragment
by 1,3-dipolar cycloaddition of N-propargyl-2H-1,4-
benzoxazin-3(4H)-one with benzyl azide in the pres-
ence of CuI [17]. This reaction was difficult to
accomplish, and much effort was made to optimize the
Scheme 7.
OH
R
CHO
RC(O)CH2Br
i-PrOH
NaBH4
MeOH, i-PrOH
POCl3, DMF
N
N
N
R
R
N
N
N
N
NH2
N
N
N3
N
COOMe
Cl
DPPA
DBU, DMF
2c, CuI (10 mol %)
Et3N, THF
N
N
Cl
74%
N
N
Cl
Cl
20
21
R = 2,4-Cl2C6H3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

POKHODYLO et al.
1314
Scheme 8.
H
N
Me
H
N
Me
Me
Me2CO, CHCl3, 50% aq. NaOH
CH2Cl2, BTEAC, 10°C, 5–7 h
BrCH2C
NaH, DMF
≡
CH
NH2
NH2
RN3 (10a–10c)
Me
N
H
O
N
O
CH
22
Scheme 9.
N3
O
CuI, Et3N, THF
N
N
N
room temp., 12 h
N
+
2d
N
O
O
90%
N
Ph
Ph
O
Ph
23
25
N
N
CHO
CH
CuI, Et3N, THF
N3
O
room temp., 12 h
O
+
R2
R1
R2
CHO
R1
10a, 10d
24a, 24b
26a (72%), 26b (87%)
10, R1 = H (a), NO2 (d); 24, R2 = H (a), Br (b); 26, R1 = H, R2 = H (a), R1 = NO2, R2 = Br (b).
conditions. Acceptable yields were achieved by heat-
ing the reactants (1.2 equiv of benzyl azide was taken)
in dioxane at 80°C using 30 mol % of CuI [17]. We
have synthesized a structural analog of the reported
products, 3,3-dimethyl-1-(prop-2-yn-1-yl)-3,4-dihy-
droquinoxalin-2(1H)-one (22), which is promising for
the design of biologically active compounds. 3,4-Di-
hydroquinoxalin-2(1H)-one was synthesized in one
step from o-phenylenediamine, and its alkylation with
propargyl bromide gave compound 22 (Scheme 8)
which failed to react with phenyl and 4-fluorophenyl
azides 10a and 10b, as well as with methyl 3-azido-
thiophene-2-carboxylate (10c), in the presence of dif-
ferent catalytic systems on prolonged heating.
of 5,5′-bitriazoles. Aminomethyl substituent in the
acetylenic component favors additional copper coor-
dination in the triazolyl–cuprate intermediate, which
accelerates the reaction and makes it possible to intro-
duce an electrophile into the 5-position of the triazole
ring. In CuAAC reactions with azides containing
a bulky lipophilic substituent, organic acids (e.g., ben-
zoic acid) act as efficient co-catalysts by mediating
copper(I) ion transfer between copper clusters to pro-
tonate the triazolyl–cuprate intermediate. The copper
catalyst in CuAAC reactions is very sensitive to coor-
dination to a heterocyclic core, and this coordination
could both accelerate and inhibit the process.
The reactions of 3-azido-1-phenylpyrrolidine-2,5-
dione (23, obtained from N-phenylmaleimide) with
phenylacetylene (2d) and of aryl azides 10a and 10d
with propargyl ethers 24a and 24b under similar con-
ditions (CuI/Et3N) afforded triazoles 25 and 26a, 26b,
respectively, in high yields (Scheme 9).
Our results led us to draw the following conclu-
sions. In the copper-catalyzed azide–alkyne cycloaddi-
tion reactions with “small” azides, the substituent does
not shield the copper ion in the triazolyl–cuprate
intermediate, so that there is the possibility of copper
coordination to one more triazole ring, which favors
oxidative coupling (dimerization) with the formation
EXPERIMENTAL
The
1H NMR spectra were recorded on Varian
Unity Plus 400 and Bruker Avance 500 spectrometers
at 400 and 500 MHz, respectively, using tetramethyl-
silane as internal standard. The mass spectra (atmo-
spheric pressure chemical ionization) were obtained on
an Agilent 1100 LC/MSD instrument. The elemental
analyses were performed with a Carlo Erba 1106
analyzer. The melting points were measured on
a Boetius hot stage. The products were isolated by
column chromatography on silica gel using hexane–
ethyl acetate (9:1) as eluent.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SOME ASPECTS OF THE AZIDE–ALKYNE 1,3-DIPOLAR CYCLOADDITION REACTION
1315
(2H, o-H, J = 7.3 Hz), 7.40–7.55 m (3H, m-H, p-H).
Found, %: C 55.68; H 3.83; N 25.76. C10H17N5O3.
Calculated, %: C 55.55; H 3.73; N 25.91.
Methyl azide (1a) [18]. A solution of 2.5 g
(0.0625 mol) of sodium hydroxide and 8.2 g
(0.126 mol) of sodium azide in 70 mL of water was
heated to 70°C, and 11.8 mL (0.125 mol) of dimethyl
sulfate was added with vigorous stirring. Water–
methylazide azeotrope (bp 26°C) was distilled off into
a receiver cooled with liquid nitrogen, and the product
was used without further purification. CAUTION!
Methyl azide is toxic and explosive.
Cycloaddition of methyl azide (1a) to alkynes
2a–2c. Alkyne 2a–2c (25 mmol), copper(I) iodide
(0.05 g), and triethylamine (2.1 mL), were quickly
added to a solution of methyl azide (1a, ~50 mmol) in
25 mL of THF cooled to –20°C. The reactor was
hermetically closed, and the mixture was vigorously
stirred for 12 h. The solvent, triethylamine, and excess
methyl azide were evaporated, the residue was dis-
solved in methylene chloride, and the solution was
filtered from inorganic materials. The filtrate was
evaporated to obtain triazoles 3a–3c. In the reaction of
azide 1a with alkyne 2a, a mixture of 3a and bitriazole
5 was formed at a ratio of 2.4:1. Pure compounds 3a
and 5 were isolated by column chromatography.
Alkyl azides 1b–1e, 6a, 6b, 15, and 23 (general
procedure). The corresponding halogen derivative,
0.1 mol (or 0.05 mol of dihalo derivative), was dis-
solved in 120 mL of methanol, and 20 mL of water and
7.8 g (0.12 mol) of sodium azide were added. The
mixture was stirred for 2 h at 50–60°C, methanol was
distilled off under reduced pressure, and 30 mL of
water was added to the residue. The product was
extracted into methylene chloride (2×15 mL), the ex-
tract was dried over Na2SO4, the solvent was distilled
off under reduced pressure, and the residue was used
without further purification. 2-Azidoethanol (1b) [19],
yield 73%; 2-azidoacetonitrile (1c) [20], yield 83%;
ethyl 2-azidoacetate (1d) [21], yield 94%.
tert-Butyl (1-methyl-1H-1,2,3-triazol-4-yl)-
methylcarbamate (3a) [24]. Yield 2.62 g (49%),
1
mp 104–105°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.41 s (9H, t-Bu), 4.03 s (3H,
CH3), 4.16 d (2H, CH2, J = 5.8 Hz), 7.00 t (1H, NH,
J = 5.8 Hz), 7.72 s (1H, 5-H). Mass spectrum: m/z 213
[M + H]+. Found, %: C 50.98; H 7.71; N 26.34.
C9H16N4O2. Calculated, %: C 50.93; H 7.60; N 26.40.
2-Azidoacetamide (1e) [22]. Yield 9.50 g (95%).
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
3.69 s (2H, CH2), 7.13 s and 7.39 s (1H each, NH).
(1-Methyl-1H-1,2,3-triazol-4-yl)methanol (3b)
1
[25]. Yield 2.66 g (94%). H NMR spectrum
1,3-Diazidopropane (6a) [23]. Yield 5.54 g (88%).
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
1.70–1.85 m (2H, CH2), 3.40 t (4H, CH2, J = 6.5 Hz).
(400 MHz, DMSO-d6), δ, ppm: 4.03 s (3H, CH3),
4.50 s (2H, CH2), 4.97 s (1H, OH), 7.79 s (1H, 5-H).
Methyl 1-methyl-1H-1,2,3-triazole-4-carboxylate
1,3-Bis(azidomethyl)-5-tert-butylbenzene (6b).
1
(3c) [25]. Yield 3.08 g (97%). H NMR spectrum
1
Yield 10.08 g (90%), viscous oil. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 3.85 s (3H, CH3O),
4.12 s (3H, CH3), 8.60 s (1H, 5-H).
(500 MHz, CDCl3), δ, ppm: 1.31 s (9H, t-Bu), 4.31 s
(4H, CH2), 7.05–7.07 m (1H, Harom), 7.27 d (2H, Harom
,
J = 1.5 Hz). 13C NMR spectrum (126 MHz, CDCl3),
δC, ppm: 31.3, 54.9, 125.0, 125.1, 135.8, 152.7. Found,
%: C 59.31; H 6.42; N 34.62. C12H16N6. Calculated, %:
C 59.00; H 6.60; N 34.40.
Di-tert-butyl [3,3′-dimethyl-3H,3′H-4,4′-bi-1,2,3-
triazole-5,5′-diylbis(methylene)]dicarbamate (5).
1
Yield 1.09 g (21%). H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.31 s (18H, t-Bu), 3.76 s (6H,
CH3), 4.16 d (4H, CH2, J = 5.8 Hz), 6.93 t (2H, NH,
J = 5.8 Hz). Mass spectrum: m/z 423 (Irel 100%)
[M + H]+. Found, %: C 51.11; H 7.21; N 26.55.
C18H30N8O4. Calculated, %: C 51.17; H 7.16; N 26.52.
4-(Azidomethyl)-1-phenyl-1H-1,2,3-triazole (15).
Yield 19.40 g (97%), mp 55–56°C. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 4.62 s (2H, CH2),
7.36–7.72 m (3H, m-H, p-H), 7.91 d (2H, o-H, J =
7.9 Hz), 8.90 s (1H, 5-H). Found, %: C 53.89; H 4.17;
N 41.83. C9H8N6. Calculated, %: C 53.99; H 4.03;
N 41.98.
Cycloaddition of methyl azide (1a) to methyl
propynoate (2c). Azide 1a, 5.7 g (0.2 mol), was
cooled to –20°C, and 8.2 mL (0.1 mol) of ester 2c in
80 mL of benzene was quickly added. The reactor was
hermetically closed, and the mixture was vigorously
stirred for 48 h. The solvent was evaporated to leave
a mixture of triazoles 3c and 4a at a ratio of 9:1.
The pure products were isolated by column chroma-
tography.
3-Azido-1-phenylpyrrolidine-2,5-dione (23).
1
Yield 19.22 g (89%), mp 106–107°C. H NMR spec-
trum (400 MHz, DMSO-d6), δ, ppm: 2.71 d.d (1H,
CH2, J = 17.7, 4.6 Hz), 3.15 d.d (1H, CH2, J = 17.6,
8.9 Hz), 5.03 d.d (1H, CH, J = 8.1, 5.2 Hz), 7.31 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

POKHODYLO et al.
1316
1.27 t (3H, CH3, J = 7.0 Hz), 4.20 q (2H, OCH2,
J = 7.0 Hz), 4.55 s (2H, CH2), 5.25 s (2H, CH2OH),
5.36 s (1H, OH), 7.86 s (1H, 5-H). Mass spectrum:
m/z 186 (Irel 100%) [M + H]+. Found, %: C 45.53;
H 5.91; N 22.84. C7H11N3O3. Calculated, %: C 45.40;
H 5.99; N 22.69.
Methyl 1-methyl-1H-1,2,3-triazole-5-carboxylate
(4a) [26]. Yield 1.41 g (9.5%), mp 50–51°C. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 3.90 s (1H,
CH3O), 4.27 s (3H, CH3), 8.10 s (1H, 4-H).
1
Noncatalytic cycloaddition of azides to alkynes
(general procedure). A solution of equimolar amounts
(2.5 mmol) of the corresponding azide and alkyne in
toluene was heated at 80–90°C for 2–8 h until the reac-
tion was complete (TLC). The solvent was removed
under reduced pressure. If a mixture of isomeric
triazoles was formed, the products were isolated by
chromatography.
Ethyl 2-[5-(hydroxymethyl)-1H-1,2,3-triazol-1-
yl]acetate (4d) [28]. Yield 0.22 g (47 %), viscous oil.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
1.28 t (3H, CH3, J = 7.0 Hz), 4.20 q (2H, OCH2,
J = 7.0 Hz), 4.55 s (2H, CH2), 5.06 s (1H, OH), 5.27 s
(2H, CH2OH), 7.51 s (1H, 4-H). Mass spectrum:
m/z 186 (Irel 100%) [M + H]+. Found, %: C 45.25;
H 5.85; N 22.64. C7H11N3O3. Calculated, %: C 45.40;
H 5.99; N 22.69.
tert-Butyl {[1-(2-hydroxyethyl)-1H-1,2,3-triazol-
4-yl]methyl}carbamate (3d). Yield 0.31 g (52%),
1
viscous oil. H NMR spectrum (400 MHz, DMSO-d6),
tert-Butyl {[1-(2-amino-2-oxoethyl)-1H-1,2,3-tri-
azol-4-yl]methyl}carbamate (3g). Yield 0.35 g
δ, ppm: 1.41 s (9H, t-Bu), 3.78 t (2H, CH2, J = 5.0 Hz),
4.19 d (2H, CH2N, J = 5.6 Hz), 4.33–4.46 m (2H,
CH2O), 4.93 s (1H, OH), 6.99 d (1H, NH, J = 4.9 Hz),
7.75 s (1H, 5-H). Mass spectrum: m/z 243 (Irel 100%)
[M + H]+. Found, %: C 49.51; H 7.41; N 23.19.
C10H18N4O3. Calculated, %: C 49.58; H 7.49; N 23.13.
1
(55%), mp 138–139°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.40 s (9H, t-Bu), 4.19 d (2H,
CH2N, J = 5.4 Hz), 4.96 s (2H, CH2), 7.01 t (1H, NH,
J = 5.4 Hz), 7.22 s and 7.52 s (1H each, CONH2),
7.74 s (1H, 5-H). Mass spectrum: m/z 256 (Irel 100%)
[M + H]+. Found, %: C 47.14; H 6.63; N 27.49.
C10H17N5O3. Calculated, %: C 47.05; H 6.71; N 27.43.
tert-Butyl {[1-(2-hydroxyethyl)-1H-1,2,3-triazol-
5-yl]methyl}carbamate (4b). Yield 0.22 g (37%),
1
viscous oil. H NMR spectrum (400 MHz, DMSO-d6),
tert-Butyl {[1-(2-amino-2-oxoethyl)-1H-1,2,3-tri-
azol-5-yl]methyl}carbamate (4e). Yield 0.26 g (40%),
δ, ppm: 1.41 s (9H, t-Bu), 3.78 t (2H, CH2, J = 5.0 Hz),
4.28 d (2H, CH2N, J = 5.6 Hz), 4.33–4.46 m (2H,
CH2O), 4.93 s (1H, OH), 7.17 d (1H, NH, J = 4.9 Hz),
7.42 s (1H, 4-H). Mass spectrum: m/z 243 (Irel 100%)
[M + H]+. Found, %: C 49.64; H 7.54; N 23.21.
C10H18N4O3. Calculated, %: C 49.58; H 7.49; N 23.13.
1
mp 150–151°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.40 s (9H, t-Bu), 4.19 d (2H,
CH2N, J = 5.4 Hz), 5.05 s (2H, CH2), 7.13 t (1H, NH,
J = 5.4 Hz), 7.27 s (1H, CONH2), 7.43 s (1H, 4-H),
7.64 s (1H, CONH2). Mass spectrum: m/z 256
(Irel 100%) [M + H]+. Found, %: C 47.00; H 6.79;
N 27.54. C10H17N5O3. Calculated, %: C 47.05; H 6.71;
N 27.43.
tert-Butyl {[1-(cyanomethyl)-1H-1,2,3-triazol-4-
yl]methyl}carbamate (3e). Yield 0.24 g (40%),
1
viscous oil. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 1.41 s (9H, t-Bu), 4.20 d (2H, CH2N, J =
5.6 Hz), 5.68 s (2H, CH2), 7.11 s (1H, NH, J = 5.6 Hz),
7.97 s (1H, 5-H). Mass spectrum: m/z 238 (Irel 100%)
[M + H]+. Found, %: C 50.71; H 6.31; N 29.54.
C10H15N5O2. Calculated, %: C 50.62; H 6.37; N 29.52.
Diethyl 1-[2-(5,6-dimethyl-1H-1,2,3-benzotri-
azol-1-yl)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylate
(18). Yield 0.94 g (97%), mp 123–124°C. H NMR
1
spectrum (400 MHz, DMSO-d6), δ, ppm: 1.19 t (3H,
CH3, J = 7.0 Hz), 1.26 t (3H, CH3, J = 7.0 Hz), 2.35 s
(6H, CH3), 4.13 q (2H, CH2O, J = 7.0 Hz), 4.29 q (2H,
CH2O, J = 7.0 Hz), 5.13 t (2H, CH2, J = 5.7 Hz), 5.18 t
(2H, CH2, J = 5.5 Hz), 7.37 s (1H, Harom), 7.74 s (1H,
tert-Butyl {[1-(cyanomethyl)-1H-1,2,3-triazol-5-
yl]methyl}carbamate (4c). Yield 0.21 g (36%), vis-
1
cous oil. H NMR spectrum (400 MHz, DMSO-d6), δ,
H
arom). Mass spectrum: m/z 387 (Irel 100%) [M + H]+.
ppm: 1.41 s (9H, t-Bu), 4.30 d (2H, CH2N, J = 5.8 Hz),
5.56 s (2H, CH2), 7.28 d (1H, NH, J = 5.6 Hz), 7.54 s
(1H, 4-H). Mass spectrum: m/z 238 (Irel 100%)
[M + H]+. Found, %: C 50.73; H 6.39; N 29.60.
C10H15N5O2. Calculated, %: C 50.62; H 6.37; N 29.52.
Found, %: C 55.87; H 5.79; N 21.81. C18H22N6O4.
Calculated, %: C 55.95; H 5.74; N 21.75.
Cycloaddition of azides to alkynes in the pres-
ence of copper(I) iodide. The corresponding azide
(1 mmol) and terminal alkyne (1 mmol or 2 mmol in
the reactions with diazides) were dissolved in 5 mL of
THF or tert-butyl alcohol. Water was added to the
Ethyl 2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-
yl]acetate (3f) [27]. Yield 0.22 g (47%), mp 72–73°C.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SOME ASPECTS OF THE AZIDE–ALKYNE 1,3-DIPOLAR CYCLOADDITION REACTION
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
1317
solution until an emulsion began to form, and a cata-
lytic amount of copper(I) iodide (1–10 mol %, de-
pending on the azide reactivity) was added. In the reac-
tions with weakly reactive azides, 0.4 mL (2.8 mmol)
of triethylamine as a co-catalyst was added. The mix-
ture was stirred at room temperature until the initial
azide disappeared (according to the TLC or IR data).
The mixture was treated with 15 mL of water and
15 mL of concentrated aqueous ammonia and extracted
with methylene chloride (3×10 mL). The extract was
dried over Na2SO4, and the solvent was evaporated
under reduced pressure. If necessary, the product was
purified by recrystallization or column chromatog-
raphy. Compounds 3d–3g were obtained as the only
products: 3d, yield 95%; 3e, yield 89%; 3f, yield 91%;
3g, yield 67%.
5.19 s (2H, CH2), 7.02 t (1H, 6-HPy, J = 6.6 Hz), 7.41 t
(1H, 7-HPy, J = 7.6 Hz), 7.47 d.d (1H, 5″-H, J = 8.3,
1.7 Hz), 7.52 d (1H, 6″-H, J = 8.2 Hz), 7.56–7.64 m
(2H, Harom), 8.47 d (1H, 5-HPy, J = 6.8 Hz), 8.70 s
(1H, 5-H). Mass spectrum: m/z 402/404/406 [M + 1]+.
Found, %: C 53.70; H 3.32; N 17.53. C18H13Cl2N5O2.
Calculated, %: C 53.75; H 3.26; N 17.41.
1-Phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)pyr-
rolidine-2,5-dione (25). Yield 0.29 g (90%), mp 189–
1
190°C. H NMR spectrum (400 MHz, DMSO-d6), δ,
ppm: 3.45 d.d (1H, CH2, J = 17.8, 5.7 Hz), 3.60 d.d
(1H, CH2, J = 17.8, 9.2 Hz), 6.15 d.d (1H, CH, J = 9.2,
5.7 Hz), 7.30–7.41 m (3H, Harom), 7.44–7.51 m (3H,
Harom), 7.55 t (2H, m-H, J = 7.3 Hz), 7.86 d (2H, o-H,
J = 7.1 Hz), 8.95 s (1H, 5-H). Mass spectrum: m/z 319
(Irel 100%) [M + H]+. Found, %: C 67.75; H 4.39;
N 17.71. C18H14N4O2. Calculated, %: C 67.92; H 4.43;
N 17.60.
Dimethyl 1,1′-(propane-1,3-diyl)bis(1H-1,2,3-tri-
azole-4-carboxylate) (7). Yield 0.22 g (74%),
1
mp 196–197°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.23–1.75 m (2H, CH2). 3.73–
3.80 m (4H, CH2), 3.86 s (6H, OCH3), 8.71 s (2H,
5-H). Mass spectrum: m/z 295 (Irel 100%) [M + H]+.
Found, %: C 44.99; H 4.73; N 28.41. C11H14N6O4.
Calculated, %: C 44.90; H 4.80; N 28.56.
2-[(1-Phenyl-1H-1,2,3-triazol-4-yl)methoxy]-
benzaldehyde (26a). Yield 0.20 g (72%), mp 155–
156°C. H NMR spectrum (400 MHz, DMSO-d6–
1
CCl4), δ, ppm: 5.47 s (2H, CH2). 7.14 t (1H, p-H, J =
7.1 Hz), 7.51 d.d (2H, 4′-H, 5′-H, J = 7.8, 14.8 Hz),
7.62 t (2H, m-H, J = 7.4 Hz), 7.71 d.d (2H, 3′-H, 6′-H,
J = 7.8, 14.9 Hz), 7.84 d (2H, o-H, J = 7.4 Hz), 8.96 s
(1H, 5-H), 10.44 s (1H, CHO). Mass spectrum:
m/z 280 [M + H]+. Found, %: C 68.60; H 4.85;
N 15.29. C16H13N3O2. Calculated, %: C 68.81; N 4.69;
N 15.05.
(1-Phenyl-1H-1,2,3-triazol-4-yl)methanol (11)
[29]. Yield 0.15 g (87%).
1-Phenyl-4-[(4-phenyl-1H-1,2,3-triazol-1-yl)-
methyl]-1H-1,2,3-triazole (16). Yield 0.27 g (91%),
1
mp 189–190°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 5.85 s (2H, CH2), 7.33 t (1H, p-H,
J = 6.9 Hz), 7.44 t (2H, m-H, J = 7.2 Hz), 7.50 t (1H,
p-H, J = 7.1 Hz), 7.60 t (2H, m-H, J = 7.2 Hz), 7.86 d
(2H, o-H, J = 7.6 Hz), 7.91 d (2H, o-H, J = 7.8 Hz),
8.66 s (1H, 5-H), 8.95 s (1H, 5-H). Mass spectrum:
m/z 303 [M + H]+. Found, %: C 67.51; H 4.77;
N 27.95. C17H14N6. Calculated, %: C 67.54; H 4.67;
N 27.80.
5-Bromo-2-{[1-(4-nitrophenyl)-1H-1,2,3-triazol-
4-yl]methoxy}benzaldehyde (26b). Yield 0.35 g
1
(87%), mp 235–236°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 5.46 s (2H, CH2), 7.31 d (2H, o-H,
J = 9.0 Hz), 7.77 s (1H, 3′-H), 8.24 d (2H, m-H, J =
9.0 Hz), 8.28 d (1H, 5′-H, J = 9.1 Hz), 8.44 d (1H,
6′-H, J = 9.1 Hz), 9.19 s (1H, 5-H), 10.40 s (1H,
CHO). Mass spectrum: m/z 403/405 (Irel 100%)
[M + H]+. Found, %: C 47.74; H 2.81; N 13.97.
C16H11BrN4O4. Calculated, %: C 47.66; H 2.75;
N 13.90.
Methyl 1-{2-(5,6-dimethyl-1H-1,2,3-benzotri-
azol-1-yl)ethyl}-1H-1,2,3-triazole-4-carboxylate
1
(19). Yield 0.28 g (94%), mp 129–130°C. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 2.39 s (3H,
CH3), 2.42 s (3H, CH3), 3.83 s (3H, OCH3), 5.13 q
(2H, CH2, J = 5.7 Hz), 5.04 q (2H, CH2, J = 5.5 Hz),
7.37 s (1H, Harom), 7.77 s (1H, Harom), 8.70 s (1H, 5-H).
Mass spectrum: m/z 301 [M + H]+. Found, %: C 55.93;
H 5.59; N 27.90. C14H16N6O2. Calculated, %: C 55.99;
H 5.37; N 27.98.
2-Ethylhexyl azide (1f). 2-Ethylhexyl bromide, 3 g
(19.3 mmol), was dissolved in 15 mL of DMSO, and
1.51 g (23.2 mmol) of sodium azide, 2 mL of water,
and a catalytic amount of potassium iodide were
added. The mixture was stirred for 24 h at 70°C,
cooled to room temperature, diluted with 200 mL of
water, and extracted with methylene chloride. The
extract was washed with brine and dried over MgSO4,
and the solvent was evaporated under reduced pres-
Methyl 1-{[2-(2,4-dichlorophenyl)imidazo-
[1,2-a]pyridin-3-yl]methyl}-1H-1,2,3-triazole-4-car-
boxylate (21). Yield 0.30 g (74%), mp 229–230°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

POKHODYLO et al.
1318
sure. Azide 1f was obtained as a light yellow liquid.
Yield 2.69 g (90%). H NMR spectrum (500 MHz,
stirring to a suspension of 16.15 g (0.075 mol) of
freshly prepared pyridinium chlorochromate (PCC) in
200 mL of anhydrous methylene chloride. The mixture
was stirred for 90 min at room temperature, 200 mL of
anhydrous diethyl ether was added, the solution was
separated from the black precipitate by decanting,
and the precipitate was washed with diethyl ether
(2 ×50 mL). The combined extracts were filtered
through 20 g of silica gel, the solvent was distilled off
under reduced pressure, and the residue was recrys-
tallized from carbon tetrachloride. Yield 6.75 g (78%).
1
CDCl3), δ, ppm: 0.89–0.97 m (3H, CH3), 0.98 t (3H,
CH3, J = 7.4 Hz), 1.23–1.50 m (8H, CH2), 2.04 d.t
(1H, CH, J = 12.1, 5.4 Hz), 4.40 d (2H, CH2N3, J =
6.7 Hz). Found, %: C 61.57; H 11.12; N 27.19.
C8H17N3. Calculated, %: C 61.89; H 11.04; N 27.07.
1-(2-Ethylhexyl)-4-phenyl-1H-1,2,3-triazole (3h).
2-Ethylhexyl azide (0.40 g, 2.6 mmol), phenylace-
tylene (0.28 mL, 2.8 mmol), copper(I) iodide (49.5 mg,
0.26 mmol), and benzoic acid (31.7 mg, 0.26 mmol)
were added to 5 mL of a 1:2 propan-2-ol–water mix-
ture. The mixture was stirred for 24 h at room tem-
perature, diluted with 100 mL of water, and extracted
with diethyl ether (2×50 mL). The extract was washed
with brine and dried over MgSO4, and the solvent was
evaporated under reduced pressure to obtain triazole
3h which did not require further purification. Yield
1
mp 96–97°C. H NMR spectrum (500 MHz,
DMSO-d6), δ, ppm: 7.57 t (1H, p-H, J = 7.2 Hz), 7.65 t
(2H, m-H, J = 7.2 Hz), 8.03 d (2H, o-H, J = 7.2 Hz),
9.59 s (1H, 5-H), 10.24 s (1H, CHO). Mass spectrum:
m/z 174 [M + H]+. Found, %: C 62.45; H 4.14;
N 24.21. C9H7N3O. Calculated, %: C 62.42; H 4.07;
N 24.27.
1
(E)-3-(1-Phenyl-1H-1,2,3-triazol-4-yl)prop-2-
enoic acid (13). A mixture of 5.3 g (0.03 mol) of
aldehyde 12 and 4.2 g (0.04 mol) of malonic acid in
20 mL of pyridine was refluxed for 3 h. Pyridine was
distilled off under reduced pressure, the residue was
treated with 35 mL of water and acidified with con-
centrated aqueous HCl, and the precipitate was filtered
off. Yield 5.61 g (87%), mp 240–242°C (decomp.).
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm:
6.64 d (1H, CH=, J = 15.7 Hz), 7.55 d (1H, p-H, J =
6.7 Hz), 7.60 d (1H, CH=, J = 15.7 Hz), 7.65 t (2H,
m-H, J = 6.8 Hz), 7.91 d (2H, o-H, J = 6.8 Hz), 9.23 s
(1H, 5-H). Mass spectrum: m/z 216 [M + H]+. Found,
%: C 61.44; H 4.28; N 19.41; C11H9N3O2. Calculated,
%: C 61.39; H 4.22; N 19.53.
0.60 g (90%), yellow viscous liquid. H NMR spec-
trum (500 MHz, DMSO-d6), δ, ppm: 0.80–1.00 m (6H)
and 1.18–1.44 m (8H) (CH3, CH2), 1.94 sept (1H, CH,
J = 5.8 Hz), 4.32 d (2H, NCH2, J = 6.7 Hz), 7.34 t
(1H, Harom, J = 7.2 Hz), 7.43 t (2H, Harom, J = 6.4 Hz),
7.76–7.99 m (3H, Harom, 5-H), Mass spectrum: m/z 258
[M + H]+. Found, %: C 74.54; H 9.12; N 16.45.
C16H23N3. Calculated, %: C 74.67; H 9.01; N 16.33.
1,1′-[5-tert-Butyl-1,3-phenylene)bis(methylene)]-
bis(4-phenyl-1H-1,2,3-triazole) (9). Diazide 6b
(0.12 g, 0.5 mmol) and phenylacetylene (0.12 mL,
1.1 mmol) were dissolved in 5 mL of DMSO, and
1 mL of water, 40 mg (0.2 mmol) of sodium ascorbate,
and 25 mg (0.1 mmol) of CuSO4·5H2O were added.
The mixture was vigorously stirred for 12 h at room
temperature, diluted with 30 mL of water, and
extracted with methylene chloride (3×10 mL). The
combined extracts were dried over MgSO4, the solvent
was evaporated under reduced pressure, and the
residue was washed with pentane and dried under
reduced pressure. Yield 0.16 g (70%), mp 109°C
4-(Bromomethyl)-1-phenyl-1H-1,2,3-triazole
(14). Phosphorus(III) bromide, 9.7 mL (0.05 mol), was
added with vigorous stirring to a solution of 8.75 g
(0.05 mol) of (1-phenyl-1H-1,2,3-triazol-4-yl)metha-
nol (11) in 200 mL of anhydrous benzene. The mixture
was heated for 2 h and cooled, 50 g of crushed ice was
added, and the mixture was neutralized with a saturat-
ed solution of sodium carbonate. The organic layer was
separated and washed with a saturated solution of
sodium carbonate, and the solvent was evaporated
under reduced pressure. Yield 10.0 g (84%), mp 124–
1
(decomp.). H NMR spectrum (300 MHz, CDCl3), δ,
ppm: 1.27 s (9H, t-Bu), 5.54 s (4H, NCH2), 7.04 s (1H,
Harom), 7.28–7.35 m (4H, Harom), 7.39 t (5H, Harom, J =
6.9 Hz), 7.71–7.89 m (5H, Harom, 5-H). Mass spectrum:
m/z 449 (Irel 100%) [M + H]+. Found, %: C 75.19;
H 6.41; N 18.59. C28H28N6. Calculated, %: C 74.97;
H 6.29; N 18.74.
1
126°C. H NMR spectrum (500 MHz, DMSO-d6), δ,
ppm: 4.84 s (2H, CH2), 7.52 t (1H, p-H, J = 7.2 Hz),
7.62 t (2H, m-H, J = 7.2 Hz), 8.92 s (1H, 5-H), 7.91 d
(2H o-H, J = 7.2 Hz). Mass spectrum, m/z (Irel, %):
238 (100), 240 (97) [M + H]+. Found, %: C 45.23;
H 3.30; N 17.62. C9H8BrN3. Calculated, %: C 45.40;
H 3.39; N 17.65.
1-Phenyl-1H-1,2,3-triazole-4-carbaldehyde (12)
[29]. A solution of 8.75 g (0.05 mol) of (1-phenyl-1H-
1,2,3-triazol-4-yl)methanol (11) in 100 mL of methy-
lene chloride was added in one portion with thorough
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SOME ASPECTS OF THE AZIDE–ALKYNE 1,3-DIPOLAR CYCLOADDITION REACTION
1319
1-(2-Azidoethyl)-5,6-dimethyl-1H-1,2,3-benzotri-
azole (17). Raney nickel, 5 g, was added to a solution
of 5 g (0.03 mol) of 4,5-dimethyl-2-nitroaniline in
150 mL of methanol, and the mixture was stirred
overnight in a hydrogen atmosphere. The mixture was
filtered through a layer of silica gel, and the solvent
was evaporated to give 4,5-dimethylbenzene-1,2-di-
amine in quantitative yield; the product was used in the
1,2,3-benzotriazol-1-yl)ethanol and 1.67 mL
(11.9 mmol) of triethylamine in 20 mL of methylene
chloride was cooled to 0°C, 0.77 mL (9.93 mmol) of
methanesulfonyl chloride was added with vigorous
stirring, and the mixture was stirred for 3 h at room
temperature. The mixture was washed with water and
with a saturated solution of sodium carbonate, and the
solvent was evaporated to obtain 2-(5,6-dimethyl-1H-
1,2,3-benzotriazol-1-yl)ethyl methanesulfonate in
1
next stage without further purification. H NMR spec-
1
trum (400 MHz, DMSO-d6), δ, ppm: 2.50 s (6H, CH3),
3.89 s (4H, NH2), 6.30 s (2H, Harom). A 3.5-g (0.026-
mol) portion of 4,5-dimethylbenzene-1,2-diamine was
dissolved in a mixture of 3 mL of acetic acid and
7.5 mL of water. The solution was cooled to 4°C, and
a solution of 1.9 g (0.027 mol) of sodium nitrite in
3 mL of water was added. The mixture was heated to
70°C, kept for 12 h at room temperature, and cooled to
0°C over a period of 1 h. The precipitate was filtered
off, washed on a filter with 12 mL of water and with
dilute aqueous alcohol, and dried. Yield of 5,6-di-
quantitative yield. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.39 s (3H, CH3), 2.42 s (3H,
CH3), 2.92 s (3H, CH3), 4.66 t (2H, CH2, J = 5.0 Hz),
4.95 t (2H, CH2, J = 5.0 Hz), 7.56 s (1H, Harom), 7.69 s
(1H, Harom). The product, 2 g (7.5 mmol), was dis-
solved in 25 mL of DMF, 1 g (15 mmol) of sodium
azide was added with stirring, and the mixture was
heated to 70–90°C. The mixture was cooled and
diluted with water, and the precipitate was filtered off
and washed with water and hexane. Yield of azide 17
1
1.1 g (68%). H NMR spectrum (400 MHz,
1
methyl-1H-benzotriazole 3 g (78%). H NMR spec-
DMSO-d6), δ, ppm: 2.39 s (3H, CH3), 2.42 s (3H,
CH3), 3.87 t (2H, CH2, J = 5.2 Hz), 4.78 t (2H, CH2,
J = 5.3 Hz), 7.53 s (1H, Harom), 7.69 s (1H, Harom).
Found, %: C 55.43; H 5.54; N 38.98. C10H12N6. Cal-
culated, %: C 55.54; H 5.59; N 38.86.
trum (400 MHz, DMSO-d6) δ, ppm: 2.39 s (6H, CH3),
7.44 s (1H, Harom), 7.69 s (1H, Harom), 15.16 s (1H,
NH). The product, 2.57 g (0.0175 mol), was dissolved
in 7 mL of DMF, 0.48 g (0.02 mol) of sodium hydride
was added with stirring, the mixture was cooled to
–5°C, and 2.1 mL (0.02 mol) of ethyl 2-bromoacetate
was added dropwise. The mixture was left to stand for
7 h and diluted with water, and the precipitate was
filtered off and washed with water and methylene
chloride–hexane (1:5). Yield of ethyl 2-(5,6-dimethyl-
1H-1,2,3-benzotriazol-1-yl)acetate 2.45 g (60%).
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
1.29 t (3H, CH3, J = 6.9 Hz), 2.41 s (3H, CH3), 2.42 s
(3H, CH3), 4.22 q (2H, CH2O, J = 7.0 Hz), 5.53 s (2H,
CH2), 7.47 s (1H, Harom), 7.72 s (1H, Harom). The prod-
uct, 2.32 g (10 mmol), was dissolved in 40 mL of THF,
the solution was cooled to 0°C, 0.4 g (10.4 mmol) of
lithium tetrahydridoaluminate was added in portions
with stirring, and the mixture was left to stand for 7 h.
The mixture was cooled, 0.4 mL of water, 0.8 mL of
10% aqueous sodium hydroxide, and an additional
0.8 mL of water were added, and the mixture was
stirred for 15 min at room temperature and filtered
through a layer of silica gel. The solvent was evaporat-
ed under reduced pressure to isolate 1.88 g (98%) of
2-(5,6-dimethyl-1H-1,2,3-benzotriazol-1-yl)ethanol.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
2.39 s (3H, CH3), 2.41 s (3H, CH3), 3.89 q (2H, OCH2,
J = 5.0 Hz), 4.64 t (2H, CH2, J = 5.2 Hz), 4.89 t (1H,
OH, J = 4.6 Hz), 7.53 s (1H, Harom), 7.68 s (1H, Harom).
A solution of 1.6 g (8.2 mmol) of 2-(5,6-dimethyl-1H-
3-(Azidomethyl)-2-(2,4-dichlorophenyl)imidazo-
[1,2-a]pyridine (20). 2-Bromo-1-(2,4-dichloro-
phenyl)ethanone, 27 g (0.1 mol), was added to a solu-
tion of 9.4 g (0.1 mol) of pyridin-2-amine in 50 mL of
ethanol, and the mixture was left overnight. It was then
refluxed for 7 h, 0.1 mL of concentrated aqueous HCl
was added, and the mixture was refluxed for 2 h more.
The mixture was cooled, the precipitate was filtered
off and dispersed in water, and the mixture was
neutralized with a solution of sodium carbonate. The
precipitate of 2-(2,4-dichlorophenyl)imidazo[1,2-a]-
pyridine was filtered off. Yield 23.14 g (88%).
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
6.88 t (1H, 6-H, J = 6.7 Hz), 7.27 t (1H, 7-H, J =
7.7 Hz), 7.45 d (1H, 5′-H, J = 8.5 Hz), 7.51–7.58 m
(2H, Harom), 8.33 d (1H, 6′-H, J = 8.5 Hz), 8.52–8.60 m
(2H, Harom). Dimethylformamide, 100 mL, was cooled
to 0°C, 10 mL (0.1 mol) of POCl3 and 12 g
(0.046 mol) of 2-(2,4-dichlorophenyl)imidazo[1,2-a]-
pyridine were added, and the mixture was kept for 1 h
in an ice bath. The mixture was slowly (over a period
of 3 h) heated to 75°C and kept for 7 h at that tem-
perature. It was then cooled, poured into water, and
neutralized with a solution of sodium hydroxide, and
the precipitate of 2-(2,4-dichlorophenyl)imidazo-
[1,2-a]pyridine-3-carbaldehyde was filtered off. Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

POKHODYLO et al.
1320
1
11.51 g (86%). H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 7.40 t (1H, 6-H, J = 6.8 Hz),
7.62 d (1H, 5′-H, J = 8.2 Hz), 7.73 d (1H, 8-H, J =
8.3 Hz), 7.78 t (1H, 7-H, J = 7.9 Hz), 7.85 s (1H,
3′-H), 7.94 d (1H, 6′-H, J = 8.9 Hz), 9.52 d (1H, 5-H,
J = 6.7 Hz), 9.71 s (1H, CHO). The product, 1.94 g
(6.7 mmol) was dissolved in 20 mL of methanol, 0.5 g
(13.5 mmol) of sodium tetrahydridoborate was added,
and the mixture was refluxed for 1.5 h. Propan-2-ol,
20 mL, was added, and the mixture was heated for
1.5 h more. The mixture was cooled and concentrated
under reduced pressure, and the residue was treated
with 10 mL of water and extracted with methylene
chloride (30 mL). Evaporation of the extract under
reduced pressure gave 1.86 g (95%) of pure {2-(2,4-di-
chlorophenyl)imidazo[1,2-a]pyridin-3-yl}methanol.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
4.71 d (2H, CH2, J = 5.2 Hz), 5.12 t (1H, OH, J =
5.1 Hz), 6.96 t (1H, 6-H, J = 6.8 Hz), 7.31 t (1H, 7-H,
J = 7.9 Hz), 7.44 d.d (1H, 5′-H, J = 8.2, 1.3 Hz), 7.53–
7.63 m (3H, Harom), 8.46 d (1H, 5-H, J = 6.8 Hz). The
product, 0.31 g (1.1 mmol), was dissolved in 2 mL of
DMF, 0.5 mL (1.1 mmol) of diphenylphosphoryl azide
(DPPA) and 0.4 mL of l,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) were added, and the mixture was stirred for
7 h at room temperature. The mixture was diluted with
water (5 mL), and the precipitate of azide 20 was
5.67 s (1H, NH), 6.54 t (1H, Harom, J = 7.0 Hz), 6.62 d
(1H, Harom, J = 7.5 Hz), 6.64–6.77 m (2H, Harom),
9.99 s (1H, CONH). The product, 1.76 g (0.01 mol),
was dissolved in 5 mL of DMF, 0.4 g (0.01 mol) of
sodium hydride and 0.9 mL (0.01 mol) of propargyl
bromide were added with stirring, and the mixture was
left overnight. The mixture was then diluted with
water, and the precipitate was filtered off and washed
with water, methylene chloride, and hexane. Yield of
1
22 1.3 g (61%), mp 130–131°C. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.26 s (6H, CH3),
2.84 s (1H, ≡CH), 4.63 s (2H, CH2), 5.90 s (1H, NH),
6.61–6.71 m (2H, Harom), 6.84 t (1H, Harom, J = 7.3 Hz),
7.01 d (1H, Harom, J = 7.6 Hz). Mass spectrum: m/z 215
[M + H]+. Found, %: C 72.93; H 6.55; N 13.01.
C13H14N2O. Calculated, %: C 72.87; H 6.59; N 13.07.
CONFLICT OF INTERESTS
No conflict of interests is declared by the authors.
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