Synthesis of (1H-1,2,3-Triazol-1-yl)acetic Acid Derivatives

Article abstract of DOI:10.1134/S1070428020080138

Abstract: A convenient synthetic approach to (1H-1,2,3-triazol-1-yl)acetic acid derivatives via the reaction of azidoacetamides with β-ketoesters and acetylacetone is proposed. Based on this strategy, 1,5-disubstituted 1,2,3-triazoles were prepared from available reagents under metal-free conditions. A one-pot protocol for the synthesis of (5-methyl-1H-1,2,3-triazol-1-yl)acetamides derived from N-substituted chloroacetamides is developed.

Full text of DOI:10.1134/S1070428020080138

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 8, pp. 1421–1431. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 8, pp. 1268–1279.
Synthesis of (1H-1,2,3-Triazol-1-yl)acetic Acid Derivatives
N. T. Pokhodyloa, R. D. Savkaa, and M. D. Obushaka,*
a Ivan Franko National University of Lviv, Lviv, 79005 Ukraine
*e-mail: mykola.obushak@lnu.edu.ua
Received April 5, 2020; revised April 13, 2020; accepted April 18, 2020
Abstract—A convenient synthetic approach to (1H-1,2,3-triazol-1-yl)acetic acid derivatives via the reaction of
azidoacetamides with β-ketoesters and acetylacetone is proposed. Based on this strategy, 1,5-disubstituted 1,2,3-tri-
azoles were prepared from available reagents under metal-free conditions. A one-pot protocol for the synthesis of
(5-methyl-1H-1,2,3-triazol-1-yl)acetamides derived from N-substituted chloroacetamides is developed.
Keywords: azides, 1,2,3-triazoles, Dimroth reaction, (1H-1,2,3-triazol-1-yl)acetic acids, 1,3-dicarbonyl compounds
DOI: 10.1134/S1070428020080138
The 1,2,3-triazole ring is a structural fragment,
whose presence in compounds make them attractive for
screening for biological activity, because it is an isostere
of the amide bond, resistant to metabolic degradation,
and can form hydrogen bonds, which is important for
binding with biological targets [1]. The introduction
of a carboxyl function in the 1,2,3-triazole ring favors
creation of convenient structural blocks for the synthe-
sis of combinatorial libraries. In particular, 1H-1,2,3-
triazole-4-carboxylic acid derivatives were used for the
synthesis of compounds that exhibited antifungal activity
[2–4], antimicrobial activity against the mycobacterium
tuberculosis strain H37Rv [5], antiviral activity against
replication of influenza A and herpes simplex virus type
1 (HSV-1) [6], as well as anticancer activity against
various cancer cell lines [7–10]. (1H-1,2,3-Triazol-1-yl)-
acetic acids were used to synthesize compounds active
against methicillin-resistant Staphylococcus aureus and
vancomycin-resistant enterococci [11], antagonists of
monoacylglycerol lipase [12], agonists and antagonists
of sphingosine-1-phosphate receptors [13], inhibitors of
stearoyl-coenzyme delta-9 [14], as well as anticancer
and antiviral agents [16]. The synthesis and biological
testing of a number of (1H-1,2,3-triazol-1-yl)acetic acid
derivatives made possible their application as inhibitors
of the HIV-1 capsid (HIV-1 CA) for the design of antiviral
drugs on their basis [17].
tions of azides to terminal acetylenes. In the present
work studied the use of Dimroth cyclocondesation of
azidoacetic acid derivatives with dicarbonyl compounds
for preparing compounds of this type. In case of success,
such approach would allow introduction of a much wider
range of substituents in the triazole ring of triazolylacetic
acids.
The reaction of 2-azidoacetamides 3a and 3b with
4-benzyl- and 4-phenoxyacetoacetic acids 2a, and 2b,
prepared from the corresponding chlorides 1a and 1b
by acylation of the Meldrumʼs acid was studied. It was
found that the reaction in the presence of K2CO3 in DMSO
in mild conditions gave triazoles 4a–4d in good yields
(Scheme 1). The K2CO3–DMSO catalytic system was
chosen, because it showed high performance in reactions
of alkyl azides (norbornan-2-yl azide, alkyl 2-azido-
3-arylpropanoates) with acetoacetic ester [18, 19] and of
azides with 2-oxophosphonates [20]. Selective cyclocon-
densations under the same conditions were reported for
β-keto esters [21], sterically hindered azides [22, 23], and
electron-deficient aromatic azides, 2-azidothiazoles, and
2-azidothiadiazoles [24]. The triazole core enhances the
reactivity of the carbonyl group, which allows selective
transformations of the ester group. The selective reduc-
tion of the ester group in compound 4b gave alcohol 5
(Scheme 1). Hydrolysis of compounds 4a–4d occurred
at room temperature and formed acids 6a–6d in quantita-
tive yields. Alkaline hydrolysis of acid 6с under heating
afforded dicarboxylic acid 7.
(1H-1,2,3-Triazol-1-yl)acetic acids were most com-
monly prepared by the 1,3-dipolar cycloaddition reac-
1421

1422
POKHODYLO et al.
Scheme 1.
3a, 3b
rt, 12 h
K2CO3
DMSO
2a, 2b
4a–4d
6a–6d
NaOH
EtOH, H2O
reflux, 1 h
1) Meldrum’s acid
2) MeOH or EtOH
LAH
THF
for 6c
0°C to rt, 12 h
1a, 1b
5
7
1, 2, X = CH2 (a), O (b); 3, R = H (a), Me (b); Alk = Me, Et; 4, 6, R = H, X = CH2 (a), R = Me, X = CH2 (b),
R = H, X = O (c), R = Me, X = O (d).
Aimed at introducing the amino group to the side chain
Searching for (1H-1,2,3-triazol-1-yl)acetic acid de-
rivatives that might be useful for developing anticancer
agents, we focused on {5-(benzo[d][1,3]dioxol-5-yl)-1H-
tetrazol-1-yl}acetic acid as a core structure for the
synthesis a series of tetrazolohydrazones that showed
activity against MCF-7, MDA-MB-231, and ZR-75 breast
cancer cells [25]. Taking into account that 1,5-disub-
stituted 1,2,3-triazoles and tetrazoles, being the closest
of triazoles, we allowed azidoacetamide 3a to react with
β-ketoester 2с containing a phthalimide fragment. It was
found that the reaction, along with the formation of the
triazole ring, involves cleavage of the phthalimide frag-
ment to form compound 4e (Scheme 2). The latter was
converted into triazole 8 by refluxing in toluene in the
presence of a catalytic amount of p-toluenesulfonic acid.
Scheme 2.
O
O
O
OH
N3
O
O
O
N
O
O
H2N
N
3a
N
OMe
N
N
K2CO3
DMSO
H
H2N
O
O
4e
ꢀɫ
O
N
N
O
O
O
N
Toluene
p-TSA
NH2
N
O
8
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 8 2020

SYNTHESIS OF (1H-1,2,3-TRIAZOL-1-YL)ACETIC ACID DERIVATIVES
1423
Scheme 3.
O
N3
R1
R2
O
O
O
O
N
N
N
N
H2N
3a, 3c–3e
OEt
OH
NaOH
N
N
O
O
OEt
EtOH
H2O
K2CO3
DMSO
O
O
O
O
R1
R1
R2
R2
O
O
H2N
H2N
2d
4f–4i
6e–6h
N
N
N
'
N
N
NaOH
N
O
O
O
O
EtOH
H2O
R1
R1
R2
10a–10d
R1 = H, R2 = H (3a, 4f, 6e, 9a, 10a); R1 = H, R2 = Me (3c, 4g, 6f, 9b, 10b);
R2
O
O
HO
H2N
9a–9d
R1 = Me, R2 = Me (3a, 4h, 6g, 9c, 10c); R1 = H, R2 = Et (3a, 4i, 6h, 9d, 10d).
isosteres of the cis-peptide bond [26, 27], have similar
biophysical properties, we have developed a convenient
synthetic approach to {5-(benzo[d][1,3]dioxol-5-yl)-1H-
triazol-1-yl}acetic acids. The earlier reported synthesis
of 5-substituted triazol-1-ylacetic acids made use of
ruthenium complexes [28, 29]. In view of the high cost
of such catalysts, we developed a different approach,
which excludes the use of transitions metal catalysts.
From the readily available ethyl 3-(benzo[d][1,3]dioxol-
5-yl)-3-oxopropanoate (2d) we prepared 5-(benzo[d]-
[1,3]dioxol-5-yl)-1H-1,2,3-triazole-4-carboxylates 4f–4i
and further converted them to acids 6e–6h (Scheme 3).
When heated to the melting points, acids 6 underwent
decarboxylation to form 1,5-disubstituted 1,2,3-triazoles
9a–9d. The latter were hydrolyzed to obtain the target
(1H-1,2,3-triazol-1-yl)acetic acids 10a–10d with a total
yield of more than 70 % (per the starting β-keto ester 2d).
The high yields make the developed approach competitive
to the ruthenium-catalyzed azide–alkyne cycloaddition,
especially in view of the high cost of the catalyst and hard
accessibility of terminal alkynes.
It was also found that, under the found conditions, azi-
doamides 3c and 3d react with acetylacetone 2e, forming
4-acetyltriazoles 11a and 11b in high yields (Scheme 4).
We earlier showed that such 4-acetyltriazoles are conve-
nient precursors for the Willgerodt–Kindler synthesis of
(1H-1,2,3-triazole-4-yl)acetic acids [30].
The example of chloroacetamides 12 was used to
demonstrate the feasibility of one-pot synthesis of (1H-
1,2,3-triazol-1-yl)acetamides. Thus, chloroacetamides
12a–12с were reacted with sodium azide and acetoacetic
ester 2f and obtained novel triazoles 13a–13с in high
yields (Scheme 5). Compounds 13a and 13с undergo
selective hydrolysis in the presence of a small excess
of alkali to afford 1,2,3-triazole-4-carboxylic acids
14a and 14b. Decarboxylation of acid 14a followed by
hydrolysis of the amide fragment allowed synthesis of
a hardly accessible 2-(5-methyl-1H-1,2,3-triazol-1-yl)-
acetic acid (16). The latter is a convenient low-molecu-
lar-weight structural block for constructing libraries of
2-(5-methyl-1H-1,2,3-triazol-1-yl)acetic acid derivatives.
Scheme 4.
N
O
O
CH3COCH2COCH3
N
N
O
2e
N3
R1
H2N
K2CO3
DMSO
H2N
Me
R2
3c, 3d
R1 = H, R2 = Me (3c, 11a); R1 = Me, R2 = Me (3d, 11b).
R1
R2
Me
11a, 11b
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 8 2020

1424
POKHODYLO et al.
Scheme 5.
NaN3
N
N
O
CH3COCH2COOEt
O
O
O
N
N
O
N
N
2f
NaOH
R
Cl
R
R
N
K2CO3
DMSO
EtOH
H2O
N
N
OH
OEt
H
H
H
Me
Me
13a–13c
12a–12c
14a, 14b
'
N
N
O
N
N
N
O
NaOH
N
EtOH
H2O
HO
H2N
Me
Me
16
15
12, 13, R = H (a), Ph (b), Mes (c); 14, R = H (a), Ph (b).
Hydrolysis of the ester group in compound 13с was
monitored by IR spectroscopy, following the changes in
the frequencies of the strong carbonyl absorption bands:
from ν(COOEt) = 1706 cm–1 and ν(NHCO) = 1655 cm–1 for
ester 13с to ν(COOH) = 1685 cm–1 and ν(NHCO) = 1669 cm–1
for acid 14b. The spectra of compounds 13с and 14b also
displayed medium bands due to stretching vibrations of
the N–H bond (ν = 3270 cm–1 for 13с and ν = 3262 cm–1
for 14b).
Synthesis of β-keto esters 2a–2c (general procedure).
Acid chloride 1a or 1b (40.8 mmol) was added in por-
tions to a stirred to a solution of 6.05 g (40.8 mmol) of
the Meldrumʼs acid in 6.8 mL (81.6 mmol) of pyridine at
0°C. The reaction mixture was stirred at 0°C for 1 h, let to
warm up to room temperature, and allowed to stand at 1 h.
Aconcentrated solution of NaCl (30 mL) was then added,
and the product was extracted with dichloromethane
(3 × 100 mL). The solvent was evaporated in a vacuum,
the residue was dissolved in 30 mL of methanol or etha-
nol, and the solution was refluxed for 5 h. The alcohol
was evaporated, and the residue was dissolved in 200 mL
of dichloromethane, and the solution was washed with
30 mL of 5% HСl. The solvent was evaporated, and the
residue was distilled in a vacuum. Compound 2с was
recrystallized from aqueous alcohol.
Thus we showed that the base-catalyzed cyclocon-
densation of 2-azidoacetamides with β-keto esters or
1,3-diketones provides a convenient synthetic approach to
(1H-1,2,3-triazol-1-yl)acetic acid derivatives. A method
of synthesis of 1,5-disubstituted 1H-1,2,3-triazoles from
available reagents and in the absence of metal catalysts,
as well as a one-pot synthesis of (1H-1,2,3-triazol-1-yl)-
acetic acid from chloroacetamides. Note that the synthe-
sized compounds all comply with the Lipinski rule of
five and they can be tested for biological activity, while
low-molecular-weight (1H-1,2,3-triazol-1-yl)acetic acids
can be used as building blocks in synthesis, as well as for
creation of combinatorial libraries.
Methyl 3-oxo-5-phenylpentanoate (2a). Yield 6.3 g
1
(75%), viscous oil. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.81 t (2H, СH2, J 7.2 Hz), 2.86 t
(2H, СH2, J 7.2 Hz), 3.58 s (2H, СH2), 3.64 s (3H СH3O),
7.16–7.23 m (3Harom), 7.24–7.33 m (2Harom). Mass
spectrum (CI), m/z: 207 [M + H]+. Found, %: C 69.81;
H 6.79. C12H14O3. Calculated, %: C 69.89; H 6.84. The
characterisics of the synthesized compound are consistent
with published data [31].
EXPERIMENTAL
The 1H NMR spectra were recorded on a VarianUnity
+400 spectrometer at 400 MHz, internal reference TMS.
The mass spectra were obtained on an Agilent 1100
LC/MSD instrument with anAPCI ionization source. The
IR spectra were measured on a Perkin Elmer Spectrum
2000 FTIR spectrometer. The elemental analyses were
obtained on a Carlo Erba 1106 analyzer. The melting
points were measured on a Boёtius hot stage.
Ethyl 3-oxo-4-phenoxybutanoate (2b). Yield 7.2 g
1
(79%), viscous oil. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 1.26 t (3H, СH3, J 7.1 Hz), 3.64 s
(2H, СH2), 4.14 q (2H, СH2O, J 7.1 Hz), 4.82 s (2H,
OСH2), 6.74 d (2Harom, J 8.1 Hz), 6.89 t (1Harom, J 8.6 Hz),
7.12 t (2Harom, J 8.1 Hz). Mass spectrum (CI), m/z: 223
[M + H]+. Found, %: C 64.78; H 6.31. C12H14O4. Cal-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 8 2020

SYNTHESIS OF (1H-1,2,3-TRIAZOL-1-YL)ACETIC ACID DERIVATIVES
1425
culated, %: C 64.85; H 6.35. The characterisics of the
synthesized compound are consistent with published
data [32].
N 49.10. The characterisics of the synthesized compound
are consistent with published data [36].
2-Azido-2-methylpropanamide (3d). Yield 10.0 g
1
(78%), mp 93–94°С. H NMR spectrum (400 MHz,
Mehtyl 5-(1,3-dioxoisoindolin-2-yl)-3-oxopentano-
ate (2с). Yield 8.90 g (79%), mp 105–106°С. 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 2.96 t (2H,
СH2, J 7.1 Hz), 3.57 s (2H, СH2), 3.65 s (3H, СH3O),
3.81 t (2H, СH2, J 7.1 Hz), 7.75–7.90 m (4Harom). Mass
spectrum (CI), m/z: 276 [M + H]+. Found, %: C 61.24;
H 4.58; N 5.23. C14H13NO5. Calculated, %: C 61.09;
H 4.76; N 5.09.
DMSO-d6), δ, ppm: 1.40 s (6H, CH3), 7.14 s (1H, NH2),
7.20 s (1H, NH2). Mass spectrum (CI), m/z: 129 [M +
H]+. Found, %: C 37.43; H 6.34; N 43.78. C4H8N4O.
Calculated, %: C 37.49; H 6.29; N 43.73. The charac-
terisics of the synthesized compound are consistent with
published data [37].
2-Azidobutanamide (3e). Yield 10.4 g (81 %), mp
1
38–39°С. H NMR spectrum (400 MHz, DMSO-d6),
Ethyl 3-(benzo[d][1,3]dioxol-5-yl)-3-oxopropano-
ate (2d) was prepared by the condensation of 1-(benzo-
[d][1,3]dioxol-5-yl)ethanone with diethyl carbonate by
the general procedure of the synthesis of ethyl 3-aryl-
3-oxopropanoates [33].
δ, ppm: 0.95 t (3H, СH3, J 7.4 Hz), 1.61–1.85 m (2H,
СH2), 3.56 t (1H, СH, J 6.8 Hz), 7.12 s (1H, NH2),
7.42 s (1H, NH2). Mass spectrum (CI), m/z: 129 [M +
H]+. Found, %: C 37.45; H 6.21; N 43.77. C4H8N4O.
Calculated, %: C 37.49; H 6.29; N 43.73. The charac-
terisics of the synthesized compound are consistent with
published data [37].
Synthesis of azides 3a–3e (general procedure).Aso-
lution of 6.5 g of NaN3 in 15 mL of water was added to a
solution of 0.1 mol of the corresponding chloroacetamide
in 50 mL of methanol, and the mixture was refluxed for
3–4 h. The solvent was evaporated in a vacuum, and the
resulting alkylazide was extracted with dichloromethane.
The solvent was evaporated with caution to obtain the
target product.
Synthesis of 1H-1,2,3-triazole-4-carboxylates
4a–4i, 11a, and 11b (general procedure). Keto ester 2
or acetylacetone (10 mmol) was dissolved in 9 mL of
DMSO, after which 9 g of K2CO3 and 10 mmol of azide
3 were added. The mixture was allowed to stand for
12 h at room temperature and then heated for 7 h at 50°С.
After cooling, 50 mL of water (in the case of compound
4e, the reaction mixture was acidified with HCl to pH 2.0)
was added, and the precipitate that formed was filtered
off and recrystallized, when necessary.
2-Azidoacetamide (3a). Yield 9.6 g (96%), mp
1
52–53°С. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 3.69 s (2H, СH2), 7.13 s (1H, NH2), 7.39 s (1H,
NH2). Mass spectrum (CI), m/z: 101 [M + H]+. Found, %:
C 23.92; H 4.11; N 55.99. C2H4N4O. Calculated, %:
C 24.00; H 4.03; N 55.98. The characterisics of the
synthesized compound are consistent with published
data [34].
Methyl 1-(2-amino-2-oxoethyl)-5-(2-phenyl-
ethyl)-1H-1,2,3-triazole-4-carboxylate (4a). Yield
1
2.25 g (78%), mp 148–149°С. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 2.86 t (2H, CH2, J
8.3 Hz), 3.12 t (2H, CH2, J 8.3 Hz), 3.88 s (3H, CH3O),
4.94 s (2H, CH2), 7.15–7.33 m (5Harom), 7.38 s (1H, NH2),
7.77 s (1H, NH2). Mass spectrum (CI), m/z: 289 [M +
H]+. Found, %: C 58.42; H 5.51; N 19.37. C14H16N4O3.
Calculated, %: C 58.32; H 5.59; N 19.43.
2-Azido-N-methylacetamide (3b). Yield 10.7 g
1
(94%), mp 43–44°С. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.66 d (3H, СH3, J 4.6 Hz), 3.70 s
(2H, СH2), 7.91 br.s (1H, NH). Mass spectrum (CI),
m/z: 115 [M + H]+. Found, %: C 31.53; H 5.37; N 49.21.
C3H6N4O. Calculated, %: C 31.58; H 5.30; N 49.10. The
characterisics of the synthesized compound are consistent
with published data [35].
Methyl 1-[2-(methylamino)-2-oxoethyl]-5-(2-
phenylethyl)-1H-1,2,3-triazole-4-carboxylate (4b).
Yield 2.23 g (74%), mp 166–167°С. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 2.70 d (3H, CH3NH, J
3.3 Hz), 2.85 t (2H, CH2, J 7.3 Hz), 3.15 t (2H, CH2, J
7.3 Hz), 3.86 s (3H, CH3O), 4.91 s (2H, CH2), 7.14–
7.32 m (5Harom), 8.24 br.s (1H, NH). Mass spectrum (CI),
m/z: 303 [M + H]+. Found, %: C 59.56; H 5.89; N 18.61.
C15H18N4O3. Calculated, %: C 59.59; H 6.00; N 18.53.
2-Azidopropanamide (3c). Yield 9.5 g (83%), mp
1
75–77°С. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 1.36 d (3H, СH3, J 6.8 Hz), 3.73 q (1H, СH, J
6.8 Hz), 7.13 s (1H, NH2), 7.41 s (1H, NH2). Mass spec-
trum (CI), m/z: 115 [M + H]+. Found, %: C 31.70; H 5.37;
N 49.21. C3H6N4O. Calculated, %: C 31.58; H 5.30;
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POKHODYLO et al.
Methyl 1-(2-amino-2-oxoethyl)-5-(phenoxy-
Ethyl 1-(1-amino-2-methyl-1-oxopropan-2-yl)-
5-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-4-car-
boxylic acid (4h). Yield 2.42 g (70%), mp 202–203°С.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 1.15 t
(3H, CH3, J 7.1 Hz), 1.67 s (6H, CH3), 4.12 q (2H, CH2O,
J 7.1 Hz), 6.07 s (2H, OCH2O), 6.77 d (1H, H6arom, J
8.0 Hz), 6.80 s (1H, H2arom), 6.87 d (1H, H5arom, J 8.0 Hz),
7.21 s (1H, NH2), 7.26 s (1H, NH2). Mass spectrum (CI),
m/z: 347 [M + H]+. Found, %: C 55.31; H 5.28; N 16.05.
C16H18N4O5. Calculated, %: C 55.49; H 5.24; N 16.18.
methyl)-1H-1,2,3-triazole-4-carboxylate (4с). Yield
1
2.20 g (76%), mp 161–162°С. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 3.91 s (3H, CH3O), 5.20 s
(2H, CH2), 5.47 s (2H, CH2), 6.95–7.06 m (3Harom), 7.29 t
3,5
(2H, H
, J 7.8 Hz), 7.36 s (1H, NH2), 7.73 s (1H,
arom
NH2). Mass spectrum (CI), m/z: 291 [M + H]+. Found, %:
C 53.65; H 4.93; N 19.37. C13H14N4O4. Calculated, %:
C 53.79; H 4.86; N 19.30.
Methyl 1-(2-(methylamino)-2-oxoethyl)-5-(phe-
noxymethyl)-1H-1,2,3-triazole-4-carboxylate (4d).
Yield 2.25 g (74%), mp 139–141°С. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 2.64 d (3H, CH3N, J
Ethyl 1-(1-amino-1-oxobutan-2-yl)-5-(benzo[d]-
[1,3]dioxol-5-yl)-1H-1,2,3-triazole-4-carboxylate (4i).
Yield 2.60 g (75%), mp 109–111°С. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 0.78 t (3H, CH3, J
7.2 Hz). 1.24 t (3H, CH3, J 7.1 Hz), 2.17–2.38 m (2H,
CH2), 4.20 d (2H, CH2O, J 7.1 Hz), 4.61 d.d (1H, CH, J
10.3, 4.7 Hz), 6.10 s (1H, OCH2O), 6.11 s (1H, OCH2O),
6.82 d (1H, H6arom, J 8.0 Hz), 6.86 s (1H, H2arom), 6.97 d
(1H, H5arom, J 7.9 Hz), 7.30 s (1H, NH2), 7.33 s (1H,
NH2). Mass spectrum (CI), m/z: 347 [M + H]+. Found, %:
C 55.54; H 5.18; N 16.24. C16H18N4O5. Calculated, %:
C 55.49; H 5.24; N 16.18.
3.3 Hz), 3.90 s (3H, CH3O), 5.18 s (2H, CH2), 5.47 s
3,5
(2H, CH2), 6.92–7.02 m (3Harom), 7.28 t (2H, H
, J
arom
7.7 Hz), 8.18 br.s (1H, NH). Mass spectrum (CI), m/z:
305 [M + H]+. Found, %: C 55.38; H 5.37; N 18.44.
C14H16N4O4. Calculated, %: C 55.26; H 5.30; N 18.41.
2-{2-[1-(2-Amino-2-oxoethyl)-4-(methoxy-
carbonyl)-1H-1,2,3-triazol-5-yl]ethylcarbamoyl}-
benzoic acid (4e). Yield 2.66 g (71%), mp 208–209°С.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
3.27 t (2H, CH2, J 6.7 Hz), 3.67 s (3H, CH3O), 3.83–
3.95 m (2H, CH2N), 5.13 s (2H, CH2), 7.37 s (1H, NH),
7.74–7.91 m (6H, Harom + NH2). Mass spectrum (CI),
m/z: 376 [M + H]+. Found, %: C 51.27; H 4.51; N 18.72.
C16H17N5O6. Calculated, %: C 51.20; H 4.57; N 18.66.
2-(4-Acetyl-5-methyl 1H-1,2,3-triazol-1-yl)propan-
1
amide (11a). Yield 1.60 g (81%), mp 174–175°С. H
NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 1.78 d
(3H, СH3СH, J 6.8 Hz), 2.44 s (3H, СH3), 2.56 s (3H,
СH3), 5.21 q (1H, СH, J 6.8 Hz), 7.45 s (1H, NH2),
7.68 s (1H, NH2). Mass spectrum (CI), m/z: 197 [M +
H]+. Found, %: C 48.90; H 6.23; N 28.51. C8H12N4O2.
Calculated, %: C 48.97; H 6.16; N 28.56.
Ethyl 1-(2-amino-2-oxoethyl)-5-(benzo[d][1,3]-
dioxol-5-yl)-1H-1,2,3-triazole-4-carboxylate (4f).
Yield 2.57 g (81%), mp 198–199°С. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.25 t (3H, CH3, J
7.0 Hz), 4.21 q (2H, CH2O, J 7.0 Hz), 4.85 s (2H, CH2),
6.09 s (2H, OCH2O), 6.90–7.01 m (3Harom), 7.31 s (1H,
NH2), 7.64 s (1H, NH2). Mass spectrum (CI), m/z: 319
[M + H]+. Found, %: C 52.70; H 4.41; N 17.71.
C14H14N4O5. Calculated, %: C 52.83; H 4.43; N 17.60.
2-(4-Acetyl-5-methyl 1H-1,2,3-triazol-1-yl)-2-
methylpropanamide (11b). Yield 1.77 g (84%), mp
168–169°С. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 1.80 s (6H, СH3), 2.44 s (3H, СH3), 2.57 s (3H,
СH3), 7.53 s (1H, NH2), 7.56 s (1H, NH2). Mass spectrum
(CI), m/z: 211 [M + H]+. Found, %: C 51.35; H 6.77;
N 26.73. C9H14N4O2. Calculated, %: C 51.42; H 6.71;
N 26.65.
Ethyl 1-(1-amino-1-oxopropan-2-yl)-5-(benzo[d]-
[1,3]dioxol-5-yl)-1H-1,2,3-triazole-4-carboxylate (4g).
Yield 2.54 g (77%), mp 124–125°С. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.22 t (3H, CH3, J
6.8 Hz), 1.77 d (2H, CH3, J 7.0 Hz), 4.19 q (2H, CH2O,
J 6.8 Hz), 4.86 q (1H, CH, J 7.0 Hz), 6.09 s (2H,
OCH2O), 6.84 d (1H, H6arom, J 7.6 Hz), 6.89 s (1H, H2arom),
6.95 d (1H, H5arom, J 7.6 Hz), 7.24 s (1H, NH2), 7.34 s (1H,
NH2). Mass spectrum (CI), m/z: 333 [M + H]+. Found, %:
C 54.25; H 4.89; N 16.74. C15H16N4O5. Calculated, %:
C 54.21; H 4.85; N 16.86.
2-[4-(Hydroxymethyl)-5-(2-phenylethyl)-1H-1,2,3-
triazol-1-yl]-N-methylacetamide (5). Lithim aluminum
hydride (0.14 g, 3.3 mmol) was added in portions to a
solution of 1.0 g (3.3 mmol) of ester 4b in 50 mL of THF
at 0°С, and the mixture was left to stand overnight, after
which 0.14 mL of water, 0.28 mL of 10% NaOH, and
0.28 mL of water were added in succession with cooling.
The mixture was stirred at room temperature for 15 min,
filtered through a thin bed of silica gel, and THF was
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SYNTHESIS OF (1H-1,2,3-TRIAZOL-1-YL)ACETIC ACID DERIVATIVES
1427
1-[2-(Methylamino)-2-oxoethyl]-5-(phenoxy-
methyl)-1H-1,2,3-triazole-4-carboxylic acid (6d).
Yield 0.54 g (93%), mp 195–196°С (decomp.). 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 2.63 d (3H,
evaporated in a vacuum to obtain a pure alcohol 5.
Yield 0.88 g (97%), mp 105–107°С. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 2.69 d (3H, CH3, J
4.1 Hz), 2.81–2.90 m (2H, CH2), 2.90–3.00 m (2H, CH2),
4.36 d (2H, CH2O, J 5.1 Hz), 4.78 s (2H, CH2), 4.85 t
CH3, J 4.3 Hz), 5.15 s (2H, CH2), 5.48 s (2H, CH2),
3,5
6.90–7.09 m (3Harom), 7.26 t (2H, H
, J 7.7 Hz),
(1H, OH, J 5.1 Hz), 7.13–7.20 m (3Harom), 7.23 t (2H,
ar om
3,5
8.16 br.s (1H, NH). Mass spectrum (CI), m/z: 291 [M +
H]+. Found, %: C 53.85; H 4.94; N 19.23. C13H14N4O4.
Calculated, %: C 53.79; H 4.86; N 19.30.
H
, J 6.9 Hz), 8.13 s (1H, NH). Mass spectrum (CI),
arom
m/z: 275 [M + H]+. Found, %: C 61.39; H 6.72; N 20.47.
C14H18N4O2. Calculated, %: C 61.30; H 6.61; N 20.42.
1-(2-Amino-2-oxoethyl)-5-(benzo[d][1,3]dioxol-
5-yl)-1H-1,2,3-triazole-4-carboxylic acid (6e). Yield
0.56 g (97%), mp 215–217°С (decomp.). 1H NMR spec-
trum (400 MHz, DMSO-d6), δ, ppm: 4.82 s (2H, CH2),
6.08 s (2H, OCH2O), 6.89–7.00 m (3Harom), 7.28 s (1H,
NH2), 7.60 s (1H, NH2), 12.59 br.s (1H, COOH). Mass
spectrum (CI), m/z: 291 [M + H]+. Found, %: C 49.73;
H 3.53; N 19.43. C12H10N4O5. Calculated, %: C 49.66;
H 3.47; N 19.30.
Synthesis of 1H-1,2,3-triazole-4-carboxylic acids
6a–6h, 14a, and 14b (general procedure). A solution of
80 mg (2 mmol) of NaOH in 1 mL of water was added to
a solution of 2 mmol of 1,2,3-triazole-4-carboxylic acid
ester 4 or 13 in 15 mL of methanol, and the mixture was
left to stand for 12 h. methanol was then evaporated in
a vacuum, the residue was dissolved in 2 mL of water,
treated with dichloromethane, the aqueous layer was
acidified with HСl, and the precipitate that formed was
filtered off.
1-(1-Amino-1-oxopropan-2-yl)-5-(benzo[d][1,3]-
dioxol-5-yl)-1H-1,2,3-triazole-4-carboxylic acid (6f).
Yield 0.58 g (96%), mp 214–215°С (decomp.). 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm: 1.76 d (3H,
CH3, J 7.1 Hz), 4.82 q (1H, CH, J 7.3 Hz), 6.09 s (1H,
OCH2O), 6.10 s (1H, OCH2O), 6.84 d (1H, H6arom, J
8.0 Hz), 6.89 s (1H, H2arom), 6.95 d (1H, H5arom, J
7.9 Hz), 7.23 s (1H, NH2), 7.31 s (1H, NH2), 12.65 br.s
(1H, COOH). Mass spectrum (CI), m/z: 305 [M + H]+.
Found, %: C 51.42; H 3.91; N 18.28. C13H12N4O5. Cal-
culated, %: C 51.32; H 3.98; N 18.41.
1-(2-Amino-2-oxoethyl)-5-(2-phenylethyl)-1H-
1,2,3-triazole-4-carboxylic acid (6a). Yield 0.53 g
1
(96%), mp 192–193°С. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.89 t (2H, CH2, J 8.4 Hz), 3.13 t
(2H, CH2, J 8.4 Hz), 4.88 s (2H, CH2), 7.17–7.23 m
3,5
(3Harom), 7.27 t (2H, H
, J 7.3 Hz), 7.36 s (1H, NH2),
arom
7.72 s (1H, NH2). Mass spectrum (CI), m/z: 275 [M +
H]+. Found, %: C 56.78; H 5.24; N 20.46. C13H14N4O3.
Calculated, %: C 56.93; H 5.14; N 20.43.
1-[2-(Methylamino)-2-oxoethyl]-5-(2-phenylethyl)-
1-(1-Amino-2-methyl-1-oxopropan-2-yl)-5-
(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-4-carbo-
xylic acid (6g). Yield 0.60 g (95%), mp 203–204°С
(decomp.). 1H NMR spectrum (400 MHz, DMSO-d6), δ,
ppm: 1.66 s (6H, CH3), 6.08 s (2H, OCH2O), 6.78 d (1H,
H6arom, J 8.0 Hz), 6.80 s (1H, H2arom), 6.87 d (1H, H5arom, J
7.9 Hz), 7.18 s (1H, NH2), 7.24 s (1H, NH2), 12.45 br.s
(1H, COOH). Mass spectrum (CI), m/z: 319 [M + H]+.
Found, %: C 52.71; H 4.49; N 17.71. C14H14N4O5. Cal-
culated, %: C 52.83; H 4.43; N 17.60.
1H-1,2,3-triazole-4-carboxylic acid (6b). Yield 0.54 g
1
(95%), mp 199–200°С. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.69 d (3H, CH3, J 4.5 Hz), 2.85 t
(2H, CH2, J 6.8 Hz), 3.13 t (2H, CH2, J 6.8 Hz), 4.84 s
3,5
(2H, CH2), 7.14–7.22 m (3Harom), 7.25 t (2H, H
, J
arom
7.3 Hz), 8.20 s (1H, NH). Mass spectrum (CI), m/z:
289 [M + H]+. Found, %: C 58.41; H 5.52; N 19.48.
C14H16N4O3. Calculated, %: C 58.32; H 5.59; N 19.43.
1-(2-Amino-2-oxoethyl)-5-(phenoxymethyl)-1H-
1,2,3-triazole-4-carboxylic acid (6c). Yield 0.52 g
1-(1-Amino-1-oxobutan-2-yl)-5-(benzo[d][1,3]-
dioxol-5-yl)-1H-1,2,3-triazole-4-carboxylic acid (6h).
Yield 0.62 g (96%), mp 131–132°С. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 0.76 d (3H, CH3, J
8.0 Hz), 2.17–2.35 m (1H, CH2), 4.52–4.63 m (1H,
CH), 6.11 s (2H, OCH2O), 6.80 d (1H, H6arom, J 7.2 Hz),
6.85 s (1H, H2arom), 6.96 d (1H, H5arom, J 7.8 Hz), 7.29 s
(2H, NH2), 12.68 br.s (1H, COOH). Mass spectrum (CI),
1
(95%), mp 196–197°С. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 5.17 s (2H, CH2). 5.49 s (2H,
2,6
CH2), 6.96 t (1H, H4arom, J 7.4 Hz), 7.01 d (2H, H
, J
arom
3,5
8.0 Hz), 7.28 t (2H, H
, J 7.9 Hz), 7.32 s (1H, NH2),
arom
7.68 s (1H, NH2). Mass spectrum (CI), m/z: 277 [M +
H]+. Found, %: C 52.11; H 4.45; N 20.12. C12H12N4O4.
Calculated, %: C 52.17; H 4.38; N 20.28.
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1428
POKHODYLO et al.
m/z: 319 [M + H]+. Found, %: C 52.76; H 4.35; N 17.55.
C14H14N4O5. Calculated, %: C 52.83; H 4.43; N 17.60.
mp 198–199°С. 1H NMR spectrum (400 MHz, DMSO-
d6), δ, ppm: 1.68 s (6H, CH3), 6.06 s (2H, OCH2O),
6.81 d (1H, H6arom, J 7.9 Hz), 6.85 s (1H, H2arom), 6.88 d
(1H, H5arom, J 8.0 Hz), 7.10 s (1H, NH2), 7.26 s (1H,
NH2), 7.48 s (1Htriazol). Mass spectrum (CI), m/z: 275
[M + H]+. Found, %: C 56.99; H 5.05; N 20.51.
C13H14N4O3. Calculated, %: C 56.93; H 5.14; N 20.43.
1-(2-Amino-2-oxoethyl)-5-methyl-1H-1,2,3-
triazole-4-carboxylic acid (14a). Yield 0.33 g (91%),
1
mp 210°С (decomp.). H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.43 s (3H, CH3). 4.99 s (2H, CH2),
7.30 s (1H, NH2), 7.68 s (1H, NH2). Mass spectrum (CI),
m/z: 185 [M + H]+. Found, %: C 39.21; H 4.33; N 30.51.
C6H8N4O3. Calculated, %: C 39.13; H 4.38; N 30.42.
2-{5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-
1-yl}butanamide (9d). Yield 0.54 g (100%), mp
114–115°С. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 0.74 t (3H, CH3, J 7.2 Hz), 2.19–2.33 m (2H,
CH2), 4.85 d.d (1H, CH, J 9.1, 6.2 Hz), 6.11 s (2H,
OCH2O), 6.87 d (1H, H6arom, J 7.7 Hz), 6.89 s (1H, H2arom),
6.97 d (1H, H5arom, J 7.8 Hz), 7.29 s (1H, NH2), 7.32 s
(1H, NH2), 7.61 s (1Htriazol). Mass spectrum (CI), m/z: 275
[M + H]+. Found, %: C 56.75; H 5.11; N 20.32.
C13H14N4O3. Calculated, %: C 56.93; H 5.14; N 20.43.
1-[2-(2,4,6-Trimethylphenylamino)-2-oxoethyl]-
5-methyl-1H-1,2,3-triazole-4-carboxylic acid (14b).
Yield 0.58 g (97%), mp 236–237°С. IR spectrum,
ν, cm–1: 3262 (NH), 2919, 2676, 2593, 1685 (COOH),
1669 (NHCO), 1580, 1537, 1485, 1455, 1307, 1265,
1
1243, 1207, 1105, 968, 939, 846, 789, 779, 709. H
NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 2.12 s
(6H, 2,6-Me2), 2.22 s (3H, 4-Me), 2.67 s (3H, Metriazol),
5.38 s (2H, СH2), 6.89 s (2Harom), 9.74 s (1H, NH). Mass
spectrum (CI): m/z 303 [M + H]+. Found, %: C 59.43;
H 5.89; N 18.62. C15H18N4O3. Calculated, %: C 59.59;
H 6.00; N 18.53.
2-(5-Methyl-1H-1,2,3-triazol-1-yl)acetamide (15).
Yield 0.28 g (100%), mp 132–133°С. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 2.25 s (3H, CH3). 4.93 s
(2H, CH2), 7.21 s (1H, NH2), 7.36 s (1Htriazol), 7.58 s
(1H, NH2). Mass spectrum (CI), m/z: 141 [M + H]+.
Found, %: C 42.73; H 5.79; N 39.91. C5H8N4O. Calcu-
lated, %: C 42.85; H 5.75; N 39.98.
Decarboxylation of triazolylcarboxylic acids
6e–6h and 14a (general procedure). Acid 6 or 14
(2 mmol) was heated at the melting point until gas no
longer evolved. After cooling, the target triazole was
obtained in quantitative yield.
Synthesis of carboxylic acids 7, 10a–10d, and 16
(general procedure). The corresponding ester (1 mmol)
was added to a solution of 80 mg (2 mmol) of NaOH in
1 mL of water, the mixture was refluxed for 2 h, acidi-
fied with HСl, and the precipitate of the target acid that
formed was filtered off.
2-{5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-
1-yl}acetamide (9a). Yield 0.50 g (100%), mp 205–
1
206°С. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 4.92 s (2H, CH2), 6.05 s (2H, OCH2O), 6.92 d
(1H, H5arom, J 7.9 Hz), 6.97 d (1H, H6arom, J 8.2 Hz),
7.03 s (1H, H2arom), 7.28 s (1H, NH2), 7.61 s (1Htriazol),
7.64 s (1H, NH2). Mass spectrum (CI), m/z: 247 [M +
H]+. Found, %: C 53.49; H 4.14; N 22.78. C11H10N4O3.
Calculated, %: C 53.66; H 4.09; N 22.75.
1-(Carboxymethyl)-5-(phenoxymethyl)-1H-1,2,3-
triazole-4-carboxylic acid (7). Yield 0.26 g (94%), mp
198–199°С. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 5.30 s (2H, CH2), 5.51 s (2H, CH2), 6.91–7.01 m
3,5
(3Harom), 7.27 t (2H, H , J 8.0 Hz). Mass spectrum (CI),
arom
m/z: 278 [M + H]+. Found, %: C 51.91; H 4.07; N 15.01.
2-{5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-
1-yl}propanamide (9b). Yield 0.52 g (100%), mp
201–202°С. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 1.79 d (3H, CH3, J 7.2 Hz), 5.14 q (1H, CH, J
7.2 Hz), 6.08 s (2H, OCH2O), 6.89 d (1H, H6arom, J
8.0 Hz), 6.93 s (1H, H2arom), 6.97 d (1H, H5arom J 8.0 Hz),
7.23 s (1H, NH2), 7.33 s (1H, NH2), 7.61 s (1Htriazol).
Mass spectrum (CI), m/z: 261 [M + H]+. Found, %:
C 55.44; H 4.54; N 21.59. C12H12N4O3. Calculated, %:
C 55.38; H 4.65; N 21.53.
C12H11N3O5. Calculated, %: C 51.99; H 4.00; N 15.16.
2-{5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-
1-yl}acetic acid (10a). Yield 0.24 g (96%), mp 191–
192°С. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm:
5.10 s (2H, CH2). 6.06 s (2H, OCH2O), 6.87–7.00 m
(3Harom), 7.63 s (1Htriazol), 13.28 br.s (1H, COOH). Mass
spectrum (CI), m/z: 248 [M + H]+. Found, %: C 53.51;
H 3.78; N 17.04. C11H9N3O4. Calculated, %: C 53.44;
H 3.67; N 17.00.
2-{5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-
1-yl}-2-methylpropanamide (9c). Yield 0.54 g (100%),
2-(5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-
1-yl)propanoic acid (10b). Yield 0.25 g (97%), mp
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SYNTHESIS OF (1H-1,2,3-TRIAZOL-1-YL)ACETIC ACID DERIVATIVES
1429
208–209°С. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 1.79 d (3H, CH3, J 7.2 Hz), 5.14 q (1H, CH, J
7.2 Hz), 6.08 s (2H, OCH2O), 6.89 d (1H, H6arom, J
8.0 Hz), 6.93 s (1H, H2arom), 6.97 d (1H, H5arom, J 7.9 Hz),
7.61 s (1Htriazol), 13.23 br.s (1H, COOH). Mass spectrum
(CI), m/z: 262 [M + H]+. Found, %: C 55.25; H 4.31;
N 16.15. C12H11N3O4. Calculated, %: C 55.17; H 4.24;
N 16.09.
Multicomponent synthesis of 1,2,3-triazole-
4-carboxylic acid esters 13a–13c (general procedure).
Sodium azide (1.25 g, 19 mmol) was added to a solution
of 16 mmol of the corresponding halo derivative 12 in
10 mL of DMSO. The suspension was stirred at room
temperature for 5 h, after which 10 g (70 mmol) K2CO3
and 2.05 mL (16 mmol) of acetoacetic ester 2f were
added. The resulting suspension was stirred at 40–50°С
for 12 h, cooled to 5°С, and diluted with 50 mL of water.
The precipitate that formed was filtered off, washed with
water, ad recrystallized from alcohol or aqueous alcohol.
2-(5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-
1-yl)-2-methylpropanoic acid (10с). Yield 0.26 g (96%),
mp 221–222°С. 1H NMR spectrum (400 MHz, DMSO-
d6), δ, ppm: 1.73 s (6H, CH3), 6.08 s (2H, OCH2O),
6.73–6.80 m (2Harom), 6.90 d (1H, H5arom, J 8.4 Hz),
7.49 s (1Htriazol), 13.33 br.s (1H, COOH). Mass spectrum
(CI), m/z: 276 [M + H]+. Found, %: C 56.75; H 4.84;
N 15.36. C13H13N3O4. Calculated, %: C 56.72; H 4.76;
N 15.27.
Ethyl 1-(2-amino-2-oxoethyl)-5-methyl-1H-1,2,3-
triazole-4-carboxylate (13a). Yield 2.51 g (74%), mp
170–171°С. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 1.39 t (3H, СH3СH2, J 7.1 Hz), 2.48 s (3H, СH3),
4.33 q (2H, СH2O, J 7.0 Hz), 5.05 s (2H, СH2), 7.34 s (1H,
NH2), 7.73 s (1H, NH2). Mass spectrum (CI): m/z 213
[M + H]+. Found, %: C 45.16; H 5.79; N 26.31.
C8H12N4O3. Calculated, %: C 45.28; H 5.70; N 26.40.
2-{5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-
1-yl}butanoic acid (10d). Yield 0.26 g (95%), mp
190–191°С. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 0.75 t (3H, CH3, J 7.2 Hz), 2.21–2.35 m (2H,
CH2), 4.87 d.d (1H, CH, J 9.1, 6.2 Hz), 6.09 s (2H,
OCH2O), 6.87 d (1H, H6arom, J 7.7 Hz), 6.89 s (1H,
H2arom), 6.97 d (1H, H5arom, J 7.8 Hz), 7.62 s (1Htriazol).
Mass spectrum (CI), m/z: 276 [M + H]+. Found, %:
C 56.59; H 4.72; N 15.19. C13H13N3O4. Calculated, %:
C 56.72; H 4.76; N 15.27.
Ethyl 5-methyl-1-[2-oxo-2-(phenylamino)-
ethyl-1H-1,2,3-triazole-4-carboxylate (13b). Yield
1
3.96 g (86 %), mp 150–151°С. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.33 t (3H, СH3СH2, J
6.7 Hz), 3.36 s (3H, СH3), 4.33 q (2H, CH2, J 6.7 Hz),
5.39 s (2H, СH2), 7.10 t (1H, H4arom, J 6.9 Hz), 7.34 t (2H,
2,6
Ha3r,5om, J 7.2 Hz), 7.58 d (2H, H
, J 7.6 Hz), 10.59 s
arom
(1H, NH). Mass spectrum (CI): m/z 289 [M + H]+.
Found, %: C 58.21; H 5.48; N 19.64. C14H16N3O4. Cal-
culated, %: C 58.32; H 5.59; N 19.43.
2-(5-Methyl-1H-1,2,3-triazol-1-yl)acetic acid (16).
1
Yield 0.13 g (91%), mp 177–178°С. H NMR spec-
Ethyl 1-[2-(2,4,6-trimethylphenylamino)-2-oxo-
ethyl]-5-methyl-1H-1,2,3-triazole-4-carboxylate (13c).
Yield 4.33 g (82%), mp 201–202°С. IR spectrum, ν, cm–1:
3270 (NH), 2992, 1706 (COOEt), 1655 (NHCO), 1576,
1537, 1477, 1438, 1373, 1347, 1296, 1246, 1196, 1104,
1088, 967, 851, 787, 726, 694, 654. 1H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm: 1.41 t (3H, CH3, J 7.0 Hz),
2.07 s (6H, 2,6-Me2), 2.22 s (3H, 4-Me), 2.65 s (3H,
СH3), 4.41 q (2H, СH2, J 7.0 Hz), 5.18 s (2H, СH2),
6.83 s (2Harom), 7.45 br.s (1H, NH). Mass spectrum (CI):
m/z 331 [M + H]+. Found, %: C 61.85; H 6.72; N 17.10.
C17H22N4O3. Calculated, %: C 61.80; H 6.71; N 16.96.
trum (400 MHz, DMSO-d6), δ, ppm: 2.26 s (3H, CH3),
5.10 s (2H, CH2), 7.37 s (1Htriazol). Mass spectrum (CI),
m/z: 142 [M + H]+. Found, %: C 42.51; H 5.12; N 29.71.
C5H7N3O2. Calculated, %: C 42.55; H 5.00; N 29.77.
Methyl 1-(2-amino-2-oxoethyl)-5-[2-(1,3-dioxo-
isoindolin-2-yl)ethyl]-1H-1,2,3-triazole-4-carboxylate
(8). Compound 4e (1 mmol) was heated in toluene with
a catalytic amount of toluenesulfonic acid for 1 h. After
cooling, the reaction mixture was washed with saturated
NaHCO3 and toluene was evaporated in a vacuum to
obtain a pure compound 8. Yield 0.33 g (92%), mp
188–189°С. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 3.27 t (2H, CH2, J 6.3 Hz), 3.67 s (3H, CH3O),
3.89 t (2H, CH2, J 6.0 Hz), 5.13 s (2H, CH2), 7.38 s (1H,
NH2), 7.73–7.88 m (5H, Harom + NH). Mass spectrum
(CI), m/z: 358 [M + H]+. Found, %: C 53.63; H 4.29;
N 19.71. C16H15N5O5. Calculated, %: C 53.78; H 4.23;
N 19.60.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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