Synthesis of 1-(R-Phenyl)-5-(R-Methyl)-1H-1,2,3-triazole-4-carboxylic acids by one-pot tandem reaction

Article abstract of DOI:10.1080/00397910903174408

Substituted 1H-1,2,3-triazole-4-carboxylic acids were synthesized by a three-component reaction of arylazides, ethyl 4-chloro-3-oxobutanoate, and either O-or S-nucleophiles in the presence of a base catalyst. The reaction most probably proceeded as a [3+2] cyclocondensation reaction between arylazide and ethyl 4-chloro-3-oxobutanoate with the further nucleophilic substitution of chlorine in the chloromethyl group. Reaction optimization was performed to carry out the reaction with an O-nucleophile. Conditions were found under which diethyl 2,5-dihydroxyterephthalate (the product of self-condensation of two molecules of ethyl 4-chloro-3-oxobutanoate with the further oxidation by azide) was obtained. Copyright

Full text of DOI:10.1080/00397910903174408

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Synthesis of 1-(R-Phenyl)-5-(R-
Methyl)-1H-1,2,3-triazole-4-carboxylic
Acids by One-Pot Tandem Reaction
Nazariy T. Pokhodylo a , Vasyl S. Matiychuk a & Mykola D. Obushak a
a Department of Organic Chemistry, Ivan Franko National University
of Lviv, Lviv, Ukraine
Version of record first published: 08 Jun 2010
To cite this article: Nazariy T. Pokhodylo, Vasyl S. Matiychuk & Mykola D. Obushak (2010): Synthesis of
1-(R-Phenyl)-5-(R-Methyl)-1H-1,2,3-triazole-4-carboxylic Acids by One-Pot Tandem Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:13, 1932-1938
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Synthetic Communications1, 40: 1932–1938, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903174408
SYNTHESIS OF 1-(R-PHENYL)-5-(R-METHYL)-1H-
1,2,3-TRIAZOLE-4-CARBOXYLIC ACIDS BY
ONE-POT TANDEM REACTION
Nazariy T. Pokhodylo, Vasyl S. Matiychuk, and
Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv,
Lviv, Ukraine
Substituted 1H-1,2,3-triazole-4-carboxylic acids were synthesized by a three-component
reaction of arylazides, ethyl 4-chloro-3-oxobutanoate, and either O- or S-nucleophiles in
the presence of a base catalyst. The reaction most probably proceeded as a [3 þ 2]
cyclocondensation reaction between arylazide and ethyl 4-chloro-3-oxobutanoate with the
further nucleophilic substitution of chlorine in the chloromethyl group. Reaction optimiza-
tion was performed to carry out the reaction with an O-nucleophile. Conditions were found
under which diethyl 2,5-dihydroxyterephthalate (the product of self-condensation of two
molecules of ethyl 4-chloro-3-oxobutanoate with the further oxidation by azide) was
obtained.
Keywords: Azides; cyclocondensation; multicomponent reactions; 1H-1,2,3-triazoles
INTRODUCTION
Multicomponent reactions are an attractive synthetic strategy for rapid and
efficient library generation because the products are formed in one step and diversity
can be achieved simply by changing the reaction components.[1,2] Unfortunately,
such a strategy is rarely applied to 1,2,3-triazole derivative synthesis. On the other
hand, 1,2,3-triazoles are an important class of heterocycles because of their range
of applications as drugs (or their precursors) and for technical purposes.[3–5] In
recent years, triazole-forming reactions have received much attention, and new con-
ditions of 1,3-dipolar cycloaddition reaction between alkynes and azides (especially
in click chemistry strategy) have been developed.[6] Base catalyst reactions of azides
with methylenic compounds are less studied. Therefore, we report our efforts toward
the development of facile, solution-phase, parallel, three-component reactions of
1,2,3-triazole synthesis using base-catalyzed reactions of azides with methylenic
compounds.
Received May 19, 2009.
Address correspondence to Nazariy T. Pokhodylo, Department of Organic Chemistry, Ivan
Franko National University of Lviv, Kyryla
pokhodylo@gmail.com
i Mefodiya St. 6, Lviv 79005, Ukraine. E-mail:
1932

1-(R-PHENYL)-5-(R-METHYL)-1H-1,2,3-TRIAZOLE-4-CARBOXYLIC ACIDS
1933
RESULTS AND DISCUSSION
It is well known that organic azides undergo base-catalyzed condensation
reactions with activated methylenic compounds.[4] The first step of the reaction is
the carbanion attack on the azido moiety to form triazenyl anions, which can then
be trapped with internal electrophiles and cyclized to triazoles.[5] In the current arti-
cle, reactions of arylazides with ethyl 4-chloro-3-oxobutanoate and nucleophiles are
reported. The starting materials are commercially available compounds that provide
a variety of triazoles. Rapid formation of the triazole ring is a perfect model of the
reaction described. Obviously, if azide slowly reacts with carbanion in position 2 of
ethyl 4-chloro-3-oxobutanoate, another molecule of this ester can be potentially
attacked. In such case, the product of alkylation is obtained. It is theoretically
possible to expect the formation of less stabilized carbanion in position 4 of ethyl
4-chloro-3-oxobutanoate (as a competition reaction), which can react with azides
to yield ethyl (4-chloro-1-phenyl-1H-1,2,3-triazol-5-yl)acetate.
Only one example of ethyl 4-chloro-3-oxobutanoate reaction with azides has
been reported previously.[7] By the reaction of 3-azido-2-amino-1,2,5-oxadiazole
with ethyl 4-chloro-3-oxobutanoate and excess of the appropriate amine (piperidine,
diethylamine, pyrrolidine), functionalized [1,2,3]triazoles were synthesized. Amines
were used as base and N-nucleophiles. To preclude the purification of the reactive
chloromethyl intermediate, [1,2,3]triazoles were prepared by a one-pot procedure.[7]
In general, reactivity of azides is insufficiently studied.
Our findings on azide reactions with ethyl 4-chloro-3-oxobutanoate demonstrate
that if the reaction occurs in a sodium methoxide–methanol system, S-nucleophiles
rapidly react with the chloromethyl group. 5-(R-Sulfanyl)methyl-1H-1,2,3-triazoles
6h–j were obtained in excellent yields (74–84%) at different temperatures. On the other
hand, the reaction of compounds 1 with 2 and O-nucleophile (methylate anion) was
Scheme 1. Synthesis of 1-(R-phenyl)-5-(R-methyl)-1H-1,2,3-triazole-4-carboxylic acids.

1934
N. T. POKHODYLO, V. S. MATIYCHUK, AND M. D. OBUSHAK
Table 1. Synthesis of acids 6a–j
Entry
Compound
R1
R2X
Yielda (%)
1
2
6a
6b
6c
6d
6e
6f
H
4-Me
4-F
MeO
MeO
MeO
MeO
MeO
MeO
MeO
EtS
43
37
56
55
40
67
65
74
77
84
3
4
4-Br
4-MeO
3-CF3
4-NO2
H
5
6
7
6g
6h
6i
8
9
10
4-Me
H
EtS
PhS
6j
aIsolated yields of acids 6a–j when the reaction occurred in a boiling
solution.
carried out under strict control of temperature to avoid undesirable reactions, and
yields of triazoles 6a–g were moderate (Scheme 1, Table 1).
From the results summarized in Table 1, the correlation between yields and
substituent in arylazide can be noted. Arylazides with electron-withdrawing groups
in the aromatic ring under the sodium methoxide–methanol system conditions
formed triazoles 6c, d, f, and g in moderate (55–67%) yields. In contrast, arylazides
with electron-donating groups under the same conditions gave poor yields of
triazoles 6a, b, and e (37–43%).
The use of methanol as a reaction medium was indispensable when the reaction
occurred with methoxide nucleophile. Apparently, a weak concentration of methox-
ide ions in equilibrium was necessary to promote the reaction. No cyclization
occurred when the reaction was carried out in the absence of a base. In addition, when
the reaction occurred in acetone and potassium carbonate was selected as a base cata-
lyst, the main product of the reaction was diethyl 2,5-dihydroxyterephthalate 10
(Scheme 2). Moreover, no triazole derivatives were found when the reaction was
carried out in morpholine or pyridine solution at 100 ꢀC.
Considerable improvements of yields were achieved under strict control of
the temperature. It was found that the reaction of azides 1 with ethyl 4-chloro-3-
oxobutanoate occurred slowly at ꢁ10 ꢀC. Yields of triazoles were less than 5%,
and in some cases triazoles were not even isolated. At 5 ꢀC and by intensive inter-
fusion, triazole yields increased but still were incidental (<10%). At room tempera-
ture and by rapid addition of reagents, triazole yields increased (20–30%), and the
Scheme 2. Concurred reaction of the diethyl 2,5-dihydroxyterephthalate formation.

1-(R-PHENYL)-5-(R-METHYL)-1H-1,2,3-TRIAZOLE-4-CARBOXYLIC ACIDS
1935
Table 2. Temperature optimization for the reaction outlined in Scheme 1
Yielda (%)
Entry
R
–10 ꢀC, 14d
þ5 ꢀC, 7d
25 ꢀC, 1d
67 ꢀC,b 1 h
1
2
3
H
Me
Br
—
—
4
5
6
9
19
18
30
43
37
55
Note. Conditions: sodium (0.25 g, 11 mmol); 5 mmol of azide 1, ester 2, and nucleo-
phile 4; MeOH (20 mL).
aIsolated yields of acids 6a, b, and d.
bBoiling solution.
greatest yields (37–67%) were observed under intensive stirring of reagents at
methanol boiling temperature (65 ꢀC) (Table 2).
In case of arylazides with electron-withdrawing groups, yields of triazoles 6
were high in all temperature modes. The reaction occurred as an exothermic process.
At all temperatures, compound 10, amines 11, and polymeric component were
identified as by-products of the reaction. In addition, ethyl (4-chloro-1-aryl-1H-
1,2,3-triazol-5-yl)acetates or products of their hydrolysis, along with possible
products of nucleophilic substitution of chlorine in position 4 of triazole, were not
detected. Furthermore, we expected a possible lactonization of the intermediate 3.
However, compounds 8 or products of their hydrolysis were not found in the
reaction mixture.
The diversification of compounds 6i and j was reached by oxidation of the
sulfide to the sulfone moiety using hydrogen peroxide. The obtained sulfones 7a
and b, containing an activated methylene group, allowed prolongation of the system
by various types of condensation.
Various substituted 1,2,3-triazole acids were obtained in good yields. They
represent a category of versatile synthetic intermediates that provide miscellaneous
building blocks in the parallel synthesis of druglike molecule libraries.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury 400 (400-MHz) and
1
Bruker 500 (500-MHz) instruments. The H chemical shifts are reported in parts
per million relative to tetramethylsilane (TMS) or the deuterated solvent as an
internal reference. Mass spectra were run using an Agilent 1100 series liquid
chromatography=mass spectra (LC=MS) instrument with an atmospheric pressure
chemical ionization (APCI) mode. Low-resolution electron impact mass spectra
(EIMS) were obtained on a 7683B LC=MS instrument (Agilent Technology), m=z
(relative intensity in percentages, %), with an ionization energy of 70 eV. The evol-
ution of the reactions and purity of the synthesized compounds were monitored
chromatographically on Silufol UV-254 plates. Azides 1a–g were prepared from
1
corresponding amines.[8] In H NMR spectra, the chemical shift of the carboxylic
proton (compounds 6a, b, d, f–h) is not observed, probably because of exchange with
water in dimethylsulfoxide (DMSO-d6).

1936
N. T. POKHODYLO, V. S. MATIYCHUK, AND M. D. OBUSHAK
General Procedure for the Synthesis of 1H-1,2,3-Triazole-4-carboxylic
Acids 6a–j
Sodium (0.5 g, 0.022 mol) was added to 20 mL of absolute methanol. The
appropriate azide 1 (0.01 mol) (0.01 mol of mercaptane in case of 6h–j synthesis)
was added to the obtained sodium methylate solution. (Caution! Hazardous mani-
pulations with azides! Azides are known to decompose explosively.) The solution
was heated under reflux, and 0.7 mL (0.01 mol) of ethyl 4-chloro-3-oxobutanoate 2
was quickly added with intensive stirring. The reaction mixture was heated under
reflux for 1 h. The solid precipitated. Hot water was added to dissolve the sediment
(50 mL); if necessary, the solution of sodium hydroxide can be added to pH 11–12
and heated under reflux for 1 h. The hot solution was poured to 10 mL of concen-
trated HCl and left to be crystallized. The obtained solid was filtered, washed with
water twice, and crystallized from ethanol.
5-(Methoxymethyl)-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid
6a. Yield: 43% as a white solid; mp 153–154 ꢀC; 1H NMR (400 MHz, DMSO-d6): d
3.28 (3H, s, Me), 4.73 (2H, s, CH2), 7.57–7.68 (5H, m, HPh); MS (m=z): 234 (Mþ þ 1).
Anal. calcd. for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C, 56.81; H, 4.68;
N, 18.11.
5-(Methoxymethyl)-1-(4-methylphenyl)-1H-1,2,3-triazole-4-carboxylic
acid 6b. Yield: 37% as a white solid; mp 167–168 ꢀC; 1H NMR (500 MHz,
DMSO-d6): d 2.42 (3H, s, Me), 3.20 (3H, s, Me), 4.71 (2H, s, CH2), 7.44 (2H, d,
3J 8.3, HAr-3,5), 7.55 (2H, d, 3J 8.3, HAr-2,6); MS (m=z): 248 (Mþ þ 1). Anal. calcd.
for C12H13N3O3: C, 58.29; H, 5.30; N, 17.00. Found: C, 58.01; H, 5.25; N, 16.89.
1-(4-Fluorophenyl)-5-(methoxymethyl)-1H-1,2,3-triazole-4-carboxylic
acid 6c. Yield: 56% as a white solid; mp 136–137 ꢀC; 1H NMR (500 MHz,
3
DMSO-d6): d 3.20 (3H, s, Me), 4.73 (2H, s, CH2), 7.49 (2H, t, J 8.8, HAr-3,5),
3
4
7.74 (2H, dd, JHH 8.8, JHF 4.9, HAr-2,6), 13.53 (1H, br.s, COOH); MS (m=z):
252 (Mþ þ 1). Anal. calcd. for C11H10FN3O3: C, 52.59; H, 4.01; N, 16.73. Found:
C, 52.24; H, 4.28; N, 16.61.
1-(4-Bromophenyl)-5-(methoxymethyl)-1H-1,2,3-triazole-4-carboxylic
acid 6d. Yield: 55% as a white solid; mp: 167–168 ꢀC; 1H NMR (400 MHz,
3
DMSO-d6): d 3.30 (3H, s, Me), 4.76 (2H, s, CH2), 7.65 (2H, d, J 8.8, HAr-3,5),
7.78 (2H, d, 3J 8.8, HAr-2,6); MS (m=z): 313 (Mþ þ 1). Anal. calcd. for
C11H10BrN3O3: C, 42.33; H, 3.23; N, 13.46. Found: C, 42.19; H, 3.04; N, 13.34.
5-(Methoxymethyl)-1-(4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylic
acid 6e. Yield: 40% as a white solid; mp 214–215 ꢀC; 1H NMR (500 MHz,
DMSO-d6): d 2.51 (3H, s, Me), 3.21 (3H, s, Me), 4.76 (2H, s, CH2), 7.73 (4H,
br.s, HAr), 13.55 (1H, br.s, COOH); MS (m=z): 264 (Mþ þ 1). Anal. calcd. for
C12H13N3O4: C, 54.75; H, 4.98; N, 15.96. Found: C, 54.43; H, 5.07; N, 16.05.
5-(Methoxymethyl)-1-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazole-4-
carboxylic acid 6f. Yield: 67% as a white solid; mp 111–112 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 3.31 (3H, s, Me), 4.78 (2H, s, CH2), 7.85–7.93 (2H, m,
3
H
Ar-4,5), 8.02 (1H, d, J 8.8, HAr-6), 8.05 (1H, s, HAr-2); MS (m=z): 302 (Mþ þ 1).

1-(R-PHENYL)-5-(R-METHYL)-1H-1,2,3-TRIAZOLE-4-CARBOXYLIC ACIDS
1937
Anal. calcd. for C12H10F3N3O3: C, 47.85; H, 3.35; N, 13.95. Found: C, 47.42; H,
3.57; N, 13.74.
5-(Methoxymethyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic
acid 6g. Yield: 65% as a white solid; mp 161–162 ꢀC; 1H NMR (400 MHz,
3
DMSO-d6): d 3.31 (3H, s, Me), 4.85 (2H, s, CH2), 8.03 (2H, d, J 8.8, HAr-3,5),
8.47 (2H, d, 3J 8.8, HAr-2,6); MS (m=z): 279 (Mþ þ 1). Anal. calcd. for
C11H10N4O5: C, 47.49; H, 3.62; N, 20.14. Found: C, 47.76; H, 3.44; N, 20.36.
5-[(Ethylsulfanyl)methyl]-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid
6h. Yield: 74% as a white solid; mp 109–110 ꢀC; 1H NMR (400 MHz, DMSO-d6): d
1.08 (3H, t, 3J 7.8, Me), 2.37 (3H, q, 3J 7.8, CH2), 4.11 (2H, s, CH2), 7.62 (5H, br.s,
H
15.96. Found: C, 54.58; H, 4.74; N, 16.06.
Ph) MS (m=z): 264 (Mþ þ 1). Anal. calcd. for C12H13N3O2S: C, 54.74; H, 4.98; N,
5-[(Ethylsulfanyl)methyl]-1-(4-methylphenyl)-1H-1,2,3-triazole-4-
carboxylic acid 6i. Yield: 77% as a white solid; mp 161–162 ꢀC; 1H NMR
3
3
(400 MHz, DMSO-d6): d 1.09 (3H, t, J 7.8, Me), 2.39 (3H, q, J 7.8, CH2), 2.47
(3H, s, Me), 4.08 (2H, s, CH2), 7.41 (2H, d, J 7.8, HAr-3,5), 7.49 (2H, d, J 7.8,
3
3
H
C13H15N3O2S: C, 56.30; H, 5.45; N, 15.15. Found: C, 56.51; H, 5.39; N, 15.00.
Ar-2,6). 13.12 (1H, br.s, COOH); MS (m=z): 278 (Mþ þ 1). Anal. calcd. for
1-Phenyl-5-[(phenylsulfanyl)methyl]-1H-1,2,3-triazole-4-carboxylic acid
1
6j. Yield: 84% as a white solid; mp 147–148 ꢀC; H NMR (400 MHz, DMSO-d6):
d 4.52 (2H, s, CH2), 7.12–7.23 (5H, m, HAr), 7.46–7.59 (5H, m, HAr), 13.10 (1H,
br.s, COOH); MS (m=z): 312 (Mþ þ 1). Anal. calcd. for C16H13N3O2S: C, 61.72;
H, 4.21; N, 13.50. Found: C, 61.84; H, 4.25; N, 13.37.
Other Conditions
The mixture of appropriate azide 1 (0.01 mol), ethyl 4-chloro-3-oxobutanoate 2
(0.7 mL, 0.01 mol), and potassium carbonate (0.01 mol) was heated under reflux for
6 h. Water was added to dissolve the sediment, and the solution was poured to
10 mL of concentrated HCl and left to be crystallized. The obtained solid was filtered
and crystallized. Diethyl 2,5-dihydroxyterephthalate 10 was isolated in 37% yield as
1
3
white needles. H NMR (400 MHz, DMSO-d6): d 1.40 (6H, t, J 6.8, Me), 4.40
(4H, q, J 6.8, CH2), 7.30 (2H, s, HAr-3,6), 9.89 (2H, s, HO), EIMS: 254 (Mþ, 32),
208 (100), 180 (25), 162 (75), 134 (16), 107 (10), 79 (7), 53 (9), 29 (4).
3
Oxidation of Sulfides 6i and j to Sulfones 7a and b
Appropriate sulfides 6i, j (0.017 mol) were dissolved in 15 mL of acetic acid
during heating. The solution was cooled to 50 ꢀC and 50 mL (approx. 0.05 mol) of
a 30% solution of hydrogen peroxide was added dropwise during 5 min keeping
the temperature below 75 ꢀC. At the end of addition the solution was left for 3 h
at 85 ꢀC. The reaction mixture was cooled, the precipitated crystals were filtered,
washed with methanole and dried.

1938
N. T. POKHODYLO, V. S. MATIYCHUK, AND M. D. OBUSHAK
5-[(Ethylsulfonyl)methyl]-1-(4-methylphenyl)-1H-1,2,3-triazole-4-
carboxylic acid 7a. Yield: 77% as a white solid; mp 161–162 ꢀC; 1H NMR
3
3
(400 MHz, DMSO-d6): d 1.19 (3H, t, J 7.8, Me), 2.47 (3H, s, Me), 3.03 (3H, q, J
7.8, CH2), 4.83 (2H, s, CH2), 7.49 (2H, d, J 8.0, HAr-3,5), 7.50 (2H, d, J 8.0,
3
3
H
C13H15N3O4S: C, 50.47; H, 4.89; N, 13.58. Found: C, 50.28; H, 4.81; N, 13.70.
Ar-2,6). 13.12 (1H, br.s, COOH); MS (m=z): 310 (Mþ þ 1). Anal. calcd. for
1-Phenyl-5-[(phenylsulfonyl)methyl]-1H-1,2,3-triazole-4-carboxylic acid
1
7b. Yield: 88% as a white solid; mp 177–178 ꢀC; H NMR (400 MHz, DMSO-d6):
d 5.08 (2H, s, CH2), 7.45–7.58 (9H, m, HAr), 7.64–7.70 (1H, m, HAr), 13.10 (1H,
br.s, COOH); MS (m=z): 345 (Mþ þ 1). Anal. calcd. for C16H13N3O4S: C, 55.97;
H, 3.82; N, 12.24. Found: C, 55.83; H, 3.76; N, 12.08.
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