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* Corresponding author.
E-mail address: pokhodylo@gmail.com (N. Pokhodylo)
© 2021 Growing Science Ltd. All rights reserved.
doi: 10.5267/j.ccl.2020.7.004
Current Chemistry Letters 9 (2021) 53–66
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Current Chemistry Letters
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Comparison of synthetic routes for fully substituted (1H-1,2,3-triazol-4-yl)acetic acids
Nazariy Pokhodyloa*, Roman Savkaa and Mykola Obushaka
aDepartment of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine
C H R O N I C L E A B S T R A C T
Article history:
Received June 1, 2020
Received in revised form
June 26, 2020
Accepted July 28, 2020
Available online
July 28, 2020
The new fully substituted (1H‐1,2,3-triazol-4-yl)acetic acids were synthesized from available
precursors (1H‐1,2,3-triazol-4-yl)ethanones and 1Н-1,2,3-triazole-4-carboxylic acids, which
are easily prepared by the Dimroth reaction from azides and 1,3-dicarbonyl compounds. The
practical methods of homologization (the Arndt–Eistert reaction and homologization as a result
of nucleophilic substitution by cyanide anion) and the Willgerodt-Kindler reaction were
compared. The Willgerodt-Kindler method starting from (5-methyl-1H‐1,2,3-triazol-4-
yl)ethanones was selected as the most convenient method for the synthesis of 2-(1-aryl-5-
methyl-1H‐1,2,3-triazol-4-yl)acetic acids, which are promising building blocks for drug
discovery. Additionally, (1H‐1,2,3-triazol-4-yl)ethanones were studied for the synthesis of
alcohols, amines and in the Johnson–Corey–Chaykovsky reaction.
© 2021 Growin
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Science Ltd. All ri
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hts reserved.
Keywords:
1,2,3-Triazoles
Dimroth reaction
Wilgerodt-Kindler reaction
Functionalization
Homologization
1. Introduction
The 1Н-1,2,3-triazoles functionalized in position 4 are well-known building blocks for construction
of diversity of triazole derivatives for drug discovery and material sciences.1 The progress of 4-
functionalized fully substituted triazoles (mostly 4-carboxylic acids or 4-keto derivatives) is caused by
a convenient and efficient Dimroth reaction, which allows a wide variation of substituents.2–6 Another
approach to 4-functionalized triazoles is the [3+2] cycloaddition reaction of EWG-functionalized
acetylenes with organic azides, which can also be performed in regioselective manner without catalyst
due to significant charge separation in alkyne, currently being DFT computationally studied.7 However,
the triazole functional groups’ transformations, especially non-isohypsic reactions (with a change in
the oxidation level of carbon atoms), remain poorly studied. Among such reactions, (1H‐1,2,3-triazol-
4-yl)ethanones and 1Н-1,2,3-triazole-4-carboxylic acids are commonly researched. For example, it was
found that 4-acetyltriazoles had significant C–H activity and easily allowed aldol condensation
reactions for the synthesis of chalcones containing the triazole moiety. A number of 1,2,3-triazole
chalcones have been tested for antimicrobial activity8 and studied as transglutaminase inhibitors.9
Moreover, such chalcones were used as starting reagents for the synthesis of (1H-1,2,3-triazol-4-
yl)pyridines by the Michael tandem cyclization,10 1,2,3-triazol-4-ylpyrazoles11 and their derivatives for
screening antimicrobial activity,12 and 1,2,3-triazolylhydro-pyrimidine-2-thiones,13 which were
54
evaluated as antibacterial agents. Recently, chalcones were used in the KF-Al2O3-catalyzed tandem
nucleophilic attachment of cyanide ion generated from activated acetonitriles, which made it possible
to synthesize a series of 2-aryl-4-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)butyronitriles.14 We have
shown that such chalcones could be used in the thionation-hetero-Diels-Alder domino-reactions
yielding 3,4-dihydro-2H-thiopyrans and thiopyrano[3,4-c]chromenones.15 In addition, it was found that
the starting 1-[1-aryl-5-methyl-1,2,3-triazol-4-yl]ethanones were convenient reagents in the synthesis
of quinoline derivatives by the Pfitzinger reaction.16 Another important class of triazoles widely used
nowadays is triazole-4-carboxylic acids and their derivatives (esters or acid chlorides). For examples,
unique ethyl 1-aryl-5-formyl-1H-1,2,3-triazole-4-carboxylates were used to provide access to
insufficiently studied 1-aryl-1,5-dihydro-4H-[1,2,3]triazolo[4,5-d]pyridazin-4-ones.17 The reaction of
1H-1,2,3-triazole-4-carboxylic acid chlorides with tryptamine and the following Bischler-Napieralski
cyclization is a convenient route to 1-(1H-1,2,3-triazol-4-yl)-3H-β-carbolines.18 The 1-aryl-1H-1,2,3-
triazole-4-carbonyl chlorides were studied in one-pot Boulton–Katritzky rearrangement with 3-amino-
5-methylisoxazole and KSCN leading to 1,2,4-thiadiazole derivatives.19 In addition, diversity of
isomeric (1H-1,2,3-triazol-4-yl)-1,3,4-oxadiazoles or 1,2,4-oxadiazoles were synthesized by the
reaction of 1,2,3-triazole-4-carbonyl chlorides with the corresponding substituted 1H-tetrazoles or N-
hydroxyamides.20 Lastly, the ligands for lanthanide ions (Pr3+, Sm3+, Nd3+, Yb3+, Eu3+ and Tb3+) were
prepared by the acylation of pyrazoline-5-one derivatives21 or 1-(2-hydroxy-5-methylphenyl)ethanone
with the following Baker–Venkataraman rearrangement with 1Н-1,2,3-triazole-4-carboxylic acid
chlorides for studying the luminescence properties of their complexes.22 In this regard, homologization
of 1Н-1,2,3-triazole-4-carboxylic acids is a matter of utmost interest. It should be noted that, as opposed
to the 1-substituted (1H‐1,2,3-triazol-4-yl)acetic acids, the synthetic approaches to fully substituted
ones remain unstudied. The 1-substituted (1H‐1,2,3-triazol-4-yl)acetic acids can be obtained by the
reaction of ethyl-4,4-dichloro-3-{[(4-methylphenyl)sulfonyl]hydrazono}butanoate with amines in the
presence of N-ethyl-N,N-diisopropylamine as the base23 or CuAAC reaction of azides with 3-butynoic
acid.24 At the latter reaction, the azides were prepared from benzyl bromides in one-pot.25 In addition,
a regioselective intramolecular reaction of the dipolar cyclic addition of azides and asymmetric alkynes
containing the acetic acid fragment was developed.26 Noteworthy that compounds containing the (1H-
1,2,3-triazol-4-yl)acetic acid fragment have been studied as squalene synthase inhibitors.27
2. Results and Discussion
In this work, we have compared alternative approaches to the synthesis of fully substituted (1H‐
1,2,3-triazol-4-yl)acetic acids from easily available (1,2,3-triazol-4-yl)carboxylic acids and ketones.
The starting ketones were obtained by the reaction of β-diketones (acetylacetone 1a, dipivaloylmethane
1b, dibenzoylmethane 1c and dimedone 1d) with arylazides 2a–m (see Scheme 1, Table 1). By
optimizing the reaction conditions, it was found that the highest yields of the target triazoles 3 in case
of acetylacetone 1a in the reaction with aryl azides with electron-donating substituents were observed
during the reaction at room temperature and with the use of sodium methylate as a main catalyst. In
contrast, in case of azides with electron-withdrawing substituents, triethylamine (weaker base) was
used. This led to increase in the reaction time, however, the formation of side and tarry products of the
reaction mixture was not observed. In case of dipivaloylmethane 1b and dibenzoylmethane 1c, the
reaction was slow at room temperature. The highest yields of compounds 3l-n were obtained by boiling
the reagents in methanol with sodium methylate. The effective K2CO3/DMSO system, previously used
for selective preparation of 1H-1,2,3-triazole-4-carboxylic acids,28 was studied in the reaction of phenyl
azide with dimedone. It was found that the reaction proceeded at room temperature with good yields.
Additionally, no strong correlations between azide reactivity and substituents constants were observed
indicating that there may be different reaction mechanisms, the implementation of which is influenced
by a number of factors, such as solvent, base, enolization degree of ketoester as mentioned earlier.2 The
optimized techniques allowed to obtain substituted high-yield triazoles 3 for their further use as
reagents. It should be noted that as an alternative method of the synthesis of (1,5-diphenyl-1H-1,2,3-
triazol-4-yl)(phenyl)methanone 3m, the oxidative [3+2] cyclic addition of phenyl azide to chalcone in
N. Pokhodylo et al. / Current Chemistry Letters 10 (2021)
55
an aqueous medium with TEMPO was recently proposed.29 Cyclic ketones, such as dimedone and
cyclohexanedione, can be used to annulate the triazole ring, but their use is limited due to the side
processes of diazo transfer observed when using strong base catalysts.18 However, application of mild
bases, such as triethylamine in catalytic amounts,30 anhydrous magnesium carbonate,31 1,1,3,3-
tetramethylguanidine (TMG)32 or DBU,33 allowed to obtain 1H-benzo[d][1,2,3]triazole-4(5H)-ones in
high yields. Furthermore, such compounds could be prepared via the Regits diazo transfer reaction of
tosylazide with 1-anilino-5,5-dimethyl-3-oxocyclohex-1-ene.34
Scheme 1. Synthesis of 1-(1-aryl-5-methyl-1,2,3-triazol-4-yl)ethanones 3a-o.
Table 1. Synthesis of 1-(1-aryl-5-methyl-1,2,3-triazol-4-yl)ethanones 3a-o.
Entry β-Diketone
(1)
Azide
R1 (2)
Hammet
constants (R1) Base t, °C Time, h Triazole
R2 (3)
Yields,
%4
1. acac1 (a) H (2a) 0.00 Et3N 60 24 Me (3a) 83
2. acac (a) 3-Me (2b) -0.07 Et3N 60 24 Me (3b) 78
3. acac (a) 2-F (2c) 0.24 Et3N 20 72 Me (3c) 85
4. acac (a) 4-F (2d) 0.06 Et3N 60 3 Me (3d) 92
5. acac (a) 2-Cl (2e) 0.20 Et3N 20 96 Me (3e) 70
6. acac (a) 3-Cl (2f) 0.37 MeONa 20 48 Me (3f) 74
7. acac (a) 4-Cl (2g) 0.23 MeONa 20 12 Me (3g) 77
8. acac (a) 4-MeO (2h) -0.27 MeONa 20 48 Me (3h) 81
9. acac (a) 3-CF3 (2i) 0.43 Et3N 20 12 Me (3i) 89
10. acac (a) 2,5-Cl2 (2j) 0.20; 0.37 Et3N 20 96 Me (3j) 72
11. acac (a) 3-Cl-4-MeO (2k) 0.37; -0.27 MeONa 20 48 Me (3k) 79
12. dpm2 (b) 4-Me (2l) -0.17 MeONa 65 1
t
Bu (3l) 88
13. dbm (c) H (2a) 0.00 MeONa 65 1
t
Bu (3m) 92
14. dbm3 (c) 4-Me (2l) -0.17 MeONa 65 1 Ph (3n) 94
15. dimedone (d) H (2a) 0.00 К2СО3 20 12 -(CH2C(CH3)2CH2)2- (3o) 72
1
acac
–
acetylacetone; 2 dpm
–
dipivaloyl methane; 3 dbm
–
dibenzoyl methane4; 4 isolated yield
The 1-[1-aryl-5-methyl-1,2,3-triazol-4-yl]ethanones were studied under conditions of the
Willgerodt-Kindler reaction for (1H-1,2,3-triazol-4-yl)acetic acids synthesis (Scheme 2, Table 2). It
was found that regardless of the substituent in the aryl moiety, thiomorpholides were formed with high
yields. However, the hydrolysis of thiomorpholides was difficult in case of some of the substituents
requiring prolonged heating. This made it possible to obtain a number of novel (5-methyl-1-aryl-1H-
1,2,3-triazol-4-yl)acetic acids in good yields. As an alternative route to (1H-1,2,3-triazol-4-yl)acetic
acids preparation, a multistep synthesis starting from triazole-4-carboxylic acids was proposed.
Diversity of triazole-4-carboxylic acids was previously synthesized by the reaction of aryl azides from
β-ketoesters.17-21, 28 The 1H-1,2,3-triazole-4-carboxylic acids 6 were converted to (1H-1,2,3-triazol-4-
yl)methanols via direct reduction or after carbonyl activation through ester or amide. It was found that
the reaction of borane, generated by the action of iodine on sodium boron hydride, in tetrahydrofuran
in case of 1H-1,2,3-triazole-4-carboxylic acid 6a with a methyl substituent in position 5 occurred with
formation of the corresponding alcohol 8 in good yields. The (5-methyl-1-phenyl-1H-1,2,3-triazol-4-
yl) methanol 8a was also synthesized from N-isopropylanilide 7a via reduction with lithium aluminium
hydride (LAH). Instead, in case of the phenyl substituent, the target alcohol was isolated in low yields
due to steric hindering and low solubility of acid. In this regard, acid was quantitatively converted to
methyl ester, which was reduced to alcohol with the action of LAH. Mesylation of alcohols 8 with the
following nitrile incorporation by the potassium cyanide and hydrolysis led to the target 1H-1,2,3-
triazol-4-yl)acetic acids 5. Finally, the Arndt–Eistert synthesis was evaluated for preparation of acid
5k. The 1,5-diphenyl-1H-1,2,3-triazole-4-carboxylic acid 6b was converted to the corresponding
chloride and by acylation of diazomethane yielded diazoketone 7c. By the Arndt–Eistert rearrangement,
56
it was converted to the corresponding amide and hydrolysed to give the target acid 5k. However, the
overall yield of the compound was lower than in case of alternative route to this acid via alcohols 8b.
The summarized data of all attempts and paths is presented in Table 2.
Reagents: a) S, morpholine or 1-methylpiperazine; b) KOH, EtOH, H2O; c) NaBH4, I2, THF d) SOCl2; e) N-
isopropylaniline; f) MeOH; g) CH2N2, MTBE; h) LAH, THF; i) MsCl, Et3N, KCN, KOH, EtOH; j) AgNO3, aq. NH3, dioxane,
KOH, EtOH.
Scheme 2. Synthesis of (5- R2-1-aryl-1H-1,2,3-triazol-4-yl) acetic acids 5a-k.
Table 2. Synthesis of (5- R2-1-aryl-1H-1,2,3-triazol-4-yl) acetic acids 5a-k.
Entry R1 R
2 Method Intermediates (Triazol-4-yl)
acetic acids Yields, %
1. H Me A 4a16 (78%) 5a16 61%
2. H Me B 7a R3 =iPrNPh (91%)
8a (84%) 5a 54%
3. 3-Me Me A 4b Х=O (75%) 5b 70%
4. 2-F Me A 4c Х=O (88%) 5c 73%
5. 4-F Me A 4d Х=O (83%) 5d 79%
6. 2-Cl Me A 4e Х=O (81%) 5e 64%
7. 3-Cl Me A 4f Х=O (85%) 5f 72%
8. 4-Cl Me A 4g Х=NMe (71%) 5g16 74%
9. 4-MeO Me A 4h Х=O (73%) 5h 67%
10. 3-CF3 Me A 4i Х=O (90%) 5i 84%
11. 2,5-Cl2 Me A 4j Х=O (78%) 5j 69%
12. H Ph B 7b R3 =OMe (100%);
8b
(
95%
)
5k 62%
13. H Ph C 7c R3 =CHN2 5k 23%
Recently, a number of 1,5-disubstituted-1,2,3-triazole alcohols containing the sulfonamide group
have been shown to have inhibitory activity for human carbonises I, II, IV and IX.35 The obtained
ketones 3 are easily reduced by sodium borohydride to alcohols 9a-c, which are attractive low
molecular weight compounds for medicinal chemistry (Scheme 3). Ketone 3 can also be converted to
amines 11 via oxime 10 prepared by boiling with hydroxylamine hydrochloride in the presence of an
equivalent amount of NaOH for 1 hour and reduction with aluminium amalgam. It is of note that there
are only a few examples of the preparation of oximes of (5-methyl-1H-1,2,3-triazol-4-yl)ethanone,
which were subsequently used to synthesize compounds for screening for insecticidal and fungicidal
N. Pokhodylo et al. / Current Chemistry Letters 10 (2021)
57
activity.36 The main use of ketones 3 is the synthesis of chalcones 13. The corresponding ketone 3 easy
reacted with aldehyde 12 in the presence of 10% sodium hydroxide solution at room temperature
leading to the formation of chalcones 13a-c in high yield. We found that chalcone 13a selectively
yielded cyclopropane 14 by the Johnson–Corey–Chaykovsky reaction with trimethylsulfoxone iodide.
On the contrary, chalcone 13b containing the phenol moiety gave a complex mixture in the reaction. It
also should be noted that starting ketone 3a does not react with (dimethyloxosulfaniumyl)methanide
generated in situ and the formation of the epoxy ring was not observed. Finally, we tested the Wolff–
Kishner reduction to convert carbonyl into the methylene group. Previously, reduction of the keto group
to methylene was used in 4-benzoyl-1H-1,2,3-triazole for the synthesis of benzyltriazoles, which were
studied as potassium channel activators.37 We used ketone 3a in the same protocol; in our case, the
target 4-ethyl-5-methyl-1-phenyl-1H-1,2,3-triazole was not found.
N
N
N
R2
R1
O
3
R3ON
N
N
Me
O
R3
NaOH
EtOH, H2O
NaOH
EtOH, H2O
[NH3OH]Cl
NaBH4
MeOH/iPrOH
(CH3)3S+O I-
N
N
N
Me
Me
NOH
10 (95%)
Me
Me
N
N
NNH2
11 (79%)
NN
N
O
14 (89%)
R2
N
N
N
R2
R1
OH
9a-c (85-95%)
Me
R2
R1
13a-c (79-88%)
12a-c
9a: R1= H, R2=Me
9b: R1= 3-Cl-4-MeO, R2=Me
9c: R1= H, R2= -(CH2C(CH3)2CH2)2-
13a: R1= H, R3 = Ph; 13b: R1= H, R3 = 2-hydroxyphenyl;
13c: R1= 3-Cl-4-MeO, R3 = 2-styryl
KOH
Al/Hg
Scheme 3.
3. Conclusions
Thus, (1H-1,2,3-triazol-4-yl)acetic acids as attractive building blocks were prepared by the
Willgerodt-Kindler reaction in high yields. The yields were higher than the results obtained by
alternative paths starting from 1Н-1,2,3-triazole-4-carboxylic acids. Furthermore, (5-methyl-1H-1,2,3-
triazol-4-yl)ethanones were shown to be suitable reagents for the synthesis of alcohols, amines and
cyclopropane derivatives, which can be used for the synthesis of drug-like compounds.
Acknowledgements
The authors are grateful to the Ministry of Education and Science of Ukraine for financial support of this
project (Grant No 0118U003610).
4. Experimental
4.1. Instruments
1H and 13C NMR spectra were recorded on Varian Unity Plus 400 (400 and 101 MHz, respectively)
and Bruker 170 Avance 500 (500 and 126 MHz, respectively) spectrometers in DMSO-d6 solutions
using TMS or the deuterated solvent as internal reference. IR spectra were measured using Thermo
Scientific Nicolet iS 10 FT-IR spectrometer. Mass spectral analyses were performed using an Agilent
58
1100 series LC/MSD with API-ES/APCI mode (200 eV). Elemental analyses were accomplished using
a Carlo Erba 1106 instrument. Melting points were determined on a Boetius melting point apparatus.
4.2. Experimental procedure and physical data for compounds
Synthesis of 1-(1-aryl-5-methyl-1,2,3-triazol-4-yl)ethanones 3a-o. To the equimolar mixture of β-
diketone (0.01 mol) and arylazide (0.01 mol) in methanol (10 mL, for diketones 2a-c) or DMSO (5mL;
for diketone 2d) base catalysis (1eq. of Et3N or NaOMe; 2eq. of K2CO3) was added. The mixture was
vigorously stirred at room temperature or under reflux until all starting azide disappeared (monitoring
by TLC). The refluxed mixture was cooled and the resulting crystals were then filtered off and washed
with cold methanol on the filter. In case of K2CO3/DMSO system, the mixture was diluted with 15 mL
of water. The sediment was filtered off. The crude products could be additionally purified by
recrystallization from ethanol to furnish the compound 3 with above 95% purity as a white solid.
1-(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethanone (3a).16 This compound was prepared by the
heating under reflux using Et3N as base catalysis. White crystals, yield 83%.
1-(5-Methyl-1-m-tolyl-1H-1,2,3-triazol-4-yl)ethanone (3b).16 This compound was prepared by the
heating under reflux using Et3N as base catalysis. White crystals, yield 78%.
1-(1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (3c). This compound was prepared
at room temperature using Et3N as base catalysis. White crystals, yield 85%; mp 81–82°C. IR: 1676
(C=O), 1516, 1417, 1282, 1246, 952, 767 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.41 s (3H,
CH3) 2.63 s (3H, CH3CO), 7.50 t (1H, H4Ar, J 7.5 Hz), 7.61 t (1H , H5Ar, J 9.3 Hz), 7.68–7.79 m (2H,
HAr); 13C NMR (101 MHz, DMSO-d6), δ, ppm: 9.73 (CH3), 28.22 (CH3), 117.74 d (CH3Ar, 2JC-F 19.0
Hz), 123.06 d (CH1Ar, 2JC-F = 11.9 Hz), 126.38 (CH5Ar), 129.64 (CH4Ar), 133.83 d (CH6Ar, 3JC-F = 8.0
Hz), 139.74 (C5Triazole), 143.13 (C4Triazole), 156.42 d (C2Ar, 1JC-F 251.7 Hz), 193.80 (C=O); LC-MS (CI),
m/z: 220 [M+H]+; Found,%: C 60.21; H, 4.49; N, 19.11. C11H10FN3O. Calculated,%: C 60.27; H 4.60;
N, 19.17.
1-(1-(4-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (3d).38 This compound was
prepared by the heating under reflux using Et3N as base catalysis. White crystals, yield 92%.
1-(1-(2-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (3e).10 This compound was
prepared at room temperature using Et3N as base catalysis. White crystals, yield 70%.
1-(1-3-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (3f).10 This compound was prepared
at room temperature using MeONa as base catalysis. White crystals, yield 74%.
1-(1-(4-Chlorophenyl) -5-methyl-1H-1,2,3-triazol-4-yl)ethanone (3g).16 This compound was
prepared at room temperature using MeONa as base catalysis. White crystals, yield 77%.
1-(1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (3h).10 This compound was
prepared at room temperature using MeONa as base catalysis. White crystals, yield 81%.
1-(5-Methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)ethanone (3i). This compound
was prepared at room temperature using Et3N as base catalysis. White crystals, yield 89%; mp 45–
46ºС; IR: 1679 (C=O), 1525, 955 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.54 s (3H, CH3),
2.64 s (3H, CH3CO), 7.90 t (1H, H5Ar, J 7.7 Hz), 7.97–8.05 m (2H, HAr), 8.09 s (1H, H2Ar); LC-MS
(CI), m/z: 270 [M+H]+; Found,%: C 53.59; H, 3.72; N, 15.76. C12H10F3N3O. Calculated,%: C 53.54;
H, 3.74; N, 15.61.
1-(1-(2,5-Dichlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (3j).10 This compound was
prepared at room temperature using Et3N as base catalysis. White crystals, yield 72%.
1-(1-(3-Chloro-4-methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (3k). This compound
was prepared at room temperature using MeONa as base catalysis. White crystals, yield 79%; mp 112–
113ºC; IR: 1682 (C=O), 1537, 1275, 952 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.48 s (3H,
CH3), 2.62 s (3H, CH3CO), 3.96 s (3H, CH3O), 7.38 d (1H, H5Ar, J 8.8 Hz), 7.60 d (1H, H6Ar, J 8.5 Hz),
7.80 s (1H, H2Ar); LC-MS (CI), m/z: 266 [M+H]+; Found,%: C 54.00; H, 4.42; N, 16.09. C12H12ClN3O2.
Calculated,%: C 54.25; H, 4.55; N 15.82.
1-(5-tert-Butyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)-2,2-dimethylpropan-1-one (3l). This compound
was prepared by the heating under reflux using MeONa as base catalysis. White crystals, yield 88%;
mp 78–79°C; IR: 1678 (C=O), 1514, 1412, 1210, 945, 820 cm–1; 1H NMR (400 MHz, DMSO-d6), δ,
ppm: 1.14 s (9H, t-Bu), 1.35 s (9H, t-Bu), 2.42 s (3H, CH3), 7.39 d (2H, H3,5Ar, J 7.8 Hz), 7.44 d (2H,
N. Pokhodylo et al. / Current Chemistry Letters 10 (2021)
59
H2,6Ar, J 7.8 Hz); LC-MS (CI), m/z: 300 [M+H]+; Found,%: C 72.12; H, 8.38; N, 13.90. C18H25N3O.
Calculated,%: C 72.21; H, 8.42; N, 14.03.
(1,5-Diphenyl-1H-1,2,3-triazol-4-yl)(phenyl)methanone (3m).17 This compound was prepared by
the heating under reflux using MeONa as base catalysis. White crystals, yield 92%.
Phenyl(5-phenyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)methanone (3n). This compound was prepared by
the heating under reflux using MeONa as base catalysis. White crystals, yield 94%, mp 190–191°C;
IR: 1652 (C=O), 1511, 1446, 1222, 919, 692 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.39 s
(3H, CH3), 7.21 d (2H, H3,5Ar, J 8.8 Hz), 7.25 d (2H, H2,6Ar, J 8.8 Hz), 7.28–7.42 m (5H, HPh), 7.52 t
(2H, H3,5Ph, J 7.6 Hz), 7.63 m (1H, H4Ph), 8.17 d (2H, H2,6Ph, J 7.2 Hz); LC-MS (CI), m/z: 340 [M+H]+;
Found,%: C 77.75; H, 4.96; N, 12.43. C22H17N3O. Calculated,%: C 77.86; H, 5.05; N, 12.38.
6,6-Dimethyl-1-phenyl-6,7-dihydro-1H-benzo[d][1,2,3]triazole-4(5H)-one (3o).33 This compound
was prepared at room temperature using K2CO3 as base catalysis. White crystals, yield 72%; mp 154-
155°C; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 0.98 s (6H, CH3), 2.18 s (1H, CH2), 2.31 m (1H, CH2),
2.99 s (2H, CH2), 7.53–7.92 m (5H, HPh); LC-MS (CI), m/z: 242 [M+H]+; Found,%: C 69.74; H 6.29;
N, 17.47. C14H15N3O. Calculated,%: C 69.69; H 6.27; N, 17.41.
Synthesis of [5-methyl-1-aryl-1H-1,2,3-triazol-4-yl]-1-(morpholin-4-yl)ethanthiones 4a-j
(Wilgerodt-Kindler reaction). The mixture of ketone 3 (0.01 mol), sulphur .64 g (0.02 mol) and amine
(0.02 mol) was heated for 5 h at 135°C (oil bath temperature). The warm mixture was carefully poured
into 50 mL of hot ethanol and triturated for crystallization. The mixture was left overnight in the
refrigerator; the product was filtered off, washed with a little cold ethanol and air-dried.
2-(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-1-morpholinoethane-1-thione (4a).16 Prepared
previously. White solid, yield 78%.
2-(5-Methyl-1-m-tolyl-1H-1,2,3-triazol-4-yl)-1-morpholinoethanethione (4b). White solid, yield
75%; mp 107–108°C; IR: 1462, 1438 (C=S), 1274, 1109, 1030, 785 cm–1; 1H NMR (400 MHz, DMSO-
d6), δ, ppm: 2.34 s (3H, CH3), 2.41 s (3H, CH3), 3.66 s (4H, CH2), 4.06 s (2H, CH2) , 4.22 s (2H, CH2),
4.32 s (2H, CH2), 7.31–7.43 m (3H, HPh), 7.49 t (1H, H5Ph, J 7.5 Hz); LC-MS (CI), m/z: 317 [M+H]+;
Found,%: C 60.77; H 6.30; N, 17.76. C16H20N4OS. Calculated,%: C 60.73; H, 6.37; N, 17.71.
2-(1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-morpholinoethanethione (4c). White
solid, yield 88%; mp 124–125°C; IR: 1441 (C=S), 1265, 1104, 1025 cm–1; 1H NMR (400 MHz, DMSO-
d6), δ, ppm: 2.23 s (3H, CH3), 3.53–3.77 m (4H, CH2), 3.96–4.14 m (2H, CH2), 4.18–4.30 m (2H, CH2),
4.35 s (2H, CH2), 7.46 m (1H, H5Ar, J 7.5 Hz), 7.58 m (1H, H4Ar, J 9.3 Hz), 7.63–7.79 m (2H, HAr); 13C
NMR (101 MHz, DMSO-d6), δ, ppm: 8.72 (CH3), 50.61 (CH2), 51.73 (2xCH2N), 66.43 (CH2O), 66.69
(CH2O), 117.67 d (CH3Ar, 2JC-F 19.3 Hz), 126.29 d (CH6Ar, 3JC-F 2.5 Hz), 129.57 (2xCH4,5Ar), 133.18 d
(C1Ar, 2JC-F 8.0 Hz), 134.04 (C5Triazole), 140.27 (C4Triazole), 156.39 d (CH2Ar, 1JC-F 251.1 Hz), 197.55
(C=S); LC-MS (CI), m/z: 321 [M+H]+; Found,%: C 56.15; H, 5.41; N, 17.44. C15H17FN4OS.
Calculated,%: C 56.23; H 5.35; N, 17.49.
2-(1-(4-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-morpholinoethanethione (4d). White
solid, yield 83%, mp 124–125°C; IR: 1437 (С=S), 1219, 1114, 1031, 886 cm–1; 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 2.33 s (3H, CH3), 3.66 br.s (4H, CH2), 4.06 br.s (2H, CH2), 4.22 br.s (2H, CH2),
4.33 s (2H, CH2), 7.45 t (2H, H3,5Ar, J 8.4 Hz), 7.65 dd (2H, H3,5Ar, J 8.4, 4.8 Hz); LC-MS (CI), m/z:
321 [M+H]+; Found,%: C 56.33; H, 5.39; N, 17.39. C15H17FN4OS. Calculated,%: C 56.23; H 5.35; N,
17.49.
2-(1-(2-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-morpholinoethanethione (4e). White
solid, yield 81%; mp 136–137°C; IR: 1438 (C=S), 1108, 1030, 860 cm–1; 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 2.16 s (3H, CH3), 3.55–3.71 m (4H, CH2), 4.03 br.s (2H, CH2), 4.23 br.s (2H, CH2),
4.36 s (2H, CH2), 7.58-7.71 m (3H, H3,5Ar), 7.79 d (1H, H6Ar, J 7.8 Hz); LC-MS (CI), m/z: 337 [M+H]+;
Found,%: C 53.41; H, 5.13; N, 16.74. C15H17ClN4OS. Calculated,%: C 53.49; H, 5.09; N, 16.63.
2-(1-(3-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-morpholinoethanethione (4f). White
solid, yield 85%; mp 96–97°C; IR: 1432 (C=S), 1111, 1028, 896 cm–1; 1H NMR (400 MHz, DMSO-
d6), δ, ppm: 2.37 s (3H, CH3), 3.66 br.s (4H, CH2), 4.05 br.s (2H, CH2), 4.22 br.s. (2H, CH2), 4.34 s
(2H, CH2), 7.58–7.68 m (3H, HAr), 7.77 s (1H, H2Ar); LC-MS (CI), m/z: 337 [M+H]+; Found,%: C
53.57; H, 5.18; N, 16.52. C15H17ClN4OS. Calculated,%: C 53.49; H, 5.09; N, 16.63.
60
2-(1-(4-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-(4-methylpiperazin-1-yl)ethanedione
(4g). White solid, yield 71%; mp 154–155°C; IR: 1496, 1462 (C=S), 1315, 1047, 1033, 998, 825 cm–
1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.19 (s, 3H), 2.36 s (3H, CH3), 2.38 br.s (4H, CH2), 4.03
br.s (2H, CH2), 4.21 br.s (2H, CH2), 4.32 s (2H, CH2), 7.64 d (2H, H3,5Ar, J 8.3 Hz), 7.68 d (2H, H2,6Ar,
J 7.9 Hz); LC-MS (CI), m/z: 350 [M+H]+; Found,%: C 54.99; H, 5.73; N, 20.14. C16H20ClN5S.
Calculated,%: C 54.92; H, 5.76; N, 20.02.
2-(1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-morpholinoethanethione (4h). White
solid, yield 73%; mp 129–130°C; IR: 1436 (C=S), 1283, 1104, 1032 cm–1; 1H NMR (400 MHz, DMSO-
d6), δ, ppm: 2.30 s (3H, CH3), 3.66 s (4H, CH2), 3.84 s (3H, CH3O), 4.07 br.s ( 2H, CH2), 4.22 br.s (2H,
CH2), 4.32 s (2H, CH2), 7.13 d (2H, H2,6Ar, J 8.7 Hz), 7.49 d (2H, H3,5Ar, J 8.7 Hz); LC-MS (CI), m/z:
333 [M+H]+; Found,%: C 57.91; H 6.15; N, 16.81. C16H20N4O2S. Calculated,%: C 57.81; H, 6.06; N,
16.85.
2-(5-Methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-1-morpholinoethanethione (4i).
White solid, yield 90%; mp 99–100°C; IR: 1433 (C=S), 1195, 1105, 1033 cm–1; 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 2.39 s (3H, CH3), 3.67 br.s (4H, CH2), 4.06 br.s (4H, CH2), 4.22 br.s (2H, CH2),
4.35 s (2H, CH2), 7.87 d (1H, H4Ar, J 7.4 Hz), 7.92–7.99 m (2H, HAr), 8.01 s (1H, H2Ar); LC-MS (CI),
m/z: 371 [M+H]+; Found,%: C 51.79; H, 4.75; N, 15.22. C16H17F3N4OS. Calculated,%: C 51.88; H
4.63; N, 15.13.
2-(1-(2,5-Dichlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl-1-morpholinoethanethionate (4j).
White solid, yield 78%; mp 124–125°C; IR: 1437 (C=S), 1110, 1032, 842, 794 cm–1; 1H NMR (400
MHz, DMSO-d6), δ, ppm: 2.19 s (3H, CH3), 3.53–3.70 (4H, CH2), 4.02 br.s (2H, CH2), 4.22 br.s (2H,
CH2), 4.36 s (2H, CH2), 7.78 dd (1H, H4Ar, J 8.7, 1.7 Hz), 7.84 d (1H, H3Ar, J 8.7 Hz), 7.91 (1H, H6Ar,
J 1.6 Hz); LC-MS (CI), m/z: 371 [M+H]+; Found,%: C 48.59; H, 4.40; N, 15.14. C15H16Cl2N4OS.
Calculated,%: C 48.52; H, 4.34; N, 15.09.
Synthesis of (5-methyl-1-aryl-1H-1,2,3-triazol-4-yl) acetic acids 5 (Method A). The crude
thiomorpholide 4 (0.01 mol) was added to a mixture of KOH solution (8 g of 50% aqueous solution)
and ethanol 14 mL (if the solution is not homogeneous, ethanol is added to complete homogenization).
The mixture was boiled for 6–12 h, then poured into water and acidified. The solution was cooled, the
precipitate formed was filtered off. The acid was recrystallized from aqueous ethanol.
2-(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)acetic acid (5a).16 Prepared previously. White solid,
yield 61%.
2-(5-Methyl-1-m-tolyl-1H-1,2,3-triazol-4-yl)acetic acid (5b). White solid, yield 70%; mp 149–
150°C; IR: 1717 (C=O), 1496, 997 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.25 s (3H, CH3),
2.40 s (3H, CH3), 3.71 s (2H, CH2), 7.34–7.39 m (2H, HAr), 7.40 s (1H, H2Ar), 7.49 t (1H, H5Ar, J 7.6
Hz), 12.55 br.s (1H, COOH). LC-MS (CI), m/z: 232 [M+H]+; Found,%: C 62.41; H, 5.78; N, 18.11.
C12H13N3O2. Calculated,%: C 62.33; H, 5.67; N, 18.17.
2-(1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)acetic acid (5c). White solid, yield 73%; mp
147–148°C; IR: 1715 (C=O), 1496, 1257, 1021 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.15 s
(3H, CH3), 3.75 s (2H, CH2), 7.45 t (1H, H5Ar, J 7.6 Hz), 7.58 t ( 1H, H4Ar, J 9.5 Hz), 7.61– 7.71 m (2H,
H3,6Ar), 12.58 s (1H, COOH); 13C NMR (101 MHz, DMSO-d6), δ, ppm: 8.28 (CH3), 31.59 (CH2),
117.64 d (CH3Ar, 2JC-F 19.3 Hz), 126.27 d (CH6Ar, 3JC-F 3.2) Hz), 129.51 s (2xCH4,5Ar), 133.09 d (C1Ar,
2JC-F 7.9 Hz), 133.95 (C5Triazole), 138.95 (C4Triazole), 156.37 d (CH2Ar, 1JC-F 250.8 Hz), 172.11 (O=C–O);
LC-MS (CI), m/z: 236 [M+H]+; Found,%: C 56.07; H 4.22; N 17.80. C11H10FN3O2. Calculated,%: C
56.17; H 4.29; N, 17.86.
2-(1-(4-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)acetic acid (5d). White solid, yield 79%; mp
159–160°C; IR: 1716 (C=O), 1497, 1221, 1125, 1030 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm:
2.25 s (3H, CH3), 3.71 s (2H, CH2), 7.46 t (2H, H3,5Ar, J 8.6 Hz), 7.66 dd (2H, H3,5Ar, J 8.2, 4.9 Hz),
12.53 s (1H, COOH); LC-MS (CI), m/z: 236 [M+H]+; Found,%: C 56.22; H, 4.34; N, 17.93.
C11H10FN3O2. Calculated,%: C 56.17; H 4.29; N, 17.86.
2-(1-(2-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)acetic acid (5e). White solid, yield 64%; mp
204–205°C; IR: 1717 (C=O), 1496, 1315, 1291, 1158, 1144, 997, 825, 771 cm–1; 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 2.09 s (3H, CH3), s (2H, CH2), 7.56 –7.64 m (2H, H3,4Ar), 7.67 t (1H , H5Ar, J 8.2
N. Pokhodylo et al. / Current Chemistry Letters 10 (2021)
61
Hz,), 7.79 d (1H, H6Ar, J 7.9 Hz), 12.54 s (1H, COOH); LC-MS (CI), m/z: 252 [M+H]+; Found,%: C
52.58 H 4.11; N, 16.74; C11H10ClN3O2. Calculated,%: C 52.50; H 4.01; N, 16.70.
2-(1-(3-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)acetic acid (5f). White solid, yield 72%; mp
171–172°C; IR: 1722 (C=O), 1492, 1012, 885 cm–1; 1H NMR (500 MHz, DMSO-d6), δ, ppm: 2.28 s
(3H, CH3), 3.72 s (2H, CH2), 7.57– 7.69 m (3H, HAr), 7.77 s (1H, H2Ar), 12.57 s (1H, COOH); LC-MS
(CI), m/z: 252 [M+H]+; Found,%: C, 52.43; H, 4.07; Cl, 14.01; N, 16.81. C11H10ClN3O2. Calculated,%:
C, 52.50; H, 4.01; Cl, 14.09; N, 16.70.
2-(1-(4-Chlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)acetic acid (5g).16 Prepared previously.
White solid, yield 74%.
2-(1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)acetic acid (5h). White solid, yield 67%;
mp 199–200°C; IR: 1726 (C=O), 1494, 1281, 1100, 999 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm:
2.22 s (3H, CH3), 3.70 s (2H, CH2), 3.84 s (3H, CH3O), 7.13 d (2H, H3,5Ar, J 8.7 Hz,), 7.49 d (2H, H2,6Ar,
J 8.6 Hz), 12.52 s (1H, COOH); LC-MS (CI), m/z: 248 [M+H]+; Found,%: C 58.24; H, 5.38; N, 16.92.
C12H13N3O3. Calculated,%: C 58.29; H, 5.30; N, 16.99.
2-(5-Methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)acetic acid (5i). White solid, yield
84%; mp 98–99°C; IR: 1727 (C=O), 1499, 1320, 1119, 1068, 830, 799, 699 cm–1; 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 2.32 s (3H, CH3), 3.74 s (2H, CH2), 7.81–7.97 m (3H, H3,5Ar), 7.99 s (1H, H2Ar),
12.51 s (1H, COOH); LC-MS (CI), m/z: 286 [M+H]+; Found,%: C 50.59; H, 3.59; N, 14.71.
C12H10F3N3O2. Calculated,%: C 50.53; H, 3.53; N, 14.73.
2-(1-(2,5-Dichlorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)acetic acid (5j). White solid, yield 69%;
mp 176–177°C; IR: 1719 (C=O), 1496, 996 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.12 s (3H,
CH3), 3.73 s (2H, CH2), 7.78 dd (1H, H4Ar, J 8.3, 1.8 Hz) , 7.84 d (1H, H3Ar, J 8.7 Hz,), 7.90 d (1H,
H6Ar, J 1.8 Hz), 12.54 s (1H, COOH); LC-MS (CI), m/z: 286 [M+H]+; Found,%: C 46.28; H, 3.09; N,
14.75. C11H9Cl2N3O2. Calculated,%: C 46.18; H 3.17; N, 14.69.
N-Isopropyl-5-methyl-N,1-diphenyl-1H-1,2,3-triazole-4-carboxamide (7a). To a cooled to 0°C
solution of the N-isopropylaniline (1.35 g, 10 mmol) and triethylamine (1.4 mL, 10 mmol) in 50 mL of
dioxane with vigorous stirring the 5-methyl-1-phenyl-1H-1,2,3-triazole-4-carbonyl chloride20 (2.21 g,
10 mmol) was added and left for 1 h at room temperature. The mixture was heated under reflux, cooled
and diluted with water (50 mL). The solid amide 7a was washed on filter with saturated NaHCO3 and
ice water. White solid, yield 91%; mp 143–144°C; IR: 1679 cm–1 (C=O); 1H NMR (400 MHz, DMSO-
d6), δ, ppm: 1.20 d (6H, CH3, J 6.7 Hz), 2.42 s (3H, CH3), 4.95–5.09 m (1H, CH), 7.15 d (2H, H2,6Ph, J
8.0 Hz), 7.26–7.38 m (3H, HPh), 7.39–7.51 m (2H, HPh), 7.54–7.60 m (3H, HPh); LC-MS (CI), m/z: 233
[M+H]+; Found,%: C 71.35; H 6.27; N, 17.44. C19H20N4O. Calculated,%: C 71.23; H 6.29; N, 17.49.
Methyl 1,5-diphenyl-1H-1,2,3-triazole-4-carboxylate (7b). The 1,5-diphenyl-1H-1,2,3-triazole-4-
carbonyl chloride (2.84 g, 10 mmol) was added to 25 mL of methanol. The mixture was heated under
reflux for 30 min. The methanol was evaporated yielding ester 7b quantitatively. White solid, mp 154-
155°C; IR: 1716 cm–1 (C=O); 1H NMR (400 MHz, DMSO-d6), δ, ppm: 7.27-7.48 m (10H, HPh), 3.79
s (3H, CH3O); LC-MS (CI), m/z: 280 [M+H]+; Found,%: C, 68.89; H, 4.54; N, 15.14;. C16H13N3O2.
Calculated,%: C, 68.81; H, 4.69; N, 15.05.
(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)methanol (8a). To a cooled to 0°C suspension of NaBH4
(1.4 g, 37.8 mmol) in 250 mL THF iodine (4.4 g, 17.3 mmol) was added portion-wise. The mixture was
maintained for 10 min after iodine was decoloured and the 5-methyl-1-phenyl-1H-1,2,3-triazole-4-
carboxylic acid 6a (2.0 g, 10 mmol) was added in one portion under vigorous stirring and slow heating
to reflux. After heating for 5 h the mixture was cooled to room temperature. The conc. HCl (5 mL) and
water (10 mL) was slowly added. The mixture was refluxed for 15 min and the solvent evaporated
under reduced pressure. To the residue, the 20%-aq. NaOH solution was added to pH~10. Water was
extracted with dichloromethane. The solvent was removed to give pure methanol 8a. White solid, yield
84%; mp 224–225°C; IR: 1283 cm–1 (C–O); 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.31 s (3H, CH3),
4.56 d (2H, CH2, J 5.0 Hz), 5.15 t (1H, OH, J 5.0 Hz). 7.54-7.69 m (5H, HPh); LC-MS (CI), m/z: 190
[M+H]+; Found,%: C 63.40; H 5.96; N, 22.29. C10H11N3O. Calculated,%: C 63.48; H, 5.86; N, 22.21.
(1,5-Diphenyl-1H-1,2,3-triazol-4-yl)methanol (8b). To the solution of methyl 1,5-diphenyl-1H-1,2,3-
triazole-4-carboxylate 7b (1.3 g, 5 mmol) in 25 mL of THF at 0°C with vigorous stirring was added in
62
portions LAH (0.19 g, 0.05 mol) and left overnight. To cooled to 0°C mixture water (0.19 mL), 10%-
aq. NaOH (0.38 mL) and water (0.19 mL) were added dropwise consequently. The mixture was stirred
at room temperature for 15 min and filtered through SiO2. The solvent was evaporated in vacuum
yielding methanol 8b. White solid, yield 95%; mp 128–129°C; 1H NMR (400 MHz, DMSO-d6), δ,
ppm: 4.50 d (2H, CH2, J 5.4 Hz), 5.21 t (1H, OH, J 5.4 Hz), 7.28– 7.36 m (4H, HPh), 7.36–7.42 m (3H,
HPh), 7.43–7.49 m (3H, HPh); LC-MS (CI), m/z: 252 [M+H]+; Found,%: C, 71.77; H, 5.29; N, 16.73.
C15H13N3O. Calculated,%: C, 71.70; H, 5.21; N, 16.72.
This protocol allowed to obtain methanol 8a from acid 6a methyl ester or amide 7a.
Synthesis of (1H-1,2,3-triazol-4-yl)acetic acids 5 (Method B). To the solution of corresponding (1H-
1,2,3-triazol-4-yl)methanol 8 (10 mmol) in methylene chloride (25 mL) and Et3N (2.0 mL, 14 mmol)
at 0°C methane sulfonyl chloride (1.1 mL, 14 mmol) was added dropwise with vigorous stirring. The
reaction was left at room temperature for 10 h. The reaction mixture was washed with water and the
saturated sodium chloride solution. The organic layer was then dried with sodium sulfate and
concentrated to yield methanesulfonate in quantitative yield, which was used without further
purification. To the solution of the methanesulfonate in methanol (25 mL), potassium cyanide (1.3 g,
20 mmol) was added. The mixture was heated and water was added dropwise until all salts dissolved.
The solution was refluxed for 5 h and KOH (1.7 g, 30 mmol) in water (10 mL) was added. The mixture
was additionally refluxed for 3 h. Methanol was removed under reduced pressure and the residue was
dissolved in a minimal quantity of water. The solution was extracted with MTBE and carefully
acidified. The solid acid 5 was separated by filtration.
2-(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)acetic acid 5a. Yield 54%.
2-(1,5-Diphenyl-1H-1,2,3-triazol-4-yl)acetic acid 5k. White solid, yield 62%; mp 224–225°С (dec.);
IR: 1722 (C=O), 1485, 990 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 3.62 s (2H, СН2), 7.22–
7.28 m (2H, НPh), 7.29–7.34 m (2H, НPh), 7.37– 7.42 m (3H, НPh), 7.42– 7.47 м (3H, НPh), 12.59 (s,
1H, СООН); LC-MS (CI), m/z: 280 [М+Н]+. Found,%: C, 68.71; H, 4.74; N, 15.13. C16H13N3O2.
Calculated,%: C, 68.81; H, 4.69; N, 15.05.
2-Diazo-1-(1,5-diphenyl-1H-1,2,3-triazol-4-yl)ethan-1-one 7c. To the vigorously stirred solution of
diazomethane (obtained from 3.8 g nitrosomethylurea and 14 mL 40%-aq. KOH) in MTBE (45 mL) at
-10°C, 1,5-diphenyl-1H-1,2,3-triazole-4-carbonyl chloride (2.8 g, 10 mmol) was added. The mixture
was left overnight and then cooled to -10ºC to filter the formed diazoketone. Light yellow solid, yield
74%; mp 96°C (dec.); IR: 2150 (C=N2), 1661 (C=O), 1504, 1432, 1211cm–1; 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 6.77 s (1H, СНN2). 7.25–7.54 m (10H, НPh); LC-MS (CI), m/z: 261 [М+Н-N2]+;
Found,%: C, 66.47; H, 3.78; N, 24.27. C16H11N5O. Calculated,%: C, 66.43; H, 3.83; N, 24.21.
2-(1,5-Diphenyl-1H-1,2,3-triazol-4-yl)acetic acid 5k (Method C). The diazoketone 7c (1.7 g, 5.6
mmol) dissolved in 15 mL of dioxane and gently heated to 70ºC with vigorous stirring. To the mixture,
15%-aq. solution of AgNO3 (1.5 mL) and 7.5 mL of ammonia solution was added. Rapid gas release
started. The mixture was refluxed for 3 h and the solvent was evaporated. The residue was dissolved in
ethanol (50 mL) and KOH (1.7 g, 30 mmol) was added. The solution was heated under reflux for 5 h.
After ethanol was removed, water (15 mL) was added and the solution was washed with MTBE and
acidified with conc. HCl. The solid acid was separated by filtration, washed with water and diluted
alcohol. Yield 23%.
Synthesis of (5-methyl-1-aryl-1H-1,2,3-triazol-4-yl) ethanols 9a-c. To a solution of the
corresponding (1,2,3-triazol-4-yl)ethanone 3 (4 mmol) in methanol (20 mL), sodium borohydride (0.15
g; 0.04 mol) was carefully added in small portions. The mixture was refluxed for 2 h. Thereafter, 10
mL of isopropanol was added and the mixture was heated for one more hour. The solvent was removed
at reduced pressure. Water (20 mL) was added and solid was filtered off and air-dried. The products
were formed pure and did not require additional crystallization.
1-(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethanol (9a). White solid, yield 89%, mp 117–118°C;
IR: 1476, 1283, 995, 790 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 1.52 d (3H, CH3, J 6.4 Hz),
2.35 s (3H, CH3), 4.91 m (1H, CH), 5.02 d ( 1H, OH, J 3.9 Hz), 7.48–7.63 (m, 5H, HPh); LC-MS (CI),
m/z: 190 [M+H]+; Found,%: C 65.20; H, 6.30; N, 20.51. C11H13N3O. Calculated,%: C 65.01; H, 6.45;
N, 20.68.
N. Pokhodylo et al. / Current Chemistry Letters 10 (2021)
63
1-(1-(3-Chloro-4-methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanol (9b). White solid, yield
93%; mp 135–136°C; IR: 1497, 1293, 1033, 998, 806, 720 cm–1; 1H NMR (400 MHz, DMSO-d6), δ,
ppm: 1.51 s (3H, CH3, J 6.8 Hz), 2.32 s (3H, CH3), 3.98 s (3H, CH3O), 4.89 m (1H, CH), 5.01 d (1H,
OH, J 3.9 Hz), 7.29 d (1H, H5Ar, J 8.7 Hz), 7.45 dd (1H, H6Ar, J 8.7, 2.0 Hz), 7.55 d (1H, H2Ar, J 2.0
Hz); LC-MS (CI), m/z: 268 [M+H]+; Found,%: C 53.68; H, 5.19; N, 15.82. C12H14ClN3O2.
Calculated,%: C 53.84; H, 5.27; N, 15.70.
6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-4-ol (9c). White solid, yield
95%; mp 199–200°C; IR: 1464, 1280, 998 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 0.88 s (3H,
CH3). 1.07 s (3H, CH3), 1.46–1.71 s (1H, CH2), 1.84–1.97 s (1H, CH2), 2.69 s (2H, CH2), 4.56–4.92 m
(1H, CH), 5.40 s (1H, OH), 7.31–7.99 m (5H, HPh); LC-MS (CI), m/z: 244 [M+H]+; Found,%: C 69.03;
H, 7.08; N, 17.21. C14H17N3O. Calculated,%: C 69.11; H, 7.04; N, 17.27.
1-(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethanone oxime (10). To the solution of (1,2,3-triazol-
4-yl)ethanone 3a (2.0 g, 10 mmol) in ethanol (10 mL), solutions of hydroxylamine hydrochloride (0.76
g, 0.011 mol) in water (5 mL) and sodium hydroxide (0.44 g, 0.011 mol) in water (5 mL) were added.
The mixture was refluxed for 2 h. The precipitate was filtered off. White solid, yield 95%; mp 185–
186°C; IR: 1692, 1499, 1418, 1260, 976, 920, 759, 694 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm:
2.29 s (3H, CH3), 2.43 s (3H, CH3), 7.62 br.s (5H, HPh), 11.33 s (1H, OH). 13C NMR (101 MHz, DMSO-
d6), δ, ppm: 11.14 (CH3), 12.65 (CH3), 125.95 (2xCH2,6Ar), 130.31 (2xCH3,5Ar), 130.38 (CH4Ar), 132.16
(C5Triazole), 136.36 (C1Ar), 141.87 (C4Triazole), 149.70 (C=N); LC-MS (CI), m/z: 217 [M+H]+; Found,%:
C 61.06; H, 5.52; N, 25.99. C11H12N4O. Calculated,%: C 61.10; H, 5.59; N, 25.91.
1-(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethanamine (11). The solution of oxime 10 (1.4 g, 6.3
mmol) in tetrahydrofuran (25 mL) was added dropwise to a stirred suspension of the aluminium
amalgam in tetrahydrofuran (15 mL) [prepared according to the following procedure: aluminium
turnings (8.00 g, 0.297 mol) washed (10-15 s) with solution of sodium hydroxide (1M, 10mL) resulting
in the evolution of hydrogen gas and the solution was decanted; the aluminium washed with water (10
mL); an aqueous solution of mercury (II) chloride (0.5%, 5 mL) was then added to aluminium and
allowed to stand for 1-2 min. This procedure was repeated, and the aluminium was washed with water
(10 mL), absolute ethanol (10 mL), and dry TBME (10 mL)]. A few drops of water were carefully
added to the reaction mixture and the reaction was stored keeping temperature below ca. 50°C by
periodically immersing the flask in cool water. After 4 h, the reaction mixture was filtered through SiO2.
The solvent was removed under reduced pressure to yield light yellow viscous oil. Yield 79%; IR: 2930,
1484, 1160, 986 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 1.39 d (3H, CH3, J 6.7 Hz), 1.81 br.s
(2H, NH2), 2.31 s (3H, CH3), 4.14 q (1H, CH, J 6.5 Hz), 7.31–7.70 m (5H, HPh); LC-MS (CI), m/z: 203
[M+H]+. Found%: C 65.39; H 6.93; N 27.76. C11H14N4 Calculated,%: C 65.32; H 6.98; N 27.70.
Synthesis of chalcones 13. The corresponding (1,2,3-triazol-4-yl)ethanone 3 (7.5 mmol) dissolved in
a minimum amount of ethanol was added to 10% solution of sodium hydroxide cooled to 0°C. Next
aldehyde (12, 7.5 mmol) was added dropwise and the reaction mixture was left overnight. The
precipitate was filtered off, washed with water and recrystallized from an ethanol-DMF mixture.
(E)-1-(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-3-phenylprop-2-en-1-one (13a). Prepared
previously.15
(E)-3-(2-Hydroxyphenyl)-1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)prop-2-en-1-one(13b).
White solid, yield 84%; mp 194–195°C; IR: 1664 (C=O), 1611 (C=C), 1493, 1023, 997 cm–1; 1H NMR
(400 MHz, DMSO-d6), δ, ppm: 2.60 s (3H, CH3), 6.90 t (1H, H5Ar, J 7.2 Hz), 6.97 d (1H, H6Ar, J 6.7
Hz) , 7.29 t (1H, H4Ar, J 7.2 Hz), 7.55–7.77 (m, 7H), 8.02–8.18 m (2H), 10.35 s (1H, OH). LC-MS (CI),
m/z: 203 [M+H]+. Found,%: C 70.79; H, 5.10; N, 13.91. C18H15N3O2. Calculated,%: C 70.81; H 4.95;
N, 13.76.
(2E,4E)-1-(1-(3-chloro-4-methoxyphenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-phenylpenta-2,4-
dien-1-one (13c). White solid, yield 88%; mp 154–155°C; IR: 1670 (C=O), 1618, 1608 (C=C), 1499,
1281, 990 cm–1; 1H NMR (400 MHz, DMSO-d6), δ, ppm: 2.56 s (3H, CH3), 3.97 s (3H, CH3O), 7.25 d
(1H, CH =, J 15.5 Hz), 7.32–7.46 m (5H), 7.57 g (1H, CH =, J 14.9 Hz), 7.59–7.74 m (4H), 7.84 s (1H,
H2Ar); LC-MS (CI), m/z: 380 [M+H]+; Found,%: C 66.52; H 4.70; N, 11.01. C21H18ClN3O2.
Calculated,%: C 66.40; H, 4.78; N, 11.06.
64
(5-Methyl-1-phenyl-1H-1,2,3-triazol-4-yl)(2-phenylcyclopropyl)methanone (14). To a KOH
suspension (1.2 g, 20 mmol) in dimethyl sulfoxide (40 mL), trimethylsulfoxonium iodide (5.6 g, 20
mmol) was gradually added and the mixture was stirred for 30 min. Then chalcone (13a, 2.5 g, 10
mmol) was added and the mixture was left for 7 h. Stirred for 1 h at 50°C and then a small amount of
water was added. The solvent was removed in vacuum. The residue was mixed with water and filtered.
The solid was washed with water (100 mL) and the saturated aqueous sodium chloride solution (20
mL) to give the title compound 14. White solid, yield 89%; mp 81–82°C; IR: 1661 (C=O), 1498, 1420,
1092, 1032, 975, 744, 690 cm–1; 1H NMR (500 MHz, DMSO-d6), δ, ppm: 1.65–1.73 td (1H, c-Pr, J 7.5,
4.4 Hz), 1.76–1.83 dt (1H, c-Pr, J 9.8 , 4.7 Hz), 2.55 s (3H, CH3), 2.59–2.66 m (1H, c-Pr), 3.43– 3.51
m (1H, c-Pr), 7.24 t (1H, HPh, J 6.8 Hz), 7.28 d (2H, H2,6Ph, J 7.4 Hz), 7.33 t (2H, H3,5Ph, J 7.3 Hz), 7.61–
7.70 m (5H, HPh); LC-MS (CI), m/z: 304 [M+H]+; Found,%: C 75.29; H, 5.72; N, 13.81. C19H17N3O.
Calculated,%: C 75.23; H, 5.65; N, 13.85.
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