One-pot synthesis of alkyl 3-aryl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanoates

Article abstract of DOI:10.1134/S1070428017050141

Reaction of 3-aryl-2-bromopropanoic acids esters, products of the Meerwein arylation, with sodium azide afforded alkyl 2-azido-3-arylpropanoates. The latter react with ethyl acetoacetate and phenylacetylene to form 1,2,3-triazole derivatives. A one-pot me

Full text of DOI:10.1134/S1070428017050141

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 5, pp. 734–737. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © N.T. Pokhodylo, R.D. Savka, M.D. Obushak, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 5, pp. 723–726.
One-Pot Synthesis of Alkyl
3-Aryl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanoates
N. T. Pokhodylo, R. D. Savka, and M. D. Obushak*
Lviv Ivan Franko National University, ul. Kyryla i Mefodiya 6, Lviv, 79005 Ukraine
*e-mail: obushak@in.lviv.ua
Received March 1, 2017
Abstract—Reaction of 3-aryl-2-bromopropanoic acids esters, products of the Meerwein arylation, with sodium
azide afforded alkyl 2-azido-3-arylpropanoates. The latter react with ethyl acetoacetate and phenylacetylene to
form 1,2,3-triazole derivatives. A one-pot method for the synthesis of 3-aryl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-
propanoic acid esters via a tricomponent reaction of alkyl 2-bromo-3-arylpropanoates, sodium azide, and
phenylacetylene in the presence of CuI was developed.
DOI: 10.1134/S1070428017050141
Many derivatives of 3-aryl-2-(1H-1,2,3-triazol-1-
yl)propanoic acids have practically useful properties:
peptidomimetics with 1,2,3-triazole rings instead of
amide fragments [1], triazole peptides that are analogs
of the Pro-Gly dipeptide [2], multi-sheeted dendrimers
[3], and organic tectones [4]. A fragment of 3-aryl-2-
(1H-1,2,3-triazol-1-yl)propanoic acids is present in the
composition of compounds that are used in the cancer
diagnostics [5], possess the anticancer activity [6], are
inhibitors of histone deacetylase 8 [7], are studied as
antidiabetic drugs [8].
were convenient reagents for the preparation of
thiazoles [15–18], selenazoles [19, 20], and benzo[b]-
thiophenes [21]. In this work we used 3-aryl-2-
bromopropionic acids esters to generate azides and to
use them in cycloaddition reactions, in particular, in
click-reactions without isolation.
Compounds 4a–4e were obtained by the reaction of
arenediazonium bromides 2a–2e with methyl or ethyl
acrylates 3a and 3b in the presence of a CuBr catalyst
[18].
The nucleophilic substitution of bromine by the
azido group in methyl (ethyl) 2-bromo-3-aryl-
propionates 4 proceeds fairly smoothly in MeOH–H2O
or DMSO practically without a side-reaction of
elimination with the formation of cinnamic acids.
Compounds 4a and 4b react with sodium azide to form
azides 5a and 5b in a quantitative yield.
Convenient approaches to the construction of
complex molecules with the 1,2,3-triazole ring
proceeding from more accessible reagents are
multicomponent reactions [9]. One of the strategies for
multicomponent synthesis of 1,2,3-triazole derivatives
is the preparation of the corresponding azides in situ
that further react with an alkyne present in the reactor.
This method makes it possible to carry out the reaction
without isolation of explosive azides. The initial
reagents for the azides generation in situ are often halo
derivatives [10–14].
Azide 5b reacts with ethyl acetoacetate in a K2CO3
–DMSO system to form triazole 6 in a 68 % yield.
Azides 5a and 5b also enter into the copper catalyzed
cycloaddition reaction with phenylacetylene 7. The
reaction proceeds at room temperature, triazoles 8a
and 8b are obtained in a good yield. The reaction
course is significantly affected both by the choice of
and the presence of a tertiary amine in the reaction
medium. In the absence of triethylamine in a THF–
H2O medium, 2 : 1, within 48 h the triazoles 8a and 8b
were obtained in 21 and 29% yields, respectively. At
the use of triethylamine as a cocatalyst as well of
In this paper, we present a convenient method of
the synthesis of 3-aryl-2-(1H-1,2,3-triazol-1-yl)pro-
panoic acids derivatives proceeding from the products
of acrylates bromoarylation with arenediazonium salts
along Meerwein reaction. We showed previously that
the esters of 3-aryl-2-bromopropionic acids obtained
by reacting arenediazonium bromides with acrylates
734

ONE-POT SYNTHESIS OF ALKYL 3-ARYL-2-(4-PHENYL-1H-1,2,3-TRIAZOL-1-YL)...
735
R2
O
R3
O
NH2
O
O
R3
N2
Br
NaNO2
HBr
3a, b
CuBr, Me2CO
R1
R2
Br
R1
1a_1e
R1
2a_2e
4a_4e
O
OEt
N
N
O
O
Me
N
Me
OEt
OEt
K2CO3, DMSO
O
O
Cl
O
R3
NaN3
6
R1
4a, 4b
CH
MeOH, H2O
or DMSO
N3
7
5a, 5b
CuI (10 mol %), Et3N,
Ph
THF or t-BuOH, H2O
N
N
N
NaN3
R1
4a_4e
+
CH
O
R3
CuI (10 mol %), Et3N,
R2
8a_8e
t-BuOH, H2O
O
7
R1 = 3-Me, R2 = H, R3 = Et (а); R1 = 2-Cl, R2 = H, R3 = Et (b); R1 = 4-Br, R2 = H, R3 = Et (c);
R1 = 3,4-Cl2, R2 = H, R3 = Me (d); R1 = 3-CF3, R2 = Me, R3 = Me (e).
anhydrous THF we managed to increase the yields of
EXPERIMENTAL
compounds 8a and 8b to 61 and 70%. A similar result
was obtained by carrying out the reaction in t-BuOH–
H2O system, 1 : 1 or 2 : 1. The ratio of solvents was
selected for each azide separately, depending on its
solubility. In tert-butanol the reaction proceeds four
times faster than in tetrahydrofuran: the total
conversion of the initial reagents is achieved after
12 hours, and with THF the reaction completes in
48 hours.
1Н NMR spectra were registered on spectrometers
Varian UnityPlus 400 and Bruker Avance 500 at ope-
rating frequencies of 400 and 500 MHz, respectively,
internal reference TMS. Elemental analysis was per-
formed on an analyzer Carlo Erba 1106. Melting
points were measured on a Boetius apparatus. Com-
pounds 4a–4e were obtained by procedures [15, 16].
Ethyl 2-azido-3-arylpropanoates 5a and 5b. To a
solution of 0.01 mol of an appropriate ethyl 2-bromo-
3-arylpropanoate 4a and 4b in 12 mL of methanol was
added 2 mL of water and 0.78 g (0.012 mol) of sodium
azide. The mixture was stirred for 2 h at 50–60 °C.
Methanol was distilled off in a vacuum, and 30 mL of
water was added to the residue. The azide was
extracted with methylene chloride (2 × 15 mL), the
extract was dried with Na2SO4. The solvent was
distilled off in a vacuum to give the azide, which was
used without further purification.
We also developed a multi-component click-
reaction based on alkyl 2-bromo-3-aryl-propionates 4.
The reaction of compounds 4 with sodium azide within
12 hours at room temperature in the presence of
phenylacetylene 7, CuI, and triethylamine in t-BuOH–
H2O, 2 : 1, leads to the formation of triazoles 8a–8e in
~ 70% yields.
Hence, we developed an effective one-pot method
of the synthesis of alkyl 3-aryl-2-(4-phenyl-1,2,3-
triazol-1-yl)propanoates by the tricomponent reaction
of alkyl 2-bromo-3-arylpropionates, sodium azide, and
phenylacetylene under mild conditions.
Ethyl 2-azido-3-(meta-tolyl)propanoate (5a).
Yield 2.21 g (95%). Viscous liquid. 1H NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

POKHODYLO et al.
736
(500 MHz, CDCl3), δ, ppm: 1.30 t (3H, СH3CH2, J
7.1 Hz), 2.37 s (3H, СН3), 3.00 d.d (1H, CН2, J 8.8,
13.8 Hz), 3.17 d.d (1H, CН2, J 5.3, 13.8 Hz), 4.06 d.d
(1H, CH, J 5.3, 8.8 Hz), 4.26 q (2H, CH3CН2, J
7.0 Hz), 7.04–7.17 m (3Harom), 7.24 t (1H, H5arom, J
7.3 Hz). Found, %: C 61.64; H 6.34; N 18.17.
C12H15N3O2. Calculated, %: C 61.79; H 6.48; N 18.01.
4e, 0.08 g (1.2 mmol) of sodium azide, and 0.11 mL
(1 mmol) of phenylacetylene 7 was dissolved. To the
solution, water was added dropwise until the emulsion
was formed, 0.4 mL of triethylamine and 0.05 g of CuI
was added. The mixture was stirred for 12 hours at
room temperature, 15 mL of water and 5 mL of con-
centrated ammonia solution was added. The product
was extracted with methylene chloride (3 × 10 mL),
the extract was dried with Na2SO4 and evaporated, the
residue was recrystallized from ethanol if necessary.
Ethyl 2-azido-3-(2-chlorophenyl)propanoate
1
(5b). Yield 2.45 g (97%). Viscous liquid. H NMR
spectrum (500 MHz, CDCl3), δ, ppm: 1.29 t (3H,
СH3CH2, J 7.1 Hz), 3.11 d.d (1H, CН2, J 9.0, 13.6 Hz),
3.38 d.d (1H, CН2, J 5.5, 13.7 Hz), 4.18–4.30 m (3H,
CH + CH3CН2), 7.23–7.33 m (3Нarom), 7.37–7.42 m
(1Нarom). Found, %: C 52.14; H 4.91; N 16.45.
C11H12ClN3O2. Calculated, %: C 52.08; H 4.77;
N16.56.
Ethyl (meta-tolyl)-2-(4-phenyl-1H-1,2,3-triazol-
1-yl)propanoate (8a). Yield 0.23 g (69%), mp 96–
1
97°С. H NMR spectrum (400 MHz, DMSO-d6 +
CCl4), δ, ppm: 1.17 t (3Н, СH3CH2, J 7.1 Hz), 2.21 s
(3H, СН3), 3.47 d.d (1Н, CH2, J 6.0, 14.3 Hz), 3.59 d.d
(1Н, CH2, J 5.7, 14.2 Hz), 4.19 q (2Н, CH3CH2, J
7.0 Hz), 5.83 d.d (1Н, CH, J 5.8, 6.0 Hz), 6.99–7.10 m
(4Harom), 7.34 t (1Нarom, J 7.3 Hz), 7.45 t (2Нarom, J
7.5 Hz), 7.82 d (2Н, HP2,h6, J 7.4 Hz), 8.69 s (1Htriazole).
Found, %: C 71.85; H 6.09; N 12.44. C20H21N3O2.
Calculated, %: C 71.62; H 6.31; N 12.53.
Ethyl [3-(2-chlorophenyl)-1-ethoxycarbonyl-
ethyl]-5-methyl-1H-1,2,3-triazole-4-carboxylate (6).
To a solution of 1.25 g (5 mmol) of azide and 0.64 mL
(5 mmol) of ethyl acetocetate in 5 mL of DMSO at
vigorous stirring was added 5 g of K2CO3 and the
mixture was stirred for 48 hours at room temperature.
The reaction mixture was diluted with water, extracted
with the methylene chloride. The solvent was distilled
off in a vacuum. Yield 1.24 g (68%). Viscous liquid. 1H
NMR spectrum (500 MHz, CDCl3), δ, ppm: 1.23 t (3H,
СH3CH2, J 7.1 Hz), 1.40 t (3Н, СH3CH2, J 7.1 Hz),
2.25 s (3Н, СН3), 3.69 t (1Н, CН2, J 11.0 Hz), 3.97 d.d
(1Н, CН2, J 4.5, 14.1 Hz), 4.25 q (2Н, CH3CН2, J
7.1 Hz), 4.39 q (2Н, CH3CН2, J 7.1 Hz), 5.36 d.d (1Н,
CH, J 4.6, 10.7 Hz), 6.92 d (1Н, H6arom, J 7.5 Hz), 7.03
t (1Н, H5arom, J 7.5 Hz), 7.16 t (1Н, H4arom, J 7.5 Hz),
7.34 d (1Н, H3arom, J 7.5 Hz). Found, %: C 55.61; H
5.34; N 19.59. C17H20ClN3O4. Calculated, %: C 55.82;
H 5.51; N 11.49.
Ethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)-3-(2-
chlorophenyl)propanoate (8b). Yield 0.23 g (65%),
1
mp 99–100°С. H NMR spectrum (500 MHz, DMSO-
d6), δ, ppm: 1.18 t (3Н, СH3CH2, J 7.1 Hz), 3.62 d.d
(1Н, CH2, J 5.9, 14.1 Hz), 3.80 d.d (1Н, CH2, J 6.0,
14.0 Hz), 4.21 q (2Н, CH3CH2, J 7.0 Hz), 5.88 d.d
(1Н, CH, J 5.9, 6.0 Hz), 7.19–7.46 m (7Нarom), 7.84 d
(2Н, HP2,h6, J 7.4 Hz), 8.81 s (1Htriazole). Found, %: C
63.93; H 4.95; N 11.93. C19H18ClN3O2. Calculated, %:
C 64.13; H 5.10; N 11.81.
Ethyl 3-(4-bromophenyl)-2-(4-phenyl-1H-1,2,3-
triazol-1-yl)propanoate (8c). Yield 0.28 g (70%) mp
89–90°С. 1H NMR spectrum (500 MHz, DMSO-d6), δ,
ppm: 1.18 t (3Н, СH3CH2, J 7.1 Hz), 3.54 d.d (1Н,
CH2, J 6.1, 14.5 Hz), 3.62 d.d (1Н, CH2, J 5.5,
14.0 Hz), 4.20 q (2Н, CH3CH2, J 7.0 Hz), 5.91 d.d
Triazoles (8a and 8b). An appropriate azide 5a and
5b (1 mmol) and 0.11 mL (1 mmol) of phenyl-
acetylene 7 were dissolved in 5 mL of tert-butanol. To
the solution water was added dropwise until an
emulsion formed, after that 0.4 mL (2.8 mmol) of
triethylamine and 0.05 g of CuI were added. The
mixture was stirred for 12 hours at room temperature,
15 mL of water and 5 mL of concentrated ammonia
solution were added. The product was extracted with
methylene chloride (3 × 10 mL), the extract was dried
with Na2SO4 and evaporated. If necessary, the product
was recrystallized from ethanol.
(1Н, CH, J 5.5, 6.0 Hz), 7.20 d (2Н, HA2,r6, J 8.5 Hz),
3,5
7.35 t (1Н, Н4Ph, J 7.5 Hz), 7.43–7.48 m (4Н, H
+
A r
HP3,h5), 7.84 d (2Н, H , J 7.5 Hz), 8.76 s(1Htriazole).
2,6
P h
Found, %: C 57.20; H 4.40; N 10.59. C19H18BrN3O2.
Calculated, %: C 57.01; H 4.53; N 10.50.
Methyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)-3-(3,4-
dichlorophenyl)propanoate (8d). Yield: 0.27 g
1
(72%), mp 102–103°С. H NMR spectrum (400 MHz,
DMSO-d6 + CCl4), δ, ppm: 3.50–3.61 m (1H, CH2),
3.66 d.d (1H, CH2, J 4.8, 14.3 Hz), 3.74 s (3H, СН3),
5.99 d.d (1H, CH, J 5.0, 6.0 Hz), 7.18 d (1Harom, J
7.5 Hz), 7.35 d (1Harom, J 7.2 Hz), 7.39–7.50 m
Triazoles (8a–8e). In 5 mL of t-butanol 1 mmol of
the corresponding alkyl 2-bromo-3-arylpropanoate 4a–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

ONE-POT SYNTHESIS OF ALKYL 3-ARYL-2-(4-PHENYL-1H-1,2,3-TRIAZOL-1-YL)...
737
Beeler, A.B., ACS Med. Chem. Lett., 2016, vol. 7,
p. 929.
(3Harom), 7.55 с (1Harom), 7.82 d (2Harom, J 7.1 Hz),
8.72 s (1H, Htriazole). Found, %: C 57.65; H 4.13; N
10.95. C18H15Cl2N3O2. Calculated, %: C 57.46; H 4.02;
N 11.17.
8. Casimiro-Garcia, A., Bigge, C.F., Davis, J.A., Padali-
no, T., Pulaski, J., Ohren, J.F., McConnell, P.,
Kane, C.D., Royer, L.J., Stevens, K.A., Auerbach, B.,
Collard, W., McGregor, C., and Song, K., Bioorg. Med.
Chem., 2009, vol. 17, p. 7113.
Methyl 2-methyl-3-(3-trifluoromethylphenyl)-2-
(4-phenyl-1H-1,2,3-triazol-1-yl)propanoate (8e).
Yield 0.23 g (59%), mp 107–108°С. 1H NMR
spectrum (500 MHz, DMSO-d6), δ, ppm: 1.79 s (3H,
СН3), 3.55 d (1H, CH2, J 13.7 Hz), 3.77 d (1H, CH2, J
13.7 Hz), 3.77 s (3H, СН3), 7.17 s (1H, Н2arom), 7.26 d
(1Harom, J 7.4 Hz), 7.35 t (1H, Н5arom, J 7.4 Hz), 7.43–
7.64 m (5Harom), 7.86 d (1Harom, J 7.4 Hz), 8.72 s (1H,
9. Pokhodylo, N.T., Top. Heterocycl. Chem., 2015, vol. 40,
p. 269.
10. Chittaboina, S., Xie, F., and Wang, Q.,
Tetrahedron Lett., 2005, vol. 46, p. 2331. doi 10.1016/
j.tetlet.2005.01.175
11. Sharpless, W.D., Wu, P., Hansen, T.V., and Lindberg, J.G.,
J. Chem. Educ., 2005, vol. 82, p. 1833.
Htriazole). Found, %: C 61.50; H 4.43; N 10.65.
12. Kacprzak, K., Synlett., 2005, p. 943. doi 10.1055/
C20H18F3N3O2. Calculated, %: C 61.69; H 4.66; N
10.79.
s-2005-864809
13. Molander, G.A. and Ham, J., Org. Lett., 2006, vol. 8,
p. 2767.
REFERENCES
14. Odlo, K., Hiydahl, E.A., and Hansen, T.V.,
Tetrahedron Lett., 2007, vol. 48, p. 2097. doi
10.1016/j.tetlet.2007.01.130
1. Angelo, N.G. and Arora, P.S., J. Am. Chem. Soc., 2005,
vol. 127, p. 17134.
15. Obushak, N.D., Matiichuk, V.S., and Ganushchak, N.I.,
2. Paul, A., Bittermann, H., and Gmeiner, P., Tetrahedron,
Russ. J. Org. Chem., 1998, vol. 34, p. 239.
2006, vol. 62, p. 8919.
16. Obushak, N.D., Matiichuk, V.S., Ganushchak, N.I., and
Burlak, Yu.E., Chem. Heterocycl. Compd., 1998,
vol. 34, p. 492. doi 10.1007/BF02290893
3. Rijkers, D.T.S., Van Esse, G.W., Merkx, R.,
Brouwer, A.J., Jacobs, H.J.F., Pieters, R.J., and
Liskamp, R.M.J., Chem. Commun., 2005, p. 4581.
17. Tsyalkovsky, V.M., Kutsyk, R.V., Matiychuk, V.S.,
Obushak, N.D., and Klyufinskaya, T.I., Pharm. Chem. J.,
2005, vol. 39, p. 245. doi 10.1007/s11094-005-0126-8
4. Plietzsch, O., Schilling, C.I., Tolev, M., Nieger, M.,
Richert, C., Muller, T., and Braese, S., Org. Biomol.
Chem., 2009, vol. 7, p. 4734.
18. Matiichuk, V.S., Obushak, N.D., and Tsyalkovskii, V.M.,
Russ. J. Org. Chem., 2005, vol. 41, p. 1050. doi
10.1007/s11178-005-0292-x
19. Obushak, M.D., Matiychuk, V.S., Tsyalkovsky, V.M.,
and Voloshchuk, R.M., Phosph., Sulfur, Silicon, 2004,
vol. 179, p. 107.
5. Kolb, H.C., Walsh, J.C., Kasi, D., Mocharla, V.,
Wang, B., Gangadharmath, U.B., Duclos, B.A.,
Chen, K., Zhang, W., Chen, G., Padgett, H.C.,
Karimi, F., Scott, P.J.H., Gao, Z., Liang, Q., Collier, T.L.,
Zhao, T., and Xia, C., WO Patent Appl.
no. 2008124703, 2008.
20. Matiichuk, V.S., Obushak, N.D., and Tsyalkovskii, V.M.,
Chem. Heterocycl. Compd., 2003, vol. 39, p. 972. doi
10.1023/A:1026119009906
21. Obushak, N.D., Matiichuk, V.S., and Martyak, R.L.,
Chem. Heterocycl. Compd., 2003, vol. 39, p. 878. doi
10.1023/A:1026190103546
6. Geurink, P.P., Liu, N., Spaans, M.P., Downey, S.L.,
van den Nieuwendijk, A.M.C.H., van der Marel, G.A.,
Kisselev, A.F., Florea, B.I., and Overkleeft, H.S.,
J. Med. Chem., 2010, vol. 53, p. 2319.
7. Ingham, O.J., Paranal, R.M., Smith, W.B., Escobar, R.A.,
Yueh, H., Snyder, T., Porco, J.A., Bradner, J.E., and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017