Sonochemistry in organocatalytic enamine-azide [3+2] cycloadditions: A rapid alternative for the synthesis of 1,2,3-triazoyl carboxamides

Article abstract of DOI:10.1016/j.ultsonch.2016.05.007

We described herein the use of sonochemistry in the organocatalytic enamine-azide [3+2] cycloadditions of β-oxo-amides with a range of substituted aryl azides. These sonochemical promoted reactions were found to be amenable to a range of β-oxo amides or a

Full text of DOI:10.1016/j.ultsonch.2016.05.007

Accepted Manuscript
Short communication
Sonochemistry in organocatalytic enamine-azide [3+2] cycloadditions: A rapid
alternative for the synthesis of 1,2,3-triazoyl carboxamides
Daiane M. Xavier, Bruna S. Goldani, Natália Seus, Raquel G. Jacob, Thiago
Barcellos, Márcio W. Paixão, Rafael Luque, Diego Alves
PII:
S1350-4177(16)30149-3
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2016.05.007
ULTSON 3216
Reference:
Ultrasonics Sonochemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 February 2016
4 May 2016
5 May 2016
Please cite this article as: D.M. Xavier, B.S. Goldani, N. Seus, R.G. Jacob, T. Barcellos, M.W. Paixão, R. Luque,
D. Alves, Sonochemistry in organocatalytic enamine-azide [3+2] cycloadditions: A rapid alternative for the
synthesis of 1,2,3-triazoyl carboxamides, Ultrasonics Sonochemistry (2016), doi: http://dx.doi.org/10.1016/
j.ultsonch.2016.05.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Sonochemistry in organocatalytic enamine-azide [3+2]
cycloadditions: A rapid alternative for the synthesis of 1,2,3-
triazoyl carboxamides.
Daiane M. Xaviera, Bruna S. Goldania, Natália Seusa, Raquel G. Jacoba, Thiago Barcellosb,
Márcio W. Paixãoc, Rafael Luqued and Diego Alvesa,*
a Laboratório de Síntese Orgânica Limpa - LASOL - Universidade Federal de Pelotas - UFPel - P.O. Box 354,
96010-900, Pelotas - RS, Brazil.
b Laboratory of Biotechnology of Natural and Synthetic Products, Universidade de Caxias do Sul, Caxias do
Sul - RS, Brazil.
c Laboratório de Síntese de Produtos Naturais, Universidade Federal de São Carlos, São Carlos - SP, Brazil.
d Departamento de Quimica Organica, Universidad de Cordoba, Campus de Rabanales, Cordoba, Spain.
* corresponding author. Tel: +55 (53) 3275-7533.
E-mail adresses: daianedamotta@yahoo.com.br (D.M. Xavier), goldanibruna@gmail.com (B.S. Goldani),
natyseus@gmail.com (N. Seus), raquel.jacob@ufpel.edu.br (R.G. Jacob), tbsilva6@ucs.br (T.B. Silva),
mwpaixao@ufscar.br (M.W. Paixão), q62alsor@uco.es (R. Luque) and diego.alves@ufpel.edu.br (D. Alves).
Abstract: We described herein the use of sonochemistry in the organocatalytic
enamine-azide [3+2] cycloadditions of !-oxo-amides with a range of substituted
aryl azides. These sonochemical promoted reactions were found to be amenable
to a range of !-oxo amides or aryl azides, providing and efficient access to new N-
aryl-1,2,3-triazoyl carboxamides in good to excellent yields and short times of
reaction.
Keywords: sonochemistry; cycloadditions; organocatalysis; 1,2,3-triazoles;
carboxamides.

1. Introduction
Heterocycles represent one of the most general structural units found in
several natural and synthetic bioactive compounds [1,2]. Particularly, 1,2,3-
triazoles comprise an interesting class of nitrogen-based heterocycles widely used
in the discovery and modulation of drug candidates and in new materials [3].
Therefore, several methodologies have been already reported for the preparation
of these scaffolds, especially via thermal 1,3-dipolar cycloaddition of azides with
alkynes [4] as well as copper or ruthenium catalyzed reactions [5-11]. In view of
the restricted applications of metal-based methodologies in chemical biology [12-
18], recent studies have been directed towards the development of metal-free
methodologies for the synthesis of 1,2,3-triazole [19-20]. In this regard,
organocatalytic approaches employing carbonyl compounds have been reported
to promote the synthesis of highly functionalized 1,2,3-triazoles [21-23]. In these
organocatalyzed [3+2] cycloadditions reactions, the generated enamines or
enolates might act as the dipolarophile partner in the 1,3-dipolar cycloadditions
with organic azides [21].
In the context of functionalized nitrogen compounds, !-oxo-amides and their
derivatives exhibit attractive structural features as versatile organic intermediates.
A large number of molecules containing these units display biological activities
[24-26] and can be found in natural products [27-29] (Figure 1).
ꢀ
Figure 1. ꢁ:ꢂ%`:Cꢀ]`QR%HꢂꢃꢀHQJꢂ:1J1J$ꢀꢄRQ6Qꢀ:I1RVꢃ.
Consequently, intensive research efforts based on the use of !-oxo-amides
have been reported for the synthesis of a plethora of heterocycles [30-36]

including 1,2,3-triazoyl-carboxamides [37-40]. As example, 1,2,3-triazole-4-
carboxamide derivatives strongly inhibited the replication of various H3N2 and
H1N1 influenza A virus strains [38]. Recently, our research group described in two
independent works the synthesis of a range of 1,2,3-triazoyl-carboxamides by the
organocatalytic enamine-azide cycloaddition of !-oxo-amides with 4-azido-7-
chloroquinoline [39] or azidophenyl arylselenides [40]. Cycloaddition products
were obtained in good to excellent yields and tolerated a series of substituted !-
oxo-amides. Based on these premises, it is evident that the design of efficient
methods using suitable, environmentally sound, cheap and high functionalized
substrates and reaction conditions for the preparation of functionalized 1,2,3-
triazoles still remains a challenge in modern Organic Synthesis.
In this sense, ultrasonic irradiation has gained popularity in the past
decades as a versatile tool in a large variety of industrial and academic
applications.[41-46]. The use of sonication as a tool in promoting organic synthesis
(sonochemistry) is well documented [45-46]. This non-conventional energy source
has been proved to be able to accelerate reactions or even to switch product
profiles and selectivities through the formation of new reactive intermediates and
compounds not usually observed under classical thermal conditions [45]. In
addition, chemistries under ultrasound irradiation can be considered
environmentally benign processes, being less energy intensive and generating
reduced quantities of side products [41-46].
Despite the large interest in the synthesis of 1,2,3-triazoles, there are only a
few contributions describing the use of sonochemistry for the preparation of such
heterocycles [47-55]. As example, Chen and co-workers described the use of
sonochemistry in the synthesis of chrysin derivatives linked with 1,2,3-triazoles by
1,3-dipolar cycloadditions. In this study, the reaction rate was significantly
accelerated under ultrasound-assisted irradiation and the corresponding products
were obtained in high yields [55].
To the best of our knowledge, the use of sonochemistry to synthesize highly
functionalized 1,2,3-triazoles via organocatalytic enamine-azide cycloaddition with
organic azides has not been explored to date. In addition, the substrate scope for
the organocatalytic synthesis of 1,2,3-triazoyl-4-carboxamides is restricted to
azidophenyl arylselenides and 4-azido-7-chloroquinoline. Therefore, our continued
interest in the synthesis of functionalized 1,2,3-triazoles, led to report herein the
use of sonochemistry in the organocatalyzed synthesis of novel N-aryl-1,2,3-

triazoyl carboxamides by reactions of !-oxo-amides with a range of substituted
aryl azides (Scheme 1).
ꢀ
Scheme 1. Synthesis of novel N-aryl-1,2,3-triazoyl carboxamides using ultrasonic irradiation.
2. Experimental
2.1. General procedure for the synthesis of N-aryl-1,2,3-triazoyl
carboxamides 3a-r under ultrasound irradiation
!-Oxo amides 1a-j (0.3 mmol), aryl azides 2a-i (0.3 mmol), Et2NH (5 mol %) and
DMSO (0.6 mL) were added to a glass tube. The ultrasound probe was placed in a
glass vial containing the reaction mixture. The amplitude of the ultrasound waves
was fixed in 40%. Then, the homogeneous reaction mixture was sonicated for 15
min. The crude product obtained was subsequently purified by column
chromatography on silica gel using a mixture of hexane/ethyl acetate (5:1) as
eluent to afford the desired products 3a-r.
5-methyl-N,1-diphenyl-1H-1,2,3-triazole-4-carboxamide [37] (3a): Yield: 0.079 g
(95%); White solid; mp 134-135 °C. 1H NMR (DMSO-d6, 400 MHz) ꢀ = 9.61 (s,
1H), 7.03 (d, J = 8.1 Hz, 2H), 6.87-6.77 (m, 5H), 6.51 (t, J = 7.6 Hz, 2H), 6.26 (t, J
= 7.6 Hz, 1H), 2.52 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) ꢀ = 159.37, 138.48,
138.18, 137.49, 135.18, 129.94, 129.60, 128.44, 125.33, 123.59, 120.33, 9.34. MS
m/z (relative intensity): 279 (9), 278 (M+, 52), 180 (5), 158 (47), 145 (7), 130 (39),
118 (29), 104 (16), 77 (100), 65 (12), 51 (26), 43 (6). HRMS calcd. for C16H15N4O:
[M + H]+ 279.1246. Found: 279.1243.
5-methyl-1-phenyl-N-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide [37] (3b): Yield:
1
0.080 g (92%); White solid; mp 133-134 °C. H NMR (DMSO-d6, 400 MHz) ꢀ =
9.88 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.24-7.21 (m, 5H), 6.72 (d, J = 8.4 Hz, 2H),
2.88 (s,3H), 2.15 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) ꢀ = 159.12, 138.19,
137.23, 135.89, 135.15, 132.48, 129.81, 129.50, 128.75, 125.23, 120.24, 20.27,
9.23. MS m/z (relative intensity): 292 (M+, 72), 221 (10), 158 (33), 147 (16), 130

(42), 119 (56), 118 (38), 104 (20), 93 (11), 77 (100), 51 (22). HRMS calcd. for
C17H17N4O: [M + H]+ 293.1402. Found: 293.1391.
N-(4-methoxyphenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamide [37]
1
(3c): Yield: 0.087 g (94%); Beige solid; mp 148-150 °C. H NMR (CDCl3, 400
MHz) ꢀ = 8.95 (s, 1H), 7.61-7.55 (m, 5H), 7.47-7.45 (m, 2H), 6.91 (d, J = 9.0 Hz,
2H), 3.80 (s, 3H), 2.65 (s, 3H). 13C NMR (CDCl3, 100 MHz) ꢀ = 159.08, 156.65,
138.75, 137.13, 135.75, 130.98, 129.96, 129.63, 125.29, 121.64, 114.38, 55.51,
9.67. MS m/z (relative intensity): 308 (M+, 75), 237 (14), 158 (18), 147 (29), 130
(46), 119 (97), 118 (38), 108 (13), 104 (33), 95 (16), 81 (20), 77 (100), 69 (31), 57
(18), 51 (22), 41 (16). HRMS calcd. for C17H17N4O2: [M + H]+ 309.1352. Found:
309.1347.
5-methyl-1-phenyl-N-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide [37] (3d): Yield:
1
0.081 g (93%); Yellow solid; mp 99-101 °C. H NMR (CDCl3, 400 MHz) ꢀ = 9.02
(s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.60-7.53 (m, 3H), 7.48-7.46 (m, 2H), 7.27-7.22
13
(m, 2H), 7.09 (t, J = 7.4 Hz, 1H), 2.66 (s, 3H), 2.41(s, 3H). C NMR (CDCl3, 100
MHz) ꢀ = 159.11, 138.71, 137.17, 135.51, 135.48, 130.39, 129.91, 129.57, 128.44,
126.63, 125.13, 124.70, 121.99, 17.60, 9.68. MS m/z (relative intensity): 292 (M+,
17), 277 (17), 264 (80), 235 (7), 158 (35), 144 (17), 130 (43), 118 (44), 104 (19),
103 (11), 93 (15), 77 (100), 65 (7), 51 (22). HRMS calcd. for C17H17N4O: [M + H]+
293.1402. Found: 293.1398.
N-(2-methoxyphenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamide [37]
1
(3e): Yield: 0.087 g (94%); White solid; mp 173-174 °C. H NMR (DMSO-d6, 400
MHz) ꢀ = 9.18 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.29-7.23 (m, 5H), 6.73-6.72 (m,
13
2H), 6.62-6.57 (m, 1H), 3.55 (s, 3H), 2.20 (s, 3H). C NMR (DMSO-d6, 100 MHz)
ꢀ = 158.26, 148.28, 137.71, 137.22, 134.98, 129.78, 129.40, 126.74, 125.09,
123.89, 120.34, 119.29, 110.87, 55.84, 8.99. MS m/z (relative intensity): 308 (M+,
12), 277 (100), 158 (22), 130 (28), 118 (23), 104 (11), 77 (61), 65 (8), 51 (14).
HRMS calcd. for C17H17N4O2: [M + H]+ 309.1352. Found: 309.1344.
N-(2-chlorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamide
[37]
(3f): Yield: 0.080 g (86%); Yellow solid; mp 117-118 °C. 1H NMR (CDCl3, 400
MHz) ꢀ = 9.67 (s, 1H), 8.53 (dd, J = 8.2 and 1.5 Hz, 1H), 7.60-7.55 (m, 3H), 7.49-

7.44 (m, 2H), 7.42 (dd, J = 8.2 and 1.5 Hz, 1H), 7.31 (dt, J = 7.8 and 1.4 Hz, 1H),
7.07 (dt, J = 7.8 and 1.4 Hz, 1H), 2.67 (s, 3H). 13C NMR (CDCl3, 100 MHz) ꢀ =
159.20, 138.47, 137.46, 135.44, 134.54, 129.99, 129.62, 129.15, 127.51, 125.16,
124.55, 123.31, 121.28, 9.74. MS m/z (relative intensity): 312 (M+, 4), 277 (100),
158 (33), 130 (37), 118 (22), 104 (10), 77 (76), 65 (5), 51 (19). HRMS calcd. for
C16H14ClN4O: [M + H]+ 313.0853. Found: 313.0851.
N-(4-chlorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamide
[37]
1
(3g): Yield: 0.079 g (84%); White solid; mp 165-166 °C. H NMR (CDCl3, 400
MHz) ꢀ = 9.09 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.58-7.56 (m, 3H), 7.47-7.45 (m,
2H), 7.31 (d, J = 8.8 Hz, 2H), 2.65 (s, 3H). 13C NMR (CDCl3, 100 MHz) ꢀ = 159.11,
138.31, 137.42, 136.28, 135.43, 130.01, 129.61, 129.15, 128.95, 125.17, 120.97,
9.68. MS m/z (relative intensity): 314 (17), 312 (M+, 49), 192 (5), 158 (45), 147
(15), 130 (49),119 (56), 104 (19), 93 (19), 77 (100), 51 (25). HRMS calcd. for
C16H14ClN4O: [M + H]+ 313.0853. Found: 313.0850.
N-(4-fluorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamide (3h):
1
Yield: 0.074 g (83%); White solid; mp 161-162 °C. H NMR (CDCl3, 400 MHz) ꢀ =
9.05 (s, 1H), 7.69-7.65 (m, 3H), 7.59-7.57 (m, 3H), 7.48-7.46 (m, 2H), 7.06 (t, J =
8.9 Hz, 2H), 2.67 (s, 3H). 13C NMR (CDCl3, 100 MHz) ꢀ = 159.42 (d, J = 244 Hz),
159.17, 138.45, 137.39, 135.53, 133.72 (d, J = 2.7 Hz), 130.08, 129.68, 125.26,
121.59 (d, J = 7.8 Hz), 115.60 (d, J = 22.4 Hz), 9.74. MS m/z (relative intensity):
296 (M+, 61), 158 (44), 147 (16), 130 (50), 119 (44), 118 (36), 104 (18), 93 (17), 83
(11), 77 (100), 51 (25). HRMS calcd. for C16H14FN4O: [M + H]+ 297.1152. Found:
297.1147.
5-methyl-N-(4-nitrophenyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamide
(3i):
1
Yield: 0.077 g (80%); Orange solid; mp 231-232 °C. H NMR (CDCl3, 400 MHz) ꢀ
= 8.25 (dt, J = 9.2 and 2.8 Hz, 2H), 8.04 (dt, J = 9.2 and 2.8 Hz, 2H), 7.63-7.61 (m,
3H), 7.53-7.50 (m, 2H), 2.68 (s,3H). 13C NMR (CDCl3, 100 MHz) ꢀ = 159.21,
143.62, 143.26, 137.79, 130.81, 129.80, 129.35, 124.94, 124.47, 120.45, 118.98,
9.17. MS m/z (relative intensity): 323 (M+, 41), 158 (70), 147 (5), 130 (55), 118
(38), 104 (14), 93 (28), 77 (100), 67 (7), 51 (23), 43 (7). HRMS calcd. for
C16H14N5O3: [M + H]+ 324.1097. Found: 324.1091.

N,1,5-triphenyl-1H-1,2,3-triazole-4-carboxamide [37] (3j): Yield: 0.083 g (81%);
Beige solid; mp 143-145 °C. 1H NMR (CDCl3, 400 MHz) ꢀ = 9.21 (s, 1H), 7.98 (d, J
= 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.48-7.24 (m, 9H), 7.12-
7.06 (m, 2H). 13C NMR (CDCl3, 100 MHz) ꢀ = 158.09, 139.51, 138.72, 136.08,
135.89, 130.40, 129.25, 128.92, 128.85, 128.80, 128.51, 128.25, 125.21, 124.28,
119.92. MS m/z (relative intensity): 340 (M+, 3), 239 (18), 220 (7), 178 (6), 120
(45), 105 (72), 93 (100), 77 (67), 69 (21), 57 (14), 51 (78), 43 (17). HRMS calcd.
for C21H17N4O: [M + H]+ 341.1402. Found: 341.1395.
5-methyl-N-phenyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide [37] (3k): Yield:
1
0.079 g (90%); Yellow solid; mp 204-205 °C. H NMR (CDCl3, 400 MHz) ꢀ = 9.08
(s, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.38-7.32 (m, 6H), 7.13 (t, J = 7.4 Hz, 1H), 2.64
(s, 3H), 2.46 (s, 3H). 13C NMR (CDCl3, 100 MHz) ꢀ = 159.26, 140.33, 138.50,
137.74, 137.33, 133.06, 130.18, 129.00, 125.06, 124.24, 119.83, 21.17, 9.70. MS
m/z (relative intensity): 292 (M+, 69), 235 (10), 221 (13), 194 (10), 172 (89), 158
(9), 144 (65), 133 (16), 118 (19), 107 (33), 93 (12), 91 (100), 77 (28), 65 (66), 51
(10), 44 (25). HRMS calcd. for C17H17N4O: [M + H]+ 293.1402. Found: 293.1397.
1-(4-methoxyphenyl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide [37]
1
(3l): Yield: 0.085 g (92%); Brown solid; mp 179-181 °C. H NMR (CDCl3, 400
MHz) ꢀ = 9.08 (s, 1H), 7.71(d, J = 8.8 Hz, 2H), 7.39-7.37 (m, 4H), 7.14 (t, J = 7.4
Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.64 (s, 3H). 13C NMR (CDCl3, 100
MHz) ꢀ = 160.75, 159.29, 138.40, 137.71, 137.50, 129.04, 128.32, 126.68, 124.27,
119.82, 114.81, 55.66, 9.71. MS m/z (relative intensity): 308 (M+, 48), 265 (6), 237
(11), 210 (10), 188 (90), 173 (16), 160 (70), 146 (35), 134 (18), 123 (17), 117 (20),
107 (23), 104 (9), 92 (59), 77 (100), 64 (34), 51 (15). HRMS calcd. for C17H17N4O2:
[M + H]+ 309.1352. Found: 309.1359.
5-methyl-N-phenyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide [37] (3m): Yield:
1
0.063 g (72%); Pale brown solid; mp 117-118 °C. H NMR (CDCl3, 400 MHz) ꢀ =
9.10 (s, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42-7.39 (m, 2H),
7.36 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.3 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 2.48 (s,
3H), 2.06 (s, 3H). 13C NMR (CDCl3, 100 MHz) ꢀ = 159.21, 138.19, 138.09, 137.68,
135.42, 134.33, 131.40, 130.72, 128.97, 127.09, 127.01, 124.22, 119.79, 17.08,
9.06. MS m/z (relative intensity): 292 (M+, 88), 221 (15), 194 (9), 172 (76), 159

(10), 144 (85), 132 (41), 118 (46), 107 (30), 93 (16), 91 (100), 77 (37), 65 (83), 51
(14), 43 (16). HRMS calcd. for C17H17N4O: [M + H]+ 293.1402. Found: 293.1406.
1-(2-fluorophenyl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide (3n):
1
Yield: 0.074 g (83%); Yellow solid; mp 88-89 °C. H NMR (DMSO-d6, 400 MHz) ꢀ
= 9.66 (s, 1H), 7.05 (d, J = 7.7 Hz, 2H), 6.93-6.87 (m, 2H), 6.76 (t, J = 9.7 Hz, 1H),
6.66 (t, J = 7.7 Hz, 1H), 6.51 (t, J = 7.7 Hz, 2H), 6.27 (t, J = 7.7 Hz, 1H), 2.54 (s,
13
3H). C NMR (DMSO-d6, 100 MHz) ꢀ = 159.13, 155.75 (d, J = 252 Hz), 138.89,
138.43, 137.95, 132.94 (d, J = 7.9 Hz), 128.93, 128.44, 125.53 (d, J = 3.8 Hz),
123.65, 122.58 (d, J = 12.4 Hz), 120.39, 116.92 (d, J = 19.1 Hz), 8.65. MS m/z
(relative intensity): 296 (M+, 100), 239 (12), 225 (13), 198 (16), 176 (76), 165 (19),
158 (23), 148 (86), 136 (96), 129 (18), 122 (57), 111 (39), 102 (14), 95 (99), 77
(38), 65 (28), 43 (51). HRMS calcd. for C16H14FN4O: [M + H]+ 297.1152. Found:
297.1147.
1-(4-fluorophenyl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide (3o):
1
Yield: 0.080 g (90%); White solid; mp 178-179 °C. H NMR (DMSO-d6, 400 MHz) ꢀ
= 9.64 (s, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.94-6.91 (m, 2H), 6.68 (t, J = 8.7 Hz, 2H),
6.54 (t, J = 7.7 Hz, 2H), 6.29 (t, J = 7.7 Hz, 1H), 2.56 (s, 3H). 13C NMR (DMSO-d6,
100 MHz) ꢀ = 162.40 (d, J = 248 Hz), 159.32, 138.47, 138.11, 137.76, 131.54 (d, J
= 3.0 Hz), 128.42, 127.82 (d, J = 9.1 Hz), 123.58, 120.34, 116.53 (d, J = 23.2 Hz),
9.24. MS m/z (relative intensity): 296 (M+, 76), 239 (9), 225 (9), 198 (9), 176 (66),
148 (67), 136 (45), 122 (23), 111 (26), 95 (100), 77 (25), 65 (18), 43 (16). HRMS
calcd. for HRMS calcd. for C16H14FN4O: [M + H]+ 297.1152. Found: 297.1148.
1-(4-chlorophenyl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide
[37]
1
(3p): Yield: 0.081 g (87%); Beige solid; mp 195-196 °C. H NMR (CDCl3, 400
MHz) ꢀ = 9.05 (s, 1H), 7.71-7.69 (m, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.7
Hz, 2H), 7.39-7.35 (m, 2H), 7.16-7.12 (m, 1H), 2.67 (s, 3H). 13C NMR (CDCl3, 100
MHz) ꢀ = 158.99, 138.71, 137.57, 137.33, 136.23, 133.94, 129.93, 129.03, 126.43,
124.36, 119.82, 9.75. MS m/z (relative intensity): 312 (M+, 82), 241 (8), 221 (10),
192 (86), 164 (68), 158 (19), 152 (44), 146 (9), 138 (21), 127 (35), 111 (100), 102
(14), 93 (42), 77 (41), 65 (27), 51 (19), 43 (11). HRMS calcd. for C16H14ClN4O: [M
+ H]+ 313.0853. Found: 313.0850.

5-methyl-1-(2-nitrophenyl)-N-phenyl-1H-1,2,3-triazole-4-carboxamide
(3q):
Yield: 0.085 g (88%); Orange solid; mp 189-190 °C. 1H NMR (DMSO-d6, 400 MHz)
ꢀ = 9.96 (s, 1H), 8.14-8.13 (m, 1H), 8.09 (ddd, J = 8.3, 2.3 and 1.0 Hz, 1H), 7.77
(ddd, J = 8.3, 2.2 and 1.0 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.49-7.47 (m, 2H),
13
6.97-6.93 (m, 2H), 6.71 (t, J = 7.4 Hz, 1H), 2.26 (s, 3H). C NMR (DMSO-d6, 100
MHz) ꢀ = 159.13, 148.29, 138.42, 138.38, 138.12, 135.99, 131.55, 131.14, 128.33,
124.50, 123.56, 120.34, 120.30, 9.16. MS m/z (relative intensity): 323 (M+, 31),
203 (13), 192 (9), 164 (25), 157 (20), 149 (17), 137 (10), 129 (18), 123(10), 117
(16), 95 (23), 81 (51), 77 (19), 71 (28), 69 (100), 57 (55), 43 (36). HRMS calcd. for
C16H14N5O3: [M + H]+ 324.1097. Found: 324.1090.
5-Methyl-N-phenyl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-
1
carboxamide [40] (3r): Yield: 0.119 g (91%); orange oil; H NMR (CDCl3, 400
MHz) ꢀ = 9.12 (s, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.41-7.25
(m, 9H), 7.13 (t, J = 7.4 Hz, 1H), 2.52 (s, 3H). 13C NMR (CDCl3, 100 MHz) ꢀ =
159.07, 138.43, 138.01, 137.66, 135.09, 134.92, 133.10, 132.85, 131.20, 129.58,
128.94, 128.72, 127.78, 127.71, 127.69, 124.17, 119.73, 9.26. MS (relative
intensity) m/z: 435 (M+, 12), 434 (47), 431 (23), 328 (14), 314 (37), 312 (20), 249
(100), 234 (26), 232 (28), 207 (37), 206 (33), 157 (25), 152 (50), 129 (19), 77 (64),
51 (20). HRMS calcd for C22H19N4OSe [M + H]+: 435.0724. Found: 435.0744.
2.2. General procedure for the synthesis of N-aryl-1,2,3-triazoyl
carboxamides under conventional conditions
!-Oxo amides 1 (0.3 mmol), aryl azides 2 (0.3 mmol), Et2NH (5 mol %) and DMSO
(0.6 mL) were added to a glass tube. The homogeneous reaction mixture was
stirred in an open vial for 8 h. The crude product obtained was subsequently
purified according to above procedure.
3. Results and Discussion
Preliminary experiments to optimize the reaction conditions using
ultrasound irradiation were performed using !-oxo-amide 1a and phenyl azide 2a
as model reaction substrates (Table 1). Firstly, based on our previous report on
the reaction under conventional conditions [40], a homogeneous mixture of
substrates 1a (0.3 mmol) and 2a in DMSO (0.6 mL) was stirred at room

temperature in the presence of 5 mol% of Et2NH as organocatalyst, providing an
excellent yield (98%) of the desired product 3a after 8 h (Scheme 2). Regarding
the mechanism of this reaction, it is thought that the enamine intermediate (A) is
formed first, after the condensation of Et2NH with the compound 1a. A subsequent
1,3-dipolar cycloaddition between the electron-rich olefin (A) and the phenyl azide
2a would give rise to triazoline intermediate (B), which can undergo a plausible
1,3-hydride shift to generate triazoline intermediate (C). Finally, the zwitterionic
form of (C), represented as intermediate (D), could undergo an elimination
reaction to regenerate Et2NH to continue the catalytic cycle and produce the
desired product 3a (Scheme 2).
ꢀ
Scheme 2. Synthesis of 1,2,3-triazoyl carboxamide 3a under conventional conditions.
Identical reaction conditions were applied for the reaction under ultrasonic
irradiation (40% of frequency) at different reaction times (Table 1, entries 1-5).
When a mixture of 1a and 2a was sonicated in the presence of Et2NH (5 mol%)
and DMSO (0.6 mL) as solvent during 5 min, the desired product 3a was obtained
in 69% yield (Table 1, entry 1). The yield of product 3a was observed to increase
with an increase in the reaction time from 10 to 20 min (Table 1, entries 2-4).
Furthermore, the desired product 3a was obtained in 95% yield after sonication for
15 or 20 min. When the reaction of substrates 1a and 2a was sonicated for 25 min,

a decrease in product 3a yield was observed (Table 1, entry 5). A significant
decrease in reaction yields were also observed (Table 1, entries 6-7) for reactions
carried out in 15 min and decreased organocatalyst loadings (from 5 to 1 mol%).
The corresponding product 3a was not obtained in the absence of organocatalyst
(Table 1, entry 8).
Insert Table 1 here
From Table 1, optimum reaction conditions to obtain 5-methyl-N,1-diphenyl-
1H-1,2,3-triazole-4-carboxamide 3a were clearly present in entry 4, in which a
homogeneous mixture of N-phenylbutanamide 1a (0.3 mmol), phenyl azide 2a (0.3
mmol) and Et2NH (5 mol%) in DMSO (0.6 mL) was sonicated at room temperature
for 15 minutes.
The scope of the proposed methodology was then extended under
optimised conditions to a range of !-oxo amides 1 and aryl azides 2 (Table 2).
Phenyl azide 2a reacted efficiently with electron-neutral and different electron-
deficient !-oxo amides to give the corresponding N-aryl-1,2,3-triazoyl
carboxamides 3a-j in good to excellent yields. Reactions of phenyl azide 2a with !-
oxo amides containing electron-donating groups (EDG) 1b-e and electron-
withdrawing (EWG) substituents 1f-i at the carboxamide moiety yielded the
corresponding products 3b-i in 80-94% yields (Table 2, entry 2-9). Generally
speaking, the reactions were found to be slightly sensitive to electronic effects in
the aromatic ring of !-oxo amides. For example, !-oxo amides containing EDG’s
at the aromatic ring provided higher yields as compared to those bearing EWG’s
(Table 2, entries 2-5 vs. 6-9). The reaction performed with !-oxo amide 1g
containing a phenyl group gave also access to the corresponding triazole 3j in
81% yield (Table 2, entry 10).
The reactivity of N-phenylbutanamide 1a with different functionalized aryl
azides 2b-i was subsequently investigated (under otherwise identical reaction
conditions). In general, the reactions were found to be insensitive to the electronic
conditions in the aryl ring of azides. Aryl azides containing either an EDG or an
EWG on the aromatic ring delivered the expected N-aryl-1,2,3-triazoyl
carboxamides 3k-q in good to excellent isolated yields (Table 2, entries 11-17).
However, an interesting steric effect could be observed when the reaction was
performed with o-tolyl azide 2d and 1-azido-2-fluorobenzene 2e, furnishing the

corresponding products 3m and 3n in 72% and 83% yield, respectively (Table 2,
entries 13 and14). Finally, extending the scope of this methodology, the reaction of
1a with azidophenyl arylselenide 2i was performed. In this case, the desired
product 3r was obtained in 91% yield (Table 2, entry 18).
Insert Table 2 here
With the aim to compare the effect of sonication in these reactions, we
performed these organocatalytic cycloadditions of !-oxo-amides and aryl azides
under conventional conditions for 8 h (Table 2, yields in brackets). The obtained
results show that the use of ultrasound irradiation is better than conventional
condition, furnishing the corresponding products in comparable yields but in very
short reaction time.
3. Conclusion
In summary, we described the use of ultrasound irradiation as an alternative
energy source in the organocatalytic enamine-azide [3+2] cycloadditions reactions.
Using diethylamine as organocatalyst, phenyl azide reacted efficiently with
electron-neutral and different electron-deficient !-oxo amides to give the
corresponding products in good to excellent yields. Under the same reaction
conditions, N-phenylbutanamide reacted smoothly with different functionalized aryl
azides delivered the expected products in high yields. The accelerating effect in
these ultrasound promoted reactions should largely be ascribed to mechanical
effects (i.e. enhanced mass transfer). In addition, these organocatalytic reactions
were performed under conventional conditions and the obtained results show that
the use of ultrasound irradiation furnished the corresponding products in
comparable yields but in very short reaction time, especially suitable for Green or
Click Chemistry concepts.
Acknowledgements
We thank the CNPq (Grants 306430/2013-4, 400150/2014-0 and 447595/2014-8),
CAPES, FAPERGS, FAPESP (15/17141-1 and 14/50249-8) and FINEP for the
financial support. Rafael Luque graftefully acknowledges support from Ciencia
sem Fronteiras Program (Grant 303415/2014-2) as Visiting Scientist to
Universidade Federal de Pelotas, RS.

Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.ultsonch.xxxxx.
References
[1] T. Eicher, S. Hauptmann, In: The Chemistry of Heterocycles, Wiley-VCH,
Weinheim, 2003, pp. 1.
[2] A. R. Katrizky, A. F. Pozharskii, In: Handbook of Heterocyclic Chemistry, 2nd
ed., Pergamon, Amsterdam, 2000, pp. 1.
[3] For a recent set of reviews in this area, see the themed issue: Applications of
click chemistry. Chem. Soc. Rev., 2010, 39, 1221-1407.
[4] R. Huisgen, 1.3-Dipolare cycloadditionen rückschau und ausblick, Angew.
Chem. (75) 1963, 604-637.
[5] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, A stepwise
Huisgen cycloaddition process: copper (I)-catalyzed regioselective “ligation” of
azides and terminal alkynes, Angew. Chem. 41 (2002), 2596-2599.
[6] C. W. Tornøe, C. Christensen, M. Meldal, Peptidotriazoles on solid phase:
[1,2,3]-triazoles by regiospecific copper (I)-catalyzed 1,3-dipolar cycloadditions of
terminal alkynes to azides, J. Org. Chem. 67 (2002), 3057-3064.
[7] A. Krasinski, Z. Radic, R. Manetsch, J. Raushel, P. Taylor, K. B. Sharpless, H.
C. Kolb, In situ selection of lead compounds by click chemistry:ꢀ target-guided
optimization of acetylcholinesterase inhibitors, J. Am. Chem. Soc. 127 (2005),
6686-6692.
[8] L. V. Lee, M. L. Mitchell, S. Huang, V. V. Fokin, K. B. Sharpless, C. Wong, A
potent and highly selective inhibitor of human ꢁ-1,3-fucosyltransferase via click
chemistry, J. Am. Chem. Soc. 125 (2003), 9588-9589.
[9] L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B. Sharpless, V. V.
Fokin, G. Jia, Ruthenium-catalyzed cycloaddition of alkynes and organic azides, J.
Am. Chem. Soc. 127 (2005), 15998-15999.

[10] B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G. Jia,
V. V. Fokin, Ruthenium-catalyzed azide-alkyne cycloaddition: scope and
mechanism, J. Am. Chem. Soc. 130 (2008), 8923-8930.
[11] J. A. Johnson, J. M. Baskin, C. R. Bertozzi, J. T. Koberstein, N. J. Turro,
Copper-free click chemistry for the in situ crosslinking of photodegradable star
polymers, Chem. Commun. 26 (2008), 3064-3066.
[12] J. M. Baskin, C. R. Bertozzi, Bioorthogonal click chemistry: covalent labeling
in living systems, QSAR Comb. Sci. 26 (2007), 1211-1219.
[13] K. Jomova, M. Valko, Advances in metal-induced oxidative stress and human
disease, Toxicology 283 (2011), 65-87.
[14] J. Gierlich, G. A. Burley, P. M. E. Gramlich, D. M. Hammond, T. Carell, Click
chemistry as a reliable method for the high-density postsynthetic functionalization
of alkyne-modified DNA, Org. Lett. 8 (2006), 3639-3642.
[15] E. Lallana, E. Fernandez-Megia, R. Riguera, Surpassing the use of copper in
the click functionalization of polymeric nanostructures: a strain-promoted
approach, J. Am. Chem. Soc. 2009, 131, 5748-5750.
[16] A. J. Link, M. K. S. Vink, D. A. Tirrell, Presentation and detection of azide
functionality in bacterial cell surface proteins, J. Am. Chem. Soc. 126 (2004),
10598-10602.
[17 L. M. Gaetke, C. K. Chow, Copper toxicity, oxidative stress, and antioxidant
nutrients, Toxicology 189 (2003), 147-163.
[18] D. C. Kennedy, C. S. McKay, M. C. B. Legault, D. C. Danielson, J. A. Blake,
A. F. Pegoraro, A. Stolow, Z. Mester, J. P. Pezacki, Cellular consequences of
copper complexes used to catalyze bioorthogonal click reactions, J. Am. Chem.
Soc. 133 (2011), 17993-18001.
[19] M. F. Debets, S. S. Van Berkel, J. Dommerholt, A. J. Dirks, F. P. J. T. Rutjes,
F. L. Van Delft, Bioconjugation with strained alkenes and alkynes, Acc. Chem.
Res. 44 (2011), 805-815.
[20] J. M. Baskin, C. R. Bertozzi, Copper-free click chemistry: bioorthogonal
reagents for tagging azides, Aldrichim. Acta 43 (2010), 15-23

[21] C. G. S. Lima, A. Ali, S. S. Van Berkel, B. Westermann, M. W. Paixão,
Emerging approaches for the synthesis of triazoles: beyond metal-catalyzed and
strain-promoted azide–alkyne cycloaddition, Chem. Commun. 51 (2015), 10784-
10796.
[22] S. S. V. Ramasastry, Enamine/enolate-mediated organocatalytic azide-
carbonyl [3+2] cycloaddition reactions for the synthesis of densely functionalized
1,2,3-triazoles, Angew. Chem., Int. Ed. 53 (2014), 14310-14312.
[23] J. John, J. Thomas, W. Dehaen, Organocatalytic routes toward substituted
1,2,3-triazoles, Chem. Commun. 51 (2015), 10797-10806.
[24] Y.-H. Chen, Y.-H. Zhang, H.-J. Zhang, D.-Z. Liu, M. Gu, J.-Y. Li, F. Wu, X.-Z.
Zhu, J. Li, F.-J. Nan, Design, synthesis, and biological evaluation of isoquinoline-
1,3,4-trione derivatives as potent caspase-3 inhibitors, J. Med. Chem. 49 (2006),
1613-1623.
[25] S. Chatterjee, D. Dunn, M. Tao, G. Wells, Z.-Q. Gu, R. Bihovsky, M. A. Ator,
R. Siman, J. P. Mallamo, P2-achiral, P'-extended ꢁ-ketoamide inhibitors of calpain
I, Bioorg. Med. Chem. Lett. 9 (1999), 2371-2374.
[26] C. E. Augelli-Szafran, C. J. Blankley, B. D. Roth, B. K. Trivedi, R. F. Bousley,
A. D. Essenburg, K. L. Hamelehle, B. R. Krause, R. L. Stanfield, Inhibitors of acyl-
CoA:cholesterol acyltransferase. 5. Identification and structure-activity
relationships of novel beta-ketoamides as hypocholesterolemic agents, J. Med.
Chem. 36 (1993), 2943-2949.
[27] G. Ding, L. Jiang, L. Guo, X. Chen, H. Zhang, Y. Che, Pestalazines and
pestalamides,
bioactive
metabolites
from
the
plant
pathogenic
fungus Pestalotiopsis theae, J. Nat. Prod. 71 (2008), 1861-1865.
[28] Y. Ye, H. Zhu, Y. Song, J. Liu, R. Tan, Structural Revision of Aspernigrin A,
reisolated from Cladosporiumherbarum IFB-E002, J. Nat. Prod. 68 (2005), 1106-
1108.
[29] Y. Zhang, T. Zhu, Y. Fang, H. Liu, Q. Gu, W. Zhu, Carbonarones A and B,
new bioactive "-pyrone and ꢁ-pyridone derivatives from the marine-derived fungus
Aspergillus carbonarius, J. Antibiot. 60 (2007), 153-157.

[30] Z. Zhang, S. Fang, Q. Liu, G. Zhang, Approach to polysubstituted 4-pyridones
from N-aryl acetoacetamides via a N to C 1,3-acyl migration mediated by sodium
persulfate, J. Org. Chem. 77 (2012), 7665-7670.
[31] Y. Ouyag, J. Huang, W. Pan, Y. Liang, Y. Yang, D. Dong, [4+2] Annulation –
convenient synthesis of substituted dihydropyranones in aqueous media, Eur. J.
Org. Chem. 2009 (2009), 2003-2009.
[32] M. N. S. Saudi, M. M. A. El-Semary, R. Y. Elbayaa, M. I. Jaeda, M. M. Eissa,
E. I. Amer, N. M. Baddour, Synthesis and biological evaluation of a novel
class as antileishmanial agent, Med. Chem. Res. 21 (2012), 257-267.
[33] H. -L. Wang, Z. Li, G. -W. Wang, S. -D. Yang, Silver catalyzed
intramolecular cyclization for
synthesis
of
3-alkylideneoxindoles via C–H
functionalization, Chem. Commun. 47 (2011), 11336-11338.
[34] D. Xiang, X. Xin, X. Liu, R. Zhang, J. Yang, D. Dong, Regioselective synthesis
of 3-arylamino- and 5-arylaminoisoxazoles from enaminones, Org. Lett. 14 (2012),
644-647.
[35] G. Tenti, M. T. Ramos, J. C. Menendez, One-pot access to a library of
structurally diverse nicotinamide derivatives via a three-component formal aza [3 +
3] cycloaddition, ACS Comb. Sci. 14 (2012), 551-557.
[36] L. Xia, Y. R. Lee, Efficient one-step synthesis of pyrrolo[3,4-c]quinoline-1,3-
dione derivatives by organocatalytic cascade reactions of isatins and !-
ketoamides, Org. Biomol. Chem. 11 (2013), 5254-5263.
[37] Z. Wang, X. Bi, P. Liao, R. Zhang, Y. Liang, D. Dong, Intramolecular hydrogen
bonding-assisted cyclocondensation of ꢁ-diazoketones with various amines: a
strategy for highly efficient Wolff 1,2,3-triazole synthesis, Chem. Commun. 48
(2012), 7076-7078.
[38] H. Cheng, J. Wan, M. -I. Lin, Y. Liu, X. Lu, J. Liu, Y. Xu, J. Chen, Z. Tu, Y. -S.
E. Cheng, K. Ding, Design, Synthesis, and in vitro biological evaluation of 1h-
1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents targeting
virus nucleoprotein, J. Med. Chem. 55 (2012), 2144-2153.

[39] E. A. Wilhelm, N. C. Machado, A. B. Pedroso, B. S. Goldani, N. Seus, S.
Moura, L. Savegnago, R. G. Jacob, D. Alves, Organocatalytic synthesis and
evaluation of 7-chloroquinoline-1,2,3-triazoyl carboxamides as potential
antinociceptive, anti-inflammatory and anticonvulsant agent, RSC Adv. 4 (2014),
41437- 41445.
[40] N. Seus, B. Goldani, E. J. Lenardão, L. Savegnago, M. W. Paixão, D. Alves,
Organocatalytic synthesis of (arylselanyl)phenyl-1h-1,2,3-triazole-4-carboxamides
by cycloaddition between azidophenyl arylselenides and !-oxo-amides, Eur. J.
Org. Chem. 2014 (2014), 1059-1065.
[41] Z. Li, J. Hong, X. Zhou, An efficient and clean CuI-catalyzed chalcogenylation
of aromatic azaheterocycles with dichalcogenides, Tetrahedron 67 (2011) 3690-
3697.
[42] M.M. Mojtahedi, M. S. Abaee, Ultrasound Applications in Synthetic Organic
Chemistry, In: D. Chen, S.K. Sharma, A. Mudhoo (Eds.), Handbook on
Applications of Ultrasound Sonochemistry for Sustainability, CRC Press, New
York, 2012, pp 281-322.
[43] G. Cravotto, P. Cintas, Power ultrasound in organic synthesis: moving
cavitational chemistry from academia to innovative and large-scale applications,
Chem. Soc. Rev. 35 (2006) 180-196.
[44] T.J. Mason, Sonochemistry and the environment – Providing a “green” link
between chemistry, physics and engineering, Ultrason. Sonochem. 14 (2007) 476-
483.
[45] M. Nüchter, B. Ondruschka, A. Jungnickel, U. Müller, Organic processes
initiated by non-classical energy sources, J. Phys. Org. Chem. 13 (2000) 579-586.
[46] T.J. Mason, Ultrasound in synthetic organic chemistry, Chem. Soc. Rev. 26
(1997) 443-451.
[47] G. Cravotto, V. V. Fokin, D. Garella, A. Binello, L. Boffa, A. Barge, Ultrasound-
promoted copper-catalyzed azide-alkyne cycloaddition, J. Comb. Chem. 12
(2010), 13–15.

[48] M. F. Mady, G. E. A. Awad, K. B. Jørgensen, Ultrasound-assisted synthesis of
novel 1,2,3-triazoles coupled diaryl sulfone moieties by the CuAAC reaction, and
biological evaluation of them as antioxidant and antimicrobial agents, Eur. J. Med.
Chem. 84 (2014) 433-443.
[49] H. Marzag, S. Alaoui, H. Amdouni, A. R. Martin, K. Bougrin, R. Benhida,
Efficient and selective azidation of per-O-acetylated sugars using ultrasound
activation: application to the one-pot synthesis of 1,2,3-triazole glycosides, New J.
Chem. 39 (2015), 5437-5444.
[50] S. B. Nallapati, B. Y. Sreenivas, R. Bankala, K. V. L. Parsa, S. Sripelly, K.
Mukkanti, M. Pal, 1,2,3-Triazoles derived from olanzapine: their synthesis via an
ultrasound assisted CuAAC method and evaluation as inhibitors of PDE4B, RSC
Adv. 5 (2015), 94623-94628.
[51] H. Naeimi, S. Dadashzadeh, M. Moradian, Facile and efficient sonochemical
synthesis of 1,4-disubstituted 1,2,3-triazole derivatives catalyzed by CuI under
mild conditions, Res. Chem. Intermed. 41 (2015), 2687–2695.
[52] H. A. Stefani, H. A. Canduzini, F. Manarin, Modular synthesis of mono, di, and
tri-1,4-disubstituted-1,2,3-triazoles
through
copper-mediated
alkyne–azide
cycloaddition, Tetrahedron Lett. 52 (2011), 6086–6090.
[53] H. A. Stefani, N. C. S. Silva, F. Manarin, D. S. Lüdtke, J. Zukerman-
Schpector, L. S. Madureira, E. R. T. Tiekink, Synthesis of 1,2,3-
triazolylpyranosides through click chemistry reaction, Tetrahedron Lett. 53 (2012),
1742–1747.
[54] H. A. Stefani, A. S. Vieira, M. F. Z. J. Amaral, L. Cooper, Synthesis of 5-
alkynyl-2,2,6-trimethyl-1,3-dioxin-4-ones and 1,4-disubstituted-1,2,3-triazoles,
Tetrahedron Lett. 52 (2011), 4256–4261.
[55] Y. Jiang, X. Chen, L. Qua, J. Wang, J. Yuan, S. Chen, X. Li, C. Qu,
Ultrasonic-assisted synthesis of chrysin derivatives linked with 1,2,3-triazoles by
1,3-dipolar cycloaddition reaction, Ultrason. Sonochem. 18 (2011), 527–533.

Tables
Table 1. Optimization studies for preparation of 1,2,3-triazoyl carboxamide 3a.a
ꢀ
Entry Et2NH (mol%) Time (min) Yield of 3a (%)b
1
2
3
4
5
6
7
8
5
5
5
5
5
3
1
-
5
69
82
95
95
82
40
17
nd
10
15
20
25
15
15
15
a Reactions were performed with !-keto amide 1a (0.3
mmol) and phenyl azides 2a (0.3 mmol) in DMSO (0.6
mL) as solvent under ultrasound irradiation (40% of the
b
amplitude) at room temperature. Yields are given for
isolated products.

Table 2. Variability in the synthesis of N-aryl-1,2,3-triazoyl carboxamides.a
Yield
(%)b,c
Entry
!-Oxo-amides 1a-j
Aryl azide 2a-i
Product
O
O
N
1
95 (98)
92 (90)
94 (91)
H
2a
1a
3a
2
3
2a
1b
1c
1d
3b
2a
3c
4
93
2a
3d
5
94 (88)
2a
1e
3e

6
86 (80)
2a
1f
3f
7
84
2a
1g
1h
1i
3g
3h
8
9
83 (76)
2a
2a
80
3i
10
11
12
13
81
90
2a
2b
1j
3j
O
O
O
O
N
H
1a
3k
O
N
H
92 (70)
2c
2d
1a
3l
O
N
H
72
1a
3m

O
O
O
N
H
14
15
83
90
2e
2f
1a
3n
3o
O
N
H
1a
O
O
N
H
16
17
87 (89)
2g
2h
2i
1a
3p
3q
3r
O
O
O
N
H
88
91
1a
O
N
H
18
1a
a
Reactions were performed with !-keto amides 1a-j (0.3 mmol) and aryl azides 2a-i (0.3 mmol),
using Et2NH (5 mol%) as catalyst in DMSO (0.6 mL) as solvent under ultrasound irradiation (40%
of amplitude) at room temperature for 15 min. b Yields are given for isolated products. c Yields in
brackets were obtained in reactions performed under conventional conditions for 8 h.

Sonochemistry in organocatalytic enamine-azide [3+2]
cycloadditions: A rapid alternative for the synthesis of
1,2,3-triazoyl carboxamides.
Daiane M. Xaviera, Bruna S. Goldania, Natália Seusa, Raquel G. Jacoba, Thiago Barcellosb,
Márcio W. Paixãoc, Rafael Luqued and Diego Alvesa,*
a Laboratório de Síntese Orgânica Limpa - LASOL - Universidade Federal de Pelotas - UFPel - P.O. Box 354, 96010-
900, Pelotas - RS, Brazil.
b Laboratory of Biotechnology of Natural and Synthetic Products, Universidade de Caxias do Sul, Caxias do Sul - RS,
Brazil.
c Laboratório de Síntese de Produtos Naturais, Universidade Federal de São Carlos, São Carlos - SP, Brazil.
d Departamento de Quimica Organica, Universidad de Cordoba, Campus de Rabanales, Cordoba, Spain.
* corresponding author. Tel: +55 (53) 3275-7533. e-mail: diego.alves@ufpel. edu.br
ꢀ
Contents
General
Information..........................................................................................................S2
Selected Spectra…….....................………...….………………………………............……..S3
ꢅꢆꢀ
ꢀ

General Information: The reactions were monitored by TLC carried out on Merck
silica gel (60 F254) by using UV light as visualizant agent and 5% vanillin in 10% H2SO4
and heat as developing agents. Baker silica gel (particle size 0.040-0.063 mm) was
used for flash chromatography. A Cole Parmer-ultrasonic processor Model CPX 130,
with a maxim power of 130 W, operating at amplitude of 40% and a frequency of 20
kHz was used. Proton nuclear magnetic resonance spectra (1H NMR) were obtained at
400 MHz on Bruker DPX 400 spectrometer. Spectra were recorded in DMSO-d6 or
CDCl3 solutions. Chemical shifts are reported in ppm, referenced to tetramethylsilane
(TMS) as the external reference. Coupling constants (J) are reported in Hertz.
Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet),
dd (doublet of doublet), dt (doublet of triplet), ddd (doublet of doublet of doublets), t
(triplet) and m (multiplet). Carbon-13 nuclear magnetic resonance spectra (13C NMR)
were obtained at 100 MHz on Bruker DPX 400 spectrometer. Chemical shifts are
reported in ppm, referenced to the solvent peak of DMSO-d6 or CDCl3. Low-resolution
mass spectra were obtained with a Shimadzu GC-MS-QP2010 mass spectrometer.
High resolution mass spectra (HRMS) were recorded on a Bruker Micro TOF-QII
spectrometer 10416.
ꢅꢇꢀ
ꢀ

SELECTED SPECTRA
Figure 1. 1H NMR (400 MHz) spectrum for compound 3a in DMSO-d6.
Figure 2. 13C NMR (100 MHz) spectrum for compound 3a in DMSO-d6.
ꢅꢈꢀ
ꢀ

Figure 3. 1H NMR (400 MHz) spectrum for compound 3b in DMSO-d6.
Figure 4. 13C NMR (100 MHz) spectrum for compound 3b in DMSO-d6.
ꢅꢉꢀ
ꢀ

Figure 5. 1H NMR (400 MHz) spectrum for compound 3c in CDCl3.
Figure 6. 13C NMR (100 MHz) spectrum for compound 3c in CDCl3.
ꢅ ꢀ
ꢀ

Figure 7. 1H NMR (400 MHz) spectrum for compound 3d in DMSO-d6.
Figure 8. 13C NMR (100 MHz) spectrum for compound 3d in DMSO-d6.
ꢅꢊꢀ
ꢀ

Figure 9. 1H NMR (400 MHz) spectrum for compound 3e in DMSO-d6.
Figure 10. 13C NMR (100 MHz) spectrum for compound 3e in DMSO-d6.
ꢅꢋꢀ
ꢀ