Cu(I)-promoted one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic acids and nitrobenzaldehydes

Article abstract of DOI:10.1080/00397911.2016.1262039

A series of 1,4-disubstituted 1,2,3-triazoles were synthesized through a one-pot process from easily available anti-3-aryl-2,3-dibromopropanoic acids and nitrobenzaldehydes in hexamethylphosphoric triamide. Inexpensive copper(I) iodide was the catalyst.

Full text of DOI:10.1080/00397911.2016.1262039

Cu(I)-promoted One-pot Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from
anti-3-Aryl-2,3-dibromopropanoic Acids and Nitrobenzaldehydes
Xia Liu1,, Changhui Su2
1College of Environment and Ecology, Jiangsu Open University, Nanjing, P.R. China
2Chemistry and Life Science College, Nanjing University Jinling College, Nanjing, P.R.
China
Corresponding author Xia Liu. E-mail: liuxia_1107@163.com
Abstract
A series of 1,4-disubstituted 1,2,3-triazoles were synthesized through a one-pot process
from easily available anti-3-aryl-2,3-dibromopropanoic acids and nitrobenzaldehydes in
hexamethylphosphoric triamide (HMPT). Inexpensive copper(I) iodide was the catalyst.
GRAPHICALABSTRACT
KEYWORDS: 1,2,3-triazoles, anti-3-aryl-2, 3-dibromopropanoic acid, click chemistry,
one-pot
INTRODUCTION
1,2,3-Triazoles have been intensively studied in recent years because of their widespread
applications in pharmaceuticals and agrochemicals.[1] In many cases, these compounds
have exhibited interesting biological activities, including antibacterial,[2] antifungicidal,[3]
antiallergic,[4] and anti-HIV activities.[5]
1

The discovery of Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides and terminal
alkynes has further stimulated the research on both the structure types and preparation
methods of these heterocycles.[6] This vigorous “click chemistry” [3+2]-cycloaddition
reactions have been very attractive and extensively used in the preparation of diverse
1,4-substituted 1,2,3-triazoles[7] due to its several advantages, such as exclusive
regioselectivity, wide substrate scope, mild reaction conditions, and excellent yields.
However, the method also has a limitation in that the starting materials of terminal
alkynes and organic azides need to be prepared and isolated respectively ahead, which
restricts its applications in wide fields. Hence, explorations for new methods that do not
employ the terminal alkynes and azides are much desired. In our previous works, we have
reported some interesting one-pot syntheses of various 1,2,3-triazole derivatives from
easily available anti-3-aryl-2,3-dibromopropanoic acids.[8] As a part of our continuing
interests in one-pot “click chemistry”, we herein report our results on the one-pot
synthesis of 1, 4-disubstituted 1,2,3-triazoles containing formyl group from easily
available nitrobenzaldehydes and anti-3-aryl-2,3-dibromopropanoic acids. In these
reactions, the anti-3-aryl-2, 3-dibromopropanoic acids served as terminal alkyne
precursors and nitrobenzaldehydes served as organic azides precursors. The direct use of
terminal alkynes and organic azides was not needed (Scheme 1).
2

RESULTS AND DISCUSSION
To identify the optimal reaction conditions, we used nitrobenzaldehyde 1a and
anti-3-phenyl-2,3-dibromopropanoic acid 2a as model substrates (Table 1). Initially, we
chose the inorganic compounds of potassium carbonate and cesium carbonate,
respectively, as the base for the solvent of hexamethylphosphoric triamide (HMPT). The
reaction was performed for 24 h at 80 °C with a catalyst system consisting of copper(I)
iodide (0.2 equiv.) and sodium ascorbate (0.4 equiv.). The moderate yield products were
isolated (Table1, entry 1–2). We then examined some organic bases and found out that no
target molecules were detected when triethylamine was used (Table1, entry 3). To our
interest, a yield of 88% was obtained when 1,8-diazabicuclo[5.4.0]undeo-7-ene (DBU)
was applied at 80 °C for 3 h (Table1, entry 4). With this result, we then investigated the
effect of the solvents, such as DMSO, DMF, NMP (N-Methyl pyrrolidone), and water.
When DMF and DMSO were used as solvent, the yields fell markedly to 56% (DMSO)
and 26% (DMF), respectively. NMP was another suitable solvent for the system, giving a
good yield of 78% at 80 °C for 24 h (Table 1, entry 6). Meanwhile, almost no conversion
was observed when water was used as solvent, which was probably due to its inefficiency
in dissolving some of the starting materials (Table1, entry 8). In addition, attempts to
reduce the quantities of copper(I) iodide and sodium ascorbate decreased the yield of
1,4-disubstituted 1,2,3-triazoles (Table1, entry 9), whereas adding more equivalents of
copper(I) iodide and sodium ascorbate showed no further effects (Table 1, entry 10). On
3

the basis of these experiments, we concluded that the reaction proceeded most efficiently
and was completed in 3 h when it was promoted by copper(I) iodide (0.2 equiv.) and
sodium ascorbate (0.4 equiv.) in the presence of DBU (1 equiv.) by using HMPT as the
solvent at 80 °C (Table 1, entry 4).
Having the optimized conditions in hand, we then examined the substrates scope of the
one-pot synthesis of 1, 4-disubstituted 1,2,3-triazoles. The starting materials of
anti-3-aryl-2,3-dibromopropanoic acids were easily prepared by bromination of the
corresponding trans-unsaturated carboxylic acids.[9] Results summarized in Table 2 show
that the method can be used for the synthesis of 1,4-disubstituted 1,2,3-triazoles carrying
either electron-donating groups, such as methyl, ethyl, and methoxy (Table 2, entries
3–5), or electron-withdrawing groups, such as bromo, chloro, fluoro, and nitro on the
aromatic ring of anti-3-aryl-2,3-dibromopropanoic acids (Table 2, entries 6–9 ).
Meanwhile, this method proved to be applicable to substrate 1 bearing an ortho-formyl
group, which gave the corresponding product 3b at 53% yield. (Table 2, entry 2). Notably,
the reaction of the pyridyl-substituted substrate 2 also proceeded smoothly, giving a
moderate yield of 73%. (Table 2, entry 10).
The proposed mechanism for the reaction of anti-3-aryl-2,3-dibromopropanoic acids and
nitrobenzaldehydes is shown in Scheme 2. Organic azide 4 and aryl alkyne 5 were
supposed to be generated in situ and then combined into 1,2,3-triazoles 3 by
4

Cu(I)-catalyzed 1,3-dipolar cycloaddition. We conducted a control experiment with
anti-3-aryl-2,3-bromopropanoic acid 2 under the optimized conditions and in the absence
of sodium azide. The corresponding terminal alkyne 5 was obtained with a 94% yield.
This result indicates that an alkyne was generated in the one-pot process probably by the
debrominative decarboxylation of the anti-3-aryl-2,3-bromopropanoic acid 2 and
subsequent elimination of hydrogen bromide in the presence of the base. Obviously, the
organic azide 4 was obtained simultaneously from the SNAr reaction of
nitrobenzaldehydes 1 and sodium azide[10] (Scheme 2).
EXPERIMENTAL
Melting points were recorded on a Fischer-Johns micro hot-stage apparatus and were
uncorrected. IR spectra were recorded on a Nexus FT-IR spectrophotometer. 1H NMR
and 13C NMR spectra were recorded in DMSO-d6 or CDCl3 with TMS as the internal
standard by using a Bruker AV400 spectrometer. Elemental analyses were performed
using a Perkin-Elmer 2400 CHNS elemental analyzer. Mass spectra were obtained using
a Finnigan MAT-95 mass spectrometer. Commercially obtained reagents were used
without further purification. All reactions were monitored by TLC on Huanghai GF 254
silica gel-coated plates. Column chromatography was carried out on 100-200 mesh silica
gel at medium pressure. The anti-3-aryl-2,3-dibromopropanic acids 2 were synthesized
according to literature procedures.[9]
5

General Procedure For The Synthesis Of 1,2,3-Triazoles (3a-J)
The solution of o/p-nitrobenzaldehyde (151 mg, 1 mmol), NaN3 (130 mg, 2 mmol),
anti-3-aryl-2,3-bromopropanoic acid (1mmol), CuI (38 mg, 0.2 mmol), DBU (152 mg, 1
mmol) and Na ascorbate (80 mg, 0.4 mmol) in HMPT (3 mL) was stirred in a
round-bottom flask. The mixture was heated to the temperature indicated in Table 2 until
the starting o/p-nitrobenzaldehyde was completely consumed (monitored by TLC). The
reaction mixture was allowed to cool to r.t., and H2O (15 mL) was added. The mixture
was extracted with CH2Cl2 or CHCl3 (3 × 20 mL). The combined organic layers were
washed with sat. brine (3 × 30 mL), dried over MgSO4, and the solvents removed under
reduced pressure to provide the crude product, which was purified via flash
chromatography (silica gel, particle size 100-200 mesh, n-hexane-CH2Cl2) or crystallized
by EtOAc-EtOH.
Spectral Characterization Of 3i
Compound 4-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (3i): Brown solid,
mp: 270.2-270.9 °C. IR (KBr): 3142, 3105, 1697, 1601, 1509, 1400 cm-1. 1H NMR (400
MHz, DMSO-d6): δ 10.11 (s, 1H), 9.74 (s, 1H), 8.40 (d, J = 7.5 Hz, 2H), 8.21 (m, 6H).
13C NMR (100 MHz, DMSO-d6): δ 192.61, 147.53, 146.21, 140.72, 136.83, 136.45,
131.84, 126.74, 125.04, 122.51, 120.87. MS (ESI): m/z 295 (M+H)+. Anal. Calcd. for
C15H10N4O3: C, 61.22; H, 3.43; N, 19.04. Found: C, 61.18; H, 3.26; N, 19.15.
CONCLUSIONS
6

In conclusion, we developed a simple and efficient one-pot method for the preparation of
1,4-disubstituted 1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic acids and
nitrobenzaldehydes catalyzed by using copper(I) iodide in moderate to high yields. The
process possesses considerable advantages in terms of its product diversity, mild reaction
conditions, and the use of precursors instead of terminal alkynes and organic azides.
Further studies on the application of the present methodology to the synthesis of
biological active compounds are currently ongoing.
SUPPLEMENTARY MATERIAL
Full experimental detail, 1H and 13C NMR spectra for this article can be found via the
“Supplementary Content” section of this article’s webpage.
ACKNOWLEDGEMENT
This work was supported by the Natural science fund for colleges and universities in
Jiangsu Province (16KJB150007; 15KJD350001), the Subject of “Twelfth
Five-Year-Plan” of Jiangsu Open University (14SEW-Y-006), and the National Natural
Science Foundation of China (NO. 21262020).
REFERENCES
7

[1] (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40,
2004-2021; (b) Katritzky, A.R.; Zhang, Y.; Singh, S. K. Heterocycles. 2003, 60,
1225-1239.
[2] (a) Tornøe, C. W; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-3064.
(b) Rostovtsev, V. V.; Green, L.G.; Fokin, V.V.; Sharpless, K. B. Angew. Chem. Int. Ed.
2002, 41, 2596-2599. (c) David, P.; Prabhavathi, F. Bioorg. Med. Chem. Lett. 2011, 21,
510-513.
[3] (a) Genin, M. J.; Allwine, D. A.; Anderson, D. J.; et al. J. Med. Chem. 2000, 43,
953-970. (b) Su, C. H.; Liu, X. Asian. J. Chem. 2014, 26, 5301-5304.
[4] (a) Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem. 1986,
29, 2262-2267. (b) Wamhoff, H.; Katritzky, A. R.; Rees, C. W. In Comprehensive
Heterocyclic Chemistry, Pergamon, Oxford, 1984, 669.
[5] (a) Alvarez, R.; Velazquez, S.; San-Felix, A.; et al. J. Med. Chem. 1994, 37,
4185-4194. (b) Kallander, L. S., Lu, Q., Chen, W., et al. J. Med. Chem. 2005, 48,
5644-567. (c) Rohrig, U. F., Awad, O. L., Grosdidier, O. A., et al. J. Med. Chem. 2010,
53, 1172-1189.
[6] (a) Heriberto, D. V.; Yara, R. G.; Matthias, V.; et al. Org. Biomol. Chem.
2014, 12, 9350-9356. (b) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org.
Chem. 2005, 2006, 51-68.
8

[7] (a) Zhang, W. S., Su, C. H.; Kuang, C. X. Synthetic. Commun. 2011, 41, 1267-1275.
(b) Jiang, Y.; Han, C.; Liang, X.; et al. Chin. J. Org. Chem. 2013, 33, 1884-1890. (c)
Zhao, F.; Chen, Z.; Jiang, Y. Chin. Chem. Lett. 2016, 27, 109-113.
[8] (a) Cheng, X. Z.; Yang, Y. W.; Kuang, C. X.; et al. Synthesis. 2011, 18, 2907-2912.
(b) Jiang, Y.; Kuang, C. X.; Yang, Q. Synthesis. 2010, 24, 4256-4260. (c) Zhang, W. S.,
Kuang, C. X.; Yang, Q. Synthesis. 2010, 2, 283-287.
[9] (a) Kuang, C. X.; Senboku, H.; Tokuda, M. Tetrahedron Lett. 2001, 42, 3893-3896.
(b) Zhang, W. S.; Kuang, C. X.; Yang, Q. Chin. J. Chem. 2009, 27, 1727-1732.
[10] Su, C. H.; Ding, Z. Y.; Liu, X.; et al. Synthetic. Commun. 2016, 46, 1068-1073.
9

Table 1. Optimization of the synthesis of
4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzaldehyde (3a) a
Entr CuI
(equiv)
Sodium ascorbate
Solvent
Base
Time
(h)
24
24
24
3
Yieldb of 3a
y
1
2
3
4
5
6
7
8
9
10
(equiv)
0.4
(%)
55
34
0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.3
HMPT
HMPT
HMPT
HMPT
DMSO
NMP
Ce2CO3
K2CO3
Et3N
0.4
0.4
0.4
DBU
DBU
DBU
DBU
DBU
DBU
DBU
88
56
78
26
0
0.4
24
24
24
24
3
0.4
0.4
DMF
0.4
H2O
0.2
HMPT
HMPT
78
86
0.6
3
aReaction conditions: Aldehyde 1a (1 mmol), 2a (1 mmol), NaN3 (2 mmol), CuI (0.1~0.3
mmol), sodium ascorbate (0.2~0.6 mmol), and base (1 mmol) in solvent (3 mL);
bIsolated yields.
10

Table 2. Preparation of 1,4-disubstituted 1,2,3-triazoles containing formyl group (3)a
Entry
Aldehyde
Alkynes
Product
3
Yieldb of 3
( % )
1
2
1
2
88
1a
1b
3a
3b
53
81
3
1a
3c
4
5
85
87
1a
1a
3d
3e
6
7
8
80
84
77
1a
1a
1a
3f
3g
3h
9
68
73
1a
1a
3i
3j
10
11

aReaction conditions: Aldehyde 1 (1 mmol), NaN3 (2 mmol), Substrate 2 (1 mmol), CuI
(0.2 mmol), sodium ascorbate (0.4 mmol), and DBU (1 mmol) in HMPT (3 mL);
bIsolated yields.
12

Scheme 1. One-pot synthesis of 1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic
acids and nitrobenzaldehydes.
13

Scheme 2. The proposed mechanism for the reaction of anti-3-aryl-2,3-dibromopropanoic
acids and nitrobenzaldehydes.
14