Cu(I)-promoted one-pot click-SNAr reaction of nitrobenzaldehydes

Article abstract of DOI:10.1080/00397911.2016.1185526

A series of 1,4-disubstituted 1,2,3-triazoles containing formyl was synthesized from a variety of readily available nitrobenzaldehydes and alkynes via a convenient one-pot, click-S_NAr reaction with moderate to excellent yields. The reactions we

Full text of DOI:10.1080/00397911.2016.1185526

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Cu(I)-promoted one-pot “Click-SNAr reaction” of
nitrobenzaldehydes
Changhui Su, Zhiyuan Ding, Xia Liu, Kai Cui & Jiejie Ma
To cite this article: Changhui Su, Zhiyuan Ding, Xia Liu, Kai Cui & Jiejie Ma (2016): Cu(I)-
promoted one-pot “Click-SNAr reaction” of nitrobenzaldehydes, Synthetic Communications,
DOI: 10.1080/00397911.2016.1185526
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1185526
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Date: 10 May 2016, At: 05:28

Cu(I)-promoted one-pot “Click-SNAr reaction” of nitrobenzaldehydes
Changhui Su1, Zhiyuan Ding1, Xia Liu1, Kai Cui1, Jiejie Ma1
1Chemistry and Life Science College, Nanjing University Jinling College, Nanjing, P.R.
China, 2College of Environment Science and Technology, Jiangsu Open University,
Nanjing, P.R. China
Address correspondence to Changhui Su, E-mail: suchanghui1982@163.com
Abstract
A series of 1,4-disubstituted 1,2,3-triazoles containing formyl was synthesized from a
variety of readily available nitrobenzaldehydes and alkynes via a convenient one-pot
“click-SNAr reaction” with moderate to excellent yields. The reactions were easily carried
out in hexamethyl phosphoramide in the absence of a base at 60 °C.
GRAPHICALABSTRACT
KEYWORDS: Click chemistry, 1,2,3-Triazoles, Heterocycle, Copper catalysis
INTRODUCTION
The 1,2,3-triazole ring is an important structure in the pharmaceutical and agrochemical
industries [1]. The discovery of the Cu (I)-catalyzed 1,3-dipolar cycloaddition of azides
and terminal alkynes has further triggered the conduct of studies on both the structure and
synthesis of this heterocycle [2]. The widely used Cu (I)-catalyzed method offers many
advantages, such as exclusive regioselectivity, wide substrate scope, mild reaction
1

conditions, and excellent yields. Moreover, the formed molecules containing the
1,2,3-triazole structure are widely found in biological activities, including antibacterial [3]
herbicidal, antifungicidal [4], antiallergic [5], and anti-HIV activities [6], and they serve as
,
selective b3 adrenergic receptor agonists [7–9]
.
The rapidly increasing need for these hetero-compounds has prompted researchers to
develop effective methods for preparing diverse 1,2,3-triazole derivatives. In our
previous work, we reported several 4(3H)-quinazolinones containing 1,2,3-triazole
moiety conjugated with Schiff base, in which 1,2,3-triazoles containing formyl were
obtained in a two-step process given that the azido benzaldehyde had to be isolated
separately [10–12]. Other groups have also reported on the synthesis of 1,4-disubstituted
1,2,3-triazoles from terminal alkynes [13]. Multicomponent reactions have offered a rapid
and efficient route to generate complex molecular frameworks from simple and rapidly
available substrates owing to their excellent catalytic efficiency in most cases [14]. In the
present study, we proposed a novel method for preparing a series of 1,2,3-triazoles
containing formyl from nitrobenzaldehydes, sodium azide, and alkynes by using a
one-pot “click-SNAr reaction” (Figure 1).
2

RESULTS AND DISCUSSION
The optimum reaction conditions were preliminarily screened using p-nitrobenzaldehyde
1a (1 mmol), NaN3 (1.2 equiv.), and alkyne 2a (1.1 equiv.) as model substrates (Table 1).
We initially investigated the effects of various solvents on the formation of triazole 3a.
Hexamethyl phosphoramide (HMPT) was considerably more effective than the other
solvents and showed an excellent yield of 89% at 60 °C within 2 h (Table 1, entry 7). No
product was obtained when water was used as solvent probably because of the low
solubility of some of the starting materials (entry 5). By contrast, the reactions using
DMSO or DMF as solvent generated products in moderate yields (entries 1–2).
N-methyl-2-pyrrolidone (NMP) as solvent was apparently suitable for the system because
of its good yield of 85% at 60 °C for 24 h (entry 6). The effects of various amounts of
CuI and sodium ascorbate were also investigated (Table 1, entries 9–11). As expected, 0.2
equiv. of CuI and 0.4 equiv. of sodium ascorbate were necessary in the cycloaddition.
Thus, the reaction should be catalyzed by copper (I) iodide (0.2 equiv.) and sodium
ascorbate (0.4 equiv.) in HMPT at 60 °C for 2 h or at room temperature for 24 h.
The substrates scope of this one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles
catalyzed by the copper (I) catalyst was investigated under optimized conditions, and the
results are summarized in Table 2. This protocol is apparently applicable to alkynes
carrying either an aryl group, including electron donating substituents (e.g., ethyl and
alkoxy, entries 3–4) and electron withdrawing substituents (e.g., chloro, fluoro, entries
5–6), or an aliphatic group, such as chloromethyl, hydroxymethyl, n-amyl, and carboxyl
(entries 8–11); this method showed moderate to excellent yields. The electronic effects
3

and the positions of the substituents did not appreciably influence the reaction. Unlike the
p-substituents, the substrates bearing an o-substituent suffer from a low reaction rate with
a low yield at 80 °C within 4 h (entry 13) probably because of the steric hindrance effect,
as well as the occurrence of the by-product benzoxazole, which was reported by Stokes et
al [15]. However, a decarboxylation product 3l was unexpectedly observed when we used
propiolic acid as substrate under the same conditions. To further investigate, we changed
the temperature from 60 °C to 25 °C for 12 h. The adduct 3k containing a carboxylic
substituent was obtained at a yield of 79%. In addition, the decarboxylation product 3m
was observed when we reacted o-nitrobenzaldehyde instead of p-nitrobenzaldehyde with
propiolic acid at 80 °C for 4 h. The decarboxylation product was previously reported by
Kuang et al. [16]. When propiolic acid was used as substrate in the presence of DBU, the
reactions produced a decarboxylation product at 130 °C and a product containing a
carboxylic substituent at temperatures below 25 °C.
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 on a Bruker AV400 MHz spectrometer by using
tetramethylsilane as internal standard and DMSO-d6 or CDCl3 as solvent at room
temperature. Elemental analyses were performed using a Perkin–Elmer 2400 CHNS
elemental analyzer. Mass spectra were obtained using a Finnigan MAT-95 mass
spectrometer. All reactions were monitored by TLC equipped with Huanghai GF 254
4

silica gel-coated plates. Column chromatography was performed using 100–200 mesh
silica gel under medium pressure. All the reagents for the synthesis were commercially
available and used as received or purified via standard methods prior to use.
General Procedure for the Synthesis of 1,2,3-triazoles (3a-m)
The solution of o- or p-nitrobenzaldehyde (151 mg, 1 mmol), NaN3 (78 mg, 1.2 mmol),
alkyne (1.1 mmol), CuI (38 mg, 0.2 mmol), and Na ascorbate (79 mg, 0.4 mmol) in
HMPT (3 mL) in a round-bottom flask was stirred under N2. The mixture was heated to
the temperature indicated in Table 2 until the starting o/p-nitrobenzaldehyde was
completely consumed (monitored by TLC). The mixture was diluted with H2O and then
extracted with EtOAc or CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with sat. brine (3 × 30 mL), dried with anhyd. Na2SO4, and concentrated under reduced
pressure to obtain the crude product, which was purified via flash chromatography (silica
gel, particle size 100–200 mesh, n-hexane-EtOAc) or crystallized by EtOAc.
Spectral Characterization of 3c
Compound 4-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (3c) was obtained as
white solid. Yield: 92%, mp: 193.5 °C–196.0 °C. IR (KBr): 3137, 2961, 1691, 1604,
1591, 1411, 1230 cm−1. 1H NMR (400 MHz, CDCl3): δ 10.10 (s, 1H), 8.27 (s, 1H), 8.10
(d, J = 8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz,
2H), 2.72 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
190.66, 149.08, 145.14, 141.06, 135.94, 131.40, 128.54, 127.13, 125.96, 120.38, 116.84,
5

28.74, 15.49. MS (ESI): m/z 278 (M+H)+. Anal. Calcd. for C17H15N3O: C, 73.63; H, 5.45;
N, 15.15. Found: C, 73.59; H, 5.46; N, 15.19.
CONCLUSIONS
A simple and efficient method used to directly prepare 1,4-disubstituted 1,2,3-triazoles
containing formyl from a variety of aromatic and aliphatic alkynes, sodium azide, and o-
and p-nitrobenzaldehyde was developed. This method displayed moderate to excellent
yields. Further studies on the applications of the proposed methodology to the synthesis
of biologically active compounds are ongoing.
ACKNOWLEDGMENT
This work was supported by the Natural Science Fund for Colleges and Universities in
Jiangsu Province (15KJD350001) and the Subject of “Twelfth Five-Year-Plan” of Jiangsu
Open University (14SEW-Y-006).
SUPPLEMENTARY MATERIAL
Complete experimental details and the 1H and 13C NMR spectra obtained in this study
can be found in the “Supplementary Content” section of this article’s webpage.
6

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8

Entry
CuI
Sodium
ascorbate
(equiv.)
Solvent
Temperature
(°C)
Time
(h)
Yield a
(equiv.)
of 3a (%)
1
2
3
4
5
6
7
8
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
DMSO
DMF
60
60
60
60
60
60
60
60
24
24
24
24
24
24
2
45
16
10
7
MeCN
Dioxane
H2O
0
NMP
80
90
75
HMPT
HMPT-H2O
(9:1)
2
9
0.2
0.5
0.1
0.4
1
HMPT
HMPT
HMPT
25
60
60
24
2
83
91
73
10
11
0.2
2
9

a
Entr Aldehyd
Alkynes
T
Tim Produc
Yiel
d b
2
y
e
(°C e (h)
)
t
3
1
of 3
(%)
1
60
80
60
2
4
2
90
68
92
1a
1b
1a
3a
3b
3c
2
3
4
60
60
60
2
2
2
87
86
90
1a
1a
1a
3d
3e
3f
5
6
10

7
8
9
60
60
60
2
2
2
83
89
87
1a
1a
1a
3g
3h
3i
10
60
2
92
1a
3j
11
12
25
60
12
2
79
86
1a
1a
3k
3l
13
80
4
73
1b
3m
a Reaction conditions: 1 (1 mmol), NaN3 (1.2 mmol), alkyne (1.1 mmol), CuI (0.2
equiv.), and sodium ascorbate (0.4 equiv.) in HMPT (3 mL); b Isolated yields.
11

Figure 1. One-pot click-SNAr reaction used to prepare 1,2,3-triazoles containing formyl
12