Copper-catalyzed cascade cyclization reaction of 2-haloaryltriazenes and sodium azide: Selective synthesis of 2 H-benzotriazoles in water

Article abstract of DOI:10.1002/chem.201303712

A new approach to the synthesis of 2 H-benzotriazoles is described. This strategy is based on the copper-catalyzed Ci￡N coupling of 2-haloaryltriazenes or 2-haloazo compounds with sodium azide and the intramolecular addition of nitrene to N=N bonds. This approach allows the synthesis of various N-amino- and N-aryl-2 H-benzotriazoles in water, in good to excellent yields. The procedure is simple and the starting materials and catalyst are easily available, offering a practical and convenient synthetic route to 2-substituted benzotriazoles.

Full text of DOI:10.1002/chem.201303712

DOI: 10.1002/chem.201303712
Communication
&
Catalysis
Copper-Catalyzed Cascade Cyclization Reaction of
2-Haloaryltriazenes and Sodium Azide: Selective Synthesis of
2H-Benzotriazoles in Water
Xiaobo Shang,[a] Shixian Zhao,[a] Wanzhi Chen,*[a] Chao Chen,[b] and Huayu Qiu*[b]
triazoles as the major products, was achieved by using silyl-
ethynyliodonium triflates as the alkynylating agents.[9]
Abstract: A new approach to the synthesis of 2H-benzo-
triazoles is described. This strategy is based on the
copper-catalyzed CÀN coupling of 2-haloaryltriazenes or
2-haloazo compounds with sodium azide and the intramo-
lecular addition of nitrene to N=N bonds. This approach
allows the synthesis of various N-amino- and N-aryl-2H-
benzotriazoles in water, in good to excellent yields. The
procedure is simple and the starting materials and catalyst
are easily available, offering a practical and convenient
synthetic route to 2-substituted benzotriazoles.
The azido group can function as a nitrene precursor and par-
ticipate in intramolecular annulation reactions. Examples in-
clude rhodium-catalyzed intramolecular cyclization reactions of
2-azidoarylalkenes,[10] gold-catalyzed intramolecular nucleophil-
ic addition of ortho-azidophenylalkyne,[11] and CuI-mediated
cascade-cyclization of a range of substituted 1-(2-azidophenyl)-
3-alkenylallenes, leading to various substituted indoles and cy-
clopentannelated indoles.[12] The synthesis of 2-azidoarylimines,
generated from N-(2-bromobenzylidene)anilines and sodium
azide in the presence of a copper catalyst, has been applied to
the synthesis of indazoles.[13] An iron(II)-catalyzed transforma-
tion of aryl and vinyl azides, with ketone or methyl oxime, into
2,1-benzisoxazoles, indazoles, or pyrazoles through the forma-
tion of an NÀO or NÀN bond has also been reported.[14]
Benzo[1,2,3]triazole derivatives are important nitrogen-contain-
ing heterocyclic compounds. They have been widely used in
material science,[1] synthetic organic chemistry,[2] pharmaceuti-
cal chemistry, and agricultural chemistry[3] owing to high reac-
tivity, interesting structures, and anticancer properties. Benzo-
[1,2,3]triazole exists as N1-, N2-, and N3-substituted isomers; the
1H isomer is predominant because of its stability.
Aryl azides can be prepared through CuI-catalyzed CÀN cou-
pling of aryl halides and sodium azide.[15] We envisioned that
the intramolecular annulation of 2-azidoaryltriazene or 2-azido-
arylazo compounds, generated from the CÀN cross-coupling
reaction of 2-halotriazene or 2-haloazo compounds with
sodium azide, could occur by means of a reaction between the
nitrene species and the N=N bond, after releasing one mole-
cule of N2. Thus, benzotriazoles could be produced with the re-
tention of the substituents at the 2-position. Herein, we de-
scribe a cascade reaction between 2-haloaryltriazene and
sodium azide to form substituted 2H-benzotriazoles in water.
Initially, the reaction between 2-iodoaryltriazene and sodium
azide was carried out, in DMSO at 1308C, by using CuI
(0.1 equivalents) and l-proline (0.2 equivalents) as the catalyst
and ligand, respectively. To our delight, the desired product, 5-
methyl-2-(pyrrolidin-1-yl)-2H-benzo[d][1,2,3]triazole (2a), was
successfully obtained in 56% yield (Table 1, entry 1). The struc-
ture of 2a was unambiguously determined by single-crystal
analysis (Figure 1). Other N donors, such as 1,2-cyclohexanedia-
mine and 1,10-phenanthroline, are also efficient ligands, pro-
viding benzotriazole in 51% and 59% yields, respectively
(Table 1, entries 2 and 3). The combination of 2,2’-bipyridyl and
CuI was found to be completely inactive (Table 1, entry 4).
When TMEDA was used as the ligand, the yield can be in-
creased to 86%. Next, various copper sources, such as CuCl,
CuBr, Cu2O, and Cu(OAc)2 were screened as catalysts. Both cop-
per(I) and copper(II) species were found to be active catalysts,
showing little difference with respect to their activities. We
also examined the influence of solvents. Polar solvents were
found to be more appropriate for the reaction. For example,
Aryl-1H-benzo[d][1,2,3]triazole can be reliably and conven-
iently prepared from the [3+2] annulation reactions of arynes
with organic azides,[4] the reaction of (Z)-1-aryl-3-hexen-1,5-
diynes with sodium azide,[5] the intramolecular cyclization of 2-
haloaryltriazenes through copper-catalyzed CÀN coupling,[6]
and 1,7-palladium migration by means of CÀH activation fol-
lowed by intramolecular amination.[7] However, to the best of
our knowledge, there are few reports on the direct and regio-
selective preparation of 2H-benzotriazole derivatives. The
direct N-arylation of unsubstituted benzotriazole with benzyne
proceeded well, but afforded a 1:3.5 mixture of N2- and N1-aryl-
ation products.[8] Recently, regioselective alkynylation at the 2-
position of benzotriazole, giving 2-silylethynyl-2H-1,2,3-benzo-
[a] X. Shang, S. Zhao, Prof. Dr. W. Chen
Department of Chemistry, Zhejiang University
Hangzhou 310028 (China)
Fax: (+86)571-88273314
E-mail: chenwzz@zju.edu.cn
[b] Dr. C. Chen, Prof. Dr. H. Qiu
College of Material, Chemistry and Chemical Engineering
Hangzhou Normal University
Hangzhou 310013 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303712.
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Table 1. Optimization of the reaction conditions.
Table 2. Reactions of 2-iodoaryltriazenes with sodium azide.[a]
Catalyst
(0.1 equiv) (0.2 equiv)
Ligand
Additive
(0.2 equiv)
Solvent Yield
[%]
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
l-proline
–
–
–
–
–
–
–
–
–
–
–
–
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
dioxane 15
p-xylene 18
DMF
H2O
56
51
59
N.R.[d]
86
56
62
60
55
1,2-cyclohexanediamine
1,10-phenanthroline
2,2’-bipyridyl
TMEDA
TMEDA
TMEDA
CuI
CuBr
CuCl
Cu2O
TMEDA
Cu(OAc)2 TMEDA
10 CuI
11 CuI
12 CuI
13 CuI
14 CuI
15 CuI
16 CuI
17 CuI
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
–
71
76
62
73
81
64
Macrogol 400[a] H2O
SDS[b]
CTAB[c]
CTAB[c]
H2O
H2O
H2O
[a] Polyethylene glycol. [b] Sodium n-dodecyl sulfate. [c] Hexadecyltrime-
thylammonium bromide. [d] N.R.=no reaction.
[a] All reactions were carried out with 2-iodoaryltriazene (1.0 mmol), NaN3
(1.5 mmol) CuI, TMEDA, and CTAB in water (2.0 mL) at 1308C, under nitro-
gen in a sealed tube, for 16 h.
Under the optimized conditions, the reactions of various 2-
iodoaryltriazenes with sodium azide were screened and the re-
sults are summarized in Table 2. 2-Iodoaryltriazenes with either
electron-donating groups or electron-withdrawing groups re-
acted smoothly, affording the corresponding benzotriazoles in
moderate to excellent yields. The effect of the amino group
was also studied and it was revealed that cyclic amino groups,
such as piperidyl and morpholinyl moieties, react favorably. For
example, the reaction of 1-(2-iodophenyl)-2-(piperidin-1-yl)dia-
zene (1d) and sodium azide afforded the corresponding prod-
uct in 91% yield. In contrast, when a triazene bearing a diiso-
propylamino group (1h) was used, only 58% of the corre-
sponding product (2h) was obtained; probably owing to the
effects of steric hindrance. 2-Bromoaryltriazene derivatives
could also be converted to benzotriazoles in moderate to ex-
cellent yields. Both electron-donating and electron-withdraw-
ing substituents at the phenyl ring can be tolerated in this re-
action.
Figure 1. X-ray crystal structure of compound 2a.
the reaction of 2-iodoaryltriazene and sodium azide in dioxane
and in p-xylene gave the desired benzotriazole in low yields
(15 and 18%, respectively), whereas when DMF and water
were used as the solvents the yields of the reaction were in-
creased to 71 and 76%, respectively, (Table 1, entries 12 and
13). The addition of a non-ionic surfactant, macrogol 400, or
an anionic surfactant, sodium n-dodecyl sulfate (SDS), did not
improve the reaction in water (Table 1, entries 14 and 15).
However, the yield increased to 81% in the presence of the
cationic surfactant, hexadecyltrimethylammonium bromide
(CTAB, Table 1, entry 16). Although the yield of the reaction in
water is slightly lower than that of the reaction in DMSO, we
chose the green solvent, water, as the final solvent for the fol-
lowing investigations. In addition, we found that the reaction
could proceed in the absence of N-donating ligands, giving
a moderate yield (Table 1, entry 17).
The reactions of 2-bromotriazenes with sodium azide were
also investigated by using a CuI/TMEDA (TMEDA=N,N,N’,N’-
tetramethylethylenediamine) catalyst. The copper-catalyzed CÀ
N coupling of aryl bromides is expected to show lower activity
than that of the corresponding aryl iodides. The reactions of
pyrrolidin-1-yl and piperidin-1-yl derivatives 3a–d with sodium
azide gave the corresponding annulation products, 2a–d, in
reduced yields at 1308C, in comparison with the iodo ana-
logues (Table 3). However, the annulation reactions of N,N-di-
methyl and N,N-diethyl derivatives provided the 2H-triazoles
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Table 3. Reactions of 2-bromoaryltriazenes with sodium azide.[a]
Scheme 1. Reactions of 2-haloazo compounds. All reactions were carried out
with 2-haloazo compound (1.0 mmol), NaN3 (1.5 mmol), CuI, TMEDA, and
CTAB in water (2.0 mL) at 1308C, under nitrogen in a sealed tube, for 16 h.
nyldiazene could be converted into their corresponding 2-phe-
nyltriazoles, in up to 95% yield, in the presence of 10mol% of
CuI.
Based on a previous report,[13] a possible mechanism is de-
scribed in Scheme 2. The copper-catalyzed CÀN coupling reac-
tion between 2-haloaryltriazene and sodium azide yields 2-
azidoaryltriazene. Thermal decomposition of 2-azidoarytriazene
could generate the active nitrene intermediate by releasing
one molecule of N2. The terminal N atom of the activated azide
is then attacked by the nucleophilic nitrogen atom of the aryl-
triazene, resulting in the formation of a NÀN bond. The loss of
one molecule of N2, followed by dissociation of the copper ion
from intermediate C, generates the final product.
[a] All reactions were carried out with 2-bromoaryltriazene (1.0 mmol),
NaN3 (1.5 mmol), CuI, TMEDA, and CTAB in water (2.0 mL) at 1308C,
under nitrogen in a sealed tube, for 16 h.
Scheme 2. A proposed mechanism.
In summary, we have described a copper-catalyzed cascade
reaction between 2-haloaryltriazenes and sodium azide in
water. The reaction is highly regioselective and a number of 2-
aryl- and 2-aminobenzotriazoles have been obtained in moder-
ate to excellent yield. The procedure is simple and the starting
materials and catalyst are easily available. This reaction offers
a practical and convenient synthetic route to 2-substituted
benzotriazoles from aryltriazenes and azo compounds.
(4j, 4k, 4n, 4p, and 4q) in yields comparable to those ob-
tained from the corresponding 2-iodotriazenes. The cascade
CÀN coupling and cyclization reaction was also applied to N-
aryltriazenes. The N-aryl-substituted triazenes, 3s–3v, could
easily be transformed into 2-(N-alkyl-N-phenylamino)-2H-
benzo[d][1,2,3]triazole (4s–4v) in moderate to excellent yield.
In the presence of a CuI/TMEDA catalyst, the 2-haloazo com-
pounds also reacted with sodium azide in water, providing 2-
arylbenzotriazoles in excellent yields. As shown in Scheme 1, 1-
(2-bromophenyl)-2-phenyldiazene and 1-(2-iodophenyl)-2-phe-
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Experimental Section
Sodium azide (1.5 equivalents), copper iodide (0.1 equivalents),
TMEDA (0.2 equivalents) and CTAB (0.2 equivalents) were added to
a solution of 2-haloaryltriazene or 2-haloazo compound (1 mmol)
in water (2 mL). The mixture was stirred at 1308C, in a sealed tube
under nitrogen, for 16 h. After completion, monitored by thin-layer
chromatography (TLC), the reaction mixture was extracted with
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This project is supported by National Science Foundation of
China (21072170).
Keywords: benzotriazoles · cascade cyclizations
azide · water
· sodium
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Published online on January 21, 2014
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