Regioselective N/C-heterocyclization of allenylindium bromide across aryl azides: One-pot synthesis of 5-methyl-1,2,3-triazoles

Article abstract of DOI:10.1055/s-0034-1378327

An unprecedented, one-pot regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles through N/C-heterocyclization of allenylindium bromide across aryl azides is described. The synthesis is carried out under mild conditions in aqueous medium and procee

Full text of DOI:10.1055/s-0034-1378327

LETTER
▌1859
lRetteergioselective N/C-Heterocyclization of Allenylindium Bromide Across Aryl
Azides: One-Pot Synthesis of 5-Methyl-1,2,3-triazoles
One-Pot Synthesis of 5-Methyl-1,2,3-triazoles
Abid H. Banday,* Victor J. Hruby
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA
Fax +1(520)6218407; E-mail: abidrrl@gmail.com
Received: 12.03.2014; Accepted after revision: 20.05.2014
pensive ruthenium complexes,14 which is economically
Abstract: An unprecedented, one-pot regioselective synthesis of
unviable.
1,5-disubstituted 1,2,3-triazoles through N/C-heterocyclization of
allenylindium bromide across aryl azides is described. The synthe-
sis is carried out under mild conditions in aqueous medium and pro-
ceeds regioselectively in moderate to good yields.
Among 1,5-disubstituted 1,2,3-triazoles, 1-aryl-5-methyl-
1,2,3-triazoles represents an interesting class of mole-
cules, and these have previously been synthesized through
very difficult methods with some involving multistep pro-
cesses. The most important methods for their synthesis in-
volve the reaction of aryl azides with β-ketoesters
resulting in the generation of 5-methyl-1,2,3-triazole-4-
carboxylic acids.15 The decarboxylation by heating above
the melting point of the compounds leads to the genera-
tion of 5-methyl-1,2,3-triazoles. However, the reaction
literally decomposes the compound, and yields are very
low. Another method involves the treatment of aryl azides
with α-keto phosphorous ylides in anhydrous benzene un-
der reflux conditions with reaction times varying from
hours to days.16 Thus, there exists a scope for the efficient
one-pot synthesis of 5-methyl-1,2,3-triazoles, and the
method under discussion17 offers a very interesting route
for the synthesis of the same. This is especially interesting
in terms of the methyl group being amenable to lots of
modifications providing a route to the efficient synthesis
of other derivatives. The aqueous condition under which
the reaction takes place offers another advantage of being
environment friendly.
Key words: heterocyclization, aryl azides, 1,2,3-triazoles, allenyl-
indium bromide, regioselective reactions
1,2,3-Triazoles are an interesting class of compounds be-
cause of their excellent biological activities,1 receptor
binding interactions, and bioconjugation properties.2
These serve as building blocks for more complex com-
pounds including numerous pharmaceutical drugs.3 Such
structures frequently exist in natural products,4 pharmaco-
logically active molecules3 and designed materials.5 Be-
sides being associated with a number of biological
properties, 1,2,3-triazole derivatives have also found in-
dustrial applications as dyes, corrosion inhibitors, sensors,
and photo-stabilizers.6 Such molecules also have a role as
synthetic intermediates,7 ligands,8 probing agents for bio-
logical molecules, and fluorescent labeling of oligonucle-
otides.9 Because of their diverse biological roles, the
synthesis of such structures has been of longstanding im-
portance to synthetic organic chemists. The most attrac-
tive synthetic route is the atom-economical azide–alkyne
cycloaddition10,5a which, however, suffers from the disad-
vantage of producing regioisomeric mixtures of 1,4- and
1,5-disbstituted 1,2,3-triazoles. However, much attention
was paid during the last decade to the development of
novel catalytic systems which can make such reactions re-
gioselective. The click chemistry protocols involving cop-
We previously reported the unprecedented regioselective
synthesis of 1-aryl-5-butynyl-1,2,3-triazoles 318 from or-
ganic azides 1 and allenylmagnesium bromide (2) under
anhydrous conditions. The reaction followed a domino
route leading to a cascade addition of two allenyl mole-
cules to aryl azides (Scheme 1).
per(I)-
and
silver(I)-catalyzed
azide–alkyne
N
Ar
–
N
+
N
cycloadditions are the most efficient regioselective meth-
ods for the synthesis of 1,4-disubstituted 1,2,3-tri-
azoles.11,12 In contrast, there are only few satisfactory
methods available for the regioselective synthesis of 1,5-
disubstituted-1,2,3-triazoles. Typical routes for the syn-
thesis of 1,5-disubstituted regioisomers employ the use of
in situ generated sodium, lithium, or magnesium
acetylides.13 However, such reactions involve the use of
large excess of strong bases and thus produce undesirable
chemical waste. Another method for the synthesis of 1,5-
disubstituted regioisomers involves the use of highly ex-
N
N
N
Ar
+
MgBr
1
2
3
Scheme 1 Synthesis of 1-aryl-5-butynyl-1,2,3-triazoles
In our efforts to avoid the cascade and allow addition of
just one allenyl molecule across azides so as to generate
synthetically more potent 5-methyl-1,2,3-triazoles, we
chose to use aqueous medium and a water-tolerant alle-
nylmetal halide, so that the reaction gets quenched after
the very first addition of this reagent. The metal of choice
turned out to be indium which forms allenylindium ha-
SYNLETT 2014, 25, 1859–1862
Advanced online publication: 12.06.2014
DOI: 10.1055/s-0034-1378327; Art ID: st-2014-r0218-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1860
A. H. Banday, V. J. Hruby
LETTER
–
I+nBr
InBr
N
–
N
+
N
Ar
n-BuNH2
N
N
N
Ar
THF–H2O
aq NH4Cl
4
1
6a–m
Plausible mechanisms:
–
+
N
N
Ar
N
N
N N
N
Ar
N
N
Ar
aq NH4Cl
THF–H2O
–
I+nBr
InBr
6
5
1
(a) concerted cycloaddition involving propargyl indium bromide
N
+
N
Ar
–
N
N
N
N
Ar
N
N
N
aq NH4Cl
Ar
THF–H2O
InBr
InBr
6
5
4
1
(b) concerted cycloaddition involving allenylindium bromide
+
InBr
–
N
N
+
N
–
N
Ar
N
N
N
N
N
Ar
N
N
Ar
Ar
aq NH4Cl
THF–H2O
N
InBr
InBr
1
4
6
5
(c) non-concerted mechanism involving allenylindium bromide
Scheme 2 Synthesis of 1-aryl-5-methyl-1,2,3-triazoles
lides when treated with propargyl halides.19 Upon treat- nitrogen atom due to delocalization of π-electrons. We at-
ment with aryl azides 1, propargyl/allenylindium bromide tempted the reaction with alkyl azides and substituted
4 (propargyl and allenylindium bromide are in equilibri- propargyl bromides, but the yields were insignificant un-
um) adds across the aryl azides in one of the probable der these reaction conditions. The use of a basic additive
ways given in Scheme 2 to generate the cyclized product
5. After quenching, the final product, i.e. 1-aryl-5-methyl-
1,2,3-triazole 6 is obtained in good yields (Scheme 2).
Table 1 Optimization of the Reaction Conditions
However unlike the cycloaddition using allenylmagne-
sium bromide, the kinetics of this reaction proved to be
slow. We used various solvents, co-solvents, and addi-
tives at different temperatures to get the best yields and
came up with the best reaction conditions for good yields
as shown below (Table 1).
Entry Solvent
T (°C) Additive
Yield (%)a
1
2
3
4
5
6
7
8
9
THF
25
25
25
50
50
25
50
25
50
–
30
45
48
77
75
25
33
30
32
THF–H2O (2:1)
THF–H2O (1:1)
THF–H2O (1:1)
THF–H2O (1:2)
MeCN–H2O (1:1)
MeCN–H2O (1:1)
DMF–H2O (1:1)
DMF–H2O (1:1)
n-BuNH2
–
As evident from the table, the best yields were obtained
when aryl azides were treated with allenylindium bromide
in a THF–H2O (1:1) solvent system at a temperature of 50
°C in presence of n-butylamine as an additive. Any further
increase in temperature did not increase the yield. An in-
crease in the water percentage of the solvent mixture had
a negative impact on the overall yields. The preferred use
of aryl azides for the present study may be attributed to the
fact that aryl azides are more reactive than alkyl azides be-
cause of the increased nucleophillicity of the neighboring
n-BuNH2
n-BuNH2
–
n-BuNH2
–
n-BuNH2
a Isolated yield for the product 6a which was used for optimization.
Synlett 2014, 25, 1859–1862
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of 5-Methyl-1,2,3-triazoles
1861
enhances the overall yield for aryl azides as the substrates.
Though there are no mechanistic inputs available for this
observation, it may however be assumed that butyl amine
probably interacts with indium centers leading to a change
in the reactivity of these systems.
Supporting Information for this article is available online
at http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
References and Notes
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6a
6b
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6e
6f
60–61
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77
75
69
72
70
73
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4-BrC6H4
3-ClC6H4
α-C10H7
77–78
116–118
44–46
4-MeOC6H4
β-C10H7
116–117
44–46
6g
6h
6i
4-EtOC6H4
4-ClC6H4
2,5-Cl2C6H3
3-BrC6H4
4-NO2C6H4
4-FC6H4
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Table 2 shows the synthesis of 5-methyl-1,2,3-triazole
derivatives 620 under the optimized reaction conditions.
In conclusion, the present method offers an unprecedent-
ed, one-pot, regioselective synthesis of 1-aryl-5-methyl-
1,2,3-triazoles through N/C-heterocyclization of allenyl-
indium bromide across aryl azides. The synthesis is car-
ried out under mild reaction conditions in aqueous
medium and proceeds regioselectively in moderate to
good yields. No traces of the 1,4-disubstituted product are
obtained. The methyl group is amenable to various modi-
fications and thus provides a route of further modification
for building up complex molecules.
Acknowledgment
AHB thanks UGC, India for the award of Raman postdoctoral fel-
lowship under Singh–Obama 21st century knowledge initiative. The
study was supported in part by the US Public Health Service, NIH
NIDA, Grant RO1 DA 13449.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1859–1862

1862
A. H. Banday, V. J. Hruby
LETTER
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(17) Typical Procedure for the Synthesis of 1-Phenyl-5-
methyl-1,2,3-triazole (6a, Table 2): In a typical procedure,
a suspension of indium powder (0.344 g, 3 mmol, 100 mesh,
99.99% pure), and propargyl bromide (00.238 g, 2 mmol) in
THF–H2O (1:1; 20 mL) was stirred at an ambient
(2 × 20 mL). The combined organic layers were dried (anhyd
Na2SO4) and evaporated under reduced pressure to afford a
crude product, which was subjected to chromatography
(Alumina, mean pore diameter 60 Å, eluent: n-hexane–
EtOAc gradient) to afford pure 1-phenyl-5-methyl-1,2,3-
triazole as a pale yellow solid (0.244 g, 1.54 mmol, 77%);
mp 61–62 °C. IR (KBr): 1234, 1494, 1549, 1593, 2922, 3138
cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 7.48–
7.50 (m, 2 H), 7.52–7.58 (m, 3 H), 7.70 (s, 1 H). 13C NMR
(400 MHz, CDCl3): δ = 10.3, 125.6, 129.6, 129.8, 130.6,
138.5, 141.2. HRMS (ESI–TOF): m/z [M + H]+ for C9H9N3:
160.0796.
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(20) Most of the compounds (6a–m) are already known in the
literature through the methods discussed in the main text
along with the required references. However, full spectral
details of all unknown analogues have been provided in the
supporting information.
temperature for 3 h until the metal dissolved completely to
form allenylindium bromide. Phenyl azide (0.238 g, 2
mmol) was charged into the reaction mixture at ambient
conditions over a period of 2 min. After 5 min, n-butylamine
(5 mol%) was charged into the reaction mixture as an
additive and the reaction was allowed to stir at 50 °C for 6 h
till TLC proved a significant conversion. The reaction was
finally quenched with aq NH4Cl solution (10 mL) followed
by dilution with another 50 mL. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
Synlett 2014, 25, 1859–1862
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