A convenient and efficient synthesis of C-carbamoyl-1,2,3-triazoles from alkyl bromide by a one-pot sequential addition: Conversion of ester to amide using Zr(Ot-Bu)4

Article abstract of DOI:10.1016/j.tetlet.2010.05.046

A convenient and efficient one-pot sequence has been developed for the synthesis of C-carbamoyl-1,2,3-triazoles from alkyl bromide using (i) sodium azide, (ii) methyl propiolate and copper iodide, and (iii) amines, zirconium tert-butoxide, and 1-hydroxybe

Full text of DOI:10.1016/j.tetlet.2010.05.046

Tetrahedron Letters 51 (2010) 3691–3695
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Tetrahedron Letters
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A convenient and efficient synthesis of C-carbamoyl-1,2,3-triazoles from alkyl
bromide by a one-pot sequential addition: conversion of ester to amide using
Zr(Ot-Bu)4
*
Dongsik Yang, Mihyun Kwon, Yujin Jang, Heung Bae Jeon
Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient one-pot sequence has been developed for the synthesis of C-carbamoyl-1,2,3-
triazoles from alkyl bromide using (i) sodium azide, (ii) methyl propiolate and copper iodide, and (iii)
amines, zirconium tert-butoxide, and 1-hydroxybenzotriazole, under microwave irradiation. The sequen-
tial reactions in one-pot provided the desired C-carbamoyl-1,2,3-triazoles in excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 16 March 2010
Revised 11 May 2010
Accepted 12 May 2010
Available online 15 May 2010
Keywords:
One-pot sequence
C-Carbamoyl-1,2,3-triazole
Zirconium tert-butoxide
Microwave irradiation
The formation of 1,2,3-triazoles using the copper(I)-catalyzed
1,3-dipolar cycloaddition of organic azides and alkynes1 has become
an increasingly attractive area because it is a highly efficient method
in bond formations among diverse building blocks for chemical syn-
thesis,2 bioconjugation,3 materials and surface science,4 combinato-
rial chemistry,5 and medicinal chemistry.6 In particular, a number of
compounds containing C-carbamoyl-1,2,3-triazoles have shown a
broad spectrum of biological activities in recent days.7 Even simple
C-carbamoyl-1,2,3-triazole compounds also showed antiaggregat-
ing and antithrombotic activities.8
C-Carbamoyl-1,2,3-triazoles have been synthesized by 1,3-
dipolar cycloaddition with alkyl azides and acetylenic amides, or
by amide formation in last step after preparing 1,2,3-triazole esters
using alkyl azides and acetylenic esters. The former method, how-
ever, has remained a problem for preparing acetylenic amides be-
cause they were synthesized in low yields,9 and the latter method
needed routine and tedious processes because of the long reaction
time and the purification of the intermediates such as alkyl azide
and 1,2,3-triazole ester. Therefore, it is still of interest to develop
more efficient process for preparing C-carbamoyl-1,2,3-triazoles.
Herein we report the convenient and efficient procedure for syn-
thesizing C-carbamoyl-1,2,3-triazoles from the corresponding alkyl
bromide by sequential addition of reagents and other reactants in
one-pot without any purification of the intermediates generated in
each stage.
We envisioned that treatment of benzyl bromide with sodium
azide would induce benzyl azide A, then addition of propiolic acid
or methyl propiolate would provide 1,2,3-triazole acid B or ester C
(Scheme 1). Without any purification of intermediates A, B, and C,
subsequent reaction of B or C with amine would afford the desired
C-carbamoyl-1,2,3-triazole D. Thus, initially we tried to prepare a
C-carbamoyl-1,2,3-triazole 2 from benzyl bromide by following
sequences in one-pot under microwave irradiation as shown in
Scheme 2: (i) substitution of benzyl bromide by sodium azide in
dimethylacetamide (DMA), (ii) copper(I)-catalyzed 1,3-dipolar
cycloaddition with propionic acid in the presence of a catalytic
amount of copper iodide to give 1,2,3-triazole-4-carboxylic acid
O
N
Ph
N
N
OR
NaN3
OR
Ph
N
N3
Ph
Br
(R = H, Me)
A
O
B, R = H
C, R = Me
R1
R2
R1
HN
Ph
N
N
N
R2
O
D
* Corresponding author. Tel.: +82 2 940 5583; fax: +82 2 911 8584.
E-mail address: hbj@kw.ac.kr (H.B. Jeon).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.046

3692
D. Yang et al. / Tetrahedron Letters 51 (2010) 3691–3695
O
(1.3 eq)
OH
N
Ph
NaN3 (1.1 eq)
DMA
CuI (0.1 eq)
DIPEA (1 eq)
N
N
Method A, B, or C
Br
OH
MW 100W
MW 100W
120 oC, 30 min
120 oC, 30 min
O
1 (~95%)
Method A
Method C
Method B
NH2
NH2
NH2
(6 eq)
(6 eq)
(6 eq)
Ph
N
Ph
Ph
Ph
N
N
H
DIC (1.2 eq)
HOBt (1.2 eq)
DMAP (cat.)
Ph
P
Cl Cl
MeO
N
OMe
N
Ph
Ph
Ph
(2.5 eq)
(1.2 eq)
N
N
O
MW 100W
2
Cl
MW 100W
120 oC, 30 min
not detected
120 oC, 30 min
DMAP (cat.)
MW 100W
120 oC, 30 min
Scheme 2.
1, and (iii) coupling with phenethylamine in the presence of diiso-
propylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt). The
first attempt afforded only 1,2,3-triazole-4-carboxylic acid 1 in
good yield. Thus, we decided to employ other coupling reagents
such as 2-chloro-4,6-dimethoxy-1,3,5-triazine10 and dichlorotri-
phenylphosphorane11 for coupling reaction with the acid 1 and
phenethylamine in the last step. All attempts, however, failed to
give the desired C-carbamoyl-1,2,3-triazole 2, and only the acid 1
was produced in good yield (Scheme 2).
lyzed 1,3-dipolar cycloaddition in second stage. Thus, the desired
product 2 was provided in 57% yield with zinc and in 40% yield
with no additive. On the other hand, when a catalytic amount of
zirconium(IV) tert-butoxide and HOBt13 was employed as additive
in the last stage, surprisingly, the sequential reaction afforded the
desired product 2 in 88% yield14 (Scheme 3 and entry 1 in Table 1).
Therefore, the generality of this sequential addition process
using sodium azide, methyl propiolate, copper iodide, zirco-
nium(IV) tert-butoxide, and HOBt from alkyl bromide for preparing
C-carbamoyl-1,2,3-triazoles was investigated with a variety of
amines under microwave irradiation. The reactions were carried
out by following sequential addition of reagents and reactants to
alkyl bromide: (i) sodium azide in dimethylacetamide (DMA), (ii)
methyl propiolate in the presence of a catalytic amount of copper
iodide, and (iii) amines in the presence of a catalytic amount of zir-
conium(IV) tert-butoxide and HOBt. All reactions performed gave
the C-carbamoyl-1,2,3-triazoles in excellent yields (Table 1). To
benzyl bromide, the above-mentioned sequential addition, (i) and
(ii), was performed. Then, primary amines such as benzylamine
and octylamine in the last step were reacted to afford the desired
C-carbamoyl-1,2,3-triazole 4 and 5 in 72% and 85% yields, respec-
tively (entries 2 and 3). In case of benzylamine, a little low yield
Next, we performed to prepare C-carbamoyl-1,2,3-triazole 2 by
way of 1,2,3-triazole-4-ester
3 according to the following
sequences in one-pot under microwave irradiation as shown in
Scheme 3: (i) substitution of benzyl bromide by sodium azide in
dimethylacetamide (DMA), (ii) copper(I)-catalyzed 1,3-dipolar
cycloaddition with methyl propiolate in the presence of a catalytic
amount of copper sulfate and sodium ascorbate to give 1,2,3-tria-
zole-4-ester 3, and (iii) coupling with phenethylamine in the
presence of zinc12 or without zinc. In this performance the desired
C-carbamoyl-1,2,3-triazole 2 was produced in 43% yield with zinc
and in 35% yield with no additive. Based on this interesting result,
we changed copper sulfate and sodium ascorbate into copper
iodide and diisopropylethylamine as reagents for copper(I)-cata-
O
(1.3 eq)
OMe
NH2
(6 eq)
N
Ph
additive
NaN3 (1.1 eq)
t-BuOH/H2O (1/1)
MW 100W
CuSO4 (0.1 eq)
Na ascorbate (0.2 eq)
Ph
N
N
H
Br
N
MW 100W
MW 100W
Ph
120 oC, 30 min
90 oC, 30 min
100 oC, 30 min
O
2
without additive: 35%
with Zn (1 eq): 43%
O
(1.3 eq)
OMe
NH2
(6 eq)
N
Ph
additive
CuI (0.1 eq)
DIPEA (1 eq)
Ph
NaN3 (1.1 eq)
DMA
N
N
H
Br
N
Ph
MW 100W
MW 100W
MW 100W
100 oC, 30 min
90 oC, 30 min
120 oC, 30 min
O
2
without additive: 40%
with Zn (1 eq): 57%
with Zr(Ot-Bu)4 (0.2 eq)
N
Ph
N
N
OMe
HOBt (0.4 eq): 88%
O
3
Scheme 3.

D. Yang et al. / Tetrahedron Letters 51 (2010) 3691–3695
3693
Table 1
Synthesis of C-carbamoyl-1,2,3-triazoles from alkyl bromide using a one-pot sequential reaction
O
(1.3 eq)
R'R''NH (6 eq)
Zr(Ot-Bu)4 (0.2 eq)
HOBt (0.4 eq)
OMe
N
R
R'
N
CuI (0.1 eq)
DIPEA (1 eq)
N
N
NaN3 (1.1 eq)
DMA
RBr
R''
MW 100W
MW 100W
MW 100W
90 oC, 30 min
100 oC, 30 min
O
2, 4-16
120 oC, 30 min
Entry
1
Alkyl bromide
Amine
Product
Yielda (%)
N
Ph
N
N
H
N
NH2
Ph
Br
88
O
2
N
N
N
N
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
H
N
2
3
4
72
85
89
NH2
O
4
H
N
NH2
5
5
O
5
H
N
NH2
OH
HO
HO
O
6
H
N
NH2
5
91
O
O
OH
7
N
N
Ph
Ph
Ph
N
N
N
N
6
7
89b
NH
N
8
CH3
N
N
N
85b
H3C
NH
O
9
N
N
N
H
N
NH2
8
81
81
Ph
Br
O
10
N
Ph
Ph
N
N
N
H
N
9
NH2
O
11
N
N
H
N
10
83
NH2
5
5
O
12
(continued on next page)

3694
D. Yang et al. / Tetrahedron Letters 51 (2010) 3691–3695
Table 1 (continued)
Entry
Alkyl bromide
Amine
Product
Yielda (%)
N
Ph
N
N
N
N
H
N
NH2
11
12
93
OH
HO
O
O
13
N
Ph
H
N
NH2
93
O
HO
14
N
Ph
Ph
N
N
N
N
N
13
14
84b
NH
O
O
15
N
CH3
N
N
82b
H3C
N
NH
16
a
Isolated yields.
MW 100 W, 120 °C in the third step.
b
NaN3 (1.1 eq)
methyl propiopate (1.3 eq)
phenethylamine (6 eq)
CuI (0.1 eq), DIPEA (1 eq)
Zr(Ot-Bu)4 (0.2 eq), HOBt (0.4 eq)
copper iodide, and (iii) amines in the presence of a catalytic
amount of zirconium(IV) tert-butoxide and HOBt one by one to al-
kyl bromide under microwave irradiation provided the desired C-
carbamoyl-1,2,3-triazoles in excellent yields. We also found that
zirconium(IV) tert-butoxide and HOBt are important reagents to
convert 1,2,3-triazole-4-esters into C-carbamoyl-1,2,3-triazoles in
one-pot sequential reaction. Moreover, this process is very conve-
nient and efficient method because it significantly reduced reac-
tion times and tedious procedures such as work-up and
purification at each step.
N
Ph
N
N
H
N
Ph
Ph
Br
DMA
O
MW 100W, 120 oC, 30 min
2 (25%)
Scheme 4.
of the desired product 4 results from the poor solubility in a mix-
ture of hexane and ethyl acetate which is the eluting solvent in col-
umn chromatography. The reaction of primary amines, such as 2-
hydroxyethylamine and 4-(2-aminoethyl)phenol, with hydroxyl
group also provided the corresponding C-carbamoyl-1,2,3-triazoles
6 and 7 in excellent yields (entries 4 and 5). However, the reaction
of cyclic secondary amines such as piperidine and N-methylpiper-
azine did not give the desired products 8 and 9 at same tempera-
ture (100 °C) with primary amines. When the reaction
temperature was elevated to 120 °C, the reactions afforded the
products 8 and 9 in 89% and 85% yields, respectively (entries 6
and 7). To 3-phenylpropyl bromide, the same sequential reactions
were performed with various amines. All amines investigated pro-
vided the desired C-carbamoyl-1,2,3-triazoles 10–16 in excellent
yields (entries 8–14). The aliphatic secondary amines such as
dibenzylamine and dihexylamine, however, were not reacted with
1,2,3-triazole-4-ester 3 even at 150 °C because of the steric hin-
drance. After performing the complete sequential reaction, the
only product was 1,2,3-triazole-4-ester 3.
On the other hand, when all reagents and reactants such as so-
dium azide, methyl propiolate, copper iodide, DIPEA, phenethyl-
amine, zirconium(IV) tert-butoxide, and HOBt to benzyl bromide
in DMA were added at once and were reacted as multi-component
one-pot reaction at 120 °C for 30 min under microwave irradiation,
the reaction was very complicated and the desired product 2 was
provided only in 25% yield (Scheme 4).
In conclusion, we have found that the one-pot sequential reac-
tions by addition of (i) sodium azide in dimethylacetamide (DMA),
(ii) methyl propiolate in the presence of a catalytic amount of
Acknowledgments
We thank for the support of Korea Research Foundation (KRF)
grant funded by the Korean Government (MOEHRD) (No. 2007-
331-C00156) and research grant of Kwangwoon University in
2008 for this work.
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14. Typical procedure for 2: A solution of benzyl bromide (100 mg, 0.59 mmol),
sodium azide (42 mg, 0.64 mmol), and DMA (1.0 mL) in a 10-mL pressurized
vial was stirred for 30 min at 120 °C in microwave reactor. After cooling to
room temperature, methyl propiolate (71 mg, 0.76 mmol), copper iodide
(11 mg, 0.058 mmol), and DIPEA (0.1 mL, 0.58 mmol) were added. The
resulting solution was stirred for 30 min at 90 °C in microwave reactor. After
cooling to room temperature, zirconium(IV) tert-butoxide (45 mg, 0.12 mmol),
HOBt (30 mg, 0.23 mmol), and phenethylamine (0.44 mL, 3.50 mmol) were
added. The resulting solution was stirred for 30 min at 100 °C in microwave
reactor. After cooling to room temperature, the reaction mixture was
concentrated to remove DMA. The residue was diluted with CH2Cl2 (30 mL)
and washed with saturated NaHCO3 solution (20 mL Â 3). The organic layer
was separated, dried over MgSO4, and concentrated. The residue was purified
by flash column chromatography (hexane/EtOAc, 5:2) to give the desired C-
carbamoyl-1,2,3-triazole 2 (159 mg, 88%) as a white solid. 1H NMR (400 MHz,
CDCl3) d 7.97 (s, 1H), 7.41–7.21 (m, 11H), 5.53 (s, 2H), 3.70 (q, J = 6.8 Hz, 2H),
2.91 (t, J = 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 159.9, 143.6, 138.6, 133.7,
129.2, 129.0, 128.7, 128.6, 128.2, 126.5, 125.2, 54.5, 40.3, 35.8. HRMS (M+Na)
calcd 329.1378, found 329.1395. Anal. Calcd for C18H18N4O: C, 70.57; H, 5.92;
N, 18.29. Found: C, 70.63; H, 5.70; N, 18.57.