Efficient one-pot synthesis of 1,2,3-triazoles from benzyl and alkyl halides

Article abstract of DOI:10.1055/s-2005-864809

An efficient one-pot method for the preparation of 1,2,3-triazoles by 1,3-dipolar cycloaddition of in situ generated azides and alkynes is presented. This facile method can be applied to benzyl or alkyl halides and pure products are isolated by simple filtration.

Full text of DOI:10.1055/s-2005-864809

LETTER
943
Efficient One-Pot Synthesis of 1,2,3-Triazoles from Benzyl and Alkyl Halides
Efficient
One-Pot
a
S
ynthesis
o
r
f
1,2,3-
T
o
riazoles from
l
B
enzyl and
K
A
lkyl
H
alides acprzak*
Department of Chemistry, Adam Mickiewicz University, ul. Grunwaldzka 6, 60-780 PoznaĔ, Poland
Fax +48(61)8658008; E-mail: k.michal@mailcity.com
Received 21 December 2004
Blass who used polymer-supported azides for azidation of
Abstract: An efficient one-pot method for the preparation of 1,2,3-
triazoles by 1,3-dipolar cycloaddition of in situ generated azides
and alkynes is presented. This facile method can be applied to ben-
zyl or alkyl halides and pure products are isolated by simple filtra-
tion.
organic halides.7
We report herein an alternative simple one-pot procedure
for the regioselective preparation of 1,2,3-triazoles (1–16)
from a number of benzyl and alkyl halides as azide precur-
sors. The reaction can be carried out at room temperature
and without any special equipment (Table 1). We as-
sumed that to ensure a high yield of the N-alkyltriazole
and eliminate the formation of the undesired NH triazole
(the product of the cycloaddition of inorganic azide with
alkyne, 17) the procedure should involve two separate
steps, carried out in one flask. It should start with an effi-
cient in situ generation of the benzyl or the alkyl azide,
followed by 1,3-dipolar cycloaddition with an alkyne
(Scheme 1).
Although there are a number of methods for the formation
of azides from halides (by nucleophilic substitution), most
of these require the use of a large excess of inorganic
azides and result in medium to low yields.8 These methods
are unsuitable for the present synthesis due to the compet-
itive NH-triazole (17) formation from the remaining inor-
ganic azide. Detailed inspection of the literature turned
our attention to the work of Alvarez, where a very effi-
cient azidation of various halides with only a slight excess
(1.1 equiv) of NaN3 in anhydrous DMSO at room temper-
ature was described.9
Key words: 1,3-dipolar cycloadditon, click chemistry, 1,2,3-tri-
azoles, one-pot synthesis
1,2,3-Triazoles are an important class of heterocycles due
to their range of applications as pharmaceuticals and their
synthetic intermediates, in agrochemicals, as optical
brighteners, or as corrosion inhibitors.1 Their formation
by the 1,3-dipolar cycloaddition of azides and alkynes has
recently been recognized as one of the most powerful
methods for linking molecules (click chemistry)2 and has
resulted in a number of excellent applications in the field
of medicinal chemistry, e.g. in discovering acetylcho-
linesterase, 1,3-fucosyl transferase VI and HIV protease
inhibitors, as well as in biochemistry and molecular biol-
ogy for bioconjugation and labeling.3
Although organic azides are generally stable at room tem-
perature and the danger of their explosive decomposition
decreases with increasing molecular weight (it is believed
that five carbon atoms per one azide group makes the mol-
ecule safe2), isolation or purification of lower organic
azides or polyazides can be problematic. In situ genera-
tion of azides from suitable precursors followed by addi-
tion of an alkyne in a one-pot procedure, to form the
desired 1,2,3-triazole would allow the difficulties associ-
ated with the explosive nature of the azide to be avoided.
Such a one-pot strategy was reported by Maksikova, how-
ever, in this procedure low yields of 1,4- and 1,5-regioiso-
meric products were obtained.4 In the course of the
preparation of this manuscript Fokin demonstrated a very
elegant, one-pot approach to the synthesis of 1,4-disubsti-
tuted 1,2,3-triazoles from mainly aryl and a few activated
alkyl halides5 as well as a microwave accelerated one-pot
synthesis of various 1,2,3-triazoles.6 The latter, however,
required the use of forcing conditions (10 min at 125 °C)
which may be not compatible with sensitive substrates,
also special sealed pressure-resistant vials were utilized,
which makes scale-up difficult. Another procedure for a
one-pot synthesis of 1,2,3-triazoles has been reported by
N
NaN3/DMSO
12–18 h, r.t.
R2
H(R2)
R1
N
N
R1 Br
R1 N3
H2O, ascorbate
CuSO4, 6–18 h, r.t.
(R2)H
R2
1-16
1,4-regio-
isomers only
N
H
N
N
(R2)H
R2
17
Scheme 1 One-pot synthesis of 1,2,3-triazoles by click chemistry.
We adapted this procedure, so as to avoid the use of
excess azide, the reaction time was increased to 12–24
hours. After the azidation step was complete, water,
alkyne, sodium ascorbate, and CuSO4 solution10 were
added and stirring was continued for 6–18 hours, during
which time the products usually precipitated and were
collected by simple filtration.
The 1,2,3-triazoles were obtained in both high yield and
purity (Table 1). Only 1,4-regioisomers were detected as
the products when monosubstituted alkynes were used.
This method can be used with a number of mono- and bis-
SYNLETT 2005, No. 6, pp 0943–0946
0
6.
0
4.
2
0
0
5
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864809; Art ID: D38304ST
© Georg Thieme Verlag Stuttgart · New York

944
K. Kacprzak
LETTER
Table 1 One-Pot Preparation of 1,2,3-Triazoles from Benzyl or Alkyl Halides and Alkynes
Compd
Product
Isolated yield Compd
(%)
Product
Isolated yield
(%)
1
70
9
97
N
COOMe
N
N
N
N
N
COOMe
N
N
N
N
COOMe
N
2
3
4
5
6
86
56a
86
94
83
10
11
12
13
14
76b
87b
98
N
N
N
N
N
N
N
N
N
COOMe
Ph
N
N
N
EtOOC
Ph
COOEt
N
N
N
N
N
PhtN
N
N
O2N
O2N
COOMe
COOMe
N
96
N
N
N
PhtN
O2N
N
Ph
NPht
92
N
N
N
N
N
N
N
Br
N
COOMe
COOMe
7
8
90
60
15
16
O2N
95
89
N
N
N
N
COOMe
N
N
COOMe
OAc
N
COOEt
COOEt
N
PhtN
N
N
N
N
N
N
N
COOMe
N
EtOOC
COOEt
a Reaction with acetylenedicarboxylic acid diethyl ester were carried out at 60 °C for 12–18 h, without copper(I) catalysis. The corresponding
1,2,3-triazole was isolated by extraction with CH2Cl2 and purified by column chromatography on silica gel using CH2Cl2 as eluent.
b A small amount of THF (0.5–1 mL) was added in the azidation step to give a homogenous solution.
benzyl halides as well as with alkyl halides, including
those containing various functional groups. This proce-
dure was usually carried out on 0.5 mmol scale but in a
few cases we have synthesized the triazoles on 1, 2, and 5
mmol scale, with the same high yields. Functionalized
1,2,3-triazoles can be further elaborated into more diverse
compounds.
In conclusion we developed an efficient, simple, and safe
one-pot procedure for the formation of 1,2,3-triazoles
from benzyl or alkyl halides, sodium azide and alkynes,
without isolation of the organic azide.
Experimental
All reagents including organic halides and alkynes were purchased
from Aldrich and Fluka and used as received. N-propargylphthal-
imide was obtained by the reaction of phthalimide-DBU salt with
propargyl bromide (71%).
1H NMR spectra were recorded on a Varian EM-360 or AC-200
spectrometer (300 MHz) in DMSO or CDCl3, with TMS as an inter-
nal standard. Mass spectra were recorded on an AMD 604/402, IR
spectra (KBr pellets) were recorded on a Brucker ITS 113v spec-
trometer. Melting points were determined by using a Boetius instru-
ment and are not corrected.
The 0.5 M NaN3 solution in anhydrous DMSO was prepared
according to a known literature procedure.7
Synlett 2005, No. 6, 943–946 © Thieme Stuttgart · New York

LETTER
Efficient One-Pot Synthesis of 1,2,3-Triazoles from Benzyl and Alkyl Halides
945
General Procedure
HRMS (FAB): m/z calcd for C11H11N3O279Br, 296.0034; found,
To a stirred anhydrous DMSO solution of NaN3 (1 mL, 0.5 M, 0.5
mmol of azide, 1 equiv) organic halide (0.5 mmol, 1 equiv) was
added and the mixture was stirred overnight (12–24 hours). Water
(2–3 mL) was added followed by solid sodium ascorbate (10%
mol), alkyne (0.5 mmol) and aq CuSO4 solution (100 mL; 1 M). The
capped flask was stirred for 3–12 h (usually overnight),11 then more
water was added slowly until the product precipitated completely
from the solution. The product was collected by filtration, washed
with water, and dried in air.
296.0028.
Bis(4-methoxycarbonyl-1,2,3-triazolyl)-1,3-methylbenzene (7)
Mp 149–153 °C.
IR: 3130, 1726, 1540, 1438, 1231, 1048, 1020, 812, 777 cm–1.
1H NMR (DMSO): d = 8.89 (s, 2 H), 7.43 (m, 4 H), 5.66 (s, 4 H),
3.83 (s, 6 H).
HRMS (FAB): m/z calcd for C16H17N6O4, 357.1311; found,
357.1341.
1-Benzyl-4-methoxycarbonyl-1,2,3-triazole (1)
Mp 104–107 °C.
Bis(4,5-ethoxycarbonyl-1,2,3-triazolyl)-1,4-methylbenzene (8)
Mp 73–75 °C.
IR: 3111, 1724, 1541, 1496, 1456, 1433, 1365, 1339, 1230, 1048,
1020, 812, 781, 714 cm–1.
IR: 1741, 1552, 1478, 1463, 1430, 1380, 1367, 1348, 1311, 1268,
1202, 1140, 1068 cm–1.
1H NMR (DMSO): d = 8.90 (s, 1 H), 7.42 (m, 5 H), 5.66 (s, 2 H),
1H NMR (DMSO): d = 7.25 (s, 4 H), 5.80 (s, 4 H), 4.35 (q, J = 7.0,
7.3 Hz, 4 H), 4.31 (q, J = 7.0, 7.3 Hz, 4 H), 1.30 (t, J = 7.0, 7.3 Hz,
6 H), 1.19 (t, J = 7.0, 7.3 Hz, 6 H).
3.82 (s, 3 H).
HRMS (EI): m/z calcd for C11H11N3O2, 217.0851; found, 217.0851.
1-Benzyl-4-phenyl-1,2,3-triazole (2)
Mp 126–130 °C.
HRMS (FAB): m/z calcd for C24H29N6O8, 529.2047; found,
529.2020.
IR: 1494, 1469, 1450, 1361, 1224, 1140, 1076, 1046, 972, 807, 769,
731 cm–1.
Bis(4-methoxycarbonyl-1,2,3-triazolyl)-1,2-methylquinoxaline
(9)
1H NMR (DMSO): d = 8.64 (s, 1 H), 7.86 (m, 2 H), 7.46–7.30 (m,
8 H), 5.65 (s, 2 H).
HRMS (EI): m/z calcd for C15H13N3, 235.1109; found, 235.1095.
Mp 277–280 °C (dec.).
IR: 2104, 1723, 1546, 1437, 1363, 1238, 1154, 1139, 1054, 1021,
818, 780, 759 cm–1.
1H NMR (DMSO): d = 8.91 (s, 2 H), 7.93 (m, 2 H), 7.86 (m, 2 H),
1-Benzyl-4,5-bis(ethoxycarbonyl)-1,2,3-triazole (3)
6.29 (s, 4 H), 3.87 (s, 6 H).
Oil.
HRMS (FAB): m/z calcd for C18H17N8O4, 409.1372; found,
409.1355.
IR (film): 1733, 1552, 1468, 1373, 1267, 1218, 1147, 1095, 1059,
1016, 724 cm–1.
1H NMR (CDCl3): d = 7.37 (m, 5 H), 5.80 (s, 2 H), 4.45 (q, J = 7.14
Hz, 2 H), 4.36 (q, J = 7.14 Hz, 2 H), 1.42 (t, J = 7.14 Hz, 3 H), 1.29
(t, J = 7.14 Hz, 3 H).
4-Methoxycarbonyl-1-octyl-1,2,3-triazole (10)
Mp 78–80 °C.
IR: 3123, 2959, 2916, 1731, 1543, 1471, 1440, 1385, 1349, 1242,
HRMS (EI): m/z calcd for C15H18N3O4, 304.1297; found, 304.1292.
1048, 1020, 946, 881, 816, 778 cm–1.
1H NMR (DMSO): d = 8.81 (s, 1 H), 4.43 (t, J = 7.14 Hz, 2 H), 3.83
1-(4-Nitrobenzyl)-4-methoxycarbonyl-1,2,3-triazole (4)
(s, 3 H), 1.88 (m, 2 H), 1.23–1.15 (m, 10 H), 0.87 (t, J = 7.14 Hz, 3
Mp 187–189 °C.
H).
IR: 1720, 1602, 1516, 1434, 1370, 1353, 1232, 1050, 860, 815, 783,
727 cm–1.
HRMS (EI): m/z calcd for C12H21N3O2, 239.1633; found, 239.1616.
1H NMR (DMSO): d = 8.97 (s, 1 H), 8.26 (dd, J = 8.8, 4.8 Hz, 2 H),
7.58 (dd, J = 8.4, 4.8 Hz, 2 H), 5.85 (s, 2 H), 3.84 (s, 3 H).
HRMS (EI): m/z calcd for C11H10N4O4, 262.0701; found, 262.0721.
1-Octyl-4-phenyl-1,2,3-triazole (11)
Mp 78–79 °C.
IR: 2954, 2918, 2847, 1465, 1216, 1079, 762, 696 cm–1.
1H NMR (DMSO): d = 8.59 (s, 1 H), 7.86 (m, 2 H), 7.48 (m, 2 H),
7.35 (m, 1 H), 4.41 (t, J = 7.1 Hz, 2 H), 1.88 (t, J = 7.1 Hz, 2 H),
1.23–1.15 (m, 10 H), 0.86 (t, J = 7.1 Hz, 3 H).
1-(4-Nitrobenzyl)-4-phenyl-1,2,3-triazole (5)
Mp 157–159 °C.
IR: 1608, 1601, 1581, 1518, 1465, 1442, 1426, 1351, 1223, 1111,
1079, 1046, 1016, 862, 802, 764 cm–1.
HRMS (EI): m/z calcd for C16H23N3, 257.1892; found, 257.1905.
1H NMR (DMSO): d = 8.70 (s, 1 H), 8.28 (dd, J = 8.8, 1.9 Hz, 2 H),
7.87 (dd, J = 8.5, 1.4 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 2 H), 7.48 (m, 2
H), 7.37 (m, 1 H), 5.85 (s, 2 H).
1-(3-Phthalimidopropyl)-4-methoxycarbonyl-1,2,3-triazole(12)
Mp 196–200 °C.
IR: 3122, 1771, 1721, 1697, 1543, 1463, 1438, 1396, 1242, 1048,
HRMS (EI): m/z calcd for C15H12N4O2, 280.0960; found, 280.0979.
1029, 987, 780 cm–1.
1H NMR (DMSO): d = 8.78 (s, 1 H), 7.89 (m, 4 H), 4.52 (t, J = 7.1
Hz, 2 H), 3.83 (s, 3 H), 3.63 (t, J = 6.6 Hz, 2 H), 2.47 (quintet, 2 H).
HRMS (EI): m/z calcd for C15H15N4O4, 315.1093; found, 315.1078.
1-(2-Bromobenzyl)-4-methoxycarbonyl-1,2,3-triazole (6)
Mp 115–118 °C.
IR: 1721, 1527, 1439, 1368, 1218, 1047, 812, 783, 747 cm–1.
1H NMR (DMSO): d = 8.84 (s, 1 H), 7.71 (dd, J = 8.0, 1.4 Hz, 1 H),
7.43 (m, 1 H), 7.36 (m, 1 H), 7.24 (dd, J = 7.4, 1.6 Hz, 1 H), 5.76 (s,
2 H), 3.83 (s, 3 H).
4-(N-Phthalimidomethyl)-1-(3-phthalimidopropyl)-1,2,3-tri-
azole (13)
Mp 194–197 °C.
Synlett 2005, No. 6, 943–946 © Thieme Stuttgart · New York

946
K. Kacprzak
LETTER
IR: 1768, 1725, 1708, 1613, 1468, 1439, 1430, 1396, 1189, 1095,
1087, 768, 714 cm–1.
1H NMR (DMSO): d = 8.08 (s, 1 H), 7.92–7.80 (m, 8 H), 4.80 (s, 2
H), 4.40 (t, J = 7.2 Hz, 2 H), 3.62 (t, J = 6.7 Hz, 2 H), 2.18 (q,
J = 6.7, 7.3 Hz, 2 H).
References
(1) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Heterocycles 2003,
60, 1225; and references cited therein.
(2) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Kolb, H. C.; Sharpless, K. B.
Drug Discov. Today 2003, 8, 1128.
HRMS (EI): m/z calcd for C22H17N5O4 415.1280 found 415.1312.
(3) (a) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.;
Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 1053. (b) Lee, L. V.;
Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.; Sharpless, K. B.;
Wong, Ch.-H. J. Am. Chem. Soc. 2003, 125, 9588. (c) Brik,
A.; Muldoon, J.; Lin, Y.-Ch.; Elder, J. H.; Goodsell, D. S.;
Olson, A. J.; Fokin, V. V.; Sharpless, K. B.; Wong, Ch.-H.
ChemBioChem 2003, 4, 1246. (d) Link, A. J.; Tirrell, D. J.
Am. Chem. Soc. 2003, 125, 11164. (e) Deiteres, A.; Cropp,
T. A.; Mukherji, M.; Chin, J. W.; Anderson, J. Ch.; Schultz,
P. G. J. Am. Chem. Soc. 2003, 125, 11782. (f) Wang, Q.;
Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn,
M. G. J. Am. Chem. Soc. 2003, 125, 3192. (g)Speers, A. E.;
Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc. 2003, 125,
4686. (h) Seo, T. S.; Li, Z.; Ruparel, H.; Ju, J. J. Org. Chem.
2003, 68, 609.
1-[2-(4-Nitrophenyl)ethyl]-4-methoxycarbonyl-1,2,3-triazole
(14)
Mp 186–190 °C.
IR: 1715, 1604, 1599, 1513, 1346, 1235, 1052, 857, 778 cm–1.
1H NMR (CDCl3): d = 8.18 (dd, J = 8.8, 4.8 Hz, 2 H), 8.00 (s, 1 H),
7.31 (dd, J = 8.5, 4.8 Hz, 2 H), 4.75 (t, J = 7.1 Hz, 2 H), 3.94 (s, 3
H), 3.43 (t, J = 7.1 Hz, 2 H).
HRMS (EI): m/z calcd for C12H12N4O4, 276.0858; found, 276.0871.
1-[2-(4-Nitrophenyl)ethyl]-4-acetoxy-1,2,3-triazole (15)
Mp 187–190 °C.
IR: 1742, 1608, 1600, 1517, 1348, 1219, 1126, 1057, 870, 855, 787
cm–1.
1H NMR (CDCl3): d = 8.17 (dd, J = 8.5, 1.6 Hz, 2 H), 7.40 (s, 1 H),
7.27 (d, J = 8.2 Hz, 2 H), 4.66 (t, J = 7.14 Hz, 2 H), 3.39 (t, J = 7.14
Hz, 2 H), 2.06 (s, 3 H).
(4) Maksikova, A. V.; Serebryakova, E. S.; Tikhonova, L. G.;
Vereshagin, L. I. Chem. Heterocycl. Compd. 1980, 1284.
(5) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004,
6, 3897.
HRMS (EI): m/z calcd for C13H14N4O4, 290.1015; found, 290.1005.
(6) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eycken, E. Org. Lett. 2004, 6, 4223.
1-(N-Phthalimidomethyl)-4-methoxycarbonyl-1,2-3-triazole
(7) Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Seible, W. L.;
Srivastava, A. Tetrahedron Lett. 2003, 44, 2153.
(8) (a) Grundmann, C. In Houben–Weyl, Methoden der
organischen Chemie, 4th Ed., Vol. 10/3; Muller, E., Ed.;
Thieme: Stuttgart, 1965, 777. (b) See also references in Ref.
7
(16)
Mp 176–180 °C.
IR: 1776, 1717, 1611, 1559, 1403, 1359, 1243, 1218, 1038, 952,
776, 760 cm–1.
1H NMR (DMSO): d = 8.84 (s, 1 H), 7.98 (m, 5 H), 6.23 (s, 2 H),
(9) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
(10) Cu(I) formed under this condition is a catalyst for highly
regioslective 1,4-triazole formation see: Rostovtsev, V. V.;
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2002, 41, 2596.
3.83 (s, 3 H).
HRMS (EI): m/z calcd for C13H11N4O4, 287.0780; found, 287.0806.
Acknowledgment
We thank the Committee for Scientific Research (KBN) for
financial support (grant no. 7 T09A 040 25) and the Foundation for
Polish Science for a stipend.
(11) Progress of the reaction can be monitored by TLC.
Synlett 2005, No. 6, 943–946 © Thieme Stuttgart · New York