One-pot, three-component copper-catalysed 'click' triazole synthesis utilising the inexpensive, shelf-stable diazotransfer reagent imidazole-1-sulfonyl azide hydrochloride

Article abstract of DOI:10.1055/s-0029-1217175

A practical and efficient one-pot procedure for the regioselective synthesis of functionalised 1,4-disubstituted 1,2,3-triazoles from primary amines and terminal acetylenes has been established utilising the inexpensive, shelf-stable diazotransfer reagent

Full text of DOI:10.1055/s-0029-1217175

LETTER
1391
One-Pot, Three-Component Copper-Catalysed ‘Click’ Triazole Synthesis
Utilising the Inexpensive, Shelf-Stable Diazotransfer Reagent Imidazole-1-
sulfonyl Azide Hydrochloride
Copper-Catalysed
e
‘Click’ Triazole Synth
l
e
sis M. Smith,* Michelle J. Greaves, Robert Jewell, Matthew W. D. Perry, Michael J. Stocks, Jeffrey P. Stonehouse
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics, LE11 5RH, UK
Fax +44(1509)644925; E-mail: neal.smith@astrazeneca.com
Received 11 February 2009
promote the azide-acetylene dipolar cycloaddition
(Scheme 1).
Abstract: A practical and efficient one-pot procedure for the regi-
oselective synthesis of functionalised 1,4-disubstituted 1,2,3-triaz-
oles from primary amines and terminal acetylenes has been
established utilising the inexpensive, shelf-stable diazotransfer re-
agent imidazole-1-sulfonyl azide hydrochloride.
Whilst the Beckmann procedure is highly optimised, there
are several practical limitations for the use of this chemis-
try in parallel or combinatorial synthesis. The principal
limitation lies in the use of TfN3, which is used to intro-
duce the azide group. The explosive nature of TfN3 and its
relatively poor shelf life necessitate its preparation in so-
lution prior to use.9 Furthermore, inconsistent yields in the
preparation of TfN3 mean that the solution must either be
standardised or used in a liberal excess. The two-step pro-
cedure, which involves the initial generation of the azide
from the corresponding amine in dichloromethane is also
of concern. It is well documented in the literature that
NaN3 can react with dichloromethane to form diazi-
domethane, a known explosive.10 The procedure involves
the generation of azides and their reaction in the same pot
with microwave heating. This could also present a signif-
icant safety issue for a parallel application if low molecu-
lar weight azides were formed as these are known to be
volatile and hazardous. Beckmann reports that the method
can be carried out in a true one-pot procedure, with slight-
ly reduced yields. Whilst this addresses some concerns,
the principal limitation for our parallel synthesis require-
ments (i.e., the use of, and robotic transfer of, TfN3 into
the reaction mixtures) was still a major concern for us.
Key words: cycloaddition, triazole, combinatorial chemistry, di-
azotransfer reagent, one-pot reaction
The development and optimisation of new, multicompo-
nent reactions to efficiently synthesise compound librar-
ies from readily available and diverse starting materials is
of paramount importance in synthesising new compounds
that might deliver future lead compounds1 for the pharma-
ceutical industry.
The discovery of the copper(I)-catalysed version of the
azide-acetylene dipolar Huisgen cycloaddition2 by
Sharpless3 has triggered much interest and application of
this reaction in both the pharmaceutical and material sci-
ence areas.4 The reaction is run under mild conditions and
is generally high yielding and regioselective, thus being a
perfect match for ‘click chemistry’.5,6
In 2004, Appukkuttan7 published a one-pot procedure for
the synthesis of functionalised 1,4-disubstituted 1,2,3-tri-
azoles from a selection of alkyl halides and terminal acet-
ylenes. This one-pot procedure involved formation of a
series of azides using sodium azide (NaN3) and various
alkyl halides, which in the presence of terminal acetylene
and copper(II) sulfate underwent azide-acetylene dipolar
cycloaddition promoted by microwave irradiation.
1) TfN3, CuSO4, NaHCO3
R1
H
R1
R2
CH2Cl2–MeOH–H2O, r.t.
N
N
H
2) sodium ascorbate,
TBTA, MW, 80 °C
N
N
R2
Recently, Beckmann8 published a one-pot, two-step pro-
cedure which sought to address this limitation through the
generation of azides in situ from primary amines. The first
step in the reported procedure was the generation of a se-
ries of azides from various primary amines using triflic
azide (TfN3) in combination with copper(II) sulfate and
solid sodium bicarbonate. The second part of the sequence
involved the addition of a terminal acetylene along with
sodium ascorbate and the copper(I) stabilising ligand
tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA).
The reaction was then subjected to microwave heating to
Scheme 1 One-pot, two-step procedure identified by Beckmann
Recently, imidazole-1-sulfonyl azide hydrochloride (1)
was described as a useful reagent for the synthesis of
azides from amines.11 Under appropriate reaction condi-
tions a one-pot, single-step reaction may be carried out
using 1, a primary amine and a terminal acetylene to gen-
erate highly functionalised 1,4-disubstituted 1,2,3-tri-
azoles (Table 1). Due to the facile nature of the
cycloaddition and the presence of the terminal acetylene,
the azides generated in situ are immediately converted
into 1,4-disubstituted 1,2,3-triazoles. A large number of
amines and terminal acetylenes are commercially avail-
able enabling significant diversity to be achieved in a sin-
gle step.
SYNLETT 2009, No. 9, pp 1391–1394
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x.
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x.
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Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217175; Art ID: D05109ST
© Georg Thieme Verlag Stuttgart · New York

1392
N. M. Smith et al.
LETTER
The reaction conditions for the one-pot procedure were Polytriazoles such as TBTA have been identified as cop-
optimised using a standard reaction between phenylacety- per(I)-stabilising ligands.13 Beckmann employed TBTA
lene (3) and benzylamine (2) in the presence of the diazo- in his original one-pot procedure (Scheme 1). During the
transfer reagent 1 (Table 1).12 Typically, the reaction was optimisation study, it was shown that the addition of
performed with 10 mol% copper(II) sulfate and 20 mol% TBTA had no added benefit (Table 1 compare entries 1
sodium ascorbate. The reactions were stirred at room tem- and 7). The most dramatic effect was seen when the reac-
perature for 20 hours, and the products were purified ei- tion was run in the absence of an inert nitrogen atmo-
ther by preparative HPLC or column chromatography sphere. The isolated yield decreased significantly
after evaporation of the reaction mixtures.
(Table 1, entry 4), and it is postulated that this is due to ox-
idation of Cu(I) catalyst to Cu(II) by atmospheric oxygen,
shutting down the Cu(I)-mediated catalytic cycle.
Investigations using the standard reaction showed that po-
tassium carbonate could be substituted by an organic base,
such as triethylamine or diisopropylethylamine. These The following compounds 5a–f have been prepared as
changes allowed water to be removed from the reaction representative examples to illustrate the applicability of
medium, which had originally been added to aid solubili- the reaction sequence with a range of electron-rich, elec-
sation of the potassium carbonate and copper salts. There tron-poor, and sterically hindered amines (Table 2). The
was no detrimental effect on yield, with the standard reac- range of amines tolerated by the reaction conditions dem-
tion proceeding efficiently with the formation of 1-ben- onstrates the versatility of this one-pot procedure. The
zyl-4-phenyl-1H-1,2,3-triazole (4) in a 90% and 97% highest yields were observed for nucleophilic aliphatic
isolated yield when performed in methanol and ethanol, amines, such as 5a, 5b, and 5c. No products were ob-
respectively (Table 1). Removal of water from the reac- served for heterocyclic amines 5g and 5h or para-cyano-
tion medium allowed other solvents to be assessed. A aniline 5i. Notably, 4-amino piperidine underwent
range of solvents were screened in the standard reaction complete conversion to the corresponding 1,4-disubstitut-
and methanol and ethanol were identified as being optimal ed 1,2,3-triazole 5b without requiring protection on the
(Table 1).
secondary amine and demonstrates that secondary amines
are inert to the reaction conditions.
Table 1 Optimisation of Experimental Conditions
O
CuSO4, sodium ascorbate
+
NH2
N
–N
N N
+
+
S
N
base, solvent, r.t.
N
N
O
N
⋅HCl
4
3
1
2
Entry
1
Solvent
MeOH
EtOH
Base
Et3N
Et3N
K2CO3
Et3N
DIPEA
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Conversion (%)a
Yield (%)
90
97
86
2
3
MeOH–H2O (5:1)
MeOHb
MeOH
4
9
5
76
58
85
6
H2O
7
MeOHc
MeCN
8
0
7
9
Et3N
10
11
12
THF
17
10
19
t-BuOH
DMSO
a Determined by LC-MS.
b Reaction run without inert (N2) atmosphere.
c Reaction run with 1 mol% TBTA.
Synlett 2009, No. 9, 1391–1394 © Thieme Stuttgart · New York

LETTER
Copper-Catalysed ‘Click’ Triazole Synthesis
1393
Table 2 Generation of Triazoles 5a–i
O
Et3N, CuSO4
+
N
R1
N
–N
N
+
+
S
N
NH2
sodium ascorbate,
MeOH, r.t.
O
⋅HCl
N
N
R1
3
1
5a–i
N
Entry
1
5
Amine R1NH2
Yield (%)a
71
OH
5a
NH2
2
3
5b
5c
97
71
NH2
HN
NH2
NH2
4
5d
31
NH2
5
6
5e
5f
33
42
O
NH2
H2N
7
8
9
5g
5h
5i
0
0
0
N
O
NH2
N
N
NH2
N
a Fully purified and characterised isolated yields.
The nature of the terminal acetylene was then explored accommodating to changes in functionality to both the
and a range of acetylenes with basic 5j, heteroaromatic amine (R1) and acetylene (R2) components of the reaction.
5k, electron-poor 5l, and electron-rich functionality 5m
and 5n were selected, using benzylamine as the standard
amine in this study (Table 3). The results show that the
Acknowledgment
We thank Mrs Hema Pancholi, Mrs Kim Lawson for their assistance
in obtaining LC-MS and HRMS data and Mr Phil Abbot for HPLC
purification.
reaction accommodates electronic changes within the
acetylene and tolerated various functionalities with gener-
ally high recovery of product. It is notable that the very
electron-rich ethoxyacetylene gave product 5m, although
in poor yield.
References and Notes
A true one-pot, single-step procedure for 1,2,3-triazole
synthesis has been developed from a diverse range of pri-
mary amines and terminal acetylenes. The procedure is
experimentally simple and suitable for parallel chemistry.
This procedure avoids the safety concerns associated with
earlier procedures. A very wide range of amines are avail-
able commercially giving the procedure wide applicabili-
ty for the pharmaceutical industry. The procedure is also
(1) For some recent applications of parallel synthesis in drug
design, see: (a) Habashita, H.; Kokubo, M.; Hamano, S.;
Hamanaka, N.; Toda, M.; Shibayama, S.; Tada, H.; Sagawa,
K.; Fukushima, D.; Maeda, K.; Mitsuya, H. J. Med. Chem.
2006, 49, 4140. (b) Edwards, P. J. IDrugs 2006, 9, 347.
(c) Lu, S.-F.; Chen, B.; Davey, D.; Dunning, L.; Jaroch, S.;
May, K.; Onuffer, J.; Phillips, G.; Subramanyam, B.; Tseng,
J.; Wei Robert, G.; Wei, M.; Ye, B. Bioorg Med. Chem. Lett.
2007, 17, 1883.
Synlett 2009, No. 9, 1391–1394 © Thieme Stuttgart · New York

1394
N. M. Smith et al.
LETTER
Table 3 Generation of Triazoles 5j–n
R2
O
Et3N, CuSO4
+
N
NH2
N
–N
N
+
S
+
N
R2
5j–n
N
N
sodium ascorbate,
MeOH, r.t.
O
N
⋅HCl
1
2
Entry
1
5
Acetylene R2CCH
Yield (%)a
94
5j
N
N
O
2
3
5k
61
91
5l
O
O
4
5
5m
5n
14
40
a Fully purified and characterised isolated yields.
(2) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984, 1–176.
(b) Huisgen, R. Pure. Appl. Chem. 1989, 61, 613.
(3) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.
(9) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H.
J. Am. Chem. Soc. 2002, 124, 10773.
(10) (a) Hassner, A.; Stern, M.; Gottlieb, H. E.; Frolow, F. J. Org.
Chem. 1990, 55, 2304. (b) Hassner, A.; Stern, M. Angew.
Chem., Int. Ed. Engl. 1986, 25, 478.
(11) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797.
(12) Typical Reaction Procedure
(4) Huisgen, R.; Szeimies, G.; Moebius, L. Chem. Ber. 1967,
100, 2494.
(5) For some recent application of the copper-catalysed Huisgen
reaction, see: (a) Sirion, U.; Bae, Y. J.; Lee, B. S.; Chi, D. Y.
Synlett 2008, 2326. (b) Vatmurge, N. S.; Hazra, B. G.; Pore,
V. S.; Shirazi, F.; Deshpande, M. V.; Kadreppa, S.;
Chattopadhyay, S.; Gonnade, R. G. Org. Biomol. Chem.
2008, 6, 3823. (c) Ankati, H.; Yang, Y.; Zhu, D.; Biehl, E.
R.; Hua, L. J. Org. Chem. 2008, 73, 6433. (d) Ackermann,
L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett.
2008, 10, 3081. (e) Lucas, R.; Neto, V.; Hadj, B. A.;
Zerrouki, R.; Granet, R.; Krausz, P.; Champavier, Y.
Tetrahedron Lett. 2008, 49, 1004. (f) Fletcher, J. T.; Walz,
S. E.; Keeney, M. E. Tetrahedron Lett. 2008, 49, 7030.
(g) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007,
36, 1249.
To a solution of 1H-imidazole-1-sulfonyl azide·HCl (210
mg, 1 mmol) in MeOH (6 mL) was added benzylamine
(0.109 mL, 1.00 mmol), phenylacetylene (0.110 mL, 1.00
mmol), copper(II) sulfate pentahydrate (25 mg, 0.1 mmol),
sodium ascorbate (40 mg, 0.2 mmol), and Et3N (0.139 mL,
1.00 mmol) under nitrogen. The resulting suspension was
stirred or shaken at r.t. for 20 h. The mixture was concen-
trated onto SiO2 and purified by flash chromatography
(SiO2), elution gradient 10–90% Et2O in isohexane. Pure
fractions were evaporated to give 1-benzyl-4-phenyl-1H-
1,2,3-triazole (211 mg, 90%) as a white solid. HRMS: m/z
calcd: 236.1188 [M + H]+; found: 236.1178 [M + H]+. 1H
NMR (500.3 MHz, CDCl3): d = 7.81 (m, 2 H), 7.66 (s, 1 H),
7.35 (m, 8 H), 5.58 (s, 2 H). 13C NMR (125.8 MHz, CDCl3):
d = 148.26, 134.69, 130.53, 129.19, 128.89, 128.20, 128.09,
125.72, 119.51, 54.27. Mp 120.8–122 °C;14 120–122 °C.
(13) Chan, T. R.; Hilgraf, H.; Sharpless, K. B.; Folkin, V. V. Org.
Lett. 2004, 6, 2853.
(6) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 11, 2004.
(7) Appukkuttan, P.; Dehaen, W.; Folkin, V. V.; Van der
Eycken, E. Org Lett. 2004, 6, 4223.
(8) Beckmann, H. S. G.; Wittmann, V. Org. Lett. 2007, 9, 1.
(14) Wang, X.-Z.; Zhao, Z.-G. J. Heterocycl. Chem. 2007, 44, 89.
Synlett 2009, No. 9, 1391–1394 © Thieme Stuttgart · New York

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