One-pot three-step synthesis of 1,2,3-triazoles by copper-catalyzed cycloaddition of azides with alkynes formed by a Sonogashira cross-coupling and desilylation

Article abstract of DOI:10.1021/ol1022036

A microwave-assisted, one-pot, three-step Sonogashira cross-coupling- desilylation-cycloaddition sequence was developed for the convenient preparation of 1,4-disubstituted 1,2,3-triazoles starting from a range of halides, acyl chlorides, ethynyltrimethyls

Full text of DOI:10.1021/ol1022036

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4936-4939
One-Pot Three-Step Synthesis of
1,2,3-Triazoles by Copper-Catalyzed
Cycloaddition of Azides with Alkynes
formed by a Sonogashira
Cross-Coupling and Desilylation
Fre´de´ric Friscourt and Geert-Jan Boons*
Complex Carbohydrate Research Center, UniVersity of Georgia, 315 RiVerbend Road,
Athens, Georgia 30602, United States
gjboons@ccrc.uga.edu
Received September 14, 2010
ABSTRACT
A microwave-assisted, one-pot, three-step Sonogashira cross-coupling-desilylation-cycloaddition sequence was developed for the convenient
preparation of 1,4-disubstituted 1,2,3-triazoles starting from a range of halides, acyl chlorides, ethynyltrimethylsilane, and azides.
The exquisite regioselectivity, high tolerance to the presence
of functional groups, and exceptional high yields of Cu(I)-
catalyzed 1,3-dipolar cycloadditions of azides with terminal
alkynes (CuAAC) to give 1,4-disubstituted triazoles1 have
made it a powerful approach for bioconjugation,2 construc-
tion, and modification of materials3 and the parallel combi-
natorial synthesis of libraries of compounds for drug dis-
covery.4 Recent efforts to further develop CuAAC have
focused on one-pot multicomponent reactions in which azides
are prepared in situ prior to the cycloaddition. The attraction
of such an approach is that it minimizes time-consuming
workup and purification protocols and avoids handling of
potentially explosive azides. Most methods for in situ
preparation of azides take advantage of the nucleophilicity
of sodium azide toward electrophiles such as aromatic
fluorides, iodides, benzylic bromides, as well as epoxides
and boronic acids.5 Organic azides have also been generated
in situ by Cu(II)-catalyzed diazo transfer of triflyl azide or
azidotrimethylsilane to amines.6 Surprisingly, one-pot mul-
(1) For the original publications, see: (a) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (b) Rostovtsev, V. V.; Green,
L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2596.
(2) (a) Pieters, R. J.; Rijkers, D. T. S.; Liskamp, R. M. J. QSAR Comb.
Sci. 2007, 26, 1181. (b) Na´jera, C.; Sansano, J. M. Org. Biomol. Chem.
2009, 7, 4567. (c) van Dijk, M.; Rijkers, D. T. S.; Liskamp, R. M. J.; van
Nostrum, C. F.; Hennink, W. E. Bioconjugate Chem. 2009, 20, 2001.
(3) (a) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018. (b) Golas,
P. L.; Matyjaszewski, K. Chem. Soc. ReV. 2010, 39, 1338.
(4) (a) Moorhouse, A. D.; Moses, J. E. Chem. Med. Chem. 2008, 3,
715. (b) Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba,
G.; Genazzani, A. A. Med. Res. ReV. 2008, 28, 278. (c) Mamidyala, S. K.;
Finn, M. G. Chem. Soc. ReV. 2010, 39, 1252.
10.1021/ol1022036  2010 American Chemical Society
Published on Web 10/13/2010

tistep reactions involving in situ generation of terminal
alkynes for click chemistry have not been reported. The
attraction of such an approach is that a wide variety of
alkynes can be generated from simple and readily available
starting materials, such as aromatic halides.
Herein, we describe a microwave-assisted one-pot, three-
step procedure entailing Sonogashira cross-coupling of
aromatic halides with ethynyltrimethylsilane (TMS-acety-
lene) to give TMS-protected alkynes, which were desilylated
and then employed in 1,3-dipolar cycloadditions with various
azides to give a range of 1,2,3-triazoles (Scheme 1). In
modified acetylenes can readily be deprotected using reagents
such as tetrabutylammonium fluoride (TBAF)7 or silver salts8
to give terminal alkynes, which can then undergo cycload-
ditions with azides. It was expected that these two steps can
be performed as a one-pot process and accelerated by
microwave irradiation.9 A temperature survey revealed that
reaction of trimethyl(phenylethynyl)silane (1a) with benzyl
azide (2a) in the presence of TBAF (1 equiv), CuI (10 mol
%), and N,N-diisopropylethylamine (20 mol %) in methanol
under microwave irradiation at 120 °C was complete within
20 min to afford the 1,4-disubstituted triazole 3a in an almost
quantitative yield as a single regioisomer (Table 1, entry 1,
method A). A similar reaction without TBAF resulted in no
triazole formation, clearly establishing that the TMS-alkyne
must be deprotected to undergo a 1,3-dipolar cycloaddition.
Furthermore, when the transformation was performed in the
absence of CuI, only a trace amount of triazole was isolated
as a mixture of regioisomers.10 The desilylation-cycloaddition
reaction could also be performed at ambient temperature;
however, in this case a prolonged reaction time of 12 h was
required to achieve complete conversion of the starting
materials.
Scheme 1. One-Pot Three-Step Synthesis of 1,2,3-Triazoles by
in Situ Formation of a Terminal Alkyne by Sonagashira
Cross-Coupling and Desilylation Followed by a Cycloaddition
with an Azide
We have found that CuF2 is an efficient reagent for
deprotecting TMS-modified alkynes and promoting 1,3-
dipolar cycloadditions with azides to give 1,4-disubstituted
triazoles.11 As expected, the use of CuF2 (2 equiv) also gave
the 1,2,3-triazole 3a in an excellent yield (Table 1, entry 1,
method B). It was found that the scope of the one-pot process
is excellent, and 1,4-disubstituted triazoles containing electron-
donating (entry 2), -withdrawing (entry 3), and bulky
functionalities (entry 6) could be obtained in excellent yield.
Furthermore, the use of CuF2 was found to be most
convenient and gave in general slightly higher yields of
product compared to the use of TBAF/CuI. It is also possible
to employ a catalytic amount of CuF2 (10 mol %); however,
in this case the addition of TBAF (1 equiv) is required to
facilitate desilylation.
addition, it was found that the use of aromatic acyl chlorides
in the Sonogashira cross-coupling gave TMS-protected
ynones, which after desilylation and Cu(I)-catalyzed cy-
cloadditions with azides led to the regioselective formation
of 1-substituted 4-phenylacyl-1H-1,2,3-triazoles.
First, optimal reaction conditions were established for a
fast and high-yielding one-pot desilylation-cycloaddition
reaction sequence (Table 1). It has been reported that TMS-
(5) (a) Dururgkar, K. A.; Gonnade, R. G.; Ramana, C. V. Tetrahedron
2009, 65, 3974. (b) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett.
2004, 6, 3897. (c) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente,
R. Org. Lett. 2008, 10, 3081. (d) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.;
Van der Eycken, E. Org. Lett. 2004, 6, 4223. (e) Yadav, J. S.; Reddy,
B. V. S.; Reddy, M.; Chary, D. N. Tetrahedron Lett. 2007, 48, 8773. (f)
Campbell-Verduyn, L. S.; Szymanski, W.; Postema, C. P.; Dierckx, R. A.;
Elsinga, P. H.; Janssen, D. B.; Feringa, B. L. Chem. Commun. 2010, 46,
898. (g) Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2007, 48, 3525.
Table 1. Microwave-Assisted One-Pot TMS-Deprotection of
Compounds 1a-g and Cycloaddition with Azides 2a-c to Give
Triazoles 3a-i
method Aa
yield (%)
method Bb
yield (%)
(6) (a) Beckmann, H. S. G.; Wittmann, V. Org. Lett. 2007, 9, 1. (b)
Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9, 1809. (c)
Lee, C.-T.; Huang, S.; Lipshutz, B. H. AdV. Synth. Catal. 2009, 351, 3139.
(7) Valverde, I. E.; Delmas, A. F.; Aucagne, V. Tetrahedron 2009, 65,
7597.
entry
R
R′
1
2
3
4
5
6
7
8
9
C6H5
Bn
Bn
Bn
Bn
Bn
Bn
Bn
98
97
98
89
81
89
82
87
98
98c
96
97
95
91
90
98
98
99
4-MeO-C6H4
4-CF3-C6H4
4-Cl-C6H4
4-Br-C6H4
2-Br-C6H4
CH2OH
(8) Aucagne, V.; Leigh, D. A. Org. Lett. 2006, 8, 4505.
(9) (a) Kappe, C. O.; Van der Eycken, E. Chem. Soc. ReV. 2010, 39,
1280. (b) Appukuttan, P.; Mehta, V.; Van der Eycken, E. Chem. Soc. ReV.
2010, 39, 1467.
(10) Heating under microwave irradiation trimethyl(phenylethynyl)silane
(1a) with benzyl azide (2a) in the presence of TBAF (1 equiv) at 120 °C
for 20 min resulted in less than 5% yield of the corresponding triazole in
a 1:1 mixture of regioisomers.
C6H5
C6H5
4-MeO-Bn
4-NO2-Bn
a A mixture of TBAF (1.0 M, 1.0 equiv), CuI (10 mol %), and DIPEA
(20 mol %) was used. b CuF2 (2.0 equiv) was used. c 3a was isolated in
yields of 22% and 57% when the reaction was performed at 60 or 90 °C,
respectively.
(11) Mechanistic studies and DFT calculations support the notion that
CuF2 catalyzes the cycloaddition. Friscourt, F.; Ledin, P. A.; Boons, G.-J.
In Abstracts of Papers, 239th ACS National Meeting (March 21-25) San
Francisco, CA, USA, 2010 and manuscript in preparation.
Org. Lett., Vol. 12, No. 21, 2010
4937

TMS-substituted alkynes are readily accessible by Sono-
gashira cross-coupling between aromatic halides and ethy-
nyltrimethylsilane.12 Furthermore, it has been found that
microwave irradiation can significantly reduce the reaction
time of metal-catalyzed cross-coupling reactions.13 Thus, we
explored whether Sonogashira cross-coupling, desilylation,
and cycloaddition can be performed under microwave
conditions as a one-pot procedure. Various aromatic io-
dides (Table 2, entries 1-6 and 10-11) were reacted with
Table 3. One-Pot, Three-Step Synthesis of 1-Substituted
4-Acyl-1H-1,2,3-triazoles 7a-e
method Aa
yield (%)
method Bb
yield (%)
entry
Ar
R
1
2
3
4
5
Ph
Bn
Bn
Bn
Bn
Bn
40
80
82
32
35
42
83
88
36
34
Table 2. One-Pot, Three-Step Synthesis of 1,4-Disubstituted
Triazoles 3
4-MeO-C6H4
4-F-C6H4
4-NO2-C6H4
2-Me-C6H4
a A mixture of TBAF (1.0 M, 2.0 equiv) and CuI (10 mol %) was used.
b CuF2 (2.0 equiv) was used.
method Aa method Bb
the Sonogashira cross-coupling reaction (7, Table 3).12b,14
Acyl chlorides did not tolerate the use of microwave
irradiation;15 however, the desired TMS-protected ynones
could be obtained by simply reacting an acyl chloride (6)
with ethynyltrimethylsilane in the presence of Pd(PPh3)2Cl2
and triethylamine in THF at room temperature for 1 h. The
resulting compounds were not isolated but immediately
submitted to the deprotection-cycloaddition protocol and
reaction with benzyl azide in the presence of CuF2 or the
TBAF/CuI-afforded 1-benzyl,4-acyl-1H-1,2,3-triazoles (7).
The Sonogashira cross-coupling reaction was found to be
sensitive to the nature of the employed acyl chloride, and
the use of electron-rich acyl chlorides (entries 2 and 3 vs
entry 4) gave the best conversions of the starting materials.
Full conversions of the 1-substituted 4-acyl-1H-1,2,3-triaz-
oles were achieved when TMS-modified ynones were puri-
fied prior to reaction with azides, establishing the Sonogash-
ira coupling of the acyl chlorides with ethynyltrimethylsilane
as the yield-limiting step of the one-pot, three-step protocol.
It is important to note that 1-substituted 4-acyl-1H-1,2,3-
triazoles have rarely been prepared by CuAAC due to side
product formation.16 Previous syntheses of this class of
triazoles involved classical thermal Huisgen 1,3-dipolar
cycloadditions with the inconvenience of separating the two
triazole regioisomers17a and condensation of amines with
R-diazo-1,3-dicarbonyls.16b The microwave conditions re-
ported here provide easy and regioselective access to this
class of biomedically important compounds.
entry
Ar-X
Ph-I
R
yield (%)
yield (%)
1
Bn
Bn
Bn
Bn
Bn
Bn
Bn
96
41
97
98
93
97
42
13
12
84
97
91
54
2
4-MeO-C6H4-I
4-CF3-C6H4-I
4-F-C6H4-I
4-Me-C6H4-I
2-Me-C6H4-I
Ph-Br
3
98
4
98
5
95
6
98
7
65
8
4-MeO-C6H4-Br Bn
15 (57c)
11 (53c)
91
9
4-NO2-C6H4-Br
Ph-I
Bn
10
11
4-MeO-Bn
4-NO2-Bn
Ph-I
98
a A mixture of TBAF (1.0 M, 2.0 equiv) and CuI (10 mol %) was used.
b CuF2 (2.0 equiv) was used. c The Sonogashira cross-coupling was
performed using Pd(PPh3)2Cl2 (5 mol %) and CuI (10 mol %) in refluxing
Et3N for 10 h.
ethynyltrimethylsilane using a catalytic amount of Pd(PPh3)4
(5 mol %) and CuI (10 mol %) in the presence of
N,N-diisopropylethylamine (2 equiv) in methanol under
microwave irradiation at 120 °C for 20 min, followed by
the introduction of an azide and TBAF/CuI or CuF2 and
further microwave irradiation at 120 °C for 20 min. Gratify-
ingly, the one-pot, three-step process produced the expected
1,4-disubstituted triazoles (3) in most cases in high yield.
As expected, aromatic bromides (entries 7-9), which are
known to couple poorly under classical Sonogashira cross-
coupling conditions, required optimization of the palladium
source, choice of amine, and reaction time. It was found that
triazoles were obtained in acceptable yields when a mixture
of an aromatic bromide, ethynyltrimethylsilane, Pd(PPh3)2Cl2
(5 mol %), and CuI (10 mol %) in Et3N was heated under
reflux prior to the desilylation-cycloaddition protocol (en-
tries 8 and 9).
In conclusion, an expedient one-pot, three-step protocol
has been developed for the preparation of 1,4-disubstituted
The scope of the one-pot, three-step protocol was further
extended to the synthesis of 1-substituted 4-acyl-1H-1,2,3-
triazoles by using acyl chlorides as the starting material in
(14) Karpov, A. S.; Muller, T. J. J. Org. Lett. 2003, 5, 3451
(15) Sashida, H. Synthesis 1998, 745.
.
(16) Synthesis of 1-substituted 4-acyl-1H-1,2,3-triazoles using CuAAC
exhibits moderate yield (< 60%). See: (a) Chassaing, S.; Kumarraja, M.;
Sido, A. S. S.; Pale, P.; Sommer, J. Org. Lett. 2007, 9, 883. (b) Xie, J.;
Seto, C. T. Bioorg. Med. Chem. 2007, 15, 458. (c) Pardin, C.; Roy, I.;
Lubell, W. D.; Keillor, J. W. Chem. Biol. Drug Des. 2008, 72, 189.
(17) (a) Calderone, V.; Giorgi, I.; Livi, O.; Martinotti, E.; Mantuano,
E.; Martelli, A.; Nardi, A. Eur. J. Med. Chem. 2005, 40, 521. (b) Dabak,
K.; Sezer, O.; Akar, A.; Anac¸, O. Eur. J. Med. Chem. 2003, 38, 215.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis
1977, 777.
(13) (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (b) Nilsson,
P.; Olofsson, K.; Larhed, M. Top. Curr. Chem. 2006, 266, 103.
4938
Org. Lett., Vol. 12, No. 21, 2010

triazoles involving Sonogashira cross-coupling to generate
in situ a variety of TMS-protected alkynes, which could
immediately be desilylated and reacted with azides in the
presence of a mixture of TBAF/CuI or CuF2. The reaction
sequence could be completed within 1 h by employing
microwave-assisted heating. Furthermore, we have shown
that 2-yn-1-ones, which were obtained by Sonogashira cross-
coupling of aromatic acyl chlorides with ethynyltrimethyl-
silane, undergo Cu-catalyzed cycloadditions with azides
when subjected to microwave heating to give regioselective
formation of 1-substituted 4-phenylacyl-1H-1,2,3-triazoles.
The new one-pot, three-step process will make it possible
to rapidly prepare compound libraries for drug discovery
programs as it avoids time-consuming and costly purification
protocols of synthetic intermediates. Furthermore, it is to be
expected that the one-pot procedure can be combined with
in situ formation of azides5 thereby further increasing the
convenience of CuAAC.
Acknowledgment. This research was supported by the
National Cancer Institute of the US National Institutes of
Health (Grant No. RO1 CA88986, G.-J.B.).
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and copies of H NMR and
13C NMR spectra of all products are available. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL1022036
Org. Lett., Vol. 12, No. 21, 2010
4939