β-Tosylethylazide: a useful synthon for preparation of N-protected 1,2,3-triazoles via click chemistry

Article abstract of DOI:10.1016/j.tetlet.2006.03.020

β-Tosylethylazide (TSE-N₃), which can be prepared in one step from p-tolyl vinyl sulfone and sodium azide/H₂SO₄, undergoes metal-catalyzed 1,3-dipolar cycloadditions with alkynes to produce TSE-protected 1,2,3-triazoles. T

Full text of DOI:10.1016/j.tetlet.2006.03.020

Tetrahedron Letters 47 (2006) 3035–3038
b-Tosylethylazide: a useful synthon for preparation of
N-protected 1,2,3-triazoles via click chemistry
Amy H. Yap and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 9 February 2006; accepted 1 March 2006
Available online 20 March 2006
Abstract—b-Tosylethylazide (TSE-N3), which can be prepared in one step from p-tolyl vinyl sulfone and sodium azide/H2SO4,
undergoes metal-catalyzed 1,3-dipolar cycloadditions with alkynes to produce TSE-protected 1,2,3-triazoles. The protecting group
can be removed using potassium tert-butoxide in THF at ꢀ78 to 0 °C.
Ó 2006 Elsevier Ltd. All rights reserved.
1,2,3-Triazoles are nitrogen heterocycles, which have a
number of important industrial, agrochemical, and
pharmaceutical uses.1 One of the most attractive ways
to prepare these compounds involves the thermal 1,3-
dipolar cycloaddition of azides with alkynes, pioneered
by Huisgen.2 One of the main drawbacks of this chem-
istry has been a lack of regioselectivity when utilizing
unsymmetrical alkynes, as well as a requirement for
elevated reaction temperatures. However, an important
advance in this field was the recent discovery that cyclo-
additions of terminal alkynes with alkyl azides cata-
lyzed by Cu(I) can be conducted at room temperature
and are highly regioselective, leading to 4-substituted-
1,2,3-triazoles.3 It is believed that this process occurs
via the stepwise addition of the azide to a copper acetyl-
ide intermediate, rather than by a concerted cycloaddi-
tion.3c This type of cycloaddition has been classified by
Sharpless as a kind of ‘click’ reaction, whereby hetero-
atom links between molecules can be generated under
very mild experimental conditions.4 Various applica-
tions of this methodology are beginning to appear at a
rapid rate.4b
N-protected amido compounds.5a,b We have introduced
b-tosylethylhydroxylamine (TSE-NHOH) and demon-
strated that it can be applied in amidyl radical/olefin
cyclizations.5c More recently, b-tosylethylhydrazine
(TSE-NHNH2) was shown to be effective in synthesis
of TSE-protected pyrazoles and 5-aminopyrazoles.5d
In all of these cases the TSE-protecting group can be
removed via a retro-Michael reaction promoted by
potassium tert-butoxide. In this letter we now report
the synthesis of b-tosylethylazide (TSE-N3) and its
application to the generation of protected 1,2,3-triazoles
via metal-catalyzed 1,3-dipolar cycloadditions with
alkynes.7
b-Tosylethylazide (2) can be easily synthesized as a crys-
talline solid in one step in good yield from commercially
available p-tolyl vinyl sulfone (1) and sodium azide/sul-
furic acid in methanol (Eq. 1).8–10 This material is puri-
fied by chromatography and can be stored indefinitely in
the freezer:
NaN , MeOH
3
H SO
2
4
0 °C-rt
ð1Þ
During the past few years we have been exploring the
use of b-tosylethyl (TSE)-containing synthons for prep-
aration of various kinds of N-protected systems.5,6 For
example, readily prepared b-tosylethylamine (TSE-
NH2) can be used to synthesize a number of types of
N
3
Ts
Ts
87%
2
1
Using the Sharpless protocol,3a it was found that treat-
ment of TSE-N3 (2) with terminal alkynes in the pres-
ence of cupric sulfate/sodium ascorbate (to generate
Cu(I) in situ) in aqueous tert-butanol at room tempera-
ture led to the 4-substituted-1,2,3-triazoles 3 (Scheme
1).11 Several examples of this cycloaddition are shown
Keywords: 1,3-Dipolar cycloadditions; Protecting groups; 1,2,3-Tri-
azoles; Nitrogen heterocycles.
*
Corresponding author. Tel.: +1 814 863 0189; fax: +1 814 865
3292; e-mail: smw@chem.psu.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.020

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A. H. Yap, S. M. Weinreb / Tetrahedron Letters 47 (2006) 3035–3038
ingly, these conditions also promoted the cycloadditions
of acetylene dicarboxylic acid (entry g) and dimethyl
acetylenedicarboxylate (entry h) with azide 2. If either
the cupric sulfate or the sodium ascorbate was omitted
from the reaction mixture, only starting materials were
recovered. Since these alkynes cannot form copper
acetylides, it is not clear exactly how these reactions
are occurring. In order to firmly establish that the regio-
selectivity of the cycloaddition with terminal alkynes
occurred as expected, the adduct of TSE-N3 with
sodium
ascorbate
1
TSE
CuSO
N N
4
R
+ 2
N
t-BuOH
4
H O, rt
R
2
3
(TSE = TsCH CH )
2
2
H
N N
N
KOt-Bu
THF
1
-78-0 °C
phenylacetylene was analyzed by both H NMR NOE
R
studies and X-ray crystallography, and was found to
indeed have the 4-substituted triazole structure as shown
in entry a.12
4
Scheme 1.
It was possible to remove the TSE-protecting group by
exposure of triazoles 3 to potassium tert-butoxide in
THF at ꢀ78 °C and then letting the reaction mixture
slowly warm to 0 °C, producing the unprotected tri-
in Table 1. The products in these cases crystallized out
of the reaction mixture in sufficiently pure form for uti-
lization without further purification. Yields of the 1,2,3-
triazoles generally ranged from 75% to 97%. Interest-
Table 1. Preparation of TSE-protected triazoles by Cu(I)-catalyzed cycloadditions of TSE-N3 with alkynes, and deprotection with KOt-Bu/THF
Entry
Alkyne
TSE-protected triazole
Isolated yield (%)
Deprotected triazole
Isolated yield (%)
TSE
H
N N
N
N N
N
a
92
77
Ph
Ph
Ph
TSE
N N
b
89
p-MePh
N
p-MePh
TSE
H
N N
N N
c
93
97
93
61
Bu
N
N
Bu
Bu
TSE
H
N N
N
N N
N
d
Hex
Hex
Hex
TSE
H
N N
N N
e
f
PhOH C
93
85
80
77
N
N
2
CH OPh
CH OPh
2
2
TSE
H
N N
N
N N
N
p-MeOPh
p-MeOPh
p-MeOPh
TSE
N N
g
HO C
CO H
75
86
N
2
2
CO H
2
CO H
2
TSE
H
N N
N
N N
h
MeO C
CO Me
88
N
2
2
CO Me
CO Me
2
2
CO Me
CO Me
2
2

A. H. Yap, S. M. Weinreb / Tetrahedron Letters 47 (2006) 3035–3038
3037
azoles 4.13 p-Tolyl vinyl sulfone is presumably formed in
this step, but polymerizes under the reaction conditions.
A few examples of such deprotections are shown in
Table 1.
1,2,3-triazoles. The TSE-protecting group on these
adducts can be removed under mildly basic conditions
via a retro-Michael reaction using potassium tert-
butoxide.
More recently, the Sharpless group has discovered that
Cp*RuCl(PPh3)2 and related ruthenium complexes effi-
ciently catalyze the cycloaddition of alkyl azides with
both terminal and internal alkynes to produce 1,2,3-
triazoles.14 However, it was found that with the ruthe-
nium catalysts, the regioselectivity of the reaction with
terminal alkynes is reversed, leading to 5-substituted-
1,2,3-triazoles. We have applied this new methodology
to cycloadditions of TSE-N3 (2) with alkynes. Thus,
Acknowledgments
We are grateful to the National Institutes of Health
(CA-034303) for financial support of this research. We
also thank Dr. G. Jia for providing details on the prep-
aration of the ruthenium catalyst.
treatment of phenylacetylene with azide
2
and
References and notes
Cp*RuCl(PPh3)2 in refluxing benzene leads to the 5-
phenyl-1,2,3-triazole 5 in good yield (Scheme 2).15 That
adduct 5 is in fact the 5-substitited 1,2,3-triazole was
1. For reviews of 1,2,3-triazoles see: (a) Fan, W.-Q.; Katri-
tzky, A. R. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 4, pp 1–126; (b)
Dehne, H. In Methoden der Organischen Chemie (Houben-
Weyl); Schaumann, E., Ed.; Thieme: Stuttgart, 1994; Vol.
E8d, pp 305–405.
2. For reviews see: (a) L’Abbe, G. Chem. Rev. 1969, 69, 345;
(b) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; (c) Sha, C.-K.;
Mohanakrishnan, A. K. In Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley:
New York, 2002; p 623.
3. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596;
(b) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057; (c) Himo, F.; Lovell, T.; Hilgraf, R.;
Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.;
Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
4. For reviews of ‘click chemistry’ see: (a) Kolb, H. C.; Finn,
M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40,
2004; (b) Bock, V. D.; Hiemstra, H.; van Maarseveen, J.
H. Eur. J. Org. Chem. 2006, 51.
5. (a) DiPietro, D.; Borzilleri, R. M.; Weinreb, S. M. J. Org.
Chem. 1994, 59, 5856; (b) Borzilleri, R. M.; Weinreb, S.
M.; Parvez, M. J. Am. Chem. Soc. 1995, 117, 10905; (c)
Artman, G. D., III; Waldman, J. H.; Weinreb, S. M.
Synthesis 2002, 2057; (d) Dastrup, D. M.; Yap, A. H.;
Weinreb, S. M.; Henry, J. R.; Lechleiter, A. J. Tetrahedron
2004, 60, 901.
6. For some examples of the use of the TSE group in
protection of preformed nitrogen heterocycles see: (a)
Faubl, H. Tetrahedron Lett. 1979, 491; (b) Gonzalez, C.;
Greenhouse, R.; Tallabs, R.; Muchowski, J. M. Can. J.
Chem. 1983, 61, 1697; (c) Rao, A. K. S. B.; Rao, C. G.;
Singh, B. B. Synth. Commun. 1994, 24, 341; (d) Bashford,
K. E.; Cooper, A. L.; Kane, P. D.; Moody, C. J.
Tetrahedron Lett. 2002, 43, 135.
7. For other examples of synthesis of N-protected 1,2,3-
triazoles via 1,3-dipolar cycloadditions with alkynes see:
(a) Kamijo, S.; Huo, Z.; Jin, T.; Kanazawa, C.; Yama-
moto, Y. J. Org. Chem. 2005, 70, 6389; (b) Katritzy, A. R.;
Takahashi, I.; Marson, C. M.; Scriven, E. F. V. Chem.
Scripta 1987, 28, 149; (c) Jin, T.; Kamijo, S.; Yamamoto,
Y. Eur. J. Org. Chem. 2004, 3789; (d) Wiley, R. H.;
Hussung, K. F.; Moffat, J. J. Org. Chem. 1956, 21, 190.
8. Cf. Bera, S.; Sakthivel, K.; Pathak, T.; Langley, G. J.
Tetrahedron 1995, 51, 7857.
1
established by H NMR NOE experiments.
Similarly, with diphenylacetylene, the protected triazole
6 could be prepared. Removal of the TSE-protecting
groups of 5 and 6 with potassium tert-butoxide under
the usual conditions afforded triazoles 7 and 8,
respectively.
Finally, since the Sharpless group had not reported a
ruthenium-catalyzed cycloaddition of an alkyl azide
with an unsymmetrical internal alkyne,14 we were
prompted to explore the reaction of TSE-N3 with alkyne
9 (Eq. 2). Interestingly, this cycloaddition gave only one
detectable 1,2,3-triazole in moderate yield, which was
proven to be the regioisomer 10 by 1H NMR NOE anal-
ysis. It should also be noted that the cycloaddition of
azide 2 and alkyne 9 does not occur under Cu(I)
catalysis:
Ts
Cp*RuCl(PPh )
PhH, reflux
3 2
N N
N
nOe
MeO C
Bu
+ 2
2
64%
CO Me
9
10
2
ð2Þ
In conclusion, we have demonstrated that readily
prepared b-tosylethylazide undergoes regioselective
cycloadditions with a variety of alkynes under either
copper or ruthenium catalysis to afford N-protected
TSE
Ph
1
Cp*RuCl(PPh )
PhH, reflux
N N
3 2
N
R
Ph
+
2
5
R
5 R = H (77%)
6 R = Ph (63%)
H
N N
N
KOt-Bu
THF
7 R = H (86%)
8 R = Ph (95%)
Ph
-78-0 °C
R
9. We thank David Dastrup for developing this synthesis of
TSE-N3.
Scheme 2.

3038
A. H. Yap, S. M. Weinreb / Tetrahedron Letters 47 (2006) 3035–3038
10. Preparation of TSE-N3 (2). A solution of concentrated
H2SO4 (0.27 mL, 19.2 mmol) in MeOH (30 mL) was
added slowly to a solution of sodium azide (2.86 g,
44 mmol) in MeOH (120 mL) at 0 °C and the mixture
was stirred for 15 min. A solution of p-tolyl vinyl sulfone
(1, 0.73 g, 4.0 mmol) in MeOH (60 mL) was slowly added
and the mixture was stirred for 72 h at rt. The reaction
mixture was diluted with 20 mL of H2O and the aqueous
layer was extracted with CH2Cl2. The organic extract was
dried over MgSO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
(20:80 EtOAc/hexanes) to afford TSE-N3 (2) as a white
crystalline solid (0.78 g, 87%). 1H NMR (300 MHz,
CDCl3) d 7.78 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz,
2H), 3,67 (t, J = 6.9 Hz, 2H), 3.31 (t, J = 6.9 Hz, 2H), 2.43
(s, 3H); 13C NMR (75 MHz, CDCl3) d 145.6, 135.8, 130.0,
127.9, 54.9, 44.7, 21.6; HRMS calcd for C9H11N3SO2
226.0650 (MH+), found 226.0643.
11. General procedure for Cu(I)-catalyzed Cycloaddition of
TSE-N3with alkynes. The alkyne (3.0 mmol) and TSE-N3
(2, 0.68 g, 3.0 mmol) were added to a solution of water/
t-BuOH (8 mL/4 mL). Solutions of sodium ascorbate
(1.0 M in H2O, 300 lL, 0.3 mmol) and copper(II) sulfate
(0.3 M in H2O, 100 lL, 0.03 mmol) were added sequen-
tially and the reaction mixture was stirred rapidly at rt for
8 h. The triazole precipitated out of the reaction mixture,
which was then diluted with 5 mL of H2O and chilled in
ice. The triazole product 3 was isolated via filtration,
washed with cold H2O, and was dried in vacuo.
12. We thank Dr. Hemant Yennawar (Penn State Small
Molecule X-Ray Crystallographic Facility) for this crystal
structure determination. CCDC 600036 contains the
supplementary crystallographic data, which can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
13. General deprotection procedure. A solution of t-BuOK in
THF (1.0 M, 0.86 mL) was slowly added to a solution of
protected triazole (200 lmol) in THF (10 mL) at ꢀ78 °C.
The solution was slowly warmed to 0 °C over a period of
1–3 h. The reaction mixture was neutralized with glacial
acetic acid (24.7 lL, 100 lmol) at 0 °C. The mixture was
concentrated in vacuo and the residue was purified by
flash column chromatography (30:70 EtOAc/hexanes) to
afford the deprotected 1,2,3-triazole.
14. Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I.
D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem.
Soc. 2005, 127, 15998.
15. General procedure for ruthenium-catalyzed synthesis of
TSE-protected 1,2,3-triazoles. The alkyne (0.50 mmol)
was added to a solution of TSE-N3 (2, 0.168 g, 0.75 mmol)
and Cp*RuCl(PPh3)2 (0.04 g, 0.05 mmol) in benzene
(2.5 mL). The reaction mixture was stirred and heated at
reflux for 2 h. After cooling the mixture to rt, the solvent
was removed in vacuo. The residue was purified by flash
column chromatography on silica gel (50:50 ether/hexanes
to 100% ether gradient) to yield the TSE-protected 1,2,3-
triazole.