Copper-free 'click': 1,3-dipolar cycloaddition of azides and arynes

Article abstract of DOI:10.1039/b812403e

Arynes formed through fluoride-promoted ortho-elimination of o-(trimethylsilyl)aryl triflates can undergo [3 + 2] cycloaddition with various azides to form substituted benzotriazoles. The rapid reaction times and mild conditions make this an attractive variation of the classical 'click' reaction of azides and alkynes.

Full text of DOI:10.1039/b812403e

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Ben L. Feringa et al.
David R. Carbery
Copper-free‘click’: 1,3-dipolar
Enamides: valuable organic substrates cycloaddition of azides and arynes

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Copper-free ‘click’: 1,3-dipolar cycloaddition of azides and arynes†
Lachlan Campbell-Verduyn,a Philip H. Elsinga,b Leila Mirfeizi,b Rudi A. Dierckxb and Ben L. Feringa*a
Received 21st July 2008, Accepted 4th August 2008
First published as an Advance Article on the web 13th August 2008
DOI: 10.1039/b812403e
Arynes formed through fluoride-promoted ortho-elimination
of o-(trimethylsilyl)aryl triflates can undergo [3 + 2] cycloaddi-
tion with various azides to form substituted benzotriazoles.
The rapid reaction times and mild conditions make this an
attractive variation of the classical ‘click’ reaction of azides
and alkynes.
scope of this reaction, and milder methods were subsequently
developed.7 Thus came examples generating arynes from o-
(trimethylsilyl)aryliodonium salts; a gentler method, but involving
a difficult synthesis of the precursors limiting the possibilities for
functionalization.8 Other examples include benzobisoxadisiloles
as precursors of benzdiynes9 and two-step deprotonation and
dehalogenation of aromatic halogen compounds.10 Currently, the
mildest way to form the benzyne intermediate is to use fluoride-
induced ortho-elimination of o-(trimethylsilyl)aryl triflates, which
can easily be prepared with various substituents on the arene
ring.11
Beginning with the cycloaddition of benzyl azide and com-
mercially available o-(trimethylsilyl)phenyl triflate, we investigated
the use of differing fluoride sources in a range of solvents for
benzyne generation (Table 1). Fluoride salts in combination with
a complementary crown ether were tested, as was tetrabutylam-
monium fluoride (TBAF). KF paired with 18-crown-6 induced
full conversion to the benzotriazole at room temperature in all
solvents tested with good yields (entries 1–5). CsF and 18-crown-6
gave faster reaction times, if somewhat lower yields (entries 8–
10). TBAF provides an alternative to fluoride salts, but both the
reaction time and yield were less favourable (entry 6). NaF in
combination with 15-crown-5 gave no product conversion, nor
did the reaction proceed in water even after 48 h. In both cases it
was possible to recover the azide starting material quantitatively
as well as the majority of the benzyne precursor. This led
us to conclude that no formation of the benzyne intermediate
occurs.
The discovery by Sharpless et al. in 2001 that copper(I) catalyzes
the 1,3-dipolar cycloaddition of azides and alkynes to form 1,4-
disubstituted triazoles strongly contributed to the popularization
of ‘click’ chemistry as a combinatorial method for functionalized
moieties.1 Significant progress has been made in the application of
this methodology to the areas of materials science, drug discovery,
polymer chemistry and bioconjugation, among others.2 Limita-
tions arise in the field of bioconjugation and in vivo imaging due to
the toxicity of copper. Furthermore, in the absence of copper, the
reaction necessitates elevated temperatures or pressures which are
incompatible with most living systems.3 The rarity and inertness
of azides and alkynes in biological environments make them ideal
bioorthogonal markers, highlighting the importance of developing
copper-free ‘click’ reactions.
To date, promising alternatives for alkyne activation have been
discovered; activation of the substrate via electron-withdrawing
functionalities adjacent to the triple bond serves to increase
reaction rates in the absence of copper4, as does the use of severely
strained acetylenes.5 In our investigation into accelerated ‘click’
reactions using new systems, we touched upon the annulation of
arynes by azides. Herein lies the potential for [3 + 2] cycloaddition
in the absence of copper while retaining those benefits commonly
associated with ‘click’ reactions – namely regioselective, fast
reactions under mild conditions. We report here our preliminary
results of a new, fast, and versatile copper-free click reaction.
Arynes, particularly benzynes, have proven to be useful reactive
intermediates for synthetic organic chemists. They are kinetically
unstable, highly strained molecules that readily undergo nucle-
ophilic coupling with various neutral species to form complex
organic molecules.6
Table 1 Reaction optimizationa
Fluoride source
Solvent
T/◦C
Time/h
Yieldb (%)
Benzyne has traditionally been formed from the diazonium
carboxylate intermediate obtained by refluxing anthranilic acid
with an organic nitrite. The harsh conditions severely hinder the
1
2c
3
4
5
6
7
8
9
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
TBAF
NaF/15-crown-5
CsF/18-crown-6
CsF/18-crown-6
CsF/18-crown-6
CsF/18-crown-6
THF
THF
THF
DCM
MeCN
THF
THF
THF
DCM
MeCN
H2O
rt
rt
60
rt
rt
rt
rt
rt
rt
rt
rt
4
29
1
8
3
20
24
1.5
30
0.5
40
85
80
71
72
87
69
0
70
58
77
0
aStratingh Institute for Chemistry, University of Groningen, Groningen, The
Netherlands. E-mail: b.l.feringa@rug.nl; Fax: +31 50 363 4278; Tel: +31 05
363 4296
bDepartment of Nuclear Medicine and Molecular Imaging, University Medi-
cal Center Groningen, University of Groningen, Groningen, The Netherlands.
E-mail: p.h.elsinga@ngmb.umcg.nl; Fax: +31 50 3696750; Tel: +31 50
3614850
10
11
a All reaction were carried out on a 0.2 mmol scale in 0.05M concentration.
b Average isolated yields from two or more experiments. c Reaction was
carried out using 1.2 eq of azide.
† Electronic supplementary information (ESI) available: General proce-
dures for the synthesis of benzyne precursors, azides and benzotriazoles;
1H and 13C spectral data of all products. See DOI: 10.1039/b812403e
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3461–3463 | 3461
©

Table 4 Click reaction with functionalized azides
Reducing the equivalents of azide (entry 2) prolongs the
reaction, and causes a slight drop in yield. At reflux the reaction
proceeds to completion in one hour, but the yield is lower
(entry 3), as it is in DCM (entry 4). In cases with lower yields,
the decrease can generally be attributed to degradation of the
benzyne precursor. Acetonitrile appears to have an accelerating
effect on the reaction, shortening conversion times for both KF
and CsF. The latter reaction is particularly satisfying, showing
full conversion in 30 min (entry 10). These conditions were thus
chosen for all subsequent experiments.
R
Product
Time/h Yielda (%)
1
2
EtO2CCH2–
1
82
Having established a methodology to obtain rapid conversion
to benzotriazole, we were interested in the effect of the crown ether
upon the reaction time (Table 2).
Cinnamyl
1.5
78
As recorded in Table 2, the optimal ratio of crown ether to
fluoride salt is 1 : 1. An extra equivalent of crown ether appears
to have an inhibitory effect, and the absence of crown ether
significantly decreases the reaction rate. In THF, virtually no
product was formed even after 48 h in the absence of crown ether.
In MeCN, after 48 h, the reaction reached completion, but the
yield was dramatically reduced. Reaction entries 3 and 5 were
performed with our regular reaction conditions using an excess of
azide, but were also attempted with a slight excess (1.2 eq) of the
o-(trimethylsilyl)phenyl triflate. The concentration of the reaction
mixture was varied from 0.05 M to 2.0 M with no significant
improvement of conversion rates or yields.12
3
p-Fluorobenzyl
0.5
59
Having confirmed the optimized reaction conditions, we sub-
sequently tested different aryne precursors (Table 3). Slightly
better yields are achieved with an electron-donating methoxy
substituent at carbon 3 with full conversion in a matter of
minutes (entry 3). The unsymmetrical benzyne precursor yields
a single regioisomer with the benzyl on the nitrogen remote to
the substituent. A naphthalene derivative can also be used; the
reaction is thus not limited to benzyne precursors (entry 2). In
the case of cycloaddition with the naphthyl precursor a mixture of
regioisomers (2 : 1) is observed. Preference is given to the product in
a Isolated yield.
which the benzyl group is positioned at the less sterically hindered
position 2.
To further ensure the generality of the reaction, some selected
and particularly challenging azides were tested under the opti-
mized reaction conditions (Table 4).
The reaction proceeds effectively with a non-aromatic function-
alized azide (entry 1), and the presence of alkenes is tolerated
(entry 2). Both products were isolated in good yields with reac-
tion times of less than 2 h with no side product formation observed.
An electron-deficient fluoroazide (entry 3) reacts completely in
30 min. An 18F-labelled analogue of this azide could be used to
apply this fast coupling protocol in radiolabelling for imaging
technologies such as 18F PET.13
This method for the development of various substituted and
functionalized benzotriazoles fulfills many of the requirements
necessary to classify any given reaction as a ‘click’ reaction. It has
rapid conversion times, proceeds at room temperature in air and
produces a single product in good yields. The extension of this
versatile methodology to more significant substrates is currently
under study.13
Table 2 Effect of crown ether
Fluoride source
Solvent
Time/h
Yielda (%)
1
2
3
4
5
CsF/18-crown-6 (1 : 1)
CsF/18-crown-6 (1 : 2)
CsF
CsF/18-crown-6 (1 : 1)
CsF
THF
THF
THF
MeCN
MeCN
1.5
20
48
0.5
48
70
67
2b
77
46
a Isolated yield. b Percent conversion as determined by GC.
Table 3 Substituted aryne precursors
Acknowledgements
Financial support from UMCG is gratefully acknowledged.
R
Time/h
Yielda (%)
Notes and references
1
2
3
H
0.50
0.25
0.25
56
75b
84
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13 Study in progress.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3461–3463 | 3463
©