COMMUNICATION
Nitrones as dipoles for rapid strain-promoted 1,3-dipolar cycloadditions
with cyclooctynesw
Craig S. McKay,ab Joseph Morana and John Paul Pezacki*ab
Received (in College Park, MD, USA) 15th October 2009, Accepted 8th December 2009
First published as an Advance Article on the web 23rd December 2009
DOI: 10.1039/b921630h
Strain-promoted cycloadditions of nitrones with cyclooctynes
(k2 = 1.5 Mꢀ1 sꢀ1 at 25 1C) are up to 25 times more rapid than
comparable reactions of azides.
Having recently become interested in nitrones for use in
Kinugasa reactions in aqueous media,15 we speculated that
these dipoles might provide faster intrinsic kinetics than azides
for reactions with strained alkynes. Given the value of increasing
reaction rates as a means for reducing the required concentration
of labeling reagents for bioorthogonal reactions, we set out to
evaluate the kinetics and generality of the nitrone cyclo-
addition with strained alkynes. Herein, we report that nitrones
serve as rapid, selective and conveniently prepared 1,3-dipoles
for cycloaddition with benzannulated cyclooctyne 216 at
ambient temperatures (Fig. 1B).
An emerging field in organic reaction methodology focuses on
the development of chemical transformations suitable for
applications in chemical biology.1 Despite intense interest,
few transformations display the appropriate selectivity,
kinetics and biocompatibility required for tracking biological
processes in living systems. While approaches based on the
Staudinger ligation,2 the Diels–Alder reaction,3 various
nucleophilic additions,4 thiol-based reactions5 and cross-
metathesis6 have been reported, most efforts have converged
on [3+2] dipolar cycloadditions of azides with alkynes, which
are rapid when promoted by potentially toxic7 copper species.8
Biocompatible copper-free variants of the ‘‘click’’ reaction with
azides have been achieved by employing strained cyclo-
octynes9 and subsequent difluoro-10 or dibenzo-11 activation of
the cyclooctyne partner (Fig. 1A), yet even these biased reactions
often take several hours to reach completion at ambient
temperatures. Faster rates may be achieved by employing more
reactive 1,3-dipoles such as nitrile oxides12 or photochemically
generated nitrile imines,13 but the use of more common
1,3-dipoles such as nitrones14 has not been described.
The nitrone scope was evaluated with respect to its
conformational flexibility and electronics (Table 1).z Acyclic
nitrones (1a–k) were prepared by micelle-promoted condensation
of an aryl aldehyde and appropriate hydroxylamine.17 Endo-
cyclic nitrones 1l and 1n were prepared by oxidation of the
amine18 while lm was prepared using a straightforward
one-pot reaction sequence.19 Expectedly, acyclic aromatic
nitrones bearing electron-withdrawing groups (entries 4–7)
reacted more rapidly than the unsubstituted parent nitrone
and those bearing electron-donating groups (entries 8–10).
Second order rate constants for nitrones 1b and 1i were found
to be 0.13 ꢁ 0.01 Mꢀ1 sꢀ1 and 0.088 ꢁ 0.004 Mꢀ1 sꢀ1
,
respectively, in C6D6 at 25 1C (Table 2, entries 1 and 2). These
rates are comparable with typical values for reactions of azides
with difluorinated cyclooctyne (DIFO).10 Encouragingly,
endocyclic nitrones showed increased reactivity relative to
their acyclic counterparts. Nitrone 1n, which features benzylic
activation and is contained within a rigid six-membered ring,
appeared qualitatively to be the most rapid by TLC analysis
and therefore warranted further quantitative study. The
second order rate constant for the reaction of 1n with 2 in
C6D6 at 25 1C was determined to be 1.5 ꢁ 0.1 Mꢀ1 sꢀ1 by
1H NMR (see ESIw). This additional rate acceleration most
likely arises at least in part due to strain in the cyclic nitrone,
making the reaction doubly strain-promoted. Put in context,
this rate is about 20 times faster than the reaction of DIFO
with benzyl azide10 and approximately 25 times faster than the
reaction of dibenzocyclooctyne with benzyl azide measured
under our conditions (see ESIw).
Fig. 1 (A) Strain-promoted [3+2] cycloadditions of azides and
cyclooctynes. (B) Strain-promoted [3+2] cycloadditions of nitrones
and cyclooctynes.
To further study the reactive nature of endocyclic nitrones,
the reaction of 1n with 2 was performed in a variety of
common deuterated solvents at ambient temperature and
monitored by 1H NMR (Table 3). At starting reaction
concentrations of 100 mM, the reaction typically achieved
95% conversion to isoxazoline 3n in less than 30 minutes, and
in under 3 minutes for some solvents (entries 2 and 4).
In conclusion, the nitrone–cyclooctyne cycloaddition is
well-positioned for development as a rapid metal-free, thermal
a Steacie Institute for Molecular Sciences, National Research Council
of Canada, 100 Sussex Drive, Ottawa, ON, Canada K1A 0R6.
E-mail: John.Pezacki@nrc-cnrc.gc.ca; Fax: +1 613-952-0068;
Tel: +1 613-993-7253
b Department of Chemistry, University of Ottawa, 10 Marie-Curie,
Ottawa, ON, Canada K1N 6N5
w Electronic supplementary information (ESI) available: Experimental
procedures, kinetic data, spectroscopic characterization for all new
compounds. See DOI: 10.1039/b921630h
ꢂc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 931–933 | 931
McKay, Craig S.
