The allylic azide rearrangement: Achieving selectivity

Article abstract of DOI:10.1021/ja050622q

Allylic azides undergo a rapid [3.3]-sigmatropic rearrangement which results in dynamic equilibrium of several isomers. Thus, reactions of allylic azides usually result in mixtures of products. However, even small differences in reactivity of the isomeric

Full text of DOI:10.1021/ja050622q

Published on Web 09/09/2005
The Allylic Azide Rearrangement: Achieving Selectivity
Alina K. Feldman, Benoˆıt Colasson, K. Barry Sharpless,* and Valery V. Fokin*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
Received January 31, 2005; E-mail: fokin@scripps.edu; sharples@scripps.edu
Scheme 1. Rearrangement of Allylic Azides
Organic azides are most commonly used to introducte an amino
group, and in this rather pedestrian role, their existence is barely
noticed. Hence, the special reactivity features1 of the azide
functionality, as revealed in cycloadditions and pericyclic reactions,
remain underappreciated, even though the latter are probably the
most powerful and useful transformations involving azides.
Copper(I)-catalyzed cycloaddition with terminal alkynes, which
results in 1,4-disubstituted 1,2,3-triazoles, is among the recent
advances in the chemistry of organic azides.2 The rare chemical
orthogonality of the azide and alkyne functionalities (that is,
inertness to acidic and basic conditions) has enabled unique
applications of this process in chemical biology, organic synthesis,
and materials science.3 Since olefins, too, are stable in most acid/
base environments, one expects that the special case of allylic azides
might possess the familial reactivity profile, and it does, even though
the azide and the olefin groups are engaged in the dynamic [3.3]-
sigmatropic equilibration process4 shown in Scheme 1.
Scheme 2. Cu(I)-Catalyzed Cycloaddition of Allylic Azides with
Phenylacetylenea
Since this rearrangement generally creates mixtures of the
interconverting allylic isomers, it has been viewed as a liability.5
The goal of our study was to achieve selective capture of one of
these isomers. We envisioned that differences in their reactivity
patterns could, in concert with their facile interconversion, prove
advantageous. Reported here are the results from two model
reactions: the Cu(I)-catalyzed azide-alkyne cycloaddition2 and
MCPBA epoxidation of olefins.6
Since both steric and electronic effects can influence reactivity
of azides and olefins, the following allylic systems were studied in
side-by-side experiments: primary vs tertiary, secondary vs tertiary,
and primary vs secondary azides. Each of the three classes was
represented by two members: the parent aliphatic azides (1, 5 and
9) and their closely related hydroxylated derivatives (3, 7, and 11),
selected to investigate the effect of the heteroatom and, in retrospect,
the apparent hydrogen-bonding effects between the hydroxyl and
the azide groups. As studies progressed, evidence grew that
H-bonding effects could significantly modulate the equilibrium
“set-points” in these dynamic systems.
Having earlier noted that the Cu(I)-catalyzed triazole synthesis
was somewhat sensitive to the steric environment of the azide,7
we looked for such effects in the selectivity of product capture.
Hence, a variety of allylic azides, all engaged in [3.3]-sigmatropy
(albeit more or less facile for a specific case), were submitted to
the Cu(I)-catalyzed cycloaddition with phenylacetylene as alkyne.
The composition of the mixtures of triazole products was deter-
mined by 1H and 13C NMR and LC-MS. The results are
summarized in Scheme 2.
Excellent selectivity was observed in the primary vs tertiary and
secondary vs tertiary azides series (Scheme 2, entries 1 and 2). No
products arising from tertiary azides were detected. Equilibration
between the tertiary and the trans-primary allylic azides is faster
than the Cu(I)-catalyzed reaction; however, the interconversion
between the tertiary azide with the cis form of the primary azide is
a Reagents and conditions: (a) azide (1 mmol), phenylacetylene (1 mmol),
CuSO4‚5H2O (0.05 mmol), sodium ascorbate (0.1 mmol), tBuOH/H2O 1:1
(2 mL), room temperature, 12 h.
generally slower.4c As a result, the amount of product derived from
the cis isomer of the azide approximated the amount of the cis
azide found at equilibrium (as in triazole 4 derived from azide 3a).
Interestingly, the Cu(I)-catalyzed cycloaddition reaction did not
distinguish well between the primary and secondary azide regioi-
somers, with composition of the resulting mixture of triazole
products being very similar to that of the starting materials (Scheme
2, entry 3).
To see if differential olefin reactivity would draw out similar
selectivity, epoxidation with MCPBA, a reagent well known to
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10.1021/ja050622q CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Epoxidation of Allylic Azides
slowly with less substituted olefins 3b and 11b, they appear to be
sufficiently long-lived to produce noticeable amounts of the
corresponding azidoepoxides 14b and 16b. In the secondary vs
tertiary azide series, azido alcohol 7 performed slightly better than
azide 5, which lacks a hydroxyl group.
In summary, an allylic azide’s existence as a dynamically
equilibrating mixture of all possible [3.3]-isomers can be manipu-
lated in interesting ways. By use of an appropriate capture trick, a
given [3.3]-rearrangement family of allylic isomers is uniquely
“siphoned off” through the isomer preferred by the “fixing” reaction.
In the cases at hand, the rearrangement process was terminated by
reactions selective for azide functionality and for olefin functional-
ity, respectively. Given the wealth of useful olefin reactions with
electrophiles and oxidants, allylic azides appear to offer many
worthwhile selectivity refinements, in the already wide world of
olefin transformations.
Acknowledgment. We thank the National Institute of General
Medical Sciences, the National Institutes of Health (GM-28384),
the W. M. Keck Foundation, and Pfizer Inc. for financial support.
B.C. thanks the French Ministe`re des Affaires Etrange`res for
Lavoisier fellowship. A.K.F. thanks the Skaggs Foundation for a
fellowship.
Supporting Information Available: Typical experimental proce-
dures and spectral characterization of all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
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a Conditions A:6b MCPBA (1.1 equiv), H2O (0.3 M NaHCO3), room
temperature, 12 h. Conditions B: MCPBA (1.3 equiv), CH2Cl2, room
temperature, 12 h. b Isolated combined yields. c Reaction time was 48 h.
be sensitive to the electronic properties of the olefin,6b was chosen.
The epoxide product mixtures were analyzed by 1H NMR,13C NMR,
and GC. Table 1 summarizes the results.
In general, good to excellent selectivity was realized. Aqueous
conditions (A), which utilize buffered MCPBA, were preferred (see
Supporting Information for details). However, for azido alcohols
3, 7, and 11, nonaqueous conditions (B) were required to achieve
complete conversion to the corresponding azidoepoxides. In the
primary vs tertiary and primary vs secondary azide systems,
excellent selectivity was observed for compounds 1 and 9 (cf. entries
1 and 5). As expected, more substituted olefins reacted faster. The
more sluggish rearrangement rates noted with azido alcohols 3 and
11 appear to be due to the interplay of inductive electronic effects8
and hydrogen bonding effects.9 Although MCPBA reacts more
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