Published on Web 04/19/2005
Thermal and Catalyzed [3,3]-Phosphorimidate
Rearrangements
Bin Chen and Anna K. Mapp*
Contribution from the Departments of Chemistry and Medicinal Chemistry,
UniVersity of Michigan, Ann Arbor, Michigan 48109
Received February 4, 2005; E-mail: amapp@umich.edu
Abstract: [3,3]-Sigmatropic rearrangements have been widely utilized for the synthesis of structurally
complex organic molecules because of the ease with which carbon-carbon bonds are formed in a regio-
and stereocontrolled manner. However, there are far fewer [3,3]-rearrangements available for the selective
formation of carbon-nitrogen bonds despite the enormous potential of such reactions for the preparation
of stereodefined allylic amines. We describe here the scope and mechanism of a [3,3]-rearrangement of
allylic phosphorimidates that provides access to stereodefined allylic amines of diverse structure. The reactive
intermediate in the reaction, an allylic phosphorimidate, is produced in situ through the combination of
readily available starting materials (allylic alcohols, chlorophosphites, and organic azides), rendering the
reaction an efficient three-component process. Analogous to other [3,3]-rearrangements, the stereochemistry
in an allylic alcohol starting material is transferred with fidelity to the allylic amine product and, further,
allylic amines are produced as single olefin isomers. In addition, a crossover experiment indicates that the
rearrangement is an intramolecular process. Finally, activation of the allylic moiety either through
incorporation of electron-deficient functional groups or through the use of a transition-metal catalyst
significantly facilitates the reaction and consequently the preparation of a wider range of substitution patterns.
Introduction
that employ readily generated precursors and provide access to
a wide range of substitution patterns thus remain highly
Since the first report of the Claisen rearrangement, numerous
[3,3]-sigmatropic rearrangements leading to the selective forma-
tion of carbon-carbon bonds have been developed.1-3 Because
of their exquisite regio- and stereocontrol, these reactions have
been widely employed for the synthesis of complex organic
molecules.1-3 In contrast, the development of [3,3]-sigmatropic
rearrangements for the formation of carbon-nitrogen bonds has
been considerably slower, despite the enormous potential of such
reactions for the synthesis of molecules containing nitrogen-
bearing stereocenters. The prototype for this reaction class is
the Overman thermal rearrangement of allylic trichloracetimi-
dates, a reaction that provides allylic amines protected as
acetamides with excellent regio- and stereocontrol.4,5 Stereo-
defined allylic amines are essential building blocks of important
targets such as R- and â-amino acids, lactams, and alkaloid
natural products.6 The development of novel reaction manifolds
desirable.7
Toward that end, we recently reported a thermally driven
[3,3]-sigmatropic rearrangement of allylic phosphorimidates for
the synthesis of protected allylic amines of varying structure.8
The concept of this reaction arose from the rearrangement of
phosphorimidates to phosphoramidates that occurs readily under
thermal conditions (Figure 1).9 As demonstrated by Challis and
co-workers, this is an intermolecular reaction with one imidate
undergoing nucleophilic attack by the nitrogen of a second
imidate molecule.10 We reasoned that replacement of one of
the phosphorimidate ester groups with an allyl substituent would
provide an intramolecular manifold by which the reaction could
proceed. The intramolecular reaction would thus lead to a 1,3-
transposition of functionality to provide a protected allylic
(7) For recent examples see: Wipf, P.; Kendall, C.; Stephenson, C. R. J. J.
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(10) Challis, B. C.; Challis, J. A.; Iley, J. N. J. Chem. Soc., Perkin Trans. 2
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J. AM. CHEM. SOC. 2005, 127, 6712-6718
10.1021/ja050759g CCC: $30.25 © 2005 American Chemical Society