A Phosphorimidate Rearrangement for the Facile and Selective Preparation of Allylic Amines

Article abstract of DOI:10.1021/ja0490469

Allylic phosphorimidates, readily prepared from the combination of an allylic alcohol, an azide, and a chlorophosphite, undergo [3,3]-rearrangement under thermal conditions to provide single isomers of allylic phosphoramidates. This new rearrangement is tolerant of a range of substitution patterns on the reactants. Treatment of the products of the rearrangement with ethanethiolate followed by acid produces a protected allylic amine. This strategy thus provides an attractive and versatile procedure for the preparation of key synthetic intermediates, allylic amines. Copyright

Full text of DOI:10.1021/ja0490469

Published on Web 04/13/2004
A Phosphorimidate Rearrangement for the Facile and Selective Preparation of
Allylic Amines
Bin Chen and Anna K. Mapp*
Departments of Chemistry and Medicinal Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
Received February 19, 2004; E-mail: amapp@umich.edu
[3,3]-Sigmatropic rearrangements have long been a mainstay of
synthetic organic chemistry due to the relative ease with which
carbon-carbon bonds can be assembled with excellent regio- and
stereocontrol to produce structurally complex targets.1 In contrast,
there are few such rearrangements available for selective carbon-
nitrogen bond formation despite the enormous potential of such
methods for the synthesis of molecules containing nitrogen-bearing
stereocenters.2 We describe here a phosphorimidate-to-phosphor-
amidate [3,3]-rearrangement for the controlled formation of carbon-
nitrogen bonds, including quaternary centers. This novel transfor-
Figure 1. Allylic imidate-to-amidate rearrangement.
mation is readily carried out in one pot, starting from readily
available allylic alcohols and thus provides rapid access to single
Table 1. Optimization of the Rearrangement
isomers of allylic amines,3,4 essential building blocks of structurally
complex targets such as R- and â-amino acids, lactams, and alkaloid
natural products.3
Simple phosphylimidates 1 are known to rearrange to phosphyl-
amidates 2 either thermally or through electrophilic catalysis, with
the formation of the phosphorus-oxygen double bond driving the
process (Figure 1).5 Under both conditions, reaction is believed to
proceed in a bimolecular fashion through initial alkylation of the
imidate nitrogen.5 We reasoned that substitution of one of the ester
groups of the phosphylimidate intermediates with an allyl substituent
as in 3 would provide an intramolecular manifold by which the
rearrangement could proceed with a 1,3-transposition of functional-
ity to provide a protected allylic amine (4).6
a Conditions: i. E-2-hexen-1-ol (1.25 equiv), 1.25 equiv of the diphen-
The substrates for this rearrangement are readily prepared in situ
by the Staudinger reaction between azides and phosphines or
phosphites (Table 1)7,8 The phosphorus substituents as well as the
solvent polarity play central roles in the reaction pathway. For
example, with phenyl substituents on the phosphorus (entries 1 and
2), the major isolated product was the undesired regioisomer 7a,
most likely obtained via the intermolecular reaction pathway. In
polar solvents such as acetonitrile (entry 1), 7a was the only
phosphoramidate product isolated. Increasing the reaction temper-
ature and decreasing solvent polarity had the combined effect of
increasing overall conversion and produced a 2:3 mixture of the
desired allylic amine 6a to the undesired 7a.
The introduction of ethoxy substituents on the phosphorus
resulted in a substantial yield increase of 6b (55%) with no 7b
observed in the crude reaction mixture (Table 1, entry 3). Increasing
the steric bulk around the phosphorus by replacing the ethyl groups
with a 2,2-dimethylpropyl group provided a further boost in yield
(88%). Similar to the results obtained with 5a, the reaction pathway
from 5c was strongly dependent upon solvent polarity as changing
the solvent to acetonitrile from xylenes provided only a low yield
(14%) of the undesired primary allylic amine 7c. The temperature
at which the reaction is run also plays an important role; the use of
benzene or toluene, while providing only the desired product, gave
low yields. Preliminary data suggest that the need for the greater
reaction temperatures stems in part from the attenuated reactivity
of the phosphite in the Staudinger reaction step.8
ylchlorophosphine (entries 1 and 2) or chlorophosphite (entries 3 and 4)
and 1.25 equiv of Et3N in Et2O; 0 °C, 20 min. ii. Benzyl azide (1 equiv),
b
reflux, 4 h. Isolated yields. Identity of 6 and 7 confirmed by conversion
to the benzyl-protected amine and comparison with an authentic sample.
This new [3,3]-rearrangement is tolerant of substitution on the
allyloxy moiety, providing good to excellent yields of allylic
phosphoramidates with a variety of substituents (Table 2). Both E-
and Z-olefins are effective substrates in the reaction, as E-2-hexen-
1-ol and Z-2-hexen-1-ol each produce allylic phosphoramidate 6c
in comparable yields (entries 1 and 2). Remarkably, quaternary
stereocenters may also be formed in this reaction, as demonstrated
by the rearrangement of a geraniol-derived phosphorimidate to
provide 10 (entry 5). Consistent with a sigmatropic process, the
phosphorimidate derived from 3-buten-2-ol (entry 6) undergoes
rearrangement to 11 with >20:1 selectivity for the E-olefin-
containing product. Furthermore, other C1 substituents are also well
tolerated (entries 7 and 8). Despite reduced conformational flex-
ibility, cyclic allylic alcohols also undergo rearrangement upon
conversion to phosphorimidates to provide useful amines such as
14 (entry 9).
An attractive feature of the phosphorimidate rearrangement is
that the product contains a fully protected amine amenable to
subsequent reaction sequences. One of the protecting groups is
derived from the azide precursor and can thus be easily varied.
Benzyl azide, p-methoxybenzyl azide, and allyl azide each serve
as effective azide sources in the reaction and provide several choices
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10.1021/ja0490469 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Rearrangementa
selective approach to allylic amines. This reaction is tolerant of a
range of substitution patterns, and by choosing appropriate com-
binations of reactants (allylic alcohol and azide source), the
preparation of a wide range of allylic amine products can readily
be envisioned. It thus serves as a valuable and versatile addition to
the current approaches for the preparation of these valuable synthetic
intermediates.
Acknowledgment. A.K.M is grateful for financial support from
the NIH (GM65330), the Burroughs Wellcome Fund (New Inves-
tigator in the Toxicological Sciences), and the March of Dimes
(Basil O’Connor Starter Scholar). We thank Prof. M. Sanford for
a critical reading of the manuscript.
Note Added in Proof. A related transformation catalyzed by
palladium was recently communicated by Batey and Lee. See
Angew. Chem., Int. Ed. 2004, 43, 1865-1868.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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a Conditions as described in Table 1. Additional details are available in
b
the Supporting Information. Due to the volatility of allyl azide, an excess
c
d
(3 equiv) was used. Isolated yield after purification. The E-olefin isomer
1
was produced with >20:1 selectivity as determined by H NMR analysis
of the crude reaction mixture.
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In summary, we have disclosed a unique [3,3]-rearrangement of
allylic phosphorimidates to phosphoramidates as a facile and
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