Palladium-catalyzed [3,3]-rearrangement for the facile synthesis of allenamides

Article abstract of DOI:10.1021/ol1007845

A [3,3]-rearrangement that is used for facile construction of chiral allenamides is described. A propargylic alcohol, a chlorophosphite, and Cbz-azide are combined to provide a propargylic phosphorimidate that, in the presence of catalytic palladium(II), rearranges to an allenamide. By varying the substitution pattern on the propargylic alcohol, mono-, di-, and trisubstituted allenamides can be accessed in good yields. Additionally, the use of an enantiomerically enriched propargylic alcohol enables the preparation of stereochemically defined allenamides.

Full text of DOI:10.1021/ol1007845

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2574-2577
Palladium-Catalyzed [3,3]-Rearrangement
for the Facile Synthesis of Allenamides
Amy M. Danowitz, Christopher E. Taylor, Tamar M. Shrikian, and Anna K. Mapp*
Departments of Chemistry and Medicinal Chemistry, UniVersity of Michigan,
Ann Arbor, Michigan 48109
amapp@umich.edu
Received April 5, 2010
ABSTRACT
A [3,3]-rearrangement that is used for facile construction of chiral allenamides is described. A propargylic alcohol, a chlorophosphite, and
Cbz-azide are combined to provide a propargylic phosphorimidate that, in the presence of catalytic palladium(II), rearranges to an allenamide.
By varying the substitution pattern on the propargylic alcohol, mono-, di-, and trisubstituted allenamides can be accessed in good yields.
Additionally, the use of an enantiomerically enriched propargylic alcohol enables the preparation of stereochemically defined allenamides.
Allenamides have attracted much attention as versatile
precursors for the preparation of an array of synthetic targets,
including 1,2-aminoalcohols,1 cyclobutanes,2 dihydrofurans,3
pyranyl heterocycles,4 and 2-amido-dienes.5 Thus, significant
efforts have been devoted toward general methodologies to
access allenamides; however, these often require complex
precursor syntheses, and the preparation of enantiomerically
enriched allenamides is particularly cumbersome.6
One of the most commonly used methods for the formation
of highly substituted chiral allenamides is the iterative
addition of functionality to a monosubstituted stucture.6a In
this stepwise approach, the synthesis of stereochemically
defined allenamides requires a chiral auxiliary.6a Another
method for forming allenamides is the use of [2,3]-rear-
rangements of propargylic sulfides. An advantage of this
strategy is that it enables predictable transfer of stereochem-
ical information to the allenamide. However, preparation
of the starting propargylic sulfide, particularly in enantio-
merically enriched form, requires several synthetic manipu-
lations.6b-d
On the basis of work that has been previously carried out
in our laboratory,7 we envisioned using a propargylic
phosphorimidate as the key intermediate in a palladium-
catalyzed [3,3]-rearrangement for the formation of fully
protected allenamides. Unlike propargylic sulfides, propar-
gylic phosphorimidates are easily prepared in a single
synthetic step from three readily available starting materials:
a propargylic alcohol, a chlorophosphite, and an azide.
Further, this could be readily applied to the synthesis of
stereochemically defined allenamides simply through the use
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10.1021/ol1007845  2010 American Chemical Society
Published on Web 05/03/2010

of a commercially available or readily synthesized8 enan-
tioenriched propargylic alcohol.
phosphinates to form allenyl phosphorus species (Figure 1).13
Indeed, in initial studies conducted with propargyl alcohol
as the substrate, trivalent phosphorus esters with either
hydrocarbon or amine substituents (Table 1, entries 1 and
Although [3,3]-rearrangements have proven useful for the
preparation of allenes,9 the application to allenamides has
garnered little attention.10 The most extensively studied
example is the Overman rearrangement of propargylic
trichloroacetimidates to form allenamides, which proceeded
in low yields (10-20%) and with limited substrate scope.10a,b
We hypothesized that a propargylic phosphorimidate would
be a good candidate for a [3,3]-rearrangement as the resulting
allenamide would be fully protected. This would provide a
more stable allenyl species, as well as allowing for the
possibility of unmasking an amine after carrying out further
reactions.7,11
Table 1. Optimization of the Rearrangement
In keeping with earlier reports,7,11 the key phosphorimidate
intermidate would be generated by combination of a prop-
argylic alcohol with a chlorophosphite to yield a phosphorus
ester that would be oxidized with an azide via a Staudinger
reduction. The resulting phosphorimidate could then undergo
the desired rearrangement under transition-metal-catalyzed
conditions (Figure 1). We expected, on the basis of similar
a Conditions: (1) propargylic alcohol (1.6 equiv), 1.3 equiv of R2PCl,
and 1.3 equiv of Et3N in Et2O, 0 °C, 20 min; (2) Cbz azide (1.0 equiv), rt,
2 h. b Phosphorimidate (1.0 equiv), PdCl2(CH3CN)2 (3 mol %), solvent to
a final concentration of 0.01 M. c Phosphorimidate species not formed as a
result of rearrangement to allenyl phosphorus species. d Isolated yields.
e NMR yields.
2) rapidly converted to the corresponding allenyl phosphi-
nates. Phosphites, however, could be converted to the desired
phosphorimidate through reaction with an electron-deficient
azide, such as Cbz-azide, and isolated for use in the
rearrangement.
Once conditions for formation of the propargylic phos-
phorimidates were identified, attention was turned to exami-
nation of the rearrangement. Consistent with the related
allylic rearrangement,7 the Cbz-functionalized phosphorimi-
date did not undergo efficient rearrangement under thermal
conditions but required a Pd(II) catalyst. The rearrangement
was sensitive to substrate concentration and catalyst load,
with higher yields obtained under more dilute reaction
conditions. Evidently, bimolecular decomposition pathways
are more readily accessible to the propargylic species in
comparison with related allylic phosphorimidates.7 As shown
in entry 3 of Table 1, when run at a concentration of 10
mM with 3 mol % Pd(II) catalyst, a 66% yield of allenamide
2a was isolated.
Figure 1. Outline of the rearrangement. In the first step, a
propargylic phosphite is formed through combination of a prop-
argylic alcohol with an activated trivalent phosphorus species in
the presence of mild base. This can be converted to a phospho-
rimidate via a Staudinger reduction with an azide. This species can
then undergo a transition-metal-catalyzed rearrangement to form a
fully protected allenamide. A possible side reaction is formation
of an allenyl phosphorus species via rearrangement of the propar-
gylic phosphite.
allylic systems,7,11,12 that regio- and stereochemistry would
be highly conserved in this reaction.
Application of these conditions to a more substituted
propargylic phosphorimidate derived from but-2-yn-1-ol
A complicating factor in the development of the phos-
phorimidate rearrangement is the well-documented spontane-
ous [2,3]-rearrangement of propargylic phosphites and
(10) (a) Overman, L. E.; Marlowe, C. K.; Clizbe, L. A. Tetrahedron
Lett. 1979, 599. (b) Overman, L. E.; Clizbe, L. A.; Freerks, R. L.; Marlowe,
C. K. J. Am. Chem. Soc. 1981, 103, 2807. (c) Padwa, A.; Cohen, L. A. J.
Org. Chem. 1984, 49, 399. (d) Ranganathan, D.; Rathi, R.; Rathi, R.;
Kesavan, K.; Singh, W. P. Tetrahedron 1986, 42, 4873.
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2000, 122, 1806. (b) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am.
Chem. Soc. 1996, 118, 10938. (c) Brown, H. C.; Ramachandran, P. V. Acc.
Chem. Res. 1992, 25, 16, and references therein.
(11) Lee, E. E.; Batey, R. A. Angew. Chem., Int. Ed. 2004, 43, 1865.
(12) (a) Overman, L. E. Angew. Chem., Int. Ed. 1984, 23, 579. (b) Itami,
K.; Yamazaki, D.; Yoshida, J. Org. Lett. 2003, 2161.
(9) Hashmi, A. S. K. Modern Allene Chemistry; Kraus, N., Hashmi,
A. S. K., Eds.; Wiley-VCH; Weinheim, 2004; Vol. 1, pp 29-33.
(13) Mark, V. Mechanisms of Molecular Migrations; Thyagarajan, B. S.,
Ed.; Wiley Interscience: New York, 1971; Vol. 2, pp 319-437.
Org. Lett., Vol. 12, No. 11, 2010
2575

produced a low yield (16%) of allenamide with a large
amount of phosphorimidate still present (Table 1, entry 4).
Attempts to drive the reaction through temperature increase
(Table 1, entry 5 for example) were unsuccessful as the
phosphorimidate species persisted even under prolonged
reaction times. We hypothesized that this could be due to
increased steric demand of the more substituted triple bond
and thus examined a less constrained phosphite. Consistently,
employment of diethyl chlorophosphite to generate the
reactive intermediate led to a 2-fold increase in yield when
the rearrangement was carried out at room temperature in
either dichloromethane (entry 6) or toluene (entry 7). Raising
the reaction temperature to 100 °C produced an additional
yield enhancement (60%, entry 8) and led to complete
depletion of the phosphorimidate. Gratifyingly, it was found
that this phosphite also worked well for the less substituted
substrate (entry 9) and was thus used in the remaining
applications.
Table 2. Scope of the Rearrangement
Upon identifying conditions that worked for both internal
and terminal alkynes, the method was applied to a broader
range of propargylic alcohols to better define the scope of
the rearrangement. Of particular utility would be substrates
that would form di- and trisubstituted allenamides as current
methods for accessing these structures require multistep
syntheses.6
Secondary propargylic alcohols were first examined as they
would produce disubstituted allenamides functionalized at
the 1 and 3 positions. As shown in Table 2 (entries 2-8),
secondary alcohols with both straight chain and branched
alkyl subsituents are excellent substrates for the rearrange-
ment. Tertiary propargylic alcohols were not, however, good
substrates for the reaction as the intermediate propargylic
phosphite underwent rapid conversion to the corresponding
allenyl phosphonate.13
1,1-Disubstituted allenamides can also be prepared via
rearrangement of internal alkynes. As in the earlier examples,
alkyl groups are well-tolerated at this position (Table 2,
entries 9 and 10). Appending aryl groups at this postion,
however, proved to be more challenging; primary alcohols
with less electron-rich aryl substituents were able to react
under these conditions, albeit with a decrease in yield relative
to their alkyl counterparts (41-25% yields, see Supporting
Information for details).
Building on the results above, trisubstituted allenamides
can also be prepared through the reaction of more substituted
propargylic alcohols (Table 2, entries 11 and 12). Trisub-
stituted allenamides such as these would be of particular use
as substrates in further synthetic transformations, such as the
formation of highly substituted 1,2-aminoalcohols.1
As noted earlier, the synthesis of enantiomerically enriched
allenamides is often synthetically challenging.6 We thus
examined whether this rearrangement could be extended to
such molecules, using enantiomerically enriched propargylic
alcohols as the starting materials. Either enantiomer of the
allenamide derived from 3-butyn-2-ol can be readily prepared
(Table 2, entries 3 and 4), both in 92% ee. Additionally, an
a Conditions as described in Table 1. See Supporting Information for
additional details. b Isolated yields. c ee of commercially available starting
alcohol found to be <95% in each case. d ee determined by chiral HPLC.
See Suppporting Information for additional details.
2576
Org. Lett., Vol. 12, No. 11, 2010

enantiomerically enriched allenamide derived from (R)-(+)-
1-octyn-3-ol was also prepared in 80% ee.14
Despite their utility in a variety of reactions, the lability
of nitrogen-substituted allenes is a recurring concern.6a,d The
fully protected allenamides produced in the phosphorimidate
rearrangement exhibit considerable stability and can be stored
neat at 0 °C for over 2 months with little decomposition.
Allenamide 2d readily undergoes a Diels-Alder reaction to
produce enamide 23. Using conditions similar to those
reported for use on allenes,15 allenamide 2d can also be
converted to the densely functionalized allyl boronate 24,
which is poised for further transformations.16 To our
knowledge, this is the first reported example of this reaction
using an allenamide (Figure 2).
In summary, we have demonstrated a straightforward
application of a [3,3]-rearrangement to form highly func-
tionalized allenamides. A key feature of the rearrangement
is its synthetic simplicity as it requires only a propargylic
alcohol, an organic azide and a chlorophosphite, all of which
are easily accessible. As enantiomerically enriched propar-
gylic alcohols are easily accessed from either commercial
sources or through straighforward synthetic manipulations,8
this strategy represents a facile entry into stereochemically
Figure 2. )
Applications of fully protected allenamides. Pv
diethylphosphate. (Top) Diels-Alder reaction. (Bottom) Formation
of boron-substituted enamide. See Supporting Information for
additional details.
defined allenamides. This methodology therefore serves as
a valuable addition to the current strategies for forming these
interesting molecules.
Acknowledgment. A.K.M. thanks Novartis (Novartis
Young Investigator), GSK (GSK Scholar), and Amgen
(Amgen Young Investigator) for supporting this work.
(14) The indicated stereochemistry is predicted on the basis of the
mechanism of closely related allylic rearrangements.6b,7,11,12 The attenuated
% ee is due to a Pd-catalyzed epimerization step that the allenamides
undergo. The mechanism of this side reaction is currently under examination.
However, one can obtain allenamides of higher stereochemical purity simply
by running the reaction for a shorter time period, albeit in lower yields.
(15) Yang, F.-Y.; Wu, M.-Y.; Cheng, C.-H. J. Am. Chem. Soc. 2000,
122, 7122.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Lessard, S.; Peng, F.; Hall, D. G. J. Am. Chem. Soc. 2009, 131,
9612. (b) Walker, J. D.; Scott, R. D.; Williard, P. G. J. Am. Chem. Soc.
1990, 112, 8971.
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