[3,3]-Rearrangements of phosphonium ylides

Article abstract of DOI:10.1021/ja058746q

Allylic phosphonium ylides are readily generated by the combination of an allylic alcohol, a carbene, and a chlorophosphite. Here we demonstrate that these intermediates undergo a thermal [3,3]-rearrangement to provide single isomers of homoallylic phosph

Full text of DOI:10.1021/ja058746q

Published on Web 03/17/2006
[3,3]-Rearrangements of Phosphonium Ylides
Marcelle L. Ferguson, Todd D. Senecal, Todd M. Groendyke, and Anna K. Mapp*
Departments of Chemistry and Medicinal Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
Received December 24, 2005; E-mail: amapp@umich.edu
Scheme 1
Ylides of phosphorus, sulfur, and nitrogen readily participate in
olefination and ring-forming reactions.1 Although sulfonium and
ammonium ylides are also well-known to undergo synthetically
useful thermal rearrangements, rearrangements of the corresponding
phosphonium ylides have rarely been observed.1c We report here a
unique reaction manifold for phosphonium ylides, a [3,3]-sigma-
tropic rearrangement by which a new C-C bond is generated. This
process provides rapid access to phosphonates of diverse and
complex structure. These products are valuable intermediates for
the preparation of R-amino phosphonic acids2 (amino acid mimics)
and a variety of complex natural products.
the [3,3]-rearrangement to provide the target product 6 in good
overall yield. Similar to the related [3,3]-rearrangement of allylic
phosphorimidates, the yield of the phosphonium ylide rearrangement
is greater when the phosphorus bears alkoxy substituents (6b, 67%;
6c, 74%) relative to carbon (6a, 42%).8 Although heating the
reaction mixture to 110 °C increases reaction efficiency, temper-
atures in excess of 140 °C lead to significantly lower yields. For
example, the yield of 6c was 54% at 140 °C, and products consistent
with carbene dimerization were observed.
The earliest characterized example of a phosphonium ylide
rearrangement was reported by Baldwin and Armstrong who
demonstrated that upon heating, ylide 1 underwent a [2,3]-
rearrangement to provide a 7% yield of 2, along with a number of
additional products (Figure 1).3 Little progress has since been
reported, likely due to the apparent propensity of phosphonium
ylides to undergo decomposition at the temperatures required for
rearrangement.1c,4 We hypothesized that structures such as 3
containing an allyloxy substituent would undergo a [3,3]-rearrange-
ment in which the product 4 would be favored thermodynamically
due to the formation of the PdO bond. In addition, incorporation
of the oxygen should increase the leaving group ability of the
phosphorus-containing moiety, thus lowering the energetic barrier
of the rearrangement.5
The reaction conditions were applied to a variety of substrates
and afforded a diverse group of phosphonates in good to excellent
yields (Table 1). Substitution on the olefin is well tolerated, with
monosubstituted (entries 1-3, 6) and 1,1-disubstituted (entries 4,
5) allylic ylides undergoing the rearrangement. 1,2-Substitution on
the olefin also has no significant effect on reactivity, and compounds
13-15 are produced via the rearrangement in good yields. In
addition, the carbene source is not limited to ethyl diazoacetate as
(trimethylsilyl)diazomethane can also be employed in this capacity
with excellent results (entries 1-10). Although significantly more
sterically hindered than ethyldiazoacetate-derived ylides, the isolated
yields of the TMS-containing phosphonates are generally higher.
Since a broad range of carbene precursors can be generated from
inexpensive starting materials,9 the rearrangement will provide
access to phosphonate products with a diversity of R-substituents.
With secondary allylic alcohols as the starting material (entries
2, 3, 6, 7), products with only E-olefin geometry are observed,
suggestive of a chair-like, six-membered transition state for the
rearrangement. Somewhat unexpectedly, incorporation of additional
substitution on the olefin (entries 7-10) provides the desired
products in good overall yield but as a mixture of diastereomers.
Theoretical computations (DFT B3LYP/6-31G*) on a model ylide
located a chair-like transition state 16.6 kcal/mol in energy above
the starting ylide (see Supporting Information for details); however,
there was little difference in energy between chair-like transition
states with the ylide substituent in the axial versus equatorial
positions. This is most likely due to a relatively long C-P bond
(1.64 Å) that minimizes 1,3-diaxial interactions and interactions
between the ylide and olefin substituents in the transition state.
Fortuitously, diastereoselectivity in this context is a relatively
unimportant consideration because, for most applications, the
R-stereocenter will be destroyed or modified in subsequent trans-
formations (vide infra). Among the disubstituted olefins investi-
gated, cyclohexene-1-ol is also a good substrate for this reaction
(entry 10), with phosphonate 15a isolated in 62% yield; this is a
Figure 1. Phosphonium ylide rearrangements.
Investigation of our hypothesis required generation of the
appropriate ylide intermediates, such as 3 (Figure 1), historically
elusive due to the propensity with which they undergo dealkylation
to produce phosphonates.1 Recently, however, the reaction of
phosphines and phosphites with transition-metal-generated carbenes
has been shown to produce the desired ylides under mild condi-
tions.6 In our initial studies, generation of the ylide in situ was
thus accomplished by first combining 3-buten-2-ol and an activated
phosphorus(III) species followed by the addition of ethyl diazo-
acetate and 1 mol % of 5,10,15,20-tetraphenyl-21H,23H-porphine
iron(III) chloride (ClFeTPP) to the reaction mixture (Scheme 1).
Monitoring of reaction progress by 31P NMR revealed that upon
heating to 40 °C for 1 h, complete conversion to ylide 5 occurred.7
Increasing the temperature of the reaction mixture then facilitated
9
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10.1021/ja058746q CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Scope of the Rearrangement
Scheme 2
product a: R
)
)
CO2Et
SiMe3
entry
substrate
b: R
yieldc
Such structures are in wide use as haptens for antibody generation,
amino acid mimics, and as enzyme inhibitors.11
In summary, we have reported a unique [3,3]-rearrangement of
phosphonium ylides that provides access to phosphonates of
complex structure and wide ranging synthetic utility. Current
investigations are focused upon asymmetric variants of this reaction,
and results will be reported in due course.
Acknowledgment. A.K.M. is grateful for financial support from
the NIH (GM65330) and the Alfred P. Sloan Foundation. We thank
B. Chen for early technical assistance, and D. Trauner for
illuminating discussions.
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.
References
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a Conditions: (i) Allylic alcohol substrate (1 equiv), chlorophosphite (1
equiv), and Et3N (1 equiv), tol, 0 °C, 1 h. (ii) Ethyl diazoacetate (1.2 equiv),
1 mol % of ClFeTPP, 40 °C, 1 h f 110 °C, 7 h. b Conditions: (i) Allylic
alcohol substrate (1 equiv), chlorophosphite (1 equiv), and Et3N (1 equiv),
tol, 0 °C, 1 h. (ii) Trimethylsilyldiazoacetate (1.2 equiv), 1 mol % of
ClFeTPP, 40 °C, 1 h f 110 °C, 7 h. c Isolated yields.
(7) Under these conditions, no conversion to ylide is observed in the absence
of ClFeTPP catalyst.
particularly notable case as phosphonates such as 15a are excellent
intermediates for the butyrolactone-containing family of natural
products.10
(8) (a) Chen, B.; Mapp, A. K. J. Am. Chem. Soc. 2004, 126, 5364-5365. (b)
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The phosphonium ylide rearrangement affords entry into a range
of desirable synthetic targets (Scheme 2). For example, employment
of phosphonates such as 9a in a Horner-Wadsworth-Emmons
reaction produces nonsymmetrical, skipped dienes (16, for example)
in excellent yields and high stereoselectivity (see Supporting
Information for additional details). In addition, the phosphonates
are excellent substrates for conversion into R-aminophosphonic
esters via amination2c (17, for example). The tandem [3,3]-
rearrangement-amination sequence should thus provide ready
access to chiral, nonracemic aminophosphonic esters and acids.
(10) See: Minami, T.; Hirakawa, K.; Koyanagi, S.; Nakamura, S.; Yamaguchi,
M. J. Chem. Soc., Perkin Trans. 1 1990, 2385-2390.
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Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992, 33, 6625-6628. (c)
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A.; Rogers, W. L.; Smith, S. A.; DeForrest, J. M.; Oehl, R. S.; Petrillo,
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