Convergent and stereoselective synthesis of trisubstituted E-alkenyl bromides and iodides via β-oxido phosphonium ylides

Article abstract of DOI:10.1021/ja8076999

β-Oxido phosphonium ylides, generated in situ from aldehydes and Wittig reagents [alkylidene(triphenyl)phosphoranes, other than ethylidene(triphenyl)phosphorane], react readily with electrophilic halogen sources to form predominantly or exclusively E-brom

Full text of DOI:10.1021/ja8076999

Published on Web 11/17/2008
Convergent and Stereoselective Synthesis of Trisubstituted E-Alkenyl
Bromides and Iodides via ꢀ-Oxido Phosphonium Ylides
David M. Hodgson* and Tanzeel Arif
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford, Mansfield Road, Oxford,
OX1 3TA, United Kingdom
Received September 29, 2008; E-mail: david.hodgson@chem.ox.ac.uk
The Wittig reaction is a widely used regiospecific and often highly
stereoselective way of making alkenes using readily available carbonyl
compounds and phosphonium ylides.1 With aldehydes 1, nonstabilized
triphenylphosphonium ylides 2 (R2 ) alkyl) are well-known to give
cis-alkenes preferentially, whereas the Wittig-Schlosser variant2
provides a synthetically important entry to trans- (“without
exception”2b) 1,2-disubstituted alkenes 4 (E) H) by way of stereo-
selective C-protonation of an intermediate ꢀ-oxido ylide 3 (Scheme
1). Trapping the intermediate ꢀ-oxido ylide 3 with electrophiles other
intermediates (e.g., alkenyl lithiums, coppers, palladiums) for such
processes,8 we sought to investigate the SCOOPY reaction to such
alkenyl halides and communicate here results which significantly
expand its utility, remarkably providing E-isomers, with high geo-
metrical integrity.
Under the conditions described by Schlosser as optimal for
generating trans-1,2-disubstituted alkenes,2b we first synthesized
2-bromo-1-phenylprop-1-ene and uneventfully obtained Z-5a as ex-
pected (47%, E/Z < 1:99 using BrCF2CF2Br, Scheme 2).4,5,9,10
Surprisingly however, we found the stereochemical outcome on
bromination is acutely sensitive to the size of the alkylidene: increasing
the latter beyond ethylidene led predominantly to E-2-bromo-1-
phenylalkenes E-5b-e (E/Z 87:13-94:6, Scheme 2). Furthermore,
stereocontrol is essentially complete for E-alkenyl bromides in the
majority of the subsequent cases we have examined: from heteroaro-
matic aldehydes (5f-i), an R,ꢀ-unsaturated aldehyde (5j), and aliphatic
aldehydes (5k-r)11 (Chart 1), thus providing a preparatively useful
Scheme 1. Wittig-Schlosser Reaction
than a proton [SCOOPY (R-Substitution plus Carbonyl Olefination
via ꢀ-Oxido Phosphorus Ylides) process]3 has the potential to generate
trisubstituted olefins 4 (E * H), which would be of significant value
provided the process occurred with high stereocontrol. The later has
been previously realized using several nonstabilized ylides and trapping
the intermediate ꢀ-oxido ylides with aldehyde electrophiles (e.g.,
formaldehyde gives Z-allylic alcohols 4, E ) CH2OH).2
Chart 1. E-Bromoalkenes 5f-r Obtained by SCOOPY Reaction
The original study by Schlosser and Christmann in 1969 reported
a single example of bromination: (Z)-2-bromo-1-phenylprop-1-ene (Z-
5a, Scheme 2) was prepared (23% yield by GC, E/Z < 10:90) from
Scheme 2. Synthesis of 2-Bromo-1-phenylalkenes 5a-e
new method for accessing such systems.12,13 In most of these examples,
the ꢀ-oxido ylide was added to BrCF2CF2Br as this was found to
maximize yields14 (stereoselectivity was not affected by the order of
addition), and addition of t-BuOK at the end of the reaction was not
required to induce elimination of Ph3PO.2
Compared with alkenyl bromides, alkenyl iodides often show
beneficial levels of increased reactivity and/or selectivity in synthetic
endeavors.8 Iodination of ꢀ-oxido ylides to give iodoalkenes 6a-n
(Chart 2) was found to display a similar selectivity profile to that
observed in the brominations. Moving from 1,2-diiodoethane to iodine
as the electrophile to which the ꢀ-oxido ylides were added improved
yields and, in particular, geometrical purities of iodooalkenes derived
from aromatic aldehydes.
Br2 and the ꢀ-oxido ylide derived from benzaldehyde and ethyliden-
e(triphenyl)phosphorane.4 In 2001 Fu and co-workers in Shanghai
improved the yield using BrCF2CF2Br as the electrophile, although
reactions using hexylidene(triphenyl)phosphorane and benzaldehyde
or hexanal were found to be nonstereoselective (E/Z 68:32 and 59:41,
respectively).5 (Z)-Iodoalkenes 4 (E ) I, R1 ) alkyl/aryl, R2 ) Me,
32-51% yield, E/Z < 10:90, Scheme 1) have been obtained using
1,2-diiodoethane with ꢀ-oxido ylides derived from aldehydes and
ethylidene(triphenyl)phosphorane.6 Analysis of all the prior halogena-
tion studies indicated that they had been mainly carried out with
ethylidenephosphorane and also that the limited studies with a higher
alkylidenephosphorane5 were likely carried out under conditions not
conducive to high stereocontrol.2b Given the enduring challenge of
developing general methods for the stereocontrolled synthesis of
trisubstituted alkenes,7 together with the importance of stereodefined
alkenyl bromides and iodides as precursors to a host of organometallic
A representative intermediate ꢀ-oxido ylide 3 (R1 ) octyl, R2 )
Pr), which on bromination led to E-alkenyl bromide 5k (octyl and Pr
groups exculsively cis), gave on standard protonation trans-1,2-
dialkylsubstituted alkene 4 [octyl (R1) and Pr (R2) groups exclusively
trans, 77%] expected2a,b from Schlosser’s studies; these results
emphasize that alkene stereochemistry arising from a ꢀ-oxido ylide 3
9
16500 J. AM. CHEM. SOC. 2008, 130, 16500–16501
10.1021/ja8076999 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Chart 2. Iodoalkenes 6a-n Obtained by SCOOPY Reaction
or iodination of the intermediate ꢀ-oxido ylide, to provide a highly
stereoselective route to E-alkenyl bromides and iodides. The conver-
gency of the process, combining CdC and CsHal bond-forming steps
in a single operation, together with the regiospecificity of the halide
introduction and ready availability of the starting materials suggests
this methodology will provide a significant alternative to alkyne hydro-
metalation strategies, where regioselectivity can also be problematic
in unbiased cases.24 Studies to clarify the origins of the stereoselectivity
and extension to other electrophiles are currently under investigation.
Acknowledgment. We thank the Higher Education Commission
of Pakistan for studentship support (to T.A.).
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
is also crucially dependent on the electrophile added.2,15 Our results
necessarily prompt a reappraisal of the origins of stereoselectivity on
trapping ꢀ-oxido phosphonium ylides with electrophiles, which needs
to account for protonation (or reaction with formaldehyde) generating
alkenes 4 with R1 and R2 trans (regardless of the size of R2),2 whereas
bromination and iodination lead to alkenes in which R1 and R2 are cis
(unless R2 ) Me). Although a ꢀ-oxido ylide in solution is likely
comprised of complex species,16 a model resembling 8 (Scheme 3)
(1) Edmonds, M.; Abell, A. In Modern Carbonyl Olefination; Takeda, T., Ed.;
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Scheme 3. Possible Origin of Dependence of Alkene
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(9) All yields reported are for chromatographically purified products. All E/Z
ratios reported were determined on crude reaction mixtures by GC/MS; in
some cases, slight variation was observed following chromatographic
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usefully diagnostic is the fact that dCH cis to Br (or I) is uniformly at
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has previously been invoked to rationalize protonation (and trapping
with carbonyl groups) which proceeds with retention of configuration
(possibly aided by prior coordination of the electrophile to LiO) Via
betaine 7.2 We tentatively suggest that reaction of noncoordinating halogen
electrophiles with the majority of ꢀ-oxido ylides examined in the present
study may predominantly occur by inversion, Via betaine 9.
So as to demonstrate utility of the above methodology, we focused
on a synthesis of (5E,9Z)-6-bromohexadeca-5,9-dienoic acid (13) isola-
ted from the Okinawan marine sponge Xestospongia sp. (Scheme 4).17
(10) See Supporting Information for details.
(11) Whilst R-branched aliphatic aldehydes were excellent substrates (giving
alkenyl bromides 5l-m, q-r), use of pivaldehyde led only to trans-1,2-
disubstituted alkene 4 (R1 ) CMe3, R2 ) (CH2)3OPh, 59%).
(12) In contrast, alkenyl halide syntheses starting with halogenated ylides
[Ph3PdCRBr (or I)] are known to be nonstereoselective (unless R ) Me,
which leads to Z-selectivity); see: (a) Smithers, R. H. J. Org. Chem. 1978,
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Scheme 4. Synthesis of Naturally Occurring Brominated Fatty Acid 13
(14) Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827–2828.
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(18) For a review, see : (a) Dembitsky, V. M.; Srebnik, M. Prog. Lipid Res.
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acetal aldehyde 11 (1 step from cyclopentene),20 and BrCF2CF2Br;21
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