Disubstituted Z-allylic esters by Wittig-Schlosser reaction using methylenetriphenylphosphorane

Article abstract of DOI:10.1039/c0cc04429f

β-Lithiooxyphosphonium ylides, generated in situ from aldehydes and methylenetriphenylphosphorane, react with halomethyl esters to form disubstituted allylic esters in good yields and with high Z-selectivity.

Full text of DOI:10.1039/c0cc04429f

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COMMUNICATION
Disubstituted Z-allylic esters by Wittig–Schlosser reaction using
methylenetriphenylphosphoranew
David M. Hodgson* and Tanzeel Arif
Received 15th October 2010, Accepted 20th December 2010
DOI: 10.1039/c0cc04429f
b-Lithiooxyphosphonium ylides, generated in situ from aldehydes
and methylenetriphenylphosphorane, react with halomethyl
esters to form disubstituted allylic esters in good yields and with
high Z-selectivity.
(4, R2 = H) was considered to lack stereoselectivity.4a,7
Z-Disubstituted allylic alcohols are typically prepared from
aldehydes in 2 steps, by Still–Gennari or Ando olefination to
give a Z-a,b-unsaturated ester8 followed by 1,2-reduction,
using DIBAL-H for example.9 Despite the unencouraging
early precedent using methylenetriphenylphosphorane, we
believed that the combination of more recent advances in the
generation of b-lithiooxyphosphonium ylides 4, particularly
using PhLi as the optimal base,10 together with the use
of a suitably reactive electrophile could lead to an efficient
and stereoselective 2-carbon homologation of aldehydes
using methylenetriphenylphosphorane to directly provide
Z-disubstituted allylic esters and alcohols. Here we communicate
our promising results on this theme.
Allylic alcohols and their derivatives are widely used in
synthetic organic chemistry and, consequently, methods to
access them from readily available starting materials and in an
experimentally straightforward and, particularly, stereo-
controlled manner are of value.1 Two-carbon homologation
of aldehydes to disubstituted E-allylic alcohols has been
accomplished (for benzaldehyde) in low yield using the Wittig
reagent from b-hydroxyethyl(triphenyl)phosphonium bromide,2
and more efficiently by a Kocien
´
ski–Julia olefination approach.3
Initially, we carried out a Wittig–Schlosser reaction under
optimal conditions5,10,11 between hydrocinnamaldehyde (1a)
and methylenetriphenylphosphorane (6), with PhLi-induced
b-lithiooxyphosphonium ylide formation (À78 1C to room
temperature), and trapping with monomeric6a,12 formaldehyde
at 0 1C (Scheme 2). In contrast to Schlosser and Coffinet’s
earlier studies,6 this gave exclusively the corresponding Z-allylic
alcohol 7a (18% yield).13 However, the Z-stereoselectivity is
consistent with that seen in Wittig reactions using b-substituted-
b-hydroxyethyl(triphenyl)phosphonium salts with aldehydes,4b,c,14
and with that observed using methyl ketone substrates with
methylenetriphenylphosphorane and formaldehyde.15
Wittig–Schlosser methodology provides a direct way to make
trisubstituted allylic alcohols 5 (E = CH2OH, R2 = alkyl,
Scheme 1) and esters from aldehydes 1.4,5 It can be an efficient
entry to such systems (particularly allylic esters),5 and is highly
Z-selective (typically 499 : 1). The process is believed to
involve Li ion-promoted P–O cleavage in the first-formed
oxaphosphetane 3, followed by lithiation giving a b-lithiooxy-
phosphonium ylide 4. This new ylide can be trapped at the
ylidic carbon by a subsequently added electrophile (in this case
formaldehyde, or an a-halomethyl ester), prior to elimina-
tion of Ph3PO. Access to disubstituted allylic alcohols by
this approach using methylenetriphenylphosphorane and
formaldehyde was reported in the early 1970s by Schlosser
and Coffinet as being inefficient (30–36%) and E-selective,6
while the trapping with non-carbonyl-based electrophiles of
the presumed intermediate b-lithiooxyphosphonium ylides
which bear no further substitution at the ylidic carbon
Scheme 2 Z-Alkenes from aldehyde 1a and methylenephosphorane 6.
Scheme 1 Wittig–Schlosser reaction.
As noted earlier, we have recently reported that a-halomethyl
esters are excellent electrophiles in the Wittig–Schlosser reac-
tion, providing access to trisubstituted Z-allylic esters 5
(E = CH2Oacyl, R2 = alkyl) from aldehydes 1.5 In the present
chemistry, using bromomethyl acetate16 (1.1 equiv.) instead of
formaldehyde as the electrophile gave allylic acetate 8 in 57%
yield and with high stereoselectivity (Z : E 94 : 6, Scheme 2).
Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: david.hodgson@chem.ox.ac.uk; Fax: +44 (0)1865 285002;
Tel: +44 (0)1865 275697
w Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data along with 1H and 13C NMR
spectra for all compounds synthesised. See DOI: 10.1039/c0cc04429f
c
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Improved yield and stereoselectivity was obtained when
inexpensive chloromethyl pivalate was used, giving allylic
pivalate 9a (Piv = pivaloyl) in 75% yield, Z 499%.17,18
The scope of the synthesis of disubstituted allylic pivalates 9
was then studied (Fig. 1).
to give the corresponding Z-allylic alcohol 7b (63% from
nonanal) in a one-pot process.
The use of chloromethyl propionate16 (1.1 equiv.) as the
electrophile in the homologation procedure provided the
enolisable allylic propionate 10 in 54% yield, Z : E 99 : 1
(Scheme 3), which proved suitable for use in a completely
diastereoselective Ireland–Claisen rearrangement.22 The relative
stereochemistry of the resulting g,d-unsaturated acid 12,
formed in 67% yield (dr 499%), was assigned on the basis
of the intermediate E-silyl ketene acetal undergoing [3,3]
sigmatropic rearrangement through a chair-like transition
state 11.
Scheme 3 Ireland–Claisen rearrangement of allylic propionate 10.
In conclusion, we have shown for the first time that simple
methylenetriphenylphosphorane is capable of delivering
good yields and high stereoselectivities in a three-component
Wittig–Schlosser process. The origins of these favourable
reaction characteristics may be a combination of efficient
generation of a LiBr-complexed b-lithiooxyphosphonium
ylide 13 (Scheme 4), bearing anti-disposed R and Ph3P groups,
which also undergoes efficient electrophile trapping with reten-
tion of configuration (possibly aided by prior co-ordination of
the electrophile to LiO). The resulting betaine 14 collapses
with loss of LiBr and standard syn-elimination of Ph3PO to
give the Z-alkene 15. As all the reagents for this chemistry are
commercially available (along with many aldehyde substrates)23
and it is straightforward to carry out, we believe the methodo-
logy provides an attractive access to disubstituted Z-allylic
esters and alcohols.
Fig. 1 Other Z-allylic pivalates 9 synthesised.13
Aliphatic aldehydes gave uniformly excellent Z-selectivity
(9a–g). The result for the a-branched system 9e, indicates that
a stereocentre a- to the aldehyde functionality can be tolerated
without racemisation.19 Silyl and MPM alcohol protection did
not interfere with the homologation process (9f,g). Slight
erosion of Z-selectivity was observed with certain aromatic
aldehydes (9h,j). a,b-Unsaturated aldehydes possessing various
substitution patterns proved to be viable substrates (9k–m),
with a slight loss of Z-selectivity only being detected with
extended aromatic conjugation (9k). Yields were slightly lower
(by B15%) for conjugated allylic pivalates (52–60% for
9h–m), compared with those pivalates derived from aliphatic
aldehydes (66–78% for 9a–g). This may reflect more favourable
direct elimination of Ph3PO from the first-formed oxaphosphetane
3 (R2 = H), where the energy of the transition state for
elimination is likely lowered due to developing conjugation.
The methodology also provides a straightforward way to
access a mono-deuterated Z-allylic pivalate such as 9a-D
(68% yield, Z 499%), by using the commercially available
Scheme 4 Possible origin of alkene stereochemistry.
We thank the Higher Education Commission of Pakistan for
studentship support (to T.A.) and Robert H. Snell (Oxford) for
assistance with chiral HPLC analysis.
Notes and references
1 D. M. Hodgson and P. G. Humphreys, in Science of Synthesis, ed.
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2 (a) M. Schlosser, K. F. Christmann, A. Piskala and D. Coffinet,
Synthesis, 1971, 29; (b) B. E. Maryanoff, A. B. Reitz and
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methyl-D -triphenylphosphonium iodide. While a disubstituted
3
Z-allylic pivalate 9 might be required for a particular synthetic
purpose,20 if instead the corresponding allylic alcohol is
desired then it can also be easily obtained: in an otherwise
identical experiment to that for the synthesis of 9b, the crude
allylic pivalate 9b was hydrolysed with KOt-Bu/H2O (2 : 1)21
3 J. Pospısil and I. E. Marko, Org. Lett., 2005, 8, 5883.
´ ´
4 (a) I. Gosney and A. G. Rowley, in Organophosphorus Reagents in
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¨
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16 Commercially available, but was prepared from the corresponding
acyl halide, paraformaldehyde and ZnCl2: G. Sosnovsky, N. U. M.
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17 As in ref. 5, the a-halomethyl esters were added following a
warm–cool cycle (À78 1C–room temperature–78 1C) in the
b-lithiooxyphosphonium ylide generation step. With 1a, if
chloromethyl pivalate was added directly at À78 1C without such
a cycle, or added at 0 1C, then 9a was obtained in lower yield
and/or stereoselectivity: 52% yield (Z 4 99%) and 71% yield
(Z : E 95 : 5), respectively.
18 Prelithiation of methylenetriphenylphosphorane using s-BuLi
(E. J. Corey, J. Kang and K. Kyler, Tetrahedron Lett., 1985, 26,
555), followed by addition of 1a (1 equiv.) and then chloromethyl
pivalate (1 equiv.) gave 9a in 13% yield, Z 4 99%.
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All E/Z ratios reported were determined on crude reaction
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