Isolation and characterisation of all four diastereomeric intermediates from a horner-wittig reaction

Article abstract of DOI:10.1080/10426507.2012.744010

The Horner-Wittig reaction between diphenyl(2-phenylpropyl)phosphine oxide and 1-naphtaldehyde affords an equal mixture of the cis and trans isomers even though the formation of the initial adduct is selective.

Full text of DOI:10.1080/10426507.2012.744010

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Phosphorus, Sulfur, and Silicon and the
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Isolation and Characterisation of All Four
Diastereomeric Intermediates from a
Horner-Wittig Reaction
Laura J. Parry a , Victoria Vinader b , Ian J. Scowen b , Vipul K. Patel
c & Kamyar Afarinkia a
a Institute of Cancer Therapeutics, University of Bradford ,
Bradford , United Kingdom
b Analytical Center, University of Bradford , Bradford , United
Kingdom
c Medicines Research Center, GlaxoSmithKline , Stevenage , United
Kingdom
Accepted author version posted online: 19 Nov 2012.Published
online: 08 May 2013.
To cite this article: Laura J. Parry , Victoria Vinader , Ian J. Scowen , Vipul K. Patel & Kamyar
Afarinkia (2013) Isolation and Characterisation of All Four Diastereomeric Intermediates from a
Horner-Wittig Reaction, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:1-3, 195-199,
DOI: 10.1080/10426507.2012.744010
To link to this article: http://dx.doi.org/10.1080/10426507.2012.744010
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Phosphorus, Sulfur, and Silicon, 188:195–199, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.744010
ISOLATION AND CHARACTERISATION OF ALL FOUR
DIASTEREOMERIC INTERMEDIATES FROM
A HORNER-WITTIG REACTION
Laura J. Parry,1 Victoria Vinader,2 Ian J. Scowen,2 Vipul K.
Patel,3 and Kamyar Afarinkia1
1Institute of Cancer Therapeutics, University of Bradford, Bradford,
United Kingdom
2Analytical Center, University of Bradford, Bradford, United Kingdom
3Medicines Research Center, GlaxoSmithKline, Stevenage, United Kingdom
GRAPHICAL ABSTRACT
Abstract The Horner-Wittig reaction between diphenyl(2-phenylpropyl)phosphine oxide and
1-naphtaldehyde affords an equal mixture of the cis and trans isomers even though the formation
of the initial adduct is selective.
Keywords Horner-Wittig; alkene; mechanism
The Horner-Wittig (HW) reaction between phosphorus stabilized carbanions, e.g.
one derived from 1, and carbonyl compounds, e.g., 2, is widely used for the synthesis of
alkenes. The reaction proceeds via the formation of a β-hydroxy phosphine oxide adduct,
e.g., 3a (1,2-anti) and 3b (1,2-syn), which then eliminates the corresponding phosphinic
acid to afford the alkenes, e.g., 4a and 4b respectively (Scheme 1).1 The elimination of
Received 14 September 2012; accepted 22 October 2012.
We thank Engineering and Physical Sciences Research Council (EPSRC) and GlaxoSmithKline (GSK) for
financial support.
Address correspondence to Kamyar Afarinkia, Institute of Cancer Therapeutics, University of Bradford,
Bradford BD7 1DP, United Kingdom. E-mail: k.afarinkia@bradford.ac.uk
195

196
L. J. PARRY ET AL.
Scheme 1
diphenylphosphinic acid from the adducts 3a and 3b is syn, meaning that trans alkene 4a is
obtained from adduct 3a, and cis alkene 4b is obtained from adduct 3b. In other words, the
configuration of the alkenes is determined by the relative configurations of the R1 and R2
groups in the adducts. Therefore, it is generally believed that the ratio of 3a/3b is expected
to determine the ratio of 4a/4b.
The HW reaction has been studied in detail over the years, and it has been shown that
if R1 is an anion stabilizing group, the first step becomes reversible resulting in accumulation
of 3a and favoring the formation of the trans isomer, 4a. However, if R1 is not an anion
stabilizing group, the reaction affords a mixture of adducts 3a and 3b and hence a mixture
of cis and trans isomers, 4a and 4b.
Our group is currently investigating if the 1,2-syn/1,2-anti ratio, i.e. the ratio of 3a/3b,
and hence the cis/trans ratio of the alkene product, i.e. the ratio of 4a/4b, can be controlled
through existing stereocenters in the R1 and R2 groups and here we report some aspects of
our early results.
For a model study, we chose diphenyl(2-phenylpropyl)phosphine oxide 52 which
contains a symmetric center at the position β to the phosphorus atom. Treatment of 5 with
lithium diisopropylamide (LDA) in tetrahydrofuran (THF) followed by 1-naphthaldehyde
at −78◦C, then warming to room temperature and heating at 55◦C afford a 1:1 mixture
of cis and trans alkenes 6 and 7 in a relatively modest yield of 15%. The use of non-
coordinating cations improves the efficiency of the elimination step. Indeed using potassium
hexamethyldisialzide (KHMDS) for the elimination step resulted in improvement of the
yield to 72% but affected no change in cis/trans ratio (Scheme 2).
Scheme 2

HORNER-WITTIG REACTION
197
Figure 1 X-ray crystal structure of all four diastereomers of compound 8 (a-d). (Color figure available online).
This observation led to a question: Is the lack of selectivity in the formation of 6 and
7 because of a lack of selectivity in the formation of the intermediate β-hydroxy phosphine
oxide adducts? To answer this question, we decided to isolate all four diastereomeric
β-hydroxy phosphine oxide adducts from the first step and investigate their elimination
individually.
Diphenyl(2-phenylpropyl)phosphine oxide 5 was treated with lithium diisopropy-
lamide (LDA) in tetrahydrofuran (THF) at −78◦C followed by naphthaldehyde to afford
only β-hydroxy phosphine oxide adducts 8a-d (Scheme 2). Under these reaction condi-
tions, no elimination to afford alkenes occurred. The ratio of a:b:c:d diastereomers was
found to be 0.10:0.47:0.11:0.32.
All four diastereomers resulting from the addition of 5 to 1-naphtaldehyde, com-
pounds 8a-d, were separated in pure form using a combination of chromatography and
fractional crystallization, and their relative configurations were assigned by X-ray crystal-
lography (Figure 1).
We note that the induction of chirality is modest. Comparing the two 2,3-syn diastere-
omers a and b combined with the two 2,3-anti diastereomers c and d, we get a ratio of 1.25.
Considering that the methyl group is fairly small, that is perhaps not surprising. In contrast,
comparing the two 1,2-syn diastereomers a and c with the two 1,2-anti diastereomers b
and d, the ratio is 3.75. Interestingly, the 1,2-syn to 1,2-anti ratio observed here is signif-
icantly different to that reported by Warren in the reaction between 5 and benzaldehyde
(Scheme 4).2

198
L. J. PARRY ET AL.
Scheme 3
As previously indicated, the ratio of 1,2-syn to 1,2-anti is relevant to the elimination.
Since the 1,2-syn affords the cis alkene on elimination and the 1,2-anti affords the trans
alkene, we should expect a roughly similar ratio of 3.75 between the cis and trans isomers
in favour of the former. Since direct conversion of 5 to 6 and 7 only affords them in an equal
ration, there must be kinetic factors, which influence the elimination step in the individual
diastereomers.
We subjected each of diastereomers 8a-d to the same conditions used for the trans-
formation of 5 to 6 and 7 (KHMDS at 55◦C for 15 h). The results are shown below
(Table 1).
From the results in Table 1 we can deduce that whilst the minor 1,2-anti diasteromers
8a and 8c efficiently afford the trans alkene, the major 1,2-syn diastereomers 8b and 8d
afford the cis alkene very inefficiently. The reactions of 1,2-syn diastereomers are accom-
panied by significant retro-addition leading to the reformation of 5 and naphthaldehyde.
The sluggishness in the elimination of 1,2-syn diastereomers of course can be easily ratio-
nalized in terms of the significant steric repulsion between the naphthyl and α-phenylethyl
substituents in the transition state leading to the elimination of phenylphosphinic acid
(Figure 2). This steric repulsion means that the molecule cannot easily adopt the required
conformation for the elimination to the cis isomer and instead fragments to naphthaldehyde
and starting material, 5.
Scheme 4

HORNER-WITTIG REACTION
199
Table 1 Results for the transformation of compound 5 to compounds 6 and 7
Isolated Yield (%)∗
5 (recovered%)
6 : 7∗∗
8a
8b
8c
8d
54
56
96
50
0
22
0
> 95 : 5
> 5 : 95
> 95 : 5
> 5 : 95
14
∗Unreacted starting material accounts for mass balance.
∗∗Single isomer within the limits of detection by NMR.
Figure 2 Proposed conformations of intermediates leading to both the cis and trans alkene products.
The observations we have described here, provide the evidence that during the HW
reaction of 5 with naphthaldehyde, the formation of the initial adduct is selective and
favours the formation of the 1,2-syn β-hydroxy phosphine oxide. However, the elimination
of this 1,2-syn β-hydroxy phosphine oxide to the cis alkene is inefficient. In contrast, the
minor 1,2-anti β-hydroxy phosphine oxide efficiently affords the trans isomer. Therefore,
in this example at least, the overall parity between the cis and trans isomers is not because
of a lack of selectivity in the formation of the β-hydroxy phosphine oxide adducts.
REFERENCES
1. Walker, B. J. Transformations via Phosphorous-stabilised anions: PO-activated olefinations. In
J. I. G. Cadogan (Ed.), Oragonophosphorus Reagents in Organic Synthesis. Academic Press:
London, 1979.
2. Gueguen, C, O’Brien, P.; Powell, H. R.; Raithby, P. R.; Warren, S. J. Chem. Soc. Perkin Trans. 1,
1998, 3405-3417.