Cross-metathesis, a versatile synthetic methodology for the construction of alkenyl phosphine oxides and bis-phosphine oxides

Article abstract of DOI:10.1016/S0040-4039(03)01842-2

Substituted vinyl and allyl phosphine oxides have been prepared by olefin cross-metathesis providing exclusive E olefin stereochemistry. The methodology has been successfully extended to the preparation of various bis-phosphine oxides.

Full text of DOI:10.1016/S0040-4039(03)01842-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7133–7135
Cross-metathesis, a versatile synthetic methodology for the
construction of alkenyl phosphine oxides and
bis-phosphine oxides
F. Bisaro and V. Gouverneur*
University of Oxford, The Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK
Received 23 June 2003; revised 16 July 2003; accepted 25 July 2003
Abstract—Substituted vinyl and allyl phosphine oxides have been prepared by olefin cross-metathesis providing exclusive E olefin
stereochemistry. The methodology has been successfully extended to the preparation of various bis-phosphine oxides.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The development of strategies for the preparation of
alkenyl phosphine oxides remains a very important area
of research as these compounds are key intermediates
for the preparation of numerous biologically active
compounds and ligands for homogeneous catalysts.1 A
number of synthetic routes have been reported for this
class of compounds with the metal-catalysed addition
of P(V)ꢀH bonds to alkynes providing one of the most
elegant methodologies to access a,b-unsaturated phos-
phine oxides with good levels of regio- and stereocon-
trol.2 Among the many transition metal catalysed CꢀC
bond forming reactions, cross-metathesis (CM) has
been neglected for the preparation of structurally
diverse alkenyl phosphine oxides despite the fact that
this reaction is now widely recognised as one of the
most powerful synthetic tools in organic chemistry.3
Two studies reported by the groups of Grubbs4 and
Hayes5 have recently revealed that vinyl and allyl phos-
phonates are viable CM partners in metathesis reac-
tions. In addition, one example of a CM reaction of a
phosphine oxide has been previously reported in the
literature.6 As part of our ongoing research program
studying the possibility of using metathesis for the
preparation of new chiral phosphine ligands,7 we had
reason to investigate the scope and limitations of CM
for the preparation of alkenyl phosphine oxides and
selected bis-phosphine oxides.
We set out to study first the reactivity of diphenyl vinyl
phosphine oxide 2 with structurally diverse olefins
(Table 1, entries 1–6).
The reactions were carried out in DCM with 2–6 mol%
of catalyst 1, one equivalent of 2 and three equivalents
of the olefin. The highly reactive ruthenium catalyst 1
was chosen for this study as it is now well established
that the presence of the non-labile sterically hindered
NHC (N-heterocyclic carbene) ligand helps to stabilise
the 14-electron ruthenium intermediates during
metathesis resulting in enhanced activity.8 All reactions
proceeded in isolated chemical yields superior to 78%
except for methyl vinyl ketone (MVK) which did not
react. The lack of reactivity of MVK is hardly surpris-
ing as this latter reaction involves two electron-deficient
alkenes.9 All other reactions give the cross-products
with excellent yield and exclusive E selectivity.10 Under
these conditions, no dimerisation of 2 could be
detected, therefore allowing for high CM selectivity. In
contrast to the metal-catalysed addition of P(V)ꢀH
bonds to alkynes, the cross-metathesis technology is not
limited to the preparation of a,b-unsaturated alkenyl
phosphine oxides. Indeed, diphenyl allyl phosphine
oxide 3 was found to be a viable CM partner with both
an electron-donating and an electron-withdrawing
olefin (Table 1, entries 7 and 8). In the presence of
5-hexen-1-yl acetate, the desired cross-product was iso-
lated in 70% yield but with a more modest stereoselec-
tivity (E/Z=8/2). We also found that 3 reacted with
MVK albeit in diminished chemical yield (46%) but
with exclusive E selectivity. No side-products resulting
* Corresponding author. Tel./fax: +44 (0) 1865 275 644; e-mail:
veronique.gouverneur@chem.ox.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01842-2

7134
F. Bisaro, V. Gou6erneur / Tetrahedron Letters 44 (2003) 7133–7135
Table 1. Synthesis of vinyl and allyl phosphine oxides by olefin cross-metathesis
Table 2. Synthesis of bis-phosphine oxides by olefin cross-metathesis

F. Bisaro, V. Gou6erneur / Tetrahedron Letters 44 (2003) 7133–7135
7135
Acknowledgements
from olefin isomerisation could be detected in the crude
reaction mixture. To probe further the synthetic scope
of these reactions, we explored next the possibility of
constructing various unsaturated bis-phosphine oxides
(Table 2).
F.B. acknowledges the EPSRC (GR/N34901/01(P)) for
financial support.
References
No dimerisation of the vinylphosphine oxide 2 was
observed by H NMR in the crude reaction mixture
1
1. For various applications, see for example: (a) Brunner,
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180; (b) Brunner, H.; Limmer, S. J. Organomet. Chem.
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(entry 1). In contrast, the homodimerisation of the
deconjugated allyl- and 4-penten-1-yl diphenyl phos-
phine oxides was feasible and afforded the homo-
dimeric products in high yields and E-selectivity
(entries 2 and 3). To access unsymmetrical bis-phos-
phine oxides, we attempted the CM of two different
alkenyl phosphine oxides. No product of CM could be
detected after 48 h upon treatment of one equivalent of
3 with three equivalents of 2 in the presence of 4 mol%
of catalyst 1, a lack of reactivity presumably due to
steric factors (entry 4). This hypothesis is supported by
the observation that 3 was found to react with the
electron-deficient olefin, methyl vinyl ketone (Table 1,
entry 8). However, by increasing the number of carbon
units between the olefin and the phosphine oxide func-
tional group, the reaction afforded excellent yields of
the desired cross-products.11 For example, cross-cou-
pling of 3 (3 equiv.) with 4-penten-1-yl diphenyl phos-
phine oxide (1 equiv.) afforded the desired
unsymmetrical bis-phosphine oxide with an isolated
yield of 94% (entry 5). We also found that 4-penten-1-yl
diphenyl phosphine oxide (1 equiv.) reacted with 2 (3
equiv.) to afford the unsymmetrical 1,5-bis-phosphine
oxide in 93% yield (entry 6). Both bis-phosphines were
produced with exclusive E-selectivity.
4. Chatterjee, A. K.; Choi, T.-L.; Grubbs, R. H. Synlett
2001, 1034–1037.
5. Lera, M.; Hayes, C. J. Org. Lett. 2001, 3, 2765–2768.
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Appl. Chem. 2002, 74, 7–10.
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This study revealed that the CM technology gives easy
access to various functionalised phosphine oxides in
addition to unsaturated 1,4- 1,5-, 1,6- and 1,8-bis-phos-
phine oxides. The positioning of the double bond is
simply programmed by a judicious choice of the reac-
tants. So far, the technology could not be applied to
1,2- or 1,3-bis-phosphine oxides. Efforts to extend the
use of the CM technology to access 1,2- and 1,3-bis-
phosphines are currently underway in our laboratory.
Applications of this technology are readily expected on
the basis of the well-established synthetic utilities of
these compounds.
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Lett. 1999, 1, 953–956.
9. For similar observations with a,b-unsaturated carbonyl
compounds, see: Choi, T.-L.; Chatterjee, A. K.;
Grubbs, R. H. Angew. Chem., Int. Ed. 2001, 40, 1277–
1279 and references therein.
10. Typical 3JP,H=20 Hz for E isomers, see: Williams, D.
H.; Fleming, I. Spectroscopic Methods in Organic
Chemistry, 5th Ed.; McGraw-Hill: London, 1995; p.
168.
11. For these reactions (entries 5 and 6, Table 2), one of
the olefins is used in excess (3 equiv.).