the synthesis of a range of cyclic and acyclic organophos-
phonates and phosphonothioates under mild conditions.9
Reactions involving diethyl thiophosphite were shown to be
particularly efficient, presumably because of the weaker P-H
bond in the thiophosphite. Following the efficient formation
of organophosphorus adducts, our attention has now turned
to the elaboration of these products to afford alkenes in
Horner-Wadsworth-Emmons (HWE)-type reactions.10 Of
particular interest is the development of a novel and flexible
one-pot method for preparing alkenes.
For comparison, the corresponding phosphonate 3 was
prepared by reacting diethyl phosphite (10 equiv) with
1-octene (1 equiv) and triethylborane (5 × 0.3 equiv) in
cyclohexane at rt. A quantitative yield of 3 was obtained,
although it should be noted that 10 equiv of diethyl phosphite
was used, whereas only 3 equiv of diethyl thiophosphite was
required for the quantitative formation of 1. On HWE
reaction of phosphonate 3 with benzophenone, under the
same conditions as for phosphonothioate 1, 1,1-diphenylnon-
1-ene 2a was isolated in 56% yield. This compares with an
80% yield from phosphonothioate 1, which supports the view
that phosphonothioates are not only formed more efficiently
than phosphonates in radical additions but are also converted
into alkenes in higher yields in HWE-type reactions.12
Our initial studies concentrated on the preparation and
reaction of O,O-diethyl octylphosphonothioate (1) as shown
in Scheme 1. This was prepared in quantitative yield by
The formation of 1,1-diphenylnon-1-ene 2a was then
attempted in one pot by a consecutive reaction of 1-octene
with diethyl thiophosphite and AIBN (in THF at reflux)
followed by sBuLi and benzophenone (at -78 °C to rt). This
resulted in an excellent 88% yield of the desired alkene 2a
after column chromatography. A similar one-pot transforma-
tion using diethyl phosphite (1.2 equiv) in place of diethyl
thiophosphite gave 2a in <5% yield.
Scheme 1. Synthesis of Di- and Trisubstituted Alkenes 2a-f
Further applications of this novel one-pot approach to al-
kenes, via intermediate phosphonothioates, were then inves-
tigated. For example, reaction of 1-nonene with diethyl thio-
phosphite followed by deprotonation and reaction with 2-de-
canone gave 9-methyloctadec-9-ene (4) in an excellent yield
of 89% (as a 2.55:1 ratio of inseparable alkene isomers)
(Figure 1). This alkene has been isolated from the veld grape
a 2e was formed in 40% yield when using LDA as the base.
reaction of diethyl thiophosphite (3 equiv) with 1-octene (1
equiv) and triethylborane (5 × 0.3 equiv) in cyclohexane at
rt. Nonstabilized phosphonates (without an anion stabilizing
group R- to phosphorus) are rarely used in HWE reactions11
but an isolated report by Corey has shown that nonstabilized
phosphonothioates can be converted into alkenes by depro-
tonation (with nBuLi at -78 °C) and reaction with aldehydes
or ketones (at rt or above).12 Under these conditions, we
found that phosphonothioate 1 gave alkenes 2a-f in higher
Figure 1. 9-Methyloctadec-9-ene (4) is prepared from 1-nonene
in 89% yield.
s
n
yields when using BuLi (rather than BuLi)13 as the base,
and ketones gave higher yields of alkenes than aldehydes.14
Interestingly, the (E)-isomers of alkenes 2b, 2d, and 2f were
formed selectively, and raising the temperature of the reaction
from -78 to 60 °C did not significantly affect the yields or
change the ratio of isomers of the alkenes.
plant (Cissus quadrangulariz), which is an indigenous
medicinal plant of India.15
A similar reaction sequence, involving addition of diethyl
thiophosphite to 4-methyl-1-pentene (5), followed by depro-
tonation and reaction with O-benzyl pregnenolone (6), gave
the steroid derivative 7 in 77% yield (as a 4:1 mixture of
double-bond isomers) (Scheme 2). Subsequent hydrogenation
of 7 (using 10% Pd/C/H2 at 10 atm) resulted in reduction of
the two CdC bonds and cleavage of the benzyl ether to
afford the naturally occurring steroid cholestanol (in 75%
yield).16 This one-pot approach offers a short and flexible
route to analogues of cholestanol, which are of interest be-
cause of their biological activities, e.g., high levels of choles-
tanol are associated with cerebrotendinous xanthomatosis.17
(9) (a) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D.
Tetrahedron Lett. 2003, 44, 479-483. (b) Jessop, C. M.; Parsons, A. F.;
Routledge, A.; Irvine, D. Tetrahedron: Asymmetry 2003, 14, 2849-2851.
(10) For recent examples, see: (a) Sano, S.; Takemoto, Y.; Nagao, Y.
Tetrahedron Lett. 2003, 44, 8853-8855. (b) Pihko, P. M.; Salo, T. M.
Tetrahedron Lett. 2003, 44, 4361-4364. (c) Yamazaki, J.; Bedekar, A. V.;
Watanabe, T.; Tanaka, K.; Watanabe, J.; Fuji, K. Tetrahedron: Asymmetry
2002, 13, 729-734. (d) Has-Becker, S.; Bodmann, K.; Kreuder, R.; Santoni,
G.; Rein, T.; Reiser, O. Synlett 2001, 1395-1398. (e) Motoyoshiya, J.;
Kusaura, T.; Kokin, K.; Yokoya, S.-i.; Takaguchi, Y.; Narita, S.; Aoyama,
H. Tetrahedron 2001, 57, 1715-1721. (f) Reichwein, J. F.; Pagenkopf, B.
L. J. Am. Chem. Soc. 2003, 125, 1821-1824.
(11) (a) Yue, X.; Li, Y. Synthesis 1996, 736-740. (b) Almeida, W. P.;
Correia, C. R. D. Tetrahedron Lett. 1994, 35, 1367-1370. (c) Hwang, S.
W.; Adiyaman, M.; Lawson, J. A.; FitzGerald, G. A.; Rokach, J.
Tetrahedron Lett. 1999, 40, 6167-6171.
(12) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654-
5656.
(15) Gupta, M. M.; Verma, R. K. Phytochemistry 1991, 30, 875-878.
(16) Fleury, B. G.; Pereira, M. G.; Da Silva, J. R. P.; Kaisin, M.; Teixeira,
V. L.; Kelecom, A. Phytochemistry 1994, 37, 1447-1449.
(17) Moghadasian, M. H.; Salen, G.; Frohlich, J. J.; Scudamore, C. H.
Arch. Neurol. 2002, 59, 527-529.
(13) Alkene 2a was formed in 33% yield when nBuLi was used in place
s
of BuLi.
(14) All new compounds gave consistent spectral and high-resolution
mass spectrometry data.
1598
Org. Lett., Vol. 7, No. 8, 2005