Convergent synthesis of conjugated 1,2-disubstituted E-allylic alcohols from two aldehydes and methylenetriphenylphosphorane

Article abstract of DOI:10.1039/c2ob26346g

β-Lithiooxyphosphonium ylides, made in situ from an aldehyde and methylenetriphenylphosphorane, react with a second aldehyde to form E-allylic alcohols. α-Branching and α,β-unsaturation in the second aldehyde, together with the lack of further substitution on the phosphorane carbon play important roles in selectivity. A range of these aldehydes, in addition to aromatic aldehydes as the second aldehyde also provided synthetically useful access to E-allylic alcohols.

Full text of DOI:10.1039/c2ob26346g

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PAPER
Convergent synthesis of conjugated 1,2-disubstituted E-allylic alcohols from
two aldehydes and methylenetriphenylphosphorane†
David M. Hodgson* and Rosanne S. D. Persaud
Received 13th July 2012, Accepted 24th August 2012
DOI: 10.1039/c2ob26346g
β-Lithiooxyphosphonium ylides, made in situ from an aldehyde and methylenetriphenylphosphorane,
react with a second aldehyde to form E-allylic alcohols. α-Branching and α,β-unsaturation in the second
aldehyde, together with the lack of further substitution on the phosphorane carbon play important roles in
selectivity. A range of these aldehydes, in addition to aromatic aldehydes as the second aldehyde also
provided synthetically useful access to E-allylic alcohols.
Allylic alcohols are widely used in organic synthesis, so exper-
imentally straightforward methods of synthesising them under
stereocontrol from readily available starting materials are of sig-
nificance.1 In 1970, Corey and Yamamoto reported a remarkable
regio- and stereoselective synthesis of E-trisubstituted allylic
alcohols 4 from ethylidenetriphenylphosphorane (1) and two
aldehydes (Scheme 1).2 A subsequent mechanistic study indi-
cated that the origin of the positional selectivity and geometry of
the double bond was due to stereocontrolled formation of a β-,β′-
di(lithiooxy)phosphonium 3 arising from addition of β-lithiooxy-
phosphorane 2 to the second aldehyde, followed by preferential
syn-elimination of Ph3PO involving the oxygen from the second
aldehyde; syn-elimination involving the oxygen from the first
(other than with one of the aldehydes being formaldehyde)4,5
–
despite the potential as an attractive route to E-1,2-disubstituted
allylic alcohols (Scheme 2). The presumed intermediate
β-lithiooxyphosphorane
6 has been generated on several
occasions from double deprotonation of a β-hydroxy primary
phosphonium salt, and has been shown to undergo the desired
synthesis of 1,2-disubstituted allylic alcohols on reaction with
aldehydes; however, these reactions require a stepwise synthesis
of the phosphonium salt, appear very sensitive to experimental
conditions, and yields are highly variable.6 Also, α-lithiomethy-
lenetriphenylphosphorane has been shown to react with 2
equivalents of (necessarily) the same aldehyde to give symmetri-
cally substituted E-allylic alcohols (for example, 10c).7 In the
present paper, we demonstrate that the coupling of two different
aldehydes with methylenephosphorane is a synthetically useful
regio- and stereocontrolled approach to E-1,2-disubstituted
allylic alcohols, but only from certain classes of aldehydes
(Scheme 2).
aldehyde would be
a higher energy process leading to
Z-stereochemistry.3
Scheme 1 Synthesis of E-trisubstituted allylic alcohols 4.2
To the best of our knowledge, the above chemistry has not
been studied with methylenephosphorane and two aldehydes
Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: david.hodgson@chem.ox.ac.uk; Fax: +44 (0)1865 285002;
Tel: +44 (0)1865 275697
†Electronic supplementary information (ESI) available: Experimental
1
procedures and spectroscopic data along with H and 13C NMR spectra
Scheme 2 Allylic alcohols using aliphatic aldehydes and methylene-
phosphorane 5.
for all compounds synthesised. See DOI: 10.1039/c2ob26346g
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Preliminary experiments were not encouraging. Under pre-
viously established preferred conditions for generation of
β-lithiooxyphosphoranes,8,9 methylenetriphenylphosphorane (5),
with acetaldehyde and nonanal as either the first or second alde-
hyde produced alcohols 7 and 8 as a mixture of chromatographi-
cally inseparable isomers in similar yield (Scheme 2).10 Varying
the concentration, the generation of β-lithiooxyphosphorane 6 by
a warm–cool cycle,8 the temperature at which the second alde-
hyde was added, the equivalents of LiBr or the second aldehyde,
adding β-lithiooxyphosphorane 6 to the second aldehyde,11 or
adding t-BuOK8 at the end of the reaction did not improve selec-
tivity. In contrast, reaction of these aldehydes under the preferred
conditions, but with ethylidenetriphenylphosphorane (1) gave
exclusively E-trisubstituted allylic alcohols 4 (58% for R1 = Me
and R2 = octyl; 63% for R1 = octyl and R2 = Me),10 in complete
accordance with Corey and Yamamoto’s initial report. These
results indicate a significant influence of phosphorane substi-
tution in the reaction pathway from β-lithiooxyphosphorane to
allylic alcohol.
elimination involving the oxygen from the second aldehyde,
with the energy of the transition state for elimination likely being
lowered due to developing conjugation. With α-branched α,β-
unsaturated aldehydes, complete stereoselectivity for the E-
isomer 9b–d was observed.12 This chemistry provides a con-
venient entry to dienols 9, such as a functionalised isoprene unit
9d, which are potentially useful in cycloadditions.13
Scheme 3 Synthesis of dienols 9.
Similarly, using aromatic aldehydes as the second aldehyde
component led to single regio- and stereoisomeric aryl-substi-
tuted allylic alcohols 10 (Table 1).14 Entry 8 illustrates the use of
Use of an α,β-unsaturated aldehyde as the second aldehyde
component proved more promising (Scheme 3). In these cases,
the newly formed double bond was always generated by
Table 1 Formation of aryl-substituted allylic alcohols 10
Entry
1
1st aldehyde
2nd aldehyde
Allylic alcohol
Yield (%)
46
2
3
41
67
4
5
6
59
60
49
7
8
56
65
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1942; (c) E. J. Corey, A. Marfat and D. J. Hoover, Tetrahedron Lett.,
1981, 22, 1587; (d) S. Schwarz, G. Weber, J. Depner and J. Schaumann,
Tetrahedron, 1982, 38, 1261; (e) S. W. Russell and H. J. J. Pabon,
J. Chem. Soc., Perkin Trans. 1, 1982, 545; (f) F. Johnson, K. G. Paul,
D. Favara, R. Ciabatti and U. Guzzi, J. Am. Chem. Soc., 1982, 104,
2190; (g) P. Yadagiri, D.-S. Shin and J. R. Falck, Tetrahedron Lett., 1988,
29, 5497; (h) T. Kubota and M. Yamamoto, Tetrahedron Lett., 1992, 33,
2603; (i) K. Okuma, Y. Tanaka, H. Ohta and H. Matsuyama, Bull. Chem.
Soc. Jpn., 1993, 66, 2623; ( j) S. El Fangour, A. Guy, J.-P. Vidal,
J.-C. Rossi and T. Durand, J. Org. Chem., 2005, 70, 989; (k) For use of a
3° (ketone-derived) β-hydroxy primary phosphonium salt, see: H. Niwa
and M. Kurono, Chem. Lett., 1977, 6, 1211.
7 (a) E. J. Corey and J. Kang, J. Am. Chem. Soc., 1982, 104, 4725;
(b) See also: E. J. Corey, J. Kang and K. Kyler, Tetrahedron Lett., 1985,
26, 555.
8 Q. Wang, D. Deredas, C. Huynh and M. Schlosser, Chem.–Eur. J., 2003,
9, 570.
acetaldehyde and veratraldehyde in the direct synthesis of a
simple natural product 10h, originally isolated from the rhizomes
of Zingiber cassumunar.15
The present work demonstrates the ability of methylenetriphe-
nylphosphorane (5) to act as a methine trianion synthon,7 con-
necting an aliphatic aldehyde with an α-branched
α,β-unsaturated or aromatic aldehyde to give conjugated 1,2-di-
substituted E-allylic alcohols.16 We anticipate that this chemistry
will find utility as a convenient method to access such allylic
alcohols, due to the one-flask operation, commercial availability
of all the reagents, together with the wide availability of
aldehyde substrates.
9 D. M. Hodgson and T. Arif, Chem. Commun., 2011, 47, 2685.
10 See the ESI† for details.
11 D. M. Hodgson and T. Arif, Org. Lett., 2010, 12, 4204.
12 Use of cyclohexane carboxaldehyde as a representative α-branched satu-
rated aldehyde was similarly completely E-stereoselective, but only 90%
regioselective; see the ESI† for details.
13 (a) A. P. Kozikowski and Y. Kitigawa, Tetrahedron Lett., 1982, 23, 2087;
(b) K. M. Miller, E. A. Colby, K. S. Woodin and T. F. Jamison, Adv.
Synth. Catal., 2005, 347, 1533.
14 Using two different aromatic aldehydes (benzaldehyde followed by fur-
fural) gave a mixture of regio- and stereoisomeric allylic alcohols; see the
ESI† for details.
Notes and references
1 D. M. Hodgson and P. G. Humphreys, in Science of Synthesis, ed.
J. Clayden, Thieme, Stuttgart, 2007, vol. 36, pp. 583–665.
2 E. J. Corey and H. Yamamoto, J. Am. Chem. Soc., 1970, 92, 226; corri-
gendum, 1970, 92, 3523.
3 (a) E. J. Corey, P. Ulrich and A. Venkateswarlu, Tetrahedron Lett., 1977,
37, 3231; (b) For a review, see: E. Vedejs and M. J. Peterson, Top. Stereo-
chem., 1994, 21, 1.
4 (a) M. Schlosser and D. Coffinet, Synthesis, 1971, 380; (b) M. Schlosser
and D. Coffinet, Synthesis, 1972, 575.
5 For use of a ketone followed by formaldehyde, see 4(b) and J. S. Yu,
T. S. Kleckley and D. F. Wiemer, Org. Lett., 2005, 7, 4803.
6 (a) E. J. Corey, H. Shirahama, H. Yamamoto, S. Terashima,
A. Venkateswarlu and T. K. Schaaf, J. Am. Chem. Soc., 1971, 93, 1490;
(b) E. J. Corey, H. Niwa and J. Knolle, J. Am. Chem. Soc., 1978, 100,
15 (a) T. Masuda and A. Jitoe, Phytochemistry, 1995, 39, 459; (b) For an
alternative synthesis, see: B. P. Joshi, N. P. Singh, A. Sharma and
A. K. Sinha, Chem. Nat. Compd., 2005, 41, 370.
16 For a strategically related process using HCI3 and CrCl2, see: K. Takai,
K. Nitta and K. Utimoto, J. Am. Chem. Soc., 1986, 108, 7408.
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