Highly (E)-selective wadsworth-emmons reactions promoted by methylmagnesium bromide

Article abstract of DOI:10.1021/ol802212e

(Chemical Equation Presented) An experimentally simple protocol for the very highly (E)-selective Wadsworth-Emmons reaction [(E):(Z) selectivities in excess of 180:1 in some cases] of a range of straight-chain and branched aliphatic, substituted aromatic, and base-sensitive aldehydes via reaction with an alkyl diethylphosphonoacetate and MeMgBr is reported.

Full text of DOI:10.1021/ol802212e

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5437-5440
Highly (E)-Selective
Wadsworth-Emmons Reactions
Promoted by Methylmagnesium Bromide
Timothy D. W. Claridge, Stephen G. Davies,* James A. Lee,
Rebecca L. Nicholson, Paul M. Roberts, Angela J. Russell,
Andrew D. Smith, and Steven M. Toms
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steVe.daVies@chem.ox.ac.uk
Received September 22, 2008
ABSTRACT
An experimentally simple protocol for the very highly (E)-selective Wadsworth-Emmons reaction [(E):(Z) selectivities in excess of 180:1 in
some cases] of a range of straight-chain and branched aliphatic, substituted aromatic, and base-sensitive aldehydes via reaction with an alkyl
diethylphosphonoacetate and MeMgBr is reported.
(E)-R,ꢀ-Unsaturated esters are versatile intermediates in
organic synthesis.1 As part of our ongoing investigations
concerned with the synthesis of libraries of ꢀ-amino acids
utilizing the conjugate addition of homochiral lithium
amides,2 we required a simple and reliable protocol for the
preparation of a structurally diverse range of (E)-R,ꢀ-
unsaturated esters. A range of methodologies to facilitate this
objective have been reported, including the Wittig,3,4 Julia,5
and Peterson6 olefinations. A useful variant of the Wittig
protocol is the Wadsworth-Emmons reaction.7,8 In this
reaction, alkali metal bases such as BuLi and NaH are
commonly used to generate the reactive metalated phospho-
nate intermediate; however, the stereoselectivity can be
heavily influenced by the nature of the metal counterion.9
Within this arena, Masamune et al.10 and Rathke et al.11 have
shown that either lithium or magnesium halides and a tertiary
(7) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733
.
(1) For general reviews on the synthesis of R,ꢀ-unsaturated esters, see:
Franklin, A. S. J. Chem. Soc., Perkin Trans. 1 1998, 2451. Shen, Y. Acc.
Chem. Res. 1998, 31, 584.
(8) (Z)-Selective variants of the Wadsworth-Emmons reaction have been
developed; see: Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
Ando, K. J. Org. Chem. 1998, 63, 8411. Ando, K. J. Org. Chem. 1999, 64,
8406. Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem.
(2) Davies, S. G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie,
L. J.; Price, P. D.; Price Mortimer, A. J.; Russell, A. J.; Smith, A. D.
Tetrahedron: Asymmetry 2006, 17, 1793. Davies, S. G.; Mulvaney, A. W.;
Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2007, 18, 1554. For
a review, see: Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron:
Asymmetry 2005, 16, 2833.
2000, 65, 4745. Touchard, F. P. Tetrahedron Lett. 2004, 45, 5336
.
(9) Walker, B. J. Organophosphorus Reagents in Organic Synthesis;
Cadogan, J. I., Ed.; Academic Press: London, 1979; p 170. Thompson, S. K.;
Heathcock, C. H. J. Org. Chem. 1990, 55, 3386.
(10) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfield, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(11) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
(12) A related protocol to facilitate the preparation of R-fluoro-R,ꢀ-
unsaturated esters from R-fluorophosphonate esters has been reported by
Nagao et al., employing Sn(OSO2CF3)2 and N-ethylpiperidine to achieve
(3) Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318. Wittig, G.;
Haag, W. Chem. Ber. 1955, 88, 1654
(4) For a review of the Wittig reaction and its variants, see: Maryanoff,
B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863
.
.
(5) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14, 4833. Baudin,
J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175.
For reviews, see: Kocienski, P. J. Phosphorus Sulfur 1985, 24, 97.
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
i
high levels of (E)-selectivity. Using MgBr2/Et3N or PrMgBr to promote
the reaction gave only modest levels of diastereoselectivity under a variety
of conditions, although in an isolated case the stereoselective formation of
the corresponding (Z)-olefin isomer [(E):(Z) ratio 5:95] was noted; see: Sano,
S.; Ando, T.; Yokoyama, K.; Nagao, Y. Synlett 1998, 777.
(6) Peterson, D. J. J. Org. Chem. 1968, 33, 780. For reviews, see: Ager,
D. J. Synthesis 1984, 384. Ager, D. J. Org. React. 1990, 38, 1.
10.1021/ol802212e CCC: $40.75
Published on Web 11/01/2008
2008 American Chemical Society

Scheme 1
.
a Determined by peak integration of the 1H NMR spectrum of the crude reaction mixture. b Isolated yield of pure (E)-olefin (g98:2 dr); yields in
parentheses refer to the combined yield of both olefin diastereoisomers. c Reaction gave a 41:3:56 mixture of (E)- and (Z)-R,ꢀ-unsaturated esters 12 and 27,
and the isomerized (E)-ꢀ,γ-unsaturated ester 35. d Isolated yield of a 43:57 mixture of 12:35.
amine base can be used to afford R,ꢀ-unsaturated esters with
improved and generally high levels of (E)-selectivity.12,13
Although these protocols are often effective for olefinations
of base-sensitive aldehydes, they typically require rigorous
application of anhydrous conditions and long reaction times
(g24 h), limiting the utility of this methodology. In this
paper, we report an experimentally simple and general
protocol for highly (E)-selective Wadsworth-Emmons reac-
tions using MeMgBr as a base.
extremely high levels of diastereoselectivity were readily
quantified using the protocol involving integration of the
13C-1H satellite peaks, introduced in the preceding manu-
script.16 For example, in the reaction with iPrCHO, integra-
tion of the 12C-1H peaks due to C(3)H for (Z)-24 and the
corresponding 13C-1H satellite peaks of (E)-9 gave a ratio
of 54:46, hence the ratio of 12C-1H of (Z)-24 to 13C-1H
satellite of (E)-9 to 12C-1H of (E)-9 is 54:46:8211, and the
(E):(Z) ratio is 152:1, or >150:1. Using BuLi as the base in
these reactions gave mixtures of the corresponding (E)- and
(Z)-R,ꢀ-unsaturated esters. Under Masamune-Roush condi-
tions (LiCl/DBU),10 high levels of selectivity were noted
although at the expense of reaction conversion. In each case
examined, the diastereoselectivity and yield obtained from
the MeMgBr promoted reaction was equal or superior to that
Under optimized conditions,14 deprotonation of tert-butyl
diethylphosphonoacetate 1 with MeMgBr at rt followed by
addition of a range of straight-chain and branched aliphatic
aldehydes and heating at reflux for 2.5 h gave complete
conversion to the corresponding (E)-R,ꢀ-unsaturated ester
in each case, with (E):(Z) selectivities in excess of 180:1 in
some cases, and in high isolated yields (g88%).15 The
Scheme 2
.
a
Determined by peak integration of the H NMR spectrum of the crude reaction mixture. b Isolated yield of product A, i.e. pure (E)-olefin (>99:1 dr);
1
yields in parentheses refer to the combined yield of products A and C.
5438
Org. Lett., Vol. 10, No. 23, 2008

Scheme 3
obtained from both the BuLi and LiCl/DBU promoted
reactions (Scheme 1).
The generality of this olefination protocol was next
established. Application to a range of substituted aromatic
aldehydes gave complete conversion to the corresponding
(E)-olefins 50-55 in uniformally high diastereoisomeric
ratios [(E):(Z) g99:1],16 although longer reaction times were
required (Scheme 4).
Olefination of CyCHO, PhCH(Me)CHO, and
PhCH2CH2CHO upon treatment with phosphonate esters 2-4
and BuLi, LiCl/DBU or MeMgBr gave the corresponding
R,ꢀ-unsaturated isopropyl, ethyl and methyl esters (E)-11-
19 and (Z)-26-34. In each case olefination promoted by
MeMgBr gave quantitative conversion to the corresponding
(E)-R,ꢀ-unsaturated ester in g98:2 diastereoselectivity (Scheme
1).
Scheme 4
.
In the case of olefination of PhCH2CHO, the yields of the
desired R,ꢀ-unsaturated esters were somewhat compromised
by competing isomerization to the corresponding (E)-ꢀ,γ-
unsaturated esters.17 When compared to the reactions em-
ploying BuLi or LiCl/DBU, in all cases olefination with
MeMgBr suppressed the isomerization (0-26%) and gave
the highest isolated yield of pure (E)-R,ꢀ-unsaturated ester
(Scheme 2).
The mechanism of this olefination protocol was next
investigated. Tanabe et al. have shown that treatment of a
phosphonate ester with TiCl4 and Et3N followed by an
aldehyde gives anti-ꢀ-hydroxyphosphonate esters with high
selectivity.18 Under these conditions, treatment of phospho-
nate 3 with TiCl4 and Et3N followed by PhCH2CHO gave a
73:27 mixture of two products, which were assigned as
ꢀ-hydroxyphosphonate diastereoisomers anti-48 and syn-49,
respectively, by analogy to the observations of Tanabe.18
Treatment of the 73:27 mixture of 48:49 with MeMgBr at
20 °C followed by quenching with satd aq NH4Cl gave a
59:30:11 mixture of 3:48:49, suggesting that the addition of
phosphonate 3 to PhCH2CHO is reversible under the reaction
conditions. Treatment of the 73:27 mixture of 48:49 with
MeMgBr followed by heating at reflux for 2.5 h resulted in
complete conversion to (E)-38 as the only product. This
implies that stereospecific syn-elimination of 49, leading to
the (E)-olefin, and equilibration of 48 and 49 via retro-
addition/addition, are both fast under the reaction conditions.
Treatment of the 73:27 mixture of 48:49 with MeMgBr
followed by heating at reflux in the presence of PhCH-
(Me)CHO gave a 94:6 mixture of (E)-R,ꢀ-unsaturated esters
15 and 38, corroborating the hypothesis that condensation
of the anion of phosphonate 3 with an aldehyde is reversible
(Scheme 3). These results are consistent with this reaction
proceeding via the accepted mechanism for the Wadsworth-
Emmons reaction.8
a Determined by peak integration of the 1H NMR spectrum of the crude
reaction mixture. b Isolated yield of pure (E)-olefin (>99:1 dr).
Olefination of the functionalized, homochiral aldehydes 56
and 59 was also investigated.19 Olefination of 56promoted by
MeMgBr proceeded with an (E)-selectivity of >180:1, while
using BuLi or LiCl/iPr2NEt gave (E):(Z) ratios of 86:14 and
96:4, respectively. Olefination of cis-dioxolane-containing al-
dehyde 59 promoted by BuLi or under Masamune-Roush
(13) ForexamplesoftheuseofotherbasestopromoteWadsworth-Emmons
reactions, see: Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281.
(14) The anion derived from deprotonation of phosphonate 1 with
MeMgBr was noted to be much less reactive toward olefination of an
aldehyde than the corresponding anion derived from deprotonation of
phosphonate 1 with BuLi.
(15) Representative experimental procedure: preparation of (E)-5:
MeMgBr (1.6 M in Et2O, 0.49 mL, 0.79 mmol) was added dropwise to a
stirred solution of tert-butyl diethylphosphonoacetate 1 (0.19 mL, 0.79
mmol) in anhydrous THF (10 mL) at rt under a nitrogen atmosphere. After
the mixture was stirred for 15 min, cyclohexanal (0.11 mL, 0.87 mmol)
was added dropwise via syringe and the reaction mixture was heated at
reflux for 2.5 h. The reaction mixture was then allowed to cool to rt, satd
aq NH4Cl (4 mL) was added, and the mixture was extracted with Et2O (3
× 10 mL). The combined organic extracts were washed with brine (15
mL), dried over magnesium sulfate, and concentrated in vacuo to give (E)-
R,ꢀ-unsaturated ester
>180:1).
5
as a colorless oil (163 mg, 98%, (E):(Z)
Org. Lett., Vol. 10, No. 23, 2008
5439

conditions gave (E)- and (Z)-olefin products 60 and 61, and
was accompanied by partial epimerization of the R-stereocenter
within 59, followed by olefination to furnish 62.20 However,
sequential treatment of phosphonate 1 with MeMgBr and then
aldehyde 59 gave (E)-60 as the only product with an (E):(Z)
ratio of >180:116 (Scheme 5).
as a latent aldehyde equivalent through DIBAL-H reduction
to the corresponding hemiaminal.21 The compatibility of the
Grignard-mediated olefination protocol to a tandem reduc-
tion/olefination reaction within this system was probed.
Treatment of N-acyloxazolidinone 63 with DIBAL-H fol-
lowed by the anion of phosphonate 1 (generated by depro-
tonation with MeMgBr) afforded the corresponding (E)-R,ꢀ-
unsaturated ester 65 with an (E):(Z) ratio of >180:1,16 and
in excellent 98% yield after chromatography. The analogous
reaction employing BuLi proceeded with significantly lower
levels of selectivity, delivering (E)-65 and (Z)-66 in an 89:
11 ratio, and in only 50% combined yield after chromatog-
raphy (Scheme 6).
Scheme 5
Scheme 6
.
We have previously demonstrated that an N-acyl Super-
Quat (5,5-dimethyloxazolidin-2-one) auxiliary is able to act
a Combined yield of both olefin diastereoisomers.
(16) Claridge, T. D. W.; Davies, S. G.; Polywka.; M, E. C.; Roberts,
P. M.; Russell, A. J.; Savory, E. D.; Smith, A. D. Org. Lett. 2008, 10, 5433
(ol802211p)
(17) Deprotonation of ethyl 4-phenylbut-2-enoate and subsequent re-
protonation has been shown to lead preferentially to the corresponding (E)-
ꢀ,γ-unsaturated ester; see: Guha, S. K.; Shibayama, A.; Abe, D.; Sakaguchi,
M.; Ukaji, Y.; Inomata, K. Bull. Chem. Soc. Jpn. 2004, 77, 2147.
(18) Katayama, M.; Nagase, R.; Mitarai, T.; Misaki, T.; Tanabe, Y.
Synlett 2006, 129.
In conclusion, MeMgBr promotes highly (E)-selective
Wadsworth-Emmons reactions between a range of alkyl
diethylphosphonoacetates and a range of straight-chain and
branched aliphatic, substituted aromatic, and base-sensitive
aldehydes. Very high (E):(Z) selectivities were observed in
all cases tested (>25 examples), with (E):(Z) selectivities
of >180:1 being noted in several cases.
(19) Aldehydes 56 and 59 were prepared and used immediately in the
olefination reaction without purification. For the preparation of aldehyde
56, see: Paquette, A.; Bailey, S. J. Org. Chem. 1995, 60, 7849. For the
preparation of aldehyde 59, see: Iida, H.; Yamazaki, N.; Kibayashi, C. J.
Org. Chem. 1987, 52, 3337.
(20) In accordance with this hypothesis olefination of the corresponding
trans-dioxolane containing aldehyde mediated by BuLi or under Masamune-
Roush conditions gave (E)-R,ꢀ-unsaturated ester 62 as a single diastereoi-
somer.
Acknowledgment. We thank New College, Oxford, for
a Junior Research Fellowship (A.D.S.).
(21) Bach, J.; Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee,
H. J.; Smith, A. D. Tetrahedron Lett. 1999, 40, 6677. Bach, J.; Blache`re,
C.; Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Price, P. D.; Sanganee,
H. J.; Smith, A. D. Org. Biomol. Chem. 2003, 1, 2001. For selected examples
of the application of this methodology in synthesis, see: Davies, S. G.;
Hunter, I. A.; Nicholson, R. L.; Roberts, P. M.; Savory, E. D.; Smith, A. D.
Tetrahedron 2004, 60, 7553. Davies, S. G.; Nicholson, R. L.; Smith, A. D.
Org. Biomol. Chem. 2005, 3, 348.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802212E
5440
Org. Lett., Vol. 10, No. 23, 2008