A New Horner-Wadsworth-Emmons type coupling reaction between nonstabilized β-hydroxy phosphonates and aldehydes or ketones

Article abstract of DOI:10.1021/ja027658s

Treatment of nonstabilized β-hydroxy phosphonic acid mono methyl esters with diisopropyl carbodiimide at ambient temperature leads to clean stereospecific elimination. The phosphonic acid mono alkyl esters are accessible by the selective partial saponification of dimethyl or diethyl alkyl phosphonates with NaOH or MgBr₂. Isolated yields over both hydrolysis and elimination steps average 55-75%.

Full text of DOI:10.1021/ja027658s

Published on Web 01/25/2003
A New Horner-Wadsworth-Emmons Type Coupling Reaction
between Nonstabilized â-Hydroxy Phosphonates and
Aldehydes or Ketones
John F. Reichwein and Brian L. Pagenkopf*
Contribution from the Department of Chemistry and Biochemistry, The UniVersity of Texas at
Austin, Austin, Texas 78712
Received July 11, 2002 ; E-mail: pagenkopf@mail.utexas.edu
Abstract: Treatment of nonstabilized â-hydroxy phosphonic acid mono methyl esters with diisopropyl
carbodiimide at ambient temperature leads to clean stereospecific elimination. The phosphonic acid mono
alkyl esters are accessible by the selective partial saponification of dimethyl or diethyl alkyl phosphonates
with NaOH or MgBr2. Isolated yields over both hydrolysis and elimination steps average 55-75%.
Scheme 1
Introduction
The Wittig,1,2 Horner,3,4 and Wadsworth-Emmons5,6 reac-
tions are classic methods for joining two complex molecular
fragments through relatively simple functional groups, and these
reliable olefin-forming reactions are well-accepted transforma-
tions in both academia and industry (Scheme 1).7 The synthetic
power inherent with these kinds of coupling and homologation
reactions has spurred research into optimizing, modifying, or
supplanting8 these methods with others that operate under
different reaction conditions,9 can be prepared from alternative
starting materials,10 or that enhance stereochemical control.11,12
The dialkyl phosphonates of the Wadsworth-Emmons reac-
tion can be prepared by Arbuzov, Michaelis-Becker,13,14 or
other methods,14 and the alkylation of R-lithio phosphonates
with aldehydes is well known. However, a carbanion-stabilizing
group in the â-position is necessary for elimination and olefin
formation, without which addition to aldehydes gives stable
â-hydroxyphosphonates.6,7,15 The elimination of nonstabilized
â-hydroxy phosphonates to olefins has long been recognized
as a difficult transformation. In pioneering studies on the
formation of olefins from nonstabilized â-hydroxy phosphonates
derived from benzophenone, Corey and Kwiatkowski reported
that the optimal yield of 1,1-diphenylethylene was at best 30%,
and benzophenone, unsaturated phosphonate, and acidic materi-
als were also formed.16 To overcome these difficulties, Corey
et al. ingeniously developed phosphonic bisamides17 and thio-
phosphonates16 as alternative coupling reagents.18 During the
intervening decades, a general protocol for the elimination of
nonstabilized â-hydroxyphosphonates has not been advanced.
In this paper, we describe a novel method for the utilization of
nonstabilized â-hydroxyphosphonates in Horner-Wadsworth-
(1) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953, 580, 44-68.
(2) For reviews, see: (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89,
863-927. (b) Maercker, A. Org. React. 1965, 14, 270-490.
(3) Horner, L.; Hoffmann, H.; Wipel, H. C.; Klahre, G. Chem. Ber. 1959, 92,
2499-2505.
(4) For reviews, see: (a) Clayden, J.; Warren, S. Angew. Chem., Int. Ed. Engl.
1996, 35, 241-270. (b) Buss, A. D.; Warren, S. J. Chem. Soc., Perkin
Trans. 1 1985, 2307-2325.
(5) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733-
1738.
(6) Boutagy, J.; Thomas, R. Chem. ReV. 1974, 74, 87-99. Wadsworth, W.
A., Jr. Org. React. 1977, 25, 73-253.
(7) Nicalaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs Ann.
Recl. 1997, 1283-1301.
(8) (a) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 3171-
3174. (b) Pederson, R. L.; Fellows, I. M.; Ung, T. A.; Ishihara, H.; Hajela,
S. P. AdV. Synth. Catal. 2002, 344, 728-735.
(9) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1994, 25, 2183-2186.
(10) For examples with diazoesters, see: (a) Lu, X.; Fang, H.; Ni, Z. J.
Organomet. Chem. 1989, 373, 77-84. (b) Herrmann, W. A.; Wang, M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1641-1643. (c) Zhou, Z.; Huang,
Y.; Shi, L. Tetrahedron 1993, 49, 6821-6830. (d) Herrmann, W. A.;
Roesky, P. W.; Wang, M.; Scherer, W. Organometallics 1994, 13, 4531-
4535. (e) Ledford, B. E.; Carreira, E. M. Tetrahedron Lett. 1997, 38, 8125-
8128. (f) Lebel, H.; Paquet, V.; Proulx, C. Angew. Chem., Int. Ed. 2001,
40, 2887-2890.
(15) Kelly, S. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, Chapter 3.1, pp 729-
817.
(16) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654-
5656.
(17) (a) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5652-
5653. (b) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88,
5653-5654. (c) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1968,
90, 6816-6821. (d) Corey, E. J.; Cane, D. E. J. Org. Chem. 1969, 34,
3053-3057.
(11) Still, W. C.; Gennari, C. Tetrahedron Lett. 1993, 24, 4405-4408.
(12) For examples with phosphonates, see: Chemler, S. R.; Coffey, D. S.; Roush,
W. R. Tetrahedron Lett. 1999, 40, 1269-1272.
(13) Bhattacharya, A. K.; Thyagarajan, G. Chem. ReV. 1981, 81, 415-430.
(14) Kosolapoff, G. M. Org. React. 1951, 6, 273-338.
(18) Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50, 369-379.
9
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J. AM. CHEM. SOC. 2003, 125, 1821-1824
1821

A R T I C L E S
Reichwein and Pagenkopf
Scheme 2
Scheme 3
Scheme 4
Emmons type reactions under ambient conditions using mild
dehydrating reagents.
With the advent of convenient olefin hydrophosphorylation
reactions,19,20 we decided to reinvestigate the conversion of
â-hydroxy phosphonates to olefins despite the discouraging
heritage for their elimination. Initially we speculated that the
use of crown ethers, which were not commercially available
three decades ago, would result in a more nucleophilic alkoxide
for generating the oxaphosphetane 9, which could then convert
to the desired olefin by a retro [2 + 2] fragmentation pathway
(Scheme 2). The more exothermic pathway a leads to the desired
olefin and meta phosphate 11,21 whereas pathway b leads to
release of aldehyde 13 and the reactive intermediate 12.
However, the alkali salts (NaH, n-BuLi, t-BuOK) of â-hydroxy
phosphonates 7 in the presence of crown ethers22 showed no
reaction at low temperatures, and the substrates underwent
decomposition to various dehydrated vinylic and â,γ-unsaturated
phosphonates as the reactions warmed to room temperature.23
Weaker bases (PhONa, wet K2CO3) have been reported to result
in olefin formation with tertiary â-hydroxy phosphonates,24 but
these methods were ineffective here, even at elevated temper-
atures (100 °C in DMF).25 Partial ester hydrolysis occurred in
the presence of Lewis acids, and only CsF in hot DMF provided
some olefin 10 (8% after 16 h).26
In the Wadsworth-Emmons reaction,6 the reversible forma-
tion of the pentavalent phosphorus species 15 is thought to
precede collapse to the stabilized anion 16, and E1cb elimination
leads to release of phosphate and the coupled enone product
17 (Scheme 3). The â-hydroxy phosphonates investigated in
this paper also likely form equilibrating pentavalent phosphorus
intermediates, but because they lack the â-electron-withdrawing
or -stabilizing group, there is no low energy pathway for collapse
leading to olefin formation.
metals.27-29 We postulated that a leaving group superior to
methoxide (or methanol) was required for oxephosphetane
formation. Dehydration of the free phosphonic acid appeared
to be an attractive strategy, and the ideal dehydrating reagent
for this task proved to be the peptide coupling reagent
diisopropylcarbodiimide (DIC). In this regard, the addition of
30
DIC to a CHCl3 solution of the free phosphonic acid 20
resulted in clean formation of olefin 10.31 Subsequent NMR
investigations revealed that the formation of oxaphosphetane 9
was nearly instantaneous after the addition of DIC to a solution
of 20, whereas the intermediate urea phosphonate 21 could not
be detected.32 The oxaphosphetane 9 slowly converted over 24
h to olefin 10 in 75% yield. The partial saponification of
dimethylphosphonate 7a to 20 was achieved with MgBr2‚OEt2
at 100 °C in dioxane or, more conveniently, by saponification
with NaOH in H2O/MeOH at room temperature (Scheme 4).
A variety of â-hydroxy phosphonates prepared from alde-
hydes and ketones were made for exploring the generality of
the elimination protocol (Table 1). An important consideration
when evaluating the alkylation yields in Table 1 is that the ratio
of phosphonate anion to carbonyl electrophile was maintained
at 1:1, and the reaction stoichiometry was not adjusted to
increase efficiency. The alkylation of octyl dimethyl phospho-
nate 19a with aliphatic or aromatic aldehydes provided the
â-hydroxy phosphonates 7a,b in 81 and 84% isolated yields,
It was clear from NMR data that no discernible amounts of
the oxephosphetane 9 were formed by treatment of 7a with alkali
(19) Han, L.-B.; Mirzaei, F.; Zhao, C.-Q.; Tanaka, M. J. Am. Chem. Soc. 2000,
122, 5407-5408.
(20) Reichwein, J. F.; Patel, M. C.; Pagenkopf, B. L. Org. Lett. 2001, 3, 4303-
4306.
(21) Westheimer, F. H. Chem. ReV. 1981, 81, 313-326.
(22) These conditions are commonly used in Wadsworth-Emmons reactions,
see: Clayden, J.; Warren, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 241-
270.
(27) Oxaphosphetane structures analogous to 9 have been isolated, some even
by distillation. See refs 28 and 29.
(23) Based on 1H and 31P NMR.
(24) Dimethyl 2-hydroxy-2,2-dibenzylethylphosphonate, K2CO3 (8 equiv) and
H2O (8 equiv) in DMF at 95 °C for 48 h gave 80% olefin: Kawashima,
T.; Ichii, T.; Inamoto, N. Chem. Lett. 1984, 1097-1100; ref 35.
(25) Abbreviations used: BHT ) 2,6-di-tert-butyl-1-hydroxy toluene, DMF )
N,N-dimethylformamide, DIC ) 1,3-diisopropylcarbodiimide.
(26) Dimethyl 2-hydroxy-2,2-diphenylethylphosphonate, CsF (3.5 equiv) and
H2O (3.5 equiv) in DMF at 55 °C for 16 h gave 83% olefin: Kawashima,
T.; Ichii, T.; Inamoto, N. Chem. Lett. 1983, 1375-1378; ref 35.
(28) Kawashima, T.; Takami, H.; Okazaki, R. Chem. Lett. 1994, 1487-1490.
(29) Henning, H.-G.; Morr, M. Chem. Ber. 1968, 101, 3963-3968.
(30) Chloroform was found to be the ideal solvent, see Supporting Information.
(31) A similar observation was reported for DCC: Kawashima, T.; Nakamura,
M.; Nakajo, A.; Inamoto, N. Chem. Lett. 1994, 1843-1486.
(32) Mitsunobu conditions were equally effective, whereas other dehydration
reagents were not: P2O5, PPh3BrBr, and 2-chloro-N-methylpyridine iodide
in the presence of Et3N or 2,6-di-tert-butyl-4-methyl-pyridine.
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1822 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

A Horner−Wadsworth−Emmons Type Coupling Reaction
A R T I C L E S
Table 1. Phosphonate Alkylation, Saponification, and Elimination
Scheme 5
1
2
3
4
c
entry 19
R
R
R COR
yield 7a
saponificationb yield 10
1
2
3
4
5
6
7
19a C7H15 Me PhCH2CH2CHO 81%b 7a
A
A
B
55% 10a
59% 10b
54% 10c
10d
55% 10e
10f
19a C7H15 Me PhCHO
19a C7H15 Me cHexCHO
19a C7H15 Me Et2CO
84%b 7b
42% 7c
60% 7d A or B
19b
19c
19c
H
H
H
Me PhCH2CH2CHO 79% 7e
Et PhCHO
83%b 7f
Et PhCH2CH2CHO 86%b 7g
B
B
B
75% 10e
Scheme 6
a Isolated yields. b Saponification methods: A, MgBr2; B, NaOH.
c Isolated yields for two steps.
but the alkylation was less efficient when â-branching was
present (entry 3). Both the aromatic and the aliphatic â-hydroxy
phosphonates underwent saponification and elimination equally
well (entries 1-3). In contrast, ketone alkylation tended to be
less efficient, and the reaction with 3-pentanone afforded the
â-hydroxy phosphonate 7d in 42% yield (entry 4). Moreover,
the saponification of 7d caused disconcerting substrate decom-
position.33 The alkylation of commercially available methyl
dimethyl phosphonate 19b or ethyl diethyl phosphonate 19c with
aliphatic or aromatic aldehydes gave >79% yield in each case
(entries 5-7), but the user must be cautioned that the use of
low molecular weight phosphonates can be complicated by poor
solubility of the anion at low temperature. The reaction of ethyl
diethylphosphonate 19c (entries 6 and 7) illustrates that phos-
phonates easily accessible by Arbuzov13 reaction can also be
saponified for use in the coupling reaction. While alkylation of
the lower molecular weight phosphonates proceeded without
incident, the subsequent saponification proved problematic with
benzylic â-hydroxy phosphonates (entry 6). From the table, it
appears that in the absence of steric bulk or enolizable ketones,
high reaction efficiency is observed in the alkylation step.
However, these test substrates revealed that to avoid substrate
decomposition with certain benzylic â-hydroxy phosphonates,
milder saponification methods are required.33
For efficient yields in the aldehyde or ketone alkylation
reactions, it was necessary to perform the entire sequence at
-78 °C, including the final addition of a proton source to
neutralize the lithium alkoxide. At higher temperatures, Tis-
chenko type products34 were formed, along with vinylic phos-
phonates 24,16,35 especially with electron-rich aldehydes (Scheme
5). For example, with anisaldehyde, the redox products
p-MeOC6H4CH2OH (25) and p-MeO C6H4CO2H (26) were
isolated from reaction mixtures that were allowed to warm to
room temperature prior to a protic workup.
intermediated 27 followed by a stereospecific collapse to the
olefin. Moreover, this method resembles the powerful Horner
reaction in that the stereochemical purity of the olefin directly
correlates with that of the intermediate â-hydroxy phosphonate
that precedes the elimination. No detectable racemization
occurred during the saponification, and the more easily handled
diesters 7 can be separated instead of the highly hydrophilic
phosphonic acids.
In summary, the first general method for the stereospecific
dehydrative elimination of secondary, tertiary, and benzylic
â-hydroxy phosphonates has been developed. The intermediate
â-hydroxy phosphonates are fairly robust under neutral reaction
conditions, which may allow them to be carried intact through
a synthetic sequence before revealing the olefin. Alkyl dimethyl
or diethyl phosphonates, accessible from Arbuzov or Michaelis-
Becker reactions, can participate in the coupling reaction, and
no special functionality on the â-hydroxy phosphonate is
required for olefin formation.
Experimental Section36
Compound 19c was obtained from commercial sources and distilled
prior to use. Compounds 19a,37 19b,37 and 19d37 were prepared
according to literature procedures. Compounds 7 and 10 were prepared
by one of the following general methods.
â-Hydroxy-phosphonic Acid Dialkyl Esters 7 from 19. To a cooled
(-78 °C) solution of 19 (0.80 mmol) in THF (2.5 mL) was added
n-BuLi in hexanes (0.80 mmol). After being stirred at -78 °C for 15
min, the aldehyde (0.80 mmol) in THF (1 mL) was added. After 60
min at -78 °C, aqueous NH4Cl was added, and the mixture was
extracted with EtOAc. The organic layer was washed with brine and
dried over MgSO4. Purification by flash chromatography afforded 7
as a colorless oil.
Olefins 10 from 7. To a solution of 7 (1.1 mmol) in MeOH (5 mL)
was added 4 M NaOH (5 mL). After being stirred at room temperature
for 16 h, the reaction mixture was acidified to pH < 2 with 1 M HCl,
extracted with CH2Cl2, dried (MgSO4), and concentrated in vacuo. The
reaction residue containing crude 20 was dissolved in CHCl3 (5 mL)
and treated with DIC (2.2 mmol), and after being stirred at room
temperature for 4 h, the reaction mixture was concentrated in vacuo.
In most instances, the â-hydroxy phosphonates were obtained
as nearly 1:1 mixtures of syn and anti diastereomers. However,
when the stereochemically pure anti diastereomer of 7c was
saponified and eliminated under the standard reaction conditions,
the Z stereoisomer 10c was formed exclusively (Scheme 6). This
observation is consistent with formation of the oxaphosphetane
(33) The mild saponification of orthogonal protective groups will be reported
elsewhere. See: Reichwein, J. F.; Pagenkopf, B. L. J. Org. Chem. 2003,
68, in press.
(34) Ogata, Y.; Kawasaki, A. Tetrahedron 1969, 25, 929-935.
(35) Kawashima, T.; Ishii, T.; Inamoto, N.; Tokitoh, N.; Okazaki, R. Bull. Chem.
Soc. Jpn. 1998, 71, 209-219.
(36) For general experimental details, see: Reichwein, J. F.; Iacono, S. T.;
Pagenkopf, B. L. Tetrahedron 2002, 58, 3813-3822.
(37) Prepared via Arbuzov reaction analogously to: Ford-Moore, A. H.; Perry,
B. J. Org. Synth. Coll. Vol. 4 1963, 325-327.
9
J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1823

A R T I C L E S
Reichwein and Pagenkopf
Purification of the residue by flash chromatography afforded 10 as a
colorless oil.
Supporting Information Available: Table of solvents tested
for the elimination. Preparation and characterization data for 7,
10, and 19 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. We thank the DOD Prostate Cancer
Research Program DAMD17-01-1-0109, the Robert A. Welch
Foundation, and the Texas Advanced Research Program 003658-
0455-2001 for financial support.
JA027658S
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1824 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003