Wittig-Horner elimination

The cyclopropylphosphonate anion undergoes the stereoselective addition reaction with aldehydes [106]. Although the Wittig-Horner elimination is not observed at this stage, the olefinic compounds are produced by treatment of the adduct alcohols 201 with NaH in the presence of 18-crown-6 as illustrated in Scheme 76. 

Allylic diphenylphosphine oxides undergo 1,3-dipolar cycloadditions with nitrile oxides to give A -isoxazolines (70) with ann -preferred stereoselectivities of up to 5 1.37 Separate reduction of y -and anti-(70) to the hydroxy amines (71), followed by Wittig-Horner elimination provides stereoselective syntheses of the homoallylic amines (72) (Scheme 9). A study of the effect of substituents on phosphorus on the diastereoselectivity in the cycloaddition of nitrones to vinylphosphine oxides (73) and sulphides (74) has been reported.38 In certain cases diastereoselectivities of >90% were achieved. 

Alternatively it is possible to have both steps, addition and elimination, occur spontaneously if appropriate reagents are employed. There are two common strategies in use the Wittig reaction and the Wittig-Horner reaction. The Wittig olefination uses a phosphorus-stabilized carbanion (ylid) as a nucleophile and a carbonyl compound as an electrophile. Typically the ylid is generated in situ from a triphenylphosphonium salt and a strong base such as LDA or an alkyl lithium. 

Fig. 11.11. Wittig-Horner synthesis of stereouniform alkenes via ketophosphine oxide B. The reaction proceeds via its Felkin-Anh-selective or chelate-controlled reduction to form the syn-configured hydroxyphosphine oxides D and the anti-configured hydroxyphosphine oxides E. D and E continue to react—after deprotonation with KO-tert-Bu—via a syn-elimination to give the trans- and cis-alkene, respectively. R1 in the formula A-C corresponds to a primary (prim-alkyl) or a secondary alkyl residue (sec-altyl).

Another variation of the Wittig reaction is the Wittig-Horner reaction, in which the anion generated ot- to phosphine oxide is used as a nucleophile to react with carbonyl compounds. The intermediate formed in this reaction, -hydroxyphosphine oxide, is isolable particularly when bases with lithium counterion are used for deprotonation. Since the j6-hydroxyphosphine oxides are diastereomers, they can be separated and subjected to elimination to form the corresponding alkenes. Since the elimination of phosphonate moiety is syn, stereospecific alkenes are obtained from the elimination step. As expected, the generation of erythro and threo isomers is dependent on the solvent and the reaction conditions. 

The Wittig-Homer reaction between C-metallated a-phosphoryl sulfides and carbonyl compounds provides a common route to a,P-unsaturated sulfides, but one which usually results in poor yields of the desired product when enolisable ketones are used. Stephan et al. have investigated the role of boron trifluoride in promoting the Wittig-Horner reaction of enolisable ketones, which usually follows a two-step process the initial condensation of the anion followed by an elimination step. It was found that when the second step occurred at a slow rate then addition of boron triflouride was necessary for completion. ... 

Asymmetric Wittig-Homer reactions Wittig-Horner reactions have usually involved phosphine oxides, phosphonates, or phosphonamides. Highly enantioselective ole-finations have now been achieved by use of this chiral phosphonamidate 1. Thus the anion (/-BuLi) reacts with 4-/-butylcyclohexane to form 2 in >98% de. Elimination with trityl triflate/2,6-lutidine provides the alkylidene 3 with essentially complete stereospecificity. The reaction was shown to be applicable to a variety of 4-aIkylcyclohexanones. 

Ubukata s synthesis [51] started with ammonolysis followed by Swern oxidation of ( )-55 [52] to give nitrile aldehyde 56. Wittig-Horner reaction of 56 with phosphonate 58 derived from glutarimide acetic acid 57 [27] gave 59. The nitrile was converted to amide 60, which was subjected to selenolac-tamization [53] to afford 61. Oxidation-elimination of the selenenide moiety gave 48 a diastereomeric mixture. 

Heterocyclic sulphoxides 65 mass spectra of 130-132 Hexahydronaphthalenols, synthesis of 310 Hofmann elimination 953 HOMO energies 1048, 1049 Homolytic substitution 1109 intramolecular 846 Horner-Wittig reaction 333 Hot electrons 892, 893 HSAB theory 282, 549 Hydrides, as reducing agents 934-941, 959 Hydrogen abstraction, photochemical 874, 876, 877, 879, 880... 

Carbanions derived from phosphine oxides also add to carbonyl compounds. The adducts are stable but undergo elimination to form alkene on heating with a base such as sodium hydride. This reaction is known as the Horner-Wittig reaction.268... 

The unique feature of the Horner-Wittig reaction is that the addition intermediate can be isolated and purified, which provides a means for control of the reaction s stereochemistry. It is possible to separate the two diastereomeric adducts in order to prepare the pure alkenes. The elimination process is syn, so the stereochemistry of the alkene that is formed depends on the stereochemistry of the adduct. Usually the anti adduct is the major product, so it is the Z-alkene that is favored. The syn adduct is most easily obtained by reduction of (3-ketophosphine oxides.269... 

Warren and coworkers have reported an interesting synthesis of nonracemic allenes by reaction of vinylphosphine oxides with aldehydes in the presence of chiral lithium [(R)-l-phenylethyl](benzyl)amide to give hydroxyvinylphosphine oxides in 33-87% yields (0-51% ee) [38]. These products underwent a Horner-Wittig elimination reaction to produce nonracemic allenes. A mechanism similar to the Baylis-Hillman reaction was suggested. 

Horner-Wittig modification Alternatively, phosphine oxide reacts with aldehydes in the presence of a base (sodium amide, sodium hydride or potassium t-butoxide) to give an alkene. The phosphine oxide can be prepared by the thermal decomposition of alkyl-triphenylphosphonium hydroxide. Deprotonation of phosphine oxide with a base followed by addition to aldehyde yields salt of (3-hydroxy phosphineoxide, which undergoes further syn-elimination of the anion Ph2P02. The lithium salt of (3-hydroxy phosphineoxide can be isolated, but Na and K salt of (3-hydroxy phosphine oxide undergoes in situ elimination to give alkene (Scheme 4.26). 

When the halogen compound employed in the first step has an activated halogen atom (RCH CHCHjX, QHjCHjX, XCH2CO2H) a simpler procedure known as the Horner phosphonate modification of the Wittig reaction is applicable. When benzyl chloride is heated with triethyl phosphite, ethyl chloride is eliminated from the initially formed phosphonium chloride with the production of diethyl benzylphosphonate. This phospho-... 

Starting from (+)-diethyl tartrate (2), bromobutenolide 18 was obtained in nine steps. Three of the four C=C double bonds were built up using a Wittig reaction (11—>12), an Ando- y Q Horner-Wadsworth-Emmons reaction (13— 15) and (3-elimination (16 18). From (-)-actinol (3) stannane 23 and sulfone 24 were synthesized in 9 and 13 steps, respectively. Their common intermediate, alkyne 22, was synthesized using methoxycarbonylation. Sharpless asymmetric epoxidation and Ci-elongation with lithio trimethylsilyldiazomethane. Stannane 23 was obtained upon hydrostannylation and TBS deprotection. Sulfone 24 was obtained after addition to methyl tetrolate, reduction, Mukaiyama redox condensation, acetylation and catalytic oxidation. 

Warren and co-workers continue to develop the use of phosphine oxides, and the Horner-Wittig elimination, to control the stereoselectivity of organic reactions ... 

Other y-bromoesters such as 31 can be made by radical bromination13 with NBS (this too is a y reaction ) and used in similar Horner-Wadsworth-Emmons reactions. It does not matter if some reaction occurs at the y position of 29 or 33 as the Wittig elimination cannot occur on such an intermediate and it reverses. The products of these aldol reactions are dienes 30 and 34 and are usually made for use in Diels-Alder reactions. We shall return to this subject later in this chapter. 

The reduction of a-phosphorus-substituted ketones of the general form 7 has also been quite thoroughly researched (Table 7 84i -84s. The product alcohols arc intermediates in Horner -Wittig type alkene syntheses, and can be induced to undergo stcreospecific syn elimination on conversion to the corresponding sodium or potassium (but not lithium) alkoxides. It is often possible to purify the alcohols by crystallization, allowing the synthesis of stereochemically homogeneous alkencs. 

An advantage of the Horner-Wittig reaction is that the two diastereomeric P-hydroxy phosphine oxides are stable, isolable compounds and can be separated. The elimination step is stereospecific, such that one diastereomeric P-hydroxy... 

Synthesis of Vinyl Sulfides. Treatment of furanoses with anion 2 induced the ring-opening reaction via addition to the aldehyde of the omega hydroxy aldehyde in equilibrium followed by the rapid elimination of the /8-hydroxysilane which afforded vinyl sulfides (eq 12) in moderate yields (50-61%) with poor stereoselectivity (ElZ 2 3). Alternatively, modified Horner-Wittig reactions afforded the desired products in much higher yields (72-100%) with improved selectivity for the E-stereoisomer (E/Z, as high as 17 1). 

The problem of directing Wittig and Horner reactions to both the ( )- and the (Z)-olefins has found a variety of solutions. One is the use of phosphine oxides as the donor component (Scheme 3.85) [137]. Thus, 445 was deprotonated and then treated with acetaldehyde to give the erythro-adduct 446 with d.r. 3 1. After separation, base-catalyzed syn-elimination of phosphinate gave (Z)-olefin 449. On the other hand, 445 was deprotonated and acylated to give ketone 447, which was then reduced with sodium borohydride to give the threo-isomer 448 with d.r. 3.5 1. Separation/syn-elimination generated the ( )-olefin 450 selectively. 

As mentioned above, the use of lithium bases in the HW reaction allows the reaction to be divided into two discrete steps [39] 1) the HW addition of a lithiated phosphine oxide to an aldehyde (or ketone) to produce a j8-hydroxy phosphine oxide, and 2) the HW elimination of a phosphinic acid to afford an alkene (Scheme 1.14). Careful manipulation of each step then allows control of the overall sequence. While the overall mechanism of the Horner-Wittig reaction is similar to that of the HWE reaction (Scheme 1.6), some additional discussion is required to understand its stereochemical outcome. The HW reaction can be carried out without isolation of the intermediate yS-hydroxy phosphine oxides in cases where a nonlithium base is used and is able to stabilize the negative charge of the phosphorus a-carbanion 9. Under these conditions, reaction of an aldehyde with the phosphine oxide to give intermediates 10 and 11 is reversible. The -alkene is then formed preferentially since elimination of intermediate 11 occurs much faster than that of 10. 

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