Horner-Wittig reactions

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... 

More recently, P-cored derivative (116) was prepared from a straightforward combination of a Heck coupling, to afford an intermediate functionalised stil-bene phosphine oxide (114),a Horner-Wittig reaction yielding the phosphine oxide (115), and finally trichlorosilane reduction (Scheme 31) [89]. Using similar strategies, both the valence isoelectronic N- (117) and C- (118) cored dendrimers have been prepared (Scheme 31). 

The Collins reagent in CH2CI2 oxidizes silylated primary alcohols in preference to the more hindered silylated secondary alcohols, as described for oxidation of the prostaglandin intermediate 2963 to the rather labile aldehyde 2964, which is immediately subjected to a Horner-Wittig-reaction to introduce the lower side chain [206] (Scheme 12.61). 

The Horner-Wittig reaction of a-phosphoryl sulphoxides 442, which are chemically stable, results in the formation of a, -unsaturated sulphoxides 443 in high yields (equation 264). The reaction has been found to be non-stereoselective, mixtures of E and Z isomers being formed from aldehydes and unsymmetrical ketones . In the case of aromatic aldehydes this reaction can also be advantageously performed in a two-phase catalytic system even without the usual PTC catalysts (Table 24). Intramolecular Horner-Wittig reaction of a-phosphoryl-5-oxosulphoxides 444 leads to a, -unsaturated cyclic sulphoxides 445 (equation 265). Starting from optically active 0,0-... 

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... 

Scheme 20.12 Enyne-allenes via the Horner-Wittig reaction.

The effect of catalysts on the stereochemistry of the Horner-Wittig reaction under liquid-liquid conditions has been studied by Mikolajczyk et al. (1975). The E/Z isomer ratios in the product [162] proved to depend on the catalyst... 

Halomethylpyridines have been used by Piechucki176 in a Horner-Wittig reaction under PTC conditions. 

Enamines are highly valued intermediates in organic synthesis. Almost invariably they are prepared by reaction of a carbonyl compound with a secondary amine. In principle, another attractive route to enamines could be based on construction of the double bond by a Wittig- or Horner-Wittig reaction. The enamines J thus obtained could be easily converted into the corresponding homologous aldehydes, if desired fitted with an extra electrophilic substituent at the original carbonyl carbon atom. 

Finally, we wish to report that the Horner-Wittig reaction has been extended to a-alkyl and a-aryl substituted a-aminomethylphos-phine oxides. After a facile hydrolysis, the homologous ketones are obtained in excellent yields (85-95%). 

With regard to the phosphorus stereochemistry, a new stereospecific synthesis of chiral 0,0-dialkyl thiophosphoric acids (6,7) has been developed which is based on the Horner-Wittig reaction of the optically active phosphonothionate carbanions containing the sulfoxide or dithioacetal moieties. The transformation of (R)-(+) 0-methyl 0-isopropyl methanephosphonothionate (10)(8) into (R)-(-) 0-isopropyl phosphorothioic acid (H) best Illustrates this method. 

Cyclocondensation of pipecolinic acid and malic acid anhydride in pyridine afforded 3-hydroxy-2,3-dimethylperhydropyrido[l,2-a]pyrazine-l, 4-dione (74CB2804). Cyclocondensation of bis(2,4,6-trichlorophenyl) mal-onates with 2-methyl-, 2-benzyl- and 2-ethoxycarbonylmethylquinoxalines and -3-ones at 250°C afforded 8-hydroxy-10//-pyrido[l,2-a]quinoxalin-10-ones and their 5,6-dihydro-6,10-dione derivatives (77M103). Under Horner-Wittig reaction conditions, the reactions of 2-formylquinoxaline and dialkyl phosphonosuccinates (314) also involved cyclization to give alkyl 10-oxo-10//-pyrido[l,2-a]quinoxahne-8-carboxylate (80LA542). 

DAST will not attack an oxygen atom bonded to phosphorus, so it can be used to prepare fluorophosphonates170, some of which are suitable for Horner-Wittig reaction (equation 94). 

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

The Horner-Wittig reaction has been applied to the synthesis of both aldehyde and ketone enamines. The substituted lithio aminomethylphosphonates (48, R1 = H, alkyl, aryl R2 = Me, Et, Ph R2N = MeNPh, morpholino) unite with aliphatic, aromatic and a,/ -unsaturated aldehydes or ketones to furnish the corresponding enamines235-245... 

The Horner-Wittig reaction of a phosphonium ylide with trifluoracetamides lead to a Z/E mixture of enamines254. A convenient synthesis of chiral enamines is described255. 

An intramolecular double Horner-Wittig reaction of dialdehyde 861 using NaOMe as base provides the naphtho-dithiophene 862 <2002BCJ1795>. 

The Horner-Wittig reaction of 1-substituted imidazole-2-aldehydes (304) gave intermediates (305) that cyclized to imidazo[l,2-a]pyridin-5-ones (306) (80LA542). 

Conjugated yne-2-ynylidene 1,3-dithioles 228 were synthesized via Wittig reactions of phosphonium salts 225 with 3-phenyl-substituted propargyl aldehydes 227 (R = H, = Ph). Diaryl-substituted derivatives 228 were prepared in Horner-Wittig reactions of phosphonates 226 with ketones 225 (R =R = Ph or -02NC6H4) (Equation 13) <2004CL1190>. 

The Horner-Wittig reaction of the carbanion generated from the phosphonate 232 with 2,5-diformylthiophene 233 afforded 1,3-dithiole derivatives 234 (Equation 15) <1997TL6107>. 

The 7t-extended 1,3-dithiole 237 containing a cycloproparene moiety was synthesized in the Horner-Wittig reaction involving the phosphonate carbanion derived from 235 and the benzoyl-substituted cycloproparene 236 (Equation 16) <2004EJ0138>. 

Synthesis of fused D-A systems such as 665 involved /-butyldiphenylsilyl protection of 4,7-dihydroxy-l,3-benzo-dithiole-2-thione 661, then the Horner-Wittig reaction of the resulting 662 with the carbanion derived from phosphonate 663 and finally deprotection of the TTF 664 to the required 665, obtained as green crystals (Scheme 94) <2003AG2871, 2004JOC2164>. 

The unsymmetrical aza-analogues of 7t-exTTFs with linear nitrogen-containing spacers were synthesized in the aza-Horner-Wittig reaction of A-(diethoxyphosphoryl)hydrazones 859 derived from l,3-dithiol-2-one, with formyl group-terminated 1,3-dithioles 860 and 861. The hydrazone 859 was prepared in the reaction of diethoxyphosphoryl hydrazine with the dithiolium cation 858 (Scheme 129) <2004TL8211>. 

The phosphonate 881 was also used in a Horner-Wittig reaction with di- and tricarbonyl compounds 883-885, containing thiophene spacer units, affording bis- and tris-(l,3-dithiole) donors 886 and 887, respectively (Scheme 133) <1995H(40)123, 1995CC557, 1997H(44)263>. 

Lithiation with LDA of trimethyl derivative 924, obtained via the Horner-Wittig reaction of 922 with 923, and subsequent reactions with various electrophiles afforded a range of functionalized 9,10-bis(l,3-dithiol-2-ylidene)-9,10-dihydroanthracene derivatives 925-929, which contained reactive functional groups attached to only one of the 1,3-dithiole rings (Scheme 140) <1999TL3271, 2000EJ051>. 

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