Horner- Emmons reaction

The reaction has been extended to include carbanions generated from phosphonates. This is often referred to as the Horner-Wittig or Homer-Emmons reaction. The Horner-Emmons reaction has a number of advantages over the conventional Wittig reaction. It occurs with a wider variety of aldehydes and ketones under relatively mild conditions as a result of the higher nucleophilicity of the phosphonate carbanions. The separation of the olefinic product is easier due to the aqueous solubility of the phosphate by-product, and the phosphonates are readily available from the Arbusov reaction. Furthermore, although the reaction itself is not stereospecific, the majority favor the formation of the trans olefin and many produce the trans isomer as the sole product. 

Alkylation of cyanohydrin acetonide 79 with the iodide 78 proceeded smoothly to give pentaacetonide 80 in 70% yield (Scheme 10). This represents the entire polyol framework of roflamycoin. An eight-step sequence involving installation of the polyene, macrocyclization via Horner-Emmons reaction, and protecting group machinations, completed the first total synthesis of roflamycoin. 

The synthetic P-o-glucopyranoside 30 was converted to the cyanoglucoside rho-diocyanoside A (38a), which was isolated from the underground part of Rhodiola quadrifida (Pall.) Fisch. et Mey. (Crassulaceae) and found to show antiallergic activity in a passive cutaneous anaphylaxis test in rat. Acetylation of 30 gave an acetate (98% yield) which was subjected to ozonolysis to afford the aldehyde 39. The Horner-Emmons reaction of 39 using diethyl (l-cyanoethyl)phosphonate furnished (Z)-40a (32% yield from 30) and ( )-40b (10% yield from 30). The physical... 

The synthetic 31 was converted to the cyanoglucoside osmaronin (41a) which was isolated from a methanolic extract of the leaves of Osmaronia cerasi-formis. Acetylation of 31 gave an acetate (99% yield) which was subjected to ozonolysis to afford a ketone 42. The Horner-Emmons reaction of 42 using diethyl cyanomethylphosphonate furnished (Z)-43a (22% yield from the acetate of 31) and ( )-43b (10% yield from the acetate of 31). Deprotection of (Z)-43a and ( )-43b gave the (3-D-glucosides 41a (83% yield) and 41b (94% yield), respectively. The spectral data of the synthetic 41a were identical with those ( H- and C-NMR) of the natural osmaronin (41a) (Fig. 5). 

OS 79] ]R 17] ]no protocol] 4-Methoxybenzaldehyde and methyl diethoxyphos-phonoacetate were reacted by means of the Wittig-Horner-Emmons reaction [85] (see a more detailed description in [42]). A modified micro reaction system consisting of two mixers, for deprotonation of the phosphonates and introduction of the aldehyde, connected to an HPLC capillary of 0.8 m length and 0.25 mm diameter was employed. The micro reactor showed higher yields than laboratory batch synthesis. 

An intramolecular cycloaddition also occurred with 3-ylidenepiperazine-2,5-diones such as 124 or 125, obtained by Wittig-Horner-Emmons reaction from phosphonate 121 and aldehydes 122 or 123, respectively. The products of the Diels-Alder reaction are the bridged bicyclo[2.2.2]diazaoctane rings 126 and 127 that have been found in biologically active secondary metabolite such as VM55599 and brevianamide A. The different type of structures employed in this case requires a chemoselective reaction in order to produce the expected products as single diastereoisomers after 20 days (Scheme 18) <2001JOC3984>. 

Only a few reactions of the substituents attached to ring carbon atoms of bicyclic systems 1-34 have been reported. Methylation of compound 100 occurs at sulfur to give 101 (Equation 6) <2005BMC1847>. Horner-Emmons reaction of phosphonate 102 with benzaldehyde leads to triazole 103 as a single /. -stereoisomer (Equation 7) <2004TL1877>. 

A variant of the Horner-Emmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins. 

An interesting example of biocatalysis and chemical catalysis is the synthesis of a derivative of y-aminobutyric acid (GABA) that is an inhibitor for the treatment of neuropathic pain and epilepsy (Scheme 10.4). The key intermediate is a racemic mixture of cis- and trons-diastereoisomer esters obtained by a hydrogenation following a Horner-Emmons reaction. The enzymatic hydrolysis of both diaste-reoisomers, catalyzed by Candida antarctica lipase type B (CALB), yields the corresponding acid intermediate of the GABA derivative. It is of note that both cis- and trans-diastereoisomers of the desired enantiomer of the acid intermediate can be converted into the final product in the downstream chemistry [10]. 

E)-and (Z)-fluoroolefin analogs (44) (R = 2-phenylethyl, 1-adamantyl, 4-fluorobenzyl) of potent DPP IV inhibitors were synthesized utilizing the Wadsworth-Horner-Emmons reaction. The use of sodium hydride as the base in the Wadsworth-Horner-Emmons transformation was central to achieving useful yields of 45 in this reaction (74%). Following amide (46) formation and reduction, the desired a-fluoro-a, S-unsatu-rated amine functionality 47 was revealed [60,61] (Scheme 16). 

Fluorofuranose precursors are prepared via Horner-Emmons reaction on L-glyceraldehyde acetonide (Figure 6.11). Due to the allylic position of the base, these compounds are much more unstable than the related saturated molecules (cf. Figure 3.17, Chapter 3). The presence of the fluorine atom enhances the hydrolytic stability of these compounds. Some of these molecules have good antiviral activities on infected cells. 

Similar applications to those reported in CHEC-II(1996) have been described for more elaborate phosphonate esters 42 and 43 which undergo Horner-Emmons reactions with carbonyl compounds following deprotonation <2000EJ051, 2002CL1002>. 

With respect to the coupling reactions of stannylthiazoles with aryl halides, the union of 4-chlorobromobenzene and 2-tributylstannylthiazole constructed arylthiazole 53 [37], The Stille reaction of 3-bromobenzylphosphonate (54) and 2-tributylstannylthiazole led to heterobiaryl phosphonate 55, which may be utilized as a substrate in a Wadsworth-Horner-Emmons reaction or a bioisosteric analog of a carboxylic acid [38]. The phosphonate did not interfere with the reaction. In addition, the coupling of 5-bromo-2,2-dimethoxy-l,3-indandione (56) and 2-tributylstannylbenzothiazole resulted in adduct 57, which was then hydrolyzed to 5-(2 -benzothiazolyl)ninhydrin [39]. 

One method for preparing imidazolylstannanes is direct metalation followed by treatment with RaSnCl [21]. l-Methyl-2-tributylstannylimidazole, derived in such manner, was coupled with 3-bromobenzylphosphonate (26) to furnish heterobiaryl phosphonate 27 [22]. Under the same reaction conditions, 4-bromobenzylphosphonate led to the adduct in 69% yield, whereas only 24% yield was obtained for 2-bromobenzylphosphonate. The low yield encountered for the ortho derivative may be attributed to the steric factors to which the Stille reaction has been reported to be sensitive [23], Heterobiaryl phosphonates such as 27 are not only substrates for the Wadsworth-Horner-Emmons reaction, but also bioisosteric analogs of the carboxylic acid group. 

A-Ethyl(diethylphosphono)methylketenimine, readily prepared from the amide, is of value as an annelating reagent (79CC900). The sodium salt of salicylaldehyde reacts at the activated central carbon atom of the ketene and a subsequent intramolecular Horner-Emmons reaction results in cyclization to the chromene. 

Few preparations of nitriles have been performed on insoluble supports (Table 13.19). Aromatic and heteroaromatic nitriles have been prepared on solid phase from the corresponding iodoarenes by metallation followed by reaction with tosyl cyanide (Entry 1, Table 13.19). Moreover, the reaction of chloromethyl polystyrene with NaCN has been used to prepare support-bound benzyl cyanide (Entry 2, Table 13.19). Cleavage with simultaneous formation of nitriles can be achieved by treating polystyrene-bound sulfonylhydrazones with KCN (Entry 3, Table 13.19) or by cleaving amides from a Rink or Sieber linker with TFA anhydride (Entry 10, Table 3.38 [262]). Support-bound benzaldehydes have been converted into 3-aryl-2-propenenitriles by means of a Horner-Emmons reaction with (Et0)2P(0)CH2CN [263]. 

Sulfanylalkanoyl amino acids and peptides are prepared by reaction of the (acetyl-sulfanyl)- or (benzoylsulfanyl)alkanoic acids or acid chlorides with a-amino esters or peptide esters, followed by deprotection of the sulfanyl and carboxy groups. 8 101114 16 27 29 For example, the 3-(acetylsulfanyl)alkanoic acids 7 are prepared from the condensation of ethyl (diethoxyphosphoryl) acetate 5 with various aldehydes according to the Horner-Emmons reaction, providing the a, 3-unsaturated ethyl esters 6 (a mixture of Z- and E-isomers, 50 50), followed by saponification of the ethyl esters and Michael addition of thiolacetic acid. The 3-(acetylsulfanyl)alkanoic acids 7 can be coupled with a-amino esters or peptide esters and subsequent hydrolysis of the 3-(acetylsulfanyl) derivatives provides the desired products 8 (Scheme 2). 14 ... 

Only one method has been used to prepare peptide vinyl sulfones. N-Terminal protected peptides are reacted with the salts of amino acid vinyl sulfones derived from the Horner-Emmons reaction of N-terminal protected aldehydes with sulfonylphosphonates in the presence of a base. 4 5 ... 

Horner-Emmons Reaction of Aldehydes with Sulfonylphosphonates... 

Horner-Emmons reaction of N-terminal blocked aldehyde 1 with sulfonylphosphonates in the presence of sodium hydride gives the amino acid vinyl sulfone 2, which is deprotected with acid and converted into its chloride or tosylate salt 3 and coupled by the mixed anhydride method with an N-terminal protected peptide or amino acid to give the desired peptide vinyl sulfones 4 (Scheme 2). 4 5 N-Terminal protected aldehydes 1 are obtained from reduction of Boc amino acid V-methoxy-A-methylamides (Weinreb amides, see Section 15.1.1) by lithium aluminum hydride. 9 The V-methoxy-V-methylamide derivatives are prepared by reaction of Boc amino acids with N,O-dimethylhydroxylamine hydrochloride in... 

In the Horner-Emmons reaction (Scheme 3), the sulfonylphosphonate carbanion 5 is formed in the presence of NaH and then reacts with an aldehyde to produce the intermediate 6 that undergoes in situ elimination to yield the vinyl sulfones and phosphonate anion. The sulfonyl group can stabilize the anion in the sulfonylphosphonate 5. The vinyl sulfones that are produced by this method using aldehydes as starting materials are exclusively the E (trans) isomers. The E-isomers of the vinyl sulfones are shown in the NMR spectra based on the coupling constants of the vinylic protons. Although strongly basic conditions are used in the Horner-Emmons reaction and a-amino aldehydes are easily racemized, the amino acid vinyl sulfones prepared by this method still show substantial optical activity. However, the enantiomeric purity of these compounds has not been determined. 5 ... 

Scheme 3 Peptide Vinyl Sulfones by the Horner-Emmons Reaction...

Nowick and Danheiser have employed the Horner-Emmons reaction of a-phosphon-oacyl silanes to prepare a,/l-unsaturated acyl silanes in 54-97% yields116. The a-phosphonoacetyl silane intermediate (21), prepared from a-iodoacetyl t-butyldimethylsilane through the Arbuzov reaction, undergoes enolate alkylation, for example using potassium t-butoxide and methyl iodide the alkylated products also underwent Horner-Emmons reaction (Scheme 53). 

The synthetic method (a) is the regioselective reduction of an a,/ -unsaturated aldehyde or ketone (Section 5.18.2, p. 798), which is most conveniently effected by the Meerwein-Ponndorf-Verley procedure (Section 5.4.1, p. 520). The further disconnection shown of the a, -carbonyl compound is a retro-aldol condensation (Section 5.18.2, p. 799) however it should be emphasised that other routes to the unsaturated carbonyl compound, such as the Horner-Emmons reaction (Section 5.18.2, p. 799), may also be feasible. 

Kawashima, T. Nakamura, M. Inamoto, N. Tandem Peterson—Michael reaction using a-silylalkylphosphine chalcogenides and Horner—Emmons reaction of in situ generated a-carbanions of its products. Heterocycles 1997, 44, 487-507. 

Seyden-Penne and co-workers45 studied the Horner-Emmons reaction at conjugated carbonyls. They found that 1,4-additions are irreversible whereas 1,2-additions are reversible, more so with Li than K enolates. Explain these results. 

---