Wittig reaction of aldehydes

Oxidative coupling55 of the acetylenic alcohol 146 under Eglinton conditions followed by acidic treatment of the product gave the aldehydes 147 (37%) and 148 (8%). Wittig reaction of aldehyde 147 and the bisphosphonium salt 120 with 1,5-diazabicyclo[4.3.0]non-5-ene as base gave the [21]annulenone 149. This on reduction with lithium aluminium hydride-aluminium chloride gave the homoannulene... 

Wittig reaction of aldehyde 148, followed by in situ intramolecular Diels-Alder reaction of intermediate 149 and desilylation, afforded eunicellin analogues 150 and 151 as 3 1 mixture (Scheme 27) <2004SL1434>. 

A Wittig reaction of aldehyde 1292 with the ylide prepared from triphenylphosphonium bromide 1293 and lithium diisopropylamide gave an ( )/(Z) mixture (1 1, when R = Me, and 5 3, when R = PhS02) of 3-(2-arylethenyl)-l//-indoles 1294 in 70-86% yield (Equation 286) <1999T4341>. 

We later published an improved synthesis of tonkinecin because of the low yield of the coupling reaction between 11 and 12 (only 30% previously) in a previous study. One major reason is that the vinyl iodide 12 was not stable enough to survive the basic reaction conditions. An alternative for the synthesis of right-side segment was then designed, in which the vinyl iodide functionality was introduced in the last step to avoid those basic conditions (Scheme 10-7). The Wittig reaction of aldehyde 15 with 16 and subsequent hydrogenation afforded ester 17, which was converted to lactone 18 by aldol reaction with lactal followed by acid treatment and [(-elimination. Selective deprotection, Dess-Martin oxidation, and Takai reaction (to introduce the vinyl iodide) afforded the precursor 19. Similar treatments of 19 with 14, as well as subsequent intermediates as described previously, finally provided tonkinecin. 

Currently accepted mechanism of the Wittig reaction of aldehydes with non-stabilized ylides involves the formation of oxaphosphetanes through a [2-I-2]-cycloaddition-like reaction . The oxaphosphetanes are thermally unstable and collapse to alkene and phosphine oxide below room temperature. Under salt-free conditions there is no formation of betaine intermediates. The salt-free ylides can be prepared by the reaction of phosphines with carbenes generated in situ. Vedejs etal proposed a puckered 4-centre cyclic transition state I for sy -oxaphosphetane and planar structure J for anff-oxaphosphetane. In general, the flnfi-oxaphosphetane J is more stable than the syn-oxaphosphetane I, and under equilibrium conditions (when stabilized ylides are used) the E-alkene product is favoured (Scheme 4.24). However, kinetic control conditions, which appear to dominate when non-stabilized ylides are used, would lead to Z-alkene. 

An improved synthesis of glutinosone (1) was also accomplished by Masamune and coworkers6 and this was based on procedure developed by Dastur7,8 for the synthesis of sesquiterpenes nootkatone. (Scheme 2) Diels-Alder reaction of 3,6-dihydro-3,5-dimethyl anisole with methyl acrylate in absence of Lewis acids afforded a 1 3 mixture of esters (17) and (18) which were converted to a,(3-unsaturated aldehydes (19) in 77% yield by oxidation with selenium (IV) oxide in dioxane. Wittig reaction of aldehydes under the usual condition yielded the dienes (20) in 63% yield which on being subjected to Grignard reaction with an excess of methyllithium produced tettiary alcohols (21) in quantitative yield. This on treatment with formic acid at room temperature gave bicyclic enone (22) and its formate (23) in 45% and 41% yield respectively. Formates (23) were hydrolyzed to enone (22) in 88% yield. 

The mechanistic studies discussed so far deal with the Wittig reactions of aldehydes and nearly always focus on the stereochemical aspects of 1,2-disubstituted alkene synthesis. By comparison, little is known regarding... 

For example, this EGB promotes Wittig reaction. Because azobenzene is electrochemically reduced at —0.9 V (Ag/AgCl), Wittig reaction of aldehyde and phosphonium salt in the presence of azobenzene under the constant voltage reduction at —0.9 V smoothly proceeds to give the corresponding product (Eq. 11) [4]. 

In a shorter synthesis of dihydrexidine [9], synthetic intermediate 51 was obtained via an FC reaction of a chiral aziridine intermediate 60 (Scheme 2.8). Styrene 58 was prepared from a Wittig reaction of aldehyde 57 as a mixture of diastereomers ( 7Z=78 22) and treated with PhINNs in the presence of the BOX ligand 59 and Cu(OTf)2. It was found that Cu(OTf)., was a dual catalyst for the enantioselective aziridination and FC reaction. The E/Z mixture of styrenes 58 provided exclusively tran5-2-amino-l-phenyltetralin 51 in 87% ee, which could be increased up to 99% after crystallization. The c/s-cyclized product was not detected. 

Sharpless asymmetric epoxidation afforded epoxide 167 in 76% yield. Lindlar reduction, followed by oxidation with Collins reagent, yielded aldehyde 168. A Wittig reaction of aldehyde 168 with the ylide 169 gave the homoallylic alcohol 171 after deprotection of 170 under acidic conditions. Alcohol 171 was converted into the corresponding iodide and reacted with triphenylphosphine to provide phosphonium salt 172. 

Extensive studies have shown that phosphonium ylides are readily generated in situ from triphenylphosphine and a-diazo carbonyl compounds through carbene transfer in the presence of a catalytic amount of a metal complex derived from Re [124-126], Ru [127-130], Ir [131], Fe [132-137], Cu [138, 139], or Co [140, 141] (Scheme 29). The conditions for carbene transfer are well compatible with aldehydes and ketones, and the metal catalyzed one-pot Wittig reaction of aldehydes (or ketones) with a-diazo carbonyl compounds proceeds smoothly to give electron-deficient alkenes with high E selectivity. 

A variety of functionalized alkenes has been directly obtained with E selectivity from the Homer-Wittig reaction of aldehydes (or ketones) with phosphine oxide-stabilized carbanions bearing in the a position certain functional groups such as aryl [197], vinyl [198-200], cyano [201], sulfonyl [202], isoxazole [203], amino [204], or alkylthio [205]. The functional group provides stabilization for the negative charge of the p-oxido phosphine oxide intermediate and lowers the activation energy for the elimination step to form an alkene (Scheme 42). 

A related example disclosed recently by McNulty et al. is a one-pot Wittig reaction of aldehydes with phosphonium salts in the presence of 10 mol% of morpholine, L-proline or p-toluenesulfonamide and 2.0 equiv. of NaHCOs (Scheme 55) [227]. This reaction gives high E selectivity. A rapid and reversible condensation of the aldehyde with the amine (derivative) catalyst has been proposed to form an iminium or an imine intermediate that is subjected to olefination with the in situ generated phosphonium ylides, though a base-catalyzed pathway is not ruled out. It has been confirmed that an N-sulfonyl imine can be formed quantitatively from the corresponding aldehyde and sulfonamide under the reaction conditions. 

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