Wittig olefination derivative

Napamezole (68) is a dihydroimidazole derivative with antidepressant activity probably as a result of its combined a 2 adrenergic receptor blockuig and serotonin uptake blocking proper ties It can be synthesized by Wittig olefination of p-tetralone (65) with diethyl (cyanomethyl) phosphonate (66) and base to give nitnle 67 Imidazoline construction on the latter was smoothly... 

The N-alkylation of a range of 2-benzoyl-3-alkylaziridines 98 with rert-butyl bromoacetate followed by Wittig olefination gave directly piperidine derivatives 99 <95JCS(P1)2739>. 

Carbohydrate derivatives with a spiroisoxazoline moiety, present in psammap-lysins and ceratinamides (metabolites isolated from marine sponges) have been prepared in good yields and excellent regio- and diastereoselectivity by a route involving Wittig olefination and 1,3-dipolar cycloaddition as key steps (477). 

Among the rare reports of chemical transformation of substituents attached to the ring, the total reduction of an aromatic ketone linked at C-l (lithium aluminium hydride (LAH)), then Et3SiH/trifluoroacetic acid (TFA), overall yield 20%) is of interest <1998H(48)1015>. One example related to Wittig olefination of the 1-formyl derivative of the parent heterocyle was reported to occur in low yield <2001CPB799>. 

The Wittig olefination of the tricyclic y-oxo ester 231f affords the 6-methylene tricycle 244. Treatment of the latter with diluted hydrochloric acid results in the formation of the 6-methyl-2-oxobicyclo[3.2.1]oct-6-ene derivative 240f in 94% yield (Scheme 70) [106,108]. This transformation maybe realized also in a one-pot procedure giving compound 240n in 70% yield (Scheme 70) [104b]. The overall yield in the step-by-step preparation of this compound, as shown in Schemes 65 and 68, was only 55% starting from the chloro ester 1-Me. 

Rauter and coworkers demonstrated that C-5-aIkylidene derivatives 112 of D-hexofuranurono-6,3-lactone can be obtained by Wittig olefination of the a-ketolactone 111 (Scheme 32) [160]. The related a-methylene lactone 114 was prepared in three steps from 3,6-anhydro-l,2-0-isopropylidene-a-D-j y/ )-5-hexulo-furanose 113 via Wittig reaction and aUylic oxidation. 

A pentopyranoside-fused butenolide is the key intermediate for the synthesis of the natural micotoxin patulin [226, 227]. Its synthesis involves Wittig olefination of a 3,4-di-O-protected arabinopyran-2-uloside, followed by protecting group removal and dehydration (Scheme 47). In other research, the glucopyranosid-2-uloside 190 was converted into the butenolide derivative 191 by aldol condensation with diethyl malonate and transesterification [228]. The latter was shown to be prone to autoxi-dation, leading to 192. Subsequent Michael addition with hydroxide ion, followed by decarboxylation, furnishes C-branched-chain sugar 193. 

Retrosynthetic considerations reveal an approach (Scheme 1.2.6) in the first step based on disconnections of the C -Cy and C12-C13 double bonds. Those can be built up using highly B-selective Wittig olefinations between allyltributylphos-phorous ylides derived from the corresponding allylic bromides 29 and 31 [31]. The aldehyde 30 is accessible from the keto ester 33, which can be prepared in high enantiomeric purity by a biocatalytic enantioselective reduction of a... 

Octoses.1 A new route to octoses involves catalytic osmylation (7, 256-257) of allylic alcohols derived from a hexose by Wittig olefination to introduce two... 

The ylid character of X5-phosphorins and their Cr(C0)3 complexes again is evident when one or both groups on phosphorus are CHR2 as one can abstract a+ protpn giving a carbanion. Reaction with electrophiles (e.g. D, CH3, and RCHO) causes side chain addition. No Wittig olefination is found with aldehydes. Instead a 1(2 -hydroxy) product 9 is formed which can be dehydrated to the X5-phosphorin derivative 10. 

Lactone 7 (derived from D-isoascorbic acid) reacted readily with the aryllithium formed from bromide 8 to produce lactol 9 (Scheme 16.3). The latter underwent a facile ring-opening and Wittig olefination with methylenetriphenylphosphorane to give 6 in excellent overall yield. After 0-trifLation, a two-carbon chain extension was performed on 10 with the azaenolate derived from A-cyclohexylacetaldimine 11 and lithium diisopropylamine (LDA). After acid hydrolysis of the product imine, aldehyde 12 was isolated in 83% yield for the two steps. The (2-azaallyl)stannane 5 was prepared from aldehyde 12 in quantitative yield by treatment with (aminomethyl)tri-n-butylstannane. 

For the synthesis of a heptanal derivative 30 (D in the retrosynthesis) from 19, we investigated two different approaches. The first approach relied on the Wittig olefination of aldehyde 25 (Scheme 3). The second was based on the attack of 2-lithio-2-methylpropionitrile (a-lithiated isobutyronitrile) [56-60] on the Payne rearrangement product 20 (Scheme 4). Our original attempt at the preparation of heptanal 30 from... 

In the pioneering work by Wilcox and Gaudino, a straightforward route to the carbocyclic analogue of D-fructofuranose, 64, and its 6-phosphate derivative was delineated [14a,b]. As shown in Scheme 9, the first move consisted of Wittig olefination of benzyl-protected arabinose 60 with carboxy-tert-butylmethylene triphenyl phosphorane to deliver unsaturated ester 61, which was then cleverly elaborated into dibromide 62 via a reaction cascade encompassing Swem oxidation of the secondary OH, ester hydrolysis, diastereoselective addition of dibromomethyl lithium, and carboxylic acid methylation. 

It has been shown that 1-hydroxycyclopropanecarboxaldehyde derivatives 171 underwent Wittig olefination with cyclohexylidenephosphorane (vide supra, Sect. 4.7,... 

By this method (Z)-monounsaturated fatty acids and esters could be obtained with an ( )-isomer content of less than 10% this stereoselectivity being however inferior to that of the commonly used acetylenic approach 55,56). However, the salt-free techniques used today in Wittig reactions allow (Z)-alkenoic acids to be synthesized with less than 2% of the ( )-isomers. Thus, Bestmann et al. prepared methyl and ethyl esters of (Z)-4,5,6,7,8,9,ll- and 13-alkenoic acids of different chain lengths 35,57 62), which served as intermediates in the synthesis of insect pheromones, both by reaction of co-alkoxycarbonyl-substituted alkyl-triphenyl-phosphonium salts with simple alkanals and of co-formylalkanoic esters with alkylidenephosphoranes. As the starting material for the synthesis of -substituted alkyl-phosphonium salts co-chloro- and -bromocarboxylic esters were used. The corresponding -substituted aldehydes can usually be obtained by ozone cleavage of suitable olefin derivatives or by oxidation of alkohols 57,58). 

The carbinol 19 (R = H) was obtained from a reduction of ketone 18 with borohydride (Scheme 2). Compound 19 was then dehydrated with p-toluenesulfonic acid to give the 5H-azaazulenone 20, whose structure was proved by NMR spectroscopy. A mixture of approximately equal amounts of 21 and 21a was formed by acid-catalyzed dehydration of 19 (R = CH3) Wittig olefination of 18 gave the exomethylene derivative 21, which on isomerization with potassium t-butoxide in dimethyl sulfoxide (DMSO) gave a mixture of 60% 21 and 40% 21a. Surprisingly, no isomers of type 17b/c were observed (82JCS(P1)1123). 

Access to derivatives with protecting groups other than benzyl was also desired. Tri-O-acetyl-D-glucal (13) was deacetylated and benzylated with p-methoxybenzyl chloride to give 14. Cleavage of the olefin in 14 gave formate aldehyde 15. Hydrolysis of the formate ester led to lactol 16 and Wittig olefination then furnished the PMB protected olefin alcohol Id (Scheme 3). 

Phosphoranes and phosphonate derived carbanions are also known to react with carbonyl compounds other than aldehydes and ketones, in reactions often referred to as non-classical Wittig reactions.35 Wittig olefination products can be obtained from the reaction of esters, anhydrides and some amides and imides with a range of stabilized and reactive phosphoranes. The reaction of stabilized and semi-stabilized phosphoranes with esters gives alkenes (Scheme 7). However, non-stabilized phosphoranes, such as methylenetriphenylphosphorane, tend to give P-keto phosphoranes on reaction with esters (Scheme 7)—the careful choice of the reaction conditions can also permit the preparation of the alkene in these reactions. 

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