Wittig phosphonium salts

A variation of the Madelung cyclization involves installing a functional group at the o-methyl group which can facilitate cyclization. For example, a triphenylphosphonio substituent converts the reaction into an intramolecular Wittig condensation. The required phosphonium salts can be prepared by starting with o-nitrobenzyl chloride or bromide[9]. The method has been applied to preparation of 2-alkyl and 2-arylindoles as well as to several 2-alkenylindoles. Tabic 3.2 provides examples. 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

Fluonnated ylides have also been prepared in such a way that fluonne is incorporated at the carhon P to the carbamonic carbon Vanous fluoroalkyl iodides were heated with tnphenylphosphine in the absence of solvent to form the necessary phosphonium salts Direct deprotonation with butyUithium or hthium dusopropy-lamide did not lead to yhde formation, rather, deprotonation was accomparued by loss of fluonde ion Flowever deprotonation with hydrated potassium carbonate in thoxane was successful and resulted in fluoroolefin yields of45-S0% [59] (equation 54) P-Fluorinated ylides may also be prepared by the reaction of an isopropyli-denetnphenylphosphine yhde with a perfluoroalkanoyl anhydnde The intermediate acyl phosphonium salt can undergo further reaction with methylene tnphenylphosphorane and phenyUithium to form a new yhde, which can then be used in a Wittig olefination procedure [60] (equation 55) or can react with a nucleophile [6/j such as an acetyhde to form a fluonnated enyne [62] (equation 56)... 

Fluoroolefins may he prepared by the reaction of Wittig reagents and other pho sphorus-containtng y tides with fluorinated carbonyl compounds. (A discussion of the fluorinated Wittig reagents or other fluonnated phosphorus reagents with nonfluorinated carbonyl compounds is on page 581.) Tnphenylphosphoranes, derived from alkyltriphenyl phosphonium salts, react with 1,1,1-trifluoroacetone [3/] or other trifluoromethyl ketones [32, iJ] (equation 26) (Table 10). 

Wittig condensation of the ylide from the phosphonium salt, 19, with the hydroxymethylene ketone, 20, affords the product,... 

In the following procedure, use is made of the basic character of epoxides. In the presence of phosphonium salts, ethylene oxide removes hydrogen halide and the alkylidenetriphenylphosphorane is produced. If a suitable carbonyl compound is present in the reaction mixture, its reaction with the in situ generated phosphorane proceeds readily to give the Wittig product. 

Since electron-donating substituents at the phosphorus atom favor addition reactions over olefination reactions, addition of 9 to aldehydes leads to the exclusive formation of the silyl-pro-tected allylic alcohols 10. No reaction products arising from Wittig alkenylation could be detected. The ylides (R,S)-9 and (S.S)-9 and their enantiomers were prepared from the corresponding optically pure l-[2-(diphenylphosphino)ferrocenyl]-A,A -dimethylethanamine diastereomers 7 via the phosphonium salts 8. 

The present preparation illustrates a general and convenient method for the fnms-iodopropenylation of an alkyl halide.4 The iodopropenyl-ated material is not usually stable but is a useful synthetic intermediate. For example, it forms a stable crystalline triphenylphosphonium salt for use in the Wittig reaction, and under Kornblum reaction conditions (DMS0-NaHC03, 130°, 3 minutes) it gives an (E)-a,/9-unsaturated aldehyde.4 In addition to the phosphonium salt described in Note 15, the following have been prepared (4-p-methoxyphenyl-2-butenyl)-triphenylphosphonium iodide [Phosphonium, [4-(4-methoxyphenyl)-2-butenyl]triphenyl-, iodide], m.p. 123-127° (2-octenyl)triphenyl-phosphonium iodide [Phosphonium, 2-octenyltriphenyl-, iodide], m.p. 98° and (2-octadecenyl)triphenylphosphonium iodide [Phosphonium, 2-octadecenyltriphenyl-, iodide], m.p. 50°. 

In the Wittig reaction an aldehyde or ketone is treated with a phosphorus ylid (also called a phosphorane) to give an alkene. Phosphorus ylids are usually prepared by treatment of a phosphonium salt with a base, and phosphonium salts are usually prepared from the phosphine and an alkyl halide (10-44) ... 

The overall sequence of three steps may be called the Wittig reaction, or only the final step. Phosphonium salts are also prepared by addition of phosphines to Michael alkenes (hke 15-8) and in other ways. The phosphonium salts are most often converted to the ylids by treatment with a strong base such as butyllithium, sodium amide, sodium hydride, or a sodium alkoxide, though weaker bases can be used if... 

However, thermolysis of the phosphonium salts (X=+PPh3) leads directly to the indolic products without need of acid catalyst or PPh3, and thus may not proceed via a normal Wittig pathway. Alternatively, Hughes has effected a solid-phase version of this reaction employing a polymer-hound phosphonium salt and potassium tert-butoxide as base <96TL7595>. In this case, the phosphine oxide by-product remains bound to the polymer resin. 

Another modification of the Hantzsch thiazole synthesis afforded C-4 thiazolylmethyl phosphonium salts (49). These ylids could then undergo Wittig condensations to furnish a wide variety of 2,4-disubstituted thiazoles <96TL983>. 

Triphenylphosphine gives Michael additions to the activated triple bond of acetylene dicarboxylic esters in presence of acidic compounds HY (Scheme 1). The reactions take place easily at room temperature, even at -10°C [1], through formation of intermediate activated vinylic phosphonium salts, which undergo a subsequent Michael addition of HY. The reactions afford various stabilized ylides which can be isolated in high yields or undergo possibly evolution, for example by intramolecular Wittig reaction [2]. 

The Wittig reaction can bo used for the double bond and with benzylic bromination In mind wc prefer phosphonium salt (15), bromide (16), and hence available acid (17) as starting materials. 

Wittig reactions are versatile and useful for preparing alkenes, under mild conditions, where the position of the double bond is known unambiguously. The reaction involves the facile formation of a phosphonium salt from an alkyl halide and a phosphine. In the presence of base this loses HX to form an ylide (Scheme 1.15). This highly polar ylide reacts with a carbonyl compound to give an alkene and a stoichiometric amount of a phosphine oxide, usually triphenylphosphine oxide. 

This accounts for the considerable discrepancy between the alkene Z/E ratio found on work-up and the initial oxaphosphetan ais/trans ratio. By approaching the problem from the starting point of the diastereomeric phosphonium salts (19) and (20), deprotonation studies and crossover experiments showed that the retro-Wittig reaction was only detectable with the erythreo isomer (19) via the cis-oxaphosphetan (17). Furthermore, it was shown that under lithium-salt-free conditions, mixtures of (19) and (20) exhibited stereochemical drift because of a synergistic effect (of undefined mechanism) between the oxaphosphetans (17) and (18) during their decomposition to alkenes. 

The chloromethyl derivatives of 1 and 2 can be converted to the corresponding phosphonium salts by treatment with triphenyl-phosphine.19 A subsequent phase transfer catalysed Wittig reaction of these salts with formaldehyde introduced pendant vinyl groups. 

Recently, water-soluble phosphonium salts were synthesized and their Wittig reactions with substituted benzaldehydes were carried out in aqueous sodium hydroxide solution (Eq. 8.114).309... 

A simple cyclization was carried out to test the ability of chloro azidoalkene cyclization to generate quinolizidines. Reduction of 6-valerolactone to the corresponding lactol was followed by a Wittig reaction onto the carbonyl function employing an appropriate phosphonium salt, and the intermediate primary alcohol thus formed afforded the chloro... 

Feist-Benary cyclo-condensation of (2,4-dioxobutylidene)-phosphoranes with a-chloroacetone gave rise to substituted furfuryl phosphonium salts, which underwent subsequent Wittig reactions to afford alkenylfurans in good yields as can be seen below <06JOC8045>. 

The olefin metathesis of 3-hydroxy-4-vinyl-l,2,5-thiadiazole 112 and a McMurry coupling reaction (Ti3+ under reductive conditions) of the aldehyde 114 were both unsuccessful <2004TL5441>. An alternative approach via a Wittig reaction was successful. With the use of the mild heterogenous oxidant 4-acetylamino-2,2,6,6-tetramethyl-piperidine-l-oxoammonium perfluoroborate (Bobbitt s reagent), the alcohol 113 was converted into the aldehyde 114. The phosphonium salt 115 also obtained from the alcohol 113 was treated with the aldehyde 114 to give the symmetrical alkene 116 (Scheme 16) <2004TL5441>. 

Phosphoniosilylotion. This combination reacts with acyclic or cyclic enones to give phosphonium salts, formed by addition of P(C6H,)3 to the p-position of the enone and silylation of the carbonyl group. The products can be converted into p-substituted enones by deprotonation (BuLi), a Wittig reaction, and hydrolysis. 

Novel alkenylphosphonium salts were subjected to the Wittig reaction (Scheme 12). Allylic deprotonation took place for phosphonium salts possessing such protons, and the olefination proceeded after double bond migration. In cases where such protons were absent, allene formation was observed. 

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