Wittig reaction with ethyl acetate

The Schrock catalyst shown in Figure 16.12 does react cleanly with benzaldehyde according to the equation shown in Figure 16.21, a Wittig- type reaction [19], The compound did not react with ethyl acetate or N,N-dimethylformamide for several weeks at room temperature. 

Wittig olefination of 5(4//)-oxazolones with triphenylphosphonium methylides affords product mixmres that depend on the ylide and the starting oxazolone. ° The product mixtures can include, apart from the expected 5(4//)-oxazolylideneace-tates, 5-oxazoleacetates, and other byproducts. Nevertheless, Wittig reaction of ethyl (triphenylphosphoranylidene)acetate with a 4,4-disubstituted-5(4//)-oxazo-lone 285 affords the corresponding ethyl 5(4//)-oxazolylideneacetates 286 in satisfactory yields (Scheme 7.93 Table 7.24, Fig. 7.26). 

A useful sabinene (767) synthesis has been described by Rousseau and Slougui. The keto ester 768 (R = O) was prepared conventionally from ethyl 4-methyl-3-oxopentanoate and converted to the methylene compound 768 (R = CH2) by a Wittig reaction. The trimethylsilylketene acetal 769 was then treated with bromoform and diethylzinc in pentane, yielding 70% of the ester 765 (R =... 

The ketophosphonate chemistry briefly discussed above indicates that the cycloalkenones 23 can be easily functionalized and, therefore, can serve as synthetic intermediates in the synthesis of bioactive products. Having this in mind, Altenbach and Holzapfel [35] devised an elegant and short synthesis of natural (+)-terrein (21) from the protected ethyl ester of (+)-(l)-tartaric acid 24. Upon reaction of 24 with diethyl lithiomethanephosphonate in the presence of acetic acid under strictly controlled reaction conditions a mixture of two cyclic products 25 and 26 was formed. The first of them, readily separated chromatograph-ically, was the desired product of an intramolecular Horner-Wittig reaction of the transiently formed bis-jS-ketophosphonate. Introduction of the unsaturated side chain was achieved via Horner-Wittig reaction with acetaldehyde. Subsequent deprotection of the chiral diol moiety with fluoride ion gave (+)-terrein (21) in 26% overall yield (Scheme 12). 

It has been reported that the hydroboration of 20(21)-methylene steroid, prepared from pregrenolone acetate by Wittig reaction, with 9-BBN produces predominantly (20 )-21-boryl steroid [3]. This boryl steroid on cross-coupling with ethyl( )-P-bromomethacrylate affords the corresponding steroid with extended side chain and having natural configurations at C-20 (Eq. 31.2). 

B. Reactions.—(/) Halides. Whereas ylides are alkylated in the normal way on treatment with a-bromo- or a-iodo-esters, quite different reactions occur with a-fluoro- and a-chloro-acetates. When salt-free ylides were refluxed in benzene with ethyl fluoroacetate or trifluoroacetate normal Wittig olefin synthesis took place with the carbonyls of the ester groups to give vinyl ethers, e.g. (14). On the other hand, methyl chloroacetate with... 

In the case of the synthesis of 10,19,19,19-2H4-vitamin A, the most useful for biological studies, three deuterium atoms were incorporated into /i-ionone 30, in >98% by deuterium exchange with excess D2O in the presence of Na02H (and pyridine). The tri-deuteriated 30, utilized in Wittig-Horner reaction with dideuterio triethyl phosphonate, provided tetradeuteriated ethyl /J-ionilidene acetate 31 with more than 98% 2H4 (by NMR). No deuterium loss in the subsequent synthetic steps was observed as evidenced by MS and NMR analysis. 

Preparation of 4-(l-phenvlethvloxvl-stvrene. This benzylic ether of p-hydroxystyrene was prepared by a Wittig reaction on the precursor aldehyde as described above. The final product was obtained in 73% yield after purification by preparative HPLC using 5% ethyl acetate in hexane as eluent. The product had analytical characteristics in agreement with the proposed structure. 

Quinazoline-4(3// )-thione condenses with ethyl bromocyanoacetate " and ethyl 2-chloro-3-oxobutanoate in the presence of sodium ethoxide in ethanol with sulfur extrusion to form ethyl 2-cyano-2-(quinazolin-4-ylidene)acetate (5, R = CN) and ethyl 2-(quinazolin-4-ylidene)-acetate (5, R = H), respectively. It has been suggested that the initial adduct of quinazoline-4(3//)-thione and a methylene compound is deprotonated to give the corresponding ylide which undergoes electrocyclic closure to a thiirane derivative and then desulfurization. A C - C double bond is formed between the methylene carbon atom and the electrophilic carbon C4, providing an alternative to the Wittig reaction. 

One of these important bases, diisopropylaminomagnesium bromide, was first introduced by Frostick and Hauser in 1949 as a catalyst for the Claisen condensation. However, the most generally useful base has turned out to be lithium diisopropylamide (LDA), which was first used by Hamell and Levine for the same purpose in 1950 (equation 3). After the introduction of LDA, it was more than 10 years before it was used by Wittig for the stoichiometric deprotonation of aldimines in what has come to be known as the Wittig directed aldol condensation.In a seminal paper in 1970, Rathke reported that the lithium enolate of ethyl acetate is formed by reaction of the ester with lithium hexamethyldisilazane in THF. - Rathke found that THF solutions of the lithium enolate are stable indefinitely at -78 °C, and that the enolate reacts smoothly with aldehydes and ketones to give p-hydroxy esters (equation 4). 

Reactions at Benzylic Positions. - The catalytic oxidation, using a cobalt bromide catalyst, of 2,5-dimethylthiophen to the dialdehydeof 3-methyl-2-ethylthiophen to 2-acetyl-3-methylthiophen and l-(3-methyl-2-thienyl)-ethyl acetate, of the four isomeric methyl acetothienones to the corresponding acetylthiophencarboxylic acids, and of 2-acetoxymethylthio-phen to thiophen-2-carboxylic acid has been reported. The Wittig reaction between 2- and 3-thenyltriphenylphosphonium salts and crocetin dialdehyde has been used for the synthesis of carotenoid analogues with terminal thiophen rings. ... 

Wittig reaction of 167 with ethyl (triphenylphosphoranylidene)acetate in methanol leads to a high yield of Z-olefin 195 containing a minor amount of the -isomer [70,71]. Acid treatment of 195 affords the separable unsaturated lactones 196 and 197 in 78% yield (7 1 ratio). Subsequent transformation of 196 provides deoxypoloxin C (198), which, when appropriately coupled with 189, affords Polyoxin J (199) [72,73] (Scheme 45). 

Recently, improved procedures have been developed [17] for the synthesis of the phosphonium bromide 30. Addition of the hydroxyaldehyde 29 to NBS/dimethylsulphide in CH2CI2 at -20°C provided (all- )-8-bromo-2,7-dimethylocta-2,4,6-trienal (31) in 86% yield. Reaction of 31 with triphenylphosphine in ethyl acetate furnished the phosphonium bromide 30 in 88% yield. In most applications carried out so far, the phosphonium salts 30 and 32 (prepared from 33 and 31) have been transformed to the corresponding dimethylacetals 27 and 28, prior to their use in Wittig condensations. However, protection of the aldehyde function of 30 is not always necessary [17]. Direct Wittig reaction between 30 and 34 afforded the Ci6-ketoaldehyde 35 in 43% yield. 

Condensation of the Grignard complex of 58 with triethyl orthoformate (59) gave a 75% yield of distilled hydroxyacetal 60. Partial hydrogenation of 60 to 61, followed by acidic hydrolysis, provided hydroxyaldehyde 62, which was isolated in the (all- -configuration. A Wittig reaction of 62 with the ylide of (a-ethoxycarbonylethyl)-tris(dimethylamino)-phosphonium bromide (63) furnished the hydroxyester 64. Treatment of 64 with ca. 0.5 mol equivalents of PBr3 in ether/hexane at -5°C in the presence of a small amount of pyridine gave an 84% yield of crystalline ester bromide 65, which could be transformed to the phosphonium bromide 55 (yield 93%) by reaction with triphenylphosphine in ethyl acetate. 

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