Enol reaction with ethyl

More recently, further developments have shown that the reaction outlined in Scheme 4.33 can also proceed for other alkenes, such as silyl-enol ethers of acetophenone [48 b], which gives the endo diastereomer in up to 99% ee. It was also shown that / -ethyl-/ -methyl-substituted acyl phosphonate also can undergo a dia-stereo- and enantioselective cycloaddition reaction with ethyl vinyl ether catalyzed by the chiral Ph-BOX-copper(ll) catalyst. The preparative use of the cycloaddition reaction was demonstrated by performing reactions on the gram scale and showing that no special measures are required for the reaction and that the dihydro-pyrans can be obtained in high yield and with very high diastereo- and enantioselective excess. 

Quenching this reaction with deuteriomethanol gave 2-methylcycloheptanone having deuterium at the 2-position (199 E = D) in 75% yield with 95% deuterium incorporation. Aldehydes and benzoyl chloride gave the desired products in 60-70% yields. Alkylation of the enolate intermediate (198) was successfully carried out with alkyl halides in the presence of HMPA in good yields. The reaction with ethyl chloroformate and chlorotri-ethylsilane gave enol carbonate (200) and sUyl enol ether (201) in 74 and 75% yield, respectively. 

However, all attempts to activate the a-position of the cyclohexanone ring in order to facilitate a subsequent diazotization, which was to be followed by rhodium carbenoid-mediated aryl C-H insertion onto C-4 [21], were unsatisfactory [22], One of the approaches was based on the generation of the silyl enol ether 35, but attempts to achieve its a-acylation led only to the formation of Paal-Knorr-type cyclization products 36. Chemoselective formylation of 34 to 37 was possible by reaction with ethyl formate in the presence of a large excess of sodium ethoxide, but in situ oxidation of the desired compound 37 to 38, which was the major isolated product, made the reaction impractical (Scheme 6). 

Enol ethers. Enol ethers are prepared from alcohols by an exchange reaction with ethyl vinyl ether using the complex of Pd(OAc)2 with 1,10-phenanthroline. 

The next stage requires formation of an extended enolate 118 and its reaction with ethyl bromoacetate. Reactions of enolates with a-bromoesters are not normally recommended as the basic enolates may remove the rather acidic proton between the ester and the bromine atom. The extra conjugation in the extended enolate makes it significantly less basic and this reaction goes... 

An indication that the 14j8-hydroxyl is not essential for cardiotonic activity comes from the synthesis of 14-desoxy-14)8-uzarigenin. Lithium aluminium hydride reduction and acetylation of the 17 0 -epoxide obtained from the enol acetate (79) gave the 17/ -alcohol (80), which underwent a Serini-Logemann reaction to afford the 14 -pregnane (81). Reformatsky reaction with ethyl bromoacetate and dehydration gave the a -unsaturated ester (82), converted by selenium dioxide to 14-desoxy-14)8-uzarigenin (83). 

Chlorotitanium etiolates (16,332-334). The titanium enolate of the N-propionyl-oxazolidonc 1, prepared with TiCl4 and C2H5N-i-Pr2, undergoes highly diastereosclective Michael reactions with ethyl vinyl ketone, methyl acrylate, and acrylonitrile. 

Several syntheses are available to the 13,14-dihydroprostaglandins, some of which are metabolites of the E and F series. The first of these routes [143, 144] started from the formyl derivative (LVII) of the enol ether of cyclo-pentan-l,3-dione which on reaction with ethyl 6-bromosorbate and tri-phenylphosphine followed by selective catalytic reduction afforded the ester (LVIII). A second formylation followed by elaboration with n-hexanoyl-methylenetriphenylphosphonium chloride 1 to the ketone (LIX) which on reduction of the exocyclic double bond and acid-catalysed solvolysis in benzyl alcohol afforded the benzyl ether (LX) and its isomeric enol ether. Reduction with lithium tri-t-butoxyaluminium hydride to the corresponding 15-hydroxy-compound and palladium-charcoal catalysed hydrogenolysis followed by prolonged catalytic hydrogenation with rhodium-charcoal led to ( )-dihydro-PGEi ethyl ester. 

The successful use of the silver complex formed from an iso-leucine-derived phosphine (L2 in Scheme 11.4) as catalyst for the multicomponent Mannich reaction of silyl enol ethers 10 with in situ formed aliphatic imines allowed its application in the enantioselective synthesis of the alkaloid sedamine (56% yield, 98% ee) [17]. Also cyclic and acyclic alkenyl trichloroacetates (10, Z = EtOCO) can be used in the reaction with ethyl glyoxylate and diverse aniline derivatives 11 catalyzed by... 

Additionally, unsubstituted and 6-substimted 2-(perfluoroalkyl)-4/f-pyran-4-ones 4 have been prepared using alkyl enolates derived from p-dicarbonyl compounds. The reaction of acetylacetone enol ether with ethyl perflnoroalkanoates in the presence of i-BuOK, followed by p-TsOH catalyzed cychzation in benzene afforded pyrones 4a,b in 57-75 % yields. Similarly, the parent compounds 4c,d were obtained from the for-mylacetone derivative in 40-64 % yields [4]. Analogue 4e was accessible in low yield from the corresponding triketone [5] (Scheme 2). 

The most common transformation involving acylation of ketone enolates is their formylation by reaction with ethyl formate. 

Optimization studies revealed that cycloaddilions of cyclic silyl enol ethers with ethyl propiolate (21a), promoted by 2 mol % Tf2NH, occurred at ambient temperature to generate cyclobutenes 22a-C in good yields. Finally, exploratory studies aimed at further optimizing the cyclobutane forming process showed that the organic acid catalyzed cycloaddition reaction could be successfully performed in various solvents, such as toluene, acetonitrile, dichloroethane, and ethyl acetate (Table 4.9). The reactions of propiolate took place even under solvent-free conditions. Although reactions of acrylates normally required careful control of temperature below —40 °C, in ethyl acetate these cycloadditions took place at more conveniently accessed ambient temperatures. 

Thus the sodio derivative (I) of the enol form of ethyl acetoacetate is obtained. This mechanism can clearly apply also to the condensation of an ester with a suitable ketone or nitrile, as in the above reactions (ii) and (iii) respectively. 

Esters of nonenolizable monocarboxylic acids such as ethyl benzoate give p diketones on reaction with ketone enolates... 

A modification of the K-R reaction was introduced by Mozingo. This method involved reacting an o-hydroxyacetophenone with an ester in the presence of metallic sodium to form a 1,3-diketone. Treatment of the diketone with an acid then delivered the chromone via an intramolecular cyclization reaction. This method was applied to the preparation of 2-ethylchromone (21). 0-hydroxyarylketone 22 was allowed to react with ethyl propionate (23) in the presence of sodium metal.The resulting sodium enolate was then quenched with acetic acid to deliver the 1,3-diketone 24. Upon heating 24 in glacial acetic acid and hydrochloric acid, 2-ethylchromone (21) was delivered in 70-75% overall yield. 

The chiral BOX-copper(ll) complexes, (S)-21a and (l )-21b (X=OTf, SbFg), were found by Evans et al. to catalyze the enantioselective cycloaddition reactions of the a,/ -unsaturated acyl phosphonates 49 with ethyl vinyl ether 46a and the cyclic enol ethers 50 giving the cycloaddition products 51 and 52, respectively, in very high yields and ee as outlined in Scheme 4.33 [38b]. It is notable that the acyclic and cyclic enol ethers react highly stereoselectively and that the same enantiomer is formed using (S)-21a and (J )-21b as the catalyst. It is, furthermore, of practical importance that the cycloaddition reaction can proceed in the presence of only 0.2 mol% (J )-21a (X=SbF6) with minimal reduction in the yield of the cycloaddition product and no loss of enantioselectivity (93% ee). 

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