Enol trifluoroacetates

An alternative approach to the synthesis of isocoumarins which probably proceeds through the intermediacy of 2-carboxybenzyl ketones is based on the oxidative cleavage of indan-1-ones (76JCS(P1)1438). Although ozonolysis of the silyl enol ether (505) leads to the 2-hydroxy-2-methylindan-l-one (506), periodate oxidation of which gives the isocoumarin, a more convenient and direct route involves ozonolysis of the enol trifluoroacetate (Scheme 182). This synthesis is especially attractive for the preparation of isotopically labelled isocoumarins, since the precursors of the indanones, arylpropanoic acids or acrylophenones, are readily available bearing labels at specific sites. 

A new catalytic cycle for the enantioselective protonation of cyclic ketone enolates with sulfinyl alcohols has been developed (Scheme 2)25 In this method, the achiral alcohol plays two roles it is involved in the turnover of the chiral proton source and also in the generation of a transient enolate through the reaction of its corresponding alkoxide with the enol trifluoroacetate precursor. Stereoselectivity was found highly dependent on the structure of the achiral alcohol. 

The reactions of (39 R = H) with aliphatic aldehydes give alkenes in yields that are strongly temperature dependent. If the reaction is carried out in the presence of TFAA, then excellent yields of the methylene compounds result. However, reaction of iphatic aldehydes with (39 R = (TtHis) in the same conditions proceeds by a most unexpected redox process to yield ketones in good yields after aqueous work-up. The appearance of ketones as products is unique in any Wittig-type of reaction at tlds oxidation level. Alkenyloxyboranes appear to be the intermediates in the reactions, and these react with excess TFAA to give enol trifluoroacetates, which can be isolated and characterized. A possible sequence is shown in Scheme 7. ... 

Isolable enols have also been produced by methanolysis of enol trifluoroacetates. Such enols rapidly undergo autoxidation at room temperature in non-polar solvents (benzene, dichloromethane or chloroform) to give hydroperoxides in high yields (Scheme 12) [29]. 

The reagent was also able to convert carbonyl compounds into enol trifluoroacetates. 3- and 4-phenylalkanoic acids were readily cyclized to 1-indanones and 1-tetralones, respectively, through the intermediary of a mixed anhydride formed with CF3S03H29 (equation 13). 

Isocoumarin formation from an indanone has been effected through involvement of an enol trifluoroacetate followed by ozonolysis. 

Mechanistically, the authors proposed that this reaction most probably proceeds by cyclodehydration of 499 with TFAA to afford a mesoionic 1,3-oxazolium-5-olate 505. Trilluoroacetylation of 505 yields 506, which is ring opened with trifluoroacetate to produce 507 from which the enol trifluoroacetate 508 is produced by decarboxylation (Scheme 1.137). Cyclization of508 gives the IV-alkyloxazolium salt 509 that is dealkylated by trifluoroactate to furnish 500. This dealkylation is consistent with the observation that 499 (Rj = Bn) are better substrates than 499... 

Wood and Moniz reported kinetic data for the Claisen rearrangement of allyl vinyl ethers that contain an enol moiety [53]. Their data underhnes the rate-accelerating effect of a substituent in the 4-position, which was nullified when the enol was converted into an enol trifluoroacetate (Scheme 11.38). 

The proposed reaction mechanism involves formation of mesoionic l,3-oxazolium-5-olate 22 through the cyclodehydration of 18 by TFAA. The intermediate 22 undergoes trifluoroacetylation followed by decarboxylation to give enol trifluoroacetate (25). Cyclization of 25 leads to oxazolinium salt (26). If the group of 25 is easily removable, the reaction could proceed efficiently. This is the reason why A-benzyl derivatives are the best substrates for this transformation. 

In some equally elegant investigations of polyene cyclization, Sutherland and his co-workers have demonstrated that enol trifluoroacetates of 2-cyclo-hexenones, as initiators of the cyclizations, offer several advantages over the use of the related 2,3-epoxycyclohexanones [e.g. (141) (142) (81%)]. 

The bis-cinchona alkaloids have been shown to be efficient and enantioselective catalysts for a wide range of asymmetric reactions. A (DHQ)2AQN (AQN 9,10-anthraquinone-l,4-diyl) compound (49) is reported to catalyze the protonation of enol trifluoroacetates in the presence of hydrogen carbonate and with formation of the products in good yield and enantioselectivity (Scheme 6.58) [122]. 

Claraz A, Leroy J, Oudeyer S, Levacher V. Catalytic enantioselective protonation of enol trifluoroacetates by means of hydrogenocarbonates and cinchona alkaloids. J. Org. Chem. 2011 76 6457-r6463. 

The following acid-catalyzed cyclizations leading to steroid hormone precursors exemplify some important facts an acetylenic bond is less nucleophilic than an olelinic bond acetylenic bonds tend to form cyclopentane rather than cyclohexane derivatives, if there is a choice in proton-catalyzed olefin cyclizations the thermodynamically most stable Irons connection of cyclohexane rings is obtained selectively electroneutral nucleophilic agents such as ethylene carbonate can be used to terminate the cationic cyclization process forming stable enol derivatives which can be hydrolyzed to carbonyl compounds without this nucleophile and with trifluoroacetic acid the corresponding enol ester may be obtained (M.B. Gravestock, 1978, A,B P.E. Peterson, 1969). 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

So do anhydrides and many compounds that enolize easily (e.g., malonic ester and aliphatic nitro compounds). The mechanism is usually regarded as proceeding through the enol as in 12-4. If chlorosulfuric acid (CISO2OH) is used as a catalyst, carboxylic acids can be ot-iodinated, as well as chlorinated or brominated. N-Bromosuccinimide in a mixture of sulfuric acid-trifluoroacetic acid can mono-brominate simple carboxylic acids. ... 

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

The spirobenzylisoquinoline 171b derived from berberine (15) (Section IV,A,1) was oxidized with m-chloroperbenzoic acid to the /V-oxide 389, which was treated with trifluoroacetic anhydride to afford dehydrohydrastine (370) in 56% overall yield (Scheme 71) through the Polonovski reaction (187). Holland et al. (188,189) reported the reverse reaction from dehydrophthalides to spirobenzylisoquinolines, namely, 370 was reduced with diisobutylalu-minum hydride to give a mixture of two diastereoisomeric spirobenzylisoquinolines 320 and 348 via the enol aldehyde. This reaction was applied to synthesis of various spirobenzylisoquinoline alkaloids such as (+)-sibiricine (352), ( + )-corydaine (347), (+ )-raddeanone (354), ( )-yenhusomidine (359), (+ )-ochrobirine (343), and ( )-yenhusomine (323). 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

Nitration of the potassium enolates of cycloalkanones with pentyl nitrate81 or nitration of silyl enol ethers with nitronium tetrafluoroborate82 provides a method for the preparation of cyclic a-nitro ketones. Trifluoroacetyl nitrate generated from trifluoroacetic anhydride and ammonium nitrate is a mild and effective nitrating reagent for enol acetates (Eq. 2.41).83... 

Addition to linear 1,1-disubstituted allylic acetates is slower than addition to monosubstituted allylic esters. Additions to allylic trifluoroacetates or phosphates are faster than additions to allylic carbonates or acetates, and reactions of branched allylic esters are faster than additions to linear allylic esters. Aryl-, vinyl, alkynyl, and alkyl-substituted allylic esters readily undergo allylic substitution. Amines and stabilized enolates both react with these electrophiles in the presence of the catalyst generated from an iridium precursor and triphenylphosphite. 

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