Enol esters, acylation preparation

Enol Esters Enol esters are rather stable, bioreversible derivatives of ketones and may be useful as prodrugs of agents containing enolizable carbonyl groups. As shown in Scheme 17, 6 -acetylpapaverine enol esters (107), prepared by acylation of the appropriate Li enolate with the respective anhydride, were hydrolyzed to 6 -acetylpapaverine (108) by esterases present in rat and human plasma, rat liver, and brain tissue supernatants. The intermediate 6 -acetylpapaver-ine cyclizes rapidly to coralyne (109), which has antitumor activity but has... 

Azabuta-l,3-dienes have been prepared in which the imino group is conjugated with an enol ester acylation of carbanions derived from N-(diphenylmethyl)arylmethanimines affords a wide range of the 2-azadienes (Scheme 197). The site selectivity for the attack of the electrophile on the aza-allyl anion depends upon the substituents on the carbanion, and on the hardness of the... 

The acylation of enamino ketones can take place on oxygen or on carbon. While reaction at nitrogen is a possibility, the N-acylated products are themselves acylating agents, and further reaction normally takes place. The first reported acylation of enamino ketones (72) was that of 129, prepared by acylation of the enamine (113), which was shown to have undergone O acylation because on mild hydrolysis the enol ester (130) could be isolated. A similar reaction took place with other aliphatic acid chlorides (80) and with dibasic acid chlorides [e.g., with succinyl chloride to give 118 above]. 

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a 8 2 mechanism. As with 10-8, the mechanism can be S l or tetrahedral. Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 10-9). The reaction is of wide scope, and many functional groups do not interfere. A base is frequently added to combine with the HX formed. When aqueous alkali is used, this is called the Schotten-Baumann procedure, but pyridine is also frequently used. Both R and R may be primary, secondary, or tertiary alkyl or aryl. Enolic esters can also be prepared by this method, though C-acylation competes in these cases. In difficult cases, especially with hindered acids or tertiary R, the alkoxide can be used instead of the alcohol. Activated alumina has also been used as a catalyst, for tertiary R. Thallium salts of phenols give very high yields of phenolic esters. Phase-transfer catalysis has been used for hindered phenols. Zinc has been used to couple... 

This novel resin-bound CHD derivative was then utilized in the preparation of an amide library under microwave irradiation. Reaction of the starting resin-bound CHD with an acyl or aroyl chloride yields an enol ester, which, upon treatment with amines, leads to the corresponding amide, thus regenerating the CHD. This demonstrates the feasibility of using the CHD resin as a capture and release reagent for the synthesis of amides. The resin capture/release methodology [126] aids in the removal of impurities and facilitates product purification. 

Electrolytic reduction, apparatus, 52, 23 Enol acetates, acylation of, 52,1 Enol esters, preparation, 52, 39 Epichlorohydrin, with boron trifluoride diethyl therate and dimethyl ether to give trimethyloxonium tetra-fluoroborate, 51,142 ESTERIFICATION OF HINDERED ALCOHOLS f-BUTYL p-TOLUATE,... 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

Several reactions are occurring in this step that have been elucidated by others (1). First, an a-ketoester is the initial condensation product of an N-acyl-aminoacid and an alkyl oxalyl chloride via a Dakin-West reaction. Second, at reflux temperatures isomeric enol esters are formed that directly condense with hydrazine to form a triazinone intermediate followed by the second ring closure. Other purines have been prepared in an analogous reaction pathway (2). 

Alkylation of enolate anions usually gives C-alkylation and is therefore not suitable for the preparation of enol ethers. The exception is when triethyloxonium tetrafluoroborate is used as the alkylating agent in a dipolar aprotic solvent. 0-Alkylation can be regioselectiveiy achieved if the enolate anion is derived from acetoacetate or a similar compound. On the other hand, 0-acylation of enols or enolate anions is quite common. Enol esters can therefore be prepared readily from the parent carbonyl compounds. For... 

Enol carbonates. O-Acylation is accomplished by rapid addition of ketone enolates, which are generated with NaH-TMEDA in refluxing THF, to chloroformate esters at 0 C. Aryl and a,/3-enone enolates are better prepared with NaN(SiMe3)2-TMEDA at -78°. 

Acyl cyanide-enol sulphonates, carboxylates, and phosphates can be prepared from enol esters of acyl cyanides, or acyl cyanides and... 

Based on our experiences with the NHC-catalyzed synthesis of dihydropyra-nones, we thought it conceivable that ot,p-unsaturated enol ester 51a could be converted to the iridoid cyclopenta[c]pyran core (i.e., 52a) (Scheme 11). In turn, it was envisaged that the required unsaturated enol ester 51a could be prepared via acylation of methyl formyl acetate (53a) with enantioenriched acyl chloride 54. The NHC-catalyzed rearrangement would only prove viable if it proceeded with chemoselectivity, due to the presence of additional ester functionality in enol ester 51a, and stereoselectively, to provide the correct diastereomer of 52a for the natural product. Although it was unclear whether these selectivities could be achieved, or whether the reaction would proceed with substrates annulated about the a,p-unsaturation, it was envisaged that this study would, at the very least, allow the limitations of the NHC catalysis to be examined. From the iridoid core 52a, completion of the total synthesis would require the chemo- and stereoselective reduction of the lactone to the lactol, followed by glycosylation. 

Initial attempts at acylating formyl acetate 53b with acyl chloride 54 using pyridine in methylene chloride at 0 °C afforded the desired enol ester 51b, unfortunately as an inseparable mixture with Knoevenagel adduct 59 in a ratio of 84 16 (Table 1, entry 1). This would not be the last time that the reactivity of the formyl acetate increased the difficulty of seemingly simple transformations. Fortunately, under the same reactimis conditions, but in the presence of less nucleophilic bases, namely either triethylamine or Hiinig s base, formation of the byproduct was reduced to 96 4 and 99 1, respectively, with 51b isolated in up to 89% yield (Table 1, entries 2 and 3). Utilizing the optimized conditions, ethyl enol ester 51c was prepared in 91% yield (Table 1, entry 4). 

Having streamlined the synthesis of acyl chloride 54, the indirect preparation of methyl enol ester 51a was addressed. As previously discussed, attempts to synthesize 53a from formyl Meldrum s acid 58 had proven unsuccessful. However, Cossy and coworkers have reported the preparation of 53a via the ozonolysis of alkene 82 and subsequent use of the crude aldehyde in the total synthesis of octalactin. Thus, methyl vinyl acetate (82) was subjected to ozonolysis at —78 °C, followed by a reductive quench to provide formyl acetate 53a (Scheme 24). The crude methyl formyl acetate was acylated with acyl chloride 54, using the previously optimized conditions, to afford methyl enol ester 51a in 74% yield over two steps. This modification to the synthesis removes a further two reactions from the sequence with a formal synthesis of (—)-7-deoxyloganin (24) now achieved in 10 steps, a length more in keeping with the complexity of this target. 

Other Methods.— The palladium-catalysed oxidation of terminal olefins to methyl ketones is very efficient using 30% hydrogen peroxide in acetic acid or t-butyl alcohol. The method offers advantages in that conversions are usually high, aldehyde production is very low, and the method requires only very low concentrations of palladium [20—40p.p.m, as palladium(li) acetate], fi-Hydroxy-o-nitrophenylselenides, or their O-acyl derivatives, on oxidation with hydrogen peroxide undergo elimination to form ketones or enol esters [equation (10)]. The starting materials can be prepared easily from alkenes via their epoxides. 

The use of dianions of carboxylic acids and ester enolates in the preparation of P-keto-esters has been reviewed. Synthetic applications of dealkoxycarbonyl-ations of p-keto-esters have also been the subject of review. Acylation of the... 

Cyclic enol-acetates and a-acetoxy-ketones are converted into keto-esters by electro-oxidative ring-cleavage. Keto-esters are prepared (in good yield) by the reduction of acyl ylides (107) with aluminium amalgam (Scheme 60). ... 

Some other ketones behave similarly, and acenaphthenone gives an analogous product with pyridine and acetic anhydride. Presumably, reaction occurs at C(2) as well as at C(4), but the product (91), which is in equilibrium with (90), rearranges to give the enol ester as shown. When the carbonyl compound is a jS-keto-ester, the initial reaction again probably causes C-C bond formation at C(2) and C(4), but the marked acidity of the j3-keto-ester makes interconversion between (90) and (91) rapid, and the product is therefore the enol ester. This is the basis of the well-known method for preparing O-acyl derivatives of enols (discussed below). Related reactions occur between 1-benzoylpyridinium chloride and methyl cyanoacetate or nitromethane 4i. In the first case the initial product (91 = Ph, R = GN,... 

PhCOCl very often gives a mixture of the O- and C-acylated products. To prepare the enol ester (kinetic conditions) a more reactive acylating agent such as Acetyl Chloride is generally used. Moreover, carboxylic acid anhydrides are generally preferred to acyl halides. Accordingly, PhCOCl is preferred to prepare 1,3-dicarbonyl compounds. Ketones (eq 10), esters (eq 11), and more commonly p-keto esters or related CH acidic compounds... 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

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