Aldehydes, reaction with anhydride enolates

This reaction was also extended to other aromatic aldehydes for the preparation of a,P unsaturated carboxyUc acids. Several mechanisms of the reaction have been proposed (45). The most accepted mechanism iavolves the reaction of the aldehyde with the enol form of the acid anhydride which is promoted by the presence of the sodium salt or of another base. The resulting reaction product is then dehydrated iato an unsaturated carboxyUc acid. 

The dimethyl acetal (94) is readily prepared from the 22-aldehyde (93) by direct reaction with methanol in the presence of hydrogen chloride. Ena-mines (95) are formed without a catalyst even with the poorly reactive piperidine and morpholine.Enol acetates (96) are prepared by refluxing with acetic anhydride-sodium acetate or by exchange with isopropenyl acetate in pyridine.Reaction with acetic anhydride catalyzed by boron trifluoride-etherate or perchloric acid gives the aldehyde diacetate. 

Benzofuran-3(2/f)-ones (396) exist in the keto form but undergo ready enolization. Acetylation with acetic anhydride and sodium acetate affords 3-acetoxybenzo[6]furans, but reaction under acidic conditions usually supplies these products admixed with 3-acetoxy-2-acetylbenzo[6]furans. Alkylation usually furnishes a mixture of O- and C-alkylated products. 3-Acetoxy-6-methoxy-4-methylbenzo[6]furan, on Vilsmeier reaction, supplies the 3-chlorobenzo[6]furan-2-carbaldehyde, the product expected from an enolizable ketone (72AJC545). Benzofuran-3(2//)-ones react normally with carbonyl reagents. Grignard reagents react in the expected way and dehydration of the intermediate affords a 3-substituted benzo[6]furan. The methylene group is reactive so that self condensation, condensation with aldehydes and ketones and reaction with Michael acceptors all occur readily. 

The Perkin synthesis of cinnamic acids is considered to involve reaction of the enolate anion derived from the acid anhydride with the aldehyde, giving rise to the alkoxide (391). Intramolecular acylation follows and the resulting /3-acyloxy derivative undergoes elimination to the unsaturated acid (Scheme 125). 

Simple aliphatic or aromatic ketones are not suitable substrates in the Pericin transformation. Similarly, aliphatic aldehydes are not generally acceptable components in this reaction. This long-known limitation was studied by Crawford and Little. They demonstrated that many aliphatic aldehydes give diacetates and enol acetates when heated with acetic anhydride, with or without sodium acetate, suggesting this side reaction causes the typical Perkin process to fail. Semmeler had previously obtained similar results. They did show, however, that several short chain aldehydes, as well as frowj-citral (16), undergo the Perkin condensation with p-nitrophenylacetic anhydride the p-nitrophenyl substituent activates the anhy-... 

A variation of this condensation involves reaction with aldehydes, and it is called the Perkin reaction. Condensation of an aldehyde (having no enolizable protons) with the enolate of an acid anhydride leads to an acetoxy ester such as 182.10 Internal acyl substitution by the alkoxide forms the 0-acetyl ester and liberates the carboxylate anion (183). Subsequent reaction with more acetic anhydride generates a new mixed... 

Another amino acid synthesis is called the azlactone synthesis. Remember from before that an azlactone is an oxazolone (see 95). When glycine (52) is converted to its AT-benzoyl derivative (112 known as hippuric acid) by reaction with benzoyl chloride, treatment with acetic anhydride (AC2O) gives the azlactone 113. This is the reaction presented in the preceding section (see compormd 95). Compound 110 has the common name of hippuric acid azlactone. As with the thiohydantoin, the -CH2- unit in 113 is susceptible to an enolate anion condensation reaction with aldehydes (Chapter 22, Section 22.7.2), and reaction with 2-methylpropanal in the presence of pyridine gives azlactone 114. Catalytic hydrogenation of the alkene unit (Chapter 19, Section 19.3.2) and acid hydrolysis lead to the amino acid leucine (55). 

Aldehydes react with the lithio-derivatives of a-diazo-esters to give /3-hydr-oxy>a-diazo-esters, which in turn undergo rhodium(ii)-catalysed decomposition to give /3-keto-esters./3-Keto-amides are obtained in moderate to high yield from the acylation of amide enolates with mixed anhydrides. In a general reaction, orthoformates react with acidic methines to give /3-keto-aldehydes, isolated as their dialkyl acetals [equation (16)]. ... 

Enol acetates have been little used as protective groups per se. They are formed from enolizable aldehydes and ketones by an acid-catalyzed exchange reaction with isopropenyl acetate [123, 124, 125, 126], by the action of acetic anhydride in the... 

Acetic anhydride can be used to synthesize methyl ketones in Friedel-Crafts reactions. For example, benzene [71-43-2] can be acetylated to furnish acetophenone [98-86-2]. Ketones can be converted to their enol acetates and aldehydes to their alkyUdene diacetates. Acetaldehyde reacts with acetic anhydride to yield ethyhdene diacetate [542-10-9] (18) ... 

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). 

Condensation products of 4(5//)-oxazolonium salts with aldehydes and orthoesters are the subject of a series of papers by Kosulina and co-workers Reaction of 2-methyl-4(5//)-oxazolonium perchlorates 44 with an ortho ester gives rise to an enol ether, which reacts with furanamides to afford the frani-eneamides 45 (Scheme 6.14). " Using electron deficient anilines in a three component condensation affords either 46 or 47 in 64-80% and 78-84% yields, respectively, depending on whether the reaction is performed in acetic acid or acetic anhydride. Electron-rich anilines are unreactive since they are merely protonated by the perchloric acid present in the reaction medium. ... 

Exercise 17-11 The direct halogenation of aldehydes under either acidic or basic conditions is complicated by side reactions involving either oxidation of the aldehyde —CHO group or additions to the—CH—0 double bond. Therefore the synthesis of a-halo aldehydes by the procedure described for ketones is not of much practical value. a-Haio aldehydes can be prepared indirectly from the enol ethanoate of the aldehyde. The enol ethanoate is made by treating the aldehyde with ethanoic anhydride and potassium ethanoate. The overall sequence follows ... 

Enols or enolates from anhydrides are not used very often in aldol reactions other than in one important application, usually known as the Perkin reaction. An acid anhydride, such as acetic anhydride, is combined with a non-enolizable aldehyde and a weak base, usually the salt of the acid. This base is used so that nucleophilic attack on the anhydride does no hami, simply regenerating the anhydride. q... 

A major structural difference between aromatic aldehydes and most aliphatic analogues is that the former lack an a-hydrogen atom. As a consequence, they are unable to enolize and so enolates/carbanions cannot be generated from them. Nevertheless, aromatic aldehydes can react with carbanions derived from, for example, aldehydes, ketones, esters and anhydrides, and so undergo a range of condensation reactions. 

Classically, this separation of roles was accomplished by utilizing substrates that differed drastically in their ability to form enolate anions. In fact, the various name reactions mentioned above are distinguished not by basic differences in mechanism, but by the nature of the components preferentially utilized as substrates. For example, in the Perkin reaction, the condensation of an aromatic aldehyde with an aliphatic acid anhydride is based on the fact that the electrophilic component, e.g. benzaldehyde, lacks a-hydrogens and therefore is incapable of forming an enolate. At the same time the utilized electrophile, acetic anhydride, contains a carbonyl group with reduced propensity to interact with nucleophiles. Hence, it is incapable of undergoing self-condensa-... 

If the reaction between an a-halo ketone and zinc is carried out in an qirotic solvent in the presence of an electrophilic reagent, the zinc enolate (6) can be trapped. Products corresponding to reaction at carbon are observed with carbon electrophiles (alkyl halides or aldehydes equation 8), but reaction occurs at oxygen with halosilanes and acid anhydrides (equation 9). " ... 

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