Acyl carbonyl compounds

Note. This strategy is not suitable for oxazoles as amides are not usually reactive enough cyclization of acylated carbonyl compounds is usually preferred... 

Stork enamine reaction. Synthesis of a-al-kyl or a-acyl carbonyl compounds from enamines and alkyl or acyl halides. 

Various organotin reagents react with acyl and aroyl halides under mild conditions without decarbonylation to give carbonyl compounds[390,39l]. Alkyl- or alkenyltin reagents react with acyl and aroyl chlorides to give ketones[548.733,734]. One example is the preparation of the a,/3-dnsaturated 7-keto esters 860 and 861, carried out under a CO atmosphere[735]. The reaction has been applied intramolecularly to the synthesis of the macrocyclic keto... 

Addition to Carbonyl Compounds. Unlike Grignard and alkykitliium compounds, trialkylboranes are inert to carbonyl compounds. The air-catalyzed addition to formaldehyde is exceptional (373). Alkylborates are more reactive and can transfer alkyl groups to acyl halides. The reaction provides a highly chemoselective method for the synthesis of ketones (374). 

Hydroxyall l Hydroperoxyall l Peroxides. There is evidence that hydroxyalkyl hydroperoxyalkyl peroxides (2, X = OH, Y = OOH) exist in equihbrium with their corresponding carbonyl compounds and other a-oxygen-substituted peroxides. For example, reaction with acyl haUdes yields diperoxyesters. Dilute acid hydrolysis yields the corresponding ketone (44). Reduction with phosphines yields di(hydroxyalkyl) peroxides and dehydration results in formation of cycHc diperoxides (4). 

In the oxaziridines (1) ring positions 1, 2 and 3 are attributed to oxygen, nitrogen and carbon respectively. The latter almost always is in the oxidation state of a carbonyl compound and only in rare cases that of a carboxylic acid. Oxaziridinones are not known. The nitrogen can be substituted by aryl, alkyl, H or acyl the substituent causes large differences in chemical behavior. Fused derivatives (4), accessible from cyclic starting materials (Section 5.08.4.1), do not differ from monocyclic oxaziridines. 

In the diaziridine field many compounds are known bearing N-YL, A/-alkyl and A-acyl groups, but here no dramatic changes in reactivity are caused by A-substituents. N-Aryldiaziridines are underrepresented. The ring carbon is in the oxidation state of a carbonyl compound or, in the diaziridinones (5) and the diaziridinimines (6) that of carbonic acid. In single cases, diaziridine carbon bears chlorine or fluorine. 

Oxaziridines are powerful oxidizing agents. Free halogen is formed from hydrobromic acid (B-67MI50800). Reduction by iodide in acidic media generally yields a carbonyl compound, an amine and two equivalents of iodine from an oxaziridine (1). With 2-alkyl-, 2-acyl and with N-unsubstituted oxaziridines the reaction proceeds practically quantitatively and has been used in characterization. Owing to fast competing reactions, iodide reduction of 2-aryloxaziridines does not proceed quantitatively but may serve as a hint to their presence. 

The dienophilic character of imines parallels that of carbonyl compounds Consequently, electron deficient imtnes are the most reactive dienophiles of this class, particularly those having C perfluoroalkyl [5, 146, 150, 228], /V-acyl [/2i5 127], or A/-sulfonyl groups [148, 229 230]... 

Since Stork et al. introduced as a new synthetic method the alkylation and acylation of carbonyl compounds via enamines, this class of compounds has been the subjeet of intensive studies 1-3). The exceptional physical and chemical behavior of the enamine structure can be ascribed to resonance by conjugation of the unshared pair of electrons of the nitrogen atom with the 77 electrons of the double bond ... 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

Both in the laboratory and in living organisms, the reactions of carbonyl compounds take place by one of four general mechanisms nucleophilic addition, nucleophilic acyl substitution, alpha substitution, and carbonyl condensation. These... 

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

Carboxylic acids, RC02H, occupy a central place among carbonyl compounds. Not only are they valuable in themselves, they also serve as starting materials for preparing numerous acyl derivatives such as acid chlorides, esters, amides, and thioesters. In addition, carboxylic acids are present in the majority of biological pathways. We ll look both at acids and at their close relatives, nitriles (RC=N), in this chapter and at acyl derivatives in the next chapter. 

The difference in behavior between aldehydes/ketones and carboxylic acic derivatives is a consequence of structure. Carboxylic acid derivatives have ai acyl carbon bonded to a group -Y that can leave as a stable anion. As soon a the tetrahedral intermediate is formed, the leaving group is expelled to general- a new carbonyl compound. Aldehydes and ketones have no such leaving grouj however, and therefore don t undergo substitution. 

We said in A Preview ofCnrbonyl Compounds that much of the chemistry of carbonyl compounds can be explained by just four fundamental reaction types nucleophilic additions, nucleophilic acyl substitutions, o substitutions, and carbonyl condensations. Having studied the first two of these reactions in the past three chapters, let s now look in more detail at the third major carbonyl-group process—the a-substitution reaction. 

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

Step 1 of Figure 29.3 Introduction of a Double Bond The /3-oxidation pathway begins when a fait)7 acid forms a thioester with coenzyme A to give a fatty acyl Co A. Two hydrogen atoms are then removed from C2 and C3 of the fatty acyl CoA by one of a family of acyl-CoA dehydrogenases to yield an a,/3-unsaturated acyl CoA. This kind of oxidation—the introduction of a conjugated double bond into a carbonyl compound—occurs frequently jn biochemical pathways and usually involves the coenzyme flavin adenine dinucleotide (FAD). Reduced FADH2 is the by-product. 

Nucleophilic acyl substitution reaction (Section 21.2) A reaction in which a nucleophile attacks a carbonyl compound and substitutes for a leaving group bonded to the carbonyl carbon. 

Iron-acyl enolates such as 1, 2, and 3 react readily with electrophiles such as alkyl halides and carbonyl compounds (see Houben-Weyl, Vol. 13/9a p418). The reactions of these enolatc species with alkyl halides and similar electrophiles are discussed in Section D.1.1.1.3.4.1.3. To date, only the simple enolates prepared by a-deprotonation of acetyl and propanoyl complexes have been reacted with ketones or aldehydes. 

Hydroxy-substituted iron-acyl complexes 1, which are derived from aldol reactions of iron-acyl enolates with carbonyl compounds, are readily converted to the corresponding /i-methoxy or /1-acetoxy complexes 2 on deprotonation and reaction of the resulting alkoxide with iodomethane or acetic anhydride (Tabic 1). Further exposure of these materials to base promotes elimination of methoxide or acetate to provide the a,/ -unsaturated complexes (E)-3 and (Z)-3 (Table 2). 

In this section alkylation, Michael additions, hydroxyalkylation (reaction with carbonyl compounds), aminoalkylation, acylation and some other reactions of a-sulphinyl carbanions will be discussed. 

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