Nucleophilic acyl additions

Ketenes undergo rapid addition by nucleophilic attack at the sp-carbon atom. The reaction of tertiary amines and acyl halides, in the absence of nucleophiles, is a general preparation for ketenes. ... 

As with nucleophilic additions and nucleophilic acyl substitutions, many laboratory schemes, pharmaceutical syntheses, and biochemical pathways make frequent use of carbonyl cr-substitution reactions. Their great value is that they constitute one of the few general methods for forming carbon-carbon bonds, thereby making it possible to build larger molecules from smaller precursors. We ll see how and why these reactions occur in this chapter. 

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. 

Biochemistry is carbonyl chemistiy. Almost all metabolic pathways used by living organisms involve one or more of the four fundamental carbonvl-group reactions we ve seen in Chapters 19 through 23. The digestion and metabolic breakdown of all the major classes of food molecules—fats, carbohydrates, and proteins—take place by nucleophilic addition reactions, nucleophilic acyl substitutions, a substitutions, and carbonyl condensations. Similarly, hormones and other crucial biological molecules are built up from smaller precursors by these same carbonyl-group reactions. 

J. Fastrez, Estimation of the Free Energies of Addition of Nucleophiles to Conjugated Carbonyl Compounds and to Acyl Derivatives, J. Am. Chem. Soc. 1977, 99, 7004. 

Tandem procedures under hydroformylation conditions cannot only make use of the intrinsic reactivity of the aldehyde carbonyl group and its acidic a-position but they also include conversions of the metal alkyl and metal acyl systems which are intermediates in the catalytic cycle of hydroformylation. Metal alkyls can undergo -elimination leading to olefin isomerization, or couplings, respectively, insertion of unsaturated units enlarging the carbon skeleton. Similarly, metal acyls can be trapped by addition of nucleophiles or undergo insertion of unsaturated units to form synthetically useful ketones (Scheme 1). 

As early as the 1960s, some syntheses based on the addition of nucleophilic reagents (vinyl magnesium bromide, HCN, isonitrile) on A-acyl trifluoroacetaldi-mines (fluoral imine) have appeared. The acidic function is further introduced by an appropriate oxidation or hydrolysis. These approaches have allowed preparation of higher fluoroalkylated homologues of trifluoroalanine and of nonracemic trifluor-oalanines (vide infra). However, preparation of the acyl imine of fluoral is rather... 

Reaction of Z-a./j-unsaturated iron-acyl complexes with bases under conditions similar to those above results in exclusive 1,4-addition, rather than deprotonation, to form the extended enolate species. However, it has been demonstrated that in the presence of the highly donating solvent hexamethylphosphoramide, y-deprotonation of the -complex 6 occurs. Subsequent reaction with electrophiles provides a-alkylated products such as 736 this procedure, demonstrated only in this case, in principle allows access to the a-alkylatcd products from both Z- and it-isomers of a,/j-unsaturated iron-acyl complexes. The hexamethylphosphoramide presumably coordinates to the base and thus prevents precoordination of the base to the acyl carbonyl oxygen, which has been suggested to direct the regioselective 1,4-addition of nucleophiles to -complexes as shown (see Section 1.1.1.3.4.1.2.). These results are also consistent with preference for the cisoid conformations depicted. 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

Know the meaning of Fischer esterification, nucleophilic addition-elimination (nucleophilic acyl substitution), tetrahedral intermediate, saponification, ammonolysis, acyl transfer. 

The resistance of the furoxan ring to chemical attack allows derivatives to be prepared via the reactions of the substituents (Section 4.22.3.4). Carboxylic acids are available by permanganate oxidation of methyl derivatives or by hydrolysis of the corresponding esters reaction with ammonia affords carboxamides. Acylfuroxans provide a source of hydroxyalkyl compounds by reduction, and oximes, for example, via nucleophilic addition. Acylation and oxidation of aminofuroxans allows the amide and nitro derivatives to be prepared. Nucleophilic displacements of nitro substituents can take place, but can be somewhat hazardous on account of the explosive nature of these compounds. Alkoxy derivatives are formed with sodium alkoxide, while reaction with thiolate anions yields sulfides, from which sulfones can be synthesized by peracid oxidation. Nitrofuroxans have also been reduced to... 

The acid or base elimination of a diastereoisomerically pure p-hydroxysilane, 1, (the Peterson olefination reaction4) provides one of the very best methods for the stereoselective formation of alkenes. Either the E- or Z-isomer may be prepared with excellent geometric selectivity from a single precursor (Scheme 1). The widespread use of the Peterson olefination reaction in synthesis has been limited, however, by the fact that there are few experimentally simple methods available for the formation of diastereoisomerically pure p-hydroxysilanes.56 One reliable route is the Cram controlled addition of nucleophiles to a-silyl ketones,6 but such an approach is complicated by difficulties in the preparation of (a-silylalkyl)lithium species or the corresponding Grignard reagents. These difficulties have been resolved by the development of a simple method for the preparation and reductive acylation of (a-chloroalkyl)silanes.7... 

The presence or absence of a leaving group on the electrophilic carbonyl carbon determines the strucmre of the product. Even though they appear somewhat more complicated, these reactions are often reminiscent of the nucleophilic addition and nucleophilic acyl substitution reactions of Chapters 21 and 22. Four types of reactions are examined ... 

The addition of nucleophiles to 1-acylpyridinium salts has surfaced as a powerful method for the synthesis of substituted pyridines. The 1-acylpyridinium salts are formed in situ by adding an acyl chloride to a pyridine in an aprotic solvent such as tetrahydrofuran. The formation of the 1-acylpyridinium salt is very rapid and will occur in the presence of various organometallics without significant competition from the reaction of the nucleophile and the acyl chloride. The addition of ethyl chloroformate to a mixture of pyridine and ethylmagnesium bromide gives 1,2- and 1-4-dihydropyridines 29 and 30 in a ratio of 64/36. Although these dihydropyridine intermediates can be aromatized with hot sulfur to 2- and 4-alkylpyridines, the poor regioselectivity makes this procedure unattractive. 

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