Acid halides reduction

Naphthenyl alcohols are formed by reduction of the acids or their simple esters. They are valuable as surfactants, solvents, and components of lubricants. The acid halides are of value mainly as chemical intermediates (1). 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Reaction No. 5 (Table 11) is part of a synthetically useful method for the alkylation of aromatic compounds. At first the aromatic carboxylic acid is reductively alkylated by way of a Birch reduction in the presence of alkyl halides, this is then followed by an eliminative decarboxylation. In reaction No. 9 decarboxylation occurs probably by oxidation at the nitrogen to the radical cation that undergoes decarboxylation (see... 

Supplemental Reference for Table 9. Organosilane Reduction of Acid Halides... 

A useful approach for the preparation of chiral (3-aminophospho-nic acids from the naturally occurring a-amino acids has been reported.139 The overall scheme (Equation 3.4) involves formation of the phthalimide-acid halide from the starting a-amino acid followed by a Michaelis-Arbuzov reaction with triethyl phosphite to give the acylphosphonate. Complete reduction of the carbonyl group in three steps followed by hydrolysis of the ester and amide linkages provides the target material in very high yield without racemization (>99% ee). 

The 7-hydroxy-a,/3-( )-alkenoic esters were prepared readily from acid halides and silver acetylenides followed by NaBH4 reduction (Table 7).515... 

Pletcher and associates [155, 159, 160] have studied the electrochemical reduction of alkyl bromides in the presence of a wide variety of macrocyclic Ni(II) complexes. Depending on the substrate, the mediator, and the reaction conditions, mixtures of the dimer and the disproportionation products of the alkyl radical intermediate were formed (cf. Section 18.4.1). The same group [161] reported that traces of metal ions (e.g., Cu2+) in the catholyte improved the current density and selectivity for several cathodic processes, and thus the conversion of trichloroacetic acid to chloroacetic acid. Electrochemical reductive coupling of organic halides was accompanied several times by hydrodehalogena-tion, especially when Ni complexes were used as mediators. In many of the reactions examined, dehalogenation of the substrate predominated over coupling [162-165]. 

Amides are the least reactive of the carboxylic acid derivatives, and undergo acid or base hydrolysis to produce the parent carboxylic acids, and reduction to appropriate amines (see Section 4.3.10). They can also be dehydrated to nitriles, most commonly with boiling acetic anhydride, (AcO)20, sulphonyl chloride (SOCI2) or phosphoms oxychloride (POCI3) (see Section 4.3.18). Amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous NaOH or KOH. This reaction is known as Hofmann rearrangement (see Section 4.3.10). 

Na-Protected a-amino aldehydes 4 are mainly obtained from their corresponding a-amino acid derivatives. Generally the synthetic route proceeds via acid halides, esters, or active amides of a-amino acids that are then reduced. The reduction of N -protected acid halides and esters is often accompanied by some overreduction to the respective alcohols. However, reduction of active amides is apparently free from overreduction. The different procedures described in this review are listed in Table 3. 

Reduction of carbonyl compounds with metal hydrides or boranes a. primary alcohols from aldehydes, acids, acid halides, and esters... 

Alternative methods for the synthesis of peptide aldehydes include reduction of acid halides, phenyl esters, thioesters, and anhydrides prepared from corresponding acids, isoxazolidides, and the hydrolysis of thiazolidine peptides 17,54-56 Enzymes such as thermolysin, subtilisin, and pronase E have proven valuable as effective semisynthetic alternatives 40,57 5 62 ... 

Reduction of acid halides with lithium tri-tert-butoxyaluminum hydride is an effective method for synthesis of amino aldehydes. Nonfunctionalized amino aldehydes 22 are readily prepared from respective reduction of the N-terminal Fmoc, Boc, or Z acid chlorides or fluorides 21 (Scheme 8, Table 9). This method afforded these aldehydes in about 60% yield with small differences in optical rotation as compared to literature values 11,33 48 54 55 ... 

The approach involves the reaction of a mid-valent metal halide with a mixture of arene, aluminium chloride (Lewis acidic halide abstractor) and aluminium powder (mild reductant). The charge on the resulting bis(arene) sandwich (n+) is generally dictated by the nature of the metal and EAN requirements, although once isolated, further reduction may be possible with stronger reductants. The approach can also be applied... 

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