Aldehyde dialkyl hydrazones

Fluorocylatwn of enarnines and enamides has been intensively studied by different groups [78, 79, 80 SI] The effectiveness of this particular electrophilic substitution reaction becomes obvious when the nitrogen atom of the enamine moiety is engaged in an aromatic system [82 S3] or when the olefinic system is part of an aromatic nucleus [84] (equations 37 and 38) A further extension of this reaction is demonstrated by the tnfluoracetylation of aldehyde dialkyl hydrazones [S5 86] (equation 39)... 

Hojo reported a selective synthesis of 4-(trifluoromethyl)imidazoles (Scheme 35) [49], The diketones, prepared from aldehyde dialkyl hydrazones via the hydrolysis of 3-(dialkylhydrazino)-l,l,l-trifluoro-2-aIkanone intermediates, were treated with 1,1-dimethylhydrazine to afford the adduct. These adducts were generally unstable even at room temperature and, thus, were immediately dehydrated using POCI3-pyridine to afford 3-aryl-l,l,l-trifluoropropane-2-,3-dione-2-dimethylhydrazone. Intramolecular cyclization of these hydrazones in refluxing toluene afforded the desired 4-(trifluoromethyl)imidazoles. 

Thiamine-catalyzed transformations are reversible, thus TV,/V-dialkyl hydrazones were selected as alternative acyl anion equivalents that were reported to react with electrophiles without acidic activation.41 One especially reactive example, formaldehyde hydrazone resin 13, was constructed from polymer-supported hydrazines and was employed in the first polymer-supported, uncatalyzed acyl anion additions (Fig. 8).38 As test substrates, nitroalkenes (as Michael acceptors) and activated aldehydes were selected. Reactivity of these acyl anion equivalents depended critically not only on the nature of the starting hydrazine, but also on the protocol for hydrazine formation. 

In DMF, benzalazine (VII) shows two, one-electron steps in CV. Preparative reduction of VII in the presence of an alkylating agent yields alkylated bis-hydrazines (VIII) or the dialkylated hydrazone (IX) [51], as in Eq. (14). An assignment of the stereochemistry of the bis-hydrazones, obtained by reduction of VII followed by protonation, could be achieved by cyclization with aldehydes to imidazolidines. 

The SAMP/RAMP Method As early as 1976, azaenolates derived from A,A-dialkyl hydrazones were studied as an alternative to direct ketone and aldehyde enolate alkylations. These species were found to exhibit higher reactivity toward electrophiles, as well as better regioselectivity for C-alkylation than their parent carbonyl compounds. A,A-diaIkyl hydrazones are stable and are relatively easy to prepare, making them appealing from a practical point of view in comparison with imines and enamines, which can be difficult to form quantitatively and are hydrolytically unstable. Given these desirable attributes, Enders undertook the development of chiral nonrace-mic A,A-diaIkyl hydrazine auxiliaries for the asymmetric a-alkylation of ketones. The result of his efforts were (5)-and (R)-l-amino-2-methoxypyrrohdine hydrazine (1 and 2, respectively), now commonly known as the SAMP and RAMP auxiliaries, respectively (Figure 7.1). Over the years, the SAMP/RAMP method has come to be considered the state-of-the-art approach to asymmetric ketone... 

Hydrazines may be nucleophiles such as when they interact with aldehyde and keto groups to form hydrazones. This is the basis for the inhibition of enzymes such as transaminases, which rely on pyridoxal phosphate as a coenzyme. Mono-substituted hydrazines can be formed as metabolites when azo groups are reduced, dialkylated hydrazines are dealkylated or hydrazides are hydrolysed. 

A novel cyclization of trifluoroacetylated hydrazones, prepared by TFAA treatment of -dialkyl aldehyde hydrazones, was reported by Hojo for the synthesis of 5-trifluoromethylimidazoles (Scheme 36) [50]. Formation of the 4-(trifluoro-methyl) isomers was observed in some cases along with the major 5-(trifluoro-methyl)imidazole products, presumably due to isomerization of trifluoroacetylated hydrazones (Table 2). This isomerization is suggested to be enhanced in the presence of silica gel and the isomeric trifluoroacetylated hydrazones cyclized to give the 4-CF3-imidazoles in refluxing toluene (c.f. Scheme 35). 

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