Hydrazone derivatives, conversion

Hydroxybenzaldehyde has extensive use as an intermediate in the synthesis of a variety of agricultural chemicals. Halogenation of Nhydroxybenzaldehyde, followed by conversion to the oxime, and subsequent dehydration results in the formation of 3,5-dihalo-4-hydroxybenzonitrile (2). Both the dibromo- and dhodo-compounds are commercially important contact herbicides, hromoxynil [1689-84-5] (2) where X = Br, and ioxynil [1689-83-4]( where X = I respectively (74). Several hydrazone derivatives have also been shown to be active herbicides (70). 

Nonoxidative cyclization of acylhydrazones in acetic anhydride yields 4-acetyloxadiazolines, as in the conversion of hydrazone (96f R = 2-benzthiazolyl) into oxadiazoline (90b) <89MI 406-03). Hydrazones derived from tetra-O-acetyl-D-arabinose cyclized (Ac20/ZnCl2) to oxadiazoles pos-... 

As noted above, it is not easy to purify unsubstituted hydrazones. Therefore, reactions of hydrazone derivatives with iodine monofluoride have also been studied (Table 1). A-Methyl-and iV,iV-dimcthylhydrazones react more slowly than unsubstituted hydrazones with iodine monofluoride higher tempteratures are often required for their conversion into ge/w-difluorides (Table 1). The reason for this behavior is that elimination of iodomethane from the intermediates is less favorable (see Scheme 1, R = Me). The use of pure derivatives increases the yield in cases sensitive to hydrolysis (cf. entries 25 and 26). 2,4-Dinitrophenylhydrazones only react with iodine monofluoride at temperatures above O C. The yields are generally lower than in the case of unsubslituted hydrazones, and 2,4-dinitrophenylhydrazones formed from aldehydes are unreaetive. 

Compound (1) and its enantiomer provide a variation on the same theme of stereospecific reductive amination. In this case, reduction of a chiral cyclic hydrazone (derived from an a-keto acid and (1)) with Aluminum Amalgam in wet DME proceeds with high stereoselectivity. Reductive cleavage of the N-N bond and ester hydrolysis complete the procedure, which produces a-amino acids with high optical purity (eq 4). The source of chirality is recovered by conversion of the resulting indoline-2-methanol back into (1). ... 

As is the case with Wolff-Kishner reactions, the application of tosylhydrazone reductions relies on the successful conversion of carbonyls to the requisite hydrazone derivatives (58). This usually presents no problem except with relatively hindered or deactivated ketones and, in fact, several failures of the methodology are traced to unsuccessful tosylhydrazone formation (i.e. for examples with 62, 63, -- diketone (9) in equation 4, and the substrate of entry 3, Table 2). 

Conversion of the aldehyde to protected derivatives at the same level of oxidation (such as ketals, oximes, hydrazones) has been long known. A new hydrazone derived from 4-aminothiomorpholine S,S-dioxide has been carefully investigated [134, 138] and some thiazolidine derivatives have been recently evaluated [136]. C-20 thioketals have been recently introduced, which are especially useful as an aldehyde-protecting group when hydrolysis of the acid-labile mycarose is not wanted their synthesis is accomplished by treatment of the aldehyde with diphenyldisulfide and a trialkylphosphine [134, 139]. The aldehyde has also been transformed into ketones with diazoalkanes [134]. 

The hydrazone derivatives, oximes, and semicarbazones discussed in this section are rather specialized compounds. Why mention them Organic chemists rely on spectroscopy (see Chapter 14) to identify the structure of organic compounds, but prior to the development of spectroscopy, chemical reactions were used as an identification tool. One such method converts unknown organic compounds to solid derivatives. The color and melting point of several derivatives are cross-referenced to a library of known derivatives to help identify the unknown. The conversion of aldehydes and ketones to phenylhydrazones, 2,4-dinitrophenylhydrazones, oximes, and semicarbazones is one method used for derivatization. 

Conversion of Hydrazones into gewi-Dibromides. Treatment of hydrazones derived from either aliphatic aldehydes or ketones with CuBr2/LiO Bu gives ewt-dibromides in fair to good yields (eq 32Moreover, LiO Bu can be conveniently replaced with EtsN without affecting yield. The hydrazoneprepared from a-tetralone leads to the vinyl bromide instead, but an aromatic aldehyde has been converted into an a,a-dibromotoluene derivative via the hydrazone intermediate. ... 

Conversion of a ketone into the corresponding chiral hydrazone derivative (19) enables alkylation to beachieved with high (<87%)enantioselectivity (Scheme 24). Even more impressive, enantioselective alkylations are observed when the chiral enamine (18) is metalated and treated with alkyl halide. ... 

Evidently, analogously to the mentioned cyclization of similar oximes to ben-zisoxazole derivatives (See Section II.A), reaction can take place only in compounds with suitable configuration. However, in case of hydrazones, due to the tautomeric equilibrium of both possible configurations, the reaction usually achieves complete conversion. The usual setup involves heating with the respective hydroxide if an ester group is present, it is partially or completely hydrolyzed to the corresponding acids, which, in addition, can also undergo decarboxylation. 

Watanabe reports a new method for the direct conversion of o-choroacetaldehyde N,N-disubstituted hydrazones into 1-aminoindole derivatives 93 by palladium-catalyzed intramolecular ring closure of 92 in the presence of P Bu3 or the bisferrocenyl ligand 94 <00AG(E)2501>. When X = Cl, this cyclizative process can be coupled with other Pd-catalyzed processes with nucleophilic reagents (e.g., amines, azoles, aryl boronic acids) so as to furnish indole derivatives with substituents on the carbocyclic ring. 

The (R)-enantiomer of (242) has also been prepared and used as a chiral auxiliary in an enantioselective aldol synthesis of (+)-(S )-gingerol (79CB3703). (R )-Glutamic acid (246) was thus converted into (i )-pyroglutamic acid by simply heating in water. Conversion of (247) to its methyl ester and LAH reduction delivered alcohol (248). Ethyl nitrite treatment of (248) gave nitrosoamine (249), which was methylated to furnish (250). Exposure of (250) to LAH completed the synthesis of the required chiral auxiliary RAMP [(R)- l-amino-2-(methoxymethyl)pyrrolidine]. The hydrazone (252), derived from RAMP and acetone, was... 

Because substituted anilines are widely available, they are ideal starting materials for the synthesis of indoles. Although anilines are often the precursors of the hydrazones used in the Fischer cyclization, more direct methods for conversion of anilines to indoles would be highly desirable. Such a process would, in general, have to involve some method for specific o -substitution of the aniline derivative. In the most successful method of this type which has been developed to date, a specific rearrangement effecting o-substitution is the key to a synthetic scheme which constructs indoles from anilines via anilinosulfonium ions. The procedure, which in appropriate circumstances can be carried out without isolation of the intermediates, involves oxidation of the aniline to an A-chloroaniline, reaction with a thiomethylmethyl ketone and a weak base, followed by cyclizative condensation (equation... 

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