Hydrazones acylated, reduction

An alternative synthesis from the Glaxo patents involves Fnedel-Crafts acylation of the 3-position of the indole intermediate 22 (Scheme 5) Reaction of hydrazine 10 with (phenylthio)acetaldehyde gave hydrazone 20, which was subjected to the Fischer indole reaction to give 3-thiophenylindole 21. It is noteworthy that this Fischer cyclization took place at room temperature because most require heat. Reductive desulfurization of 21 using Raney nickel provided indole 22. Acylation of the 3-position... 

Appropriate functionalization of C=N bonds can greatly assist their asymmetic reduction. In particular, the reduction of N-acyl hydrazones with a rhodium complex of the ligand DuPHOS (P13) represents an outstanding example. In this process (Scheme 62) a product of up to 97% e.e. is obtained in high yield. After the reduction, samarium-iodide cleavage of the N—N bond gives the product amine273,274. 

Aryl alkyl ketones are readily prepared by the Friedel-Crafts acylation process (see Section 6.11.1, p. 1006) and their Clemmensen reduction constitutes a more efficient procedure for the preparation of monoalkylbenzenes than the alternative direct Friedel-Crafts alkylation reaction (see below). Alternatively aldehydes and ketones may be reduced to the corresponding hydrocarbon by the Wolff-Kishner method which involves heating the corresponding hydrazone or semicarbazone with potassium hydroxide or with sodium ethoxide solution. 

Reductions of hydrazones with LAH may, as expected, proceed further if carbonyls or other susceptible groups are present. Thus, A -acyl hydrazones (e.g. 30) give A -alkylhydrazines along with the A -acyl derivative (equation 7), while the phenylosazone (31) gave further rearrangements of the intermediate dihydrazine to afford (32 equation... 

The reduction of cyclic acylated hydrazones like pyridazinones [59] and phthalazi-nones [81] is discussed in Chapter 18. 

In a similar way, other pyridazines [306], such as 3-phenyl-6-methoxypyridazine and 3-methyl-6-chloropyridazine, are reduced, but the dihydropyridazines are in these cases rather unstable and may lose methanol or hydrogen chloride, forming the corresponding 4,5-dihydropyridazinone, which being an acylated hydrazone is cleaved with ring opening and reduction or hydrolysis of the ketimine (Chapter 11). 

Many thiadiazoles are polarographically reducible [148, 351] not many of them have been investigated by controlled potential electrolysis. The wave height of 2,5-diphenyl-1,3,4-thiadiazole (LX) corresponds in acid solution to a two-electron reduction to a dihydro derivative, which is probably hydrolyzed to benzaldehyde thiobenzoylhydrazone. This compound is reducible at the reduction potential of LX and will thus be reduced further similarly to other acylated hydrazones (Chapter 11). 

A reduction route similar to that of phenylhydrazones [229] seems to be rather general for azomethine derivatives of hydrazine [229] as it s followed by cyclic and acylic phenylhydrazones, semicarbazones, azines, cyclic hydrazones, and acylated cyclic and acyclic hydrazones [231] under pro tic conditions in DMF, acylated hydrazones of aromatic aldehydes are reduced with saturation of the C=N bond and cleavage of the N-N bond at a more negative potential [232]. The suggestion that the cleavage of the N-N bond precedes the saturation of the azomethine bond is also an essential part of the interpretation of many of the ring contractions of heterocyclic compounds (Chapter 18). 

---