Indoles from hydrazones

Moreover an equivalent of the Fischer indolization of hydrazones proved to be a versatile method of the pyrrolotropone and -tropolone synthesis. Hydrazones like 178a (prepared from 2-hydrazinotropones and carbonyl... 

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... 

Pyridazinones were obtained from an attempted Fischer indolization of a cyclopentanone phenylhydrazone [85CI(L)697], from hydrazones of unsaturated 1,4-keto esters (87H2101) or from 3-arylhydrazones of 4-(4-methoxyphenyOglutaconic anhydride in the presence of seconday amines [83IJC(B)512]. Pyridazines 6 can be synthesized from 2-phenylhydrazones of 1,2,3-tricarbonyl compounds and phosphacumulenylides (80TL2939 85CB1709). 

The Buchwald-Hartwig amination reaction can facilitate the synthesis of nitrogen-containing heterocycles. For instance, Buchwald demonstrated that the amination reaction could be used to prepare N-arylhydrazones from hydrazones and aryl halides. Acid-catalyzed condensation of the hydrazone with a ketone then yielded the desired indoles.Hartwig described a similar arylhydrazone formation with DPPF as a ligand and CS2CO3 as a base."... 

Scheme 12 Synthesis of l-amino-lH-indole-3-carboxylates and l-benzoxy-l/7-indole-3-carboxylates from hydrazone and hydroxyamine derivatives...

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

Methylindole has been prepared from the a5-methylphenyl-hydrazone of pyruvic acid, by the action of sodium amide or sodium hydride on indole followed by methyl iodide at elevated temperatures,by treatment of indole with methyl p-toluene-sulfonatc and anhydrous sodium carbonate in boiling xylene, and by the action of inelhyl sulfate on indole previously treated... 

In general, electron donating substituents tend to direct the cyclization to the substituted position instead of the unsubstituted position, especially when there is no steric hindrance to cyclization arising from the ketone portion of the hydrazone. In contrast, when an electron withdrawing group such as CF3 or Cl is present in the orthoposition, indolization is then favored at the unsubstituted position (58). ... 

Two new polycyclic pyridoacridine alkaloids, arnoamine B, 289, and its demethylated analogue, arnoamine A, have been isolated from the ascidian Cystodytes sp. These new compounds are the first known examples of pyrroles fused to pyridoacridines, have antifungal properties, and are cytotoxic in several human tumor cell lines <1998JOC1657>. Both these compounds have been synthesized, starting from the hydrazone 290 with a Fischer indole synthesis (Scheme 73) <2000JOC5476>. 

In the first example of water as the reaction medium for Fischer indole synthesis, 2,3-dimethylindole was obtained in 67% yield from phenylhydrazine and butan-2-one, at 220 °C for 30 min (Scheme 2.15). Neither a preformed hydrazone nor addition of acid was required [33]. 

From what was plarmed as a straightforward displacement of the chloride atom in 36 with hydrazine followed by a condensation with 2-tetralone and Fischer indolization to produce 39, dihydrazone 38 was isolated as an intermediate, resulting fi om dihydrazine 37 <99JHC441>. Subsequent Fischer indole cyclization and aminolysis of 38 produced 39 a mono-hydrazone intermediate (as opposed to 38) was ruled out by the authors on the basis of H NMR. 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

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... 

In addition to preparation of arylhydrazones from the carbonyl compounds and an arylhydrazine, the Japp-Klingemann reaction of arenediazonium ions with enolates and enamines is an important method for preparation of arylhydrazones. This method provides a route to monoarylhydrazones of a-dicarbonyl compounds from /3-keto acids and to the hydrazones of pyruvate esters from / -keto esters. Enamines also give rise to monoarylhydrazones of a-diketones. Indolization of these arylhydrazones provides the expected 2-acyI-or 2-alkoxycarbonyl-indoles (equations 95-97). 

Thus to permit cyclization, there must be at least one hydrogen a to the C=N bond. If there is only one, the product will be a 3,3-disubstituted-3H-indole. However, if both substituents at the hydrazone carbon have one or more a-hydrogens, product mixtures can result. Generally, it is expected that the more branched substituent is more likely to be involved in cyclization, so typically phenylhydrazones derived from methyl alkyl ketones give 2-methylindoles. However, the selectivity is subject to the reaction conditions and with certain reagents the selectivity can be reversed to favor the 2-alkylindole. 

Acetone phenyl-hydrazoue is first prepared by mixing phenyl-hydrazine (30 gms.) with acetone (18 gms.). The mixture becomes warm and water separates it is then heated on the water-bath for half an hour, and at the end of this time heated in a dish on the water-batli, to drive off acetone and steam. The hydrazone is then mixed with five times its weight of anhydrous zinc chloride, and heated under a reflnx condenser in an oil-bath at 180°. A vigorous reaction takes place, and when completed, the dark-coloured mass is distilled with steam. The a-methyl-indole collects in the receiver and soon solidifies to a pale yellow mass. It may be purified by recrystallisiug from ligroin. M.p. 59°. Yield is over 60 per cent, of that calculated. 

In CHEC-II(1996), several applications of dihydro-2//-l,2,3-diazaphospholes, generated in situ from a ketone hydrazone and PC13, as useful intermediates for the synthesis of indoles, pyrroles, pyrrolylacetates, and 1,2-di-hydro-2-alkenyl-37/-pyrazol-3-ones are listed <1996CHEC-II(4)771>. 

The hydrazine 89 is made from the amine by nitrosation and reduction and the keto-acid 90 is available as levulinic acid. Now comes the big question when the Fischer indole synthesis is carried out on the hydrazone 91 which enamine is formed, the one we want 92, or the one we don t want 93 Since the Fischer indole is an acid- (or Lewis acid-) catalysed reaction we expect the more substituted enamine 92 to be favoured. 

The cyclization of the phosphorylated arylhydrazones, leading to compounds 168, presumably takes place through the initial formation of 3-phosphorylated indoles 69, which isomerize to compounds 168 in the course of the reaction. Such 3—>2 rearrangements are well-known [30, 180-182, 231]. The transposition of the phosphorus-containing substituent in indoles was first observed in [178, 179]. In the review [8] the data on the formation of 2-phosphorylindoles from the arylhydrazones of phosphorylpropionic aldehyde were considered proved, but the results on the cyclization of hydrazones of phosphorylacetaldehyde to the 2-isomers were placed under some doubt. 

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