Fischer indole synthesis hydrazones

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)... 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

In order to allow further transformation to an indole, the carbonyl compound 8 must contain an a-methylene group. The hydrazone 1 needs not to be isolated. An equimolar mixture of arylhydrazine 7 and aldehyde or ketone 8 may be treated directly under the reaction conditions for the Fischer indole synthesis. ... 

A microwave-assisted version of the Fischer indole synthesis was described by reaction of the hydrazone 179 [119]. The reaction was carried out on Mont-morillonite KIO doped with ZnCl2 giving reasonable yields of compound... 

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]. 

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... 

Heating of an aryl hydrazone 1 in the presence of a catalyst leads to elimination of anunonia and formation of an indole 2. This reaction is known as the Fischer indole synthesis,and is somewhat related to the Benzidine rearrangement. 

As lactams of 4-amino-3-oxobutanoic acids, tetramic acids react with amines (87JPJ858) and with phenylhydrazine. The latter reaction is catalyzed with para-toluenesulfonic acid. Thus, for example, l/2b give phenyl-hydrazone 65 in 80% yield that, in turn, under the conditions of the Fischer indole synthesis, may give rise to pyrrolo[4,3-b]indolene 66 (90TH1). (See Fig. 31.)... 

Under conditions (CaO, 200°C) different to those used to convert hydrazones in the Fischer indole synthesis, phenylhydrazides (66) give oxindoles (67) (Brunner synthesis). Treatment of /V-chloroacetyl derivatives of primary or secondary arylamines with aluminum chloride also provides oxindoles (PhNRCOCH2Cl — 68) <54Jcsi697>. 

The Fischer Indole Synthesis and Related Sigmatropic Syntheses. In the Fischer indole synthesis (26) an N-arylhydrazone is cyclized, usually under acidic conditions, to an indole. The key step is a [3,3]sigmatropic rearrangement of an enehydrazone tautomer of the hydrazone. 

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. 

Azoles can be produced from products of palladium-catalyzed hydrazone arylation and can serve as substrates for arylation reactions to produce N-aryl azoles. The Fischer indole synthesis uses N-ary I hydrazones, and these hydrazones can be generated by palladium-catalyzed chemistry. Benzophenone hydrazone was found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (24) [140,141]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields using either DPPF- or BINAP-ligated palladium. These reactions are general and occur with electron-rich, electron-poor, hindered or unhindered aryl halides. The products of these reactions can be converted to hydrazones that bear enolizable hydrogens and are suitable for indole synthesis in the presence of acid and ketone [140]. 

The Buchwald group exploited the Pd-catalyzed hydrazone synthesis for the efficient preparation of indoles. While removal of the benzophenone moiety and isolation of the free hydrazine did not proceed cleanly, the MIT workers found that Fischer indole synthesis could be effected by in situ exchange of the ketone group. The desired indoles could thus be isolated in good to excellent yield over two steps,Eq. (149) [121]. 

The synthesis of azaindoles by the Fischer indole synthesis has been tried more often than by any other method. It has given varied results, with over thirty successful ring closures of pyridyl- or quinolyl-hydrazones reported. Most of these have led to carboline deriva-... 

There is clearly a Fischer indole synthesis in the second step but the first step makes the usut. hydrazone in a most unusual way. The first reaction is diazotization so we have to combine fi diazonium salt with the enolate of the keto-ester. That creates a quaternary centre and the KC H deacylates it to give the aryl hydrazone needed for the Fischer reaction. 

Fischer indole synthesis. Formation of indoles on heating aryl hydrazones of aldehydes or ketones in the presence of catalysts such as zinc chloride, or other Lewis acids, or proton acids. 

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