Indoles, phenylhydrazines

INDOLES Phenylhydrazine. Sodium amide-Sodium r-butoxide. 

Phenylhydrazine condenses with acetoacetic ester to give a pyrazolone derivative which on methylation gives phenazone. The sulphonic acid similarly gives rise to the tartrazine dyestuffs. It is used to make indole derivatives by the Fischer process. 

Phenylhydrazine has been used in the synthesis of indole derivatives. The hydrazones of aldehydes and ketones contain-... 

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

The classic and most convenient synthesis of the indole moiety is that of Emil Fischer. Recent examples of its use for drug synthesis includes one preparation of the nonsteroidal antiinflammatory agent, indoxole (2). Reaction of ketone 1 with phenylhydrazine in acetic acid leads directly to indoxole (2). Alternately, anisoin (3) can be reacted... 

On the other hand, the nonbiogenetic approach usually adopts a convergent process such as shown in Scheme 15. When 18 is cleaved through C-6—C-7 (as 18 - 60), phenylhydrazine and a tricyclic moiety (61) which contains six chiral centers result. The synthetic problem then becomes synthesis of 61 followed by a Fischer indole synthesis and a final ring closure between C-6 and C-7 (61 -> 60 - 18). 

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]. 

Interestingly, the Fischer indole synthesis does not easily proceed from acetaldehyde to afford indole. Usually, indole-2-carboxylic acid is prepared from phenylhydrazine with a pyruvate ester followed by hydrolysis. Traditional methods for decarboxylation of indole-2-carboxylic acid to form indole are not environmentally benign. They include pyrolysis or heating with copper-bronze powder, copper(I) chloride, copper chromite, copper acetate or copper(II) oxide, in for example, heat-transfer oils, glycerol, quinoline or 2-benzylpyridine. Decomposition of the product during lengthy thermolysis or purification affects the yields. 

Allen und Wilson 4) fiihrten die E. FiscHERsche Indolsynthese mit Phenylhydrazin durch, in dem der dem Benzolkern benachbarte Stickssoff einen UberschuB an 15N enthielt. Der gesamte UberschuB an 15N wurde im erhaltenen 2-Phenyl-indol gefunden, wie es nach der Theorie von Robinson und Robinson 171) und den Versuchen von E. Fischer 79) mit asymmetrischem Methylphenylhydrazin zu erwarten war. 

Iwakawa et al. studied the reaction of 3-acetonyl-5-cyano-l,2,4-thiadiazole 72 with a series of 4-substituted phenylhydrazine hydrochlorides. When electron-donating substituents were used (e.g., methyl and methoxy) in the phenyl ring of the hydrazine, the reaction proceeded via a Fischer-indole mechanism to give indoles 73 as the sole product. In contrast, reaction of 72 with phenylhydrazine and 4-chlorophenylhydrazine gave only small amounts of indole 72, but much higher yields of the pyrazole 74. The authors described in detail the respective reaction mechanisms... 

The Sn2 reaction of quinazolinone 147 with phenylhydrazine was followed by rearrangement of the tautomerized intermediate 148 <00T7987>. The loss of both ammonia and aniline was followed by the addition of a second equivalent of phenylhydrazine to the resulting imine to produce quinazolinone hydrazone 149. Subsequent Fischer indolization of 149 followed by condensations with aldehydes led to 7-azarutacarpines. 

To 21.6 g phenylhydrazine dissolved in 300 ml 0.3N sulfuric acid, add 9.8 g concentrated sulfuric acid. Add dropwise with stirring and heating at 100°, 11.6 g methyl-beta-formyl-propionate in 300 ml 0.3 N sulfuric acid and continue heating six hours to get 14 g indole-3-acetic acid. Convert to the dialkyltryptamine as already described. 

With phenylhydrazine, a mixture of pyrazoles 587 and 3H-indoles 591 were formed via conjugate addition, C=C bond migration and cyclic animation of the nitrile group or [3,3]-sigmatropic rearrangement of 3-amino-3-alkenenitriles 585, respectively [268a],... 

Experiment. E. Fischer s Indole Synthesis.—Mix 2 g. of phenylhydrazine with 2 c.c. of acetone in a test tube. Water is eliminated and a turbidity appears. Suspend the tube in the boiling water bath for forty-five minutes, then add 6 g. of dry zinc chloride and heat the mixture for a few minutes with stirring in an oil bath at 180°. Now wash the dark-coloured melt into a small round-bottomed flask with four volumes of dilute hydrochloric acid and separate the resultant a-methylindole by distillation with steam. The substance collects as an oil which soon solidifies. After drying crystallise it from a little petrol ether. Melting point 59°. 

Indole-3-Acetic Acid. Dissolve 21.6 g of phenylhydrazine in 300 ml 0.3 N sulfuric acid. To this solution add 9.8 g of coned sulfuric acid. With stirring and heating to 100°, add dropwise 11.6 g of methyl-beta-formyl-propionate in 300 ml of 0.3 N sulfuric acid. Continue the heating and gentle stirring for 6 hours to get about 14 g of indole-3-acetic acid. This is from CA, 72, 66815 (1970). 

The most useful route to indoles is the Fischer indole synthesis, in which an aromatic phenylhydrazone is heated in acid. The phenylhydrazone is the condensation product from a phenylhydrazine and an aldehyde or ketone. Ring closure involves a cyclic rearrangement process. 

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the Rogers-Corson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10-hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3-dimethylaminopropyl chloride. There is thus obtained iprindol (25). ... 

The cyclohexanone phenylhydrazone (512), obtained by reacting cyclohexanone (510) with phenylhydrazine (511), on indolization, furnished tetrahydrocarbazole 513 which, on dehydrogenation, afforded carbazole 514. The success of the reaction is dependent on the reagent used for indolization and the dehydrogenating agent. The mechanism for the formation of the tetrahydrocarbazole involves a tautomeric equilibrium and the formation of a new C-C bond via a [3,3]-sigmatropic rearrangement followed by elimination of ammonia (495,496,498) (Scheme 5.7). 

Mechanistically, this reaction resembles the Fischer indole synthesis and is based on the condensation of the naphthyl alcohol or naphthylamine in its oxo form with phenylhydrazine, and subsequent rearrangement (496,505,508-510) (Scheme 5.11). 

Five years later, the same authors reported an improved total synthesis of arcyriaflavin A (345) starting from the TBS enol ether 1490 (for the synthesis see Scheme 5.252). This route involves two indolizations based on silyl enol ether nucleophilic attack and Fischer processes. Using Cadogan s procedure by heating in triethyl phosphite, the TBS enol ether 1490 was transformed into the ketone ( + )-1495, involving silyl enol ether-mediated indolization. Finally, Fischer indolization of (+ )-1495 by reacting with phenylhydrazine (524) led directly to arcyriaflavin A (345) in 57% yield (794) (Scheme 5.253). 

The intermediacy of phenylhydrazones 369 (R = H = Me) is suggested in the transformation of some 2-alkylindoles into the corresponding pyrazoles 370 by the reaction with phenylhydrazine hydrochloride in refluxing acetic-hydrochloric acid (Scheme 58) (76CJC1020). Here, after preliminary acetylation at C(3) of the indole by the acetic-hydrochloric... 

Most indoles are synthesized by the Fischer indolization reaction. Here a phenylhydrazine is first reacted with an aldehyde, or ketone, carrying an a-methylene group (not acetaldehyde). The corresponding hydrazone is then treated with an acid, often hydrochloric acid. Ring closure occurs, through a [3,3]-sigmatropic change, and ammonia (as the ammonium cation) is lost (Scheme 7.14). 

A variant on the traditional method is to use a phenylhydroxylamine instead of a phenylhydrazine. For example, A-(benzyloxycarbonyl)-phenylhydroxylamine can be reacted with methyl propynoate to give an adduct that spontaneously undergoes a [3,3]-sigmatropic shift and eventually yields l-(benzyloxycarbonyl)-3-(methoxycarbonyl)indole (Scheme 7.15). 

Carboxy-2-pyridylthio)propionic acids, prepared by the reaction of 2-mercatopyridin-3-carboxylic acid with 3-bromopropionic acid in aqueous KOH, undergo cyclization upon treatment with anhydrous sodium acetate and acetic anhydride to afford 2,3-dihydrothiopyrano[2,3-3]pyridin-4(4//)-ones. These products undergo further reaction with phenylhydrazine to give the phenylhydrazone (isolated) and then Fischer indole cyclization to give novel 5/7,1177-pyrido[2, 3 2,3]thiopyrano[4,3-3]indoles <2000JHC379>. 

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.)... 

Reaction of desoxyanisoin (11-1) with phenylhydrazine goes in a straightforward manner to hydrazone (11-2). Treatment of that intermediate with acetic acid leads to the formation of the indole ring and the formation of indoxole (11-3) [10]. 

When arylhydrazones of aldehydes or ketones are treated with a catalyst, elimination of ammonia takes place and an indole is formed, in the Fischer indole synthesis.515 Zinc chloride is the catalyst most frequently employed, but dozens of others, including other metal halides, proton and Lewis acids, and certain transition-metals have also been used. Arylhydrazones are easily prepared by the treatment of aldehydes or ketones with phenylhydrazine (6-2) or by aliphatic diazonium coupling (2-7). However, it is not necessary to isolate the arylhy-drazone. The aldehyde or ketone can be treated with a mixture of phenylhydrazine and the catalyst this is now common practice. In order to obtain an indole, the aldehyde or ketone must be of the form RCOCH2R (R = alkyl, aryl, or hydrogen). 

Fisher indole synthesis.1 2,3-Disubstituted indoles are formed in 70-90% yield when a ketone phenylhydrazone is treated in benzene with PC13 at 25°. The same indoles are formed when the ketone and phenylhydrazine are treated with PC13. PC15 is less satisfactory than PC13. The method is not applicable to aldehydes. 

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