Diazonium salts, reaction with indoles

Aniline 77 was converted into its diazonium salt with nitrous acid and this was followed by reduction with stannous chloride to afford the corresponding arylhydrazine 78. Condensation of 78 with 3-cyanopropanal dimethylacetal 79 gave the arylhydrazone 80. Treatment of 80 with PPE resulted in cyclization to indole 81. The nitrile group was then reduced to the primary amine by catalytic hydrogenation. Reaction of the amine with excess formalin and sodium borohydride resulted in Imitrex (82). 

Fischer disconnection of the indole 30a (chapter 39) gives methyl pyruvate and an aryl hydrazine that would have to be made from the corresponding diazonium salt that would have to be protected on the other amino group 36. They decided to take a short cut by using the Japp-Klingemann reaction on the same diazonium salt with the easily made acetoacetate 35. 

Binks and Ridd164 have made a complete kinetic study of the reaction of indole with several diazotized amines (p-nitroaniline, p-chloroaniline, sulfanilic acid, and aniline). Only the reaction with p-nitrodiazonium salt exhibits a simple kinetic form (pseudo first-order reaction) in the other cases the kinetics appear to be due to the superposition of two reactions, a normal azo-coupling reaction and an autocatalytic side reaction that removes diazonium ions, but does not form azo compounds. 

Ring closure reactions taking place by intramolecular addition of an aromatic radical to a double bond have been widely studied on both their regio- and stereochemical aspects [93]. Aryl halides and diazonium salts substituted at ortho- position with a 0-allyl or TV-allyl chain were used for the preparation of 2,3-dihydrobenzofuranes and 2,3-dihydro-1/7-indoles under different reaction conditions. The reaction pattern involves the generation of an aryl radical 20, which reacts with the double bond in a 5-exo trig fashion to afford the exocyclic radical 21, plausible of reduction by a hydrogen donor to obtain the reduced-cyclized product 22 (Sch. 23) [93d,94]. 

A related strategy is based on application of the Japp-Klingemann reaction as an alternative means for preparation of the required hydrazones. For example, the the diazonium salt 346 was reacted with the ketone 347 affording the hydrazone 348, which was subsequently cyclized to the tryptamine derivative 349 (Scheme 43) <2000H(53)665>. The Japp-Klingemann reaction has also been employed as a key step in syntheses of cyclopenta[3]indoles <2005JOG8385,... 

Diazoindoles are very similar in their properties to diazopyrroles (see Table II). 3-Diazoindoles are stable crystalline compounds sensitive to light and forming stable diazonium salts with strong acids. 3-Diazoindoles cannot be prepared by the direct reaction of the indole with nitrous acid, presumably because the nitroso compound (43) completely rearranges to the oximoimine form (44).22 (See p. 12.)... 

Indoles have been prepared from reactions of o-aminophenylketones with reactive , or stable " arsonium ylides. Oxo-stabilized ylides reacted with 2-chloro-oximes to give trans-5-acyl-A -isoxazolines, and isoxazoles have been obtained from reactive arsonium ylides and a-isonitrosoketones, and from triphenylarsonium methylide and nitrile oxides The latter ylide reacts similarly with nitrile imines to give pyrazoles. With triphenylarsonium benzylides and benzoylylides,benzene diazonium salts give 1,3,4,6-substituted 1,4-dihydro-1,2,4,5-tetrazines in a reaction in which initial coupling of the reagents is followed by a dimerisation. ... 

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. 

A colorimetric method for microdetermination of sulfonamides based on diazotization of the drug with sodium nitrite and hydrochloric acid has been reported (59). The diazonium salt is then coupled with 8-hydroxyquinoline in alkaline medium and the absorbance of the developed color measured at its maximum wavelength. A similar method involves diazotization and coupling of the sulfonamide with indole in alkaline solution to form an intense yellow azo dye which exhibits maximum absorption at 449 nm. Beer s law is obeyed over the concentration range 1-32 /ig/ml with a relative standard deviation of less than 2% (60). The reaction of sulfonamides with chloramine-T in sulfuric acid gives a yellow product which is suitable for the determination of sulfonamides in different formulations. It has an accuracy similar to that of the Bratton and Marshall method (61). 

Application of the Japp-Klingemann reaction to an arylamine can be a convenient synthesis of some indoles. In this reaction, a diazonium salt is formed in situ and is coupled with the active methylene group of ethyl 2-methyl-... 

Serotonin has been synthesised by several routes the method shown relies on a Fischer indole synthesis, the requisite aryl-hydrazone being constructed by a process known as the Japp-Klingemann reaction in which the enol of a 1,3-dicarbonyl compound is reacted with an aryl-diazonium salt, with subsequent cleavage of the 1,3-dicarbonyl unit. 

In the presence of copper, the diazonium salts 54 give the 2JF/-pyrroles 55 (Scheme 18) when R = COMe or C02Et.56 Successful cyclization apparently requires an electron-withdrawing group at the 3-position, for with 54 (R = Me) the reaction followed a different course. A spiro-2/f-pyrrole related to 55 was prepared recently under conditions for the Fischer indole synthesis.568... 

Murphy utilizies the free radical chemistry of diazonium salts rather than aryl halides in a new indole synthesis <97TL7295>. Thus, diazotization of the anilines 65 to afford the diazonium ions 66 afforded the indoles 67 after treatment with sodium iodide. This methodology is a useful complement to Murphy s approach to indolines by radical-polar crossover reactions <97JCS(P1)1549>. 

Phenylazoderivatives were synthesized by means of azocoupling reaction of benzopyrroloindole I, indolo[4,5-e]indole IV with substituted phenyldiazonium chlorides in aqueous- dioxane solution with molar ration of substrate and diazonium salt, 1 3 [4-6]. 

Amines. Reaction of PCI3 with quaternary ammonium salts yields phosphaindolizines and thiazolodiazaphospholes. Imines produce phosphonates whereas hydrazones are converted to pyrazoles, indoles, and nitriles. Nitrones undergo rearrangement to secondary or tertiary amides and primary alkylnitro compounds are reduced to nitriles (eq 3). Diazonium salts are transformed to phosphonic acids. ... 

Recently Spande and Glenner (376) reinvestigated the reaction of 3-substituted indole derivatives with diazonium salts. In earlier work, it was proposed that the reaction of diazotized sulfanilic acid with tryptophan takes place at the 3-position. On the other hand, reaction of skatole with diazotized arsanilic acid was assumed to give a 2-substituted derivative, solely by analogy to the pyrroles (259, 395). 

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