Indole, hydrogenation

The easy displacement of the amine (ammonium) group proceeds by way of an elimination, involving loss of the indole hydrogen, and thus the intermediacy of a (3-alkylidene-indolenine which then readily adds the nucleophile, regenerating the indole. This mechanism has been verified by observing (i) very much slower displacement with a corresponding 1-methylgramine, and (ii) racemisation on... 

Two types of cycloaddition reactions have found application for the Synthetic elaboration of indoles. One is Diels-Alder reactions of 2- and 3-vinylindoles which yield partially hydrogenated carbazoles. The second is cycloaddition reactions of 2,3-indolequinodimethane intermediates which also construct the carbazole framework. These reactions arc discussed in the following sections. 

In some instances, ring contraction is accompanied by cyclization to indole derivatives. For example, l-aryl-6-oxo-l,4,5,6-tetrahydropyridazines with a carboxyl or methyl group at position 3 give indoles when treated with an ethanolic solution saturated with hydrogen chloride or in the presence of BF3 etherate. 

As might be anticipated from the behaviour of the parent heterocycles, C-2 of indole, benzo[i]furan and benzo[i]thiophene (Table 13) is shifted to lower field than C-3. However, the shifts for C-2 (O, 144.8 Se, 128.8 S, 126.1 NH, 124.7 Te, 120.8) and C-7a (O, 155.0 Se, 141.3 S, 139.6 NH, 135.7 Te, 133.0) in the benzo[i] heterocycles vary irregularly (80OMR(l3)3l9), and the sequence is different to that observed for C-2 in the parent heterocycles, namely 0>Se>Te>S>NH. Also noteworthy is the upheld position of C-7, especially in indole and benzofuran, relative to the other benzenoid carbons at positions 4, 5 and 6. A similar situation pertains in the dibenzo heterocycles (Table 14), where not only are C-1 and C-8 shifted upheld in carbazole and dibenzofuran relative to the corresponding carbons in dibenzothiophene and fluorene, but similar, though smaller, shifts can be discerned for C-3 and C-6 in the former compounds. These carbon atoms are of course ortho and para to the heteroatom and the shifts reflect its mesomeric properties. Little variation in the carbon-hydrogen coupling constants is observed for these dibenzo compounds with V(qh) = 158-165 and V(c,h) = 6-8 Hz. 

Methylindole has a p/sTa of -4.6 and it is therefore a weaker base than indole itself this unusual effect has been ascribed in part to the decreased hyperconjugative stabilization of the conjugate acid (38) by the one hydrogen at position 3 compared with the two hydrogens at position 3 in the 3//-indolium ion (39). 

Hydrogenation of i-butyl nicotinate methobromide, followed by hydrolysis of the 1-methyl-3-tert-butoxycarbonyl-1,4,5,6-tetrahydro-pyridine product (205) in the presence of indole affords, on decarboxylation, the -substituted derivative (206) (325). The formation of... 

The first indolization of an arylhydrazone was reported in 1983 by Fischer and Jourdan" by treatment of pyruvic acid 1-methylphenylhydrazone 3 with alcoholic hydrogen chloride. However, it was not until the following year that Fischer and Hess identified the product from this reaction as 1-methyl indole-2-carboxylic acid 4. 

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). 

The highest yields in the Ciamician-Dennstedt reaction have been achieved using phase transfer catalysts (Table 8.3.1). In the reaction, the pyrrole or indole and a phase transfer catalyst (PTC, in this case benzyltriethylammonium chloride) are dissolved in chloroform and aqueous sodium hydroxide is added. Yields are typically in the 40s to 60s (rather than in the 20s for a typical Ciamician-Dennstedt reaction). More recently, yields as high as 80% have been reported using tetra-n-butylammonium hydrogen sulphate as the phase transfer catalyst. ... 

In an attempt to prepare ethyl 3-indolylacetate (225) by the action of ethyl chloroacetate on indole magnesium iodide, only unidentified oily products were obtained under a variety of different experimental conditions. However, when indole magnesium iodide was treated with ethyl -chloropropionate in other, a product, identified as 3-[)3-(l-indolyl)propionyl]indole (226) by its behavior on alkaline hydrolysis and by the number of active hydrogen atoms it contained, was obtained. ... 

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