2-carboxylic acid dihydroindole

In 1927 Raper showed that the red pigment obtained on oxidation of DOPA [i.e. 2,3-dihydroindole-5,6-quinone-2-carboxylic acid, dopachrome (4)] rearranged spontaneously by an autoreduction process in vacuo to 5,6-dihydroxyindole (29).72 The rearrangement process could be accelerated by the action of alkali or sulfur dioxide.72 In the latter case, decarboxylation did not accompany the rearrangement and the colorless derivative was 5,6-dihydroxyindole-2-carboxylic acid (17).72 Compounds 17 and 29 were isolated as their dimethyl ethers, (30A) and (30B).72 Immediate decolorization of epinochrome (27) solutions on addition of alkali was reported a few years later.134... 

The position of the sugar residue in the dihydroindole portion can be determined by methylation of the pigment with diazomethane and subsequent alkaline degradation of the resulting neobetanin derivative. In the case of 5-0-glycosides, 5-hydroxy-6-methoxyindole-2-carboxylic acid is obtained, whereas the 6-O-glyco-sides yield 6-hydroxy-5-methoxyindole-2-carboxylic acid (47,48). The indole carboxylic acids are easily identified by TIjC. 

Whereas N-phenylindoles are reduced to the corresponding dihydroindoles with Na/NHs (equations 46 and 47)8 -89 and indole-2-carboxylic acid is reduced to the indoline with Li/NH3/PhNH2 (equation 48), indole itself is reduced to 4,7-dihydroindole (Li/NHs, MeOH) in 51% yield. These latter conditions also reduce carbazole to 1,4-dihydrocarbazole in 73% yield. ... 

Doi and Mori performed a similar carbonylation on a dihydroindole 4-triflate leading, after dehydrogenation, to 4-carbomethoxy-l-tosylindole [156], The direct carbonylation of A-acetyl- and, V-benzoylindole leads to the corresponding C-3 carboxylic acids... 

VIII) may be briefly summarized as follows. Villalstonine is a dimeric, diacidic base, which contains one methoxycarbonyl group, two methyl-imino groups, and an ethylidene group. Its UV spectrum is consistent with the presence of indole and dihydroindole chromophores containing no substituents in the benzene rings. Alkali fusion yields 2-methylindole, indole 2-carboxylic acid, and a /3-carboline derivative selenium dehydrogenation also affords a j8-carboline derivative, so far unidentified. Acid hydrolysis of villalstonine yields pleiocarpamine (XV), one of the alkaloids of Pleiocarpa mutica Benth. 

The best catalyst for the reaction was dihydroindole 2-carboxylic acid (VI). This catalyst minimizes the repulsive steric interaction between the olefinic substrate and the arylic hydrogen. The iminium-ion predominantly adopts a (Z)-configuration (Scheme 10.8(b)), and the iminium-ion and the ylide engages in an electrostatic association via the pendant carboxylate and the thionium substituents enchancing the enantiocontrol is enhanced up to 96% ee (Scheme 10.9, A). 

Raper suggested that the red product obtained on oxidation of 3,4-dihydroxyphenylalanine (DOPA, 3) was a cyclic 2,3-dihydroindole derivative, namely indoline-5,6-quinone-2-carboxylic acid (4)[14]. It was originally believed that (4) was identical with hallachrome, a red pigment that can be isolated from the marine worm Halla parthenopaea Costa [15]. 

The starting material is a dihydroindole carboxylic acid with its nitrogen protected by being converted into an amide. 

Following the suggestion in his first paper (54) that further investigation of the possible role of glucosamine and the common amino acids (especially leucine and tyrosine) in the pernicious anemia problem might be desirable, he subsequently studied the role of tyrosine (55). Using methods employed by Raper and associates in the identification of substances present in a reaction mixture of tyrosine and tyrosinase, Jacobs concluded that the red substance in liver extract is the 5,6-quinone of dihydroindole-2-carboxylic acid. 

A traditional method for such reductions involves the use of a reducing metal such as zinc or tin in acidic solution. Examples are the procedures for preparing l,2,3,4-tetrahydrocarbazole[l] or ethyl 2,3-dihydroindole-2-carbox-ylate[2] (Entry 3, Table 15.1), Reduction can also be carried out with acid-stable hydride donors such as acetoxyborane[4] or NaBHjCN in TFA[5] or HOAc[6]. Borane is an effective reductant of the indole ring when it can complex with a dialkylamino substituent in such a way that it can be delivered intramolecularly[7]. Both NaBH -HOAc and NaBHjCN-HOAc can lead to N-ethylation as well as reduction[8]. This reaction can be prevented by the use of NaBHjCN with temperature control. At 20"C only reduction occurs, but if the temperature is raised to 50°C N-ethylation occurs[9]. Silanes cun also be used as hydride donors under acidic conditions[10]. Even indoles with EW substituents, such as ethyl indole-2-carboxylate, can be reduced[ll,l2]. 

An alternate approach, pioneered by Kunz and MacMillan, proceeds by reaction of sulfur ylides with a,(3-unsaturated iminium ions, formed by reaction of a,p-enals with enantiomerically pure amines. In this approach the sulfur ylide (9.87) reacts with a range of (3-aryl- and P-alkyl-substituted enals, including (9.88), in the presence of the dihydroindole (9.89) to give the cyclopropane with ees ranging from 89 to 96%. More recently, it has been shown that replacement of the carboxylate functional group in (9.89) with an isosteric tetrazolic acid gives an improved catalyst that effects cyclopropanation with 99% ees in all cases studied. 

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