From Indole Derivatives

Chromic acid oxidation of a variety of indoles has been used as a synthetic route to isatins. A variety of other oxidative methods 

DaSettimo, M. F. Saettone, E. Nannipieri, and P. Barili, Gazz. Chim. Ital. 97, 1304 (1967). 

Terentev and M. N. Preobrazhenskaya, Dokl. Akad. Nauk.SSSR 118,302 

Dihalogenation of oxindole followed by alkaline hydrolysis of the 3,3-dihalooxindole has been applied to the synthesis of some isa-tins. A number of oxindoles have been treated with nitrous acid to give isatin-3-oximes. ° Reduction of the oximes to 3-aminooxindoles followed by ferric chloride oxidation gave isatins. 

When this sequence was applied to 7-azaoxindole, the azaisatin 33 was 

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Some new six-membered Aplysinopsin analogues, 5-(17f-indol-3-ylmethylene)-2,4,6(17f,3/7,5//)-pyrimidinetriones 678, were prepared in 11-73% yield from indole derivatives 676 and 5-[(dimethylamino)methylene]-2,4,6(l/7,3/7,5//)-pyrimidinetriones 677 by heating in glacial acetic acid (Equation 162) <2001T3159>. 2-Methylindole reacts with pyrimidinetrione 677b (when R = Me) in a different manner from 677a (when = H). Instead of the expected 3-vinylindole 678, 3-[bis(2-methyl-l//-indol-3-yl)methyl]-2-methyl-l//-indole 679 was isolated in 71% yield (Scheme 135). 

Seven-membered ring closures via e do-cyclization are by far more widespread than the analogous gndo-modes for five- or six-membered cycles. There are some examples using substructure G (Figure 6.4) as substrate. Joseph and cowoikers [145] reported the synthesis of fused heterocycles bearing a benzazepinone moiety. Tetracycle 202 was obtained in excellent yield starting from indole derivative 201 in the presence of silver salt (Scheme 6.59). 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

The nitrosation of pyrroles and indoles is not a simple process. The 3-nitroso derivatives (84) obtained from indoles exist largely in oximino forms (85) (80IJC(B)767). Nitrosation of pyrrole or alkylpyrroles may result in ring opening or oxidation of the ring and removal of the alkyl groups. This is illustrated by the formation of the maleimide (86) from 2,3,4 -trime thylpyrrole. 

Three new papers bearing on the structure of strychnine have become available too late for inclusion in this summary of recent work. Woodward, Brehm and Nelson have compared the ultra-violet absorption spectra of strychnine and Leuchs s strychnone (p.. 559) and used the results for a discussion of the relationship of the two alkaloids. Prelog and Kathriner have investigated the oxidation of strychnine, i/t-strychnine and brucine by permanganate in weakly acid solution and Bailey and Robinson from a study of the brucones have confirmed the conclusion of Woodward et al. that Leuchs s strychnone is a true indole derivative. Mention must also be made of a paper by Clemo and King on new reduction products of strychnine, of which a preliminary account has been published with a summary of the ensuing discussion. 

Another triflate ester that recently has found growing application in organic synthesis is commercially available trimethylsilylmethyl trifluoromethanesul fonate. This powerful alkylating reagent can be used for the synthesis of various methylides by an alkylation-desilylation sequence A representative example is the generation and subsequent trapping by 1,3-dipolar cycloaddition of indolium methanides from the corresponding indole derivatives and trimethylsilylmethyl trifluoromethanesulfonate [108] (equation 54)... 

Tricyanovinylindole (57) and its 1-methyl derivative, obtainable from the parent indoles and tetracyanoethylene, combine with dimethyl acetylenedicarboxylate to give the corresponding carbazoles. That derived from indole (58) has been hydrolyzed and esterified yielding (55). 

A number of diindolylmethane derivatives including 336, 338, 339, 340, and 341 have been obtained by the action of the appropriate ketones, under fairly vigorous conditions, on the Grignard reagents derived from indole or 2-methylindole. ... 

Ingraffia studied the oxidation of the Grignard reagents derived from indole, skatole, and 2-methylindole with hydrogen peroxide and... 

During studies on the acid-induced formation of the alkaloid yuehchukene and related structures from pienylindoles, it was discovered that treatment of indole 173 with p-toluenesulfonic acid and silica gel leads to the formation of indolo-[3,2-b]carbazole 174 and the indole derivative 175 (Scheme 21). Similarly, the disubstituted product 176 could be isolated after TFA treatment of the substrate 177. Detailed mechanistic explanations have also been provided in this work (96T9455). 

A fully unsaturated tricyclic indole derivative serves as the aromatic moiety for a nonsteroid antiinflammatory agent. Preparation of this compound starts with the Michael addition of the anion from methyl diethylmalonate to cyclohexanone. The product (32) is then hydrolyzed and decarboxylated to give ketoester 33. Fischer condensation with p-chlorophenylhydrazine leads to the indole This is then esterified (35) and dehydrogenated to the carbazole 36. Saponification leads... 

It can be concluded from the publications of Rohde [2] and Freund and Lebach [3, 4] that it was Ehrlich who first suggested the use of 4-(dimethylamino)-benzalde-hyde in the presence of hydrochloric acid for color reactions with methylketols that was found also to apply to indole derivatives [S]. Auterhoff [6] designated a reagent for urobilinogen, consisting of a solution of 2 g 4-(dimethylamino)-benzaldehyde in 20 percent hydrochloric acid, correctly as Ehrlich s solution. Hence, it is essentially correct to refer to all reagents which contmn these components as Ehrlich s reagent. 

From a commercial viewpoint the most important compounds of this class are the 3,3-(bisindol-3-yl)phthalides. The first synthesis47 involved Route B as described in Scheme 7, in which a second indole derivative condenses with the indolylbenzoylbenzoic acid in acetic anhydride. However, for the preparation of symmetrical derivatives it has been shown61 that a one-pot process, avoiding isolation of the intermediate and use of aluminum chloride, is more convenient. 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

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