Indole ring construction

Two major types of transformations are usually used for the synthesis of benzazepines with the fused pyrrole and indole rings. Construction of the... 

Miyashita, K., Tsuchiya, K., Kondoh, K., Miyabe, H., Imanishi, T. Novel indole-ring construction method for the synthesis of 2-trifluoromethylindoles. Heterocycles 1996,42, 513-516. 

This chapter on nitrene cyclization is a segue to the following several chapters that employ this tactic in powerful and widely used indole ring syntheses. The use of metals, such as palladium, rhodium, and ruthenium, to generate nitrenes or their equivalent and effect indole ring construction is discussed in later chapters. Soderberg has reviewed the synthesis of heterocycles via the generation... 

Displaying remarkable molecular inventiveness, Butin and colleagues parlayed their basic reaction into a number of novel indole ring constructions (Scheme 2). The novel azulenio[7,8-h]indole salts 7 can also be obtained from the NH anilines corresponding to acetanilides 6 [3, 4], Bis-furans 6 were synthesized from u-nitrobenzaldehydes and two equivalents of furans [4], In a variation of the prototypical synthesis, Butin found that the installation of... 

We have already encountered some reduction methods en route to indole ring construction. Several classical indole name reactions feature reduction as the crucial step in indolization, and these are covered now. 

In 1999 Fnkuyama s group described a new indole ring construction based on < -alkenylthioanilides and their radical addition, followed by indolization (Scheme 4, equations 1 and 2) [21], Fukuyama apphed this variant indole synthesis to the synthesis of ( )-catharanthine [22], (H-)-vinblastine [23-25], (+)-vincristine [26], and (-)-strychnine [27], The catharanthine synthesis required hypophosphorous acid and AIBN to achieve indole formation (equation 3). 

The proclivity of radicals to add to multiple bonds has led numerous investigators to invent new indole ring construction via radical cyclization in addition to those methods previously discussed. 

Compared to other transition metals (Cu, Pd, Rh, An), platinum has not received much attention with regard to indole ring construction. Nevertheless, several interesting applications have been reported with this metal. 

These two methods are closely related but differ in the point of initial attachment of the substituent from which the carbocyclic indole ring is constructed. One strategy for building up 2-substituted pyrroles capable of... 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Palladium-catalyzed reactions of arylboronic acids have been utilized to craft precursors for constructing indole rings. Suzuki found that tris(2-ethoxyethenyl)borane (149) and catechol-derived boranes 150 readily couple with o-iodoanilines to yield 151, which easily cyclize to indoles 152 with acid [158]. Kumar and co-workers used this method to prepare 5-(4-pyridinyl)-7-azaindoles from 6-amino-5-iodo-2-methyl-3,4 -bipyridyl [159], A similar scheme with catechol-vinyl sulfide boranes also leads to indoles [160]. A Suzuki protocol has been employed by Sun and co-workers to synthesize a series of 6-aryloxindoles [161]. 

Construction of the indole ring via Fischer synthesis. Starting from a variety of 3,4-dihydro-lH-benzo[l ]azepine-2,5-diones 40 and arylhydrazines Fischer syntheses of indolo benzazepinones 41 have been reported (Scheme 8 (1999JMC2909)). Usually, the reaction comprises a two-step one-pot procedure with the formation of intermediate arylhydrazones in warm acetic acid followed... 

Pyrrole and indole rings can also be constructed by intramolecular addition of nitrogen to a multiple bond activated by metal ion complexation. Thus, 1-aminomethyl-l-alkynyl carbinols (obtained by reduction of cyanohydrins of acetylenic ketones) are cyclized to pyrroles by palladium(II) salts. In this reaction the palladium(II)-complexed alkyne functions as the electrophile with aromatization involving elimination of palladium(II) and water (Scheme 42) (81TL4277). 

The C-2 and C-3 hydroxy derivatives of pyrrole are special in the sense that the tautomeric equilibria favor the pyrrolinone structures (see Section 3.04.6.2). Furthermore, the general synthetic methods are not usually applicable so that we will call attention in this section not only to the methods of directly introducing these substituents, which are rare, but also to those ring construction processes which specifically give the pyrrolinones and indolinones. The indole derivatives have widely used trivial names, oxindole (5) for indolin-2-one and indoxyl (6) for indolin-3-one, Carbocyclic hydroxy substituents in indole and carbazole, on the other hand, for the most part act as normal aromatic phenolic groups. These compounds are usually prepared by application of the standard ring syntheses. 

Certain natural products have been used as experimental templates upon which to construct marketable products eg, 2,4-dichlorophenoxyacetic acid which was conceived from the indole ring. 

In a similar heterocyclic quinodimethane ring construction strategy, the hexacyclic adducts (64) were isolated in good yield upon condensation of appropriately functionalized indole imines with ( )-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid chloride (Equation (35)) (88JA2242). In a demonstration of the utility of this new method for indole alkaloid synthesis, further transformations conducted on compound (64 R = R2 = H, R3 = Et) were shown to lead to ( —)-16-methoxy-tabersonine. 

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