Novel indole cycloaddition

A novel indole [5 + 2] cycloaddition reaction involving an oxidopyry-lium ylide resulted in an efficient and diastereoselective construction of highly fonctionalized and stereochemically challenging oxa-cyclohepta[l ] indoles with high functional-group tolerance and unique endo selectivity under very mild reaction conditions. (14AGE11051). 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

Another route involving intramolecular cycloaddition of nitrone and nitrile oxide functionalities of the indole derivative (166) gave a novel class of mitomycin analogues which are dihydro- and tetrahydroisooxazolo[3, 4 3,4]pyrrolo[l,2-a]indole (167) and (168) (Equation (8)) <89TL1421>. 

Other reports on the [3+2] cycloadditions of indoles and nitrile oxides focus on intermolecular reactions. For example, Gribble [80] has investigated the reaction of (phenylsulfonyl)-2-(tri-n alkylstannyl)indoles 169 with tetranitromethane to give the novel isoxazolo[5,4-b]indole derivative 173 (Scheme 49). The mechanism cascade is thought to proceed through the degradation of the dinitromethyl anion to a nitrile oxide 171, followed by a 1,3-dipolar cycloaddition to form a nitroindole intermediate 172 and subsequent loss of nitrous acid or SnR3N02. Treatment of the isoxazole 173 with base then leads to the formation of the oxindole tautomer 175 as the major product. 

This review has demonstrated that indole derivatives can participate in [2+2], [3+2], and [2+2+2] cycloaddition reactions with a wide variety of reaction partners to give an astonishing array of polycyclic frameworks. While in many cases these novel ring structures are curiosities with no current utility, several research groups have employed these reactions as key steps in complex natural product syntheses. Not surprisingly, the 2,3-bond of the indole nucleus is the primary site in the majority of these reactions however, notable exceptions exist which provide unique structures that would be difficult to obtain using other methodologies. 

Bashiardes G, Salir I et al (2007) An efficient one-pot synthesis of novel fused pyrroles and indoles by dipolar cycloaddition under microwave and ctmventional ctmditions. Syn-lett 1707-1710... 

Grotjahn DB, VoUhardt KPC (1986) Cobalt-mediated [2+2+2] cycloadditions of alkynes to the indole 2,3-double bond an extremely facile entry into the novel 4a, 9a-dihydro-9H-carbazole nueleus. J Am Chem Soc 108 2091-2093... 

Quinones are widely used dienes in IDA reactions. It is therefore no surprise that a few reports have appeared in the literature which use the IDA cycloadditions of indoles with quinones to form novel heterocycles. 

In 2013, the Matsuo group reported a novel tactic to convert indoles to hydrocarbazoles via a formal [4 + 2] cycloaddition, employing the acidic decomposition of substituted cyclobutanones (Scheme 46). " ... 

A novel method has been developed for the synthesis of indole based constrained mimetic scaffolds by microwave-assisted regio- and stereo-selective 1,3-dipolar cycloadditions. Here, C-(3-indolyl)-N-phenylnitrone reacts with number of olefinic dipolarophiles to afford isoxazolidine in superior yields (Bhella et al., 2009). 

The phosporic acid (261) catalysed three component reaction involving asymmetric 1,3-dipolar cycloaddition of electron-deficient azomethine ylides (327), aromatic aldehydes (328) and 2-aminomalonates (329) to provide to novel 2,5-dihydropyrrole derivatives (330) with potential bioactivities with enantioselectivities of up to >99% ee (Scheme 86). The Bronsted acids (253) catalysed intermolecular enantioselective alkylation of indoles (332) with cx,p-unsaturated y-lactams (331) thus providing a highly enantioselective method for the synthesis of chiral pyrroli-dinones (333) containing indole moieties, with enantioselectivity (up to 95% ee), has been described by Huang et al. (Scheme 87). " ... 

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