Regioselective Synthesis of Heterospirocyclic Isobenzofuranones and Medium-Sized Lactones by Multiple Anion Capture Reactions of 1,3-Dianions

Abstract

The multicomponent reaction of 1,3-dianions with ketones and oxalic acid dichloride or diethylmalonic dichloride afforded six-to eight-membered lactones. Treatment of the dianion of 3-acetylindole with benzophenone and diethylmaDomino and multi-component reactions have found widespread applications in organic synthesis. [1] Multiple anion capture reactions involve attack of a carbanion on a relais species to form an intermediate which is subsequently reacted with an electrophile. Recent examples include the reaction of carbon nucleophiles with allenes and subsequent cyclization with acrylates, [2] and reactions involving isocyanates [3] or allenyl isothiocyanates as the relais species. [4] Multiple anion capture reactions involving nitriles as the relais species have been observed in the reaction of bislithiated 2,3-methylbutadiene with benzonitrile, [5] and in the 1,4-addition of nitriles to (butadiene)zirconocene. [6] In the course of our program [7] directed at the development of cyclization reactions of dianions [8] and dianion equivalents with dielectrophiles, we have recently studied nitriles as relais species in reactions of 1,3-dianions [9aϪ9c] and dilithiated allenes. [9d] We wish to report full details of our studies related to multiple anion capture reactions of 1,3-dianions with ketones and carboxylic acid dichlorides. [10] These reactions provide an efficient access to medium-sized lactones and novel heterospirocyclic isobenzofuranones. [11Ϫ13] Results and Discussion Synthesis of Lactones and Silyl EthersChlorosilanes were used in our first experiments aimed at demonstrating the concept of multiple anion capture reactions of dianions with ketone relais species. The dianion [14] of 1,1-diphenylacetone 1 was generated by treatment of 1 with potassium hydride and nBuLi. The dianion was condensed in situ with one equivalent of benzophenone 2a to give the dianionic intermediate A by regioselective attack of the terminal carbon atom of the dianion at the carbonyl group. Owing to steric and electronic reasons (delocaliz- [a] 1511 lonic dichloride resulted in the formation of a cyclic 1,3,5-triketooctene. The reaction of 1,3-dianions with ketones and phthalic dichloride resulted in the formation of heterospirocyclic isobenzofuranones rather than of medium-sized rings.ation of the negative charge through the phenyl rings), the carbon attached to the phenyl groups is less nucleophilic than the terminal carbon of the dianion. Subsequent addition of Me 3 SiCl gave the open-chain silyl ethers 3a and 3b in high yields (Scheme 1). Reaction of intermediate A with dichloro-diphenylsilane afforded the 1,3,2-dioxasilinane 3c in 76% yield. Scheme 1. Reaction of the dianion of 1,1-diphenylacetone with benzophenone and chlorosilanes Three-component cyclizations of dianions with ketones and dicarboxylic acid dichlorides were studied next. These reactions can, in principle, result in the formation of different regioisomeric cyclization products, as well as macrocyclic or polymeric products. In fact, we have found that...

Indoles in Multicomponent Processes (MCPs)

“…3-Acetylindole in the presence of lithium diisopropylamine (LDA) yields the dianion 291 . The later reacts with benzophenone and subsequent addition of Et 2 C­(COCl) 2 results in the isolation of 1,3,5-triketooctene 292 in 18% yield (Scheme ) . When an excess of LDA is used, regeneration of the enolate anion appears to be possible after condensation of 291 with benzophenone.…”

1-Azaallylic Anions in Heterocyclic Chemistry

“…These amino alcohols 516 and 517 could be further transformed to the oxazines 518 by reaction with 4-nitrobenzaldehyde . Similarly, reaction of the dianion of 2-methylbenzimidazole 441 with benzophenone and subsequent treatment with dielectrophilic carboxylic acid dichlorides resulted in formation of medium-sized lactones. ,

95

…”

Cyclization Reactions of Dianions in Organic Synthesis

“…The reaction of the dianion of 1,1-diphenylacetone with benzophenone and subsequent addition of diethylmalonic dichloride afforded the eight-membered [1,5]dioxocane-2,4-dione 221 (Scheme ) 79 One-Pot Reaction of the Dianion of 1,1-Diphenylacetone with Benzophenone and Diethylmalonyl Dichloride …”