Researches On The Michael Addition And Trial Asymmetric Reaction Of 3-(1-tosylalkyl)-indoles With Cyclic β-keto Esters

Indoles,a kind of important nitrogen-containing heterocyclic compounds,are a useful kind of organic synthesis intermediates and widely present in natural alkaloids and pharmaceutically active molecules.As a particular subclass of substituted indoles,3-sec-alkyl-substituted indoles are common structural motifs in a number of naturally occurring,biologically active compounds,so the development of efficient method to synthesize compounds containing 3-sec-alkyl-substituted indole skeleton is a hot research topic to organic chemists.Arenesulfonylalkylindoles are used to generate highly active vinylogous imine intermediates in situ under basic or acid conditions after elimination of ArSO2 group,and these species were then treated with nucleophiles to afford 3-substituted indole derivatives.In this paper,we first gotα-amido sulfones with the utilization of ethyl carbamate,aldehyde and sodium tosylsulfinate under acidic conditions.Thenα-amino sulfones reacted with indoles via a Friedel-Crafts reaction in the presence of Lewis acid to obtain arenesulfonylalkylindoles.The utilization of arenesulfonylalkyl-indoles as a stable precursor of alkylideneindolenine intermediates is a complemen-tary to prepare C-3 functionalized indole derivatives.Alkylideneindolenine intermediates generated in situ from arenesulfonylalkylindoles provide another effective approach to get C-3 functionalized indole derivatives,among of which could not be obtained by direct Friedel-Crafts reaction when poor electronic density substrates are used.Cyclicβ-keto ester is a valuable nucleophile,which can then be further conven-iently transformed into carboxylic acid,hydroxy and amine groups.However,to the best of our knowledge,no studies of Michael addition that use cyclicβ-keto ester as the nucleophile to alkylideneindolenines generated in situ from arenesulfonyl-alkylindoles have been reported and the reason might be that while the acidity of the hydrogen on the carbon in between the two carbonyl groups makes 1,3-dicarbonyl compounds excellent nucleophiles,that same acidity makes the corresponding nucleophilic carbonyl alkylation extremely difficult and its greater steric bulk compared to those of aldehydes and ketones.This study focused on Michael addition of ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate to alkylideneindolenines generated in situ from aenesulfonylalkylindoles under basic conditions.Through detailed screenings of reaction conditions,a combination of stoichiometric NaH,THF as solvent,arenesulfonylalkylindoles/2-oxocyclopentane-carboxylate（1/1.5）and 25℃was chosen as the optimized condition.26corresponding desired products colud be obtained under the optimized condition with good yields（up to 87%）and all of them were confirmed by IR,¹H NMR,¹³C NMR and ESI-HRMS characterization.The configuration of the major diastereoisomer was unambiguously assigned as（R,R）and（S,S）by single crystal X-ray analysis.At the end of our artwork,we also used chiral catalysts to do trial research of this enantioselective reaction and no ideal results have been got temporarily.