Diastereoselective Synthesis of Substituted Tetrahydroisoquinolines and Isoindolines via a Silver(I) Triflate‐Promoted Tandem Reaction

Abstract

An ew silver(I) triflate-promoted tandem reaction comprising the ring opening of aziridines and aM ichael reactionh as been developed. Using secondary amines or primary amines as nucleophiles,t his methodologya llows for the synthesis of cis-1-alkyl-4-aminotetrahydroisoquinolineso rcis-1,3-disubstituted isoindolines in good yields with excellent diastereoselectivities,r espectively.B esides, easy operation and mild reactionc onditions are also notable features of this tandemreaction.Keywords: aziridines; cyclization;d omino reactions;Lewis acids;M ichaela ddition Thed evelopment of efficient synthetic approachesf or the construction of cyclicc ompounds is one of the most fertile areasi no rganic synthesis.B ecause of their high efficiencyi nt he formation of chemical bonds,t andem reactions [1] stand out from numerous strategies and play an important role in the synthesis of cyclic compounds.I np articular, Lewis acid-catalyzed tandem reactions [2] have attractedm uch attention from the synthetic community for the advantages of easy operation and mild reactionconditions.TheM ichaela ddition reactiono fe lectron-deficient alkenes with nucleophiles is ap owerful tool for the formation of carbon-carbon [3] and carbon-heteroatom bonds.[4] Basedo ni t, manye legant tandem reactions have been designed for the construction of various molecular skeletons.[5] In addition, N-sulfonylaziridines are easy to react with many carbon-nucleophilic reagents [6] andh eteroatom-nucleophilic reagents, [7] Using these reactions,s everal tandem reactions have been developed for the construction of nitrogen-containing heterocycles, [8] However, to the best of our knowledge,atandem reaction that simultaneously involvesaMichael addition reactiona nd the ring opening of aziridines hasn ot been studied up to now.T he similarr eactivity of electron-deficient alkenes and aziridineswith nucleophiles couldproduce aselectivity problem. There are three possible paths for this tandem reaction( Scheme 1). Path 1: ring opening of the aziridine occurs,a nd then the newly generated nitrogen aniona ttacks the electron-deficient alkene to affordp roduct A; path 2: Michaela ddition followed by ring opening of the aziridine gives rise to product B; path 3: the nucleophile attacks to the electron-deficient alkene and the aziridine at the same timet o provide product C. On the plus side, the diversity of productse nriches the applicationc ategory of tandem reactions.B ut if the reactionc annot be selectively controlled, complexm ixtures would cause it to lose any practical applicationv alue.B esides, the relative stereochemistry in the product also needs to be regulated wells ot hat the tandem reactionc an stereospecifically give the target molecule.With these considerations in mind, we selected amines [4f~k,7c~i] as nucleophiles andb egan our study on the tandem reactioni nvolving the ring opening of aziridinesa nd aM ichael addition.T oo ur delight, the tandem reaction proceeded smoothly in the presence of AgOTf.W hen secondary amines were use...

Construction of 4‐Isochromanones through Cu(OTf)2‐Catalysed Sequential C=O and C–O Bond Formation

“…Epoxide 2a was prepared by a three‐step sequence starting from commercially sourced 2‐bromobenzaldehyde (Scheme ). 2‐Bromobenzaldehyde underwent a Stille coupling reaction[15a] and a Knoevenagel reaction[15a] to give the desired alkene 1a . Then, selective epoxidation of alkene 1a gave the required epoxide 2a (Scheme ).…”

“…However, few tandem reactions that simultaneously involve the ring opening of epoxides and the Michael addition of electron‐deficient alkenes have been reported. As a part of our ongoing research into the development of highly selective strategies for the synthesis of heterocyclic compounds with complicated structures, we designed and synthesized a new type of substrates containing both an epoxide and an electron‐deficient alkene. When we treated these compounds with DMSO in the presence of a Lewis acid, sequential oxidative ring opening of the epoxide and oxa‐Michael addition took place to give a series of 4‐isochromanones in moderate to good yields through the formation of one C=O bond and one C–O bond (Scheme ).…”

Facile, Efficient and Diastereoselective Construction of Indane‐Fused Pyrrolidin‐2‐ones via a Potassium Hydroxide‐Catalyzed Domino Reaction

“…Then several solventsw ere screened to optimize the tandem reactionc onditions (entries [10][11][12][13]. Subsequent attempts to improve the yield and the diastereoselectivity were carried out by using as erieso fi norganica nd organic bases (entries 2-9).…”

“…As eries of tandem reactions based on activated aziridines [11] and electron-deficient alkenes [12] have been successfully developed for the construction of cyclicc ompounds, respectively.H owever, few examples of tandem reactions simultaneously involving activated aziridinesa nd electron-deficient alkenes have been reported up to now.T he similar reactivity of the two synthons with nucleophiles would produce as electivity problem. [13] When secondary amines were used as nucleophiles,r ingo pening of aziridinesf ollowed by Michaela ddition led to tetrahydroisoquinolines as the sole products in good yields with good diastereoselectivities [Scheme 2, Eq. [13] When secondary amines were used as nucleophiles,r ingo pening of aziridinesf ollowed by Michaela ddition led to tetrahydroisoquinolines as the sole products in good yields with good diastereoselectivities [Scheme 2, Eq.…”

Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008

“…The method allows use of secondary amines or primary amines as nucleophiles to synthesize cis-1-alkyl-4-aminotetrahydroisoquinolines 42 in moderate to good yields (Scheme 19). [58] Xia et al have reported Ag-catalyzed decarboxylative addition/cyclization protocol using activated alkenes 43 with aliphatic carboxylic acids 29 to obtain isoquinolinediones 44. The protocol gives an efficient access to isoquinolinediones in moderate yields (Scheme 20).…”