Enantioselective synthesis of spirooxoindoles via chiral auxiliary (bicyclic lactam) controlled S_NAr reactions

Abstract

A highly efficient enantioselective S(N)Ar reaction of chiral acyl bicyclic lactam with substituted-2,4-dinitrobenzenes was developed, affording products containing quarternary stereogenic centers. They are further utilized towards an enantioselective synthesis of spirooxoindoles.

Reagent‐Based DOS: Developing a Diastereoselective Methodology to Access Spirocyclic‐ and Fused Heterocyclic Ring Systems

“…In turn, compound 2 was synthesized by acylation of compound 1 with methyl chloroformate and LDA at À78 8C. [13] By using two different hydrogenation conditions, the fused-and spiro templates (4, 4 a, 5, and 5 a) were readily synthesized. Initial hydrogenation of compound 3 (H 2 -Pd/C, 10 % w/w), followed by in situ cyclization of the resulting amine, provided the desired spirolactam (4 a) and fused bispyrrolidine (5 a).…”

“…Deprotection with TFA generated alcohol 12 in 67 % yield. With the optimized cyclization conditions in hand, we converted several crude imines into their corresponding spirotetrahydroquinolines (11)(12)(13)(14)(15)(16)(17)(18)(19)(20) in decent yields (about 65 %) and good diastereoselectivity (> 90 %). The absolute configuration of these molecules was established by X-ray crystallography of one of the representative compounds (13) for which the single crystal was generated in MeCN (Scheme 5).…”

“…Our group has previously established that C7-aminoarylsubstituted spiro-oxoindolone systems are readily accessible by nucleophilic aromatic substitution at the C7 position of bicyclic lactam 2. [13] Accordingly, we reacted lactam 2 with sodium hydride and electron-poor fluorobenzenes (2,4-nitrofluorobenzene and 5-bromo-2,4-dinitrofluorobenzene), which, in turn, generated the desired exo-arylated compounds (21 and 22). X-ray crystallography analysis of compound 21 (the single crystal was generated in MeCN) allowed its unequivocal assignment (Scheme 6).…”

Nucleophilic Aromatic Substitution

“…Carbanion attack at the chloro-substituted position is slower but may also result in substitution. 39 Carbon−carbon bond formation is also observed in the ee reaction, in ionic liquids, of cyano-and nitro-iodobenzenes with pyrrole derivatives to yield 2-aryl pyrroles. 37 There has been a review of the von Richter reaction, which involves cyanide attack on nitroarenes to give cine-substituted carboxylic acid derivatives, such as 3-chlorobenzoic acid, from 1-chloro-4-nitrobenzene.…”

Construction of Spirooxindole Skeleton Through Intramolecular Dieckmann Cyclization

“…Moreover, Carreira et al have developed a reliable methodology to access the pyrrolidinyl-spirooxindole structure via a MgI 2 -mediated ring-expansion reaction of a spiro[cyclopropane-1,3′′′oxindole] with an aldimine [18]. Other synthetic strategies of the spiro-pyrrolidone-3,3′-oxoindole frameworks also include Michael cyclization reaction [19–23] and C-selective SnAr reactions [24–26]. Besides, in our previous study, a completely different method has been achieved for the construction of the tetracyclic 3-spirooxindole through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium [27].…”