Lewis‐Acid‐Catalyzed Intramolecular Aza‐Friedel–Crafts Reaction of N‐tert‐Butanesulfinyl Imines: Efficient Synthesis of Optically Active 9‐Aminofluorene Derivatives

Abstract

Fluorene derivatives that contain a rigid planar biphenyl unit are useful cyclic structures in organic synthesis because of their ability to serve as building blocks for many kinds of functional materials and biologically active molecules. [1] Among them, 9-aminofluorene and its derivatives are known as important structural motifs that are widely used in biological materials and medicinal chemistry (Scheme 1, compounds A and B). [2] However, the synthetic approaches to access these valuable compounds have received considerably less attention to date; only examples dealing with racemic intramolecular Friedel-Crafts alkylation, [3a,b] addition of imines, [3c] benzylic arylation, [3d,e] intermolecular amination of the C sp 3 À H bond, [3f,g] or cross-coupling of the C À N bond [3h,i] have been described. To the best of our knowledge, despite the potential importance of their related optically active compounds (Scheme 1, compound C), the stereoselective construction of 9-aminofluorene derivatives is even more underexplored, with only one report that touched upon attempts at asymmetric synthesis. [3k] Therefore, the development of an efficient asymmetric method for the synthesis of 9-aminofluorene and its derivatives is a highly desirable yet challenging subject.N-tert-Butanesulfinamide is an extremely versatile chiral ammonia equivalent for the asymmetric synthesis of various chiral amines by virtue of the excellent stereocontrol that can be achieved and easy cleavage of the sulfinyl group. [4,5] During recent years we have been exploring the chemistry of N-tert-butanesulfinyl imines for the asymmetric synthesis of synthetically useful diverse chiral amines [5a-d] and amino acids. [5e-j] In these studies, we reported the successful development of simple and mild approaches for highly diastereoselective syntheses of a-(3-indolyl)-glycines [5l] and a-arylglycines [5n] by Lewis-acid-catalyzed asymmetric intermolecular Friedel-Crafts alkylations at room temperature. The chelation-controlled, configurationally rigid transition state of a Lewis acid coordinated with an N-sulfinyl imine would direct nucleophiles to attack in a highly stereospecific manner, thus leading to excellent stereoselectivity. On the basis of these findings, we envisioned that high reaction stereocontrol might also be achieved with a Lewis acid catalyst in intramolecular aza-Friedel-Crafts reactions of N-tertbutanesulfinyl imines under mild conditions (Scheme 2).Herein, in continuation of our interest in this area, we disclose a Lewis-acid-catalyzed asymmetric intramolecular aza-Friedel-Crafts alkylation of N-tert-butanesulfinyl imines for the synthesis of a variety of enantioenriched 9aminofluorene derivatives with good to excellent diastereoselectivities (up to 96:4 diastereomeric ratio (d.r.)).

Sequential Knoevenagel [4+1] Cycloaddition–Condensation–Aza-Friedel–Crafts Intramolecular Cyclization: A 4-Center-3-Component Reaction Toward Tunable Fluorescent Indolizine Tetracycles

“…In general, and akin to other aza-Friedel-Craft cyclizations, − only indolizines derived from meta -methoxy-substituted aldehydes ( 15a – d , g ) underwent cyclization and oxidation via copper triflate-mediated conditions. Conversely, tetracycle 15i was not detected from the 4-methoxybenzaldehyde-derived imine 14f.…”

“…The reaction was also compatible with cyano-methyl pyrazines 14u – w . Aza-Friedel–Crafts reactions may proceed via the intermolecular or intramolecular 1,2-addition of aromatic groups to imines, where an unoxidized secondary amine is typically generated. − Imines 14 are thus primed to undergo an aza-Friedel–Crafts cyclization, where gratifyingly the fully oxidized indolizine was commonly observed as product after reaction optimization depicted in Table .…”

Direct Asymmetric Arylation of Imines

“…Xu and coworker developed an efficient Lewis-acidcatalyzed asymmetric intra-molecular aza-Friedel-Crafts alkylation approach for the synthesis of optically active 9-aminofluorenes (Scheme 83). [99] The reaction condition was mild and it gave the desired products in good yields and high diastereoselectivities (up to 92 de).…”

Recent advances in aza Friedel–Crafts reaction: strategies for achiral and stereoselective synthesis

“…Regarding the intramolecular aza-FC reaction, they have been extensively investigated for years. [15][16][17][18][19] Seminal work describes several types of intramolecular synthesis of tetrahydro-β-carbolines, from tryptamines and various aldehydes or ketones (known as the Pictet Spengler reaction), and this reaction will not be discussed here. [20][21][22][23][24][25][26][27] In this current review, we present an overview of the most relevant works and the improvement achieved in the aza-FC reaction, classified in the following sections according to the type of catalyst used.…”

“…Regarding the intramolecular Aza-FC reaction, they have been extensively investigated for years. [15][16][17][18][19] Seminal work describes several types of intramolecular synthesis of tetrahydro-β-carbolines, from tryptamines and various aldehydes or ketones (known as the Pictet Spengler reaction), and this reaction will not be discussed here. [20][21][22][23][24][25][26][27] product 6.…”