Interrupted Plancher Rearrangement Initiated by Dearomative Epoxide-Indole Cyclization: Formal Umpolung Reactivity of Indoles.

We herein report the serendipitous discovery of the interrupted Plancher rearrangement initiated by an HFIP-promoted dearomative epoxide-indole cyclization, unlocking a new blueprint to the formal C3 umpolung reactivity of indoles. This rapid complexity generating cascade process paves the way toward a new class of fused-bridged indolines in high yields and under full regio- and diastereocontrol. The reaction is amenable to a wide range of substituents in the starting materials.

Constructing spirooxindoles from non-oxindole precursors: a one-pot nitro-reduction/double lactamization approach to spiro[indoline-3,3'-quinoline]-2,2'-diones.

2-(2-Nitrobenzyl)-2-(2-nitrophenyl)malonates, readily prepared by SAr-arylation of diethyl malonate with -fluoronitrobenzenes, followed by S2-alkylatioin of the resulting products with -nitrobenzyl bromides, undergo a tandem Fe/AcOH-promoted nitro-reduction and double lactamization sequence to afford spiro[indoline-3,3'-quinoline]-2,2'-diones in high overall yields. The method is operationally simple, economical, and has a broad substrate scope. The synthetic practicality of this methodology was illustrated by performing the reaction on a gram scale with the same efficiency.

Diastereocontrolled Construction of Spiroindolenines via Hexafluoroisopropanol-Promoted Dearomative Epoxide-Indole Cyclization.

Herein, we report the discovery of the -selective, dearomatizing spirocyclization of indole-tethered epoxides as a fundamentally new approach for constructing spiroindolenines equipped with three contiguous stereogenic centers under complete diastereocontrol (dr >99:1) and in high yields. Promoted by hexafluoroisopropanol, the protocol features a broad substrate scope, easy scale-up, and versatile transformations of the synthesized spiroindolenines.

Synthesis of benzimidazole-fused 1,4-benzoxazepines and benzosultams spiro-connected to a 2-oxindole core a tandem epoxide-opening/SAr approach.

While hundreds of literature reports describe the preparation of spirooxindole-based five- and six-membered heterocycles, the construction of seven-membered heterocyclic rings spiro-connected to a 2-oxindole core has so far been less developed. Herein, we disclose a base-mediated (4 + 3) annulation of spiro-epoxyoxindoles and 2-(2-fluoroaryl)-1-benzoimidazoles or 2-fluoro--arylbenzenesulfonamides toward the synthesis of two new classes of spirooxindole-based polycyclic systems. Mechanistically, this conceptually simple and high atom-economical reaction proceeds an S2-like intermolecular epoxide ring-opening, accompanied by a concomitant intramolecular SAr reaction.

A small molecule potent IRAK4 inhibitor abrogates lipopolysaccharide-induced macrophage inflammation in-vitro and in-vivo.

Increasing evidence supports vanillin and its analogs as potent toll-like receptor signaling inhibitors that strongly attenuate inflammation, though, the underlying molecular mechanism remains elusive. Here, we report that vanillin inhibits lipopolysaccharide (LPS)-induced toll-like receptor 4 activation in macrophages by targeting the myeloid differentiation primary-response gene 88 (MyD88)-dependent pathway through direct interaction and suppression of interleukin-1 receptor-associated kinase 4 (IRAK4) activity. Moreover, incubation of vanillin in cells expressing constitutively active forms of different toll-like receptor 4 signaling molecules revealed that vanillin could only able to block the ligand-independent constitutively activated IRAK4/1 or its upstream molecules-associated NF-κB activation and NF-κB transactivation along with the expression of various proinflammatory cytokines.

Diastereoselective Synthesis of Indoline- and Pyrrole-Embedded Tetracycles via an Unprecedented Dearomative Indole-C3-Alkylation/Aza-Friedel-Crafts Cascade Reaction.

Dearomative indole C3-alkylation─intramolecular iminium trapping cascade reaction of indole-C3-tethered nucleophiles is a well-known blueprint for accessing 2,3-fused indolines. In exploring this strategy, synthetic chemists have utilized diverse classes of electrophilic reagents. However, the tethered nucleophiles have mainly been limited to heteronucleophiles and enolates; exploitation of tethered arenes/heteroarenes remains unknown.

Hexafluoroisopropanol-Mediated Intramolecular Ring-Opening Cyclization of Indolyl--Tethered Epoxides: Tether-Length-Controlled Synthesis of 1,7- and 1,2-Fused Indoles.

Despite having the capability to construct benzo-fused heterocycles in complete atom economy and high chemo-, regio-, enantio-, and diastereoselectivities, intramolecular Friedel-Crafts epoxide arene cyclization (IFCEAC) remains underutilized in organic synthesis. The wide adaptation of this powerful Csp-Csp bond-forming reaction, therefore, requires a broad understanding of the substrate scope to better impact heterocycle synthesis. Along this line, we investigated the applicability of IFCEAC for the synthesis of 1,7- and 1,2-fused indoles.