Synthesis of an Isoindoline-Annulated, Tricyclic Sultam Library via Microwave-Assisted, Continuous-Flow Organic Synthesis (MACOS).
A microwave-assisted, continuous-flow organic synthesis (MACOS) protocol for the synthesis of an isoindoline-annulat-ed, tricyclic sultam library, utilizing a Heck-aza-Michael (HaM) strategy, is reported. This sequence involves a Heck reaction on vi-nylsulfonamides with batch microwave heating followed by a one-pot, sequential intramolecular aza-Michael cyclization/Boc-deprot-ection using MACOS. Subsequent cyclization with either 1,1'-carbonyldiimidazole or chloromethyl pivalate using MACOS provided an array of tricyclic sultams. This efficient three-step protocol requires only a few hours to produce the target sultams starting from simple starting materials. Using this strategy, a 38-member library of isoindoline-annulated sultams was generated in good to excellent overall yields (53-87%).
Department of Chemistry, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada, Fax +1(416)7365936 ; The University of Kansas Center for Chemical Methodologies and Library Development (KU-CMLD), Del Shankel Structural Biology Center, 2034 Becker Drive, Lawrence, KS 66047-3761, USA, Fax +1(785)8645396.
Farman
F
Ullah
Qin
Q
Zang
Salim
S
Javed
Patrick
P
Porubsky
Benjamin
B
Neuenswander
Gerald H
GH
Lushington
Paul R
PR
Hanson
Michael G
MG
Organ
Heck reaction; MACOS; aza-Michael addition; continuous flow; isoindolines; sultams