Accessing Stereochemically Rich Sultams via Microwave-assisted, Continuous-flow Organic Synthesis (MACOS) Scale-out

Abstract

The generation of stereochemically-rich benzothiaoxazepine-1,1′-dioxides for enrichment of high-throughput screening collections is reported. Utilizing a microwave-assisted, continuous flow organic synthesis platform (MACOS), scale-out of core benzothiaoxazepine-1,1′-dioxide scaffolds has been achieved on multi-gram scale using an epoxide opening/SNAr cyclization protocol. Diversification of these sultam scaffolds was attained via a microwave-assisted intermolecular SNAr reaction with a variety of amines. Overall, a facile, 2-step protocol generated a collection of benzothiaoxazepine-1,1′-dioxides possessing stereochemical complexity in rapid fashion, where all 8 stereoisomers were accessed from commercially available starting materials.

Synthesis of Amino-Benzothiaoxazepine-1,1-dioxides Utilizing a Microwave-Assisted, SNAr Protocol

“…15 Utilizing this enabling technology, the generation of benzofused sultams via an intramolecular S N Ar cyclization was achieved on multigram scale. 15a With this protocol in hand, the re-synthesis of benzothiaoxazepine-1,1-dioxide scaffolds 1 – 12 possessing both functional and stereochemical diversity, was achieved.…”

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

“…reported the synthesis of a benzothiaoxazepine‐1,1′‐dioxide library using a MACOS approach. They used a sulfonamide and epoxide derivatives which, via an epoxide ring opening/S N Ar cyclization in the presence of DBU, achieved the final heterocycle library with moderate yields (48–64 %), operating at 180 °C/200 W and with a short residence time (1 minute) . MACOS was also implemented in seven‐membered heterocycle synthesis, described by Ullah et al ., in the preparation of a library of 1,2,5‐thiadiazepane‐1,1‐dioxide derivatives via a one‐pot elimination and inter‐/intramolecular double aza‐Michael addition strategy.…”

Microwave‐Assisted Continuous Flow Organic Synthesis (MACOS)

“…A further study involved the synthesis of stereochemically rich benzothiaoxazepine 1,1 -dioxides as central cores for high-throughput screening collections [33]. The MACOS platform was used for the scale-out production of bicyclic scaffolds (16) sequence (Scheme 25.4).…”

“…The combination of microwave and flow chemistry allowed a dramatic rate enhancement and also safer scalability. Using this attractive approach, phenols (32), NH-containing heteroaromatic compounds (33), and carboxylic acids (34) were methylated with dimethyl carbonate (DMC), or benzylated with dibenzyl carbonate (DBC), in the presence of a suitable base (Scheme 25.10). The use of phase-transfer catalysts or ionic liquids under the same microwave conditions could further accelerate reactions, and rate increases >1900-fold could be achieved in some cases.…”