Application of a Double Aza-Michael Reaction in a ‘Click, Click, Cy-Click’ Strategy: From Bench to Flow

Abstract

The development of a ‘click, click, cy-click’ process utilizing a double aza-Michael reaction to generate functionalized 1,2,5-thiadiazepane 1,1-dioxides is reported. Optimization in flow, followed by scale out of the inter-/intramolecular double aza-Michael addition has also been realized using a microwave-assisted, continuous flow organic synthesis platform (MACOS). In addition, a facile one-pot, sequential strategy employing in situ Huisgen cycloaddition post-double aza-Michael has been accomplished, and is applicable to library synthesis.

A summary of seven- and eight-membered ring sultam syntheses via three Michael addition reactions

“…We provide a short summary of this methodology to introduce the reader to several of these highyielding routes in one place. Similar synthetic paths were reported previously by us and the Hanson group [36][37][38][39][40][41][42][43][44][45]. In this work we combine all our synthetic methods for sevenand eight-membered ring -N,N-, -N,O-, and -N,S-sultams to give readers a more complete picture of the use of vinyl sulfonamides as starting materials to generate sultams.…”

Multicapillary Flow Reactor: Synthesis of 1,2,5-Thiadiazepane 1,1-Dioxide Library Utilizing One-Pot Elimination and Inter-/Intramolecular Double aza-Michael Addition Via Microwave-Assisted, Continuous-Flow Organic Synthesis (MACOS)

“…Inspired by our recently reported batch one-pot elimination/double aza-Michael (DaM) strategy for the preparation of 1,2,5-thiadiazepane 1,1-dioxides [13], we decided to apply a one-pot elimination and DaM strategy in MACOS to generate the desired scaffold efficiently using a parallel multicapillary flow reactor.…”

“…This DaM MACOS strategy afforded the desired sultams in excellent yields on gram scale, and the process could be run as long as desired to make virtually any quantity [13]. With these results in hand, a parallel MACOS capillary reactor was used to further streamline library synthesis.…”

“…Methods that have been used to prepare these cyclic sulfonamides include the intramolecular Diels–Alder reaction [4], cyclization of aminosulfonyl chlorides [5], cycloadditions [6], radical cyclization [7], transition metal-catalyzed approaches [8], and ring-closing metathesis (RCM) [9]. Moreover, we have developed a variety of methodologies for the generation of five to eight-membered annulated and non-annulated sultams through processes we have termed “Click-Click-Cyclize” [10], “Click-Cyclize” [11], reagent-based DOS [12], “Click, Click, Cy-Click” [13], and Heck, aza-Michael (HaM) strategies [14,15]. …”

“…Previously, we reported on the MACOS preparation of 1,2,5-thiadiazepane 1,1-dioxides and their scale-up [13]. Herein, we report the full details with the production of a 50-member library utilizing multicapillary flow reactors (Scheme 1).…”