The development of a new method for the synthesis of 1,1-dioxido-1,2-benzisothiazoline-3-acetic acid by a domino process is reported whereby a classical Heck reaction is coupled to an intramolecular aza-Michael reaction. Ultimately, this method has been expanded to a one-pot, sequential three-component protocol to generate diverse benzofused γ-sultams from a range of commercially available α-bromobenzenesulfonyl chlorides, amines and Michael acceptors.
The development of new methods to skeletally diverse sultams based on a central α-halo benzene sulfonamide building block is reported. Several salient features of this building block are utilized in multiple reaction pathways, including the Heck reaction, C-and O-arylation, Sonogashira-PausonKhand, Sonogashira-intramolecular hydroamination, lithiative cyclization and domino aza-Michael Heck for the generation of 5-, 6-and 7-membered benzofused bicyclic and tricyclic sultams.
Highlights d A high-throughput screen identifies a small-molecule inhibitor of CPS1, H3B-120 d H3B-120 binds to an allosteric pocket to achieve highly selective inhibition of CPS1 d Analogs of H3B-120 block CPS1 cellular activity in primary human hepatocytes
A formal [4+3] epoxide cascade protocol utilizing ambiphilic sulfonamides and a variety of epoxides (masked ambiphiles) has been developed for the generation of benzothiaoxazepine-1,1′-dioxides and oxathiazepine-1,1′-dioxides. This protocol combines an epoxide ring-opening with either an S N Ar or oxa-Michael cyclization pathway.The development of cascade reactions, which couple two or more reactions together to produce heterocyclic scaffolds, is an important challenge in drug discovery and natural product synthesis. 1 Cascade or domino reactions are highly efficient pathways that allow for the synthesis of complex molecules from simple substrates and encompass a variety of transformations. Many of these cascade transformations involve the utilization of synthons, which contain either a nucleophilic or an electrophilic site. 2 In contrast, ambiphilic synthons possess both a nucleophilic and electrophilic site, making them ideal components for cascade protocols. 3,4 Interest in the utilization of cascade reactions for the synthesis of diverse sultam scaffolds 5 has led us to explore the titled protocol where ambiphilic sulfonamides are combined with an epoxide (a masked ambiphile), are combined in a cascade reaction termed complementary ambiphile pairing (CAP) (Figure 1 (Figure 2).Reports of the cyclization of an in situ generated epoxide-derived alkoxide via an intramolecular S N Ar cyclization have been limited. Albanese and co-workers first reported the synthesis of piperazines utilizing an epoxide-opening, S N Ar protocol. 11 More recently, a key report by Cleator and co-workers at Merck demonstrated the ring-opening of epoxides with α-fluorobenzene-sulfonamides, followed by subsequent S N Ar cyclization to give the corresponding piperazines and sultams. 12 Reports of intramolecular Michael cyclizations with vinylsulfonamides have been utilized in seminal work by Knollmüller and Hirooka, 13 to more recent applications in the area of diversity-oriented synthesis (DOS) strategies using a "Click, Click, Cyclize" approach. 14 However, the opening of an epoxide and subsequent cyclization via oxa-Michael is not known.Initial investigation into the proposed epoxide cascade focused on the development of orthogonal reaction conditions that would initiate the ring opening of the corresponding epoxide, followed by intramolecular S N Ar cyclization to yield the desired sultam in a one-pot, domino process. 15 It was found that both the choice of solvent and base was key to the overall reaction process with dioxane essential for the initial epoxide ring-opening step, and DMF for the S N Ar ring-closing step of the cascade. After screening a wide variety of bases, anhydrous Cs 2 CO 3 produced the best overall yield and crude purity when utilized in the cascade protocol. The utilization of microwave irradiation at 110 °C for 20 minutes was essential to obtain both high yields and crude purity in addition to a significant decrease in reaction times. 16,17 After optimization of reaction conditions for the synthesis of...
Go with the flow! Using a combination of continuous‐flow techniques and microwave irradiation, a 19‐member collection of 5–10 gram quantities of benzthiaoxazepine‐1,1‐dioxides has been produced (see scheme). The elimination of intermediate‐ and large‐scale process optimization by invoking the concept of scale‐out (rather than scale up) has significantly reduced the time necessary to prepare these compounds.
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