Abstract
A straightforward and transition metal-free one-pot protocol to synthesize halobenzo[b]furans has been developed employing simple and easily available starting materials such as O-aryl carbamates and alkynylsulfones. The fine-tuning of the different steps involved was key to achieving a successful one-pot procedure. Initially, a directed ortho-lithiation process, which uses the carbamate as the directed metalation group, was crucial in providing access to O-2-alkynylaryl N,N-diethyl carbamates by a direct alkynylation of the o-lithiated carbamate, with arylsulfonylalkynes as electrophilic reagents. Cyclization of the generated o-alkynylaryl carbamates was successfully accomplished through a strategy involving in situ carbamate alkaline hydrolysis under conventional heating or microwave irradiation, coupled with a subsequent heterocyclization step delivering the desired benzo[b]furans. A wide variety of new halobenzo[b]furans has been synthesized and their utility has been demonstrated by their further transformation.
Highlights
Benzo[b]furans are an important class of heterocyclic compounds that show a wide range of biological properties with medicinal significance [1,2]
To tackle the proposed target, we first needed to establish a suitable protocol for synthesizing O-o-alkynylaryl N,N-diethyl carbamates
We observed that only slight excess of the alkynylsulfone was required as the electrophilic partner for the organolithium intermediate 1a-Li generated from the regioselective ortho-lithiation of O-3-fluorophenyl N,N-diethylcarbamate 1a [17,18]
Summary
Benzo[b]furans are an important class of heterocyclic compounds that show a wide range of biological properties with medicinal significance [1,2]. They are common structural motifs of natural products and bioactive compounds [3], as well as bioisosteres of indoles [4]. Tandem Sonogashira coupling/cyclization from alkynes and o-halophenols under Pdcatalysis is one of the most used and efficient procedures [8] In this field, the regioselective preparation of halogen-functionalized benzo[b]furans is a relevant goal, as these substrates allow for further functionalization through a plethora of transition metal-catalyzed crosscouplings or halogen-lithium exchange and subsequent electrophilic trapping. Starting from preformed benzofurans, its C-4 position is the least nucleophilic one and not prone to undergo an aromatic electrophilic substitution reaction
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