A catalytic, formal homo-Nazarov-type cyclization of alkylidene cyclopropanes (ACPs) to give functionalized arenes and heteroaromatics is reported. In the presence of a Lewis acid catalyst, the ACP 1,1-ketoesters undergo distal bond cleavage to afford an allyl cation intermediate. Adjacent π-attack on the allyl cation then provides a six-membered ring that undergoes rapid aromatization. In these cases, benzenoid products are formed in up to 98% yield. Strategic choice of the substitution about the ACP allows for the generation of other useful isomeric products in good yields.
Continuous flow processing represents
an emerging technology in
the chemical and pharmaceutical industries. Herein, we describe a
tandem, bicatalytic continuous flow cyclopropanation-homo-Nazarov-type
ring-opening cyclization to form hydropyrido[1,2-a]indoles, which represents a naturally occurring chemical scaffold
present in many bioactive and therapeutically relevant molecules.
The tandem flow reactions provided high conversions (>97%) with
product
throughputs on the order of 3–5 g h–1. The
individual transformations (cyclopropanation and ring-opening cyclization)
were separately optimized in the batch then successfully transferred
to the flow. Significantly, this represents the first literature example
of continuous flow cyclopropane ring-opening cyclizations; hydropyrido[1,2-a]indoles are formed on a multigram scale (>4 g h–1 throughput) in near-quantitative yields from N-indolyl-1,1-cyclopropyl
β-amidoesters. Overall, the continuous flow technology exhibited
superior yields, relative to the batch reactions, for both the ring-opening
cyclizations and the tandem, bicatalytic reactions. These results
provide the basis for large-scale implementation of bicatalytic cyclopropanation-ring-opening
cyclization reactions for complex synthesis and represent initial
efforts toward the development of an industrially viable, four-step
continuous flow synthesis of hydropyrido[1,2-a]indoles.
An Al(OTf)3 -catalyzed intramolecular cascade ring-opening benzannulation of 2,3-dihydrofuran O,O- and N,O-acetals is described. The cascade sequence involves the dihydrofuran ring-opening by acetal hydrolysis, an intramolecular Prins-type cyclization, and aromatization to generate an array of benzo-fused (hetero)aromatic systems in up to 95 % yield. This method represents the first example of dihydrofuran acetal usage in benzannulation reactions. The approach provides excellent regiocontrol based on the choice of alkenes used to form the requisite dihydrofuran acetals.
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