A Tandem, Bicatalytic Continuous Flow Cyclopropanation-Homo-Nazarov-Type Cyclization

Abstract

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.

RhII‐Catalyzed β‐C(sp2)−H Alkylation of Enol Ethers, Enamides and Enecarbamates with α‐Diazo Dicarbonyl Compounds

“…In ap revious study, [11] treatment of N-indolyl a-diazomalonamide 2a with 3,4-dihydro-2H-pyran (DHP; 3a)i nt he presence of Rh 2 (esp) 2 formed b-alkylated DHP 4aa in 43 %y ield. Given this interesting result, we sought to directly addresst he limitations of previously reported functionalizations of enol ethers, enamines, and enecarbamates with a-diazo-1,3-dicarbonyls through systematic optimization of this diazomalonamide-DHP coupling transformation.…”

Continuous Flow Synthesis of Heterocycles: A Recent Update on the Flow Synthesis of Indoles

“…As described above in this review, flow chemistry offers the possibility to access highly complex molecular structures through continuous flow multi-step strategies applicable for industrial purposes. In this context, Pollet and France reported a tandem, bicatalytic continuous flow cyclopropanation-homo-Nazarov-type ring-opening cyclization for the preparation of a hydropyrido[1,2-a]indole framework, which is present in various bioactive compounds [112]. Remarkably, this contribution was the first example in the literature of a homo-Nazarov-type cyclization under continuous flow conditions.…”

“…In 2018, the continuous flow preparation of C-3 dicarbonyl indoles via the I2/DMSO-mediated oxidative coupling of aryl acetaldehydes with indoles was proposed by Fang and Guo [112]. Initial batch experiments were conducted, using phenylacetaldehyde 89 and N-methylindole 70 as starting materials.…”

The Catalytic, Formal Homo‐Nazarov Cyclization as a Template for Diversity‐Oriented Synthesis

“…Convinced of the potential pharmaceutical utility of the hydropyrido[1,2‐ a ]indole core and the effectiveness of our developed methodology, we endeavored to perform the ring‐opening cyclization using continuous flow technology. In that regard, we recently reported a tandem, bicatalytic continuous flow cyclopropanation homo‐Nazarov‐type ring‐opening cyclization to form hydropyrido[1,2‐ a ]indoles (Scheme ) . The tandem flow reactions provided high conversions (>97 %) with product throughputs on the order of 3–5 g h −1 .…”