Andrew S. Kleinke

Bio: Andrew S. Kleinke is an academic researcher from Massachusetts Institute of Technology. The author has contributed to research in topics: Ring (chemistry) & Residence time (fluid dynamics). The author has an hindex of 3, co-authored 5 publications receiving 165 citations.

Hydrogen‐Free Alkene Reduction in Continuous Flow.

Abstract: The first continuous hydrogenation that requires neither H2 nor metal catalysis generates diimide by a novel reagent combination. The simple flow reactor employed minimizes residence time by enabling safe operation at elevated temperature.

Bromine-catalyzed conversion of CO2 and epoxides to cyclic carbonates under continuous flow conditions.

Abstract: A continuous method for the formation of cyclic carbonates from epoxides and carbon dioxide (CO2) is described. The catalysts used are inexpensive and effective in converting the reagents to the products in a residence time (t(R)) of 30 min. The cyclic carbonate products are obtained in good to excellent yield (51-92%). On the basis of a series of kinetics experiments, we propose a reaction mechanism involving epoxide activation by electrophilic bromine and CO2 activation by an amide.

A Unified Continuous Flow Assembly-Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines

Abstract: A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N-alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst free conditions. This assembly line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four-step, telescoped synthesis of measles therapeutic, AS-136A, in a total residence time of 31.7 min (1.76 g h-1).

Three-Component Coupling Based on Flash Chemistry. Carbolithiation of Benzyne with Functionalized Aryllithiums Followed by Reactions with Electrophiles

Abstract: A flow microreactor method for three-component coupling of benzyne was developed based on flash chemistry. o-Bromophenyllithium generated from 1-bromo-2-iodobenzene and a functionalized aryllithium generated from the corresponding aryl halide were mixed at -70 °C. In the subsequent reactor o-bromophenyllithium is decomposed to generate benzyne without affecting the functionalized aryllithium at -30 °C, and carbolithiation of benzyne with the aryllithium took place spontaneously. The resulting functionalized biaryllithium was reacted with an electrophile in the subsequent reactor to give the corresponding three-component coupling product. The precise optimization of reaction conditions using the temperature-residence time mapping is responsible for the success of the present transformation. The present method has been successfully applied to the synthesis of boscalid.

Construction of Medium-Sized Rings by Gold Catalysis.

Abstract: Compounds having cyclic molecular frameworks are highly regarded for their abundance and diverse utilities. In particular, medium-sized carbocycles and heterocycles exist in a broad spectrum of natural products, bioactive therapeutics, and medicinally significant synthetic molecules. Metal-mediated methods have been developed for the preparation of compounds containing a medium-sized ring (MSR) through cyclization of different classes of substrates and acyclic precursors. This review focuses on the methodologies for construction of MSRs via gold catalysis. Given the challenges in enabling the assembly of different ring sizes, we present here accounts on Au-mediated cyclization giving notable 7-membered and medium-sized (8-11-membered ring) structures. Emphasis on the pathway and mode of cyclization and the selection of precursors ranging from structurally biased compounds were outlined. Reactivity patterns and the choice of efficient Au catalysts for controlling reaction performance and selectivity in addition to mechanistic attributes are examined.

Enantioselective Synthesis of Chiral Medium-Sized Cyclic Compounds via Tandem Cycloaddition/Cope Rearrangement Strategy

Abstract: The nine-membered ring-bearing bicyclo[5.2.2]tetrahydrooxonines frameworks have enantioselectively been constructed via a tandem [3 + 2] cycloaddition/Cope rearrangement reaction of vinylethylene carbonates (VECs) with coumalates or pyrones. Under mild conditions, palladium-catalyzed asymmetric tandem reaction of various substituted VECs and coumalates or pyrones proceeds smoothly to produce the corresponding medium-sized heterocyclic compounds in high yields with very high enantioselectivities. Moreover, the reaction on the gram scale and further diverse transformations of the products were workable. The reaction mechanism was investigated through control experiments and DFT calculations, which show the reaction proceeds via a tandem [3 + 2] cycloaddition/Cope rearrangement pathway rather than via a [5 + 4] cycloaddition pathway.