Highly functionalized 2-arylindoles were synthesized from 2-alkenylarylisocyanides and arylboronic acids using a simple, inexpensive copper catalyst. The reaction exhibits excellent functional group tolerance for both the arylisocyanide and boronic acid coupling partners. To avoid the direct handling of the pungent arylisocyanide starting materials, continuous flow chemistry is further demonstrated to provide safe and effective access to 2-arylindoles through in situ dehydration and cyclization of easy-to-handle 2-alkenyl-N-formylanilines.
Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available mate-rials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput
An electrochemically driven, nickel-catalyzed reductive coupling of N-hydroxyphthalimide esters with aryl halides is reported. The reaction proceeds under mild conditions in a divided electrochemical cell and employs a tertiary amine as the reductant. This decarboxylative C(sp3)−C(sp2) bond-forming transformation exhibits excellent substrate generality and functional group compatibility. An operationally simple continuous-flow version of this transformation using a commercial electrochemical flow reactor represents a robust and scalable synthesis of value added coupling process.
Selective N-monomethylation of anilines has been achieved under continuous flow conditions using dimethyl carbonate as a green methylating agent in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. Our methodology takes advantage of the expanded process windows available in the continuous flow regime to safely induce monomethylation in superheated solvents at high pressure. We propose selective N-monomethylation is achieved via an in situ protection-deprotection pathway, which is supported by the observed reactivities of several putative reaction intermediates. The robust and scalable method was applicable to a broad range of primary aniline substrates including ortho-, meta-, and para-substituted anilines, as well as electron-rich and electron-deficient anilines. The synthetic precursor of diazepam, 5-chloro-2-(methylamino)benzophenone, was selectively synthesized under our optimized conditions.
The direct β-selective hydrocarboxylation of styrenes under atmospheric pressure of CO2 has been developed using photoredox catalysis in continuous flow. The scope of this methodology was demonstrated with a range of functionalized terminal styrenes, as well as αsubstituted and β-substituted styrenes.
We report a method for overcoming the low stability of nitroalkynes through the development of nitrated vinylsilyltriflate equivalents. Because of their instability, nitroalkynes have only rarely been utilized in synthesis. The reactivity of these silyltriflates, which are prepared in situ, is exemplified by dipolar cycloaddition reactions with nitrones to give highly substituted 4-nitro-4-isoxazolines in high yields. This approach has proven general for several different alkyl and aryl substituted alkynes. In order to minimize the accumulation of potentially hazardous reaction intermediates, we have also developed a continuous flow variant of this method that iscapable of carrying out the entire reaction sequence in a good yield and a short residence time.
Within a total residence time of 9 min, the sodium salt of ciprofloxacin was prepared from simple building blocks via a linear sequence of six chemical reactions in five flow reactors. Sequential offline acidifications and filtrations afforded ciprofloxacin and ciprofloxacin hydrochloride. The overall yield of the eight-step sequence was 60 %. No separation of intermediates was required throughout the synthesis when a single acylation reaction was applied to remove the main byproduct, dimethylamine.
Continuous flow reactors are enabling tools that can significantly benefit chemical reactions, especially those that are path length dependent (e.g., photochemical), mixing or transport dependent (e.g., gas-liquid), exothermic, or utilize hazardous or unstable intermediates. In this review, it is demonstrated how the nearly instantaneous mixing, exceptionally fast mass transfer, safe access to high temperatures and pressures, and high surface area to volume ratio can be leveraged to improve product yield, reaction rates and/or selectivity. By showcasing five synthetic methodologies examined by our group, it is hoped that the reader will gain an appreciation of the accessible and transformative nature of flow chemistry for improving existing transformations, enabling rapid optimization, and for developing new methodologies that depend on precise parameter controls.
Flow chemistry has attracted significant interest in pharmaceutical development, where substantial efforts have been directed toward the design of continuous processes. Here, we report a total synthesis of atropine in flow that features an unusual hydroxymethylation and separation of several byproducts with high structural similarity to atropine. Using a combination of careful pH control in three sequential liquid–liquid extractions and a functionalized resin, atropine is delivered by the flow system with98% purity
In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90 % for each step. A scale-up of this five-stage process (3 bond-forming steps, one work-up, and one in-line liquid–liquid separation) provided ibuprofen at a rate of 8.09 g h−1 (equivalent to 70.8 kg y−1) using a system with an overall footprint of half the size of a standard laboratory fume hood. Aside from the high throughput, several other aspects of this synthesis expand the capabilities of continuous-flow processing, including a Friedel–Crafts acylation run under neat conditions and promoted by AlCl3, an exothermic in-line quench of high concentrations of precipitation-prone AlCl3, liquid–liquid separations run at or above 200 psi to provide solvent-free product, and the use of highly aggressive oxidants, such as iodine monochloride. The use of simple, inexpensive, and readily available reagents thus affords a practical synthesis of this important generic pharmaceutical.