Prediction of Catalyst and Substrate Performance in the Enantioselective Propargylation of Aliphatic Ketones by a Multidimensional Model of Steric Effects

The effectiveness of a new asymmetric catalytic methodology is often weighed by the number of diverse substrates that undergo reaction with high enantio­selectivity. Here we report a study that correlates substrate and ligand steric effects to enantio­selectivity for the prop­argyl­ation of aliphatic ketones. The mathematical model is shown to be highly predictive when applied to substrate/catalyst combinations outside the training set

Sequential Reduction of Nitroalkanes Mediated by CS₂ and Amidine/Guanidine Bases: A Controllable Nef Reaction

In this letter, we describe a mild, functional group-tolerant reductive Nef reaction that utilizes CS2 and an amidine or guanidine base to sequentially cleave N–O bonds. These conditions transform secondary nitroalkanes to ketones via an isolable oxime with minimal erosion at labile stereogenic carbons, show excellent compatibility with groups sensitive to oxidizing or reducing conditions, display good scalability, and are well-suited for generating useful 3-pyrrolidinone motifs from readily accessible 1,3-dipolar cycloaddition products

A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light

Visible-light-promoted organic reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solutions exist to employ these reactions for multikilogram production. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high-intensity laser to drive photochemical reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer–Lambert law as a guideline to optimize catalyst concentration and reactor depth for maximum throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochemical reactions

Chemoselective (Hetero)Arene Electroreduction Enabled by Rapid Alternating Polarity

Conventional chemical and even electrochemical Birch-type reductions suffer from a lack of chemoselectivity due to a reliance on alkali metals or harshly reducing conditions. This study reveals that a simpler avenue is available for such reductions by simply altering the waveform of current delivery, namely rapid alternating polarity (rAP). The developed method solves these issues, proceeding in a protic solvent, and can be easily scaled up without any metal additives or stringently anhydrous conditions

Mechanistic Evaluation and Solvent-Based Linear Free Energy Relationship in the Alkylation of ABT-199 Using Di-<i>tert</i>-butyl Chloromethyl Phosphate

To ensure successful scale-up for a prodrug of ABT-199, the key alkylation step was optimized, and the mechanism was explored. The use of 1,8-bis­(dimethylamino)­naphthalene was essential for high conversion and selectivity, and statistical experimental design yielded the optimal stoichiometries to maximize the yield and minimize impurities. Kinetic interrogation demonstrated that the rate-determining step was phosphate activation and not alkylation as might be presumed, and evidence for a radical chain mechanism was uncovered. Further support for a radical chain mechanism was found in a novel solvent-based linear free energy relationship between the Hansen solubility parameters and the observed rate. The level of mechanistic understanding informed successful scale up to 1, 10, and 20 kg

A Scalable Solution to Constant-Potential Flow Electrochemistry

The burgeoning interest in new electrochemical methods holds promise to provide a plethora of strategic disconnections for pharmaceutical compounds that are safer, less wasteful, and more streamlined than traditional chemical strategies. The use of organic electrochemistry in the commercial production of pharmaceuticals is exceedingly rare due to the lack of a modular infrastructure. Herein we describe the use of cascading continuous stirred tank reactors with individual cell potential control applied over reaction “stages” which demonstrate a balance between high selectivity and throughput necessary for electrochemistry to be a viable strategy in the pharmaceutical space. Using the high degree of control of cell potential afforded by this reactor design, a 1 kg demonstration was achieved in 9 h with high selectivity and yield (2.6 kg/day throughput)

Continuous Multiphase Flow Nitration and Cryogenic Flow Formylation: Enabling Process Development and Manufacturing of Pharmaceutical Intermediates

Manufacturing API and pharmaceutical intermediates requires the development of scalable, safe, and environmentally friendly processes. Reactions with high exothermicity or otherwise hazardous in nature, as well as reactions involving the formation of unstable intermediates, can benefit from continuous processing. This technology has been broadly adopted across the pharmaceutical industry due to its intrinsic ability to operate at low reaction volumes, facilitate improved temperature control, and safely accommodate higher pressures. Two such industrially relevant examples are aromatic nitration and regioselective aryl ring metalation, followed by trapping with an electrophile. Both reaction classes commonly face scale-up challenges when performed in batch processing. The nitration reaction usually features a multiphase, mixing-sensitive reaction associated with a large exotherm that can lead to the formation of potentially hazardous overnitrated byproducts. Similarly, metalation reactions of aryl rings often require cryogenic conditions, which are challenging to achieve on scale. In this study, a mixing-limited solid–liquid–liquid (S–L–L) nitration reaction was evaluated to understand the transport phenomena. The determination of the Hatta number and impact of the impeller power on the kinetics enabled the design of a safe, scalable, high-yielding, and robust continuous stirred tank (CSTR) flow process. A study of critical formylation reaction parameters led to a first-generation tubular flow reactor design to process >10 kg of a substrate in the pilot plant. A more practical CSTR reactor system in series was developed to support a resupply delivery. This reactor configuration enabled superior temperature control, alleviated the risks associated with salt formation, and increased the throughput and yield

Phase-Transfer-Catalyzed Asymmetric Acylimidazole Alkylation

2-Acylimidazoles are alkylated under phase-transfer conditions with cinchonidinium catalysts at −40 °C with allyl and benzyl electrophiles in high yield with excellent enantioselectivity (79 to >99% ee). The acylimidazole substrates are made in three steps from bromoacetic acid via the N-acylmorpholine adduct. The catalyst is made in high purity allowing for S-product formation (6−20 h) under mild conditions, consistent with an ion-pair mechanism. The products are readily converted to useful ester products using methyltriflate and sodium methoxide, via a dimethylacylimidazolium intermediate without racemization. The process is efficient, direct, and amenable to other electrophiles and transformations that proceed through an enolate intermediate

Commercial-Scale Visible Light Trifluoromethylation of 2‑Chlorothiophenol Using CF₃I Gas

Despite the growth of photoredox methods in academia, application of photoredox at scale in the pharmaceutical and fine chemical industries has been slow. In this report, a photoredox trifluoromethylation of a thiophenol was modified from the original literature report, and the mechanism was investigated to define the key scale-up parameters. The mechanistic insight was leveraged in the design and execution of two different reactor designs: an LED-based plug flow photoreactor and a laser-based continuous stirred tank photoreactor. In one of the first examples of commercial-scale photoredox chemistry, the process was scaled to provide over 500 kg of the desired intermediate and amended to fully continuous manufacturing

Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation

We report the development and demonstration of a continuous-flow process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction to provide cyclopropane 4. Designing this process with safety as a primary objective, we identified the appropriate arylsulfonyl hydrazone starting material and organic soluble base to facilitate a Bamford–Stevens diazo-generating flow process at 30 °C, well below the thermal onset temperature (Tonset = 57 °C), while also minimizing accumulation of the highly energetic diazo intermediate (ΔHD = −729 J/g). The Bamford–Stevens reaction byproducts are efficiently removed via a continuous aqueous extraction utilizing a liquid–liquid hydrophobic membrane separator. Continuous molecular sieve drying of the organic layer was demonstrated to maintain water levels <100 ppm in the final aryldiazoacetate solution, thereby ensuring acceptable reactivity, selectivity, and purity in the water sensitive cyclopropanation reaction. The full process was successfully executed on a 100 g scale, setting the foundation for the wider application of this and related chemistries on a kilogram scale