Some Items of Interest to Process R&D Chemists and Engineers

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Despite significant recent advances, the photochemistry of diazoalkanes remains largely dominated by donor/acceptor systems. Building upon previous work on triplet diphenyl carbenes, Koenigs and co-workers successfully demonstrated the synthesis of furans via the photocatalyzed reaction of acceptor/acceptor diazoalkanes with alkynes ( Adv. Synth. Catal., DOI: 10.1002/adsc.202200654). The authors found that tris[2-phenylpyridinato-κC²,κN]iridium(III) and dichloromethane are the optimal catalyst and solvent for the reaction and that the concentration has a major impact on the yield. The substrate scope is large regarding the diazoalkane partner and encompasses different types of acceptor/acceptor systems, including those leading to 2-chloromethyl-, 2-difluoromethyl-, and 2-trifluoromethyl-substituted furans. Although both internal and terminal alkyl- and (hetero)aryl-substituted alkynes were demonstrated to be competent substrates, the former led to the corresponding furans in lower yield. Mechanistic studies aimed at demonstrating the passage through a cyclopropene intermediate allowed the authors to rule out its involvement in the catalytic cycle.

Sulfoxides are a versatile class of organic compounds whose applications span from medicinal chemistry to materials science. Most synthetic methods to access them are based to date on two-electron processes. Laronov and co-workers recently described a radical-based methodology for their synthesis relying on decarboxylative sulfinylation of a carboxylic acid with a sulfinate ( Angew. Chem., Int. Ed., DOI: 10.1002/anie.202210525). In silico assessment of the chemical space that could become accessible through the application of the planned reaction revealed that products accessible via the decarboxylative sulfinylation could have a broader distribution of molecular weight, higher molecular complexity, and higher sp³ fraction than already-known sulfoxides. An optimization study allowed the authors to identify acridine A1 (see the scheme) and p-bromobenzoyl chloride as the most efficient photocatalyst and stochiometric additive for the reaction, respectively. Irradiation at 400 nm at room temperature in dichloromethane led to various dialkyl or alkyl (hetero)aryl sulfoxides in good to high yields. Primary, secondary, and tertiary alkyl carboxylic acids bearing most common functional groups are all tolerated under the reaction conditions. Moreover, the construction of sulfoxides by sequential reaction of two carboxylic acids was demonstrated on five examples by combining the developed protocol with a photochemical sulfinylation with DABSO. Mechanistic and computational studies allowed the authors to propose a catalytic cycle for the reaction involving the intermediacy of the sulfinyl sulfone derived from the sulfinate.

Cyclic phosphate monomers are essential building blocks for the synthesis of polyphosphoesters that have recently found applications in drug delivery systems and tissue engineering. Applying flow chemistry, Monbaliu and co-workers address the challenges of scaling-up the production of cyclic phosphate monomers, which can include resource- and time-intensive protocols with serious safety concerns ( Chem. Sci., DOI: 10.1039/D2SC02891C). The authors were able to successfully translate the known three-step batch sequence to a fully concatenated synthesis. Different conditions were developed to produce cyclic chlorophosphites depending on the structure of the diol engaged. The reaction of phosphorus trichloride with 1,2- and 1,3-unhindered diols can be performed under base-free conditions, while more hindered ones required a higher dilution and the addition of N-methylimidazole or 1,8-diazabicyclo[5.4.0]undec-7-ene (forming ionic liquids to prevent clogging). Productivity in the range of 10 g/h was reached in a 1 mL reactor, and scale-up of the developed conditions in a commercial 5.4 mL glass reactor led to a space-time yield of 348 kg L^–1 day^–1. Oxidation of the resulting chlorophosphite with oxygen was found to be highly mixing-dependent. At 65 °C, a residence duration of 21 s is enough to fully convert the substrates to the corresponding chlorophosphates. The resulting products needed to be converted in situ to more stable phosphates by reaction with an alcohol in the presence of pyridine in batch mode. The fully concatenated sequence was demonstrated on two examples in 39% and 49% overall yield, respectively, outperforming the reported batch procedure and mitigating the risk associated with the highly exothermic nature of the reaction and the generation of gaseous HCl. Batch and flow (co)polymerization of the obtained monomers was also demonstrated.

A wealth of synthetic methods have been developed to tackle the formation of substituted cyclobutanes. The [2 + 2] cycloaddition remains the preferred approach. One of the key issues in this reactivity mode is the reaction rates observed in intermolecular [2 + 2] additions. Activating groups are typically required on each substrate, rendering the preparation of all-alkyl substrates or sterically hindered cyclobutanes challenging. The group of Kevin Brown at Indiana University devised a modified photocycloaddition of alkenylboronates and allylic alcohols via a temporary tether with the aim to bring the two substrates into proximity ( J. Am. Chem. Soc., DOI: 10.1021/jacs.2c08777). A key feature is the need for KOtBu as the base, allowing the formation of a tetravalent borate intermediate to allow the cyclization to occur. A broad range of polysubstituted cyclobutanes were obtained in good yield and diastereocontrol. One limitation remains the use of 1,2-disubstitued alkenes, which generate a mixture of diastereoisomers. The applicability of this method was later demonstrated with the subsequent cross-coupling of cyclobutyl boronates as well as the application to the synthesis of two natural products: artochamin J and piperarborenine B.

Crystallization control could benefit from a better understanding of crystal nucleation and growth mechanisms. In addition to an insufficient understanding of the latter, there is the challenge of describing crystallization using different theoretical approaches, including both classical and nonclassical nucleation theories. Using certain simplifying assumptions, describing the formation of the crystal matter as molecule-by-molecule attachment, the classical nucleation theory has been used to understand nucleation with some success. More complex nucleation theories were developed, which invoked the existence of intermediate nucleation clusters in a multistep process. Selecting an organic dye (perylene diimide), a team from the Weizmann Institute used cryogenic transmission electron microscopy for structural imaging of the growth of this compound’s crystals in water/THF (Biran, I.; et al. Cryst. Growth Des., DOI: 10.1021/acs.cgd.2c00853). The elucidated growth mechanism includes a nonclassical self-assembly sequence of the molecular π-stacks, followed by a classical step of monomer attachments to form the final crystalline structure. The authors consider that the growth mechanism proposed is best described by a series of supramolecular events occurring over a broad size range.

Even though the use of excipients (regulatory-accepted as inactive ingredients) to influence crystallization processes has been reported, this is not a widespread method for crystallization process control. However, such crystallization methods can be useful for the development of formulations for long-acting injectable suspensions. A team from Janssen Pharmaceutica and several universities reported the successful use of excipients for polymorph and particle size control in the seeded antisolvent crystallization of indomethacin (Silva, M. H.; et al. Cryst. Growth Des., DOI: 10.1021/acs.cgd.2c00678). Using seeds of the stable form together with excipients, the authors were able to accelerate the polymorphic transformation of the kinetic metastable form to the thermodynamically stable form (48 to 4 h). Several strategies were evaluated, including the addition of seeds of various sizes before or after nucleation and formulations including either poloxamer 407 and docusate sodium salt or poloxamer 407 and sodium lauryl sulfate. This “bottom-up” technology is considered more effective than the common “top-down” approach using milling. This paper has 72 references.

An example of the use of Quality by Design (QbD) methodology for process safety analysis was reported by a team from Texas A&M University (Parker, T. F.; et al. Ind. Eng. Chem. Res., DOI: 10.1021/acs.iecr.2c02972). The model reaction was the exothermic oxidation of cyclohexanol to cyclohexanone with hydrogen peroxide using sodium tungstate dihydrate (Na₂WO₄·2H₂O) as a catalyst. A statistical design of experiments (DoE) approach was used to minimize the amount of heat released while maximizing the yield of cyclohexanone. Three process parameters were investigated: temperature, peroxide/cyclohexanol stoichiometry, and number of peroxide injections. Calibrated FTIR spectroscopy was used to quantify the amount of ketone obtained. The experiments were executed in the RC1 using operating parameters based on prior knowledge. Temperature was found to be the most statistically significant variable, and optimal reaction conditions were established. Additional scale-up investigations may be planned.

In a recent extension of their aza-Cope methodologies, the group of Professor Njardarson at the University of Arizona unveiled a method to access 2,4-disubstituted benzoate esters starting from racemic β-fluoro-substituted conjugated tert-butylsulfinyl imines and 3-substituted methyl 2-butenoates ( Org. Lett., DOI: 10.1021/acs.orglett.2c03134). The anionic cascade involves initial 1,4-addition of the lithium enolate, elimination of fluorine, and cyclization via enolate attack of the corresponding enolate ester on the sulfinimine toward a cyclic intermediate. A final elimination of the NHSOtBu completes the aromatization toward the final product. A key requirement is the use of LiHMDS to ensure reactivity and high yield. A variety of 2,4-disubstituted aromatic esters with a variety of substituents could be generated in good yields but only at a 0.2 mmol scale. This methodology might not represent the best way to synthesize simple triaromatic substrates but could be a valuable pathway toward more complex targets bearing a cyano or styrenyl group as well as deuterated building blocks and also could extend further the knowledge and applicability of amino-Cope rearrangements.

Protocols for the so-called self-optimization of processes are not optimal for mapping a design space and model fitting. To address this, scientists at RCPE are using Design of Experiments to optimize reactions amenable to flow chemistry. They have now shared their open-source software, written in Python, for building models in real time (Kappe, C. O.; et al. React. Chem. Eng., DOI: 10.1039/D2RE00208F). The end user selects the input factor, factor ranges, and objective for the study, leaving the application to automate the processing of acquired data and evaluate the resulting model. The application is agnostic to the control software with which it interfaces. As the model is updated in real time, a potential outlier is automatically repeated before moving to the next experiment. The software is applied to the optimization of space-time yields of reactions involving four and six variables. In these cases, concentrations chemometrically generated in real time from online ¹H NMR data were fed into the model.

NADPH-dependent ene reductases (EReds) have been coupled with imine reductases/reductive aminases (IReds/RedAms) to convert certain enones, including 3-methyl-2-cyclohexen-1-one and 3-methyl-2-cyclopentene-1-one, into amines containing two stereogenic centers (Knaus, T.; et al. ACS Catal., DOI: 10.1021/acscatal.2c03052). The stereogenic centers are cis, as found in melogliptin, in contrast to the use of EneIREDs, which produce the trans product. Buffering using an appropriate alkylammonium formate provides a source of the amine donor and enables deployment of a formate dehydrogenase for in situ recycling of the NADPH coenzyme. While primary and secondary amines worked well, ammonia did not lead to useful selectivities.

Scientists at J-Star have shared an approach to studying impurities incorporated as a solid solution (Abramov, Y. A.; et al. Cryst. Growth Des., DOI: 10.1021/acs.cgd.2c00957). Along with the free energy of solvation difference between the desired solute and the solute, the method uses a reverse sublimation thermodynamic cycle to consider the destabilization of the lattice of the desired solute by substitution of an impurity into it. In a study comprising of five active ingredients or intermediates, each with a key impurity, virtual screening of a short list of solvent options performed over 1–2 weeks correctly predicted the top two solvents that would minimize impurity uptake in three of the five cases studied. The approach can deal with multiple impurities or solid forms of the desired solute, as demonstrated with a further case study involving adagrasib, though interactions between multiple impurities present were neglected.

Triazoles substituted at N2 with an aryl group are found in a number of marketed products. Idorsia scientists shared an improved synthesis of a building block of a pharmaceutical development candidate, ACT-539313, using a copper(I) oxide-catalyzed coupling of 1H-1,2,3-triazole with an aryl bromide (Fleischer, T.; Schäfer, G. Helv. Chim. Acta, DOI: 10.1002/hlca.202200162). This system does not require an exogeneous ligand, benefiting the cost of goods of processing versus the first-generation process. Also, the process no longer uses 1,4-dioxane, which previously brought operator handling and environmental liabilities to the inherited process. The crystallization of the desired N2 isomer as its potassium salt took advantage of the greater solubility of the N1 impurity when water was present in the solution. Charcoal treatment between the crystallizations to remove residual copper was followed by the crystallization of the free acid to completely purge the undesired regioisomer. The article additionally covers the viability of using the high energy 1H-1,2,3-triazole material on a kilogram scale.

Bayer shared prolonged efforts that have gone onto developing an economically viable enantioselective asymmetric hydrogenation as part of the synthesis of a fungicide (Schotes, C.; Müller, S. ACS Sustainable Chem. Eng., DOI: 10.1021/acssuschemeng.2c05041). To develop a Crabtree–Pfaltz-type catalyst that displayed adequate activity, the team collaborated with the Leibniz Institute for Catalysis to develop a bespoke ligand. Catalytic BF₃·OEt₂ is used to improve the turnover frequency. For performance targets to be met at practical concentrations, the process needs hexafluoroisopropanol (HFIP) (caution: reprotoxic) as the solvent, though a switch to heptane in the workup allows its recovery with high purity ahead of recycling. Most of the iridium (90%) is recovered by scavenging with charcoal. Brief details about the custom synthesis of the ligand are also shared.

The synthesis of aldehydes on scale, especially through reduction, is often nontrivial. Partial reduction of carboxylic acids and esters often requires highly reactive reducing reagents (such as aluminum or silicon hydrides), careful temperature control, or derivatization of starting materials, all of which are potentially significant drawbacks on scale. Some classical alternatives proceed via the reduction of the acyl chloride (e.g., Rosenmund reduction) or the Weinreb amide. Finally, reduction to the alcohol with subsequent reoxidation to the aldehyde is still broadly employed as a backup strategy. Qi and Liu from Lanzhou Institute of Chemical Physics and Wuhan University recently published a viable alternative that utilizes a triflylpyridinium reagent in combination with pinacolborane as the reducing agent to accomplish the direct reduction of carboxylic acids (via their acylpyridiniums) to give the corresponding aldehydes ( Angew. Chem., Int. Ed., DOI: 10.1002/anie.202215168). The reaction conditions are mild and operationally simple, with the reaction typically complete after 10 min at room temperature. Although the triflylpyridinium needs to be prepared in a separate step, the aminopyridine byproduct can be recovered and reused after the reaction, which may be important because the much more expensive PDPP was found to be generally superior to the closely related DMAP. The more soluble option (PDPP) was also demonstrated in flow mode. In addition to its practical benefits, the reaction demonstrates unique chemoselectivity, allowing carboxylic acids to be reduced in the presence of alkynes and olefins (including α,β-unsaturation), aryl halides, cyclopropyl rings, and even aldehydes. In addition, α-stereocenters are generally untouched, although the yields for the transformation are modest in many cases. This method can also be used to obtain deuterated aldehydes simply by employing DBPin. Although the use of borane derivatives on scale does pose some safety concerns, particularly around the generation of toxic and explosive diborane, the reaction was also demonstrated in flow, which may alleviate some of these safety concerns and increase yields through removing the isolation step, which can often be challenging for alkyl aldehydes.

Although photoredox catalysis has greatly expanded the organic chemist’s toolbox of bond-forming reactions over the past decade, in practice these reactions are rarely run on scale. Part of the reason is that many classes of photoredox reactions still require or perform best with precious metal catalysts, which are cost-prohibitive on even modest scale. Acridinium derivatives are now well-established as a class of highly oxidizing metal-free photocatalysts, and versatile organic donor–acceptor species such as 4-CzIPN offer an alternative to popular heteroleptic iridium photocatalysts in many cases. However, few good organic alternatives to highly reducing photoredox metal catalysts such as Ir(ppy)₃ had been reported until recently. This perspective highlights the progress toward the design of modular organic highly reducing photocatalysts as well as some of the chemistry that can be carried out using them (Noto, N.; Saito, S. ACS Catal., DOI: 10.1021/acscatal.2c05034). The strategies required to design highly reducing organic photocatalysts that are still excitable by visible light are also discussed.

Persulfuric acid is a well-known industrial oxidant featuring low cost and ease of waste treatment. However, due to its explosive nature, it is not stored but rather is manufactured on site and has little application in organic synthesis. To overcome those limitations and expand its use, Kappe and Ötvös at the University of Graz described a continuous flow persulfuric acid generator and its function as aldehyde esterification agent in a simple, robust, and easily scalable process ( ChemSusChem, DOI: 10.1002/cssc.202201868). In the developed setup, the sulfuric acid is oxidized by hydrogen peroxide, and the formed peracid is immediately consumed by aldehyde oxidation to the corresponding ester, formed in the presence of the corresponding alcohol. The generality of the process was demonstrated by oxidative esterification of aliphatic and aromatic aldehydes, with high conversion and selectivity, and the final esters were isolated without chromatography in most cases. The scalability was demonstrated by a multigram example of pharmaceutical relevance, and the greenness was assessed by qualitative green metrics calculation and subsequent comparison with the existing batch process.

The 1,4-benzodiazepine-2-one moiety is an essential pharmacophore in the pharma industry. This class of compounds exhibit highly significant therapeutic applications as anxiolytics, hypnotics, antiarrhythmics, and vasopressin antagonists, among others, and remain among the most prescribed types of drugs in the market. Legros and co-workers at the University of Rouen described the development of a continuous flow chemistry platform for the flexible synthesis of six benzodiazepines from aminobenzophenones ( J. Flow Chem., DOI: 10.1007/s41981-022-00243-z). The optimized procedure used bromoacetyl bromide as the acylating agent and unprotected aminobenzophenones, does not require special equipment or high temperatures or pressures, and showcased highly reduced processing times. Remarkably, they were able to circumvent the N-alkylation issues by using the LDA/MeI combination, and the oxidations to prepare oxazepam and lorazepam were achieved by an acylation process using a heterogeneous BaMnO₄ cartridge. The platform furnished the benzodiazepines in overall yields ranging from 31 to 75% and constitutes an advanced solution for the strategic on-demand preparation of these key pharmaceutics.

The optimization of multistep sequences is much more efficient when all telescoped reactions are considered in a holistic fashion, in contrast to optimizing each process independently. Bourne and co-workers at the University of Leeds and industrial partners IBM, AZ, and UCB Pharma described the development of an automated continuous flow platform for the simultaneous optimization of telescoped reactions ( Angew. Chem., Int. Ed., DOI: 10.1002/ange.202214511). The authors’ approach was applied to a Heck cyclization/deprotection reaction sequence used in the synthesis of a precursor for 1-methyltetrahydroisoquinoline C-5 functionalization. A single HPLC instrument-based multipoint sampling method enabled accurate analysis of reaction pathways, and together with the integration of Bayesian optimization techniques, the team obtained an 81% overall yield in only 14 h. Moreover, the used methodology revealed the most favorable mechanistic pathway for the formation of the desired product.

Huestis and Rousseaux reported the synthesis of 1-arylcyclopropyl amines, a motif with improved metabolism and physicochemical properties that can be employed as a bioisosteric replacement for benzylamines ( Org. Lett., DOI: 10.1021/acs.orglett.2c03570). The method provides convergent access to 1-arylcyclopropyl amines via a Ni-catalyzed reductive cross-coupling of cyclopropylamine N-hydroxyphthalamide (NHPI) esters with commercial aryl halides. Chlorosilane was found to be an essential reaction additive for conversion to product, but its precise role is not well-understood. When the scope was evaluated, aryl iodides and electron-deficient aryl bromides were competent coupling partners. Ortho substituents, protic groups, and pharmaceutically relevant heterocycles were all compatible with the chemistry. The cross-coupling conditions could also be applied to four-membered α-amino rings and azabicyclo[2.1.1]hexane. The report is a valuable addition to the expanding cross-coupling chemistry of NHPI esters.

Bicyclo[2.1.1]hexanes are a valuable class of caged bicyclic aliphatics that have well-defined exit vectors and can be employed as meta-substituted benzene replacements. Rigotti and Bach reported the synthesis of bicyclo[2.1.1]hexanes via an intramolecular [2 + 2] photocycloaddition of styrene derivatives ( Org. Lett., DOI: 10.1021/acs.orglett.2c03606). The reaction proceeds by a triplet energy transfer pathway. Under this reaction manifold, the photocatalyst absorbs and transfers the energy of a photon of light to the styrene substate, which once excited to its triplet state undergoes the desired [2 + 2] intramolecular cyclization. Selection of a photocatalyst with a sufficiently high triplet-state energy (E_T) to excite the substate was essential to achieve high conversion and synthetically useful yields (photocatalyst [Ir(dFCF₃ppy)₂(dtbbpy)]PF₆ with E_T = 255 kJ/mol; substrate with E_T = 250 kJ/mol). The reaction enabled the synthesis of bicyclo[2.1.1]hexanes bearing a variety of functional groups, including cyclopropyl, pyridyl, aldehyde, carboxylic acid, and B(pin). The bicyclo[2.1.1]hexanes generated by this method were further elaborated, demonstrating the ability to access complex chemical matter.

Complementary to many well-established late-stage functionalization methods, skeletal editing enables the direct modification of the core framework of complex molecules. Sarpong and co-workers reported a skeletal editing method for the conversion of pyrimidines into pyrazoles via a formal carbon deletion ( J. Am. Chem. Soc., DOI: 10.1021/jacs.2c10746). For the reaction, N-triflation of the pyrimidine lowers the LUMO to enable attack by a hydrazine nucleophile at mild temperatures. After attack, the pyrimidine undergoes ring opening, ring closing, and extrusion of an N–C–N subunit to afford the desired pyrazole product. When the scope was evaluated, a variety of substituted pyrimidines successfully underwent formal carbon deletion. These examples included pyrimidines bearing heterocycles, electron-donating groups, electron-withdrawing groups, proton sources, and fused ring systems. The utility of the method was further highlighted by performing late-stage ring contractions on pharmaceutically relevant molecules. The reported method opens new strategies for the synthesis of complex substituted pyrazoles that can leverage the rich chemistry of pyrimidine synthesis.

Automated optimization of chemical reactions has been gaining interest in both academia and industry. The aim is to design and use an autonomous system that can run experiments, analyze them, interpret the results, and plan subsequent experiments in a closed loop. Flow chemistry has rapidly imposed itself as a key technology to perform and analyze chemical reactions, supported by process analytical technology (PAT). The advantage is that it is easy to program and control continuous variables such as temperature, stoichiometry, and residence time. Categorical variables tend to be more challenging to run and evaluate. One other issue can be the requirement for large amounts of material required by each experiment, especially in a continuous flow system. A recent contribution by McMullen and Wyvratt from Merck & Co ( React. Chem. Eng., DOI: 10.1039/D2RE00256F) brings forward a new paradigm: a dynamic flow system, where process inputs are adjusted to collect transient reaction results. More information can then be generated from a single run where inputs vary across time. An S_NAr reaction was selected as a case study, evaluating the conversion and selectivity of the transformation in relation to the process inputs and reaction time. First an IR probe was calibrated via sample collection and analysis by UPLC. Once the concentrations could be generated from the IR probe, an optimization using a relatively complex calculation workflow was performed, employing a gradient-based approach and circular dynamic DoE. Not only could a reaction optimum be found, but also a data-rich process was optimized via the number of data points collected throughout the optimization. However, gradient-based approaches may not be the most efficient algorithms to perform reaction development. The more popular SNOBFIT or Bayesian optimizations adapted to dynamic optimization could prove to be more efficient in the long term.

Knowles and co-workers reported a new strategy for the electronic activation of halophenols wherein generation of a phenoxyl radical via formal homolysis of the aryl O–H bond enables the direct nucleophilic aromatic substitution of the halide with carboxylate nucleophiles under mild conditions ( J. Am. Chem. Soc., DOI: 10.1021/jacs.2c10296). The team used pulse radiolysis and transient absorption studies, which revealed that the neutral oxygen radical (O^•) is an extraordinarily strong electron-withdrawing group [σ_p^–(O^•) = 2.79 vs σ_p^–(NO₂) = 1.27]. The established S_NAr protocol was compatible with respect to the phenolic electrophile model substrate and benzoic acid as a model nucleophile, which gave an 83% yield. Furthermore, variation of the ortho substituents on the phenol was accommodated, and phenols containing allyl, naphthyl, phenyl, and pyrenyl groups gave the desired products in yields of 46–61%. Notably, the protocol also tolerates electron-donating substituents on the phenol electrophile (61% yield), which is in contrast to the traditional S_NAr strategies. Interestingly, mechanistic and computational studies indicate that the key phenoxyl intermediate serves as an open-shell electron-withdrawing group in these reactions, lowering the barrier for nucleophilic substitution by more than 20 kcal/mol relative to the closed-shell phenol form of the substrate. The radical serves as a transient activating group and provides a homolysis-enabled electronic activation strategy that affords a powerful platform for expanding the scope of nucleophile–electrophile couplings.

The efficient construction of complex three-dimensional structures with multiple stereocenters has become increasingly valuable in synthetic organic chemistry due to the need for selective binding to target proteins and minimization of off-target activity. Dong and co-workers reported the development of Rh(I)-catalyzed intramolecular annulations between cyclobutanones and 1,5-enyne groups, which allowed the construction of complex C(sp³)-rich scaffolds ( J. Am. Chem. Soc., DOI: 10.1021/jacs.2c09814). The team obtained divergent reactivities with different catalysts and excellent diastereo- and enantioselectivity. In addition, the use of (R)-H₈-Binap as the ligand favors the formation of the bisbicyclic scaffolds with multiple quaternary stereocenters. The report indicates that subtle changes in the substrate sterics affected the overall product selectivity. For instance, with the C3-BnO-methyl-substituted substrate and the C3–H substrate, although the enantioselective reaction conditions gave low yields, excellent yields were obtained under the racemic reaction conditions using the Xantphos ligand. However, the C3-phenyl-subsituted cyclobutanone gave no desired tetrahydroazapinone product under either set of reaction conditions irrespective of the ligand used in the reaction. In addition, the C3-benzyl-substituted cyclobutanones gave excellent yields and enantioselectivity. Experimental and computational mechanistic studies supported the reaction pathway as involving enyne cyclometalation, 1,2-carbonyl addition, and then β-carbon elimination. The disclosed protocol could potentially enable access to polycyclic products exhibiting multiple all-carbon quaternary stereocenters.

The routine use of high-throughput experimentation combined with a greater-than-ever-before available data set of reaction outcomes has led to impressive advances in so-called predictive chemistry. Using machine learning, reaction deployment (e.g., retrosynthesis and outcome prediction), development (i.e., optimization), and discovery (e.g., the prediction of new mechanisms or reactions) are all now possible. A recent review highlights advances in these three areas (Coley, C. W.; et al. Chem. Sci., DOI: 10.1039/d2sc05089g) and will be of interest to process chemists or anyone engaged in reaction optimization or complex molecule synthesis. This article provides helpful definitions of key terms as well as a high-level review of important concepts and a handful of examples from the organic chemistry literature.

Saturated heterocycles are a common motif in both best-selling drugs and many drug candidates in development. As befits their privileged status, many methods for their synthesis have been reported and executed on scale. An appealing but relatively underutilized class of reactions are those that dearomatize aromatic heterocycles. Classically, this would simply involve a hydrogenation process, but many other methods such as nucleophile and radical addition now exist, which allow for the formation of additional C–C bonds during the dearomatization step and often avoid the traditional heterogeneous precious metal catalysts that have historically made this class of transformations unappealing on scale. A perspective summarizes recent progress in this field with many examples from the literature that may be of interest to process chemists (Donohoe, T. J.; et al. Chem. Sci., DOI: 10.1039/d2sc04638e).

The isocyanoalkene functionality has played a significant role in heterocycle synthesis, natural product synthesis, and the agro- and pharmaceutical industries, yet stereoselective access to (E)- and (Z)-isocyanoalkenes has been challenging. Fleming and co-workers reported the selective synthesis of (E)- and (Z)-isocyanoalkenes via sequential cross-coupling of vinyl iodides with formamide followed by dehydration ( Org. Lett., DOI: 10.1021/acs.orglett.2c03461). The optimal catalyst was generated in situ from CuI and trans-N,N′-dimethyl-1,2-cyclohexanediamine (DCD), which was coupled to the (E)- or (Z)-vinyl iodides to form the formamide and helped minimize the isomerization of the resultant vinyl formamide. The team applied the methodology efficiently to provide a range of carbocyclic, acyclic, and heterocyclic isocyanoalkenes.