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Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low‐volume optimization experiments are reported. A Buchwald–Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self‐optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using <10% of the material that would be required for standard flow operation. Finally, a chemometric model is built utilizing automated data handling and three subsequent validation experiments demonstrate good agreement between the slug flow reactor and a standard (larger scale) flow reactor. [ABSTRACT FROM AUTHOR]

The efficient copper‐catalyzed construction of imidazopyridinones is described. Beginning from iodopyridinyl ureas, Ullmann coupling provides imidazopyridinones in good yield. Manufacturing by this process is described on 473 kg scale; the scope and limitations of substrates is also detailed. [ABSTRACT FROM AUTHOR]

A novel 1,4-homofragmentation which complicated the conversion of an alpha,alpha-dichloroester to the corresponding alpha-keto acid, was investigated. The results showed a mechanism involving an [alpha]-lactone intermediate, which can lead to both the desired [alpha]-keto acid and the 1,4-homofragmentation with the product distribution being dependent upon reaction conditions.

Autonomous flow reactors are becoming increasingly utilized in the synthesis of organic compounds, yet the complexity of the chemical reactions and analytical methods remains limited. The development of a modular platform which uses rapid flow NMR and FTIR measurements, combined with chemometric modeling, is presented for efficient and timely analysis of reaction outcomes. This platform is tested with a four variable single‐step reaction (nucleophilic aromatic substitution), to determine the most effective optimization methodology. The self‐optimization approach with minimal background knowledge proves to provide the optimal reaction parameters within the shortest operational time. The chosen approach is then applied to a seven variable two‐step optimization problem (imine formation and cyclization), for the synthesis of the active pharmaceutical ingredient edaravone. Despite the exponentially increased complexity of this optimization problem, the platform achieves excellent results in a relatively small number of iterations, leading to >95% solution yield of the intermediate and up to 5.42 kg L−1 h−1 space‐time yield for this pharmaceutically relevant product. [ABSTRACT FROM AUTHOR]

[beta]-C-arylglucoside derivatives are prepared by using Lewis acid mediated ionic reduction of a peracetylated 1-C-aryl methyl glucoside derived from the addition of an aryl-Li to selectively protected [delta]-D-gluconolactone. The reduction of the 2-acetoxy-1-C-oxacarbenium ion intermediates has proceeded with a high degree of selectivity to produce [beta]-C-arylglucosides without the participation of 2-acetoxy group.

Kinetic evidence for a tertrameric transition state in the Soai autocatalytic reaction is presented. Tetrameric structures arising from the dimeric alkoxide have a similarity to the template-template entities and studies show that Soai reaction is a template treated self replicating system, which successfully maintain ideal expenditure kinetics and therefore high autocatalytic efficiency.

The reactions of benzaldehydes with electron-donating substituents on the aromic ring exhibited a more significant nonlinear effect in these reactions than the electron-withdrawing substituents. The modification of Noyori model rationalizes the apparently anomalous results that were observed through a simple extension of the Noyori model to allow for nonthermodynamically controlled monomer/dimer partitioning.

An efficient, sustainable, and broadly applicable procedure has been developed for Suzuki-Miyaura cross-coupling reactions in environmentally benign solvent (water) by employing as little as 500 ppm Pd(OAc)2 with a monophosphorus BI-DIME ligand in the presence of inexpensive and commercially available nonionic surfactant Triton X-100. This method was applied to a broad range of functionalized reaction partners, thereby affording excellent yields of the coupling products, including active pharmaceutical ingredients (APIs). An interesting kinetic study by using reaction calorimetry is also presented, which describes the effect of reaction parameters that enabled the low catalyst loading. [ABSTRACT FROM AUTHOR]

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity. [ABSTRACT FROM AUTHOR]

An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents in presence of low catalyst loadings (0.5 mol-%). Compared to batch mode, the continuous flow approach overcomes the exothermicity which enabled longer catalyst lifetime, facilitated scale-up and significantly improved the yield. To the best of our knowledge, this is the first example of flow iron-catalyzed Kumada cross-coupling reactions which addresses scale dependence issues which often plague Kumada reactions carried out in the traditional batch mode. [ABSTRACT FROM AUTHOR]

A series of efficient ruthenium catalysts has been developed for the asymmetric hydrogenation and transfer hydrogenation of ketones with high reactivities and selectivities. The new chiral bisdihydrobenzooxaphosphole (BIBOP)/diamine-ruthenium complexes catalyzed the enantioselective hydrogenation of substrates such as aryl and heteroaryl cyclic and alkyl ketones with substrate/catalyst (S/C) ratios of up to 100,000. The opposite sense of enantioselectivity can be obtained by proper selection of a diamine with a given chirality of the phosphine. The usefulness of the new system has been demonstrated in the asymmetric hydrogenation of a complex synthetic intermediate towards cholesteryl ester transfer protein (CETP) inhibitors at S/C 20,000 on large-scale operation. [ABSTRACT FROM AUTHOR]

Presents a straightforward and diastereoselective sequence to convert cyclopentanones into functionalized cycloheptanols in synthetically useful overall yields. Availability of cyclooctanols from cyclohexanones; General applicability of the transformation; Combination of a palladium-catalyzed bicycloannulation of cycloalkanones with Baeyer-Villiger oxidation.

The first continuous flow iron-catalyzed Kumada cross-coupling is developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents using low catalyst loadings (0.5 mol-%). [ABSTRACT FROM AUTHOR]

Review: 126 refs. [ABSTRACT FROM AUTHOR]

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl] 2 .

The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.

A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of sec-BuLi combined with an in situ trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale.

Kinetic studies using reaction calorimetry were conducted under synthetically relevant conditions to study the effect of additives in the cyanation of bromobenzene catalyzed by palladium complexes. This work demonstrates that the addition of a catalytic amount of ZnBr(2) facilitates the reaction with an elimination of the induction period observed without additive. This study afforded a qualitative assessment of the effect of water on the rate-limiting step and the apparent reaction order in bromobenzene.