Lewis Acid-Catalyzed Addition of Benzophenone Imine to Epoxides Enables the Selective Synthesis and Derivatization of Primary 1,2-Amino Alcohols

Benzophenone imine was found to be an effective ammonia surrogate for the selective preparation of primary 1,2-amino alcohols from epoxides, including enantiopure epichlorohydrin, in the presence of catalytic Y­(OTf)₃. High-throughput screening of 48 Lewis acids quickly identified Y­(OTf)₃ as an effective mediator of the addition reaction under mild conditions. Following acidic hydrolysis, the primary amino alcohol salt is revealed and partitions into the aqueous solution, while the benzophenone byproduct is easily removed by simple extraction with ethyl acetate. These ammonium salts can be directly Boc-protected or further derivatized without isolation to form benzamides and sulfonamides under Schotten–Baumann-type conditions in up to 79% isolated yield over three steps. This methodology has been used to prepare key intermediates for the synthesis of PRMT5 inhibitors with high enantiopurity as well as numerous other amide and sulfonamide derivatives

An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine

2,3-Dichlorobenzoyl cyanide is a key intermediate in the synthesis of Lamotrigine. An assessment of various catalytic systems for the cyanation of 2,3-dichlorobenzoyl chloride with cyanide salts is described. High-throughput experimentation identified many conditions for effecting the requisite chemistry, including amine bases and phase-transfer catalysts, as well as catalyst-free conditions utilizing acetonitrile as a polar cosolvent. A novel catalyst, CuBr₂, was identified by consideration of the possible oxidation of Cu­(I) during high-throughput screening experimentation. CuCN was found to be the best cyanide source for achieving clean conversion; however, the solubility of CuCN was the major factor limiting reaction rate under many conditions. Improving CuCN solubility by using acetonitrile as solvent enhanced the reaction rate even in the absence of the catalysts tested but significantly complicated isolation of the product. With no acetonitrile cosolvent, phase-transfer catalysts such as tetrabutyl­ammonium bromide (TBABr) are effective; however, use of TBABr led to inconsistent reaction profiles from run-to-run, due to an unexpected clumping of the CuCN solid. Switching to cetyl­trimethyl­ammonium bromide (CTAB) alleviated this clumping behavior, leading to consistent reactivity. This CTAB-catalyzed process was scaled up, giving 560 kg of 2,3-dichloro­benzoyl cyanide in 77% isolated yield

Bis(amidate)bis(amido) Titanium Complex: A Regioselective Intermolecular Alkyne Hydroamination Catalyst

An efficient and selective bis­(amidate)­bis­(amido) titanium precatalyst for the anti-Markovnikov hydroamination of alkynes is reported. Hydroamination of terminal and internal alkynes with primary alkylamines, arylamines, and hydrazines is promoted by 5–10 mol % of Ti catalyst. Various functional groups are tolerated including esters, protected alcohols, and imines. The in situ generated complex shows comparable catalytic activity, demonstrating its synthetic versatility for benchtop application. Applications of this catalyst for the synthesis of amino alcohols and a one-pot procedure for indole synthesis are described. A mechanistic proposal that invokes turnover-limiting protonolysis is presented to rationalize the observed regioselectivities

A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol

A combined high-throughput screening and reaction profiling approach to the telescoping of two reductions in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concentration of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective debenzylation. Optimization of these dual catalyst processes led to conditions that were demonstrated on 20 g scale to prepare Salbutamol in 49% isolated yield after recrystallization

Direct Heterocycle C–H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation

One of the major challenges in developing catalytic methods for C–C bond formation is the identification of generally applicable reaction conditions, particularly if multiple substrate structural classes are involved. Pd-catalyzed direct arylation reactions are powerful transformations that enable direct functionalization of C–H bonds; however, the corresponding direct alkenylation reactions, using vinyl (pseudo) halide electrophiles, are less well developed. Inspired by process development efforts toward GSK3368715, an investigational active pharmaceutical ingredient, we report that a Pd(II) palladacycle derived from tri-tert-butylphosphine and Pd(OAc)2 is an effective single-component precatalyst for a variety of direct alkenylation reactions. High-throughput experimentation identified optimal solvent/base combinations for a variety of HetAr–H substrate classes undergoing C–H activation without the need for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative catalytic mechanism, where in situ-generated Pd(0) supports a canonical Pd(0)/(II) cross-coupling cycle and the palladacycle effects C–H activation via CMD in a redox-neutral cycle. In all, 192 substrate combinations were tested with a hit rate of approximately 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale

Direct Heterocycle C–H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation

One of the major challenges in developing catalytic methods for C–C bond formation is the identification of generally applicable reaction conditions, particularly if multiple substrate structural classes are involved. Pd-catalyzed direct arylation reactions are powerful transformations that enable direct functionalization of C–H bonds; however, the corresponding direct alkenylation reactions, using vinyl (pseudo) halide electrophiles, are less well developed. Inspired by process development efforts toward GSK3368715, an investigational active pharmaceutical ingredient, we report that a Pd(II) palladacycle derived from tri-tert-butylphosphine and Pd(OAc)2 is an effective single-component precatalyst for a variety of direct alkenylation reactions. High-throughput experimentation identified optimal solvent/base combinations for a variety of HetAr–H substrate classes undergoing C–H activation without the need for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative catalytic mechanism, where in situ-generated Pd(0) supports a canonical Pd(0)/(II) cross-coupling cycle and the palladacycle effects C–H activation via CMD in a redox-neutral cycle. In all, 192 substrate combinations were tested with a hit rate of approximately 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale