The first direct intermolecular regiospecific and highly enantioselective α-allylic alkylation of linear aldehydes by a combination of achiral bench-stable Pd(0) complexes and simple chiral amines as co-catalysts is disclosed. The co-catalytic asymmetric chemoselective and regiospecific α-allylic alkylation reaction is linked in tandem with in situ reduction to give the corresponding 2-alkyl alcohols with high enantiomeric ratios (up to 98:2 e.r.; e.r.=enantiomeric ratio). It is also an expeditious entry to valuable 2-alkyl substituted hemiacetals, 2-alkyl-butane-1,4-diols, and amines. The concise co-catalytic asymmetric total syntheses of biologically active natural products (e.g., Arundic acid) are disclosed.

A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)2], 6-methyl-2,2′-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11 mmol h−1 by using a glass reactor with an inner diameter of 3 mm at a flow rate of 1 mL min−1.

A fast and efficient protocol for the palladium(II)-catalyzed production of aryl ketones from sodium arylsulfinates and various organic nitriles under controlled microwave irradiation has been developed. The wide scope of the reaction has been demonstrated by combining 14 sodium arylsulfinates and 21 nitriles to give 55 examples of aryl ketones. One additional example illustrated that, through the choice of the nitrile reactant, benzofurans are also accessible. The reaction mechanism was investigated by electrospray ionization mass spectrometry and DFT calculations. The desulfitative synthesis of aryl ketones from nitriles was also compared to the corresponding transformation starting from benzoic acids. Comparison of the energy profiles indicates that the free energy requirement for decarboxylation of 2,6-dimethoxybenzoic acid and especially benzoic acid is higher than the corresponding desulfitative process for generating the key aryl palladium intermediate. The palladium(II) intermediates detected by ESI-MS and the DFT calculations provide a detailed understanding of the catalytic cycle.

Herein we present a 200 mm × 3 mm Ø i silicon carbide (SiC) tube reactor for use in a commercially available microwave heated continuous-flow system. The SiC flow reactor enables palladium(0)-catalyzed reactions that, due to precipitation and subsequent hot spot formation, often followed by reactor failure, are unsuitable to conduct in standard microwave-transparent borosilicate glass reactors. We report continuous-flow protocols for the Mizoroki−Heck reaction (10 examples, 81−86% yield) as well as the Suzuki−Miyaura cross-coupling (14 examples, 70−87% yield), showing the utility of the SiC reactor. Furthermore, we performed a scale-out of the NSAID biphenylacetic acid, achieving outputs of 14 mmol/h of the Suzuki−Miyaura reaction, and a 72% overall yield over three steps. The SiC reactor enabled fast and efficient temperature control, high robustness, and easy maintenance. ■ INTRODUCTIONControlled microwave (MW) heating has found increased use in small-scale batch synthesis, and dedicated MW instruments are now routinely used in many research laboratories and pharmaceutical companies. 1−5 The advantages associated with MW heating are commonly attributed to the efficient direct manner of heating 6 as the reaction mixture itself will be rapidly heated, rather than the vessel, which is the case for classical heating. 7−9 Most importantly, MW instrumentation designed for organic chemistry applications has provided a safe and convenient way to perform small-scale batch chemistry at elevated temperatures and pressures.Continuous-flow (CF) chemistry is another technology which has attracted considerable interest in the last few decades due to safety, handling, and scale-up advantages. 10,11 Rather than heating a large volume of a reaction mixture in batch mode, a small volume will be heated in a CF equipment, which greatly improves safety. 4,10,11 The predominant mode of heating used in CF systems has been conductive heating. However, the combination of MW heating and CF has attracted interest, 8,12−23 and we have reported on a purposebuilt system combining CF with a nonresonant MW applicator for heating. 24−27 The most prominent feature of this system is a very uniformly distributed axial MW field, providing homogeneous heating of the reaction mixture when using 200 mm × 2−10 mm Ø i microwave transparent borosilicate tube reactors. In addition the tubular wide bore reactor design prevents clogging and facilitates physical cleaning of the reactor. 28 Palladium(0)-catalyzed reactions such as the Mizoroki−Heck reaction 29−31 and the Suzuki−Miyaura coupling reaction 32 have found great use during the last few decades. Furthermore, these cross-couplings have successfully been carried out both with MW heating 33−36 and by using CF equipment. 37 Thus, the importance of cross-coupling methods prompted us to investigate the Mizoroki−Heck and Suzuki−Miyaura reactions under MW heated CF conditions and whether it would possible to accelerate these reactions in order to achieve full conversions within minutes.One foreseeable iss...

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A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2′-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.

SummaryIn a continuous-flow system equipped with a nonresonant microwave applicator we have investigated how to best assess the actual temperature of microwave heated organic solvents with different characteristics. This is non-trivial as the electromagnetic field will influence most traditional methods of temperature measurement. Thus, we used a microwave transparent fiber optic probe, capable of measuring the temperature inside the reactor, and investigated two different IR sensors as non-contact alternatives to the internal probe. IR sensor 1 measures the temperature on the outside of the reactor whilst IR sensor 2 is designed to measure the temperature of the fluid through the borosilicate glass that constitutes the reactor wall. We have also, in addition to the characterization of the before mentioned IR sensors, developed statistical models to correlate the IR sensor reading to a correct value of the inner temperature (as determined by the internal fiber optic probe), thereby providing a non-contact, indirect, temperature assessment of the heated solvent. The accuracy achieved with these models lie well within the range desired for most synthetic chemistry applications.

A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.