Safe Palladium-Catalyzed Cross-Couplings with Microwave Heating Using Continuous-Flow Silicon Carbide Reactors

Abstract

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...

Continuous‐Flow Suzuki‐Miyaura and Mizoroki‐Heck Reactions under Microwave Heating Conditions

“…Larhed et al. has experienced failure with their borosilicate tube reactor on the MW irradiation under the rapid heating conditions . Instead, silicon carbide (SiC) has been used as the reactor material, since SiC is chemically and thermally stable, tolerant to high pressures, and capable of completely absorbing MW irradiation, leading to effective heating of the reactor itself with no direct MW heating of the reaction mixture ,.…”

“…has experienced failure with their borosilicate tube reactor on the MW irradiation under the rapid heating conditions . Instead, silicon carbide (SiC) has been used as the reactor material, since SiC is chemically and thermally stable, tolerant to high pressures, and capable of completely absorbing MW irradiation, leading to effective heating of the reactor itself with no direct MW heating of the reaction mixture ,. These characteristics of SiC as well as the extremely fast temperature response from the SiC reactor to the reaction solution were anticipated to promote the effective reaction progress without metal deposition ,.…”

“…Instead, silicon carbide (SiC) has been used as the reactor material, since SiC is chemically and thermally stable, tolerant to high pressures, and capable of completely absorbing MW irradiation, leading to effective heating of the reactor itself with no direct MW heating of the reaction mixture ,. These characteristics of SiC as well as the extremely fast temperature response from the SiC reactor to the reaction solution were anticipated to promote the effective reaction progress without metal deposition ,. The cross‐coupling reactions of various bromoarenes, including 3‐bromopyridine, with electron‐deficient and electron‐sufficient phenylboronic acids using the one‐inlet system afforded the corresponding biaryls in good yields without any precipitation of palladium metal (Scheme , 70 %–87 %, 13 examples) ,…”

“…These characteristics of SiC as well as the extremely fast temperature response from the SiC reactor to the reaction solution were anticipated to promote the effective reaction progress without metal deposition ,. The cross‐coupling reactions of various bromoarenes, including 3‐bromopyridine, with electron‐deficient and electron‐sufficient phenylboronic acids using the one‐inlet system afforded the corresponding biaryls in good yields without any precipitation of palladium metal (Scheme , 70 %–87 %, 13 examples) ,…”

“…The above‐mentioned SiC tube reactor developed by Larhed et al. was also applied to continuous‐flow Mizoroki‐Heck reactions under MW irradiation . Although the details of the optimization process of the catalysts was not reported, a variety of bromoarenes, including heteroaromatic bromides such as 3‐bromothiophene, 3‐bromopyridine, and 5‐bromoindole, were cross‐coupled with butyl acrylate in the presence of Herrmann's palladacycle, trans ‐bis(acetato)‐bis[ o ‐(di‐ o ‐tolylphosphino)benzyl]dipalladium (II) as the catalyst, to afford the corresponding disubstituted alkenes in over 80 % yields (Scheme ) …”