Smith Synthesizer

The previous methods used commercial microwave ovens. When a Smith Synthesizer was employed where one could control temperature and pressure, further improvements in time and yield were noted for the conversion of 95 and 82 into 96. Optimal conditions included the use of aqueous ammonium hydroxide as solvent and nitrogen source. The method was efficient enough to execute on a 4 x 6 array using the dicarbonyl and the aldehyde as points of diversity. The library of 24 compounds was obtained in 39-89% yields and 53-99% purity. 

Monomode reactors Prolabo, Synfhe-wave S402 and S1000 (actually not on the market). CEM, STAR system 2 and 6 and Discover. Personal Chemistry, Smith Synthesizer and Smith Creator. Temperature measurement is one of the main problems in microwave-assisted reactions. See Ref. [2] for temperature-measurement systems. 

These reactions have been performed using a Personal Chemistry Smith Synthesizer. 

Figure 2.1 Pressure profiles for aminocarbonylations at (A) 150°C and (B) 210°C using Mo(CO)6 as the carbon monoxide source (Smith Synthesizer).

Figure 2.2 Pressure profiles recorded from microwave heating at 180°C of (A) formamide and KOf-Bu (B) a preparative aminocarbonylation reaction with 4-bromotoluene and formamide and (C) pure formamide (Smith Synthesizer).

We thank Mr Gunnar Wikman and Dr Peter Nilsson for help with the manuscript. We also thank the Swedish Research Council and Knut and Alice Wallenberg Foundation. We acknowledge Personal Chemistry (now Biotage AB) for provision of the Smith Synthesizer. 

At this time, we had access to a microwave system from Personal Chemistry called the Smith Synthesizer (Personal Chemistry AB, Uppsala, Sweden) and so we attempted this difficult cycloaddition reaction13. As evident in Table 8.1, the results with the microwave were remarkably improved compared to the conventionally heated counterpart. The product yield and purity was substantially higher than what was observed in the pressure tubes. With this first positive example, we were encouraged to try systems that had not been able to produce an observable product in the pressure tubes. The condensation of a fused cyclohexyl maleimide had not produced any product in our previous efforts, but with microwave heating for a short 5 min reaction time at 180°C we were able to isolate a satisfactory amount of the desired product. 

Fig. 1. Personal Chemistry Smith synthesizer. (Photograph compliments of Personal Chemistry Inc.) (See color insert.)...

We have subsequently revisited this reaction and successfully optimized the Suzuki microwave-assisted coupling conditions using the Smith synthesizer. Several parameters were investigated, including the palladium catalysts, the reaction temperatures, and the reaction times (Table I). Optimization reactions were run in the Smith synthesizer using 50 mg of resin 7 and 6 equivalents of 4-methoxyphenylboronic acid to afford oxa-zolidinone 8. In just a few days, optimized conditions were identified that afforded the desired product in excellent yields and purities with reactions times of only 5-10 min.8... 

A small library of oxazolidinones was then synthesized using the robotics of the Smith synthesizer to run sequentially each new boronic acid in the Suzuki reaction. Cleavage of the products and filtration through a small plug of silica provided excellent yields and purities of the desired oxazolidinones, including compound 12, the previous clinical candidate E3656, in 96% yield and 96% purity (Table II). 

Baxendale and Ley [60] employed the Smith Synthesizer as well as the Emrys Optimizer from Biotage [59] for conducting neat KOf-Bu mediated trimerizations of various liquid nitriles to give aryl- and alkyl-substituted 4-... 

Silylation of the 3-hydroxyl group of 1 was achieved by Oscarson [5], who used tert-butyldimethylsUyl chloride (TBDMSCl) in the presence of pyridine or N-(methylpolystyrene)-4-(methylamino)pyridine (PDS-DMAP), in a Smith Synthesizer (Scheme 12.12). In addition to the silylated product 32a, the secondary product 33a, formed by acetal migration, was also observed. 

To a 2-mL Smithsynthesizer reaction vial containing a magnetic stir bar were added 1.0 mL acetic acid, 42 mg benzil (0.2 mmol), 25 mg 4-fluorobenzaldehyde (0.2 mmol), and 154 mg ammonium acetate (2.0 mmol). The reaction vessel was heated in the Smith-synthesizer reactor cavity for 5 min at 180°C, after which the vessel was rapidly cooled to 40°C by the unit. The reaction mixture was added dropwise to a concentrated NH4OH solution cooled to 0°C and immediately formed a white precipitate, which was collected by filtration and washed with H2O. The solid was dried in a vacuum oven for 18 h at 50°C to... 

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