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A new concept for the high-throughput screening of multiphase reactions involving molecular catalysts is described. It combines pulse injections of catalysts and substrate and mixing in a microdevice. The novelty of the concept resides in dynamic sequential vs. batchwise operations. Some advantages over traditional batch parallel operations are lower inventory of sample (down to~g) coupled with accurate control of reaction time, larger range of operating conditions (pressure, temperature), simpler and fewer electromechanical moving parts and easy automation. Results on liquid-liquid (biphasic allylic alcohol isomerization), and gas-liquid (asymmetric hydrogenation) reactions indicates that the number of tests per day can easily reach 50 d-1 with inventory of sample (Rh) per test as low as 5~g.

Today, high-throughput synthesis methodologies, such as combinatorial techniques, are applied to the discovery of pharmaceuticals, catalysts, and many other new materials. [1, 2] In the near future, huge libraries of ligands, and hence of homogeneous catalyst precursors, will be accessible. Recent reports have demonstrated the effectiveness of this approach for restricted libraries and in the case of catalysis in a single liquid phase. [2] High-throughput screening in one liquid phase should not represent a problem as long as the reactions are not too fast compared with micromixing rates. The microtitration-based apparatus (combinatorial chemistry (CC) factory) [2g] fulfils the requirement of ensuring reproducible tests on microquantities of samples, [2] despite uncertainties attributed to the agitation process. [2b] However, numerous reactions of interest, such as hydrogenation, carbonylation, and hydroformylation, operate in gas/liquid or gas/liquid/ liquid systems. [3] Inadequate control of phase and catalyst presentation, a result from nonoptimized agitation, may dramatically affect the estimation of selectivity and reactivity. Many enantio-and regioselective-catalyzed reactions, susceptible to mass transport effects, are known. [4,5] That may well be the explanation for the deceptively low enantiomeric excess (ee < 20 %) obtained in the screening of a 63-member library of rhodium/phosphane catalysts for asymmetric hydrogenation. [2a] Thus, a major challenge is to develop special reactors [1b] for rapid catalyst screening, that would ensure good mass and heat transport in a small volume. [6] Herein we describe a new concept to achieve highthroughput screening (HTS) of polyphasic fluid reactions. Two test reactions, a liquid/liquid isomerization and a gas/ liquid asymmetric hydrogenation, have been chosen to validate our approach to HTS experiments.As a liquid/liquid test reaction, the isomerization of allylic alcohols, a process currently of industrial interest in the field of geraniol chemistry [7] was targeted [Eq. (1)]. and benzylamine to yield a mixture of the ketones 6 and 5. [10,11] In the case of tert-butylethylene (2 a), only 5 a was isolated (94 % yield).In conclusion, we identified a chelation-assisted, Rh Icatalyzed ortho-alkylation reaction of ketimines with olefins. This type of ortho-alkylation shows generality as well as efficiency; the reactions of various olefins (including 1-alkenes, a,w-dienes, and even internal olefins) with ketimines result in high yields of the corresponding ortho-alkylated products. In addition, successive Rh I -catalyzed hydroacylation and ortho-alkylation of an aldehyde gave a product that has been alkylated at two sites. Experimental SectionFull experimental details can be found in the Supporting Information.A typical procedure for the preparation of 5 a [Eq. (6)]: A screw-capped pressure vial (1 mL) was charged with freshly purified benzaldehyde (0.216 mmol), 2-amino-3-picoline (4, 0.0432 mmol), benzylamine (0.216 mmol), [Rh(PPh 3 ) 3 Cl] (3, 0.0216 mmol), a...

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High throughput synthesis methodologies, such as combinatorial techniques, are now applied to the discovery of molecular catalysts. I Libraries of ligands which can be turned into catalysts by complexation to transition metals, are accessible. The effectiveness of this approach has been demonstrated for restricted libraries of compounds and in the case of single liquid phase catalysisPl However, numerous reactions of interest such as olefm oligomerisation, hydrogenation, carbonylation, hydroformylation, etc. are operated in gas-liquid or liquid-liquid systems. Inadequate control of phase and catalyst presentation, resulting from non-optimised agitation, may effectively have dramatic consequences in the estimation of selectivity and reactivity. For example, enantio-and regioselective catalysed reactions susceptible to mass transport effects, are known. Thus, a major challenge is to develop special reactors for rapid catalyst screening that would ensure good mass and heat transport, in a small volume. Application of such apparatus for intrinsic kinetic determination would also be of high interest. In this paper, a new concept to achieve High Throughput Screening (HTS) of polyphasic fluid reactions is proposed. As test reactions, a gas-liquid asymmetric hydrogenation and a liquid-liquid isomerisation have been chosen to validate our approach of HTS experiments. A preliminary work with the liquid-liquid system has been published recently? ConceptTo our knowledge,3 commercial apparatus for High Throughput Screening of multiphase catalytic reactions are all based on the very simple concept (Figure 1): several batch type tank reactors are downscaled (step a) and placed in a rack (step b). Ideally, one reaction/catalyst or substrate can thus be screened in each of the millireactors (step c).That paralleVbatchwise approach is just derived from traditional glassware and pressure apparatus adding small scale parallelisation and ca. a tenfold downscaling of reaction volumes. Most of the commercial apparatus are equipped with agitation/heating devices and the consumption of gaseous reagents can also be monitored. Because of their batchwise concept, their familiar design and the M. Matlosz et al. (eds.), Microreaction Technology