Continuous flow enantioselective arylation of aldehydes with ArZnEt using triarylboroxins as the ultimate source of aryl groups

Continuous flow enantioselective arylation of aldehydes with ArZnEt using triarylboroxins as the ultimate source of aryl groups Julien Rolland1, Xacobe C. Cambeiro1, Carles Rodríguez-Escrich1 and Miquel A. Pericàs*1,2 Full Research Paper Address: 1Institute of Chemical Research of Catalonia; Avinguda Països Catalans, 16; 43007 Tarragona, Spain and 2Departament de Química Orgànica, Universitat de Barcelona; 08028 Barcelona, Spain Email: Miquel A. Pericàs* - Open Access Beilstein Journal of Organic Chemistry 2009, 5, No. 56. doi:10.3762/bjoc.5.56 Received: 13 July 2009 Accepted: 02 October 2009 Published: 15 October 2009 Guest Editor: A. Kirschning * Corresponding author Keywords: asymmetric synthesis; continuous flow; diarylmethanols; solidsupported catalyst; triarylboroxins © 2009 Rolland et al; licensee Beilstein-Institut. License and terms: see end of document. Abstract A continuous flow system for the synthesis of enantioenriched diarylmethanols from aldehydes is described. The system uses an amino alcohol-functionalized polystyrene resin as the catalyst, and the arylating agent is conveniently prepared by transmetallation of triarylboroxins with diethylzinc. Introduction Diarylmethanols constitute the basic scaffold in several important drugs such as antihistamines and muscle relaxants (R)-neobenodine, (R)-orphenadrine or (S)-carbinoxamine (Figure 1) [1]. Despite the apparent simplicity of the structures, their asymmetric synthesis is not trivial. For instance, access to these structures through enantioselective reduction of the corresponding ketones can become troublesome when both aryl groups are similar in their electronic and steric properties [2-4]. On the other hand, enantioselective arylation of aldehydes with organozinc reagents appears as a most convenient alternative, Figure 1: Biologically active diarylmethanol derivatives. Page 1 of 8 (page number not for citation purposes) Beilstein Journal of Organic Chemistry 2009, 5, No. 56. since the initial aldehyde undergoing addition presents two very different groups (namely, a H atom and an aryl group) and hence offers good opportunities for enantiocontrol [5-7]. Whereas the catalytic enantioselective addition of diethylzinc to aldehydes has been thoroughly studied, progress in the control of the analogous asymmetric arylation has been hampered by the fact that Ar2Zn species are several orders of magnitude more active than their dialkyl counterparts [8]. In this way, when diphenylzinc has been used as the arylating species in these processes, the background, non catalyzed reaction gives rise to a racemic product, which significantly erodes the global enantioselectivity of the reactions [6,9]. The most successful approach to overcome this difficulty comes from the Bolm laboratory and has been based on the use of the comparatively less reactive mixed species PhEtZn, easily prepared from a mixture of Ph2Zn and Et2Zn [10-13]. With this strategy, it has become possible to achieve good levels of enantioselectivity in the arylation reaction, although usually at the cost of low catalytic activity, high catalytic loadings being required for the achievement of satisfactory yields [14,15]. In contrast, β-amino alcohol 1 (Figure 2), developed in our laboratory [16], showed high activity and enantioselectivity in the ethylation [16], methylation [17], and arylation [18] of a wide family of substrates at low catalyst loadings. Figure 2: Structures of (R)-1,1,2-triphenyl-2-(piperidin-1-yl)ethanol (1) and its polystyrene-immobilized analogue 2. In recent times, we have developed strategies for the immobilization of analogues of 1 onto solid supports [19-22]. Among the ligands resulting from these studies, the polystyrene-supported catalyst 2 displayed levels of catalytic activity and selectivity comparable to those of the homogeneous model 1. Noteworthy, this catalytic resin has allowed the development of the first catalytic enantioselective arylation of aldehydes employing an insoluble catalyst [22], and has been used as the basis for a single-pass, continuous flow highly enantioselective ethylation of aldehydes characterized by very short residence times (down to 2.8 min) [23]. According to these precedents, we considered that 2 could be a good candidate for a planned continuous enantioselective production of diarylmethanols. When a large scale production of diarylmethanols involving the enantioselective transfer of aryl groups from zinc to aldehydes is considered, the cost of the arylating agent becomes an important issue. From this perspective, substantial efforts have been devoted to improve the economy of this process, by replacing the expensive Ph 2 Zn by other, more convenient, aryl sources. To this end, the use of arylboron species has provided particularly good results. In contrast to what happens with diarylzinc reagents, a wide variety of arylboronic acids are commercially available at a convenient price, and these species have been explored as the ultimate source of aryl groups [24-29]. In these approaches generally good results have been obtained, but at the expense of using a large excess of diethylzinc for the transmetallation step, since two non-productive equivalents of the reagent are consumed in the initial reaction with the boronic acid (Scheme 1). Scheme 1: Generation of the mixed ArZnEt species from a boronic acid and Et2Zn. On the other hand, triarylboroxins, easily prepared from the corresponding arylboronic acids by thermally induced dehydration under vacuum, have recently been applied with success as the starting materials for the preparation of the ArZnEt species to be used in the reaction [30-32] (Scheme 2). This represents a highly atom-economical approach since, in principle, no sacrificial excess of diethylzinc is needed for the transmetallation process and up to a 74% of the molecular mass of triphenylboroxin (the less favourable example) can be transferred to the reacting carbonyl compound. Scheme 2: Generation of the mixed ArZnEt species from a triarylboroxin and Et2Zn. It is to be mentioned that other strategies for the preparation of mixed alkylarylzinc species from cheap organometallic reagents have been developed in recent times and could probably be also used for the same purpose [33-35]. Page 2 of 8 (page number not for citation purposes) Beilstein Journal of Organic Chemistry 2009, 5, No. 56. Flow chemistry [36-39] is increasingly seen as a promising methodology for the clean and economic production of complex substances. According to this, the field is experiencing a fast growth both in methodological aspects [40-43] and in applications [44-51]. In any case, examples of continuous flow enantioselective processes [52] are still scarce [22,53-57] in spite of the enormous potential of this methodology. Herein, we report the development of a continuous flow system for the preparation of enantioenriched diarylmethanols using triarylboroxins as the ultimate aryl gro (...truncated)