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In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/advances Page 1 of 33 PleaseRSC do not Advances adjust margins RSC Advances Article Substrate Induced Diastereoselective Hydrogenation/Reduction of Arenes and Heteroarenes Received 00th January 20xx, a a Accepted 00th January 20xx A. Gualandi and D. Savoia * DOI: 10.1039/x0xx00000x Chiral, either racemic or optically pure, substituted cylohexanes, piperidines, tetrahydrofurans and pyrrolidines can be prepared by the diastereoselective hydrogenation/reduction of the corresponding aromatic and heteroaromatic www.rsc.org/ precursors, exploiting the presence of one or more stereocenters present in the ring substituent(s), where the sense and level of asymmetric induction can be the result of different factors: the rigidity or flexibility of the substrate, the presence of a proper functionality in the lateral substituent which can stabilize a particular conformation of the molecule, especially in pyridine and furan derivatives, the nature of the catalyst or the reducing system, and the experimental conditions. catalysis). Alternatively using a heterogeneous supported 1. Introduction catalyst, the chiral ligand can be bound to either the metal or Manuscript the insoluble support. The reduction of properly substituted aromatic and An early review that appeared in 1996 was concerned with heteroaromatic rings leads to the corresponding partially or dissolving metal reduction and catalytic hydrogenation of totally saturated carbocyclic and heterocyclic compounds with arenes and heteroarenes. 1 The auxiliary induced, diastereo- one or more ring carbon stereocenters. Stereocontrol in these selective heterogeneous hydrogenation of arenes was reductions is important because substituted saturated rings reviewed in 1998 for substituted benzene and furan with defined configuration are common structural features of derivatives. 2 More recently, methods for the asymmetric biologically or pharmacologically active molecules. The relative configuration of one or more newly formed stereocenter(s) in hydrogenation of benzene, pyridine, pyrrole and furan derivatives with homogeneous and heterogeneous catalysts the saturated ring (simple diastereoselectivity) is dependent on 3 the reduction method, which include: a) electron transfer from have been reviewed. All these reviews only covered the items Accepted an active metal, b) dihydrogen addition or c) hydride attack. On of auxiliary- and reagent-induced stereoselective the other hand, control of the absolute stereochemistry can be hydrogenations. On the other hand, at our knowledge, an achieved by one of three general methodologies. Asymmetric exhaustive survey of diastereoselective reductions performed induction can be provided by a stereocenter present in a ring on chiral aromatic substrates, either racemic or optically active, substituent, whose configuration will be preserved in has never appeared in the literature, apart a review in 2000 subsequent transformations leading to the desired target dealing with the synthesis of enantiopure indolizidines from compound (substrate induced diastereoselectivity). By this pyrrole building blocks, that includes the diastereoselective hydrogenation of pyrroles bearing stereodefined N- strategy, it is also possible to start from a racemic compound, 4 in this case only the relative stereochemistry of old and new substituents derived from natural α-amino acids. Examples of stereocenters can be controlled, and after separation of substrate induced diastereoselective hydrogenations of Advances diastereomers a resolution step must be performed to obtain aromatic compounds were also included in the Pinel's review the desired optically active target. In a second approach, a in 2003. Thus, we aimed to provide to the readers a possibly chiral, configurationally pure functional group can be exhaustive survey of the known methods, mainly the catalytic introduced temporarily in the substituent of the aromatic ring heterogeneous hydrogenation, for the reduction of substituted and it is then removed after the stereocontrolled reduction benzene, pyridine, pyrrole and furan derivatives, all bearing at RSC step (auxiliary induced diastereoselectivity). A third option, least one stereocenter in the ring substituent. This search has which is in principle more advantageous, is the use of a chiral allowed to get useful information on the factors affecting the catalytic system (reagent induced stereoselectivity). In this case diastereoselectivity, and, possibly, to choose the most a chiral ligand is generally used to coordinates the transition convenient and effective methodology to get the desired chiral metal center, so forming a soluble complex (homogeneous target. A convenient synthetic strategy to achieve the stereoselective reduction of (hetero)aromatic rings exploits the asymmetric induction of a stereocenter already present in a This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do notadjustmargins PleaseRSC do notadjustmargins Advances Page 2 of 33 ARTICLE RSC Advances solvent, H2 pressure, temperature) are reported, allowing comparison between different methods. If not otherwise stated, reactions were performed at 1 atmosphere and room temperature. 2. Steric, haptophilic and conformational effects in the hydrogenation of benzene derivatives Scheme 1 2.1. Substituted indanes Hydrogenation of a series of racemic indanes bearing a ring substituent (Scheme 1). Such an intermediate can be substituent on the partially saturated ring were performed obtained by the proper transformation of a prochiral group using heterogeneous rhodium catalysts (5% Rh/C or 5% present in the ring substituent (route a), e.g. by reduction of a Rh/Al 2O3) under 49 atm of H 2 pressure at room temperature in carbonyl or an imine function in a stereoselective fashion 5 ethanol or n-hexane as the solvent (Scheme 2 and Table 1). (auxiliary-induced diastereoselectivity or reagent-induced Four diastereomers of the fully saturated products were stereoselectivity). The stereo-inducing asymmetric center can obtained when using Rh/C as the catalyst in ethanol, and be also created in situ during the hydrogenation process, deoxygenated products 3 were largely or in part formed from provided that the prochiral functional group is reduced prior to 1-indanylmethanol (entries 3 and 4), 1-indanol (entries 6 and the arene ring. Alternatively, the crucial intermediate can be 9) and the corresponding propyl ether (entry 17). This side prepared by transformation of an optically active molecule reaction could be largely or almost completely avoided in the while retaining the innate stereochemistry (ex-chiral pool presence of triethylamine (entry 7) or aqueous bases, although synthesis, route b). Both routes a and b usually lead to at the expense of the activity of the catalyst, and when using Manuscript mixtures of diastereoisomers which can be separated by Rh/Al 2O3 as catalyst (entries 5, 10, 11, 15 and 16), especially in crystallization or chromatographic techniques. The isolated n-hexane as the solvent. On the other hand, hydrogenolysis of diastereomers are enantiomerically pure when the induced the C-N bond in 1-aminoindane was not observed. stereocenter in the precursor is configurationally pure. On the Owing to the approximate planarity of the substrates and other hand, when the chiral substrate or intermediate is their rigidity, as well as the close proximity of the stereogenic racemic, a resolution process must be applied to the 2 center to the prochiral arene sp -carbons, the influence of the diastereoisomers of the reduced product to obtain optically substituent on the relative configuration of the newly formed active/pure compounds. stereocenters could be easily appreciated. The stereochemical In this review we report the hydrogenation of both racemic outcomes of the hydrogenation reactions were scarcely and optically pure compounds possessing arene or affected by the substrate/catalyst ratio and the hydrogen Accepted heteroarene rings. Examples, even recently reported, where pressure. The fully saturated products 2 had prevalently the cis the configuration of the reduced products were not ring junction of the fused rings, as expected, with a cis determined are reported for sake of knowledge. The steps selectivity of the substituent generally higher than 91%. On the required for the preparation of the crucial intermediate to be other hand, the relative configuration of the substituted reduced, or the final target of the overall synthetic sequence,