DOI: 10.1002/adsc.200900871 Regioselective and Enantioselective Hydroformylation of Dialkylacrylamides Gary M. Noonan, a David Newton, a Christopher J. Cobley, b AndrØs Suµrez, c Antonio Pizzano, c and Matthew L. Clarke a, * a School of Chemistry, University of St Andrews, EaStCHEM, St Andrews, KY16 9ST, Fife, U.K. Fax: (+ 44)-(0)1334-463-808; e-mail: mc28@st-andrews.ac.uk b Chirotech Technology Limited, Dr. Reddys Laboratories, 162 Cambridge Science Park, Milton Road, Cambridge, CB4 0GH, U.K. c Instituto de Investigaciones Químicas, Consejo Superior de Investigaciones Científicas and Universidad de Sevilla, Avda AmØrico Vespucio n8 49, Isla de la Cartuja, 41092 Sevilla, Spain Received: December 17, 2009; Revised: March 10, 2010; Published online: April 7, 2010 Abstract: Dimethylacrylamide can be hydroformylat- ed with very high chemo- and regioselectivity. Asym- metric hydroformylation of this substrate is possible, provided steps are taken to minimise racemisation of the aldehyde products, and this work demonstrates the effect of various conditions and variables on rac- emisation. Using the Landis diazaphospholane li- gands up to 68% ee can be realised under very mild conditions. Other dialkylacrylamides were also hy- droformylated under mild conditions giving similar or better enantioselectivities, including the Weinreb amide of acrylic acid (71% ee), and the asymmetric hydroformylation of diethylacrylamide producing the chiral aldehyde with up to 82% ee. Keywords: aldehydes; asymmetric carbonylation; hy- droaminomethylation; hydroformylation; racemiza- tion Introduction Rhodium-catalysed hydroformylation is one of the most industrially important carbon-carbon bond- forming reactions, especially in the commodity chemi- cals industry, where the use of cheap feedstocks (al- kenes and syngas) and the potential for near perfect atom economy makes it an especially desirable meth- odology. [1] Hydroformylation has been investigated in the synthesis of more complex molecules for many years, but due to selectivity problems in many early publications, the true potential of the reaction has not yet been exploited to any great extent. This situation is beginning to change, since the last two decades have seen some significant developments in the design of linear-selective catalysts, [2] more reactive catalyst systems, [3] tandem procedures using hydrofor- mylation [4,5] and the discovery of new effective chiral ligands for asymmetric hydroformylation. [1,6–14] These improvements result in the sort of levels of selectivity that make this reaction of immediate potential in aca- demic and industrial-scale organic synthesis. The hy- droformylation of more functionalised and challeng- ing alkene substrates with the new generation of cata- lysts can now be tackled with some reasons for opti- mism. We have recently reported that Rh catalysts de- rived from the monodentate phosphorus cage ligand denoted Me CgPPh show significantly enhanced reac- tivity, chemo- and a-selectivity in the hydroformyla- tion of various unsaturated ester substrates, [15] The highly efficient a-selective hydroformylation reactions of a,b-unsaturated esters are only viable for the syn- thesis of racemic compounds since formyl esters [RCHACHTUNGTRENNUNG(CHO)CO 2 R’)] are in an observable equilibri- um with their enol form and configurationally unsta- ble. The products from the a-selective hydroformyla- tion of a,b-unsaturated amides are formyl amides that should exhibit less enol character due to the delocali- sation between the C = O and C À N bonds and steric repulsion in the enol form. We felt that the catalytic asymmetric synthesis of these potentially delicate chiral building blocks represented an interesting chal- lenge with regard to both control of selectivity, and the development of a methodology that enables the aldehyde products to be isolated or utilised without racemisation. In addition, a-formyl amides have the potential to be very easily transformed into b-amino acids, hydroxy esters, 1,3 diamines and g-amino alco- hols. A publication reporting the R&D synthesis of drug candidates in clinical trials used a-formyl amides [RCHACHTUNGTRENNUNG(CHO)ACHTUNGTRENNUNG(CONEt 2 )] as the key chiral building Adv. Synth. Catal. 2010, 352, 1047 – 1054  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1047 FULL PAPERS