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Combination Amine and Metal Cascade Catalysis

Final Report Summary - COMBICAT (Combination Amine and Metal Cascade Catalysis)

Our proposal is aimed to develop new and synthetically powerful cyclisation cascades using combinations of amine organocatalysts and transition metal catalysts. Carefully chosen combinations of these catalysts should allow aldehyde and ketone functionality to be activated through conversion to a transient enamine intermediate that is then poised to attack the transition metal-activated allene (Scheme 1a) and alkyne functionality (Scheme 1b). This concept can be extended to new annulation methodology when enal Michael acceptors are employed (Scheme 1a). In this case carbon acids tethered to allene functionality can undergo an initial Michael addition under iminium ion (LUMO lowering) activation using amine organocatalysts and the generated enamine intermediate is then poised to attack the transition metal-activated allene group. Furthermore, through use of effective single enantiomer organocatalysts it is possible to render this powerful annulation reaction asymmetric (Scheme 1a and 1b).

We first decided to find the appropriate amine and metal catalyst which can effectively and also enantioselectively catalyze the first step i.e. the Michael addition step. We started our experiment with 2-(buta-2,3-dien-1-yl)malononitrile 1a as nucleophile and (E)-hex-2-enal 2 as Michael acceptor. 1a and 2 were treated with pyrrolidine and benzoic acid in toluene at room temperature overnight. Michael adduct 3 was obtained in 41% yield (Scheme 2). This result encouraged us to investigate the enantioselective version of the reaction. We first took Jorgensen catalyst 4a as an organocatalyst and screened different palladium catalysts. Results are depicted in Table 1. Palladium(II) acetate in presence of benzoic acid produced 3 in only 25% yield (table1, entry 1). Addition of triphenylphosphine gave only messy reaction mixture (table 1, entry 2). Similarly Pd2(dba)3 yielded 3 in 22% yield whereas Pd(PPh3)4 gave messy reaction mixture (table1, entry 3 and 4). PdCl2(dppf) proved to be very effective for this reaction. It afforded 71% of product in presence of benzoic acid (table 1, entry 5) and 92% in absence of it (table1, entry 6).

After having this excellent yield with PdCl2(dppf) for Michael addition step, we were interested to see the enantioselectivity of the reaction using various Jorgensen catalysts. The resulting aldehyde was converted to first alcohol using sodium borohydride and then to benzoate ester using benzoyl chloride and triethylamine for HPLC analysis. Results are summarized in Table 2. As mentioned before (table 1) the yield of the reaction with organocatalyst 4a was excellent, HPLC analysis shows that ee is also excellent (89%, entry 1, table 2). All the other amine catalysts also produced good to excellent yield and selectivity (table 2). The best yield (92%) was obtained when R is trimethylsilyl group (4a) and the best ee (95%) was obtained as when R is bulky tert-butyldimethylsilyl group (4e, table 2, entry 5).