1. Methylene carbonylation project.
Upon initial discovery hits, the newly reaction was fully optimized to obtain the desired b-lactam in high efficiency. Evaluation of different variables was performed including temperature, oxidants, additives, metals, carbon monoxide concentration and time. As a result, optimized conditions entailed 10 mol% of Pd(OAc)2, 200 mol% of benzoquinone, 300 mol% of AgOAc and 10 mol% of xantphos over an atmosphere of CO(g). These conditions were found to be the most efficient rendering 80% yield of b-lactam after 16 h. After having the optimized conditions in hand, more than 100 different substrates were prepared. After this, all these substrates were tested on the carbonylation conditions to obtain the corresponding b-lactams ranging from 20-80 % yield. The Propanolol analogue was synthesized and exposed to the carbonylative reaction conditions and the corresponding trans β-lactam was successfully obtained in 61% of yield.
Our work has been published in Angewandte Chemie International Edition. (Angew. Chem. Int. Ed. 2017, 56, 11958 –11962. DOI: 10.1002/anie.201706303). This publication is open access to general public through the University of Cambridge.
2. Azetidine synthesis project.
Recently, we described a Pd(II)-catalyzed process for β-C–H amination on hindered alkyl amines to form aziridines, which proceeded by direct intramolecular C–N reductive elimination from an aminoalkyl Pd(IV) intermediate. We speculated that reaction of a related homologated amine should undergo γ-C– H amination to form the corresponding azetidine. We were surprised to find, however, that reaction produced only the γ-C–H acetoxylation product, with no sign of azetidine, when treated under identical conditions to the aziridine forming process. We conducted computational studies and we found that the acetoxylated product could be formed via a two-step reaction at the Pd(IV) center; dissociative ionization of an axial acetate from Pd(IV) and simultaneous κ2 binding of the axial acetate forms an octahedral complex. In light of these preliminary computational studies, we re-evaluated our design hypothesis for azetidine formation. We proposed that replacing one of the acetate ligands on the aminoalkyl-Pd(IV) species with a OTs group would promote dissociative ionization of the better leaving group, to form the γ-amino tosylate. Cyclization of the amine to displace the γ-tosylate completes the formal C–N reductive elimination process to azetidine. Guided by this mechanistic blueprint, different oxidants, solvents and additives were tested to optimize the reaction conditions. The combination of benziodoxole oxidant containing the tosylate group and the silver acetate was crucial to obtain the desire azetidine in good yields. A range of fully substituted morpholinones undergo efficient C–H amination to azetidines. On the basis that the benziodoxole is less oxidizing than its acyclic counterparts, a range of enantioenriched substrates were prepared starting from different amino alcohols. At 80 ˚C, the C–H amination delivered the chiral azetidines in useful yields and excellent diastereoselectivity.
This work was presented in the American Chemical Society meeting in April 2017, San Francisco, which is one of the most important meetings in Chemistry.
Our work has just been published in Angewandte Chemie International Edition. (Angew. Chem. Int. Ed. 2018, online. DOI: 10.1002/anie.201800519). This publication is open access to general public through the University of Cambridge.
