SOMO · Application of SOMO Catalysis Towards the Synthesis of Complex Steroidal Frameworks

Periodic Report Summary - SOMO (Application of SOMO catalysis towards the synthesis of complex steroidal frameworks)

1. Publishable summary Summary description of project objectives As detailed in the midterm report, approaches to the proposed SOMO catalysis project were unsuccessful despite significant investigation. It was felt that continuation along this direction would not prove fruitful and would severely hamper the future prospects of the fellow as a result. After a period of approximately eight months into the fellowship an alternative strategy was taken into the C-H arylation of amines using photoredox catalysis. Despite the change in direction of the research the fellow has achieved all of the objectives detailed in the original proposal. The specific objectives for the research undertaken became: 1) Demonstrate applicability to a range of amine structures; 2) Apply the protocol to a diverse range of aromatic and heteroaromatic structures and 3) Demonstrate the use of a convenient protecting group. Description of work and main results Formation of benzyl amines via photoredox-mediated C-H bond funtionalisation. One of the most prominent structural motifs in medicinal agents is the benzylic amine. A sense of its importance can be garnered from the observation that 12 of the top 100 selling pharmaceuticals are embedded with this motif (and several others are related by simple derivatisation). A number of well-established methods are typically employed to construct this motif but can suffer from long, impractical synthetic sequences. Given our discovery of an aniline-cyano arene coupling reaction, we envisioned that a milder, direct method would involve conversion of an a-amino C-H bond to a C-Ar bond mediated by photoredox catalysis (scheme 8). With only visible light required, a room-temperature reaction with operationally trivial experimental protocols would be highly desirable for synthetic purposes. Visible light excitation of photocatalysts of the type Ir(ppy)3 allows facile oxidation of the aniline substrate 1 (e.g. Et2NPh,E1/2ox = 0.78 V vs. SCE in CH3CN). The photocatalyst in its now reduced form can promote single electron transfer to the cyanoarene 2 (e.g. Ir(ppy)32+ E1/2ox = -2.2 V vs. SCE in CH3CN and 1,4-dicaynobenzene, E1/2red = -1.61 V vs. SCE in CH3CN) and thus return the catalyst to its original ground state. The result of this electron shuttling is amine radical cation 3 and arene radical anion 4. The protons adjacent to the nitrogen in 3 are weakened by approximately 60 kcal/mol and the arene radical anion 4 accordingly behaves as a base leading to a pair of neutral radicals 5 and 6. Radical combination and elimination of HCN affords the rearomatised arylated product. Support for this mechanism is found from a study of related systems by Ohashi. The new arylation process has proven to be extremely general. We first began exploring the scope of the reaction by examining a range of different amine structures. Various cyclic and acyclic derivatives were easily accommodated within the new arylation reaction. Substitution of the phenyl moiety was also possible with alkyl and halide groups. In all cases, exceptionally high yields were obtained of the arylated products. As well as the amine structures in scheme 10, a selection of important amine containing motifs such as indolines, tetrahydroquinolines and tetrahydroisoquinolines were examined. The issue of regioselectivity also became apparent with these particular substrates. In the case of indoline, the arylated product 7 was obtained in 81 % yield and with a 10:1 preference for arylation at the ring site. Similarly, tetrahydroquinoline product 8 was obtained as a single isomer with arylation again occurring at the ring site in 88 % yield. Interestingly, the benzylic position was preferred of the tertrahydro isoquinoline system forming 9 in 77 % yield. Our attention then turned to the arene coupling partner.

Data: CORDIS, © European Union