Sustainable Practices in Medicinal Chemistry: Current State and Future Directions

Abstract

The medicinal chemistry subgroup of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.

Nickel Catalysts/N,N′-Bidentate Directing Groups: An Excellent Partnership in Directed C–H Activation Reactions

“…1 A reaction involving the direct functionalization of a CH bond is considered to be a greener process because it avoids the prefunctionalization of starting materials to more reactive compounds such as organometallic reagents and/or organic halides. 2 However, there are many different CH bonds in the structures of organic molecules. Even if their chemical environments are different, the strengths of the CH bonds are quite similar, making it difficult to achieve regioselectivity.…”

“…In this strategy, the transition-metal catalyst plays a central role, because it is first coordinated by the directing group, activates a CH bond in a regioselective fashion, is coordinated by the second coupling partner, ties them together, and then releases the product as a single new molecule. Furthermore, this strategy is not unique for aromatic systems, and it has also been applied to other kinds of structures, such as olefinic C(sp 2 )H and C(sp 3 )H bonds. 5 After our paper appeared in the literature, 4 the use of chelation assistance in the catalytic activation of CH bonds has been widely developed, and it is now becoming a common method for the regioselective functionalization of CH bonds.…”

“…However, these novel directing groups, especially the 8-aminoquinoline, have opened another door to the use of nonprecious metals in controlling site-selective CH functionalizations. 11 Although the pioneering example of regioselective ortho CH bond cleavage using a directing group was achieved by the cyclometalation of azobenzene with a [Cp 2 Ni] complex in 1963, 12 nickel complexes have not been used extensively in the chelation-assisted functionalization of CH bonds, in spite of the fact that nickel has played the role of a catalyst in many CH activation systems. 13 This review discusses the use of nickel catalysts 14 and N,N¤-bidentate directing groups, such as 2-pyridinylmethylamine and 8-aminoquinoline moieties, which constitute a powerful combination for the chelation-assisted functionalization of CH bonds.…”

“…This system uses an 8-aminoquinoline derivative as the directing group and Ni(OTf) 2 and PPh 3 for the in situ generation of the active catalyst and Na 2 CO 3 as the base in toluene at 140°C for 24 h. This reaction system is affected by the nature of the directing groups. Once again, it is possible to see the importance of a bidentate directing group in directed nickel CH activation.…”

“…In the absence of PPh 3 , no products were obtained. Interestingly, the catalytic activity was not exclusive of Ni(OTf) 2 and other Ni(II) complexes also afforded the alkylated compound in good yields. Surprisingly, Ni(0) also gave the desired product in moderate yield.…”