Incorporating 3D character into drug molecules is a desirable asset which can lead to improved binding interactions between a drug candidate and target. These interactions may not be possible with a flat aromatic ring, and so this structural change could in turn improve potency and selectivity. In this respect, diarylmethanes are common synthetic building blocks in organic chemistry and are present in a wide range of biologically active molecules (Figure 1). The sp2-sp3 cross-coupling of benzyl halides and heteroarylboronic acids is a conceptually attractive disconnection to prepare these molecules. However, in practice, this approach often gives reduced yields due to the instability of many heteroarylboronic acids. Figure 1. A selection of pharmaceutically relevant compounds containing the diarylmethane moiety. In this context, we have developed an electrophile-electrophile one-pot cross-coupling of (hetero)aromatic halides with benzyl halides. The in-situ generation of a key sulfinate coupling partner followed by palladium catalysed desulfinative cross-coupling circumvents the need for unstable boron building blocks. Our one-pot approach allows the synthesis of a variety of methylene-linked products in high yields (up to 99%) from commercial starting materials without the need to prepare any intermediates (Scheme 1). This streamlined method allows the fast synthesis of a library of compounds and hence will be of great value to medicinal chemists. Scheme 1. Some examples of diarylmethanes synthesised by the developed methodology.

One-pot palladium catalysed C(sp2)-C(sp3) desulfinative electrophile-electrophile cross-coupling through in-situ sulfinate formation

ACS Spring 2022

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