Modular C(sp2)-C(sp3) radical cross-coupling with PT-sulfones

The construction of sp2-sp3 carbon-carbon bonds is sometimes not trivial with standard two-electron coupling reactions such as Suzuki, Heck and Negishi. To offer chemists alternative options to form these types of carbon-carbon bonds the Baran Lab have been working on metal-catalysed radical cross-coupling (RCC) reactions. I have previously written about some of their earlier work in this area. In their latest paper (Science 360, 75 –80 (2018)) they write about their discovery that a redox-active phenyl-tetrazole (PT) sulfone could be used in these RCC reactions (figure 1).

Lewis 1

Figure 1

Some PT-sulfone reagents are commercially available but others such as (3f) can be easily made from phenyl-tetrazole (6) by sulfur-carbon bond formation (alkyl halide displacement or Mitsunobu) and then oxidation of the resulting sulphide (mCPBA or ammonium molybdate/hydrogen peroxide). These sulfones are useful building blocks and can be used in RCC reactions as they are or further functionalised such as α-alkylation or α-fluorination (figure 2).

Lewis 2

Figure 2

A small set of fluorinated sulfone building blocks (8-11) were used to introduce mono/di-fluoromethyl and mono/di-fluoroethyl moieties onto a selection of aromatics (figure 3). Unfortunately, these reaction conditions are not able to install a trifluoromethyl group. Sulfones (7-11) are not currently commercially available but 100-500 mg quantities can be requested directly from the Baran lab via this link.

Lewis 3

Figure 3

Baran ran a series a competition experiments and under these reaction conditions observed the following reactivity trend Cl/Br < SO2PT < NHPI/TCNHPI (figure 4). This observation was tested with sequential chemoselective RCC reactions. Firstly, a decarboxylative cross-coupling (DCC) was performed followed by a desulfonylative cross-coupling (SCC) (figure 5).

Lewis 4

Figure 4

Lewis 5

Figure 5

These new reagents and chemoselective reaction conditions offer a simple and general method to add to the tool box of sp2-sp3 carbon-carbon bond forming reactions. The ability to diversify and fluorinate a common building block will increase the interest from medicinal chemists as will the ability to introduce simple alkyl fluorides without the use of harsh reaction conditions or toxic reagents.

Blog written by Lewis Pennicott


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