Low-Valent Niobium-Catalyzed Reduction of alpha,alpha,alpha-Trifluorotoluenes

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070249m.html

From Prof. Takahiko Akiyama's group at Gakushuin University, Tokyo, Japan

Recent work in Org Lett ASAP focused on the use of NbCl5 together with LAH in reducing CF3 group on an aromatic ring to CH3 group.

The reaction appeared to be applicable to a wide range of substrates as shown in the table below (with conditions).

The reduction is selective to the benzylic C-F bonds as apparent in entries 5 and 6 where only the benzylic C-F bond was reduced while the aryl C-F bond remained unaffected. This is in contrast to entries 9 and 10, where both aryl C-Cl and benzylic C-F bonds were reduced completely. The biaryl substrate 11 could also be reduced completely to give 2c.

The presence of NbCl5 in the reaction is critical for a complete reduction of fluorine as the comparison studies below demonstrates.It was also found that by lowering the amount of LAH employed as in the case of 1k, one of the CF3 groups could be completely reduced while leaving the other one intact providing 1d in good yield. When higher equiv of LAH was used, complete reduction resulted.

The result of the comparison experiments above (with 3 equiv LAH) seemed to show that the reduction occurred in the step-wise fashion. And that when one fluorine is replaced by a hydrogen, the resulting CHF2 group became more prone to the reduction than the other CF3 group, thus reacting faster to give CH2F group. This group was reduced faster still than the CF3 group and underwent another reduction to give CH3 group while the other CF3 group largely remained untouched.