Wednesday, December 26, 2012

Desert Island Chemistry: Simple as Fe-S

"Damnit, Jim, I'm a Professor,
not a chemist!"
(cue the Gilligan's Island theme music)

Quick! You're on a desert island, and you have to make a heteroatom-rich drug compound. You don't have any of your fancy Pd, Pt, or Ni complexes - those unfortunately went down with the ship. Since your phone is made from coconuts, no access to Aldrich, either; boronic acids and bromoarenes are out. Your scouting party reports finding a simmering sulfur-encrusted thermal vent, and you still have a few hand warmers in your pockets...

...What do you do?

Well, if you were lucky enough to bring the latest JACS ASAP, you'd know right away: grab a jar, stir a 2-nitroaniline and a methyl-heteroarene together with equal parts iron powder and sulfur, toss the mixture into the thermal vent, and wait - about a day should do it. Et voilĂ ! Just about any benzimidazole you can think of, courtesy of a catalytic iron sulfide species formed in situ

The authors present 21 entries, most in the ~50-80% range, which includes examples where normally labile bromo- or chloroarenes (Suzuki classics!) survive the procedure unharmed. The only catch? The heteroatom must be at the 2- or 4-position of the methyl-arene (sorry, no meta). 

Source: JACS | Prof. Nguyen, CNRS
So what's going on here? The authors invoke a biologically-inspired iron sulfide cluster, like the kind one finds in redox proteins underpinning essential processes like respiration or DNA repair. Though the mechanistic details haven't been fully teased out, they claim a six-electron (6e-) reductive transfer, using evolved water and the iron sulfide cluster as electron and proton shuttles, followed by ring closure. (Extra bonus: many of the products can be directly triturated out of the reaction mixture!)

Reader challengeI'm itching to try this reaction, but don't have any iron powder, sulfur, or nitroanilines handy. Anyone want to give it a shot, and let me know how it turns out?

Be a #RealTimeChem hero!