Sunday, July 3, 2011

More copper, please - Part 2 of 4
The next focus on copper-catalyzed reactions is direct C-H functionalization.  You may be able to tell from past posts that I have a special place in my heart for direct functionalization of C-H bonds.  A few recent papers use copper to achieve these kinds of reactions; I'm going over 2 here, bulleting the key points so that there aren't paragraphs upon paragraphs to read.

The first, "Copper-Catalyzed Direct Oxidative C-H Amination of Benzoxazole with Formamides or Secondary Amines under Mild Conditions" recently in JOC (doi: features:
  • The authors developed a catalytic system to form C-N bonds of azoles by decarboxylative coupling with formamides or direct C-H amination with secondary amines using Cu(OAc)2.H2O, 2 equivalents benzoic acid, and oxygen as the oxidant [to oxidize Cu(I) back to Cu(II)].  
  • No base needed - only multiple equivalents of an acid additive. 
  • Lower temperature allows direct coupling of amines to the azole core instead of decarbonylation of a formamide.  
  • Conversion of benzoxazoles best, with drastically lowered yield for benzothiazoles and no reaction with benzimidazoles (we just can't get general methods in C-H activation can we?!). 
  • Tolerates various aliphatic and methyl benzyl amines, including morpholine (55%) and diallyl amine (20%), with higher yields for less sterically hindered, electron-rich amines. 
  • Is 20% really "catalytic"? 
  • I'm sure the yields and scope suffer because of all the HX that's getting churned out - should use two equivalents of acid AND a base, since using both works for recent direct functionalization in palladium chemistry (substoichiometric HOPiv with multiple equivalents of a carbonate base, for example). 
  • Authors they claim it's not protonating the azole in order to make it more electrophilic for the amine, or the Cu-amine complex, to attack.  The jury's still out on this mechanism, in my opinion. 
The next copper-loving paper is brought to you by the Daugulis group at the University of Houston (JACS 2011, 133, 9286-9289 doi:

  • Perfluoroalkylation of aryl iodides using 1H-perfluoroalkanes catalyzed by 10% CuI with 20% phenanthroline, whereas the group previous published perfluoroarylation conditions.
  • Existing methods rely on either stoichiometric copper or suffer in substrate scope; also usually require RFSiR3 reagents, which are limited in the number that are available.
  • Scope and conditions:

I particularly like the Daugulis paper because one doesn't normally think of polyfluorinated alkyl chains as being staple functionality to include in small molecule libraries in biologically active molecule discovery; this chemistry makes it highly accessible.   Early mechanistic studies support the following as the mechanism. 

Anyone have a favorite reaction with copper in it? 

  • Yaming Li, Yusheng Xie, Rong Zhang, Kun Jin, Xiuna Wang, & Chunying Duan (2011). Copper-Catalyzed Direct Oxidative C–H Amination of Benzoxazoles with Formamides or Secondary Amines under Mild Conditions Journal of Organic Chemistry : 10.1021/jo200447x
  • Popov I, Lindeman S, & Daugulis O (2011). Copper-Catalyzed Arylation of 1H-Perfluoroalkanes. Journal of the American Chemical Society, 133 (24), 9286-9 PMID: 21627068


  1. Reaction 1 is catalytic in acid as far as I can tell. The stoichiometric byproduct is water. Yes 20% is catalytic. Catalysis is not defined by stoichiometry.

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Constructive criticism welcome; criticism for judgement's sake, not.