Chemoselective amination of 5-bromo-2-chloro-3-fluoropyridine.
The chemoselective functionalization of 5-bromo-2-chloro-3-fluoropyridine (1c) is described. Catalytic amination conditions (Pd2dba3, Xantphos, base) afford exclusively the bromide substitution product (2) for both secondary amines and primary anilines. A reversal in chemoselectivity is observed under neat conditions in the absence of palladium catalysis, with substitution at the 2-chloro position preferred to generate 3. Last, selective substitution of the 3-fluoro group is achieved under SNAr conditions to afford the dihalo adduct (4).
Stroup
Bryan W
BW
Global Discovery Chemistry, Novartis Institutes for BioMedical Research Inc, Cambridge, MA 02139, USA.
Szklennik
Paul V
PV
Forster
Cornelia J
CJ
Serrano-Wu
Michael H
MH
D000586:Amination; D001965:Bromides / Q000737:chemistry; D002712:Chlorides / Q000737:chemistry; D005461:Fluorine / Q000737:chemistry; D006846:Hydrocarbons, Halogenated / Q000737:chemistry*; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*
C520457:5-bromo-2-chloro-3-fluoropyridine; D001965:Bromides; D002712:Chlorides; D006846:Hydrocarbons, Halogenated; D011725:Pyridines; D005461:Fluorine; C023666:pyridine