Phosphine reagents for azine fluoroalkylation

Abstract

A new set of bench-stable fluoroalkylphosphines that directly convert C—H bonds in pyridine building blocks, drug-like fragments, and pharmaceuticals, into fluoroalkyl derivatives. No pre-installed functional groups or directing motifs are required. The reaction tolerates a variety of sterically and electronically distinct pyridines and is exclusively selective for the 4-position in most cases. The reaction proceeds via initial phosphonium salt formation followed by sp 2 -sp 3 phosphorus ligand-coupling, an underdeveloped manifold for C—C bond formation.

What is claimed is: 
     
         1 . A phosphine compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 X is H, F, or —(C 1 -C 6 )perfluoroalkyl; 
 Z is O, S, or NR y  wherein R y  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; 
 R 3  and R 4  are each independently H, NR a R b , OR c , SR d , —(C 3 -C 6 )cycloalkyl, or —(C 1 -C 6 )alkyl; or
 two R 3  taken together form a 6-membered benzo-ring fused to the heterocycle of Formula II; and/or 
 two R 4  taken together form a 6-membered benzo-ring fused to the heterocycle of Formula II; 
 
 R a  and R b  are each independently H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; or
 R a  and R b  taken together form a 5-membered or 6-membered heterocycle with the nitrogen moiety of NR a R b ; 
 
 R c  and R d  are each independently H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; and 
 p and q are each independently 1, 2 or 3; 
 
       wherein each —(C 1 -C 6 )alkyl is independently unbranched or branched. 
     
     
         2 . The phosphine compound of  claim 1  wherein at least one 6-membered benzo-ring moiety is present on a heterocyclic ring of Formula II and each 6-membered benzo-ring moiety is independently substituted with R 3  when p is 3 or R 4  when q is 3. 
     
     
         3 . The phosphine compound of  claim 1  wherein the phosphine compound of Formula II is represented by a phosphine compound of Formula IIA: 
       
         
           
           
               
               
           
         
       
       wherein R 5  and R 6  are each independently H, NR a R b , OR c , SR d , —(C 3 -C 6 )cycloalkyl, or —(C 1 -C 6 )alkyl. 
     
     
         4 . The phosphine compound of  claim 1  wherein the phosphine compound of Formula II is represented by a phosphine compound of Formula IIB: 
       
         
           
           
               
               
           
         
       
       wherein R 5  and R 6  are each independently H, NR a R b , OR c , SR d , —(C 3 -C 6 )cycloalkyl, or —(C 1 -C 6 )alkyl. 
     
     
         5 . The phosphine compound of  claim 1  wherein the phosphine compound of Formula II is represented by a phosphine compound of Formula III, IV, V, VI, VII, or VIII: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The phosphine compound of  claim 5  wherein X is H, F, or CF 3 . 
     
     
         7 . The phosphine compound of  claim 1  wherein X is H, F, or CF 3 . 
     
     
         8 . The phosphine compound of  claim 1  wherein m and n are each 1. 
     
     
         9 . The phosphine compound of  claim 1  wherein R 3  and R 4  are NR a R b . 
     
     
         10 . The phosphine compound of  claim 9  wherein R a  and R b  are methyl or ethyl, or wherein NR a R b  is pyrrolidinyl or piperidinyl. 
     
     
         11 . The phosphine compound of  claim 1  wherein R 3  and R 4  are OR c . 
     
     
         12 . The phosphine compound of  claim 11  wherein R c  is methyl or ethyl. 
     
     
         13 . The phosphine compound of  claim 1  wherein X is F, and R 3  and R 4  are NR a R b . 
     
     
         14 . The phosphine compound of  claim 13  wherein R 3  and R 4  are N(CH 3 ) 2  or together 1-pyrrolidinyl. 
     
     
         15 . The phosphine compound of  claim 1  wherein X is H, and R 3  and R 4  are OR c . 
     
     
         16 . The phosphine compound of  claim 15  wherein R 1  and R 2  are methoxy or ethoxy. 
     
     
         17 . A method for fluoroalkylation of an organic compound comprising:
 a) contacting a phosphine compound of  claim 1 , an organic compound, and a solvent, under suitable reaction conditions to form a phosphonium salt of the organic compound; and   b) contacting the phosphonium salt and an aqueous solution or a mixture of an organic solvent and a base; wherein optionally the phosphonium salt is not isolated as a purified intermediate compound before contacting the intermediate with the aqueous solution;   wherein a fluoroalkylated organic compound is thereby formed.   
     
     
         18 . A phosphine compound of Formula J: 
       
         
           
           
               
               
           
         
       
       wherein
 X is H, F, —(C 1 -C 6 )perfluoroalkyl, or —(C 1 -C 6 )alkyl; 
 each J is independently H, F, —(C 1 -C 6 )perfluoroalkyl, or —(C 1 -C 6 )alkyl; 
 R 1  and R 2  are each independently NR a R b , OR c , SR d , —(C 3 -C 6 )cycloalkyl, or —(C 1 -C 6 )alkyl; 
 R a  and R b  are each independently H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; or
 R a  and R b  taken together form a 5-membered or 6-membered heterocycle with the nitrogen moiety of NR a R b ; 
 
 R c  and R d  are each independently H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; 
 m and n are each independently 1 or 2; 
 each —(C 1 -C 6 )alkyl is independently unbranched or branched, and optionally substituted; and 
 X is not F when R 1  and R 2  are CH 3 ; and X is not F when R 1  and R 2  are OCH 3 , R 1  and R 2  are each in the para-position, and m and n are each 1. 
 
     
     
         19 . A method for fluoroalkylation of an organic compound comprising:
 a) contacting a phosphine compound of  claim 18 , an organic compound, and a solvent, under suitable reaction conditions to form a phosphonium salt of the organic compound; and   b) contacting the phosphonium salt and an aqueous solution or a mixture of an organic solvent and a base; wherein optionally the phosphonium salt is not isolated as a purified intermediate compound before contacting the intermediate with the aqueous solution;   wherein a fluoroalkylated organic compound is thereby formed.