Phosphine reagents for azine fluoroalkylation
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.
1. A phosphine compound of Formula I:
wherein
X is 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; and
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.
2. The compound of claim 1 wherein R 1 and R 2 are each in the para-position and m and n are each 1.
3. The compound of claim 1 wherein X is H, F, or CF 3 .
4. The compound of claim 1 wherein R 1 and R 2 are NR a R b .
5. The compound of claim 4 wherein R a and R b are methyl or ethyl, or wherein NR a R b is pyrrolidinyl or piperidinyl.
6. The compound of claim 1 wherein R 1 and R 2 are OR c .
7. The compound of claim 6 wherein R c is methyl or ethyl.
8. The compound of claim 1 wherein X is F, and R 1 and R 2 are NR a R b .
9. The compound of claim 1 wherein X is F, and R 1 and R 2 are N(CH 3 ) 2 or 1-pyrrolidinyl.
10. The compound of claim 1 wherein X is H, and R 1 and R 2 are OR c .
11. The compound of claim 1 wherein X is H, and R 1 and R 2 are methoxy or ethoxy.
12. The compound of claim 1 wherein the compound is:
13. The compound of claim 1 wherein the compound is:
14. A composition comprising the compound of claim 1 and one or more of an acid, a base, and a solvent.
15. A method for fluoroalkylation of an organic compound comprising:
a) contacting a phosphine compound of Formula I:
wherein
X is 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; and
m and n are each independently 1 or 2;
wherein each —(C 1 -C 6 )alkyl is independently unbranched or branched, and optionally substituted;
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.
16. The method of claim 15 wherein the organic compound is a nitrogen-containing heteroaryl.
17. The method of claim 16 wherein the nitrogen-containing heteroaryl comprises a pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, naphthyridine, or quinazoline.
18. The method of claim 15 wherein a mixture of the phosphine compound, organic compound and solvent at step a) comprises a Brønsted base and sulfonic anhydride.
19. The method of claim 15 wherein the aqueous solution at step b) comprises a Brønsted acid or Brønsted base.
20. The method of claim 15 wherein the phosphine compound is: