C-H fluorination of heterocycles with silver (II) fluoride

Patent metadata

Field	Value
Publication number	US-9701635-B2
Application number	US-201414907694-A
Country	US
Kind code	B2
Filing date	Jul 28, 2014
Priority date	Jul 26, 2013
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

The present invention provides compositions and methods for the selective C—H fluorination of nitrogen-containing heteroarenes with AgF 2 , which has previously been considered too reactive for practical, selective C—H fluorination. Fluorinated heteroarenes are prevalent in numerous pharmaceuticals, agrochemicals and materials. However, the reactions used to introduce fluorine into these molecules require pre-functionalized substrates or the use of F 2 gas. The present invention provides a mild and general method for the C—H fluorination of nitrogen-containing heteroarene compounds to 2-fluoro-heteroarenes with commercially available AgF 2 . In various embodiments, these reactions occur at ambient temperature within one hour and occur with exclusive selectivity for fluorination at the 2-position. Exemplary reaction conditions are effective for fluorinating diazine heteroarenes to form a single fluorinated isomer.

First claim

What is claimed is:

1. A reaction mixture for mono-fluorinating a nitrogen atom-containing heteroarene precursor compound at a carbon atom adjacent said nitrogen atom, said reaction mixture comprising:
(i) said heteroarene precursor compound, said compound optionally substituted at one or more positions of the heteroarene ring;
(ii) AgF 2 ; and
(ii) an organic solvent.

2. The reaction mixture according to claim 1 , wherein said precursor compound is of the formula:

wherein
A is selected from N and CR 4 ;
D is selected from N and CR 5 ;
E is selected from N and CR 6 ;
G is selected from N and CR 7 ;
J is selected from N and CR 8 ,
wherein
R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, CF 3 , acyl, —SO 2 NR 9 R 10 , —NR 9 R 10 , —OR 9 , —S(O) 2 R 9 , —C(O)R 9 , —COOR 9 , —CONR 9 R 10 , —S(O) 2 OR 9 , —OC(O)R 9 , —C(O)NR 9 R 10 , —NR 9 C(O)R 10 , NR 9 C(O)NR 10 R 11 , C(NR 9 )R 10 , NR 9 SO 2 R 10 and —NO 2 , wherein two or more of R 4 , R 5 , R 6 , R 7 and R 8 , together with the atoms to which they are bonded, are optionally joined to form a ring system which is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

wherein
R 9 , R 10 , and R 11 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, and two or more of R 9 , R 10 , and R 11 , together with the atoms to which they are bonded, are optionally joined to form a 5- to 7-membered ring which is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

3. The reaction mixture according to claim 2 , wherein said precursor compound is of the formula:

4. The reaction mixture according to claim 2 , wherein said precursor compound is of a formula selected from:

wherein
a is an integer from 0 to 4; and
each R 1 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, CF 3 , acyl, —SO 2 NR 2 R 3 , —NR 2 R 3 , —OR 2 , —S(O) 2 R 2 , —C(O)R 2 , —COOR 2 , —CONR 2 R 3 , —S(O) 2 OR 2 , —OC(O)R 2 , —C(O)NR 2 R 3 , —NR 2 C(O)R 3 , —NR 2 SO 2 R 3 , NR 2 C(O)NR 3 R 12 , C(NR 2 )R 3 , and —NO 2 , wherein two or more R 1 moieties together with the atoms to which they are bonded, are optionally joined to form a ring system which is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl,
wherein
R 2 , R 3 , and R 12 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl, and two or more of R 2 , R 3 , and R 12 , together with the atoms to which they are bonded, are optionally joined to form a 5- to 7-membered ring which is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

5. The reaction mixture according to claim 1 , wherein said solvent is CH 3 CN.

6. The reaction mixture according to claim 1 , wherein said precursor compound is a substituted or unsubstituted diazine or a substituted or unsubstituted triazine.

7. The mixture according to claim 1 , wherein said reaction mixture further comprises a fluorinated product derived from said precursor compound, said fluorinated product having the formula:

8. The reaction mixture according to claim 1 , wherein said reaction mixture is essentially free of difluorinated product.

9. The reaction mixture according to claim 1 , wherein said reaction mixture is essentially free of added base.

10. The reaction mixture according to claim 1 , said reaction mixture is essentially free of a source of fluoride other than AgF 2 .

11. The reaction mixture according to claim 1 , wherein the ratio of precursor compound to AgF 2 is from about 1:1 to about 1:5.

12. The reaction mixture according to claim 1 , wherein the ratio of precursor compound to AgF 2 is about 1:3.

13. The reaction mixture according to claim 1 , wherein said precursor compound is further substituted with a member selected from amine, ether, caroxylic acid, amide, ester, halide, protected alcohol and a combination thereof.

14. The reaction mixture according to claim 1 , wherein said precursor compound is a member selected from a substituted or unsubstituted quinoline, pyrazine, pyrimidine, and pyridazine.

15. The reaction mixture according to claim 1 , wherein said precursor is other than an unsubstituted pyrimidine.

16. The reaction mixture according to claim 1 , wherein said precursor is other than a five-membered nitrogen-containing heteroarene.

17. A method for mono-fluorinating a nitrogen atom-containing heteroarene compound at a carbon a to said nitrogen atom, said method comprising:
(a) forming a reaction mixture according to claim 1 ; and
(b) incubating said reaction mixture under conditions appropriate to mono-fluorinate said nitrogen-containing heteroarene compound at said carbon atom α to said nitrogen atom.

18. The method according to claim 17 , wherein said reaction mixture is incubated at about 25° C.

19. The method according to claim 17 , wherein said reaction mixture is incubated for about one hour.

Assignees

• Univ California

Inventors

• Hartwig John
• Fier Patrick

Classifications

• C07D213/803

  Processes of preparation · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D213/63

  One oxygen atom · CPC title

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title