Fluorination of aromatic ring systems

1. A method for making a compound of Formula (3):

Ar 2 —F   3

wherein:

Ar 2 is an aryl or heteroaryl ring system;

the method comprising reacting in a polar solvent a compound MF, wherein M is a counter ion, and a compound of Formula (2):

wherein:

Ar 1 is an electron rich aryl or heteroaryl ring system;

Y is a leaving group; and

Ar 2 is as defined above;

removing the polar solvent from the reaction mixture; and

heating a solution comprising the remaining mixture and a nonpolar solvent.

2. A method for making a compound of Formula (3):

Ar 2 —F   3

wherein:

Ar 2 is an aryl or heteroaryl ring system;

the method comprising heating a mixture comprising a nonpolar solvent, a compound MF, wherein M is a counter ion, and a compound of Formula (2):

wherein:

Ar 1 is an electron rich aryl or heteroaryl ring system;

Y is a leaving group; and

Ar 2 is as defined above.

3. A method for making a compound of Formula (3):

Ar 2 —F   3

wherein:

Ar 2 is an aryl or heteroaryl ring system;

the method comprising reacting in a polar solvent a compound MF, wherein M is a counter ion, and a compound of Formula (2):

wherein:

Ar 1 is an electron rich aryl or heteroaryl ring system;

Y is a leaving group; and

Ar 2 is as defined above;

removing the polar solvent from the reaction mixture;

combining the remaining mixture with a nonpolar solvent;

filtering the resulting mixture to remove insoluble material; and

heating the filtrate.

4. A method for making a compound of Formula (3):

Ar 2 —F   3

wherein:

Ar 2 is an aryl or heteroaryl ring system;

the method comprising reacting in a nonpolar solvent a compound MF, wherein M is a counter ion, and a compound of Formula (2):

wherein:

Ar 1 is an electron rich aryl or heteroaryl ring system;

Y is a leaving group; and

Ar 2 is as defined above;

filtering the reaction mixture to remove insoluble material; and

heating the filtrate.

5. The method of any one of claims 1 - 4 , wherein Ar 1 —H is more easily oxidized than benzene.

6. The method of any one of claims 1 - 4 , wherein X is a radioactive isotope.

7. The method of any one of claims 1 - 4 , wherein Ar 1 is substituted with at least one substituent having a Hammett σ p value of less than zero.

8. The method of claim 7 , wherein the substituent is chosen from:

—(C 1 -C 10 )alkyl, —(C 1 -C 10 )haloalkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, —O—(C 1 -C 10 )alkyl, —C(O)—O—(C 1 -C 10 )alkyl, aryl, and heteroaryl.

9. The method of any one of claims 1 - 4 , wherein the F is a radioactive isotope of fluorine.

10. The method of any one of claims 1 - 4 , wherein Ar 1 and Ar 2 are the same.

11. The method of any one of claims 1 - 4 , wherein Ar 1 is:

wherein:

R 1 , R 2 , R 3 , R 4 , and R 5 are independently chosen from: H, —(C 1 -C 10 )alkyl, —(C 1 -C 10 )haloalkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, —O—(C 1 -C 10 )alkyl, —C(O)—O—(C 1 -C 10 )alkyl, aryl, and heteroaryl, or two or more of R 1 , R 2 , R 3 , R 4 , and R 5 come together to form a fused aryl or heteroaryl ring system.

12. The method of any one of claims 1 - 4 , wherein Ar 2 is chosen from a phenylalanine derivative, tyrosine derivative, typtophan derivative, histidine derivative, and an estradiol derivative.

13. The method of any one of claims 1 - 4 , wherein Ar 2 is chosen from:

wherein:

each of P 1 , P 2 and P 6 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;

each of P 3 , P 4 and P 7 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and

P 5 is a carboxylic acid protecting group.

14. The method of any one of claims 1 - 4 , wherein the nonpolar solvent is chosen from: benzene, toluene, o-xylene, m-xylene, p-xylene, ethyl benzene, carbon tetrachloride, hexane, cyclohexane, fluorobenzene, chlorobenzene, nitrobenzene, and mixtures thereof.

15. The method of claim 14 , wherein the nonpolar solvent comprises benzene.

16. The method of claim 14 , wherein the nonpolar solvent comprises toluene.

17. The method of any one of claims 1 - 4 , wherein the heating comprises heating at a temperature ranging from about 25° C. to about 250° C.

18. The method of claim 17 , wherein the heating occurs for from about 1 second to about 25 minutes.

19. The method of claim 17 , wherein the heating is accomplished by a flash pyrolysis method, a conventional heating method, or by a microwave method.

20. The method of any one of claims 1 and 2 , wherein the mixture comprising the nonpolar solvent is filtered prior to heating.

21. The method of any one of claims 1 and 3 , wherein the polar solvent is chosen from: acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, 1,2-difluorobenzene, benzotrifluoride and mixtures thereof.

22. The method of any one of claims 1 - 4 , wherein Y is chosen from triflate, mesylate, nonaflate, hexaflate, tosylate, nosylate, brosylate, perfluoroalkyl sulfonate, tetraphenylborate, hexafluorophosphate, trifluoroacetate, tetrafluoroborate, perchlorate, perfluoroalkylcarboxylate, chloride, bromide, and iodide.

23. The method of any one of claims 1 - 4 , wherein M is chosen from: potassium, sodium, cesium, complexes of lithium, sodium, potassium, or cesium with cryptands or crown ethers, tetrasubstituted ammonium cations, and phosphonium cations.

24. The method of any one of claims 3 and 4 , wherein the insoluble material comprises insoluble salts.

25. The method of any one of claims 3 and 4 , wherein the solvent is removed from the filtrate prior to heating.

26. The method of any one of claims 1 - 4 , wherein the compound of Formula (2) is chosen from:

wherein:

each of P 1 and P 2 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;

each of P 3 , and P 4 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and

P 5 is a carboxylic acid protecting group.

27. The method of any one of claims 1 - 4 , wherein the compound of Formula (3) is chosen from:

wherein:

each of P 1 and P 2 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;

each of P 3 , and P 4 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and

P 5 is a carboxylic acid protecting group.

28. The method of any one of claims 1 - 4 , wherein the compound of Formula (2) is chosen from:

29. The method of any one of claims 1 - 4 , wherein the compound of Formula (3) is chosen from:

30. The method of any one of claims 1 - 4 , wherein the compound of Formula (2) is chosen from:

wherein:

each of P 3 and P 4 are independently an alcohol protecting group.

31. The method of any one of claims 1 - 4 , wherein the compound of Formula (3) is chosen from:

wherein:

each of P 3 and P 4 are independently an alcohol protecting group.

32. The method of any one of claims 1 - 4 , wherein the compound of Formula (2) is:

wherein:

each of P 1 and P 2 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;

each of P 3 , and P 4 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and

P 5 is a carboxylic acid protecting group.

33. The method of claim 32 , wherein the compound of Formula (2) is:

34. The method of claim 32 , wherein the compound of Formula (2) is:

35. The method of any one of claims 1 - 4 , wherein the compound of Formula (3) is:

wherein:

each of P 1 and P 2 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;

each of P 3 , and P 4 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and

P 5 is a carboxylic acid protecting group.

36. The method of claim 35 , wherein the compound of Formula (3) is:

37. The method of any one of claims 1 - 4 , wherein the compound of Formula (3) is: