Process for fluorinating compounds

Patent metadata

Field	Value
Publication number	US-9878983-B2
Application number	US-201615228188-A
Country	US
Kind code	B2
Filing date	Aug 4, 2016
Priority date	Aug 4, 2015
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

Disclosed are mild temperature (e.g., from 0 to 80° C.) S N Ar fluorinations of a variety of halide and sulfonate substituted aryl and heteroaryl substrates using NMe 4 F.

First claim

What is claimed is:

1. A method of preparing a fluorinated aryl or heteroaryl substrate, comprising: combining tetramethylammonium fluoride and an aryl or heteroaryl substrate substituted with at least one chloro, bromo, iodo, nitro, or sulfonate group, at from 0° C. to 55° C.

2. The method of claim 1 , wherein the tetramethylammonium fluoride and the aryl or heteroaryl substrate are combined at from 15° C. to 50° C.

3. The method of claim 1 , wherein the tetramethylammonium fluoride and the aryl or heteroaryl substrate are combined at from 20° C. to 40° C.

4. The method of claim 1 , wherein the tetramethylammonium fluoride and the aryl or heteroaryl substrate are combined at room temperature.

5. The method of claim 1 , wherein the tetramethylammonium fluoride and the aryl or heteroaryl substrate are combined for from 1 minute to 24 hours.

6. The method of claim 1 , wherein the tetramethylammonium fluoride and the aryl or heteroaryl substrate are combined for from 1 minute to 3.5 hours.

7. The method of claim 1 , wherein the tetramethylammonium fluoride and the aryl or heteroaryl substrate are combined in the presence of a solvent.

8. The method of claim 7 , wherein the solvent is a polar aprotic solvent.

9. The method of claim 7 , wherein the solvent is one or more of dimethylformamide, dimethylacetamide, sulfolane, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, benzonitrile, or deuterated analogs thereof.

10. The method of claim 7 , wherein the tetramethylammonium fluoride and the aryl or heteroaryl substrate are combined at about room temperature and the solvent is dimethylformamide.

11. The method of claim 1 , wherein from 0.5 to 10 equivalents of the tetramethylammonium fluoride is used per equivalent of the aryl or heteroaryl substrate.

12. The method of claim 1 , wherein from 1 to 2 equivalents of the tetramethylammonium fluoride is used per equivalent of the aryl or heteroaryl substrate.

13. The method of claim 1 , wherein the tetramethylammonium fluoride is anhydrous.

14. The method of claim 1 , wherein the tetramethylammonium fluoride and the aryl or heteroaryl substrate are combined in the presence of up to 2 equivalents of water per equivalent of the tetramethylammonium fluoride.

15. The method of claim 1 , wherein the tetramethylammonium fluoride is combined with the heteroaryl substrate and the heteroaryl substrate has Formula I-A or I-B:

wherein
A is Cl, Br, I, NO 2 , or SO 3 R 3 ;
B is H, Cl, Br, I, NO 2 , or SO 3 R 3 ;
C is H, Cl, Br, I, NO 2 , or SO 3 R 3 ;
R 1 is H, CN, SO 2 R 3 , or CO 2 R 3 , wherein each R 3 is, independent of any other, optionally substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, heterocycloalkyl, heteroaryl, cycloalkyl, or aryl; and
R 2 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and the resulting fluorinated product has Formula II-A or II-B

wherein D is B or F; and G is C or F.

16. The method of claim 1 , wherein the tetramethylammonium fluoride is combined with the heteroaryl substrate and the heteroaryl substrate has Formula III-A:

wherein
one of X 1 and X 2 is N and the other is CH or C-A;
A is Cl, Br, I, NO 2 , or SO 3 R 3 ;
R 3 is, independent of any other, optionally substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, heterocycloalkyl, heteroaryl, cycloalkyl, or aryl; and
R 4 is H, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 2 -C 12 alkenyl, substituted or unsubstituted C 2 -C 12 alkynyl, CN, SO 2 R 3 , OR 3 , CO 2 R 3 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
And the fluorinated product has Formula III-B

17. The method of claim 1 , wherein the tetramethylammonium fluoride is combined with the heteroaryl substrate and the heteroaryl substrate has Formula IV-A:

wherein
A is Cl, Br, I, NO 2 , or SO 3 R 3 ;
each B is independent of the other H, Cl, Br, I, NO 2 , SO 3 R 3 , SO 2 R 3 , CN, R 3 , COR 3 , or CO 2 R 3 ;
each C is independent of the other H, Cl, Br, I, NO 2 , SO 3 R 3 , SO 2 R 3 , CN, R 3 , COR 3 , or CO 2 R 3 ;
R 3 is, independent of any other, optionally substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, heterocycloalkyl, heteroaryl, cycloalkyl, or aryl;
and the resulting fluorinated product has Formula IV-B

wherein each D is independently selected from B or F; and each G is independently selected from C or F.

18. The method of claim 1 , wherein the tetramethylammonium fluoride is combined with the aryl substrate and the aryl substrate has Formula V-A:

wherein
A is Cl, Br, I, or SO 3 R 3 ;
n is 0-5;
each B is, independent of any other, Cl, Br, I, CN, SO 2 R 3 , R 3 , COR 3 , or CO 2 R 3 ;
R 3 is, independent of any other, optionally substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, heterocycloalkyl, heteroaryl, cycloalkyl, or aryl;
and the resulting fluorinated product has Formula V-B

19. The method of claim 1 , wherein the tetramethylammonium fluoride is combined with the heteroaryl substrate and the aryl substrate has Formula VI-A, VI-B, or VI-C:

wherein
A is Cl, Br, I, NO 2 , or SO 3 R 3 ;
each B is independent of the other H, Cl, Br, I, CN, NO 2 , SO 2 R 3 , SO 2 R 3 , R 3 , COR 3 , or CO 2 R 3 ;
R 2 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R 3 is, independent of any other, optionally substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, heterocycloalkyl, heteroaryl, cycloalkyl, or aryl;
and the resulting fluorinated product can have Formula VI-D, VI-E, or VI-F:

wherein each D is independently selected from B or F.

20. The method of claim 1 , wherein the tetramethylammonium fluoride is combined with the heteroaryl substrate and the heteroaryl substrate has Formula VII-A:

wherein
A is Cl, Br, I, NO 2 , or SO 3 R 3 ;
each R 2 is independent of one another H, halide, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and
R 3 is, independent of any other, optionally substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 1

Assignees

• Dow Agrosciences Llc
• Univ Michigan Regents

Inventors

• Sanford Melanie
• Ryan Sarah
• Schimler Sydonie
• Cheng Yang
• Bland Douglas

Classifications

• C07D213/84

  Nitriles · CPC title

• C07D237/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D213/76

  to which a second hetero atom is attached (nitro radicals C07D213/61) · CPC title

• C07D213/803

  Processes of preparation · CPC title

• C07D213/79 Primary

  Acids; Esters · CPC title