Synthesis of vicinal difluoro aromatics and intermediates thereof

• US 20030149315A1
• Filed: 02/03/2003
• Published: 08/07/2003
• Est. Priority Date: 01/23/2001
• Status: Active Grant

• Current Assignee: Versum Materials US Inc.
• Original Assignee: Air Products and Chemicals Incorporated (Linde Plc)
• Inventors: Lal, Gauri Sankar, Hayes, Kathryn Sue, Klauck-Jacobs, Axel, Casteel, William, Taege, Reiner
• Granted Patent: US 6,894,200 B2
• Time in Patent Office: Days
• US Class Current: 570/143
• CPC Class Codes: C07B 39/00 Halogenation
• CPC Class Codes: C07C 17/18 of oxygen atoms of carbonyl groups
• CPC Class Codes: C07C 17/23 by dehalogenation
• CPC Class Codes: C07C 23/18 Polycyclic halogenated hydrocarbons
• CPC Class Codes: C07C 25/22 with condensed rings
• CPC Class Codes: C07C 45/512 the singly bound functional group being a free hydroxyl group
• CPC Class Codes: C07C 49/697 containing six-membered aromatic rings

Abstract

A method of preparing vicinal difluoro aromatic compounds in high yield from hydroxy aromatic compounds using various bases and a method of preparing intermediates thereof. A method for making a vicinal difluoro halogenated aromatic compound including providing a tetrafluoro derivative of a halogen substituted aromatic compound, wherein the tetrafluoro derivative has two fluorine atoms on each of two adjacent carbons and at least one additional halogen substituent; reacting the tetrafluoro derivative with a reducing agent in presence of a base for a reaction time sufficient to form the vicinal difluoro halogenated aromatic compound containing two vicinal fluorine substituents and the at least one additional halogen substituent, wherein the reducing agent is used in a reducing agent effective amount sufficient to retain the at least one additional halogen substituent.

Claims

1. A method for making an aromatic compound having two vicinal fluorine atoms comprising:

mixing a tetrafluoro derivative of an aromatic compound with a reducing agent in a presence of a base for a time needed to form an aromatic compound containing two vicinal fluorine atoms, said tetrafluoro aromatic compound having two fluorine atoms on each of two adjacent carbons on the ring.

2. The method of claim 1, wherein the tetrafluoro derivative of a halogen substituted aromatic compound is mixed with an organic solvent.

3. The method of claim 2, wherein said organic solvent is a member selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, acetonitrile, ethanol, and dimethylformamide.

4. The method of claim 1, wherein the base is ammonium hydroxide, hydroxylamine, hydrazine, or a substituted ammonium hydroxide.

5. The method of claim 4, wherein the substituted ammonium hydroxide is a member selected from the group consisting of tetramethylammonium hydroxide, ethyl ammonium hydroxide, and benzyltrimethyl ammonium hydroxide.

6. The method of claim 5, wherein the substituted ammonium hydroxide is tetramethylammonium hydroxide.

7. The method of claim 4, wherein the base is buffered to maintain a pH below 14.

8. The method of claim 1, wherein the reducing agent is present at −

25 to 90°

C.

9. The method of claim 1, wherein the aromatic compound having two vicinal fluorine atoms is a vicinal difluoro halogenated aromatic compound.

10. A method for making aromatic compounds having two vicinal fluorine atoms comprising:

(a) mixing an electrophilic fluorinating agent with a solution or suspension of a hydroxy aromatic compound in a polar aprotic solvent to form a difluoroketone derivative of an aromatic compound, said hydroxy aromatic compound having one, two or three rings, said rings being separate or fused and said rings optionally containing one or more heteroatoms and one or more substitutions in addition to hydroxy, said difluoroketone derivative having both fluorine atoms on a carbon vicinal to the ketone;

(b) mixing a deoxofluorinating agent with the difluoroketone derivative of (a) in a second solvent to form a tetrafluoro derivative of an aromatic compound; and

(c) mixing the tetrafluoro derivative of an aromatic compound of (b) with a reducing agent in a presence of a base to form an aromatic compound containing two vicinal fluorine atoms.

11. The method of claim 10, wherein the tetrafluoro derivative of a halogen substituted aromatic compound is mixed with an organic solvent.

12. The method of claim 11, wherein said organic solvent is a member selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, acetonitrile, ethanol, and dimethylformamide.

13. The method of claim 10, wherein the base is ammonium hydroxide, hydroxylamine, hydrazine, or a substituted ammonium hydroxide.

14. The method of claim 13, wherein the substituted ammonium hydroxide is a member selected from the group consisting of tetramethylammonium hydroxide, ethyl ammonium hydroxide, and benzyltrimethyl ammonium hydroxide.

15. The method of claim 13, wherein the base is buffered to maintain a pH below 14.

16. The method of claim 10, wherein the aromatic compound having two vicinal fluorine atoms is a vicinal difluoro halogenated aromatic compound.

17. A method for making a vicinal difluoro halogenated aromatic compound, said method comprising:

providing a tetrafluoro derivative of a halogen substituted aromatic compound, wherein the tetrafluoro derivative has two fluorine atoms on each of two adjacent carbons and at least one additional halogen substituent; and

reacting the tetrafluoro derivative with a reducing agent in presence of a base for a reaction time sufficient to form the vicinal difluoro halogenated aromatic compound containing two vicinal fluorine substituents and the at least one additional halogen substituent, wherein the reducing agent is used in a reducing agent effective amount sufficient to retain the at least one additional halogen substituent.

18. The method of claim 17, wherein the tetrafluoro derivative of a halogen substituted aromatic compound is mixed with an organic solvent.

19. The method of claim 18, wherein said organic solvent is a member selected from the group consisting of tetrahydrofuran, methyl tert-butyl ether, acetonitrile, ethanol, and dimethylformamide.

20. The method of claim 19, wherein the organic solvent is tetrahydrofuran.

21. The method of claim 17, wherein the base is ammonium hydroxide, hydroxylamine, hydrazine, or a substituted ammonium hydroxide.

22. The method of claim 21, wherein the substituted ammonium hydroxide is a member selected from the group consisting of tetramethylammonium hydroxide, ethyl ammonium hydroxide, and benzyltrimethyl ammonium hydroxide.

23. The method of claim 21, wherein the base is buffered to maintain a pH below 14.

24. The method of claim 17, wherein the tetrafluoro derivative of the halogen substituted aromatic compound is one or more of a substituted or unsubstituted tetrafluoro derivative of a halogenated naphthalene, a halogenated phenanthrene, a halogenated monocyclic aromatic, a halogenated bicyclic aromatic, a halogenated tricyclic aromatic, or a halogenated heterocyclic aromatic having one to three rings.

25. The method of claim 24, wherein the tetrafluoro derivative of the halogen substituted aromatic compound is 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene or 6-chloro-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene and the vicinal difluoro halogenated aromatic compound is 6-bromo-1,2-difluoronaphthalene or 6-chloro-1,2-difluoronaphthalene.

26. The method of claim 17, wherein the at least one additional halogen substituent is a member selected from the group consisting of Cl, Br, I, and F.

27. The method of claim 17, wherein the vicinal difluoro halogenated aromatic compound is provided in a yield of at least 80%.

28. The method of claim 17, wherein the reducing agent effective amount is from about 1 to less than 8 times a molar equivalent of the tetrafluoro derivative.

29. The method of claim 28, wherein the reducing agent effective amount is less than 2.5 times the molar equivalent of the tetrafluoro derivative.

30. The method of claim 28, wherein the reducing agent is zinc, copper, magnesium, or mixtures thereof.

31. The method of claim 30, wherein the reducing agent is zinc.

32. The method of claim 21, wherein the ammonium hydroxide is buffered with ammonium chloride to maintain a pH of less than 11.

33. The method of claim 17, wherein the reducing agent is present at a temperature from about −

25°

C. to about 90°

C.

34. The method of claim 33, wherein the temperature is from about 0°

C. to about 25°

C.

35. A method for making a vicinal difluoro halogenated aromatic compound, said method comprising:

(a) mixing an electrophilic fluorinating agent with a solution or suspension of a halogen substituted hydroxy aromatic compound in a polar aprotic solvent to form a difluoroketone derivative of the halogen substituted hydroxy aromatic compound, said halogen substituted hydroxy aromatic compound having one, two or three rings, said rings being separate or fused and said rings optionally containing one or more heteroatoms and one or more substitutions in addition to hydroxy and halogen, said difluoroketone derivative having both fluorine atoms on a vicinal carbon adjacent to a ketone carbon;

(b) mixing a deoxofluorinating agent with the difluoroketone derivative in a presence of a solvent to form a tetrafluoro derivative of the halogen substituted hydroxy aromatic compound, said tetrafluoro derivative having two fluorine atoms on each of the vicinal carbons; and

(c) mixing the tetrafluoro derivative of the halogen substituted aromatic compound with a reducing agent in a presence of a base for a reaction time sufficient to form the vicinal difluoro halogenated aromatic compound containing two vicinal fluorine substituents and at least one additional halogen substituent, wherein the reducing agent is used in a reducing agent effective amount sufficient to retain the at least one additional halogen substituent.

36. The method of claim 35, wherein the tetrafluoro derivative of a halogen substituted hydroxy aromatic compound is mixed with an organic solvent.

37. The method of claim 36, wherein the polar aprotic solvent is dimethylformamide, the solvent is toluene or HF, and the organic solvent is tetrahydrofuran.

38. The method of claim 35, wherein the deoxofluorinating agent is bis-(2-methoxyethyl) aminosulfur trifluoride or SF₄.

39. The method of claim 35, wherein the at least one additional halogen is at least one halogen selected from the group consisting of Cl, Br, I, and F.

40. The method of claim 35, wherein the reducing agent is zinc, magnesium, copper, or mixtures thereof.

41. The method of claim 40, wherein the reducing agent is zinc.

42. The method of claim 35, wherein the base is ammonium hydroxide, hydroxylamine, hydrazine, or a substituted ammonium hydroxide.

43. The method of claim 42, wherein the substituted ammonium hydroxide is a member selected from the group consisting of tetramethylammonium hydroxide, ethyl ammonium hydroxide, and benzyltrimethyl ammonium hydroxide.

44. The method of claim 42, wherein the base is buffered to maintain a pH below 14.

45. The method of claim 42, wherein ammonium hydroxide is buffered with ammonium chloride to maintain a pH of less than 11.

46. The method of claim 35, wherein the reducing agent effective amount is from about 1 to less than 8 times a molar equivalent of the tetrafluoro derivative.

47. The method of claim 46, wherein the reducing agent effective amount is less than 2.5 times the molar equivalent of the tetrafluoro derivative.

48. The method of claim 35, wherein the reducing agent is present at a temperature from about −

25°

C. to about 90°

C.

49. The method of claim 35, wherein the temperature is from about 0°

C. to about 25°

C.

50. The method of claim 35, wherein the vicinal difluoro halogenated aromatic compound is provided in a yield of at least 60%.

51. A method for making a vicinal difluoro halogenated aromatic compound, said method comprising:

(a) mixing a deoxofluorinating agent with a difluoroketone derivative of a halogen substituted hydroxy aromatic compound in the presence of a solvent to form a tetrafluoro derivative of the halogen substituted hydroxy aromatic compound, said difluoroketone compound having one, two or three rings, said rings being separate or fused and said rings optionally containing one or more heteroatoms and one or more substitutions in addition to halogen, said difluoroketone derivative having both fluorine atoms on a vicinal carbon adjacent to a ketone carbon;

(b) mixing the tetrafluoro derivative of the halogen substituted aromatic compound with a reducing agent in a presence of a base for a reaction time sufficient to form the vicinal difluoro halogenated aromatic compound containing two vicinal fluorine substituents and at least one additional halogen substituent, wherein the reducing agent is used in a reducing agent effective amount sufficient to retain the at least one additional halogen substituent.