Metal-catalyzed coupling of aryl and vinyl halides with alpha, alpha-difluorocarbonyl compounds

Patent metadata

Field	Value
Publication number	US-9598340-B2
Application number	US-201414782402-A
Country	US
Kind code	B2
Filing date	Apr 7, 2014
Priority date	Apr 5, 2013
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The coupling of aryl, heteroaryl, and vinyl halides with α,α-difluoroketones or silyl ethers or siylenol ethers of α,α-difluoroketones and α,α-difluoroamides and esters are described. Further derivatization of the coupling products (such as ketone cleavage and Baeyer-Villiger oxidation) is also described.

First claim

What is claimed is:

1. A composition comprising:
(i) a precursor compound having the formula
R P —X L ,

wherein R P is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted vinyl; and X L is a member selected from Cl, Br, and I;
(ii) an α,α-difluoro synthon having a formula selected from:

wherein R F is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl substituted or unsubstituted heteroalkyl OR z1 and NR z2 R z3 ,
R F1 is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
wherein R z1 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and acyl; and
R z2 and R z3 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, acyl and sulfonyl, and R z2 and R z3 , together with the nitrogen to which they are attached, are optionally joined to form a 4-8 membered ring, which is a substituted or unsubstituted heterocycloalkyl or heteroaryl ring system;
Z o is selected from H or Si(R 30 ) 3 , in which each R 30 is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl substituted or unsubstituted alkoxy, halogen, amino, and two or more of R 30 , together with the Si atom to which they are attached are optionally joined to form a 4-8-membered ring,
wherein, Z o is Si(R 30 ) 3 , the silicon enolate can have Si bound to a member selected from the alpha carbon, oxygen or a combination thereof; and
R s1 , R s2 , and R s3 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unubstituted heteroalkyl, substituted or unubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
(iii) a complex comprising palladium and a ligand, wherein said ligand comprises a trialkylphosphine moiety, wherein, when R F is substituted or unsubstituted aryl at least one of the alkyl groups of said trialkylphosphine is not a tertiary alkyl group; and
(iv) a base.

2. The composition according to claim 1 , wherein said complex is present in said composition in an amount of less than 10 mol % relative to said α,α-difluoromethyl synthon.

3. The composition according to claim 1 , wherein said complex is present in said composition in an amount of less than 10 mol % relative to said silyl enol ether.

4. The composition according to claim 1 , wherein said composition does not contain Bu 3 SnF.

5. The composition according to claim 1 , wherein said composition does not contain an organotin reagent.

6. The composition according to claim 1 , wherein R s1 , R s2 , and R s3 are independently selected from unsubstituted C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkyl.

7. The composition according to claim 6 , wherein one or more of R s1 , R s2 , and R s3 are methyl.

8. The composition according to claim 1 , further comprising a solvent.

9. The composition according to claim 1 , wherein said complex has the formula:

wherein
X c is a halogen or sufonate; and
R c1 , R c2 , and R c3 are independently selected from substituted or unsubstituted branched hydrocarbon and substituted or unsubstituted carbocycle.

10. The composition according to claim 1 , wherein said precursor compound has the formula:

wherein
R 4 , R 5 , R 6 , R 7 , and R 8 are independently members 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 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 and R 10 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 R 9 and R 10 , 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; and
X L is a member selected from Cl, Br, and I.

11. The composition according to claim 1 , wherein R P is a member selected from substituted or unsubstituted five-membered heterorayl and substituted or unsubstituted six-membered heteroaryl.

12. The composition according to claim 1 , wherein said precursor compound has the formula:

wherein
R 11 , R 12 , and R 13 are independently members 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 SO 2 R 10 and —NO 2 , wherein two or more of R 11 , R 12 , and R 13 , 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 and R 10 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 R 9 and R 10 , together with the atoms to which they are bonded, are optionally joined to form a 5- to 7-membered ring.

13. The composition according to claim 1 , wherein said complex is generated in situ.

14. A method of forming a compound having the formula:

wherein
R F is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstitu

Assignees

• Univ California

Inventors

• Hartwig John F
• Ge Shaozhong
• Chaładaj Wojciech

Classifications

• B01J23/44

  Palladium · CPC title

• C07D317/16

  Radicals substituted by halogen atoms or nitro radicals · CPC title

• C07D295/104

  with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C269/06

  by reactions not involving the formation of carbamate groups · CPC title