Slow release of organoboronic acids in cross-coupling reactions

1. A method of performing a chemical reaction, comprising:

reacting in a reaction mixture

a compound selected from the group consisting of an organohalide and an organo-pseudohalide, and

a protected organoboronic acid represented by formula (I):

R 1 —B—T  (I);

where

R 1 represents a 2-pyridyl group,

T represents a conformationally rigid protecting group,

B represents boron having sp 3 hybridization,

a corresponding unprotected organoboronic acid is unstable by the boronic acid neat stability test, and

the reaction mixture further comprises a base having a pK B of at least 1, and a palladium catalyst; and

forming a cross-coupled product in the reaction mixture.

2. The method of claim 1 , where the protected organoboronic acid is represented by formula (IV):

where R 20 , R 21 , R 22 , R 23 and R 24 independently are selected from the group consisting of hydrogen and an organic group selected from the group consisting of an alkyl group, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, and any combination thereof.

3. The method of claim 2 , where R 20 is an organic group selected from the group consisting of an alkyl group, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, and any combination thereof.

4. The method of claim 3 , further comprising forming the protected organoboronic acid represented by formula (IV) by reacting the corresponding unprotected boronic acid with a N-substituted imino-di-carboxylic acid.

5. The method of claim 3 where the protected organoboronic acid is represented by formula (V):

6. The method of claim 1 , where, when the corresponding unprotected organoboronic acid is subjected to the boronic acid neat stability test, the number of moles of the unprotected boronic acid measured in a second NMR analysis is at most 80% of the number of moles of the unprotected boronic acid measured in a first NMR analysis.

7. The method of claim 1 , where, when the corresponding unprotected organoboronic acid is subjected to the boronic acid neat stability test, the number of moles of the unprotected boronic acid measured in a second NMR analysis is at most 50% of the number of moles of the unprotected boronic acid measured in a first NMR analysis.

8. The method of claim 1 , where the compound is selected from the group consisting of an aryl halide, a heteroaryl halide, an aryl pseudohalide and a heteroaryl pseudohalide.

9. The method of claim 8 , where the compound is selected from the group consisting of an unactivated aryl chloride and an unactivated heteroaryl chloride.

10. The method of claim 1 , where the base has a pK B of at least 1.5.

11. The method of claim 1 , where the base has a pK B of at least 3.

12. The method of claim 1 , where the base comprises an anion selected from the group consisting of [PO 4 ] 3− , [C 6 H 5 O] − , [CO 3 ] 2− and [HCO 3 ] 1− .

13. A method of performing a chemical reaction, comprising:

deprotecting in a reaction mixture a protected organoboronic acid represented by formula (I):

R 1 —B—T  (I);

where

R 1 represents a 2-pyridyl group,

B represents boron having sp 3 hybridization, and

T represents a conformationally rigid protecting group, and

the reaction mixture further comprises a base and a palladium catalyst,

to form a corresponding unprotected organoboronic acid that is unstable by the boronic acid neat stability test;

reacting in the reaction mixture the unprotected organoboronic acid and a compound selected from the group consisting of an organohalide and an organopseudohalide; and

forming a cross-coupled product in the reaction mixture;

where the time required for at least 90% of the protected organoboronic acid to be deprotected in the reaction mixture is at least equal to the time required for 90% of the cross-coupled product to be formed in the reaction mixture.

14. A method of performing a chemical reaction, comprising:

reacting in a reaction mixture

a compound selected from the group consisting of an organohalide and an organo-pseudohalide, and

a protected organoboronic acid represented by formula (I):

R 1 —B—T  (I);

where

R 1 represents a 2-pyridyl group,

T represents a conformationally rigid protecting group,

B represents boron having sp 3 hybridization, and

the reaction mixture further comprises a protic solvent, a base having a pK B of at least 1, and a palladium catalyst; and

forming a cross-coupled product in the reaction mixture.

15. The method of claim 14 , where the compound is selected from the group consisting of an unactivated aryl chloride and an unactivated heteroaryl chloride.

16. The method of claim 14 , where the protected organoboronic acid is represented by formula (IV):

where R 20 , R 21 , R 22 , R 23 , and R 24 independently are selected from the group consisting of a hydrogen group and an organic group.

17. The method of claim 16 , where R 20 comprises an organic group.

18. The method of claim 14 , where the protic solvent comprises an alcohol.

19. The method of claim 14 , where the reaction mixture further comprises a copper-containing compound.

20. The method of claim 14 , where the forming the cross-coupled product in the reaction mixture comprises maintaining the reaction mixture at a temperature of from 25° C. to 150° C. for a time of from 2 hours to 72 hours.

21. The method of claim 14 , where the yield of cross-coupled product in the reaction mixture is at least 50%.

22. The method of claim 14 , where the yield of cross-coupled product in the reaction mixture is at least 70%.