Coupling process for generating reactive boron-containing derivatives of N-substituted pyrrole-2-carbonitriles to produce biaryls
A convenient preparation of boron-containing compounds, borate salts, pyrrolecarbonitrile boron-containing compounds, N-substituted-pyrrole-2-carbonitrile boron-containing compounds, and derivatives thereof is provided. The present invention also provides for the use of these boron-containing compounds and derivatives thereof in coupling reactions to provide bi-aryl compounds.
1. A method for preparing 2-cyanopyrrole borate salts comprising combining:
(a) a boron agent of the formula:
(i) B(OR 1 )(OR 2 )OR 3 ), wherein:
R 1 , R 2 , and R 3 are, independently, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, or substituted C 3 to C 8 cycloalkyl; or
(ii) B(R 4 )(R 5 )(R 6 ), wherein:
R 4 ,R 5 ,and R 6 are, independently, halogen, C 1 to C 6 alkyl, or substituted C 1 to C 6 alkyl;
(b) a substituted 2-cyanopyrrole of the formula I:
wherein:
R 7 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or COR A ;
R A is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;
Q a is H, OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ;
a is 0 to 2;
R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl; and
(c) a strong non-nucleophilic base.
2. A method for preparing 2-cyanopyrrole (i) boronic esters or borinic esters of formulae (A) or (B):
(ii)boron compounds of formulae (C) or (D):
(iii) salts thereof of formulae (B), (F), (G), or H):
wherein:
R 1 , R 2 , and R 3 are, independently, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, hetero(C 1 to C 6 )alkyl, or substituted hetero(C 1 to C 6 )alkyl;
R 4 ,R 5 , and R 6 are, independently, halogen, C 1 to C 6 alkyl, or substituted C 1 to C 6 alkyl;
R 7 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or COR A ;
Q is OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ;
a is 0 to 2;
CC + is a countercation;
comprising reacting:
(b) a boron agent of the formula:
(i) B(OR 1 )(OR 2 )(OR 3 ), wherein:
and R 1 , R 2 , and R 3 are, independently, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, hetero (C 1 to C 6 ) alkyl, or substituted hetero (C 1 to C 6 ) alkyl; or
(ii) B(R 4 )(R 5 )(R 6 ), wherein:
R 4 , R 5 , and R 6 are, independently, halogen, C 1 to C 6 alkyl, or substituted C 1 to C 6 alkyl;
(b) a substituted 2-cyanopyrrole of formula I:
wherein:
R 7 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or COR A ;
R A is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;
Q is OH NH 2 ,CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ;
a is 0 to 2;
R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 amninoalkyl, or substituted C 1 to C 6 amninoalkyl; and
(c) a strong non-nucleophilic base.
3. The method according to claim 2 , wherein R 1 , R 2 , and R 3 are selected from the group consisting of C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, and hetero (C 1 to C 6 ) alkyl.
4. The method according to claim 3 , wherein R 1 , R 2 , and R 3 are isopropyl.
5. The method according to claim 2 , wherein said 2-cyanopyrrole is of the structure:
6. The method according to claim 2 , wherein said strong non-nucleophilic base is lithium diisopropyl amine.
7. The method according to claim 2 , wherein said 2-cyanopyrrole boronic ester, boronic ester salt, borinic ester, or borinic ester salt is selected from the group consisting of:
8. A product prepared according to the method of claim 2 .