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 of preparing 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-methyl-pyrrole-2-carbonitrile comprising:
(a) reacting 1-methyl-pyrrole-2-carbonitrile, lithium di-isopropylamide and tri-isopropylborate;
(b) reacting the product of step (a) with 6-bromo-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, potassium carbonate, and a soluble palladium (0) catalyst;
(c) washing the 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-methyl-pyrrole-2-carbonitrile with water and THF;
(d) adjusting the pH of the product of step (c) to 4 to 5;
(e) adding L-cysteine to the product of step (d);
(f) removing excess cysteine;
(g) exchanging the THF for toluene;
(h) precipitating the product of step (g); and
(i) drying the purified 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-methyl-pyrrole-2-carbonitrile; and
(j) reacting said purified 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-methyl-pyrrole-2-carbonitrile and Lawesson's reagent.
2. The method according to claim 1 , further comprising:
(a) forming a salt of 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-methyl-pyrrole-2-carbonitrile;
(b) acidifying the product of step (a);
(c) dissolving the product of step (b) in acetone;
(d) precipitating the product of step (c); and
(e) drying the product of step (d).
3. The method according to claim 2 , wherein step (a) is performed with potassium t-butoxide.