Methods for forming protected organoboronic acids
Described are methods of forming protected boronic acids that provide in a manner that is straightforward, scalable, and cost-effective a wide variety of building blocks, such as building blocks containing complex and/or pharmaceutically important structures, and/or provide simple or complex protected organoboronic acid building blocks. A first method includes reacting an imino-di-carboxylic acid and an organoboronate salt. A second method includes reacting a N-substituted morpholine dione and an organoboronic acid.
1. A method of forming a protected boronic acid, comprising:
reacting in a reaction mixture
a N-substituted morpholine dione, and
an organoboronic acid represented by formula (XII):
R 1 —B(OH) 2 (XII),
wherein
R 1 is an organic group, and
the reaction mixture further comprises a polar aprotic solvent; and
thereby forming a protected organoboronic acid represented by formula (III) in the reaction mixture:
where R 10 represents an organic group, and
R 11 , R 12 , R 13 and R 14 independently are selected from the group consisting of a hydrogen group and an organic group.
2. The method of claim 1 , wherein R 1 is an alkyl group, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, or a combination of at least two of these groups.
3. The method of claim 1 , wherein R 1 is represented by formula (IV):
Y—R 5 —(R 6 ) m — (IV),
wherein
Y is a halogen group or a pseudohalogen group;
R 5 is an aryl group or a heteroaryl group;
R 6 is an alkyl group, a heteroalkyl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, or a combination of at least two of these groups; and
m is 0 or 1.
4. The method of claim 3 , wherein R 5 is a heteroaryl group.
5. The method of claim 1 , wherein R 1 is a heterocyclic group, an alkynyl group or an alkenyl group.
6. The method of claim 5 , wherein said heterocyclic group is selected from the group consisting of pyridine, indole, isoindole, indazole, purine, indolizidine, quinoline, isoquinoline, quinazoline, pteridine, quinolizidine, pyrrole, pyrazine, pyridazine, pyrimidine, imidazole, pyrasole, isoxazole, oxazole, thiazole, benzthiazole, furan, benzofuran, thiophene and benzothiophene.
7. The method of claim 1 , wherein R 1 is a 2-heterocyclic group selected from the group consisting of 2-pyridyl, 2-indolyl, 2-isoindolyl, 2-indazolyl, 2-purinyl, 2-indolizidinyl, 2-quinolinyl, 2-isoquinolinyl, 2-quinazolinyl, 2-pteridinyl, 2-quinolizidinyl, 2-pyrrolyl, 2-pyrazinyl, 2-pyridazinyl, 2-pyrimidinyl, 2-imidazolyl, 2-pyrasolyl, 2-isoxazolyl, 2-oxazolyl, 2-thiazolyl, 2-benzthiazolyl, 2-furyl, 2-benzofuryl, 2-thiophenyl, and 2-benzthiophenyl.
8. The method of claim 1 , wherein R 10 is methyl, and each of R 11 , R 12 , R 13 and R 14 is hydrogen.
9. The method of claim 1 , wherein the polar aprotic solvent is selected from the group consisting of tetrahydrofuran (THF), dioxane, acetonitrile, dimethyl formamide (DMF), toluene and xylene.
10. The method of claim 1 , wherein the polar aprotic solvent is THF.
11. The method of claim 1 , wherein the reaction mixture is maintained at a temperature of from 40° C. to 100° C.