Phosphine reagents for azine fluoroalkylation
AssigneeColorado State University Research Foundation
InventorsAndrew McNally, Kyle Nottingham, Chirag Patel, Jeffrey Levy, Xuan Zhang
Life of this patent
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Abstract
A new set of bench-stable fluoroalkylphosphines that directly convert C—H bonds in pyridine building blocks, drug-like fragments, and pharmaceuticals, into fluoroalkyl derivatives. No pre-installed functional groups or directing motifs are required. The reaction tolerates a variety of sterically and electronically distinct pyridines and is exclusively selective for the 4-position in most cases. The reaction proceeds via initial phosphonium salt formation followed by sp2-sp3 phosphorus ligand-coupling, an underdeveloped manifold for C—C bond formation.
Claims20
A phosphine compound of Formula I:
- wherein
- X is H, F, —(C1-C6)perfluoroalkyl, or —(C1-C6)alkyl;
- R1 and R2 are each independently NRaRb, ORc, SRd, —(C3-C6)cycloalkyl, or —(C1-C6)alkyl;
- Ra and Rb are each independently H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- or
- Ra and Rb taken together form a 5-membered or 6-membered heterocycle with the nitrogen moiety of NRaRb;
- Rc and Rd are each independently H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- and
- m and n are each independently 1 or 2;
- each —(C1-C6)alkyl is independently unbranched or branched, and optionally substituted;
- and
- X is not F when R1 and R2 are CH3;
- and X is not F when R1 and R2 are OCH3, R1 and R2 are each in the para-position, and m and n are each 1.
A method for fluoroalkylation of an organic compound comprising:
- a) contacting a phosphine compound of Formula I:
- wherein
- X is H, F, —(C1-C6)perfluoroalkyl, or —(C1-C6)alkyl;
- R1 and R2 are each independently NRaRb, ORc, SRd, —(C3-C6)cycloalkyl, or —(C1-C6)alkyl;
- Ra and Rb are each independently H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- or
- Ra and Rb taken together form a 5-membered or 6-membered heterocycle with the nitrogen moiety of NRaRb;
- Rc and Rd are each independently H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- and
- m and n are each independently 1 or 2;
- wherein each —(C1-C6)alkyl is independently unbranched or branched, and optionally substituted;
- an organic compound, and a solvent, under suitable reaction conditions to form a phosphonium salt of the organic compound;
- and
- b) contacting the phosphonium salt and an aqueous solution or a mixture of an organic solvent and a base;
- wherein optionally the phosphonium salt is not isolated as a purified intermediate compound before contacting the intermediate with the aqueous solution;
- wherein a fluoroalkylated organic compound is thereby formed.
Dependencies are inferred from the claim text.