Studies on the Synthesis of Specifically Fluorinated 4‐Amino‐ pyridine Derivatives by Regioselective Nucleophilic Aromatic Substitution and Catalytic Hydrodefluorination

Abstract

AbstractThe reactions of pentafluoropyridine and 2,4,6‐trifluoropyridine with a series of primary and secondary amines were studied. Whereas the nucleophilic aromatic substitution of pentafluoropyridine occurs with high regioselectivity in all cases, providing the expected 4‐aminopyridine derivatives in excellent yields, the regioselectivity of 2,4,6‐trifluoropyridine is dependent on the steric hindrance of the attacking nucleophile. Small nucleophiles such as morpholine attack the 4‐position of the pyridine ring with high preference, but more bulky diamines attack the 2‐ and 4‐positions leading to the formation of three regioisomeric products. (R,R)‐1,2‐Diaminocyclohexane as moderately bulky diamine reacted with 2,4,6‐trifluoropyridine to afford the desired bis(4‐aminopyridinyl)cyclohexane derivative in 30% yield. For hydrodefluorination two methods were examined. A two‐step procedure employing hydrazine and subsequently copper(II) sulfate removed just one fluorine substituent, but is not sufficiently high yielding for the reduction of more complex substrates. With the system titanocene difluoride as pre‐catalyst and diphenylsilane as reducing agent we were able to selectively remove fluorine substituents at positions C‐2 and C‐4 of a variety of 4‐aminopyridine derivatives. This protocol allows the synthesis of compounds such as the divalent chiral 4‐(dimethylamino)pyridine (DMAP) analogue (R,R)‐trans‐N,N′‐dimethyl‐N,N′‐bis(pyridin‐4‐yl)cyclohexane‐1,2‐diamine with fair overall yield.magnified image