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

Abstract

The 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.

Adsorption of Mono- and Divalent 4-(Dimethylamino)pyridines on Gold Surfaces: Studies by Surface-Enhanced Raman Scattering and Density Functional Theory

“…This type of nucleophilic substitution could not be applied to the corresponding 1,2- or 1,3-dihaloalkanes . For di-DMAP-2, an alternative multistep route was developed involving a catalytic hydrodefluorination of the easily available tetrafluoro-substituted compound …”

Effect of the pendent groups on biobased polymers, obtained from click chemistry suitable, for the adsorption of organic pollutants from water

“…The first step of the strategy, outlined in Scheme 1, requires the synthesis of 4‐substituted tetrafluoropyridine via nucleophilic aromatic substitution of pentafluoropyridine (1) with morpholine. The reaction was carried out in the presence of Et 3 N in THF, as reported in the literature, 51,62 giving a white crystal of 4‐morpholino‐tetrafluoropyridine (2) in 78% yield. Upon treatment of 4‐morpholine‐tetrafluoropyridine (2) with an excess (molar ratio 1:4) of sodium azide in DMF at 100°C for 7 h afforded 4‐morpholino‐2,6‐diazido‐3,5‐difluoropyridine (3) in modest isolated yield (71%).…”

Regioselective C–F Bond Activation/C–C Bond Formation between Fluoropyridines and Cyclopropyl Groups at Zirconium

“…Reactions a and b summarize the regioselectivity of formal oxidative C–F addition at titanocene and zirconocene complexes, respectively, with titanium giving selectivity for position 2, whereas zirconium is selective for position 4. In the presence of diphenylsilane, reduced difluorotitanocene catalyzes the HDF of fluoropyridines and related compounds with a significant preference for position 4, when available, not 2, pointing to the availability of different pathways. − The zirconium complex catalyzes the HDF of pentafluoropyridine with selectivity for position 4. Alanes serve as hydride sources and fluoride sinks .…”