Dedicated to the Bayer company on the occasion of its 150th anniversaryThe synthesis of specifically substituted pyridines is a permanent challenge since new derivatives of this class of heterocycles are required as building blocks for supramolecular chemistry, as components of new materials, and also in pharmaceutical science.[1]4-(Dimethylamino)pyridine (DMAP) (1) is a frequently used basic catalyst in many important synthetic transformations, [2] but it also strongly stabilizes nanoparticles by coordination of the Lewis basic nitrogen to the metal surface.[3] Due to our interest in multivalent ligands [4] we set out to synthesize divalent analogues of 1, in particular, compounds 2 and 3 (Scheme 1).[5] Whereas compound 2 was available in moderate yield by the nucleophilic substitution of 4-chloropyridine employing the appropriate diamine, the chiral divalent compound 3 with a more rigid backbone could not be prepared. Neither were the nucleophilic substitutions of 4-halopyridines with trans-1,2-diaminocyclohexane in the presence or absence of palladium catalysts successful, [6] nor were reactions with 4-(methylamino)pyridine as the nucleophile in its reactions with difunctionalized cyclohexane derivatives. [5] The high steric hindrance seems to hamper these substitution reactions.Thus we developed a new synthetic strategy for the preparation of 3 based on two key reactions: nucleophilic substitution of the (oligo)fluorinated pyridines [7] and subsequent conversion of CÀF into CÀH bonds by catalytic hydrodefluorination (HDF). [8,9] The strong electron-withdrawing effect of the fluorine substituents in fluorinated pyridine derivatives allows the selective substitution of fluoride by nucleophiles at the 4-or 2-/6-positions of the heterocyclic ring.[7] Hence 4-aminopyridine derivatives with additional fluorine substituents on the ring are easily accessible [10] and serve as potential precursors for compounds such as 2 and 3. The catalytic hydrodefluorination (HDF), that is, the conversion of CÀF into CÀH bonds, has been extensively studied; [8] however, due to the high cost of most reagents and catalysts as well as limitations in the substrate scope it is scarcely used for synthetic applications.[9] Our synthetic strategy to prepare hitherto inaccessible aminopyridine derivatives used the detour employing the nucleophilic aromatic substitution to create the CÀN bond followed by catalytic HDF. For this purpose we used the [Cp 2 TiF 2 ]/ diphenylsilane system, recently developed for the defluorination of fluoroalkenes. [11,12] To prove the viability of the catalytic HDF of fluorinated aminopyridines, we used 2,3,5,6-tetrafluoro-4-morpholinopyridine (4) as a model substrate in 1,4-dioxane as the solvent (Scheme 2). Under optimized conditions at temperatures between 90 to 110 8C with 15 mol % of the precatalyst we obtained the twofold hydrodefluorinated product 6 in 95 % yield. These conditions allow the regioselective substitution of the more reactive fluorine atoms at C-2 and C-6.[7] Lower loadings of the precatalyst...

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.

We describe a novel approach to highly functionalized ferrocenyl-substituted pyridine derivatives. Key reaction is the cyclocondensation of an easily available β-ketoenamide bearing an N-ferrocenylcarbonyl group. The resulting 4-hydroxypyridine derivatives were converted into the corresponding pyrid-4-yl nonaflates, which were employed in a range of palladium-catalyzed coupling reactions. The reaction sequence delivers a library of new 2-ferrocenyl-substituted pyridine derivatives, including compounds with two ferrocene moieties, a butadiyne derivative, a 2,4-bisferrocenylpyr-

A series of mono- and divalent fluorinated pyridine derivatives is investigated by electrospray ionization (tandem) mass spectrometry and quantum chemical calculations with respect to their capability to bind anions in the gas phase. The pyridine derivatives differ not only in valency, but also with regard to the degree of fluorination of the pyridine rings, the positions of the fluorine atoms, the rigidity of the spacers connecting the two pyridines in the divalent compounds, and the relative configuration. While the monovalent compounds did not form anion complexes, the divalent analogues exhibit anion binding even to weakly coordinating anions such as tetrafluoroborate. Three different tandem mass spectrometric experiments were applied to rank the gas-phase binding energies: (i) collision-induced dissociation (CID) experiments in a Fourier transform ion-cyclotron-resonance (FTICR) mass spectrometer on two different, simultaneously mass-selected complexes with different receptors, (ii) determination of the collision energy required to fragment 50 % of the mass-selected complexes in an ESI-QToF mass spectrometer, and (iii) CID of heterodimers formed from two different, competing pyridine receptors and indigo carmine, a dianion with two identical binding sites. All three experiments result in consistent binding energy ranking. This ranking reveals surprising features, which are not in agreement with binding through anion-π interactions. Density functional theory (DFT) calculations comparing different potential binding modes provide evidence that the ranking can instead nicely be explained, when C-H⋅⋅⋅anion interactions with the spacers are invoked. These results are supported by gas-phase IR spectroscopy and ion mobility-mass spectrometry (IM-MS) on a selected set of chloride pyridine complexes.

Fluor macht's möglich! Die regioselektive nucleophile Substitution von (Oligo)fluorpyridinen mit geeigneten Aminen und nachfolgende katalytische Hydrodefluorierung ebnen den Weg zu bisher unzugänglichen Aminopyridinen, die als neue Liganden von Interesse sind. Bis zu vier Fluoratome werden in einem Schritt mithilfe eines kostengünstigen Titankatalysators regioselektiv entfernt.