Selective Catalytic Hydrodefluorination as a Key Step for the Synthesis of Hitherto Inaccessible Aminopyridine Derivatives

Abstract

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...

To Anion–π or not to Anion–π: The Case of Anion‐Binding to Divalent Fluorinated Pyridines in the Gas Phase

“…This approach is exemplified by the reactions leading to compounds M4 , M8 , DC1 , DC2 and D5 (Figure ). Pentafluoropyridine and dimethylamine react to provide exclusively the 4‐amino‐substituted pyridine derivative M8 that was exposed to a novel titanocenium‐catalyzed hydrodefluorination reaction . Target compound M4 was regioselectively obtained in good overall yield [Eq.…”

“…The experimentally studied 4-aminopyridine receptors were prepared by nucleophilic substitution at the 4-positiono fp entafluoropyridine or 2,4,6-trifluoropyridine followed by regioselective defluorination or N-methylation. [18] This approach is exemplified by the reactions leading to compounds M4, M8, DC1, DC2 and D5 (Figure 2). Pentafluoropyridine and dimethylamine react to provide exclusivelyt he 4-amino-substituted pyridine derivative M8 that was exposed to an ovel titanocenium-catalyzed hydrodefluorination reaction.…”

Activation and Formation of Aromatic C–F Bonds

“…In 2013, Reissig et al described an example of catalytic hydrodefluorination with a [Cp 2 TiF 2 ] diphenyl silane system for access to amino pyridine derivatives [58]. This titanium system was based on a related system for catalytic hydrodefluorination of alkenes [59].…”

“…49). Complexes (55), (56), (58), and (59) were later determined to show catalytic reactivity with various aryl-substituted boronic acids affording new polyfluorinated building blocks. (62) in a distorted square planar orientation (Eq.…”

Organocatalytic C−F Bond Activation with Alanes

“…Only a few examples of early transition metal catalyzed processes are known; for example, Rosenthal described the catalytic hydrodefluorination of pentafluoropyridine by a zirconium‐hydrido‐complex and diisobutylaluminum hydride (DIBAL, Scheme ) . In addition, the titanium‐catalyzed HDF offers great opportunities in organic synthesis …”