Oxygen-Fueled Iterative Hydride Transfer Driven by a Rigid Planar Architecture

Abstract

An iterative hydride reduction/oxidation process was promoted under ambient conditions by a quasi-planar iminium cation rigidified by two concatenated quinoline units. The iminium proton was fixed by hydrogen bonding from neighboring quinoline nitrogen atoms, rendering the imine highly susceptible to hydride reduction with weak reductants, e.g., 1,4-dihydropyridines. The thus-formed amine was readily oxidized by molecular oxygen to regenerate the quasi-planar iminium cation under ambient conditions. This process was exploited for catalytic oxidation of 1,4-dihydropyridines as well as 9,10-dihydroacridine to highlight an intriguing rigidity-driven catalysis.

Introduction

Imines featuring a carbon-nitrogen double bond are generally regarded as reactive electrophilic functional groups similar to carbonyls featuring a carbon-oxygen double bond. Owing to the trivalency of the nitrogen atom, the electrophilicity of imines can be manipulated by appended groups on the imine nitrogen, thereby providing broad opportunities to couple with nucleophiles of interest. This process is widely exploited to produce a myriad of amine products in both a racemic and stereoselective fashion. In contrast, the reverse reaction, amines to imines transformation, has received significantly less attention in organic synthesis and currently available options are limited. More than stoichiometric amounts of oxidants are typically required to fulfill high conversion, suffering from relatively poor functional group tolerance^1–9) (Fig. 1A).

Fig. 1. Prior Arts of Dehydrogenation of Amines to Imines

Recent advances provide a catalytic option for this process utilizing both heterogeneous and homogeneous transition metal complexes, albeit with the use of generally stoichiometric amounts of additives^10–15) (Fig. 1B). Given the sustained interest in photocatalysis over the last decade,^16–19) a growing number of examples for greener metal-free photocatalytic transformation of amines to imines were revealed to promote this transformation as a synthetically robust reaction manifold.^20–25) In this context, we came across an amine that was spontaneously converted to the corresponding imine under ambient conditions with dioxygen (Fig. 1C). The facilitated dehydrogenation of the amine to the imine proceeded in a synthetically useful timescale, which was productively coupled with hydride reduction of the imine in the same pot to render the catalytic oxidation of hydride donors. This unusual oxidative susceptibility of the amine likely originated from its unique quasi-planar rigid structure to favor the imine state over the amine state.

Results and Discussion

We previously reported the synthesis of TriQuinoline (TQ) as a miniaturized model of a nitrogen-doped graphitic material featuring an atomic size defect surrounded by three pyridinic nitrogen atoms²⁶⁾ (Fig. 2). The key precursor for TQ, diquinoline imine (DQ-Im), was sufficiently reactive in the following formal cycloaddition with n-butyl vinyl ether 1. The assumed intermediate, dihydroquinoline 3, however, was not observed at all, suggesting that DQ-Im played a pivotal role in accepting a hydride to produce TQ with concomitant formation of diquinoline amine (DQ-Am). Unexpectedly, DQ-Am underwent spontaneous dehydrogenation under ambient conditions to regenerate DQ-Im, and the reaction of DQ-Im and 1 converged to TQ as a final product. We reasoned that the unusual oxidative susceptibility of DQ-Am could be exploited to achieve catalytic oxidation of partially reduced heterocycles, e.g., 1,4-dihydropyridines and 9,10-dihydroacridines.

Fig. 2. Final Stage of the Synthesis of TriQuinoline (TQ) (TFA Is Omitted for Clarity)

We initiated our study with a detailed analysis of the oxidation process of DQ-Am. As an analytically pure sample of DQ-Am was unavailable due to its unstable nature, DQ-Im·trifluoroacetic acid (TFA) salt was used as a starting material to generate DQ-Am with 1 equivalent (equiv.) of Hantzsch ester 4a. The initial reaction instantaneously completed in CD₃OD (9.5 mM in initial DQ-Im·TFA) to afford DQ-Am and the regeneration of DQ-Im/H⁺ was traced by ¹H-NMR analysis²⁷⁾ (Fig. 3). The initial ¹H-NMR spectra 1 h after the addition of 4a indicated that 14% of DQ-Im/H⁺ was regenerated, culminating in full recovery of DQ-Im/H⁺ from DQ-Am within 12 h at 30 °C. Adding another 1 equiv. of 4a reproduced the identical hydride reduction/dehydrogenation process at an identical timescale. Three successive reduction/oxidation cycles were performed and the gradual coproduction of hydrogen peroxide was confirmed.²⁸⁾ The dioxygen-triggered hydrogen peroxide production suggested the involvement of a radical mechanism, which was further supported by the fact that adding 2 equiv. of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) prevented the regeneration of DQ-Im·TFA from DQ-Am (Fig. 4A). The unusual spontaneous dehydrogenation of DQ-Am to DQ-Im·TFA is presumably due to their unique quasi-planar molecular architecture. Indeed, amine 5, an acyclic counterpart of DQ-Am, was synthesized in a straightforward procedure and sufficiently thermodynamically stable to be isolated in an analytically pure form. In contrast to DQ-Am, 5 gave no indication of oxidation to afford corresponding imine 6 was observed even after 48 h of exposure to an oxygen atmosphere²⁹⁾ (Fig. 4B). The reaction in the dark was barely retarded the regeneration of DQ-Im·TFA, thereby the possibility that DQ-Am or DQ-Im might work as a photocatalyst was ruled out. Based on the observations described above, we delineated the proposed mechanism of the DQ-Im/DQ-Am cycle as shown in Fig. 4C. The proton located at the center of DQ-Im·TFA was observed at 20.4 ppm in ¹H-NMR (CD₃CN) and regarded as a proton-activated form of imine, which is consistent with the instantaneous reduction to DQ-Am by weak reductant 4a with concomitant formation of pyridinium salt 7a·TFA. Taking into account the suppression of the process by TEMPO, a radical species was likely involved and radical cation 8 was presumed to be formed with a superoxide radical anion, which was responsible for further transforming 8 into iminium cation DQ-Im with the coproduction of hydrogen peroxide. TEMPO was reported to mediate the conversion of superoxide radical anions to hydrogen peroxide,³⁰⁾ thereby arresting the catalysis and decomposition of 8 to give a complex reaction mixture.

Fig. 3. Iterative Hydride Reduction/Dehydrogenation of DQ-Im/DQ-Am Traced by ¹H-NMR Analysis in CD₃OD

Fig. 4. Control Experiments and Proposed DQ-Im/DQ-Am Cycle

Having confirmed the robust DQ-Im/DQ-Am cycle, we turned our attention to the competency of the DQ-Im·TFA/O₂ system for the catalytic oxidation of 1,4-dihydropyridines 4 and 9,10-dihydroacridine 9 (Fig. 5). With as little as 5 mol% of DQ-Im·TFA as a catalyst, dehydrogenation of 4 proceeded at 40 °C in CD₃OD, which was monitored by ¹H-NMR. Atmospheric oxygen is sufficient to reach full conversion to give corresponding pyridine derivatives 7. Reaction rate was dependent on the substituents of both ester moiety and 2,6-position of 4; the reaction of sterically least hindered 4a completed within 12 h and that of bulkier derivatives exhibited slower reaction progress. While 9,10-dihydroactridine derivatives are generally not soluble in CD₃OD or CD₃CN suitable for DQ-Im·TFA, nonsubstituted 9 was compatible with DQ-Im/DQ-Am system and smoothly oxidized to acridine 10 with 5 mol% of catalyst loading.

Fig. 5. Catalytic Oxidation of 1,4-Dihydropyridine Derivatives 4 and 9,10-Dihydroacridine 9 Promoted by DQ-Im·TFA under Ambient Conditions

Conclusion

We disclosed that a rigidified planar iminium cation was capable of promoting catalytic oxidation of 1,4-dihydropyridine derivatives and 9,10-dihydroacridine with molecular oxygen as the sole oxidant. Regeneration of the imine from amine is ascribed to the characteristic rigid planar structure and hydrogen bonding interaction. Further application of the iterative imine/amine cycle in the context of hydride transfer catalysis will be reported in due course.

Acknowledgments

This work was financially supported by JSPS KAKENHI Grant Nos. JP19K22192 (Grant-in-Aid for Exploratory Research) and JP20H02746 (Grant-in-Aid for Scientific Research (B)) to N.K. N.K. thanks Toyo Gosei Memorial Foundation, Izumi Science and Technology Foundation, and Sumitomo Foundation for financial support.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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