Modular o-Quinone Catalyst System for Dehydrogenation of Tetrahydroquinolines under Ambient Conditions

Quinolines are common pharmacophores present in numerous FDA-approved pharmaceuticals and other bioactive compounds. Here, we report the design and development of new o-quinone-based catalysts for the oxidative dehydrogenation of tetrahydroquinolines to afford quinolines. Use of a Co(salophen) cocatalyst allows the reaction to proceed efficiently with ambient air at room temperature. The utility of the catalytic method is demonstrated in the preparation of a number of medicinally relevant quinolines.

C opper amine oxidases contain a tyrosine-derived oquinone in their active site that mediates aerobic oxidation of primary amines to aldehydes (e.g., topaquinone, Scheme 1A). 1 Biomimetic o-quinones such as Q1 and Q2 (Scheme 1A; Q2 red is proposed to form an o-quinone in situ) have been shown to be effective synthetic catalysts for aerobic dehydrogenation of primary amines, typically affording homocoupled imines. 2 Both topaquinone and the biomimetic quinone catalysts mediate amine oxidation via a "transamination" pathway, initiated by formation of an imine adduct of the substrate with the quinone. This mechanism accounts for the highly selective oxidation of primary over secondary and tertiary amines. We recently reported that 1,10-phenanthroline-5,6-dione (phd, Scheme 1A) promotes amine oxidation by a non-biomimetic "addition−elimination" pathway involving a hemiaminal intermediate (Scheme 1B). 3 This novel mechanism enabled the substrate scope to be expanded to include secondary amines. Aerobic dehydrogenation of a number of different nitrogen heterocycles was achieved by using phd in combination with ZnI 2 and pyridinium p-toluenesulfonate (PPTS) as a cocatalyst (Scheme 1C).
This phd/ZnI 2 catalyst system demonstrated the feasibility of aerobic secondary amine dehydrogenation, but reactions often required up to 48 h to reach completion and certain product classes were not accessible. For example, quinolines are an important class of heterocycles, but even the parent tetrahydroquinoline underwent dehydrogenation to quinoline in only 18% yield (Scheme 1C). Here, we describe an octahedral [Ru(phd) 3 ] 2+ catalyst that shows considerably higher activity for amine oxidation, including successful aerobic dehydrogenation of diverse tetrahydroquinolines at room temperature with ambient air as the source of O 2 . 4 This work highlights the modular nature of the phd o-quinone catalyst that makes it readily amenable to optimization and adaptation to different applications. Replacement of iodide with Co-(salophen) (salophen = N,N′-bis(salicylidene)-1,2-phenylenediamine) as a redox cocatalyst contributes significantly to the efficiency of the reactions.
In our initial studies, we compared the previously optimized phd/ZnI 2 catalyst system with simple octahedral [Fe(phd) 3 ] 2+ and [Ru(phd) 3 ] 2+ complexes in the oxidation of tetrahydroquinoline to quinoline ( Figure 1). The time course traces ( Figure 1) show the low activity and conversion of the previously reported phd/ZnI 2 catalyst (red trace); the catalyst loses activity ∼6−7 h into the reaction after reaching ≤20% conversion to the quinoline product. The Fe and Ru complexes (2.5 mol %) were also tested (green and blue traces, respectively). The use of Bu 4 NI (1 mol %) as a cocatalyst reflected previous observations showing that the I − /I 3 − redox couple promotes aerobic oxidation of the reduced, hydroquinone form of the phd catalyst. 5 [Fe(phd) 3 ] 2+ showed a similar initial rate to the ZnI 2 catalyst, but it exhibited somewhat improved stability. In contrast, [Ru(phd) 3 ] 2+ exhibited a significant increase in activity and a 93% yield of quinoline was obtained after 24 h. On the basis of this result, we characterized [Ru(phd) 3 ](ClO 4 ) 2 via X-ray crystallography ( Figure 2). 6,7 This [Ru(phd) 3 ] 2+ /Bu 4 NI catalyst was tested with a series of challenging N-heterocyclic substrates that had required 48 h to reach completion with the phd/ZnI 2 catalyst (Scheme 2). Improved yields and significantly decreased reaction times were observed in each case, with the most dramatic improvement observed in the dehydrogenation of tetrahydroquinoline.
Iodide was previously shown to mediate aerobic oxidation of the reduced hydroquinone form of the catalyst, and a catalytic sequence for the present dehydrogenation reactions is depicted in Scheme 3, where Co-Cat red/ox = 3I − /I 3 − . (It is not known whether dehydrogenation of the intermediate dihydroquinoline involves the catalyst.) We speculated that alternative cocatalysts could lead to even better catalytic reactivity. Backvall and others have highlighted the role of cocatalysts for aerobic oxidation of benzoquinone in multicomponent catalytic reactions, 8,9 and molecular catecholase mimics have been identified for aerobic oxidation of hydroquinones. 10 Drawing on these precedents, we tested a number of possible cocatalysts as replacements for Bu 4 NI, including Cu(pc), Fe(pc), Co(salophen), and Co(salpr) (pc = phthalocyanine; salpr = bis(salicylideneiminato-3propyl)methylamine). 11 Co(salophen) proved to be particularly effective, enabling full conversion within 3 h (Figure 3). 12 Subsequent studies showed that Co(salophen) enabled the reactions to proceed efficiently under ambient conditions (at room temperature with ambient air as the oxidant). The [Ru(phd) 3 ] 2+ catalyst structurally resembles Ru-polypyridyl complexes commonly used as photoactive catalysts, but control experiments show that the reactions exhibit identical behavior in the presence and absence of light. 13 In addition, no reaction was observed in the absence of [Ru(phd) 3 ] 2+ , suggesting that Co(salophen) is not a competent dehydrogenation catalyst under these conditions.
When probing the reactivity of polycyclic substrate 20 (Scheme 4), both dehydrogenation and benzylic oxygenation occurred to afford product 21 in 68% isolated yield. This reaction provides concise access to the indeno[2, 1-c]quinoline substructure present in numerous biologically active compounds, 17 including antiprotozoal agent 22 18 and phase II topoisomerase inhibitor  In conclusion, these results demonstrate the utility of [Ru(phd) 3 ] 2+ as a novel o-quinone catalyst for dehydrogenation of N-heterocycles. The results show that the substitutionally inert Ru 2+ ion is more effective than Zn 2+ in activating phd toward secondary amine dehydrogenation. Replacement of iodide with Co(salophen) as a redox cocatalyst to promote aerobic oxidation of the hydroquinone catalyst leads to substantial improvement in catalyst activity and enables the reactions to proceed under ambient conditions. The modular nature of the catalyst system described here has important implications for future studies targeting other aerobic quinonemediated oxidation reactions.

* S Supporting Information
Full experimental procedures and characterization data for all products, and additional screening data. This material is available free of charge via the Internet at http://pubs.acs.org.

Notes
The authors declare no competing financial interest.