Abstract
In organic molecules, the reactivity at the carbon atom next to the functional group is dramatically different from that at other carbon atoms. Herein, we report that a versatile copper-catalyzed method enables successive dehydrogenation or dehydrogenation of ketones, aldehydes, alcohols, α,β-unsaturated diesters, and N-heterocycles to furnish stereodefined conjugated dienecarbonyls, polyenecarbonyls, and nitrogen-containing heteroarenes. On the basis of mechanistic studies, the copper-catalyzed successive dehydrogenation process proceeds via the initial α,β-desaturation followed by further dehydrogenative desaturation of the resultant enone intermediate, demonstrating that the reactivity at α-carbon is transferred through carbon–carbon double bond or longer π-system to the carbon atoms at the positions γ, ε, and η to carbonyl groups. The dehydrogenative desaturation–relay is ascribed to the formation of an unusual radical intermediate stabilized by 5- or 7,- or 9-center π-systems. The discovery of successive dehydrogenation may open the door to functionalizations of the positions distant from functional groups in organic molecules.
Highlights
In organic molecules, the reactivity at the carbon atom next to the functional group is dramatically different from that at other carbon atoms
Our previous discovery of a copper-catalyzed dehydrogenative α,β-desaturation of ketone to enone led us to question whether a successive dehydrogenative desaturation of ketones bearing longer acyclic aliphatic chains might be possible, which resulted in the establishment of a versatile catalytic method for successive dehydrogenation of diverse saturated substrates (Fig. 1b)
In analogy to the proposed dienone formation, polyenone structural motif would be accessible if the polarizing effect of carbonyl group could be delivered to the remote C(sp3)–H bond by two or more than two conjugated carbon–carbon double bonds so as to activate this C–H bond for formation of a radical distant from carbonyl
Summary
The reactivity at the carbon atom next to the functional group is dramatically different from that at other carbon atoms. The methods that perform the dehydrogenative desaturation in tandem with the reaction of unsaturated compounds have been established by our group[14, 15] and others[16,17,18,19] to access the cascade approaches to β-functionalization of saturated carbonyl compounds During this investigation, we disclosed that a copper-catalyzed reaction of ketones with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO)[20] generated α,β-unsaturated ketones[15], the reaction pathway of which involved formation of carbonyl α-radical intermediate, combination of TEMPO with this α-radical intermediate[21], and final elimination of 2,2,6,6tetramethyl-N-hydroxypiperidine (TEMPOH) from the resulting α-TEMPO ketone adduct to release enone product. The dehydrogenative desaturation–relay is ascribed to formation of the radical intermediates stabilized by 5-, or 7-, or 9-center π-systems As such, this copper-catalyzed successive dehydrogenation reaction mechanistically differs from the recently pioneered dehydroaromatization of cyclohexanones[23], cyclohexenes[24], and alkanes[25] in which dehydrogenation reactions occur at the identical carbon atoms relative to functional groups
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