Selectively activating chemical bonds that are generally considered to be inert is an attractive strategy for introducing functionality into and enhancing the structural complexity of easily-prepared substrates, particularly when bond activation ultimately leads to carbon-carbon bond formation.[1] We have reported [2] several examples in which oxidative carboncarbon bond activation can be used to initiate cyclization reactions through carbon-carbon bond formation. Reaction initiation through single-electron oxidation [3] alleviates chemoselectivity problems that can arise from conventional Lewis acid initiated methods for electrophile formation. To facilitate substrate synthesis and improve reaction atom economy [4] we have initiated a program that is directed toward promoting oxidative electrophile formation by carbon-hydrogen bond activation. Toward this objective we initially chose to exploit the propensity of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form aryl-substituted oxocarbenium ions from benzylic ethers.[5] This process has been utilized for bimolecular carbon-carbon bond formation, [6] but these reactions proceed efficiently only with electron-rich arenes, and either require high temperatures with ketone nucleophiles or dicarbonyl/Lewis acid mixtures, or the addition of pregenerated nucleophiles such as enolsilanes after cation formation. [7] Successful and broad application of DDQ-mediated carbon-hydrogen bond activation and subsequent carboncarbon bond formation to annulation reactions requires that the nucleophiles be stable toward DDQ, that the reaction products not be subject to additional oxidation, and that a wide range of ethers serve as substrates. Herein we report that DDQ promotes the formation of stabilized carbocations by benzylic carbon-hydrogen bond activation under ambient conditions in the presence of appended nucleophilic groups and leads to diastereoselective carbon-carbon bond formation. Particularly important is the observation that, relative to bimolecular addition reactions, appending nucleophilic groups to the ether enhances the range of the benzylic groups that can serve as cation precursors. We also demonstrate that the scope of the process can be dramatically expanded by applying the protocol in an efficient approach to ring formation through allylic carbon-hydrogen bond activation. The incorporation of oxygen-containing groups into the substrates and the impact of arene or alkene substitution on the reaction rate is also discussed.Our initial studies focused on the conversion of paramethoxybenzyl (PMB) ether 1 into tetrahydropyrone 2 (Scheme 1) by DDQ-mediated oxocarbenium ion formation.This process proceeds most readily in 1,2-dichloroethane and in the presence of 2,6-dichloropyridine and powdered 4 molecular sieves (M.S.), which inhibit oxidative cleavage of the PMB group. Under these conditions the reaction was complete within 10 minutes at room temperature to provide 2 in 77 % yield as a single diastereomer. This reaction proceeds [8] by electron transfer from ...

Processes for the functionalization of carbon-hydrogen bonds are the focus of significant attention in organic synthesis [1] in response to the need to streamline molecular assembly. As a continuation of our efforts to generate carbocations through single-electron oxidation reactions, [2] we recently reported[3] DDQ-mediated cyclization reactions of benzylic and allylic ethers (Scheme 1; DDQ =2,3-dichloro-4,5-dicyanoquinone). Keywordscarbocations; C-H activation; macrocycles; natural products; oxidation These reactions proceed through oxidative cleavage of a carbon-hydrogen bond to form oxocarbenium ions that react with appended nucleophiles.[4] The use of relatively inert ethers as precursors to reactive electrophiles is strategically attractive, because facile substrate preparation makes etherification a useful fragment-coupling process for convergent syntheses. Oxidative carbocation generation enables the inclusion of acid-sensitive functional groups in starting materials and products, and provides an opportunity to incorporate multiple precursors to electrophiles in a synthetic intermediate. These electrophiles can later be revealed through the use of chemically orthogonal conditions. [5] Macrocyclic oxocarbenium ions are interesting synthetic intermediates as a result of their capacity to engage in transannular nucleophilic addition reactions. The viability of these intermediates was demonstrated by the Wender research group in the synthesis of bryostatin analogues.[6] Scheidt and co-workers recently reported [7] carbon-carbon bond formation via a macrocyclic oxocarbenium ion formed in a Lewis acid mediated condensation, and related examples followed.[8] However, the generality of this remarkable protocol is not clear: In the absence of conformational preorganization, the process requires the formation of highly reactive intermediates through kinetically unfavorable pathways. A potentially more general approach to the formation of macrocyclic oxocarbenium ions for carbon-hydrogen-bond functionalization is the oxidation of preformed macrocyclic ethers with DDQ (Scheme 2). Herein, we report cyclization reactions that proceed through oxidatively generated macrocyclic oxocarbenium ions (3→4→5) and demonstrate the applicability of the protocol to the construction of complex molecules through a brief formal synthesis of neopeltolide.

Neopeltolide, a potent cytotoxin from a Carribean sponge, was synthesized through a brief sequence that highlights the use of ethers as oxocarbenium ion precursors. Other key steps include an acid-mediated etherification and sequence that features a Sonogashira reaction, an intramolecular alkyne hydrosilylation reaction, and a Tamao oxidation. The alkene that is required for the oxidative cyclization can be hydrogenated to provide access to the natural product or an epimer, or can be epoxidized or dihydroxylated to form polar analogs.

Selectively activating chemical bonds that are generally considered to be inert is an attractive strategy for introducing functionality into and enhancing the structural complexity of easily-prepared substrates, particularly when bond activation ultimately leads to carbon-carbon bond formation.[1] We have reported [2] several examples in which oxidative carboncarbon bond activation can be used to initiate cyclization reactions through carbon-carbon bond formation. Reaction initiation through single-electron oxidation [3] alleviates chemoselectivity problems that can arise from conventional Lewis acid initiated methods for electrophile formation. To facilitate substrate synthesis and improve reaction atom economy [4] we have initiated a program that is directed toward promoting oxidative electrophile formation by carbon-hydrogen bond activation. Toward this objective we initially chose to exploit the propensity of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form aryl-substituted oxocarbenium ions from benzylic ethers.[5] This process has been utilized for bimolecular carbon-carbon bond formation, [6] but these reactions proceed efficiently only with electron-rich arenes, and either require high temperatures with ketone nucleophiles or dicarbonyl/Lewis acid mixtures, or the addition of pregenerated nucleophiles such as enolsilanes after cation formation. [7] Successful and broad application of DDQ-mediated carbon-hydrogen bond activation and subsequent carboncarbon bond formation to annulation reactions requires that the nucleophiles be stable toward DDQ, that the reaction products not be subject to additional oxidation, and that a wide range of ethers serve as substrates. Herein we report that DDQ promotes the formation of stabilized carbocations by benzylic carbon-hydrogen bond activation under ambient conditions in the presence of appended nucleophilic groups and leads to diastereoselective carbon-carbon bond formation. Particularly important is the observation that, relative to bimolecular addition reactions, appending nucleophilic groups to the ether enhances the range of the benzylic groups that can serve as cation precursors. We also demonstrate that the scope of the process can be dramatically expanded by applying the protocol in an efficient approach to ring formation through allylic carbon-hydrogen bond activation. The incorporation of oxygen-containing groups into the substrates and the impact of arene or alkene substitution on the reaction rate is also discussed.Our initial studies focused on the conversion of paramethoxybenzyl (PMB) ether 1 into tetrahydropyrone 2 (Scheme 1) by DDQ-mediated oxocarbenium ion formation.This process proceeds most readily in 1,2-dichloroethane and in the presence of 2,6-dichloropyridine and powdered 4 molecular sieves (M.S.), which inhibit oxidative cleavage of the PMB group. Under these conditions the reaction was complete within 10 minutes at room temperature to provide 2 in 77 % yield as a single diastereomer. This reaction proceeds [8] by electron transfer from ...

Radical cations can be formed in a spatially and temporally controlled manner by appending a sacrificial photooxidant to an easily oxidized substrate, leading to intramolecular electron transfer upon irradiation. The anthraquinone carboxyl group is an effective photooxidant that can promote single electron oxidation from an appended arene. The resulting intermediates undergo a cleavage reaction through carbon-carbon bond activation to provide either cations or radicals that react to form a range of products.