Allyl-Nickel Catalysis Enables Carbonyl Dehydrogenation and Oxidative Cycloalkenylation of Ketones

Huang, David; Szewczyk, Suzanne M.; Zhang, Pengpeng; Newhouse, Timothy R.

doi:10.1021/jacs.9b02552

“…As there are numerous desaturation methods available to the practitioner all of the results are placed into context with direct comparison to the powerful Pd, Cu, and hypervalent iodine-based systems. With regards to ketone substrates, both cyclic (from 5-15 membered rings) and acyclic derivatives could be employed (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). This stands in contrast to recently developed catalytic methods that operate smoothly on cyclic systems but fail on acyclic ones (14 and 15).…”

mentioning

confidence: 99%

“…A twostep in situ EDD protocol was also developed to afford enones 6, 12 and 17 in decent yields directly from the respective ketone starting material. Esters and lactones, substrate classes that have only recently succumbed to direct dehydrogenation, 14,17,18 can also be subjected to EDD using the corresponding diphenylphosphate ester derivatives (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Such enol derivatives are easily prepared and hydrolytically stable unlike the corresponding silyl ketene acetals.…”

mentioning

confidence: 99%

Electrochemically Driven Desaturation of Carbonyl Compounds

Gnaim¹,

Takahira²,

Wilke³

et al. 2020

Preprint

View full text Add to dashboard Cite

Electrochemical techniques have long been heralded for their innate sustainability as efficient methods for achieving redox reactions. Carbonyl desaturation, as a fundamental organic oxidation, is an oft-employed transformation to unlock adjacent reactivity. To date, the most reliable methods for achieving it have relied on transition metals (Pd/Cu) or stoichiometric reagents based on I, Br, Se, or S. Herein we report an operationally simple pathway to such structures from enol silanes and phosphates using electrons as the primary reagent. This electrochemically driven desaturation exhibits a broad scope across an array of carbonyl derivatives, is easily scalable (1-100g), and can be predictably implemented into synthetic pathways using experimentally or computationally derived NMR shifts. Mechanistic interrogation suggests a radical-based reaction pathway.

show abstract

“…12,13 Recently, two new methods have also appeared from the Newhouse and Dong groups that allow the use of catalytic amounts of palladium and copper, respectively. [14][15][16][17][18][19][20] These methods expand the scope of available desaturation methods to nitriles, esters, lactones, and lactams and do not require the preparation of enol ethers. Since the essence of this reaction involves a formal 2-electron oxidation, it stands to reason that even simpler redox approaches might be developed.…”

mentioning

confidence: 99%

Electrochemically Driven Desaturation of Carbonyl Compounds

Gnaim¹,

Takahira²,

Wilke³

et al. 2020

Preprint

View full text Add to dashboard Cite

Electrochemical techniques have long been heralded for their innate sustainability as efficient methods for achieving redox reactions. Carbonyl desaturation, as a fundamental organic oxidation, is an oft-employed transformation to unlock adjacent reactivity. To date, the most reliable methods for achieving it have relied on transition metals (Pd/Cu) or stoichiometric reagents based on I, Br, Se, or S. Herein we report an operationally simple pathway to such structures from enol silanes and phosphates using electrons as the primary reagent. This electrochemically driven desaturation exhibits a broad scope across an array of carbonyl derivatives, is easily scalable (1-100g), and can be predictably implemented into synthetic pathways using experimentally or computationally derived NMR shifts. Mechanistic interrogation suggests a radical-based reaction pathway.

show abstract

“…As pyridine is one of the most widely found heterocycles in small molecule therapeutics, we began our investigations using 2-phenethylpyridine ( 1a ) as a model substrate and Zn(TMP) 2 as base for benzylic deprotonation (see the Supporting Information for base optimization). We previously described the use of nickel catalysis and an allyl oxidant to promote β-hydride elimination for carbonyl dehydrogenation . However, for benzylic dehydrogenation, low conversions and undesired allylation byproducts were observed when allyl oxidants Ox 1–3 were used (Table ).…”

mentioning

confidence: 99%