Synthesis of Vicinal Carbocycles by Intramolecular Nickel-Catalyzed Conjunctive Cross-Electrophile Coupling Reaction

Hewitt, Kirsten A.; Herbert, Claire A.; Jarvo, Elizabeth R.

doi:10.1021/acs.orglett.2c02481

Cited by 8 publications

(4 citation statements)

References 96 publications

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“…1 H-NMR and 13 C-NMR data agree quite well with the reported data [ 31 , 32 , 33 , 34 ]. In the literature, 19 F NMR (565 MHz, CDCl3) δ –62.7 (3F) is also reported [ 34 ].…”

Section: Methodssupporting

confidence: 89%

“…H-NMR and13 C-NMR data agree quite well with the reported data[31][32][33][34]. In the literature,19 F NMR (565 MHz, CDCl3) δ -62.7 (3F) is also reported[34].Procedure for the synthesis of 3-(3-(trifluoromethyl)phenyl)propanal (II) via selective reduction with potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA) of the mixture of 1-(3,3-diethoxypropyl)-3-(trifluoromethyl)benzene (III) and ethyl 3-(3-(trifluoromethyl) phenyl)propanoate (IV)…”

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confidence: 89%

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Improved Process for the Synthesis of 3-(3-Trifluoromethylphenyl)propanal for More Sustainable Production of Cinacalcet HCl

et al. 2023

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Cinacalcet (I), sold as hydrochloride salt, is a calcimimetic drug which has been approved for the treatment of secondary hyperparathyroidism in patients with chronic renal disease and for the treatment of hypercalcemia in patients with parathyroid carcinoma. Here, an improved method for the synthesis of 3-(3-trifluoromethylphenyl)propanal (II), a key intermediate for the preparation of I, is described. The protocol required a Mizoroki–Heck cross-coupling reaction between 1-bromo-3-(trifluoromethyl)benzene and acroleine diethyl acetal, catalyzed by Pd(OAc)2 in the presence of nBu4NOAc (tetrabutylammonium acetate), followed by the hydrogenation reaction of the crude mixture of products in a cascade process. Palladium species, at the end of the reaction, were efficiently recovered as Pd/Al2O3. The procedure was developed under conventional heating conditions as well as under microwave-assisted conditions. The obtained mixture of 1-(3,3-diethoxypropyl)-3-(trifluoromethyl)benzene (III), impure for ethyl 3-(3-trifluoromethylphenyl) propanoate (IV), was finally treated, under mild conditions, with potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA) to obtain after hydrolysis 3-(3-trifluoromethylphenyl)propanal (II), in an excellent overall yield and very high purity. Microwave conditions permitted a reduction in reaction times without affecting selectivity and yield. The final API was obtained through reductive amination of (II) with (R)-(+)-1-(1-naphthyl)ethylamine (V) using a catalyst prepared by us with a very low content of precious metal.

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“…1 H-NMR and 13 C-NMR data agree quite well with the reported data [ 31 , 32 , 33 , 34 ]. In the literature, 19 F NMR (565 MHz, CDCl3) δ –62.7 (3F) is also reported [ 34 ].…”

Section: Methodssupporting

confidence: 89%

supporting

confidence: 89%

Improved Process for the Synthesis of 3-(3-Trifluoromethylphenyl)propanal for More Sustainable Production of Cinacalcet HCl

et al. 2023

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“…A series of dimesylates, separated by pendant olefins, underwent smooth cascade reactions to afford vicinal carbocycles such as 55 (Scheme 15). 35 These reactions proceed with modest diastereomeric ratios consistent with radical intermediates.…”

Section: Part Ii: Stereoablative Reactions Of Alcohol Derivativesmentioning

confidence: 99%

Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives

Herbert,

Jarvo

2023

Acc. Chem. Res.

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Conspectus Nickel-catalyzed reactions of alkyl alcohol derivatives leverage the high prevalence of hydroxyl groups in natural products, medicinal agents, and synthetic intermediates to provide access to C(sp3)-rich frameworks. This Account describes our laboratory’s development of stereospecific and stereoconvergent C–C bond forming reactions employing C(sp3)–O and C(sp3)–N electrophiles. In the context of development of new transformations, we also define fundamental characteristics of the nickel catalysts. Part I details the nickel-catalyzed cross-coupling reactions developed by our group which hinges on stereospecific formation of stable π-benzyl intermediates. Acyclic and cyclic ethers, esters, carbamates, lactones, and sulfonamides undergo Kumada-, Suzuki-, and Negishi-type coupling reactions to produce enantioenriched products with high fidelity of stereochemical information. We describe extension to include ring-opening reactions of saturated heterocycles to afford acyclic 1,3-fragments in high diastereomeric ratios. We also describe our advances in stereospecific nickel-catalyzed cross-electrophile coupling reactions. Tethered C–O and C–X electrophiles proved fruitful for construction of a variety of carbocyclic frameworks. We report an intramolecular cross-electrophile coupling of benzylic pivalates with aryl bromides for the synthesis of indanes and tetralins. We found that 4-halotetrahydropyrans and 4-halopiperidines readily undergo stereospecific ring contraction to afford substituted cyclopropanes. Mechanistic investigations are consistent with closed-shell intermediates, a Ni(0)/Ni(II) cycle, and an intramolecular SN2-type reaction of a key organonickel intermediate to form the cyclopropane. Building toward more complex cascade reactions, we have demonstrated that 2-alkynyl piperidines incorporate MeMgI in a dicarbofunctionalization of the alkyne to afford highly substituted vinyl cyclopropanes. In Part II we present our development of stereoconvergent reactions of alkyl alcohol derivatives. In order to expand the utility of the intramolecular XEC reaction, we sought to employ unactivated alkyl electrophiles. Specifically, alkyl dimesylates engage in intramolecular XEC reactions to form alkyl cyclopropanes. In contrast to our previous work, these reactions proceed through open-shell intermediates and favor stereoconvergent formation of the trans-cyclopropane. Enantioselective aldol reactions can be employed in syntheses of 1,3-diols which furnish enantioenriched cyclopropanes in high ee. Experimental and computational evidence reveals that MeMgI mediates formation of alkyl iodides in situ. The coupling reaction initiates with halogen atom abstraction at the secondary alkyl iodide. The alkyl Ni(II) complex then proceeds through a stereospecific SN2-type ring closure to form cyclopropane. In an effort to increase functional group compatibility in the synthesis of cyclopropanes from alkyl dimesylates we developed a zinc-mediated reaction of 1,3-dimesylates prepared from medicinal analogues. In cha...

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“…Different from the use of two electrically complementary alkyl reagents, recently, nickel- or titanium-catalyzed alkene dialkylation with two electrophiles was rapidly developed (Scheme c). In such cases, an excess amount of cheap reductants, usually Zn or Mn, were involved to allow the sequential installation of two alkyls to the double bonds . Due to the use of more commonly available alkyl electrophiles, the substrate scope was extended to alkyl halides or redox active alkyl esters with all sorts of functional substituents.…”

mentioning

confidence: 99%

Nickel-Catalyzed 8-Aminoquinoline Directed Reductive Dialkylcyclization/Homodialkylation of Unactivated Alkenes

Lu,

Sui,

Huang

et al. 2023

Org. Lett.

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Chemo and regioselective dialkylation of alkene is an efficient protocol for constructing useful chemicals, but challenges remain in the unrestricted application of alkylating reagents. Alkyl bromide belongs to the easy-to-access and operable alkyl electrophiles that can be used in reductive coupling with alkenes. Here, we reported convenient strategies for dialkylcyclization and homodialkylation of unactivated β,γand γ,δ-unsaturated alkenyl amides with 1,3-dibromoalkanes or primary alkyl bromides under nickel-catalyzed reductive conditions that exhibited high regioselectivity and functional-group tolerance.

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Synthesis of Vicinal Carbocycles by Intramolecular Nickel-Catalyzed Conjunctive Cross-Electrophile Coupling Reaction

Cited by 8 publications

References 96 publications

Improved Process for the Synthesis of 3-(3-Trifluoromethylphenyl)propanal for More Sustainable Production of Cinacalcet HCl

Improved Process for the Synthesis of 3-(3-Trifluoromethylphenyl)propanal for More Sustainable Production of Cinacalcet HCl

Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives

Nickel-Catalyzed 8-Aminoquinoline Directed Reductive Dialkylcyclization/Homodialkylation of Unactivated Alkenes

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