Asymmetric Cross‐Coupling of Aryl Triflates to the Benzylic Position of Benzylamines

McGrew, Genette I.; Stanciu, Corneliu; Zhang, Jiadi; Carroll, Patrick J.; Dreher, Spencer D.; Walsh, Patrick J.

doi:10.1002/anie.201201874

Cited by 76 publications

(46 citation statements)

References 33 publications

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“…We next examined the solvent composition. [18] Use of 30% toluene as cosolvent resulted in an increase in AY to 79% (86% ee, entry 6). Changing the ratio of the toluene to 2-MeTHF had a dramatic impact on the yield but maintained the ee (see Supporting Information for details).…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

“…Recently, our team introduced a strategy to employ (η 6 -C 6 H 5 CH 2 R)Cr(CO) 3 complexes as cross-coupling partners to produce di-and triarylmethanes [17] and enantioenriched diarylmethylamines [18] via direct arylations. [19] Using these pronucleophiles, we also explored palladium-catalyzed allylic substitution of diverse cyclic and acyclic electrophiles to give racemic products.…”

Section: Introductionmentioning

confidence: 99%

“…This method provides ready access to the enantioenriched "α-2-propenyl benzyl" motifs and expands the classes of nucleophiles that can be employed in AAA reactions. It is noteworthy that the optimized catalysts for both AAA reactions advanced herein, and for our palladium(Cy-Mandyphos) catalyzed enantioselective arylation of (η 6 -C 6 H 5 CH 2 NR 2 )Cr(CO) 3 complexes, [18] all contain strongly coordinating tertiary amine or amide groups on the ligands that can serve to bind the lithium counterions of the nucleophiles. This observation suggests a possible design feature for related enantioselective processes with strongly basic lithiated nucleophiles.…”

Section: Introductionmentioning

confidence: 99%

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Palladium‐Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles

et al. 2016

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The first two highly enantioselective palladium-catalyzed allylic alkylations with benzylic nucleophiles activated with Cr(CO) 3 have been developed. These methods enable the pwalsh@sas.upenn.edu, Homepage://titanium.chem.upenn.edu/walsh/. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript enantioselective synthesis of "α-2-propenyl benzyl" motifs, which are important scaffolds in natural products and pharmaceuticals. A variety of cyclic and acyclic allylic carbonates are competent electrophilic partners furnishing the products in excellent enantioselectivity (up to 99% ee and 92% yield). This approach was employed to prepare a nonsteroidal anti-inflammatory drug analogue. Keywordspalladium; asymmetric allylic alkylation; (η 6 -Arene) complexes; chromium Transition-metal-catalyzed allylic substitution reactions have emerged as a powerful method to construct C−C bonds. [1] Of these, the palladium-catalyzed asymmetric allylic alkylation (AAA) reaction has attracted the greatest interest due to its applications in total synthesis and the preparation of bioactive compounds. [2] A wide variety of stabilized or "soft" nucleophiles (originally defined as pronucleophiles with pK a < 25 [3] ) have been successfully employed in palladium-catalyzed AAA reactions, including malonates, [4] imides [5] and many others. [6] In contrast, few palladium-catalyzed allylic substitution reactions with "hard" nucleophiles (generally defined as pronucleophiles with pK a > 25) have materialized. [1a] Recent advances in palladium-catalyzed AAA with "hard" nucleophiles have been reported by Morken and co-workers with allylboronates in allyl-allyl coupling reactions [7] (Scheme 1A) and Maulide and co-workers with the use of dialkylzinc nucleophiles [8] (Scheme 1B).The most significant difference between "soft" and "hard" nucleophile classes in the TsujiTrost allylic substitution is their reaction pathways: "soft" nucleophiles react via a double inversion mechanism whereas "hard" nucleophiles are proposed to undergo single inversion, [9] wherein the nucleophile transmetallates to the palladium catalyst. Both reactions in Scheme 1 were shown to proceed by the "hard" nucleophile pathway. As a valuable complement, Fletcher and co-workers reported copper-catalyzed AAA reaction of alkylzirconium reagents (generated in situ from alkenes by hydrometallation) via dynamic kinetic asymmetric transformation. [10] The scope of this reaction, however, does not include simple benzylic nucleophiles.To broaden the synthetic utility of the palladium-catalyzed AAA, researchers have focused on expanding the classes of nucleophiles that can undergo the more controllable double inversion or "soft" nucleophile reaction pathway. This approach entails "softening" of hard nucleophiles by addition of activating agents to stabilize the resulting anionic charge. In pioneering studies, Trost and co-workers reported the highly enantioselective palladiumcatalyzed AAA with 2-methylpyridine derivatives (Scheme 2A, LG=le...

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Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Palladium‐Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles

et al. 2016

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“…We recently employed arene activation by coordination of Cr(CO) 3 in (η 2 -C 6 H 5 CH 2 NR 2 ) Cr(CO) 3 complexes, which were successfully coupled with aryl bromides, and enantioselectively with aryl triflates, under basic conditions. 9 A different approach by Oshima and co-workers 10 involved use of N -benzyl benzophenone ketimines and derivatives that were deprotonated with CsOH at 140 °C. In the presence of catalytic palladium and PCy 3 , cross-coupling of the intermediate 2-azaallyl anion with aryl chlorides was achieved in moderate yields (Scheme 2).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of diarylmethylamines via palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions

Yucel

Adrio

et al. 2014

Chem. Sci.

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Diarylmethylamines are of great interest due to their prevalence in pharmaceutical chemistry. As a result, new methods for their synthesis are in demand. Herein, we report a versatile protocol for the synthesis of diarylmethylamine derivatives involving palladium-catalyzed arylation of in situ generated 2-azaallyl anion intermediates. The 2-azaallyl anions are generated by reversible deprotonation of readily available aldimine and ketimine precursors. Importantly, the arylated aldimine and ketimine products do not undergo isomerization under the reaction conditions. Scale-up of the arylation and hydrolysis of the resulting products to furnish diarylmethylamines were also successfully performed.

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“…In the context of a broader program to functionalize weakly acidic sp 3 hybridized C–H bonds, [2–4] we became interested in the arylation of C–H bonds situated alpha to sulfur atoms, since sulfur-based compounds are commonplace in the chemistry of life and in medicinal chemistry. [5] Our initial efforts focused on the direct α-arylation of C–H bonds adjacent to sulfur(II), such as found in sulfoxides, including the parent DMSO (Scheme 1A).…”

Section: Introductionmentioning

confidence: 99%

Palladium‐Catalyzed Direct α‐Arylation of Benzyl Thioethers with Aryl Bromides

Frensch¹,

Hussain²,

Marques³

et al. 2014

Adv Synth Catal

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The arylation of sp3-hybridized C–H’s bonds is a powerful strategy to build molecular complexity and diversity. A novel and efficient palladium-catalyzed direct sp3 C–H arylation of aryl and alkyl benzyl thioether derivatives with aryl bromides is reported. The reaction involves reversible deprotonation of the benzylic C–H’s of the thioether with either LiN(SiMe3)2 or NaN(SiMe3)2 and subsequent cross-coupling to provide the functionalized products in up to 97% yield. A screen of 24 of the most successful ligands in cross-coupling chemistry led to the identification of NiXantPhos as the only viable ligand for this challenging coupling.

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Asymmetric Cross‐Coupling of Aryl Triflates to the Benzylic Position of Benzylamines

Abstract: Scheme 1. Dual catalyst cycle for the asymmetric benzylic functionalization process.Scheme 2. Tricarbonylchromium-assisted synthesis of achiral and racemic polyarylmethanes.

Cited by 76 publications

References 33 publications

Palladium‐Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles

Palladium‐Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles

Synthesis of diarylmethylamines via palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions

Palladium‐Catalyzed Direct α‐Arylation of Benzyl Thioethers with Aryl Bromides

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