Although great success has been achieved in catalytic asymmetric hydroamination of unactivated alkenes using transition metal catalysis and organocatalysis, the development of catalytic ...desymmetrising hydroamination of such alkenes remains a tough challenge in terms of attaining a high level of stereocontrol over both remote sites and reaction centers at the same time. To address this problem, here we report a highly efficient and practical desymmetrising hydroamination of unactivated alkenes catalysed by chiral Brønsted acids with both high diastereoselectivity and enantioselectivity. This method features a remarkably broad alkene scope, ranging from mono-substituted and gem -/1,2-disubstituted to the challenging tri- and tetra-substituted alkenes, to provide access to a variety of diversely functionalized chiral pyrrolidines bearing two congested tertiary or quaternary stereocenters with excellent efficiency under mild and user-friendly synthetic conditions. The key to success is indirect activation of unactivated alkenes by chiral Brønsted acids via a concerted hydroamination mechanism.
Catalytic asymmetric diamination of alkenes is a highly attractive method for creating chiral vicinal diamines, which are ubiquitous in biologically active molecules and versatile ligands as well as ...organocatalysts. We report the use of O-acylhydroxylamines as dialkylaminyl radical precursors to trigger asymmetric diamination of alkene under Cu(I)/chiral phosphoric acid dual catalysis. This reaction allows for direct alkylamine incorporation and features high enantioselectivity, a broad substrate scope, wide functional-group tolerance, and mild reaction conditions, providing convenient and practical access to a wide range of highly enantio-enriched β-alkylamine-containing pyrrolidines. We have also achieved asymmetric azidoamination of alkenes by using azidoiodinane as an azidyl radical precursor, offering a complementary method for preparing diverse chiral β-amino pyrrolidines. The application of the resultant α-tertiary pyrrolidine-derived diamine was showcased to significantly promote the enantioselectivity of an asymmetric Michael reaction.
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•Asymmetric radical diamination under copper/chiral phosphoric acid dual catalysis•Direct incorporation of alkylamine and azido moieties•Efficient synthesis of chiral α-tertiary pyrrolidines•Demonstrated great potential for application of diamine products as organocatalysts
Chiral vicinal diamines are characteristic and essential motifs embedded in numerous biologically active molecules. In addition, they are also the core scaffolds for a diverse range of chiral ligands, organocatalysts, and auxiliaries widely used in organic synthesis. For their preparation, asymmetric diamination of readily available alkenes constitutes an expedient and important method for accessing enantio-enriched vicinal diamines. However, none of the known strategies are able to directly introduce a protection-free alkyl amine moiety, mainly because of its strong coordination capability, mostly leading to transition-metal catalyst poisoning and susceptibility to oxidation. As a consequence, both the step economy and amine scope are compromised, thus limiting broad applicability. Here, we report the asymmetric radical diamination of alkenes under Cu(I)/chiral phosphoric acid dual catalysis, enabling direct incorporation of alkyl amine groups.
Liu and colleagues describe the asymmetric radical diamination of alkenes triggered by intermolecular addition of dialkylaminyl or azidyl radical to the alkene under Cu(I)/chiral phosphoric acid dual catalysis. This reaction enables direct incorporation of alkylamine moieties and provides convenient and practical access to a wide range of highly enantio-enriched β-alkylamine-containing pyrrolidines. Moreover, the resulting α-tertiary pyrrolidine-derived diamine proves to significantly promote the enantioselectivity of an asymmetric Michael reaction.
In contrast with the well-established C(sp
)-SCF
cross-coupling to forge the Ar-SCF
bond, the corresponding enantioselective coupling of readily available alkyl electrophiles to forge chiral C(sp
...)-SCF
bond has remained largely unexplored. We herein disclose a copper-catalyzed enantioselective radical C(sp
)-SCF
coupling of a range of secondary/tertiary benzyl radicals with the easily available (Me
N)SCF
reagent. The key to the success lies in the utilization of chiral phosphino-oxazoline-derived anionic N,N,P-ligands through tuning electronic and steric effects for the simultaneous control of the reaction initiation and enantioselectivity. This strategy can successfully realize two types of asymmetric radical reactions, including enantioconvergent C(sp
)-SCF
cross-coupling of racemic benzyl halides and three-component 1,2-carbotrifluoromethylthiolation of arylated alkenes under mild reaction conditions. It therefore provides a highly flexible platform for the rapid assembly of an array of enantioenriched SCF
-containing molecules of interest in organic synthesis and medicinal chemistry.
Herein, we describe a Cu(I)/phosphoric acid catalyzed intramolecular radical tertiary C(sp3)−H amination of N‐chlorosulfonamide, providing an applicable route to the pyrrolidine structural motifs ...bearing an α‐quaternary stereocenter (>20 examples with up to 94 % yield). Mechanistic studies indicate that the reaction involves an intramolecular 1,5‐hydrogen atom transfer process to form the key tertiary C‐centered radical followed by a C−N bond formation. The corresponding enantioselective amination is accordingly disclosed by Cu(I)/chiral phosphoric acid catalyst to afford the chiral products with up to 81 % enantiomeric excess (ee). This strategy is anticipated to facilitate the development of tertiary C(sp3)−H functionalization.
The direct functionalization of tertiary C−H bonds is a challenging task in organic synthesis. We disclose a Cu/phosphoric acid‐catalyzed intramolecular radical amination of tertiary C(sp3)−H bonds in N‐chlorosulfonamides via a sequential radical intramolecular 1,5‐HAT process/C−N formation. The asymmetric version is also enabled by dual Cu/chiral phosphoric acid catalysis to afford enantioenriched α‐quaternary pyrrolidines.
A mild and efficient copper-catalyzed radical oxytrifluoromethylation reaction of alkenyl oximes was successfully developed. The method provides a straightforward access to a wide range of ...CF3-containing isoxazolines in good to excellent yields.
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Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemo- and ...stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C–O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters. Partnered by one- or two-step follow-up transformations, this reaction provides a convenient and practical strategy for the rapid preparation of chiral C3 building blocks from readily available alcohols, particularly the industrially relevant glycerol. Mechanistic studies supported the proposed C–O bond coupling of acyl radicals.
The enantioconvergent C(sp3)–N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N-alkyl (hetero)aromatic amines yet has ...remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp3)–N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.
The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the ...interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.
Although great success has been achieved in selective C-C bond cleavage via the intramolecular radical remote migration process of several carbon-based groups, the development of the radical-based ...remote vinyl migration process remains a formidable challenge because of the energetically unfavorable process. To address this problem, we report here, for the first time, a novel C-C bond reorganization strategy via an unprecedented radical 1,3-, 1,4-, or 1,5-vinyl migration triggered by various types of fluoroalkylation of alkenes for the efficient realization of 1,2-fluoroalkylalkenylation reaction. This strategy provides an expedient and broadly applicable platform to access skeletally and functionally diverse fluoroalkyl-containing medium- and large-sized cyclic alkenes with excellent chemo-, regio-, and stereoselectivity. The broad substrate scope, which covers distinctly electron-neutral or electron-deficient alkenyl migrating groups and various fluoroalkyl radical precursors, the excellent functional group tolerance, the remarkable selectivity, and the operational simplicity, as well as versatile transformations of the products, make this approach practical and attractive.
•Terminal alkynes are used in trifluoromethylalkynylation of unactivated alkenes.•The design of copper/N,N,N-ligand catalyst ensures its success.•Mild conditions make it operationally simple.
A ...copper-catalyzed three-component radical trifluoromethylalkynylation of unactivated alkenes is realized from Togni-II reagent and readily available terminal alkynes under mild conditions to afford an array of β-trifluoromethylated alkynes. The utilization of a multidentate N,N,N-ligand is crucial for the efficient radical generation and the C(sp3)–C(sp) bond formation. Facile transformations of the difunctionalization products highlight its potential utility in the synthesis of various trifluoromethyl-containing building blocks.
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