An official website of the United States government
Abstract Allylation and conjunctive cross‐coupling represent two useful, yet largely distinct, reactivity paradigms in catalysis. The union of these two processes would offer exciting possibilities in organic synthesis but remains largely unknown. Herein, we report the use of allyl electrophiles in nickel‐catalyzed conjunctive cross‐coupling with a non‐conjugated alkene and dimethylzinc. The transformation is enabled by weakly coordinating, monodentate aza‐heterocycle directing groups that are useful building blocks in synthesis, including saccharin, pyridones, pyrazoles, and triazoles. The reaction occurs under mild conditions and is compatible with a wide range of allyl electrophiles. High chemoselectivity through substrate directivity is demonstrated by the facile reactivity of the β‐γ alkene of the starting material, whereas the ϵ‐ζ alkene of the product is preserved. The generality of this approach is further illustrated through the development of an analogous method with alkyne substrates. Mechanistic studies reveal the importance of the dissociation of the weakly coordinating directing group to allow the allyl moiety to bind and facilitate C(sp3)−C(sp3) reductive elimination.
more »
« less
This content will become publicly available on April 17, 2026
Chemoselective Functionalization of Tertiary C−H Bonds of Allylic Ethers: Enantioconvergent Access to sec,tert‐Vicinal Diols
Abstract While enantioenriched alcohols are highly significant in medicinal chemistry, total synthesis, and materials science, the stereoselective synthesis of tertiary alcohols with two adjacent stereocenters remains a formidable challenge. In this study, we present a dual catalysis approach utilizing photoredox and nickel catalysts to enable the unprecedented chemoselective functionalization of tertiary allylic C−H bonds in allyl ethers instead of cleaving the C−O bond. The resulting allyl‐Ni intermediates can undergo coupling with various aldehydes, facilitating a novel enantioconvergent approach to access extensively functionalized homoallylicsec,tert‐vicinal diols frameworks. This protocol exhibits nice tolerance towards functional groups, a broad scope of substrates, excellent diastereo‐ and enantioselectivity (up to 20 : 1 dr, 99 %ee). Mechanistic studies suggested that allyl‐NiIIacts as the nucleophilic species in the coupling reaction with carbonyls.
more »
« less
- Award ID(s):
- 2153972
- PAR ID:
- 10628054
- Publisher / Repository:
- Wiley VCH
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 64
- Issue:
- 17
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Aryl tosylates are an attractive class of electrophiles for cross‐coupling reactions due to ease of synthesis, low price, and the employment of C−O electrophiles, however, the reactivity of aryl tosylates is low. Herein, we report the Ni‐catalyzed C(sp2)−C(sp3) Kumada cross‐coupling of aryl tosylates with primary and secondary alkyl Grignard reagents. The method delivers valuable alkyl arenes by cross‐coupling with challenging alkyl organometallics possessing β‐hydrogens that are prone to β‐hydride elimination and homo‐coupling. The reaction is catalyzed by an air‐ and moisture stable‐Ni(II) precatalyst. A broad range of electronically‐varied aryl tosylates, including bis‐tosylates, underwent this transformation, and many examples are suitable at mild room temperature conditions. The combination of Ar−X cross‐coupling with the facile Ar−OH activation/cross‐coupling strategy permits for orthogonal cross‐coupling with challenging alkyl organometallics. Furthermore, we demonstrate that the method operates with TON reaching 2000, which is one of the highest turnovers observed to date in Ni‐catalyzed cross‐couplings. magnified imagemore » « less
-
Abstract Direct oxidative C(sp)−H/C(sp3)−H cross‐coupling offers an ideal and environmentally benign protocol for C(sp)−C(sp3) bond formations. As such, reactivity and site‐selectivity with respect to C(sp3)−H bond cleavage have remained a persistent challenge. Herein is reported a simple method for iron‐catalyzed/silver‐mediated tertiary alkylation of terminal alkynes with readily available and versatile 1,3‐dicarbonyl compounds. The reaction is suitable for an array of substrates and proceeds in a highly selective manner even employing alkanes containing other tertiary, benzylic, and C(sp3)−H bonds alpha to heteroatoms. Elaboration of the products enables the synthesis of a series of versatile building blocks. Control experiments implicate the in situ generation of a tertiary carbon‐centered radical species.more » « less
-
The synthesis of alkylphosphine-substituted α-diimine (DI) ligands and their subsequent addition to Ni(COD) 2 allowed for the preparation of ( iPr2PPr DI)Ni and ( tBu2PPr DI)Ni . The solid state structures of both compounds were found to feature a distorted tetrahedral geometry that is largely consistent with the reported structure of the diphenylphosphine-substituted variant, ( Ph2PPr DI)Ni . To explore and optimize the synthetic utility of this catalyst class, all three compounds were screened for benzaldehyde hydrosilylation activity at 1.0 mol% loading over 3 h at 25 °C. Notably, ( Ph2PPr DI)Ni was found to be the most efficient catalyst while phenyl silane was the most effective reductant. A broad scope of aldehydes and ketones were then hydrosilylated, and the silyl ether products were hydrolyzed to afford alcohols in good yield. When attempts were made to explore ester reduction, inefficient dihydrosilylation was noted for ethyl acetate and no reaction was observed for several additional substrates. However, when an equimolar solution of allyl acetate and phenyl silane was added to 1.0 mol% ( Ph2PPr DI)Ni , complete ester C–O bond hydrosilylation was observed within 30 min at 25 °C to generate propylene and PhSi(OAc) 3 . The scope of this reaction was expanded to include six additional allyl esters, and under neat conditions, turnover frequencies of up to 990 h −1 were achieved. This activity is believed to be the highest reported for transition metal-catalyzed ester C–O bond hydrosilylation. Proposed mechanisms for ( Ph2PPr DI)Ni -mediated carbonyl and allyl ester C–O bond hydrosilylation are also discussed.more » « less
-
null (Ed.)Abstract Despite remarkable recent advances in transition-metal-catalyzed C(sp 3 )−C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary -C(sp 3 )−C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp 3 ) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis. This strategy is complementary to the existing coupling protocols with tert -alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials.more » « less
