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1.
J Am Chem Soc ; 146(22): 14915-14921, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38781401

ABSTRACT

Unactivated aliphatic alkenes are particularly desirable as starting materials because they are readily accessible in large quantities, but the enantioselective intermolecular reductive coupling of unactivated alkenes with imines is challenging. In this paper, we report a method for nickel-catalyzed intermolecular reductive coupling reactions between aliphatic alkenes and imines to yield chiral amines with excellent enantioselectivities and good linear selectivities. The reaction conditions are compatible with a broad range of aliphatic alkenes, including those derived from bioactive molecules. The success of this method can be attributed to the use of newly developed monodentate chiral spiro phosphine ligands.

2.
Angew Chem Int Ed Engl ; 62(49): e202314701, 2023 Dec 04.
Article in English | MEDLINE | ID: mdl-37846814

ABSTRACT

Intermolecular carbophosphination reaction of alkynes or alkenes with unreactive C-P bonds remains an elusive challenge. Herein, we used a Ni-Al bimetallic catalyst to realize an intermolecular carbophosphination reaction of alkynes with 5-membered phosphole oxides, providing a series of 7-membered phosphepines in up to 94 % yield.

3.
Molecules ; 28(2)2023 Jan 11.
Article in English | MEDLINE | ID: mdl-36677791

ABSTRACT

Ligands play a critical role in promoting transition-metal-catalyzed C-H activation reactions. However, owing to high sensitivity of the reactivity of C-H activation to metal catalysts, the development of effective ligands has been a formidable challenge in the field. Rh(I)-catalyzed C-H cyclization of benzimidazoles with alkenes has been faced with low reactivity, often requiring very harsh conditions. To address this challenge, a phosphine oxide-enabled Rh(I)-Al bimetallic catalyst was developed for the reaction, significantly promoting the reactivity and allowing the reaction to run at 120 °C with up to 97% yield.


Subject(s)
Oxides , Rhodium , Molecular Structure , Alkenes , Cyclization , Ligands , Benzimidazoles , Catalysis
4.
Org Lett ; 25(2): 353-357, 2023 Jan 20.
Article in English | MEDLINE | ID: mdl-36606754

ABSTRACT

Compared with the widely explored exo-selective C-H cyclization, transition metal-catalyzed endo-selective C-H cyclization of benzimidazoles with alkenes has been a formidable challenge. Previous efforts mainly rely on substrate-controlled methods, rendering the product complexity restricted. Herein we report a catalyst-controlled method to facilitate endo-cyclization, in which a bulky N-heterocyclic carbene ligand and tBuOK base-enabled Ni-Al bimetallic catalyst prove critical to the endo selectivity.

5.
Nat Commun ; 13(1): 7892, 2022 Dec 22.
Article in English | MEDLINE | ID: mdl-36550165

ABSTRACT

The development of transition metal-catalyzed ß-C-H bond activation via highly-strained 4-membered metallacycles has been a formidable task. So far, only scarce examples have been reported to undergo ß-C-H bond activation via 4-membered metallacycles, and all of them rely on precious metals. In contrast, earth-abundant and inexpensive 3d transition metal-catalyzed ß-C-H bond activation via 4-membered metallacycles still remains an elusive challenge. Herein, we report a phosphine oxide-ligated Ni-Al bimetallic catalyst to activate secondary benzylic C(sp3)-H bonds of formamides via 4-membered nickelacycles, providing a series of α,ß-unsaturated γ-lactams in up to 97% yield.

6.
Chem Commun (Camb) ; 58(88): 12260-12273, 2022 Nov 03.
Article in English | MEDLINE | ID: mdl-36269303

ABSTRACT

Compared with non-ligated Ni-Al bimetallic catalysis, bifunctional ligand-ligated Ni-Al bimetallic catalysis displays stronger synergism, not only affecting the electronic properties and steric hindrance of substrates, but also producing a directing effect for facile control of reactivity, site selectivity and enantioselectivity in the activation of C-H and C-C bonds. This review will give a brief summary of research advances in this field, highlighting the development of bifunctional ligands and their applications.

7.
J Am Chem Soc ; 144(41): 18810-18816, 2022 10 19.
Article in English | MEDLINE | ID: mdl-36205623

ABSTRACT

A chiral phosphine oxide-ligated Ni-Al bimetallic catalyst was used to realize an enantioselective C2-H alkylation of pyridines without the need of a C2-block. A wide range of pyridines, including unsubstituted pyridine, C3, C4, and C2-substituted pyridines, and even complex pyridine-containing bioactive molecules are well compatible with the reaction, providing up to 81% yield and up to 97% ee.


Subject(s)
Polyenes , Pyridines , Stereoisomerism , Catalysis , Alkylation , Oxides
8.
Angew Chem Int Ed Engl ; 61(42): e202209625, 2022 Oct 17.
Article in English | MEDLINE | ID: mdl-36036435

ABSTRACT

Enantioselective Ni-catalyzed C(sp3 )-H bond activation remains an elusive challenge. Herein, we used phosphine oxide-ligated Ni-Al bimetallic catalyst to realize enantioselective Ni-catalyzed aliphatic C(sp3 )-H activation of formamides, providing a series of chiral N-containing heterocycles in 40-95 % yield and 70-95 % ee.


Subject(s)
Formamides , Nickel , Catalysis , Formamides/chemistry , Nickel/chemistry , Oxides , Stereoisomerism
9.
Nat Commun ; 13(1): 2938, 2022 May 26.
Article in English | MEDLINE | ID: mdl-35618702

ABSTRACT

Hydroarylation of alkynes with unactivated C(sp2)-H bonds via chelated C-H metalation mainly occurs at γ-position to the coordinating atom of directing groups via stable 5-membered metallacycles, while ß-C(sp2)-H bond-involved hydroarylation has been a formidable challenge. Herein, we used a phosphine oxide-ligated Ni-Al bimetallic catalyst to enable ß-C-H bond-involved hydroarylations of alkynes via a rare 7-membered nickelacycle.

10.
Nat Chem ; 13(12): 1207-1213, 2021 12.
Article in English | MEDLINE | ID: mdl-34635815

ABSTRACT

Achieving the transition metal-catalysed pyridine C3-H alkenylation, with pyridine as the limiting reagent, has remained a long-standing challenge. Previously, we disclosed that the use of strong coordinating bidentate ligands can overcome catalyst deactivation and provide Pd-catalysed C3 alkenylation of pyridines. However, this strategy proved ineffective when using pyridine as the limiting reagent, as it required large excesses and high concentrations to achieve reasonable yields, which rendered it inapplicable to complex pyridines prevalent in bioactive molecules. Here we report that a bifunctional N-heterocyclic carbene-ligated Ni-Al catalyst can smoothly furnish C3-H alkenylation of pyridines. This method overrides the intrinsic C2 and/or C4 selectivity, and provides a series of C3-alkenylated pyridines in 43-99% yields and up to 98:2 C3 selectivity. This method not only allows a variety of pyridine and heteroarene substrates to be used as the limiting reagent, but is also effective for the late-stage C3 alkenylation of diverse complex pyridine motifs in bioactive molecules.


Subject(s)
Alkenes/chemical synthesis , Coordination Complexes/chemistry , Nickel/chemistry , Pyridines/chemical synthesis , Alkynes/chemistry , Aluminum/chemistry , Catalysis , Models, Chemical
11.
Nat Commun ; 12(1): 3800, 2021 06 21.
Article in English | MEDLINE | ID: mdl-34155203

ABSTRACT

Allylic amines are versatile building blocks in organic synthesis and exist in bioactive compounds, but their synthesis via hydroaminoalkylation of alkynes with amines has been a formidable challenge. Here, we report a late transition metal Ni-catalyzed hydroaminoalkylation of alkynes with N-sulfonyl amines, providing a series of allylic amines in up to 94% yield. Double ligands of N-heterocyclic carbene (IPr) and tricyclohexylphosphine (PCy3) effectively promote the reaction.

12.
Org Lett ; 23(10): 4034-4039, 2021 May 21.
Article in English | MEDLINE | ID: mdl-33970650

ABSTRACT

Transition metal catalyzed dual C-H activation and annulation with alkynes was an attractive protocol to construct polycyclic π-extended structures. However, most of them were dominated by noble metal catalysts. Disclosed herein was the study of base-metal Ni-catalysis for dual C-H annulation of N-aromatic imidazole, which produced a range of desired polycyclic aza-quinolines in 48-95% yields. The use of bifunctional phosphine oxide ligand proved to be critical for success.

13.
Nat Commun ; 12(1): 3070, 2021 05 24.
Article in English | MEDLINE | ID: mdl-34031420

ABSTRACT

The construction of 7-membered ring via direct C7-H cyclization of benzoimidazoles with alkenes would provide a more atom- and step-economical route to tricyclic imidazoles and derivatives that widely exist in a broad range of bioactive molecules. However, transition metal-catalyzed C-H cyclization for medium-ring synthesis has been limited to reactive C-H bonds, instead, the activation of unreactive C-H bonds towards medium synthesis still remains an elusive challenge. Herein, we report a direct construction of 7-membered rings via Ni-Al co-catalyzed unreactive C7-H cyclization of benzoimidazoles with alkenes, providing a series of tricyclic imidazoles in 40-98% yield and with up to 95:5 er.

14.
J Am Chem Soc ; 142(47): 19844-19849, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33170685

ABSTRACT

A carbamoyl fluoride-enabled enantioselective Ni-catalyzed carbocarbamoylation of unactivated alkenes was developed, providing a broad range of chiral γ-lactams bearing an all-carbon quaternary center in 45-96% yield and 38-97% ee.

15.
Org Lett ; 22(6): 2230-2234, 2020 03 20.
Article in English | MEDLINE | ID: mdl-32142300

ABSTRACT

A bifunctional secondary phosphine oxide (SPO) ligand-controlled method was developed for Ni-Al-catalyzed nonchelated dual C-H annulation of arylformamides with alkynes, providing a series of substituted amide-containing heterocycles in ≤97% yield. The SPO-bound bimetallic catalysis proved to be critical to the reaction efficiency.

16.
Angew Chem Int Ed Engl ; 59(24): 9428-9432, 2020 Jun 08.
Article in English | MEDLINE | ID: mdl-32154983

ABSTRACT

Twofold C-H annulation of readily available formamides and alkynes without built-in chelating groups was achieved. Ni-Al bimetallic catalysis enabled by a bulky BINOL-derived chiral secondary phosphine oxide (SPO) ligand proved to be critical for high reactivity and high selectivity. This reaction uses readily available formamides as starting materials and provides a concise synthetic pathway to a broad range of chiral ferrocenes in 40-98 % yield and 93-99 % ee.

17.
Angew Chem Int Ed Engl ; 59(19): 7439-7443, 2020 May 04.
Article in English | MEDLINE | ID: mdl-32067290

ABSTRACT

A chiral aluminum complex controlled, enantioselective nickel-catalyzed domino reaction of aryl nitriles and alkynes proceeding by C-CN bond activation was developed. The reaction provides various indenes, bearing chiral all-carbon quaternary centers, under mild reaction conditions in yields of 32 to 91 % and ee values within the 73-98 % range. The reaction mechanism and aspects of stereocontrol were investigated by DFT calculations.

18.
Angew Chem Int Ed Engl ; 58(21): 7097-7101, 2019 May 20.
Article in English | MEDLINE | ID: mdl-30891881

ABSTRACT

An iron-catalyzed hydrofluorination of unactivated alkenes has been developed. The use of a multidentate ligand and the fluorination reagent N-fluorobenzenesulfonimide (NFSI) proved to be critical for this reaction, which afforded various fluorinated compounds in up to 94 % yield.

19.
Biochemistry ; 57(30): 4518-4525, 2018 07 31.
Article in English | MEDLINE | ID: mdl-29975048

ABSTRACT

Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Design , Furans/chemistry , Furans/pharmacology , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacology , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacology , Animals , Binding Sites/drug effects , Catalytic Domain/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Furans/pharmacokinetics , Humans , Hydrogen Bonding/drug effects , Male , Memory/drug effects , Mice, Inbred ICR , Molecular Docking Simulation , Phenyl Ethers/pharmacokinetics , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Rolipram/analogs & derivatives , Rolipram/pharmacokinetics , Rolipram/pharmacology , Stereoisomerism , Water/chemistry
20.
J Am Chem Soc ; 140(16): 5360-5364, 2018 04 25.
Article in English | MEDLINE | ID: mdl-29641189

ABSTRACT

A Ni-Al bimetallic catalyzed enantioselective C-H exo-selective cyclization of imidazoles with alkenes has been developed. A series of bi- or polycyclic imidazoles with ß-stereocenter were obtained in up to 98% yield and >99% ee. The bifunctional SPO ligand-promoted bimetallic catalysis proved to be critical to this challenging stereocontrol.

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