Synthesis of Chiral Diarylmethylamides via Catalytic Asymmetric Aza-Michael Addition of Amides to ortho-Quinomethanes.

Chiral diarylmethylamides are a privileged skeleton in many bioactive molecules. However, the enantioselective synthesis of such molecules remains a long-standing challenge in organic synthesis. Herein, we report a chiral bifunctional squaramide catalyzed asymmetric aza-Michael addition of amides to in situ generated ortho-quinomethanes, affording enantioenriched diarylmethylamides in good yields with excellent enantioselectivities. This work not only provides a new strategy for the construction of the diarylmethylamides but also represents the practicability of amides as nitrogen-nucleophiles in asymmetric organocatalysis.

Diastereo- and Enantioselective Synthesis of Eight-Membered N-Heterocycles from Benzofuran-Derived Azadienes and Ynones.

Enantioselective synthesis of eight-membered N-heterocycles represents a long-standing challenge in organic synthesis. Here, by combining the squaramide and DBU catalysis, a sequential asymmetric conjugate addition/cyclization reaction between benzofuran-derived azadienes and ynones has been well-developed, providing straightforward access to chiral eight-membered N-heterocycles in high yields with stereoselectivities. This protocol features the use of a bifunctional squaramide catalyst for controlling the enantioselectivity of products, while the DBU is utilized to achieve intramolecular cyclization and improve the diastereoselectivity of products.

Enantioselective α-Amination of Amides by One-Pot Organo-/Iodine Sequential Catalysis.

An one-pot organo- and iodine sequential catalysis strategy for reactions of amides with pyrazole-based primary amines was described to synthesize chiral α-amino amides with a quaternary stereocenter. This methodology exhibited strong asymmetric induction, resulting in a typical enantiomeric excess value exceeding 99% and diastereoselectivity up to >99:1 dr. Moreover, the reaction was conducted without the use of any metals or strong bases.

Z-Selective access to α-trifluoromethyl arylenes through Pd-catalysed fluoroarylation of 1,1-difluoroallenes.

The synthesis of stereo-defined α-trifluoromethyl arylenes is of great importance in medical chemistry, organic chemistry, and materials science. However, despite the recent advances, the Z-selective formation of α-trifluoromethyl arylenes has remained underdeveloped. Here, we describe a facile approach towards Z-α-trifluoromethyl arylenes through Pd-catalysed stereoselective fluoroarylation of 1,1-difluoroallenes in the presence of a bulky monophosphine ligand.

Non-directed Pd-catalysed C-H arylation of [2.2]paracyclophane.

We report herein the palladium-catalysed mono-selective C-H arylation of [2.2]paracyclophane (PCP) with diverse aryl iodides in the absence of any pendant directing groups, providing straightforward and modular access to C4-arylated [2.2]paracyclophanes. Moreover, a new PCP-containing biaryl monophosphine complex could be readily obtained through further derivation of the arylated product.

Metal-free and enantioselective synthesis of 1,4-benzoxazepines from para-quinone methide derivatives and α-bromohydroxamates.

A sequential asymmetric conjugate addition/cyclisation of α-bromohydroxamates with para-quinone methide derivatives has been developed, which provides enantioenriched 1,4-benzoxazepines in generally high yields (up to 95%) and good enantioselectivities (up to 97 : 3 er). This protocol not only offers a novel and straightforward strategy for constructing chiral 1,4-benzoxazepines, but also demonstrates the potential of α-bromohydroxamates as three-atom synthons in asymmetric cyclisation reactions.

Iridium-catalysed thioether-directed regioselective cycloaddition of internal alkynes with azides.

We report herein a cationic iridium-catalysed thioether-directed alkyne-azide cycloaddition reaction. Diverse 2-alkynyl phenyl sulfides can undergo cycloaddition with different azides in a regioselective fashion. The reaction features high efficiency, a short reaction time, and a broad substrate scope, providing modular access to complex S-containing triazoles.

Ni-catalysed deamidative fluorination of amides with electrophilic fluorinating reagents.

We describe here a Ni-catalysed deamidative fluorination of diverse amides with electrophilic fluorinating reagents. Different types of amides including aromatic amides and olefinic amides were well compatible, affording the corresponding acyl fluorides in good to excellent yields.

Rapid access to 9-arylfluorene and spirobifluorene through Pd-catalysed C-H arylation/deaminative annulation.

We describe here a facile synthesis of 9-arylfluorenes and spirobifluorenes from readily available 1,1-diarylmethylamines and iodoarenes through Pd-cataylsed C(sp2)-H arylation and a sequential deaminative annulation. The reaction features high efficiency and simplicity of operation, constituting an interesting shortcut to access fluorene compounds.

Copper-catalyzed asymmetric 1,6-conjugate addition of in situ generated para-quinone methides with ß-ketoesters.

A Cu-catalyzed asymmetric 1,6-conjugate addition of in situ generated para-quinone methides (p-QMs) with ß-ketoester has been developed to construct a ketoester skeleton bearing an adjacent tertiary-quaternary carbon stereocenter in good yields and high enantioselectivities. This is the first example of metal-catalyzed asymmetric transformations of the in situ generated p-QMs, avoiding using pre-synthesized p-QMs requiring bulky 2,6-substitutions and highlighting a new dual catalytic activation with the chiral bis(oxazoline)-metal complex acting as a normal Lewis acid to activate the ß-ketoesters and a source of Brønsted acid responsible for generating the p-QMs in situ.

Enantioselective Syntheses of C2-Symmetric Pyrazolones and Diones via One-Pot Organo-/Iodine Sequential Catalysis.

The catalytic diastereo- and enantioselective syntheses of C2-symmetric axially chiral 1,4-dicarbonyl derivatives with 2,3-quaternary stereocenters were achieved by utilizing an organo-/iodine binary catalytic strategy. The reactions proceeded well under mild conditions without metals or strong bases.

Pd-catalysed ß-selective C(sp3)-H arylation of simple amides.

An efficient Pd-catalysed ß-C(sp3)-H arylation of diverse native amides with aryl iodides was developed. This protocol overcomes the necessity of the Thorpe-Ingold effect and features broad substrate scope and good functional group tolerance. The potential application of this protocol is collectively demonstrated by gram-scale synthesis and the synthesis of several bioactive molecules.

In situ generation of highly reactive allenes from nitrocyclopropanes: controllable synthesis of enynes and enesters.

A new and efficient strategy for ring-opening reactions of nitrocyclopropanes is developed for the first time for the divergent synthesis of enynes and enesters via in situ generated highly reactive electron-deficient intermediate allenes. Controllable approaches resulted in enynes and enesters with up to 89% and 90% yields, respectively. The reaction features easy operation, involves green solvents and simple inorganic bases, and is transition-metal free.

Asymmetric bis(oxazoline)-Ni(II) catalyzed α-hydroxylation of cyclic ß-keto esters under visible light.

Using visible light as a driving force and molecular oxygen as a green oxidant, we developed bis(oxazoline)-Ni(acac)2 catalyzed asymmetric α-hydroxylation of ß-keto esters under low photosensitizer loading, and the protocol enabled an efficient transformation to provide the desired chiral α-hydroxy-ß-keto esters in high yields (up to 99%) and enantioselectivities (up to 99% ee) at room temperature.

Pd-Catalysed direct C(sp2)-H fluorination of aromatic ketones: concise access to anacetrapib.

The Pd-cataylsed direct ortho-C(sp2)-H fluorination of aromatic ketones has been developed for the first time. The reaction features good regioselectivity and simple operations, constituting an alternative shortcut to access fluorinated ketones. A concise synthesis of anacetrapib has also been achieved by using late-stage C-H fluorination as a key step.

Direct N-alkylation of sulfur-containing amines.

An efficient ruthenium-catalyzed method has been developed for the direct N-alkylation of sulfur-containing amines with alcohols, for the first time, by a step-economical and environmentally friendly hydrogen borrowing strategy. The present methodology features base-free conditions and broad substrate scope, with water being the only by-product. Moreover, this protocol has been applied to the synthesis of the pharmaceutical drug Quetiapine.

Catalytic Asymmetric Conjugate Addition/Hydroalkoxylation Sequence: Expeditious Access to Enantioenriched Eight-Membered Cyclic Ether Derivatives.

A sequential enantioselective conjugate addition/hydroalkoxylation between in situ generated ortho-quinomethanes and ynones by combining bifunctional squaramide and DBU catalysis has been developed. A variety of eight-membered cyclic ethers with two contiguous tertiary stereocenters were obtained in high yields with excellent stereoselectivities. This reaction not only provides a new strategy for constructing enantioenriched eight-membered cyclic ethers but also demonstrates the practicability of ynones as C4-syntons for the synthesis of chiral medium-membered rings.

Regioselective C(sp3)-H fluorination of ketones: from methyl to the monofluoromethyl group.

Herein, we report a novel strategy to access CH2F-containing ketones through Pd-catalysed ß-selective methyl C(sp3)-H fluorination. The reaction features high regioselectivity and a broad substrate scope, constituting a modular method for the late-stage transformation of the native methyl (CH3) into the monofluoromethyl (CH2F) group.

Cu-Catalyzed Regioselective C-H Alkylation of Benzimidazoles with Aromatic Alkenes.

Herein we report a novel Cu-catalyzed regioselective C2-H alkylation of benzimidazoles with aromatic alkenes. The reaction features exclusive regioselectivity and broad substrate scope in the intermolecular alkylation of benzimidazoles with terminal and internal aromatic alkenes, constituting a modular access toward benzimidazole-containing 1,1-di(hetero)aryl alkanes. The intramolecular C2-H alkylation of benzimidazoles with aromatic alkenes has been achieved in an endo-selective manner. The enantioselective C2 alkylation of benzimidazoles has also been realized with moderate to good stereocontrol.

Nitrate promoted mild and versatile Pd-catalysed C(sp2)-H oxidation with carboxylic acids.

A nitrate-promoted Pd-catalysed mild cross-dehydrogenative C(sp2)-H bond oxidation of oximes or azobenzenes with diverse carboxylic acids has been developed. In contrast to the previous catalytic systems, this protocol features mild conditions (close to room temperature for most cases) and a broad substrate scope (up to 64 examples), thus constituting a versatile method to directly prepare diverse O-aryl esters. Moreover, the superiority of the nitrate additive in this mild transformation was further determined by experimental and computational evidence.