Weipeng Li

Visible‐Light Photoredox‐Catalyzed C−H Difluoroalkylation of Hydrazones through an Aminyl Radical/Polar Mechanism

An unprecedented visible-light-induced direct C-H bond difluoroalkylation of aldehyde-derived hydrazones was developed. This reaction represents a new way to synthesize substituted hydrazones. The salient features of this reaction include difluorinated hydrazone synthesis rather than classical amine synthesis, extremely mild reaction conditions, high efficiency, wide substrate scope, ease in further transformations of the products, and one-pot syntheses. Mechanistic analyses and theoretical calculations indicate that this reaction is enabled by a novel aminyl radical/polar crossover mechanism, with the aminyl radical being oxidized into the corresponding aminyl cation through a single electron transfer (SET) process.

Visible-light-induced direct C(sp3)–H difluromethylation of tetrahydroisoquinolines with the in situ generated difluoroenolates

An effective approach to C1-difluoromethylated tetrahydroisoquinoline derivatives has been developed through C-H functionalization of tertiary amines by visible-light photoredox catalysis. This method uses stable, easily obtained α,α-difluorinated gem-diol as the CF2 source. The corresponding products were obtained in moderate to high yields at ambient temperature.

Cascade Photoredox/Iodide Catalysis: Access to Difluoro-γ-lactams via Aminodifluoroalkylation of Alkenes

The novel cascade photoredox/iodide catalytic system enables the alkene to serve as a radical acceptor capable of achieving aminodifluoroalkylation of alkenes. Cheap iodide salts play a vital role in this reaction, which could tune carbocation reactivity through reversible C-I bond formation for controlling reaction selectivity, and a series of competitive reactions are completely eliminated in the presence of multiple reactivity pathways. The present dual catalytic protocol affords a very convenient method for direct synthesis of various difluoro-γ-lactams from simple and readily available starting materials under mild reaction conditions.

Chiral Tertiary Amine Thiourea-Catalyzed Asymmetric Inverse-Electron-Demand Diels–Alder Reaction of Chromone Heterodienes Using 3-Vinylindoles as Dienophiles

A straightforward and efficient protocol for the construction of structurally and biologically interesting chiral flavanoids incorporating three privileged structures, i.e., chromanone, dihydropyran, and indole, has been developed on the basis of chiral bifunctional tertiary amine thiourea-catalyzed asymmetric inverse-electron-demand Diels-Alder reaction of chromone heterodienes and 3-vinylindoles, which were used as dienophiles.

Silver-Catalyzed Cascade Radical Cyclization: A Direct Approach to 3,4-Disubstituted Dihydroquinolin-2(1H)-ones through Activation of the P–H Bond and Functionalization of the C(sp2)–H Bond

A silver-catalyzed cascade cyclization of cinnamamides with diphenylphosphine oxide was developed, in which activation of the P-H bond and functionalization of the C(sp(2))-H bond occurred. A direct method for the synthesis of 3,4-disubstituted dihydroquinolin-2(1H)-ones was developed.

Enantioselective Construction of Dihydropyran‐Fused Indoles through Chiral Calcium Phosphate Catalyzed Oxo‐Hetero‐Diels–Alder Reactions by Using 2‐Oxoindolin‐3‐ylidenes as Heterodienes

Carbon-carbon bond formation: A highly efficient method for the oxo-hetero-Diels-Alder reaction of 2-oxoindolin-3-ylidenes based on chiral calcium phosphate is described. In general, adducts were obtained with high yields and excellent diastereo- and enantioselectivities (up to 96 % yield, >99:1 endo/exo, >99 % ee; see scheme, Boc = tert-butoxycarbonyl).

Copper-Catalyzed Cascade Phosphorylation Initiated Radical Cyclization: Access to 2-Phosphorylated Pyrrolo[1,2-a]indole

A copper-catalyzed tandem radical cyclization of 1-(3-phenylprop-2-yn-1-yl)-1H-indole with diphenylphosphine oxides was developed. C-P bond formation was achieved coupled with C(sp2)-H functionalization. It provided an access to construct the pyrrolo[1,2-a]indole motif and a series of 2-phosphinoyl-9H-pyrrolo[1,2-a]indoles.

Relay Visible-Light Photoredox Catalysis: Synthesis of Pyrazole Derivatives via Formal [4 + 1] Annulation and Aromatization

A relay visible-light photoredox catalysis strategy has been accomplished. Three successive photoredox cycles (one oxidative quenching cycle and two reductive quenching cycles) are engaged in a single reaction with one photocatalyst. This strategy enables formal [4 + 1] annulation of hydrazones with 2-bromo-1,3-dicarbonyl compounds, which functionalizes three C-H bonds of hydrazones. This method affords rapid access to a complex and biologically important pyrazole scaffold in a step-economical manner with high efficiency under mild conditions.

Exploration of C–H Transformations of Aldehyde Hydrazones: Radical Strategies and Beyond

The chemistry of hydrazones has gained great momentum due to their involvement throughout the evolution of organic synthesis. Herein, we discuss the tremendous developments in both the methodology and application of hydrazones. Hydrazones can be recognized not only as synthetic equivalents to aldehydes and ketones but also as versatile synthetic building blocks. Consequently, they can participate in a range of practical synthetic transformations. Furthermore, hydrazone derivatives display a broad array of biological activities and have been widely applied as pharmaceuticals. Owing to the weak directing group effect of simple aldehydes and ketones in C-H bond functionalizations, the C-H bond functionalizations of hydrazones that have been developed in the past five years represent a significant step forward. These novel transformations open a new door to a broader library of functionalized and complex small molecules. Moreover, a wide range of biologically important N-heterocycles (dihydropyrazoles, pyrazoles, indazoles, cinnolines, etc.) can be efficiently synthesized in an atom- and step-economical manner through single, double, or triple C-H bond functionalizations of hydrazones. Both radical C-H functionalizations and transition-metal-catalyzed directing-group strategies have enhanced the synthetic utility of hydrazones in the chemical community because these strategies solve the long-standing challenge of C-H functionalizations adjacent to aldehydes and ketones. We began this study based on our ongoing interest in visible-light photoredox catalysis. Visible-light photoredox catalysis has become a powerful tool in contemporary synthetic chemistry due to its remarkable advantages in sustainability and use of radical chemistry. By exploiting a photoredox-catalyzed aminyl radical polar crossover (ARPC) strategy, we successfully achieved visible-light-induced C(sp2)-H difluoroalkylation, trifluoromethylation, and perfluoroalkylation of aldehyde-derived hydrazones. This intriguing result was later applied in the C(sp2)-H amination of hydrazones and a cascade cyclization reaction for the synthesis of polycyclic compounds. Encouraged by this redox-neutral C-H functionalization of aldehyde hydrazones, we extended the oxidative C-H/P-H cross-coupling method, which represents a novel and efficient method for the synthesis of α-iminophosphine oxides. Furthermore, an elegant [3 + 2] cycloaddition of azides and aldehyde hydrazones for the synthesis of functionalized tetrazoles was advantageously developed during our investigation of the oxidative C(sp2)-H azidation of aldehyde hydrazones with TMSN3. The sequential C(sp2)-H/C(sp3)-H bond functionalization of aldehyde-derived hydrazones with simple 2,2-dibromo-1,3-dicarbonyls was achieved by employing relay photoredox catalysis, and it provides a novel method of accessing bioactive fused dihydropyrazole derivatives. The notable feature of this approach was further reflected in the formal [4 + 1] annulation of aldehyde-derived N-tetrahydroisoquinoline hydrazones with 2-bromo-1,3-dicarbonyls. To complement these radical C-H functionalization strategies, we recently applied a directing-group strategy in the Rh-catalyzed C(aldehyde)-H functionalization of aldehyde-derived hydrazones for the synthesis of distinctive and bioactive 1H-indazole scaffolds. In summary, this Account presents recent contributions to the exploration, development, mechanistic insights, and synthetic applications of C-H bond functionalizations of aldehyde hydrazones.

Photoredox 1,2-dicarbofunctionalization of unactivated alkenes via tandem radical difluoroalkylation and alkynyl migration

Visible-light-mediated tandem radical difluoroalkylation and alkynylation of unactivated alkenes is described in this communication. The process comprises a mild C–C bond activation via intramolecular 1,4-alkynyl migration. The general and elegant protocol can serve as a straightforward access route to obtain a wide range of synthetically valuable difluoroalkylated linear alkynyl ketones under mild reaction conditions.