Pd/IPrBIDEA-Catalyzed Hydrodefluorination of gem-Difluorocyclopropanes: Regioselective Synthesis of Terminal Fluoroalkenes.

Developing new strategies to enable chemo- and regioselective reductions is an important topic in chemical research. Herein, an efficient and regioselective Pd/IPrBIDEA-catalyzed ring-opening hydrodefluorination of gem-difluorocyclopropanes to access terminal fluoroalkenes is developed. The success of this transformation was attributed to the use of 3,3-dimethylallyl Bpin as a novel hydride donor. DFT calculations suggest that a direct 3,4'-hydride transfer via a 9-membered cyclic transition state is more favorable, which combined with the irreversibility of the reaction enables the unusual selectivity for the less thermodynamically stable terminal alkene isomer. This reaction mode is also applicable to a variety of regioselective allylic and propargyl reductions.

Amine-Induced Selective C-C Bond Cleavage of 2,2,2-Trifluoroethyl Carbonyls for the Synthesis of Ureas and Amides.

An efficient and selective transformation of 2,2,2-trifluoroethyl carbonyls into ureas/amides with amines is reported. This protocol allows the selective cleavage of the C-C bond of 2,2,2-trifluoroethyl carbonyls under transition metal-free and oxidant-free conditions, which is in contrast to the analogous C-F or C-CF3 bond functionalization. This reaction reveals the unexplored reactivity of 2,2,2-trifluoroethyl carbonyls and exhibits a broad substrate range and good functional group tolerance.

Pd-IHept-Catalyzed Ring-Opening of gem-Difluorocyclopropanes with Malonates Via Selective C-C Bond Cleavage: Synthesis of Monofluoroalkenes.

Monofluoroalkene scaffolds are frequently found in various functional molecules. Herein, we report a Pd-IHept-catalyzed (NHC = N-heterocyclic carbene) defluorinative functionalization approach for the synthesis of monofluoroalkenes from gem-difluorocyclopropanes and malonates. The flexible yet sterically hindered N,N'-bis(2,6-di(4-heptyl)phenyl)imidazol-2-ylidene ligand plays a key role in ensuring the high reaction efficiency. In addition, sterically hindered 1,1- and 1,2-disubstituted gem-difluorocyclopropanes could also be used in this transformation.

Chemo-, Stereo- and Regioselective Fluoroallylation/Annulation of Hydrazones with gem-Difluorocyclopropanes via Tunable Palladium/NHC Catalysis.

Defluorinative manipulation of polyfluorinated molecules has shown great promise due to its granting of synthetic versatility to inert C-F bonds. The development of chemo-, stereo- and regioselective strategies to realize highly efficient formation of either the linear/branched or E/Z products from gem-difluorocyclopropanes (gem-F2 CPs) is a challenging task. Herein, we have realized palladium/NHC-catalyzed fluoroallylation/annulation of hydrazones with gem-F2 CPs that incorporate the hydrazone N2 moiety into the products. The thermodynamically unstable fluorinated E-allylation products with aryl ketone hydrazones were obtained for the first time, while the di-alkyl ketone hydrazones yielded the monofluorinated products with branched selectivity under similar reaction conditions. With aldehyde hydrazones, two kinds of pyrazoles were obtained via a defluorinative allylation/annulation cascade, in which different carbon atoms of gem-F2 CPs could be incorporated into the pyrazole rings regiospecifically. DFT calculations revealed that the divergent selectivity was kinetically controlled and the final C-C bond formation proceeded through a 7-membered TS.

ß-Perfluoroalkyl Peroxides as Fluorinated C3-Building Blocks for the Construction of Benzo[4,5]imidazo[1,2-a]pyridines.

An efficient and selective protocol for the synthesis of perfluoroalkyl-group-substituted benzo[4,5]imidazo[1,2-a]pyridines has been developed in which ß-perfluoroalkyl peroxides act as novel fluorinated C3-building blocks to implement regioselective [3 + 3] annulation with 2-cyanomethyl benzimidazole under metal-free conditions. The application of the synthesized perfluoroalkylated BIPs as potent anticancer reagents versus the nonfluorinated ones demonstrated the biological utility of this method.

Three-Component Reactions of α-CF3 Carbonyls, NaN3, and Amines for the Synthesis of NH-1,2,3-Triazoles.

The development of methods for the assembly of 1,2,3-triazoles is an important topic due to the broad applications of this motif in various scientific fields. In this work, we demonstrate that the three-component assembly of α-CF3 carbonyls, NaN3, and amines was achieved for the selective construction of a variety of 5-amino NH-1,2,3-triazoles under transition-metal-free and open-air conditions. The method provides a general and operationally simple route to functionalized biologically important molecules including carbohydrates, nucleosides, and peptides and exhibits broad substrate scopes. We further demonstrate that the NH-1,2,3-triazoles can be smoothly converted to the regiospecific N-2 alkylated 1,2,3-triazole products. Mechanistic studies based on experiments and density functional theory calculations showed that this transformation proceeds via defluorination-initiated programmed substitution/cyclization/H-transfer to give the 4,5-difunctionalized captodative NH-1,2,3-triazole product.

Palladium-Catalyzed Defluorinative Alkylation of gem-Difluorocyclopropanes: Switching Regioselectivity via Simple Hydrazones.

Conventional approaches for Pd-catalyzed ring-opening cross-couplings of gem-difluorocyclopropanes with nucleophiles predominantly deliver the ß-fluoroalkene scaffolds (linear selectivity). Herein, we report a cooperative strategy that can completely switch the reaction selectivity to give the alkylated α-fluoroalkene skeletons (branched selectivity). The unique reactivity of hydrazones that enables analogous inner-sphere 3,3'-reductive elimination driven by denitrogenation, as well as the assistance of steric-embedded N-heterocyclic carbene ligand, are the key to switch the regioselectivity. A wide range of hydrazones derived from naturally abundant aryl and alkyl aldehydes are well applicable, and various gem-difluorocyclopropanes, including modified pharmaceutical and biological molecules, can be efficiently functionalized with high value alkylated α-fluorinated alkene motifs under mild conditions.

Switch in Selectivity for Formal Hydroalkylation of 1,3-Dienes and Enynes with Simple Hydrazones.

Controlling reaction selectivity is a permanent pursuit for chemists. Regioselective catalysis, which exploits and/or overcomes innate steric and electronic bias to deliver diverse regio-enriched products from the same starting materials, represents a powerful tool for divergent synthesis. Recently, the 1,2-Markovnikov hydroalkylation of 1,3-dienes with simple hydrazones was reported to generate branched allylic compounds when a nickel catalyst was used. As part of the effort, shown here is that a complete switch of Markovnikov to anti-Markovnikov addition is obtained by changing to a ruthenium catalyst, thus providing direct and efficient access to homoallylic products exclusively. Isotopic substitution experiments indicate that no reversible hydro-metallation across the metal-π-allyl system occurred under ruthenium catalysis. Moreover, this protocol is applicable to the regiospecific hydroalkylation of the distal C=C bond of 1,3-enynes.

Synergistic Relay Reactions To Achieve Redox-Neutral α-Alkylations of Olefinic Alcohols with Ruthenium(II) Catalysis.

Herein, we report a ruthenium-catalyzed redox-neutral α-alkylation of unsaturated alcohols based on a synergistic relay process involving olefin isomerization (chain walking) and umpolung hydrazone addition, which takes advantage of the interaction between the two rather inefficient individual reaction steps to enable an efficient overall process. This transformation shows the compatibility of hydrazone-type "carbanions" and active protons in a one-pot reaction, and at the same time achieves the first Grignard-type nucleophilic addition using olefinic alcohols as latent carbonyl groups, providing a higher yield of the corresponding secondary alcohol than the classical hydrazone addition to aldehydes does. A broad scope of unsaturated alcohols and hydrazones, including some complex structures, can be successfully employed in this reaction, which shows the versatility of this approach and its suitability as an alternative, efficient means for the generation of secondary and tertiary alcohols.

Palladium-Catalyzed Formal Hydroalkylation of Aryl-Substituted Alkynes with Hydrazones.

We have developed an unprecedented Pd-catalyzed formal hydroalkylation of alkynes with hydrazones, which are generated in situ from naturally abundant aldehydes, as both alkylation reagents and hydrogen donors. The hydroalkylation proceeds with high regio- and stereoselectivity to form (Z)-alkenes, which are more difficult to generate compared to (E)-alkenes. The reaction is compatible with a wide range of functional groups, including hydroxy, ester, ketone, nitrile, boronic ester, amine, and halide groups. Furthermore, late-stage modifications of natural products and pharmaceutical derivatives exemplify its unique chemoselectivity, regioselectivity, and synthetic applicability. Mechanistic studies indicate the possible involvement of Pd-hydride intermediates.

Nickel-Catalyzed Cross-Coupling of Umpolung Carbonyls and Alkyl Halides.

An effective nickel-catalyzed cross-coupling of Umpolung carbonyls and alkyl halides was developed. Complementary to classical alkylation techniques, this reaction utilizes Umpolung carbonyls as the environmentally benign alkyl nucleophiles, providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

FeCl3-Catalyzed Regio-Divergent Carbosulfenylation of Unactivated Alkenes: Construction of a Medium-Sized Ring.

A FeCl3-catalyzed regio-divergent carbosulfenylation of unactivated alkenes with electrophilic N-sulfenophthalimides has been developed. This protocol provides a straightforward and efficient access to various medium-sized rings, especially strained 7- and 8-membered carborings with a sulfur atom attached. The endo/exo selectivity in the reaction depends on the atom number of the chain between arene and alkene. Broad substrate scope, high yields, and gram-scale synthesis exemplified the utility and practicability of this protocol. In addition, this methodology can be extended to the carboselenylation of isolated alkenes.

Metal-Free and Redox-Neutral Conversion of Organotrifluoroborates into Radicals Enabled by Visible Light.

Converting organoboron compounds into the corresponding radicals has broad synthetic applications in organic chemistry. To achieve these transformations, various strong oxidants such as Mn(OAc)3 , AgNO3 /K2 S2 O8 , and Cu(OAc)2 , in stoichiometric amounts are required, proceeding by a single-electron transfer mechanism. Established herein is a distinct strategy for generating both aryl and alkyl radicals from organotrifluoroborates through an SH 2 process. This strategy is enabled by using water as the solvent, visible light as the energy input, and diacetyl as the promoter in the absence of any metal catalyst or redox reagent, thereby eliminating metal waste. To demonstrate its synthetic utility, an efficient acetylation to prepare valuable aryl (alkyl) methyl ketones is described and applications to construct C-C, C-I, C-Br, and C-S bonds are also feasible. Experimental evidence suggests that triplet diacetyl serves as the key intermediate in this process.

Silver(I)-Catalyzed Widely Applicable Aerobic 1,2-Diol Oxidative Cleavage.

The oxidative cleavage of 1,2-diols is a fundamental organic transformation. The stoichiometric oxidants that are still predominantly used for such oxidative cleavage, such as H5 IO6 , Pb(OAc)4 , and KMnO4 , generate stoichiometric hazardous waste. Herein, we describe a widely applicable and highly selective silver(I)-catalyzed oxidative cleavage of 1,2-diols that consumes atmospheric oxygen as the sole oxidant, thus serving as a potentially greener alternative to the classical transformations.

Umpolung of Carbonyl Groups as Alkyl Organometallic Reagent Surrogates for Palladium-Catalyzed Allylic Alkylation.

Palladium-catalyzed allylic alkylation of nonstabilized carbon nucleophiles is difficult and remains a major challenge. Reported here is a highly chemo- and regioselective direct palladium-catalyzed C-allylation of hydrazones, generated from carbonyls, as a source of umpolung unstabilized alkyl carbanions and surrogates of alkyl organometallic reagents. Contrary to classical allylation techniques, this umpolung reaction utilizes hydrazones prepared not only from aryl aldehydes but also from alkyl aldehydes and ketones as renewable feedstocks. This strategy complements the palladium-catalyzed coupling of unstabilized nucleophiles with allylic electrophiles by providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

Cycloalkylation of C(sp3)-H Bond with Neighboring Carboxylic Acid as Traceless Activating Group.

Selective functionalization of inert C(sp3)-H bond is one of cutting-edge challenges in chemical synthesis. A novel strategy for selective C(sp3)-H bond cycloalkylation is developed with neighboring carboxylic acid as a traceless activating group. Primary and secondary alkyl carboxylic acids undergo decarboxylation/α-C(sp3)-H cleavage/cycloalkylation to give the five-membered cyclization products, while tertiary acids undergo decarboxylation/ß-C(sp3)-H cleavage/cycloalkylation to generate the six-membered cyclization products.

Total Synthesis and Structure Revision of (±)-Clavilactone D Through Selective Cyclization of an α,ß-Dicarbonyl Peroxide.

The structure of (±)-clavilactone D was revised, and the synthesis was achieved in seven steps from a substituted benzaldehyde. The key step was the base-catalyzed cyclization of an α,ß-carbonyl peroxide, which was obtained by an iron-catalyzed three-component reaction of a benzaldehyde, an alkene, and TBHP. NaBH4-mediated reductive lactonization of the resulting cis-dicarbonyl epoxide led to the α,ß-epoxy-γ-butyrolactone skeleton highly stereoselectively. The synthesis provides a concise, reliable, and practical route to the revised structure of clavilactone D.

Iron-Catalyzed Divergent Tandem Radical Annulation of Aldehydes with Olefins toward Indolines and Dihydropyrans.

Iron-catalyzed divergent tandem radical annulations of aldehydes with olefins are reported. The new strategy allows the rapid and efficient construction of various multifunctionlized indolines (R = Ar) and dihydropyrans (R = Me), which are significant skeletons in bioactive natural products and pharmaceuticals. The substituents of tertiary amines play vital roles to facilitate the desired transformation. Mechanistic studies on indoline formation disclose that the homolytic cleavage of the carbonyl C-H bond might be involved in the rate-determining step, while dissociation of the aromatic C-H bond was most likely included in the product-determining step.

Iron-catalyzed acylation-oxygenation of terminal alkenes for the synthesis of dihydrofurans bearing a quaternary carbon.

Iron-catalyzed acylation-oxygenation of terminal alkenes is reported. Acyl radicals generated by the oxidation of aldehydes add to terminal alkenes and followed by intramolecular oxygenation give functionalized 2,3-dihydrofuran derivatives bearing a quaternary carbon.

Total synthesis of (±)-clavilactones†A, B, and proposed†D through iron-catalyzed carbonylation-peroxidation of olefin.

Biologically significant clavilactones A, B, and the previously proposed D have been synthesized through iron-catalyzed carbonylation-peroxidation of a 1,5-diene. Three steps from aldehydes, alkenes, and tert-butylhydroperoxide build up α,ß-epoxy-γ-butyrolactone skeleton as a key building block for synthesis of clavilactone family and its derivatives. Based on our results, the structure of the proposed clavilactone D is not correct and requires revision.