Photocatalytic Sulfonyl Peroxidation of Alkenes via Deamination of N-Sulfonyl Ketimines.

A photocatalytic three-component sulfonyl peroxidation of alkenes with N-sulfonyl ketimines and tert-butyl hydroperoxide is reported. The reaction takes place via the photoinduced EnT process, which allows the efficient synthesis of a variety of ß-peroxyl sulfones under mild reaction conditions in the absence of a transition metal catalyst. The downstream derivatizations of the peroxides were also performed. Furthermore, the utility of this protocol was manifested by the synthesis of 11ß-HSD1 inhibitor and the antiprostate cancer drug bicalutamide.

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.

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.

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.

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.

Copper-Catalyzed Germyl-Azidation of Alkenes with Germanium Hydrides and Trimethylsilyl Azide.

The incorporation of a germyl group and another functional fragment across the C═C bond is a challenging task due to the prevailing hydrogermylation reaction. Herein, an efficient copper-catalyzed three-component reaction of alkenes, germanium hydrides, and trimethylsilyl azide has been disclosed. This transformation allows the concomitant introduction of germyl and azide groups across the double bonds in a highly regioselective manner with tert-butyl hydroperoxides as the bystanding oxidant. The resulting ß-germyl azides could be easily converted into ß-germyl amine and 1,2,3-triazoles of significant value.

Umpolung carbonyls enable direct allylation and olefination of carbohydrates.

Mother Nature has its own arts to build a vast number of carbohydrates; however, there is still a lack of tools for selective functionalization of native carbohydrates through C─C bond formation. Such a long-standing challenge for the synthetic community lies into the intrinsic problems related to the innate properties of carbohydrates, e.g., the ease to oligomerization or polymerization, the difficulty of chemoselectivity control in the presence of multiple hydroxyl groups, the great challenge to retain the multiple chiral centers during the transformation, etc. Here, by applying an umpolung strategy of carbohydrate carbonyls, we report a direct deoxygenative allylation and olefination of carbohydrates to tackle the abovementioned issues. The reaction is compatible with a wide range of natural carbohydrates, providing a direct synthetic method to use carbohydrates as multiple C-centered chiral synthons to achieve C─C bond cross-coupling reactions. Furthermore, the synthetic applicability is demonstrated by late-stage modifications of natural products and pharmaceutical derivatives.

Copper-Catalyzed Three-Component Germyl Peroxidation of Alkenes.

The concurrent incorporation of a germyl fragment and another functional group (beyond the hydrogen atom) across the C═C double bond is a highly appealing yet challenging task. Herein we demonstrate the efficient germyl peroxidation of alkenes with germanium hydrides and tert-butyl hydroperoxide via a copper-catalyzed three-component radical relay strategy. This protocol exhibits excellent functional group tolerance and exquisite chemo- and regioselectivity under mild conditions and represents a rare example of constructing synthetically challenging metal-embedded organic peroxides.

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.

Iron-Catalyzed Ring-Opening Reactions of Cyclopropanols with Alkenes and TBHP: Synthesis of 5-Oxo Peroxides.

The ring opening of cyclopropanols is rarely used in multicomponent reactions. Herein we report the three-component reaction of cyclopropanols with alkenes and tert-butyl hydroperoxide (TBHP) catalyzed by an iron catalyst. This protocol enables the incorporation of both the ß-carbonyl fragment and a peroxy unit across the C═C double bond regioselectively, thus allowing an efficient, facile access to 5-oxo peroxides. Modification of the biologically active molecules and various downstream derivatizations of the peroxides are also demonstrated.

Iron-catalysed radical cyclization to synthesize germanium-substituted indolo[2,1-a]isoquinolin-6(5H)-ones and indolin-2-ones.

A simple and efficient strategy for iron-catalysed cascade radical cyclization was developed, by which an array of germanium-substituted indolo[2,1-a]isoquinolin-6(5H)-ones and indolin-2-ones were obtained in one pot with germanium hydrides as radical precursors. A rapid intramolecular radical trapping mode enabled the selective arylgermylation of alkenes over the prevalent hydrogermylation reaction.

Annulative π-Extension (APEX) of Indoles to Pyrido[1,2-a]indoles Using 4-Oxo Peroxides as C4 Units.

Annulative π-extension (APEX) of 3-substituted indoles to pyrido[1,2-a]indoles is developed by using 4-oxo peroxides as π-extending reagents, which are employed as versatile C4 building blocks. This transformation is initiated by Brønsted acid-mediated Hock rearrangement of the peroxyl group. Notably, the pyrido[1,2-a]indole products are obtained by elimination of the indole moiety from the corresponding dihydropyrido[1,2-a]indoles, which could be selectively formed at room temperature.

A Mn-catalyzed remote C(sp3)-H bond peroxidation triggered by radical trifluoromethylation of unactivated alkenes.

A manganese-catalyzed radical relay strategy for the remote trifluoromethylation-peroxidation of unactivated alkenes is disclosed. The electrophilic CF3 group was added to the C[double bond, length as m-dash]C double bonds to afford remote C-centered radicals upon 1,5-HAT, which could be efficiently trapped by Mnn+1OOBu-t species to deliver 1,6-difunctionalized products selectively under mild conditions. t-BuOOH serves as both the oxidant and the peroxy precursor in this transformation.

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.

Ligand-controlled regioselective and chemodivergent defluorinative functionalization of gem-difluorocyclopropanes with simple ketones.

Modulating the reaction selectivity is highly attractive and pivotal to the rational design of synthetic regimes. The defluorinative functionalization of gem-difluorocyclopropanes constitutes a promising route to construct ß-vinyl fluorine scaffolds, whereas chemo- and regioselective access to α-substitution patterns remains a formidable challenge. Presented herein is a robust Pd/NHC ligand synergistic strategy that could enable the C-F bond functionalization with exclusive α-regioselectivity with simple ketones. The key design adopted enolates as π-conjugated ambident nucleophiles that undergo inner-sphere 3,3'-reductive elimination warranted by the sterically hindered-yet-flexible Pd-PEPPSI complex. The excellent branched mono-defluorinative alkylation was achieved with a sterically highly demanding IHept ligand, while subtly less bulky SIPr acted as a bifunctional ligand that not only facilitated α-selective C(sp3)-F cleavage, but also rendered the newly-formed C(sp2)-F bond as the linchpin for subsequent C-O bond formation. These examples represented an unprecedented ligand-controlled regioselective and chemodivergent approach to various mono-fluorinated terminal alkenes and/or furans from the same readily available starting materials.

Iron-catalyzed acylation-functionalization of unactivated alkenes with aldehydes.

Herein, an iron-catalyzed acylation-functionalization of unactivated alkenes with aldehydes via distal group ipso-migration is reported. This strategy overcame the energy barrier and reversibility in the difunctionalization of unactivated alkenes with nucleophilic acyl radicals, and a variety of ß-heteroarylated, -cyanated and -oximated unsymmetrical 1,6- and 1,7-diketones were obtained regioselectively, chemoselectively and efficiently.

Light-Driven Metal-Free Direct Deoxygenation of Alcohols under Mild Conditions.

Hydroxyl is widely found in organic molecules as functional group and its deprivation plays an inevitable role in organic synthesis. However, the direct cleavage of Csp3-O bond in alcohols with high selectivity and efficiency, especially without the assistance of metal catalyst, has been a formidable challenge because of its strong bond dissociation energy and unfavorable thermodynamics. Herein, an efficient metal-free strategy that enables direct deoxygenation of alcohols has been developed for the first time, with hydrazine as the reductant induced by light. This protocol features mild reaction conditions, excellent functional group tolerance, and abundant and easily available starting materials, rendering selective deoxygenation of a variety of 1° and 2° alcohols, vicinal diols, and ß-1 and even ß-O-4 models of natural wood lignin. This strategy is also highlighted by its "traceless" and non-toxic by-products N2 and H2, as readily escapable gases. Mechanistic studies demonstrated dimethyl sulfide being a key intermediate in this transformation.

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.

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.