Nickel-Catalyzed Cross-Electrophile 1,2-Silyl-Arylation of 1,3-Dienes with Chlorosilanes and Aryl Bromides

Catalytic, three-component, cross-electrophile reactions have recently emerged as a promising tool for molecular diversification, but studies have focused mainly on the alkyl-carbonations of alkenes. Herein, the scope of this method has been extended to conjugated dienes and silicon chemistry through silylative difunctionalization of 1,3-dienes with chlorosilanes and aryl bromides. The reaction proceeds under mild conditions to afford 1,2-linear-silylated products, a selectivity that is different to those obtained from conventional methods via an intermediary of H(C)-η³-π-allylmetal species. Preliminary mechanistic studies reveal that chlorosilane reacts with 1,3-diene first and then couples with aryl bromide.     

A Photoinduced,Nickel-Catalyzed Reaction for the Stereoselective Assembly of C-Linked Glycosides and Glycopeptides

C-Alkyl glycosides and glycoproteins exist in natural products and are prized for their role as carbohydrate mimics in drug design. However, a practical strategy that merges glycosyl donors with readily accessible reagents, derived from abundant carboxylic acid and amine feedstocks, is yet to be conceived. Herein, we show that a nickel catalyst promotes C−C coupling between glycosyl halides and aliphatic acids or primary amines (converted into redox-active electrophiles in one step), in the presence of Hantzsch ester and LiI (or Et₃N) under blue LED illumination to deliver C-alkyl glycosides with high diastereoselectivity. Mechanistic studies support the photoinduced formation of alkyl radicals that react with a glycosyl nickel species generated in situ to facilitate cross-coupling. Through this manifold, innate CO₂H and NH₂ motifs embedded within amino acids and oligopeptides are selectively capped and functionalized to afford glycopeptide conjugates through late-stage glycosylation.     

Highly Chemoselective Aerobic Oxidation of Amino Alcohols into Amino Carbonyl Compounds

The direct oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has often posed serious challenges in organic synthesis and has constrained chemists to adopting an indirect route, such as a protection/deprotection strategy, to attain their goal. Described herein is a highly chemoselective aerobic oxidation of unprotected amino alcohols to their amino carbonyl compounds in which 2‐azaadamantane N‐oxyl (AZADO)/copper catalysis is used. The catalytic system developed leads to the alcohol‐selective oxidation of various unprotected amino alcohols, carrying a primary, secondary, or tertiary amino group, in good to high yield at ambient temperature with exposure to air, thus offering flexibility in the synthesis of nitrogen‐containing compounds.     

Synthesis of Amphiphilic Amino Alcohols

An efficient and general approach for the synthesis of amphiphilic 1,2-amino alcohols is reported. The use of N-benzyl protecting groups is essential for obtaining good yields when opening a long-chain terminal epoxide with an amine.     

A Chemoselective Polarity-Mismatched Photocatalytic C(sp3)−C(sp2) Cross-Coupling Enabled by Synergistic Boron Activation**

We report the development of a C(sp³)−C(sp²) coupling reaction using styrene boronic acids and redox-active esters under photoredox catalysis. The reaction proceeds through an unusual polarity-mismatched radical addition mechanism that is orthogonal to established processes. Synergistic activation of the radical precursor and organoboron are critical mechanistic events. Activation of an N-hydroxyphthalimide (NHPI) ester by coordination to boron enables electron transfer, with decomposition leading to a nucleofuge rebound, activating the organoboron to radical addition. The unique mechanism enables chemoselective coupling of styrene boronic acids in the presence of other alkene radical acceptors. The scope and limitations of the reaction, and a detailed mechanistic investigation are presented.     

Novel Stereocontrolled Preparation of Amino Polyols from 2,3-Aziridine Alcohols

Starting from 2,3-aziridine alcohols, a novel and versatile preparation of optically active amino polyol was achieved using a simple strategy with few purification steps and a good overall yield.     

Divergent Synthesis of Alcohols and Ketones via Cross-Coupling of Secondary Alcohols under Manganese Catalysis

A homogeneous manganese-catalyzed cross-coupling of two secondary alcohols for the divergent synthesis of γ-disubstituted alcohols and β-disubstituted ketones is reported. Employing the well-defined Mn-MACHO^Ph as the catalyst, this novel protocol has a broad substrate scope with good functional group tolerance and affords a diverse library of valuable disubstituted alcohols and ketones in moderate to good yields. The strong influence of the reaction temperature on the selective formation of alcohol products was theorized in preliminary DFT studies. Studies have shown that the Gibbs free energy of the formation of alcohols is thermodynamically more favourable than corresponding ketones at a lower temperature.     

Chemoselective Silylation of Alcohols1

Hexamethyldisilazane (HMDS) in pesence of a catalytic amount of Envirocat EPZG^R silylates different alcohols in high yields with absolute chemoselectivity.

     

Rapid and Modular Access to Vinyl Cyclopropanes Enabled by Air-stable Palladium(I) Dimer Catalysis

While vinyl cyclopropanes are valuable functional groups in drugs or natural products as well as established precursors to trigger a rich variety of synthetic transformations, their reactive nature can make their installation via direct catalytic approaches challenging. We herein present a modular access to (di)vinyl cyclopropanes under very mild conditions and full conservation of stereochemistry, allowing access to the cis or trans cyclopropane- as well as E or Z vinyl-stereochemical relationships. Our protocol relies on air-stable dinuclear Pd^I catalysis, which enables rapid (<30 min) and selective access to a diverse range of vinyl cyclopropane motifs at room temperature, even on gram scale.     

Chemoselective deprotection of trityl ethers using silica-supported sodium hydrogen sulfate

A highly selective method for the cleavage of trityl ethers over a wide range of functional groups has been developed using silica-supported sodium hydrogen sulfate (NaHSO₄-SiO₂) as a heterogeneous catalyst. The conversion occurred at room temperature and the yields of the alcohols were found to be excellent.     

Highly Chemoselective gem-Difluoropropargylation of Aliphatic Alcohols

Despite the potential of α-fluoroethers in medicinal chemistry, their synthetic methods, especially etherification of aliphatic alcohols, have been limited. Herein, we developed two- and three-step gem-difluoropropargylation of aliphatic alcohols including amino acid derivatives and naturally occurring bioactive molecules. Highly chemoselective etherification proceeded by using the gem-difluoropropargyl bromide dicobalt complex in the presence of silver triflate and triethylamine. Decomplexation of dicobalt complexes was achieved by using cerium ammonium nitrate or N,N,N′-trimethylethylenediamine. The thus obtained gem-difluoropropargyl ethers were converted to various α-difluoroethers which are expected to be useful for medicinal chemistry.     

Visible Light Induced Copper-Catalyzed Enantioselective Deaminative Arylation of Amino Acid Derivatives Assisted by Phenol

The exploration of value-added conversions of naturally abundant amino acids has received considerable attention from the synthetic community. Compared with the well-established asymmetric decarboxylative transformation, the asymmetric deaminative transformation of amino acids still remains a formidable challenge, mainly due to the lack of effective strategies for the C−N bond activation and the potential incompatibility with chiral catalysts. Here, we disclose a photoinduced Cu-catalyzed asymmetric deaminative coupling reaction of amino acids with arylboronic acids. This new protocol provides a series of significant chiral phenylacetamides in generally good yields and excellent stereoselectivity under mild and green conditions (42–85 % yields, up to 97 % ee). Experimental investigations and theoretical calculations were performed to reveal the crucial role of additional phenols in improving catalytic efficiency and enantiocontrol.     

Chemoselective epoxidation of dienes using polymer-supported manganese porphyrin catalysts

Manganese porphyrin catalysts supported on different polymer resins were assessed in the selective epoxidation of three dienes. The recyclability of the catalysts was examined.     

PAd2‐DalPhos Enables the Nickel‐Catalyzed C−N Cross‐Coupling of Primary Heteroarylamines and (Hetero)aryl Chlorides

Base‐metal catalysts capable of enabling the assembly of heteroatom‐dense molecules by cross‐coupling of primary heteroarylamines and (hetero)aryl chlorides, while sought‐after given the ubiquity of unsymmetrical di(hetero)arylamino fragments in pharmacophores, are unknown. Herein, we disclose the new “double cage” bisphosphine PAd2‐DalPhos ( L2 ). The derived air‐stable Ni^II pre‐catalyst C2 functions well at low loadings in challenging test C?N cross‐couplings with established substrates, and facilitates the first Ni‐catalyzed C?N cross‐couplings of primary five‐ or six‐membered ring heteroarylamines and activated (hetero)aryl chlorides, with synthetically useful scope that is competitive with Pd catalysis.     

Nickel-Catalyzed Unsymmetrical Bis-Allylation of Alkynes

The catalytic bis-allylation of alkynes is an important but challenging protocol to construct all-carbon tetra-substituted alkenes. Particularly, the catalytic unsymmetrical bis-allylation of alkynes remains as an underexplored task to date. We herein report an unprecedented unsymmetrical bis-allylation by simultaneously utilizing electrophilic trifluoromethyl alkene and nucleophilic allylboronate as the allylic reagents. With the aid of robust Ni⁰/NHC catalysis, valuable skipped trienes can be obtained in high regio- and stereo-selectivities under mild conditions. Mechanistic studies indicate that the reaction may proceed through a β-fluorine elimination of a nickelacycle followed by a transmetalation step with allylboronate. The present method exhibits a good tolerance of various functional groups. Besides, the skipped triene products can undergo an array of elaborate transformations, which highlights the potential applications of this strategy.     

A Mild and Efficient Method for Chemoselective Silylation of Alcohols Using Hexamethyldisilazane in the Presence of Silica Chloride

Reaction of alcohols with hexamethyldisilazane in the presence of silica chloride provides efficiently the corresponding trimethylsilyl ethers. This system discriminates absolutely amines and thiols from alcohols.     

Direct Arylation of Adenine by Fluoro- and Chloronitrobenzenes: Effect of Microwaves

Direct arylation of adenine with fluoro- and chloronitrobenzenes leads to mixtures of N9 and N7 substituted adenines. After separation by column chromatography, the individual isomers can be efficiently hydrogenated on Pd to give the corresponding aminophenyladenines. A significant enhancement of the reaction rate by microwave irradiation was observed. This two-step procedure was found to be a feasible route to otherwise hardly available 7-aminophenyladenines. Correlation between calculated shielding constants and experimental values of chemical shifts in ¹³C and ¹⁵N NMR was used for assignment of the site of substitution.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Enantioselective Nickel-Catalyzed Hydrosilylation of 1,1-Disubstituted Allenes

Here, we report the first example of Ni-catalyzed asymmetric hydrosilylation of 1,1-disubstituted allenes with high level of regioselectivities and enantioselectivities. The key to achieve this stereoselective hydrosilylation reaction was the development of the SPSiOL-derived bisphosphite ligands (SPSiPO). This protocol features broad substrate scope, excellent functional group, and heterocycle tolerance, thus provides a versatile method for the construction of enantioenriched tertiary allylsilanes in a straightforward and atom-economic manner. DFT calculations were performed to reveal the reaction mechanism and the origins of the enantioselectivity.     

Manganese-Catalyzed Chemoselective Coupling of Secondary Alcohols,Primary Alcohols and Methanol

Herein, we report a manganese-catalyzed three-component coupling of secondary alcohols, primary alcohols and methanol for the synthesis of β,β-methylated/alkylated secondary alcohols. Using our method, a series of 1-arylethanol, benzyl alcohol derivatives, and methanol undergo sequential coupling efficiently to construct assembled alcohols with high chemoselectivity in moderate to good yields. Mechanistic studies suggest that the reaction proceeds via methylation of a benzylated secondary alcohol intermediate to generate the final product.     

Metallaphotoredox-Catalyzed Enantioselective Cross-Electrophile Coupling Using Alcohols as Reducing Agents

The cross-electrophile coupling (XEC) represents a powerful strategy for C−C bond formation. However, controlling the enantioselectivity in these processes remains a challenge. Here, we report an unprecedented enantioselective XEC of α-amino acid derivatives with aryl bromides, enabled by alcohols as reducing agents via Ni/photoredox catalysis. This mechanistically distinct approach exploits the ability of photocatalytically generated α-hydroxyalkyl radicals to convert alkyl electrophiles to the corresponding alkyl radicals that are then enantioselectively coupled with aryl bromides. The readily scalable protocol allows modular access to valuable enantioenriched benzylic amines from abundant and inexpensive precursors, and is applicable to late-stage diversification with broad functional group tolerance. Mechanistic studies rationalize the versatility of this alcohol-based reactivity for radical generation and subsequent asymmetric cross-coupling. We expect that this alcohol-based cross-coupling will render a general platform for the development of appealing yet challenging enantioselective XECs.