Oxidation of Alkynyl Boronates to Carboxylic Acids,Esters, and Amides

A general efficient protocol was developed for the synthesis of carboxylic acids, esters, and amides through oxidation of alkynyl boronates, generated directly from terminal alkynes. This protocol represents the first example of C(sp)?B bond oxidation. This approach displays a broad substrate scope, including aryl and alkyl alkynes, and exhibits excellent functional group tolerance. Water, primary and secondary alcohols, and amines are suitable nucleophiles for this transformation. Notably, amino acids and peptides can be used as nucleophiles, providing an efficient method for the synthesis and modification of peptides. The practicability of this methodology was further highlighted by the preparation of pharmaceutical molecules.     

Base-Promoted Difunctionalization of Alkynes: One-Pot Synthesis of Polysubstituted Chromones

A transition-metal-free one-pot procedure for the difunctionalization of alkynes by C−C triple bond oxidation and transformation towards chromone derivatives has been developed. It involves cascade reactions for carbonylation of alkynes, base-promoted C−C σ-bond cleavage, and intramolecular cyclization. This procedure provides an efficient protocol for the synthesis of polysubstituted chromones from readily available starting materials.     

A General Protocol for C−H Difluoromethylation of Carbon Acids with TMSCF2Br

An efficient method for the selective C‐difluoromethylation of carbon acids with the reagent TMSCF₂Br has been developed. A variety of structurally diverse sp³‐ and sp‐hybridized carbon nucleophiles, including esters, amides, fluorenes, terminal alkynes, β‐ketoesters, malonates, and other activated C?H nucleophiles, could be efficiently and selectively transformed into the corresponding C‐difluoromethylated products under mild conditions. This protocol is also effective for the late‐stage difluoromethylation of pharmaceutically relevant molecules and can be readily scaled up. Moreover, ambident substrates with more than one reactive site towards difluorocarbene can be difluoromethylated orthogonally using TMSCF₂Br.     

A novel approach towards the preparation of functionalized alkyne derivatives via ArS-mediated AdE reaction of cobaltcarbonyl complexed conjugated enynes

A unified protocol of three-component coupling of arenesulfenyl chloride, dicobalthexacarbonyl complexed conjugated enynes, and nucleophiles of π-donor type is applied for the synthesis of functionalized alkynes.     

Click Chemistry Route to the Synthesis of Unusual Amino Acids,Peptides, Triazole‐Fused Heterocycles and Pseudodisaccharides

Conjugation of different molecular species using copper(I)‐catalyzed click reaction between azides and terminal alkynes is among the best available methods to prepare multifunctional compounds. The effectiveness of this method has provided wider acceptance to the concept of click chemistry, which is now widely employed to synthesize densely functionalized organic molecules. This article summarizes the contributions from our group in the development of new methods for the synthesis of functional molecules using copper(I)‐catalyzed click reactions. We have developed very efficient methods for the synthesis of peptides and amino acids conjugated with carbohydrates, thymidine and ferrocene. We have also developed an efficient strategy to synthesize triazole‐fused heterocycles from primary amines, amino alochols and diols. Finally, an interesting method for the synthesis of pseudodisaccharides linked through triazoles, starting from carbohydrate‐derived donor‐acceptor cyclopropanes is discussed.     

A mild, one-pot preparation of 1,3,4-oxadiazoles

A mild and efficient one-pot protocol for the synthesis of 1,3,4-oxadiazoles from carboxylic acids and acylhydrazides was developed. Diacylhydrazide formation via HATU coupling followed by addition of Burgess reagent afforded the corresponding 1,3,4-oxadiazoles in 63-96% yields at room temperature. The reaction conditions are tolerant of a variety of functional groups, including esters, nitriles, alkynes, olefins, alkyl halides, phenols, carbamates and sulfonamides.     

Markovnikov‐Selective Radical Addition of S‐Nucleophiles to Terminal Alkynes through a Photoredox Process

Direct radical additions to terminal alkynes have been widely employed in organic synthesis, providing credible access to the anti‐Markovnikov products. Because of the Kharasch effect, regioselective control for the formation of Markovnikov products still remains a great challenge. Herein, we develop a transition‐metal‐free, visible light‐mediated radical addition of S‐nucleophiles to terminal alkynes, furnishing a wide array of α‐substituted vinyl sulfones with exclusive Markovnikov regioselectivity. Mechanistic investigations demonstrated that radical/radical cross‐coupling might be the key step in this transformation. This radical Markovnikov addition protocol also provides an opportunity to facilitate the synthesis of other valuable α‐substituted vinyl compounds.     

Resin-bound sulfonyl azides: efficient loading and activation strategy for the preparation of the N-acyl sulfonamide linker

This paper describes an optimized protocol for the efficient loading of resin-bound aminoethane sulfonyl azides by either Boc- or Fmoc-protected amino thioacids. The resulting N-acyl sulfonamide is a convenient linker for use in Boc- or Fmoc-based solid-phase peptide synthesis. Activation of the N-acyl sulfonamide via a microwave-assisted alkylation procedure and subsequent treatment with functionalized nucleophiles yields C-terminally modified peptides that can be applied in chemoselective (bio)conjugation or ligation reactions.     

Combining Matteson Homologations and Claisen Rearrangements – An Efficient Protocol for Amino Acid Synthesis

The Matteson homologation with vinyl nucleophiles was found to be an efficient and versatile protocol for the synthesis of substituted chiral allyl alcohols in a highly stereoselective fashion. These alcohols can be coupled with N-protected glycine and subsequently subjected to zinc-chelated ester-enolate Claisen rearrangements to yield highly substituted unsaturated amino acids. By varying the nucleophiles used in the Matteson homologations, the method allows control over not only the stereogenic centers but also the side-chain substitution pattern in the newly formed γ,δ-unsaturated amino acids.     

Electrochemical oxidaton of N,N-dialkyl-p-phenylenediamines in the presence of arylsulfinic acids. An efficient method for the synthesis of new sulfonamide derivatives

Electrochemical oxidation of N,N-dialkyl-p-phenylenediamines have been studied in the presence of arylsulfinic acids as nucleophiles in aqueous solutions. The results indicate that the electrochemically generated quinone-imines participate in Michael type addition reaction with arylsulfinic acids and via an EC mechanism convert to the corresponding new sulfonamide derivatives. In this work, an efficient and one-pot electrochemical method for the synthesis of new sulfonamide derivatives in aqueous solution is reported.     

Copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids using (trifluoromethyl)trimethylsilane

Trifluoromethylated acetylenes and arenes are widely applicable in the synthesis of pharmaceuticals and agrochemicals. In 2010, our group has reported the copper-mediated oxidative trifluomethylation of terminal alkynes and aryl boronic acids. This method allows a wide range of functional group tolerant trifluoromethylated acetylenes and arenes to be easily prepared. After the preliminary mechanistic studies of the oxidative trifluoromethylation of terminal alkyne, an efficient copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids has been developed. The catalytic protocol is successfully achieved by adding both the substrate and a portion of CF(3)TMS slowly using a syringe pump to the reaction mixture.     

Access to Vinyl Ethers and Ketones with Hypervalent Iodine Reagents as Oxy-Allyl Cation Synthetic Equivalents

We report an Umpolung strategy of enol ethers to generate oxy-allyl cation equivalents based on the use of hypervalent iodine reagents. Under mild basic conditions, the addition of nucleophiles to aryloxy-substituted vinylbenziodoxolone (VBX) reagents, easily available in two steps from silyl alkynes, resulted in the stereoselective formation of substituted aryl enol ethers. The reaction was most efficient with phenols as nucleophiles, but preliminary results were also achieved for C- and N- nucleophiles. In absence of external nucleophiles, the 2-iodobenzoate group of the reagent was transferred. The obtained aryl enol ethers could then be transformed into α-difunctionalized ketones by oxidation. The described “allyl cation”-like reactivity contrast with the well-established “vinyl-cation” behavior of alkenyl iodonium salts.     

Aqueous bile salt accelerated cascade synthesis of 1,2,3-triazoles from arylboronic acids

A facile, efficient and mild copper catalyzed strategy for cascade synthesis of various 1,4-disubstituted 1,2,3-triazoles from arylboronic acids, sodium azide and alkynes was developed by using aqueous bile salt NaDC solution as an accelerating medium. Low catalyst loading (only 1?mol% Cu source was sufficient for in situ generation of azide followed by azide–alkyne coupling), green solvent, use of bio-surfactant as additive and short reaction time make this protocol highly accessible and environment friendly.     

Access to Vinyl Ethers and Ketones with Hypervalent Iodine Reagents as Oxy‐Allyl Cation Synthetic Equivalents

We report an Umpolung strategy of enol ethers to generate oxy‐allyl cation equivalents based on the use of hypervalent iodine reagents. Under mild basic conditions, the addition of nucleophiles to aryloxy‐substituted vinylbenziodoxolone (VBX) reagents, easily available in two steps from silyl alkynes, resulted in the stereoselective formation of substituted aryl enol ethers. The reaction was most efficient with phenols as nucleophiles, but preliminary results were also achieved for C‐ and N‐ nucleophiles. In absence of external nucleophiles, the 2‐iodobenzoate group of the reagent was transferred. The obtained aryl enol ethers could then be transformed into α‐difunctionalized ketones by oxidation. The described “allyl cation”‐like reactivity contrast with the well‐established “vinyl‐cation” behavior of alkenyl iodonium salts.     

Gold-catalyzed synthesis of oxygen- and nitrogen-containing heterocycles from alkynyl ethers: application to the total synthesis of andrachcinidine

In this paper we report that homopropargylic ethers containing pendent oxygen or nitrogen nucleophiles react with electrophilic gold catalysts in the presence of water to form saturated heterocyclic ketones. Mechanistic studies demonstrated that the reactions proceed through a sequence of alkyne hydration, alkoxy group elimination, and intramolecular conjugate addition. Diastereoselectivities for tetrahydropyran and piperidine formation are very good to excellent. This method has been applied to an efficient total synthesis of the natural product andrachcinidine. Utilizing propargylic ether substrates rather than homopropargylic ethers promotes regioselective hydration of internal alkynes, thereby expanding the scope of products that can be accessed through this protocol.     

Palladium(II)-catalyzed synthesis of functionalized indenes from o-alkynylbenzylidene ketones

An efficient method for the synthesis of functionalized indenes from o-alkynylbenzylidene ketones under palladium(II) catalysis was developed. The reaction is initiated by trans-nucleopalladation of alkynes, followed by conjugate addition and quenched by protonolysis of the carbon-palladium bond. With acetate and halide ions as nucleophiles, 3-acetoxy- and 3-halogen-substituted indenes could be obtained in high yields.     

Late-Stage Functionalisation of Peptides on the Solid Phase by an Iodination-Substitution Approach

The functionalisation of peptides at a late synthesis stage holds great potential, for example, for the synthesis of peptide pharmaceuticals, fluorescent biosensors or peptidomimetics. Here we describe an on-resin iodination-substitution reaction sequence on homoserine that is also suitable for peptide modification in a combinatorial format. The reaction sequence is accessible to a wide range of sulfur nucleophiles with various functional groups including boronic acids, hydroxy groups or aromatic amines. In this way, methionine-like thioethers or thioesters and thiosulfonates are accessible. Next to sulfur nucleophiles, selenols, pyridines and carboxylic acids were successfully used as nucleophiles, whereas phenols did not react. The late-stage iodination-substitution approach is not only applicable to short peptides but also to the more complex 34-amino-acid WW domains. We applied this strategy to introduce 7-mercapto-4-methylcoumarin into a switchable Zn^II responsive WW domain to design an iFRET-based Zn^II sensor.     

Electrochemical synthesis of β-hydroxy-, β-alkoxy-, and β-carbonyloxy sulfones by vicinal difunctionalization of olefins

Disclosed here is an oxidant-free vicinal oxysulfonylation of olefins using electrochemical conditions.     

Thiosemicarbazone salicylaldiminato palladium(II)-catalyzed alkynylation couplings between arylboronic acids and alkynes or alkynyl carboxylic acids

An efficient catalytic system has been developed for the synthesis of unsymmetrical substituted alkynes via the thiosemicarbazone salicylaldiminato palladium(II)-catalyzed alkynylation couplings between arylboronic acids and alkynes or alkynyl carboxylic acids under mild conditions.     

Anti-Markovnikov stereoselective hydroamination and hydrothiolation of (hetero)aromatic alkynes using a metal-free cyclic trimeric phosphazene base

Hydroamination and hydrothiolation are the most efficient and completely atom-economical process to construct important enamine and vinyl sulfide intermediates in pharmaceutical and organic chemistry. The cyclic trimeric phosphazene base (CTPB) showed great catalytic activity for the anti-Markovnikov stereoselective hydroamination and hydrothiolation of alkynes in good to excellent yields. A broad substrate scope of alkynes and nucleophiles was demonstrated, including aryl and heteroaryl alkynes, terminal and internal alkynes, different N-heterocycles, thiols and thiophenols. This versatile and cost-efficient approach with good stereoselectivity and excellent functional group tolerance provided new opportunity for the organocatalyzed hydrofunctionalization of alkynes.