Bicarbonate-binding catalysis for the enantioselective desymmetrization of keto sulfonium salts.

Herein, an enantioselective desymmetrization of cyclic keto sulfonium salts through enantioselective deprotonation/ring opening process by anion-binding catalysis is presented. We report a squaramide/HCO complex as catalytic active species which is able to stereo-differentiate two enantiomeric protons, triggering the ring opening event taking advantage of the great tendency of sulfonium salts to act as leaving groups. Thus, this desymmetrization methodology give rise to β-methylsulfenylated sulfa-Michael addition type products with excellent yields and very good enantioselectivities.

General electrochemical Minisci alkylation of -heteroarenes with alkyl halides.

Herein, we report, a general, facile and environmentally friendly Minisci-type alkylation of -heteroarenes under simple and straightforward electrochemical conditions using widely available alkyl halides as radical precursors. Primary, secondary and tertiary alkyl radicals have been shown to be efficiently generated and coupled with a large variety of -heteroarenes. The method presents a very high functional group tolerance, including various heterocyclic-based natural products, which highlights the robustness of the methodology.

Nickel-Catalysed Cross-Electrophile Coupling of Benzyl Bromides and Sulfonium Salts towards the Synthesis of Dihydrostilbenes.

A nickel-catalysed reductive cross-coupling reaction between benzyl sulfonium salts and benzyl bromides is reported. Simple, stable and readily available sulfonium salts have shown their ability as leaving groups in cross-electrophile coupling, allowing the formation of challenging sp -sp carbon-carbon bonds, towards the synthesis of interesting dihydrostilbene derivatives. In addition, benzyl tosyl derivatives have been demonstrated to be suitable substrates for reductive cross-coupling by in-situ formation of the corresponding sulfonium salt.

Isothiourea-catalysed enantioselective radical conjugate addition under batch and flow conditions.

The photocatalytic generation of α-amino radicals is combined with chiral isothiourea derived α,β-unsaturated acyl ammonium intermediates. The reaction proceeds a [3+2] radical-polar crossover mechanism to generate γ-lactams in good yields and enantioselectivities. The enantioselective radical conjugate addition was carried out under batch and flow conditions.

Enantioselective vinylogous Mukaiyama aldol reaction of α-ketoesters under bifunctional organocatalysis.

A highly enantioselective vinylogous Mukaiyama aldol reaction to ketoesters catalysed by a hydrogen-bond-donor-based bifunctional organocatalyst is presented. The addition of silyloxy dienol ether gives rise to multifunctional chiral tertiary alcohols bearing a versatile α,β-unsaturated aldehyde with excellent enantiocontrol.

Enantioselective Inverse-Electron Demand Aza-Diels-Alder Reaction: ipso,α-Selectivity of Silyl Dienol Ethers.

A highly efficient enantioselective inverse-electron-demand aza-Diels-Alder reaction between aza-sulfonyl-1-aza-1,3-butadienes and silyl (di)enol ethers has been developed. The presented methodology allows the synthesis of benzofuran-fused 2-piperidinol derivatives with three contiguous stereocenters in a highly selective manner, as even the hemiaminal center is completely stereocontrolled. Density functional theory (DFT) calculations support that the hydrogen-bond donor-based bifunctional organocatalyst selectively triggers the reaction through the ipso,α-position of the dienophile, in contrast to the reactivity observed for dienolates in situ generated from β,γ-unsaturated derivatives.

Enantioselective vinylogous-Mukaiyama-type dearomatisation by anion-binding catalysis.

The first enantioselective vinylogous Mukaiyama-type dearomatisation of heteroarenes under anion-binding catalysis is presented. A recyclable tetrakistriazole catalyst was used for the enantiocontrol of the remote vinylogous active position of silyl dienol ethers. This approach provided chiral heterocycles bearing α,β-unsaturated chains with complete regioselectivity and excellent enantioselectivities (up to 97.

Organocatalytic Strategies for the Development of the Enantioselective Inverse-electron-demand Hetero-Diels-Alder Reaction.

Cycloaddition reactions, in particular Diels-Alder reactions, have attracted a lot of attention from organic chemists since they represent one of the most powerful methodologies for the construction of carbon-carbon bonds. In particular, inverse-electron-demand hetero-Diels-Alder reactions have been an important breakthrough for the synthesis of heterocyclic compounds. Among all their variants, the organocatalytic enantioselective version has been widely explored since the asymmetric construction of diversely functionalized scaffolds under reaction conditions encompassed within the green chemistry field is of great interest.

Nucleophilic halo-Michael addition under Lewis-base activation.

A simple and general conjugate nucleophilic halogenation is presented. The THTO/halosilane combination has shown the ability to act as a nucleophilic halide source in the conjugate addition to a variety of Michael acceptors. In addition, a straightforward diastereoselective halogen installation using α,β-unsaturated acyloxazolidinones as platforms has been developed.

Asymmetric [2,3]-Wittig Rearrangement: Synthesis of Homoallylic, Allenylic, and Enynyl α-Benzyl Alcohols.

A highly stereoselective [2,3]-Wittig rearrangement of allylic and propargylic ethers controlled by a chiral sulfoxide moiety is presented. The activation provided by the sulfoxide at the remote ortho position allows the rearrangement of less-activated and unexplored benzylic carbanions. Thus, this general methodology gives access to the asymmetric synthesis of homoallylic, enynyl, and allenylic α-benzyl alcohol derivatives.

Asymmetric synthesis of Rauhut-Currier-type esters via Mukaiyama-Michael reaction to acylphosphonates under bifunctional catalysis.

A highly enantioselective organocatalytic Mukaiyama-Michael reaction of silyloxy dienes and α,β-unsaturated acyl phosphonates under bifunctional organocatalysis is presented. The new reactivity triggered by the catalyst conducted to Rauhut-Currier type esters, via a formal conjugate addition to α,β-unsaturated esters. This protocol proceeds under mild conditions with complete regioselectivity and excellent enantiocontrol.

Reformatsky Reaction to Alkynyl N- tert-Butanesulfinyl Imines: Lewis Acid Controlled Stereodivergent Synthesis of β-Alkynyl-β-Amino Acids.

A highly diastereoselective Refortmatsky reaction to N- tert-butanesulfinyl propargylaldimines and ketimines is presented. The reaction proceeded with excellent yields and diastereoselectivities provided by the sulfinyl group in the presence of MeAl. The use of TBSOTf as a Lewis acid promoter switched the sense of the stereoinduction.

An Interrupted Pummerer/Nickel-Catalysed Cross-Coupling Sequence.

An interrupted Pummerer/nickel-catalysed cross-coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one-pot process, involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp-, sp -, and sp -hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo- and heterocyclic alkenyl sulfonium salts for cross-coupling.

Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]-Sigmatropic/1,2-Migration Cascade of Benzothiophene S-Oxides.

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal-free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S-oxides and phenols, allyl-, or propargyl silanes in a unique cascade sequence.

Intramolecular Hydrogen Bond Activation: Thiourea-Organocatalyzed Enantioselective 1,3-Dipolar Cycloaddition of Salicylaldehyde-Derived Azomethine Ylides with Nitroalkenes.

An organocatalytic strategy for the synthesis of tetrasubstituted pyrrolidines with monoactivated azomethine ylides in high enantiomeric excess and excellent exo/endo selectivity is presented. The key to success is the intramolecular activation via hydrogen bonding through an -hydroxy group, which allows the dipolar cycloaddition to take place in the presence of azomethine ylides bearing only one activating group. The intramolecular hydrogen bond in the azomethine ylide and the intermolecular hydrogen bond with the catalyst have been demonstrated by DFT calculations and mechanistic proofs to be crucial for the reaction to proceed.

Asymmetric vinylogous Mukaiyama aldol reaction of isatins under bifunctional organocatalysis: enantioselective synthesis of substituted 3-hydroxy-2-oxindoles.

A highly enantioselective organocatalytic vinylogous Mukaiyama aldol reaction of silyloxy dienes and isatins under bifunctional organocatalysis is presented. Substituted 3-hydroxy-2-oxindoles are synthesised in good yields and enantioselectivities. These synthetic intermediates are used for the construction of more complex molecules with biological properties such as the formal synthesis of a CB2 agonist presented.

Regioselective synthesis of C3 alkylated and arylated benzothiophenes.

Benzothiophenes are heterocyclic constituents of important molecules relevant to society, including those with the potential to meet modern medical challenges. The construction of molecules would be vastly more efficient if carbon-hydrogen bonds, found in all organic molecules, can be directly converted into carbon-carbon bonds. In the case of elaborating benzothiophenes, functionalization of carbon-hydrogen bonds at carbon-number 3 (C3) is markedly more demanding than at C2 due to issues of regioselectivity (C3 versus C2), and the requirement of high temperatures, precious metals and the installation of superfluous directing groups.

Metal-free C-H thioarylation of arenes using sulfoxides: a direct, general diaryl sulfide synthesis.

Metal-free C-H thioarylation of arenes and heteroarenes using methyl sulfoxides constitutes a general protocol for the synthesis of high value diaryl sulfides. The coupling of arenes and heteroarenes with in situ activated sulfoxides is regioselective, uses readily available starting materials, is operationally simple, and tolerates a wide range of functional groups.

Synthesis of (diarylmethyl)amines using Ni-catalyzed arylation of C(sp)-H bonds.

The first nickel catalyzed deprotonative cross coupling between C(sp)-H bonds and aryl chlorides is reported, allowing the challenging arylation of benzylimines in the absence of directing group or stoichiometric metal activation. This methodology represents a convenient access to the (diarylmethyl)amine moiety, which is widespread in pharmaceutically relevant compounds.

Metal-Free CH-CH-Type Cross-Coupling of Arenes and Alkynes Directed by a Multifunctional Sulfoxide Group.

A metal-free CH-CH-type coupling of arenes and alkynes, mediated by a multifunctional sulfoxide directing group, exploits nonprefunctionalized coupling partners, proceeds under mild conditions, is operationally simple, and exhibits high functional group tolerance. The products of the CH-CH coupling are highly versatile, and the metal-free process can be used for the construction and late-stage modification of important molecular scaffolds.

General and mild Ni(0)-catalyzed α-arylation of ketones using aryl chlorides.

A general methodology for the α-arylation of ketones using a nickel catalyst has been developed. The new well-defined [Ni(IPr*)(cin)Cl] (1 c) pre-catalyst showed great efficiency for this transformation, allowing the coupling of a wide range of ketones, including acetophenone derivatives, with various functionalised aryl chlorides. This cinnamyl-based Ni-N-heterocyclic carbene (NHC) complex has demonstrated a different behaviour to previously reported NHC-Ni catalysts.

From a decomposition product to an efficient and versatile catalyst: the [Ru(η5-indenyl)(PPh3)2Cl] story.

One of the most important challenges in catalyst design is the synthesis of stable promoters without compromising their activity. For this reason, it is important to understand the factors leading to decomposition of such catalysts, especially if side-products negatively affect the activity and selectivity of the starting complex. In this context, the understanding of termination and decomposition processes in olefin metathesis is receiving significant attention from the scientific community.

Regioselective ruthenium catalysed H-D exchange using D2O as the deuterium source.

An efficient and convenient ruthenium catalysed method for a regiospecific H/D exchange using D2O is described. Organic moieties such as pyridine, oxazole, imidazole, pyrazole, ester, ketone and carboxylic acid have been found effective directing groups in this transformation. In addition, the deuteration of the enantiopure (S)-Ketoprofen leads to the incorporation of three deuterium atoms with retention of molecular chirality.

A cationic ruthenium complex for the dynamic kinetic resolution of secondary alcohols.

A synthetic protocol making use of a well-defined cationic ruthenium complex 2 enabling the racemization of enantiomerically pure secondary alcohols in the presence of a weak base (K2CO3) is described. The compatibility of 2 with Candida Antarctica lipase B (Novozym 435) allows the development of an efficient dynamic kinetic resolution of sec-alcohols in the absence of an additional strong base. This procedure involves the first example of a dynamic kinetic resolution of alcohols in the presence of a cationic ruthenium catalyst.

Iridium(I) hydroxides in catalysis: rearrangement of allylic alcohols to ketones.

The iridium(I) hydroxide complex [Ir(OH)(COD)(I(i)Pr)] has been shown to be a competent catalyst for the rearrangement of allylic alcohols to ketones. Reactions proceed in short reaction times (1-1.5 h) with microwave heating, in the absence of additives.