Step-economical Access Research Articles

Visible-light-induced dual C[sbnd]H functionalization of biaryl ynones via a 6-exo-trig domino radical addition/cyclization/dearomatization: Efficient access to alkylated spiro[5.5] trienones

A visible-light-induced 6-exo-trig tandem cyclization dearomatization of biaryl ynones with simple ethers was developed. The reaction involves selective C(sp3)H bond cleavage and dual CC bond formation providing efficient, atom and step economical access to alkylated spiro[5.5]trienones under mild conditions.

Ligand-Enabled C6-Selective C-H Arylation of Pyrrolo[2,3-d] Pyrimidine Derivatives with Pd Catalysts: An Approach to the Synthesis of EGFR Inhibitor AEE-788.

Herein, we report the Pd(II)-catalyzed direct C-H arylation of pyrrolo[2,3-d]pyrimidine derivatives with aryl iodides, which is enabled by bidentate pyridine-pyridine ligands. A range of aryl iodides proved to be suitable coupling partners affording the desired products in good yields with high levels of C6 selectivity. This protocol features good tolerance of reactive functional groups, mild reaction conditions, and a simple reaction system, which provides an expeditious route to an essential class of 6-arylpyrrolo[2,3-d]pyrimidines frequently found in bioactive compounds, and provides a step-economical access to the second-generation EGFR inhibitor AEE-788.

Iodine-Mediated Coupling of 2,2,2-Trifluorodiazoethane and Alkynes To Access Bistrifluoromethylated 1,3,5-Trienes.

Multi-component reaction of higher degree ultilization of diazo molecules for polyene formation is highly intriuging but still underexplored. We present herein an unprecedented coupling of 2,2,2-trifluorodiazoethane and aryl alkynes mediated by iodine under visible light. The multi-component reaction involving two diazo units and two alkyne units provides a straightforward and step-economic access to bistrifluoromethylated 1,3,5-trienes in high stereoselectivity by creation of three C═C bonds in a single step under mild conditions.

Intermolecular C-H Aminocyanation of Indoles via Copper-iodine Cocatalyzed Tandem C-N/C-C Bond Formation.

An efficient copper-iodine cocatalyzed intermolecular C-H aminocyanation of indoles with a broad substrate scope has been developed for the first time. This method enables highly step-economic access to 2-amino-3-cyanoindoles in moderate to good yields and provides a complementary strategy for the regioselective difunctionalization of carbon═carbon double bonds of interest in organic synthesis and related areas. Mechanistic studies suggest that these transformations are initiated by iodine-mediated C2-H amination with azoles, followed by copper-catalyzed C3-H cyanation with ethyl cyanoformate.

Alcohols as Alkylating Agents: Photoredox-Catalyzed Conjugate Alkylation via In Situ Deoxygenation.

The rapid exploration of sp3 -enriched chemical space is facilitated by fragment-coupling technologies that utilize simple and abundant alkyl precursors, among which alcohols are a highly desirable, commercially accessible, and synthetically versatile class of substrate. Herein, we describe an operationally convenient, N-heterocyclic carbene (NHC)-mediated deoxygenative Giese-type addition of alcohol-derived alkyl radicals to electron-deficient alkenes under mild photocatalytic conditions. The fragment coupling accommodates a broad range of primary, secondary, and tertiary alcohol partners, as well as structurally varied Michael acceptors containing traditionally reactive sites, such as electrophilic or oxidizable moieties. We demonstrate the late-stage diversification of densely functionalized molecular architectures, including drugs and biomolecules, and we further telescope our protocol with metallaphotoredox cross-coupling for step-economic access to sp3 -rich complexity.

Direct 1,1-Bisphosphonation of Isocyanides: Atom- and Step-Economical Access to Bisphosphinoylaminomethanes.

An atom- and step-economical strategy for the synthesis of bisphosphinoylaminomethanes is reported. This metal-free bisphosphinylation reaction proceeded smoothly through a base-mediated direct 1,1-bisphosphonation of phosphine oxides and isocyanides under mild conditions. The present method offers a facile, efficient, and general approach to a broad range of bisphosphinoylaminomethane derivatives in moderate to good yields.

Insights into Ruthenium(II/IV)-Catalyzed Distal C-H Oxygenation by Weak Coordination.

C−H hydroxylation of aryl acetamides and alkyl phenylacetyl esters was accomplished via challenging distal weak O‐coordination by versatile ruthenium(II/IV) catalysis. The ruthenium(II)‐catalyzed C−H oxygenation of aryl acetamides proceeded through C−H activation, ruthenium(II/IV) oxidation and reductive elimination, thus providing step‐economical access to valuable phenols. The p‐cymene‐ruthenium(II/IV) manifold was established by detailed experimental and DFT‐computational studies.

Palladium-Catalyzed Regio- and Enantioselective Hydrosulfonylation of 1,3-Dienes with Sulfinic Acids: Scope, Mechanism, and Origin of Selectivity.

Chiral sulfones are important structural motifs in organic synthesis because of their widespread use in pharmaceutical chemistry. In particular, chiral allylic sulfones have drawn particular interest because of their synthetic utility. However, enantioselective synthesis of 1,3-disubstituted unsymmetrical chiral allylic sulfones remains a challenge. In this article, we report a protocol for (R)-DTBM-Segphos/Pd-catalyzed regio- and enantioselective hydrosulfonylation of 1,3-dienes with sulfinic acids, which provides atom- and step-economical access to 1,3-disubstituted chiral allylic sulfones. The reaction occurs under mild conditions and has a broad substrate scope. Combined experimental and computational studies suggest that the reaction is initiated by a ligand-to-ligand hydrogen transfer followed by a C-S bond reductive elimination via a six-membered transition state. Steric repulsion between the olefinic C-H of the substrate and the tert-butyl group of (R)-DTBM-Segphos was found to be a key factor in the enantiocontrol.

Ruthenium(II)-Catalyzed Double Annulation of Quinones: Step-Economical Access to Valuable Bioactive Compounds.

Double ruthenium(II)-catalyzed alkyne annulations of quinones were accomplished. Thus, a strategy is reported that provides step-economical access to valuable quinones with a wide range of applications. C-H/N-H activations for alkyne annulations of naphthoquinones provided challenging polycyclic quinoidal compounds by forming four new bonds in one step. The singular power of the thus-obtained compounds was reflected by their antileukemic activity.

Photoinduced Heterogeneous C-H Arylation by a Reusable Hybrid Copper Catalyst.

Heterogeneous copper catalysis enabled photoinduced C−H arylations under exceedingly mild conditions at room temperature. The versatile hybrid copper catalyst provided step‐economical access to arylated heteroarenes, terpenes and alkaloid natural products with various aryl halides. The hybrid copper catalyst could be reused without significant loss of catalytic efficacy. Detailed studies in terms of TEM, HRTEM and XPS analysis of the hybrid copper catalyst, among others, supported its outstanding stability and reusability.

Rh-Catalyzed [2 + 2 + 2] Cycloadditions with Benzoquinones: De Novo Access to Naphthoquinones for Lignan and Type II Polyketide Synthesis.

The first examples of Rh-catalyzed [2 + 2 + 2] cycloadditions between diynes and benzoquinones are described. The method enables de novo and step-economical access to challenging naphthoquinones that are of relevance to lignan and type II polyketide synthesis. The value of the chemistry is demonstrated by a short total synthesis of justicidone.

Metal-free oxidative coupling of alkyl chlorides with thiols: An efficient access to sulfoxides

An efficient and step-economical access to sulfoxides from thiols and alkyl halides in the presence of I2O5 and DBU via direct oxidative couplings is described here. It is the first case that combined Williamson sulfide synthesis and subsequent sulfide oxidation into one step manipulation for sulfoxides preparation. This protocol features wide substrate scope, mild and metal-free conditons, the use of naturally abundant starting materials and avoidance of over-oxidation.

Electrophilic amination of Cu(I) catalyzed phenylmagnesium bromide with N,O-bis(trimethylsilyl)hydroxylamine in THF:N-donor solvent. Control of C–N and C–O chemoselectivity

Reaction of PhMgBr with (Me3Si)HNO(SiMe3)[TMSHA] in the presence of CuI or CuCN catalysis (10–20 mol %) in THF:cosolvent (cosolvent = HMPA or TMEDA) at room temperature can provide an atom-economic and step-economic access for arylamine synthesis starting from aryl Grignard reagents. Chemoselectivity to yield C–N or C–O coupling can be controlled by changing reaction parameters. Cu(I) catalyzed reaction of PhMgBr in THF or in THF:HMPA (or TMEDA) affords both C–N and C–O coupling products, i.e. aniline and phenol (mol ratio ≥ 7:3), whereas uncatalyzed reaction of PhMgBr gives phenol. Mechanisms were proposed for the solvent dependence of chemoselectivity in the coupling of both uncatalyzed and Cu(I) catalyzed Grignard reagent with (TMS)HNO(TMS).

Photoinitiated Cascade for Rapid Access to Pyrroloquinazolinone Core of Vasicinone, Luotonins, and Related Alkaloids.

Furylimines of aromatic o-nitro aldehydes undergo a photoinduced cascade transformation offering rapid atom- and step-economical access to complex polyheterocyclic scaffolds possessing a privileged pyrroloquinazolinone core.

Manganese(I)-Catalyzed C-H Activation/Diels-Alder/retro-Diels-Alder Domino Alkyne Annulation featuring Transformable Pyridines.

Complexity-increasing Domino reactions comprising C-H allenylation, a Diels-Alder reaction, and a retro-Diels-Alder reaction were realized by a versatile catalyst derived from earth-abundant, non-toxic manganese. The C-H activation/Diels-Alder/retro-Diels-Alder alkyne annulation sequence provided step-economical access to valuable indolone alkaloid derivatives through a facile organometallic C-H activation manifold with transformable pyridines.

Radical Cyanotrifluoromethylation of Isocyanides: Step-Economical Access to CF3-Containing Nitriles, Amines, and Imines.

A novel copper-catalyzed radical cyanotrifluoromethylation has been achieved through a multicomponent reaction of isocyanides, Togni's reagent, and trimethylsilyl cyanides, affording trifluoroacetimidoyl nitriles in good yields. This reaction demonstrates a unique feature of merging two valuable functional groups-trifluoromethyl (CF3) and cyan (CN)-onto the same C atom. The transformation proceeds by the initial addition of the CF3 radical to isocyanide and the subsequent intermolecular C-CN formation. The products can be successfully transformed to a series of CF3-containing amines and imines that may serve in the synthesis of valuable pharmaceuticals and agrochemicals.

A novel synthesis of N-hydroxy-3-aroylindoles and 3-aroylindoles.

A straightforward indole synthesis via annulation of C-nitrosoaromatics with conjugated terminal alkynones was realised achieving a simple, highly regioselective, atom- and step economical access to 3-aroylindoles in moderate to good yields. Further functionalizations of indole scaffolds were investigated and an easy way to JWH-018, a synthetic cannabinoid, was achieved.

A NaSO2CF3/NaBrO3-mediated bromotrifluoromethylation of enyne via free-radical cascade processes

A NaBrO3-induced radical bromotrifluoromethylation of enynes with NaSO2CF3 was developed. This method allows a transition-metal free, highly selective and step-economic access to diverse bromotrifluoromethylated five- and six-membered heterocycles.

An Intermolecular Azidoheteroarylation of Simple Alkenes via Free-Radical Multicomponent Cascade Reactions.

Based upon a radical polar effect, an intermolecular azidoheteroarylation of simple alkenes via a metal-free radical multicomponent cascade process was achieved. It allows a mild, rapid, and step-economic access to a broad range of azidoalkylated heteroaromatics. Given the diversity in transformations of organic azides and medicinally privileged scaffolds of heteroarenes, this strategy enables efficient synthesis and late-stage derivatization of drugs and candidates.

Iodine-Promoted Semmler-Wolff Reactions: Step-Economic Access to meta-Substituted Primary Anilines via Aromatization.

An atom- and step-economic access to an array of unprotected meta-substituted primary anilines was disclosed using the Semmler-Wolff reaction, promoted by molecular iodine. Therein, noble metal catalysts and inert atmosphere are unnecessary while the forcing reaction conditions and the lengthy synthesis can be avoided. The synthetic utility of this approach is evident in the de novo syntheses of three bioactive molecules with good total yields.