Yuya Hu

Sulfur fluoromethylylide in action: Diarylfluoromethyl sulfonium salts are efficient fluoromethylene transfer reagents. This was demonstrated by the development of a monofluorinated Johnson–Corey–Chaykovsky reaction with ketones and aldehydes, delivering uncommon 2‐unsubstituted fluoroepoxides. This is the first evidence for the feasibility of sulfur fluoromethylylide and its action as a reaction intermediate.

Abstract

Diarylfluoromethyl sulfonium salts are efficient fluoromethylene transfer reagents equivalent to fluorocarbene, which is difficult to access. This was demonstrated by the development of a monofluorinated Johnson–Corey–Chaykovsky reaction with ketones and aldehydes, delivering uncommon 2‐unsubstituted fluoroepoxides. This is the first evidence for the feasibility of sulfur fluoromethylylide and its action as a reaction intermediate.

Going long: A triphosphorylation reagent was developed, which enables access to defined polyphosphates in a one‐flask operation. These polyphosphate chains are modified on either one end or both ends with different tags.

Abstract

An iterative polyphosphorylation approach is described, which is based on a phosphoramidite (P‐amidite) derived reagent (c‐PyPA) obtained from the cyclization of pyrophosphate with a reactive diisopropylaminodichlorophosphine. This type of reagent is unprecedented as it represents a reactive P‐amidite without protecting groups. The reagent proved to be stable in solution over several weeks. Its utility is described in the context of iterative monodirectional and bidirectional polyphosphorylations. The ensuing functionalized cyclotriphosphate can be opened with a variety of nucleophiles providing ready access to diverse functionalized polyphosphate chains of defined length with several tags, including both P‐N and P‐O labels. Their interaction with exo‐ and endopolyphosphatases is described.

Expanding the library: A three‐component cross‐coupling reaction of boronic acid, sodium metabisulfite, and dimethyl carbonate is efficiently established for the construction of an aryl methyl sulfone library. Pharmaceutical synthesis and late‐stage diversification are afforded through this protocol.

Abstract

A three‐component cross‐coupling protocol of boronic acid, sodium metabisulfite, and dimethyl carbonate was developed for the construction of significant functional methyl sulfones, in which introduction of sulfur dioxide at the last stage was successfully achieved in one step. Inorganic sodium metabisulfite was used as an eco‐friendly sulfur dioxide source. Green dimethyl carbonate was employed as methyl reagent in this transformation. Diverse functional methyl sulfones were obtained from various readily available boronic acids. Notably, the last‐stage modification of pharmaceuticals and the synthesis of Firocoxib were efficiently established through this strategy.

Swimming against the tide: A new β‐diketiminate Cu^I catalyst system has been developed for C−H amidation with aroyl azides via copper nitrene intermediates. Owing to their steric bulk they target stronger, more accessible primary and secondary C−H bonds in the presence of weaker, hindered tertiary C−H bonds.

Abstract

Undirected C(sp³)−H functionalization reactions often follow site‐selectivity patterns that mirror the corresponding C−H bond dissociation energies (BDEs). This often results in the functionalization of weaker tertiary C−H bonds in the presence of stronger secondary and primary bonds. An important, contemporary challenge is the development of catalyst systems capable of selectively functionalizing stronger primary and secondary C−H bonds over tertiary and benzylic C−H sites. Herein, we report a Cu catalyst that exhibits a high degree of primary and secondary over tertiary C−H bond selectivity in the amidation of linear and cyclic hydrocarbons with aroyl azides ArC(O)N₃. Mechanistic and DFT studies indicate that C−H amidation involves H‐atom abstraction from R‐H substrates by nitrene intermediates [Cu](κ²‐N,O‐NC(O)Ar) to provide carbon‐based radicals R^. and copper(II)amide intermediates [Cu^II]‐NHC(O)Ar that subsequently capture radicals R^. to form products R‐NHC(O)Ar. These studies reveal important catalyst features required to achieve primary and secondary C−H amidation selectivity in the absence of directing groups.

The hydrogen shuffle: Transfer of hydrogens from 1,4‐cyclohexadiene to a variety of alkenes is catalyzed by simple alkaline‐earth metal amides. The proposed mechanism for this convenient and highly selective transfer hydrogenation is supported by DFT calculations.

Abstract

The alkene transfer hydrogenation (TH) of a variety of alkenes has been achieved with simple AeN′′₂ catalysts [Ae=Ca, Sr, Ba; N′′=N(SiMe₃)₂] using 1,4‐cyclohexadiene (1,4‐CHD) as a H source. Reaction of 1,4‐CHD with AeN′′₂ gave benzene, N′′H, and the metal hydride species N′′AeH (or aggregates thereof), which is a catalyst for alkene hydrogenation. BaN′′₂ is by far the most active catalyst. Hydrogenation of activated C=C bonds (e.g. styrene) proceeded at room temperature without polymer formation. Unactivated (isolated) C=C bonds (e.g. 1‐hexene) needed a higher temperature (120 °C) but proceeded without double‐bond isomerization. The ligands fully control the course of the catalytic reaction, which can be: 1) alkene TH, 2) 1,4‐CHD dehydrogenation, or 3) alkene polymerization. DFT calculations support formation of a metal hydride species by deprotonation of 1,4‐CHD followed by H transfer. Convenient access to larger quantities of BaN′′₂, its high activity and selectivity, and the many advantages of TH make this a simple but attractive procedure for alkene hydrogenation.

Copper to the rescue: A general method for the synthesis of propargylic sulfones featuring quaternary stereocenters has been developed. The method relies on a copper‐catalyzed sulfonylation of propargylic cyclic carbonates using sodium sulfinates. It provides the first example of such a transition‐metal‐catalyzed enantioselective propargylic substitution reaction with sulfur‐centered nucleophiles and gives access to functionalized tertiary sulfones.

Abstract

Tertiary propargylic sulfones are of significant importance in organic synthesis and medicinal chemistry, but to date no general asymmetric synthesis approach has been developed. We disclose a versatile copper‐catalyzed sulfonylation of propargylic cyclic carbonates using sodium sulfinates that allows the construction of propargylic sulfones featuring elusive quaternary stereocenters. This method provides the first successful example of such an enantioselective propargylic sulfonylation, features high asymmetric induction, wide functional group tolerance, and scalability, and enables attractive product diversification.

Bifunctional monosilanes are obtained by methylchlorodisilane cleavage reactions with use of phosphonium chlorides as the cleavage catalysts and reaction partners to preferably obtain bifunctional monosilanes. Such reactions increase the overall economic value of the Rochow–Müller direct process and reduce the tremendous amount of globally accumulating disilane side products.

Abstract

The Müller–Rochow direct process (DP) for the large‐scale production of methylchlorosilanes Me _n SiCl_4−n (n=1–3) generates a disilane residue (Me _n Si₂Cl_6−n , n=1–6, DPR) in thousands of tons annually. This report is on methylchlorodisilane cleavage reactions with use of phosphonium chlorides as the cleavage catalysts and reaction partners to preferably obtain bifunctional monosilanes Me _x SiH _y Cl _z (x=2, y=z=1; x,y=1, z=2; x=z=1, y=2). Product formation is controlled by the reaction temperature, the amount of phosphonium chloride employed, the choice of substituents at the phosphorus atom, and optionally by the presence of hydrogen chloride, dissolved in ethers, in the reaction mixture. Replacement of chloro by hydrido substituents at the disilane backbone strongly increases the overall efficiency of disilane cleavage, which allows nearly quantitative silane monomer formation under comparably moderate conditions. This efficient workup of the DPR thus not only increases the economic value of the DP, but also minimizes environmental pollution.

The combination of LiO‐tBu, CsF, and [18]crown‐6 efficiently promotes the direct C−H carboxylation of electron‐rich heteroarenes (see scheme; benzothiophene, thiophene, benzofuran, and furan derivatives). A variety of functional groups, including methyl, methoxy, halo, cyano, amide, and keto moieties, are compatible with this system. The reaction proceeds by the formation of a tert‐butyl carbonate species.

Abstract

We herein demonstrate that the combination of LiO‐tBu, CsF, and [18]crown‐6 efficiently promotes the direct C−H carboxylation of electron‐rich heteroarenes (benzothiophene, thiophene, benzofuran, and furan derivatives). A variety of functional groups, including methyl, methoxy, halo, cyano, amide, and keto moieties, are compatible with this system. The reaction proceeds via the formation of a tert‐butyl carbonate species.

Oat field: A method for electrophilic sulfenylation by organophosphorus‐catalyzed deoxygenative O‐atom transfer (OAT) from sulfonyl chlorides is reported. This C−S bond‐forming reaction is catalyzed by 1 (phosphetane) in conjunction with a hydrosilane terminal reductant to afford sulfenyl electrophiles, including valuable trifluoromethyl, perfluoroalkyl, and heteroaryl derivatives.

Abstract

A method for electrophilic sulfenylation by organophosphorus‐catalyzed deoxygenative O‐atom transfer from sulfonyl chlorides is reported. This C−S bond‐forming reaction is catalyzed by a readily available small‐ring phosphine (phosphetane) in conjunction with a hydrosilane terminal reductant to afford a general entry to sulfenyl electrophiles, including valuable trifluoromethyl, perfluoroalkyl, and heteroaryl derivatives that are otherwise difficult to access. Mechanistic investigations indicate that the twofold deoxygenation of the sulfonyl substrate proceeds by the intervention of an off‐cycle resting state thiophosphonium ion. The catalytic method represents an operationally simple protocol using a stable phosphine oxide as a precatalyst and exhibits broad functional‐group tolerance.

Synlett
DOI: 10.1055/s-0037-1611694

A practical Lewis acid-catalyzed Meyer–Schuster rearrangement of fluoroalkylated propargylic alcohols, leading to a series of β-fluoroalkyl-α,β-enones, is developed. The methodology reported herein features moderate to high yields and high stereoselectivity in the synthesis of β-alkyl-β-fluoroalkyl-α,β-enones.
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© Georg Thieme Verlag Stuttgart · New York

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Synlett
DOI: 10.1055/s-0037-1611663

Air- and moisture-stable secondary phosphine oxides (SPOs) enabled nickel-catalyzed Kumada–Corriu cross-couplings of various arylmethyl ethers at room temperature by challenging C–O activation.
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Georg Thieme Verlag Stuttgart · New York

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Acid‐free! Bench‐stable cyclohexa‐1,4‐diene‐based hydrogen cyanide (HCN) surrogates are reported to engage in transfer hydrocyanation of alkenes upon treatment with certain boron Lewis acids. The success also depends on the equilibrium position between the intermediate isocyano‐ and cyanoborate isomers. Tertiary nitriles are obtained with exclusive Markovnikov selectivity.

Abstract

A straightforward gram‐scale preparation of cyclohexa‐1,4‐diene‐based hydrogen cyanide (HCN) surrogates is reported. These are bench‐stable but formally release HCN and rearomatize when treated with Lewis acids. For BCl₃, the formation of the isocyanide adduct [(CN)BCl₃]⁻ and the corresponding Wheland complex was verified by mass spectrometry. In the presence of 1,1‐di‐ and trisubstituted alkenes, transfer of HCN from the surrogate to the C−C double bond occurs, affording highly substituted nitriles with Markovnikov selectivity. The success of this transfer hydrocyanation depends on the Lewis acid employed; catalytic amounts of BCl₃ and (C₆F₅)₂BCl are shown to be effective while B(C₆F₅)₃ and BF₃⋅OEt₂ are not.

Abstract

The broad prospects of trifluoromethylated compounds in materials science, agricultural chemistry, and pharmaceutical chemistry have stimulated the rapid development of asymmetric organocatalytic transformations to access these biologically important compounds. Among all types of trifluoromethylated compounds, trifluoromethylated cyclic compounds with a C−CF₃ stereogenic center have gained increasing attention in medicinal and organic chemistry because they are extensively found in many biologically active molecules, lead compounds, and listed drugs. This review attempts to summarize the developments in the organocatalytic asymmetric synthesis of cyclic compounds bearing a trifluoromethylated stereogenic center since 2012.

Synlett
DOI: 10.1055/s-0037-1611958

Whereas two equivalents of base are typically required to prepare carboxylate (CO2 –) ylides [Ph3P+C–(H)-alk-CO2 –] (alk = alkanediyl) from carboxy (CO2H) phosphonium salts [(Ph3PCH2-alk-CO2H)+] X–, we reveal, for the first time, that carboxy ylides [Ph3P+C–(H)-alk-CO2H] can be generated with one equivalent of NaHMDS at 0 °C, and that the Wittig reaction of simple aliphatic aldehydes (1 equiv) with these carboxy ylides (1.5–2 equiv) in THF at –95 to –90 °C for one hour, then at warming temperatures to 0 °C over two hours affords (Z)-alkenoic acids. Phosphonium salts containing (CH2) n alkanediyl chains (n = 2–5) showed adequate reactivity and high Z-selectivity, whereas shorter or longer alkanediyl chains resulted in a low Z-selectivity and/or a low yield. On the basis of these results with different (CH2) n chains and that obtained with a rigid methylene group, we propose that a rapid equilibrium between Ph3PCH 2-alk-CO2 – and Ph3P+C–(H)-alk-CO2 H, through an intramolecular hydrogen exchange, accounts for the success of the Wittig reaction.
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© Georg Thieme Verlag Stuttgart · New York

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