and Moisture‐Compatible s‐Block Organometallic Chemistry ...

Very Important Paper

Advancing Air- and Moisture-Compatible s-BlockOrganometallic Chemistry Using Sustainable SolventsSergio E Garciacutea-Garrido[a] Alejandro Presa Soto[a] Eva Hevia[b] andJoaquiacuten Garciacutea-Aacutelvarez[a]

Dedicated to all past and current Spanish Organometallic Researchers on the occasion of the 40th Anniversary of the ldquoGrupoEspecializado de Quiacutemica Organometalica (GEQO)rdquo from the ldquoReal Sociedad Espantildeola de Quiacutemica (RSEQ)rdquo

Challenging conventional wisdom that s-block organometallicreagents such as Grignard or organolithiums need to be usedunder protecting inert atmosphere (N2 or Ar) employing dryorganic solvents with a strict temperature control this Minire-view focusses on recent advances on the use of thesecommodity reagents while operating under air at roomtemperature and in the presence of moisture Key for thesuccess of these approaches has been the use of the followingsustainable solvents i) water ii) Deep Eutectic Solvents (DESs) oriii) biomass-derived polyols (like glycerol) or ethereal solvents[i e 2-MeTHF or cyclopentyl methyl ether (CPME)] Theversatility of these air and moisture compatible syntheticprotocols has been demonstrated for a myriad of key organictransformations including nucleophilic additions of RLiRMgXreagents to unsaturated organic molecules (i e ketones iminesesters amides or nitriles) as well as ortho- and lateral lithiation

of aromatic substrates Pd catalysed cross-couplings and anionicpolymerisation of styrenes Extension of these studies to lithiumamides (LiNR2) or phosphides (LiPPh2) has enabled the develop-ment of more sustainable and efficient methods for C N andC P bond forming processes These unconventional s-blockmetal mediated transformations have also been successfullyincorporated in one-pot tandem processes in combination withtransition-metal and organo-catalysis Remarkably in somecases the conversions and chemoselectivities observed aresuperior to those detected in common toxic organic solventswhile working under inert atmosphere conditions with stricttemperature control The key role played by the choice ofsolvent in these transformations and how it can affect theconstitution of the s-block organometallic species present insolution is also discussed

1 Introduction

Since the pioneering works by Victor Grignard and PhilippeBarbier (organomagnesium derivatives 1900)[1] and WilhelmSchlenck and Johanna Holtz (organolithium compounds1917)[2] polar s-block organometallic chemistry has become apivotal instrument in the toolbox of synthetic organic chemists

Used in academic synthetic laboratories worldwide they areespecially in high demand for functionalising aromatic andheterocyclic compounds and so are indispensable in thechemical industry (eg for the manufacture of agrochemicalselectronic materials pharmaceuticals and other medicines) Partof their popularity lies in their high reactivity as a consequenceof the large (for lithium)[3] to medium (for magnesium)[4] polarityof their metal-carbon bonds However controlling this highreactivity can be challenging and side reactions such ashydrolysisoxidation of reagents decomposition of intermedi-ates unwanted rearrangements and functional group attacksare common In order to overcome some of these limitationspolar organometallic reagents are usually employed at very lowtemperatures ( 78 degC) and the use of strict inert atmosphereconditions and carefully dried organic solvents is paramount tothis type of chemistry These problems in controlling theselectivity of these reagents can also lead to the formation ofcomplex mixtures and poor product yields which necessitateadditional separation steps and generate lots of waste Theselimitations can greatly impact large scale processes in industrydue to the extra costs and time incurred in solving theseproblems In addition hazardous volatile organic compounds(VOCs) used as common solvents in polar organometallicchemistry still represent 80ndash90 wt of the non-aqueousmaterials used in a typical chemical manufacturing processdespite their toxicity high flammability non-biodegradability

[a] Dr S E Garciacutea-Garrido Dr A Presa Soto Dr J Garciacutea-AacutelvarezLaboratorio de Compuestos Organometaacutelicos y Cataacutelisis Departamento deQuiacutemica Orgaacutenica e Inorgaacutenica (IUQOEM)Centro de Innovacioacuten en Quiacutemica Avanzada (ORFEO-CINQA)Facultad de QuiacutemicaUniversidad de Oviedo33071 Oviedo SpainE-mail garciagsergiouniovies

presaalejandrounioviesgarciajoaquinuniovies

httpwww unioviedoescomorcaJoaquin20ingleshtm[b] Prof Dr E Hevia

Departement fuumlr Chemie Biochemie und Pharmazie (DCBP)Universitaumlt BernFreiestrasse 3 3012 Bern SwitzerlandE-mail evaheviadcbunibechhttpwwwevaheviagroupcom

Part of the ldquoRSEQ-GEQO Prize Winnersrdquo Special Collection

copy 2021 The Authors European Journal of Inorganic Chemistry published byWiley-VCH GmbH This is an open access article under the terms of theCreative Commons Attribution License which permits use distribution andreproduction in any medium provided the original work is properly cited

Minireviewsdoiorg101002ejic202100347

1Eur J Inorg Chem 2021 1ndash16 copy 2021 The Authors European Journal of Inorganic Chemistrypublished by Wiley-VCH GmbH

These are not the final page numbers

Wiley VCH Mittwoch 30062021

2199 210342 [S 116] 1

and tendency to accumulate in the atmosphere[5] Furthermorethe recovery of these toxic and flammable organic compoundsonly reaches 50 to 80 in most of the cases[6]

Advances in Green Chemistry[7] have made giant stepstowards addressing some of these challenges as well as othersimposed by todays society (which are related with the limitedavailability of our natural resources and its consequences) Thus

Sergio E Garciacutea Garrido studied chemistry at theUniversity of Oviedo and received his PhDdegree in 2005 under the supervision of ProfJoseacute Gimeno and Dr Victorio Cadierno workingin the chemistry of organometallic complexes ofruthenium(II) and ruthenium(IV) as well as theirapplication in different catalytic processes ofinterest After a postdoctoral stay (2005ndash2007)at the School of Chemistry of SouthamptonUniversity (Southampton UK) working underthe supervision of Prof Philip A Gale in the fieldof supramolecular chemistry and its applicationto the recognition of anions he rejoined theDepartment of Organic and Inorganic Chemistryof Oviedo University first as contracted re-searcher (2008) later as a Ramoacuten y Cajalresearcher (2009ndash2013) Lecturer (2014ndash2018)and finally as Senior Lecturer (Associate Profes-sor) in Inorganic Chemistry position that hecurrently holds His current lines of work focuson the chemistry of organometallic complexesand the development of new supramolecularstructures as well as their applications inhomogeneous and heterogeneous catalysis Heis coauthor of more than 50 articles in interna-tional journals and 7 book chapters

Alejandro Presa Soto was born in Gijoacuten (AsturiasSpain) in 1976 He obtained his PhD at theUniversity of Oviedo (2005) working in thesynthesis and catalytic activity of chiral poly-phosphazene copolymers under the supervisionof Prof G Carriedo and Prof F J Garciacutea-AlonsoAfter exploring the self-assembly of crystallineblock copolymers in work with I Manners inBristol he returned to the University of Oviedoin 2010 first as a Juan de la Cierva researcherand later as a Ramoacuten y Cajal research fellowCurrently he is Associate Professor of InorganicChemistry and his research interest is focusedon the synthesis and self-assembly of polyphos-phazene-based block copolymers and the devel-opment of novel chemical transformations in-volving the formation of C-heteroatom bondsunder sustainable reaction media He has auth-ored more than 50 scientific publications includ-ing 3 book chapters

Eva Hevia received both her MSci degree inChemistry and her PhD degree from theUniversidad de Oviedo (Spain) in 1998 and 2002respectively After a three-year position at theUniversity of Strathclyde (Glasgow UK) workingas a Marie Curie Fellow with Professor RobertMulvey in 2006 she took up a Royal SocietyUniversity Research Fellowship and Lectureshipthere Subsequently she was promoted to FullProfessor in 2013 In February 2019 Eva movedto the University of Bern to take up a fullprofessorship in Inorganic Chemistry Researchin her group focuses on polar organometallicchemistry at the crossroads of inorganic organ-ic and green chemistry Eva is an elected fellowof the European Academy of Sciences and herresearch has been recognised with severalawards including the 2017 RSC Corday-MorganPrize and the 2019 GEQO Research ExcellenceAward

Joaquiacuten Garciacutea Aacutelvarez studied chemistry at theUniversity of Oviedo and received his PhDdegree in 2005 under the supervision of ProfJoseacute Gimeno and Dr Victorio Cadierno studyingthe coordination of iminophosphorane ligandsin arene-Ru(II) fragments Then he joined thegroup of Prof Robert E Mulvey at the Universityof Strathclyde in Glasgow (Scotland UnitedKingdom) working for two years and a half inthe field of main group chemistry (alkali-metal-mediated-metallation) In 2008 he returned tothe University of Oviedo as a postdoctoralresearcher thanks to the award of a contractfrom the regional program ldquoClariacutenrdquo of thePrincipado de Asturias The current focuses ofhis research are i) the study of metal-catalysed(Ru Cu Pd Au) and metal-mediated (Li Mg)organic reactions using environmentally friendlysolvents [water and Deep Eutectic Solvents(DESs)] as reaction media and ii) the design ofone-pot processes combining either metal-organo- and bio-catalysis This research hasbeen recognised over the last years with theaward of a postdoctoral contract ldquoJuan de laCiervardquo in 2009 and more recently (2012) witha postdoctoral contract ldquoRamoacuten y Cajalrdquo In2017 he was promoted to an AssistanceProfessor position and more recently (2018) toan Associate Professor position He has pub-lished more than 75 scientific articles and is co-author of twelve book chapters on Organo-metallic Chemistry and Catalysis in unconven-tional reaction media In 2016 he received thePrize ldquoGEQO-Young Scientist Awardrdquo in 2017the ldquoBeca Leonardo a Joacutevenes Investigadores yCreadores Culturalesrdquo from BBVA fundation andin 2018 the ldquoGreen Chemistry For Life GrantProgrammerdquo awarded by PhosAgroUNESCOIUPAC


2Eur J Inorg Chem 2021 1ndash16 wwweurjicorg copy 2021 The Authors European Journal of Inorganic Chemistry publishedby Wiley-VCH GmbH



2199 210342 [S 216] 1

great efforts have focussed on the design of organic processesthat can take place i) under aerobic ambient conditions andwith energy efficiency (i e room temperature and atmosphericpressure) ii) using sustainable solvents[8] and iii) under safeconditions (for both human beings and the environment)However until recently progress made towards upgrading s-block organometallic chemistry to these greener conditionshave been limited since a priori the cannon of this type ofchemistry is incompatible with these conditions (vide supra)

Making a seemingly impossible step change possible recentstudies from our groups and others have shown that byreplacing conventional toxic organic solvents (i e THF ortoluene) with other sustainable reaction media (such as DeepEutectic Solvents water glycerol 2-MeTHF or cyclopentyl methylether) it is possible to use these commodity s-block metalreagents under air and in the presence of moisture Further-more on many occasions under these conditions greaterperformances and selectivities of the s-block organometallicreagents are observed Overall these innovations have ren-dered an even greater scenario where the development ofmore environmentally benign synthetic procedures has un-veiled greater chemical behaviours

This Minireview summarises some of these studies on theuse of s-block polar organometallic reagents in aerobicambientconditions when using sustainable reaction media (like DeepEutectic Solvents water glycerol 2-MeTHF or cyclopentyl methylether) as solvent Specifically the Minireview is divided indifferent sections which showcase different type of reactivitiesThis includes i) chemoselective nucleophilic addition of RLiRMgX to carbonyl compounds (like ketones[9] imines[10]

esters[11] amides[12]) or nitriles[13] ii) regioselective ortho- orlateral lithiation of aromatic amides[12a] andaryltetrahydrofurans[14] respectively iii) formation of new C-heteroatom bonds (C X) by using lithium amides (LiNR2)

[15] orphosphides (LiPPh2)

[16] iv) the anionic polymerisation ofstyrenes[17] and v) cross-coupling reactions of RLi with arylhalides[18] In addition a section is included summarising currentefforts to design one-pot tandem protocols in which aerobicpolar s-block organometallic chemistry in green solvents can besynergically amalgamated with either metal-[12a19] ororganocatalysed[20] synthetic processes

The overarching aim of this Minireview is to inform andinspire other synthetic chemists who use this fundamental typeof reagents on a regular basis finding it a helpful resourcetowards the development of air and moisture compatiblesustainable s-block organometallic chemistry[21] Approachingthis area from a metal-focussed perspective a special effort hasbeen made to correlate the reactivities observed in thesesolvents with the possible constitution of the organometallicintermediates in these unconventional solvents

2 Aerobic AdditionSubstitution Reaction ofs-Block Organometallic Reagents (RLiRMgX) toCarbonyl Compounds in Sustainable Solvents

21 Chemoselective addition of RMgXRLi reagents toketones and esters in DESs and water

While the use of organolithium and Grignard reagents in bulkwater and other unconventional solvents (DESs glycerol etc) isa recent innovation[9ndash20] some previous precedents in theliterature have hinted at the influence of water on the reactivityof these commodity organometallic reagents Thus in 1975Taylor reported the reaction of n-BuLi with bromoarenes usingNa-dried solvent wetted with T2O at 70 degC as an efficientmethod to access tritiated arenes[22a] In parallel advances ininorganic chemistry have shown that water can actually be asuitable donor ligand in organolithium and organopotassiumchemistry[22bndashd] Thus in 1990 Wright and co-workers reportedthe lithiation of 2-mercaptobenzoxazole in the presence ofTMEDA (NNNN-tetramethylethylene diamine) and H2O whichfurnished [(C6H4OCSN)Li(TMEDA)(H2O)] where the coordinatedmolecule of water forms a strong H-bond between one of itsprotons and the polarised C=S bond of the ligand[22b] Scheyerand co-workers reported the structure of [LiCH(CN)2(H2O)(TMEDA)]1] resulting from the lithiation of malonitrilefollowed by addition of TMEDA and water Forming an intricatethree dimensional polymeric structure TMEDA does notcoordinate to the Li atoms whereas each water molecule bindssimultaneously to TMEDA (via H-bonding) and to the lithiumcations (acting as a Lewis base)[22c] More recently Stalke and co-workers have reported the synthesis and structural authentica-tion of a novel water-containing organopotassium complex(Figure 1) which was found to be surprisingly robust towardshydrolysis[22d] 1H NMR titration experiments in deuterated THFusing variable amounts of water revealed that full hydrolysis ofthis compound was only observed after one week using 114equivalents of water[22d]

Building on these exciting precedents our first studiesfocussed on the addition of Grignard reagents to ketones toaccess tertiary alcohols It should be noted that previous workby Holm and Madsen has shown that allyl Grignard reagents

Figure 1 Synthesis and asymmetric unit of [(18-crown-6)K(46-tBu-OCNC6H2)2CHmiddotH2O]

[22d]





2199 210342 [S 316] 1

can add to acetone in the presence of water[23] Key for thesuccess of this approach was that the rate of the ketoneaddition was comparable to that of protonation of the Grignardreagent in water However its substrate scope was very limitedand using more reactive reagents such as n-BuMgCl only tracesof the addition product were observed On the other handstudies by Song and co-workers described the activation effectof quaternary ammonium salts [like N(n-Bu)4Cl or N(n-Bu)4Br]and diglyme on the addition of Grignard reagents to ketones inTHF[24] Thus when the addition of n-BuMgBr is performed inthe absence of any additive the obtained yield for the desiredtertiary alcohol is 49 The simple addition of the ammoniumsalts N(n-Bu)4ClN(n-Bu)4Br to the reaction media (using eitherstoichiometric or catalytic amounts) triggered a remarkableincrease of the yield of the addition reaction (up to 91)(Scheme 1) In the same line the addition of a tridentate donorligand (i e diglyme) to the reaction media clearly improves theyield of the final tertiary alcohol up to 75 While the authorsacknowledge that the presence of the ammonium salt or thediglyme can affect the position of the Schlenk equilibrium forthe Grignard reagents the exact activating effect of thisadditive remained concealed

Inspired with these precedents and with the aim ofdeveloping more sustainable Grignard mediated reactions wepondered if we could export this ammonium salt activating

effect to the use of non-toxic and biodegradable ammonium-salt-based Deep Eutectic Solvents (DESs) (Scheme 2)[25] Theseneoteric sustainable and tunable reaction media can be easilyobtained just by mixing two naturally occurring compoundsthat are able to interact through a tridimensional hydrogen-bond-type network which is established between an hydrogen-bond-acceptor component and its corresponding hydrogen-bond-donor counterpart In particular for this study we usedDESs containing the biorenewable quaternary ammonium saltcholine chloride (ChCl)][26] and different hydrogen-bond-donorssuch as glycerol (Gly) ethylene glycol (EG) urea or even water(Scheme 2)[25]

Using choline-chloride-based eutectic mixtures containingglycerol (1ChCl2Gly) or water (1ChCl2H2O) we found that avariety of Grignard reagents (alkyl- vinyl- and ethynyl magne-sium bromides) can rapidly undergo selective addition to botharomatic or aliphatic ketones under bench type reactionconditions (room temperature and under air) Reactions takeplace in just 3 seconds and the relevant substituted tertiaryalcohols are obtained in good to excellent yields (up to 87)[9a]

It should be noted that the reactions require the use of twoequivalents of the RMgBr reagent but they occur with anexcellent control of the chemoselectivity without observing theformation of other by-products resulting from competingreduction or enolisation processes Demonstrating the key roleof the DESs in the absence of the quaternary ammonium-saltChCl (that is using bulk water as solvent) the addition processalmost shuts down with the yield dramatically decreasing to10 This experimental observation suggested a possiblekinetic activation of the Grignard reagents favored by ChCl (ingood agreement with previous studies reported by Song)[24]

Trying to shed some light in this activation process we studiedthe co-complexation of several Grignard reagents with N(n-Bu)4Cl We use this ammonium salt due to its solubility in THFCombining X-ray crystallographic studies with DOSY NMRexperiments we could establish the formation of mixedammonium magnesiate [N(n-Bu4)

+RMgCl2 ] species (Fig-

ure 2)[9a]

Since the formation of this mixed ammonium magnesiatespecies occurs via co-complexation of the ammonium salt andthe Grignard reagent using an ethereal solvent (THF) it is notpossible to ascertain if the same type of co-complexation is inoperation when using DESs containing ChCl as solvent Never-theless it could be expected that these type of anionic

Scheme 1 Observed improvement of the reaction yield in the addition ofGrignard reagents to ketones when ammonium salt N(n-Bu)4Br or diglymeare employed as additives[24]

Scheme 2 Ultrafast and chemoselective addition of RMgX reagents toketones under air at room temperature using ChCl-based eutectic mixturesas reaction media[9a]

Figure 2 Molecular structure of ammonium magnesiate[N(n-Bu4)

+(Me3SiCH2)MgCl2(THF) ] obtained by co-complexation of

N(n-Bu4)Cl and Me3SiCH2MgCl in THF[9a]





2199 210342 [S 416] 1

magnesiate species will exhibit enhanced nucleophilic power incomparison with that of neutral Grignard reagents[27] This couldexplain to certain extent the fast reactivity observed in theseadditions favoring the addition reactions over competinghydrolysis processes Notwithstanding other factors should alsobe taken into account as for example the activation of thesubstrate by the formation of H-bonding with the H-bonddonor component of the DES (water or Gly) Furthermore as theGrignard reagents used in this study were purchased fromcommercial sources as THF solutions and the employed DESsand THF are not miscible the heterogeneous character of thesereactions may also play an important role (vide infra for reactionldquoon-waterrdquo conditions)[28]

Building on these promising results using RMgX reagentswe next extended these studies to highly polar organolithiumreagents The greater polarity of the M C bond in these systemsin comparison to RMgX reagents generally imposes the use ofcryogenic conditions ( 78 degC) in order to control theirchemoselectivity[3] For example Ishihara and co-workers havepreviously reported the addition of n-BuLi to acetophenoneworking at 78 degC under protecting atmosphere and using dryTHF as solvent As depicted in Scheme 3a and employing theseSchlenk-type reaction conditions the authors observed theformation of a mixture of products containing the expectedtertiary alcohol in a 62 yield along with the undesired aldolcondensation by-product[29] Contrastingly when we repeatedthis reaction (but using 2-methoxy-acetophenone as electro-phile) under air at room temperature and employing 1ChCl2H2O (Scheme 3b) the corresponding tertiary alcohol isobtained as the only product of the reaction in an increased87 yield These findings show that using these unconven-tional reaction conditions not only it is possible to improve theperformance of the organometallic reagent but also to increasethe chemoselectivity of the addition process Again and aspreviously proposed for Grignard reagents we rationalise theseexperimental observations in terms of an activation effect of n-BuLi in the presence of the quaternary-ammonium-salt (ChCl)In this case whilst we were not able to obtain X-ray quality

crystals from the reaction both monodimensional (1H 13C and7Li) and bidimensional (DOSY) NMR studies hint at the possiblein-situ formation of anionic lithiate ([LiCl2R]

2 ) as a probableactive species in which two chloride anions coming from theChCl are now coordinated to the lithium atom Although itshould be noted that these experiments have been carried outusing N(n-Bu4)Cl as a mimic of ChCl and the solvent employedis deuterated THF Related to the formation of reactive atespecies Ishihara and co-workers have also reported that lithiummagnesiate (n-Bu)3MgLi can offer greater chemoselectivities forthe alkylation of ketones than conventional organolithiumreagents using THF as a solvent (see Scheme 3c using in thiscase acetophenone as the organic substrate)[29] Thus theseexperimental observations reveal the key double role of ChCl inthis transformation being at the same time i) the hydrogen-bond acceptor needed for the synthesis of the eutectic mixtureand ii) the halide source that can facilitate the in-situ formationof more activated and nucleophilic lithiate species

Thrilled by these observations we next assessed the scopeof the RLi addition reaction in terms of the nature of both theorganolithium reagents and the ketones employed as organicelectrophiles (see Scheme 4) Thus alkylaryl- or alkynyl-basedorganolithium reagents can be successfully and chemoselectiveadded to ketones (either aliphatic or aromatic groups aretolerated) after only 3 seconds of reaction giving rise to thecorresponding highly substituted tertiary alcohols in good toalmost quantitative yields It should be noted that similarconversions were observed using either 1ChCl2H2O or 1ChCl2Gly as DESs However when the same reactions were carriedout replacing the relevant DES by neat water only traces of theaddition product were observed highlighting again theimportance of DES as part of the reaction medium[9a] At thispoint it is important to mention that in those cases in whichthe desired alcohols are obtained as solids (for examplearomatic alcohols derived from benzophenone) the finalproducts could be isolated just by simple adding of a brineaqueous solution to the eutectic mixture media which favouredthe precipitation of the desired tertiary alcohols Thereforethese organic products could be isolated directly throughfiltration without using organic and toxic VOC solvents Forthose cases in which the final products are obtained as oilsliquids a liquidliquid extraction with environmentally friendlyand biomass-based ethereal solvents (like 2-MeTHF or CPME)could be also employed

Scheme 3 Comparative studies on the addition of organolithium reagentsinto ketones employing either traditional Schlenk-type (ac)[29] or DESs-typereaction conditions (b)[9a]

Scheme 4 Ultrafast and chemoselective addition of organolithium reagents(RLi) to ketones under air at room temperature and using ChCl-basedeutectic mixtures as reaction media for the synthesis of tertiary alcohols[9a]





2199 210342 [S 516] 1

Contemporary to our work and going one step furtherCapriati and co-workers reported the design of a one-pottwo-steps protocol that combines the chemoselective nucleophilicaddition of alkylaryl Grignard (RMgX) or organolithium (RLi)reagents to arylalkyl γ-chloroketones under bench-type (roomtemperature and in the presence of air) and heterogeneousconditions (water or DESs were used as sustainable solventsScheme 5) with the concomitant cyclisation of the in-situobtained arylalkyl γ-chloroalcohols thanks to the addition ofan aqueous solution of NaOH (10) to the reaction crude[9b] Byemploying this protocol the authors were able to produce 22-disubstituted tetrahydrofurans in good yields (up to 85)working ldquoon-waterrdquo[28] or ldquoon-DESsrdquo heterogeneous conditions(as the arylalkyl γ-chloroketones employed are sparinglysoluble in water or DESs) Interestingly this work also showedthat waterDESs mixture cannot be simply replaced by bulkalcohols (MeOH) as solvent suggesting that the strong andtridimensional intermolecular hydrogen bond stablished be-tween waterDESs and the substrate may play a pivotal role inthe studied transformation This special H-bonding scenario caninduce not only the activation of the C=O bond on thesubstrate towards the nucleophilic addition but also shield theorganometallic reagent from competitive hydrolysis processes

More recently in collaboration with Capriatis group wehave also reported an efficient protocol for the synthesis ofsymmetric tertiary alcohols in excellent yields (up to 98) butusing esters as organic electrophiles (Scheme 6)[11] In this casethe fast (20 sec) and chemoselective double addition of RLiRMgX reagents (intermediate ketones were not isolated) can be

performed in the sustainable choline chlorideurea eutecticmixture (1ChCl2Urea) or in bulk water This double additionprotocol tolerates a wide variety of esters and alkylatingarylating reagents (RLiRMgX) takes place straightforwardly atroom temperature in the presence of air Finally demonstratingits synthetic utility this procedure was applied to the synthesisof some representative S-trityl-L-cysteine derivatives which area potent class of Eg5 inhibitors[30]

22 Chemoselective addition of RMgXRLi reagents to iminesand nitriles in DESs water and glycerol

Imines are generally considered valuable starting materials forthe synthesis of amines[31] through the nucleophilic addition ofGrignard[32] organolithium (RLi)[33] organoaluminium (AlR3)

[34] ororganozinc (ZnR2) reagents

[35] Contrary to the aforementionedcase of ketones or esters the addition of polar main-groupreagents to imines has been less explored This is probably dueto i) the reduced electrophilic character of the iminic carbonwhen compared with their corresponding keto counterparts[36]

and ii) the high tendency of imines to suffer undesired sidereactions (deprotonationreduction) in the presence of highlypolar organometallics In order to overcome some of thesedrawbacks several protocols have been described in theliterature that focused on increasing the electrophilic characterof the iminic carbon Some of these strategies involve the useof electron-withdrawing groups on the substituents on thenitrogen atom or the activation of the imine group through theaddition of Lewis acids to the reaction media Thus and bearingin mind the foreseen activation effect of ChCl-based eutecticmixtures in the addition of organolithium reagents to ketonesand esters (Scheme 4 Scheme 5 Scheme 6)[911] some of usdecided to test non-activated imines as new electrophilicpartners (Scheme 7a)[10a] We found that the addition reaction ofeither aliphatic or aromatic RLi reagents into the selected non-activated imines took place faster (only 3 sec) than theircorresponding hydrolysis process with the protic eutecticreaction medium giving rise to the desired secondary aminesi) with high selectivity (only the starting imines andor the final

Scheme 5 Chemoselective addition of polar organometallic reagents RLiRMgX) to γ-chloroketones under air at room temperature and using eitherwater or ChCl-based eutectic mixtures as reaction media for the synthesis of22-disubstituted tetrahydrofurans[9b]

Scheme 6 Chemoselective addition of polar organometallic reagents (RLiRMgX) to esters under air at room temperature and using either water orChCl-based eutectic mixtures as reaction media for the synthesis ofsymmetric tertiary alcohols[11]

Scheme 7 (a) Chemoselective addition of organolithium reagents (RLi) toimines under air at room temperature and using the eutectic mixture 1ChCl2Gly as sustainable reaction media for the synthesis of secondary amines(b) Assessing the time-dependent formation of the addition product whenthe order of addition of reagents is reversed[10a]





2199 210342 [S 616] 1

secondary amines were observed in the NMR spectra of thereaction crudes) ii) at room temperature and under air andiii) in good to almost quantitative yields (73ndash95) Interestinglyin this study under the conditions explored the eutecticmixture 1ChCl2Gly proved to be a better choice of solvent than1ChCl2H2O Furthermore by using the 1ChCl2Gly mixture itwas possible to carry out this alkylationarylation reactionsusing just 14 equivalents of the relevant organolithiumreagents edging closer to stoichiometric conditions Moreoverthis approach could also be applied for the alkylation of themore challenging quinolines In this case while lower yieldswere observed (18ndash54) the reaction takes place with anexcellent control of the chemoselectivity furnishing exclusivelythe 12-addition products Remarkably the addition reactions toimines worked well with sterically demanding s-BuLi and t-BuLiwhich in general have a greater tendency to undergo β-hydrideelimination especially when employed at room temperature

Astonishingly when we studied the lifetime of the organo-lithium reagent in the protic eutectic mixture by reversing theorder of addition of reagents (as shown in Scheme 7b for theaddition of n-BuLi to N-Benzylideneaniline) we found that afterstirring the organolithium reagent for 15 seconds under airbefore adding imine the addition product is still obtained in aremarkably high 89 yield These findings revealed anunexpected high kinetic stability of n-BuLi in the 1ChCl2Glyeutectic mixture In fact it was only after leaving this reagent inthe DES for 35 minutes exposed to air that the addition to theimine was completely supressed (Scheme 7b)

Further work by Capriati has also shown that water can beused as a solvent to promote the same fast and selectiveaddition of organolithium reagents to imines[10b] As wepreviously observed when ChCl-based eutectic mixtures wereused as sustainable reaction media the addition of RLi toimines took place ldquoon-waterrdquo conditions at room temperatureand under air giving rise to the expected secondary amines inyields up to 99 (Scheme 8a) Additions take place undervortex conditions by the formation of emulsions resulting fromthe addition of a commercially available solution of RLi inhexanes to a suspension of the imine substrate in water Underthese heterogeneous conditions it has been previously notedthat the efficiency of the rdquoon-waterrdquo reactions can be influencedby the volume and surface area of the organic droplets[28]

Supporting this interpretation when the addition was carriedout with gently stirring (to minimise the area of interface) theyields for the amine product decreased from 99 to 66[10b]

Interestingly when using D2O as a solvent a significant HDisotope effect was revealed This supports that the observedldquoon-waterrdquo behaviour can arise from proton transfer across theorganic-water interface Other highlights of this work from apractical perspective were that reactions can be efficientlycarried out in a larger scale (up to 55 mmol using 10 mL ofwater) and also that the relevant amine product can be isolatedby simple evaporation of the organic phase without any furtherpurification

In the same work Capriati and co-workers illuminated theway to follow to produce tertiary carbinamines under greenerreaction conditions by employing a one-pottwo-steps protocol

based on the double and consecutive addition of organolithium(RLi) and Grignard reagents (RMgX) to nitriles (Scheme 8b)[10b]

At this point it is important to note that in this specific caseboth water-soluble (CH3CN) and poorly soluble (PhCN) nitrilesproved to be effectively converted into the desired carbin-amines This is a rare example for this type of chemistry wherethe outcome of the addition reactions is not dependent on thesolubility of the organic electrophile in the employed sustain-able and protic eutectic mixture (water or ChCl-based eutecticmixtures)

Another sustainable solvent that has emerged as anefficient medium for the arylation of nitriles is glycerol (GlyScheme 8c)[13] As described in the previous examples usingDESs or water these reactions which employ aryl lithiums areultrafast (2ndash3 seconds) and compatible with air and moistureArylation of the nitriles generates in-situ the relevant NH-imineswhich can then be converted into the corresponding ketonesby hydrolysis in moderate to good yields (24ndash90Scheme 8c)[13] Interestingly contrasting with the reactivitiesobserved in the studies carried out in water (vide supra) whenusing Gly[3738] only those nitriles who were insoluble in thissolvent were effective towards these arylation processes Thesefindings suggest that this addition protocol takes place underldquoon-glycerolrdquo conditions A key difference between the use ofArLi reagents in water or Gly is the greater resistance tohydrolysis in the later Thus a study reversing the order ofaddition of the reagents revealed that if benzonitrile is addedto a mixture of PhLi in Gly that has firstly been allowed to stir atroom temperature under air for 15 seconds benzophenonecan still be obtained in a 74 yield (as opposed to 83 whenthe nitrile is first mixed with Gly and then PhLi is introduced)Contrastingly no benzophenone could be detected when thesame reaction is performed in water[13] More recently expand-ing even further the synthetic potential of these approaches

Scheme 8 Addition of highly polar organometallic reagents (RLiRMgX) toimines or nitriles under air at room temperature using water[10b] orglycerol[13] (Gly) as reaction media for the synthesis of amines or ketones





2199 210342 [S 716] 1

the addition of RLiRMgX reagents N-tert-butanesulfinyl iminesusing a mixture of D-sorbitolChCl as a solvent has beenreported as an environmentally friendly procedure for thepreparation of chiral amines of pharmaceutical interest at roomtemperature and in the presence of air[10c]

23 Nucleophilic substitutionaddition of organolithiumreagents (RLi) to amides in DESs or cyclopentyl methyl ether(CPME)

Amides are key building blocks in a plethora of differentsynthetic organic protocols due to their excellent chemicalversatility and easy synthesisaccessibility[39] For the specificcase of the reactivity of aromatic amides towards highly polarorganometallic reagents (eg RLi compounds) basically twomajor reaction pathways have been reported so far i) metal-lation on the activated ortho position of the aromatic ring(DoM Direct-ortho-Metalation) and ii) the corresponding nucle-ophilic substitution of the amine group (NR2) by the incomingcarbanion (R ) present in the polar organometallic reagents(RLi)[40] When substitution reactions in aromatic amides aresought by synthetic organic chemists the employment of lesssterically hampered organolithium reagents (with reduced basiccharacter like for example MeLi PhLi n-BuLi or n-HexylLi) isrecommended However since the transitorily obtained ketonesare more reactive than the starting amides usually over-addition is observed furnishing the relevant symmetric tertiaryalcohols[41] This problem has recently been overcome byCapriati and Prandi by using a mixture of cyclopentyl methylether (CPME)[4243] and the DES 1ChCl2Gly as solvent whichallowed the preparation of the relevant ketones in good yields(Scheme 9)[12a] These products are obtained as mixtures withthe corresponding symmetric alcohols with the best ratios infavour of the ketone product when the reaction mixture iscooled down up to 0 degC While this approach works well forseveral commercially available organolithium reagents (MeLiPhLi n-BuLi or n-HexylLi) when t-BuLi was employed ortho-metalation of the benzamide was observed (see section 3)[12a]

The scope and selectivity of this nucleophilic substitutionmethod has been recently improved by using CPME as the onlysustainable solvent for this transformation and increasing thetemperature of the reaction from 0 to 25 degC[12b] Under theseoptimised conditions nucleophilic acyl substitution of a broad

range of aliphatic and hetero(aromatic) amides can be accom-plished using a variety of RLi reagents including s-BuLi orthienyl lithium NMR investigations combined with DFT calcu-lations suggest that these reactions take place via the formationof a dimeric tetrahedral intermediate which is stabilised by thecoordination of CPME[12b] Demonstrating its sustainability thisapproach could also be scaled up to gram scale withsubsequent recycling of the solvent and the amine leavinggroup to prepare additional starting material

3 Regioselective ortho- or Lateral-Lithiation ofAromatic Amides and AryltetrahydrofuransPromoted by Organolithium Reagents (RLi) inSustainable Solvents

As previously mentioned amide substituents are strong ortho-directing groups and therefore benzamides are susceptible ofmetallation[40] Pioneering work by Prandi and Capriati hasrecently shown that t-BuLi can act as a selecting ortho-metal-lating reagent of NN-diisopropylbenzamides under air at roomtemperature using a mixture of CPME and the DES 1ChCl2Gly(see Scheme 10a) a trio of conditions regarded as completelyincompatible with this highly reactive organometallicreagent[12a] The in-situ generated ortho-lithiated amides couldthen be subsequently trapped with a variety of electrophilessuch as benzaldehyde DMF I2 S2Me2 or CD3OD to name just afew (Scheme 10a) Expanding even further the syntheticpotential of this approach the resulting ortho-iodo-NN-diiso-propylbenzamide can be used as an electrophile for Pd-catalysed cross-couplings with boratesboronic acids com-pounds in the same DES medium as the one employed for thelithiationiodination step (Scheme 10b) These findings showedfor the first time the possibility of performing one-pot ortho-lithiationPd-catalysed Suzuki-Miyaura couplings in DESmixtures[12a]

Scheme 9 Nucleophilic substitution on NN-diisopropylbenzamides trig-gered by organolithium reagents using mixtures DESsCPME[12a]

Scheme 10 (a) Regioselective ortho-lithiation of NN-diisopropylbenzamidesat room temperature in the presence of air and using a CPMEDES (1ChCl2Gly) mixture as reaction media (b) One-pottwo-steps protocol that mergesdeprotonationiodation process with an in-situ Pd-catalysed Suzuki-Miyauracoupling with different boratesboronic acids[12a]





2199 210342 [S 816] 1

Prior to these studies Capriati had also reported that CPMEwas an excellent sustainable ethereal solvent to promoteregioselective lateral lithiation of 22-diaryltetrahydrofurans(Scheme 11a)[14a] In this case the presence of the tetrahydrofur-an ring acts as a directing group for the metalation Best resultswere obtained using t-BuLi although in this case reactions hadto be performed at 0 degC Interesting subsequent electrophilicquenching was more selective and efficient when ChCl-basedeutectic mixtures (1ChCl2Gly or 1ChCl2Urea) were used as co-solvents furnishing the expected products in good yields (up to98) Further extension of this work have demonstrated thatthe lateral metallation of o-tolyltetrahydrofurans can be coupledwith a C C bond formation step[14b] These processes take placeusing CPMEDESs as sustainable reaction media with the initialregioselective lithiation of the activated benzylic position of thesubstrate followed by addition of the second equivalent of theRLi reagent (s-BuLi i-PrLi or t-BuLi) This promotes the ring-opening of the furan furnishing the relevant primary alcohol ingood to quantitative yields (up to 98 see Scheme 11b)

4 Aerobic Addition of Lithium Amides LiNR2 toEstersAmides or Aromatic Olefins in 2-MeTHFas Sustainable Solvent

Along with CPME another biomass derived ethereal solventwhich has emerged as an excellent reaction medium for airmoisture compatible transformations of polar organometallicsis 2-methyl-THF (2-MeTHF) This solvent can be obtained fromfurfural in the absence of any petrochemical protocol[44]

Furthermore its inherent immiscibility with water allows its usein liquid-liquid extractions thus avoiding the employment oftoxic and non-biorenewable VOCs (Volatile Organic Compounds)as extraction solvents (i e CH2Cl2) in the purificationisolationsteps of the desired final organic products[45] Several syntheticorganic studies have already demonstrated the excellentpotential of this solvent for the use of organolithium andorganomagnesium reagents although in most cases reactionsstill have to be carried out under inert atmosphere

conditions[46] Inspired by this work some of us have inves-tigated the capability of lithium amides (LiNR2) to trigger theamidation of esters under air and using 2-MeTHF as solvent(Scheme 12a)[15a] Reactions take place at room temperaturewithout the need of external additives in just 20 seconds Thismethodology tolerates the presence of either electron-with-drawing (halogens) or electron-donating (MeO Me) groups inboth aromatic or purely aliphatic amides Regarding the lithiumamide partner both aliphatic and aromatic lithium amides wereamenable to this approach High yields and good selectivitieswere observed This approach also works for transamidationreactions of NBoc2 substituted amides (Scheme 12b)

Structural and spectroscopic studies revealed that 2-MeTHFplays a key role in these reactions ensuring full solubilisation ofthe lithium amides and favouring the formation of smallkinetically activated aggregates Thus while LiNHPh and LiNPh2exhibit dimeric structures in the solid state solvated by threeand two molecules of 2-MeTHF respectively (Figure 3) DOSYNMR studies are consistent with the formation of trisolvated[Li(NR2)(2-MeTHF)3] monomers

[47] Monomer formation shouldlead to more powerful nucleophilic lithium amides that canreact faster with the unsaturated organic substrate (ester or

Scheme 11 (a) Lateral lithiation and electrophilic quenching of diaryltetrahy-drofurans in mixtures CPMEDESs (b) Organolithium promoted one-pottwo-steps benzylic metalationring-opening of o-tolyltetrahydrofurans in CPMEDESs mixtures in the presence of air[14]

Scheme 12 (a) Ultrafast amidation of esters or (b) transamination of amidesby using lithium amides (LiNR2) under aerobic ambient temperatureconditions in 2-MeTHF[15a]

Figure 3 Molecular structures of dimeric lithium anilide [Li(NHPh)2(2-MeTHF)4] and lithium diphenylamide [Li(NPh2)2(2-MeTHF)3]





2199 210342 [S 916] 1

amide) to add across its C=O bond favoring addition overcompeting degradation by oxygen or moisture

These results prompted us to investigate other applicationson the use of lithium amides under these unconventionalconditions We next focussed our attention on hydroaminationreactions of vinylarenes with alkali-metal amides Interestinglywhile the addition of stoichiometric amounts of lithium amidesto these unsaturated organic substrates using dry 2-MeTHFunder argon atmosphere promoted the polymerisation of theolefines when the same reactions were carried under air in thepresence of moisture selective hydroamination was observedaffording the relevant amines in yields up to 97 after30 minutes (Scheme 13)[15b] Pushing the limits of this approachselective hydroamination can be also accomplished usingsodium amides which are orders of magnitude more air andmoisture sensitive than their lithium analogues and typicallysuffer from lower selectivity

To explain these findings where the presence of moistureseems to be key for the success of the hydroamination processNMR monitoring studies combined with DOSY studies suggestthat in the presence of ambient moisture some of the lithiumamide hydrolyses to generate free amine and also that 2-MeTHFfavours the formation of small reactive monomeric aggregatesof the lithium amide (as shown in Figure 4 for lithium

piperidide LiPip) which should contribute to the fast reactivityobserved in these hydroamination processes Thus consideringthe reaction of LiPip with styrene under air in the presence ofambient moisture some Pip(H) can be generated that in turncan coordinates to the lithium amide This intermediate canthen react with styrene to form the insertion intermediate IThis can be subsequently quenched by PipH or traces ofmoisture (Figure 4) However under strict inert atmosphereconditions using dry solvents I can react with some freestyrene (present in solution due to the equilibrium betweenLiPip styrene and I) initiating its polymerisation

5 Chemoselective Aerobic Addition of LithiumPhosphides (LiPR2) to Aldehydes or Epoxides inDESs

Demonstrating the versatility of the use of polar s-blockorganometallic reagents in sustainable reaction media andunder bench type reaction conditions recently we havereported the synthesis of highly polarised lithium phosphides(LiPR2) using choline chloride-based DESs as sustainable reactionmedia at room temperature and in the presence of air viadirect deprotonation of both aliphatic and aromatic secondaryphosphines (HPR2) with n-BuLi[16]

Addition of an organic electrophile such aldehydes orepoxides to the in-situ generated LiPR2 triggered fast andchemoselective addition processes uncovering an efficient andstraightforward method to access α- or β-hydroxy phosphineoxides Reactions take place under bench-type conditions (airand at room temperature) in good to excellent isolated yields(62ndash94) Remarkably this system tolerates a variety of func-tional groups in the organic electrophile being compatible witha variety of both electron-donating and electron-withdrawingsubstituents in the aldehydes or epoxides (Scheme 14)

Scheme 13 Hydroamination of vinylarenes with alkali-metal amides underair and at room temperature using 2-MeTHF[15b]

Figure 4 Proposed pathway for the reaction of lithium piperidide (LiPip)with styrene in 2-MeTHF showing how the excess piperidine or ambientmoisture supply is necessary to favour hydroamination overpolymerisation[15b]

Scheme 14 Chemoselective and fast addition of LiPR2 to aldehydes andepoxides at room temperature under air in DESs[16]





2199 210342 [S 1016] 1

6 Anionic Polymerisation of Styrenes Initiatedby Polar Organolithium Reagents (LiR) in DESsand under Aerobic Conditions

Since the pioneer work by Szwarc and co-workers back in1956[48] the anionic living polymerisation of olefin-type mono-mers promoted by organolithium reagents (RLi) has beenconsidered as the protocol of choice for the selective and well-defined synthesis of styrene-derived polymers [this allows thesynthesis of polymers with the desired macromolecular archi-tecture composition molecular weight and narrow polydisper-isty indexes (ETH=MwMn1)]

[49] This anionic polymerisation ofolefins which proceeds via an organometallic end-chainpropagation sites composed by carbanions with lithiumcounterions allows to control the aforementioned polymericparameters thus opening the door to create a plethora ofcomplex architectures (comb graft dendritic star cyclic) withmyriad of different applications such as biomedical materialselectronics or stimuli responsive surfaces[50]

Bearing in mind our previous breakthroughs in the additionof organolithium reagents (RLi) to different unsaturated organicsubstrates (i e ketones[9] imines[10] esters[11] amides[12] ornitriles[13]) some of us decided to focus our attention on thedesign of an unprecedented organolithium-initiated anionicpolymerisation of olefins (styrene-type monomers) in DESs andunder air Under these conditions using n-BuLi as initiator wewere able to promote the synthesis of a variety of polyolefinsincluding polystyrene (PS) 4-aryl substituted polystyrenes (PS-XX=F Cl MeO) poly(2-vinylpyridines) (P2VP) or poly(4-vinyl-pyridines) (P4VP) using in all these cases unpurified monomersas starting materials and performing all the polymerisationreactions in open vials (Scheme 15a)[17] Moreover the corre-sponding random (PS-r-P2VP Scheme 15b) or block (PS-b-P2VPScheme 15c) copolymers were synthesised thanks to theunexpected stability of the in-situ formed polystyryl lithiumintermediate towards hydrolysis in the eutectic mixture 1ChCl2Gly (up to 15 h) In general all the desired polymers orcopolymers were obtained in high yields (up to 90) and withlow polydispersities Taking another step forward towardsdeveloping more sustainable polymerisation processes wehave recently reported the Cu-catalysed ARGET-ATRP polymer-isation (Activator ReGenerated by Electron Transfer-Atom TransferRadical Polymerisation) under homogenous or heterogeneousconditions of methyl methacrylate by using the eutecticmixture 1ChCl2Gly as sustainable reaction media[51]

7 Fast and Chemoselective Pd-CatalysedCross-Coupling Reactions betweenOrganolithium Reagents (RLi) andAromaticHeteroaromatic Halides in DESs orWater

Pd-catalysed C C or C X (X=heteroatom) cross-couplingprocesses are considered one of the most versatile reliable and

chemoselective synthetic protocols within the organic chemiststoolbox[52] Thus unsurprisingly they are amongst the mostimportant methodologies for the synthesis of a wide variety ofchemical commodities (i e fine chemicals pharmaceuticalproducts or new materials)[53] For the specific case of the use ofDES in these Pd-catalysed C C protocols a new core ofknowledge has been achieved thanks to the pioneering work ofdifferent research groups worldwide[54] Most of these examplesuse boronic esters or acids organosilanes or organtin com-pounds terminal alkynes acrylates or anilines as couplingpartners with the corresponding aromatic halide Breaking newground in this evolving field more recently Pd-catalysed cross-couplings using organolithium reagents with organic halides inDESs have been reported These studies build on seminal workby Feringa on the fast and selective direct Pd-catalysed C Ccoupling processes employing organolithium compounds aspartners Key for the success of this approach is the use oftoluene as solvent employing diluted solutions of the relevantRLi reagents which is slowly introduced in the reactionmixtures[5556] Increasing further the sustainability of this proto-col Feringa et al have also studied the coupling between 1-bromonaphthalene and an excess (2ndash10 eq) of PhLi catalysedby Pd-PEPPSI-i-Pr (10 mol) in the eutectic mixture 1ChCl2Glyat room temperature[57] Under these conditions it was foundthat the couplings proceeds with good selectivity but inmoderate-low yields (Scheme 16) It should also be noted thatthe use of neat conditions allowed the authors to design a newhighly selective and green Pd-catalysed cross-coupling betweenorganic halides and organolithium reagents which i) proceedsin short reaction times (10 min) ii) can be used underindustrially viable catalysts loadings (down to 01 mol)

Scheme 15 Anionic polymerisation of styrene-type olefins promoted byn-BuLi in DESs in the presence of air[17]





2199 210342 [S 1116] 1

iii) presents possible scalability of the process (tested up to120 mmol) and iv) shows exceptionally favourable environ-mental impact (E factors in several cases as low as 1)

Capriati et al revisited this field by studying the use ofwater as a solvent and NaCl as additive (Scheme 17)[18]

Remarkably by replacing the ChCl-based eutectic mixture bybrine and using as catalyst Pd[P(t-Bu)3]2 (25 mol) this teamwas able to i) increase the yield of the final coupling productsup to 99 ii) promote different Pd-catalysed C C couplingprotocols [C(sp3)-C(sp2) C(sp2)-C(sp2) or C(sp)-C(sp2)] iii) avoidthe formation of side products (derived from protonolysisdehalogenations or homocoupling processes) iv) scale-up thecoupling reaction and v) recycle the catalytic system up to10 consecutive times More recently the same group hasextended the use of the NaClwater combination or the eutecticmixture 1ChCl2Urea as sustainable reaction media to the Pd-catalysed Negishi coupling of organozinc reagents (ZnR2) witharyl(heteroaryl) halides working at room temperature or 60 degCand in the presence of air[58]

8 Design of One-Pot Tandem Protocols Basedon Main-Group-Promoted OrganicTransformations in DESs or Water

During the last decade and in the framework of organicsynthesis the use of one-pot tandem protocols has emerged as

a greener alternative to standard and tedious stepwise proc-esses The main advantages are i) the drastic reduction ofisolation and purification steps of intermediates of reactionminimising both the generation of chemical waste and therequired time and energy as well as simplifying the practicalaspects of the synthetic procedures and ii) the possibility ofworking with unstable reaction intermediates as no isolation ofhighly reactive and transitory-form species is needed[59] In mostof the cases the same type of transformational tools (metal-main-group element- bio- or organo-catalysts) are usedthroughout all the tandem process whereas the number ofexamples which combine different methodologies is scarceespecially those that also employ sustainable solvents[60] In thisregard some of us have previously studied the fruitfulcombination of transition-metal-catalysed organic transforma-tions in water or DESs with the enzymatic and enantioselectivebioamination (transaminases ATA) or bioreduction (ketoreduc-tases KRED) of in-situ generated prochiral ketones[61andashe] and thebiocatalytic decarboxylation of p-hydroxycinnamic acids[61f]

Building on the success of these hybrid protocols we have alsomerged the use in tandem of transition metal-catalysis withpolar organometallics in DESs Thus we have reported anoperational simple one-pot method to access tertiary alcoholsin excellent yields (up to 99 Scheme 18) by combining theRu(IV)-catalysed isomerisation of allylic alcohols into the corre-sponding ketones (working at 75 degC and in the eutectic mixture1ChCl2Gly) with the chemoselective nucleophilic addition oforganolithium (RLi) or organomagnesium (MgR2) reagents Thissecond step takes place a room temperature and in thepresence of air It should be noted that the correspondingtertiary alcohols are obtained without the need to isolatepurifythe ketone intermediate (Scheme 18)[19] Related to thesefindings more recently as previously mentioned in section 3Prandi Capriati and co-workers have designed a one-pottwo-steps protocol that merges the lithiationiodation process ofaromatic amides with an in-situ Pd-catalysed Suzuki-Miyauracoupling using different boratesboronic acids as couplingpartners (Scheme 10b)[12a]

Opening new ground in the combination of greener polarorganometallic chemistry with other commonly used synthetictools in organic synthesis we have also reported the combina-tion of an organocatalysed oxidation protocol (the AZADONaClO mediated oxidation of secondary alcohols into ketones)followed by the nucleophilic addition of organolithium reagentsto the transitorily formed ketones to produce a range of tertiary

Scheme 16 Pd-catalysed direct coupling of 1-bromonaphthalene and PhLiin DESs[57]

Scheme 17 Pd-catalysed cross-coupling reactions between organolithiumreagents (RLi) and (hetero)aryl halides in salted water as green solvent[57]

Scheme 18 One-pot tandem combination of Ru-catalysed isomerisation ofallylic alcohols with regioselective addition of RLiRMgX reagents in DESs[19]





2199 210342 [S 1216] 1

alcohols in a one-pottwo-steps protocol without the need ofisolationpurification protocols (Scheme 19)[20] In this case theorganocatalytic oxidation system is not compatible withcholine-based eutectic mixtures (as the addition of NaClO tothe eutectic reaction media produced immediately the ex-pected formation of Cl2 gas) However we found that thesimple exchange of the chlorine-based eutectic mixture by bulkwater as solvent permits the synthesis of the desired highlysubstituted tertiary alcohols at room temperature and in thepresence of air

9 Conclusions and Outlook

Polar organometallic reagents have been and remain pivotal forthe development of synthetic chemistry Exploiting the largepolarity of their M C (M=Li Mg) bonds these reagents areused worldwide in industry and academia for the functionalisa-tion of organic molecules However despite their enormoussynthetic relevance their use is handicapped by their require-ments of low temperature in order to control their reactivity aswell as the need of dry toxic organic solvents and protectiveinert atmosphere protocols to avoid their fast decompositionThus running organolithium chemistry under aerobic andorhydrous conditions without need of dry toxic organic solventshas been traditionally seen as an insuperable challenge forsynthetic chemists Edging closer towards meeting this chal-lenge the research summarised in this Minireview shows thatby using polar organometallics in sustainable solvents such asDESs water Gly CPME or 2-MeTHF it is possible to access abroad range of valuable organic molecules while operatingunder air in the presence of moisture and at room temperatureThese examples of reactivity not only demonstrate the syntheticversatility of working under these unconventional conditionsbut have also revealed that in some cases unique chemo-selectivities and enhanced performances can be accomplishedThe possibility of using these methods in tandem with organo-catalysis or transition-metal catalysis multiplies opportunitiesfor the design of novel one-pot protocols under greenerreactions conditions

While many challenges are still pending ahead the numberof contributions on the use of polar organometallics in thesesolvents under air continues to grow at a steady paceunlocking new opportunities and catching the eye of many

synthetic chemists Advancing the understanding on theconstitution of these reagents in these solvents as well aspossible substratesolvent interactions will certainly pave theway towards new innovations in this evolving field Theseadditional challenges may not be easily met but the prospect ofdispensing with the requirement for dry toxic organic solventsor inert atmospheres will have worldwide implications for thepractice of polar organometallic chemistry both in academiaand industry

Acknowledgements

SEG-G and JGA thank the Spanish MINECO and MIC (ProjectPID2020-113473GB-I00) JG-A thanks i) the Fundacioacuten BBVA forthe award of a ldquoBeca Leonardo a Investigadores y CreadoresCulturales 2017rdquo[62] and ii) PhosAgroUNESCOIUPAC for theaward of a ldquoGreen Chemistry for Life Grantrdquo APS is indebted toSpanish MINECO (Project CTQ2014-56345-P CTQ2017-88357-Pand RYC-2012-09800) and Gobierno del Principado de Asturias(FICYT Project FC-15-GRUPIN14-106) for financial support EHacknowledges the SNF (188573) and the EPSRC (EPS0208372)for their generous financial support The authors also acknowl-edge past and present members in their groups who havecontributed to the development of the studies summarised inthis Minireview

Conflict of Interest

The authors declare no conflict of interest

Keywords Chemoselectivity middot Deep eutectic solvents middot Greenchemistry middot Organolithium reagents middot Organomagnesiumreagents

[1] a) P Barbier Compt rend Hebd Seacuteances Acad Sci 1899 128 110ndash111b) V Grignard Compt rend Hebd Seacuteances Acad Sci 1900 130 1322ndash1324 c) V Grignard Dissertation ldquoThegraveses sur les combinaisons organo-magnesienes mixtes et leur application agravedes synthegravesesrdquo University ofLyon Lyon 1901

[2] W Schlenk J Holtz Ber Dtsch Chem Ges 1917 50 262ndash274[3] For selected references dealing with organolithium chemistry see a) J

Clayden in Organolithiums selectivity for synthesis Pergamon Oxford2002 b) Z Rappoport I Marek in The chemistry of organolithiumcompounds Wiley Chichester 2005 c) V Capriati F M Perna ASalomone Dalton Trans 2014 43 14204ndash14210 d) U Wietelmann JKlett Z Anorg Allg Chem 2018 644 194ndash204

[4] For selected reviewsbooks dealing with organomagnesium chemistrysee a) J F Garst M P Soriaga Chem Soc Rev 2004 248 623ndash652b) The Chemistry of Organomagnesium Compounds (Eds Z RappoportI Marek) Patai Series Wiley Chichester 2008 c) D Seyferth Organo-metallics 2009 28 1598ndash16005

[5] D J C Constable C Jimeacutenez-Gonzaacutelez R K Henderson Org ProcessRes Dev 2007 11 133ndash137

[6] a) J H Clark S J Tavener Org Process Res Dev 2007 11 149ndash155b) P G Jessop Green Chem 2011 13 1391ndash1398

[7] a) P T Anastas J C Warner in Green Chemistry Theory and PracticeOxford University Press Oxford 1998 b) A S Matlack in Introduction toGreen Chemistry Marcel Dekker New York 2001 c) M Poliakoff J MFitzpatrick T R Farren P T Anastas Science 2002 297 807ndash810 d) MLancaster in Green Chemistry An Introductory Text RSC Publishing

Scheme 19 One-pot combination of the AZADONaClO organocatalysedoxidation of secondary alcohols with the addition of organolithium reagents(RLi) at room temperature in the presence of air in aqueous media[20]





2199 210342 [S 1316] 1

Cambridge 2002 e) R A Sheldon I W C E Arends U Henefeld inGreen Chemistry and Catalysis Wiley-VCH Weinheim 2007

[8] a) P T Anastas in Handbook of Green Chemistry Vol 4 5 and 6 GreenSolvents Volume 4 Supercritical Solvents (Eds W Leitner P G Jessop)Volume 5 Reactions in Water (Ed C-J Li) Volume 6 Ionic Liquids(Eds P Wasserschied A Stark) Wiley-VCH Verlag amp Co KGaAWeinheim 2010 b) F Kerton R Marriott in Alternative Solvents forGreen Chemistry 2nd Edition RSC Green Chemistry Series RSC Publish-ing Cambridge 2013 c) C J Clarke W-C Tu O Levers A Broumlhl J PHallett Chem Rev 2018 118 747ndash800

[9] a) C Vidal J Garciacutea-Aacutelvarez A Hernaacuten-Goacutemez A R Kennedy E HeviaAngew Chem Int Ed 2014 53 5969ndash5973 Angew Chem 2014 1266079ndash6083 b) L Cicco S Sblendorio R Mansueto F M Perna ASalomone S Florio V Capriati Chem Sci 2016 7 1192ndash1199

[10] a) C Vidal J Garciacutea-Aacutelvarez A Hernaacuten-Goacutemez A R Kennedy E HeviaAngew Chem Int Ed 2016 55 16145ndash16148 Angew Chem 2016 12816379ndash16382 b) G Dilauro M DellrsquoAera P Vitale V Capriati F MPerna Angew Chem Int Ed 2017 56 10200ndash10203 Angew Chem2017 129 10334ndash10337 c) L Cicco A Salomone P Vitale N Riacuteos-Lombardiacutea J Gonzaacutelez-Sabiacuten J Garciacutea-Aacutelvarez F M Perna V CapriatiChemSusChem 2020 13 3583ndash3588

[11] A F Quivelli G DrsquoAddato P Vitale J Garciacutea-Aacutelvarez F M Perna VCapriati Tetrahedron 2021 81 131898

[12] a) S Ghinato G Dilauro F M Perna V Capriati M Blangetti C PrandiChem Commun 2019 55 7741ndash7744 b) S Ghinato D Territo AMaranzana V Capriati M Blangetti C Prandi Chem Eur J 2021 272868ndash2874

[13] M J Rodriacuteguez-Aacutelvarez J Garciacutea-Aacutelvarez M Uzelac M Fairley C TOrsquoHara E Hevia Chem Eur J 2018 24 1720ndash1725

[14] a) V Mallardo R Rizzi F C Sassone R Mansueto F M Perna ASalomone V Capriati Chem Commun 2014 50 8655ndash8658 b) F CSassone F M Perna A Salomone S Florio V Capriati Chem Commun2015 51 9459ndash9462

[15] a) M Fairley L J Bole F F Mulks L Main A R Kennedy C T OrsquoHara JGarciacutea-Aacutelvarez E Hevia Chem Sci 2020 11 6500ndash6509 b) F F MulksL J Bole L Davin A Hernaacuten-Goacutemez A Kennedy J Garciacutea-Alvarez EHevia Angew Chem Int Ed 2020 59 19021ndash19026 Angew Chem2020 132 19183ndash19188

[16] L Cicco A Fombona-Pascual A Saacutenchez-Condado G A Carriedo F MPerna V Capriati A Presa Soto J Garciacutea-Aacutelvarez ChemSusChem 202013 4967ndash4973

[17] A Saacutenchez-Condado G A Carriedo A Presa Soto M J Rodriacuteguez-Aacutelvarez J Garciacutea-Aacutelvarez E Hevia ChemSusChem 2019 12 3134ndash3143

[18] G Dilauro A F Quivelli P Vitale V Capriati F M Perna Angew ChemInt Ed 2019 58 1799ndash1802 Angew Chem 2019 131 1813ndash18161

[19] L Cicco M J Rodriacuteguez-Aacutelvarez F M Perna J Garciacutea-Aacutelvarez VCapriati Green Chem 2017 19 3069ndash3077

[20] D Elorriaga M J Rodriacuteguez-Aacutelvarez N Riacuteos-Lombardiacutea F Moriacutes APresa Soto J Gonzaacutelez-Sabiacuten E Hevia J Garciacutea-Aacutelvarez ChemCommun 2020 56 8932ndash8935

[21] The interested readers are also encouraged to consult the followingprevious revisions in this field a) J Garciacutea-Aacutelvarez Eur J Inorg Chem2015 5147ndash5157 b) J Garciacutea-Aacutelvarez E Hevia V Capriati Eur J InorgChem 2015 6779ndash6799 c) J Garciacutea-Aacutelvarez E Hevia V Capriati ChemEur J 2018 24 14854ndash14863 d) E Hevia Chimia 2020 74 681ndash688e) T X Gentner R E Mulvey Angew Chem Int Ed 2021 60 9247ndash9262 Angew Chem 2021 133 9331ndash9348

[22] a) R Taylor Tetrahedron Lett 1975 16 435ndash436 For the first examplesof organolithium and organopotassium complexes containing water asa donating ligand see b) D Barr P R Raithby P v R Schleyer RSnaith D S Wright J Chem Soc Chem Commun 1990 643ndash645 c) CLambert P v R Schleyer U Pieper D Stalke Angew Chem Int Ed1992 31 77ndash79 Angew Chem 1992 104 78ndash79 d) I Koehne SBachmann R Herbst-Irmer D Stalke Angew Chem Int Ed 2017 5615141ndash15145 Angew Chem 2017 129 15337ndash15342 e) J Kretsch AKreyenschmidt R Herbst-Irmer D A Stalke Dalton Trans 2018 4712606ndash12612

[23] G Osztrovszky T Holm R Madsen Org Biomol Chem 2010 8 34092ndash3404

[24] H Zong H Huang J Liu G Bian L Song J Org Chem 2012 77 4645ndash4652

[25] For recent reviews covering the use of DESs as environmentally friendlyreaction media see a) E L Smith A P Abbott K S Ryder Chem Rev2014 114 11060ndash11082 b) D Alonso A Baeza A R Chinchilla GGuillena I M Pastor D J Ramoacuten Eur J Org Chem 2016 612ndash632

c) F M Perna P Vitale V Capriati Curr Opin Green Sustain Chem2020 21 27ndash33 d) B B Hansen S Spittle B Chen D Poe Y ZhangJ M Klein A Horton L Adhikari T Zelovich B W Doherty B GurkanE J Maginn A Ragauskas M Dadmun T A Zawodzinski G A BakerM E Tuckerman R F Savinell J R Sangor Chem Rev 2021 121 1232ndash1285 e) Deep Eutectic Solvents Synthesis Properties and Applications(Eds D J Ramoacuten G Guillena) Wiley-VCH Weinheim 2019

[26] Choline chloride (ChCl an essential micro- and human nutrient) ismanufactured in the scale of millions of tons per year J K BlusztajnScience 1998 284 794ndash798

[27] Anionic magnesiates (RMgX2 ) display an enhanced nucleophilic activity

when compared with neutral Grignard Reagents (RMgX) For out-standing reviews covering this topic see a) R E Mulvey Dalton Trans2013 42 6676ndash6693 b) A Harrison-Marchand F Mongin Chem Rev2013 113 7470ndash7562 c) J M Gil-Negrete E Hevia Chem Sci 2021 121982ndash1992

[28] Similar scenario has been previously observed in ldquoon-waterldquo reactionsThese heterogenic processes take place in the organicliquid waterinterface with water insoluble reagents a) A Chanda V V Fokin ChemRev 2009 109 725ndash748 b) R M Butler A G Coyne J Org Chem 201580 1809ndash1817 c) R N Buttler A G Coyle Org Biomol Chem 2016 149945ndash9960

[29] M Hatano T Matsumara K Ishihara Org Lett 2005 7 573ndash576[30] a) F Wang A D O Good J Rath H Y K Kaan O B Sutcliffe S P

Mackay F Kozielski J Med Chem 2012 55 1511ndash1525 b) D RodriguezC Ramesh L H Henson L Wilmeth B K Bryant S Kadavakollu RHirsch J Montoya P R Howell J M George D Alexander D LJohnson J B Arterburn C B Shuster Bioorg Med Chem 2011 195446ndash5453 c) W Wu S Jingbo W Xu J Liu Y Huang Q Sheng Z LvOncol Lett 2018 16 1023ndash1030

[31] The synthesis of amines is considered as one of the ldquokey green chemistryresearch areas for pharmaceutical manufacturersrdquo D J C Constable P JDunn J D Hayler G R Humphrey J L Jr Leazer R J Linderman KLorenz J Manley B A Pearlman A Wells A Zaksh T Y Zhang GreenChem 2007 9 411ndash420

[32] See for example A Desmarchelier P Ortiz S R Harutyunyan ChemCommun 2015 51 703ndash706

[33] a) S E Denmark N Nakajima O J C Nicaise J Am Chem Soc 1994116 8797ndash8798 b) D A Cogan J A Ellman J Am Chem Soc 1999121 268ndash269 c) J L Rutherford D Hoffmann D B Collum J AmChem Soc 2002 124 264ndash271 d) S A Orr E C Border P C AndrewsV L Blair Chem Eur J 2019 25 11876ndash11882

[34] See for example R Reingruber S Braumlse Chem Commun 2008 105ndash107

[35] a) K Yamada K Tomioka Chem Rev 2008 108 2874ndash2886 b) A CōteacuteA B Charette J Am Chem Soc 2008 130 2771ndash2773

[36] a) M Shimizu Pure Appl Chem 2006 78 1867ndash1876 b) J S DicksteinM C Kozlowski Chem Soc Rev 2008 37 1166ndash1173 c) M Shimizu IHachiya I Mizota Chem Commun 2009 874ndash889 d) S Hata MShimizu J Synth Org Chem Jpn 2011 69 1134ndash1144

[37] Glycerol (Gly) is obtained in an industry tone-scale as by-product in theproduction of biodiesel (ca 100 kg of glycerol per ton of biodiesel) NRahmat A Z Abdullah A R Mohamed Renewable Sustainable EnergyRev 2010 14 987ndash1000

[38] Glycerol (Gly) has been applied as biorenewable and sustainablereaction media in a variety of chemical processes a) Y Gu F JeacuterocircmeGreen Chem 2010 12 1127ndash1138 b) A E Diacuteaz-Aacutelvarez J Francos BLastra-Barreira P Crochet V Cadierno Chem Commun 2011 47 6208ndash6227 c) V Pace P Hoyos L Castoldi P Domiacutenguez de Mariacutea A RAlcaacutentara ChemSusChem 2012 5 1369ndash1379 d) J Yang J-N Tan YGu Green Chem 2012 14 3304ndash3317 e) D M Alonso S G WettsteinJ A Dumesic Green Chem 2013 15 584ndash595 f) F Chahdoura I FavierM Goacutemez Chem Eur J 2014 20 10884ndash10893

[39] a) V R Pattabiraman J W Bode Nature 2011 480 471ndash479 b) C LAllen J M J Williams Chem Soc Rev 2011 40 3405ndash3415 c) V PaceW Holzer B Olofsson Adv Synth Catal 2014 356 3697ndash3736 d) P WTan J Seayad D J Dixon Angew Chem Int Ed 2016 55 13436ndash13440Angew Chem 2016 128 13634ndash13638 e) K L White M Movassaghi JAm Chem Soc 2016 138 11383ndash11389

[40] a) P Beak R A Brown J Org Chem 1982 47 34ndash46 b) P Beak VSnieckus Acc Chem Res 1982 15 306ndash312 c) V Snieckus Chem Rev1990 90 879ndash933 d) F R Leroux J Mortier Arene Chemistry ReactionMechanisms and Methods for Aromatic Compounds John Wiley amp SonsInc Hoboken 2016





2199 210342 [S 1416] 1

[41] a) P Sureshbabu S Azeez N Muniyappan S Sabiah J Kandasamy JOrg Chem 2019 84 11823ndash11838 b) M M Mehta T B Boit J EDander N K Garg Org Lett 2019 22 1ndash5 c) C-G Yu Y Matsuo OrgLett 2020 22 950ndash955

[42] CPME is considered as an ideal green ethereal solvent due to its highhydrophobicity high boiling point and low peroxide formation UAzzena M Carraro L Pisano S Monticelli R Bartolotta V PaceChemSusChem 2019 12 40ndash70

[43] For reported examples which show the possibility to use CPME assustainable reaction media in main-group promoted organic trans-formations see a) T Okabayashi A Iida K Takai Y Nawate T MisakiY Tanabe J Org Chem 2007 72 8142ndash8145 b) Z Fei Q Wu F ZhangY Cao C Liu W-C Shieh S Xue J McKenna K Prasad M Prashad DBaeschlin K Namoto J Org Chem 2008 73 9016ndash9021 c) T TakeshiY Masanori Y Satoshi T Akira Angew Chem Int Ed 2012 51 7263ndash7266 Angew Chem 2012 124 7375ndash7378 d) K Fujii K Shiine T MisakiT Sugimura Appl Organomet Chem 2013 27 69ndash72 e) S RWisniewski C L Guenther O A Argintaru G A Molander J Org Chem2014 79 365ndash378 f) V Pace L Castoldi S Monticelli S Safranek ARoller T Langer W Holzer Chem Eur J 2015 21 18966ndash18970 g) SKobayashi K Shibukawa Y Miyaguchi A Masuyama Asian J OrgChem 2016 5 636ndash645

[44] K Dalvand J Rubin S Gunukula M C Wheeler G Hunt BiomassBioenergy 2018 115 56ndash63

[45] For reviews covering the use of 2-MeTHF as alternative solvent indifferent organic transformations see a) D F Aycock Org Process ResDev 2007 11 156ndash159 b) V Pace Aust J Chem 2012 65 301ndash302c) S Monticelli L Castoldi I Murgia R Senatore E Mazzeo JWackerlig E Urban T Langer V Pace Monatsh Chem 2017 148 37ndash48

[46] a) C Carbone P OrsquoBrien G Hilmersson J Am Chem Soc 2010 13215445ndash15450 b) V Pace A R Alcaacutentara W Holzer Green Chem 201113 1986ndash1989 c) V Pace L Castoldi P Hoyos J V Sinisterra MPregnolato J-M Saacutenchez-Montero Tetrahedron 2011 67 2670ndash2675d) V Pace L Castoldi A R Alcaacutentara W Holzer Green Chem 2012 141859ndash1863 e) A Kadam M Nguyen M Kopach P Richardson FGallou Z K Wan W Zhang Green Chem 2013 15 1880ndash1888 f) VPace K de la Vega-Hernaacutendez E Urban T Langer Org Lett 2016 182750ndash2753 g) G Parisi L Degennaro C Carlucci M de Candia PMastrorilli A Roller W Holzer C D Altomare V Pace R Luisi OrgBiomol Chem 2017 15 5000ndash5015 h) K de la Vega-Hernaacutendez RSenatore M Miele E Urban W Holzer V Pace Org Biomol Chem2019 17 1970ndash1978 i) R Senatore M Malik E Urban W Holzer VPace Tetrahedron 2021 85 131921 j) L Ielo M Miele V Pillari RSenatore S Mirabile R Gitto W Holzer A R Alcaacutentara V Pace OrgBiomol Chem 2021 19 2038ndash2043 k) D Elorriaga F de la Cruz M JRodriacuteguez-Aacutelvarez A Lara-Saacutenchez J A Castro-Osma J Garciacutea-AacutelvarezChemSusChem 2021 14 2084ndash2092

[47] For closely related examples describing other dimers of THF-solvatedlithium anilides see R Von Buumllow H Gornitzka T Kottke D Stalke JChem Soc Chem Commun 19961639ndash1640

[48] a) M Szwarc Nature 1956 178 1168ndash1169 b) M Szwarc M Levy RMilkovich J Am Chem Soc 1956 78 2656ndash2657

[49] a) A Hirao R Goseki T Ishizone Macromolecules 2014 47 1883ndash1905b) Anionic Polymerization Principles Practice Strength Consequencesand Applications (Eds N Hadjichristidis A Hirao) Springer Tokyo 2015c) G Polymeropoulos G Zapsas K Ntetsikas P Bilalis Y Gnanou NHadjichristidis Macromolecules 2017 50 1253ndash1290

[50] a) C Feng Y Li D Yang J Hu X Zhang X Huang Chem Soc Rev2011 40 1282ndash1295 b) N B Bowden Macromol Chem Phys 2006 2071917ndash1920 c) N Hadjichristidis S Pispas G Floudas Block CopolymersSynthetic Strategies Physical Properties and Applications John Wiley ampSons Hoboken 2003 d) D Baskaran A H E Meller Prog Polym Sci

2007 32 173ndash219 e) H Feng X Lu W Wang N-G Kang J W MaysPolymer 2017 9 494

[51] L Quiroacutes-Montes G A Carriedo J Garciacutea-Aacutelvarez A Presa Soto GreenChem 2019 21 5865ndash5875

[52] J A Gladysz M Bochmann D L Lichtenberger L S Liebeskind T JMarks D A Sweigart Organometallics 2010 29 5737ndash5737

[53] Y Nishihara Applied Cross-Coupling Reactions Springer Berlin 2013[54] For a recent and outstanding review that covers the use of DESs as

sustainable solvents in Pd-catalysed C C coupling processes see S EHooshmand R Afshari D J Ramoacuten R S Varma Green Chem 2020 223668ndash3692

[55] For recent examples see a) M Giannerini M Fantildeanaacutes-Mastral B LFeringa Nat Chem 2013 5 667ndash672 b) M Giannerini V Hornillos CVila M Fantildeanaacutes-Mastral B L Feringa Angew Chem Int Ed 2013 5213329ndash13333 Angew Chem 2013 125 13571ndash13575 c) V Hornillos MGiannerini C Vila M Fantildeanaacutes-Mastral B L Feringa Org Lett 2013 155114ndash5511 d) C Vila M Giannerini V Hornillos M Fantildeanas-MastralB L Feringa Chem Sci 2014 5 1361ndash1367 e) C Vila V Hornillos MGiannerini M Fantildeanaacutes-Mastral B L Feringa Chem Eur J 2014 2013078ndash13083 f) V Hornillos M Giannerini C Vila M Fantildeanaacutes-MastralB L Feringa Chem Sci 2015 6 1394ndash1398 g) L M Castelloacute VHornillos C Vila M Giannerini M Fantildeanaacutes-Mastral B L Feringa OrgLett 2015 17 62ndash65 h) D Heijnen V Hornillos B P Corbet MGiannerini B L Feringa Org Lett 2015 17 2262ndash2265 i) D Heijnen FTosi C Vila M C A Stuart P H Elsinga W Szymanski B L FeringaAngew Chem Int Ed 2017 56 3354ndash3359 Angew Chem 2017 1293402ndash3407

[56] For recent reviews covering this topic see a) V Pace R LuisiChemCatChem 2014 6 1516ndash1519 b) J D Firth P OBrien ChemCatCh-em 2015 7 395ndash397

[57] E B Pinxterhuis M Giannerini V Hornillos B L Feringa Nat Commun2016 7 11698

[58] G Dilauro C S Azzollini P Vitale A Salomone F M Perna V CapriatiAngew Chem Int Ed 202160 10632ndash10636 Angew Chem 2021 13310726ndash10730

[59] a) Y Hayashi Chem Sci 2016 7 866ndash880 b) Y Hayashi J Org Chem2021 86 1ndash23

[60] R Ye J Zhao B B Wickemeyer F D Toste G A Somorjai Nat Catal2018 1 318ndash325

[61] a) N Riacuteos-Lombardiacutea C Vidal M Cocina F Moriacutes J Garciacutea-Aacutelvarez JGonzaacutelez-Sabiacuten Chem Commun 2015 51 10937ndash10940 b) N Riacuteos-Lombardiacutea C Vidal E Liardo F Moriacutes J Garciacutea-Aacutelvarez J Gonzaacutelez-Sabiacuten Angew Chem Int Ed 2016 55 8691ndash8695 Angew Chem 2016128 8833ndash8837 c) M J Rodriacuteguez-Aacutelvarez N Riacuteos-Lombardiacutea SSchumacher D Peacuterez-Iglesias F Moriacutes V Cadierno J Garciacutea-Aacutelvarez JGonzaacutelez-Sabiacuten ACS Catal 2017 7 7753ndash7759 d) E Liardo RGonzaacutelez-Fernaacutendez N Riacuteos-Lombardiacutea F Moriacutes J Garciacutea-Aacutelvarez VCadierno P Crochet F Rebolledo J Gonzaacutelez-Sabiacuten ChemCatChem2018 10 4676ndash4682 e) L Cicco N Riacuteos-Lombardiacutea M J Rodriacuteguez-Aacutelvarez F Moriacutes F M Perna V Capriati J Garciacutea-Aacutelvarez J Gonzaacutelez-Sabiacuten Green Chem 2018 20 3468ndash3475 f) N Riacuteos-Lombardiacutea M JRodriacuteguez-Aacutelvarez F Moris R Kourist N Comino F Loacutepez-Gallego JGonzaacutelez-Sabiacuten J Garciacutea-Aacutelvarez Front Chem 2020 8 139

[62] The Fundacioacuten BBVA accepts no responsibility for the opinions state-ments and contents included in the project andor the results thereofwhich are entirely the responsibility of the authors

Manuscript received April 27 2021Revised manuscript received June 10 2021Accepted manuscript online June 15 2021





2199 210342 [S 1516] 1

MINIREVIEWS

This Minireview showcases keyadvances on the use of polar s-blockorganometallic reagents in bioins-pired solvents [water glycerol andDeep Eutectic Solvents (DESs)] underair at room temperature and in thepresence of moisture a trio of condi-tions that for decades has been con-sidered incompatible with the ma-nipulation of these reagents

Dr S E Garciacutea-Garrido Dr APresa Soto Prof Dr E Hevia Dr JGarciacutea-Aacutelvarez

1 ndash 16

Advancing Air- and Moisture-Com-patible s-Block OrganometallicChemistry Using SustainableSolvents


2199 210342 [S 1616] 1

and tendency to accumulate in the atmosphere[5] Furthermorethe recovery of these toxic and flammable organic compoundsonly reaches 50 to 80 in most of the cases[6]

Advances in Green Chemistry[7] have made giant stepstowards addressing some of these challenges as well as othersimposed by todays society (which are related with the limitedavailability of our natural resources and its consequences) Thus

Sergio E Garciacutea Garrido studied chemistry at theUniversity of Oviedo and received his PhDdegree in 2005 under the supervision of ProfJoseacute Gimeno and Dr Victorio Cadierno workingin the chemistry of organometallic complexes ofruthenium(II) and ruthenium(IV) as well as theirapplication in different catalytic processes ofinterest After a postdoctoral stay (2005ndash2007)at the School of Chemistry of SouthamptonUniversity (Southampton UK) working underthe supervision of Prof Philip A Gale in the fieldof supramolecular chemistry and its applicationto the recognition of anions he rejoined theDepartment of Organic and Inorganic Chemistryof Oviedo University first as contracted re-searcher (2008) later as a Ramoacuten y Cajalresearcher (2009ndash2013) Lecturer (2014ndash2018)and finally as Senior Lecturer (Associate Profes-sor) in Inorganic Chemistry position that hecurrently holds His current lines of work focuson the chemistry of organometallic complexesand the development of new supramolecularstructures as well as their applications inhomogeneous and heterogeneous catalysis Heis coauthor of more than 50 articles in interna-tional journals and 7 book chapters

Alejandro Presa Soto was born in Gijoacuten (AsturiasSpain) in 1976 He obtained his PhD at theUniversity of Oviedo (2005) working in thesynthesis and catalytic activity of chiral poly-phosphazene copolymers under the supervisionof Prof G Carriedo and Prof F J Garciacutea-AlonsoAfter exploring the self-assembly of crystallineblock copolymers in work with I Manners inBristol he returned to the University of Oviedoin 2010 first as a Juan de la Cierva researcherand later as a Ramoacuten y Cajal research fellowCurrently he is Associate Professor of InorganicChemistry and his research interest is focusedon the synthesis and self-assembly of polyphos-phazene-based block copolymers and the devel-opment of novel chemical transformations in-volving the formation of C-heteroatom bondsunder sustainable reaction media He has auth-ored more than 50 scientific publications includ-ing 3 book chapters

Eva Hevia received both her MSci degree inChemistry and her PhD degree from theUniversidad de Oviedo (Spain) in 1998 and 2002respectively After a three-year position at theUniversity of Strathclyde (Glasgow UK) workingas a Marie Curie Fellow with Professor RobertMulvey in 2006 she took up a Royal SocietyUniversity Research Fellowship and Lectureshipthere Subsequently she was promoted to FullProfessor in 2013 In February 2019 Eva movedto the University of Bern to take up a fullprofessorship in Inorganic Chemistry Researchin her group focuses on polar organometallicchemistry at the crossroads of inorganic organ-ic and green chemistry Eva is an elected fellowof the European Academy of Sciences and herresearch has been recognised with severalawards including the 2017 RSC Corday-MorganPrize and the 2019 GEQO Research ExcellenceAward

Joaquiacuten Garciacutea Aacutelvarez studied chemistry at theUniversity of Oviedo and received his PhDdegree in 2005 under the supervision of ProfJoseacute Gimeno and Dr Victorio Cadierno studyingthe coordination of iminophosphorane ligandsin arene-Ru(II) fragments Then he joined thegroup of Prof Robert E Mulvey at the Universityof Strathclyde in Glasgow (Scotland UnitedKingdom) working for two years and a half inthe field of main group chemistry (alkali-metal-mediated-metallation) In 2008 he returned tothe University of Oviedo as a postdoctoralresearcher thanks to the award of a contractfrom the regional program ldquoClariacutenrdquo of thePrincipado de Asturias The current focuses ofhis research are i) the study of metal-catalysed(Ru Cu Pd Au) and metal-mediated (Li Mg)organic reactions using environmentally friendlysolvents [water and Deep Eutectic Solvents(DESs)] as reaction media and ii) the design ofone-pot processes combining either metal-organo- and bio-catalysis This research hasbeen recognised over the last years with theaward of a postdoctoral contract ldquoJuan de laCiervardquo in 2009 and more recently (2012) witha postdoctoral contract ldquoRamoacuten y Cajalrdquo In2017 he was promoted to an AssistanceProfessor position and more recently (2018) toan Associate Professor position He has pub-lished more than 75 scientific articles and is co-author of twelve book chapters on Organo-metallic Chemistry and Catalysis in unconven-tional reaction media In 2016 he received thePrize ldquoGEQO-Young Scientist Awardrdquo in 2017the ldquoBeca Leonardo a Joacutevenes Investigadores yCreadores Culturalesrdquo from BBVA fundation andin 2018 the ldquoGreen Chemistry For Life GrantProgrammerdquo awarded by PhosAgroUNESCOIUPAC





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ure 2)[9a]











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[22d]





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ure 2)[9a]











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ure 2)[9a]











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Acknowledgements

















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Acknowledgements

















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Acknowledgements

















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Acknowledgements

















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Acknowledgements

















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Acknowledgements

















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Acknowledgements

















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Acknowledgements

















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Acknowledgements

















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and Moisture‐Compatible s‐Block Organometallic Chemistry ...

Documents

Transcript of and Moisture‐Compatible s‐Block Organometallic Chemistry ...