Joaquín García-Álvarez

University of Oviedo | UNIOVI · Department of Organic and Inorganic Chemistry

Dimethindene is a selective histamine H1 antagonist and is commercially available as a racemate. Upon analyzing the synthetic pathways currently available for the industrial preparation of dimethindene, we set up a sustainable approach for the synthesis of this drug, switching from petroleum-based volatile organic compounds (VOCs) to eco-friendly s...

The last decade has seen a remarkable interest in Deep Eutectic Solvents (DESs), usually obtained from biorenewable, cheap and non-toxic precursors, as effective environmentally responsible reaction media for transition-metal-catalyzed organic transformations. One of the main advantages associated with the use of these neoteric solvents is the ease...

An efficient, selective and sustainable protocol was developed for the CuCl2 /TEMPO/TMEDA-catalyzed aerobic oxidation of activated alcohols to the corresponding carbonyl compounds using water or the environmentally friendly low melting mixture (LMM) d-fructose-urea as the reaction medium. Such oxidation reactions proceed under mild (room temperatur...

Highly‐efficient and selective one‐pot/two‐step modular double addition of different highly polar organometallic reagents (RLi/RMgX) to nitriles en‐route to asymmetric tertiary alcohols (without the need for isolation/purification of any halfway reaction intermediate) has been studied, for the first time, in the absence of external/additional organ...

A family of germyl rhodium complexes derived from the PGeP germylene 2,2’‐bis(di‐isopropylphosphanylmethyl)‐5,5’‐dimethyldipyrromethane‐1,1’‐diylgermanium(II), Ge(pyrmP i Pr 2 ) 2 CMe 2 ( 1 ), has been prepared. Germylene 1 reacted readily with [RhCl(PPh 3 ) 3 ] and [RhCl(cod)(PPh 3 )] (cod = 1,5‐cyclooctadiene) to give, in both cases, the PGeP‐pin...

Iminophosphoranes (with general formula R3PNR′) have been extensively studied in coordination chemistry as reliable and easily tuning ligands capable of stabilizing a large variety of both main-group or transition-metal precursors, thus giving rise to a myriad of coordination complexes displaying a rich variety of different coordination modes and g...

The one-pot/two-step combination of enzymes and polar organometallic chemistry in aqueous media is for the first time presented as a proof-of-concept study. The unprecedented combination of the catalytic oxidation of secondary alcohols by the system laccase/TEMPO with the ultrafast addition (3 s reaction time) of polar organometallic reagents (RLi/...

An efficient and novel protocol was developed for a Cu-catalyzed Ullmann-type aryl alkyl ether synthesis by reacting various (hetero)aryl halides (Cl, Br, I) with alcohols as active components of environmentally benign choline chloride-based eutectic mixtures. Under optimized conditions, the reaction proceeds under mild conditions (80 °C) in air, i...

The Front Cover shows the special connection created between two distinct and, until now, very distant worlds. These are Polar s‐Block Organometallics (fire), which traditionally require highly restrictive reaction conditions (low temperatures, inert atmosphere, meticulously dry organic and non‐protic reaction media), and Sustainable Solvents such...

Challenging conventional wisdom that s‐block organometallic reagents such as Grignard or organolithiums need to be used under protecting inert atmosphere (N2 or Ar), employing dry organic solvents with a strict temperature control, this Minireview focusses on recent advances on the use of these commodity reagents while operating under air, at room...

Ultrafast addition of highly‐polar organometallic reagents (RMgX/RLi) into cyclic carbonates (derived from CO2 as sustainable C1 synthon) has been studied, for the first time, in 2‐MeTHF as green reaction media or in the absence of external VOC solvents, at room temperature and in the presence of air/moisture (i.e., without using protecting atmosph...

An efficient and selective N-functionalization of amides is first reported via a CuI-catalyzed Goldberg type C–N coupling reaction between aryl iodides and primary/secondary amides run either in Deep Eutectic Solvents (DESs) or water as sustainable reaction media, under mild and bench-type reaction conditions (absence of protecting atmosphere). Hig...

Highly-efficient and selective fast addition of in-situ generated lithium amides [LiN(H)R] (obtained via acid-base reaction between n-BuLi and the desired primary amine) into carbodiimides (R-N=C=N-R) or nitriles (R-C≡N) has been...

An efficient protocol was developed for the synthesis of tertiary alcohols via nucleophilic addition of organometallic compounds of s-block elements (Grignard and organolithium reagents) to esters performed in the biodegradable choline chloride/urea eutectic mixture or in water. This approach displays a broad substrate scope, with the addition reac...

The Meyer-Schuster rearrangement of propargylic alcohols into a,b-unsaturated carbonyl compounds has been revisited by setting up an atom-economic process catalyzed by a deep eutectic solvent FeCl 3 Á6H 2 O/glycerol. Isomerizations take place smoothly, at room temperature, under air and with short reaction times. The unique solubilizing properties...

The Cover Feature shows an unprecedented generation of highly polarized lithium phosphides (LiPR2) through direct selective deprotonation of secondary phosphines (HPR2) in the biodegradable choline chloride/glycerol eutectic mixture, at ambient temperature and under aerobic conditions, and their chemoselective addition to aldehydes or epoxides. Mor...

This chapter presents a comprehensive compilation of recent contributions related to the use of sustainable and bio‐renewable Deep Eutectic Solvents (DESs ) in the field of Cu‐catalyzed reactions, including (i) Click Chemistry protocols (CuAAC reaction); (ii) C–C and C–heteroatom coupling processes; and (iii) atom transfer radical polymerizations (...

The Cover Feature shows the preparation of highly enantioenriched chiral amines of pharmaceutical interest by chemoselective addition of organolithiums or Grignard reagents to chiral sulfinyl imines in the biodegradable d‐sorbitol/choline chloride eutectic mixture at ambient temperature and under aerobic conditions. More information can be found in...

This chapter presents a general overview of the progress achieved in the combination of a variety of well‐established copper‐catalyzed organic reactions (such as CuAAC reaction, CC and C–heteroatom coupling processes, and C–X activations) with the use of water as a green and environmentally friendly reaction media. In recent years, this combinatio...

Highly polarized lithium phosphides (LiPR2) have been synthesized, for the first time, in Deep Eutectic Solvents (DESs) as sustainable reaction media, at room temperature and in the absence of protecting atmosphere, through direct deprotonation of both aliphatic and aromatic secondary phosphines (HPR2) by n‐BuLi. The subsequent addition of in‐situ...

A straightforward alkali‐metal‐mediated protocol for hydroamination of styrenes using biorenewable 2‑methyltetrahydrofuran as a solvent is reported. Refuting the conventional wisdom of the incompatibility of organolithium reagents with air and moisture, we show that the presence of moisture is key in favouring formation of the target phenethylamine...

The nemesis of organo‐alkali‐metal reagents, that is, ambient moisture, can remarkably accelerate the alkali‐metal amide induced hydroamination of styrenes. A practically simple aerobic procedure for these hydroaminations under air and in renewable 2‐methyltetrahydrofuran is revealed. Abstract A straightforward alkali‐metal‐mediated hydroamination...

A tandem protocol to access tertiary alcohols has been developed which combines the organocatalytic oxidation of secondary alcohols to ketones followed by their chemoselective addition by several RLi reagents. Reactions...

We first report that highly polarized organometallic compounds of s‐block elements add smoothly to chiral N ‐ tert ‐butanesulfinyl imines in the biodegradable D‐sorbitol/choline chloride eutectic mixture, thereby granting access to enantioenriched amines after quantitatively deblocking the sulfinyl group. The practicability of the methodology was f...

Lithium amides constitute one of the most commonly used class of reagents in synthetic chemisty. However, despite many applications, their use is handicapped by their requirements of low temperatures, in order to control their reactivity, as well as the need of dry organic solvents and protective inert atmosphere protocols to avoid their fast decom...

This mini-review presents a general overview of the progress achieved during the last decade on the amalgamation of CuAAC processes (copper-catalyzed azide-alkyne cycloaddition) with the employment of sustainable solvents as reaction media. In most of the presented examples, the use of water, glycerol (Gly), or deep eutectic solvents (DESs) as non-...

The use of enzymes, organo-catalysts or transition metal catalysts, as opposed to the employment of stoichiometric quantities of other traditional promoters of different organic synthetic processes (like, inorganic/organic bases, Brønsted acids, radicals, etc.) has allowed the discovery of a great number of new synthetic protocols within the toolbo...

The self-assembly of styrene-type olefins into the corresponding stilbenes was conveniently performed in the Deep Eutectic Solvent (DES) mixture 1ChCl/2Gly under air and in the absence of hazardous organic co-solvents using a one-pot chemo-biocatalytic route. Here, an enzymatic decarboxylation of p-hydroxycinnamic acids sequentially followed by a r...

The search for new environmentally‐friendly reaction media either in transition‐metal‐catalyzed or main‐group‐mediated organic synthetic routes is receiving great attention from the point of view of both academic or industrial chemical researchers. In this sense, this chapter tries to cover the ground‐breaking and stimulating new discoveries from d...

Atom Transfer Radical Polymerisation (ATRP) is one of the most important techniques leading to well-defined polymers with predetermined molecular weight, designed microstructure and tailored-made functionalities. Although ATRP has been extensively studied in a variety of common Volatile Organic Solvents (VOCs) and water, there is significantly less...

Through mixed metal cooperativity, alkali metal magnesiates efficiently catalyse the cyclisation of alkynols.

Despite their ubiquitous presence in synthesis, the use of polar organolithium reagents under environmentally benign conditions constitutes one of the greatest challenges in sustainable chemistry. Their high reactivity imposes the use of severely restrictive protocols (e.g., moisture‐ and oxygen‐free toxic organic solvents, inert atmospheres, low t...

Two individual catalytic platforms (metal‐ and organo‐catalyzed) based on the use of an ionic liquid phase were successfully integrated for the synthesis of α‐cyano‐amine and cyanohydrin trimethylsilyl ethers from allylic alcohol. The right combination of continuous flow processes enabled access to the divergent preparation of two alternative and i...

According to a Japanese legend, the God of Water and the Goddess of Fire lived as one before being turned against each other by the Lord of Winds. The reactivity of Grignard and organolithium reagents are critically analysed here when bulk water or other bio‐based protic solvents are used as the only reaction media. The results suggest that there e...

A dual ruthenium/ketoreductase catalytic system has been developed for the conversion of β‐ketonitriles into optically active β‐hydroxyamides through an unprecedented hydration/bioreduction cascade process in aqueous medium working in concurrent mode. The ketoreductase‐mediated ketone reduction took place with exquisite stereoselectivity and it was...

The first application of Deep Eutectic Solvents (DESs) in asymmetric bioreduction of ketones has been accomplished for isolated ketoreductases (KREDs). The performance of the biocatalysts was enhanced by increasing the percentage of neoteric solvent in DES-buffer mixtures. At buffer content of 50% (w/w) and even 20% (w/w), either the combination of...

There is a strong imperative to reduce the release of volatile organic compounds (VOCs) into the environment, and many efforts are currently being made to replace conventional hazardous VOCs in favour of safe, green and bio‐renewable reaction media that are not based on crude petroleum. Recent ground‐breaking studies from a few laboratories worldwi...

This work describes the catalytic activity of palladium(II) species, in the cycloisomerization of alkynoic acids and their derivatives in aqueous media as well as in Deep Eutectic Solvents (DESs), with one of the lowest metal catalyst loadings reported so far in the literature. Different substrates such as terminal and internal alkynes or alkynyl s...

During the last decade, the combination of different metal- and bio-catalyzed organic reactions in aqueous media has permitted the flourishing of a variety of one-pot asymmetric multi-catalytic reactions devoted to the construction of enantiopure and high added-value chemicals under mild reaction conditions (usually room temperature) and in the pre...

Edging closer towards developing air and moisture compatible polar organometallic chemistry, the chemoselective and ultrafast addition of a range of aryllithium reagents to nitriles has been accomplished using glycerol as a solvent, at room temperature in the presence of air, establishing a novel sustainable access to aromatic ketones. Addition rea...

The combination of the metal-catalyzed cycloisomerization of alkynes containing a tethered nucleophile as substituent in aqueous media (followed by the spontaneous hydrolysis, hydroalkoxylation or aminolysis of the transiently formed 5-membered heterocycles), with the subsequent enantioselective ketone bioreduction (mediated by KREDs) has been achi...

This chapter covers part of the progress in the area of deep eutectic solvents (DESs) and low-melting mixtures (LMMs), providing a general overview of their application as green solvents in the fields of: metal-catalysed organic reactions; and carbohydrate conversion and extraction processes. The importance of this subject is also increasing in oth...

The Ru(IV)-catalysed redox isomerisation of allylic alcohols has, for the first time, been successfully assembled with the chemoselective addition of organolithium or organomagnesium reagents to the in situ formed ketones, en route to tertiary alcohols, employing Deep Eutectic Solvents as environmentally friendly reaction media. The overall transfo...

The synthesis and characterisation of five novel copper (II) complexes incorporating an amido pincer ligand derived from the deprotonation of N-(2-{4,4-dimethyl-4,5-Dihydrooxazol-2-yl}phenyl)picolinamide (i.e., L1H) or a chiral indanol-based congener (L2H) are described. These Cu materials are obtained from the treatment of EtOH solutions of L1H or...

New iminophosphorane-phosphine Au(I) complexes [AuCl(κ1-P-Ph2PCH2P{=NP(=S)(OR)2}Ph2)] (3a-b) and [Au2Cl2(μ2-P,S-Ph2PCH2P{=NP(=S)(OR)2}Ph2)] (4a-b) probed to be general, very efficient and recyclable (up to four consecutive runs) catalysts for the cycloisomerization of alkynyl amides using water or choline chloride-based eutectic mixtures as green s...

To overcome the well-established drawbacks of conventional organic solvents (toxicity, non-biodegradability, flammability, accumulation in the atmosphere) remarkable research efforts have been recently devoted to the replacement of traditional organic reaction media by the so-called Green Solvents. In this sense, the choice of a safe, non-toxic, bi...

The ruthenium-catalyzed redox isomerization of allylic alcohols is successfully coupled with the enantioselective enzymatic ketone reduction (mediated by KREDs) in a concurrent process in aqueous medium.

Shattering the long-held dogma that organolithium chemistry needs to be performed under inert atmospheres in toxic organic solvents, chemoselective addition of organolithium reagents to non-activated imines and quinolines has been accomplished in green, biorenewable deep eutectic solvents (DESs) at room temperature and in the presence of air, estab...

Shattering the long-held dogma that organolithium chemistry needs to be performed under inert atmospheres in toxic organic solvents, chemoselective addition of organolithium reagents to non-activated imines and quinolines has been accomplished in green, biorenewable deep eutectic solvents (DESs) at room temperature and in the presence of air, estab...

The ruthenium-catalyzed redox isomerization of allylic alcohols was successfully coupled with the enantioselective enzymatic ketone reduction (mediated by KREDs) in a concurrent process in aqueous medium. The overall transformation, formally the asymmetric reduction of allylic alcohols, took place with excellent conversions and enantioselectivities...

The ruthenium-catalyzed redox isomerization of allylic alcohols was successfully coupled with the enantioselective enzymatic ketone reduction (mediated by KREDs) in a concurrent process in aqueous medium. The overall transformation, formally the asymmetric reduction of allylic alcohols, took place with excellent conversions and enantioselectivities...

Efficient catalytic processes employing the bis(allyl)-ruthenium(IV) complexes [{RuCl(mu-Cl)(eta(3):eta(3)-C10H16)}(2)] (C10H16 = 2,7-dimethylocta-2,6-diene-1,8-diyl), [RuCl2(eta(3):eta(2):eta(3)-C12H18)] (C12H18 = dodeca-2,6,10-triene-1,12-diyl) and [RuCl2(eta(3):eta(3)-C10H16](L)] (L = neutral 2e(-) donor ligand) have been developed in our group...

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and...

This microreview is intended to cover the progress made in metal-mediated and metal-catalysed organic reactions performed in a new family of inexpensive, greener and biorenewable eutectic mixtures, the so-called Deep Eutectic Solvents (DESs), as environmentally friendly reaction media. This ambitious research is focused on studies of particular int...

Developing new green solvents in designing chemical products and processes or successfully employing the already existing ones is one of the key subjects in green chemistry and is especially important in organometallic chemistry, which is an interdisciplinary field. Can we advantageously also use unconventional reaction media in place of current ha...

Cycloisomerisation of gamma-alkynoic acids into cyclic enol-lactones was conveniently performed, for the first time, in the eutectic mixture 1ChCl/2Urea under standard bench experimental conditions (at room temperature, under air and in the absence of co-catalysts) by using a new iminophosphorane–Au( I ) complex as the catalyst. Furthermore, the ca...

Cycloisomerisation of gamma-alkynoic acids into cyclic enol-lactones was conveniently performed, for the first time, in the eutectic mixture 1ChCl/2Urea under standard bench experimental conditions (at room temperature, under air and in the absence of co-catalysts) by using a new iminophosphorane–Au( I ) complex as the catalyst. Furthermore, the ca...

The ruthenium-catalysed isomerisation of allylic alcohols was coupled, for the first time, with an asymmetric bioamination in a one-pot process in aqueous medium. In those cases involving proquiral ketones, the -TA exhibited excellent enantioselectivity, identical to that observed in the single step. As a result, amines were obtained from allylic...

Cycloisomerisation reactions of (Z)-enynols into furans can be conveniently performed, for the first time, in the eutectic mixture 1ChCl/2Gly as solvent and under standard bench conditions (at room temperature and under air) by using the new bis(iminophosphorane)-Au(I) complex [Au2Cl2(μ2-S,S-CH2{P(=NP(=S)(OPh)2)Ph2}2)] as catalyst. Furthermore, a o...

Cycloisomerisation reactions of (Z)-enynols into furans can be conveniently performed, for the first time, in the eutectic mixture 1ChCl/2Gly as solvent and under standard bench conditions (at room temperature and under air) by using the new bis(iminophosphorane)-Au(I) complex [Au2Cl2(μ2-S,S-CH2{P(=NP(=S)(OPh)2)Ph2}2)] as catalyst. Furthermore, a o...

Deep Eutectic Solvents (DESs), also known in the literature as Deep Eutectic Ionic Liquids (DEILs), Low Melting Mixtures (LMMs) or Low Transition Temperature Mixtures (LTTMs), are defined as combinations of two or three safe and inexpensive components which are able to establish hydrogen bond interactions with each other to form an eutectic mixture...

Cycloisomerisation reactions of γ-alkynoic acids into cyclic enol-lactones can be conveniently performed, for the first time, in the eutectic mixture 1ChCl/2Urea under standard bench experimental conditions (room temperature, in air and in the absence of co-catalysts) by using a new iminophosphorane-Au(I) complex as catalyst. Furthermore, the catal...

Despite their enormous synthetic relevance, the use of polar organolithium and Grignard reagents is greatly limited by their requirements of low temperatures in order to control their reactivity as well as the need of dry organic solvents and inert atmosphere protocols to avoid their fast decomposition. Breaking new ground on the applications of th...

Despite their enormous synthetic relevance, the use of polar organolithium and Grignard reagents is greatly limited by their requirements of low temperatures in order to control their reactivity as well as the need of dry organic solvents and inert atmosphere protocols to avoid their fast decomposition. Breaking new ground on the applications of th...

The combination of CuI and glycerol exhibits a versatile and high catalytic activity in the Huisgen cyclo-addition of azides and terminal or 1-iodoalkynes under standard bench experimental conditions (room temperature, under air and in the absence of a base) providing a pivotal contribution to Green Chemistry. Since the catalytic reaction: (i) is a...

This chapter examines the development of well-defined copper(I) complexes as superior catalysts for the regioselective Huisgen reaction (1,3-dipolar cycloaddition of azides and both terminal or internal alkynes) in water. This discovery can be considered as one of the masterpieces in Click Chemistry, serving as proof-of-concept of the importance of...

In this contribution, the catalytic activity of a plethora of ruthenium complexes in the isomerization of allylic and propargylic alcohols in non-conventional solvents [water, ionic liquids (ILs), glycerol and Deep Eutectic Solvents (DESs)] is reviewed. On the one hand, the search for organic reactions proceeding with efficiency, selectivity and at...

Catalytic rearrangements, isomerizations, and allylation processes of organic substrates in aqueous media are reviewed. Enhanced or completely new reactivities in comparison with those processes performed in classical organic solvents are particularly highlighted.

Bis-allyl ruthenium(IV) complexes containing N-heterocyclic ligands [Ru(3:3-C10H16)Cl2(k1-N-L)] (L = pyrazole (1a), benzimidazole (1b)) are active catalysts in the redox isomerization of allylic alcohols into saturated car-bonyl compounds using the ionic liquid [BMIM][BF 4 ] (BMIM = 1-butyl-3-methylimidazolium) as a non-conventional re-action media...

Aiming to shed new light on the stability and constitution of the organometallic intermediates involved in direct ortho-metalation processes, using trifluoromethylbenzene (1) as a case study, this paper investigates the deprotonation of 1 using group 1 alkyl bases tBuLi and nBuNa in the presence of the Lewis donors TMEDA (N,N,N′,N′-tetramethylethyl...

This chapter is intended to cover the progress made in the use of this new generation of catalysts to promote atom-economical rearrangement reactions of organic molecules. Two main families of nanocatalysts have been employed to promote rearrangement reactions: (i) those based on metal(0) nanoparticles and (ii) those based on nano-sized metal oxide...

Merging two evolving areas in synthesis, namely cooperative bimetallics and N-heterocyclic carbenes (NHCs), this study reports the isolation of the first intermediates of alkali-metal-mediated zincation (AMMZn) of a free NHC and a Zn–NHC complex using sodium zincate [(TMEDA)NaZn(TMP)(tBu) 2 ] (1) as a metallating reagent. The structural authenticat...

Iminophosphoranes R3P=NR are nitrogen analogues of phosphorus ylides that can coordinate transition metals using the lone pair on the nitrogen atom. The integration of supplementary donor sites into the iminophosphorane backbone yields polydentate ligands of increasing interest in both coordination chemistry and catalysis. Herein, a comprehensive a...

Treatment of the N-thiophosphorylated iminophosphorane ligands (PTA)═NP(═S)(OR)2 [PTA = 1,3,5-triaza-7-phosphaadamantane, 3a and 3b] and (DAPTA)═NP(═S)(OR)2 [DAPTA = 3,7-diacetyl-1,3,7-triaza-5-bicyclo[3.3.1]nonane, 4a and 4b] with an equimolecular amount of AgSbF6 leads to high-yield formation of the new one-dimensional coordination polymers [Ag{μ...

[ReBr(CO)5] reacts with the iminophosphorane-phosphine ligands Ph2PCH2P(═NR)Ph2 (R = P(═O)(OEt)2 (1a), P(═O)(OPh)2 (1b), P(═S)(OEt)2 (1c), P(═S)(OPh)2 (1d), 4-C6F4CHO (1e), 4-C6F4CN (1f), 4-C5F4N (1g)) affording the neutral complexes [ReBr(κ(2)-P,X-Ph2PCH2P{═NP(═X)(OR)2}Ph2)(CO)3] (X = O, R = Et (2a), Ph (2b); X = S, R = Et (2c), Ph (2d)) and [ReBr...

A new water- and air-stable catalytic system for the cycloisomerization of γ-alkynoic acids in aqueous media is designed furnishing exclusively five-membered enol lactones.

Catalytic rearrangements, isomerizations, and allylation processes of organic substrates in aqueous media are reviewed. Enhanced or completely new reactivities in comparison with those processes performed in classical organic solvents are particularly highlighted.

Treatment of water-soluble phosphanes PTA (1) and DAPTA (2) with an equimolecular amount of azides (RO)(2)P(=S)N-3 (R = Et, Ph) leads to high-yield formation of the N-thiophosphorylated iminophosphorane derivatives 3b and 4a,b, respectively. The reaction of these new iminophosphorane ligands with [Cu(NCCH3)(4)][PF6] (in a 2:1 molar ratio) has been...

Cycloisomerisation reactions of γ-alkynoic acids into cyclic enol-lactones can be conveniently performed in pure water as a solvent and under aerobic conditions by using a novel iminophosphorane–Pd(II) complex trans-[PdCl2{μ2-N,S-(PTA)NP(S)(OEt)2}]2 as a catalyst. It is important to note that the catalytic system could be recycled up to 10 consecut...