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A novel palladium-catalyzed hydration–olefin insertion cascade assisted by internal nucleophiles was developed for the synthesis of biologically significant 2,3-dihydro-1H-inden-1-ones under mild conditions. A detailed mechanistic study revealed that the assistance of the internal nucleophiles is crucial to trigger the cascade reaction via nucleopalladation of the alkyne moiety. The overall reaction is equivalent to regioselective hydration of alkynes followed by intramolecular Michael addition. This highly efficient and 100% atom-economical domino sequence afforded cis-2,3-disubstituted 2,3-dihydro-1H-inden-1-ones in excellent yields (up to 99%) with complete diastereoselectivity.

Addition of the in situ generated Schwartz reagent to widely available isocyanates constitutes a chemoselective, high-yielding, and versatile approach to the synthesis of variously functionalized formamides. Steric and electronic factors or the presence of sensitive functionalities (esters, nitro groups, nitriles, alkenes) do not compromise the potential of the method. Full preservation of the stereochemical information contained in the starting materials is observed. The use of formamides in the nucleophilic addition of organometallic reagents (Chida–Sato allylation, Charette–Huang addition to imidoyl triflate activated amides, Matteson homologation of boronic esters) is briefly investigated.

The addition of carbon (Grignard and organolithium reagents) and hydride nucleophiles (Schwartz reagent) to isocyanates and isothiocyanates constitutes a versatile, direct and high yielding approach to the synthesis of functionalized (thio)amide derivatives including haloamides and formamides. The chemoselective delivery of a nucleophilic (eventually configurationally stable) organometallic species to a given iso(thio)cyanate is the crucial parameter for the success of the strategy. Thus, the influence of the factors governing classical methodologies (e.g. dehydrative condensation) such as steric hindrance and electronic properties of the reactants become practically negligible.

An efficient, chemoselective homologation of Weinreb amides to the corresponding variously substituted α-oxyketones has been developed via the addition of lithiated α-oxygenated species. This one-step, experimentally easy, high yielding protocol is amenable not only for accessing simple α-oxyketones but also for more complex substituted ones ranging from primary and secondary alkyl-type to aromatic ones. Full delivery of the stereochemical information contained in the starting materials is observed through both the employment of enantioenriched Weinreb amides and optically active organolithium species.

A high-yielding, one-pot, three-component synthesis of functionalized 2-amino-4H-pyrans from β-dicarbonyl compounds, activated cyanomethylene compounds, and aldehydes, mediated by potassium-exchanged zirconium hydrogen phosphate [α-Zr(KPO4)2], is reported. The protocol shows excellent versatility, as it can be applied to aromatic, aliphatic, or α,β-unsaturated aldehydes under solvent-free conditions.

alpha-Halomethyllithium carbenoids are useful homologating reagents which - reacting under proper reaction conditions as carbanions - enable the installation via nucleophilic addition of a reactive halomethyl fragment onto a preformed carbon-heteroatom bond. The pronounced thermolability represented - since seminal studies by Kobrich - the Achilles' heel of these reagents: the use of Barbier-type methodologies (i.e., the electrophile should be present in the reaction mixture prior to the formation of the carbenoid) was pivotal in order to suppress decomposition through -elimination processes. Nowadays, the use of low temperatures (-78 degrees C) guarantees reliable procedures and, significantly, the employment of microreactor technologies allows external trapping to be performed even at higher temperatures as reported by Luisi. We will discuss the -halomethyllithium-mediated homologations of a series of carbon electrophiles such as carbonyl compounds, imines, esters, Weinreb amides, and isocyanates.

An efficient, chemoselective homologation of disulfides and diselenides to the corresponding dithio- and diselenoacetals has been developed via the addition of bromomethyllithium. Chemoselectivity is fully preserved in the presence of concomitant electrophilic sites decorating the substrates. The synthetic potential of selected dithioacetals has been evaluated in Feringa–Fananas-Mastral-type Pd-catalyzed coupling with an organolithium and in the unusual 1,4-addition to a Weinreb amide.

An efficient, chemoselective approach to spiro-epoxyoxindoles via the addition of chloromethyllithium followed by ring-closure of the intermediate alkoxide is reported. Chemoselectivity is fully preserved in the presence of different electrophilic sites. The synthetic potential of selected spiro-epoxyindoles has been exploited in the copper(I)-catalyzed intramolecular oxyarylation of an alkyne and in the formation of N,N-dimethylisoindigo via the addition of dihalocarbenoids.

The nucleophilic addition of widely available and variously functionalized organolithium reagents to isothiocyanates represents a straightforward, high-yielding, one-pot method to access secondary thioamides. The simple reaction conditions required and the broad scope (>50 cases examples) makes it a robust and reliable method to access both simple and complex thioamides, including enantiopure ones. Noxious and unpleasant-smelling sulfurating agents, usually employed in the literature established methods, are avoided during the whole synthetic procedure thus, rendering the protocol highly attractive, also for sustainability aspects.

The title method is applicable to a wide range of alkyl halides and acyl donors as well as Michael acceptors.

A synthesis of β-oxonitriles is reported via the generation of R1R2CLiCN species followed by the trapping with variously decorated Weinreb amides. The optimization study revealed that lithiation of acetonitriles is best accomplished by deprotonation with MeLi–LiBr at low temperature. The protocol can be conveniently adapted to the synthesis of α-mono or α,α-disubstituted cyanoketones. 15N- and 17O-NMR data are reported for selected compounds.

Different chemoenzymatic strategies for the preparation of carbohydrates and analogues possessing antidiabetic or anticancer activity are summarized. In this sense, some examples illustrating the use of enzymes such as aldolases, lipases or glycosidases (in some cases improved by genetic engineering techniques) are presented, showing the advantages of the implementation of chemoenzymatic protocols, which combine the flexibility of chemical synthesis with the efficiency, selectivity and sustainability of biotransformations to obtain diverse complex carbohydrates, glycoconjugates and glycomimetics.

In the case of isocyanates with optically active residues, full preservation of chiral information is observed.

Chloromethyllithium carbenoid has been chemoselectively added to cyclic enones (5-, 6- and 7-membered systems, including two natural products) to provide chloromethyl allylic alcohols. Under the optimized reaction conditions neither concomitant (n+1) homologation nor conjugate addition or Simmons–Smith-like cyclopropanation takes place. The presence of LiBr is estimated to play a dual role, namely as a carbenoid stabilizer and mild Lewis acid activator of the CO group. Notably, the mesomeric effect caused by β-heteroatom-containing substituents promotes the attack of the reagent at the most activated position.

The title reactions gives access to β-silylated lactames and amides with high yields and stereoselectivities.

The addition of lithium carbenoids to isocyanates provides a versatile access to N-substituted 2-haloacetamides: the reaction tolerates the presence of variously functionalized substituents on the nitrogen atom, including sterically demanding ones and reactive halogens. No erosion of the enantiopurity was observed in the case of optically active isocyanates. One of the substrates prepared has been employed in Charette's type chemoselective addition of a Grignard reagent to access an α-chloroketone.

A high-yielding procedure is elaborated for the conversion of Weinreb amides to unsaturated haloketones [21 examples].

Vinyl bromides bearing an arylamino group in the vicinal position are chemoselectively transformed into interesting α-arylamino-α′-bromoacetones through a straightforward oxidative hydrolysis promoted by calcium hypobromite under mild acidic conditions. Significantly, this particular combination [vinyl bromides and Ca(BrO)2] avoids bromination at both the aromatic ring and activated positions in groups substituting the amine nitrogen. The usefulness of this class of brominated ketones has been shown in a Wittig homologation.

A convenient procedure is elaborated for the asymmetric silyl transfer to unsaturated lactones.

α-Amino-α´-halomethylketones are interesting scaffolds bearing (at least) two sequential electrophilic carbons that by interacting with the nucleophilic moieties of several enzymes, represent the ideal candidates for in vivo and in vitro inhibition studies. In this work a summary of their use as optimal inhibitors of physiologically relevant serine and cysteine proteases is given with a particular emphasis on recently established SAR studies. A brief survey of the most relevant synthetic processes for their obtainment and the importance they possess in synthetic medicinal chemistry is reported.

The reaction works also well with multifunctionalized acrylate esters, providing excellent chemoselectivity.

The development of new and more economically and environmentally attractive processes to afford chiral molecules is still an open challenge in organic synthesis. During last years the combination of an enzyme-catalyzed kinetic resolution (KR) with the in situ transition metal mediated-racemization of the unreacted enantiomer in a dynamic kinetic resolution (DKR) has received great attention in the preparation of enantiomerically pure compounds, as this methodology allows one to achieve very high conversions and enantiomeric excesses. Several transition metal complexes have been found to be compatible with enzymatic catalysts and highly successful DKR processes of functionalized alcohols and amines have been developed. Those chemicals are valuable building blocks for the further production of many pharmaceuticals and fine chemicals. The aim of this review is to update the advances developed during the past decade related to the coupling of enzymes and transition metal catalysts in DKR processes, focusing on the application of this innovative technique in the synthetic route of biologically active compounds.

2-Methyl-tetrahydrofuran (2-MeTHF) can be derived from renewable resources (e.g., furfural or levulinic acid) and is a promising alternative solvent in the search for environmentally benign synthesis strategies. Its physical and chemical properties, such as its low miscibility with water, boiling point, remarkable stability compared to other cyclic-based solvents such as THF, and others make it appealing for applications in syntheses involving organometallics, organocatalysis, and biotransformations or for processing lignocellulosic materials. Interestingly, a significant number of industries have also started to assess 2-MeTHF in several synthetic procedures, often with excellent results and prospects. Likewise, preliminary toxicology assessments suggest that the use of 2-MeTHF might even be extended to more processes in pharmaceutical chemistry. This Minireview describes the properties of 2-MeTHF, the state-of-the-art of its use in synthesis, and covers several outstanding examples of its application from both industry and academia.

Regioselective ring opening of starting compound (I) with a variety of nucleophiles produces propan-2-ol derivatives which are readily oxidized to the corresponding ketones in excellent yields.

The presented synthesis of γ-hydroxy-α,β-acetylenic esters (III) involves the dehydrobromination of bromoacrylate esters to generate propiolate intermediates which subsequently undergo electrophilic addition towards aldehydes.

Key to the preparation of hitherto not described enantiopure unsymmetrical benzoin acetates is the combination of both biochemical kinetic resolution and dynamik kinetic resolution.

A straightforward chemoselective protection of anilines as N-TBS derivatives is described by using a suitable deprotonation of the amine with methyllithium in the environmentally friendly and safer substitute of THF, 2-methyltetrahydrofuran, under exceptional mild reaction conditions (0 °C, 30 min). Interestingly, the protecting group maybe cleaved efficiently by simple treatment of N-TBS-anilines with silica gel in ethanol–water.

Optimized reaction conditions allow the regioselective cyclization of aminochlorohydrins and analogues (III) to give the target compounds without any trace of azetidinols.

Lithium bromide-mediated addition of organolithium reagents towards α,β-unsaturated aldehydes and ketones proceeds with excellent 1,2-chemoselectivity to give the corresponding allylic alcohols (III) and (V) in high yields.

The presence of a network of intra- and intermolecular hydrogen bonds in β-arylamino alcohols inhibits their oxidation to ketones.

A chemoselective nitrogen functionalization of phthalimides (I) by using KF-alumina in 2-methyltetrahydrofuran, a solvent obtained from renewal sources, is described.

The oxidative hydrolysis of different trifluoroacetyl-protected N-(2-chloroallyl)anilines, promoted by calcium hypochlorite, is able to yield several not previously described α-arylamino-α′-chloropropan-2-ones, very valuable building blocks that are useful as precursors of several drugs, in excellent yields and short reaction times. The main requirement of the reaction for avoiding the undesired aromatic chlorination (N-protection) is effectively solved by the use of the easily formed and removed N-trifluoroacetyl group. Thus, it is possible to perform the oxidative hydrolysis-deprotection step using a one-pot strategy, obtaining quantitative yields in very short reaction times.

A mild and straightforward monoallylation procedure for different anilines is described using the efficient, inexpensive, noncorrosive, and environmentally friendly reagent KF-Celite. By using only a 1/1.2 stoichiometric ratio of electrophilic reagent to aniline, in very short reaction times, the monoallylated products are obtained in high isolated yields via this procedure, which works very effectively regardless of the electronic nature of the substituent on the ring, although electron withdrawing groups make the reactions go even faster.