Stereoselective Synthesis of δ- and ε-Amino Ketone Derivatives from N-tert-Butanesulfinyl Aldimines and Functionalized Organolithium Compounds.

The addition of functionalized organolithium compounds derived from 5-chloro-2-methoxy-1-pentene and 6-chloro-2-methoxy-1-hexene to N-tert-butanesulfinyl aldimines imines, and a subsequent hydrolysis of the enol ether moiety, yielded different δ- and ε-amino ketone derivatives, respectively, in moderate yields and diastereoselectivities. The application of these compounds in organic synthesis was demonstrated by the preparation of 2-substituted 6-methylpiperidines in a stereoselective manner, among them natural alkaloids (+)- and (-)-isosolenopsin A.

Alkali-Metal Mediation: Diversity of Applications in Main-Group Organometallic Chemistry.

Organolithium compounds have been at the forefront of synthetic chemistry for over a century, as they mediate the synthesis of myriads of compounds that are utilised worldwide in academic and industrial settings. For that reason, lithium has always been the most important alkali metal in organometallic chemistry. Today, that importance is being seriously challenged by sodium and potassium, as the alkali-metal mediation of organic reactions in general has started branching off in several new directions. Recent examples covering main-group homogeneous catalysis, stoichiometric organic synthesis, low-valent main-group metal chemistry, polymerization, and green chemistry are showcased in this Review. Since alkali-metal compounds are often not the end products of these applications, their roles are rarely given top billing. Thus, this Review has been written to alert the community to this rising unifying phenomenon of "alkali-metal mediation".

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach.

The reported flow-batch approach enables the easy preparation of 2H-azirines and their stereoselective transformation into highly functionalized NH-aziridines, starting from vinyl azides and organolithium compounds. The protocol has been developed using cyclopentyl methyl ether (CPME) as an environmentally benign solvent, resulting into a sustainable, safe and potentially automatable method for the synthesis of interesting strained compounds.

Dithieno[1,4]thiazines and Bis[1]benzothieno[1,4]thiazines-Organometallic Synthesis and Functionalization of Electron Density Enriched Congeners of Phenothiazine.

This mini-review summarizes the syntheses and functionalizations of dithieno[1,4]thiazines and bis[1]benzothieno[1,4]thiazines, both electron density-enriched congeners of phenothiazines with remarkable electronic properties. Diversity-oriented, straightforward, and efficient syntheses, including versatile one-pot processes, have been developed for the anellated 1,4-thiazines as well as various functionalization for the expansion of the π-systems. Thereby, syntheses of different regioisomers depending on the (benzo)thieno-thiazine anellation are discussed, which exert a deep impact on the electronic properties. The tunable photophysical and electrochemical properties of dithieno[1,4]thiazines and bis[1]benzothieno[1,4]thiazines outscore phenothiazines on many points and promise an enormous potential in molecular electronics and applications beyond.

2-Butyl-2-tert-butyl-5,5-diethylpyrrolidine-1-oxyls: Synthesis and Properties.

Nitroxides are broadly used as molecular probes and labels in biophysics, structural biology, and biomedical research. Resistance of a nitroxide group bearing an unpaired electron to chemical reduction with low-molecular-weight antioxidants and enzymatic systems is of critical importance for these applications. The redox properties of nitroxides are known to depend on the ring size (for cyclic nitroxides) and electronic and steric effects of the substituents. Here, two highly strained nitroxides, 5-(tert-butyl)-5-butyl-2,2-diethyl-3-hydroxypyrrolidin-1-oxyl (4) and 2-(tert-butyl)-2-butyl-5,5-diethyl-3,4-bis(hydroxymethyl)pyrrolidin-1-oxyl (5), were prepared via a reaction of the corresponding 2-tert-butyl-1-pyrroline 1-oxides with butyllithium. Thermal stability and kinetics of reduction of the new nitroxides by ascorbic acid were studied. Nitroxide 5 showed the highest resistance to reduction.

Water and Sodium Chloride: Essential Ingredients for Robust and Fast Pd-Catalysed Cross-Coupling Reactions between Organolithium Reagents and (Hetero)aryl Halides.

Direct palladium-catalysed cross-couplings between organolithium reagents and (hetero)aryl halides (Br, Cl) proceed fast, cleanly and selectively at room temperature in air, with water as the only reaction medium and in the presence of NaCl as a cheap additive. Under optimised reaction conditions, a water-accelerated catalysis is responsible for furnishing C(sp3 )-C(sp2 ), C(sp2 )-C(sp2 ), and C(sp)-C(sp2 ) cross-coupled products, in competition with protonolysis, within a reaction time of 20 s, in yields of up to 99 %, and in the absence of undesired dehalogenated/homocoupling side products even when challenging secondary organolithiums serve as the starting material. It is worth noting that the proposed protocol is scalable and the catalyst and water can easily and successfully be recycled up to 10 times, with an E-factor as low as 7.35.

NMR studies of dilithiostyrenes: aggregation, NMR parameters, and DFT calculations for (E)-1-Lithio-2-(o-lithiophenyl)-1-trimethylsilylethene.

The dilithio compound (E)-1-lithio-2-(o-lithiophenyl)-1-trimethylsilylethene (5) was synthesized from 2-trimethylsilylbenzo-[b]tellurophene (6) with lithium-6 and a detailed analysis of its 1 H, 6 Li, 13 C, and 29 Si NMR spectra showed 5 to form a dimer 52 in tetrahydrofuran and diethylether, while addition of tetramethylethylenediamine stabilizes a monomer 51 . A monomer-dimer equilibrium exists with K at 230 K = 1.25 and ΔG230o = -0.43 kJ mol-1 . Homonuclear 6 Li,6 Li coupling of 0.25 ± 0.07 Hz in the dimer was detected by a 1D-6 Li,6 Li INADEQUATE experiment, and scalar 6 Li,13 C coupling constants were obtained from 13 C satellites in the 6 Li spectrum, from 13 C multiplet simulation and 6 Li,13 C-HMQC spectra. In addition, structures and coupling constants of 51 and 52 were calculated by density functional theory (DFT) methods. It was found that the magnitude of the 6 Li,13 C spin-spin interactions shows an inverse correlation with the C-Li bond lengths. The intra-aggregate exchange in the dimer, caused by 180° rotation of one monomer unit within the solvent cage, was studied by 6 Li DNMR and line shape analysis and yielded ΔG298≠ = 60 ± 3 kJ mol-1 ; ΔH≠ = 84 ± 3 kJ mol-1 ; ΔS≠ = 80 ± 3 J mol-1 K-1 for this process. Copyright © 2015 John Wiley & Sons, Ltd.

Unprecedented Nucleophilic Additions of Highly Polar Organometallic Compounds to Imines and Nitriles Using Water as a Non-Innocent Reaction Medium.

In contrast to classic methods carried out under inert atmospheres with dry volatile organic solvents and often low temperatures, the addition of highly polar organometallic compounds to non-activated imines and nitriles proceeds quickly, efficiently, and chemoselectively with a broad range of substrates at room temperature and under air with water as the only reaction medium. Secondary amines and tertiary carbinamines are furnished in yields of up to and over 99 %. The significant solvent D/H isotope effect observed for the on-water nucleophilic additions of organolithium compounds to imines suggests that the on-water catalysis arises from proton transfer across the organic-water interface. The strong intermolecular hydrogen bonds between water molecules may play a key role in disfavoring protonolysis, which occurs extensively in other protic media such as methanol. This work lays the foundation for reshaping many fundamental s-block metal-mediated organic transformations in water.

Novel Organic Synthesis through Ultrafast Chemistry.

How fast are flashes? The field of flow chemistry has recently received increasing attention owing to the availability of commercial flow equipment. New syntheses with very short-lived intermediates have been enabled by sub-millisecond mixing and reaction regimes in tailor-made flow devices.

Nickel-Catalyzed Cross-Coupling of Organolithium Reagents with (Hetero)Aryl Electrophiles.

Nickel-catalyzed selective cross-coupling of aromatic electrophiles (bromides, chlorides, fluorides and methyl ethers) with organolithium reagents is presented. The use of a commercially available nickel N-heterocyclic carbene (NHC) complex allows the reaction with a variety of (hetero)aryllithium compounds, including those prepared via metal-halogen exchange or direct metallation, whereas a commercially available electron-rich nickel-bisphosphine complex smoothly converts alkyllithium species into the corresponding coupled product. These reactions proceed rapidly (1 h) under mild conditions (room temperature) while avoiding the undesired formation of reduced or homocoupled products.

1,1-Dilithioethylene: Toward Spectroscopic Identification of the Definitive Singlet Ground Electronic State of a Peculiar Structure.

1,1-Dilithioethylene is a prototypical carbon-lithium compound that is not known experimentally. All low-lying singlet and triplet structures of interest were investigated by using high-level theoretical methods with correlation-consistent basis sets up to pentuple ζ. The coupled cluster methods adopted included up to full triple excitations and perturbative quadruples. In contrast to earlier studies that predicted the twisted C2v triplet to be the ground state, we found a peculiar planar Cs singlet ground state in the present research. The lowest excited electronic state of 1,1-dilithioethylene, the twisted Cs triplet, was found to lie 9.0 kcal mol(-1) above the ground state by using energy extrapolation to the complete basis set limit. For the planar Cs singlet and twisted Cs triplet states of 1,1-dilithioethylene, anharmonic vibrational frequencies were reported on the basis of second-order vibrational perturbation theory. The remarkably low (2050 cm(-1) ) C-H stretching fundamental (the C-H bond near the bridging lithium) of the singlet state was found to have very strong infrared intensity. These highly reliable theoretical findings may assist in the long-sought experimental identification of 1,1-dilithioethylene. Using natural bond orbital analysis, we found that lithium bridging structures were strongly influenced by electrostatic effects. All carbon-carbon linkages corresponded to conventional double bonds.

Integrated one-flow synthesis of heterocyclic thioquinazolinones through serial microreactions with two organolithium intermediates.

The synthesis of pharmaceutical compounds via short-lived intermediates in a microreactor is attractive, because of the fast flow and high throughput. Additionally, intermediates can be utilized sequentially to efficiently build up a library in a short time. Here we present an integrated microfluidic synthesis of biologically active thioquinazolinone libraries. Generation of o-lithiophenyl isothiocyanate and subsequent reaction with aryl isocyanate is optimized by controlling the residence time in the microreactor to 16 ms at room temperature. Various S-benzylic thioquinazolinone derivatives are synthesized within 10 s in high yields (75-98%) at room temperature. These three-step reactions involve two organolithium intermediates, an isothiocyanate-functionalized aryllithium intermediate, and a subsequent lithium thiolate intermediate. We also demonstrate the gram-scale synthesis of a multifunctionalized thioquinazolinone in the microfluidic device with a high yield (91%) and productivity (1.25 g in 5 min).

Reactions of difunctional electrophiles with functionalized aryllithium compounds: remarkable chemoselectivity by flash chemistry.

Flash chemistry using flow microreactors enables highly chemoselective reactions of difunctional electrophiles with functionalized aryllithium compounds by virtue of extremely fast micromixing. The approach serves as a powerful method for protecting-group-free synthesis using organolithium compounds and opens a new possibility in the synthesis of polyfunctional organic molecules.

On the configurational stability of chiral, nonracemic fluoro- and iodo-[D(1)]methyllithiums.

Enantiomerically pure fluoro-[D1]methyllithium and iodo-[D1]methyllithiums of up to 92% ee were generated by transmetalation of the corresponding stannanes with MeLi in THF at various temperatures. The intermediate halo-[D1]methyllithiums were trapped with benzaldehyde or acetophenone already present in excess in the reaction mixture to either give halohydrins or to disintegrate to carbene. The fluoro-[D1]methyllithiums were found to be microscopically configurationally stable within the tested range of -95 to 0 °C, but chemically only stable at temperatures below -95 °C due to a rapidly increasing portion disintegrating to carbene. The iodo-[D1]methyllithiums were configurationally labile relative to the rate of addition to PhCHO at all temperatures tested (-95 to -30 °C). Disintegration to carbene interfered as well.

Introducing deep eutectic solvents to polar organometallic chemistry: chemoselective addition of organolithium and Grignard reagents to ketones in air.

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 these commodity organometallics in synthesis under more environmentally friendly conditions, this work introduces deep eutetic solvents (DESs) as a green alternative media to carry out chemoselective additions of ketones in air at room temperature. Comparing their reactivities in DES with those observed in pure water suggest that a kinetic activation of the alkylating reagents is taking place, favoring nucleophilic addition over the competitive hydrolysis, which can be rationalized through formation of halide-rich magnesiate or lithiate species.

Directed aromatic functionalization in natural-product synthesis: Fredericamycin A, nothapodytine B, and topopyrones B and D.

THIS IS A REVIEW OF OUR EFFORTS TOWARD THE SYNTHESIS OF A GROUP OF NATURAL PRODUCTS THAT DISPLAY NOTEWORTHY BIOLOGICAL ACTIVITY: Fredericamycin A, nothapodytine B, and topopyrones B and D. In each case, directed aromatic functionalization methodology greatly facilitated the assembly of the key molecular subunits.

Fast Addition of s-Block Organometallic Reagents to CO2 -Derived Cyclic Carbonates at Room Temperature, Under Air, and in 2-Methyltetrahydrofuran.

Fast addition of highly polar organometallic reagents (RMgX/RLi) to cyclic carbonates (derived from CO2 as a sustainable C1 synthon) has been studied in 2-methyltetrahydrofuran as a green reaction medium or in the absence of external volatile organic solvents, at room temperature, and in the presence of air/moisture. These reaction conditions are generally forbidden with these highly reactive main-group organometallic compounds. The correct stoichiometry and nature of the polar organometallic alkylating or arylating reagent allows straightforward synthesis of: highly substituted tertiary alcohols, ß-hydroxy esters, or symmetric ketones, working always under air and at room temperature. Finally, an unprecedented one-pot/two-step hybrid protocol is developed through combination of an Al-catalyzed cycloaddition of CO2 and propylene oxide with the concomitant fast addition of RLi reagents to the in situ and transiently formed cyclic carbonate, thus allowing indirect conversion of CO2 into the desired highly substituted tertiary alcohols without need for isolation or purification of any reaction intermediates.

Organolithium-Initiated Polymerization of Olefins in Deep Eutectic Solvents under Aerobic Conditions.

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 temperatures, etc.). Making inroads towards meeting this challenge, a new air- and moisture-compatible organolithium-mediated methodology for the anionic polymerization of different olefins (e.g., styrenes and vinylpyridines) was established by pioneering the use of deep eutectic solvents (DESs) as an eco-friendly reaction medium in this type of transformation. Fine-tuning of the conditions (sonication of the reaction mixture at 40 °C in the absence of protecting atmosphere) along with careful choice of components of the DES [choline chloride (ChCl) and glycerol (Gly) in a 1:2 ratio] furnished the desired organic polymers (homopolymers and random copolymers) in excellent yields (up to 90 %) and low polydispersities (IPD 1.1-1.3). Remarkably, the in situ-formed polystyril lithium intermediates exhibited a great resistance to hydrolysis in the eutectic mixture 1ChCl/2Gly (up to 1.5 h), hinting at an unexpected high stability of these otherwise highly reactive organolithium species in these unconventional reaction media. This unique stability can be exploited to create well defined block-copolymers.

Mixed aggregates of 1-methoxyallenyllithium with lithium chloride.

A combined computational and (13)C NMR study was used to investigate the formation of mixed aggregates of 1-methoxyallenyllithium and lithium chloride in tetrahydrofuran (THF) solution. The observed and calculated chemical shifts, as well as the calculated free energies of mixed aggregate formation (MP2/6-31+G(d)), are consistent with the formation of a mixed dimer as the major species in solution. Free energies of mixed dimer, trimer, and tetramer formation were calculated by using the B3LYP and MP2 methods and the 6-31+G(d) basis set. The two methods generated different predictions of which mixed aggregates will be formed, with B3LYP/6-31+G(d) favoring mixed trimers and tetramers in THF solution, and MP2/6-31+G(d) favoring mixed dimers. Formation of the sterically unhindered mixed dimers is also consistent with the enhanced reactivity of these compounds in the presence of lithium chloride. The spectra are also consistent with some residual 1-methoxyallenyllithium tetramer, as well as small amounts of higher mixed aggregates. Although neither computational method is perfect, for this particular system, the calculated free energies derived using the MP2 method are in better agreement with experimental data than those derived using the B3LYP method.