"Buttressing Effect" in the Halogen-Lithium Exchange in ortho-Bromo-N,N-dimethylanilines and Related Naphthalenes.

Non-covalent interactions such as coordination of an organolithium reagent by a directing group and steric repulsion of substituents strongly affect the halogen-lithium exchange process. Here we present the manifestation of the "buttressing effect" - an indirect interaction between two substituents issued by the presence of a third group - and its influence on the ease and selectivity of the bromine-lithium exchange and the reactivity of formed aryllithiums. The increase of the size of the "buttressing" substituent strongly affects the conformation of a NMe2 group, forcing it to hinder ortho-bromine and thus slowing down the exchange. In naphthalene substrates bearing two bromines, this suppresses regioselectivity of the reaction. The "buttressing effect" forces formed aryllithiums to deaggregate, thus boosting their reactivity. This facilitates the decomposition via protolisys by ethereal solvents even at low temperatures and in some cases initiates fast Wurtz-Fittig coupling.

Recent Advancements in the Utilization of s-Block Organometallic Reagents in Organic Synthesis with Sustainable Solvents.

This mini-review offers a comprehensive overview of the advancements made over the last three years in utilizing highly polar s-block organometallic reagents (specifically, RLi, RNa and RMgX compounds) in organic synthesis run under bench-type reaction conditions. These conditions involve exposure to air/moisture and are carried out at room temperature, with the use of sustainable solvents as reaction media. In the examples provided, the adoption of Deep Eutectic Solvents (DESs) or even water as non-conventional and protic reaction media has not only replicated the traditional chemistry of these organometallic reagents in conventional and toxic volatile organic compounds under Schlenk-type reaction conditions (typically involving low temperatures of -78 °C to 0 °C and a protective atmosphere of N2 or Ar), but has also resulted in higher conversions and selectivities within remarkably short reaction times (measured in s/min). Furthermore, the application of the aforementioned polar organometallics under bench-type reaction conditions (at room temperature/under air) has been extended to other environmentally responsible reaction media, such as more sustainable ethereal solvents (e.g., CPME or 2-MeTHF). Notably, this innovative approach contributes to enhancing the overall sustainability of s-block-metal-mediated organic processes, thereby aligning with several key principles of Green Chemistry.

α-Functionalisation of Cyclic Sulfides Enabled by Lithiation Trapping.

A general and straightforward procedure for the lithiation trapping of cyclic sulfides such as tetrahydrothiophene, tetrahydrothiopyran and a thiomorpholine is described. Trapping with a wide range of electrophiles is demonstrated, leading to more than 50 diverse α-substituted saturated sulfur heterocycles. The methodology provides access to a range of α-substituted cyclic sulfides that are not easily synthesised by the currently available methods.

A Convenient One-Pot Synthesis of a Sterically Demanding Aniline from Aryllithium Using Trimethylsilyl Azide, Conversion to ß-Diketimines and Synthesis of a ß-Diketiminate Magnesium Hydride Complex.

This work reports the one-pot synthesis of sterically demanding aniline derivatives from aryllithium species utilising trimethylsilyl azide to introduce amine functionalities and conversions to new examples of a common N,N'-chelating ligand system. The reaction of TripLi (Trip = 2,4,6-iPr3-C6H2) with trimethylsilyl azide afforded the silyltriazene TripN2N(SiMe3)2 in situ, which readily reacts with methanol under dinitrogen elimination to the aniline TripNH2 in good yield. The reaction pathways and by-products of the system have been studied. The extension of this reaction to a much more sterically demanding terphenyl system suggested that TerLi (Ter = 2,6-Trip2-C6H3) slowly reacted with trimethylsilyl azide to form a silyl(terphenyl)triazenide lithium complex in situ, predominantly underwent nitrogen loss to TerN(SiMe3)Li in parallel, which afforded TerN(SiMe3)H after workup, and can be deprotected under acidic conditions to form the aniline TerNH2. TripNH2 was furthermore converted to the sterically demanding ß-diketimines RTripnacnacH (=HC{RCN(Trip)}2H), with R = Me, Et and iPr, in one-pot procedures from the corresponding 1,3-diketones. The bulkiest proligand was employed to synthesise the magnesium hydride complex [{(iPrTripnacnac)MgH}2], which shows a distorted dimeric structure caused by the substituents of the sterically demanding ligand moieties.

An Experimental and Computational Investigation Rules Out Direct Nucleophilic Addition on the N2 Ligand in Manganese Dinitrogen Complex [Cp(CO)2 Mn(N2 )].

We have re-examined the reactivity of the manganese dinitrogen complex [Cp(CO)2 Mn(N2 )] (1, Cp=η5 -cyclopentadienyl, C5 H5 ) with phenylithium (PhLi). By combining experiment and density functional theory (DFT), we have found that, unlike previously reported, the direct nucleophilic attack of the carbanion onto coordinated dinitrogen does not occur. Instead, PhLi reacts with one of the CO ligands to provide an anionic acylcarbonyl dinitrogen metallate [Cp(CO)(N2 )MnCOPh]Li (3) that is stable only below -40 °C. Full characterization of 3 (including single crystal X-ray diffraction) was performed. This complex decomposes quickly above -20 °C with N2 loss to give a phenylate complex [Cp(CO)2 MnPh]Li (2). The latter compound was erroneously formulated as an anionic diazenido compound [Cp(CO)2 MnN(Ph)=N]Li in earlier reports, ruling out the claimed and so-far unique behavior of the N2 ligand in 1. DFT calculations were run to explore both the hypothesized and the experimentally verified reactivity of 1 with PhLi and are fully consistent with our results. Direct attack of a nucleophile on metal-coordinated N2 remains to be demonstrated.

Collective Total Synthesis of Mavacuran Alkaloids through Intermolecular 1,4-Addition of an Organolithium Reagent.

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C-fluorocurine, C-profluorocurine, C-mavacurine, normavacurine, 16-epi-pleiocarpamine and taberdivarine H. We designed a strategy involving late-stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2-indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4-addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C-profluorocurine and C-fluorocurine were finalized by the dihydroxylation of C-mavacurine and a pinacol rearrangement, respectively.

In Situ Quench Reactions of Enantioenriched Secondary Alkyllithium Reagents in Batch and Continuous Flow Using an I/Li-Exchange.

We report a practical in situ quench (ISQ) procedure involving the generation of chiral secondary alkyllithiums from secondary alkyl iodides (including functionalized iodides bearing an ester or a nitrile) in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, isocyanates, sulfides, or boronates. This ISQ-reaction allowed the preparation of a broad range of optically enriched ketones, alcohols, amides, sulfides and boronic acid esters in typically 90-98 % ee. Remarkably, these reactions were performed at -78 °C or -40 °C in batch. A continuous flow set-up permitted reaction temperatures between -20 °C and 0 °C and allowed a scale-up up to a 40-fold without further optimization.

Cyanide-Free Cyanation of sp2 and sp-Carbon Atoms by an Oxazole-Based Masked CN Source Using Flow Microreactors.

This work reports a cyanide-free continuous-flow process for cyanation of sp2 and sp carbons to synthesize aryl, vinyl and acetylenic nitriles from (5-methyl-2-phenyloxazol-4-yl) boronic acid [OxBA] reagent as a sole source of carbon-bound masked -CN source. Non-toxic and stable OxBA reagent is generated by lithiation-borylation of bromo-oxazole, and the consecutive Suzuki-Miyaura cross-coupling with aryl, vinyl, or acetylenic halides and demasking [4+2]/retro-[4+2] sequence were successfully accomplished to give the desired cyano compounds with reasonably good yields in a four-step flow manner. A unique feature of this cyanation protocol in flow enables to cyanate a variety of sp2 and sp carbons to produce a broad spectrum of aryl acetonitrile. It is envisaged that the OxBA based cyanation would replace existing unstable and toxic approaches as well as non-toxic cyanation using two different sources of "C" and "N" to incorporate the -CN group.

Design of a New Chiral Deep Eutectic Solvent Based on 3-Amino-1,2-propanediol and Its Application in Organolithium Chemistry.

A chiral glycerol derivative, namely 3-amino-1,2-propanediol, was employed for as the hydrogen bond donor (HBD) in the design of a new deep eutectic solvent (DES) with choline chloride acting as the hydrogen bond acceptor (HBA). The novel mixture was characterized and unambiguously classified as a DES. Furthermore, its synthetic usefulness was demonstrated in the room-temperature n-butyllithium-addition under air to carbonyl compounds and benzyl chloride. In some cases, pure products (100% conversion) were obtained by a simple extractive work-up in up to 72% isolated yield, thus suggesting the potential practical usefulness of this procedure as a green alternative to the classical Schenk procedure in volatile organic solvents for the synthesis of tertiary alcohols. The chirality of the HBD, bearing an interesting basic primary amino group, is an intriguing feature currently under investigation for further exploitation.

Towards Hexagonal Planar Nickel: A Dispersion-Stabilised Tri-Lithium Nickelate.

Advancing the understanding of lithum nickelate complexes, here we report a family of homoleptic organonickelate complexes obtained by reacting Ni(COD)2 and lithium aryl-acetylides in the presence of the bidentate donor TMEDA. These compounds represent rare examples of low-valent transition-metals supported solely by organolithium ligands. Whilst the solid-state structures indicate a hexagonal planar geometry around Ni0 with Ni-Li bonds, bonding analysis via QTAIM, NCI, NBO and ELI methods reveals that the Ni-Li interactions are repulsive in nature, characterising these complexes as tri-coordinated. London dispersion forces between TMEDA and the organic substituents on nickel are found to play a crucial role in the stabilisation and thus isolation of these complexes. Preliminary reactivity studies demonstrate that the homoleptic lithium nickelates undergo stoichiometric cross-coupling with PhI to give dinickel clusters containing both anionic acetylide and neutral alkyne ligands.

Supported σ-Complexes of Li-C Bonds from Coordination of Monomeric Molecules of LiCH3 , LiCH2 CH3 and LiC6 H5 to Mo≣Mo Bonds.

LiCH3 and LiCH2 CH3 react with the complex [Mo2 (H)2 (µ-AdDipp2 )2 (thf)2 ] (1⋅thf) with coordination of two molecules of LiCH2 R (R=H, CH3 ) and formation of complexes [Mo2 {µ-HLi(thf)CH2 R}2 (AdDipp2 )2 ], 5⋅LiCH3 and 5⋅LiCH2 CH3 , respectively (AdDipp2 =HC(NDipp)2 ; Dipp=2,6-i Pr2 C6 H3 ; thf=C4 H8 O). Due to steric hindrance, only one molecule of LiC6 H5 adds to 1⋅thf generating the complex [Mo2 (H){µ-HLi(thf)C6 H5 }(µ-AdDipp2 )2 ], (4⋅LiC6 H5 ). Computational studies disclose the existence of five-center six-electron bonding within the H-Mo≣Mo-C-Li metallacycles, with a mostly covalent H-Mo≣Mo-C group and predominantly ionic Li-C and Li-H interactions. However, the latter bonds exhibit non-negligible covalency, as indicated by X-ray, computational data and the large one-bond 6,7 Li,1 H and 6,7 Li,13 C NMR coupling constants found for the three-atom H-Li-C chains. By contrast, the phenyl group in 4⋅LiC6 H5 coordinates in an η2 fashion to the lithium atom through the ipso and one of the ortho carbon atoms.

Self-Sustaining Fluorination of Active Methylene Compounds and High-Yielding Fluorination of Highly Basic Aryl and Alkenyl Lithium Species with a Sterically Hindered N-Fluorosulfonamide Reagent.

Fluorination of carbanions is pivotal for the synthesis of fluorinated compounds, but the current N-F fluorinating agents have significant drawbacks due to many reactive locations that surround the reactive N-F site. By developing a sterically hindered N-fluorosulfonamide reagent, namely N-fluoro-N-(tert-butyl)-tert-butanesulfonamide (NFBB), we discovered a conceptually novel base-catalyzed, self-sustaining fluorination of active methylene compounds and achieved the high-yielding fluorination of the hitherto difficult highly basic (hetero)aryl and alkenyl lithium species. In the former, the mild and high yield fluorination of active methylene compounds exhibited wide functional group tolerance and its novel catalytic fluorination-deprotonation cycle mechanism was demonstrated by deuterium-tracing experiments. In the latter, NFBB reacted with a variety of highly basic (hetero)aryl and alkenyl lithium species to provide the desired fluoro (hetero)arenes and alkenes in unprecedented high or quantitative yields.

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition.

A convergent strategy for the synthesis of leustroducsins and phoslactomycins has been designed, relying on the synthesis and the coupling of three main fragments. The central fragment was synthesized via a regio-and stereoselective nitroso Diels-Alder reaction with an enol phosphate, followed by reductive cleavage of the phosphate to the ketone 11b. Coupling studies of this fragment with the lactone fragment was accomplished in a stereoselective fashion through a vinyllithium intermediate. An advanced synthetic intermediate was then obtained after functional group transformation.

An Easy Route to Aziridine Ketones and Carbinols.

N,N-Dimethylaziridine-2-carboxamides react with organolithium reagents yielding 2-aziridinylketones. The reaction with one equivalent of organolithium compound is selective to amide carbonyl at a low (-78 °C) temperature. These ketones, in reaction with organolithium reagents, give symmetrical and unsymmetrical aziridinyl carbinols. The usage of excess phenyllithium may serve as a special N-Boc-protecting group cleavage method for acid-sensitive substrates.

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.

The Anionic Pathway in the Nickel-Catalysed Cross-Coupling of Aryl Ethers.

The Ni-catalysed cross-coupling of aryl ethers is a powerful method to forge new C-C and C-heteroatom bonds. However, the inert C(sp2 )-O bond means that a canonical mechanism that relies on the oxidative addition of the aryl ether to a Ni0 centre is thermodynamically and kinetically unfavourable, which suggests that alternative mechanisms may be involved. Here, we provide spectroscopic and structural insights into the anionic pathway, which relies on the formation of electron-rich hetero-bimetallic nickelates by adding organometallic nucleophiles to a Ni0 centre. Assessing the rich co-complexation chemistry between Ni(COD)2 and PhLi has led to the structures and solution-state chemistry of a diverse family of catalytically competent lithium nickelates being unveiled. In addition, we demonstrate dramatic solvent and donor effects, which suggest that the cooperative activation of the aryl ether substrate by Ni0 -ate complexes plays a key role in the catalytic cycle.

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.

Nickel-Catalyzed Anionic Cross-Coupling Reaction of Lithium Sulfonimidoyl Alkylidene Carbenoids With Organolithiums.

The mechanistic platform for a novel nickel0 -catalyzed anionic cross-coupling reaction (ACCR) of lithium sulfonimidoyl alkylidene carbenoids (metalloalkenyl sulfoximines) with organometallic reagents is reported herein, affording substituted alkenylmetals and lithium sulfinamides. The Ni0 -catalyzed ACCR of three different types of metalloalkenyl sulfoximines, including acyclic, axially chiral and exocyclic derivatives, with sp2 organolithiums and sp2 and sp3 Grignard reagents has been studied. The ACCR of metalloalkenyl sulfoximines with PhLi in the presence of the Ni0 -catalyst and precatalyst Ni(PPh3 )2 Cl2 afforded alkenyllithiums, under inversion of configuration at the C atom and complete retention at the S atom. In a combination of experimental and DFT studies, we propose a catalytic cycle of the Ni0 -catalyzed ACCR of lithioalkenyl sulfoximines. Computational studies reveal two distinctive pathways of the ACCR, depending on whether a phosphine or 1,5-cyclooctadiene (COD) is the ligand of the Ni atom. They rectify the underlying importance of forming the key Ni0 -vinylidene intermediate through an indispensable electron-rich Ni0 -center coordinated by phosphine ligands. Fundamentally, we present a mechanistic study in controlling the diastereoselectivity of the alkenyllithium formation via the key lithium sulfinamide coordinated Ni0 -vinylidene complex, which consequently avoids an unselective formation of an alkylidene carbene Ni-complex and ultimately racemic alkenyllithium.

Nucleophilic Addition Reaction with Dearomatization of Naphthalene Ring.

Various aromatic lactones have been synthesized and their regioselectivity (1,2-addition vs. 1,4- or 1,6-addition) investigated in reactions with organolithium species, particularly n-BuLi and sec-BuLi. The regioselectivity varied greatly depending on various factors, such as the bulkiness of both substrates and organolithium species, and types of solvent and cosolvent. In particular, 1,4-addition with dearomatization occurred preferentially using sec-BuLi as the nucleophile in tetrahydrofuran (THF) with hexamethylphosphoramide (HMPA) or N,N'-dimethylpropyleneurea (DMPU) as cosolvent. For sec-BuLi, the reaction was estimated to proceed through a single-electron transfer mechanism.