Organolithium Reactions Research Articles

Rapid flow synthesis of fenofibrate via scalable flash chemistry with in-line Li recovery

Flash chemistry controlled organolithium reactions allow redesigning the new economically affordable synthetic routes for life-saving drugs. However, microreactors limit their applications to extend industrial-level productivity. On the other hand, there has been little attention on recycling valuable elements from organic synthesis. In this work, a new compact monolithic metal microreactor was designed to successfully control the lifetime of short-lived organolithium intermediates at a large scale for sub-second scalable synthesis of fenofibrate as an FDA-approved drug for hypertriglyceridemia. Initially, the ultrafast chemistry of highly unstable ArLi intermediate was successfully explored for the synthesis of fenofibrate by its flow-controlled coupling reaction with 4-chlorobenzoyl chloride. As needed, by 3D metal printing of the CAD-CFD simulated works, eight laminated serpentine channels integrated with four flow distributors were constructed in a monolithic metal microreactor, leading to improved productivity up to 1.18 g min−1. At the in-line work-up step, the largely consumed Li was completely recovered for the potential recycling of valuable Li resources in a continuous-flow manner.

Stereoselective Synthesis of 1-Substituted Homotropanones, including Natural Alkaloid (−)-Adaline

The stereocontrolled synthesis of 1-substituted homotropanones, using chiral N-tert-butanesulfinyl imines as reaction intermediates, is described. The reaction of organolithium and Grignard reagents with hydroxy Weinreb amides, chemoselective N-tert-butanesulfinyl aldimine formation from keto aldehydes, decarboxylative Mannich reaction with β-keto acids of these aldimines, and organocatalyzed L-proline intramolecular Mannich cyclization are key steps of this methodology. The utility of the method was demonstrated with a synthesis of the natural product (-)-adaline, and its enantiomer, (+)-adaline.

Thermal characterization of highly exothermic flash chemistry in a continuous flow calorimeter

Robust calorimetric data for highly exothermic organolithium reactions are obtained within a modular 3D printed continuous flow calorimeter.

Switchable Chemoselectivity of Reactive Intermediates Formation and Their Direct Use in A Flow Microreactor.

A chemoselectivity switchable microflow reaction was developed to generate reactive and unstable intermediates. The switchable chemoselectivity of this reaction enables a selection for one of two different intermediates, an aryllithium or a benzyl lithium, at will from the same starting material. Starting from bromo-substituted styrenes, the aryllithium intermediates were converted to the substituted styrenes, whereas the benzyl lithium intermediates were engaged in an anionic polymerization. These chemoselectivity-switchable reactions can be integrated to produce polymers that cannot be formed during typical polymerization reactions.

Radical Chain Breaking Bis(ortho-organoselenium) Substituted Phenolic Antioxidants.

The presence of a chalcogen atom at the ortho-position of phenols enhances their radical chain-breaking activity. Here, a copper(I)-catalyzed reaction of 2,6-dibromo- and 2,6-diiodophenols with diorganodiselenides has been studied for the introduction of two organoselenium substituents at both ortho-positions of the phenolic radical chain-breaking antioxidants, which afforded 2,6-diorganoseleno-substituted phenols in 80-92% yields having electron-donating CH3 , and electron-withdrawing CN and CHO functionalities. Additionally, 2,6-diiodophenols with electron-withdrawing CHO and CN groups also afforded novel 5,5'-selenobis(4-hydroxy-3-(phenylselanyl)benzaldehyde) and 5,5'-selenobis(4-hydroxy-3-(phenylselanyl)benzonitrile) consisting of three selenium and two phenolic moieties along with 2,6-diorganoseleno-substituted phenols has been synthesized. The electron-withdrawing CHO group has been reduced by sodium borohydride to the electron-donating alcohol CH2 OH group, which is desirable for efficient radical quenching activity of phenols. The developed copper-catalyzed reaction conditions enable the installation of two-arylselenium group ortho to phenolic radical chain-breaking antioxidants, which may not be possible by conventional organolithium-bromine exchange methods due to the sluggish reactivity of trianions (dicarba and phenoxide anion), which are generated by the reaction of organolithium with 2,6-dibromophenols, with diorganodiselenides. The antioxidant activities of the synthesized bis and tris selenophenols have been accessed by DPPH, thiol peroxides, and singlet oxygen quenching assay. The radical quenching antioxidant activity has been studied for the synthesized compounds by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The bis-selenophenols show comparable radical deactivating activity, while tris seleno-bisphenols show higher radical deactivating activity than α-tocopherol. Furthermore, the tris seleno-bisphenol shows comparable peroxide decomposing activity with ebselen molecules.

Continuous-flow Si–H functionalizations of hydrosilanes via sequential organolithium reactions catalyzed by potassium tert-butoxide

We herein report an atom-economic flow approach to the selective and sequential mono-, di-, and tri-functionalizations of unactivated hydrosilanes via serial organolithium reactions catalyzed by earth-abundant metal compounds.

Exploration of Mesyl Chloride in a One Pot Conversion of Carboxylic Acids to Ketones

Background: Due to the ubiquitous nature of the ketone functionality, it is considered an important functional group in organic chemistry. Hence, the synthesis of ketones from readily available starting materials is an important chemical transformation in organic synthesis. Consequently, several research efforts have been reported in the literature for the transformation of carboxylic acids to ketones in a one-pot synthesis. However, some of the procedures have limitations, such as long reaction times, harsh reaction conditions, and usage of expensive metal catalysts. Thus, a simple and convenient one-pot conversion of carboxylic acids to ketones remains desirable. Objective: We intended to develop a simple and convenient one-pot methodology for the synthesis of ketones from carboxylic acids. Our objective was to build up a carboxylic acid-based chemical template where various types of organometallic reagents can interact to produce the desired ketone. Methods: In this procedure, a carboxylic acid was converted to a mixed anhydride using mesyl chloride in the presence of a base. This mixed anhydride was then reacted with a suitable organometallic reagent at -20°C to obtain the desired ketone. The reaction was performed in a one-pot fashion. Results: Under the optimized reaction conditions, various aromatic and heteroaromatic carboxylic acids were converted to the corresponding ketones using organolithium and organomagnesium reagents with short reaction times. Moderate to good yields of the desired ketones were observed in many of these transformations. Conclusion: A simple and convenient one-pot method for the conversion of carboxylic acids to ketones has been reported. Specifically, various aromatic and `heteroaromatic carboxylic acids have been converted to the corresponding ketones in moderate to good yields. Organomagnesium and organolithium reagents were used as nucleophiles for this reaction.

Trapping of Transient Organolithium Compounds

AbstractOrganolithium chemistry has been widely utilized in organic synthesis as a reliable tool for introducing various functional groups. The intrinsic high reactivity of organolithiums allows rapid chemical transformation; however, the transient organolithiums bearing an electrophilic moiety often cause the undesired reactions such as self‐dimerization, isomerization, and decomposition, which prevent further synthetic application. In this minireview, we classify the reactions involving the short‐lived organolithiums and focus on the recent progress in flow chemistry, which allows to trap the highly reactive organolithium species. In addition, this review includes other approaches using the related organometallic species that can be performed in a conventional batch reactor. To place the recent development of this field in perspective, the established strategies controlling the reactivities of the short‐lived organolithiums provide a short‐step, efficient, and protective group‐free synthesis of functionalized organic molecules in medicinal, agrochemical, and material chemistry.

Palladium-catalysed cross-coupling of lithium acetylides

The incorporation of alkynes into organic molecules is one of the most valuable transformations for the formation of C–C bonds and provides a versatile handle for further modifications. The Sonogashira cross-coupling of acetylenes holds a prominent position among the suite of catalytic cross-coupling reactions that are key to modern synthesis. Here we present a method that is complementary to the Sonogashira reaction, demonstrating cross-coupling of lithium acetylides with aryl bromides. The reactions take place under ambient conditions with short reaction times, affording the corresponding aryl acetylenes in good to excellent yields while displaying a remarkable functional group tolerance for an organolithium reaction, allowing the presence of a variety of organolithium-sensitive carbonyl functionalities. This developed cross-coupling methodology offers ample opportunities to access a wide variety of acetylenes, as is illustrated by the facile preparation of key intermediates for chemical biology and optoelectronic materials. The Sonogashira cross-coupling is a key strategy in modern synthesis for C–C bond formation and introduction of the versatile alkyne functionality into organic molecules. Now, a complementary method is reported based on the palladium-catalysed cross-coupling of lithium acetylides with aryl bromides.

Palladium‐Catalyzed ortho‐Benzoylation of Sulfonamides through C−H Activation: Expedient Synthesis of Cyclic N‐Sulfonyl Ketimines

AbstractThe ortho‐carbonylation of sulfonylarenes by non‐hazardous aryl aldehydes as a carbonyl precursor was reported. In this method, the sulfonamide group serves as a directing group for C−H activation in the presence of a Pd catalyst under ligand‐free conditions. The scope of this strategy has been extended to the one‐pot two‐step synthesis of cyclic N‐sulfonyl ketimines under mild reaction conditions. Our approach could be considered as an alternative by circumventing the use of highly reactive organolithium or Grignard reagents to access a wide range of biologically potent cyclic N‐sulfonyl ketimines.magnified image

Synthesis of (Difluoromethyl)cycloalkenes from 2‐Cycloalkenones by Utilizing Phospha‐Brook Rearrangement

AbstractDifluoromethyl‐substituted allylic phosphates were synthesized from 2‐cycloalkenones through the addition of a (difluoromethyl)phosphonate and subsequent phospha‐Brook rearrangement. The obtained allylic phosphates were converted to the corresponding difluoromethyl‐substituted cycloalkenes using the Cu‐mediated SN2’ reaction of Grignard or organolithium reagents.magnified image

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides.

The conjugate addition of organometallic reagents to α,β-unsaturated carbonyls represents an important method to generate C-C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild "one-pot" preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic α,β-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

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.

Numerical and Experimental Quantification of the Performance of Microreactors for Scaling-up Fast Chemical Reactions

Microreactors have been utilized for controlling fast chemical reactions. However, the scale-up strategy for fast reactions is not established enough due to the difficulty in quantifying the effect of the reactor size on the mixing performance, heat removal, and observable reaction rate. We present a chart for analyzing the effect of the mixing rate on the observable kinetic constant and a chart for estimating the temperature increase in the reactor. By using these charts, the validity of the rate analysis and the maximum reactor diameter, which control the reaction temperature, were determined. Commercial computational fluid dynamics (CFD) software was employed to solve the partial differential equations and to build the charts, and experiments were conducted to validate the results. We demonstrated the concept by using the ultrafast organolithium reaction in milliseconds. The product throughput was increased eight times with a reactor diameter that was twice as wide as the original reactor.

Dichotomy within 1,4-addition of organolithium and Grignard reagents to α,β-unsaturated Fischer alkoxycarbenes: A new synthesis of Fischer carbenes

The reaction of organolithium and Grignard reagents with pentacarbonyl[(ethoxy)(2-phenylethenyl)carbene]chromium(0) gave, after the quenching of the initially formed product of the 1,4-addition, different products depending on the organometallic and quenching reagents used. The addition of organolithiums, followed by a work-up with acid (AcOH or HCl), afforded the corresponding carbene complexes. In contrast, quenching the reaction mixture with ethanol led to the stereoselective formation of (Z)-enol ethers. The usage of Grignard reagents led to the formation of the carbene complexes regardless of which quenching reagent was used.

Transition metal-catalyzed α-alkylation of amines by C(sp3)‒H bond activation

α-Substituted amines are present in a myriad of biologically active natural and synthetic products. With the objective of developing atom-economical reactions, a panel of synthetic methods allowing the direct functionalization of C(sp3)‒H bonds adjacent to the nitrogen atom have been developed. The field remains dominated by the sequence α-lithiation/addition on an electrophile even if the use of reactive organolithium reagents is not compatible with all functional groups. Over the past ten years, an increasing interest has been devoted to metal-catalyzed CH-activation, some studies being specially dedicated to C(sp3)‒H bond activation. Notably, this approach has been envisioned to perform direct α-functionalization of amines. The aim of this article is to give an overview of synthetic methods for transition metal-catalyzed α-alkylation of amines by C(sp3)‒H bond activation.

Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation.

The kinetics of lithium diisopropylamide (LDA) in tetrahydrofuran under nonequilibrium conditions are reviewed. These conditions correspond to a class of substrates in which the rates of LDA aggregation and solvation events are comparable to the rates at which various fleeting intermediates react with substrate. Substrates displaying these reactivities, by coincidence, happen to be those that react at tractable rates on laboratory time scales at -78 °C. In this strange region of nonlimiting behavior, rate-limiting steps are often poorly defined, sometimes involve deaggregation, and at other times include reaction with substrate. Changes in conditions routinely cause shifts in the rate-limiting steps, and autocatalysis is prevalent and can be acute. The studies are described in three distinct portions: (1) methods and strategies used to deconvolute complex reaction pathways, (2) the resulting conclusions about organolithium reaction mechanisms, and (3) perspectives on the concept of rate limitation reinforced by studies of LDA in tetrahydrofuran at -78 °C under nonequilibrium conditions.

Synthesis and Characterization of (Disilylanilino)Phosphines

GRAPHICAL ABSTRACTThe disilyl(4-bromo)aniline (Me3Si)2NC6H4Br (A) readily undergoes metal-halogen exchange to give the reactive organolithium derivative (Me3Si)2NC6H4Li (B). Subsequent reactions with various chlorophosphines, R(R′)PCl, or chloro(disilylamino)phosphines, (Me3Si)2NP(R)Cl, were used to prepare three varieties of the title compounds: (Me3Si)2NC6H4P(R′)R (1: R = R′ = NMe2; 2: R = R′ = OCH2CF3; 3: R = Ph, R′ = OCH2CF3; 4: R = R′ = Ph; 5: R = Ph, R′ = Me), (Me3Si)2NC6H4P(R)N(SiMe3)2 [6: R = Me; 7: R = i-Pr; 8: R = n-Bu, 9: R = OCH2CF3; 10: R = C6H4N(SiMe3)2; 11: R = Ph], and (Me3Si)2NC6H4P(Ph)R [12: R = n-Bu; 13: R = C6H4N(SiMe3)2]. The new compounds 1–13 were generally obtained as colorless, distillable liquids that were fully characterized by NMR (1H, 13C, and 31P) spectroscopy and elemental analysis.

ChemInform Abstract: Emergence of Electrophilic Alumination as the Counterpart of Established Nucleophilic Lithiation: An Academic Sojourn in Organometallics with William Kaska as Fellow Traveler

AbstractReview: 28 refs.

Inter- and intramolecular enantioselective carbolithiation reactions

In this review we summarize recent developments in inter- and intramolecular enantioselective carbolithiation reactions carried out in the presence of a chiral ligand for lithium, such as (−)-sparteine, to promote facial selection on a C=C bond. This is an attractive approach for the construction of new carbon–carbon bonds in an asymmetric fashion, with the possibility of introducing further functionalization on the molecule by trapping the reactive organolithium intermediates with electrophiles.