Mild Lewis Acid Research Articles

Efficient Flow Synthesis of Glycidyl Ether Using BuSnCl3 as a Mild Lewis Acid

AbstractA ring-opening protocol of epichlorohydrin with 2-ethylhexanol was investigated for the synthesis of the corresponding chlorohydrin ether. BuSnCl3 proved to be an efficient mild Lewis acid catalyst, yielding the product with high selectivity. A scalable flow synthesis was achieved by modifying the flow setup. The flow synthesis of the corresponding glycidyl ether from the chlorohydrin ether was also carried out in an efficient manner by using the basic treatment.

Metal-free Catalytic Hydrogenolysis of Chlorosilanes into Hydrosilanes with "Inverse" Frustrated Lewis Pairs.

The challenging metal-free catalytic hydrogenolysis of silyl chlorides to hydrosilanes is unlocked by using an inverse frustrated Lewis pair (FLP), combining a mild Lewis acid (Cy2BCl) and a strong phosphazene base (BTPP) in mild conditions (10bar of H2, r.t.). In the presence of a stoichiometric amount of the base, the hydrosilanes R3SiH (R=Me, Et, Ph) are generated in moderate to high yields (up to 95%) from their chlorinated counterparts. A selective formation of the valuable difunctional monohydride Me2SiHCl is also obtained from Me2SiCl2. A mechanism is proposed based on stoichiometric experiments and DFT calculations; it highlights the critical role of borohydride species generated by the heterolytic splitting of H2.

Adding Polypeptides to the Toolbox for Redox-Switchable Polymerization and Copolymerization Catalysis

Bis(imino)pyridine (BIP) iron alkoxide complexes act as catalysts to efficiently polymerize N-carboxyanhydrides (NCAs), including γ-benzyl-l-glutamate NCA (BLG-NCA) and sarcosine NCA (Sar-NCA), at room temperature. Reaction rates were greatly enhanced with the addition of mild Lewis acids, such as [CoCp2][BArF24], which work cooperatively with the iron-based catalysts to facilitate NCA polymerization. The reactivity of (2,6MeBIP)FeOCH2C(CH3)3 with Sar-NCA was combined with its known reactivity for ε-caprolactone polymerization to form diblock and triblock copoly(ester-b-peptides) through sequential addition of lactone and NCA monomers. Redox-switchable polymerization reactions were developed by iteratively exposing the catalyst to redox reagents and Sar-NCA or cyclohexene oxide. The orthogonal reactivity demonstrated by the catalyst in its oxidized and reduced states led to the synthesis of diblock and triblock copoly(ether-b-peptides). Polyether segments were synthesized with the catalyst in its oxidized state, while the polyamide segments were synthesized with the catalyst in its reduced state. Both copolymerization reactions developed here are rare examples where NCA polymerization reactions can be combined with other ring-opening polymerization reactions to make copolymers containing polypeptides and other functional monomers.

Facile access to 1,3-bis(boryl) dienes to build molecular complexity through cycloadditions

An operationally simple method to access 1,3-bis(boryl) dienes from parent 1,3-diones via bis-triflation and a Pd0-catalyzed double Miyaura borylation is described. The prepared 1,3-bis(boryl) dienes are bench-stable and competent in [4+2] cycloadditions with common dienophiles affording diastereoselective access to borylated bicyclo[2.2.2]octenes. The addition of LaCl3·2 LiCl, as a mild Lewis acid helps improve the outcome. A detailed computational investigation of multiborylated dienes further identifies reactivity and stability trends of these linchpin reagents with comparison to more typical dienes.

Enantioselective [3 + 2] Cycloaddition of Vinylcyclopropanes with Alkenyl N-Heteroarenes Enabled by Palladium Catalysis.

The first catalytic enantioselective [3 + 2] cycloaddition reaction between vinylcyclopropanes and alkenyl N-heteroarenes in the presence of LiBr and a Pd(0)/SEGPHOS complex was developed. LiBr plays a key role in improving the reactivity of alkenyl N-heteroarenes as a mild Lewis acid.

Zinc(II) Iodide-Directed β-Mannosylation: Reaction Selectivity, Mode, and Application.

A direct, efficient, and versatile glycosylation methodology promises the systematic synthesis of oligosaccharides and glycoconjugates in a streamlined fashion like the synthesis of medium to long-chain nucleotides and peptides. The development of a generally applicable approach for the construction of 1,2-cis-glycosidic bond with controlled stereoselectivity remains a major challenge, especially for the synthesis of β-mannosides. Here, we report a direct mannosylation strategy mediated by ZnI2, a mild Lewis acid, for the highly stereoselective construction of 1,2-cis-β linkages employing easily accessible 4,6-O-tethered mannosyl trichloroacetimidate donors. The versatility and effectiveness of this strategy were demonstrated with successful β-mannosylation of a wide variety of alcohol acceptors, including complex natural products, amino acids, and glycosides. Through iteratively performing ZnI2-mediated mannosylation with the chitobiosyl azide acceptor followed by site-selective deprotection of the mannosylation product, the novel methodology enables the modular synthesis of the key intermediate trisaccharide with Man-β-(1 → 4)-GlcNAc-β-(1 → 4)-GlcNAc linkage for N-glycan synthesis. Theoretical investigations with density functional theory calculations delved into the mechanistic details of this β-selective mannosylation and elucidated two zinc cations' essential roles as the activating agent of the donor and the principal mediator of the cis-directing intermolecular interaction.

Nenitzescu Synthesis of 5‐Hydroxyindoles with Zinc, Iron and Magnesium Salts in Cyclopentyl Methyl Ether

AbstractIn this work, mild Lewis acids and low environmental impact solvents were investigated for Nenitzescu synthesis. Cyclopentyl methyl ether can be used at room temperature in substitution of halogenated solvents with zinc, iron and magnesium salts as homogeneous catalysts to give 5‐hydroxyindoles in fair to good yields. The reaction features a straightforward workup and excellent solvent recycle.

Deaggregation of Zinc Dihydride by Lewis Acids Including Carbon Dioxide in the Presence of Nitrogen Donors.

Thermally sensitive polymeric zinc dihydride [ZnH2]n can conveniently be prepared by the reaction of ZnEt2 with [AlH3(NEt3)]. When reacted with CO2 (1 bar) in the presence of chelating N-donor ligands Ln = N,N,N',N'-tetramethylethylenediamine (TMEDA), N,N,N',N'-tetramethyl-1,3-propanediamine (TMPDA), N,N,N',N″,N''-pentamethyldiethylenetriamine (PMDTA), and 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane (Me4TACD), insertion into the Zn-H bond readily occurred. Depending on the denticity n, formates [(Ln)Zn(OCHO)2] were isolated and structurally characterized, either as a molecule (Ln = TMEDA, TMPDA, PMDTA) or a charge-separated ion pair [(Ln)Zn(OCHO)][OCHO] (Ln = Me4TACD). The reaction of [ZnH2]n with the mild Lewis acid BPh3 in the presence of chelating N-donor ligands Ln gave a series of hydridotriphenylborates, either as a contact ion pair [(L2)Zn(H)(HBPh3)] (L2 = TMEDA, TMPDA) or a separated ion pair [(Ln)Zn(H)][HBPh3] (Ln = PMDTA, Me4TACD). In the crystal, the contact ion pair [(TMEDA)Zn(H)(HBPh3)] showed a bent Zn-H-B bridge indicative of a delocalized Zn-H-B interaction. In contrast, a linear Zn-H-B bridge for [(TMPDA)Zn(H)(HBPh3)] was observed, suggesting a contact ion pair. In THF solution, both complexes show an exchange with free BPh3 as well as [HBPh3]-. DFT calculations suggest the presence of [HBPh3]- anion with a highly polarized B-H bond that interacts with the Lewis acidic zinc hydride cation [(L2)Zn(H)]+. The hydridotriphenylborates [(Ln)Zn(H)(HBPh3)] underwent CO2 insertion to give (formato)zinc (formoxy)triphenylborate complexes [(Ln)Zn(OCHO)][(OCHO)BPh3] (Ln = TMPDA, PMDTA, Me4TACD). For Ln = TMEDA, a dinuclear complex [(Ln)2Zn2(μ-OCHO)3][(OCHO)BPh3] was isolated. Hydridotriphenylborates [(Ln)Zn(H)(HBPh3)] catalyzed the hydrosilylation of CO2 (1 bar) by nBuMe2SiH in THF at 70 °C to give formoxysilane and (methoxy)silane.

ZnI2-Directed Stereocontrolled α-Glucosylation.

Here we report a glucosylation strategy mediated by ZnI2, a cheap and mild Lewis acid, for the highly stereoselective construction of 1,2-cis-O-glycosidic linkages using easily accessible and common 4,6-O-tethered glucosyl donors. The versatility and effectiveness of the α-glucosylation strategy were demonstrated successfully with various acceptors, including complex alcohols. This approach demonstrates the feasibility of the modular synthesis of various α-glucans with both linear and branched backbone structures.

Synthesis of 2-aryl-1,2,4-triazol-3-one derivatives from β-nitroenamines

The preparation of representatively selected 2-aryl-4,5-disubstituted-1,2,4-triazol-3-ones from cyclic β-nitroenamines in four steps is provided, with an overall yield of 8–70%. The nitrazone to amidrazone conversion (third step) could not proceed in absence of LiBr catalyst, and the crucial role of this mild Lewis acid is emphasized. The last cyclization step required the boosting effect of N-methylimidazole and elevated reaction temperature, as well. This reliable synthesis is highly versatile as well, and it could furnish a chemical library of 2,4,5-trisubstituted-1,2,4-triazol-3-ones with potential pharmacological activities. The usefulness of the umpolung that is accompanied by a wide transformability of nitroenamines is highlighted.

Evaluation of 2-(piperidine-1-yl)-ethyl (PIP) as a protecting group for phenols: Stability to ortho-lithiation conditions and boiling concentrated hydrobromic acid, orthogonality with most common protecting group classes, and deprotection via Cope elimination or by mild Lewis acids

A new protecting group, 2-(piperidine-1-yl)-ethyl (PIP), was evaluated as a protecting group for phenols. The PIP group was stable to ortho -lithiation conditions and refluxing with concentrated hydrobromic acid. Deprotection was accomplished by two routes, oxidation to N -oxides followed by Cope elimination (CE) and subsequent hydrolysis or ozonolysis of the vinyl ether or one-step deprotection by BBr 3 •Me 2 S. The PIP group is orthogonal to the O -benzyl, O -acetyl, O-t -butyldiphenylsilyl, O -methyl, O-p -methoxybenzyl, O -allyl, O -tetrahydropyranyl and N-t -butoxy carbonyl groups. The CE step was systematically studied and was found to give higher yields when the reaction was performed in the presence of silylating agents.

New Twists in Nazarov Cyclization Chemistry.

The defining feature of the Nazarov cyclization is a 4π-conrotatory electrocyclization, resulting in the stereospecific formation of functionalized cyclopentanones. The reaction provides access to structural motifs that are found in many natural products and drug targets. Harnessing the full potential of the Nazarov cyclization broadens its utility by enabling the development of new methodologies and synthetic strategies. To achieve these goals through efficient cyclization design, it is helpful to think of the reaction as a two-stage process. The first stage involves a 4π-electrocyclization leading to the formation of an allylic cation, and the second stage corresponds to the fate of this cationic intermediate. With a complete understanding of the discrete events that characterize the overall process, one can optimize reactivity and control the selectivity of the different Stage 2 pathways.In this Account, we describe the development of methods that render the Nazarov cyclization catalytic and chemoselective, focusing specifically on advances made in our lab between 2002 and 2015. The initial discovery made in our lab involved reactions of electronically asymmetric ("polarized") substrates, which cyclize efficiently in the catalytic regime using mild Lewis acidic reagents. These cyclizations also exhibit selective eliminative behavior, increasing their synthetic utility. Research directed toward catalytic asymmetric Nazarov cyclization led to the serendipitous discovery of a 4π-cyclization coupled to a well-behaved Wagner-Meerwein rearrangement, representing an underexplored Stage 2 process. With careful choice of promoter and loading, it is possible to access either the rearrangement or the elimination pathway. Additional experimental and computational studies provided an effective model for anticipating the migratory behavior of substiutents in the rearrangements. Problem-solving efforts prompted investigation of alternative methods for generating pentadienyl cation intermediates, including oxidation of allenol ethers and addition of nucleophiles to dienyl diketones. These Nazarov cyclization variants afford cyclopentenone products with vicinal stereogenic centers and a different arrangement of substituents around the ring. A nucleophilic addition/cyclization/elimination sequence can be executed enantioselectively using catalytic amounts of a nonracemic chiral tertiary amine.In summary, the discovery and development of several new variations on the Nazarov electrocyclization are described, along with synthetic applications. This work illustrates how strongly substitution patterns can impact the efficiency of the 4π-electrocyclization (Stage 1), allowing for mild Lewis acid catalysis. Over the course of these studies, we have also identified new ways to access the critical pentadienyl cation intermediates and demonstrated strategies that exploit and control the different cationic pathways available post-electrocyclization (Stage 2 processes). These advances in Nazarov chemistry were subsequently employed in the synthesis of natural product targets such as (±)-merrilactone A, (±)-rocaglamide, and (±)-enokipodin B.

Gold‐Catalyzed Oxidative Alkyne Functionalization by N−O/S−O/C−O Bond Oxidants

AbstractSince the beginning of this century, homogeneous gold‐catalyzed alkyne transformations have been an active area of research in pursuit of developing efficient synthetic methodologies. This emerging area of research which at the beginning exploited the mild Lewis acid character of gold and its propensity to form π‐complex with alkyne, has been reinvigorated upon the discovery of gold‐catalyzed oxidative alkyne functionalization in 2007. The gold‐catalyzed alkyne oxidation enabled direct access to α‐oxo gold carbenes and gold alkynal complex with versatile reactivity which has been applied to achieve transformations including but not limited to oxyarylation, C−H, X−H (X=N, O) insertion, cyclization, cycloaddition, ring expansion, and various cascade reactions. This review provides a comprehensive summary of methods, applications and mechanistic insight of gold‐catalyzed oxidative alkyne functionalization by N−O/S−O/C−O bond oxidants covering the literature reports appeared since 2007.magnified image

An Air‐Stable Heterobimetallic Si2M2 Tetrahedral Cluster

AbstractAir‐ and moisture‐stable heterobimetallic tetrahedral clusters [Cp(CO)2MSiR]2 (M=Mo or W; R=SitBu3) were isolated from the reaction of N‐heterocyclic carbene (NHC) stabilized silyl(silylidene) metal complexes Cp(CO)2M=Si(SitBu3)NHC with a mild Lewis acid (BPh3). Alternatively, treatment of the NHC‐stabilized silylidene complex Cp(CO)2W=Si(SitBu3)NHC with stronger Lewis acids such as AlCl3 or B(C6F5)3 resulted in the reversible coordination of the Lewis acid to one of the carbonyl ligands. Computational investigations revealed that the dimerization of the intermediate metal silylidyne (M≡Si) complex to a tetrahedral cluster instead of a planar four‐membered ring is due to steric bulk.

An Air-Stable Heterobimetallic Si2 M2 Tetrahedral Cluster.

Air‐ and moisture‐stable heterobimetallic tetrahedral clusters [Cp(CO)2MSiR]2 (M=Mo or W; R=SitBu3) were isolated from the reaction of N‐heterocyclic carbene (NHC) stabilized silyl(silylidene) metal complexes Cp(CO)2M=Si(SitBu3)NHC with a mild Lewis acid (BPh3). Alternatively, treatment of the NHC‐stabilized silylidene complex Cp(CO)2W=Si(SitBu3)NHC with stronger Lewis acids such as AlCl3 or B(C6F5)3 resulted in the reversible coordination of the Lewis acid to one of the carbonyl ligands. Computational investigations revealed that the dimerization of the intermediate metal silylidyne (M≡Si) complex to a tetrahedral cluster instead of a planar four‐membered ring is due to steric bulk.

Effect of Stannic Species Modification on the Acidity of Silicalite-1 and Its Enhancement in Transforming Ethylenediamine to Heterocyclic Amines

In this study, a series of SnO2 modified zeolite catalysts (Snx-S-1; x is the weight percentage of Sn) were prepared with SnCl2 and a defective Silicalite-1 (S-1) zeolite via facile deposition–precipitation method. It was found that the stannic species modified all-silica zeolite catalysts were active for the intermolecular condensation of ethylenediamine (EDA) to 1, 2-Diazabicyclo [2, 2, 2] octane (TEDA) and piperazine (PIP). The best catalyst Sn6-S-1 (6 wt.% Sn loading) showed 86% EDA conversion and 93% total selectivity to TEDA and PIP. By contrast, the defective S-1 zeolite parent showed only approximately 9% EDA conversion under the same conditions. With the help of catalyst characterization techniques including hydroxyl vibration and pyridine adsorption FT-IR spectroscopy (transmission mode), the enhancement of the catalytic activity of the SnO2 modified zeolite catalysts (Snx-S-1) was mainly attributed to the formation of mild Lewis acid sites in the siliceous zeolite. Both the hydroxyl nests of the defective S-1 zeolite and the dispersed SnO2 clusters should be the important factors for the formation of mild Lewis acid sites on the modified zeolite. Based on the catalytic performance of the modified zeolite in the conversion of EDA to PIP and TEDA, it is inferred that the mildly acidified defective S-1 zeolite by the SnO2 deposition modification might become a very active and durable catalyst for reactions involving strongly alkaline reactants and products.

A Facile Approach to the Synthesis of Benzothiazoles from N-Protected Amino Acids

–A simple trituration method for the synthesis of 2-substituted benzothiazoles derived from N-protected amino acids and 2-aminothiophenol using molecular iodine as a mild Lewis acid catalyst has been proposed. The reaction occurs in one step for 20–25 min in solve-free conditions and provides the target products in excellent yields.

High‐Performance Perovskite Solar Cells Using Iodine as Effective Dopant for Spiro‐OMeTAD

The p‐type dopant of spiro‐OMeTAD has been identified as a rational strategy for the enhancement of the hole transport ability in perovskite solar cells (PSCs). Herein, to enhance the conductivity and hole‐extraction ability of spiro‐OMeTAD, a low‐cost and facile method is developed by introducing iodine into the hole transport materials. Morphology observation, energy gap characterization, and photoelectrochemical measurements indicate that as a mild Lewis acid, oxidant, and p‐type dopant, iodine moderately oxidizes spiro‐OMeTAD, optimizes the energy match with perovskite, mitigates the trap state density, interface resistance, and carrier recombination, and improves the hole‐extraction ability and carrier transport capacity. Consequently, a planar PSC based on the spiro‐OMeTAD doped with 8 wt% iodine achieves a champion power conversion efficiency (PCE) of 19.69%. Conversely, the device with pristine spiro‐OMeTAD gets an efficiency of 18.04%. This work indicates a potential application of iodine as a promising p‐type dopant for spiro‐OMeTAD in PSCs.

A Three Component Protocol for the Synthesis of Aziridines using BF3·(OEt)2

Synthesis of N-(1R,2S)-2-(bromo-3-oxo-1,3-diphenylpropyl)-4-methylbenzene sulfonamide and N-(1R,2S)-(2-bromo-3-oxo-1,3-diphenylpropyl)-4-methylbenzene sulfonamide was carried out by a three component reaction using phenacyl bromide, p-toluenesulfonamide and carboxyaldehyde in presence of mild Lewis acid such as BF3·(OEt)2 in dichloromethane. The synthetic utility of this protocol was carried out with syn-isomer to yield corresponding cis-aziridines. This protocol was operationally simple for a wide variety of substituted carboxaldehydes and substituted phenacyl bromides.

Torn between two sites.

Mild Lewis and Bronsted acid sites within the confined porous structure of a Nb–Al-containing zeolite work in co-operation to efficiently break down bio-based γ-valerolactone to butenes.