Barbier-type Reaction Research Articles

Synthesis of organotin(IV) heterocycles containing a xanthenyl group by a Barbier approach via ultrasound activation: synthesis, crystal structure and Hirshfeld surface analysis.

A series of organotin heterocycles of general formula [{Me2C(C6H3CH2)2O}SnR2] [R= methyl (Me, 4), n-butyl (n-Bu, 5), benzyl (Bn, 6) and phenyl (Ph, 7)] was easily synthesized by a Barbier-type reaction assisted by the sonochemical activation of metallic magnesium. The 119Sn{1H} NMR data for all four compounds confirm the presence of a central Sn atom in a four-coordinated environment in solution. Single-crystal X-ray diffraction studies for 17,17-dimethyl-7,7-diphenyl-15-oxa-7-stannatetracyclo[11.3.1.05,16.09,14]heptadeca-1,3,5(16),9(14),10,12-hexaene, [Sn(C6H5)2(C17H16O)], 7, at 100 and 295 K confirmed the formation of a mononuclear eight-membered heterocycle, with a conformation depicted as boat-chair, resulting in a weak Sn...O interaction. The Sn and O atoms are surrounded by hydrophobic C-H bonds. A Hirshfeld surface analysis of 7 showed that the eight-membered heterocycles are linked by weak C-H...π, π-π and H...H noncovalent interactions. The pairwise interaction energies showed that the cohesion between the heterocycles are mainly due to dispersion forces.

Facile synthesis of homoallylamines via α-regioselectivity in ultrasonic mediation and γ-adduct syn-stereoselective allylation with AlCl3-catalysis

The allylation reaction of aldimines with allyl metal reagents is an important synthetic method for the preparation of homoallylamines. Therefore, we wish to report a highly regioselective and stereoselective allylation reaction under sonochemical Barbier-type reaction conditions. The high yields of regioselective α-adducts were achieved by reacting cinnamyl bromide, zinc, 1,2-dibromoethane, and aldimine in THF under sonochemical Barbier-type conditions. Highly regioselective and stereoselective allylation reactions were also achieved under Lewis acid-promoted Barbier-type reaction conditions.

Syntheses and Synthetic Applications of Functionalized Propargylic and Allylic Fluorides.

This account presents the synthesis and application of propargylic and allylic fluorides containing hydroxy or carbonyl functional groups. In particular, the Barbier-type reaction of difluoropropargyl bromides with aldehydes or chloroformates provides versatile propargylic fluorides, and the organocatalytic fluorination of dienamine intermediates has been demonstrated as an effective method to obtain allylic fluorides stereoselectively. Additionally, mechanistic insights into such reactions are discussed with the aid of density functional theory calculations. The report also describes the preparation of fluorinated 1,7-diyne or 1,7-enyne derivatives of these compounds. These propargylic and allylic fluorides can be used as building blocks for fluorinated heterocycles, such as fluorinated furans, tetrahydrofurans, and lactams. Additionally, fluorinated bi- or tri-heterocyclic compounds can be synthesized via transition-metal-catalyzed reactions with fluorinated 1,7-diyne or 1,7-enyne derivatives.

Visible-Light Photocatalytic Barbier-Type Reaction of Aziridines and Azetidines with Nonactivated Aldehydes

AbstractBarbier-type reactions are a classic group of reactions for carbon–carbon bond formation; however, their common use of stoichiometric metals restricts their widespread application. Considering the ready availability and diversity of cyclic amines, we report a visible-light photocatalytic Barbier-type reaction of aziridines and azetidines with nonactivated aldehydes. A series of important γ- and δ-amino alcohols were synthesized in the presence of amines as electron donors. Moreover, this transition-metal-free protocol displays mild reaction conditions, broad functional-group tolerance, and a wide substrate scope. Mechanistic investigations indicated that carbon radicals and carbanions might be generated as key intermediates.

Photoredox Promoted Barbier-Type Reaction of Alkyl Iodides with N-Alkyl and N-Aryl Imines

The reaction of organozinc reagents with unactivated imines is accelerated when performed in the presence of a photocatalyst under blue light irradiation. Coordination between Lewis acidic zinc iodide and the imine is a key factor responsible for the reaction efficiency. The method can be carried out using alkyl iodides under Barbier conditions.

Electrochemical Deoxygenative Barbier-Type Reaction.

An effective deoxygenative C(sp3)-C(sp3) bond formation reaction is achieved through electrochemical reduction of alcoholic phosphates or sulfonates with aldehydes or ketones. Alcohol derivatives of phosphates undergo single-electron reduction under electrochemical conditions followed by a spontaneous cleavage of the C-O bond with the exothermic loss of phosphate resulting in an alkyl radical species. Subsequently, radical intermediates are further reduced to carbanions at the cathode, which are in situ trapped by carbonyl compounds, thus accomplishing a deoxygenative Barbier-type reaction.

Exploring Short and Efficient Synthetic Routes Using Titanocene(III)-Catalyzed Reactions: Total Synthesis of Natural Meroterpenes with Trisubstituted Unsaturations.

The stereo- and regioselective total syntheses of OMe derivatives of the scarce bioactive meroterpenoids makassaric acid (1) and fascioquinol B (2) have been accomplished. The synthetic sequences are based on the following three efficient and selective catalytic reactions: Cu-catalyzed addition of Grignard compounds to an epoxide; a regioselective Barbier-type reaction, catalyzed by Cp2TiCl; and regio- and stereoselective bioinspired cyclization, also catalyzed by Cp2TiCl. These three key processes allow us to obtain the main skeletons of 1 and 2 in a few steps. The valuable synthetic proposal shown in this work provides fast access to scarce, structurally complex meroterpenes with promising biological activities, which are a sustainable source for later studies and applications in medicine.

Silver(I)-catalyzed hydroamination of (3S, 4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsiloxy)ethyl]azetidine-2-one derivatives for the synthesis of carbapenem skeleton

From (3S, 4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsiloxy)ethyl]azetidine-2-one (AOSA), a common precursor for the synthesis of β-lactam antibiotics, zinc-mediated Barbier-type reaction and subsequent silver(I)-catalyzed hydroamination were conducted to build the carbapenem skeleton bearing carboxylate ester at the C-3 position. Depending on catalysts used, a new type of rearrangement was observed. It was also affected by reaction time and the quantities of catalysts.

TBAF-initiated vinylation of aldehydes with trimethyl[(Z)-2-(phenylsulfanyl)-1-(trifluoromethyl)vinyl]silane

The titular compound trifluromethylated vinylsilane was readily prepared in 84% yield from stereodefined (Z)-2‑bromo-2-(trifluoromethyl)vinyl phenyl sulfide and chlorotrimethylsilane in the presence of magnesium under Barbier-type reaction conditions. The TBAF-initiated reaction of the vinylsilane and various aldehydes proceeded smoothly to give the corresponding 2-(trifluoromethyl)allyl alcohol derivatives in moderate to good yields.

Photoredox Activation of Organozinc Reagents: Barbier-Type Reaction of Alkyl Halides with α-(Trifluoromethyl)styrenes.

Organozinc reagents may be activated under blue light irradiation using an organic photocatalyst to generate alkyl radicals. The radicals are trapped by α-(trifluoromethyl)styrenes leading to gem-difluorinated products after elimination of fluoride. The reaction can be conveniently performed under Barbier conditions starting from organic iodides and bromides and elemental zinc.

Neodymium-Promoted Highly Selective Carbon–Carbon Double Bond Formation of Ketones with Allyl Halides in the Presence of Diethyl Phosphite

The carbon–carbon double bond formation via neodymium-mediated Barbier-type reaction of ketones and allyl halides in the presence of diethyl phosphite is reported for the first time. The reaction is highly α-regioselective and was conveniently carried out under mild conditions in a one-pot fashion. From a synthetic point of view, a series of conjugated alkenes were obtained in moderate to good yields in this one-pot reaction with feasible reaction conditions.

Synthesis of 12‐epi‐Protopanaxadiol and Formal Synthesis of Ginsenoside Chikusetsusaponin‐LT8

In the context of the total synthesis of protopanaxadiol, two strategies were explored. One strategy from an optically active trienic epoxide, possessing a 5‐membered ring, prepared from (S)‐epoxy‐limonene and (S)‐epoxyfarnesol, which was submitted to Ti‐(III)‐mediated radical cascade to afford an original tetracyclic structure resulting from a 6‐endo‐trig 6‐endo‐trig 8‐endo‐trig process. A second strategy, starting from a Wieland‐Miescher‐type ketone, using a “ring‐by‐ring” synthesis allowed the synthesis of 12‐epi‐protopanaxadiol. In this latter strategy, an efficient sequence of reactions to install the two vicinal C8–C14 quaternary centers involves: i) a Barbier type reaction; ii) an oxidative allylic transposition and iii) a nickel‐catalyzed addition of trimethylaluminium. By using this second strategy, 20‐hydroxydammar‐24‐ene‐3,12‐dione was synthesized which represents a formal synthesis of chikusetsusaponin‐LT8, isolated from Panax japonicus.

An Example of Ketone Olefination via Praseodymium-Mediated Barbier Reaction in the Presence of Diethyl Phosphite

The first example of carbon double-bond formation via praseodymium-mediated Barbier type reaction of ketones and allyl halides in the presence of diethyl phosphite is reported. The reaction is highly α-regioselective and conveniently carried out under mild conditions in a one-pot fashion. From a synthetic point of view, a series of conjugated alkenes were obtained in moderate to good yields in this one-pot reaction with practical reaction conditions.

(2R,3R)-3-[(1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl]-4-oxoazetidin-2-yl Acetate in Zinc- and Samarium-Promoted Substitution Reactions with Methyl 2-Bromopropanoate and Methyl (2-Bromomethyl)prop-2-enoate. Unusual Cleavage of the N1‒C4 Bond in Azetidin-2-one Derivative with Migration of Methoxycarbonyl Group in Synthetic Approaches to Carbapenems and Their Analogs

The use of zinc in Barbier-type reactions of (2R,3R)-3-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-ethyl]-4-oxoazetidin-2-yl acetates with halogen derivatives led to the formation of expected substitution products. The reaction of the title compound with a reagent prepared from samarium powder, a catalytic amount of iodine, and methyl 2-bromopropanoate in THF gave an anomalous substitution product, methyl 2-{(2S,3S)-3-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-4-oxoazetidin-2-yl}-2(R,S)-methyl-3-oxopentanoate. Alkylation of the latter with methyl bromoacetate afforded methyl 2-{(2S,3S)-3-[(1R)-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl]-1-(2-methoxy-2-oxoethyl)-4-oxoazetidin-2-yl}-2(RS)-methyl-3-oxopentanoate which underwent fragmentation through cleavage of the N1–C4 bond under the action of sodium bis(trimethylsilyl)-amide in THF at–78°C. The resulting acyclic amide, dimethyl {(2R,S,3Z)-2-[(1R)-1-{[tert-butyl(dimethyl)-silyl]oxy}ethyl)]-4-methyl-5-oxohept-3-enoylamino}malonate, was smoothly converted to new functionalized N-substituted pyrrolidinones via intramolecular Michael type cyclization in methylene chloride in the presence of NEt3–DMAP–Boc2O.

Tin powder-promoted allylation and cyclization of 2-(benzylideneamino)isoindoline-1,3-diones

Abstract α-Methylene-γ-lactams were synthesized from readily available N-acylhydrazones by a tin-mediated Barbier-type reaction. The method avoids the use of toxic allylstannanes and the reaction proceeds smoothly under mild conditions.

Johnson Matthey to offer Gusev Ester Hydrogenation Catalysts via an exclusive global licensing agreement with GreenCentre Canada

From (3S, 4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsiloxy)ethyl]azetidine-2-one (AOSA), a common precursor for the synthesis of β-lactam antibiotics, zinc-mediated Barbier-type reaction and subsequent silver(I)-catalyzed hydroamination were conducted to build the carbapenem skeleton bearing carboxylate ester at the C-3 position. Depending on catalysts used, a new type of rearrangement was observed. It was also affected by reaction time and the quantities of catalysts.

Convergent Strategy to Dizocilpine MK-801 and Derivatives.

A convergent total synthesis of MK-801 has been achieved. Key synthetic transformations include a multicomponent Barbier-type reaction to construct the α-branched amine, a selective Heck α-coupling tactic to generate the exocyclic alkene skeleton, and a late-stage intramolecular hydroamination reaction between the exocyclic alkene and the secondary protected amine. The efficacy of this method was demonstrated by the synthesis of two news analogues substituted on the aromatic rings.

Convergent Total Synthesis of Paecilomycin B and 6'- epi-Paecilomycin B by a Barbier-Type Reaction Using 2,4,6-Triisopropylphenyllithium.

The convergent total synthesis of the natural product paecilomycin B and its 6'-epimer was investigated. The aryl- C-glycoside skeleton was constructed by an intramolecular Barbier-type reaction using 2,4,6-triisopropylphenyllithium and subsequent deoxygenation of the resulting anomeric hydroxy group. Starting from aryl iodide 24, the addition reaction afforded the thermodynamically stable C-β macrocyclic adduct 41a in 29% yield and the C-α adduct 41b in 1% yield. Meanwhile, aryl iodide 43 (6'-epimer of 24) gave only the C-α adduct 44 in 76% yield. The stereoselectivities of these nucleophilic addition reactions are also discussed.

Photocatalytic Barbier reaction - visible-light induced allylation and benzylation of aldehydes and ketones.

We report a photocatalytic version of the Barbier type reaction using readily available allyl or benzyl bromides and aromatic aldehydes or ketones as starting materials to generate allylic or benzylic alcohols. The reaction proceeds at room temperature under visible light irradiation with the organic dye 3,7-di(4-biphenyl)1-naphthalene-10-phenoxazine as a photocatalyst and DIPEA as sacrificial electron donor. The proposed cross-coupling mechanism of a ketyl- and an allyl or benzyl radical is supported by spectroscopic investigations and cyclic voltammetry measurements.

α-Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters.

The stereoselective reagent-controlled homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (-)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid-base side-reactions under the reaction conditions for homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of α-magnesiated benzoates with either enantiomer of Andersen's readily available menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl benzoates, we have prepared a range of highly enantiopure mono- and disubstituted α-sulfinyl benzoates, some bearing sensitive functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into lithium (t-BuLi) and magnesium (i-PrMgCl·LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly stereospecific homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to steric hindrance, allows sterically encumbered carbon-carbon bonds to be forged. We have also shown that these building blocks can be used consecutively in three- and four-step iterative homologation processes, without intervening column chromatography, to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity.