Barbier Conditions Research Articles

Radical Substitution of Polyfluoroarenes and Heteroarenes Promoted by Photoredox Activation of Organozinc Iodides

AbstractAromatic compounds interact with organozinc reagents under photoredox conditions, leading to the substitution products. The reaction is performed under blue light irradiation via in situ generated organozinc reagents (Barbier conditions), which are oxidized by the photocatalyst, followed by radical attack at the aromatic substrate. The method works with polyfluorinated arenes, 2‐chlorobenzoxazoles, and 2‐sulfonyl‐substituted benzothiazole.

Total Synthesis of Aculenes B and D

AbstractThe first total synthesis of aculene D, a structurally rare nordaucane‐type natural product exhibiting quorum sensing inhibitory activity, has been accomplished from a known five‐membered hydroxy carboxylic acid. Nucleophilic addition of methallylzinc bromide to a β‐keto aldehyde intermediate under Barbier conditions to install the secondary hydroxy group on the seven‐membered ring of aculene D gave the corresponding alcohol with an undesired configuration predominantly. On the other hand, the protection of its keto group as the ethylene acetal induced a reversal of diastereoselectivity, affording a desired diastereomer in a selective manner. The construction of the seven‐membered ring was realized by ring‐closing metathesis using a triethylsilyl‐protected monocyclic diene ester precursor. An additional five‐step manipulation on the cyclization product including the installation of an ethyl group on the five‐membered ring completed the synthesis of aculene D, whose esterification with an N‐protected l‐proline followed by deprotection also achieved the first total synthesis of aculene B.

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.

Design, synthesis, and evaluation of new vanin-1 inhibitors based on RR6

Fourteen novel vanin-1 inhibitors coded OMP-# were designed from RR6 and successfully synthesized by a nucleophilic addition–elimination reaction of the pantetheinic acid-derived Weinreb amide as a key step under Barbier conditions. The synthesized OMP compounds exhibited inhibitory activity against human serum vanin-1 in vitro. Among the synthesized compounds, OMP-7, which possesses a trifluoromethoxy group at the para-position on the phenyl ring, exhibited the most potent activity, approximately 20 times that of the mother compound RR6. OMP-7 was further subjected to an in vivo assay using a normal hamster. More potent activity was observed than that of RR6 against both serum and renal vanin-1. The activity lasted for 4 h after injection against serum vanin-1 and 1 h after injection against renal vanin-1, whereas RR6 did not show the desired activity.

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.

Halogen–Lithium Exchange of Sensitive (Hetero)aromatic Halides under Barbier Conditions in a Continuous Flow Set-Up

AbstractA halogen–lithium exchange reaction of (hetero)aromatic halides performed in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, and imines using BuLi as exchange reagent and a commercially available flow set-up is reported. The organolithiums generated in situ were instantaneously trapped with various electrophiles (Barbier conditions) resulting in the formation of polyfunctional (hetero)arenes. This method enables the functionalization of (hetero)arenes containing highly sensitive functional groups such as esters­, which are not tolerated in batch conditions.

Continuous Flow Preparation of (Hetero)benzylic Lithiums via Iodine-Lithium Exchange Reaction under Barbier Conditions.

Herein we report the generation of benzylic lithiums via an iodine-lithium exchange reaction on benzylic iodides performed in continuous flow using tBuLi as the exchange reagent. The resulting benzylic lithium species are trapped in situ by carbonyl electrophiles under Barbier conditions, resulting in benzylic secondary and tertiary alcohols. This flow procedure further allows the generation of highly reactive heterobenzylic lithium compounds, which are difficult to generate under batch conditions. A general scale-up was possible without further optimization.

Barbier Self-Condensing Ketyl Polymerization-Induced Emission: A Polarity Reversal Approach to Reversed Polymerizability.

SummaryCarbon-carbon bond formation through polarity reversal ketyl radical anion coupling of carbonyls has inspired new reaction modes to this cornerstone carbonyl group and played significant roles in organic chemistry. The introduction of this resplendent polarity reversal ketyl strategy into polymer chemistry will inspire new polymerization mode with unpredicted discoveries. Here we show the successful introduction of polarity reversal ketyl approach to polymer chemistry to realize self-condensing ketyl polymerization with polymerization-induced emission. In this polarity reversal approach, it exhibits intriguing reversed polymerizability, where traditional excellent leaving groups are not suitable for polymerization but challenging polymerizations involving the cleavage of challenging C-F and C-CF3 bonds are realized under mild Barbier conditions. This polarity reversal approach enables the polymer chemistry with polarity reversal ketyl mode, opens up a new avenue toward the polymerization of challenging C-X bonds under mild conditions, and sparks design inspiration of new reaction, polymerization, and functional polymer.

Magnesium promoted autocatalytic dehydrogenation of amine borane complexes: A reliable, non-cryogenic, scalable access to boronic acids

Owing to the unusual reactivity of dialkylamine-borane complexes, a methodology was developed to simply access boronic acids. The intrinsic instability of magnesium aminoborohydride was tweaked into a tandem dehydrogenation borylation sequence. Proceeding via an autocatalytic cycle, amineborane dehydrogenation was induced by a variety of Grignard reagents. Overall, addition of the organomagnesium species onto specially designed dialkylamine-borane complexes led to a variety of boronic acids in high yields. In addition, the reaction can be performed under Barbier conditions, on a large scale.

Low-Temperature Intermolecular Addition of RCF2Li Compounds to Various Carbonyl Electrophiles for a Practical Synthesis of CF2-Containing Building Blocks

The addition of various RCF2Li compounds to a wide range of carbonyl electrophiles (aldehydes, ketones, acylsilanes, esters, and lactones) is reported. The reaction proceeds at very low temperature under Barbier conditions through a Br/Li exchange from the corresponding RCF2Br compounds. In contrast with existing methods that use more stable, but less reactive, organometallic species, there is efficient addition to esters, lactones and poorly reactive ketones.

Preparation and reactions of 4-iodobutyl pinacolborate. Synthesis of substituted alkyl and aryl pinacolboronates via 4-iodobutyl pinacolborate utilizing tetrahydrofuran as the leaving group

Iodine reacts with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin), under ambient reaction conditions in THF, to form the iodoalkylborate species 2-(4-iodobutoxy)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4-IboxBpin). Apparently, one-half equivalent of I2 reacts with HBpin to form IBpin in pentanes, which in turn cleaves THF to form the 4-IboxBpin. Alkyl and aryl Grignard reagents, prepared under Barbier conditions, then react with 4-IboxBpin to form the corresponding alkyl and aryl pinacolboronates while reforming and liberating THF as the leaving group.

ChemInform Abstract: Reaction of Grignard Reagents with Diisopropylaminoborane. Synthesis of Alkyl, Aryl, Heteroaryl and Allyl Boronic Acids from Organo(diisopropyl)aminoborane by a Simple Hydrolysis.

AbstractBoronic acids (III) are synthesized by Grignard reaction of aminoborane (I), whereas boronic acids (V) are synthesized by reaction of (I) with in situ formed Grignard reagents (Barbier conditions).

Multicomponent Synthesis of a N-Protected α-Amino Ester: Ethyl 2-((4-Methoxyphenyl)amino)-3-phenylpropanoate

This laboratory experiment describes the preparation of a N-protected phenylalanine ethyl ester by a zinc-mediated Mannich-like multicomponent reaction between benzyl bromide, p-anisidine, and ethyl glyoxylate. The one-step reaction involves the in situ metallation of benzyl bromide into a benzylzinc reagent and its addition onto imine (Barbier conditions). The multicomponent procedure is suitable for a 4-to-5 h undergraduate organic laboratory.

ChemInform Abstract: Nature of the Intermediates Formed During Indium Mediated Allylation under Barbier Conditions. Spectroscopic and Experimental Data on Allylindium Species

AbstractReview: 105 refs.

Hydride as a Leaving Group in the Reaction of Pinacolborane with Halides under Ambient Grignard and Barbier Conditions. One-Pot Synthesis of Alkyl, Aryl, Heteroaryl, Vinyl, and Allyl Pinacolboronic Esters

Grignard reagents (aliphatic, aromatic, heteroaromatic, vinyl, or allylic) react with 1 equiv of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (pinacolborane, PinBH) at ambient temperature in tetrahydrofuran (THF) to afford the corresponding pinacolboronates. The initially formed dialkoxy alkylborohydride intermediate quickly eliminates hydridomagnesium bromide (HMgBr) and affords the product boronic ester in very good yield. Hydridomagnesium bromide (HMgBr) in turn disproportionates to a 1:1 mixture of magnesium hydride (MgH(2)) and magnesium bromide (MgBr(2)) on addition of pentane to the reaction mixture. DFT calculations (Gaussian09) at the B3LYP/6-31G(d) level of theory show that disproportionation of HMgBr to MgH(2) and MgBr(2) is viable in the coordinating ethereal solvents. This reaction also can be carried out under Barbier conditions, where the neat PinBH is added to the flask prior to the in situ formation of Grignard reagent from the corresponding organic halide and magnesium metal. Pinacolboronic ester synthesis under Barbier conditions does not give Wurtz coupling side products from reactive halides, such as benzylic and allylic halides. The reaction between PinBH and various Grignard reagents is an efficient, mild, and general method for the synthesis of pinacolboronates.

ChemInform Abstract: 1,2‐Addition of Phenylacetylene to Aldimines Catalyzed by InCl3/CuCl in Water under Barbier Conditions.

AbstractA simple procedure is developed for the synthesis of various propargylamines.

ChemInform Abstract: Zinc‐Mediated Allylation of Aldoxime Esters.

AbstractThe title reaction proceeds under Barbier conditions to afford the corresponding homoallylic hydroxylamine esters.

1,2-Addition of Phenylacetylene to Aldimines Catalyzed by InCl3/CuCl in Water under Barbier Conditions

A new and efficient method for the preparation of various propargylamines has been achieved by the simple Barbier― Grignard-type reaction of phenylacetylene with a variety of aldimines under aqueous conditions, catalyzed by a bimetallic In―Cu system.

ChemInform Abstract: Silatranes from Reactions of Chloromethylsilatrane with Chlorosilanes and Magnesium in Tetrahydrofuran.

Abstract Some silatranylmethylsilanes have been obtained by reaction of chloromethylsilatrane with chloro- silanes and magnesium in THF (i.e. under Barbier conditions).

Indium-mediated alkynylation of sugars: synthesis of C-glycosyl compounds bearing a protected amino alcohol moiety

The coupling of glycals with an alkynyl iodide bearing a protected amino alcohol moiety was achieved in the presence of metallic indium under Barbier conditions. It gave functionalized C-glycosyl compounds, precursors of C-glycosyl amino acids with α configuration.