Benzylic Bromination Research Articles

Parallel Paired Photoelectrochemical Bromination of Alkylarenes with Electrochemical Pinacol Coupling.

A paired electrochemical method for paralleling benzylic bromination of alkylarenes under irradiation with reductive pinacol coupling in a divided cell has been developed. A variety of benzyl bromides at the anode and pinacols at the cathode were obtained simultaneously in moderate-to-high faradaic efficiency. This parallel paired electrochemical protocol showed a broad substrate scope and high chemoselectivity as well as high synthetic and faradaic efficiencies.

Photochemical radical benzylic bromination with Br2: Computational modeling of the mechanism and microkinetic

Halogenation of organic compounds is an important functionalization process for further chemical transformation and the benzylic hydrogen is reactive towards the photochemically generated Br atom. This work reports the free energy profile of the several steps of the reaction of the Br atom with toluene leading to benzyl bromide, (dibromomethyl)benzene, and (tribromomethyl)benzene using reliable theoretical B2GP-PLYP method. A detailed microkinetic analysis of the reaction rate and product distribution was also performed. Our analysis points out that polar solvent increases the reaction rate in relation to apolar one. Substitution on the aromatic ring cannot be explained by the electrophilic mechanism in an apolar medium. The reactivity of different benzylic substrates was evaluated, and we have found that the cyano electron-withdrawing group in the aromatic ring retards the reaction, while the ortho-methoxy group, and oxygen and nitrogen atoms bonded to the benzylic carbon, enhance the reaction rate.

Radical-Based Route to Functionalized Tetralin: Formal Total Synthesis of (±)-Hamigeran B

A formal synthetic route to hamigeran B, an antiviral marine natural product with a unique tricyclic molecular architecture, has been developed. The key chemical transformations in the present route include a novel zinc(II)porphyrin-catalyzed photoredox radical cascade cyclization to access a functionalized tetralin, a catalyst-free benzylic radical bromination with NBS by visible-light irradiation, and a samarium(II)-induced cyclization of brominated tetralone possibly via an orthoquinodimethane-like intermediate.

Indium chloride catalysed benzyl bromination using continuous flow technology.

This report describes the development of a water-tolerant green catalyst for benzyl bromination. The catalyst, indium chloride, exhibits high catalytic activity with a variety of toluene derivatives in continuous flow. Good yields (59-77%) were obtained in all the cases. Improved selectivity was observed under flow conditions, when compared to batch operation.

Photocatalytic Oxidative Bromination of 2,6-Dichlorotoluene to 2,6-Dichlorobenzyl Bromide in a Microchannel Reactor.

Photocatalytic oxidative benzylic bromination with hydrobromic acid (HBr) and hydrogen peroxide (H2O2) is a green process for the synthesis of benzyl bromides, but suffers from the risk of explosion when performing it in a batch reactor. This disadvantage could be overcome by running the reaction in a microchannel reactor. In this work, a green and safe process for the synthesis of 2,6-dichlorobenzyl bromide (DCBB) was developed by conducting selective benzylic bromination of 2,6-dichlorotoluene (DCT) with H2O2 as an oxidant and HBr as a bromine source in a microchannel reactor under light irradiation. The reaction parameters were optimized, and the conversion of DCT reached up to 98.1% with a DCBB yield of 91.4% under the optimal reaction conditions.

Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination

We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associate...

Reactivity of substrates with multiple competitive reactive sites toward NBS under neat reaction conditions promoted by visible light

Regioselectivity of visible-light-induced transformations of a range of (hetero)aryl alkyl-substituted ketones bearing several competitive reactive sites (α-carbonyl, benzyl and aromatic ring) with N-bromosuccinimide (NBS) was studied under solvent-free reaction conditions (SFRC) and in the absence of inert-gas atmosphere, radical initiators and catalysts. An 8-W energy-saving household lamp was used for irradiation. Heterogeneous reaction conditions were dealt with throughout the study. All substrates were mono- or dibrominated at the α-carbonyl position, and additionally, some benzylic or aromatic bromination was observed in substrates with benzylic carbon atoms or electron-donating methoxy groups, respectively. Surprisingly, ipso-substitution of the acyl group with a bromine atom took place with (4-methoxynaphthyl) alkyl ketones. While the addition of the radical scavenger TEMPO (2,2,6,6-tetramethylpiperidin-1-yloxy) decreased the extent of α- and ring bromination, it completely suppressed the benzylic bromination and α,α-dibromination with NBS under SFRC.

Kinetic Investigations To Enable Development of a Robust Radical Benzylic Bromination for Commercial Manufacturing of AMG 423 Dihydrochloride Hydrate

During development of a radical benzylic bromination, observation of polymerized by-products and variation in isolated yields warranted an in-depth mechanistic investigation to ensure process under...

A Safe and Green Benzylic Radical Bromination Experiment

Radical chemistry is an essential part of the organic chemistry curriculum. Free radical halogenation experiments provide an excellent opportunity to introduce important topics related to the outcome and mechanism of organic reactions. In this communication, a green photochemically activated benzylic bromination of p-toluic acid is described. In contrast with previous versions of this reaction, visible light provides the energy necessary to homolytically cleave the Br—Br bond and initiate the radical cascade. Thus, photochemical activation allows a safer, faster, and cheaper alternative to chemical free radical initiators. Furthermore, the reaction is conveniently performed in environmentally friendly acetonitrile, as a replacement for toxic and ozone-depleting chlorinated solvents, such as the usual carbon tetrachloride.

Enhancement of alkaline conductivity and chemical stability of quaternized poly(2,6-dimethyl-1,4-phenylene oxide) alkaline electrolyte membrane by mild temperature benzyl bromination.

A series of quaternized polyphenylene oxide (QPPO) based alkaline electrolyte membranes with different degrees of quaternization were synthesized via a benzyl bromination method at mild temperature (75 °C). Quite a high hydroxide conductivity under the reduced water uptake and swelling was exhibited by this method. When the degree of bromination measured from 1H NMR analysis was 30%, the corresponding hydroxide ion conductivity was 0.021 S cm−1. The chemical stability of the QPPO membranes was excellent, showing only 3% weight loss in 3 M NaOH solution during 1 month. The fuel cell performance test under H2/O2 exhibited the power density of 77 mW cm−2 and the current density of 190 mA cm−2 at 70 °C. Such excellent properties of QPPO membranes resulted from the achievement of the quaternization at the benzyl position, specifically.

Continuous photochemical benzylic bromination using in situ generated Br2: process intensification towards optimal PMI and throughput

Using a Br2 generator in flow process intensified conditions has been developed for photochemical benzylic bromination on a kg scale.

Comb-shaped 2-Methylimidazolium Poly(arylene ether sulfone) Anion Exchange Membranes with High Alkaline Stability

A series of comb-shaped poly(arylene ether sulfone)s containing pendant 2-methyl-3-alkylimidazolium group(ImPAES-Cx, x=1, 6, 10) was prepared and characterized as novel anion exchange membranes. These Im-PAES-Cx membranes were obtained by benzylic bromination and imidazolium functionalization. The characteristic nano-phase separation structure was formed in membranes with longer alkyl side chains, as confirmed by small-angle X-ray scattering. The nano-phase separation structures endowed ImPAES-Cx membranes with improved ionic conductivity, dimensional stability(at least 60% decrease water uptake and swelling ratio at 60 °C) and mechanical properties, together with excellent alkaline stability. Especially, ImPAES-C6 membranes possessed enhanced hydroxide conductivity and chemical stability simultaneously. These results suggest that it is a feasible strategy to introduce appropriate length of alkyl side chains into anion exchange membranes(AEMs) to improve the performance.

Photochemical benzylic bromination in continuous flow using BrCCl3 and its application to telescoped p-methoxybenzyl protection.

BrCCl3 represents a rarely used benzylic brominating reagent with complementary reactivity to other reagents. Its reactivity has been revisited in continuous flow, revealing compatibility with electron-rich aromatic substrates. This has brought about the development of a p-methoxybenzyl bromide generator for PMB protection, which was successfully demonstrated on a pharmaceutically relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br space-time-yield of 1.27 kg L-1 h-1.

Mechanically robust poly[vinyl-(4-benzyl-N,N,N-trimethylammonium bromide) ketone]/polybenzimidazole blend membranes for anion conductive solid electrolytes

In this study, a novel poly[vinyl-(4-benzyl-N,N,N-trimethylammonium bromide) ketone] (QA-PVBK) homopolymer was synthesized by conventional free-radical polymerization, followed by benzyl bromination, and in-situ quaternization reaction, successively. Blend membranes were further constructed between QA-PVBK and commercially available polybenzimidazole (PBI), as novel anion exchange membrane materials. Owing to the short repeating unit of QA-PVBK, the ion-clusters for the ion transport were highly aggregated on the microscale, which significantly contributed to the excellent hydroxide conductivity of the blend membranes. The PBI was introduced as a physical reinforcement, strengthening the membranes’ robustness and suppressing excessive swelling. Membrane PBI/QA-PVBK-OH(70%), with the QA-PVBK-OH (hydroxide form) content of 70% over the entire membrane matrix, exhibited a high hydroxide conductivity of 50.8 mS cm−1 at 60 °C, and, consequently, a good peak power density of 170.6 mW cm−2 at 60 °C/100% relative humidity condition in a H2/O2 single cell test. The blend membranes also demonstrated acceptable chemical stability towards the alkaline condition (1 M NaOH at 60 °C) with the residual conductivity over 59.4% after 168 h. In light of these promising results, the present study demonstrates a facile blending process for simultaneously addressing the ion conductivity and mechanical properties of anion exchange membranes.

Continuous Flow Photochemical Benzylic Bromination of a Key Intermediate in the Synthesis of a 2‐Oxazolidinone

AbstractA continuous flow procedure for the benzylic photobromination of methyl N,N‐bis (tert‐butoxycarbonyl) phenylalaninate is presented. This photochemical transformation generating the brominated intermediate is the critical step in the synthesis of the oxazolidinone methyl (4S,5R)‐3‐N‐tert‐Butoxycarbonyl‐5‐phenyl‐1,3‐oxazolidin‐2‐oxo‐4‐carboxylate, a key intermediate for the preparation of active pharmaceutical ingredients. The reaction was optimized in three continuous flow photoreactors: A self‐made reactor based on a T5 8 W black light lamp, as well as the commercially available VapourTec® UV‐150 and Corning® Advanced‐Flow™ reactors, both equipped with LED light sources. Under optimal conditions, concentrated solutions (95 g/L) of the starting material could be processed on a multi‐gram scale, providing high conversion (96 %) within 7 min at 30 °C, using 2 equivalents of N‐bromosuccinimide (NBS).

Benzylic Functionalisation of Phenyl all-cis-2,3,5,6-Tetrafluorocyclohexane Provides Access to New Organofluorine Building Blocks.

Selectively fluorinated hydrocarbons continue to attract attention for tuning pharmacokinetic properties in agrochemical and pharmaceutical discovery programmes. This study identifies benzylic bromination of phenyl all-cis-2,3,5,6-tetrafluorocyclohexane 2 as a key reaction for accessing building blocks containing the all-cis-2,3,5,6-tetrafluorocyclohexane ring system. These cyclohexanes are of interest as the fluorines are only on one face of the cyclohexane, and this imparts an unusual polar aspect, very different to an otherwise hydrophobic cyclohexane. Ritter type reactions of benzyl bromide 4 with DMF and acetonitrile generated the corresponding benzyl alcohol 6 and benzylacetamide 7 respectively. Benzylacetamide 7 was hydrolysed to benzyl amine 8 and syn-amino-alcohol 9, and separately the phenyl ring was oxidatively cleaved to furnish carboxylic acid acetamide 10, which after hydrolysis gave the tetrafluorocyclohexyl amino acid 11. A trans-halogenation of benzylbromide 4 with AgF2 gave benzyl fluoride 13. Oxidative cleavage of the aryl ring then gave pentafluorocyclohexyl carboxylic acid 14. This carboxylic acid was readily converted to amides 23-26 and the preferred conformations of these α-fluoroamides were explored by DFT, X-ray structure and 1 H-19 F HOESY NMR analysis.

A Detailed Study of Irradiation Requirements Towards an Efficient Photochemical Wohl‐Ziegler Procedure in Flow

AbstractA platform has been developed to enable standardization of light sources, allowing consistent scale‐up from high‐throughput screening in batch to flow, using the same pseudo‐monochromatic light source. The impact of wavelength and light intensity on a photochemical reaction was evaluated within this platform using the Wohl‐Ziegler benzylic bromination of 4‐methyl‐3‐(trifluoromethyl)benzonitrile with N‐bromosuccinimide as a model system. It was found that only 40 % of the maximum light intensity was required while still maintaining reaction rate, allowing more reliable temperature control and lower energy consumption. The optimized reaction conditions were subsequently applied to a range of synthetically relevant (hetero)aromatic compounds under continuous conditions, exploring the scope of the process within a mild and scalable procedure.

Synthesis and characterization of poly(ether sulfone) block copolymers containing pendent quaternary ammonium- and imidazolium groups as anion exchange membranes

A class of poly(ether sulfone) (FPES) block copolymers containing pendent quaternary ammonium (QA) and imidazolium (IM) groups were prepared as anion exchange membranes by reaction involving nucleophilic substitution, benzylic bromination, quaternization and anion exchange with hydroxide ions. Highly reactive hexafluorobenzene (HFB) was utilized as a linkage group for relatively low temperature (e.g., 105°C) coupling between hydrophobic and precursor hydrophilic oligomer blocks. The phase separated morphology, water uptake, swelling ratio, conductivity, and chemical stability of the resultant copolymer membranes were also investigated. The hydroxide conductivity of the ionomer membranes (IEC~2.0 mequiv./g) was 21–22mS/cm and 56–63mS/cm at 30°C and 80°C respectively. The FPES-IM membrane showed relatively very good dimensional integrity in high pH solution, whereas under the similar condition the FPES-QA membrane broke into pieces. However, the degradation of the imidazolium cations in FPES-IM was relatively faster in comparison to the ammonium cations in FPES-QA.

Benzylic bromination catalyzed by triphenylphosphine selenide via Lewis basic activation

The synthesis of benzyl bromides was achieved under mild reaction conditions using N-bromosuccinimide as a bromine source and triphenylphosphine selenide as a catalyst. These conditions were compatible with a variety of substrates including boronic esters, protected amines to give imines, and carboxylic acids (to give phthalides when ortho to the benzylic center). A preliminary mechanistic investigation utilizing calculated bond dissociation energies (BDE) is employed to rationalize how a Lewis base can activate a radical mechanism.

Benzylic Brominations with N-Bromosuccinimide in 1,2-Dichlorobenzene: Effective Preparation of (2-Bromomethyl-phenyl)-Methoxyiminoacetic Acid Methyl Ester

The benzylic bromination of methoxyimino-o-tolyl-acetic acid methyl ester (1) into (2-bromomethyl-phenyl)-methoxyimino-acetic acid methyl ester (2) using N-bromosuccinimide in the presence of 2,2'-azobisisobutyronitrile in various reaction solvents were investigated. The efficiency of the reaction was found to be sensitive to the kind of reaction solvents. We found the benzylic bromination of 1 to 2 can be performed in 1,2-dichlorobenzene as reaction solvent superior to the classic Wohl-Ziegler procedure in both reaction time and isolated yield (8 h vs 12 h, 92 vs 79%). This system provides clean, rapid, and high-yielding reactions with replacement of conventional solvents, such as tetrachloromethane, by less-toxic 1,2-dichlorobenzene.