N-bromosuccinimide Research Articles

Sequential Bromination/Dearomatization Reactions of 2-Methoxyphenols en route to Bromo-Substituted ortho-Quinonemonoacetals

AbstractA novel method involving the sequential dibromination and dearomatization of 2-methoxyphenols with N-bromosuccinimide (NBS) is described, providing rapid access to brominated ortho-quinone monoacetals (o-QMAs). Our method demonstrates two notable aspects: (1) the introduction of a bromo group(s) into the aromatic ring and its subsequent conversion into o-QMAs in a single operation, and (2) the use of NBS as a convenient oxidant in oxidative dearomatization reactions.

Kinetic Resolution of Electron-Deficient Bromohydrins via Copper(II)-Catalyzed C-C Bond Cleavage.

Herein, we report a nonenzymatic kinetic resolution (KR) of α,β-unsaturated ketone-derived bromohydrins (up to s = 211) with N-bromosuccinimide (NBS) in the presence of a chiral Cu(II)-Box catalyst via the C-C bond cleavage of the fast reacting enantiomer. A one-pot synthesis-KR approach of the same has also been realized with excellent enantioselectivities (up to 99% ee). Both protocols are found to be effective for a variety of substrates, leading to enantioenriched bromohydrins. The synthetic utility of this process has been demonstrated by exploring a new strategy to convert the resolved enantiomer to an optically active epoxide.

Spectroscopic and Computational Study of the Organocatalytic Umpolung of Bromocations: An Accelerated Stereoselective Dibromination Protocol.

Herein, organocatalytically achieved polarity reversal of cationic bromine is presented. The proven bromocation source N-bromosuccinimide (NBS) was converted to a superior bromoanion reagent by H/Br exchange with a secondary amine, substantiated with spectroscopic and computational evidence. The concept has further been used in a successfully accelerated organocatalyzed dibromination of olefins in a non-hazardous, commercially viable process with a wide range of substrate scope. The reactivity of key entities observed through NMR kinetics and reaction acceleration using only 10 mol % of catalyst account for its major success. The nucleophilicity of the bromoanion was found to be superior in comparison to other nucleophiles such as MeOH and H2 O also the protocol dominates over the competing allylic bromination reaction.

Metal‐Free and NBS‐Mediated Direct Thiol‐Disulfide Exchange Reaction to Access Unsymmetrical Disulfides

AbstractA metal‐free and N‐Bromosuccinimide (NBS)‐mediated direct thiol‐disulfide exchange reaction at room temperature is developed. A variety of unsymmetrical disulfides have been prepared with good to excellent yields. Efficient late‐stage modification of amino acids and drugs demonstrates the utility of this strategy. In addition, easy to operate, broad substrate scope and good functional group tolerance further demonstrate that this reaction provides an essential complementary route to access unsymmetrical disulfides.

Use of Chemical Reagents in Non-fluorescent Pharmaceutical Labels: A Comprehensive Review

Abstract: Spectrofluorimetry is an analytical technique with high sensitivity, specificity, and simplicity, and is very economical. Drugs that lack native fluorescence are derivatized with reagents so that highly fluorescent compounds are formed that can be readily detected by spectrofluorimetry. There are different reagents such as 4-chloro-7-nitrobenz-2-oxa-1,3-diazole (NBD-Cl), N- methylnicotinamide chloride (NMNCl), 9-flurenylmethylchloroformate (FMOC-Cl), dansylchloride (DNS-Cl), 3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH), 1,2- naphthoquinone-4-sulfonate (NQS), 1,4- benzoquinone, 4-fluro-7-nitrobenzofurazan (NBD-F), ninhydrin, benzoin, N- bromo succinimide (NBS), acetylacetone & HCHO, ortho-phthalaldehyde (OPA), and 2-cyanoacetamide used in spectrofluorimetric determination of the drugs that lack native fluorescence. The present review highlights these reagents with principle, reaction conditions, and their applications.

Impact of the bromination of carbazole-based D-π-A organic dyes on their optical and electrochemical properties and visible-light-driven hydrogen evolution.

Brominated dyes, 2C-n (n = 1-5), 3C-4 and 4C-4, were prepared through bromination of three carbazole-based D-π-A dyes, 2C, 3C and 4C with N-bromosuccinimide (NBS). The detailed structures of the brominated dyes were confirmed by 1H NMR spectroscopy and mass spectrometry (MS). The introduction of the Br atom on the 1,8-positon of carbazole moieties led to blueshifted UV-vis and photoluminescence (PL) spectra, increased initial oxidation potentials and enlarged dihedral angles, indicating bromination enhanced non-planarity of the dye molecules. In the hydrogen production experiments, with the increase of the Br content in brominated dyes, the photocatalytic activity increased continuously (except 2C-1). The dye-sensitized Pt/TiO2, 2C-4@T, 3C-4@T and 4C-4@T, exhibited high hydrogen production efficiencies of 655.4, 877.9 and 905.6 μmol h-1 g-1, respectively, which were 4-6-fold higher than those of 2C@T, 3C@T and 4C@T. The enhanced performance of photocatalytic hydrogen evolution was attributed to decreased dye aggregation resulting from the highly non-planar molecular structures of the brominated dyes.

Bromination of indazoles enhanced by organic-dye, visible-light photoredox catalysis

A variety of functionalized indazoles are brominated in moderate to excellent yields using N-bromosuccinimide (NBS) under visible-light activated conditions. A screening of organic dye catalysts resulted in the identification of rose bengal as the most efficient catalyst to use with NBS toward indazoles. According to mechanistic studies, the reaction is speculated to proceed via a single electron oxidation of NBS that amplifies the electrophilicity of the bromine atom, thus leading to enhanced reactivity as a brominating reagent. Differing intermediate indazole species have been observed depending upon the electronic nature of the indazole substituents. The indazole-containing pharmaceutical Benzydamine has been brominated in good yield using the optimized reaction conditions as a demonstration of the bromination method.

Monobromination of 2-hydroxy-6-methoxyacetophenone and studies of the non-covalent interactions in the crystal structure of 3-bromo-2-hydroxy-6-methoxyacetophenone

In principle both position C-3 and C-5 of 2-hydroxy-6-methoxyacetophenone (1) should be able to react with N-bromosuccinimide (NBS), being jointly activated by the meta directing effect of the carbonyl group and strongly so by the ortho-para directing resonance effects of the hydroxyl and methoxy group, respectively. However, this acetophenone derivative reacted with NBS in acetic acid to afford 3-bromo-2-hydroxy-6-methoxyacetophenone (2), exclusively. Intramolecular hydrogen (CO…HO) bonding interaction in ortho-hydroxycarbonyl compounds result in a thermodynamically stable six-membered ring with the resultant complex resembling naphthalene. C-3 becomes the α-position of this naphthaneloid scaffold and therefore the most activated/nucleophilic for electrophilic attack by NBS. The molecular electrostatic potential (MEP) map of substrate 1 shows that C-3 accommodates higher negative charge than that on C-5 making the former centre more susceptible to electrophilic attack. Moreover, density functional theory (DFT) method also predicted the 3-Br isomer to be more stable and favoured than the 5-Br form in acetic acid solution and also in the gas phase. Single crystals of the monobrominated acetophenone 2 were obtained and the structure of this compound was accurately established with the aid of X-ray diffraction technique complemented with spectroscopic (NMR, FT-IR, Uv-Vis and HR-MS) and DFT methods. The intermolecular interaction pattern was studied by Hirshfeld surface analysis along with 2D fingerprint diagrams. The DFT calculations were also performed in the gas phase to correlate the experimental results with the simulated data.

Development of the paper-based colorimetric sensor for simple and fast determination of quercetin in guava leaf extract.

This present study aimed to develop a paper-based colorimetric sensor in the form of paper-microzone plates (PµZP), for simple and fast quercetin determination in guava leaf extract samples. Here, N-bromosuccinimide (NBS) solution was immobilized on the microzone as a sensing probe, where quercetin solution can be dropped on it to form red-purplish color adducts which can be seen by the naked eye or captured using a flatbed scanner. The color intensity of the microzone can be quantified against a blank solution and used as analytical data in scanometric assay. The sensor showed a response time of 8min, a linear interval of 1-10mM with a detection limit at 1.274mM toward quercetin, and exhibited good reproducibility (RSD < 1%) and accuracy (98-99% recovery). The quercetin level of guava leaf extract determined by the PµZP-scanometric method was found comparable with that of the TLC-densitometric method, suggesting its use as an alternative method for quercetin analysis in the guava leaf extract.

Synthesis of chiral salen-MnIII complexes tagged with ionic liquid as recoverable homogeneous catalysts for the oxidative kinetic resolution of (±)-secondary alcohols

New chiral salen ligands tagged with imidazolium based ionic liquids (ILs) were synthesized from the 5-bromopentyl benzoate functionality at C-5 position of salicylaldehyde moiety, N-methylimidazole, and (1R,2R)-1,2-diphenylethane-1,2-diamine/(1R,2R)-cyclohexane-1,2-diamine in 81–92% yields. The chiral salen ligands were further reacted with Mn(OAc)2.4H2O in dry methanol under N2 atmosphere, followed by air oxidation with LiCl to produce the IL tagged chiral salen-MnIII complexes 1(a–c) and 2(a–c) in 79-86% yields. The catalytic activities of these complexes were evaluated in the oxidative kinetic resolution of (±)-1-phenylethanol (8a) with N-bromosuccinimide (NBS) as an oxidizer in biphasic solvent system [H2O - organic solvent (2: 1, v/v)] at 0 °C. The enantioselective oxidation of various (±)-secondary alcohols catalyzed by complex 1c (1 mol%) afforded the chiral secondary alcohols with up to 99% enantiomeric excess and 29.6 krel (selectivity factor) value. The IL tagged chiral salen-MnIII complex 1c was easily recovered with hexane and subsequently reused for five recycles with no significant loss in conversion of (±)-1-phenylethanol (8a) and ee of the resolved product.

Novel Benzylamine Derivatives: Synthesis, Anti-Mycobacterium Tuberculosis Evaluation and Predicted ADMET Properties

Background: Tuberculosis (TB), a disease caused by the bacillus bacteria Mycobacterium tuberculosis is one of the major contributors of ill health in the world. TB is ranked in the top 10 causes of death globally and it is the leading killer associated with a single infectious agent. According to the World Health Organization (WHO), global number of deaths associated with TB have been slowly declining with 1.3 million in reported 2016 and 2017, and 1.2 million reported in 2018 and 2019. Objective: The synthesis, characterisation, biological evaluations, and the prediction of ADMET properties of the novel benzylamine derivatives. Methods: Commercially available reagents and solvents were purchased from Sigma Aldrich and Merck (South Africa). All chemicals were used as received, unless otherwise stated. The synthesised crude compounds were purified by flash silica gel column chromatography (5 – 30% ethyl acetate in hexane). The successful formation and purity of the synthesised compounds was confirmed by NMR, HRMS and melting point. Results: The respective organic compounds were synthesised by treating 3-ethoxysalcyladehyde, 5-bromo-3-ethoxysalcyladehyde, 5-chloro-3-ethoxysalcyladehyde with various aromatic amines and the products were obtained in good to excellent yields. The 1H and 13C NMR spectra of all the products showed the appearance of the methylene signals ranging from 3.88 – 4.68 ppm and 42.25 – 52.57 ppm respectively. Additionally, most compounds showed anti-Mycobacterium tuberculosis activity that ranged between 20 and 28 µM. Conclusion: A total of 36 compounds were synthesised and successfully biologically evaluated against Mycobacterium tuberculosis (Mtb) H37RV strain. All compounds showed activity against Mtb at concentrations of &gt; 20 µM &lt; 28 µM with the exception of compound one that was active against Mtb at higher concentration (MIC90 &gt; 125 µM).

N-Halosuccinimides mediated deprotection of cysteine-S protecting groups for one-pot regioselective synthesis of disulfide bonds in peptides under mild aqueous conditions

Cysteine (Cys) with side chain protected by groups acetamidomethyl (Acm), 1,3-thiazolidine-4-carbonyl (Thz) and t-butyl (tBu) has been commonly used for the synthesis of correct disulfide bonds in peptides. Deprotection of these protected groups can be achieved by use of metal salts under harshly removing conditions. In this work, N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS) are demonstrated to deprotect these protecting groups to directly form an intramolecular disulfide bond in peptide. In addition, all the deprotection reactions were complete within 10 min, conferring fast reaction rates. Moreover, formation of a hydrolytic stable halosulfonium cation was revealed to play a critical role in these deprotection reactions. When NCS and NBS were employed for deprotecting these groups, two disulfide bonds in α-conotoxin SI, α-conotoxin IMI and apamin were synthesized regioselectively by an one-pot approach, rendering satisfied yields.

One-Pot Tandem Oxidative Bromination and Amination of Sulfenamide for the Synthesis of Sulfinamidines.

The sulfinamidines as aza analogues of sulfinamides received limited attention from both organic chemists and pharmaceutical chemists. Herein, we present a tandem oxidative/nucleophilic substitution approach for the synthesis of sulfinamidines in high yield (up to 98%). This cascade reaction method is enabled by N-bromosuccinimide (NBS) as an oxidant and diverse readily available amines as nucleophiles without any additives or catalysts. Notably, this method is highly time-economical, safe to operate, and easy to scale up and has excellent functional group compatibility.

Nonbasic Synthesis of Thioethers via Nickel-Catalyzed Reductive Thiolation Utilizing NBS-Like N-Thioimides as Electrophilic Sulfur Donors.

The nonbasic synthesis of unsymmetrical thioethers via nickel-catalyzed reductive thiolation between aryl(hetero) iodides and N-thioimides is illustrated. N-Bromosuccinimide (NBS)-like N-thioimides were found quite reactive toward thiolation with carbon electrophiles, and a series of structurally varied thioethers were successfully prepared under mild reaction conditions. The transformation was featured with the new application of the NBS-like reagents, good functional group tolerance, and late-stage modification of biologically active scaffolds, thus providing an expeditious and efficient platform to construct polyfunctional thioethers.

Polyhalogenation-Facilitated Spirolactonization at the meta-Position of Phenols

A novel dearomative spirolactonization/polyhalogenation of phenols that employs hypervalent iodine PhICl2 (iodobenzene dichloride) as both an oxidant and chlorine source with an indispensable base, or only using NBS (N-bromosuccinimide) without any additives, is presented. Halide participations are a vital factor in the cascade reaction of 3'-hydroxy-[1,1'-biphenyl]-2-carboxylic acids with good selectivities and reactivities and induced the rapid constructions of multiple C-halogen bonds and directional C═O bonds in a one-step operation under mild conditions. In gaining a good understanding of the mechanism, the increase in number of bromine atoms was inferred rationally from the spirolactonization process, assisted by DFT calculations and high-resolution mass spectrometry. Mechanistic experiments suggest that the formation of a stable carbocation intermediate plays a great role in the migration of oxygen to spirolactonization.

CsPbBr3 in the Activation of the C–Br Bond of CBrX3 (X = Cl, Br) under Sunlight

A newly synthesized green-fluorescent, orthorhombic, bromide-rich, perovskite nanocrystal (Φ ∼ 0.93, τ ∼ 12.5 ns, Eox = +1.6 V) obtained from an unprecedented bromide precursor dibromoisocyanuric acid was found to be an excellent visible-light (sunlight or blue-light-emitting diode (LED)) photocatalyst toward the synthesis of gem-dihaloenones for the first time. The photoactivated CsPbBr3 catalyzed the homolytic cleavage of CBrX3 (X = Cl, Br) to generate the •CX3 radical, which underwent cascaded C–C cross-coupling with terminal alkynes into the corresponding gem-dihaloenones. Radical-trapping experiments and luminescence-quenching studies helped establish a single-electron-transfer (SET) mechanism. Interestingly, other highly stable CsPbBr3 NCs, obtained from N-bromosuccinimide (NBS) and dibromohydantoin (DBHT) precursors, are unable to carry out these transformations. These results not only enrich the CsPbBr3 synthetic methodology but also encourage the research community to develop efficient and cost-effective photocatalytic materials.

Allylic and Retro‐Allylic Rearrangements upon Bromination of 8,9‐Substituted 4,4,6‐Trimethyl‐4H‐Pyrrolo[3,2,1‐ij]Quinoline‐1,2‐Diones. New Aspects and Synthetic Applications

AbstractBromination of 4,4,6‐trimethyl‐4H‐pyrrolo[3,2,1‐ij]quinoline‐1,2‐diones containing an allylic moiety with N‐bromosuccinimide (NBS) in carbon tetrachloride in the presence of benzoyl peroxide (BPO) and in DMF solution were studied. When using an equimolar amount of NBS in the BPO‐CCl4 system, the reaction proceeds regioselectively and standardly at the methyl group at position 6 with the formation of 6‐bromomethylene derivatives. In the NBS‐DMF system, monobromination proceeds at position 5 with the migration of a multiple bond by the allylic rearrangement. With a twofold excess of NBS, in both cases a (Z)‐5‐bromo‐6‐bromomethylene derivative is formed. The 5‐monobromine isomers undergo retro‐allylic rearrangement in N‐ and S‐alkylation reactions, resulting exclusively in 6‐N‐alkyl and 6‐S‐alkyl derivatives, respectively. Similar products are formed by the same reactions with the use of 6‐bromomethylene derivatives.

Synthesis of gem-dibromo 1,3-oxazines by NBS-mediated electrophilic cyclization of propargylic amides.

We present a highly efficient and practical method for synthesizing gem-dibromo 1,3-oxazines through 6-endo-dig cyclization of propargylic amides, using N-bromosuccinimide (NBS) as an electrophilic source. The metal-free reaction can be conducted under mild conditions with good functional group compatibility, delivering excellent yields of the desired products. Mechanistic studies suggest that the reaction proceeds via a double electrophilic attack by NBS on the propargylic amide substrate.

Spectrophotometric Determination of Catecholamine Containing Drugs Using Calcon Dye

Calcon dye has been used for spectrophotometric determination of catecholamine-containing drugs, namely, adrenaline, methyldopa and dopamine in their pure forms and pharmaceutical formulations. The method is based on the oxidation of the above drugs with an excess of Nbromosuccinimide (NBS) in an acidic medium. The residual oxidizing agent bleaches the blackish-brown color of calcon measured at 510 nm. The decolorization of the dye is proportional to the residual amount of NBS, which is proportional to the concentration of the drug. Linear calibration graphs were obtained in the concentration range 0.5-16.0, 2.0-40.0 and 1.036.0 μgmL -1 with molar absorptivity values 1.10×104 , 3.2×103 and 4.3×103 Lmol-1 cm-1 for above drugs, respectively. The method is simple, sensitive, accurate, precise and free from excipients. The developed method was successfully applied to determine the drugs in their pharmaceutical formulations.

Biphasic oxidation of diaquadichloro(1,10‐phenanthroline)chromium(III) by N‐bromosuccinimide and the formation of chromium(IV) and chromium(V)

AbstractThe kinetics of oxidation of diaquadichloro(1,10‐phenanthroline)chromium(III) complex, [CrIII(phen)(H2O)2Cl2]+, by N‐bromosuccinimide (NBS) is biphasic. The first faster step involves the oxidation of Cr(III) to Cr(IV). The second slower step is due to the oxidation of Cr(IV) to Cr(V). The reaction product is isolated and characterized by electron spin resonance (ESR), IR, and elemental analysis. The chromium(V) product is consistent with the formula [CrV(phen)Cl2(O)]Br. The rate constants kf and ks, for the faster and the slower steps respectively, were obtained using an Origin 9.0 software program. Values of both kf and ks, varied linearly with [NBS] at constant reaction conditions. The effect of pH on the reaction rate is investigated over the pH (4.11–6.01) range at 25.0°C. The rate constants kf and ks increased with increasing pH. This is consistent with hydroxo forms of the chromium species being more reactive than the aqua forms. Chromium(III) complexes, more often than not, are inert. The oxidation of the Cr(III) complex to Cr(IV), most likely, proceeds by an outer sphere mechanism. Since chromium(IV) is labile the mechanism of its oxidation to chromium(V) is not certain.