[128-08-5]  · C4H4BrNO2  · N-Bromosuccinimide  · (MW 177.99)

(radical bromination of allylic and benzylic positions; electrophilic bromination of ketones, aromatic and heterocyclic compounds; bromohydration, bromoetherification, and bromolactonization of alkenes)

Alternate Names: NBS; 1-bromo-2,5-pyrrolidinedione.

Physical Data: mp 173-175 °C (dec); d 2.098 g cm-3.

Solubility: sol acetone, THF, DMF, DMSO, MeCN; slightly sol H2O, AcOH; insol ether, hexane, CCl4 (at 25 °C).

Form Supplied in: white powder or crystals having a faint odor of bromine when pure; widely available.

Purification: in many applications the use of unrecrystallized material has led to erratic results. Material stored for extended periods often contains significant amounts of molecular bromine and is easily purified by recrystallization from H2O (AcOH has also been used). In an efficient fume hood (caution: bromine evolution), an impure sample of NBS (200 g) is dissolved as quickly as possible in 2.5 L of preheated water at 90-95 °C. As filtration is usually unnecessary, the solution is then chilled well in an ice bath to effect crystallization. After most of the aqueous portion has been decanted, the white crystals are collected by filtration through a bed of ice and washed well with water. The crystals are dried on the filter and then in vacuo. The purity of NBS may be determined by the standard iodide-thiosulfate titration method.

Handling, Storage, and Precautions: should be stored in a refrigerator and protected from moisture to avoid decomposition. One of the advantages of using NBS is that it is easier and safer to handle than bromine; however, the solid is an irritant and bromine may be released during some operations. Therefore, precautions should be taken to avoid inhalation of the powder and contact with skin. All operations with this reagent are best conducted in an efficient fume hood. In addition, since reactions involving NBS are generally quite exothermic, large-scale operations (>0.1 mol) should be approached with particular caution.


N-Bromosuccinimide is a convenient source of bromine for both radical substitution and electrophilic addition reactions. For radical substitution reactions, NBS has several advantages over the use of molecular Bromine, while 1,3-Dibromo-5,5-dimethylhydantoin is another reagent of use. N-Chlorosuccinimide and N-Iodosuccinimide generally do not facilitate analogous substitution reactions. For electrophilic substitutions, Bromine, N-Bromoacetamide, Bromonium Di-sym-collidine Perchlorate, 1,3-Dibromoisocyanuric Acid, and 2,4,4,6-Tetrabromo-2,5-cyclohexadienone also have applicability and the analogous halogenation reactions are generally possible using NCS, NIS, and I2. Possible impurities generated during NBS brominations include conjugates of succinimide and, if basic conditions are employed, b-alanine (formed by the Hofmann reaction) and its derivatives may be isolated.

Allylic Bromination of Alkenes.2

Standard conditions for allylic bromination involve refluxing of a solution of the alkene and recrystallized NBS in anhydrous CCl4 using Dibenzoyl Peroxide, irradiation with visible light (ordinary 100 W light bulb or sunlamp3), or both to effect initiation. Both NBS and the co-product succinimide are insoluble in CCl4 and succinimide collects at the surface of the reaction mixture as the reaction proceeds.4 High levels of regioselectivity operate during the hydrogen-abstraction step of the chain mechanism, such that allylic methylene groups are attacked much more rapidly than allylic methyl groups.5 However, a thermodynamic mixture of allylic bromides is generally isolated since both the allylic radical and the allylic bromide are subject to isomerization under the reaction conditions.6 High levels of functional group selectivity are characteristic of this reaction, for example alkenic esters may be converted to allylic bromides prior to intramolecular cyclization (eq 1).7 Brominations of a,b-unsaturated esters (eq 2)8 and lactones (eq 3) are also successful.9

Benzylic Bromination of Aromatic Compounds.

Using the conditions described above, NBS also effects the bromination of benzylic positions.10 Bromine is also regularly used for benzylic bromination (eq 4);11 however, many functional groups are sensitive to the generation of HBr during the reaction, including carbonyl groups which suffer competing acid-catalyzed bromination. These considerations render NBS as the reagent of choice for bromination of polyfunctional aromatic compounds. Selectivity can be anticipated with polyfunctional molecules based on the predicted stabilities of the radical intermediates (eq 5).12 Accordingly, the use of NBS allows the bromination of alkyl groups attached to sensitive heterocyclic compounds (eq 6).13 Complications which may arise from this method include gem-dibromination (eq 7)14 of methyl substituents as well as in situ elimination of the product benzylic bromide (see also 1,3-Dibromo-5,5-dimethylhydantoin).

The regioselective cleavage of benzylidene acetals using NBS has been used widely in the synthesis of natural products from carbohydrates (eq 8)15 and other chiral materials (eq 9).16 It is rather important that the reaction be conducted in anhydrous CCl4 (passage through activated alumina is sufficient), since in the presence of water the hydroxy benzoate is formed.17 Barium carbonate is generally added to maintain anhydrous and acid-free conditions, and the addition of Cl2CHCHCl2 often improves solubility of the substrate. Selectivity is usually very high in cases in which a primary bromide can be produced, but may also be obtained in systems such as shown in eq 10.18 As alkoxy substituents serve to further stabilize the adjacent radicals, these reactions proceed with high selectivity in the presence of other functional groups. Other applications in the carbohydrate field include the cleavage of benzyl ethers and benzyl glycosides (to the corresponding glycosyl bromides) and the bromination of pyranoses in the 5-position.19

Unsaturation and Aromatization Reactions.20

Unsaturated aldehydes, esters, and lactones can be accessed via strategies involving radical bromination and subsequent elimination. The allylic bromination of unsaturated lactones may be followed by elimination with base to obtain dienoic and trienoic lactones (eqs 11 and 12).21 Conversion of an aldehyde to the enol acetate allows the radical bromination at the Cb position to proceed smoothly and, upon ester hydrolysis, the a,b-unsaturated aldehyde is obtained (eq 13).22

The direct bromination of b-alkoxylactones at the b position initially generates the a,b-unsaturated lactones (eq 14); however, the required radical abstraction is not so facile and further bromination of the a,b-unsaturated lactone proceeds competitively to afford the mono- and dibrominated products.23 NBS is also used for the oxidative aromatization of polycyclic compounds, including steroids and anthraquinone precursors (eq 15).24

a-Bromination of Carbonyl Derivatives.

Although simple carbonyl derivatives are not attacked in the a-position under radical bromination conditions, substitution by electron-donating groups stabilizes the radical intermediates by the capto-dative effect25 and thus facilitates the substitution reaction which has been applied to a number of useful synthetic strategies. Protected glycine derivatives are easily brominated by NBS and benzoyl peroxide in CHCl3 or CCl4 at reflux to afford the corresponding a-bromoglycine derivatives.26 These compounds are stable precursors of N-acyliminoacetates, which may be alkylated by silyl enol ethers in the presence of Lewis acids, organometallic reagents, and other nucleophiles to afford novel a-amino acids (eq 16).27 Diketopiperazines and related heterocycles are also substituted in good yields (eq 17).28 Furthermore, in contrast to aldehydes which undergo abstraction of the aldehydic hydrogen (see below), O-trimethylsilylaldoximes are readily brominated at the a-position under radical bromination conditions and can be converted to substituted nitrile oxides (O-trimethylsilylketoximes react similarly).29

The use of NBS in the presence of catalytic Hydrogen Bromide has proven to be more convenient than Br2 for the conversion of acid chlorides to a-bromo acid chlorides.30 The reaction of the corresponding enolates, enol ethers, or enol acetates with NBS (and other halogenating agents) offers considerable advantages over direct acid-catalyzed halogenation of ketones and esters.31 Although both reagents may afford the a-brominated products in high yields, NBS is more compatible than is bromine with sensitive functional groups and has been used in the asymmetric synthesis of a-amino acids.32 The bromination of cyanoacetic acid proceeds rapidly with NBS to afford dibromoacetonitrile33 and, similarly, b-keto esters, b-diketones, and b-sulfonyl ketones may be reacted with NBS in the presence of base to afford the products of bromination and in situ deacylation (see N-Chlorosuccinimide).34 (5E)-Bromovinyluridine derivatives are readily prepared by bromodecarboxylation of the corresponding a,b-unsaturated acids with NBS (eq 18).35

Reaction with Vinylic and Alkynic Derivatives.

NBS is a suitable source of bromine for the conversion of vinylcopper and other organometallic derivatives to the corresponding vinyl bromides.36 Vinylsilanes, prepared from the corresponding 1-trimethylsilylalkyne by reduction with Diisobutylaluminum Hydride, can be isomerized from the (Z) to the (E) geometry by irradiation with NBS and Pyridine, thus making (E)-vinylsilanes readily available stereoselectively in three steps from the corresponding alkyne (eq 19).37 Allylsilane can be brominated by NBS under radical conditions, whereas more reactive allylsilanes are bromodesilated by NBS in CH2Cl2 at -78 °C.38 1-Bromoalkynes can be prepared under mild conditions by reaction with NBS in acetone in the presence of catalytic Silver(I) Nitrate.39

Bromination of Aromatic Compounds.

Phenols, anilines, and other electron-rich aromatic compounds can be monobrominated using NBS in DMF with higher yields and higher levels of para selectivity than with Br2.40 N-Trimethylsilylanilines and aromatic ethers are also selectively brominated by NBS in CHCl3 or CCl4.41 N-Substituted pyrroles are brominated with NBS in THF to afford 2-bromopyrroles (1 equiv) or 2,5-dibromopyrroles (2 equiv) with high selectivity, whereas bromination with Br2 affords the thermodynamically more stable 3-bromopyrroles.42 The use of NBS in DMF also achieves the controlled bromination of imidazole and nitroimidazole.43 Thiophenes are also selectively brominated in the 2-position using NBS in acetic acid-chloroform.44

Bromohydration, Bromolactonization, and Other Additions to C=C.45

The preferred conditions for the bromohydration of alkenes involves the portionwise addition of solid or predissolved NBS (recrystallized) to a solution of the alkene in 50-75% aqueous DME, THF, or t-butanol at 0 °C. The formation of dibromide and a-bromo ketone byproducts can be minimized by using recrystallized NBS. High selectivity for Markovnikov addition and anti stereochemistry results from attack of the bromonium ion intermediate by water. Aqueous DMSO can also be used as the solvent; however, since DMSO is readily oxidized under the reaction conditions, significant amounts of the dibromide byproduct may be produced.46,47 In the bromohydration of polyalkenic compounds, high selectivity is regularly achieved for attack of the most electron-rich double bond (eq 20).48 With farnesol acetate, squalene, and other polyisoprenes, choice of the optimum proportion of water is used to effect the selective bromohydration at the terminal double bond (eq 21),49 and the two-step sequence shown is often the method of choice for the preparation of the corresponding epoxides.50

Bromoetherification of alkenes can be achieved using NBS in the desired alcohol as the solvent. The reaction of 1,3-dichloropropene with NBS in methanol yields an a-bromo dimethyl acetal in the first step in a convenient synthesis of cyclopropenone.51 Using propargyl alcohol the reaction depicted in eq 22 has been extended to an annulation method for the synthesis of a-methylene-g-butyrolactones.52 Intramolecular bromoetherification and bromoamination reactions are generally very facile (eq 23).53 In natural products synthesis, bromoetherification has been used for the synthesis of cyclic ethers (by subsequent debromination, see Tri-n-butylstannane) and for the protection of alkene appendages as cyclic bromoethers (regenerated by reaction with zinc).54

NBS is also an effective reagent for bromolactonization of unsaturated acids and acid derivatives with the same high stereo- and Markovnikov selectivity (see also Iodine). Dienes, such as the cycloheptadiene derivative shown, may react exclusively via syn-1,4-addition (eq 24).55 Alkynic acids are converted to the (E)-bromo enol lactones by NBS in a biphasic medium, whereas the combination of bromine and silver nitrate afford the (Z)-bromo enol lactones (eq 25).56 a,b-Unsaturated acylprolines react with NBS in anhydrous DMF to afford the corresponding bromolactones having diastereomeric excesses up to 93%, which can be converted to chiral a-hydroxy acids by debromination followed by acidic hydrolysis (eq 26).57 In contrast to alkenic amides, which generally react with NBS to afford bromolactones (via the cyclic iminoether derivatives), alkenic sulfonamides readily undergo cyclization on nitrogen when reacted with NBS to afford the bromosulfonamides in high yields.58 N-Methoxyamides have also proven effective for bromolactamization, leading to diketopiperazines (eq 27)59 (see also Bromonium Di-sym-collidine Perchlorate).

Addition of NBS to an alkene in the presence of aqueous Sodium Azide affords fair yields of the corresponding b-bromoazides, which can be converted by Lithium Aluminum Hydride reduction to aziridines.60 Intermolecular reactions of alkenes with NBS and weaker nucleophiles can be achieved if conducted under anhydrous conditions to avoid the facile bromohydration reaction. In this manner, bromofluorination of alkenes has been extensively studied using Pyridinium Poly(hydrogen fluoride), triethylammonium dihydrogentrifluoride or tetrabutylammonium hydrogendifluoride as the fluoride ion source.61

Oxidation and Bromination of Other Functional Groups.

Conjugate bases of other functional groups can be a-brominated with NBS. Nitronate anions of aliphatic nitro compounds react with NBS to afford the gem-bromonitro compounds in high yield.62 The a-bromination of sulfoxides can be performed in the presence of pyridine and proceeds more satisfactorily using NBS in the presence of catalytic Br2 than with either reagent alone.63 NBS also reacts with sulfides to afford sulfoxides when methanol is used as a solvent, or to form a-bromo sulfides in anhydrous solvents.64 NBS is a favored reagent for the deprotection of dithianes and dithioacetals to regenerate carbonyl groups (eq 28)65 (see also N-Chlorosuccinimide and 1,3-Diiodo-5,5-dimethylhydantoin).

In polar media, NBS effectively oxidizes primary and secondary alcohols to carbonyl compounds via hypobromite or alkoxysuccinimide intermediates. Although this transformation is more commonly effected by the use of chromium reagents or activated Dimethyl Sulfoxide, the most notable application of NBS and related reagents lies in its selectivity for the oxidation of axial vs. equatorial hydroxy groups in steroid systems (see N-Bromoacetamide).66 Often, a single secondary alcohol may be converted to the ketone in the presence of many other alcohol groups.

Under radical conditions, aldehydes are readily oxidized by NBS to acid bromides.67 The oxidation of aldoximes to nitrile oxides using NBS and Triethylamine in DMF is superior to the use of aqueous hypochlorite.68 Tosylhydrazones are cleaved by reaction with NBS in methanol,69 and hydrazines and hydrazides are oxidized to azo compounds.70

Related Reagents.

N-Bromosuccinimide-Dimethylformamide; N-Bromosuccinimide-Dimethyl Sulfide; N-Bromosuccinimide-Hydrogen Fluoride; N-Bromosuccinimide-Sodium Azide; Triphenylphosphine-N-Bromosuccinimide.

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Scott C. Virgil

Massachusetts Institute of Technology, Cambridge, MA, USA

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