Redefining N‐Bromosuccinimide: Chemistry Beyond Allylic Bromination

ABSTRACT

Bromination or subsequent reactions followed by bromination have become easier and more convenient after the invention of N‐bromoamides. As a brominating agent, molecular bromine has limitations like decomposition, volatility, high reactivity, and toxicity. Hence, N‐bromoamides have emerged as a widely used laboratory reagent for bromination. Among the other N‐bromoamides, N‐bromosuccinimide (also called NBS) is the most commonly used laboratory reagent. Apart from its most common use in allylic/benzylic bromination and as an electrophilic brominating agent, this reagent has paved its way through various rearrangements, hydrolysis, multicomponent reaction, C─C bond cleavage of β‐keto amides, benzylic bromination, stereoselective synthesis, oxidation, catalysis, aromatization, and one‐pot tandem reaction. The present review will highlight applications of NBS in organic chemistry apart from bromination. It will focus on how this reagent facilitates various chemical transformations, thereby proving its versatility beyond a mere brominating agent.

NBS is known for its allylic bromination in various organic synthesis. Despite its brominating agent capability, its uses in the rearrangements, hydrolysis, cyclization, oxidation, catalysis, aromatization, and one‐pot reactions were compiled in this review till year 2025. This compilation helps other researchers to explore the multipurpose reachability of this tiny agent.

1. Introduction

N‐Bromosuccinimide (NBS) is a convenient, inexpensive, and widely available crystalline compound (m.p. 153°C) that has become a staple reagent in synthetic organic chemistry. Typically prepared by the reaction of succinimide with bromine in alkaline ice‐water medium, NBS was first introduced by Ziegler [1, 2] and coworkers in the late 1930s in their seminal studies on allylic bromination. Since then, it has steadily gained prominence as a safer and more selective alternative to elemental bromine and bromine water. Unlike bromine, which is volatile, corrosive, and prone to uncontrolled over‐bromination, NBS is a stable crystalline solid that can be weighed accurately, stored safely, and dispensed reproducibly. Its solid‐state nature and milder release of bromine equivalents account for its superior handling, higher chemoselectivity, and wider synthetic applicability. Structurally, the succinimide framework stabilizes the N–Br bond and confers a unique dual reactivity to NBS. Under radical conditions, homolysis generates bromine radicals, enabling efficient allylic and benzylic brominations. In contrast, under ionic conditions, the polarized N–Br bond provides an electrophilic bromine source for olefin, aromatic, and carbonyl brominations. This mechanistic versatility has made NBS indispensable not only in selective halogenation but also in a broad spectrum of transformations. While the mechanistic pathway of bromination, whether bromination is mediated by the bromine radical or succinimidyl radical‐ remains a subject of debate, the synthetic utility of NBS is beyond question [3, 4, 5, 6, 7, 8, 9, 10, 11, 12].

Beyond conventional bromination chemistry, NBS‐mediated processes often proceed through bromination–substitution sequences, enabling hydroxylation, methoxylation, and acetoxylation of unsaturated systems. The reagent has further expanded its role in modern synthesis by facilitating diverse transformations such as bromo‐aziridination, bromo‐fluorination, and amino‐bromination, when combined with suitable nucleophilic partners, all of which have already been well documented [12]. More recently, NBS has found application in oxidative transformations, rearrangements, cyclizations, and even catalytic conversions, underscoring its adaptability as a synthetic mediator.

Nevertheless, the utility of NBS is not without limitations. Issues such as limited solubility in nonpolar solvents, competitive radical pathways, and the occasional generation of unwanted byproducts have prompted the development of modified protocols, greener reaction media, and catalytic systems to expand its efficiency and reliability.

The primary objective of this review is to present an in‐depth exploration of the multifaceted chemistry of NBS. By analyzing its dual radical–electrophilic reactivity, we aim to critically evaluate the methodologies that harness its power. This broader perspective highlights how NBS has evolved far beyond a simple halogenating agent, serving instead as a versatile and indispensable reagent in the design of innovative synthetic strategies across organic chemistry.

1.1. General Mode of Action of NBS

N‐Bromosuccinimide (NBS) can act either as a source of a bromonium ion or as a bromine radical, depending on the reaction conditions. Substrates containing multiple bonds or nucleophilic functional groups typically react with NBS through electrophilic addition of a bromonium ion. This process leads to the formation of a cyclic bromonium intermediate, which may subsequently undergo rearrangement or nucleophilic substitution. In contrast, when NBS acts as a source of bromine radicals, bromination preferentially occurs at the allylic position of the substrate. These two pathways are commonly represented as Mode A and Mode B (Figure 1).

FIGURE 1.

Probable mode of action of NBS.

The rearrangement reactions usually exploit NBS as an electrophilic source or a source of bromonium ion, as shown in various mechanisms.

2. NBS‐Mediated Rearrangement Reactions

Under this category, we will discuss the different rearrangement reactions observed through NBS.

2.1. Rearrangement of 1‐Cyclopropylallenes and 2,3‐Allenols Using NBS

The brominium ions generated from NBS are utilized in rearrangement reactions for their electrophilic properties. When NBS is present, it facilitates specific transformations of the substrate along with bromination. When 1‐cyclopropylallenes are exposed to NBS in acetone and water as the medium, the allene system is polarized by the bromonium ion, causing the strained cyclopropyl ring to open with the attack of a water molecule. This results in the formation of alternate double bonds, yielding 5‐bromohexa‐3,5‐dien‐1‐ols in moderate to good yields [13] (Scheme 1).

SCHEME 1.

Rearrangement reaction in cyclopropane.

Similarly, 2,3‐allenols undergo rearrangement in the presence of NBS in CH₃CN and water as solvents. The type of rearrangement depends on the substituent at the C4 position. If both substituents are H, the bromonium ion facilitates semi‐pinacolone rearrangement, leading to the migration of one substituent from C1 to C2. On the other hand, if either substituent R₁ or R₂ at C1 is an alkyl group, the rearrangement results in the formation of 1,2‐allenylketones. When at least one alkyl substituent is present at the 4‐position of tertiary 2,3‐allenols, an electrophilic reaction was observed with NBS under the same conditions to produce 3‐bromo‐2,5‐dihydrofurans [14] (Scheme 2).

SCHEME 2.

Rearrangement reaction in allenes.

2.2. Preparation of Bromo‐allenes From Propargyl Alcohols

Jiang et al. [15] devised a convenient pathway to prepare bromo‐allenes from propargyl alcohols using a combination of NBS and dimethyl sulfide. In this process, dimethyl sulfide undergoes bromination followed by the attack of the hydroxyl group of the propargyl alcohol. The released bromide ion subsequently adds to the alkyne group, leading to the shifting of the double bond and the consequent formation of bromo‐allene observed, as illustrated in (Scheme 3).

SCHEME 3.

Synthesis of allenes.

Another intriguing approach for preparing bromo‐allenes from propargyl alcohols is reported by Bao and coworkers [16], who employed a combination of NBS and triphenylphosphine (Scheme 4).

SCHEME 4.

Synthesis of allenes.

Fandrick demonstrated an alternative method for synthesizing bromoallene by performing regioselective bromination of propargyl diethanolamine (DEA) boronates [17] (Scheme 5). Treatment of propargyl DEA boronates with NBS at 20°C for 3 h resulted in the formation of allenyl bromide.

SCHEME 5.

Synthesis of allenes and rearranged alkynes.

Furthermore, Arai et al. conducted a reaction of (silyloxy)allenes, obtained during the reaction with NBS, and reported the synthesis of tetrasubstituted α‐bromo‐β‐cyanoenones in high yields with good Z‐selectivity [18] (Scheme 6).

SCHEME 6.

Synthesis of enones.

Using NBS in conjunction with a combination of two metal complexes, namely Ph₃PAuNTf₂ and MoO₂(acac)₂, along with Ph₃PO (5−10 mol %) as an additive [19], resulted in the formation of α‐bromo α, β‐unsaturated carbonyl compounds from propargylic alcohols (Scheme 7). Rosenthal et al. [20] discovered a method to obtain α‐bromoacylsilanes from (trimethylsilyl)acetylenes through a hydroboration‐oxidation reaction, followed by treatment of the intermediate boronated ester with NBS (Scheme 8).

SCHEME 7.

Rearrangement reaction in propargylic alcohols.

SCHEME 8.

Synthesis of α‐bromoacylsilanes.

2.3. Rearrangements in Cyclic Compounds Involving NBS

Ring expansions or intramolecular rearrangements can be generalized as given in Figure 2, which shows that NBS, by rendering brominium ion triggers the departure of the nucleophilic part present in substrate causing carbocation formation, which drives the substrate to rearrange itself. Spirocyclic cyclobutane N‐halo aminals underwent ring expansion in the presence of NBS, alleviating the strain of the cyclobutane (Scheme 9). The ring expansion was triggered by the bromination of the α‐NH groups, leading to N−Br bond cleavage and migration of 1,2‐C to N, forming a cyclopentane ring [21].

FIGURE 2.

Rearrangement assisted by NBS.

SCHEME 9.

Rearrangement reaction in cyclic compounds.

Kelly et al. conducted an oxidative rearrangement, which afforded 2‐substituted‐3‐furfurals [22] from furyl alcohol by the addition of an organometallic reagent and NBS (Scheme 10). Methyl 1‐substituted‐1,2,3,4‐tetrahydro‐β‐carboline‐3‐carboxylate hydrochlorides underwent rearrangement in the presence of NBS in an acidic medium, yielding indolyl‐diketopiperazines (Scheme 11) [23].

SCHEME 10.

Oxidative rearrangement of furyl alcohol.

SCHEME 11.

Rearrangement reaction in cyclic aromatic compounds.

NBS has proven to be a valuable reagent for classical organic rearrangements such as the semi‐pinacol rearrangement. Tu et al. carried out NBS‐mediated semi‐pinacol rearrangement [24, 25, 26], subjecting allylic alcohols in 2‐propanol or isobutanol at room temperature (Scheme 12a,b). Hurley [27] demonstrated another semi‐pinacol rearrangement, where they treated substituted 1‐(1,4,5,6‐tetrahydro‐1‐tosylpyridin‐2‐yl)‐2‐alkylcyclobutanol with NBS in 2‐propanol (Scheme 13).

SCHEME 12.

(a) Semi‐pinacol rearrangement assisted by NBS in allylic alcohol. (b) Semi‐pinacol rearrangement of allylic alcohol in 2‐propanol or isobutanol.

SCHEME 13.

Semipinacol rearrangement in the presence of NBS.

Bennett and Paquette investigated the NBS and dimethylsulfide mediated reaction of methyl‐3‐hydroxy‐4‐methyl‐2‐methylenepentanoate in dichloromethane at 0°C. This reaction yielded the corresponding methyl (Z)‐2‐(bromomethyl)‐4‐methylpent‐2‐enoate in good yield [28] (Scheme 14).

SCHEME 14.

Rearrangement of enones in the presence of NBS.

Tan and co‐workers [29] developed a 1,2 –boryl –migratory semipinacol rearrangement. They reported the transformation of α‐hydroxyallylboronates and α‐hydroxypropargylboronates into α‐boryl ketones and stereodefined trisubstituted alkenes, respectively, by using NBS and 2,2,2‐trifluoroethanol (TFE). NBS leads to the formation of carbocationic intermediates by electrophilic bromination at the hydroxy‐bearing carbon, hence inducing 1,2‐ boryl migration (Scheme 15). Shen et al. [30] demonstrated semipinacol rearrangements of cyclobutanols with NBS in the presence of stereogenic‐at‐cobalt(III) complexes, which leads to the formation of a series of chiral β‐bromo cycloketones (Scheme 16).

SCHEME 15.

1,2–boryl–migratory semipinacol rearrangement in the presence of NBS.

SCHEME 16.

Semipinacol rearrangements of cyclobutanols with NBS.

Flustramine C, a marine natural product [31], was obtained through the rearrangement of 2‐tert‐prenyltryptamines. While conducting this rearrangement reaction, Howell unexpectedly observed an NBS‐mediated skeletal rearrangement of oxetane alcohol, leading to the formation of epoxytetrahydrofuran [32] (Scheme 17).

SCHEME 17.

Rearrangement of oxetane alcohol mediated by NBS.

Meijer et al. discovered that tetraalkyl‐ethylene undergoes allylic bromination with NBS and tert‐butyl hypochlorite, shifting the double bond [33] (Scheme 18).

SCHEME 18.

Allylic bromination with NBS and tert‐butyl hypochlorite, shifting the double bond.

Furthermore, treatment of (+)‐methylene‐camphor with NBS in the presence of pyridine caused a rapid rearrangement, leading to the production of brominated (+)‐methylenefenchone in high yield and purity [34] (Scheme 19).

SCHEME 19.

Rearrangement of (+)‐methylene camphor with NBS in the presence of pyridine to yield brominated (+)‐methylenefenchone.

2.4. Hoffmann Bromamide Rearrangement

NBS exhibits the ability to mediate the Beckmann rearrangement due to the electrophilic nature of its bromine. When acetophenone o‐(4‐pentyl)‐oxime undergoes this rearrangement with NBS, it produces N‐phenylacetamide in excellent yield. In the traditional Beckmann rearrangement, an acidic medium catalyzed the N─O bond breakage in the oxime, facilitating the migration of an alkyl/aryl group to the nitrogen atom. In this case, the brominium ion plays the role of the acidic medium. The mechanism involves the formation of a cationic tetrahydrofuranium intermediate, which subsequently undergoes a reaction to give rise to the migration of the phenyl group, resulting in the formation of the amide [35] (Scheme 20).

SCHEME 20.

Synthesis of amide using Hoffmann bromamide rearrangement.

Additionally, NBS is involved in the Hoffmann Bromamide rearrangement, where it is used for the bromination of an amide. In the presence of bases like sodium ethoxide or DBU, the reaction is further promoted, leading to the formation of an amine (Scheme 21). For instance, Huang and Keillor reported the conversion of para‐substituted aromatic and primary aliphatic carboxamides to their corresponding primary amino methyl carbamates in nearly quantitative yields with NBS and NaOMe in methanol at reflux temperature. This modified Hofmann rearrangement is particularly useful for preparing para‐substituted anilines. Various para‐substituted amides, such as 4‐methoxybenzamides, 4‐methylbenzamides, and 3,4‐dimethoxybenzamides, can undergo this rearrangement [36, 37, 38].Limolenes having highly substituted double bond can be epoxidized selectively using NBS and NaOH [39]. The treatment of privalimide with NBS, NaOEt, and benzyl alcohol results in tert‐butylcarbamate. To improve the yield, Jew et al. introduced the addition of Hg(OAc)₂, which was found to be beneficial [40, 41]. Reider et al. demonstrated that the use of KOH increased the urea formation from the corresponding nicotinamide (Scheme 22). In the absence of the base, when NBS was used, only bromination was observed with some urea formation. However, by adding the base to NBS at ‐5°C, an oxidizing species, N‐bromosuccinimic dipotassium salt, is formed, which serves as the actual brominating agent. This modification led to a high yield of about 95% [42].

SCHEME 21.

Synthesis of amine by bromination of amide using NBS.

SCHEME 22.

Hoffmann bromamide rearrangement using NBS.

2.5. Miscellaneous Reactions

An intriguing reaction can be observed in NBS‐mediated one‐pot synthesis of pharmaceutically important α‐aminoketones from benzylic secondary alcohols and amines. This reaction proceeds via three consecutive steps involving oxidation of alcohols, α‐bromination of ketones, and nucleophilic substitution of α‐bromoketones to give α‐aminoketones [43] (Scheme 23).

SCHEME 23.

Rearrangement of amide to ketones.

Chatterjee et al. [44] reported a conversion of aryl boronic acid to an amine by using the PIFA‐NBS system in the presence of cyanamide and aqueous NaOH in acetonitrile (Scheme 24a). In this process, PIFA reacts with NBS to form a succinimidyl radical, which then abstracts a proton from cyanamide, generating a cyanimidyl radical. This radical reacts with aryl boronic acid, ultimately producing the corresponding amines (Scheme 24b).

SCHEME 24.

(a) A conversion of aryl boronic acid to an amine. (b) Succinimidyl radical‐assisted amination of aryl boronic acid.

Ding and coworkers developed another NBS‐mediated rearrangement of Ynsulfonamides, leading to the stereoselective synthesis of (2Z)‐2,4‐dienamides in DCE. The electrophilic substitution of the brominium ion to Ynsulfonamide results in the formation of a bromo ketene iminium intermediate. Subsequent attack by allylic alcohol, followed by a Claisen sigmatropic rearrangement, leads to diene formation [45] (Scheme 25). This reaction involves allyloxyl addition–Claisen rearrangement–dehydrobromination cascade reactions.

SCHEME 25.

Claisen sigmatropic rearrangement leads to diene formation.

Wang et al. demonstrated the synthesis of thiocyanate enaminones and thiazoles using different reaction media. The reaction involves the use of KSCN in the presence of NBS (Scheme 26). Initially, α‐bromination of enaminones occurs, followed by the nucleophilic substitution of the bromo group with a thiocyanate group [46]. The obtained intermediate undergoes cyclization involving an attack of amino group at the thiocyanate group to afford thiazoles.

SCHEME 26.

Synthesis of thiocyanate enaminones and thiazoles.

Rearrangements triggered by the radical nature of NBS are also of great interest. Recently, Parsons and coworkers [47] reported an NBS‐mediated ring expansion of the cyclobutanol moiety attached to benzofuran, resulting in the formation of heteroaromatic fused 4‐cyclohexanone in CH₃CN at room temperature. In this case, the radical nature of NBS is effectively exploited, as the bromine radical, in the presence of the hydroxyl group of cyclobutanol, forms a hypobromite intermediate, which then drives the ring expansion via a free radical mechanism (Scheme 27).

SCHEME 27.

Ring expansion reaction.

Furthermore, Jiang and coworkers [48] developed the synthesis of 1‐naphthol through carbon‐carbon triple bond breaking and rearranging reactions of benzene‐linked allene‐ynes, mediated by NBS, followed by hydrolysis in acetonitrile. The proposed mechanism involves intramolecular 2+2 cycloaddition of the benzene‐tethered‐allene‐yne to form a cyclobutene fused intermediate, which undergoes halohydroxylation by NBS and water, and further rearrangements provide brominated naphthol (Scheme 28).

SCHEME 28.

Intramolecular 2 + 2 cycloaddition of the benzene‐tethered‐allene‐yne to form brominated naphthol.

Korzhenko et al. synthesized 2‐aroyl‐1,2‐dihydrinaphtho[2,1‐b]furans [49] by the oxidative rearrangement of pyran ring in 3‐aryl‐1H‐benzo‐[f]chromenes with NBS in the presence of water. NBS efficiently promotes the oxidative rearrangement which included bromination of oxyvinyl fragment, attack of water molecule followed by intramolecular nucleophilic substitution, representing a rare ring‐constriction process in this chromene series (Scheme 29).

SCHEME 29.

Synthesis of 2‐aroyl‐1,2‐dihydrinaphtho[2,1‐b]furans by the oxidative rearrangement of pyran ring in 3‐aryl‐1H‐benzo‐[f]chromenes with NBS.

Liang and co‐workers [50] reported the synthesis of fully functionalised six membered oxygen/nitrogen heterocycles by using biomass‐derived furfuryl alcohols. This reaction proceeds through Achmatowicz rearrangement (AchR). NBS plays a role of efficient oxidant to convert furfuryl alcohols into dihydropyranones (Scheme 30).

SCHEME 30.

Achmatowicz rearrangement of furfuryl alcohols using NBS.

After critical examinations of previously reported literature, it was concluded that NBS is an efficient reagent for the rearrangement reactions, along with the bromination, which follows electrophilic and radical pathways. Electrophilic rearrangement pathways of NBS include structural reorganisations such as ring expansion, ring contraction, sigmatropic shifts, and skeletal rearrangements across acyclic and cyclic systems. Whereas radical pathways (Br·) are also effective in ring expansion and oxidative rearrangements, highlighting the dual mechanistic nature of NBS. In some reactions, NBS itself participates as a brominating agent and yields a rearranged product. Some limitations were also observed from these reactions, such as competing pathways, sensitivity to substituents, and reaction condition dependence persist.

3. Hydrolysis

NBS is also highly effective in hydrolysis as well as deprotection of various protecting groups (Figure 3). Hydrolysis can be understood as a reaction where a leaving group in a substrate, becomes more labile in the presence of bromoium ion, thus once it leaves, a subsequent nuclophilic attack of water takes place at that position of substrate (Via Mode A).

FIGURE 3.

Hydrolysis assisted by NBS.

For instance, NBS can convert hydrazones to their corresponding aldehydes and ketones with excellent efficiency [51]. Additionally, Bandgar showed the use of NBS under mild conditions to convert selective oximes into carbonyl groups [52] while Reddy and coworkers demonstrated the conversion of selective oximes into carbonyl compounds using NBS, with water in the presence of β‐cyclodextrin [53] (Scheme 31).

SCHEME 31.

Conversion of selective oximes into carbonyl groups.

In the work by Patricino et al., it was discovered that silyl‐1,3‐dithianes can be easily deprotected to acylsilanes by using 4 to 6 equivalents of NBS in aqueous acetone or acetonitrile [54, 55] (Scheme 32). Furthermore, the use of equimolar or slight excess of NBS was found to deprotect 1,3‐oxathiolanes [56], 1,3‐dithiolanes, and 1,3‐dithianes [54] in the presence of diols or alcohols [57] (Scheme 33).

SCHEME 32.

Deprotection of silyl‐1,3‐dithianes using NBS.

SCHEME 33.

Deprotection of 1,3‐oxathiolanes, 1,3‐dithiolanes, and 1,3‐dithianes using NBS.

NBS also plays a crucial role in the enantioselective synthesis of β‐hydroxy‐γ‐ketoester, where ester enolate undergoes an aldol reaction with 2‐acyl‐2‐alkyl‐1,3‐dithiane‐1‐oxide, and dithiane oxide undergoes hydrolysis in a 9:1 acetone‐water system to yield β‐hydroxy‐γ‐ketoester (Scheme 34A) [58]. Additionally, NBS can be used for the oxidative deprotection of TBDMS ethers in the presence of β‐cyclodextrin in water, enabling cleavage of the Si─O bond [59]. Rao et al. achieved oxidative deprotection of tetrahydropyranyl ethers and tert‐butyldimethylsilyl (TBDMS) ethers with NBS in water in the presence of β‐cyclodextrin [60, 61] (Scheme 34B).

SCHEME 34.

(A) Oxidative deprotection of dithianes using NBS. (B) Oxidative deprotection of tetrahydropyranyl ethers and tert‐butyldimethylsilyl ethers using NBS.

Furthermore, NBS efficiently catalyzes the solvent‐free deprotection of 1,1‐diacetals to their corresponding aldehydes, utilizing wet SiO₂ as a solid support [62]. Additionally, Binkley et al. proposed a regioselective method for partial deprotection of carbohydrates, protected as benzylidine acetals, by irradiating the protected sugar with NBS in water to yield methyl pyranoside (Scheme 35A) [63]. N‐Benzylamides are also hydrolyzed with NBS in chlorobenzene or ethyl acetate under reflux conditions [64] (Scheme 35B).

SCHEME 35.

(A) Role of NBS in regioselective bromination and deprotection. (B) Role of NBS in the hydrolysis reaction.

NBS follows a free radical mechanism in chloroform, in the presence of light or oxygen, leading to the cleavage of benzyl groups in N‐mono and disubstituted carboxamides [65]. This reaction initiates with the bromination of N‐methyl‐acetamide, generating an active brominating agent, N‐bromo‐N‐methyl‐acetamide. Decomposition in the presence of light or oxygen releases a free bromine radical (Scheme 36), leading to the bromination of N‐benzyl carboxamide, followed by hydrolysis and debenzylation.

SCHEME 36.

Role of NBS in debenzylation reaction.

Moreover, when NBS is added to boiling water, it can induce decarboxylation in unsaturated acids like fumaric and maleic acid, resulting in the formation of acetaldehyde, CO₂, HBr, and succinimide, while oxalic acid yields only CO₂, HBr, and succinimide [66]. Yoshizaki and coworkers utilized NBS‐promoted deprotection of the dithioacetal group of the precursor molecule for the synthesis of 3‐deoxy‐D‐manno‐2‐octulosic acid (KDO) derivatives [67].

Das and co‐workers [68] reported allylic bromination of allyl glycosides by using NBS/AIBN reagents in the solution of (EtO)₂CO and PhCF₃. They synthesized lactol by refluxing O‐benzoyl‐protected allyl glycoside, NBS/AIBN and (EtO)₂CO as a solvent, followed by addition of water (Scheme 37).

SCHEME 37.

Allylic bromination of Allyl glycosides.

After critical examinations of previously reported literature, it was concluded that NBS is an efficient reagent for the hydrolysis of esters, ethers, carbonyl compounds, and diacetals. It follows free radical mechanism to do such hydrolysis reactions, particularly under light or oxygen. NBS facilitates selective bond cleavage via bromine radical generation. NBS‐mediated processes enable regioselective carbohydrate deprotection, oxidative debenzylation, and even decarboxylative transformations, highlighting its versatility across diverse functional groups. A few limitations, such as over‐oxidation or competing radical pathways, may arise, which depend on the reaction conditions.

4. Catalysis

4.1. NBS as a Catalyst for Hydroamination and Hydroalkoxylation

Usually, it has been observed that NBS follows radical mode B when while acting as catalyst. Sudalai et al. reported that NBS (20 mol %) in DCM at room temperature acts as a catalyst for the hydroamination and hydroalkoxylation of activated styrenes with any formation of amino‐bromination product (Scheme 38). This metal‐free method utilizes tosyl amides, carbamates, and alcohols as nucleophiles, and provides excellent regioselectivity as per Markonikov's rule, to afford amino acid and ether derivatives [69].

SCHEME 38.

NBS mediated hydroamination and hydroalkoxylation of activated styrenes.

4.2. Transesterification and Esterification Reactions

Bandgar et al. demonstrated the transesterification of β‐ketoesters using NBS as a catalyst under neutral conditions (Scheme 39A) [70]. The reaction efficiently produces hindered esters such as tert‐butylpivalate [71]. NBS also catalyzes the esterification of the tert‐hydroxyl groups of cyproterone and medroxyprogesterone using acid anhydrides or acid chlorides in DCM [72]. Furthermore, N‐alkoxyamides can be converted into esters via oxidative homocoupling of N‐brominated alkoxamides, induced by NBS [73] (Scheme 39B).

SCHEME 39.

(A) Transesterification of esters. (B) Conversion of N‐alkoxyamides into esters.

4.3. Enantioselective Synthesis of α‐Hydroxy Carbonyl Compounds

Jiao et al. achieved the synthesis of α‐hydroxy carbonyl compounds from α, α′‐disubstituted carbonyl compounds using catalytic amounts of NBS and moist DMSO as an oxidant [74]. This reaction proceeds through α‐bromination and allows the hydroxylation of otherwise challenging sp³─H bonds (Scheme 40).

SCHEME 40.

Synthesis of α‐hydroxy carbonyl compound using NBS.

4.4. Oxidative Olefination Reactions

Wang and coworkers reported oxidative olefination between primary amines and benzylic C─H in the presence of NBS and TBHP as an oxidant [75]. The reaction involves the bromination of benzylic amines, followed by the formation of benzylimines and subsequent hydrolysis to yield benzaldehydes. These aldehydes then undergo condensation with heteroaromatic methyl quinolones and naphthalenes to afford the heterocycles like 2‐methylquinolines and 2‐methylquinoxalines (Scheme 41).

SCHEME 41.

Catalytic role of NBS.

4.5. Acetylation and Thioacetylation Reactions

Karimi and co‐workers achieved the acetylation of alcohols using acetic anhydride in the presence of a catalytic amount of NBS in DCM [76] (Scheme 42). Additionally, NBS [77] can catalyze the acetylation of carbonyl compounds and hydroxyl groups in sugars [78, 79, 80]. Moreover, the NBS‐mediated reaction with phenyl thioacetals leads to the formation of O‐glycosides and related acetals [80] (Scheme 43).

SCHEME 42.

Acetylation of alcohols using acetic anhydride in the presence of catalytic NBS.

SCHEME 43.

Catalytic role of NBS in acetylation.

4.6. O‐Glycoside Formation and C─C Bond Cleavage

Enzley and coworkers developed the synthesis of O‐glycosides with free C‐2 hydroxyl groups from thioglycosides through 1,2‐acyl group migration in the presence of NBS and a catalytic amount of TMS(OTf) at 0°C in DCM:water (100:1) mixture (Scheme 44) [81, 82]. Additionally, NBS can catalyse the reaction between disaccharides or glycosides and selenides, leading to the formation of alkyl‐2‐deoxy‐2‐phenylselenyl glycoside (Scheme 45).

SCHEME 44.

Synthesis of O‐glycosides using NBS.

SCHEME 45.

Catalytic role of NBS in glycoside formation.

4.7. Oxathioacetal, Thioacetal, and Dithioacetal Formation

Both aromatic and aliphatic aldehydes can be converted to their corresponding oxathioacetals, thioacetals, and dithioacetals using 30 mol% NBS as a catalyst in DCM [83]. Chemoselective acetylation of carbonyl groups has been reported using propane‐1,3‐diol, silylated diols, and pentaerythrytal [84, 85]. The chemoselectivethioacetylation of aldehydes can also be achieved using NBS under solvent‐free conditions [86, 87] (Scheme 46). NBS can catalyze the trimethylsilylation of alcohols using hexamethyldisilazane (HMDS) under solvent‐free conditions [88] (Scheme 47).

SCHEME 46.

Chemoselective acetylation of carbonyl groups using NBS.

SCHEME 47.

(A) NBS as a catalyst in the trimethylsilylation of alcohols. (B) NBS as a catalyst in the thiglycosides to form ethereal bond.

The combination of NBS with Bi(OTf)₃ activates thio and selenoglycosides in DCM at −30°C to facilitate ethereal bond formation (Scheme 47B). The leaving groups, thioaryl/thioalkyl and selenoaryl/selenoalkyl, are efficiently displaced upon bromination, allowing the attack by another alcohol to form the desired ethereal bonds [89].

4.8. Other NBS‐Catalyzed Reactions

Parthasarathy and Rao developed a combination of ferric salts with NBS to obtain polyacrylonitrile from acrylonitrile [90]. Banik and coworkers [91] reported the reductive dimerization of aldehydes and ketones in the presence of samarium metal and NBS to give 1,2‐diols in 63%−79% yields with 2.3:1−3:1 diastereoselectivities for the DL‐diols (Scheme 48).

SCHEME 48.

Reductive dimerization of aldehydes and ketones.

NBS is also used to promote the dimerization of 6‐amino‐5‐cyano‐2‐methyl‐4‐arylnicotinates in the presence of BPO in acetonitrile to afford (E)‐diethyl (diazene‐1,2‐diyl)bis(5‐cyano‐2‐methyl‐4‐phenylnicotinate) [92] (Scheme 49). Sugimura et al. demonstrated the use of NBS as a promoter for the synthesis of nucleoside derivatives from thioglycosides. They also reported coupling reactions between thioglycosides and silylated nucleoside bases in the presence of NBS [93, 94, 95] (Scheme 50).

SCHEME 49.

Dimerization of 6‐amino‐5‐cyano‐2‐methyl‐4‐arylnicotinates using NBS.

SCHEME 50.

Coupling reactions between thioglycosides and silylated nucleoside bases in the presence of NBS.

When p‐bromophenyl‐benzyl ether was treated with NBS under reflux conditions in CCl₄; (D)(L)‐N‐[α‐(p‐bromophenoxy)benzyl]succinimide was formed in good yield [96]. The reaction proceeds through bromination at an ethereal position, followed by the attack of succinimide. Mancheño et al. used NBS as a halting agent for the synthesis of N‐cyanosulfilimines [97]. The reaction was performed by the treatment of the corresponding sulfides with cyanogen amine in the presence of t‐BuOK and NBS as halogenating agents at room temperature (Scheme 51).

SCHEME 51.

Catalytic role of NBS with sulfides.

Ogawa and coworkers presented the reaction of validoxylamine A and its derivatives with NBS to cleave the imino bond, leading to the synthesis of valeinamine, validamine, cyclohexanone, and cyclohexenone derivatives [98, 99]. Stillbene can be synthesized from (α‐bromobenzyl)benzylidinephenylphosphonium salts in the presence of NBS and bases like 2,2,6,6‐tetramethylpiperidine in chloroform at room temperature [100] (Scheme 52).

SCHEME 52.

Synthesis of stilbene in the presence of NBS.

Chong et al. reported the formation of aziridinium salts by the bromination of a series of N, N‐disubstituted‐β‐amino alcohol using NBS and triphenylphospine [101] (Scheme 53). Caristi presented a substitution reaction of the amino group in N,N‐dimethylamide with succinamide in the presence of NBS and BPO under reflux conditions [102]. Another substitution of 2‐aminobenzoxazole is carried out by deprotonation using LiHMDS followed by electrophilic bromination at the 2^nd position (Scheme 54) [103].

SCHEME 53.

Formation of aziridinium salts from the bromination of a series of N,N‐disubstituted‐β‐amino alcohol.

SCHEME 54.

NBS promoted the substitution reaction of 2‐aminobenzoxazole.

Cai et al. reported an enantioselective β‐amination of chalcones with NBS, resulting in β‐imidoketones in the presence of a bis(oxazoline) ligand and DBU [104]. Gopinath et al. reported the synthesis of thioesters from carboxylic acids using NBS and PPh₃, followed by reaction with various electrophiles [105] (Schemes 55, 56). Ferreira et al. converted (α‐hydroxypropargyl)silanes to the corresponding α‐silyl‐β‐halo enones (tetrasubstituted olefins) by using NBS under mild conditions [106] (Scheme 57), which can be used as a substrate for sequential cross‐coupling reaction to achieve multifunctional enones. Qiu et al. reported a C─C bond cleavage of β‐keto amides using acetic acid as the catalyst, leading to the formation of α‐dibromosubstituted arylamides [107].

SCHEME 55.

β‐amination of chalcones with NBS.

SCHEME 56.

Synthesis of thioesters from carboxylic acids using NBS and PPh_3.

SCHEME 57.

Conversion of (α‐hydroxypropargyl)silanes to the corresponding α‐silyl‐β‐halo enones using NBS and cross‐coupling reactions.

Ye et al. reported the aerobic oxidation of benzylic C(sp³)─H bond by using NBS [108] as a metal free photocatalyst and O₂ as an oxidant under visible light irradiation for the synthesis of a variety of synthetically and biologically activated compounds (Scheme 58).

SCHEME 58.

Aerobic oxidation of benzylic C(sp³)─H bond by using NBS as a catalyst.

After critical examinations of previously reported literature, it was concluded that NBS can act as a catalyst in many reactions under mild conditions, like RT or at low temperature. It works well as a catalyst in the presence of solvents like methanol, ACN, and DCM.

5. C─C Bond Cleavage of β‐Keto Amides and Benzylic Bromination and Stereoselective Synthesis

Qiu et al. reported the C─C bond cleavage of β‐ketoamides using acetic acid as the catalyst to get α‐dibromosubstituted arylamides [109]. Furthermore, NBS‐induced synthesis of 10‐phenanthrenols was achieved from intramolecular cycloaromatization of the electron‐withdrawing group containing 1‐biphenyl‐2‐ylethanones [110] (Scheme 59).

SCHEME 59.

Intramolecular cycloaromatization using NBS.

Thompson and Mundal [111] demonstrated a stereoselective synthesis of diene from allyl hydrazone using NBS in DCM, followed by treatment with DBU. The process involves the initial bromination of allyl hydrazine, leading to the formation of an azo bond and subsequent release of bromide ions, inducing a [3,3]‐sigmatropic shift. This shift results in the selective formation of E‐dienes (Scheme 60).

SCHEME 60.

Formation of E‐dienes in the presence of NBS.

Raihan et al. reported a reaction involving NBS‐mediated C─C bond cleavage of cyclohexene fused isoxaline N‐oxide in acetonitrile. The initiation of this reaction occurs through allylic bromination [112] (Scheme 61).

SCHEME 61.

NBS‐mediated C─C bond cleavage of cyclohexene fused isoxaline N‐oxide.

Wei and Sun demonstrated the activation of sulfoxides bearing a tert‐butyl group using NBS under acidic conditions, followed by treatment with various nitrogen, carbon, or oxygen nucleophiles. This reaction affords a wide range of corresponding sulfinic acid amides, new sulfoxides, and sulfinic acid esters [113] (Scheme 62). Kyasa and Dussault [114] achieved the synthesis of 1,1‐difluoroalkyl ethers from S,S,O‐orthoesters. This process involves the lithiation of 1,3‐dithianes, followed by the addition of peroxide. The resulting S,S,O‐diesters undergo fluorination using NBS and pyridinium fluoride in DCM at −78°C (Scheme 63). NBS, in conjunction with (N, N‐dimethylaminosulfur trifluoride), is known to mediate fluorination in oligosaccharides [115].

SCHEME 62.

Activation of sulfoxides bearing a tert‐butyl group using NBS under acidic conditions.

SCHEME 63.

Formation of sulfinic acid amides, new sulfoxides, and sulfinic acid esters.

NBS is one of the reagents that is found to be useful for multipurpose reactions. Stereoselective synthesis are also possible with NBS, and also activate the formation of C─C bonds in various cyclization reactions.

6. Multicomponent Reactions

NBS serves both as a source of radical as well as brominim ion (Mode A) based on substrate when involved in multi‐component reactions. NBS mediates the synthesis of dihydropyrimidones, 14‐aryl‐14H‐dibenzo[a,j]xanthenes, 1,4‐disubstituted‐5‐iodo‐1,2,3‐triazoles, and (acetoamidobenzyl)naphthols [116, 117, 118, 119, 120] (Schemes 64, 65, 66, 67). Additionally, NBS mediates the synthesis of guanidine, reboxetine intermediate, and carnitine acetyltransferase inhibitor.

SCHEME 64.

NBS in cyclisation of benzaldehyde and thiourea.

SCHEME 65.

NBS in cyclisation of benzaldehyde and beta‐naphthol.

SCHEME 66.

NBS in the synthesis of triazoles.

SCHEME 67.

NBS in the multicomponent reaction under MW conditions.

Kuo et al. used NBS as a catalyst in the synthesis of 1, 5‐benzodiazepine derivative by condensation of aryl/alkyl ketones with substituted o‐phenyldiammine [121] (Scheme 68). Nazarov cyclization of dihydropyran substrates is also catalyzed by NBS and P(OPh)₃. The reaction was effectively catalyzed by 10 mol % NBS−P(OPh)₃ complex, and the products were isolated in good to excellent yields with excellent diastereocontrol [122] (Scheme 69).

SCHEME 68.

NBS as a catalyst in the synthesis of 1, 5‐benzodiazepine derivative.

SCHEME 69.

NBS as a catalyst for cyclization of dihydropyran substrates.

Yeung and coworkers reported a one‐pot method for the synthesis of guanidine using NBS as the promoter [123]. This method involves treating an olefin with nitrile, an amine, and NBS at room temperature, followed by heating the resulting intermediate at 80°C (Scheme 70). Zhao et al. [124]. achieved the oxidative cyclization of 2‐aryl‐3‐arylamino‐2‐alkene nitrile to N‐aryl indole‐3‐carbonitrile, using NBS/zinc acetate acting as the mediator (Scheme 71).

SCHEME 70.

Treatment of olefin with nitrile, an amine, and NBS.

SCHEME 71.

Oxidative cyclization of 2‐aryl‐3‐arylamino‐2‐alkene nitrile to N‐aryl indole‐3‐carbonitrile with NBS.

Yeung et al. reported an NBS‐induced electrophilic multicomponent reaction for the synthesis of the reboxetine intermediate, a highly potent norepinephrine reuptake inhibitor, and carnitine acetyltransferase inhibitor [125]. The reaction involves the synthesis of the morpholine core by reacting NBS, 1,1‐disubstituted olefin, nosylamide, and epichlorohydrin (Scheme 72).

SCHEME 72.

Synthesis of the morpholine core using NBS.

6.1. Lactone Formation

The role of NBS in various cyclization reactions, particularly halolactonization. The presence of a double bond in a substrate leads to the formation of a cyclopropyl intermediate of brominium ion (Mode B), which then gets substituted with a ─COOH group, leading to the formation of a lactone ring [126, 127] as shown in Figure 4. Ortho‐substituted iodo benzene catalyzed bromo‐lactonization using NBS in CDCl₃ at room temperature (Scheme 73) was successfully achieved. Amino thiocarbamate has proven to be a useful catalyst in lactonization reactions involving 1,2‐disubstituted olefins with NBS, leading to the formation of γ‐lactones with two chiral centres and excellent yields [128, 129] (Scheme 74).

FIGURE 4.

NBS‐assisted lactonization.

SCHEME 73.

Ortho‐substituted iodobenzene catalyzed bromolactonization using NBS.

SCHEME 74.

Use of NBS in lactone ring formation.

Zhang et al. carried out enantioselective bromolactonization of Z‐enynes in DCM using NBS as the reagent [130] (Scheme 75). Falck reported bromo boronolactonization of (o‐alkenylaryl)boronic acid with NBS in a mixture of THF and water [131] (Scheme 76). Peng et al. reported bromo‐cyclization reactions of [2‐(1‐alkynyl)phenyl]phosphonic acid diester and aryl‐substituted alkynyl phosphonic monoester, yielding phosphor‐isocoumarins and bromoenolphosphanes, respectively [132, 133] (Scheme 77).

SCHEME 75.

Enantioselective bromolactonization of Z‐enynes.

SCHEME 76.

Bromo boromolactonization of (o‐alkenylaryl) boronic acid with NBS.

SCHEME 77.

Bromocyclization reactions of [2‐(1‐alkynyl)phenyl]phosphonic acid diester and aryl‐substituted alkynyl phosphonic monoester.

Bromolactonization of N‐Boc‐derivatives of unsaturated amides using NBS and lithium tert‐butoxide in THF results in the formation of N‐Boc‐α‐lactams [134] (Scheme 78). Mellegaard et al. presented a bromo‐lactonization reaction of unsaturated acids with NBS in MeCN at −30°C, utilizing diphenyl selenide as a catalyst [135] (Scheme 79). Tang et al. developed a syn‐1,4‐bromolactonization process of enynic acid using NBS in the presence of DABCO in chloroform at room temperature [136, 137].

SCHEME 78.

Bromolactonization of N‐Boc‐derivatives of unsaturated amides.

SCHEME 79.

Bromocyclization and bromolactonization reaction with NBS.

To et al. reported the bromo‐lactonization reaction of conjugated‐ unsaturated carboxylic acid with NBS in HFIP, which leads to the formation of ɛ‐caprolactone as an endocyclization product and δ‐valerolactone as an exocyclization product (Scheme 80).

SCHEME 80.

Synthesis of ɛ‐caprolactone and δ‐valerolactone by bromolactonization and cyclization reaction using NBS.

6.2. Asymmetric Bromocyclization and Bromo‐lactonization Protocols

Ohfume and Kurukuwa [138, 139, 140] reported the synthesis of (3‐Boc‐amino)‐5‐(bromomethyl)‐dihydrofuran‐2(3H)‐one derivative from corresponding chiral allyl glycine substrates. Huang et al. developed asymmetric bromo‐cyclization protocols using chiral phosphoric acids as catalysts and NBS (Scheme 81) [141]. Enantioselective bromination has been achieved through NBS while cyclo‐etherification of 5‐arylpentenols using achiral Lewis base and chiral Bronsted acid [142].

SCHEME 81.

Asymmetric bromo‐cyclization protocols using NBS.

In the presence of NBS, long‐chain olefinic acids can undergo bromo‐lactonization using a zwitterion catalyst [143]. Kumar et al. reported the bromo‐lactonization of alkenoic acids with NBS, employing K₂CO₃ as a catalyst and isoselenazolone as a promoter [144] (Scheme 82). NBS [144] facilitates bromo‐esterification of a series of alkenes and bromo‐lactonization of alkenoic acids. Hajra and coworkers [145] used NBS with metal triflate as a catalyst for the synthesis of 1,5‐disubstituted tetrazoles from alkenes, nitriles, and (TMS)N₃ at room temperature, with a catalytic amount of Zn(OTf)₂ (Scheme 83).

SCHEME 82.

Bromocyclization and bromolactonization reaction with NBS.

SCHEME 83.

Synthesis of 1,5‐disubstituted tetrazoles from alkenes, nitriles, and (TMS)N₃ using NBS.

NBS, in combination with DBU, promotes the regioselective cyclization of (N‐alkylthioureido)indoles and alkyl N‐(indol‐5′‐yl) dithiocarbamates, yielding corresponding 2‐(alkylamino)‐ and 2‐(alkylthio)thiazole[5,4‐e]indoles [146] (Scheme 84). Yeung et al. achieved the formation of imidazoline using olefin, nitrile, amine, and NBS [147] (Scheme 85). Obika et al. [148]. utilized NBS in MeCN at 60°C for the Friedel‐Crafts cyclization of 2‐ketopiperazine, leading to the CDE ring system of tetrahydroisoquinoline antitumor alkaloids such as saframycins, renieramycins, and ecteinascidins (Scheme 86).

SCHEME 84.

Regioselective cyclization of (N‐alkylthioureido)indoles and alkyl N‐(indol‐5′‐yl) dithiocarbamates using NBS.

SCHEME 85.

Regioselective cyclization in the presence of NBS.

SCHEME 86.

Friedel–Crafts cyclization of 2‐ketopiperazine using NBS.

NBS promoted cyclization of α‐ethoxy‐enolate in acetonitrile at 20°C, yielding 1‐β‐methylcarbapenem [149] (Scheme 87). Bicyclo[3.2.0] hept‐3‐ene‐6‐ones undergo fragmentation cyclization to give unsaturated lactones under the action of NBS with chemoselectivity and regioselectivity [150] (Scheme 88). Tsubuki and coworkers used the fragmentation of cyclic ketones in the presence of NBS to synthesize (−)‐swainsonine [151] (Scheme 89). NBS reacts with 1,4‐butanediol and 1,5‐pentadiol to produce γ‐butyrolactone and δ‐valerolactones, respectively [152, 153]. Sniady et al. performed 5‐endo‐dig‐electrocyclization of 1,4‐diarylbut‐3‐yn‐1‐ones with NBS in acetone at room temperature, resulting in the formation of 3‐bromo‐2,5‐diaryl furans [154] (Scheme 90).

SCHEME 87.

Cyclization of α‐ethoxy‐enolate in acetonitrile using NBS.

SCHEME 88.

Fragmentation cyclization of bicyclo[3.2.0]hept‐3‐ene‐6‐ones using NBS.

SCHEME 89.

Fragmentation of cyclic ketone in the presence of NBS.

SCHEME 90.

NBS‐mediated cyclization for furan synthesis.

6.3. NBS‐Mediated Cyclization for Heterocycle Synthesis

NBS is used to mediate the cyclization over the aldol product of silyloxyfuran with an aldehyde in the presence of a Lewis acid, resulting in the formation of a 2,7‐dioxa‐bicyclo[2.2.1]heptan‐3‐one ring [155] (Scheme 91). Treatment of o‐(1‐alkynyl)‐substituted arene carbonyl compounds with NBS and various alcohols or carbon‐based nucleophiles provides highly substituted oxygen heterocycles [156]. For the synthesis of trioxaspiroketals, NBS efficiently promotes the cyclization of two proximal hydroxyl groups in the presence of a THF/H₂O medium, leading to the formation of [5–5]‐trioxaspiroketal and [5–6]‐trioxadispiroketal [157] (Scheme 92).

SCHEME 91.

Formation of a 2,7‐dioxa‐bicyclo[2.2.1]heptan‐3‐one ring using NBS.

SCHEME 92.

NBS‐mediated synthesis of trioxaspiralketals.

Treatment of 2‐ethynylbenzaldehyde with o‐benzenediamine and NBS in the presence of a catalytic amount of CuI in DMSO at 120°C affords the bromoisoquinoline‐fused benzimidazoles [158] (Scheme 93). McErlean used NBS‐mediated electrophilic bromocyclization to synthesize the furan framework in (+)‐luzofuran [159]. Chalcones and oxazoles can be obtained through the bromocyclization using NBS. Alkenes react with nitriles in the presence of NBS, NaHCO₃, and Lewis acids like zinc and copper triflates in water, resulting in the formation of 4,5‐dihydrooxazole [160] (Scheme 94).

SCHEME 93.

Treatment of 2‐ethynylbenzaldehyde with o‐benzenediamine and NBS.

SCHEME 94.

Reaction of alkenes with nitriles using NBS.

N‐Tosylcarmbamates undergo bromocyclization catalyzed by a chiral phosphine‐Sc(OTf)₃ complex, yielding optically active oxazolodinones [161] (Scheme 95). Enaminoesters undergo a Michael addition reaction with ethynyl ketones, followed by bromocyclization, to yield substituted pyridines [162] (Scheme 96).

SCHEME 95.

Bromocyclization of N‐tosylcarmbamates.

SCHEME 96.

Synthesis of substituted pyridine.

NBS reacts with amidoesters in DCM at 0°C as part of the palladium‐catalyzed asymmetric allylic alkylation of glycine iminoester in the presence of chiral phase transfer catalysts, to afford 5,6‐dihydro‐4H‐[1,3]‐oxazines [163] (Scheme 97). NBS promotes the cyclization of carbohydrates, leading to the formation of 5‐(hydroxymethyl)furfural [164] (Scheme 98).

SCHEME 97.

NBS‐mediated electrophilic bromocyclization.

SCHEME 98.

NBS promoted the cyclization of carbohydrate.

Stevens et al. [165]. carried out the synthesis of 2,5‐difunctional‐3,3‐dimethylpiperidines by the addition reaction of a nucleophile to piperidinium salts, which were formed by electrophile‐induced cyclization of γ, δ‐unsaturated imines with NBS in alcohol (Scheme 99).

SCHEME 99.

Synthesis of 2,5‐difunctional‐3,3‐dimethylpiperidines.

Sasaki and Yudin reported the formation of 2‐(1‐bromoalkyl)‐6‐alkyl‐1‐azabicyclo[3.1.0]hexanes in good yields [166] when 2‐alkyl‐3‐(3‐alkenyl)aziridine was treated with NBS in the mixture of 1,2‐dimethoxyethane (DME) and water (Scheme 100).

SCHEME 100.

Bromoaminocyclization for heterocyclic formation.

Bera and Mal performed a one‐pot synthesis of phenanthridinones and their halogenated derivatives using NBS and solvent‐free ball‐milling mechanochemical conditions. They reported bifunctionality of NBS, initially assisting an oxidative C─N coupling reaction followed by a halogenation reaction [167] (Scheme 101) [168]. Xiao and coworkers carried out NBS‐mediated synthesis of indolizino [8,7‐b]indole derivatives using NBS and DCM as solvent at room temperature. They synthesized 9‐bromo‐6,11‐dihydro‐5H‐indolizino[8,7‐b]indole derivative (Scheme 102).

SCHEME 101.

Synthesis of phenanthridinones and their halogenated derivatives using NBS.

SCHEME 102.

NBS mediated synthesis of indolizino [8,7‐b]indole derivatives.

6.4. Bromo‐Aminocyclization for Heterocycle Formation

Aminothiocarbamates, in conjunction with NBS, act as catalysts to promote bromo‐aminocyclization, leading to the formation of heterocycles such as pyrrolidines [169, 170, 171]and piperidines [172] (Scheme 103). 1,4‐Diols, in combination with triphenylphosphine and NBS, undergo cyclization to yield tetrahydrofuran [173] (Scheme 104). Marquez group carried out cyclization of homoallylic alcohols in the presence of NBS in DCM, leading to the formation of bromotetrahydrofuran [174] (Scheme 105).

SCHEME 103.

NBS as a catalyst in bromo‐aminocyclization.

SCHEME 104.

Synthesis of tetrahydrofuran using NBS.

SCHEME 105.

Formation of bromotetrahydrofuran using NBS.

Demole demonstrated the bromination of 3‐methylhepta‐1,6‐diene‐3‐ol with NBS in CCl₄, yielding (Z)‐4‐methylcyclohept‐4‐enone [175, 176]. N–benzyl‐3‐diphenylpropiolamide undergoes intramolecular ipsobromo‐cyclization mediated by NBS in water and acetonitrile at 120°C, leading to the formation of spiro[4,5]trienones [177] (Scheme 106).

SCHEME 106.

Formation of spiro[4,5]trienones using NBS in water and acetonitrile.

Oxidative cyclization induced by NBS for 3‐indolepropanethiol and 3‐indolepropanol results in the formation of thiopyranoindoles and pyranoindoles, respectively [178]. NBS‐mediated cyclization of α‐formyl‐ketenedithioacetals yields 2,3,5‐trisubstituted furans in good yield [179] (Scheme 107). Liu reported NBS‐promoted 1,4‐bromo‐cyclization of conjugated 1,3‐enynes in the presence of a catalytic amount of DABCO [180] (Scheme 108).

SCHEME 107.

NBS‐mediated cyclization of α‐formylketenedithioacetals.

SCHEME 108.

Bromoaminocyclization for heterocyclic formation.

δ‐Dienoamino esters undergo bromocyclization mediated by NBS, leading to the synthesis of a series of polysubstituted pyrroles from primary amines, as shown by Agami et al. [181] (Scheme 109). Ring‐opening of benzoxazoles with secondary amines followed by NBS‐mediated oxidative C─H amination leads to the formation of 2‐aminobenzoxazoles [182] (Scheme 110). 2‐Aminothiazole can be synthesized by the reaction between different acetophenones and thiourea in PEG‐400 at room temperature in the presence of an excess of NBS [183].

SCHEME 109.

Bromocyclization of δ‐dienoamino esters using NBS.

SCHEME 110.

Formation of 2‐aminobenzoxazoles using NBS.

Wei et al. developed C─O bond formation via carbonyl acid‐catalyzed reaction of 1‐acetylcyclopropane carboxamide with NBS, leading to the formation of 5‐amino‐3(H)‐furanones at 80°C [184] (Scheme 111). Hewlett reported the total synthesis of dibromophakellin by the addition of protected guanidine across a double bond by using NBS in a mixture of DMF and DCM at room temperature [185] (Scheme 112).

SCHEME 111.

Formation of 5‐amino‐3(H)‐furanones at 80°C using NBS.

SCHEME 112.

Synthesis of dibromophakellin using NBS.

Aziridine esters can be obtained by the cyclization of aminoseleno esters [186] (Scheme 113). Pannecouke and coworkers reported the synthesis of azetidine derivatives via the cyclization of β‐selenoamines using NBS. The phenyl seleno group is brominated, making it a better leaving group during the attack by amino groups and cyclization [187, 188, 189].

SCHEME 113.

Cyclization of β‐selenoamines using NBS.

Reaction of dimethylbis(phenylethynyl)silane with lithium napthalenide in THF followed by addition of ZnCl₂ and NBS affords 2,5‐dibromodimethyl‐3,4‐diphenyl‐1H‐silole [190] as shown by Morra and Pagenkopf (Scheme 114). Cyclohexanones and ethanedithiol or 2‐mercaptoethanol undergo a cyclization reaction in the presence of NBS at 0°C to produce 1,4‐dithiane or 1,4‐oxathiane compounds [191].

SCHEME 114.

Bromoaminocyclization for heterocyclic formation.

NBS‐mediated multicomponent aminocyclization process via aziridine ring expansion provides a highly stereoselective route for the synthesis of azepane [192] (Scheme 115) and pyrrolidines [193] (Scheme 116) as reported by Yeung and coworkers.

SCHEME 115.

Synthesis of azepane using NBS.

SCHEME 116.

Synthesis of pyrrolidines using NBS.

N‐aryl‐N‐methyl acrylamides, on treatment with NBS and NH₄Cl in DCM in the presence of iodobenzamide (catalyst), produce oxoindolines [194]. α, β‐Unsaturated carboxylic acids react with NBS and alkali metal acetate to give β‐bromostyrenes, while α, β‐unsaturated aromatic amides yield α‐bromo‐β‐lactams [195] (Scheme 117). NBS promotes radical cyclization under irradiation of 2‐azido‐N‐phenylacetamide to give quinoxalin‐2‐(1H)‐ones or spiro[cyclohexene‐1,2′‐imidazol]‐4′‐ones (Scheme 118) and 3‐arylallyl azides to give quinolones (Scheme 119) via iminyl radical formation that drives cyclization [196, 197].

SCHEME 117.

Treatment of N‐aryl‐N‐methyl acrylamides with NBS.

SCHEME 118.

Radical cyclization using NBS.

SCHEME 119.

Synthesis of heterocycles in the presence of NBS.

Xiao et al. demonstrated the cyclization of β,γ‐unsaturated hydrazones, yielding 4,5‐dihydropyrazoles in DCM [198] in the presence of NBS. Wang et al. synthesized 4‐bromo‐2,5‐dihydroisoxazole from propagylic alcohols and N‐tosylhydroxylamine using NBS in the presence of Yb(OTf)₂ [199] (Scheme 120). Bandopadhyay et al. [200] reported that condensation reactions between heteroaryl/cycloaryl aldehydes and 5,6‐diamino‐1,3‐dimethyl uracils in acetonitrile are promoted by NBS and AIBN as catalysts, leading to the synthesis of xanthine (Scheme 121). NBS, in combination with cyclic β‐diesters or β‐diamides such as Meldrum's acid or barbituric acid derivatives, catalyzes the formation of σ‐symmetric spiroheterobicyclics from aldehydes and urea without the use of any solvent [201] (Scheme 122).

SCHEME 120.

Synthesis of 4‐bromo‐2,5‐dihydroisoxazole using NBS.

SCHEME 121.

Synthesis of xanthine using NBS.

SCHEME 122.

Synthesis of fused heterocyclic in the presence of NBS.

6.5. Electrophilic Cyclization

A tetrahydrofuran analogue of FR901464 was synthesized by the treatment of γ,δ‐unsaturated alcohol (Compound 2) with NBS in CH₂Cl₂ at 0°C by Pohorilets and co‐workers [202]. They proposed an electrophile‐mediated cyclization reaction (Scheme 123) [203]. Deng et al. synthesized a series of 3,6,8‐tribromoquinoline compounds by treating N‐(3‐phenylprop‐2‐ynyl)aniline with NBS in DCM (Scheme 124).

SCHEME 123.

Synthesis of tetrahydofuran analogue using NBS.

SCHEME 124.

Synthesis of 3,6,8‐tribromoquinoline compounds.

Chang and group synthesised tricyclic benzofused cyclobutaoxepanones by using NBS and DABCO [204]. They reported this synthesis by DABCO/NBS‐ mediated Baylis‐Hillman type annulation of o‐cinamyloxy chalcones (Scheme 125). Zhang and coworkers reported the synthesis of gem‐dibromo 1,3‐oxazines through NBS‐mediated electrophilic cyclization of propargylic amides [205] (Scheme 126).

SCHEME 125.

Synthesis of tricyclic benzo fused cyclobutaoxepanones.

SCHEME 126.

Synthesis of gem‐dibromo1,3‐oxazines.

6.6. Radical Cyclization

Yan and co‐workers reported metal‐free radical cyclization of enynones for the synthesis of various haloazide‐substituted 1‐indanones [206]. They used TMSN₃ as an azide source and NBS as the source of halogen for the completion of this reaction (Scheme 127).

SCHEME 127.

Radical cyclization of enynones.

After reviewing previous literature it was concluded that NBS has vast application as catalyst for the cyclization reactions while using multicomponent reaction under green conditions like MW assisted reactions and at RT conditions. It has been proved as a catalyst not only for the allylic bromination but also for the lactone ring formation under mild conditions. It was observed from the research article studies that NBS is a catalyst which will work with solvents like ACN, water, alcohol and many more.

7. Oxidation

7.1. Oxidation of Aldehyde, Ketones, Alcohols, Sulfides, and Acetals

NBS facilitates oxidation through two distinct mechanisms, either by first brominating the site and then undergoing dehydrobromination, or by nucleophilic attack of the oxidant at the site where a departure of the leaving group has taken place with the help of the brominium ion, as shown in Figure 5.

FIGURE 5.

Oxidation assisted by NBS.

When ketones are heated with NBS and pyridine in CCl₄ or aqueous dioxane, they undergo dibromination at the α‐site, followed by hydration to give diketones [207]. This analogy has been employed by Sim et al. [208]. to convert naphthoquinones to 1,2‐naphthoquinone derivatives (Scheme 128). The reaction is carried out in a solvent mixture of DMSO and DCM with 4 equivalents of NBS and pyridine. Cyclic acetals are oxidized to bromine‐containing esters in the presence of NBS and AIBN [209] (Scheme 129).

SCHEME 128.

Conversion of naphthoquinones to 1,2‐naphthoquinone derivatives.

SCHEME 129.

Cyclic acetals are oxidized to bromine‐containing esters.

Aromatic and aliphatic sulfides are converted into corresponding sulfoxides using equimolar amounts of NBS and sulfides with 70% dioxane and H₂O as the oxidant [210]. Alcohols are transformed into aldehydes or ketones in the presence of NBS, NaNO₂, and DDQ [211]. Under the O₂ atmosphere in acetonitrile, NBS catalyses the conversion of alcohols to acids [212]. In the cyclohexyl system, the axial hydroxyl group undergoes oxidation preferentially in trans‐3,3,5‐trimethylcyclohexanol over the equatorial hydroxyl group in cis‐3,3,5‐trimethylcyclohexanol [213]. Tertiary amines undergo dehydrobromination after being brominated by NBS, subsequently yielding aldehydes and secondary amines upon hydrolysis [214]. 4β‐Hydroxycholesterol is transformed into 3‐keto‐4β,5α,6β‐trihydroxycholesterol in the presence of NBS under solid‐phase conditions [215].

When NBS is treated with N, N′‐dicyclohexylthiourea in the presence of pyridine, it forms dicyclohexylcarboxamide and N, N′‐dicyclohexylurea [216] (Scheme 130). Salicyclic hydrazide undergoes oxidation in the presence of NBS and hydrogen peroxide or DMSO and base, producing salicylic acid [217] (Scheme 131). Various aromatic alcohols are oxidized to corresponding ketones and aromatic aldehyde in the presence of NBS [218]. Silylethers of type RCHMeOSiMe₃ yield ketones when oxidized with NBS under UV irradiation [219]. For example, oxidation of Me(CH₂)₅OSiMe₃ and PhCH₂OSiMe₃ produces Me(CH₂)₄CO₂(CH₂)₅Me and benzaldehyde, respectively (Scheme 132). Tributylalkoxystannane Bu₃SnOCH₂R reacted with NBS in CCl₄, yielding aldehyde [220]. He et al. demonstrated the conversion of diarylmethanes into ketones using NBS with water as the oxidant in chloroform under reflux conditions [221]. This method follows the concept of dibromination at a specific site, followed by hydrolysis to generate the keto group.

SCHEME 130.

Treatment of N,N′‐dicyclohexylthiourea with NBS in the presence of pyridine.

SCHEME 131.

Oxidation of salicylic hydrazide using NBS.

SCHEME 132.

NBS‐assisted oxidation reactions of aldehyde, ketones, alcohols, sulfides, and acetals.

Zhang et al. [222] reported a method for the conversion of β‐keto sulfides into enones and dienones. (E)‐4‐phenylbut‐3‐en‐2‐one was obtained on reaction of 4‐(hexylthio)‐4‐phenylbutan‐2‐one with NBS in the presence of an inorganic base K₂CO₃ and a polar aprotic solvent. This reaction involves the oxidation, followed by an elimination step (Scheme 133).

SCHEME 133.

Conversion of β‐keto sulfides into enones and dienones.

7.2. Oxidation of Ethers, Epoxides, Glycols, Allylic, and Benzylic Alcohols

Mayoub et al. [223] reported the oxidation of benzyl methyl ether to yield aldehydes and esters. One equivalent of NBS leads to the formation of aldehydes via the release of methyl bromide, while 2 equiv result in ester formation through dibromination followed by hydrolysis (Scheme 134).

SCHEME 134.

Oxidation of benzyl methyl ether using NBS.

Gauna et al. demonstrated a similar mechanism in the conversion of aromatic ethers to aromatic esters. They synthesized alkyl 4,5‐dibromo‐2‐methylbenzoate derivatives from 1,2‐dibromo‐4‐(alkoxymethyl)‐5‐methylbenzene in the presence of NBS as a radical initiator [224]. The process involves dibromination, followed by hydrolysis to form the ester.

Mathiyalagan and Okawara also reported the oxidation of benzyl ethers using NBS. In these cases, benzaldehydes are formed from the benzyl ethers by the action of NBS in the presence of BPO in CCl₄, following the same dibromination‐hydrolysis mechanism [225, 226].

Tatsugi conducted a study wherein they reported the selective NBS‐DMSO [227] mediated oxidation of α‐methylene ketones, leading to the formation of vicinal diketones and triketones. Li and colleagues investigated the dehydrogenation of diaryl carbazones using NBS and pyridine in an NBS‐water system [228]. Krishnaveni et al. [229] demonstrated the oxidation of various alcohols and epoxides with NBS and β‐cyclodextrin in water (Scheme 135). The presence of the bromonium ion increased the electrophilicity of the alcoholic oxygen, driving the formation of carbonyl compounds. The efficiency of oxidation by NBS was adjustable by using various additives, such as ammonium chloride [230] and ionic liquids [231] like (BMIM)BF₄.

SCHEME 135.

NBS‐assisted oxidation reactions of ethers and epoxides.

Yulin et al. reported the selective oxidation of exo‐cyclic double bonds in spiroacetal enol ether by using NBS in the presence of AgNO₃, resulting in spiropyranones [232] (Scheme 136). Additionally, solvent‐free oxidation was achieved using the NBS‐alumina system as an oxidant [233], capable of converting alcohols to aldehydes and benzoins from hydrobenzoins. Benzyl alcohols and secondary alcohols were oxidized by NBS and tert‐butylammonium iodide in acetonitrile at room temperature [234]. Fan et al. reported aliphatic and aromatic alcohol oxidation using NBS in polythenol glycol [235]. Furthermore, secondary alcohols were oxidized under anhydrous conditions [236, 237]. NBS, along with selenium as an oxidant, also achieved oxidation in the presence of secondary alcohols [238]. Sekar et al. showed the oxidation of secondary benzylic alcohols to ketones by using NBS in dioxane at room temperature [239].

SCHEME 136.

Selective oxidation of exo‐cyclic double bonds in spiroacetal enol ether by using NBS.

Glycols can be oxidized in the presence of NBS and catalysts like Ir (III) and Os (VI) [240, 241]. Ganpathy et al. presented the oxidation of allylic alcohol by NBS [242], and the use of heterogeneous catalysts like Ru (III) and Os (III) facilitated the reaction [243, 244]. Rathore and coworkers demonstrated the oxidation of para‐substituted benzhydrols to benzophenones using NBS in the presence of Hg(OAc)₂ [245].

Benzylic alcohols were selectively oxidized to aldehydes with NBS in the presence of water and dioxane, as shown by Adimurthy and coworkers [246]. Moreover, chemoselective oxidation of secondary alcohols over primary alcohols was achieved with NBS by using thiourea as a catalyst in DCM at low temperature (Scheme 137) [247]. The selectivity was attributed to (thio)urea derivatives, which brought electrophilic bromine to the secondary alcohol, promoting its oxidation via Lewis base catalysis.

SCHEME 137.

Chemo selective oxidation of secondary alcohols over primary alcohols.

Sun et al. [248]. showed the oxidative kinetic resolution of secondary alcohols using the Mn (III)−salen complex as the catalyst and NBS as the oxidant. Uzaghare et al. described a method for the oxidation of nucleoside phosphite trimesters to phosphate trimesters using NBS‐DMSO in MeCN [249]. Hannesan and Roy achieved the selective oxidation of the secondary 4‐(R)‐hydroxyl group over axially (C‐1) and (C‐9) hydroxyl groups of sugar derivatives selectively by the action of NBS and (Bu₃Sn)₂O in benzene (Scheme 138) [250]. By employing polymer‐supported NBS, such as poly(ethylene–g‐NBS), secondary benzyl alcohols, polyvinyl alcohol, and benzoin were oxidized to their corresponding aldehydes and ketones [251].

SCHEME 138.

Selective oxidation of the secondary 4‐(R)‐hydroxyl group over axially (C‐1) and (C‐9) hydroxyl groups of sugar derivatives.

Indoles underwent oxidation to form isatins when treated with NBS at 60°C in anhydrous DMSO [252]. Jensen et al. achieved the oxidation of aldehydes to esters by using 1.5 equivalents of NBS in MeOH, in an enantioselective synthesis of γ‐nitro esters by asymmetric Michael addition/oxidative esterification of α,β‐unsaturated aldehydes [253]. In this case, the electrophilic bromonium ion facilitated the nucleophilic attack of MeOH at the carbonyl group for ester formation. Bajpai and coworkers achieved the oxidation of substituted pyrrolidines with NBS to give 3,4‐disubstituted maleimides (Scheme 139) [254].

SCHEME 139.

NBS‐assisted oxidation reactions of glycols, allylic and benzylic alcohols.

7.3. Oxidation of Aryl Compounds

p‐Nitrobenzaldehydes can be transformed into p‐nitrobenzamides and p‐nitrobenzoic acids when reacted with NBS in the presence of ammonia and water under CO₂ [255]. Kim demonstrated the oxidation of fused naphthalene and 1,4‐dimethoxybenzenes [256] using NBS, resulting in the formation of benzoquinone. Furthermore, under aqueous THF conditions in the presence of a catalytic amount of H₂SO₄ oxidative demethylation of 5,8‐dimethoxy‐2‐methylquinoline was achieved 2‐methylquinoline‐5,8‐dione in 98% yield without bromination (Scheme 140). Fuchs and Funks demonstrated the conversion of 3‐alkyl‐6‐bromoindole into 3‐alkyl‐6‐bromoindolin‐2‐one using NBS in a mixture of tert‐butyl alcohol, THF, and water [257] (Scheme 141). Tian et al. also observed a similar oxidation of indoline‐2‐one [258].

SCHEME 140.

Oxidation of fused naphthalene and 1,4‐dimethoxybenzenesusing NBS.

SCHEME 141.

Conversion of 3‐alkyl‐6‐bromoindole into 3‐alkyl‐6‐bromoindolin‐2‐one using NBS.

Omura et al. investigated the asymmetric oxidation of 1,2‐diols using NBS in the presence of copper(II) triflate and (R,R)‐Ph‐BOX (Scheme 142) [259]. Surendra et al. used cerium ammonium nitrate as an oxidant along with NBS to convert epoxides and aziridines into α‐hydroxy ketones and α‐amino ketones (Scheme 143) [260]. NBS can oxidize benzylamides to aldehydes and ketones [261]. Reddy et al. achieved NBS‐mediated oxidative cleavage of arylaziridines in the presence of β‐cyclodextrin in water to give α‐aminoketones (Scheme 144) [262]. Kong and Grindley used NBS with dibutylstannylene acetals in chloroform, which favors terminal acetals to produce ketones instead of hydroxyl aldehydes (Scheme 145) [263].

SCHEME 142.

Asymmetric oxidation of 1,2‐diols using NBS.

SCHEME 143.

Conversion of epoxides and aziridines into α‐hydroxy ketones and α‐amino ketones using NBS.

SCHEME 144.

NBS‐mediated oxidative cleavage of aryl aziridines in the presence of β‐cyclodextrin in water.

SCHEME 145.

NBS‐assisted oxidation reactions of aryl compounds and diols.

Previously, sulfides were converted to sulfoxides with NBS in the presence of anhydrous solvents [264]. Then other solvent systems, such as hydrated silica [265], anhydrous MeOH [266], and β‐cyclodextrin [267] work equally efficiently for this oxidation (Scheme 146). Ghafuri et al. presented the preparation of symmetrical aliphatic, aromatic, and heteroaromatic disulfides using NBS under catalyst‐free conditions in dichloromethane in good yields (Scheme 147) [268].

SCHEME 146.

Conversion of aromatic sulfides to sulfoxides using NBS.

SCHEME 147.

Preparation of symmetrical aliphatic, aromatic, and heteroaromatic disulfides using NBS.

7.4. Oxidation Using NBS in the Presence of Organic Solvents

Lorance et al. [269] used NBS in the reaction of (Z,Z)‐1,4‐bis(tert‐butylthio)‐1,4‐bis(trifluoromethyl)1,3‐butadiene and (Z,Z)‐1,4‐bis(tert‐butylthio)‐1,4‐bis(pentafluoroethyl)‐1,3‐butadiene in CH₃CN under red light to produce 3,6‐bis(trifluoromethyl)‐1,2‐dithiin and 3,6‐bis‐(pentafluoroethyl)‐1,2‐dithiin (Scheme 148). Benzils and aliphatic 1,2‐diketones can be obtained from the corresponding hydrobenzoins and 1,2‐diols through refluxing with NBS in carbon tetrachloride in the presence or absence of pyridine (Scheme 149) [270].

SCHEME 148.

Formation of 3,6‐bis(trifluoromethyl)‐1,2‐dithiin and 3,6‐bis‐(pentafluoroethyl)‐1,2‐dithiin using NBS.

SCHEME 149.

Formation of benzils and aliphatic 1,2‐diketones using NBS.

When 5‐amino‐4‐cyanopyrazole is treated with NBS in DMF at room temperature, it gives azo‐dye followed by oxidation (Scheme 150) [271]. Azo compounds can also be obtained using NBS in the presence of a base like pyridines in CCl₄ [271]. These oxidative coupling reactions involve the bromination of an amino group in the pyrazole system, leading to dimerization and subsequent oxidation to produce azo compounds. Additionally, Carpino et al. [272] presented the dehydrobromination of tert‐butyl hydrazodiformate using NBS and an equimolar amount of pyridine in dichloromethane, resulting in the formation of tert‐butyl azodiformate.

SCHEME 150.

Treatment of 5‐amino‐4‐cyanopyrazole with NBS.

In the presence of DBU and NBS in DMSO, olefins undergo epoxidation [273] (Scheme 151) [274]. This reaction was demonstrated by Shibasaki in the total synthesis of (+)‐lentiginosine. Baik et al. [275] achieved the oxidation of symmetrically hindered 4‐methylphenol using NBS and DMSO, resulting in the formation of p‐benzoquinone methide. In the presence of DMSO, p‐benzoquinone methide further reacts to form hydroxybenzaldehyde (Scheme 152). The reaction follows a radical mechanism, where initially a phenoxide radical is formed.

SCHEME 151.

Oxidation using NBS in the presence of organic solvents.

SCHEME 152.

Oxidation of symmetrically hindered 4‐methylphenol using NBS and DMSO.

Treatment of aldehyde and 2‐aminoalcohol in the presence of NBS in DCM and subsequent base workup provides substituted 2‐oxazolines (Scheme 153) [276]. Kobayashi et al. reported the conversion of 2‐substituted furans into trans‐4‐oxo‐2‐enals using NBS in the presence of pyridine in a mixture of THF, acetone, and water (Scheme 154) [277]. An interesting transformation of 2‐alkynyl benzoates to benzyl o‐carboxylates has been reported by Qui et al. [278]. The mechanism involves NBS‐mediated 6‐endo cyclization, forming a bromo‐incorporated isocoumarin cation intermediate, followed by water‐based nucleophilic addition and oxidative ring‐opening. The resulting dibromo hydrative intermediate is hydrolyzed in situ to yield benzil‐o‐carboxylate. Notably, the oxygen of the ester carbonyl in the starting material is transferred to a triple bond to form one of the keto carbonyl groups (Scheme 155).

SCHEME 153.

Synthesis of substituted 2‐oxazolines using NBS.

SCHEME 154.

Conversion of 2‐substituted furans into trans‐4‐oxo‐2‐enals using NBS.

SCHEME 155.

Oxidation using NBS in the presence of organic solvents.

7.5. Oxidation of Heterocyclic Compounds

Martin et al. successfully synthesized 2,5‐dialkoxy‐2,5‐dihydrofuran from 3‐substituted furans through NBS‐assisted oxidation, which provides butenolide by alcoholysis [279]. Numerous transformations have been reported involving the oxidation of furan derivatives. For instance, Georgiadis et al. [280] demonstrated the conversion of 2H‐furfuryl alcohols to 2H‐pyran‐3‐(6H)‐ones using NBS as the oxidant (Scheme 156). The reaction was conducted by stirring 1 equivalent of furfuryl alcohol in the mixture of THF and water in a 4:1 ratio at 0°C. Additionally, they selectively oxidized 2‐furfuryl alcohol derivatives in the presence of aryl thioethers.

SCHEME 156.

Conversion of 2H‐furfuryl alcohols to 2H‐pyran‐3‐(6H)‐ones using NBS as the oxidant.

Similarly, furyl zinc alkoxides react in the mixture of water and THF in the presence of NBS to afford pyranones (Scheme 157) [281]. In another study, Fujioka and co‐workers performed a condensation reaction of aliphatic/aromatic aldehydes with diamines, to afford the formation of imidazolines mediated by NBS at room temperature (Scheme 158) [255, 282, 283, 284, 285].

SCHEME 157.

Synthesis of pyranones in the presence of NBS.

SCHEME 158.

Oxidation of heterocyclic compounds and aldehydes.

7.6. Oxidation of Keto Esters

Yin et al. demonstrated that aldehydes undergo cyanoimidation in the presence of NBS as the oxidant and sodium tert‐butoxide to afford N‐cyanoimidates (Scheme 159) [286]. In the presence of NBS in MeOH, phenyl methoxymethyl sulfide is converted to phenyl sulfinate (Scheme 160).

SCHEME 159.

Cyanoimidation of aldehyde in the presence of NBS.

SCHEME 160.

Formation of phenyl sulfinate using NBS.

Huayue reported the NBS‐promoted synthesis of symmetrical and unsymmetrical thiosulfonates (Scheme 161) [287, 288]. NBS, in combination with DMSO and DBU, can be utilized for the oxidative coupling of styrenes with an aldehyde to produce α, β‐epoxy ketones, as shown by Sudalai et al. (Scheme 162) [289]. In this reaction, NBS and DMSO first convert styrene to α‐bromoketone. Subsequently, N‐heterocyclic carbene (NHC) substitutes bromine, followed by an attack of the aldehyde to yield the oxidative coupling product of the aldehyde and styrene, i.e., α, β‐epoxyketone.

SCHEME 161.

Synthesis of symmetrical and unsymmetrical thiosulfonates.

SCHEME 162.

Oxidative coupling of styrene with an aldehyde to produce α, β‐epoxy ketones.

Furthermore, another NBS‐promoted oxidative coupling has been established, leading to the formation of single and double bonds between two units of β‐ketoesters in the presence of potassium tert‐butoxide as a base (Scheme 163) [290].

SCHEME 163.

Oxidation of keto esters.

7.7. Oxidation of Amino Acids and Peptides

Rangappa group demonstrated the oxidative action of NBS on amino acids [291], dipeptides [292], and tripeptides [293], leading to the formation of ammonia, succinimide, carbon dioxide, and an aldehyde bearing the R group (Scheme 164). Similarly, a comparable study was conducted with phenylalanine [294], yielding 2‐phenylacetaldehyde in the presence of the catalyst of Iridium(III). Proline [295] also undergoes such oxidation by NBS.

SCHEME 164.

Oxidative action of NBS on amino acids [277], dipeptides [278], and tripeptides.

Upadhayay and co‐workers [296] performed the oxidation of ethylamine, diethylamine, triethylamine, and amine alcohols like NH₂(CH₂)₂OH, (CH₂CH₂OH)₂NH, and [(CH₂CH₂OH)]₃NH, using excess NBS in aqueous HClO₄ for 72 h at 40°C. This resulted in the major products, acetaldehyde and formaldehyde. The process was catalysed by Hg(OAc)₂, PdCl₂, and Ru (III) [297] in an acidic medium. In some cases, an alkaline medium was also used [298, 299]. Additionally, different acids such as aspartic acids and maleic acids undergo oxidation by NBS [300, 301].

7.8. Summary of Oxidation Reactions Using NBS

After reviewing previous literature, it was concluded that NBS can also work as an oxidizing agent to do various organic oxidation reactions. It was observed that it works well as an oxidizing agent under basic conditions, mostly in the presence of pyridine. At some places in place of pyridine, sodium or potassium butoxide may be used with NBS.

8. Aromatization

The use of NBS for bromination followed by dehydrobromination allows the generation of double bonds, leading to the aromatization of certain cyclic compounds. Compared to traditional oxidants, NBS provides a milder approach for the aromatization process, making it advantageous in various reactions. For aromatization, it has usually been seen that NBS, as a source of bromine radical, brominates an allylic site, thereby facilitating dehydrohalogenation (Figure 6).

FIGURE 6.

Dehydrogenation assisted by NBS.

Barnes [302] initially reported the synthesis of phenanthrenes and naphthalene through dehydrobromination using acetate after bromination with NBS in CCl₄. Aromatization of 5,6‐dihydroquinazoline‐4(3H)‐ones has been achieved using NBS under microwave conditions [303] (Scheme 165). Ma et al. applied this method to the condensation product of L‐valine benzyl ester toluenesulfonic acid salt with a substituted cyclohexadione, resulting in the formation of N‐aryl L‐valine benzyl ester [304] (Scheme 166).

SCHEME 165.

Aromatization of 5,6‐dihydroquinazoline‐4(3H)‐ones using NBS under MW conditions.

SCHEME 166.

Formation of N‐aryl L‐valine benzyl ester.

Meyers and coworkers reported the oxidation of oxazolines to 1,3‐oxazoles using NBS and AIBN in CCl₄, where dehydrobromination leads to the formation of 5‐bromo‐1,3‐oxazole [305]. A similar strategy was employed for the conversion of 1,2,3,5,6,10b‐hexahydropyrrolo[2,1‐a]isoquinolines into 5,6‐dihydropyrrolo[2,1‐a]isoquinolines [306] (Scheme 167). Geissman and group showed that treatment of the acetate of dihydrovisnaginone with NBS in CCl₄ in the presence of BPO produced the dehydrogenated product visnaginones [307] (Scheme 168).

SCHEME 167.

Conversion of 1,2,3,5,6,10b‐hexahydropyrrolo[2,1‐a]isoquinolines into 5,6‐dihydropyrrolo[2,1‐a]isoquinolines.

SCHEME 168.

Oxidation of amino acids and peptides.

Recently, Lokahnde and coworkers reported aromatization and halogenation of 3,3a,4,5‐tetrahydro‐3‐aryl‐2‐phenyl‐2H‐benzo[g]indazoles using NBS [308] (Scheme 169). Hati [309] achieved the synthesis of β‐carbolines and 3,4‐dihydro‐β‐carbolines from tetrahydrocarbolines through NBS in toluene (Scheme 170). Pratap and coworkers reported the NBS mediated aromatization for the synthesis of 2‐oxo‐2H‐benzo[h]chromene‐3 carbonitriles (Scheme 170) [310].

SCHEME 169.

Aromatization and halogenation of 3,3a,4,5‐tetrahydro‐3‐aryl‐2‐phenyl‐2H‐benzo[g]indazoles using NBS.

SCHEME 170.

Aromatization using NBS.

Yang and co‐workers [311] reported multibromination‐dehydrogenation of tetrahydroquinoline, which leads to the formation of multibromoquinoline, which was further used for the synthesis of various substituted quinolines bearing electron‐withdrawing and electron‐donating groups using NBS and CHCl₃ as solvent (Scheme 171).

SCHEME 171.

Multibromination‐Dehydrogenation of tetrahydroquinoline.

Use of NBS as a reagent for aromatization has been observed in heterocyclic rings as well as cyclohexane to benzene. Most of the reactions showed use of mild bases to conclude the aromatization. Also, at some places, NBS showed aromatization followed by bromination.

9. NBS Mediated One‐Pot Tandem Reaction

A novel approach has been developed for the synthesis of C‐alkenyl‐o‐carboranes by utilizing a Cu(OTf)₂/NBS‐mediated tandem reaction of 1‐cinnamyl alcohol‐o‐carboranes. Mechanistic studies revealed that the key step involved the Cu(OTf)₂‐promoted ring opening of oxetane with electron‐rich arenes acting as soft nucleophiles. This method offers an alternative strategy for the synthesis of C‐alkenyl‐o‐carboranes, providing valuable references for the formation of diverse o‐carborane derivatives (Scheme 172) [312].

SCHEME 172.

Synthesis of C‐alkenyl‐o‐carboranes by utilizing a Cu(OTf)₂/NBS‐mediated tandem reaction of 1‐cinnamyl alcohol‐o‐carboranes.

A convenient and efficient one‐pot three‐component cycloaddition reaction using easily accessible malonic acid derivatives, nitrosoarenes, and alkenes has been successfully established with the aid of NBS. This method allows for the direct synthesis of highly functionalized isoxazolidine derivatives in good to excellent yields with broad functional group compatibility, and excellent regio‐ and diastereo‐selectivities under mild conditions. Mechanistic studies indicate that the formation of bromomalonic acid observed from malonic acid and the synthesis of nitrone intermediates via the reaction of bromomalonic acid with nitrosoarenes are crucial steps in this process [313].

(2,3‐Dihydrobenzo[b][1,4]oxathiin‐3‐yl)methanols were synthesized through reactions of aryloxymethylthiiranes and N‐bromosuccinimide (NBS) in DMSO under microwave irradiation. The proposed mechanism involves an intramolecular aromatic electrophilic substitution of 1‐bromo‐2‐(aryloxymethyl)thiiran‐1‐iums, generated from aryloxymethylthiiranes and NBS. Subsequently, a DMSO mediated nucleophilic ring‐opening reaction of thiiran‐1‐iums followed by water displacement occurs. This method provides an efficient and straightforward route for the preparation of (2,3‐dihydrobenzo[b][1,4]oxathiin‐3‐yl)methanols using readily available aryloxymethylthiiranes [314].

A modular synthesis of 1‐bromomethylene‐THIQs has been disclosed, involving a Catellani reaction of aryl iodides, aziridines, and terminal alkynes, followed by an N‐bromosuccinimide (NBS)‐mediated cyclization. This approach offers mild reaction conditions, wide substrate scope, good step‐economy, and scalability. Utilizing this method, the total synthesis of (±)‐cularine, the formal synthesis of 8‐oxopseudopalmatine, and the first total synthesis of dactyllactone A have been accomplished, showcasing the broad synthetic potential of this strategy [315].

Ganai et al. [316] reported DBU‐mediated one‐pot synthesis of [1,2,4]triazolo[1,5‐a][1,3,5]triazines analogs. They treated substituted aryl/heteroaryl benzaldehydes and substituted 2‐hydrazinyl‐1,3,5‐triazine with methanol at room temperature, followed by the addition of NBS and DBU. This strategy involved a Dimroth‐type rearrangement (Scheme 173) [317]. Banda and co‐workers synthesised substituted five‐ and six‐membered fused dihydropyridines by using PPh₃–NBS in aqueous medium. The reaction proceeded via a [3 + 2 + 1] annulation involving β‐enaminones and 1,3‐bisnucleophiles. PPh₃–NBS was used as an electrophile to activate carbonyl oxygen (Scheme 174).

SCHEME 173.

One‐pot synthesis of [1,2,4]triazolo[1,5‐a][1,3,5]triazines analogs.

SCHEME 174.

Synthesis substituted five‐ and six‐membered fused dihydropyridines by using PPh₃–NBS.

Liu and co‐workers reported one‐ pot cascade reaction for the synthesis of bioactive spirobarbiturate‐dihydrofurans and dihydrofuro[2,3‐d]pyrimidines by reacting barbiturate‐based olefins with ethyl acetoacetate in presence of NBS [318], DBU and K₂CO₃ (Scheme 175). Hazara and group [319] reported the role of NBS in one‐pot oxyfunctionalization of styrenes. NBS played a very important role in generating benzylic radicals or bromonium intermediates which further reacts with an azide ion in one pot leads to the generation of desired α‐azidoketone (Scheme 176).

SCHEME 175.

Synthesis of dihydrofuro[2,3‐d]pyrimidines.

SCHEME 176.

One‐pot oxyfunctionalization of styrenes using NBS.

9.1. Bromination of 1,2,3‐Triazole‐Based Chalcones Using NBS Under Acidic Conditions

Abdel and coworkers reported bromination of 1,2,3‐triazole‐based chalcones to α‐methoxyl bromides under acidic conditions using NBS, PTSA in MeOH, where the mechanism involves the ionic fragmentation of NBS [320] (Scheme 177).

SCHEME 177.

Bromination of 1,2,3‐triazole‐based chalcones.

9.2. Bromination of Paracetamol by Acidic NBS

Srivastava and co‐workers reported bromination of paracetamol to N‐(3‐bromo‐4‐hydroxyphenyl)acetamide using NBS and Os(VIII) as a catalyst. This was done to observe the kinetic, mechanistic, and quantum chemical study of Os(VIII) catalyzed bromination of paracetamol [321]. (Scheme 178)

SCHEME 178.

Bromination of paracetamol.

9.3. Visible Light Green Approach Method Using NBS

In recent years, visible‐light‐induced methods have emerged as efficient and eco‐friendly strategies for the synthesis of various useful products [322]. Tu et al. reported the synthesis of of α‐keto‐N‐acyl sulfoximines from NH sulfoximines and gem‐difluoroalkenes in the presence of NBS. It was a photo‐catalyst free method (Scheme 179). α‐Haloketones were synthesised from terminal alkynes using N‐halosuccinimides as the source of halogen by Shah and coworkers. They reported photo‐induced homolytic cleavage of NBS to generate bromine radicals under blue LED irradiation [323] (Scheme 180).

SCHEME 179.

Synthesis of α‐keto‐N‐acyl sulfoximines using NBS.

SCHEME 180.

Synthesis of α‐haloketones using NBS.

Rajput et al. [324]. demonstrated the use of NBS for the synthesis of 2,4‐disubstituted thiazoles from methyl aryl ketones and thioamides in water. The reaction proceeds through in situ α‐bromination, where NBS acts as a source of bromine (Scheme 181). Tyagi and coworkers reported the synthesis of various amides from abundant carboxylic acids using deoxygenated amidation [325]. This reaction proceeds through the formation of intermediate bromophosphonium ion and acyloxyphosphonium ion. They treated benzoic acid and p‐toluene sulfonyl hydrazide in the presence of PPh₃/NBS to get the desired product (Scheme 182).

SCHEME 181.

Synthesis of 2,4‐disubstituted thiazoles using NBS.

SCHEME 182.

Synthesis of amides from carboxylic acids.

9.4. C─N, S─N Bond Formation Using NBS

Zhao and coworkers reported radical‐mediated click‐clip reactions between phenothiazines and amines [326]. The synthesis of sulfilimine adduct took place on oxidative click reaction between N‐methylphenothiazine and n‐butylamine on addition of NBS. NBS was used as an oxidant (Scheme 183).

SCHEME 183.

Synthesis of sulfilimine adduct using NBS.

Roy et al. developed a visible‐light‐mediated method for the amination of the C─H bond of cyclic and acyclic ethers. They used this strategy to construct the C─N bond and the C─C bond. NBS‐THF was used as an electron donor─acceptor whose function is to act as an initiator to functionalize both α‐diazoketones and dialkyl azodicarboxylates [327] (Scheme 184). Duan and coworkers [328] reported NBS‐promoted C─H amination of enaminones for the synthesis of N‐heterocycle‐substituted enaminones. The reaction proceeds through the bromination of enaminones followed by intermolecular substitution with N‐nucleophile to form a C─N bond. NBS contributed to the formation of a highly reactive intermediate (Scheme 185).

SCHEME 184.

C─H amination from dialkyl azodicarboxylates and from α‐diazoketones.

SCHEME 185.

C─H amination of enaminones for the synthesis of N‐heterocycle substituted enaminones.

Zeng and coworkers reported an efficient radical‐mediated strategy for the activation of C─N bond in a monocyclic pyrazole using NBS [329]. NBS plays a key role in generating nitrogen‐centered radicals under mild, metal‐free conditions, enabling the cleavage of two C─N bonds in 3,5‐diamino‐4‐nitro‐1H‐pyrazole and the formation of a novel acrylonitrile derivative (Scheme 186).

SCHEME 186.

Activation of the C─N bond in a monocyclic pyrazole using NBS.

A metal‐free as well as NBS‐mediated direct thiol‐disulfide exchange reaction was reported by Yang and coworkers [330] to develop a variety of unsymmetrical disulfides. BnSH and PhSSPh was reacted in the solvent 1,4‐dioxane and 20 mol% of NBS at room temperature to get the desired product. NBS acts as a promoter for the reaction by reacting with BnSH and forming succinimide and sulfenyl bromide, which further reacts with unreacted BnSH to yield BnSSBn and HBr, followed by an exchange reaction between PhSSPh and BnSSBn to give the desired product (Scheme 187).

SCHEME 187.

NBS‐ mediated direct thiol‐disulfide exchange reaction.

Unsymmetrical disulfides were built up by [331] Yang et al. by C(sp³)─S bond cleavage of thioethers. It was done by using the electrophilic halogenations reagent NBS, which efficiently cleaves the furfuryl C(sp3)─S bonds in furfuryl alkylthioethers (Scheme 188). Wang and co‐workers reported a [332] NBS/HCl‐mediated reduction of sulfoxides to sulfides. The reaction proceeds through the attack of sulfoxide and NBS to form succinimide anion, which further reacts with HCl to provide an intermediate and HOBr followed by the reaction between the intermediate and chloro anion to give sulfide and Cl₂ (Scheme 189).

SCHEME 188.

C(sp³)─S bond cleavage of thioethers by using NBS.

SCHEME 189.

NBS/HCl mediated reduction of sulfoxides to sulfides.

Above reactions showed a versatile role of NBS where it is a great source of electrophilic bromine, radical initiator, and oxidant/promoter, thereby enabling diverse mechanistic pathways. The Cu(OTf)₂/NBS‐mediated tandem reaction, and multicomponent cycloadditions showed how NBS can trigger key intermediates such as bromonium ions, brominated active methylene species, nitrones, and radical species, which subsequently undergo rearrangement, cyclization, or nucleophilic interception. Such NBS‐mediated one‐pot reactions have been successfully applied in the synthesis of structurally complex and biologically relevant frameworks such as isoxazolidines, fused heterocycles, triazines, spirocycles, and functionalized o‐carboranes. Despite these advantages, certain limitations such as competing radical pathways and sensitivity to reaction conditions remain.

10. Conclusions

This review highlights the versatility of N‐bromo succinimide (NBS) as a multi‐use reagent in organic chemistry. Usually, NBS is well‐known as a halogenating agent but it also has tremendous applications for other types of reactions. In this manuscript, we focused on the recent developments in various NBS‐mediated chemistry other than halogenation, such as cyclization, catalysis, hydrolysis, oxidation, rearrangements, and aromatization reactions. This manuscript provides an idea that NBS can be used beyond its traditional role as a brominating agent. Moreover, with the increasing demand for sustainable and environmentally friendly chemical transformations, the use of NBS can significantly reduce the reliance on toxic metal catalysts, making it a desirable option for many transformations. Overall, the present review emphasizes the importance of exploring the diverse capabilities of existing compounds and underscores the potential of NBS to revolutionize the field of organic chemistry.

Funding

This research work was funded by Umm Al‐Qura University, Saudi Arabia, under grant number: 26UQU4281757GSSR01. ANRF for funding via project number: EEQ/000121/2023.

Conflicts of Interest

The authors declare no conflicts of interest.

Biographies

Pooja is working at Sri Venkateswara College, University of Delhi, for the past 9 years as an assistant professor. She has completed her graduation in Chemistry (Hons.) and post‐graduation in chemistry (Hons.) from Delhi University. Thereafter, she completed her PhD from the Institute of Nuclear Medicine and Allied Sciences (INMAS), DRDO. She has also published various research papers in her specified field in national or international journals. She has also developed MOOCs and published books or book chapters for B.Sc. (H) Chemistry students as part of the CBCS curriculum. She is running one major research project funded by ANRF, INDIA.

Trisha Ghatak has done her Ph. D. from the University of Delhi. She had completed her B.Sc. (H) in Chemistry and M.Sc. Chemistry from the University of Delhi. After that, she started her Ph.D. in organic chemistry under the supervision of Prof. M. Nath and Prof. R. Pratap. Her work revolves around the synthesis and characterization of heterocyclic compounds of biological relevance and exploring new synthetic pathways for such scaffolds. So far, she has published 3 research papers in international journals, she has also published book chapters, and some of her ongoing works are about to be published.

Ankita has been pursuing her post‐graduation in Chemistry (Hons) from the Department of Chemistry, University of Delhi. She has done the SRIVIPRA Research project under Dr. Pooja. She has also published a book chapter under the guidance of her professor.

Ismail Althagafi is a professor at the Department of Chemistry, Faculty of Sciences, Umm Al‐Qura University, Makkah (Saudi Arabia). He got his bachelor's degree from Umm Al‐Qura University, master's degree, and Ph.D. from Cardiff University (United Kingdom). His current research interests include areas of physical organic chemistry, synthetic chemistry, and bio‐organic chemistry. He has published more than 100 research publications in different journals.

Dharmendra Kumar Yadav has completed his Ph.D degree in Biological Science from CSIR‐CIMAP, Lucknow, India, postdoctoral studies from Hanyang University, Korea, and the University of Delhi, India. Presently, he is working as an assistant professor in the College of Pharmacy at Gachon University, Korea. He received the Young Scientist award from the SERB, New Delhi and worked atthe AIIMS, Jodhpur, India. He has published more than 150 papers in reputed journals, 03 book chapters, and patent. He is continuing his research in Computer‐Aided Drug Design, etc. He is also a member of several scientific societies and academic bodies.

Ramendra Pratap completed his master's from the University of Gorakhpur in 2001, and Ph.D. from CSIR‐CDRI, Lucknow, India. He worked on nucleoside modification chemistry as a postdoctoral fellow at the CUNY, USA, for 2 years. He received a renowned Humboldt fellowship and shifted to the University of Saarland, Germany. In September 2010, he joined the University of Delhi, as an assistant professor. Currently, he is working as a full professor. Till now, he has published more than 115 research papers in various international Journals. He also received a JSPS invitation fellowship. His chemistry focuses on developing various heterocycles, carbocycles, materials.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.