Recent Advances in Bromination of Aromatic and Heteroaromatic Compounds

Abstract

This review covers recent advances in C–H bromination of aromatic substrates. Transition-metal-catalyzed/-mediated reactions and transition-metal-free methods are discussed.

1 Introduction

2 Transition-Metal-Catalyzed Bromination

2.1 Palladium-Catalyzed Reactions

2.2 Rhodium-, Cobalt- and Ruthenium-Catalyzed Reactions

2.3 Copper-Mediated Reactions

2.4 Gold-Catalyzed Reactions

3 Transition-Metal-Free Bromination

3.1 Conventional Electrophilic Bromination

3.2 Oxidative Bromination

3.3 Bromination of Heterocyclic N-Oxides

4 Conclusions

Biographical Sketches

Prof. Leonid G. Voskressensky was born in 1968 in Moscow, Russia. He obtained his B.Sc. in chemistry from Peoples’ Friendship University of Russia (PFUR) in 1992, and his M.Sc. in 1994. He obtained his Ph.D. in organic chemistry from the same university in 1999. In 2001 he joined the group of Prof. Cosimo Altomare (Universita degli Studi di Bari, Italy) as a postdoctoral fellow in medicinal chemistry. In 2001, he became assistant professor, in 2006 associate professor and in 2011 full professor in the organic chemistry department at PFUR. Since 2013 he is the Dean of the Science Faculty at PFUR. His group’s scientific interests focus mainly on domino reaction methodology, new multicomponent reactions, and medicinal chemistry.

Dr Nikita Golantsov was born in 1980 in Tula, Russia. Нe graduated in chemistry from Lomonosov­ Moscow State University in 2002 and received his Ph.D. there in 2006 under the guidance of Prof. M. A. Yurovskaya. From 2006 to 2014 he worked at Moscow State University as a researcher. He is now a member of Prof. L. G. Voskressensky’s group at Peoples’ Friendship University of Russia. His current research interests focus on organic synthesis, heterocyclic chemistry, natural compounds, and transition-metal-catalyzed reactions.

Prof. Abel M. Maharramov graduated in chemistry from Baku State University, Azerbaijan, in 1971. He obtained his Ph.D. from Moscow State University in 1976. Since 1991, he is a full professor at Baku State University. He served as the Head of the Department of Chemistry from 1993 to 1999, and since 1999 he is the Rector of the university. His research group focuses on organic, coordination and supramolecular chemistry, and in particular on the development of noncovalent interactions in the synthesis, catalysis and crystal engineering. He has authored 71 books and has co-authored 650 research publications and 55 patents.

Introduction

Aromatic and heteroaromatic bromides represent a key building block in organic synthesis, especially with the emergence of cross-coupling reactions.[1] [2] Therefore, they are important intermediates in the synthesis of natural products, physiologically active compounds, and novel materials.[2,3] A significant number of halogenated products,[4–7] approximately half of which are bromo derivatives,[4] [5] in particular, mono- and polybrominated phenols, pyrroles, indoles, and carbazoles, have been isolated from primarily marine organisms in the last 30 years. Several compounds with useful biological properties have been among them.[6] [7] Many brominated aromatic derivatives have already been used as pharmaceuticals, dyes, pesticides, and flame retardants.[8] Bromoarenes are also interesting for medicinal chemistry owing to their ability to form weak halogen bonds with receptor proteins. Incorporation of a bromine atom into a ligand (potential drug) could allow its affinity to be fine-tuned.[9] It should be noted that iodine and bromine form stronger halogen bonds than chlorine, although bromine is preferred over iodine because of the lower atomic weight and greater stability of brominated compounds.[9] A similar scenario is observed in cross-coupling reactions in that iodo- and bromoarenes are more reactive than chloroarenes,[1] but replacing the heavier iodine causes a greater loss of molecular weight. Thus, the bromine atom provides an excellent compromise for many situations arising in medicinal and synthetic chemistry.

The classical method for preparing bromoarenes is the uncatalyzed electrophilic aromatic substitution for substrates with an excess of π-electrons and Lewis acid catalyzed reactions for unactivated compounds.[10] [11] [12] The selectivity of these reactions is determined mainly by the electron-density distribution in the substrate. Another approach based on directed ortho-metalation (DoM) followed by treatment with an electrophilic brominating reagent can produce the ortho isomer selectively.[13] A drawback of this approach is the need to use stoichiometric amounts of strong bases (as a rule, organolithium compounds) and, as a result, the low tolerance for electrophilic and acidic functional groups. Bromination methods can be divided into ordinary and oxidative ones depending on the bromine source. In ordinary methods, reagents containing bromine bonded to another electronegative atom (Br, N, O) are used. Oxidative methods involve the generation of an electrophilic brominating agent in situ from an inorganic bromide and a suitable oxidant.[14] [15] Such methods are often referred to as biomimetic or green.[14] Radical bromination is usually used to introduce bromine into a side chain.[16]

Recently, C–H activation using transition-metal catalysts has been developed extensively.[17] [18] [19] [20] [21] [22] [23] The catalysts are uniquely positioned with respect to selectivity and mild reaction conditions. These methods have turned out to be applicable for creating carbon–bromine bonds[17,24] and are being developed further.

Bromoarenes can also be prepared by substitution of atoms other than hydrogen, as in the classical Sandmeyer[25] and Hunsdiecker[26] reactions, or by conversion of heteroaromatic hydroxy compounds into the corresponding halides.[27]

The goal of this Review is to highlight the most recent progress in C–H bromination of aromatic and heteroaromatic compounds published in the last five to six years.

Transition-Metal-Catalyzed Bromination

Transition-metal compounds can play different roles in bromination reactions. First, they can act as Lewis acids by activating a brominating agent. Second, they can activate aromatic substrates via various mechanisms.[17] [18] [19] [20] [21] [22] [23] ^, [28] In particular, this could be electrophilic C–H activation to form a C–M bond or one-electron oxidation of a substrate to produce a cation-radical. Furthermore, a transition-metal compound can form a complex with a suitable directing group before the activation step and provide the required regioselectivity. The mechanisms of C–H activation have been described in detail.[17] [18] [19] [20] [21] [22] [23] ^, [28] An important advantage is the ability to develop highly efficient catalytic procedures using extremely small (fractions of a percent) amounts of transition-metal catalysts. The majority of the recent publications have focused on the use of palladium.

Palladium-Catalyzed Reactions

The palladium-catalyzed bromination with ligand-directed C–H activation has recently been extensively developed with an expanded repertoire of substrates and directing groups.[17] Palladium(II) acetate is used most frequently as the palladium source, and N-bromosuccinimide as the bromine source. The directing groups include both simple functional groups such as amide, carbamate, ester, nitrile, azo, oxime ether, and heterocyclic substituents, and specially developed ancillary groups that can subsequently be easily removed or transformed. Several mechanisms have been proposed for these bromination reactions.[17] [20] In particular, a typical Pd(II)–Pd(IV) catalytic cycle includes electrophilic C–H activation of a substrate 1 upon reaction with a Pd(II) derivative, oxidation of the resulting palladacycle 2 by a brominating agent to form Pd(IV) complex 3, and reductive elimination leading to the formation of a C–Br bond and regeneration of Pd(II) (Scheme [1]).

Bedford et al. succeeded in using palladium-catalyzed C–H activation to achieve selective ortho-bromination of activated aromatic substrates, namely anilides.[29] The reaction occurred at room temperature for a short time and in most instances did not form the para isomer, the product of ordinary randomized electrophilic substitution (Scheme [2]). The presence of p-toluenesulfonic acid was critical to the successful bromination. Use of acetic and trifluoroacetic acids instead of p-toluenesulfonic acid gave dramatically reduced yields; of tetrafluoroboric acid, an increased fraction of the para isomer. The substitution did not occur at all in the presence of sodium tosylate. Increasing the bulk of the anilide acyl group did not seriously affect the reaction yield, although the presence of an electron-accepting substituent in the benzene ring decreased the yield. A significant amount of the ordinary electrophilic substitution product 4 formed for 3-methyl-substituted acetanilide.

ortho-Bromination of O-arylcarbamates occurred in a similar manner but at higher temperatures[30] (Scheme [3]). Electron-accepting substituents in the benzene ring also did not reduce the reaction yield. Furthermore, the ordinary­ electrophilic substitution product 5 formed for 2-ethyl-substituted carbamate although the selectivity depended strongly on the temperature.

The approach to ortho-bromination using ligand-directed C–H activation was largely universal and was expanded to arenes containing nitrile[31] and ester[32] electron-accepting directing groups that typically coordinated weakly to palladium.

The ortho-bromination conditions for a series of benzonitriles were practically the same as those described above for O-arylcarbamates. High yields were observed for substrates containing both electron-donating and electron-accepting­ substituents (Scheme [4]).[31]

ortho-Bromination of aromatic carboxylate esters required the use of sodium persulfate as a co-oxidant in addition to the palladium catalyst and acid.[32] The researchers used trifluomethanesulfonic acid (TfOH) as the acid. A wide variety of 2-bromobenzoate esters containing various electron-accepting and electron-donating groups were prepared in this manner in moderate to high yields (Scheme [5]). Esters of meta-substituted benzoic acids gave only the less sterically hindered regioisomers. The method was also successfully extended to condensed and heteroaromatic derivatives.

In addition, the researchers found that 2,6-dibromobenzoate esters could be obtained in the presence of an excess of the reagent, TfOH, and co-oxidant. The developed method was then used to synthesize various dihalo derivatives, that were difficult to access by other methods, by combining, in different orders, bromination and chlorination (using NCS instead of NBS) of 3-substituted benzoate esters (Scheme [6]).[32]

The researchers also extended the developed method to phenylacetate esters and showed that the ester has a directing effect in this instance as well (Scheme [7]).[32]

Aldehydes are poor directing groups although they themselves are highly reactive. The preliminary conversion of benzaldehydes into O-methylbenzaldoximes was proposed in order to prepare o-bromobenzaldehydes using the palladium-catalyzed ligand-directed C–H activation strategy.[33] The O-methyloxime group was a good directing moiety and could subsequently be converted back into the aldehyde. Using this strategy, the researchers prepared a series of o-bromobenzaldehydes 6 containing various electron-accepting­ and electron-donating substituents (Scheme [8], Table 1).[33]

It was found during optimization of the bromination conditions for O-methylbenzaldoximes 7 that adding silver trifluoroacetate led to complete conversion, whereas using potassium persulfate was ineffective. Adding acetic acid also accelerated the reaction. Moreover, the amount of the dibromo side product increased in the presence of silver trifluoroacetate. This could be partially compensated by reducing the excess of NBS. Table 1 summarizes the ortho-bromination conditions for various o-methylbenzaldoximes and the product yields. The yields from the reactions of O-methylhydroxylamine with the starting aldehydes were close to quantitative. The two geometric isomers of the O-methyloximes 7 were not separated if they were formed, but were instead used as a mixture in the bromination. The O-methyloxime directing group was also removed in high yield so that the efficiency of synthesizing the 2-bromoaldehydes 6 was determined by the bromination step.

An analogous strategy was employed to synthesize chiral [2.2]paracyclophane derivatives 8 (Scheme [9]).[34] The bromination occurred selectively at the benzene ring containing the directing group and was carried out for both the racemic and enantiomerically pure substrates rac-9 and (S_p )-9. The obtained bromoaldehyde was a convenient building block for preparing a series of disubstituted [2.2]paracyclophanes.

In addition, the palladium-catalyzed bromination of a series of O-methyloximes of benzophenones 10 was studied.[35] Conditions and reagents analogous to those described above were chosen for the reactions (Scheme [10]). The monobrominated benzophenones 11 were formed in good yields. The dibromination products either did not form or were minor products. However, in this instance, bromination directed by the O-methyloxime could in principle occur at the two benzene rings and give different regioisomers. The researchers found that the halogen atom added to the benzene ring that was positioned trans to the azo­methine methoxy group. Electronic effects from the substituents on the benzene rings had no influence on the re­gio­selectivity of the reaction (Scheme [10]).

These results indicated that the bromination occurred through the formation of the palladacycle 12 with the palladium coordinated to the nitrogen atom whereas the palladacycle 13 with the palladium coordinated to the oxygen atom did not participate in the process (Figure [1]). It was also obvious that the configuration of the azomethine did not change under the selected conditions.[35] The performed study was based on the previously proposed stereospecific method for synthesizing the E- and Z-isomers of benzophenone oxime ethers.[36]

Selective ortho-bromination of only one benzene ring using the typical set of reagents was demonstrated for a series of symmetric aromatic azo-compounds 14 containing electron-accepting or weakly electron-donating groups (Scheme [11]).[37] The solvents MeCN, toluene, DCE, or nitromethane were used successfully, depending on the solubility of the starting azo-compound. The benzene ring without the deactivating substituent (Cl) was brominated when an asymmetric substrate was used. The azo-compound containing an activating methoxy group on one of the benzene rings gave the ordinary electrophilic substitution product 15 both with the palladium catalyst and without it. Therefore, in this instance, the electronic effects of the substituents as well as the directing action of the azo group played key roles.

A heterocyclic (e.g., 2-pyridyl) substituent can act as an effective directing group in palladium-catalyzed C–H functionalization.[17] The list of heterocyclic directing groups for bromination reactions has expanded in the last five years owing to the use of triazole,[38] 5-aminotetrazole,[39] pyrazolone,[40] and pyrimidine[41] derivatives.

Thus, a series of 2-aryl-substituted 1,2,3-triazoles 16 were selectively ortho-brominated using Pd(OAc)₂, NBS, and pivalic acid, which turned out in this instance to be more effective as the acid component than PTSA, TFA, and AcOH (Scheme [12]).[38] The bromination product yields varied from good to high. The researchers also showed that selective directed bromination was observed at the naphthyl β-position on going from a phenyl substituent in the triazole 2-position to an α-naphthyl (compound 17). This result was in contrast to the aforementioned (Scheme [5]) palladium-catalyzed bromination of a naphthalene-1-carboxylate ester in which the Br atom was directed to the peri-position. Furthermore, the method was expanded to benzannelated triazole derivatives 18. It is noteworthy that 1-phenyl-1,2,3-triazole (19) was not brominated under these conditions.

A study of the bromination of 1,N-diaryltetrazol-5-amines 20 under conditions analogous to those described above found that the N-aryl group was selectively functionalized (Scheme [13]).[39] The presence of either electron-donating­ or electron-accepting substituents on the 1- or N-aryl rings did not change the regioselectivity. Also, adding donor groups to the N-aryl ring increased the amount of dibrominated products with an overall yield close to quantitative.

Use of the palladium–N-heterocyclic carbene complex 21 for selective ortho-bromination of a series of 1-pyrazol-5-ones 22 was proposed (Scheme [14]).[40] The reaction occurred in the presence of silver oxide. The carbene complex itself was easily prepared from Pd(OAc)₂ and thiamine hydrochloride (vitamin B₁) in 80% yield.[40]

Palladium-catalyzed oxidative bromination of 2-arylpyrimidines was elaborated using calcium bromide as the bromine source and Cu(tfa)₂ with atmospheric oxygen as the oxidizing system (Scheme [15]).[41] The reaction typically gave high yields and exclusive monobromination. The compound containing a 2-naphthyl substituent was substituted in the 3-position of the naphthalene ring, apparently due to steric issues, to produce bromide 23.

A method for the palladium-catalyzed oxidative bromination of N-benzylpicolinamides 24 was also developed (Scheme [16]).[42] It was found that the Pd(OAc)₂/KBrO₃/K₂S₂O₈ system could be used to achieve a high degree of selective directed ortho-bromination. Adding NaBr enabled the yield to be increased slightly. The researchers noted that Br₂ could be formed in situ via disproportionation of KBrO₃ or by reaction of KBrO₃ with NaBr. However, K₂S₂O₈ played a critical role as a co-oxidant because the bromination did not occur without it. The reaction yields varied from moderate (probably because of oxidative degradation of the substrate) to good. The substrate containing an α-naphthyl group was brominated in the β-position. Subsequent hydrolysis of the amide bond in the obtained products afforded the o-bromobenzylamines.

Gevorgyan and co-workers proposed a pyridyldiisopropylsilyl directing group that could be easily removed or transformed for C–H functionalization of aromatic compounds.[43] [44] Mild and efficient rhodium-catalyzed cross-coupling of aryliodides and 2-(diisopropylsilyl)pyridine was used to introduce this directing group (Scheme [17]).[43] The catalyst for the coupling was 2,5-norbornadienerhodium(I) chloride dimer ([RhCl(NBD)]₂). Subsequent ortho-bromination of the obtained derivatives occurred in good and high yields in the presence of Pd(OAc)₂, NBS, and PhI(OAc)₂. After the C–H functionalization, the pyridyldiisopropylsilyl group could be removed using AgF in methanol. Use of NIS and AgF in THF caused iododesilylation and produced 2-bromo-4-chloro-1-iodobenzene (25).[43]

An extension of this approach was the double palladium-catalyzed C–H functionalization directed by the pyridyldiisopropylsilyl group that included bromination and oxygenation (Scheme [18]).[44] Removal of the directing group and pivaloyl protection in the obtained compounds 26 enabled selective preparation of the m-bromophenols.

A method for brominating 2-arylbenzoxazoles used palladacycle catalyst 27, which was prepared from the corresponding ferrocenylimine (Scheme [19]).[45]

The bromination occurred at the benzoxazole 6-position and was obviously not ligand-directed. In this instance, palladacycle 27 probably acted as a Lewis acid.[45] It is noteworthy that this catalyst was highly efficient. High bromination product yields were attained with only 1 mol% of palladacycle 27. The researchers compared the efficiency of the proposed catalyst with that of several palladium compounds (Table 2) but none of the tested compounds was as efficient. Moreover, it was found that dinuclear complex 27 was more efficient than palladacycle 28. The reaction yield was <30% without a catalyst.

Rhodium-, Cobalt- and Ruthenium-Catalyzed Reactions

Glorius and co-workers recently proposed a highly promising and efficient method for ligand-directed bromination that used cyclopentadienylrhodium(III) complexes as catalysts.[46] [47] It was found that benzoic acid diisopropylamides in the presence of [RhCp*Cl₂]₂, AgSbF₆, and pivalic acid were smoothly monobrominated in the position ortho to the amide (Scheme [20]).[46] The regioselectivity did not change if the benzene ring contained a strongly electron-donating methoxy group.

The process tolerated various functional groups, e.g., a reactive chloromethyl, but more forcing conditions (temperature increased to 120 °C) were required for electron-accepting­ substituents. However, a substituent in the position ortho to the diisopropylamide turned out to be critical so that bromo derivative 30 was formed only in trace amounts. Obviously, this was caused by steric factors. The diisopropylamide containing a 2-naphthyl substituent was substituted in the 3-position of the naphthalene ring. The tertiary amide could be successfully replaced by a secondary amide. Moreover, an ortho-substituent in this instance did not hinder bromination (bromo derivatives 31 and 32; Scheme [21]).[46] Next, the researchers extended the developed method to aromatic ketones. It was found that tert-butyl phenyl ketone, which cannot enolize, reacted smoothly under the proposed conditions. However, bromination of acetophenone and isopropyl phenyl ketone occurred successfully if pivalic acid was replaced by Cu(OAc)₂ (Scheme [21]).[46] The method had to be modified in the same way for ethyl benzoate.

Next, the kinetics with deuterated diisopropylamide 33 were studied in order to elucidate the reaction mechanism (Scheme [22]).[46]

The observed kinetic isotope effect (KIE) was characteristic of C–H activation processes. The ratio of the rate constants for the labeled and unlabeled substrates suggested that C–H activation was the rate-limiting step (RLS). Furthermore, unreacted 33 contained a significant amount of the H/D-scrambling product. This suggested that the cyclometalation step was reversible.

Two possible reaction mechanisms were proposed based on the experimental results (Scheme [23]).[46] Rhodacycle 34 was formed initially and could be oxidized by NBS to rhodium(V) complex 35, which gave bromo derivative 36 as a result of reductive elimination. Also, rhodacycle 34 could act as a nucleophile in the reaction with NBS to form the reaction product directly.

An important enhancement of the aforementioned method was its extension to heterocyclic substrates.[47] As it turned out, furan-2-carboxamides and thiophene-2-carboxamides in the presence of [RhCp^*(MeCN)₃](SbF₆)₂ (37) and N-bromophthalimide (NBP) were smoothly brominated in the 3-position (Scheme [24]).

In this instance, addition of pivalic acid or Cu(OAc)₂ was not required. The reaction did not require an inert atmosphere or special drying of the glassware in order to remove moisture. Unfortunately, however, 1-methylpyrrole-2-carboxylic acid diethylamide, under the proposed conditions, underwent ordinary undirected electrophilic substitution at the 5-position, resulting in product 38.

It is noteworthy that bromination of 5-methylfuran-2-carboxamide without a catalyst in a control experiment gave the product from H-substitution in the methyl group, along with the 4-bromo derivative (Scheme [25]).[47] This emphasized that the rhodium(III)-catalyzed bromination was highly efficient with respect to control of the regioselectivity.

An analysis of the reasons for the highly regioselective directed bromination of the furan and thiophene derivatives revealed that the rate of the second bromination of 39 using NBP (Scheme [26])[47] was strongly retarded in the presence of 1 mol% of the rhodium catalyst 37 or AgSbF₆. The reaction occurred as an ordinary aromatic electrophilic substitution. The electrophile was Br₂, which was formed from NBP and trace amounts of HBr. The researchers hypothesized that the rhodium complex 37 acted as an HBr acceptor, thereby slowing Br₂ formation. Thus, the rhodium catalyst performed a dual role in the examined processes: it accelerated bromination directed by the amide, and inhibited ordinary aromatic electrophilic substitution.

Also, it was found that the amount of the rhodium catalyst 37 for bromination of furan-2-carboxamide could be reduced to 0.1 mol% if AgSbF₆ was added to the reaction mixture in order to bind trace amounts of HBr (Scheme [27]).[47] The number of catalytic cycles for this example indicated that the rhodium(III)-catalyzed bromination was highly efficient.

The bromination of 2-arylbenzo[d]thiazoles was carried out under conditions analogous to those proposed by Glorius and co-workers[47] (Scheme [28]).[48] The thiazole ring acted as a directing group even for substrates containing an amine. Dibromo derivatives 40 could be obtained in the presence of 2.1 equivalents of NBS.

It is interesting that an ortho-substituent in the phenyl ring and a free 6-position in the benzothiazole (most nu­cleophilic) destroyed the regioselectivity and formed the product of undirected bromination (Scheme [29]).[48]

A catalytic system using [RhCp^*Cl₂]₂, sodium bromide as the bromine source, and PhI(OAc)₂ as the oxidant was proposed for the bromination of a series of aryl-substituted heterocycles (Scheme [30]).[49] Pyridine, isoquinoline, pyrimidine, and pyrazole moieties played effective roles as directing groups.

Glorius and co-workers also showed that a cyclopentadienylcobalt(III) complex, a lighter congener of the rhodium complex, could be used for ligand-directed C–H bromination. The classic substrates, 2-arylpyridines, were selected (Scheme [31]).[50] The reaction gave moderate yields, required an inert atmosphere, and took a rather long time. Nevertheless, the low cost of the cobalt catalyst could surely be counted among the advantages of the method.

Ackermann was the first to demonstrate ruthenium-catalyzed ortho-bromination.[51] Benzoic acid diisopropylamides were used as the substrates. The highest yields were attained in the presence of the silver salt of adamantanecarboxylic acid. The meta-substituted benzamides formed different major regioisomers 41 and 42 depending on the nature of the substituents (Scheme [32]). The sterically less accessible C–H bond of the m-fluoro derivative was functionalized. Kinetic studies with deuterated benzamides did not show a significant isotope effect. This suggested that the C–H activation was not the rate-limiting step. It was also observed that adding TEMPO inhibited the catalytic reaction. These results were in contrast with those observed in the palladium- and rhodium-catalyzed reactions and argued in favor of a single-electron-transfer (SET) mechanism for the ruthenium-catalyzed bromination.[51]

Quite recently, Greaney and co-workers, and somewhat later Huang and co-workers, proposed effective ruthenium-catalyzed procedures for meta-selective C–H bromination via ortho-C–H metalation.[52] [53] Currently, few examples of directed meta-functionalization of arenes by C–H activation are known, although this is an exceedingly active research area.[23] The meta-bromination substrates in the work of Greaney et al. and Huang et al. were 2-arylpyridines and related heterocyclic compounds; the catalyst, a ruthenium(II) cymene complex (Scheme [33]).[52] [53] The reaction mechanism involved initial ortho-metalation of a benzene ring to form a ruthenacycle, followed by attack of a brominating agent at the position para to the ruthenium.[23] [52] [53] The bromine source in the work of Greaney et al. was tetrabutylammonium tribromide (Br₂, NBS, and pyridinium tribromide gave only little conversion), a carboxylate additive was used, and the optimum solvent was dioxane (Scheme [33], method a).[52] Furthermore, it was noted that the reaction was air-sensitive, thus it was carried out in a Schlenk tube under nitrogen. In contrast with the aforementioned procedure, Huang et al. used NBS in DMA for the bromination without a carboxylate additive and in air (Scheme [33], method b).[53] In both instances, the bromo derivatives were obtained in good and high yields for substrates containing various substituents (with the exception of formyl and bulky tert-butyl) in the para-position relative to pyridine and for benzo[h]quinoline. Furthermore, Huang et al. succeeded in extending their procedure to ortho- and meta-substituted substrates and those containing pyrimidine, isoquinoline, and 3-halopyrazole substituents in place of pyridine (Scheme [33]).

Huang and co-workers proposed a possible NBS bromination mechanism that was based on their results and included a Ru(II)–Ru(IV) catalytic cycle (Scheme [34]).[53] The researchers suggested that ruthenium complex 43, with two phenylpyridyl ligands, formed as a result of two successive C–H activation steps. Then, oxidative addition produced ruthenium(IV) complex 44. The target product resulted from SET bromination in the position para to the ruthenium atom, followed by protonation.

Copper-Mediated Reactions

Brominations using copper derivatives are highly diverse with respect to reaction conditions and mechanisms. The required amounts of copper compounds vary from 5–10 mol% to stoichiometric and greater; that is, the copper compounds can act as catalysts or reagents, which is not a problem given the low cost of copper. The reaction mechanisms include[28] [54] (a) ordinary aromatic electrophilic substitution, where the role of copper consists of generating the electrophile; (b) one-electron oxidation of an aromatic substrate by a copper(II) derivative; and (c) electrophilic C–H activation of the substrate. The mechanisms are discussed in more detail within the examination of actual examples.

Both catalytic and non-catalytic methods have been developed in the last five years. In the simplest case, two or more equivalents of CuBr₂ are used and serve only as a source of molecular Br₂, which is formed in situ via reversible dissociation of CuBr₂ to form CuBr.[55] The bromination itself is ordinary aromatic electrophilic substitution.

A method for brominating monosubstituted anilines using an excess of CuBr₂ in ionic liquids was proposed.[56] The reaction occurred selectively at room temperature in high yields through mono-substitution at the para-position (Scheme [35]). It is noteworthy that the nitrogen atom was unprotected. The reaction time for most anilines was less than one hour, although it increased to three hours for p-nitroaniline.

Anilides and related compounds were also mono-brominated selectively and in high yields by a mixture of CuBr₂ and Cu(OAc)₂ without a solvent (Scheme [36]).[57]

Stahl showed earlier that the amount of CuBr₂ could be reduced to a catalytic level if the reaction was carried out under an oxygen atmosphere in the presence of an additional source of bromide.[58] Thus, an effective bromination method for electron-rich aromatic compounds was developed (Scheme [37]).

The range of substrates comprised phenol ethers and condensed five-membered heterocycles. Mono-bromination of phenol ethers occurred in high yields in the presence of one equivalent of LiBr. Doubling the amount of LiBr produced dibromo derivatives 45 and 46 in high yields. It was noted that a brown Br₂ color appeared if the reaction mixture was heated. The role of O₂ in the proposed mechanism consisted of re-oxidation of CuBr to CuBr₂ (Scheme [38]).[58]

Aerobic bromination using CuBr₂ produced mono- and dibromo derivatives of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) (Scheme [39]).[59] The unusual optical properties of this heterocyclic system are attractive for research purposes. It was found that selective mono-bromination required a reduced amount of CuBr₂ and a base, with K₂CO₃ being the most effective of those tested.

Yang and co-workers showed that the commercially available oxidant Oxone^® could be used in reactions with CuBr₂.[60] Thus, a mild and efficient method for brominating aromatic amines was developed (Scheme [40]).

Selective mono-bromination occurred in good and high yields in the presence of 0.5 equivalent of CuBr₂ and Oxone^® without adding other bromides. The reaction occurred at the para-position with respect to the amine, if it was not occupied, for primary, secondary, and tertiary amines. Reducing the temperature to 0–5 °C led to successful bromination of oxidation-sensitive aldehydes. The researchers pointed out that, in this instance, atmospheric O₂ was not involved (did not interfere) in the reaction because identical product yields were obtained under air and nitrogen atmospheres. The use of CuBr₂ was critical: KBr, NH₄Br, TBAB, and CuBr gave much lower product yields. The use of an aprotic solvent, such as MeCN, was just as important: water and methanol, which are usually used with Oxone^®, gave poor results. The method was expanded to include amines of pyridine and carbazoles, although acetanilide did not react under these conditions.

The researchers also established that the bromination of aromatic amines was well controlled and that sequentially increasing the amounts of CuBr₂ and Oxone^® could produce polybrominated derivatives (Scheme [41]).[60]

The SET mechanism was proposed for the examined bromination of aromatic amines (Scheme [42]).[60] Oxidation of the substrate by copper(II) produced cation-radical 47, which quickly captured bromide to give radical 48, a second one-electron oxidation of which produced arenonium ion 49, which was transformed via proton loss into the reaction product. The SET mechanism was confirmed in one sense by the fact that the nature of the reaction changed in the presence of a radical trap (TEMPO). A large number of products were formed; among them was the target bromo derivative, found only in trace quantities.

Shen and co-workers studied catalytic bromination of 2-arylpyridines in the presence of Cu(NO₃)₂ and LiBr.[61] [62] Oxygen[61] and CrO₃ [62] were used as oxidants. ortho-Bromination ensued with both mono- and dibromo derivatives being formed (Scheme [43]). The second substitution was suppressed if a methyl was introduced into the 3-position of the pyridine ring.

The lack of an isotope effect was demonstrated earlier in Yu’s pioneering work that focused on copper-catalyzed ortho­-functionalization of the C–H bonds of 2-arylpyridines (Scheme [44]).[63]

This was in contrast to analogous palladium-catalyzed reactions. An SET mechanism involving a pyridyl directing group was proposed (Scheme [45]). The rate-limiting step was electron transfer from the aromatic ring to the coordinated copper(II), which produced cation-radical 50. The observed ortho-selectivity was explained by intramolecular transfer of a bromide from the copper(I) bound to the pyridyl nitrogen atom.

Han and co-workers proposed a method for brominating 2-arylpyridines via a reaction with stoichiometric amounts of CuBr and NBS under an inert atmosphere (Scheme [46]).[64] The substitution occurred in the position ortho to the pyridyl ring. A carboxylic acid had to be added to the reaction mixture in order to increase the yield. Acetic, butyric, and benzoic acids gave the best results of the tested acids. Pivalic, isobutyric, trichloroacetic, and TFA gave lower yields. PTSA turned out to be completely ineffective. Small amounts of the dibromo derivatives were formed as side products and were formed primarily if the amount of NBS was increased. The reaction conditions were tolerant of various functional groups (Scheme [46]). However, an electron-donating p-methoxy group caused ordinary electrophilic substitution to be competitive (a mixture of products 51a–c was formed).

Next, deuterated 2-phenylpyridine was investigated under the developed conditions.[64] A significant isotope effect was observed and was in contrast with Yu’s observations[63] (Scheme [44]). Based on the experimental results with the deuterated substrate, a Cu(I)–Cu(II) mechanism for the examined transformation was proposed (Scheme [47]). Initially, Cu(I) was coordinated to the pyridine nitrogen atom (complex 52). Then, acylhypobromite, which was produced by the reaction of NBS with the carboxylic acid, oxidized Cu(I) to Cu(III). The resulting intermediate 53 underwent intramolecular attack of the benzene ring by the highly electrophilic Cu(III). Proton loss produced complex 54 containing a C–Cu bond. Finally, reductive elimination formed the reaction product and regenerated Cu(I).

Wang and co-workers discovered that Cu(II) compounds could activate the C–H bonds of macrocyclic arenes (Scheme [48]).[65]

The azacalix[1]arene[3]pyridine 55 reacted with a stoichiometric amount of Cu(ClO₄)₂ under aerobic conditions to form the Cu(III) complex 56 containing a C–Cu bond. The obtained product was found to react readily with alkali-metal bromides to form brominated macrocycles 57 and CuBr. Both reactions gave close to quantitative yields. It was also found that the complex could be produced and the reactions with the bromides could be carried out in one pot.

A method using removable pyridyl-containing directing groups was developed for directed Cu-catalyzed bromination.[66] [67]

Specifically, N-(2-pyridyl)sulfonylanilines underwent selective ortho-bromination in the presence of NBS and CuBr_2­ under aerobic conditions (Scheme [49]).[66] Both electronic and steric factors in the substrate affected the reaction mechanism. Thus, the more acidic and more sterically hindered C–H bond was functionalized to form bromo derivatives 58 and 59. The regioselectivity changed with bulkier isopropyl and trifluoromethyl groups in the position meta to the sulfonamide.

The obtained bromoanilines were then used in indole synthesis, with subsequent reductive elimination of the pyridylsulfonyl by magnesium in methanol (Scheme [50]).[66]

Furthermore, 2-(2-pyridyl)isopropylamide was proposed as a directing group.[67] It was found that aromatic acid amides reacted with NBS in the presence of a catalytic amount of CuBr and zinc acetate (1 equiv) to give the ortho-bromo derivatives (Scheme [51]).

Zinc acetate, being a Lewis acid, activated NBS. The reaction was carried out in open air. Good yields were obtained for the para-substituted benzamides. However, dibromo derivatives were observed in several instances. Both isomers were formed in the nonselective reactions of meta-substituted benzamides. The procedure could be extended to heterocyclic and condensed aromatic substrates. The directing group could be removed by acid hydrolysis to give the corresponding bromo-substituted aromatic acids.

Gold-Catalyzed Reactions

Wang and co-workers proposed a mild and effective bromination of benzene and activated and moderately deactivated aromatic substrates using NBS with gold(III) chloride as catalyst.[68] The reaction occurred even at room temperature and did not require any additives. Yields close to quantitative were obtained for a broad array of substrates (Scheme [52]).

The amount of catalyst could be reduced to 0.01 mol% and still result in high yields from activated aromatic compounds. The regioselectivity was consistent with substituent electronic effects. In particular, methyl benzoate formed the meta-isomer. Nitrobenzene, a highly unreactive substrate, gave only traces of the bromo derivative. Unsubstituted benzene was monobrominated in practically quantitative yield at 80 °C for 11 hours with 1 mol% of AuCl₃. In comparison, the bromobenzene yield after 24 hours under analogous conditions was only 27% when 20 mol% of iron(III) chloride, the traditional catalyst, was used.

A dual role was proposed for the catalyst (Scheme [53]),[68] which was largely responsible for the high effectiveness. On one hand, AuCl₃ could act as an ordinary Lewis acid to activate NBS by coordinating to a carbonyl oxygen atom; on the other, it could induce electrophilic C–H activation of the substrate by forming an arylgold(III) complex. In this instance, directing groups were obviously not involved in C–H activation, in contrast with most of the aforementioned examples.

A magnetic polymer nanocomposite carrier for AuCl₃ was proposed.[69] This catalyst was just as effective as the homogeneous catalyst discussed above.

Transition-Metal-Free Bromination

Drawbacks of the aforementioned highly effective transition-metal catalysts are related to their high cost and toxicity. Furthermore, most of the transition-metal bromination methods developed to date are ligand-directed. Their regioselectivity complements that of ordinary electrophilic substitution. Therefore, the development of transition-metal­-free bromination methods is a continuing research topic.

Conventional Electrophilic Bromination

Elemental bromine (Br₂) has obvious deficiencies as an electrophilic reagent. It is toxic, volatile, and corrosive. The side product HBr has the same deficiencies. Alternatives to Br₂ are NBS, which has a long and successful history,[16] [70] [71] and related compounds with an N–Br bond,[16] including 1,3-dibromo-5,5-dimethylhydantoin[72] (DBDMH) or tribromoisocyanuric acid (TBCA).[73] Other possible alternatives to Br₂ are ionic tribromides, such as pyridinium tribromide.[74] [75] Both these classes of reagents were recently developed.

As mentioned above, NBS is a typical bromine source in modern transition-metal-catalyzed bromination reactions. In general, NBS and related compounds can be activated by protonation or coordination of a Lewis acid to a carbonyl oxygen atom.[70] NBS can also be activated by a Lewis base that coordinates to the bromine atom, or full transfer of positively charged bromine atom to the Lewis base donor center can even take place.[76] Thus, Miller and co-workers proposed an elegant enantioselective bromination of aromatic compounds using NBP and chiral Lewis acid catalysts.[77] This refers to tribromobiphenyls 60, which possess axial chirality (Scheme [54]).

Naturally, biaryl phenols were susceptible to bromination, which hindered rotation around the C–C bond joining the benzene rings and resulted in significant enantiomeric excesses of configurationally stable derivatives 60. The catalyst was tripeptide 61, which had sites for binding biaryl carboxyls and phenols and a tertiary amide that acted as a Lewis base for activating NBP. NBS was slightly less enantio­selective. It is noteworthy that the yield of racemic bromination product was <15% without a catalyst. Adding the tertiary amine DIPEA (10 mol%) increased the yield to 30%. The yield increased to 91% with N-Boc-valine dimethylamide. This emphasized the catalytic role of the amide. Replacing benzoic acid by pyrrolecarboxylic acid gave tetrabromide 62 with slightly less enantioselectivity. Subsequent Suzuki functionalization of the tribromides expanded considerably the range of optically active biaryls that were readily available due to the developed strategy.[78]

The aforementioned method was adapted to atropisomeric tertiary benzamides with a meta hydroxy substituent (Scheme [55]).[79]

Double ortho-functionalization in compounds of type 63 created a rather high barrier to racemization due to rotation around the C–C bond between the benzene ring and the amide carbonyl carbon atom. In this instance, DBDMH was used as the brominating agent; tripeptide 64 that could adopt the β-hairpin structure, as the catalyst. Tribromination occurred if the position para to the amide was free; dibromination, if it was occupied. The ratio of enantiomers was of the same order of magnitude in both instances. The enantioselectivity practically disappeared if any of the positions ortho to the amide were initially occupied by a bromine atom. Furthermore, the more sterically hindered product 65 was formed if catalyst 64 was used and the reaction was stopped at the monobromination stage (Scheme [56]). A mixture of two of the other isomers was obtained if the reaction was uncatalyzed or if common tertiary amines were used. This suggested that the first monobromination played a critical role in the stereoselectivity in general.

Triphenyl- and tributylphosphine sulfides (66 and 67) were proposed as Lewis bases for activating NBS. The reaction occurred quickly at room temperature with high yields and accommodated an assortment of substrates (Scheme [57]).[80] The proposed Lewis bases were highly promising with respect to the design of new catalysts for enantioselective halogenation.

A chiral Bronsted acid, namely, phosphoric acid derivative 68, was used as the catalyst in an effective enantioselective bromination of biphenyls 69 (Scheme [58]).[81]

The brominating agent was NBP; the substrates, biaryls containing a resorcinol moiety. The method was highly enantioselective because it occurred in two sequential bromination steps catalyzed by derivative 68 (Scheme [59]). The first destroyed the symmetry of the starting C _s-symmetric biaryls by forming enantiomeric monobromides 70 and 71. The second step involved kinetic resolution, wherein minor monobromide 71 was consumed faster. Correspondingly, the enantiomeric excess of target monobromide 70 was increased. The enantioselectivity was lost if the alkoxymethyl in starting biaryls 69 was replaced by an ethyl or vinyl. This group obviously participated in hydrogen-bond formation in the transition state.

Even highly unreactive aromatic substrates could be brominated by TBCA if strong protic acids were used.[82] [83] For example, the reaction of m-dinitrobenzene in H₂SO₄ (98%) for four hours at room temperature gave the corresponding monobromide in 79% yield. Nitrobenzene in oleum (7%) was converted in only two minutes at room temperature into the corresponding pentabromide.[82] Calculations showed that protonation of one, two, and three TBCA carbonyls successively increased its brominating activity.[82] However, TBCA in trifluoroacetic acid (TFA) turned out to be more universal.[83] A large variety of aromatic substrates, including some that were moderately and highly unreactive, gave good yields (Scheme [60]).

DBDMH activated by H₂SO₄ was applied to the synthesis in aqueous solution of mono- and polybrominated derivatives of the simplest five-membered nitrogen-containing heterocycles.[84]

N,N-Dibromo-p-toluenesulfonamide (TsNBr₂) was proposed for the bromination of anilines and phenols (Scheme [61]).[85] The reaction occurred quickly and was accompanied by the formation of polybromides.

N,N,N′,N′-Tetrabromobenzene-1,3-disulfonamide (72) and poly(N-bromobenzene-1,3-disulfonamide) (73) were slightly more active.[86] They were reported earlier and used for monobromination of substrates containing electron-donating­ groups and condensed aromatic compounds.[86] Furthermore, these reagents were highly para-selective. Several unreactive substrates could be brominated in strongly acidic solution by using these reagents (Scheme [62]).[87] Obviously, the activation mechanism of N-bromosulfonamides is analogous to that for TBCA and related compounds in acidic solution.

Tetrapropylammonium nonabromide was the first ionic polybromide to be proposed for organic brominations (Scheme [63]).[88] This compound was readily obtained by the reaction of Br₂ with tetrapropylammonium bromide,[89] was sufficiently stable during storage (at 4 °C), and could be manipulated in air.[88] An obvious advantage of this reagent over other polybromides is the high active bromine content (71 mass%) and the resulting reduction of waste.

A series of imidazolium-based tribromides were proposed for monobromination of phenols and aromatic amines (Figure [2]).[90] [91] [92]

Compounds 74 and 75 contained two imidazolium groups and were solids at room temperature.[91] [93] Compound 76 was a room-temperature ionic liquid (RTIL).[92] All these salts are stable during storage and are much less hazardous than Br₂. The imidazolium bromides obtained after the reaction could be easily extracted with water, dried, and reused to prepare the tribromides. The reactions with solids 74 and 75 were performed in solution (CH₂Cl₂ and MeCN, respectively) whereas RTIL 76 did not require a solvent. This was an additional advantage with respect to green chemistry. Furthermore, tribromide 76 was more active than the other two reagents.

The CaBr₂–Br₂ system was also proposed for bromination of anilines and phenols containing various substituents including electron-accepting ones.[94] In this instance, adding one or two equivalents of Br₂ to an aqueous CaBr₂ solution formed the tribromide ion. Then, the aromatic substrate was added to the reaction mixture. The CaBr₂ solution remaining after separation of the product could be neutralized with calcium hydroxide or carbonate and recycled.

Aromatic electrophilic bromination using traditional reagents including Br₂ has been exceedingly broadly employed to synthesize a variety of products comprising alkaloids,[95] [96] [97] [98] [99] [100] physiologically active compounds,[99–102] nucleoside analogues,[103] and dyes.[104] [105] In many instances, successful selective bromination depended on the structure of the aromatic substrate. In turn, the regioselectivity of the bromination was responsible for the ability to introduce some groups or others into the required positions.

A strategy based on sequential functionalization of a pyrrole ring using a combination of bromination with lithium–bromine exchange and a Suzuki reaction was implemented in order to synthesize the marine alkaloids lamellarins L and N (Scheme [64]).[95] Boc-protected pyrrole was smoothly brominated in the 2- and 5-positions.[106] Treatment with one equivalent of butyllithium allowed one of the bromine atoms to be exchanged for lithium and the methoxycarbonyl­ group to be introduced. The remaining bromine atom was replaced by an aryl group via reaction with arylboronic acid 77a. Then, a combination of bromination and cross-coupling with arylboronic acids 77b and 77c at the 4- and 3-positions gave triarylpyrrole 78, a key intermediate in lamellarin synthesis.

Pyrrole was brominated in the final step of the synthesis of the alkaloid breitfussin B (79) that was proposed by Khan and Chen (Scheme [65]).[96]

However, the selectivity of the bromination was problematic for breitfussin precursor 80 (and related compounds) in solvents such as MeCN and THF. The reaction occurred slowly and formed primarily products disubstituted on both the isoxazole and pyrrole rings or the undesired monosubstituted isoxazole 81. Compound 81 was the major product in acetone (Scheme [65]). As it turned out, the re­gioselectivity could be switched to such that it was directed toward formation of the target compound by adding pyridine. In this instance, a deprotonated pyrrole fragment could be rapidly brominated. Furthermore, it was found that undesired regioisomer 81 converted into breitfussin B (79) during chromatography over silica gel.

Compound 82 with an iodo-isoxazole underwent regio­selective bromination of the pyrrole in an alternate method for synthesizing breitfussin B (Scheme [66]).[97] In this instance, the iodine acted as a specific protecting group.

An approach to the preparation of mono- and dibromo derivatives 83–85 of the highly active substrate 3-phenyl-4,6-dimethoxyindole was reported.[107] It required preliminary introduction of an electron-withdrawing accepting group into the indole 1-position (Scheme [67]).[107] Attempts to perform the reaction with 3-phenyl-4,6-dimethoxyindole itself were unsuccessful and resulted in complicated product mixtures; that is, the reaction was uncontrolled. The slightly reduced reactivity of the indole nitrogen atom after introduction of an acyl or sulfonyl group allowed the mono- or dibromo derivatives to be formed in a controlled manner. The second bromination of substrates containing an acyl group occurred at the 7-position (product 83) whereas a bulkier phenylsulfonyl group directed the substituent into the 5-position (product 85). The target bromoindoles were obtained by removing the protecting groups in alkaline solution.

Oxidative Bromination

Despite the obvious advantages of reagents such as NBS or tribromides over Br₂, it should be noted that these same reagents are synthesized, as a rule, using Br₂. Oxidative methods in which the electrophile is generated by oxidizing bromide provide an alternative. Aromatic compounds are brominated in nature in just this manner.[108] The oxidant is H₂O₂; the catalyst, a haloperoxidase, namely a special vanadium- or iron-containing enzyme. A significant number of studies focussing on synthetic oxidative bromination methods, including green approaches, have been published in the last 20 years.[14] [15] The bromine sources were usually HBr or potassium, sodium, or ammonium bromide. The oxidant could be oxygen or H₂O₂ in the presence of a suitable catalyst[14] in addition to inorganic oxidants such as NaBrO₃,[109] [110] HNO₃,[111] H₅IO₆,[112] and Oxone^®.[113] The regioselectivity of oxidative bromination was determined mainly by the substrate’s electron-density distribution and correlated with the regioselectivity of ordinary electrophilic bromination.

Obviously, atmospheric oxygen is the most attractive oxidant. The capacity for aerobic bromination in nitrate-containing ionic liquids was demonstrated earlier.[114] An outcome of this approach was the development of a method for brominating alkylbenzenes, phenols, and their ethers using simple ionic liquids such as mixtures of alkylammonium nitrates; in particular, ethylammonium nitrate, with concentrated HBr (Scheme [68]).[115]

Mixtures of ortho- and para-isomers were formed from monoalkylbenzenes and phenol, whereas anisole was selectively brominated. An electron-accepting nitro group in the benzene ring caused the yield to drop considerably. The method could be extended to thiophene derivatives (Scheme [68]).

A method for aerobic oxidative bromination of a series of alkylbenzenes, phenols, and their ethers in aqueous solution in the presence of a small excess of HBr and catalytic amounts of 2-methylpyridinium nitrate was also proposed.[116]

Nitrate was essential to the reaction mixture in the aforementioned methods. The oxidative bromination mechanism could be represented as successive redox cycles involving oxygen, nitrate, and bromide (Scheme [69]).[14] [116] Spent ionic liquids could be regenerated and recycled.

A effective procedure using ammonium bromide and Oxone^® as the oxidant was proposed for bromination of phenols and their ethers, aromatic amines, polyalkylbenzenes, and naphthalene derivatives.[117] The reaction occurred at room temperature in aqueous (50%) methanol in good and high yields. Aromatic amines gave significant quantities of the dibromo derivatives.[117]

The combination of NaBr with Oxone^® was used for the solvent-free bromination of phenols promoted by mechanical milling.[118] The method was used to produce di- and tribromo derivatives in high yields.

The combination of NaBr and orthoperiodic acid in aqueous solution was proposed for the oxidative bromination of activated substrates, mainly anilines.[119] The reaction occurred at room temperature and afforded the corresponding monobromo derivatives in high yields.

The combination of NaBr and NaIO₄ in dilute aqueous H₂SO₄ (~1:1) was reported to monobrominate unreactive substrates, such as chloro-, nitro-, and dinitrobenzene, benzoic acid, and o- and m-nitrobenzaldehydes, in high yields.[120]

The use of iodine(V) oxide as an oxidant in combination with KBr was also proposed. High yields were obtained for the monobromination of anisole derivatives substituted with various electron-accepting substituents (Scheme [70]).[121] Dibromo derivatives were prepared from several substrates without electron-accepting groups and also for p-bromoaniline. Nitrobenzene did not react under these conditions.

DMSO is available and cheap and can oxidize HBr.[122] [123] [124] This method was found to be suitable for electron-rich substrates. In particular, a convenient method using a mixture of equal volumes of DMSO and concentrated HBr was proposed for the bromination of various alkyl-substituted anilines and pyrroles containing an electron-accepting substituent in the 2-position.[123] Significant excesses of the reagents were used. However, mono- or dibromoanilines were isolated in high yields depending on the reaction temperature and time.

An effective bromination procedure for a broad array of electron-rich substrates using stoichiometric amounts of DMSO and HBr was recently reported (Scheme [71]).[124]

Furthermore, many π-electron-rich heterocycles, in addition to several natural compounds containing a phenol or indoline moiety, were brominated using the developed method (Scheme [72]).[124]

The electrophile in these methods could be either bromodimethylsulfonium bromide (86) or Br₂ formed via the reaction of DMSO and HBr (Scheme [73]).[124] [125]

Heterocycles, an important class of substrates, can be brominated by various oxidants including those described above.

In particular, a method for bromination of N-substituted indoles using the commercially available fluorinating reagent Selectfluor^® (87) was developed (Scheme [74]).[126] The optimum bromine source in this instance was tetrabutylammonium bromide (TBAB).

A reagent system comprising NaBr and NaBrO₃ was applied successfully to the production of monobromo derivatives of 2- and 3-aminopyridines (Scheme [75]).[127]

A 2:1 mixture of NaBr and NaBrO₃ reacted in acidic solution to form three equivalents of the electrophile hypobromous acid.[110] [127] A stoichiometric amount of these reagents was sufficient to attain high yields.

1-Butylpyridinium bromide and the green oxidant H₂O₂ were used to brominate a large series of 2-aminopyridines.[128] The reaction was carried out in DME at 80 °C in the presence of PTSA in order to avoid formation of the N-oxide. The method could tolerate alkyl groups on the exocyclic nitrogen atom and, more interestingly, various substituents in the pyridine ring (methyl, methoxy, halo, cyano, and nitro groups).

The electrochemical bromination of pyrazoles was carried out with a platinum anode and bromide ions (Scheme [76]).[129]

The reaction was carried out in a thermostatted glass cell with a porous glass diaphragm separating the electrodes. The cell was filled with NaBr solution. The heterocyclic substrate was placed in the anodic compartment. An organic solvent (CHCl₃) could also be added in order to reduce side-product formation. The reaction mixture was stored for one hour after the required amount of electrical current had passed. In many instances, good and high yields of bromination products were obtained (Scheme [76]).[129]

Bromination of Heterocyclic N-Oxides

The introduction of a bromine atom in the pyridine 2-position without strongly electron-donating hydroxy or amino substituents in a suitable position is a challenging synthetic problem. A strategy based on lithiation could be used to solve this.[130] An alternate version involved bromination of the N-oxides of the corresponding hetarenes. The N-oxides could be easily prepared via oxidation of the hetarenes themselves. However, subsequent bromination required forcing conditions and was frequently associated with side reactions. In 2013, Baran and co-workers proposed the regioselective conversion of N-oxides of condensed azines into the corresponding heterocyclic bromo derivatives under exceptionally mild conditions (Scheme [77]).[131]

The reaction mechanism included activation of the N-oxides by sulfonylation of the oxygen atom using p-toluenesulfonic anhydride, followed by nucleophilic attack of bromide at the 2-position and final elimination of PTSA. The method produced brominated quinolines and isoquinolines in good and high yields and was extended to several other condensed pyridine systems. However, it was not applicable to pyridine itself. A similar method was used to synthesize an antiviral drug based on 6-azaindole.[132]

It was also reported that fluoroborate complexes of 1-aryl-4,5-dimethylimidazole N-oxides were converted into the corresponding 2-bromoimidazoles upon heating with tosylbromide and pyridine in THF by a mechanism analogous to that described above.[133]

Conclusions

Aromatic bromo derivatives are a very important class of intermediates in organic synthesis, are definitely interesting in medicinal chemistry, and form a significant group of natural compounds. The methodology for producing bromoarenes via C–H functionalization has recently been extensively developed. Research is focused on the design of reactions with inherent regioselectivity and green methods, using conveniently accessible and safe reagents. Ligand-directed­ transition-metal-catalyzed bromination is becoming a more universal tool for introducing a bromine atom into the ortho-position. Both ordinary functional substituents, including those coordinating weakly to metals, and specially developed removable or functionalizable directing groups can be used. In several instances, the developed transition-metal-catalyzed reactions can be very effective. The required amount of catalyst can be reduced to fractions of a mol%, thus compensating for its high cost. The activation of N-bromoimides by Lewis bases enables the unique enantioselective synthesis of a broad spectrum of compounds with axial chirality. A large number of convenient preparative methods for various bromoarenes, including heterocyclic derivatives, have been designed. Convenient oxidative bromination methods using accessible and cheap oxidants, atmospheric oxygen and DMSO in particular, have been developed. Research on the bromination of aromatic compounds will undoubtedly be critical and necessary in the future, especially with respect to heterocyclic and electron-deficient substrates.

Acknowledgment

The financial support of the Russian Foundation for Basic Research (grants # 14-03-00311 and 14-03-93001) is gratefully acknowledged.

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