Bromine and NBS

In view of this apparent resistance of triazolium to bromination with electrophilic bromine, it is interesting to discover that 1,3-dimethyl-1,2,3-triazolium tosylate (71) was 4-brominated by bromine and NBS. When the 4-bromo salt (72) is dissolved in base, an equilibrium is established containing unbrominated salt (71) and 4,5-dibromo salt (73). Presumably, base converts 72 into an ylid, which is further brominated by 72. A similar product mixture was obtained from the isomeric 5-bromo tosylate (74) [69ACS(B)2733 71ACS(B)249] (Scheme 27). 

Sulfoxides are best a-brominated with a combination of bromine and NBS in pyridine. ... 

The stereospedfic and regioselective hydrobromination of alkynes with chlorobis(T -cyclopentadienyl)hydrozirconium and NBS produces ( )-vinylic bromides in good yields. The bromine atom usually adds regioselectively to the carbon atom that bears the smaller substituent and stereoselectively trans to the larger substituent (D.W. Hart, 1975 M. Nakatsuka,... 

Bromination using NBS has been used to provide acetylpyrazine derivatives from the corresponding ethylpyrazines. Bromination of 2-ethyl-3-methylpyrazine gives 2-bromoethyl-3-methylpyrazine in quantitative yield this may be oxidized using the sodium salt of 2-nitropropane or with pyridine AT-oxide to yield 2-acetyl-3-methylpyrazine in yields of 66 and 25% respectively (Scheme 14). 

Isoxazoles can be halogenated in the 4-position (63AHC(2)365). Ring bromination of oxazoles with bromine or NBS occurs preferentially at the 5-position and, if this is occupied, at the 4-position (74AHCI 17)99). Aminooxazoles are readily halogenated. 

Current views (100) on the mechanism of bromination by NBS invoke the formation of molecular bromine and bromine atoms in low concentration, which subsequently act as the brominating agent. The bromination reaction was studied in detail in this laboratory under a variety of conditions using 93 (R = Ms) as a model. The product 94 (R = Ms) was indeed formed (42%) when NBS was substituted by 1.1 equivalents of bromine which was added at a slow rate to the reaction mixture. The yield was 68% when benzoyl peroxide was used as a catalyst. Using NBS alone or in the presence of reagents such as barium carbonate, pyridine, or s-trinitrobenzene, the yield was 60-70%. 

This allylic bromination with NBS is analogous to the alkane halogenation reaction discussed in the previous section and occurs by a radical chain reaction pathway. As in alkane halogenation, Br- radical abstracts an allylic hydrogen atom of the alkene, thereby forming an allylic radical plus HBr. This allylic radical then reacts with Br2 to yield the product and a Br- radical, which cycles back... 

Electrophilic bromination (and nitration) of pyrido[l, 2-a]benzimidazole (analogous to 132) cannot take place in the imidazole moiety. Initial substitution, using NBS as reagent, was shown to occur at the 8-position, and subsequently at C-4 and C-6 (90JOU1166). 

It was not possible to brominate the [l,2,4]triazolo[l,5-a]pyridine species (137) directly with bromine or NBS, but the 5- and 8-bromo (66CPB523) and 3-chloro (66JOC265) derivatives were made from the diazonium salts. More recently regiospecific 5-lithiation of 137 has provided access to the 5-bromo derivative in 94% yield (92JOC5538). 

Fig. 1. Plots of dielectric constant vs selectivity of bromination of phenol with Br2 (left) and NBS (solid powder) (right). ort/io-Bromophenol (A), para-Bromophenol ( ).

We considered A-bromoamines which generated in situ from the reaction of NBS and various amines, should promote the o/t/io-dibromination of phenol. The results of the bromination with NBS in the presence of amines are summarized in Table 2. 

Consequently the bromine adduct was obtained in high yield (83 %). Using NBS and a catalytic amount of the amine, the ratio of the ort/io-brominated phenols was remarkably raised. 2-Allylphenol and o-cresol were considerably orr/io-brominated by NBS even without the amine. In NBS-amine system dibromides as by-products were obtained slightly and any p jra-bromide and bromine adduct in the case of 2-allylphenol were not detected. 

It is generally supported that the bromination with NBS proceeded by a radical (ref. 11) or an ionic mechanism via bromine molecule. For instance, the former was suggested in benzylic and allylic bromination with NBS for Whol-Ziegler reaction (ref. 12). Calo et al. (ref. 5) accounted NBS brominated phenol by the latter mechanism. 

Because the tertiary amines cannot be brominated by NBS, they do not influence the o/tAo-bromination of phenols. Though the hydrogen bonding between the phenolic OH and NBS will be formed, the bonding is inferred to be weaker than that between the OH and the (V-bromoamines. The nucleophilicity (or basicity) of the nitrogen atom of A -bromoamines is stronger than that of NBS. This is why traces of A -bromoamines can react with phenols continuously. 

The compounds 12,14 and 15 can be prepared from parent lysergic acid amides by bromination with NBS or PHT, but not the compounds of the type 12. The latter structure is very sensitive and under these circumstances only degradation products were obtained. Besides it was necessary to use much milder reagent, e.g. bromine bonded onto polymeric matrix with polyvinylpyrrolidone or polyvinylpyridine structure (29) ... 

The bromination was carried out with N-bromosuccini . ide NBS, 19), a source of molecular bromine, and the rycllsation proved as easy as expected,... 

The first stable derivative of methylene cyclopropene was the quinocyclopropene 108 reported in 1964 by Kende98 it was prepared from the cyclopropenium cation 106 which underwent pyrolysis and bromination with NBS to the p-hydroxy-phenyl substituted cation 107, which gave quinocyclopropene 108 by deprotonation ... 

Syntheses of the 1,2- and the 3,4-dihydrodiols of MBA via Methods II and IV have been described (74). The 1,2- and 3,4-diol dibenzoates of 1,2,3,4-tetrahydro-MBA prepared from MBA via the Li/-NH reduction route were readily separable by crystallization. Introduction of the olefinic bond into the 1,2-position of the 3,4-diol dibenzoate by the usual bromination-dehydrobromination procedure was complicated by the greater facility of bromination by NBS on the methyl group than the 1-position. This problem was solved (Figure 14) by allowing bromination to proceed to the dibromo stage, followed by selective reduction of the bromomethyl group with NaBH in diglyme. The monobromo derivative underwent dehydrobromination... 

The reaction of nitrones of the 3-imidazoline series (295) with bromine and amyl nitrite, in the presence of base, gives a-tribromomethyl-(296) and a-hydroxyaminomethyl derivatives (297) (538). Bromination of nitrones (295) with N -bromosuccinimide (NBS) in CCI4 or bromine in methanol leads to the formation of a-bromoalkyl (298 a,b, Hal = Br) and a-dibromomethyl (299) nitrones (539-541). The reaction with iodine in methanol gives the mono iodo derivative (300) (541). The reaction with A-chlorosuccinimide (NCS) in CCI4 leads to a-chloroethyl nitrones (298b, Hal = Cl) and a,a-dichloromethyl nitrones (301) (Scheme 2.118) (225). 

Condensation of 2-bromoethylamine hydrobromide with benzoyl chloride in benzene in the presence of 5 equivalents of EtsN gave 2-phenyl-4,5-dihydrooxazole (1) in 67% yield [1]. Treatment of 1 with 3 equivalents of NBS in boiling CCL in the presence of AIBN led to 5-bromo-2-phenyloxazole (2). Presumably, sequential bromination and dehydrobromination of 1 led to 2-phenyloxazole, which underwent further bromination to afford 2. 

Bromination of olefines by NBS is also known as Wohl-Ziegler bromination and as already written, the reaction is specific at allylic position and good yields are obtained. 

That the mechanism of bromination by NBS was a free radical one was first suggested by Goldfinger et al (1953, 1956) and later supported by Dauben and Me Coy in 1959 and also by Tedder et al in 1960 and 1961. The strongest point in favour of the reaction being a free radical one is that it is catalysed by free radical initiators like peroxides and is also promoted by light. Indeed new substitution at the allyl position is often used to detect free radicals. Like free radical reactions, it is also retarded by inhibitors. 

---