Bromination by A -bromosuccinimide

Saturated large rings can form nitrogen radicals by H abstraction from N, or abstraction may occur in the - or -positions in non-nitrogen systems. Oxepane gives the radical in the 2-position, with subsequent cleavage and reclosure of the intermediate carbenoid to cyclohexanol. In unsaturated large systems, a variety of reactions, unexceptional in their nature, are found. Some azepines can be brominated by A-bromosuccinimide others decompose under similar conditions. 

Bis(trifluoromethyl)-5,6,7,8-tetrahydroquinazoline is brominated by A -bromosuccinimide at both benzylic positions. The resulting dibromo derivative 3 undergoes elimination of hydrogen bromide in the presence of a tertiary amine to afford 2,4-bis(trifluoromethyl)quinazoline... 

Another case where formation of a favorable cyclopropylmethyl cation supersedes the usual radical-chain mechanism of bromination by A-bromosuccinimide has been described in the literature. Direct evidence for the intermediacy of cation A was obtained by trapping it with methanol. When bromination was carried out in the presence of low concentrations of methanol three methoxy bromides were formed which, however, were thermally unstable. In order to alleviate the thermal instability the mixture of methoxy bromides was reduced with sodium//er/-butyl alcohol in tetrahydrofuran, which produced three methyl ethers in the ratio 80 18 2. By comparison with authentic materials the main component appeared to be 3-methoxy-tricyclo[3.2.1.0 ]octane (51) while the second was exo-7-methoxybicyclo[3.2.1]oct-2-ene (52). The structure of the 2% component was not confirmed. Both 51 and 52 result from methoxy bromides that are expected from trapping of the postulated cation A. It is noted that in both reactions of A, deprotonation (as in the formation of 50 from 48 in the absence of methanol) and addition of methanol, the formation of a tricyclic product is favored. However, methanol apparently can also add to (one of) the other positively charged carbon atoms of A, whereas of the three possible modes of deprotonation of A only the one leading to 50 is realized. ... 

The treatment of stannylenes (see Section 5.1.5) dissolved in benzene with a bromine solution in the same solvent in the presence of molecular sieves or BujSnOMe as base, gives, at room temperature, the hydroxyl ketone at the rate of titration (David and Thieffrey 1979). The reaction is nearly uniformly regiospecific, that is to say that it gives only one of the two possible hydroxyl ketones (reaction 5.15). The same selective activation by stannylation, already observed in benzylation, allylation, and acylation, is found here. Thus, compound 5.28 is prepared from diol 5.27 in 75% yield. The replacement of bromine by A -bromosuccinimide without any other reagent has recently been recommended (Kong and Grindley 1993). 

T. L. Hullar and S. B. Siskin, Facile bromination by A-bromosuccinimide of benzylidene acetals of carbohydrates. Application to the synthesis of 2,6-imino carbohydrates (substituted... 

Bromination with A-bromosuccinimide generally gives the same result as bromination with free bromine or hypobromous acid. The reaction is considered to proceed with a small concentration of free bromine and does not generate an appreciable concentration of acid. Conditions are therefore mild. In addition, A-bromosuccinimide has been used to brominate the allylic position of a, -unsaturated ketones in the presence of free-radical promoters or with irradiation, and thus gives access to dienones by dehydro-halogenation, for exaraple " ... 

Allylic bromination, with A -bromosuccinimide (NBS), of 4-ethoxy-l,2-dihydrocyclo-pent[rf]azepine (8), formed by ethylation (with Meerwein s reagent) of the corresponding 4-oxo derivative, followed by in situ dehydrobromination of the resulting bromo compound with basic alumina, produces a low yield of l-bromo-2-ethoxycyclopent[c/]azepine (9) as a photosensitive, sapphire-blue, crystalline solid.55... 

Benzodioxocin (14) can also be prepared starting from the dihydro derivative 17.14 Whereas an attempted bromination-didehydrobromination procedure was not successful, the required dehydrogenation was achieved by bromination with A -bromosuccinimide and treatment with triethylamine, by double bromination with iV-bromosuccinimide and debromination with zinc, or by pyrolysis of a diacetate derived from 17 by bishydroxylation and acetylation.14... 

Heterocycle, 30, is brominated at the expected position by A -bromosuccinimide in excellent yield (Equation 2) <2004H(63)2475>. 

Dihydro-1,4-oxathiins (336 Z = 0) and 5,6-dihydro-1,4-dithiins (336 Z = S) are easily obtained from 1,3-oxathiolanes (335 Z = 0) and 1,3-dithiolanes (335 Z=S), respectively, by treatment with bromine (9IS223), A-bromosuccinimide (94T7265), chlorine (87JOC5374, 91S223), or sulfuryl chloride (88JCR(M)1401>. 

Stannylenes are oxidized to keto-alcohols by dropwise addition of bromine in di-chloromethane. The reaction proceeds at room temperature at the speed of a titration. The attention of chemists who want to check their reaction by infrared (IR) examination in situ is drawn to the fact that the ketone may be chelated to tin in these conditions (vqj 1685 cm-1). The reaction is regiospecific, giving only one of the two possible keto-alcohols. It has been used in total synthesis for instance, in the synthesis of (+)-spectinomycin (described under Sec. QI.G) [12,13]. The replacement of bromine by IV-bromosuccinimide as oxidant has been reported [14]. 

The presence of an electron-withdrawing substituent on the five-membered ring of the indole system generally deactivates that ring to electrophilic attack by both elemental bromine and A-bromosuccinimide. Thus, ethyl indole-3-carboxylate and 3-formylindole are brominated on the benzenoid ring (72HC(25-2)127,79HC(25-3)357). The 2-carboxylic ester, however, yields the 3,5-dibromo derivative. 

Tetrahydrobenzo[ ]thiophene behaves like thiophene in electrophilic substitution reactions. Thus, it is formylated with a mixture of vV-methylformanilide and phosphorus oxychloride,436 iodinated in the presence of mercuric oxide,193 and brominated by V-bromosuccinimide,193 all in the 2-position in Friedel-Crafts reactions with acetyl chloride,194-436 propionyl chloride,436 succinic... 

Table 4-1 compares two different reactions, namely, anode oxidation and oxidation with cerium ammonium nitrate (which are bona fide electron-transfer processes) and bromination by /V-bromosuccinimide in the presence of azobis(iso-butyro)nitrile (which is bona fide hydrogen-atom-transfer process). Both electron-transfer and hydrogen-atom-transfer processes have the benzylic radical as a common intermediate, but positional selectivity is stronger for electron-transfer processes. Another important point is the preference of the 2-positioned methyl group over the 1-positioned group, in terms of selectivity. For 1,2,3-tetramethylbenzene, such a preference reaches values from 16 to 55, and it is over 200 for 5-methoxy-1,2,3-tctramcthylbcnzcnc. 

Only benzylic (or ally lie) hydrogens are replaced by A-bromosuccinimide. Among the four bromines in 3,4,5-tribromobenzyl bromide, three are substituents on the ring and are not capable of being introduced by benzylic bromination. The starting material must therefore have these three bromines already in place. 

Bromination of thiophene derivatives by A-bromosuccinimide (NBS) in 50 50 (v/v) chloroform-acetic acid proceeds by an electrophilic rather than a radical mechanism.91 Many experimental facts favor such a hypothesis (i) only ring-substituted products are formed, with exclusion of addition or side-chain substitution (ii) the reaction is very selective, only a-substituted products are formed and (in) the... 

Halogenation proceeds through N- halotriazoles or triazolium derivatives that have been discussed under Section 4.12.3.2.4. Also the bromination of AT-substituted triazoles by A-bromosuccinimide in chloroform (75BSF64 ) is thought to involve AT-bromotriazolium intermediates. If so, the same applies to halogenations with N- halotriazoles (69ZC32s). 

Another pathway that has attracted much attention is the dehydrogenation of chromanes. Bromination with A -bromosuccinimide followed by base treatment gives fair yields,but the reaction may bo complicated by the formation, sometimes exclusive,of a 3- or... 

Since the only by-product of the reaction is ethyl acetate, the silylated product can be employed for further reactions without purification. Examples include the fluoride-catalyzed aldol reaction and bromination with A -bromosuccinimide. ... 

Quinocydopropenes were first synthesized via addition of chlorophenylcarbene to (4-benzyl-oxyphenyl)phenylacetylene (22), ionization to the cyclopropenylium ion, thermal debenzyl-ation, and treatment with triethylamine. The 4-hydroxyphenyl moiety of the cation was smoothly brominated at the 3- and 5-positions by A-bromosuccinimide, leading to the dibromo-quinocyclopropene. While quinocyclopropene 23, with no substituents in the six-membered ring, was unstable, dibromo compound 24 was stable to light and heat but reactive to alkali. 

Oct-OPV5 and Ooct-OPV5 were prepared following a procedure that was used to prepare terf-butyl-end-substituted oligo(phenylene vinylenes) [43], Benzyltri-phenylphosphonium bromide was lengthened by a styryl unit via a Wittig reaction with 4-methylbenzaldehyde. The methyl group of the stilbene was functionalized by bromination with A -bromosuccinimide (NBS). The phosphonium salt of the stilbene was obtained by a subsequent reaction with triphenylphosphine in toluene. 

Bromination in the 8-position of diethyl 3-methylpyrido[3,4-6]pyrazine-5,7-dicarbamate (7) is accomplished by A-bromosuccinimide.98... 

Phenylcyclopenta[e][l,2,3,4]tetrazine (1) undergoes electrophilic substitution reactions preferentially at C7, as has been demonstrated by bromination with A-bromosuccinimide, formy-lation with phosphoryl chloride/dimethyl formamide and trifluoroacetylation with trifluo-roacetic anhydride/triethylamine.37 Addition of tetrafluoroboric acid to 1 results in the formation of the protonated salt 2.37... 

However, 2-benzyl-3,5-diamino-2/f-l,2,6-thiadiazine 1,1-dioxide (118) is brominated at C-4 in high yield (83%) by A -bromosuccinimide in methanol (Equation (7)) <91AF264>. Under similar conditions 5-amino-2-benzyl-4/f-l,2,6-thiadiazin-3(2//)-one 1,1-dioxide (119) yields the 4,4-di-bromo derivative (120) (Equation (8)). 

In the case of 4-methyl-2,5-disubstituted oxazoles, bromination with either bromine or A-bromosuccinimide affords the 4-bromomethyl compound.307 2-Bromomethyl-4,5-diphenyloxazole is obtained by bromination of the corresponding oxazole with NBS in the presence of dibenzoyl peroxide.121 Reaction with phosphorus pentachloride similarly gives the side-chain-chlorinated products.80... 

In a similar way, prodrug 59 was obtained from methyl ortho-tolyl uronate 66 (67) by (i)-bromination with A-bromosuccinimide to 67, (ii)-hydrolysis to 68, (iii)-activation using disuccinimidocarbonate to 69, and (iv)-condensation with doxorubicin to 70, which was finally deprotected in situ into 59 during in vitro test of enzymatic behaviour (Fig. 5) (66). 

Two methods are available for direct side-chain halogenation of alkylated iV-heterocycles (a) halogenation in glacial acetic acid containing sodium or potassium acetate,754,755 the mechanism of which is the same as that of bromination of ketones 756 and (b) bromination by iV-bromosuccinimide. 

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