Bromination nucleophilic displacement

Less activated substrates such as uorohaloben2enes also undergo nucleophilic displacement and thereby permit entry to other useful compounds. Bromine is preferentially displaced in -bromofluoroben2ene [460-00-4] by hydroxyl ion under the following conditions calcium hydroxide, water, cuprous oxide catalyst, 250°C, 3.46 MPa (500 psi), to give -fluorophenol [371-41-5] in 79% yield (162,163). This product is a key precursor to sorbinil, an en2yme inhibitor (aldose reductase). 

Similarly, the reaction with bromine yields the corresponding 5-bromo derivatives, which are suitable substrates for nucleophilic displacement or dehydrohalogenation reactions. Typical nucleophiles (Nu) are H2O, NH, RNH2, and sodium barbiturates ... 

Substitution reactions on dialkyl peroxides without concurrent peroxide cleavage have been reported, eg, the nitration of dicumyl peroxide (44), and the chlorination of di-/ fZ-butyl peroxide (77). Bromination by nucleophilic displacement on a-chloro- or a-hydroxyalkyl peroxides with hydrogen bromide produces a-bromoalkyl peroxides (78). 

Imidazo[l,2-c]pyrimidine, 2,5,7-trichloro-nucleophilic displacement reactions, 5, 627 Imi dazo[ 1,2-a]pyrimidines pK, 3, 338 reactivity, 5, 627 synthesis, 5, 647 Imidazo[ 1,2-c]pyrimidines reactions, 5, 627 structure, 5, 610 synthesis, 5, 648-649 lmidazo[ 1,5-a]pyrimidines reactions, 5, 628 synthesis, 5, 649 lmidazo[l,5-6]pyrimidines synthesis, 5, 649-650 Imidazopyrrolopyridines bromination, 4, 506 lmidazo[4,5-6]quinoxaline nomenclature, 1, 22... 

With bromine monochloride at 0°C in a variety of solvents, 1 was converted into addition products, the product distribution being a function of solvent. A change in halogenating agent also altered the product ratio. (Scheme 4) Nucleophilic displacement reactions between these products and silver fluoride was found to cause preferential bromine substitution (83G149). 

Benzofurazan (benz-1,2,5-oxadiazole) reacted with bromine by addition to give a4,5,6,7-tetrabromo adduct. Bromine in hydrobromic acid solution 4-brominated both 5-methyl- and 5-bromo-benzofurazans (74JHC8I3). When 4,7-dinitrobenzofurazan was treated with ammonium chloride in refluxing acetic acid, nucleophilic displacement gave rise to the 4-chloro-7-nitro derivative (83URP1004375). Naphtho[l, 2-c]furazans (42) are mainly 4-halogenated, but there is minor substitution in the 8-position (73CHE1331). 

Nucleophilic substitution reactions, to which the aromatic rings are activated by the presence of the carbonyl groups, are commonly used in the elaboration of the anthraquinone nucleus, particularly for the introduction of hydroxy and amino groups. Commonly these substitution reactions are catalysed by either boric acid or by transition metal ions. As an example, amino and hydroxy groups may be introduced into the anthraquinone system by nucleophilic displacement of sulfonic acid groups. Another example of an industrially useful nucleophilic substitution is the reaction of l-amino-4-bromoanthraquinone-2-sulfonic acid (bromamine acid) (76) with aromatic amines, as shown in Scheme 4.5, to give a series of useful water-soluble blue dyes. The displacement of bromine in these reactions is catalysed markedly by the presence of copper(n) ions. 

Figure 27.4 Reaction of guanine bases with N-bromosuccinimide causes bromination at the C-8 position of the ring. Amine nucleophiles can be coupled to this active derivative by nucleophilic displacement. Reaction of diamine compounds results in amine-terminal spacers that can be further modified to contain detectable components.

In the case where R = Ph, a bromine cleavage of one phenyl group of 29 allows, by subsequent nucleophilic displacement of the resulting bromide, the preparation of several other alkyl or phenyl-substituted derivatives of germanium65. 

The nucleophilic substitution of 1,2,3-triazole is also activated by A-oxidation. In 3-substituted 1,2,3-triazole 1-oxides, a halogen substituent at C(4) is more reactive than one at C(5) <87ACS(B)724>. Therefore, the C(4) chlorine of compound (221) (Equation (19)) is displaced by methoxide under much milder conditions than the corresponding C(5) chlorine of (222) (Scheme 39), and the only C(5) bromine is displaced in the case of 4,5-dibromotriazole 1-oxide <88BSB573>. 

Nucleophilic displacement of Z-, 4-, and 6-halo substituents by alkoxy or aryloxy ions occurs readily except in the presence of strongly electron-releasing substituents in the ring <1994HC(52)1>. Stepwise reaction can be achieved with di- and trihalo-pyrimidines, with the more reactive 4-position being the first site of reaction. For example, even with the presence of a bulky ortho substituent such as a 5-bromine atom, selective methanolysis at the 4-position was still observed with 5-bromo-2,4-dichloropyrimidine 179 <2006TL4415>. 

The same procedure failed to work with 2-bromopyrimidine due to direct nucleophilic displacement of the bromine by the amine component <2007TL2339>. 

Treatment of the bromide 93 with the potassium salt of 1,1-dicyanothioacetanide 94 gave the dihydrothiadiazole 95 via initial nucleophilic displacement of the bromine by the sulfur atom in 94, cyclization and then loss of malononitrile <99JCR(S)184>. 

In delineating the scope of the bromination-nucleophilic sulfur reaction, two difficulties have been encountered. Bromination with bromine is not successful with tertiary hydrogens such as those present in prolyl derivatives (72CB625). Bromination can be accomplished by means of N-bromosuccinimide in presence of 2,2 -azobisisobutyronitrile however, in this case, 3,6-dialkylpiperazine-2,5-diones yield tetrabromo derivatives. These could be successfully utilized for the required purpose, as shown in Scheme 37. The trick consisted of displacing the bromine atoms attached to the ring by methoxy groups, followed by debromination and thiolation (75BCJ605). 

An alternate and more controlled approach to the synthesis of phenothiazines involves sequential aromatic nucleophilic displacement reactions. This alternate scheme avoids the formation of the isomeric products that are sometimes observed to form from the sulfuration reaction when using substituted aryl rings. The first step in this sequence consists of the displacement of the activated chlorine in nitrobenzene (30-1) by the salt from orf/io-bromothiophenol (30-2) to give the thioether (30-3). The nitro group is then reduced to form aniline (30-4). Heating that compound in a solvent such as DMF leads to the internal displacement of bromine by amino nitrogen and the formation of the chlorophenothiazine (30-4). Alkylation of the anion from that intermediate with 3-chloro-l-dimethylaminopropane affords chlorpromazine (30-5) [31]. 

The activated bromine atom in bromomethyl phenyl ketone (1) can be replaced by fluorine by refluxing with sodium fluoride in methanol for several hours,12 but besides fluoromethyl phenyl ketone (2), the product of nucleophilic displacement by methoxide ion, methoxymethyl phenyl ketone (3) is also formed. 

One research group has exploited the concept of polymer site-isolation in a multistep/one-chamber solution-phase synthesis in which all the reagents, catalysts, and downstream reactants required for a multistep synthesis were combined in one reaction chamber. For instance, a one-chamber/three-step synthesis of substituted acetophenones has been reported (Scheme 10).84 An a-phenethyl alcohol was introduced into a reaction chamber containing the polymer-supported reagents and reactants necessary to accomplish oxidation by polymer-supported pyridinium dichromate 60 bromination by the A-26 perbromide resin 61 and nucleophilic displacement by the A-26 phenoxide resin 62. Filtration afforded the... 

Halogen atoms in pyrones and pyridones e.g. 902) are unreactive toward SAE nucleophilic displacement. 3-Halopyridines are less reactive than the a- and 7-isomers but distinctly more reactive than unactivated phenyl halides. Thus, a bromine atom in the 3-position of pyridine or quinoline can be replaced by methoxy (NaOMe-MeOH, 150°C), amino (NH3-H20-CuS04, 160°C) or cyano (CuCN, 165°C). 5-Halogens in pyrimidines are also relatively unreactive. 

The normal reactions of benzo[6]thiophene 1,1-dioxides have been reviewed (70AHC(11)177). Electrophilic substitution (nitration, bromination) takes place at position 6. 3-Halo derivatives undergo normal nucleophilic displacement reactions, but 2-bromobenzo[6]thiophene dioxide gives the 3-ethoxy derivative in ethanolic NaOH. The reaction of 3-methoxy derivatives with secondary amines can give rise either to enamines... 

All four isomeric selenolopyridines which can be derived from benzoselenophene (423— 426 Scheme 123) have been described. Ethyl 3-hydroxyselenolo[2,3-fe]pyridine-2-carboxy-late (429) has been prepared as shown in Scheme 124 (73BSF704). Treatment of ethyl 2-chloropyridine-3-carboxylate with methaneselenol yields (427). Nucleophilic displacement of bromine in bromoacetic acid with subsequent loss of methyl bromide yields (428), which after esterification is cyclized under Dieckmann conditions to give (429). The parent compound (423 colorless oil with b.p. 92 °C/1 mmHg) is prepared either by cyclization of compound (430) and subsequent decarboxylation of the intermediate acid (equation 57) or by reduction of 2-nitroselenophene and subsequent condensation of the amino compound with malonaldehyde bis(diethyl acetal) in the presence of zinc chloride (equation 58) (76BSF883). Selenolo[3,2-6]pyridine (426 b.p. 127-129°C/10 mmHg m.p. 35.5-37.0°C) has been obtained in an analogous manner. 

Pyrazino[2,3-d]pyridazines undergo nucleophilic displacements readily. Pyrazino-[2,3-d]pyridazine-5,8-dione can be chlorinated in a mixture of phosphorus oxychloride and phosphorus pentachloride to give 5,8-dichloropyrazino[2,3-d]pyridazine. The corresponding dibromo product is prepared by reaction of the starting dione with phosphorus oxy-bromide and bromine. However, all attempts to chlorinate pyrazino[2,3-d]pyridazin-5-one failed (69JHC93). 

Cyclization of allylic alcohols to form epoxides has been particularly problematical, and the reactions have been more of mechanistic than of synthetic interest. For reactions conducted under basic conditions, it is possible that epoxide formation involves initial halogen addition followed by nucleophilic displacement to form the epoxide. Early examples of direct formation of epoxides from allylic alcohols with sodium hypobromite," bromine and 1.5 M NaOH,12 and r-butyl hypochlorite13 have been reviewed previously.fr Recently it has been shown that allylic alcohols can be cyclized effectively with bis(jym-collidine)iodine(I) perchlorate (equation 3).14 An unusual example of epoxide formation competing with other cyclization types is shown in equation (4).15 In this case, an allylic benzyl ether competes effectively with a -/-hydroxyl group as the nucleophile. 

Although brominated derivatives of the five-membered heterocycles may be prepared by reactions of the co-ordinated ligands, these may then undergo further reactions with nucleophiles. As an example, the nucleophilic displacement of bromide from 8.15 by sulfide has been used to form new macrocyclic systems (Fig. 8-12). The palladium probably serves a dual function in this reaction. First, it organises the open-chain ligand such that the two reactive sites are held in proximity, so allowing the intramolecular formation of the sulfide and, second, it may activate the pyrrolic ring to nucleophilic displacement of bromide. 

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