Bromomethylation

The above mechanism for chloromethylation seems to be general for halo-methylation since bromomethylation gives the same ortho para ratio for toluene, ethylbenzene, and i-propylbenzene, which is entirely in accord with the halogen being substituted in a non rate-determining step of the reaction386. 

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From ehloromethyl or bromomethyl aromatic compounds by heating with hexamethylenetetramine (hexamine) in aqueous alcohol or aqueous acetic acid. A quaternary ammonium compound is formed, which yields the aldehyde upon treatment with water in the presence of hexamine for example... 

The higjily water-soluble dienophiles 2.4f and2.4g have been synthesised as outlined in Scheme 2.5. Both compounds were prepared from p-(bromomethyl)benzaldehyde (2.8) which was synthesised by reducing p-(bromomethyl)benzonitrile (2.7) with diisobutyl aluminium hydride following a literature procedure2.4f was obtained in two steps by conversion of 2.8 to the corresponding sodium sulfonate (2.9), followed by an aldol reaction with 2-acetylpyridine. In the preparation of 2.4g the sequence of steps had to be reversed Here, the aldol condensation of 2.8 with 2-acetylpyridine was followed by nucleophilic substitution of the bromide of 2.10 by trimethylamine. Attempts to prepare 2.4f from 2.10 by treatment with sodium sulfite failed, due to decomposition of 2.10 under the conditions required for the substitution by sulfite anion. 

A suspension of 3.90 g (19.6 mmol) of p-(bromomethyl)benzaldehyde (2.8) and 4.00 g (31.7 mmol) of sodium sulfite in 40 ml of water was refluxed for two hours, after which a clear solution was obtained. The reaction mixture was cooled on an ice bath resulting in precipitation of some sodium sulfite. After filtration, the solvent was evaporated. Ethanol was added to the remaining solid and the suspension was refluxed for 10 minutes. After filtering the hot solution, the filtrate was allowed to cool down slowly to -18 °C whereupon sodium (p-oxomethylphenyl)methylsulfonate (2.9) separated as colourless crystals. The extraction procedure was repeated two more times, affording 2.29 g (10.3 mmol, 53%) of the desired product. H-NMR (200 MH D2O) 5(ppm) =4.10 (s,2H) 7.44 (d,2H) 7,76 (d,2H) 9.75 (s,lH). 

Bromomethyl)- or (hydroxymethyl)cycIopropane derivatives undergo acid-catalyzed homoallyiic rearrangements to yield trans-olefins (J.P. McCormick, 1975 S.F. Brady, 1968 M. Julia, 1974). This rearrangement is the basis of Julia s terpene synthesis (see. p. 70). 

If a bromomethyl- or vinyl-substituted cyclopropane carbon atom bears a hydroxy group, the homoallyiic rearrangement leads preferentially to cyclobutanone derivatives (J. Sa-laun, 1974). Addition of amines to cydopropanone (N. J. Turro, 1966) yields S-lactams after successive treatment with tert-butyl hypochlorite and silver(I) salts (H.H. Wasserman, 1975). For intramolecular cyclopropane formation see section 1.16. 

Unsymmetrically substituted dipyrromethanes are obtained from n-unsubstitued pyrroles and fl(-(bromomethyl)pyiToIes in hot acetic acid within a few minutes. These reaction conditions are relatively mild and the o-unsubstituted pyrrole may even bear an electron withdrawing carboxylic ester function. It is still sufficiently nucleophilic to substitute bromine or acetoxy groups on an a-pyrrolic methyl group. Hetero atoms in this position are extremely reactive leaving groups since the a-pyrrolylmethenium( = azafulvenium ) cation formed as an intermediate is highly resonance-stabilized. 

With the catalysis of strong Lewis acids, such as tin(IV) chloride, dipyrromethenes may aiso be alkylated. A very successful porphyrin synthesis involves 5-bromo-S -bromomethyl and 5 -unsubstituted 5-methyl-dipyrromethenes. In the first alkylation step a tetrapyrrolic intermediate is formed which cyclizes to produce the porphyrin in DMSO in the presence of pyridine. This reaction sequence is useful for the synthesis of completely unsymmetrical porphyrins (K.M. Smith, 1975). 

Benzyl indole-5-carboxylate Methyl 4-(bromomethyl)-3- 45 methoxybenzoate, DMF, 80°C [9]... 

Enantioselective synthesis of tryptophans has been accomplished via alkylation of 2,5-diethoxy-3,6-dihydropiperazines by the method developed by Schbllkopf[18]. For example, I> - -)-6-methoxytryptophan ethyl ester was prepared using l-(phcnylsulfonyl)-3-(bromomethyl)-6-methoxyindolefor alkyl-ationfl 9],... 

Bromomethyl-l-adamantyl ketones were condensed with thioamides of carboxylic or carbonic acids to give the corresponding thiazoles (613). 

Thiazoles with Heterocyouc Substituents. Thiazoles with heterocyclic substituents in the 2- or 4-position have been synthesized (Table II-9). Thus thioacetamide (or its a-substituted derivatives) react with bromomethyl heteroarylketones under reflux in alcohol to give the corresponding 2-methyl-4-heteroarylthiazoles heteroaryl groups in the 4-position were 2 -thienyl (213, 692) a-pyrrolyl and 3-method derivatives... 

Can you think of how bromomethyl phenyl ketone might be prepared" ... 

Analyzing the target molecule in this way reveals that the required alkyl halide IS an a halo ketone Thus a suitable starting material would be bromomethyl phenyl ketone... 

Interpenetrating networks of DMPPO and polymers such as polystyrene, polybutadiene, poly(urethane acrylate), and poly(methyl methacrylate) have been prepared by cross-linking solutions of DMPPO containing bromomethyl groups with ethylenediamine in the presence of the other polymer (68). 

In spite of the good yields of L-foUc acid obtained in this reaction, all of the pubHshed methods for the synthesis of 6-bromomethylpterin (20) are multistep procedures with low overall yields (33—36). For example, the route starting from 2,4,5,6-tetraanainopyrimidine [5392-28-9] (21) gave 6-bromomethylpterin (20) in three steps with an overall yield of only 18% (33,35,36). This synthesis is not economical because the intermediate 6-bromomethyl-2,4-diamino-4-pterin (22) has to be deaminatedin an additional step to form 6-bromomethylpterin (20). 

Hydrogen bromide adds to acetylene to form vinyl bromide or ethyHdene bromide, depending on stoichiometry. The acid cleaves acycHc and cycHc ethers. It adds to the cyclopropane group by ring-opening. Additions to quinones afford bromohydroquinones. Hydrobromic acid and aldehydes can be used to introduce bromoalkyl groups into various molecules. For example, reaction with formaldehyde and an alcohol produces a bromomethyl ether. Bromomethylation of aromatic nuclei can be carried out with formaldehyde and hydrobromic acid (6). 

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