Bromination with hydroxy groups

CPO has been applied almost exclusively as biocatalyst for the hydroxyhalo-genation. Recently, lactoperoxidase-catalyzed bromination of laurediols was reported [141,142]. In this reaction, cyclic ethers were unspecifically formed by intramolecular trapping of the carbocation with hydroxy groups (Eq. 8). 

When unsubstituted, C-5 reacts with electrophilic reagents. Thus phosphorus pentachloride chlorinates the ring (36, 235). A hydroxy group in the 2-position activates the ring towards this reaction. 4-Methylthiazole does not react with bromine in chloroform (201, 236), whereas under the same conditions the 2-hydroxy analog reacts (55. 237-239. 557). Activation of C-5 works also for sulfonation (201. 236), nitration (201. 236. 237), Friede 1-Crafts reactions (201, 236, 237, 240-242), and acylation (243). However, iodination fails (201. 236). and the Gatterman or Reimer-Tieman reactions yield only small amounts of 4-methyl-5-carboxy-A-4-thiazoline-2-one. Recent kinetic investigations show that 2-thiazolones are nitrated via a free base mechanism. A 2-oxo substituent increases the rate of nitration at the 5-position by a factor of 9 log... 

Deletion of the 17a-hydroxy group similarly leads to an effective topical antiinflammatory agent. Treatment of 16a-methylpregnenolone (244) (obtained by conjugate addition of an organometallic to pregnenolone) sequentially with bromine and acetate ion affords the 21 acetate, 245 (see, for example, the transformation of 196 to 198). In an interesting variation on the method for the introduction of a fluorine atom at 6, the... 

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. 

Quinophthalone (6.229) and its derivatives [86] also fall into the methine category, although they appear in the Colour Index under quinoline colouring matters. The parent compound was discovered in 1882 by Jacobsen, who condensed 2-methylquinoline (quinaldine) with phthalic anhydride. The product, quinoline yellow, is used as a solvent dye (Cl Solvent Yellow 33). The light fastness is improved by the presence of a hydroxy group in the quinoline ring system. Derivatives of this type provide greenish yellow disperse dyes for polyester. The moderate sublimation fastness of Cl Disperse Yellow 54 (6.230 R = H) is improved by the introduction of an adjacent bromine atom in Cl Disperse Yellow 64 (6.230 R = Br). 

The transformation of L-arabinose (58) to lactone 57 was based on a route developed by Marquez and Sharma [51] Selective protection of the primary hydroxy group with TBDPSCl and oxidation of the lactol moiety with bromine afforded lactone 59. Subsequent selective deoxygenation a to the carbonyl group proceeded under Barton-McCombie conditions providing lactone 57 in 21% yield (Scheme 14). 

Aldono-1,4-lactones, having six or more carbon atoms also form an exocyclic aceteoxonium ion between the primary and the neighbouring hydroxy group when treated with hydrogen bromide in acetic acid. By the opening of this ion, bromine is easily introduced at the primary carbon (Scheme 1, entry II). Pento-nolactones also yield 5-bromo-5-deoxy-lactones when treated with HBr-HOAc, although the reaction requires 1-4 days. Since no exocyclic acetoxonium ion can be formed, a direct substitution probably takes place in these cases. 

Sorm and Beranek39 used an intramolecular acylation in their synthesis of l-azoniumtricyclo[3.3.3.0]undecane (66). Condensation of nitromethane with acrylonitrile in the presence of an alkaline catalyst resulted in the formation of tris-(2-cyanoethyl)nitromethane (60), which afforded the triethyl ester 61 on hydrolysis followed by esterification. The ester was reduced catalytically to give a pyrrolidone (62). The derivative (62) gave rise to 8-(j8-carboethoxyethyl)-3,5-dioxo-pyrrolizidine (63) on heating. Reduction of 63 resulted in the formation of 8-(y-hydroxypropyl)pyrrolizidine (64). Replacement of the hydroxy group by bromine (65), followed by cyclization, afforded the tricyclic compound 66. 

A simple example involves the reaction of the silyl ether 213, made from the corresponding 4-hydroxy-alkene by treatment with (bromomethyl)chloro-dimethylsilane, with tributyltin hydride and a radical initiator. Bromine abstraction and intramolecular cyclization with the double bond leads to the bicyclic 214, which upon oxidation with hydrogen peroxide gives the branched-chain 215 in an overall yield of 73% from the alcohol precursor of 213 (Scheme 21). When the sequence is conducted with the C-4 epimeric starting alcohol, the final product again has the hydroxymethyl group cis-related to the hydroxy group.217... 

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