Water → Cinnoline

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Reaction Steps

As shown in Scheme 7, halogenated azaarenes 23, exemplified by 4-chloro-7-trifluoromethylquinoline or cinnoline, are treated with H2SO4 (70-95%) at 180-220° C. for about 16 to 48 hours in a sealed reaction vessel. The solution is cooled, poured into water and neutralized with base to pH ˜3-4. The product is dissolved in aqueous base and precipitated by acidification to yield 7-carboxy-4-chloroquinoline or cinnoline. This material is converted to the alkyl ester, such as methyl (24) or ethyl, by standard methods. 7-Alkyloxycarbonyl-4-chloroquinoline or cinnoline is dissolved in an anhydrous, aprotic solvent (THF or ether). The solution is cooled (−60 to −95° C.) and treated with a reducing agent such as lithium aluminum hydride. The solution is warmed (to approximately −40 to −50° C.) for about 15 to 30 minutes and quenched with a solvent such as ethyl acetate. Standard workup gives the product 7-hydroxymethyl-4-chloroquinoline, or cinnoline (25). Material 25 is treated with 45-50% HBr and heated to about 100-140° C. for about 45 to 90 minutes. After cooling and standard workup, 7-bromomethyl-4-chloroquinoline (or cinnoline) 26 is obtained. Alkylation as described before provides 4-chloroquinoline (or cinnoline) 27 followed by deprotection under the usual acidic conditions gives 4-chloroquinoline (or cinnoline) 28.

Provenance & Evidence