Reimer-Tiemann conditions formylation

In addition to phenols, naphthols, their alkyl derivatives and the heterocyclic compounds mentioned above, a large variety of substituted monocyclic as well as condensed phenols have been subjected to the Reimer-Tiemann reaction. Although with a few exceptions the yields are only moderate, the facile reaction conditions, at least on a laboratory scale, have assured the reaction a permanent place among the variety of methods by which an aldehyde group can be attached to an aromatic nucleus. For example, phenolphthalein (1) has been formylated under standard Reimer-Tiemann conditions by van Kampen to yield the o-hydroxy aldehyde in 59% yield (equation 5)."... 

Hydroxy-4-methylthiazole failed to react when submitted to Friedel-Crafts benzoylation conditions (349) on the other hand, it reacted normally in Gattermann and in Reimer-Tiemann formylation reactions, affording the 5-formyl derivative (348). 4-Methylthiazole is insufficiently activated and fails to react under the same conditions. 2,4-Dimethylthiazole undergoes perfluoroalkylation when heated at 200° for 8 hr in a sealed tube with perfluoropropyl iodide and sodium acetate (116) (358). 

Using Reimer-Tiemann reaction conditions on 3-alkyl-6-hydroxy-1,2-benzisoxazoles results in formylation occurring at the 7-position (77UC(B)1056). 

Both the Reimer-Tiemann and the Vilsmeier reactions lead to formylation in the 5-position in pyrimidines with at least two strongly releasing substituents <1994HC(52)1>. The reaction of metallated intermediates with acyl electrophiles can be used to give acyl derivatives <2001T4489>, and direct carbamoylation of 6-aminouracil derivatives 87 has been achieved under microwave-assisted conditions to give 88 <2005S2713>. 

M.E. Jung and co-workers have developed a synthesis of selectively protected L-Dopa derivatives from L-tyrosine via a Reimer-Tiemann reaction followed by the modified Dakin oxidation. The formyl group introduced by the Reimer-Tlemann reaction had to be converted to the corresponding phenol. After trying many sets of conditions, the Syper process was chosen, which uses arylselenium compounds as activators for the oxidation. Treatment of the aromatic aldehyde with 2.5 equivalents of 30% hydrogen peroxide in the presence of 4% diphenyl diselenide in dichloromethane for 18h gave the aryl formate in excellent yield. This ester was cleaved by treatment with methanolic ammonia for 1h to afford the desired phenol in good yield. 

The best way to introduce the formyl group in the proper position is through a Reimer-Tiemann reaction. This involves treating a phenol with chloroform in the presence of base. Under these conditions, chloroform sequentially loses a proton and a chloride anion in an a-elimination (elimination with both leaving groups on same carbon) to form a dichlorocarbene. 

Nevertheless, compared to other formylation reactions, such as the Duff Formylation, Gattermann Aldehyde Synthesis, and Gattermann-Koch Formylation, the Reimer-Tiemann reaetion is the only one that occurs under basic conditions, and in certain cases, it is the only feasible method for the direct formylation, e.g., the formylation of oestrogens. ... 

The Reimer-Tiemann formylation of phenols with chloroform was attempted under sonication, in order to improve the frequently unsatisfactory yields. Optimal conditions make use of aqueous sodium hydroxide, and the electrophilic attack of the carbene on the ring is followed by the hydrolysis of the dichloromethyl group to the aldehyde. The advantages of the sonochemical method are not clearly apparent. The positive effect of sonication is limited to the reaction of 4-chlorophenol, and 4-methyl- and 4-methoxyphenol react with a yield lower than conventionally found. 

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