Formyllation of phenols

Formylation of phenols and anilines with hexanethylane tetramine. 

The idea that dichlorocarbene is an intermediate in the basic hydrolysis of chloroform is now one hundred years old. It was first suggested by Geuther in 1862 to explain the formation of carbon monoxide, in addition to formate ions, in the reaction of chloroform (and similarly, bromoform) with alkali. At the end of the last century Nef interpreted several well-known reactions involving chloroform and a base in terms of the intermediate formation of dichlorocarbene. These reactions included the ring expansion of pyrroles to pyridines and of indoles to quinolines, as well as the Hofmann carbylamine test for primary amines and the Reimer-Tiemann formylation of phenols. 

The applicability of the Reimer-Tiemann reaction is limited to the formylation of phenols and certain reactive heterocycles like pyrroles and indoles. Yields are usually below 50%. In contrast to other formylation procedures, the Reimer-Tiemann reaction is ort/zo-selective it is therefore related to the Kolb e-Schmitt reaction. 

Reimer-Tiemann formylation of phenols.1 Yields in this reaction can be increased by use of solid, powdered NaOH and addition of water (2 equiv. per phenol). 

The formylation of phenols with the electron-rich olefin to give imidazolidin-2-yl-phenols is very selective and avoids mixtures of o- and p-isomers which are frequently obtained by methods commonly employed for the synthesis of phenolaldehydes. Para substitution of the cyclic aminal group in the phenol is preferred. If the p-position is blocked or sterically hindered, the reaction proceeds via the ortho- aminals to salicylaldehydes. Incorporation of more than one aldehyde group in the benzene nucleus is often achieved with hydroxy- and aminophenols. 

Formic acid, methyl ester [107-31-3J, 61, 1 Formylation of phenols, 60, 52... 

Formylation of Phenols (or Amines) with Hexamine (Duff)... 

Formylation of Phenols with Chloroform (Reimer-Tiemann). 

REIMER - TIEMANN Phenol Formylalion Formylation of phenols with CHCb-base (dichiorocarbene)... 

Triethyl orthoformate has been used for formylation of phenols in methylene chloride in the presence of aluminum chloride."... 

Duff reaction. The ortho-formylation of phenols or para-formylation of aromatic amines with hexamethylenetetramine in the presence of an acidic catalyst. 

Synthesis of aromatic aldehydes by formylation of phenols, pyrroles with CHCU-base (dichlorocarbene) (see 1st edition). 

Increased selectivity has also been obtained using polyethylene glycol as complexing agent.Using toluene as solvent, the authors report a 1 10 para. ortho ratio in the formylation of phenol. 

Salicylaldehydes. o-Formylation of phenols with paraformaldehyde takes place under the influence of MgCl2-Et3N. 

Fig. 4.2. Mechanism of pflra-selective formylation of phenol using CyDs as catalysts.

SalicylaTdehydes. Formylation of phenols generally gives mixtures of o- and... 

An ice-cooled soln. of formic acid in dry ether satd. with ketene, the excess of which is then removed by a stream of dry air, ether and N-hydroxysuccinimide added to the soln. of the resulting acetic formic anhydride, stirred 3 hrs. at room temp., and allowed to stand overnight -> succinimide formate. Y 85.6%. Also formylation of phenols and f. procedures s. S. Sofuku, I. Muramatsu, and A. Hagi-tani. Bull. Chem. Soc. Japan 40, 2942 (1967). 

Pyridine (s. a. under POClg) S-Formylation of phenols with acetic formic anhydride... 

ABSTRACT. Selective formylation of phenol at the 4-position is achieved by using 3-cyclodextrin as catalyst in the reaction of phenol with chloroform in aqueous alkali. The reactions of 1,3-dihydroxybenzene and indol, respectively, in the place of phenol give 2,4-dihydroxybenz-aldehyde and indole-3-aldehyde in virtually 100% selectivies and high yields. The reactions of para-substituted phenols, 4-methylphenol and 5,6,7,8-tetrahydro-2-naphthol, instead of phenol, effect the selective dichloromethylation at the para-positions. Selective carboxylation of phenol at the 4-position is achieved in the reaction of phenol with carbon tetrachloride in aqueous alkali by using 3-cyclodextrin and copper powder as catalyst. 

TABLE I. FORMYLATION OF PHENOL BY DROPWISE ADDITION OF CHLOROFORM ... 

The dependence of the selectivity for para-dichloromethylation on the initial molar ratio of 3-CyD to phenol was similar to that for para-formylation of phenol as shown in Fig. 1. The dropwise method required only a small amount of 3 CyD, i.e., 10 mol % to 4-methylphenol for 96 % selectivity [5]. 

Formylations of phenol, resorcinol and indole, dichloromethylations of 4-methylphenol and 5,6,7,8-tetrahydro-2-naphthol, carboxylation of phenol, and allylation of 2,4,6-trimethylphenol proceed site-selec-tively in high yields by using 3-cyclodextrin as catalyst. The formation of ternary inclusion complex composed of cyclodextrin, substrate, and dichlorocarbene, trichloromethyl cation or allyl cation in the reaction mixture is an important factor of the site-selective reactions. The cyclodextrin is also effective by limiting the molecular size of the reaction intermediate. 

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. 

The use of these intermediates to produce shikimates is shown in Figure 6.32. In principle, anethole (53) and estragole (methyl chavicol) (52) are available from phenol, but in practice, the demand is met by extraction from turpentine. Carboxylation of phenol gives salicylic acid (38) and hence serves as a source for the various salicylate esters. Formylation of phenol by formaldehyde, in the presence of a suitable catalyst, has now replaced the Reimer-Tiemann reaction as a route to hydroxybenzaldehydes. The initial products are saligenin (189) and p-hydroxybenzyl alcohol (190), which can be oxidized to salicylaldehyde (191) and p-hydroxybenzaldehyde (192), respectively. Condensation of salicylaldehyde with acetic acid/acetic anhydride gives coumarin (50) and 0-alkylation ofp-hydroxybenzaldehyde gives anisaldehyde (44). As mentioned earlier, oxidation of phenol provides a route to catechol (184) and guaiacol (188). The latter is a precursor for vanillin, and catechol also provides a route to heliotropin (61) via methylenedioxybenzene (193). 

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