REIMER-TIEMANN Phenol Formylation

REIMER TIEMANN Phenol formylation 314 REISSERT-GROSHEINTZ FISCHER Cyanoamme reaction 315 REPPE Acetylano reaction 3t6 von RICHTER Aromatic carboxylalion 317 von RICHTER - WIDMAN - STOERMER Cmndme synthesis 3t8 RILEY Selenaim dioxide oxidation 319 Rimmi 4... 

REIMER - TIEMANN Phenol Pormylation Formylation ot phenols with CHCt3-base (dichiorocarbene)... 

REIMER - TIEMANN Phenol Formylalion Formylation ol phenols with CHCb-base (dichtorocarbene)... 

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 Reimer-Tiemann formylation of several phenols in the quinohne and pyrimidine series is known, but the reaction is unsuccessful with hydroxypyridines 3-hydroxypyridine gave a polymer. No 2-hydroxyquinoline appears to have been studied the 4-hydroxy... 

The formylation of a phenol 1 with chloroform in alkaline solution is called the Reimer-Tiemann reaction. It leads preferentially to formation of an ortho-formylated phenol—e.g. salicylic aldehyde 2 —while with other formylation reactions, e.g. the Gattermann reaction, the corresponding /jara-formyl derivative is obtained as a major product. The Reimer-Tiemann reaction is mainly used for the synthesis of o-hydroxy aromatic aldehydes. 

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. 

Phenols are smoothly converted into phenolic aldehydes by reaction with chloroform in the presence of base (the Reimer-Tiemann reaction). This overall formylation reaction is of interest in that it involves the generation from chloroform and alkali of the reactive intermediate, dichlorocarbene (2). This effects electrophilic substitution in the reactive phenolate ions giving the benzylidene dichloride (3) which is hydrolysed by the alkaline medium to the corresponding hydroxyaldehyde. The phenolic aldehyde is isolated from the reaction medium after acidification. 

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). 

Treatment of a phenol with chloroform (trichloromethane) in the presence of hydroxide ion results in the synthesis of a 2-hydroxybenzalde-hyde through C-formylation. Dichlorocarbene, CCl2, is generated by the action of base on chloroform and this highly reactive electrophile then attacks the phenoxide. The mechanism of the Reimer-Tiemann reaction, is given in Scheme 4.12. 

Formylation of Phenols with Chloroform (Reimer-Tiemann). 

In the Reimer-Tiemann reaction, aromatic rings are formylated by reaction with chloroform and hydroxide ion." ° The method is useful only for phenols and certain heterocyclic compounds such as pyrroles and indoles. Unlike the previous formyla-tion methods (11-18), this one is conducted in basic solution. Yields are generally... 

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. 

Reimer-Tiemann reaction Preparation of formylated phenols from substituted phenols 378... 

Thoer, A., Denis, G., Delmas, M., Gaset, A. The Reimer-Tiemann reaction in slightly hydrated solid-liquid medium a new method for the synthesis of formyl and diformyl phenols. Synth. Common. 1988,18, 2095-2101. 

Reimer-Tiemann reaction The formylation of aromatic rings using CHC13 and OH-. Useful only for phenol, and a few heterocyclic compounds. 

The formylation, i.e., formal carbon monoxide (CO) insertion, of phenols using chloroform and aqueous base is known as the Reimer-Tiemann reaction (Scheme l).73 It is generally accepted that base-induced a-elimination of chloroform (CHC13) yields the rate-determining, electrophilic dichlorocarbene (CC12) intermediate, which... 

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)."... 

Phenolic aldehydes can be obtained by the Duff reaction, in which the phenol is heated with urotropine, boric acid, and glycerol for 30 minutes at 150-160° 857 the yields are not high (15-20%), but the procedure is simpler and less time -consuming than the Reimer-Tiemann synthesis the products are the ortho-derivatives. Dialkylanilines can be formylated in the same way,858 but here the products are the para-aldehydes. 

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. 

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). 

Formylation of phenol with chloroform in a basic medium was first proposed in 1876 by Reimer and Tiemann. Treatment of phenol with aqueous chloroform and aqueous... 

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