By the Reimer-Tiemann reaction

The starting material for the 1,2-disubstituted tetrahydro-naphthalenes was 5,6,7,8-tetrahydro-2-naphthol. This compound was converted in low yield to the known Via by the Reimer-Tiemann reaction. VI6 and Vic both were prepared from 1-bromo-2-methoxy-5,6,7,8-tetrahydronaphthalene. Although VI6 was prepared according to the method of O Farrell et al. [3], we obtained a much higher yield,... 

Eydroxy-5,6,7,8-tetrahydro-l-napMhaldehyde was prepared [7] by the Reimer-Tiemann reaction cn 5,6,7,8-tetrahydro- 2-naphthol. Three recrystallizations from aqueous alcohol afforded a very low yield of pure aldehyde, m.p. 86-8-87-8° (spectral sample) lit. m.p. 86-87° [7J. 

The classical synthesis of vanillin from eugenol or isoeugenol was developed in 1896 and it remained the preferred method for about 50 years. Vanillin is now prepared industrially in large amounts by the Reimer-Tiemann reaction, starting with... 

Kemp, D. S. Relative ease of 1,2-proton shifts. Origin of the formyl proton of salicylaldehyde obtained by the Reimer-Tiemann reaction. J. Org. Chem. 1971, 36, 202-204. 

C7H6O2 Oily liquid of aromatic odour b.p. 196°C. (t is prepared by the action of chloroform and caustic potash on phenol (the Reimer-Tiemann reaction) or by the oxidation of the glucoside salicin. It is easily reduced to salicyl alcohol or oxidized to salicylic acid. 

Although 4-hydroxybenzaldehyde can be made by the saligenin route, it has been made historically by the Reimer-Tiemann process, which also produces sahcylaldehyde (64). Treatment of phenol with chloroform and aqueous sodium hydroxide results in the formation of benzal chlorides, which are rapidly hydrolyzed by the alkaline medium into aldehydes. Acidification of the phenoxides results in the formation of the final products, sahcylaldehyde and 4-hydroxybenzaldehyde. The ratio of ortho and para isomers is flexible and can be controlled within certain limits. The overall reaction scheme is shown in Figure 1. Product separation is accomphshed by distillation, but this process leads to environmental problems because of the quantities of sodium chloride produced. 

A variant of the Reimer-Tiemann reaction, using chloroform or bromoform with ethanohc sodium ethoxide, has been apphed (mainly by Plancher and co-workers) to certain pyrroles and indoles with interesting results. Thus Bocchi has shown that 2,5-dimethylpyrrole gave 3-halogeno-2,6-dimethylpyridine, and 2,4-dimethylpyrrole with bromoform gave two isomeric bromodimethylpyridines [Eq. (11)]. 

The structure of the product of the Reimer-Tiemann reaction of 1,2,3-trimethylindole (24) has been confirmed as 3-dichloromethyl-1,3-dimethyl-2-methyleneindoline (25) by spectroscopy and oxidation to the iV -methyloxindole when the dichlorocarbene was generated under neutral conditions a ring-expanded product, 3-chloro-1,4-dimethyl-2-methylene-1,2-dihydroquinoline (26) could be isolated and oxidized to the corresponding a-quinolone. These reactions presumably proceed by mechanisms similar to those discussed for 2,3-di-... 

Because of the differential partitioning of hydroxide and phenoxide anions into organic solvents by quaternary ammonium cations, the catalysts generally have little effect on the Reimer-Tiemann reaction of phenols with dihalocarbenes [15]. Cetyltrimethylammonium bromide has been used in the two-phase dichloromethyl-ation of polysubstituted phenols (Scheme 7.21, Table 7.10) under Makosza s conditions [16,17] ring expansion of the reaction products provides an effective route to tropones. The rate of the reaction is enhanced by ultrasonic radiation [16]. 

Under favourable circumstances, the initially formed /V-ylid reacts further through C-N cleavage. Thus, in the presence of a strong nucleophile, such as a phenoxide anion, the quaternary dichloromethylammonium cation forms an ion-pair with the phenoxide anion (Scheme 7.27), which decomposes to yield the alkyl aryl ether and the /V-formyl derivative of the secondary amine [22, 23]. Although no sound rationale is available, the reaction appears to be favoured by the presence of bulky groups at the 4-position of the aryl ring. In the absence of the bulky substituents, the Reimer-Tiemann reaction products are formed, either through the breakdown of the ion-pair, or by the more direct attack of dichlorocarbene upon the phenoxide anion [22,23],... 

Other reported syntheses include the Reimer-Tiemann reaction, in which carbon tetrachloride is condensed with phenol in the presence of potassium hydroxide. A mixture of the ortho- and para-isomers is obtained the para-isomer predominates. -Hydroxybenzoic acid can be synthesized from phenol, carbon monoxide, and an alkali carbonate (52). It can also be obtained by heating alkali salts of -cresol at high temperatures (260—270°C) over metallic oxides, eg, lead dioxide, manganese dioxide, iron oxide, or copper oxide, or with mixed alkali and a copper catalyst (53). Heating potassium salicylate at 240°C for 1—1.5 h results in a 70—80% yield of -hydroxybenzoic acid (54). When the dipotassium salt of salicylic acid is heated in an atmosphere of carbon dioxide, an almost complete conversion to -hydroxybenzoic acid results. They>-aminobenzoic acid can be converted to the diazo acid with nitrous acid followed by hydrolysis. Finally, the sulfo- and halogenobenzoic acids can be fused with alkali. 

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. 

The Reimer-Tiemann reaction used to be an important way of making ortho-substituted phenols, but the yields are often poor, and modern industly is wary of using large quantities of chlorinated solvents. On a small, laboratory scale it has largely been superseded by ortholithiation (Chapter 9) and by modern methods outside the scope of this book. The mechanism probably goes something like this. 

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. 

Reimer-Tiemann Reaction. —Both the ortho- and para-hydroxy benzaldehydes are important. They may both be synthesized by what is known as the Reimer-Tiemann reaction. This consists of the interaction between a salt of a phenol and chloroform in the presence of an excess of alkali. The result is the introduction of the aldehyde group, (—CHO), into the benzene ring of the phenol as follows ... 

It may be synthesized by the Reimer-Tiemann or Gattermann-Koch reactions from pyrocatechinol, 1-2-di-hydroxy benzene. 

Just as protocatechuic aldehyde may be synthesized by the Reimer-Tiemann or Gattermann-Koch reactions from the -di-phenol pyro-catechinol, so vanillin may be made by the same reactions from the mono-methyl ether of pyrocatechinol, Le.f guaiacol (p. 621). 

From Phenols by CCI4.—The Reimer-Tiemann reaction for the synthesis of hydroxy aldehydes (p. 659) is ... 

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... 

The Reimer-Tiemann reaction involves electrophilic substitution on the highly reactive phenoxide ring. The electrophilic reagent is dichlorocarbene, CCl2, generated from chloroform by the action of base. Although electrically neutral, dichlorocarbene contains a carbon atom with only a sextet of electrons and hence is strongly electrophilic. 

Tropolone undergoes the Reimer-Tiemann reaction, couples with diazonium ions, and is nitrated by dilute nitric acid. It gives a green color with ferric chloride, and does not react with 2,4-dinitrophenyIhydrazine. Tropolone is both acidic (ilTa = 10 ) and weakly basic, forming a hydrochloride in ether. 

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 development of a novel h ten for radioimmunoassay of the lignan, enterolactone in plasma (serum) was accomplished by T. Makela et al. The essay utilized enterolactone derivatives that have a carboxylic acid moiety for the production of antiserum and tracer. The preparation of (+)-frans-5-carboxytrimethylenoxyenterolactone utilized the Reimer-Tiemann reaction for the formyiation of 2-benzyloxyphenol. 

Neumann, R., Sasson, Y. Increased para selectivity in the Reimer-Tiemann reaction by use of polyethylene glycol as complexing agent. Synthesis 1986, 569-570. 

Cochran, J. C Melville, M. G. The Reimer-Tiemann reaction, enhanced by ultrasound. Synth. Common. 1990, 20, 609-616. 

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