Reimer Tiemann Reaction

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 

Several attempts were made to shift the regioselectivity towards the para-product. Phenols irradiated in chloroform are converted in the corresponding 2- and 4-substituted benzaldehydes by a mechanism involving attack by the dichloromethyl radical to produce 

Increased para selectivity has been reported by using potassium, cesium and ammonium hydroxide as bases instead of sodium hydroxide.The addition of 6-cyclodextrin (BCD) afforded 100% para selectivity due to formation of a preferentially para ternary molecular complex between the phenolate ion, BCD and the dichlorocarbene intermediate.Although the presence of BCD does not enhance the total aldehyde production, it reduces the proportion of other isomeric aldehydes formed in favour of the para-product. Recently Zhang et. reported the synthesis of p- 

A modified Reimer-Tiemann reaction was performed using tertiary amines to give the para-aldehyde as main product. A total phenol conversion of 74% together with 66% and 7% para-and orf/ o-aldehyde yield respectively, were obtained.Similarly, reaction of phenol and CHCI3 in an aqueous alkali solution in the presence of polyethylene glycol (PEG) gave after acid hydrolysis the para- and orf/ o-aldehyde in 75% and 16% yield 

The formylation of a phenol 1 with chlorofonn 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 actual formylation process is preceded by the formation of dichlorocarbene 3 as the reactive species. In strongly alkaline solution, the chloroform is deproto-nated the resulting trichloromethide anion decomposes into dichlorocarbene and a chloride anion  

In alkaline solution, the phenol 1 is deprotonated to the phenolate 4, which reacts at the orr/to-position with dichlorocarbene 3. The initial addition reaction product 5 isomerizes to the aromatic o-dichloromethyl phenolate 6, which under the reaction conditions is hydrolyzed to the o-formyl phenolate.  

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 orf/to-selective it is therefore related to the Kolbe-Schmitt reaction. 

By a modified procedure using polyethyleneglycol as complexing agent a -selective reaction can be achieved.  

Synthesis of o-formylphenol from phenols and chloroform in alkaline medium. 

Example 1, photo Reimer-Tiemann reaction without base 

Reimer, K. Tiemann, F. Ber. Dtsch. Chem. Ges. 1876, 9, 824. Karl L. Reimer (1845—1883) was bom in Leipzig, Germany. He interrupted his study to serve in the Bohemian War in 1866. After the war, Reimer returned to his study and obtained his Ph.D. in 1871. He held several jobs but at the end had to resign because of poor health. The discovery of the Reimer-Tiemann reaction was the beginning of his shortlived career in organic chemistry. Johann K. F. Tiemann (1848—1899) was born in Riibeland, Germany. He was a student and a big fan of W. Hofmann, from whom Tiemann received his Ph.D. in 1871. Tiemann then became a Professor of Chemistry at Berlin. 

The carbonyl substrate 3 to be reacted with the organozinc compound 2 can be an aldehyde or ketone that may contain additional functional groups. With a vinylogous halo ester—i.e. a y-halocrotyl ester—the corresponding y-crotylzinc derivative is formed. 

With special techniques for the activation of the metal—e.g. for removal of the oxide layer, and the preparation of finely dispersed metal—the scope of the Refor-matsky reaction has been broadened, and yields have been markedly improved. The attempted activation of zinc by treatment with iodine or dibromomethane, or washing with dilute hydrochloric acid prior to use, often is only moderately successful. Much more effective is the use of special alloys—e.g. zinc-copper couple, or the reduction of zinc halides using potassium (the so-called Rieke procedure ) or potassium graphite. The application of ultrasound has also been reported.  

O-alkyl, CO2H, NO2, Cl, Br, I R = H, alkyl dichlorocarbene precursor CHCI3, CI3CCO2H, CI3CCHO, CI3CNO2  

The total synthesis of the tricyclic sesquiterpene (+)-P-copaene was accomplished by E. Wenkert and co-workers. The required bicyclic starting material was prepared in three steps from carvacrol. In the first step, carvacrol was subjected to typical Reimer-Tiemann conditions. The abnormal Reimer-Tiemann product, 6-dichloromethyl-3-isopropyl-6-methyl-cyclohexa-2,4-dienone, was obtained, and upon treatment with sodium carbonate in DMSO, cyclization occurred to afford a bicyclic halo ketone. The double bonds were then hydrogenated in the presence of Pd(C) catalyst. 

Zimmermann et al. developed an efficient synthesis of 2-amino-1,8-naphthyridines that can serve as building blocks for host-guest and self-assembling systems. The synthesis commenced with the Reimer-Tiemann formyiation of 2,6-diaminopyridine to afford 2,6-diaminopyridine-3-carbaldehyde in modest yield. Next, the Friediander reaction using activated ketones gave rise to the target compounds. 

7-Acetylamino-2-chloro-[1,8]naphthyridine-3-carboxylic acid ethyl ester 

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. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 214, Springer-Verlag Berlin Heidelberg 2009 

Example 1, Photo-Reimer-Tiemaim reaction without base  

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 229, Springer International Publishing Switzerland 2014 

225th ACS National Meeting, New Orleans, LA, USA, March 23-27, (2003), ORGN-399. 

Castillo, R. Moliner, V. Andres, J. Chem. Phys. Lett. 2000, 318, 270. 

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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. 

From phenols by interaction with chloroform and sodium hydroxide solution (Reimer - Tiemann reaction), for example ... 

Phenyhsonitrile has a powerful characteristic odor it is used as a qualitative test (the carbylamine test) for chloroform or primary aromatic amines. Chloroform reacts with phenols in alkaline solution to give hydroxyaromatic aldehydes in the Reimer-Tiemann reaction eg, phenol gives chiefly Nhydroxyben2aldehyde and some sahcylaldehyde (11) (see Hydroxybenzaldehydes). 

Aminotriazole is carboxylated at the 5-position by heating with aqueous sodium bicarbonate in a Kolbe-type reaction (7lJCS(C)l50l). 2-Thiazolinones undergo the Gatter-mann and Reimer-Tiemann reactions at the 4-position, and 3- and 4-pyrazolinone anions on alkylation give 4-alkyl as well as O- and N-alkyl derivatives. 

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

Reimer-Tiemann reaction, 2, 209-210 Oxycarboxin as fungicide, 1, 193 Oxydimethiin... 

Pyrrolo[2,3-6]pyridine, 2-methyl-Reimer-Tiemann reaction, 4, 508 Pyrrolo[2,3-6]pyridine, 4-methyl-hydrogen exchange, 4, 502 reaction with aldehydes, 4, 503 reaction with benzaldehyde, 4, 511... 

The Ciamician-Dennstedt reaction can be thought of as the complement to the Reimer-Tiemann reaction (Scheme 8.3.2). The first step of both reactions is cyclopropanation of one of the carbon-carbon double bonds of a pyrrole with a dichlorocarbene, resulting in intermediate 3. The Ciamician-Dennstedt reaction results from cleavage of the internal C-C bond and elimination of chloride (path a), while the Reimer-Tiemann reaction results from cleavage of the exocyclic bond, and subsequent hydrolysis of the dichloromethyl moiety to furnish aldehyde 5 (path b). 

Under conditions more similar to those of the Reimer-Tiemann reaction 3-bromopyridine was obtained from pyrrole and bromo-form. Treatment of pyrrole with chloroform and aqueous alkali gave pyrrole-2-aldehyde curiously, the formation of 3-chloropyridine under these conditions does not appear to have been reported, in spite of being frequently quoted. However, indole gave both indole-3-aldehyde and 3-chloroquinoline under these conditions [Eq. (10)]. 

The Reimer-Tiemann reaction has also been used to formylate 2,5-dimethylpyrrole and its iV-methyl derivative and indoles having methyl, methoxyl, and phenyl substituents. Significantly, 3-methylindole gave only 3-chloro-4-methylquinoline. ... 

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 latter reaction has been repeatedly misquoted (e.g. ref. 50) as involving 2,3-dimethylpyrrole, but the Reimer-Tiemann reaction of this pyrrole has not been investigated. In this case the methyl groups should activate the 2,3-bond sufficiently to make the 3-halogeno-2,4-dimethylpyridine the major—if not the sole— product. 

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-... 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vdsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

Formylation with Chloroform The Reimer-Tiemann Reaction... 

In the Reimer-Tiemann reaction, chloroform and hydroxide ion are used to... 

The Reimer-Tiemann reaction of phenol with chloroform, in the presence of 50% NaOH, gives a much higher ratio of para to ortho hydroxy benzaldehyde when polyethylene glycol is used as compared to the established procedure without any addition of a hydrotope. A para to ortho ratio of 1 1 has been realized (Neumann and Sasson, 1986). 

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