CHAPTER 1 THE REIMER-TIEMANN REACTION HANS WYNBERG AND EGBERT W. MEUER The University, Groningen, The Netherlands CONTENTS, IntRopuction MECHANISM Peete ee Dihalocarbene Reaction with Phenoxide Anion BEEEESSee EEE EH Dihalocarbene Reaction with Ortho- and/or Para-Substituted Phenoxide Anions Dihalocarbene Reaction with Substrates Other than Phenoxide Anion Scope AND LIMITATIONS Phenols and ‘Alig phenols Halophenols PEE HEHE Hydroxy- and Alkoxyphenols Rote tree Carboxy and Sulfonic Acid Substituted Phenols . Heterocyclic Phenols Pyrroles and Related Compounds Miscellaneous Compounds : Abnormal Products. Hee eeHeee Cyclohexadienones and Related Nonaromatics Ring-Expansion Products COMPARISON wit OTHER METHODS EXPERIMENTAL CONDITIONS Introduction Effect of the Base Effect of the Solvent Phasc-Transfer Catalysis . Other Reagents cere eat Carbon Tetrachloride under Basic Conditions By-products . EXPERIMENTAL PROCEDURES. 2-Hydroxy-5-methoxybenzaldehyde Indole-3-carboxaldehyde . ee 1-Dichloromethy!-1-methyl-2(1H)-naphthalenone 3-Chloro-4-methylquinoline : TABULAR SURVEY EEE 7 Table I. Formylation of Phenol and Alkylphenols Table Il. Formylation of Naphthols and Alkylnaphthols 1i ORGANIC REACTIONS Table III. Formylation of Halophenols Eee a Table [V. Formylation of Hydroxy- and Alkoxyphenols 2 Table V. Formylation of Carboxy and Sulfonic Acid Substituted Phenols. 23 Table VI. Formylation of Heterocyclic Phenols =. ee 4 Table VII. Formylation of Substituted Pyrimidines © 2. 25 Table VII. Formylation of Pyrroles and Related Compounds . 26 Table IX. Formylation of Miscellaneous Compounds. : 2 Table X._ Cyclohexadienones Obtained from Substituted Phenols. =| ss 8 Table XI, Cyclohexadienones Obtained from Substituted Naphthols . 29 Table XI. Abnormal Products Obtained ftom Miscellaneous Compounds. 30 Table XIII. Ring-Expansion Products Obtained from Pyrroles and Indoles 31 Table XIV. Formylation under Unusual Conditions EES eee eee REFERENCES eee eeeeeeeeies BEECHES eHe Eee HEPeHEe EEE HES: INTRODUCTION The Reimer-Tiemann reaction owes its name to two young German chemists, Karl Reimer and Ferdinand Tiemann. In 1876 they isolated and identified hydroxyaldehydes as the principal reaction products of phenol and chloroform in alkaline medium.'!~* The scope of this reaction was enlarged in 1884 by von Auwers, who discovered the chlorine-containing cyclohexa- dienones as by-products in the formylation of alkylphenols.°-!? The ring- expansion products, namely, chloropyridines, were first noted by Ciamician when he subjected pyrroles to Reimer-Tiemann reaction conditions.'5-15 Nearly half a century passed before Woodward recognized that the conver- sion of an alkylphenol to a substituted cyclohexadienone could lead to the synthesis of terpenes and steroids containing an angular methyl group.'® Although the method failed as a preparatively useful approach to thesynthesis of steroids,!7-!9 an A/B trans-fused hexahydrophenanthrene was prepared using a Reimer-Tiemann reaction.?° The reaction was last reviewed some 20 years ago.” Itis convenient to divide the Reimer-Tiemann reaction into a normal and abnormal transformation depending on the reaction products. A normal Reimer-Tiemann reaction is one in which a phenol (or electron-rich aromatic such as pyrrole) yields one or more aldehydes on treatment with chloroform and alkali.*~* OH OH OH CHO 0% 19%)THE REIMER-TIEMANN REACTION 3 The abnormal Reimer-Tiemann reaction product can be subdivided further into cyclohexadienones and ring-expansion products: 1. When ortho- or para-substituted phenols are subjected to the Reimer- Tiemann reaction conditions, 2,2- or 4,4-disubstituted cyclohex- adienones may be obtained in addition to the normal products.7~! Ou OH 9 CHO 4. NAOH, CHC, ener ane + CH, CH, CH; CHCl, 25%) (26%) OH CH, 9. NOH, Cer, eae oh, OH 9 9 OHG, CH, CH, CH, + CHCL + I cu, cH, CH; CHCl, (uy) (trace) 30%) Several alkylphenols, alkyInaphthols, and tetralols have been con- verted into cyclohexadienones, whereas some alkylpyrroles are con- verted to pyrrolines in this manner. 2. A variety of five-membered tings yield ring-expansion products when subjected to the Reimer-Tiemann reaction conditions. These products are formed in addition to the normal products.!3-!5 CHO. fs [ ' sxonc, J \ A Bam Oy k tk et (3%)