CHAPTER 1 ‘THE REIMER-TIEMANN REACTION HANS Wywarrc AND Eonert W. MEER The University, Groningen, The Netherlands CONTENTS yiopucrion icant Dialocarbene Reaction with Phenoxide Anion Dialocarbene Reaction with Ortho- andjor Para-Substituted Phenoxide Anions Dihalocarbene Reaction with Substrates Other than Phenoxide Anion ‘Score aND LasTaTiONs Phenols and Alkyiphenols Halophenols Hydroxy-and Alkoxyphenols Carboxy and Sulfonie Acid Substituted Phenols Heterocyclic Phenols Pyrroles and Related Compounds Miscellaneous Compounds Abnormal Products Cyclohexadienones and Related Nonaromatics ‘Ring-Expansion Products| ‘Conpanison wrrt! Or Meuops Exreniuentat, CONDITIONS Introduction Effct ofthe Base Effect ofthe Solvent Phase Transfer Catalysis Other Reagents Carbon Tetrachtoride under Be By-produets [Expeninasctat PROCEDURES 2-Hydroxy-S-methoryboenzaldehyde Indole--carhoxaldehyde [-DichtoromethyI--methyl-2(1H)-naphthalenone 3.Chloro-4-methyiquinoline Conditions TTaRvLaR SURVEY Table |. Formylation of Phenol and Atkyiphenols ‘Table Il, Formation of Naphthols and Alkylnaphuhots Organic Reactions, Vol. 28, Eited by William G. Dauben e (© 1982 Organie Reactions, Ic. Published by John Wiley & Sons, Ie.ORGANIC REACTIONS Table I. Formylation of Halophenols a Table IV, Formstaion of Hydroxy. and Alkoxyphenots 2 ‘Table V.Formylation of Carboxy and Sulfonic Acid Substituted Phenols B ‘Table VI. Formylation of Heterocyclic Phenols 24 Table VII. Formylation of Substituted Pyeimidines as Table VIN Formylation of Pyrroles and Related Compounds 26 ‘Table IX. Formylation of Miscellaneous Compounds n Table X." Cycloheradienones Obtained feom Substituted Phenols 28 Table Xi. Chclohexadienones Obined from Substitsted Naphthols 2 ‘Table XII. Abnormal Products Obtained from Miscellaneous Compounds 30 Table XII. Ring-Expansion Products Obtained from Pyteoles and Indoles 31 Table XIV. Formylation under Unesual Conditions 2 Resiarncis a 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 Ciamici when he subjected pyrroles to Reimer-Tiemanin reaction conditions.!°~!$ ‘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 the synthesis of steroids,'"~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 on CHO mon, +f) Ss CHO‘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.”-"° oH oH 9 CHO cH, CH, CH; CHCI, CH, ou ° ° One. cH, | CH, cH, + cH, + ony cH cu, cua, Several alkylphenols, alkylnaphthols, and tetralols have been con- verted into cyclohexadienones, whereas some alkylpyrroles are con- verted to pyrrolines in this manner. 2A variety of five-membered rings yield ring-expansion products when subjected to the Reimer-Tiemann reaction conditions, These products are formed in addition to the normal produets.!®-"* CHO. OHH, & * cy N’4 ORGANIC REACTIONS In addition to aromatic aldehydes, cyclohexadienones, pyrrolines, and ring-expansion products, a variety of other products have been noted, isolated, and identified in a few cases. All these by-products are discussed in in the Experimental Conditions section. MECHANISM, The classical work of Hine,??-** followed by that of von Doering,?? Skell?2°"" Parham,2?° Robinson,*® and others?” clearly established that ditalocarbenes were formed when a haloform was treated with alkali; direct nucleophilic substitution of the phenolate carbanion on chloroform is thus ruled out.” The recognition that dichlorocarbene was the reactive intermediate set the stage for the formulation ofa rational mechanism.°? Itis convenient to consider separately the two reactions, namely, the hydrolysis of Chloroform and the reaction of a phenol with dichlorocarbene. ‘The first reaction involves the generation of the carbene in a rate-determin- ing step by the unimolecular elimination of a chloride ion from the trichloro- CHCI, + NaOH NaCCh, +H,0 CCl, aed 3CCl, + C1 Cl, + H,O f{H,6—Ccl,] HOCHCI, HOCHCI, + 2NaOH ~——* CO + 2NaCl + 2H,0 ° co+ NOH —B RaOeH on methyl anion.?"2 Although Hine’s original mechanism assumed simul- taneous formation of carbon dioxide and formate,?* Robinson's work clarified this point.”* Dichlorocarbene reacts rapidly with water to generate ‘carbon monoxide, while the latter slowly hydrolyzes to sodium formate in the alkaline medium. Superficially these last wo steps appear unimportant to the ‘main reaction, which involves bond formation between the carbene and the phenol. However, the hydrolysis of carbene consumes alkali and competesTHE REIMER-TIEMANN REACTION s With the formylation reaction. The low conversions and subsequent recovery of starting phenol noticed by numerous investigators are often due to the fact, that most if not all ofthe alkali becomes neutralized as the reaction proceeds. Unfortunately only limited use can be made of the apparently ideal phase- transfer conditions under which this reaction might be run, since the phenolic substrate remains in the aqueous alkaline layer while the carbene is largely present in the chloroform layer. The reaction of the dihalocarbene with the Phenolate ion comprises the product-forming reaction. No significant changes in the overall mechanism have been proposed since its formulation 25 years ago.?? Dihalocarbene Reaction with Phenoxide Anion Electrophilic attack of the dihalocarbene on each of the resonance forms of the phenoxide anion gives the anion having resonance forms I Il, and I (Eq. 2): (4.2)6 ORGANIC REACTIONS 9 O—CHCI, 0 oH CHOC,H)s “ O + CO+HCO; + Cl 43) The O-alkylation product, namely, anion I, either decomposes or reacts further to form small amounts of orthoformic esters (Eq. 3). The details of the transformation of anions H and III (Eq. 4 is given only for the ortho- substituted phenoxide anion) to the corresponding hydroxyaldehydes have been the subject of considerable speculation, ° cue, a ‘oan Pa Rn : es) : CHC, Neither the anion IV nor one of the neutral products V, 2-dichloromethyl- 3,5-cyclohexadienone and VI, 2-dichloromethylphenol, hasever been isolated from a Reimer-Tiemann reaction mixture despite claims to the contrary.*? ‘The elimination sequence suggested in Eq. 5 seems more reasonable. The 1,2-proton shift of the anion Ito the anion IV (Eq. 4) appears unlikely in view of Hiickel and orbital-symmetry calculations“! Tritium isotope experiments show complete transfer of the isotope from tritium oxide to the‘THE REIMER-TIEMANN REACTION 7 formyl group.*'-*? Proton exchange between water and the aldehydic proton of salicylaldehyde is absent under the reaction conditions. These experiments favor a mechanism involving the neutral intermediate V. ‘The ncutral intermediate VI is hydrolyzed to the aldehyde VII in alkaline ‘medium (Eq. 5). Without speculating on the details of the intermediate steps, an explanation must be given for the fact that ortho- and para-hydroxybenzal halides (such as VB) have not been isolated, while benzal halides without ortho- ot para-hydroxy functions are isolable. Iti easily seen from Eq. 5 that a driving force exists that clearly aids the decomposition of VI into the aldehyde. fa 9 ¢ CHCl, _on-.w,0. CH — 7 Os 7 . . CHC! Zn cHO soni, OY 7 (ta. §) Note that the abnormal products are not tautomeric with their phenols since they lack the needed proton on the or j-carbon atom Dihalocarbene Reaction with Ortho- and/or Para-Substituted Phenoxide Anions The first two steps of the mechanism of the abnormal reaction and the normal reaction are the same. Afier proton abstraction from the solvent, the intermediate does not hydrolyze to the corresponding aldehyde. It is worthy of note that both the ortho and para abnormal products represent a dihalo- alkyl structure similar to that of a neopentyl halide, whose hydrolysis exceedingly slow. CH ‘CHCl, cap cH, CHC,‘ ORGANIC REACTIONS Dihalocarbene Reaction with Substrates Other than Phenoxide Anion In theabsence of a large excess of strongly nucleophilic reagents (phenoxide, hydroxide), dichlorocarbene can add to a double bond. The mechanism of the addition of dihalocarbene to double bonds has been well described in a SCOPE AND LIMITATIONS Phenols and Atkylphenols Virtually all the phenols and alkylphenols that have been subjected to the action of chloroform and base have been found to give ortho- and/or para- aldehydes. Consistent exceptions are 2,4,6-trialkylphenols, which form alkyl dichloromethyleyclohexadicnones. OH CH, OH ou onc, A cn, CHy Y + + abnormal product * CHO. wo a LO CHO sax Although early isolation and identification procedures may not have been ideal compared to present-day methods, no serious discrepancies with the early work have been uncovered. ‘A recent report states that traces of hydroxyaldehydes are formed when L-naphthol is treated with chloroform and base.** Earlier studies also men- tioned the failure of this pheno! to yield Reimer-Tiemann reaction products.** Even more astonishing, and in need of careful verification, is the report by the same workers that in addition to the well-known 2-hydroxy-I-naphthalene- carboxaldehyde, a trace (2%) of 2-hydroxy-4-naphthalenecarboxaldehyde, the meta product, is formed from 2-naphthol.** It has been proven con-‘THE REIMER-TIEMANN REACTION clusively that the major product from the formylation of 2-hydroxy-5,6,7,8- tetrahydronaphthalene is 2-hydroxy-5,6,7,8-tetrahydro-I-naphthalenecar- boxaldehyde, as previously reported.'® Traces of the 3-naphthalenecarbox- aldehyde are also formed.*® ‘CHO “= ow Halophenols All the halophenols studied yield normal Reimer-Tiemann reaction products.*°+7-*7 Noteworthy is a patent describing the formylation of 2- fluorophenol in the presence of dimethylformamide to furnish the ortho- substituted hydroxybenzaldehyde to the exclusion of the para-isomer.*¢ In a few cases dialdehydes have been isolated in unspecified low yield.°?-** Chloral instead of chloroform has been found effective in some cases.** For example, a 41% yield of S-chloro-2-hydroxybenzaldehyde could be isolated when 4-chlorophenol was treated with chloral in the presence of $0' aqueous sodium hydroxide.** Hydroxy- and Alkoxyphenols Catechol, resorcinol, and hydroquinone as well as their monomethyl ethers have been formylated successfully.*?-** In the reaction of 3-methoxyphenol with chloroform and aqueous alkali, 2-hydroxy-6-methoxybenzaldchyde has never been isolated, although itis one ‘of the possible products.® The evidence is questionable for the formation of dialdchydes in the Reimer-Tiemann reaction of resorcinol and resorcinol ‘monomethyl ether. The yield of vanillin from guaiacol is said to be affected favorably by the addition of ethanol. 2° oH on oH cH, OH A och, Jo10 ORGANIC REACTIONS. Carboxy and Sulfonic Acid Substituted Phenols In view of the accepted mechanism (electrophilic carbene attack on the phenolate anion) of the Reimer-Tiemann reaction, it is not surprising that phenols containing clectron-withdrawing groups furnish hydroxyaldchydes in lower yields Formylation of salicyelic acid, one of the earliest Reimer-Tiemann reac- tions, yields hydroxyaldehydes lacking the carboxyl group in addition to the expected products. *°5-*? on Sp ers 2 wr * OH OH OH owe con Teo Leto + | +1 ye A CHO Attack by dichlorocarbene at the | position of the salicylate dianion followed by decarboxylation of the resulting dienone intermediate is a possible mechanism, Even two carboxyl groups do not prevent nuclear formylation; both 4- and 5-hydroxyisophthalic acid yield the corresponding aldehydes? Inaseries of patents®**® the successful formylation of naphthoimonosulfonic acid and naphtholdisulfonic acid was reported. No analytical data, yields, or structure proofs are available for these products. Heterocyclic Phenols Phenolic properties associated with hydroxy-substituted aromatics are exhibited only by certain nitrogen-containing heteroaromatic phenols. Thus 3-hydroxypyridine, hydroxyquinolines, and hydroxypyrimidines represent the important classes of heterocyclic phenols that undergo the Reimer: Tiemann reaction ‘The reported conversion”? of 8-hydroxyquinoline to the hydroxyaldehydes in high yield could not be verified.”! This important conversion has also been reported using chloral instead of chloroform, and this report has been duplicated.”*-7?THE REIMER-TIEMANN REACTION " Pyrroles and Related Compounds ‘A number of electron-rich heteroaromatics not containing a phenolic hydroxy group are nevertheless subject to formylation. Pyrrole and 2,5-di- methylpyrrole give the 2-aldchydeand the 3-aldehyde, respectively, and indole sives the 3-aldehyde. In addition to the heterocyclic aldchydes the ring- expansion products are also formed. No detailed studies have been published to explain these phenomena. ‘Miscellaneous Compounds In view of the hundred-and-fith anniversary of the discovery of the Reimer-Tiemann reaction at the date of this writing it is surprising that only about a dozen examples ofthe formation of hydroxyaldehydes are known to fall outside the six categories described thus far. The high yield of product from phenolphthalein is noteworthy (corrected from the original data).”? CHO HO. on It seems reasonable that an increasing number of hydroxyaldehydes of ‘varying structure will become accessible using the Reimer-Tiemann reaction under phase-transfer conditions”* as employed for some nitrogen hetero- cycles.”® The introduction of a formyl group is unsuccessful when benzalde- hyde,”*7” thiophenol,’® or hydroxyphenylarsonic acid”? are used under Reimer~Tiemann reaction conditions. Abnormal Products Appropriately substituted phenols subjected to Reimer~Tiemann reaction conditions are transformed into cyclohexadienones.*? Although history has ordained that the hydroxyaldehydes are called normal products, whereas the dihalomethyl cyclohexadienones and ring-expansion compounds are called abnormal products, an increasing number of high-yield abnormal reactions have been reported in the literature.*® Several aspects of the ab- normal reaction have contributed to its present use. The reaction with certain alkylphenols leads to nonaromatic products under basic conditions. The introduction of potential gem-dialkyl groups or an angular methyl group via the abnormal reaction has attracted interest in steroid and terpene2 ORGANIC REACTIONS synthesis °° Many abnormal products ate formed in good to excellent yields, in contrast to the yields of normal products. Cyelohexadienones and Related Nonaromaties. The conversion of ap- propriately substituted alkyl (or aryl) phenols, pyrroles, and indoles to angularly alkylated eyclohexadienones, pyrrolines, and indolines is well known.??-*°-9 A classic example is the transformation of 2-hydroxy- 5,6,1,8-etrahydronaphthalene, which is of potential use in steroid syn- thesis.1° cual, HO" o a Examples of reactions that proceed in high yield with and without regio- selectivity are shown below.!?:8° on ° CHa J cate CaM, CiHet J — CH, chy CHI, co ona OH) semoncna,, (~ ‘CHCl, CH, cH, aa ceo CHy. : cH, cH, Oo. 9 CH, chy CH. CH, chic, + CH, CH, CHCI,‘THE REIMER-TIEMANN REACTION B The original papers should be consulted fora discussion of regioselectivity. ‘The ratio of ortho to para isomers in the conversion of mesitol is dependent on the reaction conditions, varying from 1:1 to 2:1 (ortho:para);'?-*® with cyclodeatrins, only para product was found.'®* A careful study has been published of normal, abnormal, and ring-expansion products resulting from the Reimer-Tiemann reaction with a series of 4-alkyl guaiacols.°** Ring-Expansion Products. The discussion on ring-expansion products is limited to those in which the normal Reimer~Tiemann reaction products are also formed. Carbene-insertion reactions on substrates other than phenols or electron-rich heteroaromatics have been treated extensively in other re- views.*2° ‘The first and only example of a phenol yieldingaring-expansion product has been uncovered by careful work ofa group that was able to isolate tropolone (in less than 1% yield) *** on ° cH. aq NOH. CHL, ‘OH + other products avy R R ‘The Reimer~Tiemann reaction on pyrroles and indoles to furnish pyridines and quinolines is of limited utility; the yields are moderate, even when the reaction is catalyzed by a phase-transfer catalyst.”° COMPARISON WITH OTHER METHODS Direct i possible with the Gattermann,*” Gattermann-Koch,'* Vilsmeier, Duff’? and Reimer-Tiemann reactions. All except the Reimer~Tiemann reaction are conducted under acidic and/or anhydrous conditions. Only the Gattermann and Duff reactions are applicable to phenols. Since in the Gattermann reaction the entering aldehyde group usually occupies the position para to the hydroxyl group and the Duff reaction fails with poly- hydric phenols and phenols carrying electron-donating substituents, the Reimer-Tiemann reaction is occasionally the only method for the direct formylation of phenols. Thus 2-nitrophenol, pyrrole, and indole, which do not furnish aldehydes in a Gattermann reaction, are formylated successfully under Reimer-Tiemann reaction conditions. For example, the yields of 2- hydroxy-1-naphthalenecarboxaldehyde obtained when 2-hydroxynaph- thalene is formylated using the Reimer~Tiemann, Gattermann, Vilsmeier, roduction of an aldehyde group into an aromatic nucleus is4 ORGANIC REACTIONS and Dulf reactions are respectively 66, 45, 85, and 20%,°" Clearly in terms of cease and safety of operations the Reimer-Tiemann reaction is the reaction of choice in this case. EXPERIMENTAL CONDITIONS. Introduction Even 105 years after its discovery, conditions for the Reimer-Tiemann reaction cannot be said to have been optimized. This is not too surprising for a reaction in which a quantitative yield has never been reported, and in which uscful yields (of abnormal products) of 3-10 % are not unusual. The discussion that follows concerns itself with the choice of the base, the solvent, and other variables, and must therefore be judged mainly from the point of view of complete literature coverage. Effect of the Base Some differences in the yields of ortho- and para-hydroxyaldehydes have been observed depending on the alkali hydroxide used. The ortho-para ratio of products obtained from phenol was determined in the presence of sodium, potassium, and cesium hydroxides as well as with triethylmethylammonium hydroxide? Although the reported ortho-para ratio of 2:1 with 15 N sodium hydroxide appears at variance with an earlier ratio of 6: 10,°" the unmistakable trend toward increased para substitution with increasing size of the cation appears significant. The effect is attributed to a decrease in the coordination of the cation with the phenoxide ion as the cation increases in size, Inthe case of ring-expansion products it appears advantageous to use the potassium salts exclusively. Effect of the Solvent Normally the phenol is dissolved in 10-40% aqueous alkali, a large excess of chloroform is added, and the resulting two-phase system is stirred and/or refluxed for some time, With the increase in understanding of the mechanism of the Reimer Tiemann reaction and the role of the dichlorocarbene, more attention has been paid to the role of the solvent. Nevertheless, trivial factors such as the insolubility of the alkali salt of the phenol in the solvent or cosolvent may significantly change the yield.°?"* No general pattern appears at present, although a patent claims that para substitution is favored by the addition of ethanol ® Phase-Transfer Catalysi High-yield dichlorocarbene reactions have recently been reported under phase-transfer conditions.”**? Attempts to inerease the yielt of normal Reimer-Tiemann reaction products using such phasc-transfer conditions have been somewhat disappointing thus far.°® Possibly the solubility of the‘THE REIMER-TIEMANN REACTION 5 phenolate ion and of the product in the aqueous phase is a contributing factor to the lack ofimmediate success. Nevertheless, high concentrations of carbene can be generated at room temperature when chloroform and aqueous alkali are treated with a quaternary ammonium salt.”* Alkali concentration can be kept near 10% and, although the yields are not greatly improved, the reaction is somewhat cleaner.”! Cyclodextrins influence the ortho-para ratio, giving high yield of para product.'#3-!8° Other Reagents Trichloroacetic acid,°*:°” chloral,** trichloronitromethane,”* and other dichlorocarbene precursors yield Reimer-Tiemann reaction products. Recently phenolic aldehydes have been prepared by irradiation of a mixture of phenols, chloroform, and diethylamine in acetonitrile.®® Trichloromethyl radicals were suggested as the active species. Whether the normal Reimer- ‘Tiemann reaction is concurrently operative is not evident from the evidence presented, Carbon Tetrachloride under Basic Conditions Reimer and Tiemann showed hydroxy acids could be obtained when carbon tetrachloride was substituted for chloroform.*:!2°-!5 Although this is superfically reminiscent of the Kolbe reaction, fundamental differences ‘must exist, since 2-nitrophenol, which is unreactive in the Kolbe carboxyla- tion reaction,!°* is reported to furnish the two isomeric carboxylic acids when treated with carbon tetrachloride in alkali, with the ortho isomer predomin- ating. 10° By-products By-products that are formed in yields not exceeding 3% each are the triphenylmethane-type dyes (A), their tautomers, and the orthoformic esters (B)27°"-1°° Tn the case of phenol itself “tars” amounting to 10% yield are probably mixtures of A and B.°* Contrary to one report, acetals ofthe phenolic aldehydes have never been definitely identified as reaction products.*7*° a Oj as d wt CH OH6 ORGANIC REACTIONS EXPERIMENTAL PROCEDURES Procedures for the preparation of 2-hydroxy-1-naphthalenecarboxalde- hyde in 38-40% yield can be found in Organic Syntheses. The preparation of p-hydroxybenzaldehyde (8-10% yield) and salicylaldehyde (20% yield) are found in a standard text.""° ‘2-Hydroxy-S-methoxybenzaldehyde.''? In a 2-L., three-necked, round- bottomed flask, fitted with a mercury seal stirrer, a long reflux condenser, separatory funnel, and a thermometer, were placed 125 g (I mol) of p- methoxyphenol and a hot solution of 320 g of sodium hydroxide in 400 mL of water. It is convenient to add the sodium hydroxide solution to the phenol shortly after the alkali has been dissolved in the water. In this way the hot alkaline solution readily dissolves the phenol and excess carbonate formation isavoided. Chloroform (240 g, 160 mL, 2 mol) was added dropwise when the solution was brought to a temperature of 70°, and this temperature was ‘maintained throughout the addition, which required 3-4 hours. When all the chloroform had been added, the reaction mixture, which had become dark brown and filled with a thick sludge, was stirred at 70-72° for another 15-20 minutes. The mixture was cooled, transferred to a 5-L round-bottomed flask with the aid of 400-500 mL of hot water, cooled again, and acidified to litmus by the careful addition of 150-200 mL of 10 N sulfuric acid, The 2-hydroxy-5- methoxybenzaldehyde was steam-distilled; from this mixture 5-6 L of distillate was collected. The aldehyde, a yellow oil, was extracted from the distillate with ether. The ether was dried over anhydrous sodium sulfate and theether was removed by distillation. The residual light-brown oil (106-120 g, ‘70-79 %) was distilled under diminished pressure in an atmosphere of nitro- gen, From 166 g of the above product there was obtained 98 g of pure 2-hydroxy-5-methoxybenzaldehyde, bp 133°/15 mm. Indole-3-carboxakiehyde.'? Indole (20 g) was dissolved in a mixture of chloroform (150 mL) and 96% ethanol (400 mL, contained in a 2-L, three- necked flask fitted with a rubber stopper carrying a reflux condenser, a stirer, and a dropping funnel, The mixture was kept gently boiling and stirred while a solution of potassium hydroxide (250 g) in water (300 mL) was gradually added over a period of 4-5 hours. The mixture was boiled for another 30 minutes after the last addition of potassium hydroxide. When the contents of the flask had cooled, the potassium chloride was collected on a Biichner funnel and washed with ethanol. The combined filtrate and washings were then steam-distilled, the receiver being changed when the chloroform and ‘most of the alcohol had passed over. The distillation was continued for 30 ‘minutes after the distillate was no longer turbid owing to the presence of 6- chloroquinoline. The hot aqueous liquid in the flask was decanted from the‘THE REIMER-TIEMANN REACTION 0 tarry residue and set aside to cool. The tarty material remaining was dis- solved in the minimum quantity of hot ethanol, the alcoholic solution was poured into I L of hot water, and the whole solution was again boiled until the tarry globules had coalesced (an action that can be hastened by the addition of alittle sodium chloride to the solution) and then filtered through a fluted filter paper using a heated funnel. The tar remaining on the filter was extracted once again in the same manner. Aldehyde separated from all three aqueous solutions. This was filtered and the combined filtrates amount- ing to some 2.5-3.0 L were concentrated to ca. 300 mL. This concentrated solution yielded a further crop of aldehyde on cooling. The total yield of aldehyde thus obtained amounted to 7.5 g (31 %). The crude material melted at 194°, and at 198° after recrystallization from water (lit. 194-196").1! 1-Dichloromethyl-1-methyl-2(1H)-naphthalenone.'” A solution of 33.0 g of I methyl-2-naphthol and 66.0 g of sodium hydroxide in 660 mL of water ‘was heated to 75°. Chloroform (132 g) was added over 3 hours. The resulting mixture was heated for an additional hour. The organic layer was separated from the aqueous layer, which was then extracted with 100 mL. of chloro- form. The combined chloroform solution was washed first with a dilute sodium hydroxide solution, then with water, and dried with magnesium sulfate. The chloroform was then removed by distillation. Distillation of the residual yellow oil under vacuum gave I-dichloromethyl-1-methyl-2(1H)- naphthalenone (38.5 g, 77%), bp 131-134°/2.5 mm. Most of the material distilled at 131-132°/2.5 mm, On standing, the yellow distillate slowly crystallized. After one crystallization from ethanol-water (1:1) the product G45 g) melted at 64-65° 3-Chloro-4-methylquinoline (phase-transfer eatalysis).’* A 33% solution of sodium hydroxide (5 mL.) was added to a vigorously stirred solution of 3- methylindole (1.0 g) and triethylbenzylammonium chloride (173 mg) in chloroform (10 mL) under ice-cooling, Stirring was continued under cooling for 6 hours and then at room temperature for 24 hours. The aqueous layer was separated and extracted with chloroform. The combined organic layer was extracted with 20% hydrochloric acid (3 x 30 mL), The aqueous layer was made alkaline with 10% sodium hydroxide and extracted with chloroform, The extract was dried over sodium sulfate and concentrated to give crystals of 3-chloro-4-methylquinoline (720 mg, 53%, mp 53.5-54.5 from n-hexane). ‘TABULAR SURVEY The following tables summarize data in the literature through November 1981. Tables I-IX are compiled on the basis of the type of compound that is formylated. Tables X-XIII list compounds that give abnormal reactionORGANIC REACTIONS products. All are tabulated according to increasing number of carbon atoms in the substrate. Yield. The yield, listed in parentheses after the produet, refers to product formed with the conditions cited; in most cases the highest value is reported. ‘A dash indicates that the yield is not stated or is unavailable in the references cited. References, The first reference cited refers to the conditions listed, which lead to the highest yield, Reactions, Since most reactions have been carried out under closely similar conditions, no details ate given in the tables. An exception is Table XIII, in which the source is recorded for the dihalocarbene. An asterisk indicates that the reaction in question is also listed in Table XIV, which gives those reactions that have been carried out under unusual conditions.THE REIMER-TIEMANN REACTION 2 REFERENCE Reimer, Ber, 9, 4231876) Romer and F Tieman, er, 9, 8241875) Reimer an Taran, Ber. 9 1265 (1876) Reimer and F-Tiemar, Ber, 9, 1285 (1876) ‘ers, Ber, 17,296 (18) ‘Numern, Ber 1, 2555 (188) ‘ues, Ber, 29,1109 (196) Auer, Ber, 32,3598 (199), ‘Auer ad F. Witerait, Ber 3,45 (1902), ‘Auwers and G. Kel Ber 3, 407 (912). ‘Auwers and G. Kell Ber, 261861 (190), ‘Auwess and Ke, er 96, 9021909. 1-Gimician and Pier, Ber, 18, 721 (1885). Ghamiin and PSiber Ber, 20, 191 (188), 8G. Giaminn, Ber, 37, 4201 (1908. RB Woodmad, J. dn Cher. Soe, 6, 1208 (1940) 5 RLM Dodson and W.P, Webby J. Chom Sox 73, 2767 (1980. ML, Giuon, Experientia, 7, 16 (1980. 1, Wynbergand W-8. Jonson, J. Or. Chem, 24, 14241859), 2° Wenkert and T-E. Stevens, J. Am Chem So. 7, $27 (950) 24 Wyaterg, Chem. 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