CHAPTER 7 THE LEUCKART REACTION Mavuaice L. Moon: Smith, Kline and French Laboratories CONTENTS vAGR INTHODUCTION 6 6g 302 Mecuanism or tie Reaction 2 6. ee 303, Scors or Trt Rracrion 306 Methylation of Amines with Formaldehyde a 307 Reactions of Higher Aliphatie Aldehydes 2... . . . 808 Reactions of Aromatic and Heterocyclic Aldehydes... Lioure B09 Teactions of Aliphalic Ketones. 20. 0 . 810 Reactions of Alipbatic-Aromatic and Aliphatic-Heterovyclic Ketones... B11 ons of Aromatic Ketones 6 5 6 ee 313 ons of Alicyelie Ketones. 2. 6... tae . Blt Reactions of Quinones 6. oe ee ee .. 814 Reactions of a Pyrazolone and an Oxindole 2. 31S Give REACTIONS 60 BLS. Exrarncentan, CONDITIONS 6. ee : . 316 ‘The Ammonium Formate er Pormamide 2 0 2... ce ee 816 Temperature, Le BIT Solvent oe Loe Le. BIT Hydrolysis 0 318 Isolation . 318 UxeReMentaL Procepees. 2... ee 319 Tri-n-amylumine (Use of Ammonium Formate and Pormie Acid)... 6. 319 N,N-Dimothylfurfurylamine (Use of Dimethylformamide and Formie Acid) 319 a-(@-Naphthylethylamine (Preparation and Use of Formamide-Formic Acid Reagent from Ammonitun Curbonate-Carbamate and Formic Acid)... 320 Methyl-ter-butylearbinamine (Use of a Solvent, Nitrobenzene). . 2... 821 -p-Chilorophenethylamine (Use of Formamide and Formic Acid)... B2L e-Aminodadeeylbenzene (Use of Ammonia and Fortnie Acid) 2 6... 322 a-(o-Chlorohenzyethylamine (Use of Formamide) 2... ee 323 N,N-Dimetbiylbenzylamine (Eschweiler-Clarke Procedure). . 2... . . 828 3013802 ORGANIC RMNACLIONS Tanvran Survey or tp Luvcwarr Reacroon .. 6... ee 323 TABLE I. With Aliphatic Aldehydes . . 325 II. With Aromatic and Heterocy 326 IIL, With Aliphatic Ketones... 0... 327 IV. With Aliphatic-Aromatie and Aliphatic-Heterocyclie Ketones... 328 VY. With Aromatic Ketones 2. 2 ee ee 829 VIL With Alioyclic Ketones. 2 ee 330 VIL. With Quinones 330 INTRODUCTION The Leuckart reaction Is a process for the reductive alkylation of ammonia or primary or secondary amines by certain aldehydes and ketones. Tt is distinguished by the fact that the reduction is accom- plished by formic acid or a derivative of formic acid and should be compared with the reductive alkylation using hydrogen diseussed in Chapter 3 of Volume IV of Organic Reactions, ‘The reaction is carried out by heating a mixture of the carbonyl compound and the formic acid salt or formyl derivative of ammonia or the amine. Primary and secondary amines produced in the reaction often are obtained as the formyl derivatives and must be recovered by hydrolysis; tertiary amines are obtained as the formates. The reaction may be illustrated by the following equations. qn Rr’ CO + 2HCONIly > >YCHNHCTIO -- 220 -}- NHs + COz R R ’ , >CHNHCTIO + 1,0 > >CHNIin + TICOLH R R Leuckart t discovered the reaction in an attempt to prepare benzyl- idenediformamide, CgHs;CH(NHCHO),», by heating benzaldehyde with formamide in an experiment patterned after the preparation by Roth * of the corresponding acetamide derivative. The reaction with formam- ide was found to take a different course, leading to benzylamine and its formyl derivative, dibenzylamine and its formyl derivative, and tribenzylamine. Ammonium formate was found to react in the same Leuckart and co-workers, Ber., 18, 2341 (1885); 19, 2128 (1886); 20, 104 (1887); 22, 1409, 1851 (1889). ® Roth, Ann, Chem. Pharm., 154, 72 (1870),“THE LEUCKART REACTION 303 way as the amide, and benzophenone could be converted to benzo- hydrylamine by the use of conditions somewhat more drastic than those required with benzldchyde. Leuckurt’s experiments with aliphatic aldchydes and ketones were not extensive,’ but Wallach ¢ and Kijner # applied the reaction to many such compounds. ‘The method received little attention from other investigators until Ingersoll and his assoei- ates ° reviewed the subject and applied the reaction to the synthesis of a series of substituted a-phencthylamines; since the appearance of this work the method has becn employed extensively. Among the better known modifications of the process are the preparation of trimeth tuning 7 from. ammonia, formalded: id and the wveilex-Clarke ® proche for the methylation of primary and second: ary amines by the aid of formaldehyde and formic acid. MECHANISM OF THE REACTION Assingle mechanism capable of accounting for all the variations of the Leuckart, process can be postulated on the basis of the decomposition of the ammonjum salt or of the amide, by thermal or hydrolytic means, respectively, to formic acid and ammonia or an amine. The base 50 formed may then react with the carbonyl compound to give an addition product Se which ig reduced by formic acid to an amine (dom-x); reaction of this amine with more formic ucid leads to the salt or the amide. These transformations appear to be the only ones concerned in the formation of a tertiary amine from a earbonyl com- pound and the formate or formyl derivative of » secondary amine, but there are numerous other possible intermediates in the synthesis of primary and secondary amines, Por extunple, the addition product from a carbonyl compound and ammonia or a primary amine may undergo Leuckart, J. prakt. Chem., (2} 41, 330 (1890), 4 Wallach and co-workers, (a) Ber., 24, 3992 (1891); (6) Ann, 269, 347 (1892); (¢} 272, 100 (18953) ; @} 276, 296 (1893); (¢) 289, 338 (1896); (7) 300, 283 (4895); (g) 843, 54 (1908). * Kijner, J. Russ. Phys. Chem. Soc., 31, 877, 1033 (1899); 32, 381 (1900) [J, Chem. Soc, (Ads), 78 ©, 277, 333, 629 (1900}], © Ingersoll, Brown, Kim, Beaneliarp, and Jennings, J. Am. Chem, Soc., 88, 180 (1936). FSommelet and Vertand, Hull, soc. chim, Prance, (Aj 26, 446 (1924), 8 Eschweiler, er., $8, 88 (1905). * Clarke, Gillospic, and Weishaus, J Am, Chem, Soc., 85, 4574 (1933).