Reductive amination of ketones: novel one-step transfer hydrogenations in batch and continuous-flow mode Péter Falus a , Zoltán Boros a , Gábor Hornyánszky a , József Nagy a , Ferenc Darvas b , László Ürge c , László Poppe a,⇑ a Department for Organic Chemistry and Technology, Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, Budapest University of Technology and Economics, Müegyetem rkp. 3., H-1111 Budapest, Hungary b Department of Cellular Biology and Pharmacology, Herbert Weinheim College of Medicine, Florida International University, 11200 S.W. 8th Street, Miami, FL 33199, USA c ThalesNano Inc., Graphisoft Park, Záhony u. 7., H-1031 Budapest, Hungary article info Article history: Received 26 November 2010 Revised 21 December 2010 Accepted 14 January 2011 Available online 20 January 2011 Keywords: Ketone Amine Ammonium formate Zinc dust Palladium on charcoal Continuous-flow reductive amination abstract Various ketones were efficiently transformed into the corresponding amines using ammonium formate in the presence of Zn dust or 10% Pd/C. The low-cost Zn dust method proved to be effective in amine forma- tion from carbonyl groups at the benzylic side-chain position of aromatic systems, whereas 10% Pd/C was an efficient catalyst in the reductive aminations of carbonyl groups non-conjugated with any p-system. The 10% Pd/C-catalyzed reductions were performed more effectively in a continuous-flow X-Cube reactor than in the batch system. Ó 2011 Elsevier Ltd. All rights reserved. Amines are indispensable building blocks in numerous drugs, 1,2 pesticides 3 , and color pigments. 4 Thus, development of general and efficient methods to prepare amino compounds is still required. One of the most convenient methods to synthesize amines is the reductive amination of carbonyl compounds. 5 The classical Leuck- art–Wallach (LW) 6 reaction is clean and very simple, but it has sev- eral drawbacks such as the requirement of harsh conditions, formation of N-formyl derivatives, and the difficulty of selective synthesis of primary amines from ammonia. Nowadays, reductive transformations of ketones into amines are performed in the presence of catalysts. A wide range of me- tal-containing catalysts, usually as metal complexes, such as Pd, 7–9 Ir, 10 Rh, 10 Ru, 10 and Ti 11 are utilized in these processes. Although some of these catalysts are widely used, they have limi- tations with regard to chemoselectivity, recyclability, safety, and costs. Metals (Na, 12 Ni, 13 Raney-Ni, 14 Pd, 15 Pt 16 or Ru 15 ), or metals on activated charcoal (Pd/C, 15 Ru/C 15 ) are also used in reductive amin- ations of ketones. In these cases, either the metal is dissolved in a protic solvent in the presence of an ammonia source, or the metal serves as the catalyst under an H 2 atmosphere in the presence of NH 3 or other ammonia source. 17 Sometimes, these processes result in various side reactions such as formation of alcohols, Schiff- bases, imines, and bis-amines. 15 Amines can be formed stereoselectively by employing chiral complexes 18–21 or enzymes. 22,23 In many cases, however, cost, recyclability or environmental issues make such methods unsuit- able for large scale production. As the formation of oximes from carbonyl compounds is a well established process, 12,24 and that amines can be prepared by reduction of oximes with LiAlH 4 , 25 or by various metals such as Zn 26–28 or Mg, 29 the combination of these two methods can pro- vide a synthetic pathway to amines from ketones. Metals or metal-containing catalysts can be applied for reduc- tive aminations with various reducing agents. 5 In these processes, molecular hydrogen, 13–16,18 metal hydrides such as NaBH 4 11,30 or NaBH 3 CN, 31 or various transfer hydrogenating agents such as Han- tzsch esters 19 can serve as the reducing agents. In addition, reduc- tive amination of ketones requires a nitrogen source such as ammonia, 13–16,20,32 ammonium salts (NH 4 Cl, 15,16,30 NH 4 OAc 31 ), L- alanine 22,23 or isopropylamine. 23a,b Ammonium formate is an inexpensive, non-toxic, and environ- mentally safe reagent, and could serve as both the nitrogen source and the transfer hydrogenating agent simultaneously. 7,8,10,20,21 Ammonium formate was successfully applied previously in metal 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.01.062 ⇑ Corresponding author. Tel.: +36 1 463 3299; fax: +36 1 463 3697. E-mail address: poppe@mail.bme.hu (L. Poppe). Tetrahedron Letters 52 (2011) 1310–1312 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet