FOCUS REVIEW DOI: 10.1002/ajoc.201300012 Catalytic Methods for Imine Synthesis Rajendra D. Patil and Subbarayappa Adimurthy*[a] Asian J. Org. Chem. 2013, 2, 726 – 744 726 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Rajendra D. Patil and Subbarayappa Adimurthy Abstract: This Focus Review describes different methods that have been reported for the synthe- sis of imines. It is organized according to the methods used for imine synthesis starting with metal catalysis, including Ru, Au, V, Cu, Mn, Co and Pd catalysis. Other methods, such as photo- catalysis, electrocatalysis, organocatalysis, and so on, are also emphasized. Ample information on the condensation of carbonyl compounds/alcohols with amines and direct oxidation of amines to give imines is discussed. Furthermore, among various metal-catalyzed reactions, specific atten- tion has been paid to copper-catalyzed imine synthesis, as copper is less toxic than other heavy metals, comparatively inexpensive, and is easily accessible. Keywords: amines · carbonyl compounds · catalysis · imine synthesis · oxidation 1. Introduction Much information on the synthesis and chemistry of imines is scattered throughout the literature.[5,6,14–28] Howev- An imine has the general formula R’RC=NR’’, in which R, er, to our knowledge, there has not been a specific and R’, and R’’ can be hydrogen atoms, alkyl groups or aryl comprehensive review on imine synthesis to date. In contin- groups. If R’’ is alkyl or aryl group (not hydrogen) then the uation of our research interest in the development of effi- imine functionality is known as a “Schiff base”, named cient and sustainable methods for imine synthesis,[29–31] as after Hugo Schiff who discovered them in 1864.[1] There are well as for the wider interest of the scientific community, other similar functional groups which slightly differ from an overview of imine chemistry is presented. It is hoped the definition of an imine at the nitrogen center, for exam- that by assembling a comprehensive survey of the widely ple, when R’’=NR2 as in hydrazones and R’’=OH as in scattered information on imine synthesis, it will focus the oximes, and these compounds are not included in this Focus attention of a broad readership because of the potential ap- Review. In the present article, the term imines mainly plications of these compounds. This Focus Review collates refers to Schiff bases. much of the information that is available in the literature Imines are important intermediates in the synthesis of on methods and catalysts used for the synthesis of imines to various biologically active N-heterocyclic compounds and date. in industrial synthetic processes.[2–4] Imines react reversibly Significant progress has been made in recent years in the with amines and aldehydes under particular reaction condi- synthesis of imines, which have been prepared by various tions under thermodynamic control so that initially formed, methods from aldehydes and/or amines and their chemical kinetically competitive intermediates are replaced by ther- equivalents. As depicted in Scheme 1, these methods in- modynamically stable products over time. For this funda- mental reason, the formation of a dynamic covalent imine bond (dynamic covalent bond refers to the influence of re- active substrates, reagents, and particular reaction condi- tions) is an emerging and versatile method with various ap- plications. Formation of imines underlies a discipline known as dynamic covalent chemistry (DCC), which is now used widely in the construction of exotic molecules and ex- tended structures, such as rotaxanes, catenanes, and so on.[5,6] Imines can act as electrophiles in a number of reac- tions, including reductions, additions, condensations, and cy- cloadditions.[7,8] The presence of the lone pair of electrons on the nitrogen atom of the imine group enables coordina- tion to numerous metals, especially when the imine func- tionality is located at the ortho position of aromatic hetero- cycles, such as pyridines. Such molecules are used for inter- esting applications as ligands in homogeneous catalysis.[9,10] Prochiral imines have been widely used for the synthesis of chiral amines.[11–13] [a] R. D. Patil, S. Adimurthy Central Salt & Marine Chemicals Research Institute (CSIR) G.B. Marg, Bhavnagar 364002, Gujarat (India) Fax : (+91)0278-2567562 Scheme 1. Various synthetic methods that have been reported for imine E-mail: [email protected] synthesis. Asian J. Org. Chem. 2013, 2, 726 – 744727 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Rajendra D. Patil and Subbarayappa Adimurthy clude condensation of aldehydes/ketones (A) with amines the reverse reaction, so that azeotropic distillation by (B, method I), addition of aryl halides and liquid ammonia Dean–Stark apparatus is necessary to push the reaction in to aldehydes/ketones (method II), hydroamination of al- the forward direction to favor the imine formation.[32, 33] kynes (method IV), oxidative coupling of amines (B) to There are various factors which influence the equilibrium give imines (method V), oxidative coupling of alcohols and between the imine and the starting aldehyde and amine. amines (method VI), dehydrogenation of secondary amines These factors include concentration, steric and electronic (method VII), coupling of aldehydes/ketones with nitro effects, pH, temperature, and solvents. Condensation reac- compounds (method VIII), and the reaction between chem- tions between carbonyl compounds and amines have been ical equivalents of aldehydes/ketones (X and Y) and carried out in the presence of various catalysts, such as [34] [35] ACHTUNGRE [36] ACHTUNGRE [37] amines (method III). TiO2, CeCl3·H2O, Cu(NO3)2, Er(OTf)3, P2O5/ [38] [39] [40] ACHTUNGRE [41] Al2O3, P2O5/SiO2, NaHSO4·SiO2, Mg(ClO4)2, mo- [42–44] [45–49] lecular sieves, TiCl4, MgSO4–pyridinium p-toluene- [50] [51] [52] [53] [54] 2. Imine Synthesis from Amines and Aldehyde sulfonate, ZnCl2, alumina, Ti(OR)4, CuSO4, and and Ketones montmorillonite K-10 clay.[55,56] In such reactions, these cat- alysts act as Lewis acids to catalyze the nucleophilic attack The synthesis of imines originally reported by Schiff in- of the amine on the carbonyl group and also serve as dehy- volves condensation of a carbonyl compound with an drating agents through irreversible binding with water to fa- amine.[32] Such reactions proceed by nucleophilic addition cilitate the removal of water in the final step. The use of to give a hemiaminal (<-C> C(OH)(NHR)ACHTUNGRE <-C>) inter- dehydrating solvents, such as tetramethyl orthosilicate[57] mediate, then the elimination of water provides the imine and trimethyl orthoformate,[56, 58] were reported to avoid (Scheme 2). The equilibrium in this reaction usually favors azeotropic distillation. In the past two decades, researchers have shown remark- able interest in developing sustainable processes because of environmental concerns, for example, the synthesis of imines with microwaves,[56, 59–64] ultrasound,[65] and IR[66] as energy sources. Furthermore, imine synthesis has also been Scheme 2. Equilibrium in the synthesis of an imine from an aldehyde reported under solvent free conditions.[35,38,39,67,68] Recently, and an amine. ethyl lactate as a tunable solvent has been reported for aryl aldimine synthesis.[59,69] Ethyl lactate can be tuned with a co-solvent to create polarity conditions that are ideal for the synthesis of aryl aldimines, which crystalize directly out Dr. S. Adimurthy was born in 1972 in Ra- of solution in minutes in high yields.[69] Simple, water-medi- mojipalli, Karnataka State, in India. He re- ated procedures for the synthesis of various imines that re- ceived his B.Sc. and M.Sc. degrees in Chemistry from Bangalore University in quire neither catalyst nor any additive were also report- [70–72] 1994 and 1997, respectively. From 2000 to ed. date, he has worked as a Scientist at the In 1962, a review by Layer[73] on imines synthesis focused Central Salt & Marine Chemicals Research on the condensation of carbonyl compounds and amines.[74] Institute, Bhavnagar. He received his Ph.D. in 2005 from Bhavnagar University, India. However, these classical methods have some general limita- He took up a postdoctoral position at the tions. For example, the condensation of primary aliphatic University of Hohenheim, Stuttgart, Germa- aldehydes and amines does not lead to the desired imines, ny, (2007-2008) with Professor U. Beifuss. but instead provides polymeric materials with unreacted He has published over 40 papers and holds amines.[73] Reactions between aliphatic aldehydes and ali- six US patents. His research interests in- clude the synthesis of heterocycles through phatic amines do not easily give imines. Similarly, ketones CÀH activation, sustainable halogenation, react with amines very slowly and generally require harsh and the development of new oxidative reaction conditions. Moreover, the efficiency of the report- methods. ed procedures is limited to the reaction of highly electro- Rajendra D. Patil was born in 1983 in Var- philic carbonyl compounds and strongly nucleophilic dhane, India. He received his B.Sc. and amines. Therefore an alternative and efficient strategy with M.Sc. in organic chemistry in 2004 and a broad scope of imine products is highly desirable. Oxida- 2006, respectively, from North Maharashtra tive dehydrogenation of amines (ODH) to give imines has University, India. He joined the Central Salt that potential. and Marine Chemicals Research Institute, Bhavnagar, India in 2007