ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 12, pp. 2617–2627. © Pleiades Publishing, Ltd., 2010. Original Russian Text © N.V. Ivanova, N.V. Tkach, E.N. Belykh, I.V. Dlinnykh, E.V. Babaev, 2009, published in Rossiiskii Khimicheskii Zhurnal, 2009, Vol. 53, No. 5, pp. 105–115. Reductive Amination with a Scavenger: The Most “Combinatorial” of Two-Component Reactions N. V. Ivanova, N. V. Tkach, E. N. Belykh, I. V. Dlinnykh, and E. V. Babaev Lomonosov Moscow State University, Vorob’evy Gory 1, Moscow, 119991 Russia e-mail: [email protected] Received July 10, 2009 Abstract―Synthesis of amine libraries from aldehydes via the liquid-phase parallel reductive amination with a simple scavenger (a Dowex resin) is described. Three parallel protocols are compared: reactions in well plates, SynCore apparatus, glass vials (without specific equipment). The presented detailed protocols can be useful for practical training of students. DOI: 10.1134/S1070363210120285 INTRODUCTION HNR'R'' (1) Reactions of liquid-phase parallel synthesis are X CH2=O NR'R'' HNR'R'' subject to quite stringent requirements by quite CH2 CH2 (2) different criteria. Collections of starting reagents e.g. X = Cl should be cheap and diverse, reaction conditions H HNR'R'' (3) should be simple and mild, and the products should be O [H] obtained in high yields and without complicated purification. For biological tests, the final molecule should contain a predeterminedly “pharmacophore” alkylation. The third strategy (conversion of carbonyl fragment. Many reactions fail to meet such criteria; for group into aminoalkyl) is the only which is practically example, certain С–С bond formation reactions can a universal in nature, as reflected in detail in a series of priori be considered unsuitable (Diels–Alder reactions reviews [1–4]. The popularity of this reaction is largely and even condensations produce a lot of admixtures, associated with the wide distribution and accessibility cross coupling makes use of hardly accessible rea- of aldehydes, since there are numerous ways to intro- gents, etc.). Much more suitable are reactions in- duce aldehyde group into a great variety of substrates. volving nucleophilic nitrogen atom (formation of The key feature of reaction (3) is that it involves amides, sulfamides, hydrazides, or hydrazones), the intermediate formation of imines (Schiff bases). best of which is formation of compounds with an NHR H H aminoalkyl group. NH2R OH O Substituted aminoalkyl group (NHRCH2– or NR2CH2–) is a well-known pharmacophore group in a NR'R'' great variety of medicines and natural compounds. NHR − H There are several strategies for introducing this group H2O [H] CH2 into a desired substrate: Mannich reaction (1), N- (4) +H O alkylation (2), and reductive amination (3). 2 The first two reactions have natural limitations, This stage is reversible. Provided imine has been since not every substrate can be introduced into the selectively reduced into amine (in the presence of Mannich reaction, and not any combination of amine aldehyde), the reaction can be brought to completion to and alkylating agent results in unambiguous mono- obtain the final amine in high yield. In the reaction of 2617 2618 IVANOVA et al. aldehydes with secondary amines, reduction is ex- laboratories, using quite interesting techniques. perienced by the equilibrially formed iminium salt. Finally, the third version represents the adaptation of The problem is to properly choose a selective reducer this task to SynСore apparatus, performed at the MSU which fast reacts with imine and not reacting (or by the request of the producer company Buchi. This slowly reacting) with aldehyde [5]. The best reagents synthesis was highly appreciated by the Swiss [6] were found to be Na[BH(OAc)3] and Na[BH3CN]. company, and our procedures were included in the “Best at Buchi” booklet [7]. The reactions performed The standard admixtures in this reaction are traces at the MSU by the simplest, first scheme (5) and of alcohol (side reduction of aldehyde), as well as subsequent in vivo tests resulted in the discovery of a unreacted starting materials. The reaction occurs under new family of anxiolytics [8]. heterogeneous conditions in DCM or DCE, and efficient agitation of the heterogeneous mixture is the Synthesis without Special Equipment principal condition for complete reaction. The training reductive amination reaction (like the Products can be purified by using the simplest Ugi reaction [9]) is a facile and an illustrative example scavenger, specifically a Dowex ion-exchange resin. highlighting specific features of parallel organic This resin is a styrene–divinylbenzene copolymer synthesis. The suggested training task was perfected by containing sulfonic acid groups which bond amines a group of students during the special laboratory into salts. As a result, aldehyde is filtered throught the course in combinatorial chemistry at the MSU in resin and removed with the filtrate. The amine bound 2002–2004. In its chemical essence, it is a one-stage by the cationite is expelled from the resin by another reductive amination reaction between series of amine, say, diethylamine (in methanol). It is quite clear heterocyclic aldehydes and aliphatic amines, with that the final product (amine 2) of the “aldehyde + Na[BH(OAc)3] as the reducer. The task involves the amine 1 = amine 2” reaction cannot be purified from stage of parallel purification of products by means of the starting reagent (amine 1) in this way, and the the simplest scavenger, viz. an ion-exchange resin. solution eluted from the resin necessitates further N R purification. R' Having called the reductive amination reaction the N CH=O most “combinatorial,” we would like to focus on R'' certain details of its implementation in the parallel NR H N R 2 R' mode. Such details are rarely described in scientific Na[BH(OAc) ] (5) 3 N publications. At the same time, it is just in Russia that CH2NR2 this reaction has received a great deal of attention. The R'' reaction was one of the most popular objects at Each student performed six syntheses of four target Moscow research laboratories of the ChemBridge compounds by reductive amination (1 aldehyde + company, as a result of which at the Global Market 4 amines), and, therewith, in three cases the aldehydes/ tens (if not hundreds) thousands of compounds for amine molar ratio was varied). Over the course of six testing comprise just this structural motif. Owing to the lessons (2–3 h each) each student performed six facility for implementation, this reaction is convenient parallel reactions, preliminary purification of the to use for teaching for the basic principles of liquid- reaction product on a Dowex cation exchanger, and phase parallel synthesis: It does not require chromatographic purification of products, after which sophisticated equipment and can be used even at low- their NMR were measured. At the final lesson students budget training laboratories. had to draw conclusion as to optimal reaction For this reason, the present paper is built as a conditions and analyze the yields and purity of the training task (with protocols and instructions for products. students), as it was suggested to students of the Reagents and Solvents: Moscow State University (MSU) over many years. The task is given in three versions. The first version is the (1) Dichloroethane (DCE), dichloromethane simplest and requires virtually no equipment. The (DCM), isopropanol, potassium carbonate, anhydrous second version is based on a real practice of the sodium sulfate, silica gel for chromatography, and implementation of this work at ChemBridge Silufol plates; RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 12 2010 REDUCTIVE AMINATION WITH A SCAVENGER 2619 Scheme 1. N S N X N Ar Ar Ar N N Ar CH=O N CH=O CH=O IA IC DMF N N POCl S N 3 R'' N N Ar X N R' Ar N N Ar N CH=O I CH=O IB ID I CH=O (a) (b) (c) NH2 N DMF N N X POCl3 N N Ar Ar X N N − O CH2 CONR2 CH=O Br IIIA IA IVa: X = R = Me; Ar IVb: X = Cl, R = Me; (d) (e) (2) Na[BH(OAc)3] as the reducer and anhydrous for synthesis of aldehydes I [10] and their precursors III oxalic acid for precipitating oxalates; [11] can be found in the literature. (3) Dowex ion-exchange resin for purification of As a result, the short synthetic sequence leading to products from aldehydes admixtures; aldehydes I allows flexible variation of the hetero- cyclic and aryl residues in the aldehyde, and com- (4) a series of 5–10 secondary aliphatic amines, for pounds II formed by the reductive amination reaction example, cyclic (pyrrolidine, piperidine, morpholine, are structurally definitely related (drug likeness) to etc.). We additionally used a series of amines on the known drugs IVa (zolpidem) and IVb (alpidem) basis of 4-substituted piperazines (4-alkyl and 4-acyl (Scheme 1e). derivatives) and piperidine-4-carboxamides (substituents in such amines can be readily varied, provided 1-Boc- Equipment: piperazine or N-Boc-isonipecotic acids are available in (1) a set of automatic one-channel pipettes of sufficient amounts); various volumes with a set of tips for them; (5) a series of 5–10 aromatic aldehydes. We used a (2) a set of glass vials with screw caps (three times specific set of heterocyclic aldehydes of the imidazole the number of reactions) and any shaker for agitation; series of general formula I, in which R' and R" form a (3) a set of plastic syringes with a porous dia- different heteroring (Scheme 1): pyridine (IA), pyri- phragm (Fig. 1) for passing reaction mixtures through midine (IB), thiazole (IC), or benzothiazole (ID). Such the cation-exchange resin. Syringes can also be used as aldehydes I are can be easily prepared by the Wils- mini-columns for chromatography, but it is better to meyer reaction by formylation of the corresponding pass the mixtures through a short silica bed on a glass condensed imidazoles III (Scheme 1c).