A One-Pot Parallel Reductive Amination of Aldehydes with Heteroaromatic Amines Andrey V. Bogolubsky, † Yurii S. Moroz,* ,†,‡ Pavel K. Mykhailiuk,* ,†,§ Dmitriy M. Panov, † Sergey E. Pipko, ‡ Anzhelika I. Konovets, †,∥ and Andrey Tolmachev †,‡ † Enamine Ltd., 23 Matrosova Street, Kyiv 01103, Ukraine ‡ ChemBioCenter, Kyiv National Taras Shevchenko University, 61 Chervonotkatska Street, Kyiv 02094, Ukraine § Department of Chemistry, Kyiv National Taras Shevchenko University, 64 Volodymyrska Street, Kyiv 01601, Ukraine ∥ The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov Street, Building 5, Kyiv 03187, Ukraine * S Supporting Information ABSTRACT: A parallel reductive amination of heteroaro- matic amines has been performed using a combination of ZnCl 2 −TMSOAc (activating agents) and NaBH(OAc) 3 (reducing agent). A library of diverse secondary amines was easily prepared on a 50−300 mg scale. KEYWORDS: heteroaromatic amines, reductive amination, trimethylsilyl acetate, one-pot approach, parallel synthesis T he reductive amination of carbonyl substrates (aldehydes or ketones) 1,2 has attracted considerable attention among other approaches toward secondary amines. 3−7 The reductive amination reaction consists of (i) formation of an imine from a primary amine and a carbonyl substrate and (ii) reduction of the imine with a suitable hydride source. 8−15 There are two distinct approaches for the reductive amination: the direct approach, which uses the in situ-generated imine (Scheme 1), and the indirect approach, which uses the previously isolated imine. The direct approach allows for the quick generation of sets of amines when the synthesis is conducted in a one-pot fashion and therefore is widely utilized. One of our projects was to apply the reductive amination approach to a parallel synthesis of secondary amines derived from aldehydes and heteroaromatic amines. The approach must satisfy the following conditions of the parallel synthesis: (a) one- pot procedure with a simple “in vial” setup; (b) stable, compatible reagents that would allow the creation of highly diverse sets of compounds and be easily separated from the product; and (c) addition of the reagents without control of the temperature. Despite the fact that heteroaromatic amines are common building blocks in the synthesis of drugs and agrochemicals 16 (Figure 1), literature reports on reductive amination with these amines are rare and nonsystematic. 2,17,18 The amino group of heteroaromatic amines, which is generally electron-deficient, often affords poor yields of the intermediate imines in direct reductive amination. Gutierrez et al. 18 proposed a one-pot reductive amination approach employing a combination of a Lewis acid, TiCl(OiPr) 3 , to facilitate the imine formation and NaBH(OAc) 3 as a reducing agent, which satisfies criterion (a) of the parallel synthesis. However, this approach has drawbacks that result in its incompatibility with criteria (b) and (c): an exothermic reaction with gas evolution occurs during the addition of NaBH(OAc) 3 because of the interaction of the reductant with a byproduct (HCl), and laborious workup is required because of the amorphous precipitate of titanic acid formed after hydrolysis of TiCl(OiPr) 3 . We recently employed trimethylsilyl chloride (TMSCl) 19 as a promoter and a water scavenger in the reductive amination reaction. However, similar to TiCl(OiPr) 3 , its application in combination with NaBH(OAc) 3 to the one-pot parallel synthesis is limited because of the HCl release. We then chose trimethylsilyl acetate (TMSOAc), resulting in AcOH as the byproduct, which is compatible with NaBH(OAc) 3 . Initial experiments, however, showed poor yields in reactions with some substrates because of the low reactivity of TMSOAc. Therefore, we added ZnCl 2 as an additional promoter for the reductive amination. 12 The experimentally established optimal amount of ZnCl 2 (0.05 equiv) allowed for the effective imine formation and had no effect on the purity of the final product. Herein we report our results on the use of this combination of reagents, a TMSOAc/ZnCl 2 mixture and NaBH(OAc) 3 , in the parallel reductive amination of aldehydes with heteroaromatic amines. We selected 10 aldehydes (Figure 2) and 20 amines (Figure 3) from our internal database to test the proposed combination. For Received: April 8, 2014 Revised: June 16, 2014 Published: June 23, 2014 Scheme 1. Direct Reductive Amination Technology Note pubs.acs.org/acscombsci © 2014 American Chemical Society 375 dx.doi.org/10.1021/co5000568 | ACS Comb. Sci. 2014, 16, 375−380