A straightforward and efficient method for the synthesis of diversely substituted β-aminoketones and γ-aminoalcohols from 3-(N,N-dimethylamino)propiophenones as starting materials

A http://dx.doi.org/10.5935/0103-5053.20130177 J. Braz. Chem. Soc., Vol. 24, No. 9, 1396-1402, 2013. Printed in Brazil - ©2013 Sociedade Brasileira de Química 0103 - 5053 $6.00+0.00 Article A Straightforward and Efficient Method for the Synthesis of Diversely Substituted β-Aminoketones and γ-Aminoalcohols from 3-(N,N-Dimethylamino)propiophenones as Starting Materials Rodrigo Abonia,* Danny Arteaga, Juan Castillo, Braulio Insuasty, Jairo Quiroga and Alejandro Ortíz Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia Bibliotecas de novos β-aminocetonas e γ-aminoálcoois que mostram uma grande diversidade estrutural foram facilmente obtidas a partir de uma abordagem simple, utilizando os derivados da 3-(N,N-dimetilamino)propiofenona como material de partida chave. O procedimento envolveu inicialmente a N-alquilação de benzilaminas secundárias com derivados de propiofenona produzindo as desejadas β-aminocetonas. A redução química ou catalítica dos grupos carbonilo atinge a obtenção dos γ-aminoálcoois em bons rendimentos. Este protocolo mostrou ser uma via alternativa conveniente para a síntese do anestésico local Falicain® e para a droga tópica antifúngica Naftifina®. Libraries of novel β-aminoketones and γ-aminoalcohols showing a wide structural diversity were easily obtained from a simple approach, using 3-(N,N-dimethylamino)propiophenone derivatives as key starting material. The procedure involved initially an N-alkylation of secondary benzylamines with propiophenone salts yielding the desired β-aminoketones. Chemical or catalytic reduction of their carbonyl groups provided the final γ-aminoalcohols in good yields. This protocol proved to be convenient as an alternative route for the synthesis of the local anesthetic Falicain® and for the topic antifungal drug Naftifine®. Keywords: benzylamines, propiophenones, β-aminoketones, g-aminoalcohols, Mannich type reaction Introduction Amino-ketones and aminoalcohols are compounds with superior importance not only for their practical applications displayed by themselves but also because they have been found forming part of the structure of synthetic and naturally occurring compounds of diverse practical interest.1 Thus, Falicain® (a local anesthetic and bronchomotor),2 compound BE-2254 (antihypertensive and very selective α1-adrenoceptor antagonist, precursor of the 3-125I-derivative),3 Moban (a neuroleptic)4 and the benzylamine derivative 1 (a potent Jak3 kinase inhibitor),5 are representative examples of this large family of amino‑compounds (Figure 1), as well as the naturally occurring aminoalcohols Anisomycin (a potent activator of stress-activated protein kinases (JNK/SAPK) and *e-mail: p38 MAP kinase) 6 and Castanospermine (a potent inhibitor of α- and β-glucosidases inhibits HIV syncytium formation and replication),7 the synthetic aminoalcohols Salbutamol (a non-selective β-adrenergic agonist, more potent for β2 than β1 receptors)8 and the phenyl/thienylγ-aminoalcohols 2 (direct precursors for the synthesis of Fluoxetine (Ar = Ph) and Duloxetine (Ar = 2-thyenyl), selective serotonin reuptake inhibitors).9 Particularly, Guarna et al.10 reported the synthesis of new γ-aminoalcohols 7 as potential 125I-radioligands for dopamine and serotonin receptors. The synthesis of these compounds was achieved in a four-step sequence as described in Scheme 1. Continuing with our studies toward the synthesis and functionalization of benzylamine derivatives,11-13 herein, we report our results on alternative and simple approaches for the synthesis of new β-aminoketones 10 and their subsequent reduction to the corresponding γ-aminoalcohols 11, structurally Vol. 24, No. 9, 2013 Abonia et al. 1397 disks and films. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 spectrometer operating at 400 and 100 MHz, respectively, using CDCl3 as solvent and tetramethylsilane as internal standard for 1H NMR. Mass spectra were run on a Shimadzu 2010‑DI‑2010 GCMS apparatus (equipped with a direct inlet probe) operating at 70 eV. Microanalyses were performed on an Agilent elemental analyzer and the results are within ± 0.4% of the theoretical values. Silica gel plates (Merck 60 F254) were used for analytical TLC. The starting amines 8a-d and 8f-h (Figure 2) were purchased from Aldrich, Fluka and Acros and were used without further purification. Owing that benzylamine 8e is commercially unavailable, it was synthesized by a reductive amination from benzylamine and 3,4,5-trimethoxybenzaldehyde, following a similar procedure as described previously.11,12 The 3-(N,N‑dimethylamino) propiophenone hydrochlorides 9a-d were synthesized from their respective acetophenones by following a procedure similar to that described in the literature.14 Figure 1. Some amino-ketones and aminoalcohols of biological interest. related to the active compounds 1, 2 and 7, from secondary benzylamines and 3-(N,N-dimethylamino)propiophenone derivatives, as easily accessible starting materials (Scheme 2). Experimental Melting points were determined on a Büchi B-450 melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Shimadzu FTIR 8400 spectrophotometer in KBr General procedure for the synthesis of the β-aminoketones (10) A mixture of amine 8 (500 mg) and the corresponding 3-(N,N-dimethylamino)propiophenone hydrochloride 9 (1 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and triethylamine (TEA, 1 mL). The solution was stirred at reflux for 0.5-2 h until the starting materials were not further detected by TLC. After cooling, the solvent was removed under reduced pressure and the crude was purified by column chromatography on silica gel, using a mixture of CH2Cl2:AcOEt (5:1) as eluent. Scheme 1. Four-step synthesis of the 125I-radioligands 7 for dopamine and serotonin receptors (X, Y = H, F, Br, I); (i) NaBH4, MeOH, 0 oC; (ii) phthalimide, KF, DMF, 120 oC, 8 h; (iii) H2N−NH2, H2O-MeOH-HCl, reflux, 3 h; (iv) 4-R-C6H4CHO (R = H, F), NaBH3CN, MeOH, 24 h, temperature. Adapted from reference 10. Scheme 2. Proposed sequence for the synthesis of β-aminoketones (10) and γ-aminoalcohols (11) from the benzylmethylamine derivatives (8). 1398 A Straightforward and Efficient Method for the Synthesis of Diversely Substituted β-Aminoketones and γ-Aminoalcohols Figure 2. Diversity of benzylamines (8) and propiophenones (9) employed as reagents for the synthesis of products 10 and 11. General procedure for the synthesis of γ-aminoalcohols (11) Approach A: Raney-nickel was added (100 mg) to a sample of aminoketone 10 (300 mg) dissolved in ethanol (15 mL), and then was stirred for 3-4 h at room temperature under hydrogen pressure (50 psi) in a Parr apparatus. When the starting material was not detected by TLC and by the IR spectrum, the catalyst was filtered off, the solvent was removed under reduced pressure and the residue was purified by col (...truncated)