Diastereoselective Synthesis of 2,6‐Disubstituted‐1,2,3,6‐Tetrahydropyridines through a Palladium‐Catalyzed Intramolecular Allylic Amination

Abstract

An efficient synthesis of 2,6-disubstituted-1,2,3,6tetrahydropyridines is reported, featuring a highly diastereoselective palladium-catalyzed intramolecular allylic amination Scheme 1. Previous work toward the synthesis of 2,6-disubstituted-piperidines. Current methodology toward the preparation of 2,6-disubstituted-TP.[a] 7686 from non-activated alcohols. This method allowed a straightforward access to 2,6-trans-1,2,3,6-tetrahydropyridines with de up to 100 % under mild conditions, in moderate to good yields.Mitsunobu [1c] reactions, allyl nitrone cyclization, [7] aza-[2,3]-Wittig rearragements of vinylaziridines [8] or diastereoselective C-H functionalization. [9] However, methods leading to trans-2,6disubstituted-TP/piperidines are less reported, because the trans relative configuration is thermodynamically disfavored. [10] For example, trans-2,6-disubstituted-TP/piperidines can be obtained by C-N bond formation and ring closure, the TP substituents at 2-and 6-positions being already present in the structure. These methods employed allylic alcohols or their activated counterparts as precursors, and used Brønsted acid conditions, S N 2 or Mitsunobu reactions affording nitrogen attack, to form the unsaturated 6-membered ring.Knowing the importance of stereocenter configuration for biological activities, the development of new stereoselective syntheses of trans-2,6-disubstituted-TP/piperidines remains an important challenge. During our previous studies, we developed a methodology to prepare stereoselectively either 2,6-cis or 2,6-trans-disubstituted-piperidines via a Michael-type cyclization. [11] This methodology used ′-carbamate-α, -unsaturated ketone [3a] as a key precursor. We further envisioned that 2,6disubstituted-TP could be formed via a palladium-catalyzed Eur.7691 saturated aqueous NH 4 Cl solution and extracted 3 times with EtOAc. Then the organic layer was dried with MgSO 4 , filtered, and concentrated under vacuum. The crude was purified by silica gel column chromatography as described in the corresponding synthetic procedure to give the ketone 2a-x. Benzyl (R,E)-(6-Oxo-8-phenyloct-7-en-4-yl)carbamate (2e):was prepared from benzyl (R)-(1-(diethoxyphosphoryl)-2-oxoheptan-4yl)carbamate 1e (1 g, 2.50 mmol). The crude product was purified by silica gel column chromatography (SiO 2 , 100 % cyclohexane to 8:2 cyclohexane/EtOAc) providing 2e as a white solid in 91 % yield (800 mg, 2.28 mmol). TLC R f = 0.49 (cyclohexane/EtOAc, 7:3); Mp 93°C; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.62-7.48 (m, 3H), 7.42-7.37 (m, 3H), 7.36-7.27 (m, 5H), 6.72 (d, J = 16.1 Hz, 1H), 5.27 (d, J = 8.7 Hz, 1H), 5.08 (s, Benzyl (S,E)-(3-Oxo-1,5-diphenylpent-4-en-1-yl)carbamate 2f:was prepared from benzyl (S)-(4-(diethoxyphosphoryl)-3-oxo-1phenylbutyl)carbamate 1f (100 mg, 0.231 mmol). The crude product was purified by silica gel column chromatography (SiO 2 , 100 % cyclohexane to 8:2 cyclohexane/EtOAc) providing 2f as a beige solid in 81 % yield (71.6 mg, 0.186 mmol). TLC R f = 0.47 (cyclohexane/ EtOAc, 7:3); Mp 114°C; 1 H NMR (400 MHz,...