Trimethylsilyl Iodide‐Promoted Aza‐Prins Cyclization for the Synthesis of 4‐Iodopiperidines

Abstract

The aza-Prins cyclization of homoallyl N-tosylamine with aliphatic aldehydes gives trans-2-alkyl-4-iodo-1-tosylpiperidines. This method is chemoselective as it works only with the aliphatic aldehydes, and, in the case of aromatic aldehydes, the starting materials are recovered.The aza-Prins cyclization [1], in which alkenes are used as intramolecular nucleophile, is a simple and direct method for the preparation of trans-2,4-disubstituted piperidines. Earlier, we have studied [2] the use of Me 3 SiI (TMSI) in Prins cyclization reactions for the synthesis of tetrahydropyrans. In continuation, here we report TMSIpromoted aza-Prins reaction for the synthesis of 4-iodopiperidines from N-tosyl homoallylic amines and aldehydes.Thus, treatment of 3-phenylpropanal with N-tosylbut-3-enamine in the presence of 1 equiv. of TMSI in MeCN at 08 to room temperature was found to be completed in 2 h, and the corresponding trans-4-iodo-2-(2-phenylethyl)-1-tosylpiperidine (3a) was isolated as the major isomer in 85% yield (Scheme 1). The structure of the product was established by NMR spectroscopy and NOE studies.To evaluate the scope of the reaction, several aliphatic aldehydes such as butanal, hexanal, isobutanal, cyclopentanecarbaldehyde, and cyclohexanecarbaldehyde were studied, and they were found to give the corresponding piperidines in good yields when treated with N-tosylbut-3-enamine. In all cases, the trans-diastereoisomer was obtained as the major product, and the trans-configuration was confirmed by NOE experiments. This reaction does not require any additives. Under these conditions, the aza-Prins cyclization works well only with aliphatic aldehydes, whereas, the reaction does not work with the aromatic aldehydes. Accordingly, the aza-Prins reaction using TMSI is selective. Reactions of aldehydes containing aromatic rings located in a distal position (Entries a and e; Table in Exper. Part) relative to the C¼O group, proceeded Scheme 1

Preparation of trans-2-Substituted-4-halopiperidines and cis-2-Substituted-4-halotetrahydropyrans via AlCl3-Catalyzed Prins Reaction

“…trans -2-Ethyl-4-iodo-1-tosyl­piperidine (major diastereomer, white solid, mp = 97–99 °C): 1 H NMR (400 MHz, CDCl 3 ) δ = 7.64 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 4.21 (tt, J = 12.7, 4.1 Hz, 1H), 3.75 (dd, J = 13.8, 7.1 Hz, 1H), 3.62–3.55 (m, 1H), 3.01–2.90 (m, 1H), 2.37 (s, 3H), 2.20–2.08 (m, 2H), 1.98 (td, J = 13.1, 5.4 Hz, 1H), 1.81 (qd, J = 12.7, 4.8 Hz, 1H), 1.60–1.47 (m, 1H), 1.49–1.36 (m, 1H), 0.80 (t, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ = 142.3, 137.1, 128.8, 125.9, 56.0, 41.2, 40.1, 37.1, 21.7, 20.5, 18.4, 9.9. NMR data were in agreement with the reported result …”

“…trans -4-Iodo-2-iso­propyl-1-tosyl­piperidine (major diastereomer, white solid, mp = 85–86 °C): 1 H NMR (400 MHz, CDCl 3 ) δ = 7.65 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 4.19 (tt, J = 12.8, 4.0 Hz, 1H), 3.64–3.56 (m, 1H), 3.38 (dd, J = 10.9, 5.0 Hz, 1H), 2.98–2.89 (m, 1H), 2.41–2.29 (m, 4H), 2.05 (dd, J = 13.0, 1.8 Hz, 1H), 1.96–1.67 (m, 3H), 0.87 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 143.3, 138.4, 129.8, 127.0, 61.9, 42.8, 39.0, 37.7, 26.4, 21.6, 20.1, 20.0, 19.6. NMR data were in agreement with the reported results …”

“…13 C NMR (100 MHz, CDCl 3 ) δ = 143.3, 138.2, 130.0, 127.0, 55.6, 42.6, 41.5, 38.2, 31.4, 30.0, 261, 22.6, 21.6, 20.0, 14.1. NMR data were in agreement with the reported results …”

Iodine-Catalyzed Aza-Prins Cyclization: Metal-Free Synthesis and Antiproliferative Activity of Hexahydrobenzo[f]isoquinolines

“…1,2 Thus, preparations of piperidines and tetrahydropyridines by a wide range of protocols have been reported. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] However, aza-Prins reactions have been used less frequently in the construction of other ring systems. [19][20][21][22][23] In this context, we describe the synthesis under mild and metal-free conditions of a series of hexahydrobenzo[f]isoquinolines through an iodine-catalyzed aza-Prins cyclization.…”

“…For more-hindered aliphatic aldehydes, such as 2d-e, the reaction time increased to one to two days, and yields were lower, although still within the practical range (entries 4 and 5). We also performed the reaction with aromatic aldehydes, including aldehydes substituted with electron-withdrawing and or electron-donating groups, and the reaction times in these cases were as much as three days (entries [6][7][8]. The nitro-substituted aldehyde 2h gave a low yield of the corresponding product (entry 8).…”