S. Y. Kim, K. Kim, H. Moon
2016
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0
Influential Citations
5
Citations
Journal
Bulletin of The Korean Chemical Society
Abstract
Tetrahydropyridine-3-carboxylic acid derivatives have shown many interesting biological activities. The syntheses of tetrahydropyridine-3-carboxylic acids have been carried out by phosphine-catalyzed ring-forming reactions between allenoates and imines, ring-closing metathesis (RCM) reaction of homoallylic amine derivatives, chemical transformations of Morita–Baylis–Hillman (MBH) adducts, and intramolecular 1,6-conjugate addition of 2,4dienylamines. MBH adducts have been used for the synthesis of many interesting cyclic compounds. Recently the MBH adducts ofα,β-unsaturated aldehydes have been studied extensively by us and other groups. During our recent studies using the MBH adducts of cinnamaldehydes, we reasoned out that introduction of a primary amine such as benzylamine at the primary position of MBH acetate 1a could provide methyl tetrahydropyridine-3-carboxylate 2a, as shown in Scheme 1. The SN20 reaction between 1a and benzylamine would afford 1:1 adduct I, and the following intramolecular 1,6conjugate addition would provide 1,2,5,6-tetrahydropyridine-3-carboxylate 2a. At the outset of our experiment, the reaction of 1a and benzylamine (4.0 equiv) was examined in CH3CN. 6 The corresponding 1:1 adduct I (E-isomer) was formed as a major product at room temperature in short time (1 h); however, the separation of I-E in pure form was somewhat difficult due to the formation of many side products including unreactive 1:1 adduct I-Z and 1:2 adduct IV, as also shown in Scheme 1. Thus, we decided to carry out the synthesis of 2a without separation of I-E. The cyclization of crude I to 2a did not proceed at room temperature even after a long time (20 h). After some trials, we found that 2a could be formed in a reasonable yield (52%) under the influence of K2CO3 in refluxing CH3CN for 20 h. The cyclization was less effective in the absence of K2CO3 even under refluxing CH3CN condition. The role of K2CO3 is unclear at this stage; however, similar observation for the requirement of base in conjugate addition reactions was reported. Encouraged by the successful synthesis of 2a, the reactions with some representative MBH acetates of α,β-unsaturated aldehydes 1a–e were examined, and the results are summarized in Table 1. The reactions of 1a with p-methoxybenzylamine, 2-phenethylamine, 3-phenyl-1-propylamine, and n-octylamine afforded 2b–2e in moderate yields (48–58%). The reaction of MBH acetate of crotonaldehyde 1b and benzylamine provided 2f in good yield (68%). The reaction of 1b and 1-phenethylamine afforded 2g in a similar yield (63%) as an inseparable diastereomeric mixture (3:1). The reaction of 4-methyl derivative 1c and benzylamine afforded double bond-isomerized product 2h in good yield (79%) instead of generally expected product 2h0. As shown in Scheme 2, a double bond isomerization of initially formed product 2h did not occur presumably due to stabilizing hyperconjugation effect of the methyl group. Similar observation