An Efficient Synthesis of Oxa- and Aza-Condensed Tetrahydropyridines from Cyclic Enones

Abstract

A simple and efficient one-pot synthesis of tetrahydrooxazolo[3,2-a]pyridines and hexahydroimidazo[1,2-a]pyridines, and some related oxa-and aza-condensed tetrahydropyridines, from the reaction of 2-alkoxy-5-(trifluoroacetyl)-2,3-dihydro-2H-pyrans (cyclic enones) with amino alcohols and primary diamines, is reported. Products were isolated with high purity and in very good yields.Cyclic enones have been extensively used for the last few decades to obtain various heterocyclic compounds, such as isoxazoles, 1 pyrazoles, 2 pyrimidines, 3 3-(aminomethylene)dihydrofuran-2-ones, 4 analogues of cyclophosphamide, 5 furan-3-carboxamides, 6 3-alkoxy-3-cyanocarboxylic acids, 7 pyrroles, 8 and tetrahydropyridines. 9 The use of cyclic enones such as 4-(trihaloacetyl)-2,3-dihydrofuran and 5-(trihaloacetyl)-3,4-dihydro-2H-pyran has attracted much attention because these compounds can easily react with nucleophiles, generating new aliphatic or heterocyclic systems by a process that involves opening of the furan or pyran ring by the nucleophile, and subsequent closure of the alkyl-hydroxy side chain. [8][9][10][11][12][13] However, 2-alkoxy-5-(trifluoroacetyl)-3,4-dihydro-2H-pyrans have rarely been explored as starting reagents in organic synthesis. 10 In a recent publication our group reported an important application of 2-alkoxy-5-(trifluoroacetyl)-3,4-dihydro-2H-pyrans as a highly chemoselective method for the synthesis of a large series of novel 2-alkoxy-1-alkyl(aryl)-5-(trifluoroacetyl)-1,2,3,4-tetrahydropyridines and 1-alkyl(aryl)-2-amino-5-(trifluoroacetyl)-1,2,3,4-tetrahydropyridines. 9In this study we wish to report a simple and efficient onepot synthesis of a series of new tetrahydrooxazolo[3,2-a]pyridines and hexahydroimidazo[1,2-a]pyridines, and some related oxa-and aza-condensed tetrahydropyridines, from the cyclocondensation reaction of 2-alkoxy-5-(trifluoroacetyl)-3,4-dihydro-2H-pyrans with amino alcohols and diamines.Very few reports on the synthesis of tetrahydrooxazolopyridines are described in the literature. 13-16 Tetrahydrooxazolopyridines have been prepared from the condensation between unsaturated carbonyls and carboxylic esters and N-(hydroxyethyl)enamines, 14 by iodocyclization of 1,4-dihydropyridines with properly attached substituents at the nitrogen atom, 15 or through the self-cyclization of Nphenylglycinol substituted dihydropyridines, derived from the reaction of Zincke salts 16 with (-)-(R)-phenylglycinol. 17 Recently, the synthesis of chiral 6-carbonyl-2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridines through the condensation of (S)-phenylglycinol with tricarbonyl compounds derived from the Michael addition of b-dicarbonyl compounds to acrolein and methyl vinyl ketones, was reported. 18 More recently the same group reported an interesting one-pot synthesis of tetrahydrooxazolopyridines by a multicomponent reaction. 19 Chiral 6-carbonyl-2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridines have been used to prepare (-)-deoxocassine, which is an analogue of natural alkaloid (-)-cassine 20 and a quinolizidine ...

Synthesis of 1-Arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines and Related Compounds with Potential Cell Efflux Pump Inhibition

“…The cyclic enones 3 and 4 were obtained by acylation of 2‐methoxy(ethoxy)‐3,4‐dihydro‐2 H ‐pyran ( 1 and 2 ) by trifluoroacetic anhydride under basic conditions as described by Okada et al and more recently by our research group . The reaction of cyclic enones 3 and 4 with 2‐substituted ethanamines was carried out in either methanol (for enone 3 ) or ethanol (for enone 4 ), at a molar ration 1:2 (enone:amine, respectively) at room temperature for 5 min, as shown in Scheme .…”

“…Although the syntheses of tetrahydropyridines have been reported since the late 19th century, methods to obtain 2‐amino substituted tetrahydropyridines are scarce [22,22(a),22(b),23,24].…”

“…However, the synthetic potential of 2‐alkoxy‐5‐trifluoroacetyl‐3,4‐dihydro‐2 H ‐pyrans as the starting material in organic synthesis has been explored very little . Recently, our research group used 2‐alkoxy‐5‐trifluoroacetyl‐3,4‐dihydro‐2 H ‐pyrans for the synthesis of an extensive series of tetrahydropyridines and 6‐trifluoroacetyl tetrahydropyridine oxa‐geminated and aza‐geminated heterocycles . Many compounds of these two series showed cell efflux inhibition double that of the control drug verapamil and, in particular, the compound known as THP 124 (shown in Fig.…”

Aldo‐X Bifunctional Building Blocks for the Synthesis of Heterocycles

“…The addition of pyridine avoided the removal of the ethoxy group. By using 1,2‐diamine or 2‐aminoethanol as the counter‐reagents, polycyclic heterocycles can also be synthesized …”

Targeted Molecular Dynamics Simulations Suggest Direct Ligand Competition as a Plausible Efflux Inhibition Mechanism in the Multidrug Resistance Pump AcrB

“…If structures are available only for the unliganded protein, as is the case for AcrB in this work, plausible I and F states can be generated using molecular docking calculations. TMD calculations were performed for both ethidium bromide (EtBr) and a tetrahydropyridine derivative NUNL02 (7)(8) (Fig. A1) to characterize possible transport pathways in AcrB for the ligands from the intracellular surface to the TolC domain.…”