One-pot synthesis of (1RS,21SR)-diethyl 2-[23-amino-22-ethoxycarbonyl-8,11,14-trioxa-25-azatetracyclo[19.3.1.02,7.015,20]pentacosa-2,4,6,15(20),16,18,22-heptaen-25-yl]but-2-endioate

A new macrocycle obtained by the Michael reaction of azacrown ether with dimethyl acetylenedicarboxylate was studied by X-ray diffraction, and its potential bioactivity was estimated from the structural data.

In our previous work, we have studied the Michael addition of azacrown ethers to dimethyl acetylenedicarboxylate (Anh et al., 2012a,b;Hieu et al. 2013a,b). We have also found recently that the expected N-vynilation proceeded smoothly with the formation of an N-maleinate derivative of the aza-crown system. Modification of the reaction by the addition of NH 3 (aq.) and continuous stirring for three days at 298 K produced the unexpected -amino-N-propylpiperidine (4) in a yield of 40% (Fig. 1). According to the PASS program (Prediction of Activity Spectra for Substances -i.e. computer prediction of biological activities; Sadym et al., 2003), the title compound has the potential to exhibit antiallergic (72% probability), antiasthmatic (67%) and membrane permeability inhibiting (65%) activities. The obtained compound was studied by X-ray diffraction analysis (Fig. 2). .
The molecule of 4 possesses two asymmetric centers at the C1 and C21 carbon atoms and potentially can have four diastereomers. The crystal of 4 is racemic and consists of enantiomeric pairs with the following relative configuration of the centers: 1R,21S.

Supramolecular features
In the crystal, molecules of 4 form hydrogen-bonded chains propagating along [100] through strong intermolecular N-HÁ Á ÁO hydrogen bonds (Fig. 3, Table 1). The chains are stacking along the b-axis direction.

Synthesis and crystallization
A solution of 1.30 g (10.00 mmol) of ethyl acetoacetate (1), 3.14 g (10.00 mmol) of 1,5-bis-(2-formylphenoxy)-3-oxaopetane (2) and 1.00 g (13.00 mmol) of ammonium acetate in a mixture of 30 ml ethanol and 1 ml acetic acid was stirred at   The modified reaction yielding the -amino-N-propylpiperidine 4. 298 K. The reaction was monitored by TLC and found to be complete after 6 h. The reaction mixture was allowed to cool to room temperature before being neutralized with sodium carbonate solution; the product was then extracted with chloroform (3 Â 50 ml). By TCL, compound 3 was determined to be successfully synthesized. The solvent (CDCl 3 ) was evaporated under vacuum until 30ml of CDCl 3 was left, 1.42 g (10 mmol) of DMAD was added and the solution was stirred for 30 minutes at 298 K. Then NH 3 (aq.) was added to the reaction mixture, which was stirred continuously. After three days, the residue was purified by column chromatography and recrystallized from ethanol to obtain 2.27 g of the pure azacrown ether 4 as light-yellow crystals (yield 60%). T m = 525-526 K. R f = 0.85 [n-hexane:ethyl acetate = 1:1 (v:v)].

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The hydrogen atoms of the amino group were localized in difference-Fourier maps and refined isotropically with constrained thermal displacement parameters [U iso (H = 1.2U eq (N)]. Other hydrogen atoms were placed in calculated positions with C-H bond lengths of 0.95-1.00 Å and refined using a riding model with constrained isotropic displacement parameters [U iso (H) = 1.5U eq (C) for the CH 3 groups and 1.2U eq (C) for all others]. The hydrogen-bonded chains of 4 along the a axis. Dashed lines indicate the intramolecular N-HÁ Á ÁO and C-HÁ Á ÁO and the intermolecular N-HÁ Á ÁO hydrogen bonds. Table 1 Hydrogen-bond geometry (Å , ).  Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXTL (Sheldrick, 2015); program(s) used to refine structure: SHELXTL (Sheldrick, 2015); molecular graphics: SHELXTL (Sheldrick, 2015); software used to prepare material for publication:

D-HÁ
SHELXTL (Sheldrick, 2015). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.