Synthesis and Crystal Structure of a Novel Bis(ethoxycarbonyl)glycoluril Macrocycle①

CAI Qun YANG Qin-Wan ZHANG Jian-Ming



Synthesis and Crystal Structure of a Novel Bis(ethoxycarbonyl)glycoluril Macrocycle①

CAI Qun YANG Qin-Wan ZHANG Jian-Ming②

(430079)

syntheses, crystal structure, bis(ethoxycarbonyl)glycoluril, macrocycle

1 INTRODUCTION

The macrocyclic structures play an significant role not only in drug development[1], but also in areas as diverse as material sciences and supramolecular chemistry[2]. Efficient synthetic approaches to the macrocyclic compound with a new skeleton have attracted great attention from chemists. This rational design of Mannich mul- ticomponent reactions (MCRs) have gained con- siderable popularity in macrocycle synthesis due to their efficiency, intrinsic atom economy, high selectivity, and procedural simplicity[3].

Recently, many synthetic approaches to macro- cycle via Mannich MCRs have been developed[4-13]. But till now, rare covalent macrocycles based on propargylamine backbone containing bis(ethoxycar- bonyl)glycoluril group have been reported. In this paper, we report the synthesis and crystal structure of a novel [2+4+2]-macrocycle via Mannich three- component reaction of propargylamine, piperazine and formaldehyde in one pot.

2 EXPERIMENTAL

2. 1 General procedure

All chemicals and reagents were obtained from commercial suppliers and used without further purification. TLC analysis was performed using pre- coated glass plates. Column chromatography was performed using silica gel (200～300 mesh). Melting point was determined on an XT4A micro- melting point apparatus and uncorrected. IR spectra were recorded on a Perkin-Elmer PE-983 infrared spectrometer as KBr pellets with absorption in cm-1. NMR was performed in CDCl3on a Varian Mercury 400 spectrometer and resonances were given in ppm () relative to TMS. HRMS were obtained on a Bruker Apex-Ultra 7.0T FTMS equipped with an electrospray source (APCI). X-ray crystal analysis was carried out on the Bruker SMART APEX CCD system/diffractometer.

2. 2 Synthesis

The title compound 3 was synthesized according to Scheme 1.

Compound 1 was produced according to a previously reported method[14].

Preparation of compound 2: Compound 1 (1.43 g, 5.0 mmol) and 37% aqueous formaldehyde (5 mL) were added in methanol (60 mL). The solution was stirred as the methanol solution of propargylamine was added at reflux temperature for 24 h. Then the solvent was removed under reduced pressure and the product was separated by silica gel column chromatography (methanol-chloroform, 1:150). Yield: 80%; m.p.: 120～122℃. IR (KBr): 3249(≡C–H, s), 2978(–CH3, s), 2876(–CH3, s), 2841(–CH2, s), 2124(C≡C, s), 1742(-OC=O, s), 1724(-NC=O, s), 1418(–CH2, m), 1372(–CH3, s), 1236(C–O, s), 727(–CH2, w) cm–1.1H NMR (400 MHz, CDCl3):= 1.26 (t, J = 6.6 Hz, 6H), 2.30 (s, 2H), 3.35(s, 4H), 4.13～4.28 (m, 8H), 4.81 (d, J = 12.8 Hz, 4H).13C NMR (100 MHz, CDCl3):= 13.73, 40.59, 59.27, 63.22, 73.54, 75.32, 77.43, 157.94, 164.88. HRMS (APCI):/[M+H]+calcd. for C20H24N6O6: 445.1830; found: 445.1831.

Preparation of compound 3: Compound 2 (0.444 g, 1.0 mmol), 37% aqueous formaldehyde (0.8 mL), piperazine (0.086 g, 1.0 mmol) and CuCl (0.15 g, 1.5 mmol) were added in dioxane (50 mL). The solution was stirred at 90 ℃ for 2 h. Then the solvent was removed under reduced pressure and the product was separated by silica gel column chromatography (methanol-chloroform, 1:25). Yield: 30%; m.p. > 300 ℃. IR (KBr): 2958(-CH3, s), 2927(-CH2, s), 2856(-CH3, s), 2361(C≡C, m), 1731(-C=O, s), 1466(-CH2, m), 1370(-CH3, s), 1287(C–O, s), 1233(C–O, s), 724(-CH2, w) cm–1.1H NMR (400 MHz, CDCl3):= 1.29 (t, J = 7.0 Hz, 12 H), 2.42～2.84 (b, 16H), 3.31 (s, 8 H), 3.41 (s, 8 H), 4.17～4.31 (m, 16 H), 4.91 (d, J = 13.2 Hz, 8 H).13C NMR (100 MHz, CDCl3):= 13.90, 41.20, 46.99, 51.75, 59.47,63.30, 75.64, 79.39, 80.12, 158.06, 165.21. HRMS (APCI):/[M+H]+calcd. for C52H69N16O12: 1109.52754; found: 1109.52700.

Scheme 1. Synthesis route of the title compound 3

2. 3 Structure determination

Crystal of the title compound 3 for X-ray struc- ture determination was obtained via slow evapora- tion in chloroform solution at room temperature.A colorless single crystal with approximate dimen- sions of 0.12mm × 0.10mm × 0.10mm was mounted on a glass fiber in a random orientation at 273(2) K. The unit cell determination and data collection were performed with Moradiation (= 0.71073 Å) on a Bruker SMART 1000 APEX-CCD diffractometer using an-2scan mode. 3954 independent reflec- tions (int= 0.0441) were collected in the range of 2.16<<25.01º at room temperature, of which 3034 were observed (> 2()) and used in the structure determination and refinements. The data were corrected for absorption by using program SAD- ABS[15]. The structure was solved by direct methods using SHELXS-97[16]program and refined with SHELXL-97[17]by full-matrix least-squares on2. All non-hydrogen atoms were refined anisotro- pically. The final= 0.0818,= 0.2346 (= 1/[2(F2) + (0.1797)2+ 0.0000], where= (F2+ 2F2)/3),= 1.006, (Δ/)max= 0.000, (Δ)max= 1.057 and (Δ)min= –0.327 e/Å3.

3 RESULTS AND DISCUSSIONS

The1H NMR,13C NMR, IR and H RMS for the final product are concordant with the title com- pound. The selected bond lengths and bond angles, torsion angles and hydrogen bonding interactions are respectively given in Tables 1 and 2. The molecular structure with atomic labeling scheme is shown in Fig. 1, and hydrogen bonding interactions with water and crystal packing of the molecule in Fig. 2.

Table 1. Selected Bond Lengths (Å) and Bond Angles (°)

Symmetry transformation: #:1: –+2, –+1, –

Table 2. Hydrogen Bond Lengths (Å) and Bond Angles (°)

Symmetry codes: (a) 1–, 1–, –; (b), –1+,

Fig. 1. Molecular structure of the title complex

Fig. 2. Crystal packing of the title compound. The hydrogen bonds with water are shown as dashed lines

The title compound consists of two bis(ethoxy- carbonyl)glycoluril groups, two piperazine groups and four alkynyl groups. As shown in Fig. 1, the bis(ethoxycarbonyl)glycoluril group is built up from four fused rings, two five-membered nearly planar imidazole rings and two six-membered triazine rings with chair conformations. Two of the ester groups (O3:O3a and O5:O5a) show positional disorder in the 0.658(14):0.342(14) and 0.488(17): 0.512(17) ratios, separately. The distance between two carbonyl oxygen atoms (O(1)/O(2)) of the glycoluril moiety is 5.279 Å. The dihedral angle between the two imidazole rings (C(20)–N(6)– C(11)–C(15)–N(8) and C(19)–N(5)–C(11)–C(15)– N(7)) is 63.27º. Two piperazine groups are paral- leled with stable chair conformations. The whole macrocycle shows an approximate oblong cavity with 15.062 Å length and 6.001 Å width. Fig. 2 shows the hydrogen bonds between the title molecule and water. The strong O–H···N (O(7)– H(7B)×××N(2) = 2.935(4) Å) and C–H···O (C(8)– H(8C)×××O(7) = 3.411(5) Å) hydrogen bonds are formed. These hydrogen bonds[18]further connect the neighboring molecules into a ribbon extending along theaxis. Meanwhile, strong O–H···N (O(8)– H(8A)×××N(1) = 2.923(8) Å) and C–H···O (C(22)– H(22B)···O(8) = 3.446(12) Å) hydrogen bonds connect the neighboring molecules into a ribbon extending along theaxis. They play an important role in stabilizing the structure. The title macrocy- cles are stacked parallelly and in register to one another into the adjective stratiform in the limitless three-dimensional space.

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1 November 2013;

3 January 2014 (CCDC 965073)

① This work was supported by Central China Normal University and the National Science Foundation of China (No. 21272085). We are also grateful to Pro. Wu An-Xin for his guidance

. Male, 50, engineer. E-mail: xiangjiachen2013@163.com