Synthesis and Crystal Structure of (S)-N-(hexahydro-2-oxo-1H-azepin-3-yl)-3-phenyl-2-propenamide①

LI Xio-Lin FANG Zheng ZHANG Feng

ZENG Wen-Bob GUO Kaib②

a (School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing 211816, China)

b (College of Biotechnology and Pharmaceutical Engineering,Nanjing University of Technology, Nanjing 211816, China)

1 INTRODUCTION

The development of high-performance, environmentally degradable polymers usable as engineering plastics from renewable resources is important for the establishment of a sustainable society[1]. Biodegradable resins provide a solution for overcoming the plastic waste problem[2-4]. Conventional polyamides such as nylon account for a substantial percentage of engineering plastics[5], and thus bioderived polyamide development is desirable in various fields from automobile parts to medical materials[6]. About 2.5 billion tons of nylon 6 is produced annually on a worldwide basis. The production of nylon 6 is accomplished by the ring opening polymerization of the monomer ε-caprolactam[7]. In this study, a novel monomer (S)-N-(hexahydro-2-oxo-1H-azepin-3-yl)-3-phenyl-2-propenamide was synthesized by the reaction of (S)-α-amino-εcaprolactam (ACL)with 3-phenyl-2-propenoyl chloride[8-12]. This monomer has similar structure to ε-caprolactam and it could be selected as a potential monomer of nylon 6. ACL was prepared from L-lysine which is an important bio-based feedstock[13-15]. In order to confirm its structure, a single crystal of the title compound was obtained from ethanol and the molecular structure was determined by X-ray diffraction.

2 EXPERIMENTAL

2. 1 Synthesis of (S)-α-amino-εcaprolactam hydrochloride

A stirred mixture of L-lysine hydrochloride (11 g,60 mmol)and NaOH (2.4 g, 60 mmol)in hexanol(240 mL)was heated to reflux with a Dean-Stark trap used to remove H2O. The suspension was refluxed for 8 h until all starting materials were consumed (which was determined by TLC). The suspension was then cooled and filtered to remove the byproduct NaCl. The filtrate was concentrated and the resulting crude ACL was dissolved in water.After acidification to pH 6 with the addition of concentrated HCl and partial concentration, the crystal was formed at room temperature to afford ACL hydrochloride (7.4 g)in 75% yield. ESIHRMS for C6H12N2O [M+H]+calcd.: 129.0950;found: 129.1044.1H NMR (500 MHz, CD3OD): δ(ppm)= 7.19 (br s, 2 H), 5.12 (d, J = 11.1 Hz, 1 H),3.58 (s, 1 H), 3.15 (m, 2 H), 1.49～1.14 (m, 6 H).13C NMR (125 MHz, CD3OD): δ (ppm)= 178.26,52.82, 41.01, 33.72, 28.17, 27.94.

2. 2 Synthesis of (S)-N-(hexahydro-2-oxo-1H-azepin-3-yl)-3-phenyl-2-propenamide

ACL hydrochloride (1.65 g, 10 mmol)and Na2CO3(3.18 g, 30 mmol)in water (30 mL)were added to a solution of 3-phenyl-2-propenoylchlorid(1.67 g, 10 mmol)in dichloromethane (30 mL)at ambient temperature and the reaction was stirred for 8 h. The organic layer was then separated, and the aqueous phase was extracted with additional dichloromethane (2 × 15 mL). The combined organic layers were dried over Na2CO3and reduced in vacuo.The residue was recrystallized from CH2Cl2/hexanes to give (S)-N-(hexahydro-2-oxo-1H-azepin-3-yl)-3-phenyl-2-propenamide (1.91 g)in 74% yield, m.p.233.3～234.1 ℃. ESI-HRMS for C15H18N2O2[M+H]+calcd.: 259.1368; found: 259.1437.1H NMR (500 MHz, CDCl3): δ (ppm)= 7.64～7.05 (m,6 H), 6.52～5.63 (m, 3 H), 4.70～4.65 (m, 1 H),3.40～3.27 (m, 2 H), 2.22～1.36 (m, 6 H).13C NMR(125 MHz, CDCl3): δ (ppm)= 175.59, 164.84,140.86, 134.87, 129.62, 128.78, 127.79, 120.82 52.34, 42.20, 31.68, 28.91, 27.93. The colorless single crystal was cultured from ethanol by slow evaporation at room temperature.

2. 3 Crystal structure determination

A colorless single crystal with dimensions of 0.30mm × 0.10mm × 0.10mm was selected and mounted on the top of a glass fiber. The data were collected by an Enraf-Nonius CAD4 EXPRESS diffractometer equipped with a graphite-monochromatized MoKα radiation (λ = 0.71073 ?)at 293(2)K. A total of 2573 reflections were collected in the range of 1.66≤θ≤25.38o by using an ω-2θ scan mode, of which 2473 were independent (Rint=0.0322)and 1393 with I ＞ 2σ(I)were observed and used for the structure determination and refinements.The structure was solved by direct methods with SHELXS-97[16]. The structure was refined with SHELXL-97[17]on F2by successive full-matrix least-squares techniques for the non-hydrogen atoms which were located from an E-map and refined anisotropically. All H atoms were placed in the calculated positions and included in the refinement in riding-model approximation. The final refinement gave R = 0.0671 and wR = 0.1925 (w =1/[σ2(Fo2)+ (0.0800P)2+ 0.5000P], where P = (Fo2+ 2Fc2)/3), S = 1.001, (Δ/σ)max= 0.00, (Δρ)max=0.199 and (Δρ)min= ?0.205 e/?3.

3 RESULTS AND DISCUSSION

The title compound was prepared according to Scheme 1.1H NMR,13C NMR and H RMS for the product are in good agreement with the title compound. In order to confirm the configuration of the product, a single crystal of the title compound is cultured for X-ray diffraction analysis. The selected bond distances and bond angles are listed in Table 1.As shown in Fig. 1, most bond lengths in the system fall in the range of single and double bonds[18]. For example, the bond lengths of C(7)–C(8), C(9)–O(1)and C(11)–O(2)are in accord with the double bond distance. In aromatic rings, the molecular dimensions are shorter than the normal aromatic C–C bond(1.40 ?)with distances between 1.367(6)and 1.388(5)?, and these bond lengths are even. The aromatic C–C–C bond angles ranging from 116.8(4)to 122.0(4)oare almost within the normal ranges[19].The monomeric unit with atomic numbering scheme and the crystal packing diagram are shown in Figs. 1 and 2, respectively. The C(7)–C(8)double bond adopts a trans conformation. The N–H··O hydrogen bonds and weak C–H··O hydrogen bonds in Table 2 contribute to the stability and packing of the structure respectively. The title compound has similar structure to ε-caprolactam and it could be selected as a potential monomer of polyamide. Further study of polymerization is still underway.

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

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

Fig. 2. Packing diagram of the title compound, showing the hydrogen bonds (dashed lines)

Fig. 1. Molecular structure of the title compound,showing the atomic labeling scheme

(1)Mathers, R. T.; Meier, M. A. R. Green Polymerization Methods: Renewable Starting Materials, Catalysis and Waste Reduction. Wiley-VCH:Weinheim 2011.

(2)Kaneko, T.; Thi, T. H.; Shi, D. J.; Akashi, M. Environmentally degradable, high-performance thermoplastics from phenolic phytomonomers. Nat.Mater. 2006, 5, 966?970.

(3)Yabannavar, A. V.; Bartha, R. Environmental and public health microbiology methods for assessment of biodegradability of plastic films in soil.Appl. Environ. Microbiol. 1994, 60, 3608?3614.

(4)Swift, G. Directions for environmentally biodegradable polymer research. Acc. Chem. Res. 1993, 26, 105?110.

(5)Kotek, R.; Jung, D.; Tonelli, A. E.; Vasanthan, N. Novel methods for obtaining high modulus aliphatic polyamide fibers.Polym. Rev. 2005, 45, 201?230.

(6)Ali, M. A.; Tateyama, S.; Oka, Y.; Kaneko, D.; Okajima, M. K.; Kaneko, T. Syntheses of high-performance biopolyamides derived from itaconic acid and their environmental corrosion. Macromolecules 2013, 46, 3719?3725.

(7)Frost, J. W. Synthesis of caprolactam from lysine. US7977450B2 2011.

(8)Uchikawa, O.; Fukatsu, K.; Aono, T. Aminothiazole derivatives. I. A convenient synthesis of monocyclic and condensed 5-aminothiazole derivatives. J. Heterocycl. Chem. 1994, 31, 877?887.

(9)Uchikawa, O.; Fukatsu, K.; Suno, M.; Aono, T.; Doi, T. In vivo biological activity of antioxidative aminothiazole derivatives.Chem. Pharm. Bull. 1996, 44, 2070?2077.

(10)Fox, D. J.; Reckless, J.; Wilbert, S. M.; Greig, I.; Warren, S.; Grainger, D. J. Identification of 3-(acylamino)azepan-2-ones as stable broad-spectrum chemokine inhibitors resistant to metabolism in vivo. J. Med. Chem. 2005, 48, 867?874.

(11)Fox, D. J.; Reckless, J.; Lingard, H.; Warren, S.; Grainger, D. J. Highly potent, orally available anti-inflammatory broad-spectrum chemokine inhibitors. J. Med. Chem. 2009, 52, 3591–3595.

(12)Grainger, D. J.; Fox, D. J. Anti-inflammatory agents. WO2005/053702A2 2005.

(13)Tarkin-Tas, E.; Lange, C. A.; Mathias, L. J. Hydrogen-bonded supramolecular polymers from derivatives of α-amino-?-caprolactam: a bio-based material. J. Polym. Sci. Part A: Polym. Chem. 2011, 49, 2451?2460.

(14)Rezler, E. M.; Fenton, R. R.; Esdale, W. J.; McKeage, M. J.; Russell, P. J.; Hambley, T. W. Preparation, characterization, DNA binding, and in vitro cytotoxicity of the enantiomers of the platinum(II)complexes N-methyl-, N-ethyl- and N,N-dimethyl-(R)-and -(S)-3-aminohexahydroazepinedichloroplatinum(II). J. Med. Chem. 1997, 40, 3508?3515.

(15)Metelkina, O.; Schubert, U. Reaction of metal alkoxides with lysine: substitution of alkoxide ligands vs. lactam formation.Monatsh. Chem. 2003, 134, 1065–1069.

(16)Sheldrick, G. M. SHELXS-97, Program for Crystal Structure Solution. University of Gottingen, Germany 1990.

(17)Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refinement. University of Gottingen, Germany 1997.

(18)Wei, Y.; Cao, C.; Jin, L.; Huang, N.; Zou, K. Synthesis and crystal structure of N-methyl-N-((2-(p-tolyl)quinolin-4-yl)methyl)aniline.Chin. J. Struct. Chem. 2013, 32, 1199–1203.

(19)Feng, F.; Li, Y. P.; Zhou, H. Y.; Tian, D. T.; Hu, W. B. Synthesis and crystal structure of 10-(3,4-dichlorophenymethylidyne)-9,10-dihydrofluorene.Chin. J. Struct. Chem. 2011, 30, 1111–1114.