Synthesis and Characterization of [1]Benzopyrano[4,3-d][1,3]benzooxazocin-13-one and its Derivatives

Abstract

This work describes the efficient synthesis of functionalized cleft molecules 6, 6a, 16, 16a, 17, 19 and 20 derived from benzopyrano[4,3-d][1,3]benzooxazocin-13-one. X-ray crystal structure analysis of compounds 6a and 16a revealed that the cleft angles of the planes of the benzopyran moiety and the p-methoxybenzene ring are 109.4° and 108.6°, respectively. The conformation of the aromatic ring at the bridgehead of 16, 16a and 20 is restricted by the gem-dimethyl groups on the C-9 position and the methyl group on the nitrogen atom in the ring.

heterocycles - ring closure - ring opening - steric hindrance - bicyclic compounds

References and Notes

1 Tröger J. J. Prakt. Chem.  1887,  36:  225 

2 Demeunynck M. Tatibouet A. Recent Developments in Tröger’s Base Chemistry, In Progress in Heterocyclic Chemistry   Vol. 11:  Gribble GW. Gilchrist TL. Pergamon; Oxford, UK: 1999.  p.1 

3 Bailly C. Laine W. Demeunynck M. Lhomme J. Biochem. Biophys. Res. Commun.  2000,  273:  681 

4 Johnson RA. Gorman RR. Wnuk RJ. Crittenden NJ. Aiken JW. J. Med. Chem.  1993,  36:  3202 

5a Harmata M. Kahraman M. Tetrahedron: Asymmetry  2000,  11:  2875 

5b Blaser HU. Jalett HP. Lottenbach W. Studer M. J. Am. Chem. Soc.  2000,  122:  12675 

6 Levkin PA. Strelenko YA. Lyssenko KA. Schurig V. Kostyanovsky RG. Tetrahedron: Asymmetry  2003,  14:  2059 

7 Chen JS. Watson WH. Kagan J. Agdeppa DA. Chen S.-A. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem.  1978,  34:  3627 

8 Molina P. Arques A. Tarraga A. del Rosario Obon M. Tetrahedron  1998,  54:  997 

9 Stoncius S. Butkus E. Zyilinskas A. Larsson K. Ohrstrom L. Berg U. Warnmark K. J. Org. Chem.  2004,  69:  5196 

10 Naemura K. Fukunaga R. Komatsu M. Yamanaka M. Chikamatsu H. Bull. Chem. Soc. Jpn.  1989,  62:  83 

11 Harmata M. Murray T. J. Org. Chem.  1989,  54:  3761 

12 Harmata M. Kahraman M. Tetrahedron Lett.  1999,  40:  4133 

13

Representative Procedure for the Preparation of 6a.
To a solution of 11a (100 mg, 0.4 mmol) in benzene (10 mL) was added six drops of SOCl₂. The mixture was stirred for 10 min at r.t., and the solution was then evaporated. The crude product was added to 4-hydroxycoumarin (162 mg, 1.0 mmol) and excess Et₃N in benzene (10 mL). After the mixture was stirred for another 10 min at r.t., the solution was evaporated. Then, H₂O (5 mL) was added to the mixture and the product was extracted twice with CH₂Cl₂. The combined organic extracts were dried over MgSO₄, filtered and concentrated. The resulting crude product was purified by column chromatography (EtOAc-hexane, 1:9) to give a light orange solid with a 45% yield; mp 210-211 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.36 (d, J = 9.0 Hz, 2 H), 7.96 (dd, J = 8.1, 1.8 Hz, 1 H), 7.85 (d, J = 8.7 Hz, 2 H), 7.55 (td, J = 9.0, 1.8 Hz, 2 H), 7.32 (td, J = 6.9, 1.5 Hz, 2 H), 7.20 (td, J = 7.5, 1.5 Hz, 1 H), 6.87 (td, J = 9.3, 1.8 Hz, 2 H), 2.86 (s, 3 H), 2.41, 2.30 (ABdq, J = 13.5, 2.7 Hz, 2 H), 1.26 (t, J = 3.0 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 161.6, 158.2, 152.2, 148.2, 148.0, 142.7, 131.9, 127.9, 127.8, 127.4, 126.6, 124.2, 124.0, 122.2, 119.5, 116.8, 115.5, 112.3, 105.6, 92.2, 36.6, 34.6, 29.6. IR (KBr): ν = 2361, 1703, 1342, 1030 cm^-1. HRMS (EI): m/z calcd for C₂₅H₁₈N₂O₅: 426.1216; found: 426.1219 [M⁺].

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Representative Procedure for the Preparation of 16a.
To a solution of 15a (100 mg, 0.29 mmol) in CH₂Cl₂ (10 mL) was added 4-hydroxycoumarin (47 mg, 0.29 mmol) and a catalytic amount of p-TsOH. After the mixture was stirred at 80 °C for 16 h and cooled to r.t., H₂O (10 mL) was added and the product was extracted twice with CH₂Cl₂. The combined organic extracts were dried over MgSO₄, filtered and concentrated. The resulting crude product was purified by column chromatography (1:9 EtOAc-hexane) to give a yellow solid with a 85% yield; mp 317-318 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.38 (dd, J = 8.7, 2.4 Hz, 1 H), 8.30 (dd, J = 8.7, 2.4 Hz, 1 H), 8.02 (dd, J = 8.7, 1.8 Hz, 1 H), 7.88 (dd, J = 8.4, 1.8 Hz, 1 H), 7.61 (dd, J = 8.7, 1.8 Hz, 1 H), 7.54 (ddd, J = 8.1, 7.2, 1.8 Hz, 1 H), 7.34-7.28 (m, 2 H), 7.08 (d, J = 2.7 Hz, 1 H), 6.76 (d, J = 8.7 Hz, 1 H), 6.71 (dd, J = 8.7, 2.7 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 1 H), 2.81 (s, 3 H), 0.94 (s, 3 H), 0.91 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 161.9, 158.0, 153.1, 152.3, 148.0, 144.4, 136.7, 131.8, 130.2, 130.0, 127.4, 124.0, 123.5, 122.8, 122.2, 116.8, 115.2, 113.7, 113.5, 113.2, 105.8, 99.9, 55.7, 42.2, 36.3, 34.8, 23.2, 22.8. IR (KBr): ν = 2939, 1626, 1572, 1343, 1184, 811 cm^-1. HRMS (EI): m/z calcd for C₂₈H₂₄N₂O₆: 484.1634; found: 484.1636 [M⁺].

15 Annunziata R. Cinquini M. Cozzi F. Molteni V. Schupp O. Tetrahedron  1997,  53:  9715 

16 Huang JL. Liu HG. Yang DY. Bioorg. Med. Chem. Lett.  2003,  13:  927 

17 Chen DU. Kuo PY. Yang DY. Bioorg. Med. Chem. Lett.  2005,  15:  2665 

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Crystallographic data (excluding structure factors) for 6a and 16a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC-263524 and CCDC-263525, respectively. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone].

19 Kimber MC. Try AC. Painter L. Harding MM. Turner P. J. Org. Chem.  2000,  65:  3024