Synthesis of cis-4,5-Diarylazepanes

Abstract

Substituted cis-4,5-diarylazepanes are synthesized in modest overall yields starting from 5,5-diarylazepan-4-ones by a ­reduction, mesylation, rearrangement, and hydrogenation reaction sequence.

cis-4,5-diarylazepanes - boron trifluoride etherate - heterocycles - 1,2-sigmatropic shift - spiro compounds

References and Notes

For reviews on the synthesis of azepane, see:

1a Yet L. Chem. Rev.  2000,  100:  2963 

1b Kantorowski EJ. Kurth MJ. Tetrahedron  2000,  56:  4317 

1c Maier ME. Angew. Chem. Int. Ed.  2000,  39:  2073 

For syntheses of benzazepine, see:

2a Qing L. Sasikumar TK. Bunett DA. Su J. Tang H. Ye Y. Mazzola RDJ. Zhu Z. McKittrick BA. Greenlee WJ. Fawzi A. Smith M. Zhang H. Lachowicz JE. Bioorg. Med. Chem. Lett.  2010,  20:  836 

2b Zhang J. Chen X. Yu L. Zhen X. Zhang A. Bioorg. Med. Chem.  2008,  16:  9425 

2c Shimada I. Maeno K. Kondoh Y. Kaku H. Sugasawa K. Kimura Y. Hatanaka K.-i. Naitou Y. Wanibuchi F. Sakamoto S. Tsukamoto S.-i. Bioorg. Med. Chem.  2008,  16:  3309 

2d Bailey JM. Scott JS. Basilla JB. Bolton VJ. Boyfield I. Evans DG. Fleury E. Heightman TD. Jarvie EM. Lawless K. Matthews KL. MaKay F. Mok H. Muir A. Orlek BS. Sanger GJ. Stemp G. Stevens AJ. Thompson M. Ward J. Vaidya K. Westaway SM. Bioorg. Med. Chem. Lett.  2009,  19:  6452 

For syntheses of phenazepine, see:

3a Diamond J. Bruce WF. Tyson FT. J. Med. Chem.  1964,  7:  57 

3b Scheiner JJ. Richards DJ. Curr. Ther. Res. Clin. Exp.  1974,  16:  928 

4a Jacobi PA. Lee KA. J. Am. Chem. Soc.  2000,  122:  4295 

4b Boeckman RK. Clark TJ. Shook BC. Org. Lett.  2002,  4:  2109 

4c Smith AB. Cho YS. Pettit GR. Hirschmann R. Tetrahedron  2003,  59:  6991 

4d Painter GF. Eldridge PJ. Falshaw A. Bioorg. Med. Chem.  2004,  12:  225 

4e Li H. Bleriot Y. Mallet JM. Rodriguez-Garcia E. Vogel P. Zhang Y. Sinay P. Tetrahedron: Asymmetry  2005,  16:  313 

4f Wipf P. Spencer SR. J. Am. Chem. Soc.  2005,  127:  225 

4g Li H. Bleriot Y. Chantereau C. Mallet J.-M. Sollogoub M. Zhang Y. Rodriguez-Garcia E. Vogel P. Jimenez-Barbero J. Sinay P. Org. Biomol. Chem.  2004,  2:  1492 

5 Lee SJ. Beak P. J. Am. Chem. Soc.  2006,  128:  2178 

6 Lyga JW. J. Heterocycl. Chem.  1996,  33:  1631 

7 Lindstrom UM. Somfai P. J. Am. Chem. Soc.  1997,  119:  8385 

8a Chang M.-Y. Kung Y.-H. Ma C.-C. Tetrahedron Lett.  2007,  48:  199 

8b Chang M.-Y. Kung Y.-H. Wu T.-C. Tetrahedron  2007,  63:  3098 

9

Representative Procedure for Skeleton 5
BF₃˙OEt₂ (1.0 mmol) was added to a stirring solution of the skeleton 4 (0.5 mmol) in CH₂Cl₂ (10 mL) at r.t. The reaction mixture was stirred at reflux for 40 h. The total procedure was monitored by TLC until the reaction was completed.
A sat. NaHCO₃ solution (1 mL) was added to the reaction mixture, and the solvent was concentrated under reduced pressure. The residue was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexane-EtOAc = 8:1 to 4:1) afforded skeleton 5.

10

CCDC 810260 (5b), 810167 (5e), 805710 (7b), and 817429 (8b) contain the supplementary crystallographic data for this paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; e-mail: [e-mail]].

11

Representative Procedure for Skeleton 7
Et₃N (500 mg, 5.0 mmol), skeleton 2 (1.0 mmol), and CH₂Cl₂ (6 mL) were added to a sealed tube at r.t. The reaction mixture was stirred at reflux temperature for 25 h and then cooled to r.t. CH₂Cl₂ (10 mL) was added to the reaction mixture, and then HCl solution (1 N, 10 mL) was also added to the reaction mixture. The reaction mixture was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were washed with brine, dried, filtered, and eva-porated to afford crude product. Purification on silica gel (hexane-EtOAc = 4:1 to 2:1) afforded skeleton 7.

12a Mas M. Sola J. Solans X. Aguilo M. Inorg. Chim. Acta  1987,  133:  217 

12b Almarzoqi B. George AV. Isaacs NS. Tetrahedron  1986,  42:  601 

12c Rudine AB. Walter MG. Wamser CC. J. Org. Chem.  2010,  75:  4292 

12d Munavalli S. Poziomek EJ. Landis WG. Heterocycles  1986,  24:  7 

13 For a review on the synthesis of spiropiperidine, see: Dake G. Tetrahedron  2006,  62:  3467 

For a MnO₂/TFA-mediated reaction, see:

14a Wang K. Hu Y. Li Z. Wu M. Liu Z. Su B. Yu A. Liu Y. Wang Q. Synthesis  2010,  1083 

For a MCPBA/TFA-mediated reaction, see:

14b Wang K. Hu Y. Wu M. Li Z. Liu Z. Su B. Yu A. Liu Y. Wang Q. Tetrahedron  2010,  66:  9135 

For a VOF₃/TFA-mediated reaction, see:

14c Niphakis MJ. Georg GI. Org. Lett.  2011,  13:  196 ; and references cited therein

15a Zhang X. Jiang X. Zhang K. Mao L. Luo J. Chi C. Chan HSO. Wu J. J. Org. Chem.  2010,  75:  8069 

15b Jiao C. Huang KW. Chi C. Wu J. J. Org. Chem.  2011,  76:  661 

16

Representative Procedure for Skeleton 8
Skeleton 5 (0.13 mmol) was dissolved in EtOAc (10 mL; free of oxygen) and was irradiated under a nitrogen atmosphere with a lamp (λ = 3060 Å), using a Pyrex glass filter at r.t. for 80 h. The solvent was evaporated to afford crude product. Purification on silica gel (hexane-EtOAc = 4:1 to 2:1) afforded skeleton 8.