Convenient and Versatile Synthesis of Spiro(furan-2,3-indol[2]ones) and Spiro(pyran-2,3-indol[2]ones)

Abstract

Novel functionalized spiro-3-oxindoles of potential use for the synthesis of natural product analogues and pharmaceutically active compounds were prepared from substituted isatins by a convenient and versatile base-catalyzed condensation and ring-closure reaction. Moreover, a side product consisting of an at present unknown bicyclic skeleton has been isolated.

Key words

spiro compounds - ring closure - heterocycles - isatin - base-catalyzed condensation

References

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• See for instance
• 2a Rehn S. Bergman J. Stensland B. Eur. J. Org. Chem.  2004,  413 
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• 3a Chatani N. Amako K. Tobisu M. Asaumi T. Fukumoto Y. Murai S. J. Org. Chem.  2003,  1591 
• 3b Nair V. Rajesh C. Dhanya R. Rath NP. Tetrahedron Lett.  2002,  5349 
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• 3d Tobisu M. Chatani N. Asaumi T. Amako K. Ie Y. Fukumoto Y. Murai S. J. Am. Chem. Soc.  2000,  12663 
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General Procedure for the Synthesis of the Spiro-3-oxindoles 3a,b,e,g,h,k-p.
To a solution of the appropriate isatin 1 (1.0 mmol) and chlorocarbonyl compound 2 (1.5 mmol) in DMF (10 mL; p.a. quality when K₂CO₃ was used, dried over molecular sieves when NaH was used) under argon at r.t. was added the appropriate base (1.5 mmol) under continuous stirring. Stirring was continued overnight at r.t. To this mixture, Et₂O (30 mL) was added and then the mixture was washed with aq HCl (1 M; 20 mL) and brine (20 mL). The organic layer was dried over MgSO₄ and evaporated under reduced pressure. The desired compounds were separated by column chromatography over SiO₂ using a CH₂Cl₂-Et₂O mixture (20:1 to 5:1 depending on the actual compound).

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Representative spectral data for the diastereomers of 3g: (2 R ,3 S )- and (2 S ,3 R )-5′-bromo-3-methylcarbonyl-4,5 H -spiro-{furan-2,3′-indol[2]one}: ¹H NMR (300 MHz, CDCl₃): δ = 8.60 (s, 1 H, NH), 7.39 (dd, J = 8.7 Hz, J = 1.5 Hz, 1 H, 6′-H), 7.22 (d, J = 1.5 Hz, 1 H, 4′-H), 6.79 (d, J = 8.7 Hz, 1 H, 7′-H), 4.37-4.27 (m, 2 H, 5-H), 3.71 (dd, J = 9.5 Hz, J = 7.3 Hz, 1 H, 3-H), 2.71-2.61 and 2.45-2.36 (2 × m, 2 H, 4-H), 1.82 (s, 3 H, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 204.3, 179.0, 140.0, 133.6, 129.7, 129.3, 116.4, 112.3, 83.7, 70.1, 62.6, 59.9, 30.7, 29.0 ppm. (2 R ,3 R )- and (2 S ,3 S )-5′-bromo-3-methylcarbonyl-4,5 H -spiro{furan-2,3′-indol[2]one}: ¹H NMR (300 MHz, CDCl₃): δ = 8.06 (s, 1 H, NH), 7.37 (dd, J = 8.7 Hz, J = 1.5 Hz, 1 H, 6′-H), 7.36 (d, J = 1.5 Hz, 1 H, 4′-H), 6.73 (d, J = 8.7 Hz, 1 H, 7′-H), 4.47 (td, J = 8.8 Hz, J = 2.9 Hz, 1 H, 5-H), 4.27 (q, J = 8.8 Hz, 1 H, 5-H), 3.50 (dd, J = 11.7 Hz, J = 8.8 Hz, 1 H, 3-H), 2.95-2.87 and 2.60-2.57 (2 × m, 2 H, 4-H), 2.14 (s, 3 H, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 204.9, 177.7, 152.7, 141.4, 133.4, 130.4, 127.6, 115.4, 112.2, 83.3, 68.9, 62.1, 29.7, 28.8 ppm.

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CCDC-239324 contains the supplementary crystallographic data and can be obtained free of charge via internet at
http://www.rsc.org/suppdata/cc/2004/239324/ [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; or [e-mail]].