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Multicomponent condensation strategies are capable of providing in a single step durable core structures and

Fluorous Synthesis: Fluorous Protocols for the Ugi and Biginelli Multicomponent Condensations.

JOURNAL OF ORGANIC CHEMISTRY, no. 9 (1997): 2917-2924

Cited: 317|Views25
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Abstract

A new protocol for multicomponent condensation reactions that uses fluorous (highly fluorinated) substrates is introduced. This method takes advantage of the ease of purification of fluorous compounds by liquid-liquid extractions between fluorous and organic solvents. The application of this method to the Ugi and Biginelli reactions is de...More

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Introduction
  • Combinatorial chemistry has rapidly become an important method for the identification and optimization of lead compounds in drug discovery.[1] In contrast to traditional solution organic synthesis, which often requires time-consuming purification procedures, combinatorial chemistry has been conducted almost exclusively on solid polymer supports.[2] Solid phase synthesis allows very simple product isolation by filtration, but this advantage at the isolation stage can be a detraction at the synthesis stage because reaction mixtures are inhomogeneous.
Highlights
  • Combinatorial chemistry has rapidly become an important method for the identification and optimization of lead compounds in drug discovery.[1]
  • Solid phase synthesis allows very simple product isolation by filtration, but this advantage at the isolation stage can be a detraction at the synthesis stage because reaction mixtures are inhomogeneous
  • Reactions of polymers that are soluble under certain conditions and insoluble under others have been introduced.[3]
  • Reactions should be planned such that the phase of the desired product is different from the phases of all the other reaction components and undesired products
  • Multicomponent condensation strategies are capable of providing in a single step durable core structures and
Methods
  • General Procedure for the Ugi Four

    Component Condensation (General Procedure 1). 4-Tris((2-(perfluorodecyl)ethyl)silyl)benzoic acid (7) (26.2 mg, 0.015 mmol), the amine (0.25 mmol), the aldehyde (0.25 mmol), and the isonitrile (0.25 mmol) were added to a sealed tube with CF3CH2OH (0.3 mL). (For some examples, the preformed imine was used.) The suspension was heated under argon to 90 °C for 48 h.
  • The combined fluorous phases were evaporated to yield the perfluorosilylated amino acid amide.
  • The amino acid amide was dissolved at 25 °C in THF (2 mL); TBAF (1 M in THF, 0.022 mL, 0.022 mmol) was added, and the resulting solution was stirred at 25 °C for 30 min.
  • After evaporation of the solvent, the residue was diluted with Et2O and washed with 0.1 N HCl, saturated aqueous Na2CO3, and brine.
  • The combined toluene phases were extracted with saturated aqueous NaHCO3 solution (3 × 10 mL) and brine (3 × 10 mL), dried (Na2SO4), filtered, and concentrated.
  • The reaction was followed by TLC, and after completion (1-2 d), the reaction mixture was concentrated in vacuo and the residue purified by chromatography on SiO2 to provide the dihydropyrimidine 14
Results
  • Multicomponent condensation strategies are capable of providing in a single step durable core structures and (7) (a) Gladysz, J.
Conclusion
  • This work shows that a highly fluorinated silyl group containing 63 fluorine atoms can be used as a “fluorous phase marker” to replace the solid polymer support in combinatorial synthesis. “Organic” molecules with molecular weights of up to almost 500 were rendered “fluorous” upon attachment to this fluorous tag.
  • This work shows that a highly fluorinated silyl group containing 63 fluorine atoms can be used as a “fluorous phase marker” to replace the solid polymer support in combinatorial synthesis.
  • “Organic” molecules with molecular weights of up to almost 500 were rendered “fluorous” upon attachment to this fluorous tag.
  • The fluorous Ugi and Biginelli products have molecular weights of about 2000, of which roughly 3/5 is fluorine, 1/5 is other atoms of the tag (C, H, Si), and 1/5 is the tagged organic moiety itself.
Tables
  • Table1: Examples of Fluorous Ugi Condensations
  • Table2: Yields of Fluorous and Standard Biginelli Reactions according to Scheme 5
Download tables as Excel
Funding
  • P.W. acknowledges support from the A
  • We thank the National Institutes of Health for funding and the 3M Corporation for a gift of FC-72. Supporting Information Available: 1H NMR spectra of the precursors and products of the Ugi and Biginelli condensations (25 pages)
Reference
  • (12) Hudlicky, M. Chemistry of Organic Fluorine Compounds; Ellis Horwood: Chichester, U.K., 1992.
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  • (13) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science, in press.
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  • 2918 J. Org. Chem., Vol. 62, No. 9, 1997
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  • (14) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810. (15) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) Kappe, C. O. Tetrahedron 1993, 49, 6937 and references cited therein.
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  • (16) See, for example: (a) Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org. Chem. 1996, 61, 924. (b) Mjalli, A. M. M.; Sarshar, S.; Baiga, T. J. Tetrahedron Lett. 1996, 37, 2943. (c) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996, 37, 4869. (d) Gordeev, M. F.; Patel, D. V.; Wu, J.; Gordon, E. M. Tetrahedron Lett. 1996, 37, 4643. (e) Kolodziej, S. A.; Hamper, B. C. Tetrahedron Lett. 1996, 37, 5277. (f) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937.
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  • (17) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. (18) (a) Greene, W. T.; Wuts, P. G. Protective Groups in Organic Synthesis; John Wiley & Sons, Inc: New York, 1991. (b) Armitage, D. A. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 2, p 1.
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  • (19) Boutevin, B; Guida-Pietrasanta, F.; Ratsimihety, A.; Caporiccio, G.; Gornowicz, G. J. Fluorine Chem. 1993, 60, 211.
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  • (22) In the 1H NMR spectrum of orthothioester 4 we could always observe some fluorous impurities. Attempts to purify 4 were not successful.
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  • (24) For Ugi reactions on solid polymer supports, see ref 17.
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  • (26) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819.
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  • (27) For a related solid-phase modification of the Biginelli reaction, see: Robinett, L. D.; Yager, K. M.; Phelan, J. C. 211th National Meeting of the American Chemical Society, New Orleans, 1996; American Chemical Society: Washington, DC, 1996; ORGN 122.
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