Polymer-Bound 3-N,N-(Dimethylamino)-2-isocyanoacrylate for the Synthesis of Thiazoles via a Multicomponent Reaction

Abstract

The synthesis of resin-bound 3-N,N-(dimethylamino)-2-isocyanoacrylate is described. This bifunctional reagent can be used for the synthesis of thiazoles via a multicomponent reaction. Several examples are reported.

solid-phase synthesis - thiazole heterocycles - multicomponent reaction - combinatorial chemistry - isocyanide

References

<A NAME="RG24103ST-1A">1a</A> Obrecht D. Abrecht C. Grieder A. Villalgordo J.-M. Helv. Chim. Acta  1997,  80:  65 

<A NAME="RG24103ST-1B">1b</A> Masquelin T. Sprenger D. Bär R. Gerber F. Mercadal Y. Helv. Chim. Acta  1998,  81:  646 

<A NAME="RG24103ST-1C">1c</A> Dodd DS. Wallace OB. Tetrahedron Lett.  1998,  39:  5701 

<A NAME="RG24103ST-1D">1d</A> Schwarz MK. Tumelty D. Gallop MA. J. Org. Chem.  1999,  64:  2219 

<A NAME="RG24103ST-1E">1e</A> Schwarz MK. Tumelty D. Gallop MA. Tetrahedron Lett.  1998,  39:  8397 

<A NAME="RG24103ST-1F">1f</A> Lee J. Gauthier D. Rivero RA. J. Org. Chem.  1999,  64:  3060 

<A NAME="RG24103ST-1G">1g</A> Lee J. Murray WV. Rivero RA. J. Org. Chem.  1997,  62:  3874 

<A NAME="RG24103ST-1H">1h</A> Morales GA. Corbett JW. DeGrado WF. J. Org. Chem.  1998,  63:  1172 

<A NAME="RG24103ST-1I">1i</A> Wei GP. Phillips GB. Tetrahedron Lett.  1998,  39:  179 

<A NAME="RG24103ST-1J">1j</A> Lee J. Gauthier D. Rivero RA. Tetrahedron Lett.  1998,  39:  201 

<A NAME="RG24103ST-1K">1k</A> Tumelty D. Schwarz MK. Needels MC. Tetrahedron Lett.  1998,  39:  7467 

<A NAME="RG24103ST-2">2</A> Schöllkopf U. Porsch P.-H. Lau H.-H. Chem. Ber.  1979,  112:  1444 

<A NAME="RG24103ST-3A">3a</A> Allgeier H. inventors; Eur. Pat. Appl., EP  0248414A2.  ; Chem. Abstr. 1987, 108, 112460

<A NAME="RG24103ST-3B">3b</A> Helal CJ. Lucas JC. Org. Lett.  2002,  4:  4133 

<A NAME="RG24103ST-4">4</A> Bienaymé H. Bouzid K. Tetrahedron Lett.  1998,  39:  2735 

<A NAME="RG24103ST-5A">5a</A> Bossio R. Marcaccini S. Pepino R. J. Chem. Res., Synop.  1993,  1:  1 

<A NAME="RG24103ST-5B">5b</A> Bossio R. Marcaccini S. Pepino R. Paoli P. Pollo C. J. Heterocycl. Chem.  1993,  30:  575 

<A NAME="RG24103ST-6A">6a</A> Heck S. Dömling A. Synlett  2000,  424 

<A NAME="RG24103ST-6B">6b</A> Henkel B. Sax M. Dömling A. Tetrahedron Lett.  2003,  44:  3679 

<A NAME="RG24103ST-7">7</A> Kaiser E. Colescott RL. Bossinger CD. Cook PI. Anal. Biochem.  1970,  34:  595 

<A NAME="RG24103ST-8A">8a</A> Hoppe I. Schöllkopf U. Chem. Ber.  1976,  109:  482 

<A NAME="RG24103ST-8B">8b</A> Henkel B. Sax M. Dömling A. Tetrahedron Lett.  2003,  44:  7015 

<A NAME="RG24103ST-9A">9a</A> Henkel B. inventors; PCT Int. Appl., WO  2003051795.  ; Chem. Abstr. 2003, 139, 68959

<A NAME="RG24103ST-9B">9b</A>

Resin-bound 3-N,N-(dimethyl-amino)-2-isocyanoacrylate is available from Priaton, Bahnhofstrasse 9-15, 82327 Tutzing, Germany (www.priaton.de).

<A NAME="RG24103ST-10">10</A> Henkel B. Weber L. Synlett  2002,  1877 

<A NAME="RG24103ST-11">11</A>

Representative example:
Synthesis of 2-[1-(Acetylbenzylamino)-2-methyl-propyl]thiazole-4-carboxylic Acid
Benzylamine (0.11 mL, 1 mmol) and iso-butyraldehyde (0.092 mL, 1 mmol) were dissolved in a 1:1 mixture of absolute CH₂Cl₂-MeOH (2 mL). This mixture was stirred for 2 h followed by the addition of HMBA-resin bound 3-N,N-(dimethyl-amino)-2-isocyanoacrylate (500 mg, 0.19 mmol), thioacetic acid (0.071 mL, 1 mmol) and 2 mL of the above solvent mixture. After agitating for 16 h the resin was filtered off and washed with CH₂Cl₂ (3 ×) and MeOH (3 ×). The resin was dried under high vacuum. Cleavage was performed with LiOH (18 mg, 0.75 mmol) in water (2 mL) and THF (2 mL) for 16 h. Thereafter the resin was filtered off and washed with a THF-water mixture. The resulting solvent mixture was neutralized with 2 N HCl and evaporated to dryness. The crude product was purified by preparative HPLC (column Grom-Sil 120 ODS-5, 50 × 20 mm, 5 µm, flow 30 mL/min, gradient 30-100% A in 15 min, solvent A = MeOH + 0.5% HOAc, solvent B = water + 0.5% HOAc). Yield 35 mg (56%). ¹H NMR (400 MHz, CDCl₃): δ = 0.85 and 0.98 (dd, J = 6.3 Hz; 6 H), 2.10 (s, 3 H), 2.79-2.90 (m, 1 H), 4.57-4.80 (q, J = 17.2 Hz; 2 H), 5.37-5.48 (m, 1 H), 6.83 (d, J = 7.0 Hz, 2 H), 7.12-7.18 (m, 3 H), 8.07 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.4, 20.2, 22.4, 29.8, 125.8, 127.2, 127.9, 128.5, 128.9, 136.6, 145.6, 162.7, 168.5, 172.1.

<A NAME="RG24103ST-12A">12a</A> Sheppard RC. Williams BJ. Int. J. Peptide Protein Res.  1982,  20:  451 

<A NAME="RG24103ST-12B">12b</A> Atherton E. Sheppard RC. Solid Phase Peptide Synthesis: A Practical Approach   IRL Press; Oxford: 1989.