Efficient Solid-Phase Synthesis of Disubstituted 1,3-Dihydro-imidazol-2-ones

Abstract

A bromoacetal linker was used to achieve the synthesis of ureas on a solid support. The resulting ureido acetals were treated with TFA and were converted in an intramolecular cyclization via N-acyliminium ion to disubstituted 1,3-dihydro-imidazol-2-ones.

Key words

heterocycles - acetals - solid-phase synthesis - nucleophiles - cyclizations

References

• 1a Hermkens PHH. Ottenheijm HCJ. Rees D. Tetrahedron  1996,  52:  4527 
• 1b Hermkens PH. Ottenheijm HC. Rees DC. Tetrahedron  1997,  53:  5643 
• 1c Obrecht D. Villalgordo JM. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries   Elsevier Science Ltd; Oxford: 1998. 
• 1d Bunin BA. Dener JM. Livingston DA. Annu. Rep. Med. Chem.  1999,  34:  267 
• 1e Guillier F. Orain D. Bradley M. Chem. Rev.  2000,  100:  2091 
• 1f Franzen RG. J. Comb. Chem.  2000,  2:  195 
• 2a Speckamp WN. Hiemstra H. Tetrahedron  1985,  41:  4367 
• 2b Maryanoff BE. Zhang H.-C. Cohen JH. Turchi IJ. Maryanoff CA. Chem. Rev.  2004,  104:  1431 
• 3a Vojkovsky T. Weichsel A. Patek M. J. Org. Chem.  1998,  63:  3162 
• 3b Eguchi M. Lee M. Nakanish H. Stasiak M. Lovell S. Kahn M. J. Am. Chem. Soc.  1999,  121:  1204 
• 3c Kohn WD. Zhang L. Tetrahedron Lett.  2001,  42:  4453 
• 3d Eguchi M. McMillan M. Nguyen C. Teo JL. Chi EY. Henderson WR. Kahn M. Comb. Chem. High Throughput Screening  2003,  6:  611 
• 4 Lee YS. Kim CS. Park H. Heterocycles  1994,  38:  2605 
• 5 Wright WB. Brabander HJ. Hardy RA. J. Med. Chem.  1966,  9:  858 
• 6 Himmelsbach F, Pieper H, Austel V, Linz G, Guth B, Mueller T, and Weisenberger J. inventors; Eur. Pat. Appl. EP 0612741  A1. 
• 7 Moon MW. Chidester CG. Heier RF. Morris JK. Collins RJ. Russell RR. Francis JW. Sage GP. Sethy VH. J. Med. Chem.  1991,  34:  2314 
• 8a Naylor EM. Parmoo ER. Colandres VJ. Perkins L. Brockunier L. Candelore MR. Cascieri MA. Colwell LF. Deng L. Foeney WP. Forrest MJ. Hom GJ. MacIntyre DE. Strader CD. Tote L. Wang P.-R. Wyvratt MJ. Fisher MH. Weber AE. Bioorg. Med. Chem. Lett.  1999,  9:  755 
• 8b Schwink L, Stengelin S, Gossel M, Boehme T, Hessler G, Rosse G, and Walser A. inventors; WO Patent  2004011438A1. 
• 9a Wang PC. Heterocycles  1985,  23:  3041 
• 9b Lee YS. Kim CS. Park H. Heterocycles  1994,  38:  2605 
• 9c Cheng JF. Kaiho C. Chen M. Arrhenius T. Nadzan A. Tetrahedron Lett.  2002,  43:  4571 
• 9d Cheng JF. inventors; WO Patent  2002020493A2.  ; see also ref.

10

Bromoacetal resin has been prepared as described in ref.^3a. Bromoacetal linker attached on TentaGel or polystyrene resin is now commercially available from Novabiochem (www.novabiochem.com), Rapp Polymers (www.rapp-polymer.com) and LCC Technologies (http://www.chemsupply.ch).

11

The synthesis of 4a and 4b are representative of the procedure used for the parallel synthesis of the libraries.
Benzyl-amino-acetal Resin (2a): Bromoacetal LCC-Dynosphere polystyrene resin (100 mg, 0.16 mmol, 203 µ, batch#F-BAS/270-F146.1, 1.6 mmol/g as determined by elemental analysis, from LCC Engineering, Switzerland) was swollen once with NMP (5 mL). A mixture of DMSO-NMP 1:1 (2 mL) was added followed by benzylamine (257 µL, 2.4 mmol). The reaction mixture was shaken for 16 h at 80 °C, filtered off, washed three times with DMF (3 mL), three times with i-PrOH (3 mL) and four times with DMF (3 mL) each. A sample of the resin was washed five times with i-PrOH (3 mL) and dried under high vacuum: 94% conversion based on elemental analysis. Anal. Found: N, 2.03; Br, 0.33.
1-Benzyl-3-phenyl-1,3-dihydro-imidazol-2-one (4a): NMP (2 mL) and phenylisocyanate (285 µL, 2.4 mmol) were successively added to resin 3a (0.16 mmol). The reaction mixture was shaken for 7 h at 70 °C, filtered off, washed three times with DMF (3 mL), three times with i-PrOH (3 mL) and five times with CH₂Cl₂ (3 mL) each. After drying the resin for 30 min under vacuum (ca. 20 mbar house vacuum), TFA (3 mL) was added and the reaction mixture was shaken for 17 h. This eluate and one subsequent wash with TFA (2 mL) were collected and combined. The solvent was evaporated and the residue was purified by preparative LC-MS with a Waters Fractionlynx system (YMC Pack Pro C₁₈ column, 5 µ, 120Å, 50 × 20 mm) using a gradient of H₂O and MeCN (in 7 min from 5% MeCN to 85% MeCN, in 0.1 min from 85% MeCN to 95% MeCN, 1.2 min at 95% MeCN, in 0.1 min from 95% MeCN to 5% MeCN, flow: 35 mL/min, an autoblend method was used to ensure a concentration of 0.1% TFA throughout the complete run). Compound 4a: 21 mg (37%). ESI-MS: m/z (%) = 251.1 (100) [M + H]⁺. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.65 (d, J = 2.6 Hz, 2 H), 7.23-7.47 (m, 8 H), 6.59 (d, J = 1.0 Hz, 1 H), 6.28 (d, J = 1.0 Hz, 1 H), 6.40 (s, 1 H), 4.90 (s, 2 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 151.1, 137.3, 137.1, 128.7, 128.3, 126.7, 121, 112.2, 109.8, 66.1.
1-Benzyl-3-(5-tert-butyl-1 H -pyrazol-3-yl)-1,3,-dihydro-imidazol-2-one (4b): 5-tert-butyl-1H-3-aminopyrazol (334 mg, 2.40 mmol) was dissolved in NMP (2.4 mL). CDI (389 mg, 2.40 mmol) was dissolved in NMP (2.4 mL) and then added to the aminopyrazole solution. The solution was shaken for 10 min and added to the resin 3a (0.16 mmol). The reaction mixture was shaken for 7 h at 70 °C and filtered off. Washing of the resin, cleavage of the compound from the resin and purification using LC-MS were performed as described for 4a. Compound 4b: 51 mg (77%). ESI-MS: m/z (%) = 297.2 (100) [M + H]⁺. ¹H NMR (600 MHz, DMSO-d ₆): δ = 7.34-7.36 (m, 2 H), 7.27-7.30 (m, 3 H), 6.91 (d, J = 1.0 Hz, 1 H), 6.72 (d, J = 1.0 Hz, 1 H), 6.40 (s, 1 H), 4.78 (s, 2 H), 1.28 (s, 9 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 150.4, 137.7, 128.5, 127.4, 119.5, 112.5, 107.6, 91.1, 46.1. 30.7, 29.8.