Microwave-Assisted Soluble Polymer-Supported Synthesis of Benzo­piperazinones

Abstract

Microwave-assisted liquid-phase combinatorial synthesis of quinoxaline-2-ones is reported. Immobilized aryl fluoride was aminated via ipso-fluoro displacement and then reduced the adjacent nitro group to give polymer bound o-phenylenediamine in the microwave oven. Spontaneous condensation and intramolecular cyclization of diamines with chloroacetyl chloride under microwave irradiation resulted in the formation of quinoxaline-2-ones as a combinatorial scaffold. Analytically pure target molecules were isolated after cleavage of the polymer support. All reactions involved were performed completely within a few minutes under microwave exposure.

microwave-assisted - combinatorial synthesis - quinoxaline-2-ones

References

<A NAME="RU09803ST-1A">1a</A> Czarnik AW. DeWitt SH. A Practical Guide to Combinatorial Chemistry   American Chemical Society; Washington D.C.: 1997. 

<A NAME="RU09803ST-1B">1b</A> Fenniri H. Combinatorial Chemistry   Oxford University Press, Inc.; New York: 2000. 

<A NAME="RU09803ST-1C">1c</A> Seneci P. Solid-Phase Synthesis and Combinatorial Technologies   John Wiley and Sons, Inc.; New York: 2000. 

<A NAME="RU09803ST-2A">2a</A> Sun CM. Comb. Chem. High Throughput Screening  1999,  2:  299 

<A NAME="RU09803ST-2B">2b</A> Toy PH. Janda KD. Acc. Chem. Res.  2000,  33:  546 

<A NAME="RU09803ST-2C">2c</A> Sun CM. Soluble Polymer-Supported Synthesis of Heterocyclic Libraries, In Combinatorial Chemistry Methods and Protocols, Methods in Molecular Biology Series   Bellavance L. The Humana Press, Inc.; New Jersey: 2002.  Chap. 10. p.345-371  

For reviews of microwave-assisted reactions in solution phase and solvent free condition, see:

<A NAME="RU09803ST-3A">3a</A> Caddick S. Tetrahedron  1995,  51:  10403 

<A NAME="RU09803ST-3B">3b</A> Galema SA. Chem. Soc. Rev.  1997,  26:  233 

<A NAME="RU09803ST-3C">3c</A> Varma RS. Green Chem.  1999,  1:  43 

<A NAME="RU09803ST-3D">3d</A> Loupy A. Perreux L. Tetrahedron  2001,  57:  9199 

<A NAME="RU09803ST-3E">3e</A> Lidström P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 

For microwave-assisted solid-phase combinatorial synthesis, see:

<A NAME="RU09803ST-4A">4a</A> Stadler A. Kappe CO. J. Comb. Chem.  2001,  3:  624 

<A NAME="RU09803ST-4B">4b</A> Lew A. Krutzik PO. Hart ME. Chamberlin RA. J. Comb. Chem.  2002,  4:  95 

<A NAME="RU09803ST-4C">4c</A> Martin B. Sekljic H. Chassaing C. Org. Lett.  2003,  5:  1851 

<A NAME="RU09803ST-5">5</A> Larhed M. Hallberg A. Drug Discovery Today  2001,  6:  406 

<A NAME="RU09803ST-6">6</A> Sarges R. Lyga JW. J. Heterocycl. Chem.  1988,  25(5):  1474 

<A NAME="RU09803ST-7A">7a</A> TenBrink RE. Im WB. Sethy VH. Tang AH. Carter DB. J. Med. Chem.  1994,  37:  758 

<A NAME="RU09803ST-7B">7b</A> Jacobsen EJ. Stelzer LS. TenBrink RE. Belonga KL. Carter DB. Im HK. Im WB. Sethy VH. Tang AH. VonVoigtlander PF. Petke JD. Zhong WZ. Mickelson JW. J. Med. Chem.  1999,  42:  1123 

<A NAME="RU09803ST-8A">8a</A> Sanna P. Carta A. Loriga M. Zanetti S. Sechi L. Farmaco  1999,  54:  161 

<A NAME="RU09803ST-8B">8b</A> Ali MM. Ismail MMF. El-Gaby MSA. Zahran MA. Ammar YA. Molecules  2000,  5:  864 

<A NAME="RU09803ST-9A">9a</A> Sanna P. Carta A. Loriga M. Zanetti S. Sechi L. Farmaco  1999,  54:  169 

<A NAME="RU09803ST-9B">9b</A> Carta A. Sanna P. Gherardini L. Usai D. Zanetti S. Farmaco  2001,  56:  933 

<A NAME="RU09803ST-10">10</A> Carta A. Sanna P. Loriga M. Setzu MG. Colla PL. Loddo R. Farmaco  2002,  57:  19 

<A NAME="RU09803ST-11A">11a</A> Meichsner C, Riess G, Kleim JP, Roesner M, Paessens A, and Blunck M. inventors; Eur. Pat. Appl. EP  657166 A1 950614. 

<A NAME="RU09803ST-11B">11b</A> Billhardt UM, Roesner M, Riesser G, Winkler I, and Bender R. inventors; Eur. Pat. Appl. EP  509398 A1 921021. 

<A NAME="RU09803ST-12A">12a</A> Pan PC. Sun CM. Tetrahedron Lett.  1998,  39:  9505 

<A NAME="RU09803ST-12B">12b</A> Pan PC. Sun CM. Tetrahedron Lett.  1999,  40:  6443 

<A NAME="RU09803ST-12C">12c</A> Yeh CM. Tung CL. Sun CM. J. Comb. Chem.  2000,  2:  341 

<A NAME="RU09803ST-12D">12d</A> Wu CY. Sun CM. Tetrahedron Lett.  2002,  43:  1529 

<A NAME="RU09803ST-13">13</A>

Discover focused microwave oven from CEM was used for our study.

<A NAME="RU09803ST-14A">14a</A> Lee J. Murray WV. Rivero RA. J. Org. Chem.  1997,  62:  3874 

<A NAME="RU09803ST-14B">14b</A> Morales GA. Corbett JW. DeGrado WF. J. Org. Chem.  1998,  63:  1172 

<A NAME="RU09803ST-15A">15a</A> Jacobsen EJ. TenBrink RE. Stelzer LS. Belonga KL. Carter DB. Im HK. Im WB. Sethy VH. Tang AH. VonVoigtlander PF. Petke JD. J. Med. Chem.  1996,  39:  158 

<A NAME="RU09803ST-15B">15b</A>

Jacobsen et al. reported the solution phase synthesis of 1,2,3,4-tetrahydroquinoxalin-2-ones using similar cyclization. They observed primary amino group stands to be more nucleophilic than adjacent substituted NH group. Probably steric hindrance of t-butyl group is the key factor to facilitate the acid chloride to opt primary amine in their work (Scheme [3] ).

<A NAME="RU09803ST-16">16</A>

General Experimental Procedure to Prepare 1,2,3,4-Tetrahydroquinoxalin-2-ones: All the microwave assisted polymer-supported reactions described here were performed in a 100 mL round bottom flask (attached to the reflux condenser) with CEM Discover Microwave System at a frequency of 2450 Hz (0-300 W). A mixture of PEG bound diamine 5m, freshly distilled chloroacetyl chloride (4 equiv), and Et₃N (4 equiv) in CH₂CL₂ (10 mL) was irradiated under CEM focused microwave (150 W) for 6 min. Completion of the reaction was confirmed by monitoring on ¹H NMR. Reaction mixture was then precipitated out by addition of EtOH (80 mL) under vigorous stirring. The separated precipitate of PEG bound quinoxalinone 8m was filtered and washed thoroughly with Et₂O and dried in vacuum. Polymer support of 8m was cleaved by exposing it to microwave (150 W) for 10 min in sodium methoxide solution. Progress of cleavage was monitored on TLC [solvent: EtOAc-n-hexane (1:2)]. Separation of 2-arm PEG from the desired products was achieved by precipitation in ethanol to give crude mixtures of compounds 9m and 10m in 90% combined yield and 93% (53% and 40%) HPLC purity (UV detection at λ = 254 nm. Column: Sphereclone 5u Si (250 × 4.6 nm); gradient: 50% EtOAc/n-hexane; flow rate: 1 mL/min).