Synlett 2015; 26(04): 484-488
DOI: 10.1055/s-0034-1378925
letter
© Georg Thieme Verlag Stuttgart · New York

Mild Microwave-Assisted Synthesis of Dipyrromethanes and Their Analogues

Ruisheng Xiong
Department of Chemistry – BMC, Uppsala University, Husargatan 3, Box 576, Uppsala, 75123, Sweden   Fax: +46(18)4713818   Email: eszter.borbas@kemi.uu.se
,
K. Eszter Borbas*
Department of Chemistry – BMC, Uppsala University, Husargatan 3, Box 576, Uppsala, 75123, Sweden   Fax: +46(18)4713818   Email: eszter.borbas@kemi.uu.se
› Author Affiliations
Further Information

Publication History

Received: 16 September 2014

Accepted after revision: 12 October 2014

Publication Date:
18 November 2014 (online)


Abstract

The Mannich reaction between pyrroles or indoles and ­Eschenmoser’s salt (dimethylmethylideneammonium iodide) forms N,N-dimethylamino-methylated derivatives in good to excellent yields. The reaction is highly regioselective, and for pyrroles both 2- and 3-substituted derivatives could be obtained. The N,N-dimethylaminomethylpyrroles and indoles underwent substitution with pyrrole under microwave irradiation, affording the appropriate dipyrromethanes, N-confused, and indolo-dipyrromethanes in moderate to excellent overall yield.

Supporting Information

 
  • References and Notes

  • 1 Battersby AR. Nat. Prod. Rep. 2000; 17: 507
    • 2a Wood TE, Thompson A. Chem. Rev. 2007; 107: 1831
    • 2b Loudet A, Burgess K. Chem. Rev. 2007; 107: 4891
    • 2c Chen Y, Ruppel JV, Zhang XP. J. Am. Chem. Soc. 2007; 129: 12074
    • 2d Liu W, Huang X, Cheng M.-J, Nielsen RJ, Goddard WA. III, Groves JT. Science 2012; 337: 1322
    • 2e Lindsey JS, Bocian DF. Acc. Chem. Res. 2011; 44: 638
  • 3 Schmuck C, Rupprecht D. Synthesis 2007; 3095
    • 4a Lindsey JS. Acc. Chem. Res. 2010; 43: 300
    • 4b Shanmugathasan S, Edwards C, Boyle RW. Tetrahedron 2000; 56: 1025
    • 4c Plunkett S, Senge MO. ECS Trans. 2011; 35: 147
  • 5 Pereira NA. M, Pinho e Melo TM. V. D. Org. Prep. Proced. Int. 2014; 46: 183
  • 6 Yao Z, Bhaumik J, Dhanalekshmi S, Ptaszek M, Rodriguez PA, Lindsey JS. Tetrahedron 2007; 63: 10657
  • 7 Littler BJ, Miller MA, Hung C.-H, Wagner RW, O’Shea DF, Boyle PD, Lindsey JS. J. Org. Chem. 1999; 64: 1391
  • 8 Laha JK, Dhanalekshmi S, Taniguchi M, Ambroise A, Lindsey JS. Org. Process Res. Dev. 2003; 7: 799
    • 9a Herz W, Toggweiler U. J. Org. Chem. 1964; 29: 213
    • 9b Hinz W, Jones RA, Anderson T. Synthesis 1986; 620
    • 9c Rawal VH, Jones RJ, Cava MP. J. Org. Chem. 1987; 52: 19
    • 9d Kumar S, Mani G, Mondal S, Chattaraj PK. Inorg. Chem. 2012; 51: 12527
    • 9e Mani G, Guchhait T, Kumar R, Kumar S. Org. Lett. 2010; 12: 3910
    • 10a Fan D, Taniguchi M, Yao Z, Dhanalekshmi S, Lindsey JS. Tetrahedron 2005; 61: 10291
    • 10b Schmidt I, Jiao J, Thamyongkit P, Sharada DS, Bocian DF, Lindsey JS. J. Org. Chem. 2006; 71: 3033
    • 10c Borbas KE, Kee HL, Holten D, Lindsey JS. Org. Biomol. Chem. 2008; 6: 187
    • 10d Muresan AZ, Lindsey JS. Tetrahedron 2008; 64: 11440
    • 10e Lahaye D, Muthukumaran K, Hung C.-H, Gryko D, Reboucas JS, Spasojevic I, Batinic-Haberle I, Lindsey JS. Bioorg. Med. Chem. 2007; 15: 7066
  • 11 Dogutan DK, Ptaszek M, Lindsey JS. J. Org. Chem. 2007; 72: 5008
  • 12 Ptaszek M, McDowell BE, Taniguchi M, Kim H.-J, Lindsey JS. Tetrahedron 2007; 63: 3826
  • 13 Toganoh M, Furuta H. Chem. Commun. 2012; 48: 937
  • 14 Jolicoeur B, Chapman EE, Thompson A, Lubell WD. Tetrahedron 2006; 62: 11531
    • 15a Kim H.-J, Lindsey JS. J. Org. Chem. 2005; 70: 5475
    • 15b Borbas KE, Ruzie C, Lindsey JS. Org. Lett. 2008; 10: 1931
  • 16 General Procedure for the Mannich ReactionA sample of the heterocycle was dissolved in CH2Cl2 or MeCN (ca. 0.15–0.2 M). Eschenmoser’s salt (2 equiv) was added in a single portion. The reaction mixture was stirred at r.t. until TLC analysis indicated the complete consumption of the starting material (20 min to 26 h). The reaction mixture was diluted with CH2Cl2 or EtOAc (for MeCN as solvent) and sat. aq NaHCO3. The phases were separated, and the aqueous layer was extracted once. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The crude product was used without further purification in the next step.Dipyrromethane SynthesisThe Mannich product was placed in a microwave vial. Pyrrole was added to afford a 0.2–0.3 M solution. The vial was capped. The vial was placed in a microwave reactor and was irradiated at 150 °C for 30 min. The reaction mixture was cooled to r.t., and the pyrrole was evaporated. The dark brown oily residue was purified by column chromatography (silica, PE–EtOAc) to afford the products.Compound 2e: yellow oil (62%); IR (thin film): ν = 3003, 2945, 2866, 2709, 1568, 1481, 1463, 1417, 1406, 1298, 1262, 1225, 1172, 1133, 1051, 1016 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.08 (d, J = 7.4 Hz, 18 H), 1.43 (sept, J = 7.4 Hz, 3 H), 2.25 (s, 6 H), 3.42 (s, 2 H), 6.23–6.27 (m, 1 H), 6.64–6.69 (m, 1 H), 6.70–6.74 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 11.6, 17.8, 44.6, 56.2, 111.7, 121.4, 123.6, 124.3. ESI-HRMS: m/z calcd for C16H32N2Si [M + H]+: 281.2363; found: 281.2406.Compound 3e: colorless oil (54%); IR (thin film): ν = 3676, 3341, 2959, 2867, 1563, 1534, 1464, 1407, 1394, 1383, 1272, 1258, 1236, 1210, 1116, 1067, 1016 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.19 (d, J = 7.6 Hz, 18 H), 1.50 (sept, J = 7.6 Hz, 3 H), 3.95 (s, 2 H), 5.97 (s, 1 H), 6.18–6.24 (m, 1 H), 6.25–6.29 (m, 1 H), 6.65–6.73 (m, 2 H), 6.79–6.87 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 11.8, 17.9, 25.5, 105.0, 108.3, 111.3, 116.0, 122.2, 122.7, 124.7, 132.2. ESI-HRMS: m/z calcd for C18H30N2Si [M + H]+: 303.2251; found: 303.2247.Compound 2f: colorless oil (quant.); 1H NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.2 Hz, 3 H), 2.02 (s, 1.5 H), 2.17 (s, 4 H), 2.31 (s, 1.5 H), 3.33 (d, J = 11.9 Hz, 2 H), 4.12 (q, J = 7.6 Hz 1 H), 4.67 (s, 0.5 H), 7.01 (dd, J = 15.3, 8.2 Hz, 2 H), 7.38 (d, J = 10.6 Hz, 1 H), 7.66 (dd, J = 9.3, 7.7 Hz, 2 H). 10.4 (br, 1 H). 13C NMR (100 MHz, CDCl3): δ = 14.2, 14.4, 42.7, 44.8, 52.5, 54.0, 59.4, 70.4, 92.1, 114.2, 123.2, 124.4, 127.7, 128.1, 132.6, 132.8, 134.3, 136.4, 136.6, 164.6. ESI-HRMS: m/z calcd for C16H19N2O2I [M + MeOH + Na]+: 456.0888; found: 456.0894.Compound 3f: pale solid (52%); 1H NMR (400 MHz, CDCl3/ CD3OD): δ = 1.14 (dt, J = 7.1, 1.2 Hz, 3 H), 3.76 (s, 1 H), 4.08 (q, J = 7. 2 Hz 2 H), 5.72–5.81 (m, 1 H), 5.94–6.05 (m, 1 H), 6.58–6.63 (m, 1 H), 7.04 (d, J = 8. 4 Hz, 2 H), 7.33–7.39 (m, 1 H), 7.61 (d, J = 8. 4 Hz, 2 H). 13C NMR (100 MHz, CDCl3/CD3OD): δ = 13.7, 24.0, 59.4, 91.3, 105.6, 107.5, 113.3, 116.8, 121.1, 124.1, 128.8, 129.0, 132.4, 134.8, 136.4, 165.8. ESI-HRMS: m/z calcd for C16H19N2O2I [M + MeOH + Na]+: 456.0888; found: 456.0894.