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Synlett 2016; 27(02): 287-293
DOI: 10.1055/s-0035-1560582
letter
© Georg Thieme Verlag Stuttgart · New York

Sequential C–C, C–O, and C–N Bond-Forming Reaction of Methyl (–)-3-Dehydroshikimate, Malononitrile, and Bromoalkanes: Simple Synthesis of 2-(Alkylamino)-3-cyanobenzofurans from a Biomass-Derived Substrate

Autor*innen

  • Dejian Wang

    b   Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou, 510650, P. R. of China
    c   University of Chinese Academy of Sciences, Beijing 100039, P. R. of China

  • Ensheng Zhang

    d   School of Chemistry and Chemical Engineering, Yan’an University, Yan’an 716000, P. R. of China

  • Tianlong Xu

    b   Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou, 510650, P. R. of China
    c   University of Chinese Academy of Sciences, Beijing 100039, P. R. of China

  • Jianfei Sheng

    a   School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, P. R. of China   eMail: zou_jinan@163.com

  • Yong Zou*

    a   School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, P. R. of China   eMail: zou_jinan@163.com
Weitere Informationen

Publikationsverlauf

Received: 25. August 2015

Accepted after revision: 18. September 2015

Publikationsdatum:
28. Oktober 2015 (online)

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Graphical Abstract

Abstract

An interesting and simple method was developed for the synthesis of 2-(alkylamino)-3-cyanobenzofurans by consecutive C–C, C–O, and C–N coupling reaction of methyl (–)-3-dehydroshikimate with malononitrile and a bromoalkane or dibromoalkane under microwave conditions. This process represents a metal-free sustainable strategy for the construction of 2-(alkylamino)-3-cyanobenzofurans from a biomass-derived starting material.

Key words

benzofurans - coupling - nitriles - bromoalkanes - cascade reaction - green-chemistry

Supporting Information

 

  • References and Notes

  • 1 Ashwood VA, Field MJ, Horwell DC, Julien-Larose C, Lewthwaite RA, McCleary S, Pritchard MC, Raphy J, Singh L. J. Med. Chem. 2001; 44: 2276
    CrossrefSuche in Google Scholar
  • 2 Fuganti C, Serra S. Tetrahedron Lett. 1998; 39: 5609
    CrossrefSuche in Google Scholar
  • 3 Tsai IL, Hsieh CF, Duh CY. Phytochemistry 1998; 48: 1371
    CrossrefSuche in Google Scholar
  • 4 Van Beeren HC, Jong WM, Kaptein E, Visser TJ, Bakker O, Wiersinga WM. Endocrinology 2003; 144: 552
    CrossrefSuche in Google Scholar
  • 5 Cowart M, Faghih R, Curtis MP, Gfesser GA, Bennani YL, Black LA, Pan LP, Marsh KC, Sullivan JP, Esbenshade TA, Fox GB, Hancock AA. J. Med. Chem. 2005; 48: 38
    CrossrefSuche in Google Scholar
  • 6 Malamas MS, Sredy J, Moxham C, Katz A, Xu WX, McDevitt R, Adebayo FO, Sawicki DR, Seestaller L, Sullivan D, Taylor JR. J. Med. Chem. 2000; 43: 1293
    CrossrefPubMedSuche in Google Scholar
  • 7 McCallion GD. Curr. Org. Chem. 1999; 3: 67
    Suche in Google Scholar
  • 8 Ebiike H, Masubuchi M, Liu PL, Kawasaki K.-i, Morikami K, Sogabe S, Hayase M, Fujii T, Sakata K, Shindoh H, Shiratori Y, Aoki Y, Ohtsuka T, Shimma N. Bioorg. Med. Chem. Lett. 2002; 12: 607
    CrossrefSuche in Google Scholar
  • 9 Maeda S, Masuda H, Tokoroyama T. Chem. Pharm. Bull. 1994; 42: 2536
    CrossrefSuche in Google Scholar
  • 10 Gaszner P, Miklya I. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2006; 30: 5
    CrossrefSuche in Google Scholar
  • 11 Ono M, Kawashima H, Nonaka A, Kawai T, Haratake M, Mori H, Kung M.-P, Kung HF, Saji H, Nakayama M. J. Med. Chem. 2006; 49: 2725
    CrossrefSuche in Google Scholar
  • 18 Methyl 2-(Alkylamino)-3-cyanobenzofuran-5-carboxylates 4a–j and 7a–g; General Procedure A 25 mL round-bottomed flask was charged with 3-MDHS (1; 0.19 g, 1 mmol), malononitrile (2; 1.5 mmol), and H2O (10 mL). The flask was placed in a microwave synthesizer, and the mixture was irradiated (240 W) at 85 °C for 10 min. The mixture was then filtered under reduced pressure to give the crude intermediate A, which was used in step 2 without further purification. Intermediate A, inorganic base [NaHCO3 (2 mmol) for 4a–j; K2CO3 (2 mmol) for 7a–g], bromoalkane 3 [monobromoalkane (2 mmol) for 4a–4; dibromoalkane for 7a–g], and DMSO (8 mL) were added to a flask and irradiated (240 W) at 120 °C for 5 min then cooled. The mixture was then poured into brine (40 mL), extracted with EtOAc (3 × 20 mL), and dried (MgSO4). The organic layer was concentrated and the residue was purified by column chromatography (silica gel, EtOAc–PE). Methyl 3-Cyano-2-(ethylamino)-1-benzofuran-5-carboxylate (4a) Light-yellow solid; yield: 82%; mp 189–190 °C. IR (KBr): 3442, 3288, 3058, 2972, 2206, 1728, 1712, 1645, 1533, 1448, 1344, 1294, 1248, 1184, 1107, 997, 958, 885, 762, 729, 654, 584 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 8.93 (t, J = 5.60 Hz, 1 H), 7.74 (d, J = 1.60 Hz, 1 H), 7.71 (dd, J 1 = 8.40 Hz, J 2 = 1.60 Hz, 1 H), 7.49 (d, J = 8.40 Hz, 1 H), 3.86 (s, 3 H), 3.47 (m, 2 H), 1.25 (t, J = 4.00 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 165.9, 164.6, 150.4, 128.9, 125.8, 123.2, 116.5, 115.1, 110.0, 59.3, 52.1, 37.1, 14.8. HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H13N2O3: 245.0921; found: 245.0923. Methyl 3-Cyano-2-(propylamino)-1-benzofuran-5-carboxylate (4c) White solid; yield: 70%; mp 168–169 °C. IR (KBr): 3435, 3288, 3047, 2980, 2200, 1703, 1628, 1531, 1450, 1288, 1250, 1176, 1165, 1101, 976, 766, 731, 644, 600 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 8.89 (d, J = 8.40 Hz, 1 H), 7.75 (s, 1 H), 7.71 (dd, J 1 = 8.40 Hz, J 2 = 1.20 Hz, 1 H), 7.50 (d, J = 8.40 Hz, 1 H), 4.05 (m, 1 H), 3.86 (s, 3 H), 1.27 (d, J = 8.00 Hz, 6 H). 13C NMR (100 MHz, DMSO-d 6): δ = 166.0, 163.9, 150.5, 129.0, 125.9, 123.3, 116.5, 115.2, 110.0, 59.3, 52.2, 45.0, 22.6. HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H15N2O3: 259.1077; found: 259.1074. Methyl 2-(sec-Butylamino)-3-cyano-1-benzofuran-5-carboxylate (4e) White needles; yield: 83%; mp 142–143 °C. IR (KBr): 3427, 3278, 3224, 3095, 2964, 2214, 1714, 1649, 1460, 1298, 1246, 1184, 1082, 991, 899, 822, 764, 656 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 8.86 (d, J = 8.80 Hz, 1 H), 7.74 (d, J = 1.60 Hz, 1 H), 7.71 (dd, J 1 = 8.80 Hz, J 2 = 2.00 Hz, 1 H), 7.49 (d, J = 8.40 Hz, 1 H), 3.86 (s, 3 H), 3.82 (m, 1 H), 1.61 (m, 2 H), 1.25 (d, J = 6.40 Hz, 3 H), 0.92 (t, J = 7.60 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 166.0, 164.2, 150.4, 129.1, 125.9, 123.3, 116.5, 115.3, 110.0, 59.1, 52.2, 50.6, 29.0, 20.4, 10.3. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H17N2O3: 273.1234; found: 273.1236. Methyl 3-Cyano-2-[(3-methylbutyl)amino]-1-benzofuran-5-carboxylate (4h) White needles; yield: 81%; mp 136–137 °C. IR (KBr): 3429, 3224, 3086, 2951, 2879, 2214, 1718, 1662, 1460, 1369, 1294, 1248, 1190, 1119, 1101, 991, 957, 895, 822, 764, 669, 623 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 8.94 (t, J = 6.00 Hz, 1 H), 7.74 (d, J = 1.20 Hz, 1 H), 7.70 (dd, J 1 = 8.40 Hz, J 2 = 1.60 Hz, 1 H), 7.49 (d, J = 8.40 Hz, 1 H), 3.86 (s, 3 H), 3.44 (m, 2 H), 1.69 (m, 1 H), 1.52 (m, 2 H), 0.92 (d, J = 6.40 Hz, 6 H). 13C NMR (100 MHz, DMSO-d 6): δ = 166.0, 164.7, 150.5, 129.0, 125.9, 123.3, 116.5, 115.2, 110.0, 59.3, 52.2, 40.7, 37.9, 25.1, 22.3. HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H19N2O3: 287.1396; found: 287.1397. Methyl 3-Cyano-2-[(3-hydroxypropyl)amino]-1-benzofuran-5-carboxylate (4j) Brown solid; yield: 60%; mp 150–151 °C. IR (KBr): 3469, 3286, 3242, 3084, 2947, 2881, 2202, 1713, 1651, 1456, 1363, 1302, 1244, 1190, 1144, 1099, 1063, 978, 885, 829, 760, 698, 658, 590 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 8.89 (t, J = 5.60 Hz, 1 H), 7.74 (d, J = 1.20 Hz, 1 H), 7.70 (dd, J 1 = 8.40 Hz, J 2 = 2.00 Hz, 1 H), 7.49 (d, J = 8.40 Hz, 1 H), 4.59 (s, 1 H), 3.86 (s, 3 H), 3.50 (m, 4 H), 1.78 (m, 2 H). 13C NMR (100 MHz, DMSO-d 6): δ = 166.0, 164.8, 150.5, 129.0, 125.9, 123.2, 116.5, 115.2, 110.0, 59.4, 57.8, 52.2, 32.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H15N2O4 : 275.1032; found: 275.1031. Methyl 3-Cyano-2-pyrrolidin-1-yl-1-benzofuran-5-carboxylate (7c) White needles; yield: 81%; mp 185–186 °C. IR (KBr): 3431, 3064, 2960, 2879, 2191, 1724, 1637, 1450, 1352, 1300, 1246, 1178, 1097, 960, 881, 858, 818, 764, 733, 662, 517 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 7.71 (d, J = 1.20 Hz, 1 H), 7.69 (dd, J 1 = 8.40 Hz, J 2 = 2.00 Hz, 1 H), 7.48 (d, J = 8.40 Hz, 1 H), 3.87 (s, 3 H), 3.68 (t, J = 6.00 Hz, 4 H), 2.00 (t, J = 6.40 Hz, 4 H). 13C NMR (100 MHz, DMSO-d 6): δ = 166.0, 161.8, 150.7, 129.3, 126.0, 123.3, 116.6, 115.8, 110.1, 60.2, 52.2, 48.1, 24.9. HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H15N2O3: 271.1083; found: 271.1085. Methyl 3-Cyano-2-piperidin-1-yl-1-benzofuran-5-carboxylate (7e) White crystals; yield: 87%; mp 147–148 °C. IR (KBr): 3448, 3425, 3107, 2939, 2856, 2197, 1724, 1610, 1585, 1450, 1383, 1363, 1302, 1234, 1186, 1142, 1097, 962, 851, 800, 760, 665, 609 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 7.76 (d, J = 1.20 Hz, 1 H), 7.73 (dd, J 1 = 8.40 Hz, J 2 = 1.60 Hz, 1 H), 7.50 (d, J = 8.40 Hz, 1 H), 3.87 (s, 3 H), 3.73 (s, 4 H), 1.67 (s, 6 H). 13C NMR (100 MHz, DMSO-d 6): δ = 165.9, 162.8, 150.2, 129.2, 126.0, 123.7, 116.7, 115.6, 110.2, 61.0, 52.2, 47.0, 24.8, 23.1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H17N2O3: 285.1239; found: 285.1238.