PEG/ZnBr₂-Assisted Multicomponent Reactions: A Novel Procedure for the Synthesis of Functionalized 5,6-Dihydropyran-2-ones

Abstract

We report a catalytic multicomponent reaction of isocyanides, oxiranes, and malonates under mild conditions, allowing the transformation of a wide range of substrates into 5,6-dihydropyran-2-one products in acceptable yields. We have also examined the leaving group selectivity using an unsymmetrical malonate. This novel method demonstrates the benefits of combining different activation modes in oxiranes.

Key words

5,6-dihydropyran-2-ones - PEG-400 - oxiranes - isocyanides - malonates - catalytic multicomponent reactions

• References and Notes

• 1 Rao PN. P. Amini M. Li H. Habeeb AG. Knaus EE. J. Med. Chem. 2003; 46: 4872
• 2 McGlacken GP. Fairlamb IJ. S. Nat. Prod. Rep. 2005; 22: 369
• 3 Wang M. Sun M. Hao H. Lu C. J. Nat. Prod. 2015; 78: 3067
• 4 Zhou FS. Tang WD. Mu Q. Yang GX. Wang Y. Liang GL. Lou LG. Chem. Pharm. Bull. 2005; 53: 1387
• 5 Aristoff PA. Drugs Future 1998; 23: 995
• 6 Chad KM. Rajab NF. Ishak MH. A. Ali AM. Yusoff K. Din LB. Inayat-Hussain SH. Chem. Biol. Interact. 2006; 159: 129
• 7 Kikuchi H. Sasaki K. Sekiya J. Maeda Y. Amagai A. Kubohara Y. Oshima Y. Bioorg. Med. Chem. 2004; 12: 3203
• 8 Creech GS. Kwon O. Org. Lett. 2008; 10: 429
• 9 Zhang ML. Wu ZJ. Zhao JQ. Luo Y. Xu XY. Zhang XM. Yuan WC. Org. Lett. 2016; 18: 5110
• 10 Lin L. Kuang Y. Liu X. Feng X. Org. Lett. 2011; 13: 3868
• 11 Fan Q. Lin L. Liu J. Huang Y. Feng X. Zhang G. Org. Lett. 2004; 6: 2185
• 12 Li Y. Hu Y. Zhang S. Sun J. Li L. Zha Z. Wang Z. J. Org. Chem. 2016; 81: 2993
• 13 Dieter RK. Guo F. Org. Lett. 2006; 8: 4779
• 14 Marco JA. Carda M. Murgaband J. Falomir E. Tetrahedron 2007; 63: 2929
• 15 Huang J. Li L. Chen H. Xiao T. He Y. Zhou L. J. Org. Chem. 2017; 82: 9204
• 16 Sil D. Sharon A. Pratap R. Maulik PR. Ram VJ. Synlett 2004; 2163
• 17 Ul Lah H. Rasool F. Yousuf SK. RSC Adv. 2015; 5: 78958
• 18 Schreiber SL. Science 2000; 287: 1964
• 19 Dalpozzo R. Lattanzi A. Pellissier H. Curr. Org. Chem. 2017; 21: 1143
• 20 Kern OT. Motherwell WB. Chem. Commun. 2005; 1787
• 21 Ghazanfarpour-Darjani M. Babapour-Kooshalshahi M. Mousavi-Safavi SM. Akbari-Neyestani J. Khalaj M. Synlett 2016; 27: 259
• 22 Yavari I. Ghazanfarpour-Darjani M. Hossaini Z. Sabbaghan M. Hosseini N. Synlett 2008; 889
• 23 Samzadeh-Kermani A. Synlett 2016; 2213
• 24 Samzadeh-Kermani A. Tetrahedron 2016; 72: 5301
• 25 Samzadeh-Kermani A. Ataeifar S. Monatsh. Chem. 2018; 149: 47
• 26 Tumanov VV. Tishkov AA. Mayr H. Angew. Chem. Int. Ed. 2007; 46: 3563
• 27 Saegusa T. Taka-ishi N. Takami M. Ito Y. Synth. Commun. 1971; 1: 99
• 28 Yamaguchi M. In Comprehensive Organic Synthesis . Vol. 1. Trost BM. Fleming I. Pergamon Press; Oxford: 1991: 342-345
• 29 Ahn KH. Kim JS. Jin CS. Kang DH. Han DS. Shin YS. Kim DH. Synlett 1992; 306
• 30 Karame I. Tommasino ML. Lemaire M. Tetrahedron Lett. 2003; 44: 7687
• 31 5,6-Dihydropyran-2-ones 4; General Procedure A mixture of ZnBr₂ (0.2 mmol, 76 mg), malonate 3 (2.0 mmol) and oxirane 2 (1.0 mmol) in PEG-400 (2.0 mL) was stirred for 40 min at 50 °C. Isocyanide 1 (1.0 mmol) dissolved in PEG-400 (1.0 mL) was added slowly and the mixture was stirred for the appropriate period at 50 °C (see Tables 2 and 3). The crude reaction mixture was diluted with EtOAc (5 mL) and saturated aqueous NH₄Cl (10 mL). The mixture was stirred for an additional 30 min and the two layers were separated. The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, hexane/EtOAc, 5:1 to 2:1) to give pure 4. Methyl 6-Methyl-2-oxo-4-[(2,4,4-trimethylpentan-2-yl)amino]-5,6-di­hydro-2H-pyran-3-carboxylate (4a) Colorless oil; yield: 0.23 g (79%); IR (KBr): 3273, 2971, 1738, 1717, 1460, 1305, 1080 cm^–1. ¹H NMR (500.1 MHz, CDCl₃): δ = 0.98 (s, 9 H, 3 Me), 1.21 (d, ³ J = 5.9 Hz, 3 H, Me), 1.40 (s, 2 H, CH₂), 1.55 (s, 6 H, 2 Me), 2.26 (dd, ² J = 12.8, ³ J = 6.7 Hz, 1 H, CH), 2.41 (dd, ² J = 12.8, ³ J = 10.1 Hz, 1 H, CH), 3.65 (s, 3 H, OMe), 4.99–5.08 (m, 1 H, CH), 11.47 (s, 1 H, NH); ¹³C NMR (125.7 MHz, CDCl₃): δ = 21.2 (Me), 28.1 (2 Me), 32.8 (3 Me), 33.4 (C), 40.6 (CH₂), 55.2 (CH₂), 56.5 (C), 57.2 (OMe), 79.0 (CH), 101.7 (C), 163.1 (C), 167.4 (C), 177.2 (C); ESI-MS: m/z (%) = 297 (1) [M]⁺, 282 (17), 223 (39), 152 (25), 128 (79), 96 (100); Anal. Calcd for C₁₆H₂₇NO₄: C, 64.62; H, 9.15; N, 4.71. Found: C, 64.83; H, 9.32; N, 4.88 Methyl 2-Oxo-6-(phenoxymethyl)-4-[(2,4,4-trimethylpentan-2-yl)amino]-5,6-dihydro-2H-pyran-3-carboxylate (4b) Colorless solid, yield: 0.33 g (84%); mp 44–46 °C; IR (KBr): 3281, 3035, 2983, 1735, 1715, 1480, 1355, 1056 cm^–1; ¹H NMR (500.1 MHz, CDCl₃): δ = 0.94 (s, 9 H, 3 Me), 1.38 (s, 2 H, CH₂), 1.52 (s, 6 H, 2 Me), 2.32 (dd, ² J = 12.1, ³ J = 6.2 Hz, 1 H, CH), 2.41 (dd, ² J = 12.1, ³ J = 10.0 Hz, 1 H, CH), 3.69 (s, 3 H, OMe), 4.41–4.52 (m, 2 H, 2 CH), 5.17–5.26 (m, 1 H, CH), 6.89 (d, ³ J = 6.8 Hz, 2 H, CH), 6.96 (t, ³ J = 6.0 Hz, 1 H, CH), 7.22 (t, ³ J = 6.0 Hz, 2 H, CH), 11.55 (s, 1 H, NH); ¹³C NMR (125.7 MHz, CDCl₃): δ = 31.7 (2 Me), 32.9 (3 Me), 33.4 (C), 41.2 (CH₂), 54.0 (CH₂), 55.3 (C), 57.5 (OMe), 68.5 (CH₂), 81.5 (CH), 102.3 (C), 114.1 (2 CH), 120.8 (CH), 128.2 (2 CH), 159.6 (C), 162.5 (C), 166.8 (C), 176.0 (C); EI-MS: m/z (%) = 389 (4) [M]⁺, 331 (14), 224 (35), 223 (58), 128 (71), 107 (41), 96 (89), 77 (100); Anal. Calcd for C₂₂H₃₁NO₅: C, 67.84; H, 8.02; N, 3.60. Found: C, 68.01; H, 8.19; N, 3.76. Methyl 6-Methyl-2-oxo-6-propyl-4-[(2,4,4-trimethylpentan-2-yl)amino]-5,6-dihydro-2H-pyran-3-carboxylate (4c) Colorless oil; yield: 0.26 g (76%); IR (KBr): 3292, 2972, 1740, 1723, 1478, 1354, 1067 cm^–1; ¹H NMR (500.1 MHz, CDCl₃): δ = 0.88–0.93 (m, 12 H, 4 Me), 1.33–1.40 (m, 4 H, 2 CH₂), 1.45–1.52 (m, 11 H, 3 Me, CH₂), 2.18 (d, ² J = 11.6 Hz, 1 H, CH), 2.35 (d, ² J = 11.6 Hz, 1 H, CH), 3.72 (s, 3 H, OMe), 11.42 (s, 1 H, NH); ¹³C NMR (125.7 MHz, CDCl₃): δ = 15.1 (Me), 18.7 (CH₂), 24.7 (Me), 32.5 (2 Me), 34.1 (3 Me), 34.6 (C), 42.1 (CH₂), 44.7 (CH₂), 53.1 (CH₂), 54.4 (C), 56.8 (OMe), 93.1 (C), 101.6 (C), 162.2 (C), 167.0 (C), 177.8 (C); ESI-MS: m/z (%) = 339 (9) [M]⁺, 324 (18), 281 (27), 223 (48), 152 (69), 128 (81), 96 (100); Anal. Calcd for C₁₉H₃₃NO₄: C, 67.22; H, 9.80; N, 4.13. Found: C, 67.41; H, 9.98; N, 4.21. Dimethyl 2-Methyl-6-oxo-4-[(2,4,4-trimethylpentan-2-yl)amino]-3,6-dihydro-2H-pyran-2,5-dicarboxylate (4d) Pale yellow oil; yield: 0.26 g (72%); IR (KBr): 3289, 2961, 1741, 1732, 1718, 1472, 1338, 1055 cm^–1; ¹H NMR (500.1 MHz, CDCl₃): δ = 0.97 (s, 9 H, 3 Me), 1.41 (s, 2 H, CH₂), 1.53 (s, 6 H, 2 Me), 1.58 (s, 3 H, Me), 2.41 (dd, ² J = 12.0, ³ J = 6.7 Hz, 1 H, CH), 2.57 (dd, ² J = 12.0, ³ J = 9.6 Hz, 1 H, CH), 3.70 (s, 3 H, OMe), 3.75 (s, 3 H, OMe), 11.24 (s, 1 H, NH); ¹³C NMR (125.7 MHz, CDCl₃): δ = 22.4 (Me), 29.9 (2 Me), 32.5 (3 Me), 33.1 (C), 41.5 (CH₂), 53.5 (CH₂), 56.1 (C), 55.5 (OMe), 57.2 (OMe), 85.1 (C), 103.6 (C), 162.1 (C), 166.3 (C), 171.1 (C), 176.7 (C); ESI-MS: m/z (%) = 355 (1) [M]⁺, 284 (24), 228 (31), 170 (48), 128 (71), 110 (100); Anal. Calcd for C₁₈H₂₉NO₆: C, 60.83; H, 8.22; N, 3.94. Found: C, 61.07; H, 8.38; N, 4.15.