Synthesis of 3-Benzylphthalide Derivatives by Using a TDAE Strategy

Abstract

A one-pot synthesis of new 3-benzylphthalide derivatives was developed by using a strategy based on tetrakis(dimethylamino)ethylene (TDAE). The reactions in the presence of TDAE of substituted benzyl chlorides with methyl 2-formylbenzoate or of substituted methyl-2-formylbenzoates with 4-nitrobenzyl chloride furnished the corresponding isobenzofuran-1(3H)-one products in moderate to good yields.

Key words

benzylphthalides - methyl formylbenzoate - nitrobenzyl chlorides - isobenzofuranones

Publication History

Received: 17 June 2020

Accepted after revision: 15 October 2020

Accepted Manuscript online:
15 October 2020

Article published online:
12 November 2020

• References and Notes

• 1 Suzuki M, Ueoka R, Takada K, Okada S, Ohtsuka S, Ise Y, Matsunaga S. J. Nat. Prod. 2012; 75: 1192
• 2 Yoshikawa M, Uchida E, Chatani N, Murakami N, Yamahara J. Chem. Pharm. Bull. 1992; 40: 3121
• 3a Karmakar R, Pahari P, Mal D. Chem. Rev. 2014; 114: 6213
• 3b Li Y, Zhang J, Li D, Chen Y. Org. Lett. 2018; 20: 3296
• 3c Renzetti A, Fukumoto K. Molecules 2019; 24: 824
• 3d Tang Y, Meador RI. L, Malinchak CT, Harrison EE, McCaskey KA, Hempel MC, Funk TW. J. Org. Chem. 2020; 85: 1823
• 3e Takakura R, Ban K, Sajiki H, Yoshinari Sawama Y. Synlett 2019; 30: 1919
• 3f Nozawa-Kumada K, Kurosu S, Shigeno M, Kondo Y. Asian J. Org. Chem. 2019; 8: 1080
• 3g Capaldo L, Riccardi R, Ravelli D, Fagnoni M. ACS Catal. 2018; 8: 304
• 3h Mahendar L, Satyanarayana G. J. Org. Chem. 2016; 81: 7685
• 4 Mukherjee S, Roy SC. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2018; 57: 85
• 5a Takechi N, Aït-Mohand S, Médebielle M, Dolbier WR. Jr. Tetrahedron Lett. 2002; 43: 4317
• 5b Pooput C, Médebielle M, Dolbier WR. Jr. Org. Lett. 2004; 6: 301
• 5c Pooput C, Médebielle M, Dolbier WR. Jr. J. Org. Chem. 2006; 71: 3564
• 6a Giuglio-Tonolo G, Terme T, Médebielle M, Vanelle P. Tetrahedron Lett. 2003; 44: 6433
• 6b Giuglio-Tonolo G, Terme T, Médebielle M, Vanelle P. Tetrahedron Lett. 2004; 45: 5121
• 6c Giuglio-Tonolo G, Terme T, Vanelle P. Synlett 2005; 251
• 6d Juspin T, Laget M, Terme T, Azas N, Vanelle P. Eur. J. Med. Chem. 2010; 45: 840
• 6e Khoumeri O, Giuglio-Tonolo G, Crozet MD, Terme T, Vanelle P. Tetrahedron 2011; 67: 6173
• 6f Khoumeri O, Terme T, Vanelle P. Synthesis 2018; 2617
• 6g Montana M, Terme T, Vanelle P. Lett. Org. Chem. 2010; 7: 453
• 6h Roche M, Terme T, Vanelle P. Molecules 2013; 18: 1540
• 7a Amiri-Attou O, Terme T, Vanelle P. Synlett 2005; 3047
• 7b Khoumeri O, Montana M, Terme T, Vanelle P. Tetrahedron 2008; 64: 11237
• 7c Khoumeri O, Terme T, Vanelle P. Tetrahedron Lett. 2012; 53: 2410
• 7d Montana M, Terme T, Vanelle P. Tetrahedron Lett. 2005; 46: 8373
• 7e Montana M, Terme T, Vanelle P. Tetrahedron Lett. 2006; 47: 6573
• 7f Amiri-Attou O, Terme T, Vanelle P. Molecules 2005; 10: 545
• 8 3-Benzyl-2-benzofuran-1(3H)-ones 3a–o; General Procedure The appropriate substituted benzylic chloride 2a–o (1 mmol, 1 equiv) in anhyd THF (15 mL) was added to methyl 2-formylbenzoate (1a; 328 mg, 2 mmol, 2 equiv) under nitrogen in a two-necked flask. TDAE (200 mg, 1 equiv) was added dropwise, and the solution was cooled to –20 °C, maintained at this temperature for 1 h, and then kept at rt for 3 h. The solution was then extracted with EtOAc (3 × 20 mL) and the extracts were washed with brine (3 × 20 mL), dried (MgSO₄), and concentrated. The crude product was purified by chromatography [silica gel, CH₂Cl₂–PE (1:1)] and recrystallized from EtOH. 3-(4-Nitrobenzyl)-2-benzofuran-1(3H)-ones (3a) White solid; yield: 190.99 mg (71%); mp 169 °C. ¹H NMR (250 MHz, DMSO-d ₆): δ = 3.24 (dd, J = 14.3, 7.8 Hz, 1 H, CH₂), 3.63 (dd, J = 14.3, 4.1 Hz, 1 H, CH₂), 5.99 (dd, J = 7.7, 4.1 Hz, 1 H, CH), 7.54 (d, J = 8.7 Hz, 2 H, ArH), 7.59 (t, J = 7.4 Hz, 3 H, ArH), 7.74 (d, J = 7.6 Hz, 1 H, ArH), 8.16 (d, J = 8.6 Hz, 2 H, ArH). ¹³C NMR (62.5 MHz, DMSO-d ₆): δ = 38.9, 80.4, 122.9, 123.2 (2 C), 124.9, 125.4, 129.4, 130.8 (2 C), 134.3, 144.4, 146.4, 149.0, 169.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₂NO₄: 270.0761; found: 270.0763.
• 9a Dhanasekaran S, Bisai V, Unhale RA, Suneja A, Singh VK. Org. Lett. 2014; 16: 6068
• 9b He Y, Cheng C, Chen B, Duan K, Zhuang Y, Yuan B, Zhang M, Zhou Y, Zhou Z, Su YJ, Cao R, Qiu L. Org. Lett. 2014; 16: 6366
• 10 3-(4-Nitrobenzyl)-2-benzofuran-1(3H)-ones 4b–j; General Procedure A two-necked flask equipped with a N₂ inlet was charged with a solution of 4-nitrobenzyl chloride (2a; 171 mg, 1 mmol, 1 equiv) and the appropriate methyl 2-formylbenzoate 1b–j (2 mmol, 1.5 equiv) in anhyd DMF (15 mL) at –20 °C under nitrogen, and then TDAE (200 mg, 1 equiv) was added dropwise. The solution was maintained at –20 °C for 1 h and then kept at rt for 2 h at –20 °C. The product workup was as described above for products 3a–o. 6-Chloro-3-(4-nitrobenzyl)-2-benzofuran-1(3H)-one (4b) White solid; yield: 139.69 mg (46%); mp 157 °C. ¹H NMR (250 MHz, DMSO-d ₆): δ = 3.26 (dd, J = 14.3, 7.8 Hz, 1 H, CH₂), 3.63 (dd, J = 14.3, 4.2 Hz, 1 H, CH₂), 6.00 (dd, J = 7.7, 4.2 Hz, 1 H, CH), 7.53 (d, J = 8.7 Hz, 2 H, ArH), 7.78 (d, J = 8.1 Hz, 1 H, ArH), 7.84 (d, J = 1.6 Hz, 1 H, ArH), 7.87 (dd, J = 8.1, 1.9 Hz, 1 H, ArH), 8.16 (d, J = 8.7 Hz, 2 H, ArH). ¹³C NMR (62.5 MHz, DMSO-d ₆): δ = 39.8, 80.5, 123.2 (2 C), 124.5, 124.9, 127.5, 130.9 (2 C), 134.2, 134.3, 144.2, 146.4, 147.7, 168.1. HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₁₅H₁₄ClN₂O₄: 321.0637; found: 321.0636.