Lewis Acid Mediated Selective Monohydrolysis of Geminal Diesters: Synthesis of Functionalized Malonic Acid Half Esters

Abstract

Geminal diesters, N-alkyl/aryl-2,2-bis(ethoxycarbonyl)vinylamines, were found to undergo selective hydrolysis in the presence of BF₃·OEt₂ at room temperature to give the corresponding half esters. Neighboring group participation by nitrogen in the hydrolysis was observed. This method is useful for the preparation of highly functionalized malonic acid half esters.

Key words

Lewis acid - boron trifluoride - geminal diesters - hydrolysis - esters

• References and Notes

• 1a Guler MO, Stupp SI. J. Am. Chem. Soc. 2007; 129: 12082
• 1b Drescher M, Hammerschmidt F, Kählig H. Synthesis 1995; 1267
• 2 Iosub V, Haberl AR, Leung J, Tang M, Vembaiyan K, Parvez M, Back TG. J. Org. Chem. 2010; 75: 1612
• 3 Pridmore SJ, Williams JM. J. Tetrahedron Lett. 2008; 49: 7413
• 4 Ryu Y, Scott AI. Tetrahedron Lett. 2003; 44: 7499
• 5 Kanth JV. B, Periasamy M. J. Org. Chem. 1991; 56: 5964
• 6 Baudoux J, Lefebvre P, Legay R, Lasne M.-C, Rouden J. Green Chem. 2010; 12: 252
• 7a Niwayama S, Cho H, Moghaddam MZ, Whittlesey BR. J. Org. Chem. 2010; 75: 3775
• 7b Niwayama S, Cho H. Chem. Pharm. Bull. 2009; 57: 508
• 7c Niwayama S. J. Org. Chem. 2000; 65: 5834
• 7d Durham LJ, McLeod DJ, Cason J. Org. Synth. Coll. Vol. IV 1963; 635
• 8a de María PD, Burgos CA. G, Bargeman G, van Gemert RW. Synthesis 2007; 1439
• 8b Liang X, Lohse A, Bols M. J. Org. Chem. 2000; 65: 7432
• 8c Kedrowski BL. J. Org. Chem. 2003; 68: 5403
• 9a Abaee MS, Sharifi R, Mojtahedi MM. Org. Lett. 2005; 7: 5893
• 9b Corma A, García H. Chem. Rev. 2003; 103: 4307
• 10 Sabitha G, Srividya R, Yadav YS. Tetrahedron 1999; 55: 4015
• 11 Basso A, Banfi L, Riva R, Guanti G. J. Org. Chem. 2005; 70: 575
• 12 Englund EA, Gopi HN, Appella DH. Org. Lett. 2004; 6: 213
• 13 Shapira M, Gutman AL. Tetrahedron: Asymmetry 1994; 5: 1689
• 14 Ilangovan A, Kumar RG. Chem.–Eur. J. 2010; 16: 2938
• 15 McQuaid KM, Long JZ, Same D. Org. Lett. 2009; 11: 2972
• 16 Yamada K, Maekawa M, Akindele T, Nakano M, Yamamoto Y, Tomioka K. J. Org. Chem. 2008; 73: 9535
• 17 Kim BM, So SM. Tetrahedron Lett. 1998; 39: 5381
• 18 Carruthers W, Qureshi M. J. Chem. Soc. C 1970; 2238
• 19 Komatsu H, Iwasawa N, Citterio D, Suzuki Y, Kubota T, Tokuno K, Kitamura Y, Oka K, Suzuki K. J. Am. Chem. Soc. 2004; 126: 16353
• 20 Kaul R, Brouillette Y, Sajjadi Z, Hansford KA, Lubell WD. J. Org. Chem. 2004; 69: 6131
• 21 Mattsson S, Dahlstrom M, Karlsson S. Tetrahedron Lett. 2007; 48: 2497
• 22 Bruice BY. Organic Chemistry . Prentice Hall; Englewood Cliffs: 1995. Chap. 24 §
• 23a Walder JA, Johnson RS, Klotz IM. J. Am. Chem. Soc. 1978; 100: 5156
• 23b Sugiura M, Robvieux F, Kobayashi S. Synlett 2003; 1749
• 23c Bethell D. Advances in Physical Organic Chemistry . Academic Press; New York: 1993. 28 and 17
• 23d Bowden K. Chem. Soc. Rev. 1995; 24: 431
• 24 Compound 6a and 8a both belong to a monoclinic system with space group P2₁/n and P2₁, respectively. Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre [CCDC-832627 (6a) and 832624 (8a)]. The crystal information file (CIF) can be obtained free of charge from www.ccdc.cam.ac.uk/products/csd/request/.
• 25 Half esters of substituted aniline were coupled with some substituted aniline and amino acid methyl esters to obtain novel amide derivatives such as (E)-ethyl 2-(2-bromophenylcarbamoyl)-3-(phenylamino)acrylate and found to show good antibacterial (e.g., E. coli) and antifungal (e.g., C. albicans) activity.
• 26 For details on racemization, isomerization and in situ NMR studies see the Supporting Information.
• 27 Bruice TC, Sturtevant JM. J. Am. Chem. Soc. 1959; 81: 2860
• 28 McCoy PC, Morrow RJ, Edwards CR, Jones DS, Gorman SP. Bioconjugate Chem. 2007; 18: 209
• 29 General procedure for BF₃·OEt₂-mediated hydrolysis of diethyl 2-[(aryl/alkyl-amino)methylene]malonate: To a solution of diethyl 2-[(aryl/alkyl-amino)methylene]-malonate (1.0 equiv) in chloroform (3 × w/v), BF₃·OEt₂ (1.0 equiv) was added and the mixture was stirred at r.t. under a nitrogen atmosphere (the reaction was monitored by TLC). Upon completion, the reaction mixture was quenched with water (1 × w/v) and extracted with chloroform (3 × 5 mL). The combined organic layer was dried (anhyd. Na₂SO₄) and evaporated in a rotary evaporator. The crude product was passed through a short column (silica gel) using a suitable eluent to obtain the corresponding product in 40–92% yield. Preparation of 2-(p-tolylaminomethylene)malonic acid monoethyl ester (2b): The reaction was carried out according to the general procedure using diethyl 2-(p-tolylaminomethylene)malonate¹ (1b; 500 mg, 1.8 mmol), and BF₃·OEt₂ (453 μL, 1.8 mmol) in chloroform (1.5 mL) at r.t. for 20 min. The title compound 2b (0.40 g, 90%) was obtained as a white solid after passing through a short silica gel column (hexane–EtOAc, 9:1). Mp 92 °C; ¹H NMR (400 MHz, CDCl₃): δ = 1.35 (t, J = 7.2 Hz, 3 H), 2.33 (s, 3 H), 4.32 (q, J = 7.2 Hz, 2 H), 7.06 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 8.44 (d, J = 13.6 Hz, 1 H), 11.62 (d, J = 13.2 Hz, 1 H), 13.0 (br s, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 14.3, 20.7, 61.3, 89.0, 177.7, 130.3, 135.9, 136.0, 151.6, 169.9, 170.7; IR (KBr): 3183, 2978, 2688, 1696, 1630, 1512, 1473, 1407, 1268, 1205, 1089, 1017, 887, 831, 811 cm^–1; MS: m/z calcd. for C₁₃H₁₅NO₄: 249.10; found: 250.2 [M + 1]; Anal. Calcd for C₁₃H₁₅NO₄: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.62; H, 6.08; N, 5.60.