A Highly Efficient Approach for the Synthesis of Novel Trifluoroacetylated Enaminones using DBU as a Base

Abstract

An efficient methodology has been developed for the synthesis of a variety of novel trifluoroacetylated enaminones by using trifluoroacetic anhydride in DCE as solvent and DBU as a base via electrophilic trifluoroacetylation. X-ray crystallographic studies confirmed the trifluoroacetylation and E stereoisomeric form of the novel compounds. The synthetic strategy has the advantage of using an inexpensive and non-toxic base for producing excellent yields. Synthons bearing variety of functional groups may be further extended for the formation of heterocyclic compounds.

Keywords

trifluoroacetylation - electrophilic - enaminones - trifluoroacetic anhydride - DBU

• References and Notes

• 1a Gouverneur V. Muller K. Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications. Imperial College Press; London: 2012
• 1b Begue J.-PD. Biorganic and Medicinal Chemistry of Fluorine . Wiley-VCH; Hoboken: 2008
• 1c Ojima I. Fluorine in Medicinal Chemistry and Chemical Biology . Wiley; Blackwell, Chichester: 2009
• 2a Ladner Y. D’Orly F. Perre C. Silva B.-D. Guyon C. Tatoulian M. Plasma Process. Polym. 2014; 11: 518
• 2b Kimura T. Kasuya MC. Hatanaka K. Matsuoka K. Molecules 2016; 21: 358
• 2c Narita T. Polymer J. 2011; 43: 497
• 3a Theodoridis G. Adv. fluorine Sci. 2006; 2: 121
• 3b Ritter SK. Chem. Eng. News 2012; 90: 10
• 3c Shimizu M. Hiyama T. Angew. Chem. Int. Ed. 2005; 44: 214
• 4a Franz J.-E. Kaufman R.-J. PCT Int. Appl WO 4180394, 1979
• 4b Franz J.-E. Kaufman R.-J. PCT Int. Appl WO 4195983, 1980
• 5 Zhou S. Gu Y. Liu M. Wu C. Zhou S. Zhao Y. Jia Z. Wang B. Xiong L. Yang N. Li Z. J. Agric. Food Chem. 2014; 62: 11054
• 6 Ohno I. Tomizawa M. Aoshima A. Kumazawa S. Kagabu S. J. Agric. Food Chem. 2010; 58: 4999
• 7a Kamitori Y. Hojo M. Masuda R. Fujitani T. Kobuchi T. Nishigaki T. Synthesis 1986; 340
• 7b Hojo M. Masuda R. Okada E. Mochizuki Y. Synthesis 1992; 455
• 7c Moriguchi T. Endo T. J. Org. Chem. 1995; 60: 3523
• 8 Roper WL. Toxicological Profile for Pyridine. Toxic Substances and Disease Registry; US Public Health Service: 1992: 52
• 9a Nikseresht A. Bakavoli M. Bayraq SS. Synth. Commun. 2014; 44: 2662
• 9b Kumari S. Singh H. Khurana JM. Tetrahedron Lett. 2016; 57: 3081
• 9c Rajeswari M. Saluja P. Khurana JM. RSC Adv. 2016; 6: 1307
• 10a Dieter RK. Tetrahedron 1986; 42: 3029
• 10b Junjappa H. Ila H. Asokan CV. Tetrahedron 1990; 46: 5423
• 10c Kolb M. Bi X. Liu Q. Chem. Soc. Rev. 2013; 42: 1251
• 10d Pan L. Liu Q. Synlett 2011; 1073
• 10e Liu Q. Nielsen MB. Krause N. Marek I. Schaumann E. Wirth T. Science of Synthesis Knowledge Updates 2014/2. Georg Thieme; Stuttgart, Germany: 2014. section 24.2.11.3, 245
• 10f Wang L. He W. Yu Z. Chem. Soc. Rev. 2013; 42: 599
• 11 Zhang L. Dong J. Xu J. Liu Q. Chem. Rev. 2016; 116: 287
• 12 Hojo M. Masuda R. Okada E. Yamamoto H. Morimoto K. Okada K. Synthesis 1990; 195
• 13 Barabanov MA. Sevenard DV. Sosnovskikh VY. Russ. Chem. Bull., Int. Ed. 2012; 61: 1646
• 14 Sharma N. Chundawat TS. Mohapatra SC. Bhagat S. Synthesis 2016; 48: 4495
• 15 Sharma N. Chundawat TS. Mohapatra SC. Bhagat S. RSC Adv. 2013; 3: 16336
• 16 Sharma N. Kumari N. Chundawat TS. Bhagat S. RSC Adv. 2017; 7: 10150
• 17 Yang CW. Bai YX. Zhang NT. Zeng CC. Hua LM. Tian HY. Tetrahedron 2012; 68: 10201
• 18 General Procedure for the Synthesis of Trifluoroacetylated Enaminones 3a–s: To a solution of enaminones 2a–s (1 equiv) in DCE (5 mL) was added DBU (2 equiv) under a N₂ atmosphere. TFAA (2.5 equiv) was added dropwise over 10 min, keeping the temperature at 0 °C. When addition was complete, the mixture was allowed to warm slowly to r.t. and stirred for 2 h, monitoring by TLC. After completion of the reaction, the mixture was quenched with aq NaHCO₃, then washed with dilute HCl and finally H₂O. The mixture was extracted with CH₂Cl₂ and the organic layer was dried over anhyd Na₂SO₄. After filtering and concentrating by rotary evaporation, a solid product was obtained that was crystallized from Et₂O–pentane (5%) to give the pure compounds 3a–s. (E)-1-(4-Chlorophenyl)-2-[(cyclohexylamino)(methylthio)methylene]-4,4,4-trifluorobutane-1,3-dione (3l): The compound was obtained as a white solid; mp 108–110 °C; yield: 0.36 g (94%). IR (KBr): 3448, 2933, 1726, 1654, 1574, 1460 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 12.07 (br s, 1 H, NH), 7.75 (t, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 3.95 (s, 1 H, NHCH), 2.19 (s, 3 H, SMe), 1.87–1.90 (m, 3 H), 1.72–1.74 (m, 2 H), 1.55–1.57 (m, 1 H), 1.24–1.46 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 191.17, 174.01 (COCF₃), 167.94, 139.44, 137.82, 130.57, 128.83, 128.64, 128.44, 118.75, 115.88 (COCF₃), 107.74 (=CCOCF₃), 55.21, 33.36, 24.95, 24.16, 19.43 (SMe). ¹⁹F NMR (376 MHz, CDCl₃): δ = –70.68 (s, 3 F, COCF₃). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₉ClF₃NO₂S: 406.0855; found: 406.0853. (E)-4,4,4-Trifluoro-2-1-(4-chlorophenyl)-2[(methylthio)(propylamino)methylene]-1-[3-(trifluoromethyl)phenyl]butane-1,3-dione (3q): The compound was obtained as a white solid; mp 60–62 °C; yield: 0.37 g (95%). IR (KBr): 3418, 2903, 1723, 1621, 1562, 1464 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 11.95 (br s, 1 H, NH), 8.06 (s, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.54 (d J = 7.6 Hz, 1 H), 3.58 (q, J = 6.1 Hz, 2 H), 2.15 (s, 3 H, SMe), 1.65–1.74 (m, 2 H), 1.00 (t, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 190.76, 174.42 (COCF₃), 169.21, 140.03, 132.26, 129.21, 128.08, 125.77, 115.78 (COCF₃), 107.67 (=CCOCF₃), 48.06, 23.14, 18.48 (SMe), 11.29 (Me). ¹⁹F NMR (376 MHz, CDCl₃): δ = –63.73 (s, 3 F, ArCF₃), –71.87 (s, 3 F, COCF₃). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₅F₆NO₂S: 400.0806; found: 400.0801.