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Synlett 2017; 28(10): 1219-1223
DOI: 10.1055/s-0036-1588154
DOI: 10.1055/s-0036-1588154
letter
‘Wake-Up Call of A Sleeping Beauty’: Straightforward Synthesis of Functionalized β-(2-Pyridyl) Ketones from 2,6-Lutidine
Further Information
Publication History
Received: 10 February 2017
Accepted after revision: 13 February 2017
Publication Date:
22 March 2017 (online)
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Abstract
β-(2-Pyridyl) ketones are a unique class of heterocycles with valuable physicochemical properties and emerging relevance as pharmacophores. Herein we report a one-step process for the preparation of various substituted β-(2-pyridyl) ketones from the common starting material, 2,6-lutidine. Furthermore, we demonstrate the utility of this building block by synthesizing of a small set of antimalarial natural products.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1588154.
- Supporting Information
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References and Notes
- 1a Martins P, Jesus J, Santos S, Raposo LR, Roma-Rodrigues C, Baptista PV, Fernandes AR. Molecules 2015; 20: 16852-16852
- 1b Kaushik NK, Kaushik N, Attri P, Kumar N, Kim CH, Verma AK, Choi EH. Molecules 2013; 18: 6620-6620
- 1c Baumann M, Baxendale IR. Beilstein J. Org. Chem. 2013; 9: 2265-2265
- 2 Marco-Contelles J, Pérez-Mayoral E, Samadi A, do Carmo Carreiras M, Soriano E. Chem. Rev. 2009; 109: 2652-2652
- 3a Koteeswari P, Sagadevan S, Mani P. Int. J. Phys. Sci. 2013; 8: 1988-1988
- 3b Samuel ID. W, Turnbull GA. Chem. Rev. 2007; 107: 1272-1272
- 3c Wang GT, Mui C, Musgrave CB, Bent SF. J. Am. Chem. Soc. 2002; 124: 8990-8990
- 4a Meister S, Plouffe D, Kuhen K, Bonamy G, Barnes S, Bopp S, Borboa R, Bright A, Che J, Cohen S. Science 2011; 334: 1372-1372
- 4b Eastman RT, Fidock DA. Nat. Rev. Microbiol. 2009; 7: 864-864
- 5 Hoepfner D, McNamara CW, Lim CS, Studer C, Riedl R, Aust T, McCormack SL, Plouffe DM, Meister S, Schuierer S, Plikat U, Hartmann N, Staedtler F, Cotesta S, Schmitt EK, Petersen F, Supek F, Glynne RJ, Tallarico JA, Porter JA, Fishman MC, Bodenreider C, Diagana TT, Movva NR, Winzeler EA. Cell Host Microbe 2012; 11: 654-654 ;and references cited therein
- 6 Scott PM, Van Walbeek W, MacLean WM. J Antibiot. 1971; 24: 747-747
- 7 Oshimi S, Deguchi J, Hirasawa Y, Ekasari W, Widyawaruyanti A, Wahyuni TS, Zaini NC, Shirota O, Morita H. J. Nat. Prod. 2009; 72: 1899-1899
- 8a Press NJ, Taylor RJ, Fullerton JD, Tranter P, McCarthy C, Keller TH, Arnold N, Beer D, Brown L, Cheung R, Christie J, Denholm A, Haberthuer S, Hatto JD. I, Keenan M, Mercer MK, Oakman H, Sahri H, Tuffnell AR, Tweed M, Trifilieff A. J. Med. Chem. 2015; 58: 6747-6747
- 8b Li B, Wei H, Li H, Pereshivko OP, Peshkov VA. Tetrahedron Lett. 2015; 56: 5231-5231
- 8c Crawford JJ, Young WB. WO 2013067277, 2013
- 8d Elsner J, Harris RL, Lee B, Mortensen D, Packard G, Papa P, Perrin-Ninkovic S, Riggs J, Sankar S, Sapienza J. WO 2010062571, 2010
-
9
General Procedure for the Preparation of Weinreb Amide
Method A In a dry round-bottom flask, the corresponding carboxylic acid (1 equiv, 0.5 mmol) was added to a solution of SOCl2 (20 equiv), and stirred under reflux over a period of 5 h. The excess of SOCl2 was then removed under reduced pressure. Under inert atmosphere, the crude residue was taken into CH2Cl2, added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (1.1 equiv) and pyridine (2.2 equiv) at 0 °C (NB: final concentration must not exceed 0.1 mol/L) and slowly warmed to r.t. After completion of the reaction, the crude mixture was diluted with CH2Cl2, and rinsed three times with water. The organic phase was decanted and was washed with a sat. solution of NaHCO3, and neutralized with a solution HCl (1 M) until pH 7. The organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient of eluent from 100% heptane to 100% EtOAc) to afford the corresponding Weinreb amide. Method B Diisopropylethylamine (4 equiv, 0.1 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 equiv were sequentially added to a dry solution of the corresponding carboxylic acid (1 equiv) in CH2Cl2 and stirred for 10 min at r.t. N,O-Dimethylhydroxylamine hydrochloride (2 equiv) was added, and the resulting mixture was stirred until all starting materials were consumed (TLC and LC–MS monitoring). The crude reaction was quenched with a sat. aq NH4Cl solution and extracted with EtOAc. The organic layers were washed with a sat. solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient of eluent from 100% heptane to 100% EtOAc) affording the desired Weinreb amides. See the Supporting Information for full characterization and spectra. - 10a Cernak T, Dykstra KD, Tyagarajan S, Vachal P, Krska SW. Chem. Soc. Rev. 2016; 45: 546-546
- 10b Dai H.-X, Stepan AF, Plummer MS, Zhang Y.-H, Yu J.-Q. J. Am. Chem. Soc. 2011; 133: 7222-7222
- 11 Ke Q, Ferrara E, Radicchi F, Flammini A. Proc. Natl. Acad. Sci. U.S.A. 2015; 112: 7426-7426
- 12a Muir CW, Kennedy AR, Redmond JM, Watson AJ. B. Org. Biomol. Chem. 2013; 11: 3337-3337
- 12b Anderson H, Wang N.-C. Can. J. Chem. 1977; 55: 4103-4103
- 13a Miyabe H, Asada R, Takemoto Y. Org. Biomol. Chem. 2012; 10: 3519-3519
- 13b Nicola T, Schwarzrock D, Keller M, Eberbach W. Tetrahedron 2001; 57: 1771-1771
- 13c Wiles JA, Hashimoto A, Thanassi JA, Cheng J, Incarvito CD, Deshpande M, Pucci MJ, Bradbury J. J. Med. Chem. 2006; 49: 39-39
- 13d Birchler AG, Liu F, Liebeskind LS. J. Org. Chem. 1994; 59: 7737-7737
- 15 A ratio in favor of the enol form compared to the ketone form was observed in the case of carbonyls bearing electron-withdrawing aromatic groups. When reacting in the presence of heteroaromatic rings, such as thiophene, pyridine, and indole rings, the equilibrium was in favor of the ketone form.
- 16 General Procedure for the Preparation of β-Keto-Pyridyls In a 50 mL dry three-neck round-bottom flask was introduced a solution of 2,6-lutidine (2 equiv, 0.09 mmol) in THF under argon. The solution was cooled to –78 °C and a solution of s-BuLi (1.4 M in cyclohexane, 2.3 equiv) was added dropwise to the reaction mixture, which was then stirred for 15–30 min at –78 °C. A solution of the electrophile of choice (1 equiv) in THF was then added dropwise and stirred for 15–60 min at –78 °C. The crude reaction was quenched with a sat. aq NH4Cl solution at –78 °C and allowed to warm up to r.t. The aqueous phase was then extracted three times with EtOAc. The combined organic layers were washed with a sat. solution of NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (gradient of eluent from 100% heptane to 100% EtOAc) to afford the desired products (6a,b, 9 and 9′ series, and 12; for 15 see the Supporting Information). See the Supporting Information for full characterization and spectra. (±)-(4R)-4,8-Dimethyl-1-(6-methylpyridin-2-yl)non-7-en-2-ol (9n) Compound 9n was obtained in 69% yield as a colorless oil. The compound was isolated as a mixture of two diastereoisomers (dr = 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 7.4 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.97 (d, J = 7.3 Hz, 1 H), 5.18–5.06 (m, 1 H), 4.19–4.06 (m, 1 H), 2.96–2.76 (m, 2 H), 2.56 (s, 3 H), 2.13–1.91 (m, 2 H), 1.70 (s, 3 H), 1.62 (s, 3 H), 1.55–1.39 (m, 2 H), 1.34–1.11 (m, 3 H), 0.96 (dd, J = 6.6, 4.7 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.1, 156.7, 136.8, 130.6, 124.4, 120.6, 120.1, 68.6, 68.2, 44.3, 44.2, 43.1, 42.4, 37.5, 36.4, 28.8, 28.3, 25.2, 25.0, 24.9 ppm. LC–MS (t R = 1.00 min for a 2 min run): m/z calcd for [C17H27NO + H+]: 262.4 [M + H]+. (±)-5-(4-Fluorophenyl)-5-hydroxy-6-(6-methylpyridin-2-yl)hexanoic Acid (12) Compound 12 was obtained in 78% yield as a white solid. 1H NMR (400 MHz, (CD3)2SO): δ = 7.49 (t, J = 7.7 Hz, 1 H), 7.40 (dd, J = 8.8, 5.6 Hz, 2 H), 7.09–6.98 (m, 3 H), 6.90 (d, J = 7.6 Hz, 1 H), 3.26–3.08 (m, 2 H), 2.39 (s, 3 H), 2.08 (td, J = 7.8, 2.5 Hz, 2 H), 1.89–1.74 (m, 1 H), 1.67 (td, J = 13.4, 12.5, 4.7 Hz, 1 H), 1.51 (qd, J = 12.3, 7.5 Hz, 1 H), 1.18 (dt, J = 12.0, 5.8 Hz, 1 H) ppm. 13C NMR (101 MHz, (CD3)2SO): δ = 174.37, 161.65, 159.25, 157.89, 156.18, 142.80, 136.82, 127.41/127.34, 121.62, 120.78, 114.16, 113.95, 75.83, 47.93, 41.83, 33.93, 23.85, 18.94 ppm. LC-MS (t R = 0.74 min for a 2 min run): m/z calcd for [C18H20FNO3+H+]: 318.3 [M + H]+. (±)-6,8-Dimethoxy-3-[(6-methyl-pyridin-2-yl)methyl]isochroman-1-one (15) Compound 15 was obtained in 60% yield as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.57 (t, J = 7.5 Hz, 1 H), 7.17 (d, J = 7.4 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.41 (d, J = 2.2 Hz, 1 H), 6.30 (d, J = 2.2 Hz, 1 H), 4.92–4.83 (m, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.36–3.30 (m, 1 H), 3.23–3.12 (m, 1 H), 3.02–2.86 (m, 2 H), 2.57 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.8, 166.3, 162.8, 158.3, 157.7, 143.1, 137.0, 122.4, 119.5, 108.6, 104.1, 98.5, 79.9, 55.8, 55.2, 39.8, 33.3, 24.6 ppm. LC–MS (t R = 0.73 min for a 2 min run): m/z calcd for [C18H19NO4+H+]: 314.3 [M + H]+.
- 17a The work around the design, synthesis and biological evaluation of analogues of cladosporin will be reported in a separated publication.
- 17b Mohapatra DK, Maity S, Rao TS, Yadav JS, Sridhar B. Eur. J. Org. Chem. 2013; 2859-2859
- 17c Zheng H, Zhao C, Fang B, Jing P, Yang J, Xie X, She X. J. Org. Chem. 2012; 77: 5656-5656
For examples of alternative syntheses of related systems, see: