Synlett, Table of Contents CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 417-422DOI: 10.1055/s-0037-1610861 letter Copyright with the author Access to 3D Alicyclic Amine-Containing Fragments through Transannular C–H Arylation Melissa Lee a Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, USA Email: mssanfor@umich.edu , Ashley Adams b Discovery Chemistry and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA , Philip B. Cox b Discovery Chemistry and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA , Melanie S. Sanford * a Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, USA Email: mssanfor@umich.edu › Author Affiliations Recommend Article Abstract All articles of this category Abstract In this Letter, we adapt a recently reported Pd-catalyzed transannular C(sp3)–H arylation of alicyclic amines for applications in fragment-based drug discovery (FBDD). We apply this method to the synthesis of a series of 6-arylated 3-azabicyclo[3.1.0]hexanes that are rule-of-three compliant fragments. Several modifications were made to the Pd-catalyzed C–H arylation method to enhance its utility in fragment synthesis. These include the use of microwave heating to shorten reaction times to under 1 h and the development of new approaches for directing group cleavage. Finally, we demonstrate that this fragment library falls within desirable physicochemical space for FBDD applications. Key words Key wordsdirected C–H functionalization - fragment based drug discovery - amines - palladium - arylation - microwave - directing group Full Text References References and Notes 1a Topczewski JJ, Cabrera PJ, Saper NI, Sanford MS. Nature 2016; 531: 220 1b Cabrera PJ, Lee M, Sanford MS. J. Am. Chem. Soc. 2018; 140: 5599 2 Daugulis O, Roane J, Tran LD. Acc. Chem. Res. 2015; 48: 1053 For papers and reviews on FBDD, see: 3a Hann MM, Leach AR, Harper G. J. Chem. Inf. Comput. Sci. 2001; 41: 856 3b Leach AR, Hann MM. Curr. Opin. Chem. Biol. 2011; 15: 489 3c Scott DE, Coyne AG, Hudson SA, Abell C. Biochemistry 2012; 51: 4990 3d Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H. Nat. Rev. Drug Discovery 2016; 15: 605 3e Johnson CN, Erlanson DA, Jahnke W, Mortenson PN, Rees DC. J. Med. Chem. 2018; 61: 1774 4a Lawrence SA. Amines: Synthesis, Properties and Applications . Cambridge University Press; Cambridge: 2004 4b Dorwald FZ. Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds. Wiley-VCH; Weinheim: 2012 4c Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257 5a Murray CW, Rees DC. Angew. Chem. Int. Ed. 2016; 55: 488 5b Foley DJ, Nelson A, Marsden SP. Angew. Chem. Int. Ed. 2016; 55: 13650 5c Morely AD, Pugliese A, Birchall K, Bower J, Brennan P, Brown N, Chapman T, Drysdale M, Gilbert IH, Hoelder S, Jordan A, Ley SV, Merritt A, Miller D, Swarbrick ME, Wyatt PG. Drug Discovery Today 2013; 18: 1221 6a Epstein JW, Brabander HJ, Fanshawe WJ, Hofmann CM, McKenzie TC, Safir SR, Osterberg AC, Cosulich DB, Lovell FM. J. Med. Chem. 1981; 24: 481 6b Lunn G, Roberts EL, Content S, Critcher SD, Fenwick AE, Gethin DM, Goodwin G, Greenway D, Greenwood S, Hall K, Thomas M, Thompson S, Williams D, Wood G, Wylie A. Bioorg. Med. Chem. Lett. 2012; 22: 2200 6c Bakonyi B, Furegati M, Kramer C, Vecchia LL, Ossola F. J. Org. 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Chem. 2002; 4: 95 9 General Procedure for Arylation of S-1To a large microwave tube (Biotage®, 10–20 mL) equipped with a stir bar was added Pd(OAc)2 (23.4 mg, 0.10 mmol, 10 mol%), S-1 (400 mg, 1.04 mmol, 1 equiv), cesium pivalate (731 mg, 3.12 mmol, 3 equiv), aryl iodide (2–3 equiv), and anhydrous tert-amyl alcohol (9.6 mL). The cap was crimped, and the vessel was flushed with nitrogen. The microwave tube was heated with the following parameters: 1 min pre-stirring, followed by a ramp (normal) to 180 °C, and held at temperature for 30–50 min. Hydrazine (500 μL of 35% aq) was added to the reaction and allowed to stir at 60 °C for 1 h or at room temperature overnight. The tert-amyl alcohol was removed in vacuo, and the resulting residue was dissolved in EtOAc, filtered through a plug of Celite, and concentrated under vacuum. The crude reaction was purified via flash column chromatography, eluting with EtOAc/heptanes. Isolated yield of compound 2: 42% (210.2 mg). LC-MS: APCI+: m/z [M + H]+ calcd for C22H19F8N2O: 479.129; found: 479.119. 1H NMR (CDCl3, 500 MHz): δ = 7.27 (m, 2 H), 6.78 (t, J = 8.5 Hz, 2 H), 6.48 (br s, 1 H), 2.94 (d, J = 9.0 Hz, 2 H), 2.89 (ddd, J = 9.0, 2.0 Hz, 1.0 Hz, 2 H), 2.04 (t, J = 8.0 Hz, 1 H), 1.87 (m, 2 H), 1.14 (s, 6 H). 13C NMR (CDCl3, 126 MHz): δ = 175.7, 161.1 (d, J C–F = 246 Hz), 133.7, 129.6 (d, J C–F = 7.6 Hz) Hz), 61.1, 45.1, 27.1, 22.2, 20.9. 20.1. The carbon resonances of the directing group (perfluoroarene, C7F7) appear as complex multiplets and are not listed. 19F NMR (CDCl3, 376 MHz): δ = –56.1 (t, J = 21.8 Hz, 3 F), –116.4 (m, 1 F), –141.4 (m, 2 F), –143.1 (m, 2 F). 10 Kimbrough R, Gaines TR. Nature 1966; 211: 146 11 McDonald CE, Ramsey JD, Sampsell DG, Butler JA, Cecchini MR. Org. Lett. 2010; 12: 5178 12 General Procedure for Directing Group Removal with SmI2 To a round-bottom flask under a flow of nitrogen was added the starting material (1 equiv), 0.1 M SmI2 (12 equiv), anhydrous triethylamine (80 equiv), anhydrous methanol (40 equiv), and tris(N,N-tetramethylene)phosphoric acid triamide (5.5 equiv). The reaction was allowed to stir at room temperature for 3 h. The reaction vessel was then exposed to air, and a white precipitate was observed within 30 min. The reaction was quenched with 1 N HCl. To this mixture was added ethyl acetate, and the product was extracted into the aqueous acidic layer. The organic layer was set aside, and the aqueous layer was basified with solid NaOH until pH 11–12. The aqueous layer was extracted with ethyl acetate (3 × 100 mL) and dried over sodium sulfate. After the volatiles were removed, a viscous yellow oil remained and was purified by reverse-phase HPLC (Waters XBridge™ C-18 column, 5 μm, 30 × 100 mm, flow rate 40 mL/min, 5–100% gradient of acetonitrile in buffer (0.025 M aq ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide or 0.1% TFA)). Isolated yield of compound 2A: 49% (57.9 mg). LC-MS: APCI+: m/z [M + H]+ calcd for C11H13FN: 178.103; found: 178.069. 1H NMR (CDCl3, 400 MHz): δ = 10.85 (br s, 1 H), 7.19 (t, J = 8.4 Hz, 2 H), 7.08 (t, J = 8.4 Hz, 2 H), 5.94 (br s, 1 H), 3.58 (d, J = 11.2 Hz, 2 H), 3.30 (d, J = 11.2 Hz, 2 H), 2.39 (t, J = 8.0 Hz, 1 H), 2.22 (m, 2 H). 13C NMR (CDCl3, 101 MHz): δ = 162.6 (d, J C–F = 249 Hz), 131.2 (d, J C–F = 8.1 Hz), 127.2 (d, J C–F = 3.0 Hz), 116.9 (d, J C–F = 22.2 Hz), 45.0, 23.3. 22.0. 19F NMR (CDCl3, 376 MHz): –75.8 (s, 3 F), –113.2 (s, 1 F). 13 Low yields for the directing group removal procedure with SmI2 are attributed to the double extraction process carried out before the reverse-phase HPLC purification. 14a Procter DJ, Flowers RA, Skrydstrup F. Organic Synthesis Using Samarium Diiodide: A Practical Guide . Royal Society of Chemistry; Cambridge: 2010 15a Kamochi Y, Kudo T. Heterocycles 1993; 36: 2383 15b Kuishima M, Hoiki K, Kono K, Takayuki S, Tani S. Chem. Pharm. Bull. 1994; 42: 2190 16 Dave PR, Kumar KA, Duddu R. J. Org. Chem. 2000; 65: 1207 17 General Procedure for Directing Group Removal with Acetyl ChlorideTo a medium microwave tube (Biotage®, 2–5 mL vial) equipped with a stir bar was added the starting material (0.217 mmol, 1 equiv) and acetyl chloride (neat, 3.0 mL). The reaction was heated to 150 °C for 3 h. The acetyl chloride was removed under reduced pressure, and the product was redissolved in DCM (10 mL). NaOH (1 M, 10 mL) was added. The product was extracted with DCM (2 × 10 mL). The volatiles were removed in vacuo, and the product was purified by reverse-phase HPLC. Isolated yield of compound 1B: 25% yield (11 mg). LC-MS: APCI+: m/z [M + H]+ calcd for C13H16NO: 202.123; found: 202.153. 1H NMR (CDCl3, 400 MHz): δ = 7.30 (t, J = 7.6 Hz, 2 H), 7.21 (multiple peaks, 3 H), 4.92 (d, J = 12.4 Hz, 1 H), 3.59 (dd, J = 11.0, 4.0 Hz, 1 H), 3.32 (d, J = 11.0 Hz, 1 H), 3.39 (dd, J = 12.4, 4.0 Hz, 1 H), 2.23 (t, J = 8.0 Hz, 1 H), 1.97 (m, 2 H), 1.47 (s, 3 H). Hindered rotation of acetyl group breaks symmetry of molecule. 13C NMR (CDCl3, 101 MHz): δ = 168.9, 133.8, 128.8, 128.5, 126.9, 46.8, 44.6, 22.5, 21.6, 20.6, 20.1. 18 Physicochemical properties were calculated using ChemAxon (ChemAxon Component collection for Pipeline Pilot version 1.9_j55) for cLogD and BioVia’s Pipeline Pilot version 9.1 calculators for NRB, NAR, HBA, HBD, MW, TPSA, N+O, Fsp3, NPR, and PBF, with minor customization as needed. Additionally we used BioByte’s cLogP calculator for calculating the octanol–water partition coefficient. Additional calculations and visualizations were conducted using PerkinElmer’s Tibco Spotfire. 19 Sauer WH. B, Schwarz MK. J. Chem. Inf. Comput. Sci. 2003; 43: 987 20 Firth NC, Brown N, Blagg J. J. Chem. Inf. Model. 2012; 52: 2516 Supplementary Material Supplementary Material Supporting Information
