Access to 3D Alicyclic Amine-Containing Fragments through Transannular C–H Arylation

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

directed C–H functionalization - fragment based drug discovery - amines - palladium - arylation - microwave - directing group

• 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. Chem. 2013; 78: 9328
• 6d Runyon SP, Kormos CM, Gichinga MG, Mascarella SW, Navarro HA, Deschamps JR, Imler GH, Carroll FI. J. Org. Chem. 2016; 81: 10383
• 6e Jones S, Ahmet J, Ayton K, Ball M, Cockerill M, Fairweather E, Hamilton N, Harper P, Hitchin J, Jordon A, Levy C, Lopez R, McKenzie E, Packer M, Plant D, Simpson I, Simpson P, Sinclair I, Somervaille TC. P, Small H, Spencer GJ, Thomson G, Tonge M, Waddell I, Walsh J, Waszkowycz B, Wigglesworth M, Wiseman DH, Ogilvie D. J. Med. Chem. 2016; 59: 11120
• 6f Harris MR, Li Q, Lian Y, Xiao J, Londregan AT. Org. Lett. 2017; 19: 2450
• 7a Congreve M, Carr R, Murray C, Jhoti H. Drugs Discovery Today 2003; 8: 876
• 7b Palmer N, Peakman TM, Norton D, Rees DC. Org. Biomol. Chem. 2016; 14: 1599
• 8 Lew A, Krutzik PO, Hart ME, Chamberlin RA. J. Comb. 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