One-Pot Deprotonative Synthesis of Biarylazacyclooctynones

Abstract

Deprotonative formation of biarylazacyclooctynone (BARAC) from the corresponding enol triflate is described. The reaction furnished the azacyclooctynone within one hour at –78 °C. This process could be performed in one pot from the starting ketone to provide a range of BARAC derivatives in moderate to excellent yields. The protocol enabled the gram-scale formation of the BARAC skeleton by reducing the number of reaction steps. Furthermore, the established method was applied to the synthesis of the BARAC derivative bearing a coumarin moiety.

Key words

alkynes - bioorganic chemistry - enolate - one-pot reaction - strained molecules

• References and Notes

• 1a Miller MJ, Wei SH, Parker I, Cahalan MD. Science 2002; 296: 1869
• 1b Blum G, Mullins SR, Keren K, Fonovič M, Jedeszko C, Rice MJ, Sloane BF, Bogyo M. Nat. Chem. Biol. 2005; 1: 203
• 1c Michalet X, Pinaud FF, Bentolita LA, Tsay JM, Doose S, Li JJ, Sundaresan G, Wu AM, Gambhir SS, Weiss S. Science 2005; 307: 538
• 1d Miller EW, Tulyathan O, Isacoff EY, Chang CJ. J. Nat. Chem. Biol. 2007; 3: 263
• 1e Laughlin ST, Baskin JM, Amacher SL, Bertozzi CR. Science 2008; 320: 664
• 1f Chang PV, Prescher JA, Sletten EM, Baskin JM, Miller IA, Agard NJ, Lo A, Bertozzi CR. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 1821
• 1g Sletten EM, Bertozzi CR. Acc. Chem. Res. 2011; 44: 666
• 1h Yao JZ, Uttamapinant C, Poloukhtine A, Baskin JM, Codelli JA, Sletten EM, Bertozzi CR, Popik VV, Ting AY. J. Am. Chem. Soc. 2012; 134: 3720
• 1i McKay CS, Finn MG. Chem. Biol. 2014; 21: 1075
• 1j Agarwal P, Bertozzi CR. Bioconjugate Chem. 2015; 26: 176
• 1k Pickens CJ, Johnson SN, Pressnall MM, Leon MA, Berkland CJ. Bioconjugate Chem. 2018; 29: 686
• 2a Sletten EM, Bertozzi CR. Angew. Chem. Int. Ed. 2009; 48: 6974
• 2b Debets MF, van der Doelen CW. J, Rutjes FP. J. T, van Delft FL. ChemBioChem 2010; 11: 1168
• 2c Jewett JC, Bertozzi CR. Chem. Soc. Rev. 2010; 39: 1272
• 2d Debets MF, van Berkel SS, Dommerholt J, Dirks AJ, Rutjes FP. J. T, van Delft FL. Acc. Chem. Res. 2011; 44: 805
• 2e Dommerholt J, Rutjes FP. J. T, van Delft FL. Top. Curr. Chem. 2016; 374: 16
• 2f Chupakhin EG, Krasavin MY. Chem. Heterocycl. Compd. 2018; 54: 483
• 2g Yoshida S. Bull. Chem. Soc. Jpn. 2018; 91: 1293

BARAC:
• 3a Jewett JC, Sletten EM, Bertozzi CR. J. Am. Chem. Soc. 2010; 132: 3688
• 3b Jewett JC, Bertozzi CR. Org. Lett. 2011; 13: 5937
• 3c Gordon CG, Mackey JL, Jewett JC, Sletten EM, Houk KN, Bertozzi CR. J. Am. Chem. Soc. 2012; 134: 9199

OCT:
• 4a Agard NJ, Prescher JA, Bertozzi CR. J. Am. Chem. Soc. 2004; 126: 15046
• 4b Agard NJ, Baskin JM, Prescher JA, Lo A, Bertozzi CR. ACS Chem. Biol. 2006; 1: 644

DIBO:
• 5a Ning X, Guo J, Wolfert MA, Boons GJ. Angew. Chem. Int. Ed. 2008; 47: 2253
• 5b Mbua NE, Guo J, Wolfert MA, Steet R, Boons GJ. ChemBioChem 2011; 12: 1912
• 5c Sanders BC, Friscourt F, Ledin PA, Mbua NE, Arumugam S, Guo J, Boltje TJ, Popik VV, Boons GJ. J. Am. Chem. Soc. 2011; 133: 949
• 5d Terzic V, Pousse G, Méallet-Renault R, Grellier P, Dubois J. J. Org. Chem. 2019; 84: 8542

DIFO:
• 6a Ref 4b.
• 6b Baskin JM, Prescher JA, Laughlin ST, Agard NJ, Chang PV, Miller IA, Lo A, Codelli JA, Bertozzi CR. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 16793
• 6c Codelli JA, Baskin JM, Agard NJ, Bertozzi CR. J. Am. Chem. Soc. 2008; 130: 11486
• 6d Sletten EM, Nakamura H, Jewett JC, Bertozzi CR. J. Am. Chem. Soc. 2010; 132: 11799

BCN:
• 7a Dommerholt J, Schmidt S, Temming R, Hendriks LJ. A, Rutjes FP. J. T, van Hest JC. M, Lefeber DJ, Friedl P, van Delft FL. Angew. Chem. Int. Ed. 2010; 49: 9422
• 7b Leunissen EH. P, Meuleners MH. L, Verkade JM. M, Dommerholt J, Hoenderop JG. J, van Delft FL. ChemBioChem 2014; 15: 1446

DIBAC:
• 8a Debets MF, Van Berkel SS, Schoffelen S, Rutjes FP. J. T, van Hest JC. M, van Delft FL. Chem. Commun. 2010; 46: 97
• 8b Kuzmin A, Poloukhtine A, Wolfert MA, Popik VV. Bioconjugate Chem. 2010; 21: 2076
• 8c Campbell-Verduyn LS, Mirfeizi L, Schoonen AK, Dierckx RA, Elsinga PH, Feringa BL. Angew. Chem. Int. Ed. 2011; 50: 11117
• 8d Chadwick RC, Van Gyzen S, Liogier S, Adronov A. Synthesis 2014; 46: 669 . A scalable synthesis of DIBAC was reported in the literature;^8d however, the authors reported that this method was not effective for the synthesis of BARACs 6b and 6d

DIMAC:
• 9a Sletten EM, Bertozzi CR. Org. Lett. 2008; 10: 3097

Sondheimer diyne:
• 9b Orita A, Hasegawa D, Nakano T, Otera J. Chem. Eur. J. 2002; 8: 2000
• 9c Kii I, Shiraishi A, Hiramatsu T, Matsushita T, Uekusa H, Yoshida S, Yamamoto M, Kudo A, Hagiwara M, Hosoya T. Org. Biomol. Chem. 2010; 8: 4051
• 9d Lau YH, Wu Y, Rossmann M, Tan BX, de Andrade P, Tan YS, Verma C, McKenzie GJ, Venkitaraman AR, Hyvönen M, Spring DR. Angew. Chem. Int. Ed. 2015; 54: 15410

DACN:
• 9e Ni, R.; Mitsuda, N.; Kashiwagi, T.; Igawa, K.; Tomooka, K. Angew. Chem. Int. Ed. 2015, 54, 1190. TMTH:
• 9f de Almeida G, Sletten EM, Nakamura H, Palaniappan KK, Bertozzi CR. Angew. Chem. Int. Ed. 2012; 51: 2443

PYRROC:
• 9g Gröst C, Berg T. Org. Biomol. Chem. 2015; 13: 3866

SNO-OCT:
• 9h Burke EG, Gold B, Hoang TT, Raines RT, Schomaker JM. J. Am. Chem. Soc. 2017; 139: 8029
• 10a Hioki Y, Okano K, Mori A. Chem. Commun. 2017; 53: 2614
• 10b Hioki Y, Yukioka T, Okano K, Mori A. Asian J. Org. Chem. 2018; 7: 1298
• 11 Experimental Procedures and Characterization Data A flame-dried 500 mL two-necked flat-bottomed flask equipped with a Teflon-coated magnetic stirring bar, a rubber septum, and an inlet adapter with a three-way stopcock was charged with ketolactam 4a (1.65 g, 6.56 mmol) and PhNTf₂ (2.35 g, 6.56 mmol) in THF (39 mL). After the resulting solution was cooled to –78 °C, KHMDS (0.50 M in toluene, 32.8 mL, 16 mmol) was added dropwise over 6 min. After stirring at –78 °C for 1 h, the reaction mixture was treated with water (80 mL) and diluted with diethyl ether (30 mL). The mixture was allowed to warm to room temperature for 15 min. The aqueous layer was extracted twice with diethyl ether (2 × 15 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane/diethyl ether = 1:3) to afford N-methyl BARAC 6a (1.45 g, 6.22 mmol, 95%) as a brown solid. R_f = 0.38 (hexane/diethyl ether = 1:3); mp decomp. (120 °C). IR (ATR): 2924, 1657, 1468, 1447, 1333, 1214, 1180, 1079, 1039, 761, 715, 630 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.65–7.58 (m, 2 H), 7.50–7.35 (m, 6 H), 2.73 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.9, 156.6, 149.4, 130.0, 129.5, 129.4, 128.9, 128.2, 127.6, 126.5, 125.6, 122.31, 122.27, 109.5, 108.7, 38.8. HRMS (DART⁺): m/z calcd for C₁₆H₁₂NO: 234.0919 [M + H]⁺; found: 234.0928.
• 12 Chigrinova M, McKay CS, Beaulieu L.-PB, Udachin KA, Beauchemin AM, Pezacki JP. Org. Biomol. Chem. 2013; 11: 3436
• 13 Cao Y, Galoppini E, Reyes PI, Lu Y. Langmuir 2013; 29: 7768