Thieme Chemistry Journals Awardees: Where Are They Now? One-Pot Synthesis of Versatile Buckle Units for Click Chemistry: 4,8-Diazacyclononynes (DACNs)

Abstract

Newly designed buckle units for copper-free click chemistry: 4,8-diazacyclononynes (DACNs) were efficiently synthesized with a one-pot procedure from commercially available 2-butyne-1,4-diol. The synthesized DACNs possess versatile connectors for the introduction of functional units and exhibit high click reactivity.

Key words

click chemistry - Huisgen reaction - strained alkyne - ­Nicholas reaction - one-pot synthesis

• References and Notes


For representative reports on cyclooctyne derivatives for copper-free click chemistry, see:
• 1a Agard NJ. Prescher JA. Bertozzi CR. J. Am. Chem. Soc. 2004; 126: 15046
• 1b Codelli JA. Baskin JM. Agard NJ. Bertozzi CR. J. Am. Chem. Soc. 2008; 130: 11486
• 1c Ning X. Guo J. Wolfert MA. Boons G.-J. Angew. Chem. Int. Ed. 2008; 47: 2253
• 1d Debets MF. van Berkel SS. Schoffelen S. Rutjes FP. J. T. van Hest JC. M. van Delft FL. Chem. Commun. 2010; 46: 97
• 1e 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
• 1f Jewett JC. Sletten EM. Bertozzi CR. J. Am. Chem. Soc. 2010; 132: 3688
• 1g 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
• 2a Wittig G. Krebs A. Chem. Ber. 1961; 94: 3260
• 2b Sletten EM. Nakamura H. Jewett JC. Bertozzi CR. J. Am. Chem. Soc. 2010; 132: 11799
• 2c Stöckmann H. Neves AA. Stairs S. Ireland-Zecchini H. Brindle KM. Leeper FJ. Chem. Sci. 2011; 2: 932
• 2d de Almeida G. Sletten EM. Nakamura H. Palaniappan KK. Bertozzi CR. Angew. Chem. Int. Ed. 2012; 51: 2443
• 3 van Geel R. Pruijn GJ. M. van Delft FL. Boelens WC. Bioconjugate Chem. 2012; 23: 392
• 4 Ni R. Mitsuda N. Kashiwagi T. Igawa K. Tomooka K. Angew. Chem. Int. Ed. 2015; 54: 1190

For reports on other cyclononyne derivatives for copper-free click chemistry, see:
• 5a Tummatorn J. Batsomboon P. Clark RJ. Alabugin IV. Dudley GB. J. Org. Chem. 2012; 77: 2093
• 5b Sletten EM. de Almeida G. Bertozzi CR. Org. Lett. 2014; 16: 1634
• 5c Kaneda K. Naruse R. Yamamoto S. Org. Lett. 2017; 19: 1096

DACNs have been utilized for the synthesis of functional materials. See:
• 6a Nakayama A. Nishino S. Otani A. Mera A. Osawa A. Tanino K. Namba K. Chem. Pharm. Bull. 2016; 64: 830
• 6b Mihara N. Yamada Y. Takaya H. Kitagawa Y. Aoyama S. Igawa K. Tomooka K. Tanaka K. Chem. Eur. J. 2017; 23: 7508
• 7 The eluate contained not only 1 but also significant amount of cobalt residues, thus further treatment with silica gel and aminopropylated silica gel was needed to remove them.
• 8 The yield was determined by ¹H NMR spectroscopic analysis with 1,3,5-trimethoxybenzene as an internal standard.
• 9 General Procedure for the One-Pot Synthesis of DACN in 10 mmol Scale: To a solution of 2 (1.03 g, 12.0 mmol) in CH₂Cl₂ (400 mL) was added Co₂(CO)₈ (4.27 g, 12.5 mmol) at 30 °C and stirred for 1.5 h, and then the reaction mixture was diluted with additional CH₂Cl₂ (1 L). The diamine derivative 4a (3.83 g, 10.0 mmol) and BF₃·OEt₂ (5.2 mL, 41 mmol) were sequentially added to the reaction mixture at 30 °C. After confirmation of the consumption of 4a by TLC analysis, silica gel (84 g) was added to the mixture. CAN (16.4 g, 30.0 mmol) was added to the mixture, and stirred at 30 °C for 1.5 h. After confirmation of the consumption of 5a by TLC analysis, to the mixture was added pyridine (3.2 mL, 40 mmol) and aminopropylated silica gel (100 g). After stirring for 1 h, the mixture was filtrated with filter paper using EtOAc as an eluent, and the solvent was removed by rotary evaporator, then CH₂Cl₂ (400 mL), silica gel (12 g), and aminopropylated silica gel (12 g) were added to the residue. The mixture was filtered using CH₂Cl₂ and the solvent was removed under reduced pressure. The crude product was purified by recrystallization from CH₂Cl₂ (10 mL) with slow addition of hexane (100 mL) to afford 3.33 g (77%) of 1a as a colorless crystal. ¹H NMR (300 MHz, CDCl₃): δ = 7.66 (d, J = 8.1 Hz, 4 H), 7.33 (d, J = 8.1 Hz, 4 H), 3.78 (s, 4 H), 3.26 (m, 4 H), 2.44 (s, 6 H), 2.11 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.0, 133.9, 130.1, 127.4, 88.2, 44.8, 41.3, 33.0, 21.6.
• 10 Although Boelens and colleagues reported addition reactions of cellular peptidylcysteines to cyclooctynes, Bertozzi, Boons, and Boelens reported that thiol additions to OCTs, dibenzocyclooctaynes, and DIBACs were not observed in a simple reaction with thiol, respectively: see, ref. 1a, 1c, and 3. To clarify the bioorthogonality of DACNs, control experiments with cellular peptidylcysteines are in progress.
• 11 Cheng and colleagues reported that amine base catalysts, e.g. Hünig base, substantially promote thiol addition reactions of cyclooctynes. Thus, we performed a control experiment of 1a with similar conditions to their report: Sun Y. Ma X. Cheng K. Wu B. Duan J. Chen H. Bu L. Zhang R. Hu X. Deng Z. Xing L. Hong X. Cheng Z. Angew. Chem. Int. Ed. 2015; 54: 5981
• 12 The structure of 13d was determined by X-ray single crystallographic analysis (CCDC 1535839), and the authentic sample of 13e was prepared from 13d. For details, see the Supporting Information.