Simple Apparatus for Adding Small Amounts of Powder Materials under an Inert Atmosphere

Abstract

Addition of reactants under an inert atmosphere is a fundamental but extremely important technique in synthetic chemistry. Although this is achievable in many cases by using a glove box or a Schlenk-and-syringe technique, the direct addition of powder (solid) materials without contamination by air or moisture has been difficult, especially in the later stages of a reaction. Here, we offer a simple and small apparatus to realize powder addition with easy handling. Use of this apparatus permitted one-pot glycosylation reactions that required extremely dry conditions to be performed in a highly reproducible manner.

Key words

apparatus - powder handling - glycosylation - inert atmosphere - moisture sensitivity

• References and Notes

• 1 M.K. and J.H. contributed equally to this work. M.K.’s new address is the Department of Chemistry, University of California, Irvine, CA 92697-2025, USA.
• 2a Rowan JH. Anal. Chem. 1956; 28: 402
• 2b Shriver FD, Drezdzon MA. The Manipulation of Air-Sensitive Compounds, 2nd ed. Wiley; New York: 1986
• 2c Synthetic Methods of Organometallic and Inorganic Chemistry, Vol. 1. Herrmann WA, Salzer A. Thieme; New York: 1996

Although methods for adding solids by using Schlenk tubes are known, it is difficult to add powder materials without opening the reaction flask, see:
• 3a Millar, S.; Tips and Tricks for the Lab: Air-Sensitive Techniques (1), In ChemistryViews; May 7, 2013: https://www.chemistryviews.org/details/education/3728881/ Tips_and_Tricks_for_the_Lab_Air-Sensitive_Techniques_1.html (accessed Sept. 27, 2019).
• 3b Millar, S.; Tips and Tricks for the Lab: Air-Sensitive Techniques (2), In ChemistryViews; June 4, 2013: https://www.chemistryviews.org/details/education/ 4308331/Tips_and_Tricks_for_the_Lab_Air-Sensitive_Techniques_2.html (accessed Sept. 27, 2019).
• 3c Millar, S.; Tips and Tricks for the Lab: Air-Sensitive Techniques (3), In ChemistryViews; July 2, 2013: https://www.chemistryviews.org/details/education/4360441/Tips_and_Tricks_for_ the_Lab_Air-Sensitive_Techniques_3.html (accessed Sept. 27, 2019).
• 4a Errington RJ. Advanced Practical Inorganic and Metalorganic Chemistry . Blackie Academic and Professional; London: 1997
• 4b Advanced Practical Organic Chemistry, 3rd ed. Leonard J, Lygo B, Procter G. CRC Press; Boca Raton: 2013
• 5 Karak M, Joh Y, Suenaga M, Oishi T, Torikai K. Org. Lett. 2019; 21: 1221 . Note that all the one-pot reactions were conducted by using an SAF
• 6 For a previously developed SAF, see: Bloomfield JJ, Nunamaker H. J. Chem Educ. 1962, 39, 255, Ref. 3, (c) also describes a traditional solid-transfer method. The use of a transfer tube between flasks is an alternative method, but in our hands, the solid often remained in the joint part.
• 7 The authors declare the following competing financial interest: a patent regarding this work is pending (Kyushu University. Japanese Patent Application No. 2018-143585, July 31, 2018; PCT Application No. PCT/JP2019/027788, July 12, 2019).
• 8 Salmasan RM, Manabe Y, Kitawaki Y, Chang T.-C, Fukase K. Chem. Lett. 2014; 43: 956
• 9 Although we monitored the complete consumption of 1 by TLC, a slight amount of 5 (~5%) was formed even in successful cases (e.g., Table 1, entry 5). This might be due to the rise in temperature of the reaction solution in the glass capillary before spotting on the TLC plate, but we did not address the temperature issue further to avoid undesired activation of the 2-O-acyl donor 3.
• 10 Trisaccharide 4 (Table [1], entry 5) In a 10 mL Schlenk flask, compounds 1 (50.6 mg, 84.2 μmol) and 2 (48.1 mg, 84.3 μmol) were dissolved in anhyd toluene (1 mL), and the resultant solution was evaporated to dryness. This process was performed three times to remove water from the reactants as an azeotropic mixture with toluene. The system then was purged with argon. After rapid attachment of our SAF to the flask, the system was purged again with argon and maintained under a positive pressure of argon by using a balloon. Activated powdered 4Å molecular sieves (MS4A; 50.0 mg) were added through the SAF to the reaction mixture. As shown in Step 1 of Figure 2, chamber A (Figure 1) was purged with argon followed by opening of the septum cap and addition of MS4A, which had been pre-activated by microwave irradiation (700 W, 40 s), drying, and cooling in a vacuum (×3). The septum cap was then immediately reattached and chamber A, containing the powdered molecular sieves, was evacuated and purged with argon, as shown in Step 2 of Figure 2. Finally, the powder was added to the flask by turning the handle of the SAF, as shown in Step 3 of Figure 2. After the addition of MS4A, anhyd CH₂Cl₂ (1.0 mL) was added from a branch of the Schlenk tube through a syringe. The reaction mixture was stirred at r.t. for 30 min then cooled to –78 °C, NIS (68.1 mg, 303 μmol) and In(OTf)₃ (141 mg, 251 μmol) were added sequentially through the SAF in an identical manner to the MS4A, as described above. The mixture was then stirred at –78 to –40 °C for 45 min until TLC showed that both 1 and 2 were almost consumed to form the intermediate 3. The mixture was then cooled again to –78 °C and a 1 M solution of Ph(CH₂)₃OH in CH₂Cl₂ (125 μL, 125 μmol) was added through a cannula. The mixture was stirred at –78 to 0 °C for 1 h before the reaction was quenched with Et₃N (140 μL, 1.00 mmol) to pH 10. Sat. aq NaHCO₃ (2 mL) and Na₂S₂O₃ (2 mL) solutions were added and the mixture was stirred at r.t. for 10 min then extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with sat. aq NaCl (2 mL) and dried (Na₂SO₄). The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel, hexane–EtOAc (10:1 to 5:1)] to give compound 4 as a colorless amorphous solid (yield: 58.7 mg, 54.0 μmol, 64%), together with byproduct 5 (yield: 2.5 mg, 4.0 μmol, 5%). For spectroscopic characterization data, see ref. 5.