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TCI Practical Example: Methyl Esterification of Carboxylic Acid Using TMS-Diazomethane

We are proud to present the methyl esterification of the protected serine using TMS-diazomethane as an esterification agent. TMS-diazomethane is safer and easier to handle than diazomethane.

Used Chemicals

• Boc-D-Ser(Bzl)-OH [B1863]
• Trimethylsilyldiazomethane (ca. 10% in Hexane, ca. 0.6mol/L) (= TMS-diazomethane) [T1146]
• Diethyl ether
• Methanol

Procedure

TMS-diazomethane (0.6 mol/L hexane solution, 4.0 mL, 2.4 mmol) was added dropwise for 5 minutes to a stirred solution of Boc-D-Ser(Bzl)-OH (596 mg, 2.02 mmol) in diethyl ether/methanol (7:2, 18 mL) at 0 °C and the mixture was stirred at the same temperature. After 2 hours, TMS-diazomethane (0.4 mL, 0.24 mmol) was added and stirred for further 3 hours. The reaction mixture was allowed to warm to room temperature and concentrated in vacuo to give O-Bn-N-Boc-D-Ser-OMe (625 mg, 100% yield) as a pale brown oil.

Experimenter’s Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 3:1, Rf = 0.52).
Nitrogen gas evolution was observed when TMS-diazomethane was added dropwise.

Analytical Data

O-Bn-N-Boc-D-Ser-OMe

¹H NMR (400 MHz, CDCl₃); δ 7.36-7.26 (m, 5H), 5.40 (brd, J = 8.8 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.42 (td, J = 3.4, 9.2 Hz, 1H), 3.87 (dd, J = 3.2, 9.6 Hz, 1H), 3.74 (s, 3H), 3.68 (dd, J = 3.2, 9.2 Hz, 1H), 1.45 (s, 9H).

¹³C NMR (101 MHz, CDCl₃); δ 171.13, 155.43, 137.49, 128.35 (2C), 127.76, 127.52 (2C), 79.92, 73.14, 69.88, 53.91, 52.39, 28.25 (3C).

Other References

• New Methods and Reagents in Organic Synthesis. 14. A Simple Efficient Preparation of Methyl Esters with Trimethylsilyldiazomethane (TMSCHN₂) and Its Application to Gas Chromatographic Analysis of Fatty Acids
• • N. Hashimoto, T. Aoyama, T. Shioiri, Chem. Pharm. Bull. 1981, 29, 1475.