Mild and Catalytic Transesterification Reaction Using K₂HPO₄ for the Synthesis of Methyl Esters

Abstract

K₂HPO₄ is an efficient catalyst for the transesterification reaction to produce methyl esters. Various functional groups are compatible under the mild reaction conditions.

Key words

transesterification - K₂HPO₄ - methyl ester - catalyst

References and Notes

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• 9a

  Transesterification of the Ortho Ester 38 to 40: In a similar manner to the reported method,⁶ 38 was synthesized from Fmoc-Gly-OH in 45% yield (two steps). Analytical data of 38: IR (ATR): 3347, 3066, 2944, 2881, 1722, 1525, 1450, 1402, 1245, 1049, 1004, 910 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 7.3 Hz, 2 H), 7.60 (d, J = 7.3 Hz, 2 H), 7.38 (t, J = 7.3 Hz, 2 H), 7.27 (t, J = 7.3 Hz, 1 H), 5.09 (br s, 1 H), 4.38 (d, J = 6.9 Hz, 2 H), 4.23 (t, J = 6.9, 2 H), 3.92 (s, 6 H), 3.43 (br d, J = 6.0 Hz, 2 H), 0.82 (s, 3 H). HRMS (FAB): m/z [M + H]⁺ calcd for C₂₂H₂₄NO₅: 382.1655; found: 382.1654.

• 9b

  A mixture of 38 (130 mg, 0.33 mmol) in AcOH-THF-H₂O (5:1:1, 0.7 mL) was stirred for 12 h and concentrated under reduced pressure. The remaining AcOH and H₂O were removed as an azeotropic mixture of toluene. The crude 39 was subjected to the next step without purification. Analytical data of 39: ^¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, J = 7.3 Hz, 2 H), 7.60 (d, J = 7.3 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 2 H), 5.45 (br s, 1 H), 4.41 (d, J = 7.1 Hz, 2 H), 4.21-4.25 (m, 3 H), 4.01 (br s, 1 H), 3.55 (br s, 4 H), 0.85 (s, 3 H).

• 9c

  To a solution of 39 in MeOH (3.5 mL) was added K₂HPO₄ (0.11 mmol). The mixture was heated to reflux for 1 h and concentrated under reduced pressure. The crude mixture was diluted with EtOAc-hexane (1:1, 10 mL) and filtered through a thin silica gel pad. The filtrate was concentrated under reduced pressure to give 40 in 94% yield. The analytical data were identical to the authentic data.^¹0

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• 13 Catalytic activity and selectivity of various inorganic salts except for K₂HPO₄ have been evaluated for the transesterification reactions of sunflower oil to produce long-chain fatty acid methyl esters (biodiesel), see: Arzamendi G. Arguinarena E. Campo I. Zabala S. Gandia LM. Catal. Today  2008,  133-135:  305 

8

Typical Synthetic Procedure: To a solution of the N-Cbz-threonine ethyl ester (7; 1 mmol) in MeOH (10 mL) was added K₂HPO₄ (0.1 equiv). The mixture was heated at reflux for 1 h and concentrated under reduced pressure. The crude material was then dissolved in EtOAc-hexane (1:1, 10 mL). The mixture was filtered through a thin silica gel pad. The filtrate was concentrated under reduced pressure to give the N-Cbz-threonine methyl ester(8) in 92% yield.

11

The role of K₂HPO₄ in the mild transesterification reaction has been unclear. In our experiments using various inorganic salts, the reaction rate and product yield were varied and not necessarily dependent on the cationic or anionic nature of inorganic salts.