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.

transesterification - K₂HPO₄ - methyl ester - catalyst

References and Notes

For reviews, see:

<A NAME="RU03510ST-1A">1a</A> Chenevert R. Pelchat N. Jacques F. Curr. Org. Chem.  2006,  10:  1067 

<A NAME="RU03510ST-1B">1b</A> Grasa GA. Singh R. Nolan SP. Synthesis  2004,  971 

<A NAME="RU03510ST-1C">1c</A> Hoydonckx HE. De Vos DE. Chavan SA. Jacobs PA. Top. Catal.  2004,  27:  83 

<A NAME="RU03510ST-1D">1d</A> Otera J. In Esterification   Wiley-VCH; Weinheim: 2003. 

<A NAME="RU03510ST-1E">1e</A> Larock R. In Comprehensive Organic Transformations   2nd ed.:  Wiley; New York: 1996. 

<A NAME="RU03510ST-1F">1f</A> Otera J. Chem. Rev.  1993,  93:  1449 

<A NAME="RU03510ST-1G">1g</A> Mulzer J. In Comprehensive Organic Synthesis   Vol. 6:  Trost BM. Fleming I. Pergamon Press; New York: 1992. 

For recent progress on the catalytic transesterification, see:

<A NAME="RU03510ST-2A">2a</A> Iwasaki T. Maegawa Y. Hayashi Y. Ohshima T. Mashima K. J. Org. Chem.  2008,  73:  5147 

<A NAME="RU03510ST-2B">2b</A> Ishihara K. Niwa M. Kosugi Y. Org. Lett.  2008,  10:  2187 

<A NAME="RU03510ST-2C">2c</A> Kondaiah GCM. Reddy LA. Babu KS. Gurav VM. Huge KG. Bandichhor R. Reddy PP. Bhattacharya A. Anand RV. Tetrahedron Lett.  2008,  49:  106 

<A NAME="RU03510ST-2D">2d</A> Inahashi N. Fujiwara T. Sato T. Synlett  2008,  605 

<A NAME="RU03510ST-2E">2e</A> Ohshima T. Iwasaki T. Maegawa Y. Yoshiyama A. Mashima K. J. Am. Chem. Soc.  2008,  130:  2944 

<A NAME="RU03510ST-2F">2f</A> Remme N. Koschek K. Schneider C. Synlett  2007,  491 

<A NAME="RU03510ST-2G">2g</A> Jiang P. Zhang D. Li Q. Lu Y. Catal. Lett.  2006,  110:  101 

<A NAME="RU03510ST-2H">2h</A> de Sairre MI. Bronze-Uhle ES. Donate PM. Tetrahedron Lett.  2005,  46:  2705 

<A NAME="RU03510ST-2I">2i</A> Singh R. Kissling RM. Letellier M.-A. Nolan SP. J. Org. Chem.  2004,  69:  209 

<A NAME="RU03510ST-3">3</A> Hamada M. Shinada T. Ohfune Y. Org. Lett.  2009,  11:  4664 

<A NAME="RU03510ST-4">4</A> Green TW. Wuts PG. In Protecting Groups in Organic Synthesis   4th ed.:  John Wiley & Sons, Inc.; New York: 2007. 

<A NAME="RU03510ST-5">5</A> Corey EJ. Raju N. Tetrahedron Lett.  1983,  24:  5571 

<A NAME="RU03510ST-6">6</A> Rose NGW. Blaskovich MA. Evindar G. Wilkinson S. Luo Y. Fishlock D. Reid C. Lajoie GA. Org. Synth., Coll. Vol. X   Wiley; New York: 2004.  p.73 

For recent examples, see:

<A NAME="RU03510ST-7A">7a</A> Winkler JD. Fitzgerald ME. Synlett  2009,  562 

<A NAME="RU03510ST-7B">7b</A> Jahn U. Dinca E. Chem. Eur. J.  2009,  15:  58 

<A NAME="RU03510ST-7C">7c</A> Zhdanko AG. Nenajdenko VG. J. Org. Chem.  2009,  74:  884 

<A NAME="RU03510ST-7D">7d</A> Ichige T. Okano Y. Kanoh N. Nakata M. J. Org. Chem.  2009,  74:  230 

<A NAME="RU03510ST-7E">7e</A> Tange S. Fukuhara T. Hara S. Synthesis  2008,  3219 

<A NAME="RU03510ST-7F">7f</A> Codelli JA. Baskin JM. Agard NJ. Bertozzi CR. J. Am. Chem. Soc.  2008,  130:  11486 

<A NAME="RU03510ST-7G">7g</A> Nicolaou KC. Dethe DH. Leung GYC. Zou B. Chen DY.-K. Chem. Asian J.  2008,  3:  413 

<A NAME="RU03510ST-7H">7h</A> Martynow JG. Jozwik J. Szelejewski W. Achmatowicz O. Kutner A. Wisniewski K. Winiarski J. Zegrocka-Stendel O. Golebiewski P. Eur. J. Org. Chem.  2007,  689 

<A NAME="RU03510ST-7I">7i</A> Bowen ME. Monguchi Y. Sankaranarayanan R. Vagner J. Begay LJ. Xu L. Jagadish B. Hruby VJ. Gillies RJ. Mash EA. J. Org. Chem.  2007,  72:  1675 

<A NAME="RU03510ST-7J">7j</A> Raghavan B. Johnson RL. J. Org. Chem.  2006,  71:  2151 

<A NAME="RU03510ST-7K">7k</A> Snider BB. Gao X. Org. Lett.  2005,  7:  4419 

<A NAME="RU03510ST-7L">7l</A> Bernad PL. Khan S. Korshun VA. Southern EM. Shchepinov MS. Chem. Commun.  2005,  3466 

<A NAME="RU03510ST-7M">7m</A> Paek S.-M. Seo S.-Y. Kim S.-H. Jung J.-W. Lee Y.-S. Jung J.-K. Suh Y.-G. Org. Lett.  2005,  7:  3159 

<A NAME="RU03510ST-7N">7n</A> Hansen DB. Wan X. Carroll PJ. Joullie MM. J. Org. Chem.  2005,  70:  3120 

<A NAME="RU03510ST-7O">7o</A> Kai T. Sun X.-L. Faucher KM. Apkarian RP. Chaikof EL. J. Org. Chem.  2005,  70:  2606 

<A NAME="RU03510ST-7P">7p</A> Ichige T. Kamimura S. Mayumi K. Sakamoto Y. Terashita S. Ohteki E. Kanoh N. Nakata M. Tetrahedron Lett.  2005,  46:  1263 

<A NAME="RU03510ST-7Q">7q</A> Giner J. Org. Lett.  2005,  7:  499 

<A NAME="RU03510ST-8">8</A>

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.

<A NAME="RU03510ST-9A">9a</A>

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.

<A NAME="RU03510ST-9B">9b</A>

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).

<A NAME="RU03510ST-9C">9c</A>

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

<A NAME="RU03510ST-10">10</A> Mineno T. Kansui H. Chem. Pharm. Bull.  2006,  54:  918 

<A NAME="RU03510ST-11">11</A>

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.

<A NAME="RU03510ST-12">12</A> The transesterification reaction of methyl esters to other esters using K₂CO₃ has been reported, see: Barry J. Bram G. Petit A. Tetrahedron Lett.  1988,  29:  4567 

<A NAME="RU03510ST-13">13</A> 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