An Efficient Approach to α-Aryl β-Amino Esters through 1,2-Aryl Migration of p-Toluenesulfonic Acid Mediated Diazo Decomposition

Abstract

A new method for the synthesis of α-aryl β-amino esters has been developed. The key step in this preparation is the chemoselective 1,2-aryl migration of diazo carbonyl compounds catalyzed by TsOH.

diazo compounds - 1,2-aryl migration - amino acids - hydrogenations - α-aryl β-amino esters

References

For reviews, see:

1a Cole DC. Tetrahedron  1994,  50:  9517 

1b Juaristi E. Quintana D. Escalante J. Aldrichimica Acta  1994,  27:  3 

1c Enantioselective Synthesis of b-Amino Acids   Juaristi E. Wiley-VCH; New York: 1997. 

1d Juaristi E. Lopez-Ruiz H. Current Medical Chemistry  1999,  6:  983 

2 For example, see: Kim S. Lee PH. Lee TA. J. Chem. Soc., Chem. Commun.  1988,  1242 

3 For example, see: Jefford CW. Wang JB. Tetrahedron Lett.  1993,  34:  2911 

4 For example, see: Jefford CW. Wang JB. Tetrahedron Lett.  1993,  34:  3119 

5 For a review on β-peptides, see: Gellman SH. Acc. Chem. Res.  1998,  31:  173 

6 Leonard F. Wajngurt A. Klein M. Smith CM. J. Org. Chem.  1961,  26:  4062 

7 Arvanitis E. Ernst H. Ludwig AL. Robinson AJ. Wyatt PB. J. Chem. Soc. Perkin Trans. 1  1998,  521 

8 Jiang N. Qu Z. Wang J. Org. Lett.  2001,  3:  2989 

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General procedure for the TsOH catalyzed diazo decomposition: To a solution of TsOH (1 mg) in anhydrous CH₂Cl₂ (20 mL) at 0 °C under N₂, was added dropwise a solution of diazo compound in anhydrous CH₂Cl₂ (5 mL). The reaction was complete within 30 min as indicated by TLC check. Solvent was removed by evaporation, and the residue was purified by flash column chromatography to give cis and trans α-aryl-β-enamino esters as a mixture.

10 Cimarelli C. Palmieri G. J. Org. Chem.  1996,  61:  5557 

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General procedure for the hydrogenation of a-aryl-b-enamino esters: To a solution of α-aryl-β-enamino esters (50 mg, cis and trans mixture) in absolute MeOH (25 mL) was added 10% Pd/C catalyst (10 mg). The reaction mixture was stirred for 10 h under 1 atm hydrogen atmosphere. Then catalyst was removed by filtration and solvent was evaporated to give a residue, which was purified by flash column chromatography. 3a: ¹H NMR (200 MHz, CDCl₃): δ 1.13 (t, 3 H), 2.36 (s, 3 H), 3.19-352 (m, 2 H), 3.79-3.86 (q, 1 H), 4.04-4.17 (m, 2 H), 5.13 (t, 1 H), 7.13 (m, 7 H), 7.72 (d, 2 H); ¹³C NMR (50 MHz, CDCl₃): δ 13.88, 21.42, 45.62, 51.72, 61.27, 126.91, 127.82, 127.84, 128.88, 129.68, 135.63, 136.86, 143.40, 172.34; MS m/z (relative intensity): 347 (M⁺, 17%), 118 (100%). 3b: ¹H NMR (200 MHz, CDCl₃) δ 1.18 (t, 3H), 2.42 (s, 3 H), 3.16-3.50 (m, 2H), 3.77-3.81 (m, 1 H), 3.79 (s, 3H), 4.04-4.17 (m, 2 H), 5.07 (t, 1 H), 6.83 (d, 2 H), 7.06 (d, 2 H), 7.29 (d, 2 H), 7.72 (d, 2 H); ¹³C NMR (50 MHz, CDCl₃): δ 13.90, 21.41, 45.67, 50.82, 55.14, 61.18, 114.25, 126.91, 127.60, 128.90, 129.65, 136.90, 143.36, 159.14, 172.56; MS m/z (relative intensity): 377 (M⁺, 10%), 194 (100%). 3c: ¹H NMR (200 MHz, CDCl₃) δ 1.19 (t, 3 H), 2.39 (s, 3 H), 3.21-3.55 (m, 2 H), 3.84-3.91(q, 1 H), 4.04-4.20 (m, 2 H), 5.07 (t, 1 H), 7.20-7.57 (m, 1 1H), 7.71 (d, 2 H); ¹³C NMR (50 MHz, CDCl₃): δ 13.96, 21.45, 45.65, 51.40, 61.39, 126.95, 127.45, 127.60, 128.30, 129.71, 134.60, 136.89, 140.26, 140.82, 143.45, 172.36. m/z (relative intensity): 423 (M⁺, 11%), 240 (100%). 3d: ¹H NMR (200 MHz, CDCl₃) δ 1.17 (t, 3 H), 2.42 (s, 3 H), 3.15-3.50 (m, 2 H), 3.78-3.85 (q, 1 H), 4.04-4.18 (m, 2 H), 5.20 (t, 1 H), 6.92-7.30 (m, 6 H), 7.70 (d, 2 H); ¹³C NMR (50 MHz, CDCl₃): δ 13.87, 21.41, 45.57, 50.92, 61.37, 115.55, 115.98, 126.89, 129.44, 129.60, 129.69, 136.79, 143.47, 172.19. m/z (relative intensity): 365 (M⁺, 24%), 182 (100%). 3e: ¹H NMR (200 MHz, CDCl₃) δ 1.18 (t, 3 H), 2.42 (s, 3 H), 3.20-3.55 (m, 2 H), 3.87-3.94 (q, 1 H), 4.04-4.17 (m, 2 H), 5.13 (t, 1 H), 7.29 (m, 2 H), 7.31-7.56 (m, 4 H), 7.70 (m, 2 H); ¹³C NMR (50 MHz, CDCl₃): δ 13.84, 21.42, 45.44, 51.55, 61.61, 124.74, 124.81, 126.91, 129.42, 131.44, 136.68, 136.78, 143.62, 171.70. m/z (relative intensity): 415 (M⁺, 8%) 184 (100%). 3f: ¹H NMR (200 MHz, CDCl₃) δ 1.22 (t, 3 H), 1.97 (m, 2 H), 2.39 (s, 3 H), 2.83 (t, 2 H), 3.89 (d, 2 H), 4.02-4.20 (m, 4 H), 5.15 (t, 1 H), 7.23 (d, 2 H), 7.68 (d, 2 H); ¹³C NMR (50 MHz, CDCl₃): δ 14.32, 21.40, 23.74, 31.15, 39.35, 59.84, 72.16, 76.36, 76.99, 77.63, 98.03, 127.10, 129.11, 137.59, 142.79, 167.55, 173.76. m/z (relative intensity): 339 (M⁺, 14%), 184 (100%).

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For the α-aryl-β-enamino esters 5f and 6f, the hydrogenation gave a product with the furanyl moiety being partially hydrogenated. The structure of the 3f (Figure) is as follows.

Figure