A Versatile Synthesis of α-Amino Acid Derivatives via the Ugi Four-­Component Condensation with a Novel Convertible Isonitrile

Abstract

The Ugi four-component condensation (4CC) reaction with the carbonate-type isonitrile 9 proceeded smoothly, and subsequent base treatment of the Ugi products 10 provided the N-acyloxazolidinones 11 in high yield. The N-acyloxazolidinones derivatives can be reacted with several hetero-nucleophiles, namely, reaction of 11 with thiolates gave thiol ester derivatives 16 efficiently.

Ugi four-component condensation (4CC) - α-amino acid derivatives - convertible isonitrile - N-acyloxazolidinones - thiol esters

References

For reviews of multicomponent reactions with isonitriles, see:

1a Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 

1b Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

1c Gokel G. Lüdke G. Ugi I. In Isonitrile Chemistry   Ugi I. Academic; New York: 1971.  p.145-199  

2a Ugi I. Myer R. Fetzer U. Steinbrückner C. Angew. Chem.  1959,  71:  386 

2b Ugi I. Steinbrückner C. Angew. Chem.  1960,  72:  267 

3a Endo A. Yanagisawa A. Abe M. Tohma S. Kan T. Fukuyama T. J. Am. Chem. Soc.  2002,  124:  6552 

3b Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3200 

4a For a recent example of the stereoselective Ugi 4CC reaction using a chiral amine component, see: Ross GF. Herdtweck E. Ugi I. Tetrahedron  2002,  58:  6127 ; and references therein

4b Recently, the first example of catalytic asymmetric α-addition of isonitrile to an aldehyde was reported, see: Denmark SE. Fan Y. J. Am. Chem. Soc.  2003,  125:  7825 

5a Keating TA. Armstrong RW. J. Am. Chem. Soc.  1996,  118:  2574 

5b Strocker AM. Keating TA. Tempest PA. Armstrong RW. Tetrahedron Lett.  1996,  37:  1149 

6 Lindhorst T. Bock H. Ugi I. Tetrahedron  1999,  55:  7411 

7 Geller J. Ugi I. Chem. Scr.  1983,  22:  85 

8 Mjalli AMM. Sarshar S. Baiga TJ. Tetrahedron Lett.  1996,  37:  2943 

9 Linderman RJ. Binet S. Petrich SR. J. Org. Chem.  1999,  64:  336 

10a For the use of N-tert-butoxycarbonylation to activate amides, see: Flynn DL. Zelle RE. Grieco PA. J. Org. Chem.  1983,  48:  2425 

10b For its application to the Ugi 4CC reaction, see: Hulme C. Ma L. Cherrier M.-P. Romano JJ. Morton G. Tetrahedron Lett.  2000,  41:  1883 

For the use of N-nitrosation to activate amides, see:

11a White EH. J. Am. Chem. Soc.  1955,  77:  6011 

11b Evans DA. Carter PH. Dinsmore CJ. Barrow JC. Katz JI. Kung DW. Tetrahedron Lett.  1997,  38:  4535 

11c Berenguer R. Garcia J. Vilarrasa J. Synthesis  1989,  305 

11d For its applications to the Ugi 4CC reaction, see: Isenring HP. Hofheinz W. Synthesis  1981,  385 

11e Also see: Isenring HP. Hofheinz W. Tetrahedron  1983,  39:  2591 

12

Synthesis of Isonitrile 9: To a stirred solution of 4,4-dimethyloxazoline (0.997 g, 10.1 mmol) in THF (10 mL) under Ar atmosphere at -78 °C, was added dropwise n-BuLi (1.1 M solution in hexane, 9.60 mL, 10.6 mmol) in a duration of 5 min and stirred at same temperature for 1 h followed by dropwise addition of phenyl chloroformate (1.40 mL, 10.7 mmol). After stirring for 5 min, the reaction mixture was warmed to ambient temperature and diluted with Et₂O, and water was added to the mixture. The organic layer was separated and washed with brine, dried over Na₂SO₄ and filtered. The solvent was removed under reduced pressure, the resulting residue was purified by silica gel chromatography (EtOAc-hexane = 1:9-1:4) to afford 1.10 g of 9 (49.7%). IR (film): 2991, 2136, 1767, 1592, 1496, 1457, 1401, 1378, 1258, 1074, 1024, 970, 879, 835, 775, 735 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.45-7.19 (m, 5 H), 4.21 (s, 2 H), 1.53 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.1, 153.1, 150.8, 129.4, 126.1, 120.8, 72.9, 56.1, 25.6. HRMS (FAB): m/z calcd for C₁₂H₁₃NO₃: 219.0895; found: 219.0900.

13 Meyers AI. Collington EW. J. Am. Chem. Soc.  1970,  92:  6676 

14

General Procedure for the Ugi 4CC with Isonitrile 9, Synthesis of 10a: To a stirred solution of isonitrile 9 (223 mg, 1.02 mmol), isobutylaldehyde (0.310 mL, 3.40 mmol), and benzoic acid (128 mg, 1.05 mmol) in MeOH (3.5 mL, 0.19 M) was added dropwise benzylamine (74 µL, 0.68 mmol) within 2 min at ambient temperature. After stirring for 60 min, the solvent was removed under reduced pressure. The resultant crude mixture was purified by silica gel chromatography (EtOAc-hexane = 1:9-1:2) to afford 310 mg of 10a (91%) as a pale yellow foam. IR (film): 3301, 3063, 2968, 1764, 1680, 1620, 1545, 1496, 1457, 1367, 1263, 1211, 1066, 963, 918, 774, 734 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.60-7.05 (m, 15 H), 4.67 (d, J = 16 Hz, 1 H), 4.45 (m, 2 H), 4.29 (d, J = 11 Hz, 2 H), 2.80 (m, 1 H), 1.36 (m, 6 H), 1.02 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.0, 170.2, 153.6, 151.1, 136.6, 136.5, 129.8, 129.5, 128.5, 128.4, 127.8, 127.7, 126.7, 126.0, 121.0, 76.7, 72.1, 54.0, 52.8, 27.2, 24.3, 23.8, 19.8, 19.5. HRMS (FAB): m/z calcd for C₃₀H₃₄N₂O₅: 502.2468; found: 502.2485.

15

General Procedure for the Synthesis of N -Acyloxazol-idinones, Synthesis of 11a: To a stirred solution of 10a (220 mg, 0.44 mmol) in anhyd THF (2.0 mL, 0.22 M) at 0 °C was added freshly activated MS 4 Å (powder, 280 mg), and stirred for 10 min, followed by dropwise addition of 1.0 M t-BuOK in t-BuOH (0.45 mL, 0.45 mmol) in a duration of
2 min. After stirring for 5 min, 10% aq citric acid was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO₄ and filtered. The solvent was removed under reduced pressure, the resultant crude mixture was purified by silica gel chromatography (EtOAc-hexane = 1:9-1:2) to afford 11a (149 mg, 83%) as a pale yellow foam. IR (film): 2968, 2360, 1779, 1701, 1646, 1496, 1374, 1305, 1231, 1173, 1089, 1031, 761, 734 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.36-7.19 (m, 10 H), 5.63 (m, 1 H), 4.88 (m, 2 H), 3.94 (m, 2 H), 2.43 (m, 1 H), 1.49 (s, 3 H), 1.33 (s, 3 H), 0.93 (d, J = 15 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.8, 173.9, 172.3, 152.9, 138.7, 136.7, 129.6, 128.6, 128.3, 128.2, 127.4, 126.8, 126.3, 75.1, 61.0, 29.5, 24.3, 23.8, 19.4, 18.6. HRMS (FAB): m/z calcd for C₂₄H₂₈N₂O₄: 408.2049; found: 408.2033.

16

In the absence of MS 4 Å, the reaction resulted in low yields, accompanied by the N-acylamino alcohols 12 and/or carboxylic acid 13 (Figure [2] ).

17 Evans DA. Bartroli J. Shih TL. J. Am. Chem. Soc.  1981,  103:  2127 

18 For recent examples, see: Orita A. Nagano Y. Hirano J. Otera J. Synlett  2001,  637 ; and the detailed references cited therein

For C-N bond cleavage in N-acyl-4,4-dimethyl-2-oxazolidinones, see:

19a MeOMgBr: Chevliakov MV. Montgomery J. J. Am. Chem. Soc.  1999,  121:  11139 

19b Me(OMe)₂: Kanemasa S. Kanai T. J. Am. Chem. Soc.  2000,  122:  10710 

19c Sm(OTf)₃-MeOH: Sibi MP. Gorikunti U. Liu M. Tetrahedron  2002,  58:  8357 

19d NaOH-t-BuOH: Ito Y. Terashima S. Tetrahedron  1991,  47:  2821 

20a Tokuyama H. Yokoshima S. Lin S.-C. Li L. Fukuyama T. Synthesis  2002,  1121 

20b Tokuyama H. Yokoshima S. Yamashita T. Fukuyama T. Tetrahedron Lett.  1998,  39:  3189 

21a Nishide K. Ohsugi S. Shiraki H. Tamakita H. Node M. Org. Lett.  2001,  3:  3121 

21b Node M. Kumar K. Nishide K. Ohsugi S. Miyamoto T. Tetrahedron Lett.  2001,  42:  9207 

22 Tokuyama H. Miyazaki T. Yokoshima S. Fukuyama T. Synlett  2003,  1512 

23

General Procedure for the Synthesis of Thiolesters, Synthesis of 16a: To a solution of n-dodecanethiol (0.26 mL, 1.08 mmol) in anhyd THF (2.5 mL) at 0 °C was added dropwise n-BuLi (1.0 M solution in hexane, 0.40 mL, 0.40 mmol) for 2 min. After stirring for 5 min, the resulting white suspension was added to a solution of N-acyloxazolidinone 11a (93 mg, 0.23 mmol) in THF (1.5 mL) at 0 °C. After stirring for 10 min, 10% aq citric acid was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO₄ and filtered. The solvent was removed under reduced pressure, the resultant crude mixture was purified by silica gel chromatography (EtOAc-hexane = 1:9-1:2) to afford 16a (94 mg, 83%) as a white solid. IR(film): 2915, 2854, 1684, 1653, 1457, 1300, 1129, 731 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.58-6.98 (m, 10 H), 4.88 (d, J = 14 Hz, 1 H), 4.65 (d, J = 15 Hz, 1 H), 4.10 (d, J = 7.3 Hz, 1 H), 2.77 (t,
J = 15 Hz, 2 H), 2.43 (m, 1 H), 1.30-1.00 (m, 20 H), 0.88 (t, J = 14 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.8, 173.5, 138.1, 136.2, 129.7, 128.5, 128.3, 128.1, 127.8, 127.5, 126.8, 73.5, 62.7, 50.3, 45.8, 31.9, 29.6, 29.5, 29.4, 29.1, 29.0, 22.7, 19.5, 19.1, 14.1. HRMS (FAB): m/z calcd for C₂₄H₂₈N₂O₄: 495.3171; found: 495.3169.

24

In order to avoid the thiolate addition to the carbonyl group on the oxazolidinone ring, the reaction should be carried out at a temperature lower than 0 °C. Reactions at higher temperature often provided the undesired N-acylamino alcohols 12. This tendency was notably observed in compounds possessing a bulky substituent at the Z-position.