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DOI: 10.1055/s-2003-43355
A Versatile Synthesis of α-Amino Acid Derivatives via the Ugi Four-Component Condensation with a Novel Convertible Isonitrile
Publikationsverlauf
Publikationsdatum:
26. November 2003 (online)
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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.
Key words
Ugi four-component condensation (4CC) - α-amino acid derivatives - convertible isonitrile - N-acyloxazolidinones - thiol esters
- 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 ChemistryUgi 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 - 13
Meyers AI.Collington EW. J. Am. Chem. Soc. 1970, 92: 6676 - 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
References
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.
14General 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.
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] ).
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.
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.