BEMP-Promoted C(4)-Alkylation of 4-Alkyloxazol-5(4H)-ones: A Rapid and Efficient Route to α,α-Dialkyl-α-amino Acids

Abstract

Rapid and efficient C(4)-alkylation of 4-alkyloxazol-5(4H)-ones has been achieved by the utilization of BEMP as base. 4,4-Dialkyloxazol-5(4H)-ones, which can easily be hydrolyzed into free α,α-dialkyl-α-amino acids, were obtained in high yields (up to 99%) within a few minutes (1–18 min). BEMP, a sterically hindered strong base with low nucleophilicity facilitated the desired reaction, while decreasing the rate of side reactions such as O-alkylation, C(2)-alkylation and the breakage of oxazolone.

Key words

α,α-dialkyl-α-amino acid - oxazol-5(4H)-one - C(4)-­alkylation - BEMP - protecting group - chemoselectivity

• References and Notes

• 1a Di Blasip B, Pavone V, Lombardi A, Pedone C, Benedetti E. Biopolymers 1996; 40: 3
• 1b Tanaka M. Chem. Pharm. Bull. 2007; 55: 349
• 2a Piriou F, Lintner S, Fermadjian S, Khosla MC, Smeby RR, Bumpus FM. Proc. Natl. Acad. Sci. U.S.A. 1980; 77: 82
• 2b Khosla MC, Stachowiak K, Smeby RR, Bumpus FM, Pirious F, Lintner K, Fermandjian S. Proc. Natl. Acad. Sci. U.S.A. 1981; 78: 757 ; and references cited therein
• 3a Karle IL, Rao RB, Pasad S, Kaul R, Balaram P. J. Am. Chem. Soc. 1994; 116: 10355
• 3b Kaul R, Balaram P. Bioorg. Med. Chem. 1999; 7: 105
• 3c Toniolo C, Crisma M, Formaggio F, Peggion C. Biopolymers 2001; 60: 396
• 3d Venkatraman J, Shankaramma SC, Balaram P. Chem. Rev. 2001; 101: 3131
• 4a Takahashi A, Naganawa H, Ikeda D, Okami Y. Tetrahedron 1991; 47: 3621
• 4b Benedetti E, Gavuzzo E, Santini A, Kent DR, Zhu YF, Zhu Q, Mahr C, Goodman M. J. Pept. Sci. 1995; 1: 349
• 4c Bryant SD, Guerrini R, Salvadori S, Bianchi C, Tomatis R, Attila M, Lazarus LH. J. Med. Chem. 1997; 40: 2579
• 4d Bloommaert AG. S, Dhotel H, Ducos B, Durieus C, Goudreau N, Bado A, Garbay C, Roques BP. J. Med. Chem. 1997; 40: 647

For recent reviews on the synthesis of ααAAs, see:
• 5a Vogt H, Bräse S. Org. Biomol. Chem. 2007; 5: 406
• 5b Ohfune Y, Shinada T. Eur. J. Org. Chem. 2005; 5127
• 5c Cativiela C, Diaz-de-Villegas MD. Tetrahedron: Asymmetry 2000; 11: 645
• 5d Cativiela C, Diaz-de-Villegas MD. Tetrahedron: Asymmetry 1998; 9: 3517
• 6 For a recent review on the diverse chemistry of oxazol-5(4H)-ones, see: Fisk JS, Mosey RA, Tepe JJ. Chem. Soc. Rev. 2007; 36: 1432

For recent reviews on the use of oxazol-5(4H)-ones in amino acid syntheses, see:
• 7a Alba A.-NR, Rios R. Chem. Asian J. 2011; 6: 720
• 7b Mosey RA, Fisk JS, Tepe JJ. Tetrahedron: Asymmetry 2008; 19: 2755
• 8a Goodman M, Levine L. J. Am. Chem. Soc. 1964; 86: 2918
• 8b De Jersey J, Zerner B. Biochemistry 1969; 8: 1967
• 9a Steglich W, Höfle G. Chem. Ber. 1969; 102: 883
• 9b Steglich W, Höfle G. Tetrahedron Lett. 1970; 11: 4727
• 9c Ruble JC, Fu GC. J. Am. Chem. Soc. 1998; 120: 11532
• 9d Shaw SA, Aleman P, Vedejs E. J. Am. Chem. Soc. 2003; 125: 13368
• 9e Nguyen HV, Butler DC, Richards CJ. Org. Lett. 2006; 8: 769
• 9f Dietz FR, Gröger H. Synlett 2008; 663
• 10a Trost BM, Ariza X. Angew. Chem. Int. Ed. 1997; 36: 2635
• 10b Trost BM, Ariza X. J. Am. Chem. Soc. 1999; 121: 10727
• 10c Trost BM, Dogra K. J. Am. Chem. Soc. 2002; 124: 1256
• 10d Trost BM, Czabaniuk LC. J. Am. Chem. Soc. 2012; 134: 5778
• 11a Cabrera S, Reyes E, Alemán J, Milelli A, Kobbelgaard S, Jørgensen KA. J. Am. Chem. Soc. 2008; 130: 12031
• 11b Alemán J, Milelli A, Cabrera S, Reyes E, Jørgensen KA. Chem. Eur. J. 2008; 14: 10958
• 11c Balaguer A.-N, Companyó X, Calvet T, Font-Bardía M, Moyano A, Rios R. Eur. J. Org. Chem. 2009; 199
• 11d Hayashi Y, Obi K, Ohta Y, Okamura D, Ishikawa H. Chem. Asian J. 2009; 4: 246
• 11e Alba A.-NR, Companyó X, Valero G, Moyano A, Rios R. Chem. Eur. J. 2010; 16: 5354
• 12a Kübel B, Gruber W, Rudolf H, Steglich W. Chem. Ber. 1979; 112: 128
• 12b Gelmi ML, Pocar D, Rossi LM. Synthesis 1984; 763
• 12c Obrecht D, Bohdal U, Ruffieux R, Müller K. Helv. Chim. Acta 1994; 77: 1423
• 12d Hugener M, Heimegartner H. Helv. Chim. Acta 1995; 78: 84
• 12e Uraguchi D, Asai Y, Ooi T. Synlett 2009; 658
• 12f Tarí S, Avila A, Chinchilla R, Nájera C. Tetrahedron: Asymmetry 2012; 23: 176
• 13 Bullerwell RA. F, Lawson A. J. Chem. Soc. 1952; 1350
• 14a Mamdani HT, Hartley RC. Tetrahedron Lett. 2000; 41: 747
• 14b Kondo Y In Superbases for Organic Synthesis . Ishikawa T. John Wiley & Sons; West Sussex: 2009: 145
• 15 Typical Procedure for the BEMP-Promoted C(4)-Alkylation of 4-Alkyloxazol-5(4H)-one (Table 1 Entry 9): An oven-dried round-bottom flask with magnetic stir bar was charged with 1a (88 mg, 0.50 mmol) and anhyd THF (0.5 mL). Benzyl bromide (89 μL, 0.75 mmol) was added in one portion followed by the dropwise addition (1 min) of BEMP (217 μL, 0.75 mmol) at r.t. The resulting mixture was directly loaded onto the silica gel column and purified by flash chromatography (5% EtOAc–n-hexane) to afford 2a (170 mg, 0.64 mmol, 85% yield) as a colorless oil.
• 16 Analytical data for the new compounds: 4-Methyl-2-phenyl-4-[4-(trifluoromethyl)benzyl]oxazol-5(4H)-one (Table 2, Entry 5): ¹H NMR (300 MHz, CDCl₃): δ = 7.84 (d, J = 7.1 Hz, 2 H), 7.39–7.55 (m, 5 H), 7.27–7.30 (m, 2 H), 3.20 (dd, J = 18.0, 13.6 Hz, 2 H), 1.60 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 179.8, 160.0, 138.7, 132.8, 130.5, 129.6, 129.4, 128.8, 128.4, 127.8, 125.5, 125.1, 125.0, 123.0, 70.4, 43.8, 23.7. IR (KBr): 2930, 1818, 1655, 1452, 1325, 1166, 1124, 1068, 1066, 944, 893, 778, 696 cm^–1. MS (FAB⁺): m/z = 334 [M + H]⁺. 4-Benzyl-2-phenyl-4-[4-(trifluoromethyl)benzyl]oxazol-5(4H)-one (Table 2, Entry 11): ¹H NMR (300 MHz, CDCl₃): δ = 7.67 (d, J = 7.8 Hz, 2 H), 7.29–7.50 (m, 7 H), 7.14–7.18 (m, 5 H), 3.33 (dd, J = 13.6, 4.0 Hz, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 178.4, 160.1, 138.5, 133.9, 132.6, 130.5, 130.1, 129.6, 129.3, 128.6, 128.2, 127.6, 127.3, 125.3, 125.1 (3 ×), 125.0, 75.4, 43.6, 42.9. IR (KBr): 2925, 1816, 1654, 1496, 1453, 1325, 1166, 1120, 1066, 981, 892, 698 cm^–1. MS (FAB⁺): m/z = 410 [M + H]⁺. 4-Ethyl-4-isopropyl-2-phenyloxazol-5(4H)-one (Table 2, Entry 14): ¹H NMR (300 MHz, CDCl₃): δ = 8.00 (d, J = 7.0 Hz, 2 H), 7.44–7.58 (m, 3 H), 2.09–2.19 (m, 1 H), 1.53 (q, J = 2.1 Hz, 2 H), 0.91–1.02 (m, 6 H), 0.80 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 180.5, 160.0, 132.5, 128.7, 127.9, 125.9, 55.7, 34.6, 25.4, 16.8, 8.2. IR (KBr): 2970, 2932, 2119, 1819, 1655, 1453, 1292, 1181, 1019, 919, 878, 780, 694 cm^–1. MS (FAB⁺): m/z = 232 [M + H]⁺. 4-Isopropyl-2-phenyl-4-[4-(trifluoromethyl)-benzyl]oxazol-5(4H)-one (Table 2, Entry 17): ¹H NMR (300 MHz, CDCl₃): δ = 7.77 (d, J = 7.1 Hz, 2 H), 7.49–7.19 (m, 7 H), 3.21–3.15 (m, 2 H), 2.28–2.19 (m, 1 H), 1.05–1.00 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 179.2, 160.1, 139.0, 132.6, 130.5, 129.1, 128.8, 128.6, 127.7, 125.4, 125.0, 124.9 (3 × ), 60.3, 40.8, 65.3, 17.3. IR (KBr): 2968, 1815, 1655, 1454, 1325, 1292, 1166, 1127, 1067, 1020, 970, 881, 843, 777, 695 cm^–1. MS (FAB⁺): m/z = 362 [M+H]⁺. 4-Isobutyl-4-methyl-2-phenyloxazol-5(4H)-one (Table 2, Entry 19): ¹H NMR (300 MHz, CDCl₃): δ = 7.98 (d, J = 6.9 Hz, 2 H), 7.37–7.58 (m, 3 H), 1.75–1.94 (m, 2 H), 1.52–1.69 (m, 1 H), 1.47 (s, 3 H), 0.85 (dd, J = 12.8, 6.6 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 181.5, 159.4, 132.5, 128.7, 127.8, 126.0, 69.1, 34.9, 25.3, 24.0, 22.9. IR (KBr): 2931, 2119, 1822, 1654, 1452, 1294, 1181, 1116, 1072, 1004, 882, 779, 698 cm^–1. MS (FAB⁺): m/z = 232 [M + H]⁺. 4-Ethyl-4-isobutyl-2-phenyloxazol-5(4H)-one (Table 2, Entry 20): ¹H NMR (300 MHz, CDCl₃): δ = 8.00 (d, J = 8.2 Hz, 2 H), 7.44–7.59 (m, 3 H), 1.75–1.96 (m, 4 H), 1.55–1.67 (m, 1 H), 0.77–0.94 (m, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 181.0, 159.6, 132.5, 128.7, 127.8, 125.3, 73.6, 46.0, 31.9, 24.9, 24.1, 23.0, 7.8. IR (KBr): 2961, 2119, 1820, 1656, 1454, 1320, 1291, 1174, 1019, 934, 881, 779, 698 cm^–1. MS (FAB⁺): m/z = 246 [M + H]⁺. 4-Isobutyl-2-phenyl-4-[4-(trifluoromethyl)benzyl]oxazol-5(4H)-one (Table 2, Entry 23). ¹H NMR (300 MHz, CDCl₃): δ = 8.32 (d, J = 6.9 Hz, 2 H), 7.72–8.05 (m, 7 H), 3.65–3.70 (m, 2 H), 2.39–2.57 (m, 2 H), 2.09–2.20 (m, 1 H), 1.37 (dd, J = 13.7, 6.8 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 179.9, 159.8, 138.2, 132.7, 130.6, 129.6, 129.3, 128.7, 127.7, 125.4, 125.0 (2 ×), 124.9 (2 ×), 74.0, 46.2, 44.4, 25.0, 24.0, 23.0. IR (KBr): 2961, 1816, 1655, 1452, 1325, 1293, 1167, 1127, 1068, 1021, 976, 883, 778, 698 cm^–1. MS (FAB⁺): m/z = 376 [M + H]⁺.