Chelated Ester Enolates as Versatile Nucleophiles for Direct Nucleophilic Attack on Aromatic Nitro Groups

Abstract

Chelated amino acid ester enolates react with aromatic nitro compounds at the nitrogen atom. Best results were obtained with TFA-protected glycinates.

Key words

amino acids - chelates - enolates - nitroarenes

References and Notes

• 1a Rosini G. Ballini R. Synthesis  1988,  833 
• 1b Ono N. The Nitro Group in Organic Synthesis   VCH; New York: 2001. 
• 1c Marcelli T. van der Haas RNS. Van Maarseveen JH. Hiemstra H. Synlett  2005,  2817 
• 1d Sohtome Y. Hashimoto Y. Nagasawa K. Adv. Synth. Catal.  2005,  347:  1643 
• 1e Marcelli T. van der Haas RNS. Van Maarseveen JH. Hiemstra H. Angew. Chem. Int. Ed.  2006,  45:  929 ; Angew. Chem. 2006, 118, 943
• 2a Purushothama Chary K. Raja Ram S. Iyengar DS. Synlett  2000,  683 
• 2b Shojiro M. Makiko O. Toshimichi M. Takashi H. Haruki N. Tetrahedron Lett.  2003,  44:  3717 
• 3a Rosso JA. Bertolotti SG. Braun AM. Martire DO. Gonzalez MC. J. Phys. Org. Chem.  2001,  14:  300 
• 3b Feng S.-H. Zhang S.-J. Yu H.-Q. Li Q.-R. Chem. Lett.  2003,  32:  718 
• 4a Mukaiyama T. Hoshino T. J. Am. Chem. Soc.  1960,  82:  5339 
• 4b Torssell K. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis   VCH; New York: 1988. 
• 5 Czekelius C. Carreira EM. Angew. Chem. Int. Ed.  2005,  44:  612 ; Angew. Chem. 2005, 117, 618
• 6 Mendler B. Kazmaier U. Org. Lett.  2005,  7:  1715 
• 7a Kharash HS. Reimnuth O. Grignard Reactions of Nonmetallic Substances   Prentice-Hall; New York: 1954.  p.384 
• 7b Buck P. Angew. Chem., Int. Ed. Engl.  1969,  8:  120 
• 7c Nutzel K. Methoden der Organischen Chemie (Houben-Weyl)   Vol. 13:  Thieme; Stuttgart: 1973.  p.47 
• 8 Kursanov DN. Solodkov PA. Zh. Obshch. Khim., Ser. A  1935,  5:  1487 ; Chem. Abstr. 1936, 30, 2181
• 9a Barboni L. Bartoli G. Marcantoni E. Petrini M. Dalpozzo R. J. Chem. Soc., Perkin Trans. 1  1990,  2133 
• 9b Bartoli G. Palmieri G. Petrini M. Bosco M. Dalpozzo R. Gazz. Chim. Ital.  1990,  120:  247 
• 10a Bartoli G. Bosco M. Dalpozzo R. Marcantoni E. Tetrahedron Lett.  1988,  29:  2251 
• 10b Bartoli G. Marcantoni E. Petrini M. Dalpozzo R. J. Org. Chem.  1990,  55:  4456 
• 11 Bartoli G. Palmieri G. Bosco M. Dalpozzo R. Tetrahedron Lett.  1989,  30:  2129 
• 12 Bosco M. Dalpozzo R. Bartoli G. Palmieri G. Petrini M. J. Chem. Soc., Perkin Trans. 2  1991,  657 
• 13 Dean FM. Patampongse C. Podimuang V. J. Chem. Soc., Perkin Trans. 1  1974,  583 
• Reviews:
• 14a Kazmaier U. Amino Acids  1996,  11:  283 
• 14b Kazmaier U. Liebigs Ann. Chem./Recl.  1997,  285 
• 14c Kazmaier U. Recent Res. Dev. Org. Chem.  1998,  2:  351 
• 15 Mendler B. Kazmaier U. Synthesis  2005,  2239 
• 16 Mendler B. Kazmaier U. Huch V. Veith M. Org. Lett.  2005,  7:  2643 

17

Probably, attack of the glycine nucleophile occurs according to Scheme [2] and one equiv of the enolate is necessary to reduce the nitro group. Attempts to trap the oxidized glycine species are currently under investigation.

18

Additions of Chelated Enolates towards Nitroarenes - General Procedure. The base used for enolate formation was prepared directly before use. In a Schlenk flask HMDS (428 mg, 2.65 mmol) was dissolved in THF (2 mL) under N₂. Then, n-BuLi (1.6 M, 1.64 mL, 2.63 mmol) was added dropwise at -20 °C and the mixture was allowed to stir at r.t. for 10 min. After cooling at -78 °C a solution of ZnCl₂ (187 mg, 1.38 mmol, dried previously in vacuo with a hot-air gun) was added with the amino acid derivative (1.25 mmol) in THF (3 mL). The suspension was stirred for further 30 min at -78 °C to form the chelated ester enolate. After that the nitroarene (0.5 mmol) was added in THF (1 mL). The solution was allowed to warm to r.t. overnight before it was diluted with Et₂O (10 mL) and hydrolyzed in an ice bath with NH₄OAc/HOAc buffer (pH 6, 10 mL). The layers were separated and the aqueous layer was extracted twice with Et₂O. The combined organic layers were dried (Na₂SO₄) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, hexane-EtOAc).

19

Selected Spectroscopic and Analytical Data. tert -Butyl [(4-Chlorophenyl)(hydroxy)amino][(trifluoro-acetyl)amino]acetate ( 3a). Compound 3a was obtained from 2a (79 mg, 0.5 mmol) as a colorless solid; yield 175 mg (0.47 mmol, 95%); mp 101 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.40 (s, 9 H), 5.68 (d, J = 7.9 Hz, 1 H), 5.90 (s, 1 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.8 Hz, 2 H), 7.56 (d, J = 7.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 27.8, 72.6, 84.8, 115.6 (q, J _C,F = 286.1 Hz), 118.2, 128.7, 128.8, 147.4, 157.3 (q, J _C,F = 37.2 Hz), 164.7. HMRS (CI): m/z [M]⁺ calcd for C₁₄H₁₆N₂O₄F₃Cl: 368.0751. Found: 368.0746. Anal. Calcd for C₁₄H₁₆N₂O₄F₃Cl (368.77): C, 45.59; H, 4.38; N, 7.59. Found: C, 45.28; H, 4.30; N, 7.57.
tert -Butyl [(4-Bromophenyl)(hydroxy)amino][(trifluoro-acetyl)amino]acetate ( 3b). Compound 3b was obtained from 2b (51 mg, 0.25 mmol) as a colorless solid; yield 91 mg (0.22 mmol, 88%); mp 98 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.39 (s, 9 H), 5.68 (d, J = 8.0 Hz, 1 H), 6.16 (br s, 1 H), 7.06 (d, J = 8.5 Hz, 2 H), 7.35 (d, J = 8.5 Hz, 2 H), 7.56 (d, J = 7.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 27.8, 72.5, 84.9, 114.3, 116.2, 118.5, 131.7, 147.9, 157.4 (q, J _C,F = 38.5 Hz), 165.0.
HMRS (CI): m/z [M]⁺ calcd for C₁₄H₁₆N₂O₄F₃Br: 412.02. Found: 412.0247. Anal. Calcd for C₁₄H₁₆N₂O₄F₃Br (413.19): C, 40.69; H, 3.90; N, 6.78. Found: C, 40.82; H, 3.80; N, 6.76.
tert -Butyl [(4-Cyanophenyl)(hydroxy)amino][(trifluoro-acetyl)amino]acetate ( 3d). Compound 3d was obtained from 2d (104 mg, 0.70 mmol) as a colorless solid; yield 215 mg (0.60 mmol, 85%); mp 151 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.35 (s, 9 H), 5.80 (d, J = 7.5 Hz, 1 H), 6.32 (s, 1 H), 7.31 (d, J = 9.0 Hz, 2 H), 7.56 (d, J = 8.5 Hz, 2 H), 7.67 (d, J = 7.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 27.8, 71.8, 85.1, 105.4, 116.2, 116.6, 119.0, 133.1, 152.9, 157.4 (q, J _C,F = 39.9 Hz), 164.1. HMRS (CI): m/z [M]⁺ calcd for C₁₅H₁₆N₃O₄F₃: 359.1093. Found: 359.1082. Anal. Calcd for C₁₅H₁₆N₃O₄F₃ (359.34): C, 50.14; H, 4.50; N, 11.69. Found: C, 50.18; H, 4.55; N, 11.53.
Methyl 4-[{2- tert -Butoxy-2-oxo-1-[(trifluoroacetyl)ami-no]ethyl}(hydroxy)amino]benzoate ( 3e). Compound 3e was obtained from 2e (18 mg, 0.10 mmol) as a colorless solid; yield 33 mg (84.1 µmol, 85%); mp 114 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.35 (s, 9 H), 3.86 (s, 3 H), 5.84 (d, J = 7.6 Hz, 1 H), 6.30 (br s, 1 H), 7.25 (d, J = 8.5 Hz, 2 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.94 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 27.8, 51.9, 72.0, 84.8, 115.5 (q, J _C,F = 286.1 Hz), 115.5, 124.4, 130.7, 153.0, 157.1, 164.5, 166.9. HMRS (CI): m/z [M]⁺ calcd for C₁₆H₁₉N₂O₆F₃: 392.1195. Found: 392.1201. Anal. Calcd for C₁₆H₁₉N₂O₆F₃ (392.37): C, 48.98; H, 4.89; N, 7.14. Found: C, 49.17; H, 4.87; N, 7.10.