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.

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.