Enantioselective Synthesis of (R)-α-(p-Nitroaryl)prolines via Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes

Abstract

Optically pure (R)-α-(p-nitroaryl)prolines are synthesized via oxidative nucleophilic substitution of hydrogen in nitroarenes using chiral carbanion of l-proline protected as N,O-acetal of pivalaldehyde.

Key words

amino acids - nitroarenes - oxidative substitution - ­carbanions

References and Notes

• 2 Magaard VW. Sanches SR. Bean JW. Moore ML. Tetrahedron Lett.  1993,  34:  381 
• 3a Madger AB. Witkop B. Chem. Rev.  1966,  66:  47 
• 3b Harrison T. Williams BJ. Swain CJ. Bioorg. Med. Chem. Lett.  1994,  4:  2733 
• 4a Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2004,  53:  5183 
• 4b Vingola N. List BJ. J. Am. Chem. Soc.  2003,  125:  450 
• 5 Seebach D. Boes M. Naef R. Schweizer WB. J. Am. Chem. Soc.  1983,  105:  5390 
• 6 Tayama E. Kimura H. Angew. Chem. Int. Ed.  2007,  46:  886 
• 7 Bajgrowicz J. Achquar AE. Roumestant M.-L. Pigiere C. Viallefont P. Heterocycles  1986,  24:  2165 
• 8 Van Betsbrugge J. Tourwe D. Kaptein D. Kierkels H. Broxterman R. Tetrahedron  1997,  52:  9233 
• 9 Mąkosza M. Surowiec M. Szczepańska A. Sulikowski D. Maltsev O. Synlett  2007,  470 
• 11

  (a) Synthesis of 1 was carried out according a literature procedure (see ref. 10b) with slight modification.
  Preparation of Compound 1
  To a solution of trimethylsilyl ester of N-trimethylsilyl-l-proline (28.8 g, 0.111 mol) in dry n-pentane (23 mL) under argon, pivalaldehyde (12.1 mL, 0.111 mol) was added very slowly. During the addition temperature must be kept below 20 °C cooling in water bath with ice, reaction is exothermic. Overheating the reaction mass above 30 °C cause partial decomposition of the product. After 1 h, the resulting solution was cooled to -70 °C and the crystalline product was filtered and dried; yield 20.3 g, 82%.

• 10b Annunziata R. Ferrari M. Papeo G. Resmini M. Synth. Commun.  1997,  27:  23 
• 12a Usse S. Guillaumet G. Viaud M.-C. J. Org. Chem.  2000,  914 
• 12b Papillon JPN. Taylor RJK. Org. Lett.  2000,  2:  1987 
• 13a Mąkosza M. Winiarski J. Acc. Chem. Res.  1987,  20:  282 
• 13b Mąkosza M. Surowiec M. Tetrahedron  2003,  59:  6261 

1

Summer Trainee from Higher Chemical College, Moscow.

14

General Procedure
To a solution of 1 (1 mmol), nitroarene (2 mmol) in THF (10 mL), and DMF (2 mL), cooled to -78 °C, 0.5 M solution of KHMDS in toluene (3 mL, 1.5 mmol) was added dropwise during 10 min. The resulting dark-colored mixture was stirred for 30 min at the same temperature and then treated with a solution of DDQ (1.2 mmol) in THF (1 mL). After stirring for further 5 min at -78 °C, a brown slurry was slowly allowed to reach r.t. Aqueous workup gave crude product, which was purified by column chromatography.
Selected Analytical Data Compound 2a: mp 88-90 °C (MeOH); [α]_D ²² +0.8 (c 1.000, CHCl₃). IR (KBr): 2970, 2870, 1772, 1521, 1351, 1194, 1091, 853, 753 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.19 (d, J = 9.0 Hz, 2 H), 7.96 (d, J = 9.0 Hz, 2 H), 4.50 (s, 1 H), 3.36 (dt, J = 6.7, 11.5 Hz, 1 H), 3.09 (dt, J = 5.8, 11.5 Hz, 1 H), 2.56 (dt, J = 6.7, 12.8 Hz, 1 H), 2.00 (dt, J = 7.2, 12.8 Hz, 1 H), 1.90-1.80 (m, 2 H), 0.86 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 175.1, 149.0, 147.3, 126.6, 123.5, 106.3, 74.0, 58.9, 42.5, 36.8, 25.5, 24.3. MS (EI, 70 eV): m/z = 304 [M⁺], 289, 261, 247, 219, 191, 145.
Compound 2b: mp 94-96 °C (MeOH); [α]_D ²² +2.1 (c 1.000, CHCl₃). IR (KBr): 2961, 2901, 1781, 1536, 1364, 1196, 895, 811, 744 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.07-7.92 (m, 3 H), 4.49 (s, 1 H), 3.34-3.23 (m, 1 H), 3.13-3.03 (m, 1 H), 2.74-2.64 (m, 1 H), 2.36-2.24 (m, 1 H), 1.91-1.75 (m, 2 H), 0.89 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.3, 160.2 (d, J = 250 Hz), 148.2 (d, J = 9 Hz), 135.8 (d, J = 12 Hz), 128.5 (d, J = 4 Hz), 118.5 (d, J = 3 Hz), 112.6 (d, J = 28 Hz), 105.4, 73.4 (d, J = 4 Hz), 57.4 (d, J = 1 Hz), 39.6 (d, J = 3 Hz), 36.8, 25.2, 24.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = 105.5. MS (ESI⁺): m/z = 323 [M + H]⁺.

15

Hydrolysis - General Procedure
A solution of 2 (0.5 mmol) in 48% aq HBr (1 mL) was heated to 100 °C for 20 h. The aq acid was removed in vacuo and the dry residue was dissolved in dry EtOH (1 mL). To this solution propylene oxide (5 mL) was added carefully, and stirred at r.t. for 2 h. Precipitated solid was filtered and washed with cold EtOH. Drying under reduced pressure gave product as a white, amorphous solid.
Selected Analytical Data
Compound 3a: mp >320 °C; [α]_D ²² +2.3 (c 0.667, 0.1 M HCl). IR (KBr): 3444 (bs), 3064 (bs), 1651, 1617, 1526, 1345, 854, 737 cm^-1. ¹H NMR (400 MHz, D₂O-DCl): δ = 8.34 (d, J = 9.1 Hz, 2 H), 7.77 (d, J = 9.1 Hz, 2 H), 3.74-3.65 (m, 1 H), 3.60-3.52 (m, 1 H), 3.10-3.05 (m, 1 H), 2.70-2.60 (m, 1 H), 2.40-2.29 (m, 1 H), 2.24-2.12 (m, 1 H). ¹³C NMR (125 MHz D₂O-DCl): δ = 171.7, 148.5, 140.8, 128.1, 124.7, 74.7, 45.7, 33.5, 22.2. MS (ESI⁺): m/z = 237 [M + H]⁺.
Compound 3b: mp >320 °C; [α]_D ²² +86.5 (c 0.500, 0.1 M HCl). IR (KBr): 3107 (bs), 2720 (bs), 1634, 1624, 1348, 809 cm^-1. ¹H NMR (400 MHz, D₂O-DCl): δ = 8.21 (ddd, J = 0.8, 2.3, 8.8 Hz, 1 H), 8.17 (dd, J = 2.2, 10.9 Hz, 1H), 7.92 (t, J = 7.7 Hz), 3.82-3.60 (m, 1 H), 3.60-3.42 (m, 1 H), 3.00-2.87 (m, 1 H), 2.87-2.70 (m, 1 H), 2.43-2.25 (m, 1 H), 2.25-2.07 (m, 1 H). ¹³C NMR (100 MHz D₂O-DCl): δ = 170.8, 159.7 (d, J = 250 Hz), 149.6 (d, J = 10 Hz), 130.4 (d, J = 4 Hz), 128.2 (d, J = 14 Hz), 120.5 (d, J = 3 Hz), 112.1 (d, J = 27 Hz), 70.9, 46.4, 33.9, 22.1. MS (ESI⁺): m/z = 255 [M + H]⁺.