Simple and General Synthesis of α-(p-Nitroaryl) Derivatives of Alanine and Serine

Mieczysaw Mąkosza; Marek Surowiec; Agnieszka Szczepańska; Daniel Sulikowski; Oleg Maltsev

doi:10.1055/s-2007-967952

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Synlett 2007(3): 0470-0474
DOI: 10.1055/s-2007-967952

LETTER

Simple and General Synthesis of α-(p-Nitroaryl) Derivatives of Alanine and Serine

Mieczysaw Mąkosza*, Marek Surowiec, Agnieszka Szczepańska, Daniel Sulikowski, Oleg Maltsev
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01224 Warsaw, Poland
Fax: +48(22)6326681; e-Mail: icho-s@icho.edu.pl;

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Publication History

Received 5 December 2006
Publication Date:
07 February 2007 (online)

Abstract
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Abstract

α-(p-Nitroaryl)alanine and α-(p-nitroaryl)serine alkyl esters are efficiently synthesized via oxidative nucleophilic substitution of hydrogen in nitroarenes with carbanions of protected alanine and serine.

Key words

amino acids - nucleophilic aromatic substitution - arenes - carbanions

References and Notes

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1

Summer Trainee from Higher Chemical College, Moscow, Russian Federation.

17

General Procedure for Oxidative Nucleophilic Substitution (Compounds 2a-8a and 2b-5b): To a stirred solution of t-BuOK (1.5 mmol) in THF (10 mL) cooled to -78 °C under an argon atmosphere were added dropwise a solution of nitroarene (2 mmol) and the respective protected alanine ester (1 mmol) dissolved in DMF (2 mL). The resulting dark mixture was stirred at this temperature for 30 min and treated with DDQ (1.2 mmol) in THF (2 mL). The dark brown solution was stirred for 5 min at - 78 °C, then the mixture was allowed to reach r.t. (ca. 30 min) and was then filtered trough a ca. 5 cm pad of silica gel and eluted subsequently with EtOAc-hexane. Evaporation of the solvents gave a residue that was purified by column chromatography (2b-5b) and recrystallized from EtOH or directly hydrolyzed (2a-8a). General Procedure for Oxidative Nucleophilic Substitution (Compounds 2c-11c):
To a stirred solution of nitroarene (2 mmol), 4-carboethoxy-2-phenyl-2-oxazoline (1c; 1 mmol) in THF (10 mL) and DMF (2 mL) cooled to -40 °C [22] was added 1 M solution of t-BuOK (1.1 mmol) dropwise during 15 min. The resulting dark colored mixture was stirred at this temperature for 30 min and treated with DDQ (1.1 mmol) in THF (2 mL). After 5 min the reaction mixture was allowed to reach r.t. (ca. 15 min) and treated with 5% aq solution of NH₄Cl (30 mL). Extraction with CH₂Cl₂, drying of the organic phase with anhyd Na₂SO₄ and evaporation of the solvent gave a residue that was purified by column chromatography (EtOAc-hexane). Procedures for HydrolysisFor Compounds 2a-8a; General Procedure: The crude ONSH product (2a-8a, 1 mmol), was dissolved in EtOH (5 mL) and treated with concd aq HCl (1 mL). The solution was stirred for 24 h at r.t. and then evaporated to dryness. This residue was dissolved in CH₂Cl₂ (25 mL) and extracted with H₂O (3 × 25 mL). The aqueous layer was basified with solid Na₂CO₃ to pH 9 and extracted with CH₂Cl₂ (3 × 50 mL). The combined extracts were dried and evaporated to dryness. Purification by column chromatography gave the desired products 2d-8d. For Compounds 2b-5b; Typical Procedure: A stirred solution of 2b (1 mmol), p-TosOH (0.1 mmol) in MeCN (5 mL) and 100% formic acid (5mL) was cooled to 0-4 °C in an ice-bath and treated with 30% aq H₂O₂ (10 mmol). The mixture was stirred at this temperature for further 3 h and then at r.t. for 48 h. After this time an excess of solid Na₂SO₃ was added and the solvents were evaporated under reduced pressure. The residue was dissolved in H₂O (10 mL) and treated with solid Na₂CO₃ to pH 9. Extraction with CH₂Cl₂ (3 × 25 mL), and purification by column chromatography gave pure 2e. For Compounds 2c-11c; Typical Procedure: Compound 9c was dissolved in 6 M aq HCl (3 mL) and THF (1.5 mL) and the mixture was then heated at reflux for 48 h. After cooling to r.t., the solvents were removed on rotary vapor. This residue was dissolved in EtOH (1.5 mL), treated with propylene oxide (1 mL) and stirred for 2 h at r.t. The resulting solid, being the free amino acid, was filtered off and washed with cold EtOH and Et₂O. Physical Data of Selected ProductsCompound 2b: mp 96-99 °C. IR (KBr): 2984, 2941, 1732, 1583, 1521, 1349, 1238, 1094, 897, 764 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.20 (d, J = 1.9 Hz, 1 H), 8.14 (d, J = 2.3 Hz, 1 H), 8.11 (s, 1 H), 5.08 (sept, J = 6.3 Hz, 1 H), 3.53-3.62 (m, 2 H), 3.30-3.39 (m, 2 H), 1.89 (s, 3 H), 1.17 (dd, J = 0.9, 6.3 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.1, 167.7, 147.5, 147.3, 133.8, 131.0, 125.1, 121.1, 70.4, 69.5, 40.5, 33.5, 21.3, 21.8, 20.6. MS (ESI): m/z = 389 [M + H]⁺.
Compound 4b: mp 108-109 ºC. IR (KBr): 3101, 2983, 1726, 1599, 1523, 1356, 1243, 1096, 848, 722 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.89 (d, J = 1.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.61 (dd, J = 2.0, 8.7 Hz, 1 H), 5.04 (sept, J = 6.3 Hz, 1 H), 3.58-3.74 (m, 2 H), 3.38-3.52 (m, 2 H), 1.77 (s, 3 H), 1.22 (d, J = 6.2 Hz, 3 H), 1.13 (d, J = 6.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.0, 170.2, 150.0, 146.5, 130.0, 127.0, 125.4, 125.3, 70.8, 69.6, 40.3, 34.4, 22.5, 21.4, 21.2. MS (ESI): m/z = 389 [M + H]⁺. Compound 5b: mp 123-125 ºC. IR (KBr): 3111, 3043, 2982, 2234, 1723, 1592, 1530, 1355, 1246, 1096, 927, 848 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.29 (d, J = 8.3 Hz, 1 H), 8.27 (d, J = 2.2 Hz, 1 H), 8.00 (dd, J = 2.2, 8.8 Hz, 1 H), 5.03 (sept, J = 6.3 Hz, 1 H), 3.60-3.76 (m, 2 H), 3.39-3.54 (m, 2 H), 1.80 (s, 3 H), 1.22 (d, J = 6.3 Hz, 3 H), 1.11 (d, J = 6.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 170.6, 151.6, 147.2, 133.9, 131.4, 125.4, 115.1, 107.9, 70.8, 70.0, 40.5, 34.6, 22.6, 21.5, 21.2. MS (ESI): m/z = 380 [M + H]⁺. Compound 2c: oil. IR (film): 2982, 1734, 1641, 1529, 1357, 1257, 1098, 694 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.07-8.12 (m, 2 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.74 (d, J = 1.9 Hz, 1 H), 7.44-7.59 (m, 4 H), 5.38 (d, J = 8.9 Hz, 1 H), 4.40 (d, J = 8.9 Hz, 1 H), 4.26 (dq, J = 5.2, 7.2 Hz, 2 H), 1.25 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.7, 166.3, 147.4, 147.2, 132.4, 129.5, 128.9, 128.5, 127.7, 126.4, 126.0, 125.0, 80.1, 76.20, 62.8, 13.9. MS (ESI): m/z = 375 [M + H]⁺. Compound 4c: mp 82-84 ºC. IR (KBr): 3104, 2978, 1738, 1634, 1528, 1355, 1248, 1101, 976, 692 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.28 (d, J = 2.3 Hz, 1 H), 8.16 (dd, J = 2.3, 8.8 Hz, 1 H), 8.05-8.12 (m, 2 H), 8.03 (d, J = 8.8 Hz, 1 H), 6.50-7.60 (m, 1 H), 7.43-7.51 (m, 2 H), 5.66 (d, J = 9.2 Hz, 1 H), 4.35 (d, J = 9.2 Hz, 1 H), 4.26-4.35 (m, 1 H), 4.13-4.22 (m, 1 H), 1.21 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.7, 167.0, 147.9, 147.7, 132.4, 132.4, 129.8, 128.9, 128.5, 126.5, 124.7, 122.0, 80.1, 76.1, 62.9, 13.9. MS (ESI): m/z = 375 [M + H]⁺. Compound 3c: mp 134-136 ºC. IR (KBr): 3038, 2988, 2973, 2238, 1736, 1641, 1533, 1348, 1247 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.34 (d, J = 8.8 Hz, 1 H), 8.07-8.13 (m, 3 H), 7.29 (dd, J = 1.9, 8.8 Hz, 1 H), 7.65-7.61 (m, 1 H), 7.46-7.51 (m, 2 H), 5.40 (d, J = 8.9 Hz, 1 H), 4.43 (d, J = 8.9 Hz, 1 H), 4.26 (q, J = 7.2 Hz, 2 H), 1.25 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.3, 166.8, 149.1, 147.8, 133.5, 132.6, 131.2, 128.9, 128.6, 126.1, 125.8, 114.7, 108.4, 80.0, 76.1, 63.1, 29.7, 13.9. MS (ESI): m/z = 366 [M + H]⁺. Compound 10c: mp 80-83 ºC. IR (KBr): 3109, 2981, 1736, 1643, 1521, 1345, 1246, 1022, 801, 740 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.06-8.10 (m, 2 H), 7.89 (dd, J = 2.2, 8.3 Hz, 1 H), 7.81 (d, J = 8.3 Hz, 1 H), 7.72 (d, J = 2.2 Hz, 1 H), 7.52-7.57 (m, 1 H), 7.41-7.48 (m, 2 H), 5.56 (d, J = 9.1 Hz, 1 H), 4.25-4.34 (m, 1 H), 4.19 (d, J = 9.1 Hz, 1 H), 4.06-4.15 (m, 1 H), 3.93 (s, 3 H), 1.17 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.5, 166.6, 155.7, 148.6, 138.7, 132.2, 128.8, 128.4, 127.8, 126.9, 116.2, 105.2, 78.2, 76.5, 62.1, 56.0, 14.0. MS (ESI): m/z = 371 [M + H]⁺.
Compound 4d: oil. IR (film): 2984, 1737, 1524, 1350, 1187, 1098, 766, 747 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.23 (d, J = 2.4 Hz, 1 H), 8.16 (dd, J = 2.4, 8.6 Hz, 1 H), 8.03 (d, J = 8.6 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 2.06 (br s, 2 H), 1.72 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.1, 148.5, 147.4, 133.5, 128.0, 125.4, 121.9, 61.9, 60.3, 25.3, 13.9. MS (ESI): m/z = 273 [M + H]⁺. Compound 5d: mp 50-52 ºC. IR (KBr): 3384, 3366, 3019, 3042, 2236, 1724, 1528, 1350, 1172, 1019 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.30 (d, J = 8.8 Hz, 1 H), 8.22 (d, J = 2.2 Hz, 1 H), 8.03 (dd, J = 2.2, 8.8 Hz, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 2.11 (br s, 2 H), 1.73 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.0, 151.9, 147.3, 133.1, 131.1, 125.4, 115.0, 107.8, 62.3, 60.4, 28.1, 14.0. MS (ESI): m/z = 264 [M + H]⁺. Compound 6d: oil. IR (film): 3384, 3112, 2985, 1738, 1529, 1355, 1193, 811, 742 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.07 (ddd, J = 0.7, 2.4, 8.6 Hz, 1 H), 7.87-7.93 (m, 2 H), 4.20 (qd, J = 1.3, 7.2 Hz, 2 H), 2.05 (br s, 1 H), 1.67 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.8, 159.6 (d, J _C-F = 249.4 Hz), 147.9 (d, J _C-F = 9.5 Hz), 139.2 (d, J _C-F = 12.9 Hz), 127.6 (d, J _C-F = 5.2 Hz), 119.4 (d, J _C-F = 3.5 Hz), 111.4 (d, J _C-F = 27.6 Hz), 61.8, 58.2. MS (ESI): m/z = 257 [M + H]⁺. Compound 7d: oil. IR (film): 3385, 2984, 1736, 1577, 1531, 1360, 1101, 864 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.24 (d, J = 8.3 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 1 H), 4.21 (dd, J = 1.7, 7.2 Hz, 2 H), 2.19 (br s, 1 H), 1.74 (s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.9, 167.0, 142.6, 135.1, 119.4, 62.6, 62.1, 25.9, 14.0. MS (ESI): m/z = 274 [M + H]⁺. Compound 2e: oil. IR (film): 3383, 2983, 1736, 1733, 1524, 1350, 1096, 767, 747 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.23 (d, J = 2.4 Hz, 1 H), 8.15 (dd, J = 2.4, 8.8 Hz, 1 H), 8.02 (d, J = 8.8 Hz, 1 H), 5.07 (sept, J = 6.2 Hz, 1 H), 2.15 (br s, 2 H), 1.72 (s, 3 H), 1.19 (d, J = 6.2 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.4, 148.4, 147.4, 133.4, 128.1, 125.4, 121.9, 69.4, 60.3, 25.2, 20.40, 20.39. MS (ESI): m/z = 287 [M + H]⁺. Compound 2f: mp >350 °C(dec.). IR (film): 3215, 3080, 2517, 1649, 1607, 1521, 1390, 134 cm^-1. ¹H NMR (400 MHz, D₂O-DCl): δ = 8.26 (d, J = 9.1 Hz, 2 H), 7.69 (d, J = 9.1 Hz, 2 H), 4.42 (d, J = 12.1 Hz, 1 H), 4.19 (d, J = 12.1 Hz, 1 H). ¹³C NMR (100 MHz, D₂O-DCl): δ = 170.5, 148.5, 139.3, 127.6, 124.7, 66.8, 63.8. MS (ESI): m/z = 227 [M + H]⁺.

22

With 2-chloronitrobenzene, the reaction was carried out at -78 °C.