Synlett 2007(20): 3188-3192  
DOI: 10.1055/s-2007-990912
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Stable, Convertible Isonitrile as a Formic Acid Carbanion [-COOH] Equivalent and Its Application in Multicomponent Reactions

Oliver Kreye, Bernhard Westermann, Ludger A. Wessjohann*
Leibniz Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, 06120 Halle, Germany
Fax: +49(345)55821309; e-Mail: wessjohann@ipb-halle.de;
Further Information

Publication History

Received 28 September 2007
Publication Date:
21 November 2007 (online)

Abstract

The application of 2-(2,2-dimethoxyethyl) phenyl iso­nitrile in Ugi, Passerini, and Ugi-Smiles reactions is described. The simple transformation to highly activated indolyl amides allows functional-group conversion of the isonitrile moiety into a variety of carboxylic acid derivatives, overall acting as a neutral, nucleophilic COOH equivalent.

12

Representative Procedure for Ugi Reactions of Convertible Isonitrile 7
Primary amine 12 (10.5 mmol) and oxo compound 13 (10.5 mmol) were dissolved in MeOH (20 mL) in the presence of Na2SO4 (5.30 g) and stirred for 2 h at r.t. to preform the imine. Subsequently, carboxylic acid 11 (10.46 mmol) and convertible isonitrile 7 (2.00 g, 10.46 mmol) were added and the mixture was stirred overnight. When TLC monitoring (CH2Cl2-MeOH, 19:1) indicated complete formation of the Ugi reaction products, the mixture was evaporated to dryness under reduced pressure. The residue was either used directly for the next step, or dissolved in EtOAc (50 mL) and H2O (30 mL). In the latter case, the water layer was discarded and the organic layer was washed with citric acid solution (3 × 30 mL, pH 2), H2O (2 × 30 mL), sat. NaHCO3 solution (3 × 30 mL), and finally with brine (3 × 30 mL). The organic solvent was dried over Na2SO4, filtered, and evaporated to give the crude Ugi reaction products.

13

Representative Procedure for Conversions of Ugi Products into Indolyl Amides 14
To the crude Ugi reaction products (2.92 mmol) in benzene (40 mL), pyridinium p-toluenesulfonate (PPTS; 37 mg, 0.15 mmol) was added as catalyst. This mixture was heated to reflux for 1.5-3 h until TLC (CH2Cl2-MeOH, 19:1) indicated complete conversion. The solution was cooled to r.t. and washed with H2O (2 × 20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to the give the crude indolyl amides 14a-d. These were either isolated and purified, or directly converted into the corresponding carboxylic acids or derivatives.

14

N -Benzyl- N -[2-(1 H -indolyl)-2-oxoethyl]acetamide (14b)
Recrystallization of crude compound 14b from EtOAc gave a white powder (95% recovery). TLC: R f = 0.86 (CH2Cl2-MeOH, 19:1); mp 129-130 °C(benzene). 1H NMR [400 MHz, CDCl3, s-cis(minor) and s-trans(major) isomers]: δ = 2.15, 2.30 (2 s, 3 H, CH3), 4.67 (s, 2 H, CH2), 4.73 (s, 2 H, CH2), 6.60, 6.64 (2d, J = 3.7 Hz, 1 H, CH), 7.19-7.39 (m, 8 H, 8 CH), 7.52 (d, J = 8.2 Hz, 1 H, CH), 8.39 (d, J = 8.1 Hz, 1 H, CH) ppm. 13C NMR [100 MHz, CDCl3,
s-cis(minor) and s-trans(major) isomers]: δ = 21.36, 47.82, 52.74, 109.89, 116.35, 120.77, 123.48, 123.84, 125.16, 126.58, 127.85, 128.27, 128.62, 128.94, 129.93, 135.45, 135.69, 166.27, 171.44 ppm. ESI-MS of C19H18N2O2: m/z = 329.1 [M + Na+], 307.2 [M + H+], 305.0 [M - H-]. IR (ATR): ν = 1711.5, 1634.6, 1534.7, 1485.4, 1471.0, 1450.5, 1431.1, 1383.4, 1367.5, 1350.5, 1315.5, 1262.2, 1227.7, 1202.7, 1154.7, 1108.4, 1087.7, 1040.6, 997.8, 976.6, 949.7, 918.0, 820.9, 793.9, 772.7, 746.6, 723.2, 696.1, 663.6 cm-1. HRMS: m/z calcd for C19H18N2O2 [M + Na]+: 329.12659; found: 329.12602.
N -Acetyl- N -benzylglycine (15b)
Treatment of indolyl amide 14b with methanolic NaOH (1 N, contains 5% H2O) overnight gave carboxylic acid derivative 15b as a light brown solid. TLC: R f = 0.19 (EtOAc-MeOH, 2:1); mp 119-120 °C (EtOAc). 1H NMR [300 MHz, CDCl3, s-cis(minor) and s-trans(major) isomers]: δ = 2.16, 2.24 (2 s, 3 H, CH3), 3.92, 4.08 (2 s, 2 H, CH2), 4.62, 4.64 (2 s, 2 H, CH2), 7.17-7.39 (m, 5 H, 5 CH), 10.85 (br s, 1 H, OH) ppm. 13C NMR [75 MHz, CDCl3, s-cis(minor) and s-trans(major) isomers]: δ = 21.02, 21.18, 46.92, 48.86, 49.61, 52.94, 126.54, 127.53, 127.85, 128.23, 128.50, 128.88, 135.18 135.98, 171.26, 172.14, 172.50, 172.69 ppm. ESI-MS of C11H13NO3: m/z = 230.2 [M + Na+], 208.1 [M + H+], 206.1 [M - H-]. IR (ATR): ν = 1712.8, 1585.6, 1484.9, 1440.6, 1398.9, 1354.2, 1247.9, 1202.3, 1173.0, 998.7, 947.1, 801.6, 751.3, 737.6, 704.3, 682.9 cm-1. HRMS: m/z calcd for C11H13NO3 [M + Na]+: 230.07931; found: 230.07832.
Methyl N -Acetyl- N -benzylglycinate (16b)
1H NMR [300 MHz, CDCl3, s-cis(minor) and s-trans(major) isomers]: δ = 2.13, 2.22 (2 s, 3 H, CH3), 3.71 (s, 3 H, CH3), 3.93, 4.06 (2 s, 2 H, CH2), 4.62, 4.64 (2 s, 2 H, CH2), 7.18-7.39 (m, 5 H, 5 CH) ppm.
N ² -Acetyl- N -allyl- N ² -benzylglycine Amide (17b) 1H NMR [400 MHz, CDCl3, s-cis(minor) and s-trans(major) isomers]: δ = 2.14, 2.21 (2 s, 3 H, CH3), 3.78-3.86 (m, 2 H, CH2), 3.91, 3.98 (2 s, 2 H, CH2), 4.62, 4.67 (2 s, 2 H, CH2), 5.06-5.19 (m, 2 H, CH2), 5.65-5.86 (m, 1 H, CH), 6.33, 6.60 (2 br s, 1 H, NH), 7.16-7.39 (m, 5 H, 5 CH) ppm.

15

Representative Procedure for a Passerini Reaction of Convertible Isonitrile 7
Convertible isonitrile 7 (2.00 g, 10.46 mmol) and oxo compound 13 (10.46 mmol) were dissolved in CH2Cl2 (15 mL). Subsequently, carboxylic acid 11 (10.46 mmol) was added. The mixture was stirred overnight at r.t., or followed by TLC (EtOAc-MeOH, 9:1) until completion. The organic layer was washed with a sat. NaHCO3 solution (4 × 10 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give the crude Passerini products.
Conversion into the indolyl amides 18a and 18b was achieved by procedures identical to those used for 14a-d.
1-(1 H -Indolylcarbonyl)-2-methylpropyl (4-Methoxy­-phenyl)acetate (18a)
After purification by column chromatography (EtOAc-PE, 1:1), the indolyl amide 18a was obtained as a brown oil in a yield of 93%. TLC: R f = 0.78 (EtOAc-PE, 1:1). 1H NMR (300 MHz, CDCl3): δ = 0.99, 1.01 (2 d, J = 6.6 Hz, 6 H, 2 CH3), 2.32-2.38 (m, 1 H, CH), 3.71 (s, 2 H, CH2), 3.77 (s, 3 H, CH3), 5.44 (d, J = 5.9 Hz, 2 H, CH2), 6.61 (d, J = 3.8 Hz, 1 H, CH), 6.82-6.86 (m, 2 H, 2 CH), 7.18-7.37 (m, 4 H, 4 CH), 7.46 (d, J = 3.8 Hz, 1 H, CH), 7.52-7.55 (m, 1 H, CH), 8.45 (d, J = 8.2 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.53, 19.00, 30.76, 39.94, 55.22, 77.00, 109.81, 113.86, 116.63, 120.71, 123.94, 123.99, 125.16, 125.26, 130.07, 130.27, 135.56, 158.55, 167.81, 171.45 ppm. ESI-MS of C22H23NO4: m/z = 388.5 [M + Na+], 366.2 [M + H+], 365.3 [M - H-]. IR (ATR): ν = 1707.9, 1611.9, 1585.6, 1539.8, 1511.8, 1451.3, 1404.5, 1332.8, 1310.0, 1245.0, 1226.4, 1205.7, 1177.7, 1143.3, 1100.7, 1080.7, 1025.9, 908.0, 879.6, 855.9, 818.4, 765.6, 749.7, 726.2 cm-1. HRMS: m/z calcd for C22H23NO4 [M + Na]+: 388.15248; found: 388.15290.

16

2-Hydroxy-3-phenylpropanoic Acid (19) α-Hydroxy acid 19 was obtained as a light brown oil. TLC: R f = 0.54 (EtOAc-MeOH, 1:1). 1H NMR (300 MHz, CDCl3): δ = 2.90-3.19 (m, 2 H, CH2), 4.40-4.44 (m, 1 H, CH), 7.20-7.36 (m, 5 H, 5 CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.23, 70.94, 126.61, 128.18, 129.34, 136.47, 176.11 ppm. ESI-MS of C9H10O3: m/z = 189.2 [M + Na+], 167.1 [M + H+], 164.9 [M - H-]. IR (ATR): ν = 3442.3, 1722.9, 1495.1, 1455.0, 1429.5, 1237.5, 1188.6, 1088.2, 1065.5, 1029.3, 1000.7, 910.2, 878.5, 793.6, 738.4, 698.2 cm-1. HRMS: m/z calcd for C9H10O3 [M - H]-: 165.05517; found: 165.05592.
2-{[(4-Methoxyphenyl)acetyl]oxy}-3-methylbutanoic Acid (20) Indolyl amide 18a (0.25 g, 0.69 mmol) was dissolved in a mixture of t-BuOH (20 mL) and H2O (10 mL). Then, DMAP (21 mg, 0.17 mmol) was added and the reaction mixture was heated at reflux for 2 h, after which TLC (EtOAc-PE, 1:1) indicated the saponification of the indolyl amide to the carboxylic acid. The reaction mixture was concentrated to a volume of 10 mL in a rotary evaporator. Saturated NaHCO3 solution (15 mL) and CH2Cl2 (30 mL) were added. After separation of the organic layer, the water layer was extracted with CH2Cl2 (2 × 30 mL). Then the water layer was acidified with NaHSO4 (2 M) and extracted with EtOAc (3 × 20 mL). The combined organic solutions of the acidic extraction were dried over Na2SO4, filtered, and evaporated to give carboxylic acid derivative 20 (0.12 g, 63%) as a slightly reddish oil. TLC: R f = 0.69 (EtOAc-MeOH, 1:1). 1H NMR (300 MHz, CDCl3): δ = 0.87-0.90 (m, 6 H, 2 CH3), 2.12-2.21 (m, 1 H, CH), 3.59 (s, 2 H, CH2), 3.70 (s, 3 H, CH3), 4.80 (d, J = 4.2 Hz, 1 H, CH), 6.75-6.80 (m, 2 H, 2 CH), 7.10-7.17 (m, 2 H, 2 CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.04, 18.76, 30.01, 39.96, 55.21, 76.39, 113.82, 113.94, 125.41, 130.24, 158.47, 171.50, 175.05 ppm. ESI-MS of C14H18O5: m/z = 289.1 [M + Na+], 264.9 [M - H-]. IR (ATR): ν = 1720.1, 1620.3, 1611.2, 1587.8, 1512.9, 1495.7, 1461.0, 1435.1, 1378.6, 1289.9, 1246.1, 1179.3, 1036.3, 963.9, 818.6, 757.1, 729.4, 694.5 cm-1. HRMS: m/z calcd for C14H18O5 [M + Na]+: 289.10519; found: 289.10467.
Methyl 2-{[(4-Methoxyphenyl)acetyl]oxy}-3-methyl­-butanoate (21) 1H NMR (300 MHz, CDCl3): δ = 0.93 (d, J = 6.8 Hz, 6 H, 2 CH3), 2.18-2.24 (m, 1 H, CH), 3.66 (s, 2 H, CH2), 3.71 (s, 3 H, CH3), 3.78 (s, 3 H, CH3), 4.83 (d, J = 4.6 Hz, 1 H, CH), 6.84-6.88 (m, 2 H, 2 CH), 7.20-7.26 (m, 2 H, 2 CH) ppm.

17

Representative Procedure for an Ugi-Smiles Reaction of Convertible Isonitrile 7 Benzyl amine (1.12 g, 10.46 mmol) and isobutyraldehyde (0.76 g, 10.46 mmol) were dissolved in MeOH (20 mL) in the presence of Na2SO4 (5.30 g) and stirred for 2 h at r.t. to preform the imine. Then p-nitrophenol (1,46 g, 10.46 mmol) and convertible isonitrile 7 (2.00 g, 10.46 mmol) were added and the mixture was stirred overnight. After TLC indicated the reaction to be complete (CH2Cl2-MeOH, 19:1), the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in EtOAc (50 mL) and H2O (30 mL). The water layer was discarded and the organic layer was washed with citric acid solution (3 × 30 mL, pH 2), H2O (2 × 30 mL), sat. NaHCO3 solution (3 × 30 mL), and finally with brine (3 × 30 mL). It was dried over Na2SO4, filtered, and evaporated to give the crude Ugi-Smiles reaction product. Conversion into the activated indol was achieved by procedures identical to those used for 14a-d.
N -Benzyl- N -[1-(1 H -indol-1-ylcarbonyl)-2-methyl­-propyl]-4-nitroaniline (22) TLC: R f = 0.91 (EtOAc-PE, 1:2); mp 113-114 °C (EtOAc). 1H NMR [300 MHz, CDCl3, s-cis(minor) and s-trans(major) isomers]: δ = 1.05, 1.13 (2 d, J = 6.8 Hz, 6 H, 2 CH3), 2.81-2.94 (m, 1 H, CH), 4.62-4.88 (m, 2 H, CH2), 5.01 (d, J = 10.4 Hz, 1 H, CH), 6.61 (d, J = 3.8 Hz, 1 H, CH), 6.77-6.93 (m, 7 H, 7 CH), 7.04-7.57 (m, 4 H, 4 CH), 8.04-8.15 (m, 3 H, 3 CH) ppm. 13C NMR [75 MHz, CDCl3,
s-cis(minor) and s-trans(major) isomers]: δ = 19.14, 20.10, 28.43, 49.61, 65.40, 110.54, 112.02, 115.57, 116.50, 120.65, 123.27, 124.05, 125.28, 126.02, 126.20, 126.67, 128.20, 130.18, 135.49, 135.59, 138.47, 153.25, 167.27 ppm. ESI-MS of C26H25N3O3: m/z = 450.3 [M + Na+], 428.4 [M + H+], 426.3 [M - H-]. IR (ATR): ν = 1691.8, 1590.7, 1494.5, 1449.6, 1384.2, 1315.2, 1287.3, 1251.5, 1205.5, 1160.8, 1111.5 1017.9, 973.2, 949.7, 907.1, 850.9, 822.6, 792.3, 749.5, 723.7, 691.1, 667.0 cm-1. HRMS: not detectable.

18

N -Benzyl- N -(4-nitrophenyl)valine (23) Indolyl amide 22 (0.57 g, 1.34 mmol) is dissolved in THF (10 mL) and H2O (5 mL). After cooling to ca. 0 °C with an ice bath, LiOH·H2O (0.14 g, 3.35 mmol) is added. The mixture is stirred for one day, then acidified with NaHSO4 (2 M) and extracted with EtOAc (5 × 30 mL). The combined organic solutions are dried over Na2SO4, filtered, and evaporated to give the pure carboxylic acid derivative 23 (0.39 g, 88%) as reddish oil. 1H NMR [300 MHz, CDCl3, s-cis(minor) and s-trans(major) isomers]: δ = 0.89-1.23 (m, 6 H, 2 CH3), 2.39-2.71 (m, 1 H, CH), 3.68, 3.71 (s, 1 H, CH), 4.24-4.87 (m, 2 H, CH2), 6.78-6.92 (m, 2 H, 2 CH), 7.11-7.38 (m, 5 H, 5 CH), 8.01-8.17 (m, 2 H, 2 CH) ppm.