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

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.

Key words

multicomponent reaction - convertible isonitrile - Ugi reaction - Passerini reaction - Ugi-Smiles reaction - formyl synthon

References and Notes

• 1 Zhu J. Bienayme H. Multicomponent Reactions   Wiley-VCH; Weinheim: 2005. 
• 2a Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
• 2b Dömling A. Chem. Rev.  2006,  106:  17 
• 3 Wessjohann LA. Ruijter E. Mol. Diversity  2005,  9:  159 
• 4 Banfi L. Riva R. The Passerini Reaction, In Organic Reactions   Vol. 65:  Overman LE. Wiley; New York: 2005. 
• 5 El Kaim L. Grimaud L. Oble J. Angew. Chem. Int. Ed.  2005,  44:  7961 
• 6a Wessjohann LA. Voigt B. Rivera DG. Angew. Chem. Int. Ed.  2005,  44:  4785 
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• 11 Kobayashi K. Yoneda K. Mitzumoto T. Umakoshi H. Morikawa O. Konishi H. Tetrahedron Lett.  2003,  44:  4733 
• During the preparation of this manuscript we became aware of advanced-online-published articles (now published in print) with a similar use of isonitrile 7 in a singular utilization in an Ugi reaction:
• 19a Gilley C. Buller MJ. Kobayashi Y. Org. Lett.  2007,  9:  3631 
• 19b Isaacson J. Gilley C. Kobayashi Y. J. Org. Chem  2007,  72:  3913 
• 19c Vamos M. Ozboya K. Kobayashi Y. Synlett  2007,  1595 

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.