LETTER
Isonitrile as a Formic Acid Carbanion Equivalent
3191
172.69 ppm. ESI-MS of C11H13NO3: m/z = 230.2 [M + Na+],
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: Rf = 0.69 (EtOAc–MeOH, 1:1). 1H NMR
(300 MHz, CDCl3): d = 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):
d = 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):
n = 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)
208.1 [M + H+], 206.1 [M – H–]. IR (ATR): n = 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]: d = 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.
N2-Acetyl-N-allyl-N2-benzylglycine Amide (17b)
1H NMR [400 MHz, CDCl3, s-cis(minor) and s-trans(major)
isomers]: d = 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-(1H-Indolylcarbonyl)-2-methylpropyl (4-Methoxy-
phenyl)acetate (18a)
1H NMR (300 MHz, CDCl3): d = 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
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: Rf = 0.78 (EtOAc–PE, 1:1). 1H NMR
(300 MHz, CDCl3): d = 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): d = 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): n = 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.
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-(1H-indol-1-ylcarbonyl)-2-methyl-
propyl]-4-nitroaniline (22)
TLC: Rf = 0.91 (EtOAc–PE, 1:2); mp 113–114 °C (EtOAc).
1H NMR [300 MHz, CDCl3, s-cis(minor) and s-trans(major)
isomers]: d = 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,
(16) 2-Hydroxy-3-phenylpropanoic Acid (19)
a-Hydroxy acid 19 was obtained as a light brown oil. TLC:
Rf = 0.54 (EtOAc–MeOH, 1:1). 1H NMR (300 MHz,
CDCl3): d = 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): d = 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): n = 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.
s-cis(minor) and s-trans(major) isomers]: d = 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): n = 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)
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
Indolyl amide 22 (0.57 g, 1.34 mmol) is dissolved in THF
Synlett 2007, No. 20, 3188–3192 © Thieme Stuttgart · New York