Checked by Katerina Matcheva and Ekkehard Winterfeldt.
1. Procedure
2. Notes
1.
Sodium methoxide, 3-methyl-4-nitroanisole, diethyl oxalate, 30% hydrogen peroxide, 97% sodium hydride, methyl acetoacetate, sodium sulfate, 10% palladium on activated carbon, ammonium formate, and 5-methoxy-2-nitrophenylacetic acid were purchased from Aldrich Chemical Company, Inc., and were used without further purification.
3. Water was added in portions of 300–400 mL each to the reaction flask. The mixture was stirred for 5–10 min and the red solution was decanted into a separate flask. This procedure was repeated until all the solid went into solution.
6. The melting point of the crude compound is
50–60°C; the NMR and IR correspond to starting material.
7. The physical properties are as follows: m.p.
175–176°C (lit value:
3 174–176°C); IR (KBr) cm
−1: 3140–2740, 2660, 1715, 1620, 1580, 1510, 1410, 1340, 1320, 1290, 1260, 1200, 1175, 1090, 1040, 955, 850, 830, 760, 710, 630; NMR (DMSO-d
6) δ: 3.86 (s, 3 H, OCH
3), 3.97 (s, 2 H, CH
2), 7.04–7.10 (m, 2 H, H
4, H
6), 8.13 (d, 1 H, J = 8.8, H
3); MS m/e 212 (M+1).
8. It is essential to have compound
2 as a colorless product; otherwise the yield in the next step is poor.
9.
Thionyl chloride was purchased from Aldrich Chemical Company, Inc., and distilled prior to use.
10. If a clear solution did not result at the end of 16–18 hr, the mixture was warmed at 35–40°C for 1 hr or until a clear solution resulted; then it was cooled to room temperature.
12. A
500-mL, pressure-equalizing funnel was
oven-dried and then cooled under
argon.
14. Depending on the purity of the starting material, the yield of
3 has been as high as 80%.
15. The analytical sample melted at
78–79°C after crystallization from
methanol. The spectra are as follows: IR (KBr) cm
−1: 2960, 2850, 1710, 1620–1390, 1350–1250, 1190, 1090, 1035, 950, 910, 890, 840, 760, 730, 630; NMR (CDCl
3) δ: 2.40 (s, 3 H, COCH
3), 3.84 (s, 3 H, COOCH
3), 3.99 (s, 3 H, OCH
3), 4.50 (s, 2 H, CH
2), 6.77 (d, 1 H, J = 2.6, H
6), 6.90 (dd, 1 H, J = 2.8, 9.0, H
4), 8.19 (d, 1 H, J = 9.0, H
3); MS m/e 310 (M+1).
16. If there is no precipitate, a few crystals of starting material
3 are added to the reaction flask to initiate crystallization.
18. The physical properties are as follows: mp
85–87°C; IR (KBr) cm
−1: 3470, 3130, 2980, 2850, 1710, 1590, 1500, 1440, 1400, 1200, 1065, 1010, 865, 850, 760, 750, 700, 630, 620; NMR (CDCl
3) δ: 3.66 (s, 2 H, CH
2), 3.77 (s, 3 H, COOCH
3), 3.87 (s, 3 H, OCH
3), 4.20 (s, 2 H, ArCH
2), 6.73 (d, 1H, J=2.8, H
6), 6.89 (dd, 1 H, J = 2.8, 9.2, H
4), 8.19 (d, 1 H, J = 9.2, H
3); MS m/e 268 (M+1).
22. If an oil resulted, it was taken up in
ethyl acetate (150 mL) and the two layers were separated. The aqueous layer was extracted with
ethyl acetate (2 × 50 mL); the organic layers were combined, dried (Na
2SO
4) and concentrated under reduced pressure at 35–40°C to give
12.7–13.5 g (
80–85%) of product
5 as an oil that solidifies on cooling in the freezer.
23. The physical properties are as follows: mp
96–98°C; IR (KBr) cm
−1: 3370, 3020, 2970, 2840, 1720, 1595, 1485, 1445, 1395, 1330, 1205, 1120, 1035, 1010, 980, 950, 845, 810, 770, 735, 695, 625
−1; NMR (CDCl
3) δ: 3.74 (s, 3 H, COOCH
3), 3.82 (s, 2 H, CH
2), 3.83 (s, 3 H, CH
3), 6.27 (d, 1 H, J = 1.0, H
3), 6.81 (dd, 1 H, J = 2.4, 8.8, H
6), 7.01 (d, 1 H, J = 2.4, H
4), 7.23 (d, 1 H, J = 8.8, H
7), 8.53 (s, 1 H, NH); MS m/e 220 (M+1). The product must be stored in the freezer; on the bench top it turns red.
24. The physical properties for
methyl (2-nitrophenylacetyl)acetoacetate are as follows: mp
82–83°C; IR (KBr) cm
−1: 2960, 1705, 1515, 1400, 1335, 1080, 860, 790, 720 cm
−1; NMR (CDCl
3) δ: 2.41 (s, 3 H, COCH
3), 3.85 (s, 3 H, COOCH
3), 4.20 (s, 2 H, CH
2), 4.50 (s, 2 H, CH
2), 7.36–7.65 (m, 3 H), 8.16 (t, 1 H).
25. The physical properties for
methyl 4-(2-nitrophenyl)-3-oxobutyrate are as follows: mp
50–51°C; IR (KBr) cm
−1: 2960, 1750, 1715, 1610, 1575, 1520, 1440, 1340, 1265, 1200, 1070, 1010, 795, 730, 705 cm
−1; NMR (CDCl
3) δ: 3.66 (2 H, COCH
2COOMe), 3.76 (s, 3 H, COOCH
3), 4.25 (s, 2 H, Ar-CH
2), 7.30 (d, 1 H, J = 7.2), 7.50 (t, 1 H), 7.6 (t, 1 H), 8.10 (d, 1 H, J = 6.8).
26. The physical properties for
methyl indole-2-acetate are as follows: mp
71–74°C; IR (KBr) cm
−1: 3430, 3405, 3320, 3220, 1740, 1720, 1660, 1620, 1565, 1525, 1430, 1340, 1300, 1280, 1190, 1170, 1030, 860, 820, 790, 780, 730, 700 cm
−1; NMR (CDCl
3) δ: 3.61 (s, 3 H, COOCH
3), 3.71 (s, 2 H, CH
2), 7.42–7.58 (m, 4 H), 7.93 (m, 1 H), 7.97 (d, 1 H, J = 1.8).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The corresponding 5-H analogs of the title compound are prepared using the procedure described for compounds 3, 4, and 5 in 55–61%, 65–70%, and 80–86% yield, respectively.
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