2050
4. MuraliDhar, T.; Borden, L.; Tyagarajan, S.; Smith, K.; Branchek, T.; Weinshank, R.; Gluchowski, C.; J. Med. Chem. 1995,
38, 942.
5. Kuroda, T.; Takahashi, M.; Kondo, K.; Iwasaki, T. J. Org. Chem. 1996, 61, 9560.
6. (a) As evidence for the formation of the ortho-quinonoid we have trapped this intermediate using a 4+2 cycloaddition
reaction. The initial report of this work was presented at the 218th ACS National Meeting in New Orleans, Aug. 22–26,
1999, Abstract ORGN490; Tetrahydroquinolines Generated from Anthranilic Alcohols; Parker, D. T.; Mugrage, B.; Parker,
T. S.; Li, H.; Boehm, C. (b) Organic Syntheses Based on Named and Unnamed Reactions; Hassner, A.; Stumer, C.; Pergamon
Press: Oxford, 1994; p. 5.
7. Moser, P.; Sallmann, A.; Wiesenberg, I. J. Med. Chem. 1990, 33, 2358.
8. Medicinal Chemistry Vol. 13–1: Antiinflammatory Agents, Chemistry and Pharmacology; Scherrer, R.; Ed.; Academic Press:
New York, 1974; pp. 45–89.
9. (a) Brown, H.; Kim, S.; Krishnamurthy, S.; J. Org. Chem. 1980, 45, 1. (b) Brown, H.; Kim, S. Synthesis 1977, 635.
10. Representative procedures for the conversion of benzylic alcohols to dimethylphosphonates are as follows: Dimethyl 2-
(20,60-dichloroanilino)phenylmethylphosphonate (9a): Trimethyl phosphite (20 ml, 170 mmol) was added, at rt to a
colorless solution of 2-(20,60-dichloroanilino)benzyl alcohol (8a),(2.38 g, 8.9 mmol) in anhydrous CH2Cl2 (50 ml). MsOH
(0.93 ml, 14 mmol) was added dropwise as a slightly exothermic reaction was observed. After stirring under an inert
atmosphere for 2 h, the reaction mixture was diluted with 1:1 Et2O:EtOAc (200 ml), washed with sat. aqueous NaHCO3
(2×50 ml), brine (50 ml), dried over MgSO4, and concentrated on a rotovap. Upon standing the resulting oil crystallized.
Trituration with hexanes/Et2O and filtration gave 1.6 g (50% yield) of an orange solid (mp 122–125°C). H NMR (CDCl3,
300 MHz): δ 7.31 (d, 1H, J=7.31 Hz), 7.20 (d, 2H, J=7.72 Hz), 7.09 (t, 1H, J=7.72 Hz), 6.98–6.91 (m, 2H), 6.55 (d, 1H,
J=6.55 Hz), 3.74 (s, 3H), 3.70 (s, 3H), 3.36 (d, 2H, J=21.33 Hz); P NMR (CDCl3, 300 MHz): δ 30.88, (s); MS(ESI+):
359.8 m/e; IR(KBr): 3250, 1585, 1575, 1452 cm−1. Dimethyl 2-(20,30-dimethylanilino)phenylmethylphosphonate (9e):
Trimethylphosphite (20 ml, 170 mmol) was added, at rt to a solution of 2-(20,30-dimethylanilino)benzyl alcohol (8e) (2.0 g,
8.8 mmol) in anhydrous CH2Cl2 (30 ml). MsOH (0.93 ml, 14 mmol) was added dropwise as a slightly exothermic reaction
was observed. After stirring under an inert atmosphere for 2 h, the reaction mixture was diluted with 1:1 Et2O:EtOAc
(200 ml), washed with sat. aqueous NaHCO3 (2×50 ml), brine (50 ml), dried over MgSO4, and concentrated on a rotovap.
The resulting oil was purified by flash chromatography (SiO2, 4:1 EtOAc:hexane) to give 2.8 g (95% yield) of the title
phosphonate as a light-yellow oil. H NMR (CDCl3, 300 MHz): δ 7.26–7.21 (m, 2H), 7.09 (t, 1H, J=7.72 Hz), 6.95 (t, 1H,
J=7.72 Hz), 6.85 (t, 1H, J=7.35 Hz), 6.75–6.73 (m, 3H), 3.65 (s, 3H), 3.62 (s, 3H), 3.32 (d, 2H, J=21.32 Hz), 2.24 (s, 3H),
2.06 (s, 3H); P NMR (DMSO-d6, 300 MHz): δ 31.49, (s); MS(ESI+): 320.0 m/e; IR (thin film):1602, 1583, 1517, 1483,
1473, 1461, 1303, 1232, 1056, 1031, 825 cm−1
.
11. Freeman, S.; Irwin, W.; Schwalbe, C. J. Chem. Soc., Perkin Trans. 2 1991, 263.
12. (a) Marshall, P.; Kulmacz, R.; Lands, W. J. Biol. Chem. 1986, 262, 3510. (b) Wennogle, L.; Liang, H.; Quintavalla, J. FEBS
Lett. 1995, 371, 315.