PAPER
Synthesis and Wagner-Meerwein Rearrangement of 9-(a-Hydroxyalkyl)xanthenes
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1H NMR (400 MHz, CDCl3): d = 3.36, 3.42 (2 × s, 3 H, NCH3; 6f/
7f = 70:30), 6.65 (s, 1 H), 6.90 (dd, 0.7 H), 6.95–7.0 (dd, 0.3 H),
7.05 (s, 0.7 H), 7.10–7.43 (m, 7 H), 7.50–7.60 (2 × s, 0.7 H + 0.3 H),
7.80 (dd, 0.3 H).
Anal. Calcd for C15H13NO (223.27) + 3% H2O: C, 78.26; H, 6.03;
N, 6.08. Found: C, 77.95; H, 5.94; N, 5.79.
6m
Yellowish resin [chromatography; hexane–EtOAc].
IR (film): 3310 (NH), 1709 (C=O), 1552 (amide II) cm–1.
1H NMR (400 MHz, CDCl3): d = 4.65–4.70 (d, 2 H), 6.65 (br s, 1
H, NHCO), 6.90 (s, 1 H), 7.15–7.48 (m, 8 H).
13C NMR (125 MHz, CDCl3): d = 44.3, 111.9, 114.2, 116.5, 118.8,
120.5, 121.6, 124.7, 125.0, 125.8, 128.4, 128.8, 128.9, 129.7, 129.8,
130.4, 133.7, 156.7, 157.4, 158.0.
13C NMR (125 MHz, CDCl3): d = 29.9, 30.5, 113.5, 116.2, 116.4,
117.5, 117.6, 117.8, 118.3, 118.8, 119.0, 120.0, 121.9, 122.0, 122.2,
126.2, 126.3, 126.6, 127.0, 127.8, 128.0, 128.1, 131.2, 136.9, 137.1,
137.6, 143.5, 151.6, 151.9, 152.0, 152.2.
HR–MS (EI): m/z calcd for C18H15N2O [MH+]: 275.1184; found:
275.1184.
6g
MS (ESI): m/z = 318 [M – H–].
Brown crystals.
1H NMR (400 MHz, DMSO): d = 7.05–7.12 (m, 2 H), 7.15–7.18 (s,
1 H), 7.20–7.27 (d, 1 H), 7.25–7.32 (m, 3 H), 7.38–7.43 (m, 2 H),
7.48–7.52 (d, 1 H), 7.72–7.75 (d, 1 H), 7.89–7.95 (d, 1 H).
13C NMR (125 MHz, DMSO): d = 116.6, 116.7, 117.2, 120.7,
122.9, 123.6, 124.4, 125.8, 125.9, 127.5, 127.7, 128.4, 129.2, 130.2,
139.1, 150.8, 152.3.
Anal. Calcd for C17H12NO2F3 (319.28) + 2% EtOAc: C, 63.76; H,
3.89; N, 4.30. Found: C, 63.28; H, 4.05; N, 4.07.
9
Yellowish crystals.
IR (KBr): 1718 (s, C=O).
1H NMR (400 MHz, CDCl3): d = 1.05 (d, 3 H), 4.31 (d, 1 H), 5.25
(m, 1 H), 7.12–7.39 (m, 8 H), 8.12 (s, 1 H, OCHO).
13C NMR (125 MHz, CDCl3): d = 15.20, 43.65, 75.16, 116.55,
116.72, 120.17, 121.24, 123.29, 123.42, 128.67, 129.60, 130.01,
152.27, 153.04, 160.61.
MS (EI): m/z = 276 [M+].
Anal. Calcd for C18H12OS (276.36): C, 78.23; H, 4.38; S, 11.60; O,
5.79. Found: C, 78.00; H, 4.49; S, 11.31; O, 6.02.
6h
MS (EI): m/z = 254 [M+].
Yellowish crystals.
Raman (film): 1610 (endocyclic C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.2–7.3 (m, 2 H), 7.3–7.4 (m, 2
H), 7.40–7.50 (m, 4 H), 7.5–7.7 (m, 2 H), 7.78 (s, 0.76 H), 7.8–7.9
(m, 0.24 H), 7.9–8.2 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 113.6, 116.0, 116.3, 117.4, 117.5,
117.6, 118.8, 120.5, 121.0, 121.3, 121.7, 121.9, 122.2, 125.3, 126.4,
126.5, 126.9, 127.3, 128.0, 128.1, 135.9, 138.1, 144.5, 151.0, 151.9,
152.2, 155.4, 160.9.
Acknowledgment
We gratefully acknowledge the skillful technical assistance of Ms.
Maria Testa and Mr. Bernhard Fest. Dr. Hans Hirt is thanked for
some reference standards and Drs. Thomas Allmendinger and
Ching-Pong Mak for their continued support and encouragement.
HR–MS (EI): m/z calcd for C21H14NOS [MH+]: 328.0796; found:
328.0797.
References
(1) Current address: Amgen Inc., One Amgen Center Drive, P.
O. Box, Thousand Oaks, CA 91320-1799, USA.
6i
(2) Burke, E. R.; Kholodilov, N. G. Ann. Neurol. 1998, 44, 126.
(3) (a) Zimmermann, K.; Waldmeier, P. C.; Tatton, W. G. Pure
Appl. Chem. 1999, 71, 2039. (b) Mück-Šeler, D.; Pivac, N.
IDrugs 2000, 3, 530. (c) Cloos, P. A. C.; Jensen, F. R.;
Boissy, P.; Stahlhut, M. WO 2004039773, A20513, 2004.
(4) (a) Waldmeier, P. C.; Boulton, A. A.; Cools, A. R.; Kato, A.
C.; Tatton, W. G. Adv. Res. Neurodegen. 2000, 8, 197.
(b) Sagot, Y.; Toni, N.; Perrelet, D.; Lurot, S.; King, B.;
Rixner, H.; Mattenberger, L.; Waldmeier, P. C.; Kato, A. C.
Br. J. Pharmacol. 2000, 131, 721. (c) LeWitt, P. A.
Neurology 2004, 63, S23.
Yellowish waxy solid [chromatography; hexane–EtOAc].
IR (KBr): 2218 (C≡N) cm–1.
Raman (powder): 1612 (endocyclic C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.22–7.31 (m, 2 H), 7.45–7.51 (m,
5 H), 7.61–7.63 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 114.5, 117.0, 118.4, 118.9, 121.8,
122.2, 122.4, 123.7, 124.4, 125.3, 125.9, 126.1, 126.4, 126.7, 128.5,
128.8, 129.2, 129.3, 129.7, 130.3, 130.5, 130.9, 132.4, 133.3, 135.2,
142.8, 158.0, 158.8.
(5) (a) Olivera, R.; SanMartin, R.; Churruca, F.; Dominguez, E.
J. Org. Chem. 2002, 67, 7215. (b) SanMartin, R.; Olivera,
R.; Churruca, F.; Tellitu, I.; Dominguez, E. Trends
Heterocycl. Chem. 2003, 9, 259.
MS (EI): m/z = 219 [M+].
Anal. Calcd for C15H9NO (219.24) + 3% EtOAc: C, 81.35; H, 4.29;
N, 6.20. Found: C, 81.76; H, 4.63; N, 5.49.
(6) Bischoff, S. In Novel Antipsychotic Drugs; Meltzer: New
York, 1992, 117–134.
6l
Yellowish oil [chromatography; toluene–EtOH].
IR (film): 3380 (NH2) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.85 (br s, 2 H, NH2), 3.8 (s, 2
H), 6.98 (s, 1 H), 7.18–7.42 (m, 7 H), 7.48–7.52 (m, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 45.9, 120.6, 121.4, 125.1,
125.2, 125.3, 126.7, 129.1, 129.3, 130.0, 130.4, 131.0, 142.0, 156.9,
157.7.
(7) (a) Mercep, M.; Mesic, M.; Pesic, D. PCT Int. Appl., WO
2003099822, 20031204, 2003. (b) Kiyama, R.; Honma, T.;
Hayashi, K.; Ogawa, M.; Hara, M.; Fujimoto, M.; Fujishita,
T. J. Med. Chem. 1995, 38, 2728. (c) Lambrou, G. N.;
Latour, E.; Waldmeier, P. WO 2004066993, A10812, 2004.
(8) (a) Zimmermann, K.; Roggo, S.; Kragten, E.; Fürst, P.;
Waldmeier, P. Bioorg. Med. Chem. Lett. 1998, 8, 1195.
(b) Kanno, S.; Okita, T. JP 2000044568, A20215, 2000.
(c) Arnold, L. A.; Wenchen, L.; Guy, R. K. Org. Lett. 2004,
6, 3005.
MS (ESI): m/z = 224 [MH+], 207 [MH+ – NH3].
Synthesis 2005, No. 15, 2562–2570 © Thieme Stuttgart · New York