5336
P. S. Humphries et al. / Tetrahedron Letters 47 (2006) 5333–5336
Drugs 2003, 12, 1489; (d) Willson, T. M.; Brown, P. J.;
Sternbach, D. D.; Henke, B. R. J. Med. Chem. 2000, 43,
527.
(di-tert-butylphosphino)-1,10-binaphthyl 2 (10 mol %) and
cesium carbonate (3 equiv). The flask was then evacuated
and back-filled with nitrogen and fitted with a rubber
septum. Anhydrous toluene (2.5 mL) followed by halo-
2. For PPARa, see: (a) van Raalte, D. H.; Li, M.; Pritchard,
P. H.; Wasan, K. M. Pharm. Res. 2004, 21, 1531; (b)
Miyachi, H. Expert Opin. Ther. Pat. 2004, 14, 607.
3. For PPARc, see: (a) Henke, B. R. Prog. Med. Chem. 2004,
42, 1; (b) Fajas, L.; Auwerx, J. Handbook of Obesity, 2nd
ed.; Marcel Dekker: New York, 2004; p 559; (c) Evans, R.
M.; Barish, G. D.; Wang, Y.-X. Nat. Med. 2004, 10, 355;
(d) Pershadsingh, H. A. Expert Opin. Invest. Drugs 2004,
13, 215.
4. For PPARd, see: Tan, N. S.; Michalik, L.; Desvergne, B.;
Wahli, W. Expert Opin. Ther. Targets 2004, 8, 39.
5. Hulin, B. WO 91/19702 A1, 1991; Chem. Abstr. 1991, 117,
26552.
pyridine
6 (0.144 g, 0.5 mmol), alcohol 4 (0.203 g,
1.0 mmol) and additional anhydrous toluene (2.5 mL)
was added via a syringe. The flask was then sealed under
nitrogen and placed in a pre-heated oil bath to allow the
solution to reflux for 16 h. The reaction mixture was
cooled to ambient temperature, diluted with diethyl ether
(2 mL), and filtered through a pad of Celite, washing with
additional diethyl ether (10 mL). The filtrate was then
concentrated in vacuo and purified (Biotage Sp4) by silica
gel chromatography (hexanes to ethyl acetate over 10
column volumes) to afford ester 7 as a pale yellow oil
1
(0.174 g, 85%). H NMR (300 MHz, CDCl3) d 7.97–7.95
6. Czarnik, A. W. Acc. Chem. Res. 1996, 29, 112.
7. (a) Lindley, J. Tetrahedron 1984, 40, 1433; (b) Keegstra,
M. A.; Peters, T. H. A.; Brandsma, L. Tetrahedron 1992,
48, 3633; (c) Capdevielle, P.; Maumy, M. Tetrahedron
Lett. 1993, 34, 1007; (d) Lee, S.; Frescas, S. P.; Nichols, D.
E. Synth. Commun. 1995, 25, 2775; (e) Fagan, P. J.;
Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem.
Soc. 2000, 122, 5043.
8. Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 10770.
9. For an excellent review, see: Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 2002, 41, 4176.
10. (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1996, 118, 10333; (b) Mann, G.; Hartwig, J. F.
J. Am. Chem. Soc. 1996, 118, 13109; (c) Watanabe, M.;
Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1999, 40, 8837;
(d) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J.
Am. Chem. Soc. 2000, 122, 10718; (e) Torraca, K. E.;
Kuwabe, S.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
12907; (f) Parrish, C. A.; Buchwald, S. L. J. Org. Chem.
2001, 66, 2498.
11. Han, R. Y.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119,
8135.
12. All new compounds were characterized by full spectro-
scopic data, yields refer to chromatographed material with
purity >95%.
(m, 1H), 7.92 (d, J = 2.1 Hz, 2H), 7.43–7.39 (m, 4H), 6.63
(d, J = 8.5 Hz, 1H), 4.52 (t, J = 6.8 Hz, 2H), 3.70 (s, 3H),
3.32–3.28 (m, 3H), 2.96–2.90 (m, 4H), 2.33 (s, 3H), 1.33 (s,
3H). ESIMS (m/z): 411 (M+H).
14. A modified microwave-assisted intermolecular palladium-
catalyzed procedure was never attempted during these
investigations.
15. General procedure for the microwave-assisted hydrolysis
reaction. A Smith Process Vial (2–5 mL) was charged,
under nitrogen, with a stir bar, methyl ester 7 (0.174 g,
0.42 mmol), 1 N aq sodium hydroxide (1.26 mL,
1.26 mmol), and acetonitrile (2 mL). The reaction vessel
was sealed and heated at 100 ꢁC for 10 min (fixed hold
time) in a Biotage Emrys Creator. After cooling, the vessel
was uncapped and the reaction mixture acidified to pH 5–7
with 1 N aq hydrochloric acid. The resulting mixture was
extracted with ethyl acetate (3 · 15 mL) and the combined
organic extracts were dried (anhydrous magnesium sul-
fate), filtered, and concentrated in vacuo. Purification
(Biotage Sp4) by silica gel chromatography (ethyl acetate
to 50% methanol/ethyl acetate over 10 column volumes)
1
afforded acid 24 as a white solid (0.153 g, 92%). H NMR
(300 MHz, DMSO-d6) d 7.93–7.89 (m, 3H), 7.52–7.46 (m,
4H), 7.42–7.38 (m, 3H), 6.69 (d, J = 8.5 Hz, 1H), 4.44 (t,
J = 6.7 Hz, 2H), 3.45–3.43 (m, 2H), 3.18 (s, 3H), 2.91–2.87
(m, 2H), 2.31 (s, 3H), 1.19 (s, 3H). ESIMS (m/z): 395
(MꢀH). Anal. Calcd for C22H24N2O5: C, 66.65; H, 6.10;
N, 7.07. Found: C22H24N2O5.0.06H2O: C, 66.16; H, 6.15;
N, 6.96.
13. General procedure for the intermolecular palladium-cat-
alyzed synthesis of pyridyl ethers. An oven-dried flask was
charged with palladium(II) acetate (8 mol %), racemic-2-