716
A. Benjahad et al. / Bioorg. Med. Chem. Lett. 17 (2007) 712–716
precipitate was filtered off, washed with water, dried
8. Kobayashi, K.; Koyama, E.; Namatame, K.; Kitaura, T.;
Kono, C.; Goto, M.; Obinata, T.; Furukawa, N. J. Org.
Chem. 1999, 64, 3190.
thoroughly under vacuum at room temperature, and then
suspended in DMF (20 mL). The mixture was refluxed for
l h and the solvent was evaporated under vacuum. Purifi-
cation by silica-gel flash chromatography (CH2Cl2/EtOH;
98:2) provided 4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-6-
methyl-2(1H)-pyridinone 3 (4.3 g, 91%) as colorless micro-
crystals; mp 240 ꢁC. 1H NMR (CDCl3) d 13.35 (1H, br s), 6.68
(1H, s), 6.46 (2H, s), 2.44 (3H, s), 2.35 (2H, q, J = 7.3 Hz), 2.26
(6H, s), 0.96 (3H, t, J = 7.2 Hz). Step 2: to a mixture of
compound 3 (1.0 g, 2.6 mmol) and palladium tetrakistriphe-
nylphosphine (300 mg, 10% mol) in toluene (15 mL) at room
temperature was added tributyl(vinyl) tin (0.91 mL,
3.1 mmol), and the mixture was refluxed for 12 h. Water
(8 mL) was then added and the aqueous layer was extracted
with CH2Cl2 and the combined organic layers were dried over
MgSO4. Thesolvent wasremovedand the residue waspurified
by flash chromatography (neutral alumina; CH2Cl2/EtOH
(98:2)) to give the title compound 4j as colorless microcrystals
(520 mg, 70%); mp 208 ꢁC. 1H NMR (CDCl3) d 12.28 (1H, br
s), 6.40–6.70 (4H, m), 5.32 (1H, dd, J = 10.3 and 4.4 Hz), 3.73
(3H, s),. 2.39 (3H, s), 2.20–2.35 (8H, m), 0.97 (3H, t,
J = 7.4 Hz) MS (ES): m/z 282.2 (MꢀH).
9. 4-(3,5-Dimethylphenoxy)-5-ethyl-3-methoxy-6-methyl-2(1H)-
pyridinone 4w. To a solution of copper(I) iodide (2 g,
10.53 mmol) in DMF (15 mL) was added at room
temperature iodopyridinone 3 (1.5 g, 3.9 mmol) then
sodium methoxide (7.5 mL, 30% w/w solution in MeOH).
The mixture was stirred at 90 ꢁC in a oil bath for 48 h,
followed by addition of H2O and extraction with EtOAc.
The combined organic layers were dried (MgSO4) and
concentrated. The residue was silica-gel column chro-
matographed (CH2Cl2/i-PrOH; 97:3) as the eluent. Crys-
tallization from acetone/MeOH (80/20) gave pyridinone
1
4w (0.32 g, 29%) as a white solid: mp 178 ꢁC. H NMR
(CDCl3) d 13.1 (1H, br s), 6.69 (1H, s), 6.56 (2H, s), 3.73
(3H, s), 2.38 (5H, m), 2.29 (6H, s), 1.04 (3H, t, J = 7.4 Hz)
Anal. Calcd for (C17H21NO3): C, 71.06; H, 7.37; N, 4.87.
Found: C, 70.76; H, 7.42; N,4.82.
10. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Castro, B. R. Org.
React. 1983, 29, 1.
11. Chen, Q.-Y.; Wu, S.-W. J. Chem. Soc., Chem. Commun.
1989, 705.
5. Dickens, M. J.; Gilday, J. P.; Mowlem, T. J.; Widdowson,
D. A. Tetrahedron 1991, 47, 8621.
6. Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39,
8621.
12. All compounds were tested for potency (IC50, nM) to
achieve 50% protection of MT-4 cells from HIV-1 cyto-
pathicity as determined by the MTT method: Pauwels, R.;
Balzarini, J.; Baba, M.; Snoek, R.; Schols, D.; Herdewijn,
P.; Desmyter, J.; De Clercq, E. J. Virol. Methods 1988, 20,
309, Unless noted otherwise, the LAI strain of HIV-1 was
the infecting virus. Other infecting mutant (in the reverse
transcriptase) strains of virus are characterized in the tables
by the mutated amino acid position and the one letter codes.
For instance, 181C refers to replacement of tyrosine at
position 181 with cysteine. All determinations are average
values for three or more tests.
13. Himmel, D. M.; Das, K.; Clark, A. D., Jr.; Hughes, S. H.;
Benjahad, A.; Oumouch, S.; Guillemont, J.; Coupa, S.;
Poncelet, A.; Csoka, I.; Meyer, C.; Andries, K.; Nguyen, C.
H.; Grierson, D. S.; Arnold, E. J. Med. Chem. 2005, 48, 7582.
14. Hopkins, A. L.; Ren, J.; Tanaka, H.; Baba, M.; Okamato,
M.; Stuart, D. I.; Stammers, D. K. J. Med. Chem. 1999,
42, 4500.
7. 4-(3,5-Dimethylphenoxy)-5-ethyl-6-methyl-3-methylsulfanyl-
2(1H)-pyridinone 4s. n-Butyllithium (1.6 M in hexane,
2.44 mL, 3.9 mmol) was added dropwise at ꢀ78 ꢁC to a
solution of 3 (575 mg, 1.5 mmol) in THF (25 mL) under
nitrogen. The mixture was stirred at ꢀ78 ꢁC for 20 min. and
dimethyl disulfide (0.67 mL, 7.5 mmol) in THF (3 mL) was
added dropwise. The mixture was stirred at room temper-
ature for 2 h and methanol (20 mL) was added. The mixture
as then concentrated under vacuum and the residue was
purified by silica-gel flash chromtography (CH2Cl2/EtOH;
97:3) providing compound 4s as a yellow solid (156 mg,
35%) mp 186–188 ꢁC 1H NMR (CDCl3) d 13.33 (1H, br s),
7.25 (1H, s), 6.44 (2H, s), 2.42 (3H, s), 2.34 (3H, s), 2.31
(2H, q, J = 7.3 Hz), 2.25 (6H, s), 0.98 (3H, t, J = 7.3 Hz)
MS (ES): m/z 302.1 (MꢀH).