J. B. Laursen et al. / Bioorg. Med. Chem. Lett. 12 (2002) 171–175
175
the methyl ester on TLC. Complete conversion was observed
within 1 h. 1 mL of the solution was added to a silylated glass
tube (see above) or plastic syringe containing on-resin 1 (0.1
equiv) and DMAP (0.66 equiv) in CH2Cl2 (1 mL). The mixture
was shaken for 16 h and washed (2ꢁDMF, 2ꢁCH2Cl2). Con-
versions: 40–100%.
2H, H3, H8), 7.71–7.25 (m, 7H, H10, 6ꢁAr–H), 6.85 (m, 2H,
Ar–H), 5.19 (s, 2H, CH2–Ar), 2.40(s, 3H, Me–Ar), 1.78 (d,
3H, H20, J1 ,2 =7 Hz). 17: d 8.99 (dd, 1H, H2, J2,3=7.4 Hz,
J2,4=1.5 Hz), 8.56 (dd, 1H, H4, J3,4=9.2 Hz), 8.10(dd, 1H,
H9, J8,9=8.7 Hz, J7,9=1.2 Hz), 8.03 (dd, 1H, H7,
J7,8=7.8 Hz), 7.96 (br.s, 1H, H3), 7.74–7.69 (m, 2H, H8, Ar–
H), 7.51–7.28 (m, 7H, H10, 6ꢁAr–H), 6.98 (d, 1H, Ar–H,
J=8.4 Hz), 5.18 (br.s, 2H, CH2–Ar), 2.27 (s, 3H, Me), 1.81 (d,
0
0
Procedure for formation of acid chloride of 8 and coupling to
on-resin 1. Benzoic acid derivative 8 (115 mmol, 5 equiv) and
3-nitrotriazole (2 equiv) were dissolved in CH2Cl2 (DMF
added to assist dissolvation). N,N0-Dicyclohexylcarbodiimide
(2 equiv) and DMAP (1 equiv) were added and the mixture
was poured into a silylated glass tube (see above) containing
on-resin 1 (1 equiv). The reaction mixture was shaken for 16 h
and washed (2ꢁMeOH, 2ꢁDMF and 3ꢁCH2Cl2). The ester-
ification was repeated. Conversion: 1st: 53%; 2nd: 66%.
General procedure for cleavage of derivatives 15–26 from
resin. The resin was reacted with TFA–CH2Cl2 (5:995) for
40min and washed (2 ꢁCH2Cl2).
3H, H20, J1 ,2 =6.5 Hz). 18: d 9.00 (d, 1H, H2, J2,3=11 Hz),
0
0
8.60(d, 1H, H4, J8,9=11 Hz), 8.25–7.97 (m, 4H, H9, H7, H3,
0
H8), 7.61–7.10(m, 5H, H1 0, 4ꢁAr–H), 1.90(d, 3H, H2
,
9.00 (dd, 1H, H2, J2,3=7.3 Hz,
0
J1 ,2 =7 Hz). 19:
0
d
J2,4=ꢂ1 Hz), 8.59 (dd, 1H, H4, J3À4=11.4 Hz), 8.21 (dd, 1H,
H9, J8,9=7.0Hz, J7,9=ꢂ1 Hz), 8.09–7.94 (m, 4H, H7, H3,
H8, Ar–H), 7.82 (m, 1H, Ar–H), 7.52–7.41 (m, 2H, H10, Ar–
H), 7.25 (m, 1H, Ar–H), 1.95 (d, 3H, H20, J1 ,2 =6.4 Hz). 20: d
9.00 (dd, 1H, H2, J2,3=7.7 Hz, J2,4=ꢂ1 Hz), 8.59 (dd, 1H,
H4, J3,4=9.9 Hz), 8.23–7.96 (m, 6H, H9, H7, H3, H8, 2ꢁAr–
H), 7.43 (q, 1H, H10), 7.15 (m, 2H, Ar–H), 1.89 (d, 3H, H20,
0
0
14. Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147.
15. Foye, W. O.; Lemke, T. L.; Williams, D. A. In Principles
of Medicinal Chemistry, 4th ed.; Balado, D. Ed.; Williams &
Wilkins: Boston, 1995; pp. 759–821.
16. Marquerettaz, X.; O’Neill, R.; Fitzmaurice, D. J. Am.
Chem. Soc. 1994, 116, 2629.
0
J1 ,2 =6.7 Hz). 22:
0
d 9.01 (dd, 1H, H2, J2,3=7.3 Hz,
J2,4=1.2 Hz), 8.61 (dd, 1H, H4, J3,4=9.4 Hz), 8.24 (dd, 1H,
H9, J7,9=0.7 Hz, J8,9=9.2 Hz), 8.14 (m, 1H, H7), 8.07 (m, 1H,
H3), 8.02 (m, 1H, H8), 7.53–7.38 (m, 5H, 4ꢁAr–H, H10), 1.90
(d, 3H, H20, J1 ,2 =6.8 Hz). 23:
d 8.90(dd, 1H, H2,
0
0
17. Wissner, A.; Grudzinskas, C. V. J. Org. Chem. 1978, 43,
3972.
18. Petersen, L.; Jensen, K. J. J. Org. Chem. 2001, 66, 6268.
19. Laursen, J. B.; Petersen, L.; Jensen, K. J. Org. Lett. 2001,
3, 687.
J2,3=7.3 Hz, J2,4=1.5 Hz), 8.50(dd, 1H, H4, J3,4=8.8 Hz),
8.15 (dd, 1H, H7, J7,8=8.7 Hz, J7,9=1.5 Hz), 8.05–7.90 (m,
5H, H3, H8, H9, 2ꢁAr–H), 7.49 (m, 1H, Ar–H), 7.37 (q, 1H,
H10), 7,35 (t, 1H, Ar–H), 1.91 (d, 3H, H20, J1 ,2 =6.6 Hz). 26: d
8.99 (dd, 1H, H2, J2,3=7.3 Hz, J2,4=1.5 Hz), 8.59 (dd, 1H,
H4, J3,4=9.8 Hz), 8.21 (m, 1H, H9), 8.06 (m, 1H, H7), 8.05–
0
0
20. Nielsen, J.; Lyngsø, L. O. Tetrahedron Lett. 1996, 37, 8439.
21. In the up-scaled reaction, 23 and 27 were isolated as yel-
low crystalline compounds with mp 176–178 and 168–171 ꢀC,
respectively.
7.90(m, 3H, H3, H8, Ar–H), 7.81–7.60(m, 3H, Ar–H), 7.47
0
(q, 1H, H10), 1.90(d, 3H, H2 , J1 ,2 =6.4 Hz). 27: 1H NMR
(CDCl3): d 9.00 (dd, 1H, H2, J2,3=6.8 Hz, J2,4=1.7 Hz), 8.65
(dd, 1H, H4, J3,4=9.0Hz), 8.57 (m, 1H, H7), 8.46 (dd, 1H,
H2, J2,3=9 Hz, J2,4=1.5 Hz), 8.35 (dd, 1H, H4, J3,4=7 Hz),
8.25 (dd, 1H, H9, J8,9=7 Hz, J7,9=1.5 Hz), 8.21 (m, 1H, H7),
8.14 (m, 1H, H200), 8.03–8.09 (m, 3H, H3, H8, H600), 8.00 (dd,
1H, H9, J8,9=5 Hz, J7,9=ꢂ1 Hz), 7.92–7.88 (m, 2H, H3, H8),
7.67 (q, 1H, H10), 7.57 (m, 1H, H-400), 7.49 (dq, 1H, H10,
0
0
1
22. Selected H NMR data (CDCl3): 15: d 8.99 (dd, 1H, H2,
J2,3=7.1 Hz, J2,4=ꢂ1 Hz), 8.58 (dd, 1H, H4, J3,4=11.9 Hz),
8.19 (dd, 1H, H9, J8,9=11 Hz, J7,9=ꢂ1 Hz), 8.15–7.78 (m,
3H, H7, H3, H8), 7.32–7.09 (m, 9H, H10, 8ꢁAr–H), 4.97 (m,
2H, CH2–Ar), 2.33 (s, 3H, Me–Ar), 1.91 (d, 3H, H20,
0
J1 ,2 =7.2 Hz). 16:
0
d
8.98 (dd, 1H, H2, J2,3=6 Hz,
J2,4=ꢂ1 Hz), 8.57 (dd, 1H, H4, J3,4=11.4 Hz), 8.10(d, 1H,
J=2.1 Hz), 7.43 (t, 1H, H500, J=7.7 Hz), 1.96 (d, 3H, H20,
0
0
J1 2 =6.4 Hz), 1.91 (d, 3H, H2 , J1 2 =6.8 Hz).
0
0 0
H9, J8,9=11 Hz), 8.01 (d, 1H, H7, J7,8=11 Hz), 7.93–7.83 (m,