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L. Revesz et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3595–3599
R3
R3
R3
Piperidinyl substituted oxazoles 32, 34 and thiazoles 36,
37 were obtained according to Scheme 3 by condensing
bromoketone4 4 or 5 with the amide or thioamide4 of N-
protected piperidine-4-carboxylic acid. Thiazole 28 was
available in 70% yield, while the yields for oxazoles 27
and 29 were lower with 11% and 40%. Fluorides 27, 28
and sulfoxide 30 heated with cyclohexylamine or S-())-
1-phenylethylamine provided oxazoles 31, 33 and thia-
zole 35. Removing the protecting groups generated the
piperidinyl-NH substituted oxazoles 32, 34 and thiazole
36. N-methylation of 36 rendered thiazole 37.
N
Y
N
Y
N
Y
Br
O
X
N
X
N
a) b)
c) d) e) f)
F
N
HO
F
F
4: R3=F; Y=CH
5: R3=SMe; Y=N
6: R3=F; X=O; Y=CH
7: R3=F; X=NH; Y=CH
13: R3=F; X=O; Y=CH
14: R3=F; X=N-SEM; Y=CH
15: R3=F; X=S; Y=CH
8: R3=F; X=N-SEM; Y=CH
9: R3=F; X=S; Y=CH
16: R3=SMe; X=O; Y=N
17: R3=SMe; X=N-SEM; Y=N
18: R3=S(O)Me; X=O; Y=N
19: R3=S(O)Me; X=N-SEM; Y=N
20: R3=c; X=N-SEM; Y=CH
21: R3=c; X=N-SEM; Y=N
22: R3=c; X=O; Y=CH
10: R3=SMe; X=O; Y=N
11: R3=SMe; X=NH; Y=N
12: R3=SMe; X=N-SEM; Y=N
23: R3=c; X=O; Y=N
1,2,4-Substituted imidazoles 44 and 45 were prepared
according to Scheme 4, starting from 2-aryl-4-bromo-
imidazoles5 38 and 39, which were regioselectively con-
verted into 4-imidazol-1-ylpyrimidines 40 and 42. The
corresponding sulfoxides were subsequently heated with
S-())-1-phenylethylamine and cyclopentylamine to
provide pyrimidines 41 and 43. Br/Li exchange and
treatment with N-methyl-4-piperidone at low tempera-
ture gave the desired 4-hydroxy-1-methylpiperidine
substituted imidazoles 44 and 45.
24: R3=c; X=S; Y=CH
25: R3=c; X=NH; Y=CH
26: R3=c; X=NH; Y=N
Scheme 2. Reagents and conditions: (a) Formamide, H2SO4 cat.,
150 °C, 15 min, 25–50% 6, 10. Ammonium formate, formamide, formic
acid, 165 °C, 20 min, 30–45% 7, 11. Formamide, P2S5, 30 min, 90 °C,
44% 9. (b) KN(TMS)2, THF/DMF (1:2), SEM-Cl, )78 °C to rt, 54–
59% 8, 12. (c) nBuLi, THF, N-methyl-4-piperidone, )100 or )78 or
)40 °C depending upon substrate; 20–60% 13–17. (d) mCPBA,
CH2Cl2/HOAc (1:2) 0 °C, 10 min, 60–70% 18, 19. (e) S-())-1-Phenyl-
ethylamine, 140–190 °C, 30 min to 4 h; 35–70% 20–24. (f) EtOH/HCl
concd (1:1) rt, 20 min, 80–90% 25, 26.
1,2,4-Substituted imidazoles 53 and 55 were prepared
according to Scheme 5, starting with the regioselective
pyrimidinylation of 2-phenyl-4-(4-piperidinyl)-imidaz-
oles5 46 and 47 to generate 48 and 50. The corre-
sponding sulfoxides 49 and 51 were heated with
cyclohexylamine and provided imidazol-1-yl pyrim-
idines 52 and 54. Removal of the ethylcarbamate pro-
13–17. The R3 group in 20–24 was introduced by
heating sulfoxides 18, 19 and fluorides 13–15 with S-())-
1-phenylethylamine. Removing the SEM-protecting
group from imidazoles 20 and 21 delivered 25 and 26.
R3
R3
R3
N
Y
N
Y
N
Y
Br
O
X
N
X
N
c) d) e) f)
a) b)
N
R4
N
R4
F
F
F
31: R3=b; R4=COOtBu; X=O; Y=CH
32: R3=b; R4=H; X=O, Y=CH
33: R3=b; R4=COOtBu; X=O; Y=N
34: R3=b; R4=H; X=O; Y=N
35: R3=c; R4=COOEt; X=S; Y=CH
36: R3=c; R4=H; X=S; Y=CH
37: R3=c; R4=Me; X=S; Y=CH
4: R3=F; Y=CH
5: R3=SMe; Y=N
27: R3=F; R4=COOtBu; X=O; Y=CH
28: R3=F; R4=COOEt; X=S; Y=CH
29: R3=SMe; R4=COOtBu; X=O; Y=N
30: R3=S(O)Me; R4=COOtBu; X=O; Y=N
Scheme 3. Reagents and conditions: (a) 4-Carbamoylpiperidine-1-carboxylic acid tert butyl ester, melt at 160 °C, 20 min. (ii) EtOH/HCl concd (1:1)
rt, 10 min. (iii) BOC2O, THF, rt, 1 h, 11% 27. 4-Thiocarbamoylpiperidine-1-carboxylic acid ethyl ester,4 DMF, 60 °C, 30 min, 70% 28. DMPU, 4-
carbamoylpiperidine-1-carboxylic acid tert butyl ester, 150 °C, 15 min, 40% 29. (b) mCPBA, CH2Cl2/HOAc (1:2) 0 °C, 10 min, 90% 30. (c)
(i) Cyclohexylamine, 200 °C, 70 min. (ii) BOC2O, THF, rt, 1 h, 79% 31. Cyclohexylamine, 110 °C, 1 h, 65% 33. S-())-1-Phenylethylamine, 195 °C, 5 h,
67% 35. (d) EtOH/HCl concd (1:1), 10 min, rt, 70–80% 32, 34. (e) CHCl3, TMSI, 4.5 h, 60 °C, 80% 36. (f) LiAlH4, THF, reflux, 30 min, 80% 37.
R3
R3
N
N
N
N
HN
a) b) c)
d)
Br
N
N
N
Br
N
N
HO
N
R2
R2
R2
38: R2=4-F
39: R2=3-CF3
40: R2=4-F; R3=SMe
41: R2=4-F; R3=c
42: R2=3-CF3; R3=SMe
43: R2=3-CF3; R3=a
44: R2=4-F; R3=c
45: R2=3-CF3; R3=a
Scheme 4. Reagents and conditions: (a) 4-Chloro-2-methylthio pyrimidine, toluene, KN(TMS)2, 24 h, 80 °C, 60–90% 40, 42. (b) mCPBA, CH2Cl2,
0 °C, 15 min, 90%. (c) S-())-1-Phenylethylamine, 5 min, 120 °C, 78% 41. Cyclopentylamine, 30 min, 60 °C, 80% 43. (d) nBuLi, THF, N-methyl-4-
piperidone, )100 °C (for 45) or )78 °C (for 44), 36–42%.