Journal of Medicinal Chemistry Scheme 1. Unsubstituted Piperazines Previously Disclosed evaluate the corresponding eﬀects on potency as well as a means to improve oral exposure. ■ CHEMISTRY On the basis of the designed molecules, it was clear that previous synthetic routes were not amenable for the desired compounds because we could not utilize the 3 + 2 cyclization.6 Distinct syntheses were designed and executed to obtain substitution at diﬀerent positions of a piperazine ring. Scheme 2 summarizes how the 8-substituted piperazines were prepared. The synthesis started with an alkylation reaction between Article Cbz-protected glycine derivative 2 and bromide 3. Adduct 4 was then reﬂuxed with NH4OAc in toluene to give imidazole 5 with removal of water using a Dean−Stark apparatus.7 Regioselective N-alkylation with ethyl 2-bromoacetate followed by a one-pot deprotection/cyclization sequence furnished the lactam core, which was reduced by borane to furnish amine 8. The quaternary β-carbon did not pose a signiﬁcant amount of steric hindrance for the HATU mediated amidation reaction with N-Boc-glycine. Amide 9 was obtained at room temper- ature in decent yield and further was brominated to provide intermediate 10. Then a standard Buchwald−Hartwig amina- tion reaction with substituted aniline followed by deprotection ﬁnished the synthesis of compound 12 with the desired alkyl modiﬁcation at position 8. The overall sequence involved nine steps with an overall yield of 17%. Scheme 3 describes the synthesis of 6,6-dimethyl analogues. Analogous chemistry to compound 12 was used for the ﬁrst two steps to provide imidazole 5a. The compound was regioselectively N-alkylated with methallyl chloride to obtain the key intermediate for the piperazine cyclization step. The intramolecular hydroamination reaction proved to be diﬃcult, and after extensive screening, treating the substrate 5a with a 5:1 mixture of acetic acid and methanesulfonic acid at 210 °C produced the cyclized core with simultaneous loss of the Figure 1. Central piperazine ring oxidation is a major metabolic and chemical instability site in compound 1. Scheme 2. Modiﬁcation on the 8 Position of Imidazolopiperazine Corea aReagents and conditions: (a) K2CO3, DMF, rt, 84%; (b) NH4OAc, toluene, reﬂux, 88% (c) ethyl 2-bromoacetate, Cs2CO3, DMF, rt, 83%; (d) Pd/ C, H2 (balloon), MeOH, rt, 91%; (e) BH3·THF, THF, reﬂux, 95%; (f) HATU, DIEA, CH2Cl2, rt, 70%; (g) Br2, AcOH, CH2Cl2, rt, 100%; (h) ArNH2, Pd2(dba)3, xantphos, Cs2CO3, dioxane, 150 °C, 89% (for example 22, Ar = 4F-Ph and R1 = R2 = Me); (i) TFA, CH2Cl2, rt, 52% (for example 22, Ar = 4F-Ph and R1 = R2 = Me). 4245 dx.doi.org/10.1021/jm300041e | J. Med. Chem. 2012, 55, 4244−4273