Journal of Medicinal Chemistry ARTICLE Scheme 1. General Synthetic Route to 3,4-Dihydroquinazoline Analogues (Also See Schemes S1, S3, and S4 of the Supporting Information; For Details of Individual Substituents, See Tables 2 5; Note That Products of This Route Are Racemates)a a Reagents and conditions: (i) R2COCl, DMAP, pyridine, CH2Cl2, 25 C, 16 h; (ii) H2N(CH2)nR3, EtOH, 160 C (MW), 2 h; (iii) NaBH4, DMF, or EtOH, 50 C, 16 h; (iv) POCl3, CH2Cl2, 0 25 C, 16 h; (v) EtOH, 160 C (MW) 2 h; (vi) NaBH4, EtOH, 78 C, 16 h. Scheme 2. Synthetic Routes for the Preparation of Two 3,4-Dihydroquinazoline Amide Arrays (For Additional Details, See Scheme S3 of the Supporting Information; For Details of Individual Substituents, See Table 3)a a Reagents and conditions: (i) (1) HCl, dioxane/THF, 25 C, 2 h; (2) RCOCl, pyridine, CH2Cl2, 40 C, 16 h. Scheme 3. Synthetic Routes for the Preparation of Bi-aryl 3,4-Dihydroquinazoline Analogues (See Schemes S4 and S5 of the Supporting Information for the Synthesis of 15c and 18, Respectively; For Details of Individual Substituents, See Table 4)a a Reagents and conditions: (i) (HO)2B-R6/8, K3PO4, Pd(PPh3)4, dioxane/H2O, 120 C (MW), 0.5 h. small collection of R4 analogues (32a g). Benzoxazinone 24 was converted into quinazolinone 30 by reaction with 1-(2-ami- noethyl)piperidine and subsequent microwave-assisted cyclocon- densation.33 Reaction of 30 with either substituted phenyl Grignard reagents or benzylmagnesium chloride aﬀorded the 4-substituted 3,4-dihydroquinazolin-4-ols 31a h.34 However, the attempted reactions between 30 and cyclohexylmagnesium or cyclopentyl- magnesium chloride were unsuccessful, suggesting a limitation in the range of R4 groups that could be incorporated via this route. Benzylic alcohols 31a g were subsequently reduced by treatment with Et3SiH and BF3 3 OEt2 to give the desired 3,4-dihydroquina- zolines 32a g. 6516 dx.doi.org/10.1021/jm200312v |J. Med. Chem. 2011, 54, 6514–6530