Chapter I. Synthesis, modification and bioactivity of bicyclic thieno[3,2-D]pyrimidines

A.

B.

Reagents and conditions: (a) formamide, 6−8 h, 60−65%; (b) HNO3, conc. H2SO4, 7e (for 6e), 7f (for 6f), 7g (for 6g), 0 °C, 6−8 h, 50− 70%. (c) Triethylamine, DCM, propionyl bromide (for 23e), butanoyl bromide (for 23f), benzoyl chloride (for 23g), rt, 4−8 h, 80−85%; (d) 30% NH4OH, 23e (for 7e), 23f (for 7f), 23g (for 7g), 23h (for 7h), rt, 6−8 h, 28−60%; (e) acetic anhydride, 14 h, 75%.
A wide range of substituents were installed at the N3- position of 6a as shown in Scheme to generate a library of N3-alkylated analogues. For example, 9a−9h were prepared by reacting 6a with various (un)substituted phenylalkyl halides in the presence of potassium carbonate in dimethylformamide (DMF). To avoid complexity associated with multiple nitrated products during the synthesis of target compounds 10a−10d, we began the synthetic sequence with a selective nitration of the thiophene substrate 23a. Thus, intermediate 23a was nitrated using concentrated sulfuric acid and fuming nitric acid to produce 26. Intermediate 26 was hydrolyzed in the presence of lithium hydroxide to yield 27, which was subsequently cyclized using acetic anhydride under reflux conditions to obtain isatoic anhydride-like intermediate 28. Intermediate 28 was then condensed with substituted anilines to produce target compounds 10a−10d. 30 To prepare analogues with N3-ester (11a and 11b), -carboxylic acid (11c), and -amide (11d−11f) substituents, 6a was subjected to N-alkylation using respective halides in the presence of potassium carbonate and DMF to yield 11a and 11b. 32 The ester 11a was subjected to lithium hydroxide-mediated hydrolysis to obtain 11c, and the resulting carboxylic acid was coupled with aromatic/aliphatic amines to yield 11d− 11f.