Fig. 3. Mitsunobu reaction-based derivatization resulting in O-alkylated pyrrolopyrimidine and N-alkylated pyrrolopyrimidin-4-one EGFR inhibitors. (A) Synthesis of compounds 19 and 29,^a (B) separation of SEM-protected compounds 28a and 28b, (C) HMBC NMR spectroscopic analysis reveals the structure of the separated constitutional isomers, (D) small-molecule crystal structure of compound 28a, revealing the N-ethyl-substituted pyrrolopyrimidin-4-one structure (CCDC ID: ; 1876852). ^aReagents and conditions: (i) N-iodosuccinimide, DMF, rt, 97%; (ii) SEM-Cl, NaH, THF, 0 °C, 71%; (iii) meta-nitrobenzeneboronic acid, Pd(PPh₃)₄, K₂CO₃, MeCN : H₂O (2 : 1), 150 °C, 90 min, μw, 74%; (iv) N-bromosuccinimide, MeCN, rt, quant.; (v) 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol ester, Pd(PPh₃)₄, K₂CO₃, DME : H₂O (5 : 1), 150 °C, 90 min, μw, 68%; (vi) iron powder, NH₄Cl, EtOH : H₂O (4 : 1), reflux, 94%; (vii) acryloyl chloride, DIPEA, THF, 0 °C, 76%; (viii) ROH, DIAD, PPh₃, THF, 40 °C, 30 min, sonication; (ix) TFA : CH₂Cl₂ (1 : 3), rt, then NaOH : THF (1 : 1), rt, 4–79% over two steps.