Review The Recent Impact of Solid-Phase Synthesis on Medicinally Relevant Benzoannelated Nitrogen Heterocycles Stefan Bra¨se,* Carmen Gil and Kerstin Knepper Kekule ´-Institut fu ¨r Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universita ¨t Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany Received 7 November 2001; accepted 7 January 2002 Dedicated to Professor Dr. Heinrich Wamhoff on the occasion of his 65th birthday Abstract—Benzoannelated heterocycles such as benzodiazepines and indoles can be prepared efficiently through cyclization on solid supports, although no single approach is currently universal for the preparation of all benzoannelated N-heterocycle chemistries. In this review, a number of synthetic strategies for the generation of benzoannelated nitrogen heterocycles using resin-bound sub- strates have been described. Classical heterocycle forming reactions such as the Fischer indole, the Bischler–Napieralski tetra- hydroisoquinoline, the Pictet–Spengler tetrahydro-b-carboline, the Tsuge, the Nenitzescu and the Richter cinnoline reaction are presented. In addition, the Heck, Sonogashira, Wittig, Diels–Alder, and olefin metathesis reactions have been also used. Multi- component reactions such as the Grieco three-component assembly have been exploited for the synthesis of heterocycles. Cyclative cleavage from the solid support is particularly suitable for the synthesis of heterocycles while particular emphasis has been focused on the synthesis of libraries and the use of combinatorial chemistry techniques. In addition, the most relevant pharmacological properties of benzoannelated nitrogen heterocycles are included. # 2002 Elsevier Science Ltd. All rights reserved. 0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(02)00025-1 Bioorganic & Medicinal Chemistry 10 (2002) 2415–2437 Contents Introduction ............................................................................................................................................................. 2416 Benzoannelated five-membered heterocycles ............................................................................................................ 2417 Indoles and related heterocycles ........................................................................................................................... 2417 Benzimidazoles ..................................................................................................................................................... 2420 Benzotriazoles ....................................................................................................................................................... 2421 Indazoles ............................................................................................................................................................... 2421 Abbreviations: Ac, acetyl; AMEBA, acid-sensitive methoxy benzalde- hyde linker; BOP, benzotriazol-1-yloxytris(dimethylamino)-phospho- nium hexafluorophosphate; BSA, bis(trimethylsilyl)acetamide; CSA, 10- camphorsulfonic acid; DBU, 1,8-diazabicyclo[5,4,0]undec-7-ene; DCC, N,N-dicyclohexylcarbodiimide; DIC (DIPC), N,N 0 -diisopropylcarbodi- imide; DMA, N,N 0 -dimethylacetamide; DMAP, 4-dimethylaminopyri- dine; DMF, N,N-dimethylformamide; DMSO, dimethylsulfoxide; DNA, desoxyribonucleic acid; EDC, (3-dimethylaminopropyl)-3-ethylcarbodii- mide; Fmoc, fluorenylmethyloxycarbonyl; HATU, o-(7-azabenzotriazol- 1-yl)-1,1,4,4-tetramethyluronium-hexafluorophosphate; HBTU, 2-(1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HEPS, 2-hydroxyethyl polystyrene; HIV, human immunodeficiency virus; HOAt, 1-hydroxy-7-azabenzotriazole; HOBt, N-hydro- xybenzotriazole; 5-HT, 5-hydroxytryptamine; HTS, high throughput screening; Ms, mesyl; NMP, N-methylpyrrolidinone; PyBroP, bromo- tris-pyrrolidino-phosphonium hexafluorophosphate; SPOS, solid phase organic synthesis; TBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tet- ramethyluronium tetrafluoroborate; Tf, trifluoromethylsulfonyl; TFA, trifluoroacetic acid; THF, tetrahydrofuran; THP, tetrahydropyranyl; TMOF, trimethylorthoformate; TPCD, [Co(pyridine) 4 (HCrO 4 ) 2 ]; Trt, trityl; Ts, tosyl. *Corresponding author. Fax: +49-228-739608; e-mail: braese@uni- bonn.de