Solution-phase parallel synthesis of a multi-substituted benzo[b]thiophene library

Abstract

Generation of a library using parallel syntheses of multi-substituted benzo[b]thiophenes is described. The requisite 3-iodobenzo[b]thiophenes are readily prepared in excellent yields from various alkynes bearing electron-rich aromatic rings by electrophilic cyclization using I(2) in CH(2)Cl(2). The heteroaromatic carbon-iodine bonds allow further diversification by palladium-catalyzed Suzuki-Miyaura, Sonogashira, Heck, and carboalkoxylation chemistry to give multi-substituted benzo[b]thiophene derivatives.

Figure 1

Chemical structures of raloxifene (1), arzoxifene (2), combretastatin A-4 (3), and 3-aroyl-2-aryl-6-methoxybenzo[b]thiophene analogues 4

Figure 2

3-Iodobenzo[b]thiophene library 8{1-18}

Figure 3

Boronic acid 9{1-20} sublibrary

Figure 4

Terminal alkyne 10{1-14} sublibrary

Figure 5

Styrene 11{1-5} and alcohol 12{1-2} sublibrary

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Method A (Suzuki-Miyaura coupling): 10 mol % Pd(PPh₃)₄, K₂CO₃ (2.5 equiv), (Het)ArB(OH)₂ (9, 1.5 equiv), toluene/EtOH/H₂O (20/5/1), reflux; Method B (Sonogashira coupling): 3 mol % PdCl (PPh₃)₂, 3 mol % CuI, Et₂NH, R⁵C≡CH (10, 1.2 equiv), DMF, 100 °C, 20 min, using microwave irradiation; Method C (Heck coupling): 5 mol % Pd(OAc)₂, n-Bu NI (1.0 equiv), Na₂CO₃ (2.5 equiv), R⁵CH=CH₂ (11, 1.2 equiv), DMF, 80 °C; Method D (carboalkoxylation): CO (1 atm), 3 mol % Pd(OAc)₂, 5 mol % dppf, TEA (2.0 equiv), R⁵OH (12, 1.5 equiv), DMF, 70 °C.