Hydrochloric Acid → Methyl 5-[2-(benzyloxy)phenyl]-6-cyclohexyl-3-formyl-4-(methoxymethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate

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Reaction Conditions

Reaction Steps

Methyl 5-bromo-6-cyclohexyl-4-(methoxymethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate, 2-benzyloxyphenyl boronic acid (1.8 eq.) and Pd(PPh3)2Cl2 (0.3 eq.) were dissolved in dioxane (0.09M). 2M Na2CO3-solution (8.5 eq.) was added and after degassing the mixture was heated for 5 h to 110° C. All volatiles were evaporated i. vac. and the residual material was subjected to chromatography (PE:EtOAc, 4:1). The product fractions were evaporated and the sticky solid obtained was dissolved in MeOH/THF (1:1, 0.15 M) and 1M KOH-solution (excess) was added. The mixture was left stirring for 3 days at 40° C. All volatiles were evaporated i. vac. and the residual material was dissolved in water. The solution was acidified with 1N aq. HCl. The resulting suspension was extracted DCM. The organic phase was washed with brine and dried over Na2SO4. All volatiles were evaporated and the remaining solid was dissolved in THF (0.2M). This solution was added slowly at −78° C. to a mixture of TMEDA (5 eq.) and 1.6M n-butyl lithium (5 eq.) in THF, followed by the addition of an excess of DMF. After stirring for 30 min at −78° C. an excess of sat. aq. NH4Cl-solution was added and the mixture was left standing for 90 min at −78° C. Then the mixture was transferred into an excess of 0.2N aq. HCl. The mixture was extracted with DCM, the organic phase was washed with brine, dried over Na2SO4 and all volatiles were evaporated i. vac. The residual material was dissolved in DMF (0.5M) and an excess of K2CO3 was added, followed by an excess of methyl iodide. The mixture was left stirring over night, then all volatiles were evaporated. The residual material was purified by chromatography (PE:EtOAc, 8.5:1.5) to give a yellow solid (28%). MS (ES+) m/z 518 (M+H)+.

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