Cyclopropyl building blocks in organic synthesis, part 84. A new and productive route to 1-heteroarylcyclopropanols

(E/Z)-2-(1-Allyloxycyclopropyl)-3-methoxyacrylonitrile (4-All) was designed and prepared in five steps (58% overall yield) from ethyl cyclopropylidenacetate as a valuable precursor to various 1-heteroarylcyclopropanols. Its condensation with amidines, guanidine, hydrazine, and methyl thioglycolate and subsequent removal of the allyl protecting group yields 1-heteroarylcyclopropanols such as 1-OH (36% over 2 steps), a very potent NO-independent stimulator of soluble guanylate cyclase. Direct cleavage of the allyl ether protecting group [by palladium-catalyzed substitution with lithium p-toluenesulfinate in AcOH or treatment with c-HexMgBr/Ti(OiPr)(4)] gives highly functionalized, sterically congested 1-heteroarylcyclopropanols 29, 30, and 34 with intact amino and ester groups. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).