A General Approach to 5-Substitution of 3-Furaldehydes

Article abstract of DOI:10.1021/jo00037a032

Herein we report the details of the conversion of 3-furaldehyde into 2-substituted 4-furaldehydes and the transformations of 2-substituted 4-furaldehydes and 4-substituted 3-furaldehydes into tri- and tetrasubstituted furans.We have developed a new disubstituted furan synthesis by applying metalation to the direct conversion of 3-substituted furans into 2,4-disubstituted furans.In situ protection of 3-furaldehyde with lithium morpholide followed by metalation at the C-5 position and quenching with several electrophiles affords 2-substituted 4-furaldehydes in 30-70 percent yield.The electrophiles include chlorosilanes, chlorostannanes, aldehydes, ketones, and primary iodides.This work provides a general route to a previously relatively inaccessible furan substitution pattern and is the first example of selective metalation at the C-5 position of 3-substituted furans.Other bulky α-alkoxy substituents at C-3 direct remote metalation to C-5 of furan.We examined other 3-furaldehyde metalations.The amino alkoxide intermediate derived from lithio N,N,N'-trimethylethylenediamine and 3-furaldehyde, when treated with BuLi and electrophiles, provided a product mixture which included metalation at the C-4 position of 3-furaldehyde.Several approaches to enhance this unusual C-4 metalation were unsuccessful.Using this amino alkoxide-metalation chemistry, 4-alkyl- or 4-phenyl-3-furaldehyde could be substituted at C-2 or C-5 selectively.Finally we converted trisubstituted furans into tetrasubstituted furans with metalation/electrophilic trapping.