Synthesis and Use of Bicyclo[1.1.1]pentylaldehyde Building Blocks

Abstract

The bicyclo[1.1.1]­pentane (BCP) motif is an emerging scaffold in medicinal chemistry because of its bioisosterism to 1,4-phenylene and 1,2-alkynyl functions. The current drawback of its use is the lack of stable versatile synthetic building blocks. Aldehydes are among the most useful functionalities in organic chemistry. In this paper, a simple one-pot procedure from aryl-halides and [1.1.1]­propellane is described. Preparation of various BCP molecules is conducted to showcase the versatility of these stable intermediates.

Metal- and photocatalyst-free three-component strategy to prepare benzylalcohol-, aldehyde-substituted BCP building blocks

“…4 Therefore, the development of efficient protocols for constructing BCP aldehydes and BCP alcohols can be expected to increase the availability of BCP-containing compounds, which is vital for exploring the structure–activity relationships of these compounds. 5 However, most of the known methods for synthesizing BCP alcohols 6 and BCP aldehydes 7 require multiple steps with poor atom and step economy. There are two common routes for preparing BCP aldehydes from [1.1.1]propellane (Scheme 1B): (1) the formation of BCP esters and their subsequent three-step transformation into BCP aldehydes and (2) the formation of metalated BCP intermediates that can attack DMF to form BCP aldehydes.…”

“…There are two common routes for preparing BCP aldehydes from [1.1.1]propellane (Scheme 1B): (1) the formation of BCP esters and their subsequent three-step transformation into BCP aldehydes and (2) the formation of metalated BCP intermediates that can attack DMF to form BCP aldehydes. 7 BCP alcohols are usually synthesized by means of nucleophilic addition of metalated BCPs to aldehydes (Scheme 1C). 6 However, these multistep routes require the use of reactive organometallic reagents or external oxidants, which severely limits the scope of their applications.…”

“…6 However, these multistep routes require the use of reactive organometallic reagents or external oxidants, which severely limits the scope of their applications. 7,8 Therefore, new methods for the direct construction of BCP aldehydes and alcohols in an environmentally friendly manner, especially in the absence of organometallic reagents or external oxidants, are urgently needed.…”