Multi-Bond Forming Processes in Efficient Synthesis

Abstract

An increasing number of synthetic organic chemists are embracing the philosophy of efficiency. Herein we highlight multi-bond forming processes, which form two or more new covalent bonds in a single synthetic operation. Such processes, which have the ability to rapidly increase structural complexity, are preeminent in contemporary synthetic organic chemistry. In this short review we classify, analyse, and contrast contemporary multi-bond forming processes, frame these cutting edge contributions within a historical context, and speculate on likely future developments in the area.

Multicomponent Diene‐Transmissive Diels–Alder Sequences Featuring Aminodendralenes

“…[14] Then ew dendralene 2a readily decomposed upon attempted isolation or standing in solution, thereby resulting in complex mixtures of products including the two geometrical isomers of isomeric conjugated dienal 1a' '. [14,15] Thef ormation of cycloadduct 3a confirmed our expectation that 1-amino- [3]dendralene 2a would undergo ahighly site-selective addition of adienophile to the more substituted 1,3-butadiene residue.T he sequential addition of the dienophile to the preformed trienamine was not necessary,s ince optimal yields of products 3a-n were obtained by premixing skipped dienal 1a and the dienophile,then adding the amine last. [12] Conjugated dienal 1a' ' was not converted into trienamine 2a,i nstead yielding the products of aza-Michael additions upon exposure to morpholine and NMM.…”

“…[12] Conjugated dienal 1a' ' was not converted into trienamine 2a,i nstead yielding the products of aza-Michael additions upon exposure to morpholine and NMM. [14,15] Thef ormation of cycloadduct 3a confirmed our expectation that 1-amino- [3]dendralene 2a would undergo ahighly site-selective addition of adienophile to the more substituted 1,3-butadiene residue.T he sequential addition of the dienophile to the preformed trienamine was not necessary,s ince optimal yields of products 3a-n were obtained by premixing skipped dienal 1a and the dienophile,then adding the amine last. Presumably,i ti sb etter to generate the reactive trienamine in low concentration and trap it quickly with ad ienophile,rather than allow it to increase in concentration.…”

“…These reactions are extraordinarily easy to perform in the laboratory,i nm ost cases involving the mixing of simple precursors.The incorporation of a1-amino-substituent on the [3]dendralene backbone simultaneously augments both its reactivity and selectivity in diene-transmissive Diels-Alder sequences, [24] at the same time delivering highly functionalized multicyclic products akin to alkaloids and medicinal agents.T his study demonstrates the diversity of multicomponent transformations with only one amine group at aspecific position of the simplest possible dendralene structure.E vidently,t he possibilities for step-economic synthesis with aminodendralenes are vast. These reactions are extraordinarily easy to perform in the laboratory,i nm ost cases involving the mixing of simple precursors.The incorporation of a1-amino-substituent on the [3]dendralene backbone simultaneously augments both its reactivity and selectivity in diene-transmissive Diels-Alder sequences, [24] at the same time delivering highly functionalized multicyclic products akin to alkaloids and medicinal agents.T his study demonstrates the diversity of multicomponent transformations with only one amine group at aspecific position of the simplest possible dendralene structure.E vidently,t he possibilities for step-economic synthesis with aminodendralenes are vast.…”

“…[1,2] Therapid generation of structural complexity is inexorably linked with processes that form several new covalent bonds.S uch multiple singlebond-forming transformations [1] have several subclassifications,with those involving successive reactions at sequentially generated functional groups featuring strongly in current research endeavors. [3] In addition to maximizing useful structural complexity gains,anew synthetic method should ideally be atom-economic, [4] operationally simple,a nd robust. [5] Dendralenes [6] are cross-conjugated olefins of significant value in the step-economic synthesis of complex molecules owing to their multiple-1,3-butadiene character,w hich permits their participation in diene-transmissive [7] Diels-Alder (DA) cycloaddition sequences.…”

Bio‐inspired Domino oxa‐Michael/Diels–Alder/oxa‐Michael Dimerization of para‐Quinols

“…[1] Akey consideration in the design of any multiple-bond-forming process is the starting material, which must be suitably reactive to undergo multiplebond-forming events,y et not so difficult to synthesize or handle as to render its use impractical. [1] Akey consideration in the design of any multiple-bond-forming process is the starting material, which must be suitably reactive to undergo multiplebond-forming events,y et not so difficult to synthesize or handle as to render its use impractical.…”