37.9 Product Class 9: 1,4-Dioxanes

Abstract

In this chapter, the synthesis of substituted 1,4-dioxanes and their saturated bridged, fused, and spirocyclic derivatives is discussed for the first time in Science of Synthesis. Partially unsaturated compounds, in particular benzo, 2-oxo, and related derivatives, are excluded from this review. Methods based on the construction of the 1,4-dioxane core, as well as on functionalization of the parent 1,4-dioxane and 2,3-dihydro-1,4-dioxine are presented.

Synthesis of 2,2-Disubstituted and 2,2,3-Trisubstituted 1,4-Dioxane-Derived Building Blocks

“…Common approaches for the construction and modification of the 1,4-dioxane core were comprehensively reviewed in a recent monography. 33 Predominating meth- ods rely on intramolecular cyclizations of 1,2-diol derivatives bearing an electrophilic moiety at the appropriate position 28,29,[34][35][36][37][38][39][40][41][42][43][44][45] or Lewis acid-mediated reaction of epoxides with -halohydrins [46][47][48][49] or 1,2-diols, 50 followed by intramolecular cyclization. Among all present methods, oxirane ring-opening with ethylene glycol monosodium salt followed by cyclization of the intermediate diol has been evaluated as a straightforward and efficient approach for the preparation of 1,4-dioxanes.…”

Oxetan-3-ols as 1,2-bis-Electrophiles in a Brønsted-Acid-Catalyzed Synthesis of 1,4-Dioxanes

“… 6 Despite this, synthetic methods to access 1,4-dioxanes are limited, and multistep processes are often required. 7 Typically, complex hydroxy-ether precursors bearing a leaving group or pseudoleaving group (e.g., an epoxide) are prepared through lengthy synthetic sequences to assemble the 1,4-dioxane ring through an intramolecular cyclization ( Figure 1 B). 8 Such strategies do not readily allow the rapid generation of further analogues that may be necessary in library synthesis in medicinal chemistry, as each example requires a separate synthetic sequence.…”

“…Cyclic sp 3 -rich fragments have received increased recent interest in medicinal chemistry given the potential positive effect on pharmacokinetic properties and three-dimensional scaffolding . Despite this, synthetic methods to access 1,4-dioxanes are limited, and multistep processes are often required . Typically, complex hydroxy-ether precursors bearing a leaving group or pseudoleaving group (e.g., an epoxide) are prepared through lengthy synthetic sequences to assemble the 1,4-dioxane ring through an intramolecular cyclization (Figure B) .…”