On the Winstein rearrangement: equilibrium and mechanism

Abstract

Allylic azides are underutilized in organic synthesis when compared to other organic azides or other allylic functionality. This is likely because allylic azides rearrange at room temperature, resulting in a potentially complex mixture of azides. This rearrangement has been termed the Winstein rearrangement. Understanding the mechanism and basic principles governing the allylic azide equilibrium may aid in developing applications for these molecules based on either alkene or azide functionalization. Presented herein is a compilation of the key observations regarding the nature of the allylic azide rearrangement. Mechanistic considerations are explicitly addressed with key examples from the literature.

Insight on the Factors Controlling the Equilibrium of Allylic Azides

“…[7][8][9][10] Allylic azides are building blocks for the synthesis of natural products and nitrogen-containing heterocycles of pharmacological relevance. [11][12][13][14] Despite the importance of these useful synthons, their applicability in synthetic schemes has been difficult due to their existence as a regioisomeric mixture that interconverts rapidly at room temperature, being in general inseparable (Figure 1). 15,16 The allylic azide rearrangement was first reported by Gagneux, Winstein, and Young in 1960 (known as Winstein's rearrangement).…”

Insight into the factors controlling the equilibrium of allylic azides

“…[7][8][9][10] Allylic azides are the building blocks for the synthesis of many natural products and nitrogen-containing heterocycles of pharmacological relevance. [11][12][13][14] Despite the importance of these useful synthons, their applicability in synthetic schemes has been difficult due to their existence as regioisomeric mixtures that interconvert rapidly at room temperature, thus being, in general, inseparable ( Fig. 1).…”

Stereocontrolled Microwave-Assisted Domino [3,3]-Sigmatropic Reactions: A Winstein–Overman Rearrangement for the Formation of Differentiated Contiguous C–N Bonds

“…The ratio of the allylic hydroxy azides 4/4′ appears to reflect modest preferences for a proximal relationship between the azide and hydroxyl functionalities (i.e., isomer 4), and a distal relationship between the azide and sterically more encumbered groups. 10 Interestingly, the use of the lower temperature Method C (Table 1) over Method A resulted in a product ratio favoring the initially formed product 4h over 4h′, indicating that under these milder conditions that a kinetic ratio of the hydroxyallylic azides is obtained. Stereospecific transformation of the hydroxy allylic azides 4/4′ with trichloroacetonitrile and DBU led to the azido imidates 5/5′ (Schemes 1 and 2, Table 1).…”

“…9 The position of the allylic azide equilibrium is affected by several factors. 10 Electronic effects (Coulombic interactions) 11 favor a proximal relationship between azide and neighboring hydroxyl functionality. 12 Conjugation of the double bond of the allylic azide with phenyl 13 or ester 14 groups, or the presence of a sterically bulky group adjacent to an azide group, usually results in a high degree of regioselective control.…”

“…The rearrangement occurs more slowly in cyclic systems necessitating the use of higher temperatures . The position of the allylic azide equilibrium is affected by several factors . Electronic effects (Coulombic interactions) favor a proximal relationship between azide and neighboring hydroxyl functionality .…”