Synthesis of Highly Substituted Cyclopropanes via the Quasi-Favorskii Rearrangement of α,α-Dichlorocyclobutanols

Abstract

A method for the synthesis of highly substituted cyclopropanes via a quasi-Favorskii rearrangement is described. The method includes the combination two chemical transformations starting from α,α-dichlorocyclobutanones prepared via the [2 + 2] Staudinger ketene cycloaddition between either terminal- or cis-olefins and dichloroketene. First, α,α-dichlorocyclobutanones are reacted with organocerium reagents to afford the corresponding tertiary alcohols in good to excellent yields through a nucleophilic addition reaction that provided exclusively anti-products. Second, upon irreversible deprotonation, the tertiary α,α-dichlorocyclobutanols underwent a ring-contraction reaction (i.e., quasi-Favorskii rearrangement) to form structurally diverse cyclopropanes in moderate to good yields. The syn-stereoselectivity during the quasi-Favorskii rearrangement was evaluated using DFT analysis.

Halocyclobutanol Dehydration En Route to Halocyclobutenes

“…At the beginning of our work, we excluded elimination under basic conditions (Table 1 , entry 1), as the formation of the quasi-Favorskii rearrangement product 7 should only be a side reaction. 28b 31 Indeed, this assumption was confirmed by dehydration of alcohol 2aa with MsCl/TEA, SOCl 2 /pyridine and POCl 3 /TEA, which gave a significant amount of ketone 7 . The dehydration of alcohol 2aa with p -toluenesulfonic acid or potassium hydrogen sulfate gave complex mixtures of halocyclobutenes 3aa and 4 and ketone 7 (Table 1 , entries 2 and 3).…”

Transition‐Metal‐Free Ring‐Opening Reaction of 2‐Halocyclobutanols through Ring Contraction

“…The starting chloroketone 1 b was prepared by [2 + 2] cycloaddition between dichloroketene and indene, [26] which proceed diastereoselectively, [33] followed by reduction with zinc. [34] The relative configuration of the chlorine atom was determined by NOE experiments.…”

“…[25] Similar trend in reactivity was also observed in the addition of organocerium reagents to dichloro ketones. [26] Other approaches for the preparation of halocyclobutanols cover carbonyl group reduction, [27] double-bond hydroxylation, [28] epoxide opening, [29] and other means. [30] It is worth noting that the relative configuration of substituents for 2-bromocyclobutanols 3 has not been determined.…”

Unlocking mild-condition benzene ring contraction using nonheme diiron N-oxygenase

“…The typical prerequisites for RCT encompass four key elements: rstly, the imperative incorporation of activating factors like heat, nucleophilic reagents, Lewis acid, light, oxidation, or heavy metals; [16][17][18][19][20][21][22] secondly, the generation of active intermediates, be they ions, carbenoids, or radicals, in facilitating the contraction process; [23][24][25] thirdly, the strategic positioning of functional groups, such as sulfones, halogen Cite this: Chem. Sci., 2023, 14, 11907…”

“…The typical prerequisites for RCT encompass four key elements: firstly, the imperative incorporation of activating factors like heat, nucleophilic reagents, Lewis acid, light, oxidation, or heavy metals; 16–22 secondly, the generation of active intermediates, be they ions, carbenoids, or radicals, in facilitating the contraction process; 23–25 thirdly, the strategic positioning of functional groups, such as sulfones, halogen atoms, diazole, azide, organic boron, organic silicon, thioether, enol ethers, vicinal diols, or enolized ketones, adjacent the contracting site; 26 fourthly, the requirement of a spontaneous or environmentally triggered chemical rearrangement, such as the pinacol rearrangement, Favorskii rearrangement, Wolff rearrangement, cyclic silyl-enol ether rearrangement, etc. , in stabilizing the active intermediates and ensuring the fulfilment of the contractions.…”