Tertiary Cyclopropanols Research Articles

Photocatalytic O- to S-Rearrangement of Tertiary Cyclopropanols.

Despite the importance of heteroatom-substituted cyclopropane derivatives in drug design and organic synthesis, cyclopropanethiols remain critically underexplored. Inspired by the wide use of the Newman-Kwart rearrangement to access valuable thiophenols from phenol feedstocks, we report the development of a photocatalytic approach for efficient ambient temperature aliphatic O- to S-rearrangement on tertiary cyclopropanol derivatives. After demonstrating that a range of cyclopropanethiols-that are difficult to access by other methods-can be obtained with this strategy, we show that these rearranged products can be easily hydrolyzed and further derivatized. We conclude this study with mechanistic findings that enabled an initial extension of this approach toward other classes of aliphatic alcohols.

Photocatalytic O‐ to S‐Rearrangement of Tertiary Cyclopropanols

AbstractDespite the importance of heteroatom‐substituted cyclopropane derivatives in drug design and organic synthesis, cyclopropanethiols remain critically underexplored. Inspired by the wide use of the Newman‐Kwart rearrangement to access valuable thiophenols from phenol feedstocks, we report the development of a photocatalytic approach for efficient ambient temperature aliphatic O‐ to S‐rearrangement on tertiary cyclopropanol derivatives. After demonstrating that a range of cyclopropanethiols—that are difficult to access by other methods—can be obtained with this strategy, we show that these rearranged products can be easily hydrolyzed and further derivatized. We conclude this study with mechanistic findings that enabled an initial extension of this approach toward other classes of aliphatic alcohols.

Ring‐Opening Coupling Reaction of Cyclopropanols with Electrophilic Alkenes Enabled by Decatungstate as Photoredox Catalyst

AbstractWe introduce a methodology for the photocatalytic generation of β‐ketoalkyl radicals from tertiary cyclopropanols, utilizing tetrabutylammonium decatungstate (TBADT) as a photoredox catalyst. The application is demonstrated by the synthesis of distantly functionalized ketones via the redox‐neutral addition of the cyclopropanol‐derived β‐ketoalkyl radicals to the double bond of electrophilic olefins. The transformation occurs under ambient temperature conditions and is suitable for coupling a wide range of cyclopropanol and alkene substrates. This was demonstrated by the preparation of 33 ketone products with 35–92% yield. The method's preparative robustness has been validated through upscaled preparations conducted under continuous flow conditions. Mechanistic investigations support the role of TBADT as a photoredox catalyst, which facilitates the single electron oxidation of cyclopropanols, followed by the electron transfer from the reduced form of decatungstate to the electrophilic double bond of alkene. Moreover, we found that electron‐rich aromatic cyclopropanols and electron‐deficient olefins form photoactive electron donor‐acceptor (EDA) complexes. This property allows the reaction to proceed under UV light irradiation via the photoinduced charge transfer in the absence of the photocatalyst.

Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates.

Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates in aprotic solvents (dichloromethane, chloroform, toluene) produces mixed anhydrides. The fragmentation reaction is especially facile with phenyliodine(III) reagents bearing electron-withdrawing carboxylate ligands (trifluoroacetyl, 2,4,6-trichlorobenzoyl, 3-nitrobenzoyl), and affords 95−98% yields of the corresponding mixed anhydride products. The latter can be straightforwardly applied for the acylation of various nitrogen, oxygen and sulfur-centered nucleophiles (primary and secondary amines, hydroxylamines, primary alcohols, phenols, thiols). Intramolecular acylation yielding macrocyclic lactones can also be performed. The developed transformation has bolstered the synthetic utility of cyclopropanols as pluripotent intermediates in diversity-oriented synthesis of bioactive natural products and their synthetic congeners. For example, it was successfully applied for the last-stage modification of a cyclic peptide to produce a precursor of a known histone deacetylase inhibitor.

General Synthesis of Cyclopropanols via Organometallic Addition to 1-Sulfonylcyclopropanols as Cyclopropanone Precursors.

The addition of organometallic reagents to ketones constitutes one of the most straightforward synthetic approaches to tertiary alcohols. However, due to the absence of a well-behaved class of cyclopropanone surrogates accessible in enantioenriched form, such a trivial synthetic disconnection has received very little attention in the literature for the formation of tertiary cyclopropanols. In this work, we report a simple and high-yielding synthesis of 1-substituted cyclopropanols via the addition of diverse organometallic reagents to 1-phenylsulfonylcyclopropanols, acting here as in situ precursors of the corresponding cyclopropanones. The transformation is shown to be amenable to sp-, sp2-, or sp3-hybridized organometallic C-nucleophiles under mild conditions, and the use of enantioenriched substrates led to highly diastereoselective additions and the formation of optically active cyclopropanols.

Copper(II)-Mediated Ring Opening/Alkynylation of Tertiary Cyclopropanols by Using Nonmodified Terminal Alkynes.

The copper(II)-mediated ring opening/alkynylation of cyclopropanol by employing inexpensive and commercially available terminal alkyne is developed. The reactions proceeded efficiently to afford synthetically useful alk-4-yn-1-ones in moderate to good yields with good functional group tolerance. Control experiments showed that the reaction presumably proceeds via the formation of intermediates of copper homoenolate and/or alkynylcopper species.

Visible‐Light‐Induced, Manganese‐Catalyzed Tandem Cyclization of 2‐Biphenyl Isocyanides with Cyclopropanols for the Synthesis of 6‐β‐Ketoalkyl Phenanthridines

AbstractA visible‐light‐induced, manganese‐catalyzed protocol for the synthesis of 6‐β‐keto alkyl phenanthridines has been developed efficiently from 2‐biphenyl isocyanides and cyclopropanols in the absence of an external oxidant. This transformation is amenable to various isocyanides and tertiary cyclopropanols under catalytic amounts of Mn(acac)3 (10 mol%).

AgII‐Mediated Synthesis of β‐Fluoroketones by Oxidative Cyclopropanol Opening

A regioselective synthesis of β‐fluorinated ketones by silver(II)‐mediated ring opening is described. Commercially available AgF2 serves as both an oxidant and fluorine‐atom source. A variety of β‐fluorinated ketones are efficiently prepared from tertiary cyclopropanol precursors, offering a straightforward approach for the introduction of a fluorine atom at a remote site. Selectivity is observed in the site of bond cleavage, which leads to fluorination at the more substituted site. A radical mediated sequential homolytic C–C bond cleavage and C–F bond formation is suggested.

Enantioselective One-Pot Synthesis of α,β-Epoxy Ketones via Aerobic Oxidation of Cyclopropanols.

An efficient, mild, and environmentally benign method was developed for the asymmetric synthesis of 2-oxyranyl ketones from easily available tertiary cyclopropanols. The one-pot protocol includes the aerobic oxidation of cyclopropanol derivatives catalyzed by Mn(III) complexes followed by the poly-l-leucine-assisted stereoselective elimination of water from the intermediate peroxides with DBU to afford the corresponding epoxy ketones in high yields and good-to-excellent enantioselectivities (up to 97%).

Synthesis of γ-keto sulfones by copper-catalyzed oxidative sulfonylation of tertiary cyclopropanols.

Tertiary cyclopropanols undergo ring-opening oxidative sulfonylation to afford γ-keto sulfones when reacting with sulfinate salts in the presence of a copper(ii) acetate catalyst and an oxidant (tert-butyl hydroperoxide or atmospheric oxygen). Various fluoroalkyl, aryl and alkyl sulfinate salts are successfully employed as sulfonylation reagents, affording the corresponding sulfones in up to 94% yields. The experimental protocol is mild and tolerates a number of functionalities in the cyclopropanol substrate. The reaction proceeds via a one-pot oxidation-Michael addition mechanism and can serve as a useful addition to the existing methods for the preparation of γ-keto sulfones based on the sulfa-Michael reaction.

Two-step conversion of carboxylic esters into distally fluorinated ketones via ring cleavage of cyclopropanol intermediates: application of sulfinate salts as fluoroalkylating reagents.

Tertiary cyclopropanols easily available from carboxylic esters have been used in the synthesis of distally fluorinated ketones. Cyclopropane ring cleavage reactions in methanol with aqueous tert-butyl hydroperoxide in the presence of a copper(ii) acetate catalyst and sodium triflinate (Langlois reagent) afford β-trifluoromethyl ketones in 16-74% isolated yields. Sodium triflinate serves as a precursor of reactive trifluoromethyl copper species, enabling ring-opening trifluoromethylation, as evidenced by mechanistic studies. We also demonstrate here that other sulfinate salts, such as sodium 1,1-difluoroethanesulfinate, sodium 2-(4-bromophenyl)-1,1-difluoroethanesulfinate and sodium 1-(trifluoromethyl)cyclopropanesulfinate, can be used as fluoroalkylation reagents, resulting in the corresponding fluorinated ketones.

ChemInform Abstract: Silver‐Catalyzed Ring‐Opening Strategy for the Synthesis of β‐ and γ‐Fluorinated Ketones.

AbstractStarting from tertiary cyclopropanol and cyclobutanol precursors, a variety of β‐ and γ‐fluorinated ketones are efficiently synthesized via silver‐catalyzed ring opening reactions.

Site-Selective Approach to β-Fluorination: Photocatalyzed Ring Opening of Cyclopropanols.

To expand upon the recent pioneering reports of catalyzed sp(3) C-H fluorination methods, the next rational step is to focus on directing "radical-based fluorination" more effectively. One potential solution entails selective C-C bond activation as a prelude to selective fluorination. Herein, we report the tandem photocatalyzed ring-opening/fluorination reactions of cyclopropanols by 1,2,4,5-tetracyanobenzene (TCB) and Selectfluor to afford a process tantamount to site-selective β-fluorination of carbonyl-containing compounds. This new approach provides a synthetically mild and operationally simple route to otherwise difficult-to-prepare β-fluorinated products in good yields and with good-to-excellent regioselectivity. Remarkably, substrates that contain other usually reactive (e.g., benzylic) sites undergo ring-opening fluorination preferably. The versatility of this method to give cyclic β-fluorides from tertiary cyclopropanols and γ-fluoro alcohols is also highlighted.

Silver-Catalyzed Ring-Opening Strategy for the Synthesis of β- and γ-Fluorinated Ketones

A regioselective synthesis of β- and γ-fluorinated ketones via silver-catalyzed ring opening is described. A variety of β- and γ-fluorinated ketones are efficiently prepared, respectively, from tertiary cyclopropanol and cyclobutanol precursors, providing a straightforward approach for the introduction of a fluorine atom into complex molecules. Preliminary mechanistic studies suggest that a radical-mediated sequential C-C bond cleavage and C-F bond formation pathway is involved.

ChemInform Abstract: The First Synthesis of Spirocyclic Sulfates from Tertiary Cyclopropanols and Their Reaction with Normant Homocuprates.

AbstractThe reaction of the sulfates with Normant homocuprates occurs stereospecifically with complete inversion of the configuration as exemplified by the transformation of (R)‐IIb to (R)‐VIII.

Simple access to β-trifluoromethyl-substituted ketones via copper-catalyzed ring-opening trifluoromethylation of substituted cyclopropanols.

Tertiary cyclopropanols react rapidly with Togni reagent in methanol at room temperature in the presence of catalytic amounts (3 mol%) of CuCl affording β-trifluoromethyl ketones in 65-73% isolated yields. Ring opening in 1,2-dialkylsubstituted cyclopropanols gives a mixture of isomeric β-trifluoromethyl ketones in about 50% combined yield.

The First Synthesis of Spirocyclic Sulfates from Tertiary Cyclopropanols and Their Reaction with Normant Homocuprates

Spirocyclic sulfates of 2- and 3-(hydroxyalkyl)cyclopropanols, obtainable through the Kulinkovich reaction from β-and γ-hydroxy carboxylic acid esters, respectively, were synthesized for the first time. The possibility of regio- and stereoselective alkylating the spirocyclic sulfates by using Normant homocuprates has been demonstrated.

ChemInform Abstract: Synthesis of α‐Methyl Ketones by a Selective, Iridium‐Catalyzed Cyclopropanol Ring‐Opening Reaction.

Abstract A mild method for synthesizing α-methyl ketones from substituted cyclopropanols is reported. This process, catalyzed by [Cp∗IrCl2]2, cleaves cyclopropanol rings regioselectively and more efficiently than the other conditions examined. While tertiary cyclopropanols afford α-methyl ketones, secondary cyclopropanols and cyclopropyl silyl ethers are less reactive and yield other isomerization products.

Synthesis of α-methyl ketones by a selective, iridium-catalyzed cyclopropanol ring-opening reaction

A mild method for synthesizing α-methyl ketones from substituted cyclopropanols is reported. This process, catalyzed by [Cp∗IrCl2]2, cleaves cyclopropanol rings regioselectively and more efficiently than the other conditions examined. While tertiary cyclopropanols afford α-methyl ketones, secondary cyclopropanols and cyclopropyl silyl ethers are less reactive and yield other isomerization products.

ChemInform Abstract: Synthesis of (+)‐Disparlure (I) from Diethyl (‐)‐Malate via Opening and Fragmentation of the Three‐Membered Ring in Tertiary Cyclopropanols.

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