Synthesis Of Cyclopropanes Research Articles

Catalyst-free photocyclopropanation of dibromomalonates with alkenes: an approach to multisubstituted cyclopropanes

We report herein a novel photocyclopropanation of dibromomalonates with alkenes in the presence of Hünig base. This protocol provides an environmentally benign approach for the synthesis of multisubstituted cyclopropanes, since no catalyst is required. The Photo-induced Electron Transfer (PET) from Hünig base to dibromomalonate is the key process during this transformation.

Diastereoselective Synthesis of Trisubstituted Cyclopropanes by Palladium-Catalyzed Intramolecular Allylic Alkylation of α-Aryl Esters­

We have developed a novel method for synthesizing trisubstituted cyclopropane derivatives by a palladium-catalyzed intramolecular allylic alkylation of α-aryl esters. By using α-aryl α-(methoxycarbonyl) γ-vinyl γ-lactones as substrates, decarboxylative formation of π-allylpalladium(II) intermediates followed by an intramolecular allylic alkylation of the ester enolates proceeded in the presence of 5 mol% of a palladium catalyst, producing 1-aryl-1-(methoxycarbonyl)-2-vinylcyclopropanes in good to excellent yields and high diastereoselectivities. The relative configuration of the major isomer was determined by transforming the product into a known intermediate of milnacipran synthesis. When we extended our method to asymmetric catalysis, we obtained methyl (1<i>S</i>,2<i>S</i>)-1-phenyl-2-vinylcyclopropanecarboxylate in up to 55% ee by using (<i>S</i>)-[2′-(diphenylmethoxy)-1,1′-binaphthalen-2-yl](diphenyl)phosphine as a chiral monodentate phosphorus ligand.

One-Pot Asymmetric Synthesis of Cyclopropanes with Quaternary Centers Starting From Bromonitroalkenes under Aminocatalytic Conditions.

Cyclopropanes with a quaternary center are efficiently synthesized starting from bromonitroalkenes and alkyl aldehydes under aminocatalysis, giving good yield, excellent enantioselectivities, and moderate to excellent diastereoselectivities. This work is a novel approach using bromonitroalkenes as starting material instead of the usual synthesis with bromine-activated methylene derivatives. The cyclization process is analyzed by DFT calculations, which suggests an SN 2 mechanism. Theoretical data indicate that diastereoselectivity results from the energetic balance as a consequence of distortion the in trigonal bipyramid transition states and the relative stabilities of both starting rotamers and final products arising from distinct steric repulsions.

Copper‐Catalyzed (2+1) Annulation of Acetophenones with Maleimides: Direct Synthesis of Cyclopropanes

AbstractA practical copper‐catalyzed direct oxidative cyclopropanation of electron‐deficient alkenes with acetophenone derivatives is reported. The dehydrogenative annulation involves a double CH bond functionalization at the α‐position of the ketone using di‐tert‐butyl peroxide as oxidant. The broad scope of the reaction and excellent functional‐group tolerance is demonstrated for the stereoselective synthesis of fused cyclopropanes. The developed transformation revealed an unprecedented reactivity for copper‐catalyzed processes.

Copper-Catalyzed (2+1) Annulation of Acetophenones with Maleimides: Direct Synthesis of Cyclopropanes.

A practical copper-catalyzed direct oxidative cyclopropanation of electron-deficient alkenes with acetophenone derivatives is reported. The dehydrogenative annulation involves a double C-H bond functionalization at the α-position of the ketone using di-tert-butyl peroxide as oxidant. The broad scope of the reaction and excellent functional-group tolerance is demonstrated for the stereoselective synthesis of fused cyclopropanes. The developed transformation revealed an unprecedented reactivity for copper-catalyzed processes.

ChemInform Abstract: Difluoromethyl Vinyl Sulfonium Salt: A One‐Pot Access to Difluoromethyl‐Containing Cyclopropanes.

Abstract We demonstrate the first preparation of difluoromethyl (CF2H) vinyl sulfonium salt as a new difluoromethylated building block, followed by its application to the synthesis of CF2H-containing cyclopropanes in one step. The salt itself is readily prepared from 3-bromo-3,3-difluoropropene in three steps, in high overall yields, and is stable. A wide range of active methylene compounds participated in the cyclopropanation reaction using this salt, providing the corresponding products in high-to-excellent yields.

ChemInform Abstract: Visible Light Induced Cyclopropanation of Dibromomalonates with Alkenes via Double‐SET by Photoredox Catalysis.

AbstractThe green synthesis of cyclopropanes (III) is carried out under visible light or sunlight with similar high yields.

Synthesis and reactions of donor cyclopropanes: efficient routes to cis- and trans-tetrahydrofurans

A detailed study on the synthesis and reactions of silylmethylcyclopropanes is reported. In their simplest form, these donor-only cyclopropanes undergo Lewis acid promoted reaction to give either cis- or trans-tetrahydrofurans, with the selectivity being reaction condition-dependant. The adducts themselves are demonstrated to be an important scaffold for structural diversification. The combination of a silyl-donor group in a donor-acceptor cyclopropane with novel acceptor groups is also discussed.

Asymmetric synthesis of enantiopure fluorinated cyclopropyl carbohydrate analogues

Abstract A simple and convenient method for the synthesis of cyclopropanes substituted with carbohydrate analogues is described. The addition of trifluoromethyl diazo compounds to 5-(R)-hydroxypyridazin-3-one derivative of d -(+)-galactose proceeded in almost quantitative yields and high syn -selectivity. The observed π-facial selectivity is determined by the configuration at C-5. The exo -selectivity was complete in all the cases. Steric interactions and electronic factors seem to be the main ones responsible for the observed exo selectivity and π-facial selectivity of reactions with trifluoromethyl diazo compounds.

Difluoromethyl vinyl sulfonium salt: a one-pot access to difluoromethyl-containing cyclopropanes

We demonstrate the first preparation of difluoromethyl (CF2H) vinyl sulfonium salt as a new difluoromethylated building block, followed by its application to the synthesis of CF2H-containing cyclopropanes in one step. The salt itself is readily prepared from 3-bromo-3,3-difluoropropene in three steps, in high overall yields, and is stable. A wide range of active methylene compounds participated in the cyclopropanation reaction using this salt, providing the corresponding products in high-to-excellent yields.

Synthesis of cycloalkanone-fused cyclopropanes by Au(I)-catalyzed oxidative ene-yne cyclizations

Au(I)-catalyzed oxidative cyclizations that successfully convert 1,5-ene-ynes and a 1,6-ene-yne to the corresponding cycloalkanone-fused cyclopropanes are described. This Au(I)-catalyzed oxidative cyclization can be effectively applied to various substrates and is an alternative to the previously used intramolecular cyclopropanation that required potentially explosive diazo compound.

Stereoselective synthesis of polysubstituted piperazines and oxopiperazines. Useful building blocks in medicinal chemistry.

Many pharmaceutical agents include piperazines or oxopiperazines as part of their core structures. The presence of substituents on these heterocycles has a significant influence on the biological activity, thus the search for efficient routes to control the substitution at different ring positions might have a crucial impact, especially to promote the use of such scaffolds in SAR studies. Many research groups have been engaged in the stereoselective synthesis of polysubstituted piperazines and oxopiperazines and in the majority of cases the stereochemistry of the final compounds is dependent on the starting material configuration. In the present minireview we have summarized some of the most significant approaches towards the stereoselective synthesis and functionalization of substituted piperazines and oxopiperazines, with a particular focus on our own contributions mainly based on readily available natural amino-acids as "chiral pool" starting materials. An efficient and scalable route to orthogonally protected 2-oxopiperazines has been developed using the corresponding diamines as key intermediates: diastereoselective elaboration of the resulting heterocycles was possible by metalation and reaction with electrophiles, leading to anti 3,5-disubstituted-oxopiperazines, in agreement with the model for a conventional 1,3-asymmetric induction. Both piperazines and tetrahydropyrazines could be prepared via LiAlH4-mediated reduction of 2-oxopiperazines, depending on reaction conditions. Finally, the diastereoselective synthesis of cyclopropane- containing analogs 2,5-diaza-bicyclo[4.1.0]heptanes was demonstrated by application of the classic Simmons-Smith reaction on enantiomerically enriched dihydro-2H-pyrazines.

Copper-Catalyzed Stereoselective Synthesis of (Borylmethyl)cyclopropanes

Key words copper - (borylmethyl)cyclopropylamines - 1,2-bis(diphenylphosphino) benzene ligand

ChemInform Abstract: One‐Pot Synthesis of Multisubstituted Quaterphenyls and Cyclopropanes.

AbstractSimple and metal‐free protocols for the efficient synthesis of a broad range of the title compounds from chalcones and allyl sulfones are presented.

Solvent-free, one-pot synthesis of pentasubstituted cyclopropanes in the presence of BrCN and EtONa by milling

A solvent-free, one-pot process for the preparation of pentasubstituted 3-arylcyclopropane-1,1,2,2-tetracarbonitriles in the presence of solid sodium ethoxide by milling was achieved. The one-pot reaction of aromatic aldehydes and dialdehydes with malononitrile, cyanogen bromide, and solid sodium ethoxide afforded pentasubstituted cyclopropanes in excellent yield under solvent-free conditions. The structures were characterized and confirmed by IR, 1H NMR, 13C NMR spectroscopy, and mass spectrometry. Its advantages are easy workup, mild reaction conditions, and excellent yields.

One-pot synthesis of multifunctionalized cyclopropanes

A facile one-step synthetic protocol toward multifunctionalized cyclopropanes 4 is developed from substituted chalcones 1 and sulfones 2 in good yields via a [2C+1C] annulation.

Tandem halogenation/Michael-initiated ring-closing reaction of α,β-unsaturated nitriles and activated methylene compounds: one-pot diastereoselective synthesis of functionalized cyclopropanes

An efficient one-pot synthetic route to highly substituted cyclopropanes has been developed from readily available α,β-unsaturated nitriles and doubly activated methylene compounds under very mild conditions in a highly diastereoselective manner, which involves halogenation, Michael addition and intramolecular ring-closing reaction sequences.

ChemInform Abstract: Synthesis of Mono‐Fluorinated Functionalized Cyclopropanes and Aziridines Using the α‐Fluorovinyl Diphenyl Sulfonium Salt.

The α-fluorovinyl diphenyl sulfonium salt 1 is attractive due to its high potential for the synthesis of mono-fluorinated cyclopropanes and aziridines as useful three-membered rings. The synthetically useful salt 1 is readily prepared from α-fluorovinyl phenyl sulfide and diphenyl iodonium salt in one step.

One-pot synthesis of multisubstituted quaterphenyls and cyclopropanes

An efficient one-step synthetic route toward multifunctionalized quaterphenyls 3 or cyclopropanes 4 is developed from substituted chalcones 1 and sulfones 2 in good yields via a regioselective [3C+3C] or [1C+2C] annulation. The reaction features mild conditions, multisubstitution, and functional groups tolerance and is transition metal catalyst-free. The protocol provides a novel alternative to the conventional methodologies for the synthesis of quaterphenyls or cyclopropanes.

Cobalt(II)‐Catalyzed Asymmetric Olefin Cyclopropanation with α‐Ketodiazoacetates

Cyclopropanes are a unique class of structure elements found in a number of biologically important compounds and have been demonstrated for a wide range of fundamental and practical applications.[1] One particularly attractive strategy for enantioselective synthesis of chiral cyclopropanes is based on transition metal-catalyzed asymmetric olefin cyclopropanation with diazo reagents.[2] In principle, chiral cyclopropane derivatives with all substitution patterns may be accessible in enantioenriched form by asymmetric cyclopropanation due to the diverse availability of both alkenes and diazo reagents. Among different classes of diazo reagents with various combinations of α-substituents, many acceptor- and donor/acceptor-substituted diazo reagents have been successfully employed as effective carbene sources for metal-catalyzed asymmetric cyclopropanation.[2] In contrast, the capacity of catalytic asymmetric cyclopropanation has not been fully explored with acceptor/acceptor-substituted diazo reagents, which would afford synthetically useful cyclopropane compounds bearing geminal electron-withdrawing functionalities.[3,4] Although there have been some recent successes in this area,[5–9] several important types of acceptor/acceptor-substituted diazo reagents remain challenging for asymmetric olefin cyclopropanation.