Showing papers on "Cyclopropane published in 2020"

Rhodium(III)-Catalyzed Enantio- and Diastereoselective C-H Cyclopropylation of N-Phenoxylsulfonamides: Combined Experimental and Computational Studies.

Abstract: Cyclopropane rings are a prominent structural motif in biologically active molecules. Enantio- and diastereoselective construction of cyclopropanes through C-H activation of arenes and coupling with readily available cyclopropenes is highly appealing but remains a challenge. A dual directing-group-assisted C-H activation strategy was used to realize mild and redox-neutral RhIII -catalyzed C-H activation and cyclopropylation of N-phenoxylsulfonamides in a highly enantioselective, diastereoselective, and regioselective fashion with cyclopropenyl secondary alcohols as a cyclopropylating reagent. Synthetic applications are demonstrated to highlight the potential of the developed method. Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a RhV nitrenoid intermediate, and Noyori-type outer sphere concerted proton-hydride transfer from the secondary alcohol to the Rh=N bond produces the observed trans selectivity.

Electrochemical oxidation-induced etherification via C(sp3)─H/O─H cross-coupling

Abstract: Direct electrochemical construction of C─O bonds through C(sp3)─H functionalization still remains fundamentally challenging. Here, electrochemical oxidation-induced benzylic and allylic C(sp3)─H etherification has been developed. This protocol not only offers a practical strategy for the construction of C─O bonds using nonsolvent amounts of alcohols but also allows direct electrochemical benzylic and allylic C(sp3)─H functionalization in the absence of transition metal catalysis. A series of alcohols and benzylic and allylic C(sp3)─H compounds were compatible with this transformation. Mechanistically, the generation of aryl radical cation intermediates is the key to this C(sp3)─H etherification, as evidenced by radical probe substrate (cyclopropane ring opening) and electron paramagnetic resonance experiments.

Highly Stereoselective Synthesis of Fused Cyclopropane-γ-Lactams via Biocatalytic Iron-Catalyzed Intramolecular Cyclopropanation

Abstract: We report the development of an iron-based biocatalytic strategy for the asymmetric synthesis of fused cyclopropane-γ-lactams, which are key structural motifs found in synthetic drugs and bioactive...

Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation.

Abstract: Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.

The Cyclopropane Ring as a Reporter of Radical Leaving-Group Reactivity for Ni-Catalyzed C(sp3)-O Arylation.

Abstract: The ability to understand and predict reactivity is essential for the development of new reactions. In the context of Ni-catalyzed C­(sp3)–O functionalization, we have developed a unique strategy employing activated cyclopropanols to aid the design and optimization of a redox-active leaving group for C­(sp3)–O arylation. In this chemistry, the cyclopropane ring acts as a reporter of leaving-group reactivity, since the ring-opened product is obtained under polar (2e) conditions, and the ring-closed product is obtained under radical (1e) conditions. Mechanistic studies demonstrate that the optimal leaving group is redox-active and are consistent with a Ni­(I)/Ni­(III) catalytic cycle. The optimized reaction conditions are also used to synthesize a number of arylcyclopropanes, which are valuable pharmaceutical motifs.

Regioselective Brønsted Acid-Catalyzed Annulation of Cyclopropane Aldehydes with N'-Aryl Anthranil Hydrazides: Domino Construction of Tetrahydropyrrolo[1,2-a]quinazolin-5(1H)ones.

Abstract: A highly regioselective synthesis of tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one derivatives was achieved by reacting cyclopropane aldehydes with N′-aryl anthranil hydrazides in the presence of p-t...

Accessing Dihydro-1,2-oxazine via Cloke-Wilson-Type Annulation of Cyclopropyl Carbonyls: Application toward the Diastereoselective Synthesis of Pyrrolo[1,2-b][1,2]oxazine.

Abstract: A convenient additive-free synthesis of dihydro-4H-1,2-oxazines via a Cloke-Wilson-type ring expansion of the aryl-substituted cyclopropane carbaldehydes with the hydroxylamine salt is introduced. Comparatively less active cyclopropyl ketones also follow a similar protocol if supplemented by catalytic p-toluene sulfonic acid monohydrate. The transformation is performed in an open-to-air flask as it shows negligible sensitivity toward air/moisture. Dihydro-4H-1,2-oxazines when subjected to cycloaddition with the cyclopropane diester afford a trouble-free formulation of the valued hexahydro-2H-pyrrolo[1,2-b][1,2]oxazine derivatives. A cascade one-pot variant of this two-step strategy offers a comparable overall yield of the final product.

Total Synthesis of (-)-Pepluanol B: Conformational Control of the Eight-Membered-Ring System.

Abstract: The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo-epoxidation to control the eight-membered-ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight-membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif.

Complex Carbocyclic Skeletons from Aryl Ketones through a Three-Photon Cascade Reaction.

Abstract: Starting from readily available 7-substituted 1-indanones, products with a tetracyclo[5.3.1.01,7 04,11 ]undec-2-ene skeleton were obtained upon irradiation at λ=350 nm (eight examples, 49-67 % yield). The assembly of the structurally complex carbon framework proceeds in a three-photon process comprising an ortho photocycloaddition, a disrotatory [4π] photocyclization, and a di-π-methane rearrangement. The flat aromatic core of the starting material is converted into a functionalized polycyclic hydrocarbon with exit vectors in three dimensions. Ring opening reactions at the central cyclopropane ring were explored, which enable the preparation of tricyclo[5.3.1.04,11 ]undec-2-enes and of tricyclo[6.2.1.01,5 ]undecanes.

Extension of the Simmons-Smith reaction to metal-carbynes: efficient synthesis of metallacyclopropenes with σ-aromaticity.

Abstract: The Simmons–Smith reaction offers a direct route for conversion of an alkene into a cyclopropane with a zinc carbenoid as the active intermediate. Zinc carbenoids, however, have never delivered a methylene unit to substrates with metal–carbon multiple bonds. Herein, we describe this type of reaction and the construction of three-membered rings has now been applied in organometallic systems by combining classical zinc carbenoid reagents with a range of structurally and electronically diverse metal carbynes. A variety of metallacyclopropene derivatives prepared in this way represent rare examples with σ-aromaticity in an unsaturated three-membered ring. The structures of such products are supported by experimental observations and theoretical calculations.

Engaging Sulfonamides: Intramolecular Cross-Electrophile Coupling Reaction of Sulfonamides with Alkyl Chlorides

Abstract: The application of amine derivatives as coupling partners is rare due to the inherent strength of the C-N bond. Herein, we report the first cross-electrophile coupling reaction of unstrained benzylic sulfonamides. Nickel-catalyzed intramolecular cross-electrophile coupling reactions of acyclic and cyclic benzylic sulfonamides with pendant alkyl chlorides generate cyclopropane products. Mechanistic experiments and DFT calculations are consistent with initiation of the reaction by magnesium iodide accelerated oxidative addition of the benzylic sulfonamide. This work establishes neutral and unstrained amine derivatives as XEC partners, furnishes structural rearrangement of benzylic sulfonamides, and provides valuable information regarding catalyst design for the development of new cross-electrophile coupling reactions of carbon-heteroatom bonds.

Tuning Rh(II)-catalysed cyclopropanation with tethered thioether ligands.

Abstract: Dirhodium(II) paddlewheel complexes have high utility in diazo-mediated cyclopropanation reactions and ethyl diazoacetate is one of the most commonly used diazo compounds in this reaction. In this study, we report our efforts to use tethered thioether ligands to tune the reactivity of RhII-carbene mediated cyclopropanation of olefins with ethyl diazoacetate. Microwave methods enabled the synthesis of a family of RhII complexes in which tethered thioether moieties were coordinated to axial sites of the complex. Different tether lengths and thioether substituents were screened to optimise cyclopropane yields and minimise side product formation. Furthermore, good yields were obtained when equimolar diazo and olefin were used. Structural and spectroscopic investigation revealed that tethered thioethers changed the electronic structure of the rhodium core, which was instrumental in the performance of the catalysts. Computational modelling of the catalysts provided further support that the tethered thioethers were responsible for increased yields.

An In-Depth Computational Study of Alkene Cyclopropanation Catalyzed by Fe(porphyrin)(OCH3) Complexes. The Environmental Effects on the Energy Barriers.

Abstract: Iron porphyrin methoxy complexes, of the general formula [Fe(porphyrin)(OCH3)], are able to catalyze the reaction of diazo compounds with alkenes to give cyclopropane products with very high effici...

Correction to “Cyclopropane Hydrogenation vs Isomerization over Pt and Pt–Sn Intermetallic Nanoparticle Catalysts: A Parahydrogen Spin-Labeling Study”

Abstract: Hyperpolarized propane produced by heterogeneous hydrogenation of cyclopropane with parahydrogen has been proposed as a safe inhalant for sensitivity-enhanced in vivo magnetic resonance imaging. Th...

A Vinyl Cyclopropane Ring Expansion and Iridium-Catalyzed Hydrogen Borrowing Cascade

Abstract: A vinyl cyclopropane rearrangement embedded in an iridium-catalyzed hydrogen borrowing reaction enabled the formation of substituted stereo-defined cyclopentanes from Ph* methyl ketone and cyclopropyl alcohols. Mechanistic studies provide evidence for the ring-expansion reaction being the result of a cascade based on oxidation of the cyclopropyl alcohols, followed by aldol condensation with the pentamethyl phenyl-substituted ketone to form an enone containing the vinyl cyclopropane. Subsequent single electron transfer (SET) to this system initiates a rearrangement, and the catalytic cycle is completed by reduction of the new enone. This process allows for the efficient formation of diversely substituted cyclopentanes as well as the construction of complex bicyclic carbon skeletons containing up to four contiguous stereocentres, all with high diastereoselectivity.

The mechanisms of gallium-catalysed skeletal rearrangement of 1,6-enynes - Insights from quantum mechanical computations.

Abstract: The transition metal-catalysed skeletal reorganization of 1,6-enynes can lead to three types of products – a type I product occurring via the cleavage of the alkene C–C bonds and the migration of the terminal alkene carbon to the terminus of the alkyne; a type II product arising from cleavage of both the double and the triple bonds followed by insertion of the terminal alkene carbon into the alkyne C–C triple bond; and a type III product which is obtained when there is a cleavage of the olefinic bond followed by formation of two new bonds from each carbon to each of the acetylenic carbons. The course of these reactions is highly dependent on the metal catalyst used and type of substitution at the alkene and alkyne moieties of the enyne. In this mechanistic study of the re-organization of 1,6-enynes catalysed by GaCl3, performed at the DFT M06/6-311G(d,p) level of theory, the parent reaction selectively leads to the formation of the type I product through the formation of the open cyclopropane ring. The presence of substituents at the acetylenic moiety governs the preferred position of the metal along the alkyne bond within the pi-complex: with electron-withdrawing groups (EWGs), the metal prefers the terminal carbon while electron-donating groups (EDGs) lead to the metal preferring the internal carbon. EWGs at the alkyne moiety efficiently favour the formation of the type I product. Substituents at the olefin moiety alter the mechanism of the reaction which may favour the selective formation of the type I or III product depending on the type of substituent. EWGs at the olefinic moiety favour formation of the type III product when the alkyne moiety is unsubstituted whiles EDGs forms the type I product selectively. Solvent and temperature have no substantial effects on the energetic trends and product distribution. Hence, gas-phase calculations are deemed adequate for the problem at hand.

Versatility of the Cyano Group in Intermolecular Interactions.

Abstract: Several cyano groups are added to an alkane, alkene, and alkyne group so as to construct a Lewis acid molecule with a positive region of electrostatic potential in the area adjoining these substituents. Although each individual cyano group produces only a weak π-hole, when two or more such groups are properly situated, they can pool their π-holes into one much more intense positive region that is located midway between them. A NH3 base is attracted to this site, where it forms a strong noncovalent bond to the Lewis acid, amounting to as much as 13.6 kcal/mol. The precise nature of the bonding varies a bit from one complex to the next but typically contains a tetrel bond to the C atoms of the cyano groups or the C atoms of the linkage connecting the C≡N substituents. The placement of the cyano groups on a cyclic system like cyclopropane or cyclobutane has a mild weakening effect upon the binding. Although F is comparable to C≡N in terms of electron-withdrawing power, the replacement of cyano by F substituents substantially weakens the binding with NH3.

Stereoelectronic and Resonance Effects on the Rate of Ring Opening of N-Cyclopropyl-Based Single Electron Transfer Probes

Abstract: N-Cyclopropyl-N-methylaniline (5) is a poor probe for single electron transfer (SET) because the corresponding radical cation undergoes cyclopropane ring opening with a rate constant of only 4.1 × 104 s-1, too slow to compete with other processes such as radical cation deprotonation. The sluggish rate of ring opening can be attributed to either (i) a resonance effect in which the spin and charge of the radical cation in the ring-closed form is delocalized into the phenyl ring, and/or (ii) the lowest energy conformation of the SET product (5•+) does not meet the stereoelectronic requirements for cyclopropane ring opening. To resolve this issue, a new series of N-cyclopropylanilines were designed to lock the cyclopropyl group into the required bisected conformation for ring opening. The results reveal that the rate constant for ring opening of radical cations derived from 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] (6) and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] (7) are 3.5 × 102 s-1 and 4.1 × 102 s-1, effectively ruling out the stereoelectronic argument. In contrast, the radical cation derived from 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline (8) undergoes cyclopropane ring opening with a rate constant of 1.7 × 108 s-1, demonstrating that loss of the resonance energy associated with the ring-closed form of these N-cyclopropylanilines can be amply compensated by incorporation of a radical-stabilizing phenyl substituent on the cyclopropyl group. Product studies were performed, including a unique application of EC-ESI/MS (Electrochemistry/ElectroSpray Ionization Mass Spectrometry) in the presence of 18O2 and H218O to elucidate the mechanism of ring opening of 7•+ and trapping of the resulting distonic radical cation.