Cyclopropane Formation Research Articles

Unusual photorearrangement of 1,7-disubstituted 7-azabenzonorbornadiene

1-(11-Benzoyl-11-azatricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraen-1-yl)ethanone was synthesized by cycloaddition of 2-acetyl-N-benzoylpyrrole to benzyne. Direct photolysis of 1-(11-benzoyl-11-azatricyclo-[6.2.1.02,7]undeca-2,4,6,9-tetraen-1-yl)ethanone in benzene gave N-(4-acetylnaphthalen-1-yl)benzamide. The formation of this product is discussed in terms of radical-stabilizing and destabilizing effect of electron-withdrawing group in the formation of cyclopropane ring.

Asymmetric Synthesis of Aminocyclopropanes and N‐Cyclopropylamino Alcohols Through Direct Amidocyclopropanation of Alkenes Using Chiral Organozinc Carbenoids

AbstractChiral N‐(diethoxymethyl)oxazolidinones, prepared from the corresponding oxazolidinones by heating in triethyl orthoformate, can be used as organozinc carbenoid precursors for the direct enantioselective amidocyclopropanation of alkenes. The reaction is successful with a wide range of oxazolidinones and alkenes and proceeds with moderate to excellent yield and stereoselectivity. In most cases the trans/exo amidocyclopropane product is favoured, although certain cyclicalkenes such as indene favour the formation of the endo cyclopropane. The products can be readily elaborated to produce cyclopropylamino alcohols and amino acids.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

DFT analysis of propane cyclization over binuclear Ga-clusters in mordenite

Molecular and dissociative adsorption of propane on binuclear (Ga 2O 2) 2+ cluster located at the cation positions of Ga-exchanged mordenite zeolite are modeled using DFT calculations via the isolated cluster approach. Relative energies of the dissociative intermediates show the most stable bidentate complexes, i.e., via both primary C atoms of propane to both Ga atoms. This structure really is the suitable precursor of cyclo-propane formation. The hypothesis of cyclo-propane intermediate was proposed by Derouane et al. to explain the 13C/ 12C exchange migration within propane molecules in Ga-exchanged zeolites.

Crystallographic Evidence for Cyclopropane Ring Formation in Isotwistenes Obtained by Thermal Cascade Reactions of Cyclopentadienone with Acyclic Conjugated Dienes

The molecular structure of the double Diels-Alder (DDA) adduct derived from three-step thermal cascade reactions of 2,5-bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone with ethyl sorbate is elucidated by single crystal X-ray analysis. The structural features and the reaction mechanism of the adduct are discussed on the basis of density functional theory (DFT) calculation results.

Catalytic cyclopropanation of olefins using copper(I) diphosphinoamines

Catalytic cyclopropanation reactions of olefins with ethyl diazoacetate were carried out using copper(I) diphosphinoamine (PPh 2) 2N(R) (R = i Pr, H, Ph and –CH 2–C 6H 4–CH CH 2) complexes at 40 °C in chloroform. High yields of the cyclopropanes were obtained in all cases. The rate of the reaction was influenced by the nuclearity of the complex and the binding mode of the ligand which was either bridging or chelating. Comparison of isostructural complexes shows that the rate follows the order R = i Pr > H > Ph, where R is the substituent on the N. However, cyclopropane formation versus dimerization of the carbene, and trans to cis ratios of cyclopropane was similar in all cases. The nearly identical selectivity for different products formed was indicative of a common catalytic intermediate. A labile “copper–olefin” complex which does not involve the phosphine or the counterion is the most likely candidate. The differences in the reaction rates for different complexes are attributed to differences in the concentration of the catalytically active species which are in equilibrium with the catalytically inactive copper–phosphinoamine complex. To test the hypothesis a diphosphinoamine polymer complexed to copper(I) was used as a heterogeneous catalyst. Leaching of copper(I) and deactivation of the catalyst confirmed the proposed mechanism.

An Additional Spirocyclization for Duocarmycin SA

A unique alternative to the p-spirocyclization for activation of compounds containing the duocarmycin SA alkylation subunit was established involving indole NH deprotonation and subsequent cyclopropane formation. The structural characterization of an alternative spirocyclization product and the establishment of its relative reactivity, intrinsic reaction regioselectivity, biological activity, and DNA alkylation properties (selectivity, rate, and efficiency) including the isolation, characterization, and quantitation of its adenine N3 adduct are disclosed.

A new mechanism for the Favorskii rearrangement

The title reaction was investigated by the use of ONIOM-RB3LYP calculations. A reaction system composed of alpha-chlorocyclohexanone, a methoxide ion and 8 MeOH solvent molecules was adopted. Two reaction channels, the semibenzilic acid mechanism (A) and cyclopropanone mechanism (B), were compared. B is found to be more favorable than A. The rate-determining step of B is the (MeOH)(3) addition transition state (TS3B) to the cyclopropanone intermediate. While TS3B involves a concerted function of MeO(-) addition and proton relays, it has a large activation energy. A new route was found, where the chloride ion evolved at the cyclopropane formation step (TS2B) works as a nucleophile to the cyclopropanone intermediate. Thus, a cyclopentane-carbonyl chloride intermediate is formed with a small activation energy. A new cyclopropanone mechanism is proposed.

A new strategy of the chemical route to the cyclopropane structure: direct transformation of benzylidenemalononitriles and malononitrile into 1,1,2,2-tetracyanocyclopropanes

The new reaction was found: the direct formation of cyclopropanes from activated olefins and C–H acids. The action of free halogen or active halogen containing compounds on the equal amounts of benzylidenemalononitriles and malononitrile in basic alcohol solutions results in the formation of 3-aryl-1,1,2,2-tetracyanocyclopropanes in 65–95% yields. Thus, the new simple and efficient way to 3-aryl substituted tetracyanocyclopropanes was found directly from such simple and reasonable starting compounds as benzylidenemalononitriles and malononitrile.

Functionalisation of terpenoids at C-4 via organopalladium dimers: cyclopropane formation during oxidation of homoallylic σ-organopalladium intermediates with lead tetraacetate

The synthesis of new potential adjuvant saponin aglycons was investigated by selective palladium mediated C–H functionalisation of appropriately functionalised derivatives of lanosterol, cholesterol, and friedelin. The desired equatorial aldehyde functionality was successfully introduced into the lanosterol skeleton as expected. Cyclopalladation of a cholesterol derivative proceeded as expected, but during oxidation of the organopalladium intermediate, participation of the adjacent alkene functionality led to stereoselective formation of a cyclopropane and introduction of an acetate group into the steroid backbone at C-6. Further investigation of this unusual cyclopropane formation on a model decalin system confirmed the result, but C–H activation on a related open chain system was prevented by complexation of the alkene functionality to the palladium.

Synthesis of 2,5,5-trimethylcycloheptanone

The synthesis of 2,5,5-trimethylcycloheptanone from 3-carene was described. It was demonstrated that hydrogenolysis of cis-caran-trans-4-ol on nickel-and copper-containing catalysts occurred with cleavage of the internal C1–C6 bond of the cyclopropane ring and predomonant (up to 95%) formation of 2,5,5-trimethylcycloheptanone.

Construction of stereodefined 1,1,2,2-tetrasubstituted cyclopropanes by acid catalyzed reaction of aryldiazoacetates and α-substituted acroleins

Michael-initiated ring closure of aryldiazoacetates and alpha-substituted acroleins under acid catalysis offers a unique opportunity for the stereoselective formation of various tetrasubstituted cyclopropanes.

Substrate versus Catalyst Control of Stereoselectivity in the Cyclopropanation of a Carbon‐Carbon Double Bond Linked to the Reactant Diazoacetate through a Chiral Linker

AbstractThe trajectory of a carbon‐carbon double bond onto a metal carbene for cyclopropane formation is dependent on the the configurations of the catalyst and the reacting substrate. Diazoacetates prepared from the butane‐2,3‐diacetals (BDA) of (L)‐ and (D)‐threitol were employed to examine the influence of a remote conformational bias on diastereoselectivity in cyclopropanation. Diastereoselectivities in the dirhodium(II) carboxamidate‐catalyzed diazo decomposition reactions are as high as a 91 : 9 with match/mismatch selectivites, dependent on catalyst configuration, and are favored in the order: Rh2(MEPY)4>Rh2(MEOX)4>Rh2(MEAZ)4> Rh2(MPPIM)4. The reactions catalyzed by the Cu(CH3CN)4PF6/(S,S)‐t‐Bu‐BOX produce as major isomers those in which the relative stereochemistry of the cyclopropane products is the same, regardless of which diazoacetate enantiomer is employed.

Synthesis of Cyclopropane Derivatives Starting from the Baylis-Hillman Adducts Using Sulfur Ylide Chemistry

Cyclopropane moiety is a fundamental class of functional group that is the focus of many organic synthesis programs and performs a key structural role in a wide range of biologically active molecules. The importance of cyclopropanes is reflected in the enormous effort that has been invested in their diastereoand enantioselective synthesis. In addition, cyclopropane derivatives could be transformed to structurally diverse compounds. During the extensive studies on the chemical transformations of Baylis-Hillman adducts, we examined the introduction of cyclopropane moiety at the primary position of Baylis-Hillman adducts to form vinyl cyclopropane derivatives 2 (Scheme 1). Such vinyl cyclopropane backbone is an important entity in many naturally occurring and synthetic pyrethroidal insectides, and could be used for further chemical transformations. Our synthetic rationale is shown in Scheme 1. The starting cinnamyl bromide 1a was prepared from the Baylis-Hillman adduct and HBr according to the reported method. The reaction of 1a and dimethyl sulfide in CH3CN generated the sulfonium salt (I), which was converted into the corresponding sulfur ylide (II) by treatment with NaOH. The in situgenerated sulfur ylide (II) reacted with methyl vinyl ketone to give the desired cyclopropane derivative 2a in 45% yield as shown in Scheme 1 via the intermediate (III). The synthesis of 2a was carried out in CH3CN at room temperature within 12 h. Encouraged by the successful results we prepared other cyclopropane derivatives 2b-h and the results are summarized in Table 1. The use of Cs2CO3 instead of NaOH showed similar yield of 2a. However, the use of K2CO3 gave 2a in only trace amounts. When we used nitrogen ylide, which was made from the reaction of 1a and DABCO in the presence of NaOH, we could not observe the formation of 2a at all. Variation of the electron-withdrawing substituents (-COOMe, -COOEt, -COMe, -CN) of the starting materials 1a-f did not alter the reactivity for the formation of cyclopropanes. Ethyl vinyl ketone (entry 2) could also be used successfully as the Michael acceptor in the reaction with 1a. However, we failed to obtain the corresponding products when we replaced methyl vinyl ketone with other Michael acceptors such as methyl acrylate, acrylonitrile, and 2-cyclohexen-1one. In these cases we could not observe any major component on TLC. The reason for the failure could be explained either by the hydrolysis or low reactivity of these Michael acceptors. Fortunately, 2-chloroacrylonitrile could be used as the Michael acceptor efficiently to give 2g (entry 7) as inseparable cis-trans mixtures in 57% yield. The relative stereochemistry of the two substituents of cyclopropane was trans in all cases as reported in similar systems. We could not isolate the other stereoisomer from the reaction mixtures. Further synthetic applications of the cyclopropane products are currently underway.

Acid catalyzed reactions of α,β-unsaturated aldehydes and ethyl diazoacetate

The formation of cyclopropanes from α,β-unsaturated aldehydes and diazo compounds has been a rather challenging goal due to the extremely reactive aldehyde starter. Herein, our group reports the first formation of ethyl 2-formyl-1-cyclopropanecarboxylate in 100% yield from the acid catalyzed reaction between acrolein and ethyl diazoacetate (EDA).

Study of the origin of enantioselectivity in cyclopropanation reactions using the chiral iron carbene complex [(η 5-C 5H 5)(CO) 2Fe [dbnd]CH[(η 6- o-MeOC 6H 4)Cr(CO) 3]] +

During our low temperature NMR studies we observed two rotational isomers of the carbene complex [(η 5-C 5H 5)(CO) 2Fe CH[(η 6- o-MeOC 6H 4)Cr(CO) 3]]+ ( 3) with the O–Me group either anti or anti to the Fp moiety. While the Cr(CO) 3 group very effectively shields one face of the carbene complex from attack by the olefin, the presence of anti and anti isomers allows for the formation of both R and S configuration on C-1 of the cyclopropane through a backside or a frontside ring closure mechanism. The reaction of olefin with anti R-3 can result in R-configuration of the cyclopropane carbon C-1 through a frontside closure mechanism, or in S-configuration if backside closure takes place. In a similar manner, anti R-3 may produce S-configuration through frontside closure or R-configuration through backside closure. We previously have shown by crystallography that reaction the R-isomer of 3 with 2-methyl-propene induces predominantly a R-configuration at C-1 of the resulting cyclopropane ( RR-(−)-2,2 dimethyl-1- o-methoxyphenyl(tricarbonyl chromium)cyclopropane, whereas the S-carbene results in the corresponding SS isomer. These findings are consistent with cyclopropane formation from the syn isomer through a frontside closure mechanism or from anti isomer through a backside closure mechanism. In the case of [(η 5-C 5H 5)(CO) 2Fe CH[(η 6- o-MeC 6H 4)Cr(CO) 3]]+ ( 4), only anti isomer is observed and optical rotation data indicate that the methylcarbene exhibits the same asymmetric induction (i.e., R-carbene yields R-cyclopropane C-1 and S-carbene yields S-cyclopropane C-1) as the methoxy analogue, and the assumption of the anti isomer being the reactive one then implies that the reaction proceeds through a backside closure mechanism rather a frontside mechanism. It is very likely that this preference is also valid for the methoxy substituted complex 4. Our results on 4 indicate that the enantioselectivity of the cyclopropanation reaction is not determined by the relative abundance of the isomers. As the syn isomer is the more abundant one, the anti isomer has to be the more reactive one compared to the syn isomer. Interchange of syn and anti isomers occurs fast compared to the rate of reaction of the carbene with olefin. The fast rate of interchange of syn and anti isomers relative to the rate of reaction with olefin precludes the direct observation of any differential reactivity form a change in the syn to anti ratio in the NMR spectrum. However, the in general lower ee values observed for 3 compared with 4 are consistent with the fact that the reactive isomer is less abundant in this case. Our data thus show that enantioselectivity of cyclopropanation with “chiral at carbene” complexes is controlled by the higher reactivity of the anti isomer and occurs through a backside ring closure mechanism.

The Activity of Escherichia coli Cyclopropane Fatty Acid Synthase Depends on the Presence of Bicarbonate

Cyclopropane fatty acid (CFA) synthases catalyze the formation of cyclopropane rings on isolated and unactivated olefinic bonds within various fatty acids; the methylene carbon is derived from the activated methyl group of (S)-adenosylmethionine. The E. coli enzyme is the prototype for this class of enzymes, which include the cyclopropane mycolic acid (CMA) synthases, which are potential targets for the design of antituberculosis agents. Crystal structures of several CMA synthases have recently been solved, and electron density attributed to a bicarbonate ion was found in or near the active site. Because a functional assay for CMA synthases has not been developed, the relevance of the bicarbonate ion has not been established. CFA synthase is 30-35% identical to the CMA synthases that have been analyzed structurally, suggesting that the mechanisms of these enzymes are conserved. In this work, we show that indeed the activity of CFA synthase requires bicarbonate, and that it is inhibited by borate, a planar trigonal molecule that mimics the structure of bicarbonate. We also show that substitutions of the conserved amino acids that act as ligands to the bicarbonate ion based on the structure of CMA synthases result in drastic losses in the activity of the protein.

Enantioselective Organocatalytic Cyclopropanations. The Identification of a New Class of Iminium Catalyst Based upon Directed Electrostatic Activation.

A new method for enantioselective organocatalytic cyclopropanation is described. This study outlines the identification of a new class of iminium catalyst based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide and enal substrates through a proposed electrostatic activation and stereodirected protocol. Formation of trisubstituted cyclopropanes with high levels of enantio- and diastereoinduction is accomplished for a variety of α,β-unsaturated aldehydes and sulfonium ylides. In addition, mechanistic studies have found that this cyclopropanation reaction exhibits enantioselectivity and reactivity profiles that are in accord with the proposed DEA step.

Catalytic Coupling of Ethylene and Internal Olefins by Dicationic Palladium(II) and Platinum(II) Complexes: Switching from Hydrovinylation to Cyclopropane Ring Formation

The dicationic palladium(II) and platinum(II) complexes [(PNP)M(C2H4)](BF4)2 (1a, M = Pt; 1b, M = Pd; PNP = 2,6-bis((diphenylphosphino)methyl)pyridine) and [(PPP)Pt(C2H4)](BF4)2 (7; PPP = triphos) catalyze a cross-coupling reaction of ethylene with tri- and tetrasubstituted olefins, which can lead to both hydrovinylation and cyclopropanation products. The product ratio is strongly affected by the choice of the ligand and of the metal, the two limiting cases being 1a and 7, which selectively give the hydrovinylation and the cyclopropanation products, respectively.

A Combined Theoretical and Experimental Study of Efficient and Fast Titanocene-Catalyzed3-exoCyclizations

The mechanism of titanocene mediated 3-exo cyclizations was investigated by a combined theoretical and experimental study. A gradient corrected density functional theory (DFT) method has been scaled against titanocene dichloride, the parent butenyl radical, and in bond dissociation energy (BDE) calculations. The BP86 method using density fitting, and a basis set of triple-zeta quality emerged as a highly reliable tool for studying titanocene mediated radical reactions. The computational results revealed important kinetic and thermodynamic features of cyclopropane formation. Surprisingly, the beta-titanoxy radicals, the first intermediates of our investigations, were demonstrated to possess essentially the same thermodynamic stabilization as the corresponding alkyl radicals by comparison of the calculated BDEs. In contrast to suggestions for samarium mediated reactions, the cyclization was shown to be thermodynamically favorable in agreement with earlier kinetic studies. It was established that stereoselectivity of the cyclization is governed by the stability of the intermediates and thus the trans disubstituted products are formed preferentially. The observed ratios of products are in good to excellent agreement with the DFT results. By a combination of computational and experimental results, it was also shown that for the completion of the overall cyclopropane formation the efficiency of the trapping of the cyclopropylcarbinyl radicals is decisive.

Stereochemistry of Contiguous Cyclopropane Formation from Cascade Cyclization of a Skipped Dienyl Homoallyl Triflate.

AbstractFor Abstract see ChemInform Abstract in Full Text.