Cyclopropenes in the 1,3-dipolar cycloaddition with carbonyl ylides: experimental and theoretical evidence for the enhancement of sigma-withdrawal in 3-substituted-cyclopropenes

The carbonyl ylide dipoles generated by the dirhodium tetra-acetate-catalyzed decomposition of diazocarbonyl precursors 1, 5, and 8 cycloadd to 3-substituted 1,2-diphenylcyclopropenes 3a-e and 3,3-disubstituted cyclopropenes 13, 14, 19, and 20 to give polycyclic compounds with 8-oxatricyclo[3.2.1.0(2,4)]octane and 9-oxatricyclo[3.3.1.0(2,4)]nonane frameworks. Generally, reactions proceed stereoselectively to give adducts of exo stereochemistry with the approach of the carbonyl ylide dipoles from the less-hindered face of cyclopropenes. The electronic properties of the substituent at the C3 position of cyclopropenes play an important role in governing the reactivity of cyclopropenes: when the C3 position is substituted by electron-acceptors such as the methoxycarbonyl or cyano groups, the yields of adducts are decreased significantly or no adducts can be detected at all. Relative reactivities of cyclopropenes were quantified by competition experiments to give the best correlation with sigmaF-Taft constants. Both measured photoelectron spectra and ground-state calculations of a series of 1,2-diphenylcyclopropenes indicate considerable lowering of cyclopropene pi-HOMO energies by substitution with an acceptor group. Such changes in electronic structures of cyclopropenes may cause the inversion of frontier molecular orbital (FMO) interactions from HOMO(cyclopropene)-LUMO(ylide) to LUMO(cyclopropene)-HOMO(ylide) type. In terms of philicity, nucleophilic properties of acceptor-substituted cyclopropenes are diminished to such an extent that these species are no longer good nucleophiles in the reaction with carbonyl ylides, and neither are they good electrophiles, being unreactive. This was shown by the B3LYP calculations of addends.     

Theoretical study of the mechanism of the abstraction reactions of heavy cyclopropenes by alcohol

The potential energy surfaces for the abstraction reactions of heavy cyclopropenes with alcohol have been characterized in detail using density functional theory (B3LYP/LANL2DZdp), including zero-point corrections. Five heavy cyclopropene species including cyclopropene, cyclotrisilene, cyclotrigermene, cyclotritinene, and cyclotrileadene, have been chosen in this work as model reactants. All the interactions involve a hydrogen shift via a two-center transition state. The activation barriers and enthalpies of the reactions were compared in order to determine the relative reactivity of the heavy cyclopropenes. The present theoretical investigations suggest that the relative heavy cyclopropene reactivity increases in the order cyclopropene < cyclotrisilene < cyclotrigermene < cyclotritinene < cyclotrileadene. That is, for alcohol dehydrogenations there is a very clear trend toward lower activation barriers and less endothermic reactions on going from C to Pb. Besides this, our theoretical findings indicate that the final abstraction-addition products should adopt the anti geometry, rather than the syn geometry, from a thermodynamic viewpoint. Furthermore, a configuration mixing model based on the work of Pross and Shaik is used to rationalize the computational results. The results obtained allow a number of predictions to be made.     

One‐bond 13C–13C coupling constants in alkyl‐substituted cyclopropenes: experimental and theoretical studies

Measurements of one‐bond carbon–carbon coupling constants, ¹J(C, C), were performed for two series of compounds, alkyl‐substituted cyclopropenes and cyclopropanes. The experimental data were complemented by a set of DFT‐calculated J couplings for the parent cyclopropene ( 1 ), its methyl and silyl derivatives and, additionally, for 1‐methylcyclobutene ( 3 ), 1‐methylcyclopentene ( 4 ) and 1‐methylcyclohexene ( 5 ) and good agreement was observed between the experimental and the calculated data; all the trends are perfectly maintained, including a dramatic decrease in the couplings across endocyclic single bonds in cyclopropene and its derivatives, and a significant decrease in the corresponding couplings in cyclobutene. Using the data obtained, the s characters of the carbon hybrid orbitals involved in the formation of the cyclopropene were calculated. The results clearly show that the ring closure and the related strain exerted upon the cyclopropene molecule only slightly disturb the electron structure of the double bond. The s character of the corresponding carbon orbital is 0.314 in cyclopropene vs the theoretical value of 0.333 in ethene. This is at variance with the endo‐ and exocyclic single bonds, where the s characters of the orbitals forming the endocyclic single bonds are much smaller than those of the bonds in the open‐chain compounds, i.e. 0.229 (C‐1 and/or C‐2) and 0.166 (C‐3). The s values calculated for the exocyclic CH bonds are 0.334 for C‐3 and 0.456 for C‐1 and/or C‐2. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

Substituted cyclopropenes have recently attracted attention as stable “mini‐tags” that are highly reactive dienophiles with the bioorthogonal tetrazine functional group. Despite this interest, the synthesis of stable cyclopropenes is not trivial and their reactivity patterns are poorly understood. Here, the synthesis and comparison of the reactivity of a series of 1‐methyl‐3‐substituted cyclopropenes with different functional handles is described. The rates at which the various substituted cyclopropenes undergo Diels–Alder cycloadditions with 1,2,4,5‐tetrazines were measured. Depending on the substituents, the rates of cycloadditions vary by over two orders of magnitude. The substituents also have a dramatic effect on aqueous stability. An outcome of these studies is the discovery of a novel 3‐amidomethyl substituted methylcyclopropene tag that reacts twice as fast as the fastest previously disclosed 1‐methyl‐3‐substituted cyclopropene while retaining excellent aqueous stability. Furthermore, this new cyclopropene is better suited for bioconjugation applications and this is demonstrated through using DNA templated tetrazine ligations. The effect of tetrazine structure on cyclopropene reaction rate was also studied. Surprisingly, 3‐amidomethyl substituted methylcyclopropene reacts faster than trans‐cyclooctenol with a sterically hindered and extremely stable tert‐butyl substituted tetrazine. Density functional theory calculations and the distortion/interaction analysis of activation energies provide insights into the origins of these reactivity differences and a guide to the development of future tetrazine coupling partners. The newly disclosed cyclopropenes have kinetic and stability advantages compared to previously reported dienophiles and will be highly useful for applications in organic synthesis, bioorthogonal reactions, and materials science.     

Synthesis of stable derivatives of cycloprop-2-ene carboxylic acid

Large-scale syntheses of 3-(cycloprop-2-en-1-oyl)oxazolidinones from acetylene and ethyl diazoacetate are described. Unlike other cyclopropenes that bear a single substitutent at C-3, these compounds are stable to long-term storage. Although the cyclopropene derivatives are unusually stable, they are reactive toward cyclic and acyclic dienes in stereoselective Diels-Alder reactions.     

Catalytic Synthesis of Trifluoromethyl Cyclopropenes and Oligo-Cyclopropenes

The synthesis of trifluoromethylated cyclopropenes is often associated with important applications in drug discovery and functional materials. In this report, we describe the use of readily available chiral rhodium(II) catalysts for a highly efficient asymmetric cyclopropenation reaction of fluorinated donor–acceptor diazoalkanes with a broad variety of aliphatic and aromatic alkynes. Further studies highlight the unique reactivity of fluorinated donor–acceptor diazoalkanes in the synthesis of oligo-cyclopropenes. Subsequent C−H functionalization of trifluoromethyl cyclopropenes furnishes densely substituted cyclopropene frameworks and also allows the alternative synthesis of bis-cyclopropenes.     

Synthesis and Chemistry of Bicyclo[4.1.0]hept-1,6-ene

Bicyclo[4.1.0]hept-1,6-ene has been generated by elimination of 1-chloro-2-(trimethysilyl)bicyclo[4.1.0]heptane in the gas phase over solid fluoride at 25 degrees C. The cyclopropene dimerizes by a rapid ene reaction forming two diastereomeric cyclopropenes. In tetrahydrofuran or chloroform the ene dimers couple to form a single crystalline triene tetramer, whereas a mixture of tricyclohexane tetramers is formed when the neat dimers are allowed to warm to room temperature. Oxidation by dimethyldioxirane or dioxygen gives carbonyl products. Quantum mechanical calculations yielded an increase in strain of approximately 17 kcal/mol over that for 1,2-dimethylcyclopropene. The potential enegy barrier to flexing (folding) along the fused double bond of bicyclo[4.1.0]hept-1,6-ene is only approximately 1 kcal/mol at the highest level of theory investigated.     

Allylgallation of cyclopropenes. Crystal structure of a novel cyclopropylgallium compound prepared by allylgallation of hydroxy-bearing cyclopropene

Allylgallation of cyclopropenes with allylgallium sesquibromide has been investigated; a novel cyclopropylgallium compound was isolated via allylgallation of hydroxy-bearing cyclopropene, and its structure was fully characterized by X-ray crystallography.     

Dianion approach to chiral cyclopropene carboxylic acids

[reaction: see text] In this Letter, we describe a general method for preparing the dianions of cyclopropene carboxylic acids, and we show that their subsequent reactions with electrophiles provide a general means for selectively introducing diverse types of functional groups. This provides a general method for the synthesis of chiral 1,2-disubstituted cyclopropenes, and opens new avenues for the enantioselective preparation of cyclopropenes.     

Cobalt-Catalyzed Facial-Selective Hydroalkylation of Cyclopropenes

Cyclopropene hydrofunctionalization has been a promising strategy for accessing multi-substituted cyclopropanes; however, cyclopropene hydroalkylation remains underdeveloped. Herein, we report a low-valent CoH-catalyzed facial-selective cyclopropene hydroalkylation to access multi-substituted cyclopropanes. This reaction exhibits a broad substrate scope of alkyl halides and cyclopropenes and tolerates many functional groups. Moderate-to-good facial-selectivity is obtained without any directing groups. Mechanism studies provide evidence that alkyl radicals are generated from alkyl halides and irreversible CoH insertion is responsible for the facial-selectivity. Our preliminary exploration demonstrates that asymmetric cyclopropene hydroalkylation can be realized without conspicuous auxiliary groups.     

Rh(II)-Catalyzed Isomerizations of Cyclopropenes Evidence for Rh(II)-Complexed Vinylcarbene Intermediates

The thermocatalytic rearrangements of cyclopropenes 1-4 have been investigated in the presence of Rh(IT) perfiuorobutyrate. 1, 2, 3-Triphenylcyclopropene ( 1a ) undergoes rearrangement lo diphenylindene 5a or, with alkoxycyclopropene derivatives, to α, β-unsaturated ketone 6. Furan formation occurs with 2, 3-diphenylcyclo-propenecarboxylate 2, but the diethyl counterpart 3 rearranges to dienoate 8. 2-Alkylcyclopropenecarboxylates 4 afforded (E)-methylidenecyclopentane derivatives 9 as the only isolable product in yields of ca. 35 %. A mechanism involving regio- and stereospecific cyclopropene ring opening to a Rh-complexed vinylcarbene and insertion of the latter into the C? H bond to give 9 is proposed. An analogous mechanism should account for the rearrangement products of 1 to 3 .     

Photoinduced Electron Transfer Reactions of 3,3‐Dialkylated 4,5‐Diphenyl‐3H‐Pyrazoles: A New Route to the Formation of the Solvent Adducts

3,3‐Dialkyl‐4,5‐diphenyl‐3H‐pyrazoles undergo readily photoinduced electron transfer (PET) reaction with 2,4,6‐triphenylpyrylium tetrafluoroborate (TPP⁺) in acetonitrile to produce cyclopropenes and 2H‐pyrroles. During prolonged irradiation, the new ring‐closure products derived from 2H‐pyrroles as the secondary photoproducts are also produced. However, the corresponding ester analog exhibits different behavior to obtain the cyclopropene as the primary photoproduct and a [2+2] dimer of the cyclopropene as the secondary photoproduct. A rationale for the different behavior is offered.     

The organometallic chemistry of nitrogenases

Nitrogenases mediate the reduction of many substrates other than dinitrogen and a summary is given. Several chemical systems that mimic aspects of nitrogenase reactivity, including transition metal complexes of alkynes and olefins, are outlined. Their protonation has been studied and their relevance to reduction of alkynes and olefins by nitrogenase is assessed. Cyclopropene is reduced by molybdenum nitrogenase to propene and cyclopropane. The reactions of cyclopropene with different transition metal complexes are discussed and a study of interactions of cyclopropenes with models for the active site of the nitrogenase enzyme are described. These models include transition metal hydrides, such as [FeH(H₂)(dmpe)₂][BPh₄] and [MoH₄(dppe)₂] reducing 3,3-dimethylcyclopropene and cyclopropene. Products observed upon protonation and deuteration of several platinum-cyclopropene complexes are presented and a mechanism for their formation is proposed.     

Biosynthetic,studies of marine lipids. 21. Experimental demonstration of a biosynthetic interconversion of cyclopropene sterols in the sponge calyx nicaeensis

In vivo isomerization of cyclopropenes has been demonstrated for the first time through feeding experiments of appropriately labeled cyclopropene sterols (1c-4c) in the sponge Calyx nicaeensis.     

Recent developments of cyclopropene chemistry

This critical review discusses recent developments in the field of cyclopropene chemistry. Although several excellent reviews that mainly focused on the thermolysis and pyrolysis as well as metal-mediated reactions of cyclopropenes have been published, significant new developments have also been achieved in recent years. This brand new review provides an overview of the progress from 2007 to 2011 on the syntheses and transformations of cyclopropenes as well as their related mechanistic studies (238 references).     

Metal-catalyzed rearrangement of cyclopropenes to allenes

A novel transition-metal-catalyzed rearrangement of silylated cyclopropenes to the corresponding allenes is described. The presence of both the trimethylsilyl group on the cyclopropene and the platinum catalyst are crucial for this rearrangement.     

Thermolysis and Photosensitized Oxygenation of Tetrasubstituted Cyclopropenes

Bicyclic cyclopropenes 14a, 14b, and 26 were prepared by various synthetic routes. Polymer rose Bengal (p-RB) photosensitized oxygenation of bicyclooctenes 14a,b in CDCl(3) proceeded sluggishly (variable O(2) uptake of ca. 0.35-0.75 equiv in 8 h) and was accompanied by sensitizer bleaching. Preparative gas chromatography of the complex product mixtures from 14a and 14b yielded both dienes (Z- and E-29, 30, and 31) and enones (E- and Z-12, 32, 34). By contrast, p-RB photosensitized oxidation of bicyclononene 26 in CDCl(3) proceeded somewhat more rapidly (O(2) uptake of ca. 1 equiv in 2.5 h) yielding enones (20, 42-45) exclusively upon GC separation. The diene products, observed in the case of 14, result from the thermolysis of the remaining unreacted cyclopropenes, while the enones are the oxygenation products. The oxygenation was slowed by radical inhibitors, but not by (1)O(2) quenchers; nor were any oxidation products observed when these cyclopropenes were reacted with triphenylphosphine ozonide, a chemical (1)O(2) source. The data indicates that a photosensitizer-initiated free radical autoxidative process is involved. Likely intermediates in this oxygenation are epoxide 27 or 37 and hydroperoxide 28 or 38, for the bicyclooctene (14) and bicyclononene (26) systems, respectively. The absence of (1)O(2) product in these cyclopropene systems, in contradistinction to their higher homologues, may be attributable to either the relatively long C(alpha)-H(allylic) distance in alkylcyclopropenes, which places the abstractable allylic hydrogen "out of reach", or their relatively high IP. Either, or both, of these factors may have slowed the rate of the singlet oxygenation of the cyclopropenes to a point where free radical processes compete favorably. In the course of this study, we also explored the singlet oxygenation (DABCO inhibited) of enones 12a,b and 20. These generated, respectively, a mixture of peroxides identified as alpha-keto hydroperoxides 51/54 and hemiperketals 52/55 (the cyclic form of beta-keto hydroperoxides 53/56). Phosphine reduction of these peroxides yields the corresponding alcohols 33/43 and 32/42.     

Transition metal-catalyzed hydro-, sila-, and stannastannation of cyclopropenes: stereo- and regioselective approach toward multisubstituted cyclopropyl synthons

The first highly efficient, stereo- and regioselective palladium-catalyzed hydro-, sila-, and stannastannation of cyclopropenes to give multisubstituted cyclopropylstannanes have been developed. It was shown that the addition across the double bond of cyclopropene is generally controlled by steric factors and proceeds from the least hindered face. The directing effect of alkoxymethyl substituents in the hydrostannation reaction of 3,3-disubstituted cyclopropenes was demonstrated. This methodology represents a powerful and atom-economic approach toward a wide variety of highly substituted cyclopropylstannanes, important building blocks unavailable by other methods.     

Divergent outcomes of gold(I)-catalyzed indole additions to 3,3-disubstituted cyclopropenes

Depending on the conditions employed, gold(I)-catalyzed addition of indoles to 3,3-disubstituted cyclopropenes can be controlled to yield either 3-(E)-vinylindoles (3) or bis-indolylalkanes (4). If the cyclopropene substituents are sterically bulky, unprecedented gold-catalyzed oxidation under air occurs to yield bis-indolylalkene (5) and epoxide (6) at room temperature.     

Gold-Catalyzed Divergent Ring-Opening Rearrangement of Cyclopropenes Enabled by Dichotomous Gold−Carbenes

The gold-catalyzed ring-opening rearrangement of cyclopropenes affords an efficient route to either polysubstituted naphthols or aryl-substituted furans. Owing to the unique dichotomy of gold−carbenes, this protocol provides a switchable reaction selectivity between naphthols and furans enabled by the use of TFP−Au(MeCN)SbF₆ (tri(2-furyl) phosphine) or PNP(AuNTf₂)₂ (bis(diphenylphosphino)(isopropyl) amine) as catalysts respectively. It is proposed that the gold−carbene intermediate might be involved in the cyclopropene→naphthol rearrangement while the gold-carbocation is more likely to be involved in the cyclopropene→furan rearrangement.