The vinylcyclopropane rearrangement or vinylcyclopropane-cyclopentene rearrangement is a ring expansion reaction, converting a vinyl-substituted cyclopropane ring into a cyclopentene ring. [1] [2] [3]
Cyclopropyl groups adjacent to vinyl groups can undergo ring expansion reactions. This reactivity can be exploited to generate unusual cyclic compounds, such as cyclobutenes, [4] or bicyclic species such as the cycloheptene shown below. [5]
Experimental and computational investigations show that mechanistically, the vinylcyclopropane rearrangement can be thought of as either a diradical-mediated two-step and/or orbital-symmetry-controlled pericyclic process. The amount by which each of the two mechanisms is operative is highly dependent on the substrate.
Due to its ability to form cyclopentene rings the vinylcyclopropane rearrangement has served several times as a key reaction in complex natural product synthesis.
In 1959, a young research chemist with Humble Oil and Refining (Esso, now Exxon) named Norman P. Neureiter was instructed to find new uses for the excess butadiene produced from one of the refinery processes. Discussions about carbene chemistry with one of the company's most respectable consultants at the time, William von Eggers Doering, then a professor at Yale, led the young Ph.D. graduate from Northwestern University to follow a recent procedure combining both, carbenes and butadiene. [6] In particular the procedure described the reaction of 1,3-butadiene with carbenes generated from the action of base on chloroform or bromoform, which had been studied previously by Doering. [7] Neureiter then took the resulting 1,1-dichloro-2,2-dimethylcyclopropane and under pyrolysis conditions (above 400 °C) discovered a rearrangement to 4,4-dichlorocyclopentene which today is considered to be the first thermal vinylcyclopropane-cyclopentene rearrangement in history. [8]
The corresponding all-carbon version of the reaction was independently reported by Emanuel Vogel [9] and Overberger & Borchert just one year after the Neureiter publication appeared. [10] [11] Doering, although interacting with Humble Oil and Refining - and therefore also with Neureiter - as a consultant, in a 1963 publication stated the following : "Credit for discovery that vinylcyclopropane rearranges to cyclopentene is due to Overberger and Borchert, and Vogel et al., who appear to have developed several examples of the rearrangement independently." [12] The development of further vinylcyclopropane rearrangement variants didn't take long as demonstrated by Atkinson & Rees in 1967, [13] Lwowski in 1968. [14] and Paladini & Chuche in 1971. [15]
The classical vinylcyclopropane rearrangement was discovered well after two of its heteroatom variants had already been reported. Although it is believed that the vinylcyclopropane rearrangement must have occurred during Nikolay Demyanov's preparation of vinylcyclopropane by Hofmann elimination at elevated temperatures in 1922, [16] the cyclopropylimine-pyrroline rearrangement by Cloke in 1929 [17] and Wilson's cyclopropylcarbaldehyde-2,3-dihydrofuran rearrangement in 1947 [18] are really the only examples of vinylcyclopropane-like rearrangements.
This last reaction type is also known as the Cloke–Wilson Rearrangement [19]
The mechanistic discussion on whether the vinylcyclopropane rearrangement proceeds through a diradical-mediated two-step or a fully concerted orbital-symmetry-controlled mechanism has been going on for more than half a century. Kinetic data together with the secondary kinetic isotope effects observed at the vinyl terminus of the vinylcyclopropane suggest a concerted mechanism whereas product distribution indicates a stepwise-diradical mechanism. [20] In the 1960s, shortly after the rearrangement was discovered, it was established that the activation energy for the vinylcyclopropane rearrangement is around 50 kcal/mol. [21] The kinetic data obtained for this rearrangement were consistent with a concerted mechanism where cleavage of the cyclopropyl carbon-carbon bond was rate-limiting. Albeit a concerted mechanism seemed likely it was shortly recognized that the activation energy to break the carbon-carbon bond in unsubstituted cyclopropane was with 63 kcal/mol [22] exactly 13 kcal/mol higher in energy than the parent activation energy, a difference remarkably similar to the resonance energy of the allyl radical. [23] Immediately people started to appreciate the possibility for a diradical intermediate arising from homolytic cleavage of the weak C1-C2-cyclopropane bond under thermal conditions.
The discussion on whether the vinylcyclopropane rearrangement proceeds via a fully concerted or a two-step, non-concerted mechanism was given further careful consideration when Woodward and Hoffmann used the vinylcyclopropane rearrangement to exemplify [1,3]-sigmatropic concerted alkyl shifts in 1969. [24] They hypothesized that if a concerted mechanism was operative the consequences of orbital-symmetry controlled factors would only allow the formation of certain products. According to their analysis of a vinylcyclopropane substituted with three R groups the antarafacial [1,3]-shift of bond 1,2 to C-5, with retention at C-2, leading to the ar cyclopentene and the suprafacial [1,3]-shift of bond 1,2 to C-5, with inversion at C-2, leading to cyclopentene si are symmetry allowed whereas the suprafacial [1,3]-shift of bond 1,2 to C-5, with retention at C-2, leading to cyclopentene sr and the antarafacial [1,3]-shift of bond 1,2 to C-5, with inversion at C-2, leading to the ai cyclopentene are symmetry-forbidden.
Woodward and Hoffmann based their analysis solely on the principles of the conservation of orbital symmetry theory without however making any mechanistic or stereochemical prediction.
The attention directed towards the vinylcyclopropane rearrangement by Woodward and Hoffmann as a representative example for [1,3]-carbon shifts clearly enhanced the interest in this reaction. Furthermore, their analysis revealed potential experiments that would allow to distinguish between a concerted or stepwise mechanism. The stereochemical consequences of a concerted reaction pathway on the reaction outcome suggested an experiment where one would correlate the obtained reaction stereochemistry with the predicted reaction stereochemistry for a model substrate. Observing the formation of ai- and sr-cyclopentene products would support the notion that a stepwise, non-concerted mechanism is operative whereas their absence would point towards a fully concerted mechanism. As it turned out finding an appropriate substituted model substrate to study the stereochemical outcome of the vinylcyclopropane rearrangement was much more challenging than initially thought since side reaction such as the homodienyl [1,5]-hydrogen shifts and more so thermal stereomutations tend to scramble stereochemical distinctions much faster than rearrangements lead to the cyclopentene products.
Even though deconvolution of the complex kinetic scenarios underlying these rearrangements was difficult there have been several studies reported where exact and explicit deconvolutions of kinetic and stereochemical raw data to account for the stereochemical contributions arising from competitive stereomutations was possible. [20] [25] [26] [27]
Thereby rate constants for all four stereochemically distinct pathways of the vinylcyclopropane rearrangement could be determined.
The data clearly indicated that the mechanistic preferences of the rearrangements are system dependent. Whereas trans-vinylcyclopropanes tend to form more of the symmetry-allowed ar- and si-cyclopentenes supportive of a concerted mechanism, the cis-vinylcyclopropanes preferentially yield the symmetry-forbidden ai- and sr- products suggesting a more stepwise, diradical mechanism. The influence of substituent effects on the reaction stereochemistry also becomes apparent from the data. Substituents with increased radical stabilizing ability not only lower the rearrangements activation energy but also reclosure of the initially formed diradical species becomes slower relative to the rate of cyclopentene formation resulting in an overall more concerted mechanism with less stereomutation (e.g. entry 6 & 7). In all cases though all the four products were formed indicating that both orbital-symmetry controlled pericyclic, as well as diradical-mediated two-step mechanisms are operative either way. The data is consistent with the formation of biradical species on a relatively flat potential energy surface allowing for restricted conformational flexibility before the products are formed. The amount of conformational flexibility and therefore conformational evolution accessible to the diradical species before forming product depends on the constitution of the potential energy surface. This notion is also supported by computational work. [28] One transition state with a high diradicaloid character was found. Following the potential energy surface of the lowest energy path of the reaction it was found that a very shallow regime allows the diradical species to undergo conformational changes and stereoisomerization reactions with minor energetic consequences. Furthermore, it was shown that substituents can favor stereoselective pathways by destabilizing species that allow stereochemical scrambling.
Arguably the biggest drawback of the vinylcyclopropane rearrangement as a synthetic method is its intrinsically high activation barrier resulting in very high reaction temperatures (500-600 °C). Not only do these high temperatures allow side reactions with similar activation energies, such as homodienyl-[1,5]-hydrogen shifts, to occur but also do they significantly limit the functional groups tolerated in the substrates. It was well recognized by the chemical community that in order for this reaction to become a useful synthetic method, hopefully applicable in complex natural product settings at some point, some reaction development had to be done. It was found that the reaction temperature could be lowered drastically when the cyclopropane ring contained a dithiane group. Even though the dithiane-substituted vinylcyclopropane substrates required two synthetic steps starting from the corresponding 1,3-dienes the method proved itself successful for the synthesis of a variety of substituted cyclopentenes. The immediate rearrangement products could be easily converted to the corresponding cyclopentenones. [29]
Methoxy-substituted vinylcyclopropanes show significantly faster reaction rates allowing the rearrangement to take place at 220 °C. [30]
It was found that siloxyvinylcyclopropanes [31] as well as the analogous sulfinylvinylcyclopropanes [32] could be used as substrates to build annulated cyclopentene structures. Albeit these reactions still required reaction temperatures above 300 °C they were able to make useful products arising from the annulation of cyclopentene to a present ring system.
Vinylcyclopropane rearrangements can also be mediated photochemically. [33] [34] In a particularly intriguing example he was able to show that vinylcyclopropanes embedded within a cyclooctane core can be converted to the corresponding [5-5]-fused ring systems.
Vinylcyclopropane rearrangements are amenable to transition metal catalysts. Dirhodium acetate catalyzes the rearrangements from room temperature to 80 °C.y [35] [36]
Analogous to the rate acceleration observed in the anionic-oxy-Cope rearrangement Danheiser reported a very similar effect for vinylcyclopropane substrates bearing [alkoxy] substituents. [37]
Another intriguing result was reported by Larsen in 1988. [38] He was able to promote vinylcyclopropane rearrangements with substrates such as the one shown in the reaction below at temperatures as low as -78 °C. The substrates were generated in situ upon ringcontracting thiocarbonyl Diels-Alder adducts under basic conditions. This methodology allowed the formation of numerous highly functionalized cyclopentenes in a stereoselective manner.
The methodology is allows the formation of various [5-5]- as well as [5-6]-carbon scaffolds. [39]
Five-membered carbon rings are ubiquitous structural motifs in natural products. In contrast to the larger, fully "consonant" cyclohexane scaffold cyclopentanes and their derivatives are "dissonant" according to the Lapworth-Evans model of alternating polarities. The dissonance in polarity clearly limits the ways by which cyclopentanes can be disconnected which becomes evident in the decreased number of general methods available for making five-membered rings versus the corresponding six-membered rings. Especially the fact that there is no Diels-Alder-equivalent for the synthesis of five-membered rings has been bothering synthetic chemists for many decades. Consequentially, after the vinylcyclopropane rearrangement was discovered around 1960 it didn't take long for the synthetic community to realize the potential inherent to form cyclopentenes by means of the vinylcyclopropane rearrangement. As the vinylcyclopropane rearrangement progressed as a methodology and the reaction conditions improved during the 1970s, first total syntheses making use of the vinylcyclopropane rearrangement started to appear around 1980. Key figures to apply this reaction in total synthesis were Barry M. Trost, Elias J. Corey, Thomas Hudlicky, Leo A. Paquette,
A synthesis of Aphidicolin use methodology around the vinylcyclopropane rearrangement developed in their own laboratory . [40] A key step converts a late stage siloxyvinylcyclopropane into a cyclopentene that contained the [6-6-5]-fused carbon skeleton found within the natural product. The rearranged product into the natural product by further manipulations.
The synthesis of zizaene is another early example for the application of a vinylcyclopropane rearrangement as a key disconnection. [41]
The methodology has also been applied to the synthesis hirsutene [42] and isocomene [43]
Cinylcyclopropane rearrangement has been used to build the spirocyclic natural product alpha-vetispirene in 1982. [44]
Antheridiogen-An was prepared using a Lewis-acid mediated late-stage vinylcyclopropane rearrangement. [45]
Copper-catalyzed heteroatom-vinylcyclopropane rearrangement was used to form the tetrahydrothiophene core of biotin and the thiophene unit of Plavix respectively. [46]
An acid-mediated vinylcyclopropane rearrangement was used to synthesize the natural product salviasperanol. [47]
In organic chemistry, an electrocyclic reaction is a type of pericyclic, rearrangement reaction where the net result is one pi bond being converted into one sigma bond or vice versa. These reactions are usually categorized by the following criteria:
In organic chemistry, a sigmatropic reaction is a pericyclic reaction wherein the net result is one sigma bond (σ-bond) is changed to another σ-bond in an intramolecular reaction. In this type of rearrangement reaction, a substituent moves from one part of a π-system to another part with simultaneous rearrangement of the π-system. True sigmatropic reactions are usually uncatalyzed, although Lewis acid catalysis is possible. Sigmatropic reactions often have transition-metal catalysts that form intermediates in analogous reactions. The most well-known of the sigmatropic rearrangements are the [3,3] Cope rearrangement, Claisen rearrangement, Carroll rearrangement, and the Fischer indole synthesis.
In organic chemistry, the ene reaction is a chemical reaction between an alkene with an allylic hydrogen and a compound containing a multiple bond, in order to form a new σ-bond with migration of the ene double bond and 1,5 hydrogen shift. The product is a substituted alkene with the double bond shifted to the allylic position.
The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen. Hence, the reaction is sometimes referred to as the Huisgen cycloaddition. 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives. The dipolarophile is typically an alkene or alkyne, but can be other pi systems. When the dipolarophile is an alkyne, aromatic rings are generally produced.
The Cope rearrangement is an extensively studied organic reaction involving the [3,3]-sigmatropic rearrangement of 1,5-dienes. It was developed by Arthur C. Cope and Elizabeth Hardy. For example, 3-methyl-hexa-1,5-diene heated to 300 °C yields hepta-1,5-diene.
The Bamford–Stevens reaction is a chemical reaction whereby treatment of tosylhydrazones with strong base gives alkenes. It is named for the British chemist William Randall Bamford and the Scottish chemist Thomas Stevens Stevens (1900–2000). The usage of aprotic solvents gives predominantly Z-alkenes, while protic solvent gives a mixture of E- and Z-alkenes. As an alkene-generating transformation, the Bamford–Stevens reaction has broad utility in synthetic methodology and complex molecule synthesis.
The Claisen rearrangement is a powerful carbon–carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl, driven by exergonically favored carbonyl CO bond formation (Δ = −327 kcal/mol.
The Favorskii rearrangement is principally a rearrangement of cyclopropanones and α-halo ketones that leads to carboxylic acid derivatives. In the case of cyclic α-halo ketones, the Favorskii rearrangement constitutes a ring contraction. This rearrangement takes place in the presence of a base, sometimes hydroxide, to yield a carboxylic acid, but usually either an alkoxide base or an amine to yield an ester or an amide, respectively. α,α'-Dihaloketones eliminate HX under the reaction conditions to give α,β-unsaturated carbonyl compounds. Note that trihalomethyl ketone substrates will result in haloform and carboxylate formation via the haloform reaction instead.
The Masamune-Bergman cyclization or Masamune-Bergman reaction or Masamune-Bergman cycloaromatization is an organic reaction and more specifically a rearrangement reaction taking place when an enediyne is heated in presence of a suitable hydrogen donor. It is the most famous and well-studied member of the general class of cycloaromatization reactions. It is named for Japanese-American chemist Satoru Masamune and American chemist Robert G. Bergman. The reaction product is a derivative of benzene.
Bullvalene is a hydrocarbon with the chemical formula C10H10. The molecule has a cage-like structure formed by the fusion of one cyclopropane and three cyclohepta-1,4-diene rings. Bullvalene is unusual as an organic molecule due to the C−C and C=C bonds forming and breaking rapidly on the NMR timescale; this property makes it a fluxional molecule.
The Wolff rearrangement is a reaction in organic chemistry in which an α-diazocarbonyl compound is converted into a ketene by loss of dinitrogen with accompanying 1,2-rearrangement. The Wolff rearrangement yields a ketene as an intermediate product, which can undergo nucleophilic attack with weakly acidic nucleophiles such as water, alcohols, and amines, to generate carboxylic acid derivatives or undergo [2+2] cycloaddition reactions to form four-membered rings. The mechanism of the Wolff rearrangement has been the subject of debate since its first use. No single mechanism sufficiently describes the reaction, and there are often competing concerted and carbene-mediated pathways; for simplicity, only the textbook, concerted mechanism is shown below. The reaction was discovered by Ludwig Wolff in 1902. The Wolff rearrangement has great synthetic utility due to the accessibility of α-diazocarbonyl compounds, variety of reactions from the ketene intermediate, and stereochemical retention of the migrating group. However, the Wolff rearrangement has limitations due to the highly reactive nature of α-diazocarbonyl compounds, which can undergo a variety of competing reactions.
In organic chemistry, cyclopropanation refers to any chemical process which generates cyclopropane rings. It is an important process in modern chemistry as many useful compounds bear this motif; for example pyrethroid insecticides and a number of quinolone antibiotics. However, the high ring strain present in cyclopropanes makes them challenging to produce and generally requires the use of highly reactive species, such as carbenes, ylids and carbanions. Many of the reactions proceed in a cheletropic manner.
The divinylcyclopropane-cycloheptadiene rearrangement is an organic chemical transformation that involves the isomerization of a 1,2-divinylcyclopropane into a cycloheptadiene or -triene. It is conceptually related to the Cope rearrangement, but has the advantage of a strong thermodynamic driving force due to the release of ring strain. This thermodynamic power is recently being considered as an alternative energy source.
A (4+3) cycloaddition is a cycloaddition between a four-atom π-system and a three-atom π-system to form a seven-membered ring. Allyl or oxyallyl cations (propenylium-2-olate) are commonly used three-atom π-systems, while a diene plays the role of the four-atom π-system. It represents one of the relatively few synthetic methods available to form seven-membered rings stereoselectively in high yield.
In organic chemistry, enone–alkene cycloadditions are a version of the [2+2] cycloaddition. This reaction involves an enone and alkene as substrates. Although the concerted photochemical [2+2] cycloaddition is allowed, the reaction between enones and alkenes is stepwise and involves discrete diradical intermediates.
Rearrangements, especially those that can participate in cascade reactions, such as the aza-Cope rearrangements, are of high practical as well as conceptual importance in organic chemistry, due to their ability to quickly build structural complexity out of simple starting materials. The aza-Cope rearrangements are examples of heteroatom versions of the Cope rearrangement, which is a [3,3]-sigmatropic rearrangement that shifts single and double bonds between two allylic components. In accordance with the Woodward-Hoffman rules, thermal aza-Cope rearrangements proceed suprafacially. Aza-Cope rearrangements are generally classified by the position of the nitrogen in the molecule :
Thermal rearrangements of aromatic hydrocarbons are considered to be unimolecular reactions that directly involve the atoms of an aromatic ring structure and require no other reagent than heat. These reactions can be categorized in two major types: one that involves a complete and permanent skeletal reorganization (isomerization), and one in which the atoms are scrambled but no net change in the aromatic ring occurs (automerization). The general reaction schemes of the two types are illustrated in Figure 1.
In organic chemistry, the oxy-Cope rearrangement is a chemical reaction. It involves reorganization of the skeleton of certain unsaturated alcohols. It is a variation of the Cope rearrangement in which 1,5-dien-3-ols are converted to unsaturated carbonyl compounds by a mechanism typical for such a [3,3]-sigmatropic rearrangement.
In organometallic chemistry, the activation of cyclopropanes by transition metals is a research theme with implications for organic synthesis and homogeneous catalysis. Being highly strained, cyclopropanes are prone to oxidative addition to transition metal complexes. The resulting metallacycles are susceptible to a variety of reactions. These reactions are rare examples of C-C bond activation. The rarity of C-C activation processes has been attributed to Steric effects that protect C-C bonds. Furthermore, the directionality of C-C bonds as compared to C-H bonds makes orbital interaction with transition metals less favorable. Thermodynamically, C-C bond activation is more favored than C-H bond activation as the strength of a typical C-C bond is around 90 kcal per mole while the strength of a typical unactivated C-H bond is around 104 kcal per mole.
Rick L. Danheiser is an American organic chemist and is the Arthur C. Cope Professor of Chemistry at the Massachusetts Institute of Technology and chair of the MIT faculty. His research involves the invention of new methods for the synthesis of complex organic compounds. Danheiser is known for the Danheiser annulation and Danheiser benzannulation reactions.