Domino Reactions with Fluorinated Five-membered Heterocycles – Syntheses of Trifluoromethyl Substituted Butenolides and γ-Ketoacids

Summary. A new approach to trifluoromethyl substituted butenolides and their thioanalogues is described starting from 2-fluoro-3-trifluoromethylfurans and -thiophenes, respectively. The reaction sequence includes three steps – nucleophilic displacement reaction, Claisen, and finally Cope rearrangement – which can be run as domino reaction. A modification of the domino reaction (transesterification instead of Cope rearrangement) provides a concise access to α-trifluoromethyl-γ-ketoacids.     

Domino Reactions with Fluorinated Five-membered Heterocycles – Syntheses of Trifluoromethyl Substituted Butenolides and γ-Ketoacids

A new approach to trifluoromethyl substituted butenolides and their thioanalogues is described starting from 2-fluoro-3-trifluoromethylfurans and -thiophenes, respectively. The reaction sequence includes three steps – nucleophilic displacement reaction, Claisen, and finally Cope rearrangement – which can be run as domino reaction. A modification of the domino reaction (transesterification instead of Cope rearrangement) provides a concise access to α-trifluoromethyl-γ-ketoacids.     

Addition of a Functionalized Isoprene Unit to an Allyl Alcohol. III. The reaction with optically active cis-carveol

Provided the temperature is kept under 150°, diene ethers of allyl alcohols rearrange in the double Claisen-Cope reaction largely by a sigmatropic process in both stages. This was demonstrated by using the 2-methylbutadienyl ether of (?)-cis-carveol, when the product obtained after the two rearrangements was optically active. To check the extent of chirality loss, the same product was synthesized by a route involving only one sigmatropic reaction instead of two. When the reaction occurs at higher temperature, much more chirality is lost, corresponding to the intervention of a diradical process.     

A Stereospecific `2‐Aza‐divinylcyclopropane' Rearrangement

The stereochemical course of the thermal 2‐aza‐Cope rearrangement of the optically pure acyl azide (−)‐(1S)‐ 5 was investigated by determination of the absolute configuration of the rearrangement product (1R,8S)‐ 9 . The reaction proceeds by a sequence of stereospecific steps from 5 to an equilibrating mixture of exo‐ and endo‐isocyanates 6 and 7 . The endo‐isomer 7 undergoes Cope rearrangement to the putative intermediate 8 , which is trapped and characterized as the adduct 9b of butan‐1‐ol. The absolute configuration of 9b was determined by its reduction to the amide 20 , and determination of the X‐ray structure of the N‐camphanoylamide 21 derived from camphanic acid of known absolute configuration.     

Cycloaddition Reaction of 1,4‐Dihydronaphthalene 1,4‐Epoxide with Cyclooctatetraene: Cope Rearrangement in an Adduct

The reaction of 1,4‐dihydro‐1,4‐epoxynaphthalene with cyclooctatetraene at 130±5° for 14 days gave the four products 2a,3,3a,4,9,9a,10,10a‐octahydro‐4,9‐epoxy‐3,10‐ethenocyclobuta[b]anthracene ( 13 ), 25‐oxanonacyclo[10.10.2.2^5,9.1^14,21.0^2,11.0^3,10.0^4,6.0^13,22.0^15,20]heptacosa‐7,15,17,19,23,26‐hexaene ( 14 ), 5,5a,6,6a,6b,6c,12a,12b,12c,13,13a,14‐dodecahydro‐5,14‐epoxy‐6,13‐ethenocycloocta[3′,4′]cyclobuta[1′,2′:3,4]cyclobuta[1,2‐b]anthracene ( 15 ) and bis‐adduct 16 . The structures of the products were determined by spectroscopic methods. It was observed that adduct 14 undergoes a Cope rearrangement. The Cope rearrangement of this adduct was investigated in the temperature range of ?85° to 100° by NMR spectroscopy.     

Density Functional Study of the Oxy‐Cope Rearrangement

With the goal of explaining the very large rate acceleration in the anion‐assisted Cope rearrangement, the behavior of the prototypes of the Cope rearrangements, namely hexa‐1,5‐diene ( 4 ), hexa‐1,5‐dien‐3‐ol ( 5 ), and the oxy anion 6 of the latter were compared. For this purpose, two‐dimensional DFT (hybrid B3LYP functionals with 6‐31G* basis set) potential‐energy surfaces (PESs) were computed, based on two interatomic distances. As the reliability of DFT/B3LYP‐computed energies can not be taken for granted, we first performed model computations on the experimentally well‐studied bridged homotropylidenes 1 – 3 . Then, the transition states of the Cope rearrangements of 3‐methylhexa‐1,5‐dien‐3‐ol ( 7 ), (2Z,4Z,7Z)‐cyclonona‐2,4,7‐trien‐1‐ol ( 9 ), 1‐methoxy‐2‐endo‐vinylbicyclo[2.2.2]oct‐5‐en‐2‐exo‐ol ( 11 ), and (1S,2R)‐2‐hydroxy‐1‐methyl‐2‐vinylbicyclo[4.4.0]dec‐6‐en‐8‐one (arbitrary numbering; 13 ) and of their oxy anions 8 , 10 , 12 , and 14 , respectively, were computed by the same method. These examples were chosen because kinetic data have been measured for most of them (except for 13 and 14 ) and/or because they furnished already important contributions to the discussion of the character of the Cope rearrangement. The computation of ΔG^≠ for a given temperature allowed to calculate the rate constants at that temperature for the different rearrangements and to compare them with the experimental data. In the cases of the neutral and anionic oxy‐Cope rearrangements, the equation ΔΔG^≠=2.3026⋅RT⋅ΔpK_a suggested a correlation between the difference in the pK_a values of the pair of reactants and the pair of transition states and the change of the two free energies of activation.     

β-Cleavage of Bis(homoallylic) Potassium Alkoxides. Two-Step Preparation of Propenyl Ketones from Carboxylic Esters. Synthesis of ar-Turmerone, α-Damascone, β-Damascone,and β-Damascenone

The transformation of 36 bis(homoallylic) alcohols VII to alkenones IX and X via β-cleavage of their potassium alkoxides VIIa in HMPA has been investigated (cf. Scheme 2). These studies have established an order of β-cleavage for 2-propenyl, 1-methyl-2propenyl, 2-methyl-2-propenyl, 1,1-dimethyl-2propenyl, and benzyl groups in alkoxides 49a – 56a and have allowed a comparison between the β-cleavege reaction and the oxy-Cope rearrangement in alkoxides 74a – 83a . As illustrative syntheti applications, a two-step preparatio of propenyl ketones 15 – 42 from carboxylic esters is described, together with syntheses of ar-turmerone ( 48 ), α-damascone ((E)- 71 ), β-damascone ((E)- 109 ), and β-damascenone ((E)- 111 ).     

A Fused Benzocyclooctene Ring System via an Aromatic Cope Rearrangement: Thermal Reactions of trans‐1‐Aryl‐2‐ethenylcyclobutanecarbonitriles

The results of an aromatic Cope rearrangement of a trans‐1‐aryl‐2‐ethenylcyclobutanecarbonitrile are reported (Scheme). The use of this rearrangement for the construction of the fused benzocyclooctene ring system and a preliminary study of the electronic requirements to favor such a transformation are also described.     

Über den Mechanismus der Cope-Umlagerung

On the Mechanism of the Cope Rearrangement The rates of the Cope rearrangement of 2,5-dicyano-3-methyl-hexa-1, 5-diene ( 12 ), (E)- and (Z)-2, 5-dicyano-hepta-1,5-diene ((E)- and (Z)- 14 ) as well as of 2, 5-dimethoxycarbonyl-3-methyl-hexa-1,5-diene ( 13 ) and (E)- and (Z)-2,5-dimethoxycarbonyl-hepta-1,5-diene ((E)- and (Z)- 15 ) were measured in decane solution in the temperature range of 50 to 150° (see Tables 5 and 8 to 12). A detailed English summary of this work is given in [1 b].     

Synthese von natürlichen Haloindolen via Hetero-Cope-Umlagerung von Vinyl-N-phenylhydroxamaten

Synthesis of Natural, Halogenated Indoles via Hetero-Cope Rearrangement of Vinyl N-Phenylhydroxamates An efficient method for the synthesis of natural 4-chloro-6-methoxyindole (the promutagen from fava beans) and of the two 4,6- dibromo- and 3,4,6-tribromoindoles (produced by acorn worms, Enteropneusta) is presented. The key step is a hetero-Cope rearrangement of the intermediate N-phenyl-O-vinylhydroxylamine derivatives.     

Photocyclisierungen von 1, 1'-Polymethylen-di-2-pyridonen. 46. Mitteilung über Photoreaktionen

Photocyclization of 1, 1′-Polymethylene-di-2-pyridones . Benzophenone sensitized irradiation of the four dipyridones 1-4 gave the internal photocyclization products 6 (64%, Scheme 4), 7 (60%, Scheme 5), 8 (Scheme 6), and 11 (26%, Scheme 7), respectively. The decamethylene compound 5 yielded only polymeric material. The primary [2+2] photoproduct 8 from dipyridone 3 (Scheme 6) is relatively unstable. Further irradiation or heating to 65° induced a Cope rearrangement to give compound 9 which, on heating to 137°, was converted into the isomeric compound 10 . This product, as well as the other photoproducts mentioned, are rearranged back to their respective starting materials upon direct irradiation with 254 nm light or by heating to higher temperatures. The various possibilities for cycloadditions of pyridones are discussed as well as the possible factors which are responsible for the highly regioselective photoreactions of the dipyridones 1–4 .     

Der Zugang zum Antitumor-Antibiotikum CC-1065 mittels Hetero-Cope-Umlagerung von Vinyl-N-phenylhydroxamaten

The Access to the Three Subunits of the Antitumor Antibiotic CC-1065 by Hetero-Cope Rearrangement of Vinyl N-Phenylhydroxamates . The use of the hetero-Cope rearrangement of vinyl N phenylhydroxamates to indoles for the preparation of the 1,2-dihydro-3H, 6H-benzo[1,2-b:4,3-b′]dipyrrole skeleton, the structural subunits characteristic of the antitu-mor antibiotic CC-1065 as well as the phosphodiesterase inhibitors PDE-I and PDE-II is described.     

Comparative study of the cope rearrangement of hexa-1,5-diene and barbaralane

The classical rules for Cope rearrangements predict a transition state with chair form to be favored over the boat form. On the other hand, bridged homotropylidenes, which allow only a boat-form transition state by steric reasons, have extremely low barriers. A controversy about the correct pathway and the different possible intermediates and transition states of the reaction has gone on for years. In this work, the hypersurfaces of barbaralane, in comparison with the boat- and chair-form of hexa-1,5-diene, are computed by the ab inito CASSCF (6,6)/6-31G** method starting with UMP2/6-31G** natural orbitals (NO's). All three hypersurfaces show characteristic features, and, moreover differ from each other. A hitherto undiscussed intermediate, bicyclo[2.2.0]hexane, was localized on the boat-hexa-1,5-diene pathway. So it is noteworthy that our transition state for the boat-hexa-1,5-diene does not correspond to the transition states found by other authors for this conformation. The computed enthalpies of activation of boat- and chair-hexa-1,5-diene, and barbaralane are in good agreement with the experimental data.     

Die Cope-Umlagerung als Prinzip einer repetierbaren Ringerweiterung

The Cope Rearrangement, a Reaction for Repeatable Ring Expansions Starting with the unsaturated β-ketoesters of type I, a vinyl group is introduced into the β-position by 1,4-addition of vinyl magnesium chloride to give II (Scheme 3). Treatment of the β-ketoester II with phenyl vinyl sulfoxide in the presence of sodium hydride yields the sulfoxides III, which on thermolysis lead to the α, β-divinyl ketoesters of type IV via elimination of sulfinic acid (Scheme 3). The Cope-System IV undergoes rearrangement to V, which is again an unsaturated β-ketoester. The latter is suitable for a further ring expansion sequence. These reaction steps were carried out with the nine-, twelve- and fifteen-membered ketoesters 32, 33 and 34 , as well as with the open-chain compound 35 (Table 1). With the cyclohexane derivative 31 , ring expansion could not be achieved with the described sequence.     

Comparison of 13C- and 1H-Magnetic Resonance Spectroscopy as Techniques for the Quantitative Investigation of Dynamic Processes. The cope rearrangement in bullvalene

The potential advantages of ¹³C-(¹H-noise decoupled) spectroscopy (in the Fourier transform mode) over ¹H-spectroscopy for the quantitative investigation of molecular dynamic process is discussed. The Cope rearrangement in bullvalene, an example of complex exchange of spins over different magnetic sites, has been studied by both kinds of spectroscopy as a test.     

Synthese von 2,3-unsubstituierten,N-acylierten Indolen durch sigmatrope[3,3]-Umlagerung von O-Vinyl-N-phenylhydroxylaminderivaten

Synthesis of 2,3-Unsubstituted N-Acylindoles by [3,3]-Rearrangement of the N-Phenyl-O-vinylhydroxylamine Derivatives Summary, Treatment of N-phenylhydroxamic acids with vinylacetate in the presence of Li₂PdCl₄ affords 2,3-unsubstituted N-acylindoles via hetero-Cope-rearrangement of the intermediate N-O-vinylhydroxylamine derivatives.     

Note on the Synthesis of 1, 1-Dichloro-2, 3-divinylcyclopropane and Other Functionalized Dichlorocyclopropanes

The title compound 1 was synthesized via addition of dichlorocarbene to dimethyl trars-3-hexenedioate ( 5 ), using o-nitrophenylselenic acid-elimination to form the double bonds. Reaction of dichlorocyclopropane 8 with ozone on silica gel furnished the monoketone 10 ; no diketone 11 could be isolated upon further exposure of 10 to O₃/SiO₂. When the bis(p-toluenesulfonate) 13b was treated with t-BuOK, 16 was obtained in low yield as the only isolable product. It is believed to arise from Cope-rearrangement of an intermediate cis-divinylcyclopropane 14 to cycloheptadiene 15 , which undergoes a subsequent allylic rearrangement to 16 .     

A Model Study towards a Conceptually New Synthetic Entry into the Seco‐ and Heteroyohimbine Alkaloid Families

A model study is presented that paves the way to a new and flexible synthetic approach towards the seco‐ and heteroyohimbine alkaloid class. The key step involves a highly diastereoselective Cope rearrangement of an (E,E)‐azacyclodeca‐3,7‐diene grafted onto a 3‐ethylindole moiety to furnish a trans‐3,4‐divinylpiperidine derivative in 83% yield.     

Synthesis and Rearrangement of Silylated Oxy-Cope Systems

Addition of allyl or vinyl organometallic reagents to chiral a,b\alpha,\beta- or b,g\beta,\gamma -unsaturated acylsilanes afforded stereoselectively 3-silylated 3-hydroxy-1,5-dienes that are stereoselectively converted to d,e\delta,\varepsilon-unsaturated acylsilanes by the thermal oxy-Cope rearrangement. The rearrangement is restricted to compounds possessing an (alkoxy)methyl substituent at the silicon moiety; upon heating, analogous compounds with the t-BuMe₂_2Si group in the 3-position led to decomposition only. The (alkoxy)methyl group at silicon is supposed to act as a weak internal base, which accelerates the rearrangment reaction.     

Reactions of (1E)‐Buta‐1,3‐dien‐1‐yl Acetate with Diazocarbonyl Compounds

Carbene transfer to appropriate substrates is a highly versatile tool for the construction of carbon frameworks with increased functional and structural complexity. In this study, some novel cyclopropane derivatives were synthesized via carbenoid reactions and their further reactivities were investigated. (1E)‐Buta‐1,3‐dien‐1‐yl acetate was reacted with four different diazocarbonyl compounds, ethyl diazoacetate, dimethyl diazomalonate, 1‐diazo‐1‐phenylpropan‐2‐one, and methyl (3E)‐2‐diazo‐4‐phenylbut‐3‐enoate, in the presence of two catalysts. All synthesized substituted cyclopropanes were obtained chemoselectively with respect to less‐hindered C?C bonds. Under the applied conditions, while cyclopropanes 7a and 7d underwent further reactions, cyclopropanes 7b and 7c were stable enough. Cyclopropanes 7a and an additional equivalent of ethyl diazoacetate yielded polyfunctionalized cyclohexenes. Cyclopropanes from methyl (3E)‐2‐diazo‐4‐phenylbut‐3‐enoate yielded polyfunctionalyzed cycloheptadiene isomers by Cope rearrangement.