Effect of a methoxy substituent on the vinylcyclobutane carbon migration

Over the temperature range 250-300 degrees C, 8-exo-methoxybicyclo[4.2.0]oct-2-ene (1a) undergoes a [1,3] sigmatropic rearrangement to 5-exo- and 5-endo-methoxybicyclo[2.2.2]oct-2-enes, 2a and 2b, respectively, with a clear preference for the si product: si/sr = 3.2. Both 1a and its 8-endo epimer 1b experience appreciable epimerization and fragmentation. A long-lived intermediate with weakly interacting diradical centers, one of which is stabilized by a methoxy substituent, can account for all such observations.     

Thermal chemistry of bicyclo[4.2.0]oct-2-enes

At 300 degrees C, bicyclo[4.2.0]oct-2-ene (1) isomerizes to bicyclo[2.2.2]oct-2-ene (2) via a formal [1,3] sigmatropic carbon migration. Deuterium labels at C7 and C8 were employed to probe for two-centered stereomutation resulting from C1-C6 cleavage and for one-centered stereomutation resulting from C1-C8 cleavage, respectively. In addition, deuterium labeling allowed for the elucidation of the stereochemical preference of the [1,3] migration of 1 to 2. The two possible [1,3] carbon shift outcomes reflect a slight preference for migration with inversion rather than retention of stereochemistry; the si/sr product ratio is approximately 1.4. One-centered stereomutation is the dominant process in the thermal manifold of 1, with lesser amounts of fragmentation and [1,3] carbon migration processes being observed. All of these observations are consistent with a long-lived, conformationally promiscuous diradical intermediate.     

Thermal isomerizations of cis,anti,cis-tricyclo[7.4.0.0(2,8)]tridec-10-ene

cis,anti,cis-Tricyclo[7.4.0.0(2,8)]tridec-10-ene (13TCT) undergoes [1,3] sigmatropic rearrangements at 315 °C in the gas phase to the si product 1 and to the sr product 2 with si/sr = 2.1. The dominant thermal isomerization process, however, is epimerization at C8 to afford product 3. That stereomutation at C8 occurs 50% faster than the si and sr shifts combined.     

Thermal reactions of 7-d- and 8-d-bicyclo[4.2.0]oct-2-enes

The gas phase thermal reactions exhibited by bicyclo[4.2.0]oct-2-ene and 7-d and 8-d analogues at 300 degrees C have been followed kinetically through GC and 2H NMR spectroscopic analyses. In contrast to the pattern of transformations exhibited by bicyclo[3.2.0]hept-2-ene and deuterium-labeled analogues, no reactions initiated by C1-C6 bond cleavage are seen, epimerization at C8 is much faster than [1,3] shifts leading to bicyclo[2.2.2]oct-2-ene, and the ratio of rate constants for [1,3] carbon migration with inversion versus migration with retention is approximately 1.4. Homolysis of C1-C8 to give a conformationally flexible diradical intermediate having a relatively long lifetime and multiple options for further reaction (re-formation of C1-C8 with or without net epimerization, fragmentation to 1,3-cyclohexadiene and ethylene, migration to the original C3 with inversion or retention) accords well with the observations. Clearly, orbital symmetry control does not govern stereochemistry for the [1,3] sigmatropic carbon shifts.     

Alkoxide-Accelerated [1,3] Sigmatropic Shift of Bicyclo[3.2.1]oct-6-en-2-ols to 8-endo-Hydroxybicyclo[3.3.0]oct-2-en-4-ones

Bicyclo[3.2.1]oct-6-en-2-ols 6 are shown to undergo [1,3] sigmatropic shift to afford 8-endo-hydroxy-bicyclo[3.3.0]oct-2-en-4-ones 8 under the influence of potassium hydride.     

Conformations and reactions of bicyclo[3.2.1]oct-6-en-8-ylidene

Bicyclo[3.2.1]oct-6-en-8-ylidene (1) can assume either the conformation of "classical" carbene 1a or that of foiled carbene 1b in which the divalent carbon bends toward the double bond. Oxadiazoline precursors for the generation of 1 were prepared, followed by photochemical and thermal decomposition as well as flash vacuum pyrolysis (FVP) of a tosyl hydrazone sodium salt precursor, to give a number of rearrangement products. Matrix isolation experiments demonstrate the presence of a diazo intermediate and methyl acetate in all photochemical and thermal precursor reactions. The major product from rearrangements of "classical" bridged carbene 1a is bicyclo[3.3.0]octa-1,3-diene as a result of an alkyl shift, while dihydrosemibullvalene formed from a 1,3-C-H insertion. In contrast, thus far unknown strained bicyclo[4.2.0]octa-1,7-diene formed by a vinyl shift in foiled carbene 1b. The experimental results are corroborated by density functional theory (DFT), MP2, and G4 computations.     

Thermal disrotatory electrocyclic isomerization of cis-bicyclo[4.2.0]oct-7-ene to cis,cis-1,3-cyclooctadiene

[reaction: see text] The ratio of observed rate constants, k/k', for thermal isomerizations of cis-bicyclo[4.2.0]oct-7-ene and its 2,2,5,5-d(4) analogue to cis,cis-1,3-cyclooctadienes at 250 degrees C is 1.17, indicative of a secondary, not a primary, deuterium kinetic isotope effect. The reaction does not occur through a [1,5] hydrogen shift from the transient cis,trans-1,3-cyclooctadiene intermediate to form the observed cis,cis-diene product.     

Regioselektive [4+3]-cycloadditionen von heterosubstituierten allylium-2-olaten (oxallylen) an 2-methylfuran

1,1-Dichloro- and 1,3-dichloro-2-alkanones react with 2-methylfuran in the presence of lithium perchlorate/triethylamine to form 2-chloro-1-methyl-8-oxabicyclo [3.2.1]oct-6-ene-3-ones predominantly.     

Photochemical rearrangement of 8-oxabicyclo[3.2.1]oct-6-en-2-ones

Irradiation of 8-oxabicyclo[3.2.1]oct-6-en-2-ones results in a 1,3-acyl rearrangement. The initial photoproduct undergoes a subsequent reaction involving hydrogen transfer followed by intramolecular cycloaddition of a ketene intermediate.     

Thermal isomerization of cis,anti,cis-tricyclo[6.3.0.0(2,7)]undec-3-ene to endo-tricyclo[5.2.2.0(2,6)]undec-8-ene

[reaction: see text] The gas-phase thermal isomerization of cis,anti,cis-tricyclo[6.3.0.0(2,7)]undec-3-ene (1) to endo-tricyclo[5.2.2.0(2,6)]undec-8-ene (2) at 315 degrees C occurs cleanly through a symmetry-forbidden [1,3] suprafacial,retention (sr) pathway.     

Polyfluorobicyclo[2, 2, 2]octanes. Part II. Syntheses of polyfluorobicyclo[2, 2, 2]oct-2-enes from polyfluoro-cyclohexa-1,3-dienes

Diels-Alder reactions between ethylene and octa-, 1$\text{H}$-hepta-, and 1H, 4H-hexa-fluorocyclohexa-1,3-diene gave, respectively, 1,2,3,4,5,5,6,6-octa-, 1,2,3,5,5,6,6-hepta-, and 2,3,5,5,6,6-hexa-fluorobicyclo[2, 2, 2]oct-2-ene, each characterised by oxidation to the corresponding polyfluorocyclohexane-1,4-dicarboxylic acid.     

Electron ionization mass spectra and crystal structures of some [1,2,4]triazolo[1,2-b]- and [1,3,4]thiadiazolo[3,4-b]phthalazines

The mass spectra of ten 1,3-dithioxo[1,2,4]triazolo[1,2,-b]phthalazines, five 3-iminosubstituted 1-thioxo-[1,3,4]thiadiazolo[3,4-b]phthalazines, three 3-iminosubstituted-1-thioxo[1,2,4]triazolo[1,2-b]phthalazines, and 1,3-dithioxo-5,10-dihydro[1,3,4]thiadiazolo[3,4-b]phthalazine were recorded under electron ionization. The fragmentation pathways were elucidated by metastable ion analysis and exact mass measurements. The changes in the ring-system had little effect on the fragmentation mechanism, but the effect on peak intensities was considerable. The most important fragmentations began with the opening of the triazole ring. Substituents at nitrogen atoms also had a marked effect on the mass spectral behavior. The aryl substituents prompted a whole new fragmentation. The X-ray crystal structure was determined for a few compounds. Two of the three structures of the 1,3-dithioxo[1,2,4]triazolo[1,2-b]phthalazines that were studied proved to be relatively planar, whereas the structure of 1,3-dithioxo-5,10-dihydro[1,3,4]thiadiazolo[3,4-b]phthalazine was considerably bent similarly to the 2-(4-chlorophenyl)-1,3-dithioxo-2,3,5,10-tetrahydro[1,2,4]triazolo[1,2-b]-phthalazine. The triazole and the thiadiazole rings had a strong double bond nature.     

Thermal isomerizations of cis,anti,cis-tricyclo[6.4.0.0]dodec-3-ene to trans- and cis,endo-tricyclo[6.2.2.0]dodec-9-ene: diradical conformations and stereochemical outcomes in [1,3] carbon shifts

The gas-phase thermal isomerizations at 315 °C of cis,anti,cis-tricyclo[6.4.0.0^2,7]dodec-3-ene to trans-tricyclo[6.2.2.0^2,7]dodec-9-ene and to cis,endo-tricyclo[6.2.2.0^2,7]dodec-9-ene favor the former, the more geometrically strained product, by a ratio of 2.4:1. These products correspond to suprafacial inversion (si) and suprafacial retention (sr) stereochemical outcomes. The reaction stereochemistry shown by the 11-carbon homolog, cis,anti,cis-tricyclo[6.3.0.0^2,7]undec-3-ene, is strikingly different: the [1,3] carbon shift takes place to give only the ‘forbidden’ sr product. Two related bicyclic vinylcyclobutanes, 8-deuterio- and 8-exo-methylbicyclo[4.2.0]oct-2-enes, evidence contrasting reaction stereochemical predilections in [1,3] shifts, but the 12-carbon tricyclic system and the 8-exo-methyl bicyclic analog isomerize with the same si:sr ratio! These observations prompt fresh considerations of structural influences on conformational preferences available to the alkyl, allyl diradical reactive intermediates involved.     

First Synthesis of 5-Chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol by Pd-Catalyzed Arylation

5-Chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol was synthesized by a Pd-catalyzed arylation, which proceeds efficiently with 2 equivalents of benzylated clioquinol and 1 equivalent of oxazolo[4,5-b]pyridine. The product was smoothly debenzylated by boron trichloride in dichloromethane.     

The Synthesis and Chemistry of 8-Substituted Bicyclo[5.1.0]oct-1(8)-ene

8-Bromobicyclo[5.1.0]oct-1(8)-cne (7), an intermediate for the preparation of 8-substituted bicyclo[5.1.0]oct-1(8)-enes, was synthesized by denomination of 1,8,8-tribromobicyclo[5.1.0]octane (6). Compound 7 underwent bromo-lithium exchange followed by nucleophilic substitution reactions to generate bicyclo[5.1.0]oct-1(8)-ene (5), 8-methylbicyclo[5.1.0]oct-1(8)-ene (10), and 8-trimethylsilylbicyclo[5.1.0]oct-1(8)-ene (11). The bicyclic cyclopropenes 7, 5, 10, and 11 reacted with cyclopentadiene to form adducts 12, 13, 14, and 15, respectively. All of these Diels-Alder adducts are endo-exo isomers (endo-addition from the view of the cyclopropene and exo-addition from the view of the cyclooctene).     

The Reaction of Bicyclo [3.2.1] octenyl Halides with Metal Hydrides

Reduction of 2-phenyl- and 2-methyl-exo-3,4-dichlorobicyclo[3.2.1]oct-2-enes with lithium aluminium hydride (LAH) or tributyltin hydride (TBTH) gave endo-2-phenyl-3-chlorobicyclo[3.2.1]oct-3-ene, 2-phenyl-3-chlorobicyclo[3.2.1]oct-2-ene and their methyl analogues. The action of both reagents on 2-phenyl-exo-3, 4-dibromobicyclo[3.2.1]oct-2-ene similarly resulted in reductive monodebromination to give normal and allylically rearranged products. Additionally, further reduction occurred to give endo-2-phenylbicyclo[3.2.1]oct-3-ene and 2-phenylbicyclo[3.2.1]-oct-2-ene. In all cases, LAH gave mainly the allylic rearrangement product whereas TBTH gave mostly unrearranged product. The reason for these differences could have been due either to the intervention of allylic radicals in the TBTH reduction or to differences in nucleophilicity. The results also show that LAH is equally efficaceous as TBTH in the reduction of these allylic halides and equally selective in the reduction of the vinyl bromides. The stereochemistry of the allylic rearrangement was shown to be synfacial in that hydride replaced halide on the same face of the molecule.     

Gold-catalyzed tandem 1,3-migration/[2 + 2] cycloaddition of 1,7-enyne benzoates to azabicyclo[4.2.0]oct-5-enes

A synthetic method that relies on gold(I)-catalyzed tandem 1,3-migration/[2 + 2] cycloaddition of 1,7-enyne benzoates to prepare azabicyclo[4.2.0]oct-5-enes is described.     

Synthesis of 2,6-dioxatricyclo[3.3.1.0]nonanes by intramolecular haloetherification and/or transannular hydroxycyclization of alkenes in [4+3]-cycloadducts

The synthesis of new difunctionalized 2,6-dioxatricyclo[3.3.1.0^3,7]nonanes is described. This type of structure is an interesting synthetic building block for potential bioactive molecules and it was prepared from 8-oxabicyclo[3.2.1]oct-6-en-3-one having a NHBoc function on C-1. This precursor was obtained by a [4+3] cycloaddition reaction of 2-tert-butoxycarbonylaminofuran and the oxyallyl cation generated in situ from 2,4-dibromo-3-pentanone. Reduction of the carbonyl group at C-3 was accomplished in high yield and stereoselective manner to afford the corresponding axial alcohol at C-3 as a major product. Further intramolecular haloetherification of this type of alcohols with NBS and I(py)2BF₄ led to the corresponding bromo and iodo-derivatives at C-8 of the 2,6-dioxatricyclo[3.3.1.0^3,7]nonane framework, in high yield. Epoxidation of 8-oxabicyclo[3.2.1]oct-6-en-3-ol followed by treatment with NaCN, NaN₃, and/or NaOH in MeOH afforded 8-hydroxy-2,6-dioxatricyclo[3.3.1.0^3,7]nonanes in high yield via a transannular hydroxycyclization mediated by a base and through an alkoxide intermediate. The new 2,6-dioxatricyclo[3.3.1.0^3,7]nonanes were tested for biological activity against HIV-1 virus and MT-4 lymphoid cell line, showing a low anti-HIV activity and a high degree of cytotoxicity.     

Deuterium kinetic isotope effects and mechanism of the thermal isomerization of bicyclo[4.2.0]oct-7-ene to 1,3-cyclooctadiene

The thermal conversion of cis-bicyclo[4.2.0]oct-7-ene to cis,cis-1,3-cyclooctadiene might involve a direct disrotatory ring opening, or it might possibly take place by way of cis,trans-1,3-cyclooctadiene. This cis,trans-diene might possibly form the more stable cis,cis isomer through a [1,5] hydrogen shift or a trans-to-cis isomerization about the trans double bond. Deuterium kinetic isotope effect determinations for the isomerizations of 2,2,5,5-d(4)-bicyclo[4.2.0]oct-7-ene and 7,8-d(2)-bicyclo[4.2.0]oct-7-ene rule out these two alternatives because the observed effects are much smaller than would be anticipated for these mechanisms: k(H)/k(D)(d(4)) at 250 degrees C is 1.17 (1.04 per D), and k(H)/k(D)(d(2)) at 238 degrees C is 1.20 (1.10 per D). The direct disrotatory ring opening route remains the preferred mechanism.     

Thermal stereomutations and stereochemically elucidated [1,3]-carbon sigmatropic shifts of 1-(E)-propenyl-2-methylcyclobutanes giving 3,4-dimethylcyclohexenes

The thermal stereomutations and [1,3] carbon sigmatropic shifts shown by (+)-(1S,2S)-trans-1-(E)-propenyl-2-methylcyclobutane and by (-)-(1S,2R)-cis-1-(E)-propenyl-2-methylcyclobutane in the gas phase at 275 degrees C leading to 3,4-dimethylcyclohexenes have been followed. The reaction-time-dependent data for concentrations and enantiomeric excess values for substrates and [1,3] shift products have been deconvoluted to afford rate constants for the discrete isomerization processes. Both trans and cis substrates react through four stereochemically distinct [1,3] carbon shift paths. For one enantiomer of the trans reactant the relative rate constants are k(si) = 58%, k(ar) = 5%, k(sr) = 33%, and k(ai) = 4%. For a single enantiomer of the cis reactant, k'(si) = 18%, k'(ar) = 11%, k'(sr) = 51%, and k'(ai) = 20%. A trans starting material reacts through orbital symmetry allowed suprafacial,inversion and antarafacial,retention paths to give trans-3,4-dimethylcyclohexenes 63% of the time. A cis isomer reacts to give the more stable trans-3,4-dimethylcyclohexenes through orbital symmetry-forbidden suprafacial,retention and antarafacial,inversionpaths 71% of the time. The [1,3] carbon sigmatropic shifts are not controlled by orbital symmetry constraints. They seem more plausible rationalized as proceeding through diradical intermediates having some conformational flexibility after formation and before encountering an exit channel. The distribution of stereochemical outcomes may well be conditioned by dynamic effects. The thermal stereomutations of the 1-(E)-propenyl-2-methylcyclobutanes take place primarily through one-center epimerizations. For the trans substrate, the relative importance of the three distinction rate constants are k(2) = 48%, k(1) = 34%, and k(12) = 18%. For the cis isomer, k'(2) = 44%, k'(1) = 32%, and k'(12) = 24%. These patterns are reminiscent of ones determined for stereomutations in 1,2-disubstitued cyclopropanes.