Synthesis of 2-heterobicyclo[3.2.1]octanes and the corresponding monoenes and dienes

Synthesis of the theoretically interesting 2-heterobicyclo[3.2.1.]octa-3,6-dienes and their dihydro-and tetrahydro-derivatives has been achieved in the oxygen, nitrogen and sulphur series. The parent compound of the nitrogen series appears to exist as 2-azabicyclo[3.2.1]octa-2,6-diene rather than as the enamine (3, R=H). The Cope rearrangement equilibrium (2, X=NR)?(3) lies more to the side of the diene 3 when nitrogen is substituted with an electron withdrawing group than when an alkyl substituent is present. These effects seem to suggest no special bishomoconjugative stabilisation in the dienes 3.     

Synthesis of versatile bicyclo[5.4.0]undecane systems from tetrachlorocyclopropene

2,2,3,4-Tetrachloro-8-oxabicyclo[3.2.1]octa-2,6-diene, derived in a single step from the cyclocondensation of furan and tetrachlorocylopropene, serves as a key intermediate for the construction of bicyclo[5.4.0]undecane synthons. Conversion to a meso-1,3 diketone is followed by a high yielding Robinson annulation reaction. Studies on the reduction of the enone product reveals a powerful preference for formation of the cis-ring fusion.     

Rhodium complexes of some cyclo-olefins

Dicarbonyl(pentane-2,4-dionato)rhodium(I) does not form a complex with, or induce a skeletal rearrangement in, cycloheptatriene. 5-Exo-methylene-2-norbornene is present as an impurity in cycloheptatriene and is complexed by Rh(I) complexes as its endocyclic tautomer. Rhodium complexes of 1,3,5-cyclooctatriene, bicyclo [3.2.1] octa-2,6-diene, cyclooctatetraene, cyclooctatetraene epoxide, bicyclo [6.1.0] nonatriene and 9,9-dimethyl bicyclo [6.1.0] nonatriene are also reported.     

Reaction of bicyclo[3.2.1]octadiene with 4-methyl-1,2,4-triazoline-3,5-dione: competitive dipolar and homo-cycloaddition

The nonconjugated bicyclo[3.2.1]octa-2,6-diene ($\text{1}$) affords with 4-methyl-1,2,4-triazolin-3,5-dione (MTAD) the homo-cycloadduct ($\text{2}$) product and the rearranged urazoles ($\text{3}$) and ($\text{4}$) through dipolar cycloaddition, while ene-reaction and (2+2)-cycloaddition are not observed.     

Reactions of the 1-halo-7-(2-hydroxyethoxy)cycloheptenes and the 3-halo-4-(2-hydroxyethoxy)bicyclo[3.2.1]oct-2-enes with potassium t-butoxide

Reactions of 1 - bromo - 7 - (2 - hydroxyethoxy)cycloheptene 2 and its chloro analogue 3 with potassium t-butoxide in dimethyl sulphoxide or tetrahydrofuran gave cycloheptatriene and cis - 8,11 - dioxabicyclo[5.4.0]undec - 2 - ene 18 as the major products together with small amounts of the trans-isomer 17,8,11-dioxabicyclo[5.4.0]undec - 1(7) - ene 14, 8,11 - dioxabicyclo[5.4.0] - undec - 1 - ene 19, cyclohept - 2 - enone ethylene ketal 15, cyclohept - 3 - enone ethylene ketal 16, and 1- and 2 - t - butoxycyclohepta - 1,3 - diene 20. Similar reactions of 3 - bromo - and 3 - chloro - 4 - (2 - hydroxyethoxy)bicyclo[3.2.1]oct - 2 - ene 4 and 5 gave 4,7 - dioxatricyclo[7.2.1.0^3,8]dodeca - 2 - ene 26 as the major product together with small amounts of 3,6 - dioxatricyclo[7.2.1.0^2,7]dodeca - 2(7) - ene 27 and bicyclo[3.2.1]oct - 3 - ene - 2 - one ethylene ketal 28. Mechanisms for these transformations are discussed.     

Reaction of dicobalt octacarbonyl with acetylene and carbon monoxide at low temperature and pressure: Formation of cyclic enone products

Dicobalt octacarbonyl is shown to react with acetylene and carbon monoxide under mild conditions in dimethoxyethane or benzene to produce, in low yields, bicyclo[3.3.0]octa-3,7-diene-2,6-dione, benzoquinone, and the cyclopentadienone-derived products 3a,4,7,7a-tetrahydro-2,7-methanoindene-1,10-dione, 1-indanone, tetracyclo[5.5.2.0^2,60^8,12]tetradeca-4,10,13-triene-3,9-dione, and tetracyclo[5.5.2.0^2,60^8,12]tetradeca-4,9,13-triene-3,11-dione. Possible mechanisms for the formation of these products are discussed.     

Thermal rearrangement of divinylcyclopropane systems. Preparation of functionalized,stereochemically defined bicyclic and tricyclic products containing the bicyclo[3.2.1]octane skeleton

A study involving the preparation and thermolysis of substituted 6-$\text{exo}$-(1-alkenyl)bicyclo[3.1.0]hex-2-ene systems (14, 15, 23, 29, 40) shows (a) that C-8 functionalized bicyclo[3.2.1]octa-2,6-dienes can be prepared readily $\text{via}$ this methodology (14 → 16; 15 → 17), (b) that the rearrangement reaction is stereospecific even when the 6-(1-alkenyl) group is substituted with a sterically bulky isopropyl group (23 → 24; 29 → 30), and (c) that the method can be extended to include the preparation of tricyclic systems (40 → 41).     

Photobehaviour of 2- and 3-heteroaryl substituted o-divinylbenzenes; formation of fused 2,3- and 3,2-heteroareno-benzobicyclo[3.2.1]octadienes and 3-heteroaryl benzobicyclo[2.1.1]hexenes

New β-3-thienyl (8) and β-3-furyl derivatives of o-divinylbenzene (9) have been synthesised and their photochemical behaviour compared with 2-thienyl (7) and 2-furyl derivatives (2). Whereas the β-(2-heteroaryl) substituted o-divinylbenzenes (7 or 2) give only bicyclo[3.2.1]octadiene structure (14 or 1) by 1,6-ring closure of the biradical intermediate, β-(3-heteroaryl) substituted o-divinylbenzenes (8 or 9) give bicyclo[3.2.1]octadiene structure (23 or 24) and bicyclo[2.1.1]hexene structure (25 or 26) by 1,6- and 1,4-ring closure, respectively. This photochemical approach provides a simple method to 2,3- and 3,2-fused thiophene and furan polycyclic compounds.     

Carbon-13 chemical shifts of bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane derivatives

¹³C chemical shifts of more than fifty bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane derivatives (hydrocarbons, alcohols, ketones and esters) have been determined. The usefulness of ethyl derivatives for the assignment of close ¹³C chemical shifts in bicyclic methyl derivatives is shown both for the bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane series. Comparison of substituent effects on α-, β-, γ- and δ-carbons in both series of compounds shows remarkable differences in steric interactions. In contrast to the rigid bicyclo[2.2.1]heptane system, both chair and boat conformations can be predominant in the bicyclo[3.2.1]octane series with the conformationally flexible 6-membered ring.     

Orbital control of stereochemistry in acid-catalysed addition reactions of endo -tricyclo[3.2.1.02,4]0ct-6-ene

The reaction of endo-tricyclo[3.2.1.0^2,4]oct-6-ene 1 with methanol in the presence of catalytic amounts of toluene-p-sulphonic acid has been shown to give 2-exo- and endo-methoxybicyclo[3.2.1]oct-3-ene (2c) and (2d) and 2-endo-methoxybicyclo[3.2.1]oct-6-ene (13). The formation of 2-exo- methoxybicyclo[3.2.1]oct-3-ene (2c), the major product of reaction, has been probed by deuterium labelling experiments and a series of 6-exo-7-exo- dideuterobicyclo[3.2.1]oct-3-enes synthesised for ²H, ¹H and ¹³C NMR spectral analysis in order unambiguously to determine the stereochemistry of proton attack on endo-tricyclo[3.2.1 0^2,4]oct-6-ene (1). The formation of 2-exo-methoxybicyclo[3.2.1]oct-3-ene (2c) has been determined to involve corner protonation of the cyclopropyl moiety and skeletal rearrangement to an allylic cation with a small but measurable memory effect     

The predictable behaviour of cations deriving from endo-4-chlorotetracyclo[3.3.0.0.2,8O.3,6]octane.

Silver cation-initiated ionization of the title compound in aqueous dioxane gives the exo and endo-tetracyclo[3.3.0.0.^2,8O.^4,6]octane-3-ols (35 and 65%). Thermal isomerization in chloroform gives the exo and endo isomers of 4-chlorobicyclo[3.2.1]octa-2,6-dienes (3.5 and 1.5%) and 6-chlorotricyclo[3.2.1.0.^2,7]oct-3-ene (90 and 5%). The behaviour of the cations involved is compatible with MINDO/3 calculations.     

Vibrational circular dichroism DFT study on bicyclo[3.3.0]octane derivatives

The absolute configurations of four bicylco[3.3.0]octane derivatives: endo-bicyclo[3.3.0]octane-2,6-diol, endo-2,6-diacetoxybicyclo[3.3.0]octane, endo-bicyclo[3.3.0]octane-2,6-dione and bicyclo[3.3.0]octa-2,6-dien-2,6-bistriflate were studied by vibrational circular dichroism (VCD). These chiral derivates are of interest as intermediates in the asymmetric synthesis of enantiomerically pure natural products and chiral ligands for asymmetric catalysis. VCD has been used to determine the absolute configuration of each compound, proving the capability of VCD for molecules with several stereogenic centres. IR and VCD spectra have been simulated at the B3LYP/6-31G¹ level for all possible diastereomers. Based on the agreement between the experimental and the calculated spectrum, the stereochemistry of each compound could be assigned. The predicted absolute configurations are found to agree with literature data.     

A new and convenient synthesis of substituted benzobarrelenes

Bromination of 3-bromo-6,7-benzobicyclo [3.2.1] octa-2,6-diene at ?50°C gave anti-tribromo adduct (5) in essentially quantitative yield. The double dehydrobromination of (5) was achieved using potassium tert.- butoxide to give 2-bromo-benzobarrelene (7). Reaction of (7) with n-BuLi and subsequent quenching with CH₃I, CO₂, and dimethylformamide afforded the corresponding substituted benzobarrelenes in high yield.     

Conjugative and homoconjugative effects in 2-heterobicyclo[3.2.1]octa-3,6-dienes

The ¹H-NMR, ¹³C-NMR and photoelectron spectra of a variety of 2-heterobicyclo[3.2.1]octa-3,6-dienes 6 give evidence of conjugative and homoeonjugative effects in these compounds, but there is no suggestion from the data of any special contribution from the (4n+2)π neutral bishomoaromatic system. Reaction of the dienes6 with TCNE invariably yielded the product of [2+2] addition in cases where a fully characterisable product was obtained.     

The Bromination of 3-Bromo-6,7-benzobicyclo [3,2,1] octa-2,6-diene and characterization of the products

The bromination of 3-bromo-6,7-benzobicyclo [3.2.1] octa-2,6-diene at -50°C has been found to give only one product, the tribromide 8 produced via Wagner-Meerwein rearrangement with accompanying aryl migration. The bromination at 0°C produced nonrearranged tribromides beside the rearranged tribromide and the ketone 12. The structures of the products were determined by ¹H-, ¹³C-NMR data and single X-ray structural analysis. The addition mechanism is discussed in terms of exo- and endo-attack.     

Synthesis and phototransformations of novel styryl-substituted furo-benzobicyclo[3.2.1]octadiene derivatives

Novel cis- and trans-(o-H/Me/vinyl) substituted styryl furo-benzobicyclo[3.2.1]octadiene derivatives (7a,b, 8) were prepared and transformed to the novel naphthofuran derivatives of benzobicyclo[3.2.1]octadiene (6a,b) and novel phenanthrene-benzobicyclo[3.2.1]octadiene derivative (11) by photochemical electrocyclic ring closure in the presence of iodine and by intramolecular photoinduced [4+2] cycloaddition, respectively. These novel annelated bicyclo[3.2.1]octadiene derivatives (6a,b, 11) are especially interesting for their rigid methano-bridged junction of two aromatic units at defined geometrical arrangement and thereby as potentials for molecular clips.     

Synthesis of a novel series of tetracyclic opioid antagonists incorporating an 8-aminobicyclo[3.2.1]oct-6-ene sub-unit

The bridged bicyclo[3.2.1]oct-ene and -ane amines 9-13 have been prepared via [3+2]cycloaddition of allylic alcohols 6 to alkynes 7, and assessed as ligands at opioid receptors. Amine 10b is a potent antagonist at μ receptors.     

A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes

A convenient and efficient synthesis of N⁶-substituted 3,6-diazabicyclo[3.2.1]octanes (6a-c) has been achieved starting from suitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-diazabicyclo[3.2.1]octane-2-ones in good yields. These bicyclic lactams were then reduced to the corresponding 3,6-diazabicyclo[3.2.1]octanes and converted to the required N³,N⁶-disubstituted 3,6-diazabicyclo[3.2.1]octanes (7a-h), which were screened for α₁-adrenoceptors antagonistic activities.     

Rearrangements Involving C8H8F-Cations of the Cage Type

The homo-l, 4 adduct obtained from difluorocarbene and bicyclo [2.2.1]hepta-2, 5-diene ( 1 ) was treated successively with HCl, FSO₃H and SbF₅ in SO₂ClF at low temperature. The protic acids underwent electrophilic addition to the cyclopropane part of 1 , giving the corresponding derivatives. However, in FSO₃H at ? 50°, protonation of the gem-difluoro grouping also occurred to give the 2-fluoro-6-fluorosulfonylbicyclo [3.2.1]oct-2-en-3-yl cation. The reaction of 1 with SbF₅ at ?78° led initially to the formation of the 2-fluorobicyclo [3.2.1 ]octa-2, 6-dien-4-yl cation, which rearranged to 4-fluorotricyclo [5.1.0.0^5,8]oct-3-en-2-yl cation at ?40°. These rearrangements are discussed in the light of those expected for C₈H₈F square pyramidal cations.     

Bicyclo[3.2.1]octa-3,6-dien-2-yl cation: a bishomoantiaromate

Antiaromatic compounds with a closed loop of 4n p-electrons are relatively unstable and often difficult to study. We report in this article the synthesis of alcohols 2-(4'-fluorophenyl)bicyclo[3.2.1]octan-2-ol 11, 2-(4'-fluorophenyl)bicyclo[3.2.1]oct-3-en-2-ol 12, and 2-(4'-fluorophenyl)bicyclo[3.2.1]octa-3,6-dien-2-ol 13 and their transformations into corresponding carbocations 14-16, respectively, in a superacidic medium (FSO3H/SO2ClF) at -120 degrees C. Cations 14-16 are characterized by NMR analysis (1H, 13C, 19F), and 15 and 16 are further characterized by quenching in NaOCH3/H3COH at -120 degrees C. The relative stabilities of 14-16 are determined experimentally by 19F NMR spectroscopy. Cation 16 is found to be experimentally less stable than cation 15 by 3.7 kcal/mol. DFT calculations (structure and energy: B3LYP/6-31G(d); NMR: B3LYP/6-311+G(2d,p)) are performed for alcohols 11-13 and bicyclo[3.2.1]octyl cations 6, 7, 9, 14-16, 26, 28, and 30. In the case of 11-16, data from DFT calculations is in good agreement with experimental data. Because 6,7-dimethylenebicyclo[3.2.1]oct-3-en-2-yl cation 26 is more stable than cation 7 by 1.69 kcal/mol, the inductive effect of sp(2)-hybridized carbon atoms C6 and C7 in carbocations 6 and 16 cannot be the reason for the destabilization of 6 relative to 7 and 16 relative to 15. Destabilization of 6 relative to 7 and 16 relative to 15 and the calculated NICS of 6 (+4.17 ppm) and 16(+3.3 ppm) document that 6 and 16 are bishomoantiaromates.