Synthesis of Bridged Bicyclic Molecules using Halocarbenes. Derivatives of bicyclo[4.2.1]nonane

The addition of dichlorocarbene (generated by the interaction of sodium methoxide and ethyl trichloroacetate) to bicyclo[3.2.1]oct-2-ene, its 3-chloro and exo-3,4-dichloro derivatives gives the exo 1 : 1 adducts in yields of 94, 89 and 48%. By suitable chemical reactions of these adducts, convenient syntheses of bicyclo[4.2.1]nona-2,4-diene and bicyclo[4.2.1]non-3-ene, together with their monochloro, dichloro and trichloro derivatives are obtained. Bicyclo[4.2.1]-nonan-3-one is also obtained from bicyclo[4.2.1]non-3-ene in a synthesis starting from the readily available 5-hydroxymethylnorborn-2-ene in an overall yield of 20%.     

Differential Bridging in the Solvolysis of Epimeric Bicyclic Sulfonates,Norbornanes, Part 17

The solvolysis rates and products of the 2-exo- norbornyl, bicyclo[3.2.1]oct-8-yl, bicyclo[3.3.1]non-2-yl, bicyclo[3.2.1]oct-6-yl, bicyclo[3.2.1]oct-2-yl and bicyclo[3.2.2]non-6-yl p-toluenesulfonates 10–15 , respectively, are reported. The exo/endo rate ratios for these epimeric secondary tosylates in 80% EtOH varied from 1125 for 11 to 1.6 for 15 . The relative rates varied between 2278 for exo- 10 and 4 ·10^?3 for endo- 11 . The hydrolysis products were mainly rearranged alcohols and olefins. The unrearranged alcohols from the exo-tosylates were formed with complete or predominant retention of configuration, whereas those derived from the endo-tosylates were mostly inverted. These results confirm the hypothesis that relative rates, as well as products, are largely determined by the degree of bridging between the cationic center and a dorsal C-atom in the transition state and in the resulting ion pairs. Since bridging is a directed bonding interaction, it is subject to the same angle and conformational strains as ordinary covalent bonds. But bridging requires less geometrical change than the formation of normal bonds and of nonclassical ions.     

Vibrational spectra and stable conformations of N-methylacetamide and (1S,5S,6R)-6-acetylamino-(5′-methoxyindolo[2,3-b])bicyclo[3.2.1]oct-2-ene

IR absorption and Raman spectra of N-methylacetamide and (1S,5S,6R)-6-acetylamino-(5′-methoxyindolo[2,3-b])bicyclo[3.2.1]oct-2-ene are investigated. Optimized structures and harmonic force fields of stable conformers of both compounds are obtained by means of MP2 and DFT (B3LYP) methods using the 6-31+G** basis set. Based on quantum mechanical calculations, a detailed interpretation of spectra is proposed and vibrational frequencies of the most stable conformations are assigned. Correlations between structures and the spectra of N-methylacetamide and (1S,5S,6R)-6-acetylamino-(5′-methoxyindolo[2,3-b])bicyclo[3.2.1]oct-2-ene were considered and analytical spectral regions were proposed.     

The bromination of bicyclo[3.2.1]octa-2,6-diene with N-bromosuccinimide

The bromination of bicyclo[3.2.1]octa-2,6-diene (3) by NBS does not follow the familiar free-radical course but proceeds through the cyclopropylcarbinyl cation 7. 7 can be trapped by addition of small amounts of methanol. The bicyclo[3.2.1]octa-2,6-dien-4-yl radical is involved in the reduction of exo-6-bromotricyclo [3.2.1.0^2,7]oct-3-ene by tributyltin hydride.     

Mn(III)-Based Oxidative Free-Radical Cyclizations of Unsaturated Ketones

Mn(III)-based oxidative free-radical cyclization of unsaturated ketones is a versatile synthetic procedure with broad applicability. For example, oxidation of cyclopentanone 1a with 2 equiv of Mn(OAc)(3).2H(2)O and 1 equiv of Cu(OAc)(2).H(2)O in AcOH at 80 degrees C for 1.5 h affords 75% of bicyclo[3.2.1]oct-3-en-8-one 8a and 15% of bicyclo[3.2.1]oct-2-en-8-one 9a. Bridged bicyclic ketones that cannot enolize further are isolated in good yield. Monocyclic beta,gamma-unsaturated ketones that can enolize are oxidized further to give gamma-acetoxy enones. The formation of bicyclo[3.3.1]non-2-en-9-one (57a) in 52% yield from 2-allylcyclohexanone (56a) suggests that kinetically controlled enolization is the rate-determining step in alpha-keto radical formation. A wide variety of examples delineating the scope, limitations, and stereoselectivity of this reaction are presented.     

Bicyclo[3.2.1]oct-6-enes via (3+2)cycloaddition

(3+2)Cycloaddition of alkynes to allyl cations, generated from 3-chlorocyclohexenes and zinc chloride, provides a simple and direct route to bicyclo[3.2.1]oct-6-enes.     

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.     

Foiled carbenes revisited: When sigma-stabilization surpasses pi-stabilization

The bicyclic alkenylidenes 9 (bicyclo[3.2.1]oct-2-en-8-ylidene) and 17 (bicyclo[3.3.1]non-2-en-9-ylidene) were claimed to be stabilized foiled carbenes. Our B3LYP and MP2 computations confirm previous experimental data. Moreover, they show that these carbenes are very reactive and rearrange rapidly, mainly through a 1,2-vinyl shift by overcoming a low barrier (1.2 to 5.4 kcal/mol). This is in contrast to the high barriers (up to 30 kcal/mol) predicted for the same type of rearrangements in norborn-2-en-7-ylidene derivatives. In 17 and bicyclo[4.1.1]oct-2-en-7-ylidene (23), the divalent carbon atom is even bent away from the double bond!     

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.     

New Synthesis of dl-sativene,dl-copacamphene,dl-cis-sativenediol and dl-helminthosporal

Photocycloadducts from dl-piperitone and 1,1-dimethoxyethylene afforded bicyclo[3.2.1]oct-6-en-8-one derivatives under glc conditions in excellent yields. The synthesis of the title sesquiterpenes was accomplished using the bridged bicyclic compounds as intermediates.     

Chiral synthons from α-pinene: enantioselective syntheses of bicyclo[3.3.0] and [3.2.1]octanones

Enantioselective syntheses of bicyclo[3.3.0]octan-3-one, bicyclo[3.2.1]octan-3-one and bicyclo[3.2.1]octan-2-one derivatives were accomplished by employing a chiron based approach, using intramolecular rhodium carbenoid C–H insertion, acid catalysed cyclisation of α-diazo ketone and intramolecular type II carbonyl ene reactions as key steps.     

Synthesis of bicyclo[3.2.1]octanones via ketyl radical promoted rearrangements under reductive PET conditions

Photoinduced electron transfer (PET) reactions from triethylamine (TEA) to ketones have been utilized for a clean and efficient route to bicyclo[3.2.1]octanones. A one-pot conversion of bicyclo[2.2.2]octenones to such molecules has been described. MeOH as well as acetonitrile/LiClO₄ combinations have been found to be the most effective solvents for these reactions.     

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.     

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     

Group 6 heteroatom- and non-heteroatom-stabilized carbene complexes. beta,beta'- and alpha,beta,beta'-annulation reactions of cyclic enamines

Cyclization reactions of group 6 Fischer carbene complexes with cyclopentanone and cyclohexanone enamines are described. Enamine 3a undergoes thermal alpha,beta,beta'-annulation with alkenylcarbene complexes 1 and 2 (THF, 60 degrees C), affording semibullvalenes 5. The metalate intermediates 6, resulting from beta,beta'-annulation of the enamines 3a and 4a, were quantitatively formed by running the reaction in hexane at room temperature. Acid-promoted demetalation of 6 afforded endo-2-bicyclo[3.2.1]octen-8-ones 7 and endo/exo-2-bicyclo[3.3.1]nonen-9-ones 8 (endo/exo = 5:1). Using (S)-methoxymethylpyrrolidine-derived enamines 3b and 4b,c allowed highly enantioenriched cycloadducts endo-(+)-7 as well as endo-(-)-8 and exo-(-)-8 to be accessed. The non-heteroatom-stabilized carbene complex 10 was formed from complex 6 by Me(3)SiOTf-promoted elimination of the methoxy group, characterized by (13)C NMR, and transformed into the organic compounds 7, 7-d, and 11 as well as into bicyclo[3.2.1]octan-2,8-diones 14 and cycloheptanones 15. On the basis of this sequence, enantioenriched cycloheptanones (+)-15 were efficiently prepared in one pot from carbene complexes 2 and enamine 3b (51-55% yield, 91-96% ee). Extension of this work to simple Fischer carbene complexes 16 allowed an appropriate way to generate the nonstabilized pentacarbonyl[(phenyl(alkyl)carbene]tungsten complex 17 to be designed, for which the thermal and chemical behavior leading to compounds 18-21 is described.     

Reactions of (E)-3,3,3-trichloro(trifluoro)-1-nitropropenes with enamines derived from cycloalkanones. A new type of ring-chain tautomerism in a series of cyclobutane derivatives and stereochemistry of the products

Depending on the reaction conditions, the reactions of (E)-3,3,3-trichloro-1-nitropropene with cyclohexanone enamines led to bicyclo[4.2.0]octanes or trisubstituted enamines, which are the ring-chain tautomers capable of reversible transformations. Diastereoselectivity of the reactions of (E)-3,3,3-trichloro(trifluoro)-1-nitropropenes with cycloalkanone enamines were studied, a series of hitherto unknown CX₃-containing nitroalkylated enamines and γ-nitro ketones were synthesized, the structures of novel compounds were determined by NMR spectroscopy and X-ray diffraction.     

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.     

Remote Tricarbonyl(diene)iron Substituent Effect on Ester Heterolysis. The Solvolyses of 5,6,7,8-Tetramethylidenebicyclo[2.2.2]oct-2-yl Methanesulfonate and of its Tricarbonyliron Mono- and Dinuclear Complexes

Buffered acetolyses and hydrolyses of 5,6,7,8-tetramethylidenbicyclo[2.2.2]oct-2-yl methanesulfonate ( 17 ), of its ‘syn-endo’ ( 18 ), ‘syn-exo’ ( 19 ), ‘anti-endo’ ( 20 ), ‘anti-exo’ ( 21 ) tricarbonyliron complexes and of its ‘anti-exo,syn-endo’ ( 22 ) and ‘anti-endo,syn-exo’ ( 23 ) bis(tricarbonyliron) dinuclear complexes have been investigated (product analysis and kinetics). In contract with the solvolyses of the uncomplexed mesylate 17 , the solvolyses of the complexed esters can be highly chemo- and stereoselective. The nature of the products (non-rearranged bicyclo[2.2.2]oct-2yl vs. rearranged bicyclo[3.2.1]oct-2-yl derivatives) depends on the relative configuration of the tricarbonyl(diene)iron moieties and on the medium. The rates of solvolyses of 17 are only slightly affected by complexation of one or both s-cis-butadiene units with Fe(CO)₃ groups, except in the cases where the diene moiety ‘anti’ with respect to the mesylate is complexed onto its ‘endo’ face ( 20,23 ). In these cases, significant rate-retardation effects are observed, consistent with the inductive effect of the Fe(CO)₃ substituent. Such retardation effects are overwhelmed by competing accelerating homoallylic participation by uncoordinated ‘anti’ -diene moieties ( 18,19 ) or, as in the case of the ‘anti-exo’-Fe(CO)₃ complexes 21 and 22 , by possible direct metal participation to the ionization process.     

Synthesis and photochemistry of beta,beta'-di(2-furyl)-substituted o-divinylbenzenes: intra- and/or intermolecular cycloaddition as an effect of annelation

New heteroaryl-substituted o-divinylbenzenes, 2,2'-(1,2-phenylenedivinylene)difuran (9), 2,2'-(1,2-phenylenedivinylene)bisbenzo[b]furan (10), and 2,2'-(1,2-phenylenedivinylene)bisnaphtho[2,1-b]furan (11), were prepared and irradiated at various concentrations; intramolecular photocycloaddition and intermolecular [2+2] twofold photoaddition reactions took place to give bicyclo[3.2.1]octadiene derivatives 12-14 and cyclophane derivatives 15-17, respectively. Compound 11 was the most selective of these o-divinylbenzenes, which, owing to pi-pi intra- or intermolecular complexation, gave only the exo-bicyclo[3.2.1]octadiene derivative 14 at low concentrations, and only the cyclophane derivative 17 at high concentrations.     

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.