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     

Reaction of benzyne with cycloheptatriene preparation and thermolysis of some benzo(C9H10) hydrocarbons

The title reaction gave a 2+2 cycloadduct, 8,9-benzo-cis-bicyclo[5.2.0]nona-2,4,8-triene 7, together with ene product, 7-phenylcycloheptatriene. The structure of 7 was confirmed by catalytic reduction to give 8,9-benzo-cis-bicyclo[5.2.0]non-8-ene, which was also obtained in the reaction of benzyne with cycloheptene, and by reduction of the known 8,9-benzobicyclo[5.2.0]nona-1,8-diene. Other benzo(C₉H₁₀) hydrocarbons which have been synthesised are 7,8-benzobicyclo[4.2.1]nona-2,4,7-triene 5, 2,3-benzobicyclo[6.1.0]nona-2,4,6-triene 28 and 4,5-benzobicyclo[6.1.0]nona-2,4,6-triene 29. The thermolysis of 7, 28, 29 and of 3,4-benzo-exo-endo-tetracyclo[4.3.1.0^3,4.0^7,9]dec-3-en-10-one, 25, is described.     

Improved syntheses of precursors for PET radioligands [F]XTRA and [F]AZAN

Improved syntheses of 7-methyl-2-exo-[3′-(2-bromopyridin-3-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptanes (3) and 7-methyl-2-exo-[3’-(6-bromopyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptanes (4), precursors for PET radioligands [¹⁸F]XTRA (1) and [¹⁸F]AZAN (2), involving a key Stille coupling step followed by deprotection of Boc group and N-methylation are described. The new synthetic procedures provided the title compounds in more than 40% overall yields.     

Die stereoisomeren bicyclo[4.2.0]octan-cis-Diole-(7,8)

The stereochemical assignment of the bicyclo[4.2.0]octane-cis-7,8-diols is reinvestigated. It is shown that the cis-diols prepared by different routes are indeed stereoisomers, the lower melting being the exo-isomer (1), the higher melting the endo-isomer (2). The synthesis of the previously unknown trans-fused bicyclo[4.2.0]octane-cis-7,8-diol (3) via photosensitized cycloaddition of vinylene carbonate to cyclohexene is described.     

Stereoselective synthesis and characterization of novel trans-4-(thiophenyl)pyrazolyl-β-lactams and their C–3 functionalization

A stereoselective synthesis and C–3 functionalization of a long series of novel hybrid 4-(thiophenyl)pyrazolyl-β-lactams have been carried out. The divergent substrate scope and mechanistic insights were examined to delineate the generality of reaction that favored trans-β-lactams 4a-q almost exclusively in all cases. The C–3 functionalization was achieved by Lewis acid assisted nucleophilic substitution reaction of cis-3-chloro-β-lactams 6a-e to afford cis-3-monosubstituted-β-lactams 7a-e. The cis stereochemistry of β-lactams 7a-e was further established by stereospecific desulfurization with Raney-nickel, in representative cases (7a,b), leading to the formation of cis-β-lactams 8a,b. The structures and stereochemical assignments for synthesized β-lactams have been unambiguously confirmed using FT-IR, 1D NMR (¹H and ¹³C), 2D NMR (¹H–¹H COSY, ¹H–¹³C HSQC and ¹³C DEPT–135), elemental analysis (CHN), mass spectrometry (ESI-MS) and single crystal X-ray crystallography, in representative cases (4b,e). The cis and trans configuration of the hydrogen/chloro/nucleophile substituent at C–3 was assigned with respect C4–H of the β-lactam ring.     

Structures of the tricyclododecenes prepared by the catalytical intramolecular cyclisation of 1,5,9-cyclododecatriene

The internal cyclisation of 1,5,9-cyclododecatriene, induced by a catalytical amount of Cp₂TiCl₂-LAHδ, leads to a mixture of cis, anti, cis-tricyclo[7.3.0.0^2,6]-7-dodecene (1), cis,syn,trans-tricyclo[7.3.0.0^2,6]-7-dodecene (2), trans,syn-tricyelop[7.3.0.0^2,6]-6-dodecene (3) and 5,6,7,8,9,10-hexahydrobenzocyclooctene (4). The structures of the main products were determined from the spectra of a number of derivatives taking into account symmetry properties and configurational flexibility.     

Synthesis and chemistry of tricyclic cyclopropene-tricyclo[3.2.2.0]nona-2(4),6-diene

The 1,2-bridged tricyclic cyclopropene, tricyclo[3.2.2.0^2,4]nona-2(4),6-diene (1), has been synthesized by the elimination of 2-bromo-4-chlorotricyclo[3.2.2.0^2,4]-non-6-ene (5). Cyclopropene 1 will undergo different isomerizations in ether solution and in neat conditions. Compound 1 rearranged to an anti-Bredt compound 4 via diradical mechanism in ether and tricyclic compound 6 via vinyl carbene mechanism in neat conditions. Compound 1 can be trapped with DPIBF at different temperatures yielding different results: the exo-endo adduct 2 (exo-addition from the view of the cyclopropene and endo-addition from the view of bicyclo[2.2.2]octene) is a sole product at 0°C by slowly addition of methyllithium, and the exo-endo adduct 2, endo-endo adduct 9, anti-Bredt adduct 3, and styrene 8 are isolated at ether refluxing temperature. Styrene 8 is proposed to be formed from endo-endo adduct 9 by diradical mechanism. The chemistry of exo-endo adduct 2 and endo-endo adduct 9 is as well studied. The exo-endo adduct 2 undergoes hydration in trifluoroacetic acid to generate 1,3-cis-diol 11 followed by eliminations of water and formaldehyde to give naphthalene 12. The endo-endo adduct 9 reacts with water in tetrahydrofuran-containing silica gel to yield 1,4-cis-diol 10. Both 9 and 10 react with trifluoroacetic acid to form trans-3-hydroxy trifluoroacetate 13. Compound 13 will undergo hydrolysis and isomerization to generate 1,3-cis-diol 11 in trifluoroacetic acid.     

Electrocyclic reactions of tetraenes: Influence of terminal substituents

Conjugated tetraenes with both central double bonds of cis configuration undergo a series of thermal reactions, the observable products being markedly dependent on the nature of the terminal substituents. Dimethyl 2E,4Z,6Z,8E-decatetraene-1,10-dioate (16) was prepared and found to cyclize readily at 50° to trans dimethyl 2,4-bicyclo[4.2.0)octadiene-6,7-dicarboxylate (18). This reaction proceeds to equilibrium, and the rates and equilibrium constants at the indicated temperatures are: 3.0 × 10^-5 sec^-1 ?40°; 8.2 × 10^-5 sec^-1, 16.0,50°; ?10.0,75°; ?7.47,100° with the equilibrium favoring (18). A sample of 1,8-diphenyl-1E,3Z,5Z;7E-octatetraene (1) showed no reaction below 120°, and at 175° all trans 1,8-diphenyl-octatetraene, cis and trans stilbenes, trans-5-phenyl-6(cis-styryl)-1,3-cyclohexadiene cis-5-phenyl-6-(trans-styryl)-1,3-cyclohexadiene, and cis and trans 6,8-diphenyl-tricyclo[3.2.1.0^2.7]oct-3-enes were formed. At 100° in the presence of excess dimethyl acetylenedicarboxylate 1 gave dimethyl trans-3,4-diphenyltricyclo[4.2.2.0^2.5]deca-6,9-dien-6,7-dicarboxylate. Finally 1,4-di(1-cyclohexen-1-yl)-1,3-batadiyne, hydrogenated over a Lindlar catalyst, gave only tricyclo[10.4.0.0^6,11]hexadeca-1,3,5-triene.     

Diastereospecific addition of Grignard reagents to 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde

The reaction of both enantiomers of 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde 1 with EtMgBr and PhMgBr has been studied. It has been found that addition of a Grignard reagent to the carbonyl group of 1 proceeds diastereospecifically. The configuration of the sp³ stereogenic centre formed in this reaction has been determined by single crystal X-ray diffraction and can be explained assuming exo-attack of the nucleophile on the s-cis-conformation of 1. The circular dichroism spectra of the product 1,1′-diphosphaferrocenyl alcohols are also reported and discussed.     

Ring currents that survive bond alternation in constrained 8π and 6π monocycles

Current density maps are computed at the ipsocentric CTOCD-DZ/6-31G^**//RHF/6-31G^** level for angle-constrained planar 1,3,5,7-cyclooctatetraenes (COT) and benzene. Constraint of α(CCH) angles to 90° in D_4h COT (3b) leads to endo-4 and exo-4 valence isomers. The exo structure, with CH bonds perpendicular to long sides of the octagon, is lower in energy by 202 kJ/mol and has stronger bond alternation (ΔR 0.265 Å). However, endo-4, exo-4 and COT 3b at its best planar geometry all sustain intense paratropic ring currents, attributed to the rotational character of the HOMO–LUMO transition, and consistent, mutatis mutandis, with the diatropic current in D_3h benzene 5.     

Solvolysis of 2-aryl-exo-5,6-trimethylene-2-norbornyl p-nitrobenzoates as a reference of 2-aryl-2-norbornyl p-nitrobenzoates solvolysis: Further evidence for the unimportance of σ-participation in the solvolysis of 2-aryl-2-norbornyl derivatives

The rates of solvolysis of 2 - aryl - exo - 5,6 - trimethylene - exo - and endo - 2 - norbornyl p-nitrobenzoates (7 and 8, respectively) with representative substituents [p-CH₃O, p-CH₃, H, m-CF₃, p-CF₃, and 3,5-(CF₃)₂] were determined in 80% aqueous acetone and compared with those of the parent 2-aryl-exo- and endo-2-norbornyl p-nitrobenzoates (5 and 6, respectively). The rate ratios for the endo-p-nitrobenzoates ($\text{6}\text{8}$) are essentially constant and close to unity for these substituents, indicating that the perturbation of the trimethylene bridge toward the C₂-position is virtually negligilbe. The rate ratios for the exo-p-nitrobenzoates ($\text{5}\text{7}$) can also be regarded as invariant over the reactivity range studied. The exo/endo rate ratios ($\text{7}\text{8}$) are 246 (p-CH₃O), 196 (P-CH₃), 129 (H), 80 (m-CF₃), 90 (p-CF₃), and 89 [3,5-(CF₃)₂], being similar to the corresponding $\text{5}\text{6}$ rate ratios. The solvolyses of these p-nitrobenzoates (7 and 8) afford predominantly ( > 97%) exo-alcohols. Since the secondary exo-5,6-trimethylene-2-norbornyl system, with its low exo/endo rate ratio, 11.2, is known to solvolyse without significant σ-participation, the tertiary derivatives should also undergo solvolysis without σ-participation. Consequently, the similarities in the solvolytic behaviors between the two systems (5 vs 7; 6 vs 8) strongly support the previous conclusion that σ-participation is unimportant in the solvolysis of 5.     

Stereoselective (exo-specific) synthesis, dynamic 1H NMR and quantum chemical conformational and configurational analysis of norbornene-aziridine-E-imidoyl system

Stereoselective (exo-specific) synthesis, dynamic ¹H NMR and computational analysis of exo-N??-{3-azatricyclo[3.2.1.0.^2,4]oct-3-yl)mesithyloxy)methylene}-1-benzensulfunamide (3) were investigated. Aziridine nitrogen inversion gives rise to two sets of configurations where the N-substituent is Syn (S) or Anti (A) to C7 of the norbornyl ring. At lower temperature, the proton signals of aziridine exo-E-3 decoalesces to show two syn conformers and one anti conformer (exo-E-3 ^{1 S} ? $ \leftrightharpoons $ ?exo-E-3 ^{2 S} ? $ \leftrightharpoons $ ?exo-E-3 ^{3 A} ) with ratio of 60:20:20, respectively. Experimentally, the Gibbs free energy of activations [??G ^? (kcal/mol) ?±?0.08] were calculated 11.96, 12.45 for 3 isomerizations. The standard Gibbs free energy (??G ^o kcal/mol) 0.174, 0, 0.174, and 0.298 at 213?K and energy minimum 6.64, 4.77 and 1.78 were calculated for 3 ^1S? $ \leftrightharpoons $ ?3 ^2S, 3 ^2S? $ \leftrightharpoons $ ?3 ^{3 A} , 3 ¹ S? $ \leftrightharpoons $ ?3 ^{3 A} isomerizations, respectively. The enthalpy (??H ^?, kcal/mol) and entropy (??S ^?, cal?mol^?1?K^?1) of activation for the nitrogen inversion of aziridine of 3 were calculated 11.2 and ?0.80, respectively.     

Photoinduced Double Addition of Acetylene to 3-Oxocyclopent-1-ene-1-carbonitrile or 3-oxocyclopent-1-enyl acetate leading to 2,3-dihydro-1H-inden-1-one and other rearranged products

UV Irradiation of 3-oxocyclopent-1-enyl acetate ( 17 ) and acetylene in MeCN at 0° gives, besides the product of normal enone-alkyne [2 + 2] cycloaddition (cis-4-oxobicyclo[3.2.0] hept-6-en-1-yl acetate, 18 ) and its product of oxa-di-π-methane rearrangement (5-oxotricyclo[4.1.0.0^2,7]hept-2-yl acetate, 19 ), unexpected products of further addition of a molar equivalent of acetylene. These are indanone ( = 2,3-dihydro-1H-inden-1-one, 16 ), in 21% yield, cis-1-cisoid-1,2-cis-2- ( 20 ) and cis-1-transoid-1,2-cis-2-7-oxotricyclo[4.3.0.0^2,5]non-3-en-1-yl acetate ( 21 ), 4-oxo-7-‘exo’-vinyltricyclo[3.2.0.0^2,6]hept-2-yl acetate ( 22 ), cis-4-oxo-6-‘endo’- ( 23 ) and cis-4-oxo-6-‘exo’-vinylbicyclo[3.2.0]hept-1-yl acetate ( 24 ), and cis-4-oxo-7-‘exo’-vinylbicyclo[3.2.0]hept-1-yl acetate ( 25 ). At least in part, indanone must be formed via intermediates 20 and 21 . In fact, on heating a 9:1 mixture 20/21 , indanone is obtained quantitatively. With 3-oxocyclopent-1-ene-1-carbonitrile ( 15 ) in place of 17 , indanone is formed in lower (8%) yield besides much tars.     

Asymmetric syntheses of (1R,1R,5R,7R) and (1S,1R,5R,7R)-1-hydroxy-exo-brevicomin and a formal synthesis of (+)-exo-brevicomin

Asymmetric syntheses of (1R,1^′R,5^′R,7^′R) and (1S,1^′R,5^′R,7^′R)-1-hydroxy-exo-brevicomins 1 and 2, volatiles of the male mountain pine beetle, and a formal synthesis of (+)-exo-brevicomin 3, a component of the attracting pheromone system of several bark beetles have been achieved. The key steps are Birch reduction of commercially available α-picoline, selective Wittig olefination, and Sharpless asymmetric dihydroxylation.     

Analyse conformationnelle de derives bicyclo (4.1.0) heptaniques cis—I

¹H NMR conformational studies of cis-3(4) epoxy bicyclo (4.1.0) heptanes endo and exo, and of related alcohols (3-norcaranols) has been carried out using Eu(dpm)₃ as shift reagent. Comparatively the conformational analysis of cis and trans-1(2), -4(5) diepoxy cyclohexanes has been performed. The experimental data agree with a predominant planar conformation of the two -3(4) epoxy bicyclo (4.1.0) heptanes and of the cis diépoxy cyclohexane, but do not distinguish between the planar conformation and the $\text{1}\text{1}$ equilibrium of the two equivalent boat conformations of the trans diepoxyde. For the two alcohols, they adopt the same semi chair form in which the hydroxyl group is axial for the exo isomer and equatorial for the endo.     

A new chiral oxazoline derived from camphor and its conversion to (R)-2-methylalkanoic acids

(1S,5R,7R)-(−)-10,10-Dimethyl-3-ethyl-4-oxa-2-azatricyclo[5.2.1.0^1,5]dec-2-ene 2 was prepared in 95% yield from (1S)-1-amino-2-exo-hydroxyapocamphane 1. The chiral oxazoline could be alkylated (LDA/THF/−78°C/RX, RX=ethyl, n-propyl, n-butyl iodides or benzyl bromide) to 3 in 95% yield and >95% diastereoselectivity, and the products hydrolysed to (R)-2-methylalkanoic acids 4 (43–47% yield, 93–98% e.e.).     

Synthesis and structure of some cis-and trans-myrtanylstannanes

Enantiomerically pure cis- and trans-myrtanylstannanes cis-MyrSnPh₃ (1), trans-MyrSnPh₃ (2), cis-MyrSnPh₂Cl (3), trans-MyrSnPh₂Cl (4), cis-MyrSnPhCl₂ (5), trans-MyrSnPhCl₂ (6), cis-MyrSnCl₃ (7), trans-MyrSnCl₃ (8) were synthesized and fully characterized by ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopy. The molecular structures of 1, 3, 6, 7, and [trans-MyrSn(OH)Cl₂ · H₂O]₂ (8a) a hydrolysis product of 8, were determined by X-ray crystallography.     

Thiocarbonyl ylides : Reactions and stereochemical properties of some 4-t-butylcyclohexyl derivatives

The azine from 4-t-butylcyclohexanone on treatment with hydrogen sulfide under pressure is converted to a mixture of stereoisomeric 1,3,4-thiadiazolidines. Dehydrogenation of this mixture with an alkyl azodicarboxylate afforded in quantitative yield (based on azine) a mixture of the three possible Δ³-1,3,4-thiadiazolines. These three isomers have been isolated and their structures have been established as trans,trans-3,11-di-[1,1-dimethylethyl]-14,15-diaza-7-thiadispiro[5.1.5.2]pentadeca-14-ene(5); the cis,cis-isomer (6), and the cis,trans-isomer (7). Pyrolysis of either 5 or 6 leads in quantitative yield to cis,trans-3,10-di-[1,1-dimethylethyl]thiadispiro[5.0.5.2]tridecane (8), the formation of which is rationalized by conrotatory ring closure of the same thiocarbonyl ylide (24) formed from either 5 or 6. Pyrolysis of 7 leads exclusively to a thiirane isomeric with 10 and which is assigned the cis,cis-structure (9). The thiiranes 8 and 9 are desulfurized by tri-n-butylphosphine to the anti- and syn-1-(1,1-dimethylethyl)-4-[4-(1,1-dimethylethyl)cyclohexylidene]cyclohexanes (11 and 12), respectively. The cycloadditions of the thiocarbonyl ylides derived from 5–7 with dimethyl acetylenedicarboxylate and dimethylazodicarboxylate have been examined but stereochemistries have not been assigned to these products. Cis additions to the olefins (11 and 12) have been investigated with the most attention having been paid to the reactions with osmium tetroxide. The configurations of the glycols expected from these reactions have been correlated by comparison with the three possible glycols (16–18) obtained from pinacol reduction of 4-t-butylcyclohexanone. These three glycols have been separated and their configurations assigned from PMR and IR data. A discussion of the stereochemical implications of the various results is given.     

Synthesis and conformational analysis of exo-and endo-7-substituted-3-azabicyclo[3.3.1]nonanes

The synthesis of some 7-substituted-3-azabicyclo[3.3.1]nonanes is described. Routes followed were the debenzoylation of the 7-benzoyl derivative 7 and the decarboxylation of the 7-carboxy compounds 21 and 27. The so-obtained 7-oxo-N-tosyl-3-azabicyclo[3.3.1]nonanes 8and 11 show an extremely low reactivity towards a series of nucleophilic reagents. From analysis of the ¹H NMR spectral data of a series of derivatives, the twin-chain conformation for the 7-exo compounds and the chair-boat conformation for the 7-endo compounds is indicated.     

Chemo-, stereo- and regioselective hydrogenolysis of carbohydrate benzylidene acetals. Synthesis of benzyl ethers of benzyl α-d-, methyl β-D-mannopyranosides and benzyl α-D-rhamnopyranoside by ring cleavage of benzylidene derivatives with the LiAlH4-AlCl3 reagent

Treatment of benzyl α-(1) and methyl β-d-mannopyranoside (2) with α,α-dimethoxytoluene gave the exo and endo isomers (3,5 and 4,6) of the dibenzylidene derivatives of 1 and 2. Hydrogenolysis of the exo isomers (3 and 5) with a molar equivalent of AlH₂Cl gave the 3-0-benzyl-4,6-0-benzylidene derivatives (7 and 21), whereas the endo isomers (4 and 6) gave the 2-0-benzyl-4,6-0-benzylidene compounds (8 and 22). The 2-0-allyl ether 9 of 7, the 3-0-allyl derivative (10) of 8 and compounds 21 and 22 were treated with an additional molar equivalent of AlH₂Cl at reflux and the products were the 4-0-benzyl-6-hydroxyl derivatives (11, 12, 23 and 24), whereas in the case of 22 the 6-0-benzyl-4-hydroxyl isomer (25) was also isolated. By deallylation of 11 and 12, 3,4-(13) and 2,4-di-0-benzyl (14) ethers of 1 were prepared. Tosylation of 11 and 12, and subsequent reduction of the products (15 and 16) made possible the preparation of the partially protected benzyl α-d-rhamnopyranoside derivatives (17–20). The structures of the compounds synthesized were characterized by ¹H and ¹³C NMR spectroscopic investigation and by chemical methods.