Novel ligands based on bromosubstituted hydroxycarbonyl [2.2]paracyclophane derivatives: synthesis and application in asymmetric catalysis

New planar-chiral hydroxycarbonyl [2.2]paracyclophane derivatives, 4-acetyl-13-bromo-5-hydroxy[2.2]paracyclophane (Br-АНРС, 63%) and 4-benzoyl-13-bromo-5-hydroxy[2.2]paracyclophane (Br-BHPC, 53%), were synthesized and reacted with the enantiomers of α-phenylethylamine to form corresponding Schiff bases, 12-bromo-4-hydroxy-5[1-(1-phenyl-ethylimino)-ethyl]-[2.2]paracyclophane and 12-bromo-4-hydroxy-5[1-(1-phenyl-ethylimino)-(phenyl)methylen-[2.2]paracyclophane. The diastereomers of the imines were resolved and their absolute configurations and consequently the corresponding configurations of the enantiomers of Br-АНРС were determined by X-ray diffraction. Enantiomerically pure Schiff bases were applied as ligands to form catalysts for the enantioselective addition reaction of diethylzinc with benzaldehyde where 1-phenylpropanol was obtained with 77–91% ee.     

Preparation of planar chiral amino phenols based on the [2.2]paracyclophane backbone

The synthesis of various planar and central chiral secondary and tertiary amino phenols based on the [2.2]paracyclophane backbone is described. Planar chiral tertiary amino phenols are prepared by reductive amination of 5-formyl-4-hydroxy[2.2]paracyclophane (FHPC) with secondary amines. The reduction of imine and ketimine precursors, as well as the 1,2-addition to these compounds is also described.     

Diastereoselective Hartwig-Buchwald reaction of chiral amines with rac-[2.2]paracyclophane derivatives

A Hartwig-Buchwald addition of a variety of chiral amines to rac-4-bromo-[2.2]paracyclophane and rac-trifluoromethanesulfonic acid (4-[2.2]paracyclophane) ester was performed with high diastereoselectivities. Kinetic racemic resolution of the starting materials was achieved, providing a rapid access to enantiomerically enriched 4-bromo-[2.2]paracyclophane and the corresponding enantiomerically pure [2.2]paracyclophane amines. Additionally, the first reaction of a secondary amine with a [2.2]paracyclophane halide was achieved.     

Phane properties of [2.2]paracyclophane/dehydrobenzoannulene hybrids

A series of [2.2]paracyclophane/dehydrobenzo[14]annulene (PC/DBA) hybrids (hydrocarbons 5, 6, 9, 10 b, and 10 c), [2.2]paracyclophane/dehydro[14]annulene (PC/DA) hybrids (7 and 8) and suitable model systems (11, 12, and 33) has been synthesized. Comparison of the electronic absorption spectra in each series of compounds provides further insight into the global communication between the decks in the [2.2]paracyclophane unit.     

A preparative microwave method for the isomerisation of 4,16-dibromo[2.2]paracyclophane into 4,12-dibromo[2.2]paracyclophane

4,16-Dibromo[2.2]paracyclophane (4) is isomerised to 4,12-dibromo[2.2]paracyclophane (1) by the application of microwaves in DMF solution.     

Synthesis of perfluoro[2.2]paracyclophane

A synthesis of perfluoro[2.2]paracyclophane has been sought ever since the partially fluorinated octafluoro[2.2]paracyclophane (AF4) was prepared and its chemistry studied. This compound has now been prepared in 39% yield from the precursor, 1,4-bis(chlorodifluoromethyl)-2,3,5,6-tetrafluorobenzene by its reaction with Zn when heated in acetonitrile at 100 degrees C. Two preparations of the precursor, first from 1,4-dicyano-2,3,5,6-tetrachlorobenzene and an improved method beginning from 1,2,4,5-tetrachlorobenzene, are also described as are key comparisons to our related synthesis of AF4.     

The first three aromatic tribromides of the [2.2]paracyclophane series

From the reaction mixtures in the uncatalyzed polybromination of [2.2]paracyclophane by the action of excess Br₂ in CCl₄, there have been found along with the known products — 4,15- and 4,16-dibromo[2.2]paracyclophanes — two new aromatic tribromides of this series, which have been isolated in pure form: 4,12,15- and 4,15,16-tribromo[2.2]paracyclophanes. Special experiments demonstrated that the mixtures of these tribromides are formed as a result of competitive monobromination of 4,15-dibromo[2.2]paracyclophane; the 4,15,16-tribromo[2.2]paracyclophane, together with still another newly isolated isomer of this series — 4,8,12-tribromo[2.2]paracyclophane — is formed as a result of competitive monobromination of 4,16-dibromo[2.2]paracyclophane. As an explanation of the features of the orienting effect of substituents in these competing reactions, a rule was proposed: On the conventional orientation (from the electronic point of view) of entry of the bromine atom into the substituted ring (para > ortho > meta), a steric limitation is imposed on its attack in the pseudo-gem-position, owing to the bulky bromine atom that is transannularly positioned above it in the neighboring aromatic ring. The structures of all of the tribromides were established on the basis of elemental analyses, mass spectrometry, and¹H NMR spectrometry (including PMR using the homonuclear Overhauser effect). The data obtained in this work indicate that the 4,12,15-tribromo[2.2]paracyclophane and 4,15,16-tribromo[2.2]paracyclophane are predecessors of the two tetrabromides previously obtained by Cram — 4,7,12,15- and 4,5,15,16-tetrabromo[2.2]paracyclophanes; and the 4,8,12-tribromo[2.2]paracyclophane is a possible predecessor of 4,8,12,16-tetrabromo[2.2]paracyclophane, which is unknown up to the present time.A. N. Nesmeyanov Institute of Heteroorganic Compounds, Russian Academy of Sciences, 117813 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 8, pp. 1837–1843, August, 1992.     

The synthesis and directed ortho-lithiation of 4-tert-butylsulfinyl[2.2]paracyclophane

The ortho-lithiation of one diastereoisomer of 4-tert-butylsulfinyl[2.2]paracyclophane is the key step to the synthesis of a range of 4,5-disubstituted [2.2]paracyclophane derivatives.     

Suzuki aryl cross-coupling chemistry using derivatives of 1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane

An exploration into the scope of Suzuki aryl cross-coupling chemistry using derivatives of 1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane is reported. The coupling of 4-iodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane with various aryl boronic acids and boronic acid pinacol esters was successful, with the exception of very sterically demanding systems, such as mesityl. The synthesis of the previously unreported 1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanyl-4-boronic acid is described, together with various Suzuki aryl cross-coupling reactions of this new system. Using standard Suzuki methodology, it was possible to prepare dicyclophanes bearing two octafluoro[2.2]paracyclophane units separated by both one and two benzene rings.     

Nitrosonium complexes of [2.2]paracyclophane

The reaction of [2.2]paracyclophane with nitrosonium tetrachloroaluminate was studied by NMR (¹H, ¹³C) spectroscopy using deuterium isotopic perturbation technique. The resulting cationic complexes containing one and two nitrosonium ions are involved in fast (on the NMR time scale) interconversion. Quantum-chemical calculations performed on the DFT level (using triple zeta basis set) indicate the higher stability of 2η single-charged π-complexes relative to σ complexes corresponding to the addition of NO⁺ ion at the ipso and ortho positions. The formation of the single-charged π-complex is energetically more favorable, compared to the double-charged π-complex. The affinity of NO⁺ for [2.2]paracyclophane is much greater than for p-xylene, presumably due to stacking interaction between the aromatic rings in the π-complex.     

Water-soluble [2.2]paracyclophane chromophores with large two-photon action cross sections

A series of alpha,omega-donor-substituted distyrylbenzene dimers held together by the [2.2]paracyclophane core were designed, synthesized, and characterized. Different substituents were chosen to modulate the strength of the donor nitrogen groups and to allow the molecules to be either neutral and soluble in nonpolar organic solvents or charged and water-soluble. The specific neutral structures are (in order of decreasing donor strength) 4,7,12,15-tetra[N,N-bis(6' '-chlorohexyl)-4'-aminostyryl]-[2.2]paracyclophane (1N), 4,7,12,15-tetra[(N-(6' '-chlorohexyl)carbazol-3'-yl)vinyl]-[2.2]paracyclophane (2N), and 4,7,12,15-tetra[N,N-bis(4' '-(6' '-chlorohexyl)phenyl)-4'-aminostyryl]-[2.2]paracyclophane (3N). The charged species are 4,7,12,15-tetra[N,N-bis(6' '-(N,N,N-trimethylammonium)hexyl)-4'-aminostyryl]-[2.2]paracyclophane octaiodide (1C), 4,7,12,15-tetra[(N-(6' '-(N,N,N-trimethylammonium)hexyl)carbazol-3'-yl)vinyl]-[2.2]paracyclophane octaiodide (2C), and 4,7,12,15-tetra[N,N-bis(4' '-(6' '-(N,N,N-trimethylammonium)hexyl)phenyl)-4'-aminostyryl]-[2.2]paracyclophane octaiodide (3C). Two-photon excitation spectra, measured using the two-photon induced fluorescence technique, show in toluene the following trend for the two-photon cross sections (delta): 3N > 2N > 1N. In water the delta values follow the same order, 3C approximately 2C > 1C, but are smaller (approximately one-third). Significantly, the fluorescence quantum yield (eta) in water decreases much more for 1, relative to 2 and 3. The two-photon action cross sections (deltaeta) of 2C and 3C are 294 GM and 359 GM, respectively. These values are among the highest reported thus far. These results show that, to maximize the deltaeta in this class of chromophores, one needs to fine-tune the magnitude of the charge transfer character of the excited state, to minimize fluorescence quenching in polar media.     

An exploration of Suzuki aryl cross coupling chemistry involving [2.2]paracyclophane derivatives

Suzuki aryl cross coupling reactions using derivatives of [2.2]paracyclophane were examined. A variety of aryl boronic acids and pinacolate esters were successfully cross coupled with 4-bromo[2.2]paracyclophane under standard Suzuki conditions. Whilst an excellent tolerance for electron donating and withdrawing groups was observed, cross coupling reactions with highly sterically demanding borates (e.g. mesityl) were unsuccessful. The preparation and stability of the previously unreported [2.2]paracyclophanyl-4-boronic acid, -pinacolate ester and -dimethyl ester are described, along with the utility of these systems in Suzuki aryl cross coupling reactions. Application of this methodology led to a dicyclophane containing two [2.2]paracyclophane units separated by a 4-4' connected biphenyl spacer group.     

Conformational rigidity and flexibility of the paracyclophane skeleton in substituted [2.2]paracyclophanes

The character of distortions of the paracyclophane skeleton in various substituted [2.2]paracyclophanes was analyzed based on X ray diffraction data. The rigidity of the skeleton is provided by ethylene bridges and flexibility of the benzene rings, which adopt a boat conformation. The flexibility of the skeleton is manifested in the displacement of the benzene rings with respect to each other and conformational changes of ethylene bridges. The changes in these characteristics are very sensitive to intra- and intermolecular steric factors and are indicative of the absence of strong specific stacking interactions between the be nzene rings. Precision X-ray diffraction study and quantum-chemical calculations for unsubstituted [2.2]paracyclophane and 4,7-benzoquinono[2.2]paracyclophane demonstrated that there are no attractive interactions between the benzene rings, and the electron density is localized predominantly on the outer surface of the rings. This fact can be considered as the cage molecular effect of the [2.2]paracyclophane skeleton.Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1707–1732, September, 2004.     

Synthesis of planar chiral [2.2]paracyclophane Schiff bases for the enantioselective Henry reaction

A series of diastereomerically pure Schiff base ligands based on [2.2]paracyclophane backbones were synthesized and separated. The new planar chiral [2.2]paracyclophane Schiff bases were used as ligands in Cu-catalyzed asymmetric Henry reactions with high yields and enantioselectivities.     

Design and synthesis of planar chiral heterocyclic carbene precursors derived from [2.2]paracyclophane

A unique family of planar chiral symmetrical N-heterocyclic carbene precursors with restricted flexibility derived from [2.2]paracyclopane were obtained by a new synthetic route. The resolution of 4-amino-13-bromo[2.2]paracyclophane was achieved with relatively high efficiency. Starting from (4 S p,13 R p)-4-amino-13-bromo[2.2]paracyclophane, the planar chiral pseudogem-disubstituted [2.2]paracyclophanyl dihydroimidazoliums were prepared in a four-step sequence with good yields. The resulting dihydroimidazolium salts were fully characterized with a series of methods including single-crystal X-ray diffraction technique.     

Structure Determination of an Unusual [2.2]paracyclophane Derivative by NMR Spectroscopy

Our ongoing study on cycloaddition reactions of dienes with different dienophiles afforded a great variety of derivatives with interesting molecular structures and electronic behavior. A new type of angularly annelated [2.2]paracyclophane (3) has been synthesize by the Diels–Alder reaction of 4-(2-propenyl[2.2]paracyclophane (1) and 1,4-benzoquinone (2) under high pressure conditions. The structure determination of this compound has been achieved by NMR measurements and semiempirical calculations.     

Novel multichiral diols and diamines by highly stereoselective pinacol coupling of planar chiral [2.2]paracyclophane derivatives

The TiCl4/Zn-mediated intermolecular pinacol coupling of the planar chiral carbonyl compounds [2.2]paracyclophane-4-carbaldehyde, 4-acetyl[2.2]paracyclophane (ketone) and the four regioisomeric 5-, 7-, 12- and 13-methoxy[2.2]paracyclophane-4-carbaldehydes as well as the pTosOH-Zn/Cu-promoted coupling of their N-substituted imines is described. Coupling of the enantiomerically pure substrates (most of carbonyl compounds and all imines) occurs stereoselectively giving rise to diastereomerically pure 1,2-diols and 1,2-diamines. Racemic aldehydes and ketone react with different degrees of stereoselectivity (depending on the substituents in certain positions) and produce one to three diastereomers. 7-methoxy[2.2]paracyclophane-4-carbaldehyde undergoes a tandem pinacol coupling-pinacol rearrangement to yield bis-(7-methoxy[2.2]paracyclophane-4-yl)acetaldehyde. Coupling of the racemic imines produces a mixture of single racemic D,L-diamine and single meso-diamine in each case. The stereoselective formation of the asymmetric centres is governed by the planar chiral [2.2]paracyclophanyl moiety. The techniques elaborated are extended to the intramolecular coupling of [2.2]paracyclophane-4,13-dicarbaldehyde and its bis-N-phenylimine, resulting in stereoselective formation of the chiral triply-bridged diol and exclusive formation of the meso-diamine. X-Ray investigations of several diols and diamines have been carried out and the structural features of these derivatives are discussed.     

The synthesis of enantiomerically pure [2.2]paracyclophane derivatives

[2.2]Paracyclophane is a fascinating molecule that offers great potential in a wide range of chemical disciplines. Currently, the synthesis of the majority of enantiomerically pure [2.2]paracyclophane derivatives is based on the resolution of a small number of starting materials or individual resolution procedures are developed for each new compound. The development of more general routes to these valuable compounds via the resolution of a common intermediate is discussed. Ultimately, it would be preferable to synthesise these valuable compounds without recourse to resolution and ideas for this rewarding goal are postulated.     

Synthesis of new planar chiral [2.2]paracyclophane Schiff base ligands and their application in the asymmetric Henry reaction

A series of new planar and central chiral ligands based on [2.2]paracyclophane backbones were designed and prepared from enantiomerically pure 4-amino-13-bromo[2.2]paracyclophane and commercially available chiral amino alcohols. Their application in a copper-catalyzed asymmetric Henry reaction resulted in secondary alcohols with high yield and excellent selectivity for active aldehydes (up to 94% ee). This is a successful example of employing planar chiral [2.2]paracyclophane ligands in copper-catalyzed reaction.     

Synthesis of novel planar-chiral [2.2]paracyclophane derivatives as potential ligands for asymmetric catalysis

The synthesis of a variety of new 4,5-disubstituted [2.2]paracyclophane derivatives has been achieved employing different cross-coupling reactions. By this methodology, a heteroatom-variation of successful catalyst ligands was achieved, giving rise to a modular ligand system. The X-ray structure of 4-hydroxy-5-(1′-hydroxy-1′-phenylethyl)-[2.2]paracyclophane was determined to elucidate the configuration. Additionally, a diastereoselective synthesis of planar- and central-chiral 4-([2.2]paracyclophanyl)ethylamine was achieved, thus resulting in a planar- and central-chiral phenyl ethylamine analogue.