Synthesis and conformations of [ 2 . n ] metacyclophan-1-ene epoxides and their conversion to [ n . 1 ] metacyclophanes

A series of synand anti-[2.n]metacyclophan-1-enes are prepared in good yields by a McMurry cyclization of 1,n-bis(5-tert-butyl-3-formyl-2-methoxyphenyl)alkanes. Interestingly, acid catalyzed rearrengements of [2.n]metacyclophan-1-enes afforded [n.1]metacyclophanes in good yield. The ratio of the products is strongly regulated by the number of methylene bridges present. The percentage of the rearrangement product increases with increasing length of the carbon bridge. Characterization and the conformational studies of these products are described. Single crystal X-ray analysis revealed the adoption of synand anticonformations. DFT calculations were carried out to estimate the energyminimized structures of the synthesized MCPs.


Introduction
Cyclophanes 1 have been well-studied in organic chemistry and found to adopt unusual chemical conformations due to build-up of strain.Although the parent [2.2]metacyclophane(MCP = metacyclophane) was first reported as early as 1899 by Pellegrin, 2 the synthesis of syn- [2.2]MCP was not realized until 85 year later.Mitchell et al. 3 have efficiently prepared syn- [2.2]MCP at low temperature by using (arene)chromiumcarbonyl complexation to conduct the stereochemistry.Later, Itô et al. 4 have also isolated and characterized syn- [2.2]MCP; we note that syn- [2.2]MCP isomerizes conveniently to its anti-isomer above 0°C.On the other hand, Boekelheide 5 and Staab 6 have successfully designed intra-annularly substituted syn- [2.2]MCPs.However, reports on the synthesis and reaction chemistry of syn- [2.n]MCP have not thus far been published.
On the other hand, Merz et al. 7 reported the stereospecific epoxidation of (E)-and (Z)-stilbene crown ethers with mchloroperbenzoic acid to afford the epoxy crown ethers.Oda et al. 8 also published the epoxidation of trans-diethylstilbestrol with mchloroperbenzoic acid to afford the racemic trans-diethylstilbestrol oxide.Thus, there is considerable interest in synthesizing the [2.n]MCP-1-enes and their conversion to 1,2-epoxy-[2.n]MCP,which can enforce the syn-conformation, whilst restricting the flexibility resulting from ring inversion.
Although [n.1]MCPs have been prepared by various workers, these previous synthetic routes were too tedious for practical application.Vögtle 9 reported the first synthesis of both [4.1] and [5.1]MCP by the appliance of a new method, namely sulfone pyrolysis.Later, Lin et al. 10 suceeded in preparing the lower [3.1]homologue by implementing a photochemical method.However, it was quite difficult to obtain sufficient amounts of the products for any subsequent studies by following such a route.
Recently, we have reported the formation of 1,2-dimethyl[2.n]MCP-1-enes 11by employing the reductive coupling of carbonyl compounds by low-valent titanium, i.e. deploying the McMurry reaction [12][13][14][15][16] as a key step.In this paper, we report the synthesis of [2.n]MCP-ene using the McMurry cyclization reaction and subsequent conversion to 1,2-epoxy[2.n]MCP.The latter compounds were further modified to [n.1]MCPs by an acid catalyzed rearrangement.Conformational studies of these MCPs both in solution and the solid state are also described.

Results and Discussions
8][19] In the presence of dichloromethyl ether and titanium tetrachloride (TiCl4), a regioselective Friedel-Crafts acylation reaction 20, 21 at the meta positions of 1,6-bis(2-methoxyphenyl)hexane and 1,8-bis(5-tertbutyl-2-methoxyphenyl)octane was achieved at room temperature to afford the required 1a and 1b in 68 and 74% yield, respectively.To a solution of methylmagnesium iodide in Et2O was added a solution of compounds 1a and 1b in tetrahydrofuran (THF) dropwise under relatively mild conditions (refluxing for 12 h) to afford 1,6-bis(5tert-butyl-3-(1-hydroxyethyl)-2-methoxyphenyl)hexane 2a and 1,8bis(5-tert-butyl-3-(1-hydroxyethyl)-2-methoxyphenyl)octane 2b in 74 and 77% yield, respectively.Thus, the reductive coupling reaction of 3 was carried out by using TiCl4-Zn in the presence of pyridine in refluxing THF under high dilution conditions to afford the required compounds anti-and syn-5,17-di-tert-butyl-8,20-dimethoxy-1,2-dimethyl[2.6]MCP-1-ene4a in 23 and 13% yields, respectively and anti-and syn-5,19-di-tertbutyl-8,22-dimethoxy-1,2-dimethyl[2.8]MCP-1-ene4b in 21 and 64% yields, respectively.This result was different from that of the related McMurry cyclization of 1,3-bis(5-acetyl-2-methoxyphenyl)propane, which afforded the corresponding [3.1]MCP by TiCl4 or acid induced pinacol rearrangement. 31he structures of 4a and 4b were elucidated based on their elemental analyses and spectral data.In particular, the mass spectral data for 4a and 4b (M + = 462 for 4a and 490 for 4b) fully support the cyclic structure.The conformations of 4a and 4b were readily apparent from their 1 H NMR spectrum.The 1 H NMR spectrum of anti-4a in CDCl3 exhibits a singlet at  3.34 ppm for the methoxy protons, a singlet at  1.31 ppm for the tert-butyl protons and a pair of doublets at  6.89 and 7.04 (J = 2.7 Hz) ppm for the aromatic protons, which are in the deshielded region of the bridged double bond.Thus, the methoxy protons appear upfield because of the ring current of the opposite aromatic ring.The structure of the synconformer is also easily evaluated from the chemical shift of the methoxy protons at  3.67 ppm.Here, the tert-butyl proton of syn-4a is observed at higher field, viz  1.11 ppm, due to the shielding effect of the aromatic ring.The aromatic protons of syn-4a are reported at much higher field ( 6.64 and 6.77 ppm) than those of compound anti-4a.These data confirm the assigned anti and syn structures for both of the two 4a conformers.
The X-ray structure of anti-4a (Figure 2) clearly reveals that it is the anti-conformer in the solid state and that the two methoxy groups lie on the correlative side of the inner ring, which consists of a long bridging C16-C21 chain pointing outwards to minimize the steric repulsion with the bridge chain.The bond lengths of C21-C20 and C22-C21 in the hexamethylene chains and C2-C24 and C1-C5 in the ethylenic chains have standard values at 1.53, 1.50, 1.50 and 1.49 Å, respectively.The length of the double bond in C1-C2 is 1.34 Å, which is similar to that of ethylene.The bond angles defined by C1-C2-C24 and C2-C1-C5 are 123.3(2)°and 122.7(2)°, showing that compound anti-4a displays a non-distorted conformation.The two benzene rings of 4a slightly deviate from planarity.The intramolecular distances of C5-C24, C6-C23, C9-C29, C10-C25, C7-C22, C8-C27 are 2.97, 3.45, 8.08, 5.18, 4.69 and 6.11 Å.
The 1 H NMR spectrum of anti-4b in CDCl3 possesses a singlet at  3.52 ppm for the methoxy protons, and a singlet at  1.28 ppm for the tert-butyl protons.For the aromatic protons, a pair of doublets was observed at  6.86 and 7.01 (J = 2.7 Hz) ppm which are in the deshielding region of the bridged double bond.Thus, the methoxy protons experience an upfield shift due to the ring current of the opposite aromatic ring.From the chemical shift of the methoxy protons at  3.69 ppm, the structure of the syn conformer is confirmed.Also, the tert-butyl proton of syn-4b occurs to higher field, i.e.  1.12 ppm, due to the shielding effect of the benzene ring.The aromatic protons of syn-4b are observed at much higher field ( 6.74 and 6.82 ppm) than those of anti-4b.These data allow for the assignment of the anti and syn structures of the two conformers of 4b.
The X-ray structure of anti-4b (Figure 2) clearly demonstrates that the anti-conformer is adopted in the solid state and that the two methoxy groups lie on the correlative side of the inner ring, which contains the long bridging C16-C23 chain pointing outwards to keep the steric repulsion with the bridge chain to a minimum.The bond lengths of C23-C22 and C24-C23 in the octamethylene chains and C2-C26 and C1-C5 in the ethylenic chains have standard values at 1.44, 1.43, 1.45 and 1.45 Å, respectively.The length of the double bond in C1-C2 is 1.34 Å, which is similar to that of ethylene.The bond angles defined by C1-C2-C26 and C2-C1-C5 are 121.4(2)°and 121.3(2)°, showing that compound 4b displays a non-distorted conformation.The two benzene rings of 4b moderately deviate from planarity.The intramolecular distances of C5-C26, C6-C25, C9-C31, C10-C27, C7-C24, C8-C29 are 2.86, 3.70, 6.29, 5.80, 4.89 and 4.85 Å.
The epoxidation 32 of 4 with m-chloroperbenzoic acid in the presence of dichloromethane at room temperature for 40 h afforded the desired 1,2-epoxy[2.n]MCP5 as colourless prisms in quantitative yield (Scheme 3).The 1 H NMR spectrum (300 MHz) of anti-5a exhibited a doublet for the benzene proton at  7.38 ppm (J = 2.4 Hz) in addition to resonances at  6.95 and 7.29 ppm for the other two protons of the aromatic rings.These observations strongly suggest that the structure corresponds exclusively to the anti-conformation.These findings strongly suggest that the exo-epoxide structure of 5a and the syn-epoxidation resulting from exo-attack at the double bond of syn-5a formed during the ring inversion of anti-5a might be sterically favourable.
The protons of the hexamethylene bridge gave rise to a complicated signal pattern as expected for a rigid syn-[2.6]MCP.The protons of the benzylic CH2 group were observed as two multiplets centered at  2.28 and 2.49 ppm which were further split by coupling with the protons of the other CH2 groups.The peak pattern ascribed to twelve chemically distinct protons of the alkane bridge proved the absence of a anti-anti interconversion which would exchange HA and HB of each CH2 group.
The 1 H NMR spectrum of syn-5b revealed a doublet for the aromatic proton at  7.11 (J = 2.4 Hz) ppm in addition to the resonances at  6.84 ppm for the other two protons of the aromatic rings.These observations suggest that the structure consists exclusively of the syn-conformation.These estimations strongly suggest the exo-epoxide structure of syn-5b and syn-epoxidation from exo-attack at the double bond of syn-4 formed at the time of the ring inversion of syn-4b might be sterically favourable.
a Isolated yields are shown in parentheses.
The protons of the octamethylene bridge gave rise to a complex signal pattern as expected for a rigid syn- [2.8]MCP.The protons of the benzylic CH2 group were observed as two multiplets centered at  2.21 and 2.91 ppm which were further split by coupling with the protons of the CH2 groups.The peak pattern ascribed to sixteen chemically distinct protons of the alkane bridge proved the absence of syn-syn interconversion which would exchange HA and HB of each CH2 group.These findings suggest a rigid structure for syn-4b at this temperature.This result suggests that the introduction of an oxirane ring into the ethano bridge can strongly reduce the flexibility arising from ring inversion.
Compound anti-5a crystallized in the centrosymmetric space group P21/a.There are independent molecules (Z = 4) at general positions in the asymmetric unit of the crystal structure.It is clear   The crystal structure shows that the conformation adopted by compound syn-5b is the syn-conformation, in which two aromatic rings are part of a non-planar chain (Figure 3).Here, the bond lengths of C16-C17 and C16-C7 in the octamethylene chains and C5-C1 and C26-C2 in the ethylenic chains have typical values at 1.54, 1.51, 1.50 and 1.51 Å, respectively.The bond angles defined by C25-C26-C2 and C1-C5-C6 are 121.6 and 122.8 Å, showing that 5b displays a slightly distorted conformation.The two benzene rings of 5b slightly deviate from planarity.The intramolecular distances of C5-C26, C1-C6, C7-C24, C9-C28 are 3.08, 4.41, 5.88 and 4.95 Å.Both methoxy groups on the benzene rings of 5b point outwards, away from the decamethylene bridge chain.This contributes to the lack of steric crowding with the hydrogens and carbons of the bridge chains.Thus, it is a meso compound.
In the case of the treatment of compounds 5a and 5b with BF3.Et2O as catalyst in CH2Cl2, the desired acid catalyzed rearrangement 33 products [6.1]MCP 6a and [8.1]MCP 6b were obtained as the main products in 51 and 41% yield, respectively.No formation of dehydration product or ring-cleavage product was observed.The yields of the rearrangement products 6 decrease with the number of the methylene bridges.This result might be attributed to the decrease of carbon ring strain in the [n.1]MCPs.
Similarly, the conformation of the [n.1]MCPs 6a and 6b was readily apparent from their 1 H NMR spectra.For example, in the 1 H NMR spectrum of [6.1]MCP 6a in CDCl3 upfield shifts and different chemical shifts for the internal aromatic protons at  7.25 and 7.28 ppm due to the ring current of the opposite aromatic ring were observed.This data strongly suggests that the structure of 6a is the anti-conformer.
Furthermore, the two methoxy groups exhibit different chemical shifts at 3.29 and 3.41 ppm, each as a singlet.The four external aromatic protons were also observed as different chemical shifts at  7.12 and 7.05 ppm; the latter proton is in a strongly deshielding region of the oxygen atom of the acetyl group on the methylene bridge.The compound 6a exhibits a split pattern for the benzyl protons as two multiplets centred at  2.25 and 2.41 ppm.The central CH2 groups were also observed as two multiplets centred at  0.88 and 1.32 ppm.These findings suggest a rigid structure of [6.1]MCP 6a at this temperature.
a Isolated yields are shown in parentheses.
In the 1 H NMR spectrum of [8.1]MCP 6b in CDCl3 upfield shifts and different chemical shifts for the aromatic protons at  6.86 and 6.87 ppm strongly suggest that the structure of 6b is the synconformer.Furthermore, the two methoxy groups appear as a singlet with chemical shift 3.71 ppm.A splitting pattern for the benzyl protons as two multiplets centred at  2.30 and 2.89 ppm was exhibited for this compound.The CH2 groups were also observed as two multiplets centred at  0.78 and 1.59 ppm.These findings suggest a rigid structure of [8.1]MCP 6b at this temperature.The chiral properties of the compound anti-6a in solution were investigated by chromatographic resolution using a chiral column.Interestingly, anti-6a exhibits two well resolved peaks in the ratio of 50:50 for the P-and M-enantiomers.This finding strongly suggests that the resolution of racemic anti-6a could be accomplished by chromatographic separation using a chiral column.In fact, we have succeeded in resolving each P-and M-enantiomers.The circular dichroism (CD) spectra of the separated enantiomer with precise mirror images are shown in Figure 4. Indeed, we have succeeded in generating inherent chirality in the metacyclophane system containing two aromatic rings by the regio-selective rearrangement of [6.1]metacyclophane 6a.
Density functional theory (DFT) computational studies were carried out to demonstrate the geometry-optimized energies of compounds 5-6 (Figure 5).The starting structures were generated with the initial geometries based upon their own X-ray crystal structures.The DFT level of theory using the prominent B3LYP (Becke, three-parameter, Lee-Yang-Parr) 34 exchange-correlation functional with the 6-31G(d) basis set.By using Gaussian-09, the individual geometry-optimized structures of these molecules were first conducted in the gas phase and after that in solvent (chloroform) with the B3LYP/6-31G(d) basis set. 35The DFT-geometry optimized B3LYP/6-31G(d) energies for compounds 5-6 reveal that the order (in both the gas-phase or with the solvent correction term) of increasing stability is 6a> 6b>5a>5b.
The trend for the stabilities of 6 and 5 could tentatively be rationalized on the basis of the anti-conformations of 6a and 5a vs the syn-conformations of 6b and 5b.However, the geometryoptimized energy of the syn-structure is sufficiently higher than that of the anti-structure.
Both the single crystal and DFT-optimized structures of 5a indicate that it adopts an anti-conformation and that the methoxy groups are positioned opposite to the benzene rings (Figures 3 and 5).The greater activity may be attributed to the higher solubility of the compounds.We have calculated the energies of the HOMO and LUMO orbitals.The difference between the energies of the HOMO and LUMO (the HOMO-LUMO gap) shows the stability or reactivity of the molecules, pointing out the possible structures, such as electron rich or electron deficient regions.obtained on a Nippon Denshi JMS-HX110A Ultrahigh Performance Mass Spectrometer at 75 eV using a direct-inlet system.Elemental analyses were performed with a Yanaco MT-5 analyser.Elemental analyses were performed by Yanaco MT-5.Gas-liquid chromatograph (GLC) analyses were performed by Shimadzu gas chromatograph, GC-14A; silicone OV-1, 2 m; programmed temperature rise, 12 °C min -1 ; carrier gas nitrogen, 25 mL min -1 .
anti-5a adopt the anti-conformation in which two benzene rings are in a non-planar chain form.The measured torsional angles between the planes C6-C8-C10-C7, C4-C5-C6 and C8-C3-C7 planes, and those of C22-C27-C25-C24 with C27-C28-C29 and C24-C25-C26 are 116.9°,121.1°, 117.1° and 120.9°, respectively, showing that this molecule has an asymmetrical strain between the 'top' and 'bottom' rings, and that the amount of strain is much greater at the internal carbons than at the external carbons.The C6-C5-C1-C3 and C4-C2-C26-C25 planes are twisted out of coplanarity and have a dihedral angle of 5.2°, and thus the two carbonyl groups, C6-O2 and C25-O3 do not lie in the same plane where the adjacent two carbon atoms are included.
In conclusion, a new synthesis of [2.n]MCP-1-enes by a McMurry cyclization has been developed.Acid catalysed rearrangements of 4a and 4b can be applied to the synthesis of [n.1]MCPs.Further studies on the ring contraction of [2.n]cyclophanes with glycol units at the ethylene bridge to afford [n.1]cyclophanes are now in progress.This journal is © The Royal Society of Chemistry 2013

Table 3 .
DFT geometry-optimized computed energies for the compounds 5-6 generated from the solid-state X-ray coordinates.
a Based on DFT using the B3LYP/6-31G(d) basis set-up.