Synthesis and Structures of [2. n ]Metacyclophan-1-enes and their Conversion to Highly Strained [2. n ]Metacyclophane-1-ynes

: The syntheses of s yn -[2. n ]metacyclophan-1-enes ( n = 5, 6, 8) in good yields using the McMurry cyclization of 1, n -bis(3-formyl-4-methoxyphenyl)alkanes are reported. Conversion of s yn - [2.6]- and [2.8]metacyclophan-1-enes to the corresponding highly strained syn -type [2.6]- and [2.8]metacyclophane-1-ynes was achieved by successive bromination and dehydrobromination reactions. An attempted trapping reaction of the putative corresponding [2.5]metacyclophane-1-yne by Diels-Alder reaction with 1,3-diphenylisobenzofuran failed due to its smaller ring size and strained structure. X-ray crystallographic analyses show that the triple bonds in syn -[2.6]- and [2.8]metacyclophane-1-ynes are distorted from linearity with bond angles of 156.7° and 161.4°, respectively. A DFT (Density Functional Theory) computational study was conducted to determine the stabilities of different conformations of the target compounds.


Introduction
Cyclophanes are an important class of compounds that have been shown to possess unique properties.This has attracted the interest of many research groups.These properties include having highly strained and unusual conformers with distorted aromatic ring components and this has resulted in much ongoing research into the fundamental aspects of aromaticity. 1  Among the cyclophanes, the highly strained cyclophynes containing at least one ethyne bridging group have proven to be elusive.The formation of a paracyclophyne (Fig. 1) was inferred by Psiorz and Hopf as the transient intermediate that led, via its cyclotrimerization reaction, to the formation of the novel C3-symmetrical hydrocarbon trifoliaphane. 2 Meijere 3a,b and Wong 3c,d and their respective coworkers used reactive trapping reagents such as furan, to confirm the formation of other strained cyclophynes as transient intermediates leading to the observed formed cycloaddition products.The syntheses of several medium-sized [n.n]metacyclophane-diynes such as [4.n]metacyclophyne, were reported by Ramming and Gleiter.4a Under different reaction conditions the triple bonds of some of these diynes could be isomerized into the corresponding cis double bonds and in others into allenic moieties.Kawase and coworkers reported the syntheses of [2n]metacyclophane-nynes such as [2.2.2]metacyclophyne (Fig. 1) which are considerably strained and have bent triple bonds, via sequential bromination-dehydrobromination reactions of the corresponding metacyclophan-n-enes. 4b-d  Previously, we reported our own attempts to produce the shorter chain-length [2.3]-and [2.4]metacyclophane-1-ynes by the dehydrobromination of the corresponding 1,2-dibromo- [2.n]metacyclophanes, but only 1-bromo [2.n]metacyclophan-1enes together with [2.n]metacyclophan-1-ones were obtained.5a,b Later, we reported the successful preparation of syn-and anti- [2.8]metacyclophan-1-enes using the low-valent titanium-induced McMurry coupling reaction and their conversion to syn-and anti- [2.8]metacyclophane-1-ynes, in a ratio of 35:65. 6The bromine adduct of [2.10]metacyclophan-1ene on the other hand, gave the [2.10]metacyclophane-1-yne as the major product, along with a monodehydrobrominated product 1-bromo [2.10]metacyclo-phan-1-ene as a by-product. 6 We also recently reported the synthesis, structures and DFT (Density Functional Theory) computational studies of several [2.n]metacyclophanes 7a-g  and  [3.3]metacyclophanes 8  as well as ring-expanded metacyclophanes containing three aromatic rings. 9 In this paper, in continuation of our previous work related to the synthesis of [2.n]metacyclophane-1-ynes, 6 we now report the first synthesis of highly strained [2.n]metacyclophane-1-ynes (n = 5, 6 and 8) using the bromination-dehydrobromination reactions of their corresponding [2.n]metacyclophan-1-ene precursors.

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The McMurry TiCl4/Zn reductive coupling reaction of carbonyl compounds catalyzed by low-valent titanium 13 has been extensively used to synthesize cyclophanes. 14,15In the present work, using the reductive coupling reaction, intramolecular cyclization of 1,5-bis(3-formyl-4-methoxyphenyl)pentane 2a successfully afforded 4,17-dimethoxy [2.5] metacyclophan-1-ene 3a in 78% yield.Similarly,4,18dimethoxy[2.6]-metacyclophan-1-ene 3b and 4,20-dimethoxy [2.8]metacyclophan-1-ene 3c were obtained in 62% and 65% yields, respectively.No formation of any of the corresponding (E)-isomers were observed with 2a-c but with 1,10-bis(3-formyl-4-methoxyphenyl)decane 2d as previously reported, a mixture of the corresponding (E)-and (Z)-4, 22dimethoxy[2.10]metacyclo-phan-1-enes(E)-3d and (Z)-3d was obtained (Scheme 1). 16  [2.n]Metacyclophan-1-enescan adopt either a "staircase" anti-conformation or a syn-conformation by overlapping of their aromatic rings (Fig. 2). 17Syn-anti interconversion can occur by ring flipping, and is dependent upon both the length of the bridges 18 and also on the nature of the intra-annular substituents. 19  The 1 H-NMR spectrum of 3a clearly showed the doublet of the intra-annular protons at  7.05 ppm (d, J = 2.2 Hz) separated from the other protons of the aromatic rings at  6.80 (d, J =8.4 Hz) and 6.91 (dd, J = 2.2, 8.4 Hz) ppm.Previously, we had reported that the intra-annular aromatic potons in the anti- [2.n]metacyclophan-1-enes (n = 3-6) were shifted upfield at 6.05-6.77ppm, due to the shielding effect of the ring current of the opposite benzene ring. 20Thus, the observed chemical shift for the intra-annular protons of 3a strongly suggests that the molecule adopts a syn-conformation.Previous work has shown the chemical shifts of olefinic protons for (E)and (Z)-olefins to be at  >7.4 ppm and  <6.9 ppm repectively. 21In the case of 3a the olefinic bridge protons were observed as a singlet at  6.79 ppm indicating that the structure of 3a is a (Z)-syn-isomer.Similarly, the spectra of [2.6]metacyclophan-1-ene (3b) and [2.8]metacyclophan-1-ene (3c), indicate that they exisist as (Z)syn-isomers.Fast interconversion on the NMR timescale between the two conformations of 3a can be observed since the three multiplets centered at  1.03, 1.28 and 2.32 ppm, which are due to the protons of the pentane bridge, do not change upon decreasing the temperature to -100°C in a 1:3 mixed CDCl3-CS2 solvent.Thus the larger cyclophane ring size and the smaller intraannular protons in 3a allow for a more flexible structure compared to, for example, anti-6,14-dimethoxy-1,2dimethyl [2.4] Conversion of the double bonds to the corresponding triple bonds was accomplished by the bromination-dehydrobromination sequence of reactions.First, using equimolar amounts of benzyltrimethylammonium tribromide (BTMA-Br3) 22  in dichloromethane solution at room temperature, syn-3a and syn-3b afforded quantitatively the racemic trans-dibromo adducts syn-4a (endo-exo-Br) and endo-exo syn-4b (endo-exo-Br), respectively in which the bromine atoms are endo or exo to the macrocycle with R,R and/or S,S configurations (Scheme 2).However, with syn-3c a mixture of dibromo meso-syn-4c (endoendo-Br) with the bromine atoms in R,S configurations and syn-4c (endo-exo-Br) was formed quantitatively in a 53:47 ratio.Interestingly, the bromination reactions of the syn-3a-c compounds afforded the corresponding syn-4a-c dibromo products, without any of the corresponding anti-conformers.In these bromination reactions no syn-to anti-ring inversion occurs.

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For internal use, please do not delete.Submitted_Manuscript The structures of these products were determined from their elemental analyses and spectral data.The 1 H-NMR signals of 4a-d in CDCl3, were assigned based upon the trans-addition of bromine to the double bonds with endo-exo-and endo-endoarrangements of the two bromine atoms with respect to the macrocycle.The two intra-annular aromatic protons which are located ortho to the two bridging aromatic carbon atoms in 4a now appeared as two distinct doublets at  = 6.93 (J = 2.2 Hz) and 7.00 (J = 2.2 Hz) ppm, which is supportive for 4a being in a syn-conformation.Furthermore, the methine protons at the dibromoethano bridge also appear as a pair of doublets (J = 10.4Hz) at  = 5.57 and 6.62 ppm.The lower field signal is attributed to one of the exo-methine protons which is in a strongly shielding region of the oxygen atom of the methoxy group on the aromatic ring.The data are strong evidence that the two methine protons at the ethano bridge are in an exo-endo arrangement with respect to the macrocycle (Figure S18).Thus, 4a is assigned as being a racemic pair i. e. rac-or dl-syn-12-endo-bromo-13-exobromo-9,15-dimethoxy[5.2]metacyclophane, or dl-syn-4a as shown in Fig. 3 (where n = 5).None of the corresponding antiisomer was observed under the conditions used here.The protons of the -(CH2)5-bridge generated a complicated signal pattern, as to be expected for a rigid structure.The bridged methylene protons in syn-4a are clearly located in different spaces with one of them folded into the -cavity formed by the two benzene rings and high-field signals at  -0.13and -0.03ppm are observed.The individual signals of the methylene protons for the middle CH2 group in the pentane bridge do not coalescence below 130°C in CDBr3 and the energy barrier to conformational wobbling is above 25 kcal mol -1 .
The structure of 4b was similarly confirmed by elemental analysis, 1 H-NMR spectroscopic data and additionally, with a single crystal X-ray crystallographic analysis.The 1 H-NMR spectrum of 4b exhibits two singlets at  3.71 and 3.82 ppm for the methoxy protons.The two intra-annular aromatic protons at  = 6.96 and 6.99 ppm are at lower fields than those seen for the corresponding anti- [2.n]metacyclophan-1-enes. 20 The data is supportive for 4b being in a syn-conformation.Furthermore, similar to syn-4a the two methine protons at the ethano bridge appear as a pair of doublets (J = 10.2Hz) at  = 5.66 and 6.67 ppm.The lower field absorption is attributed to the exo-methine proton in a strongly shielding region of the oxygen atom of the methoxy group on the aromatic ring (Figure S20).Thus, the two methine protons at the ethano bridge are similarly in an exoendo arrangement and thus 4b is assigned as being a racemic pair i. e. rac-or dl-syn-13-endo-bromo-14-exo-bromo-10,16dimethoxy[6.2]metacyclophanedl-syn-4b.As in the case of 4a the protons of the -(CH2)6-bridge generated a similarly complicated signal pattern.The single crystal X-ray structure of syn-4b is illustrated in Fig. 4. The compound crystallized in the monoclinic space group P21/a (CCDC 1547285 and SI Table S1) and clearly reveals that the conformation is syn in which two aromatic rings are face-toface and mostly cause distortion in a boat-like shape and deviate from planarity to some extent as can be seen from the side view of the ORTEP drawing.Further, the X-ray analysis shows an unsymmetrical structure with a staggered orientation of the two methine protons on the ethano bridge and located distally from the bridging methylene groups.These results suggest that the introduction of the two bromine atoms at the ethano bridge might dominate the potential for interconversion of the two syn conformations of 4 by ring flipping.
Interestingly, the 1 H-NMR spectrum of 4c showed it to be a mixture of meso-syn-4c (endo-endo-Br) and dl-syn-4c (endoexo-Br) in the ratio of 53:47.The presence of the diastereomeric meso-syn-4c can be inferred by the presence of singlet signals for the its methoxy protons at  = 3.54 ppm and for the ethylene bridge methine protons at  = 6.12 ppm.The intra-annular protons appear as a broad singlet signal at  = 7.30 ppm due to their being in the strongly deshielding region of the endo-Br atoms on the ethylene bridge.This data strongly supports the assignment of having the two Br atoms in an endo-arrangement.In contrast, dl-syn-4c showed a similar 1 H-NMR spectrum to those of 4a and 4c, which suggests an unsymmetrical syn-endoexo-dibromo-structure.
Treatment of 4b and 4c with t-BuOK in t-BuOH at 80°C for 24 h gave the doubly dehydrobrominated products, [2.n]metacyclophane-1-yne 6b and 6c in 95% and 98% yields, respectively (Scheme 3).Similar treatment of 4a however, afforded only the t-butoxide product 5a in 83% yield and none of the desired [2.5]metacyclophane-1-yne 6a (Scheme 4).In this case, it could be supposed that when the highly strained acetylenic moiety in 6a formed in the dehydrobromination reaction, that it immediately reacts with the solvent t-BuOH to produce the addition product 5a.Other attempts to Br Br meso-4

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For internal use, please do not delete.Submitted_Manuscript dehydrobrominate this shorter chain cross-linked compound 4a using different t-BuOK/t-BuOH reaction conditions however failed.Attempts to trap putative 6a as its Diels-Alder adduct 7a with 3-diphenylisobenzofuran in t-BuOH were unsuccessful affording only 5a again.However attempts to form the corresponding Diels-Alder adducts from the reaction of the isolated [2.n]metacyclophane-1-ynes 6b and 6c with 1,3diphenylisobenzofuran under the same reaction conditions shown in Scheme 4 also failed and only the unreacted starting comounds were recovered.Presumably the sterically crowded bridged acetylene moiety having the methoxy groups on the benzene rings likely suppress the approach of the 1,3diphenylisobenzofuran (Scheme 4).The structure of 5a was determined by elemental analyses and spectral data.The mass spectra showed the predicted molecular ion for 5a at m/z = 380.19.The 1 H-NMR spectrum of shows the two methoxy protons as singlets at  = 3.79 and 3.87 ppm.The tert-butoxy protons and the olefinic proton appear at  = 1.31 ppm (9H) and 6.52 ppm (1H) as nine-and one-proton singlets, respectively.
The structures of 6b and 6c were also determined by elemental analyses and spectral data.The intra-annular aromatic protons of 6b appear as a doublet at  7.52 (H8,20, J = 2.4 Hz) ppm and the other aromatic protons appear at  6.82 (H5,17, d, J = 8.5 Hz) and 7.06 (H6,16, dd, J = 2.4, 8.5 Hz) ppm.As with the previous examples, the syn-conformer structure is assigned to 6b.The lower-field signal of the intra-annular protons in comparison with the other aromatic protons indicate that are situated within the deshielding region owing to the electrons of the triple bond.
The X-ray structure of a single-crystal 6b obtained from slow evaporation of a saturated dichloromethane solution clearly indicates that it is also the syn-conformer in the solid state (Fig. 5).This compound crystallized in the same monoclinic space group P21/a (CCDC 1547283; SI Table S2).The side view shown in Fig. 5 shows that the two methoxy groups are situated away from the direction of macrocyclic ring to constrain steric repulsion with the bridge chain.The C13-C14 bond distance is 1.203 Å, which is almost equal to the normal distance between the carbon atoms in acetylene.The C11-C13 and C14-C15 bond distances are both 1.440 Å, and are much shorter than those of C6-C7 (1.521 Å) and C1-C19 (1.521 Å).Interestingly, the acetylenic moiety in the bridge does not adopt a different linear structure than reference compound 11 shown below in Scheme 5.The C11-C13-C14 and C15-C14-C13 bond angles of 156.74° and 156.74° are unusual.This clearly shows that 6b is a moderately bent molecule and is consistent with the lower field chemical shifts of the signals of the acetylenic carbons in its solution state 13 C NMR spectrum (see below).The structure of the syn-confomer for [2.8]metacyclophane-1-yne 6c is also readily assigned from its NMR spectra and the chemical shift of the intra-annular aromatic protons at  7.50 ppm.
The perspectives of the structure of the syn-6c are illustrated in Fig. 6.This compound crystallized in the same monoclinic space group P21/a (SI Table S3).The X-ray crystallography (CCDC 1547284) clearly reveals that the conformation of 6c is also syn.The bond distance of C14-C15 is 1.203 Å and the bond angles of C13-C14-C15 and C16-C15-C14 are unusual values, 161.91° and 161.43°.The two aromatic rings diverge similarly from planarity to some extent, to avoid -electron repulsion.The chemical shifts of the 1 H-and 13 C-NMR signals arising from the benzene rings of 6b, 6c and 6d (n = 10) 16 are comparable to those of the acyclic compound 11, which was prepared from 2-formyl-6-methylanisole in 3 steps using the same procedure as for the [2.n]metacyclophane-1-ynes 6b-d by following our previous report (Scheme 5). 16The signals of the acetylenic carbons (Table 1) in 6b-d are located at lower fields than those of 11 ( 89.7 ppm).This reflects the appreciable strain in the triple bonds due to bending.In particular, the chemical

Computational Details
Computational studies were conducted to explore the conformational properties of the conformers of 3a-c and 6b-6c.
All computations were carried out with the Gaussian 09.e01 package. 25The molecular geometries of the conformers shown were fully optimized in the gas phase, at the DFT level of theory using the B3LYP (Becke, three-parameter, Lee-Yang-Parr), 26  exchange-correlation with the 6-31G(d) basis set.The individual geometry-optimized structures and their energies are summarized in Fig. 7 and Table 2.The energies of the less energetically-favoured conformers for each compound are presented as ΔE values relative to the most energeticallyfavoured conformer for that compound.As can be seen, the syn conformers are the lower energy ones in each case.

Conclusions
We have synthesized, for the first time, the highly strained syn-

General procedures
All melting points (Yanagimoto MP-S1) are uncorrected.NMR spectra were determined at 300 MHz with a Nippon Denshi JEOL FT-300 spectrometer with Me4Si as an internal reference: J values are given in Hz.IR spectra were measured for samples as KBr pellets or as liquid films on NaCl plates in a Nippon Denshi JIR-AQ2OM spectrophotometer.UV spectra were measured by a Shimadzu 240 spectrophotometer.Mass spectra were obtained on a Nippon Denshi JMS-01SG-2 mass spectrometer at an ionization energy of 70 eV using a direct inlet system through GLC.Elemental analyses were performed by Yanaco MT-5.G.L.C. analyses were performed with a

Figure 4 .
Figure 4. ORTEP figures of 4b with top (left) and side (right) views.Thermal ellipsoids are drawn at the 50% probability level.Only hydrogen atoms at the ethano bridge are shown.Other hydrogen atoms are omitted for clarity.

Figure 5 .
Figure 5. ORTEP figures of 6b with top (left) and side (right) views.Thermal ellipsoids are drawn at the 50% probability level.All hydrogen atoms are omitted for clarity and the carbon numbering system is shown.

Figure 6 .
Figure 6.ORTEP figures of 6c with top (left) and side (right) views.Thermal ellipsoids are drawn at the 50% probability level.All hydrogen atoms are omitted for clarity.

Figure 7 .
Figure 7.The B3LYP molecular geometry optimized structures of the various conformers of 3 and 6 MCPs in gas phase.Colour code: carbon = green; hydrogen = white; oxygen atom = red.
[2.6]metacyclophane-1-yne 6b and[2.8]metacyclophane-1-yne syn-6c, of the metacyclophane-1-yne systems.Single-crystal Xray structures of the dibromo precursors 4b and 4c adducts were determined and their NMR spectra analysed.The subsequent double-dehydrobromination of the bromine adducts of[2.n]metacyclophan-1-enes with base will also open up new mechanistic aspects for cyclophane chemistry.The conformations were also determined by DFT studies and were cosistent with the experimental results.Further studies on the chemical properties of [2.n]metacyclophane-1-ynes are now in progress.