Studies on Lewis-Acid Induced Reactions of 8-Methoxy[2.2]metacyclophanes: A New Synthetic Route to Alkylated Pyrenes

: Anti-8-methoxy[2.2]metacyclophanes (MCPs) 5a–b were obtained via pyrolysis of the corresponding syn-thiatetraoxide cyclophanes 4a–b. Coupling reactions of 4-tert-butyl-1-methoxy-2,6-bis(mercaptomethyl)benzenes 1a–b and 1,5-bis(chloro-methyl)-2,4-dimethylbenzene 2 under high dilution conditions afforded only the syn-conformers of 9-methoxy-2,11-dithia[3.3]metacyclophanes 3a–b, which with m-CPBA formed the corresponding syn-tetraoxides 4a–b. Lewis acid (TICl4/AlCl3-MeNO2) or iodine-catalyzed reactions of 5b under various conditions led to transannular cyclization to afford tetrahydropyrene 6b and pyrene derivative 7b and/or de-tert-butylated 6a. Iodine-catalyzed reaction of 5a afforded tetrahydropyrene 6a. These findings suggest the potential for a new route to alkylated pyrenes via strained and alkylated metacyclophanes. Density functional theory (DFT) studies were carried out to investigate the conformational characteristics of 3–5. Abstract: Anti -8-methoxy[2.2]metacyclophanes (MCPs) 5a – b were obtained via pyrolysis of the corresponding syn thiatetraoxide cyclophanes 4a – b . Coupling reactions of 4- tert -butyl-1-methoxy-2,6-bis(mercaptomethyl)benzenes 1a – b and 1,5-bis(chloro-methyl)-2,4-dimethylbenzene 2 under high dilution conditions afforded only the syn -conformers of 9-methoxy-2,11-dithia[3.3]metacyclophanes 3a – b , which with m -CPBA formed the corresponding syn -tetraoxides 4a – b . Lewis acid (TICl 4 /AlCl 3 MeNO 2 ) or iodine-catalyzed reactions of 5b under various conditions led to transannular cyclization to afford tetrahydropyrene 6b and pyrene derivative 7b and/or de- tert butylated 6a . Iodine-catalyzed reaction of 5a afforded tetrahydropyrene 6a . These findings suggest the potential for a new route to alkylated pyrenes via strained and alkylated metacyclophanes. Density functional theory (DFT) studies were carried out to investigate the conformational characteristics of 3 – convenient preparation of the title compounds and their treatment with various Lewis acid catalysts. A proposed mechanism for the Lewis acid-induced reaction of [2.2]MCP 5b to the corresponding pyrene derivatives is also presented, as well as a DFT and quantum chemical computational study of the possible conformational structures. A simple and effective method for the synthesis of [2.2]meta-cyclophanes, and Lewis acid induced transannular reactions leading also to new alkylated pyrenes are reported along with a DFT computational study.


Introduction
Cyclophanes are macrocycles in which one or more arene rings (most commonly, benzene or substituted benzenes) are linked by methylene (-CH2-) group bridges of different lengths. The pioneering work in the cyclophane field was initiated by Cram in 1951, [1] and in recent decades cyclophane chemistry has attracted much attention from organic chemists. This is primarily due to cyclophanes having unusual and highly strained geometries, the stereochemical aspects of their structural flexibility such as ring-flipping, ring-tilting, bridge-wobbling as well as syn−anti isomerization [2] and the structures of many different types of cyclophanes have been reported. [3] When the meta or para positions of the component benzene rings are linked via short bridges, the rings can be forced to adopt syn and/or anti conformations with respect to each other. Studies on small meta-and para-cyclophanes have firmly established that a benzene ring can be distorted from planarity to a considerable extent (up to 30°) while fully retaining its aromaticity, as testified by various structural and physical parameters. [2a,4] Due to their flexibility, cyclophanes [5] have significant importance in theoretical studies and there are continuous efforts to synthesize novel cyclophanes of different sizes with numerous modes of ring attachments. [6] Although syn-and anti-conformers (e.g. see Fig.1) of [2.2]MCPs have been reported, it is still not clear what the effects are of not only internal substituents, but also of having unsymmetrically-substituted benzene rings with respect to the charge-transfer-type interactions between the two aromaticrings as well as steric effects of substituents onthe benzene ring(s).
We have previously shown that the introduction of substituents on one of the benzene rings can increase the strain in the cyclophane when compared with a corresponding unsubstituted cyclophane; for example, a deformation of 15° was measured in the para-substituted benzene ring of 8methyl[2.2]MPCP. [7] The introduction of a single methyl group at one of the benzene rings of [2.2]cyclophane also increases the strain in the cyclophane. In order to investigate the relationship between strain and the reactivity of variablyfunctionalized cyclophanes we have been interested in the preparation of various polymethyl-substituted [2.2]MPCPs. [8] Recently, syntheses of 8-methyl-and 8-hydroxy[2.2]MPCPs via the AlCl3-MeNO2-catalyzed retro-Friedel-Crafts trans-tertbutylation of the corresponding tert-butyl derivatives in benzene were described by us. [7,9] The research reported herein describes the synthesis and the Lewis acid-induced transannular reactions of 5-tert-butyl-8-methoxy-12,14dimethyl[2.2]MCP 5b under different conditions, and the

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For internal use, please do not delete. Submitted_Manuscript convenient preparation of the title compounds and their treatment with various Lewis acid catalysts. A proposed mechanism for the Lewis acid-induced reaction of [2.2]MCP 5b to the corresponding pyrene derivatives is also presented, as well as a DFT and quantum chemical computational study of the possible conformational structures.

Results and Discussion
In recent years, pyrene and pyrene derivatives have generated much research interest due to their different photophysical properties such as blue emissive property as well as good hole-transporting ability make them promising candidates for different application possibility. [10] As part of our own on-going interest in the synthesis, conformational aspects and studies of Lewis acid-induced transannular reactions of such methylsubstituted cyclophanes to get pyrene derivatives, we conducted a systematic investigation of 8-methoxy-12,14dimethyl[2.2]MCPs 5a-b. [11] The macrocyclic [2.2]MCP frameworks were synthesized via the cyclocondensation reactions of bis(mercaptomethyl)-anisoles 1a-b with 1,5bis(chloromethyl)-2,4-dimethylmethyl-benzene 2 as outlined in Scheme 1. [8,9,12,13] Scheme 1. Synthesis of 9-methoxy-14, 16-dimethyl The 2,11-dithia[3.3]MCPs 3a and 3b were thus obtained in 60% and 70% yields, respectively. Surprisingly, we found only the syn and none of the corresponding anti-conformers of 3a and 3b were obtained, which were assigned by the 1 H NMR chemical shifts of the aromatic, methoxy and methyl protons. 1 H-NMR spectra (CDCl3, 300 MHz) of 3a and 3b each exhibited singlets in the low field region at δ 3.73 and 3.70 ppm, respectively, for the methoxy protons, which are consistent for syn isomers. [14] The aromatic protons,in the region of δ 6.57-6.97 ppm (Table 1) for 3a and 3b can clearly be seen to be shielded by the adjacent rings, a consequence of the face-to-face benzene-benzene ring interactions, indicative of syn-conformers. [15] The tert-butyl protons were also observed at a higher field, at δ 1.08 ppm, for compound 3b which is also Scheme 2. Synthesis of 8-methoxy-12,14-dimethyl[2.2]MCPs 5a-b.
supportive for the syn-conformer. Oxidation of syn-3a and 3b with m-chloroperbenzoic acid in CHCl3 afforded the corresponding bis(sulfone)s syn-4a-4b in 60% and 71% yields, respectively (Scheme 1). Their structures were confirmed by spectral analysis and mass data. Their syn conformations were assigned by 1 H-NMR as before deduced for 3a-b ( Table 1). Pyrolyses of bis(sulfone)s syn-4a and 4b under reduced pressure (1 torr) at 465°C were conducted using the previously reported method [12a,14] to afford exclusively 5a and 5b in 55% and 60% yields, respectively (Scheme 2). 1 H-NMR spectra (CDCl3, 300 MHz) of 5a and 5b exhibit slightly low-field shielded singlets at  3.01 and 3.00 ppm respectively, for their methoxy protons at the 8-position, indicating formation of the respective anti-conformers (see Fig. 1). The internal aromatic protons at the 16-positions were now shifted to the high field region and were observed at δ 3.98 and 3.90 ppm respectively, indicating that syn to anti isomerization occurred. The tert-butyl protons of 5b were also shifted to low field at δ 1.35 ppm compared with the corresponding signals for syn-3b and syn-4b (Table 1) indicating that in each compound, the two benzene rings are opposite to each other with the methoxy groups being shielded by the benzene rings. Thus, it appears that the anti-conformers 5a-b are more stable than the synconformers in this [2.2]MCP system.

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For internal use, please do not delete. Submitted_Manuscript Single crystal of 5b (CCDC 1945511) was grown by diffusing hexane into CH2Cl2 at room temperature, and the structures were determined by X-ray crystallography. The crystal structure was found to belong to the monoclinic crystal system with space group P2/1 (Table S1) and it adopts an anticonformation as predicted from the 1 H-NMR spectrum (CDCl3, 300 MHz) (Figure 2). The mean distance between the mean geometric centres of the benzene rings of 5b is equal to 3.99 Å, as shown in Figure 3.

Computational Details
Computational studies were conducted to explore the conformational properties of the conformers of 3-5. All computations were carried out with the Gaussian 09.e01 package. [16] The 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), [16] exchange-correlation with the 6-31G(d) basis set. The individual geometry-optimized structures and their energies are summarized in Figure 4 and Table 2. The energies of the less energetically-favoured conformers for each compound are presented as ΔE values relative to the most energetically-favoured conformer for that compound. The resulting calculations suggest that the relative stabilities of the syn-chair-chair shaped structures are the most energetically favoured among the various conformational isomers of compounds 3-4 in the following order: syn-chair-chair> synchair-boat> syn-boat-boat. The anti conformers of 3a and 3b are relatively more stable than their syn-boat-boat conformers. Similarly, the anti conformers of 4a and 4b are relatively more stable than their chair-boat and boat-boat conformers. For 5a and 5b the anti conformers are relatively more stable than their syn-boat-boat conformers which are consistent with the experimental results.
The HOMO and LUMO of conformers 3-5 were also calculated, and are shown in Fig. S1. They reveal that the HOMOs show purely π character and are delocalized over the aryl rings. The relative energies (E kJmol -1 ), HOMO-LUMO energies (Eg; eV) and HOMO-LUMO energy gaps (E; eV) of the conformers calculated at the B3LYP/6-31G(d) levels of theory are listed in the Supporting Information). The HOMO-LUMO energy gaps of all conformers are relatively large (between 5.111 eV to 5.553 eV) thus confirming the relatively high chemical stability and low chemical reactivity of the respective conformers. [17,18]

E) = E(chair-chair)-E(chair-chair); E(chair-chair)-E(chair-boat) and E(boat-boat)-E(chair-chair).
It is presumed that these products were formed via a proposed iodine-aryl σ-complex intermediate B as shown in Scheme 4, and by analogy with the mechanisms proposed previously [7,11] for similar transannular cyclizations with other [2.2]MCPs. Here, iodonium ion attacks the ipso-position of 5b to afford B, which produces 6b via C and D and elimination of I + and MeOH from D. Treatment of 5b with TiCl4 in DCM afforded the transannular cyclization product 6b and the corresponding pyrene derivative 7b within 1.5 h in 51% and 27% yields along with unreacted 5b in 12% yield. Similar treatment of 5b at 50 °C in benzene for 3 h led to only transanunular cyclization reaction to afford 6b in 81% yield.

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For internal use, please do not delete. Submitted_Manuscript Scheme 3. Treatment of 5a and 5b with iodine and Lewis acids in benzene.
By contrast, treatment of 5b with AlCl3-MeNO2 at 50 °C in benzene for 3 h afforded 6b in 87% yield along with only very small amounts of 5b and 7b.
A mechanism for the formation of 6b from the Lewis acidcatalyzed reactions can only be conjectured upon, as we have previously rationalized [11] and summarized in Scheme 5. Thus, protonation (or, as above, Lewis-acid complexation) at the ortho (or para) position of the methoxy-containing benzene ring of 5 could result in the formation of the stabilized cationic intermediates E, F, G and H via stepwise rearrangement and intramolecular cyclization. An alternative mechanism via a stepwise deprotonation-methoxy group elimination to form methanol (or methoxy-Lewis acid complex) followed by a methyl cation-Lewis acid complex could also potentially lead to the formation of 6b and intramolecular cyclization (Scheme 5). [11] Dehydrogenation of 6a and 6b with DDQ in benzene afforded the corresponding pyrenes 7a and 7b respectively, in good yields.
No trans-tert-butylation of 7b to form 7a occurred under the conditions of AlCl3-MeNO2 at 50°C in benzene. Only recovery of the starting compound 7b was observed under the conditions used. However, a similar reaction of 6b (AlCl3-MeNO2 at 50°C) led to the effective removal of the tert-butyl group to give 7a together with tert-butylbenzene.
The present findings suggest that the reaction pathway bb6a7a could be exploited for the preparation of pyrene derivatives possessing alkyl groups in a variety of positions.

Conclusion
Using the sulfur extrusion method, anti-8-methoxy[2.2]MCPs 5a and 5b were synthesized from syn-dithia-9methoxy[3.3]MCPs 3a and 3b via syn-[3.3]MCP-2,2,11,11tetraoxide 4a and 4b. Lewis acid-catalyzed reactions of 5b led to transannular cyclization and de-tert-butylation reactions to form considerably less strained pyrene derivatives in good yields. These findings strongly suggest that the 8-methoxy group plays an important role in the transannular cyclization reactions and that the pathways observed in this study could afford alternative routes to new pyrene derivatives. DFT geometry optimized calculations suggest that the relative stability of the syn-chair-chair shaped structures are most favored energetically among the various conformational isomers of the [3.3]MCPs precursor compounds 3-4 in the following order: syn-chair-chair> syn-chair-boat> syn-boatboat.