Cyclophanes 5 metacyclophane

From this important subgroup of cyclophanes [2.2]metacyclophane (5) and its derivatives (including [3.3]precursors for synthetic purposes) as well as some related carbo- and heterophanes have attracted much attention. Syntheses 30), the stereochemistry as well as several reactions and spectra 12) have been reviewed earlier. 

Figure 2.28 The cyclophanes, [2,2] metacyclophane (2.117a) and [2,2]paracyclophane (2.117b), showing the original (Vogtie and Neumann) and lUPAC nomenclatures.

The inherent plane of chirality in the metal carbene-modified cyclophane 45 was also tested in the benzannulation reaction as a source for stereoselectivity [48]. The racemic pentacarbonyl(4-[2.2]metacyclophanyl(methoxy)carbene)-chromium 45 reacts with 3,3-dimethyl-1-butyne to give a single diastereomer of naphthalenophane complex 46 in 50% yield the sterically less demanding 3-hexyne affords a 2 1 mixture of two diastereomers (Scheme 30). These moderate diastereomeric ratios indicate that [2.2]metacyclophanes do not serve as efficient chiral tools in the benzannulation reaction. 

The chemistry of cyclophanes may be traced back to the work of Pellegrin on [2.2]metacyclophane in 1899 (1). Although the first... 

These structural data demonstrate that 12 is a rather less distorted molecule than [2.2]paracyclophane. However, a dramatic effect of the strong cr(Si—Si)—w interaction was observed in UV spectra as shown in Fig. 5. In the UV spectrum of phenylpentamethyldisilane, an intramolecular crfSi—Si)—7T charge-transfer band appears around 231 nm (11a, 12). Octamethyltetrasila[2.2]ortho- (15) and metacyclophane (16) show similar absorptions, but the band splits into two bands at 223 nm (e = 19,100) and 263 nm (e = 22,500) in 12. This type of red shift in the UV spectra occurs only in 12 among other polysilapara-cyclophanes such as 13 and 14. 

The properties of the cyclophanes are best illustrated by the para-cyclophanes. In contrast to the metacyclophanes and metapara-cyclophanes 2>, where aromatic nuclei come into close proximity, there are in paracyclophane molecules two aromatic nuclei pressed one on top... 

Lindner (171) developed his own tt-SCF MO force field that is similar to MMPI in construction. This program was applied to simulate racemization of metacyclophane (48) and hexahelicene (50). In metacyclophane the m-phenylene ring flips readily at room temperature. Two mechanisms can be conceived one operates by way of a high steric energy conformation (48b) the other involves a biradical intermediate (49). The calculated activation energies are 17 and 32 kcal/mol, respectively. The experimental value is 17.7 kcal/mol, in accord with the first mechanism (172). The structures and energies of seven types of cyclophane have been calculated (172). 

Although a number of alkaloids belonging to the simple arylquinolizidine class and the lactonic type had been synthesized, no successful synthesis of cyclophane alkaloids was accomplished until that of lythranidine (94), a unique alkaloid with a 2,6-trans disubstituted piperidine structure, was reported (28, 29). Quinolizidine metacyclophane alkaloids lythrancepines II (95) and III (96) have also been synthesized recently (30, 31). A review on the synthesis of lythranidine (94) is available in Japanese (32). 

Even the distorted boat-like deck in [2.2]metacyclophanes can be constructed by an intramolecular version of the benzannulation. A suitable precursor bears a chromium vinylcarbene and an allcyne moiety linked to a meta-phenylene core by two-atom bridges, as shown for complexes 80. Benzannulation under the typical conditions affords hydro-quinonophanes 81 in fair yields (Scheme 31) [73]. Interestingly, the intramolecular benzannulation approach even tolerates heteroatom bridges, which impose both additional strain and helicity on the cyclophane skeleton [73b]. 

The relation to the larger group of substituted cyclophanes (see Figure 15 in Chapter 2) is noted namely, calix[2]arene is an abbreviated name for 2,2 -dihydroxy-[l,l]-meta, metacyclophane. 

Imidazole-containing [10]metacyclophane 7 was efficiently synthesized from cyclododecanone and the racemic 7 obtained was effectively resolved to a pair of enantiomers by chiral HPLC (on a Daicel OD-H column) [22], The absolute configuration of the first-eluted (-)-isomer was determined to be Sj, by the X-ray crystal structural analysis of (+)-10-camphorsulfonic acid salt of 7, which displayed a negative Cotton effect at the imidazole band. Unfortunately, the CD intensities are not clear as the concentration of the cyclophane is not stated in the report (Fig. 1). 

Although nowadays the term calixarene tends to be used for all [l ]-meta-cyclophanes, this chapter will deal with [l ]-metacyclophanes bearing phenolic OH groups in the intraannular (endo, e.g. calix[ ]arenes) or extraannular (exo, e.g. resorc[4]arenes) position. 

This name, used throughout this article, is justified mainly by its similarity to calixarenes which indicates the cup-like shape (calix) and the aromatic units (arenes) of the macrocycle. In the line with newly created names such as calixpyrroles, calixfuranes, calixindoles, etc. it would be reasonable to distinguish between calixphenols (I) and calixresorcinols (II) or calixpyrogallols etc. and to use calixarenes as the general name for the whole class of [l ]-metacyclophanes (or -cyclophanes). 

Related work in our group led to the synthesis of the cyclophanes 21-23 (Scheme 7) [20]. It was found that 21 adopted the syn conformation exclusively and 23 adopted the anti conformation exclusively. However, cyclophane 22 was observed to exist in a ca. 6 1 antv.syn ratio at equilibrium. The two conformers can be separated by flash chromatography and the return to the equilibrium ratio monitored by H NMR. Noteworthy here is the direct observation of an anti to syn flip of a [2.2]metacyclophane. There have been only two other reports of such anti to syn flips [21], Also noteworthy is the chemical shift of the internal proton of the inner ring of anti-22, which appears at S 3.03. 

The dependence of the yield of cyclization leading to dithia[2.2]cyclophanes as e.g. 88 on the combination of base and solvent was investigated thoroughly by Vdgtle and Meurer [81]. By rising a combination of aUcaU metal hydroxides and ethanol/ben ne (12 1) as solvent under application of dilution conditions, the highest yields of the dithia[2.2]metacyclophane 88 were achieved. The use of alkali metal carbonates in DMF led to somewhat lower yields of 88 (Table 9). In both solvents the appUcation of cesium salts led to the highest yields. 

The application of reaction conditions as optimized in the preparation of the dithia[2.2]phane 88 allowed Meurer and Vogtle [83] to synthesize the first helically chiral dihetera[2.2]metacyclophanes 91 and 92 in 1.9 and 9% yield. It was impossible to isolate these cyclophanes in all the previous attempts where cesium salts had not been applied [84, 85]. 

Similar [2.2]metacyclophanes 74a-k were obtained by pyrolysis as well [39]. The yields of these reactions vary without systematic pattern between 10 and 95%. Several tetrafluoro[2.2]metacyclophanes 76a,c,d and an octafluoro[2.2]meta-cyclophane with a completely fluorinated aromatic moiety 76b were also accessible by sulfone pyrolysis [40]. 

Cyclizations by formation of carbon—selenium bonds represent a modern method with a high synthetic potential in the chemistry of cyclophanes. Selenocyanates such as 16 are accessible usually in excellent yields through the reaction of bromides with KSeCN [27], The reaction with benzylic bromides under reductive conditions using the dilution principle results in good to excellent yields of [3.3]di-selenacyclophanes which can be deselenized photochemically, pyrolytically (without previous oxidation), or by reaction with arynes, Stevens rearrangement and subsequent reaction with Raney nickel. [2.2]Metacyclophane (18), for example, is accessible in 47% total yield by using this sequence of reactions starting with... 

Figure 3.28 Some representative cycLophanes [2.2]paracycLophane (top Left), [3.3.1] para-cycLophane (top right), an azacycLophane (bottom Left), [3.3]metacycLophane (bottom right)...

Metacyclophane synthesis. Parham and Rinehart14 synthesized a new elass of metacyclophanes by reaction of (1) with 2 equiv. of phenyl(triehloromethyl)mercury in boiling benzene the intermediate dichlorocyclopropane (2) suffers spontaneous ring opening to give the cyclophane (3) in 73% yield (pure). 

More than 90 years after the first reported synthesis of [2.2]metacyclophane [1] and nearly 50 years after the synthesis of [2.2]paracyclophane, [2] cyclophane chemistry is still a field of ongoing research. In the beginning, work had been focused on the development of new synthetic methods yielding cyclophanes and ansa-compounds and the investigation of their physical properties. Later, the scope was extended to the incorporation of heterocycles into phanes and the more sophisticated techniques allowed the synthesis of multibridged and multilayered phanes. All this has been extensively reviewed [3]. 

The linkage of two meta-cyclophanes by alkyne groups gave bis-cyclophane 106. Extraction experiments revealed a moderate binding of purine- and pyrimidine by these molecular tweezers [65]. The preferred conformation of [2.2]-metacyclophanes is the azzfz -arrangement [66]. Bodwell et al. [67] showed now that a 13-membered bridge levels the energy of syn- and anfz-conformer of 107. They slowly interconvert in solution at room temperature. 

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