Macrocyclization dialdehydes

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

Quite a number of mixed sulfur-nitrogen macrocycles have been prepared, but these have largely been by the methods outlined in Chaps. 4 and 5 for the respective heteroatoms. An alternative method, involves the formation of a Schiff base, followed by reduction to the fully saturated system, if desired. An interesting example of the Schiff base formation is found in the reaction formulated in (6.12). Dialdehyde 14 is added to ethylenediamine in a solution containing ferrous ions. Although fully characterized, the yield for the reaction is not recorded. To avoid confusion with the original literature, we note the claim that the dialdehyde [14] was readily prepared in good yield by reaction of the disodium salt of 3-thiapentane-l, 5-diol . The latter must be the dithiol rather than the diol. 

A completely different kind of macro cycle, a calix-salen type macrocycle, was obtained in good yield by microwave irradiation of various dialdehydes and diamines [165]. This was the first example of a calix-type synthesis under microwave conditions and without the presence of a metal template. An example of a [3 -1- 3] cyclocondensed macrocycle 265, obtained from a bis aldehyde and a chiral diamine is reported in Scheme 97. 

B. Macrocyclics. Full details have appeared of the synthesis of the bicyclo[6,2,0]decapentaene (152). Benzocyclobutanedione and the bis-ylide (153) gave only acyclic compounds. The dibenzocyclononatetraene (155) has been obtained from the dialdehyde (151) and the bis-ylide (154). 

A large number of concave pyridines 3 have been synthesized starting from pyridine-2,6-dicarbaldehydes 4, heteroatom containing a,o>-diamines 5 and diacyl dichlorides 8 (Scheme 1). In the first macrocyclization, the dialdehyde 4 and the diamine 5 were condensed in the presence of an alkaline earth metal ion to give a complex of a macrocyclic diimine 6 which was then reduced to the macrocyclic diamine 7. The yields of this reaction are excellent ( > 90%) when the size of the metal ion is adjusted to the size of the macrocycle formed. Mg was used for the formation of 15-membered, Ca for 18-membered and Sr for 21-membered rings. The macrocyclic diamines 7 were oils which could be purified in some cases. However, for the synthesis of the concave pyridines 3 the purity of the crude diamines 7 was sufficient. 

The synthetic strategy used for the construction of concave pyridine bislactams 3 (Scheme 1) can also be applied to other concave bases. When instead of a pyridine-2,6-dialdehyde 4, l,10-phenanthroline-2,9-dicarbaldehyde (9) was used in a metal ion template directed synthesis of macrocyclic diimines, after reduction, also macrocyclic 1,10-phenanthroline diamines 10 could be obtained in good yields. Here too, the crude diamines 10 were used in the next reaction step. Bridging of 10 with diacyl dichlorides 8 gave concave 1,10-phenanthroline bislactams 11. Scheme 2 summarizes the synthesis and lists the synthesized bimacrocycles 11 [18]. 

Macrocyclic ketones. This reagent has been used for cycloolefination of acetylenic dialdehydes (Wittig-Horner reaction) as a route to muscone, exaltone, and civetone. A synthesis of the last ketone (3) is formulated (equation 1). 

The reaction of imidazole-4,5-dicarbaldehyde with 2-aminoethylpyridine in the presence of copper(II) chloride has enabled the preparation of a binuclear complex (equation 2).29 A more common class of binuclear complex is based on template reactions of a phenolic dialdehyde with various amines and includes the copper complexes (14)30 31 and (15).32 Reactions of this type can be extended to the synthesis of macrocyclic binuclear complexes such as (16).33,34... 

Template reactions of dicarbonyl compounds and diamines have been extended recently to include the dialdehydes (3O)60>61 and (32)62-63 and a range of new diamines such as (31) and (33).64 Examples are shown in equations (6) and (7). The new diamines have also been used in the template synthesis of macrocyclic complexes based on 2,6-diacetylpyridine.60,65... 

Aminobenzaldehyde structural fragments have been incorporated into diatninodialdehydes, which can act as precursors for macrocyclic complexes. The initial work in this area involved template reactions between dialdehydes and diamines in the presence of hydrated metal(II) acetates in methanol (equation 26).153-155 Benzene-1,2-diamines could also be used in these syntheses. 

Although the metal ions promoted macrocycle formation, in some cases the free macrocycles could be synthesized in non-template conditions of high dilution. The free macrocycles have sometimes been prepared by means of template reactions involving zinc(II) acetate. The dialdehydes (68) were prepared by a sequence of reactions involving a poor initial alkylation step, but a superior approach has been developed (Scheme 26).156-158 Alkylation of isatin compounds can be carried out in high yield and substituted isatins are readily available. 

An early approach to suitable dialdehydes made use of a nucleophilic aromatic substitution process which enabled the synthesis of nitro-substituted complexes to be achieved (Scheme 27)159,160 Yery recently, a similar approach has been used to incorporate pyrimidine rings into macrocyclic complex structures (Scheme 28).161... 

The construction of suitable dialdehydes for macrocycle formation by metal template methods has more recently been extended to include a range of oxamides. In the first case, the simple 2,2 -(oxalyldiimino)bisbenzaldehyde underwent rather sluggish template reactions but yielded extremely stable macrocyclic complexes (Scheme 31).167 168 These products could be sulfonated in oleum, without destruction of the macrocyclic structure. This general synthetic route has been extended to include reactions of diketones and the formation of complexes of macrocyclic ligands such as (70) and (71). Attempts to incorporate a malonamide fragment in place of the oxamide... 

Reinhoudt and co-workers (101-105) have reported a series of Schiff base macrocyclic polyether ligand complexes prepared via barium cation-templated Schiff base condensation of the appropriate polyether dialdehyde with a diamine, in the presence of a transition metal or uranyl acetate, followed by removal of the Ba2+ template cation on subsequent addition of guanidinium sulfate (Scheme 19). The copperdl) and nickeldl) complexes (62) and (63) exhibit reversible redox couples... 

Macrocycles with 2 nitrogen and 3 sulfur donors have been prepared (14) by a template synthesis in which the dialdehyde (XCI) is condensed with primary diamines, e.g., ethylenediamine gives XCII in boiling acetonitrile containing Fe(II) perchlorate. The reaction is typical of template condensation between carbonyl compounds and primary amines. An unusual monanionic macrocyclic ligand was produced (2) when formaldehyde was condensed with the hydrazine (XCIII) instead of a primary amine in the presence of Ni(II) salts, and complexes XCIV have been characterized. 

Fig. 9 DCL of macrocyclic anion receptors (12-16) obtained by reversible imine chemistry between the dialdehyde 9 and diamines 10, 11...

E2 is OCH2CH2OCH2CH2OCH2CH2O). In this case, under dehydrating conditions, the dialdehyde-diammonium rotaxane (Fig. 9c5) regenerate the bis-imine rotaxane (Fig. 9c3). It is thus possible to control the position of the macrocycle by alternating hydrolytic and dehydrating conditions. Moreover, a control through temperature was demonstrated as well. Indeed, under hydrolytic conditions, at 100°C there is more than 95% bis-imine (Fig. 9c3), while at 0°C there is more than 95% dialdehyde-diammonium (Fig. 9c5). 

To have an idea about the values of the molecular diameters, one may note that reaction of dialdehyde 50 where R = CH3 with the diamine 52 produces at 5 mM a [2 + 2] macrocycle (not shown) that has, according to DOSY [60, 61] studies (that provide the hydrodynamic radius of the species) in CDC13, a diameter of 16.4 A, while at 50 mM higher diameter species with a diameter of 80 A are observed. After several weeks even species having a diameter of 200 A have been observed [59]. 

Fig. 15 (a) Formation of a polymer (53 or 55) on reaction of a pyridine-hydrazone-pyridine derived dialdehyde 50 with 1 equiv. of diamine (51 or 52), and its reversible conversion into a macrocycle (54 or 56) in the presence of the appropriate metal ions (b) stylized representation of the polymer/macrocycle reversible switch... 

Other large macrocycles 117 and 118 have also been reported from similar condensations between the poly pyrrole dialdehydes 119 and 120 and substituted phenylenediamines (Schemes 14 and 15) [61]. However, at present, little published information is available for these systems. 

A variety of other poly-furans have been employed in Wittig reactions as either the aldehyde or the ylide component. Condensation of 5,5 -thiodi-2-furaldehyde (176), for instance, with the 2,2 -bifuryl-5,5 -diylbis-(methylenetriphenyl-phospho-nium bromide) (177) under basic conditions, gave the macrocycle 178 as orange crystals in 1.3% yield (Scheme 29) [148]. Two macrocyclic annulenones 182 and 184 were also obtained [149] from the base induced condensation of 181 with the dialdehydes 180 or 183, respectively. Both products are obtained in moderate yields (12-15%) and are highly colored solids (Schemes 30 and 31, respectively). 

With the original reports of the successM synthe of the sapphyrins [26,66,152] and uranyl superphthalocyanine [112, 118, 119], interest in other expanded porphyrin systems, was kindled. The next logical step (after sapphyrin), in the expanding series of all-pyrrole systems, was the pentaphyrin macrocycle 231 which contains five pyrroles and five meso-like methine bridgra. In 1983 Gossauer et al. reported the synthesis of the first prototypical member 231 of this macrocyclic family [158, 182, 183, 185-187]. This first synthesis was achieved by a 2 + 3 MacDonald-type condensation between an oc-firee dipyrromethane 233 and a tripyrrane dialdehyde 236. More recently, the synthesis of pentaphyrin 231 has l n achieve by using a dipyrromethane 5,5 -dicarboxylic acid 235 in place of an a-firee dipyrromethane [21]. Here, as is the case in many of these kind of reactions [21,26,27,66,155], decarboxylation occurs under the reaction conditions to produce the corresponding a-free species 233 in situ. (Scheme 40) [21]. 

The Mibs concept is, of course, not restricted to isocyanide-based MCRs. Wessjohann recently demonstrated that multiple Staudinger reaction is highly effective for the construction of marcocycles [110]. Thus, the reaction of diamine 83, dialdehyde 91 and acylchloride 92 in the presence of triethylamine afforded macrocycle 93 incorporating four p-lactam units in 82% yield. The c/s-stereo-chemistry of all the four-membered rings was established based on the coupling... 

The stretched porphycene 4.142 ([26]-porphyrin-(6.0.6.0)) was also recently reported by Vogel, et al. This macrocycle was prepared in 50% yield via a McMurry-type dimerization of dialdehyde 4.140, followed by a spontaneous dehydrogenation of the presumed non-aromatic intermediate (Scheme 4.3.11). The free-base form of [26]-porphyrin-(6.0.6.0) (4.142a) proved to be rather fluctional in a variety of solvents over the temperature range of 25 to -50 °C. This hindered... 

The synthesis of the novel tetrafuran-containing macrocycle 4.178 was reported in 1992. This macrocycle was prepared by the aldol-type condensation between diketone 4.176 and dialdehyde 4.177 in 20% yield (Scheme 4.5.2). Subjecting this macrocycle to reductive deoxygenation using lithium aluminum hydride and aluminum trichloride afforded the tetraoxaporphyrinogens-(3.0.3.0) 4.179 and 4.180 in combined 35% yield (Scheme 4.5.3). These two isomeric products, formed in 55% and 45% relative abundance, respectively, could not be readily separated. Instead, they were treated together (i.e., as a mixture) with p-chloranil to afford the conjugated tetraoxa[22]porphyrin-(3.0.3.0) species 4.181 in 15% yield (Scheme 4.5.4). 

In 1994 Cava and coworkers reported the synthesis of the tetrathiophene-containing systems 4.183 and 4.184. The first of these was the non-conjugated tetrathiaporphyrinogen-(2.1.2.1) 4.183. This species was isolated in remarkably high yield (78%) from the reductive McMurry coupling of dialdehyde 4.182 (Scheme 4.5.5). Dehydrogenation of this macrocycle was effected by treatment with DDQ, followed by hydrazine. This afforded the neutral aromatic tetrathia[22]porphyrin-(2.1.2.1) systems 4.184 in 82% yield. 

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