Macrocyclic alkylation

Diarsenaaza-crowns, 494 Diarsenic-containing macrocycles, 493, 494 Diaza-crown macrocycles alkyl-substituted. 249, 250. 256, 259, 260, 262, 263... 

Nickel-allyl complexes prepared from Ni(CO)4 and allyl bromides are useful for the ole-fination of alkyl bromides and iodides (E.J. Corey, 1967 B A.P. Kozikowski, 1976). The reaction has also been extended to the synthesis of macrocycles (E.J. Corey, 1967 C, 1972A). 

Various organotin reagents react with acyl and aroyl halides under mild conditions without decarbonylation to give carbonyl compounds[390,39l]. Alkyl- or alkenyltin reagents react with acyl and aroyl chlorides to give ketones[548.733,734]. One example is the preparation of the a,/3-dnsaturated 7-keto esters 860 and 861, carried out under a CO atmosphere[735]. The reaction has been applied intramolecularly to the synthesis of the macrocyclic keto... 

The original cyclooligomerization noted above was conducted using alkyl aluminum, zinc and magnesium compounds ". Both open-chained and cyclic polymers were obtained in addition to dioxane. The principal macrocyclic component of the mixture was apparently 12-crown-4 (EO-4) which was said to be valuable as a high boiling neutral solvent... . " The reaction is shown below in Eq. (1.2). 

Although the first all-sulfur macrocycles were prepared many years ago " the first systematic study of such compounds was initiated by Busch and his coworkers , who were interested in the cation binding properties of such ligands. A sequential synthesis was utilized to produce 1,4,8,11-tetrathiacyclotetradecane [tetrathia-14-crown-4 (70)] . In the first step, 1,3-propanedithiol is metallated using sodium and alkylated with 2-chloroethanol. The diol was then treated with thiourea to form the dimercapto-dithioether compound 9. The latter was once again metallated with sodium and allowed to react with 1,3-dibromopropane. The yield of 70 in the ring closure step, conducted at high dilution in absolute ethanol, was 7.5% after recrystallization. The entire sequence is illustrated in Eq. (6.8) . ... 

Kyba and eoworkers prepared the similar, but not identical compound, 26, using quite a different approach. In this synthesis, pentaphenylcyclopentaphosphine (22) is converted into benzotriphosphole (23) by reduction with potassium metal in THF, followed by treatment with o "t/20-dichlorobenzene. Lithium aluminum hydride reduction of 23 affords l,2-i>/s(phenylphosphino)benzene, 24. The secondary phosphine may be deprotonated with n-butyllithium and alkylated with 3-chlorobromopropane. The twoarmed bis-phosphine (25) which results may be treated with the dianion of 24 at high dilution to yield macrocycle 26. The overall yield of 26 is about 4%. The synthetic approach is illustrated in Eq. (6.16), below. 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

The Ciamician-Dennstedt reaction has been used to prepare macrocycles. Reaction of 2,3-alkyl linked indole derivatives 10, 11, 13, and 15 with phenyl(trichloromethyl)-... 

Macrocyclic ligands such as crown ethers have been widely used for metal ion extraction, the basis for metal ion selectivity being the structure and cavity size of the crown ether. The hydrophobicity of the ligand can be adjusted by attachment of alkyl or aromatic ligands to the crown. Impressive results have been obtained with dicyclohexano-18-crown-6 as an extractant for Sr in [RMIM][(CF3S02)2N] IL/aque-... 

The synthesis of homoporphyrins in which one methine bridge of the parent porphyrin is extended to a two-carbon bridge is one of the earliest and simplest examples of an expanded porphyrin.3a b>4 The synthesis of homoporphyrin 4 is based on the ability of N-alkylated porphyrin 1 to undergo nickel-induced rearrangement to form an expanded macrocycle 2. De-metalation of 2 by means of concentrated hydrochloric acid yields the cyclically conjugated [20]porphyrin(2.1.1.1) 4 and a macrocyclic side product 3 in which the cyclic conjugation is interrupted. 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

By reaction of 2-alkyl-4,6-dichloro-l,3,5-trimethylborazines (alkyl = methyl, ethyl, i-propyl) with bis(trimethylsilyl)amine the tetrameric borazine ring systems 4-6 are produced (Fig. 2) they can be purified by several successive vacuum sublimations (yields 4-60%). If the borazines carry n-propyl and tert-butyl groups in the 2-position or if methylbis(trimethylsilyl)amine is used to bridge the borazine molecules, the macrocyclic ring formation is inhibited [17, 18]. 

Condensation of dicesium 2-thioxo-l,3-dithiole-4,5-diselenolate with fo/s-alkylating polythioethers under high dilution conditions afforded the TTF-containing macrocycles possessing soft donor sites and 12-, 15-, and 18-membered rings <%JCS(P1)1995>. 

Alkylation of cyanohydrin acetonide 79 with the iodide 78 proceeded smoothly to give pentaacetonide 80 in 70% yield (Scheme 10). This represents the entire polyol framework of roflamycoin. An eight-step sequence involving installation of the polyene, macrocyclization via Horner-Emmons reaction, and protecting group machinations, completed the first total synthesis of roflamycoin. 

A useful method to synthesize ten and fourteen-membered ring imides 346 involved an initial condensation of macrocyclic -ketoestes 343 with alkyl or aryl isocyanates and carbodiimides, respectively, in the presence of a base [68]. After a nucleophilic attack of the enolate on the isocyanate C, the resultant amide N anion 344 induced a ring closure by addition to the keto group. Then, the intermediately formed four-membered ring 345 underwent a fragmentation... 

Cyclization of substituted phenylacetylene sequences afforded functionalized macrocycles that were amenable to subsequent manipulation. For example, transesterification of 42 with octanol in the presence of 18-crown-6 ether and potassium carbonate gave the corresponding ester in 85% yield (Scheme 13). The ester functionalities could be reduced by DIBALH to give the hydroxymethyl-substituted macrocycle (43) in 61 % yield. The low yield of this particular transformation is attributed to mechanical losses during purification, due to the highly polar nature of the product. Macrocycle 43 could then be treated with alkyl bromides to give a group of benzyl ether derivatized PAMs. 

Analysis of DSC experiments on various alkyl-substituted trimers gave even more disappointing results. Although more thermally resilient, these macrocycles polymerized with very broad exotherms. For the hexyl-substituted trimer, melting occurred around 150 °C, while polymerization extended from ca. 170 to 230°C. This pattern was thought to be indicative of a random polymerization process. Overall, polymerization of trimeric macrocycles occurred at sufficiently high temperatures that the resultant materials were intractable brown tars. 

Many polyazamacrocycles have been alkylated with chloroacetic acid leading to compounds which contain both amine and carboxylic acid functions, e.g. [63] (Stetter et al., 1981). These compounds are similar to EDTA (ethylenediamine tetraacetate). Although the ring size of this class of macrocycles and the number of N—CH2—COOH groups has been modified... 

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