Syntheses of 18-Crown

The fourth of Pedersen s general methods is expressed as method Y. In this approach, a single unit may be both nucleophile and electrophile and react with the corresponding portions of its counterpart to yield a macrocycle. This is illustrated in Eq. (3.6). Note that there are really two possibilities here. The first of these is that two units will react as illustrated, but the other possibility is that the single unit will cyelize to afford a crown of half the size. It is precisely this approach which Pedersen used in the first synthesis of 18-crown-6 (see Sect. 3.2). 

These four methods suggested by Pedersen serve as a useful starting point for the eonsideration of other approaches and should eertainly not be considered an overview of existing methodology. Nevertheless, this work was pioneering and a good deal of what follows is based to a greater or lesser extent upon it. 

Over the years, 18-crown-6 has probably been utilized in more applications than any other erown with the possible exception of dibenzo-18-crown-6. There are several reasons for this. First, simple syntheses of 18-crown-6 have been available for a long time and the molecule may be prepared from very inexpensive starting materials. Equally important, however, is the fact that 18-crown-6 is a very strong binder for a number of alkali metals, especially sodium and potassium cations. 

The first synthesis of 18-crown-6 was reported by Pedersen in his first full paper on erowns . The method used was potassium r-butoxide catalyzed cyclization of hexa-ethlyene glycol monochloride in 1,2-dimethox ye thane, as shown in Eq. (3.7), below. Unfortunately, the yield by this approach was only 1.8%.  

At the same time, Dale and Kristiansen reported a successful synthesis of 18-crown-6 from the diol and ditosylate just as shown in Eq. (3.2), but using benzene as solvent. They obtained the product as its potassium tosylate complex (mp 164°) in 33% yield. The free macrocycle was liberated by chromatography over a column of alumina, eluting with a benzene-cliloroform mixture. Dale and Kristiansen note that the cyclic ether cannot be liberated from its complex by simple heating .  

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In 1976, Johns, Ransom and Reese reported improvements in the previously reported syntheses of 18-crown-6 and 15-crown-5. By using tetraethylene glycol rather than triethylene glycol and the correspondingly shorter dichloride (2.5 equivalents of the latter) in concert with KOH (no water added), they were able to realize a 6% yield improvement in the synthesis of 18-crown-6 over the previously published method . The improvement in the yield of 15-crown-5 was of somewhat greater interest, being 38% compared to Liotta s previous report of 15% . ... 

Improved preparation. Reese et al. have published new, improved syntheses of 18-crown-6 (1) and 15-crown-5 (2), both of which use the readily accessible bis[2-chloroethyl] ether (Aldrich, Eastman) [equations I and II). 

Many of the crown ether syntheses with which we are concerned in this book are one form or another of the Williamson ether synthesis. Although the simplest example of such a reaction would involve an co-haloethylene glycol oligomer which undergoes intramolecular cyclization, it is more common for two new bonds to be formed in crown syntheses. An early example of the formation of a crown by a double-Williamson can be found in Dale s synthesis of 18-crown-6. The rather obvious chemical steps are shown in Eq. (2.1). 

Template contributions. Alkali metal ions have been documented to play a template role in a number of crown syntheses. Thus, for example, the presence of K+ has been shown to promote the formation of 18-crown-6 in syntheses such as [4.2] (Green, 1972) intermediates of type (174) are... 

The reaction of a -halocarboxylic acids with sodium nitrite has been used to synthesize ni-tromethane, nitroethane and nitropropane, although the reaction fails for higher nitroalkanes. " A number of other reactions have been reported which use nitrite anion as a nucleophile, including (1) reaction of alkyl halides with potassium nitrite in the presence of 18-crown-6, (2) reaction of alkyl halides with nitrite anion bound to amberlite resins, (3) synthesis of 2-nitroethanol from the acid-catalyzed ring opening of ethylene oxide with sodium nitrite, and (4) reaction of primary alkyl chlorides with sodium nitrite in the presence of sodium iodide. ... 

Astatination of the diazonium salt of 4-amino-methylene blue led to only 10% yield of 4-astato-methylene blue (VI). Alternatively, 4-astato-methylene blue was rapidly synthesized by heterogeneous nucleophilic isotopic exchange in the presence of 18-crown-6 ether at 80° C, with 4-iodo-methylene blue. The product was separated and identified by TLC yields ranged from 50 to 65% 41). Additionally, 2-astato-8-iodo-methylene blue (VII) has similarly been prepared in 60% yield from 2,8-diiodo-methylene blue 41). 

As noted in Chapter 3, Pedersen synthesized dibenzo-18-crown-6 44 which marked the beginning of inclusion (or host-guest) chemistry as a minor product obtained as a result of the presence of catechol as an impurity in the reaction... 

Chloroalkyl carbonates do not undergo direct nucleophilic substitution with fluorine on heating with potassium fluoride either neat or in solution in the presence of 18-crown-6. They easily fragment to aldehydes and fluoroformates. This reaction has been exploited to synthesize valuable tertiary alkyl fluoroformates and benzyl fluoroformate. fert-Butyl fluoroformate (Boc-F) is a superior reagent for the preparation of Boc-amino acids.51... 

This reaction has been used to make crystalline triphenylmethyl derivatives that have been characterized by X-ray structure determinations,22 and a technique has been developed for the reduction of hydrocarbons by liquid cesium activated by ultrasound irradiation in the presence of ethers such as diglyme.23 The blue solutions obtained when cesium metal is dissolved in THF in the presence of [18]-crown-6 have been used to metallate a series of 1,4- or 1,5-hexadienes. The organocesium compounds have not been isolated but they have been identified by derivatization by carbonation and trimethylsilylation.24 Substituted cyclopentadienyl derivatives of sodium have also been synthesized by this method.25... 

The catalytic influence of 18-crown-6 on the production of fluorobenzene from diphenyliodonium tetrafluoroborate and KF in dichloroethane was documented some years ago [123]. More recently, diaryliodonium salts have been used for direct syntheses of [18F]-fluoroarenes [124,125]. After an initial study in which various counterions were surveyed, this was finally accomplished by the treatment of diaryliodonium triflates and trifluoroacetates with 18F K+-APE 2.2.2 (i.e., the aminopolyether 4,7,13,16,21,24,27-hexaoxa-l,10-diazabicyclo-[8.8.8]hexacosane) or Cs 18F in acetonitrile (Scheme 44). An added feature of these studies is rather extensive confirmation that nucleophiles are preferentially directed to the more deactivated ring of unsymmetrical diaryliodonium ions, unless one of the rings possesses ortho-substituents [125]. 

Chloroformates, carbonyl chlorides and acid chlorides are converted into the corresponding fluorides 1 in excellent yield upon treatment with potassium fluoride in the presence of 18-crown-6 at room temperature. Fluoroformates are also synthesized from chloroformates by fluorination with potassium fluoride in acetylacetone at 60"C under UV irradiation, with potassium fluoride in nitrobenzene,- with potassium fluoride in the absence of a solvent at temperatures in the range 100-250 and with thallium(I) fluoride. 

Compound 13b was synthesized in four steps via key intermediate 52, in which the configuration of the hydroxyl group at the C-3 position of 50 was inverted. Compound 50 was reacted with trifluoromethanesulfonyl anhydride and pyridine to give triflate 51 (96% yield), which was then reacted with KN02 in the presence of 18-Crown-6, followed by post-treatment of the resulting nitrous ester with water to afford key intermediate 52 (80% yield) [55, 56]. Reduction of the azide moiety of 52 by trimethylphosphine or hydrogenation on Pd on carbon, followed by hydrolysis of the ester moieties gave 13b (48% yield). 

Yano and coworkers synthesized the 18-crown-6-thiazolium conjugate 7. It was found that the conjugate accelerated the flavin-dependent oxidative trapping of the enamine produced from pyruvate decarboxylation in the presence of alkali metal cations such as and Na" ", but not Li, indicating the specificity of the particular crown ether for the larger cations. The authors suggested that the pyruvate anion is held by the crown-ether-bound metal ion in the proximity of the thiazolium ion, thereby accelerating the nucleophilic attack. 

Bioactive units can be attached to a polyphosphazene chain by coordination or by covalent linkage. These two methods are considered separately. An attempt has been made to utilize a prototype, water-soluble polyphosphazene as a carrier for Pt antitumor agents . Such species are synthesized by the interaction of [NP(NHCH3)2] with K2[PtCl4] in CHCI3 in the presence of 18-crown-6 ether. 

Miscellaneous Syntheses of Oxirans. Vitamin Ki and a model compound, 2,3-dimethyl-1,4-naphthoquinone, have been oxidized at room temperature by KO2 in the presence of 18-crown-6 in benzene under a stream of O2 to yield (76 R = phytyl) and (76 R = Me) in 16% and 7% yields, respectively. The... 

Perhaps the most efficient stimulus in cyclophane chemistry goes back to the discovery of crown ethers by C. J. Pedersen in 1967 [(1967) J Am Chem Soc 89 7017] being the starting signal for a very promising field of research called Host-Guest or Supramolecular Chemistry. Actually the first crown ether that was synthesized, dibenzo-18-crown-6, was a cyclophane. 

A very interesting development in this area is an application of crown chemistry to the malonic ester synthesis. A one-pot hydrolysis and decarboxylation procedure, using 18-crown-6 and potassium hydroxide in an organic solvent system, has been developed for esters with activating groups (Scheme 52). This procedure, which relies on the ability of 18-crown-6 both to catalyse ester hydrolysis and to facilitate decarboxylation under mild conditions, offers a simplification of what is often the yield-determining part of conventional malonate syntheses. 

While the aforementioned ionophores are microbial metabolites, the crown polyethers, the depicted prototype of which is dicyclohexyl-18-crown-6 (Fig. 2D) are synthetic macrocyclic ethers. The first crown ether synthesized, dibenzo-18-crown-6, is the first multidentate synthetic macrocycle with the ability to form stable complexes with alkali and alkaline earth compounds. The complexing abilities of this crown ether led to the preparation of many others in rapid succession. Different size crown rings have been synthesized containing benzyl, cyclohexyl and naphthyl moieties Optically pure dinaphthyl crown ethers have been used to resolve asymmetric amine salts by enantioselective extraction from an aqueous solution into chloroform... 

The central reaction is, of course, the Williamson ether synthesis. Early reports on the preparation of tartaric acid ethers [11], suggested that the base thallous ethoxide, (TlOEt), was essential to avoid epimerization of the chiral centers. The first syntheses thus utilized this base in dimethyformamide (DMF), and oligo-ethylenglycol diiodides for the preparation of di- and tetra-carboxylate crown ethers [4, 12]. More recently, we found that by strict control of stoichiometry, sodium hydride could be used successfully to displace tosylate without loss of chiral integrity [5]. Scheme 1 shows a recent synthesis of an 18-crown-6 hexaacid from three units of (H-)tartaric acid [13]. This route illustrates all the key features in the syntheses of polycarboxylate crown ethers. 

Oxidation. Huoromethyl /7-tolyl sulfide, which can be oxidized to fluoromethyl /7-tolyl sulfoxide with (V-bromo-succinimide in methanol, is synthesized by the reaction of chloromethyl />-tolyl sulfide with potassium fluoride in the presence of 18-crown-6 (eq 11). Chloromethyl />-tolyl sulfoxide can be S3mthesized by a one-pot operation from methyl />-tolyl sulfide with silver(I) nitrate and sulfuryl chloride via the intermediacy of chloromethyl p-tolyl sulfide (eq 12). ... 

The crown ethers described so far are able to bind simple metal cations and, in the case of 18-crown-6, the ammonium cation. The latter observation led one of Pedersen s fellow Nobel Laureates, Donald Cram, to consider if crown ethers could be used to resolve racemic mixmres of amino acids. None of the crown ethers prepared by Pedersen was chiral however, the Cram group was able to synthesize 18-crown-6 derivatives that incorporated one, two, or three binaphthyl groups. These crown ethers could be separated into their enantiomers and attached to a silica support. The modified silica was subsequently used to separate racemic mixtures of amino acids by chromatography. Early experiments gave separation factors for racemic mixtures of simple amino acid methyl esters in the region of 1.5-3.5. 

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