High-dilution synthesis

ATad provides direct information on the exothermic effect of the chemical reaction. Therefore it is of special importance for the safety assessment of chemical processes. Typical values range from 10 K for either highly diluted syntheses or for reactions with a very small exothermicity, up to 400 K for highly concentrated or strongly exothermic reactions. Decompositions may even have significantly higher values. 

The cyclization of compound (65) to a 17-membered lactone with a PS-bound 7c-allyl palladium catalyst, shown in Scheme 29, was carried out with 0.7 fi substrate, a concentration 1(X) times higher than in most high dilution syntheses. The competing intermolecular reaction of one polymer-bound disulfonyl carbanion with a second polymer-bound 7r-allyl palladium is severely retarded. 

Kyba EP, Chou S-SP (1981) Phosphino-macrocycles. 8. High-dilution syntheses of 14-membered tetiadentate macrocycles incorporating the diars moiety. J Organomet Chem 46 860-863... 

Scheme 3.16 High-dilution synthesis of diaza[18]crown-6 and thence [2.2.2] and [2.2.1] cryptands. Note the use of acid chloride groups to enhance reaction rate.9...

The synthesis of podand hosts is conceptually relatively straightforward and is generally achieved using conventional synthetic methods such as ether, sulfide or amide bond formation however, the synthesis of macrocycles is a little more challenging and is accomplished by one or both of two general procedures, i.e. high-dilution synthesis and template synthesis. 

Scheme 12.76 High dilution synthesis of P,S-containing cyclophanes 217...

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

Synthesis by high-dilution techniques requires slow admixture of reagents ( 8-24 hrs) or very large volumes of solvents 100 1/mmol). Fast reactions can also be carried out in suitable flow cells (J.L. Dye, 1973). High dilution conditions have been used in the dilactam formation from l,8-diamino-3,6-dioxaoctane and 3,6-dioxaoctanedioyl dichloride in benzene. The amide groups were reduced with lithium aluminum hydride, and a second cyclization with the same dichloride was then carried out. The new bicyclic compound was reduced with diborane. This ligand envelops metal ions completely and is therefore called a cryptand (B. Dietrich, 1969). 

Synthesis of large heterocycles usually involves condensation reactions of two difunctional molecules. Such molecules tend to polymerize. So far two special techniques have been described above to avoid this important side-reaaion , namely high dilution and use of templates. The general procedure to avoid polymerizations in reactions between difunctional molecules is, of course, the application of protecting groups as described in sections 4.1.2 and 2.6. 

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

Synthesis. Iminoboranes, thermodynamically unstable with respect to oligomerization can be isolated under laboratory conditions by making the oligomerization kineticaHy unfavorable. This is faciUtated by bulky substituents, high dilution, and low temperatures. The vacuum gas-phase pyrolysis of (trimethylsilylarnino)(aLkyl)haloboranes has been utilized as an effective method of generating iminoboranes RB=NR as shown in equation 19 for X = F,... 

I E G L E R Macrocyclic synthesis Synthesis ol macrocyclic ketones from dinitnles using high dilution... 

At about the same time, Vogtle and Frensch reported the synthesis of a similar bis-crown based on the papaverine nucleus. This synthesis also was executed in the Williamson fashion using doubly-demethylated papaverine and tetraethylene glycol dichloride. The base, if used, was not specified but it was noted that the high dilution technique was not used. It was presumed that the major product was 10, shown below, but there was also evidence of other components, presumably 11 and 12. 

The synthesis of 1,10-diaza-l 8-crown-6 (9) has been an important problem because this is the key starting material in the synthesis of numerous cryptands (see Chap. 8). Although first synthesized some years ago, the process has recently been patented. Di-azacrown 9 is prepared by a high dilution condensation of 1,8-diamino-3,7-dioxaoctane with ethylene glycol diacetyl chloride. The resulting diamide is then reduced with lithium aluminum hydride to give 9 in 56% overall yield from the open-chained diamine. The synthesis is illustrated In Eq. (4.8), below. 

In the course of experiments directed at the synthesis of open-chained equivalents of macrocyclic polyethers (see Chap. 7), Rasshofer and Vogtle found that 9 or its derivatives were formed rather than the desired compounds . Although the yields obtained by this method are modest, the facts that the reaction is conducted without the use of high dilution and in one-pot recommend it. 

The one-pot synthesis of 9 described above appears to afford only modest yields of azacrowns. One might wonder why any crown at all would be formed under non-high dilution conditions intended to yield only open-chained material. Vogtle suggests that this can be explained in terms of template, steric and entropy effects . These factors are of doubtless significance, but it is interesting to note that in the synthesis of poly-azamacrocycles, Richman and Atkins found that there was no significant template effect observed. The question of the template effect in Ihe syntheses of 9 has recently been addressed by Kulstad and Malmsten They conclude that the formation of 9 is assisted by the presence of alkali metal cations. 

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. 

Although Lehn and his coworkers prepared a large number of cryptands and derived complexes over the years, the synthetic approach to these compounds remained essentially similar for most of them. Details are presented for a number of such compounds in ref. 26. The essential features of these syntheses were use of amide-forming reactions in the absence of templating ions with reliance on a high dilution step to form the second ring. An alternative approach for the synthesis of cryptands was developed by Dye and his coworkers. Their approach involved the use of a flow synthesis to replace the high dilution step. 

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