Basic Chain Analogues

Cyclic basic-chain analogues essentially having (a) Imidazoline,... 

A comparison between concave pyridines [13] monomacrocychc compounds [14] and [15] and open-chain analogues [16] shows a macrocyclic effect. The open-chain analogues [16] possess very small basicities [(log K)re = —1.3 to —1.6]. In the monomacrocychc systems, those which contain ether oxygens, [14] and [15b], had larger (log A)rei values. 

A variety of concave pyridines 3 (Table 1) and open-chain analogues have been tested in the addition of ethanol to diphenylketene (59a). Pseudo-first-order rate constants in dichloromethane have been determined photometrically at 25 °C by recording the disappearance of the ketene absorption [47]. In comparison to the uncatalyzed addition of ethanol to the ketene 59a, accelerations of 3 to 25(X) were found under the reaction conditions chosen. Two factors determine the effectiveness of a catalyst basicity and sterical shielding. Using a Bronsted plot, these two influences could be separated from one another. Figure 4 shows a Bronsted plot for some selected concave pyridines 3 and pyridine itself (50). 

The basicities of saturated heterocycles are similar to those of analogous open chain systems, with the exception of three-membered heterocycles, in which the basicity is markedly reduced. Table 1 gives pvalues for the equilibria between free and monoprotonated heterocycles. As the ring size increases, the protonated species become more stable and the pKa values approach those of the open chain analogues. Increasing basicity (thiirane < oxirane < aziridine) prevails in gas phase proton affinities (Table 2) (80JA5151). 

There are, however, two exceptions to this rule, (i) Amines with highly branched alkyl substitutents are significantly less active than their straight chain analogues, (ii) Pyridine (pl a 5.2) has roughly the same initiating power as the far more basic aliphatic amines. These apparent anomalies are evident in both formaldehyde and vinyl polymerizations. 

The synthesis of (Z)-2-methoxy-5-hexadecenoic acid (10) was done in a similar fashion, but it first required the preparation of (Z)-4-pentadecenal. In this case, the aldehyde was made starting with commercially available 1-dodecyne that was coupled with 2-(2-bromoethyl)-l,3-dioxolane and n-BuLi in tetrahydrofuran-hexamethylphosphoramide, resulting in the expected 2-(3-tetradecyne)-1,3-dioxolane, Fig. (13). Subsequent catalytic hydrogenation using Lindlar s catalyst afforded the expected 2-(3-tetradecenyl)-l,3-dioxolane. The dioxolane was removed with 5% HC1 in acetone-water (1 1), and the equilibrium favored (Z)-4-pentadecenal. Addition of trimethylsilyl cyanide to (Z)-4-pentadecenal under triethylamine catalysis as described by Mukaiyama for other shorter-chain analogues [36] resulted in 2-trimethylsilyloxy-5-hexadecenonitrile. Under basic conditions the... 

Macrocyclic ligands and their open-chain analogues have added a new dimension to the coordination chemistry of lanthanide ions. In particular, they allowed the study of high and unusual coordination numbers, e.g. 11-coordination. Basic thermodynamic data are still needed to get a better understanding of the complexation process and of both macrocyclic and macrobicyclic effects. Moreover, kinetic data on ligand exchange remain scarce and studies in this field are certainly desirable. 

The four-step synthesis involves an aromatic nucleophihc substitution, the formation of an azo compound by a reduction reaction in the presence of zinc powder under basic conditions, and the reduction of this compound into a hy-drazo analogue. The diamine monomer is then obtained by a rearrangement in acidic conditions. However, the overall yields of these syntheses remain rather low (respectively 39.5 and 30% for 2,2 - and 3,3 -isomers). Watanabe et al. [86] report a much longer ahphatic chain analogue (n = 10) by a similar procedure. 

Modification of the basic side-chain of metoclopramide has been the subject of numerous investigations. Earlier work led to the synthesis of YM 09151-2 (15a) [8], clebopride (15b) [9], dazopride (15c) [10] and cisapride (15d) [11]. Modification of the basic side-chain and aromatic ring substitution led to the synthesis of alizapride (4a) [5], sulpiride (16a) [ 12] and cinitapride (16b) [13]. Although a number of analogues have found clinical use for various indications,... 

Only a few important representatives of the non-proteinogenic amino acids are mentioned here. The basic amino acid ornithine is an analogue of lysine with a shortened side chain. Transfer of a carbamoyl residue to ornithine yields citrulline. Both of these amino acids are intermediates in the urea cycle (see p.l82). Dopa (an acronym of 3,4-dihydroxy-phenylalanine) is synthesized by hydroxyla-tion of tyrosine. It is an intermediate in the biosynthesis of catecholamines (see p.352) and of melanin. It is in clinical use in the treatment of Parkinson s disease. Selenocys-teine, a cysteine analogue, occurs as a component of a few proteins—e.g., in the enzyme glutathione peroxidase (see p.284). 

Finally, one example of trityl salt analogues in the phase-transfer catalysis is presented. The highly stable triazatriangulenium cations 62 [161, 162] were jnst recently introduced to the phase-transfer chemistry [163], Persistent to strongly basic and nncleophilic conditions, these salts revealed efficient catalytic activity in addition reactions (Scheme 64). Modification of the alkyl side chains on nitrogen allowed matching the fair hydro/lipophilicity with the optimised conditions in the alkylation, epoxidation, aziridination and cyclopropanation reactions. The results are comparable to those of tetrabutylammonium salts and in some cases showed even a better outcome. 

This intermediate, like 6-APA, incorporates a primary amine that can be coupled with a host of side chains. The presence of an additional reactive function, the allylic acetate at the 3 position, provides an additional center that can be modified. The observation that both types of modifications provided unproved antibiotics has resulted in the synthesis of hundreds of analogues. The very few examples discussed below barely scratch the surface in this field. One of the earliest examples of a doubly derivatized 7-ACA derivative, cephalothin (19-1), is stUl widely used as an antibiotic. Acylation of (18-4) with 2-thiophenylacetyl chloride gives the corresponding amide (19-2). Heating that product with pyridine leads to the displacement of the allyl acetate by the basic nitrogen. The resulting product, cephalothin (19-3), is isolated as the internal betaine [23]. 

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