Carbocation-Based Approaches

As another example of the skills-based approach. Chapter 7, Substitution Reactions, places special emphasis on the skills necessary for drawing all of the mechanistic steps for Simechanistic steps (proton transfers, carbocation rearrangements, etc.). This chapter contains a novel approach that trains students to identify the number of mechanistic steps required in a substitution process. Students are provided with numerous examples and are given ample opportunity to practice drawing mechanisms. 

In 2003, Williams and Mander reported a method designed to access the hetisine alkaloids (Scheme 1.3) [27]. This approach, based upon a previously disclosed strategy by Shimizu et al. [28], relied on arylation of a bridgehead carbon via a carbocation intermediate in the key step. Beginning with (1-keto ester 46, double Mannich reaction provided piperidine 47. Following a straightforward sequence, piperidine 47 was transformed to the pivotal bromide intermediate 48. In the key step, bromide 48 was treated with silver (I) 2,4,6-trinitrobenzenesulfonate in nitro-methane (optimized conditions) to provide 49 as the most advanced intermediate of the study, in 54 % yield. 

It was soon realized that there are problems with this approach.24,25 Log ionization ratios for weak bases that are not primary aromatic amines, while linear in H0, do not give the unit slope required by equation (8). This soon led to many other acidity functions, defined for other types of weak base, HA for amides,24 Hq for tertiary aromatic amines,25 C0 or HR for carbocations,26,27 and so on. In a recent review of addity functions,28 28 different ones were listed... 

The most general method for the synthesis of tetrahydrofurans based upon the IMSC methodology was developed by Overman et al. [53, 54, 94—96] For example, condensation of alcohol 221 with an aldehyde or a ketone in the presence of a Lewis acid leads to the formation of the carbocations 222a,b. The tertiary carboca-tion 222a undergoes a pinacol rearrangement and forms the desired heterocycle 224 (Scheme 13.82). Overman et al. used this approach during the synthesis of the various cladiellin diterpenes, which possess the core skeleton 224 [53]. 

This method cannot be used with tertiary alkyl halides, because the competing elimination reaction predominates. The elimination reaction occurs because the rearward approach that is needed for an S 2 mechanism is impossible due to steric hindrance. An S 1 mechanism is likewise unfavored, because as the 3° carbon attempts to become a carbocation, the hydrogens on the adjacent carbons become acidic. Under these conditions, the alkoxide ion begins to show less nucleophilic character and, correspondingly, more basic character. This basic character leads to an acid-base reaction, which results in the generation of an elimination product (an alkene). 

Another approach to alkene isomerization would be to use a catalyst. Base catalysis is of no use as there are no acidic protons in the alkene. Acid catalysis can work (Chapter 19) if a carbocation is formed by protonation of the alkene. 

Recently, a paper was published in which the acidities of aliphatic carboxylic acids were analysed in terms of a quantum mechanical model. The inductive effect of Taft was shown to be composed of one electrostatic and one polarization term [37]. We will discuss examples of similar approaches based on the hardness and electronegativity as strictly defined concepts of density functional theory in the chapter on amides and peptides, and also discuss the problem of ill-defined terms a bit further in the chapter on carbocations, coming next. 

One of the earliest examples of the synthetic promise of radical reactions for preparing polycyclic products was provided by Corey s y-lactone synthesis. This approach was actually based on a well-known reaction of a-carbonyl radicals, generated by manganese(iii) oxidation of carboxylic acids, with unsaturated substrates. The mechanism of the basic steps shown for the preparation of lactone 418 (Scheme 2.140) involves initial addition of the a-carbonyl radical 419 to the double bond of styrene, followed by oxidation of the radical intermediate 419a to carbocation 419b, and subsequent intramolecular reaction with the carboxyl nucleophile to yield the lactone product. 

Several linkers have been developed that rely on the formation of highly stabilized aromatic carbocations. The most frequently used are the eponymous Sieber amide linker 36 [3] and Barany s 3-XAL linker 6 [4]. Both are based on a 3-methoxyxanthine scaffold, which owing to the highly stabilized nature of the xan-thenium ion can provide primary amides on treatment with 1% TFA in DCM, making them excellent tools for the synthesis of protected peptide carboxamides. The Sieber amide resin has also been used to prepare secondary amides via reductive alkylation of the amino group, acylation of the resultant amine and cleavage with dilute TFA [88]. Brill et al. [67] have effected transamination of trifluoroacety-lated Sieber amide resin in good yield. This approach offers considerable potential for the immobilization of amines on this support. 

The relative strengths of weakly basic solvents are evaluated from the extent of protonation of hexamethylbenzene by trifluoro-methanesulfonic acid (TFMSA) in those solvents or from the effect of added base on the same protonation in solution in trifluoroacetic acid (TFA), the weakest base investigated. The basicity TFA < di-fluoroacetic acid < dichloroacetic acid (DCA) < chloroacetic acid < acetic acid parallels the nucleophilicity. 2-Nitropropane appears to be a significantly stronger base than DC A by the first approach, although in the second type of measurement, the two have essentially equal basicity. The discrepancy is due to an interaction, possible for hydroxylic solvents such as DC A, with the anion of TFMSA. This anion stabilization is a determining factor of carbocationic reactivity in chemical reactions, including solvolysis. A distinction is made between carbocation stability, determined by structure, and persistence (existence at equilibrium, e.g., in superacids), determined by environment, that is, by anion stabilization. 

More promising appears an approach based on the direct measurement of elementary rate constants of 1,2-shifts in carbocations generated under the longlife conditions. The approach embodying the notions of a fundamental role of kinetic characteristics of degenerate rearrangements finds its substantiation in Marcus theory cf. Ref. This theory was initially worked out in application... 

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