Carboxylic acids, silyl-substituted, acidity

The cationic pathway allows the conversion of carboxylic acids into ethers, acetals or amides. From a-aminoacids versatile chiral building blocks are accessible. The eliminative decarboxylation of vicinal diacids or P-silyl carboxylic acids, combined with cycloaddition reactions, allows the efficient construction of cyclobutenes or cyclohexadienes. The induction of cationic rearrangements or fragmentations is a potent way to specifically substituted cyclopentanoids and ring extensions by one-or four carbons. In view of these favorable qualities of Kolbe electrolysis, numerous useful applications of this old reaction can be expected in the future. 

Whereas cycHzation of the cu-keto-co -hydroxyamide 1466 in boihng toluene or xylene in the presence of camphorsulfonic acid (CSA) results in decomposition of the starting material 1466, heating of 1466 with excess TMSOTf 20 and N-methyl-morphoHne in 1,2-dichloroethane affords 46% of the desired cycHzation product 1467 [30] (Scheme 9.16). The close relationship of product 1467 to d -oxazolines suggests that reaction of carboxylic acids 11 with free (or C-substituted) ethanola-mines 1468 and HMDS 2/TCS 14 might lead analogously, via the silylated intermediates 1469, to d -oxazolines 1470 and HMDSO 7. As demonstrated in the somewhat related cyclization of 1466 to 1467, combination of TMSOTf 20 with N-... 

The ruthenium carbene catalysts 1 developed by Grubbs are distinguished by an exceptional tolerance towards polar functional groups [3]. Although generalizations are difficult and further experimental data are necessary in order to obtain a fully comprehensive picture, some trends may be deduced from the literature reports. Thus, many examples indicate that ethers, silyl ethers, acetals, esters, amides, carbamates, sulfonamides, silanes and various heterocyclic entities do not disturb. Moreover, ketones and even aldehyde functions are compatible, in contrast to reactions catalyzed by the molybdenum alkylidene complex 24 which is known to react with these groups under certain conditions [26]. Even unprotected alcohols and free carboxylic acids seem to be tolerated by 1. It should also be emphasized that the sensitivity of 1 toward the substitution pattern of alkenes outlined above usually leaves pre-existing di-, tri- and tetrasubstituted double bonds in the substrates unaffected. A nice example that illustrates many of these features is the clean dimerization of FK-506 45 to compound 46 reported by Schreiber et al. (Scheme 12) [27]. 

Amidation of W-BOC-tetrahydro-l,2-oxazine-6-carboxylic acid 47 with free oxanipecotic acid afforded amide 48 <2003TL3447>. The 3-methyl-substituted 1,2-oxazine Woxide 280 can be selectively transformed into 2-silyloxy-1,2-oxazines 281, upon treatment with silylating reagents (ClSiMe3). Now, the synthetic utility of 2-silyloxy-l,2-oxazine 281 is extended and it can be rearranged into 3-silyloxymethyl-l,2-oxazine 282 and can further react with morpholine to produce 3-morpholinomethyl-l,2-oxazine 283 which exists in a tautomeric equilibrium with the corresponding open-chain oxime <2003JOC9477>. 

The carboxyl group reacts relatively easily even with mild silylating agents, so silyla-tion is often used as a derivatization reaction for carboxylic acids. The advantage of these derivatives applies particularly to substituted acids, which are almost always involved when the analysis of biochemically important acids is concerned. The usually necessary two-step preparation of the derivatives may be obviated the disadvantages are the sensitivity of the derivatives towards moisture and sometimes their low stability. 

Alternative reaction pathways exploring different synthetic possibilities have been studied. For instance, electron-rich dihydroazines also react with isocyanides in the presence of an electrophile, generating reactive iminium species that can then be trapped by the isocyanide. In this case, coordination of the electrophile with the isocyanide must be kinetically bypassed or reversible, to enable productive processes. Examples of this chemistry include the hydro-, halo- and seleno-carba-moylation of the DHPs 270, as well as analogous reactions of cyclic enol ethers (Scheme 42a) [223, 224]. p-Toluenesulfonic acid (as proton source), bromine and phenylselenyl chloride have reacted as electrophilic inputs, with DHPs and isocyanides to prepare the corresponding a-carbamoyl-(3-substituted tetrahydro-pyridines 272-274 (Scheme 42b). Wanner has recently, implemented a related and useful process that exploits M-silyl DHPs (275) to promote interesting MCRs. These substrates are reacted with a carboxylic acid and an isocyanide in an Ugi-Reissert-type reaction, that forms the polysubstituted tetrahydropyridines 276 with good diasteroselectivity (Scheme 42c) [225]. The mechanism involves initial protiodesilylation to form the dihydropyridinum salt S, which is then attacked by the isocyanide, en route to the final adducts. 

Single electron oxidation of the non-activated carbonyl group, e.g. in aliphatic or aromatic aldehydes, ketones and carboxylic acid derivatives, is, on the other hand, much less feasible and only a handful of methods and synthetic applications are known. Useful methods for synthetic applications are chemical modifications to lower the oxidation potentials by peripheral donor substitution and a-silylation, or redox umpolung via oxidation of the corresponding carbonyl enols or enol ethers. 

The efficiency and specificity of the fragmentation of 3-silyl-substituted derivatives have great value in the design of new protecting groups — a subject treated in greater detail in part 3 of this volume. Carboxylic acids, for example, are easily protected as their 2-(trimethylsilyl)ethyl esters, which are about as stable as ethyl esters under most reaction conditions. However, on treatment with TBAF they frag-... 

The linker was prepared starting from serine benzyl ester 68 according to Scheme 30. First, the hydroxyl function was protected as a silyl ether. The amino group was then reacted with phosgene to allow for further reaction with a substituted phenol (the educt). Finally, the benzyl ester was subjected to hydrogenolysis yielding unit 69, with the latter bearing a carboxylic acid function for attachment to the solid support to yield 66 ready for use in combinatorial synthesis. 

Another route to amino substitution is the exchange of alkoxy or siloxy groups, which arc accessible by Oalkylation, e.g. by a Mitsunobu reaction with methanol,331 or O-silylation of hydroxy or oxo functions.83 Thus, piperazine reacts with 2-alkoxy-8-ethyl-5-oxo-5,8-dihy-dropyrido[2,3-rf]pyrimidine-6-carboxylic acids, e.g. 8,335,336 or with 8-ethyl-2,5-dioxo-l,2,5,8-tetrahydropyrido[2,3-c/]pyrimidine-6-carboxylic acid (9), after silylation by hexamcthyldisila-zane.337 338... 

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