Acid-sensitive substrates, hydrogenation

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

The decomposition of acid-sensitive substrates during Swern oxidations can also be explained by the presence of adventitious hydrogen chloride. This can be avoided by the use of freshly distilled oxalyl chloride and carefully dried DMSO.174... 

Improved selectivity may be obtained with acid-sensitive substrates due to avoidance of accumulation of hydrogen halide, and in the case of iodination the reverse reaction can be suppressed. 

Aromatic iodides (3,287). The definitive paper on the synthesis of aromatic iodides by the reaction of arylthallium dilrifluoroacetates with potassium iodide has been published. Four procedures have been developed. I) Thallalion is carried out as usual and then an aqueous solution of potassium iodide is added directly. 2) The intermediate arylthallium ditrifluoroacctatc is isolated and then treated with potassium iodide. 3) For acid-sensitive. substrates solid TTFA in acetonitrile is used for thallalion. 4)These methods are unsuccessful with highly reactive compounds such as naphthalene and diphenyl. In such cases molecular iodine is used as the electrophilic reagent and TTFA is used as oxidant for the hydrogen iodide formed in the reaction. 

Addition of H2 to acetylenes is easy and can be directed to either olefin group or alkane according to the choice of catalyst and conditions. A triple bond is hydrogenated to the alkane in nearly quantitative yield over Pd-on-carbon or over Pd—Ba sulfate for acid sensitive substrates. ... 

Although phosphinite- and NHC-based iridium catalysts show very similar enantiose-lectivities in the hydrogenation of various olefins, replacement of the phosphinite group by an A-heterocyclic carbene (NHC) unit results in particularly effective catalysts which are much better suited for the hydrogenation of acid-sensitive substrates beeause of the lower acidity of iridium hydride intermediates produced. The new NHC-pyridine ligands are also likely to prove useful for other applications in asymmetric catalysis." ... 

Asymmetric hydrogenation of vinyl ether alcohols proceeded in better selectivity than the ester counterparts, but acid sensitivity was observed for 66a-d, and a stoichiometric equivalent of potassium carbonate relative to the substrate was... 

Aminothiazolines are usually prepared by the acid catalysed cyclization of AT-(2-hydroxyethyl)thioureas or the cyclization of the hydrogen sulfate of thioureas in aqueous basic conditions. These methods give low yields of 2-aminothiazolines and are not suitable for acid sensitive or racemization prone substrates. Mitsunobu reaction of thioureas such as 33 afforded 2-methylaminothiazolines 34 in good to excellent yields <99TL3125>. 

A sequence of reactions that was recently reported by Hanessian and Alpegiani nicely illustrates how the allylstannane method is useful for functionalization of complex, sensitive substrates and, more generally, how stereochemistry can be controlled in radical addition reactions (Scheme 40).138 Dibromo- 3-lac-tam (25) can be monoallylated with a slight excess of allyltributylstannane and then reduced with tributyltin hydride to provide 3-allylated (3-lactam (26) (the acid salt of which shows some activity as a 3-lactamase inhibitor). Stereochemistry is fixed in the reduction step hydrogen is delivered to the less-hindered face of the radical. Alternatively, monodebromination, followed by allylation, now delivers the allyl group from the less-hindered face to provide stereoisomer (27). Finally, allylation of (25) with excess allylstannane produces the diallylated product (not shown). 

In summary, peracetic acid in aqueous solution is an efficient reagent for the epoxidation of a variety of substrates, however, it should be used relatively quickly after its preparation. Sensitive substrates like isoamylene also require a buffer such as sodium hydrogen carbonate to affect high yield of the epoxide. Solvent extraction of an appropriate source of a peracid can lead to organic solutions of the oxidation species. Such methods have been available for many years,43 however, very few are amenable to more than a small scale operation. 

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