Carboxyl acid scavengers

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

Lee and Chang (1978) have compared the ability of linear polyethers, crown ethers, and quaternary ammonium compounds to catalyse oxidations with KMn04 under liquid-liquid and liquid-solid conditions. In the presence of acetic acid as a scavenger for the KOH produced, the products of olefin oxidation were carboxylic acids, diones, diols and ketols. The three different classes of catalysts exhibited about the same activity in liquid-solid systems. 

Following a similar strategy, an ingenious mixed resin bed quench and purification strategy was devised for the Dess-Martin periodinane mediated conversion of alcohols to carbonyls. This hypervalent iodine oxidant was viewed as containing an inherent masked carboxylic acid functionality that was revealed at the end of the reaction (Species (11) Scheme 2.30). Therefore purification was easily achieved by treatment of the reaction mixture with a mixed-resin bed containing both a thiosulfate resin and a polymeric base. The thiosulfate polymer was used to reduce excess hypervalent iodine lodine(V) and (III) oxidation states species to 2-iodoben-zoic acid (11), which was in turn scavenged by the polymeric base [51]. 

This method is easier than the reaction of an alcohol with a carboxylic acid (described in the preceding section) because acid chlorides are more reactive than acids. The reaction forms HCl with either a hydroxide ion or pyridine, aiding in the removal of the HCl. The general reaction is in Figure 12-21 and the reaction using pyridine to scavenge the HCl is in Figure 12-22. 

Oxidation of a,p-enals. Sodium chlorite is superior to other reagents for oxidation of oc,/l-unsaturated aldehydes to the corresponding carboxylic acid, particularly of aldehydes containing an ct-methylene group. In addition, the oxidation is stereospecific. 2-Methyl-2-butene2 was used as the chlorine scavenger. 

Some useful resins that have found their way into quite substantial applications are the carbonate resins. For instance, trimethylammonium bicarbonate resin (8) is used to neutralize carboxylic acids or strong mineral acids formed in situ in specific reactions. An interesting example is the quenching/scavenging of acid bromide reported by Staufer and Kat-zenellenbogen74 during the synthesis of tetra-substituted pyrazoles (40) from immobilized starting materials as seen in Fig. 18. 

The convertible isocyanide also enables transformation of the secondary amide in the Ugi product to a carboxylic acid, ester, or thioester, which is thus amenable to further functionalization. The aforementioned templates are all readily accessible via manufacture in 96-well plates using 96-well plate liquid handlers. The initial condensations are optimal with excess aldehyde (2 equiv.), which can be subsequently removed via a simple scavenging and filtration step with PS-TsNHNH2.18 Several universal resin-bound isocyanides have also been developed to exploit UDC methodology for the generation of the above heterocyclic products. 

Once bearing some substituents, the decrease of polarity of the sucrose derivatives makes them soluble in less-polar solvents, such as acetone or tert-butanol, in which some lipases are able to catalyze esterifications. Unlike proteases, which necessitate most often the use of an activated acyl donor (such as vinyl or trifluoroethyl esters), lipases are active with simple esters and even the parent carboxylic acids in the presence of a water scavenger. The selectivity of the lipase-catalyzed second esterification is specific for OH-6 allowing the synthesis of mixed T,6 -diesters.123,124 For some lipases, a chain-length dependence on the regiochemistry was observed.125 Selectively substituted monoesters were thus prepared and studied for their solution and thermotropic behavior.126,127 Combinations of enzyme-mediated and purely chemical esterifications led to a series of specifically substituted sucrose fatty acid diesters with variations in the chain length, the level of saturation, and the position on the sugar backbone. This allowed the impact of structural variations on thermotropic properties to be demonstrated (compare Section III.l).128... 

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