Carboxylic acids ketene addition

Acetylsultam 15 is also used for stereoselective syntheses of a-unsubstituted /1-hydroxy-carboxylic acids. Thus, conversion of 15 into the silyl-A/O-ketene acetal 16 and subsequent titanium(IV) chloride mediated addition to aldehydes lead to the predominant formation of the diastereomers 17. After separation of the minor diastereomer by flash chromatography, alkaline hydrolysis delivers /f-hydroxycarboxylic acids 18, with liberation of the chiral auxiliary reagent 1919. 

The addition of water to enol ethers causes hydrolysis to aldehydes or ketones (10-6). Ketenes add water to give carboxylic acids in a reaction catalyzed by acids " ... 

However, in subsequent work it was found that carboxylic acid groups readily add to ketene acetals to form carboxyortho ester linkages (24). These are very labile linkages and on hydrolysis regenerate the carboxylic acid group which then exerts its catalytic function. Because carboxylic acids add so readily to ketene acetals, very labile polymers can be prepared by the addition of diacids to diketene acetals. The utilization of such polymers is currently under investigation. 

Thus, it would be reasonable to expect that the acetylenic group would be metabolized to a carboxylic acid. While the acid metabolite has not been detected, ethinyl estradiol is a suicide substrate inhibitor of CYP2B6 consistent with a reactive ketene being formed as an intermediate (142). In addition, there is a rearrangement product (4) shown in Figure 4.75. 

Attack on Unsaturated Carbon. The annual addition of phosphites to every variety of activated double bond continues. These include nitro-alkenes,9 a/S-unsaturated carboxylic acid derivatives,10 maleimides,11 fulvenes,12 and pyridinium salts.13 The reaction of diethyl phosphite with keten 0,N-, S,N, and Al,AT-acetals has been used to prepare the enamine phosphonates (19).14... 

Although there are other unsaturated compounds that will undergo addition-elimination with free radicals, the benzyl ketene acetal XIV appears to be the most active double bond as far as rate of addition is concerned and the most efficient as far as regards to the extent of elimination is concerned. A comparison with the list of chain transfer agents listed in the Polymer Handbook (23) indicated that only the sulfur compounds appear to be more effective than XIV. Hydrolysis of the end-capped oligomer gives a macromer that is terminated with a carboxylic acid group. 

Nucleophilic Addition. Reagents with labile hydrogen atoms, such as alcohols, thiols, phenols, carboxylic acids and amines, add to ketenes giving the corresponding carboxylic acid derivatives (1) as shown in Figure 1 (38). Not many are of practical importance, as there are better ways to such... 

Carboxylic acids are obtained when water is added to the carbon-carbon double bond of ketenes (equation 200).301 The addition is acid catalyzed, and involves protonation at the -carbon. 

In practice several problems have had to be overcome before this apparently attractive method of sizing could be implemented efficiently. Since the ketene or the anhydride have to react with hydroxyl groups, they will also react readily with water i.e. the molecules are hydrolysed to give non-reacting carboxylic acids (Figure 2). Some means must therefore be found to permit addition of the sizes to the wet-end of a paper machine, and then to ensure that they are retained within the wet paper web in such a way that an adequate size film is deposited on fibres in the dried sheet. This is made more awkward by the essentially hydrophobic nature of the molecules. The means adopted is to prepare emulsions of the sizes, often using cationic starch as a stabiliser and retention aid. 

Fig. 8.13. Arndt-Eistert homologation of carboxylic acids—addition of H20 to a ketene in part 2 of the third reaction of this three-step reaction sequence.

Among the procedures which have been developed for /J-lactam syntheses (as reviewed [58] [59]) are the cyclization of /3-haIopropionamides [60] from azetidine-2-carboxylic acids and esters [61] the addition of ketenes to Schiff bases [62] ring-contraction procedures [63] [64] [65] [3+1] cyclizations of a-phenylthioacetamide [66] the cyclization of aminoacids [67], and styrene and N-chlorosulphonyl isocyanate [68]. 

Irradiation of alkoxycarbene complexes in the presence of aUcenes and carbon monoxide produces cyclobutanones. A variety of inter- and intramolecular [2 + 2]cycloadditions have been reported. The regioselectivity is comparable with those obtained in reactions of ketenes generated from carboxylic acid derivatives. Cyclobutanones can be obtained with a high degree of diastereoselectivity upon reaction of alkoxy carbenes with chiral A-vinyloxazolidinones. For example, photolysis of (19) in the presence of (20) gives cyclobutanone (21) (Scheme 31). In addition to aUcoxycarbenes, carbenes having a thioether or pyrrole substituent can also be employed. Related intramolecular cycloadditions of y,5-unsaturated chromimn carbenes afford bicyclo[2.1. IJhexanones (Scheme 32). 

BINOL-Me, and stoichiometric amounts of 2,6-dimethylphenol as an achiral proton source, protonation of the ketene bisftrime-thylsilyl)acetal derived from 2-phenylpropanoic acid proceeds at —80°C to give the (5)-carboxylic acid with 94% ee. (/ )-BINOL-Me is far superior to (/ )-BINOL as a chiral proton source during the catalytic protonation, and 2,6-dimethylphenol is the most effective achiral proton source. In addition, it is very important that the molar quantity of SnCU should be less than that of (/ )-BINOL-Me to achieve a high enantioselectivity. For the reaction of 2-phenylcyclohexanone, however, the use of tin tetrachloride in molar quantities lower than BINOL-Me remarkably lowers the reactivity of the chiral LBA (eq 3). Excess SnCLt per chiral proton source, in contrast, promotes this protonation. In the protonation of silyl enol ethers less reactive than ketene bis(trialkylsilyl) acetals, chelation between excess tin tetrachloride and 2,6-dimethylphenol prevents the deactivation of the chiral LBA. 

Oxetanones ( -lactones) are useful synthetic intermediates which have been most often prepared by cyclization of p-halo or p-hydroxy acid derivatives or by addition of ketenes " to carbonyl compounds. They are starting materials for useful polymers and copolymers and have been used for the synthesis of alkenes and carboxylic acid derivatives. P-Lactones possessing antimicrobial activity have recently been found in bacterial cultures. ... 

By far the most useful method for making cyclopropanones has involved the addition of diazoalkanes to ketenes, a reaction which was first explored by Turro and Hammond and by de Boer and coworkers . The cyclopropanone formed (Scheme 1) is immediately trapped by the addition of a nucleophile such as water, an alcohol or carboxylic acid. Turro found that although cyclopropanone itself is not isolable, a dilute solution of this ketone (0.5-0.8 M) may be stored at — 78°C for several days. 

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