Oxetanones -Lactones

Battistini, P. Crotti, and F. Macchia, Gazz. Chim. Ital., 1978, 100, 619. 

Treatment of the /3-lactones (66) with MgBf2 in ether at room temperature brings about quantitative, stereospecific conversion into y-lactones by a novel dyotropic Wagner-Meerwein rearrangement this is a reaction of considerable synthetic potential. A number of additions e.g. of nitrenes, carbenes, and diazo-compounds) to diketen to give spiro-/3-lactones, which can be further transformed, have been described.For example, photolysis of acyl azides in the presence of diketen leads to pyrrolinone derivatives (67), presumably as shown.With phenyl(trichloromethyl)mercury, the spiro-lactone (68), in which 

Photoaddition of p-benzoquinone to unsymmetrical keten dimers gives the spiro-adduct (70) together with (71) and (72), which are thought to arise by 

Suzuki, and M. Sato, Chem. Pharm. Bull., 1979, 27, 1181. 

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Oxetanones (-lactones) are readily attacked by nucleophilic reagents. Reactions occur by ... 

Oxetanes are commonly obtained by intramolecular ether synthesis from a suitably functionalized alcohol. Leaving groups employed include halides, tosylates, and others. The base can range from an alkoxide to a non-nucleophilic amine . The classical, straightforward approach to 2-oxetanones (-lactones) is by the lacto-nization of the salts of -halocarboxylic acids and similar precursors . Thietanes and -thio-lactones are obtained analogously . 

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. ... 

Simple olefins do not usually add well to ketenes except to ketoketenes and halogenated ketenes. Mild Lewis acids as well as bases often increase the rate of the cyclo addition. The cycloaddition of ketenes to acetylenes yields cyclobutenones. The cycloaddition of ketenes to aldehydes and ketones yields oxetanones. The reaction can also be base-cataly2ed if the reactant contains electron-poor carbonyl bonds. Optically active bases lead to chiral lactones (41—43). The dimerization of the ketene itself is the main competing reaction. This process precludes the parent compound ketene from many [2 + 2] cyclo additions. Intramolecular cycloaddition reactions of ketenes are known and have been reviewed (7). 

DimeriZa.tlon. A special case of the [2 + 2] cyclo additions is the dimerization of ketenes. Of the six possible isomeric stmctures, only the 1,3-cyclobutanediones and the 2-oxetanones (P-lactones) are usually formed. Ketene itself gives predominandy (80—90%) the lactone dimer, 4-methylene-2-oxetanone (3), called diketene [674-82-8], approximately 5% is converted to the symmetrical dimer, 1,3-cyclobutanedione [15506-53-3] (4) which undergoes enol-acetylation to so-called triketene [38425-52-4] (5) (44). 

Very Htde is known about the toxicology of other dimeric ketenes. For the dimeric dimethylketene there is equivocal evidence of tumors resulting from massive exposure in rats reported for the P-lactone form (3,3-dimethyl-4-isopropyhdene-2-oxetanone), whereas the symmetric form (2,2,4,4 tetramethylcyclobutane-l,3-dione) induces tumors in mice after lengthy skin appHcations. 

Chemical Designations - Synonyms Betaprone Hydracrylic acid, beta-lactone 2-Oxetanone Propanolide beta-Propionolactone Chemical Formula OCH2CH2CO. 

Methods for the synthesis of optically active (3-lactones (2-oxetanones) 99T6403. 

The existence of ketenes was established over a hundred years ago, and, in recent years, asymmetric synthesis based on [2 + 2] cycloadditions of ketenes with carbonyl compounds to form chiral p-lactones has been achieved with high yields and high stereoselectivities. In 1994, Miyano et al. reported the use of Ca-symmetric bis(sulfonamides) as ligands of trialkylaluminum complexes to promote the asymmetric [2 + 2] cycloaddition of ketenes with aldehydes. The corresponding oxetanones were obtained in good yields and enantioselectivities... 

The method outlined here competes well with the method developed earlier by Danheiser, et al.618 Its superiority is based on the fact that phenyl ester enolates give almost the same results as the S-phenyl thiolester enolates. However, handling the malodorous benzenethiol for the preparation of the active acid derivative and during workup of the p-lactone can be avoided. In addition, phenol is much cheaper than benzenethiol. The method is well suited for the preparation of p-lactones from symmetrical and unsymmetrical ketones. In addition to 3,3-dimethyM-oxaspiro[3.5]nonan-2-one, ( )-3-ethyl-1-oxaspiro[3.5]nonan-2-one and (3R, 4R )- and (3R, 4S )-4-isopropyl-4-methyl-3-octyl-2-oxetanone were prepared by this procedure in high yields (Notes 11 and 12). In the case of unsymmetrical ketones the less sterically crowded diasteroisomer is formed preferentially. With aldehydes as the carbonyl component the yields are unsatisfactory, because of the competitive formation of 1,3-dioxan-4-ones.6... 

Synonyms AI3-24257 AIDS-6024 Betaprone BPL BRN 0001360 Caswell No. 709 CCRIS 536 EINECS 200-340-1 EPA pesticide chemical code 010901 Hydracrylic acid p iactone 3-Hydroxypropionic acid lactone p Lactone NSC 21626 Oxetan-2-one 2-Oxetanone Propano-lide Propiolactone 1,3-Propiolactone 3-Propiolactone p Propionolactone 3-Propionolactone p Propro-lactone UN 2810. 

Methyleneoxetanes are readily obtained from the corresponding 2-oxetanones (yields 20-86%) by reaction with Cp2TiMe2 even when a substituent includes olefinic or carbonyl functions <99JOC7074>. A one-pot conversion of P-lactones into P-lactams in a two-step process in good to excellent 3delds is reported <99JOC7657>. 

For similar reasons, activity on 2-oxetanones, also known as /3-lactones, has been very intense in recent years. 

The mechanism of decarboxylation of /3-lactones has attracted much attention. The gas-phase decomposition of 2-oxetanone is a unimolecular first-order process. It has a considerably lower energy of activation than the pyrolysis of oxetane and a much higher entropy of activation, indicating a loose activated complex (69JA7743). The ease of the reaction is greatly affected by the electronic effect of substituents at position-4, but not at position-3. The Hammett treatment of a series of rrans-4-aryl-3-methyl-2-oxetanones gave a good correlation with [Pg.374]

Oxetanes and 2-oxetanones seem to be generally not very reactive with oxidizing agents, and such reactions have received relatively little study. Photooxidation of oxetane has been found to occur readily, presumably to form 2-oxetanone (equation 37), although this was not positively identified. The reaction was similar to, but more rapid than, the photooxidation of THF, which was shown to give the corresponding lactone (69JOC1345). 

There are an extremely large number of reactions of 2-oxetanones with nucleophilic reagents, and space will allow inclusion of only representative examples. /3-Lactones show the interesting Bal.2 mechanism for base-catalyzed hydrolysis and the Aal2 mechanism for acid-catalyzed hydrolysis, according to data on kinetics and optical rotation studies of optically active lactones. The mechanistic interpretations are complicated, however, by the possibilities for subsequent elimination and addition reactions to occur, so that both of the two sites for nucleophilic attack on the 0-lactone skeleton, C-2 and C-4, may become involved. In fact 0-lactones are unusually insensitive to base, as well as acid, catalysis, the slow reaction with neutral water predominating between pH 1 and 9 (74JCS(P2)377). 

As can be seen in some of the above examples, the reactions of nucleophiles with /3-lactones are subject to modifications depending on the structure of the lactone. A good example can be seen in reactions of 3,3-dichloro-2-oxetanones, which react with various nucleophiles only by acylation (acyl-oxygen cleavage) (equation 57) (73JHC239). 

Oxetanones can be generally prepared by displacement processes on various /3-substituted carboxylic acids or by halolactonization of /3,y-unsaturated acids. A very general and reliable method consists of treatment of a /8-hydroxy acid with benzenesulfonyl chloride and pyridine at 0°C (equation 91). The yields of /3-lactones are usually in excess of 80% (79JOC356, 74JOC1322). An alternative method involves cyclization of the benzenethiol ester of a /3-hydroxy carboxylic acid by means of mercury(II) methanesulfonate in acetonitrile (equation 92). The yields were excellent in the two cases reported (76JA7874). 

Ketene dimerization is the principal synthetic route to 4-methylene-2-oxetanones. This reaction proceeds very satisfactorily for ketene and methylketene, but disubstituted ketenes dimerize only to cyclobutane-1,3-diones. The cycloaddition reaction of r-butylcyanoketene to ketene and to methylketene gives a-cyanoalkylidene-/3-lactones in about 40% yield in addition to the cyclobutane-1,3-dione dimer of f-butylcyanoketene. A mechanism has been proposed for the formation of both types of dimers from a common zwitterionic intermediate (equation 111), with the relative amount of each product determined by the configurational equilibrium of the intermediate (80JOC4483, 75JOC3417). 

A very promising synthesis of /3-lactones has been recently reported, involving the palladium-catalyzed carbonylation reaction of halogeno alcohols. For example, 3-phenyl-2-oxetanone was obtained in 63% yield from 2-phenyl-2-bromoethanol in DMF solution at room temperature under 1 atmosphere pressure of carbon monoxide (equation 115). A proposed mechanism, in which palladium metal inserts into the carbon-halogen bond, followed by insertion of a molecule of carbon monoxide into the carbon-palladium bond and then ring closure, fits kinetics data (80JA4193). 

Deprotonation of (S-lactones.1 Deprotonation of the 2-oxetanone (1) with LDA in THF at —78° generates 2, which is stable below room temperature. The anion reacts with electrophiles with high stereoselectivity at the fran.r-position at C3. The paper discusses reasons for the unexpected stability of 2. 

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