Lactones bromo-, formation

It has been reported that concentrated H2SO4 (98%) promotes conversion of 3,5-dibromolevulinic acid 47 into 4-bromo-5-(bromomethylene)-2(5// )-furanones 48 (R = Br R = H) along with minor products, while similar treatment using 20% oleum gives the isomeric 5-(dibromomethylene)-2(5// )-furanone 49 (R = H R = Br) as the major product (63AJC165). Spectroscopic data and chemical structures were not provided for the minor substances, but the formation of the major product was explained on the basis of the enol-lactonization process followed by oxidation (63AJC165). 

Improvement to the Reformatsky reactions was achieved (53) by the use of a highly activated zinc - silver couple dispersed on the surface of graphite. T reatment of protected aldono-1,4-lactones 10b or 25b and 1,5-lactones 51a or 51b with a Reformatsky reagent prepared from a-haloesters or alkyl 2-(bromomethyl)acrylates resulted in the formation of the corresponding 3-or 4-glyculofuranos (or pyranos)onates 49a,b-50a,b, or 52a,b, respectively, under mild conditions (— 40 ° to 00) and in very good yields. Ethyl 2-deoxy-2-fluoro (and 2-bromo)-a-D-wa o-3,6-furanos-3-octulosonate derivatives were also obtained. 

Formation of 12 tol6-membered lactones in 66 to 75% yield from the corresponding u-bromo carboxylic acids can be carried out by addition of a solution of ex situ formed (33) to a dilute solution of the carboxylic acid at low temperature (—60°G) [116]. A crucial point in the selective reaction seems to be R4N+, which stabilizes the carboxylate ion and slows down bimolecular reactions for steric reasons. The yield of the cycKc product increases with increasing size of R [116]. 

A clever application of this reaction has recently been carried out to achieve a high yield synthesis of arene oxides and other dihydroaromatic, as well as aromatic, compounds. Fused-ring /3-lactones, such as 1-substituted 5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-ones (32) can be readily prepared by bromolactonization of 1,4-dihydrobenzoic acids (obtainable by Birch reduction of benzoic acids) (75JOC2843). After suitable transformation of substituents, mild heating of the lactone results in decarboxylation and formation of aromatic derivatives which would often be difficult to make otherwise. An example is the synthesis of the arene oxide (33) shown (78JA352, 78JA353). 

Olefins react with manganese(III) acetate to give 7-lactones.824 The mechanism is probably free-radical, involving addition of CH2COOH to the double bond. Lactone formation has also been accomplished by treatment of olefins with lead tetraacetate,825 with a-bromo carboxylic acids in the presence of benzoyl peroxide as catalyst,826 and with dialkyl malonates and iron(III) perchlorate Fe(C104)3-9H20.827 Olefins can also be converted to 7-lactones by indirect routes.828 OS VII, 400. 

Cyclizations of (3,7-un saturated acids form -lactones (4-exo cyclization) when the reactions are conducted under conditions of kinetic control.1 - The most common procedure for (3-lactone formation, developed by Barnett, involves halolactonization in a two-phase system using an aqueous solution of the carboxylate salt of the substrate with the halogen (Br2 or I2) added in an organic solvent.18 Cyclization with bis(, ym-collidine)iodine(I) perchlorate provides a higher yield than the Barnett procedure in cases where cyclization is not favored by geminal a-substitution (Table 2, entries 1 and 2).14 Iodo- and bromo-... 

Reaction of C-5 activated pentonolactones 13) and of 2,7-diactivated heptonolactones lib, 13) with ammonia gave in both cases 6-membered imino sugars by similar formation of epoxide intermediates (Scheme 4). The 6-bromo-2,6-dideoxy-D-anz6z> 0-hexono- 1,4-lactone gave by reaction with ammonia the 7-membered lactam 14) (Scheme 4). 

Oxidation and Reduction.—The Baeyer-Villiger oxidation of a 4-en-3-one normally inserts an oxygen atom between C-3 and C-4, but in the presence of a 6/3-bromo-substituent (198) it leads to formation of the alternative 3-oxa-product (199). Some of the normal 4-oxa-product appears also to be formed, but reacts to give the ester-lactone (200) by further oxidative steps.176... 

Macrolides (10, 124).1 The tin-mediated lactonization of to-hydroxy carboxylic acids is particularly useful for formation of 13- to 17-membered macrolides. Highest yields are obtained when di-n-butyltin oxide is used in stoichiometric amounts. The method is not useful for macrocyclization of ca-bromo or ca-mercapto carboxylic acids. 

Table I. > - Versus 5-Lactone Formation Upon lodo- and Bromo-lactonization of ( )-4-Alkenoic Acids...

The a-bromine atom is stable during lactone formation from a,y-dibromo-butyryl bromide the yield of a-bromo lactone is 94%. Under similar conditions the /3-bromine atom of /3,y-dibromohexanoic acid is eliminated as hydrogen bromide to give the lactone of 4-hydroxy-2-hexenoic acid. Cyclization of alkali salts of 15-bromopentadecanoic acid has been studied using various solvents and concentrations. Best yields of the O)-lactone are obtained from the potassium salt in methyl ethyl ketone. ... 

The course of the reaction may be considered to follow either path a or path b. By analogy to the proposed mechanism of formation of the spiro-lactone of dioxindolepropionic acid (XCI — XCIII), the concerted displacement reaction (path a) is preferred to the displacement of a C-bromo atom in a tribromodienone (path b). 

Finally, stereochemical or simply chemical considerations have led several authors to postulate the formation of a p-lactone whenever they have had to deal with a reaction involving ammonia or an amine in aqueous or alooholic solution and a P-halo aoid. Some of the older literature on this subject has been discussed by Darapsky and others, > notably the formation of 3-phenylhydracrylamidu by t-hc reaction of ammoDium hydxosidc with 3-bromo-3-phenyl-propionic acid ... 

The structure of ophiobolin A (5.137) was established by chemical degradation and by X-ray crystallography of a bromo derivative. The spectroscopic characteristics of ophiobolin A led to the identification of the oxygen functions and the double bonds. The relationship between the aldehyde and the cyclo-pentanone was revealed by the formation of a y-lactone on reduction and partial re-oxidation. A cyclic pyridazine was formed with hydrazine. Tetra-hydro-ophiobolin A formed an unusual cyclic peroxide involving these two groups. Vigorous oxidation of tetrahydro-ophiobolin A afforded a heptanoic acid lactone, which revealed the structure of the side-chain. 

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