Halolactones from 1,4-dihydrobenzoic acids

Abstract

H C0,-In an effort to increase the utility of 1,4-dihydrobenzoic acids, which are readily available by the Birch reduction2 of benzoic acids, and in connection with studies aimed a t defining the scope of a new b-lactone ~y n t h e s i s ,~ we have examined the iodolactonization and bromolactonization of 1,4-dihydrobenzoic acids. However, such low yields of lactones have been obtained in the iodolactonization of several 1,4-dihydrobenzoic acids that the reaction cannot be considered as a reliable synthetic method. In contrast, the bromolactonization reaction consistently affords good yields of stable crystalline bromolactones.The ring size of the lactone formed in the bromolactonization of a 1,4-dihydrobenzoic acid depends upon substitution at the sites of unsaturation. Either a p-lactone or a ylactone may be favored. Thus 2-methyl-l,4-dihydrobenzoic acid (la), affords a p-lactone. Of the two possible @-lactones only one is formed, lactone formation in this case being directed toward the more substituted double bond to produce 2a. In the bromolactonization of the isomeric carboxylate salt, lb, lactonization is directed once again toward the more substituted double bond; however, there is a difference in lactone ring size. The major product is ylactone 3b.This selectivity of halolactonization for the more substituted double bond can be rationalized in terms of a probable mechanism of the reaction.* In the addition reactions of bromine to oleFinic sites, three-membered cyclic bromonium ions have often been postulated as intermediates in a two-step mechanism, but only until recently have such intermediates received experimental ~u p p o r t .~The change in lactone ring sine which results from the shift of a methyl group from the /3 to the y position in dihydrobenzoic acid substrates la and lb is consistent with a brominum ion intermediate having more carbonium ion character6 a t the more substituted carbon atom, 4a -. 5. An intermediate with character as shown by 5 could promote intramolecular Markovnikov-type regiospecificity controlling the formation of 2a from la.A similar argument applies to the formation of a y-lactone in the case of the isomeric acid salt lb. An intermedi4a, R1 = CHJ; R2 = H b, R, = H; R, = CH, CO? -c0, -4b 'Br 5 6ate having carbonium ion character as shown by 6 would tend to promote y-lactone formation leading to 3b. In both of the cases, owing to the stability of the tertiary carbonium ions, 5 and 6, the ring closure step would be expected to possess a great deal of S N 1 character.On the other hand, the bromonium ion involved in the reaction of IC is not as stable; therefore, the ring closure step would be expected to possess primarily s N 2 character. Since it is known that in intramolecular SN2 ring closure reactions the geometry of the molecule is such that the formation of four-membered rings is favored over the formation of five-membered rings,' the expected product from IC is the @-lactone 2c; indeed, 2c is the exclusive lactone product.Another example in which Markovnikov control is ...

Formation of Four-Membered Heterocycles through Electrophilic Heteroatom Cyclization

“…In order to show the utility of 1,4‐dihydrobenzoic acids 12 , Barnett and Needham12a examined iodo‐ and bromolactonizations of these acids, substituted in the 2‐ and 3positions. Low yields of the β‐lactones were obtained on iodolactonization.…”

Catalytic Desymmetrization of Cyclohexadienes by Asymmetric Bromolactonization

“…We also tested the reaction of the 3,5-dimethylcyclohexadiene substrate. In this case, γ-lactone 11 was unexpectedly formed with only 37% ee, probably due to the formation of an electronically more stable tertiary carbocation intermediate …”

A new approach to substituted arene oxides. Total synthesis of senepoxide and seneol

“…Barnett and Needham reported in 1975 that bromination of a sodium 1,4-dihydrobenzoate salt in bicarbonate solution led to a fouror five-membered lactone, depending upon the substitution pattern of the ring-sp2 carbons. 16 The unsubstituted parent 2a thus formed only the bicyclic trans-bromo-i3-lactone 3a in 42% yield, probably by a concerted bromonium ion cyclization. We have subjected the series of 1-alkylated dihydrobenzoates (Table I) lacking olefinic substituents to identical reaction conditions and observed, as expected, that they afforded only four-membered lactones.…”