Construction of phthalein skeleton by catalytic dehydration and internal esterification of allyl alcohol

The author of the paper: danyan phthalides are a kind of very common natural products, which have very important biological activities Some of them have entered the clinical research stage (Figure 1) So far, nearly 200 compounds have been isolated from more than 100 plants The structure of these compounds is characterized by the presence of benzo - γ - butyrolactone fragments on the aromatic and lactone γ sites This fragment is also present in various terpene natural products (e.g pyrethrone 6, figure 1) Because of its wide distribution in different kinds of natural products, it has become the core focus of developing new synthesis strategies Recently, an effective strategy for the construction of phthalein and γ - butyrolactone (DOI: 10.1021 / ACS Orglett 8b01063) was reported on organic letters by Aaron aponick group of University of Florida (photo source: Organic letters) the author proposes to introduce a lactone (path a, scheme 1) through the reaction of S N 2 'of carboxylic acid and CIS allyl alcohol The key substrate 8 involved can be obtained by coupling cheap and easily available benzoic acid 9 and propargylic alkynyl raw material 10 through Sonogashira and partial reduction Once successful, the strategy can directly introduce an ethylene group, which is helpful to provide a reaction site for subsequent transformation The author found that there are few examples of this kind of reaction with CIS olefins as the substrate, which may be due to the formation of seven membered cyclolactone (path B, scheme 1) under the action of BR ø nsted Acid or Lewis acid catalyst Kitamura reported that ruthenium catalyzed cyclization of trans allyl alcohol was the best way to prepare phthalein It is pointed out that lactones can open the ring reversibly in the more traditional π - allylic metal system, which may be the reason why there are few reports on the synthesis of phthalein using π - allylic substrate (photo source: Organic letters) when studying dehydration and cyclization reaction, the author found that in the presence of BR ø nsted Acid or traditional Lewis acid, Au (I) and Pd (II) catalysts as π - acid may affect S N 2 'reaction Therefore, these complexes may realize the above assumption (path a, scheme 1) and avoid the formation of heptagonolactone Firstly, the catalyst was screened with benzoic acid 11a as the model (Table 1) The experimental results show that the reactivity is very low when AuCl is used as catalyst, and the mixture of 5-membered-cyclolactone-12a and 7-membered-cyclolactone-13a (83:17) is obtained in 48% yield under the catalysis of more electrophilic-3 Using the iron catalyst reported by cossy, the chemical selectivity of the reaction was reversed and more 13A was generated However, under the action of PH3 paucl / agotf or PdCl2 (ch3cn2), the expected product γ - butyrolactone 12a was obtained with excellent selectivity The control experiment of agotf and tfoh and the catalysis experiment of other protonic acids show that silver salt and protonic acid can't make the reaction produce γ - butyrolactone, but form lactone 13A These results further indicate that there is a competitive relationship between 13A and metal catalysts of protonic acid or Lewis acid (photo source: Organic letters) under the catalysis of Au and PD, the author screened the application scope of the reaction using a and B conditions respectively (Table 2) In addition to a few substrates, various substrates can yield phthalein in high yield Under the catalysis of Au, the reaction activity of carboxylic acid ester and allyl alcohol containing electron donating group is better than that of corresponding electron absorbing substitute Using Pd catalyst, these electronic effects are not obvious, and the substrates with various substituents can get phthalein products in high yield Both Au and Pd catalysts can catalyze the formation of 6-lactone 12j, which indicates that the strategy can also be used for the construction of lactones in other non phthalic compounds (photo source: Organic letters) in order to further expand the scope of application of this reaction, the author attempts to apply this strategy to the synthesis of aliphatic butenolide It can be seen from table 3 that the reaction can be carried out well for simple butenolide Under the catalysis of PD (II), all the substrates can get the expected products with high yield, but the reaction catalyzed by Au is not so smooth It is worth mentioning that the lactone 16e with cyclomethylene was obtained by using 15E as catalyst in 90% yield (photo source: Organic letters) the product from the above reaction contains vinyl group, which can be used for further functionalization Considering the substitution mode of natural product family, it is very important for the synthesis of phthalein to be able to oxidize at the end position In order to explore this point, the author tried to synthesize simple natural products isooctacinic acid and isooctacinol After phenol 12b is protected by silica ether, the end olefin is oxidized by Wacker to produce aldehyde 17, which is further oxidized to carboxylic acid or reduced to alcohol, and then deprotected to obtain natural products 18 and 19 (scheme 3), respectively Conclusion: the author has developed a simple strategy for the synthesis of phthalein and γ - butyrolactone by S N 2 'reaction of easily available carboxylic acid derivatives and allyl alcohol catalyzed by Au (I) and Pd (II) Using the above catalyst, only the expected five membered lactone products are generated, and the production of other competitive cyclization products such as seven membered lactone ring is completely avoided This mild and simple method can tolerate epicyclic methylene, and can be used in the synthesis of phthalein and terpene.