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Investigation of Iodolactonization of Benzoallenylether for the Synthesis of Benzodioxinone Skeleton

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Heterocyclic benzodioxinone compounds and their derivatives have been attracted in the area of the drug research and synthetic processes including natural products.1,2,3 Several unique ways for the synthesis of these heterocyclic skeleton have been developed over many years.4 Dual Michael cascade approach,5 tandem hydroxylation and etherification,6 and oxidative cyclization promoted by AgOAc7 are representative approaches for the structure. Herein the authors report a new way to vinyliodide 2 by iodolactionization of benzoallenylether, which would be a potential precursor to benzodioxinone derivatives through Pd catalyzed coupling reactions. As an extension of our study on cyclization of benzoallenylether,8 we wanted to explore if the benzoallenylether having an amide group 1 would afford the desired precursor 2 which could be a precursor for 3 through Pd catalyzed coupling reactions (Scheme 1).


In order to examine the iodolactonization of 1 under a conventional condition first,9 we prepared the compound through 4-step sequence from salicylic acid 4 as a starting material: Acid chloride formation from 4 with SOCl2 followed by pyrrolidine addition to afford 5 (86%), propargylation of the alcohol group in 5 using propargyl bromide in the presence of K2CO3 to 6 (96%), and isomerization to allene 1 with CsOH in DMF (50%) (Scheme 2).


Treatment of compound 1 with 1 equiv. of N-iodosuccimide (NIS) in CH2Cl2 at 0 °C provided a mixture of four notable products, the desired cyclized compound 2 (7%), di-iodinated derivative 7 (21%), mono-iodinated derivative 8 (16%), and compound 5 (11%).10 Compounds 7, 8, and 5 do not have the allenylether moiety present in the starting material, which was presumably removed through hydrolysis rather than cyclization through iodination of allene. We assumed that the cyclization might be so slow that complete anhydrous condition of the solution should be maintained to protect the hydrolysis process. And as for the iodination of the benzene ring, we thought the iodination might be carried out after the removal of the allenylether group. When the alcohol protected compound 6 was treated with NIS under the same condition, no reaction was detected, and complete starting material was recovered. However, compound 5 provided products 7 (30%) and 8 (18%), confirming that the iodinated products from 1 were synthesized after hydrolysis of the allene group to alcohol (Scheme 4).


For the desired cyclization, we tried to find an optimized condition (Table 1). The presence of 4 A° molecular sieve, lower temperature, and an excess of NIS provided an acceptable yield (41%, entry 6). And the compound 2 could be coupled to product 11 (61%) using phenylboronic acid, Pd(0), Ag2CO3 in benzene/EtOH (2:1).


Optimizing condition of cyclization of 1


In summary, iodolactonization of benzoallenylether has been investigated to synthesize a benzodioxinone skeleton and an acceptable yield of 2 was obtained. From the precursor, various derivatives are expected to be prepared, and an example of the following coupling reaction was suggested. In due course, we plan to report full results.



This work was supported by Research Fund of Chungnam National University.



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Treatment of N-bromosuccinimide (NBS) did not afford any change.