Synthesis of Isochroman and Tetrahydroisoquinoline Derivatives from Baylis-Hillman Adducts by Radical Cyclization

Abstract

Recently we were interested in radical cyclizations of modified Baylis-Hillman adducts. We reported the synthesis of various heterocyclic compounds including 2,3dihydrobenzofuran derivatives using radical cyclization process. Meantime we reasoned that six-membered heterocyclic compounds such as isochroman and tetrahydroisoquinoline derivatives could be prepared by radical cyclization from suitably modified Baylis-Hillman adducts (vide infra, Scheme 1). Isochroman and tetrahydroisoquinoline derivatives are important backbone in many biologically interesting substances and their synthesis have been studied extensively. Especially, appropriately substituted tetrahydroisoquinolines are an important class of natural and synthetic compounds, which exhibit various biological activities including antitumor, antibacterial, antiplasmodial and β-adrenergic receptor antagonism. As an initial trial we examined the synthesis of isochroman derivative 4a as shown in Scheme 1. The starting material 3a was synthesized from the reaction of BaylisHillman acetate 1a and 2-bromobenzyl alcohol (2a) in good yield (82%). With this compound 3a in our hand we examined the radical cyclization under the influence of nBu3SnH/AIBN in benzene and we obtained desired 4,4disubstituted isochroman derivative 4a in 89% yield (Scheme 1). We did not observe the formation of sevenmembered ring compound or reduction product. Most of the radical cyclizations of aryl radical toward tethered unsaturated ester occurred at the β-position of unsaturated moiety. However, we observed the selective formation of sixmembered ring compound 4a presumably due to the special stability of the intermediate benzylic radical as in our previous synthesis of 2,3-dihydrobenzofuran. Encouraged by the results we prepared starting materials 3b-f (vide infra, Table 1 and Scheme 2) and carried out radical cyclizations under the same conditions, and the results are summarized in Table 1. As shown we prepared three isochroman derivatives 4a-c (entries 1-3) and two tetrahydroisoquinolines 4d and 4e (entries 4 and 5) in good yields (85-89%). However, unfortunately, radical cyclization was not completed in the case of nitrile derivative 3f and we isolated isochroman 4f and reduction compound 5 together (1:1 mixture based on H NMR) as a mixture. The separation of 4f and 5 was very difficult by column chromatography due to their same mobility on TLC. At this stage the reason for low yield of cyclized compound 4f is not clear. Synthesis of starting materials 3a-e required somewhat different synthetic approaches depending upon the substrates as shown in Scheme 2. Synthesis of 3a and 3b was carried out by the reaction of Baylis-Hillman acetate 1a and 2bromobenzyl alcohol (2a) in the presence of K2CO3 in acetonitrile (79-82%). The compound 3c was synthesized from cinnamyl alcohol 1b and 5-bromo-6-bromomethyl1,3-benzodioxole (2b) in moderate yield (56%) by using potassium tert-butoxide in DMF. The compounds 3d and 3e were prepared from the reaction of rearranged aza-BaylisHillman adduct 1c and 2b or 2-bromobenzyl bromide (2c) in the presence of K2CO3 in DMF in good yields (81-91%). Nitrile derivative 3f was prepared by the reaction of 2a and the corresponding Baylis-Hillman acetate in 79% yield by following the same procedure for the synthesis of 3a. In summary, we disclosed the synthesis of some isochroman and tetrahydroisoquinoline derivatives by the radical cyclization process starting from the Baylis-Hillman adducts.