Microwave Heating Outperforms Conventional Heating for a Thermal Reaction that Produces a Thermally Labile Product: Observations Consistent with Selective Microwave Heating

Abstract

Microwave( MW) heatingi sm ore effective than conventional (CONV)h eating for promoting ah igh-temperature oxidative cycloisomerization reaction that was previously reported as ak ey step in at otal synthesis of the naturalp roduct illudinine.T he thermal reaction pathway as envisioned is an inverse electron-demand dehydro-Diels-Alder reaction with in situ oxidation to generate as ubstituted isoquinoline, which itself is unstablet ot he reaction conditions. Observed reaction yields were higher at am easured bulk temperature of 200 8Ct han at 180 8C or 220 8C; at 24 hours than at earliero rl ater time points; and when the reaction solution was heatedu sing MW energy as opposedt oC ONV heating with am etal heat block. Selective MW heating of polar solutea ggregates is postulated to explain these observations. We recently reported as ynthesis of illudinine [1] in conjunction with broader efforts to produce targets of interestb earing neopentylene ring fusions. [2] Previously reported syntheses of illudinine required 14 [3] to 16 [4] steps, many of which were dedicated to craftingt he neopentylene ring fusion. Our reported synthesis of illudinine featured tandem fragmentation and olefination methodology from our lab, [5] and it was relativelye fficient, providings ynthetic illudinine in 8steps and 14 %o verall yield from commerciallyavailable dimedone (Scheme 1).Our synthesis of illudinine featured ak ey oxidative cycloisomerization (Scheme 2). Related oxidative cycloisomerizations of styrenes have been reported recently, [6] along with evidence that they proceed by way of an intramolecular Diels-Alder (IMDA) cycloadditionf ollowed by concerted extrusion of molecular hydrogen. [6b] We built from this work to examine inverse electron-demand vinylpyridine Diels-Alders ubstrates (e.g., 1), finding that the bromoalkyne( as opposed to the terminal alkyne) was necessary for cycloisomerization to outcom-pete general decomposition in the reaction mixture. The 40 % yield of isoquinoline 2 that we observedw as sufficient to advance materialthrough to the final target, but it was the weakest link in our chain of synthetic reactions.Here we report ar e-examinationo ft his reaction, paying particular attention to any differences between microwave (MW) and conventional (CONV) heating. [7] In contrast to the 40 % yield we reported using MW heating( Scheme 2), CONV heating produced isoquinoline 2 in only 15 %y ield after 12 hours. The yield of 2 increased to 39 %a fter 24 hours of CONV heating, but it diminished to 23 %a fter 36 hours. These observations gave us cause for concern that the isoquinoline product was not stable to the high-temperature reactionc onditions. We confirmed the thermal instability of isoquinoline 2 by heating it at 220 8Ci n1 ,2-dichlorobenzene and monitoring its disappearanceo ver time as it decomposed into ac omplex mixture of unidentified products (Table 1).In total, we examined three reaction temperatures (180 8C, 200 8C, and 220 8C) at varioust ime-points using both MW and CONV heating (Table 2). Twot...

Synthesis of Illudinine from Dimedone and Identification of Activity as a Monoamine Oxidase Inhibitor

“…We later reexamined this reaction systematically, focusing on temperature, time, and heating mode (MW v CONV). 30 Yields were consistently highest at 200 °C and 24 h compared with temperatures and times above and below these values. It was also found that solutions of the substrate heat more efficiently in the microwave than solutions of the product (faster and to higher temperature at constant MW power) and that isolated yields of product were consistently higher under MW compared to CONV heating, despite essentially identical temperature profiles and other reaction variables.…”

“…First-Generation Synthesis. 29,30 The synthesis of illudinine as previously reported is outlined in Scheme 4. The hydroxycycloalkenyl triflate (6) needed for fragmentation/olefination can be reached in two steps from dimedone (cf.…”

“…We recapitulate the first iteration of this approach (Scheme 3, bottom, EWG = CO 2 Et), updating it to include a recent focused examination of the microwave-mediated oxidative cycloisomerization. 30 For the revised approach, we used a nitrile (CN) functional group instead of an ethyl ester as the precursor to the carboxylic acid of illudinine (EWG = CN). The nitrile requires harsher conditions for late-stage hydrolysis to the carboxylic acid, but illudinine itself is robust to hydrolysis.…”

“…Here, we report our synthesis of illudinine from dimedone, building on preliminary communications and with a key tactical innovation compared to our first-generation approach. We recapitulate the first iteration of this approach (Scheme , bottom, EWG = CO 2 Et), updating it to include a recent focused examination of the microwave-mediated oxidative cycloisomerization . For the revised approach, we used a nitrile (CN) functional group instead of an ethyl ester as the precursor to the carboxylic acid of illudinine (EWG = CN).…”

Synthesis of 4,4-Dimethyl-1,6-heptadiyne and Alcyopterosin O

“…Notable illudalane syntheses include that of illudalic acid and illudinine by Woodward and Hoye in 1977, that of illudinine by Teske and Deiters in 2008, that of alcyopterosin A by Sato in 2002 and by Iglesias in 2006, and those of several other alcyopterosins by Witulski in 2010 . We reported syntheses of alcyopterosin A in 2016 and illudinine in 2017, with the latter synthesis updated in 2020 . Eight additional publications on the synthesis of illudalane sesquiterpenes have appeared since the beginning of 2018, as these targets increasingly attract attention for natural product synthesis.…”