(Tert-Butyl)-3-Methyl-2,3,5,6,7,8- Hexahydroquinazolin-4(1H)-One, an Example of † Singlet Oxygen Ene Reaction
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molecules Article Photooxidation of 2-(tert-Butyl)-3-Methyl-2,3,5,6,7,8- Hexahydroquinazolin-4(1H)-one, an Example of y Singlet Oxygen ene Reaction Adrian Méndez, Jonathan Román Valdez-Camacho and Jaime Escalante * The Center for Chemical Research, Autonomous University of Morelos State, Av. Universidad 1001, Chamilpa, Cuernavaca 62210, Mexico; [email protected] (A.M.); [email protected] (J.R.V.-C.) * Correspondence: [email protected]; Tel.: +52-777-329-7997 Dedicated to Professor Eusebio Juaristi on the occasion of his 70th birthday. y Academic Editors: M. Graça P. M. S. Neves and Gianfranco Favi Received: 7 September 2020; Accepted: 26 October 2020; Published: 29 October 2020 Abstract: Singlet oxygen ene reactions produce 2-(tert-butyl)-4a-hydroperoxy-3-methyl-2,4a, 5,6,7,8-hexahydroquinazolin-4(3H)-one quantitatively during diffusion crystallization of 2-(tert- butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one in n-hexane/CH2Cl2 solvent mixture. 1 To confirm this photo-oxidation, a H-NMR study in CDCl3 was performed with exposure to ambient conditions (light and oxygen), with neither additional reactants nor catalysts. A theoretical study at the B3LyP/6311++G** level using the QST2 method of locating transition states suggests a two-step mechanism where the intermediate, which unexpectedly did not come from the peroxide intermediate, has a low activation energy. Keywords: singlet oxygen ene reaction; peroxidation; quinazolinone; singlet oxygen; intermediates; activation energy; transition state; reaction coordinate; B3LyP/6311++G**; QST2 method; IRC calculations 1. Introduction Molecular oxygen is a key agent in a variety of photooxidation processes [1,2]. As a reagent, there are mainly three pathways to incorporate molecular oxygen into the product: (1) by the triplet 3 O2, which plays the role of a radical scavenger agent; (2) by the superoxide radical anion generated 1 through a single electron transfer (SET) process; and (3) by the singlet O2 which is usually produced 3 through the energy transfer between the excited photocatalyst and O2 [3,4]. Photooxidative reactions involve initial light absorption by so-called photosensitizers, which then transfer the absorbed energy 3 to other molecules, including dissolved oxygen ( O2)[5–7]. Olefins containing allylic hydrogen could form allylic hydroperoxides under the action of singlet oxygen [8,9]. Direct and selective oxygenation of C-H bonds to C-O bonds are still associated with challenges, such as harsh reaction conditions, as well as the use of expensive transition metal catalysts and the use of oxidant reagents in stoichiometric amounts. If these reactions can be achieved using metal-free catalysts, this could contribute to the 1 development of green chemistry [10–12]. In this way, singlet molecular oxygen O2 plays a growing 1 role in many processes. For example, the O2-mediated allylic oxidation was used as an essential step in the synthesis of natural products or their synthetic analogues [13]. Although this reaction has been studied for many years, its mechanistic details are still a matter of debate either by theoretical or experimental results [13]. Herein we report a hydroperoxidated product (12) by a spontaneous photooxidation where hexahydroquinazolinone (11) is crystallized by overnight diffusion in an n-hexane/CH2Cl2 (80:20) solvent mixture, Scheme1. The scheme makes use of oxygen in the environment and at the same time Molecules 2020, 25, 5008; doi:10.3390/molecules25215008 www.mdpi.com/journal/molecules Molecules 20202020,, 2525,, 5008xx FORFOR PEERPEER REVIEWREVIEW 2 of 16 15 solvent mixture, Scheme 1. The scheme makes use of oxygen in the environment and at the same istimetime able isis to ableable avoid toto avoidavoid the use thethe of useuse photosensitizers ofof photosensitizersphotosensitizers (metallic (metallic(metallic catalysts catalystscatalysts or natural oror colorants),naturalnatural colorants),colorants), which is whichwhich a constant isis aa challengeconstant challenge [14,15]. [14,15]. Scheme 1.1. SpontaneousSpontaneous photooxidation photooxidation reaction reaction of 11.. 2. Results and Discussion 2. Results and Discussion A recent topic of our research group has been the total reduction of the aromatic ring in 4-quinazolin- A recent topic of our research group has been thethe totaltotal reductionreduction ofof thethe aromaticaromatic ringring inin (1H)-one (3). Here, enantiomerically pure quinazolinone 3 was reduced diastereoselectively by 4-quinazolin-(1H)-one)-one ((3).). Here,Here, enantiomericallyenantiomerically purepure quinazolinonequinazolinone 3 waswas reducedreduced hydrogenation with PtO2 resulting in octahydroquinazolinone diastereomers 4, 5, and 6 in a ratio diastereoselectively by hydrogenation with PtO22 resulting in octahydroquinazolinone diastereomers of 6:3:1. We found that the resulting cis-annelated derivatives 4 and 5 could be epimerized in the 4,, 5,, andand 6 inin aa ratioratio ofof 6:3:1.6:3:1. WeWe foundfound thatthat thethe resultingresulting cis-annelated-annelated derivativesderivatives 4 andand 5 couldcould bebe presence of KOtBu, giving the corresponding trans-fused derivatives 6 and 7, respectively, in good epimerized in the presence of KOttBu, giving the corresponding transtrans-fused-fused derivativesderivatives 6 andand 7,, yields (Scheme2)[16]. respectively, in good yields (Scheme 2) [16]. Scheme 2. HydrogenationHydrogenation reacti reactionreaction of quinazolinone 33.. InIn thethe searchsearch forfor aa newnewnew synthesissynthesissynthesis routeroute withwith thethe samesame purposepurpose asas inin 33,,, quinazolinonequinazolinonequinazolinone 8 was proposedproposed asas a a starting starting material material and and via via Birch Birch reduction reduction [17 ],[17], generating generating the possiblethe possible intermediates intermediates9a–c. Afterwards,9a–c.. Afterwards,Afterwards, without withoutwithout purification, purification,purification, the thethe catalytic catalyticcatalytic hydrogenation hydrogenation of of olefin olefin [ 18[18][18]] systems systemssystems produceproduce octahydroquinazolinone 1010,,, asasas shownshownshown ininin SchemeSchemeScheme3 3.3.. Scheme 3. DesignDesign ofof thethe total total reduction reduction of of the the aromatic aromatic ring of quinazolinone 88 inin stages.stages. Molecules 2020, 25, 5008 3 of 15 MoleculesMolecules 2020 2020,, ,25 25,, ,xx x FORFOR FOR PEERPEER PEER REVIEWREVIEW REVIEW 33 of of 16 16 Previously,Previously, our ourour research researchresearch was waswas focused focusedfocused on onon the thethe preparation preparationpreparation of of theof thethe starting startingstarting material materialmaterial (8) following((88)) followingfollowing the themethodologythe methodology methodology reported reported reported in [19 in in] [19] where[19] where where a reaction a a reaction reaction between between between isatoic isatoic isatoic anhydride anhydride anhydride1 and 1 1 methylamine and andand methylamine methylaminemethylamine in ethyl in inin ethylacetateethyl acetateacetate at 40 ◦ C atat results 4040 °C°C inresultsresultsresults the corresponding ininin thethethe correspondingcorrespondingcorresponding aminobenzamide aminobenzamideaminobenzamideaminobenzamide2 in 92% yield. 22 ininin 92%92% In92% this yield.yield.yield. work, InInIn instead, thisthisthis work,work,work,8 is producedinstead,instead,instead, 88 by isisis theproducedproducedproduced cyclocondensation bybyby thethethe cyclocondensationcyclocondensationcyclocondensation of 2 with pivalaldehyde ofofof 22 withwithwith in pivalaldehydepivalaldehydepivalaldehyde dichloromethane ininin dichloromethanedichloromethane anddichloromethanep-toluenesulfonic andandand pacidp-toluenesulfonic-toluenesulfonic monohydrate acid acid with monohydrate monohydrate 90% yield (Scheme with with 90% 90%4). yield yield (Scheme (Scheme 4). 4). SchemeScheme 4.4. Synthesis SynthesisSynthesis of ofof quinazolinone quinazolinonequinazolinone ( ((88).). TheThe resultresult isis confirmedconfirmedconfirmed byby aa X-rayX-rayX-ray didiffractiondiffractionffraction fromfromfrom suitablesuitablesuitable single-crystalsingle-crystalsingle-crystal wherewhere thethe tert terttert-butyl-butyl-butyl groupgroup ofof quinazolinonequinazolinone (((888))) is isis shown shownshown to toto adopts adoptsadopts aa a pseudo-axialpseudo-a pseudo-axialxial conformationconformation conformation (Figure(Figure (Figure1 1). ).1). FigureFigure 1.11..Structure . StructureStructure and andand single-crystal single-crystalsingle-crystal X-ray X-ra diX-raffractionyy diffractiondiffraction of quinazolinone ofof quinazolinonequinazolinone (8) showing ((8 the8)) showingshowing pseudo-axial thethe pseudo-axialconformationpseudo-axial conformation ofconformationtert-butyl group. of of tert-butyl tert-butyl group. group. TheThe Birch Birch reductionreduction ofof quinazolinonequinazolinone ((88)) waswas carriedcarried out out (stage (stage 1), 1), without without purification, purification,purification, and and we we proceededproceeded with withwith stage stagestage 2 (catalytic22 (catalytic(catalytic hydrogenation). hydrogenation)hydrogenation) When.. WhenWhenWhen the productthethethe productproductproduct of step ofofof2 stepstep wasstep purified222 waswaswas purifiedpurifiedpurified by column bybyby 1 1 columnchromatographycolumn chromatographychromatography and characterized andand characterizedcharacterized by H-NMR, byby 11H-NMR, hexahydroquinazolinoneH-NMR, hexahydroquinazolinonehexahydroquinazolinone (11) (yield ((11 28%,11))