(Tert-Butyl)-3-Methyl-2,3,5,6,7,8- Hexahydroquinazolin-4(1H)-One, an Example of † Singlet Oxygen Ene Reaction

molecules

Article Photooxidation of 2-(tert-Butyl)-3-Methyl-2,3,5,6,7,8- Hexahydroquinazolin-4(1H)-one, an Example of † 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. † 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)) (yield(yield Scheme 28%,28%,5) wasSchemeScheme obtained 5) 5) was was instead obtained obtained of 10instead instead. of of 10 10.. .

SchemeScheme 5.5. Stepwise StepwiseStepwise reduction reductionreduction of ofof quinazolinone quinazolinonequinazolinone ( ((88).).

1 The 1 H-NMR spectrum of 11 shows a tert-butyl signal at 0.92 ppm, N-Me at 3.06 ppm, and C2 TheThe 11H-NMRH-NMR spectrumspectrum ofof 1111 showsshows aa terttert-butyl-butyl signalsignal atat 0.920.92 ppm,ppm, NN-Me-Me atat 3.063.06 ppm,ppm, andand C2C2 hydrogen at 4.2 ppm. The lack of an aromatic zone signals and two multiple signals between 1.41–1.74 hydrogenhydrogen atat 4.24.2 ppm.ppm. TheThe lacklack ofof anan aromaticaromatic zonezone signalssignals andand twotwo multiplemultiple signalssignals betweenbetween and 2.04–2.27 ppm are of the new methylenes previously from the aromatic ring of 8, which indicates 1.41–1.741.41–1.74 andand 2.04–2.272.04–2.27 ppmppm areare ofof thethe newnew methylenesmethylenes previouslypreviously fromfrom thethe aromaticaromatic ringring ofof 88,, , that only partial reduction occurred. whichwhich indicates indicates that that only only partial partial reduction reduction occurred. occurred. Once the amorphous solid product 11 was characterized, it was recrystallized by diﬀusion OnceOnce thethe amorphousamorphous solidsolid productproduct 111111 waswaswas characterized,characterized,characterized, ititit waswaswas recrystallizedrecrystallizedrecrystallized bybyby diffusiondiffusiondiffusion overnight in n-hexane/CH22Cl2 (80:20) solvent mixture (Scheme6). overnightovernight in in n n-hexane/CH-hexane/CH22ClCl22 (80:20) (80:20)(80:20) solvent solventsolvent mixture mixturemixture (Scheme (Scheme(Scheme 6). 6).6).

SchemeScheme 6. 6. Recrystallization RecrystallizationRecrystallization by by diffusion didiffusionﬀusion of of 11 11 overnight. overnight.overnight.

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MoleculesFinally,2020, 25 after, 5008 filtering, hexahydroquinazolinone (12) (Figure 2) was obtained whose structure4 of 15 was also confirmed by X-ray diffraction where a hydroperoxy group at the alpha position to the carbonyl group was noted. Finally,As expected, after filtering, the orientation hexahydroquinazolinone of the tert-butyl group (12) (Figure in a pseudo-axial2) was obtained position whose in quinazolinone structure was also(8) (Figure confirmed 1) causes by X-ray a significant diffraction steric where effect a hydroperoxy and as a consequence, group at the which alpha forced position the tohydroperoxide the carbonyl groupgroup wasto attach noted. to the opposite side, as observed in the X-ray structure of compound 12.

FigureFigure 2.2. StructureStructure andand single-crystalsingle-crystal X-rayX-ray didiﬀffractionraction ofof hexahydroquinazolinonehexahydroquinazolinone ((1212).). ItIt shouldshould bebe notednoted thatthat thethe hydroperoxyhydroperoxy groupgroup isis orientedoriented toto thetheopposite oppositeside sideas asthe thetert tert-butyl-butyl group. group.

tert AsThe expected, 1H-NMR the spectrum orientation of the of compound the -butyl 12 groupshows in the a pseudo-axialtert-butyl signals position at 0.98 in quinazolinoneppm, N-Me at (3.058) (Figure ppm, 1the) causes single a signal significant for C2 steric hydrogen e ffect at and 4.86 as ppm, a consequence, and aliphatic which hydrogens forced the between hydroperoxide 1.55 and group2.89, respectively. to attach to the In oppositeaddition, side, from as observedthe characteristic in the X-ray signals structure of compound of compound 1212, .the 13C-NMR 1 spectrumThe H-NMRalso shows spectrum the quaternary of the compound signals for12 C8ashows at 170.32 the tert ppm-butyl and signalsC4a at 76.32 at 0.98 ppm. ppm, N-Me at 3.05 ppm,To confirm the single that signal the forhydroperoxidizedC2 hydrogen at 4.86compound ppm, and 12 aliphaticwas produced hydrogens by betweena photooxidation 1.55 and 13 2.89,reaction respectively. by exposure In addition, to ambient from conditions, the characteristic a kinetic signals study of was compound carried 12out, the by meansC-NMR of spectrum1H-NMR also shows the quaternary signals for C8a at 170.32 ppm and C4a at 76.32 ppm. (Figure 3). Once compound 11 was purified, its 1H-NMR spectrum was immediately acquired (t0 = 0 To confirm that the hydroperoxidized compound 12 was produced by a photooxidation reaction h), and the characteristic signals of this product were noted. After 72 h (t1) and without opening the 1 byNMR exposure tube, a to spectrum ambient was conditions, acquired a again. kinetic study was carried out by means of H-NMR (Figure3). 1 OnceIt compound is interesting11 was to observe purified, that its theH-NMR signals spectrum at 1.00 ppm was immediately(10′), 3.06 ppm acquired (11′), and (t0 = 4.840 h), ppm and the(2′) characteristic signals of this product were noted. After 72 h (t ) and without opening the NMR tube, ppm at (t1) already increased, albeit only slightly. These signals1 eventually developed to be the Moleculesacorresponding spectrum 2020, was 25, xhydrogens acquiredFOR PEER again.REVIEW of 12 mentioned above. This is to show that even with the short span5 of 16of light exposure before the first spectrum was obtained, the small amount of oxygen remained inside the NMR tube was enough to react with compound 11. Next, the NMR tube was exposed to the laboratory ambient conditions for three days with the spectrum obtained every 24 h (t2 = 96 h, t3 = 120 h, and t4 = 144 h). The spectrum of t4 shows that, by then, most of 11 was transformed into product 12. It is important to comment that during the exposure time the volume of CDCl3 decreased, hence it was necessary to maintain a volume of 0.5 mL when spectra were taken.

Figure 3. Kinetic study by 1H-NMR of environmental exposure of 11. Figure 3. Kinetic study by 1H-NMR of environmental exposure of 11.

It is interesting to observe that the signals at 1.00 ppm (100), 3.06 ppm (110), and 4.84 ppm (20) It is also noted that, in 1H-NMR spectra, only signals corresponding to raw materials and ppm at (t1) already increased, albeit only slightly. These signals eventually developed to be the products are observed, confirming the high yield and absence of competing mechanisms. This result corresponding hydrogens of 12 mentioned above. This is to show that even with the short span of demonstrates that the oxygen in the environment is responsible for the photooxidation reaction of light exposure before the ﬁrst spectrum was obtained, the small amount of oxygen remained inside the compound 11 when it was recrystallized overnight. NMR tube was enough to react with compound 11. To demonstrate that the absence of oxygen does not allow the hydroperoxidation reaction to occur, compound 11 was placed in a closed vial and after 72 h we observed only the original compound by TLC (from left, first spot with a Rf = 0.68, Figure 4). On the other hand, when 11 was placed in an open vial and covered with aluminum foil for 14 h, 12 was observed by TLC (Rf = 0.96, second spot). The third spot from the left (marked M) corresponds to a mixture of 11 and 12, with the right spot, 12 as a reference.

Figure 4. Thin layer chromatography (hexane:AcOEt, 6:4) for 1b) without oxygen, C) with oxygen and covered with aluminum foil, M) mixture of 11 and 12, and OOH) compound 12 for reference.

To confirm the role of light in the reaction, a control TLC experiment was also performed. Compound 11 was placed in a vial under a N2 atmosphere and covered with aluminum foil for 24 h which resulted in only 11 was observed with Rf = 0.35 (Figure 5).

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Molecules 2020, 25, 5008 5 of 15

Next, the NMR tube was exposed to the laboratory ambient conditions for three days with the spectrum obtained every 24 h (t2 = 96 h, t3 = 120 h, and t4 = 144 h). The spectrum of t4 shows that, by then, most of 11 was transformed into product 12. It is important to comment that during the exposure time the volumeFigure 3 of. Kinetic CDCl 3studydecreased, by 1H-NMR hence of it environmental was necessary exposure to maintain of 11. a volume of 0.5 mL when spectra were taken. It isis alsoalso notednoted that,that, inin 11H-NMR spectra, only signals corresponding to raw materialsmaterials and products areare observed,observed, conﬁrmingconfirming thethe highhigh yieldyield andand absenceabsence ofof competingcompeting mechanisms.mechanisms. This result demonstrates that the oxygen in the environmentenvironment is responsibleresponsible for thethe photooxidationphotooxidation reaction of compound 11 when itit waswas recrystallizedrecrystallized overnight.overnight. To demonstratedemonstrate that that the the absence absence of oxygenof oxygen does does not not allow allow the hydroperoxidationthe hydroperoxidation reaction reaction to occur, to compoundoccur, compound11 was placed11 was in placed a closed in viala closed and after vial 72 and h we after observed 72 h we only observed the original only compound the original by TLCcompound (from left,by TLC ﬁrst (from spot withleft, first a Rf spot= 0.68, with Figure a Rf 4=). 0.68, On theFigure other 4). hand,On the when other11 hand,was when placed 11 in was an openplaced vial in andan open covered vial withand covered aluminum with foil aluminum for 14 h, 12 foilwas for observed14 h, 12 was byTLC observed (Rf = by0.96, TLC second (Rf = spot). 0.96, Thesecond third spot). spot The from third the spot left (markedfrom the left M) corresponds(marked M) corresponds to a mixture to of a11 mixtureand 12 of, with 11 and the 12 right, with spot, the 12rightas aspot, reference. 12 as a reference.

Figure 4.4. ThinThin layerlayer chromatographychromatography (hexane:AcOEt,(hexane:AcOEt, 6:4)6:4) forfor (1b) 1b) withoutwithout oxygen,oxygen, (C)C) with oxygenoxygen and covered withwith aluminumaluminum foil,foil, (M)M) mixture mixture of of 1111 andand 1212,, and and OOH) (OOH) compound compound 1212 forfor reference. reference.

To conﬁrmconfirm thethe rolerole ofof lightlight inin thethe reaction,reaction, a control TLC experiment was also performed. Compound 11 was placed in a vialvial underunder aa NN22 atmosphere and covered with aluminum foil for 24 h which resulted in only 11 was observed with Rf = 0.35 (Figure5). Moleculeswhich resulted 2020, 25, x in FOR only PEER 11 REVIEW was observed with Rf = 0.35 (Figure 5). 6 of 17

Figure 5 5.. Thin layer chromatography (hexane:AcOEt, 8:2)8:2) ofof (Rx)Rx) in in N N22 atmosphereatmosphere and and without without light; light; compound 12 for reference.

Furthermore, the reaction occurs very quickly, for even a short exposure to light and oxygen was sufficient to show traces of 12, as can be seen in t0 in Figure 3. Finally, we found that with exposure to light for 6 h we were able to obtain the same result as overnight crystallization. To confirm the importance of light exposure, it was necessary to make a detailed analysis of the kinetic study of Figure 3. Thus, Table 1 shows the 1H-NMR proportions of the raw material 11 and product 12. Figure 6 illustrates the data in Table 1, where we can see that there is a sharp change in the rate of formation of 12 after 72 h where light was introduced to the vial.

Molecules 2020, 25, x FOR PEER REVIEW 6 of 16

Figure 5. Thin layer chromatography (hexane:AcOEt, 8:2) of Rx) in N2 atmosphere and without light; Moleculescompound2020, 25, 500812 for reference. 6 of 15

Furthermore, the reaction occurs very quickly, for even a short exposure to light and oxygen Furthermore, the reaction occurs very quickly, for even a short exposure to light and oxygen was was sufficient to show traces of 12, as can be seen in t0 in Figure 3. Finally, we found that with suﬃcient to show traces of 12, as can be seen in t0 in Figure3. Finally, we found that with exposure to exposure to light for 6 h we were able to obtain the same result as overnight crystallization. light for 6 h we were able to obtain the same result as overnight crystallization. To confirm the importance of light exposure, it was necessary to make a detailed analysis of the To conﬁrm the importance of light exposure, it was necessary to make a detailed analysis of the kinetic study of Figure 3. Thus, Table 1 shows the 1H-NMR proportions of the raw material 11 and kinetic study of Figure3. Thus, Table1 shows the 1H-NMR proportions of the raw material 11 and product 12. Figure 6 illustrates the data in Table 1, where we can see that there is a sharp change in product 12. Figure6 illustrates the data in Table1, where we can see that there is a sharp change in the the rate of formation of 12 after 72 h where light was introduced to the vial. rate of formation of 12 after 72 h where light was introduced to the vial.

Table 1. Proportions of compounds 11 and 12 by 1H-NMR. Table 1. Proportions of compounds 11 and 12 by 1H-NMR. 1H-NMR Spectra Exposure Time (h) 11 (%) 12 (%) 12 (%) 1H-NMR Spectra Exposure Time (h) 11 (%) 12 (%) 12 (%) 1 a 0 87 13.0 a 5.6 2 b 1 024 8781 13.0 18.6 b 5.6 b 2 24 81 18.6 5.6 2 48 75 24.2 5.6 2 b 48 75 24.2 5.6 2 b 72 70 29.8 5.6 2 b 72 70 29.8 24.2 3 96 46 54.0 24.2 3 96 46 54.0 25 4 120 21 79.0 25 4 120 21 79.0 13 13 5 5 144144 88 92 92 a b a FromFrom sample sample preparation preparation to its to introduction its introduction into the into NMR the equipment.NMR equipment.b The sample The was sample a weekend was a withinweekend the NMRwithin equipment. the NMR equipment.

100 90 80 70 12 60 50 40

% Compound 30 20 10 0 0 24 48 72 96 120 144 Time (h)

Figure 6. Proportion of 12 and time by 1H-NMR. Percentage of 12 was calculated relative to the signals 1 MoleculesofFiguretert 2020-butyl , 625. ,Proportion xgroups FOR PEER of 11 ofREVIEW and12 and12 . time by H-NMR. Percentage of 12 was calculated relative to the7 of 16 signals of tert-butyl groups of 11 and 12. Based on the experimental evidence that has been shown, a possible reaction mechanism for the formation of hydroperoxidized 1212 isis proposedproposed inin SchemeScheme7 7..

Scheme 7. Proposed mechanism for the formation of product 12..

We argue that hydroperoxided 12 comes from the intermediate 11 through a Schenck reaction, also called an ene reaction, which additionally involves the singlet oxygen (1O2) as a reactant (Scheme 8) [20,21].

Scheme 8. Spontaneous ene reaction of compound 11.

In a previous study [22], we showed that, in the presence of light, photoinduced elimination of the tert-butyl group in quinazolinones achieved a high reactivity. This gives us motive to propose (Figure 7) that 11 could also absorb energy from light and interact with oxygen from the environment (3O2) to give rise to the formation of singlet oxygen (1O2) through an energy transfer mechanism [23], which would result in a self-sensitizing process [24].

Figure 7. Formation of singlet oxygen (1O2).

The general proposed pathway consists of two variants: A concerted or a stepwise mechanism [13]. The concerted pathway requires both a hydrogen atom at the allylic position and a favorable geometry in order to access the transition state kinetically [25]. Since the right-hand side ring has

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Based on the experimental evidence that has been shown, a possible reaction mechanism for the formation of hydroperoxidized 12 is proposed in Scheme 7.

Molecules 2020, 25, 5008 7 of 15 Scheme 7. Proposed mechanism for the formation of product 12.

We argueargue thatthat hydroperoxidedhydroperoxided 12 comes from the intermediate 11 through a Schenck reaction, 1 also called called an an eneene reaction,reaction, which which additionally additionally involves involves the singlet the singlet oxygen oxygen (1O2) as ( aO reactant2) as a (Scheme reactant (Scheme8) [20,21].8)[ 20,21].

Molecules 2020, 25, x FOR PEER REVIEWScheme 8. Spontaneous ene reaction of compound 11. 8 of 17

In a previous study [22], we showed that, in the presence of light, photoinduced elimination of In a previous study [22], we showed that, in the presence of light, photoinduced elimination of the tert-butyl group in quinazolinones achieved a high reactivity. This gives us motive to propose the tert-butyl group in quinazolinones achieved a high reactivity. This gives us motive to propose (Figure7) that 11 could also absorb energy from light to give 11* and interact with oxygen from the (Figure 7)7) that that 11 11could could also also absorb absorb energy energy from lightfrom to light give 11*and and interact interact with with oxygen oxygen from from the 3 1 environment (3 O2 ) to give rise to the formation of singlet oxygen ( 1O2) through an energy transfer environment (3O2) to give rise to the formation of singlet oxygen (1O2) through an energy transfer mechanism [23], which would result in a self-sensitizing process [24]. mechanism [23], which would result in a self-sensitizing process [24].

FigureFigure 7.7. Formation ofof singlet oxygenoxygen ((11O2).). Figure 7. Formation of singlet oxygen (1O2).

The generalgeneral proposedproposed pathway pathway consists consists of of two two variants: variants: A concertedA concerted or aor stepwise a stepwise mechanism mechanism [13]. The general proposed pathway consists of two variants: A concerted or a stepwise mechanism The concerted pathway requires both a hydrogen atom at the allylic position and a favorable geometry [13]. The concerted pathway requires both a hydrogen atom at the allylic position and a favorable in order to access the transition state kinetically [25]. Since the right-hand side ring has locked the geometry in order to access the transition state kinetically [25]. Since the right-hand side ring has amine lockedhydrogen the amine in hydrogen its position, in makingits position, it too making rigid to beit too able rigid to form to be a bond able withto form the oxygena bond molecule,with the weoxygen eliminate molecule, this pathway.we eliminate this pathway. For the stepwisestepwise mechanism, we explore probableprobable intermediatesintermediates following the theoretical and experimental study by Alberti and Orfanopoulos [[1133].]. For our theoretical model, we have removed the cyclohexane ringring fromfrom 1111 toto formform 1111’0 (Scheme9 9).). TheThe completecomplete moleculemolecule 11 was used in a detailed study of orbital analysis, whereas model 1111’0 was used in order to reduce the computationalcomputational cost in subsequent calculations ofof bothboth locatinglocating thethe transitiontransition statestate andand itsits conﬁrmationconfirmation byby IRC.IRC.

Scheme 9. Proposed model molecule 11’, which comes from 11.

To validate the use of 11’, as a preliminary study we performed an orbital analysis of both 11 and 11’ at the B3LYP/6-311++G** level where we observed that 11’ shares a very similar HOMO and LUMO with 11. This strongly suggests the use of 11’ in explore the second pathway. The product 12’ is defined in the same way. As suggested by Alberti and Orfanopoulos [13], we consider the following intermediates: (a) biradical/dipolar, (b) perepoxide, and (c) 1,2-dioxetane (Figure 8).

Molecules 2020, 25, x FOR PEER REVIEW 8 of 16 Molecules 2020, 25, x FOR PEER REVIEW 8 of 16 locked the amine hydrogen in its position, making it too rigid to be able to form a bond with the lockedoxygen the molecule, amine hydrogenwe eliminate in itsthis position, pathway. making it too rigid to be able to form a bond with the oxygenFor molecule, the stepwise we eliminate mechanism, this wepathway. explore probable intermediates following the theoretical and experimentalFor the stepwise study by mechanism, Alberti and we Orfanopoulos explore probab [13].le For intermediates our theoretical following model, the we theoretical have removed and experimentalthe cyclohexane study ring by fromAlberti 11 and to formOrfanopoulos 11′ (Scheme [13]. 9). For The our complete theoretical molecule model, we11 havewas usedremoved in a thedetailed cyclohexane study of ring orbital from analysis, 11 to whereasform 11′ model(Scheme 11′ 9).was The used complete in order moleculeto reduce 11the was computational used in a Moleculesdetailedcost in subsequent2020 study, 25, 5008of orbital calculations analysis, of whereasboth locating model the 11 transition′ was used state in order and itsto reduceconfirmation the computational by IRC.8 of 15 cost in subsequent calculations of both locating the transition state and its confirmation by IRC.

Scheme 9. Proposed model molecule 11′, which comes from 11. SchemeScheme 9.9. Proposed model molecule 110′, which comes from 11. To validate the use of 11′, as a preliminary study we performed an orbital analysis of both 11 To validate the use of 11 , as a preliminary study we performed an orbital analysis of both 11 and To11′ validateat the B3LYP/6-311++G** the use of 110′, as level a preliminary where we studyobserved we performedthat 11′ shares an orbitala very similaranalysis HOMO of both and 11 and 11 at the B3LYP/6-311++G** level where we observed that 11 shares a very similar HOMO and andLUMO 110′ atwith the 11 B3LYP/6-311++G**. This strongly suggests level where the use we of observed 11′ in explore that 11the0′ shares second a pathway.very similar The HOMO product and 12′ LUMO with 11. This strongly suggests the use of 11 in explore the second pathway. The product 12 LUMOis defined with in 11 the. This same strongly way. suggests the use of 110′ in explore the second pathway. The product 120′ is deﬁned in the same way. is definedAs suggested in the same by way.Alberti and Orfanopoulos [13], we consider the following intermediates: (a) As suggested by Alberti and Orfanopoulos [13], we consider the following intermediates: biradical/dipolar,As suggested (b)by perepoxide,Alberti and andOrfanopoulos (c) 1,2-dioxetane [13], we (Figure consider 8). the following intermediates: (a) (a)biradical/dipolar, biradical/dipolar, (b) (b)perepoxide, perepoxide, and and (c) (c)1,2-dioxetane 1,2-dioxetane (Figure (Figure 8).8 ).

(a) (b) (c) (a) (b) (c) FigureFigure 8.8. TheThe proposedproposed intermediatesintermediates studiedstudied ofof thethe peroxidationperoxidation reaction:reaction: ((aa)) BiradicalBiradical oror zwitterionzwitterion Figure 8. The proposed intermediates studied of the peroxidation reaction: (a) Biradical or zwitterion (dipolar),(dipolar), ( b(b)) perepoxide, perepoxide, and and ( c(c)) 1,2-dioxetane. 1,2-dioxetane. (dipolar), (b) perepoxide, and (c) 1,2-dioxetane. GeometriesGeometries of these these intermediates intermediates were were optimize optimizedd at the at thesame same theoretical theoretical level levelwhich which we found we Geometries of these intermediates were optimized at the same theoretical level which we found foundthat only that the only Zwitterionic the Zwitterionic and the and 1,2-dioxet the 1,2-dioxetaneane intermediates intermediates (labeled (labeled herein herein after after as asIz IandZ and ID that only the Zwitterionic and the 1,2-dioxetane intermediates (labeled herein after as Iz and ID Iintermediates,D intermediates, respectively) respectively) were were able able to to conver convergege to to stable stable structures whereas thethe perepoxideperepoxide intermediates, respectively) were able to converge to stable structures whereas the perepoxide intermediateintermediate resultedresulted in in the the partial partial dissociation dissociation of of the the oxygen oxygen molecule molecule from from11 110.′. intermediate resulted in the partial dissociation of the oxygen molecule1 1 from 11′. InIn thethe nextnext step, with the the optimized optimized structure structure of of 1111′ 0andand O2O as2 asreactant reactant and and Iz asIZ product,as product, the In the next step, with the optimized structure of 11′ and 1O2 as reactant and Iz as product, the thecorresponding corresponding TS1TS1Z wereZ were collocated collocated byby the the QST2 QST2 method. method. This This transition transition state state is is the the result ofof aa corresponding TS1Z were collocated by the QST2 method. This transition state is 1the result1 of a nucleophilicnucleophilic attack attack from from the theα-carbon α-carbon of of the theα,β α-unsaturated,β-unsaturated system system to theto the electrophilic electrophilicO2 (FigureO2 (Figure9a). 1 nucleophilic attack from the α-carbon of the α,β-unsaturated system1 to the1 electrophilic O2 (Figure The9a). secondThe second transition transition state TS1 stateD ,TS1 fromD, thefrom same the reactionsame reaction of 110 and of 11O′ and2 where O2 IwhereD is the ID product, is the product, shows 1 the9a).shows firstThe the oxygensecond first transitionoxygen···α-carbonα state bond-carbon TS1 (Figure bondD, from9 b)(Figure whilethe same 9b) the reaction nucleophilicwhile the of nucleophilic11 attack′ and fromO2 where attack the second I Dfrom is the oxygenthe product, second to ··· α theshowsoxygen positive the to thefirstβ-carbon positive oxygen··· to β form-carbon-carbon the to second bondform the(Figure bond second strongly 9b) bond while suggests stro thengly nucleophilic a secondsuggests intermediate. a attack second from intermediate. the second β oxygenResults to the from positive IRC calculations-carbon to whichform the connect second a transitionbond strongly state suggests to the correct a second reactant intermediate. and product 1 show that TS1Z leads to the intermediate IZ whereas TS1D did not lead to the reactants 110 and O2 but to IZ instead. Combining the two results gives us a two-step mechanism: the first transition state leads to intermediate IZ. From there, a second transition state leads to the second intermediate ID. In the next step, again we use the combination of QST2 and IRC methods to study the reactions between intermediates IZ, ID and the final product 120. For the formation of 120 from intermediate IZ we found a six-member transition state TS2Z where a nucleophilic attack of the negatively charged oxygen to the partially positive hydrogen attached to the nitrogen atom N1 is observed (Figure 10). IRC calculations were used to confirm the connection between this transition state to intermediate IZ and 120, respectively. Molecules 2020, 25, x FOR PEER REVIEW 9 of 16

MoleculesMolecules2020 2020, ,25 25,, 5008 x FOR PEER REVIEW 99 of of 15 16 (a) (b)

Figure 9. TS from QST2 calculation starting from the 1O2 and 11′ as reactants, and: (a) the dipolar intermediate, TS1Z (E = –687.577821 Hartree) or (b) the 1,2-dioxetane, TS1D (E = –687.562242 Hartree) as product.

In the next step, again we use the combination of QST2 and IRC methods to study the reactions between intermediates Iz, ID and the final product 12′. For the formation of 12′ from intermediate Iz (a) (b) we found a six-member transition state TS2Z where a nucleophilic attack of the negatively charged 1 1 oxygenFigureFigure to the 9.9.TS partiallyTS fromfrom QST2QST2 positive calculation calculation hydrog starting startingen attached from from the theto theOO22 and nitrogenand11 110 ′as as atomreactants, reactants, N1 isand: and: observed ((aa)) thethe dipolar(Figuredipolar 10). IRC calculationsintermediate,intermediate, wereTS1 TS1ZZ (Eused (E= = –687.577821 to687.577821 confirm Hartree)Hartree) the connectio oror( (bb)) the then between 1,2-dioxetane, 1,2-dioxetane, this transitionTS1 TS1DD(E (E= = state–687.562242687.562242 to intermediate Hartree)Hartree) Iz − − and 12asas′ product., product. respectively.

Results from IRC calculations which connect a transition state to the correct reactant and product show that TS1Z leads to the intermediate Iz whereas TS1D did not lead to the reactants 11′ and 1O2 but to Iz instead. Combining the two results gives us a two-step mechanism: the first transition state leads to intermediate Iz. From there, a second transition state leads to the second intermediate ID. In the next step, again we use the combination of QST2 and IRC methods to study the reactions between intermediates Iz, ID and the final product 12′. For the formation of 12′ from intermediate Iz we found a six-member transition state TS2Z where a nucleophilic attack of the negatively charged Figure 10.10. TS2ZZ from QST2 calculation starting from thethe IIZZ as reactant and the hydroperoxidehydroperoxide asas oxygenproductproduct to the PP (E(E partially == –687.571828687.571828 positive Hartree). Hartree). hydrog en attached to the nitrogen atom N1 is observed (Figure 10). IRC calculations were− used to confirm the connection between this transition state to intermediate Iz and The12′, transitionrespectively.transition state state of of the the reaction reaction between between intermediate intermediateID and ID and120, 12 however,′, however, is the is same the same as TS1 asZ sinceTS1Z thesince hydrogen the hydrogen atom at theatomN1 at position, the N1 again position, due to again its rigid due conformation, to its rigid cannotconformation, participate cannot and, asparticipate a result, theand, reaction as a result, proceeds the reaction to the same proceedsTS1Z totransition the same state.TS1Z transition state. Finally, takingtaking intointo accountaccount allall thethe hithertohitherto theoreticaltheoretical andand experimentalexperimental evidence,evidence, wewe proposepropose thethe followingfollowing mechanismmechanism forfor thethe transformationtransformation ofof 1111 toto 1212.. In the firstfirst step,step, thethe singletsinglet oxygenoxygen molecule approaches 1111 fromfrom thethe oppositeopposite sitesite ofof thethe tert-Bu-Bu substituent, thenthen a nucleophilic attackattack toto thethe αα-carbon results in an unstableunstable dipolardipolar/zwitterion/zwitterion intermediate IIzZ via the transition state TS1Z.. TheThe X-rayX-ray didiffractionffraction structurestructure (Figure(Figure2 2)) gives gives evidence evidence supporting supporting this this step. step. InIn thethe secondsecond step,step, another intermolecular nucleophilic attack from the remaining free oxygen of the peroxide to thethe positively-chargedpositively-chargedFigure 10. TS2 hydrogenZhydrogen from QST2 (at (at Ncalculation 1)N via1) via the startingthe second second from transition transitionthe IZstate as reactant TS2stateZ thatTS2and Z leadsthe that hydroperoxide toleads the final to the product as final 12product(Schemeproduct 12 (Scheme10 P). (E = –687.571828 10). Hartree). To further confirm the proposed mechanism, in which the hydrogen atom plays a crucial role, an acetylationThe transition at N1 state by means of the of reaction a Birch reductionbetween intermediate and catalytic I hydrogenationD and 12′, however, were carriedis the same out inas quinazolinoneTS1Z since the8 .hydrogen Subsequently, atom purification at the N1 ofposition, compound again11 Ndue-acylation to its rigid was performed,conformation, obtaining cannot compoundparticipate13 and,(Scheme as a result, 11). the reaction proceeds to the same TS1Z transition state. ProductFinally, 13takingwas theninto crystallizedaccount all the in the hitherto same waytheoretical as for compound and experimental11 (Scheme evidence, 12). Subsequently, we propose thethe crystals following was mechanism obtained and for analyzed the transformation by 1H and 13 Cof NMR, 11 to and12. itIn was the confirmed first step, that the photooxidationsinglet oxygen didmolecule not occur. approaches In the 111H-NMR from the spectrum, opposite site signals of the of terttert-Bu-butyl substituent, are observed then a at nucleophilic 0.89 ppm, N attack-Me at to 2.13the α ppm,-carbon and results a protecting in an unstable group ofdipolar/zwitterion hydrogens remains intermediate at 3.03 ppm. Iz via On the the transition other hand, state in TS1 theZ. 13TheC-NMR X-ray spectrum, diffraction four structure quaternary (Figure carbons 2) gives are ev observed:idence supporting two carbonyls this step. at 163.5 In the and second 170.8 ppm, step, C4aanotherat 122.3 intermolecular ppm, and C8a nucleophilic140.9 ppm. attack from the remaining free oxygen of the peroxide to the positively-chargedThe single crystals hydrogen obtained (at from N1) compound via the second13 were transition diffracted; state again, TS2 theZ that X-ray leads structure to the shows final aproduct pseudo-axial 12 (Scheme position 10). of the tert-butyl group in the acquired structure (Figure 11).

Molecules 2020, 25, x FOR PEER REVIEW 10 of 16

Molecules 2020, 25, 5008 10 of 15 Molecules 2020, 25, x FOR PEER REVIEW 10 of 16

Scheme 10. Reaction coordinate which describes the most probable reaction mechanism of the formation of 12 from 11.

To further confirm the proposed mechanism, in which the hydrogen atom plays a crucial role, an acetylation at N1 by means of a Birch reduction and catalytic hydrogenation were carried out in quinazolinone 8. Subsequently, purification of compound 11 N-acylation was performed, obtaining compound 13 (Scheme 11). Scheme 10. Reaction coordinate which describes the most probable reaction mechanism of the formation of 12 from 11.

To further confirm the proposed mechanism, in which the hydrogen atom plays a crucial role, an acetylation at N1 by means of a Birch reduction and catalytic hydrogenation were carried out in SchemeScheme 10. Reaction 10. Reaction coordinate coordinate which which describes describes the most the most probable probable reaction reaction mechanism mechanism of the of formation the quinazolinone 8. Subsequently, purification of compound 11 N-acylation was performed, obtaining of 12 formationfrom 11. of 12 from 11. compound 13 (Scheme 11). Scheme 11. Synthesis of 13. To further confirm the proposed mechanism, in which the hydrogen atom plays a crucial role, Productan acetylation 13 wasat N 1 thenby means crystallized of a Birch reductionin the same and catalyticway as hydrogenation for compound were carried11 (Scheme out in 12). Subsequently,quinazolinone the crystals8. Subsequently, was obtained purification and analyzedof compound by 1 H11 andN-acylation 13C NMR, was and performed, it was confirmed obtaining that photooxidationcompound 13 did (Scheme not occur. 11). In the 1H-NMR spectrum, signals of tert-butyl are observed at 0.89 ppm, N-Me at 2.13 ppm, and a protecting group of hydrogens remains at 3.03 ppm. On the other hand, in the 13C-NMR spectrum, four quaternary carbons are observed: two carbonyls at 163.5 and 170.8 ppm, C4a at 122.3 ppm, and C8aScheme 140.9 ppm. 11. Synthesis of 13.

Product 13 was then crystallized in the same way as for compound 11 (Scheme 12). Subsequently, the crystals was obtainedScheme and analyzed 11. Synthesis by of1H 13 and. 13C NMR, and it was confirmed that photooxidation did not occur. In the 1H-NMR spectrum, signals of tert-butyl are observed at 0.89 ppm, N-MeProduct at 2.13 13 ppm,was andthen acrystallized protecting ingroup the sameof hydrogens way as forremains compound at 3.03 11 ppm. (Scheme On the12). other 1 13 hand,Subsequently, in the 13C-NMR the crystals spectrum, was obtainedfour quaternary and analyzed carbons by H are and observed: C NMR, andtwo it carbonylswas confirmed at 163.5 that and photooxidation did not occur. In the 1H-NMR spectrum, signals of tert-butyl are observed at 0.89 170.8 ppm, C4a at 122.3 ppm, and C8a 140.9 ppm. ppm, N-Me at 2.13 ppm, and a protecting group of hydrogens remains at 3.03 ppm. On the other Scheme 12. Overnight crystallization of 13. Moleculeshand, 2020 in, 25the, x 13FORC-NMR PEER spectrum,REVIEWScheme four 12. quaternary Overnight carbons crystallization are observed: of 13. two carbonyls at 163.5 and11 of 16 170.8 ppm, C4a at 122.3 ppm, and C8a 140.9 ppm. The single crystals obtained from compound 13 were diffracted; again, the X-ray structure shows a pseudo-axial position of the tert-butyl group in the acquired structure (Figure 11).

Scheme 12. Overnight crystallization of 13.

Figure 11.11. Structure and X-ray didiffractionﬀraction ofof hexahidroquinazolinonehexahidroquinazolinone ((1313).). The single crystals obtainedScheme from 12. compound Overnight crystallization 13 were diffracted; of 13. again, the X-ray structure showsWehaveWe a pseudo-axialhaveThe shownsingle shown crystals that thatposition by by exchangingobtained exchanging of the fromtert allylic-butyl allyliccompound hydrogen group hydrogen 13 in inwere theN in1, acquir Ndiffracted; the1, photooxidationtheed photooxidation structure again, the (Figure of X-ray compound of 11).compoundstructure 13 does 13 notdoes occur showsnot under a occurpseudo-axial crystallization under position crystallization by of di theﬀusion. tert-butyl Weby group suggestdiffusion. in the that acquir theWe stabilityed suggeststructure of hexahydroquinazolinone (Figurethat the11). stability of (hexahydroquinazolinone13) increases and as a result (13 the) increases pair of electrons and as isa not result available the pair to promote of electrons the nucleophilic is not available attack ofto thepromote Cα on the singlet nucleophilic oxygen (Schemeattack of7 ).the Cα on singlet oxygen (Scheme 7). 1 1H-NMR evidence evidence shows shows that that the thephotooxidation photooxidation reaction reaction of 11 occurs of 11 inoccurs good yield. in good However, yield. However,the corresponding the corresponding yield of the yield precursor of the precursor 11 was 11ratherwas ratherlow. It low. has Itbeen has beenreported reported [26–30] [26 –that30] thatendocyclic endocyclic enamines enamines can canbe berearomatized rearomatized in inth thee presence presence of of catalysts, catalysts, such such as as Pd/C, Pd/C, PdCl22, PdBrPdBr22, Pd(COD)Pd(COD)22,, Pd(OAc)Pd(OAc)22,, oror Pd(TFA) Pd(TFA)2.2. WeWe note note the the enamine enamine moiety moiety of 11of 11(Scheme (Scheme1, purple 1, purple box), box), which which has beenhas been described described as a possible as a possible product product of the Birch of th reactione Birch (stepreaction 1, Scheme (step 31,). TheScheme same 3). observation The same observation applies to 9a or 9c. These observations strongly suggest that the presence of Pd/C would accelerate the rearomatization process when catalytic hydrogenation takes place (Scheme 13). This would explain the low yields mentioned above.

O O O

N N N Birch reduction

N N N H H H 8 9a 9c

Enamines Rearomatization Pd / C Scheme 13. Rearomatization of hexahidroquinazolinones (9a or 9c).

3. Materials and Methods Dichloromethane, ethyl acetate, and hexane were distilled before use. Toluene, acetonitrile, tert-butanol, isatoic anhydride, methylamine, p-toluene sulfonic acid, pivalaldehyde, sodium bicarbonate, sodium sulfate, sodium, palladium/carbon, 4,4-dimethylamino pyridine, and acetyl chloride were acquired from Sigma-Aldrich (St. Louis, MI, USA)and used without further purification. Reactions were monitored by thin layer chromatography (TLC) on Al plates coated with silica gel with fluorescent indicator 60 F254 (Merck-Mexico, Mexico City, MEXICO). Column chromatography was performed on silica gel 60 (0.040–0.063 mm, Merck-Mexico, Mexico City, MEXICO).

3.1. Analytical Methods NMR spectra of products as well as the proportions of each product in the reaction mixture were recorded on Varian Gemini at 200 MHz and Varian Mercury 400 MHz (1H-NMR), and 50 and 100 MHz (13C-NMR) spectrometers, using CDCl3 as a solvent and tretramethylsilane (TMS) as an internal standard. A mass spectrometric analysis was performed using an Agilent 6530 quadrupole time-of-flight (QTOF) LCMS with an electrospray ionization (ESI) source (Agilent Technologies, Santa Clara, CA, USA). A mass spectrometry analysis was conducted in positive ion mode, set for a detection of mass-to-charge ratio (m/z) of 100–1000. The X-ray structures were obtained using an APEX-Bruker apparatus.

Molecules 2020, 25, x FOR PEER REVIEW 11 of 16

Figure 11. Structure and X-ray diffraction of hexahidroquinazolinone (13).

We have shown that by exchanging allylic hydrogen in N1, the photooxidation of compound 13 does not occur under crystallization by diffusion. We suggest that the stability of hexahydroquinazolinone (13) increases and as a result the pair of electrons is not available to promote the nucleophilic attack of the Cα on singlet oxygen (Scheme 7). 1H-NMR evidence shows that the photooxidation reaction of 11 occurs in good yield. However, the corresponding yield of the precursor 11 was rather low. It has been reported [26–30] that Molecules 2020, 25, 5008 11 of 15 endocyclic enamines can be rearomatized in the presence of catalysts, such as Pd/C, PdCl2, PdBr2, Pd(COD)2, Pd(OAc)2, or Pd(TFA)2. We note the enamine moiety of 11 (Scheme 1, purple box), which has been described as a possible product of the Birch reaction (step 1, Scheme 3). The same applies to 9a or 9c. These observations strongly suggest that the presence of Pd/C would accelerate the observation applies to 9a or 9c. These observations strongly suggest that the presence of Pd/C would rearomatizationaccelerate the process rearomatization when catalytic process hydrogenationwhen catalytic hydrogenation takes place (Scheme takes place 13 ).(Scheme This would 13). This explain the lowwould yields explain mentioned the low yields above. mentioned above.

O O O

N N N Birch reduction

N N N H H H 8 9a 9c

Enamines Rearomatization Pd / C SchemeScheme 13. 13.Rearomatization Rearomatization ofof hexahidroquinazolinones (9a ( 9aor 9cor).9c ).

3. Materials3. Materials and and Methods Methods Dichloromethane,Dichloromethane, ethyl ethyl acetate, acetate, andand hexanehexane were distilled distilled before before use. use. Toluene, Toluene, acetonitrile, acetonitrile, tert-butanol,tert-butanol, isatoic isatoic anhydride, anhydride, methylamine, methylamine, p-toluene-toluene sulfonic sulfonic acid, acid, pivalaldehyde, pivalaldehyde, sodium sodium bicarbonate,bicarbonate, sodium sodium sulfate, sulfate, sodium, sodium, palladiumpalladium/carbon,/carbon, 4,4-dimethylamino 4,4-dimethylamino pyridine, pyridine, and andacetyl acetyl chloride were acquired from Sigma-Aldrich (St. Louis, MI, USA)and used without further chloride were acquired from Sigma-Aldrich (St. Louis, MI, USA) and used without further puriﬁcation. purification. Reactions were monitored by thin layer chromatography (TLC) on Al plates coated Reactionswith silica were gel monitored with fluorescent by thin layerindicator chromatography 60 F254 (Merck-Mexico, (TLC) on Mexico Al plates City, coated MEXICO). with silica Column gel with ﬂuorescentchromatography indicator was 60 F254performed (Merck-Mexico, on silica gel Mexico 60 (0.040–0.063 City, Mexico). mm, Merck-Mexico, Column chromatography Mexico City, was performedMEXICO). on silica gel 60 (0.040–0.063 mm, Merck-Mexico, Mexico City, Mexico).

3.1. Analytical3.1. Analytical Methods Methods NMRNMR spectra spectra of productsof products as as well well as as thethe proportionsproportions of of each each product product in the in thereaction reaction mixture mixture werewere recorded recorded on Varianon Varian Gemini Gemini at at 200 200 MHz MHz andand Varian Mercury Mercury 400 400 MHz MHz (1H-NMR), (1H-NMR), and and50 and 50 and 100 MHz13 (13C-NMR) spectrometers, using CDCl3 as a solvent and tretramethylsilane (TMS) as an 100 MHz ( C-NMR) spectrometers, using CDCl3 as a solvent and tretramethylsilane (TMS) as an internalinternal standard. standard. A massA mass spectrometric spectrometric analysisanalysis was performed performed using using an anAgilent Agilent 6530 6530 quadrupole quadrupole time-of-flight (QTOF) LCMS with an electrospray ionization (ESI) source (Agilent Technologies, time-of-ﬂight (QTOF) LCMS with an electrospray ionization (ESI) source (Agilent Technologies, Santa Clara, CA, USA). A mass spectrometry analysis was conducted in positive ion mode, set for a Santa Clara, CA, USA). A mass spectrometry analysis was conducted in positive ion mode, set for detection of mass-to-charge ratio (m/z) of 100–1000. The X-ray structures were obtained using an a detectionAPEX-Bruker of mass-to-charge apparatus. ratio (m/z) of 100–1000. The X-ray structures were obtained using an APEX-Bruker apparatus.

3.2. Theorical Study All calculations were carried out using the Gaussian 09 suite of programs [31]. Geometry optimizations were carried out at the B3LYP/6-311++G** level of theory [32–36] followed by characterization by frequency calculations at the same level of the theory, in which zero-point energy corrections (ZPE) and thermal corrections at the standard state (298.15 K and 1 atm) were obtained. Initial geometry for the model molecule 110 was constructed from the optimized geometry of 11 by substituting the cyclohexyl moiety by suitable hydrogen atoms. Similar methodology was applied in order to obtain the geometric parameters for the product, which has taken advantage of X-ray parameters from the obtained structure. The intermediates, such as perepoxide and biradical/dipolar, were constructed from the optimized geometry of 110 placing the O2 residue into the endo position and then optimized at the same level of theory. In order to obtain the initial coordinates for the transition state, QST2 [37] calculations were performed starting from the product and reactants’ optimized geometries. The resulting transition states were conﬁrmed by frequency calculation. An intrinsic reaction coordinate (IRC) calculation [38] was performed at the same level of theory in order to verify that the TS structure connects with the reactant and product. Coordinates for selected structures and thermochemistry data are given in the Supplementary Material. Molecules 2020, 25, 5008 12 of 15

3.3. Chemistry

3.3.1. Synthesis of 2-(tert-butyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one (8) Quinazolinone (8) was prepared according to a known procedure [19] from isatoic anhydride (6 g, 30.68 mmol), methylamine in isobutanol (18.2 mL, 122.7 mmol), and ethyl acetate (50 mL). The resulting material was filtered and concentrated in a rotavapor. The crude mixture (2.06 g), p-toluenesulfonic acid (0.10 g, 5% w/w), pivalaldehyde (1.86 mL, 1.2 equiv.), and dichloromethane (60 mL) was refluxed for 5 h and the resulting material was filtered and evaporated under reduced pressure, purified over SiO2 using hexane-ethyl acetate (9:1 to 6:4). Its structure was confirmed by 1H and 13C-NMR, and compared with available information in the literature [18]. Yield: 2.71 g, 90%; white solid, mp: 145–146 ◦C. 1 H NMR (200 MHz, CDCl3): δ 0.80 (s, 9H), 2.28 (s, 3H), 5.88 (s, 1H), 7.14–7.32 (m, 1H), 7.36 (dd, J = 7.6, 1.2 Hz, 1H), 7.55 (td, J = 7.7, 1.6 Hz, 1H), 7.67 (s, 1H), 8.02 (dd, J = 7.7, 1.7 Hz, 1H). 13C NMR (CDCl3, 50 MHz): δ 26.3, 38.5, 41.9, 79.9, 113.1, 116.6, 118.1, 128.1, 133.4, 146.5, 163.8. HREIMS m/z 218.1440 (calculated for C13H18N2O, 218.1419. Crystallographic data is deposited at Cambridge Crystallographic Data Center: CCDC no. 2006915.

3.3.2. Synthesis of 2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one (11) Ammonia (50 mL) was condensed to 78 C before the slow addition of 1.0 g (4.6 mmol) − ◦ of 2-(tert-butyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one (8), and sodium (0.64 g, 28 mmol). The resulting solution was stirred for 30 min and then treated with 1.4 mL (14 mmol) of tert-butanol. The reaction mixture was stirred at this temperature for 1 h. The reaction was quenched adding ammonium chloride (0.64 g, 18.5 mmol). Ammonia was evaporated at ambient temperature and reaction crude was dissolved in dichloromethane, dried with Na2SO4 and the excess solvent was evaporated under reduced pressure. A suspension of reaction crude (0.8 g), Pd/C (0.04 g, 5% w/w), and methanol (60 mL) was placed in a 100 mL flask containing a stir bar, then the system was closed with a septum. Two balloons were placed with hydrogen and the reaction was stirred overnight. The reaction mixture was filtered and concentrated in a rotavapor, then purified by column chromatography on silica, eluting with hexane-ethyl acetate (9:1 to 2:8). Yield: 130 mg, 28%; light-yellow solid; mp: 134–137 ◦C. 1 H NMR (200 MHz, CDCl3) δ 4.18 (d, 1H, J = 4.6 Hz, 1H), 3.88 (s, 1H), 3.06 (s, 3H), 2.27–2.04 (m, 4H), 1.77–1.36 (m, 4H), 0.91 (s, 9H). 13C NMR of this compound was acquired for 72 h, however many signals were observed due to the high reactivity of 11.

3.3.3. Synthesis of 2-(tert-Butyl)-4a-hydroperoxy-3-methyl-2,4a,5,6,7,8-hexahydroquinazolin- 4(3H)-one (12) Hexahydroquinazolin-4(1H)-one 11 (0.071 g, 0.32 mmol) was dissolved in 2 mL dichloromethane inside a suitable test tube, then 8 mL of hexane was added carefully, the system was closed with a cotton septum and left exposed to the environment overnight. Compound 12 was thus isolated as a 1 white crystal. Yield: 81 mg (quantitative); mp: 152–154 ◦C; H NMR (500 MHz, CDCl3) δ 1.02 (s, 9H), 1.55-1.67 (m, 3H), 1.94–1.97 (m, 1H), 2.08-2.11 (m, 1H), 2.39-2.47 (m, 2H), 2.94–2.95 (m, 1H) 3.10 (s, 3H), 13 4.90 (s, 1H). C NMR (125 MHz, CDCl3) δ 170.3, 168.6, 85.3, 76.3, 40.1, 37.0, 34.2, 33.7, 28.5, 27.2, 20.5. HREIMS m/z 254.1654 (calculated for C13H22N203, 254.1630). Crystallographic data is deposited at Cambridge Crystallographic Data Center: CCDC no. 2006916.

3.3.4. Synthesis of 1-Acetyl-2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one (13) Hexahydroquinazolin-4(1H)-one (11) (0.8 g, 3.6 mmol), 4-dimethylaminopyridine (0.43 g, 3.6 mmol) and toluene/acetonitrile solution 9:1 (40 mL) was added to a 100 mL flask. It was placed in an ice bath and the system purged with nitrogen. Acetyl chloride (0.3 mL, 4.3 mmol) was added dropwise and the reaction was stirred overnight. The reaction crude was filtered, evaporated, and purified by column chromatography on silica, eluting with hexane-ethyl acetate (9:1 to 3:7). Yield: quantitative; white solid; 1 mp: 146–148 ◦C; H NMR (200 MHz, CDCl3) δ 5.44 (s, 1H), 3.03 (s, 3H), 2.79–2.54 (m, 2H), 2.13 (s, 3H), Molecules 2020, 25, 5008 13 of 15

13 2.09–1.98 (m, 2H), 1.91–1.36 (m, 4H), 0.89 (s, 9H). C NMR (50 MHz CDCl3) δ 170.8, 163.5, 122.3, 38.4, 37.1, 30.5, 27.1, 27.0, 24.1, 22.6, 22.5, 21.6. HREIMS m/z 264.1843 (calculated for C15H24N202, 264.1838). Crystallographic data is deposited at Cambridge Crystallographic Data Center CCDC: no. 2007030.

4. Conclusions We have shown that the photooxidation reaction of compound 11 occurs in the absence of sensitizers and only with exposure to ambient air. 1H-NMR kinetics evidence also shows that it is a process with very reasonable yield. The presence of allylic hydrogen in N-H bond plays an important role in the mechanism which facilitates the nucleophilic attack of α-C by singlet oxygen, and in the formation of the six-member cyclical transition state. The low yield of compound 11 could be explained by the aromatization reaction of enamines in the presence of Pd/C. Theoretical study supports a 1 stepwise mechanism for the ene reaction between 11 and O2. The two-step reaction proceeds via a dipolar intermediate in which the ﬁrst TS corresponds to the nucleophilic attack of the α-carbon 1 to the O2 yielding the dipolar intermediate. The second step involves a nucleophilic attack from the negative oxygen to the partial positive hydrogen leading to the ﬁnal product 12. Applications of this methodology to other related 4-quinazolinone derivatives are currently being carried out in our laboratory.

Supplementary Materials: The following are available online, Figure S1: 1H spectrum (200 MHz, CDCl3) of 8, Figure S2: 13C spectrum (100 MHz, CDCl3) of 8, Figure S3: 1H spectrum (200 MHz, CDCl3) of 11, Figure S4: 13C spectrum (50 MHz, CDCl3) of 11, Figure S5: 1H spectrum (500 MHz, CDCl3) of 12, Figure S6: 13C spectrum (125 MHz, CDCl3) of 12, Figure S7: 1H spectrum (200 MHz, CDCl3) of 13, Figure S8: 13 C spectrum (50 MHz, CDCl3) of 13, Figure S9: Cartesian coordinates from optimized structure of 11 at the B3LYP/6-311++G** level of theory, Figure S10: Cartesian coordinates from optimized structure of 12 at the B3LYP/6-311++G** level of theory, Figure S11: Cartesian coordinates from optimized structure of the R at the B3LYP/6-311++G** level of theory, Figure S12: Cartesian coordinates from optimized structure of the P at the B3LYP/6-311++G** level of theory, Figure S13: Cartesian coordinates from optimized structure of the TS1Z at the B3LYP/6-311++G** level of theory, Figure S14: Cartesian coordinates from optimized structure of the TS1D at the B3LYP/6-311++G** level of theory, Figure S15: Cartesian coordinates from optimized structure of the TS2Z at the B3LYP/6-311++G** level of theory, Figure S16: Cartesian coordinates from optimized structure of the TS2D at the B3LYP/6-311++G** level of theory, Figure S17: Cartesian coordinates from optimized structure of the IZ at the B3LYP/6-311++G** level of theory, Figure S18: Cartesian coordinates from optimized structure of the ID at the B3LYP/6-311++G** level of theory, Table S1: Crystal data and structure refinement for 135leo (2-(tert-butyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one (8)), Table S2: Crystal data and structure refinement for leo144a (2-(tert-butyl)-4a-hydroperoxy-3-methyl-2,4a,5,6,7,8-hexahydroquinazolin- 4(3H)-one (12), Table S3: Crystal data and structure refinement for redn (1-acetyl-2-(tert-butyl)-3-methyl-2,3, 5,6,7,8-hexahydroquinazolin-4(1H)-one (13), Table S4: Bond Lengths for 135leo (2-(tert-butyl)-3-methyl-2,3- dihydroquinazolin-4(1H)-one (8)), Table S5: Bond Angles for 135leo (2-(tert-butyl)-3-methyl-2,3- dihydroquinazolin-4(1H)-one (8)), Table S6 Hydrogen Atom Coordinates (Å 104) and Isotropic Displacement × Parameters (Å2 103) for 135leo (2-(tert-butyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one (8)), Table S7: Crystal data and× structure refinement for leo144a (2-(tert-butyl)-4a-hydroperoxy-3-methyl-2,4a,5,6,7,8- hexahydroquinazolin-4(3H)-one (12), Table S8: Fractional Atomic Coordinates ( 104) and Equivalent × Isotropic Displacement Parameters (Å2 103) for leo144a (2-(tert-butyl)-4a-hydroperoxy-3-methyl-2,4a,5,6, 7,8-hexahydroquinazolin-4(3H)-one (12)× Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor, Table S9: Anisotropic Displacement Parameters (Å2 103) for leo144a (2-(tert-butyl)-4a-hydroperoxy- 3-methyl-2,4a,5,6,7,8-hexahydroquinazolin-4(3H)-one (12). The× Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+ ... ], Table S10: Bond Lengths for leo144a (2-(tert-butyl)-4a-hydroperoxy- 3-methyl-2,4a,5,6,7,8-hexahydroquinazolin-4(3H)-one (12), Table S11: Bond Angles for leo144a (2-(tert-butyl)- 4a-hydroperoxy-3-methyl-2,4a,5,6,7,8-hexahydroquinazolin-4(3H)-one (12), Table S12: Torsion Angles for leo144a (2-(tert-butyl)-4a-hydroperoxy-3-methyl-2,4a,5,6,7,8-hexahydroquinazolin-4(3H)-one (12), Table S13: Hydrogen Atom Coordinates (Å 104) and Isotropic Displacement Parameters (Å2 103) for leo144a (2-(tert- butyl)-4a-hydroperoxy-3-methyl-2,4a,5,6,7,8-hexahydroquinazolin-4(3H)-one× (12),× Table S14: Crystal data and structure refinement for redn (1-acetyl-2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one (13), Table S15: Fractional Atomic Coordinates ( 104) and Equivalent Isotropic Displacement Parameters × (Å2 103) for redn (1-acetyl-2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one (13). Ueq is defined× as 1/3 of of the trace of the orthogonalised UIJ tensor, Table S16: Anisotropic Displacement Parameters (Å2 103) for redn (1-acetyl-2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one (13). The Anisotropic× displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+ ... ], Table S17: Bond Lengths for redn (1-acetyl-2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one (13), Molecules 2020, 25, 5008 14 of 15

Table S18: Bond Angles for redn (1-acetyl-2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one (13), Table S19: Hydrogen Atom Coordinates (Å 104) and Isotropic Displacement Parameters (Å2 103) for redn (1-acetyl-2-(tert-butyl)-3-methyl-2,3,5,6,7,8-hexahydroquinazolin-4(1H)-one× (13). × Author Contributions: A.M., J.R.V.-C., and J.E. conceived and designed the experiments; J.E. wrote the paper. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Acknowledgments: We would like to thank CONACyT for financial support (project no. CB2015/256653). Adrian Méndez gratefully acknowledges CONACyT for a scholarship (573014). Conflicts of Interest: The authors declare no conflict of interest.

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