9,10-Phenanthrenedione As Visible-Light Photoredox Catalyst

catalysts

Article 9,10-Phenanthrenedione as Visible-Light Photoredox Catalyst: A Green Methodology for the Functionalization of 3,4-Dihydro-1,4-Benzoxazin-2- Ones through a Friedel-Crafts Reaction

Jaume Rostoll-Berenguer, Gonzalo Blay , José R. Pedro * and Carlos Vila * Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, 46100 Burjassot, València, Spain; [email protected] (J.R.-B.); [email protected] (G.B.) * Correspondence: [email protected] (J.R.P.); [email protected] (C.V.); Tel.: +34-9-6354-4329 (J.R.P.); +34-9-6354-3043 (C.V.) Received: 12 November 2018; Accepted: 6 December 2018; Published: 12 December 2018

Abstract: A visible-light photoredox functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones through a Friedel-Crafts reaction with indoles using an inexpensive organophotoredox catalyst is described. The reaction uses a dual catalytic system that is formed by a photocatalyst simple and cheap, 9,10-phenanthrenedione, and a Lewis acid, Zn(OTf)2. 5W white LEDs are used as visible-light source and oxygen from air as a terminal oxidant, obtaining the corresponding products with good yields. The reaction can be extended to other electron-rich arenes. Our methodology represents one of the most valuable and sustainable approach for the functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones, as compared to the reported procedures. Furthermore, several transformations were carried out, such as the synthesis of the natural product cephalandole A and a tryptophol derivative.

Keywords: visible-light photocatalysis; organophotoredox catalysis; Friedel-Crafts reaction; indoles; 1,4-benzoxazin-2-ones

1. Introduction Visible-light (sunlight) is a safe, renewable, abundant, inexpensive, and non-polluting source of energy, which means that sunlight is the most “green” energy source that we can use. Therefore, the development of methodologies using visible-light has become one of the greatest challenges in the scientific community in the last century [1,2]. In this context, the development of methodologies to increase the use of visible-light to control chemical reactivity and achieve molecular complexity with higher levels of efficiency have become a hot topic in the last years and many challenging organic reactions have been described [3–9]. For this purpose, intensive research has been devoted to develop photoredox catalysts that are capable of absorbing visible light and transfer this energy to the organic molecules. Many elegant works on photocatalysis have been reported using transition metal ruthenium or iridium polypyridyl complexes as efficient photosensitizers [10–13]. However, these transition metals are expensive and they have potential toxicity that has limited their usefulness. Therefore, for the development of more sustainable visible-light photoredox methodologies the use of organic dyes is more convenient due to the low cost, high availability, and low toxicity that offer this kind of catalyst. However, some of the organophotoredox catalysts are expensive, such as pyrilium [14–18] or acridinium [19–24] salts (Figure1). Organic dyes, such as Rose Bengal and Eosin Y, are more convenient due to their lower cost [25–31]. Nevertheless, the development of new methodologies using simpler organophotoredox catalysts that improve the sustainability of the “green” chemical

Catalysts 2018, 8, 653; doi:10.3390/catal8120653 www.mdpi.com/journal/catalysts Catalysts 2018,, 8,, 653x FOR PEER REVIEW 22 of of 2122 methodologies using simpler organophotoredox catalysts that improve the sustainability of the process“green” ischemical highly desirable. process Inis thishighly context, desirable.α-diketones In this represent context, a classα-diketones of compounds represent that cana class exhibit of absorptioncompounds bands that can in the exhibit visible absorption range and bands that have in the been visible used forrange photochemical and that have processes been used [32– 34for]. Forphotochemical example, 9,10-phenanthrenedione processes [32–34]. For isexample, an inexpensive 9,10-phenanthren organic compoundedione is withan inexpensive very low molecular organic weightcompound (Figure with1 )very when low compared molecular withweight other (Figure organophotoredox 1) when compared catalysts. with other This organophotoredoxα-diketone has absorptioncatalysts. This bands α-diketone in the visible has absorption region (412 bands and 505 innm the invisible acetonitrile, region see(412 Supplementary and 505 nm in Materials acetonitrile, for further35, see supplementary details) and therefore materials could for befurther excited details) by visible-light. and therefore However, could be it hasexcited been by rarely visible-light. used in visible-lightHowever, it photochemicalhas been rarely processesused in visible-light [35–37]. photochemical processes [35–37].

Figure 1. ComparisonComparison ofof commercially commercially available available common common visible-light visible-light photoredox photoredox catalysts catalysts and 9,10- and 9,10-phenanthrenedionephenanthrenedione (source: (source: Sigma-Aldrich Sigma-Aldrich (2018)). (2018)).

On the other hand, tertiary amines represent an important class of compounds in organic synthesis, wherewhere functionalization functionalization is ofis greatof great interest interest for the for chemical the chemical community, community, medicinal medicinal chemistry, pharmaceutical,chemistry, pharmaceutical, and agrochemical and agrochemical industry. In indust this context,ry. In thethis combinationcontext, the ofcombination visible-light of catalysis visible- andlight C-Hcatalysis bond and functionalization C-H bond functionalization adjacent to a tertiaryadjacent amine to a tertiary has been amine successfully has been developed successfully in 3 thedeveloped last years in [the38– last41]. years Normally, [38–41]. this Normally, sp -C-H functionalizationthis sp3-C-H functionalization involves the oxidationinvolves the of theoxidation amine toof the iminium amine ion,to iminium which canion, bewhich attacked can be by attacked various by kind various of nucleophiles. kind of nucleophiles. Nonetheless, Nonetheless, the major the numbermajor number of examples of examples are regarded are rega torded the functionalization to the functionalization of N-aryl of tetrahydroisoquinolines N-aryl tetrahydroisoquinolines [42–52], N[42–52],,N-dimethylanilines N,N-dimethylanilines [53–57], [53–57], and N and-aryl N-aryl glycine glycine derivatives derivatives [58– [58–662].2]. Hence, Hence, exploring exploring other substrates is highly desirable.desirable. In In this this context, 1,4-dibenzoxazinone skeleton skeleton is is present in a wide number of compounds with biological activities and its functionalization could be signiﬁcantsignificant and 3 interesting for medicinal chemistry [[63–69].63–69]. Very recently, HuoHuo describeddescribed thethe ironiron catalyzedcatalyzed spsp3-C-H functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones3,4-dihydro-1,4-benzoxazin-2-ones [70,71] [70,71] using as a terminal oxidant tert-Butyl hydroperoxide (TBHP)(TBHP) [ 70[70]] or or 2,3-dichloro-5,6-dicyanobenzoquinone 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (DDQ) [71 ].[71]. We envisionedWe envisioned that thisthat functionalizationthis functionalization could becould achieved be achieved by a visible-light by a visible-light photochemical photochemical process. Herein, process. continuing Herein, withcontinuing our interest with our in interest the synthesis in the ofsynthesis multisubstituted of multisubstituted 1,4-dihydrobenzoxazin-2-ones 1,4-dihydrobenzoxazin-2-ones [72] and [72] the Friedel-Craftsand the Friedel-Crafts reactions withreactions indoles with [73 –indoles75], we [73–75], described we the described visible-light the photoredoxvisible-light Friedel-Crafts photoredox reactionFriedel-Crafts of indoles reaction with of benzoxazin-2-ones indoles with benzoxazin-2-ones using as catalyst using a simple as catalyst and cheap a simple diketone and such cheap as thediketone 9,10-phenanthrenedione, such as the 9,10-phenanthrenedione, and oxygen as terminal and oxidant.oxygen Duringas terminal our experimental oxidant. During work andour theexperimental preparation work of manuscript, and the preparation a photoredox of functionalization manuscript, a photoredox of 3,4-dihydro-1,4-benzoxazin-2-ones functionalization of 3,4- wasdihydro-1,4-benzoxazin-2-ones reported [76,77]. In both cases, was thereported expensive [76,77]. Ru(bpy) In both2Cl cases,2 was usedthe expensive as photocatalyst. Ru(bpy)2 Besides,Cl2 was unlikeused as the photocatalyst. photoredox catalyticBesides, systemunlike describedthe photor earlieredox [catalytic76], the resultssystem that described were obtained earlier with[76], ourthe methodresults that are were not affected obtained by with the stericour method hindrance are no aroundt affected the C3by carbonthe steric atom hindrance of the indole around skeleton. the C3 Thecarbon second atom paperof the [indole77] deals skeleton. with theThe functionalization second paper [77] of deals 3,4-dihydro-1,4-quinoxalin-2(1 with the functionalization Hof)-one 3,4- skeletondihydro-1,4-quinoxalin-2(1 and only one exampleH)-one skeleton of 3,4-dihydro-1,4-benzoxazin-2-ones and only one example of 3,4-dihydro-1,4-benzoxazin-2- was reported with low yieldones was (44%). reported with low yield (44%).

Catalysts 2018, 8, x FOR PEER REVIEW 3 of 22

2. Results Initially, we choose the Friedel-Crafts reaction between indole 1a and 4-benzyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-one 2a in acetonitrile at room temperature under air atmosphere and the irradiation of white LEDs (5W). Under these conditions, a survey of photocatalyst were screened, and the results are summarized in Table 1. In a preliminary study of the photocatalyst (entries 1–6), Ru(bpy)2Cl2 (A), Rose Bengal (B), Fukuzumi photocatalyst (E), and 9,10-phenanthrenedione (F) afforded product 3aa with similar yields, around 30%, after 24 h. With these catalysts, we decided to change the molar ratio of 1a:2a from 0.15:0.1 to 0.1:0.15 (entries 7–10). The best yield for compound 3aa was obtained when Rose Bengal (B) and 9,10-phenanthrenedione (F) were used as photocatalyst (53% yield in both cases). In view of the good performance of the photocatalyst F, we decided to carry out the reaction using another α-diketone, such as benzyl (G), however the yield of 3aa drop to only

Catalysts15%. In2018 view, 8, 653of the results, we decided to continue the optimization of the reaction conditions using3 of 21 9,10-phenanthrenedione as a photocatalyst, due to its low molecular weight and its lower price in relation to the other photocatalysts tested. 2. ResultsIn order to improve the yield of 3aa, we decided to investigate a dual catalytic protocol combiningInitially, Brønsted we choose or Lewis the Friedel-Crafts acid catalysis reaction and visible-light between indolephotoredox1a and catalysis 4-benzyl-3,4-dihydro-2 [58] (Table 2). ForH -benzo[this purpose,b][1,4]oxazin-2-one different Brøn2astedin acids, acetonitrile such as atPhCO room2H temperature or AcOH, were under tested, air however atmosphere product and 3aa the irradiationwas obtained of whitewith lower LEDs yield (5W). (entri Underes 2 these and conditions,3, respectively). a survey After of we photocatalyst decided to test were Zn screened, salts as andLewis the acid, results obtaining are summarized an improvement in Table of1. the In aca preliminarytalytic performance study of when the photocatalyst we used 10 mol% (entries of Zn(OTf)2. In these conditions, the functionalized benzoxazinone 3aa was obtained in 76% after 9 h 1–6), Ru(bpy)2Cl2 (A), Rose Bengal (B), Fukuzumi photocatalyst (E), and 9,10-phenanthrenedione (F) afforded(entry 5).product Other Lewis3aa with acids, similar such yields,as Fe(OTf) around2, Cu(OTf) 30%, after2, and 24 Sc(OTf) h. With3 thesewere catalysts,evaluated we (entries decided 6–8), to changeobtaining the lower molar yields ratio offor1a the:2a correspondingfrom 0.15:0.1 to product 0.1:0.15 3aa (entries. The 7–10).lowering The of best the yield catalyst for compoundloading of 3aaZn(OTf)was2 obtained to 5 mol% when did Rosenot influence Bengal (B in) andthe 9,10-phenanthrenedioneyield of product 3aa (entry (F) 10). were Subsequently, used as photocatalyst different (53%solvents yield such in both as toluene, cases). InCH view2Cl2, ofDMF, the goodTHF, performance or MeOH were of the screen photocatalysted (entriesF 11–14),, we decided obtaining to carry the outfunctionalized the reaction benzoxazinone using another 3aaα-diketone, with much such lower as benzyl yields. ( GWe), howevercould diminish the yield the of photocatalyst3aa drop toonly and 15%.Lewis In acid view loadings of the results, maintaining we decided the yield to continue of product the 3aa optimization (entries 15 of and the 16). reaction Finally, conditions some control using 9,10-phenanthrenedioneexperiments were carried as aout. photocatalyst, Thus, in duethe to ab itssence low molecularof visible-light weight and(entry its lower19) or price 9,10- in relationphenanthrenedione to the other photocatalysts(entry 20), the product tested. 3aa was not detected or the conversion was very low.

a Table 1.1. PreliminaryPreliminary optimizationoptimization ofof thethe reactionreaction conditionsconditionsa ..

Entry Photocatalyst (mol%) 1a (mmol) 2a (mmol) t (h) Yield of 3aa (%) b Entry Photocatalyst (mol%) 1a (mmol) 2a (mmol) t (h) Yield of 3aa (%) b 1 1 A (1%)A (1%) 0.15 0.15 0.1 0.1 24 24 28 28 2 2 B (5%)B (5%) 0.15 0.15 0.1 0.1 27 27 38 38 3 3 C (5%)C (5%) 0.15 0.15 0.1 0.1 46 46 27 27 4 D (5%) 0.15 0.1 48 13 4 D (5%) 0.15 0.1 48 13 5 E (5%) 0.15 0.1 48 35 5 E (5%) 0.15 0.1 48 35 6 F (10%) 0.15 0.1 25 33 6 7 F (10%)A (1%) 0.15 0.1 0.1 0.15 24 25 48 33 7 8 A (1%)B (5%) 0.1 0.1 0.15 0.15 24 24 53 48 8 9 B (5%)E (5%) 0.1 0.1 0.15 0.15 48 24 27 53 9 10 E (5%)F (10%) 0.1 0.1 0.15 0.15 24 48 53 27 10 11 F (10%)G (10%) 0.1 0.1 0.15 0.15 24 24 15 53 11 G (10%) 0.1 0.15 24 15 a Reaction conditions: 1a, 2a, x mol% of photocatalyst in 1 mL of CH CN at rt under white LEDs 5W irradiation a 3 and Reaction air atmosphere. conditions:b Isolated 1a, 2a yield, x mol% of 3aa of. photocatalyst in 1 mL of CH3CN at rt under white LEDs 5W irradiation and air atmosphere. b Isolated yield of 3aa. In order to improve the yield of 3aa, we decided to investigate a dual catalytic protocol combining

Brønsted or Lewis acid catalysis and visible-light photoredox catalysis [58] (Table2). For this purpose, different Brønsted acids, such as PhCO2H or AcOH, were tested, however product 3aa was obtained with lower yield (entries 2 and 3, respectively). After we decided to test Zn salts as Lewis acid, obtaining an improvement of the catalytic performance when we used 10 mol% of Zn(OTf)2. In these conditions, the functionalized benzoxazinone 3aa was obtained in 76% after 9 h (entry 5). Other Lewis acids, such as Fe(OTf)2, Cu(OTf)2, and Sc(OTf)3 were evaluated (entries 6–8), obtaining lower yields for the corresponding product 3aa. The lowering of the catalyst loading of Zn(OTf)2 to 5 mol% did not inﬂuence in the yield of product 3aa (entry 10). Subsequently, different solvents such as toluene, CH2Cl2, DMF, THF, or MeOH were screened (entries 11–14), obtaining the functionalized benzoxazinone 3aa with much lower yields. We could diminish the photocatalyst and Lewis acid loadings maintaining the yield of product 3aa (entries 15 and 16). Finally, some control experiments Catalysts 2018, 8, 653 4 of 21 were carried out. Thus, in the absence of visible-light (entry 19) or 9,10-phenanthrenedione (entry 20), Catalysts 2018, 8, x FOR PEER REVIEW 4 of 22 the product 3aa was not detected or the conversion was very low.

Table 2. Optimization of the reaction conditions a. Table 2. Optimization of the reaction conditions a.

Entry Photocat. (mol%) Additive (mol%) Solvent t (h) Yield of 3aa (%) b Entry Photocat. (mol%) Additive (mol%) Solvent t (h) Yield of 3aa (%) b 1 1 F (10%)F (10%)- - CH3CNCH3CN 2424 53 53 F 2 2 F (10%) (10%)PhCO PhCO2H2H (10 (10 mol%) mol%) CH3CN CH3CN 2424 36 36 3 F (10%) AcOH (10 mol%) CH CN 24 26 3 F (10%) AcOH (10 mol%) 3 CH3CN 24 26 4 F (10%) Zn(OAc)2 (10 mol%) CH3CN 24 37 4 F (10%) Zn(OAc)2 (10 mol%) CH3CN 24 37 5 F (10%) Zn(OTf)2 (10 mol%) CH3CN 9 76 5 F (10%) Zn(OTf)2 (10 mol%) CH3CN 9 76 6 F (10%) Fe(OTf)2 (10 mol%) CH3CN 20 22 6 F (10%) Fe(OTf)2 (10 mol%) CH3CN 20 22 7 F (10%) Cu(OTf)2 (10 mol%) CH3CN 17 19 2 3 7 8 F (10%)F (10%)Cu(OTf) Sc(OTf)3 (10(10 mol%) mol%) CH3CN CH CN 1917 16 19

8 9 F (10%)F (10%)Sc(OTf) Zn(OTf)3 (102 (5 mol%) mol%) CH3CN CH3CN 919 74 16

9 10 F (10%)F (10%)Zn(OTf) Zn(OTf)2 2(5(5 mol%) mol%) Toluene CH3CN 89 40 74 10 11 F (10%)F (10%)Zn(OTf) Zn(OTf)2 2(5(5 mol%) mol%) CH2Cl Toluene2 20 8 30 40 11 12 F (10%)F (10%)Zn(OTf) Zn(OTf)2 2(5(5 mol%) mol%) DMF CH2Cl2 7220 12 30 13 F (10%) Zn(OTf) (5 mol%) THF 9 34 12 F (10%) Zn(OTf)2 2(5 mol%) DMF 72 12 14 F (10%) Zn(OTf)2 (5 mol%) MeOH 17 22 13 F (10%) Zn(OTf)2 (5 mol%) THF 9 34 15 F (5%) Zn(OTf)2 (5 mol%) CH3CN 10 74 14 F (10%) Zn(OTf)2 (5 mol%) MeOH 17 22 16 F (5%) Zn(OTf)2 (2.5 mol%) CH3CN 10 75 15 F (5%) Zn(OTf)2 (5 mol%) CH3CN 10 74 17 B (5%) Zn(OTf)2 (2.5 mol%) CH3CN 17 38 16 c F (5%) Zn(OTf)2 (2.5 mol%) CH3CN 10 75 18 F (5%) Zn(OTf)2 (2.5 mol%) CH3CN 15 45 d 2 3 e 17 19 B (5%)F (5%)Zn(OTf) Zn(OTf) 2(2.5(2.5 mol%) mol%) CH3CN CH CN 7217 n.d. 38 c e 18 20F (5%) -Zn(OTf) Zn(OTf)2 2(2.5(2.5 mol%) mol%) CH3CN CH3CN 7215 <5 45 19 d F (5%) Zn(OTf)2 (2.5 mol%) CH3CN 72 n.d. e a 20 Reaction conditions:- 1a (0.1 mmol), 2aZn(OTf)(0.15 mmol),2 (2.5 x mol%mol%) of photocatalyst, CH x3 mol%CN of additive72 in 1 mL of solvent <5 e at rt under white LEDs 5W irradiation and air atmosphere; b Isolated yield of 3aa; c 0.12 mmol of 2a was used; a Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), x mol% of photocatalyst, x mol% of additive in 1 mL of d Reaction performed under darkness; e Conversion to product 3aa by 1H NMR of the crude reaction mixture. solventN.d. at =rt not under detected. white LEDs 5W irradiation and air atmosphere; b Isolated yield of 3aa; c 0.12 mmol of 2a was used; d Reaction performed under darkness; e Conversion to product 3aa by 1H NMR of the crude reaction mixture.With N.d. the = optimizednot detected. reaction conditions in hand (entry 13, Table2), the scope of the Friedel-Crafts reaction was explored with a range of indoles 1 with several substituents in different positions (SchemeWith1). the Indoles optimized bearing reaction electron-donating conditions in (Me, hand Ph, (entry OMe, 13, OH) Table or 2), electron-withdrawing the scope of the Friedel-Crafts (F, Cl, Br) groupsreaction furnished was explored the corresponding with a range functionalized of indoles 1 benzoxazinoneswith several substituents3 in 54–80% in yield, different independently positions of(Scheme the position 1). Indoles or the bearing electronic electron-donating character of the (Me, substituents. Ph, OMe, Moreover,OH) or electron-withdrawing disubstituted indoles, (F, such Cl, Br) as 1ngroups–1p, affordedfurnished the correspondingthe corresponding products functionalized3na–3pa, with benzoxazinones high yields (up to3 77%).in 54–80% It is interesting yield, toindependently note the good of the results position that or were the obtainedelectronic withcharacter 2- and of the 4-substituted substituents. indoles, Moreover, despite disubstituted the steric hindranceindoles, such around as 1n the–1p, reactive afforded carbon the corresponding atom. Thus, forproducts example, 3na– 2-methyl-3pa, with andhigh 4-methylindol yields (up to 77%). gave theIt is correspondinginteresting to note reaction the good products results with that yields were ofobtained 58% and with 64%, 2- respectivelyand 4-substituted (versus indoles, 13% and despite 26% describedthe steric inhindrance the literature around [76]). the Also reactive 2-phenyl-, carbon 4-ﬂuoro-, atom. and Thus, 1,2-dimethylindole for example, give2-methyl- yields and of 80%, 4- 79%,methylindol and 70%, gave respectively. the corresponding reaction products with yields of 58% and 64%, respectively (versusAfterwards, 13% and we26% examined described the in scopethe literature of the Friedel-Crafts[76]). Also 2-phenyl-, alkylation 4-fluoro-, with a rangeand 1,2- of 3,4-dihydro-1,4-benzoxazin-2-onesdimethylindole give yields of 80%, 79%,2 using and indole 70%, respectively.1a as nucleophile (Scheme2). An assortment of derivativesAfterwards, with differentwe examined groups the onscope the of benzyl the Friedel-Crafts moiety reacted alkylation smoothly with in thea range optimized of 3,4-dihydro- reaction conditions,1,4-benzoxazin-2-ones obtaining the 2 using corresponding indole 1a productsas nucleophile3ab–3ad (Schemewith good 2). An yields assortment (56–88%). of derivatives A thienylmethyl with groupdifferent on thegroups nitrogen on ofthe the benzyl benzoxazinone moiety reacted1e could smoothly be used in in the the Friedel-Crafts optimized reactionreaction obtaining conditions, the correspondingobtaining the corresponding product 3ae with products a high 3ab yield–3ad (77%). with Additionally, good yields 3,4-dihydro-1,4-benzoxazin-2-ones(56–88%). A thienylmethyl group 1gon andthe nitrogen1h, with methylof the benzoxazinone substituents at 61e and could 7 positions be used workedin the Friedel- well inCrafts this Friedel-Crafts reaction obtaining reaction. the corresponding product 3ae with a high yield (77%). Additionally, 3,4-dihydro-1,4-benzoxazin-2-ones 1g and 1h, with methyl substituents at 6 and 7 positions worked well in this Friedel-Crafts reaction.

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F (5 mol%) R O O F (5 mol%) R O O O O Zn(OTf)2 (2.5 mol%) R O O R Zn(OTf)2 (2.5 mol%) + + N White LEDs (5W) N White LEDs (5W) N N N CH CN, rt Bn CH 3 HN Bn 1 NH Bn 3CN, rt HN Bn 1 H 2a 3 2a 3 O O O O O O MeO O O O O O O O MeO O

N N N N N N N N Bn N Bn Bn Bn HN N Bn HN Bn N Bn HN Bn Me HN Me NH Me Me H 3aa, 10h, 75% yield 3ba, 15h, 58% yield 3ca, 11h, 58% yield 3da, 12h, 64% yield 3aa, 10h, 75% yield 3ba, 15h, 58% yield 3ca, 11h, 58% yield 3da, 12h, 64% yield F O O Me MeO HO F O O Me O O MeO O O HO O O O O O O O O N N N N N Bn N N N N Bn Bn NH HN Bn HN Bn HN Bn H HN Bn HN HN Bn 3ea, 14h, 79% yield 3fa, 11h, 63% yield 3ga, 11h, 68% yield 3ha, 11h, 66% yield 3ea, 14h, 79% yield 3fa, 11h, 63% yield 3ga, 11h, 68% yield 3ha, 11h, 66% yield O O O O Br O O O O O O Br O O Me O O O O Me N N N N N N N Bn Me Bn Cl N HN Bn Me HN Bn HN Bn Bn HN HN Cl HN Bn HN Bn HN 3ja, 14h, 77% yield 3la, 16h, 59% yield 3ia, 14h, 54% yield 3ja, 14h, 77% yield 3ka, 14h, 71% yield 3ia, 14h, 54% yield 3ka, 14h, 71% yield 3la, 16h, 59% yield O O O O O O MeO O O O O O O MeO O O O O N N N N N N N Bn Bn N Bn N HN HN Bn Bn HN Bn HN Ph N Me Me HN Bn Ph Me Me Me HN Bn 3pa, 14h, 77% yield 3ma, 14h, 80% yield Me 3pa, 14h, 77% yield 3ma, 14h, 80% yield 3na, 12h, 70% yield 3oa, 11h, 70% yield 3na, 12h, 70% yield 3oa, 11h, 70% yield SchemeScheme 1.1. ScopeScope ofof thethe Friedel-CraftsFriedel-Crafts Friedel-Crafts reactionreaction reaction withwith with differentdifferent different indolesindoles indoles 1 1andand 2a2a2a.. Reaction.Reaction Reaction conditions:conditions: conditions: 1 (0.1 mmol), 2a (0.15 mmol), F (5 mol%) and Zn(OTf)2 (2.5 mol%) in 1 mL of CH3CN at rt under white 1(0.1(0.1 mmol), mmol), 2a2a (0.15(0.15 mmol), mmol), FF (5(5 mol%) mol%) and and Zn(OTf) Zn(OTf)22 (2.5(2.5 mol%) mol%) in in 1 1 mL mL of of CH CH3CNCN at at rt rt under white LEDsLEDs irradiation.irradiation. Isolated yields afterafter columncolumn chromatography.chromatography.

Scheme 2. Scope of the Friedel-Crafts reaction with indole 1a and different benzoxazinones 2. Reaction Scheme 2. ScopeScope ofof thethe Friedel-CraftsFriedel-Crafts reactionreaction withwith indoleindole 1a andand differentdifferent benzoxazinonesbenzoxazinones 2.. conditions:Reaction conditions:1a (0.1 mmol), 1a (0.12 (0.15 mmol), mmol), 2 (0.15F (5 mmol), mol%), F and (5 mol%), Zn(OTf) and2 (2.5 Zn(OTf) mol%)2 in (2.5 1 mL mol%) of CH in3 CN1 mL at of rt Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), F (5 mol%), and Zn(OTf)2 (2.5 mol%) in 1 mL of underCH3CN white at rt LEDsunder irradiation. white LEDs Isolated irradiation. yields Isolated after column yields after chromatography. column chromatography. CH3CN at rt under white LEDs irradiation. Isolated yields after column chromatography. We also extended our methodology to other electron-rich arenes, such as pyrrole (4a), We also extended our methodology to other electron-rich arenes, such as pyrrole (4a),), N-- N-methylpyrrole (4b), and 1,3,5-trimethoxybenzene (5) (Scheme3), which were reacted with methylpyrrole (4b),), andand 1,3,5-trimethoxybenzene1,3,5-trimethoxybenzene ((5)) (Scheme(Scheme 3),3), whichwhich werewere reactedreacted withwith 3,4-3,4- 3,4-dihydro-1,4-benzoxazin-2-ones 2a under the optimized reaction conditions, obtaining the dihydro-1,4-benzoxazin-2-ones 2a underunder thethe optimizedoptimized reactionreaction conditions,conditions, obtainingobtaining thethe corresponding functionalized benzoxazinones 6a, 6b, and 7 with good yields (55–83%). Again, it is corresponding functionalized benzoxazinones 6a,, 6b,, andand 7 withwith goodgood yieldsyields (55–83%).(55–83%). Again,Again, itit isis interesting to note the good result obtained with 1,3,5-trimethoxybenzene, a starting material with a interestinginteresting toto notenote thethe goodgood resultresult obtainedobtained withwith 1,3,5-trimethoxybenzene, a starting material with a large steric hindrance. The reaction product was obtained with a yield of 83% (versus 23% described largelarge stericsteric hindrance.hindrance. TheThe reactireaction product was obtained with a yield of 83% (versus 23% described in the literature [76]). inin thethe literatureliterature [76]).[76]).

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SchemeScheme 3. 3. ScopeScope ofof thethe Friedel-CraftsFriedel-Crafts reactionreaction reaction withwith otherother other electron-richelectron-rich electron-rich arenesarenes arenes andand and benzoxazinonebenzoxazinone benzoxazinone 2a2a2a.. . ReactionReaction conditions: conditions: arenearene (0.1(0.1(0.1 mmol), mmol),mmol),2a 2a2a(0.15 (0.15(0.15 mmol), mmol),mmol),F FF(5 (5(5 mol%), mol%),mol%), and andand Zn(OTf) Zn(OTf)Zn(OTf)2 (2.522 (2.5(2.5 mol%) mol%)mol%) in inin 1 mL11 mLmL of

ofCHof CHCH3CN33CNCN at atat rt rt underrt underunder white whitewhite LEDs LEDsLEDs irradiation. irradiation.irradiation. Isolated IsIsolatedolated yields yieldsyields after afterafter column columncolumn chromatography. chromatography.chromatography.

Furthermore,Furthermore, inin orderorder toto demonstrate demonstrate thethe sust sustainabilitysustainabilityainability ofof our our visi visible-lightvisible-lightble-light photoredox photoredox methodology,methodology, thethe the reactionreaction reaction waswas was performedperformed performed usingusing using susun-lightn-light sun-light (Scheme(Scheme (Scheme 4).4). Therefore,Therefore,4). Therefore, whenwhen thethe when Friedel-Friedel- the CraftsFriedel-CraftsCrafts reactionreaction reaction waswas placedplaced was outdoorsoutdoors placed outdoors underunder sun-sun- underlightlight sun-light irradiation,irradiation, irradiation, thethe correspondingcorresponding the corresponding productproduct 3aa product3aa waswas obtained3aaobtainedwas obtained withwith 87%87% with yieldyield 87% inin 55 yield h.h. in 5 h.

SchemeScheme 4. 4. Friedel-CraftsFriedel-Crafts alkylationalkylation ofof indoleindole 1a1a withwith benzoxazinonebenzoxazinone 2a2a2a usingusing sun-lightsun-light irradiation.irradiation. Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), F (5 mol%) and Zn(OTf) (2.5 mol%) in 1 mL of ReactionReaction conditions:conditions: 1a1a (0.1(0.1 mmol),mmol), 2a2a (0.15(0.15 mmol),mmol), FF (5(5 mol%)mol%) andand Zn(OTf)Zn(OTf)22 (2.5(2.5 mol%)mol%) inin 11 mLmL ofof CH CN at rt under sun-light irradiation. Isolated yield after column chromatography. CHCH33CNCN atat rtrt underunder sun-lightsun-light irradiation.irradiation. IsIsolatedolated yieldyield afterafter columncolumn chromatography.chromatography.

Based on previous literature reports [3,70] and control experiments (see Supplementary BasedBased onon previousprevious literatureliterature reportsreports [3,70][3,70] andand controlcontrol experimentsexperiments (see(see supplementarysupplementary Materials for further details) a possible mechanism for the reaction is proposed in Scheme5. materialsmaterials forfor furtherfurther details)details) aa possiblepossible mechanismmechanism forfor thethe reactionreaction isis proposedproposed inin SchemeScheme 5.5. Initially,Initially, Initially, under visible-light irradiation, 9,10-phenanthrenedione F is excited to F*. Subsequently, underunder visible-lightvisible-light irradiatioirradiation,n, 9,10-phenanthrenedione9,10-phenanthrenedione FF isis excitedexcited toto FF*.*. Subsequently,Subsequently, thisthis excitedexcited this excited state, by a single-electron transfer (SET), transforms 4-benzyl-3,4-dihydro-2H state,state, byby aa single-electronsingle-electron transfertransfer (SET),(SET), transformstransforms 4-benzyl-3,4-dihydro-24-benzyl-3,4-dihydro-2HH-benzo[-benzo[bb][1,4]oxazin-2-][1,4]oxazin-2- -benzo[b][1,4]oxazin-2-one 2a into a nitrogen radical cation I, with the consequent reduction of F* to.- oneone 2a2a intointo aa nitrogennitrogen radicalradical cationcation II,, withwith thethe consequentconsequent reductionreduction ofof FF** toto thethe radicalradical anionanion FF.-,, .- the radical anion F , which can be oxidized by molecular oxygen (O2) regenerating the photocatalyst whichwhich cancan bebe oxidizedoxidized byby molecularmolecular oxygenoxygen (O(O22)) regeneratingregenerating thethe photocatalystphotocatalyst FF.. OnOn thethe otherother hand,hand, F. On the other hand, deprotonation of the nitrogen radical cation I can generate the α-amino radical deprotonationdeprotonation ofof thethe ninitrogentrogen radicalradical cationcation II cancan generategenerate thethe αα-amino-amino radicalradical IIII,, whichwhich cancan bebe II, which can be further oxidized to the iminium ion III. After the nucleophilic attack of indole 1a to furtherfurther oxidizedoxidized toto thethe iminiumiminium ionion IIIIII.. AfterAfter thethe nucleophilicnucleophilic attackattack ofof indoleindole 1a1a toto thethe iminiumiminium ionion the iminium ion III, product 3aa is obtained. The radical mechanism was conﬁrmed by an experiment IIIIII,, productproduct 3aa3aa isis obtained.obtained. TheThe radicalradical mechanismmechanism waswas confirmedconfirmed byby anan experimentexperiment controlcontrol usingusing aa control using a radical scavenger (TEMPO). Under these conditions, a trace amount of product 3aa radicalradical scavengerscavenger (TEMPO).(TEMPO). UnderUnder thesethese conditions,conditions, aa tracetrace amountamount ofof productproduct 3aa3aa waswas observedobserved byby 1 was1 observed by H NMR of the crude reaction mixture and the corresponding adduct formed from 1HH NMRNMR ofof thethe crudecrude reactionreaction mixturemixture andand thethe correspondingcorresponding adductadduct formedformed fromfrom radicalradical IIII andand radical II and TEMPO was detected by HRMS. In this mechanism, the O2 is the terminal oxidant that TEMPOTEMPO waswas detecteddetected byby HRMS.HRMS. InIn thisthis mechanism,mechanism, thethe OO22 isis thethe terminalterminal oxidantoxidant thatthat isis reducedreduced inin is reduced in H2O2. The role of molecular oxygen was also studied in a control experiment. When we HH22OO22.. TheThe rolerole ofof molecularmolecular oxygenoxygen waswas alsoalso studiedstudied inin aa controlcontrol experiment.experiment. WhenWhen wewe performedperformed performed the photocatalyzed Friedel-Crafts reaction under argon atmosphere, the conversion to thethe photocatalyzedphotocatalyzed Friedel-CraftsFriedel-Crafts reactionreaction undeunderr argonargon atmosphere,atmosphere, thethe conversionconversion toto productproduct 3aa3aa product 3aa was very low (12%). However, the role of Zn(OTf)2 is not clear, with this Lewis acid, waswas veryvery lowlow (12%).(12%). However,However, thethe rolerole ofof Zn(OTf)Zn(OTf)22 isis notnot clear,clear, withwith thisthis LewisLewis acid,acid, thethe reactionreaction isis the reaction is accelerated, activating either the electrophile or the nucleophile, or both. accelerated,accelerated, activatingactivating eithereither thethe elecelectrophiletrophile oror thethe nucleophile,nucleophile, oror both.both. To showcase the utility of our catalytic protocol, we performed several synthetic transformations (Scheme6). Compound 3aa was catalytically deprotected using H2 and 10% Pd/C in THF/EtOH, and then the addition of 1 equivalent of DDQ for 1 h, allowed us to obtain the natural product cephalandole A [78](8) in 91% yield in a one-pot reaction. Moreover, compounds 3 can be used to prepare tryptophol derivatives by a reduction of the carbonyl group of the benzoxazin-2-one. Tryptophols are a class of indoles bearing a 3-(hydroxyethyl) side chain. These class of compounds have been isolated from a variety of natural sources, and some of them possess biological activity [79–82].

Catalysts 2018, 8, x FOR PEER REVIEW 7 of 22

Catalysts 2018, 8, 653 7 of 21

Therefore, compound 3aa has been reduced with LiAlH4 affording tryptophol derivative 9 with 57%Catalysts yield. 2018, 8, x FOR PEER REVIEW 7 of 22

Scheme 5. Pausible mechanism for the visible-light photoredox Friedel-Crafts alkylation of 1a with 2a.

To showcase the utility of our catalytic protocol, we performed several synthetic transformations (Scheme 6). Compound 3aa was catalytically deprotected using H2 and 10% Pd/C in THF/EtOH, and then the addition of 1 equivalent of DDQ for 1 h, allowed us to obtain the natural product cephalandole A [78] (8) in 91% yield in a one-pot reaction. Moreover, compounds 3 can be used to prepare tryptophol derivatives by a reduction of the carbonyl group of the benzoxazin-2-one. Tryptophols are a class of indoles bearing a 3-(hydroxyethyl) side chain. These class of compounds have been isolated from a variety of natural sources, and some of them possess biological activity [79–82]. Therefore, compound 3aa has been reduced with LiAlH4 affording tryptophol derivative 9 with 57% yield.SchemeScheme 6. 6.Synthetic Synthetic transformations. transformations. Isolated Isolated yields yields after after column column chromatography. chromatography. 3. Materials and Methods 3. Materials and Methods 3.1. General Information 3.1. General Information Reactions were carried out in 5 mL vials under air, unless otherwise indicated. Commercial reagentsReactions were used were as carried purchased. out in Reactions 5 mL vials were under monitored air, unless by thin-layer otherwise chromatography indicated. Commercial (TLC) analysisreagents using were Merck used Silicaas purchased. Gel 60 F-254 Reactions (Sigma-Aldrich, were monitored St. Louis, by thin-layer MO, USA) chromatography thin layer plates (TLC) and theseanalysis are visualizedusing Merck using Silica both Gel an 60 UV F-254 lamp (Sigma-Aldrich, (254 nm) and then St. Louis, a CAM MO, solution USA) (an thin aqueous layer plates solution and ofthese ceric are ammonium visualized molybdate). using bothFlash an UV column lamp (254 chromatography nm) and then was a CAM performed solution on (an Merck aqueous Silica solution Gel 60

(Sigma-Aldrich,of ceric ammonium St. Louis, molybdate). MO, USA), Flash 0.040–0.063 column chro mm.matography NMR (Nuclear was performed Magnetic Resonance) on Merck Silica spectra Gel Scheme 6. Synthetic transformations. Isolated yields after column chromatography. were60 (Sigma-Aldrich, run in a Bruker DPX300 St. Louis, spectrometer MO, USA), (Bruker, 0.040–0 Billerica,.063 mm. MA, NMR USA) at(Nuclear 300 MHz Magnetic for 1H and Resonance) 75 MHz spectra13 were run in a Bruker DPX300 spectrometer (Bruker, Billerica, MA, USA) at 300 MHz for 1H for C using residual nondeuterated solvent as internal standard (CHCl3: δ 7.26 and δ 77.00 ppm, 3. Materials and Methods13 respectively,and 75 MHz MeOH: for Cδ using3.34 ppm residual and δnondeuterated49.87 ppm, respectively, solvent as Acetone:internal standardδ 2.05 ppm (CHCl and 3δ: δ29.84 7.26ppm, and δ 77.00 ppm, respectively, MeOH: δ 3.34 ppm and δ 49.87 ppm, respectively, Acetone: δ 2.05 ppm and respectively).3.1. General Information Chemical shifts are given in ppm. The carbon multiplicity was established by DEPT (Distortionlessδ 29.84 ppm, respectively). Enhancement Chemical by Polarization shifts are Transfer) given in experiments.ppm. The carbon High multiplicity resolution was mass established spectra (HRMS-ESI)by DEPTReactions (Distortionless were were recorded carried Enhancement on out a TRIPLETOF in 5 mL by vials TPolarizatio5600 under spectrometer nair, Transfer) unless (AB otherwiseexperiments. Sciex, Warrington, indicated. High UK),resolution Commercial equipped mass T withreagentsspectra an electrospray (HRMS-ESI)were used as source were purchased. recorded with a capillaryReactions on a TRIPLETOF voltage were monitored of 4.55600 kV spectrometer (ESI). by thin-layer (AB chromatography Sciex, Warrington, (TLC) UK), analysisequippedAll using photocatalysts, with Merck an electrospray Silica Gel indoles, 60source F-254 with and(Sigma-Aldrich, a capillary related voltage arenesSt. Louis, of were4.5 MO, kV USA)(ESI). commercially thin layer plates available. and 3,4-dihydro-benzoxazin-2-onesthese are visualized using both an derivatives UV lamp (2542a, nm)2b ,and and then2c a wereCAM synthesizedsolution (an aqueous according solution to a procedureof ceric ammonium that was publishedmolybdate). in Flash the literature column andchro thematography spectroscopic was performed data (1H-NMR on Merck and 13 SilicaC-NMR) Gel match60 (Sigma-Aldrich, with those reported. St. Louis, 3,4-dihydro-benzoxazin-2-ones MO, USA), 0.040–0.063 mm. derivativesNMR (Nuclear2d, 2e Magnetic, 2f, 2g, and Resonance)2h were synthesizedspectra were accordingrun in a Bruker to the DPX300 same procedurespectrometer and (Bruker, were characterizedBillerica, MA, byUSA)1H-NMR, at 300 MHz13C-NMR, for 1H and HRMS75 MHz (see for Supplementary13C using residual Materials nondeuterated for further solvent details). as internal standard (CHCl3: δ 7.26 and δ 77.00 ppm, respectively, MeOH: δ 3.34 ppm and δ 49.87 ppm, respectively, Acetone: δ 2.05 ppm and δ 29.84 ppm, respectively). Chemical shifts are given in ppm. The carbon multiplicity was established by DEPT (Distortionless Enhancement by Polarization Transfer) experiments. High resolution mass spectra (HRMS-ESI) were recorded on a TRIPLETOFT5600 spectrometer (AB Sciex, Warrington, UK), equipped with an electrospray source with a capillary voltage of 4.5 kV (ESI).

Catalysts 2018, 8, x FOR PEER REVIEW 8 of 22

All photocatalysts, indoles, and related arenes were commercially available. 3,4-dihydrobenzoxazin-2-ones derivatives 2a, 2b, and 2c were synthesized according to a procedure that was published in the literature and the spectroscopic data (1H-NMR and 13C-NMR) match with those reported. 3,4-dihydro-benzoxazin-2-ones derivatives 2d, 2e, 2f, 2g, and 2h were synthesized according to the same procedure and were characterized by 1H-NMR, 13C-NMR, and HRMS (see Catalysts 2018, 8, 653 8 of 21 supplementary materials for further details).

3.2. General Procedure: Friedel-Cr Friedel-Craftsafts Reaction between 4-benzyl-3 4-Benzyl-3,4-Dihydro-1,4-Benzoxazin-2-Ones,4-dihydro-1,4-benzoxazin-2-ones and and IndolesIndoles,, Pyrroles and 1,3,5-Trimethoxybenzene1,3,5-trimethoxybenzene In a 5 5 mL mL vial vial were were placed placed the the proper proper aromatic aromatic compound compound (1 (,1 4,,4 or, or 5, 50.10, 0.10 mmol), mmol), the the proper proper 4- benzyl-3,4-dihydro-1,4-benzoxazin-2-one4-benzyl-3,4-dihydro-1,4-benzoxazin-2-one (2 (,2 0.15, 0.15 mmol), mmol), Zn(OTf) Zn(OTf)2 2(1.0(1.0 mg, mg, 0.0025 0.0025 mmol, mmol, 2.5 2.5 mol%), mol%), and 9,10-phenanthrenedione9,10-phenanthrenedione (F (,F 1.0, 1.0 mg, mg, 0.005 0.005 mmol, mmol, 5 mol%). 5 mol%). Subsequently, Subsequently, the mixture the wasmixture dissolved was dissolvedin non-dried in non-dried acetonitrile acetonitrile (1 mL) and (1 was mL) placed and wa at twos placed centimetres at two fromcentimet theres white from LEDs. the white The reaction LEDs. wasThe reaction monitored was by monitored TLC and wasby TLC stopped and was when stopped the corresponding when the corresponding indole was consumed indole was (NOTE: consumed It is (NOTE:important It is to important analyse frequently to analyse the frequently conversion the andconversion to stop and the reactionto stop the in thereaction precise in momentthe precise to momentavoid product to avoid decomposition. product decomposition. The reaction The should reaction not beshould left overnight not be left under overnight irradiation under conditions).irradiation Theconditions). resulted reactionThe resulted mixture reaction was puriﬁed mixture by column was purified chromatography by column using chromatography hexane:EtOAc mixtures using (fromhexane:EtOAc 95:5 to 85:15) mixtures to afford (from pure 95:5 product to 85:15)3 ,to6, afford or 7. pure product 3, 6, or 7.

3.3. Characterization Data for Compounds 3, 6 and 7 4-Benzyl-3-(1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one4-Benzyl-3-(1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3aa3aa))

Using indole indole (1a (1a, ,11.7 11.7 mg, mg, 0.1 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2H-benzo[H-benzo[b][1,4]oxazin-2-oneb][1,4]oxazin-2-one (2a, 35.8 (2a, mg,35.8 0.15 mg, mmol), 0.15 mmol), in accordance in accordance with withGeneral General Procedure, Procedure, the product the product 3aa was3aa obtainedwas obtained (26.6 mg, (26.6 0.075 mg, 1 mmol, 75% yield) after 10 h as a colourless oil. 1H NMR 1(300 MHz, CDCl3) δ 8.12 (s, 1H), 7.51 (d, J = 0.075 mmol, 75% yield) after 10 h as a colourless oil. H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.97.51 Hz, (d, 1H),J = 7.9 7.38–7.27 Hz, 1H), (m, 7.38–7.27 5H), 7.24–7.17 (m, 5H), (m, 7.24–7.17 1H), 7.16–7.04 (m, 1H), (m, 7.16–7.04 3H), 6.91 (m, (td, 3H), J 6.91= 7.7, (td, 1.4J Hz,= 7.7, 1H), 1.4 6.82 Hz, 1H),(dd, J 6.82 = 8.0, (dd, 1.2 JHz,= 8.0, 1H), 1.2 6.72 Hz, (d, 1H), J = 2.6 6.72 Hz, (d, 1H),J = 5.41 2.6 Hz,(s, 1H), 1H), 4.62 5.41 (d, (s, J 1H),= 14.9 4.62 Hz,(d, 1H),J =4.15 14.9 (d, Hz, J = 1H),14.8 13 Hz, 1H); 13C NMR (75 MHz,13 CDCl3) δ 164.56 (C), 141.84 (C), 136.08 (C), 135.78 (C), 134.13 (C), 128.81 4.15 (d, J = 14.8 Hz, 1H); C NMR (75 MHz, CDCl3) δ 164.56 (C), 141.84 (C), 136.08 (C), 135.78 (C), 134.13(CH), 127.77 (C), 128.81 (CH), (CH), 126.05 127.77 (C), 125.37 (CH), (CH), 126.05 122.87 (C), 125.37 (CH), (CH),122.79 122.87(CH), 120.41 (CH), 122.79(CH), 119.85 (CH), (CH), 120.41 119.09 (CH), (CH), 116.53 (CH), 113.87 (CH), 111.27 (CH), 108.69 (C), 55.86 (CH), 51.55 (CH2). The spectroscopic 119.85 (CH), 119.09 (CH), 116.53 (CH), 113.87 (CH), 111.27 (CH), 108.69 (C), 55.86 (CH), 51.55 (CH2). Thedata spectroscopicmatch with those data reported match with in the those literature reported [70]. in the literature [70].

4-Benzyl-3-(1-methyl-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one4-Benzyl-3-(1-methyl-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ba3ba))

Using NN-methylindole-methylindole (1b(1b,, 13.1 13.1 mg, mg, 0.1 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2H-benzo[H-benzo[b][1,4]oxazin-2-oneb][1,4]oxazin-2- (one2a, 35.8(2a, mg,35.8 0.15mg, mmol), 0.15 mmol), in accordance in accordance with General with General Procedure, Procedure, the product the product3ba was 3ba obtained was obtained (21.2 mg, 1 (21.2 mg, 0.058 mmol, 58% yield) after 15 h as a white1 solid. 1H NMR (300 MHz, CDCl3) δ 7.48 (dt, J = 0.058 mmol, 58% yield) after 15 h as a white solid. H NMR (300 MHz, CDCl3) δ 7.48 (dt, J = 8.0, 1.0 Hz, 1H),8.0, 1.0 7.38–7.21 Hz, 1H), (m, 7.38–7.21 7H), 7.16–7.10 (m, 7H), (m, 7.16–7. 2H),10 7.10–7.04 (m, 2H), (m, 7.10–7.04 1H), 6.92 (m, (td,1H),J 6.92= 7.7, (td, 1.5 J Hz,= 7.7, 1H), 1.5 Hz, 6.82 1H), (dd, 6.82J = 8.0, (dd, 1.4 J = Hz, 8.0, 1H), 1.4 Hz, 6.59 1H), (d, J 6.59= 0.6 (d, Hz, J = 1H), 0.6 Hz, 5.40 1H), (d, J5.40= 0.6 (d, Hz, J = 1H),0.6 Hz, 4.61 1H), (d, J4.61= 14.9 (d, Hz,J = 14.9 1H), Hz, 4.16 1H), (d, 13 4.16 (d, J = 14.9 Hz, 1H), 3.64 (s,13 3H); 13C NMR (75 MHz, CDCl3) δ 164.5 (C), 141.8 (C), 136.7 (C), 136.2 J = 14.9 Hz, 1H), 3.64 (s, 3H); C NMR (75 MHz, CDCl3) δ 164.5 (C), 141.8 (C), 136.7 (C), 136.2 (C), 134.1(C), 134.1 (C), 128.8(C), 128.8 (CH), (CH), 127.8 127.8 (CH), (CH), 127.7 127.7 (CH), (CH), 127.2 127.2 (CH), (CH), 126.7 126.7 (C), 125.3 (C), 125.3 (CH), (CH), 122.4 122.4 (CH), (CH), 120.0 (CH),120.0 (CH), 119.8 (CH), 119.2 (CH), 116.6 (CH), 113.8 (CH), 109.4 (CH), 107.1 (C), 55.8 (CH), 51.5 (CH2), 32.9 119.8 (CH), 119.2 (CH), 116.6 (CH), 113.8 (CH), 109.4 (CH), 107.1 (C), 55.8 (CH), 51.5 (CH2), 32.9 (CH3). CatalystsThe(CH3 spectroscopic). The2018 ,spectroscopic 8, x FOR data PEER match REVIEW data withmatch those with reported those reported in the literature in the literature [70]. [70]. 9 of 22

4-Benzyl-3-(2-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ca3ca))

Using 2-methylindole (1c, 13.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ca was obtained (21.2 mg, 0.058 mmol, 58% yield) after 11 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.98 (bs, 1H), 7.29–7.22 (m, 4H), 7.18 (dd, J = 7.9, 1.5 Hz, 1H), 7.16–7.03 (m, 5H), 6.95 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 6.89 (td, J = 7.7, 1.4 Hz, 1H), 6.80 (dd, J = 8.1, 1.4 Hz, 1H), 5.34 (s, 1H), 4.59 (d, J = 16.1 Hz, 1H), 3.98 (d, J = 16.1 Hz, 1H), 2.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.0 (C), 140.7 (C), 136.6 (C), 135.4 (C), 135.2 (C), 134.6 (C), 128.7 (CH), 127.3 (CH), 127.2 (CH), 126.5 (C), 125.5 (CH), 121.7 (CH), 120.2 (CH), 119.1 (CH), 118.7 (CH), 117.0 (CH), 113.2 (CH), 110.5 (CH), 106.0 (C), 55.8 (CH), 49.9 (CH2), 11.6 (CH3). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(4-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3da)

Using 4-methylindole (1d, 13.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3da was obtained (23.6 mg, 0.064 mmol, 64% yield) after 12 h as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.07 (bs, 1H), 7.34–7.29 (m, 3H), 7.21 (dd, J = 6.6, 3.0 Hz, 2H), 7.19–7.04 (m, 4H), 6.97–6.83 (m, 3H), 6.64 (d, J = 2.5 Hz, 1H), 5.70 (s, 1H), 4.63 (d, J = 14.4 Hz, 1H), 4.07 (d, J = 14.4 Hz, 1H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8 (C), 141.5 (C), 136.0 (C), 135.7 (C), 134.6 (C), 130.8 (C), 128.8 (CH), 128.1 (CH), 127.8 (CH), 125.4 (CH), 124.8 (C), 122.7 (CH), 122.6 (C), 122.4 (CH), 119.7 (CH), 116.5 (CH), 113.4 (CH), 110.2 (C), 109.2 (CH), 55.3 (CH), 51.0 (CH2), 20.5 (CH3). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(4-fluoro-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ea)

Using 4-fluoroindole (1e, 13.5 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ea was obtained (29.4 mg, 0.079 mmol, 79% yield) after 14 h as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.14 (dd, J = 7.9, 1.6 Hz, 1H), 7.11–7.08 (m, 2H), 7.00 (td, J = 7.7, 1.6 Hz, 1H), 6.89 (td, J = 7.7, 1.5 Hz, 1H), 6.85–6.77 (m, 1H), 6.74–6.63 (m, 2H), 5.71 (s, 1H), 4.46 (d, J = 15.5 Hz, 1H), 4.35 (d, J = 15.5 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ -121.20 (s); 13C NMR (75 MHz, CDCl3) δ 164.9 (C), 156.6 (d, JC-F = 246.6 Hz, C), 141.8 (C), 138.2 (d, JC-F = 10.9 Hz, C), 136.5 (C), 133.7 (C), 128.7 (CH), 127.4 (CH), 127.2 (CH), 125.3 (CH), 123.3 (d, JC-F = 7.9 Hz, CH), 123.1 (CH), 119.8 (CH), 116.4 (CH), 115.2 (d, JC-F = 19.4 Hz, C), 114.7 (CH), 107.7 (d, JC-F = 3.9 Hz, C), 107.6 (d, JC-F = 3.8 Hz, CH), 105.8 (d, JC-F = 19.6 Hz, CH), 56.8 (d, JC-F = 3.2 Hz, CH), 51.7 (d, JC-F = 1.5 Hz, CH2); HRMS (ESI) m/z: 373,1342 [M + H]+, C23H18FN2O2 required 373,1347.

Catalysts 2018, 8, x FOR PEER REVIEW 9 of 22 Catalysts 2018, 8, x FOR PEER REVIEW 9 of 22

4-Benzyl-3-(2-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ca) 4-Benzyl-3-(2-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ca)

Catalysts 2018, 8, 653 9 of 21

Using 2-methylindole (1c, 13.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using 2-methylindole2-methylindole (1c(1c,, 13.1 13.1 mg, mg, 0.1 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2H-benzo[H-benzo[b][1,4]oxazin-2-oneb][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ca was obtained (one2a, 35.8(2a, mg,35.8 0.15mg, mmol),0.15 mmol), in accordance in accordance with General with General Procedure, Procedure, the product the product3ca was obtained3ca was obtained (21.2 mg, (21.20.058 mg, mmol, 0.058 58% mmol, yield) 58% after yield) 11 h as after a white 11 h solid. as a 1whiteH NMR solid. (300 1H MHz, NMR CDCl (300 )MHz,δ 7.98 CDCl (bs, 1H),3) δ 7.29–7.227.98 (bs, (21.2 mg, 0.058 mmol, 58% yield) after 11 h as a white solid. 1H NMR (3003 MHz, CDCl3) δ 7.98 (bs, 1H), 7.29–7.22 (m, 4H), 7.18 (dd, J = 7.9, 1.5 Hz, 1H), 7.16–7.03 (m, 5H), 6.95 (ddd, J = 8.1, 6.9, 1.1 Hz, (m,1H), 4H), 7.29–7.22 7.18 (dd, (m, J4H),= 7.9, 7.18 1.5 (dd, Hz, J 1H),= 7.9, 7.16–7.03 1.5 Hz, 1H), (m, 5H),7.16–7.03 6.95 (ddd,(m, 5H),J = 6.95 8.1, 6.9,(ddd, 1.1 J Hz,= 8.1, 1H), 6.9,6.89 1.1 Hz, (td, 1H), 6.89 (td, J = 7.7, 1.4 Hz, 1H), 6.80 (dd, J = 8.1, 1.4 Hz, 1H), 5.34 (s, 1H), 4.59 (d, J = 16.1 Hz, 1H), 1H),J = 7.7, 6.89 1.4 (td, Hz, J 1H), = 7.7, 6.80 1.4 (dd, Hz,J 1H),= 8.1, 6.80 1.4 Hz,(dd, 1H), J = 8.1, 5.34 1.4 (s, 1H),Hz, 1H), 4.59 (d,5.34J =(s, 16.1 1H), Hz, 4.59 1H), (d, 3.98 J = (d,16.1J = Hz, 16.1 1H), Hz, 1H),3.98 (d, 2.02 J = (s, 16.1 3H); Hz,13C 1H), NMR 2.02 (75 (s, MHz, 3H); 13 CDClC NMR) δ (75166.0 MHz, (C), 140.7CDCl (C),3) δ 166.0 136.6 (C), (C), 140.7 135.4 (C), (C), 136.6 135.2 (C), 135.4 134.6 3.98 (d, J = 16.1 Hz, 1H), 2.02 (s, 3H); 13C NMR3 (75 MHz, CDCl3) δ 166.0 (C), 140.7 (C), 136.6 (C), 135.4 (C), 135.2 (C), 134.6 (C), 128.7 (CH), 127.3 (CH), 127.2 (CH), 126.5 (C), 125.5 (CH), 121.7 (CH), 120.2 (C), 128.7135.2 (CH),(C), 134.6 127.3 (C), (CH), 128.7 127.2 (CH), (CH), 127.3 126.5 (CH), (C), 127.2 125.5 (CH),(CH), 121.7126.5 (CH),(C), 125.5 120.2 (CH), (CH), 121.7 119.1 (CH), (CH), 120.2 118.7 (CH), 117.0119.1 (CH),(CH), 113.2118.7 (CH),(CH), 110.5 117.0 (CH), (CH), 106.0 113.2 (C), (CH), 55.8 110.5 (CH), (CH), 49.9 (CH106.0), (C), 11.6 55.8 (CH (CH),). The 49.9 spectroscopic (CH2), 11.6 (CH), 119.1 (CH), 118.7 (CH), 117.0 (CH), 113.2 (CH), 110.5 (CH), 106.02 (C), 55.8 (CH),3 49.9 (CH2), 11.6 (CHdata3). match The spectroscopic with those reported data match in the with literature those [reported70]. in the literature [70]. (CH3). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(4-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3da3da)) 4-Benzyl-3-(4-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3da)

Using 4-methylindole (1d, 13.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using 4-methylindole4-methylindole (1d(1d,, 13.1 13.1 mg, mg, 0.1 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2H-benzo[H-benzo[b][1,4]oxazin-2-oneb][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3da was obtained (one2a, 35.8(2a, mg,35.8 0.15mg, mmol),0.15 mmol), in accordance in accordance with General with General Procedure, Procedure, the product the product3da was 3da obtained was obtained (23.6 mg, (23.6 mg, 0.064 mmol, 64% yield) after 12 h as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.07 (bs, 1H), (23.60.064 mg, mmol, 0.064 64% mmol, yield) 64% after yield) 12 h after as a yellow 12 h as oil. a yellow1H NMR oil. (3001H NMR MHz, (300 CDCl MHz,) δ CDCl8.07 (bs,3) δ 1H), 8.07 7.34–7.29(bs, 1H), 7.34–7.29 (m, 3H), 7.21 (dd, J = 6.6, 3.0 Hz, 2H), 7.19–7.04 (m, 4H), 6.97–6.833 (m, 3H), 6.64 (d, J = 2.5 (m,7.34–7.29 3H), 7.21 (m, (dd,3H),J 7.21= 6.6, (dd, 3.0 Hz,J = 6.6, 2H), 3.0 7.19–7.04 Hz, 2H), (m, 7.19–7.04 4H), 6.97–6.83 (m, 4H), (m, 6.97–6.83 3H), 6.64 (m, (d, J3H),= 2.5 6.64 Hz, (d, 1H), J = 5.70 2.5 13 Hz, 1H), 5.70 (s, 1H), 4.63 (d, J = 14.4 Hz, 1H), 4.07 (d, J = 14.4 Hz, 1H), 2.4813 (s, 3H); 13C NMR (75 MHz, (s,Hz, 1H), 1H), 4.63 5.70 (d, (s, J1H),= 14.4 4.63 Hz, (d, 1H),J = 14.4 4.07 Hz, (d, 1H),J = 14.4 4.07 Hz,(d, J 1H), = 14.4 2.48 Hz, (s, 1H), 3H); 2.48C (s, NMR 3H); (75C MHz,NMR (75 CDCl MHz,3) δ CDCl3) δ 164.8 (C), 141.5 (C), 136.0 (C), 135.7 (C), 134.6 (C), 130.8 (C), 128.8 (CH), 128.1 (CH), 127.8 164.8CDCl3 (C),) δ 164.8 141.5 (C), 136.0141.5 (C), 135.7136.0 (C),(C), 134.6135.7 (C),(C), 130.8134.6 (C), (C), 128.8 130.8 (CH), (C), 128.8 128.1 (CH), (CH), 128.1 127.8 (CH), 127.8 125.4 (CH), 125.4 (CH), 124.8 (C), 122.7 (CH), 122.6 (C), 122.4 (CH), 119.7 (CH), 116.5 (CH), 113.4 (CH), 110.2 (CH), 125.4 124.8 (CH), (C), 122.7 124.8 (CH), (C), 122.7 122.6 (CH), (C), 122.4 122.6 (CH), (C), 122.4 119.7 (CH), (CH), 119.7 116.5 (CH), (CH), 116.5 113.4 (CH), (CH), 113.4 110.2 (CH), (C), 110.2 109.2 (C), 109.2 (CH), 55.3 (CH), 51.0 (CH2), 20.5 (CH3). The spectroscopic data match with those reported (CH),(C), 109.2 55.3 (CH), (CH), 55.3 51.0 (CH), (CH 51.0), 20.5 (CH (CH2), 20.5). The (CH spectroscopic3). The spectroscopic data match data withmatch those with reportedthose reported in the in the literature [70]. 2 3 inliterature the literature [70]. [70]. 4-Benzyl-3-(4-fluoro-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ea) 4-Benzyl-3-(4-fluoro-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one4-Benzyl-3-(4-ﬂuoro-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ea3ea))

Using 4-fluoroindole (1e, 13.5 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one Using 4-fluoroindole (1e, 13.5 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (Using2a, 35.8 4-ﬂuoroindole mg, 0.15 mmol), (1e, 13.5in accordance mg, 0.1 mmol) with andGeneral 4-benzyl-3,4-dihydro-2 Procedure, the productH-benzo[ 3ea bwas][1,4]oxazin-2-one obtained (29.4 (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ea was obtained (29.4 (mg,2a, 35.80.079 mg, mmol, 0.15 mmol),79% yield) in accordance after 14 h withas a Generalcolourless Procedure, oil. 1H NMR the product (300 MHz,3ea wasCDCl obtained3) δ 8.28 (29.4 (s, 1H), mg, mg, 0.079 mmol, 79% yield) after 14 h as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.140.079 (dd, mmol, J = 7.9, 79% 1.6 yield) Hz, after1H), 147.11–7.08 h as a colourless(m, 2H), 7.00 oil. (td,1H NMRJ = 7.7, (300 1.6 MHz,Hz, 1H), CDCl 6.89) (td,δ 8.28 J = (s,7.7, 1H), 1.5 7.14Hz, 7.14 (dd, J = 7.9, 1.6 Hz, 1H), 7.11–7.08 (m, 2H), 7.00 (td, J = 7.7, 1.6 Hz, 1H), 6.893 (td, J = 7.7, 1.5 Hz, (dd,1H), J6.85–6.77= 7.9, 1.6 (m, Hz, 1H), 1H), 6.74–6.63 7.11–7.08 (m, (m, 2H), 2H), 5.71 7.00 (s, (td, 1H),J = 4.46 7.7, 1.6(d, Hz,J = 15.5 1H), Hz, 6.89 1H), (td, 4.35J =7.7, (d, 1.5J = Hz,15.5 1H),Hz, 1H), 6.85–6.77 (m, 1H), 6.74–6.63 (m, 2H), 5.71 (s, 1H), 4.46 (d, J = 15.5 Hz, 1H), 4.35 (d, J = 15.5 Hz, 19 13 19 1H);6.85–6.77 19F NMR (m, 1H), (282 6.74–6.63 MHz, CDCl (m,3 2H),) δ -121.20 5.71 (s, (s); 1H), 13C 4.46 NMR (d, J(75= 15.5MHz, Hz, CDCl 1H),3 4.35) δ 164.9 (d, J =(C), 15.5 156.6 Hz, (d, 1H); JC-F F= 1H); F NMR (282 MHz, CDCl3) δ -121.2013 (s); C NMR (75 MHz, CDCl3) δ 164.9 (C), 156.6 (d, JC-F = 246.6NMR Hz, (282 C), MHz, 141.8 CDCl (C),3 )138.2δ -121.20 (d, JC-F (s); = 10.9C NMR Hz, C), (75 136.5 MHz, (C), CDCl 133.73) δ 164.9(C), 128.7 (C), 156.6(CH), (d, 127.4JC-F (CH),= 246.6 127.2 Hz, 246.6 Hz, C), 141.8 (C), 138.2 (d, JC-F = 10.9 Hz, C), 136.5 (C), 133.7 (C), 128.7 (CH), 127.4 (CH), 127.2 (CH),C), 141.8 125.3 (C), (CH), 138.2 123.3 (d, JC-F (d,= JC-F 10.9 = 7.9 Hz, Hz, C), CH), 136.5 123.1 (C), 133.7 (CH), (C), 119.8 128.7 (CH), (CH), 116.4 127.4 (CH), (CH), 115.2 127.2 (d, (CH), JC-F = 125.3 19.4 (CH), 125.3 (CH), 123.3 (d, JC-F = 7.9 Hz, CH), 123.1 (CH), 119.8 (CH), 116.4 (CH), 115.2 (d, JC-F = 19.4 (CH),Hz, C), 123.3 114.7 (d, (CH),JC-F = 107.7 7.9 Hz, (d, CH),JC-F = 123.13.9 Hz, (CH), C), 107.6 119.8 (d, (CH), JC-F116.4 = 3.8 (CH),Hz, CH), 115.2 105.8 (d, J C-F(d, J=C-F 19.4 = 19.6 Hz, Hz, C), 114.7CH), Hz, C), 114.7 (CH), 107.7 (d, JC-F = 3.9 Hz, C), 107.6 (d, JC-F = 3.8 Hz, CH), 105.8 (d, JC-F = 19.6 Hz, CH), (CH),56.8 (d, 107.7 JC-F = (d, 3.2J Hz,C-F =CH), 3.9 Hz,51.7 C),(d, J 107.6C-F = 1.5 (d, Hz,JC-F CH= 3.82); HRMS Hz, CH), (ESI) 105.8 m/z: (d,373,1342JC-F = [M 19.6 + Hz,H]+, CH),C23H18 56.8FN2O (d,2 56.8 (d, JC-F = 3.2 Hz, CH), 51.7 (d, JC-F = 1.5 Hz, CH2); HRMS (ESI) m/z: 373,1342 [M + H]+, C23H18FN2O2 requiredJ = 3.2 373,1347. Hz, CH), 51.7 (d, J = 1.5 Hz, CH ); HRMS (ESI) m/z: 373,1342 [M + H]+,C H FN O requiredC-F 373,1347. C-F 2 23 18 2 2 Catalystsrequired 2018 373,1347., 8, x FOR PEER REVIEW 10 of 22 4-Benzyl-3-(5-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3fa) 4-Benzyl-3-(5-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3fa)

Using 5-methylindole (1f, 13.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3fa was obtained (23.2 mg, 0.063 mmol, 63% yield) after 11 h as a brown oil. 1H NMR (300 MHz, CDCl3) δ 8.01 (bs, 1H), 7.37–7.27 (m, 5H), 7.24 (dd, J = 1.6, 0.8 Hz, 1H), 7.20 (dd, J = 8.3, 0.7 Hz, 1H), 7.12 (dd, J = 7.9, 1.5 Hz, 1H), 7.04 (ddd, J = 9.4, 8.0, 1.6 Hz, 2H), 6.92 (td, J = 7.7, 1.5 Hz, 1H), 6.82 (dd, J = 8.0, 1.4 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 5.37 (d, J = 0.7 Hz, 1H), 4.61 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 2.41 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 164.6 (C), 141.9(C), 136.1 (C), 134.3 (C), 134.1 (C), 129.7 (C), 128.8 (CH), 127.9 (CH), 127.8 (CH), 126.4 (C), 125.3 (CH), 124.4 (CH), 122.9 (CH), 119.8 (CH), 118.7 (CH), 116.5 (CH), 113.9 (CH), 110.9 (CH), 108.2 (C), 55.8 (CH), 51.5 (CH2), 21.4 (CH3). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(5-methoxy-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ga)

Using 5-methoxyindole (1g, 14.7 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ga was obtained (26.1 mg, 0.068 mmol, 68% yield) after 11 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.05 (bs, 1H), 7.40–7.27 (m, 5H), 7.19 (dd, J = 8.8, 0.7 Hz, 1H), 7.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.08 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 6.91 (ddd, J = 7.5, 1.5 Hz, 1H), 6.88–6.79 (m, 3H), 6.72 (dd, J = 2.6, 0.6 Hz, 1H), 5.34 (d, J = 0.6 Hz, 1H), 4.62 (dd, J = 14.7, 0.8 Hz, 1H), 4.10 (d, J = 14.7 Hz, 1H), 3.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.7 (C), 154.6 (C), 141.8 (C), 136.1 (C), 134.3 (C), 130.8 (C), 128.8 (CH), 127.9 (CH), 127.8 (CH), 126.4 (C), 125.5 (CH), 123.7 (CH), 119.8 (CH), 116.6 (CH), 113.7 (CH), 113.6 (CH), 112.1 (CH), 108.7 (C), 100.3 (CH), 55.8 (CH), 55.7 (CH3), 51.3 (CH2). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(5-hydroxy-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ha)

Using 5-hydroxyindole (1h, 13.3 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ha was obtained (24.4 mg, 0.066 mmol, 66% yield) after 11 h as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 8.05 (bs, 1H), 7.38–7.23 (m, 5H), 7.13 (d, J = 8.7 Hz, 1H), 7.11–7.02 (m, 2H), 6.89 (td, J = 7.7, 1.4 Hz, 1H), 6.86– 6.79 (m, 2H), 6.76 (dd, J = 8.7, 2.3 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 5.28 (s, 1H), 4.60 (d, J = 14.9 Hz, 1H), 4.12 (d, J = 14.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.7 (C), 150.1 (C), 141.7 (C), 136.1 (C), 134.1 (C), 131.0 (C), 128.8 (CH), 127.8 (CH), 126.7 (C), 125.4 (CH), 123.8 (CH), 119.8 (CH), 116.6 (CH), 113.9 (CH), 112.8 (CH), 112.0 (CH), 108.0 (C), 103.6 (CH), 56.0 (CH), 51.6 (CH2); HRMS (ESI) m/z: 371,1393 [M + H]+, C23H19N2O3 required 371,1390.

Catalysts 2018, 8, x FOR PEER REVIEW 10 of 22 Catalysts 2018, 8, x FOR PEER REVIEW 10 of 22 4-Benzyl-3-(5-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3fa) 4-Benzyl-3-(5-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3fa)

Catalysts 2018, 8, 653 10 of 21

Using 5-methylindole 1f(1f, 13.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H H-benzo[b b][1,4]oxazin-2- Using 5-methylindole5-methylindole ((1f,, 13.1 13.1 mg, mg, 0.1 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2-benzo[H-benzo[][1,4]oxazin-2-oneb][1,4]oxazin-2- one2a (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product3fa 3fa was obtained (one, 35.8(2a, mg,35.8 0.15mg, mmol), 0.15 mmol), in accordance in accordance with General with General Procedure, Procedure, the product the productwas obtained3fa was obtained (23.2 mg, 1 1 (23.20.063 mg, mmol, 0.063 63% mmol, yield) 63% after yield) 11 h after as a brown 11 h as oil. a brownH NMR oil. (300H NMR MHz, (300 CDCl MHz,3) δ 8.01CDCl (bs,3) δ 1H), 8.01 7.37–7.27(bs, 1H), (23.2 mg, 0.063 mmol, 63% yield) after 11 h as a brown oil. 1H NMR (300 MHz, CDCl3) δ 8.01 (bs, 1H), 7.37–7.27 (m, 5H), 7.24J (dd, J = 1.6, 0.8 Hz, 1H), 7.20J (dd, J = 8.3, 0.7 Hz, 1H), 7.12J (dd, J = 7.9, 1.5 Hz, (m,7.37–7.27 5H), 7.24(m, 5H), (dd, 7.24= 1.6,(dd, 0.8 J =Hz, 1.6, 1H),0.8 Hz, 7.20 1H), (dd, 7.20= (dd, 8.3, J 0.7 = 8.3, Hz, 0.7 1H), Hz, 7.12 1H), (dd, 7.12 (dd,= 7.9, J = 1.5 7.9, Hz, 1.5 1H),Hz, 1H), 7.04 (ddd,J J = 9.4, 8.0, 1.6 Hz, 2H), 6.92 J(td, J = 7.7, 1.5 Hz, 1H), 6.82 (dd,J J = 8.0, 1.4 Hz, 1H), 6.67 7.041H), (ddd,7.04 (ddd,= 9.4, J = 8.0,9.4, 1.68.0, Hz, 1.6 2H),Hz, 2H), 6.92 6.92 (td, (td,= 7.7, J = 7.7, 1.5 Hz,1.5 Hz, 1H), 1H), 6.82 6.82 (dd, (dd,= 8.0,J = 8.0, 1.4 1.4 Hz, Hz, 1H), 1H), 6.67 6.67 (d, (d,J J = 2.5 Hz, 1H), 5.37 (d,J J = 0.7 Hz, 1H), 4.61 (d,J J = 14.8 Hz, 1H), 4.12 (d, JJ = 14.8 Hz, 1H), 2.41 (s, (d,= J 2.5 = 2.5 Hz, Hz, 1H), 1H), 5.37 5.37 (d, (d,= J 0.7= 0.7 Hz, Hz, 1H), 1H), 4.61 4.61 (d, (d, =J = 14.8 14.8 Hz, Hz, 1H), 1H),4.12 4.12 (d,(d, J == 14.8 Hz, 1H), 2.41 (s, 13 2H); CC NMR NMR (75 (75 MHz, MHz, CDCl CDCl33)) δδ 164.6164.6 (C), (C), 141.9(C), 141.9(C), 136.1 136.1 (C), (C), 134.3 (C), 134.1 (C), 129.7 (C), 128.8 2H); 13C NMR (75 MHz, CDCl3) δ 164.6 (C), 141.9(C), 136.1 (C), 134.3 (C), 134.1 (C), 129.7 (C), 128.8 (CH), 127.9 (CH), 127.8 (CH), 126.4 (C), 125.3 (CH), 124.4 (CH), 122.9 (CH), 119.8 (CH), 118.7 (CH), (CH), 127.9 (CH), 127.8 (CH), 126.4 (C), 125.3 (CH), 124.4 (CH), 122.9 (CH), 119.8 (CH), 118.7 (CH), 116.5 (CH), 113.9 (CH), 110.9 (CH),(CH), 108.2108.2 (C),(C), 55.855.8 (CH),(CH), 51.551.5 (CH(CH22), 21.4 (CH3). The The spectroscopic spectroscopic data 116.5 (CH), 113.9 (CH), 110.9 (CH), 108.2 (C), 55.8 (CH), 51.5 (CH2), 21.4 (CH3). The spectroscopic data match with those reported in the literature [70]. match with those reported in the literatureliterature [[70].70]. 4-Benzyl-3-(5-methoxy-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ga3ga)) 4-Benzyl-3-(5-methoxy-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ga)

Using 5-methoxyindole (1g, 14.7 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using 5-methoxyindole5-methoxyindole ( 1g(1g,, 14.7 14.7 mg, mg, 0.1 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2H-benzo[H-benzo[b][1,4]oxazin-2-oneb][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ga was obtained (one2a, ( 35.82a, 35.8 mg, mg, 0.15 0.15 mmol), mmol), in in accordance accordance with with General General Procedure, Procedure, the the product product 3ga3ga waswas obtained (26.1 mg, 0.068 mmol, 68% yield) after 11 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.05 (bs, (26.1 mg, 0.0680.068 mmol,mmol, 68% yield)yield) afterafter 1111 hh asas aa whitewhite solid.solid. 11H NMR (300 MHz, CDCl 3)) δδ 8.05 (bs, 1H), 7.40–7.27 (m, 5H), 7.19 (dd, J = 8.8, 0.7 Hz, 1H), 7.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.08 (ddd,3 J = 8.0, 7.5, 1H), 7.40–7.27 (m,(m, 5H),5H), 7.197.19 (dd,(dd, JJ == 8.8, 0.7 Hz, 1H), 7.13 (dd, JJ = 7.9, 1.5 Hz, 1H), 7.08 (ddd, J = 8.0, 8.0, 7.5, 7.5, 1.5 Hz, 1H), 6.91 (ddd, J = 7.5, 1.5 Hz, 1H), 6.88–6.79 (m, 3H), 6.72 (dd, J = 2.6, 0.6 Hz, 1H), 5.34 (d, J = 1.5 Hz, 1H), 6.91 (ddd, (ddd, JJ == 7.5, 7.5, 1.5 1.5 Hz, Hz, 1H), 1H), 6.88–6.79 6.88–6.79 (m, (m, 3H), 3H), 6.72 6.72 (dd, (dd, J =J 2.6,= 2.6, 0.6 0.6Hz, Hz, 1H), 1H), 5.34 5.34 (d, (d,J = 0.6 Hz, 1H), 4.62 (dd, J = 14.7, 0.8 Hz, 1H), 4.10 (d, J = 14.7 Hz, 1H), 3.72 (s, 3H); 13C NMR (75 MHz, J0.6= 0.6Hz, Hz, 1H), 1H), 4.62 4.62 (dd, (dd, J =J 14.7,= 14.7, 0.8 0.8 Hz, Hz, 1H), 1H), 4.10 4.10 (d, (d, J J= =14.7 14.7 Hz, Hz, 1H), 1H), 3.72 3.72 (s, (s, 3H); 3H); 1313CC NMR NMR (75 (75 MHz, MHz, CDCl3) δ 164.7 (C), 154.6 (C), 141.8 (C), 136.1 (C), 134.3 (C), 130.8 (C), 128.8 (CH), 127.9 (CH), 127.8 CDCl3)) δδ 164.7 (C), 154.6 (C), 141.8 (C), 136.1 (C), 134.3134.3 (C), 130.8 (C), 128.8 (CH), 127.9 (CH), 127.8 (CH), 3126.4 (C), 125.5 (CH), 123.7 (CH), 119.8 (CH), 116.6 (CH), 113.7 (CH), 113.6 (CH), 112.1 (CH), (CH), 126.4 (C), 125.5 (CH), 123.7 (CH), 119.8 (CH), 116.6 (CH), 113.7 (CH), 113.6 (CH), 112.1 (CH), (CH), 108.7 (C), 100.3 (CH), 55.8 (CH), 55.7 (CH3), 51.3 (CH2). The spectroscopic data match with those 108.7 (C),(C), 100.3100.3 (CH),(CH), 55.855.8 (CH),(CH), 55.755.7 (CH(CH3),), 51.351.3 (CH(CH2).). The spectroscopic data match with those reported in the literature [70]. 3 2 reported in the literature [[70].70]. 4-Benzyl-3-(5-hydroxy-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ha) 4-Benzyl-3-(5-hydroxy-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ha3ha))

Using 5-hydroxyindole (1h, 13.3 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using 5-hydroxyindole (1h, 13.3 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- oneUsing (2a 5-hydroxyindole, 35.8 mg, 0.15 mmol), (1h, 13.3 in mg, accordance 0.1 mmol) with and General 4-benzyl-3,4-dihydro-2 Procedure, theH product-benzo[b 3ha][1,4]oxazin-2-one was obtained one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ha was obtained ((24.42a, 35.8 mg, mg, 0.066 0.15 mmol, mmol), 66% in accordanceyield) after with11 h Generalas a colourless Procedure, oil. 1 theH NMR product (3003ha MHz,was obtainedCDCl3) δ (24.48.05 (bs, mg, (24.4 mg, 0.066 mmol, 66% yield) after 11 h as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 8.05 (bs, 1H),0.066 7.38–7.23 mmol, 66% (m, yield)5H), 7.13 after (d, 11 J = h 8.7 as aHz, colourless 1H), 7.11–7.02 oil. 1H (m, NMR 2H), (300 6.89 MHz,(td, J = CDCl 7.7, 1.4) δ Hz,8.05 1H), (bs, 6.86– 1H), 1H), 7.38–7.23 (m, 5H), 7.13 (d, J = 8.7 Hz, 1H), 7.11–7.02 (m, 2H), 6.89 (td, J = 7.7, 1.43 Hz, 1H), 6.86– 6.797.38–7.23 (m, 2H), (m, 6.76 5H), (dd, 7.13 J (d, = 8.7,J = 2.3 8.7 Hz, 1H), 6.67 7.11–7.02 (d, J = (m, 2.5 2H),Hz, 1H), 6.89 (td,5.28J (s,= 7.7,1H), 1.4 4.60 Hz, (d, 1H), J = 14.9 6.86–6.79 Hz, 1H), (m, 6.79 (m, 2H), 6.76 (dd, J = 8.7, 2.3 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 5.28 (s, 1H), 4.60 (d, J = 14.9 Hz, 1H), 4.122H), (d, 6.76 J (dd,= 14.9J =Hz, 8.7, 1H); 2.3 Hz,13C 1H),NMR 6.67 (75 (d,MHz,J = 2.5CDCl Hz,3)1H), δ 164.7 5.28 (C), (s, 1H),150.1 4.60 (C), (d, 141.7J = 14.9(C), Hz,136.1 1H), (C), 4.12 134.1 (d, 4.12 (d, J = 14.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.7 (C), 150.1 (C), 141.7 (C), 136.1 (C), 134.1 (C),J = 14.9 131.0 Hz, (C), 1H); 128.813C (CH), NMR 127.8 (75 MHz, (CH), CDCl 126.7 )(C),δ 164.7 125.4 (C), (CH), 150.1 123.8 (C), (CH), 141.7 (C),119.8 136.1 (CH), (C), 116.6 134.1 (CH), (C), 113.9 131.0 (C), 131.0 (C), 128.8 (CH), 127.8 (CH), 126.73 (C), 125.4 (CH), 123.8 (CH), 119.8 (CH), 116.6 (CH), 113.9 (C),(CH), 128.8 112.8 (CH), (CH), 127.8 112.0 (CH), (CH), 126.7 108.0 (C), (C), 125.4 103.6 (CH), (CH), 123.8 56.0 (CH), (CH), 119.8 51.6 (CH), (CH2 116.6); HRMS (CH), (ESI) 113.9 m/ (CH),z: 371,1393 112.8 (CH), 112.8 (CH), 112.0 (CH), 108.0 (C), 103.6 (CH), 56.0 (CH), 51.6 (CH2); HRMS (ESI) m/z: 371,1393 + + (CH),[M + H] 112.0, C23 (CH),H19N2 108.0O3 required (C), 103.6 371,1390. (CH), 56.0 (CH), 51.6 (CH2); HRMS (ESI) m/z: 371,1393 [M + H] , [M + H]+, C23H19N2O3 required 371,1390. CatalystsC H N2018O, 8, requiredx FOR PEER 371,1390. REVIEW 11 of 22 23 19 2 3 4-Benzyl-3-(5-bromo-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ia3ia))

Using 5-bromoindole (1i, 19.6 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ia was obtained (23.4 mg, 0.054 mmol, 54% yield) after 14 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.40–7.32 (m, 3H), 7.32–7.24 (m, 3H), 7.17 (d, J = 8.6 Hz, 1H), 7.15–7.05 (m, 2H), 6.93 (td, J = 7.7, 1.4 Hz, 1H), 6.84 (dd, J = 8.0, 1.3 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 5.29 (s, 1H), 4.62 (d, J = 14.6 Hz, 1H), 4.06 (d, J = 14.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.46 (C), 141.84 (C), 135.73 (C), 134.39 (C), 134.02 (C), 128.89 (CH), 127.95 (CH), 127.73 (CH), 126.45 (C), 125.75 (CH), 125.51 (CH), 124.02 (CH), 121.78 (CH), 120.15 (CH), 116.60 (CH), 114.07 (CH), 113.75 (C), 112.73 (CH), 108.37 (C), 55.32 (CH), 51.54 (CH2). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(6-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ja)

Using 6-methylindole (1j, 13.1 mg, 0,1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ja was obtained (28.3 mg, 0.077 mmol, 77% yield) after 14 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.98 (bs, 1H), 7.43–7.26 (m, 6H), 7.16–7.07 (m, 2H), 7.06 (td, J = 7.7, 1.6 Hz, 1H), 6.96 (dd, J = 8.2, 1.4 Hz, 1H), 6.91 (td, J = 7.7, 1.5 Hz, 1H), 6.81 (dd, J = 8.0, 1.4 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 5.37 (d, J = 0.7 Hz, 1H), 4.61 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 2.44 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 164.6 (C), 141.9 (C), 136.3 (C), 136.1 (C), 134.2 (C), 132.7 (C), 128.8 (CH), 127.8 (CH), 127.7 (CH), 125.3 (CH), 123.9 (C), 122.3 (CH), 122.2 (CH), 119.8 (CH), 118.7 (CH), 116.5 (CH), 113.8 (C), 111.2 (CH), 108.6 (C), 56.0 (CH), 51.5 (CH2), 21.6 (CH3). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(7-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ka)

Using 7-methylindole (1k, 13.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ka was obtained (26.1 mg, 0.071 mmol, 71% yield) after 14 h as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.33 (m, 6H), 7.12 (dd, J = 7.9, 1.5 Hz, 1H), 7.09–6.98 (m, 3H), 6.91 (td, J = 7.7, 1.4 Hz, 1H), 6.81 (dd, J = 8.1, 1.4 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 5.39 (d, J = 0.7 Hz, 1H), 4.61 (d, J = 14.9 Hz, 1H), 4.16 (d, J = 14.9 Hz, 1H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.5 (C), 141.9 (C), 136.1 (C), 135.4 (C), 134.2 (C), 128.8 (CH), 127.8 (CH), 127.8 (CH), 125.7 (C), 125.3 (CH), 123.3 (CH), 122.6 (CH), 120.7 (CH), 120.5 (C), 119.8 (CH), 116.8 (CH), 116.5(CH), 113.9 (CH), 109.2 (C), 56.0 (CH), 51.6 (CH2), 16.4 (CH3). The spectroscopic data match with those reported in the literature [70].

Catalysts 2018, 8, x FOR PEER REVIEW 11 of 22 Catalysts 2018, 8, x FOR PEER REVIEW 11 of 22 4-Benzyl-3-(5-bromo-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ia) 4-Benzyl-3-(5-bromo-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ia)

Catalysts 2018, 8, 653 11 of 21

Using 5-bromoindole (1i, 19.6 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one Using 5-bromoindole (1i,, 19.6 mg, 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ia was obtained (23.4 ((2a,, 35.835.8 mg,mg, 0.150.15 mmol), mmol), in in accordance accordance with with General General Procedure, Procedure, the the product product3ia 3iawas was obtained obtained (23.4 (23.4 mg, mg, 0.054 mmol, 54% yield) after 14 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 7.54 1 1 0.054mg, 0.054 mmol, mmol, 54% 54% yield) yield) after after 14 h14 as h aas white a white solid. solid.H H NMR NMR (300 (300 MHz, MHz, CDCl CDCl)3)δ δ8.21 8.21 (s,(s, 1H),1H), 7.54 (d, J = 1.8 Hz, 1H), 7.40–7.32 (m, 3H), 7.32–7.24 (m, 3H), 7.17 (d, J = 8.6 Hz, 1H), 7.15–7.053 (m, 2H), 6.93 (d,(d, J == 1.8 1.8 Hz, Hz, 1H), 1H), 7.40–7.32 7.40–7.32 (m, (m, 3H), 3H), 7.32–7.24 7.32–7.24 (m, (m, 3H), 3H), 7.17 7.17 (d, (d,J = 8.6J = Hz, 8.6 Hz,1H), 1H), 7.15–7.05 7.15–7.05 (m, 2H), (m, 2H),6.93 (td, J = 7.7, 1.4 Hz, 1H), 6.84 (dd, J = 8.0, 1.3 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 5.29 (s, 1H), 4.62 (d, J = 6.93(td, J (td, = 7.7,J = 1.4 7.7, Hz, 1.4 1H), Hz, 1H),6.84 6.84(dd, (dd,J = 8.0,J = 1.3 8.0, Hz, 1.3 Hz,1H), 1H), 6.71 6.71(d, J (d, = 2.6J = Hz, 2.6 Hz,1H), 1H), 5.29 5.29 (s, 1H), (s, 1H), 4.62 4.62 (d, (d,J = 14.6 Hz, 1H), 4.06 (d, J = 14.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.46 (C), 141.84 (C), 135.73 (C), 13 13 J14.6= 14.6 Hz, Hz, 1H), 1H), 4.06 4.06 (d, (d,J = 14.6J = 14.6 Hz,Hz, 1H); 1H); C NMRC NMR (75 MHz, (75 MHz, CDCl CDCl3) δ 164.46) δ 164.46 (C), (C),141.84 141.84 (C), (C),135.73 135.73 (C), 134.39 (C), 134.02 (C), 128.89 (CH), 127.95 (CH), 127.73 (CH), 126.453 (C), 125.75 (CH), 125.51 (CH), (C),134.39 134.39 (C), (C),134.02 134.02 (C), (C), 128.89 128.89 (CH), (CH), 127.95 127.95 (CH), (CH), 127.73 127.73 (CH), (CH), 126.45 126.45 (C), (C), 125.75 125.75 (CH), (CH), 125.51 125.51 (CH), (CH), 124.02 (CH), 121.78 (CH), 120.15 (CH), 116.60 (CH), 114.07 (CH), 113.75 (C), 112.73 (CH), 108.37 (C), 124.02 (CH), 121.78 (CH), 120.15 (CH), 116.60 (CH), 114.07 (CH), 113.75 (C), 112.73 (CH), 108.37 (C), 55.32 (CH), 51.54 (CH2). The spectroscopic data match with those reported in the literature [70]. 55.32 (CH), 51.54 (CH22). The The spectroscopic spectroscopic data match with those reported in the literature [[70].70]. 4-Benzyl-3-(6-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ja3ja)) 4-Benzyl-3-(6-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ja)

Using 6-methylindole (1j, 13.1 mg, 0,1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using 6-methylindole (1j, 13.1 mg, 0,1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Usingone (2a 6-methylindole, 35.8 mg, 0.15 (mmol),1j, 13.1 mg,in accordance 0,1 mmol) with and 4-benzyl-3,4-dihydro-2 General Procedure, theH -benzo[productb ][1,4]oxazin-2-one3ja was obtained one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ja was obtained ((28.32a, 35.8 mg, mg, 0.077 0.15 mmol, mmol), 77% in accordanceyield) after with 14 h General as a white Procedure, solid. 1H the NMR product (3003ja MHz,was CDCl obtained3) δ (28.37.98 mg,(bs, (28.3 mg, 0.077 mmol, 77% yield) after 14 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.98 (bs, 0.0771H), 7.43–7.26 mmol, 77% (m, yield) 6H), after7.16–7.07 14 h as (m, a white2H), 7.06 solid. (td,1H J NMR= 7.7, (3001.6 Hz, MHz, 1H), CDCl 6.96) (dd,δ 7.98 J = (bs, 8.2, 1H), 1.4 7.43–7.26Hz, 1H), 1H), 7.43–7.26 (m, 6H), 7.16–7.07 (m, 2H), 7.06 (td, J = 7.7, 1.6 Hz, 1H), 6.963 (dd, J = 8.2, 1.4 Hz, 1H), (m,6.91 6H),(td, 7.16–7.07J = 7.7, 1.5 (m, Hz, 2H), 1H), 7.06 6.81 (td, (dd,J = J 7.7,= 8.0, 1.6 1.4 Hz, Hz, 1H), 1H), 6.96 6.66 (dd, (d,J J= =8.2, 2.5 1.4Hz, Hz, 1H), 1H), 5.37 6.91 (d, (td,J = 0.7J = Hz, 7.7, 6.91 (td, J = 7.7, 1.5 Hz, 1H), 6.81 (dd, J = 8.0, 1.4 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 5.37 (d, J = 0.7 Hz, 1.51H), Hz, 4.61 1H), (d, J 6.81 = 14.8 (dd, Hz,J =1H), 8.0, 4.15 1.4 Hz,(d, J 1H),= 14.8 6.66 Hz, (d, 1H),J = 2.44 2.5 (s, Hz, 3H): 1H), 13C 5.37 NMR (d, (75J = MHz, 0.7 Hz, CDCl 1H),3) 4.61δ 164.6 (d, 1H), 4.61 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 2.44 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 164.6 J(C),= 14.8 141.9 Hz, (C), 1H), 136.3 4.15 (C), (d, 136.1J = 14.8 (C), Hz, 134.2 1H), (C), 2.44 132.7 (s, 3H): (C),13 128.8C NMR (CH), (75 127.8 MHz, (CH), CDCl 127.7) δ 164.6 (CH), (C), 125.3 141.9 (CH), (C), (C), 141.9 (C), 136.3 (C), 136.1 (C), 134.2 (C), 132.7 (C), 128.8 (CH), 127.8 (CH), 127.73 (CH), 125.3 (CH), 136.3123.9 (C),(C), 136.1122.3 (C),(CH), 134.2 122.2 (C), (CH), 132.7 119.8 (C), 128.8(CH), (CH), 118.7 127.8(CH), (CH), 116.5 127.7 (CH), (CH), 113.8 125.3 (C), 111.2 (CH), (CH), 123.9 108.6 (C), 122.3 (C), 123.9 (C), 122.3 (CH), 122.2 (CH), 119.8 (CH), 118.7 (CH), 116.5 (CH), 113.8 (C), 111.2 (CH), 108.6 (C), (CH),56.0 (CH), 122.2 51.5 (CH), (CH 119.82), 21.6 (CH), (CH 118.73). The (CH), spectroscopic 116.5 (CH), data 113.8 match (C), 111.2with (CH),those reported 108.6 (C), in 56.0 the (CH), literature 51.5 56.0 (CH), 51.5 (CH2), 21.6 (CH3). The spectroscopic data match with those reported in the literature (CH[70]. ), 21.6 (CH ). The spectroscopic data match with those reported in the literature [70]. [70].2 3 4-Benzyl-3-(7-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ka) 4-Benzyl-3-(7-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ka) 4-Benzyl-3-(7-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ka)

Using 7-methylindole (1k, 13.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using 7-methylindole7-methylindole (1k(1k,, 13.1 13.1 mg, mg, 0.1 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2H-benzo[H-benzo[b][1,4]oxazin-2-oneb][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ka was obtained (one2a, 35.8(2a, mg,35.8 0.15mg, mmol), 0.15 mmol), in accordance in accordance with General with General Procedure, Procedure,1 the product the product3ka was 3ka obtained was obtained (26.1 mg, (26.1 mg, 0.071 mmol, 71% yield) after 14 h as a yellow1 oil. H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 0.071(26.1 mg, mmol, 0.071 71% mmol, yield) 71% after yield) 14 h after as a yellow14 h as oil.a yellowH NMR oil. 1 (300H NMR MHz, (300 CDCl MHz,) δ CDCl8.03 (s,3) δ 1H), 8.03 7.33(s, 1H), (m, 7.33 (m, 6H), 7.12 (dd, J = 7.9, 1.5 Hz, 1H), 7.09–6.98 (m, 3H), 6.91 (td, J = 7.7, 1.43 Hz, 1H), 6.81 (dd, J = 6H),7.33 (m, 7.12 6H), (dd, 7.12J = (dd, 7.9, 1.5J = 7.9, Hz, 1.5 1H), Hz, 7.09–6.98 1H), 7.09–6.98 (m, 3H), (m, 6.91 3H), (td, 6.91J =(td, 7.7, J = 1.4 7.7, Hz, 1.41H), Hz, 1H), 6.81 (dd,6.81 (dd,J = 8.1, J = 8.1, 1.4 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 5.39 (d, J = 0.7 Hz, 1H), 4.61 (d, J = 14.9 Hz, 1H), 4.16 (d, J = 1.48.1, Hz, 1.4 1H),Hz, 1H), 6.73 (d,6.73J =(d, 2.6 J Hz,13= 2.6 1H), Hz, 5.39 1H), (d, 5.39J = (d, 0.7 J Hz, = 0.7 1H), Hz, 4.61 1H), (d, 4.61J = 14.9(d, J Hz, = 14.9 1H), Hz, 4.16 1H), (d, J4.16= 14.9 (d, Hz,J = 14.9 Hz, 1H), 2.4213 (s, 3H); C NMR (75 MHz, CDCl3) δ 164.5 (C), 141.9 (C), 136.1 (C), 135.4 (C), 134.2 1H),14.9 Hz, 2.42 1H), (s, 3H); 2.42 (s,C NMR3H); 13 (75C NMR MHz, (75 CDCl MHz,) δ CDCl164.53 (C),) δ 164.5 141.9 (C), (C), 141.9 136.1 (C), (C), 136.1 135.4 (C), (C), 135.4 134.2 (C), 128.8134.2 (C), 128.8 (CH), 127.8 (CH), 127.8 (CH), 125.73 (C), 125.3 (CH), 123.3 (CH), 122.6 (CH), 120.7 (CH), 120.5 (CH),(C), 128.8 127.8 (CH), (CH), 127.8 127.8 (CH), (CH), 127.8 125.7 (CH), (C), 125.3125.7 (CH),(C), 125.3 123.3 (CH), (CH), 123.3 122.6 (CH), (CH), 122.6 120.7 (CH), (CH), 120.7 120.5 (CH), (C), 120.5 119.8 (C), 119.8 (CH), 116.8 (CH), 116.5(CH), 113.9 (CH), 109.2 (C), 56.0 (CH), 51.6 (CH2), 16.4 (CH3). The (CH),(C), 119.8 116.8 (CH), (CH), 116.8 116.5(CH), (CH), 113.9116.5(CH), (CH), 109.2113.9 (C),(CH), 56.0 109.2 (CH), (C), 51.6 56.0 (CH (CH),), 16.4 51.6 (CH (CH).2 The), 16.4 spectroscopic (CH3). The spectroscopic data match with those reported in the literature [70]. 2 3 Catalystsdataspectroscopic match 2018, with8, x data FOR those PEERmatch reported REVIEW with those in the reported literature in [ 70the]. literature [70]. 12 of 22

4-Benzyl-3-(7-chloro-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3la3la))

Using 7-chloroindole (1l, 15.2 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one Using 7-chloroindole (1l, 15.2 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3la was obtained (22.9 (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3la was obtained (22.9 mg, mg, 0.059 mmol, 59% yield) after 16 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.29 (bs, 1H), 0.059 mmol, 59% yield) after 16 h as a white solid. 1H NMR (300 MHz, CDCl ) δ 8.29 (bs, 1H), 7.39 7.39 (d, J = 8.0 Hz, 1H), 7.36–7.24 (m, 5H), 7.21 (dd, J = 7.6, 0.7 Hz, 1H), 7.15–7.023 (m, 3H), 6.92 (td, J = 7.7, 1.4 Hz, 1H), 6.85 (dd, J = 8.0, 1.3 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 5.35 (s, 1H), 4.64 (d, J = 14.7 Hz, 1H), 4.12 (d, J = 14.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.20 (C), 141.83 (C), 135.83 (C), 134.00 (C), 133.15 (C), 128.87 (CH), 127.88 (CH), 127.45 (C), 125.48 (CH), 123.41 (CH), 122.22 (CH), 121.29 (CH), 120.13 (CH), 117.93 (CH), 116.76 (C), 116.64 (CH), 113.92 (CH), 110.01 (C), 55.73 (CH), 51.63 (CH2). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(2-phenyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ma)

Using 2-phenylindole (1m, 19.3 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ma was obtained (34.4 mg, 0.080 mmol, 80% yield) after 14 h as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.27 (bs, 1H), 7.54–7.46 (m, 2H), 7.42–7.32 (m, 4H), 7.22–7.14 (m, 3H), 7.11–7.05 (m, 3H), 7.04–6.96 (m, 2H), 6.96–6.91 (m, 2H), 6.90–6.82 (m, 1H), 6.69 (dd, J = 8.1, 1.4 Hz, 1H), 5.57 (s, 1H), 4.42 (d, J = 16.2 Hz, 1H), 3.87 (d, J = 16.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.2 (C), 140.5 (C), 139.4 (C), 136.4 (C), 135.9 (C), 134.2 (C), 131.3 (C), 129.0 (CH), 128.9 (CH), 128.7 (CH), 128.4 (CH), 127.0 (CH), 126.9 (CH), 126.3 (C), 125.5 (CH), 122.9 (CH), 120.7 (CH), 120.0 (CH), 118.9 (CH), 116.9 (CH), 113.1 (CH), 111.1 (CH), 107.6 (C), 56.1 (CH), 50.0 (CH2). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(1,2-dimethyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3na)

Using 1,2-dimethylindole (1n, 14.5 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3na was obtained (26.7 mg, 0.070 mmol, 70% yield) after 12 h as a brown oil. 1H NMR (300 MHz, CDCl3) δ 7.31–7.22 (m, 4H), 7.19–7.14 (m, 3H), 7.14–7.08 (m, 2H), 7.05 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.96 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.88 (ddd, J = 7.9, 7.5, 1.4 Hz, 1H), 6.78 (dd, J = 8.1, 1.4 Hz, 1H), 5.38 (d, J = 0.5 Hz, 1H), 4.57 (d, J = 16.2 Hz, 1H), 3.99 (d, J = 16.2 Hz, 1H), 3.63 (s, 3H), 2.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.1 (C), 140.9 (C), 140.7 (C), 137.0 (C), 136.8 (C), 134.6 (C), 128.7 (CH), 127.2 (CH), 127.1 (CH), 125.8 (C), 125.5 (CH), 121.3 (CH), 120.0 (CH), 119.0 (CH), 118.6 (CH), 117.0 (CH), 113.2 (CH), 109.0 (CH), 105.3 (C), 56.2 (CH), 49.9 (CH2), 29.6 (CH3), 10.3 (CH3). The spectroscopic data match with those reported in the literature [70].

Catalysts 2018, 8, x FOR PEER REVIEW 12 of 22 Catalysts 2018, 8, x FOR PEER REVIEW 12 of 22

4-Benzyl-3-(7-chloro-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3la) 4-Benzyl-3-(7-chloro-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3la)

Using 7-chloroindole (1l, 15.2 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one CatalystsUsing 7-chloroindole2018, 8, 653 (1l, 15.2 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one12 of 21 (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3la was obtained (22.9 (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3la was obtained (22.9 mg, 0.059 mmol, 59% yield) after 16 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.29 (bs, 1H), mg, 0.059 mmol, 59% yield) after 16 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.29 (bs, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.36–7.24 (m, 5H), 7.21 (dd, J = 7.6, 0.7 Hz, 1H), 7.15–7.02 (m, 3H), 6.92 (td, J = (d,7.39J (d,= 8.0 J = Hz, 8.0 1H),Hz, 1H), 7.36–7.24 7.36–7.24 (m, 5H),(m, 5H), 7.21 7.21 (dd, (dd,J = 7.6, J = 0.77.6, Hz,0.7 Hz, 1H), 1H), 7.15–7.02 7.15–7.02 (m, 3H),(m, 3H), 6.92 6.92 (td, (td,J = 7.7,J = 7.7, 1.4 Hz, 1H), 6.85 (dd, J = 8.0, 1.3 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 5.35 (s, 1H), 4.64 (d, J = 14.7 Hz, 1.47.7, Hz,1.4 1H),Hz, 1H), 6.85 6.85 (dd, (dd,J = 8.0, J = 1.38.0, Hz, 1.3 1H),Hz, 1H), 6.80 6.80 (d, J (d,= 2.6 J = Hz, 2.6 1H),Hz, 1H), 5.35 5.35 (s, 1H), (s, 1H), 4.64 (d,4.64J =(d, 14.7 J = Hz,14.7 1H),Hz, 1H), 4.12 (d, J = 14.7 Hz, 1H);13 13C NMR (75 MHz, CDClδ 3) δ 164.20 (C), 141.83 (C), 135.83 (C), 134.00 4.121H), (d,4.12J =(d, 14.7 J = Hz,14.7 1H);Hz, 1H);C NMR13C NMR (75 MHz,(75 MHz, CDCl CDCl3) 164.203) δ 164.20 (C), (C), 141.83 141.83 (C), (C), 135.83 135.83 (C), (C), 134.00 134.00 (C), (C), 133.15 (C), 128.87 (CH), 127.88 (CH), 127.45 (C), 125.48 (CH), 123.41 (CH), 122.22 (CH), 121.29 133.15(C), 133.15 (C), 128.87(C), 128.87 (CH), (CH), 127.88 127.88 (CH), (CH), 127.45 127.45 (C),125.48 (C), 125.48 (CH), (CH), 123.41 123.41 (CH), (CH), 122.22 122.22 (CH), (CH), 121.29 121.29 (CH), (CH), 120.13 (CH), 117.93 (CH), 116.76 (C), 116.64 (CH), 113.92 (CH), 110.01 (C), 55.73 (CH), 51.63 120.13(CH), 120.13 (CH), 117.93(CH), 117.93 (CH), 116.76(CH), 116.76 (C), 116.64 (C), 116.64 (CH), 113.92(CH), 113.92 (CH), 110.01(CH), 110.01 (C), 55.73 (C), (CH), 55.73 51.63(CH), (CH 51.632). (CH2). The spectroscopic data match with those reported in the literature [70]. The(CH2 spectroscopic). The spectroscopic data match data withmatch those with reported those reported in the literature in the literature [70]. [70].

4-Benzyl-3-(2-phenyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ma3ma)) 4-Benzyl-3-(2-phenyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ma)

Using 2-phenylindole (1m, 19.3 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using 2-phenylindole2-phenylindole (1m(1m,, 19.3 19.3 mg, mg, 0.1 0.1 mmol) mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2H-benzo[H-benzo[b][1,4]oxazin-2-oneb][1,4]oxazin-2- one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ma was obtained (one2a, ( 35.82a, 35.8 mg, mg, 0.15 0.15 mmol), mmol), in in accordance accordance with with General General Procedure, Procedure, the the product product3ma 3ma waswas obtained (34.4 mg, 0.080 mmol, 80% yield) after 14 h as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.27 (bs, 1H), (34.4 mg, 0.080 mmol,mmol, 80%80% yield)yield) afterafter 1414 hh asas aa yellowyellow oil.oil. 1H NMR (300 MHz, CDCl 3)) δδ 8.278.27 (bs, (bs, 1H), 1H), 7.54–7.46 (m, 2H), 7.42–7.32 (m, 4H), 7.22–7.14 (m, 3H), 7.11–7.05 (m, 3H), 7.04–6.96 (m,3 2H), 6.96–6.91 7.54–7.46 (m, 2H), 7.42–7.32 (m, 4H), 7.22–7.14 (m, 3H), 7.11–7.05 (m, 3H), 7.04–6.96 (m, 2H), 6.96–6.91 (m, 2H), 6.90–6.82 (m, 1H), 6.69 (dd, J = 8.1, 1.4 Hz, 1H), 5.57 (s, 1H), 4.42 (d, J = 16.2 Hz, 1H), 3.87 (d, (m, 2H), 6.90–6.82 (m, 1H), 6.69 (dd, J = 8.1, 1.4 Hz, 1H), 5.57 (s, 1H), 4.42 (d, J = 16.2 16.2 Hz, Hz, 1H), 1H), 3.87 3.87 (d, (d, J = 16.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.2 (C), 140.5 (C), 139.4 (C), 136.4 (C), 135.9 (C), 134.2 J = 16.3 16.3 Hz, 1H); 13CC NMR NMR (75 (75 MHz, MHz, CDCl CDCl3)) δδ 166.2166.2 (C), (C), 140.5 140.5 (C), (C), 139.4 139.4 (C), (C), 136.4 136.4 (C), 135.9 (C), 134.2 (C), 131.3 (C), 129.0 (CH), 128.9 (CH), 128.73 (CH), 128.4 (CH), 127.0 (CH), 126.9 (CH), 126.3 (C), 125.5 (C), 131.3 (C), 129.0 (CH), 128.9 (CH), 128.7 (CH), 128.4 (CH), 127.0 (CH), 126.9 (CH), 126.3 (C), 125.5 (CH), 122.9 (CH), 120.7 (CH), 120.0 (CH), 118.9 (CH), 116.9 (CH), 113.1 (CH), 111.1 (CH), 107.6 (C), (CH), 122.9122.9 (CH),(CH), 120.7 120.7 (CH), (CH), 120.0 120.0 (CH), (CH), 118.9 118.9 (CH), (CH), 116.9 116.9 (CH), (CH), 113.1 113.1 (CH), (CH), 111.1 111.1 (CH), (CH), 107.6 107.6 (C), 56.1(C), 56.1 (CH), 50.0 (CH2). The spectroscopic data match with those reported in the literature [70]. (CH),56.1 (CH), 50.0 (CH50.0 2(CH). The2). The spectroscopic spectroscopic data data match match with with those those reported reported in the in literature the literature [70]. [70]. 4-Benzyl-3-(1,2-dimethyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3na) 4-Benzyl-3-(1,2-dimethyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3na3na))

Using 1,2-dimethylindole (1n, 14.5 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- Using 1,2-dimethylindole (1n, 14.5 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- Using2-one ( 1,2-dimethylindole2a, 35.8 mg, 0.15 mmol), (1n, 14.5 in accordance mg, 0.1 mmol) with and General 4-benzyl-3,4-dihydro-2 Procedure, the productH-benzo[ 3nab ][1,4]oxazin-2-was obtained 2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3na was obtained one (2a, 35.8 mg, 0.15 mmol), in accordance with General1 Procedure, the product 3na was obtained (26.7 mg, 0.070 mmol, 70% yield) after 12 h as a brown oil. 1H NMR (300 MHz, CDCl3) δ 7.31–7.22 (m, (26.7 mg, 0.070 mmol, 70% yield) after 12 h as a brown oil. H1 NMR (300 MHz, CDCl3) δ 7.31–7.22 (m, (26.74H), 7.19–7.14 mg, 0.070 (m, mmol, 3H), 70%7.14–7.08 yield) (m, after 2H), 12 7.05 h as (ddd, a brown J = 8.1, oil. 7.4,H 1.6 NMR Hz, (300 1H), MHz, 6.96 (ddd, CDCl J3 =) δ8.0,7.31–7.22 6.9, 1.1 4H), 7.19–7.14 (m, 3H), 7.14–7.08 (m, 2H), 7.05 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.96 (ddd, J = 8.0, 6.9, 1.1 (m,Hz, 4H),1H), 7.19–7.146.88 (ddd, (m, J = 3H),7.9, 7.5, 7.14–7.08 1.4 Hz,(m, 1H), 2H), 6.78 7.05 (dd, (ddd, J = 8.1,J = 1.4 8.1, Hz, 7.4, 1H), 1.6 5.38 Hz, (d, 1H), J = 6.96 0.5 Hz, (ddd, 1H),J = 4.57 8.0, Hz, 1H), 6.88 (ddd, J = 7.9, 7.5, 1.4 Hz, 1H), 6.78 (dd, J = 8.1, 1.4 Hz, 1H), 5.38 (d, J = 0.5 Hz, 1H), 4.57 6.9,(d, J 1.1= 16.2 Hz, Hz, 1H), 1H), 6.88 3.99 (ddd, (d,J J= =7.9, 16.2 7.5, Hz, 1.4 1H), Hz, 3.63 1H), (s, 6.78 3H), (dd, 2.12J =(s, 8.1, 3H); 1.4 13 Hz,C NMR 1H), (75 5.38 MHz, (d, J CDCl= 0.5 Hz,3) δ (d, J = 16.2 Hz, 1H), 3.99 (d, J = 16.2 Hz, 1H), 3.63 (s, 3H), 2.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 1H),166.1 4.57(C), (d,140.9J = (C), 16.2 140.7 Hz, 1H),(C), 137.0 3.99 (d,(C),J =136.8 16.2 (C), Hz, 134.6 1H), (C), 3.63 128.7 (s, 3H), (CH), 2.12 127.2 (s, 3H); (CH),13C 127.1 NMR (CH), (75 MHz,125.8 166.1 (C), 140.9 (C), 140.7 (C), 137.0 (C), 136.8 (C), 134.6 (C), 128.7 (CH), 127.2 (CH), 127.1 (CH), 125.8 CDCl(C), 125.53) δ 166.1(CH), (C),121.3 140.9 (CH), (C), 120.0 140.7 (CH), (C), 137.0119.0 (C),(CH), 136.8 118.6 (C), (CH), 134.6 117.0 (C), (CH), 128.7 (CH),113.2 (CH), 127.2 109.0 (CH), (CH), 127.1 (C), 125.5 (CH), 121.3 (CH), 120.0 (CH), 119.0 (CH), 118.6 (CH), 117.0 (CH), 113.2 (CH), 109.0 (CH), (CH),105.3 (C), 125.8 56.2 (C), (CH), 125.5 49.9 (CH), (CH 121.32), 29.6 (CH), (CH 120.03), 10.3 (CH), (CH 119.03). The (CH), spectroscopic 118.6 (CH), 117.0data match (CH), 113.2with (CH),those 105.3 (C), 56.2 (CH), 49.9 (CH2), 29.6 (CH3), 10.3 (CH3). The spectroscopic data match with those 109.0reported (CH), in 105.3the literature (C), 56.2 [70]. (CH), 49.9 (CH2), 29.6 (CH3), 10.3 (CH3). The spectroscopic data match with reported in the literature [70]. Catalyststhose reported 2018, 8, x FOR in the PEER literature REVIEW [ 70 ]. 13 of 22

4-Benzyl-3-(5-methoxy-7-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3oa3oa))

3-(1H-benzo[g]indol-3-yl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3pa)

Using 1H-benzo[g]indole (1p, 16.7 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3pa was obtained (31.0 mg, 0.077 mmol, 77% yield) after 14 h as a brown solid. 1H NMR (300 MHz, Acetone) δ 11.25 (bs, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.58–7.29 (m, 8H), 7.18–7.02 (m, 2H), 6.99–6.87 (m, 3H), 5.68 (d, J = 0.6 Hz, 1H), 4.68 (d, J = 15.1 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H); 13C NMR (75 MHz, Acetone) δ 165.05 (C), 143.02 (C), 138.04 (C), 135.22 (C), 131.87 (C), 131.47 (C), 129.52 (CH), 129.40 (CH), 128.60 (CH), 128.32 (CH), 126.48 (CH), 126.08 (CH), 125.02 (CH), 123.09 (C), 123.00 (C), 122.23 (CH), 121.56 (CH), 121.12 (CH), 120.64 (CH), 119.68 (CH), 116.95 (CH), 115.37 (CH), 110.99 (C), 57.46 (CH), 52.53 (CH2); HRMS (ESI) m/z: 405,1592 [M + H]+, C27H21N2O2 required 405,1598.

3-(1H-indol-3-yl)-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ab)

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 2-one (2b, 40.4 mg, 0.15 mmol), in accordance with General Procedure, the product 3ab was obtained (21.5 mg, 0.056 mmol, 56% yield) after 10 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.09 (bs, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.35–7.30 (m, 1H), 7.24–7.16 (m, 3H), 7.16–7.04 (m, 3H), 6.92 (dd, J = 7.7, 1.4 Hz, 1H), 6.90–6.83 (m, 3H), 6.71 (d, J = 2.4 Hz, 1H), 5.37 (d, J = 0.4 Hz, 1H), 4.57 (d, J = 14.4 Hz, 1H), 4.07 (d, J = 14.3 Hz, 1H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.54 (C), 159.22 (C), 141.93 (C), 135.76 (C), 134.29 (C), 129.22 (CH), 127.80 (C), 126.10 (C), 125.34 (CH), 122.79 (CH), 122.76 (CH), 120.40 (CH), 119.81 (CH), 119.20 (CH), 116.50 (CH), 114.21 (CH), 113.86 (CH), 111.21 (CH), 108.75 (C), 55.30 (CH), 50.90 (CH2). The spectroscopic data match with those reported in the literature [70].

Catalysts 2018, 8, x FOR PEER REVIEW 13 of 22 Catalysts 2018, 8, x FOR PEER REVIEW 13 of 22 4-Benzyl-3-(5-methoxy-7-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3oa) 4-Benzyl-3-(5-methoxy-7-methyl-1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3oa)

Using 5-methoxy-7-methylindole (1o, 16.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H- Using 5-methoxy-7-methylindole (1o, 16.1 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3oa was obtained (27.9 mg, 0.070 mmol, 70% yield) after 11 h as a colourless oil. 1H NMR Catalystsproduct2018 3oa, 8 ,was 653 obtained (27.9 mg, 0.070 mmol, 70% yield) after 11 h as a colourless oil. 1H 13NMR of 21 (300 MHz, CDCl3) δ 7.98 (bs, 1H), 7.40–7.27 (m, 5H), 7.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.07 (td, J = 7.7, 1.5 (300 MHz, CDCl3) δ 7.98 (bs, 1H), 7.40–7.27 (m, 5H), 7.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.07 (td, J = 7.7, 1.5 Hz, 1H), 6.91 (td, J = 7.7, 1.4 Hz, 1H), 6.82 (dd, J = 8.1, 1.3 Hz, 1H), 6.74–6.62 (m, 3H), 5.33 (s, 1H), 4.61 Hz, 1H), 6.91 (td, J = 7.7, 1.4 Hz, 1H), 6.82 (dd, J = 8.1, 1.3 Hz, 1H), 6.74–6.62 (m, 3H), 5.33 (s, 1H), 4.61 (d,(td, JJ == 14.8 7.7, 1.4Hz, Hz, 1H), 1H), 4.10 6.82 (d, (dd, J = 14.7J = 8.1, Hz, 1.3 1H), Hz, 3.71 1H), (s, 6.74–6.62 3H), 2.36 (m, (s, 3H), 3H); 5.33 13C (s,NMR 1H), (75 4.61 MHz, (d, J =CDCl 14.83 Hz,) δ (d, J = 14.8 Hz, 1H), 4.10 (d, J = 14.7 Hz, 1H), 3.71 (s, 3H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.7 (C), 154.7 (C), 141.8 (C), 136.1 (C), 134.3 (C), 130.613 (C), 128.8 (CH), 127.9 (CH),δ 127.8 (CH), 125.8 1H),164.7 4.10 (C), (d, 154.7J = 14.7(C), 141.8 Hz, 1H), (C), 3.71 136.1 (s, (C), 3H), 134.3 2.36 (s,(C), 3H); 130.6C (C), NMR 128.8 (75 (CH), MHz, 127.9 CDCl (CH),3) 164.7 127.8 (C), (CH), 154.7 125.8 (C), (C), 125.4 (CH), 123.3 (CH), 121.6 (C), 119.8 (CH), 116.5 (CH), 114.1 (CH), 113.8 (CH), 109.1 (C), 97.8 141.8(C), 125.4 (C), 136.1(CH), (C), 123.3 134.3 (CH), (C), 121.6 130.6 (C), (C), 119.8 128.8 (CH), (CH), 116.5 127.9 (CH), 127.8114.1 (CH),(CH), 125.8113.8 (C),(CH), 125.4 109.1 (CH), (C), 123.3 97.8 (CH), 55.8 121.6 (CH), (C), 119.855.6 (CH (CH),3), 116.551.2 (CH (CH),2), 114.116.4 (CH (CH),3); HRMS 113.8 (CH), (ESI) 109.1m/z: 399,1708 (C), 97.8 [M (CH), + H] 55.8+, C (CH),25H23N 55.62O3 (CH), 55.8 (CH), 55.6 (CH3), 51.2 (CH2), 16.4 (CH3); HRMS (ESI) m/z: 399,1708 [M + H]+, C25H23N2O3 required 399,1703. + (CHrequired3), 51.2 399,1703. (CH2), 16.4 (CH3); HRMS (ESI) m/z: 399,1708 [M + H] ,C25H23N2O3 required 399,1703. 3-(1H-benzo[g]indol-3-yl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3pa)) 3-(1H-benzo[g]indol-3-yl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3pa)

Using 1H-benzo[g]indole (1p, 16.7 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- Using 1H-benzo[g]indole]indole ((1p1p,, 16.716.7 mg,mg, 0.10.1 mmol)mmol) and and 4-benzyl-3,4-dihydro-2 4-benzyl-3,4-dihydro-2HH-benzo[-benzo[b][1,4]oxazin-2-b][1,4]oxazin- 2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3pa was obtained one2-one (2a (2a, 35.8, 35.8 mg, mg, 0.15 0.15 mmol), mmol), in in accordance accordance with with General General Procedure, Procedure, thethe productproduct 3pa3pa waswas obtained (31.0 mg, 0.077 mmol, 77% yield) after 14 h as a brown solid. 1H NMR (300 MHz, Acetone) δ 11.25 (31.0 mg, 0.077 mmol, 77% yield) after 1414 hh asas aa brownbrown solid.solid. 11H NMR (300 MHz, Acetone) δ 11.25 (bs, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.58–7.29 (m, 8H), (bs, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.58–7.29 (m, 8H), 7.18–7.02 (m, 2H), 6.99–6.87 (m, 3H), 5.68 (d, J = 0.6 Hz, 1H), 4.68 (d, J = 15.1 Hz, 1H), 4.40 (d, J = 15.1 7.18–7.02 (m, 2H), 6.99–6.87 (m, 3H), 5.68 (d, JJ == 0.6 Hz, 1H), 4.68 (d, JJ = 15.1 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H); 13C NMR (75 MHz, Acetone) δ 165.05 (C), 143.02 (C), 138.04 (C), 135.22 (C), 131.87 (C), 131.47 Hz, 1H); 13CC NMR NMR (75 (75 MHz, MHz, Acetone) Acetone) δδ 165.05165.05 (C), (C), 143.02 143.02 (C), (C), 138.04 138.04 (C), (C), 135.22 135.22 (C), 131.87 (C), 131.47 (C), 129.52 (CH), 129.40 (CH), 128.60 (CH), 128.32 (CH), 126.48 (CH), 126.08 (CH), 125.02 (CH), 123.09 (C), 129.52 (CH), 129.40 (CH), 128.60 (CH), 128.32 (CH), 126.48 (CH), 126.08 (CH), 125.02 (CH), 123.09 (C), 123.00 (C), 122.23 (CH), 121.56 (CH), 121.12 (CH), 120.64 (CH), 119.68 (CH), 116.95 (CH), 115.37 (C), 123.00 (C), 122.23 (CH), 121.56 (CH), 121.12 (CH), 120.64 (CH), 119.68 (CH), 116.95 (CH), 115.37 (CH), 110.99 (C), 57.46 (CH), 52.53 (CH2); HRMS (ESI) m/z: 405,1592 [M + H]+, C27H21N2O2 required (CH), 110.99110.99 (C),(C), 57.4657.46 (CH), (CH), 52.53 52.53 (CH (CH);2); HRMS HRMS (ESI) (ESI)m m/z/:z: 405,1592 405,1592 [M [M + + H] H]+,C+, C27HH21NN2O2 required 405,1598. 2 27 21 2 2 405,1598. 3-(1H-indol-3-yl)-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ab) 3-(1H-indol-3-yl)-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ab3ab))

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 2-oneUsing ( indole2b, 40.4 (1a mg,, 11.7 0.15 mg, mmol), 0.1 mmol) in accordance and 4-(4-methoxybenzyl)-3,4-dihydro-2 with General Procedure, the productH-benzo[ 3abb ][1,4]oxazin-2-was obtained 2-one (2b, 40.4 mg, 0.15 mmol), in accordance with General Procedure, the product 3ab was obtained (21.5one ( 2bmg,, 40.4 0.056 mg, mmol, 0.15 mmol),56% yield) in accordance after 10 h as with a white General solid. Procedure, 1H NMR the (300 product MHz, CDCl3ab was3) δ obtained8.09 (bs, (21.5 mg, 0.056 mmol, 56% yield) after 10 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.09 (bs, 1H),(21.5 7.50 mg, (d, 0.056 J = mmol,7.9 Hz,56% 1H), yield) 7.35–7.30 after (m, 10 1H), h as a7.24–7.1 white6 solid. (m, 3H),1H NMR7.16–7.04 (300 (m, MHz, 3H), CDCl 6.92 (dd,) δ 8.09 J = 7.7, (bs, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.35–7.30 (m, 1H), 7.24–7.16 (m, 3H), 7.16–7.04 (m, 3H), 6.923 (dd, J = 7.7, 1H),1.4 Hz, 7.50 1H), (d, 6.90–6.83J = 7.9 Hz, (m, 1H), 3H), 7.35–7.30 6.71 (d, J (m, = 2.4 1H), Hz, 7.24–7.16 1H), 5.37 (m, (d, 3H),J = 0.4 7.16–7.04 Hz, 1H), (m, 4.57 3H), (d, J 6.92 = 14.4 (dd, Hz,J = 1H), 7.7, 1.4 Hz, 1H), 6.90–6.83 (m, 3H), 6.71 (d, J = 2.4 Hz, 1H), 5.37 (d, J = 0.4 Hz, 1H), 4.57 (d, J = 14.4 Hz, 1H), 4.071.4 Hz, (d, 1H),J = 14.3 6.90–6.83 Hz, 1H), (m, 3.82 3H), (s, 6.71 3H); (d, 13JC= NMR 2.4 Hz, (75 1H), MHz, 5.37 CDCl (d, J =3) 0.4δ 164.54 Hz, 1H), (C), 4.57 159.22 (d, J (C),= 14.4 141.93 Hz, 1H),(C), 4.07 (d, J = 14.3 Hz, 1H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.54 (C), 159.22 (C), 141.93 (C), 135.764.07 (d, (C),J = 134.29 14.3 Hz, (C), 1H), 129.22 3.82 (CH), (s, 3H); 127.8013C (C), NMR 126.10 (75 MHz,(C), 125.34 CDCl (CH),) δ 164.54 122.79 (C), (CH), 159.22 122.76 (C), (CH), 141.93 120.40 (C), 135.76 (C), 134.29 (C), 129.22 (CH), 127.80 (C), 126.10 (C), 125.34 (CH),3 122.79 (CH), 122.76 (CH), 120.40 135.76(CH), 119.81 (C), 134.29 (CH), (C), 119.20 129.22 (CH), (CH), 116.50 127.80 (CH), (C), 114.21 126.10 (CH), (C), 125.34 113.86 (CH), (CH), 122.79 111.21 (CH), (CH), 122.76 108.75 (CH), (C), 120.40 55.30 (CH), 119.81 (CH), 119.20 (CH), 116.50 (CH), 114.21 (CH), 113.86 (CH), 111.21 (CH), 108.75 (C), 55.30 (CH), 50.90 119.81 (CH (CH),2). The 119.20 spectroscopic (CH), 116.50 data (CH), match 114.21 with (CH), those 113.86 reported (CH), in 111.21the literature (CH), 108.75 [70]. (C), 55.30 (CH), 50.90 (CH2). The spectroscopic data match with those reported in the literature [70]. (CH),Catalysts 50.90 2018, (CH8, x FOR2). ThePEER spectroscopic REVIEW data match with those reported in the literature [70]. 14 of 22

4-(4-cyanobenzyl)-(3-(1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one4-(4-cyanobenzyl)-(3-(1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ac3ac))

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(4-cyanobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(4-cyanobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one one (2c, 39.6 mg, 0.15 mmol), in accordance with General Procedure, the product 3ac was obtained (2c, 39.6 mg, 0.15 mmol), in accordance with General Procedure, the product 3ac was obtained (33.4 mg, (33.4 mg, 0.088 mmol, 88% yield) after 13 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.15 (bs, 0.088 mmol, 88% yield) after 13 h as a white solid. 1H NMR (300 MHz, CDCl ) δ 8.15 (bs, 1H), 7.66–7.59 1H), 7.66–7.59 (m, 2H), 7.52 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.353 (d, J = 8.1 Hz, 1H), 7.26– 7.19 (m, 1H), 7.18–7.11 (m, 2H), 7.04 (td, J = 7.7, 1.6 Hz, 1H), 6.94 (td, J = 7.7, 1.5 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.65 (dd, J = 8.0, 1.4 Hz, 1H), 5.39 (s, 1H), 4.60 (d, J = 16.0 Hz, 1H), 4.27 (d, J = 16.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.1 (C), 142.1 (C), 141.9 (C), 135.8 (C), 133.4 (C), 132.7 (CH), 128.1 (CH), 126.0 (C), 125.4 (CH), 123.1 (CH), 122.9 (CH), 120.7 (CH), 120.6 (CH), 118.9 (CH), 118.6 (C), 116.8 (CH), 113.9 (CH), 111.6 (C), 111.4 (CH), 108.5 (C), 57.0 (CH), 51.7 (CH2); HRMS (ESI) m/z: 380,1398 [M + H]+, C24H18N3O2 required 380,1394.

4-(3-bromobenzyl)-3-(1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ad)

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(3-bromobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2d, 47.7 mg, 0.15 mmol), in accordance with General Procedure, the product 3ad was obtained (25.5 mg, 0.059 mmol, 59% yield) after 13 h as a brown oil. 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 7.54–7.49 (m, 1H), 7.46–7.41 (m, 2H), 7.35–7.31 (m, 1H), 7.25–7.18 (m, 3H), 7.17–7.11 (m, 2H), 7.05 (dd, J = 7.9, 1.6 Hz, 1H), 6.93 (td, J = 7.7, 1.4 Hz, 1H), 6.81–6.69 (m, 2H), 5.39 (d, J = 0.5 Hz, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.12 (d, J = 15.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.4 (C), 141.9 (C), 138.7 (C), 135.8 (C), 133.7 (C), 130.9 (CH), 130.7 (CH), 130.4 (CH), 126.2 (CH), 126.0 (C), 125.4 (CH), 122.9 (C), 122.9 (CH), 122.9 (CH), 120.6 (CH), 120.2 (CH), 119.0 (CH), 116.7 (CH), 113.9 (CH), 111.3 (CH), 108.6 (C), 56.3 (CH), 51.2 (CH2); HRMS (ESI) m/z: 433,0539 [ M + H]+, C23H18BrN2O2 required 433,0546.

3-(1H-indol-3-yl)-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ae)

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(thiophen-2-ylmethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-one (2e, 36.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ad was obtained (27.8 mg, 0.077 mmol, 77% yield) after 24 h as a brown solid. 1H NMR (300 MHz, CDCl3) δ 8.13 (bs, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 5.0, 1.0 Hz, 1H), 7.25–7.17 (m, 1H), 7.17–7.06 (m, 3H), 6.99–6.90 (m, 4H), 6.74 (d, J = 2.4 Hz, 1H), 5.45 (s, 1H), 4.77 (d, J = 15.1 Hz, 1H), 4.35 (d, J = 15.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.6 (C), 142.0 (C), 139.3 (C), 135.8 (C), 133.7 (C), 126.9 (CH), 126.6 (CH), 126.0 (C), 125.7 (CH), 125.4 (CH), 123.2 (CH), 122.8 (CH), 120.4 (CH), 120.3 (CH), 119.1 (CH), 116.7 (CH), 114.0 (CH), 111.3 (CH), 108.5 (C), 55.5 (CH), 46.7 (CH2); HRMS (ESI) m/z: 361,1008 [M + H]+, C21H17N2O2S required 361,1005.

Catalysts 2018,, 8,, xx FORFOR PEERPEER REVIEWREVIEW 14 of 22

4-(4-cyanobenzyl)-(3-(1H-indol-3-yl)-3,,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ac)

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(4-cyanobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- UsingCatalysts indole2018, 8, 653(1a, 11.7 mg, 0.1 mmol) and 4-(4-cyanobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-14 of 21 one (2c,, 39.639.6 mg,mg, 0.150.15 mmol),mmol), inin accordanceaccordance withwith GeneralGeneral Procedure,Procedure, thethe productproduct 3ac waswas obtainedobtained 1 3 (33.4 mg, 0.088 mmol, 88% yield) after 13 h as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.158.15 (bs,(bs, (m,1H), 2H), 7.66–7.59 7.52 (d, (m,J =2H), 7.9 7.52 Hz, (d, 1H), J == 7.41 7.97.9 (d,Hz,Hz,J 1H),1H),= 8.5 7.417.41 Hz, (d,(d, 2H), J ==7.35 8.58.5 Hz,Hz, (d, J2H),2H),= 8.1 7.357.35 Hz, (d,(d, 1H), J == 7.26–7.198.18.1 Hz,Hz, 1H),1H), (m, 7.26–7.26– 1H), 7.197.18–7.11 (m, 1H), (m, 7.18–7.11 2H), 7.04 (m, (td, 2H),J = 7.7, 7.04 1.6 (td, Hz, J == 1H), 7.7,7.7, 6.941.61.6 Hz,Hz, (td, 1H),1H),J =7.7, 6.946.94 1.5 (td,(td, Hz, J == 1H), 7.7,7.7, 6.761.51.5 Hz,Hz, (d, 1H),1H),J = 2.5 6.766.76 Hz, (d,(d, 1H), J == 13 2.56.65 Hz, (dd, 1H),J = 6.65 8.0, 1.4(dd, Hz, J == 1H),8.0,8.0, 1.41.4 5.39 Hz,Hz, (s, 1H),1H), 1H), 5.395.39 4.60 (s,(s, (d, 1H),1H),J = 16.04.604.60 Hz,(d,(d, J 1H), == 16.016.0 4.27 Hz,Hz, (d, 1H),1H),J = 4.274.27 16.0 (d,(d, Hz, J == 1H); 16.016.0 Hz,Hz,C NMR 1H);1H); 13 3 (7513C NMR MHz, (75 CDCl MHz,3) δ 164.1CDCl (C),3) δ 164.1164.1 142.1 (C),(C), (C), 142.1142.1 141.9 (C),(C), (C), 141.9141.9 135.8 (C),(C), (C), 135.8135.8 133.4 (C),(C), (C), 133.4133.4 132.7 (C),(C), (CH), 132.7132.7 128.1 (CH),(CH), (CH), 128.1128.1 126.0 (CH),(CH), (C), 125.4126.0 (C), (CH), 125.4 123.1 (CH), (CH), 123.1 122.9 (CH), (CH), 122.9 120.7 (CH), (CH), 120.7 120.6 (CH), (CH), 120.6 118.9 (CH), (CH), 118.9 118.6(CH), (C), 118.6 116.8 (C), (CH),116.8 (CH), 113.9 2 ++ (CH),113.9 (CH), 111.6 111.6 (C), 111.4 (C), 111.4 (CH), (CH), 108.5 108.5 (C), (C), 57.0 57.0 (CH), (CH), 51.7 51.7 (CH (CH2); HRMS2); HRMS (ESI) (ESI)m /mz/:z: 380,1398: 380,1398380,1398 [M [M[M + ++ H]H]H]+,,, 24 18 3 2 C24HH1818NN3O3O2 required2requiredrequired 380,1394.380,1394. 380,1394. 4-(3-bromobenzyl)-3-(1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ad) 4-(3-bromobenzyl)-3-(1H-indol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ad)

Using indoleindole ((1a1a,,, 11.7 11.711.7 mg, mg,mg, 0.1 0.10.1 mmol) mmol)mmol) and andand 4-(3-bromobenzyl)-3,4-dihydro-2 4-(3-bromobenzyl)-3,4-dihydro-24-(3-bromobenzyl)-3,4-dihydro-2H-benzo[H-benzo[b][1,4]oxazin-2-oneb][1,4]oxazin-2- (one2d, 47.7(2d,, mg,47.747.7 0.15 mg,mg, mmol), 0.150.15 mmol),mmol), in accordance inin accordanceaccordance with General withwith GeneralGeneral Procedure, Procedure,Procedure, the product thethe productproduct3ad was 3ad obtained waswas obtainedobtained (25.5 mg, 1 (25.5 mg, 0.059 mmol, 59% yield) after 13 h as a brown1 oil. 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), (25.50.059 mg, mmol, 0.059 59% mmol, yield) 59% after yield) 13 h after as abrown 13 h as oil. a brownH NMR oil. (300H NMR MHz, (300 CDCl MHz,3) δ 8.13CDCl (s,3) 1H),δ 8.13 7.54–7.49 (s, 1H), (m,7.54–7.49 1H), 7.46–7.41(m, 1H), 7.46–7.41 (m, 2H), 7.35–7.31(m, 2H), 7.35–7.31 (m, 1H), (m, 7.25–7.18 1H), 7.25–7.18 (m, 3H), (m, 7.17–7.11 3H), 7.17–7.11 (m, 2H), (m, 7.05 2H), (dd, 7.05J = (dd, 7.9, J = 7.9, 1.6 Hz, 1H), 6.93 (td, J = 7.7, 1.4 Hz, 1H), 6.81–6.69 (m, 2H), 5.39 (d, J = 0.5 Hz, 1H), 4.54 (d, J = 1.6J = 7.9, Hz, 1.6 1H), Hz, 6.93 1H), (td, 6.93J = 7.7,(td, 1.4J = Hz,7.7, 1.4 1H), Hz, 6.81–6.69 1H), 6.81–6.69 (m, 2H), (m, 5.39 2H), (d, J5.39= 0.5 (d, Hz, J = 1H),0.5 Hz, 4.54 1H), (d, J 4.54= 15.2 (d,Hz, J = 13 15.2 Hz, 1H), 4.12 (d, J = 15.3 Hz,13 1H); 13C NMR (75 MHz, CDCl3) δ 164.4 (C), 141.9 (C), 138.7 (C), 135.8 1H),15.2 Hz, 4.12 1H), (d, J4.12= 15.3 (d, J Hz, = 15.3 1H); Hz, C1H); NMR C (75NMR MHz, (75 MHz, CDCl 3CDCl) δ 164.43) δ 164.4 (C),141.9 (C), 141.9 (C), 138.7(C), 138.7 (C), (C), 135.8 135.8 (C), (C), 133.7 (C), 130.9 (CH), 130.7 (CH), 130.4 (CH), 126.2 (CH), 126.0 (C), 125.4 (CH), 122.9 (C), 122.9 133.7(C), 133.7 (C), 130.9(C), 130.9 (CH), (CH), 130.7 130.7 (CH), (CH), 130.4 130.4 (CH), (CH), 126.2 126.2 (CH), (CH), 126.0 126.0 (C), 125.4 (C), 125.4 (CH), (CH), 122.9 122.9 (C), 122.9 (C), (CH),122.9 (CH), 122.9 (CH), 120.6 (CH), 120.2 (CH), 119.0 (CH), 116.7 (CH), 113.9 (CH), 111.3 (CH), 108.6 (C), 122.9(CH), (CH),122.9 120.6(CH), (CH), 120.6 120.2 (CH), (CH), 120.2 119.0 (CH), (CH), 119.0 116.7 (CH), (CH), 116.7 113.9 (CH), (CH), 113.9 111.3 (CH), (CH), 111.3 108.6 (CH), (C), 56.3108.6 (CH), (C), + 56.3 (CH), 51.2 (CH2); HRMS (ESI) m/z: 433,0539+ [ M + H]+, C23H18BrN2O2 required 433,0546. 56.351.2 (CH), (CH2); 51.2 HRMS (CH (ESI)2); HRMSm/z: (ESI) 433,0539 m/z: [433,0539 M + H] [,C M23 +H H]18BrN, C232HO182 BrNrequired2O2 required 433,0546. 433,0546.

3-(1H-indol-3-yl)-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (((3ae3ae))

Using indole (1a,, 11.711.7 mg,mg, 0.10.1 mmol)mmol) andand 4-(thiophen-2-ylmethyl)-3,4-dihydro-24-(thiophen-2-ylmethyl)-3,4-dihydro-2H- Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- benzo[b][1,4]oxazin-2-one (2e,, 36.836.8 mg,mg, 0.150.15 mmol),mmol), inin accordanceaccordance withwith GeneralGeneral Procedure,Procedure, thethe 2-one (2e, 36.8 mg, 0.15 mmol), in accordance with General Procedure, the product 3ad was1 obtained product 3ad waswas obtainedobtained (27.8(27.8 mg,mg, 0.0770.077 mmol,mmol, 77%77% yield)yield) afterafter 2424 hh asas aa brownbrown solid.solid. 1H NMR (300 (27.8 mg, 0.077 mmol, 77% yield) after 24 h as a brown solid. 1H NMR (300 MHz, CDCl ) δ 8.13 (bs, 3 3 MHz, CDCl3) δ 8.138.13 (bs,(bs, 1H),1H), 7.567.56 (d,(d, J == 7.97.9 Hz,Hz, 1H),1H), 7.327.32 (d,(d, J == 8.08.0 Hz,Hz, 1H),1H), 7.277.27 (dd,(dd, J == 5.0,5.0, 1.01.0 Hz,Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 5.0, 1.0 Hz, 1H), 7.25–7.17 (m, 1H), 1H), 7.25–7.17 (m, 1H), 7.17–7.06 (m, 3H), 6.99–6.90 (m, 4H), 6.74 (d, J == 2.42.4 Hz,Hz, 1H),1H), 5.455.45 (s,(s, 1H),1H), 4.774.77 7.17–7.06 (m, 3H), 6.99–6.90 (m, 4H), 6.74 (d, J =13 2.4 Hz, 1H), 5.45 (s, 1H), 4.77 (d, J = 15.1 Hz, 1H), 4.35 (d, J = 15.1 Hz, 1H), 4.35 (d, J = 15.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.6 (C), 142.0 (C), 139.3 (d, J = 15.1 Hz, 1H), 4.3513 (d, J = 15.4 Hz, 1H); C NMR (75 MHz, CDCl3) δ 164.6 (C), 142.0 (C), 139.3 (d, J = 15.4 Hz, 1H); C NMR (75 MHz, CDCl3) δ 164.6 (C), 142.0 (C), 139.3 (C), 135.8 (C), 133.7 (C), (C), 135.8 (C), 133.7 (C), 126.9 (CH), 126.6 (CH), 126.0 (C), 125.7 (CH), 125.4 (CH), 123.2 (CH), 122.8 126.9 (CH), 126.6 (CH), 126.0 (C), 125.7 (CH), 125.4 (CH), 123.2 (CH), 122.8 (CH), 120.4 (CH), 120.3 (CH), 120.4 (CH), 120.3 (CH), 119.1 (CH), 116.7 (CH), 114.0 (CH), 111.3 (CH), 108.5 (C), 55.5 (CH), 46.7 (CH), 119.1 (CH), 116.7 (CH), 114.0 (CH), 111.3+ (CH), 108.5 (C), 55.5 (CH), 46.7 (CH2); HRMS (ESI) m/z: (CH2); HRMS (ESI) m/z: 361,1008 [M + H]+, C21H17N2O2S required 361,1005. (CH2); HRMS (ESI)+ m/z: 361,1008 [M + H] , C21H17N2O2S required 361,1005. 361,1008Catalysts 2018 [M, 8 +, xH] FOR,C PEER21H REVIEW17N2O2 S required 361,1005. 15 of 22

3-(1H-indol-3-yl)-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3af3af))

4-Benzyl-3-(1H-indol-3-yl)-7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ag)

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-benzyl-7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- one (2g, 38.0 mg, 0.15 mmol), in accordance with General Procedure, the product 3ag was obtained (25.4 mg, 0.069 mmol, 69% yield) after 16 h as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.11 (bs, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.38–7.26 (m, 6H), 7.24–7.17 (m, 1H), 7.16–7.10 (m, 1H), 6.93 (d, J = 1.4 Hz, 1H), 6.86 (ddd, J = 8.1, 1.9, 0.6 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 5.37 (d, J = 0.4 Hz, 1H), 4.56 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8 (C), 141.9 (C), 136.3 (C), 135.8 (C), 131.7 (C), 129.9 (C), 128.8 (CH), 127.8 (CH), 127.7 (CH), 126.2 (C), 125.7 (CH), 122.8 (CH), 122.8 (CH), 120.4 (CH), 119.2 (CH), 117.1 (CH), 114.0 (CH), 111.2 (CH), 108.8 (C), 56.0 (CH), 51.8 (CH2), 20.5 (CH3). The spectroscopic data match with those reported in the literature [70].

3-(1H-indol-3-yl)-6-methyl-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ah)

Using indole (1a, 11.7 mg, 0.1 mmol) and 6-methyl-4-(3-phenylpropyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-one (2h, 38.0 mg, 0.15 mmol), in accordance with General Procedure, the product 3ah was obtained (23.8 mg, 0.060 mmol, 60% yield) after 16 h as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 8.08 (bs, 1H), 7.71–7.61 (m, 1H), 7.39–7.25 (m, 3H), 7.24–7.09 (m, 5H), 6.93 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.64 (ddd, J = 8.1, 1.8, 0.6 Hz, 1H), 6.50 (d, J = 1.5 Hz, 1H), 5.37 (d, J = 0.6 Hz, 1H), 3.41 (ddd, J = 13.9, 8.0, 5.8 Hz, 1H), 3.13–2.98 (m, 1H), 2.68 (td, J = 7.4, 3.1 Hz, 2H), 2.30 (s, 3H), 2.10–1.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 164.4 (C), 141.1 (C), 139.6 (C), 135.9 (C), 135.0 (C), 133.4 (C), 128.5 (CH), 128.4 (CH), 126.1 (CH), 126.0 (C), 122.9 (CH), 122.7 (CH), 120.4 (CH), 119.6 (CH), 119.1 (CH), 116.2 (CH), 113.5 (CH), 111.3 (CH), 109.5 (C), 56.9 (CH), 47.2 (CH2), 32.9 (CH2), 28.3 (CH2), 21.4 (CH3); HRMS (ESI) m/z: 397,1918 [M + H]+, C26H25N2O2 required 397,1911.

Catalysts 2018, 8, x FOR PEER REVIEW 15 of 22 Catalysts 2018, 8, x FOR PEER REVIEW 15 of 22 3-(1H-indol-3-yl)-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3af) 3-(1H-indol-3-yl)-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3af)

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using indole (1a, 11.7 mg, 0.1 mmol) and 4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Catalystsone (2f,2018 40.1, 8 ,mg, 653 0.15 mmol), in accordance with General Procedure, the product 3af was obtained15 of 21 one (2f, 40.1 mg, 0.15 mmol), in accordance with General Procedure, the product 3af was obtained (28.3 mg, 0.074 mmol, 74% yield) after 24 h as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 8.07 (bs, (28.3 mg, 0.074 mmol, 74% yield) after 24 h as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 8.07 (bs, 1H), 7.66 (dd, J = 7.7, 0.5 Hz, 1H), 7.33–7.25 (m, 3H), 7.25–7.11 (m, 5H), 7.11–7.04 (m, 2H), 6.86 (ddd, J 1H), 7.66 (dd, J = 7.7, 0.5 Hz, 1H), 7.33–7.25 (m, 3H), 7.25–7.11 (m, 5H), 7.11–7.04 (m, 2H), 6.86 (ddd, J (dd,= 8.1,J 7.4,= 7.7, 1.4 0.5 Hz, Hz, 1H), 1H), 6.75 7.33–7.25 (dd, J = (m, 8.0, 3H), 1.3 7.25–7.11Hz, 1H), (m,6.69 5H), (d, J 7.11–7.04 = 2.2 Hz, (m, 1H), 2H), 5.40 6.86 (d,(ddd, J = 0.7J =Hz, 8.1, 1H), 7.4, = 8.1, 7.4, 1.4 Hz, 1H),J 6.75 (dd, J = 8.0, 1.3 Hz, 1H),J 6.69 (d, J = 2.2 Hz, 1H),J 5.40 (d, J = 0.7 Hz, 1H), 1.43.50–3.36 Hz, 1H), (m, 6.75 1H), (dd, 3.16–3.00= 8.0, 1.3(m, Hz,1H), 1H), 2.68 6.69 (t, J (d, = 7.4= 2.2Hz, Hz, 2H), 1H), 2.09–1.94 5.40 (d, (m,= 0.72H); Hz, 13C 1H), NMR 3.50–3.36 (75 MHz, (m, 1H),3.50–3.36 3.16–3.00 (m, 1H), (m, 1H),3.16–3.00 2.68 (t,(m,J = 1H), 7.4 Hz,2.68 2H), (t, J 2.09–1.94= 7.4 Hz, (m,2H), 2H); 2.09–1.9413C NMR (m, (752H); MHz, 13C NMR CDCl (75) δ MHz,164.3 CDCl3) δ 164.3 (C), 141.6 (C), 141.1 (C), 135.9 (C), 133.8 (C), 128.5 (CH), 128.4 (CH), 126.1 (CH),3 125.9 CDCl3) δ 164.3 (C), 141.6 (C), 141.1 (C), 135.9 (C), 133.8 (C), 128.5 (CH), 128.4 (CH), 126.1 (CH), 125.9 (C), 141.6125.3 (C),(CH), 141.1 122.8 (C), (CH), 135.9 122.8 (C), 133.8(CH), (C), 120.5 128.5 (CH), (CH), 119.1 128.4 (CH), (CH), 119.1 126.1 (CH), (CH), 116.6 125.9 (CH), (C), 112.9 125.3 (CH), (CH), 122.8(C), 125.3 (CH), (CH), 122.8 122.8 (CH), (CH), 120.5 122.8 (CH), (CH), 119.1 120.5 (CH), (CH), 119.1 119.1 (CH), (CH), 116.6 119.1 (CH), (CH), 112.9 116.6 (CH), (CH), 111.3 (CH),112.9 (CH), 109.4 111.3 (CH), 109.4 (C), 56.8 (CH), 47.3 (CH2), 32.9 (CH2), 28.3 (CH2); HRMS (ESI) m/z: 383,1759 [M + + (C),111.3 56.8 (CH), (CH), 109.4 47.3 (C), (CH 56.8), 32.9(CH), (CH 47.3), 28.3(CH2 (CH), 32.9); HRMS(CH2), 28.3 (ESI) (CHm/z2);: 383,1759HRMS (ESI) [M + m H]/z: ,C383,1759H N [MO + H]+, C25H23N2O2 required2 383,1754. 2 2 25 23 2 2 requiredH]+, C25H 383,1754.23N2O2 required 383,1754. 4-Benzyl-3-(1H-indol-3-yl)-7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((3ag3ag)) 4-Benzyl-3-(1H-indol-3-yl)-7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ag)

Using indole (1a, 11.7 mg, 0.1 mmol) and 4-benzyl-7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- Using indole (1a, 11.7 mg, 0.1 mmol) and 4-benzyl-7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- oneUsing (2g indole, 38.0 (mg,1a, 11.70.15 mg,mmol), 0.1 mmol) in accordance and 4-benzyl-7-methyl-3,4-dihydro-2 with General Procedure, theH product-benzo[b 3ag][1,4]oxazin-2-one was obtained one (2g, 38.0 mg, 0.15 mmol), in accordance with General Procedure, the product 3ag was obtained ((25.42g, 38.0 mg, mg, 0.069 0.15 mmol, mmol), 69% in yield) accordance after 16 with h as General a yellow Procedure, oil. 1H NMR the product (300 MHz,3ag CDClwas obtained3) δ 8.11 (25.4(bs, 1H), mg, 1 (25.4 mg, 0.069 mmol, 69% yield) after 16 h as a yellow1 oil. H NMR (300 MHz, CDCl3) δ 8.11 (bs, 1H), 7.520.069 (d, mmol, J = 7.9 69% Hz, yield)1H), 7.38–7.26 after 16 h(m, as 6H), a yellow 7.24–7.17 oil. H(m, NMR 1H), (3007.16–7.10 MHz, (m, CDCl 1H),3) 6.93δ 8.11 (d, (bs, J = 1H),1.4 Hz, 7.52 1H), (d, 7.52 (d, J = 7.9 Hz, 1H), 7.38–7.26 (m, 6H), 7.24–7.17 (m, 1H), 7.16–7.10 (m, 1H), 6.93 (d, J = 1.4 Hz, 1H), 6.86J = 7.9 (ddd, Hz, J 1H), = 8.1, 7.38–7.26 1.9, 0.6 Hz, (m, 1H), 6H), 6.73 7.24–7.17 (d, J = (m, 2.5 1H),Hz, 1H), 7.16–7.10 6.70 (d, (m, J 1H),= 8.2 6.93Hz, (d,1H),J =5.37 1.4 (d, Hz, J 1H),= 0.4 6.86Hz, 6.86 (ddd, J = 8.1, 1.9, 0.6 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 5.37 (d, J = 0.4 Hz, (ddd,1H), 4.56J = 8.1,(d, J 1.9,= 14.8 0.6 Hz, Hz, 1H), 1H), 4.12 6.73 (d, (d, JJ == 14.8 2.5 Hz,Hz, 1H),1H), 6.702.31 (d,(s, 3H);J = 8.2 13C Hz, NMR 1H), (75 5.37 MHz, (d, JCDCl= 0.43 Hz,) δ 164.8 1H), 13 1H), 4.56 (d, J = 14.8 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 2.31 (s, 3H);13 C NMR (75 MHz, CDCl3) δ 164.8 (C),4.56 141.9 (d, J = (C), 14.8 136.3 Hz, 1H),(C), 135.8 4.12 (d, (CJ),= 131.7 14.8 Hz,(C), 1H),129.9 2.31 (C), (s, 128.8 3H); (CH),C NMR 127.8(75 (CH), MHz, 127.7 CDCl (CH),3) δ 126.2164.8 (C), (C), (C), 141.9 (C), 136.3 (C), 135.8 (C), 131.7 (C), 129.9 (C), 128.8 (CH), 127.8 (CH), 127.7 (CH), 126.2 (C), 141.9125.7 (C),(CH), 136.3 122.8 (C), (CH), 135.8 122.8 (C), (CH), 131.7 (C),120.4 129.9 (CH), (C), 119.2 128.8 (CH), (CH), 117.1 127.8 (CH), (CH), 114.0 127.7 (CH), (CH), 111.2 126.2 (CH), (C), 108.8 125.7 125.7 (CH), 122.8 (CH), 122.8 (CH), 120.4 (CH), 119.2 (CH), 117.1 (CH), 114.0 (CH), 111.2 (CH), 108.8 (CH),(C), 56.0 122.8 (CH), (CH), 51.8 122.8 (CH (CH),2), 20.5 120.4 (CH (CH),3). 119.2The spectroscopic (CH), 117.1 (CH), data 114.0 match (CH), with 111.2 those (CH), reported 108.8 (C), in 56.0the (C), 56.0 (CH), 51.8 (CH2), 20.5 (CH3). The spectroscopic data match with those reported in the (CH),literature 51.8 [70]. (CH 2), 20.5 (CH3). The spectroscopic data match with those reported in the literature [70]. literature [70]. 3-(1H-indol-3-yl)-6-methyl-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ah) 3-(1H-indol-3-yl)-6-methyl-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ah) 3-(1H-indol-3-yl)-6-methyl-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (3ah)

Using indole (1a, 11.7 mg, 0.1 mmol) and 6-methyl-4-(3-phenylpropyl)-3,4-dihydro-2H- Using indoleindole (1a ,(1a 11.7, mg,11.7 0.1mg, mmol) 0.1 and mmol) 6-methyl-4-(3-phenylpropyl)-3,4-dihydro-2 and 6-methyl-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]H- benzo[b][1,4]oxazin-2-one (2h, 38.0 mg, 0.15 mmol), in accordance with General Procedure, the oxazin-2-onebenzo[b][1,4]oxazin-2-one (2h, 38.0 mg, ( 0.152h, mmol),38.0 mg, in 0.15 accordance mmol), within accordance General Procedure, with General the product Procedure,13ah wasthe product 3ah was obtained (23.8 mg, 0.060 mmol, 60% yield) after 16 h1 as a colourless oil. H NMR obtainedproduct 3ah (23.8 was mg, obtained 0.060 mmol, (23.8 60% mg, yield) 0.060after mmol, 16 h60% as ayield) colourless after oil.16 h Has NMRa colourless (300 MHz, oil. CDCl1H NMR3) δ (300 MHz, CDCl3) δ 8.08 (bs, 1H), 7.71–7.61 (m, 1H), 7.39–7.25 (m, 3H), 7.24–7.09 (m, 5H), 6.93 (d, J = 8.08(300 (bs,MHz, 1H), CDCl 7.71–7.613) δ 8.08 (m, (bs, 1H), 1H), 7.39–7.25 7.71–7.61 (m, (m, 3H), 1H), 7.24–7.09 7.39–7.25 (m, (m, 5H), 3H), 6.93 7.24–7.09 (d, J = 8.1(m, Hz, 5H), 1H), 6.93 6.72 (d, (d,J = 8.1 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.64 (ddd, J = 8.1, 1.8, 0.6 Hz, 1H), 6.50 (d, J = 1.5 Hz, 1H), 5.37 (d, J8.1= 2.3Hz, Hz, 1H), 1H), 6.72 6.64 (d, (ddd,J = 2.3J Hz,= 8.1, 1H), 1.8, 6.64 0.6 (ddd, Hz, 1H), J = 8.1, 6.50 1.8, (d, J0.6= 1.5Hz, Hz, 1H), 1H), 6.50 5.37 (d, (d,J = 1.5J = Hz, 0.6Hz, 1H), 1H), 5.37 3.41 (d, J = 0.6 Hz, 1H), 3.41 (ddd, J = 13.9, 8.0, 5.8 Hz, 1H), 3.13–2.98 (m, 1H), 2.68 (td, J = 7.4, 3.1 Hz, 2H), 2.30 (ddd,J = 0.6J Hz,= 13.9, 1H), 8.0, 3.41 5.8 (ddd, Hz, 1H),J13 = 13.9, 3.13–2.98 8.0, 5.8 (m, Hz, 1H), 1H), 2.68 3.13–2.98 (td, J = 7.4,(m, 3.11H), Hz, 2.68 2H), (td, 2.30 J = 7.4, (s, 3H), 3.1 Hz, 2.10–1.88 2H), 2.30 (m, (s, 3H),13 2.10–1.88 (m, 2H); C NMR (75 MHz, CDCl3) δ 164.4 (C), 141.1 (C), 139.6 (C), 135.9 (C), 135.0 2H);(s, 3H),C 2.10–1.88 NMR (75 (m, MHz, 2H); CDCl 13C NMR) δ 164.4 (75 MHz, (C), 141.1 CDCl (C),3) δ 139.6164.4 (C),(C), 135.9141.1 (C),(C), 135.0139.6 (C),(C), 133.4135.9 (C), 128.5135.0 (C), 133.4 (C), 128.5 (CH), 128.43 (CH), 126.1 (CH), 126.0 (C), 122.9 (CH), 122.7 (CH), 120.4 (CH), 119.6 (CH),(C), 133.4 128.4 (C), (CH), 128.5 126.1 (CH), (CH), 128.4 126.0 (CH), (C), 126.1 122.9 (CH), (CH), 126.0 122.7 (C), (CH), 122.9 120.4(CH), (CH), 122.7 119.6(CH), (CH),120.4 119.1(CH), (CH),119.6 (CH), 119.1 (CH), 116.2 (CH), 113.5 (CH), 111.3 (CH), 109.5 (C), 56.9 (CH), 47.2 (CH2), 32.9 (CH2), 28.3 116.2(CH), (CH), 119.1 113.5(CH), (CH), 116.2 111.3(CH), (CH), 113.5 109.5(CH), (C), 111.3 56.9 (CH), (CH),+ 109.5 47.2 (C), (CH 56.92), 32.9 (CH), (CH 47.22), 28.3(CH2 (CH), 32.92), 21.4(CH2 (CH), 28.33); (CH2), 21.4 (CH3); HRMS (ESI) m/z: +397,1918 [M + H] , C26H25N2O2 required 397,1911. CatalystsHRMS(CH2), 21.4 (ESI)2018, (CH8m, x/ FOR3z);: 397,1918HRMS PEER REVIEW (ESI) [M +m H]/z: 397,1918,C26H25 N[M2O +2 H]required+, C26H25 397,1911.N2O2 required 397,1911. 16 of 22

4-Benzyl-3-(1H-pyrrol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one4-Benzyl-3-(1H-pyrrol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((6a6a))

Using pyrrole (4a, 7 μL, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a, 35.8 Using pyrrole (4a, 7 µL, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, mg, 0.15 mmol), in accordance with General Procedure, the product 6a was obtained (16.7 mg, 0.055 0.15 mmol), in accordance with General Procedure, the product 6a was obtained (16.7 mg, 0.055 mmol, mmol, 55% yield) after 12 h as a brown oil. 1H NMR (300 MHz, CDCl3) δ 7.95 (bs, 1H), 7.45–7.27 (m, 55% yield) after 12 h as a brown oil. 1H NMR (300 MHz, CDCl ) δ 7.95 (bs, 1H), 7.45–7.27 (m, 5H), 5H), 7.15–7.07 (m, 2H), 6.97–6.87 (m, 2H), 6.67 (td, J = 2.7, 1.5 Hz,3 1H), 6.06 (dd, J = 6.1, 2.7 Hz, 1H), 5.92–5.83 (m, 1H), 5.03 (s, 1H), 4.65 (d, J = 14.3 Hz, 1H), 4.08 (d, J = 14.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.15 (C), 141.39 (C), 135.58 (C), 133.73 (C), 128.96 (CH), 128.12 (CH), 128.04 (CH), 127.73 (CH), 125.67 (CH), 123.09 (C), 120.34 (CH), 119.12 (CH), 116.79 (CH), 113.85 (CH), 108.87 (CH), 56.86 (CH), 51.60 (CH2). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6b)

Using N-methylpyrrole (4b, 9 μL, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 6b was obtained (18.4 mg, 0.058 mmol, 58% yield) after 11 h as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.37–7.30 (m, 5H), 7.10 (dd, J = 7.9, 1.5 Hz, 1H), 7.06–7.00 (m, 1H), 6.89 (dd, J = 7.7, 1.5 Hz, 1H), 6.76 (dd, J = 8.0, 1.3 Hz, 1H), 6.42 (t, J = 2.5 Hz, 1H), 6.31 (t, J = 2.0 Hz, 1H), 5.75 (dd, J = 2.6, 1.9 Hz, 1H), 4.93 (s, 1H), 4.55 (d, J = 14.5 Hz, 1H), 4.07 (d, J = 14.5 Hz, 1H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.64 (C), 141.93 (C), 136.25 (C), 134.19 (C), 128.80 (CH), 127.96 (CH), 127.70 (CH), 125.17 (CH), 122.33 (CH), 120.54 (CH), 119.68 (CH), 116.36 (CH), 115.67 (C), 113.82 (CH), 107.83 (CH), 56.93 (CH), 51.18 (CH2), 36.24 (CH3). The spectroscopic data match with those reported in the literature [70].

4-Benzyl-3-(2,4,6-trimethoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (7)

Using 1,3,5-trimethoxybenzene (5, 16.8 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 7 was obtained (33.6 mg, 0.083 mmol, 83% yield) after 19 h as a yellowish solid. 1H NMR (400 MHz, CDCl3) δ 7.25–7.21 (m, 2H), 7.21–7.15 (m, 3H), 7.04 (dd, J = 7.9, 1.5 Hz, 1H), 6.88 (ddd, J = 8.0, 7.6, 1.5 Hz, 1H), 6.70 (td, J = 7.7, 1.4 Hz, 1H), 6.50 (dd, J = 8.1, 1.3 Hz, 1H), 6.04 (s, 2H), 5.87 (s, 1H), 4.37 (d, J = 16.6 Hz, 1H), 4.22 (d, J = 16.6 Hz, 1H), 3.77 (s, 3H), 3.59 (s, 6H);13C NMR (75 MHz, CDCl3) δ 167.51 (C), 161.76 (C), 159.31 (C), 140.98 (C), 137.86 (C), 133.86 (C), 128.35 (CH), 126.80 (CH), 126.53 (CH), 124.63 (CH), 117.37 (CH), 115.70 (CH), 111.83 (CH), 106.70 (C), 90.68 (CH), 55.51 (CH3), 55.33 (CH), 53.89 (CH3), 50.71 (CH2). The spectroscopic data match with those reported in the literature [70].

3.4. Synthesis and Characterization of Cephalandole A (8) In a 25 mL round bottomed flask were placed compound 3aa (30 mg, 0.085 mmol) and Pd/C 10% w/w (18.1 mg, 0.017 mmol, 20 mol%). Subsequently, THF (2 mL) and EtOH (1 mL) were added and the resulting suspension was bubbled with H2. After this, the reaction mixture was stirred at room temperature for 16 h with a H2 balloon. The reaction was monitored by TLC, and, when compound

Catalysts 2018, 8, x FOR PEER REVIEW 16 of 22 Catalysts 2018, 8, x FOR PEER REVIEW 16 of 22 4-Benzyl-3-(1H-pyrrol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6a) 4-Benzyl-3-(1H-pyrrol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6a)

Using pyrrole (4a, 7 μL, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a, 35.8 CatalystsUsing pyrrole2018, 8, 653 (4a, 7 μL, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (2a16, 35.8 of 21 mg, 0.15 mmol), in accordance with General Procedure, the product 6a was obtained (16.7 mg, 0.055 mg, 0.15 mmol), in accordance with General Procedure, the product 6a was obtained (16.7 mg, 0.055 mmol, 55% yield) after 12 h as a brown oil. 1H NMR (300 MHz, CDCl3) δ 7.95 (bs, 1H), 7.45–7.27 (m, mmol, 55% yield) after 12 h as a brown oil. 1H NMR (300 MHz, CDCl3) δ 7.95 (bs, 1H), 7.45–7.27 (m, 5H),7.15–7.07 7.15–7.07 (m, 2H), (m, 6.97–6.872H), 6.97–6.87 (m, 2H), (m, 6.67 2H), (td, 6.67J = (td, 2.7, J 1.5 = 2.7, Hz, 1.5 1H), Hz, 6.06 1H), (dd, 6.06J = 6.1,(dd, 2.7 J = Hz, 6.1, 1H), 2.7 5.92–5.83Hz, 1H), 5H), 7.15–7.07 (m, 2H), 6.97–6.87 (m, 2H), 6.67 (td, J = 2.7, 1.5 Hz, 1H), 6.06 (dd, J = 6.1, 2.7 Hz, 1H), 5.92–5.83(m, 1H), 5.03(m, (s,1H), 1H), 5.03 4.65 (s, (d,1H),J = 4.65 14.3 (d, Hz, J = 1H), 14.3 4.08Hz, (d,1H),J = 4.08 14.3 (d, Hz, J = 1H); 14.313 Hz,C NMR 1H); 13 (75C NMR MHz, (75 CDCl MHz,) δ 5.92–5.83 (m, 1H), 5.03 (s, 1H), 4.65 (d, J = 14.3 Hz, 1H), 4.08 (d, J = 14.3 Hz, 1H); 13C NMR (75 MHz,3 164.15CDCl3) (C), δ 164.15 141.39 (C), (C), 141.39 135.58 (C), (C), 135.58 133.73 (C), (C), 133.73 128.96 (CH),(C), 128.96 128.12 (CH), (CH), 128.12 128.04 (CH), (CH), 128.04 127.73 (CH), (CH), 127.73 125.67 CDCl3) δ 164.15 (C), 141.39 (C), 135.58 (C), 133.73 (C), 128.96 (CH), 128.12 (CH), 128.04 (CH), 127.73 (CH), 125.67 123.09 (CH), (C), 120.34 123.09 (CH), (C), 120.34 119.12 (CH), (CH), 119.12 116.79 (CH), (CH), 116.79 113.85 (CH), (CH), 113.85 108.87 (CH), (CH), 108.87 56.86 (CH), 56.86 51.60 (CH), 125.67 (CH), 123.09 (C), 120.34 (CH), 119.12 (CH), 116.79 (CH), 113.85 (CH), 108.87 (CH), 56.86 (CH),(CH2). 51.60 The spectroscopic(CH2). The spectroscopic data match data with match those reportedwith those in reported the literature in the [70 literature]. [70]. (CH), 51.60 (CH2). The spectroscopic data match with those reported in the literature [70]. 4-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((6b6b)) 4-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (6b)

Using N-methylpyrrole (4b, 9 μL, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one Using N-methylpyrrole ( 4b, 9 μµL, 0.1 mmol) and 4-benzyl-3,4-dihydro-2 H-benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the product 6b was obtained (18.4 (2a, 35.835.8 mg,mg, 0.150.15 mmol), mmol), in in accordance accordance with with General General Procedure, Procedure, the the product product6b was6b was obtained obtained (18.4 (18.4 mg, mg, 0.058 mmol, 58% yield) after 11 h as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.37–7.30 (m, 5H), mg,0.058 0.058 mmol, mmol, 58% 58% yield) yield) after after 11 h11 as h aas yellow a yellow oil. oil.1H 1H NMR NMR (300 (300 MHz, MHz, CDCl CDCl3)) δδ 7.37–7.30 (m, 5H), 5H), 7.10 (dd, J = 7.9, 1.5 Hz, 1H), 7.06–7.00 (m, 1H), 6.89 (dd, J = 7.7, 1.5 Hz, 1H), 6.763 (dd, J = 8.0, 1.3 Hz, 7.10 (dd, J = 7.9, 1.5 Hz, 1H), 7.06–7.00 (m, 1H), 6.89 (dd, J = 7.7, 7.7, 1.5 1.5 Hz, 1H), 6.76 (dd, J = 8.0, 8.0, 1.3 1.3 Hz, Hz, 1H), 6.42 (t, J = 2.5 Hz, 1H), 6.31 (t, J = 2.0 Hz, 1H), 5.75 (dd, J = 2.6, 1.9 Hz, 1H), 4.93 (s, 1H), 4.55 (d, J 1H), 6.42 (t, J = 2.5 2.5 Hz, Hz, 1H), 1H), 6.31 6.31 (t, (t, JJ == 2.0 2.0 Hz, Hz, 1H), 1H), 5.75 5.75 (dd, (dd, J J== 2.6, 2.6, 1.9 1.9 Hz, Hz, 1H), 1H), 4.93 4.93 (s, (s, 1H), 1H), 4.55 4.55 (d, (d, J = 14.5 Hz, 1H), 4.07 (d, J = 14.5 Hz, 1H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.64 (C), 141.93 =J =14.5 14.5 Hz, Hz, 1H), 1H), 4.07 4.07 (d, (d, J J== 14.5 14.5 Hz, Hz, 1H), 1H), 3.53 3.53 (s, (s, 3H); 3H); 1313CC NMR NMR (75 (75 MHz, MHz, CDCl CDCl3)) δδ 165.64165.64 (C), 141.93 (C), 136.25 (C), 134.19 (C), 128.80 (CH), 127.96 (CH), 127.70 (CH), 125.17 (CH),3 122.33 (CH), 120.54 (C), 136.25136.25 (C),(C), 134.19 134.19 (C), (C), 128.80 128.80 (CH), (CH), 127.96 127.96 (CH), (CH), 127.70 127.70 (CH), (CH), 125.17 125.17 (CH), (CH), 122.33 122.33 (CH), (CH), 120.54 120.54 (CH), (CH), 119.68 (CH), 116.36 (CH), 115.67 (C), 113.82 (CH), 107.83 (CH), 56.93 (CH), 51.18 (CH2), 36.24 119.68(CH), 119.68 (CH), 116.36(CH), 116.36 (CH), 115.67(CH), 115.67 (C), 113.82 (C), 113.82 (CH), 107.83(CH), 107.83 (CH), 56.93(CH), (CH), 56.93 51.18(CH), (CH 51.182), (CH 36.242), (CH 36.243). (CH3). The spectroscopic data match with those reported in the literature [70]. The(CH3 spectroscopic). The spectroscopic data match data withmatch those with reported those reported in the literature in the literature [70]. [70]. 4-Benzyl-3-(2,4,6-trimethoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one (7) 4-Benzyl-3-(2,4,6-trimethoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-one ((77))

Using 1,3,5-trimethoxybenzene (5, 16.8 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H- Using 1,3,5-trimethoxybenzene (5, 16.8 mg, 0.1 mmol) and 4-benzyl-3,4-dihydro-2H- benzo[Usingb 1,3,5-trimethoxybenzene][1,4]oxazin-2-one (2a, 35.8 (5, 16.8mg, mg,0.15 0.1mmol), mmol) in and accordance 4-benzyl-3,4-dihydro-2 with General HProcedure,-benzo[b][1,4] the benzo[b][1,4]oxazin-2-one (2a, 35.8 mg, 0.15 mmol), in accordance with General Procedure, the productoxazin-2-one 7 was (obtained2a, 35.8 mg, (33.6 0.15 mg, mmol), 0.083 mmol, in accordance 83% yield) with after General 19 h as a Procedure, yellowish solid. the product 1H NMR7 (400was 1 product 7 was obtained (33.6 mg, 0.083 mmol, 83% yield) after 19 h as a yellowish1 solid. H NMR (400 MHz,obtained CDCl (33.63) δ mg, 7.25–7.21 0.083 mmol, (m, 2H), 83% 7.21–7.15 yield) after (m,19 3H), h as 7.04 a yellowish (dd, J = 7.9, solid. 1.5 Hz,H NMR 1H), (4006.88 MHz,(ddd, CDClJ = 8.0,3) MHz, CDCl3) δ 7.25–7.21 (m, 2H), 7.21–7.15 (m, 3H), 7.04 (dd, J = 7.9, 1.5 Hz, 1H), 6.88 (ddd, J = 8.0, 7.6,δ 7.25–7.21 1.5 Hz, (m,1H), 2H), 6.70 7.21–7.15(td, J = 7.7, (m, 1.4 3H), Hz, 7.041H), (dd, 6.50J (dd,= 7.9, J = 1.5 8.1, Hz, 1.3 1H), Hz, 6.881H), (ddd,6.04 (s,J =2H), 8.0, 5.87 7.6, (s, 1.5 1H), Hz, 4.37 1H), 7.6, 1.5 Hz, 1H), 6.70 (td, J = 7.7, 1.4 Hz, 1H), 6.50 (dd, J = 8.1, 1.3 Hz, 1H), 6.04 (s, 2H), 5.87 (s, 1H), 4.37 (d,6.70 J (td,= 16.6J = Hz, 7.7, 1H), 1.4 Hz, 4.22 1H), (d, 6.50J = 16.6 (dd, Hz,J = 8.1,1H), 1.3 3.77 Hz, (s, 1H), 3H), 6.04 3.59 (s, (s, 2H), 6H); 5.8713C (s, NMR 1H), (75 4.37 MHz, (d, J =CDCl 16.63 Hz,) δ (d, J = 16.6 Hz, 1H), 4.22 (d, J = 16.6 Hz, 1H), 3.77 (s, 3H), 3.59 (s, 6H);13C NMR (75 MHz, CDCl3) δ 1H),167.51 4.22 (C), (d, 161.76J = 16.6 (C), Hz, 159.31 1H), (C), 3.77 140.98 (s, 3H), (C), 3.59 137.86 (s, 6H); (C),13C 133.86 NMR (C), (75 MHz,128.35 CDCl (CH),) 126.80δ 167.51 (CH), (C), 126.53 161.76 167.51 (C), 161.76 (C), 159.31 (C), 140.98 (C), 137.86 (C), 133.86 (C), 128.35 (CH),3 126.80 (CH), 126.53 (CH),(C), 159.31 124.63 (C), (CH), 140.98 117.37 (C), (CH), 137.86 115.70 (C), 133.86 (CH), (C), 111.83 128.35 (CH), (CH), 106.70 126.80 (C), (CH), 90.68 126.53 (CH), (CH),55.51 124.63(CH3), (CH),55.33 (CH), 124.63 (CH), 117.37 (CH), 115.70 (CH), 111.83 (CH), 106.70 (C), 90.68 (CH), 55.51 (CH3), 55.33 117.37(CH), 53.89 (CH), (CH 115.703), 50.71 (CH), (CH 111.832). The (CH), spectroscopic 106.70 (C), 90.68data match (CH), 55.51with those (CH3 ),reported 55.33 (CH), in the 53.89 literature (CH3), (CH), 53.89 (CH3), 50.71 (CH2). The spectroscopic data match with those reported in the literature [70].50.71 (CH ). The spectroscopic data match with those reported in the literature [70]. [70]. 2 3.4. Synthesis Synthesis and Charact Characterizationerization of Cephalandole A ( 8) 3.4. Synthesis and Characterization of Cephalandole A (8) In a 25 25 mL mL round round bottomed flask flask were placed compound 3aa3aa (30(30 mg,mg, 0.0850.085 mmol)mmol) andand Pd/CPd/C 10% 10% In a 25 mL round bottomed flask were placed compound 3aa (30 mg, 0.085 mmol) and Pd/C 10% w/w (18.1 (18.1 mg, mg, 0.017 0.017 mmol, mmol, 20 20 mol%). mol%). Subsequently Subsequently,, THF THF (2 (2 mL) mL) and and EtOH EtOH (1 mL) were added and w/w (18.1 mg, 0.017 mmol, 20 mol%). Subsequently, THF (2 mL) and EtOH (1 mL) were added and the resulting suspension was bubbled with H 2.. After After this, this, the the reaction reaction mixture mixture was was stirred stirred at at room the resulting suspension was bubbled with H2. After this, the reaction mixture was stirred at room temperature for 16 h with a HH2 balloon. The The reaction was monitored by TLC, and, when compound temperature3aa was consumed, for 16 h DDQ with (19.3 a H2 mg,balloon. 0.085 The mmol) reaction was added was monitored directly to by the TLC, reaction and, mixture. when compound After 1 h, the reaction mixture was filtered through a pad of Celite, the solvents were removed by reduced pressure and the resulting residue was purified by column chromatography using a hexane:EtOAc 95:5 mixture as eluent to afford Cephalandole A, 8 (20.3 mg, 0.077 mmol, 92% yield) as a bright yellow solid. Catalysts 2018, 8, x FOR PEER REVIEW 17 of 22 Catalysts 2018, 8, x FOR PEER REVIEW 17 of 22

3aa was consumed, DDQ (19.3 mg, 0.085 mmol) was added directly to the reaction mixture. After 1 h, the reaction mixture was filtered through a pad of Celite, the solvents were removed by reduced pressure and the resulting residue was purified by column chromatography using a hexane:EtOAc Catalysts 2018, 8, 653 17 of 21 95:5 mixture as eluent to afford Cephalandole A, 8 (20.3 mg, 0.077 mmol, 92% yield) as a bright yellow solid. 3-(1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one (Cephalandole A, 8) 3-(1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one (Cephalandole A, 8)

Bright yellow solid; 1H NMR (300 MHz, Acetone) δ 11.04 (s, 1H), 8.88–8.82 (m, 1H), 8.78 (t, J = 1.5 Hz, Bright yellow solid; 1HH NMR NMR (300 (300 MHz, MHz, Acetone) Acetone) δ 11.04 (s, 1H), 8.88–8.82 (m, 1H), 8.78 (t, J = 1.5 1.5 Hz, Hz, 1H), 7.87–7.83 (m, 1H), 7.57–7.49 (m, 1H), 7.49–7.35 (m, 2H), 7.35–7.28 (m, 1H), 7.28–7.21 (m, 2H); 13C 1H), 7.87–7.83 7.87–7.83 (m, (m, 1H), 1H), 7.57–7.49 7.57–7.49 (m, (m, 1H), 1H), 7.49–7.35 7.49–7.35 (m, (m, 2H), 2H), 7.35–7.28 7.35–7.28 (m, (m, 1H), 1H), 7.28–7.21 7.28–7.21 (m, (m,2H); 2H); 13C NMR (75 MHz, Acetone) δ 153.00 (C), 149.05 (C), 146.22 (C), 137.86 (C), 134.58 (CH), 133.20 (C), 129.58 NMR13C NMR (75 MHz, (75 MHz, Acetone) Acetone) δ 153.00δ 153.00 (C), 149.05 (C), 149.05 (C), 146.22 (C), 146.22 (C), 13 (C),7.86 137.86(C), 134.58 (C), 134.58(CH), 133.20 (CH), (C), 133.20 129.58 (C), (CH), 128.88 (CH), 127.36 (C), 126.12 (CH), 124.18 (CH), 124.10 (CH), 122.47 (CH), 116.75 (CH), 112.77 (CH),129.58 128.88 (CH), (CH), 128.88 127.36 (CH), (C), 127.36 126.12 (C), (CH), 126.12 124.18 (CH), (CH), 124.18 124.10 (CH), (CH), 124.10 122.47 (CH), (CH), 122.47 116.75 (CH), (CH), 116.75 112.77 (CH), (CH), 112.37 (C). The spectroscopic data match with those reported in the literature [70]. (CH),112.77 112.37 (CH), 112.37(C). The (C). spectroscopic The spectroscopic data matc datah matchwith those with reported those reported in the literature in the literature [70]. [70].

3.5. Synthesis Synthesis and Charac Characterizationterization of Compound 9 In a 10 mL round bottomed flask ﬂask was placed compound 3aa (15.5 mg, 0.044 mmol) and it was purgued with N2. Afterwards, dry THF (1 mL) was added via syringe and the resulted solution was purgued with N2.. Afterwards, Afterwards, dry dry THF THF (1 (1 mL) mL) was was added added vi viaa syringe syringe and and the resulted solution was cooled down to 0 °C.◦ After 5 min, LiAlH4 (0.08 mL 1 M in THF, 0.087 mmol, two equivalents) was cooled down to 0 °C.C. After 5 min, LiAlH 4 (0.08(0.08 mL mL 1 1 M M in in THF, 0.087 mmol, two equivalents) was added viavia syringesyringe and and the the mixture mixture was was stirred stirred for 1.5for h1.5 at 0h◦ C.at Subsequently,0 °C. Subsequently, the reaction the reaction was stopped was stopped with the addition of saturated aqueous NH4Cl solution (1 mL) and saturated aqueous stoppedwith the additionwith the ofaddition saturated of aqueoussaturated NH aqueous4Cl solution NH4Cl (1 mL)solution and saturated(1 mL) and aqueous saturated Rochelle aqueous Salt Rochellesolution (5Salt mL). solution The resulting(5 mL). The mixture resulting was mixt extractedure was with extracted EtOAc with (three EtOAc times), (three washed times), with washed brine, with brine, and dried over anhydrous MgSO4. The solvent was removed by reduced pressure and the withand driedbrine, over and anhydrousdried over anhydrous MgSO4. The MgSO solvent4. The was solvent removed was byremoved reduced by pressure reduced andpressure the resulting and the resultingresidue was residue puriﬁed was by purified column by chromatography column chromato usinggraphy hexane: using EtOAc hexane: mixtures EtOAc as mixtures eluent (from as eluent 90:10 (fromto 60:40) 90:10 to affordto 60:40) compound to afford 9compound(9.0 mg, 0.025 9 (9.0 mmol, mg, 0.025 57% yield)mmol, as 57% a colourless yield) as a oil. colourless oil. 2-(Benzyl(2-hydroxy-1-(1H-indol-3-yl)ethyl)amino)phenol (9) 2-(Benzyl(2-hydroxy-1-(1H-indol-3-yl)ethyl)amino)phenol (9)

Brown oil; 1H NMR (300 MHz, CDCl3:CD3OD) δ 8.59 (bs, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36–7.27 (m, Brown oil; 1H NMR (300 MHz, CDCl3:CD3OD) δ 8.59 (bs, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36–7.27 (m, Brown oil; 1H NMR (300 MHz, CDCl :CD OD) δ 8.59 (bs, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36–7.27 (m, 5H), 7.25–7.20 (m, 1H), 7.11 (t, J = 7.6 Hz,3 2H),3 7.03–6.95 (m, 2H), 6.70 (d, J = 7.8 Hz, 2H), 6.55 (d, J = 7.9 5H), 7.25–7.20 (m, 1H), 7.11 (t, J = 7.6 Hz, 2H), 7.03–6.95 (m, 2H), 6.70 (d, J = 7.8 Hz,13 2H), 6.55 (d, Hz, 1H), 4.29–4.21 (m, 3H), 4.12 (dd, J = 10.8, 6.1 Hz, 1H), 4.01 (dd, J = 10.8, 7.7 Hz, 1H); 13C NMR (75 Hz, 1H), 4.29–4.21 (m, 3H), 4.12 (dd, J = 10.8, 6.1 Hz, 1H), 4.01 (dd, J = 10.8, 7.7 Hz, 1H); C 13NMR (75 MHz,J = 7.9 CDCl Hz, 1H),3) δ4.29–4.21 144.42 (C), (m, 138.92 3H), 4.12 (C), (dd, 136.28J = 10.8,(C), 128.45 6.1 Hz, (CH), 1H), 4.01 127.68 (dd, (CH),J = 10.8, 127.16 7.7 Hz, (CH), 1H); 126.90C NMR (C), MHz, CDCl3) δ 144.42 (C), 138.92 (C), 136.28 (C), 128.45 (CH), 127.68 (CH), 127.16 (CH), 126.90 (C), (75 MHz, CDCl ) δ 144.42 (C), 138.92 (C), 136.28 (C), 128.45 (CH), 127.68 (CH), 127.16 (CH), 126.90 (C), 121.85 (CH), 121.773 (CH), 120.18 (CH), 119.32 (CH), 119.08 (CH), 116.17 (C), 116.10 (C), 114.15 (CH), 121.85112.24 (CH), 111.08 121.77 (CH), (CH), 111.03 120.18 (CH), (CH), 66.23 119.32 (CH (CH),2), 48.79 119.08 (CH (CH),2), 44.63 116.17 (CH); (C), HRMS 116.10 (ESI) (C), m 114.15/z: 359,1757 (CH), 112.24 (CH), 111.08 (CH), 111.03 (CH), 66.23 (CH2), 48.79 (CH2), 44.63 (CH); HRMS (ESI) m/z: 359,1757 112.24 (CH),+ 111.08 (CH), 111.03 (CH), 66.23 (CH ), 48.79 (CH ), 44.63 (CH); HRMS (ESI) m/z: 359,1757 [M + H]+, C23H23N2O2 required 359,1754. 2 2 [M + H] +, C23H23N2O2 required 359,1754. [M + H] ,C23H23N2O2 required 359,1754. 4. Conclusions 4. Conclusions Conclusions In summary, we have described a visible-light functionalization of 3,4-dihydro-1,4-benzoxazin- 2-onesIn with summary, indoles we and have other described electron-rich a visible-light arenes using functionalization a dual catalytic of 3,4-dihydro-1,4-benzoxazin-system that was formed by 2-ones with with indoles indoles and and other other electron-rich electron-rich arenes arenes using using a dual a dual catalytic catalytic system system that that was was formed formed by a Lewis acid (Zn(OTf)2) and 9,10-phenanthrenedione as photocatalyst. Under our reaction conditions, a Lewis acid (Zn(OTf)2) and 9,10-phenanthrenedione as photocatalyst. Under our reaction conditions, theby acorresponding Lewis acid (Zn(OTf) products2 )are and obtained 9,10-phenanthrenedione with good yields. Unlike as photocatalyst. the photoredox Under catalytic our reaction system theconditions, corresponding the corresponding products are productsobtained with are obtained good yields. with Unlike good the yields. photoredox Unlike catalytic the photoredox system described earlier [76], the results that were obtained with our method are not affected by the steric hindrancecatalytic system around described the reactive earlier carbon [76], theatom. results Thus, that 2- were and obtained 4-substituted with ourindoles method and are 1,3,5- not hindranceaffected by around the steric the hindrance reactive around carbon the atom. reactive Thus, carbon 2- atom.and 4-substituted Thus, 2- and 4-substitutedindoles and indoles 1,3,5- trimethoxybenzene give the corresponding reaction products with good yields. Besides our method usesand 1,3,5-trimethoxybenzeneone of the cheapest, givesimple, the correspondingand commercially reaction available products organophotocatalyst with good yields. Besides (9,10- usesour methodone of usesthe onecheapest, of the cheapest,simple, and simple, comme andrcially commercially available available organophotocatalyst organophotocatalyst (9,10- (9,10-phenanthrenedione) and oxygen from air as oxidant, providing a valuable contribution for the development of more “green” chemical synthesis. Moreover, several transformations have been carried out with the reaction products. Studies to further extend the scope of this reaction are currently underway in our laboratory. Catalysts 2018, 8, 653 18 of 21

Supplementary Materials: The following materials are available online at http://www.mdpi.com/2073-4344/8/ 12/653/s1, Complete experimental procedures and characterization of new products, 1H and 13C NMR spectra for all compounds. Author Contributions: C.V. and J.R.-B. conceived and designed the experiments; J.R.-B. performed the experiments; J.R.-B. and C.V. analyzed the data; G.B. contributed reagents/materials/analysis tools; C.V. and J.R.P. wrote the paper. All authors read, revised and approved the final manuscript. Funding: Agencia Estatal de Investigación (AEI, Spanish Government) and Fondo Europeo de Desarrollo Regional (FEDER, European Union) (CTQ2017-84900-P). Acknowledgments: Financial support from the Agencia Estatal de Investigación (AEI, Spanish Government) and Fondo Europeo de Desarrollo Regional (FEDER, European Union) (CTQ2017-84900-P) is acknowledged. J.R-B thanks the Ministerio de Ciencia, Innovación y Universidades for a predoctoral grant and C.V. thanks the Spanish Government for RyC contract (RYC-2016-20187). Access to NMR, MS and X-ray facilities from the Servei Central de Suport a la Investigació Experimental (SCSIE)-UV is also acknowledged. Conflicts of Interest: The authors declare no conflict of interest.

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