Article Porphyrin Cobalt(III) “ ” Reactivity; Hydrogen Atom Transfer from Ortho-YH Substituents to the Nitrene Moiety of Cobalt-Bound Aryl Nitrene Intermediates (Y = O, NH)

Monalisa Goswami, Christophe Rebreyend and Bas de Bruin *

Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands; [email protected] (M.G.); [email protected] (C.R.) * Correspondence: [email protected]; Tel.: +31-205-256-495

Academic Editor: Klaus Banert Received: 16 January 2016; Accepted: 16 February 2016; Published: 20 February 2016

Abstract: In the field of cobalt(II) porphyrin-catalyzed metallo-radical reactions, organic have emerged as successful nitrene transfer reagents. In the pursuit of employing ortho-YH substituted (Y = O, NH) aryl azides in Co(II) porphyrin-catalyzed nitrene transfer reactions, unexpected hydrogen atom transfer (HAT) from the OH or NH2 group in the ortho-position to the nitrene moiety of the key radical-intermediate was observed. This leads to formation of reactive ortho-iminoquinonoid (Y = O) and phenylene diimine (Y = NH) species. These intermediates convert to subsequent products in non-catalyzed reactions, as is typical for these free organic compounds. As such, the observed reactions prevent the anticipated cobalt-mediated catalytic radical-type coupling of the nitrene radical intermediates to or . Nonetheless, the observed reactions provide valuable insights into the reactivity of nitrene-radical intermediates, and give access to ortho-iminoquinonoid and phenylene diimine intermediates from ortho-YH substituted aryl azides in a catalytic manner. The latter can be employed as intermediates in one-pot catalytic transformations. From the ortho-hydroxy aryl substrates both phenoxizinones and benzoxazines could be synthesized in high yields. From the ortho-amino aryl azide substrates azabenzene compounds were obtained as the main products. Computational studies support these observations, and reveal that HAT from the neighboring OH and NH2 moiety to the nitrene radical moiety has a low energy barrier.

Keywords: aryl azides; cobalt(II) porphyrins; nitrene radicals; hydrogen atom transfer; azabenzenes; ortho-iminoquinonoid; phenylene diimine

1. Introduction In the context of homogeneously catalyzed organic transformations and nitrene transfer reactions provide interesting possibilities [1–7]. In these transformations metal catalysts that can activate carbene or nitrene precursors are employed, typically leading to the formation of metal carbenoid or nitrenoid species. The thus formed carbenoids and nitrenoids can then add to a variety of unsaturated bonds in alkenes and alkynes. In addition, metal-catalyzed carbene transfer can be used in reaction in which carbene moieties formally insert into X´H bonds (X = O, N, S, Si) [2]. Given the ubiquity of atoms in biologically active compounds, it is also interesting to find ways in which C–N bonds can be formed by addition or insertion of nitrenoids to a C=C or C”C bond or into a C–H bond. Metal-catalyzed nitrene transfer reactions are therefore promising and worth investigating. Cobalt(II) porpyhrins have proven to be quite successful in this field [2,8–25]. Besides being efficient in carbene transfer reactions, cobalt(II) porphyrins have also attracted attention in several

Molecules 2016, 21, 242; doi:10.3390/molecules21020242 www.mdpi.com/journal/molecules Molecules 2016, 21, 242 2 of 16 nitrene transfer reactions [11,14–16,18,21,22,26–28]. In the early stages of this type of it was quite common to use iminoiodanes or haloamine-T compounds as nitrene sources for transfer to other moleculesMolecules [201629–,33 21,]. 242 These are, however, not the most convenient and benign nitrene sources,2 of as 16 they are poorly soluble and lead to the formation of undesirable side products like phenyl iodide and otherquite halogen-containing common to use iminoiodanes compounds. Organicor haloamine-T azides arecompounds potentially as nitrene more interesting sources for nitrene-transfer transfer to reagentsother [molecules3,5,6], as [29–33]. they are These more are, soluble however, and not the the only most byproduct convenient formed and benign during nitrene the sources, generation as of nitrenesthey are from poorly azides soluble is dinitrogen. and lead to the formation of undesirable side products like phenyl iodide and otherMechanistically halogen-containing these compounds. systems are Organic quite uniqueazides are as potentially they operate more via inte cobalt(III)resting nitrene-transfer nitrene radical species,reagents formed [3,5,6], by as they are transfermore soluble from and cobalt(II) the only to byproduct the nitrene formed moiety during upon the activationgeneration ofof the from azides is dinitrogen. azide. This leads to discrete radical character of the reactive nitrenoid intermediate. The detailed Mechanistically these systems are quite unique as they operate via cobalt(III) nitrene radical mechanistic aspects of two such catalytic nitrene transfer reactions with cobalt porphyrins have species, formed by electron transfer from cobalt(II) to the nitrene moiety upon activation of the azide. ´ beenThis elucidated leads to discrete by our radical group character previously of the (Scheme reactive1 nitrenoid)[ 12,18 ,intermediate.34,35]. The The mechanism detailed mechanistic of C H bond aminationaspects of two ethylbenzene, such catalytic toluene, nitrene transfer and tetralin reaction (1,2,3,4-s with cobalt tetrahydronaphthalene) porphyrins have been was elucidated studied by with a varietyour group of organic previously azides (Scheme like N 1)3 C(O)OMe,[12,18,34,35]. N The3SO mechanism2Ph, etc. using of C− densityH bond amination functional of theoryethylbenzene, (DFT) and electrontoluene, paramagnetic and tetralin (1,2,3,4- tetrahydronaphthalen (EPR) spectroscopye) was (Scheme studied1 a)with [ 18 a ].variety The mechanismof organic azides of cobalt(II) like porphyrin-mediatedN3C(O)OMe, N3SO aziridination2Ph, etc. using ofdensity styrene functional with PhSO theory2N 3(DFT)was alsoand electron studied paramagnetic (Scheme1b)[ resonance21]. For both amination(EPR) and aziridination (Scheme reactions,1a) [18]. The the mechanism DFT calculations of cobalt(II) revealedporphyrin-me a stepwisediated aziridination radical process of involvingstyrene coordinationwith PhSO2N3 of was the also azide studied to the (Scheme cobalt(II) 1b) center,[21]. For followed both amination by release and ofaziridination dinitrogen to producereactions, an unusual the DFT calculations “nitrene radical” revealed intermediate a stepwise radicalC (Scheme process 1involving). In addition, coordination experimental of the azide EPR spectroscopicto the cobalt(II) studies, center, combined followed with by release DFT EPR of di propertynitrogen calculationsto produce an being unusual in good “nitrene agreement radical” with intermediate C (Scheme 1). In addition, experimental EPR spectroscopic studies, combined with DFT the experimental data, revealed the formation of a (por)CoIII´N‚Y nitrene radical adduct C from EPR property calculations being in good agreement with the experimental data, revealed the formation the catalyst in the presence of an excess of the azide in . Formation of a nitrene moiety at of a (por)CoIII−N•Y nitrene radical adduct C from the catalyst in the presence of an excess of the azide cobalt(II)porphyrin effectively leads to electron transfer from the metal to the nitrene, thus reflecting in benzene. Formation of a nitrene moiety at cobalt(II)porphyrin effectively leads to electron transfer the redoxfrom the non-innocence metal to the nitrene, of the nitrenethus reflecting substrate the .redox non-innocence The spin density of the of nitrene this intermediate substrate ligand. resides almostThe entirely spin density on the of this nitrogen intermediate atom of resides the nitrene almost moiety.entirely Moreon the recently,nitrogen atom the intermediate of the nitrene Cmoiety.was fully characterizedMore recently, using the anintermediate array of spectroscopic C was fully characterized methods [ 12using]. an array of spectroscopic methods [12].

SchemeScheme 1. Mechanisms 1. Mechanisms of of cobalt(II) cobalt(II)porphyrin porphyrin catalyzed amination amination (a () aand) and aziridination aziridination (b). (b).

Molecules 2016, 21, 242 3 of 16 Molecules 2016, 21, 242 3 of 16

In orderorder toto expandexpand thethe scopescope ofof cobalt(II)cobalt(II) porphyrinporphyrin catalyzedcatalyzed nitrenenitrene transfertransfer reactions we sought to to use use ortho-ortho-substitutedsubstituted aryl aryl azides azides as substrates, as substrates, which which on activation on activation by Co(II) by Co(II) porphyrins porphyrins could couldundergo undergo subsequent subsequent reactions reactions with unsaturated with unsaturated bonds. The bonds. idea The was idea in part was inspired in part inspiredby our work by our on workrelated on ortho- relatedhydroxyarylortho-hydroxyaryl carbene radicals carbene [20]. radicals Activation [20]. Activationof the carbene of the precursor carbene and precursor subsequent and subsequentreaction of reactionthe thus of generated the thus generated cobalt(III) cobalt(III) carbene carbene radical radical with phenyl with phenyl acetylene acetylene allowed allowed us usto tosynthesize synthesize 2H 2-chromenesH-chromenes in in good good yields yields (Scheme (Scheme 2a).2a). The The me mechanismchanism of this reaction isis particularlyparticularly interesting, and DFT calculations calculations reveal reveal the the formation formation of of the the salicyl salicyl−´vinylvinyl radical radical intermediate intermediate by by a ametalloradical-mediated metalloradical-mediated process. process. Unexpectedly, Unexpectedly, su subsequentbsequent hydrogen hydrogen atom atom transfer transfer (HAT) (HAT) from the hydroxyl moiety to the vinyl radical leads to formation of an o-quinone methide intermediate. This intermediate dissociates immediately from the metal center. This then undergoes an endocyclic, sigmatropic ring-closing to give the chromene (Scheme(Scheme2 2a).a). ThisThis waswas confirmedconfirmed byby EPREPR experimentsexperiments and radicalradical poisoningpoisoning experimentsexperiments usingusing thethe 2,2,6,6-tetramethyl-1-piperidinyloxylyl2,2,6,6-tetramethyl-1-piperidinyloxylyl (TEMPO) free radical. This reaction inspired us to extend the prot protocolocol to related ring-closing reactions, but this time using a nitrene precursor instead of a carbene precursor. This was expected to produce heterocycles like benzoxazines, which findfind applications in the pharmaceutical industry (Scheme 2 2b).b). TheThe reactions, however, taketake aa different coursecourse thanthan expectedexpected and these unexpected results of the investigations are disclosed in this paper.

Scheme 2.2. Proposed mechanism of previously reported catalyticcatalytic 2H-chromene-chromene formationformation based onon DFT calculations (a); and the envisionedenvisioned related pathwaypathway for thethe synthesissynthesis ofof benzoxazinesbenzoxazines usingusing ortho-hydroxy-aryl azides ((bb).).

2. Results Results and and Discussion Discussion

2.1. Experimental Studies As an an initial initial test test reaction, reaction, o-azidophenolo-azidophenol 1 was1 reactedwas reacted with CoP1 with (FigureCoP1 1)(Figure in the 1presence) in the of presencephenyl acetylene, of phenyl expecting acetylene, formation expecting of formationbenzoxazine of 2 benzoxazine as the product2 as (Scheme the product 3). However, (Scheme 3on). However,analyzing onthe analyzingcrude reaction the crude mixture reaction the expected mixture product the expected 2 was product not detected.2 was Instead, not detected. new 1H-NMR Instead, newpeaks1 H-NMRwere detected, peaks and were the detected, azide was and fully the consumed azide was. The fully main consumed. product in the The reaction main product was separated in the from the reaction mixture by column chromatography, and proved to be phenoxizinone 3 (Scheme 3).

Molecules 2016, 21, 242 4 of 16 reaction was separated from the reaction mixture by column chromatography, and proved to be phenoxizinoneMolecules 20163, 21(Scheme, 242 3). 4 of 16 Molecules 2016, 21, 242 4 of 16

Molecules 2016, 21, 242 4 of 16

Figure 1. Different cobalt(II) porphyrins employed in this study. FigureFigure 1. 1.Different Different cobalt(II) cobalt(II) porphyrins employed employed in inthis this study. study.

Figure 1. Different cobalt(II) porphyrins employed in this study.

Scheme 3. Formation of phenoxizinone 3 from o-azidophenol 1 and CoP1. SchemeScheme 3. 3. Formation of phenoxizinone 33 from o-azidophenolo 1 and1 CoP1CoP1. Formation of phenoxizinone from -azidophenol and . The unexpected formation of product 3 can be rationalized by considering HAT from the The unexpectedScheme formation 3. Formation of productof phenoxizinone 3 can be 3 from rationalized o-azidophenol by considering 1 and CoP1. HAT from the hydroxyl group in the ortho-position of the cobalt(III) nitrenoid intermediate formed on activation of Thehydroxyl unexpected group in formation the ortho-position of product of the3 can cobalt(III) be rationalized nitrenoid intermediate by considering formed HAT on from activation the hydroxyl of the azide by the catalyst CoP1. This should result in the formation of the reactive ortho-imino-quinonoid groupthe in azide theTheortho byunexpected the-position catalyst formation CoP1 of the. This cobalt(III) of should product result nitrenoid 3 canin the be formation intermediate rationalized of the by formed reactive considering onortho activation-imino-quinonoid HAT from of the the azide compound 4 (Scheme 4). Attack of the N atom of 4 on the para position (w.r.t to the carbonyl by thecompoundhydroxyl catalyst group 4CoP1 (Scheme in. the This 4).ortho Attack should-position of the result of iminethe incobalt(III) N the atom formation ofnitrenoid 4 on the of intermediate para the position reactive formed (w.r.tortho onto-imino-quinonoid theactivation carbonyl of group) of another of 4, followed by 1,5-sigmatropic migration of a H atom, subsequent group)the azide of by another the catalyst molecule CoP1 .of This 4, followedshould result by 1,5-sigmatropicin the formation migrationof the reactive of a ortho H atom,-imino-quinonoid subsequent compounddeprotonation4 (Scheme and 4oxidation). Attack would of the lead imine to formation N atom ofof the4 on phenoxazine the para position product 3. (w.r.t Such to a pathway the carbonyl deprotonationcompound 4 (Scheme and oxidation 4). Attack would of the lead imine to formation N atom of 4the on phenoxazine the para position product (w.r.t 3. Such to the a pathwaycarbonyl group)using of anotherortho-aminophenol molecule (OAP) of 4, has followed been reported by 1,5-sigmatropic before using manganese migration porphyrins of a H atom, that use subsequent H2O2 usinggroup) ortho of another-aminophenol molecule (OAP) of 4has, followed been reported by 1,5-sigmatropic before using manganesemigration ofporphyrins a H atom, that subsequent use H2O2 deprotonationas the external and oxidant oxidation [36]. would In our leadcase,to the formation deprotonation of the and phenoxazine oxidation steps product probably 3. Such took aplace pathway asdeprotonation the external andoxidant oxidation [36]. In would our case, lead theto formation deprotonation of the and phenoxazine oxidation productsteps probably 3. Such tooka pathway place usinginortho air during-aminophenol column chromatography. (OAP) has been reported before using manganese porphyrins that use H2O2 inusing air duringortho-aminophenol column chromatography. (OAP) has been reported before using manganese porphyrins that use H2O2 as theas external the external oxidant oxidant [36 ].[36]. In ourIn our case, case, the the deprotonation deprotonation andand oxidationoxidation steps steps probably probably took took place place in air duringin air during column column chromatography. chromatography.

Scheme 4. Proposed mechanism for formation of 3 from 1 mediated by CoP1. Scheme 4. Proposed mechanism for formation of 3 from 1 mediated by CoP1.

Compound 3 has anti-inflammatory and immunomodulatory properties and is, therefore, CompoundScheme 3 has 4. anti-inflammatory Proposed mechanism and for formationimmunomodula of 3 fromtory 1 mediated properties by CoP1 and. is, therefore, valuable forScheme its medicinal 4. Proposed properties. mechanism As mentioned for formation before, of 3 from other1 mediatedreported bymethodsCoP1. involving valuable for its medicinal properties. As mentioned before, other reported methods involving

Compound 3 has anti-inflammatory and immunomodulatory properties and is, therefore, valuable for its medicinal properties. As mentioned before, other reported methods involving

Molecules 2016, 21, 242 5 of 16

Compound 3 has anti-inflammatory and immunomodulatory properties and is, therefore, MoleculesvaluableMoleculesMolecules 2016 2016 2016, for 21, ,21 ,242 its21, 242, 242 medicinal properties. As mentioned before, other reported methods involving5 of5 516of of 16 16 MoleculesMolecules 2016 2016,, 21, 21,, 242242, 242 5 of5 of 16 16 metalloporphyrin-catalyzedMoleculesMolecules 2016 2016, 21, 21, 242, 242 synthesis of 3 from OAP make use of more powerful oxidants5 5 likeof of 16 16 metalloporphyrin-catametalloporphyrin-catametalloporphyrin-catalyzedlyzedlyzed synthesis synthesis synthesis of of 3of from3 3 from from OAP OAP OAP make make make use use use of of moreof more more powerful powerful powerful oxidants oxidants oxidants like like like hydrogenmetalloporphyrin-catametalloporphyrin-cata peroxide, andlyzedlyzedlyzed are believed synthesissynthesis synthesis to ofof beof 3formed 3fromfrom from OAP viaOAP OAP different makemake make useuse mechanismsuse ofof of moremore more [powerfulpowerful36 powerful]. oxidantsoxidants oxidants likelike like hydrogenmetalloporphyrin-catahydrogenmetalloporphyrin-catahydrogen peroxide, peroxide, peroxide, and and and arelyzedlyzed are arebelieved believed synthesis believedsynthesis to tobe toof be of formedbe 3 formed3 formedfrom from via OAP via OAP viadifferent different differentmake make mechanisms use mechanismsuse mechanisms of of more more [36]. powerful [36]. powerful[36]. oxidants oxidants like like hydrogenhydrogenTo see peroxide, ifperoxide, formation and and of are are3 couldbelieved believed be avoidedto to be be formed formed by using via via different andifferent excess mechanisms mechanisms of the , [36]. [36]. the reaction was also hydrogenhydrogenToTo seeTo see seeif peroxide, peroxide,formationif if formation formation and andof of3are of are could3 3believedcould believedcould be be avoidedbe toavoided toavoided be be formed formedby by usingby using usingvia via an different andifferent excessan excess excess of mechanisms mechanisms ofthe of the thealkyne, alkyne, alkyne, [36].the [36]. the thereaction reaction reaction was was was also also also performedToTo see see inif if formation neat formation alkyne. of of However,3 3couldcould could bebe bealso avoidedavoided avoided in this byby by case usingusing using almost anan an excessexcess excess exclusive ofof of thethe the formation alkyne,alkyne, alkyne, thethe ofthe reaction compoundreaction reaction waswas was3 alsowasalso also performedperformedperformedToTo see insee inneatif inif formationneat formationneat alkyne. alkyne. alkyne. ofHowever, of However,3 However,3 could could bealso be also avoided alsoavoided in inthis in this this caseby by case usingcase usingalmost almost almost an an exclusiveexcess excess exclusive exclusive of of theformation the formation formationalkyne, alkyne, of the theofcompound of reactioncompound reactioncompound was 3was was3 3 alsowas alsowas observed.performedperformed In in in addition neat neat alkyne. alkyne. to that, However, However, simple also aziridination also in in this this casecase case of almostalmost alkenes almost exclusiveexclusive likeexclusive cyclohexene formationformation formation and ofof of styrenecompoundcompound compound were 3 3 alsowaswas was observed.performedobserved.performedobserved. In In additioninIn in addition neataddition neat alkyne. alkyne.to tothat, to that, that, However, However,simple simple simple aziridinatio alsoaziridinatio alsoaziridinatio in in this thisn caseofn casen ofalkenes of almostalkenes almostalkenes like exclusive likeexclusive like cyclohexene cyclohexene cyclohexene formation formation and and and styreneof of styrenecompound styrenecompound were were were also3 3 wasalso wasalso attemptedobserved.observed. In using In addition additiono-azidophenol to to that, that, simple 1simple, which aziridinatio aziridinatio in all casesn nof led of alkenes toalkenes formation like like cyclohexene cyclohexene of only one and identifiable and styrene styrene andwere were major also also attemptedobserved.attemptedobserved.attempted using In using Inusing addition addition o- azidophenolo- o-azidophenolazidophenol to to that, that, simple 1simple, 1which 1, ,which which aziridinatio aziridinatio in in allin all casesall cases ncasesn of ofled alkenes ledalkenes ledto to formationto formation like formationlike cyclohexene cyclohexene of of onlyof only only one and andone one identifiable styrene styreneidentifiable identifiable were were and alsoand alsoand product,attemptedattempted the using using phenoxizinone o- o-azidophenolazidophenol3 (Table 1 ,,1 which,which 1which). inin in allall all casescases cases ledled led toto to formationformation formation ofof of onlyonly only oneone one identifiableidentifiable identifiable andand and majorattemptedmajorattemptedmajor product, product, product, using using the the the phenoxizinoneo- o- phenoxizinoneazidophenol phenoxizinoneazidophenol 31 1,(Table 3,which 3 which(Table (Table 1). in in1). 1).all all cases cases led led to to formation formation of of only only one one identifiable identifiable and and majormajor product, product, the the phenoxizinone phenoxizinone 3 3(Table(Table (Table 1).1). 1). majormajorTable product, product, 1. Reaction the the phenoxizinone phenoxizinone of o-hydroxy phenyl 3 3 (Table (Table azide 1). 11). with different substrates under reaction conditions a,b,*. TableTableTable 1. Reaction1. 1. Reaction Reaction of ofo -hydroxyof o -hydroxyo-hydroxy phenyl phenyl phenyl azide azide azide 1 with 1 1with with different different different substrates substrates substrates under under under reaction reaction reaction conditions conditions conditions a,b, *.a,b, a,b,*.*. TableTable 1. 1. Reaction Reaction of of o -hydroxyo-hydroxy phenyl phenyl azide azide 1 1with with different different substrates substrates under under reaction reaction conditions conditions a,b,a,b, a,b,*.*. TableTableTable 1.1. 1. ReactionReaction Reaction ofof of oo -hydroxy-hydroxyo-hydroxy phenylphenyl phenyl azideazide azide 11 1withwith with differentdifferent different substratessubstrates substrates underunder under reactionreaction reaction conditionsconditions conditions a,b, a,b,*.*. *. EntryEntryEntryEntry Substrate Substrate Substrate Substrate Expected Expected Expected Product(s) Product(s) Product(s) Obtained Obtained Obtained Obtained Product Product Product EntryEntry Substrate Substrate Expected Expected Product(s) Product(s) Obtained Obtained Product Product EntryEntryEntry Substrate Substrate Substrate Expected Expected Expected Product(s)Product(s) Product(s) Obtained Obtained Obtained ProductProduct Product

1 11 1 1 1 1 11

2 22 2 22 2 22

3 33 3 3 3 33 3

* Reaction* *Reaction Reaction conditions conditions conditions: a: :0.5 a:: a0.5: mmol 0.5 mmol mmol of azideof of azide azide 1, 11 ,mmol1 1, 1mmol mmol of substrate,of of substrate, substrate, 5 mol% 5 5mol% mol% CoP1 CoP1 CoP1 (w.r.t. (w.r.t. (w.r.t. azide), azide), azide), 4 mL 4 4mL mLtoluene, toluene, toluene, * Reaction* Reaction conditions conditions:: aa:: a0.50.5: 0.5 mmolmmol mmol ofof of azideazide azide 1, ,1 11, mmol1mmol mmol ofof of substrate,substrate, substrate, 55 mol%5mol% mol% CoP1 CoP1 (w.r.t.(w.r.t. (w.r.t. azide),azide), azide), 44 mL4mL mL toluene,toluene, toluene, 50 *°C, *Reaction Reaction 18 h; b conditions: 0.6conditionsb b mmol: a:of: aa 0.5: 0.5azide mmol mmol 1, 15of of azidemL azide of 1 substrate, ,1 1, 1mmol mmol of 5of substrate,mol% substrate, CoP1 5 5mol%, mol%50 °C, CoP1 CoP118 h. (w.r.t. These (w.r.t. azide), different azide), 4 4mL reactionmL toluene, toluene, 5050* °C,Reaction °C, 18 18 h; h; conditionsb :b 0.6: 0.6 mmol mmol: : 0.5of of azide mmolazide 1 of,1 15, azide15 mL mL 1of ,of 1substrate, mmolsubstrate, of substrate,5 5mol% mol% CoP1 5CoP1 mol%, 50, 50CoP1 °C, °C, 18 18(w.r.t. h. h. These These azide), different different 4 mL toluene, reaction reaction 5050 °C, °C,˝ 18 18 h; h; b:: b0.60.6: 0.6 mmolmmol mmol ofof of azideazide azide 1 ,,1 1515, 15 mLmL mL ofof of substrate,substrate, substrate, 55 5mol%mol% mol% CoP1 CoP1,, 5050, 50 ˝°C,°C, °C, 1818 18 h.h. h. TheseThese These differentdifferent different reactionreaction reaction conditions50conditions50conditions50 °C, °C,C, 18 18 18 (h;a,b h; ()b a,b:(gaveb 0.6a,b::) 0.6 )gave 0.6 gavemmol mmolidentical mmol identical identical of of of azide azide azideresults. results. results.1 1, ,15, 1515No mL mLmLNo nitreneNo of ofofnitrene substrate,nitrene substrate,substrate, transfer transfer transfer 5 5 5mol% mol%to mol% tothe to the CoP1 solventthe CoP1 solvent solvent,, 5050, 50 (toluene) °C,C, °C, (toluene) 18(toluene)18 18h. h. h. These Thesewas These was was observeddifferent different observeddifferent observedreaction in reaction reaction inany in any any conditionsconditionsconditions (a,b (a,b a,b(a,b)) )gavegave) gavegave identicalidentical identical identical results.results.results. results. No NoNo No nitrene nitrenenitrene nitrene transfer transfertransfer transfer to thetoto to thethe solvent the solventsolvent solvent (toluene) (toluene)(toluene) (toluene) was observedwaswas was observedobserved observed in any inin case in anyany any caseconditionscaseconditionscase under under under the (the a,b (theapplieda,b) )gaveapplied gaveapplied identical reactionidentical reaction reaction results.conditions. results. conditions. conditions. No No nitrene nitrene transfer transfer to to the the solvent solvent (toluene) (toluene) was was observed observed in in any any casecaseunder under under the appliedthe the applied applied reaction reaction reaction conditions. conditions. conditions. casecasecase underunder under thethe the appliedapplied applied reactionreaction reaction conditions.conditions. conditions. ToTo beTo be ablebe able able to totrap to trap trap the the theproposed proposed proposed reactive reactive intermediate intermediate 4 with4 4 with with a differenta a different different substrate substrate substrate we we wedecided decided decided to to to ToTo bebe be ableable able toto to traptrap trap thethe the proposedproposed proposed reactivereactive reactive intermediateintermediate intermediate 44 4withwith with aa a differentdifferent different substratesubstrate substrate wewe we decided decided to to protectprotectprotectTo theTo thebe thephenylbe ablephenyl ablephenyl to ringto trapring trapring on theon theon theproposed the5-position,proposed 5-position, 5-position, reactive reactive so sothat so that thatintermediate cointermediate uplingco couplingupling of oftwo 4of 4 twowith twowith iminoquinone iminoquinone iminoquinonea a different different ssubstrate substratetos s togive to give give products we productswe products decided decided like like like to to protectprotect thethe the phenyl phenyl ring ring on on the the 5-position, 5-position, so so that that co coupling couplingupling of of two two iminoquinone iminoquinones iminoquinones s to to give give products products like like 3 isprotect3protect3 isprevented. is prevented. prevented. the the phenyl phenyl As As Assuch, ringsuch, ringsuch, 2-azido-5-nitrophenol on on2-azido-5-nitrophenol 2-azido-5-nitrophenol the the 5-position, 5-position, so so that that5 was5 co5 wasco wasupling synthesized.upling synthesized. synthesized. of of two two iminoquinoneAs iminoquinone As Asa testa a test test reaction reaction reactions sto to wegive give we wetried products triedproducts tried to totrap to traplike traplike 3 3isis is prevented.prevented. prevented. As As As such,such, such, 2-azido-5-nitrophenol2-azido-5-nitrophenol 2-azido-5-nitrophenol 5 5waswas was synthesized. synthesized. AsAs As aa atest test test reaction reaction reaction we we we tried tried tried to to to trap trap trap the3the 3the correspondingis is correspondingprevented. correspondingprevented. As Aso-quinone such, o such,-quinoneo-quinone 2-azido-5-nitrophenol 2-azido-5-nitrophenol monoamine monoamine monoamine intermediate intermediate intermediate 5 5 was was synthesized. withsynthesized. with with 1- butoxyethene1- 1-butoxyethenebutoxyethene As As a a test test inreaction reaction in anin an Inversean Inverse weInverse we tried triedElectron Electron Electronto to trap trap thethethe correspondingcorresponding corresponding o -quinone-quinoneo-quinone monoaminemonoamine monoamine intermediate intermediate with with 1- 1-butoxyethene 1-butoxyethenebutoxyethene in in an an InverseInverse Inverse ElectronElectron Electron DemandtheDemandtheDemand corresponding corresponding Diels Diels Diels Alder Alder Alder (IEDDA) o -quinoneo(IEDDA) -quinone(IEDDA) reaction reactionmonoamine reactionmonoamine (Scheme (Scheme (Scheme intermediate intermediate 5). 5). For5). For Forthis this this transformation,with with transformation, transformation, 1- 1-butoxyethenebutoxyethene however, however, however, in in an noan no Inverse fruitful noInverse fruitful fruitful resultsElectron Electron results results DemandDemand Diels Diels Diels Alder AlderAlder (IEDDA) (IEDDA) reaction reaction reaction (Scheme (Scheme (Scheme 5). 5). 5For). For Forthis this thistransformation, transformation, transformation, however, however, however, no no fruitful fruitful no fruitful results results wereDemandwereDemandwere obtained obtained obtained Diels Diels when Alderwhen Alderwhen using (IEDDA)using (IEDDA)using CoP1 CoP1 CoP1 reaction reactionas as theas the thecatalyst. (Scheme (Schemecatalyst. catalyst. The 5). 5).The TheFor crudeFor crude thiscrude this reaction transformation, transformation,reaction reaction mixtures mixtures mixtures however, however,showed showed showed noformation no formationfruitful formationfruitful resultsof results of aof a a resultswerewere obtained obtained were obtained when when using when using CoP1 using CoP1 asCoP1as as thethe the ascatalyst.catalyst. catalyst. the catalyst. TheThe The crudecrude Thecrudecrude reactionreaction reaction reaction mixturesmixtures mixtures mixtures showedshowed showed showed formationformation formation formation ofof of aa a mixtureweremixtureweremixture obtained ofobtained ofproducts of products products when when containing containing using containingusing CoP1 CoP1 a lot a aaslot ofaslot the ofazide theof azide catalyst.azide catalyst. starting starting starting The The material. crudematerial. crudematerial. reaction Thisreaction This This is mostismixtures ismixtures most most likely likely likely showed showeddue due due to toformationthe toformation the theinherent inherent inherent of of a a ofmixturemixture a mixture of of products products of products containing containing containing a alot lot of aof azide lot azide of starting azide starting starting material.material. material. material. ThisThis This isis is mostmost This most likely islikely likely most duedue due likely toto to thethe the due inherentinherent inherent to the inabilitymixtureinabilitymixtureinability of of of CoP1 ofof productsCoP1 productsCoP1 to toactivate to activatecontaining activatecontaining the the theazide aazide a azidelot lot under of ofunder azideunder azide the thestarting thestartingapplied applied applied material. material.re actionre reactionaction Thisconditions. This conditions. conditions. is is most most However,likely likely However, However, due due onto to on theswitchingon the switching switchinginherent inherent inherentinabilityinabilityinability ofof inability of CoP1 CoP1 toto ofto activateactivate activateCoP1 to thethe the activate azideazide azide underunder theunder azide thethe the appliedapplied underapplied therere reactionaction applied conditions. conditions. reaction However, conditions.However, on on switching However, switching to inabilitytoCoP2inabilityto CoP2 CoP2, the, of, the of the desiredCoP1 CoP1 desired desired to to transformationactivate activatetransformation transformation the the azide azide could could under couldunder be be theachieved bethe achieved appliedachieved applied and re and reandaction productaction product product conditions. conditions. 6 was6 6 was was obtained However,obtained However,obtained in in on80% inon 80% switching80% switching yield. yield. yield. ontoto CoP2switching CoP2,, the,the the desired todesired desiredCoP2 ,transformationtransformation thetransformation desired transformation couldcould could bebe be achievedachieved achieved could beandand and achieved productproduct product and 6 6waswas productwas obtainedobtained obtained6 was inin inobtained 80%80% 80% yield.yield. yield. in Non-catalytictoNon-catalytictoNon-catalytic CoP2 CoP2, ,the the trapping desired trappingdesired trapping transformationof transformation of oof-quinone o -quinoneo-quinone monoimines could monoimines couldmonoimines be be achieved achievedhas has has been been beenand and report report product reportproducteded edearlier, 6 earlier, 6 earlier,was was butobtained obtainedbut but the the themethod in method inmethod 80% 80% uses yield. yield.uses uses 80%Non-catalyticNon-catalytic yield. Non-catalytic trapping trapping of trappingof o -quinoneo-quinone of o -quinonemonoimines monoimines monoimines has has been been has report report beened reporteded earlier, earlier, earlier, but but the the but method method the method uses uses stoichiometricNon-catalyticstoichiometricNon-catalyticstoichiometric amounts trapping amounts trappingamounts of of halogen of halogeno halogen-quinoneo-quinone containing containing containing monoimines monoimines oxidants, oxidants, oxidants, has has which been whichbeen which isreport report avoidedis is avoided avoidededed earlier, inearlier, inthe in the the reactionbut butreaction reaction the the depictedmethod method depicted depicted uses inuses in in usesstoichiometricstoichiometric stoichiometric amounts amounts amounts of of halogen halogen of halogen containing containing containing oxidants, oxidants, oxidants, which which which is is avoided isavoided avoided in in the in thethe reaction reaction reaction depicted depicted depicted in in SchemestoichiometricSchemestoichiometricScheme 5 [37].5 5 [37]. [37]. amounts amounts of of halogen halogen containing containing oxidants, oxidants, which which is is avoided avoided in in the the reaction reaction depicted depicted in in inSchemeScheme Scheme 5 5[37].5 [[37].37]. SchemeSchemeScheme 55 5 [37].[37]. [37].

SchemeSchemeScheme 5. Trapping5. 5. Trapping Trapping of ofthe of the theo-quinone o -quinoneo-quinone monoimine monoimine monoimine in inan in anIEDDA an IEDDA IEDDA reaction. reaction. reaction. SchemeScheme 5. 5. Trapping Trapping of of the the o -quinoneo-quinone monoimine monoimine in in an an IEDDA IEDDA reaction. reaction. SchemeSchemeScheme 5. 5. 5. TrappingTrapping Trapping ofof of thethe the oo -quinone-quinoneo-quinone monoiminemonoimine monoimine inin in anan an IEDDAIEDDA IEDDA reaction.reaction. reaction. SubstrateSubstrateSubstrate 5 was5 5 was was also also also tested tested tested in in reactionsin reactions reactions with with with other other other potential potential potential reaction reaction reaction pa pa rtners,partners,rtners, in in whichin which which we we we SubstrateSubstrate 5 5waswas was alsoalso also testedtested tested inin in reactionsreactions reactions withwith with otherother other potential potential reaction reaction pa partners,rtners, in in which which we we expectedexpectedexpectedSubstrateSubstrate to tobe to be able be able5 able5 towas was totrap to trapalso trapalso the the thetested iminoquinonetested iminoquinone iminoquinone in in reactions reactions intermediate intermediate intermediate with with other other with with withpotential differentpotential different different reaction C=Creaction C=C C=C and and and paCpa≡ rtners,CC rtners,C≡ bonds≡CC bonds bonds in in (Table which (Tablewhich (Table 2). we 2). we 2). expectedexpected to to be be able able to to trap trap the the iminoquinone iminoquinone intermediate intermediate with with different different C=C C=C and and C C≡C≡C bonds bonds (Table (Table 2). 2). WithexpectedWithexpectedWith phenyl phenyl phenyl to toacetylene be beacetylene acetyleneable able to to no trap trapno reactionno thereaction thereaction iminoquinone iminoquinone involving involving involving the intermediate theintermediate theC≡ C CC≡ ≡CbondC bond bond withwas with was was observed.different different observed. observed. C=C OtherC=C Other Otherand and alkenes C alkenes C≡alkenes≡CC bonds bondsalso also also proved(Table (Table proved proved 2). 2). WithWith phenyl phenyl acetylene acetylene no no reaction reaction involving involving the the C C≡C≡C bond bond was was observed. observed. Other Other alkenes alkenes also also proved proved unreactiveWithunreactiveWithunreactive phenyl phenyl in in this inacetylene acetylenethis this process. process. process. no no Apparently, reaction reactionApparently, Apparently, involving involving only only only electron the electronthe electron C C≡≡C Crich bond bondrich rich alkenes wasalkenes wasalkenes observed. observed.like like like 1-butoxyethene 1-butoxyethene 1-butoxyethene Other Other alkenes alkenes are arealso arealsosuitable suitable proved suitableproved unreactiveunreactive in in this this process. process. Apparently, Apparently, only only electron electron rich rich alkenes alkenes like like 1-butoxyethene 1-butoxyethene are are suitable suitable reactionunreactivereactionunreactivereaction partners partners partners in in this thisin in this process.in process.this this process. process. process. Apparently, Apparently, only only electron electron rich rich alkenes alkenes like like 1-butoxyethene 1-butoxyethene are are suitable suitable reactionreaction partners partners in in this this process. process. reactionreactionreaction partnerspartners partners inin in thisthis this process.process. process.

Molecules 2016, 21, 242 5 of 16 metalloporphyrin-catalyzed synthesis of 3 from OAP make use of more powerful oxidants like hydrogenMolecules peroxide,2016, 21, 242 and are believed to be formed via different mechanisms [36]. 6 of 16 To see if formation of 3 could be avoided by using an excess of the alkyne, the reaction was also performed in neat alkyne. However, also in this case almost exclusive formation of compound 3 was Substrate 5 was also tested in reactions with other potential reaction partners, in which we observed. In addition to that, simple aziridination of alkenes like cyclohexene and styrene were also expected to be able to trap the iminoquinone intermediate with different C=C and C”C bonds (Table2). attempted using o-azidophenol 1, which in all cases led to formation of only one identifiable and With phenyl acetylene no reaction involving the C”C bond was observed. Other alkenes also proved major product, the phenoxizinone 3 (Table 1). unreactive in this process. Apparently, only electron rich alkenes like 1-butoxyethene are suitable reactionTable 1. Reaction partners of in o-hydroxy this process. phenyl azide 1 with different substrates under reaction conditions a,b,*. MoleculesMoleculesMolecules 2016 2016, 21 2016, ,21 242, ,242 21 , 242 6 of6 of16 6 16 of 16 MoleculesMolecules 2016 2016, 21, 21, 242, 242 6 of6 of 16 16 MoleculesMoleculesMolecules 2016 20162016, 21,, 201621,21 242,, 242242, 21 , 242 6 of66 ofof16 16 166 of 16 Entry SubstrateTable 2. Reaction Expected of azide Product(s)5 with different substrates Obtaineda,b,*. Product a,b,* a,b,* TableTable 2. Reaction 2. Reaction of azide of azide 5 with 5 with different different substrates substratesa,b,* a,b,*. . TableTable 2. 2.Reaction Reaction of ofazide azide 5 with5 with different different substrates substrates a,b,*. a,b,*. a,b,* Molecules 2016, 21, 242 TableTableTable 2.Table 2.Reaction 2. ReactionReaction Reaction 2. Reaction of of ofazide of azideazide azideof 5 azide with55 withwith5 with different5 withdifferentdifferent different different substrates substratessubstrates substrates substrates a,b,* a,b,*. .. . . 5 of 16 Entry Substrate Expected Product(s) Obtained Product EntryEntryEntry Substrate Substrate Substrate Expected Expected Expected Product(s) Product(s) Product(s) Obtained Obtained Obtained Product Product Product EntryEntryEntry Entry Substrate Substrate Substrate Substrate Expected Expected Expected Expected Product(s) Product(s) Product(s) Product(s) Obtained Obtained Obtained Obtained Product Product Product Product metalloporphyrin-cataEntry 1 Substratelyzed synthesis of Expected3 from OAP Product(s) make use of more powerful Obtained oxidantsProduct like hydrogen1 peroxide, 1 1 and are believed to be formed via different mechanisms [36]. 1 1 1 1 1 1 (~10%)(~10%) To see if formation of 3 could be avoided by using an excess of the alkyne, the reaction(~10%)(~10%) was also (~10%)(~10%)(~10%)(~10%)(~10%) performed in neat alkyne. However, also in this case almost exclusive formation of compound 3 was observed. In addition to that, simple aziridination of alkenes like cyclohexene and styrene were also 2 2 2 22 —------2 2 2 2 ------attempted2 using o-azidophenol 1, which in all cases led to formation of only one identifiable--- and major product, the phenoxizinone 3 (Table 1).

3 3 3 a,b, Table3 1.3 Reaction33 3 of o-hydroxy phenyl azide 1 with different substrates under reaction conditions *. 3 3 (80%)(80%)(80%) (80%)(80%)(80%) (80%) Entry Substrate Expected Product(s) Obtained Product (80%) * Reaction conditions: a: 0.5 mmol of azide 1, 1 mmol of substrate, 5 mol% CoP1 (w.r.t. azide), 4 mL toluene, 50 °C, 18 h; b: 0.6 mmol of azide 1, 15 mL of substrate, 5 mol% CoP1, 50 °C, 18 h. These different reaction 4 4 4 ------conditions4 4 4 41 4( a,b) gave identical results. No nitrene transfer to the solvent (toluene) was observed—------in any

case under the applied reaction conditions.

a a * Reaction* Reaction conditions conditionsa: a 0.5: 0.5mmol mmol of azideof azide 1, 1 1 mmol, 1 mmol of substrate,of substrate, 5 mol% 5 mol% CoP2 CoP2 (w.r.t. (w.r.t. azide), azide), 4 mL 4 mL * Reaction* Reaction conditions conditions: : 0.5a 0.5a mmol ammol of ofazide azide 1, 11, mmol1 mmol of ofsubstrate, substrate, 5 mol%5 mol% CoP2 CoP2 (w.r.t. (w.r.t. azide), azide), 4 mL4 mL To be* Reactionable* Reaction to trapconditions conditions thea proposeda: 0.5: 0.5mmol mmol reactive of azideof azide intermediate 1, 11 ,mmol 1 mmol of 4 substrate,of with substrate, a different 5 mol% 5 mol% substrateCoP2 CoP2 (w.r.t. (w.r.t. we azide), decided azide), 4 mL 4to mL * Reaction** ReactionReaction conditions conditionsconditions: :b : 0.5a 0.50.5b mmol mmolmmol of of ofazide azideazide 1 , 111,, 1mmol1 mmolmmol of of ofsubstrate, substrate,substrate, 5 5mol%5 mol%mol% CoP2 CoP2 (w.r.t. (w.r.t.(w.r.t. azide), azide),azide), 4 4mL4 mLmL˝ toluene,toluene,* Reaction 50 °C, 50 conditions °C,18 h.b 18 b: h.0.6 0.5 mmol0.6 mmol mmol of of azide azideof azide 1,, 115 mmol1 ,mL 15 mLof of substrate, substrate, of substrate, 5 5 mol% mol% 5 mol%CoP2 CoP2 (w.r.t.CoP2, 50 azide),,°C, 50 °C,18 4h. 18 mL These h. toluene, These different different 50 C, toluene,toluene, 50 50 °C, °C, 18 18 h. h. 0.6 b 0.6b mmol mmolb of ofazide azide 1, 151, 15 mL mL of ofsubstrate, substrate, 5 mol% 5 mol% CoP2 CoP2, 50, 50 °C, °C, 18 18 h. h.These These different different protect thetoluene, phenyltoluene,b 50 ring °C,50 °C,18 onb h.18b the h.0.6 5-position, 0.6mmol mmol of azide of so azide that1, 15 1 , co mL15upling mL of substrate, of substrate, of two˝ 5 iminoquinonemol% 5 mol% CoP2 CoP2, 50, s°C,50 to °C,18 give h.18 These h.products These different different like toluene,toluene,toluene,18 h.50 5050 °C,0.6 °C,°C, 18 mmol 1818 h. h. h. of0.6 0.6 azide0.6a,b mmol mmolmmola,b1, 15of of of mLazide azideazide of substrate,1, 1115,, 1515 mL mLmL of 5 mol%of ofsubstrate, substrate,substrate,CoP2 ,5 50 mol% 55 mol%mol%C, 18 CoP2 h. CoP2 These, 50,, 5050 °C, different °C,°C, 18 1818 h. h. h. reactionThese TheseThese differentconditions differentdifferent reactionreactionreactiona,b conditions conditions conditions (a,b ()a,b gave ) (gave) gaveidentical identical identical results. results. results. No No nitrene Nonitrene nitrene transfer transfer transfer to tothe theto solvent thesolvent solvent (toluene) (toluene) (toluene) was was was reaction( )2 gave conditions identicala,b results.(a,ba,b) gavea,b No identical nitrene transfer results. to theNo solvent nitrene (toluene) transfer was to observed the solvent in any (toluene) case under was the 3 is prevented.reactionreactionreactionreactionreaction conditions Asconditionsconditions conditions such, conditions (2-azido-5-nitrophenol (() a,b ()gave) gave)gave( gave ) identical gaveidenticalidentical identical identical results. results.results. results. 5 results.was No NoNo Nosynthesized.nitrene nitrenenitreneNo nitrene nitrene transfer transfertransfer transfer Astransfer toa to totest theto thethe tothereactionsolvent solventsolventthe solvent solvent (toluene) we(toluene)(toluene) (toluene) tried (toluene) was to waswas wastrap was observedobservedobservedapplied in inany reaction any in case any case conditions.under case under under the the applied theapplied applied reaction reaction reaction conditions. conditions. conditions. the correspondingobservedobservedobservedobserved in in any in any o any-quinonecasein case any case under undercase under monoamine theunder the appliedthe applied the applied applied reaction reaction reaction conditions. conditions. conditions. conditions.with 1- butoxyethene in an Inverse Electron Demand Diels Alder (IEDDA) reaction (Scheme 5). For this transformation, however, no fruitful results ToTo investigate investigateTo investigate the the generality thegenerality generality of of the the of observed theobserved observed HAT HAT HATreactivity, reactivity, reactivity, we we decided wedecided decided to to explore explore to explore the the reactivity thereactivity reactivity were obtainedToTo investigateTo investigate To investigate wheninvestigate the using the thegenerality generality the generality CoP1 generality as of ofthe the of the catalyst. the observedof observed the observed observed observed The HAT HAT crudeHAT HAT reactivity, HAT reactivity, reactivity, reaction reactivity, we wemixtures wedecided decided we decided decided showedto to explore to explore explore to formation explore the the the reactivity reactivity the reactivity reactivity of reactivity a To investigate the generality 2of the2 observed HAT reactivity, we decided to explore the reactivity ofof aryl arylof azide aryl azide azide 7, 7containing, containing 7, containing an an NH NHan2 substituentNH2 substituent substituent in in the the in ortho theortho -positionortho-position-position instead instead instead of of an an ofOH OHan substituent. OH substituent. substituent. The The The ofof aryl aryl of arylazide azide 3azide 7 ,7 containing, containing 7, containing an an NH an NH2 NH substituent2 substituentsubstituent2 substituent in in the the in ortho the ortho ortho-position-position-position instead instead instead of of an an of OH anOH substituent.OH substituent. substituent. The The The mixtureofof aryl aryl azide of azide products 7 ,7 containing,, containingcontaining containing an anan NH aNHNH lot2 substituent2 of substituentsubstituent azide starting in inin the thethe orthomaterial. orthoortho-position-position-position This insteadis instead insteadmost likelyof ofof an anan OHdue OHOH substituent. to substituent.substituent. the inherent The TheThe o-aminoo-aminoo-amino phenylazide phenylazide phenylazide 7 was7 was 7 synthesizedwas synthesized synthesized and and testedand tested tested under under under th the samee thsamee same reaction reaction reaction conditions, conditions, conditions, using using using CoP1 CoP1 CoP1 inabilityo-aminoo-aminoo-aminoo-amino of phenylazide phenylazideCoP1 phenylazidephenylazide phenylazide to activate 7 7was 77was was was the 7synthesized wassynthesized synthesizedazidesynthesized synthesized under and and and theand tested testedandapplied tested tested testedunder under under underre action underth th thee thesame samee conditions.th samee reactionsame reaction reaction reaction However, conditions, conditions,conditions, conditions, conditions, on using switching usingusing using CoP1usingCoP1 CoP1 CoP1 CoP1as asaso the-amino theas catalyst thecatalyst phenylazide catalyst (Scheme (Scheme (Scheme 76). was6). In 6).In contrastsynthesized contrastIn contrast to to our and ourto expectations, our testedexpectations, expectations, under however, th however,e samehowever, azabenzenereaction azabenzene azabenzene conditions, 8 was8 was 8 obtainedwas obtainedusing obtained CoP1 as as as asas theasthe *the Reaction asthecatalyst catalyst catalystthe catalyst conditionscatalyst (Scheme (Scheme (Scheme (Scheme :(Scheme a: 0.5 66). ). 6).mmol In6). In contrast6).In ofcontrast Incontrastazide contrast toto1 , toto1 ourour mmolto ourour our to expectations,expectations, expectations,expectations,ofour expectations, substrate, expectations, 5 however,however, mol% however,however, however, CoP1however, azabenzeneazabenzene (w.r.t.azabenzeneazabenzene azabenzene azabenzene azide), 8 4 8 wasmL 8waswas wastoluene, 8 obtainedobtained wasobtainedobtained obtained obtained asas asas the as as to theasCoP2 the themajor, catalystthemajor product.desired product. (Scheme transformation This This 6). observation In observation contrast could intrigued to intriguedbeour achieved expectations, us, us,as andformationas formation producthowever, of 6 azaof azabenzenewas aza compounds obtained compounds 8 wasin as 80% productsasobtained productsyield. asin in thethe major major product. product.b This This observation observation intrigued intrigued us, us, as as formation formation of of aza aza compounds compounds as as products products in in Non-catalyticthethe themajormajor50 major the°C, major 18 product.majorproduct. h;product. trapping product.: 0.6 product. mmol This This This ofThisobservation of observation oThisazideobservation-quinone observation observation1, 15 intriguedmL monoiminesintrigued ofintrigued intriguedsubstrate, intrigued us, us, as us, has 5 us, asformationmol% as us, formationbeenas formation CoP1asformation reportformation of, 50 aza of°C, edof aza compoundsof18 earlier,aza h.of azacompounds These compoundsaza compounds but compoundsdifferent asthe products asmethod asreaction productsas products asproducts in productsuses reaction in in in in reactionreactionthereaction major of of azides product. azidesof azides with with This withcobalt(II) cobalt(II) observation cobalt(II) porphyrin porphyrin porphyrin intrigued catalyzed catalyzed catalyzed us, asprocesses processesformation processes has has of been has beenaza beenreported compounds reported reported only only asonceonly onceproducts oncebefore, before, before, in reactionreactionreactionreactionofconditions azidesreaction of ofof azides of withazidesazides ( a,bazidesof) gaveazides cobalt(II)with withwith with identical cobalt(II) with cobalt(II)cobalt(II) cobalt(II) porphyrin cobalt(II) results. porphyrin porphyrinporphyrin porphyrin No catalyzedporphyrin nitrene catalyzed catalyzedcatalyzed catalyzedtransfer processes catalyzed processes to processesprocesses theprocesses has processessolvent been has hashas (toluene) has reportedbeen beenbeenhas been reported been reportedreported was reported only reportedobserved onceonly onlyonly only before,once in only onceonce anyonce before, once andbefore,before, before, onlybefore, stoichiometricandreactionand only only of as azides aamountsas minor a minor with side of cobalt(II)sidehalogen product product containing porphyrin[38]. [38]. oxidants,catalyzed which processes is avoided has been in reportedthe reaction only depicted once before, in andandas caseonly aonly minorunder as as a minor athe side minor applied product side side reactionproduct product [38]. conditions. [38]. [38]. Schemeandandand only onlyand 5only [37].as onlyas a as aminor minoraas minor a minorside side side product sideproduct product product [38]. [38]. [38]. [38]. To be able to trap the proposed reactive intermediate 4 with a different substrate we decided to protect the phenyl ring on the 5-position, so that coupling of two iminoquinones to give products like 3 is prevented. As such, 2-azido-5-nitrophenol 5 was synthesized. As a test reaction we tried to trap the corresponding o-quinone monoamine intermediate with 1-butoxyethene in an Inverse Electron

Demand Diels Alder (IEDDA) reaction (Scheme 5). For this transformation, however, no fruitful results Scheme 5. Trapping of the o-quinone monoimine in an IEDDA reaction. were obtainedSchemeScheme whenScheme 6. using 6.Reaction Reaction 6. ReactionCoP1 of ofo-aminophenyl as o-aminophenyl of the o-aminophenyl catalyst. azide Theazide azide7 crude with7 with 7 cobalt(II) withreaction cobalt(II) cobalt(II) porphyrin mixtures porphyrin porphyrin catalystshowed catalyst catalyst CoP1 formationCoP1 .CoP1 . . of a SchemeSchemeSchemeScheme 6. 6.Reaction 6. Reaction Reaction 6. Reaction of of o-aminophenyl of o-aminophenyl o-aminophenylof o-aminophenyl azide azide azide 7 azide with7 with7 with cobalt(II)7 withcobalt(II) cobalt(II) cobalt(II) porphyrin porphyrin porphyrin porphyrin catalyst catalyst catalyst catalyst CoP1 CoP1 CoP1. CoP1. . . mixture of productsScheme containing 6. Reaction a of lot o-aminophenyl of azide starting azide material. 7 with cobalt(II) This is porphyrin most likely catalyst due to CoP1 the. inherent Substrate 5 was also tested in reactions with other potential reaction partners, in which we inabilityTwoTwo of Twomechanistic CoP1 mechanistic mechanistic to activate proposals proposals theproposals azide for for formation under forformation formation the ofapplied of aza azaof compounds aza compoundsreaction compounds conditions. in in cobalt(II) cobalt(II)in cobalt(II) However, porphyrins porphyrins porphyrins on switching catalyzed catalyzed catalyzed expectedTwoTwo Twoto mechanistic be Twomechanistic mechanisticable mechanistic to trap proposals proposals the proposals iminoquinoneproposals for for forformation formation for formation formationintermediate of of aza of aza azaofcompounds compoundscompoundswithaza compounds compounds different in inin cobalt(II) inC=C cobalt(II)cobalt(II) cobalt(II)in andcobalt(II) porphyrinsC porphyrins≡porphyrins C porphyrins bonds porphyrins (Tablecatalyzed catalyzedcatalyzed catalyzed catalyzed2). toreactions reactionsCoP2reactions, the have have desired havebeen been beensuggested: transformation suggested: suggested: (I) (I) Attack Attack (I)could Attack of of bethe the ofachieved azide theazide azide starting starting and starting productcompound compound compound 6 was on on the obtained theon nitrene thenitrene nitrene in intermediate, intermediate,80% intermediate, yield. reactionsreactionsreactionsreactionsreactions have havehave have been have beenbeen been suggested: been suggested:suggested: suggested: suggested: (I) (I)(I) Attack (I) Attack Attack(I) Attack of of the of the theazideof azide the azide startingazide starting starting starting compound compound compound compound on on theon the onthenitrene nitrene the nitrene nitrene intermediate, intermediate, intermediate, intermediate, Withreactionsreactions phenyl have acetylene have been been suggested:no suggested: reaction (I) involving (I) Attack Attack of the ofthe 2 theC azide≡2C azide bond starting starting was observed.compound compound Other on on the thealkenes nitrene nitrene also intermediate, intermediate, proved Non-catalyticproducingproducingproducing azabenzene azabenzenetrapping azabenzene ofwith witho-quinone withsimultaneous simultaneous simultaneous monoimines N 2N-loss,2 -loss,N has-loss, and and been (II)and (II) dinuclearreport (II)dinuclear dinucleared earlier,N-N N-N N-Ncoupling butcoupling coupling the involvingmethod involving involving uses two two two producingproducingproducing azabenzene azabenzene azabenzene with with with simultaneous simultaneous simultaneous N N2 -loss,2 -loss,N2-loss, and and and(II) (II) dinuclear(II) dinuclear dinuclear N-N N-N N-N coupling coupling coupling involving involving involving two two two unreactiveproducingproducingproducing inazabenzene azabenzenethis azabenzene process. with with Apparently, with simultaneous simultaneous simultaneous only N electronN2-loss, N2-loss,-loss,-loss, and andrichand and (II) (II)alkenes(II) (II)dinuclear dinucleardinuclear dinuclear like N-N1-butoxyethene N-NN-N N-N coupling couplingcoupling coupling involving involvingareinvolving involving suitable two twotwo two stoichiometricnitrenenitrenenitrene complexes complexes complexes amounts (Scheme (Scheme of(Scheme halogen 7). 7). 7). containing oxidants,2 which is avoided in the reaction depicted in reactionnitrenenitrenenitrenenitrene complexespartners complexes complexes complexes in (Schemethis (Scheme (Scheme process. (Scheme 7). 7). 7 7). ). 7). Scheme 5 [37].

Scheme 5. Trapping of the o-quinone monoimine in an IEDDA reaction.

Substrate 5 was also tested in reactions with other potential reaction partners, in which we expected to be able to trap the iminoquinone intermediate with different C=C and C≡C bonds (Table 2). SchemeSchemeScheme 7. 7.Proposed Proposed 7. Proposed mechanisms mechanisms mechanisms for for formation forformation formation of ofaza aza of compounds azacompounds compounds in incobalt(II) cobalt(II) in cobalt(II) porphyrin porphyrin porphyrin catalyzed catalyzed catalyzed With phenylSchemeSchemeSchemeScheme acetylene7. 7.Proposed 7.Proposed Proposed 7. Proposed no mechanisms reactionmechanisms mechanisms mechanisms involving for for formationfor formation forformation the formation C of≡ of Caza of azabond azacompoundsof compounds aza compoundswas compounds observed. in in cobalt(II) in cobalt(II) cobalt(II)in Other cobalt(II) porphyrin porphyrin alkenes porphyrin porphyrin catalyzed also catalyzed catalyzed proved catalyzed Schemereactions 7. Proposed with organic mechanisms azides. for formation of aza compounds in cobalt(II) porphyrin catalyzed unreactivereactionsreactions in withthis with process.organic organic azides. Apparently,azides. only electron rich alkenes like 1-butoxyethene are suitable reactionsreactionsreactionsreactionsreactions with withwith with organic withorganicorganic organic organic azides. azides.azides. azides. azides. reaction partners in this process.

Molecules 2016, 21, 242 6 of 16

Table 2. Reaction of azide 5 with different substrates a,b,*.

Entry Substrate Expected Product(s) Obtained Product

1 (~10%)

2 ---

3 (80%)

4 ---

* Reaction conditions: a 0.5 mmol of azide 1, 1 mmol of substrate, 5 mol% CoP2 (w.r.t. azide), 4 mL toluene, 50 °C, 18 h. b 0.6 mmol of azide 1, 15 mL of substrate, 5 mol% CoP2, 50 °C, 18 h. These different reaction conditions (a,b) gave identical results. No nitrene transfer to the solvent (toluene) was observed in any case under the applied reaction conditions.

To investigate the generality of the observed HAT reactivity, we decided to explore the reactivity of aryl azide 7, containing an NH2 substituent in the ortho-position instead of an OH substituent. The o-amino phenylazide 7 was synthesized and tested under the same reaction conditions, using CoP1 as the catalyst (Scheme 6). In contrast to our expectations, however, azabenzene 8 was obtained as the major product. This observation intrigued us, as formation of aza compounds as products in reaction of azides with cobalt(II) porphyrin catalyzed processes has been reported only once before, and only as a minor side product [38].

Scheme 6. Reaction of o-aminophenyl azide 7 with cobalt(II) porphyrin catalyst CoP1.

Two mechanistic proposals for formation of aza compounds in cobalt(II) porphyrins catalyzed reactions have been suggested: (I) Attack of the azide starting compound on the nitrene intermediate,

Moleculesproducing2016 ,azabenzene21, 242 with simultaneous N2-loss, and (II) dinuclear N-N coupling involving7 oftwo 16 nitrene complexes (Scheme 7).

Scheme 7.7. Proposed mechanisms for formation of azaaza compoundscompounds in cobalt(II)cobalt(II) porphyrinporphyrin catalyzedcatalyzed reactions withwith organicorganic azides.azides.

It is not so clear which reaction conditions lead to the formation of azabenzenes and which not. Molecules 2016, 21, 242 7 of 16 One suggested possibility was that in the presence of a large excess of another reaction partner, the concentrationIt is ofnot the so clear nitrene which intermediate reaction conditions cannot build-uplead to the information a sufficient of azabenzenes manner to and allow which formation not. of aza compoundsOne suggested via dinuclearpossibility N–Nwas that coupling in the presence [39]. To of check a large this excess hypothesis, of another we reaction repeated partner, the reaction the of azide 7concentrationin the presence of the of nitrene a large intermediate excess of cannot phenyl bu acetyleneild-up in a or sufficient styrene manner in refluxing to allow toluene. formation However, of once againaza compounds the aza compound via dinuclear8 N–Nwas coupling obtained [39]. as To the chec majork this product. hypothesis, This we ledrepeated us to the believe reaction that of there azide 7 in the presence of a large excess of phenyl acetylene or styrene in refluxing toluene. However, is something unique about the NH substituent in azide 7 that relates to formation of only the aza once again the aza compound 8 was2 obtained as the major product. This led us to believe that there is o- compound.something We speculateunique about that the this NH relates2 substituent to rapid in formation azide 7 that of relatesphenylenediimine to formation of (OPDI) only the undergoing aza furthercompound. reactions We to formspeculate8. that this relates to rapid formation of o-phenylenediimine (OPDI) undergoing Thefurther formation reactions of to azabenzeneform 8. 8 from ortho-aminophenyl azides via the proposed phenylene diimine intermediateThe formation9 can of azabenzene be reasoned 8 infrom the ortho mechanism-aminophenyl depicted azides in via Scheme the proposed8. Activation phenylene of azide 7 by thediimine cobalt(II) intermediate catalysts 9 leadscan be toreasoned formation in the of mechanism a reactive depicted nitrene in radical Scheme intermediate.8. Activation of azide Subsequent 7 by the cobalt(II) catalysts leads to formation of a reactive nitrene radical intermediate. Subsequent rapid rapid HAT from the ortho-NH2 group to the nitrene radical moiety in this intermediate produces OPDI. HAT from the ortho-NH2 group to the nitrene radical moiety in this intermediate produces OPDI. This This is followed by intermolecular coupling of two OPDI molecules to form aza compound 8. The ODPI is followed by intermolecular coupling of two OPDI molecules to form aza compound 8. The ODPI couplingcoupling steps steps could could also also be be catalyzed catalyzed by by trace trace amou amountsnts of orthophenylenediamine of orthophenylenediamine (generated (generated by some by some minorminor side-reaction), side-reaction), as ashas has been been suggested suggested in literature in literature [40]. [40].

Scheme 8. Proposed mechanism of formation of azabenzene 8 from azide 7 involving the intermediate OPDI. Scheme 8. Proposed mechanism of formation of azabenzene 8 from azide 7 involving the intermediateIt is worth OPDI. mentioning that this reaction of ortho-amino substituted phenyl azides to give the azabenzene compounds as the major product is one of the few catalytic examples reported so far to synthesize aza compounds in high yields [41–43]. An example involving a ruthenium metallo-radical system proceeds via a free nitrene intermediate and works catalytically only for aryl azides with electron rich substitutents like OMe and OEt [43]. Another iron based example is limited in the sense that only azides with bulky substitutents like mestiyl groups result in formation of aza compounds [41]. With trifluoromethyl and methyl substituents dimers of the metal complex are obtained. The other example involves a nickel complex, but this system produces only stoichiometric amounts of aza compounds [42].

Molecules 2016, 21, 242 8 of 16

It is worth mentioning that this reaction of ortho-amino substituted phenyl azides to give the azabenzene compounds as the major product is one of the few catalytic examples reported so far to synthesize aza compounds in high yields [41–43]. An example involving a ruthenium metallo-radical system proceeds via a free nitrene intermediate and works catalytically only for aryl azides with electron rich substitutents like OMe and OEt [43]. Another iron based example is limited in the sense that only azides with bulky substitutents like mestiyl groups result in formation of aza compounds [41]. With trifluoromethyl and methyl substituents dimers of the metal complex are obtained. The other example involves a nickel complex, but this system produces only stoichiometric amounts of aza Moleculescompounds 2016, 21 [42, 242]. 8 of 16

2.2. Computational Studies To estimateestimate the the reaction reaction barriers barriers for thefor assumed the assumed facile HATfacile process HAT fromprocess the orthofrom-YH the substituent ortho-YH substituent(Y = O, NH) (Y to = theO, NH) nitrene to the moiety, nitrene we moiety, investigated we investigated this process this with process DFT with for bothDFT thefor both OH andthe OH the andNH2 thesubstituents. NH2 substituents. Starting from the cobalt(III) nitrene radical sp speciesecies the intramolecular HAT HAT reaction of the cobalt(III)nitrene radical radical of of the the azide azide 55 was found to proceed via a 6-membered , state, further stabilized stabilized by by a a hydrogen hydrogen bonding bonding interact interactionion between between the the transferred transferred hydrogen hydrogen atom atom and and a pyrrolea pyrrole nitrogen nitrogen atom atom of of the the porphyrin porphyrin (Figure (Figure 2,2, Computational Computational details in Table S1).S1). TheThe barrierbarrier isis ´ very low (+1.0 kcalkcal·mol¨ mol−1),1 ),thus thus explaining explaining the the experimental experimental observations. observations. Overall, Overall, the the HAT HAT process ´ is exergonic by ´−10.810.8 kcal·mol kcal¨ mol−1. 1.

Figure 2. TheThe DFT DFT calculated calculated barrier barrier for for HAT HAT from from the the ortho ortho hydroxyl hydroxyl group group to to the the nitrene nitrene moiety. moiety. ˝ −1 ´1 Δ∆G°G 298K298K inin kcal·mol kcal¨ mol, calculated, calculated at the at the BP86, BP86, def2-TZVP def2-TZVP level level with with dispersion dispersion corrections. corrections.

We further evaluated the changes in spin density distribution (see Figure 3 and Table 3) during We further evaluated the changes in spin density distribution (see Figure3 and Table3) during the HAT process (see also Figure 2). The spin density distribution of the transition state is very similar the HAT process (see also Figure2). The spin density distribution of the transition state is very similar to that in the initial cobalt(III) nitrene radical, but after the HAT barrier and transfer of the hydrogen to that in the initial cobalt(III) nitrene radical, but after the HAT barrier and transfer of the hydrogen atom from the –OH group, most of the spin density moves back to cobalt (Figure 3 and Table 3). atom from the –OH group, most of the spin density moves back to cobalt (Figure3 and Table3). Simultaneously, the bond length of the Co-N bond elongates from 1.818 Å in the nitrene radical to Simultaneously, the bond length of the Co-N bond elongates from 1.818 Å in the nitrene radical to 1.923 Å in the as depicted in Table 4. 1.923 Å in the imide as depicted in Table4.

(2A) (2B)(2C)

Figure 3. Changes in the spin density distribution during the HAT process shown in Figure 2.

Molecules 2016, 21, 242 8 of 16

2.2. Computational Studies To estimate the reaction barriers for the assumed facile HAT process from the ortho-YH substituent (Y = O, NH) to the nitrene moiety, we investigated this process with DFT for both the OH and the NH2 substituents. Starting from the cobalt(III) nitrene radical species the intramolecular HAT reaction of the cobalt(III)nitrene radical of the azide 5 was found to proceed via a 6-membered transition state, further stabilized by a hydrogen bonding interaction between the transferred hydrogen atom and a pyrrole nitrogen atom of the porphyrin (Figure 2, Computational details in Table S1). The barrier is very low (+1.0 kcal·mol−1), thus explaining the experimental observations. Overall, the HAT process is exergonic by −10.8 kcal·mol−1.

Figure 2. The DFT calculated barrier for HAT from the ortho hydroxyl group to the nitrene moiety.

ΔG°298K in kcal·mol−1, calculated at the BP86, def2-TZVP level with dispersion corrections.

We further evaluated the changes in spin density distribution (see Figure 3 and Table 3) during the HAT process (see also Figure 2). The spin density distribution of the transition state is very similar to that in the initial cobalt(III) nitrene radical, but after the HAT barrier and transfer of the hydrogen atom from the –OH group, most of the spin density moves back to cobalt (Figure 3 and Table 3). Molecules 2016Simultaneously,, 21, 242 the bond length of the Co-N bond elongates from 1.818 Å in the nitrene radical to 9 of 16 1.923 Å in the imide as depicted in Table 4.

(2A) (2B)(2C)

Figure 3. Changes in the spin density distribution during the HAT process shown in Figure 2. Figure 3. Changes in the spin density distribution during the HAT process shown in Figure2.

Table 3. Changes of the N, O and Co atom spin populations during the HAT process shown in Figure2.

Atom 2A 2B 2C Co 11.1% 8.5% 60.6% Molecules 2016, 21, 242 9 of 16 N 39.6% 33.5% 16.1% Table 3. Changes of the N, O and CoO atom spin 5.3% populati10.0%ons during9.4% the HAT process shown in Figure 2.

Atom 2A 2B 2C Table 4. Relevant bond lengthCo (Å)11.1% changes during8.5% the HAT60.6% process shown in Figure2. N 39.6% 33.5% 16.1% StructureO Co–N5.3% N–C 10.0% C–C C–O9.4% N–H

Table 4. Relevant2A bond length1.81769 (Å) changes 1.32018 during 1.47138 the HAT 1.34208process shown 1.86203 in Figure 2. 2B 1.81731 1.31667 1.48868 1.30627 1.33591 Structure2C Co–1.92289N N 1.32157–C 1.50424C–C 1.24441C–O 1.03461N–H 2A 1.81769 1.32018 1.47138 1.34208 1.86203 2B 1.81731 1.31667 1.48868 1.30627 1.33591 The almost barrierless2C abstraction 1.92289 of a1.32157 neighboring 1.50424 hydrogen 1.24441 atom 1.03461 by the reactive cobalt(III) nitrene radical thus prevents any intermolecular coupling reactions of the nitrene moiety with exogenous The almost barrierless abstraction of a neighboring hydrogen atom by the reactive cobalt(III) substrates. A similar process was also calculated for the NH substituted azide, and once again the nitrene radical thus prevents any intermolecular coupling reactions2 of the nitrene moiety with exogenous barrier forsubstrates. intramolecular A similar HAT process between was also thecalculated NH2 forgroup the NH and2 substituted the nitrene azide, moiety and once was again found the to be low ´1 (see Figurebarrier4). The for freeintramolecular energy required HAT between to reach the NH the2 group transition and the statenitrene is moiety only was +9.1 found kcal to¨ mol be low implying that this intramolecular(see Figure 4). The processfree energy is required fast, even to reac ath the room transition temperature. state is only The+9.1 kcal·mol overall−1 transformationimplying is that this intramolecular process is fast, even at room temperature. The overall transformation is exergonic by ´3.1 kcal¨ mol´1. exergonic by −3.1 kcal·mol−1.

Figure 4. The DFT calculated barrier for HAT from the ortho-amino group to the nitrene moiety. Figure 4. The DFT calculated barrier for HAT from the ortho-amino group to the nitrene moiety. ΔG°298K in kcal·mol−1, calculated at the BP86, def2-TZVP level with dispersion corrections. ˝ ´1 ∆G 298K in kcal¨ mol , calculated at the BP86, def2-TZVP level with dispersion corrections. The computed changes in the spin density distributions are once again in line with the HAT process, and similar to those computed for HAT from the OH substituent (See Figure 5 and Table 5). During the HAT process the spin population shifts from the nitrene radical in 3A to cobalt in 3C, and after the HAT process the spin density is mostly concentrated at the cobalt atom. The bond distance analysis of the relevant bonds are shown in Table 6. Here the Co-N bond in the final structure elongates from 1.8521 Å in the transition state 3B to 1.9604 Å in the final structure 3C. Interestingly, the adduct remains coordinated to the cobalt complex, as is evident from the bond distances.

Molecules 2016, 21, 242 10 of 16

The computed changes in the spin density distributions are once again in line with the HAT process, and similar to those computed for HAT from the OH substituent (See Figure5 and Table5). During the HAT process the spin population shifts from the nitrene radical in 3A to cobalt in 3C, and after the HAT process the spin density is mostly concentrated at the cobalt atom. The bond distance analysis of the relevant bonds are shown in Table6. Here the Co-N bond in the final structure elongates from 1.8521 Å in the transition state 3B to 1.9604 Å in the final structure 3C. Interestingly, the adduct Moleculesremains 2016 coordinated, 21, 242 to the cobalt complex, as is evident from the bond distances. 10 of 16

(3A) (3B) (3C)

FigureFigure 5. 5. ChangesChanges in in spin spin density density distribution distribution for for HAT HAT depicted in Figure 4 4..

Table 5. Changes of the N, O and Co atom spin populations during the HAT process shown in Figure 4. Table 5. Changes of the N, O and Co atom spin populations during the HAT process shown in Figure4. Atom 3A 3B 3C Co Atom8% 3A11% 3B 3C 63% N Co36% 8% 11%24% 63% 10% O N10% 36% 24%20% 10% 9% O 10% 20% 9%

Table 6. Relevant bond length (Å) changes during the HAT process shown in Figure 4. Table 6. Relevant bond length (Å) changes during the HAT process shown in Figure4. Structure Co–N N–C C–C C–N N–H 3A Structure 1.8411 Co–N 1.3161 N–C C–C1.4835 C–N1.3576 N–H 2.1848 3B 3A 1.8521 1.8411 1.3126 1.3161 1.48351.5060 1.35761.3262 2.1848 1.3213 3C 3B 1.9604 1.8521 1.3152 1.3126 1.50601.5022 1.32621.4378 1.3213 1.0340 3C 1.9604 1.3152 1.5022 1.4378 1.0340 While the barrier for the HAT process depicted in Figure 4 is low, it is not barrierless. Hence, to excludeWhile the thepossibility barrier forof theintermolec HAT processular coupling depicted of in the Figure nitrene4 is low,radical it isto not phenyl barrierless. acetylene Hence, (see Schemeto exclude 2b) thebeing possibility in competition of intermolecular with the intramolecular coupling of HAT the nitrene process radical (Figure to 4), phenyl we decided acetylene to make (see aScheme direct 2computationalb) being in competition comparison with of the the intramolecular two processes. HAT Attack process of the (Figure porp4hyrin), we cobalt(III) decided to nitrene make radicala direct on computational the alkyne to comparison form the γ-radical of the two species processes. 4C (C’ Attackin Scheme of the 2b) porphyrin was computed cobalt(III) at the nitrene same DFTradical level on (see the Figure alkyne 6). to The form latter the γ process-radical is species exergonic4C ((C’−10.8in Schemekcal·mol2−b)1), wasbut has computed a computed at the barrier same ofDFT +13.4 level kcal·mol (see Figure−1. This6). Thebarrier latter is almost process 4 is kcal·mol exergonic−1 higher ( ´10.8 than kcal ¨themol barrier´1), but for has intramolecular a computed barrier HAT (seeof +13.4 Figure kcal 4),¨ moland ´hence1. This this barrier process is cannot almost effici 4 kcalently¨ mol compete´1 higher with than the the intramolecular barrier for intramolecular HAT reaction. FormationHAT (see Figure of the4 OPDI), and intermediate hence this process by HAT cannot is expected efficiently under compete all reaction with conditions. the intramolecular HAT reaction. Formation of the OPDI intermediate by HAT is expected under all reaction conditions. The spin density distribution changes were once again calculated for the structures 4A, 4B and 4C. Interestingly, in contrast to the structures shown in Figures3 and5 the spin density in structure 4C is strongly delocalized over the carbon atoms of the γ- radical and the adjacent phenyl ring, with barely any spin density at the cobalt atom (see Figure7).

Figure 6. DFT computed reaction barrier for attack of the cobalt(III) nitrene radical on phenyl

acetylene leading to formation of a γ-alkyl radical intermediate. ΔG°298K in kcal·mol−1 computed at the BP86, def2-TZVP level with dispersion corrections.

Molecules 2016, 21, 242 10 of 16

(3A) (3B) (3C)

Figure 5. Changes in spin density distribution for HAT depicted in Figure 4.

Table 5. Changes of the N, O and Co atom spin populations during the HAT process shown in Figure 4.

Atom 3A 3B 3C Co 8% 11% 63% N 36% 24% 10% O 10% 20% 9%

Table 6. Relevant bond length (Å) changes during the HAT process shown in Figure 4.

Structure Co–N N–C C–C C–N N–H 3A 1.8411 1.3161 1.4835 1.3576 2.1848 3B 1.8521 1.3126 1.5060 1.3262 1.3213 3C 1.9604 1.3152 1.5022 1.4378 1.0340

While the barrier for the HAT process depicted in Figure 4 is low, it is not barrierless. Hence, to exclude the possibility of intermolecular coupling of the nitrene radical to phenyl acetylene (see Scheme 2b) being in competition with the intramolecular HAT process (Figure 4), we decided to make a direct computational comparison of the two processes. Attack of the porphyrin cobalt(III) nitrene radical on the alkyne to form the γ-radical species 4C (C’ in Scheme 2b) was computed at the same DFT level (see Figure 6). The latter process is exergonic (−10.8 kcal·mol−1), but has a computed barrier of +13.4 kcal·mol−1. This barrier is almost 4 kcal·mol−1 higher than the barrier for intramolecular HAT

Molecules(see Figure2016 4),, 21 and, 242 hence this process cannot efficiently compete with the intramolecular HAT reaction.11 of 16 Formation of the OPDI intermediate by HAT is expected under all reaction conditions.

Molecules 2016, 21, 242 11 of 16

TheFigure spin 6.6. DFTdensityDFT computed computed distribution reaction reaction changes barrier barrier for were attackfor attackonce of the againof cobalt(III) the calculated cobalt(III) nitrene for radicalnitrene the onstructuresradical phenyl on acetylene 4Aphenyl, 4B and acetylene leading to formation of a γ-alkyl radical intermediate.˝ ΔG°298K in kcal·mol´1 −1 computed at the 4C. Interestingly,leading to formation in contrast of a γ to-alkyl the radicalstructures intermediate. shown in∆ GFigures298K in 3 kcal and¨ mol 5, the computedspin density at the in BP86,structure 4C isdef2-TZVPBP86, strongly def2-TZVP delocalized level with level dispersion with over dispersion thecorrections. carbon corrections. atoms of the γ-alkyl radical and the adjacent phenyl ring, with barely any spin density at the cobalt atom (see Figure 7).

(4A) (4B) (4C)

Figure 7. ChangesChanges in in spin spin density density distributions during the HAT depicted in Figure6 6..

3. Experimental Section 3. Experimental Section

3.1. General Information All chemicals were purchased purchased from from commercially commercially available available sources sources unless unless otherwise otherwise mentioned. mentioned. Solvents for reactions that were performed in inert conditions were freshly distilled from sodium and 1 degassed prior to use. All NMR spectra for these experiments were recorded at 293 K.K. ForFor 1H-NMR a 400 MHz Avance 400400 (Bruker,(Bruker, Karlsruhe,Karlsruhe, Germany) or a 300 MHz Advance 300 machine (Bruker, Karlsruhe, Germany) was used. These spectra were re referencedferenced internally to re residualsidual solvent resonance of CDCl3 (δ = 7.26 ppm) or DMSO (2.50). For 13C{11H}-NMR a Bruker Avance 400 (101 MHz) or Bruker of CDCl3 (δ = 7.26 ppm) or DMSO (2.50). For C{ H}-NMR a Bruker Avance 400 (101 MHz) or Bruker Avance 500500 (126 MHz) machine was used. These spectra we werere referenced internally to residual solvent resonance of CDCl3 (δ = 77.2 ppm) or DMSO-d6 (39.5). UV-vis spectra were recorded on a Hewlett resonance of CDCl3 (δ = 77.2 ppm) or DMSO-d6 (39.5). UV-vis spectra were recorded on a Hewlett Packard 8453 spectrophotometer (Waldbronn, Germany).Germany).

3.2. Synthetic Details Compounds 11 [[1]1] andand7 7[ 2[2]] were were prepared prepared according according to literatureto literature reports reports and and their their analytical analytical data datamatched matched those those reported. reported.

3.2.1. Synthesis of 2-Azido-5-nitrophenol (5) 2-Amino-5-nitrophenol (72.4 mmol) was added to aq.HCl (6 M, 100 mL) at 0 °C. To this a solution of NaNO2 (96.5 mmol) in water (20 mL) was added dropwise. After stirring this mixture for 5 min (96.5 mmol) that was predissolved in water (60 mL) was added dropwise and stirred for 45 min. The precipitate was extracted with chloroform and then washed with water. The organic layer was dried over MgSO4. On evaporation of the solvent a dark pink brownish solid was obtained (80% crude yield). This was purified further by flash chromatography over silica (EtOAc-Hex = 1:1) to give a dark pink solid (75% yield). 1H-NMR (400 MHz, chloroform-d) δ 7.87 (dd, J = 8.7, 2.5 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 5.65 (s, 1H). 13C-NMR (75 MHz, chloroform-d) δ 147.46, 145.53, 133.08, 118.25, 116.92, 111.66.

3.2.2. Synthesis of the Catalyst CoP2

Perfluorinated tetraphenylporphyrin TPPH2F20 (0.5 mmol, 480 mg) was refluxed in acetic acid (300 mL) with an excess of CoCl2·6H2O (2.6 mmol, 620 mg) and sodium acetate (15 mmol, 1.24 g) for 1 h. The mixture was allowed to cool down and the solvent was evaporated until most solids precipitated out. The red solids thus obtained were washed with water, aqueous sodium bicarbonate

Molecules 2016, 21, 242 12 of 16

3.2.1. Synthesis of 2-Azido-5-nitrophenol (5) 2-Amino-5-nitrophenol (72.4 mmol) was added to aq.HCl (6 M, 100 mL) at 0 ˝C. To this a solution of NaNO2 (96.5 mmol) in water (20 mL) was added dropwise. After stirring this mixture for 5 min sodium azide (96.5 mmol) that was predissolved in water (60 mL) was added dropwise and stirred for 45 min. The precipitate was extracted with chloroform and then washed with water. The organic layer was dried over MgSO4. On evaporation of the solvent a dark pink brownish solid was obtained (80% crude yield). This was purified further by flash chromatography over silica (EtOAc-Hex = 1:1) to give a dark pink solid (75% yield). 1H-NMR (400 MHz, chloroform-d) δ 7.87 (dd, J = 8.7, 2.5 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 5.65 (s, 1H). 13C-NMR (75 MHz, chloroform-d) δ 147.46, 145.53, 133.08, 118.25, 116.92, 111.66.

3.2.2. Synthesis of the Catalyst CoP2

Perfluorinated tetraphenylporphyrin TPPH2F20 (0.5 mmol, 480 mg) was refluxed in acetic acid (300 mL) with an excess of CoCl2¨ 6H2O (2.6 mmol, 620 mg) and sodium acetate (15 mmol, 1.24 g) for 1 h. The mixture was allowed to cool down and the solvent was evaporated until most solids precipitated out. The red solids thus obtained were washed with water, aqueous sodium bicarbonate and finally with a minimum amount of cold methanol. The solid was then dried in-vacuo to give CoP2 (90% yield). UV-vis spectrum (THF), λmax/nm: 408, 520, 558.

3.2.3. Catalytic Reaction of Compound 1 to Give Product 3 In a flame dried Schlenk flask loaded with a stirrer 1 mmol of 1 was added followed by 0.05 mmol of CoP1. The Schlenk flask was then evacuated and refilled with nitrogen (three times). Subsequently 4 mL of dry chlorobenzene was added, and the flask was thermostatted at 50 ˝C for 18 h. After evaporating the solvent the mixture was directly loaded on a silica gel column. The product was eluted with Hex:EtOAc (1:1) to give product 3 in 80% isolated yield. 1H-NMR (400 MHz, Chloroform-d) δ 7.79–7.72 (m, 1H), 7.45 (ddd, J = 8.3, 6.9, 1.6 Hz, 1H), 7.42–7.32 (m, 2H), 6.48 (s, 1H), 6.42 (s, 1H), 13 5.11 (s, 2H). C-NMR (75 MHz, CDCl3) δ 180.00, 149.72, 142.25, 133.23, 129.59, 128.29, 125.05, 115.56, 114.24, 103.61. For the other reactions of compound 1 with other substrates, the same stoichiometry was used (also see the footnote in Table1).

3.2.4. Catalytic Reaction of Compound 5 to Give Product 6 In a flame dried Schlenk flask loaded with a stirrer 1 mmol of 5 was added followed by 0.05 mmol of CoP2. The Schlenk flask was then evacuated and refilled with nitrogen (three times). Subsequently 4 mL of chlorobenzene was added, and the reaction was thermostatted at 50 ˝C for 18 h. After evaporating the solvent, the mixture was directly loaded on a silica gel column. The product was eluted with Hex:EtOAc (1:1) to give product 6 in 80% yield. 1H-NMR (300 MHz, Chloroform-d) δ 7.82–7.65 (m, 2H), 6.53 (d, J = 8.7 Hz, 1H), 5.27 (t, J = 2.4 Hz, 1H), 4.57 (s, 1H), 3.85 (dt, J = 9.7, 6.7 Hz, 1H), 3.62 (dt, J = 9.7, 6.6 Hz, 1H), 3.58–3.46 (m, 1H), 3.51–3.38 (m, 1H), 1.54 (dq, J = 8.6, 6.8 Hz, 2H), 13 1.29 (dt, J = 14.9, 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 4H). C-NMR (75 MHz, CDCl3) δ 140.14, 139.16, 138.81, 119.53, 113.78, 112.78, 93.85, 68.60, 44.42, 31.54, 19.25, 13.86. For the other reactions of compound 5 with other substrates, the same stoichiometry was used (also see footnote in Table2).

3.2.5. Catalytic Reaction of 7 to Give Compound 8 In a flame dried Schlenk flask loaded with a stirrer compound 7 (67 mg, 0.5 mg) and CoP1 (17 mg, 0.025 mmol) was added and the flask was evacuated and backfilled with dinitrogen (three times). Subsequently 4 mL of PhCl was added, and the reaction mixture was thermostatted at 50 ˝C for 18 h. Molecules 2016, 21, 242 13 of 16

The reaction mixture was then subjected to preparative TLC and a bright orange band was obtained which was analyzed and found to be compound 8.

3.2.6. Catalytic Reaction of Aminophenyl Azide 7 to Give 8 In a flame dried Schlenk flask loaded with a stirrer compound 7 (67 mg, 0.5 mg) and CoP1 (17 mg, 0.025 mmol) were added and the flask was evacuated and backfilled with dinitrogen (three times). Subsequently 4 mL of PhCl was added. The reaction mixture was then thermostatted at 50 ˝C for 18 h. The resulting mixture was subjected to preparative TLC and a bright orange band was obtained which was analyzed and found to be compound 8. 1H-NMR (400 MHz, Chloroform-d) δ 7.68 (dd, J = 8.0, 13 1.6 Hz, 1H), 7.23–7.06 (m, 1H), 6.93–6.63 (m, 2H), 5.48 (s, 2H). C-NMR (126 MHz, CDCl3) δ 143.11, 137.73, 131.37, 124.29, 117.66, 117.04.

3.3. Computational Details Geometry optimizations were carried out with the Turbomole program package [44] coupled to the PQS Baker optimizer [45,46] via the BOpt package [47] at the DFT level using the b3-lyp [48–50] functional and def(2)-TZVP basis set [51] for the geometry optimizations of all stationary points. Grimme’s D3 dispersion corrections were used in all calculations (disp3, zero damping) [52]. All minima (no imaginary frequencies) and transition states (one imaginary frequency) were characterized by numerically calculating the Hessian matrix. ZPE and gas-phase thermal corrections (entropy and enthalpy, 298 K, 1 bar) from these analyses were calculated.

4. Conclusions

While trying to employ ortho-YH substituted phenyl azides (Y = OH, NH2) as substrates in nitrene transfer reactions catalyzed by cobalt(II) porphyrins, we discovered that the hydrogen atom of the YH moiety is readily abstracted by the reactive cobalt(III) nitrene radical intermediate. This leads to formation of reactive intermediates like o-quinone monoimines (OQMI; Y = OH) and orthophenylinendiimines (OPDI; Y = NH2). These reactive compounds rapidly undergo several follow-up reactions (Scheme9), thus preventing any direct (radical-type) coupling reactions of the nitrene radical intermediate with C=C or C”C bonds of other substrates. The o-quinone monoimines (Y = OH) easily dimerize and produce phenoxizinone 3 under aerobic conditions. In the presence of 1-butoxyethene the o-quinone monoimine can also be trapped in an IEDDA reaction, producing benzoxazine 6. Formation of orthophenylinendiimine (OPDI) from ortho-NH2-phenylazide (Y = NH2) is also associated with hydrogen atom abstraction of the Co(III) nitrene radical from the NH2 substituent in the ortho position. As a result, aza compound 8 is obtained. Attempts to react ortho substituted azides with other reaction partners by altering the reaction conditions were not successful. DFT computations are in agreement with the experiments; HAT from the ortho-YH substitutent (Y= O or NH) to the nitrene moiety has a (very) low barrier in both cases. The observed facile HAT from the ortho-YH substitutent (Y= O or NH) to the nitrene moiety is perhaps a potential disadvantage of using these systems, as it prevents the initially anticipated radical-type coupling of the cobalt(III) nitrene radical intermediate to C=C and C”C bonds of other substrates. On the other hand, it does provide a rather mild route to prepare highly reactive o-iminoquinonoids and o-phenylenediimines which can be employed in several follow up reactions. At the same time, the possibility of further reactivity of these intermediates occurring in the coordination sphere of the catalyst cannot be ruled out at the moment and might even be plausible based on the bond distance data that we obtained from the DFT optimized structures of these compounds after HAT. This suggests that diastereo- or enantioselective reactions may be accessible in synthetically useful transformations [42], mediated by chiral cobalt catalyst. This is a current topic of investigations in our group. Molecules 2016, 21, 242 13 of 16

by numerically calculating the Hessian matrix. ZPE and gas-phase thermal corrections (entropy and enthalpy, 298 K, 1 bar) from these analyses were calculated.

4. Conclusions

While trying to employ ortho-YH substituted phenyl azides (Y = OH, NH2) as substrates in nitrene transfer reactions catalyzed by cobalt(II) porphyrins, we discovered that the hydrogen atom of the YH moiety is readily abstracted by the reactive cobalt(III) nitrene radical intermediate. This leads to formation of reactive intermediates like o-quinone monoimines (OQMI; Y = OH) and orthophenylinendiimines (OPDI; Y = NH2). These reactive compounds rapidly undergo several follow-up reactions (Scheme 9), thus preventing any direct (radical-type) coupling reactions of the nitrene radical intermediate with C=C or C≡C bonds of other substrates. The o-quinone monoimines (Y = OH) easily dimerize and produce phenoxizinone 3 under aerobic conditions. In the presence of 1-butoxyethene the o-quinone monoimine can also be trapped in an IEDDA reaction, producing benzoxazine 6. Formation of orthophenylinendiimine (OPDI) from ortho-NH2-phenylazide (Y = NH2) is also associated with hydrogen atom abstraction of the Co(III) nitrene radical from the NH2 substituent in the ortho position. As a result, aza compound 8 is obtained. Attempts to react ortho substituted azides with other reaction partners by altering the reaction conditions were not successful. MoleculesDFT2016 computations, 21, 242 are in agreement with the experiments; HAT from the ortho-YH substitutent14 of 16 (Y= O or NH) to the nitrene moiety has a (very) low barrier in both cases.

SchemeScheme 9. 9.Transformations Transformations observed observed in in this this study. study.

The observed facile HAT from the ortho-YH substitutent (Y= O or NH) to the nitrene moiety is Supplementary Materials: Details of the newly synthesized compounds and catalytic reactions are available perhaps a potential disadvantage of using these systems, as it prevents the initially anticipated online at http://www.mdpi.com/1420-3049/21/2/242/s1. See the Supporting Information (SI) for NMR spectra and DFTradical-type tables. coupling of the cobalt(III) nitrene radical intermediate to C=C and C≡C bonds of other substrates. On the other hand, it does provide a rather mild route to prepare highly reactive Acknowledgments: Financial support from the Netherlands Organization for Scientific Research (NWO-CW VICI o-iminoquinonoids and o-phenylenediimines which can be employed in several follow up reactions. project 016.122.613) and the University of Amsterdam is gratefully acknowledged. At the same time, the possibility of further reactivity of these intermediates occurring in the coordination Authorsphere Contributions: of the catalystM.G. cannot and be B.B. ruled conceived out at the and moment designed and the might experiments. even be plausible M.G. performed based on the the experiments bond and part of the calculations. C.R. performed calculations and interpreted computational data. M.G. and B.B. wrote distance data that we obtained from the DFT optimized structures of these compounds after HAT. the paper. This suggests that diastereo- or enantioselective reactions may be accessible in synthetically useful Conflictstransformations[42], of Interest: The authorsmediated declare by chiral no conflict cobalt ofcatalyst. interest. This is a current topic of investigations in our group. References Supplementary Materials: Details of the newly synthesized compounds and catalytic reactions are available 1. Davies, H.M.L.; Manning, J.R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. online at http://www.mdpi.com/1420-3049/21/2/242/s1. See the Supporting Information (SI) for NMR spectra and NatureDFT tables.2008 , 451, 417–424. [CrossRef][PubMed] 2. Doyle, M.P.; Forbes, D.C. Recent advances in asymmetric catalytic metal carbene transformations. Chem. Rev. Acknowledgments: Financial support from the Netherlands Organization for Scientific Research (NWO-CW 1998VICI, project98, 911–935. 016.122.613) [CrossRef and the][ PubMedUniversity] of Amsterdam is gratefully acknowledged. 3. Driver, T.G. Recent advances in transition metal-catalyzed N-atom transfer reactions of azides. Org. Biomol. Chem. 2010, 8, 3831–3846. [CrossRef][PubMed] 4. Godula, K.; Sames, D. C–H bond functionalization in complex organic synthesis. Science 2006, 312, 67–72. [CrossRef][PubMed] 5. Intrieri, D.; Zardi, P.; Caselli, A.; Gallo, E. Organic azides: Energetic reagents for the Inter molecular amination of C–H bonds. Chem. Commun. 2014, 50, 11440–11453. [CrossRef][PubMed] 6. Manca, G.; Gallo, E.; Intrieri, D.; Mealli, C. DFT mechanistic proposal of the ruthenium porphyrin-catalysed allylic amination by organic azides. ACS Catal. 2014, 4, 823–832. [CrossRef] 7. Lu, H.; Zhang, X.P. Catalytic C–H functionalization by metalloporphyrins: Recent developments and future directions. Chem. Soc. Rev. 2011, 40, 1899–1909. [CrossRef][PubMed] 8. Chen, Y.; Ruppel, J.V.; Zhang, X.P. Cobalt-catalyzed asymmetric cyclopropanation of electron-deficient olefin. J. Am. Chem. Soc. 2007, 129, 12074–12075. [CrossRef][PubMed] 9. Dzik, W.I.; Xu, X.; Zhang, X.P.; Reek, J.N.H.; de Bruin, B. Carbene radicals in CoII(por) -catalyzed olefin cyclopropanation. J. Am. Chem. Soc. 2010, 132, 10891–10902. [CrossRef][PubMed] 10. Dzik, W.I.; Zhang, X.P.; de Bruin, B. Redox noninnocence of carbene : Carbene radicals in (Catalytic) C–C bond formation. Inorg. Chem. 2011, 50, 9896–9903. [CrossRef][PubMed] 11. Gao, G.; Jones, J.E.; Vyas, R.; Harden, J.D.; Zhang, X.P. Cobalt-catalyzed aziridination with diphenylphosphoryl azide (DPPA): Direct synthesis of N-phosphorus-substituted from alkenes. J. Org. Chem. 2006, 71, 6655–6658. [CrossRef][PubMed] 12. Goswami, M.; Lyaskovskyy, V.; Domingos, S.R.; Buma, W.J.; Woutersen, S.; Troeppner, O.; Ivanovi´c-Burmazovi´c,I.; Lu, H.; Cui, X.; Zhang, X.P.; et al. Characterization of porphyrin-Co(III)-‘nitrene radical’ species relevant in catalytic nitrene transfer reactions. J. Am. Chem. Soc. 2015, 137, 5468–5479. [CrossRef][PubMed] Molecules 2016, 21, 242 15 of 16

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