Nitrene Radical Intermediates in Catalytic Synthesis

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Kuijpers, P.F.; van der Vlugt, J.I.; Schneider, S.; de Bruin, B. DOI 10.1002/chem.201702537 Publication date 2017 Document Version Final published version Published in Chemistry-A European Journal License CC BY-NC-ND Link to publication

Citation for published version (APA): Kuijpers, P. F., van der Vlugt, J. I., Schneider, S., & de Bruin, B. (2017). Nitrene Radical Intermediates in Catalytic Synthesis. Chemistry-A European Journal, 23(56), 13819-13829. https://doi.org/10.1002/chem.201702537

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& MetalloradicalCatalysis Nitrene Radical Intermediates in Catalytic Synthesis Petrus F. Kuijpers,[a] Jarl Ivar van der Vlugt,[a] Sven Schneider,[b] and Bas de Bruin*[a]

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reactions are often associated with low selectivities.[2] Free or- Abstract: Nitrene radical complexes are reactive inter- ganic radicals indeedoften lead to radical disproportionation mediates with discrete spin density at the nitrogen-atom and other side reactions, generating insoluble materials. Never- of the nitrene moiety.These species have become impor- theless, many selectivereactions based on free N-centered rad- tant intermediates for organic synthesis, being invoked in icals have since been achieved, taking advantage of kinetic abroad range of C Hfunctionalization and aziridination control (desired reactions outcompeting undesired ones).[3] À reactions. Nitrene radical complexes have intriguing elec- Better control can be achieved in the coordination sphereofa tronic structures,and are best described as one-electron metal,and transitionmetal bound N-centered radicals are in- reduced Fischer type nitrenes. They can be generatedby creasingly recognized as important intermediates to enable intramolecular single electron transfer to the “redox non- controlled radical typeC Nbond formation reactions.[4] Transi- À innocent” nitrene moiety at the metal. Nitrene radicals tion metal-bound N-centered radicals can be catalytically gen- generated at open-shell cobalt(II) have thusfar received erated, in low and controlled amounts, therebygiving rise to most attention in terms of spectroscopic characterization, much higher selectivities than typically achieved with free or- reactivity screening, catalytic nitrene-transfer reactions ganic radicals. and (computational and experimental) mechanistic stud- Ligands surrounding the metal are used to fine-tune the re- ies, but someinteresting iron and precious metal catalysts activity of these intermediates, both sterically and electronical- have also been employed in related reactions involving ni- ly.[5] Transition metal-bound nitrene/imido-based nitrogen-cen- trene radicals.Insome cases, redox-active ligands are tered radicals M N·R (i.e. nitrene- and imidyl radicalcom- À used to facilitateintramolecular single electron transfer plexes; see Figure 1and Figure 2), have received quite some from the complex to the nitrenemoiety.Organicazides attention,asthey enable avariety of useful nitrene-insertion are among the most attractive nitrene precursors in this and nitrene-transfer reactions. Such reactions are typically field, typically requiring pre-activatedorganic azides (e.g. more selectivethan those involving free N-centered radicals or RSO2N3,(RO)2P(=O)N3,ROC(=O)N3 and alike) to achieveef- free nitrenes. ficient and selective catalysis. Challenging, non-activated aliphatic organic azides were recently added to the palette of reagents useful in synthetically relevant reactions proceedingvia nitrene radicalintermediates.This concept article describes the electronic structure of nitrene radical complexes, emphasizesontheir usefulness in the catalytic synthesis of variousorganic products, and highlights the important developments in the field.

Introduction

The use of nitrogen-centered radicals in synthesis, although in- itially perhaps not recognized as such, dates back to the late Figure 1. Simplified frontier molecularorbital diagramsof: a) Schrock type th imido complex (metal–nitrogen p-interactions stabilizing in two directions, 19 century Hofmann–Lçffler–Freytag reactionfor the synthe- nitrogensp-hybridization and linear coordination modes favored). b) Schrock sis of pyrrolidines.[1] The free organic radicals involved in these type imidyl radicalcomplex (one-electron oxidized Schrock type imido).

[a] Dr.P.F.Kuijpers, Dr.Ir. J. I. vander Vlugt, Prof. Dr.B.deBruin Van‘tHoffInstitute for Molecular Sciences (HIMS) University of Amsterdam (UvA) The scientific literature is highly inconsistent aboutthe elec- Science Park 904, 1098 XH Amsterdam tronic structure description and nature of M NR species in À (The Netherlands) general,and frequently confusing descriptions are presented E-mail:[email protected] that are based on formal oxidation state counting arguments. [b] Prof. S. Schneider As such, the NR ligand is most typicallyconsidered as an imido Institut fürAnorganische Chemie 2 fragment (R N À), and frequently even as aredoxinactive UniversitätGçttingen, Tammannstr.4 À 37077 Gçttingen (Germany) moiety. This description fails to reflect the electrophilic and The ORCID identification number(s) for the author(s) of this articlecan be radical-type reactivity observed for many late transition metal found under https://doi.org/10.1002/chem.201702537. M-NR species.[6] The metal-nitrogen p-interactionsofagenuine 2017 The Authors. Published by Wiley-VCH Verlag GmbH&Co. KGaA. imido complex are stabilizing in case of early transition metals This is an open access article under the terms of Creative Commons Attri- (electropositive,relativelyhigh-energy emptyd-type orbitals; bution NonCommercial-NoDerivs License, which permits use and distribu- p tion in any medium, provided the originalwork is properly cited, the use is see Figure 1a), in whichcase the imido moiety should have a non-commercial and no modifications or adaptations are made. tendency to bind in alinear manner due to the presence of

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Obviously,the simplified Fischer and Schrock type MO diagrams in Figures 1and 2are merely extremes of acontinuum of intermediate cases, and these simplified and generalized picturesget severelyblurred, with increasing covalency,inparticular for second and third row transition metalswhere relativ- istic effects furthercomplicate the electronic structure via spin- orbit coupling. However, for most first row transition metals the diagrams should be quite useful to understand their reactivity,including the redoxactivity of the imido/nitrene moiety. With the frontier orbitals shown in Figure 1and Figure 2in mind, it should be clear that both Schrock type imido complexes (HOMO dominated by the nitrogen p-orbital) and Fisch- er type nitrene complexes (LUMOdominated by the nitrogen p-orbital) are potentially redox-active at the nitrogen atom, and hence they can easily form M N·Rradicals. Twodistinct À electronic structures are possible for such species: (1) Schrock type imidylradicals (Figure 1b), formed by 1e-oxidation of (Schrock type) p-stabilized imido species, or (2) Fischertype nitrene radical complexes (Figure 2b). The latter can be formed either by 1e-reduction of (Fischer type) nitrene radicalspecies (Figure 2a to 2b), or by 1e-oxidation of a p-destabilizedimido complex(Figure 2c to 2b). Schrock type imidyl radicalspecies are distinctly different from Fischertypenitrene radicals. In the first case the singly occupied molecular orbital (SOMO) is a half-filled metal–nitrogen p-bonding orbital, while in the second it is ahalf-filled metal–nitrogen p-antibonding orbital. Few examples of Schrock typeimidyl radicals formed in stoichiometric reactions exist,[7] butthey are very scarce and, to Figure 2. Simplified frontier molecularorbitaldiagramsof: a) Fischer type ni- our best knowledge,nounequivocal examples of such species trene complex (nitrogen sp2 hybridizationand bentcoordination modes fa- involved in catalytic reactions have been reported to date. This voredfor late transitionmetal complexes);.b)Nitrene radicalcomplex (one- is perhaps not very surprising, as the strong M Nbonding in- electronreducedFischer type nitrene);c)p-destabilized imidocomplex. À teractions and the linear coordination mode of these species are likely to hamper nitrene-transfer reactivity (Figure1b). The situation is quite different for Fischertype nitreneradical com- two stabilizing p-interactions between the electropositive plexes, which have weaker metal–nitrogenbonds and for metal and the sp-hybridized imido nitrogen atom. In analogy which several catalytically relevant examples have already with the Fischer/Schrock terminology used to explain the reac- been reported. Nitrene radicalcomplexes can be considered as tivity of transition-metal carbene complexes,such speciesare the nitrogen analogues of carbene radical complexes.[8] This best described as Schrock type nitreneorp-stabilizedimido Conceptpaper provides an overview of their spectroscopic complexes (Figure1a). The corresponding p-interactions in a properties, electronic structure and catalytic reactivity.The genuineimido complex involving alate transition metal (elec- paper primarily focusses on reactions and complexes forwhich tronegative, relativelylow-energyand filled dp-type orbitals) clear indications for the involvement of nitreneradicals in cata- are destabilizing, thus favoring abentcoordination mode. lytic reactions are reported. Such complexesare perhaps bestcharacterizedasp-destabilized imido complexes or two-electron reduced Fischer type ni- Typicallyused nitrene-precursor reagents trene complexes (Figure 2). In both cases,the imido fragments are expected to be relativelynucleophilic at nitrogen.[5] Howev- Nitrene radical complexes can in principle be generated in sev- er,many of the catalytically relevant late transition metal M eral ways, but in most catalytic examples areactionbetween a À NR speciesare in fact electrophilicatnitrogen, and hence are low-valent transition-metalcomplex and an oxidizing nitrene- better described as Fischertype nitrenecomplexes rather than transfer reagent is the methodofchoice. These reagents typi- imido species. They have a p-stabilized empty p-orbital on ni- cally contain good leaving groups, and have astrong driving trogen being the LUMO of the complex (Figure 2), thus ex- force for nitrene transfer to the metal. Bromamine-Tand imi- plainingtheir electrophilicnature. For late transition metal noiodanes were frequently used as nitrene source in early Fischertype nitrene complexes the bent coordination mode is studies, but these reagents suffer from waste formation, over- favored,inorder to avoid unfavorable p-conflicts between the oxidation andother selectivity issues. Organic azides have filled metal dp-type orbitals and the remaining lone pair at the been used as the nitreneprecursor of choiceinmost of the re- sp2 hybridized nitrogen atom (Figure 2). cently reported catalytic reactions proceeding via nitreneradi-

Chem. Eur.J.2017, 23,13819–13829 www.chemeurj.org 13821 2017 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Concept cal intermediates. Azidesare quite attractive nitreneprecursors, not only because they produce only dinitrogen as aside product, but also because of their ease of synthesis and long bench stabilityatroom temperature.Furthermore, with avariety of availableazides it is easier to introduce versatility of the nitrogen substituents in the products.

Characterization of nitrene radical complexes Figure 3. Changes in the X-band EPR spectrafor amixture of cobalt porphyrin and an azide over time (left) and zoom of the nitreneradicalcomplex Distinguishing various types of nitrene radical complexes can (right).[9,10] be quite challenging, and most often the combination of different spectroscopic and analytical techniques is needed to properly establish their identity. Electron paramagnetic reso- Aclear EPR signal around a g-value of 2.0 revealing small nance (EPR) and X-ray absorption spectroscopy (XAS) are fre- but detectable cobaltand nitrogen hyperfinecoupling indi- quently used to determinethe locus of the unpaired electron cates anitrogen-centered radicalrather than ametal-centered and the oxidation state of the metal, respectively.For iron radicalupon reaction with the azide (Figure 3, right). All other complexes,Mçssbauer spectroscopy has also proven highly spectroscopic and analyticaldata (XANES, IR, ESI-MS) data are useful.Inaddition, computational tools such as those based in agreement with this assignment.[10] DFT calculated spectro- on density functional theory (DFT) are frequently used to de- scopic properties match well with the experimental data, terminethe nature of the short-lived reactive nitreneradicalin- showingthat the computed electronic structure (Figure 4) termediates in synthetic reactions. In particular, spectroscopic closely matches the experimentally derived configuration. The property calculations have proven highly usefulinthis field. data show that the nitreneligand formed at cobalt(II) under- Such detailed spectroscopic and computational studies were goes one-electron reduction by the cobalt(II) center to produce recently performed by de Bruin and co-workerstocharacterize acobalt(III)–nitrene radicalcomplex. The unpairedelectron re- aseries of catalytically relevant cobalt porphyrin nitreneradical sides in aCo Nantibonding p-bond (Figure4,right), reminis- [8,10] À species. EPR spectroscopy provedparticularly useful to cent of aFischertype nitrene radicalcomplex (Figure 2b). As a characterize these species. Upon mixing of acobalt–porphyrin result, the spin density of the complexes is almost exclusively complex and an azide (Scheme 1, right) the characteristicsig- nitrogen-centered (Figure 4, left). nals of the cobaltporphyrin gradually decrease to form anitrene radicalspecies, as is clear from the EPR spectra (Figure 3).

Figure 4. SOMO (left) and spin density (right) plots of acobalt(III) porphyrin [9,10] nitrene radical complex [(por)Co(NR)] (R=-SO2Ph). Interestingly,formation of the key cobalt(III) nitreneradical intermediate is the result of an intramolecular electron transfer process from cobalt(II) to the redox-active(redox-noninnocent) nitrenemoiety,once generated at the metal (Scheme 2). This gives direct access to controlled and catalytic radical-type reactions taking place in the coordinationsphereofcobalt. Surprisingly,nitrene radical species formed in the reactionof cobalt porphyrins with iminoiodanes yieldedentirely different EPR spectra,which could be assigned to bis-nitrene radical species(Scheme 1, left). In this case the second nitreneligand formed at the cobaltcenterisreduced by the porphyrin ligand Scheme1.Formation of bis-nitrene radicalspecies upon reaction of cobal- ring to yield acomplex containing three unpairedelectrons; t(II) porphyrins with iminoiodanesasnitrene precursor (left), in contrastto formation of mono-nitrene radical complexeswhen using organic azide sub- one on each nitreneradical moiety,and one delocalized over strates (right). the p-system of the porphyrin ring (antiferromagnetically cou-

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Scheme2.Intramolecular single-electron transferfrom the cobalt(II) metal- Scheme3.Generalized nitreneradicalreactivity and mechanisms of loradical to the redox-activenitrenemoiety generated upon azide activation cobalt(II)–porphyrin metalloradical-catalyzednitrene-transfer reactions. at the metal, thus producing acobalt(III)–nitrene radicalcomplex (one-electron-reduced Fischer type nitrene). pled to one of the nitrene radicals). While thesebis-nitrene radicalspecies have an intriguing electronic structure, they are less useful for catalysis, because these over-oxidized complexes easily decompose, resulting in rapid, unwanted and nonselec- tive catalyst deactivation. The bis-nitrene radicals decompose much more rapidly than the mono-nitrene analogues, clearly showingthe additional advantage of using (activated) organic azides as the nitreneprecursor,asthese generate only the mono-nitreneradical species.[10] These results emphasizethe importance of the nitrene transfer reagent choice. Figure 5. Selectionofthe various productsthat can be synthesized by cobalt(II) porphyrin catalyzednitrene insertion protocols involving nitrene radicals. Catalytic reactionsvia nitreneradical species producedfrom activated nitrene precursors Cobalt porphyrinshave been used in avariety of nitrene-trans- scope. As aresult,inmost subsequentstudies involving ni- fer and nitrene-insertion reactions, including aziridination,[11] trene-transfer or nitrene-insertion reactions mediated by co- C Hamination[12] andC Hamidation.[13] Cobalt(III) nitrenerad- balt(II) porphyrins, organic azides were chosen as the preferred À À ical complexes, similar to those described above,are proposed nitreneprecursors (includingmost aziridination and C Hbond À as the key-reactiveintermediates (Scheme 3). They are typically amination studies reported by the Zhang group after 2005; generated in reactions between cobalt(II)–porphyrin complexes vide infra). The mechanism of the aziridination reaction was in- with nitrene precursors, such as iminoiodanes or activated or- vestigated in our group (de Bruin and co-workers)in2010 ganic azides. Cobalt(III) nitrene radicalintermediates react via using DFT methods, confirming formation of nitreneradical in- discrete radical-type mechanisms. Radicaladdition to C=C termediates as the key reactive speciesinthe catalytic cycle double bondsorhydrogen atom transfer (HAT) from (activated (Scheme3).[17] benzylic or allylic) C Hbonds (Scheme 3) leads to avariety of Initial reports of C Hamination with cobalt porphyrins À À desirable N-containing organic products such as amides,[13] using aromatic azides suggested that acobalt(II)–azide adduct linear and cyclic amines,[12] aziridines,[11] dihydrobenzoxazine, is formed, which reacts directly with the hydrocarboninthe and azabenzenes[14] (Figure 5). rate limiting step without forming adetectable intermedia- The first cobalt–porphyrin-catalyzed aziridinationwas de- te.[12c,16] However,subsequentstudies of C Hamination reac- À scribed by Zhang and co-workers in 2005, in which the authors tions with cobalt(II) porphyrins and non-aromatic azides have used Bromamine-Tasthe nitrene precursor.[15] Interestingly,a clearlyshown these reactions to proceed via discrete nitrene few years earlier (2000) the group of Cenini andco-workers radicalintermediates.[9,12e] Experimentally,the presence of the has shownthat organic azides are also suitable nitrenetransfer nitreneradicalintermediate was verified using EPR spectrosco- agents in cobalt(II)–porphyrin-catalyzed C Hbond amination py (see above),[9,10] and by the use of aradical clock substrate. À reactions.[16] These, when compared to Bromamine-T,are easier The latterreactionreveals partial radical-type ring-opening of to work with, more sustainable, and have abroader synthetic the cyclopropane-ring probe after HAT(Scheme 4).[12f, g] DFT

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Scheme5.Left:Chiral aziridines obtained in cobalt(II)–porphyrin catalyzed Scheme4.Radical probeexperiment confirming the radical-type mecha- aziridinationreactions. Right:Cooperative H-bonding interactions between nism. the nitreneradical substrate and amide functionalities of the ligand in the second coordination sphere enhance the rate of the reaction and mediate efficient chirality transfer. computational studies of the C Hamination mechanismreveal À apathway involving cobalt(III) nitreneradicalformation, HAT from the hydrocarbon to the nitrogen-centered radical,fol- aziridination and C Hbond amination reactions reported by À lowed by a“radical-substitution”reaction with the free carbon J.-L. Zhang and co-workers,catalysed by iron(III)complexes radicalattackingthe antibonding orbitalofthe weak Co N with fluorinated porpholactone ligandsand using TsN as the À 3 bond, thus leading to simultaneous C Nbond formation and nitreneprecursor,proceed most likely via nitreneradicalinter- À Co Nbond homolysistoliberate the product and regenerate mediates.[18d] Another interesting precursor leadingtocon- À the catalystinthe cobalt(II) oxidation state (Scheme 3).[9] For trolled metal-bound nitrogen-centred radicalreactivity is N-flu- reasonsofsimilarity with mechanismsproposed for (enzymat- orobenzenesulfonamide (NSFI), whichhas been used in some ic) C Hbond functionalization reactions mediated by other interesting coppercatalysed amination reactions to give a À metallo-porhyrins, the last step of this mechanism is conven- wide range of difunctionalized products in moderate to excel- iently referred to as a“radical rebound” step. lent yield (up to 91 %).[18e–g] However,while showing interesting One of the important advantages of using nitreneradical related chemistry,the “aminyl-radical” intermediates formed in complexes insteadoffree N-centered radicals or free nitrenes the latter reactions do not belong to the class of nitrene radi- in organic synthesis is the ability to perform reactions in an cals and are therefore not discussed in any furtherdetail. enantioselective manner.Chiral information can be efficiently Very recently,the groups of Ji, Bao, and Wang reported on transferred from chiral porphyrin ligands to the nitreneradical the interesting cobalt(II)-catalyzed formation of sulfonyl guani- substrates, as was elegantly demonstrated by the group of dines in aseries of tri-component reactions between sulfonyla- Zhang.[10] By changing the substituents on the porphyrin zides, isonitriles and secondary amines (Scheme 6). Computa- ligand,highly enantioselective synthesis of awide range of tional and EPR studies suggest the reactions proceed via co- chiral aziridines provedpossible (Scheme 4, left). balt(III)–nitrene radicalintermediate.[19] Acooperative, chiral H-bond donor motif in the second co- While these intermediates are quite similar to the ones de- ordination sphere (amide functionality of the porphyrin ligand) scribed above for the Co(por)systems, the availability of cis- enhances the activity of the catalyst,[17] and enables efficient chirality transfer (Scheme 5, right).[12] The enantioselective reactions as reported by the Zhang group were thus far all based on the use of activated organic azides (e.g. RSO2N3,(RO)2P-

(=O)N3,ROC(=O)CN3 and so forth) as the nitreneprecursors, which are activated by the chiral cobalt(II) catalysts at rather mild reaction temperatures(40 8C). In 2013, the group of PØrez proposed on the basis of DFT calculations that tris-pyrazolylborate copper nitrenecomplexes react on the triplet surface, involving nitrene radical reactivity of the key coppernitrenoid intermediate, while the corresponding silver complexes react on the singlet surface leading to closed-shellelectrophilc nitrenereactivity.[18a,b] Similarly,the groups of Manca andGallo proposed on the basis of DFT cal- culationsthat nitrene transfer catalysis via the mono- and bis- imido intermediates [Ru(TPP)(NR)(CO)] and [Ru(TPP)(NR)2]in- Scheme6.Cobalt(II)-catalyzedtri-componentcoupling of sulfonylazides, iso- volves the triplet spin state of these species, again leading to nitriles and secondaryamines, proceeding via achelating nitreneradicalin- nitreneradicalreactivityalso for these Ru catalysts.[18c] Also the termediate.

Chem. Eur.J.2017, 23,13819 –13829 www.chemeurj.org 13824 2017 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Concept vacant sites in the catalystused in the reactions described by Li lead to achelating coordination mode of the sulfonyl-based nitreneradicalmoiety.For the same reason,coupling of this nitrene radical moiety to the isonitrile substrate occurs via inter- nal attack of a cis-coordinated isocyanide, producing acobalt- coordinated carbodimide intermediate. The lattersubsequently reacts with the secondary amine substrate to produce the sulfonyl guanidine product in excellent yield (up to 96%). In addition to the cobalt-catalyzedreactions described above,the groups of Yoshizawa and Itoh recently reported an interesting catalytic approach to generate nitreneradicals at a diamagnetic RhIII complex precursor by making use of aredox- active ligand. The latter is involved in the required intramolecular single-electron transfer from the complex to the nitrene moiety generated at rhodium (Scheme 7).[20] The complex showedefficient intermolecularC Hamination from an acti- À vated tosyl azide (73 %amination product was obtained under Scheme8.Activation of an aliphatic azide at palladium(II) to anitrene radical optimized conditions). The nitreneradical complexisformed intermediate made possible by the presence of aredox-active NNO-ligand. by one-electrontransfer from the redox-active ligand to the rhodium(III)-bound nitrenemoiety,and the metal stays in the RhIII oxidation state throughout the entire catalytic cycle. As a chiometric amounts of the saturated N-heterocyclic ring prod- result, the key-intermediate has two unpairedelectrons:One ucts could be isolated.[21a] at the 1e-reduced Fischertype nitrene moiety,and one at the The palladiumcenter remains in the PdII oxidation state 1e-oxidized redox-activeligand. throughout the process. Using an isotopically labeled substrate analogue, an intramolecular kineticisotope effect (KIE) of 3.35 was experimentally observed and computationally reproduced.

Careful removal of CHCl3 from the crystal latticeofthe Pd-catalyst enabled catalytic turnover,but unfortunately only very low

turnover numbers(TONmax =2.8, 28%yield) could be achieved with this system.[21b] Other examples of catalystsystems capable of activating aliphatic azides, producing aminated products via nitrene radical intermediates with higher turnover numbers, are described in the next section.

Catalytic reactions via nitreneradical species produced from aliphatic nitrene precursors Most of the catalytic reactions described above require aromat-

ic or pre-activated organic azides (e.g. RSO2N3,(RO)2P(=O)N3,

ROC(=O)CN3 and alike) to achieve efficient and selectiveturn- over.These azides are typically easier to activate than aliphatic azides, and hence more efficient reactions proceeding at lower temperatures are possible using thesepre-activated reagents. Scheme7.Proposed mechanism for nitrene radical C Hamination with a Similar reactions with aliphatic azides are more cumbersome, À rhodium(III) complex containinga“redox non-innocent” ONNO-ligand. and generally require more reactive catalysts and higher reaction temperatures. The use of aliphatic azides, however,sub- stantially broadens the scope of these reactions, leading to a The approachofItoh and Yoshizawa (Scheme 8) is quite sim- broad range of interesting N-containing (cyclic) products. ilar to the redox-activeligand approach used abit earlier by Hence, efforts in developing new protocolstoactivate aliphatic van der Vlugt andco-workerstogenerate nitrene radicals at a azidesare desirable. Recent developments in the field indeed diamagnetic palladium(II) complex.[21] The palladium(II) com- show that it is possible to convert (less reactive) aliphatic plex used contains aredox-active (non-innocent) NNO ligand, azidesincatalytic reactions, which are all processes that in- capable of electron transfer to the nitrene moiety generated at volve the intermediacy of nitrene radicalcomplexes. palladium. Interestingly,this system is capable of activating the The first reports on the activation of aliphatic azides were aliphatic azide 4-(azidobutyl)benzene (Scheme 8). The nitrene published quite recently by the group of Betley,who used radicalintermediate undergoes ring-closure via HATand radical iron-catalysts based on “half-porphyrin” dipyrromethene li- II reboundsteps, and in the presence of Boc2Omore or lessstoi- gands.The Fe complexesprovedactiveinboth intermolecu-

Chem. Eur.J.2017, 23,13819 –13829 www.chemeurj.org 13825 2017 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Concept lar[22] and intramolecular[23] C Hbond amination reactions. The À initial paper published in 2011reports on intermolecular C H À bond amination with aromatic andbulky aliphatic azides (Scheme 9).[22a] The nitrene intermediate has arather compli- cated electronic structure, with one of the five unpairedelectrons at the (high spin) FeIII centerbeing antiferromagnetic coupled to the nitrene radical moiety,leading to an S=2 ground state. As aresult, it is not so clear if this intermediate

Scheme10. Proposed mechanisms for intramolecularC Hbond amination À leadingtoN-heterocycles. After formation of the Fe-bound N-radical intermediate, formalnitreneinsertion can proceed via astepwise HAT-radical rebound mechanism as well as in aconcerted manner.

Scheme9.Nitrene-transfer/insertion reactivity (left) of the high-spin iron(II) resultinginchemoselectivity issues. TheFeII-catalysts also pro- catalyst (right) developed by Betley and co-workers. duce significant amounts of unwanted linear (Boc-protected) amine side-products in some of the reported reactions, which should be regarded as aFischertype nitrene radical (Figure 2), is probablyarelatedissue. or rather as aSchrock type imidyl radical complex (Figure1). In As proposed for the intermolecular reaction, the authors any case, the intermediate exhibits discrete nitrogen-centered suggest the involvement of Fe-boundN-radical intermediates spin density and seems to react as an N-radical. The mecha- in the intramolecular ring-closing amination reactions nisms proposed for these reactions are very similar to those (Scheme 10). In order to explain the reactivity towardsseveral described for most other catalysts discussed above:HAT from different C Hbonds, the authors suggestthat the Fe-bound À the hydrocarbonbythe metal-bound N-radical, followed by a N-radical intermediate not only reacts via astepwise HAT-radi- radicalreboundstep to produce the aminated organic prod- cal rebound mechanism, but also react in aconcerted (electro- uct, which is in line with the high chemoselectivity for allylic philic)manner with C Hbonds. À C Hinsertion over aziridination.[22b] The nitreneradical charac- Recent studies performed by van der Vlugt, de Bruin and co- À ter can also lead to undesired side-reactionswith aromatic workers focusedonimproving the stabilityofanFe-based cat- azides as nitrene sources. Spin-delocalization into the phenyl alyst andincreasingthe TONs of these type of reactions. In- ring of the transient phenylnitrene catalystspecies resultsin spired by the positive effects of using redox-active ligands ob- bimolecular coupling of two nitrene fragments inhibiting catal- servedincatalytic reactions with Pd and Rh (vide supra), an ysis.[22] air- andmoisture-stable FeIII-basedcatalyst with aredox-active Althoughthe turnover numbers(TONs) reported thus far for NNO ligand was synthesized and used in the intramolecular C À intermolecular nitrene transfer are modest (TONs up to 12 for Hbondamination ring-closure reactions of aliphatic azides to the C Hamination of toluene, and TONs up to 17 for aziridina- N-heterocycles.[24] The respective iron complex (Figure 6) À tion of styrene) the reactivity can likely be expanded by varia- provedremarkablystable, andthe catalystcan be efficiently tion of the catalyst and the azides used. recycled after the reactions.Furthermore, the catalystgives Later studies reported by the same group showedthat simi- rise to quite high catalytic turnover numbers (TONs up to 620). lar catalysts have aquite broad synthetic scopeinintramolecu- Some selectivity issues still arise from the non-discriminating lar ring-closing C Hamination reactions of (unactivated)ali- À phatic azides (Scheme 10). Alarge substrate scope was ex- plored to produce awide variety of N-heterocyclic organic ring compounds.[23] For mostofthese reactions the TONs are still rather low,but catalyst screening using differentligands is expected to improvethe catalytic efficiency.Anadditional point of attention is the selectivity of these catalysts. The key-reactive N-radical intermediate does not seem to be very discrimi- native, as it reacts with several C Hbonds within aquite À broad range of different bond dissociation enthalpies (BDEs), Figure 6. Stable,recyclable Fe-catalyst for intramolecular C Hamination. À

Chem. Eur.J.2017, 23,13819 –13829 www.chemeurj.org 13826 2017 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Concept reactivity of the Fe-nitrenoid intermediate reacting with differ- determining step, and the C Hbond activation step is thus À ent C Hbonds in acomparable range of BDEs, as observed in not rate limiting. All the available data point to azide activation À the Fe-catalysed reactions reported by Betley.Inparticular, for- being the slowest step. Experimentally determined Eyringand mation of substantial amounts of linear (Boc-protected) amine Arrhenius activation parameters are reproduced well by sup- side products is currently adisadvantage of this system. porting DFT calculations. Interestingly,kinetic studies reveal the reactiontobefirst Remarkably,inreactions with achiral porphyrin catalyst order in [Fe],zero order in [azide] and first order in [Boc2O]. enantiomerically enriched N-heterocycles are obtained (ee up This unusual and unexpected kinetic behavior is suggestive of to 46 %at808C), representing the first example of enantiose-

(rate-limiting) catalystactivation by the Boc2Oreagent for this lectiveradical-typering-closure of aliphatic azides using metal- system.The exact mechanism remains rather unclear at pres- lo-radical catalysis (Scheme 11). Furthermore, this observation ent. The underlying chemistry of the kinetic effect of Boc2Ois has mechanistic implications, strongly suggesting that the not understood and the precise nitrene-transfer mechanism ring-closing steps occur in the coordination sphere of cobalt and electronic structure of the key intermediates remainunre- (see Scheme 3). Formation of free nitrenes, as observed for solved,due to the complex electronic structure of these type some Fe and Ru systems,[26] seems rather unlikely for these of Fe(NNO)complexes (severalspin-state possibilities of the ex- Co(por)systems. change-coupled system,potentially involving Fe and the The ability of the Fe and Co catalysts, as well as the Pd and redox-active ligand and substrate). However,while the mecha- Rh systems described in this section to activate aliphatic azides nism is currentlystill under investigation, most likelyalso these is amajor advancement, both from fundamental inorganic and reactions proceed via (Fischer type) nitrene-radicalspecies or catalytic understanding as wellasfrom an organicchemistry (Schrock type) imidyl radical intermediates. viewpoint, as it provides straightforward synthetic routes to Most recently,deBruin and co-workersinvestigated the ac- the synthesis of awide variety of N-heterocycles in moderate tivity of cobalt(II) porphyrins in ring-closing C Hamination of to excellent yields (27–96%) (Figure 7). À aliphatic azides (Scheme 11).[25] Thesecatalysts are also air and moisture stable. In addition, almostnounwanted linear (Boc- protected) amine side products are formed.

Figure 7. Variety of N-heterocyclic organic products synthesized by the radical-typenitreneradical C Hamination protocols describedinthis section. À

Furthermore, the prospects of performing these reactions in an enantioselective manner bodes well forfuture studies aimed atdeveloping new synthetically useful protocols to chiral N-heterocycles based on metalloradical catalysis.

Scheme11. Nitrene radicalintermediate for enantioselective C Hamination. À Summary and Future Prospects The use of nitreneradical complexes in synthesis has rapidly Athorough experimental kinetic study combined with sup- expanded over the last decade. This development is accompa- porting computational investigations confirmed the reaction nied by amuch better understandingofthe nature of the ni- mechanism to proceed throughanitrene radicalintermediate. trene radicalspecies. Detailed computational and experimental In this case the reactionisfirst order in [Co],first order in studies have revealed that most metal-bound nitrene/imido- [azide] and zero order in [Boc O].Kinetic isotope measure- based nitrogen-centered M N·R radical species applicable in 2 À ments reveal aclear intramolecular kinetic isotope effect(KIE= catalytic synthesis are best described as one-electron-reduced 7), but no kinetic isotope effect (KIE=1) in intermolecular com- Fischertype nitreneradicalcomplexes. Besides their intriguing petitionexperiments. Hence, Boc2Oisnot involved in the rate electronic structures, such nitrene radicalcomplexes are of syn-

Chem. Eur.J.2017, 23,13819 –13829 www.chemeurj.org 13827 2017 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Concept thetic interest due to their selective catalytic radical-type reac- Conflict of interest tivity.They are key intermediates in avariety of radical-type nitrene-transfer and nitrene-insertion reactions, including aziridi- The authors declare no conflict of interest. nation, C Hamination and C Hamidation. Organicazides are À À among the most attractive nitrene precursors in this field, al- Keywords: C Hamination · electronic structure–reactivity thoughtypically pre-activated derivatives (e.g. RSO N , À 2 3 correlations · metalloradicalcatalysis · noninnocent ligands · (RO) P(=O)N ,ROC(=O)N and alike) are used to achieveeffi- 2 3 3 radicals cient and selective catalysis. More recently,challenging, non- activatedaliphatic organic azides wereadded to the palette of reagentsuseful in synthetically relevant reactions proceeding [1] L. 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