ÂŒH Bond Amination Strategies for the Synthesis Of

InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 895

doi:10.2533/chimia.2020.895 Chimia 74 (2020) 895–903 © J. Zhang, M. H. Pérez-Temprano Intramolecular C(sp3)–H Bond Amination Strategies for the Synthesis of Saturated N-containing Heterocycles

Jiayu Zhang and Mónica H. Pérez-Temprano*a

Dedicated to the memory of Prof. Kilian Muñiz

Abstract: The selective functionalization of C(sp3)–H bonds via intramolecular amination reactions represents a very attractive strategy for the construction of saturated N-containing heterocycles (SNHets). Over the past decades, the chemical community has devoted its efforts towards expanding the synthetic toolbox with the aim of facilitating access to these key fragments in a controllable, reproducible and efficient manner. This review covers selected examples of the most recent advances in intramolecular C(sp3)–N bond-forming reactions by three main approaches: (1) the Hofmann-Löffler-Freytag (HLF) reaction; (2) transition-metal-catalyzed nitrene C(sp3)–H insertion; and (3) transition-metal-catalyzed ligand-assisted C(sp3)–N bond-forming reactions via a reductive elimination step. We will discuss reactivity, selectivity and the major mechanistic insights into these transformations. Keywords: Amination · C–H functionalization · Catalysis · Cyclization · Heterocycle

Jiayu Zhang was born in Shaanxi, China, 1. Introduction in 1993. She received her BSc and MSc Saturated nitrogen-containing heterocycles (SNHets), such as degrees from Shaanxi Normal University azetidine, pyrrolidine or piperidine are among the most prevalent (2016) and Xi’an Jiaotong University molecular fragments in chemical space, especially in medicinal (2019), respectively. During her Master chemistry.[1] Their presence in druglike architectures usually en- studies, Jiayu developed different synthetic hances their biological activities, so these motifs are found in a protocols, involving radical cyclization and wide variety of top-selling pharmaceuticals (Scheme 1a). Despite cyanoalkylations. In October 2019, she their prevalence and importance, the synthesis of these cyclic joined the Muñiz group at the Institute of amines is far from trivial. In this context, intramolecular C(sp3)–N Chemical Research of Catalonia (ICIQ) in bond-forming processes represent a very efficient and practical Tarragona, Spain, to pursue her PhD.After the unexpected passing route for accessing these attractive moieties. These approaches of Prof. Muñiz in March 2020, Jiayu joined the Pérez-Temprano pose different initial challenges such as (i) the thermodynamic and group, also at ICIQ. Currently, her PhD is focused on exploring kinetic stability of the C(sp3)–H bonds or (ii) the site-selectivity new venues for promoting C–heteroatom bond-forming reactions. control of the C–H bond cleavage. Therefore, the synthetic community has devoted tremendous efforts to tackle them, provid- Mónica H. Pérez-Temprano received her ing a versatile toolkit for streamlining the construction of these European PhD degree in 2011 from the molecules.[2] In this work, we cover the principal intramolecular University of Valladolid, under the super- C(sp3)–H amination strategies. We have classified the methods vision of Prof. Espinet and Prof. Casares, into three categories (Scheme 1b): (1) the Hofmann-Löffler- in the field of organometallic chemistry. Freytag (HLF) reaction; (2) transition-metal-catalyzed nitrene In 2012, she joined the research group of C(sp3)–H insertion; and (3) transition-metal-catalyzed ligand-as- Prof. Melanie Sanford at the University of sisted C(sp3)–H activation. We will mainly focus on selected and Michigan as Post-doctoral fellow. In 2015, representative synthetic examples reported over the past 5 years, she began her independent career as Junior since different reviews have revised these reactions previously.[3] Group Leader at the Institute of Chemical We will also gather the most relevant mechanistic information on Research of Catalonia (ICIQ). Her research program is focused on the operative pathways behind each of these reactions. developing mechanism-driven tools for streamlining the development of sustainable chemical transformations. 2. Hofmann-Löffler-Freytag (HLF) Reaction Intramolecular amination of remote aliphatic C–H bonds via hydrogen atom transfer (HAT) reactions stands out as a very attractive and general procedure for generating mainly pyrrolidine derivatives.[4] These transformations are triggered by the thermal or photochemical homolysis of the N–X bond of an N-halogenated amine in acidic media.[5] The protonated aminyl radical thus generated *Correspondence: Dr. M. H. Pérez-Temprano, E-mail: [email protected] Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of participates in an intramolecular 1,5-HAT to give a carbon-centered Science and Technology, Avinguda Països Catalans 16, Tarragona 43007, Spain radical.[6] Subsequently, this species is trapped by recombination 896 CHIMIA 2020, 74, No. 11 InnovatIve tools In organIc / organometallIc chemIstry

(a) Drugs containing saturated N-heterocycles (SNHets) scaffolds such as starting materials containing acid-sensitive groups or to the synthesis of key natural product intermediates.[3b] OH O O N HO N SH N N NH Hofmann, 1885 Löffler &Freytag, 1909 Captopril Varenicline Nicotine addiction H SO ,140 oC H SO ,140 oC Procyclidine Hypertension 2 4 N 2 4 N N Br Anti-Parkinson drug then KOH N then NaOH H Br N N N Nicotine O Suárez's modification O I (1 equiv) N 2 N R1 PhI(OAc)2 (3 equiv) R1 1,5-HAT R1 −HI N R1 O NH h or ∆ N I N I N R2 O R2 R2=NO ,CN, PO(OEt) R2 H 2 Azelastine 2 2 in situ R F Paroxetine Antihistamine Heterocyclic structures synthesized by using neutral HFL conditions Antidepressant drug Cl O O gelsemicine (b) Intramolecular C(sp3)−H amination strategies for synthesizing SNHets OMe R TM-catalyzed O N O N N HLF reaction R nitrene insertion FG NH NH gelsedine Et OMe Et X N NX OMe H H n n n Scheme 3. Seminal reports on δ C(sp3)–H amination via N-centered radi- X=halogen X=H2,N2,IAr TM-catalyzed FG =electron- cals via N–X homolysis. ligand-assisted withdrawing group C(sp3)−N bond formation Inspired by these literature precedents, over the past years, dif- DG NH ferent research groups have contributed to develop more robust and straightforward cyclization events. For example, major accomplish- H n ments have been made in developing iodine-catalyzed methodolo- Scheme 1. (a) Bioactive molecules containing saturated N-containing gies. The presence of stoichiometric amounts of I tends to provide 2 heterocycles (SNHets). (b) Current synthetic strategies for accessing undesired oxidation reactions of weaker α-aminyl C–H bonds, SNHets via intramolecular C(sp3)–H amination reactions. which compete with 1,5-HAT processes, due to theAcOI homolysis- derived radicals.[11] In this context, Muñiz and co-workers designed with a caged X•, or participates in halogen atom abstraction from very elegant strategies to suppress these side-reactions. In 2015, the protonated starting material, usually to generate a δ-halogenated they reported the first example of an HLF reaction using iodine as a amine. The final cyclization proceeds via an S 2 reaction, usually catalyst (Scheme 4a). In this work, the authors used 10 mol% of I in N 2 upon treatment with a base (Scheme 2). The formation of six-mem- the presence of a hypervalent iodine oxidant, PhI(mCBA) (mCBA 2 bered rings is rare and is typically observed in systems where the = 3-chlorobenzoate).[12a] This method is applicable to the amina- formation of pyrrolidine derivatives is not viable. tion of a wide variety of primary, secondary, and tertiary C(sp3)–H The first example of the conversion of an N-halogenated amine bonds in excellent yields. From a mechanistic perspective, this reac- into a SNHet was reported in the early 1880s by Hofmann. In this tion is proposed to proceed by two interconnected catalytic cycles seminal work, the treatment of N-bromo-2-propylpiperidine with encompassing a radical chain reaction induced by visible light. In hot sulfuric acid, and subsequent basification, afforded the forma- 2017, the same group reported a dual light-activated cooperative tion of a bicyclic tertiary amine.[7] In 1909, Löffler and Freytag iodine and photoredox catalysis protocol for the synthesis of 2-aryl- extended the scope to the use of secondary amines, providing a pyrrolidines (Scheme 4b).[12b] In this work, the iodine catalyst ac- versatile method for the synthesis of pyrrolidines.[8] In the 1960s, tivates a remote C(sp3)–H bond (1,5-HAT process) under visible Corey and Wawzonek provided the first experimental evidence sup- light irradiation, while the organic photoredox catalyst (TPT) al- porting the radical reaction pathway, such as the observation of no lows the regeneration of I , after the product release. In order to 2 cyclized product in the absence of radical initiators.[9] Despite these overcome the unfavorable kinetics of 1,6-H abstraction from ami- remarkable synthetic advances, the early reports on HLF reactions nyl radical,[6a] the Muñiz group fine-tuned the reaction conditions were limited by the pre-formation of the haloamine and/or the harsh of their previous iodine-catalyzed methodologies to access six- and acidic reaction conditions. In this context, Suárez and co-workers seven-membered rings in a selective manner (Scheme 4c).[12c] In surmounted these limitations by two major breakthroughs (Scheme this report, the authors envisioned the synergistic cooperation of 3).First, the authors were capable of generating the N–halogen bond two catalytic cycles. In the first cycle, an N-centered succinimidoyl in situ from the corresponding amine in the presence of iodine and radical, generated from NBS, abstracts a hydrogen atom from the hypervalent iodine reagents. Second, the use of electron-withdraw- benzylic position of the corresponding starting material, which is ing groups (–CN, –NO , etc.) on the nitrogen atom makes the result- the weakest C–H bond. In the second one, the resulting benzylic 2 ing N-centered radical reactive enough to participate in the HAT radical abstracts an I atom from an I –NBS adduct, affording a 2 process under neutral conditions.[10] Due to these improvements, it benzyl iodide intermediate that undergoes cyclization. In a follow- has been possible to apply these methodologies to more complex up work, Muñiz explored, as a proof of principle, the use of bromine as catalyst in the intramolecular amination of C(sp3)–H bonds (Scheme 4d).[12d] It is worth noting that bromine-based procedures R2 usually provide low turnover rates, associated with catalyst deacti- N Hofmann-Löffler-Freytag Reaction X N 2 vation through different side reactions (overoxidation to unreactive H R BrV species and/or disproportionation). However, after careful opti- 1 R1 R mization of the reaction conditions, combining 20 mol% of NBu Br 4 H base and 2 equiv of mCPBA, the authors were able to develop an efficient H R2 H R2 H R2 H R2 protocol upon photochemical activation with normal daylight. In N X h or ∆ N 1,5-HAT N X N H addition, in this work it was possible to detect and unambiguously H − X H H X hydrogen radical characterize, for the first time, the N-halogenated intermediate in R1 homolysis R1 atom transfer R1 trap R1 a catalytic HLF reaction. More recently, the group accomplished Scheme 2. Hofmann-Löffler-Freytag mechanism. the formation of SNHets involving the unprecedented homolytic InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 897

cleavage of N–F bonds (Scheme 4e).[12e] This elegant copper(i/ii) (a) Herrera catalysis manifold allows the construction of both pyrrolidine and Single hydrogen atom Multiple hydrogen piperidine cores, under uniform reaction conditions using fluori- transfer (SHAT) atom tansfer (MHAT) PhI(OAc)2 PhI(OAc)2,(5-7 mmol) nated starting materials. R R R I2,(5-7 mmol) I2,(0.15 M) O N DCE (0.1 M) NH NaHCO3 (100%) N DCE (0.03 M) (a) (b) Ts portionwise addition Ts Ts R3 R3 R2 I2 (2.5 mol%) I2 (5 mol%) R2 of PhI(OAc)2 slow addition of I2 PhI(mCBA)2 (1 equiv) TPT (1 mol%) 1 1 N R DCE, rt HFIP/DCE N R Selected Substrates R4 visible light blue LED, rt R4 NHTs NHTs NHTs 32 examples H 2 3 20 examples R R H OTs 65−99% yield N 60−96% yield R1 R4 SHAT: 61% SHAT: 65% SHAT: 72% 3 MHAT: 77% MHAT: 78% MHAT: 88% R2 R I2 (5 mol%) Bu4NBr (20 mol%) R2 R3 NBS (2 equiv) mCPBA (2 equiv) (b) Nagib 1 1 DCE, rt MeCN, rt R 2 N R N NaI (4 equiv) R visible light H R4 R4 (c) (d) H PhI(OAc)2 (4 equiv) 30 examples 20 examples N 1 1 3 N R 36−81% yield 38−98% yield R R2 R MeCN, visible light 3 (e) R 2 2 X X R1 R X Ar 1% TpiPr2Cu(NCMe) R R2 or [O] N n Ar I Toluene, 100 ºC, 24 h N N Ar I I2 I3 F H H −HF R1 R1 iodide transient iodine triiodide (oxidized (reduces (sequesters in situ) byproducts) iodine) Proposed N mechanism for 4b Ts Ts Selected Examples Ph N H Ts h 2TPT* I N Me O 2HI H N Ph 2TPT Ph C PG N H2O A Ph N N 2TPT h 93% (PG =Ts) Ts Ts 1/2 O HI B Ts 2 I2 N Ts +2H+ 87% (PG =Ns) 85% (1.2:1) 69% 79% H2O 92% (PG =Ms) Ph − TPT Ts BF4 HOI N Ph Initiation Scheme 5. Alternative approaches for overcoming undesired I - I 2 I mediated reactions. Ph O Ph sm H2O Ph

Proposed mechanism for 4c NHTs O N O NBS In 2015, Yu and co-workers uncovered a novel protocol for Br I2 HBr the δ-iodo-γ-lactamization of aliphatic amides by reaction with

NHTs I N-iodosuccinimide (NIS) and trimethyl azide (TMSN ), via 1,5- O N O 3 I IBr [15] Br HI and 1,6-abstractions (Scheme 6). The proposed mechanism, for this unexpected transformation, involves the iodination of the I N Ph Ts starting amide by treatment with NIS to give an N–I intermedi- I NHTs O N O ate that, following the Suárez-HLF method, provides the corre- H I sponding lactam. Subsequently, an azide radical generated in situ sm O O N IBr promotes a β-C−N bond scission, to afford a terminal olefin. The h -Br final iodinated product is obtained after radical 5-exo-trig cycli- NBS zation and recombination with an iodo free radical. The authors Scheme 4. Iodine-catalyzed HLF approaches by the Muñiz group. exploited this reactivity not only to synthesize a wide variety of iodolactams, but also to subsequently diversify them into 1,2-amino alcohol and allylic amide derivatives, some of them closely At the same time that Muñiz reported the first catalytic HFL related to drug analogs, such as vigabatrin. methodology, Herrera and co-workers described the chemose- Over the past years, the use of photocatalyst and the imple- lective amination of primary C(sp3)–H bonds by using sulfon- mentation of electrochemical strategies have opened innovative amides as N-centered radical precursors (Scheme 5a).[13] This and appealing avenues in the context of HFL transformations. In work showed the potential of these reactions beyond traditional 2015,Yu reported a visible light photoredox-mediated protocol for weak aliphatic C–H bonds (benzylic, tertiary, α-oxy). In addition, it also demonstrated that it is possible to obtain pyrrolidine or Me 2-pyrrolidinone derivatives selectively, via single or multiple HAT H nBuLi (1.05 equiv) N PG processes (SHAT or MHAT) respectively, by controlling the addi- THF (0.1 M) 3 1 1 O H R R H TMSN3 (4 equiv) R -78 oCtort O tion of oxidant. Therefore, this work offers an alternative to avoid H N NIS (4 equiv) 91 %(PG1), 93% (PG2) PG N DCE, 100 oC, 14 h, air 2 PG undesirable I -mediated oxidations. In this regard, in 2016, Nagib R4 R2 O R PG 3 I HN 2 R NaOMe (5 equiv) 1 2 CF3 and co-workers reported another strategy to circumvent the side- PG F PG R4 MeO OMe MeOH (0.1 M), rt F C F Me reactions associated to the employment of excess of I .[14] The 3 O 2 82% F authors described a triiodide-mediated amination strategy where O S F I – acts as a I reservoir (Scheme 5b). Triiodide is generated in O 3 2 Selected Examples situ by the oxidation of NaI to I , which in the presence of excess 2 I O – – of I forms I . This dynamic equilibrium reduces the amount of O O O 3 N I O N N N N PG1 available I in the reaction media, attenuating the negative effect PG2 Me PG2 PG2 2 PG2 I of the excess of AcOI in solution. Nagib applied this strategy to a 72% 70% 72% 71% 44% wide variety of scaffolds containing biologically relevant motifs, Scheme 6. γ,δ,ε-C(sp3)−H functionalization through directed radical such as esters, ketones and arenes. H-abstraction. 898 CHIMIA 2020, 74, No. 11 InnovatIve tools In organIc / organometallIc chemIstry

the remote amination of N-chlorosulfonamides (NCSs) (Scheme tems, ranging from catalysts based on noble metals, such as Rh 7a).[16] This methodology proceeds with good to excellent yields or Ru,[22] to more sustainable ones, such as Mn or Fe. Here, we at room temperature, under mildly basic conditions, and using will highlight a selection of the most relevant works over the past very low catalyst loading (0.1 mol%) of Ir(ppy) (dtbbpy)PF . In few years, paying special attention to first-row-transition-metal- 2 6 this transformation, the nitrogen-centered radical is proposed to catalyzed methodologies. be generated through an oxidative quenching of the excited state III* Ir with the corresponding NCS. The authors demonstrated the 1 concerted R synthetic potential of this approach by (i) scaling up the reaction C−H insertion H [M] N to gram scale and (ii) applying it to the late-stage functionalization R [M] N [M] of complex and biologically relevant N-containing compounds, [M] R R N M N + + R 1 1 such as (–)-cis-myrtanylamine or (+)-dehydroabietylamine. Nitrene Metal Nitrenoid R H R NHR Another major breakthrough in the field is the use of electric Highly Reactive Reactivity & H PoorSelectivity Selectivity Modulated [M] N stepwise radical current as reagent, which has the potential of obviating the need R HAA R1 rebound for metal catalysts, halogenated reagents, and/or stoichiometric TraditionalEmployed Nitrenoid Sources O O O Y O O O O O amounts of chemical oxidants. For example, in 2018 Lei and co- S S S O NH X NH RN N workers disclosed an electrochemical oxidatively induced amina- Precursor 2 O NH2 X NH2 2 O NHOX 3 3 tion of primary, secondary and tertiary C(sp )−H bonds (Scheme X=NR, Y=O, NR X=NR, O-NR X=Ts,Ms [17] X=O,Y=NR 7b). This site-selective electrosynthetic protocol enables the Is an external oxidant YesYes YesYes No No access to a wide variety of pyrrolidine derivatives and is compat- required? ible with different N-protecting groups. A plausible mechanism heterocycle ring-size n 5or6 55 5or6 5 5or6 for this electro-oxidative HLF reaction involves the generation of the aminyl radical by a single-electron oxidation at the anode. Scheme 8. Overview of C–H amination reactions via intramolecular ni- After 1,5-HAT, the corresponding C-centered radical undergoes trene insertion. another anodic oxidation to afford a carbocation intermediate that provides the desired product after nucleophilic attack by the sul- fonamidyl group. Recently, Stahl and co-workers have combined In the context of direct intramolecular C(sp3)–H amination photo- and electrochemical strategies to promote the intramolecu- via nitrenoid insertion, one of the most efficient and robust cata- lar amination of C(sp3)−H bonds (Scheme 7c).[18] A key feature of lytic systems is metalloporphyrin complexes (MPC), a biomi- this iodide-mediated process is its broad functional group compat- metic model of the cytochrome P450.[2b,23] These systems present ibility due to the combination of low applied potentials and the unique ligand environment and metal coordination modes, often photochemically induced cleavage of intermediate N–I bonds. leading to high selectivity and turnover number (TON). This is associated with longer catalyst lifetime and/or the minimization of side-reactions due to the absence of vacant coordination sites. (a) PC (0.1 mol%) (b) C(+) Pt(-) R2 X Na2HPO4,CH3CN H (15 mA, 5.6 F/mol) X Since the seminal report by Che, in 2002, of a direct intramo- white LED strips, rt H nBu NOAc, (1.0 equiv) 1 N 4 1 +H 3 N R 1 3 N R 2 lecular C(sp )–H amidation with ruthenium porphyrins, by the then NaOH (s), rt R R2 R DCE/HFIP,rt R3 R3 (PC =[Ir(ppy)2(dtbbpy)]PF6) reaction of sulfamate esters with PhI(OAc) ,[24a] this group and 19 examples (c) TBAI (10 mol%) 35 examples 2 traces−94% yield graphite II Pt 35−98% yield KPF6 (0.1 M) others have exploited different porphyrin-based catalytic systems (Yu, 2015) CFL (20 W) (Lei, 2018) CH3CN/TFE (17:1), rt for the synthesis of SNHets (Scheme 9). The current state of the R2 X 9examples art, especially involving 3d metalloradical catalysis, shows how 44−82% yield 1 tailor-made changes in the porphyrin system enhance the effi- N R (Stahl, 2019) R3 ciency, regio- and stereoselectivity, enabling their application to Selected Examples the late-stage functionalization of complex scaffolds. For exam- H Ph O Me OTBS ple, in 2018, Che disclosed an iron(iii)-porphyrin system bearing H N Ph R N III N SO2Ph axial N-heterocyclic carbene ligands, [Fe (TDCPP)(IMe) ] (10 2 Ts Ts O S H 2 N Me [24b] 83% (a) 34% (R =Ph, a) N 82% (c) mol%), for the intramolecular amination of alkyl azides. In 93% (b) 90% (R =Ph, b) Ts 61% (b) 86% (a) NTs this work, the authors achieved the selective functionalization of 71% (c) 71% (R =H,c) 62% (a) d.r.>20:1 OMe benzylic, allylic, tertiary, secondary, and even primary C(sp3)–H Scheme 7. Visible light- and electrochemical oxidation-induced remote bonds, in good to excellent yields, under thermal (Scheme 9a) intramolecular C(sp3)–H aminations. or micro-wave irradiation conditions (Scheme 9b). This protocol was applied to the preparation of relevant alkaloids, such as leelamine derivatives and nornicotine. In a follow-up paper, the 3. Transition-Metal-catalyzed Nitrene C(sp3)–H group was capable of reducing the catalyst loading to just 3 mol% Insertion Reactions for the synthesis of 5- and 6-membered ring heterocycles using a Since the seminal example reported by Breslow in the early biocompatible iron complex, [FeIII(TF DMAP)Cl] (TF DMAP = 4 4 1980s,[19] TM-catalyzed intramolecular nitrene transfer processes meso-tetrakis(o,o,m,m-tetrafluoro-p-(dimethylamino)phenil)por- have become a very powerful and useful method for the synthesis phyrinato dianion) (Scheme 9c).[24c] This work demonstrated the of saturated N-containing heterocycles.[2d,20] The proposed mech- profound effect of ligand on metalloporphyrin catalysis (MPC). anisms involve the formation of a metal–nitrenoid species which Another first-row metal that has been widely exploited in MPC is responsible for the subsequent cleavage of the C(sp3)–H bond. is cobalt. Since 2007, Zhang and co-workers have reported mul- This step can occur via a concerted C–H insertion, preferred for tiple CoII porphyrin-catalyzed examples of intramolecular amina- singlet species, or a stepwise hydrogen atom abstraction (HAA), tion of aliphatic C–H bonds using organic azides as nitrenoid pre- usually followed by triplet intermediates (Scheme 8). Since the cursors.[23] In this regard, their recent advances on the use of chi- pioneering finding that iminoiodinanes (ArSO N=IPh) could ral D -symmetric cobalt(ii)-amidoporphyrins for controlling the 2 2 serve as nitrene precursors,[21] the field has evolved to the use of enantioselectivity of 1,5- and 1,6-radical processes is particularly readily available nitrogen sources such as azides, sulfonamides, noteworthy (Scheme 10).[25] Very recently, the authors developed or carbamates.[20] The synthetic methods developed over the past a new generation of chiral ligands to accomplish enantiodivergent decades comprise a wide variety of transition-metal-based sys- radical 1,5-C(sp3)–H amination reactions of sulfamoyl azides. In InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 899

Scheme 9. Iron(III)-porphyrin- (a) FeIII(TDCPP)(IMe) (10 mol%) 2 catalyzed intramolecular C(sp3)–H Boc2O(1equiv), PhMe,reflux Me NN 115 oC, Ar Me I amination of alkyl azides. n-1 Ar H III 4 R1 N3 (b) Fe (TDCPP)(IMe)2 (10 mol%) R R2 N N n Ar R4 Boc O(1equiv), microwave (50 W) R3 N 1 Fe Ar 2 3 2 R N R R 140 oC, air Boc N Ar (c) [FeIII(TF DMAP)Cl] (3 mol%) Me Me 4 NN Boc2O(1.2 equiv), DCE, reflux Ar =2,6-Cl2C6H3 Selected Examples FeIII(TDCPP)(IMe) Me 2 74% (a) 75% (a) 63% (a) Cl N Ph 90% (b) N 88% (b) 86% (b) BocN H Me N F F 2 F 66% (c) 82% (c) NBoc 62% (c) F NMe2 Boc Boc Me F N F F F N Fe N 65% (a) 84% (a) F F Me N N N 85% (b) N 76% (c) F F Ph F F Boc N Boc Boc Ph Me Me Me2N F F NMe2 78% (c) 78% (a) Fe(TF4DMAP)Cl this work, the authors fine-tuned the cavity size and environment In 2015, White and co-workers reported a very remarkable of the cobalt-amidoporphyrin complexes by modifying the length manganese-based catalyst, containing a nitrogen porphyrin ana- of the distal alkyl bridges along with the nature of the remote logue, for the synthesis of dioxooxathiazinanes (Scheme 11).[27] nonchiral substituents.[25c] Based on detailed mechanistic stud- This system exhibits an exquisite chemoselectivity towards the ies performed by the group, these cobalt-catalyzed transforma- amination of strong primary C–H bonds over weaker secondary/ tions are proposed to occur through a stepwise radical reaction tertiary C–H bonds, surmounting one of the major historical limi- pathway, wherein a α-CoIII-aminyl radical intermediate cleaves tations associated with C(sp3)–H amination reactions. This proto- the aliphatic C–H bond by HAA. Besides Zhang, de Bruin and col features a broad functional group tolerance, enabling the late- co-workers have also explored the activity of CoII porphyrins for stage functionalization of complex architectures. Interestingly, constructing saturated heterocycles from aliphatic azides.[26] In based on different mechanistic studies, the authors proposed an this work, the authors used di-tert-butyldicarbonate (Boc O) to unusual reaction pathway for the nitrene transfer, which lies be- 2 enhance the reaction rate by preventing the competitive coordina- tween a concerted insertion, usually operative for Rh (II) catalytic 2 tion of the final amine product. systems, and the stepwise HAA/rebound process, proposed for iron(iii) complexes. (Scheme 11) Apart from synthetic metalloporphyrins, over the past few

R R years, the implementation of directed evolution strategies for the O O 3 2 S Me intramolecular amination of C(sp )–H bonds has opened very in- R N NH Me [Co(P1)] (2 mol%) + N H H 1 2 teresting avenues (Scheme 12). Dawson and Breslow reported, MTBE, rt, 48 h R (a) H O N2,4ÅMS O O for the first time in 1985, the participation of microsomal cyto- 24 examples NH O O HN 3 H H O 72−95% yield chrome P450 in intramolecular C(sp )–H amination reactions.[28] S 64−98% ee N N R1 X Co n N3 However, it was not until very recently that Arnold and Fasan 2 N N X=NR ,CH2 NH O HN revisited, independently, the catalytic potential of mutated cy- (b) O H O [Co(P2)] (2 mol%) O N O tochromes (P411 and P450 , respectively) in the synthesis H + N BM3 BM3 CHCl ,N 50 ºC, 48 h O S 2 H 3 2, R H of benzosultam derivatives (Schemes 12a and 12b).[29a,30a] These Me 14 examples H works display high enantioselectivities along with high turnover 62−98% yield R 7−99% ee R [Co(P1)]: R=H; [Co(P2)]: R=Me numbers with catalyst loadings lower than 0.5 mol%. Since then, Selected Examples both groups have showcased the tremendous potential of biocata- Method a Method b H 3 O H lytic nitrenoid C(sp )–H insertions. For example, Arnold has em- O O O O N S 93% yield, S S O S Bn N NH Bn N NH 92% ee O ployed two different engineered variants of P450 to provide di- BM3 Ph C H S O 6 13 H vergent reactivity patterns from sulfonyl azide substrates (Scheme H H O N H NH S 93% yield, 90% ee 88% yield, 89% ee O H R3 R O 92% yield, 93% ee O 88% yield, 95% ee Bn S tBu N NH H (R =OMe) 3 O H [Mn(tBuPc)]Cl (5 mol%) tBu 94% yield, 95% ee (R =H) N 94% yield, 99% ee O O 3 S 93% yield, 92% ee (R =Me) O (R =CF3) AgSbF (5 mol%) H O H OSO2NH2 6 S 3 89% yield, 93% ee 1 N N − 93% yield, 95% ee (R =OMe) R PhI(OPiv)2 (2 equiv) HN SbF6 (R =NO ) Mn 92% yield, 98% ee (R3 =F) 62% yield, 80% ee 2 R2 R3 1 R 3 N N 4Å MS, 9:1 C6H6/MeCN R R2 O O O O rt, 8-24 h tBu Method c O O S 2 t R2 S [Co(P3)] R S [Co(P4)] R [Mn(tBuPc)]SbF Bu N NH 1 N HN N 6 N3 H H 2 Selected Examples R1 R R1 (R) H H (S) O O more than 20 substrates O O O O O O S O S O O S O S HN O HN O O H HN O S HN O H n O HN O O Ph H H Ar N t O MeO Bu O NPhth TMS NH HN 79% 64% 90% 69% Ph 63% N N Ar = Ar = H >20:1 d.r. >20:1 d.r. oxaprozin derivative Co n=3 n=2 O N N O 2º tBu MeO betulinic acid derivative NH HN O S H [Co(P3)] O [Co(P4)] site- and diastereoselective O HN H H Ar H amination of aprimary C(sp3)−H 1º H H bond in the presence of an H O H 76% O OMe accessible 2º position O n O O

Scheme 10. Cobalt(II)-based metalloradical approaches for intramolecu- Scheme 11. Manganese-catalyzed intramolecular C(sp3)–H amination of lar heterocyclization of sulfamoyl and sulfonyl azides. sulfamate esters. 900 CHIMIA 2020, 74, No. 11 InnovatIve tools In organIc / organometallIc chemIstry

12c).[29b] Fasan has also reported the efficient C(sp3)–H activation amination involving a nitrene transfer pathway. This protocol al- and subsequent cyclization of carbonazidate scaffolds to afford lows the access to γ-alkynyl γ-aminoalcohols with excellent yields oxazolidinones by the involvement of a nitrene-heme intermedi- and enantioselectivity (90–99% ee) (Scheme 13c).[35] DFT calcu- ate (Scheme 12d).[30b] More recently, the same group has reported lations support that the structural modifications introduced into the a mechanism-driven approach to rationally design and develop BOX-type ligand facilitate the differentiation between prochiral a series of P450 variants for increasing the efficiency of in- protons during the enantio-determining HAT step. BM3 tramolecular C(sp3)–H aminations. Currently, these engineered catalysts are among the most active nitrene tranfererases reported Betley [30c] AdF C F to date, with over 10,000 turnovers. Interestingly, Hartwig and ( L)Ni(py) (1−10 mol%) R2 6 5 C D 25−80 ºC, 2−48 h N 1 co-workers reported in 2017 that while a Ir-porphyrin was inert (a) 6 6, R N N in the intramolecular amination of sulfonyl azides, artificial P450 Boc Ni 26 examples py metalloenzymes containing an abiological Ir(Me) mesoporphyrin R2 N3 35−95% yield AdF IX cofactor provide yields up to 98% with good turnover (approx. R1 ( L)Ni(py) 2 t 200 TON).[31] This work demonstrates the potential of engineered (b) Boc2O(1equiv) R Bu [FeIII(NNOISQ)Cl ](5mol%) tBu 2 O Cl biocatalysts versus more traditional porphyrin-based systems. 1 C H /toluene,100 oC, 24 h N R N Fe 6 6 Cl vander Vlugt/de Bruin Boc N 9examples (a) Arnold 39−96% yield [FeIII(NNOISQ)] P411BM3 (0.1 mol%) 1 Selected Examples R O DMSO, Kpi (pH 8.0) R1 Method aMethod b O O O 2 S rt, 24 h 2 R R S Me N3 NH NTs N Ph NBoc 46% 5 H R R5 N 72% 95% 3 R3 R Boc R4 R P450 (0.2 mol%) R4 Boc Ph O Ph Kpi (pH 8.0), rt, 16 h O 95% yield (R =H) Ph N (b) Fasan 94% yield (R =F) Me Ph N N 51% Selected Examples 82% yield (R =Br) Boc 90% O Boc Method aMethod b 89%, 4.3:1dr Boc MeO2C O O O O O O O NH2 (c) Schomaker O S S O S 83%, 90% ee (R =Me) NH S NH AgClO (5 mol%) NH 4 HN O 77%, 95% ee (R = iPr) NH H O O Min-BOX (2.5 mol%) 97%, 96% ee (R = tBu) TTN: 26 TTN: 36 TTN: 20;66% ee TTN: 388 PhIO (2 equiv), 4 Å MS 84%, 96% ee (R =TMS) (P450 #139-3) (P450(FL#62)) o R CH2Cl2,-10 C R 19 examples 96%, 93% ee (R =Ph) 51−96% yield (c) Arnold 89−99% ee O O O O O O O 2 O R S R2 S P411 R2 S P411 NH BM3 BM3 NH N N t t Variant A N3 Variant B Bu Bu R1 R1 R1 Selected Examples Min-BOX O O O O O O t t O O nPr nBu Bu Bu nPr S S nBu S S NH NH NH NH Scheme 13. TM-catalyzed intramolecular amination.

Et n 99% ee 99% ee Et 99% ee 99% ee Pr Variant A TTN: 361; 97:3 TTN: 178;90:10 Variant B TTN: 181; 30:70 TTN: 128;30:97 Following an alternative strategy, Meggers and co-workers (d) Fasan O have accomplished very interesting advances in the stereocon- R1 P450 (0.05 mol%) 12 examples 3 O N3 O NH trolled insertion of metal nitrenoids into C(sp )–H bonds by the R2 up to 100 TONs KPi (pH 8.0) 1 [36a–c] O rt, 16 h R utilization of chiral-at-metal catalysts (Scheme 14). Although R2 all the ligands are achiral, the stereogenicity of the metal center Scheme 12. Enantioselective intramolecular C(sp3)–H amination cata- is responsible for the overall helical chirality of the catalyst. The lyzed by engineered cytochrome. authors have demonstrated the potential of different bis(pyridyl- NHC) ruthenium complexes for accessing chiral Boc-protected imidazolidine-4-ones, γ-lactams and cyclic ureas in excellent Over the past 5 years, transition metal-based systems bearing yields and enantioselectivities. In the synthesis of 2-aryl pyrro- other types of ligands have also participated in intramolecular ni- lidines, Meggers and co-workers proposed a dual ruthenium and trene transfer processes, exhibiting very interesting reactivity pat- phosphine catalysis, where an iminophosphorane intermediate is terns and broad substrate scope. Inspired by previous iron-based responsible for transferring the nitrene unit to the metal center.[36d] systems,[32a] Betley and co-workers have reported the employment One of the major synthetic challenges in intramolecular TM- of nickel-dipyrrin complexes as catalysts in the intramolecular catalyzed C(sp3)–H amination reactions involving nitrene transfer ring-closing C–H bond amination of unactivated aliphatic azides is the construction of γ-lactams. The proposed key carbonyl nitrene (Scheme 13a).[32b] This procedure proceeds under mild reac- intermediates usually participate in competing Curtius-type rear- tion conditions, with high chemoselectivity and broad substrate rangements, resulting in the undesired formation of isocyanates. In scope. Van der Vlugt and de Bruin have also demonstrated the order to suppress this side-reaction, in 2018, Chang and co-workers participation of an air-stable iron(iii) complex, containing a re- engineered a series of Cp*IrIII complexes containing electron-do- dox-active pyridine-aminophenol ligand in intramolecular nitrene nating auxiliary bidentate ligands, to promote the intramolecular transfer events (Scheme 13b).[33] This system catalyzes efficient- amination by lowering the C–H insertion barrier.[37a] Combining ly the synthesis of pyrrolidine and piperidine derivatives using these catalysts with the use of 1,4,2-dioxazol-5-ones as nitrene pre- alkyl azides as substrates with high turnover numbers ( >600). cursors, the authors successfully achieved the synthesis of a wide Plieker and co-workers have applied a nucleophilic Fe complex, variety of racemic γ-lactams (Scheme 15a). This protocol was ap- Bu N[Fe(CO) (NO)], to the construction of substituted indoline plied to the activation of primary, secondary and tertiary C(sp3)−H 4 3 and tetrahydroquinoline derivatives.[34] Schomaker and co-workers bonds in good yields, along with the late-stage functionalization have designed novel bis(oxazoline) (BOX) ligands for achieving of complex scaffolds such as high-value amino acids. The same a general silver-catalyzed intramolecular asymmetric C(sp3)−H type of lactam products can be obtained by the photosensitization InnovatIve tools In organIc / organometallIc chemIstry CHIMIA 2020, 74, No. 11 901

metalation-deprotonation pathway, the resulting metallacycle can R O O participate in a wide variety of bond-forming processes after re- N3 1Ru-a (1 mol%) 1 21 examples (PF ) R1 N R N 31−95% yield N N 6 2 Boc O(1.2 equiv) acting with the corresponding coupling partner (Scheme 16a). In 2 N 23−95% ee (S) N R2 85 oC, 48 h R2 Mes NCMe Boc Ru 3 Mes N the context of C(sp )–H amination processes, one of the major NCMe N N N synthetic challenges associated with this approach is the suscep- R H O 12Ru (1 mol%) 17 examples R N O 14−95% yield O 1,2-dichlorobenzene R tibility of metal–alkyl intermediates to undergo β-hydride elimi- up to 96:4 e.r O o 3 4 C, 30 h 1Ru-a (R =SiMe3) nation instead of C(sp )–N reductive elimination.[3e] However, in- 1Ru-b (R = p-C6H4CF3) O O spired by seminal stoichiometric examples of oxidatively-induced 1 2 24 examples R OBz 1Ru-a (0.05-1 mol%) H R Ph N N N N 29−99% yield 3 K CO (3 equiv) (BF4)2 intramolecular C(sp )–N bond-forming reactions from Hillhouse 2 H 2 3 88−99% ee (S) Me R CH Cl ,rt, 16 h N [40] 2 2 R1 N tBu (Scheme 16b), different research groups have surmounted this C N Ph Ru limitation and developed different catalytic procedures for the 1 -b (1 mol%) Ru Boc N 20 examples N N3 P(4-F-Ph)3 synthesis of N-containing heterocycles. Ar N 15−57% yield C Boc O(1equiv) tBu 2 Ar 77−99% ee 1,2-dichlorobenzene N 95 ºC 2Ru Me (a) DG DG H Scheme 14. Enantioselective ring-closing C(sp3)–H amination using cat. [TM] chiral-at-metal ruthenium catalysts.

C−H metalation DG of hydroxamates using 5 mol% of Ru(bpy) (PF ) .[37b] In 2019, the [TM] 3 6 2 group accomplished the asymmetric C(sp3)–H amination of dioxa- key reactive zoles, with excellent yields and enantioselectivities, by developing intermediates a second generation of iridacycles bearing chiral diamine scaffolds (b) 1 R R1 (Scheme 15b).[37c] Computational studies suggest that the exqui- N Ni(bpy) oxidant, C6H6,rt N site stereoselectivity displayed is associated with an intramolecular 69−87% yield oxidant =O2,I2, R hydrogen-bonding interaction between the carbonyl of the starting R R + R [(AcCp)2Fe] 1 material and the NH of the chiral ligand. A comparable methodolo- 1Nia =H(R), Tol(R ) 1 gy was simultaneously reported byYu, using cymene-ruthenium(ii) 1Nib =Me(R), Ph (R ) complexes with chelating (R,R)-diphenyl-1,2-ethylenediamine Scheme 16. (a) Mechanism of ligand-assisted TM-catalyzed C–H activa- (dpen) ligands.[38] Subsequently, the Chang group extended the tion. (b) Early examples of TM-mediated intramolecular C(sp3)–N reduc- application of their protocols to the synthesis of chiral γ-alkyl-γ- tive elimination. lactams, by using Cp*Ir-based systems containing α-amino-acid- based chiral ligands (Scheme 15c).[37d] The employment of analogous Cp*CoIII(LX) catalysts containing 8-hydroxyquinoline ligands In this context, over the past few years, the use of bidentate has enabled the formation of 5- and 6-membered cyclic carbamates directing groups has emerged as a very powerful tool for develop- using azidoformates as the nitrenoid source (Scheme 15d).[37e] ing TM-catalyzed intramolecular oxidative C(sp3)–H amination protocols. Taking advantage of the effective chelating behavior of the picolinamide (PA) group (Scheme 17a), Daugulis and O R1 O O Chen reported, independently, access to azetidine and pyrro- (a) O (c) R O II/IV N N3 lidine derivatives, via a Pd catalytic cycle, using PhI(OAc) as R2 H 2 1Ir-Cl (2-10 mol%) H H 3Ir-Cl (2.5 mol%) [41,42] F 1 -Cl (2 mol%) oxidant. Subsequently, Wu applied an analogous methodol- NaBAr 4 (10 mol%) HFIP/H2O(1:2) Co (b) (d) F DCM, 12 h 2Ir-Cl (5 mol%) or HFIP NaBAr 4 (2 mol%) F ogy for the construction of polycyclic nitrogen-containing hetero- NaBAr 4 (5 mol%) HFIP -CO2 20 ºC, 1-2 h 3 TCE, 35 ºC, 24 h 60 ºC, 12 h cycles by activating γ- or δ-C(sp )–H bonds.[43] 8-Aminoquinoline O O O O has also demonstrated its versatility as a bidentate directing group O NH NH HN NH in a wide variety of TM-catalyzed intramolecular C(sp3)–H ami- 1 R R [44] H R R2 nations (Scheme 17b), not only using palladium catalysts, >45examples >30examples >30examples >10examples up to 99% yield up to 98% yield up to 95% yield up to 99% yield but also those based on earth-abundant metals such as cobalt, up to 99:1 e.r. up to 99.8:0.2 e.r. nickel and copper.[45,46] Particularly interesting is the ability of these first-row metal-catalyzed protocols to access azetidinone 3 -Cl Ir derivatives. 1Ir-Cl Ir Ir 1 -Cl Cl Ts N Co N Cl N Ir HN N Co Despite the utility exhibited by these bidentate DGs, they pres- O N N Cl O Cl ent an obvious disadvantage: the necessity for extra synthetic steps Meoc PhthN Cl for their installation and removal. To address this limitation, Gaunt OMe 2 -Cl Cl Ir Ar Ar and co-workers have exploited the coordinating capability of the nitrogen lone pair to promote the intramolecular cyclization of alkyl Scheme 15. Cp*MIII-catalyzed intramolecular C(sp3)–H amidation pro- amines in the absence of additional chelating moieties (Scheme 18). cesses. In 2014, the group reported the first Pd-catalyzed intramolecular C(sp3)–H amination to form strained heterocycles using 2,2,6,6-tet- ramethylpiperidine derivatives as substrates.[47a] Following this 4. Transition-metal-catalyzed C(sp3)–H Activation pioneering work, in 2017, Gaunt and co-workers reported the Over the past decades, ligand-assisted transition-metal-cat- enantioselective version of the aziridination protocol.[47b] The au- alyzed C–H functionalization reactions have become a corner- thors achieved high enantioselective ratios by using chiral BINOL- stone of modern synthetic organic chemistry.[39] These strategies derived phosphoric acid ligands. The same group disclosed in allow control of the site-selectivity of C–H bond-cleavage by the 2018 the synthesis of azetidines by replacing PhI(OAc) with the 2 employment of directing groups (DGs). These chelating moieties combination of benzidazole tosylate and AgOAc.[47c] This reac- are usually Lewis basic groups present in the substrates that bind tion shows broad functional group tolerance, which enabled the the metal center, bringing into close proximity a specific C–H application of this protocol to enantioenrich substrates derived bond. After the initial C–H activation step, often via a concerted from amino alcohols. 902 CHIMIA 2020, 74, No. 11 InnovatIve tools In organIc / organometallIc chemIstry

(a) Intramolecular amidation of sustrates containing picolinamide as DG there are still unsolved challenges. The use of simple and readily O available aliphatic amines as starting materials, without the ne- R1 N cessity of converting them into more reactive nitrogen sources, H N H R Pd(OAc)2 (10 mol%) remains extremely limited. In addition, even now it is rare to find Pd(OAc)2 (5 mol%) picolinamide AgOAc (3 equiv) directing group (PA) synthetic protocols that allow the synthesis of highly substituted PhI(OAc)2 (2 equiv) C6F5I(10 equiv) 80-120 oC, PhMe, 24 h BQ (0.5 equiv) SNHets or the formation of usually hindered products, such as Pd(OAc) (5 mol%) AcOH, (2 equiv) 2 Na3PO4 (3 equiv) o three-, four- or seven-membered heterocycles. Further explora- PhI(OAc)2 (2.5 equiv) PhMe, Ar,110 C TCE, mv,130 oC, 4h tions towards tackling these, and other synthetic difficulties, will PA PA 1 N 1, 2 R R undoubtedly provoke ground-breaking advances in the field. R N R1 N R1 R PA Daugulis,2012 Chen,2012 Wu,2017 Acknowledgements 14 examples, 12 examples 34 examples We thank the CERCA Programme/Generalitat de Catalunya and the up to 88% yield up to 91% yield up to 94% yield Spanish Ministry of Economy, Industry and Competitiveness (MINECO: (b) Intramolecular amidation of sustrates containing quinolinamide as DG CTQ2016-79942-P, AIE/FEDER, EU) for the financial support. J. Z. O Q Pd(OAc)2 (5 mol%) Cu(OAc)2 (20 mol%) Q O thanks the China Scholarship Council for the predoctoral fellowship. N PhI(OAc)2 (2.5 equiv) N Ag2CO3 (3 equiv) N R O 1 R1 PhMe, Ar,24h H R o 1 N DCE, 140 C, 24 h R 70-110 oC H R R Chen,2013 quinolinamide Kanai,2014 Received: October 5, 2020 19 examples directing group (Q) 18 examples up to 94% yield up to 93% yield CuCl (20 mol%) [Ni(DME)2I2](10 mol%) [1] a) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103, 893; b) Q O duroquinine TEMPO (3 equiv) Q O V. Froidevaux, C. Negrell, S. Caillol, J.-P. Pascault, B. Boutevin, Chem. Rev. N PhCCO2Na K2HPO4,TBAI N 2016, 116, 14181; c) R. Tohme, N. Darwiche, H. Gali-Muhtasib, Molecules o-xylene, 160 oC nPrCN/PhCN, 150 oC Me R 2011, 16, 9665; d) D. O’Hagan, Nat. Prod. Rep. 2000, 17, 435. R Bn Co(OAc)2 (10 mol%) [2] a) A. Trowbridge, S. M. Walton, M. J. Gaunt, Chem. Rev. 2020, 120, 2613; b) Ge,2014 Ge,2014 Ag2CO3 (2.5equiv) 20 examples 27 examples R. Singh, A. Mukherjee, ACS Catal. 2019, 9, 3604; c) M. Zhang, Q. Wang, PhCO2Na up to 94% yield PhCl, 150 oC up to 93% yield Y. Peng, Z, Chen, C. Wan, J. Chen, Y. Zhao, R. Zhang, A. Q. Zhang, Chem. Q O Commun. 2019, 55, 13048; d) H. Hayashi, T. Uchida, Eur. J. Org. Chem. Ge,2015 N 2020, 2020, 909; e) C. Le,Y. Liang, R. W. Evans, X. Li, D. W. C. MacMillan, 41 examples up to 90% yirld Me Nature 2017, 547, 79. R Bn [3] a) S. Minakata, Acc. Chem. Res. 2009, 42, 1172; b) J. L. Jeffrey, R. Sarpong, Scheme 17. Intramolecular TM-catalyzed C(sp3)–N bond-forming reac- Chem. Sci. 2013, 4, 4092; c) T. Xiong, Q. Zhang, Chem. Soc. Rev. 2016, 45, tions using bidentate directing groups. 3069; d) D. Šaki , H. Zipse, Adv. Synth. Catal. 2016, 358, 3983; e) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117, 9247; f) J. C. K. Chu, T. Rovis, Angew. Chem. Int. Ed. 2018, 57, 62; g) L. M. Stateman, K. M. Nakafuku, D. A. Nagib, Synthesis 2018, 50, 1569. R2 [4] a) J. M. Mayer, Acc. Chem. Res. 2011, 44, 36; b) S. Chiba, H. Chen, Org. R=Me O R=Et Biomol. Chem. 2014, 12, 4051; c) Y. Zhao, W. Xia, Chem. Soc. Rev. 2018, NH OTs O Pd(OAc) 47, 2591. Pd(OAc) (5 mol%) 2 2 R1 R (10 mol%) I Ac O, PhMe or PhCl [5] a) M. E. Wolff, Chem. Rev. 1963, 63, 55; b) E. J. Corey, W. R. Hertler, J. Am. 2 AgOAc, DCE, O 70-80 oC Chem. Soc. 1960, 82, 1657. 60-80 oC O [6] a) M. Nechab, S. Mondal, M. P. Bertrand, Chem. Eur. J. 2014, 20, 16034; R2 R2 Gaunt,2014 O O Gaunt,2018 b) J. Robertson, J. Pillai, R. K. Lush, Chem. Soc. Rev. 2001, 30, 94; c) L. 14 examples 23 examples N N Capaldo, D. Ravelli, Eur. J. Org. Chem. 2017, 2017, 2056. up to 81% yield O O up to 83% yield R1 R1 [7] A. W. Hofmann, Ber. Dtsch. Chem. Ges. 1883, 16, 558. Selected Examples [8] K. Löffler, C. Freytag, Ber. 1909, 42, 3427. 3 O Me 80% (R =Et) NTs O O [9] a) E. J. Corey, W. R. Hertler, J. Am. Chem. Soc. 1960, 82, 1657; b) S. O 52% (R3 =CH Ph) O Me 2 Wawzonek, P. J. Thelen, J. Am. Chem. Soc. 1950, 72, 2118; c) S. Wawzonek, N 73% (R3 =OTIPS) N 4 N 73% N O 44% (R3 =Cl) O Me M. F. Nelson, P. J. Thelen, J. Am. Chem. Soc. 1951, 73, 2806; d) S. 3 Me R 3 Me O 56% (R =F) 81% Wawzonek, T. P. Culbertson, J. Am. Chem. Soc. 1959, 81, 3367. Me 81% (R3 =Me) Ts [10] a) R. Hernández, A. Rivera, J. A. Salazar, E. Suárez, J. Chem. Soc. Chem. O O O Me 62% (R3 =Et) N O Commun. 1980, 958; b) R. Carrau, R. Hernandez, E. Suárez, J. Chem. Soc. N 66% (R3 =OTIPS) O N Et N Perkin Trans. 1 1987, 937; c) P. de Armas, C. G. Francisco, R. Hernandez, 61% (R3 =OAc) O 83% 3 53% (R3 =F) Et 35% J. A. Salazar, E. Suárez, J. Chem. Soc. 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