molecules

Review C-H Functionalization via Iron-Catalyzed Carbene-Transfer Reactions

Claire Empel, Sripati Jana and Rene M. Koenigs * Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany; [email protected] (C.E.); [email protected] (S.J.) * Correspondence: [email protected]



Academic Editor: Hans-Joachim Knölker
 Received: 4 January 2020; Accepted: 5 February 2020; Published: 17 February 2020 Abstract: The direct C-H functionalization reaction is one of the most efficient strategies by which to introduce new functional groups into small organic molecules. Over time, iron complexes have emerged as versatile catalysts for carbine-transfer reactions with diazoalkanes under mild and sustainable reaction conditions. In this review, we discuss the advances that have been made using iron catalysts to perform C-H functionalization reactions with diazoalkanes. We give an overview of early examples employing stoichiometric iron carbene complexes and continue with recent advances in the C-H functionalization of C(sp2)-H and C(sp3)-H bonds, concluding with the latest developments in enzymatic C-H functionalization reactions using iron-heme-containing enzymes.

Keywords: iron; carbene; diazoalkane; C-H functionalization

1. Introduction C-H bonds belong to the most common motifs in organic molecules and their direct functionalization is one of the main challenges in synthesis methodology, which impacts on the step economy and sustainability of chemical processes. In recent decades, this research area has flourished and different approaches have been realized to enable C-H functionalization reactions via different strategies: (a) by the directing group-assisted C-H activation, (b) via the innate reactivity of organic molecules, or (c) via direct C-H functionalization (Scheme1)[ 1–4]. While the introduction and subsequent removal of directing groups is a prerequisite for directed C-H activation, direct C-H functionalization allows the introduction of new functional groups into organic molecules without the needMolecules for 20 directing20, 25, x FOR groups. PEER REVIEW It thus represents the most efficient and step-economic strategy by which2 of to16 conduct C-H functionalization reaction. The challenge of this strategy lies within the selective activation ofenvironmental only one type offootprint C-H bond; of elegant organic methods synthesis have methodolog been developedies, but in recent also years,that of mainly access relyinging new on thereactivity use of expensivethat is unique and mostlyto iron. toxicIn this precious review, metal we discuss catalysts the based advances on rhodium, made in iridium, this research palladium, area andwith others a focus to on direct C-H the functionalization C-H functionalization reactions reaction with carbenes. as either the catalyst or the substrate [5–7].

a) directing-group-assisted C-H activation b) innate reactivity of organic molecules c) direct C-H functionalization of C-H bonds

DG H DG R R H X

H [M] [M] F3C M X

X = NR, CR1R2 N H N CF3 SchemeScheme 1. 1.Strategies Strategies for for the functionalizationthe functionalization of C-H of bonds. C-H (bonds.a) directing-group-assisted (a) directing-group C-H-assisted activation, C-H (activation,b) innate reactivity (b) innate of reactivity organic molecules, of organic (moleculesc) direct C-H, (c) functionalizationdirect C-H functionalization of C-H bonds. of C-H bonds.

2. IronHigh in Carbene costs of catalysts,-Transfer limited Reaction resources,s and toxicity of precious metals are the main drivers in the exploration of new synthesis methods based on third-row transition metals. Among these, iron Carbene-transfer reactions are one of the key strategies used today to conduct highly efficient and selective C-H functionalization reactions. The earliest examples date back to reports by Molecules 2020, 25, 880; doi:10.3390/molecules25040880 www.mdpi.com/journal/molecules Meerwein and Doering from 1942 and 1959, in which they described metal-free photochemical C-H functionalization reactions with diazoalkanes using high-energy UV light via free carbene intermediates (Scheme 2) [15,16]. However, the high reactivity of the free carbene intermediate led to unselective reactions and, as a consequence, a lack of applications in organic synthesis. In the subsequent decades, these shortcomings led to the development of metal-catalyzed carbine-transfer reactions using noble metals such as Rh(II), Ru(II), Ir(III), Au(I), Pd(II), or Cu(I) [17–21].

H N H 2 H O mercury lamp CH2 O O H 350 g 30.8 g 42.3 g mixture of C-H functionalization Scheme 2. Photochemical C-H functionalization of diethyl ether with diazomethane.

More recently, carbene-transfer reactions with iron complexes have gained significant attention in organic synthesis methodology for their potential to overcome the limitations of precious metal complexes. In 1992, Hossain et al. described the first iron-catalyzed carbene-transfer reaction using the cationic CpFe(CO)2(THF)BF4 complex in cyclopropanation reactions of styrene 1 and ethyl diazoacetate 2 (Scheme 3a) [22]. Following this strategy, different groups have since reported on their efforts to conduct iron-catalyzed carbene-transfer reactions [11–13].

Scheme 3. (a) Seminal iron-catalyzed cyclopropanation by Hossain et al. [22]. (b) Privileged iron catalysts in carbene-transfer reactions.

Molecules 2020, 25, 880 2 of 16 Molecules 2020, 25, x FOR PEER REVIEW 2 of 16 playsenvironmental a pivotal role. footprint It is the of second organic most synthesis abundant methodolog metal in theies, Earth’s but also crust that following of access aluminum,ing new andreactivity catalysts that based is unique on iron to iron. are currently In this review, emerging we discuss as new andthe advances important made catalysts in this able research to improve area thewith environmental a focus on C-H impact functionalization of chemical reactio processesns with [8–13 carbenes.]. In nature, iron-containing enzymes play an importanta) directing-gro role,up-assi e.g.,sted inC-H the acti hemoglobinvation b) innate or re myoglobinactivity of organ enzymesic molecules that arec) d importantirect C-H funct forional oxygenization of C transport-H bonds in mammals. They can also be found in cytochrome P450 enzymes or iron-sulfur clusters, amongst DG H others, and are pivotalDG for the detoxification,R e.g., by C-HR oxidation reactions,H of xenobiotics [14X ].

AgainstH this[ background,M] [ theM] development of C-HF3C functionalization reactions withM ironX catalysts has received significant attention over the years with the goal of reducing the economic and environmental N H N CF X = NR, CR1R2 footprint of organic synthesis methodologies, but also that of accessing3 new reactivity that is unique to iron.Scheme In this 1. Strategies review, we for discuss the functionalization the advances of made C-H in bonds. this research(a) directing area-group with-assisted a focus C on-H C-H functionalizationactivation, (b) reactionsinnate reactivity with carbenes. of organic molecules, (c) direct C-H functionalization of C-H bonds.

2.2. Iron in Carbene-TransferCarbene-Transfer ReactionsReactions Carbene-transferCarbene-transfer reactionsreactions are are one one of of the the key key strategies strategies used used today today to conductto conduct highly highly efficient efficient and selectiveand selective C-H functionalization C-H functionalization reactions. reactions. The earliest The examples earliest date examples back to date reports back by Meerweinto reports and by DoeringMeerwein from and 1942 Doering and 1959, from in 1942 which and they 1959, described in which metal-free they described photochemical metal-free C-H photochemical functionalization C-H reactionsfunctionalization with diazoalkanes reactions using with high-energy diazoalkanes UV light using via free high carbene-energy intermediates UV light via (Scheme free2 )[ carbene15,16]. However,intermediates the high(Scheme reactivity 2) [15,16 of] the. However, free carbene the high intermediate reactivity of led the to free unselective carbene reactionsintermediate and, led as to a consequence,unselective reactions a lack of applications and, as a co innsequence organic synthesis., a lack In of theapplications subsequent in decades, organic these synthesis. shortcomings In the ledsubsequent to the development decades, these of metal-catalyzed shortcomings led carbine-transfer to the development reactions of usingmetal noble-catalyzed metals carbine such as-transfer Rh(II), Ru(II),reactions Ir(III), using Au(I), noble Pd(II), metals or such Cu(I) as [17 Rh(II),–21]. Ru(II), Ir(III), Au(I), Pd(II), or Cu(I) [17–21].

H N H 2 H O mercury lamp CH2 O O H 350 g 30.8 g 42.3 g mixture of C-H functionalization Scheme 2. Photochemical C-HC-H functionalization of diethyl ether with diazomethane.

More recently,recently, carbene-transfercarbene-transfer reactionsreactions withwith ironiron complexescomplexes havehave gainedgained significantsignificant attentionattention inin organicorganic synthesissynthesis methodologymethodology forfor theirtheir potentialpotential toto overcomeovercome thethe limitationslimitations ofof preciousprecious metalmetal complexes.complexes. InIn 1992,1992, HossainHossain et et al. al. described described the the first first iron-catalyzed iron-catalyzed carbene-transfer carbene-transfer reaction reaction using using the cationicthe cationic CpFe(CO) CpFe(CO)2(THF)BF2(THF)BF4 complex4 complex in cyclopropanation in cyclopropanation reactions reactions of styrene of1 and styrene ethyl diazoacetate1 and ethyl 2diazoacetate(Scheme3a) 2 [ 22(Scheme]. Following 3a) [22] this. Follow strategy,ing di thisfferent strategy, groups different have since groups reported have sinceon their reported efforts on to conducttheir efforts iron-catalyzed to conduct carbene-transferiron-catalyzed carbene reactions-transfer [11–13 reactions]. [11–13]. In the following years, several groups reported their efforts in the field of iron-catalyzed carbine-transfer reactions. Woo et al. reported an important milestone in this research area when they uncovered the cyclopropanation of styrenes with ethyl diazoacetate 2 using an iron porphyrin complex (4a) in 1995 [23]. In this report and in further reports by the Che (4c) and Aviv (5) groups, the fine-tuning of iron porphyrin complexes by the axial ligand and/or electronics of the porphyrin ring system was demonstrated (Scheme3b) [ 24–26]. Today, iron porphyrin complexes and derivatives thereof are important cheap and readily available catalysts to enable carbine-transfer reactions under mild conditions. Khade and Zhang studied the formation of iron carbene complexes via quantum chemical studies using ethyl phenyldiazoacetate (8) as a model compound. They were able to identify a reaction intermediate (9a) in which ethyl phenyldiazoacetate (8) coordinated to the iron porphyrin complex 7 via the carbon atom. In a next step, nitrogen was expelled via transition state 9b and the iron carbene complex 9c was formed. In these studies, the authors were also able to show that N-methyl imidazole reduced both the reaction energy ∆G and the activation energy ∆GTS (Scheme4)[27].

Scheme 3. (a) Seminal iron-catalyzed cyclopropanation by Hossain et al. [22]. (b) Privileged iron catalysts in carbene-transfer reactions.

Molecules 2020, 25, x FOR PEER REVIEW 2 of 16

environmental footprint of organic synthesis methodologies, but also that of accessing new reactivity that is unique to iron. In this review, we discuss the advances made in this research area with a focus on C-H functionalization reactions with carbenes.

a) directing-group-assisted C-H activation b) innate reactivity of organic molecules c) direct C-H functionalization of C-H bonds

DG H DG R R H X

H [M] [M] F3C M X

X = NR, CR1R2 N H N CF3 Scheme 1. Strategies for the functionalization of C-H bonds. (a) directing-group-assisted C-H activation, (b) innate reactivity of organic molecules, (c) direct C-H functionalization of C-H bonds.

2. Iron in Carbene-Transfer Reactions Carbene-transfer reactions are one of the key strategies used today to conduct highly efficient and selective C-H functionalization reactions. The earliest examples date back to reports by Meerwein and Doering from 1942 and 1959, in which they described metal-free photochemical C-H functionalization reactions with diazoalkanes using high-energy UV light via free carbene intermediates (Scheme 2) [15,16]. However, the high reactivity of the free carbene intermediate led to unselective reactions and, as a consequence, a lack of applications in organic synthesis. In the subsequent decades, these shortcomings led to the development of metal-catalyzed carbine-transfer reactions using noble metals such as Rh(II), Ru(II), Ir(III), Au(I), Pd(II), or Cu(I) [17–21].

H N H 2 H O mercury lamp CH2 O O H 350 g 30.8 g 42.3 g mixture of C-H functionalization Scheme 2. Photochemical C-H functionalization of diethyl ether with diazomethane.

More recently, carbene-transfer reactions with iron complexes have gained significant attention in organic synthesis methodology for their potential to overcome the limitations of precious metal complexes. In 1992, Hossain et al. described the first iron-catalyzed carbene-transfer reaction using the cationic CpFe(CO)2(THF)BF4 complex in cyclopropanation reactions of styrene 1 and ethyl Moleculesdiazoacetate2020, 25 2, 880(Scheme 3a) [22]. Following this strategy, different groups have since reported3 of on 16 their efforts to conduct iron-catalyzed carbene-transfer reactions [11–13].

Molecules 2020, 25, x FOR PEER REVIEW 3 of 16

In the following years, several groups reported their efforts in the field of iron-catalyzed carbine-transfer reactions. Woo et al. reported an important milestone in this research area when they uncovered the cyclopropanation of styrenes with ethyl diazoacetate 2 using an iron porphyrin complex (4a) in 1995 [23]. In this report and in further reports by the Che (4c) and Aviv (5) groups, the fine-tuning of iron porphyrin complexes by the axial ligand and/or electronics of the porphyrin ring system was demonstrated (Scheme 3b) [24–26]. Today, iron porphyrin complexes and derivatives thereof are important cheap and readily available catalysts to enable carbine-transfer reactions under mild conditions. Khade and Zhang studied the formation of iron carbene complexes via quantum chemical studies using ethyl phenyldiazoacetate (8) as a model compound. They were able to identify a reaction intermediate (9a) in which ethyl phenyldiazoacetate (8) coordinated to the iron porphyrin complex 7 via the carbon atom. In a next step, nitrogen was expelled via transition state 9b and the iron carbene complex 9c was formed. In these studies, the authors were also able to show that Scheme 3. 3. (a) Seminal Seminal iron-catalyzed iron-catalyzed cyclopropanationcyclopropanation by Hossain Hossain et et al. al. [[22].22]. (b) Privileged Privileged iron iron N-methyl imidazole reduced both the reaction energy ΔG and the activation energy ΔGTS (Scheme 4) catalysts inin carbene-transfercarbene-transfer reactions.reactions. [27].

N2 N2 R R' R R' R R' N2 II N Fe FeII FeII FeII 2 R R'

R1 R2 Int TS P1 P2 7 8 9a 9b 9c

R = Ph = porphyrin ligand R' = CO2Et Scheme 4. Mechanism of the formation of iron carbene complexes.

3. Stoichiometric Stoichiometric C C-H-H Functionalization Initial applicationsapplications ofof iron iron carbene carbene complexes complexes in in C-H C-H functionalization functionalization reactions reactions involved involve thed usethe useof preformed of preformed iron carbene iron carbene complexes complexes10 that were 10 that used were in intramolecular used in intramolecular C-H insertion C reactions.-H insertion The reactions.nature of the The preformation nature of the of preformation the iron carbene of the complex iron carbene renders complex these applications renders these stoichiometric applications in stoichiometriciron. Following in this iron. methodology, Following C-H this insertion methodology, occurs selectively C-H insertio to formn occurs cyclopentane selectively ring to systems form (cyclopentane13,14). The corresponding ring systems bi- (13 and,14 tricyclic). The corresponding target structures bi can- and be obtained tricyclic with target high structurestrans-selectivity can be (Schemeobtained5 with)[ 28 high]. The trans same-selectivity authors investigated(Scheme 5) [28] the. selectivityThe same authors of this process investigated in further the selectivity studies and of thisexplained process the in observed further stud reactionies and outcome explained viaa the concerted observed C-H reaction insertion outcome reaction via that a concerted proceeds viaC-H a insertionchair-like reaction cyclic transition that proceeds state( via12, Schemea chair-like5)[29 cyclic,30]. transition state (12, Scheme 5) [29,30].

PhS O O O O Fe(CO)2Cp H H (CH3)3OBF4 R Ph DCM, 0 - 25 °C, 3 h R 10 13 H H 13a, 72% 13b, 90%

O H O H O H Ph Fe(CO)2CH2PH2 O Fe(CO)2CP H H H R H 11 12 R H H H 13c, 52% 14, 92%

Scheme 5. 5. IntramolecularIntramolecular C-H C-H insertion insertion reactions reactions for thefor synthesis the synthesis of cyclopentane of cyclopentane derivatives deriv (atives13,14) (by13, Helquist14) by Helquist and coworkers and cow [orkers29,30]. [29,30].

4. C-H functionalization Reactions of Aromatic C-H Bonds The direct C-H functionalization of benzene or alkyl benzenes (15) via carbene or metal-carbene intermediates can give access to three different products, which arise from (a) insertion into a C(sp2)-H bond (17), (b) insertion into a side-chain C(sp3)-H bond (18), or (c) a cycloaddition reaction

Molecules 2020, 25, 880 4 of 16

4. C-H Functionalization Reactions of Aromatic C-H Bonds Molecules 2020, 25, x FOR PEER REVIEW 4 of 16

MoleculesThe 20 direct20, 25, x C-H FORfunctionalization PEER REVIEW of benzene or alkyl benzenes (15) via carbene or metal-carbene4 of 16 intermediateswith the aromatic can givesystem access to togive three a norcaradiene different products, 19 that which can undergo arise from a (a)Buchner insertion reaction into a to C(sp give2)-H a bondcycloheptatrienewith the (17 ),aromatic (b) insertion 20 system (Scheme into to a 6)give side-chain. The a challengenorcaradiene C(sp3 lies)-H in19 bond the that chemoselective (18 can), or undergo (c) a cycloaddition adifferentiation Buchner reaction reaction of these to with give three the a aromaticreactioncycloheptatriene system pathways. to 20 give ( Moreover,Scheme a norcaradiene 6) . Thea C -challengeH19 insertionthat can lies undergointo in the a chemoselective C(sp a Buchner2)-H bond reaction differentiation may to give give arise cycloheptatriene of to these different three 20regioisomers.reaction(Scheme pathways.6). The challenge Moreover, lies ina C the-H chemoselective insertion into di a ff C(sperentiation2)-H bond of these may three give reaction rise to pathways. different Moreover,regioisomers. a C-H insertion into a C(sp2)-H bond may give rise to different regioisomers. Me N2 Me R N2R' 15 16 R R' 15 16

R' Me R’ R R R R' R R’ Me R’ R Me Me R’R R R Me 18 R’ 19 Me 20 17 R’ insertion into insertion into cycloaddition 17 18 19 20 C(sp2)-H bond C(sp3)-H bond norcaradiene cycloheptatriene insertion into insertion into cycloaddition Scheme 6. PossibC(sple 2product)-H bond s in the ironC(sp-3catalyzed)-H bond functionalizationnorcaradiene of toluenecycloh 15ep tabytrie carbenene Schemeinsertion. 6.6. PossiblePossible productsproducts inin thethe iron-catalyzediron-catalyzed functionalization functionalization of of toluene toluene15 15by by carbene carbene insertion. insertion. In this context, Luis, Perez Perez,, and cow coworkersorkers reported on the use of iron(II) iron(II)-complex-complex (23) bearing a pytacnIn ligandthis context, in the Luis, reaction Perez of, and ethylethyl cow diazoacetatediazoacetateorkers reported 2 withwith on aromaticaromatic the use of hydrocarbonsh ydrocarbonsiron(II)-complex ((2121).). ( 23 Under) bearing these a reactionpytacn ligand conditions, in the ethylreaction diazoacetate of ethyl diazoacetate( 2) underwent 2 with a chemoselective aromatic hydrocarbons C-HC-H functionalization (21). Under ofthese the 2 aromaticreaction conditions, C(sp2))-H-H bond bond ethyl of of diazoacetate benzene and (2 )alkyl underwent benzene a chemoselectivederivatives derivatives,, and C -only H functionalization trace amounts of of thethe norcaradienenorcaradiene/cycloheptatrienearomatic C(sp/cycloheptatriene2)-H bond of benzene reactionreaction and pathway alkyl benzene were observedobserved derivatives [[31]31].,. Theand substrate only trace scope amounts of benzene of the 2 derivativesnorcaradiene/cycloheptatriene was was further further studied studied byreaction bythe thesame pathway same authors authors were and, observed in and all, cases,in [31] allexclusive cases. The ,substrate exclusive C(sp )-H scope C(sp bond of2)- insertionHbenzene bond occurredinsertionderivatives inoccurred moderate was further in tomoderate good studied yields to by good as the a mixtureyields same as authors of a regioisomers.mixture and ,of in regioisomers. all Electron-withdrawing cases, exclusive Electron C(sp-withdrawi groups2)-H bond (e.g.,ng Cl)groupsinsertion had a (e.g. occurred detrimental, Cl) in had moderate eff ect a detrimental onthe to good C-H functionalization effectyields as on a themixture C reaction,-H of functionalization regioisomers. and the corresponding Electron reaction-withdrawi, products and theng werecorrespondinggroups obtained (e.g., withproductsCl) reducedhad were a detrimental yields obtained (Scheme with effect7 )[reduced 32 on]. the yield Cs-H (Scheme functionalization 7) [32]. reaction, and the corresponding products were obtained with reduced yields (Scheme 7) [32]. Fe -pytacn complex R N R CO Et 2 Fe-pytacn 2 Fe -pytacn complex R N CO2Et R CO Et 2 Fe-pytacn 2 21 2 22 CO2Et 21 2 Me 22

CO2Et N Me Me CO2Et CO2Et N X CO2Et FeN Me Me MeCO2Et CO2Et 22a,72% 22c, 42% N N X X 43:27:30 Me 22b, 60%Me alpha:beta 63:37 NFe 22a,72% 22c, 42% N X 43:27:30 22b, 60% alpha:beta 63:37 N CO2Et CO Et 23 MeO Cl 2 22d, 75% CO2Et CO Et 23 MeO 60:10:30 Cl 22e, 2< 10% 22d, 75% Scheme 7. (Left):): functionalization 60:10:30 ofofarenes arenes21 21with with22e ethyl,

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2 BAr N 2 BArF N O Fe OEt N C + EDA, 2 N N N2 H N2 - EDA, 2 2 - EDA, 2 23b

2 BArF 2 BArF N - 2 NaX N N N X + 2 NaBArF N N O Fe Fe Fe Fe OEt N X + 2 NaX N N C N N - 2 NaBArF N N H 23 23a 23c 2 BArF N N O H Fe OEt X N C H CO Et 21 CO2Et N H 21 X H H X 23d 22 23d 22 X Scheme 8. 8. ProposedProposed reaction reaction pathway pathway for for the the C-H C- functionalizationH functionalization reaction reacti ofon arenes of arenes (21) using (21) using ethyl diazoacetateethyl diazoacetate2. 2.

The direct C-HC-H functionalizationfunctionalization reaction of aromatic compounds (used as solvents)solvents) was also studied by by Woo Woo and and coworkers coworkers using using dimethyl dimethyl diazomalonate diazomalonate25 and 25 an and iron(III) an iron(III)porphyrin porphyrin complex (complex4a) as a catalyst (4a) as at a elevated catalyst reaction at elevated temperatures. reaction However, temperatures. only moderate However, chemoselectivity only moderate of 2 3 C(spchemoselectivity)-H bond vs. of C(sp C(sp2)-H)-H bond insertionvs. C(sp3) could-H bond be achievedinsertion couldin this be reaction achieved (26 : in27 , this 2:1 reaction to 10:1). Di(26ff:27erent, 2:1 substituted to 10:1). aromatic Different systems substituted such as toluene, aromatic mesitylene, systems 4-chloro-toluene, such as toluene, or anisole mesitylene, were shown4-chloro to-toluene, be compatible or anisole with were the present shown reactionto be compatible conditions. with In contrastthe present to the reaction previously conditions. described In 3 reaction,contrast to the the product previously from described the C(sp reaction,)-H bond the insertion product reaction from the was C(sp obtained3)-H bond as the insertion major productreaction (Schemewas obtained9)[34 ].as the major product (Scheme 9) [34].

C(sp3)-H functionalization C(sp2 )-H functionalization

CO2Me N2 Fe(TPP)Cl (2 mol%, 4a) 2 MeO C MeO2C X MeO2C X MeO2C CO2Me 110 °C X CO2Me

24 25 26 27 as solvent as solvent X yield (26/27) ratio (26:27) X = H 68% 2:1 X = Cl 51% 10:1 X = Me 76% 5:1 2 3 Scheme 9. 9.Chemoselectivity Chemoselectivity between between C(sp C(sp)-H bond2)-H and bond C(sp and)-H C(sp bond3)- insertionH bond reaction insertion investigated reaction byinvestigated Woo and coworkersby Woo and [34 cow]. orkers [34].

In 2015, ZhouZhou and coworkerscoworkers studied the reaction ofof donor–acceptordonor–acceptor diazo compounds 29 with electron-richelectron-rich aromatics 28.. Using Using a a simple, non non-porphyrin-porphyrin iron complex, the authors were able to 2 demonstrate the C(sp 2))-H-H functionalization reaction of N,N-dialkyl-dialkyl aniline derivatives (28)) with high yield andand selectivity.selectivity. In all cases,cases, selective C-HC-H functionalizationfunctionalization in the 4 positionposition occurred,occurred, whichwhich could bebe rationalized rationalized by by the the high high nucleophilicity nucleophilicity of N ,N of-dialkyl N,N-dialkyl aniline aniline derivatives derivatives in the para in theposition. para Fromposition. the viewpoint From the ofviewpoint the catalyst, of the a very catalyst, simple a iron very catalyst simple was iron used catalys thatt could was used be obtained that could in situ be from FeCl , 1,10-phenanthroline, and NaBAr (Scheme 10)[35]. More recently, Deng and coworkers obtained in3 situ from FeCl3, 1,10-phenanthroline,F and NaBArF (Scheme 10) [35]. More recently, Deng reportedand coworkers on a similar reported transformation on a similar usingtransformation a bis(imino)pyridine using a bis(imino iron complex,)pyridine which iron couldcomplex, be used which in thecould direct be used C-H functionalizationin the direct C-H offunctionalizationN,N-dimethylaniline of N,N28-dimethylanilineto give 30a with 28 a 71%to give yield 30a [36 with]. a 71% yield [36].

Molecules 2020, 25, x FOR PEER REVIEW 6 of 16 Molecules 2020, 25, 880 6 of 16 Molecules 2020, 25, x FOR PEER REVIEW FeCl (5 mol%) 6 of 16 3 CO2Me N2 1,10-phenanthroline (6 mol%) O FeCl (5 mol%) Ph NaBAr3 F (15 mol%) CO2Me N N2 1,10-phenanthroline (6 mol%) O 70 °C, DCE N 30a, 93% O NaBArF (15 mol%) scale up:Ph 29 N28 1.5 g 93% O 70 °C, DCE N 30a, 93% scale up: 28 29 1.5 g 93% N 30b, R = 4-MeC6H4, 88% N N N 30c, R = 2-ClC H , 83% 6 4 Cl Cl 30d, R = 3-MeOC H , 80% N 30b, R = 4-MeC6H64, 488% N N N 30e30c,, R == 22-n-CalCphHtyl,, 86%83% 6 4 Cl Cl 30d, R = 3-MeOC6H4, 80% O30e, R = 2-naphtyl, 86% O O O R O O O O O S O O O R 30f, 92% 30g, 17% 30h, 90% O S O O O Scheme 10. Iron-catalyzed arylation of donor30f-acceptor, 92% diazo compound30g, 17% 29 with N30h,N,- dialkyl90% anilines 28 by the Zhou group [36]. Scheme 10. Iron-catalyzedIron-catalyzed arylation of donor-acceptordonor-acceptor diazo compound 2929 with NN,,NN-dialkyl-dialkyl anilines 2828 byby thethe ZhouZhou groupgroup [[36]36].. 5. C-H Functionalization Reactions of Heteroaromatic C-H Bonds 5. C-H Functionalization Reactions of Heteroaromatic C-H Bonds 5. C-NH- Functionalizationheterocycles like indoles Reactions or pyrroles of Heteroaromatic are privileged C- motifsH Bonds in drugs and natural products, and N-heterocycles like indoles or pyrroles are privileged motifs in drugs and natural products, and a broadN-heterocycles variety of strategies like indoles for ortheir pyrroles construction are privileged or their motifs functionalization in drugs and has natural been products described, and in a broad variety of strategies for their construction or their functionalization has been described in recenta broad decades. variety Aof particular strategiesly for intriguing their construction transformation or their is the functionalization direct C-H bond has functionalization been described ofin recent decades. A particularly intriguing transformation is the direct C-H bond functionalization heterocyclesrecent decades., which A particular would ly streamline intriguing current transformation synthesis is strategies the direct ofC -H drugs bond or functionalization natural products. of of heterocycles, which would streamline current synthesis strategies of drugs or natural products. Furthermore,heterocycles, which it would would also streamline allow the current intr oduction synthesis of strategies molecular of drugs diversity or natural into late products.-stage Furthermore, it would also allow the introduction of molecular diversity into late-stage functionalization functionalizationFurthermore, it reactions. would also This allowapproach the, in intr combinationoduction ofwith molecular the benefits diversity of iron catalysts into late, would-stage reactions. This approach, in combination with the benefits of iron catalysts, would enable important enablefunctionalization important reactions. applications This approach of C-H , in functionalization combination with strategies the benefits in of medicinal iron catalysts chemistry,, would applications of C-H functionalization strategies in medicinal chemistry, agrochemistry, or total synthesis. agrochemistry,enable important or total applications synthesis. of C-H functionalization strategies in medicinal chemistry, In 2006, Woo et al. reported on the iron-catalyzed functionalization of N-heterocycles with ethyl agrochemistry,In 2006, Woo or ettotal al. synthesis.reported on the iron-catalyzed functionalization of N-heterocycles with ethyl diazoacetate 2 as a carbene precursor. While no reaction was observed with indole 31, the closely diazoacetateIn 2006, 2Woo as aet carbene al. reported precursor. on the Whileiron-catalyzed no reaction functionalization was observed of with N-heterocycles indole 31, the with closely ethyl related pyrrole 32 underwent C-H functionalization without concomitant N-H functionalization to relateddiazoacetate pyrrole 2 as32 aunderwent carbene precursor. C-H functionalization While no reaction without was concomitant observed with N-H indole functionalization 31, the closely to give 33 in a 37% yield (Scheme 11)[37]. giverelated 33 inpyrrole a 37% 32 yield underwent (Scheme C11)-H [37] functionalization. without concomitant N-H functionalization to give 33 in a 37% yield (Scheme 11) [37]. N2 Fe(TPP)Cl (1 mol%, 4a) no reaction CO2Et N DCM, rt N2 H Fe(TPP)Cl (1 mol%, 4a) 2 31 no reaction CO Et N DCM, rt 2 H 2 31 N2 Fe(TPP)Cl (1 mol%, 4a) CO2Et N H DCM, rt N CO2Et Fe(TPP)Cl (1 mol%, 4a) N CO Et 2 H 2 2 32N 33, 37% CO Et H DCM, rt 2 C-H inseNrtion reaction H 2 32 33, 37% Scheme 11. IronIron-catalyzed-catalyzed reaction of ethyl diazoacetate 2 withC-H indoleinsertion 31 re aandction pyrrole 32.. Scheme 11. Iron-catalyzed reaction of ethyl diazoacetate 2 with indole 31 and pyrrole 32. Thereafter, Zhou Zhou and-coworkers and-coworkers reported reported on anon enantioselective an enantioselective C-H functionalization C-H functionalization of indole of heterocycles.indole heterocycles. For this For purpose, this purpose, they studiedthey studied the reaction the reaction of silyl-protected of silyl-protected indole indole heterocycles heterocycles (34) with Thereafter,α-aryl-α-diazoesters Zhou and (29-coworkers) in the presence reported of Fe(ClO on an enantiosel) and a chiralective spirobisoxazoline C-H functionalization ligand 36 of. (34) with α-aryl-α-diazoesters (29) in the presence of Fe(ClO4 2 4)2 and a chiral spirobisoxazoline ligand indole heterocycles. For this purpose, they studied the reaction of silyl-protected indole heterocycles This36. This strategy strategy allowed allowed the C-H the functionalization C-H functionalization of indole of heterocycles indole heterocycles under mild under reaction mild conditions reaction (34) with α-aryl-α-diazoesters (29) in the presence of Fe(ClO4)2 and a chiral spirobisoxazoline ligand withconditions moderate with enantioselectivity. moderate enantioselectivity. Importantly, di Importantly,fferent substituents different at the substituents indole heterocycles at the indole were tolerated,36. This strategy such as chlorineallowed andthe methylC-H functionalization (Scheme 12)[38]. of indole heterocycles under mild reaction heterocyclesconditions with were moderatetolerated, such enantioselectivity. as chlorine and Importantly, methyl (Scheme different 12) [38] substituents. at the indole heterocycles were tolerated, such as chlorine and methyl (Scheme 12) [38].

Molecules 2020, 25, 880 7 of 16 MoleculesMolecules 20202020,, 2255,, xx FORFOR PEERPEER REVIEWREVIEW 77 ofof 1616

PhPh Fe(ClO ) (5 mol%) Fe(ClO44)22 (5 mol%) ** COCO22MeMe chchiirarall ligandligand (6(6 momoll%%)) NN22 NNaaBArBArFF (6(6 momoll%%)) NN Ph CO Me NN Ph CO22Me CHClCHCl3,, 4040 °C°C TTBSBS 3 TTBSBS 3434 2929 35a35a,, 92%,92%, 73%73% eeee

RR PhPh 35b35b,, RR == 44-C-Cll,, 89%,89%, 71%71% eeee ** COCO22MeMe OO 35c35c,, RR == 44-Me-Me,, 86%,86%, 65%65% eeee RR NN ** COCO22MeMe 35d35d,, RR == 33-F-F,, 86%,86%, 67%67% eeee PhPh N 35e35e,, RR == 33-Me-MeOO,, 76%,76%, 60%60% eeee NN N PhPh 35f, R = 3-CF , 90%, 76% ee TBS 35f, R = 3-CF33, 90%, 76% ee TBS OO NN 35g35g,, RR == 22-Me-Me,, 60%,60%, 39%39% eeee 35h35h,, RR == Cl,Cl, 80%,80%, 73%73% eeee 36, chiral ligand TBS 36, chiral ligand TBS 35i35i,, RR == MeMe,, 94%,94%, 60%60% eeee SchemeScheme 12.12.12. EnantioselectiveEnantioselectiveEnantioselective iron iron iron-catalyzed--catalyzedcatalyzed C C C-H--HH functionalization functionalization functionalization of of of TBS TBSTBS-indole--indoleindole ( (3434)) with with αα--aryl--arylaryl--αα--diazoesters-diazoestdiazoestersers ( (2929)),),, described described by by Zhou Zhou et et al al.al.. [[38][38]38]...

AsAs described described by by Woo Woo andand coworkers,cowcoworkers,orkers, thethe directdirect functionalizationfunctionalization of of indole indole heterocycles heterocycles in in the the C3C3 position position doesdoes notnot readilyreadily readily occuroccur occur whenwhen when usingusing using ethylethyl ethyl diazoacetatediazoacetate diazoacetate [37][37] [37.. ].TheThe The directdirect direct functionalizationfunctionalization functionalization ofof indoleofindole indole withwith with acceptoracceptor acceptor-only--onlyonly diazoalkanesdiazoalkanes diazoalkanes wouldwould would openopen open upup up avenuesavenues avenues towardstowards towards thethe the efficientefficient efficient synthesissynthesis synthesis ofof tryptaminesoftryptamines tryptamines and and and related related related alkaloids. alkaloids. alkaloids. In In In recentrecent recent years,years, years, differen differen differenttt groups groups groups havehave have focusedfocused focused their their their efforts effortsefforts on on identifyingidentifying iron ironiron catalysts catalystscatalysts and/or andand/or/or reaction reaction conditions conditions that that wouldwould allowallow thisthis importantimportant transformation.transformation. transformation. InIn 2019,2019, KoenigsKoenigsKoenigs andandand Weissenborn WeissenbornWeissenborn et etet al. al.al. reported reportedreported the thethe iron-catalyzed ironiron--catalyzedcatalyzed C-H CC--HH functionalization functionalizationfunctionalization reaction reactionreaction of ofindolesof indolesindoles37 3737in inin the thethe C3 C3C3 position positionposition using usingusing the thethe same samesame catalyst catalystcatalyst as asas the thethe Woo WooWoo group, group,group, but butbut using usingusing diazoacetonitrilediazoacetonitrile 3838.. UsingUsing thisthis methodology,methodology, protected protectedprotected and andand unprotected unprotectedunprotected indole indoleindole and andand indazole indazoleindazole heterocycles heterocyclesheterocycles underwent underwentunderwent selectiveselective functionalizationfunctionalizationfunctionalization in inin the thethe C3 C3C3 position. position.position. Importantly, Importantly,Importantly, no nono reaction reactionreaction was waswas observed observedobserved when whenwhen blocking blockingblocking the theC3the position C3 C3 positionposition (Scheme ( (SchemeScheme 13). This 13) 13).. approach This This approach approach has now hashas enabled now now enabled enabled a two-step aa two two approach--stepstep approach approach towards the towards towards synthesis thethe synthesisofsynthesis important ofof importantimportant tryptamine tryptaminetryptamine derivatives derivativesderivatives [39]. [39][39]..

CNCN

NN22 FFee(T(TPP)CPP)Cll (1(1 momoll%%,, 4a4a)) NN CNCN DDCCM,M, HH22OO NN 3737 3838 39a39a,, 92%92% ggeenneeraratteedd inin flowflow

CN CNCN CNCN CN

N RR RR N N NN NN N NN H HH PhPh H 39b39b,, RR == H,H, 86%86% 39e39e,, RR == H,H, 75%75% 4040,, 64%64% 4141,, nono rereaactctiioonn 39c39c,, RR == 55-O-OMeMe,, 91%91% 39f39f,, RR == 22-Me-Me,, 41%41% 39d39d,, RR == 66-O-OMeMe,, 75%75% 39g39g,, RR == 66-C-COO22MeMe,, 40%40% 39h, R = 5-OMe, 54% 39h, R = 5-OMe, 54% SchemeScheme 13.13. ReactionReaction of of diazoacetonitrile diazoacetonitrile 3838 withwith indole indole heterocycles heterocycles using using Fe(TPP)C Fe(TPP)Cl,Fe(TPP)Cll,, reported reported by by Koenigs,Koenigs, Weissenborn, Weissenborn, andand coworkerscoworkers [[39][39]39]... To date, various proposals for the C-H functionalization of indole heterocycles have been reported ToTo date date,, variousvarious proposalsproposals for for the the C C--HH functionalization functionalization of of indole indole heterocycles heterocycles havehave been been in the literature. One important mechanistic proposal suggests the initial formation of an iron carbene reportedreported inin thethe literature.literature. OneOne importantimportant mechanisticmechanistic proposalproposal suggestssuggests thethe initialinitial formationformation ofof anan complex 43 that undergoes nucleophilic addition of an indole followed by a [1,2]-proton transfer ironiron carbene carbene complex complex 4343 thatthat undergoes undergoes nucleophilic nucleophilic addition addition of of anan indoleindole followed followed by by a a reaction (Scheme 14a). Zhou and coworkers reported a KIE (= kinetic isotope effect) of 5.06 in [1,2][1,2]--protonproton transfertransfer reactionreaction ((SchemeScheme 14a14a).). ZhouZhou andand cowcoworkersorkers repreportorteded aa KIEKIE (=(= kinetickinetic isotopeisotope the reaction of N-methyl indole and deuterated N-methyl indole, which led them to conclude a effect)effect) ofof 5.065.06 inin thethe reactionreaction ofof NN--methylmethyl indoleindole andand deuterateddeuterated NN--methylmethyl indole,indole, whichwhich ledled themthem toto proton-transfer reaction to be the rate-determining step (Scheme 14b) [38]. Koenigs, Weissenborn, and concludeconclude a a proton proton--transfertransfer reaction reaction to to be be the the rate rate--determiningdetermining step step (Scheme (Scheme 14b) 14b) [38][38].. Koenigs,Koenigs, coworkers observed a similar trend in the reaction of N-methyl indole and deuterated N-methyl indole WeissenbornWeissenborn,, andand cowcoworkersorkers o observebservedd aa similar similar trend trend in in the the reaction reaction of of NN--methylmethyl indole indole and and with diazoacetonitrile using both a synthetic and an enzymatic iron catalyst. However, investigations deuterateddeuterated NN--methylmethyl indole indole with with diazoacetonitrile diazoacetonitrile using using both both a a synthetic synthetic and and an an enzymatic enzymatic iron iron using TEMPO 46 as a radical scavenger revealed a complete inhibition of the C-H functionalization catalyst.catalyst. However, However, investigations investigations using using TEMPO TEMPO 4646 asas aa radicalradical scavenger scavenger revealed revealed a a complete complete inhibiinhibitiontion of of the the C C--HH functionalization functionalization reaction. reaction. Based Based on on th theseese experimentalexperimental data data,, thethe authors authors

Molecules 2020, 25, 880 8 of 16 Molecules 2020, 25, x FOR PEER REVIEW 8 of 16 assumereaction.d Baseda radical on these reaction, experimental yet it wa data,s not the yet authors clear assumed in which a radical particular reaction, reaction yet it step was radicalnot yet intermediatesclear in which we particularre involved reaction (Scheme step 14c) radical [39] intermediates. were involved (Scheme 14c) [39].

N2 a) mechanistic proposal by Zhou et al. 29 Ar CO2Me metal carbene complex formation

42 FeL*n Ar FeL*n MeO2C 43 Ar CO2Me Ar H CO2Me FeL*n N

N 44' 37 N 45 1,2-proton nucleophilic addition transfer Ar CO2Me H FeL*n

N 44

b) experimental evidence from the reaction with methyl phenyldiazoacetate competition experiment H/D Ph D/H CO2Me N2 Fe catalyst (42) 5.06 : 1 H/D ratio N Ph CO2Me N 37, H/D = 1:1 29 45

c) experimental evidence from the reaction with diazoacetonitrile reaction with deutero indole D D CN N 2 Fe(TPP)Cl 73% yield N CN 55% deuterium content N d-37 38 d-39a competition experiment D/H H/D CN N 2 Fe(TPP)Cl 35% yield 5 :1 H/D ratio N CN N

37, H/D = 1:1 38 39a reaction in the presence of radical scavenger H N 2 no product formation TEMPO Fe(TPP)Cl observed N CN 37 38 46 Scheme 14. HypothesizeHypothesizedd mechanism mechanism for for the the C C-H-H functionalization of of indole with iron carbene complexes and experimental evidence. ( a)) mechanistic mechanistic proposal proposal by Zhou et al al.,., [38], [38], ( b) experimental evidence from the reaction with methyl phenyldiazoacetate [38] [38],, ( c) evidence from the reaction with diazoacetonitrile [39]. [39].

The reaction mechanism of the C C-H-H functionalization reaction of indole heterocycles with iron carbene intermediates still remains unclear. It would be valuable to investigate this reaction via DFT calculations to g gainain knowledge of the exact spin state of the the participating participating iron catalyst and to to identify identify the exact reaction mechanism.

6. C-H Functionalization Reactions of Aliphatic C-H Bonds The direct C-H functionalization reaction of aliphatic C-H bonds is an important strategy for the introduction of new functional groups onto a hydrocarbon skeleton; the difficulties lie in the

Molecules 2020, 25, 880 9 of 16

6. C-H Functionalization Reactions of Aliphatic C-H Bonds The direct C-H functionalization reaction of aliphatic C-H bonds is an important strategy for Molecules 2020, 25, x FOR PEER REVIEW 9 of 16 the introduction of new functional groups onto a hydrocarbon skeleton; the difficulties lie in the didifferentiationfferentiation of of chemically chemically very very similar similar C-H C-H bonds. bonds. Over the years, years, metal-catalyzed metal-catalyzed insertion insertion reactions of carbene fragments have emerged as a promising strategy for this purpose,purpose, and a variety 3 of precious-metal-catalyzed precious-metal-catalyzed C(sp3))-H-H bond functionalization reactions have been described in the literature,literature, rangingranging from from site-selective site-selective C-H C functionalization-H functionalization to late-stage to late functionalization-stage functionalization of complex of moleculescomplex molecules [5,40,41]. [5,40,41]. The application application of of non-toxic non-toxic and and highly highly active active iron iron catalysts catalysts has blossomedhas blossomed in the in last the few last years, few andyears today,, and iron-catalyzed today, iron-catalyzed carbine-transfer carbine reactions-transfer have reactions emerged have as an emerged important, as environmentally an important, 3 benignenvironmentally strategy bybenign which strategy to conduct by which C(sp to)-H conduct bond C functionalization(sp3)-H bond functionalization reactions. In thisreactions. context, In Woothis context,and coworkers Woo and reported coworkers their studies reported in C-H their functionalization studies in C-H reactions functionalization of cyclohexane reactions47 and of tetrahydrofurancyclohexane 47 and49 astetrahydrofuran substrates. Using 49 as a substrates. donor–acceptor Using diazoalkanes a donor–acceptor (29) as diazoalkanes a carbene precursor (29) as a andcarbene a Fe(TPP)Cl precursor (4a and) catalyst, a Fe(TPP)Cl the authors (4a) catalyst, demonstrated the authors proof-of-concept demonstrate studiesd proof in-of this-concept research studies area. Cyclohexanein this research47 area.underwent Cyclohexane smooth 47 C-H underwent functionalization smooth C to-H give functionalization product 48 with to agive 66% product yield. No 48 C-Hwith functionalizationa 66% yield. No wasC-H observedfunctionalization when ethyl was diazoacetate observed when2 or dimethylethyl diazoacetate diazomalonate 2 or dimethyl25 were useddiazomalonate as carbene 25 precursors. were used Similarly, as carbene tetrahydrofuran precursors.49 Similarly,underwent tetrahydrofuran selective C-H functionalization 49 underwent reactionselective in C the-H β functionalizationposition (50). A byproduct reaction arising in the from β position ring-opening (50). of A the byproduct THF ring was arising observed from asring a- minoropening reaction of the product THF ring51 withwas ~20%observed yield. as In a aminor competition reaction experiment product 51 with with mesitylene ~20% yield. (52) In as a 3 2 substrate,competition the experiment authors obtained with mesitylene the product (52 from) as a C(spsubstrate,)-H bond the authors and C(sp obtained)-H bond the inproduct a 1.5:1 from ratio (SchemeC(sp3)-H 15bond)[34 and]. C(sp2)-H bond in a 1.5:1 ratio (Scheme 15) [34].

N 2 O O O Fe(TPP)Cl (2 mol%, 4a) O 80 °C 47 29 as solvent 48, 66%

N2 O O O O Fe(TPP)Cl (2 mol%, 4a) O O O O 80 °C O 49 29 as solvent 50 62% (3.4:1) 51

Ph CO2Me Ph CO2Me N2

CO2Me Fe(TPP)Cl (2 mol%, 4a)

80 °C 52 29 53 82% (1:1.5) 54 as solvent Scheme 15. Reaction of α--aryl-aryl-α--diazoestersdiazoesters with cyclohexane (47), THF (49),), and mesitylene (52).).

The C-HC-H functionalizationfunctionalization of of cyclohexane cyclohexane represents represents one one of the of simplestthe simplest examples, examples as all, C-Has all bonds C-H withinbonds cyclohexane within cyclohexane are identical. are identical.Contrarily, Contrarily, linear or branched linear or hydrocarbons branched hydrocarbons are more challenging, are more as dichffallengingerent C-H, as bonds different are presentC-H bonds that are need present to be dithatfferentiated need to be by differentiated the catalyst. by Zhu the et catalyst. al. studied Zhu the et reactional. studied of thesethe reaction substrates of these with substrates donor–acceptor with donor diazoalkanes–acceptor using diazoalkanes an iron catalyst. using an When ironn catalyst.-hexane 56Whenwas n used-hexane as a56 substrate, was used selective as a substrate, C-H functionalization selective C-H functionalization of secondary C-H of secondary groups occurred, C-H groups but withoutoccurred, any but meaningful without any selectivity meaningful of the C2 selectivity vs. C3 positon. of the When C2 vs. studying C3 positon. 2-metylpentane When studying59, the C-H2-metylpentane functionalization 59, the occurred C-H functionalization preferentially atoccurred the tertiary preferentially C-H group. at Nothe C-H tertiary functionalization C-H group. No of primaryC-H functionalization C-H bonds was of observed, primary C and-H the bonds reactivity was observed order for, and the C-H the reactivity functionalization order for decreased the C-H fromfunctionalization tertiary > secondary decrease>dallylic from/ benzylic tertiary >> > secondaryprimary C-H > allylic/benzylic bonds (Scheme >>16 ). primary It is of note C-H that bonds this (Scheme 16). It is of note that this catalyst can be applied in the C-H functionalization of cyclohexane with turnover numbers of up to 690 on gram scale. In this reaction, the authors observed a KIE of 2.0 for kH/kD [42].

Molecules 2020, 25, 880 10 of 16 catalyst can be applied in the C-H functionalization of cyclohexane with turnover numbers of up to

690Molecules on gram 2020, 2 scale.5, x FOR In PEER this REVIEW reaction, the authors observed a KIE of 2.0 for kH/kD [42]. 10 of 16

Fe(ClO ) (1 mol%) Fe(ClO4)2 (1 mol%) N ligandligand (55, 1.2 moll%) N2 NaBAr (1.2 mol%) NaBArF (1.2 mol%) Ph CO Me Ph CO2Me CHCl3 Ph CO Me Ph CO Me 3 Ph CO2Me Ph CO2Me 56 29 57, 20% 58, 19% N N

N N Fe(ClO ) (1 mol%) Fe(ClO4)2 (1 mol%) ligand 55 ligandligand (55, 1.2 moll%) ligand 55 N NaBAr (1.2 mol%) N2 NaBArF (1.2 mol%) Ph CO Me CHCl Ph CO Me Ph CO2Me Ph CO2Me CHCl3 Ph CO2Me 2 59 29 60, 43% 61, 19% dr 1.4:1 3 SchemeScheme 16.16. StudiesStudies onon thethe selectivityselectivity ofof iron-catalyzediron-catalyzed C(spC(sp3)-H)-H insertion reactions.reactions.

3 While intermolecular C(sp 3)-H functionalization reactions suffer from missing selectivity and While intermolecular C(sp3)-H functionalization reactions suffer from missing selectivity and reactivity, the development of intramolecular processes would enable important steps to be taken reactivity, the development of intramolecular processes would enable important steps to be taken in 3 in the understanding of iron-catalyzed C(sp3 )-H functionalization. In this context, the White group the understanding of iron-catalyzed C(sp3)-H functionalization. In this context, the White group explored an intramolecular cyclization via C-H functionalization using an iron phthalocyanin complex explored an intramolecular cyclization via C-H functionalization using an iron phthalocyanin as the carbene-transfer catalyst; importantly, weakly coordinating counterions needed to be used to complex as the carbene-transfer catalyst; importantly, weakly coordinating counterions needed to be bis increaseused to theincrease electrophilicity the electrophilicity of the iron of complex. the iron Under complex. these Under conditions, these the conditions,-acceptor the diazoalkanes bis-acceptor 62 63 (diazoalkanes) underwent (62 smooth) underwent intramolecular smooth intramolecular C-H functionalization C-H functionalization reaction to yield reaction product to yieldin moderate product to63good in moderate yields with to good broad yields functional with broad group functional tolerance (Scheme group tolerance 17). It is ( importantScheme 17) to. noteIt is important that the C-H to functionalization reaction selectivity occurred in the allylic, benzylic position or in the α position to a note that the C-H functionalization reaction selectivity occurred in the allylic, benzylic position or in heteroatomthe α position [43 to]. a heteroatom [43].

BAr BArF N O OEt FePc (10 moll%) O O O O N N NaBAr (10 mol%) N O NaBArF (10 mol%) S O OEt N Fe N S N O OEt N O S N2 DCM, 1 h, slow addition O DCM, 1 h, slow addition N N O R 45 °C, 2-12 h R 62 63 N

FePc

O O O O O O O O O O O O O S O O O O O O S OEt S O O S S O OEt O OEt S O OEt O OEt O S OEt O OEt SO Ph N SO2Ph OTBDPS OMe 63a, 57% 63b, 68% 63c, 73% 63d, 65% 63e, 64% SchemeScheme 17.17. IntramolecularIntramolecular cyclisationcyclisation viavia C-HC-H functionalizationfunctionalization forfor thethe synthesissynthesis ofof sulfonatesulfonate esters.esters.

3 Recently,Recently, CostasCostas andand coworkerscoworkers reportedreported onon thethe intramolecularintramolecular functionalizationfunctionalization ofof C(spC(sp3)-H)-H FF bondsbonds usingusing the the electrophilicelectrophilic [Fe([Fe(Fpda)-(THF)]pda)-(THF)]2 complexcomplex ( (6767)) as as catalyst and a lithiumlithium saltsalt withwith a a weaklyweakly coordinatingcoordinating counterion counterion as as a a co-catalyst. co-catalyst. Importantly, Importantly, the the lithium lithium salt salt is required is required to activate to activate the diazoesterthe diazoester under under mild conditions, mild conditions, while the while iron complex the iron is needed complex for is the needed actual carbene-transfer for the actual 3 reaction.carbene-transfer Following reaction. this strategy, Following intramolecular this strategy, C-H intramolecular functionalization C-H reactions functionalization of C(sp )-H reactions could beof realizedC(sp3)-H to could selectively be realized obtain to theselectively five membered obtain the ring five products membered (65 ).ring Following products this (65 strategy,). Following bi- andthis spirocyclicstrategy, bi systems- and spirocyclic were synthesized systems were (Scheme synthesized 18). Under (Scheme these 18) conditions,. Under these the five conditions, membered thering five wasmembered is favored, ring e.g., was over is benzylicfavored, C-H e.g., functionalization over benzylic C (-65fH functionalization). The formation of (65α,fβ).-unsaturated The formation esters of (α,β66)- occurredunsaturated via esters a β-hydride (66) occurred elimination via a reaction β-hydride [44 elimination]. reaction [44].

Molecules 2020, 25, 880 11 of 16 Molecules 2020, 25, x FOR PEER REVIEW 11 of 16

C6F5

C6F5 N O N Fe N2 Fe catalyst (67, 2.5 mol%) L L F O N O LiAl(OR )4 (25 mol%) O R Fe R C F 25 °C, 24 h, DCM O N 6 5 O R 64 65, (anti:syn) 66 C6F5 67 L = THF

O O O O O O O O O O

R

65a, R = H, 60% (76:24) 65d, 76% 65e, 59% 65f, 71% 65g, 71% 65b, R = MeO, 73% (77:23) (95:5) (23:77) 65c,R = Cl, 53% (77:23) Scheme 18. IntramolecularIntramolecular alkylation alkylation reaction for the synthesis of five five membered rings.rings. 7. Biocatalytic C-H Functionalization Reactions of Aromatic C-H Bonds 7. Biocatalytic C-H Functionalization Reactions of Aromatic C-H Bonds Over the years, the development of non-natural activity of enzymes has developed as an important Over the years, the development of non-natural activity of enzymes has developed as an strategy by which to conduct highly efficient carbene-transfer reactions [45,46]. In this section, we important strategy by which to conduct highly efficient carbene-transfer reactions [45,46]. In this have focused on the recent developments in this research area, with a focus on applications in C-H section, we have focused on the recent developments in this research area, with a focus on functionalization reactions. applications in C-H functionalization reactions. In the report of Koenigs, Weissenborn, and coworkers, the reaction of N-methyl indole (37) with In the report of Koenigs, Weissenborn, and coworkers, the reaction of N-methyl indole (37) with diazoacetonitrile (38) was also studied with the bacterial dye-decolorizing peroxidase YfeX from E. coli. diazoacetonitrile (38) was also studied with the bacterial dye-decolorizing peroxidase YfeX from E. A library of YfeX variants and the wild-type protein were studied and, under the best conditions, coli. A library of YfeX variants and the wild-type protein were studied and, under the best a turnover number of 37 was achieved with the wild-type enzyme. This TON (= turnover number) conditions, a turnover number of 37 was achieved with the wild-type enzyme. This TON (= turnover could be improved to 80 by using the I230A variant of YfeX. This variant was also studied in the reaction number) could be improved to 80 by using the I230A variant of YfeX. This variant was also studied of N-methyl indole with ethyl diazoacetate 2, which led to an increased TON of 236 (Scheme 17)[39]. in the reaction of N-methyl indole with ethyl diazoacetate 2, which led to an increased TON of 236 At the same time, the Fasan group reported on the application of an engineered myoglobin enzyme (Scheme 17) [39]. At the same time, the Fasan group reported on the application of an engineered in the C3-functionalization reaction of unprotected indoles using ethyl diazoacetate 2 as a carbene myoglobin enzyme in the C3-functionalization reaction of unprotected indoles using ethyl precursor. The Mb(H64V,V68A) variant gave the highest conversion and a TON of 82 in a whole-cell diazoacetate 2 as a carbene precursor. The Mb(H64V,V68A) variant gave the highest conversion and setup, and 68a was obtained as the only product of C-H functionalization. In their report, Fasan and a TON of 82 in a whole-cell setup, and 68a was obtained as the only product of C-H coworkers also investigated the functional group tolerance of this reaction, and different substitution functionalization. In their report, Fasan and coworkers also investigated the functional group patterns on the indole heterocycle were tolerated. Notably, in the case of N-protected indoles, the tolerance of this reaction, and different substitution patterns on the indole heterocycle were Mb(L29F,H64V) variant was required to achieve a similar activity of the enzyme (Scheme 19)[47]. tolerated. Notably, in the case of N-protected indoles, the Mb(L29F,H64V) variant was required to Fasan and coworkers studied the reaction mechanism of the enzymatic C-H functionalization achieve a similar activity of the enzyme (Scheme 19) [47]. reaction. For this purpose, the reaction of 3-deutero-indole d-31 and ethyl diazoacetate 2 was investigated.Koen Theigs, W C-Heisse functionalizationnborn, and co-worke productrs 68a was obtained as the protonated product exclusively, and no deuterium label was found in the reaction product. Moreover,CN in a competition experiment, no N2 YfeX (I230A) difference in reaction kinetics of the deuterated and non-deuterated starting3% con materialversion was observed. The N 100% C-H functionalization absence of a kinetic isotopeCN effect led the authors to the conclusionN that no C-H insertion mechanism occurred. Based37 on this38 evidence, Fasan and coworkers39a concluded a nucleophilic attack by the Fasan and co-workers indole substrate 31 to generate a zwitterionic intermediate 69/690, which underwent a solvent-assisted CO2Et proton-transfer reactionN to2 give the desired C-H functionalization product (Scheme 20)[47]. At this Mb(H64V,V68A) conversion > 99%, point, it is noteworthyN that Koenigs and Weissenborn et al. were100% able C-H tofun observectionalizatio an retention of the CO2Et deuterium label inH the reaction of deuterated N-methyl indoleN d-47 with diazoacetonitrile [39]. 31 2 68a H

CO2Et CO2Et CO2Et CO2Et R R

N N N H H N H

68b, R = Me, >99% 68f, (12%) 68g, (26%) 68h, R = Me, (10%) 85% 68c, R = F, >99% Mb(L29F,H64V); 52% Mb(L29F,H64V); 40% 68i, R = Cl, (14%), 50% 68d, R = Cl, > 99% 68j, R = OMe, (10%), 80% 68e, R = OMe, 77%

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

C6F5

C6F5 N O N Fe N2 Fe catalyst (67, 2.5 mol%) L L F O N O LiAl(OR )4 (25 mol%) O R Fe R C F 25 °C, 24 h, DCM O N 6 5 O R 64 65, (anti:syn) 66 C6F5 67 L = THF

O O O O O O O O O O

R

65a, R = H, 60% (76:24) 65d, 76% 65e, 59% 65f, 71% 65g, 71% 65b, R = MeO, 73% (77:23) (95:5) (23:77) 65c,R = Cl, 53% (77:23) Scheme 18. Intramolecular alkylation reaction for the synthesis of five membered rings.

7. Biocatalytic C-H Functionalization Reactions of Aromatic C-H Bonds Over the years, the development of non-natural activity of enzymes has developed as an important strategy by which to conduct highly efficient carbene-transfer reactions [45,46]. In this section, we have focused on the recent developments in this research area, with a focus on applications in C-H functionalization reactions. In the report of Koenigs, Weissenborn, and coworkers, the reaction of N-methyl indole (37) with diazoacetonitrile (38) was also studied with the bacterial dye-decolorizing peroxidase YfeX from E. coli. A library of YfeX variants and the wild-type protein were studied and, under the best conditions, a turnover number of 37 was achieved with the wild-type enzyme. This TON (= turnover number) could be improved to 80 by using the I230A variant of YfeX. This variant was also studied in the reaction of N-methyl indole with ethyl diazoacetate 2, which led to an increased TON of 236 (Scheme 17) [39]. At the same time, the Fasan group reported on the application of an engineered myoglobin enzyme in the C3-functionalization reaction of unprotected indoles using ethyl diazoacetate 2 as a carbene precursor. The Mb(H64V,V68A) variant gave the highest conversion and a TON of 82 in a whole-cell setup, and 68a was obtained as the only product of C-H functionalization. In their report, Fasan and coworkers also investigated the functional group tolerance of this reaction, and different substitution patterns on the indole heterocycle were tolerated.Molecules 2020 Notably,, 25, 880 in the case of N-protected indoles, the Mb(L29F,H64V) variant was required12 of to 16 achieve a similar activity of the enzyme (Scheme 19) [47].

Koenigs, Weissenborn, and co-workers CN N2 YfeX (I230A) 3% conversion N CN 100% C-H functionalization Molecules 2020, 25, x FOR PEER REVIEW N 12 of 16 37 38 39a Fasan and co-workers Scheme 19. Enzyme-catalyzed C3-alkylation reaction of indoles. CO2Et N2 Fasan and coworkers studied Mbthe(H reaction64V,V68A) mechanism of the coenzymaticnversion > 99%, C-H functionalization N CO Et 100% C-H functionalization reaction. For thisH purpose, 2 the reaction of 3-deutero-indoleN d-31 and ethyl diazoacetate 2 was 31 2 68a H investigated. The C-H functionalization product 68a was obtained as the protonated product exclusively, and noCO deuterium2Et label was foundCO2Et in the reaction product. Moreover, inCO a2 Etcompetition CO2Et experimentR , no difference in reaction kinetics of the deuterated and non-Rdeuterated starting material was observed. The absence of a kinetic isotope effect led the authors to the conclusion that no C-H N N N N insertion mechanismH occurred. BasedH on this evidence, Fasan and coworkersH concluded a nucleophilic68b, R attack = Me, >9 by9% the indole substrate68f, (12%) 31 to generate68g a, zwitterionic(26%) 68hintermediate, R = Me, (10 %69) /85%69′, which 68c, R = F, >99% Mb(L29F,H64V); 52% Mb(L29F,H64V); 40% 68i, R = Cl, (14%), 50% underwent68d, Ra = solven Cl, > 99%t-assisted proton-transfer reaction to give the desired68j, R C=- OHMe functionalization, (10%), 80% product 68e(Scheme, R = OMe 20), 77% [47]. At this point, it is noteworthy that Koenigs and Weissenborn et al. were able to observe a retentionScheme of 19.theEnzyme-catalyzed deuterium label C3-alkylationin the reaction reaction of deuterate of indoles.d N-methyl indole d-47 with diazoacetonitrile [39].

mechanistic proposal by Fasan et al. N2

H CO2Et N2 2

H CO2Et FeII Phe29 Fe His93 His93 H NH EtO2C CO2Et FeII 69'

His93 N H N 68a H Phe29 31

H NH EtO2C

Fe 69 His93 Scheme 20. MechanisticMechanistic investigations investigations and and proposed catalytic cycle by the Fasan group.

Shortly after after the the reports reports by Koenigs, by Koenigs, Weissenborn. Weissenborn and Fasan,. and the enzymatic Fasan, the C-H functionalization enzymatic C-H functionalizationof indole and other of heterocyclesindole and other with heterocycles an engineered with cytochrome an engineered P411 enzyme cytochrome was studiedP411 enzyme by Arnold was studiedand coworkers. by Arnold They and reported coworkers. on the They directed reported evolution on ofthe a “carbenedirected evolutiontransferase” of enzyme a “carbene that transferase”enables the highly enzyme effi cient, that enables chemoselective, the highly and efficien biocatalytict, chemoselective C-H functionalization, and biocatalytic of indole C and-H pyrrolefunctionalization heterocycles. of Using indole a andUV-Vis pyrrole spectrophotometry-based heterocycles. Using high-throughput a UV-Vis spectrophotomet screening, thery authors-based werehigh-throughput able study several screening, thousand the authors mutants were to engineerable study enzymes several to thousand conduct mutants chemoselective to engineer C-H enzymesfunctionalization to conduct reactions. chemoselecti Cytochromeve C P411-H functionalization variants were tested reactions. in reactions Cytochrome with N-Me P411 pyrrole variants (71), wereand two tested different in variantsreactions allowed with theN-Me regioselective pyrrole (71 C-H), functionalizationand two different in the variants C3 position allowed or the the C2 positionregioselective as well C- asH enantioselectivefunctionalization C-H in the functionalization C3 position or of the indole C2 position heterocycles as well with as diazopropionateenantioselective (SchemeC-H functionalization 21)[48]. of indole heterocycles with diazopropionate (Scheme 21) [48].

Molecules 2020, 25, 880 13 of 16 Molecules 2020, 25, x FOR PEER REVIEW 13 of 16

enantioselective C-H functionalization of N-Me indole Molecules 2020, 25, x FOR PEER REVIEW 13 of 16 Me CO2Et enantioselective C-H functiNon2alization of N-Me P4indole11-HF Y263E A328Y L437M 775 TTN N Me CO2Et Me 49% ee N CO2Et N 37 702 P411-HF 71 Y263E A328Y L437M 775 TTN N Me CO2Et 49% ee regioselective C-H functionalization of N-Me pyrrole N CO Et 37 70 2 71 P411-HF CO Et 705 TTN M263T G181E A82T 2 regioselective C-H functionalization of N-Me pyrrole N N 9:91 (72:73) CO2Et P411-HF 72 73 CO Et 705 TTN N M263T G181E A82T 2 2 N N 9:91 (72:73) N CO Et CO Et 2 2 P411-HF 72 73 CO2Et 485 TTN N2 M263T T78W G181K 71 2 N N 98:2 (72:73) N CO Et CO Et 2 2 P411-HF CO Et 485 TTN M263T T78W G181K 72 73 2 71 2 N N 98:2 (72:73) SchemeScheme 21. Indole 21. Indole C3-alkylation C3-alkylation with with engineered engineered P411 P411-HF-HF enzymes; enzymes; regioselective regioselective alkylation alkylation of of 72 73 1-methylpyrrole1-methylpyrrole53. 53. Scheme 21. Indole C3-alkylation with engineered P411-HF enzymes; regioselective alkylation of In further1In-methylpyrrole further reports, reports, 53 the. the Arnold Arnold group group studied studied engineered cytochrome cytochrome P411 P411 enzymes enzymes in benzylic in benzylic C-H functionalizationC-H functionalization reactions reactions of alkyl of alkyl arenes arenes with with ethyl ethyl diazoacetate diazoacetate (2). (2 A). cytochrome A cytochrome P411 P411 variant with anvariant axialIn furtherwith serine an reports, axial ligand serine the served Arnold ligand as groupserved the starting studied as the starting engineered point forpoint thecytochrome for directed the directed P411 evolution, evolution,enzymes which in which benzylic led led to the Cto- Hthe functionalization P411-CHF variant reactions that gave of a TTN alkyl (= arenes total turnover with ethyl number) diazoacetate of 2020 and (2). an A enantiomeric cytochrome P411ratio P411-CHF variant that gave a TTN (= total turnover number) of 2020 and an enantiomeric ratio of variantof 96.7:3.3 with (74a an, axialScheme serine 22) .ligand In further served studies, as the the starting C-H functionalizationpoint for the directed of allylic evolution, and propargylic which led 74a 96.7:3.3tosubstrates the ( P411, Scheme -asCHF well variant as22 alkyl). that In amines further gave a was TTN studies, studied (= total the ( turnover75, C-H 76, Scheme functionalization number) 22) of [49] 2020. Only and of recently, an allylic enantiomeric Arnold and propargylic ratioet al. substratesofwere 96.7:3.3 able as well to(74a further as, Scheme alkyl extend amines 22) .the Inwas substratefurther studied studies, scope (75 of,the76 carbene ,C Scheme-H functionalization precursors 22)[49]. to Only trifluoro of recently,allylic diazoethane, and Arnold propargylic which et al. were able tosubstrateswas further studied as extend well in the as the αalkyl-C(sp substrate amines3)-H functionalization scopewas studied of carbene (75 , of76 precursors, N,N Scheme-dialkyl 22) to aniline[49] trifluoro. Only derivatives. recently, diazoethane, Arnold By directed which et al. was studiedwereevolution in able the αto of-C(sp further the3 )-H wild extend functionalization-type the cytochrome substrate scope of P411 N,N-dialkyl of enzymecarbene precursors the aniline C-H derivatives. functionalization to trifluoro Bydiazoethane, directed reaction evolution which with of the wild-typewastrifluoro studied cytochrome diazoethane in the α -C(sp P411 was3 )-enzyme realizedH functionalization. the Further C-H functionalization studies of N,N focused-dialkyl onaniline reaction the derivatives. access with trifluoro of the By oppositedirected diazoethane was realized.evolutionstereoisomer. Further of the Starting wildstudies -type from focused cytochrome a P411 on variant the P411 access that enzyme of provided the the opposite C the-H opposite functionalization stereoisomer. stereochemistry, Starting reaction from direct with a P411 varianttrifluoroevolution that provided diazoethaneled to a variant the wasopposite providing realized stereochemistry, the. Further inverse stereochemistry. studies direct focused evolution This on example the led access to showcases a variant of the the providing opposite power the stereoisomer.of biocatalytic Starting transformations from a P411 and the variant fact that both provided enantiomers the opposite of a desired stereochemistry, product can direct be inverse stereochemistry. This example showcases the power of biocatalytic transformations and the evolutionobtained b ledy means to a variant of directed providing evolution the inverse (77, Scheme stereochemistry. 22) [50]. This example showcases the power fact that both enantiomers of a desired product can be obtained by means of directed evolution (77, of biocatalytic transformations and the fact that both enantiomers of a desired product can be Scheme 22)[50]. P411-CHF obtained by meansH of directed evolution OR(77, Scheme 22) [50]. N 2 P411-PFA R’’ COR’’’ R R' R’’ EWG P411-CHF H OR R R’ N 2 P411-PFA R’’ COR’’’ R R' R’’ EWG benzylic C-H alkylation allylic and propaRgylicR’ substrates CO2Et CO2Et CO2Et CO2Et CO2Et benzylic C-H alkylaOtioMen Me allylic and propagylic substrates OMe CO2Et CO2Et OMe CO2Et CO2Et MeO MeO CO2Et MeO OMe Me 74a 74b 75a 75b 75c OMe 2150 TTN 530 TTN 3750 TTNOMe 70 TTN 190 TTN MeO 96.7:3.3 e.r. MeO 97.9:2.1 e.r. 93.6:4.6 e.r. MeO 97.0:3.0 e.r. 99.0:1.0 e.r. 74a 74b 75a 75b 75c alkyle ami2150nes TTN 530 TTN P4375011-PF TTNA catalyzed reaction70 p roTTNducts 190 TTN 96.7:3.3 e.r. 97.9:2.1 e.r. 93.6:4.6 e.r. 97.0:3.0 e.r. 99.0:1.0 e.r. CO2Et CO2Et N N alkyle amines P411-PFA catalyzed rea*ction products * N N CF N CO2Et CO2Et MeO 3 CF3 N * N P411-PFA P411-PF*A 76aN N 76b 2330 TTN 2030 TTN 77a, 2100 TTN, 95% ee CF 77b, 180N TTN, 88% ee MeO 3 CF3 82.8:17.2 e.r. 76a 76b P4P4111-PF1-PFA-(S)A P4P4111-PF1-PFA-(S)A 2330 TTN 2030 TTN ent-77a77a, 2100, 1620 TTN, TTN, 95% 82% ee ee ent-77b,77b 180,180 TTN, TTN, 88% 72% ee ee 82.8:17.2 e.r. Scheme 22. C-H functionalization using engineeredP4 P41111-PF-A-(S)CHF and P411-PFA enzymes.P411-PFA-(S) ent-77a, 1620 TTN, 82% ee ent-77b,180 TTN, 72% ee SchemeScheme 22. 22.C-H C- functionalizationH functionalization usingusing engineered P411 P411-CHF-CHF and and P411 P411-PFA-PFA enzymes. enzymes.

Molecules 2020, 25, 880 14 of 16

8. Conclusions and Perspectives Over the years, the application of iron complexes has gained significant attention for the conduction of C-H functionalization reactions with diazoalkanes under mild and sustainable reaction conditions. A variety of iron complexes have been described to date to perform C-H functionalization reactions with high efficiency, which have leveraged iron-catalyzed carbine-transfer reactions as an important tool for organic chemists to functionalize unreactive C-H bonds. In light of the recent developments in enzyme-catalyzed carbene-transfer reactions and directed evolution, iron-heme enzymes are now developing as important tools with which to conduct highly chemo-, regio-, and stereoselective C-H functionalization reactions. Building upon these advances, future developments of iron-catalyzed C-H functionalization might include, for example, the site-selective activation of unactivated C(sp3)-H bonds, the broadening of the substrate scope to include non-activated aromatic systems, or development of an understanding of the reaction mechanisms and the spin state of iron within the catalytic cycle.

Author Contributions: R.M.K., C.E. and S.J. wrote the manuscript and schemes. All authors have read and agreed to the published version of the manuscript. Funding: This article was funded by Deutsche Forschungsgemeinschaft. Conflicts of Interest: The authors declare no conflict of interest.

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