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 elegantorganic methods synthesis have methodolog been developedies, but in recentalso 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 theof secondorganic most synthesis abundant methodolog metal in theies, Earth’sbut 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 discussthe functionalization the advances of made C-H inbonds. 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 dateexamples back to date reports back by Meerweinto reports andby 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 lightusing via freehigh 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 applicationsand, as a co innsequence organic synthesis., a lack Inof 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