Catalytic C(sp3)−H Alkylation via an Iron Carbene IntermediateJennifer R. Griffin, Chloe I. Wendell, Jacob A. Garwin, and M. Christina White*

Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States

*S Supporting Information

ABSTRACT: The catalytic transformation of a C(sp3)−Hbond to a C(sp3)−C bond via an iron carbeneintermediate represents a long-standing challenge. Despitethe success of enzymatic and small molecule iron catalystsmediating challenging C(sp3)−H oxidations and amina-tions via high-valent iron oxos and nitrenes, C(sp3)−Halkylations via isoelectronic iron carbene intermediateshave thus far been unsuccessful. Iron carbenes have beeninert, or shown to favor olefin cyclopropanation andheteroatom-hydrogen insertion. Herein we report an ironphthalocyanine-catalyzed alkylation of allylic and benzylicC(sp3)−H bonds. Mechanistic investigations support thatan electrophilic iron carbene mediates homolytic C−Hcleavage and rebounds from the resulting organoironintermediate to form the C−C bond; both steps aretunable via catalyst modifications. These studies suggestthat for iron carbenes, distinct from other late metalcarbenes, C−H cleavage is partially rate-determining andmust be promoted to effect reactivity.

I ron is one of the most abundant elements, totaling one-thirdof the Earth’s mass, and is emerging as an important metal

for homogeneous catalysis.1a−f Iron small molecule catalystshave been demonstrated to catalyze challenging C−H oxidationand amination processes via high-valent metal oxos andnitrenes1b−d,f. In contrast, no iron catalyst has beendemonstrated to alkylate C(sp3)−H bonds via an isoelectronicmetallocarbene intermediate.Naturally occurring and engineered P450 enzymes form only

inert carbenes or carbenes active for lower energy processesthan C−H alkylation (e.g., cyclopropanations, heteroatom-hydrogen bond insertions)2 (Figure 1). Small molecule iron

catalysts capable of forming carbenes also fail to catalyze C−Halkylation, favoring alternative reaction pathways.3 Curiously,nearly all other late metals, including copper,4a,b cobalt,4c

silver,4a palladium,4d rhodium,4e and ruthenium,4f form metal-locarbenes catalytically active for C−H alkylation. Herein wereport an iron-catalyzed alkylation of allylic and benzylicC(sp3)−H bonds and provide evidence of an iron carbeneintermediate. Distinct from other late metal carbenes, C−Hcleavage is partially rate-determining and tunable via catalystmodifications.Iron carbene complexes have been generated stoichiometri-

cally at low temperatures, isolated,5a and/or demonstrated toundergo C−H insertion in a separate step at elevatedtemperatures (e.g., 80 °C).5b,c We hypothesized that onereason these reactions are not catalytic is due to the distinctenergetic requirements for each step. At the elevatedtemperatures needed for C−H insertion, thermal decom-position of the diazoester or metal carbene into a free carbenemay occur. Literature reports claiming iron-catalyzed C−Halkylation with methyl phenyldiazoacetate at 80 °C areambiguous6a because this diazoester is reported and observedby us (Supporting Information, SI) to show significantnonmetal mediated alkylation reactivity at this temperature.6b

We hypothesized that with iron, there is a higher kineticbarrier to C−H insertion than in rhodium and copper systemswhere metallocarbene formation is rate-determining.4a,7,8 Thisdifference may explain the predominance of lower energypathways in iron carbene reactions, such as competitivedimerization to furnish olefins.7 Reactivity and selectivity ofmetal carbenes is highly tunable;4e,9a therefore, we aimed toelectronically and sterically tune the catalyst and carbeneprecursor to form a metallocarbene intermediate reactiveenough to insert into C(sp3)−H bonds at temperatures thatmitigate deleterious pathways and do not decompose thediazoprecursor.We first evaluated iron catalysts used for metallocarbene-

mediated cyclopropanations and heteroatom-hydrogen inser-tions for the intramolecular alkylation of allylic C−H bonds(Table 1A).3,5b,10 We examined a series of substituted diazocompounds (acceptor 1, donor−acceptor 2, acceptor−acceptor3) with varying degrees of electrophilicity and steric bulk.9a

With iron porphyrin and phthalocyanine catalysts, diazoester 1converted to olefin dimer (4, 93% and 84%, respectively),suggestive of iron carbene formation.9a Bulkier disubstitutedcarbene precursor 2 disfavored dimerization with all catalysts,but favored ketone product 5 over alkylation.9a

Received: July 20, 2017Published: September 12, 2017

Figure 1. Challenges of iron carbene C−H activation.

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© 2017 American Chemical Society 13624 DOI: 10.1021/jacs.7b07602J. Am. Chem. Soc. 2017, 139, 13624−13627

We hypothesized that augmenting the electrophilicity of thedisubstituted diazo compound would increase its reactivity byproducing a strongly electrophilic metallocarbene that couldmore readily engage in higher energy C−H insertion pathways.Under rhodium catalysis, such electrophilic diazo compoundsrequire very active catalysts to form the metallocarbene;however, once formed, the resulting carbene is more reactivetoward C−H insertion.9a Acceptor−acceptor diazoester 3resulted in predominately recovered starting material. Uponexamination of the 13C shifts of the α-carbon of variousacceptor−acceptor diazo precursors, we observed that sulfonateesters appeared to be the most electrophilic and thusinvestigated their diazoesters (6) for C−H alkylationreactivity.9b The catalyst with the greatest π-accepting character,iron phthalocyanine chloride ([FeIIIPc]Cl), formed C−Halkylated δ-sultone product 7 in low yield (3%) but withexcellent selectivity (97% rsm).Examination of noncoordinating counterions to render the

iron catalyst more electrophilic led to a significant increase inyield with both AgSbF6 (45%, SI) and NaBArF4 (48%) (Table1B). Adding the substrate to [FeIIIPc] over an hour furtherincreased the yield (53%). Catalysts with halogenatedphthalocyanine ligand frameworks formed C−H alkylatedproduct in lower yield than the unsubstituted, commercialcatalyst (e.g., [(FeIIICl8Pc)Cl]). Iron(II) phthalocyanine andiron porphyrin complexes gave very little or no C−H alkylation(see SI), highlighting the significance of the FeIII oxidation stateand the ligand framework.10 NaBArF4 alone gave no product(see SI).Allylic C−H alkylations are rare under both noble and base

metal catalysis. Specifically, under rhodium and coppercatalysis, chemoselectivity issues arise wherein cyclopropana-tion of the olefin competes with C−H insertion.4a,e,9 Weinvestigated the scope of this iron-catalyzed reaction across arange of allylic diazosulfonate esters (Table 2A). Bulky

trisubstituted olefins, olefins with proximal, protected oxygenfunctionality, and styrenyl substrates all undergo alkylation inpreparative yields (8−13). Consistent with an electrophilicmetallocarbene intermediate, [FeIIIPc]-catalyzed C−H alkyla-tion is sensitive to substrate electronics (13 vs 10).4c,11 Thiscontrasts observations with metalloradical intermediatesinvoked in cobalt catalysis, where substrate electronics do notaffect reactivity.4c Chemoselectivity for iron-catalyzed allylic C−H alkylation is maintained with more proximal olefins wherecyclopropanation would form the geometrically preferred 6-membered sultone9b (14, 15). In contrast, rhodium catalysisshows poor chemoselectivity for C−H insertion, formingcyclopropanated products. We also demonstrate one exampleof ethereal C−H alkylation (16).Benzylic C(sp3)−H bonds were evaluated under these

reaction conditions and shown to readily undergo alkylation(Table 2B). Substrates containing electron rich aryl rings arealkylated in high yield (17, 18), with no cyclopropanationobserved even for a naphthalene-containing substrate (19).[FeIIIPc] promotes C−H alkylation adjacent to chromene andindole heterocycles (20, 21), and tolerates lactam and

Table 1. Reaction Optimization Table 2. Substrate Scope

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thiophene motifs (23, 24). A substrate containing abenzodioxole moiety is readily alkylated (22), despite theactivated methylenedioxy functionality2a (Figure 1A).We investigated the application of this reaction to the late-

stage functionalization of δ-tocopherol, a chromane antioxidant(Table 2C). Tocopherol derivative 25 was subjected to[FeIIIPc]-catalyzed C−H alkylation and furnished 26 in 78%yield. The δ-sulfone motif has been demonstrated to be readilyderivitized.9b Accordingly, a three step elaboration of the δ-sultone via nucleophilic displacement yielded 27, bearing anunsymmetrical tertiary center with two new functional grouphandles, in 44% overall yield.Next we sought to investigate the mechanism and the

involvement of an iron carbene intermediate in this reaction.We hypothesized that C−H alkylation occurs via an iron-boundcarbene intermediate that, analogous to iron oxos1b,f and ironnitrenes,1c,d promotes homolytic cleavage of the C−H bondfollowed by recombination with the resulting carbon-centeredradical to form the new C−C bond (Figure 2A). Alternatively,

[FeIIIPc] could serve as a Lewis acid to decompose thediazosulfonate ester to a free carbene capable of inserting intoproximal C−H bonds. We investigated unligated iron salts andUV light with no added catalyst, conditions demonstrated toform reactive free carbenes from acceptor-acceptor diazospecies.12 FeCl3 and FeCl2 resulted in predominately recovered

starting material (Figure 2B), whereas irradiation of 6 with UVlight gave compound 28, generated from C−H insertion of thefree carbene into the dichloromethane solvent (Figure 2B).Product 28 is not observed under [FeIIIPc]-catalysis, which isalso run in dichloromethane. These divergent outcomessupport the hypothesis that [FeIIIPc]-catalyzed C−H alkylationdoes not proceed via free carbene intermediates.We then sought to probe the involvement of an iron-bound

carbene intermediate in both the C−H bond cleavage and C−Cbond formation steps (Figure 2C,D). In rhodium-catalysisproceeding via metallocarbene intermediates, varying thecarboxylate ligands has been shown to influence both theintramolecular kinetic isotope effect (KIE) of C−H cleava-ge7,11,12b and the selectivity of C−C bond formation.4e,9a,13 Weobserved a change in the KIE with varied ligand electronics:[FeIIIPc] gave the highest KIE (5.0), followed by [FeIIICl8Pc](4.8) and [FeIIICl16Pc] (4.5). These data support involvementof the iron complex in the C−H cleavage step. The larger KIEvalues for iron versus rhodium (1.8), support the proposedstepwise versus concerted mechanism (Figure 2C).7 A stepwisemechanism accounts for the improved chemoselectivity of ironrelative to rhodium catalysts for C−H insertion over cyclo-propanation; a stabilized allylic radical is preferred over thesecondary aliphatic radical formed during stepwise olefinoxidation processes.1c,4c

We also probed the effect of ligand electronics on the C−Cbond forming step. We performed a study on Z-olefin substrate32 to determine if scrambling of the double bond geometryoccurred during allylic C−H alkylation (Figure 2D). UnderRh2(OAc)4 catalysis, no isomerization of the olefin wasobserved, consistent with a concerted mechanism of C−Hinsertion. In contrast, under [FeIIIPc] catalysis we observedscrambling of olefin geometry, consistent with a stabilizedcarbon radical intermediate. The extent of olefin isomerizationis dependent on the electronic substitution of the ligand, withthe electron deficient chlorinated iron catalysts affordingproducts with less isomerization than the unsubstitutedphthalocyanine (10:1 vs 3:1). Under cobalt porphyrin catalysis,in the absence of a chiral pocket, isomerization duringfunctionalization of Z-olefins occurs to a greater extent thanin the iron system.4c This suggests that C−H alkylation withiron proceeds with less free radical character than cobalt.4c

Electron withdrawing ligands may destabilize an iron-alkylspecies prompting recombination at a faster rate.We hypothesized that C−H insertion is rate-determining for

iron-catalyzed alkylation, unlike rhodium and copper catalysi-s.4a,7,8 Intermolecular KIE studies that measured initial rates onparallel reactions with benzylic substrate 30 and 30-d2 revealeda primary KIE of 3.1 under [FeIIIPc] catalysis (Figure 2C). Thisis consistent with C−H cleavage being part of the rate-determining step of the reaction. Initial rate measurements with[FeIIICl16Pc] showed a lower KIE of 1.4 suggesting that with amore electron deficient iron catalyst, formation of themetallocarbene, which requires donation of electron densityfrom the metal center to extrude nitrogen, competes energeti-cally with C−H cleavage.7

We report an iron-catalyzed C(sp3)−H alkylation via ametallocarbene intermediate. [FeIIIPc] alkylates allylic andbenzylic C(sp3)−H bonds with broad scope. Mechanisticstudies demonstrate the ability to exert catalyst control on thereactivity and selectivity during C−H cleavage and functional-ization. Future studies will be aimed at elucidating the nature ofthe iron carbene intermediate, as well as further development of

Figure 2. Mechanistic studies.

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this highly tunable species to access stronger aliphatic C(sp3)−H bond types and intermolecular C−H alkylations.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/jacs.7b07602.

Experimental details and characterization data andspectral data (PDF)

■ AUTHOR INFORMATIONCorresponding Author*mcwhite7@illinois.eduORCIDM. Christina White: 0000-0002-9563-2523NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSFinancial support provided by the NIGMS MIRA (R35GM122525). J.R.G. is a National Science Foundation andSpringborn Graduate Fellow. C.I.W. is an Illinois DistinguishedGraduate Fellow. We thank L. Zhu for assistance with NMRand Dr. J. R. Clark for checking our experimental procedure.

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