Copper-Catalyzed sp3 CâH Amination - American Chemical Society

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Copper-Catalyzed sp3 C−H Amination Raymond T. Gephart, III and Timothy H. Warren* Department of Chemistry, Georgetown University, Box 571227-1227, Washington, D.C. 20057, United States ABSTRACT: Among the transition metals, copper-based catalyst systems enable the widest range of N-containing reagents in C−H amination to allow for the direct incorporation of versatile N-based functionalities via ubiquitous C−H bonds. In addition to nitrene-based approaches involving sulfonyliminoiodinanes (PhINSO2R), diverse non-nitrene protocols have been developed that allow for the direct use of organic amides, nitrosoarenes, and hydroxylamines, strained heterocycles such as oxaziridines, acetonitrile, secondary sulfonylamines, and even alkylamines and arylamines. Synthetic, mechanistic, and theoretical studies reveal discrete copper nitrenes [Cu]NR and copper amides [Cu]−NHR to be key reactive intermediates in C−H amination. Copper-catalyzed sp3 C−H amination is reviewed, connecting catalytic reactivity patterns with likely copper intermediates wherever possible, with the goal to stimulate the further development of C−H functionalization reactions with copper which possess significant sustainability advantages over other contemporary approaches involving noble metals.

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INTRODUCTION C−N bond formation is a crucial endeavor in chemical synthesis, due to the ubiquity of this structural unit in myriads of molecules of biological and technological importance. C−H amination, the direct conversion of C−H to C−N bonds, offers a method to streamline the introduction of N-based groups into molecules without traditional functional group manipulations. This approach offers a potentially highly atom economical synthesis of amines with minimal environmental impact. The wide range of catalyst systems developed for catalytic C−H amination reflects the importance of this C−H functionalization reaction.1−4 While the past decade has seen the use of Rh,5,6 Ru,6−9 and Pd10,11 systems for catalytic C−H amination with applications in complex molecule synthesis, cost, sustainability, and toxicity concerns strongly motivate the development of selective catalyst systems based on earthabundant metals. Similarly inspired, even metal-free systems have been recently introduced.12 Of all the first-row metals that participate in catalytic C−H amination such as Mn,13 Fe,14 and Co,15,16 the diverse combinations of catalyst precursors, nitrogen sources, and oxidants that have been examined for copper have led to the broadest range of N-substituents that may be directly incorporated via C−H amination. We specifically focus on the copper-catalyzed amination of sp3 C−H bonds. The earliest examples of C−H amination involved the copper-promoted functionalization of sp3 C−H bonds over 45 years ago,17 which spurred great interest in the development of efficient catalyst systems and concomitant attention to their mechanistic understanding. Nonetheless, there are many examples of copper-catalyzed sp2-C−H amination of arenes18 (especially electron-deficient arenes),19 aldehydes,20 azoles,21 and other heterocycles,22 including carbazoles,23 as well as the sphybridized C−H bonds of terminal alkynes24 that offer rapid © XXXX American Chemical Society

construction of C−N bonds from C−H bonds without functional group manipulations. Previous reviews on metal-catalyzed C−H amination1−4,25 have featured sections on copper, and recent reviews on copper in C−H functionalization26,27 have discussed C−H amination. Herein, we have attempted to cover copper-catalyzed sp3 C−H amination rather comprehensively with discussion organized around the various classes of N-sources successfully deployed for C−N bond formation. Wherever possible, we bring into focus key, enabling reactive copper intermediates in an attempt to connect structure, reactivity, and mechanism to further stimulate the development of efficient and versatile C−H functionalization protocols with this versatile and earthabundant metal.

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IN THE BEGINNING THERE WAS COPPER... The earliest example of metal-catalyzed C−H bond amination dates to a report by Kwart and Khan in 1967 that involves the reaction between benzenesulfonyl azide and cyclohexene in the presence of a vast excess of copper powder (Scheme 1).17 While the major nitrogen-containing product of the reaction was benzenesulfonyl amine, the aziridination and allylic C−H amination products were identified in 15 and 3% yields, respectively. Other products also formed, such as a vinylamine that likely resulted from a catalyzed 1,3-dipolar addition of the electron-poor azide to the alkene. Importantly, the coppernitrene species “CuNSO2Ph” were suggested by the authors as key, enabling intermediates directly responsible for the formation of aziridine and allylic C−H amination products. Special Issue: Copper Organometallic Chemistry Received: August 31, 2012

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dx.doi.org/10.1021/om300840z | Organometallics XXXX, XXX, XXX−XXX

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Scheme 1

Scheme 4

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FIRST SYNTHETICALLY USEFUL APPLICATIONS OF COPPER NITRENES: ALKENE AZIRIDINATION Due to the close relationship between aziridination and C−H amination revealed through early studies with sulfonylnitrene precursors via the putative copper sulfonyl nitrene intermediates [Cu]NSO2R, we briefly examine copper-catalyzed aziridination, which first developed into a valuable synthetic methodology for C−N bond formation.4,34 Even in the absence of additional ligands, simple copper salts and complexes such as CuClO4, Cu(acac)2, and Cu(OTf)2 catalyze efficient alkene aziridination with PhINTs with alkenes such as cyclohexene, α-methylstyrene, and β-methylstyrene,35,36 which possess mildly activated allylic/benzylic C−H bonds (C−H BDE = 80−82 kcal/mol)31 (Scheme 5). Largely owing to pioneering

When DMSO (Me2SO) was added to the reaction, these products were absent and Me2S(O)(NTs) formed in 50% yield as a result of N-tosylnitrene transfer to DMSO. Inspired by the possibility of reactive copper−nitrene intermediates for C−N bond formation, Turner and colleagues stirred chloramine-T (TsNClNa) with 1 equiv of copper powder in dioxane at room temperature and obtained a 70% yield of the corresponding C−H amination product (Scheme 2).28 Scheme 2

Scheme 5

The next key advances in metal-catalyzed C−H amination came in the early 1980s, when iminoiodinanes ArINR,29 hypervalent iodine reagents that are related to iodosylbenzene PhIO, were identified as promising nitrene-transfer reagents. Using the Fe and Mn porphyrin complexes Fe(TPP)Cl and Mn(TPP)Cl (TPP = tetraphenylporphyrin) in conjunction with PhINTs, Breslow and Gellman reported the C−H amination of cyclohexane in 3.1% and 6.8% yields, respectively (Scheme 3).30 Undoubtedly, the choice of a substrate with a

studies by Evans, who employed bis(oxazoline) ligands,35−37 and Jacobsen, who employed chiral diimines,38,39 alkene aziridination with soluble copper complexes has become a useful methodology for the enantioselective construction of these synthetically valuable three-membered heterocycles.4,34,40 Copper bis(oxazolines) have also been used with Ntosyloxycarbamates (HN(Ts)C(O)OR) in the asymmetric aziridination of styrenes.41 Tris(pyrazolyl)borate ligands (Tp) represent another important early class of ligands employed by Pérez in alkene aziridination42,43 that eventually would see great utility in C−H amination. Two basic classes of stereochemical experiments interrogated the nature of the active intermediates in these nitrene-transfer reactions. Evans employed stereochemical probes to infer that copper-catalyzed aziridination reactions typically proceeded in a concerted manner since cis-alkenes, especially with alkyl groups on the double bond, were rarely isomerized upon conversion to the corresponding aziridine.35 The formation of trans-aziridines, however, occurred occasionally when an aryl ring was in direct conjugation with the alkene, a finding also echoed in contemporary studies by Jacobsen38 as well as later by others such as Comba44 and Kühn.45 Importantly, use of a radical clock type substrate led to exclusive formation of the ringclosed aziridine, supporting a nonradical mechanism for nitrene

Scheme 3

weaker C−H bond would have given higher yields, since cyclohexane has a particularly strong C−H bond (C−H BDE = 97).31 A year later, Breslow and Gellman demonstrated the possibility of efficient intramolecular C−H amination through the use of 2,5-diisopropylphenylsufonyl imidoiodinanes (Scheme 4),32 which present well-positioned C−H bonds of modest strength (C−H BDE = 83 kcal/mol).31 Both the previously studied metalloporphyrin M(TPP) (M = Fe, Mn) and the dirhodium acetate Rh2(OAc)4 were examined,32 foreshadowing the great promise of metalloporphyrin33 and dirhodium species1,5,6 for C−H amination. B


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transfer (Scheme 6). Several Hammett studies have been performed with PhINTs or related in situ generated

from sulfonylnitrene insertion into an allylic C−H bond to give a six-membered ring (Scheme 9).50

Scheme 6

Scheme 9

iminoiodinanes and para-substituted styrenes46,47 or cinnamate esters.48 While a range of catalysts and Hammett parameters (σ, σ+, σ•) were examined, these studies generally pointed to modest buildup of positive charge or radical character at the benzylic carbon during a mildly asynchronous transfer of the nitrene to the C atoms of the CC bond.

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DEVELOPMENT OF C−H AMINATION CATALYSTS FROM ALKENE AZIRIDINATION CATALYSTS Taylor provided an early example that connected coppercatalyzed aziridination to C−H amination. Aiming to develop an aziridination catalyst, Taylor employed chloramine-T with a catalyst mixture containing the N-pentyl imine of pyridine-2carboxaldehyde 3 with copper(I) triflate (Scheme 10).51 While

C−H AMINATION COMPETES WITH AZIRIDINATION In Evans’ key study that outlined the scope of aziridination with simple copper salts, he reported only two examples of C−H amination that occurred alongside alkene aziridination when using PhINTs (Scheme 7).35 The use of 5 mol % of CuOTf

Scheme 10

Scheme 7

aryl alkenes such as styrene gave moderate to good yields, cyclohexene gave little aziridine. Instead, the allylic C−H amination product was formed in ca. 22% yield with the remainder of the PhINTs reagent converted to the tosylamine H2NTs. This prompted the examination of the benzylic substrate tetrahydronapthalene with a modest C−H bond strength (C−H BDE = 83 kcal/mol),31 which gave an approximate benzylic C−H amination yield of 46%. Peréz’s use of copper(I) tris(pyrazolyl)borates (Figure 1) in alkene aziridination and C−H aminination further illustrates the close connection between these two methodologies and the copper nitrene species that mediate them. In 1993 Pérez, Brookhart, and Templeton described the use of Tp*Cu(η2CH2CH2) in the aziridination of styrene, cis-cyclooctene, and 1-

as catalyst in nitromethane solvent in the reaction with cyclohexene gave both the aziridine and allylic C−H amination products in 17 and 10% yields, respectively. Similarly, reaction of methyl cinnamyl ether under catalysis by CuClO4 gave the aziridine in 31% yield along with a 20% yield of the N-tosyl imine that resulted from loss of methanol from the initial allylic C−H amination product. Further exploration of copper-catalyzed aziridination with PhINTs nonetheless led to occasional examples of allylic C− H amination. An early example of copper-catalyzed C−H amination in total synthesis involved the installation of a Ntosyl group into an allylic position by Overman in the synthesis of (−)-hispidospermidin.49 Instead of aziridination at the somewhat hindered CC double bond of 1, net allylic C−H amination occurred to give 2 (Scheme 8). While coppercatalyzed reactions of a family of ω-alkenyl iminoiodinanes generally resulted in bicyclic aziridines, Dauban and Dodd did observe intramolecular allylic C−H amination that resulted Scheme 8

Figure 1. Family of TpXCu catalysts. C


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hexene in good yields (90, 75, and 40% yields, respectively).42 In a later report, they extended these studies to a range of substituted TpCu complexes (Figure 1) and found that the perbromo-substituted derivative TpBr3Cu is particularly effective with PhINTs, aziridinating 1-hexene in 91% yield at a 5 mol % catalyst loading (Scheme 11).43

Scheme 13

Scheme 11

demonstrated by high aziridination yields with cyclooctene.43 Similarly, structurally related TpAg catalysts mediate C−H amination with PhINTs with unactivated C−H bonds and also catalyze alkene aziridination over allylic C−H amination.54 While strictly not C−H amination, the use of a C−SiMe3 proxy for the C−H group in an allylic position allowed for the formation of allylamines with Cu(OTf)2 and PhINTs. Using Cu(OTf)2 as catalyst, the silyl or stannyl functionalities served as leaving groups in the oxidation of CH2CH2CH2TMS to CH2CH2CH2NHTs with PhINTs (Scheme 14).55 One suggested mechanism involved initial formation of the aziridine followed by desilylation or destannylation.

The TpBr3Cu catalyst is also quite active in the amination of 3 sp -hybridized C−H bonds with PhINTs (Scheme 12).52 Scheme 12

Scheme 14

Employing neat C−H substrate as solvent and a 5 mol % catalyst loading, toluene and mesitylene underwent C−H amidation with PhINTs in >95% yield. Importantly, substrates with much stronger C−H bonds such as cyclohexane (BDE = 97 kcal/mol)31 and benzene (BDE = 113 kcal/mol)31 also participated in C−H amination, giving the CyNHTs and PhNHTs products in 65% and 40% yields, respectively, with the balance of the PhINTs reagent converted to H2NTs. Pérez also reported the use of chloramine-T in the C−H amination of 1° benzylic and ether α-C−H bonds, though occasionally with greater production of H2NTs than with PhI NTs.53 By considering the sites of C−H functionalization by the TpBr3Cu/PhINTs system, it becomes clear that in the amination of sp3-hybridized bonds the strength of the reacting C−H bonds is an important consideration.53 For instance, a very high yield was obtained with toluene (only one site for sp3 functionalization), while ethylbenzene gave a 56/14 mixture of the 2° and 1° C−H amination products along with 30% H2NTs.53 C−H amination of cumene is even more selective toward the 1° site (3°:1° = 30:20) but gave an overall lower yield (Scheme 13). Strong evidence that a copper−nitrene species serves as an active intermediate comes from a comparison of the catalyst structure vs site of functionalization for cumene (Scheme 13). While the overall conversion to product trailed off from 50% to 17%, C−H amination selectivity actually switched from mildly favoring the 3° site to favoring the 1° site by a factor of 16:1 (Scheme 13). Notably, C−H amination is not favored for allylic C−H bonds. Aziridination took place essentially exclusively, as

Vedernikov and Caulton designed a new tripodal ligand L for use in copper complexes [LCu]+ (Scheme 15) that possess Scheme 15

built in strain relative to related, non-macrocycligc ligands. Copper(II) complexes such as LCuCl2 were effective in the aziridination of alkenes with PhINTs, achieving high yields with a range of simple unactivated alkenes at 1−10 mol % loadings (Scheme 15). Notably, C−H amination began to compete with aziridination with 1-butene, cyclopentene, and cyclohexene as substrates. Reduced aziridine yields accompanied the formation of the allylic C−H amination products, observed in 12−28% yields.56 A particularly fascinating aspect of this system is its ability to dehydrogenate alkanes to the corresponding alkenes, which then serve as substrates for D


Organometallics

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amine-T gave higher yields of benzylic C−H amination than did the hydrate (TsNClNa·3H2O) with decreased amounts of byproducts such as H2NTs. Depending on the nature of the allylic substrate, either aziridination or C−H amination was favored. This system exhibited somewhat nonspecific reactivity with alkenes (Scheme 18). Cyclooctene led to aziridination,

aziridination. Thus, the reaction of LCu(OTf)2 (activated by 2 equiv of NaBArF4) with PhINTs in the presence of cyclopentane, cyclohexane, and cyclooctane gave both the cycloalkenes and the corresponding aziridines, with the highest aziridination yields for cyclopentane (Scheme 16).57 Scheme 16

Scheme 18

Simple copper salts such as CuCl or [Cu(NCMe)4]PF6 may also be used for C−H amination with chloramine-T hydrate. Taylor identified that electron-rich C−H substrates led to high yields in C−H amination with chloramine-T as catalyzed by 10 mol % CuCl in MeCN (Scheme 17).58 For instance, 4Scheme 17 while cyclohexene gave the allylic C−H amination product in 58% yield along with a small amount of a chloramidation product; chloramidation also took place with 1-octene in low yield. Both the stereochemistry of the cyclohexene product and the regiochemistry of the 1-octene chloramidation products were inconsistent with aziridine formation followed by chloride attack.59 Nicholas also employed chiral diimine ligands in intermolecular60 and intramolecular61 C−H amination to examine the potential of these systems in enantioselective C−H amination (Scheme 19). In combination with [Cu(NCMe)4]PF6, the Scheme 19

methoxy- and 3,4-dimethoxy-substituted ethylbenzenes gave the benzylic amination product in 62 and 74% yields, employing only a slight excess of chloramine-T relative to the C−H substrate in MeCN (1.3:1). The α-methylene group of aliphatic and benzylic ethers served as a ready site for C−H amination. Heterocycles such as isochromane and THF gave the new α-substituted tosylamines in 74 and 62% yield (Scheme 17a). A range of acyclic ethers with otherwise unactivated or benzylic α-C−H bonds underwent amination to give mixtures of the hemiaminal and the corresponding N-tosyl aldimine (Scheme 17b). Nicholas employed anhydrous chloramine-T with the simple commercially available copper(I) source [Cu(NCMe)4]PF6 and showed that it was effective in the C−H amination of a range of 1°, 2°, and 3° benzylic substrates such as toluene, indane, and triphenylmethane as well as the cyclic ethers THF and dioxane.59 Good yields were generally obtained (54−77%) using a low C−H substrate:chloramine-T ratio (1.3:1). The system appears to work best with electron-rich benzylic substrates: the electron-poor benzylic substrate 4-nitro-1ethylbenzene gave a particularly low C−H amination yield (15%). Significantly, Nicholas found that anhydrous chlor-

trans-1,2-diaminocyclohexane diimine ligands 5 and 6 led to good yields in benzylic C−H amination but only gave a 4% ee in the C−H amination of 4-methoxy-1-ethylbenzene. Of the diimine ligands screened, which also included an isopropylsubstituted bis(oxazoline), the chiral biphenyl-based 7 gave the highest enantioselectivies. Both the yield and enantioselectivity increased with the use of the electron-rich benzylic substrate 4methoxy-1-ethylbenzene as compared to ethylbenzene. SucE


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catalytic system for C−H amination of related β-diketone or βdiketo esters at the α-position (Scheme 21b).63

cessful intramolecular C−H amination was examined with the diimine ligand 5 with a series of carbamates and sulfamates that featured remote benzylic, 3° alkyl, or ethereal α-C−H bonds in 32−80% yields (Scheme 20). Carbamates gave a preference for

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SEARCHING FOR INTERMEDIATES The success in C−H aziridination and amination by nitrene sources such as PhINTs and chloramine-T spurred interest in the chemical nature of the putative copper nitrene intermediates that enable these nitrene transfer reactions. An early key experiment by Jacobsen provided clear support for the notion that PhI-free, reactive copper nitrene species [Cu] NTs mediate the aziridination reaction.39 Using a chiral diimine ligand L* in conjunction with CuPF6, identical ee’s in the aziridination of styrene were obtained with either PhINTs or photochemically generated [NTs] (from tosyl azide) under otherwise analogous conditions (Scheme 22). Thus, Jacobsen

Scheme 20

Scheme 22 five-membered rings, whereas the sulfamates preferred sixmembered rings. Very low yields were observed when cyclization would require reaction with an unactivated 2° C− H bond. Unfortunately, low ee’s (13−18%) resulted for intramolecular C−H amination when optically pure chiral diimine ligands were used. Chan developed an elegant route to α-acyl-β-amino acid and 2,2-diacyl diacyl derivatives by the reaction of 2-substituted βdiketones and β-keto esters with either 1.2 or 2−3 equiv of PhINTs employing Cu(OTf)2/1,10-phenanthroline as a catalyst (Scheme 21a).62 C−H amination is regioselective,

provided firm evidence for the intermediacy of a {(diimine)CuNTs}+ species. This {[Cu]=NTs}+ intermediate may be considered as a copper(I) nitrene or a copper(III) imide depending on whether the NTs ligand is treated as a neutral or dianionic entity, respectively. Vedernikov and Caulton later described the addition of PhINTs to their copper(I) catalyst [LCu] + [BAr F 4 ] (4[BArF4]; see Scheme 15) to provide the purple substance {[LCu]2(NTs)}2+. This diamagnetic species was characterized by NMR spectroscopy56 as well as ESI mass spectrometry, which provided evidence for the ions {[LCu]2(NTs)}2+ and {LCu-NHTs}+.57 Unfortunately, no direct reaction between {[LCu]2(NTs)}2+ and alkenes or alkanes occurred. Inspired by the use of strongly donating, β-diketiminato ligands that led to the isolation of the three-coordinate cobalt and nickel imido complexes [Me2NN]CoNAd64 and [Me3NN]NiNAd,65,66 Warren prepared the purple dicopper nitrene {[Me3NN]Cu}2(μ-NAr′) (9; Ar′ = 3,5-Me2C6H3) from the reaction of the copper(I) β-diketiminate {[Me3NN]Cu}2(μ-benzene) with N3Ar, which was isolated in 77% yield (Scheme 23).67 The X-ray crystal structure of 9 revealed short Cu−Nnitrene distances of 1.794(5) and 1.808(5) Å with a Cu···Cu separation of 2.911(1) Å. This species is similar to the dicopper carbene {[Me2NN]Cu}2(μ-CPh2) investigated for alkene cyclopropanation that has Cu−C distances of 1.922(4) and 1.930(4) Å, but a much shorter Cu...Cu distance of

Scheme 21

owing to the pseudo-allylic C−H bond present in the copperbound, deprotonated form of the β-diketone or β-diketo ester. Since alkene byproducts 8 could be isolated when only employing 1.2 equiv of PhINTs, one mechanistic possibility suggested for the net aziridination was elimination of H2NTs from the amination product to give the alkene 8, which undergoes aziridination with an additional 1 equiv of PhI NTs. Consistent with this suggestion, reaction of 8 with PhI NTs under catalytic conditions cleanly delivered the corresponding aziridine. This appears to be a directed version of Vedernikov and Caulton’s “alkane to aziridine” transformation (Scheme 16). A followup report by Chan described a similar

Scheme 23

F


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2.4635(7) Å.68 While the isolation of a terminal copper nitrene has not been reported, evidence for a [Cu]NAr species in solution was provided by exchange reactions with the chemically similar anilidoimine complex [Me2AI]Cu, which gave rise to a mixture of the new unsymmetric binuclear species [Me2AI]Cu(μ-NAr)Cu[Me3NN] (10) (Scheme 24) and

considerably more thermally sensitive than is arylnitrene counterpart 9. Upon standing at room temperature, a C−H bond in an o-Me group of 11 cleanly underwent intramolecular C−H amination to give an amine-bridged species.69 Such intramolecular C−H amination with o-C−H bonds of the βdiketiminato N-aryl substituents appears to be general for these copper nitrenes. For instance, addition of N3Ad to the bulkier [Me2NNtBu]Cu(benzene), possessing backbone tBu groups, led to the mononuclear intramolecular C−H amination product 12 (Scheme 26). Aiming to focus C−H amination activity on exogenous substrates, the chlorinated β-diketiminate {[Cl2NN]Cu}2(μbenzene) (13) was prepared that presents no easily accessible C−H bonds to copper nitrene intermediates. Addition of N3Ad to 13 led to diamagnetic {[Cl2NN]Cu}2(μ-NAd) (14) isolated in 63% yield. The β-diketiminato N-aryl o-Cl substituents significantly increased the solution lifetime of 14 in benzene relative to that of 11, allowing room-temperature measurement of its diamagnetic NMR spectrum along with its optical spectrum, which features an intense charge transfer band at 717 nm (ε = 5870 M−1 cm−1). Dicopper nitrene 14 underwent essentially quantitative, stoichiometric nitrene transfer to the benzylic C−H bonds in indane (C−H BDE = 85 kcal/mol)31 at room temperature, while heating to 80 °C ensured complete nitrene transfer to the stronger C−H bonds of toluene (C−H BDE = 90 kcal/mol)31 and cyclohexane (C−H BDE = 97 kcal/mol).31 In each case, the copper(I) β-diketiminate [Cl2 NN]Cu was formed, suggesting the possibility of catalytic nitrene transfer using the organoazide N3Ad. Indeed, heating N3Ad at 110 °C with the neat substrates cumene, indane, ethylbenzene, toluene, and cyclohexane gave excellent C−H amination yields with 5 mol% [Cl2NN]Cu (Scheme 27). Use of 1 equiv of the C−H

Scheme 24

symmetric dicopper nitrene {[Me2AI]Cu}2(μ-NAr′). Dicopper nitrene 9 is electrophilic, undergoing clean transfer to PMe3 and CNtBu to give Me3PNAr and tBuNCNAr in 94% and 92% yields, accompanied by the formation of the [Me3NN]Cu(PMe3) and [Me3NN]Cu(CNtBu) adducts, respectively (Scheme 25). Somewhat disappointingly, this copper Scheme 25

Scheme 27 nitrene did not undergo aziridination reactions with styrene. Instead, the diazene Ar′NNAr′ was released with formation of [Me3NN]Cu(η2-styrene). In the absence of an additional donor, H2NAr and ArNH−NHAr species also formed during the room-temperature decomposition of 9 in benzene-d6, suggesting the possibility of H atom abstraction by the copper nitrene species. Reaction of the bulkier, electron-rich azide N3Ad with {[Me3NN]Cu}2(μ-toluene) led to the isolation of the green dicopper nitrene {[Me3NN]Cu}2(μ-NAd) (11; Scheme 26)69 with Cu−N distances of 1.785(6) and 1.821(5) Å and a Cu···Cu separation of 2.901(2) Å in a structure very similar to that of dicopper arylnitrene 9.67 Dicopper alkylnitrene 11 is Scheme 26

substrates cumene and ethylbenzene in benzene solvent provided the product amines in 80 and 82% yields, respectively. A lower yield of toluene amination under 1 equiv conditions (32%) resulted from overoxidation of the product PhCH2NHAd to the imine PhCHNAd. This report marked the first successful use of an alkyl azide for intermolecular C−H amination. While electron-poor organo azides such as N3Ts have been employed in C−H amination,70 there are only sparse reports of using aryl azides8,15,71 in C−H amination.72 G


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Lewis acid adducts of a cationic copper tosylnitrene supported by a tridentate amine have been recently reported.73 Addition of the substituted iminoiodinane 2-tBuSO2C6H4I NTs to a cationic copper(I) complex supported by a tridentate amine donor led to an extremely reactive copper nitrene intermediate that may be somewhat stabilized by Lewis acids such as Sc(OTf)3 (Scheme 28). While this species 15 has not

(radical rebound) by the metal amide results in the metalbound functionalized product [M](NH(R)R′). Limited mechanistic evidence available for copper-catalyzed C−H amination systems seem to favor the stepwise HAA/RR pathway for most systems, though in some cases a concerted pathway may also participate. The most convincing evidence comes from the use of radical clock substrates or other stereochemical probes. Using a cationic {[diimine]Cu}+ catalyst prepared from [Cu(NCMe)4]PF6 and ligand 5 (see Scheme 19), Nicholas reported the amination of the radical clock substrate 1-phenyl-2-benzylcyclopropane with anhydrous chloramine-T, which gave a mixture of ring-closed (6%) and ringopened (18%) products (Scheme 30a).74 This distribution of

Scheme 28

Scheme 30

been crystallographically characterized, XAS and resonance Raman studies at low temperature alongside DFT studies point to a κ2N,O-NTs binding mode in which the nitrene N-donor engages a Lewis acid such as Sc(OTf)3. Reactivity studies carried out at low temperature (−90 °C) reveal a propensity toward H atom abstraction reactions, such as the conversion of 1,4-cyclohexadiene to benzene. Nonetheless, C−H amination reactivity was observed with toluene at −90 °C and with cyclohexane upon warming to 25 °C.

products reflects a major contribution from the HAA/RR pathway for C−H functionalization. The ring-closed product could result from either a concerted insertion or an extremely fast RR step following HAA, since the unimolecular rate constant for ring opening of the corresponding cyclopropanecontaining benzylic radical is [3.6(5)] × 108 s−1 at 25 °C.75 In further support for the stepwise HAA/RR pathway is the 1:1 mixture of cis and trans amination products observed in the related amination of the 3° benzylic C−H bond in cis-1-tertbutyl-4-phenylcyclohexane (Scheme 30b). Kinetic isotope effect measurements also have been used to deduce information about the nature of C−H functionalization mechanisms. Low kinetic isotope effects (e.g., kH/kD < 2) have been correlated with asynchronous concerted nitrene insertions into C−H bonds similar to propositions by Müller76 and Du Bois77 for reactions of iminoiodinanes with dirhodium tetracarboxylate catalysts. These relatively low primary KIEs are consistent with a concerted TS in which the C−H−N angle is much less than the 180° that is required to obtain a maximum kH/kD value.58 On the other hand, higher KIEs in the range of 4−12 have been reported for C−H amination systems such as (porph)Ru(NTs)2 believed to proceed via HAA/ RR.7,78 Higher KIEs result from nearly linear C···H···N vectors in the HAA transition state (Scheme 28). For instance, the nickel imide [Me3NN]NiNAd undergoes HAA with ethylbenzene with an experimental KIE of 4.6(4). DFT calculations predict a C···H···N angle of 170.5° in the transition state with tight N···H and C···H separations of 1.305 and 1.346 Å.66 Albone’s system employing chloramine-T trihydrate with CuCl in MeCN (see Scheme 17) in the amination of THF and THF-d8 gave kH/kD = 1.5,58 similar to the value of 1.9(2) observed by Du Bois in an intramolecular C−H amidation of a sulfamate.79 Use of PhCH2OCD2Ph gave a higher value of ∼4, suggesting a TS “position” along the continuum of asymmetric concerted insertion vs a two-step H atom abstraction/radical

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MECHANISTIC STUDIES INVOLVING NITRENE TRANSFER Mechanistically, two limiting pathways may be envisioned for the C−H amination of a sp3-hybridized C−H bond with a latetransition-metal nitrene species (Scheme 29). First, a Scheme 29

concerted, likely asynchronous insertion of a metal nitrene intermediate may occur in which an electrophilic [M]NR′ unit attracts electron density from a C−H bond in R−H en route to insertion of the nitrene moiety to give the amine product coordinated to the metal center in [M](NH(R)R′). Second, H atom abstraction/radical rebound (HAA/RR) could occur in which a H atom is abstracted from the C−H substrate R−H by the metal nitrene [M]NR′ to give the radical R• and the metal amido species [M]−NHR′. Capture of the radical R• H


Organometallics

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favored in all cases, especially for ligands featuring aryl groups on the diimine and sulfonyl nitrene moieties. The singlet and triplet species differ appreciably in Cu−N (1.894, 2.048 Å) and Cu−O (1.890, 1.996 Å) bond distances to the κ2-sulfonylnitrene, with the triplet distances being longer. The triplet squareplanar species 16 features significant unpaired electron density at the nitrene N atom. For instance, the simple model with R = H and R″ = Me possesses a spin density of 1.21 e− at the nitrene N atom, 0.46 e at Cu, and 0.16 e at O. In the context of alkene aziridination, a biradical transition state for addition to ethylene to form the corresponding aziridine was identified. Employing a full biaryl diimine ligand that bears N-aryl o-Cl groups successfully deployed in the efficient asymmetric aziridination of a substituted chromene,81 Deeth and coworkers identified a κ1N sulfonylnitrene bonding mode in {(Cl2diimine)CuNSO2(p-tolyl)}+ with a Cu−N distance of 1.799 Å (Figure 2a).48 On the basis of the additional nitrene

recombination mechanism (HAA/RR). Nicholas’s {[diimine]Cu}+ system (prepared from [Cu(NCMe)4]PF6 and ligand 5) employing PhINTs and cumene/cumene-d8 gave a KIE of 4.6, which was primarily attributed to a stepwise HAA/RR mechanism and further supported by the use of radical clock and stereochemical probe substrates (Scheme 30).74 Warren’s neutral copper β-diketiminate [Cl2NN]Cu gave KIEs of 5.3(2) and 6.6(1) for the catalytic C−H amination of ethylbenzene and cyclohexane with N3Ad at 110 °C (Scheme 27).69 Heating the discrete dicopper nitrene {[Cl2NN]Cu}2(μ-NAd) (14) at 110 °C in an ethylbenzene/ethylbenzene-d10 mixture gave the same KIE (5.1(2)) within experimental error, suggesting that the same species is responsible for both catalytic and stoichiometric C−H amination, likely the terminal nitrene [Cl2NN]CuNAd. Ray’s Lewis acid copper tosylimide adduct 15 exhibited a KIE of 5.1 at −90 °C in the HAA reaction of dihydroanthracene (see Scheme 28).73 When the stepwise HAA/RR mechanism is operative, rates of reaction are often correlated with the strength of the reacting C−H bond.7,66,69 For the β-diketiminato copper catalyst [Cl2NN]Cu (see Scheme 27), rates of catalytic C−H amination tracked the reacting C−H bond strength illustrated by a linear plot of ln(kR‑H/kethylbenzene) vs C−H BDE.69 Normalizing for the number of C−H bonds present in a given substrate, a C−H bond in cyclohexane (C−H BDE = 97 kcal/mol)31 reacted 480 times more slowly than a C−H bond in indane (C−H BDE = 85 kcal/mol).31 H atom abstraction rates for the copper tosylnitrene species 15 (see Scheme 28) were similarly linearly correlated with C−H bond strengths that span ca. 68−90 kcal/ mol.73 On the other hand, mechanistic studies employing parasubstituted benzylic ethers with the simple CuCl/chloramine-T system (see Scheme 17) allowed for the construction of a Hammett plot that gave a ρ value of −0.63 (R2 = 0.95), indicating a modest preference for electron-rich substrates that was inconsistent with highly charged or radical benzylic intermediates.58 Instead, a concerted, asynchronous insertion of the copper nitrene intermediate was suggested.

Figure 2. (a) Biaryl diimine and (b) bis(oxazoline) ligands in copper nitrenes examined by theory.

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N···O (1.776 Å) and diimine Cu···Cl (2.783 Å) contacts identified in this DFT study, it is likely that the singlet state was investigated, though this was not explicitly mentioned in the study. These additional interactions suggest ways that substituents on the nitrene as well as the ancillary ligand can stabilize an electrophilic copper nitrene complex. Qu and colleagues studied a large set of related cationic and neutral {[Cu]NR}0/+ (R = Me, CO2Me, SO2Me, SO2Ph) species that employed related bis(oxazoline) and other N,N-donor ligands (Figure 2b).82 While not explicitly stated, the singlet state was assumed for this family of (N−N)CuNR species that featured short Cu−NR distances of 1.71−1.74 Å and a bent Cu−N−R linkage (118−146°) that result from a relatively covalent Cu−NR π-back-bonding interaction between the filled d orbital of a copper(I) d10 center and the empty p orbital of a singlet nitrene (see Figure 3; single-determinant π-bonding). In a study by Comba and colleagues employing tetradentate bispidine ligands,83 κ1N binding of the NSO2Me moiety (Cu− N = 1.919 Å) was favored by 4.5 kcal/mol over the κ2N,O binding mode (Cu−N = 1.945 Å; Cu−O = 2.156 Å) in these triplet species. The triplet−singlet separation was only 0.8 kcal/ mol in the κ2N,O binding mode of this pentacoordinate species, suggesting the possibility of reactivity from either spin state. Motivated by the experimental success in isolating terminal metal imides [M]NR′ of Fe,84 Co,64 and Ni65,66 using βdiketiminates as supporting ligands, Ghosh and Cundari separately performed DFT studies on this class of three-

THEORYNATURE OF COPPER NITRENE INTERMEDIATES Since no mononuclear copper nitrene complex [Cu]NR′ has been isolated and subjected to rigorous spectroscopic and kinetic study, theory provides an opportunity to obtain insight into the nature of these key intermediates in C−H amination. Given the prevalent use of arylsulfonimides NSO2Ar in aziridination, early DFT studies focused on {(diimine)Cu}+ species with sulfonylnitrenes. Norrby and co-workers employed simple diimine ligands to model the binding and activation of PhI=NTs to give square-planar{(diimine)Cu(κ2-NSO2R)}+ species 16 (Scheme 31).80 Notably, no κ1N binding mode of the sulfonylnitrene was found. The triplet species 16 was Scheme 31

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Figure 3. Bonding in β-diketiminato terminal copper nitrenes.

bond strength (105 kcal/mol)31 and global abundance. Interestingly, the enthalpy of methane functionalization to give [β-dik]M(HNMe2) species becomes more favorable upon moving from Fe to Cu, identifying terminal copper nitrene complexes as particularly attractive species for this challenging C−H functionalization reaction. An important driver for this reaction calculated along the HAA/RR pathway is the N−H bond strength in the corresponding metal amido complex [M]−NHR that would result from HAA by [M]NR. While the simple [H5C3N2]M−NHMe species (M = Fe, Co, Ni) have calculated amido N−H bond enthalpies in the range 82.9−84.0 kcal/mol, which can be increased to 93.5−95.2 kcal/mol by addition of the electron-withdrawing N−CF3 substituent in [H5C3N2]M−NHCF3,88 the experimentally isolated [Cl2NN]Cu−NHAd that would result from HAA by the putative copper nitrene [Cl2NN]CuNAd has a calculated N−H bond enthalpy of 98.4 kcal/mol.66 Thus, the high N−H bond strengths in experimentally accessible [β-dik]Cu-NHR species provide a significant driving force for the functionalization of strong sp3 C−H bonds. Additionally, a concerted directinsertion pathway for methane C−H functionalization was identified for [H5C3N2]CuNH.89 Houk and Nicholas employed multiconfigurational techniques to more accurately assess the singlet and triplet states of cationic {[diimine]Cu(κ2-NSO2R)}+ species for C−H amination.74 In these square-planar species, the triplet state was found to be lower than the singlet by 2.8−13.2 kcal/mol in free energy, depending on the size of the basis set and computational method employed. The singlet state was best described as a open-shell singlet with a 1.39/0.61 distribution of paired electron density among the HOMO/LUMO single-determinant orbitals best described as Cu−N σ and σ* in this squareplanar species.74 In the reaction of {[diimine]Cu(κ2-NSO2R)}+ with toluene, triplet and singlet transition states were identified 8.2 and 10.2 kcal/mol higher in free energy than the separated reactants (Scheme 33). The triplet species leads to an HAA/RR pathway that results in a separated radical pair that may “rebound” to complete C−N bond formation in the copperbound product complex 17. In contrast, the singlet transition state is slightly higher in free energy but leads directly to the product complex 16 in a concerted manner. These transition states were predicted to decrease in energy with electron-rich benzylic C−H substrates. Similar to the β-diketiminato metal systems that appear in Scheme 32, substitution of the nitrene with electron-withdrawing substituents (NSO2−Me → NSO2− CF3) led to a decrease in the transition state energies by as much as 5 kcal/mol.

coordinate, late-metal imides. Initial studies by Ghosh examined [Me2NN]CuNMe and [Me2NN]CuNPh species (Figure 3), predicting them to be triplets by a clear margin (10.4 (NMe) to 29.5 kcal/mol (NPh)).85 Recognizing that the singlet form of the simple, metal-free phenylnitrene PhN possesses an open-shell singlet (“paired biradical”) electronic structure,86 Cundari applied multiconfigurational methodologies to mononuclear copper arylnitrenes [Cu]NAr. Application of complete active space self-consistent-field (CASSCF) techniques revealed that simple ([H5C3N2]Cu NPh; no β-diketiminate substituents)87 and full ([Me3NN]CuNAr′ (Ar′ = 3,5-Me2C6H3)87 and [Cl2NN]CuNAd69) models predict open-shell ground states by a large margin (Ar′ 21.5 kcal/mol and NAd 18.0 kcal/mol; full models). These singlet species possess short Cu−N bonds (e.g. 1.82 Å for [Cl2NN]CuNAd) with bent Cu−N−R linkages (129−130°) orthogonal to the β-diketiminato backbone (Figure 3). The singlet ground state for these species cannot be adequately described by a single electronic configuration as is typically employed in DFT (Figure 3). Whereas a simple singledeterminant calculation would give integral occupancies of 2 and 0 e− for the Cu−N π and π* orbitals, the multireference techniques predict occupations of these molecular orbitals of approximately 1.5 and 0.5 e, respectively (Figure 3).69,87 Furthermore, the singlet biradical character for the Cu−Nnitrene bond serves to decrease the overall Cu−Nnitrene bond order via population of the Cu−N π* orbital with electrons from the Cu−N π level, enhancing the reactivity of the [Cu]NR species. Cundari surveyed a series of simple [β-dik]MNR complexes (M = Fe−Ni, R = Me;88 M = Cu, R = H89) in the context of methane C−H functionalization (Scheme 32), a difficult but tantalizing sp3 C−H substrate due to its high C−H Scheme 32

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Scheme 33

Scheme 34

Fu showed that N,N-dialkylanilines were excellent substrates for C−H amination with 1° and 2° organic amides employing either tBuOOH93 or N-halosuccinimides94 as oxidant (Scheme 35). Only a modest excess of the C−H substrate N,NScheme 35

DFT studies indicate that Ray’s copper nitrene species 15 featuring a Lewis acid stabilized [Cu](κ2O,N-NTs) bonding motif is best described as a copper(II) center bound to a NTs radical anion (Figure 4).73 The absence of a high-energy shift in dialkylanilines with respect to the organic amide (2:1 mole ratio) was required in each case. The oxidant tBuOOH enabled the use of a lower CuBr catalyst loading with yields up to 79% but required heating to 80 °C. NCS as oxidant gave yields up to 63% at room temperature, provided a 20 mol % catalyst loading was employed. Lactams such as ε-caprolactam as well as succinimide led to the corresponding N-functionalized products in good yield, whereas a simple N-phenyl-substituted amide (R1 = Ph) gave a poor yield.93 Employing the α-C−H bond of N,N-dimethylaniline as an intramolecular target for C− H amidation led to the formation of a six-membered heterocycle (Scheme 36). Interestingly, reactions of N-benzyl-

Figure 4. Resonance forms for cation 15+.

the pre-edge (1s → 3d) XAS transition for 15 relative to its copper(I) synthetic precursor (see Scheme 28) supported the presence of a copper(II) center in 15.

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Scheme 36

C−H AMINATION VIA NON-NITRENE ROUTES While much of the early development of C−H amination methodologies for copper (and other metals) has focused on nitrene-based approaches, the requirement of [M]NR′ intermediates places specific limitations on the range of Nbased reagents that may be directly deployed in C−H amination. For instance, only relatively reactive nitrogen sources derived from 1° amines (e.g., PhINTs and N3Ad) may be directly used in the amination of C−H substrates R−H that result in the formation of 2° amines R−NHR′; the direct formation of 3° amines is not possible by this route. Fortunately, a number of non-nitrene protocols are available for copper-catalyzed C−H functionalization that greatly expand the range of N-substituents that may be directly introduced via a single C−H functionalization step.

N-methylaniline led to dephenylation of the benzyl group with C−N bond formation at this position, which accounted for the major product alongside the otherwise analogous C−H amidation product at the N-methyl group (Scheme 37). The oxidant N-bromosuccinimide enabled a modest expansion of C−H substrate scope to include all-carbonbased 2° benzylic substrates, although 1° aromatic amides

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Scheme 37

ORGANIC AMIDES N,N-Dialkylanilines and related heterocycles bearing α-C−H bonds, especially benzylic bonds, are particularly good C−H substrates for C−H functionalization reactions. Despite their relatively strong α-C−H bond strengths (∼85−92 kcal/mol),31 tertiary amines often participate preferentially in C−H functionalization reactions, owing to their ease of oxidation to the corresponding aminyl radical cation, which upon facile loss of H• leads to an iminium cation poised for nucleophilic attack by mild nucleophiles (Scheme 34).90 Such substrates with activated C−H bonds91 have often served as early examples in a range of copper-catalyzed C−H functionalization reactions.26,92 K


Organometallics

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(H2NC(O)Ar), alkyl amides (H2NC(O)CH2R), or sulfonamides (H2NSO2Ar) were required (Scheme 38).94 Isochroman

Scheme 40

Scheme 38

Motivated by Sharpless’s use of a molybdenum C-nitroso adduct [Mo](η2-ArNO) in stoichiometric reactions with alkenes to give the corresponding allylic amines100 derived from the corresponding ene hydroxylamine product as well as success with Mo-101 and Fe-catalyzed102 routes, Srivastava intensively investigated the use of copper complexes for catalytic C−H amination with nitrosoarenes ArNO and Naryl hydroxylamines ArNHOH.103−107 A detailed investigation of copper catalysts built upon an initial report by Lau demonstrated that simple copper(I) and copper(II) salts could catalyze allylic amination with PhNHOH, albeit in generally poor to modest yields.108 The use of [Cu(NCMe)4]PF6 as catalyst with N-phenylhydroxylamine led to C−H amination at the least hindered position of the alkene to form the corresponding N-allylic aniline (Scheme 41).103 Cyclic alkenes such as 1-methylcyclo-

was also examined and underwent amidation in the benzylic position adjacent to the ether O atom. Temperatures of 40−60 °C were required, delivering up to 79% yield employing a 2:1 C−H substrate:organic amide ratio. Since 1° organic amides were required, a nitrene-based mechanism was suggested in which the amide H2NC(O)R is oxidized to the N-bromoamide H(Br)NC(O)R that leads to the formation of CuNC(O)R species upon formal 1,1-elimination of HBr.94 A domino reaction beginning with a Cu-catalyzed crosscoupling of the 2-halobenzamide Ar−X with the benzylamine H2NAr′ followed by intramolecular C−H amination/oxidation resulted in a quinazolinone derivative (Scheme 39).95 Although

Scheme 41

Scheme 39

hexene were particularly poor substrates, while especially electron-deficient hydroxylamines such as 2,3,4,5-tetrafluorophenylhydroxylamine give higher yields. A subsequent report detailed the direct use of nitroarenes ArNO in allylic amination employing a catalyst mixture of CuCl2·2H2O and Cu powder.104 A series of mechanistic studies suggested that free nitrosoarenes ArNO are not the active species in this allylic C−H amination reaction (Scheme 42).105,106 For instance, use of 2,3dimethylbutene led to the corresponding amination product, not the Diels−Alder adduct which forms from PhNO under uncatalyzed conditions. Importantly, Srivastava demonstrated the presence of [Cu(κ1-N(O)Ar)3]+ cations as active species through their isolation and subsequent stoichiometric studies with alkenes. Reaction of [Cu(NCMe)4]PF6 with either excess

conceptually related to above examples of intramolecular C−H amination, it is likely that the benzylic C−N bond-forming step takes place only after an N-aryl benzylamine formed in a sp2C−N cross-coupling reaction becomes oxidized to form an imine that is susceptible to intramolecular addition of the amide N−H across the imine.

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AROMATIC C-NITROSO COMPOUNDS FOR ALLYLIC AMINATION C−H amination with aromatic C-nitroso compounds ArNO or their corresponding reduced hydroxylamines ArNHOH is an attractive method to functionalize allylic C−H bonds, since many of the nitrene-based routes with iminoiodinanes PhI NSO2R or related reagents lead to aziridination. Moreover, there is a wide range of C-nitroso compounds synthetically available96 that potentially allows for the direct installation of various NHAr groups via C−H amination. Nitrosoarenes ArNO have been known to undergo ene reactions with electron-rich alkenes since 1965, when the particularly potent eneophile CF3NO was allowed to react with isobutylene.97 Even less activated C-nitroso compounds such as PhNO react with the particularly electron-rich 2,3dimethylbut-2-ene to give the hydroxylamine ene product 18 (Scheme 40). Aziridine N-oxides are thought to be intermediates, themselves rearranging to the ene product,98 though computational studies suggest that the uncatalyzed nitroso ene reaction may also proceed in a concerted fashion.99

Scheme 42

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PhNO or PhNHOH led to [Cu(κ1-N(O)Ph)3]PF6, illustrating the copper-catalyzed conversion of ArNHOH to copperbound ArNO. An X-ray structure of [Cu(κ1-N(O)ArNEt2)3]PF6 (ArNEt2 = 4-Et2N-C6H4) revealed trigonal-planar coordination at copper with each nitrosoarene exhibiting κ1N bonding.105,109 The tris(nitrosoarene) complex [Cu(κ1-N(O)Ph)3]PF6 stoichiometrically aminates allylic C−H bonds; the activation parameters ΔH⧧ = 9.9 kcal/mol and ΔS⧧ = −44 cal/ (mol K) were obtained with α-methylstyrene (Scheme 42). Competition studies employing a 1:1 mixture of Ph(CH3)C CH2 and Ph(CD3)CCH2 led to the modest primary kinetic isotope effect kH/kD = 2.2. Supported by calculations, Srivastava proposed a mechanistic cycle that features coordination of the alkene followed by an intramolecular H transfer from the coordinated alkene to a coordinated ArNO to give a copper(III) allyl/N-hydroxyamido species subject to reductive elimination to give the N-phenyl allylamine (Scheme 43). One

facile deprotection to the corresponding primary allylic amine with trifluoroacetic acid. An interesting prospect for further development is the use of ketones for α-C−H amination reactions. For instance, PhNHOH reacted with cyclohexanone to give the α-aminated, α,β-unsaturated ketone in low yield employing CuCl2·2H2O as catalyst (Scheme 45).108 Scheme 45

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STRAINED HETEROCYCLES AS C−H AMINATION REAGENTS Yoon has examined the use of oxaziridines112 principally as aminohydroxylation reagents via their copper-catalyzed 1,2addition to alkenes.113,114 If well-positioned benzylic C−H bonds in the oxaziridine are present, however, efficient intramolecular cyclization can take place via C−H amination (Scheme 46).115 The reaction of dihydrostilbene-derived

Scheme 43

Scheme 46 drawback to this methodology is that the copper species present must also reduce the initially formed N-allylhydroxylamine to the allylamine C−H amination product, which can lead to other byproducts. Careful analysis of the products in the reaction of PhNHOH with α-methylstyrene catalyzed by [Cu(κ1-N(O)Ph)3]PF6 revealed a mixture of PhNH2, PhN NPh, and PhNN(O)Ph along with the desired N-phenyl allylamine.106 The copper-catalyzed disproportionation of PhNHOH to PhNO, PhNH2, and H2O has been described.108 Nicholas also reported the use of the commercially available Boc-hydroxylamine Boc-NHOH for related reactions using CuBr·SMe2 as catalyst, though in most cases the pure ene product N-allylic hydroxylamine was isolated rather than the corresponding Boc-protected allylic amine (Scheme 44).110 Use Scheme 44

oxaziridines 19 with CuCl2 in the presence of LiCl gave an intermediate N,O-aminal that is also present in its ring-opened form. Reduction of this mixture with NaBH(OAc)3 provided the corresponding tetrahydroisoquinoline product in 61−87% yield (Scheme 46a). The N,O-aminal generally was not isolated but rather subjected to a number of other reactions, including oxidation to the N-sulfonyl isoquinoline, the lactam of the ringclosed hemiaminal. In the case of the related biphenyl-derived oxaziridine 19, the ring-closed N,O-aminal was isolated in 84% yield (Scheme 46b). Mechanistically the reaction is thought to proceed via κ1N coordination of the oxaziridine to [CuCl3]−,114 followed by a coupled ring opening of the oxaziridine and HAA of the benzylic C−H bond, concluded by ring closure via

of 1,3-cyclohexadiene gave the corresponding Diels−Alder adduct of BocNO, suggesting the intermediacy of the free nitroso compound. Use of CuCl catalyst with H2O2 as a oxidant increased the yield of the allylic hydroxylamine, a tactic also employed to generate highly reactive acylnitroso species RC(O)NO for ene reactions from isolable N-acylhydroxylamines RC(O)NHOH.111 The addition of a stoichiometric amount of P(OEt)3 along with catalytic CuBr resulted in the isolation of the desired N-Boc allylic amine, which underwent M


Organometallics

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Review

NFSIA REAGENT FOR PRIMARY OVER SECONDARY C−H BOND AMINATION SELECTIVITY N-Fluorobenzenesulfonimide (NFSI) has been introduced as a sterically hindered, non-nitrene source for copper-catalyzed C− H amination that gives unique selectivity for the amidation of 1° benzylic over 2° benzylic sites.120 Michael showed in 2009 that NFSI could serve as both an oxidant and a source of electrophilic nitrogen employing Pd catalysis. Using amidebased aromatic directing groups, Zhang utilized NFSI as a C−H amination reagent to target both aromatic p-C−H121 as well as p-benzylic C−H122 bonds in Pd-catalyzed protocols. Examination of related copper-catalyzed processes has revealed efficient C−H functionalization of 1° and 2° benzylic C−H bonds in the absence of directing groups.120 Heating 1 equiv of the benzylic C−H substrate with 1.1 equiv of NFSI in dichloroethane at 110 °C for 3 h in the presence of 10 mol % CuCl and 5 mol % of 1,10-phenanthroline in open air led to the corresponding Nbenzylic N-(phenylsulfonyl)benzenesulfonamides in 57−91% yield (Scheme 49). A range of electron-donating and

capture of the resulting tethered radical by the copper(III) amide to return [CuCl3]− (Scheme 47). Scheme 47

Shi developed a unique approach to C−N bond formation through the use of N,N-di-tert-butyldiaziridinone116 (20) and related three-membered heterocycles such as N,N-di-tertbutylthiaziridine 1,1-dioxide117 (21) and N,N-di-tert-butyl-3(cyanimino)diaziridine (22) (Scheme 48a).118 While the principal focus has been on the diamination of alkenes and conjugated dienes,116 Shi observed α-C−H amination of aryl acetate esters using N,N-di-tert-butyldiaziridinone.119 Use of a 1:1 mixture of CuCl and PBu3 as catalyst in 20 mol % loading with the aryl acetate and 2 equiv of 20 gave the corresponding hydantoin products 23 in good to excellent yields, provided that the site of C−H functionalization was either benzylic or allylic (Scheme 48b). Deprotection with triflic acid in hexane allowed for removal of the N-tBu groups to provide access to the N-unsubstituted hydantoins. A mechanism was proposed (Scheme 48c) that begins by oxidative addition of 20 to CuCl(L) to give the intriguing Cu(III) intermediate 24, which may be in equilibrium with a closely related Cu(II) species bearing a dangling amidyl radical, 25. Reaction of the radical form 25 with a mildly activated benzylic or allylic C−H bond in the ester C−H substrate would give the Cu(III) organometallic 26, subject to reductive elimination to give 27, which can close to form a six-membered ring upon loss of methanol. Recent mechanistic studies have revealed a likely equilibrium between Cu(III) and Cu(II) species of types 24 and 25. In particular, a three-line EPR pattern has been obtained in the reaction of 20 and a 1:1.5 CuCl:P(OPh)3 mixture at −50 °C in toluene, consistent with the presence of the amidyl radical in 25.116 While this radical is undoubtedly more stable than a free urea N-based radical due to its coordination to copper, the high N−H bond strength in urea (111 kcal/mol)31 nonetheless suggests high HAA reactivity for the N-based radical 25.

Scheme 49

-withdrawing ring substituents R2 are tolerated. Rather remarkably, the system exhibits selectivity for the functionalization of 1° benzylic C−H bonds in the presence of 2° benzylic C−H bonds (Scheme 49). For instance, reaction of 1-ethyl-4methylbenzene with 1.1 equiv of NFSI under these conditions led to a 70% yield of the 1° C−H amination product with only a 7% yield of the 2° C−H amination product. Despite the extra steric hindrance at the 2° C−H bond where R = C(O)OEt (Scheme 50), the 1°:2° selectivity decreased somewhat to 55:18. A mechanistic proposal put forward involves Cu(I), Cu(II), and Cu(III) species (Scheme 51a).120 Oxidation of the copper(I) catalyst by NFSI may deliver the Cu(III) species 28, capable of H atom abstraction of either a 1° or 2° benzylic C−H bond in R−H to give the corresponding benzylic radical

Scheme 48

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Scheme 50

Scheme 52

Scheme 51 water. Hydrolysis of the acetamides with 3 N HCl at 110 °C for 24 h delivered the corresponding amine. This methodology was then applied to unactivated hydrocarbons possessing strong C−H bonds such as cyclohexane to give the C−H functionalized acetamides in 28−90% yield at room temperature in MeCN solvent employing only 1 equiv of C−H substrate (Scheme 53). The mechanism was rationalized Scheme 53

R• along with HF and the copper(II) species 29. Akin to the Kharasch−Sosnovsky mechanism (see Scheme 54), the benzyl radical could be captured by the copper(II) species to give the functionalized product R−N(SO2Ph)2, regenerating the copper(I) species. A competition experiment employing equal amounts of toluene and toluene-d8 allowed for the primary KIE of 4.0 to be determined, suggesting that C−H activation is involved in (or precedes) the turnover-limiting step. The authors suggested that the remarkable 1°/2° C−H selectivity could result from the last amination step, which involves the bulky amide in copper(II) complex 29. This is inconsistent with a H atom abstraction pathway, however, since the site of HAA should determine the ultimate location of amination. Perhaps instead an inner-sphere pathway predominates, in which the Cu(III) organometallic species 30 directly forms, favoring the formation of a sterically less hindered 1° Cu−C bond over a 2° Cu−C bond (Scheme 51b). C−N reductive elimination would then deliver the product amine. Clearly, further mechanistic studies are warranted to elucidate the origin of this important switch in C−H bond selectivity to apply this to other copperbased C−H functionalization systems.

along the lines of the Ritter reaction,125 with the hydrocarbon R−H being oxidized to R• by CuBr2/F-TEDA+ followed by further oxidation of R• to the corresponding carbocation R+ by a copper species in solution. Capture of the carbocation R+ by MeCN would give the nitrilium cation, subject to conversion to the acetamide R-NHC(O)Me upon hydrolysis. A competition experiment employing a 1:1 mixture of cyclohexane and cyclohexane-d12 gave a KIE of 3.5. A radical-based mechanism was also supported by the inhibition of C−H amination with 5 equiv of TEMPO, a stable nitroxide-based free radical.126 It is quite possible that Cu(III) intermediates exist in this protocol; oxidation of CuBr to reactive copper(III) fluorides has been proposed in the α-C−H oxidation of amides RC(O)NHCH2R′ to imides RC(O)NHC(O)R′ with F-TEDA-BF4 and stoichiometric CuBr.127

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PEROXIDES AS OXIDANTS IN C−H AMINATION Known for over 50 years, the Kharasch−Sosnovsky reaction between peresters R′C(O)OOtBu and allylic C−H substrates represents one of the first efficient copper-catalyzed C−H functionalization reactions128 and provides an instructive mechanistic framework to consider C−H amination reactions that involve the use of peroxides. In the Kharasch−Sosnovsky reaction, peresters such as PhC(O)OOtBu are used with allylic C−H substrates R−H along with either neutral or cationic copper(I) complexes as catalysts to deliver the allylic benzoate R−C(O)OPh in good to excellent yields (Scheme 54a).129−131 Mechanistically, this reaction is thought to involve an initial reaction between the peroxy ester PhC(O)OOtBu with a Cu(I) source, resulting in the Cu(II) benzoate CuII−O2CPh along with generation of the reactive tBuO• radical (Scheme

RITTER-TYPE C−H AMINATION OF UNACTIVATED C−H BONDS Baran recently reported a unique reagent combination to prepare 1,3-amino alcohols from alcohols as well as to functionalize unactivated hydrocarbons such as cyclohexane via copper-catalyzed C−H amination (Scheme 52).123 Using FTEDA-PF6 (prepared by ion exchange of commercially available F-TEDA-BF4 with NH4PF6)124 in conjunction with acetonitrile, Baran was able to synthesize the six-membered heterocycle 31 in good yield with 25 mol % of CuBr2 and 50 mol % of Zn(OTf)2 followed by workup with only 1 equiv of NaOH. A range of 1,3-acetamide alcohols or 1,3-acetimide ketones (32) could be prepared by using this methodology in 42−91% yield, followed by hydrolysis with NaOH in MeCN/ O


Organometallics

Review

mate; a mechanistic proposal involving the formation of a copper(II) amide CuII−NHR was offered (Scheme 55b). Focusing on the N-tosyl peroxycarbamate, tetrahydronapthalene, cyclohexene, and cyclopentene could be aminated in 45, 27, and 53% yield employing 10 mol % Cu(OTf)2 as catalyst and a 4:1 C−H substrate:oxidant ratio. The use of a coligand such as 1,10-phenanthroline or a chiral bis(oxazoline) in conjunction with Cu(OTf)2 did not increase the yield of indane amidation. Curiously, the use of a copper tris(oxazoline) complex of Cu(OTf)2, 33, gave a poor yield of the N-arylfunctionalized product but gave a measurable enantioselectivity (Scheme 56).

Scheme 54

Scheme 56

Clark and Roche extended the use of peroxycarbamates for asymmetric allylic C−H amination by screening a range of bis(oxazoline) ligands with cyclohexene and cyclopentene (Scheme 57).140 Employing the phenyl-substituted bis-

54b).129−131 Driven by the high O−H bond strength in the product alcohol tBuO−H (BDE = 105 kcal/mol),31 this alkoxy radical participates in facile HAA reactions with sp3-hybridized C−H substrates R−H (typically allylic) to give the corresponding radial R• with bimolecular rate constants typically in the range of 106−108 M−1 s−1.132 Capture of this radical R• by the copper(II) benzoate initially formed upon tBuO• generation gives the allylic ester, likely via a copper(III) organometallic,130 reducing the copper(II) species to copper(I). 133 The intermediacy of a copper(III) species in which the distal O atom of the carboxylate attacks the γ-C atom of a κ1-allyl ligand bound to Cu130 rationalizes important regio- and stereochemical data on this reaction134 such as the essentially exclusive formation of 2° allylic esters.135 Importantly, the use of bis(oxazolines)136 and other chiral ligands137 with cationic copper(I) sources has led to high enantioselectivities in this C− H functionalization reaction.131

Scheme 57

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(oxazoline) 34 along with the copper(I) source [Cu(NCMe)4]PF6, these allylic substrates underwent C−H amination with tert-butyl N-tosyl peroxycarbamate at room temperature to give the corresponding allylic amines in modest yield (14−44%) using a 5:1 alkene:oxidant ratio. Importantly, ee’s as high as 70% were obtained by employing acetone as a solvent; the observed ee’s and the direction of asymmetric induction were rather solvent dependent. Although only in low yield (15%), allylbenzene also underwent allylic C−H amination with TsNHC(O)OOtBu to give the corresponding 2° allylic amine with encouraging enantioselectivity (47% ee). Clark and Roche found that use of N-aryl peroxycarbamates with the [Cu(NCMe)4]PF6/bis(oxazoline) system 34 led to the formation of allylic carbamates rather than the anticipated allyic amine products (Scheme 58). N-Aryl peroxycarbamates led to moderate yields but with more consistent ee’s in this novel allylic C−H oxidation procedure. An increased tendency to decarboxylate under these reaction conditions correlated with increased acidity of the parent amines, clearly favoring decarboxylation for the N-tosyl peroxycarbamate. This is in contrast to the decarboxylation observed for N-aryl peroxycarbamates in Katsuki’s initial study employing ligand free CuOTf, though low yields of the N-aryl allyl amines were obtained.139 A disadvantage to the use of peroxycarbamates is

PEROXYCARBAMATES AS C−H AMINATION REAGENTS Katsuki cleverly employed peroxycarbamates RNHC(O)OOtBu (R = Ts, Ar) (prepared by addition of tBuOOH to isocyanates RNCO)138,139 in a variation of the Kharasch− Sosnovsky reaction for the oxidation of allylic and benzylic C− H bonds (Scheme 55).139 Using Cu(OTf)2 alone or in conjunction with bis(oxazoline) or tris(oxazoline) ligands, indane was aminated to give the corresponding benzylic amine rather than benzylic carbamate (Scheme 55a). Presumably, CO2 extrusion took place upon activation of the peroxycarbaScheme 55

P


Organometallics

Review

of copper catalysts led to the use of 10 mol % Cu(OTf)2 (delivered in two 5 mol % doses) and 5 mol % 1,10phenanthroline in dichloroethane at 60 °C. Yields of 60−78% were obtained in the amination of indane with a series of 1° arylsulfonylamines, and only a modest excess of C−H susbtrate was required relative to the amine (3:1). Similarly, the 2° sulfonamide PhSO2NHMe gave good yields (47−64%) in the amination of a range of 2° benzylic substrates. Allylic C−H amination of cyclohexene with either PhSO 2 NH 2 or PhSO2NHMe proceeded in 75 and 61% yields, respectively. Notable is amination of a 3° C−H bond of adamantane in 56% yield with N-methyl phenylsulfonamide. A subsequent report focused on the amination of 1° benzylic C−H bonds with 1° and 2° sulfonamides (Scheme 61).142 This

Scheme 58

their modest thermal stability, which requires their preparation and use on a small scale (90% spectroscopic yield (λmax(benzene) = 471 nm (2950 M−1 s−1)) that could be isolated as red crystals in 53% yield from pentane (Scheme 65).148 Copper(II) alkoxide 43 possesses a structure similar to

Scheme 67

Scheme 65

that of copper(II) amide 42 with a short Cu−O distance of 1.785(2) Å. Importantly, copper(II) alkoxide 43 swiftly reacted with H2NAd in benzene at room temperature to provide an equilibrium mixture of [Cl2NN]Cu-NHAd (42) and HOtBu (Scheme 65).148 Despite the large difference in the pKa’s of the amine H2NAd (∼35) and alcohol HOtBu (∼17), the preference of copper for the softer amido donor allows for the generation of the key C−H amination intermediate [Cl2NN]Cu−NHAd (42) via simple acid/base chemistry. The stoichiometric transformations in Schemes 64 and 65 were woven together to form a new protocol for C−H amination with alkyl amines employing tBuOOtBu as oxidant, catalyzed by the copper(I) β-diketiminate [Cl 2NN]Cu (Scheme 66). Combination of 1 equiv of H2NAd, 1 equiv of t BuOOtBu, and 10 equiv of indane in heptane at room temperature along with 20 mol % of [Cl2NN]Cu led to a 78% yield of (1-indanyl)NHAd after 5 days. Spectroscopic analysis of catalytic solutions revealed a prominent band at λmax 572 corresponding to [Cl2NN]Cu−NHAd (42), indicating that 42 serves as the resting state; no [Cl2NN]Cu−OtBu was observed under catalytic conditions that employ large H 2 NAd: [Cl2NN]Cu−OtBu ratios. Increasing the reaction temperature to 90 °C allowed for a significant decrease in reaction time to 24 h as well as catalyst loading down to 1 mol % in the C−H amination of neat indane, ethylbenzene, and even cyclohexane (72 h) in 98, 93, and 91% yields, respectively (Scheme 67).148 The amination of cyclohexane is particularly notable, since it possesses particularly strong C−H bonds (BDE = 97 kcal/mol). Other 1° alkylamines bearing 2° and 1° α-C substituents such as

H2NCy and H2CH2CH2Ph could also be employed, and the use of the 2° alkylamine morpholine underscores the nonnitrene nature of this protocol. The amount of C−H substrate could be reduced to 10 equiv relative to the oxidant to give yields of 40−83% with indane and ethylbenzene. The use of only 1 equiv of indane with H2NAd led to 46% of the functionalized amine. Notably, the sole stoichiometric byproduct of this C−H amination protocol is the relatively benign, easily removed tBuOH. Despite the relative ease of oxidation of aromatic amines H2NAr to diazenes ArNNAr, particularly with copper-based systems,151 the copper β-diketiminate [Cl2NN]Cu/tBuOOtBu catalyst system also successfully employed aromatic amines in C−H amination of allylic, benzylic, and even unactivated sp3 C−H substrates.152 Scouting studies in the amination of ethylbenzene with H2NMes revealed that conversion of the aniline is high but that formation of the diazene MesNNMes was competitive with C−H amination (Scheme 68). Two key observations suggested a competition between productive C− H amination and bimolecular combination of two copper(II) Scheme 68

T


Organometallics anilide intermediates [Cl2NN]Cu−NHAr to ultimately give the diazene ArNNAr. Lowering the catalyst loading from 10 mol % to 1 mol % and increasing the amount of neat ethylbenzene (20 mL) led to an increase in the yield of C−H amination product from 21% to 62%. Additionally, the efficiency of the amination of a range of benzylic and unactivated substrates generally improved with decreasing C−H bond strength. While a C−H amination yield of 95% was obtained in neat 1,2,3,4tetrahydronapthalene (C−H BDE = 83 kcal/mol), the yield dropped to 40% in neat cyclohexane (C−H BDE = 97 kcal/ mol); toluene was an outlier with a yield of only 18% (C−H BDE = 90 kcal/mol). A Hammett-type study examined electronic effects in the C− H amination of ethylbenzene with para-substituted anilines, pXC6H4NH2, and revealed a linear, positive correlation between the C−H amination yield and the Hammett−Brown σ+ constant, giving higher yields with more electron-poor anilines. The electron-poor aniline H2NArCl3 (ArCl3 = Cl3C6H2) was particularly resistant to diazene formation, leading to C−H amination yields of 99% and 97% in neat ethylbenzene and cyclohexane, respectively (Scheme 69).

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CONCLUSIONS AND OUTLOOK

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AUTHOR INFORMATION

Review

An extremely wide range of N-containing reagents may be successfully used in copper-catalyzed sp3 C−H amination to install N-based molecular diversity that extends the reach of this C−H functionalization reaction well beyond the use of the initial sulfonyl azide (N3SO2R) and iminoiodinane (PhI NSO2R) reagents responsible for the early development of C− H amination. Synthetic, mechanistic, and theoretical studies indicate discrete copper nitrenes [Cu]NR as extremely reactive intermediates capable of functionalizing strong, unactivated C−H bonds. In particular, a unique multiconfigurational electronic structure in trigonal species weakens the Cu− N π interactions and may lead to heightened C−H amination reactivity. Alkene aziridination and C−H amination are competing reactions for electron-poor copper nitrene intermediates [Cu]NR, in which alkene aziridination usually is quite favored over allylic C−H amination. Fortunately, a wide range of non-nitrene protocols have been developed to expand the C−H substrate scope that involve the use of organic amides R1NHC(O)R2, nitrosoarenes ArNO, hydroxylamines ArNHOH, strained heterocycles such as oxaziridines, acetonitrile, secondary sulfonylamines, and even alkylamines and arylamines in C−H amination. Developed through a detailed mechanistic study of copper(II) amide intermediates, the use of unactivated alkyl- and arylamines in catalytic C−H amination is extremely uncommon.11,154 These examples illustrate the potential of copper-based systems to enable the installation of desired Nbased substituents in a single C−H functionalization step without the requirement of deprotection/refunctionalization at nitrogen, as may be necessary with N-sulfonyl-based reagents. Key challenges remain for copper-catalyzed C−H amination to become a widely utilized synthetic method for the construction of C−N bonds in more highly functionalized molecules. The broad range of C−H amination reagents and oxidants available should offer plentiful opportunities to examine and develop a wider range of copper-based enantioselective C−H amination systems.3 A detailed understanding of the structure and reactivity patterns of discrete copper nitrene and copper amide intermediates that mediate C−H amination should stimulate the development of enantioselective systems as well as tactics to control the regioselectivity of sp3 C−H amination, which currently favors functionalization at activated allylic or benzylic C−H bonds. The likelihood of copper(III) organometallic intermediates155 in some catalytic protocols, particularly those with strong “F+” based oxidants such as NFSI and F-TEDA, motivates a deeper understanding of the structure and discrete reactivity patterns of these copper(III) species. Such studies could provide insights that suggest alternative routes to generate reactive copper(III) intermediates that may lead to different regiochemical preferences for C−H amination. The extremely diverse range of N-based reagents in copper-catalyzed C−H amination coupled with the inherent sustainability advantages of this metal ensures the continued, active development of copperbased systems for this and other C−H functionalization reactions.

Scheme 69

A series of anilines was investigated for the allylic C−H amination of cyclohexene.152 Despite relatively strong η2 binding of cyclohexene to the [Cl2NN]Cu catalyst, the use of 10 equiv of cyclohexane under otherwise essentially solventless conditions gave isolated C−H amination yields up to 97%. Consistent with the Hammett-type study, electron-rich anilines typically gave poor to moderate yields, while electron-poor anilines gave good to excellent yields. N-Methyl and Nethylanilines also participated in allylic C−H amination of cyclohexene in 18−64% yields (Scheme 70). Mechanistic studies are required to fully establish the reactivity patterns of the putative copper(II) anilide intermediates [CuII]−NHAr in catalytic C−H amination with anilines, especially given the use of peroxide oxidants which can serve multiple roles in oxidation catalysis153 (see Schemes 54 and 55). Scheme 70

Corresponding Author

*E-mail: [email protected]. U


Organometallics Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Each contributed equally.

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ACKNOWLEDGMENTS

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REFERENCES

Review

T.H.W. is grateful to the NSF (CHE-1012523) for support of our efforts in the development and mechanistic understanding of C−H amination by late, first-row transition metals. T.H.W. thanks the many students at Georgetown involved in C−H amination for their creativity and efforts as well as Prof. Tom Cundari for a multitude of insightful discussions during our ongoing experiment-theory collaboration concerning active intermediates in C−H functionalization.

Notes

The authors declare no competing financial interest. Biographies

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Timothy H. Warren was born in 1970 and raised in Hillside, IL, a suburb of Chicago. After earning a B.S. summa cum laude from the University of Illinois at UrbanaChampaign in 1992, where he performed undergraduate research with Prof. Gregory S. Girlolami, he pursued graduate work with Prof. Richard R. Schrock at MIT and received his Ph.D. in 1997. NSF-NATO and Alexander von Humboldt fellowships supported postdoctoral studies with Prof. Gerhard Erker at the University of Münster in Münster, Germany. In 1999, he began his independent career at Georgetown University, where he is currently Professor of Chemistry. He is an NSF CAREER award recipient. His research interests include C−H functionalization by earth-abundant metals such as copper and the discrete intermediates responsible for these transformations. The bioinorganic chemistry of nitric oxide at copper model complexes and metal-free capture and activation of nitric oxide represent additional active areas of research.

Raymond Gephart received a B.A. in mathematics and chemistry from Gettysburg College (2002). Following a year and a half of working in quality control, he returned to school to receive a M.S. in inorganic chemistry from UNC Wilmington (2006) under Prof. Robert D. Hancock, studying ligand preorganization and metal ion recognition. He then continued his studies at Georgetown University, where he received his Ph.D. in inorganic chemistry (2012) under Prof. Timothy H. Warren, developing new methods for copper-catalyzed C−H bond amination. Currently, he is a postdoctoral fellow at the Naval Research Laboratories, where he is studying self-decontaminating surfaces under James Wynne. V


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