Taming Azide Radicals for Catalytic C–H Azidation - ACS Catalysis

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Taming Azide Radicals for Catalytic C−H Azidation Xiongyi Huang and John T. Groves* Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States ABSTRACT: Reactions that directly transform aliphatic C−H bonds into alkyl azides are noticeably lacking in the repertoire of synthetic reactions, despite the importance of molecules containing C−N3 bonds in organic synthesis, chemical biology, and drug discovery. Harnessing the ubiquity of C−H bonds in organic molecules and the versatility of the azide functional group, such transformations could have broad applications in various disciplines. Radical C−H activation represents an appealing strategy to achieve aliphatic C−H azidation, as it overcomes many drawbacks of conventional organometallic approaches in activating inert aliphatic C−H bonds. Novel C−H azidation methodologies could be realized by combining radical C−H activation via hydrogen atom abstraction with suitable azide-transfer reagents. In this perspective, we survey the history of radical C−H azidation and summarize several significant recent advances in the field. All radical C−H azidations to date follow a general approach comprising an initial radical C−H abstraction step and a subsequent azide transfer to the incipient carbon-centered radicals. A particular focus of this perspective is on the beneficial effects of using transition-metal catalysts in C−H azidation reactions, which have “tamed” azide radicals and led to reactions that proceed efficiently under much milder conditions and provide broader substrate scope and higher regioselectivities and stereoselectivities, compared to previous approaches. KEYWORDS: C−H activation, radical, azidation, catalysis, organic azides

1. INTRODUCTION Organic azides, since their first synthesis in 1858, have become an important class of compounds, having broad application in a variety of disciplines.1 The vast utility of azide-containing molecules lies in the flexible synthetic versatility of this functional group, which can be readily transformed to amines, imines, amides, aziridines, and triazoles (see Figure 1).1 The blossoming of “click chemistry” in recent decades has given organic azides irreplaceable roles in chemical biology, drug discovery, and materials science.2 The diverse value of azides has driven the development of numerous synthetic routes to access this important functionality from a plethora of precursors, including organic halides, amines, alcohols, hydrazines, epoxides, aldehydes, etc.,1 which have greatly expanded the synthetic availability of organic azides and facilitated their broad applications. Among these transformations, direct C−H azidation is of particular interest, because it harnesses the ubiquitous C−H bonds in molecules and incorporates the azide in a single step. Thus, direct C−H azidation is generally more cost- and time-effective, compared to other methodologies. Moreover, when performed at a late stage, this type of reaction can facilitate extensive diversification of currently available molecular libraries and unleash new potential of known chemical entities. These features are highly desirable for pharmaceutical discovery and late-stage diversification, as well as for developing new biochemical probes.2f The past decade has witnessed substantial achievements in constructing C−N bonds through C−H activation.3 Very © XXXX American Chemical Society

Figure 1. Examples of functional transformations that can be accessed from organic azides.

recently, significant progress has been achieved in accessing aryl azides via C−H activation using transition-metal catalysis (Cu, Pd, or Rh) or hypervalent iodine reagents.4 In sharp contrast, Received: November 3, 2015 Revised: December 14, 2015

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or CH3−I (70.3 and 57.1 kcal/mol). As observed with other pseudo-halogens, azide can form pseudo-interhalogen compounds, depicted as XN3 (X = Cl, Br, I). The BDEs of X−N3 bonds are ∼7 kcal/mol weaker than the corresponding X−I bonds. For example, the BDE of Cl−I and I−I bonds are 49.8 and 35.6 kcal/mol, respectively, whereas the BDE of Cl−N3 and I−N3 are 42.9 and 28.6 kcal/mol. It is also worth noting the bond energies of common organic azidation reagents, as they are widely used in various radical azidation reactions. Table 1 summarizes the BDEs of common organic azidation

methods to synthesize aliphatic azides through direct C−H activation have been noticeably lacking. One major challenge to the development of aliphatic C−H azidation lies in the kinetic recalcitrance of such strong, nonpolar bonds. The notably low acidity (pKa = 43−59 in dimethylsulfoxide (DMSO))5 and weak coordination ability of aliphatic C−H bonds make them very difficult to activate with organometallic methodologies such as oxidative addition and electrophilic activation. Although several organometallic systems, such as Shilov chemistry, are known to functionalize unactivated aliphatic C−H bonds,6 they generally require forcing conditions and apply mostly to simple hydrocarbons. To broaden the substrate scope and achieve high selectivity and mild conditions, directing-group strategies are commonly used, in which functionalities with lone pairs and/or π-systems are preinstalled to aid the coordination of molecules with metal centers.7 The incorporation of directing groups limits the structural variety of substrates and additional steps are required to install and remove the directing groups, which diminishes the overall synthetic efficiency. These restraints, however, are not present in radical-based C−H functionalization modalities, which activate aliphatic C−H bonds through hydrogen atom abstraction, and, thus, the C−H reactivity is mainly dependent on the homolytic bond dissociation energies (BDEs).8 Many organic and transition-metal systems are known to activate aliphatic C−H bonds efficiently via hydrogen atom transfer under mild conditions with good selectivity and functional group tolerance.8,9 It is conceivable that combining these H atom abstractors with suitable azide-transfer agents could present a general strategy to achieve aliphatic C−H azidation (see Scheme 1). In this perspective, we provide a brief

Table 1. X−N3 Bond Dissociation Energies (BDEs) of Common Organic Azides

a All BDEs are from ref 12a, unless mentioned otherwise. bCalculated value with computational methods in ref 12b.

reagents. It can be seen that different azidoiodinanes display very similar I−N3 BDE values, ranging from 29−34 kcal/mol. Tosylazide, which is one of the most widely used sulfonyl azides, has an S−N3 BDE of 48 kcal/mol, which is more than 10 kcal/mol larger than the I−N3 BDEs of azidoiodananes. 2.2. Aliphatic C−H Azidation Mediated by Organic Hydrogen Atom Abstractors. The weak BDEs of halogen− N3 bonds suggest their facile homolytic cleavage to generate azide radicals. This feature has enabled several radical azidation reactions. The pioneering work of Hassner et al. has shown that halogen azides undergo facile addition to alkenes.13 A radical pathway was determined for ClN3 addition, while the nature of BrN3 and IN3 additions depends on the reaction conditions employed. Later, Zbiral et al. and Khosrowshahi et al. reported that subjecting olefins to a mixture of iodine(III) reagents and azide ion afforded vicinal diazidation products from olefins.14 It was shown that azidoiodinanes were generated in situ under these conditions and were responsible for the observed reactivity. Employing this iodine(III)/azide approach, Magnus et al.15 and Kita et al.18 have developed a series of aliphatic C−H azidation reactions that can transform weak aliphatic C−H bonds into C−N3 bonds (see Scheme 2). In 1992, Magnus et al. reported that treating triisopropylsilyl enol ethers with PhIO and trimethylsilyl azide (TMSN3) led to efficient C−H azidation at the β carbon of enol ethers.15 They further discovered that the same reagents were also capable of performing direct N-alkyl azidation of N,N-dialkylarylamines and α-azidation of amides, carbamates, and ureas (Scheme 2A).16 In all of these reactions, the azidoiodinane intermediate (I or II, see Scheme 2A) was formed upon mixing TMSN3 and iodosylbenzene. Although azidoiodinanes are capable of generating azide radicals, mechanistic studies of these reactions suggested an ionic pathway, where a hydride abstraction led to the formation of iminium cation intermediates that were

Scheme 1. Reaction Scheme for Radical Aliphatic C−H Azidation

historical overview of radical aliphatic C−H azidation and summarize recent progress. A particular focus will be on how metal catalysts are deployed to enhance reaction efficiencies and facilitate the desired regioselectivities and stereoselectivities in C−H azidation reactions.

2. RADICAL ALIPHATIC C−H AZIDATION 2.1. Thermodynamic Properties of the Azide Radical. The azide radical has properties similar to those of halogens. The redox potential of the N3•/N3− couple is 1.32 ± 0.01 V vs NHE, which is similar to that of the I/I− couple (1.33 V) but much lower than that of Br/Br− (1.93 V).10 Unlike hydroiodic and hydrobromic acids, which are strong acids, hydrazoic acid shows moderate acidity with an aqueous pKa of 4.72. Using the Bordwell equation,5b,11 the H−N3 BDE is calculated to be 92.7 kcal/mol, indicating that N3• is a much stronger hydrogen atom abstractor than either I• or Br• (BDE(H−I) = 71.3 kcal/mol, BDE(H−Br) = 86.5 kcal/mol).12 The C−X (where X is a halogen or azide) bond energies follow a similar trend. For example, the C−N bond in CH3−N3 has a much larger BDE (80.1 kcal/mol) than those of CH3−Br 752

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ACS Catalysis Scheme 2. Aliphatic C−H Azidation with (A) PhIO/TMSN3 and (B) PIFA/TMSN3

Scheme 3. (A) C−H Azidation Mediated with IN3; (B) C−H Azidation with Stable Aziodoiodinanes and Radical Initiators

subsequently trapped by azide anions.17 At almost the same time, Kita et al. reported that phenyliodine(III) bis(trifluoroacetate) (PIFA) could also be used in combination with TMSN3 to azidate aliphatic C−H bonds.18 With PIFA/ TMSN3, direct alkyl azidation of p-alkylanisoles was achieved (see Scheme 2B). Azidoiodinane intermediate I was also shown to be responsible for the observed reactivity. Different from the Magnus reactions, a radical pathway was proposed by Kita’s group, which involved an initial generation of azide radical from II and a subsequent hydrogen abstraction by the azide radical (Scheme 2B). It is worth noting that Kita et al. also examined Magnus’ conditions for azidation of p-alkylanisoles and only observed a few percent of azidation product. Following these pioneering studies, in 2001, Bols et al. showed that iodonium azide (IN3) was capable of azidating weak ethereal C−H bonds (see Scheme 3A, method A).19 The reaction followed a free-radical chain mechanism with azide radical formed by homolysis of the I−N3 bond. As IN3 is notoriously hazardous and explosive, the same group discovered that a TMSN3−PhI(OAc)2 mixture, which is similar to the PIFA/TMSN3 reagent combination reported by Kita et al., can serve as a substitute of IN3 (Scheme 3A, method B).20 The order of reagent addition was critical, working only when TMSN3 was added subsequent to PhI(OAc)2 and substrates. One significant drawback of all of the azidation reactions depicted above is the restriction of their application to very reactive substrates, mainly because of the low thermal stability of IN3 and the azidoiodinanes generated in situ, and the relatively weak hydrogen-abstracting ability of the azidyl radical. In this regard, Zhdankin et al. developed a series of highly

stable azidoiodinane reagents,21 which, after I−N3 homolytic cleavage, will generate benzoyloxyl or cumoxyl radicals that are much stronger hydrogen-atom abstractors than N3• (corresponding O−H BDEs are 106 and 104 kcal/mol) (see Scheme 3B). The development of these reagents has greatly expanded the substrate scope of aliphatic C−H azidation. Zhdankin et al. further demonstrated that, at elevated temperatures (80−132 °C), with catalytic amount of radical initiators, benzoyl peroxide (BzOOBz), unactivated tertiary and secondary aliphatic C−H bonds can be efficiently converted to the corresponding azides. When both secondary and tertiary C−H bonds are present in the substrate molecule (e.g., adamantane and 2,2,3-trimethylbutane), the tertiary C−H bond was selectively activated (Scheme 3B). Although Zhdankin’s method can be applied to unactivated tertiary and secondary C−H bonds, the reaction requires high temperatures and can only be applied to simple hydrocarbons. Metal catalysts can serve as efficient initiators to generate azide radicals or alkyl radicals, which could provide ways to overcome the shortcomings of previous methods. Minisci et al. in the 1960s, reported efficient olefin diazidation by generating azide radicals with Fe2+ salts and oxidizing agents such as H2O2 and Ce4+.22 Recently, following this strategy, by combining azidoiodinane reagents and metal catalysts, many alkene difunctionalization reactions have been developed, which can be performed at room temperature and tolerate broad range of functionalities.23 Metal catalysts were also used to generate alkyl radicals under mild conditions, which could be subsequently trapped by azide transfer reagents such as sulfonyl azides or azidoiodinanes to afford alkyl azides. Recent progress using this approach include hydroazidation of olefins, silvercatalyzed decarboxylative azidations, and the synthesis of γazidoketones through manganese-mediated radical ring opening of cyclobutanols.24 753

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addition of radical traps BHT or TEMPO completely inhibited the reaction. With ethylbenzene and ethylbenzene-d10 as substrates, a large deuterium kinetic isotope effect (KIE = 5.0) was determined for the C−H(D) scission step. A catalystbound azide is likely to be involved in the azide transfer step, because of a much higher diastereomeric ratio observed for azidation of cis-decalin with the iron catalyst than that observed with BzOOBz. With these results, the reaction is likely to proceed via hydrogen abstraction using a 2-iodobenzoxyl radical and azide transfer from an azidoiron(III) intermediate, formed via interaction between azidoiodinane 1 and the iron pybox catalyst (Scheme 4). Besides azidoiodinanes, sulfonyl azide is another type of radical azidation reagent. The coupling of this reagent to various radical generation processes has led to the development of several new azidation reactions, such as alkene hydroazidation and decarboxylative azidation.24c,26 Very recently, Tang et al. extended the reaction scope of sulfonyl azide to include aliphatic C−H azidation (Scheme 5).27 Potassium

Early in 2015, Hartwig et al. developed an elegant ironcatalyzed aliphatic C−H azidation reaction.25 With an iron pybox catalyst and the azidoiodinane reagent 1 developed by Zhdankin, this method is capable of azidating tertiary and benzylic C−H bonds under mild conditions (Scheme 4). Scheme 4. Fe-Catalyzed Selective Tertiary C−H Azidation

Scheme 5. Metal-Free C−H Azidation with Potassium Persulfate and Sulfonyl Azide

persulfate was employed as an oxidant, which upon heating, would generate sulfate radicals that can abstract the hydrogen from the substrate. The generated substrate radical would be subsequently trapped by the sulfonyl azide, yielding azidation product. This metal-free method has mild conditions and can be applied to azidate complex molecules such as artemisinin and a pleuromutilin derivative with moderate yield (33% and 24%, respectively). 2.3. Metal-Mediated Selective Aliphatic C−H Azidation. Most radical C−H azidation reactions are based on simple organic H atom abstractors such as azidyl, benzoyloxyl, or alkoxyl radicals. Accordingly, the site selectivity of the hydrogen abstraction step is dependent mostly on the intrinsic strength of the scissile aliphatic C−H bond. Generally, more electron-rich, less-polarized, and weaker C−H bonds will be preferentially activated. Overriding this bond-strength restriction and designing catalytic systems that can selectively functionalize stronger secondary and primary C−H bonds could significantly expand the application of aliphatic C−H azidations. There are several metal catalysts that can perform aliphatic C−H activations, most of which are synthetic models of biological redox enzymes.8,9e They utilize high-valent metal intermediates, such as metal-oxo complexes, to abstract hydrogens from substrates. Unlike simple organic hydrogen atom abstractors, the site selectivity of these metal-mediated

Compared to Zhdankin’s method, which used the same azidoiodinane reagent and catalytic amount of benzoyl peroxide (BzOOBz) as a radical initiator,21b the use of the iron pybox catalyst in Hartwig’s system significantly lowered the required reaction temperatures, thus increasing the reaction yield and functional group tolerance (Scheme 4). These features enabled the late-stage functionalization of a plant-hormone gibberellic acid derivative, which has four tertiary C−H bonds and multiple chiral centers. The azidation occurred specifically at C(8) with a 75% yield, while the conditions employing a catalytic amount of BzOOBz afforded only 15% azidation product with a complex mixture of side products (lower portion of Scheme 4). These results clearly demonstrate the benefits of employing transition-metal catalysts in aliphatic C−H azidation. Preliminary mechanistic studies of this reaction showed that the reaction proceeded through a radical pathway, as the 754

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will generate an FeIV-oxo (ferryl) intermediate with a ciscoordinated chloride. This oxoiron(IV) intermediate abstracts a hydrogen from C(4) of L-threonine appended to the carrier protein, SyrB1 (Thr-S-SyrB1) and forms a chlorohydroxoiron(III) intermediate that traps the substrate radical by chlorine transfer, affording the chlorination product. Bollinger et al. discovered that replacing the chloride in SyrB2 with azide led to the formation of an azidation product, presumably following a similar mechanism to that of chlorination (Figure 2B). With L-d2-aminobutyrate (3-d2-Aba) as the substrate, wildtype SyrB2 yielded only ∼1% azidation products, relative to the total 3-d2-Aba, and ∼4%, relative to the 3-d2-Aba starting material being consumed. A single A118G mutation enhanced the azidation reactivity by ∼13-fold. As A118 is conserved in all Fe(II)/αKG-dependent halogenases and is crucial for chloride binding, the authors reasoned that mutation at this position from alanine to a smaller glycine opened space for the binding of the larger azide anion. Besides nonheme αKG-dependent halogenases and hydroxylases, cytochrome P450 (CYP) is another important family of enzymes that can perform radical C−H activations.16b,31 The key intermediate is a highly reactive oxoiron(IV) porphyrin cation radical species, known as Compound I, which activates substrates by C−H abstraction and forms hydroxylation products through the OH recombination of substrate radicals (Figure 3A).6a,7b,c,32 It is well-known that synthetic metalloporphyrins can exhibit similar chemistry when activated by suitable oxo-transfer oxidants.6b,7a,33 Very recently, our group discovered a series of manganese-catalyzed fluorination reactions based on this biomimetic paradigm.23a,28a−c,34 A key mechanistic finding from these reactions is that, with fluoride as the axial ligand, the original MnIV−OH intermediate for OH recombination of substrate radicals can be diverted to a MnIV− F intermediate, which was found to trap substrate radicals by an analogous and surprisingly efficient f luorine rebound process to yield alkyl fluoride products (Figure 3B). Inspired by these findings, we wondered whether a C−H azidation would be possible using the same chemical logic. Indeed, very recently, we have successfully developed an aliphatic C−H azidation reaction.35 As shown in Scheme 6, this method can be used to functionalize secondary, tertiary, and benzylic C−H bonds. The regioselectivity of C−H activation can be regulated by the ligand properties. For example, with adamantane as the substrate, a manganese tetramesitylporphyrin catalyst (Mn(TMP)Cl) afforded tertiary and secondary azides in a 1:1 ratio, while a 4:1 ratio was observed for an analogous manganese salen catalyst. This regioselectivity is very different from previous reactions utilizing azide or benzoyloxyl radicals as hydrogen atom abstractors, where tertiary adamantyl azide was observed as the only azidation product. Furthermore, with the bulky Mn(TMP)Cl catalyst, azidation of trans-decalin only yielded 3% tertiary azide, while secondary azides comprised a total yield of 50%. The method can also be applied to the late-stage functionalization of complex molecules, as exemplified by the successful azidation of many bioactive molecules, including estrone and artemisinin derivatives. Mechanistic studies supported a catalytic cycle similar to that of manganese-catalyzed C−H fluorinations, wherein an oxo-manganese(V) intermediate abstracts a hydrogen atom from the substrate and the resulting carbon-centered substrate radical is captured via azide rebound from an azidomanganese(IV) intermediate to form C−N3 bonds. With norcarane, which is a radical clock mechanistic probe, the radical lifetime of this

hydrogen abstractions can be tuned by the electronic and steric properties of the ligand. Based on these systems, many aliphatic C−H oxidation, chlorination, and fluorination reactions have been developed,3c,9d,23a,28 which displayed regioselectivities that are distinct from simple organic H atom abstractors. Conceivably, with a suitable azide source, it should be possible to develop new selective aliphatic C−H azidations, based on these metal-mediated C−H activation processes. In 2014, Bollinger et al. reported that SyrB2, a nonheme FeII/α-ketoglutarate (αKG)-dependent halogenase, can catalyze direct C−H azidation.29 SyrB2 normally catalyzes the C−H chlorination of threonine in syringomycin E biosynthesis. The mechanism of this chlorination is shown in Figure 2A.30 The chloride will first bind to the iron(II) center of SyrB2. O2 activation and a subsequent oxidative decarboxylation of αKG

Figure 2. (A) SyrB2-catalyzed aliphatic C−H chlorination; (B) SyrB2catalyzed aliphatic C−H azidation. 755

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Scheme 6. Mn-Catalyzed Aliphatic C−H Azidation

constant of 105 M−1 s−1.38 However, none of these reagents has been developed in a chiral form. Even if it should be possible to design chiral azide transfer reagents, using them in stoichiometric amounts as radical traps would be unlikely to be practical. Some metal azides are known to be good alkyl radical traps, even more efficient than the organic reagents discussed above. Kochi et al. systematically studied the trapping of alkyl radicals by oxidative ligand transfer of copper(II) halides and pseudo-halides. For all tested halides and pseudo-halides, the second-order rate constants were determined to be in the range of 108−109 M−1 s−1, which approaches the diffusion-controlled limit. It is reasonable to consider that, with a suitable chiral ligand, high-valent metal azides might be used as a chiral azide agents and facilitate an enantioselective azide transfer to alkyl radicals. There are several recent reports suggesting the feasibility of this strategy. In 2013, Gade reported a highly enantioselective azidation of α-hydrogens of β-keto esters and oxindoles catalyzed by Fe(OAc)2 with a “boxmi” ligand (67%−94% ee) (Scheme 7A).39 Soon afterward, Waser et al. reported a similar reaction with a copper bis(oxazoline) catalyst.40 Although neither group discussed the nature of the azide transfer step, the enantioselectivity was only observed with redox active metals such as copper and iron. Redox-inactive Lewis-acid metals (Zn2+, Mg2+, Sc3+) also catalyze the reaction in high yield but afford no enantioselectivity (see Scheme 7B). One possible explanation for this difference could be that, for redoxinactive metals, the azidation was proceeded through the electrophilic attack of iodine(III) at the α-carbon of β-keto esters,41 while for redox-active metals, the azidation might go through a similar radical mechanism as that proposed by Hartwig et al. in their iron-catalyzed C−H azidation,25,42 in which a highly valent metal azide intermediate is responsible for

Figure 3. (A) Oxygen rebound mechanism of cytochrome P450catalyzed C−H hydroxylations. (B) A heteroatom rebound process could lead to the formation of C−X bonds.

C−H azidation was determined to be ∼30 ns for both manganese porphyrin and salen catalysts. 2.4. Radical Azide Transfer and Enantioselective Aliphatic C−H Azidation. Enantioselective C−H azidation is highly desired, because of the wide applications of organic azides in biological studies and pharmaceutical discovery. Unlike aliphatic C−H aminations, which proceed through metal nitrenoid intermediates and for which enantioselectivity can be achieved with suitable chiral ligands coordinated to the metal,36 the development of enantioselective radical azidations is far more challenging, as it requires stereospecific trapping of diffusing alkyl radicals with a suitable chiral metallo-azide transfer agent. Many organic azide reagents, such as sulfonyl azides and azidoiodinanes, are known to efficiently trap alkyl radicals, affording corresponding azides.37 For example, sulfonyl azides can trap secondary alkyl radicals with a second-order rate 756

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ACS Catalysis Scheme 7. Enantioselective Azidation of α-Hydrogens of βKeto Esters and Oxindoles

the enantioselective C−N3 bond formation. Further mechanistic studies are needed to evaluate this hypothesis. In addition to the discoveries by Gade and Waser, in a recent C−H azidation reaction reported by our group,35 we detected a 70% ee for the azidation product of celestolide with the chiral manganese Jacobsen catalyst (see Figure 4A). The radical nature of this reaction was confirmed by observing the radical rearranged product using a diagnostic substrate norcarane. Computational studies revealed that incoming alkyl radicals can interact with either the internal or terminal nitrogens of the metal-bound azide with transition states of comparable energy. In both azide transfer pathways, the alkyl radicals are in close proximity to the salen ligand (3.1−3.3 Å) and thus would be affected by its chirality (Figure 4B).

Figure 4. (A) Azidation of celestolide with a Mn-salen catalyst. (B) Density functional theory (DFT)-computed energy profiles for azide transfer via the internal (1N) azido nitrogen (red) and the terminal (3N) pathway (blue). Both triplet and quintet manifolds are presented.

challenging. The notion that azide transfer can occur through two different nitrogens of the azide further complicates the ligand design, as the steric environment of both internal and terminal nitrogens of azide should be taken into consideration. It would be highly desirable to incorporate other radical C− H activation systems into C−H azidation, such as photoredox catalysis. A variety of photocatalysts have been shown to efficiently activate aliphatic C−H bonds and have been successfully used to develop novel aliphatic C−H fluorinations and C−C bond coupling reactions.44 Merging these lightcontrolled hydrogen atom abstractors with suitable azidetransfer agents would lead to new C−H azidations that will complement or even exceed current approaches. Another interesting topic would be to achieve site-selective C−H azidation with organic hydrogen atom abstractors. By changing the electronic and steric properties of organic hydrogen atom abstractors such as Zhdankin’s azidoiodinanes, it may be possible to override the intrinsic bond energy preferences for C−H activation mediated by organic radicals. Finally, the notion that metal azides can be used as radical trapping intermediates and to effect stereoselective and enantioselective azide transfer to carbon-centered radicals might have broader implications for the development of novel radical C−H functionalization reactions. This ligand transfer trapping strategy, pioneered by Kochi in the 1960s, can also be used to construct bonds other than carbon azide bonds,

3. CONCLUSION AND PERSPECTIVE With the renaissance of organic radical chemistry in recent years,43 radical-based C−H activation has gained broad attention and expanding applicability. Radical aliphatic C−H azidation, by combining the desirable features of radical C−H activation and the broad versatility of organic azides, represents a powerful catalytic tool for preparing new molecules and diversifying known compounds. This expanded repertoire will have broad applications considering the burgeoning use of click chemistry in chemical biology and pharmaceutical discovery. Recent developments in aliphatic C−H azidation, especially the use of transition-metal catalysis, have provided methods that employ much milder conditions, achieve broader substrate scope and display exceedingly high regioselectivity and stereoselectivity, compared to previous methodologies. With these advancements, however, there are still challenges in aliphatic C−H azidation. Enantioselective aliphatic C−H azidation remains difficult. Since azide transfer to alkyl radicals would have a very low energy barrier and thus an early transition state, the design of a chiral ligand with the right geometrical and steric properties to control this step will be 757

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which might include the formation of C−F, C−N, C−S, and even C−C bonds. We envision that a variety of novel aliphatic C−H functionalization methods could be developed by combining these ligand transfer steps with currently available radical C−H activation systems.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the U.S. National Science Foundation Award (No. CHE-1464578, to J.T.G.) and in part by the Center for Catalytic Hydrocarbon Functionalization, an Energy Frontier Research Center, U.S. Department of Energy, Office of Science, Basic Energy Sciences, under Award No. DE SC0001298 (to J.T.G.). X.H. thanks the Howard Hughes Medical Institute and Merck, Inc., for fellowship support.

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