Dirhodium(II)-Catalyzed C(sp3)–H Amination Using Iodine(III) Oxidants

CHAPTER THREE

Dirhodium(II)-Catalyzed C(sp3)–H Amination Using Iodine(III) Oxidants Julien Buendia, Gwendal Grelier, Philippe Dauban* Institut de Chimie des Substances Naturelles, Centre de Recherches de Gif, Gif-sur-Yvette, France *Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Historical Background 3. Methodological and Catalyst Developments 3.1 Development of Catalytic C(sp3)–H Amination 3.2 Mechanistic Studies and Recent Catalysts Design 3.3 The Quest for Selective C(sp3)–H Amination 4. Synthetic Applications 4.1 Intramolecular C(sp3)–H Amination 4.2 Intermolecular C(sp3)–H Amination 5. Conclusion Acknowledgments References

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1. INTRODUCTION The development of organometallic catalysis has had a tremendous impact on organic synthesis in the last 50 years with the discovery of new reactions that were previously deemed impossible. The “Nobel-prize winning” Heck reaction stands as the prototypical example to illustrate how the chemistry of transition metals has allowed organic chemists in both academia and industry to complete the synthetic toolbox.1 In parallel to the classical functional group transformations, the metal-catalyzed processes give the opportunity to assemble building blocks in a highly efficient and selective manner that cannot be envisioned otherwise. Catalytic cross-couplings, particularly, are now routinely applied for the synthesis of small molecules Advances in Organometallic Chemistry, Volume 64 ISSN 0065-3055 http://dx.doi.org/10.1016/bs.adomc.2015.08.001

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2015 Elsevier Inc. All rights reserved.

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on scales that range from milligram to multiton. The Buchwald–Hartwig cross-coupling reaction, for the formation of arylamines, belongs to this class of transformations with relevant applications in the pharmaceutical industry owing to the ubiquity of nitrogen-containing drugs.2 The rise of organometallic catalysis has also been highly helpful to investigate the field of catalytic CdH functionalization that has outstandingly expanded in the last decade. The possibility to directly convert a CdH bond to a CdC or a CdX bond (X: O, N, …) was reported long ago with the discovery, for example, of the Hofmann-L€ offler–Freytag reaction3 or the 4 Barton ester nitrite reaction. However, the use of transition metal complexes has allowed chemists to significantly improve the selectivity and the scope of CdH functionalization reactions. New efficient step- and atom-economical reactions, thus, have recently been discovered.5 They prove to be as efficient as the traditional catalytic cross-couplings, but, in addition, they avoid the need to introduce a sacrificial functional group. Several relevant applications in synthesis nicely highlight that catalytic CdH functionalization reactions are now part of the toolbox of the synthetic chemists.6 These reactions provide access to a new molecular space, and, therefore, to a new intellectual property space. Of particular relevance is the possibility to apply these transformations to complex natural products and pharmaceutical agents. Accordingly, the late-stage CdH functionalization opens unique opportunities to increase the molecular diversity and improve the pharmacodynamic and pharmacokinetic properties of bioactive compounds.7 To this end, catalytic CdH amination holds significant interest given the crucial influence of nitrogen on such parameters. The search for reactions allowing the direct amination of CdH bonds is an exciting challenge. Contrary to the CdH hydroxylation reaction that is catalyzed by several natural oxidases to afford alcohols with high levels of efficiency and selectivity, the analogous catalytic CdH amination is unknown in nature.8 Needless to mention, discovering such a transformation has challenged the creativity of organic chemists and should provide a truly unique synthetic tool with unprecedented application in synthesis. Gratifyingly, despite the fact that inspiration cannot be derived from nature, the application of organometallic catalysis has proved helpful to uncover appropriate conditions to perform efficient CdH amination reactions. The last 15 years, thus, has witnessed significant progress in this domain with the report of several catalytic systems that have revealed highly efficient to functionalize various types of CdH bonds.9 Among these different studies, those that are based on catalytic nitrene CdH insertions probably stand as

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Scheme 1 Dirhodium(II)-catalyzed C(sp3)–H amination with iodine(III) oxidants.

the methods of choice for the amination of C(sp3)–H bonds.10 Various nitrene sources have been reported in this context. Azides,11 Nsulfonyloxycarbamates,12 and, to a lesser extent, haloamines13 have recently led to efficient CdH amination reactions that have a limited impact on the environment with the production of nontoxic and easily removable sideproducts. However, it is well acknowledged that the most significant achievements in terms of synthetic application have been made with the use of iodine(III) oxidants (Scheme 1).14 Intra- and intermolecular processes have been described in the presence of various transition metal complexes, giving access to a variety of substituted amines with high levels of chemo-, regio- and, sometimes, stereoselectivity. Elegant applications in total synthesis nicely highlight the efficiency of the iminoiodinane-mediated C(sp3)–H amination reactions, which are the purpose of this review. This overview will concentrate exclusively on the use of dirhodium(II) complexes as these are the most active catalysts for this transformation. The preparation of rhodium(II) carboxylate complexes was first reported in 1960 by the group of Chernyaev following the reaction of rhodium(III) chloride in refluxing formic acid.15 Their ability to decompose diazo compounds for the formation of a metallocarbene was then discovered by Teyssie´ and coworkers a decade later.16 This seminal study has opened the vast domain of dirhodium(II)-catalyzed carbene additions that has proved highly successful.10d,17 Their use in catalytic nitrene addition, though less extensively investigated, has also led to significant achievements that are summarized below with an emphasis on the latest developments made in the last 5 years.

2. HISTORICAL BACKGROUND The first examples of metal-catalyzed C(sp3)–H amination were reported at the end of the 1960s. Kwart and Khan18 demonstrated the

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capacity of copper to decompose benzenesulfonyl azide in cyclohexene to afford a mixture of aminated products from which the cyclohex1-en-2-ylamine derivative was isolated in 3% yield. Soon after this seminal work, the combination of chloramines with zinc19 or copper20 offered the opportunity to functionalize cyclohexane or dioxane, respectively. The reaction of chloramine-T with ferrous chloride also proved appropriate for the amination of adamantane,21 however, all these results have remained of marginal synthetic interest. More significant achievements were reported through the application of hypervalent iodine chemistry. Aza-analogs of the well-known oxidizing agent iodosylbenzene (PhI]O),22 the trivalent iodine reagents of general formula PhI]NR, or iminoiodinanes, were prepared for the first time from sulfonamides in the mid-1970s.23 A decade later, these were shown to be relevant nitrene precursors for the functionalization of alkanes and alkenes in the presence of several metal porphyrin complexes.24 Importantly, in these studies aimed at mimicking cytochrome P-450 enzymes for the formation of CdN bonds, a single result has set the foundation for the successful development of rhodium(II)-catalyzed C(sp3)–H amination. Dirhodium(II) tetraacetate Rh2(OAc)4, thus, proved to be a relevant catalyst to promote the conversion of the 2,5-isopropylbenzenesulfonamide-derived iminoiodinane 1 to a cyclic sulfonamide through an efficient intramolecular C(sp3)–H amination reaction (Scheme 2).25 Compound 2 was isolated with an excellent yield of 86%, a result that already underscored the unique reactivity of rhodium(II) dimers. By comparison, the use of an iron(III) porphyrin catalyst afforded the same product in only 77% yield. Another decade later, the first synthetically useful catalytic nitrene additions were reported with PhI]NTs as the nitrene source in the presence of copper complexes.26 The aziridination of various classes of alkenes, thus, was shown to proceed in very good yields to afford the corresponding aziridines that are useful synthons for the preparation of substituted amines. The relevance of this reaction was further demonstrated by the capacity of chiral

Scheme 2 First dirhodium(II)-catalyzed intramolecular C(sp3)–H amination with an iminoiodinane.

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copper complexes to catalyze its asymmetric version with excellent enantioselectivities starting from aromatic alkenes.27 Further elegant synthetic applications have also highlighted the value of the copper-catalyzed alkene aziridination.28 With respect to the mechanism, the formation of a copper-bound nitrene species with the concomitant release of iodobenzene is, now, well acknowledged; however, the subsequent nitrene addition step has long remained a matter of debate, depending either on the nature of the substrate or the copper complex. A general mechanism, nevertheless, has recently been proposed that suggests the involvement of both singlet and triplet pathways, and of minimum-energy crossing points (MECP) between the corresponding surfaces.29 In the course of their study, the group of Evans has also pointed out, in a single experiment, the capacity of Rh2(OAc)4 to catalyze the aziridination of styrene in 48% yield.26a This observation was then confirmed by the work of Mu¨ller and coworkers who have investigated the intermolecular rhodiumcatalyzed aziridination of olefins with the p-nitro analog of PhI]NTs, i.e., PhI]NNs.30 Interestingly, the authors have observed a process of allylic C(sp3)–H amination in the case of cyclohexene, a result that stands in sharp contrast to the exclusive formation of the aziridine using copper complexes.26a This group, thus, undertook the systematic study of the rhodium(II)-catalyzed CdH insertion with PhI]NNs.31 Although the synthetic value of the process is limited by the necessity to use an excess of the substrate (20 equiv.) to secure good conversions, this work has established fundamental results which were later confirmed by the Du Bois’ group (see below). The rhodium(II)-catalyzed C(sp3)–H amination reaction is sensitive to steric and electronic effects. Accordingly, it preferentially allows the efficient functionalization of secondary benzylic and allylic sites, as well as of methylene groups in α-position to ethers (Scheme 3). But with simple alkanes such as adamantane, the reaction selectively takes place at the tertiary center. Higher yields are also obtained in the presence of electron donating groups. In terms of stereoselectivity, Mu¨ller and coworkers have performed asymmetric C(sp3)–H amination with chiral rhodium complexes, though the induction remained modest (31% ee). They have also underscored the stereospecificity of the nitrene CdH insertion that takes place with retention of configuration from (R)-2-phenylbutane. More significantly, they have also addressed the issue of the chemoselectivity in the case of the allylic amination. As observed in carbene chemistry,32 the product distribution was found to depend on the nature of the substrate and the

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Scheme 3 Rhodium(II)-catalyzed intermolecular C(sp3)–H amination with PhI]NNs.

Scheme 4 Chemoselectivity issue in the rhodium(II)-catalyzed intermolecular C(sp3)–H amination of cyclic alkenes.

rhodium complex (Scheme 4). Thus, whereas the amination of cyclohexene affords the allylic amine as the major product, the exclusive formation of the aziridine is observed from cyclooctene. As such, the studies of the Mu¨ller group not only highlighted the synthetic opportunities of dirhodium(II) catalysis in nitrene chemistry but also the issues associated with the design of an efficient intermolecular protocol. Dramatic improvements in the efficiency of catalytic nitrene additions, then, arose from the development of practical procedures for the formation of iminoiodinanes. Though PhI]NTs and PhI]NNs remain widely used in the search for catalytic nitrene transfers with improved efficiency,33 it is now well accepted that iminoiodinanes are difficult to prepare and are of limited stability. Moreover, the use of sulfonamides imposes the presence of a sulfonyl-protecting group that often leads to dead ends in synthesis.

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Scheme 5 Rhodium(II)-catalyzed intramolecular C(sp3)–H amination of carbamates.

The discovery of simple protocols for the in situ generation of iminoiodinanes has, thus, addressed these issues and boosted the area of catalytic nitrene transfers. Three studies have appeared, independently, in the early 2000s, involving manganese porphyrin,34 copper,35 and rhodium complexes.36 Among these reports, the latter is of particular relevance in the context of this review. It has been the first of many significant papers from the Du Bois’ group that describe their extensive investigation of the rhodium-catalyzed intramolecular C(sp3)–H amination. Thus, the reaction between a carbamate and the commercially available PhI(OAc)2 in the presence of magnesium oxide and Rh2(OAc)4 was shown to afford an oxazolidinone through the oxidative cyclization of a rhodium-bound nitrene (Scheme 5). This seminal paper has been a source of inspiration for several groups. Several transition metal complexes derived from ruthenium,37 silver,38 and iron39 have been reported to catalyze the same transformation from various nitrogen functions. It has also culminated in the development of a new efficient synthetic tool that is now part of the toolbox of organic chemists.

3. METHODOLOGICAL AND CATALYST DEVELOPMENTS 3.1 Development of Catalytic C(sp3)–H Amination 3.1.1 Intramolecular C(sp3)–H Amination The intramolecular C(sp3)–H amination of carbamates developed by Du Bois and coworkers36 can be performed from substrates derived from primary, secondary, and tertiary alcohols. The reaction allows the efficient functionalization of benzylic, allylic,40 and tertiary C(sp3)–H bonds, as well as that of secondary unactivated positions, but, to a lesser extent. Its efficiency, in specific cases, can be improved by replacing Rh2(OAc)4 with Rh2(tpa)4.41 An important feature is the stereospecificity of the nitrene CdH insertion that was unambiguously demonstrated to proceed with retention of configuration using a stereochemical probe prepared from (S)-2-methyl-1-butanol (Scheme 6A). This transformation, thus, is an efficient method for the formation of oxazolidinones that can be considered as precursors of vicinal amino

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Scheme 6 Intramolecular C(sp3)–H amination of carbamates.

alcohols. This trend results from the selective insertion of the nitrene at the β-position of the carbamate to afford exclusively the five-membered ring product. Recent results, however, have demonstrated that six-membered rings can be obtained under specific conditions, but these remain rare and involve the highly active dirhodium(II) complex Rh2(esp)2 3 (Scheme 6B).42 It should be also pointed out that a competitive ipso activation of the α-CdH bond can occur with secondary alcohol-derived carbamates to afford the corresponding ketone through the formal extrusion of HN]C]O.43 This study was immediately followed by a second seminal paper describing the use of sulfamates in the rhodium(II)-catalyzed intramolecular C(sp3)–H amination.44 The starting materials of general formula RdOSO2dNH2, easily accessible from primary and secondary alcohols, proved to be more active nitrene sources than carbamates as excellent yields of up to 91% were obtained using a lower amount, i.e., 2 mol%, of the commercially available Rh2(OAc)4 or Rh2(oct)4 (Scheme 7). The stereospecificity of the reaction was again clearly highlighted but, unlike with carbamates, the nitrene addition proceeds at the γ-position of the sulfamate. The preferred formation of six-membered cyclic sulfamates has been rationalized by the ring strain imposed by the longer SdO and SdN bonds as well as by the NdSdO angle. Interestingly, whereas the expected five-membered rings are not accessible from phenethyl alcohol derivatives with rhodium(II) complexes, the use of ruthenium45 or iron46 complexes successfully addresses this issue. Occasionally, sevenmembered rings can also be prepared according to the structure of the substrate that can exacerbate the reactivity of a specific C(sp3)–H bond. Conformational factors, for example, have been invoked to rationalize the formation of compound 5 from the piperidine derivative 4.47 This reaction with sulfamates, at first glance, might appear simply as complementary to the one with carbamates because both afford cyclic

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Scheme 7 Rhodium(II)-catalyzed intramolecular C(sp3)–H amination of sulfamates.

Scheme 8 Rhodium(II)-catalyzed intramolecular C(sp3)–H amination at ethereal α-CdH bond.

products that are, respectively, precursors of 1,3- and 1,2-amino alcohols. This is, however, a naive view as the rhodium(II)-catalyzed intramolecular C(sp3)–H amination of sulfamates is a much more versatile synthetic tool. In addition to permit the functionalization of tertiary, benzylic, secondary, and primary C(sp3)–H bonds, here classified in decreasing order of reactivity, the catalytic intramolecular C(sp3)–H amination of sulfamates, contrary to carbamates,40 also occurs efficiently at ethereal α-CdH bond to produce N,O-acetals. The latter can react in situ with various nucleophiles to produce relevant building blocks for total synthesis (Scheme 8).48 Another important synthetic opportunity offered by cyclic sulfamates is their capacity to undergo nucleophilic ring opening after introduction of an electron-withdrawing group on the NH group. The SN2-type attack of a nucleophile at the CdO center, thus, leads to the formation of complex nitrogen compounds after removal of the SO3 moiety by acidic hydrolysis (see Section 4.1.2).44 On the other hand, the catalytic intramolecular C(sp3)–H amination can also be applied from aromatic sulfamates that can react efficiently with various organomagnesium reagents in nickel-catalyzed cross-coupling reactions (Scheme 9).49

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Scheme 9 Catalytic C(sp3)–H amination of aromatic sulfamates and subsequent crosscoupling with Grignard reagents.

The efficiency and scope of the intramolecular C(sp3)–H amination reaction was significantly enhanced with the discovery of a highly effective dirhodium(II) complex, Rh2(esp)2 3.50 The use of a dicarboxylic acid as the ligand for the dinuclear rhodium core, thus, led to the isolation of a new catalyst with improved activity. This results from the chelate effect that avoids any ligand dissociation from the metal center, which is generally observed with classical tetracarboxylate dimers. Use of a m-xylene spacer, to this end, proved optimal according to a perfect geometrical arrangement of the bridging ligands than could not be achieved with other strapped dicarboxylate complexes.14b The unique profile of 3 is highlighted by the high yields observed for the intramolecular C(sp3)–H amination reaction of sulfamates, even using 0.15 mol% of the catalyst (Scheme 10). Additionally, the use of Rh2(esp)2 has extended the intramolecular C(sp3)–H amination reaction to other types of nitrene precursors (Scheme 11). Application of the reaction conditions to ureas and guanidines, thus, gives access to valuable building blocks for the synthesis of drug candidates or natural products.51 A diverse range of 1,3- and 1,2-diamines is, also, easily accessible, respectively from sulfamides52 and hydroxylaminederived sulfamates.53 In each case, 1–2 mol% of catalyst 3 is sufficient to isolate the expected cyclic products with excellent yields of up to 99%. Even the scope of the intramolecular C(sp3)–H amination of carbamates has been improved by the excellent performance of the Rh2(esp)2 catalyst. As previously depicted in Scheme 6B, the unprecedented formation of sixmembered rings has been reported with this complex.42a More recently, a general procedure for the propargylic C(sp3)–H amination of alkynes has been successfully described (Scheme 12).54 It is worth mentioning that such a propargylic C(sp3)–H amination does not occur from the analogous sulfamates as the corresponding nitrene, in this case, adds to the alkyne to afford complex cyclic compounds through the intermediacy of a rhodium-bound carbene.55 This result clearly highlights the effect of the

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Scheme 10 Rh2(esp)2-catalyzed intramolecular C(sp3)–H amination of sulfamates.

Scheme 11 Scope of the Rh2(esp)2-catalyzed intramolecular C(sp3)–H amination.

Scheme 12 Rh2(esp)2-catalyzed intramolecular propargylic C(sp3)–H amination.

nitrene substituent on the course of the reaction, a feature of the synthetic nitrene chemistry that will be underscored in the following sections. 3.1.2 Intermolecular C(sp3)–H Amination The high reactivity of metallanitrenes makes the search for an efficient catalytic intermolecular C(sp3)–H amination reaction challenging. This is an issue that still remains to be addressed since many procedures, even now, are reported with the use of an excess of substrate to increase the possibility to intercept the unstable metallanitrene and avoid its competitive decomposition. Few methods are available to functionalize alkanes, alkenes, and

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aromatic compounds used in limiting amounts. Historically, the first solution to circumvent this limitation was described by the group of Che through the discovery of polyfluorinated Ru(II) porphyrin complexes.34 The design of new ligands and nitrene sources has led to the development of simple protocols in the presence of dirhodium(II) complexes. The emergence of the Rh2(esp)2 complex 3, thus, proved of paramount importance to design appropriate conditions for the efficient intermolecular C(sp3)–H amination of various hydrocarbons.56 Fundamentally, this study has clearly showcased the influence of the nitrogen substituent on the efficiency of the nitrene addition. Whereas the use of sulfonamides leads to yields of up to 35%, sulfamate-derived nitrenes generally display a higher reactivity, as also observed for the intramolecular additions. Of particular relevance is the electron-deficient trichloroethoxysulfonamide 6 (TcesNH2) that generates the CdH aminated product from ethylbenzene in 72% yield (Scheme 13). Generally, the reaction proceeds efficiently with secondary benzylic C(sp3)–H bonds that could be selectively functionalized in the presence of a tertiary site. The latter can, nevertheless, be aminated though with lower conversions. The reaction with allylic substrates, on the other hand, mainly leads to aziridines that arise from the nitrene addition to the olefin, allylic amines being observed as competitive side-products only from cycloalkenes such as cyclopentene.57 The rhodium(II)-catalyzed intermolecular C(sp3)–H amination reaction involves the use of the more soluble hypervalent iodine oxidant PhI(OCOtBu)2 which enables its slow addition over several hours, a protocol that increases the yield of the nitrene insertion. But contrary to the intramolecular process, it does not require the presence of magnesium oxide, a point that puts into question its presumed role of acid scavenger.43 It should be mentioned that these conditions have also proved appropriate to perform the

Scheme 13 Rh2(esp)2-catalyzed intermolecular benzylic C(sp3)–H amination with TcesNH2.

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oxidative conversion of aldehydes to N-(sulfonyl)carboxamides through a putative nitrene insertion into the aldehydic C(sp2)–H bond (Scheme 14).58 The discovery of the exceptional reactivity of the sulfonimidamide 7 as a chiral nitrene source has culminated in the design of a highly efficient catalytic intermolecular C(sp3)–H amination reaction with a broad substrate scope.59 In addition to perfect stereoselectivity (see Section 3.3.3), excellent yields of up to 99% can be observed using a stoichiometric amount of various hydrocarbons, on a scale of up to 20 mmol and with low catalytic amounts of the dirhodium(II) complex Rh2(S-nta)4 8.59d As a highlight of this methodology, the amination of 1,3-dimethyladamantane proceeds with an excellent yield of 94% affording a protected derivative of Memantine that was approved for the treatment of Alzheimer’s disease. Similarly, the highest yields reported so far for the amination of cycloalkanes used in limiting amounts have been obtained through this procedure (Scheme 15). This efficient intermolecular C(sp3)–H amination reaction has recently been used to address the issue of the unavoidable formation of iodobenzene as a side-product in iodine(III)-mediated oxidative aminations, as depicted in Scheme 1. In line with the recent reports on PhI-catalyzed reactions, the search for iodine-catalyzed amination involving a cooxidant has been investigated but this strategy has been unsuccessful in nitrene chemistry, until

Scheme 14 Rh2(esp)2-catalyzed sulfamidation of aldehydes.

Scheme 15 Rh-catalyzed intermolecular C(sp3)–H amination of alkanes with sulfonimidamides.

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Scheme 16 Tandem catalytic C(sp3)–H amination/sila-Sonogashira–Hagihara crosscoupling.

now.60 More significant results, however, have been obtained by considering the iodoarene side-product as a building block that can be valued in a subsequent one-pot palladium-catalyzed cross-coupling reaction. Accordingly, a new tandem CdN and CdC bond-forming reaction has been devised by combining the catalytic intermolecular C(sp3)–H amination with a palladium-catalyzed Sila-Sonogashira–Hagihara coupling reaction.61 The tandem reaction can be applied to several alkanes and alkenes using various (diacetoxy)iodoarenes to afford complex nitrogen-containing compounds isolated in excellent yields and with complete stereoselectivity (Scheme 16).

3.2 Mechanistic Studies and Recent Catalysts Design In their seminal paper on the rhodium(II)-catalyzed CdH insertion with PhI]NNs, the group of Mu¨ller reached the conclusion that the reaction proceeds through the concerted asynchronous insertion of a rhodiumbound nitrene species.31 This hypothesis was supported by a Hammett analysis (ρ ¼  0.90 vs. σ +), the absence of ring-opened products in reactions involving cyclopropyl radical clocks, and the stereospecific C(sp3)–H amination of (R)-2-phenylbutane that occurs with complete retention of configuration. However, the very low yields obtained for these test reactions as well as the kinetic isotope effect measured for the reaction from (1,3-D2)adamantane (KIE ¼ 3.5  0.2) put this conclusion into question as these did not rule out the possible involvement of radicals that could undergo fast recombination. Nevertheless, this initial study already highlighted the discrepancies that could be observed between the carbene and nitrene chemistries in terms of mechanism. The electronic structure of nitrenes, contrary

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to that of singlet dirhodium-carbenes, is characterized by a singlet state close in energy to the triplet state. This confers to nitrenes the capacity to react in one state or the other, a feature that, moreover, varies according to the substitution of the nitrene. The results uncovered by Mu¨ller have been corroborated by the subsequent studies from the Du Bois’ group, particularly with respect to the intramolecular reaction. The stereospecific C(sp3)–H insertion of the carbamate-derived nitrene depicted in Scheme 6A was the first relevant reaction in favor of the asynchronous concerted addition.36 More significantly, the extensive analysis of the rhodium-catalyzed intramolecular C(sp3)–H amination of sulfamates has led to the same conclusion.62 The Hammett analysis (ρ ¼  0.55 vs. σ +) and the kinetic isotope effect observed from the monodeuterated phenylpropyl sulfamate 9 (KIE ¼ 2.6  0.2) clearly argue in favor of this mechanistic scenario (Scheme 17). Additionally, the reaction from the cyclopropyl radical clock 12 supports this hypothesis by furnishing a single product isolated with an excellent yield of 91%. DFT calculations carried out from carbamates and sulfamates are in line with these experimental observations and the hypothetical mechanism.63 However, according to the nature of either the substrate or the dirhodium(II) complex, the formation of the CdN bond could proceed differently. It can occur through the direct insertion of a singlet nitrene, or according to a two-step process involving a triplet species and the formation of a diradical that, then, would recombine via an open-shell singlet state resulting from an intersystem crossing process from the triplet state. Another point worth the discussion is the exact nature of the nitrene precursor. The rhodium-catalyzed C(sp3)–H amination reported by the group

Scheme 17 Mechanistic studies of the intramolecular C(sp3)–H amination of sulfamates.

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of Mu¨ller was based on the use of iminoiodinanes which are presumed to be generated in the studies from the Du Bois’ group. Any attempt to detect these iodine(III) oxidants by NMR long proved unsuccessful.56,62 However, a recent study based on the application of desorption electrospray ionization mass spectrometry (DESI-MS) demonstrates that this intermediate can be observed, even as a complex with the Rh2(esp)2 catalyst.64 Several experimental observations, such as the imidation of thioanisole56 or the kinetic resolution of racemic sulfonimidamides,59b suggest that the formation of iminoiodinanes is a dynamic equilibrium between various iodonium species, shifted toward the starting materials. It would be the rate limiting step of the reaction, at least in the early stage of the intramolecular C(sp3)–H amination.62 In addition, whereas magnesium oxide was initially considered as a simple acid scavenger, it could be conjectured that its presence is required to shift this equilibrium toward the iminoiodinanes, at least in the case of carbamates. Parallel investigations of the rhodium-catalyzed intermolecular reaction have shown that, at first glance, its mechanism is identical in all respects to the intramolecular process.56 The Hammett analysis (ρ ¼ 0.73 vs. σ +), the stereospecific amination of compound 14, and the result obtained with the radical clock substrate 16 give support to this hypothesis (Scheme 18). However, the difference in chemoselectivity observed between the intra- and the intermolecular C(sp3)–H amination reactions—tertiary centers preferentially react in the former case while benzylic positions are more efficiently functionalized in the latter case—as well as the extensive study of the Rh2(esp)2 complex 3 have led to propose a competitive pathway for the intermolecular transformation.

Scheme 18 Mechanistic studies of the intermolecular C(sp3)–H amination.

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With the aim to better understand the exceptional reactivity of the Rh2(esp)2 catalyst, Du Bois has demonstrated that dirhodium(II) complexes undergo an one-electron oxidation to give a mixed-valent Rh2+/Rh3+ species.65 While classical dirhodium tetracarboxylate complexes decompose under these conditions, the Rh2 ðespÞ52 + species proves to be kinetically stable partly because of the chelate effect imposed by the dicarboxylic acid ligand. This is a critical issue as the stable Rh2 ðespÞ52 + species can then be reduced by the pivalic acid released from the iodine(III) oxidant PhI(OCOtBu)2, to Rh2(esp)2 which is supposed to be the active catalyst. This hypothesis was corroborated by the higher yield obtained for the intermolecular C(sp3)–H amination of ethylbenzene in the presence of an iodine(III) oxidant derived from the more reducing 2-methyl-2-phenylpropanoic acid (Scheme 19). Use of cyclic voltammetry and controlled potential electrolysis measurements reported by the group of Berry has identified the mixed-valent Rh2 + /Rh3+ amido species 19 that would be generated through a protoncoupled electron transfer (PCET).66 It remains unclear whether the intermediate 19 is directly involved in the oxidative C(sp3)–H amination reaction, but it is conjectured that a second PCET, then, would lead to the rhodium-bound nitrene 20. Accordingly, the Rh2(esp)2-catalyzed intermolecular C(sp3)–H amination reaction would proceed through two different mechanistic pathways. As it is the case for the intramolecular amination, the classical catalytic cycle A involving the iminoiodinane would operate in the early stages of the reaction when the substrate concentration is sufficiently high to intercept the rhodium-bound nitrene 20 efficiently. At lower concentrations or with poorly reacting substrates, this pathway would be much less effective. Accordingly, catalytic cycle B based on two PCETs, which is more robust over time, would prevail (Scheme 20). Fundamentally, both intermediates 19 and 20, in addition to the iminoiodinane precursor, have been detected by DESI-MS.64 The dirhodium nitrene 20, particularly, has been observed under two different oxidation states64 thereby suggesting its capacity to react also through a

Scheme 19 Intermolecular C(sp3)–H amination: influence of the iodine(III) oxidant on the efficiency of the reaction.

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Scheme 20 Possible mechanisms for the Rh2(esp)2-catalyzed intermolecular C(sp3)–H amination.

hydrogen atom abstraction–radical recombination pathway. Taken all together, these experimental observations strongly support the hypothesis that two different catalytic cycles operate in the intermolecular C(sp3)–H amination reaction. It should be pointed out that DFT calculations performed by the group of Bach are broadly in line with these conclusions.67 They have come to the conclusion that, in contrast to the concerted pathway proposed for the intramolecular C(sp3)–H amination, the intermolecular reaction occurs through a hydrogen atom transfer/recombination pathway on the singlet surface. The involvement of mixed-valent Rh2+/Rh3+ species in the intermolecular C(sp3)–H amination reaction has been further confirmed by the preparation of new complexes analogous to Rh2(esp)2 3. On one hand, the design of a resorcinol-derived ligand, that is structurally comparable to the esp ligand, has enabled the synthesis of the new complex 21 that is an active catalyst in intramolecular C(sp3)–H amination.68 However, the redox properties of the resorcinol-based compound make the formation of a stable Rh2+/Rh3+ species unlikely, thereby leading to poor conversions for the intermolecular reaction in agreement with the hypothesis of the oneelectron mechanism (Scheme 21). On the other hand, the dicarboxamide derived from the esp ligand has allowed the preparation of the mixed-valent Rh2+/Rh3+ complex 22. The latter efficiently catalyzes the intramolecular C(sp3)–H amination of sulfamates as the use of only 0.05 mol% of 22 allows for isolating the cyclic sulfamate with a yield of 72% corresponding to a TON around 1450

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Scheme 21 C(sp3)–H amination catalyzed by a rhodium complex bearing redox noninnocent ligands.

Scheme 22 Rh2(espn)2+-catalyzed intramolecular C(sp3)–H amination.

(Scheme 22).69 By comparison, complex 3 was found to achieve TONs in the 500600 range under the same conditions. However, use of 22 in the intermolecular C(sp3)–H amination did not prove really successful as good yields have only been obtained with reactions run in neat substrate.

3.3 The Quest for Selective C(sp3)–H Amination 3.3.1 Chemoselectivity A major issue to address in catalytic C(sp3)–H functionalization is the search for conditions enabling the discrimination of a specific CdH bond, of course ubiquitous in any organic compound. With respect to the intramolecular C(sp3)–H amination of sulfamates, competition experiments have led to delineate the relative reactivity of different types of CdH bonds (see Section 3.1.1).62 Secondary benzylic CdH bonds, for example, are more reactive than unactivated secondary positions; however, this chemoselectivity can be reversed according to the catalyst used, as it is the case by replacing Rh2(OAc)4 by the more sterically hindered complex Rh2(tpa)4 (Scheme 23). In addition to the influence of the catalyst, it has recently been demonstrated that the chemoselectivity for the intermolecular C(sp3)–H amination can also be fine-tuned by the nitrogen substituent. As mentioned above, the intermolecular reaction favors secondary benzylic CdH bonds over tertiary positions, a reversed reactivity scale when compared to the intramolecular

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Scheme 23 Chemoselectivity in intramolecular C(sp3)–H amination: influence of the Rh-catalyst.

Scheme 24 Chemoselectivity in intermolecular C(sp3)–H amination: influence of the sulfamate.

process. The design of appropriate sulfamates has led to modify this chemoselectivity.70 Thus, whereas the use of TcesNH2 6 affords a 8:1 mixture of CdH aminated products from isoamylbenzene in favor of the benzylic amine, the reaction with aromatic sulfamates such as 23 tends to give equal amounts of compounds arising from the nitrene addition either at the benzylic or tertiary position (Scheme 24). Accordingly, the 2,6-difluorophenol-derived sulfamate 23 is an efficient nitrene precursor for the functionalization of tertiary CdH bonds (Scheme 25A). Subsequent experiments combined with theoretical studies involving Hammett parameters and computed IR vibrational data have enabled chemists to identify the steric and electronic factors at play in the reactivity of the system.71 Unexpectedly, intermolecular synergistic interaction between the isoamylbenzene substrate and the sulfamoylnitrene has been detected. Ultimately, these studies have tailored a pentafluorosulfamate 24 that preferentially reacts with benzylic CdH bonds (Scheme 25B). The catalytic allylic C(sp3)–H amination raises another critical issue in terms of chemoselectivity given the capacity of nitrenes to add to alkenes. The dirhodium-catalyzed intramolecular additions generally lead to mixtures of compounds for which the aziridines are the major products. Rhodium-bound nitrenes, indeed, have a great tendency to react with the π-electron rich systems. And in line with the previous observations (see Scheme 23), the ratio of products varies according to the rhodium tetracarboxylate complex (Scheme 26).

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Scheme 25 Chemoselective intermolecular C(sp3)–H amination reactions with tailored sulfamates.

Scheme 26 Chemoselectivity in intramolecular allylic C(sp3)–H amination.

Highly chemoselective intramolecular allylic C(sp3)–H amination reactions with nitrenes have been reported through the development of ruthenium and iron complexes.37c,40 It is worth mentioning that the reaction proceeds in a stepwise manner via a hydrogen atom abstraction with the mixed-valent Ru2+/Ru3+ species. In the case of the rhodium catalysis, a chemoselective allylic amination, nevertheless, has been reported with the design of the chiral rhodium complex Rh2(S-nap)4 25.72 The latter is a rare example of a rhodium tetracarboxamidate species that withstands the oxidizing reaction conditions, a feature partly supported by its redox potential, which is higher than that of other carboxamidate complexes. Exclusive formation of allylic amines, thus, has been reported with yields of up to 70% (Scheme 27). These results have been corroborated by recent DFT calculations. These suggest that strong donating groups on the dinuclear rhodium

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Scheme 27 Chemoselective intramolecular allylic C(sp3)–H amination catalyzed by the Rh2(S-nap)4 complex.

core would favor the allylic C(sp3)–H amination. The latter would proceed via a mixed singlet–triplet pathway where the initial more stable triplet species would convert to a singlet via a MECP.73 With respect to the intermolecular nitrene addition to alkenes, the formation of aziridines is generally observed.57 Nevertheless, the use of sulfonimidamides has allowed the discovery of a highly chemoselective intermolecular allylic C(sp3)–H amination that can be applied to several classes of alkenes. Various terpenes and allyl enol carbonates, particularly, undergo allylic amination in excellent yields of up to 98% (Scheme 28).59c The chemoselectivity was supposed to be controlled by the substrate. Hyperconjugation of the allylic CdH bonds with the adjacent π-system would increase their reactivity, a result corroborated by the exclusive formation of the aziridine from β-caryophyllene whose structure does not display such a hyperconjugative effect for the allylic CdH bonds. 3.3.2 Stereoselectivity Driven by the Substrate Application of the catalytic intramolecular C(sp3)–H amination reaction to cyclic substrates has enabled the development of highly stereoselective processes. For example, as carbamates generally lead to the formation of oxazolidinones, cis-bicyclic products are mostly isolated from cycloalkanol-derived substrates, an observation that also accounts for the reactions carried out from ureas or guanidines (Scheme 29).36,51,74 Such a stereochemical bias can be helpful to control the chemoselectivity of the insertion when two CdH bonds are in the vicinity of the nitrene.51 Starting from sulfamates and sulfamides that both afford six-membered rings, perfect diastereocontrol can be achieved according to chair-like transition states.75 1,2-trans- and 1,3-cis-products can be isolated exclusively from sulfamates, a result rationalized by a model based on the pseudoequatorial arrangement of the substituents that would induce minimized gauche interaction (Scheme 30A). In the case of sulfamides, the presence of a nitrogen-protecting group such as a Boc would be responsible for

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Scheme 28 Chemoselective sulfonimidamides.

intermolecular

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with

Scheme 29 Stereoselective formation of cis-products from ureas.

Scheme 30 Diastereocontrol in intramolecular C(sp3)–H amination reactions with sulfamates and sulfamides.

an allylic strain that could be avoided by placing the α-substituent at the pseudoaxial position. Accordingly, 1,3-trans-products are preferentially obtained (Scheme 30B).52 The stereocontrol also results from the selective nitrene insertion into the equatorial CdH bond as the reaction with the axial CdH bond would be disfavored according to unfavorable torsional effects. A recent study from the group of Bach has uncovered excellent acyclic stereocontrol in the intermolecular C(sp3)–H amination of secondary benzylic positions bearing an adjacent stereogenic center.67,76 According to the substituent located α- to the benzylic site, moderate to excellent syn

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diastereoselectivities are observed using the Rh2(esp)2 catalyst in combination with the sulfamate TcesNH2, the best results both in terms of yields and diastereomeric excesses being obtained with a bromo substituent (Scheme 31A). A model supported by DFT calculations has been depicted to rationalize the diastereoselective outcome of the reaction. The latter would result from a preferred conformation in which the α-substituent is antiperiplanar to the reacting C(sp3)–H bond and the steric strain between the other substituents is reduced. Such perfect diastereocontrol has also been observed with cyclic substrates; however, the anti-isomers are preferentially isolated in this case. Interestingly, in addition to its influence on the stereoselectivity, the presence of the bromo substituent leads to a highly chemoselective intermolecular C(sp3)–H amination that exclusively occurs at the vicinal benzylic center (Scheme 31B). 3.3.3 Stereoselectivity Driven by the Catalyst and the Reagent The search for an efficient and versatile dirhodium-catalyzed asymmetric C(sp3)–H amination reaction is an issue for which there is still ample room for improvement.10g The field was pioneered again by Mu¨ller who had designed chiral rhodium(II) complexes for inter- and intramolecular reactions, though with limited success as the ees did not exceed 66%.31,77 With respect to the catalytic asymmetric intramolecular nitrene C(sp3)–H insertion, the best results reported so far have been obtained with the rhodium(II) carboxamidate species Rh2(S-nap)4 25.72 This complex affords the corresponding cyclic sulfamates with excellent ees (ees: enantiomeric excesses) of up to 99% (Scheme 32). However, the scope is limited to benzylic substrates as, despite the excellent chemoselectivity, the ees remain below 84%

Scheme 31 Diastereocontrol in intermolecular C(sp3)–H amination reactions with sulfamates.

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Scheme 32 Enantioselective intramolecular C(sp3)–H amination catalyzed by Rh2(S-nap)4.

Figure 1 Chiral dirhodium(II) complexes for intermolecular C(sp3)–H amination reactions.

for the allylic C(sp3)–H amination. It should be pointed out that the chiral ruthenium(II)–pybox complex reported by Blakey suffers from the same limitation.37b As far as the intermolecular reaction is concerned, the group of Hashimoto has developed several efficient chiral dirhodium complexes for the asymmetric C(sp3)–H amination of silyl ketene acetals78 and silyl enol ethers.79 The ligands are derived from α-amino acids protected with a per-halo-phthalimido group on the nitrogen (Fig. 1). Of particular relevance is the capacity of the Rh2(S-tcpttl)4 26 and Rh2(S-tfpttl)4 27 complexes to afford the expected products in good yields and excellent ees from substrates used in limiting amounts. In addition, the fluoro ligand can be modified for its subsequent immobilization on a solid support by copolymerization with styrene, to afford the only example, to date, of a polymer-supported dirhodium(II) complex able to catalyze the oxidizing nitrene addition.80 Increasing the bulk of the chloro species 26 by replacing the tert-butyl side chain by the more sterically demanding adamantyl substituent has led to the preparation of complex 28 that is an efficient catalyst for the intermolecular benzylic C(sp3)–H amination.81 Ees up to 94%, together with excellent yields, can be obtained with 28 providing, however, that an excess of substrate (5 equiv.) is used, a point that limits the applicability of this process.

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Accordingly, there are still a very limited number of efficient protocols for the dirhodium(II)-catalyzed stereoselective intermolecular C(sp3)–H amination. The group of Bach has recently reported a cleverly designed bifunctional analog of the Rh2(esp)2 catalyst, i.e., complex 29, that is able to engage supramolecular interaction with the substrate to allow its enantioselective C(sp3)–H amination with ees of up to 74% (Scheme 33).82 This approach relies on the two-point hydrogen bonding provided by a chiral lactam that allows its coordination to a 3-benzylquinolone and the discrimination of one of the enantiotopic benzylic CdH bond. Despite the elegance of the reaction, it remains limited in scope to a unique class of substrates. The most efficient method for the stereoselective formation of amines through rhodium(II)-catalyzed intermolecular C(sp3)–H amination, to date, involves a diastereoselective approach based on the synergistic interaction between the sulfonimidamide (S)-7 and the chiral rhodium complex Rh2(S-nta)4 8.59 Benzylic and allylic amines are isolated from various complex substrates used as the limiting component, in excellent yields of up to 99% and complete stereocontrol (Scheme 34). Of course, the other enantiomer is also efficiently accessible through the use of the other matched pair of reagents. A comparable strategy has been reported with the combination of a chiral rhodium(II) complex and a chiral N-mesyloxycarbamate. This affords the corresponding amines from benzylic and propargylic substrates with comparable high levels of optical purity.83 But in terms of sustainability and synthetic application, this process is more efficient as it produces benign side-products, and the resulting carbamates can be more easily converted to the corresponding free amines.

Scheme 33 Enantioselective intermolecular C(sp3)–H amination reaction by supramolecular catalysis.

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Scheme 34 Stereoselective intermolecular benzylic and allylic C(sp3)–H amination with sulfonimidamides.

4. SYNTHETIC APPLICATIONS 4.1 Intramolecular C(sp3)–H Amination 4.1.1 Intramolecular C(sp3)–H Amination of Carbamates Several recent reviews have highlighted various significant examples that demonstrate the synthetic utility of the intramolecular C(sp3)–H amination for the functionalization of complex advanced intermediates.10f,i,14c,43 In order to avoid repetition and for the sake of brevity, we have thus decided hereafter to focus our attention on the latest achievements made in this field. Over the last decade, the status of the rhodium-catalyzed intramolecular C(sp3)–H amination has evolved quickly from a new attractive method to a versatile standard procedure in organic synthesis. This is proved by the increasing number of publications describing the use of Rh-catalyzed CdH amination as a key step for the total synthesis of complex molecules. The first significant example, undoubtedly, is the stereoselective synthesis of ()-tetrodotoxin reported by Du Bois in 2003.84 In this synthesis, a complex advanced carbamate 30, properly outfitted for the critical insertion step, undergoes stereospecific CdH amination to give the desired oxazolidinone 31 (Scheme 35). It should be pointed out that the reaction is performed with 10 mol% Rh2(HNCOCF3)4, while the classic Rh2(OAc)4 only gave trace amounts of product. 31 is then converted to ()-tetrodotoxin via a straightforward sequence of reactions. The stereospecific nitrene CdH insertion of carbamates has been later used by Yakura et al. to prepare optically active oxazolidinones, which are key intermediates for the preparation of (+)-conagenin.85 In their

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Scheme 35 Intramolecular CdH amination of carbamate 30 for the synthesis of (–)-tetrodotoxin.

Scheme 36 Influence of the substituent on the alkyl side chain on the CdH amination of carbamates 32a–c.

contribution, the authors show the influence of the substituents on the alkyl chain of the acyclic carbamates 32a–c, and in particular the importance of the protecting group used for the hydroxy group of 32b and c. The stereospecific Rh-catalyzed cyclization of the carbamate 32c bearing a TBDMS ether gives the corresponding oxazolidinone with a satisfactory yield of 63%, a yield that is slightly improved by the use of the Rh2(esp)2 catalyst (Scheme 36). Interestingly, the corresponding N-tosyloxycarbamate 33, prepared in two steps from 32c, could be converted into the desired oxazolidinone under milder reaction conditions following application of Lebel’s procedure.85c It is worth mentioning that this hypervalent iodine-free reaction affords the expected oxazolidinone with a slightly lower yield (Scheme 37). Very recently, Chelliah et al. exploited the high regioselectivity of the Rh-nitrene insertion of carbamates to prepare novel spirocyclic oxazolidinone analogs of vorapaxar.86 The stereospecific Rh-catalyzed CdH amination, therefore, leads to the corresponding spirocyclic products 34 in moderate yields (Scheme 38), giving access to an interesting range of bioactive molecules showing excellent in vitro activities. The relatively high amount of rhodium catalyst required for the transformation, as well as the

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Scheme 37 Intramolecular C(sp3)–H amination of N-tosylcarbamate 33.

Scheme 38 Rh-catalyzed CdH amination of carbamates 34 for the synthesis of spirocyclic oxazolidinones.

Scheme 39 Synthesis of Boc-protected bicycloproline via Rh-catalyzed CdH amination of carbamate 35.

yields demonstrate that the intramolecular C(sp3)–H amination of carbamates can sometimes proceed sluggishly. The first synthesis of an enantiopure N-protected bicycloproline relies on the Rh-catalyzed intramolecular C(sp3)–H amination of carbamate 35. This reaction is the key step to install the quaternary aminated center of the substituted cyclopentene ring.87 After a large screening of reaction parameters, the desired cis-oxazolidinone 36 was obtained in 35% yield, along with the secondary CdH insertion product 37, and small amounts of the aziridine 38 (Scheme 39). It should be noticed that the Ag(I)-catalyzed

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Scheme 40 Rhodium- and silver-catalyzed CdH amination of pleuromutilin carbamate 39.

conditions described recently by He and Cui38a failed to give the expected insertion product 36. In 2011, pleuromutilin derivatives have been synthesized via a CdH amination step, using the carbamate 39 as a suitable precursor.88 Despite the different conditions tested with the Rh2(esp)2 catalyst, the oxazolidinone 40 could not be isolated in more than 29% yield (Scheme 40). It should be pointed out that the eight-membered ring allows for isolating a fused transoxazolidinone. With the aim to improve the efficiency of the transformation, silver nitrate associated with the tridentate ligand tBu3tpy proved to be a more efficient catalytic system,38a and the desired pleuromutilin oxazolidinone 40 was obtained in 72% yield on a multigram scale. Such an observation has also been made by the group of Garg in the course of their total synthesis of welwitindolinones.74 4.1.2 Intramolecular C(sp3)–H Amination of Sulfamates As already highlighted above, sulfamates are a very interesting class of precursors for the intramolecular C(sp3)–H amination, since they allow the insertion of the aminated moiety with a different regioselectivity from the one generally obtained with carbamates. The higher efficiency of the sulfamate-derived nitrenes is also demonstrated in the examples described below. For example, the Rh-catalyzed amination of sulfamate 41 leads to the remote CdH functionalization of the C-ring of the androstane, as reported by Yamashita et al.89 Under the reaction conditions described by Du Bois, the nitrene insertion proceeds with complete regio- and stereoselectivity to give the corresponding oxathiazinane intermediate which enables the preparation of various derivatives of epiandrosterone (Scheme 41). The selectivity of the Rh-nitrene CdH insertion of sulfamates is strongly dependent on the nature of the targeted CdH bond and of its close chemical environment, as illustrated by Matsuda et al. in the synthesis of enantiopure N-protected L-epi-capreomycidine.90 The first attempts

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Scheme 41 Remote CdH functionalization of androstane by Rh-catalyzed CdH amination of sulfamate 41.

Scheme 42 Reverse stereoselectivity in the Rh-catalyzed intramolecular CdH amination of sulfamate 42.

performed with the sulfamate 42, thus, lead to very unsatisfactory regio- and diastereoselectivity, along with a poor yield of 16% (Scheme 42).90a Based on a theoretical study of the possible transition states for the Rh-nitrene insertion, this reverse selectivity has been attributed to the presence of a free hydrogen atom attached to the nitrogen group in the α-position of the amination site. Accordingly, the authors have designed sulfamate 43, analog of 42, in which the Cbz-protecting group of the nitrogen atom has been replaced by a phthaloyl group (Pht).90b On the other hand, the side chain has been masked by an aryl ring, thus allowing the nitrene CdH insertion to take place on a benzylic position known to be suitable for C(sp3)–H amination reactions. This newly devised sulfamate 43 was treated with 10 mol% Rh2(esp)2 in the presence of PhI(OAc)2 and magnesium oxide, and afforded the desired oxathiazinane as a single diastereoisomer with an excellent yield of 92% (Scheme 43). The selectivity of the intramolecular CdH amination of sulfamates, sometimes, can lead to unexpected results, as reported in the case of the complex advanced molecule 44 derived from abamectin.91 Treatment of this sulfamate with Rh2(OAc)4 under the conditions described by Du Bois, therefore, leads to the formation of the seven-membered ring 45 via nitrene insertion into the primary CdH bond of the methoxy group, and to the five-membered ring 46 via insertion into the tertiary CdH bond bearing the methoxy group followed by elimination of MeOH (see Scheme 44).

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Scheme 43 Regio- and diastereoselective Rh-catalyzed CdH amination of the sulfamate 43.

Scheme 44 Formation of seven- and five-membered ring fused products 45 and 46 by Rh-catalyzed CdH amination of 44.

The unprecedented modified avermectins 45 and 46 have been functionalized to give highly active molecules, and valuable intermediates for further structure–activity studies. Recently, Hatakeyama and coworkers have described an elegant stereocontrolled synthesis of ()-kaitocephalin, by combining the distinct regioselectivity of sulfamates and carbamates via two Rh-catalyzed CdH

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Scheme 45 Synthesis of intermediate 50 via two Rh-catalyzed CdH aminations of sulfamate 47 and carbamate 49.

amination steps.92 As expected, the first CdH insertion takes place at the benzylic position of sulfamate 47 by treating the latter with 2 mol% of Rh2(OAc)4 according to the procedure reported by Du Bois. Interestingly, the oxathiazinane 48 was obtained regio- and stereoselectively in 74% yield, and no other isomers were detected. Intramolecular nucleophilic attack of the trichloroacetamide at the CdO center of the oxathiazinane, followed by deprotection of the PMBM group and carbamoylation of the resulting alcohol, then, led to carbamate 49. Finally, the desired Rh2(esp)2-catalyzed allylic CdH amination of 49 proceeds efficiently to give oxazolidinone 50 with a very good yield (86%, Scheme 45). This last synthetic application nicely highlights the capacity of the Rh-catalyzed intramolecular CdH amination to functionalize efficiently CdH bonds of complex molecules with very high selectivities.

4.2 Intermolecular C(sp3)–H Amination As mentioned earlier in the review (see Section 3.1.2), the intermolecular C(sp3)–H amination reaction is particularly challenging, and, until now, this approach has been very rarely applied in total synthesis.10f In this context, the important contribution of Movassaghi, which describes the synthesis of aminocyclotryptamines via catalytic intermolecular CdH amination, can be considered as a landmark application.93 Diversely N-protected cyclotryptamines have, thus, been aminated stereospecifically with satisfactory yields by reaction with an arylsulfamate under the reaction

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Scheme 46 Intermolecular C(sp3)–H amination of cyclotryptamine 51a and subsequent hydrolysis of sulfamate 52.

Scheme 47 Two-step amination/hydrolysis sequence for the preparation of aminocyclotryptamine 53b.

conditions previously reported by Du Bois, as shown for cyclotryptamine 51a (Scheme 46). Hydrolysis of the sulfamate ester 52, then, affords the desired amine 53a, the key intermediate for the total synthesis of mesochimonanthine and related alkaloids. The authors also discovered that amine 53b, another key intermediate of this synthesis, can be directly obtained from the starting cyclotryptamine 51b in a two-step sequence, without purification of the intermediate sulfamate ester obtained by C(sp3)–H amination (Scheme 47).93 This very straightforward approach clearly underlines the advantages of the intermolecular C(sp3)–H amination. Amino groups can be attached regioand stereoselectively to complex molecules without any prefunctionalization step, contrary to the intramolecular version that still requires the preinstallation of a sulfamate or a carbamate group in a strategic position of the substrate to perform the reaction. This key feature holds great promise in medicinal chemistry as the introduction of a nitrogen substituent should significantly impact the pharmacokinetic properties of a bioactive compound. Interestingly, the dirhodium(II)-catalyzed intermolecular C(sp3)–H amination reaction could also find relevant application in chemical biology. A recent study from the Romo’s group has applied this transformation to the site-selective derivatization of natural products with the aim to investigate the mechanism underlying their biological activity.94 The design of the alkynyl sulfamate nitrene precursor 54, thus, has allowed the selective functionalization of various compounds that could be further conjugated with a

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Scheme 48 Intermolecular C(sp3)–H amination for the bioconjugation of eupalmerin acetate.

tag to turn them into useful cellular probes (Scheme 48). In the case of the marine anticancer natural product eupalmerin acetate, this has led to the identification of various proteins targeted by this molecule and associated with cancer proliferation.

5. CONCLUSION Catalytic C(sp3)–H amination has recently emerged as a powerful tool in synthesis with the discovery of simple protocols involving both iodine(III) oxidants and dirhodium(II) complexes. These paddlewheel tetracarboxylate or -carboxamidate structures are unique in their capacity to catalyze the efficient amination of complex substrates with high levels of chemo- and stereoselectivity.95 Particularly, the discovery of the highly active Rh2(esp)2 complex has significantly enhanced the scope of the intramolecular reaction that can be performed from various nitrene precursors with very low catalyst loadings, sometimes in the 100 ppm range. The intermolecular C(sp3)–H amination reaction also provides straightforward access to different classes of amides. In parallel to the opportunities provided again by the Rh2(esp)2 complex, the use of a matched pair of a chiral dirhodium(II) complex and a sulfonimidamide gives access to a broad scope of optically pure materials. However, despite these significant achievements, improvements are still necessary, particularly with respect to the intermolecular C(sp3)–H amination. Mechanistic investigations have revealed that multiple pathways are at play according to the substrate concentration. They involve rhodium

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complexes with different oxidation states, a crucial point that has a strong influence on the nature of the nitrene species. Further studies are needed to design appropriate conditions that will warrant their application on an industrial scale.96 The chemoselective allylic C(sp3)–H amination also remains an issue to address. Electrophilic dirhodium-bound nitrenes have a tendency to add to the alkene; however, the design of carboxamidate ligands might provide a solution to favor functionalization of the allylic position. In addition, as already observed in the carbene chemistry, the nitrene substitution could offer a parallel opportunity to fine-tune its reactivity. Finally, the quest for the catalytic asymmetric C(sp3)–H amination is the ultimate challenge for which satisfactory solution has, yet, to be reported.

ACKNOWLEDGMENTS We wish to thank the French National Research Agency (program CHARMMMAT ANR11-LABX-0039) for support and fellowship (J.B., G.G.). Support from the Institut de Chimie des Substances Naturelles and the EC (PIEF-GA-2013-623255) is kindly acknowledged.

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