Intramolecular C(sp3)–H Bond Oxygenation by Transition‐Metal Acylnitrenoids

Abstract This study demonstrates for the first time that easily accessible transition‐metal acylnitrenoids can be used for controlled direct C(sp3)‐H oxygenations. Specifically, a ruthenium catalyst activates N‐benzoyloxycarbamates as nitrene precursors towards regioselective intramolecular C−H oxygenations to provide cyclic carbonates, hydroxylated carbamates, or 1,2‐diols. The method can be applied to the chemoselective C−H oxygenation of benzylic, allylic, and propargylic C(sp3)−H bonds. The reaction can be performed in an enantioselective fashion and switched in a catalyst‐controlled fashion between C−H oxygenation and C−H amination. This work provides a new reaction mode for the regiocontrolled and stereocontrolled conversion of C(sp3)‐H into C(sp3)−O bonds.


Introduction
Thed irect functionalization of non-activated C(sp 3 ) À H bonds represents an atom-and step-economic strategy for chemical synthesis,opening new opportunities for the streamlined synthesis of complex organic molecules. [1] One attractive mechanistic scenario proceeds through the direct or stepwise insertion of transition metal carbenoids (M=CR 2 ), nitrenoids (M = NR), or transition-metal oxo species (M = O) into C À H bonds (Figure 1a). [2] Intramolecular,r ing-closing versions of transition metal carbenoid [3] and nitrenoid [4] C À Hi nsertions are of particular current interest because they provide asynthetic tool for the regio-and stereocontrolled alkylation and amination of C(sp 3 )ÀHb onds under typically very mild reaction conditions and without the requirement for directing groups.A nalogous intramolecular C(sp 3 )-H oxygenations [5] through metal oxo species would be highly desirable but are unfortunately not feasible owing to the lower valence of oxygen relative to nitrogen and carbon.
We hypothesized that intramolecular CÀHo xygenations might be feasible from well-known metal N-acylnitrenoid intermediates as shown in Figure 1b.The design plan assumes at riplet metal nitrenoid which abstracts intramolecularly ah ydrogen from aC (sp 3  Herein we introduce aring-closing C(sp 3 )-H oxygenation that proceeds through at ransition-metal nitrenoid and permits ar egioselective intramolecular CÀHo xygenation to generate cyclic carbonates,h ydroxylated carbamates,o r1 ,2diols ( Figure 1c).

Results and Discussion
We commenced our study with the substrate 1aa,w hich bears at osylate leaving group at ac arbamate nitrogen (Table 1). Such N-tosyloxycarbamates were previously introduced by Lebel [6] as as ource of metal nitrenes for C À H insertions and aziridinations and Davies [7] subsequently reported an enantioselective intramolecular CÀHa mination with ac hiral dirhodium tetracarboxylate catalyst to provide non-racemic cyclic carbamates.W ei nstead started with ar ecently developed class of ruthenium catalysts in which two bidentate N-(2-pyridyl)-substitutedN -heterocyclic carbenes and two acetonitrile ligands are coordinated to the ruthenium center in a C 2 -symmetric fashion. [8] AC (sp 3 )-H amination should afford cyclic carbamate 2a whereas the desirable C(sp 3 )-oxygenation should furnish instead the cyclic carbonate 3a.W henw er eacted N-tosyloxycarbamate 1aa with catalytic amounts of ac atalyst (2.0 mol %) containing CF 3 substituents at the coordinated pyridine ligands (RuCF 3 ) [9] in the presence of the base K 2 CO 3 ,c arbamate 2a was isolated in 30 %yield but the desired carbonate 3a could not be detected (entry 1). Switching to ab enzoate leaving group (1ab)a fforded the carbamate 2a in 87 %y ield, thus revealing avery efficient intramolecular C(sp 3 )-H amination (entry 2).
Encouragingly,s mall amounts (4 %) of the desired carbonate 3a could also be identified. We next attempted to increase the yield of the desired carbonate by modifying the catalyst. Accordingly,using aruthenium catalyst with plain N-(2-pyridyl)-substituted N-heterocyclic carbene ligands (RuH) improved the yield of the carbonate 3a to 18 %( entry 3). Increasing the steric bulk by introducing at rimethylsilyl (TMS) group into the pyridine ligand (RuTMS)further raised the yield of the carbonate 3a to 79 %(entry 4). Finally,using an even more bulky triethylsilyl (TES) group (RuTES,see Xray structure) provided the optimal result with the formation of carbonate 3a in 85 %i solated yield (entry 5). Increasing the bulkiness of the catalyst further by replacing the TES group with atri-n-propylsilyl group (RuTPS)did not provide improved results but alower catalytic activity (entry 6). Some control experiments were performed. Introducing an electron-donating methoxy (1ac)o re lectron-withdrawing CF 3 (1ad)g roup into the benzoyl moiety resulted in reduced yields (entries 7and 8). Reducing the catalyst loading, adding water or molecular sieves,o rp erforming the reaction under air resulted in ar eduction of the carbonate yield (entries 9-12). Finally,without base the reaction proceeded very sluggish (entry 13).
Thep roposed mechanism starts with the reaction of the ruthenium catalyst with the N-benzoyloxycarbamate substrate 1 under base-promoted release of benzoic acid to provide ar uthenium nitrenoid intermediate (I,F igure 2). [10] This nitrenoid species subsequently performs a1 ,5-hydrogen atom transfer (HAT) from the benzylic CÀHb ond to the nitrenoid nitrogen to generate the diradical II.I nt his diradical intermediate II,t he nitrogen radical is conjugated to the adjacent carbonyl group so that adelocalization of the spin can be expected. If the lifetime of this diradical is long enough, ac onformational change will now allow ar adicalradical recombination with the oxygen moiety of the ruthenium N-coordinated amide,thereby forming anew CÀObond (III). This is consistent with the observed trend that am ore sterically crowded catalyst active site shifts the otherwise preferred C-N to the previously elusive C À Obond formation.
Presumably the competing C À Nb ond formation is suppressed by the bulky ruthenium catalyst which is directly coordinated to the nitrogen while the oxygen is more remote and thus less sensitive to steric effects.T he formed iminocarbonate III then dissociates from the ruthenium and provides the cyclic carbonate 3 upon hydrolysis of the exocyclic imine.
Experimental and computational results validate the proposed mechanism. Ruthenium nitrenoid species have been reported to efficiently transfer the nitrene unit to phosphines and sulfides. [11] Indeed, when we performed the ruthenium-catalyzed reaction with substrate 1ab under Table 1: Initial experiments and optimization of reaction conditions. [a] Entry Catalyst Substrate Conditions [b] Conv standard conditions in the presence of 2equivalents of PPh 3 , the iminophosphorane 4 was formed in 88 %yield so that this experiment supports the intermediate formation of the ruthenium nitrenoid species I (Figure 2a). Experimental support for ar adical pathway comes from ar eaction with the alkene substrate (Z)-1b which was converted to the cyclic carbonate (E)-3b under complete Z!E isomerization of the configuration (Figure 2b). [12,13] This can be explained with aconversion of the Z-isomer to the thermodynamically more stable E-isomer at the stage of the diradical intermediate II, which for the alkene substrate 1binvolves aconfigurationally fluctional allylic radical. At rapping experiment of substrate (E)-1b with 4-methoxy-TEMPO which afforded the TEMPO adduct 5 (11 %) provides af urther indication for ar adical pathway (Figure 2c). Finally,density functional theory (DFT) calculations were performed and provide additional support for the proposed radical mechanism with a1 ,5-HATf rom at riplet state of the ruthenium intermediate I being the favored pathway (I!II)( see Supporting Information for details on the calculations). [15][16][17] Evidence for the intermediate formation for the iminocarbonate IV,w hich we were not able to isolate,s tems from areaction shown in Figure 2d.Whenweused substrate 1c,in which the phenyl group is functionalized with a para-methoxy group,weobtained under ruthenium catalysis the carbamate 6c instead of the cyclic carbonate.T his product can be rationalized by ar ing opening hydrolysis of the protonated intermediate iminocarbonate IV. [14] In summary,t he control experiments provide strong support for the proposed radical pathway,w hich can explain the competing C À Oa nd C À N bond formations.
With the optimal conditions in hand, we investigated the scope of this reaction. N-Benzoyloxycarbamates derived from 2-phenylethanol with substituents in the phenyl moiety were investigated first. As shown in Figure 3, cyclic carbonates with electron-withdrawing bromine (3d,8 8%), chlorine (3e, 87 %), or fluorine (3f,8 5%)s ubstituents in para-position of the phenyl moiety were obtained in high yields.S ubstituents are also accommodated in meta-position as demonstrated for an electron-withdrawing CF 3 (3g,7 0%)a nd an electrondonating methoxy group (3h,6 2%). As already discussed in the mechanistic section (Figure 2), for as ubstrate with am ethoxy substituent in the para-position of the phenyl moiety,the intermediate iminocarbonate hydrolyzes to aring-
In preliminary experiments,wealso started to investigate the enantioselective version of this C À Hf unctionalization. Thec lass of ruthenium catalysts used in this study,a lthough containing only achiral ligands,f eature as tereogenic metal center, which results in overall chirality with a L (left-handed helical twist of the bidentate ligands) and D (right-handed helical twist) enantiomer. [18] Whereas for all preceding experiments ar acemic mixture of RuTES was employed, we next synthesized non-racemic RuTES according to ar ecently developed chiral-auxiliary-mediated method. [8] Indeed, when enantiomerically pure L-RuTES (2.0 mol %) was reacted with the N-benzoyloxycarbamate 1ab under standard conditions,the cyclic carbonate (R)-3awas obtained with an enantiomeric excess of 90:10 er (Figure 4). Interestingly,w hen the same nitrene precursor 1ab was instead reacted with the enantiomerically pure catalyst L-RuCF 3 (2.0 mol %) under identical reaction conditions,t he cyclic carbamate (S)-2a was obtained in 88 %y ield and with 89:11 er. Thus,d epending on as ingle functional group at the catalyst, either an enantioselective CÀHo xygenation or enantioselective CÀHa mination [19,20,21] can be obtained starting from an identical nitrene precursor.Acatalystdependent switch between CÀHa mination and oxygenation was recently also reported by Lu and co-workers in aphotoredox dual catalysis reaction from N-benzoyloxycarbamates. [22] White and co-workers reported acatalyst-controlled diastereoselective allylic CÀHa mination versus oxygenation using ac ombination of palladium(II) catalyst and Lewis acid. [23] However, experiments in both reports were not performed in an enantioselective fashion and occurred by different mechanisms.

Conclusion
We here introduced anovel reactivity of transition metal nitrenoids complexes,leading to C À Hoxygenation instead of the expected and established C À Hn itrogenation. Metalcatalyzed intramolecular carbene and nitrene insertion reactions previously only allowed for the formation of CÀCa nd CÀNb onds,r espectively,w hereas the here reported work expands on this limitation. Furthermore,w ed emonstrated that the reactivity of the transition metal nitrenoid towards C À Ho xygenation or nitrogenation can be tuned simply by changing one substituent on the ruthenium catalyst scaffold and also provides ah andle for creating new stereogenic centers in an enantioselective fashion. We believe that this new reaction mode of transition metal nitrenoids will provide untapped opportunities for the streamlined synthesis of alcohols by regiocontrolled and stereocontrolled C(sp 3 )-H oxygenation. Furthermore,cyclic carbonates are useful building blocks for av ariety of transformations. [24] the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (Grant OCI-1053575). We thank Marcel Hemming for the synthesis of some substrate intermediates.Open access funding enabled and organized by Projekt DEAL.

Conflict of interest
Theauthors declare no conflict of interest.