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

Article abstract of DOI:10.1002/anie.202009335

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.

Full text of DOI:10.1002/anie.202009335

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Intramolecular C(sp3)-H Bond Oxygenation through Transition
Metal Acylnitrenoids
Authors: Yuqi Tan, Shuming Chen, Zijun Zhou, Yubiao Hong, Sergei
Ivlev, K. N. Houk, and Eric Meggers
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009335
Link to VoR: https://doi.org/10.1002/anie.202009335

10.1002/anie.202009335
Angewandte Chemie International Edition
RESEARCH ARTICLE
Intramolecular C(sp3)-H Bond Oxygenation through Transition
Metal Acylnitrenoids
Yuqi Tan, Shuming Chen, Zijun Zhou, Yubiao Hong, Sergei Ivlev, K. N. Houk,* and Eric Meggers*
[Dedication here]
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.
delocalized over the adjacent carbonyl group, we expected that a
C-O bond formation could occur instead of the standard C-N bond
formation. Such a C(sp3)-H oxygenation pathway through an
intermediate transition metal nitrenoid has been elusive.
Herein we introduce a ring-closing C(sp3)-H oxygenation that
proceeds through a transition metal nitrenoid and permits a
regioselective intramolecular C-H oxygenation to generate cyclic
carbonates, hydroxylated carbamates or 1,2-diols (Figure 1c).
Introduction
The direct functionalization of non-activated C(sp3)-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=CR2), nitrenoids
(M=NR), or transition metal oxo species (M=O) into C-H bonds
(Figure 1a).[2] Intramolecular, ring-closing versions of transition
metal carbenoid[3] and nitrenoid[4] C-H insertions are of particular
current interest because they provide a synthetic tool for the regio-
and stereocontrolled alkylation and amination of C(sp3)-H bonds
under typically very mild reaction conditions and without the
requirement for directing groups. Analogous intramolecular
C(sp3)-H oxygenations[5] through metal oxo species would be
highly desirable but are unfortunately not feasible due to the lower
valence of oxygen relative to nitrogen and carbon.
We hypothesized that intramolecular C-H oxygenations might
be feasible from well-known metal N-acylnitrenoid intermediates
as shown in Figure 1b. The design plan assumes a triplet metal
nitrenoid which abstracts intramolecularly a hydrogen from a
C(sp3)-H bond to form a diradical intermediate. The established
pathway continues with a C-N bond formation under release of
the metal catalyst. However, we envisioned that under certain
circumstances, the lifetime of this intermediate might be long
enough for a conformational reorganization of the radical
intermediate. Considering that the spin at the nitrogen should be
Figure 1. Intramolecular C(sp3)-H insertion through intermediate transition
metal carbenoids and nitrenoids and design plan for this study.
Results and Discussion
We commenced our study with the substrate 1aa which bears
a tosylate leaving group at a carbamate nitrogen (Table 1). Such
N-tosyloxycarbamates were previously introduced by Lebel[6] as
a source of metal nitrenes for C-H insertions and aziridinations
and Davies[7] subsequently reported an enantioselective
[*]
Y. Tan, Z. Zhou, Y. Hong, Dr. S. Ivlev, Prof. Dr. E. Meggers
Fachbereich Chemie, Philipps-Universität Marburg
Hans-Meerwein-Straße 4, 35043 Marburg (Germany)
E-mail: meggers@chemie.uni-marburg.de
intramolecular C-H amination with
a
chiral dirhodium
Dr. S. Chen, Prof. Dr. K. N. Houk
tetracarboxylate catalyst to provide non-racemic cyclic
carbamates. We instead started with a recently developed class
of ruthenium catalysts in which two bidentate N-(2-pyridyl)-
substituted N-heterocyclic carbenes and two acetonitrile ligands
are coordinated to the ruthenium center in a C2-symmetric
Department of Chemistry and Biochemistry, University of California,
Los Angeles, California 90095-1569 (USA)
E-mail: houk@chem.ucla.edu
Supporting information for this article can be found under: xxx
This article is protected by copyright. All rights reserved.

10.1002/anie.202009335
Angewandte Chemie International Edition
RESEARCH ARTICLE
fashion.[8] A C(sp3)-H amination should afford cyclic carbamate 2a
whereas the desirable C(sp3)-oxygenation should furnish instead
the cyclic carbonate 3a. When we reacted N-tosyloxycarbamate
1aa with catalytic amounts of a catalyst (2.0 mol%) containing CF3
substituents at the coordinated pyridine ligands (RuCF3)[9] in the
presence of the base K2CO3, carbamate 2a was isolated in 30%
yield but the desired carbonate 3a could not be detected (entry 1).
Switching to a benzoate leaving group (1ab) afforded the
carbamate 2a in 87% yield, thus revealing a very efficient
intramolecular C(sp3)-H amination (entry 2).
Increasing the bulkyness of the catalyst further by replacing the
TES group with a tri-n-propylsilyl group (RuTPS) did not provide
improved results but a lower catalytic activity (entry 6). Some
control experiments were performed. Introducing an electron-
donating methoxy (1ac) or electron-withdrawing CF3 (1ad) group
into the benzoyl moiety resulted in reduced yields (entries 7 and
8). Reducing the catalyst loading, adding water or molecular
sieves, or performing the reaction under air resulted in a reduction
of the carbonate yield (entries 9-12). Finally, without base the
reaction proceeded very sluggish (entry 13).
The proposed mechanism starts with the reaction of the
ruthenium catalyst with the N-benzoyloxycarbamate substrate 1
under base-promoted release of benzoic acid to provide a
ruthenium nitrenoid intermediate (I, Figure 2).[10] This nitrenoid
species subsequently performs a 1,5-hydrogen atom transfer
(HAT) from the benzylic C-H bond to the nitrenoid nitrogen to
generate the diradical II. In this diradical intermediate II, the
nitrogen radical is conjugated to the adjacent carbonyl group so
that a delocalization of the spin can be expected. If the lifetime of
this diradical is long enough, a conformational change will now
allow a radical-radical recombination with the oxygen moiety of
the ruthenium N-coordinated amide, thereby forming a new C-O
bond (III). This is consistent with the observed trend that a more
sterically crowded catalyst active site shifts the otherwise
preferred C-N to the previously elusive C-O bond formation.
Presumably the competing C-N bond 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. The 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 standard conditions in the presence of
2 equivalents of PPh3, 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 a radical pathway comes from a reaction
with the alkene substrate (Z)-1b which is converted to the cyclic
carbonate (E)-3b under complete ZE isomerization of the
configuration (Figure 2b).[12,13] This can be explained with a
conversion of the Z-isomer to the thermodynamically more stable
E-isomer at the stage of the diradical intermediate II, which for the
alkene substrate 1b involves a configurationally fluctional allylic
radical. A trapping experiment of substrate (E)-1b with 4-
methoxy-TEMPO which affords to the TEMPO adduct 5 (11%)
provides a further indication for a radical pathway (Figure 2c).
Finally, density functional theory (DFT) calculations were
performed and provide additional support for the proposed radical
mechanism with a 1,5-HAT from a triplet state of the ruthenium
intermediate I being the favored pathway (III) (see Supporting
Information for details on the calculations).[15-17]
Table 1. Initial experiments and optimization of reaction conditions.[a]
Entry Catalyst Substrate
Conditions[b]
Conv. (%)[c]
Yield (%)[d]
2a
3a
1
RuCF3
RuCF3
RuTMS
RuTES
RuTES
RuTPS
RuTES
RuTES
RuTES
RuTES
RuTES
RuTES
RuTES
1aa
1ab
1ab
1ab
1ab
1ab
1ac
1ad
1ab
1ab
1ab
1ab
1ab
standard
standard
standard
standard
standard
standard
standard
standard
1.0 mol% cat.
100
100
100
100
100
88
30
87
68
17
11
12
10
14
12
12
14
10
5
0
2
4
3
18
79
85
73
76
35
62
81
76
47
2
4
5
6
7
100
84
8
9
79
10
11
12
13
1% H2O added 100
4 Å MS added
under air
100
58
no base
12
[a] Standard reaction conditions: Substrates 1aa-1ad (0.2 mmol), K2CO3 (0.6
mmol), Ru catalyst (0.004 mmol) in CHCl3 (4.0 mL) stirred at room temperature
for 16 h under an atmosphere of N2 unless noted otherwise, then washed with
water, and stirred with 1 N HCl (0.2 mL, 0.2 mmol) for 15 min. [b] Deviations
from standard conditions shown. [c] Determined by 1H NMR of the crude
products using 1,3,5-trimethoxybenzene as internal standard. [d] Isolated
yields.
Encouragingly, small 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 a ruthenium 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 a trimethylsilyl (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 X-ray structure) provided the optimal result with the
formation of carbonate 3a in 85% isolated yield (entry 5).
Evidence for the intermediate formation for the
iminocarbonate IV, which we were not able to isolate, stems from
a reaction shown in Figure 2d. When we used substrate 1c, in
which the phenyl group is functionalized with a para-methoxy
group, we obtained under ruthenium catalysis the carbamate 6c
instead of the cyclic carbonate. This product can be rationalized
by a ring opening hydrolysis of the protonated intermediate
This article is protected by copyright. All rights reserved.

10.1002/anie.202009335
Angewandte Chemie International Edition
RESEARCH ARTICLE
iminocarbonate IV.[14] In summary, the control experiments
provide strongl support for the proposed radical pathway, which
can explain the competing C-O and C-N bond formations.
yield), para-tert-butylphenyl 7l, 66%), 4-biphenyl (7m, 67%), 1,3-
benzodioxol-5-yl (7n, 60%), 2-naphthyl (7o, 79%), or 1-naphthyl
(7p, 72%). A 2-thiophene moiety leads to lower 48% yield (7q).
The oxygenated C(sp3)-H bond can also be flanked by an alkenyl
group. Both E- and Z-configured alkenes 1b afford the diol (E)-7b
in a diastereoconvergent reaction in 78% and 72% yield,
respectively. Additional examples for an allylic C-H hydroxylation
are the obtained isopropenyl substituted cyclic carbonate 3r
(38%) and the hydroxylated terpene nopol 7s (45% yield). C-H
oxygenation in propargylic position is also feasible as shown for
the cyclic carbonate 3t (67%), whereas unactivated C-H groups
do not provide any C-H oxygenation product (e.g. 3u and 3v, 0%).
However, the C-H oxygenation is applicable to tertiary C-H groups
as shown for compounds derived from the drugs naproxen (7w,
62%), ibuprofen (7x, 52%), flurbiprofen (7y, 50%), and the
sterically congested tertiary alcohol
7z (40%). N-
Benzoyloxycarbamates of 2-phenylethanol with one (3za, 37%)
or two methyl substituents (3zb, 68%) in the 1-position also
provide the cyclic carbonate. Overall, the developed C-H
oxygenation can be applied to benzylic, allylic, and propargylic
secondary and tertiary C(sp3)-H bonds with yields of up to 88%.
A few substrates provide only modest C-H oxygenation yields
which can be explained with a certain degree of competing C-H
amination. Depending on the nature of the substrate, the
intermediate iminocarbonate either hydrolyzes to the cyclic
carbonate, the hydroxylated carbamate, or a mixture of both. Both
can be converted to the corresponding vicinal diols by a brief
basic hydrolysis, resulting in an overall vicinal C(sp3)-H
hydroxylation of the initial alcohol starting materials.
Figure 2. Proposed mechanism and supporting experiments. Reactions
performed under standard conditions shown in Table 1. [a] Formed together
with the corresponding acyclic carbamate. See Supporting Information for more
details.
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, 88%), chlorine (3e, 87%), or
fluorine (3f, 85%) substituents in para-position of the phenyl
moiety were obtained in high yields. Substituents are also
accommodated in meta-position as demonstrated for an electron-
withdrawing CF3 (3g, 70%) and an electron-donating methoxy
group (3h, 62%). As already discussed in the mechanistic section
(Figure 2), for a substrate with a methoxy substituent in the para-
position of the phenyl moiety, the intermediate iminocarbonate
hydrolyzes to a ring-opened C-H hydroxylated carbamate instead
of forming a cyclic carbonate (1c  6c, 53% yield). A methoxy
group in ortho-position of the phenyl ring increases the yield of the
C-H hydroxylated carbamate to 82% (6i). For some substrates,
mixtures of cyclic carbonate and C-H hydroxylated carbamate
were observed. For those cases, a basic hydrolysis was applied
before silica gel chromatography to isolate the corresponding
diols. For example, 1-aryl-1,2-ethanediols were obtained with the
aryl group being ortho-tolyl (7j, 59% yield), para-tolyl (7k, 71%
This article is protected by copyright. All rights reserved.

10.1002/anie.202009335
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 3. Substrate scope for C(sp3)-H oxygenations. Conditions for the
optional basic hydrolysis: Dioxane / NaOH (1 N) 1:1 at 80 °C for 2 hours. [a]
From (E)-1b. Starting from (Z)-1b, the yield is 72%. [b] Performed at 60 °C.
that this new reaction mode of transition metal nitrenoids will
provide untapped opportunities for the streamlined synthesis of
alcohols by regiocontrolled and stereocontrolled C(sp3)-H
oxygenation. Furthermore, cyclic carbonates are useful building
blocks for a variety of transformations.[24]
In preliminary experiments, we also started to investigate the
enantioselective version of this C-H functionalization. The class of
ruthenium catalysts used in this study, although containing only
achiral ligands, feature a stereogenic metal center which results
in overall chirality with a  (left-handed helical twist of the
Acknowledgements
E.M. gratefully acknowledges funding from the Deutsche
Forschungsgemeinschaft (ME 1805/15-1). K.N.H is grateful to the
National Science Foundation (Grant CHE-1764328) for financial
support. Calculations were performed on the Hoffman2 cluster at
the University of California, Los Angeles, and 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.
bidentate ligands) and

(right-handed helical twist)
enantiomer.[18] Whereas for all preceding experiments a racemic
mixture of RuTES was employed, we next synthesized non-
racemic RuTES according to a recently developed chiral-
auxiliary-mediated method.[8] Indeed, when enantiomerically pure
-RuTES (2.0 mol%) was reacted with the N-
benzoyloxycarbamate 1ab under standard conditions, the cyclic
carbonate (R)-3a was obtained with an enantiomeric excess of
90:10 er (Figure 4). Interestingly, when the same nitrene
precursor 1ab was instead reacted with the enantiomerically pure
catalyst -RuCF3 (2.0 mol%) under identical reaction conditions,
the cyclic carbamate (S)-2a was obtained in 88% yield and with
89:11 er. Thus, depending on a single functional group at the
catalyst, either an enantioselective C-H oxygenation or
enantioselective C-H amination[19,20,21] can be obtained starting
from an identical nitrene precursor. A catalyst-dependent switch
between C-H amination and oxygenation was recently also
reported by Lu and coworkers in a photoredox dual catalysis
reaction from N-benzoyloxycarbamates.[22] White and coworkers
reported a catalyst-controlled diastereoselective allylic C-H
Keywords: C-H functionalization • oxygenation • nitrenoid •
enantioselective • ruthenium • chiral-at-metal
[1] a.) J. F. Hartwig, M. A. Larsen, ACS Cent. Sci. 2016, 2, 281-292; b.) T.
Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem. Soc. Rev.
2016, 45, 546-576; c.) H. M. L. Davies, D. Morton, ACS Cent. Sci. 2017, 3, 936-
943; d.) D. J. Abrams, P. A. Provencher, E. J. Sorensen, Chem. Soc. Rev. 2018,
47, 8925-8967; e.) S. K. Sinha, G. Zanoni, D. Maiti, Asian J. Org. Chem. 2018,
7, 1178-1192; f.) J. C. K. Chu, T. Rovis, Angew. Chem. Int. Ed. 2018, 57, 62-
101; g.) C. Zheng, S.-L. You, RSC Adv. 2014, 4, 6173-6214.
[2] a.) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417-424; b.) M. P.
Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110, 704-724; c.) C.-
M. Che, V. K.-Y. Lo, C.-Y. Zhou, J.-S. Huang, Chem. Soc. Rev. 2011, 40, 1950-
1975; d.) M. Milan, M. Salamone, M. Costas, M. Bietti, Acc. Chem. Res. 2018,
51, 1984-1995.
amination versus oxygenation using
a
combination 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.
[3] M. P. Doyle, M. Ratnikov, Y. Liu, Org. Biomol. Chem. 2011, 9, 4007-4016.
[4] a.) J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res. 2012, 45, 911-
922; b.) G. Dequirez, V. Pons, P. Dauban, Angew. Chem. Int. Ed. 2012, 51,
7384-7395; c.) B. Darses, R. Rodrigues, L. Neuville, M. Mazurais, P. Dauban,
Chem. Commun. 2017, 53, 493-508; d.) D. Hazelard, P.-A. Nocquet, P.
Compain, Org. Chem. Front. 2017, 4, 2500-2521; e.) Y. Park, Y. Kim, S. Chang,
Chem. Rev. 2017, 117, 9247-9301; f.) P. F. Kuijpers, J. I. van der Vlugt, S.
Schneider, B. de Bruin, Chem. Eur. J. 2017, 23, 13819-13829; g.) T.
Shimbayashi, K. Sasakura, A. Eguchi, K. Okamoto, K. Ohe, Chem. Eur. J. 2019,
25, 3156-3180; h.) K. M. van Vliet, B. de Bruin, ACS Catal. 2020, 10, 4751-4769.
[5] a.) T. Newhouse, P. S. Baran, Angew. Chem. Int. Ed. 2011, 50, 3362-3374;
b.) W. N. Oloo, L. Que, Jr., Acc. Chem. Res. 2015, 48, 2612-2621; c.) Y.-F.
Liang, N. Jiao, Acc. Chem. Res. 2017, 50, 1640-1653; d.) G. Olivo, O. Cussó,
M. Borrell, M. Costas, J. Biol. Inorg. Chem. 2017, 22, 425-452; e.) M. C. White,
J. Zhao, J. Am. Chem. Soc. 2018, 140, 13988-14009; f.) H. Sterckx, B. Morel,
B. U. W. Maes, Angew. Chem. Int. Ed. 2019, 58, 7946-7970.
[6] a.) H. Lebel, K. Huard, S. Lectard, J. Am. Chem. Soc. 2005, 127, 14198-
14199; b.) K. Huard, H. Lebel, Chem. Eur. J. 2008, 14, 6222-6230; c.) H. Lebel,
C. Spitz, O. Leogane, C. Trudel, M. Parmentier, Org. Lett. 2011, 13, 5460-5463.
Figure 4. Enantioselective intramolecular C(sp3)-H oxygenation and amination.
Standard reaction conditions: Catalyst (2 mol%), K2CO3 (3 equivalents), in
CHCl3 at room temperature for 16 hours.
[7] R. P. Reddy, H. M. L. Davies, Org. Lett. 2006, 8, 5013-5016.
[8] Y. Zheng, Y. Tan, K. Harms, M. Marsch, R. Riedel, L. Zhang, E. Meggers, J.
Am. Chem. Soc. 2017, 139, 4322-4325.
[9] Z. Zhou, S. Chen, J. Qin, X. Nie, X. Zheng, K. Harms, R. Riedel, K. N. Houk,
E. Meggers, Angew Chem. Int. Ed. 2019, 58, 1088-1093.
Conclusion
[10] S. Huh, S. Y. Hong, S. Chang, Org. Lett. 2019, 21, 2808-2812.
We here introduced a novel reactivity of transition metal
nitrenoids complexes, leading to C-H oxygenation instead of the
expected and established C-H nitrogenation. Metal catalyzed
intramolecular carbene and nitrene insertion reactions previously
only allowed for the formation of C-C and C-N bonds, respectively,
whereas the here reported work expands on this limitation.
Furthermore, we demonstrated that the reactivity of the transition
metal nitrenoid towards C-H oxygenation or nitrogenation can be
tuned simply by changing one substituent on the ruthenium
catalyst scaffold and also provides a handle for creating new
stereogenic centers in an enantioselective fashion. We believe
[11] a.) H. F. Sleiman, S. Mercer, L. McElwee-White, J. Am. Chem. Soc. 1989,
111, 8007-8009; b.) E. W. Harlan, R. H. Holm, J. Am. Chem. Soc. 1990, 112,
186-193; c.) P. J. Perez, P. S. White, M. Brookhart, J. L. Templeton, Inorg.
Chem. 1994, 33, 6050-6056; d.) V. Bizet, L. Buglioni, C. Bolm, Angew. Chem.
Int. Ed. 2014, 53, 5639-5642.
[12] S. M. Paradine, J. R. Griffin, J. Zhao, A. L. Petronico, S. M. Miller, M. C.
White, Nat. Chem. 2015, 7, 987-994.
[13] Y. Yang, I. Cho, X. Qi, P. Liu, F. H. Arnold, Nat. Chem. 2019, 11, 987-993.
[14] C. R. Flynn, J. Michl, J. Org. Chem. 1974, 39, 3442-3443.
[15] A. Varela-ꢀlvarez, T. Yang, H. Jennings, K. P. Kornecki, S. N. Macmillan,
K. M. Lancaster, J. B. C. Mack, J. Du Bois, J. F. Berry, D. G. Musaev, J. Am.
Chem. Soc. 2016, 138, 2327-2341.
This article is protected by copyright. All rights reserved.

10.1002/anie.202009335
Angewandte Chemie International Edition
RESEARCH ARTICLE
[16] X. Lin, C. Zhao, C.-M. Che, Z. Ke, D. L. Phillips, Chem. Asian J. 2007, 2,
1101-1108.
[17] Our previous DFT study on an analogous system with a simple amide
substrate favored a concerted singlet C–H amination pathway. See: Z. Zhou, S.
Chen, Y. Hong, E. Winterling, Y. Tan, M. Hemming, K. Harms, K. N. Houk, E.
Meggers, J. Am. Chem. Soc. 2019, 141, 19048-19057.
[18] L. Zhang, E. Meggers, Chem. Asian J. 2017, 12, 2335-2342.
[19] H. Hayashi, T. Uchida, Eur. J. Org. Chem. 2020, 909-916.
[20] For related interesting recent examples of enantioselective intramolecular
C(sp3)-H aminations, see: a.) L. Ye, Y. Tian, X. Meng, Q.-S. Gu, X.-Y. Liu,
Angew. Chem. Int. Ed. 2020, 59, 1129-1133; b.) C.-J. Yang, C. Zhang, Q.-S.
Gu, J.-H. Fang, X.-L. Su, L. Ye, Y. Sun, Y. Tian, Z.-L. Li, X.-Y. Liu, Nat. Catal.
2020, 3, 539-546.
[21] See Supporting Information for more information on stereochemical
aspects of the C-H oxygenation versus C-H amination.
[22] Q. Guo, X. Ren, Z. Lu, Org. Lett. 2019, 21, 880-884.
[23] I. I. Strambeanu, M. C. White, J. Am. Chem. Soc. 2013, 135, 12032-12037.
[24] S. Singha, E. Serrano, S. Mondal, C. G. Daniliuc, F. Glorius, Nat. Catal.
2020, 3, 48-54.
This article is protected by copyright. All rights reserved.

10.1002/anie.202009335
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
COMMUNICATION
Y. Tan, S. Chen, Z. Zhou, Y. Hong, S.
Ivlev, K. N. Houk,* and E. Meggers*
Page No. – Page No.
Intramolecular C(sp3)-H Bond
Oxygenation through Transition Metal
Acylnitrenoids
Discovery of a new C-H oxygenation method: Transition metal nitrenoids are well
established for their C-H amination chemistry but this work demonstrates that N-
acylnitrenoids can surprisingly undergo C(sp3)-H oxygenations instead, even in an
enantioselective fashion.
This article is protected by copyright. All rights reserved.