Unprecedented Dearomatized Spirocyclopropane in a Sequential Rhodium(III)-Catalyzed C?H Activation and Rearrangement Reaction

Article abstract of DOI:10.1002/anie.201800803

An unprecedented dearomatized spirocyclopropane intermediate was discovered in a sequential Cp*Rh^III-catalyzed C?H activation and Wagner–Meerwein-type rearrangement reaction. How the oxidative O?N bond is cleaved and the role of HOAc were uncov

Full text of DOI:10.1002/anie.201800803

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Unprecedented Dearomatized Spirocyclopropane in a Sequential
Rh(III)-catalyzed C-H Activation and Rearrangement Reaction
Authors: Xiaoming Wang, Yingzi Li, Tobias Knecht, Constantin
Daniliuc, Ken Houk, and Frank Glorius
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.201800803
Angew. Chem. 10.1002/ange.201800803
Link to VoR: http://dx.doi.org/10.1002/anie.201800803
http://dx.doi.org/10.1002/ange.201800803

Angewandte Chemie International Edition
10.1002/anie.201800803
COMMUNICATION
Unprecedented Dearomatized Spirocyclopropane in a Sequential
Rh(III)-catalyzed C–H Activation and Rearrangement Reaction
†§
‡§
†
†
*‡
*†
Xiaoming Wang, Yingzi Li, Tobias Knecht, Constantin G. Daniliuc, K. N. Houk, Frank Glorius
Abstract: An unprecedented dearomatized spirocyclopropane
intermediate was discovered in a sequential Cp*Rh(III)-catalyzed C–
H activation and Wagner–Meerwein-type rearrangement reaction.
How the oxidative O–N bond is cleaved and the role of HOAc were
an unprecedented dearomatized spirocyclopropane intermediate
which undergoes further intramolecular rearrangement reaction.
To the best of our knowledge, this is the first time that the coupling
of
a
phenol-derived precursor and an olefin leads to
a
[
5,6]
uncovered in this study. Furthermore,
a
Cp*Rh(III)-catalyzed
dearomatized spiro structure with a cyclopropane unit.
Both
dearomatization reaction of N-(naphthalen-1-yloxy)acetamide with
experimental and DFT studies suggest that protonation of an
olefin-insertion intermediate by HOAc, followed by intramolecular
attack, are the key steps for the formation of the dearomatized
strained olefins was developed, affording
spirocyclopropanes.
a
variety of
spirocyclopropane intermediate. Inspired by this finding,
Cp*Rh(III)-catalyzed dearomatization reaction of N-(naphthalen-
-yloxy)acetamide with strained olefins was successfully
a
Rh(III)-catalyzed C–H activation is an attractive mode of
1
[
1]
catalysis for the synthesis of small molecules. The use of
developed, affording a variety of spirocyclopropanes.
ox
oxidizing directing groups (DG ), which function as both the
A stable cyclometalated Rh(III) complex A was synthesized
directing group and the internal oxidant, has become a powerful
strategy in this area.[2] While the concept of oxidizing directing
groups has become more widely popular, it is crucial to
understand their underlying mechanisms of action for the further
development of novel catalysis on a rational basis. In our previous
work, we coupled N-phenoxyacetamides with an internal oxidizing
O–NHAc bond[ and 7-azabenzonorbornadienes to deliver
bridged polycyclic molecules via an unexpected Wagner–
Meerwein-type rearrangement (Scheme 1). This methodology
provided an efficient way to construct the highly complex
polycyclic products. However, the underlying causes driving force
for the rearrangement and how the O–N bond is cleaved, remains
unclear.
2 2
upon treatment of the substrate 2 with [RhCp*Cl ] . Our first
objective was to gain insight into the formation and the reactivity
of the olefin-insertion intermediate B (Scheme 2). To our delight,
the reaction of complex A with one equivalent of olefin 1a at -40
o
C afforded the expected intermediate B in 91% yield as
1
[7]
determined by H NMR. However, this complex was consumed
almost completely when the temperature was increased to room
temperature and ~15% NMR yield of the complex 4 was
3]
[
4]
[8]
detected. No rearrangement product 3 was formed. During the
formation of the Rh(III) complex A, HOAc is also formed. To probe
the potential role of HOAc in this reaction, two equivalents of
HOAc were added to the solution of intermediate B in NMR tube
o
at -40 C. To our surprise, the formation of a new species 5 was
o
immediately observed at -40 C and B was fully converted into
this new species at -20 oC in 90% yield (Scheme 2). The
spirocyclopropane structure of 5, which was formed via the
dearomatization of the phenol ring, was elucidated by 2D-NMR.
o
This new species 5 was stable at 26 C for ~30 min. Afterwards
the final rearrangement product 3 was formed slowly. After 48 h,
the product 3 was detected in 85% yield. These results illustrated
that B must first react with HOAc to form the key intermediate 5,
which ultimately forms the final rearrangement product 3. A
2 2
catalytic reaction using Cp*Rh(OAc) •H O (2 mol%) as catalyst
Scheme 1. The discovery of the dearomatized spirocyclopropane intermediate.
also shown the formation of 5 and the subsequent consumption
of 5 to 3 in the NMR tube (For details, see the Supporting
Information (SI)). Unfortunately, neither isolation of 5 or traps with
further transformations failed, and only the final product 3 could
be isolated. The investigation of the electronic effects on the
stability of the spirocyclopropane intermediate suggested that
both the electron-withdrawing group on the N-phenoxyacetamide
and the electron-donating group on the olefin part could
destabilize the intermediate and promote the further
rearrangement (see SI).
Herein, we report our new finding in the Cp*Rh(III)-catalyzed
reaction of N-phenoxyacetamide with 7-azabenzonorbornadiene.
An unconventional reactivity for Rh(III)-catalysis was revealed
(
Scheme 1). The N-phenoxyacetamide derivatives act as a formal
one-carbon component in an unexpected [1 + 2] annulation giving
[†
[‡
[§
]
]
]
Dr. X. Wang, T. Knecht, Dr. C. G. Daniliuc and Prof. F. Glorius
Westfälische Wilhelms-Universität Münster
Organisch-Chemisches Institut
Corrensstraße 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.
Y. Li, and Prof. K. N. Houk
University of California, Los Angeles
Department of Chemistry and Biochemistry
California 90095, United States
E-mail: houk@chem.ucla.edu.
These authors contributed equally to this work.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201800803
COMMUNICATION
of the experiments, two possible pathways have been proposed
in Scheme 5. After C–H activation and the generation of
rhodacycle A, olefin insertion forms the seven-membered
rhodacycle B. The protonation of B by acetic acid to afford the
intermediate D was proposed to be the next step because the
dearomatized intermediate 5 is formed from the interaction of the
intermediate B with HOAc according to the experiments. In
pathway 1, intermediate
D is proposed to undergo an
intramolecular nucleophilic attack reaction to afford the
spirocyclopropane product 5. In pathway 2, the N–O bond
cleavage in complex D by oxidative addition is proposed to deliver
a Rh(V) species E. Reductive elimination of the C–C bond from E
would release the product 5 and the same intermediate F in which
rhodium is reduced to Rh(III).
Scheme 2. The discovery of the formation of the dearomatized intermediate 5.
To learn about the process for the formation of this key
intermediate 5, we investigated the reactions of (2-
hydroxyphenyl)boronic acid 6 and the olefin 1a with stoichiometric
2 2
amounts of Cp*Rh(OAc) •H O (Scheme 3). A rhodium(III)
complex 7 was proposed to be formed from the transmetalation
of the arylboronic acid followed by the olefin-insertion. However,
a new rhodium complex 8 was observed in 80% NMR yield which
is formed by the β-N elimination of the complex 7. The structure
was confirmed by single-crystal X-ray diffraction. No
rearrangement product 3, dearomatized intermediate 5 or C–O
bond reductive elimination product 9 was detected in this case,
suggesting that the in-situ generated Rh(III) species 7 prefers to
undergo the β-N elimination.[9,10]
Scheme 5. The plausible mechanisms.
The free energy profiles of the two possible pathways for the
formation of spirocyclopropane intermediate 5 are given in Figure
1. B is formed from the insertion of the rhodacycle A into the olefin.
Protonation of B by one acetic acid can readily proceed via
transition state ts-1 with a barrier of 6.0 kcal/mol. Intermediate cp2
can subsequently undergo an intramolecular attack to give the
cyclized product 5 with an overall barrier (17.6 kcal/mol) from
intermediate B. The O−N bond cleaves simultaneously in this
cyclopropanation step.[11] The formation of the spiro-product 5
requires minimal distortion of CP2. In path 2, the N−O bond
oxidative addition via transition state ts-3 leads to the formation of
a Rh(V) intermediate cp4. However, the overall barrier reaches
up to 54.7 kcal/mol, which is 37.1 kcal/mol higher than that in path
Scheme 3. The reactivity of the in-situ generated complex 7.
To study the possibility of a Rh(V) pathway[11-13] involving the
Rh(V) nitrenoid intermediate C (Scheme 4), we investigated the
reactions of (2-hydroxyphenyl)boronic acid 6 and olefin 1a with
the amidation reagent 10[13] using Cp*Rh(OAc)
•H O as the
2 2
catalyst. In the Cp*Rh(III)-catalyzed C–H amidation using 10, a
key Rh(V) nitrenoid intermediate was proposed by Chang.[12] As
shown in Scheme 4, the reaction afforded the amidation product
1
1
1 in 43% NMR yield and the olefin carboamidation product 12 in
5% yield.[8] In the presence of HOAc, the reactions still gave
similar results. These results indicate that intermediate 7 could
react with 10 to form a Rh(V) nitrenoid intermediate C which can
further give the amidation product 11 and 12. These also suggest
that the intermediate 5 is unlikely to be generated from a Rh(V)
species.
1. Thus it is clearly disfavored in comparison to the intramolecular
attack step in path 1. In addition, we cannot locate a transition
state for an intramolecular attack of C–Rh bond to O atom to
deliver the product 12 from cp2.[3] It is essentially a S
Ar reaction,
N
with C1-C2 bond formation accompanying N−O cleavage.[
14]
N
Direct attack of C1 on O1 would require a disfavored frontside S 2
process. In addition, as the natural population analysis (NPA)
charge of the carbon C2 in intermediate cp2 is -0.039, which
suggests the nucleophilic attack of carbon C1 (-0.339) toward C2
via ts-2 could generate the spirocyclopropane product facilely.
The strong nucleophilicity of both C1 (-0.339) and O1 (-0.422)
indicates that the cyclization should not occur to form 12. In order
to further understand the role of HOAc in the reaction, we also
performed calculations on the possible pathways without the
protonation of B (See Figure S5 in SI). O−N oxidative addition can
occur to generate a Rh(V) nitrenoid complex C with a high barrier
of 28.6 kcal/mol from the intermediate B. However, this
Scheme 4. The investigation of the possible Rh(V) pathway.
DFT calculations (see SI for computational details) were also
conducted to understand the reaction mechanism. On the basis
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201800803
COMMUNICATION
intermediate prefers to afford a N-(2-hydroxyphenyl)acetamide
product and carbon-amidation product which is in line with the
results in Scheme 4. Furthermore, an acid-promoted
rearrangement of the intermediate 5 to the product 3 is proposed
Our calculations show that the reaction of complex B is greatly
facilitated by protonation with an additional HOAc, followed by the
subsequent intramolecular attack. This pathway is much more
favorable than the O–N bond oxidative addition in complex B or
cp2 by Rh(V) pathways. These results are consistent with the
experimental observation that the addition of HOAc is necessary
for the formation of 5 from the intermediate C. These also fit the
results shown in Scheme 4 that the intermediate 5 is
(
For details, see SI). The aromatization of the cyclohexadienone
unit by the cleavage of C–C bond and a Wagner–Meerwein-type
rearrangement of the bicyclic framework are thought to be the key
steps.
Figure 1. Free energy profiles for the formation of the spirocyclopropane
unlikely to be generated from Rh(V) species. Moreover, O–N
bond is proposed to cleave through an intramolecular attack
during the cyclopropanation step. Combining the experimental
and DFT results, path 1 in Scheme 5 is the most reasonable
mechanism.
Due to the wide occurrence of spirocyclopropanes in drugs
and pharmaceutically active compounds,[15] it is highly desirable
to develop the dearomatized spirocyclopropane reactions based
on the above mentioned finding. In order to isolate a stable
dearomatized product, we explored a starting material from α-
naphthol as this motif can easily undergo a dearomatization
process.[5] To our delight, the reaction between 13a and the olefin
1a indeed afforded a stable and isolable product 14a in 82% yield
(
Scheme 6). Crystal structure of 14a clearly showed that the
molecule adopts a structure analogous to that proposed for
intermediate 5. A spirocyclopropane unit is found in this structure,
wherein the naphthol ring is dearomatized to a naphthalen-1(2H)-
one motif. Two new C–C bonds are formed in the key
cyclopropanation step and thus the starting material acts as a
formal one-carbon component in this [1 + 2] annulation reaction.
7-azabenzonorbornadienes with different groups on the arene,
including methyl-, bromo- and benzo-structure, performed well
affording the corresponding products in moderate yields. The
reaction with 7-oxabenzonorbornadiene as coupling partner
delivered the product 14e in 45% yield. However, norbornene was
tested in this reaction and only led to a complex reaction mixture.
The dibromo substituted starting material also afforded the
product 14f in 63% yield. In addition, further transformations of
the product were investigated. 14a could rearrange to the product
o
1
5 by heating it to 80 C in toluene. The ketone could be easily
Scheme 6. Cp*Rh(III)-catalyzed dearomatization reaction of N-(naphthalen-1-
yloxy)acetamide with strained olefins. For details, see the supporting
information.
reduced to alcohol and the double bond could be transferred to
an oxirane unit without the destruction of the spirocyclopropane
scaffold.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201800803
COMMUNICATION
Experimental and DFT investigations have elucidated the
mechanism of Cp*Rh(III)-catalyzed C–H activation followed by
Wagner–Meerwein-type rearrangement. N-phenoxyacetamide
functions as a formal one-carbon component in a [1 + 2]
annulation with 7-azabenzonorbornadiene, to afford an
unprecedented dearomatized spirocyclopropane intermediate.
Inspired from this finding, a Cp*Rh(III)-catalyzed dearomatization
reaction of N-(naphthalen-1-yloxy)acetamide with strained olefins
affording several spirocyclopropanes was successfully developed.
[
5] For selected reviews on dearomatization, see: a) A. R. Pape, K. P. Kaliappan,
E. P. Kꢀndig, Chem. Rev. 2000, 100, 2917; b) S. P. Roche, J. A. Jr. Porco,
Angew. Chem. Int. Ed. 2011, 50, 4068; Angew. Chem. 2011, 123, 4154; c)
C.-X. Zhou, W. Zhang, S.-L. You, Angew. Chem. Int. Ed. 2012, 51, 12662;
Angew. Chem. 2012, 124, 12834; d) Q. Ding, X. Zhou, R. Fan, Org. Biomol.
Chem. 2014, 12, 4807; e) W.-T. Wu, L. Zhang, S.-L. You, Chem. Soc. Rev.
2016, 45, 1570; f) S. Quideau, L. Pouysegu, D. Deffïeux, Synlett 2008, 467.
[
6] For the cooperative C−H activation/dearomatization strategy of phenol
derivatives, see: a) S. Gu, L. Luo, J. Liu, L. Bai, H. Zheng, Y. Wang, X.
Luan, Org. Lett. 2014, 16, 6132; b) Z. Zuo, X. Yang, J. Liu, J. Nan, L. Bai,
Y. Wang, X. Luan, J. Org. Chem. 2015, 80, 3349; c) C. Zheng, J. Zheng,
S.-L. You, ACS Catal. 2016, 6, 262; d) S. Kujawa, D. Best, D. J. Burns, H.
W. Lam, Chem. Eur. J. 2014, 20, 8599; e) J. Zheng, S.-B. Wang, C. Zheng,
S.-L. You, J. Am. Chem. Soc. 2015, 137, 4880; f) A. Seoane, N. Casanova,
N. Quiñones, J. L. Mascarenñas, M. Gulías, J. Am. Chem. Soc. 2014, 136,
7607; g) J. Nan, Z. Zuo, L. Luo, L. Bai, H. Zheng, Y. Yuan, J. Liu, X. Luan,
Y. Wang, J. Am. Chem. Soc. 2013, 135, 17306; h) Z. Zuo, X. Yang, J. Liu,
J. Nan, L. Bai, Y. Wang, X. Luan, J. Org. Chem. 2015, 80, 3349. For a
Cp*Rh(III)-catalyzed C−H activation/ cyclopropanation, see: i) T. Piou, T.
Rovis, J. Am. Chem. Soc. 2014, 136, 11292.
Acknowledgements
The authors acknowledge generous financial support from the
Alexander von Humboldt Foundation (X.W.) and Deutsche
Forschungsgemeinschaft (Leibniz Award). We are grateful to
Michael Teders for NMR experimental assistance. The authors
thank Dr. Suhelen Vásquez-Céspedes, Dr. Michael J. James and
Andreas Lerchen (all WWU Münster) for helpful discussions. We
are grateful to the National Science Foundation of the USA (CHE-
[7] Z. Qi, X. Li, Angew. Chem. Int. Ed. 2013, 52, 8995; Angew. Chem. 2013,
125, 9165;
[8] X. Wang, T. Gensch, A. Lerchen, C. G. Daniliuc, F. Glorius, J. Am. Chem.
Soc. 2017, 139, 6506.
1361104) and the National Science Foundation supported CCI
[9] F. Wang, S. Yu, X. Li, Chem. Soc. Rev. 2016, 45, 6462.
Center for Selective C−H Functionalization (CHE-1205646). The
author Y.L. thanks for the financial support from China
Scholarship Council.
[
10] For selected reviews, see: a) M. Lautens, K. Fagnou, S. Hiebert, Acc. Chem.
Res. 2003, 36, 48; b) K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169;
c) D. K. Rayabarapu, C.-H. Cheng, Acc. Chem. Res. 2007, 40, 971; d) C.-
H. Ding, X.-L. Hou, Bull. Chem. Soc. Jpn. 2010, 83, 992.
Keywords: Rh(III)-catalysis • Spirocyclopropane • Oxidizing
directing groups • Strained olefins
[11] S. Vásquez-Céspedes, X. Wang, F. Glorius, ACS Catal. 2018, 8, 242.
[
[
[
12] a) K. Shin, H. Kim, S. Chang, Acc. Chem. Res. 2015, 48, 1040; b) K. Shin,
Y. Baek, S. Chang, Angew. Chem. Int. Ed. 2013, 52, 8031; Angew. Chem.
2013, 125, 8189; c) S. H. Park, J. Kwak, K. Shin, J. Ryu, Y. Park, S. Chang,
[
1] For reviews on Rh(III)-catalyzed C−H activations, see: a) D. A. Colby, R. G.
Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624; b) T. Satoh, M. Miura,
Chem. Eur. J. 2010, 16, 11212; c) G. Song, F. Wang, X. Li, Chem. Soc.
Rev. 2012, 41, 3651; d) D. A. Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman,
Acc. Chem. Res. 2012, 45, 814; e) F. W. Patureau, J. Wencel-Delord, F.
Glorius, Aldrichimica Acta 2012, 45, 31; f) N. Kuhl, N. Schröder, F. Glorius,
Adv. Synth. Catal. 2014, 356, 1443; g) G. Song, X. Li, Acc. Chem. Res.
J. Am. Chem. Soc. 2014, 136, 2492; d) Y. Park, J. Heo, M.-H. Baik, S.
Chang, J. Am. Chem. Soc. 2016, 138, 14020.
13] a) Y. Park, K. T. Park, J. G. Kim, S. Chang, J. Am. Chem. Soc. 2015, 137,
4534; b) Y. Park, S. Jee, J. G. Kim, S. Chang, Org. Process Res. Dev. 2015,
19, 1024; c) H. Wang, G. Tang, X. Li, Angew. Chem. Int. Ed. 2015, 54,
13049; Angew. Chem. 2015, 127, 13241; d) J. Park, S. Chang, Angew.
Chem. Int. Ed. 2015, 54, 14103; Angew. Chem. 2015, 127, 14309.
2015, 48, 1007; h) B. Ye, N. Cramer, Acc. Chem. Res. 2015, 48, 1308.
14] a) R. A. Abramovitch, M. Inbasekaran, S. Kato, J. Am. Chem. Soc. 1973,
[
2] For reviews of oxidizing directing groups, see: a) F. W. Patureau, F. Glorius,
Angew. Chem. Int. Ed. 2011, 50, 1977; Angew. Chem. 2011, 123, 2021; b)
H. Sun, Y. Huang, Synlett 2015, 26, 2751; c) J. Mo, L. Wang, Y. Liu, X. Cui,
Synthesis 2015, 47, 439; d) H. Huang, X. Ji, W. Wu, H. Jiang, Chem. Soc.
Rev. 2015, 44, 1155.
95, 5428; b) Y. Endo, K. Shudo, T. Okamoto, J. Am. Chem. Soc. 1982, 104,
6393; c) Y.-T. Wang, M. Novak, J. Org. Chem. 2009, 74, 7697.
[
[
15] a) L. A. Wessjohann, W. Brandt, T. Thiemann, Chem. Rev. 2003, 103, 1625;
b) M. Tanasova, S. J. Sturla, Chem. Rev. 2012, 112, 3578.
16] CCDC-1579105 (8) and CCDC-1579103 (14a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_ request/cif.
[
[
3] For a pioneering work, see: G. Liu, Y. Shen, Z. Zhou, X. Lu, Angew. Chem.
Int. Ed. 2013, 52, 6033; Angew. Chem. 2013, 125, 6149.
4] X. Wang, A. Lerchen, T. Gensch, T. Knecht, C. G. Daniliuc, F. Glorius,
Angew. Chem. Int. Ed. 2017, 56, 1381; Angew. Chem. 2017, 129, 1401.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201800803
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Xiaoming Wang,†§ Yingzi Li,‡§ Tobias
Knecht, Constantin G. Daniliuc,† K. N.
Houk,*‡ Frank Glorius*†
†
Page No. – Page No.
Unprecedented Dearomatized
Spirocyclopropane in a Sequential
Rh(III)-catalyzed C–H Activation and
Rearrangement Reaction
Unprecedented dearomatized spirocyclopropane intermediate was discovered in
the sequential Cp*Rh(III)-catalyzed C–H activation and Wagner–Meerwein-type
rearrangement reaction. N-phenoxyacetamide was found to act as a formal one-
carbon component in this unexpected Rh(III)-catalyzed [1 + 2] annulation process.
This article is protected by copyright. All rights reserved.