Ruthenium-catalyzed cascade C-H activation/annulation of: N -alkoxybenzamides: Reaction development and mechanistic insight

Article abstract of DOI:10.1039/d0sc04434b

A highly selective ruthenium-catalyzed C-H activation/annulation of alkyne-tethered N-alkoxybenzamides has been developed. In this reaction, diverse products from inverse annulation can be obtained in moderate to good yields with high functional group compatibility. Insightful experimental and theoretical studies indicate that the reaction to the inverse annulation follows the Ru(ii)-Ru(iv)-Ru(ii) pathway involving N-O bond cleavage prior to alkyne insertion. This is highly different compared to the conventional mechanism of transition metal-catalyzed C-H activation/annulation with alkynes, involving alkyne insertion prior to N-O bond cleavage. Via this pathway, the in situ generated acetic acid from the N-H/C-H activation step facilitates the N-O bond cleavage to give the Ru-nitrene species. Besides the conventional mechanism forming the products via standard annulation, an alternative and novel Ru(ii)-Ru(iv)-Ru(ii) mechanism featuring N-O cleavage preceding alkyne insertion has been proposed, affording a new understanding of transition metal-catalyzed C-H activation/annulation.

Full text of DOI:10.1039/d0sc04434b

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Song, X. Zhang,
X. Tang, L. Van Meervelt, J. Van der Eycken, J. Harvey and E. V. Van der Eycken, Chem. Sci., 2020, DOI:
10.1039/D0SC04434B.
Volume
Number
9
1
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
7
January 2018
Pages 1-268
Chemical
Science
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
rsc.li/chemical-science
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Xinjing Tang et al.
Caged circular siRNAs for photomodulation of gene
expression in cells and mice
rsc.li/chemical-science

Please do not adjust margins
Page 1 of 8
Chemical Science
View Article Online
DOI: 10.1039/D0SC04434B
ARTICLE
Ruthenium-catalyzed cascade C-H activation/annulation of N-
alkoxybenzamides: reaction development and mechanistic insight
Liangliang Song,‡a Xiaoyong Zhang,‡b Xiao Tang,c Luc Van Meervelt,d Johan Van der Eycken,e Jeremy
Received 00th January 20xx,
Accepted 00th January 20xx
N. Harvey*b and Erik V. Van der Eycken*af
DOI: 10.1039/x0xx00000x
A highly selective ruthenium-catalyzed C-H activation/annulation of alkyne-tethered N-alkoxybenzamides has been
developed. In this reaction, diverse products from inverse annulation can be obtained in moderate to good yields with high
functional group compatibility. Insightful experimental and theoretical studies indicate that the reaction to the inverse
annulation follows the Ru(II)-Ru(IV)-Ru(II) pathway involving N-O bond cleavage prior to alkyne insertion. This is highly
different compared to the conventional mechanism of transition metal-catalyzed C-H activation/annulation with alkynes,
involving alkyne insertion prior to N-O bond cleavage. Via this pathway, the in situ generated acetic acid from the N-H/C-H
activation step, serves to facilitate the N-O bond cleavage to give the Ru-nitrene species. Besides the conventional
mechanism forming the products via standard annulation, an alternative and novel Ru(II)-Ru(IV)-Ru(II) mechanism featuring
N-O cleavage preceding alkyne insertion has been proposed, affording a new understanding of transition metal-catalyzed C-
H activation/annulation.
oxidant is explored for the construction of isoquinolone
Introduction
analogues
in
Rh(III)-
or
Ru(II)-catalyzed
C-H
activation/annulation reactions and results in a number of
examples, which indicated the potential of internal oxidizing
directing groups in transition metal-catalyzed C-H activation.
One such example was reported by Park,5e who described a
rhodium(III)-catalyzed intramolecular annulation reaction of N-
alkoxybenzamides to offer a new approach to isoquinolones
(Scheme 1a). Subsequently, the internal oxidizing N-O bond has
been used to synthesize structurally complex polycyclic
compounds.7 In 2014, Lin’s group developed a Rh(III)-catalyzed
Transition metal-catalyzed C-H activation plays an important
role in synthetic organic chemistry.1 In particular, C-H activation
followed by annulation with alkynes has emerged as an
increasingly effective and attractive strategy for the
construction of heterocycles and carbocycles in a step- and
atom-economical manner.2 In this regard, Rh(III)3 or Ru(II)4
catalysts have been employed in cascade C-H
activation/annulation reactions with various types of alkynes,
leading to the synthesis of isoquinolone derivatives through the
use of external oxidants.
arylative
cyclization
of
N-hydroxybenzamides
with
cyclohexadienone-containing 1,6-enynes for the synthesis of
tetracyclic isoquinolones.7c A Ru(II)-catalyzed regioselective
intermolecular annulation of aryl substituted 2-acetylenic
ketones with N-methoxybenzamides or acrylamides was
reported by Chegondi in 2016.7f Recently, we demonstrated a
Rh(III)-catalyzed sequential C(sp2)-H activation and C(sp3)-H
amination for the preparation of polycyclic compounds
(Scheme 1b).7b,7d
The utilization of internal oxidants exhibits a significant move
forward in the area, avoiding the stoichiometric amount of
external oxidants and potentially facilitating milder reactions.5,6
For instance, the employment of a N-O bond as an internal
a. Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of
Chemistry, KU Leuven Celestijnenlaan 200F, 3001, Leuven, Belgium. E-mail:
erik.vandereycken@kuleuven.be
Mechanistically (Scheme 2), these annulations have been
explained in the light of an initial C-H activation to generate
intermediate I, followed by alkyne insertion into the C-M bond
leading to the seven-membered intermediate II, which delivers
the isoquinolone products through sequential reductive
elimination and oxidative addition into the N-O bond (path a,
Mn-Mn-2-Mn pathway). Alternatively, intermediate II possibly
undergoes oxidative addition into the N-O bond followed by
reductive elimination to deliver the isoquinolones (path b, Mn-
Mn+2-Mn pathway).8 However, they are always restricted to
alkyne insertion prior to N-O bond cleavage. Mechanistic
investigations of the key intermediates in C-H
b. Theoretical and Computational Chemistry, Department of Chemistry, KU Leuven
Celestijnenlaan 200F, 3001, Leuven, Belgium. E-mail: jeremy.harvey@kuleuven.be
c. School of Chemistry, Physics and Mechanical Engineering, Queensland University
of Technology, Gardens Point Campus, Brisbane, QLD 4001, Australia
d. Biomolecular Architecture, Department of Chemistry, KU Leuven Celestijnenlaan
200F, 3001, Leuven, Belgium
e. Laboratory for Organic and Bio-Organic Synthesis, Department of Organic and
Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S.4), B-9000 Ghent,
Belgium
f. Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya
Street 6, Moscow, 117198, Russia
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/x0xx00000x
‡These authors contributed equally to this work
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 2 of 8
ARTICLE
Journal Name
a) Park:
O
R
Results and discussion
View Article Online
O
Reaction Optimization. We initiated DoOuI:r10s.t1u0d39ie/Ds0wSCit0h44t3h4Be
O
R
Rh(III)
NH
N
H
n
OH
n
exploration
of
the
ruthenium-catalyzed
C-H
activation/annulation of alkyne-tethered N-alkoxybenzamide
1a. To our delight, when 1a was treated in the presence of
[Ru(p-cymene)Cl2]2 (10 mol %) and NaOAc (2 equiv) in MeOH at
60 °C for 4 h, the product 3a from inverse annulation was
obtained in 81% yield, together with the product 2a from
standard annulation in 10% yield (Table 1, entry 1). Next various
solvents were screened, such as DCE, CH3CN, THF, acetone, 1,4-
dioxane, toluene and DMF, and MeOH was identified as the
preferred reaction medium (Table 1, entries 2-8). Adding PivOH
(1 equiv) did not improve the reaction (Table 1, entry 9).
Replacing the additive NaOAc with CsOAc (2 equiv) did not
significantly influence the yield (Table 1, entry 10). The
employment of AgSbF6 (1 equiv) instead of NaOAc completely
inhibited the reaction (Table 1, entry 11). Decreasing the
catalyst loading to 5 mol%, made the reaction much slower
(Table 1, entry 12). We also evaluated the performance of other
Ru(II)-catalysts, such as [Ru(C6Me6)Cl2]2 and [(C6H5)3P]3RuCl2
(Table 1, entries 13-14), but very low conversions were
observed.
b) Our previous work:
O
OH
O
Rh(III)
N
O
N
H
R
R
c) This work:
O
O
NH
R2
R1
O
N
[Ru(p-cymene)Cl2]2
R1
H
n
n = 0, 1, 2, 3, 4
Ru(II)-Ru(IV)-Ru(II)
n
N-O bond cleavage
prior to alkyne insertion
R2
OH
O
O
R1
N
R1
Cy
N
O
O
RuIV
Cy
RuIV
O
O
R2
H
O
H
R2
O
n
n
Scheme 1 Previous works and this approach.
O
NH
O
R2
R2
R2
OR1
R2
N
Examination of Substrate Scope. With the optimal reaction
conditions in hand, we next investigated diverse substrates to
evaluate the scope of the protocol (Table 2 and Scheme 3).
Substrates with a wide range of electron-rich and -deficient
groups at the para position of the benzamide proceeded
smoothly to afford the products 3b-g (67-85%) from inverse
annulation (Table 2). The structure of 3c has been confirmed by
X-ray diffraction. In particular, the meta-methyl benzamide
gave excellent regioselectivity in support of the sterically more
accessible C-H bond, delivering product 3h in 63% yield. The
ortho-methyl-substituted derivative was also a productive
substrate, leading to the product 3i in 61% yield. The annulation
reaction also worked well with electron-donating and -
withdrawing groups in the aryl substituent of the alkyne,
affording the products 3j-o in 67-83% yield. When the aryl
group of the alkyne was replaced by n-butyl group (Scheme 3),
the products 2w (59%) and 2x (65%) from standard annulation
were isolated as the main products, along with concomitant
products 3w (27%) and 3x (31%) from inverse annulation.
Moreover, only products 2y and 2z from standard annulation
were obtained in 89% and 68% yield from the TMS-substituted
derivative and the substrate bearing a terminal alkyne
respectively (Scheme 3), while previous approaches5e,7b were
limited to internal alkynes. Next, we evaluated the length of the
tethers between the oxygen atom and the alkyne. Substrates
with five-, six- and seven-carbon-atom tethers delivered the
products 3p-t from inverse annulation in 76-87% yield. The
substrate with a three-carbon-atom tether delivered the
product 2a’ (58%) from standard annulation as the main
product, together with the product 3a’ from inverse annulation
in 31% yield (Scheme 3). To further demonstrate the synthetic
utility of this methodology, the annulation reaction was
performed using N-alkoxybenzamides derived from the
Mn
I
O
OR1
N
H
Conventional pathway
O
O
OR1
O
path b
Mn
N
N
OR1
Mn
R2
N
Mn+2
R2
OR1
R2
R2
II
R2
R2
IV
V
Mn-2
O
path a
OR1
N
R2
R2
III
Scheme
2 Previously proposed catalytic cycle for C-H
activation/annulation reactions.
activation/annulation processes are still somewhat limited, so it
is not clear whether the mechanistic possibilities in Scheme 2
are sufficient to account for all observed reactivity in these
systems. Formation of Rh(V) or Ru(IV) intermediates has been
proposed from the experimental results,9 but usually the
mechanisms are assumed to involve alkyne insertion prior to N-
O bond cleavage (path b). To the best of our knowledge, no
unambiguous high-valent Cp*Rh(V) or (p-cymene)Ru(IV)
complexes have been isolated to date, but DFT calculations
have provided strong support for treating Rh(V) or Ru(IV)
species as intermediates in reaction mechanisms.10
In comparison to previous hypotheses, we set out to
investigate whether a catalytic cycle involving N-O bond
cleavage prior to alkyne insertion might also play a role in some
of these reactions.11 The high-valent metal complex generated
from N-O bond cleavage should increase the driving force for
alkyne insertion and sequential reductive elimination (Scheme
1c). For this purpose, the ruthenium-catalyzed C-H
activation/annulation of alkyne-tethered N-alkoxybenzamides
is regarded as a platform for verifying this hypothesis.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 8
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
pharmaceuticals bexarotene and probenecid, resulting in the 4c formed, suggest that the N-O bond cleavage occurs prior to
View Article Online
products 3u (64%) and 3v (56%) from inverse annulation.
Table 1 Optimization of the reaction conditions.a
the alkyne insertion. Therefore, pathwayDsOinI: 1S0c.h10e3m9/eD04SaCa0n44d344Bc
can be ruled out. Also, from DFT calculation results, pathway in
Scheme 4a is less favorable (see SI).12d We also did the crossing
experiment of 1c and 1j under the standard conditions (Scheme
5e), resulting in four annulation products. This result further
indicates that the N-O bond cleavage occurs prior to the alkyne
insertion. Under the standard conditions, the reaction of 4a and
4b could not deliver the annulation products (Scheme 5f), and
only minor amount of product 3a was obtained when Cu(OAc)2
(2 equiv) was added. This indicates that the formation of 2a and
3a does not follow the pathway involving 4a and 4b from the
cleavage of 1a. Thus pathway in Scheme 4b can be ruled out.
O
O
O
O
N
Catalyst
NH
H
NH
Ph
3a
+
OH
NaOAc (2 equiv)
Solvent (0.1 M)
60 C, 4 h
4
Ph
2a
4
1a
HO
Ph
Entry
2ab
3ab
Catalyst
Solvent
MeOH
DCE
(%)
(%)
1
[Ru(p-cymene)Cl2
]
2 (10 mol%)
10
81
2
[Ru(p-cymene)Cl2
[Ru(p-cymene)Cl2
[Ru(p-cymene)Cl2
[Ru(p-cymene)Cl2
[Ru(p-cymene)Cl2
[Ru(p-cymene)Cl2
[Ru(p-cymene)Cl2
[Ru(p-cymene)Cl2
[Ru(p-cymene)Cl2
]2 (10 mol%)
]2 (10 mol%)
]2 (10 mol%)
]2 (10 mol%)
]2 (10 mol%)
]2 (10 mol%)
]2 (10 mol%)
]2 (10 mol%)
]2 (10 mol%)
45
28
38
22
32
42
10
12
11
39
16
32
67
19
29
21
76
78
3
CH3CN
THF
4
5
Acetone
1,4-Dioxane
Toluene
DMF
6
Table 2 Scope for N-alkoxybenzamide substrates.
7
8
O
O
O
O
9c
10d
11e
12
[Ru(p-cymene)Cl2]2 (10 mol%)
R1
MeOH
NH
R2
N
NH
R1
H
+
R1
NaOAc (2 equiv)
n
OH
MeOH
n
R2
1
R2
MeOH (0.1 M)
n

60 C, 4 h
[Ru(p-cymene)Cl2
]
2 (10 mol%)
MeOH
MeOH
0
6
0
3 (major)
2
(minor)
OH
[Ru(p-cymene)Cl2
]
2 (5 mol%)
43
O
O
3a
R = H, , 81% (8:1)
Me
13
14
[Ru(C6Me6)Cl2
]
2 (10 mol%)
MeOH
MeOH
< 5%
< 5%
< 5%
< 5%
NH
Ph
3b
R = Me, , 79% (7:1)
NH
Ph
3c
R = OMe, , 83% (8:1)
[(C6H5 3P]3RuCl2 (20 mol%)
)
R
3d
R = tBu, , 80% (8:1)
3e
R = Cl, , 85% (9:1)
3h
, 63% (4:1)
a
3f
, 72% (7:1)
R = CF3
,
Condition: 1a (0.3 mmol), [Ru(p-cymene)Cl2]2, NaOAc (0.6
OH
Me
3c
3g
OH
R = CN, , 67% (4:1)
b
c
mmol), solvent (3.0 mL). Isolated yield. PivOH (1 equiv) was
added. CsOAc (2 equiv) instead of NaOAc. AgSbF6 (1 equiv)
instead of NaOAc.
O
O
d
e
O
NH
NH
Ph
NH
3j
R = Me, , 79% (6:1)
MeO
3k
R = OMe, , 82% (8:1)
3l
R = Cl, , 83% (8:1)
Me
3n, 67% (5:1)
R
3m
, 80% (7:1)
Mechanistic Studies. Based on above experimental results,
three possible reaction pathways from conventional
mechanism for the inverse annulation were firstly proposed.
That is, intramolecular annulation via bridged Ru(II)-
intermediate (Scheme 4a), or intermolecular annulation from
cleavage products (Scheme 4b), or intermolecular version via
homo-annulation (Scheme 4c). To gain more mechanistic
insight of the present reaction, a series of control experiments
were performed. Reversibility experiments concerning the C-H
activation step, using 1a in the presence of deuterated
methanol (Scheme 5a), showed that there is no deuterium
incorporation in the recovered substrate and products, which
indicates that the C-H activation step is irreversible. To further
investigate the C-H activation process, kinetic isotope effect
(KIE) experiments were performed (Scheme 5b). The
competitive experiment gave kH/kD = 1.1 for the formation of 3a
and kH/kD = 1.0 for the formation of 2a, while the parallel
experiment delivered kH/kD = 1.4 for the formation of 3a and
kH/kD = 1.5 for the formation of 2a, clearly indicating that the C-
H bond cleavage process is not involved in the rate-limiting step,
which is different from Park’s work5e. When 1a was treated
under [Ru(p-cymene)Cl2]2 (5 mol %) at r.t for 0.5 h (Scheme 5c),
the product 3a and alcohol 4b were obtained in 5% and 2%
yields respectively, while only <1% product 2a and trace amount
of benzamide 4a were detected. We did not observe the
formation of compound 4c. When benzofuran substrate 5 was
employed under the standard conditions, the product 6b from
inverse annulation was isolated in 20%, together with the
product 6c (29%) from standard annulation, benzamide 6a
(33%) and alcohol 4b (31%) (Scheme 5d). The isolation of
cleavage products amide and alcohol as well as no compound
R = CF3
,
3i
, 61% (3:1)
OH
OH
OH
O
O
O
NH
Ph
NH
NH
Ph
Me
R
R
3
3p
R = H, , 87% (9:1)
3r
R = H, , 84% (8:1)
2
3o
, 71% (5:1)
3q
R = OMe, , 76% (8:1)
3s
R = OMe, , 80% (7:1)
OH
OH
OH
O
O
O
NH
NH
Ph
NH
Ph
N
S
Ph
O
O
4
3v
, 56% (3:1)
3u
, 64% (4:1)
3t
, 80% (7:1)
from probenecid
from bexarotene
OH
OH
OH
Conditions: 1 (0.3 mmol), [Ru(p-cymene)Cl2]2 (0.03 mmol),
NaOAc (0.6 mmol) and MeOH (3.0 mL). 3 was isolated by
column chromatography. The ratio of 3:2 shown in parenthesis
was determined by 1H NMR analysis of the crude reaction
mixture.
O
O
O
O
N
standard conditions
NH
NH
H
+
OH
R
R
R
4
4
HO
R = OMe,
1w
R = OMe, 3w (27%)
R = Cl, 3x (31%)
R = OMe, 2w (59%)
R = Cl, 2x (65%)
R = Cl, 1x
O
O
O
N
standard conditions
NH
H
OH
R
R
R = TMS, 2y (89%)
R = H, 2z (68%)
R = TMS, 1y
R = H, 1z
O
O
O
O
N
standard conditions
NH
NH
Ph
H
+
OH
1a'
Ph
2a'
(58%)
3a'
(31%)
Ph
HO
Scheme 3 Ruthenium-catalyzed C-H activation/annulation.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 4 of 8
ARTICLE
Journal Name
Scheme 4 Possible mechanisms from initial assumption.
To provide more light on the formation of annulation
View Article Online
DOI: 10.1039/D0SC04434B
a) Reversibility experiment
products, DFT calculations employing B3LYP-D3/def2-TZVP
method were performed with the Ru(OAc)2(p-cymene) catalyst
A and the three-carbon-atom (1a’) tether substrate. We first
consider the previously proposed Ru(II)-Ru(0)-Ru(II) mechanism
(Scheme 6),5e,7,10 which involves an initial two-step C-H
activation (TS1), followed by the rate-determining step (RDS),
alkyne insertion through TS2. These steps are followed by
reductive elimination (TS3) and N-O oxidative cleavage (TS4).
The overall free energy barrier is 28.5-30.1 kcal mol-1, and only
the product 2a’ from the standard annulation reaction can be
formed.12
Based on the experimental observations and DFT
calculations, we then propose an alternative competitive Ru(II)-
Ru(IV)-Ru(II) mechanism (Scheme 7) featuring N-O cleavage
preceding alkyne insertion, and which can lead to formation of
both the standard 2a’ and inverse 3a’ annulation products. As
in the previous mechanism, the first steps are N-H
deprotonation and C-H activation (TS1, 17.8-21.6 kcal mol-1)
forming metallacycle B. At this point, as well as the previously
suggested alkyne insertion, the system can undergo an acid-
assisted N-O cleavage process (TS5, 27.2-31.7 kcal mol-1) to
afford the Ru(IV)-nitrene species G (4.5-5.5 kcal mol-1), in which
the forming alcohol (5-phenylpent-4-yn-1-ol) is H-bonded to the
acetate ligand. Dissociation of alcohol from G is weakly
endergonic by 1.8 kcal mol-1 in solution relative to A, consistent
with the experimental observation of small amounts of alcohol
side-product. The N-O cleavage is strongly acid-assisted: in the
absence of HOAc, the barrier to this process is much higher
(TS10, 50.1-54.6 kcal mol-1 in Scheme 8a), while TS2 is acid-
insensitive.12a Analysis of the electronic structure of the TS
indicates that this is because this step is a direct heterolytic
cleavage between two atoms with small electronegativity
difference (Scheme 8b). Natural population analysis (NPA)
shows that the alkoxyl oxygen atom in TS10 has a large negative
charge (-0.71 e), which can be stabilized by proton transfer in
TS5, and the resulting acetate base could delocalize the
negative charge.13 These results suggest that the in situ
generated acetic acid from N-H/C-H activation step could serve
D
O
0%
D
O
0%
D
O
0%
[Ru(p-cymene)Cl2]2 (10 mol%)
O
NH
NH
N
H
NaOAc (2 equiv)
+
+
1a
Ph
CD3OD (0.1 M)
60 C, 0.5 h
no deuterium incorporation
OH
D
3
0%
3
3
Ph
Ph
-3a
d1
1a
d2-
-2a
d1
OH
b) KIE experiment
competitive experiment
[Ru(p-cymene)Cl2]2 (10 mol%)
2a
+
3a
1a
NaOAc (2 equiv)
kH/kD = 1.0
+
kH/kD = 1.1
MeOH (0.1 M)
60 C, 0.5 h
-1a
d5
-3a
d4
d4-2a
+
parallel experiment
[Ru(p-cymene)Cl2]2 (10 mol%)
1a
3a
2a
+
NaOAc (2 equiv)
MeOH (0.1 M)
60 C, 0.5 h
kH/kD = 1.5
kH/kD = 1.4
[Ru(p-cymene)Cl2]2 (10 mol%)
-1a
-2a
d4
d5
-3a
d4
+
NaOAc (2 equiv)
MeOH (0.1 M)
60 C, 0.5 h
O
c) Control experiment
NH
Ph
O
[Ru(p-cymene)Cl2]2
OH
(5 mol%)
+
3a
(5%)
+
Ph
2a
+
(<1%)
NH2
1a
+
NaOAc (2 equiv)
4c
(0%)
4a
(trace)
O
MeOH (0.1 M)
r.t, 0.5 h
Ph
(2%)
O
4b
N
Ph
H
O
d) Benzofuran substrate
O
O
NH
Ph
O
NH2
O
3
O
O
N
[Ru(p-cymene)Cl2]2 (10 mol%)
6b
(20%)
OH
O
6a
(33%)
+
H
NaOAc (2 equiv)
MeOH (0.1 M)
60 C, 4 h
OH
O
NH
Ph
OH
3
5
3
Ph
Ph
6c
(29%)
4b
(31%)
e) Crossing experiment
O
O
O
O
N
NH
NH
Ph
H
MeO
MeO
MeO
4
4
1c
HO
3n
Me
HO
Ph
3c
(32%)
[Ru(p-cymene)Cl2]2 (10 mol%)
(35%)
+
NaOAc (2 equiv)
+
O
MeOH (0.1 M)
O
O
O
Ph
N
60 C, 4 h
H
NH
Ph
NH
4
4
HO
HO
Me
to facilitate the N-O bond cleavage.
1j
3j
(<10%)
3a
(<10%)
Me
a) Intramolecular annulation via bridged Ru(II)-intermediate
O
O
O
O
NH
Ph
Ph
N
f) Reaction of benzamide and alcohol
N
standard conditions
O
O
O
H
Ru2+
Ph
OH
O
NH
[Ru(p-cymene)Cl2]2 (10 mol%)
NH
+
+
Ph
NH2
OH
4
NaOAc (2 equiv)
MeOH (0.1 M)
60 C, 4 h
Ph
1a
via
2a
Ph
4
Ph
4a
4b
Ph
HO
3a
OH
b) Intermolecular annulation from cleavage products
2a
without Cu(OAc)2
0%
0%
trace
O
with Cu(OAc)2 (2 equiv)
<10%
O
OH
NH
standard conditions
Scheme
experiments.
5 Control experiments and deuterium-labeling
+
Ph
NH2
Ph
4a
4b
2a
Ph
Further coordination of the alkyne fragment in 5-phenylpent-
4-yn-1-ol to the metal from intermediate G is very exothermic
and can form two different Ru(IV) intermediates (Scheme 7), H1
and H2, which differ based on the orientation of the phenyl
substituent of 5-phenylpent-4-yn-1-ol. They thereby lead to
different annulation products, with H1 forming 2a’, while H2
yields 3a’, in each case through a sequence of steps involving
alkyne insertion (TS6/TS8), reductive elimination (TS7/TS9) and
OH
c) Intermolecular version via homo-annulation
O
O
O
NH
Ph
standard
conditions
standard
conditions
NH
Ph
O
OH
Ph
Ph
2
N
H
+
2
O
2a
1a
4c
4b
Ph
O
N
Ph
OH
H
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 8
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
protonation. The corresponding barriers are much smaller than
that of the N-O cleavage process,14 and similar in the standard
annulation case, consistent with the observation of both types
solely from computation which mechanismVieswhAortuiclledOnlbinee
dominant, especially as the relative free energies are somewhat
DOI: 10.1039/D0SC04434B
sensitive to the nature of the density functional used in the
computations (see SI). In additional calculations with the four-
carbon-atom tethered substrate, the two mechanisms are also
found to have similar activation free energies (Scheme 8c). For
both the three- (1a’) and four-carbon-atom (1a) tethered
substrates, TS5 is lower (by 1.3 kcal mol-1, and 4.0 kcal mol-1,
respectively) in the gas phase free energy, but relatively higher
(by 1.6 kcal mol-1, and 0.6 kcal mol-1, respectively) in the solution
phase free energy than TS2. In experiments, reaction with 1a’
yields more standard annulation product 2a’ (58 %) than the
inverse annulation product 3a’ (31 %), while reaction with 1a
leads to more inverse annulation product 3a (81 %) and less
standard annulation product 2a (10 %). The calculated slightly
lower solution phase free energies for TS2 than for TS5 should
make the traditional mechanism, and thereby the standard
annulation product, dominant in both cases. However, given
the small calculated energy difference and the expected error
bars (the two TSs differ significantly in electronic structure, so
favorable error compensation cannot be expected), our results
are consistent with the new mechanism via TS5 playing an
important role. Therefore, our DFT calculations combined with
experimental observations suggest that formation of the
inverse annulation products follows the Ru(II)-Ru(IV)-Ru(II)
cycle, while the “standard” annulation products could be
formed by either the Ru(II)-Ru(0)-Ru(II) or Ru(II)-Ru(IV)-Ru(II)
mechanism, or both.
of annulation products.
[(RuIICyCl2)2]
O
O
1a'
HO
NH
Gsoln(Ggas
)
O
4 NaOAc
4 NaCl
N
kcal mol-1
H
Ph
Cy : p-cymene
2a'
Ph
[RuIICy(OAc)2
]
2
-81.8 (-79.8)
HOAc
1a'
A
2 HOAc
0.0 (0.0)
TS1
21.6 (17.8)
Protonation
N-H Deprotonation
C-H Activation
Cy
O
RuII
O
O
N
O
N
F
RuII
H
O
O
-67.6 (-66.6)
Ph
Ph
Traditional Mechanism
Cy
Oxidative
Addition
B
Ru(II)-Ru(0)-Ru(II)
TS4
11.4(16.8)
11.8 (6.6)
Standard Annulation
HOAc
Cy
Ru0
O
O
O
N
O
N
Redu
Elimi
nation
Ph
RuII
E
ct
Cy
Ph
3.8 (-4.1)
i
ve
TS3
O
C
Alkyne
19.5 (19.0)
O
N
RuII
6.5 (6.0)
Insertion
Cy
Rate Determining Step
(RDS)
D
Ph
11.9 (9.0)
Scheme 6 Traditional mechanistic cycle leading to the standard
annulation product. Computed relative free energies (kcal mol-
1, B3LYP-D3/def2-TZVP (SMD:methanol)).
The TS of the RDS step (acid-assisted N-O cleavage process,
TS5) in the present Ru(II)-Ru(IV)-Ru(II) mechanism (Scheme 7) is
only slightly different in free-energy to that of the key TS (for
alkyne insertion, TS2) in the traditional Ru(II)-Ru(0)-Ru(II)
mechanism (Scheme 6), which makes it difficult to determine
O
O
2a'
O
1a'
3a'
HO
NH
Standard Annulation
Inverse Annulation
O
NH
Ph
OH
N
H
Ph
2a'
-81.8
(-79.8)
Ph
O
Gsoln(Ggas
kcal mol-1
)
Cy
O
O
Cy
HOAc
HOAc
RuII
O
O
RuII
Start Here
[RuIICy(OAc)2
A
N
Cy : p-cymene
H
Protonation
O
J2
N
]
O
Protonation
J1
O
H
-
-49.4 ( 53.1)
Ph
-61.8 (-68.9)
0.0 (0.0)
1a'
Ph
TS9
-10.5 (-5.1)
TS1
21.6 (17.8)
TS7
-7.8 (-5.2)
N-H Deprotonation
Reductive
C-H Activation
Reductive
Elimination
Elimination
HOAc
O
O
O
N
O
N
O
O
Cy
N
Standard Annulation
Ru(II) - Ru(IV) - Ru(II)
Inverse Annulation
RuII
H
O
RuIV
O
RuIV
H
Ru(II) - Ru(IV) - Ru(II)
Cy
Ph
O
B
Cy
O
O
O
11.8 (6.6)
Ph
I1
H
Ph
-26.9
(-24.2)
Acid-Assisted
N-O Cleavage
O
TS5
31.7 (27.2)
I2
Alkyne
-24.0 (-18.6)
Alkyne
Insertion
RDS
O
Insertion
O
TS6
-2.5 (0.9)
O
N
TS8
-2.0 (3.2)
N
RuIV
Cy
H
N
O
Alkyne
ination
RuIV
H
O
Cy
RuIV
Ph
O
O
O
Alkyne
ination
O
Coord
G
Cy
Ph
H1
-19.9 (-19.8)
Ph
Coord
4.5 (5.5)
H
O
O
O
H2
-11.4 (-13.1)
N
O
H
+
RuIV
O
Cy
Ph
O
(Experimentally detected)
H3
1.8 (10.5)
Scheme 7 New suggested mechanism. Computed relative free energies (kcal mol-1, B3LYP-D3/def2-TZVP (SMD:methanol)).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 6 of 8
ARTICLE
Journal Name
O
O
O
TS10
50.1
(54.6)
(c)
(a)
Gsoln(Ggas
kcal mol-1
)
TS10
View Article Online
DOI: 10.1039/D0SC04434B
O
n
O
H
N
Ph
N
n
N
RuII
H
O
RuII
O
Two-step C-H
activation
Cy : p-cymene
Cy
TS5
31.7
(27.2)
Cy
Ph
O
Ph
N-O cleavage step
Ru(OAc)2Cy
HOAc
Ph
Present
B
Traditional
Ru(II) - Ru(IV) - Ru(II)
Ru(II) - Ru0) - Ru(II)
B
Alkyne Insertion
N-O Cleavage
11.8
(6.6)
C
G
4.5
(5.5)
O
O
6.5 (6.0)
HOAc
HOAc
O
TS5
N
O
N
O
n
O
N
H
H
RDS
H2
Cy
RuII
O
RuII
Ru
Cy
-11.4 (-13.1)
H1
-19.9 (-19.8)
n
Cy
O
O
O
Ph
Ph
TS2
30.1
25.4
TS5
Ph
31.7 (27.2)
26.0 (24.0)
n = 0
n = 1
(28.5)
(28.0)
(b)
G
NPA
NPA
NPA
Reductive
Elimination
Ru : -0.14
N : -0.21
O : -0.42
H : 0.53
Ru : -0.03 Ru : 0.30
N : -0.18 N : -0.20
O : -0.58 O : -0.71
O
O
Cy
Ru0
H2
H1
O
E
N
N
H : 0.52
Ru
O
1.94
1.82
2.18
2.06
O
1.91
N
N 1.42
RuIV
Ph
RuIV
H
n
O
Cy
O
O1.61
1.02
1.51
Cy
Ph
n
H 1.00
O
O
H
n
Ph
O
N-O Clevage
Protonation
Alkyne Insertion
Reductive Elimination
Protonation
O
O
B
TS5
TS10
NH
Ph
NH
n
OH
Ph
Standard Annulation
OH
n
Inverse Annulation
Scheme 8 Role of acetic acid in the N-O cleavage. (a) Energy profiles (kcal mol-1) for the N-O cleavage step in the Ru(II)-Ru(IV)-Ru(II)
pathway. (b) Structures of the N-O cleavage transition states, including NPA charges of key atoms and selected interatomic
distances (in Å). (c) Schematics pathways for Ru-catalyzed annulation reaction.
Council (CSC) for providing a doctoral scholarship. LVM thanks
the Hercules Foundation for supporting the purchase of the
diffractometer through project AKUL/09/0035. We
acknowledge the FWO [Fund for Scientific Research-Flanders
(Belgium)] and the Research Council of KU Leuven (BOF) for
financial support. We acknowledge the support of RUDN
University Program 5-100. The computational resources and
Conclusions
In summary, we have developed a ruthenium-catalyzed C-H
activation/annulation process of alkyne-tethered N-
alkoxybenzamides with high selectivity. This methodology is
compatible with various kinds of N-alkoxybenzamides including
bexarotene and probenecid derivatives, providing a wide range
services used in this work are provided by the VSC (Flemish
of products from inverse annulation. Detailed experimental
Supercomputer Center), funded by the Research Foundation-
investigations and DFT calculations reveal that the inverse
Flanders (FWO) and the Flemish Government-department EWI.
annulation follows a Ru(II)-Ru(IV)-Ru(II) mechanism featuring N-
O cleavage preceding alkyne insertion. Formation of the
putative Ru-nitrene intermediate is assisted by the in situ
generated acetic acid from N-H/C-H activation step. Formation
Notes and references
1
For selected reviews on catalytic C-H bond activation, see: (a)
J. He, M. Wasa, K. S. Chan, Q. Shao and J.-Q. Yu, Chem. Rev.
2016, 117, 8754; (b) K. Murakami, S. Yamada, T. Kaneda and
K. Itami, Chem. Rev. 2017, 117, 9302; (c) J. C. Chu and, T. Rovis,
Angew. Chem. Int. Ed. 2018, 57, 62; (d) P. Gandeepan, T.
Müller, D. Zell, G. Cera, S. Warratz and L. Ackermann, Chem.
Rev. 2018, 119, 2192; (e) Y. Park, Y. Kim and S. Chang, Chem.
Rev. 2017, 117, 9247; (f) G. Rouquet and N. Chatani, Angew.
Chem. Int. Ed. 2013, 52, 11726; (g) X.-S. Zhang, K. Chen and Z.-
J. Shi, Chem. Sci. 2014, 5, 2146; (h) N. Kuhl, N. Schroeder and
F. Glorius, Adv. Synth. Catal. 2014, 356, 1443.
For reviews, see: (a) G. Song, F. Wang and X. Li, Chem. Soc.
Rev. 2012, 41, 3651; (b) T. Satoh and M. Miura, Chem. Eur. J.
2010, 16, 11212; (c) L. Ackermann, Acc. Chem. Res. 2014, 47,
281; (d) M. Gulías and J. L. Mascareñas, Angew. Chem. Int. Ed.
2016, 55, 11000; (e) Y. Yang, K. Li, Y. Cheng, D. Wan, M. Li and
J. You, Chem. Commun. 2016, 52, 2872; (f) S. Prakash, R.
Kuppusamy and C.-H. Cheng, ChemCatChem 2018, 10, 683.
For rhodium-catalyzed annulation with external oxidants, see:
(a) S. Mochida, N. Umeda, K. Hirano, T. Satoh and M. Miura,
Chem. Lett. 2010, 39, 744; (b) T. K. Hyster and T. Rovis, J. Am.
Chem. Soc. 2010, 132, 10565; (c) G. Song, D. Chen, C.-L. Pan,
R. H. Crabtree and X. Li, J. Org. Chem. 2010, 75, 7487; (d) N. S.
Upadhyay, V. H. Thorat, R. Sato, P. Annamalai, S.-C. Chuang
and C.-H. Cheng, Green Chem. 2017, 19, 3219; (e) L. Song, G.
Tian, Y. He and E. V. Van der Eycken, Chem. Commun. 2017,
of the standard annulation products might follow either the
traditional Ru(II)-Ru(0)-Ru(II) pathway involving alkyne insertion
prior to N-O bond cleavage, or the newly proposed Ru(II)-
Ru(IV)-Ru(II) mechanism featuring N-O cleavage preceding
alkyne insertion. The balance between the two mechanisms and
between the inverse and standard routes will depend on the
catalyst (e.g. Rh(III) vs. Ru(II)), the nature of the substrate (alkyl
chain or benzylidene linker) and other factors (e.g, solvents,
additives). Kinetic studies and theoretical studies suggest that
C-H bond cleavage process is not involved in the rate-limiting
step.
2
3
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Liangliang Song appreciates the Postdoctoral Mandate (PDM) of
KU Leuven. Xiaoyong Zhang appreciates the China Scholarship
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
53, 12394; (f) P. Tao and Y. Jia, Chem. Commun. 2014, 50,
7367; (g) J. Zheng, S. B. Wang, C. Zheng and S. L. You, Angew.
Chem. 2017, 129, 4611; (h) J. Li, J. Liu, J. Yin, Y. Zhang, W. Han,
9
(a) C. Q. Wang, Y. Zhang and C. Feng, Angew. Chem. Int. Ed.
View Article Online
2017, 56, 14918; (b) Z. Zhou, G. Liu, Y. Shen and X. Lu, Org.
DOI: 10.1039/D0SC04434B
Chem. Front. 2014, 1, 1161.
J. Lan, D. Wu, Z. Bin and J. You, J. Org. Chem. 2019, 84, 15697; 10 (a) S. Vasquez-Cespedes, X. Wang and F. Glorius, ACS Catal.
(i) L. Song, G. Tian, A. Blanpain, L. Van Meervelt and E. V. Van
der Eycken, Adv. Synth. Catal. 2019, 361, 4442.
For ruthenium-catalyzed annulation with external oxidants,
see: (a) L. Ackermann, A. V. Lygin and N. Hofmann, Angew.
Chem. Int. Ed. 2011, 50, 6379; (b) L. Ackermann, A. V. Lygin
and N. Hofmann, Org. Lett. 2011, 13, 3278; (c) R. P. Tulichala,
M. Shankar and K. K. Swamy, J. Org. Chem. 2017, 82, 5068; (d)
2018, 8, 242; (b) Z. Wang, P. Xie and Y. Xia, Chin. Chem. Lett.
2018, 29, 47; (c) G. Duarah, P. P. Kaishap, T. Begum and S.
Gogoi, Adv. Synth. Catal. 2019, 361, 654; (d) L. Xu, Q. Zhu, G.
Huang, B. Cheng and Y. Xia, J. Org. Chem. 2012, 77, 3017; (e)
B. Ling, Y. Liu, Y.-Y. Jiang, P. Liu and S. Bi, Organometallics
2019, 38, 1877; (f) Y.-F. Yang, K. N. Houk and Y.-D. Wu, J. Am.
Chem. Soc. 2016, 138, 6861.
4
5
H. Lin, S.-S. Li, L. Dong and Org. Biomol. Chem. 2015, 13, 11 (a) S. Huh, S. Y. Hong and S. Chang, Org. Lett. 2019, 21, 2808;
11228; (e) D. N. Garad and S. B. Mhaske, J. Org. Chem. 2019,
84, 1863.
(b) E. Azek, M. Khalifa, J. Bartholoméüs, M. Ernzerhof and H.
Lebel, Chem. Sci. 2019, 10, 718.
For rhodium-catalyzed annulation with internal oxidants, see: 12 (a). In the traditional mechanism, the acetic acid has a
(a) N. Guimond, C. Gouliaras and K. Fagnou, J. Am. Chem. Soc.
2010, 132, 6908; (b) N. Guimond, S. I. Gorelsky and K. Fagnou,
J. Am. Chem. Soc. 2011, 133, 6449; (c) S. Rakshit, C.
Grohmann, T. Besset and F. Glorius, J. Am. Chem. Soc. 2011,
133, 2350; (d) H. Wang, C. Grohmann, C. Nimphius and F.
Glorius, J. Am. Chem. Soc. 2012, 134, 19592; (e) X. Xu, Y. Liu
and C. M. Park, Angew. Chem. Int. Ed. 2012, 51, 9372; (f) L.
Song, G. Tian and E. V. Van der Eycken, Mol. Catal. 2018, 459,
129; (g) X. Wu, B. Wang, Y. Zhou and H. Liu, Org. Lett. 2017,
19, 1294; (h) S. Lee, N. Semakul and T. Rovis, Angew. Chem.
Int. Ed. 2020, 59, 4965; (i) M. Xu, C. Wang, W. Jiang and B.
Xiao, Adv. Synth. Catal. 2020, 362, 1706; (j) T. J. Saiegh, H.
Chédotal, C. Meyer and J. Cossy, Org. Lett. 2019, 21, 8364; (k)
E. Tan, O. Quinonero, M. Elena de Orbe and A. M. Echavarren,
ACS Catal. 2018, 8, 2166; (l) H. Gao, M. Sun, H. Zhang, M. Bian,
M. Wu, G. Zhu, Z. Zhou and W. Yi, Org. Lett. 2019, 21, 5229;
(m) T. Yamada, Y. Shibata, S. Kawauchi, S. Yoshizaki and K.
negligible effect on the barrier height of the rate determining
alkyne insertion step, since TS2 in the presence of acid
(Scheme S2 in SI) is calculated to be 30.7 kcal mol-1,
comparable to the one (30.1 kcal mol-1) in the absence of acid;
(b) The pathway with alkyne insertion into the Ru-N bond
prior to C-C reductive elimination is less favorable with a
barrier of 35.4 kcal mol-1; (c) After alkyne insertion into the
Ru-C bond, the pathway with N-O oxidative cleavage prior to
reductive elimination involves TS13 and TS14 (>23.2 kcal mol-
1), higher in energy than TS3 (19.5 kcal mol-1) and TS4. (d)
Alkyne insertion following the intramolecular annulation to
inverse annulation product is calculated to involve a transition
state more than 10.0 kcal mol-1 (Scheme S13) higher than that
to standard annulation product. Thus, the formation of
inverse annulation product cannot be explained by the
tradition mechanism. More details can be found in Supporting
Information.
Tanaka, Chem. Eur. J. 2018, 24, 5723; (n) J. F. Tan, C. T. 13 The effect of methanol was explicitly considered in the N-O
Bormann, K. Severin and N. Cramer, ACS Catal. 2020, 10,
3790; (o) W. J. Cui, Z. J. Wu, Q. Gu and S. L. You, J. Am. Chem.
Soc. 2020, 142, 7379.
For ruthenium-catalyzed annulation with internal oxidants,
see: (a) B. Li, H. Feng, S. Xu and B. Wang, Chem. Eur. J. 2011,
17, 12573; (b) L. Ackermann and S. Fenner, Org. Lett. 2011,
13, 6548; (c) H. Huang, S. Nakanowatari and L. Ackermann,
Org. Lett. 2017, 19, 4620; (d) X. Wu, B. Wang, S. Zhou, Y. Zhou
cleavage step. In absence of acetic acid, the methanol could
also transfer its hydrogen to neutralize alkoxyl oxygen atom
of the substrate, and result into a negative methoxyl group.
However, the calculated barrier is much higher (>46.9 kcal
mol-1) than that of the acetic acid assisted mechanism
(Scheme S9), which could be explained by the stronger acid of
acetic acid to promote proton transfer, and the more
stabilization of negative charge in the carboxylate group.
6
7
and H. Liu, ACS Catal. 2017, 7, 2494; (e) F. Yang and L. 14 In the new suggested mechanism, once N-O cleavage
Ackermann, J. Org. Chem. 2014, 79, 12070; (f) E. Tan, A. I.
Konovalov, G. A. Fernández, R. Dorel and A. M. Echavarren,
Org. Lett. 2017, 19, 5561.
completes, the barriers of alkyne insertion and reductive
elimination in the absence of the acetic acid are at least 6.0
kcal mol-1 higher in energy (SI, Scheme S11), than that of the
route (H2 to J2 in Scheme 6) in the presence of the acetic acid.
(a) S. Y. Hong, J. Jeong and S. Chang, Angew. Chem. Int. Ed.
2017, 56, 2408; (b) L. Song, X. Zhang, G. Tian, K. Robeyns, L.
Van Meervelt, J. N. Harvey and E. V. Van der Eycken, Mol.
Catal. 2019, 463, 30; (c) Y. Fukui, P. Liu, Q. Liu, Z.-T. He, N.-Y.
Wu, P. Tian and G.-Q. Lin, J. Am. Chem. Soc. 2014, 136, 15607;
(d) L. Song, G. Tian, J. Van der Eycken and E. V. Van der Eycken,
Beilstein J. Org. Chem. 2019, 15, 571; (e) J.-P. Krieger, D.
Lesuisse, G. Ricci, M.-A. Perrin, C. Meyer and J. Cossy, Org.
Lett. 2017, 19, 2706; (f) K. K. Gollapelli, S. Kallepu, N.
Govindappa, J. B. Nanubolu and R. Chegondi, Chem. Sci. 2016,
7, 4748; (g) M. Shankar, K. Ghosh, K. Mukherjee, R. K. Rit and
A. K. Sahoo, Org. Lett. 2018, 20, 5144.
(a) J.-Q. Wu, S.-S. Zhang, H. Gao, Z. Qi, C.-J. Zhou, W.-W. Ji, Y.
Liu, Y. Chen, Q. Li, X. Li and H. Wang, J. Am. Chem. Soc. 2017,
139, 3537; (b) X. Wang, T. Gensch, A. Lerchen, C. G. Daniliuc
and F. Glorius, J. Am. Chem. Soc. 2017, 139, 6506; (c) S. H.
Park, J. Kwak, K. Shin, J. Ryu, Y. Park and S. Chang, J. Am. Chem.
Soc. 2014, 136, 2492; (d) Y. F. Liang, L. Yang, T. Rogge and L.
Ackermann, Chem. Eur. J. 2018, 24, 16548; (e) M. Simonetti,
D. M. Cannas, X. Just-Baringo, I. J. Vitorica-Yrezabal and I.
Larrosa, Nat. Chem. 2018, 10, 724.
8
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Chemical Science
Page 8 of 8
View Article Online
DOI: 10.1039/D0SC04434B
O
O
NH
R2
R1
O
[Ru(p-cymene)Cl2]2
N
R1
H
n
n = 0, 1, 2, 3, 4
Ru(II)-Ru(IV)-Ru(II)
n
N-O bond cleavage
prior to alkyne insertion
R2
OH
O
O
R1
N
R1
Cy
N
O
O
RuIV
RuIV
Cy
O
O
R2
H
O
H
R2
O
n
n
A highly selective ruthenium-catalyzed C-H activation/annulation through a pathway involving N-
O bond cleavage prior to alkyne insertion is developed.