Palladium-Catalyzed Site-Selective [3+2] Annulation via Benzylic and meta C?H Bond Activation

Article abstract of DOI:10.1002/anie.202015054

The palladium-catalyzed [3+2] annulation of aromatic amides with maleimides via the activation of ortho benzylic C?H and meta C?H bonds is reported. Carboxamide and anilide type substrates that contain a 2-methylthiophenyl group both participate in this [3+2] annulation, indicating that the presence of a 2-methylthiophenyl directing group is a key for the success of the reaction. The first C?H bond activation at the benzylic C?H bond is followed by a second C?H bond activation at the meta C?H bond to give five-membered cyclic products. The cleavage of these C?H bonds is irreversible.

Full text of DOI:10.1002/anie.202015054

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Palladium-Catalyzed Site-Selective [3+2] Annulation via Benzylic
and meta C-H Bond Activation
Authors: Naoto Chatani and Qiyuan He
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.202015054
Link to VoR: https://doi.org/10.1002/anie.202015054

10.1002/anie.202015054
Angewandte Chemie International Edition
COMMUNICATION
Palladium-Catalyzed Site-Selective [3+2] Annulation via Benzylic
and meta C-H Bond Activation
Qiyuan He and Naoto Chatani*
Abstract: The palladium-catalyzed [3+2] annulation of aromatic
amides with maleimides via the activation of ortho benzylic C-H and
meta C-H bonds is reported. Carboxamide and anilide type substrates
that contain a 2-methylthiophenyl group both participate in this [3+2]
annulation, indicating that the presence of a 2-methylthiophenyl
directing group is a key for the success of the reaction. The first C-H
bond activation at the benzylic C-H bond is followed by a second C-H
bond activation at the meta C-H bond to give five-membered cyclic
products. The cleavage of these C-H bonds is irreversible.
harsh condition or substrates with special structures.[8] Although
benzylic C-H functionalization reactions, which proceed through a
six-membered metallacycle have been widely studied, most
examples involve C-H bond functionalization reactions at
secondary and tertiary benzylic positions, where radical species
are easily generated.[9] However, to the best of our knowledge,
there are no examples of [3+2] annulation reactions that proceed
via the activation of both a primary benzylic C-H bond and a meta
C-H bond.[10] We herein report on the palladium-catalyzed site-
selective [3+2] annulation of secondary aromatic amides with
maleimides in which both the benzylic C-H bond and meta C-H
bond participate in the reaction (Figure 1c). This reaction was
achieved only by the use of a N,S-bidentate chelation system,
which was first used by Daugulis in 2010.[11] In the present
reaction, none of the products arising from ortho-C-H/N-H
annulation, alkylation products at the ortho C-H bond, and
alkylation products at a benzylic C-H bond were observed.
Furthermore, this [3+2] annulation reaction can be applied to
anilide type substrates. The presence of both an NH bond and a
SMe group in the substrates is essential for the reaction to
proceed.
Catalytic annulation reactions via C-H bond activation are now
recognized as one of the more attractive methods for the
synthesis of cyclic compounds because the reaction is
straightforward and highly atom efficient.[1] The catalytic [4+2]
annulation of aromatic amides or carboxylic acids with alkynes or
alkenes, which involves the activation of the ortho C-H bond and
the cleavage of N-H or O-H bonds have been extensively studied
in the last decades (Figure 1a).[2] Compared with C-H annulation
via mono C-H bond activation, the preparation of cyclic
compounds through double C-H activation is more attractive and
challenging because the reaction can be used to construct
complex frameworks which might be difficult to prepare by other
existing methods. The [2+2+2] annulation with alkynes, leading to
the production of naphthalene derivatives, is one of the most
extensively studied C-H annulation reaction (Figure 1b).[3] On the
other hand, there are only a few examples of the construction of
four or five-membered annulation compounds via [2+2][4] or
[3+2][5] annulation involving double C-H bond activation. In 2019,
Li reported on the rhodium-catalyzed [3+2] annulation of aromatic
amides with 7-azabenzonorbornadienes, in which a nitrogen atom
bearing an electron-withdrawing group functions as one coupling
atom to form five-membered rings.[5a] Yan and Cao reported on
the visible-light-induced intermolecular [3+2] cycloaddition of
indolizines and alkynes.[5b] Yu recently reported on a Pd-catalyzed
[3+2] annulation of aliphatic amides with maleimides, which
involves dual C(sp3)-H bond activation.[6]
a. [4+2] annulation via mono C-H activation
O
O
X
H
[M]
X
+
R'
R'
H
X = NR, O
R'
R'
many examples
b. [2+2+2], [2+2], [3+2] annulation via double C-H activation
DG
DG
DG
DG
R'
[M]
RN
H
R'
R'
H
R'
many examples
Yu (2015)
O
Li (2019)
O
O
H
[Pd]
R
R
NR''
O
Yu (2020)
N
H
N
Me R'
Me R'
In the chelation-assisted transition-metal catalyzed C-H
activation of aromatic compounds, most of the reactions occur at
the ortho C-H bond because five-membered metallacycles are
kinetically and thermodynamically favored.[7] The formation of six-
membered metallacycles are less favored and typically require
c. Present work: [3+2] annulation via double C-H activation
benzamide type [3+2] annulation
no reaction
[Pd]
H
O
H
O
O
N
H
N
+
NR
SMe
H
SMe
H
O
H
H
H
O
O
N
R
anilide type [3+2] annulation
O
[*]
Q. He, Prof. Dr. N. Chatani
Department of Applied Chemistry, Faculty of Engineering
Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: Chatani@chem.eng.osaka-u.ac.jp
O
O
H
O
[Pd]
N
H
H
N
H
+
NR
RN
MeS
H
MeS
H
O
O
Supporting information for this article is given via a link at the end of
the document.
Figure 1. Transition-metal-catalyzed C-H annulation reactions.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202015054
Angewandte Chemie International Edition
COMMUNICATION
After optimizing the reaction conditions using 2-methyl-N-(2-
(methylthio)phenyl)benzamide (1a) (see SI for more details), the
following reaction conditions were determined as standard
reaction conditions: 1a (0.3 mmol), maleimide (2.2 equiv),
Pd(OPiv)2 (15 mol%), CuO (2 equiv), PivOH (4 equiv) and NaOTf
(1 equiv) in 1,1,2,2-tetrachloroethane (TCE, 1 mL) at 160 °C for
18 h.
applicable to the 2-methyl-1-naphthamide 1m to give the
corresponding product 2m. Curiously, in the reaction of 1d with
N-methoxycarbonylmaleimide as a coupling partner, the free N-H
product 2da was selectively formed. The reaction with the free N-
H maleimide gave 2da in low yield probably because the free N-
H maleimide is only sparingly soluble in TCE. Using N-
Methoxycarbonylmaleimide can be used as an alternative of free
N-H maleimide.
Encouraged by these results, we hypothesized that similar
transformations would occur when anilide type substrates 3 are
used, in which a 2-thiomethylbenzoyl group is attached to the
aniline nitrogen. Gratifyingly, similar [3+2] annulation products
were obtained under reaction conditions similar to those used in
the reaction of benzamides 1 (Scheme 2). [3+2] Annulation of
anilide type substrates also showed a high functional group
compatibility.
O
Pd(OPiv)2 15 mol%
CuO 2 equiv
PivOH 4 equiv
NaOTf 1 equiv
DG1
O
O
R
+
N
N
R
R
H
H
TCE, 160 °C, 18 h
H
SMe
O
O
O
N
R
2
1
0.3 mmol
0.66 mmol
O
O
O
O
Pd(OPiv)2 15 mol%
CuO 2 equiv
PivOH 4 equiv
NaOTf 1 equiv
Me
F
Cl
R
DG1
DG1
DG1
DG1
O
O
R
H
O
DG2
O
N
+
N
N
Me
H
H
TCE
160 °C, 18 h
MeS
MeN
O
O
O
O
O
H
O
O
O
O
N
N
N
N
3
0.3 mmol
0.66 mmol
4
Me
Me
Me
Me
iPr
CF3
Me
2a 66%
2b 60%
2c 75%
2d 71%
DG2
O
DG2
DG2
DG2
DG2
O
O
DG2
O
O
O
O
O
N
H
N
N
H
N
H
H
Br
F3C
MeO
O2N
MeN
MeN
MeN
DG1
DG1
DG1
DG1
MeN
O
O
O
O
4d 75%
4c 40%
4a 50%
OMe
4b 42%
O
O
O
O
Cl
Br
F
O
O
O
O
N
N
N
N
Me
Me
Me
Me
DG2
O
O
DG2
O
DG2
O
2e 62%[a]
2f 80%
2g 69%
2h 78%
N
H
N
H
N
N
H
H
MeN
MeN
MeN
MeN
F
O
O
O
NO2 O
O
O
O
O
4e 50%[a]
4h
4g 65%
55%
4f 75%
DG1
DG1
DG1
DG1
COMe
COOMe
Me
F
F
Me
O
DG2
DG2
O
O
DG2
O
O
O
O
O
N
N
O
N
H
O
O
O
N
H
N
N
N
N
H
H
Me
Me
Me
Me
MeN
MeN
MeN
MeN
2l 46%
2i 52%
2j 44%
2k 43%
O
O
O
O
41%[a]
F
4j
4l
35%
4k
4i
58%
DG2
67%
O
O
O
Cl
NC
Cl
DG1
DG1
O
DG2
O
DG1
O
DG2
O
N
N
N
H
H
H
MeN
MeN
MeN
N
COOMe
O
N
O
O
O
O
O
O
N
O
O
H
4n
53%
O
Ph
4m
4o
45%
45%
N
Me
2da 45%
2aa 61%
2m 30%
Scheme 1. Pd(II)-catalyzed [3+2] of benzamide type substrates. [a] Without
NaOTf.
Scheme 2. Pd(II)-catalyzed [3+2] of anilide type amides. [a] Without NaOTf.
The scope of the reaction for aromatic amides bearing various
substituents is shown in Scheme 1. The reaction of 1a under the
standard reaction conditions gave 2a as a single diastereomer in
66% isolated yield. The reaction shows a high functional group
tolerance. Halogen atoms, such as fluoro, chloro, and even bromo
were tolerated in this catalytic reaction to give 2c-2e, 2j, and 2l.
Nitro-substituted amides 1h and 1k also participated in the
reaction to give good yields of the corresponding annulation
products 2h and 2k. 4-Substitued aromatic amides also gave the
corresponding annulation products 2i and 2j, even though the
meta C-H bonds are sterically hindered. The reaction was also
To gain insights into the mechanism for this [3+2] annulation
reaction, some mechanistic experiments were conducted. We first
examined the effect of directing groups (Scheme 3a). No
expected annulation products were obtained when the NH group
in the substrate was changed to an O atom or when a SMe group
was changed to an OMe group. The same results were observed
in the case of anilide type substrates. These results indicate that
both the presence of NH and SMe groups are crucial for this
transformation to proceed. Deuterium-labeling experiments were
carried out in the absence of maleimide (Scheme 3b). In the
reaction of 1a-d7, unexpectedly, no H/D exchange was detected
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202015054
Angewandte Chemie International Edition
COMMUNICATION
a. Ineffective Directing groups
determining step. A competition experiment was carried out to
evaluate the electronic effect of a substituent on the aromatic
amides. The reaction of an equal molar ratio of 1f and 1g under
the standard conditions gave 2f and 2g in 51% and 33% yields,
respectively. This result indicates that the presence of an
electron-withdrawing group causes a slight increase in substrate
reactivity. Finally, a radical trap experiment was performed
(Scheme 3d). When the reaction was carried out in the presence
of 1 equiv of TEMPO, 2c was produced in 55% yield, indicating
that the reaction does not proceed through a radical mechanism.
A proposed mechanism for the [3+2] annulation reaction of
aromatic amides, based on the results of mechanistic
experiments is shown in Scheme 4. A six-membered palladacycle
A is generated through the coordination of 1a to the palladium(II)
complex followed by the activation of a benzylic C-H bond, the
latter step being irreversible. The syn-insertion of the maleimide
into a Pd-C bond in A and protonation of the Pd-N bonds by pivalic
acid gives intermediate B. Activation of the meta C-H bond (3-
position) gives another six-membered palladacycle C. Finally, the
annulation product 2a is formed through reductive-elimination
with the palladium catalyst being regenerated by oxidation by
copper pivalate. H/D exchange at both the 5- and 6-postion was
observed in the recovered starting amide (Scheme 3b). H/D
exchange at the 6-postion commonly occurs in many C-H
functionalization reactions that involve aromatic systems. To
explain the unexpected result of the deuterium-labeling
experiment in which H/D exchange occurred at the 5-position, we
propose the intermediacy of two intermediates D and F. The
formation of D is known to be kinetically favored because of the
formation of a five-membered palladacycle through ortho C-H
bond activation. However, the insertion of the maleimide into the
Pd-C bond in a five-membered palladacycle in D is energetically
unfavorable.[10] An alternative route for H/D exchange at the 5-
position proceeds through the Pd-Cu complex E, in which a
copper atom is coordinated with the sulfur atom and a pivalate ion
functions as a bridging ligand between palladium and copper.[12]
Because these steps are reversible, H/D exchange took place at
both the 5- and 6-poitions.
O
O
O
O
O
O
N
N
H
H
SMe
OMe
MeS
MeO
b. Deuterim-labeling experiments
0.8 H
Pd(OPiv)2 15 mol%
CuO 2 equiv
PivOH 4 equiv
NaOTf 1 equiv
D/H
O
O
6
0.5 H
D/H
N
H
5
N
D4
H
SMe
0 H
TCE 1mL
160 °C, 3 h
SMe
D
CD3
3
CD3
D
0 H
1a-d7
D
0 H
O
D
D
D
D4
O
standard conditions
3 h
N
H
N
H
MeS
CD3
0 H
MeS
CD3
0 H
3a-d7
0.8 H
D/H
O
0.2 H
O
D/H
D
O
N
H
D
D
N
standard conditions
18 h
SMe
+
D4
H
NMe
SMe
CD3
O
O
O
N
1a-d7
0.3 mmol
0.66 mmol
Me
33%
D
D
O
D
O
O
O
D4
standard conditions
18 h
O
N
H
MeS
+
NMe
N
H
CD3
D
MeN
MeS
34%
O
D
3a-d7
0.3 mmol
0.66 mmol
c. Competitive experiment
O
O
F3C
O
N
H
O
NMe
0.66 mmol
F3C
SMe
MeO
+
DG1
CH3
DG1
O
1f
0.3 mmol
standard conditions
3 h
+
O
O
O
O
N
O
N
MeO
Me
Me
N
H
SMe
2g
CH3
33%
2f
51%
1g
0.3 mmol
d. Radical trap experiment
O
Pd(OPiv)2 15 mol%
O
N
F
CuO 2 equiv
PivOH 4 equiv
NaOTf 1 equiv
TEMPO 1 equiv
DG1
O
O
O
Pd SMe
F
6
N
5
+
H
NMe
D
N
H
SMe
H
O
TCE 1mL
160 °C, 18 h
SMe
O
N
Me
O
O
O
H
H
6
1c
0.3 mmol
0.66 mmol
2c
55%
5
N
O
N
O
N
H
Cu
O
SMe
R
SMe
5
2a
CuO + PivOH
1a
Pd
Pd(OPiv)2
O
O
Scheme 3. Mechanistic studies.
tBu
O
tBu
Cu(OPiv)2
O
PivOH
E
at the benzylic position and at the 3-position, but a significant
amount of H/D exchange took place at the ortho position (6-
position) (0.8 H) and the 5-position (0.5 H). These results indicate
that the activation of the 5-and 6-positions is very fast and
reversible, however these processes are a non-productive route.
In contrast, the activation of the benzylic C-H bond and the C-H
bond at the 3-position is irreversible. In sharp contrast to 1a-d7,
no H/D exchange was detected in the anilide substrate 3a-d7.
Essentially the same results were observed even in the presence
of maleimide. It is particularly noteworthy that the annulation
product was obtained in only 33% yield when the deuterated
substrate 1a-d7 was used, while 1a gave 2a were produced in
66% yield, indicating that the C-H bond cleavage is the rate
O
N
H
N
SMe
Pd SMe
H
Pd
O
C
A
H
NR
O
O
N
H
SMe
PivOH
+ PivOH
3
H
O
N
O
O
H
R
Pd
H
PivO
NR
O
B
Scheme 4. Plausible mechanism.
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202015054
Angewandte Chemie International Edition
COMMUNICATION
Morris, S. Wright, G. Meyer, T. Clark, J. Org. Chem. 2020, DOI:
10.1021/acs.joc.0c01706.
In summary, we report herein on the site-selective Pd(II)-
catalyzed [3+2] annulation of aromatic amides with maleimides
via double C-H bond activation. This [3+2] annulation can occur
on both of benzamide type and anilide type substrates, in which
the presence of both N-H and SMe moieties is required for the
reaction to proceed. The activation of the benzylic C-H bond and
the meta C-H bond is irreversible.
[10] A [3+2] annulation product was formed as a by-product. Q. He, Y. Ano,
N. Chatani, Chem. Commun. 2019, 55, 9983-9986.
[11] D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965-3972.
[12] a) L. Fang, T. Sanit-Denis, B. H. Taylor, S. Ahlquist, K. Hong, S. Liu, L.
Han, K. N. Houk, J.-Q. Yu, J. Am. Chem. Soc. 2017, 139, 31, 10702–
10714. (b) W. Feng, T. Wang, D. Liu, X. Wang, Y. Dang, ACS Catal.
2019, 9, 6672–6680.
Acknowledgements
This work was supported by a Grant in Aid for Specially Promoted
Research by MEXT (No. 17H06091) and The Naito Foundation.
QH gratefully acknowledges financial support from the China
Scholarship Council (No. CSC201908050207).
Keywords: [3+2] annulation • palladium • C-H activation •
Palladium • site-selectivity
[1]
For recent selected reviews dealing with the synthesis of cyclic
compounds through C-H annulation, see: a) Peneau, A; Guilou, C.;
Chabaude, L. Eur. J. Org. Chem. 2018, 5777-5794; b) Y. Xiang, C. Wang,
Q. Ding, Y, Peng. Adv. Synth. Catal. 2019, 361, 919–944; c) Y. Nishi, M.
Miura, ACS. Catal. 2020, 10, 9747-9757; d) O. Baudoin, Angew. Chem.
Int. Ed. 2020, 59, 17798-17809; e) A. Marchese, E. Larin, B. Mirabi, M.
Lautens, Acc. Chem. Res. 2020, 53, 1605−1619; f) Woźiak, L.; Tan, J.-
F.; Nguyen, Q.-H.; du Vigné, A. M.; Smal, V.; Cao, Y.-X.; Cramer, N.
Chem. Rev. 2020, 120, 10516-10543; g) Lam, H.; Lautens, M. Synthesis
2020, 52, 2427-2449; h) Qin, J.-H.; Li, J.-H.; An, D.-L. Synthesis. DOI:
10.1055/s-0040-1707355
[2]
For recent reviews of [4+2] annulation reactions, see: a) Y. Kommagalla,
N. Chatani, Chem. Rev. 2017, 350, 117-135; b) C. Sambiagio, D.
Schönbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T.
Wiesinger, M. Zia, J. Wencel-Delord, T. Besset, B. W. Maes, M.
Schnürch, Chem. Soc. Rev. 2018, 47, 6603-6743; c) S. Prakash, R.
Kuppusamy, C.-H. Cheng, ChemCatChem 2018, 10, 683-705; d) P.
Gandeepan, T. Mueller, D. Zell, G. Cera, S. Warratz, L. Ackermann,
Chem. Rev. 2019, 119, 2192-2452.
[3]
For, recent reviews of [2+2+2] annulation reactions, see: a) M. Feng, X.
Jiang, Synthesis 2017, 49, 4414-4433; b) S. Rej, Y. Ano, N. Chatani,
Chem. Rev. 2020, 120, 1788-1887.
[4]
[5]
X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu, S. Li, K. M. Engle, J.-Q. Yu,
Nature 2015, 519, 334-338.
For selected recent reports on [3+2] C-H annulation reactions, see: a) R.
Mi, G. Zheng, Z. Qi, X. Li, Angew. Chem. Int. Ed. 2019, 58, 17666–
17670; b) Y. Zhang, Y. Yu, B.-B. Liang, Y.-Y. Pei, X. Liu, H.-G. Yang, H.
Cao, J. Org. Chem. 2020, 85, 10719-10727.
[6]
[7]
H. Park, J.-Q. Yu, J. Am. Chem. Soc. 2020, 142, 16552-16556.
For selected examples of the isolation of five-membered metallacycles,
see: a) G. He, S.-Y. Zhang, W. Nack, Q. Li, G. Chen, Angew. Chem. Int.
Ed. 2013. 52, 11124-11128; b) M. Iwasaki, W. Kaneshika, Y. Tsuchiya,
K. Nakajima, Y. Nishihara, J. Org. Chem. 2014, 79, 11330-11338; c) Z.
Liu, X. Li, T. Zeng, K. M. Engle, ACS Catal. 2019, 9, 3260-3265; d) Z.
Bai, Z. Bai, F. Song, H. Wang, G. Chen, G. He, ACS. Catal. 2020, 10,
933-940.
[8]
[9]
For selected recent examples of C-H functionalization via a six-
membered metallacycle, see: a) Y.-Q. Chen, Z. Wang, Y. Wu, S.
Wisniewski, J. Qiao, W. Ewing, M. Eastgate, J.-Q. Yu, J. Am. Chem. Soc.
2018, 140, 17884-17894; b) K. Meng, T. Li, C. Yu, C. Shen, J. Zhang, G.
Zhong, Nat. Commun. 2019, 10, 1-10; c) B. S. Schreib, E. M. Carreira, J.
Am. Chem. Soc. 2019, 141, 8758-8763; d) L. Liu, Y.-H. Liu, B.-F. Shi,
Chem. Sci. 2020, 11, 290-294.
For selected reviews of benzylic C-H functionalization reactions, see: a)
F. Wang, P. Chen, G. Liu, Acc. Chem. Res. 2018, 51, 2036-2046; b) R.
Yazaki, T. Oshima, Tetrahedron Lett. 2019, 60, 151225-151237; c) K.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202015054
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
O
N
R
H
O
R
SMe
(DG1)
O
DG1
or
H
H
R
DG2
O
N
cat. Pd(II)
H
N R
or
+
RN
O
O
O
R
O
O
N
R
H
N
H
H
MeS
(DG2)
The palladium-catalyzed site-selective [3+2] annulation of amides with maleimides via the activation of ortho benzylic C-H and meta
C-H bonds is reported. The presence of a 2-methylthiophenyl directing group is a key for the success of the reaction.
5
This article is protected by copyright. All rights reserved.