Rh/Cu-Catalyzed Ketone β-Functionalization by Merging Ketone Dehydrogenation and Carboxyl-Directed C-H Alkylation

Article abstract of DOI:10.1021/acscatal.8b00923

An efficient Rh/Cu-catalyzed method has been developed for the direct β-arylation or alkenylation of ketones using (hetero)aryl or alkenyl carboxylic acids as coupling partners. This direct ketone β-functionalization reaction proceeded via the merging of Cu-catalyzed ketone dehydrogenative desaturation and Rh-catalyzed carboxyl-directed C-H alkylation, exhibiting a broad substrate scope for both coupling partners. TEMPO proved to be essential for both dehydrogenation process and generation of the active Rh catalyst for C-H activation.

Full text of DOI:10.1021/acscatal.8b00923

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Rh/Cu-catalyzed Ketone #-Functionalization via Merging
Ketone Dehydrogenation and Carboxyl-directed C-H Alkylation
Hongyi Li, Quandi Jiang, Xiaoming Jie, Yaping Shang, Yuanfei Zhang, Lukas J. Gooßen, and Weiping Su
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00923 • Publication Date (Web): 20 Apr 2018
Downloaded from http://pubs.acs.org on April 20, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
ACS Catalysis
1
2
3
4
5
6
7
8
9
Rh/Cuꢀcatalyzed Ketone βꢀFunctionalization via Merging Ketone Deꢀ
hydrogenation and Carboxylꢀdirected CꢀH Alkylation
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hongyi Li, †,‡ Quandi Jiang, †,‡ Xiaoming Jie, † Yaping Shang, † Yuanfei Zhang, † Lukas J. Goossen*,§and
Weiping Su*,†
†State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Acad-
emy of Sciences, Fuzhou 350002, People’s Republic of China
‡University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
§Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum, Germany
ABSTRACT: An efficient Rh/Cu-catalyzed method has been developed for the direct β-arylation or alkenylation of ketones
using (hetero)aryl or alkenyl carboxylic acids as coupling partners. This direct ketone β-functionalization reaction proceed-
ed via merging Cu-catalyzed ketone dehydrogenative desaturation and Rh-catalyzed carboxyl-directed C-H alkylation, ex-
hibited a broad substrate scope for both coupling partners. TEMPO proved to be essential for both dehydrogenation process
and generation of the active Rh-catalyst for C-H activation.
KEYWORDS: Dehydrogenation • Cascade reaction • Ketone • Carboxylic acid • Alkylation
b,
c
β-arylated saturated ketones are the structural motifs
that are embedded in many natural products and bioactive
compounds.1 Consequently, efficient methods for con-
structing such structures are always the goal sought after
by chemists. Traditionally, β-arylated ketone architectures
arylation of α-substituted esters10a,
and N-Boc-
piperidines with aryl halides,10d and Pihko’s β-C-H indola-
tion of β-keto esters.11 As for the tandem sequence to ac-
cess β-arylated ketone, Dong and Li have established the
Pd-catalyzed β-arylation reaction of ketones with aryl io-
dides,12a diaryliodonium salts12b and arylboronic acids12c
via ketone dehydrogenative desaturation respectively
(Scheme 1b). Newhouse and co-workers have developed
are
constructed through the
aldol condensa-
tion/hydrogenation two-step procedure,2 or rhodium-
catalyzed Michael addition of aryl organometallic reagents
to enones.3 These conventional methods either require
harsh reaction conditions such as strong bases that limit
substrate scope, or employ the reactants that are often
prepared by way of multi-step synthetic sequences, which
prompts chemists to invent the efficient methods that pro-
duce β-arylated ketones in atom- and step-economical
manner staring from simple reactants. Recently, a break-
through has been achieved in the development of the bi-
dentate directing group-assisted β-C(sp3)-H activation
reaction of carbonyl compounds.4 In this context, Yu and
the
cascade
Pd-catalyzed
ketone
dehydrogena-
tion/organocuprate conjugate addition process to realize
β-functionalization or α,β-difunctionalization of cyclic ke-
tones, including ketone β-arylation.13 Very recently, our
group has discovered a Cu-catalyzed radical-based ketone
dehydrogenative desaturation process that could merge
conjugate addition of nucleophiles to the newly formed
enones to furnish β-functionalized saturated ketones.14
Herein, we report a novel method for facile synthesis of β-
arylated or β-alkenylated ketones via merging Cu(II)-
catalyzed ketone dehydrogenation and Rh-catalyzed car-
boxyl-directed ortho-C-H alkylation of (hetero)aryl- or
alkenyl carboxylic acids with enone (Scheme 1c). 15
4a
co-workers have realized β-C(sp3)-H arylation reaction
of ketones with aryl iodides as arylating reagents (Scheme
1a) by using amino acid as a transient directing group.
MacMillan and co-workers have demonstrated that merg-
ing the organocatalysis and photoredox catalysis enabled
β-C(sp3)-H arylation reaction of aliphatic ketones using
dicyanobenzene as an arylating reagent (Scheme 1b).5
Scheme 1. The Metal-catalyzed Direct β-Csp3-H Aryla-
tion of Ketones
On the other hand, due to the importance of olefins in
organic synthesis, transition metal-catalyzed dehydro-
genative desaturation of various compounds to generate
olefins has recently attracted considerable interest.6-8
Moreover, efforts to achieve the tandem metal-catalyzed
dehydrogenation/secondary olefin reaction sequence have
led to the inventions of diverse interesting chemical trans-
formations,9-13 including Baudoin’s Pd-catalyzed β-C-H
ACS Paragon Plus Environment

ACS Catalysis
Actually, the implementation of the tandem dehydro-
Page 2 of 6
ing loading of [Rh(COD)Cl]2 to 3 mol% led to a decrease in
the yield of 3a (entry 6). However, increasing the amount
of TEMPO to 1.2 equivalents gave 70% yield with 3 mol%
[Rh(COD)Cl]2 catalyst (entry 7). Then, we checked the ef-
fect of bases on the reaction outcome. Although acetate
and carbonate salts have a negative effect on the reaction
(see Table S1 in the Supporting Information), 10 mol% CsF
could increase the yield to 82% (entry 8).
1
2
3
4
5
6
7
8
genative desaturation/C-H alkylation of arene with enone
to construct β-aryl saturated ketone represents a challenge
for the following reasons: 1) the compatibility between the
dehydrogenative desaturation and the C-H fuctionalization
is required; 2) the β-aryl ketone products compete with
ketone starting materials for dehydrogenation to form the
overoxidized side-product;16 3) the expected alkyl-M in-
termediate in the C-H alkylation catalysis tends to undergo
β-H elimination to form overoxidized side-products. One of
our strategies to address these problems is the identifica-
tion of a suitable catalyst system responsible for C-H alkyl-
ation with olefin, which is compatible with the Cu-
catalyzed dehydrogenative desaturation process.14 We
hypothesized that if the C(sp3)-M bond of the alkyl-M in-
termediate generated is enough polar, this intermediate
would prefer protonolysis over β-elimination. Since in-
creasing the concentration of ketone could accelerate Cu-
catalyzed ketone dehydrogenation to enone, 14a the use of
excessive ketone starting material would suppress dehy-
drogenation of β-aryl ketone products.
Scheme 2. The Scope of Carboxylic Acid a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table1. The Selected Result of the Optimization Stud-
ies on the Ketone β-Arylation a
aReaction conditions: 1a (0.6 mmol), 2 (0.2 mmol), All isolat-
ed yields. b1a (0.8 mmol), TEMPO (2.4 equiv.).
With the optimized reaction conditions in hand, we
evaluated the substrate scope of carboxylic acids (Scheme
2). Ortho-substituted benzoic acids gave good-to-excellent
yields and variation of the ortho-substituents of these ben-
zoic acids did not significantly affect the reaction outcomes
(3a-3g, 3t). Although nonsubstituted benzoic acids gave
di-substituted product (3q), the reaction of 3-t-butyl ben-
zoic acid occurred only on the less sterically hindered posi-
tion (3h). A series of multi-substituted benzoic acids could
be smoothly transformed into the corresponding products
in good yields (3i-3m, 3r, 3u). Heteroaryl carboxylic acids
were also suitable substrates as illustrated by 3n and 3o.
Interestingly, this protocol was amenable to carboxyl-
directed alkenylic C-H alkylation of alkenyl carboxylic ac-
ids (3v-3x), further highlighting the generality of this pro-
tocol.
b
aReaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), yield as
determined by NMR.
With these considerations in mind, we chose the reac-
tion of propiophenone (1a) with ortho-methoxy benzoic
acid (2a) as a model system for the optimization of reac-
tion conditions (Table 1). Benzoic acids were used as ary-
lating reagents because benzoic acids are readily available,
versatile arylating reagents via decarboxylative cross-
17
coupling reactions or carboxyl-directed ortho-C-H func-
tionalization reactions. 18 Our targeted reaction aimed at
the carboxyl-directed C-H alkylation to produce 3a of
which carboxyl group is able to undergo protodecarboxy-
lation or various decarboxylative cross-coupling reaction,
and therefore allow for the further elaboration of products.
The undesired lactone by-product 3aa came from overoxi-
dation of 3a via further dehydrogenation of 3a and subse-
quent conjugate addition of carboxyl to enone. Initially, we
screened a variety of metal catalysts in the presence of one
Next, we explored the substrate scope of saturated ke-
tones (Scheme 3). A variety of electronically diverse func-
tionalities on 4-positions of phenyl rings in propiophe-
nones were well tolerated to give the β-arylation ketones
in excellent yields (4a-4f and 4j). Changing the substitu-
tion position to meta-position of phenyl ring in propiophe-
nones had no effect on the reaction yields (4g-4i). Propio-
phenones containing multi-substituted phenyl rings were
also suitable for this transformation (4k-4m). Additionally,
heteroaromatic ketones such as 2-propionylfuran and 2-
propionylthiophene participated in the targeted β-
arylation reaction without side reactions occurring at their
reactive C-2 or C-3 positions of heteroaromatic rings (4o
and 4p). As exemplified in the cases of 4q-4t, aliphatic
equivalent
of
2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) and 20 mol% Cu(OAc)2, and found that the metal
catalysts, which are regularly used for C-H activation reac-
tions, allowed for the reaction of 1a with 2a to occur but
gave overoxidized product 3aa (entries 1-4). Gratifyingly,
we obtained the targeted product in 65% yield using
[Rh(COD)Cl]2 (5 mol%) 15b, 19 as a catalyst (entry 5). Reduc-
ACS Paragon Plus Environment

Page 3 of 6
ACS Catalysis
ketones also underwent β-arylation reaction which oc-
pleased to find that adding AgOAc (1 equiv.), K2CO3 (1
equiv.) and HOAc to the reaction system after Rh/Cu catal-
ysis process allowed for protodecarboxylation of these β-
arylation products to generate 1,3,5-trisubstituted ben-
zenes as final products in synthetically useful yields
(Scheme 5).
1
2
3
4
5
6
7
8
curred exclusively on less sterically hindered ethyl moiety.
This selective β-arylaton of aliphatic ketones circumvented
the formidable synthesis of the alkyl vinyl ketones used in
Ru-catalyzed hydroarylation of olefins, and provided a
solution to the selectivity issue encountered in the synthe-
sis of β-aryl ketone via aldol reaction of unsymmetrical
ketone.
To gain an insight into the Rh/Cu catalyzed β-arylation
of ketone, we conducted preliminary mechanism investiga-
tions (See Supporting Information for details). By means of
a H/D exchange experiment, we initially explored the ef-
fect of TEMPO on [Rh(COD)Cl]2-mediated carboxyl-
directed ortho C-H activation. In the presence of D2O (20
equiv.) and TEMPO (1.2 equiv.), 30% of C-H bond ortho to
carboxyl group in 2-methoxy-benzoic acid was deuterated,
indicating that the reversible C-H cyclorhodation occurred.
Control experiments revealed that only negligible H/D
exchanges occurred in the absence of TEMPO, suggesting
that TEMPO played a key role in the [Rh(COD)Cl]2-
mediated C-H activation step. Moreover, TEMPO was es-
sential for [Rh(COD)Cl]2-catalyzed carboxyl-directed C-H
alkylation of benzoic acids with enone, consistent with
H/D exchange experiments. In light of these observations,
we reasoned that TEMPO would promote the generation of
the active Rh catalyst for C-H bond activation, likely by
Scheme 3. The Scope of Saturated Ketones a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
oxidation of Rh(I) to Rh(III) species as proposed by Studer
21
and co-workers
for the Rh-catalyzed oxidative cross-
coupling reactions with TEMPO as the only terminal oxi-
dant. Moreover, we conducted the reaction of 1(3-
methoxyphenyl)propan-1-one with [D5]benzoic acid un-
der standard reaction conditions and found that 45% of
deuterium on ortho-position of [D5]benzoic acid was in-
corporated to α-position of β-arylated ketone product, and
35% to β-position.
aReaction conditions: 1 (0.6 mmol), 2 (0.2 mmol). All isolated
yields. b Cu(OAc)2 (40 mol%) was used.
Our Rh/Cu catalyzed method also enabled one-step
gram-scale synthesis of a kind of matrix metalloproteinase
inhibitor in 71% yield using commercially available start-
ing materials. In sharp contrast, this matrix metallopro-
teinase inhibitor was previously synthesized by way of a
Scheme 6. Proposed Mechanism.
six-step
synthetic
route
starting
from
3-(1-
bromnaphthalen-2yl) propan-1-ol (Scheme 4). 20
Scheme 4. One Step Synthesis of a kind of matrix met-
alloproteinase inhibitor
Scheme 5. One-pot procedure for Rh/Cu-catalyzed ke-
tone β-arylation and protodecarboxylationa
The identification of enone intermediate in the reaction
system and the experiments described by Scheme S1-S3
supported that the Rh/Cu-catalyzed ketone β-arylation
occurred via the in-situ ketone dehydrogenation and C-H
alkylation with the enone. Scheme 6 shows a proposed
mechanism for the Rh-catalyzed carboxyl-directed ortho C-
H alkylation with the enone. Initially, the catalytically ac-
tive Rh(III)(TEMPO)2Ln I is generated via oxidation of
[Rh(COD)Cl]2 by TEMPO (2 equiv.). After carboxylate coor-
dinates to Rh(III) catalyst I, ortho C-H metalation proceeds
via a concerted metalation/deprotonation mechanism
o
aReaction conditions: 1 (0.6 mmol), 2 (0.2 mmol), 120 C,
24 h, N2. All isolated yields.
To test the feasibility of further transformation of these
ketone β-arylation products, we investigated one-pot two-
step procedure for Rh/Cu catalyzed carboxyl-directed C-H
alkylation and subsequent protodecarboxylation. We are
22
(CMD) to form aryl-Rh(III) species II, in which TEMPO-
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 6
Scavenging Activity: A Structure–Activity Study of C-Methylated
Dihydrochalcones from Myrica gale and Structurally Related Ace-
tophenones. Free Radical Bio & Med. 1997, 22, 307-311.
2. Thebtaranonth, C.; Thebtaranonth, Y. The Chemistry of Enones.;
Patai, S.; Rappoport, Z. Eds.; John Wiley & Sons: New York, 1989.
Vol. 29, p 199.
anion ligand accepts proton by its nitrogen atom to pro-
mote C-H metalation. Olefin insertion into aryl-Rh bond
leads to formation of alkyl-Rh intermediate III that under-
goes protonolysis via proton transfer from the nitrogen
atom of coordinating TEMPO ligand to the carbon atom of
C-Rh bond to release product VI. Meanwhile, Product VI is
also produced through protonolysis of isomeric alkyl-Rh
intermediate V, which is generated from intermediate III
via β-H elimination and subsequent re-insertion pro-
cess,15b, 23 since deuterium atoms were incorporated to
both α and β positions of β-arylated ketone product in the
deuterium-labeling experiment. The fact that 80% of or-
tho-deuterium atoms of [D5]benzoic acid were incorpo-
rated into the final product implicates that after accepting
proton in the C-H metalation process, TEMPO still coordi-
nates to Rh atom in the form of zwitterion, and therefore
makes it easy to deliver proton to the proximal Rh-C bond
of alkyl-Rh intermediate.
1
2
3
4
5
6
7
8
3. (a) Sakai, M.; Hayashi, H.; Miyaura, N. Rhodium-Catalyzed Con-
jugate Addition of Aryl- or 1-Alkenylboronic Acids to Enones.
Organometallics. 1997, 16, 4229-4231. (b) Hayashi, T.; Takahashi,
M.; Takaya, Y.; Ogasawara, M. Catalytic Cycle of Rhodium-
Catalyzed Asymmetric 1,4-Addition of Organoboronic Acids. Aryl-
rhodium, Oxa-π-allylrhodium, and Hydroxorhodium Intermedi-
ates. J. Am. Chem. Soc. 2002, 124, 5052-5058. (c) Fagnou, K.;
Lautens, M. Rhodium-Catalyzed Carbon−Carbon Bond Forming
Reactions of Organometallic Compounds. Chem. Rev. 2003, 103,
169-196. (d) Hayashi, T.; Yamasaki, K. Rhodium-Catalyzed Asym-
metric 1,4-Addition and Its Related Asymmetric Reactions. Chem.
Rev. 2003, 103, 2829-2844.
4. (a) Zhang, F.-L.; Hong, k.; Li, T.-J.; Park, H.; Yu, J.-Q. Function-
alization of C(sp3)–H bonds using a transient directing group.
Science. 2016, 351, 252-256. (b) Zhu, R-Y.; Liu, R.-Y.; Park, H.S.;
Hong, K.; Wu, Y.; Senanayake, H.; Yu, J.-Q. Versatile Alkylation of
(Hetero)Aryl Iodides with Ketones via β-C(sp3)–H Activation. J.
Am. Chem. Soc. 2017, 139, 16080-16083. (c) Huang, Z.; Dong, G.
Catalytic C-C bond forming transformations via direct β-C-H func-
tionalization of carbonyl compounds. Tetrahedron. 2014, 55,
5869-5889. (d) He, G.; Wang, B.; Nack, W. A.; Chen, G. Syntheses
and Transformations of α‑Amino Acids via Palladium-Catalyzed
Auxiliary-Directed sp3 C−H Functionalization. Acc. Chem. Res.
2016, 49, 635-645. (e) Yang, K.; Li, Q.; Liu, Y.; Li, G.; Ge, H. Catalyt-
ic C−H Arylation of Aliphatic Aldehydes Enabled by a Transient
Ligand. J. Am. Chem. Soc. 2016, 138, 12775-12778.
5. (a) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W.
C. Photoredox Activation for the Direct β-Arylation of Ketones
and Aldehydes. Science. 2013, 339, 1593-1596. (b) Petronijevic, F.
R.; Nappi, M.; MacMillan, D. W. C. Direct β-Functionalization of
Cyclic Ketones with Aryl Ketones via the Merger of Photoredox
and Organocatalysis. J. Am. Chem. Soc. 2013, 135, 18323-18326.
6. (a) Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. A New Method for
the One-Step Synthesis of α,β-Unsaturated Carbonyl Systems from
Saturated Alcohols and Carbonyl Compounds. J. Am. Chem. Soc.
2000, 122, 7596-7597. (b) Uyanik, M.; Akakura, M.; Ishihara, K. 2-
Iodoxybenzenesulfonic Acid as an Extremely Active Catalyst for
the Selective Oxidation of Alcohols to Aldehydes, Ketones, Car-
boxylic Acids, and Enones with Oxone. J. Am. Chem. Soc. 2009,
131, 251-262.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, we have developed the Rh/Cu catalyzed di-
rect β-arylation or alkenylation of ketones with aryl or
alkenyl carboxylic acids as coupling partners via combina-
tion of Cu/TEMPO-promoted ketone dehydrogenation pro-
cess with Rh-catalyzed carboxyl-directed C-H alkylation
with enone. Both aryl alkyl ketones and dialkyl ketones
underwent β-functionalization reactions with a broad
range of aryl carboxylic acids as well as alkenyl carboxylic
acids with good selectivity in good-to-excellent yields. The
strategy to merge the dehydrogenative desaturation and
the C-H activation reaction would bring about discoveries
of various new transformations due to versatile reactivity
of olefins and diversity of C-H activation reactions.
ASSOCIATED CONTENT
Supporting Information. Experiment procedures, character-
1
ization data, H, 13C and 19F spectra for compounds, mecha-
nism study. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
7. (a) Diao, T.; Stahl, S. S. Synthesis of Cyclic Enones via Direct
Palladium-Catalyzed Aerobic Dehydrogenation of Ketones. J. Am.
Chem. Soc. 2011, 133, 14566-14569. (b) Diao, T.; Wadzinski, T. J.;
Stahl, S. S. Direct aerobic α, β-dehydrogenation of aldehydes and
ketones with a Pd(TFA)2/4,5-diazafluorenone catalyst. Chem. Sci.
2012, 3, 887-891. (c) Bigi, M. A.; White, M. C. Terminal Olefins to
Linear α, β-Unsaturated Ketones: Pd(II)/Hypervalent Iodine Co-
catalyzed Wacker Oxidation–Dehydrogenation. J. Am. Chem. Soc.
2013, 135, 7831-7834. (d) Chen, M.; Dong, G. Direct Catalytic
Desaturation of Lactams Enabled by Soft Enolization. J. Am. Chem.
Soc. 2017, 139, 7757-7760. (e) Wang, Z.; He, Z.; Zhang, L.; Huang,
Y. Iridium-Catalyzed Aerobic α, β-Dehydrogenation of γ, δ-
Unsaturated Amides and Acids: Activation of Both α- and β-C–H
bonds through an Allyl–Iridium Intermediate. J. Am. Chem. Soc.
2018, 140, 735-740.
8. (a) Yi, C. S.; Lee, D. W. Efficient Dehydrogenation of Amines
and Carbonyl Compounds Catalyzed by a Tetranuclear Rutheni-
um-μ-oxo-μ-hydroxo-hydride Complex. Organometallics. 2009,
28, 947-949. (b) Kusumoto, S.; Akiyama, M.; Nozaki, K. Acceptor-
less Dehydrogenation of C–C Single Bonds Adjacent to Functional
Groups by Metal–Ligand Cooperation. J. Am. Chem. Soc. 2013, 135,
18726-18729.
* wpsu@fjirsm.ac.cn
* lukas.goossen@rub.de
ORCID
Weiping Su: 0000-0001-5695-6333
Lukas J. Goossen: 0000-0002-2547-3037
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by NSFC (21431008, 21332001,
u1505242 and 21602221), the CAS/SAFEA International
Partnership Program for Creative Research Teams, the Strate-
gic Priority Research Program of the Chinese Academy of Sci-
ences (XDB20000000), and the Key Research Program of
Frontier Sciences, CAS (QYZDJ-SSW-SLH024).
REFERENCES
1. (a) Mathiesen, L.; Malterud, E.; Sund, R. B. Antioxidant activity
of fruit exudate and C-methylated dihydrochalcones from Myrica
gale. Planta. Med. 1995, 61, 515-518. (b) Mathiesen, L.; Malterud,
E.; Sund, R. B. Hydrogen Bond Formation as Basis For Radical
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
9. (a) Stang, E. M.; White, M. C. Molecular Complexity via C–H Ac-
System for the Addition of Heteroarenes to both Alkenes and
Alkynes by a C-H Bond Activation. Angew. Chem. Int. Ed. 2012, 51,
3677-3681. (c) Yang, L.; Qian, B.; Huang, H. Brøsted Acid En-
hanced Rhodium-Catalyzed Conjugate Addition of Aryl C-H Bonds
to α, β-Unsaturated Ketones under Mild Conditions Chem. Eur. J.
2012, 18, 9511-9515. (d) Yang, L.; Correia, A. C.; Li, C.-J. Rhodium-
catalyzed C–H activation and conjugate addition under mild con-
ditions. Org. Biomol. Chem. 2011, 9, 7176-7179.
16. (a) Izawa, Y.; Pun, D.; Stahl, S. S. Palladium-Catalyzed Aerobic
Dehydrogenation of Substituted Cyclohexanones to Phenols. Sci-
ence. 2011, 333, 209-213. (b) Pun, D.; Diao, T.; Stahl, S. S. Aerobic
Dehydrogenation of Cyclohexanone to Phenol Catalyzed by
Pd(TFA)2/2-Dimethylaminopyridine: Evidence for the Role of Pd
Nanoparticles. J. Am. Chem. Soc. 2013, 135, 8213-8221. (c) Ueno,
S.; Shimizu, R.; Kuwano, R. Nickel-Catalyzed Formation of a Car-
bon–Nitrogen Bond at the β Position of Saturated Ketones. Angew.
Chem. Int. Ed. 2009, 48, 4543-4545. (d) Moon, Y.; Kwon, D.; Hong,
S. Palladium-Catalyzed Dehydrogenation/Oxidative Cross-
Coupling Sequence of β-Heteroatom-Substituted Ketones. Angew.
Chem. Int. Ed. 2012, 51, 11333-11336. (e) Shang, Y.; Jie, X.; Zhou,
J.; Hu, P.; Huang, S.; Su, W. Pd-Catalyzed C–H Olefination of (Het-
ero)Arenes by Using Saturated Ketones as an Olefin Source. An-
gew. Chem. Int. Ed. 2013, 52, 1299-1303. (f) Gandeepan, P.; Ra-
jamalli, P.; Cheng, C.-H. Palladium-Catalyzed Dehydrogenative β‑
Arylation of Simple Saturated Carbonyls by Aryl Halides. ACS.
Catal. 2014, 4, 4485-4489.
tivation: A Dehydrogenative Diels–Alder Reaction. J. Am. Chem.
Soc. 2011, 133, 14892-14895. (b) Goldman, A. S.; Roy, A. H.;
Huang, Z.; Ahuja, R.; Schinski, W.; Brookhart, M. Catalytic Alkane
Metathesis by Tandem Alkane Dehydrogenation-Olefin Metathe-
sis. Science. 2006, 312, 257-261. (c) Jia, X.; Huang, Z. Conversion of
alkanes to linear alkylsilanes using an iridium–iron-catalysed
tandem dehydrogenation–isomerization–hydrosilylation. Nat.
Chem. 2016, 8, 157-161. (d) Wang, B.; Du, H.; Shi, Y. A Palladium-
Catalyzed Dehydrogenative Diamination of Terminal Olefins. An-
gew. Chem. Int. Ed. 2008, 47, 8224-8227. (e) Li, C.-J. Cross-
Dehydrogenative Coupling (CDC): Exploring C-C Bond Formations
beyond Functional Group Transformations. Acc. Chem. Res. 2009,
42, 335-344.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. (a) Renaudat, A.; Jean-Gérard, L.; Jazzar, R.; Kefalidis, C.
E.;Clot, E.; Baudoin, O. Palladium-Catalyzed β Arylation of Carbox-
ylic Esters. Angew. Chem. Int. Ed. 2010, 49, 7261-7265. (b) Larini,
P.; Kefalidis, C. E.; Jazzar, R.; Renaudat, A.; Clot, E.; Baudoin, O. On
the Mechanism of the Palladium-Catalyzed β-Arylation of Ester
Enolates. Chem. Eur. J. 2012, 18, 1932-1944. (c) Aspin, S.;
Goutierre, A.-S.; Larini,P.; Jazzar, R.; Baudoin, O. Synthesis of Aro-
matic α-Aminoesters: Palladium-Catalyzed Long-Range Arylation
of Primary Csp3-H Bonds. Angew. Chem. Int. Ed. 2012, 51, 10808-
10811. (d) Millet, A.; Larini, P.; Clot, E.; Baudoin, O. Ligand-
controlled β-selective C(sp3)–H arylation of N-Boc-piperidines.
Chem. Sci. 2013, 4, 2241-2247.
11. (a) Leskinen, M. V.; Yip, K.-T.; Valkonen, A.; Pihko, P. M. Palla-
dium-Catalyzed Dehydrogenative β’-Functionalization of β-Keto
Esters with Indoles at Room Temperature. J. Am. Chem. Soc. 2012,
17. For reviews on decarboxylative cross-coupling reactions, see
(a) Rodríguez, N.; Goossen, L. J. Decarboxylative coupling reac-
tions: a modern strategy for C–C-bond formation. Chem. Soc. Rev.
2011, 40, 5030-5048. (b) Larrosa, I.; Cornella, J. Decarboxylative
Carbon-Carbon Bond-Forming Transformations of (Het-
ero)aromatic Carboxylic Acids. Synthesis 2012, 44, 653-676. (c)
Wei, Y.; Hu, P.; Zhang, M.; Su, W. Metal-Catalyzed Decarboxylative
C–H Functionalization. Chem. Rev. 2017, 117, 8864-8907.
18. (a) Engle, M. k.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak Coordina-
tion as a Powerful Means for Developing Broadly Useful C-H Func-
tionalization Reactions. Acc. Chem. Res. 2012, 45,788-802. (b) De
Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Weakly Coor-
dinating Directing Groups for Ruthenium(II)-Catalyzed C-H Acti-
vation. Adv. Synth. Catal. 2014, 356, 1461-1479. (c) Mochida, S.;
Hirano, K.; Satoh, T.; Miura, M. Synthesis of Stilbene and Dis-
tyrylbenzene Derivatives through Rhodium-Catalyzed Ortho-
Olefination and Decarboxylation of Benzoic Acids. Org. Lett. 2010,
12, 5776-5779. (d) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M.
Rhodium-Catalyzed Regioselective Olefination Directed by a Car-
boxylic Group. J. Org. Chem. 2011, 76, 3024-3033.
19. (a) Fu, G. C. Modern Rhodium-Catalyzed Organic Reactions.;
Evans, P. A., Eds.; Wiley-VCH: Weinheim, 2005, Chapter 4, p 79.
(b) Colby, D.A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed C-
C Bond Formation via Heteroatom-Directed C-H Bond Activation.
Chem. Rev. 2010, 110, 624-655. (c) Dong, Z.; Ren, Z.; Thompson, S.
J.; Xu, Y.; Dong, G. Transition-Metal-Catalyzed C−H Alkylation Us-
ing Alkenes. Chem. Rev. 2017, 117, 9333-9403.
20. Hajduk, P. J.; Shuker, S. B.; Nettesheim, G. D.; Craig, R.; Augeri,
D. J.; Betebenner, D.; Albert, D. H.; Guo, Y.; Meadows, R.P.; Xu, L.;
Michaelides, M.; Davidsen, S. K.; Fesik, S. W. NMR-Based Modifica-
tion of Matrix Metalloproteinase Inhibitors with Improved Bioa-
vailability. J. Med. Chem. 2002, 45, 5628-5639.
134, 5750-5753. (b) Leskinen, M. V.; Madarász, A.; Yip, K.-T.; Vuo-
rinen, A.; Papai, I.; Neuvonen, A. J.; Pihko, P. M. Cross-
́
Dehydrogenative Couplings between Indoles and β‑Keto Esters:
Ligand-Assisted Ligand Tautomerization and Dehydrogenation
via a Proton-Assisted Electron Transfer to Pd(II). J. Am. Chem. Soc.
2014, 136, 6453-6462. (c) Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M
A. Three-Component Palladium-Catalyzed Oxidative C-C Coupling
Reaction: A Domino Process in Two Dimensions. Angew. Chem.
Int. Ed. 2013, 52, 4818-4822.
12. (a) Huang, Z.; Dong, G. Catalytic Direct β‑Arylation of Simple
Ketones with Aryl Iodides. J. Am. Chem. Soc. 2013, 135, 17747-
17750. (b) Huang, Z.; Sam, Q. P.; Dong, G. Palladium-catalyzed
direct β-arylation of ketones with diaryliodonium salts: a stoichi-
ometric heavy metal-free and user-friendly approach. Chem. Sci.
2015, 6, 5491-5498. (c) Hu, X.; Yang, X.; Dai, X.-J.; Li, C.-J. Palladi-
um-Catalyzed Direct β-C-H Arylation of Ketones with Arylboronic
Acids in Water. Adv. Synth. Catal. 2017, 359, 2402-2406.
13. (a) Chen, Y.; Romaire, J. P.; Newhouse, T. R. Palladium-
Catalyzed α,β-Dehydrogenation of Esters and Nitriles. J. Am. Chem.
Soc. 2015. 137, 5875-5878. (b) Chen, Y.; Turlik, A.; Newhouse, T.
R. Amide α,β-Dehydrogenation Using Allyl-Palladium Catalysis
and a Hindered Monodentate Anilide. J. Am. Chem. Soc. 2016. 138,
1166-1169. (c) Chen, Y.; Huang, D.; Zhao, Y.; Newhouse, T. R. Allyl-
Palladium-Catalyzed Ketone Dehydrogenation Enables Telescop-
ing with Enone α, β-Vicinal Difunctionalization. Angew. Chem. Int.
Ed. 2017. 56, 8258-8262. (d) Zhao, Y.; Chen, Y.; Newhouse, T. R.
Allyl-Palladium-Catalyzed α, β-Dehydrogenation of Carboxylic
Acids via Enediolates. Angew. Chem. Int. Ed. 2017. 56, 13122-
13125.
14. (a) Jie, X.; Shang, Y.; Zhang, X.; Su, W. Cu-Catalyzed Sequential
Dehydrogenation−Conjugate Addition for β‑Functionalization of
Saturated Ketones: Scope and Mechanism. J. Am. Chem. Soc. 2016,
138, 5623-5633. (b) Shang, Y.; Jie, X.; Jonnada, K.; Zafar, S. N.; Su,
W. Dehydrogenative desaturation-relay via formation of multi-
center-stabilized radical intermediates. Nat. Commun. 2017, 8,
2273-2280.
21. (a) Vogler, T.; Studer, A. Oxidative Coupling of Arylboronic
Acids with Arenes via Rh-Catalyzed Direct C-H Arylation. Org.
Lett. 2008, 10, 129-131. (b) Vogler, T.; Studer, A. Rhodium-
Catalyzed Oxidative Homocoupling of Boronic Acids. Adv. Synth.
Catal. 2008, 350, 1963-1967.
22. TEMPO assisted dehydrogenation via N-H bond formation,
see: Ryland, B. L.; McCann, S. D.; Brunold, T.C.; Stahl, S.S. Mecha-
nism of Alcohol Oxidation Mediated by Copper(II) and Nitroxyl
Radicals. J. Am. Chem. Soc. 2014, 136, 12166-12173.
15. (a) Rouquet, G.; Chatani, N. Ruthenium-catalyzed ortho-C–H
bond alkylation of aromatic amides with α, β-unsaturated ketones
via bidentate-chelation assistance. Chem. Sci. 2013, 4, 2201-2208.
(b) Ryu, J.; Cho, S. H.; Chang, S. A Versatile Rhodium(I) Catalyst
23. (a) Tsui, G.C.; Menard, F.; Lautens, M. Regioselective Rhodi-
um(I)-Catalyzed Hydroarylation of Protected Allylic Amines with
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 6
Arylboronic Acids. Org. Lett. 2010, 12, 2456-2459. (b) Tsui, G. C.;
Lautens, M. Linear-Selective Rhodium(I)-Catalyzed Addition of
Arylboronic Acids to Allyl Sulfones. Angew. Chem. Int. Ed. 2010,
49,8938-8941.
1
2
3
4
5
SYNOPSIS TOC
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment