Manganese-Catalyzed Redox-Neutral C?H Olefination of Ketones with Unactivated Alkenes

Article abstract of DOI:10.1002/anie.201806287

Since 1987, stoichiometric cyclomanganation of ketones and subsequent reactions with olefins in the presence of either palladium salts or trimethylamine N-oxide (Me₃N⁺O^?) have been reported, but the catalytic versions remain untouched so far. Herein, the first manganese-catalyzed redox-neutral C?H olefination of ketones with unactivated alkenes is described, and shows a distinct reactivity with its parent stoichimetric reactions. Remarkably, mechanistic experiments and DFT calculations uncovers a unique concerted bis-metalation deprotonation (CBMD) mechanism of the Mn-Zn-enabled C?H bond activation.

Full text of DOI:10.1002/anie.201806287

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Manganese-Catalyzed Redox-Neutral C-H Olefination of Ketones
with Unactivated Alkenes
Authors: Yuanyuan Hu, Bingwei Zhou, Hui Chen, and Congyang Wang
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.201806287
Angew. Chem. 10.1002/ange.201806287
Link to VoR: http://dx.doi.org/10.1002/anie.201806287
http://dx.doi.org/10.1002/ange.201806287

10.1002/anie.201806287
Angewandte Chemie International Edition
COMMUNICATION
Manganese-Catalyzed Redox-Neutral C-H Olefination of Ketones
with Unactivated Alkenes
Yuanyuan Hu, Bingwei Zhou, Hui Chen,* and Congyang Wang*
Abstract: Since 1987, stoichiometric cyclomanganation of ketones
and following reactions with olefins in the presence of palladium
salts or trimethylamine N-oxide (Me3N+O–) had been reported, while
the catalytic versions remain untouched so far. Herein, the first
manganese-catalyzed redox-neutral C-H olefination of ketones with
unactivated alkenes is described, which shows a distinct reactivity
with its parent stoichimetric reactions. Remarkably, mechanistic
experiments and DFT calculations uncovers a unique Concerted Bis-
Metalation Deprotonation (CBMD) mechanism of Mn-Zn-enabled C-
H bond activation.
acceptor, thus providing the C-H olefinated benzylic alcohols in
highly efficient way. Remarkably, such products are
inaccessible by C-H olefination of the corresponding unprotected
benzylic alcohols due to the incapability of benzylic hydroxyl as
an efficient directing group.[7]
a
a) Rh-/Ru-catalyzed oxidative C-H olefination: previous work
O
O
R2
R2
cat. Rh, Ru
R1
R1
R3
+
oxidant
H
R3
b) Manganese-mediated stoichiometric reactions: previous work
O
PdCl2 (1.0 eq.)
LiCl (3.0 eq.)
Me
Ketones are among the most important building blocks in
organic synthesis. The electrophilicity of the carbonyl group and
nucleophilicity of the α-carbon anion/enolate constitute the
majority of classic reaction patterns of ketones. Recently,
carbonyl-directed C-H activation reactions have largely
expanded the chemical space of ketones in synthetic
chemistry.[1] The ortho C-H alkylation of ketones with alkenes
has been well established since Murai’s pioneering work in
1993.[2] However, the oxidative C-H olefination of ketones were
scarcely explored and only two examples were reported by
Glorius and Jeganmohan using precious Rh- and Ru-catalyst
respectively (Scheme 1a).[3] Of note, external oxidants such as
Cu(OAc)2 were inevitably required in these reactions. To the
best of our knowledge, no example of the first-row transition-
metal catalyzed C-H olefination of ketones with alkenes has
been documented so far.
Me
MnBn(CO)5
Me
CO2Me
O
H
MeO
R
Mn
(CO)4
R
O
Li2PdCl4
(1.0 eq.)
HO
Me
R'
Me3N+O-
+
Me
CO2Me
R'
(1.5 eq.)
LiCl (3.0 eq.)
R
c) Manganese-catalyzed redox-neutral C-H olefination: this work
O
OH
R2
Mn
R2
+
R1
R1
R3
redox-neutral
H
R3
an unprecedented reaction pattern
earth-abundant manganese catalysis
a dual role of the carbonyl group
unique Mn-Zn bimetallic synergy
Scheme 1. Aromatic C-H olefination reactions of ketones and alkenes.
Since 1987, Nicholson, Main and Woodgate had disclosed
the stoichiometric cyclomanganation of ketones and the ensuing
reactions with olefins in the presence of PdCl2, Li2PdCl4, or
Me3N+O– (Scheme 1b).[4] Diverse products were obtained upon
varied reaction conditions, whilst the corresponding catalytic
versions have remained untouched so far. As our persistent
interest on earth-abundant manganese catalyzed C-H
activation,[5,6] we herein disclose the first manganese-catalyzed
redox-neutral C-H olefination of ketones with unactivated
alkenes (Scheme 1c). The carbonyl of ketone plays a dual role
both as a weak-coordination directing group and as a hydrogen
At the outset, acetophenone 1a and styrene 2a were selected
as model substrates to screen reaction parameters (Table 1).
While no reaction occurred in the presence of Me2Zn (entry 1),
the reaction proceeded smoothly with MnBr(CO)5 as a catalyst
giving product 3aa in 42% NMR yield with high E/Z selectivity
(entry 2). Mn2(CO)10 showed lower efficiency and non-carbonyl
manganese as well as other transition-metal carbonyls didn’t
promote the reaction at all (entries 3-5).[8] Surprisingly, other
alkyl zinc, magnesium and aluminum species completely failed
in the reaction (entries 6-8). To our delight, a catalytic amount of
CuBr2 enhanced the reaction yield, which proved to be the best
among additives examined (entries 9-10).[8] Variations on the
ratio of substrates led to nearly quantitative formation of 3aa
(entry 11). At last, the catalyst dosage and reaction time could
be further reduced without influencing the reaction outcome
(entry 12). Of note, no ortho-alkylation product 4aa was
detected during the optimization process.
[*]
Dr. Y. Hu, Dr. B. Zhou, Prof. Dr. C. Wang
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, CAS
Research/Education Center for Excellence in Molecular Sciences,
Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190 (China)
University of Chinese Academy of Sciences, Beijing 100049 (China)
E-mail: wangcy@iccas.ac.cn
Prof. Dr. H. Chen
Table 1. Screening of reaction parameters.[a]
BNLMS, CAS Key Laboratory of Photochemistry, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190 (China)
E-mail: chenh@iccas.ac.cn
Supportinginformation for this article can be found under:
http://dx.doi.org/
Entry
Catalyst
Base
Additive
Yield[c]
This article is protected by copyright. All rights reserved.

10.1002/anie.201806287
Angewandte Chemie International Edition
COMMUNICATION
[d]
[e]
[e]
[e]
[e]
[e]
[e]
[e]
[e]
1
2
-
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Et2Zn
-
-
-
-
-
-
-
-
0
of olefins had little influence on the reaction outcome (3ai-m).
Pentafluorinated styrene worked equally well (3an). 2-
Vinylnaphthalene was also susceptible to the reaction conditions
giving the desired product successfully (3ao). Indolyl skeleton
was well tolerated in the protocol (3ap, 3av). Remarkably, the
reaction was applicable to a variety of aliphatic olefins with
varied chain lengths and functionalities (3aq-w). Vinyl silane was
shown compatible with the current process (3ax).
MnBr(CO)5
Mn2(CO)10
MnCl2
42% (10:1)
3
24% (11:1)
4
0
5
Ru3(CO)12
MnBr(CO)5
MnBr(CO)5
MnBr(CO)5
MnBr(CO)5
MnBr(CO)5
MnBr(CO)5
MnBr(CO)5
0
6
0
7
MeMgBr
Me3Al
0
8
0
9
Me2Zn
Me2Zn
Me2Zn
Me2Zn
ZnBr2
CuBr2
CuBr2
CuBr2
51% (11:1)
71% (11:1)
98% (11:1)
98% (11:1)
10
11[f]
12[f,g]
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), catalyst (10 mol%),
additive (10 mol%), base (0.3 mmol), solvent (0.5 mL), 60 oC, 12 h. [b] Major
E-isomer was shown. [c] Determined by 1H NMR analysis and the ratio of E/Z
isomers was shown in parentheses. [d] No catalyst. [e] No additive. [f] 1a:2a =
1:2. [g] MnBr(CO)5 (5 mol%), 6 h.
With the optimal conditions in hand, the scope of ketones was
examined (Scheme 2).[8] A wide range of functionalities including
halogens was tolerated on ketones. Thus, acetophenones
bearing both electron-donating and -withdrawing groups
delivered the corresponding ortho-olefinated benzylic alcohols in
good to excellent yields (3aa-ia). A substituent at the ortho
position was also compatible (3ja). When a meta-substituted
ketone with two available C-H bonds was used, formation of a
regioisomer derived from the more sterically accessible C-H
bond was preferred (3ka). The reactions of other alkyl aryl
ketones proceeded smoothly as well (3la-pa). Delightedly, diaryl
ketone was also applicable to this reaction (3qa). Cyclic ketones
proved to be suitable substrates affording the desired products
in synthetically useful yields (3ra-sa).
Scheme 3. Scope of olefins. Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol),
MnBr(CO)5 (0.025 mmol), Me2Zn (0.75 mmol), CuBr2 (0.05 mmol), DCE (1.25
mL), 60 oC, 6 h. Isolated yields are given with E/Z ratios in parentheses and
major isomers were shown. [a] Isolated yield of E-product. [b] MnBr(CO)5 (0.05
mmol), 1a:2 = 1:3, 80 oC. [c] 80 oC. [d] Single isomer. [e] MnBr(CO)5 (0.05
mmol), DCE (2.5 mL), Me2Zn (0.75 mmol, 1.0 M). [f] MnBr(CO)5 (0.05 mmol).
To shed light on the possible reaction mechanism, a range of
experiments were conducted. Stoichiometric reactions of
acetophenone 1a and MnBr(CO)5 were first explored (Scheme
4a). No reaction occurred without any additive or with CuBr2,
while the addition of Me2Zn gave manganacycle Mn-I in 24%
isolated yield. MnMe(CO)5 was believed to form in situ and
contribute to the cyclomanganation step.6e Therefore, the
reaction of 1a and MnMe(CO)5 was then examined (Scheme
4b). Surprisingly, no formation of Mn-I was detected, neither
was the reaction with CuBr2. In contrast, the addition of Me2Zn
resulted in the formation of Mn-I, which indicated that Me2Zn
was not just a transmetalation reagent, rather, it must play a
dual role in the C-H activation step. The addition of CuBr2
together with Me2Zn further increased the yield of Mn-I.
Meanwhile, ZnBr2 gave the similar result. We surmised that the
addition of ZnBr2/CuBr2 might result in the formation of
MeZnBr/MeCuBr through a Schlenk equilibrium (Scheme 4c).
Next, the reaction of Mn-I with styrene 2a was investigated and
3aa was obtained in 39% NMR yield (Scheme 4d). The addition
Scheme 2. Scope of ketones. Reaction conditions: 1 (0.5 mmol), 2a (1.0
mmol), MnBr(CO)5 (0.025 mmol), Me2Zn (0.75 mmol), CuBr2 (0.05 mmol),
DCE (1.25 mL), 60 oC, 6 h. Isolated yields are given with E/Z ratios in
parentheses and major isomers were shown. [a] MnBr(CO)5 (0.05 mmol), 1:2a
= 1:3, 80 oC. [b] Two regioisomers with a ratio of 11:1. [c] Isolated yield of E-
product. [d] 1:2a = 1:3.
The scope of olefins was further tested using acetophenone
as a model substrate (Scheme 3). A plethora of electronically-
varied para-functionalized styrenes were amenable to this
protocol (3ab-h). ortho- and meta-Substitutions on the aryl ring
This article is protected by copyright. All rights reserved.

10.1002/anie.201806287
Angewandte Chemie International Edition
COMMUNICATION
of CuBr2 showed comparable reaction outcome; in contrast,
Me2Zn again accelerated the reaction dramatically, which
implied a possible Mn-Zn bimetallic pathway in the reaction.
Finally, the reaction of 1a and 2a could proceed smoothly by
using Mn-I or MnMe(CO)5 as a catalyst (Scheme 4e).
D
O
D
HO
H
D
98%
D3
5 mol% MnBr(CO)5
10 mol% CuBr2
D
O
D
98%
D3
D3
a)
b)
+
H
1.5 eq. Me2Zn
DCE, 60 oC, 0.5 h
1a-D5: 98% D
98%
C6F5
+
C6F5
2n
1a-D5
3an-D4: 19%
5 mol% MnBr(CO)5
10 mol% CuBr2
OH
O
kH
+
+
Ph
2a
1.5 eq. Me2Zn
DCE, 60 oC
Ph
Ph
1a
3aa
OH
D
5 mol% MnBr(CO)5
10 mol% CuBr2
O
kD
Ph
1.5 eq. Me2Zn
DCE, 60 oC
D5
D3
1a-D5: 98% D
3aa-D4
2a
KIE = kH/kD = 1.37
OH
10 mol% MnBr(CO)5
10 mol% CuBr2
O
D
96%
PMP
D
c)
d)
PMP
+
1.5 eq. Me2Zn
Ph
1a
D
DCE, 80 oC, 6 h
Scheme 4. Mechanistic experiments. [a] Isolated yield. [b] 1H NMR yield. [c]
The E/Z ratio determined by 1H NMR was shown in parentheses.
D
2d-D2: 96% D
95%
3ad-D2: 63% (5:1)
10 mol% MnBr(CO)5
H
D
10 mol% CuBr2
C6F5
+
PMP
3ad-
D
1a
1a
+
+
3an
+
2
Furthermore, deuterium-labeling experiments were carried out
to explore more details of this process. Specifically, treatment of
pentadeuterated acetophenone 1a-D5 with olefin 2n under the
standard reaction conditions resulted in no H/D scrambling at
the ortho positions of the remained substrate 1a-D5 and the
product 3an-D4 (Scheme 5a). Also, no deuterium was detected
at both the olefinic and benzylic positions of 3an-D4. Then, two
parallel reactions of 1a and 1a-D5 with styrene 2a respectively
were conducted and a kinetic isotope effect (KIE) value of 1.37
was observed, implying that the C-H bond cleavage was not
involved in the turnover-limiting step (Scheme 5b).[9] To
ascertain origin of the benzylic hydrogen in the product,
terminally deuterated olefin 2d-D2 was synthesized and treated
with 1a under the standard conditions (Scheme 5c). Product
3ad-D2 with a benzylic deuterium was obtained in 63% isolated
yield. Importantly, no H/D cross-over products were detected
when olefin 2n and 2d-D2 were subjected to the reaction
together (Scheme 5d), which suggested an intramolecular H-
transfer step occurring in the reaction. Furthermore, the external
addition of benzaldehyde to the reaction of 1a and 2a gave no
benzylic alcohol 5 after the reaction. These results indicated that
the formation of Mn-H species via traditional β-H elimination
might not occur in the reaction.
To further probe the possible dual role of Me2Zn in the
catalytic cycle, we resorted to density functional theory (DFT)
calculations (Figure 1). To our delight, a bimetallic species Mn-
Zn-I is located from the ligand-exchange between MnMe(CO)5
and acetophenone 1a in the presence of MeZnBr, which
originates from transmetalation and/or Schlenk equilibria in the
reaction. The Mn-Zn distance of 2.55 Å in Mn-Zn-I is shorter
than the sum of their atomic radii (3.03 Å),[10a] but longer than
the sum of their covalent radii (2.37 Å),[10b] indicating the
strength of interaction between the bimetallic centers of Mn and
Zn. The ensuing C-H activation occurs to give intermediate Mn-
Zn-II with low activation energy of 8.0 kcal/mol via transition
1.5 eq. Me2Zn
DCE, 80 oC, 6 h
H
D
no H/D cross
-over products!
2d-D2: 96% D
2n
5 mol% MnBr(CO)5
10 mol% CuBr2
O
H
H
2a
+
3aa
+
1.5 eq. Me2Zn
DCE, 60 oC, 6 h
Ph
OH
Ph
H
5: not detected
Scheme 5. Deuterium-labeling experiments. Isolated yield was given with the
E/Z ratio in parenthesis.
state TSI-II. Interestingly, the zinc ion is above the plane of the
benzene ring in TSI-II and this backside cation-π interaction
increases the acidity of the C-H bond and facilitates the
concerted C-H deprotonation by the Mn-Me moiety. This is
consistent with the fact that addition of Me2Zn promoted the C-H
bond cleavage of 1a (Scheme 4a, b). Such a synergetic mode
of C-H activation via Concerted Bis-Metalation Deprotonation
(CBMD) mechanism is unprecedented, in view that the CMD
mechanism is well established.[11] Of note, the related Mn-Cu
bimetallic pathway is not favored due to the higher activation
energy by 6.7 kcal/mol,[8] indicating that MeCuBr is not helpful in
this C-H activation step, and instead, MeZnBr plays the key role
(Scheme 4b, c). The extra subtle role of MeCuBr awaits further
explorations. Subsequently, the coordination of styrene 2a
provides Mn-Zn-III, which overcomes a barrier of 19.4 kcal/mol
to undergo olefin-insertion into the C-Mn/Zn bond affording Mn-
Zn-IV via transition state TSIII-IV. Next, a direct intramolecular H-
transfer process is enabled by Mn-Zn bimetallic synergy to
deliver Mn-Zn-V with an energy barrier of 20.5 kcal/mol. The
formation of E-configurated product was thermodynamically
preferred, as indicated by more stable Mn-Zn-IV in trans over
cis form. Of note, the traditional β-H elimination/insertion
pathway via Mn-H species is not favored in this step,[8] which
correlates well with the experimental results in Scheme 5d.
Transmetalation of Mn-Zn-V with Me2Zn and the ensuing ligand
exchange with ketone 1a regenerates Mn-Zn-I and delivers
product 3aa after hydrolysis. Overall, the entire catalytic cycle is
exothermic by 7.7 kcal/mol.
This article is protected by copyright. All rights reserved.

10.1002/anie.201806287
Angewandte Chemie International Edition
COMMUNICATION
Guari, S. Sabo-Etienne, B. Chaudret, J. Am. Chem. Soc. 1998, 120,
4228-4229; c) C. P. Lenges, M. Brookhart, J. Am. Chem. Soc. 1999,
121, 6616-6623; d) R. Martinez, M.-O. Simon, R. Chevalier, C. Pautigny,
J.-P. Genet, S. Darses, J. Am. Chem. Soc. 2009, 131, 7887-7895; e) G.
E. M. Crisenza, N. G. McCreanor, J. F. Bower, J. Am. Chem. Soc. 2014,
136, 10258-10261; f) N. Kimura, T. Kochi, F. Kakiuchi, J. Am. Chem.
Soc. 2017, 139, 14849-14852.
MnBr(CO)5 + Me2Zn + CuBr2
Mn-Zn-enabled
intramolecular
H-transfer
Mn-Cu bimetallic
pathway is not favored
MnMe(CO)5 + MeZnBr + MeCuBr
- 2CO 1a
3aa
CO
CO
Me
Me
- MeZn+
Me
Zn
H+
CO
O
Me
CO
Zn
O
O
CO
CO
Mn
H
Mn
CO
CO
Zn
H
H
H
Me
Mn
Me
CO
[3]
[4]
a) F. W. Patureau, T. Besset, F. Glorius, Angew. Chem. Int. Ed. 2011,
50, 1064-1067; Angew. Chem. 2011, 123, 1096-1099; b) K. Padala, M.
Jeganmohan, Org. Lett. 2011, 13, 6144-6147.
H
1a + Me2Zn
Me
0.0
Mn-Zn-I
H
H
-38.7
-12.2
(-12.1)
TSIV-V
Mn-Zn-V
(-36.6)
a) L. H. P. Gommans, L. Main, B. K. Nicholson, J. Chem. Soc., Chem.
Commun. 1987, 761-762; b) R. C. Cambie, M. R. Metzler, P. S.
Rutledge, P. D. Woodgate, J. Organomet. Chem. 1990, 381, C26-C30.
c) R. C. Cambie, M. R. Metzler, P. S. Rutledge, P. D. Woodgate, J.
Organomet. Chem. 1990, 398, C22-C24.
G‡ = 20.5
G‡ = 8.0
CO
Me
Zn
O
Me
O
CO
CO
Zn
CO
Mn
H
Me
H
CO
G = -7.7 kcal/mol
Mn
CO
Me
H
H
Me
[5]
[6]
For reviews: a) Y. Hu, B. Zhou, C. Wang, Acc. Chem. Res. 2018, 51,
816-827; b) W. Liu, L. Ackermann, ACS Catal. 2016, 6, 3743-3752; c)
Wang, C. Synlett 2013, 24, 1606-1613.
-32.7
(-30.0)
8.0
TSI-II
Mn-Zn-IV
C-H activation
via CBMD
Me
Zn
Me
O
Me
a) B. Zhou, H. Chen, C. Wang, J. Am. Chem. Soc. 2013, 135, 1264-
1267; b) B. Zhou, P. Ma, H. Chen, C. Wang, Chem. Commun. 2014, 50,
14558-14561; c) R. He, Z. Huang, Q. Zheng, C. Wang, Angew. Chem.
Int. Ed. 2014, 53, 4950-4953; Angew. Chem. 2014, 126, 5050-5053; d)
R. He, X. Jin, H. Chen, Z.-T. Huang, Q.-Y. Zheng, C. Wang, J. Am.
Chem. Soc. 2014, 136, 6558-6561; e) B. Zhou, Y. Hu, C. Wang, Angew.
Chem. Int. Ed. 2015, 54, 13659-13663; Angew. Chem. 2015, 127,
13863-13867; f) X. Yang, X. Jin, C. Wang, Adv. Synth. Catal. 2016, 358,
2436-2442; g) Hu, Y.; Wang, C. Sci. China Chem. 2016, 59, 1301-1305;
h) B. Zhou, Y. Hu, T. Liu, C. Wang, Nat. Commun. 2017, 8, 1169-1177;
For selected examples from other groups: i) Y. Kuninobu, Y. Nishina, T.
Takeuchi, K. Takai, Angew. Chem. Int. Ed. 2007, 46, 6518-6520;
Angew. Chem. 2007, 119, 6638-6640; j) W. Liu, D. Zell, M. John, L.
Ackermann, Angew. Chem. Int. Ed. 2015, 54, 4092-4096; Angew.
Chem. 2015, 127, 4165-4169; k) L. Shi, X. Zhong, H. She, Z. Lei, F. Li,
Chem. Commun. 2015, 51, 7136-7139; l) S. Sueki, Z. Wang, Y.
Kuninobu, Org. Lett. 2016, 18, 304-307; m) N. P. Yahaya, K. M.
Appleby, M. Teh, C. Wagner, E. Troschke, J. T. W. Bray, S. B. Duckett,
L. A. Hammarback, J. S. Ward, J. Milani, N. E. Pridmore, A. C.
Whitwood, J. M. Lynam, I. J. S. Fairlamb, Angew. Chem. Int. Ed. 2016,
55, 12455-12459; Angew. Chem. 2016, 128, 12643-12647; n) Q. Lu, F.
J. R. Klauck, F. Glorius, Chem. Sci. 2017, 8, 3379-3383; o) H. Wang, M.
M. Lorion, L. Ackermann, Angew. Chem. Int. Ed. 2017, 56, 6339-6342;
Angew. Chem. 2017, 129, 6436-6439; p) C. Wang, A. Wang, M.
Rueping, Angew. Chem. Int. Ed. 2017, 56, 9935-9938; Angew. Chem.
2017, 129, 10067-10070; q) S.-Y. Chen, X.-L. Han, J.-Q. Wu, Q. Li, Y.
Chen, H. Wang, Angew. Chem. Int. Ed. 2017, 56, 9939-9943; Angew.
Chem. 2017, 129, 10071-10075; r) Y.-F. Liang, V. Müller, W. Liu, A.
Münch, D. Stalke, L. Ackermann, Angew. Chem. Int. Ed. 2017, 56,
9415-9419; Angew. Chem. 2017, 129, 9543-9547; s) Q. Lu, S. Greßies,
S. Cembellín, F. J. R. Klauck, C. G. Daniliuc, F. Glorius, Angew. Chem.
Int. Ed. 2017, 56, 12778-12782; Angew. Chem. 2017, 129, 12954-
12958; t) C. Zhu, J. L. Schwarz, S. Cembellín, S. Greßies, F. Glorius,
Angew. Chem. Int. Ed. 2018, 57, 437-441; Angew. Chem. 2018, 130,
445-449; u) Q. Lu, S. Cembellín Santos, S. Greßies, S. Singha, C.
Daniliuc, F. Glorius, Angew. Chem. Int. Ed. 2018, 57, 1399-1403;
Angew. Chem. 2018, 130, 1413-1417.
Me
CO
CO
Zn
Ph
2a
Zn CO
O
Me
O
Me
CO
CO
CO
G‡ = 19.4
Mn
CO
CO
Mn
CO
Mn
CH4
CH4
-21.3
-24.2
(-25.0)
-4.8
TSIII-IV
Mn-Zn-II
Mn-Zn-III
(-6.1)
Figure 1. A plausible mechanism with DFT calculations. The DFT-computed
relative Gibbs free energies and barriers (kcal/mol) are marked in red, and the
energetic data for species in cis-configuration are shown in parentheses.
In conclusion, we have developed the first redox-neutral C-H
olefination reaction of ketones with unactivated alkenes enabled
by Mn-Zn bimetallic synergy. This protocol is well tolerant of
diverse functional groups and applicable for broad substrate
scopes under mild reaction conditions. Mechanistic experiments
and DFT calculations revealed a Mn-Zn synergetic mode of C-H
activation via an unprecedented Concerted Bis-Metalation
Deprotonation (CBMD) mechanism and a direct intramolecular
H-transfer step instead of traditional β-H elimination/insertion
pathway in the catalytic cycle. Further mechanistic explorations
and synthetic applications of CBMD-enabled C-H activation
reactions are undergoing in our laboratory.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (21472194, 21772202, 21521002, 21473215) are
gratefully acknowledged.
Conflict of interest
[7]
For selected C-H activation reactions of protected benzylic alcohols: a)
K. Guo, X. Chen, M. Guan, Y. Zhao, Org. Lett. 2015, 17, 1802-1805; b)
Z. Ren, J. E. Schulz, G. Dong, Org. Lett. 2015, 17, 2696-2699.
For more details, please see the Supporting Information.
The authors declare no conflict of interest.
Keywords: manganese • C-H activation • olefination • ketones •
[8]
[9]
E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066-
3072; Angew. Chem. 2012, 124, 3120-3126.
alkenes
[10] a) E. Clementi, D. L. Raimond, W. P. Reinhardt, J. Chem. Phys. 1967,
47, 1300-1307; b) P. Pyykkö, M. Atsumi, Chem. Eur. J. 2008, 15, 186-
197.
[1]
[2]
a) Q.-Z. Zheng, N. Jiao, Tetrahedron Lett. 2014, 55, 1121-1126; b) Z.
Huang, H. N. Lim, F. Mo, M. C. Young, G. Dong, Chem. Soc. Rev. 2015,
44, 7764-7786.
[11]
D. L. Davies, S. A. Macgregor, C. L. McMullin, Chem. Rev. 2017, 117,
For selected examples: a) S. Murai, F. Kakluchi, S. Sekine, Y. Tanaka,
A. Kamatani, M. Sonoda, N. Chatani, Nature 1993, 366, 529-531; b) Y.
8649-8709.
This article is protected by copyright. All rights reserved.

10.1002/anie.201806287
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Y. Hu, B. Zhou, H. Chen*, C.
Wang*
The Beauty of Synergy: The
first manganese-catalyzed redox-
neutral C-H olefination of
Page No. – Page No.
ketones with unactivated alkenes
is described. Mechanistic studies
uncovered a unique Concerted
Bis-Metalation Deprotonation
(CBMD) mechanism of Mn-Zn-
enabled C-H bond activation and
a direct intramolecular H-transfer
step instead of traditional β-H
elimination/insertion pathway in
the catalytic cycle.
Manganese-Catalyzed Redox-
Neutral C-H Olefination of
Ketones with Unactivated
Alkenes
This article is protected by copyright. All rights reserved.