Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt-Catalyzed Multiple C(sp3)?H Activation Strategy

Article abstract of DOI:10.1002/anie.201707638

A cobalt-catalyzed dual C(sp³)?H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformation-induced methylene C(sp³)?H activation of the resulting cobaltabicyclo[4.n.1] intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide, by a triple C(sp³)?H activation, has also been demonstrated.

Full text of DOI:10.1002/anie.201707638

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Synthesis of Bicyclo[n.1.0]alkanes via Cobalt-Catalyzed Multiple
C(sp3)-H Activation Strategy
Authors: Zhuo-Zhuo Zhang, Ye-Qiang Han, Bei-Bei Zhan, Sai Wang,
and Bing-Feng Shi
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.201707638
Angew. Chem. 10.1002/ange.201707638
Link to VoR: http://dx.doi.org/10.1002/anie.201707638
http://dx.doi.org/10.1002/ange.201707638

10.1002/anie.201707638
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Bicyclo[n.1.0]alkanes via Cobalt-Catalyzed Multiple
C(sp3)-H Activation Strategy
Zhuo-Zhuo Zhang,[a] Ye-Qiang Han,[a] Bei-Bei Zhan,[a] Sai Wang,[a] and Bing-Feng Shi*[a,b]
Abstract: A cobalt-catalyzed dual C(sp3)-H activation strategy has
been developed, providing a novel strategy for the synthesis of
bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the
success of this reaction is the conformation-induced methylene
C(sp3)-H activation of the resulting cobaltabicyclo[4.n.1]
intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from
pivalamide via triple C(sp3)-H activation has also been demonstrated.
Recently, cobalt metals have emerged as robust and versatile
catalysts for directed C-H activation, due to their abundance, cost
effectiveness, and unique modes of action.[9-12] Daugulis first
realized that the monoanionic, bidentate 8-aminoquinoline
(AQ)[13] could enable the use of bench-stable cobalt(II) salts as
pre-catalysts via the in situ generation of high valent Co(III)
species.[11a,b] This reactivity mode was then used for the
functionalization of C(sp3)-H by Ge,[11i] Zhang,[11j] Sundararaju,[11k]
Gaunt,[11l] and Lei.[11m] Inspired by the unique reactivity of AQ
auxiliary in cobalt-catalyzed C(sp3)-H activation and our
continuous interest in C(sp3)-H activation,[14] we speculated that a
cobalt-catalyzed methyl C(sp3)-H activation followed by
intramolecular migratory insertion could afford bridged
cobaltacycle intermediate A, which underwent a methylene C-H
activation to form intermediate B. Subsequent C-C bond reductive
elimination would provide the bicyclo[n.1.0] skeletons (Figure 2).
Cyclopropanes and related polycyclic compounds have profound
applications in medicinal and synthetic chemistry.[1] In particular,
bicyclo[n.1.0] ring systems are prevalent structures in biologically
important agents, such as isodebromolaurinterol,[2a] Phlain I,[2b]
and chromolaevane dione[2c] for the bicyclo[3.1.0]hexanes;
curcumenone,[2d]
and sesquicaranoic
acids
B,[2e]
as
bicyclo[4.1.0]heptane (Figure 1). Owing to these facts, the
synthesis of [n.1.0] bicycles has been the subject of intensive
research. Many elegant methods have been developed, including
transition metal-catalyzed diazo decomposition/alkene insertion,
Michael-initiated ring closure, metal-catalyzed cycloisomerization
O
O
This Work
[Co]
R
R
O
NHQ
( )n
NHQ
Q
N
n = 1, 2
( )n
H
H
H
of
1,6-enynes,
and
intramolecular
Simmons-Smith
( )n
3
cyclopropanation.[3] An attractive and complementary strategy is
reaction sequences that involve C(sp3)-H activation.[4] Recently,
transition-metal-catalyzed direct C(sp3)-H functionalization of
cyclopropanes has been well investigated.[5] However, the de
novo synthesis of cyclopropanes via C(sp3)-H functionalization
remains rare.[6-8] Sato, Mukai and Tanaka have reported the Rh(I)-
catalyzed oxidative cycloaddition of 1,6-enynes followed by
rhodacycle-directed C(sp3)-H bond activation.[6] Another
interesting strategy involves oxidative addition of Pd(0) to
arylhalides, Heck-type carbopalladation to form C(sp3)-Pd(II)
complex, which enables a subsequent C(sp3)-H bond activation.[7]
Here we report the successful synthesis of [3.1.0] and [4.1.0]
bicycloalkanes via a Co-catalyzed dual C(sp3)-H bond activation.
–
methyl C(sp ) H activation
C–C R. E.
& migratory insertion
( )n
X
O
( )n O
methylene
protonation
C(sp3) H activation
N
N
R
R
–
Co
Ln
N
Co
N
H
Ln
B
-H
elimination
A
C–N R. E.
O
Q
N
O
H
( )n
( )n
N
Q
Figure 2. Design of a cobalt-catalyzed dual C(sp3)-H activation to access
bicyclo[n.1.0] ring systems.
However, the development of such kind of transformation was
expected to face several formidable challenges. First, Co-
catalyzed transformation of unactivated C(sp3)-H bond is
extremely underdeveloped.[11i-n,12] Especially, the presence of an
alkene group in the starting material might outcompete the
interaction of cobalt with the aliphatic C-H bond, thus preventing
the C-H cleavage. Second, it was unclear whether methylene
C(sp3)-H activation could occur from the cobaltacycle
intermediate A and whether this pathway would be faster than the
competitive side reactions of the cobaltacycle, such as C-N
reductive elimination, β-H elimination, or protonation (Figure 2).
Nevertheless, encouraged by recent reports on conformation-
induced C-H activation,[15] we anticipated that the pre-distortion of
the bridged cobaltacycle would induce a strong proximity between
one methylene C(sp3)-H bond on the one carbon bridge and the
Co(III) center, making the subsequent C-H cleavage much more
favorable as compared to a typical Co-catalyzed methylene C-H
activation.[16] Third, whether the high ring strain energy in the
resulting bicyclo[n.1.0] ring systems would be survived under the
rather complicated reaction conditions.
OH
Me
H
O
O
H
H
MeO
Me
OMe
H
O
Chromolaevane dione
Phlain I
HOOC
Isodebromolaurinterol
H
H
O
O
OH
OH
Curcumenone
Sesquicaranoic acids
B
Figure 1. Pharmaceutical agents and natural products containing bicyclo[n.1.0]
skeletons.
[a]
[b]
Z.-Z. Zhang, Y.-Q. Han, B.-B. Zhan, S. Wang, Prof. Dr. B.-F. Shi
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
E-mail: bfshi@zju.edu.cn.
Homepage: http://mypage.zju.edu.cn/en/bfshi/.
Prof. Dr. B.-F. Shi
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071 (China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/anie.201707638
Angewandte Chemie International Edition
COMMUNICATION
We initiated our investigation by chose 2,2-dimethyl-N-(quinolin-
8-yl)hept-6-enamide (1a) as the model substrate. The desired
product 2a was obtained in 68% isolated yield with 20 mol%
Co(OAc)2·4H2O, 2.5 equiv Ag2CO3, 1.0 equiv TOAB, 1.0 equiv
Na2HPO4, 5 mol% 2,5-dihydroxybenzoquinone (2,5-DHBQ) in n-
hexane at 140 oC for 24 h under argon atmosphere (Table 1, entry
1). The choices of catalyst, silver salt, and quaternary ammonium
salt are crucial for this transformation. Control experiments
revealed that no product was observed in the absence of either
Co(OAc)2·4H2O, Ag2CO3 or TOAB (entries 2-4). Other metal
catalysts, such as Rh2(OAc)4, Mn(OAc)2, and Ni(OAc)2·6H2O,
were ineffective for this transformation (see SI for details). Since
TOAB was crucial for the reaction, we further tested various other
quaternary ammonium salts (see Table S5 for details). The
replacement of TOAB with TBAI resulted in a slightly reduced
yield (entry 8, 52%). We hypothesized that those quaternary
ammonium salts may act as phase transfer catalyst to enhance
the solubility of the reactants.[11j,17] The removal of Na2HPO4 or
2,5-DHBQ resulted in slightly lower yields (entries 9-10). In
addition, a systemic investigation of various solvents revealed
that the reaction was very sensitive to solvent effect and only
proceeded in nonpolar alkanes (entries 11-15 and Table S1).
in 70% yield. The α-aryl-substituted substrates were also
evaluated under the optimized conditions. α-Phenyl substrate
gave the desired compound in 60% yield (2h). When α-tolyl
substrates (1i-1k) were examined, 1i with an ortho-methyl
substituent led to lower yield (2i, 32%), compared to the meta-
and para-methyl substituted substrates (2j, 56%; 2k, 71%). These
results indicated that the reaction was strongly influenced by
steric hindrance. In addition, halides, such as fluoride and
bromide, were also tolerated (2l and 2m). Substrates bearing
strong electron-donating methoxy groups on the aryl ring were
also compatible with the reaction, giving the target products in
moderate yields (2n and 2o). Finally, the feasibility of extending
this methodology to α-benzyl and naphthyl substrates was also
demonstrated in moderate yields (2q, 52%; 2r, 65%).
Table 2. Scope for the synthesis of bicyclo[4.1.0]heptanes[a]
Table 1. Optimization of reaction conditions[a]
O
O
NHQ
"standard conditions"
NHQ
H
H
1a
2a
entry
derivation from standard conditions
yield (%)[b]
1
2
none
no Co(OAc)2·4H2O
68[c]
0
3
no Ag2CO3
0
4
no TOAB
0
5
Rh2(OAc)4 instead of Co(OAc)2·4H2O
Mn(OAc)2 instead of Co(OAc)2·4H2O
Ni(OAc)2·6H2O instead of Co(OAc)2·4H2O
TBAI instead of TOAB
no Na2HPO4
0
6
0
7
0
8
52
55
52
50
54
15
0
9
10
11
12
13
14
15
no 2,5-DHBQ
cyclohexane instead of n-hexane
n-pentane instead of n-hexane
n-decane instead of n-hexane
HFIP
DCE
0
[a] Standard conditions: 1a (0.10 mmol), Co(OAc)2·4H2O (0.02 mmol), Ag2CO3
(0.25 mmol), TOAB (0.10 mmol), Na2HPO4 (0.10 mmol), 2,5-DHBQ (0.005
mmol), n-hexane (1.5 mL), under argon for 24 h at 140 °C. [b] Yield was
determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard.
[c] Isolated yield. 2,5-DHBQ = 2,5-dihydroxy-p-benzoquinone, TOAB = tetra-n-
octylammonium bromide, TBAI
= tetra-n-butylammonium iodide, HFIP =
hexafluoroisopropyl alcohol, DCE = dichloroethane, Q = quinolin-8-yl.
Under
the
optimized
reaction
conditions,
various
With the optimized conditions in hand, we then examined the
scope of the synthesis of bicyclo[4.1.0]heptanes 2 (Table 2). To
our delight, this C–H cyclopropanation reaction proceeded in
good yields to substrates bearing various linear chains (2a–2g).
The methyl ether was well tolerated, giving the desired product in
62% yield. When two terminal alkenes were present in the
substrate, the remote alkene was survived and the ε-olefin
reacted exclusively to afford the desired bicyclo[4.1.0]heptane 2g
bicyclo[3.1.0]hexanes were also synthesized (Table 3). The α-
methyl and phenyl substituted-5-enamides were viable, affording
the desired product 2s and 2t in 42% and 65% yields, respectively.
X-ray analysis of 2t unambiguously established its structure
having a bicyclo[3.1.0]hexane skeleton.[18] Unfortunately, this
protocol was unfeasible for the synthesis of bicyclo[5.1.0]octane
2u.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707638
Angewandte Chemie International Edition
COMMUNICATION
Table 3. Scope for the synthesis of other bicyclo[n.1.0]alkanes.
the following experimental results. Upon exposure to the standard
conditions, substrates 1v and 1w, having hydrogen at the allylic
position, gave the desired products (2v, 19% and 2w, 47%) along
with the monocyclic products 2va and 2wa in 21% and 10% yields,
respectively (eq 2). The formation of monocyclic products 2va and
2wa could be explained by β-H elimination of an analogous
cobaltabicyclo[4.n.1] INT-C’.
O
O
( )n
N
N
H
H
Ag(I)
CoX2Ln
N
N
H
H
H
( )n
1
2
Ag(I), HX
reoxidation
complexation/
oxidation of Co(II)
O
( )n
N
O
( )n
N
Co
Ln
N
H
X
X
Co
Ln
N
INT-A
INT-E
Encouraged by these results, we then investigate the feasibility
of synthesis of bicyclo[3.1.0]hexane 2s from pivalamide 4 via
triple C(sp3)-H activation. To our delight, 2s was prepared in 35%
yield via a C(sp3)-H allylation/cyclopropanation sequence that
involved the cleavage of three C(sp3)-H bonds under slightly
modified conditions (Scheme 1). Notably, this also represents the
first cobalt-catalyzed C(sp3)-H allylation.[10c-e]
methyl C(sp3)H
activation
reductive
elimination
( )n
O
N
O
( )n
N
Co
Ln
INT-D
N
H
N
Co
X
methylene C(sp3)H
Ln
insertion
O
( )n
X
activation
INT-B
N
Co
Ln
INT-C
N
H
Figure 3. Proposed catalytic cycle.
O
Scheme 1. Synthesis of bicyclo[3.1.0]hexane 3a via triple C(sp3)-H activation.
O
H
O
NHQ
H
standard
conditions
NHQ
NHQ
N
R
(2)
R
Co
Ln
N
To gain insight into the reaction mechanism, H/D exchange
experiment was performed in the presence of H2O (eq 1). No D/H
exchange was observed when 1a-[d3] was treated under
standard conditions. This result indicated that an irreversible
process might exist in the C–H activation step.
R
H
X
H
H
Me
R
2va,
2wa
1v
, R = Me
2v,
R = Me, 19%
2w
, R = H, 47%
R = Me, 21%
, R = H, 10%
INT-C'
1w
, R = H
Recently, Zhang et al. revealed that Co(II)-catalyzed
cyclopropanation of alkenes proceeded through an unusual
Co(III)-carbene radical intermediate undertaking a stepwise
radical addition-substitution pathway.[20] To verify this possibility,
substrae 1x was subjected to the standard reaction conditions.[19b]
The corresponding tricyclic cyclopropanation product 2x was
obtained exclusively without the observation of any ring opening
products of the cyclopropane (eq 3). This result might rule out the
formation of Co(III)-carbene radical intermediate INT-F and INT-
G.
The mechanism of this protocol is tentatively rationalized on the
basis of precedents11,19 and our mechanistic studies (Figure 3).
Co(II) catalyst first coordinates with substrate 1 and is then
oxidized by Ag(I) to generate INT-A.[11m] INT-A undergoes
irreversible methyl C(sp3)-H activation to afford cobaltacyle INT-
B. Subsequent intramolecular alkene insertion into the Co(III)-C
bond affords the cobaltabicyclo[4.n.1] intermediate INT-C. As
rationalized above, conformation-induced methylene C−H
activation of INT-C leads to the cobalta-cyclobutane intermediate
INT-D,[15] which undergoes C−C reductive elimination to give INT-
E. Protonation of the N−Co(I) bond and reoxidation of the Co(I)
species with Ag(I) will release the bicyclo[n.1.0]alkane 2 and
regenerates the active Co(III) species. The occurrence of
cobaltabicyclo[4.n.1] intermediate INT-C is strongly supported by
O
O
O
O
NHQ
standard
N
N
conditions
(3)
NHQ
N
N
Co
Ln
Co
X
X
H
H
Ln
INT-G
INT-F
1x
2x,
22%
Finally, the directing group could be removed by oxidation when
a 5-methoxyquinolyl was used as the directing group. 8-Amino-5-
methoxyquinoline enamides gave product 4a in 60% yield. The
auxiliary
can
be
readily
cleaved
affording
2-
This article is protected by copyright. All rights reserved.

10.1002/anie.201707638
Angewandte Chemie International Edition
COMMUNICATION
[6]
[7]
a) Y. Oonishi, Y. Kitano, Y. Sato, Angew. Chem. Int. Ed. 2012, 51, 7305;
b) C. Mukai, Y. Ohta, Y. Oura, Y. Kawaguchi, F. Inagaki, J. Am. Chem.
Soc. 2012, 134, 19580; c) K. Masutomi, K. Noguchi, K. Tanaka, J. Am.
Chem. Soc. 2014, 136, 7627.
a) S. Schweizer, Z.-Z. Song, F. E. Meyer, P. J. Parsons, A. de Meijere,
Angew. Chem. Int. Ed. 1999, 38, 1452; b) F. Liron, P. Knochel,
Tetrahedron Lett. 2007, 48, 4943; c) H. S. Kim, S. Gowrisankar, S. H.
Kim, J. N. Kim, Tetrahedron Lett. 2008, 49, 3858; d) Mao, J.; Zhang, S.-
Q.; Shi, B.-F.; Bao, W. Chem. Commun. 2014, 50, 3692.
methylbicyclo[4.1.0]heptane-2-carboxamide 5a in 62% yield
(Scheme 2).[21]
[8]
[9]
For an example of Rh(III)-catalyzed cycloparopanation initiated by
olefinic C-H activation, see: T. Piou, T. Rovis, J. Am. Chem. Soc. 2014,
136, 11292.
For recent reviews, see: a) S. I. Kozhushkov, H. K. Potukuchi, L.
Ackermann, Catal. Sci. Technol. 2013, 3, 562; b) K. Gao, N. Yoshikai,
Acc. Chem. Res. 2014, 47, 1208; c) L. Ackermann, J. Org. Chem. 2014,
79, 8948; d) M. Moselage, J. Li, L. Ackermann, ACS Catal. 2016, 6, 498;
e) D. Wei, X. Zhu, J.-L. Niu, M.-P. Song, ChemCatChem. 2016, 8, 1242;
f) T. Yoshino, S. Matsunaga, Adv. Synth. Catal. 2017, 359, 1245.
Scheme 2. Removal of the Quinolyl Group.
In summary, we have developed a highly efficient strategy for
the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes
via cobalt-catalyzed dual C(sp3)-H activation. A key to the
success of this reaction is the conformation-induced methylene
C(sp3)-H activation of the resulting cobaltabicyclo[4.n.1]
intermediate. Importantly, the synthesis of bicyclo[3.1.0]hexane
from pivalamide via triple C(sp3)-H activation has also been
demonstrated. Further studies on the synthetic applications of this
strategy is underway.
[10] For selected examples using high-valent Cp*Co(III), see: a) T. Yoshino,
H. Ikemoto, S. Matsunaga, M. Kanai, Angew. Chem. Int. Ed. 2013, 52,
2207; b) T. Yoshino, H. Ikemoto, S. Matsunaga, M. Kanai, Chem. Eur. J.
2013, 19, 9142; c) H. Ikemoto, T. Yoshino, K. Sakata, S. Matsunaga, M.
Kanai, J. Am. Chem. Soc. 2014, 136, 5424; d) D.-G. Yu, T. Gensch, F.
de Azambuja, S. Vasquez-Cespedes, F. Glorius, J. Am. Chem. Soc.
2014, 136, 17722; e) D. Zhao, J. H. Kim, L. Stegemann, C. A. Strassert,
F. Glorius, Angew. Chem. Int. Ed. 2015, 54, 4508; f) J. Li, L. Ackermann,
Angew. Chem. Int. Ed. 2015, 54, 8551; g) J. Li, L. Ackermann, Angew.
Chem. Int. Ed. 2015, 54, 3635; h) J. R. Hummel, J. A. Ellman, J. Am.
Chem. Soc. 2015, 137, 490; i) J. R. Hummel, J. A. Ellman, Org. Lett. 2015,
17, 2400; j) J. Park, S. Chang, Angew. Chem. Int. Ed. 2015, 54, 12711;
k) P. Patel, S. Chang, ACS Catal. 2015, 5, 853; l) L. Kong, S. Yu, X. Zhou,
X. Li, Org. Lett. 2016, 18, 588; m) F. Wang, H. Wang, Q. Wang, S. Yu, X.
Li, Org. Lett. 2016, 18, 1306; n) Y. Liang, N. Jiao, Angew. Chem. Int. Ed.
2016, 55, 4035; o) X.-G. Liu, S.-S. Zhang, C.-Y. Jiang, J.-Q. Wu, Q. Li, H.
Wang, Org. Lett. 2015, 17, 5404; p) Z.-Z. Zhang, B. Liu, C.-Y. Wang, B.-
F. Shi, Org. Lett. 2015, 17, 4094; q) Z.-Z. Zhang, B. Liu, J.-W. Xu, S.-Y.
Yan, B.-F. Shi, Org. Lett. 2016, 18, 1776.
[11] For selected examples using Co(II) as pre-catalyst that assisted by
bidentate directing groups, see: a) Grigorjeva, L.; Daugulis, O. Angew.
Chem. Int. Ed. 2014, 53, 10209; b) L. Grigorjeva, O. Daugulis, Org. Lett.
2014, 16, 4688; c) L.-B. Zhang, X.-Q. Hao, S.-K. Zhang, Z.-J. Liu, X.-X.
Zheng, J.-F. Gong, J.-L. Niu, M.-P. Song, Angew. Chem. Int. Ed. 2015,
54, 272; d) L.-B. Zhang, X.-Q. Hao, Z.-J. Liu, X.-X. Zheng, S.-K. Zhang,
J.-L. Niu, M.-P Song, Angew. Chem. Int. Ed. 2015, 54, 10012; e) S. Maity,
R. Kancherla, U. Dhawa, E. Hoque, S. Pimparkar, D. Maiti, ACS Catal.
2016, 6, 5493; f) N. Thrimurtulu, A. Dey, D. Maiti, M. R. C. Volla, Angew.
Chem. Int. Ed. 2016, 55, 12361; g) P. Gandeepan, P. Rajamalli, C.-H.
Cheng Angew. Chem. Int. Ed. 2015, 55, 4308; h) G. Tan, S. He, X. Huang,
X. Liao, Y. Cheng, J. You, Angew. Chem. Int. Ed. 2015, 55, 10414; i) X.
Wu, Yang, K.; Y. Zhao, H. Sun, G. Li, H. Ge, Nat. Commun. 2015, 6,
6462; j) J. Zhang, H. Chen, C. Lin, Z Liu, C. Wang, Y. Zhang, J. Am.
Chem. Soc. 2015, 137, 12990; k) N. Barsu, S. K. Bolli, B. Sundararaju,
Chem. Sci. 2017, 8, 2431; l) P. Williamson, A. Galván, M. J. Gaunt, Chem.
Sci. 2017, 8, 2588; m) L. Zeng, S. Tang, D. Wang, Y. Deng, J.-L. Chen,
J.-F. Lee, A. Lei, Org. Lett. 2017, 19, 2170.
Acknowledgements
Financial support from the NSFC (21422206, 21572201), the
National Basic Research Program of China (2015CB856600) and
Zhejiang Provincial NSFC (LR17B020001) is gratefully
acknowledged. We thank Prof. Xin Hong and Mr. Shuo-Qing
Zhang for helpful discussions.
Keywords: cobalt • multiple C(sp3)-H activation • distortion •
cyclopopanation • bicyclo[n.1.0]alkanes
[1]
[2]
For selected reviews, see: a) A. de Meijere, S. I. Kozhushkov, H. Schill,
Chem. Rev. 2006, 106, 4926; b) M. Shi, J.-M. Lu, Y. Wei, L.-X. Shao,
Acc. Chem. Res. 2012, 45, 641; c) L. Jiao, Z.-X. Yu, J. Org. Chem. 2013,
78, 6842.
a) G. M. König, A. D. Wright, O. Sticher, C. K. Angerhofer, J. M. Pezzuto,
Planta Med. 1994, 60, 532; b) S. Nakamura, J. Iwami, H. Matsuda, H.
Wakayama, Y. Pongpiriyadacha, M. Yoshikawa, Chem. Pharm. Bull.
2009, 57, 1267; c) H.-J. Zhang, N. V. Hung, N. M. Cuong, D. D. Soejarto,
J. M. Pezzuto, H. S. Fong, G. T. Tan, Planta Med. 2005, 71, 452; d) H.
Matsuda, T. Morikawa, K. Ninomiya, M. Yoshikawa, Tetrahedron 2001,
57, 8443; e) Y.-H. G.-J. Zhang, Li, J.-D. Jiang, S.-S. Yu, X.-J. Wang, P.-
Y. Zhuang, Y. Zhang, J. Qu, S.-G. Ma, Y. Li, Y.-B. Liu, D.-Q. Yu,
Tetrahedron 2014, 70, 4494.
[12] a) Sen, M.; Emayavaramban, B.; Barsu, N.; Premkumar, R. J.;
Sundararaju, B. ACS Catal. 2016, 6, 2792; b) Barsu, N.; Rahman, Md.
A.; Sen, M.; Sundararaju, B. Chem. Eur.–J. 2016, 22, 9135.
[13] For pioneering report and selected reviews on the use of bidentate
auxiliaries, see: (a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am.
Chem. Soc. 2005, 127, 13154; For representative reviews, see: (b) G.
Rouquet, N. Chatani, Angew. Chem., Int. Ed. 2013, 52, 11726; (c) B.
Zhang, H.-X. Guan, B. Liu, B.-F. Shi, Chin. J. Org. Chem. 2014, 34, 1487;
(d ) O. Daugulis, J. Roane, L. D. Tran, Acc. Chem. Res. 2015, 48, 1063;
(e) M. R. Yadav, R. K. Rit, M. Shankar, A. K. Sahoo, Asian J. Org. Chem.,
2015, 4, 846; (f) G. He, B. Wang, W. A. Nack, G. Chen, Acc. Chem. Res.
2016, 49, 635.
[14] a) K. Chen, F. Hu, S.-Q. Zhang, B.-F. Shi, Chem. Sci. 2013, 4, 3906; b)
Q. Zhang, K. Chen, W.-H. Rao, Y. Zhang, F.-J. Chen, B.-F. Shi, Angew.
Chem. Int. Ed. 2013, 52, 13588; c) K. Chen, B.-F. Shi, Angew. Chem. Int.
Ed. 2014, 53, 11950; d) Q. Zhang, X.-S. Yin, K. Chen, S.-Q. Zhang, B.-
F. Shi, J. Am. Chem. Soc. 2015, 137, 8219; e) J.-W. Xu, Z.-Z. Zhang, W.-
H. Rao, B.-F. Shi, J. Am. Chem. Soc. 2016, 138, 10750; f) G. Liao, X.-S.
Yin, K. Chen, Q. Zhang, S.-Q. Zhang, B.-F. Shi, Nat. Commun. 2016, 7,
12901; g) Y.-J. Liu, Y.-H. Liu, Z.-Z. Zhang, S.-Y. Yan, K. Chen, B.-F. Shi,
Angew. Chem. Int. Ed. 2016, 128, 14603.
[3]
[4]
a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev.
2003, 103, 977; b) M. P. Doyle, D. C. Forbes, Chem. Rev. 1998, 98, 911;
c) H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103, 2861; d) S.
I. Lee, N. Chatani, Chem. Commun. 2009, 371; e) E. Jiménez-Núñez, A.
M. Echavarren, Chem. Rev. 2008, 108, 3326; f) J. A. Bull, A. B. Charette,
J. Am. Chem. Soc. 2010, 132, 1895.
For selected reviews on C(sp3)-H activation, see: a) X. Chen, K. M. Engle,
D.-H. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094; b) O.
Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 2009, 42, 1074; c)
R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer, O. Baudoin, Chem.
Eur. J. 2010, 16, 2654; d) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010,
110, 1147; e) H. Li, B.-J. Li, Z.-J. Shi, Catal. Sci. Technol. 2011, 1, 191; f)
J. F. Hartwig, M. A. Larsen, ACS Cent. Sci. 2016, 2, 281; g) O. Baudoin,
Acc. Chem. Res. 2017, 50, 1114.
For selected examples, see: a) P. M. Holstein, D. Dailler, J. Vantourout,
J. Shaya, A. Millet, O. Baudoin, Angew. Chem. Int. Ed. 2016, 55, 2805;
b) J. Pedroni, N. Cramer, Angew. Chem. Int. Ed. 2015, 54, 11826; c) T.
Saget, N. Cramer, Angew. Chem. Int. Ed. 2012, 51, 12842; d) K. S. L.
Chan, H.-Y. Fu, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137, 2042; e) C. W.
Liskey, J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 3375; f) D. S. Roman,
A. B. Charette, Org. Lett. 2013, 15, 4394; g) C. L. Ladd, D. S. Roman, A.
B. Charette, Org. Lett. 2013, 15, 1350; h) R. Parella, B. Gopalakrishnan,
S. A. Babu, Org. Lett. 2013, 15, 3238; i) R. Giri, X. Chen, J.-Q. Yu, Angew.
Chem. Int. Ed. 2005, 44, 2112. And references therein.
[5]
[15] a) W. Cui, S. Chen, J.-Q. Wu, X. Zhao, W. Hu, H. Wang, Org. Lett. 2014,
16, 4288; b) J. J. Topczewski1, P. J. Cabrera1, N. I. Saper1, M. S.
Sanford, Nature 2016, 531, 220.
[16] Only a few examples of Co-catalyzed methylene C(sp3)-H activation
have been reported, which were limited to the relatively activated
benzylic and cyclopropyl C(sp3)-H bonds, see references 11i, 11k-m.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707638
Angewandte Chemie International Edition
COMMUNICATION
[17] Quaternary ammonium salts are known to facilitate C-H activation and
stabilize the catalysts, see also: a) a) T.-S. Mei, D.-H. Wang, J.-Q. Yu,
Org. Lett. 2010, 12, 3140; b) D.-W. Gao,Y.-C. Shi, Q. Gu, Z.-L. Zhao, S.-
L. You, J. Am. Chem. Soc. 2013, 135, 86; c) W. Li, N. Dastbaravardeh,
G. Li, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 18056; d) F.-J. Chen, G.
Liao, X. Li, J. Wu, B.-F. Shi, Org. Lett. 2014, 16, 5644.
[20] a) H. Lu, W. I. Dzik, X. Xu, L. Wojtas, B. de Bruin, X. P. Zhang, J. Am.
Chem. Soc. 2011, 133, 8518; b) J. L. Belof, C. R. Cioce, X. Xu, X. P.
Zhang, B. Space, H. L. Woodcock, Organometallics, 2011, 30, 2739; c)
W. I. Dzik, X. Xu, x. P. Zhang, J. N. H. Reek, B. de Bruin, J. Am. Chem.
Soc. 2010, 132, 10891.
[21] G. He, S.-Y. Zhang, W. A. Nack, Q. Li, G. Chen, Angew. Chem. Int. Ed.
2013, 52, 11124.
[18] CCDC 1525079 (2t) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[19] a) D. Zell, Q. Bu, M. Feldt, L. Ackermann, Angew. Chem. Int. Ed. 2016,
55, 7408; b) R. Mei, H. Wang, S. Warratz, S. A. Macgregor, L. Ackermann,
Chem. Eur. J. 2016, 22, 6759.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707638
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
O
O
Zhuo-Zhuo Zhang, Ye-Qiang Han, Bei-Bei
Zhan, Sai Wang, Bing-Feng Shi*
R
R
NHQ
R1
[Co]
( )n
NHQ
n = 1, 2
( )n
R2
R1
R2
H
H
Page No. – Page No.
methyl C(sp3)–H activation
C–C R. E.
& migratory insertion
Synthesis of Bicyclo[n.1.0]alkanes via
Cobalt-Catalyzed Multiple C(sp3)-H
Activation Strategy
O
O
( )n
( )n
R1
R1
methylene
C(sp3) H activation
N
N
R
R
–
R
R
2N
2N
Co
Co
Ln
H
X
Ln
A cobalt-catalyzed dual C(sp3)-H activation strategy has been developed, providing
novel strategy for the synthesis of bicyclo[4.1.0]heptanes and
a
bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformation-
induced methylene C(sp3)-H activation of the resulting cobaltabicyclo[4.n.1]
intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide via
triple C(sp3)-H activation has also been demonstrated.
This article is protected by copyright. All rights reserved.