Palladium-Catalyzed Divergent Cyclopropanation by Regioselective Solvent-Driven C(sp3)?H Bond Activation

Article abstract of DOI:10.1002/anie.201809133

Reported is a tandem palladium-catalyzed Heck/regioselective C(sp³)?H activation reaction for the divergent synthesis of spiro- and fused-cyclopropanated indolines from N-methallylated 2-bromoarylamides. The regioselectivity of the C?H bond activation in the σ-alkylPd^II intermediate is controlled by the solvent used. DFT calculations suggest that the polarity of solvent molecules could influence the transition-state energy, leading to a bifurcation of the C?H bond activation in the σ-alkylPd^II intermediate.

Full text of DOI:10.1002/anie.201809133

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Palladium-Catalyzed Tandem Divergent Cyclopropanation via
Solvent-Driven Regioselective C(sp3)-H Bond Activation
Authors: Da Sol Chung, Jae Sung Lee, Ho Ryu, Jiong Park, Hyunjoong
Kim, Joo Hyun Lee, U Bin Kim, Won Koo Lee, Mu-Hyun Baik,
and Sang-gi Lee
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809133
Angew. Chem. 10.1002/ange.201809133
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http://dx.doi.org/10.1002/ange.201809133

10.1002/anie.201809133
Angewandte Chemie International Edition
COMMUNICATION
Palladium-Catalyzed Tandem Divergent Cyclopropanation via
Solvent-Driven Regioselective C(sp3)–H Bond Activation
Da Sol Chung+, Jae Sung Lee+, Ho Ryu, Jiyong Park, Hyunjoong Kim, Joo Hyun Lee, U Bin Kim, Won
Koo Lee,* Mu-Hyun Baik,* and Sang-gi Lee*
Abstract:
We
report
a
palladium-catalyzed
tandem
catalytic processes involving -alkylPd (II) intermediates,[6] we
envisioned
tandem Heck/regiodivergent C(sp3)-H bond
activation reaction where using a solvent “switch”, manipulation
of the spatial conformation of -alkylPd(II)-intermediate arising
from Heck-type oxidative addition of 1 with Pd(0) catalyst would
Heck/regioselective C(sp3)–H activation for divergent synthesis of
spiro- and fused-cyclopropanated indolines from N-methallylated 2-
bromoarylamides. The regioselectivity of the C–H bond activation of
–alkylPd(II) intermediate could be controlled by the choice of the
solvent used. DFT calculations suggest that the polarity of solvent
molecules could influence the transition state energy, leading to a
bifurcation of the C–H bond activation by the -alkylPd(II)
intermediate.
a
lead to
palladium-catalyzed carbopalladation cascades have been
utilized for construction of carbo- and heterocyclic motifs,[7]
regiodivergent activation of different C(sp3)-H bonds mediated
a
regiodivergent outcome. Although Heck-type
a
by
the
common
-alkylPd(II)-intermediates
remain
unprecedented.
Divergent catalysis, which can provide different products
from a common precursor through intricate yet precise control of
different catalytic pathways, is a highly attractive synthetic
manoeuvre.[1] In particular, transition metal catalyzed C-H
functionalization represents one of the most straightforward,
powerful, and atom-economical methods to realize site-selective
catalysis.[2] During last decades, the directing group-guided
regioselective functionalization of (hetero)arene C(sp2)-H bonds
has been extensively studied.[3] However, the divergent
activation of less reactive C(sp3)-H bonds in a molecule remain
far less demonstrated.[4] For example, Yang and co-workers
(A) Base-driven divergent C(sp3)-H functionalization (Yang et al. 2015)4a
R1
R1
O
N
R1
O
Hb
O
Pd/L
tBuOK
Pd/L
NH
N
Ar
K2CO3
Ar
Ar
O2(1 atm)
O2(1 atm)
Ha
benzylic C-Ha activation
amide C-Hb functionalization
(B) Ligand-driven divergent C(sp3)-H activation (Schomaker et al. 2014)4b
O
H2N
O
O
O
O
S
reported
base-controlled
divergent
C(sp3)-H
bond
O
S
S
L2AgOTf
Ha
O
HN
R1
O
Hb
L1AgOTf
Hb
Ha
O
NH
R2
functionaliztions of -alkylPd(II) intermediates formed by Pd-
catalyzed aminoalkylation of unsaturated anilides (Scheme
1A).[4a] Schomaker and co-workers utilized different ligands on
Ag catalyst to tune for steric and electronic factors and
regioselectively activate different C(sp3)-H bonds of alkyl
sulfamates (Scheme 1B).[4b] Herein, we report a conceptually
distinctive solvent-driven regiodivergent C(sp3)-H bond activation
for tandem one-pot selective synthesis of spiro-(2) and fused-(3)
cyclopropanated indolines from the same N-methallyl 2-
bromoarylamides 1 (Scheme 1C).
R1
R2
R2
R1
C-Ha activation
C-Hb activation
(C) Solvent-driven divergent C(sp3)-H activation (This work)
Br
Hb Ha
Pd/L
Pd/L
Ar
Ar
Ar
nonpolar
solvent
polar
H
N
N
N
solvent
O
O
R
O
R
R
3
C-Hb activation
C-Ha activation
1
2
Cyclopropanated N-heterocycles are ubiquitous scaffolds
that feature prominently in natural products and bioactive
molecules.[5] During our studies on divergent yet tandem
Scheme 1. Regiodivergent C(sp3)–H Activations.
To effect the proposed solvent-controlled tandem
Heck/regiodivergent C(sp3)-H activation reaction, we employed
1a as a test substrate under Pd catalysis (Table 1, for details
see Tables S1 and S2 in SI). In polar coordinating solvents such
as DMF and NMP, the C-Ha bond of the methyl group was
activated in presence of Pd(OAc)2/PPh3 to afford spiro-
cyclopropanated 2a as a major product along with significant
amounts of dimethylated indoline 4a (entries 1 and 2, Table 1).
When 1.0 equivalent of pivalic acid was added, increased
conversion was achieved, although the reaction was largely
unselective, furnishing a mixture of 2a:3a:4a with ratio of
48%:12%:21% (entry 3, Table 1). Replacing the polar NMP
solvent with non-polar p-xylene altered the regioselectivity to
result in the formation of 2a/3a in a 9%:12% ratio, but undesired
protonated compound 4a (27%) was formed as the major
product (entry 4, Table 1). Conversion and selectivity did not
increase when using other bases such as Cs2CO3 in NMP or
p-xylene (entries 5 and 6, Table 1) or when using bidentate
[*]
D. S. Chung, J. H. Lee, Dr. U B. Kim, Prof. Dr. S.-g. Lee
Department of Chemistry and Nanoscience (BK21 PLUS)
Ewha Womans University, Seoul 03760 (Republic of Korea)
E-mail: sanggi@ewha.ac.kr
J. S. Lee, Prof. Dr. W. K. Lee
Department of Chemistry
Sogang University, Seoul 04107 (Republic of Korea)
E-mail: wonkoo@sogang.ac.kr
H. Ryu, Dr. J. Park, Hyunjoong Kim, Prof. Dr. M.-H. Baik
Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST),
Daejeon 34141 (Republic of Korea)
Center for Catalytic Hydrocarbon Functionalizations
Institute for Basic Science (IBS), Daejeon 34141 (Republic of Korea)
E-mail: mbaik2805@kaist.ac.kr
[+]
These authors contributed equally to this work.
Supporting information and the ORCID identification numbers(s) for
the author(s) of this article can be found under:
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10.1002/anie.201809133
Angewandte Chemie International Edition
COMMUNICATION
phosphine ligands such as Xantphos (see Tables S1 and S2 in
SI). To our delight, when the reaction was carried out in the
presence of 10 mol% Pd(PPh3)4 in polar NMP, the conversion
and selectivity of the reaction was increased dramatically,
furnishing 2a as the major product in 75% yield along with 16%
yield of 3a (entry 7, Table 1). A further increase in selectivity was
observed when the reaction was run in DMSO, where spiro-
cyclopropanted indoline 2a was isolated in 80% yield (entry 8,
Table 1). Under such optimal conditions, only trace amounts of
3a and 4a were detected. Use of different acid additives such as
1-adamantyl carboxylic acid proved unfavourable for selective
formation of 2a (entry 9, Table 1).
With the two-different optimal reaction parameters, i.e.,
conditions a (entry 8, Table 1) and b (entry 15, Table 1), in hand
for selectively activating different C(sp3)-H bonds, a variety of
spiro- 2 and fused-cyclopropanated indolines 3 were selectively
synthesized from common starting material 1 (Table 2).
Table 2. Regiodivergent Synthesis of Cyclopropanated Indolines 2 and 3.[a]
Table 1. Selected Examples for Reaction Optimization.[a]
Yield [%][b]
2a/3a/4a
Entry
Pd/ligand
solvent
base
additive
34/-/16
1
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(PPh3)4
DMF
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
tBuOK
-
43/>5/14
2
NMP
-
48/12/21
9/12/27
3
NMP
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
AdOH
PivOH
PivOH
PivOH
4
p-xylene
NMP
28/>5/12
16/39/19
75/16/8
5
6
p-xylene
NMP
7
8[c]
9
Pd(PPh3)4
DMSO
DMSO
p-xylene
p-xylene
p-xylene
80/9/-
66/11/10
Pd(PPh3)4
17/48/19
22/71/>5
18/65/8
10
11
12
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2/
-/5/9
6/5/19
8/81/-
0/0/99
13
p-xylene
p-xylene
p-xylene
DMF/H2O
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
PivOH
P(p-MeOPh)3
Pd[Pt(Bu)3]2
Pd(OAc)2/
14
PivOH
15[c],[d]
PivOH
PCy3·HBF4
16
Pd(PPh3)4
HCO2NH4
[a] Reaction conditions: 1a (0.3 mmol), Pd (10 mol%), ligand (20 mol%), base
(1.2 equiv), and additive (1.0 equiv) in a solvent (1.0 mL, 0.3 M) for 24 h at
120 °C. Determined by 1H NMR using 1,2-dimethoxy ethane as an internal
[b]
[a]
reference. [c] Isolated yields of 2a and 3a. [d] Reaction at 125 °C.
Reaction conditions: 1 (0.3 mmol) and solvent (1.0 mL, 0.3 M). Isolated
yields. [b] 3g was also isolated in 15% yield. [c] 3l was also isolated in 29% yield.
[d]
[e]
[f]
3n was also isolated in 10% yield.
Reaction at 115 °C. Reaction at
Interestingly, the regioselectivity of C-H activation could be
inversely altered by using non-polar, non-coordinating p-xylene
as solvent to afford fused-cyclopropanated indoline 3a as a
major product, but this was accompanied by moderate selectivity
(entry 10, Table 1). Varying the base and carboxylic acid
additives did not improve the selectivity. Propitiously, after
screening different palladium catalyst/ligand combinations, it
was found that treating 1a with 10 mol% Pd(OAc)2 and 20 mol%
PCy3·HBF4 in p-xylene led to highly selective activation of the
endo C-Hb bond, furnishing 3a in 81% isolated yield (entry 15,
Table 1). It was also possible to achieve efficient reductive
trapping of the -alkylPd(II)-intermediate by using ammonium
formate as an additive in a mixture of DMF/H2O to produce 4a
as the sole product in almost quantitative yield (entry 16, Table
1). The structures of both 2a and 3a were established
unambiguously by X-ray analysis.[8]
[g]
[h]
120 °C. 2m was also isolated in 11% yield. 2n was also isolated in 12%
yield.
In general, substrates showed excellent regioselectivity, and
under condition a selectively afforded 2 (top in Table 2) and 3
under condition b (bottom in Table 2). Although the use of
substrates 1g and 1l under condition a did produce noticeable
amounts of minor products 3g and 3l alongside expected major
products 2g and 2l, these were easily separated by silica
column chromatography. The utility of this methodology was
demonstrated by preparing spiro-cyclopropanated indoline 2k,
which is a key intermediate towards various PDE4 enzyme
inhibitors.[9] Analogous fused-cyclopropanated indoline 3k was
prepared in high yield under condition b. Replacement of the N-
Ac group with N-Boc (1m) or N-Bz groups (1n) showed a similar
trend of regioselectivity and efficiency under established optimal
conditions, resulting in the corresponding 2m-2n and 3m-3n.
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Interestingly, ethylallylated 2-bromoarylamide 1o exhibited
modified reactivity under condition a, furnishing inseparable
mixture of vinylated indoline 5 and protonated 4o (5/4o = 10:1,
activation reactions likely follow the inner-sphere pivalate-
assisted concerted-metalation-deprotonation (CMD) mechanistic
pathway, which was proposed for related Pd-catalyzed C(sp3)-H
activation reactions.[12]
1
determined by H NMR analysis) in 74% yield (Scheme 2). This
observation suggested that -alkylPd(II)-intermediate, generated
from 1o, underwent 1,4-Pd migration followed by -H elimination
to afford 5 as a major product.[10] In contrast, subjecting 1o
under the condition b led to the expected fused-cyclopropanated
indoline 3o in 64% yield, alongside 5 in 21% yield. When using
substrate 1p (R = Ph) however, the phenyl C(sp2)-H bond
proved to be more activated than C(sp3)-H bonds, affording 6 as
the sole product under both conditions a and b.
Initially we anticipated that the intramolecular coordination
between Pd(II) and the amide carbonyl may affected by the
solvent polarity, controlling the regioselectivity in C-H activation.
Therefore, we initially monitored the amide C=O absorption
bands of the -alkylPd(II)-complexes generated by reaction of
1a and 1.0 equivalent of Pd(PPh3)4 at 100 °C in both DMSO and
p-xylene using time-resolved infrared spectroscopy. The amide
carbonyl stretching vibration in 1a was slightly shifted to shorter
wave numbers (∆ = 11 cm-1 in p-xylene, ∆ = 4 cm-1 in DMSO)
(see SI), but these shifts are too small to imply that Pd(II)
coordinates to the amide carbonyl, leading to the observed
regioselectivity. Next, we carried out density functional theory
(DFT) calculations and located the transition states leading to
both products. Surprisingly, these calculations indicate that the
indoline skeleton is too rigid to allow the -alkylPd(II)-moiety to
reach across the five-membered ring to bind to the amide-
carbonyl. Instead, a subtle effect based on the polarity of the
solvents is suggested. The observed selectivity indicates that
the energy difference governing the divergence of these
reactions is small, within ~1 kcal/mol. Solvation corrected
quantum chemical calculations, including DFT-methods, are not
accurate enough to reliably model these effects, but some
plausible insight can be derived nonetheless.
Scheme 2. Modified reactivity of ethylallylated and benzylallylated 2-
bromoarylamides under optimized conditions a and b.
To discern the rate-determining step of these tandem Heck
/C(sp3)-H bond activation reactions,[11] intermolecular kinetic
isotope effect (KIE) experiments were carried out with a 1 :1
molar mixture of 1a and deuterated [d]-1a (Scheme 3).
D
D
Br
D
D
condition a
+
N
N
N
Ac
Ac
Ac
2a
[d]-2a
1a
kH/kD = 6.0 at 36% conversion
( kH/kD = 6.4 from individual kinetics)
+
Br
D
H3C
D3C
D
CD3
N
+
Ac
H
D
N
N
condition b
[d]-1a
Ac
Ac
3a
[d]-3a
kH/kD = 4.5 at 29% conversion
(kH/kD = 3.8 from individual kinetics)
Scheme 3. Kinetic Isotope Effects.
Under the optimized conditions a and b affording 2a and 3a
respectively, significant KIEs were observed in the NMR
analysis at low conversion, i.e., kH/kD = 6.0 at 36% conversion
for 2a and kH/kD = 4.5 at 29% conversion for 3a. Similar KIEs
have also been observed in the early stage kinetics obtained
from the independent reactions of 1a and [d]-1a under
conditions a and b affording indolines 2a (kH/kD = 6.4) and 3a
(kH/kD = 3.8), respectively (Figure S1 in SI). These results clearly
implicate C-H bond cleavage to be the turnover limiting step in
both conditions a and b. In addition, the optimal reaction
conditions suggest that both of C(sp3)-Ha and C(sp3)-Hb
Scheme 4. DFT-calculated transition states and energies. The unit of energy
is kcal/mol.
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10.1002/anie.201809133
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COMMUNICATION
As summarized in Scheme 4 and Figure 1, our calculations
show that the transition state A-TSa leading to the spiro-
cyclopropanated product is slightly disfavored over A-TSb,
which gives the fused-cyclopropanated product, by 0.3 kcal/mol
in gas phase. This energy difference is slightly increased to 0.6
kcal/mol between D-TSa and D-TSb, when the PCy3 ligand is
used instead of PPh3. Interestingly, the molecular surface areas
of the two transition states are quite different and we found that
the transition states leading to the spiro-cyclopropanated
products A/D-TSa have larger surface areas of 543 and 548 Å2,
whereas 526 and 545 Å 2 are found in A/D-TSb, respectively.
Consequently, A/D-TSa have slightly higher solvation energy
than A/D-TSb, as illustrated in Figure 1. In p-Xylene with a
dielectric constant of 2.27, the difference in solvation energy is
not enough to reverse the order of the two transition states, and
D-TSb is calculated to be at 30.8 kcal/mol, which is slightly lower
than D-TSa at 31.1 kcal/mol. As the DMSO solvent is more polar,
the solvation energy difference becomes larger and ultimately
renders A-TSa slightly lower in energy than A-TSb, as illustrated
in Figure 1. Whereas these energy differences are too small to
be trusted in a quantitative sense, the qualitative rationale
behind these numbers is plausible, namely, the regioselectivity
is connected to the molecular surface area of the transition
states leading to the spiro-cycloproanated product being favored
in the more polar DMSO solvent.
Acknowledgements
This work was made possible by the support of the National Re-
search Foundation (NRF-2016R1A2B2013727). D. S. Chung
thanks to the Solvay Fellowship. We thank Dr Y. Kim for X-ray
analysis. We also thank Prof. S. Chang at KAIST for sharing
time-resolved infrared spectrometry. MHB acknowledges the
financial support from the Institute for Basic Science (IBS-R10-
D1).
Keywords: Divergent catalysis • Palladium • C-H activation •
Cyclopropanation • Indolines
[1]
a) L. Li, Z. Chen, X. Zhang, Y. Jia, Chem. Rev. 2018, 118,
3752-3832; b) J. Hou, A. Ee, W. Feng, J.-H. Xu, Y. Zhao,
J. Wu, J. Am. Chem. Soc. 2018, 140, 5257-5263; c) H.
Zhou, W. Chen, Z. Chen, Org. Lett. 2018, 20, 2590-2594;
d) F. A. Cruz, V. M. Dong, J. Am. Chem. Soc. 2017, 139,
1029-1032; e) Q.-Q. Cheng, M. Lankelma, D. Wherritt, H.
Arman, M. P. Doyle, J. Am. Chem. Soc. 2017, 139, 9839-
9842; f) T.-R. Li, L.-Q. Lu, Y.-N. Wang, B.-C. Wang, W.-J.
Xiao, Org. Lett. 2017, 19, 4098-4101; g) Y. Wei, M. Shi,
ACS Catal. 2016, 6, 2515-2524; h) J.-Y. Liao, P.-L. Shao,
Y. Zhao, J. Am. Chem. Soc. 2015, 137, 628-631.
[2]
a) N. Della Ca’, M. Fontana, E. Motti, M. Catellani, Acc.
Chem. Res. 2016, 49, 1389-1400; b) C. Liu, J. Yuan, M.
Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015, 115,
12138-12204; c) L. Yang, H. Huang, Chem. Rev. 2015,
115, 3468-3517; d) J. Wencel-Delord, F. Glorius, Nat.
Chem. 2013, 5, 369; e) J. Yamaguchi, A. D. Yamaguchi, K.
Itami, Angew. Chem. Int. Ed. 2012, 51, 8960-9009; f) P. B.
Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012,
112, 5879-5918; g) J. Wencel-Delord, T. Dröge, F. Liu, F.
Glorius, Chem. Soc. Rev. 2011, 40, 4740-4761; h) O.
Baudoin, Chem. Soc. Rev. 2011, 40, 4902-4911; i) I. A. I.
Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy, J. F.
Hartwig, Chem. Rev. 2010, 110, 890-931; j) D. A. Colby, R.
G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624-
655; k) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-
Kreutzer, O. Baudoin, Chem. Eur. J. 2010, 16, 2654-2672.
a) L. Ping, D. S. Chung, J. Bouffard, S.-g. Lee, Chem. Soc.
Rev. 2017, 46, 4299-4328; b) J. A. Leitch, Y. Bhonoah, C.
G. Frost, ACS Catal. 2017, 7, 5618-5627; c) O. Daugulis,
J. Roane, L. D. Tran, Acc. Chem. Res. 2015, 48, 1053-
1064; d) Z. Huang, H. N. Lim, F. Mo, M. C. Young, G.
Dong, Chem. Soc. Rev. 2015, 44, 7764-7786; e) M. Zhang,
Y. Zhang, X. Jie, H. Zhao, G. Li, W. Su, Org. Chem. Front.
2014, 1, 843-895; f) G. Rouquet, N. Chatani, Angew.
Chem. Int. Ed. 2013, 52, 11726-11743; g) G. Rousseau, B.
Breit, Angew. Chem. Int. Ed. 2011, 50, 2450-2494; h) T. W.
Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147-1169.
a) W. Du, Q. Gu, Z. Li, D. Yang, J. Am. Chem. Soc. 2015,
137, 1130-1135; b) J. M. Alderson, A. M. Phelps, R. J.
Scamp, N. S. Dolan, J. M. Schomaker, J. Am. Chem. Soc.
2014, 136, 16720-16723; c) J. Mahatthananchai, A. M.
Dumas, J. W. Bode, Angew. Chem. Int. Ed. 2012, 51,
10954-10990; d) A. Renaudat, L. Jean-Gérard, R. Jazzar,
C. E. Kefalidis, E. Clot, O. Baudoin, Angew. Chem. Int. Ed.
2010, 49, 7261-7265; e) A. Kros, W. Jesse, G. A.
[3]
Figure 1. DFT-calculated energies and solvation energy corrections. The unit
of energy is kcal/mol.
In summary, we have developed a conceptually distinctive
tandem Heck/regiodivergent C(sp3)-H bond activation reaction to
selectively construct both spiro- and fused-cyclopropanated
indolines starting from the same N-methallylated N-acyl-2-
bromoanilines. DFT-calculations suggest that the regioselectivity
is governed by the fact that the fused-product is favored in gas
phase and also in low dielectric media, where the solvation
energies are relatively small. The transition state leading to the
spiro-fused product shows a larger molecular surface and
becomes more favorable in high dielectric media. Further
studies on other solvent-driven divergent catalytic reactions are
currently underway.
[4]
Metselaar, J. J. L. M. Cornelissen, Angew. Chem. Int. Ed.
2005, 44, 4349-4352.
[5]
a) S. Arai, M. Nakajima, A. Nishida, Angew. Chem. Int. Ed.
2014, 53, 5569-5572; b) M. Zhang, F. Jovic, T. Vickers, B.
Dyck, J. Tamiya, J. Grey, J. A. Tran, B. A. Fleck, R. Pick,
A. C. Foster, C. Chen, Bioorg. Med. Chem. Lett. 2008, 18,
3682-3686.
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COMMUNICATION
[6]
[7]
J. H. Kim, J. Bouffard, S.-g. Lee, Angew. Chem. Int. Ed.
2014, 53, 6435-6438.
G.-Q. Lin, Angew. Chem. Int. Ed. 2018, 57, 5871-5875; c)
T. Kesharwani, R. C. Larock, Tetrahedron 2008, 64, 6090-
6102; d) S. Ma, Z. Gu, Angew. Chem. Int. Ed. 2005, 44,
7512-7517.
a) H. Wang, C. Grohmann, C. Nimphius, F. Glorius, J. Am.
Chem. Soc. 2012, 134, 19592-19595; b) Y. Wei, I. Deb, N.
Yoshikai, J. Am. Chem. Soc. 2012, 134, 9098-9101; c) E.
M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012,
51, 3066-3072.
a) T. Saget, N. Cramer, Angew. Chem. Int. Ed. 2013, 52,
7865-7868; b) E. Larionov, M. Nakanishi, D. Katayev, C.
Besnard, E. P. Kündig, Chem. Sci. 2013, 4, 1995-2005; c)
D. García-Cuadrado, A. A. C. Braga, F. Maseras, A. M.
Echavarren, J. Am. Chem. Soc. 2006, 128, 1066-1067; d)
M. Lafrance, C. N. Rowley, T. K. Woo, K. Fagnou, J. Am.
Chem. Soc. 2006, 128, 8754-8756.
a) T. Yao, D. He, Org. Lett. 2017, 19, 842-845; b) H. Yoon,
A. Lossouarn, F. Landau, M. Lautens, Org. Lett. 2016, 18,
6324-6327; c) A. Düfert, D. B. Werz, Chem. Eur. J. 2016,
22, 16718-16732; d) K. Yuan, J.-F. Soulé, V. Dorcet, H.
Doucet, ACS Catal. 2016, 6, 8121-8126; e) W. Kong, Q.
Wang, J. Zhu, J. Am. Chem. Soc. 2015, 137, 16028-
16031; f) H. Ohno, Asian J. Org. Chem. 2013, 2, 18-28.
X-ray data: 2a (CCDC: 1473532) and 3a (CCDC:
1473531), for details, see SI. CIF files are also available
free from charge on http://www.ccdc.cam.ac.uk
A. Nardi, F. Jakob, I. Konetzki, T. Craan, C. Hesslinger, R.
Doodeman, WO2016008593A1, 2014. For details of 2k
preperation please see supporting information.
a) F. Shi, R. C. Larock, in C-H Activation (Eds.: J.-Q. Yu, Z.
Shi), Springer Berlin Heidelberg, Berlin, Heidelberg, 2010,
pp. 123-164; b) T.-J. Hu, M.-Y. Li, Q. Zhao, C.-G. Feng,
[11]
[12]
[8]
[9]
[10]
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10.1002/anie.201809133
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
Solvent paves the way: Choice of
solvent for Pd-catalyzed tandem
Heck/regiodivergent C(sp3)-H bond
activation enables construction of
different C-C bonds selectively from a
Da Sol Chung+, Jae Sung Lee+, Ho
Ryu, Jiyong Park, Joo Hyun Lee, U Bin
Kim, Won Koo Lee,* Mu-Hyun Baik* and
Sang-gi Lee*
Page No. – Page No.
common precursor, affording spiro- or
C(sp3)-Ha
fused cyclopropanated indolines at
activation
Ar
will.
DMSO
N
Br
N
Palladium-Catalyzed Tandem Divergent
Cyclopropanation via Solvent-Driven
Regioselective C(sp3)–H Bond Activation
Hb Ha
O
Pd0
Ar
R
p-xylene
R
O
Ar
C(sp3)-Hb
activation
H
N
O
R
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