Palladium(II)-Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp3)?H Bonds Enabled by a 2-Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids

Article abstract of DOI:10.1002/anie.201804197

Enantioselective functionalizations of unbiased methylene C(sp³)?H bonds of linear systems by metal insertion are intrinsically challenging and remain a largely unsolved problem. Herein, we report a palladium(II)-catalyzed enantioselective arylation of unbiased methylene β-C(sp³)?H bonds enabled by the combination of a strongly coordinating bidentate PIP auxiliary with a monodentate chiral phosphoric acid (CPA). The synergistic effect between the PIP auxiliary and the non-C₂-symmetric CPA is crucial for effective stereocontrol. A broad range of aliphatic carboxylic acids and aryl bromides can be used, providing β-arylated aliphatic carboxylic acid derivatives in high yields (up to 96 %) with good enantioselectivities (up to 95:5 e.r.). Notably, this reaction also represents the first palladium(II)-catalyzed enantioselective C?H activation with less reactive and cost-effective aryl bromides as the arylating reagents. Mechanistic studies suggest that a single CPA is involved in the stereodetermining C?H palladation step.

Full text of DOI:10.1002/anie.201804197

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Pd(II)-Catalyzed Enantioselective Arylation of Unbiased
Methylene C(sp3)-H Bonds Enabled by 2-Pyridinylisopropyl
Auxiliary and Chiral Phosphoric Acids
Authors: Sheng-Yi Yan, Ye-Qiang Han, Qi-Jun Yao, Xing-Liang Nie,
Lei Liu, and Bing-Feng Shi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804197
Angew. Chem. 10.1002/ange.201804197
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http://dx.doi.org/10.1002/ange.201804197

10.1002/anie.201804197
Angewandte Chemie International Edition
COMMUNICATION
Pd(II)-Catalyzed Enantioselective Arylation of Unbiased
Methylene C(sp3)–H Bonds Enabled by 2-Pyridinylisopropyl
Auxiliary and Chiral Phosphoric Acids
Sheng-Yi Yan,† Ye-Qiang Han,† Qi-Jun Yao, Xing-Liang Nie, Lei-Liu and Bing-Feng Shi*
Abstract: Enantioselective functionalization of unbiased methylene
C(sp3)-H bonds of linear systems via metal insertion is intrinsically
challenging and remains a largely unsolved problem. Herein, we
report a Pd(II)-catalyzed enantioselective arylation of unbiased
methylene β-C(sp3)-H bonds enabled by the combination of
strongly coordinating bidentate PIP auxiliary and monodentate
chiral phosphoric acids (CPAs). A synergistic effect between PIP
auxiliary and a non-C2-asymmetric CPA (L16) is crucial for the
effective stereocontrol. A broad range of aliphatic carboxylic acids
and aryl bromides can be used, providing β-arylated aliphatic
carboxylic acid derivatives in high yields (up to 96%) with good
enantioselectivity (up to 95:5 er). Notably, this also represents
the first Pd(II)-catalyzed enantioselective C-H activation using
less reactive and cost-effective aryl bromides as arylating
reagents. Mechanistic studies suggest that a single CPA is
responsible for the stereodetermining C-H palladation step.
H
bonds,[10,11] or those adjacent to heteroatom,[12] or on
conformationally rigid cyclic systems,[13,14] have also been widely
investigated. To date, enantioselective functionalization of
unbiased methylene C(sp3)-H bonds of linear systems via metal
insertion is intrinsically challenging.[10a,15]
a) Weak monodentate directing group and bidentate acetyl-protected aminoethyl quinoline ligand
F
O
Ar
H
Et
cat. Pd(OAc)2
F
CF3
N
O
H
H
ArF
ligand
cat.
ArF
tBu
Alkyl
N
Ar
I
H
AcHN
Alkyl
N
H
F
up to 89% yield
up to 92% ee
F
ligand
tBu
b) Strong bidentate directing group and monodentate chiral C2-symmetric ligand
Q
O
Ar
H
O
cat. [PdCl2(CH3CN)2]
cat. ligand
H
H
Q
R
N
O
O
R
N
H
P
Ar
I
H
R = nPr, 68%, 63:37 er
R = iPr, 20%, 64:36 er
O
NH2
N
two isolated examples
low yield and er
ligand
c) Evolution of stereoinduction in postulated transition state and reaction development
O
O
R
DG
Pd
N
The creation of chiral centers via enantioselective C-H
functionalization can potentially change the strategy of organic
synthesis and streamline the access of complex molecules from
L
N
Pd
N
Pd
R
H
R
H
N
L
O
O
H
H
H
O
HN
O
O
H
O
P
P
B
R'
O
O
simple
and
abundant
sources
of
hydrocarbons.[1]
A
C
bidentate ligand:
steric communication:
monodentate ligand:
effective conformationl restriction restricted rotational freedom
free rotation around Pd N bond
Enantioselective metallocarbene and metallonitrene insertion
into aliphatic C-H bonds has been well investigated in the
stereoselective formation of C-C and C-N bonds.[2] On the other
hand, enantioselective metal insertion into C(sp3)-H bonds could
be considered as a more appealing strategy, especially when
considering that the newly formed chiral organometallic
intermediate could be diversely functionalized to C-C and C-
hetereoatom bonds other than C-N bond.[1,3] Recent efforts
have led to significant achievements in Pd-catalyzed
This work
R
F
O
H
H
PIP
cat. PdCl2
O
Ar
H
L16
cat.
PIP
Alkyl
N
O
O
O
Alkyl
N
H
Ar Br
P
N
H
OH
the first Pd(II)-catalyzed enantioselective C-H arylation using ArBr
broad substrate scopes (41 examples)
high yields (up to 96%) and good enantioselectivity (up to 95:5)
synergistic effect between PIP and non-C2-symmetric CPA ligand
L16
R = 4-CF3C6H4
R
Scheme 1. State-of-the-art and strategies for Pd(II)-catalyzed enantioselective
arylation of unbiased methylene C(sp3)-H bonds.
enantioselective
C(sp3)-H
functionalization
through
desymmetrization of prochiral methyl groups.[4-9] For example,
Kagan, Kündig, Baudoin, and Cramer have realized the highly
enantioselective Pd(0)-catalyzed intramolecular cyclization using
chiral N-heterocyclic carbene or phosphine ligands.[4-7] By the
combination of monodentate directing groups with bidentate
chiral ligands, Yu and co-workers have achieved the Pd-
catalyzed enantioselective desymmetrization of prochiral methyl
groups via C(sp3)-H activation.[8] Gaunt reported the Pd(II)-
catalyzed desymmetric amination of methyl C(sp3)-H bonds
The major breakthrough was made by the Yu group in 2016.
They revealed that the combination of a weak monodentate
directing group and a bidentate acetyl-protected aminoethyl
quinoline ligand could dramatically enhance the reactivity and
high enantioselectivity (Scheme 1b, up to 89% yield, up to 92%
ee).[15] In a seminal report by Duan and coworkers, they
achieved the first Pd(II)-catalyzed arylation of benzylic C(sp3)-H
bonds in moderate enantiomeric ratios (er, 74:26 to 91:9) by the
use of a strong bidentate 8-aminoquinoline (AQ) directing group
and a monodentate chiral C2-symmetric phosphoric amide ligand.
However, both of yields and enantioselectivities dropped
drastically when this protocol was adopted to electronically
unbiased methylene C-H bonds (Scheme 1a, R = nPr, 68%,
using
a
CPA
ligand.[9]
Additionally,
Pd-catalyzed
enantioselective functionalization of methylene C(sp3)-H bonds
at positions activated via hyperconjugation, such as benzylic C-
i
63:37 er; R = Pr, 20%, 64:36 er).[10a] There are two major
hurdles for the poor selectivity: First, the strongly coordinating
bidentate auxiliary AQ could promote the cleavage of C-H bonds
in the absence of a chiral ligand as exemplified by Daugulis,[16]
thus leading to the erosion of enantioselectivity. Second, due to
the lack of vacant coordination sites in the bidentate system,
only monodentate chiral ligand can be used. In the pretransition
state intermediate C, the chiral phosphoric amide is realtively
free to rotate (Scheme 1c), which could result in different chiral
[a] S.-Y. Yan, Y.-Q. Han, Q.-J. Yao, X.-L. Nie, L. Liu, 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/.
[b] Prof. Dr. B.-F. Shi
State Key Laboratory of Elemento-organic Chemistry, Nankai
University,
Tianjin 300071 (China)
[†] These authors contributed equally to this work.
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10.1002/anie.201804197
Angewandte Chemie International Edition
COMMUNICATION
environments with opposite stereoinduction and erode the
enantioselectivity. Considering a rich wealth of aliphatic C-H
functionalization reactions that enabled by bidentate directing
groups,[3g-j] the realization of suitable chiral ligands to enable
stereocontrol of unbiased aliphatic C-H bonds with bidentate
auxiliaries would be highly desirable.
desired β-arylation product 3aa was afforded in 55% yield and
30:70 er. Considering that the acetate anion would compete with
ligands to inhibit the formation of the chiral Pd-complex and
erode enantioselectivity. We then evaluated a range of Pd(II)
salts with different counter anions and were delighted to find that
the use of PdCl2 with ligand L2 could increase the er to 15:85
(see the supporting infromation for details). Improving the
reaction temperature to 125 oC slightly increased the yield
without erossion of enantioselectivity (Table 1, 63%, 16:84 er).
A
comprehensive evaluation of CPA ligands was then
performed (Table 1). We first investigated substitutions on the
3,3’-positions. The use of 3,3’-bismethyl and 3,3’-
bistrifluoromethyl substituted CPAs (L3 and L4) resulted in
significant erosion in enantioselectivity. Sterically more
To achieve high enantioselectivity, the chiral ligands should be
capable of creating a steric environment to induce stereocontrol
and accelerating or enabling the cleavage of C-H bonds.[17] We
have disclosed a Pd-catalyzed arylation of secondary C(sp3)-H
bonds with aryl bromides assisted by our newly developed 2-
pyridinylisopropyl (PIP) auxiliary.[18,19] The use of PivOH as
ligand could significantly improve the reactivity (eq 1); thus, we
imagined that this reaction may provide an opportunity for
outcompeting the background reaction. We also hypothesized
that the steric communication between gem-dimethyl group in
PIP auxliliary and backbone of CPA ligand could limit the free
rotation to create a rigid and stronger chiral environment around
the substrate (Scheme 1c, B). Herein we report a Pd(II)-
catalyzed enantioselective arylation of unbiased methylene
C(sp3)–H bonds with aryl bromides enabled by cooperative
effects between PIP auxiliary and CPA ligands.[20] It is worth
noting that this reaction represents the first Pd(II)-catalyzed
enantioselective C-H arylation using less reactive and cost-
effective aryl bromides as arylating reagents while previous
reports could only use aryl iodides.[10,11,12a,15]
demanding 3-phenyl substituted CPA (L5) almost gave
a
racemic mixture of products (49:51 er). To our delight, L6
bearing fluorine atom at 3,3’-position increased the er to 11:89.
Next, the effects of substitutions on 6,6’-position of CPAs were
examined
bis(trifluoromethyl)phenyl]
(L8-L10).
Notably,
(L9)
6,6’-bis[3,5-
6,6’-bis(4-
CPA
and
trifluoromethylphenyl) CPA (L10) gave improved er (9:91 and
10.5:89.5, respectively). When (S)-L2 was used, the opposite
isomer of the product could be afforded with similar
enantioselectivity (85:15 er).
We then thoroughly investigated the substituents on both 3,3’-
and 6,6’-positions (L12-L19). Interestingly, non-C2-symmetric
CPAs (L14 and L16) with only one fluorine atom at 3-position
gave best results with 92:8 er. Preliminary structure-
enantioselectivity relationships of ligand are rationalized based
on the results in Tables 1 and S5: 1) in contrast to the
importance of steric bulk at the 3,3’-positions in other
asymmetric reactions, bulky substituents led to reduced ers in
this C-H arylation protocol; 2) a unique effect of fluoro-containing
substituents has been observed (fluoro at the 3,3’-positions: L2
vs L6; (bis)trifluoromethyl-substituted phenyl at 6,6’-positions: L2
vs L9 and L10, L16 vs L20; trifluoro at the 3,6,6’-positions: L18);
3) 3-fluoro-substituted non-C2-symmetric CPAs gave higher ee
than their 3,3’-difluoro analoges (L14 vs L15; L16 vs L17; L20
vs L21). Further experimental and theoretical studies are
needed to elucidate the underlying factors that could influence
the enantioselectivity.
Table 1. Ligand optimization[a]
Ac
PdCl2 (10 mol%)
H
O
Ac
L (20 mol%)
+
PIP
O
N
2.5 equiv K2CO3
Br
H
t-BuOH, 125 oC, N2, 24 h
PIP
1a
2a
*
N
H
3aa
(R)- , R1 = R2 = R3 = H, 55%, 30:70 er[b]
L2
(R)- , R1 = R2 = R3 = H, 63%, 16:84 er
L2
, R1 = R2 = Me, R3 = H, 66%, 26:74 er
R3
R1
L3
, R1 = R2 = CF3, R3 = H, 41%, 21:79 er
L4
We futher optimized the conditions using L16 as the ligand
and discovered that the desired product 3aa could be produced
in 72% yield with 93.5:6.5 er under the following optimized
conditions (standard conditions): 6 mol% PdCl2, 6 mol% L16 and
, R1 = R3 = H, R2 = Ph, 56%, 49:51 er
L5
O
O
O
R
P
, R1 = R2 = F, R3 = H, 66%, 11:89 er
L6
, R1 = R2 = H, R3 = 1-naphthyl, 36%, 25:75 er
L8
, R1 = R2 = H, R3 = 3,5-(CF3)2C6H3, 86%, 9:91 er
R3
R3
R2
L9
, R1 = R2 = H, R3 = 4-CF3C6H4, 85%, 10.5:90.5 er
L10
o
1.5 equiv K2CO3 in 1 mL t-BuOH at 125 C under N2 for 24 h
(S)-L2, R1 = R2 = R3 = H, 63%, 85:15 er
L12, R1 = R2 = H, R3 = F, 66%, 90:10 er
L13, R1 = R2 = H, R3 = 3,4,5-F3C6H2, 73%, 85:15 er
(see supporting information for details).
R1
At the very beginning of the design of PIP auxiliary,[19] we
have envisioned that its sterically and electronically tuneable
structure could significant affect the reactivity. Thus, we
subsequently undertook a study to investigate the influence of
the modified directing groups in greater details (Table 2). As
expected, the modification of PIP auxiliary displayed a very
pronounced influenece on both the reactivity and
enantioselectivity. For example, the replacement of gem-
dimethyl group with sterically more demanding longer chains or
cyclic structures resulted in less reactivity and eroded
enantioselectivity (5a-5f). All substitutions on the pyridyl ring led
to a decrease in enantioselectivity and/or yield (5g-5m). Not
surprisingly, substitution at the C6 position of pyridine led to loss
in reactivity (5m). The enantioselective C-H arylation directed by
AQ auxiliary was also investigated. The reaction of 4a under the
standard reaction conditions gave 5a in low yield (31%) with
L14, R1 = H, R2 = F, R3 = 3,5-(CF3)2C6H3, 70%, 92:8 er
L15, R1 = R2 = F, R3 = 3,5-(CF3)2C6H3, 79%, 90.5:9.5 er
O
O
O
P
, R1 = H, R2 = F, R3 = 4-CF3C6H4, 74%, 92:8 er
OH
L16
, R1 = R2 = F, R3 = 4-CF3C6H4, 77%, 90.5:9.5 er
L17
R3
R2
, R1 = H, R2 = R3 = F, 75%, 91:9 er
L18
, R1 = F, R2 = R3 = H, 54%, 80:20 er
L19
, R1 = H, R2 = F, R3 = CF3, 72%, 91.5:8.5 er
L20
, R1 = H, R2 = F, R3 = 4-MeC6H4, 62%, 85:15 er
L21
[a] Reaction conditions: 1a (0.15 mmol), 2a (0.3 mmol), PdCl2 (10 mol%), L
(20 mol%), K2CO3 (2.5 equiv) in t-BuOH (1.5 mL) at 125 oC under N2 for 24 h.
Yields were determined by 1H NMR using CH2Br2 as internal standard, the er
value was determined by chiral HPLC. [b] Pd(OAc)2 (10 mol%), 120 oC.
To test this hypothesis, we commenced our investigations by
replacing PivOH with L2 under otherwise identical conditions we
reported previously (Table 1).[18] Thus, using butyric amide 1a
and p-acetyl bromobenzene 2a as the model system, the
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10.1002/anie.201804197
Angewandte Chemie International Edition
COMMUNICATION
poor er (72:28). The use of (S)-L2 under Duan’s conditions
using aryl iodide as arylation reagents gave an improved yield
(63%) but led to erosion of the er (51:49).[10a] Previously, Pd(II)-
catalyzed arylation of methylene C(sp3)-H bonds with aryl
bromide has also been reported.[21] The use of (S-L2 under such
conditions again gave poor reactivity and er (21%, 59:41 er).
However, the use of L16 as chiral ligand under identical
conditions gave better er than (S)-L2 (65:35). These results
indicated that the newly designed fluoro-containing non-C2-
symmetric CPA possesses unique effects on enantiocontrol and
might find further applications in C-H activation.
3hj, 3hm, 3hn, 3ho and 3hq), presumably because of the
suppression of background reaction. Other electrophiles, such
as aryl chlorides, aryl triflates and vinyl bromides, didn’t give any
desired product. The absolute configuration of the products was
confirmed by X-ray crystallographic analysis of 3hf.[22]
Table 3. The scope of aliphatic amides.[a]
Ac
PdCl2 (6 mol%)
O
H
H
Ar
*
O
L16 (6 mol%)
PIP
PIP
+ Ar
Ar =
Br
2a
Alkyl
N
Alkyl
O
N
1.5 equiv K2CO3
t-BuOH, 125 oC, N2, 24 h
H
H
1
3
Ar
O
Ar
Ar
( )2
Ar
O
O
PIP
PIP
PIP
PIP
( )4
N
N
N
N
H
H
H
H
Table 2. Evaluation of the directing ability of PIP-NH2 analogues.[a,b]
3aa
3ba
, 74%, 93:7 er
3ca
40%, 94:6 er[b]
3da
, 54%, 86:14 er
, 72%, 93.5:6.5 er
, 96%, 91:9 er
Ar
Ar
Ar
Ar
( )2
O
O
Ph
O
O
PIP Ph
PIP
PIP
Ph
PIP
( )3
N
N
N
N
H
H
H
H
3ea
3fa
3ga
3ha
, 88%, 94:6 er
, 76%, 94:6 er
, 71%, 92:8 er
, 93%, 93:7 er
d.r = 1.1:1
F
Ar
( )2
O
N
Ar
O
Ar
O
PIP
PIP
N
H
PIP
( )2
N
N
H
H
[a]
[a]
3ia
3ja
3ka
, 88%, 89:11 er
, 78%, 90:10 er
, 64%, 83.5:16.5 er
49%, 88:12 er[d]
53%, 92:8 er[c]
Ar
( )2
O
Ar
( )2
O
Ar
O
PIP
PIP
PIP
N
N
N
H
H
H
3la, 53%, 93:7 er
3ma, 68%, 92.5:7.5 er
3na, 81%, 90:10 er
R
3oa
3pa
, R=H, 78%, 94:6 er
, R=F, 86%, 94.5:5.5 er
R
Ar
O
3qa, R=Cl, 42%, 94:6 er
3ra, R=Br, 76%, 94:6 er
Ar
O
PIP
PIP
N
N
3sa
, R=Me, 66%, 94:6 er
H
H
3ta
, R=OMe, 82%, 91.5:8.5 er
R
3ua, R=NO2, 41%, 92:8 er
3va
, R=H, 76%, 95:5 er
3wa, R=F, 70%, 95:5 er
[a] Standard conditions. [b] PdCl2 (3 mol%), L14 (3 mol%), t-BuOH (1.0 mL),
0.3 mmol scale. [c] PdCl2 (3 mol%), L16 (3 mol%), t-BuOH (1.0 mL), 0.3 mmol
scale. [d] PdCl2 (3 mol%), L16 (3 mol%), t-BuOH (0.5 mL), 0.3 mmol scale.
[a] Standard conditions. [b] Isolated yield and the er value was determined by
chiral HPLC. [c] Conditions reported in Ref. [10a] using (S)-L2 as chiral ligand.
[d] Conditions reported in Ref. [21] using (S)-L2 as chiral ligand. [e] Conditions
reported in Ref. [21] using L16 as chiral ligand.
In order to gain some insights into the mechanism of this
reaction, a series of experiments have been performed. First,
the kinetic isotope effect was investigated using β-deuterium-
labeled substrate [D2]-1f and kH/kD = 2.1 was observed (see
supporting information for details). This indicates that the C−H
bond cleavage might be the rate-limiting step in this reaction. To
find out how CPAs effect the enantioselective of this Pd(II)-
catalyzed arylation reaction, the linear relationship between the
ee value of ligand and the ee value of product was conducted
using 1a and L2 (Figure S1). The result reveals a clear linear
effect, suggesting that a single CPA ligand is responsible for the
stereodetermining C-H palladation step.[23] This is in sharp
contrast to Pd(II)-catalyzed enantioselective arylation of benzylic
methylene C(sp3)-H bonds directed by picolamide, in which a
nonlinear effect was observed.[10b]
With the optimized reaction conditions in hand, the scope of
aliphatic amides was examined (Table 3). Aliphatic amides
bearing various linear chains gave comparable yields and
selectivities (3aa-3ca). Although aliphatic amide bearing
sterically demanding isopropyl group at β-position led to reduced
yield and er (3da, 54%, 86:14 er), this result is still promising
compared the lower reactivity and selectivity using AQ auxiliary
(Scheme 1b, 20%, 64:36 er). The presence of sterically
demanding groups at γ- or distal positions didn’t significantly
affect the enantioselectiviy (3ea-3wa). Various substituents,
such as halides, methyl, methoxyl and nitro, at γ-phenyl ring,
also gave good ers (3oa-3ua, 91.5:8.5 to 94.5:5.5).
Next, the scope of aryl bromides was explored (Table 4). In
general, a broad range of electron-donating and electron-
withdrawing substituents on the aryl bromides were well
tolerated. Aryl bromides with strong electron-withdrawing groups,
such as methoxycarbonyl (2h), cyano (2k), nitro (2l) and acetyl
(2o), were also compatible. Notably, halides, such as fluoro (2i)
and chloro (2j), at the para position of aryl bromides performed
well. We have found that fluoro-containing substituents at the
3,3‘- or 6,6‘-positions could improve the enantioselectivity.
Therefore, improved enantioslectivity could be achieved by
judicious choice of CPA ligands with suitable fluoro-containing
substituents (L14, 3ca and 3hh; L18, 3hc and 3hr; L19, 3hd). In
certain cases, the enantioselectivity could also be improved by
reducing the loading of PdCl2 to 3 mol% (3ja, 3ka, 3hb, 3he, 3hi,
In conclusion, we have described
a
Pd-catalyzed
enantioselective arylation of unbiased methylene C(sp3)-H
bonds in aliphatic amides assisted by PIP auxiliary. This protocol
respresents the first universal method to generate enantioriched
β-arylated carboxylic acid derivatives using less reactive and
cost effective aryl bromides as the arylating reagents. A non-C2-
symmetric CPA ligand has been identified to have prominent
effects on the control of enantioselectivity and a single CPA
ligand is responsible for the stereodetermining C-H palladation
step. Considering the wealth of aliphatic C-H functionalization
reactions enabled by bidentate directing groups, we expect this
approach might open intriguing opportunities for other types of
C-H functionalization reactions in the future.
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10.1002/anie.201804197
Angewandte Chemie International Edition
COMMUNICATION
Table 4. The scope of aryl bromides.[a]
Baudoin, Chem. Soc. Rev. 2011, 40, 4902; d) H. Li, B.-J. Li, Z.-J. Shi,
Catal. Sci. Technol. 2011, 1, 191; e) G. Rouquet, N. Chatani, Angew.
Chem. Int. Ed.2013, 52, 11726; f) O. Daugulis, J. Roane, L.D. Tran, Acc.
Chem. Res. 2015, 48, 1053; g) G. He, B. Wang, W. A. Nack, G. Chen,
Acc. Chem. Res. 2016, 49, 635; h) X. Lu, B. Xiao, R. Shang, L. Liu,
Chin. Chem. Lett. 2016, 27, 305; i) J. He, M. Wasa, K. S. L. Chan, Q.
Shao, J.-Q. Yu, Chem. Rev. 2017, 117, 8754; j) Y. Xu, G. Dong, Chem.
Sci. 2018, 9, 1424.
PdCl2 (6 mol%)
Ar
( )2
H
O
O
H
L16
(6 mol%)
+
PIP
Ar Br
PIP
Ph
Ph
( )2
N
N
K2CO3 (1.5 equiv)
H
H
1h
2
t-BuOH, 125 oC, N2, 24 h
3
Me
OMe
SCF3
O
O
O
O
PIP
PIP
PIP
PIP
Ph
Ph
Ph
Ph
( )2
( )2
( )2
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3he
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CF3
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89%, 92:8 er[d]
, 91%, 90.5:9.5 er
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( )2
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H
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H
H
3hh
, 80%, 89:11 er
85%, 90.5:9.5 er[e]
NO2
3hi
3hj
3hk
, 85%, 85:15 er
50%, 93.5:6.5 er[b]
, 46%, 89.5:10.5 er
59%, 93:7 er[b]
, 50%, 89.5:10.5 er
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Me
MeO
Ph
Ac
O
O
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PIP Ph
PIP
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( )2
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H
H
H
H
3hl, 52%, 94:6 er 3hm, 82%, 89.5:10.5 er 3hn, 68%, 91.5:8.5 er
3ho, 85%, 91:9 er
42%, 93:7 er[f]
OMe
79%, 91:9 er[b]
F
44%, 92.5:7.5 er[f]
Me
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N
H
H
H
H
3hp, 56%, 90:10 er 3hq, 77%, 82.5:17.5 er 3hr, 63%, 90.5:9.5 er 3hs, 69%, 92.5:7.5 er
70%, 89.5:10.5 er[b] 68%, 94:6 er[g]
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Financial support from the NSFC (21772170, 21572201,
21422206), the National Basic Research Program of China
(2015CB856600), the Fundamental Research Funds for the
Central
Universities
(2018XZZX001-02)
is
gratefully
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acknowledged.
Keywords: enantioselectivity • C-H activation • cooperative
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[22] CCDC 1835310 (3hf) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[23] Consistent with this result, the use of a well-defined Pd(L16)2(CH3CN)2
complex as catalyst resulted in a slightly lower ee than the optimized
conditions using 6 mol% PdCl2 and 6 mol% CPA L16 (Table S6, entries
13 and 9).
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10.1002/anie.201804197
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Sheng-Yi Yan,† Ye-Qiang Han,† Qi-Jun
Yao, Xing-Liang Nie, Lei-Liu and Bing-
Feng Shi*
Page No. – Page No.
Pd(II)-Catalyzed
Enantioselective
Enantioselective C-H arylation of unbiased methylene C-H bonds: A Pd(II)-
catalyzed enantioselective arylation of unbiased methylene β-C(sp3)-H bonds
enabled by the combination of strongly coordinating bidentate PIP auxiliary and
monodentate chiral phosphoric acids (CPAs) has been reported. A synergistic
effect between PIP auxiliary and a non-C2-asymmetric CPA is crucial for the
effective stereocontrol. Notably, this also represents the first Pd(II)-catalyzed
enantioselective C-H activation using less reactive and cost-effective aryl bromides
as arylating reagents.
Arylation of Unbiased Methylene
C(sp3)–H Bonds Enabled by 2-
Pyridinylisopropyl Auxiliary and Chiral
Phosphoric Acids
This article is protected by copyright. All rights reserved.