NHC Ligand-Enabled, Palladium-Catalyzed Non-Directed C(sp3)-H Carbonylation to Access Indanone Cores

Article abstract of DOI:10.1021/acscatal.9b03426

A palladium-catalyzed C(sp³)-H carbonylation of alkylated aryl triflates or bromides under 1 atm of CO has been developed, in which no directing group or oxidant was required. The essence of this reaction is the combination of appropriate NHC l

Full text of DOI:10.1021/acscatal.9b03426

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Letter
NHC Ligand-Enabled, Palladium-Catalyzed Non-Directed
C(sp3)–H Carbonylation to Access Indanone Cores
Shou-Le Cai, Yan Li, Chi Yang, Jie Sheng, and Xi-Sheng Wang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03426 • Publication Date (Web): 14 Oct 2019
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ACS Catalysis
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NHC Ligand-Enabled, Palladium-Catalyzed Non-Directed
C(sp3)–H Carbonylation to Access Indanone Cores
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Shou-Le Cai, Yan Li, Chi Yang, Jie Sheng, and Xi-Sheng Wang*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in
Molecular Synthesis of CAS, University of Science and Technology of China, 96 Jinzhai Road, Hefei 230026, China.
Supporting Information Placeholder
ABSTRACT: A palladium-catalyzed C(sp3)–H carbonylation of alkylated aryl triflates or bromides under 1 atm of CO has been
developed, in which no directing group or oxidant were required. The essence of
R2
R2 Me
Me
Me
this reaction is the combination of appropriate NHC ligands with palladium to
facilitate the formation of five-membered cyclopalladium intermediate.
Mechanism studies suggest that the insertion of carbon monoxide into two five-
membered cyclopalladium species generated via palladium migration might be the
crucial step of this transformation. This method offers an efficient solution for
expedient construction of indanone cores, which are valuable synthons and
pharmacophores ubiquitously found in numerous natural products.
cat. Pd(0)
+
CO
R1
R1
(1 atm)
X
O
X = OTf, ONf, Br
C(sp3)H carbonylation
two CC bonds formed
all-carbon indanone framework
no directing groups and oxidants
28 examples
up to 82% yield
KEYWORDS: palladium, C–H activation, carbonylation, indanone, NHC ligand
Transition-metal-catalyzed C−H bond functionalization has
emerged as a straightforward and efficient strategy for the
synthesis of complex natural products and functional
molecules, due to its step- and atom-economical manner
induced by the direct transformation from ubiquitous C−H
bonds.1 As one of the most important and readily available
carbonylating sources, the insertion of carbon monoxide (CO)
into organic molecules via direct C−H bond functionalization
has been developed as an efficient method for incorporation of
carbonyl group.2 While a variety of transition-metal-catalyzed
carbonylations of C(sp2)–H bonds have been established, only
few examples have been demonstrated on the C(sp3)–H
carbonylation due to its high stability. Since Fujiwara’s
pioneering work in 1989,3 direct carbonylation reactions of
simple alkanes and toluenes have been established via Pd, Cu,
or Rh-catalyzed alkyl and benzylic C−H activation (Scheme
1a).4 However, such methods normally required high pressure
of CO (10-50 atm), a large excess of substrates, and/or lack of
regioselectivity, thus clearly hampering their application in
organic synthesis.
Scheme 1. Transition-Metal-Catalyzed Carbonylation of
C(sp3)−H Bonds
a) Non-Directed Carbonylation of Alkanes or Toluenes
O
H
Nu
[Pd], [Cu], [Rh], etc.
+
CO
(10-50 atm)
or
NuH
or
H
Nu
O
> 20 equiv
b) Carbonylation Directed by N-Containing Functional Groups
R
R
N
N
[Pd], [Ru], [Co], etc.
H
+
CO
(1-10 atm)
O
H
c) This Work: Pd(0)-Catalyzed Carbonylation without Directing Group
R2 Me
R2
Me
H
Pd(0)
R1
+
CO
R1
(1 atm)
X
X = OTf, ONf, Br
O
Chart 1. Samples of Natural Products Containing
Indanone Cores
To solve the perennial problems of low reactivity and poor
site selectivity in non-directed C(sp3)–H carbonylation,
directing group strategy has been employed. The Yu group
and the Chatani group have reported Pd and Ru-catalyzed β-
carbonylation of alkyl amides for synthesis of succinimides,
respectively.5 Inspired by these results, a series of directing
groups, including 8-aminoquinoline, oxalyl amide, secondary
aliphatic amine and others, have been exploited by many
research groups to facilitate the carbonylation of C(sp3)–H
(Scheme 1b).6 However, these reactions require N-containing
directing groups, which are also used as building blocks, fur-
OMe
Me
O
Me
MeO
O
O
OMe
O
OH
MeO
Me
CO2H
Me
HO
Me
Me
Me
Me
trigoxyphin M
acerolanin C
carexane L
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Table 1. Pd-Catalyzed C(sp3)−H Carbonylation:
cores, which can be use as valuable synthons and
pharmacophores ubiquitously found in numerous natural
products (Chart 1).10
Optimization of Conditionsa
1
2
3
Me
Me Me
Me
[Pd] (10 mol%)
Our study commenced with t-butyl biphenyl triflate 1a as
the pilot substrate in the presence of a catalytic amount of
Pd(OAc)2 (10 mol%) in ethylbenzene under 1 atm of CO at
140 °C (Table 1). A variety of phosphine ligands, which
facilitated the formation of five-membered cyclopalladium,9
failed to promote this transformation (entries 1-4). To our
delight, NHC ligand L1 enabled the desired C(sp3)–H
carbonylation to furnish 2a successfully, albeit with a pretty
low yield (5%, entry 5). Stimulated by this result, a number of
NHC ligands were synthesized and investigated in this
reaction. With the decreasing of the steric hindrance of the
NHC ligands (L2-L4), interestingly, the yield was gradually
promoted to 43% (entries 6-8). Additionally, compared with
L4, IMes•HCl (L5) was a more suitable ligand to facilitate this
reaction (entry 9). Next, after careful screening of palladium
sources (entries 10-13), Pd(TFA)2 was indicated as the optimal
choice with 69% GC yield. To further improve the yield,
further modifications of NHC ligands on the imidazole ring
and aryl ring were next performed (entries 14-16). To our
satisfaction, the examination showed that NHC ligand with
dimethyl groups on the 4,5-position of imidazole ring
(IMesMe•HCl, L7) gave the best result (76%, entry 15).
However, the yields of 2a decreased when a more electron-
rich ligand (L8) was investigated, suggesting that a critical
demand of both steric and electronic effects of the NHC ligand
was required in this system (entry 16). Finally, by increasing
the catalyst loading to 15 mol% and prolonging reaction time
to 48 h, the isolated yield of 2a was improved to 72% (entry
17).
H
ligand (20 mol%)
4
5
6
7
8
9
CsOPiv (2.0 equiv)
PhEt, CO (1 atm), 140 C
Ph
Ph
OTf
1a
O
2a
, R = H, R1 = R2 iPr, R
H, X = Cl
=
H, X = Cl
3
L1
L2
=
=
=
, R = H, R1 = R2 Et, R
3
R
N
R
R1
L3, R = H, R1 = Et, R2 = Me, R3 = H, X = Cl
R1
, R = H, R1 = R2 Me, R
H, X= Cl
3
L4
L5
L6
=
=
=
N
, R = H, R1 = R2
R
3
=
Me, X = Cl
3
R3
, R,R = (CH2)4, R1 = R2
, R = Me, R1 = R2
R3
X
=
=
=
R Me, X = Br
Me, X = Cl
R2
R2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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42
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57
58
59
60
L7
L8
=
=
R
, R = Me, R1 = R2 Me, R
OMe, X = Cl
3
=
Entry
[Pd]
Ligand
Yield (%)b
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
PdCl2
PPh3
0
0
2
P(o-tol)3
3
PCy3
trace
0
4
(tBu3PH)BF4
5
L1
L2
L3
L4
L5
L5
L5
L5
L5
L6
L7
L8
L7
5
6
23
7
41
8
43
9
49
10
11
12
13
14
15
16
17c
62
52
Pd(OPiv)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
66
69
With the optimized reaction conditions in hand, we next
explored the scope of this C(sp3)–H carbonylation reaction. As
shown in Table 2, a large number of aryl substrates were
carbonylated smoothly, furnishing the corresponding indanone
products 2 in medium to good yields. Notably, aryl triflates,
nonaflates as well as bromides were all compatible with this
catalytic reaction (2a, 2b). Impressively, aryl triflates installed
with electron-withdrawing groups at the meta-position of aryl
rings, including amides (2c-2e), ketones (2f, 2g), and esters
(2h, 2i), showed high reactivity for this transformation. In
contrast, aryl triflates with electron-donating groups gave
relatively lower yields (2j, 2k), which was consistent with the
proposal that the cleavage of C(sp3)–H bond underwent
through the concerted metalation-deprotonation (CMD)
mechanism.11 Moreover, the subjection of aryl triflate 1m into
the reaction system furnished indanone 2m as the sole product,
indicating that the cleavage of methyl C(sp3)–H was more
favorable over the methylene C(sp3)–H and the formation of a
five-membered cyclopalladium was prefered over a six-
membered ring. Yet intriguingly, 2-t-butyl-6-methylphenyl
triflate (1n) was carbonylated only at the most steric hindered
position of the aryl ring without any migration product
(vide infra). More interestingly, julolidine derivate 1p was also
well tolerated in this reaction, affording tetracyclic indanone
2p in an acceptable yield.
74
76
70
82 (72)
aReaction conditions: 1a (0.2 mmol, 1.0 equiv), [Pd] (10 mol%),
ligand (20 mol%), CsOPiv (2.0 equiv), PhEt (1.5 mL), CO (1
atm), 140 °C, 24 h. bYields were determined by GC using
dodecane as an internal standard; number in parentheses was
isolated yield. c[Pd] (15 mol%), ligand (30 mol%), 48 h.
nishing only cyclic amides or their derivatives. Besides, the
addition of extra oxidants goes against the the atom-economy
of such C–H functionalizations. As one part of our continuous
efforts to develop novel methods via C–H activation,7, 6c we
envision that Pd(0)-catalyzed C–H activation, also known as a
redox-neutral process with high selectivity, could handle those
problems. Our strategy relies on the use of oxidative addition
of a carbon-leaving group bond to Pd(0) species to induce
intramolecular C(sp3)−H activation8-9 and the subsequent
insertion of CO into the in situ-formed cyclopalladium
intermediate.
Herein, we described a palladium-catalyzed C(sp3)–H
carbonylation of alkylated aryl triflates or halides under 1 atm
of CO, in which no directing group or oxidant were required.
The essence of this reaction is the combination of appropriate
NHC ligands with palladium to facilitate the formation of five-
membered cyclopalladium intermediate. This method offers an
efficient solution for the expedient synthesis of indanone
To further investigate the scope of aryl triflates in this
carbonylation system, para-substituted aryl triflates were next
examined. As expected, the desired indanones were isolated as
mixtures of regioisomers for the carbonylation occurred at
either 1- or 3-positions of the aryl rings, which clearly
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indicated a palladium migration was involved via a ring-
the sole product showed phenyl ring was also bulky enough to
control the regioselectivity. Gratifyingly, halogen substituents
such as fluoro (1v) and chloro (1w) were also well tolerated,
while furnishing the migration products in majority.
Importantly, while aryl triflate installed with electron-donating
group such as methoxy (1x) gave two regioisomers in a ratio
of 1:1, triflate with electron-withdrawing substituent afforded
indanone 2y as as the single regioisomer. These results
indicated that the electronic effect also played a key role in
controlling in controlling the regioselectivity of this
transformation as well.
opening C(sp2)–H activation of the cyclopalladium
intermediate. To
1
2
3
4
5
6
7
8
Table 2. Pd-Catalyzed C(sp3)–H Carbonylationa
Me R2
R2
Me
Pd(TFA)2 (10 mol%)
IMesMe•HCl (20 mol%)
H
R1
R1
CO (1 atm), CsOPiv (2 equiv)
PhEt, 140 o
C
X
1
O
2
2- and 3-substituted substrates:
9
Me
Me
Me
Me
Me
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
To demonstrate the synthetic potential of this novel method,
further transformations of the produced indanone were next
elucidated (Scheme 2). According to the literatures,12 the
nitration of 2b with fresh prepared nitric acid followed by Pd-
catalyzed hydrogenation could afford aniline 3 in 97% yield
(Scheme 2a). Meanwhile, indanone 2b could be brominated at
the α-carbon of carbonyl group using N(n-Bu)4Br3 as a mild
brominating reagent (4, Scheme 2b). Next, after oximation of
2b with hydroxylamine, a Beckmann rearrangement of the
corresponding ketoxime was performed to afford lactam 5 in
85% yield. Additionally, a classical Baeyer-Villiger oxidation
of ketone 2b by m-CPBA at room temperature could furnish
lactone 6 in 85% yield. Finally, a Wittig reaction of 2b also
afford exocyclic alkene 7 in 71% yield.
N
O
N
Ph
O
O
O
O
O
2d
2a
2b
b,c
b,c
2c
, 77%
, 73%
X = OTf, 72%b,c
X = ONf, 68%b,c
X = OTf, 65%
X = ONf, 62%
X = Br, 55%
Me
Me
Me
Me
Me
Me
Me
Me
N
Ph
Ac
MeO2C
O
O
O
O
O
O
b
b
2e
%
2f
%
2g
2h
, 74 b,c
, 53
, 71%
, 61%
Me
CO2Me
Me
Me
Me
Me
Me
Me
nBuO2C
2i
Me
AcHN
2k
O
O
O
O
b,c
2j
2l
,
, X = Br 38%
, 70%b,c
, 50%
Me
, 40%
Me
Scheme 2. Synthetic Transformations of Indonane 2b
Me
Me
Me
Me
Et
Me
Me
O
Me
Me
Me Me
Me
Br
Me
N
O
O
Me
O
Me
Me
b
H2N
N
H
, 85%
O
2m
2n
2o
2p
, 67%
, 42%
, 56%
, 41%
O
O
4
, 88%
5
3
, 97%
c
a
4-substituted substrates
b
Me
Me
Me
Me
3
3
Me
Me
Me Me
Me
Me
Me
Et
tBu
Me
Me
d
e
1
1
O
O
O
O
O
2b
O
6
7
, 71%
, 85%
2s
, 48%
Me
2q
2r
, 56% (1-:3- = 1.6:1)
, 66% (1-:3- = 1.3:1)
Me
Me
Me
Me
3
Me
Me
Et
Et
Ph
F
a) KNO3, H2SO4, -5 °C; Pd/C, H2, MeOH; b) (n-Bu)4NBr3,
CHCl3, 0 °C; c) NH2OH•HCl, NaOAc, EtOH, reflux; CBr4, PPh3,
1
t
toluene, 80 °C; d) m-CPBA, CH2Cl2, rt; e) PPh3PCH3Br, BuOK,
O
b,c
O
O
b,c
THF, rt.
2t
2u
2v
, 53%
, 62%
, 82% (1-:3- = 1:4)
Me
Me
Me
Me
Me
3
3
Me
Scheme 3. Mechanistic Experiments
Cl
MeO
MeO2C
1
1
O
O
O
b
b
b,c
2w
2x
2y
, 43%
, 62% (1-:3- = 1:1.6)
, 63% (1-:3- = 1:1)
aReaction Conditions: 1 (0.2 mmol, 1.0 equiv), Pd(TFA)2 (10
mol%), IMesMe•HCl (20 mol%), CsOPiv (2.0 equiv), PhEt (1.5
mL), CO (1 atm), 140 °C, 24 h; unless otherwise noted, X = OTf.
bPd(TFA)2 (15 mol%), IMesMe•HCl (30 mol%). c48 h.
our interest, as shown in Table 2, both steric and electronic
effects had subtle influence on our catalytic system. For
example, while indanone 2q was afforded in 66% yield as a
mixture of two regioisomers in 1.3:1 ratio, 2r was obtained at
a slightly higher ratio of 1.6:1in the reaction of 1r. From the
collective results above, they indicated that a bulkier para-
substituent on the aryl rings might suppress the palladium
migration of cyclopalladium intermediate. To verify this
speculation, aryl triflates installed with large steric hindrance
groups at the para-position were tested in this catalytic
reaction, which gave the less steric hindered products as the
only products (2s and 2t). Meanwhile, the isolation of 2u as
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Ph
O
Ph
Ph Ph
standard conditions
standard conditions
1
2
3
4
COCl
(1)
8
9,
0%
Me Me
Me
Me
Me
5
6
7
8
(2)
(3)
COCl
10
O
2b
, 0%
D3C
H3C
CO2Me
+
CO2Me
D3C CH3
standard conditions
kH/kD = 2.5
12a 12b
CO2Me
9
Br
38% (
:
= 2.5:1)
O
O
12b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11
12a
45% D
H/D
CD3
CD3
D3C
CO2Me
standard conditions
CO2Me
(4)
(5)
Br
13
14
, 40%
O
Me
Me
IMesMe•HCl (2.0 equiv)
CsOPiv (5.0 equiv)
Cl
Me
Pd
15
Me
PhEt, CO (1 atm)
140 C, 12 h
O
2b
, 31%
Me
Me
IMesMe•HCl (2.0 equiv)
CsOPiv (5.0 equiv)
PhEt, CO (1 atm)
Pd
16
(6)
Me
Me
140 C, 12 h
O
2b,
50%
Scheme 4. Proposed Mechanism
Me
Me
Me
Me Me
Me
Me
R
R
+
Me
Me
R
OTf
Pd(0)L
O
2
O
R
2'
1
2
O
PivOH
OPiv
Me Me
Me Me
Pd
Me Me
Pd
R
Me Me
Pd
Me Me
Me
O
H
R
R
Pd
L
O
O
OTf
R
R
L
L
L
G
Pd
F
L
path c
CO
Me Me
J
O
path b
A
Me
Me
PivOH
R
-PivOH
+PivOH
OPiv
CsOPiv
CsOTf
CO
Pd
Pd
L
L
R
Me Me
Me
Me Me
R
-PivOH
E
D
R
H
+PivOH
OPiv
L
CO
Me
Me
Pd
OPiv
path a
Pd
L
R
O
I
-PivOH
+PivOH
Pd
B
C
L
To gain some insights into the mechanism of this reaction, a
series of control experiments were next carried out. Firstly, the
subjection of acid chloride 8 or 10 into the standard conditions
gave none of the desired product, which indicated that the
carbonylation step might happen after the C−H activation step
(Eq. 1-2, Scheme 3).13 Next, the reaction of partially
deuterated aryltriflate 11 under the optimized conditions
allowed the determination of a primary intramolecular isotope
effect of 2.5 (Eq. 3, Scheme 3), which indicated that the
cleavage of C–H bond might be the rate-determining step.
Furthermore, the ortho-deuterated product 14 was isolated
when 13 was used as the deuterated substrate, which
demonstrated a palladium migration might be involved in the
catalytic cycle (Eq. 4, Scheme 3). Finally, the reaction of the
putative palladium species 15 and its cyclopalladium
intermediate 16 under the standard conditions could furnished
the target indanone 2b in 31% yield and 50% yield,
respectively (Eq. 5-6, Scheme 3).14 Both results suggested that
the five-membered cyclopalladium was generated via C–H
bond cleavage before the insertion of carbon monoxide.
On the basis of collective results and previous reports,9 a
plausible mechanism of Pd-catalyzed C(sp3)–H activation/CO
insertion was described as Scheme 4. Initially, oxidative
addition of aryl triflate 1 to Pd(0) forms cationic aryl
palladium complex A, which transformed to palladium
complex B quickly via ligand exchange. The palladium
complex B might be inserted by CO, followed by C(sp3)–H
bond activation to give product 2 (path a). However, the
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Org. Chem. 2015, 2015, 7859-7868. (i) Ye, B.; Cramer, N. Chiral
detection of migration products (2q, 2r, 2v-x, Table 2) could
exclude this assumption. On the contrary, intramolecular
C(sp3)−H activation of Pd(II) species B will generate
cyclopalladium C before the insertion of CO. While
cyclopalladium C might coexist in equilibrium with E via the
formation of the alkyl palladium intermediate D, The carbonyl
palladium complexes F and G were then afforded by the
subsequent insertion of CO (path b).15 The final reductive
elimination from F and G furnishes the indanone products 2
and 2’, and regenerates Pd(0) catalyst. On the other hand, the
proposal described in path c that alkyl palladium intermediate
D might be inserted by CO could also be excluded by our
control experiment (eq. 1, Scheme 3).
Cyclopentadienyls: Enabling Ligands for Asymmetric Rh(III)-
Catalyzed C–H Functionalizations. Acc. Chem. Res. 2015, 48, 1308-
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First-Row Transition-Metal-Catalyzed Carbonylative Transformations
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In conclusion, we have developed a novel palladium-
catalyzed C(sp3)–H carbonylation of alkylated aryl triflates or
bromides under 1 atm of CO. The combination of appropriate
NHC ligands with palladium facilitates this transformation
successfully. Mechanism studies suggest that the insertion of
carbon monoxide into two five-membered cyclopalladium
species, which are generated via palladium migration, is the
crucial step of this transformation. This method offers a
solution for construction of all carbon indanones, and paves an
efficient way for synthesizing bioactive compounds containing
such valuable synthons and pharmacophores. Further
exploration of the detailed mechanism and application of this
strategy to synthesize bioactive molecules are still ongoing in
our laboratory.
(3) Fujiwara, Y.; Takaki, K.; Watanabe, J.; Uchida, Y.; Taniguchi,
H. Thermal Activation of Alkane C–H Bonds by Palladium Catalysts.
Carbonylation of Alkanes with Carbon Monoxide. Chem. Lett. 1989,
1687-1688.
(4) For selected examples, see: (a) Ryu, I.; Tani, A.; Fukuyama, T.;
Ravelli, D.; Fagnoni, M.; Albini, A. Atom-Economical Synthesis of
Unsymmetrical Ketones through Photocatalyzed C–H Activation of
Alkanes and Coupling with CO and Electrophilic Alkenes. Angew.
Chem., Int. Ed. 2011, 50, 1869-1872. (b) Xie, P.; Xie, Y.; Qian, B.;
Zhou, H.; Xia, C.; Huang, H. Palladium-Catalyzed Oxidative
Carbonylation of Benzylic C–H Bonds via Nondirected C(sp3)–H
Activation. J. Am. Chem. Soc. 2012, 134, 9902-9905. (c) Okada, M.;
Fukuyama, T.; Yamada, K.; Ryu, I.; Ravelli, D.; Fagnoni, M. Sunlight
Photocatalyzed Regioselective β-alkylation and Acylation of
Cyclopentanones. Chem. Sci. 2014, 5, 2893-2898. (d) Li, Y.; Zhu, F.;
Wang, Z.; Wu, X.-F. Copper-Catalyzed Carbonylative Synthesis of
Aliphatic Amides from Alkanes and Primary Amines via C(sp3)–H
Bond Activation. ACS Catal. 2016, 6, 5561-5564. (e) Li, Y.; Dong,
K.; Zhu, F.; Wang, Z.; Wu, X.-F. Copper-Catalyzed Carbonylative
Coupling of Cycloalkanes and Amides. Angew. Chem., Int. Ed. 2016,
55, 7227-7230. (f) Lu, L.; Cheng, D.; Zhan, Y.; Shi, R.; Chiang, C.-
W.; Lei, A. Metal-Free Radical Oxidative Alkoxycarbonylation and
Imidation of Alkanes. Chem. Commun. 2017, 53, 6852-6855.
ASSOCIATED CONTENT
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* xswang77@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(5) (a) Yoo, E. J.; Wasa, M.; Yu, J.-Q. Pd(II)-Catalyzed
Carbonylation of C(sp3)–H Bonds: A New Entry to 1,4-Dicarbonyl
Compounds. J. Am. Chem. Soc. 2010, 132, 17378-17380. (b)
Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N.
Highly Regioselective Carbonylation of Unactivated C(sp3)–H Bonds
by Ruthenium Carbonyl. J. Am. Chem. Soc. 2011, 133, 8070-8073.
(6) For selected examples, see: (a) Wu, X.; Zhao, Y.; Ge, H. Direct
Aerobic Carbonylation of C(sp2)–H and C(sp3)–H Bonds through
Ni/Cu Synergistic Catalysis with DMF as the Carbonyl Source. J. Am.
Chem. Soc. 2015, 137, 4924-4927. (b) Wang, C.; Zhang, L.; Chen, C.;
Han, J.; Yao, Y.; Zhao, Y. Oxalyl Amide Assisted Palladium-
Catalyzed Synthesis of Pyrrolidones via Carbonylation of γ-C(sp3)–H
Bonds of Aliphatic Amine Substrates. Chem. Sci. 2015, 6, 4610-4614.
(c) Wang, P.-L.; Li, Y.; Wu, Y.; Li, C.; Lan, Q.; Wang, X.-S. Pd-
Catalyzed C(sp3)–H Carbonylation of Alkylamines: A Powerful
Route to γ-Lactams and γ-Amino Acids. Org. Lett. 2015, 17, 3698-
3701. (d) Hernando, E.; Villalva, J.; Martínez, Á. M.; Alonso, I.;
Rodríguez, N.; Arrayás, R. G.; Carretero, J. C. Palladium-Catalyzed
Carbonylative Cyclization of Amines via γ-C(sp3)–H Activation:
Late-Stage Diversification of Amino Acids and Peptides. ACS Catal.
2016, 6, 6868-6882. (e) Willcox, D.; Chappell, B. G. N.; Hogg, K. F.;
Calleja, J.; Smalley, A. P.; Gaunt, M. J. A General Catalytic β-C–H
Carbonylation of Aliphatic Amines to β-Lactams. Science 2016, 354,
851-857. (f) Cabrera-Pardo, J. R.; Trowbridge, A.; Nappi, M.; Ozaki,
K.; Gaunt, M. J. Selective Palladium(II)-Catalyzed Carbonylation of
Methylene β-C–H Bonds in Aliphatic Amines. Angew. Chem., Int. Ed.
2017, 56, 11958-11962. (g) Barsu, N.; Bolli, S. K.; Sundararaju, B.
We gratefully acknowledge the National Basic Research Program
of China (973 Program 2015CB856600), the National Science
Foundation of China (21772187, 21522208) for financial support.
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