Catalytic activation of carbon-carbon bonds in cyclopentanones

Article abstract of DOI:10.1038/nature19849

In the chemical industry, molecules of interest are based primarily on carbon skeletons. When synthesizing such molecules, the activation of carbon-carbon single bonds (C-C bonds) in simple substrates is strategically important: it offers a way of disconnecting such inert bonds, forming more active linkages (for example, between carbon and a transition metal) and eventually producing more versatile scaffolds. The challenge in achieving such activation is the kinetic inertness of C-C bonds and the relative weakness of newly formed carbon-metal bonds. The most common tactic starts with a three- or four-membered carbon-ring system, in which strain release provides a crucial thermodynamic driving force. However, broadly useful methods that are based on catalytic activation of unstrained C-C bonds have proven elusive, because the cleavage process is much less energetically favourable. Here we report a general approach to the catalytic activation of C-C bonds in simple cyclopentanones and some cyclohexanones. The key to our success is the combination of a rhodium pre-catalyst, an N-heterocyclic carbene ligand and an amino-pyridine co-catalyst. When an aryl group is present in the C3 position of cyclopentanone, the less strained C-C bond can be activated; this is followed by activation of a carbon-hydrogen bond in the aryl group, leading to efficient synthesis of functionalized α-tetralones - a common structural motif and versatile building block in organic synthesis. Furthermore, this method can substantially enhance the efficiency of the enantioselective synthesis of some natural products of terpenoids. Density functional theory calculations reveal a mechanism involving an intriguing rhodium-bridged bicyclic intermediate.

Full text of DOI:10.1038/nature19849

LETTER
doi:10.1038/nature19849
Catalytic activation of carbon–carbon bonds in
cyclopentanones
Ying Xia1,2, Gang Lu3, Peng Liu3 & Guangbin Dong1,2
In the chemical industry, molecules of interest are based primarily on block in organic synthesis. Furthermore, this method can
carbon skeletons. When synthesizing such molecules, the activation substantially enhance the efficiency of the enantioselective synthesis
of carbon–carbon single bonds (C–C bonds) in simple substrates is of some natural products of terpenoids. Density functional theory
strategically important: it offers a way of disconnecting such inert calculations reveal a mechanism involving an intriguing rhodium-
bonds, forming more active linkages (for example, between carbon bridged bicyclic intermediate.
and a transition metal) and eventually producing more versatile
The most common strategy for cleaving a C–C bond uses a ring
scaffolds1–13. The challenge in achieving such activation is the kinetic system, in which the unfavourable energetics of C–C cleavage can
inertness of C–C bonds and the relative weakness of newly formed be compensated for by the release of strain in the ring. However,
carbon–metal bonds6,14. The most common tactic starts with a three- although there has been success in activating C–C bonds in cyclo-
or four-membered carbon-ring system9–13, in which strain release propane and cyclobutane derivatives (Fig. 1a)9–13, the catalytic C–C
provides a crucial thermodynamic driving force. However, broadly activation of less strained or non-strained rings is underdeveloped.
useful methods that are based on catalytic activation of unstrained The rhodium-mediated decarbonylation of cycloalkanones has
C–C bonds have proven elusive, because the cleavage process is much been described3; unfortunately, however, C–C activation for the less
less energetically favourable. Here we report a general approach to strained cyclopentanone showed low efficiency (Fig. 1b). For larger
the catalytic activation of C–C bonds in simple cyclopentanones and cyclic structures, an innovative chelation-based strategy has also been
some cyclohexanones. The key to our success is the combination developed, in which ketimines prepared from the corresponding
of a rhodium pre-catalyst, an N-heterocyclic carbene ligand and an ketones and 2-amino-3-picoline allowed a directed C–C activation
amino-pyridine co-catalyst. When an aryl group is present in the through a five-membered metallacycle8,15. However, although medium
C3 position of cyclopentanone, the less strained C–C bond can be to large cyclic ketimines can be efficiently activated in this way, the
activated; this is followed by activation of a carbon–hydrogen bond strategy is problematic for cyclopentanone- and cyclohexanone-
in the aryl group, leading to efficient synthesis of functionalized derived ketimines (Fig. 1c)15. Our laboratory recently developed a
α-tetralones—a common structural motif and versatile building catalytic C–C activation of isatins, a less strained ring system, to afford
a
d
O
O
M catalyst
X
X
O
M catalyst
Y
Oxidative addition
M
Various products
M
Y
or
Y
M
n
R
n
n
R
Reductive elimination
n = 1 or 2
X, Y = oxygen, nitrogen or carbon substituent
O
O
b
e
Catalyst [Rh(C2H4)2Cl]2
Ligand N-heterocyclic carbene
1 equiv. Rh(PPh3)3Cl
O
R′
R
H
R
Toluene, reꢀux, 8 days
Co-catalyst 2-aminopyridine
57%
Ph
Ph
H
R′
c
O
Me
Catalyst [Rh(coe)2Cl]2
DG
Rh
N
DG
Rh
nBu
Ligand PCy3
n
DG
Rh
N
N
C–C
activation
C–H
activation
+
N
Toluene, 150 °C
nBu
or
N
O
R
Then H+/H2O
R
H
nBu
nBu
n
R
H
n = 2, 3, 5, 7 or 10, 76%–89% yield
n = 0, 9% yield; n = 1, 5% yield
R′
R′
R′
A
B
C
Figure 1 | Activation of C–C bonds in ring systems. a, Catalytic
the thermodynamic driving forces do not always allow oxidative
addition with a transition metal, instead favouring the reverse process
(C–C reductive elimination). R, hydrocarbon side chain. e, Our
strategy for catalytic C–C activation of cyclopentanones: merging
the unfavourable C–C activation with C–H activation, to produce an
overall thermodynamically favoured reaction. Specifically, when using
a cyclopentanone with an aryl group in the C3 position, the imine
intermediate (A; with a pendant directing group, DG) should allow the
transient C–C activation intermediate (B) to undergo an intramolecular
C–H activation, producing rhodacycle (C). Subsequent reductive
elimination will lead to α-tetralone derivatives.
C–C activation of strained rings (for example, in cyclopropane or
cyclobutanone). The unfavourable energetics of C–C activation can
be compensated by the release of strain in the ring. M, transition
metal. b, Stoichiometric rhodium-mediated C–C activation of less
strained cycloketones. This reaction is less efficient than that shown
in a. Ph, phenyl. c, Directed catalytic C–C activation of less strained
cycloketimines. The yield is high for large cycloketimines, but low
for smaller ones. Bu, butyl; coe, cyclooctene; Me, methyl; PCy3,
tricyclohexylphosphine. d, The challenge in terms of activating the C–C
bonds of cyclopentanones is that C–C activation is reversible;
1Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA. 2Department of Chemistry, University of Chicago, Chicago, Illinois 60637, USA. 3Department of Chemistry,
University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
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© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

RESEARCH LETTER
2-quinolinones via decarbonylation and alkyne insertion16; however, three- or four-membered rings, cyclopentanones lack sufficient ther-
a pre-installed pyridine directing group proved essential. Hence, to modynamic driving forces to favour oxidative addition with a transition
our knowledge, catalytic C–C activation of normal cyclopentanones metal6; instead, the reverse process—C–C reductive elimination—is
remains an unmet challenge17,18
.
often preferred (Fig. 1d)1,19. We hypothesized that such a problem could
It has been postulated that the major difficulty comes from the be solved by merging an unfavourable C–C activation with a tandem
reversibility of the C–C activation step (Fig. 1d)1,6,19. In contrast to sp2 C–H functionalization to enable an overall thermodynamically
O
a
5 mol% [Rh(C2H4)2Cl]2
10 mol% IMes
10 mol% TsOH H2O
O
Me
Me
O
1
•
N
N
5
Ar
R
Ar
2
+
R
R
Me
Me
NH2
N
50 mol% H2O, 1,4-dioxane, 48 h
4
3
Me Me
IMes
Me
Me
1b–29b
1c–29c
Condition A: 25 mol% C1, 140 ºC
Condition B: 50 mol% C1, 150 ºC
C1
Ar
1a–29a
Major
Minor
O
Para-substituted aryl
O
O
O
O
O
O
O
O
O
nBu
Me
Me
MeO
Ph
PhO
Me
O
Me
1b
Me
8b
Me
Me
7b
Me
Me
Me
2b
4b
5b
Me
6b
3b
Condition A
66% (>10:1)
68% (1 mmol scale)
Condition B, 73% (5.8:1)
Condition A
64% (>10:1)
Condition A
65% (>10:1)
Condition A
75% (>10:1)
Condition A
69% (>10:1)
Condition A
64% (>10:1)
Condition A, 43% (>10:1)
Condition B, 63% (>10:1)
Condition A, 54% (>10:1)
Condition B, 71% (>10:1)
Me
Me
O
O
O
O
O
O
O
O
O
O
O
O
Me
Me
NC
S
HO
F
Cl
B
H2N
F3C
Me
O
Me
16b
Me
14b
Me
12b
13b Me
15b
Me
Me
9b
10b
Me
11b
Me
Condition B
72% (>10:1)
Condition B
82% (>10:1)
Condition B
73% (>10:1)
Condition B
66% (>10:1)
Condition B
85% (>10:1)
Condition B
53% (>10:1)
Condition A
45% (>10:1)
Condition A
66% (8.2:1)
Meta-substituted aryl
Ortho-substituted aryl
Naphthyl
Substituents on cyclopentanone
O
O
O
O
O
O
O
O
Ph
Ph
Cl
Me
Me
20b
Me
21b
Condition A
74% (9.0:1)
Me
Me Ph
23b
Me
Me
Me Me
19b
22b
17b
18b
Me
23a
Condition A
71% (8.0:1)
Condition B
53% (65%) (4.3:1)
Condition B
42% (72%) (1.4:1)
Condition A
Condition B
Condition B
63% (>10:1)
70% (94%) (3.5:1)
44% (63%) (3.0:1)
O
O
O
O
O
O
O
O
O
Me
Ph
H
Me
+
Ph
H
Me
Ph
Ph
Ph
Ph
26a
25a
Me
27b
25b
Me Me
24a
N
24b
N
26b
Me
NTs
27a
Me
27c
Ts
d.r. = 15:1
Ts
Condition A, 73% (95%) (3.9:1)
Condition B, 30% (6.0:1)
Condition A, 44% (57%) (5.2:1)
Condition A, 48% (78%) (1.8:1)
Derivatization of complex targets
O
Me
H
Me
H
Me
H
O
Me
H
Me
H
Me
H
H
O
H
H
O
O
O
H
H
H
H
H
O
O
O
From oestrone
29a
From cholesterol
29b
28b
Condition B, 72% (>10:1)
O
Me
Me
28a
Condition B, 47% (61%) (3.8:1)
O
O
1
5 mol% [Rh(C2H4)2Cl]2
15 mol% IPr
20 mol% MeSO3H
O
b
iPr
iPr
2
6
Ar
+
3
X
Ar
Me
X
N
N
Ar
X
5
100 mol% 2-amino-6-picoline
20 mg 4 Å MS
1,4-dioxane (1.0 M), 150 ºC, 48 h
Condition C
4
Me
Me
30c–36c
Me
iPr
iPr
Me
30b–36b
X = CH2 or O
Not observed
IPr
30a–36a
O
O
O
O
Ring-fused cyclohexanone
O
O
Me
MeO
O
F
O
O
Me
Ph
Me
Me
Me
Me
Me
Me
Me
34c
Me
Me
33c
28%
Me
35c
<5%
30c
31c
32%
32c
31%
(68% b.r.s.m.)
H
21%
(77% b.r.s.m.)
Me
34% (73% b.r.s.m.)
46% (67% b.r.s.m.)
36a
36c
(76% b.r.s.m.)
(66% b.r.s.m.)
14%
Figure 2 | Substrate scope. a, Scope of the cyclopentanones. The
shaded box at the top shows the basic reaction: the substrates are
3-arylcyclopentanones (1a–29a); the major products, α-tetralones
(1b–29b), come from cleavage of the more hindered C1–C2 bond,
while the minor products, α-indanones (1c–29c), are generated through
cleavage of the less hindered C1–C5 bond. [Rh(C2H4)2Cl]2 is the catalyst
precursor and 2-aminopyridine (C1) is the co-catalyst; TsOH is toluene
sulfonic acid. Ar, aryl group. Below the shaded box are shown the major
products and their isolated yields. b, Scope of the cyclohexanones.
See Supplementary Information for further experimental details.
The regioselective ratios (r.r.) were determined by gas chromatography-
mass spectrometry or 1H nuclear magnetic resonance (NMR) of the crude
products. The percentages in parentheses are the total yields or the
b.r.s.m. (based on recovered starting material) yields determined by
1H NMR, using 1,1,2,2-tetrachloroethane (TCE) as the internal standard.
d.r., diastereomeric ratio; IMes, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-
ylidene; IPr, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene;
MS, molecular sieve.
2
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© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

LETTER RESEARCH
favoured transformation13. As depicted in Fig. 1e, installing an aryl this reaction, although the regioselectivity decreased to some extent
group at cyclopentanone’s C3 position should allow the transient C–C (products 23b, 24b). As expected, the reaction was sluggish for cyclo-
activation intermediate (B) generated using Jun’s temporary directing pentanones bearing a C2 substituent (for example, 25a); nevertheless,
strategy8 to undergo an intramolecular ortho C–H activation, to give C–C activation still occurred predominantly at the more hindered site
rhodacycle (C). Subsequent sp2–sp2 reductive elimination would ulti- (to produce 25b). Moreover, the 3,4-disubstituted and ring-fused cyclo-
mately lead to α-tetralone derivatives—well known building blocks pentanones are also suitable substrates, and the relative configuration is
used by the chemical industry and common structural motifs found in preserved during the reaction (products 26b, 27b). Finally, this method
bioactive compounds20–23. The whole catalytic process would convert allows the preparation of unusual derivatives of complex bioactive
an aliphatic ketone to a more stable aryl ketone, accounting for the molecules (28b and 29b). For example, a fused ring can be conveniently
overall thermodynamic benefits of this transformation (ΔG would be installed on oestrone (to produce 29b).
about −6kcalmol−1).
To test our hypothesis, we chose 3-phenylcyclopentanone
O
a
5 mol% [Rh(C2H4)2Cl]2
10 mol% IMes
10 mol% TsOH H2O
O
(1a in Fig. 2) as the model substrate. After a survey of various reaction
parameters (see Supplementary Information and Supplementary
Figs 1, 2), we found that using [Rh(C2H4)2Cl]2 as the catalyst pre-
cursor and 2-aminopyridine (C1) as the co-catalyst in 1,4-dioxane
indeed offered the desired C–C activation products, with an
85% yield (Supplementary Table 1, entry 1). We observed two
skeleton-rearranged products, in a 6.4:1 ratio. The major product,
α-tetralone (1b), came from the cleavage of the more hindered C1–C2
bond; the minor product, α-indanone (1c), was generated from the
cleavage of the less hindered C1–C5 bond. Further study revealed that
[Rh(C2H4)2Cl]2 is a superior pre-catalyst, while others are much less
efficient (Supplementary Table 1, entries 2–4). We investigated a series
of 2-aminopyridines, and the simple 2-aminopyridine (C1) remained
optimal; in contrast, the secondary amines (C2 and C3) exhibited
almost no reactivity (Supplementary Table 1, entries 5–7). In terms of
ligands, the unsaturated N-heterocyclic carbenes IMes (1,3-bis(2,4,6-
trimethylphenyl)imidazol-2-ylidene) and the bulkier IPr (1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene) afforded comparable results
(Supplementary Table 1, entry 8); in contrast, saturated N-heterocyclic
carbenes (such as SIMes: 1,3-bis(2,4,6-trimethylphenyl)-4,
5-dihydroimidazol-2-ylidene) showed substantially diminished
reactivity (Supplementary Table 1, entry 9). Note that phosphine
ligands, such as PCy3 and BINAP (2,2′-bis(diphenylphosphino)-1,1′
-binaphthyl), failed to promote the transformation (Supplementary
Table 1, entries 10, 11). Interestingly, lowering the loading of amine
co-catalyst C1 enhanced the regioselectivity, such that the α-tetralone
product was formed almost exclusively, albeit with a compromised yield
(Supplementary Table 1, entry 12). Increasing the reaction temperature
failed to improve the yield (Supplementary Table 1, entry 13), but
addition of 50mol% of water increased the yield to 86% without loss
of regioselectivity (Supplementary Table 1, entry 14).
Cl
•
50 mol% 2-aminopyridine
50 mol% H2O
1,4-dioxane (1.0 M, 7 ml)
Me
r.r. (9b:9c) = 97:3
9b, 1.13 g, 83% yield
Cl
9a, 1.36 g
7 mmol scale
150 ºC, 48 h
O
O
2.5 mol% [Rh(C2H4)2Cl]2
5 mol% IMes
O
•
10 mol% TsOH H2O
+
Me
Me
25 mol% 2-aminopyridine
50 mol% H2O
1,4-dioxane (1.0 M, 7 ml)
Me Me
24b
Me
24c
24a, 1.22 g
7 mmol scale
r.r. (24b:24c) = 2.5:1
24b + 24c, 1.0 g, 82% yield
150 ºC, 48 h
b
OH
O
O
Pd(OAc)2/SPhos
K3PO4, PhB(OH)2
Cl
Bn
Ph
PhCHO, tBuOK
90 °C, 16 h
Cl
30 °C
9b
Me
Me
Me
6b, 99%
37, 65%
CH2 = PPh3
0 °C to
H
O
room temperature
N
Cl
Cl
Cl
Me
Me
Me
38, 88%
40, 85%
39, 75%
c
O
Me
B(OH)2
O
1. Asymmetric
addition
Me
Six steps
Me
+
2. This method
28% yield
Me
64% yield (over two steps)
93.3:6.7 e.r.
(94.5% chirality transfer)
Me
(R)-2b
We then investigated the substrate scope of this C–C activation
reaction (Fig. 2). Under optimized reaction conditions (condition
A: 25mol% of the co-catalyst 2-aminopyridine; temperature 140°C),
standard substrate 1a gave a somewhat lower yield when the reaction
was run on a 0.2mmol or 1.0mmol scale. Under a slightly modified
condition (condition B: 50mol% of 2-aminopyridine; temperature
150°C), the conversion of 1a increased and the major product (1b)
was isolated at a yield of 73%, although the regioselective ratio (r.r.)
dropped from >10:1 to 5.8:1. Substrates bearing an electron-neutral or
electron-rich substituent at the para-position of the aryl ring afforded
comparable yields (products 2b–6b). For cyclopentanones with an
electron-deficient aryl group, the reactions were much slower under
condition A; however, a decent yield and excellent regioselectivity could
be achieved under condition B (products 7b–14b). A wide range of
functional groups—such as ester, ketone, fluoride, aryl chloride,
cyano, sulfonyl, aryl boronate, olefin and free hydroxyl groups—are
well tolerated in the products (7b–16b, 20b). Meta-substituted arenes
are also competent substrates, in which C–H activation occurred site
selectively at the less hindered position (products 17b, 18b). The more
sterically encumbered (ortho-substituted) substrates 19a and 20a still
exhibited high reactivity. In particular, naphthyl-substituted cyclopen-
tanones were smoothly converted to tricyclic compounds (21b, 22b);
Seven steps
from racemic 2b
Three steps
from (R)-2b
Six steps
from racemic 2b
Me
Me
OMe
OH
O
Me
Me
Me
Me
Me
H
Me
Me
(–)-heliophenanthrone
Me
(R)-ar-himachalene
Me
Erogorgiaene
Figure 3 | Gram-scale synthesis and synthetic applications. a, Gram-
scale reactions. Compared with the small-scale reaction, using substrate
9a in a gram-scale reaction produced a higher percentage yield; similarly,
when using substrate 24a, less catalyst was needed. b, Standard protocols
can be used to add several new functional groups to our C–C activation
product α-tetralone 9b. Bn, benzyl group. c, Applications in asymmetric
total syntheses of terpenoids. It is known that α-tetralone (2b) is an
intermediate for accessing erogorgiaene20,21, (R)-ar-himachalene22 and
(−)-heliophenanthrone23 in three to seven steps (shown at the bottom).
However, enantioselective preparation of α-tetralones with a C4 stereocentre
is non-trivial and generally requires many steps22 (top left, pale grey).
In our technique (top right, dark grey), we synthesized optically enriched
3-arylcyclopentanones in a single step through asymmetric conjugate
addition of cyclopentenone and arylboronic acids24; then, using our C–C
activation approach, we isolated α-tetralone ((R)-2b) in 64% yield over two
a quaternary centre at the C3 position did not affect the efficiency of steps, with 94.5% chirality transfer. e.r., enantiomeric ratio.
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© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

RESEARCH LETTER
L
L
L
a
Me
Me
N
N
N
ΔGsol
(ΔHsol
N
N
N
N
N
L
=
Rh
Rh
Rh
)
6
6
Cl
Me
Me
6
H
6
L
Me
Me
37.5
N
5
(33.1)
N
IMes
43b
TS4
TS6
Rh
L
TS4
6
Cl
C1
H
29.4
(25.1)
31.6
(28.2)
N
N
Rh
C1-HCl
TS6
Cl
TS3
TS3
L
1
23.5
(19.0)
44b
Rh
N
Ph
TS5
27.2
(23.6)
C1
21.5
(20.1)
43b
2
44b
N
L
C1-HCl
Cl
TS1
L
N
L
N
NH2
43a
21.3
(19.7)
N
44a
20.7
(17.3)
N
2
Rh
N
Rh
C1
N
Ph
Ph
1
1a + C1-HCl
N
11.2
(8.0)
Rh
L
Cl
N
H
L
5
42a
TS1
N
N
H
N
H
C1
41a
N
5
Rh
TS5
N
TS2
10.4
(7.4)
Cl
Rh
1a + C1-HCl
6
3.0
(0.9)
42a
44a
C1-HCl
1.2
(0.6)
C1
41a
43a
–4.7
(–4.8)
N
42b
0.7
(–0.6)
O
N
1
2
Ph
L
O
41b
0.0
(0.0)
O
L
1
N
41b + 1c
N
Rh
N
N
Rh
Cl
5
5
Rh
Cl
Cl
Ph
Ph
41b + 1b
–6.1
Ph
L
Me
Me
41b
TS2
42b
1a
1b
1c
(–7.0)
C–H metallation
C–C reductive elimination
Protonation
C–C activation
C1–C2 cleavage (black line); C1–C5 cleavage (grey line)
b
c
2.13 Å
2.08 Å
6
6
5
6
L
L
Cl
N
N
N
N
L
1
Rh
5
Rh
N
6
N
1
6
Rh
N
Ph
Cl
H
Cl
H
6
L
2
Rh
Cl
N
5
Ph
TS1
‡ = 11.2 kcal mol–1
TS2
ΔG
‡ = 10.4 kcal mol–1
TS3 (favoured)
TS4 (disfavoured)
ΔG
‡ = 37.5 kcal mol–1
‡ = 31.6 kcal mol–1
ΔG
Δ
G
C–C bond activation. ΔG‡, Gibbs free energy of activation. c, Transition
states during C–H bond cleavage. Energies are computed at the M06/
SDD–6-311+G(d,p)/SMD (1,4-dioxane) level of theory, with geometries
optimized at the B3LYP/LANL2DZ–6-31G(d) level (see Supplementary
Information for more details and references).
Figure 4 | DFT-computed pathways for the activation of C–C bonds in
cyclopentanones. a, The computed reaction energy profile of the reaction
with cyclopentanone 1a. L, ligand; TS, transition state; ΔGsol, Gibbs
free energy with respect to 41b (given in kcal mol−1); ΔHsol, enthalpy
with respect to 41b (given in kcal mol−1). b, Transition states during
Compared with cyclopentanones, cyclohexanones are generally less above and Fig. 2) or a lower catalyst loading (when using substrate 24a).
strained (see the computed ring strains in Supplementary Information), To show the versatile nature of α-tetralones in organic synthesis, we
and thus are more challenging substrates for C–C activation15. Indeed, introduced several new functional moieties to C–C activation product
under our standard conditions (A or B), no C–C activation or rear- 9b through standard protocols (Fig. 3b). The synthetic potential of this
rangement product was observed when using 3-arylcyclohexanones method can be further demonstrated in the asymmetric syntheses of
(for example, 30a or 35a) as the substrate. However, when using the natural products (Fig. 3c). For example, α-tetralone (2b) is a known
bulkier IPr as the ligand and 2-amino-6-picoline as the co-catalyst intermediate for accessing erogorgiaene20,21, (R)-ar-himachalene22 and
(Fig. 2b, condition C), the C–C activation product 30c was isolated in (−)-heliophenanthrone23 in three to seven steps; however, enantiose-
34%–46%yield(67%–73%yieldonthebasisofrecoveredstartingmaterial). lective preparation of α-tetralones with a C4 stereocentre is non-trivial
For example, the C1–C6 bond of cyclohexanone 30a was exclusively and generally requires many steps22. Given that optically enriched
cleaved to furnish the product α-indanone, giving the opposite regiose- 3-arylcyclopentanones can be synthesized in a single step from asym-
lectivity from cyclopentanones. In addition, cyclohexanone substrates metric conjugate addition between cyclopentenone and arylboronic
containing electron-rich or electron-deficient aryl groups show compa- acids24, using the C–C activation approach we isolated α-tetralone
rable reactivity (products 31c–33c). Moreover, heterocyclic substrates, ((R)-2b) in 64% yield over two steps, with 94.5% chirality transfer.
such as 34a, also underwent the C–C activation/rearrangement to The slight decrease in enantioselectivity was probably caused
produce alkoxy-substituted α-indanone (34c). The quaternary centre by a reversible β-H elimination process with the C–C activation
in the cyclohexanones appears to facilitate the C–C/C–H activation intermediate (see rhodacycle B above; Fig. 1e). With an efficient route
process, as 3-phenylcyclohexanone (35a) only afforded a trace amount to (R)-2b, the synthesis of the aforementioned terpenoids is markedly
of the product (35c). The 6,6-fused cyclohexanone 36a can also streamlined.
undergo this transformation to afford a spirocyclic α-indanone (36c).
To better understand the origin of the regioselectivity and the
To demonstrate the practicability of this transformation, we carried mechanism of the C–H metallation step, we carried out density func-
out gram-scale reactions (Fig. 3a), which offered either a higher yield tional theory (DFT) calculations. The computed free energy profile
compared with the small-scale reaction (when using substrate 9a; see of the key steps in the catalytic cycle is shown in Fig. 4a. Through the
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LETTER RESEARCH
12. Mack, D. J. & Njardarson, J. T. Recent advances in the metal-catalyzed ring
expansions of three- and four-membered rings. ACS Catal. 3, 272–286 (2013).
13. Masarwa, A. et al. Merging allylic carbon–hydrogen and selective carbon–
carbon bond activation. Nature 505, 199–203 (2014).
14. Halpern, J. Determination and significance of transition-metal-alkyl bond
dissociation energies. Acc. Chem. Res. 15, 238–244 (1982).
15. Jun, C.-H., Lee, H. & Lim, S.-G. The C–C bond activation and skeletal
rearrangement of cycloalkanone imine by Rh(I) catalysts. J. Am. Chem. Soc.
123, 751–752 (2001).
16. Zeng, R. & Dong, G. Rh-catalyzed decarbonylative coupling with alkynes via
C–C activation of isatins. J. Am. Chem. Soc. 137, 1408–1411 (2015).
17. Mukai, C., Ohta, Y., Oura, Y., Kawaguchi, Y. & Inagaki, F. Csp3–Csp3 and Csp3–H
bond activation of 1,1-disubstituted cyclopentane. J. Am. Chem. Soc. 134,
19580–19583 (2012).
18. Li, G., Arisawa, M. & Yamaguchi, M. Rhodium-catalyzed synthesis of
unsymmetrical di(aryl/heteroaryl)methanes using aryl/heteroarylmethyl
ketones via CO–C bond cleavage. Chem. Commun. 50, 4328–4330 (2014).
19. Albrecht, M., Gossage, R. A., Spek, A. L. & van Koten, G. Metal-mediated C–C
bond making and breaking: first direct evidence for a reversible migration
of a benzyl group along a metal-carbon bond. J. Am. Chem. Soc. 121,
11898–11899 (1999).
20. Davies, H. M. L. & Walji, A. M. Direct synthesis of (+)-erogorgiaene through a
kinetic enantiodifferentiating step. Angew. Chem. Int. Ed. 44, 1733–1735
(2005).
21. Elford, T. G., Nave, S., Sonawane, R. P. & Aggarwal, V. K. Total synthesis of
(+)-erogorgiaene using lithiationborylation methodology, and stereoselective
synthesis of each of its diastereoisomers. J. Am. Chem. Soc. 133,
16798–16801 (2011).
22. Chavan, S. P. & Khatod, H. S. Enantioselective synthesis of the essential oil
and pheromonal component ar-himachalene by a chiral pool and chirality
induction approach. Tetrahedron Asymmetry 23, 1410–1415 (2012).
23. Mukherjee, P. & Sarkar, T. K. Heteroatom-directed Wacker oxidations.
A protection-free synthesis of (−)-heliophenanthrone. Org. Biomol. Chem. 10,
3060–3065 (2012).
24. Hayashi, T. & Yamasaki, K. Rhodium-catalyzed asymmetric 1,4-addition
and its related asymmetric reactions. Chem. Rev. 103, 2829–2844 (2003).
25. Lapointe, D. & Fagnou, K. Overview of the mechanistic work on the concerted
metallation deprotonation pathway. Chem. Lett. 39, 1118–1126 (2010).
26. Matsuda, T., Shigeno, M. & Murakami, M. Asymmetric synthesis of
3,4-dihydrocoumarins by rhodium-catalyzed reaction of 3-(2-hydroxyphenyl)
cyclobutenones. J. Am. Chem. Soc. 129, 12086–12087 (2007).
27. Seiser, T., Roth, O. A. & Cramer, N. Enantioselective synthesis of indanols from
tert-cyclobutanols using a rhodium-catalyzed C–C/C–H activation sequence.
Angew. Chem. Int. Ed. 48, 6320–6323 (2009).
28. Shigeno, M., Yamamoto, T. & Murakami, M. Stereoselective restructuring of
3-arylcyclobutanols into 1-indanols by sequential breaking and formation of
carbon–carbon bonds. Chem. Eur. J. 15, 12929–12931 (2009).
29. Matsuda, T., Suda, Y. & Takahashi, A. Double 1,4-rhodium migration
cascade in rhodium-catalysed arylative ring-opening/spirocyclisation
of (3-arylcyclobutylidene)acetates. Chem. Commun. 48, 2988–2990 (2012).
30. Matsuda, T. & Yuihara, I. A rhodium(I)-catalysed formal intramolecular
C–C/C–H bond metathesis. Chem. Commun. 51, 7393–7396 (2015).
installation of a temporary directing group, the resulting ketimines
(both E and Z isomers) can initially bind to the rhodium in a biden-
tate fashion to form 41a and 41b. The pyridyl group remains bound
to the metal and promotes C–C oxidative addition (via transition
states TS1 and TS2, Fig. 4b). While cleavage of the sterically more
hindered C1–C2 bond in TS1 is slightly less favoured, activations
of the C1–C2 and C1–C5 bonds are both reversible, with a rela-
tively low activation barrier. Indeed, the regioselectivity is deter-
mined in the subsequent C–H metallation step (via TS3 and TS4)
and C–C reductive elimination step (via TS5 and TS6)—both
steps requiring much higher activation energies than that of the
C–C cleavage. The pathway with rhodacycle 42a (derived from activa-
tion of the C1–C2 bond) has lower barriers in both C–H metallation
(TS3) and C–C reductive elimination (TS5) than the corresponding
reaction with rhodacycle 42b (derived from activation of the
C1–C5 bond).
The substantial destabilization of the disfavoured transition states
(TS4 and TS6) is caused mainly by the steric repulsions between the
C5 methylene group in the forming six-membered rhodacycle and the
ortho methyl group on the IMes ligand. This unfavourable interac-
tion in TS4 is evidenced by the short hydrogen–hydrogen distance
of 2.08Å (Fig. 4c). In contrast, these steric repulsions are diminished
in TS3 and TS5, in which the methylene group is positioned further
away from the IMes ligand owing to the shorter tether in the forming
five-membered metallacycle. The strong kinetic preference for the
pathway involving the 5,6-bridged rhodacycle 43a explains the high
level of regioselectivity for the C1–C2-activation product. The sub-
sequent protonation (Supplementary Fig. 12) requires lower barriers
and provides thermodynamic driving forces to finally form α-tetralone
(1b) upon hydrolysis. Regarding the C–H metallation step, we found
that a chloride-mediated metallation-deprotonation pathway25 was
more favourable; in contrast, concerted 1,4-rhodium migration26–30
through σ-bond metathesis can be ruled out owing to the much higher
activation energy required.
This computationally proposed mechanism is also consistent with
observed kinetic isotope effects and with isotope labelling experi-
ments (see Supplementary Information). First, the small primary
kinetic isotope effect suggests that the C–H metallation and C–C
reductive elimination are both turnover limiting. Second, the incom-
plete deuterium transfer seen in a reaction with deuterated substrate
provides further evidence against the concerted 1,4-rhodium migration
mechanism.
Supplementary Information is available in the online version of the paper.
Acknowledgements This project was supported by the Cancer Prevention
Research Institute of Texas (grant R1118), the National Institute of General
Medical Science (grant R01GM109054) and the Welch Foundation (grant
F1781). G.D. is a Searle Scholar and Sloan fellow. Y.X. acknowledges the
International Postdoctoral Exchange Fellowship Program 2015 from the
Office of China Postdoctoral Council (OCPC, document 38, 2015). We thank
Johnson Matthey for a donation of Rh salts, and Chiral Technologies for
donation of chiral high-performance liquid-chromatography columns.
We are grateful to Y. Xu for providing 1,4-dioxane, F. Mo for providing some
3-aryl cyclopentanones, and H. Lim for checking the experimental procedures.
DFT calculations were performed using supercomputer resources at the Center
for Simulation and Modeling at the University of Pittsburgh, and the Extreme
Science and Engineering Discovery Environment supported by the National
Science Foundation.
Received 27 December 2015; accepted 6 September 2016.
Published online 2 November 2016.
1. Gozin, M., Weisman, A., Ben-David, Y. & Milstein, D. Activation of a carbon–
carbon bond in solution by transition-metal-insertion. Nature 364, 699–701
(1993).
2. Jones, W. D. The fall of the C–C bond. Nature 364, 676–677 (1993).
3. Murakami, M., Amii, H. & Ito, Y. Selective activation of carbon−carbon bonds
next to a carbonyl group. Nature 370, 540–541 (1994).
4. Rybtchinski, B. & Milstein, D. Metal insertion into C–C bonds in solution.
Angew. Chem. Int. Ed. 38, 870–883 (1999).
5. Murakami, M. & Ito, Y. Cleavage of carbon−carbon single bonds by transition
metals. Top. Organomet. Chem. 3, 97–129 (1999).
6. Jun, C.-H. Transition metal-catalyzed carbon–carbon bond activation. Chem.
Soc. Rev. 33, 610–618 (2004).
7. Miura, M. & Satoh, T. Catalytic processes involving β-carbon elimination.
Top. Organomet. Chem. 14, 1–20 (2005).
Author Contributions Y.X. and G.D. conceived and designed the experiments.
Y.X. performed the experiments. G.L. performed the DFT calculations. Y.X., G.L.,
P.L. and G.D. co-wrote the manuscript.
8. Park, Y. J., Park, J.-W. & Jun, C.-H. Metal–organic cooperative catalysis in C–H
and C–C bond activation and its concurrent recovery. Acc. Chem. Res. 41,
222–234 (2008).
9. Dong, G. (ed.) C–C bond activation Vol. 346 of Topics in Current Chemistry
(Springer, 2014)
10. Souillart, L. & Cramer, N. Catalytic C–C bond activations via oxidative addition
to transition metals. Chem. Rev. 115, 9410–9464 (2015).
11. Seiser, T., Saget, T., Tran, D. N. & Cramer, N. Cyclobutanes in catalysis. Angew.
Chem. Int. Ed. 50, 7740–7752 (2011).
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial
interests. Readers are welcome to comment on the online version of the paper.
Correspondence and requests for materials should be addressed to
P.L. (pengliu@pitt.edu) and G.D. (gbdong@uchicago.edu).
Reviewer Information Nature thanks J. Harvey, M. Lautens and the other
anonymous reviewer(s) for their contribution to the peer review of this work.
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