Two-carbon ring expansion of 1-indanones via insertion of ethylene into carbon-carbon bonds

Article abstract of DOI:10.1021/jacs.9b07445

A rhodium-catalyzed direct insertion of ethylene into a relatively unstrained carbon-carbon bond in 1-indanones is reported, which provides a two-carbon ring expansion strategy for preparing seven-membered cyclic ketones. As many 1-indanones are commercially available and ethylene is inexpensive, this strategy simplifies synthesis of benzocycloheptenones that are valuable synthetic intermediates for bioactive compounds but challenging to prepare otherwise. In addition, the reaction is byproduct-free, redox neutral, and tolerant of a wide range of functional groups, which may have implications on unconventional strategic bond disconnections for preparing complex cyclic molecules.

Full text of DOI:10.1021/jacs.9b07445

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Communication
Two-Carbon Ring Expansion of 1-Indanones via
Insertion of Ethylene into Carbon-Carbon Bonds
Ying Xia, Shusuke Ochi, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07445 • Publication Date (Web): 07 Aug 2019
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Journal of the American Chemical Society
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Two-Carbon Ring Expansion of 1-Indanones via Insertion of
Ethylene into Carbon−Carbon Bonds
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Ying Xia, Shusuke Ochi and Guangbin Dong*
Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
Supporting Information Placeholder
strained or unstrained systems. Moreover, the preference to break
ABSTRACT: A rhodium-catalyzed direct insertion of ethylene
into a relatively unstrained carbon–carbon bond in 1-indanones is
reported, which provides a two-carbon ring-expansion strategy for
preparing seven-membered cyclic ketones. As many 1-indanones
are commercially available and ethylene is inexpensive, this
strategy simplifies synthesis of benzocycloheptenones that are
valuable synthetic intermediates for bioactive compounds but
challenging to prepare otherwise. In addition, the reaction is
byproduct-free, redox neutral, and tolerant of a wide range of
functional groups, which may have implications on
unconventional strategic bond disconnections for preparing
complex cyclic molecules.
the stronger aryl−carbonyl bond (e.g. in 1-indanones), enabled by
transition-metal catalysts, could offer complementary selectivity
to the conventional1 or radical-mediated C−C cleavage
reactions14. Herein, we describe our preliminary development of a
Rh-catalyzed two-carbon ring expansion of 1-indanones via
insertion of ethylene into C−C bonds (Scheme 1d).
Scheme 1. Representative direct methods for ring
expansion of cyclic ketones
a Diazo-carbon insertion (one-carbon ring expansion)
R1
equiv
O
O
O
R2
R1
R2
R1 R2
+
n [ ]
n [ ]
n [ ]
Ring expansion reactions of carbonyl compounds, such as
Baeyer−Villiger oxidation, Beckmann rearrangement and various
carbon-insertion reactions, are highly valuable transformations
and have been frequently utilized in complex molecule syntheses.1
With a few exceptions, most direct ring-expansion reactions could
add only a one-atom unit to the existing structures. Compared to
the well-established one-carbon homologation methods2 (Scheme
1a), limited approaches are known for direct two-carbon ring
expansions of ketones.3 After an accidental discovery in 1974,
Proctor elucidated that carbocyclic β-ketoesters could undergo a
[2+2] cycloaddition with an activated alkyne, followed by an
accelerated retro-4π cyclization, to give two-carbon extended
products4 (Scheme 1b). Later, Kuninobu and Takai discovered a
similar but efficient rhenium-catalyzed reaction for insertion of
terminal alkynes with β-ketoesters5, though the reaction was not
suitable for preparing 7-membered rings. As a mechanistically
related transformation, Caubere6, and Stoltz7, reported an
intriguing two-carbon ring expansion method via benzyne
insertion (Scheme 1b).
b Alkyne or aryne insertion (two-carbon ring expansion)
HO
E
E
O
E
E
E
E
CO2R
CO2R
n
n
O
O
E: CO2R'
OR
n
O
O
n
CO2R
n
CO2R
c Activation of highly strained ketones
O
O
activated olefin
cat. TM
R
+
or
alkyne
n
n
n = 0 or 1
d This work
sp2sp2
Alternatively, it could be attractive to directly insert a common
unsaturated unit into a cyclic ketone through transition metal-
catalyzed C−C activation8-10, which should offer a straightforward
and byproduct-free approach for multi-atom ring expansions. The
reaction involves oxidative addition of C−C bond to a low-valent
transition metal8b, followed by 2π-insertion to give an enlarged
O
cat. Rh
cat. amine
O
R
+
R
Cut
Sew
DG
Rh
metallocycle and C−C reductive elimination. Such
a
DG
transformation, also known as a “cut-and-sew” process9b, has
been extensively demonstrated in strained three- and four-
membered ring systems (Scheme 1c).11 However, for unstrained
systems,10 the scope of the process has been primarily limited to
the use of polar C−CN bonds12 or some special intramolecular
reactions13. In addition, ethylene, as the most highly produced
organic compound, may serve as an appealing two-carbon
coupling partner; to the best of our knowledge, the “cut-and-sew”
reaction using ethylene as a 2π unit has been elusive for either
N
Rh
R
R
N
To explore the proposed ethylene-insertion reaction,
unsubstituted 1-indanone (1a) was used as the model substrate,
and the Jun’s ketimine directing mode8d,10b was employed for
C−C activation. The reaction parameters, including different
aminopyridines (serving as the temporary directing group),
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Page 2 of 6
ligands, solvents, additives, temperature and pressure of ethylene,
1
were
carefully
2
3
Chart 1. Scope of the Ethylene-Insertion Reactiona
4
5
6
7
8
9
1
4
9
5
O
8
7
7
Me
Me
5 mol% [Rh(C2H4)2Cl]2
10 mol% IMes
2
R1
3
6
R1
5
Me
2
O
N
N
+
20 mol% TsOH H2O
R2
6
Me
Me
N
NH2
R2
DG-1
100 mol%
3
4
Me Me
IMes
100 mol% H2O
1a-46a
1b-46b
DG-1
THF (0.5 mL), 150 o
C
100 psi
MeO
1.0 mmol
6-substituted 1-indanones
5-substituted 1-indanones
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19
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22
23
24
25
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60
Me
O
BnO
O
TIPSO
O
O
O
O
O
F
1b
, 71%
2b
3b
, 78%
4b
, 76%
5b
, 62%
, 62%
19b
, 75%
9b
20a
, 70% (from
)
H
O
F3C
F
Cl
HO
N
O
S
O
EtO
O
O
O
O
Me
O
O
Cl
O
14b
, 68% (from
22a
)
b
10b
, 52% (from
21a
)
8b
, 76%
9b
, 76%
10b
, 77%
6b
, 34%
7b
, 61%
4-substituted 1-indanones
O
O
Ph
Br
Me
EtO
Me
O
O
O
O
O
O
O
O
Cl
25b
Me
23b
OMe
24b
a
12b
, 74%
11b
, 44%
13b
14b
, 72%
15b
, 67%
, 80%
, 65%
, 61%
, 58%
di- and tri-substituted 1-indanones
7-substituted 1-indanone
O
F
Me3Si
B
F
HO
O
O
O
O
O
O
O
5
6
7
16b
17b
F
, 78%
, 46%
26b
, 40%
26a
, 12%)
18b
, 50%
c
26c
(
, 22%;
28b
, 68%
27b
, 47%
3-substituted 1-indanones
F
F3C
Cl
MeO
F
MeO
MeO
O
O
O
O
O
O
O
O
Me
Me
Ph
Me
Me
36b
Me
38b
Cl
d
d
d
d
, 48%
37b
, 90%
c
c,d
c,d
35b
, 86%
, 85%
33b
34b
, 42%
30b
, 17% , 33%
, 58%
29b
, 68%
F
F
F
F
F
O
O
O
O
O
O
O
F
Cl
Me
Me
F
d
d
d
d
d
31b
32b
, 60%
, 56%
40b
42b
, 59%
, 74%
39b
, 85%
41b
43b
, 76%
, 70%
PhO
PivO
Me
application to natural product scaffolds
O
O
Me
H
Me
Me
H
H
Me
H
H
O
H
Me
H
H
H
Me
H
O
H
O
H
O
O
H
H
O
46a
from Estrone
O
O
46b
, 60% yield
44a
from Cholesterol
44b
, 63% yield
O
O
Me
Me
Me
H
H
Me
H
O
H
H
H
O
O
H
H
45a
O
45b
, 70% yield
from Androsterone
46b
X-Ray structure of
aUnless otherwise noted, all the reactions were carried out on 1.0 mmol scale in 72 hours under the standard conditions and yields are of material isolated by
silica gel chromatography. The reaction was carried out at 130 C. Yields were determined by H NMR using 1,1,2,2-tetrachloroethane as the internal
b
o
c
1
standard. dIn the absence of IMes ligand and use of 50 mol% water. For details, see Supporting Information.
optimized (see Table S1). Ultimately, the desired
benzocycloheptenone product 1b was obtained in 76% yield from
1-indanone (1a) and ethylene gas (100 psi) in the presence of 5
trimethylphenyl)imidazol-2-ylidene (IMes), 20 mol% p-
toluenesulfonic acid monohydrate (TsOH.H2O), 100 mol% 2-
amino-3-picoline (DG-1) and 100 mol% H2O in THF (Table S1,
entry 1). The only observable side product was the ketone α-C−H
mol%
[Rh(C2H4)2Cl]2,
10
mol%
1,3-bis(2,4,6-
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insertion product,15 2-ethyl-1-indanone (1c), which was formed in
From a practical viewpoint, the limits of the reaction condition,
i.e. the lowest catalyst loading/temperature that could still afford
good synthetic efficiency, were probed. To our delight, when
decreasing the loading of the rhodium/IMes from 10 mol% to 3
mol% and decreasing DG-1 from 100 mol% to 50 mol%, the
reaction still worked well to give 85% conversion and 65% yield
of product 9b (Scheme 2a, entry 2 vs. entry 1). Using 5 mol%
rhodium/IMes and 50 mol% DG-1, the reaction efficiency almost
reached to the level of the original conditions (Scheme 2a, entry
1
2
3
4
5
6
7
8
8% yield. Interestingly, in the absence of the strong σ-donating
IMes ligand, the reaction still afforded the desired product 1b in
60% yield, but gave a poorer selectivity with the α-alkylation
product formed in 15% yield (Table S1, entry 2). The Rh catalyst,
TsOH.H2O and the DG-1 are all critical for this transformation,
and no desired product can be produced without any of them
(Table S1, entries 3-5). When decreasing DG-1 to 30 mol% and
50 mol%, the seven-membered ring product 1b could still be
obtained in 54% and 69% yield, respectively (Table S1, entries 6
and 7), suggesting that DG-1 exhibits some catalytic activity.
Other temporary directing groups were found either less efficient
or less selective (Table S1, entries 8-11), but it is worth noting
that simple 2-aminopyridine DG-2 favors forming the ketone α-
alkylation product (For more control experiments, see Supporting
Information, Section 3).
o
3). Besides, when running at a lower temperature (130 C), the
reaction still proceeded smoothly even with
5
mol%
9
rhodium/ligand (Scheme 2a, entry 4). The reaction is also
scalable. On gram scales, good yields could still be obtained with
1-indanones bearing either an electron-donating or -withdrawing
group, and DG-1 could be easily recycled (Scheme 2b).
Moreover, synthesis of enantiomerically enriched 5-substituted
benzocycloheptanone (Scheme 2c) could be achieved using chiral
1-indanone R-35a that was prepared in three steps from
commercially available arylboronic acid 47 and α,β-unsaturated
ester 48 via asymmetric conjugate addition16. The slight erosion
of enantioselectivity was likely due to the unproductive C−C
activation at the C1−C2 position, which led to reversible β-
hydrogen elimination17.
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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
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40
41
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With the optimized conditions in hand, the substrate scope of
this ethylene-insertion reaction was then explored (Chart 1). First,
C6-substituted 1-indanone substrates were tested. The electronic
property of the 6-substituent only had a marginal influence on this
reaction, as 1-indanones bearing either electron-donating (2a-7a)
or -withdrawing groups (8a-15a) all gave comparable results to
the model substrate 1a. A series of functional groups, including
free phenol (6a), sulfonamide (7a), chloride (10a), ester (14a),
methyl ketone (15a), silyl (16a) and free hydroxyl group (17a),
are tolerated. Besides, substrates containing aryl bromide (11a)
and boronate (18a), which are generally reactive moieties in
transition-metal catalysis, still afforded the desired products in
moderate yields. Notably, for the substrate that contains two
ketone carbonyls (15a), C−C activation occurred exclusively at
the indanone site. 1-Indanones bearing substituents at the 4- or 5-
position exhibited similar reactivity, yielding the corresponding
benzocycloheptenones in 52-75% yields (19a-25a). As expected,
substitutions at the 7-position resulted in lower reactivity due to
the increased steric hindrance around the carbonyl functionality
(26a). In addition, several disubstituted 1-indanones (27a-31a) or
naphthyl-fused cyclopentanone (32a) proved to be competent
substrates, affording the desired seven-membered ring products in
moderate to good yields.
Scheme 2. Synthetic applications
a Pushing the limits of the reaction conditions
O
x mol% [Rh(C2H4)2Cl]2
F
F
2x mol% IMes
+
O
20 mol% TsOH H2O
DG-1
y mol%
9a
100 mol% H2O
THF (0.5 mL), T oC, 72 h
9b
1.0 mmol
100 psi
[Rh(C2H4)2Cl]2/IMes
T
DG-1
Entry
Conversion Yield
150 o
C
1
2
5 mol%/10 mol%
100 mol%
50 mol%
>95%
85%
77%
65%
150 o
C
1.5 mol%/3 mol%
150 o
C
3
4
50 mol%
2.5 mol%/5 mol%
2.5 mol%/5 mol%
>95%
86%
74%
74%
130 o
C
100 mol%
b Gram-scale syntheses
O
2.5 mol% [Rh(C2H4)2Cl]2
5 mol% IMes
R
R
After examining the steric and electronic influence of the arene
part on reactivity, the substitution effect at the aliphatic positions
of 1-indanones was next investigated. 3-Methyl-1-indanone (33a)
showed substantially reduced reactivity under the standard
conditions; however, the yield could be improved in the absence
of the IMes ligand with a reduced amount of water (50 mol%).
Under these new reaction conditions, 3-phenyl 1-indanone (34a)
afforded the desired product in 42% yield. Gratifyingly, the
reaction efficiency was significantly improved when substrates
containing an additional substituent on the benzene ring (35a-
40a), though the exact reason is unclear. For example, 6-
trifluoromethyl-3-methyl-1-indanone (37a) produced the desired
product (37b) in 90% yield. Besides methyl and phenyl groups,
other alkyl substituents at the 3-position were also tolerated (41b-
43b). Unsurprisingly, substitution at the α-position (C2) of 1-
indanones shut down the reactivity because the steric congestion
around the ketone would inhibit forming the imine intermediate.
Finally, this reaction can be applied to natural product-derived or
tethered indanones. Indanone 44a with an ester-linked cholesterol
and 45a with an ether-linked androsterone smoothly participated
in this two-carbon ring-expansion reaction. Similarly, starting
from estrone-fused cyclopentanone 46a, a seven-membered
ketone moiety can be efficiently introduced to give a unique 7-6-
6-6-5 pentacyclic structure, which was unambiguously confirmed
by X-ray crystallography.
DG-1
O
+
20 mol% TsOH H2O
recycled
83-88%
DG-1
50 mol%
100 mol% H2O
THF, 150 o
8.0 mmol
100 psi
3b
9b
, 66% yield, 1.00 g
, 77% yield, 1.10 g
C
3a
9a
, R = OMe, 1.30 g
, R = F, 1.20 g
c Enantiospecific synthesis
Me
1 mol% [Rh(NBD)2]BF4
1.1 mol% (R)-BINAP
1 equiv. NEt3
CO2i-Pr
B(OH)2
CO2i-Pr
+
Me
49
F
F
1,4-dioxane/H2O, 40 o
C
100% yield, 98.6:1.4 er
48
47
O
F
1) LiOH.H2O
F
ethylene insertion
O
2) (COCl)2,
then AlCl3
Me
Me
35b
(R)-
35a
(R)-
84% yield, 93.5:6.5 er
98% yield, 97.6:2.4 er
Benzocycloheptenones have been frequently used in the
synthesis of bioactive compounds that contain seven-membered
rings; however, the conventional approaches for preparing
benzocycloheptenones are often inefficient18-20 (Scheme 3). Thus,
this two-carbon homologation approach could contribute to
shortening the syntheses of those complex pharmaceutical agents.
F o r e x a m p l e , t h e t r i f l u o r o m e t h y l - s u b s t i t u t e d
benzocycloheptanone (8b), prepared in a single step using this
method, was the key intermediate in the synthesis of anti-obesity
agent 50 (Scheme 3a). As a comparison, the prior approach
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required five steps from 2-iodo-4-trifluoromethyl-aniline 5118. In
In summary, we disclose a two-carbon ring expansion method
that inserts ethylene into relatively unstrained C−C bonds in 1-
indanones, which offers a straightforward but strategically distinct
approach for preparing benzocycloheptenones. The reaction is
chemoselective, scalable and redox-neutral, which could be used
to simplify the syntheses of benzocycloheptene-derived bioactive
compounds. Efforts on extending the reaction scope to other
cyclic ketones and unsaturated coupling partners,22 as well as
detailed mechanistic studies, are ongoing.
1
2
3
4
5
6
7
the second case, CEP-28122 is a highly potent and selective
inhibitor of ALK (anaplastic lymphoma kinase), showing
promising antitumor activity in human cancers19. One key
structural motif is the benzocycloheptene moiety, which was
synthesized from methoxyl-substituted benzocycloheptenone 24b.
The previous synthesis of 24b used three steps from 1-methoxy-
2,3-dimethylbenzene 52 with a 33% overall yield19. Now, 24b can
b e p r e p a r e d s t r a i g h t f o r w a r d l y v i a t h e “ c u t - a n d -
8
9
Scheme 3. Application Potentials in the Syntheses of
Bioactive Molecules
ASSOCIATED CONTENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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34
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38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information
Experimental
procedures;
a
O
F3
C
F3
C
F3
C
crystallographic data of 46b and 57; spectral data. This material is
N
ref. 18
Chart 1, entry 8
O
N
available free of charge via the Internet at http://pubs.acs.org.
H
one step, 76% yield
8a
8b
50, anti-obesity agent
commercially available
Previous route:
AUTHOR INFORMATION
NH2
5 steps, 42% yield
F3
C
I
51
Corresponding Author
O
b
Cl
gbdong@uchicago.edu
ref. 19
Chart 1,entry 24
one step, 58% yield
N
O
N
O
N
H
N
N
H
24a
OMe
24b
OMe
OMe
H2
N
O
Notes
commercially available
CEP-28122,
ALK inhibitor
The authors declare no competing financial interests.
Previous route:
Me
3 steps, 33% yield
ACKNOWLEDGMENT
Me
OMe
52
O
c
Ph
This project was supported by NIGMS (R01GM109054). We
thank Mr. Ki-Young Yoon for X-ray crystallography and thank
Dr. Jun Zhu for checking the experiment. Chiral Technologies is
acknowledged for their generous donation of chiral HPLC
columns. We also thank Umicore AG & Co. KG for generous
donation of rhodium salts.
reductive
amination
Cl
Cl
Cl
Chart 1,entry 10
O
NH
one step, 77% yield
ref. 20
10a
53
, NMDA receptor
10b
commercially available
(~$5/g)
3 steps, 9.3%
Previous route:
1b
from
O2
N
HNO3/H2SO4
O
O
O
2.7:1
+
1b
NO2
$400/g
REFERENCES
O
d
NH
Chart 1,entry 1
PhNHNH2
(1) For recent reviews of ring expansion reactions, see: (a) Hesse, M.
Ring Enlargement in Organic Chemistry. VCH: Weinheim, Germany,
1991. (b) Roxburgh, C. J. Syntheses of Medium Sized Rings by Ring
Expansion Reactions. Tetrahedron 1993, 49, 10749–10784. (c)
Kantorowski, E. J.; Kurth, M. J. Expansion to Seven-membered Rings.
Tetrahedron 2000, 56, 4317–4353. (d) Donald, J. R.; Unsworth, W. P.
Ring-expansion Reactions in the Synthesis of Macrocycles and Medium-
sized Rings. Chem. Eur. J. 2017, 23, 8780–8799.
(2) For a recent review, see: Candeias, N. R.; Paterna, R.; Gois, P. M. P.
Homologation Reaction of Ketones with Diazo Compounds. Chem.
Rev. 2016, 116, 2937–2981.
(3) Dowd, P.; Zhang, W. Free Radical-mediated Ring Expansion and
Related Annulations. Chem. Rev. 1993, 93, 2091–2115.
(4) (a) Lennon, M.; McLean, A.; McWatt, I.; Proctor, G. R.
Azabenzocycloheptenones. Some Substitution Reactions in Tetrahydro-l-
benzazepin-5-ones. J. Chem. Soc., Perkin Trans. I 1974, 1828–1833. (b)
Frew, A. J.; Proctor, G. R. Ring-expansion of Carbocyclic π-Ketoesters
with Acetylenic Esters. J. Chem. Soc., Perkin Trans. I 1980, 1245–1250.
(5) Kuninobu, Y.; Kawata, A.; Kazuhiko, T. Efficient Catalytic Insertion
of Acetylenes into a Carbon−carbon Single bond of Nonstrained Cyclic
Compounds under Mild Conditions. J. Am. Chem. Soc. 2006, 128, 11368–
11369.
(6) Caubere, P.; Guillaumet, G.; Mourad, M. S. Synthese Generale de
Benzocyclenones Non Substituees; Mecanisme de Condensation du
Benzyne Surles Enolates de Cetones. Tetrahedron 1973, 29, 1857–1863.
(7) Tambar, U. K.; Stoltz, B. M. The Direct Acyl-alkylation of Arynes.
J. Am. Chem. Soc. 2005, 127, 5340–5341.
(8) (a) Rybtchiski, B.; Milstein, D. Metal Insertion into C−C Bonds in
Solution. Angew. Chem. Int. Ed. 1999, 38, 870–883. (b) Souillart, L.;
Cramer, N. Catalytic C–C bond Activations via Oxidative Addition to
Transition Metals. Chem. Rev. 2015, 115, 9410−9464. (c) Murakami, M.;
Ishida, N. Potential of Metal-catalyzed C–C Single Bond Cleavage for
Organic Synthesis. J. Am. Chem. Soc. 2016, 138, 13759–13769. (d) Kim,
D.-S.; Park, W.-J.; Jun, C.-H. Metal–organic Cooperative Catalysis in C–
H and C–C Bond Activation. Chem. Rev. 2017, 117, 8977–9015.
O
CH3CO2
H
one step, 71% yield
1a
1b
commercially available
54
, 88% yield
NaN3
H2SO4/toluene
NaN3
desaturation
CF3CO2
H
ref. 21
O
N
O
N
N
NH
N
57
57
X-ray of
55
, 75% yield
, 80% yield
56
, 77% yield
sew” process from commercially available 4-methoxy-1-indanone
24a (Scheme 3b). The third example involves the synthesis of
amine 53, which is a NMDA (N-methyl-D-aspartate) receptor for
the potential treatment of various neurological disorders.20 The
existing route prepared the key intermediate 10b in three steps
from unsubstituted benzocycloheptenone 1b that is either very
expensive or requires an additional two or three steps for
preparation. In addition, the electrophilic aromatic substitution
used in this synthetic route exhibited poor site-selectivity, leading
to a low overall yield. Analogously, through the two-carbon
homologation, compound 10b was made available in one-step
from relatively inexpensive 6-chloro-1-indanone 10a (Scheme
3c).
Moreover,
simple
transformations
of
the
benzocycloheptanone moiety could afford a range of synthetically
useful scaffolds, and here symmetrical benzocycloheptenone 1b
was used to avoid forming regioisomers. For instance, tetracyclic
compound 54 was afforded in 88% yield via Fischer indole
synthesis. Conjugated seven-membered enone 55 can be prepared
in a good yield via ketone desaturation.21 Treatment with sodium
azide under different conditions delivered either eight-membered
lactam 56 (77% yield) or tetrazole-fused 6-8-5 tricycle 57 (75%
yield), in which the structure of 57 was unambiguously confirmed
by X-ray crystallography (Scheme 3d).
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(9) (a) Fumagalli, G.; Stanton, S.; Bower, J. F. Recent Methodologies
Studies of Glun2b-Selective NMDA Receptor Antagonists with a
That Exploit C–C Single-Bond Cleavage of Strained Ring Systems by
Transition Metal Complexes. Chem. Rev. 2017, 117, 9404–9432. (b)
Chen, P.; Billett, B.; Tsukamoto, T.; Dong, G. “Cut and Sew”
Transformations via Transition-metal-catalyzed Carbon–Carbon Bond
Activation. ACS Catal. 2017, 7, 1340–1360.
(10) (a) Murakami, M.; Amii, H.; Ito, Y. Selective Activation of
Carbon−Carbon Bonds next to a Carbonyl Group. Nature 1994, 370,
540−541. (b) Jun, C.-H.; Lee, H. Catalytic Carbon−Carbon Bond
Activation of Unstrained Ketone by Soluble Transition-Metal Complex. J.
Am. Chem. Soc. 1999, 121, 880−881. (c) Chen, F.; Wang, T.; Jiao, N.
Recent Advances in Transition-metal-catalyzed Functionalization of
Unstrained Carbon–Carbon Bonds. Chem. Rev. 2014, 114, 8613–8661. (d)
Song, F.; Gou, T.; Wang, B.-Q.; Shi, Z.-J. Catalytic Activations of
Unstrained C–C Bond Involving Organometallic Intermediates. Chem.
Soc. Rev. 2018, 47, 7078–97115.
Benzo[7]annulen-7-amine Scaffold. ChemMedChem 2017, 12,
1212−1222.
(21) Albrecht, S.; Al-Lakkis-Wehbe, M.; Orsini, A.; Defoin, A.; Pale, P.;
Salomon, E.; Tarnus, C.; Weibel, J.-M. Amino-benzosuberone: A Novel
Warhead for Selective Inhibition of Human Aminopeptidase-N/CD13.
Bioorg. Med. Chem. 2011, 19, 1434–1449.
(22) Use of non-ethylene olefins or saturated cyclopentanones is
challenging at this initial stage, likely due to a slow migratory insertion
step.
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(11) For examples on two-carbon ring expansion via transition metal-
catalyzed C−C activation of highly strained ketones with activated olefins
or alkynes, see: (a) Kondo, T.; Nakamura, A.; Okada, T.; Suzuki, N.;
Wada, K.; Mitsudo, T.-a. Ruthenium-catalyzed Reconstructive Synthesis
of Cyclopentenones by Unusual Coupling of Cyclobutenediones with
Alkenes Involving Carbon−Carbon Bond Cleavage. J. Am. Chem. Soc.
2000, 122, 6319−6320. (b) Kondo, T.; Taguchi, Y.; Kaneko, Y.; Niimi,
M.; Mitsudo, T.-a. Ru- and Rh-catalyzed C−C Bond Cleavage of
Cyclobutenones: Reconstructive and Selective Synthesis of 2-Pyranones,
Cyclopentenes, and Cyclohexanones. Angew. Chem. Int. Ed. 2004, 43,
5369−5372. (c) Kondo, T.; Niimi, M.; Nomura, M.; Wada, K.; Mitsudo,
T.-a. Rhodium-catalyzed Rapid Synthesis of Substituted Phenols from
Cyclobutenones and Alkynes or Alkenes via C–C Bond Cleavage.
Tetrahedron Lett. 2007, 48, 2837−2839. (d) Juliá-Hernández, F.; Ziadi,
A.; Nishimura, A.; Martin, R. Nickel-catalyzed Chemo-, Regio- and
Diastereoselective Bond Formation through Proximal C−C Cleavage of
Benzocyclobutenones. Angew. Chem. Int. Ed. 2015, 54, 9537−9541.
(12) Tobisu, M.; Chatani, N. Catalytic Reactions Involving the Cleavage
of Carbon–Cyano and Carbon–Carbon Triple Bonds. Chem. Soc. Rev.
2008, 37, 300–307.
(13) Though not ring expansion reactions, some related examples are:
(a) Dreis, A. M.; Douglas, C. J. Catalytic Carbon−Carbon σ Bond
Activation: An Intramolecular Carbo-acylation Reaction with
Acylquinolines. J. Am. Chem. Soc. 2009, 131, 412−413. (b) Wentzel, M.ꢀ
T.; Reddy, V.ꢀJ.; Hyster, T.ꢀK.; Douglas, C.ꢀJ. Chemoselectivity in
Catalytic C−C and C−H Bond Activation: Controlling Intermolecular
Carboacylation and Hydroarylation of Alkenes. Angew. Chem. Int. Ed.
2009, 48, 6121−6123. (c) Rong, Z.-Q.; Lim, H. N.; Dong, G.
Intramolecular Acetyl Transfer to Olefins via Catalytic C−C Bond
Activation of Unstrained Ketones. Angew. Chem. Int. Ed. 2018, 57,
475−479.
(14) (a) Hu, A.; Chen, Y.; Guo, J.-J.; Yu, N.; An, Q.; Zuo, Z. Cerium-
Catalyzed Formal Cycloaddition of Cycloalkanols with Alkenes through
Dual Photoexcitation. J. Am. Chem. Soc. 2018, 140, 13580−13585. (b)
Zhao, K.; Yamashita, K.; Carpenter, J. E.; Sherwood, T. C.; Ewing, W. R.;
Cheng, P. T. W.; Knowles, R. R. Catalytic Ring Expansions of Cyclic
Alcohols Enabled by Proton-Coupled Electron Transfer. J. Am. Chem.
Soc. 2019, 141, 8752−8757.
(15) Mo, F.; Dong, G. Regioselective Ketone α-Alkylation with Simple
Olefins via Dual Activation. Science 2014, 345, 68–72.
(16) Itooka, R.; Iguchi, Y.; Miyaura, N. Rhodium-catalyzed 1,4-
Addition of Arylboronic Acids to α, β-Unsaturated Carbonyl Compounds:
Large Accelerating Effects of Bases and Ligands. J. Org. Chem. 2003, 68,
6000–6004.
(17) Xia, Y.; Lu, G.; Liu, P.; Dong, G. Catalytic Activation of Carbon-
Carbon Bonds in Cyclopentanones. Nature 2016, 539, 546–550.
(18) Boussard, M.-F.; Guette, J. P.; Wierzbicki, M.; Beal, P.; Fournier,
J.; Boulanger, M.; Della-Zuanad, O.; Duhault, J. Preparation and
Pharmacological Profile of 2-Trifluoromethyl-benzo(8,9)-1,3-diaza-
spiro(4,6)-undeca-2,8-diene and Its Enantiomers As New Anti-obesity
Agents. Arzneim.-Forsch./Drug Res. 2000, 50, 1084–1092.
(19) Gingrich, D. E; Lisko, J. G.; Curry, M. A.; Cheng, M.; Quail, M.;
Lu, L.; Wan, W.; Albom, M. S.; Angeles, T. S.; Aimone, L. D.; Curtis
Haltiwanger, R.; Wells-Knecht, K.; Ott, G. R.; Ghose, A. K.; Ator, M. A.;
Ruggeri, B.; Dorsey, B. D. Discovery of an Orally Efficacious Inhibitor of
Anaplastic Lymphoma Kinase. J. Med. Chem. 2012, 55, 4580−4593.
(20) Gawaskar, S.; Temme, L.; Schreiber, J. A.; Schepmann, D.;
Bonifazi, A.; Robaa, D.; Sippl, W.; Strutz-Seebohm, N.; Seebohm, G.;
Wünsch, B. Design, Synthesis, Pharmacological Evaluation and Docking
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sp2sp2
O
cat. Rh/NHC
cat. amine
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O
R
+
R
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Cut
Sew
DG
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N
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R
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N
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