Intermolecular [5+2] Annulation between 1-Indanones and Internal Alkynes by Rhodium-Catalyzed C–C Activation

Article abstract of DOI:10.1002/anie.202106007

Herein, we report a [5+2] cycloaddition between readily accessible 1-indanones and internal alkynes through Rh-catalyzed activation of less strained C?C bonds. The reaction is enabled by a strongly σ-donating NHC ligand and a carefully modified temporary directing group. A wide range of functional groups is tolerated, and the method provides straightforward access to diverse benzocycloheptenones that are hard to access otherwise. DFT studies of the reaction mechanism imply the migration insertion as the turnover-limiting step and suggest beneficial π–π interactions in the transition states.

Full text of DOI:10.1002/anie.202106007

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How to cite:
International Edition: doi.org/10.1002/anie.202106007
German Edition: doi.org/10.1002/ange.202106007
C–C Activation
Intermolecular [5+2] Annulation between 1-Indanones and Internal
Alkynes by Rhodium-Catalyzed C–C Activation
Rui Zhang, Ying Xia, and Guangbin Dong*
Dedicated to Professor Robert H. Grubbs on the occasion of his 80th birthday
Abstract: Herein, we report a [5+2] cycloaddition between
readily accessible 1-indanones and internal alkynes through
À
Rh-catalyzed activation of less strained C C bonds. The
reaction is enabled by a strongly s-donating NHC ligand and
a carefully modified temporary directing group. A wide range
of functional groups is tolerated, and the method provides
straightforward access to diverse benzocycloheptenones that
are hard to access otherwise. DFT studies of the reaction
mechanism imply the migration insertion as the turnover-
limiting step and suggest beneficial p–p interactions in the
transition states.
Introduction
Seven-membered carbocycles are prevalent in natural
products and other biologically important molecules.[1] They
also frequently appear in emerging non-planar organic
materials.[2] Compared to five or six-membered rings, signifi-
cant challenges remain for synthesizing medium-sized cyclo-
heptanes due to limited disconnection approaches and
increased activation enthalpy during the ring-forming pro-
cesses. Among established seven-membered-ring construc-
tion methods,[3] formal [5+2] cycloadditions-the annulations
between a five-carbon synthon and a two-carbon one-have
proved to be highly versatile and effective (Scheme 1a).[4]
À
They render multiple C C bond formations in one step in an
atom-economical,[3] regio- and stereo-selective manner, and
Scheme 1. [5+2] reactions for constructing seven-membered carbo-
cycles.
have found wide success in elegant syntheses of complex
natural products.[4] While the two-carbon synthons generally
come from readily available alkenes and alkynes, the
corresponding five-carbon moieties, such as vinylcyclopro-
panes,[5] (oxido)pyrylium ions,[6] 3-acyloxy-1,4-enynes[7] and
pentadienyl-metal complexes,[8] are less accessible, which
typically contain high-energy or special functional groups
(FGs) and need to be prepared through multi-step sequences.
Thus, it could be attractive to use common, more native FGs
as the five-carbon building blocks in constructing seven-
membered carbocycles.
through oxidative addition with a low-valent transition metal,
À
the relatively inert C C bond in a five-membered ring is
cleaved and converted into two reactive C-M (M = transition
metal) termini, which then add across unsaturated 2p-units to
provide a 7-membered carbocycle (Scheme 1b).[10] Such so-
called a “cut-and-sew” strategy has shown good efficiency
with three- or four-membered-ring substrates.[11,12] It was only
until recently that a preliminary study on the catalytic
À
One complementary and straightforward [5+2] approach
would be to directly employ an easily accessible five-
membered ring as the synthon.[9] One can imagine that,
insertion of ethylene gas into 1-indanone C C bonds was
reported by us.[13] This transformation provides a benzene-
fused cycloheptanone in a rapid and byproduct-free manner;
however, it requires high-pressure ethylene gas and other
alkenes were not effective at this stage, which hampers
forming a- or b-substituted products. In addition, mechanistic
[*] R. Zhang, Dr. Y. Xia, Prof. G. Dong
Department of Chemistry, The University of Chicago
5735 S Ellis Ave, Chicago, IL 60637 (USA)
E-mail: gbdong@uchicago.edu
À
understanding of this C C activation method remains elusive.
Hence, we conceived exploring alkynes as the coupling
partner in the C C activation-mediated [5+2] cycloaddition
for preparing a- or b-substituted seven-membered-ring ke-
tones. In contrast to alkenes, alkynes with a smaller HOMO/
À
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202106007.
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Table 1: Selected optimization of the [5+2] reaction.[a]
LUMO gap typically show high coordination affinity with
transition metals, which could ease 2p-insertion.[14] Besides,
the resulting enone moiety can provide a convenient handle
to permit further functionalizations of the products. However,
compared to the prior ethylene insertion, substantial chal-
lenges can be envisioned for using alkynes as the 2p-units in
an intermolecular [5+2] cycloaddition: 1) due to the high
reactivity of the triple bond, alkynes easily undergo various
catalyzed dimerization or trimerization pathways;[15] 2) the
À
strong binding affinity of alkynes will compete with the C C
s-bond coordination to the metal center, which is the key
À
intermediate for C C activation; and 3) the bulkiness of
internal alkynes (versus simple ethylene) during the steric
demanding carbometallation step cannot be overlooked.
Herein, we describe the development of a catalytic intermo-
lecular [5+2] cycloaddition between 1-indanones and internal
alkynes and show how the aforementioned challenges could
be addressed through careful selection of ligands and
temporary directing groups (TDGs) (Scheme 1c). Further-
more, computational studies have been carried out to provide
useful information about the reaction mechanism and reveal
important roles of the p–p ligand/substrate interactions in this
transformation.
Entry Variation
Yield[b]
82%(80%[d]) 11
Entry Variation
Yield[b]
69%
1
2
none
IMes instead of
MeIMxy[c]
w/o [Rh-
<5%
<5%
12
MeIMes instead of 76%
(C2H4)2Cl]2
w/o TDG-6
TDG-1 instead trace
of TDG-6
MeIMxy[c]
3
4
13
14
w/o TsOH·H2O
w/o H2O
<5%
56%
Results and Discussion
5
TDG-2 instead trace
of TDG-6
15
16
17
18
19
20
w/o MeIMxy·TsOH 78%
Our study started with using 6-fluoro-1-indanone (1a) and
3-hexyne (2a) as the model substrates (Table 1). After an
extensive survey of various reaction parameters, the desired
[5+2] product 3a was obtained in 80% isolated yield
(entry 1), using 5 mol% [Rh(C2H4)2Cl]2, 10 mol% MeIMxy,
75 mol% TDG-6, 20 mol% TsOH·H2O, 10 mol%
MeIMxy·TsOH and 100 mol% H2O in 2-methyltetrahydrofur-
an (MeTHF). Control experiments showed that both the Rh
catalyst and the TDG are essential to this reaction (entries 2
6
TDG-3 instead 46%
of TDG-6
toluene instead of 57%
MeTHF
1,4-dioxane in-
stead of MeTHF
1308C
7
TDG-4 instead 48%
of TDG-6
47%
60%
51%
73%
8
TDG-5 instead 61%
of TDG-6
9
50 mol%
TDG-6
53%
24 h
48 h
10
w/o MeIMxy[c]
36%
and 3). Given the important role of TDG in activation of less
[16]
[a] All the reactions were run with 0.2 mmol of 1a, 0.8 mmol of 2a,
0.15 mL MeTHF in a 4 mL vial at 1408C for 72 h. [b] Yields were
À
strained C C bonds, different TDGs were then examined
(entries 4–8). While simple 2-aminopyridine (TDG-1)[17] or 2-
amino-6-methylpyridine (TDG-2) proved ineffective, the 3-
substituted aminopyridines were found to greatly enhance the
reactivity (entries 4–6). Further improvement was observed
when having an additional substituent at the C5 position
(entries 7 and 8); ultimately, the optimal TDG-6 was identi-
fied with an electron-deficient 3,5-ditrifluoromethylphenyl
group.[18] Reducing the TDG loading decreased the yield to
some extent (entry 9).
1
determined by H-NMR analysis of the crude mixture with 1,1,2,2-
tetrachloroethane as the internal standard. [c] Without 10 mol%
MeIMxy·TsOH as the additive. [d] Isolated yield.
evident for more challenging substrates (see Supporting
Information, Scheme S2). Other solvents besides MeTHF,
such as toluene and 1,4-dioxane, were less effective (en-
tries 15 and 16). Finally, somewhat lower yields were obtained
when running the reaction at lower temperature or in
a shortened period (entries 17–20).
With the optimized conditions in hand, the substrate
scope was then studied (Scheme 2).[19] Both the electron-
withdrawing (3b–g) and -donating groups (3h–3k) at the C6-
position of 1-indanones were tolerated. In the presence of
other carbonyl moieties, such as linear ketone or ester (3d,
3e), the C–C activation selectively took place on the indanone
ring. Relatively reactive FGs, including ester (3d), ketone
(3e), benzyl ether (3g), alkene (3j), trimethylsilyl (3k),
thienyl (3l), cyano (3m), and amide (3n), were compatible in
this transformation. 1-Indanones with substituents at the C5
The reaction can proceed in the absence of the N-
heterocyclic carbene (NHC) ligand (entry 10), suggesting that
[Rh(C2H4)2Cl]2 alone can catalyze the “cut-and-sew” reac-
tion, albeit in lower efficiency. Compared with the more
electron-rich MeIMxy ligand, IMes and MeIMes gave slightly
lower yields. TsOH was indispensable to this transformation
(entry 13), which is anticipated to promote forming the key
ketimine intermediate. The addition of H2O increased the
reaction efficiency (entry 14), possibly by accelerating the
hydrolysis of the 7-membered-ring ketimine product to
minimize side reactions.[13] Notably, the MeIMxy·TsOH addi-
tive proved beneficial (entry 15), and the effect was more
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Scheme 2. Scope of the [5+2] reaction[a] [a] Unless otherwise mentioned, all reactions were carried out on 0.2 mmol scale in 72 h under the
standard conditions. [b] Conversions were determined by 1H-NMR with 1,1,2,2-tetrachloroethane as the internal standard. [c] 2 equiv of the alkyne
2d was added first before another 2 equiv of 2d was added after 6 h. [d] The reactions were run under 1608C.
(3p, 3q, 3r, 3s) or C4 positions (3t, 3u) and the one derived
from naphthalene (3v) were also competent substrates. More
steric demanding substrates with either the C3 (3w) or C7
(3x) substitution gave much lower conversion, and the C2
substituted indanone (3y) was probably too bulky to react.
More complex substrates, for instance, those derived from
cholesterol (3z) and lithocholic acid (3aa) reacted smoothly
to deliver the desired ring-expansion products. Notably,
comparing to 1-indanones, saturated cyclopentanone was
not reactive under the current conditions (see DFT calcu-
lations below).
Regarding the scope of the alkyne coupling partners, the
reaction worked well for alkynes with different alkyl sub-
stituents (3ab–3ad). When unsymmetrical alkynes were
employed, the reaction moderately favored forming the
products with the bulkier substituent at the a-position (3ae–
3ah). Interestingly, while diaryl-substituted alkynes did not
provide the desired products (with 1-indanone substrates
mostly recovered probably owing to increased steric hin-
drance on alkynes), the mono-aryl-alkynes were reactive with
good regioselectivity, albeit in lower yields (3ai–3aj). Termi-
nal alkynes were not suitable under the current conditions,
which only led to alkyne trimerization byproducts with 1-
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indanones mostly recovered.[20] Efforts of further improving
equatorial ligands (i.e. the aryl and pyridyl groups). The
alkyne compatibility are underway in our laboratory.
subsequent migration insertion (TS2) was found to be the
turnover-limiting step (TLS), with an activation barrier of
32.2 kcalmolÀ1. The subsequent reductive elimination and
catalyst regeneration are straightforward, and the overall
process is thermodynamically favored by 15.8 kcalmolÀ1,
therefore driving the reaction to completion.
To show synthetic utility of this method, first, a gram-scale
reaction with a reduced catalyst loading provided ring-
expanded product 3a in 65% yield with 57% of TDG-6
recovered (Scheme 3a). The benzocycloheptenone product
To understand why the reaction works well with 1-
indanones but not with saturated cyclopentanones, the path-
way for simple cyclopentanone was also computed and
À
compared (Scheme 4, red). The C C activation step for
cyclopentanone is analogous to that of 1-indanone, while the
migration-insertion step shows significant difference. The
alkyne coordination is strongly disfavored, and the inter-
mediate (Int2-C5) is 5.9 kcalmolÀ1 less stable than the
corresponding one with 1-indanone. As such, the activation
energy of the 2p-insertion step (44.7 kcalmolÀ1) is much
higher. On the other hand, as a side reaction, the b-hydrogen
elimination (the blue pathway, Scheme 4a) exhibits a low
barrier, though the product Int3H-C5 is 9.7 kcalmolÀ1 uphill.
In addition, distortion-interaction analysis of the 2p-insertion
transition states (TSs) reveals that even with a much earlier
À
TS (the forming C C bond is 2.01 ꢀ in TS2 but 2.20 ꢀ in TS2-
C5), the distortion energy of the metal-imine complex in TS2-
C5 is still 19.7 kcalmolÀ1 higher than that in TS2 (Scheme 4c).
This could account for the major reactivity difference between
the two substrates. Further distortion/interaction analysis
along the intrinsic reaction coordinate (IRC) indicates that
the difference mainly arises from the alkyne coordination
instead of the migratory insertion step (see Supporting
Information Figure S1 for details).
Scheme 3. Synthetic applications.
can readily undergo various transformations to access diverse
structural motifs (Scheme 3b). For example, direct reduction
with NaBH4 gave allylic alcohol 4 in 95% yield, which can be
transformed to epoxide 5 in excellent diastereoselectivity.
Baeyer–Villiger oxidation with oxone[21] as the oxidant
selectively gave the 8-membered-ring vinyl migration product
(6). When IBX was used as the oxidant, the dehydration
product 7 was isolated in 80% yield,[22] which further under-
went the Pd-catalyzed conjugated addition to deliver the b-
arylation product (8) in almost quantitative yield.[23] The a-
arylation was smoothly realized with a Pd catalyst and
Buchwald ligand (9).[24] Hence, both the a and b positions
of the benzocycloheptenone can be efficiently functionalized.
Finally, an interesting 6-7-5-6 tetracyclic compound (10) was
obtained after subjecting 3a to the Fischer-indole synthesis.
Finally, DFT calculation was performed to gain insights
into the reaction mechanism (Scheme 4). TDG-3 was em-
ployed instead of TDG-6 to simplify the calculation process
with limited computational resources. First, starting from the
imine intermediate (Int0) derived from 1-indanone and TDG-
To gain deeper understanding of the TLS, the structures
before and after alkyne coordination were carefully reex-
amined. As shown in Scheme 4b, before alkyne coordination
(Int1), the chloride stays at the axial position with the NHC
ligand bending towards the equatorial position to minimize
unfavored steric repulsion with the imine backbone. How-
ever, in Int2 and TS2, with alkyne being a much larger ligand,
the chloride has to occupy an equatorial position instead,
which leads to distortion of the NHC ligand to adopt a more
sterically encumbered conformation. In the case of 1-inda-
none, one aryl ring of the NHC ligand happens to be at
slipped parallel geometry with the phenyl group of 1-
indanone. The centroid distance between these two aromatic
rings is only 3.52 ꢀ, thus indicating a strong p–p interaction
that could partially offset the steric repulsion caused by the
alkyne coordination.[25] The existence of “double p–p inter-
actions” between the two NHC aryls and the aromatic
moieties of 1-indanone and 2-aminopyridine, respectively, in
this key TS was further substantiated by non-covalent
interaction (NCI) analysis (Scheme 4d).[26,27] The large green
areas represent weak van der Waals attractions between the
arenes. For comparison, the corresponding reaction with
cyclopentanone lacks stabilization by such “double p–p
interactions”, therefore resulting in a much higher barri-
er.[28,29]
À
3 (see Supporting Information, Section 7.4), the C C activa-
tion step (TS1) is rather facile with an activation barrier of
8.9 kcalmolÀ1 and the resulting six-membered rhodacycle Int1
is slightly exergonic by 0.5 kcalmolÀ1, indicating possible
equilibrium between Int0 and Int1. The following alkyne
coordination gives an 18-electron closed-shell complex Int2,
which is endergonic by 16.5 kcalmolÀ1. The enhanced energy
of the alkyne-coordinated complex is likely due to the
increased steric repulsion between the NHC ligand and the
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Scheme 4. DFT calculations. [a] Computed energy profiles at wB97X-V/def2-TZVPP/SMD(THF)//B3LYP-D3(BJ)/SDD-6-31G(d) level of theory. The
reaction pathway of 1-indanone 1o is shown in black. The reaction pathway of cyclopentanone is shown in red and blue, and their structures are
omitted for clarity. [b] Distances are in angstroms. [c] Energies are in kcalmolÀ1. NCI: non-covalent interaction.
Conclusion
tetrasubstituted olefins. The reaction is scalable, redox-
neutral, and chemoselective. Diverse structures can be
obtained through derivatizing the enone products. The
mechanistic insights gained through detailed DFT studies
should shed light on future reaction development and better
catalyst design. Efforts on expanding the reaction scope and
We have disclosed a new intermolecular [5+2] cyclo-
addition strategy between 1-indanones and internal alkynes
through the Rh-catalyzed C C activation, which provides
a straightforward access to benzocycloheptenones containing
À
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Acknowledgements
NIGMS (2R01GM109054) and the University of Chicago are
acknowledged for research support. We thank Mr. Shusuke
Ochi and Dr. Alexander Filatov for X-ray crystallography.
Umicore AG & Co. KG is acknowledged for a generous
donation of Rh salts. We are grateful for the support of the
University of Chicagoꢁs Research Computing Center for the
DFT calculations carried out in this work. We thank Prof.
Peng Liu (from University of Pittsburgh) for DFT advice and
Dr. Zhao Wu for checking the procedure.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: [5+2] annulation · C–C activation · ketones ·
seven-membered rings · p–p interactions
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a stronger Ar Rh bond due to the para-F substituent, which can
retard the turnover-limiting migratory insertion.
Manuscript received: June 2, 2021
Revised manuscript received: June 21, 2021
Accepted manuscript online: July 2, 2021
Version of record online: && &&
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Research Articles
C–C Activation
R. Zhang, Y. Xia,
G. Dong*
&&&& — &&&&
Intermolecular [5+2] Annulation between
1-Indanones and Internal Alkynes by
Rhodium-Catalyzed C–C Activation
The Rh-catalyzed intermolecular [5+2]
annulation between 1-indanones and
alkynes is reported. It provides a rapid
and straightforward entry to benzocyclo-
heptenones. DFT calculation reveals the
beneficial p–p interactions between the
ligand and the substrate in the turnover-
limiting migration insertion step.
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!