Distal-Bond-Selective C?C Activation of Ring-Fused Cyclopentanones: An Efficient Access to Spiroindanones

Article abstract of DOI:10.1002/anie.201611642

A site-selective rhodium-catalyzed C?C activation of ring-fused cyclopentanones was achieved to afford efficient access to a range of spiroindanones. The use of bulky 2-amino-6-picoline as a cocatalyst is key to the excellent selectivity of this C?C bond cleavage in cyclopentanones.

Full text of DOI:10.1002/anie.201611642

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611642
German Edition: DOI: 10.1002/ange.201611642
À
C C Activation
À
Distal-Bond-Selective C C Activation of Ring-Fused
Cyclopentanones: An Efficient Access to Spiroindanones
Ying Xia, Jianbo Wang, and Guangbin Dong*
Dedicated to Professor David Milstein on the occasion of his 70th birthday
À
Abstract: A site-selective rhodium-catalyzed C C activation
of ring-fused cyclopentanones was achieved to afford efficient
access to a range of spiroindanones. The use of bulky 2-amino-
6-picoline as a cocatalyst is key to the excellent selectivity of
À
this C C bond cleavage in cyclopentanones.
À
C
arbon–carbon bond (C C) activation, a process involving
À
the conversion of relatively inert C C bonds into more
À
reactive M C (M = transition metal) bonds, provides unusual
bond disconnection strategies to access various versatile
scaffolds.[1] However, owing to the kinetic inertness of C C
À
s bonds, the applications of such strategies have been largely
focused on ring-strained systems, including cyclopropane and
cyclobutane derivatives, in which strain relief becomes a main
driving force of the reaction.[2,3] In contrast, despite the
À
success of broadly useful methods involving C CN bond
cleavage,[4] the C C activation of less- or non-strained
À
systems,[1d,e,5] particularly five- or six-membered rings, is
rather challenging and underdeveloped.[6,7]
Recently, our group developed a general approach for the
À
catalytic activation of C C bonds in simple 3-aryl-substituted
cyclopentanones (Scheme 1a).[8] Using [Rh(C2H4)2Cl]2 as
a precatalyst, IMes (1,3-bis(2,4,6-trimethylphenyl)imidazol-
2-ylidene) as a ligand, and 2-aminopyridine as a cocatalyst,
Scheme 1. Catalytic C C bond activation in 3-aryl cyclopentanones.
IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene, IPr=1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
À
À
the proximal C1 C2 bond of cyclopentanones can be
selectively activated through a temporary directing mode,[9]
À
followed by intramolecular C H activation of the aryl group
to ultimately provide functionalized a-tetralone products.
a complementary catalyst system? To the best of our knowl-
edge, this has not been realized with less strained structures.[10]
Herein, we describe our efforts in developing a “distal-
À
Through a similar sequence, cleavage of the distal a-C C
bond (C1 C5 bond) would provide a-indanones. However,
these have only been observed as minor products in some
examples. An intriguing question thus arose: is it possible to
steer the site selectivity of a C C activation reaction with
À
À
selective” C C activation of 3-arylcyclopentanones with
a new catalyst system for applications in a-indanone syn-
thesis[11,12]. While the focus is given to the activation of ring-
fused cyclopentanones for the synthesis of diverse spiroinda-
À
À
none scaffolds (Scheme 1b), initial success with distal C C
activation of regular 3-arylcyclopentanones was also realized.
[*] Y. Xia, J. Wang
À
To overcome the challenge of activating the distal C1 C5
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking University
Beijing 100871 (China)
bond, our strategy is to destabilize the intermediate generated
À
from the cleavage of the proximal C1 C2 bond of cyclo-
pentanones. We hypothesized that, using a combination of
a bulky NHC (N-heterocyclic carbene) ligand with a bulky
aminopyridine cocatalyst, the steric repulsion between the
aryl group and the ligands would disfavor Rh insertion into
Y. Xia, G. Dong
Department of Chemistry, University of Texas at Austin
Austin, TX 78712 (USA)
Y. Xia, G. Dong
À
the proximal C1 C2 bond (intermediate A1, Figure 1). In
Department of Chemistry, University of Chicago
Chicago, IL 60637 (USA)
E-mail: gbdong@uchicago.edu
addition, the buttressing effect in intermediate A1 would
restrict rotation of the aryl group, which in turn would hamper
À
subsequent ortho C H activation. As a result, activation and
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201611642.
À
subsequent conversion of the distal C1 C5 bond is expected
to be preferred.
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Table 1: Selected optimization studies of C C bond activation with ring-
fused cyclopentanone 1a.[a]
Entry Variation from
standard conditions
Total
Ratio 1b/
yield [%][b]
1c[b]
Figure 1. Proposed model for the distal-bond selectivity.
1
2
original conditions[c]
None
78
90 (84)
75
36:64
>99:1
60:1
3
without pyridine
To test this hypothesis, ring-fused cyclopentanone 1a,
which is conveniently prepared through a Pauson–Khand
reaction and aryl conjugate addition sequence (for details, see
the Supporting Information), was chosen as the initial model
substrate (Table 1). Under the previous reaction conditions,
the fused a-tetralone 1c was found as the major product,
together with spiroindanone 1b, which was formed in only
28% yield, as an inseparable mixture (entry 1).[8] Indeed,
when employing a more sterically hindered 2-amino-6-pico-
line (C1) as a cocatalyst with IPr as a bulkier ligand, the site
selectivity was completely switched to favoring the formation
of the spiroindanone 1b. After further optimization, the
standard reaction conditions were secured (Table 1, entry 2).
Under these conditions, the desired a-indanone product 1b
was afforded in excellent yield with > 99:1 distal/proximal
selectivity. The structure of a-indanone product 1b was
unambiguously confirmed by X-ray crystallography.[13]
4
5
6
7
8
9
10
11
12
13
14
15
16
17
without H2O
78
71
61
59
63
41
76
80
74
<1
43
70
80
70:1
42:1
53:47
38:1
without pyridine and H2O
IMes/C2 instead of IPr/C1
IMes instead of IPr
C2 instead of C1
C3 instead of C1
C4 instead of C1
C5 instead of C1
C6 instead of C1
C7 instead of C1
THF instead of 1,4-dioxane
0.5 m
65:35
53:47
48:52
56:44
>99:1
–
>99:1
>99:1
>99:1
>99:1
1308C instead of 1408C
PPTS instead of pyridine and
TsOH·H2O
85
À
To gain further insight into this distal-selective C C
activation reaction, control experiments were performed
(Table 1, entries 3–17). In the absence of pyridine or water
or both, the reaction still gave excellent site selectivity, albeit
with somewhat lower yields (entries 3–5). It is reasonable to
propose that pyridine helps to stabilize the RhI catalyst when
it is off the cycle,[14] and water enhances the turnover
frequency through promoting imine hydrolysis to release
the C1 cocatalyst. When using a combination of the IMes
ligand with 2-aminopyridine (C2), although the proportion of
the a-indanone product 1b slightly increased compared to the
original conditions (entry 1), there was nearly no selectivity
between the two products (entry 6). In addition, changing the
NHC ligand from IPr to IMes resulted in much lower
efficiency and reduced site selectivity (entry 7). The C6
substitution on the amine cocatalyst was found to be crucial
for the site selectivity (entries 8–13 vs. entry 2). In contrast,
employing cocatalysts C3–C5, which are substituted at other
positions, resulted in poor site-selectivity (entries 9–11).
Variation of the methyl group in the cocatalyst to an ethyl
group gave lower yield but with no influence on the site
selectivity (entry 12); however, the use of 6-phenyl substi-
tuted cocatalyst C7 completely shut down the reaction
(entry 13). THF was found to be less efficient as a solvent
than 1,4-dioxane (entry 14). High reaction concentration
(1.0m) proved beneficial to the conversion (entry 15). 80%
yield was still obtained at 1308C (entry 16). The use of PPTS
instead of a combination of TsOH·H2O and pyridine gave
1
[a] Run on a 0.2 mmol scale in a 4 mL vial. [b] Determined by H NMR
using 1,1,2,2-tetrachloroethane as the internal standard. [c] Reported in
our previous work (Ref. [8]). Conditions: 5 mol% [Rh(C2H4)2Cl]2,
10 mol% IMes, 10 mol% TsOH·H2O, 25 mol% 2-aminopyridine (C2)
and 50 mol% H2O in 1,4-dioxane (0.5 m) at 1408C for 48 h.
PPTS=pyridinium p-toluenesulfonate.
With the optimized reaction conditions in hand, the
substrate scope was then tested (Table 2). Nitrogen-tethered
ring-fused cyclopentanones were first explored (Table 2,
entries 1–6). Electron-rich or electron-neutral aryl-substi-
tuted substrates afforded the desired spirocycles in compara-
ble yields (oxygen atoms in entries 1, 2 and 4), while an
electron-deficient one resulted in a decreased yield and
reduced site selectivity (entry 3). This trend proved to be
general for substrates with other linkers as well. The oxygen-
linked substrates showed equal or slightly higher reactivity
than the corresponding nitrogen-linked ones (entries 7–15). A
broad range of functional groups, including methyl or benzyl
ether, aryl chloride, furan, terminal olefin, ester, and silyl
ethers, are tolerated. Meta- and ortho-substituted substrates
also worked smoothly to afford the corresponding products
with no decrease in site selectivity (entries 12 and 13). The
naphthyl-substituted ring-fused cyclopentanones are compat-
ible substrates, affording naphthyl-fused spiroindanones in
a
comparable yield and equally excellent selectivity
(entry 17).
2
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[a]
À
Table 2: Substrate scope of the C C bond activation with ring-fused cyclopentanones.
[a] Run on a 0.2 mmol scale in a 4 mL vial. [b] Total yields of isolated product were provided and the distal/proximal (d/p) ratio is >40:1 unless
otherwise noted. [c] d/p=13:1. [d] 5 mol% [Rh(C2H4)2Cl]2, 15 mol% IPr, 20 mol% MeSO3H, 100 mol% C1, 20 mg 4 ꢀ molecular sieves in 1,4-dioxane
(1 m) at 1508C for 48 h.[8] [e] d/p=4.8:1.
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good yields (entries 14 and 15). It should be noted that C H
activation occurred at the less hindered position when meta-
or 2-naphthyl-substituted substrates were employed
(entries 12 and 14). Besides forming heterocycle-based prod-
ucts, the use of carbon tethers is also effective to provide all-
carbon spirocycles (entries 16 and 17). In addition, the six-
membered ring-fused cyclopentanone (18a) was found to be
a suitable substrate, albeit giving lower reactivity and
selectivity (entry 18). The ring-fused cyclohexanone substrate
19a showed low reactivity under the current reaction
conditions, although the spiroindanone product 19b was
isolated in 21% yield in our previous work[8] (entry 19).[15]
achieved. While it is clear that the substitution pattern on the
cyclopentanone ring significantly affects the site selectivity of
the reaction, a more detailed understanding of this system
remains to be disclosed. Future work will focus on improve-
ment of the site selectivity for non-ring-fused substrates and
À
the development of a general distal-selective C C activation
of cyclopentanones through in-depth mechanistic studies.
Acknowledgements
This project was supported by NIGMS (R01GM109054). 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). Johnson Matthey is acknowl-
edged for a generous donation of Rh salts. Prof. Dr. M. C.
Young, and Mr. K.-Y. Yoon are thanked for the X-ray
structure.
À
The feasibility of promoting distal-selective C C activa-
tion of other types of 3-aryl cyclopentanones was next
investigated (Table 3). To our delight, when employing the
IPr/C1 catalyst system, the site selectivity for the 3-methyl-3-
phenyl cyclopentanone (20a) was completely switched from
21:79 to 78:22 favoring indanone formation.[16] In addition,
while far from being satisfactory, significant improvements in
the distal/proximal (d/p) ratio were observed for simple o-
tolyl and phenyl-substituted cyclopentanones (21a and 22a).
À
In summary, we have realized the distal-selective C C
Conflict of interest
activation of ring-fused 3-aryl cyclopentanones, which pro-
vides a distinct method for the synthesis of spiroindanones.
The key to the site selectivity is the use of a bulky 2-amino-6-
picoline cocatalyst. Preliminary success with distal-selective
The authors declare no conflict of interest.
À
Keywords: C C activation · cyclopentanones ·
À
C C activation of other 3-aryl cyclopentanones was also
homogeneous catalysis · rhodium · spirocycles
À
Table 3: Switching the site-selectivity of C C bond activation in cyclo-
pentanones.[a]
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[2] Selected reviews on C C activation in cyclopropane derivatives:
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[4] a) M. Tobisu, N. Chatani, Chem. Soc. Rev. 2008, 37, 300; b) Y.
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[a] Run on a 0.2 mmol scale in a 4 mL vial. IMes/C2 conditions: 5 mol%
[Rh(C2H4)2Cl]2, 10 mol% IMes, 10 mol% TsOH·H2O, 25 mol% 2-
aminopyridine (C2) and 50 mol% H2O in 1,4-dioxane (0.5 m) at 1408C
for 48 h; The IPr/C1 conditions: 5 mol% [Rh(C2H4)2Cl]2, 10 mol% IPr,
10 mol% TsOH·H2O, 50 mol% 2-amino-6-picoline (C1) in 1,4-dioxane
(1.0 m) at 1408C for 48 h. [b] Determined by 1H NMR using 1,1,2,2-
tetrachloroethane as the internal standard. [c] See Ref. [8].
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118, 8285; c) C.-H. Jun, H. Lee, S.-G. Lim, J. Am. Chem. Soc.
2001, 123, 751.
À
[7] C C activation in some special five-membered ring systems:
a) C. Mukai, Y. Ohta, Y. Oura, Y. Kawaguchi, F. Inagaki, J. Am.
Chem. Soc. 2012, 134, 19580; b) R. Zeng, G. Dong, J. Am. Chem.
4
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Soc. 2015, 137, 1408; c) R. Zeng, P. Chen, G. Dong, ACS Catal.
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Sci. 2015, 6, 5440.
[8] Y. Xia, G. Lu, P. Liu, G. Dong, Nature 2016, 539, 546.
[9] a) C.-H. Jun, H. Lee, J. Am. Chem. Soc. 1999, 121, 880; b) Y. J.
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[13] CCDC 1519473 and 1520309 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[14] Addition of 10 mol% of pyridine substantially reduced the
formation of Rh-mirror. A study on the pyridine effect in Rh/
NHC catalysis: A. Di Giuseppe, R. Castarlenas, J. J. Pꢀrez-
Torrente, M. Crucianelli, V. Polo, R. Sancho, F. J. Lahoz, L. A.
Oro, J. Am. Chem. Soc. 2012, 134, 8171.
À
[10] Examples of site-selective C C activation of cyclobutane
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Soc. 2002, 124, 13976; b) L. Liu, N. Ishida, M. Murakami, Angew.
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[15] For reactivity exploration of other types of substrates, see the
Supporting Information.
[11] Synthesis of a-indanones mainly uses intramolecular Friedel–
Crafts reactions: a) G. Olah, Friedel – Crafts Chemistry, Wiley-
Interscience, New York, 1973; b) H. Heaney in Comprehensive
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[12] Selected examples of transition-metal-catalyzed synthesis of a-
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[16] For non-fused 3-aryl cyclopentanone substrates, the addition of
pyridine resulted in decreased yields. For example, the yield for
substrate 20a dropped from 92% to 68% with no effect on the
site selectivity when 10 mol% of pyridine was used as the
additive.
Manuscript received: November 29, 2016
Revised: December 27, 2016
Final Article published: && &&, &&&&
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À
C C Activation
Y. Xia, J. Wang, G. Dong*
&&& — &&&
À
Distal-Bond-Selective C C Activation of
Ring-Fused Cyclopentanones: An
Efficient Access to Spiroindanones
À
So far, so good: Rhodium-catalyzed C C
activation of ring-fused cyclopentanones
was achieved site selectively for the distal
over the proximal position. Key to this
outcome is the combination of a bulky 2-
amino-6-picoline (C1) with a bulky NHC
ligand. This unusual intramolecular skel-
eton rearrangement offers rapid access to
a diverse range of spiroindanones.
6
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