Rh-catalyzed reagent-free ring expansion of cyclobutenones and benzocyclobutenones

Article abstract of DOI:10.1039/c5sc01875g

Here we report a reagent-free rhodium-catalyzed ring-expansion reaction via C-C cleavage of cyclobutenones. A variety of poly-substituted cyclopentenones and 1-indanones can be synthesized from simple cyclobutenones and benzocyclobutenones. The reaction condition is near pH neutral without additional oxidants or reductants. The potential for developing a dynamic kinetic asymmetric transformation of this reaction has also been demonstrated. Further study supports the proposed pathway involving Rh-insertion into the cyclobutenone C-C bond, followed by β-hydrogen elimination, olefin insertion and reductive elimination.

Full text of DOI:10.1039/c5sc01875g

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Rh‐catalyzed Reagent‐Free Ring Expansion of Cyclobutenones and Benzocyclobutenones
Peng‐hao Chena, Joshua Sieberb, Chris H. Senanayakeb and Guangbin Dong*a
a The University of Texas at Austin, Department of Chemistry, Austin, TX 78712, United States
b Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury
Road/P.O. Box 368, Ridgefield, Connecticut 06877‐0368, United States
Abstract: Here we report a reagent‐free rhodium‐catalyzed ring‐expansion reacꢀon via C−C cleavage of
cyclobutenones. A variety of poly‐substituted cyclopentenones and 1‐indanones can be synthesized
from simple cyclobutenones and benzocyclobutenones. The reaction condition is near pH neutral
without additional oxidants or reductants. The potential for developing a dynamic kinetic asymmetric
transformation of this reaction has also been demonstrated. Further study supports the proposed
pathway involving Rh‐insertion into the cyclobutenone C−C bond, followed by β‐hydrogen elimination,
olefin insertion and reductive elimination.
1

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INTRODUCTION
Ring expansion reactions, generally with cyclic ketones, are highly valuable transformations for
constructing complex ring skeletons.1 Conventional approaches for direct one‐carbon homologation of
cyclic ketones primarily rely on addition of a carbene reagent or its equivalent (Scheme 1a).2 For
example, diazoalkanes have been frequently employed for preparing cyclopentanones from
cyclobutanones.3 In contrast, the corresponding transformations with unsaturated enones (e.g.
cyclobutenones) are much rarer largely due to the competing reactions with the olefin moiety (e.g.
conjugate addition and cyclopropanation)4 and lack of regioselectivity.5 Moreover, most existing
methods for one‐carbon ring expansion of four‐membered ring ketones6 involve forming cyclobutanols7
(or cyclobutenols8) as a transient or isolatable intermediate (Scheme 1a). Considering that, as important
classes of organic compounds, cyclopentenones and 1‐indanones are frequently employed as building
blocks and widely found in a number of bioactive molecules (Figure 1), herein we describe a unique,
simple, and atom‐economical strategy for the direct catalytic ring expansion of alkyl cyclobutenones and
benzocyclobutenones to five‐membered unsaturated ketones.9
Scheme 1. One‐carbon Homologation of Four‐membered Ring Ketones.
2

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Figure 1. Representative examples of related bioactive molecules
RESULTS AND DISCUSSION
Research Hypothesis. Our proposed strategy is described in Scheme 1b. Driven by strain release,
cyclobutenones are known to undergo ring openings with transition metals (e.g. RhI) through cleavage
of the C1‐C4 bond.10 We hypothesized that subsequent β‐hydrogen elimination with the resulting acyl
metallacycle would lead to a metal hydride‐olefin complex, which can undergo hydride re‐insertion
followed by reductive elimination to furnish the ring expanded product.
While numerous elegant methods have been developed for synthesis of cyclopentenones and
indanones,11 such as Pauson‐Khand (PK)12 and Nazarov13 reactions, this approach nevertheless exhibits a
number of complementary features. First, poly‐substituted cyclobutenones and benzocyclobutenones
are readily available through many approaches,14 including a [2+2] cycloaddition between an alkyne (or
aryne) and a ketene equivalent (see SI). Second, it operates under near pH and redox‐neutral conditions,
which would tolerate many functional groups (Nazarov reactions generally require use of a strong acid).
Third, this transformation shows a complete regioselectivity when forming α‐substituted
cyclopentenones (vide infra, Table 4); in contrast, it is non‐trivial to control the regioselectivity for
intramolecular PK reactions.
Optimization Studies and Substrate Scope. To test this hypothesis, benzocyclobutenone 1a was
employed as the model substrate, and the reaction was investigated by examining a number of
parameters (Table 1). When Wilkinson’s complex [RhCl(PPh3)3] was used as the catalyst, no desired
product was observed (entry 1, Table 1), and 1a remained intact. It is known that bidentate ligands can
facilitate migratory insertion and reductive elimination.15 Thus, a series of bisphosphine ligands were
evaluated (entries 2‐5, Table 1). To our delight, all these ligands provided the desired ring expansion
product, whereas dppp proved to be the most efficient. Using dppp as the ligand, the reaction occurred
smoothly at 80 oC albeit requiring a longer reaction time (entries 5‐9, Table 1). When performed at 90 oC,
the desired 1‐indanone product was isolated in 93% yield (entry 9, Table 1). A survey of different
3

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solvents revealed that 1,4‐dioxane was optimal, although THF and ethyl benzene worked almost equally
well (entries 9‐13, Table 1). Finally, control experiments showed that both the rhodium pre‐catalyst and
the phosphine ligand were essential for the success of this ring‐expansion reaction (entries 14‐15, Table
1).
Table 1. Selected Optimization for Ring Expansion of 8‐Ethyl Benzocyclobutenone
3
O
O
1
8
2
4
5 mol % [Rh(COD)Cl]2
Me
5
7
12 mol % ligand, T, t, solv.
Et
6
2a
Time
24 h
24 h
24 h
24 h
24 h
24 h
24 h
48 h
1a
Entry
1
Ligand
T (oC)
110
110
110
110
110
120
100
80
Solvent
Yielda
0
b
PPh3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
2
dppe
dppb
dppf
75%
61%
64%
84%
68%
73%
77%
3
4
5
dppp
dppp
dppp
dppp
6
7
8
9
dppp
90
dioxane
48 h
93%c
dppp
90
THF
48 h
90%
10
11
12
13
14
15
dppp
dppp
dppp
90
90
90
PhEt
48 h
48 h
48 h
89%
81%
76%
benzene
toluene
dppp w/o [Rh]
no ligand
90
90
dioxane
dioxane
48 h
48 h
0
0
a) Unless otherwise noted, all yields were determined by 1H NMR using 1,1,2,2‐tetrachloroethane as the internal
standard. b) Wilkinson's catalyst [RhCl(PPh3)3] was used. c) Isolated yield.
With the optimal condition established, we next investigated the substrate scope of the reaction
(Table 2). Benzocyclobutenones bearing different substituents at the C8 position all afforded the desired
products (2a‐2d, 2m16, 2n). Substituents at all positions on the benzene ring can be tolerated (2d‐2h).
The 3,5‐dimethyl substituted substrate required a higher temperature but still provided the desired
product (2d) in a good yield. Functional groups, such as aryl bromides, chlorides, anisoles, free phenols
and silyl ethers (2i‐2l and 2n) were compatible under the reaction conditions, albeit giving moderate
yields. Interestingly, olefin migration was observed when 8‐allyl‐substituted substrate (2o) was used.
Table 2. Scope for the Ring Expansion of 8‐Alkyl Benzocyclobutenonesa.
4

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a) All yields are isolated yields, and the numbers in parenthesis are yields based on recovered starting material. All
reactions were carried out in a sealed vial under N2 atmosphere. b) The reaction was run at 110 oC for 48 h. c) The
reaction was run at 150 oC for 48 h. d) The reaction was run at 130 oC for 48 h.
To explore whether the benzo‐moiety is essential for the ring‐expansion transformation, we next
investigated simple cyclobutenone derivatives (Table 3). Compound 3a was employed as the model
substrate. It was surprising to note that when the optimal conditions for the benzocyclobutenones (vide
supra) were applied, no desired ring‐expansion product was found even at elevated temperatures (entry
1, Table 3), suggesting a significant difference in reactivity between the two closely related compounds.
A survey of other ligands also remained unfruitful, and unlike benzocyclobutenones, compound 3a
remained inactive under these conditions (entries 2‐4, Table 3). However, by switching the precatalyst
from [Rh(COD)Cl]2 to [Rh(COD)OH]2 or [Rh(COD)OMe]2,17 cyclopentenone 4a could be isolated in
moderate to good yields (entries 5 and 6, Table 3). The analogous [Ir(COD)OMe]2 failed to give any
desired product (entry 7, Table 3). A number of bidentate phosphine ligands were subsequently
evaluated (entries 8‐11, Table 3), and dppb showed enhanced reactivity (entry 9, Table 3). Control
experiments further revealed that both the metal and the ligand were required (entries 12‐14, Table 3),
and NaOH alone failed to catalyze the reaction, indicating that the transformation was not solely
catalyzed by the hydroxy anion (entry 15, Table 3). It is worth noting that the reaction can occur at 80 oC
(entry 21, Table 3). Considering the overall reaction efficiency, 110 oC was chosen as the temperature for
further optimization (entry 18, Table 3). Finally, the solvent effect was investigated, and ethyl benzene
gave the best results (95%, entry 26, Table 3).
Table 3. Selected Optimization for Ring Expansion of Cyclobutenone 3a
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a) Unless otherwise noted, all yields were determined by 1H NMR using 1,1,2,2‐tetrachloroethane as
the internal standard. Values in the parentheses are yields based on recovered starting material. b) 30
mol % of PPh3 was used as the ligand. c) Isolated yields. d) 20 mol % of NaOH was used.
The substrate scope with simple cyclobutenones was then explored (Table 4). Substrates containing
various aromatic or aliphatic substituents at the 2 and 3‐positions all provided the desired
cyclopentenones smoothly. Interestingly, simple α‐methylated cyclopentenone 4b has not been
synthesized previously. The more sensitive thiophene (4e) and naphthalene rings (4h) can be tolerated.
Although the 3,4‐disubstituted cyclobutenones (no substitution at the C2 position) are known to be
highly unstable and prone to undergo olefin isomerization,18 the desired ring‐expansion product (4i,
Table 2) can still be obtained, suggesting the mildness of the reaction conditions.
Table 4. Scope for the Ring Expansion of 4‐Alkyl Cyclobutenonesa
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a) All yields are isolated yields, and the numbers in parenthesis are yields based on recovered
starting material. All reactions were carried out in a sealed vial under N2 atmosphere.
Preliminary studies have revealed that chiral bidendate phosphine ligands, such as segphos, effect
the dynamic kinetic asymmetric transformation (DYKAT) of benzocyclobutenone 1a with a promising
level of enantioselectivity (eq. 1, 49% ee).19 This result suggests this reagent‐free ring‐expansion reaction
is amenable to asymmetric catalysis, and work on this topic is ongoing.
The utility of this method was demonstrated by converting ring‐expansion product 4h to an
interesting picene‐derived ketone (5) using a light‐mediated dehydrogenative cyclization (eq. 2).20
Notably, picene 5 is nontrivial to prepare via a conventional approach. The application of picene 5 as an
organic transistor material21 is under exploration.
Mechanistic Studies. To explore the proposed mechanistic pathway in Scheme 1b, we first
conducted
a
deuterium labelling experiment (Scheme 2a). When the ‐CD3 substituted
benzocyclobutenone (1c‐3D) was used as the substrate, indeed, a near complete deuteration (95%) was
found at the α‐position of the 1‐indanone product, and 82% deuterium incorporation was observed at
one of the β‐hydrogen. This result is consistent with the proposed β‐hydrogen elimination and re‐
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insertion pathway. Subsequently, a positive kinetic isotope effect (KIE) was observed when a 1:1 molar
ratio of 1c and 1c‐3D were mixed and reacted under the standard conditions (Scheme 2b). While only a
moderate KIE (1.8) was observed, this intermolecular competition experiment suggested the β‐hydrogen
elimination either occurs before the rate‐limiting step or is the rate‐limiting step.22
Scheme 2. Mechanistic Exploration.
Byproducts from a catalytic reaction often provide useful information about the reaction
intermediates. Consequently, the byproducts of this ring‐expansion reaction were investigated.
Benzocyclobutenone 1p was subjected to the standard conditions at an elevated temperature. While the
desired 2‐phenyl‐indanone product was afforded, two major byproducts, aldehyde 6 and stilbene 7,
were isolated and characterized (Scheme 2c). The presence of these two ring‐opening products supports
the pathway of C1−C8 bond cleavage of benzocyclobutenone and Rh‐hydride 8 as a possible
intermediate. A direct acyl‐hydrogen reductive elimination should lead to aldehyde 6, while
decarbonylation of intermediate 8 followed by aryl‐hydrogen reductive elimination should result in
stilbene 7.23 Compared to the standard substrate (1a), the presence of significant side reactions with
substrate 1p can be explained by an inefficient migratory insertion and/or reductive elimination with a
trans‐stilbene‐like olefin (vide supra, Table 2, 2m).24
Finally, we investigated whether the cleavage of benzocyclobutenone C1−C8 bond is catalyzed by the
Rh catalyst or simply triggered by thermal heat (Scheme 3). If the C−C cleavage was caused by the
thermal heat alone, a vinyl ketene intermediate would be generated. Vinyl ketenes are highly reactive
species, and are known to react with various nucleophiles or dienophiles.25 However, treatment of the
benzocyclobutenone 1g with benzyl alcohol or maleic anhydride at the same reaction temperature did
not yield any coupling products, which suggested that the rhodium catalyst played an important role in
assisꢀng the C−C cleavage.10
8

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Scheme 3. Capture of the Vinyl Ketene Intermediate.
CONCLUSION
In summary, we have developed a unique Rh‐catalyzed ring expansion of cyclobutenones and
benzocyclobutenones via C─C bond cleavage. A range of poly‐substituted cyclopentenones and 1‐
indanones can be prepared. This approach is featured by: 1) the substrates are relatively simple and do
not require pre‐installation of an additional reacting group; 2) no additional stoichiometric reagents are
needed for the ring expansion, and the transformation is atom‐economical; and 3) the reaction
conditions are near pH and redox neutral allowing for tolerance of many functional groups. Finally, the
preliminary mechanistic study supports the proposed pathway involving Rh‐oxidative addition into the
C─C bond, followed by β‐hydrogen elimination, olefin migratory insertion and reductive elimination.
Efforts on developing a highly enantioselective DYKAT of this reaction for asymmetric synthesis is
currently undertaken in our laboratories.
ACKNOWLEDGEMENT
We thank CPRIT (R 1118), NIGMS (R01GM109054‐01) and the Welch Foundation (F 1781) for research
grants. GD is a Searle Scholar and a sloan fellow. Prof. Anslyn is acknowledged for advices on the kinetic
isotope effect. Dr. Lynch is acknowledged for X‐ray crystallography. We thank A. Spangenberg for her
advice on NMR spectroscopy. We are also grateful to Johnson Matthey for a generous donation of the
Rh salts.
NOTES & REFERENCE
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4. For selected examples of cyclopropanation of α,β unsaturated ketones with diazo‐compounds,
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Matsuda, M. Shigeno, M. Makino, M. Murakami, Org. Lett., 2006, 8, 3379.
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K. Takahashi, Y. Ito, J. Am. Chem. Soc., 1998, 120, 9949. For an example of atom‐economical ring
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Am. Chem. Soc., 2008, 130, 17258.
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Liebeskind, W. T. Pennington, Organometallics, 1990, 9, 2194. (b) M. A. Huffman, L. S.
Liebeskind, W. T. Pennington, Organometallics, 1992, 11, 255.
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Frongia, J. Ollivier, P. P. Piras, Synthesis, 2014, 46, 1. For selected examples of synthesis of 1‐
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12. For a recent review on Pauson‐Khand reaction, see: T. Shibata, Adv. Synth. Catal., 2006, 348.
2328.
13. For a recent review on Nazarov cyclization, see: D. R. Wenz, J. R. de Alaniz, Eur. J. Org. Chem.,
2014, 23.
14. For reviews on synthesis of cyclobutenones and benzocyclobutenones, see: refs 3a and 6a. For a
recent example of synthesis of benzocyclobutenones via [2+2] with ketene silyl acetals and
benzyne, see: P.‐H. Chen, N. A. Savage, G. Dong, Tetrahedron, 2014, 70, 4135.
15. For a kinetic study on the effect of bite angle on reductive elimination, see: J. E. Marcone, K. G.
Moloy, J. Am. Chem. Soc., 1998, 120, 8527.
16. For substrate 1m, the ring‐opening byproduct 2m’ ((E)‐2‐styrylbenzaldehyde) was isolated in
48% yield. For a discussion of the side reactions, see Scheme 2.
17. The exact reason why [(COD)Rh(OH)]2 and [(COD)Rh(OMe)]2 are superior for ring expansion of
simple cyclobutenones is unclear. These two catalysts were also found to be effective as the
[Rh(COD)Cl]2 for the ring expansion of benzocyclobutenones. Cyclobutanone derivatives failed
to give the ring‐expansion product under the current conditions; work on this topic is still
ongoing.
18. For an example of olefin migration of 3,4‐disubstituted cyclobutenones to give the more
substituted isomers, see: R. L. Danheiser, S. Savariar, Tetrahedron Lett., 1987, 28, 3299.
19. Attempts to increase the enantioselectivity using (R)‐MeO‐biphep ligand resulted in a similar
yield but 41% ee. Use of chiral phosphoramidite ligands did not afford any desired product.
20. For a related procedure, see: Y. Ji, X. Verdaguer, A. Riera, Chem. Eur. J., 2011, 17, 3942.
21. For a recent review on picenes as organic transistor material, see: Y. Kubozono, X. He, S. Hamao,
K. Teranishi, H. Goto, R. Eguchi, T. Kambe, S. Gohda, Y. Nishihara, Eur. J. Inorg. Chem., 2014,
3806.
22. For an essay on the deuterium kinetic isotope effects, see: E. M. Simmons, J. F. Hartwig, Angew.
Chem. Int. Ed., 2012, 51, 3066.
23. For recent examples of synthetic methods involving a decarbonylation/β‐hydride elimination
pathway, see: (a) X. Tao, N. A. Savage, G. Dong, Angew. Chem. Int. Ed., 2014, 53, 1891. (b) S. K.
Murphy, J.‐W. Park, F. A. Cruz, V. Dong, Science, 2015, 2, 56.
24. The direct intramolecular hydroacylation with aldehyde substrates containing a trans‐stilbene‐
like olefin, e.g. 6 or 2m’, remains unreported.
25. For selected examples, see: (a) M. P. Cava, R. J. Spangler, J. Am. Chem. Soc., 1967, 89, 4550 . (b)
P. Schiess, M. Eberle, M. Huys‐Francotte, J. Wirz, Tetrahedron Lett., 1984, 25, 2201.
11