Chemo- and Regioselective Catalyst-Controlled Carbocyclization of Alkynyl Ketones: Rapid Synthesis of 1-Indanones and 1-Naphthols

Article abstract of DOI:10.1002/chem.201901860

A catalyst-controlled intramolecular carbocyclization of 2-alkynyl aryl ketones is presented. Under rhodium(III) catalysis, 1-indanones are formed through 5-exo-dig carbocyclizations with exclusive chemo-, regio- and stereoselectivity. When catalyzed by copper(I), 1-naphthols are obtained through 6-endo-dig carbocyclizations with exclusive chemo- and regioselectivity.

Full text of DOI:10.1002/chem.201901860

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Accepted Article
Title: Chemo- and Regioselective Catalyst-Controlled Carbocyclization
of Alkynyl Ketones: Rapid Synthesis of 1-Indanones and 1-
Naphthols
Authors: Erik Van der Eycken, Liangliang Song, and Guilong Tian
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To be cited as: Chem. Eur. J. 10.1002/chem.201901860
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Chemo- and Regioselective Catalyst-Controlled Carbocyclization
of Alkynyl Ketones: Rapid Synthesis of 1-Indanones and 1-
Naphthols
Liangliang Song,[a] Guilong Tian[a] and Erik V. Van der Eycken*[a][b]
Abstract: A catalyst-controlled intramolecular carbocyclization of 2-
alkynylarylketones is developed. Under rhodium(III) catalysis, 1-
indanones are formed through 5-exo-dig carbocyclization in exclusive
chemo-, regio- and stereoselectivity. When catalyzed by copper(I), 1-
naphthols are delivered via 6-endo-dig carbocyclization in exclusive
chemo- and regioselectivty.
enone derivatives through 5-exo-dig carbocyclization (Scheme
1b). However, the substrate scope is mainly focused on 1,3-
dicarbonyl compounds.[8] To date, only one approach has been
reported for the intramolecular 5-exo-dig carbocyclization of 2-
alkynylarylketones.[9a] In 2011, Gevorgyan and co-workers
successfully established the Pd-catalyzed regio- and
stereoselective
5-exo-dig
carbocyclization
of
2-
alkynylarylketones. It is also known that 2-alkynylarylketones
preferentially undergo 6-endo-dig carbocyclization to form the
useful naphthol (Scheme 1c). However, the substrate scope is
limited to 1,3-dicarbonyl compounds and silyl enol ethers.[10] In
comparison to 1,3-dicarbonyl compounds, it would be a challenge
to realize the catalyst-controlled 5-exo-dig and 6-endo-dig
carbocyclization selectivity of 2-alkynylarylketones with exclusive
chemo- and regioselectivity. Herein, we report a rhodium(III)-
catalyzed 5-exo-dig carbocyclization to synthesize 1-indanones
with exclusive chemo-, regio- and stereoselectivity, and a
copper(I)-catalyzed 6-endo-dig carbocyclization to produce 1-
naphthols with exclusive chemo- and regioselectivty (Scheme 1d).
Site-selective C(sp3-H) bond functionalization has remained as an
attractive and challenging topic in organic chemistry.[1] This
approach can avoid the employment of preformed organometallic
reagents for conventional cross-couplings, making the synthesis
easier and greener.[2] The α-olefination of ketones generally
requires strong base-promoted addition of potassium enolates or
silyl enol ethers to alkynes.[3] 1-Indanones are important
carbocyclic compounds and are present in lots of natural and
pharmaceutical products;[4] 1-Naphthols are essential organic
compounds that are employed in organic catalysts, organic
synthesis and in ligands for transition metal catalysts, and they
form the core of numerous natural products and
pharmaceuticals.[5]
In the past decades, 2-alkynylarylcarbonyl species have
widely been explored as versatile precursors for many important
targets with chemical and biomedical potential, because these
compounds have multiple reactive sites, allowing them to undergo
a variety of transformations, including nucleophilic additions and
Diels-Alder reactions.[6] Among the 2-alkynylarylcarbonyl
compounds, 2-alkynylarylketones have attracted great attention
from lots of organic chemists. The Lewis/Brønsted acid induced
intramolecular electrophilic cyclization of 2-alkynylarylketones
has been well established as a versatile synthetic method for a
variety of biological heterocycles and carbocycles.[7] However,
they mainly focus on oxocyclizations. Generally, 5-exo-dig
oxocyclization reactions of 2-alkynylarylketones are performed to
undergo nucleophilic additions from isobenzofuranium
intermediates
(Scheme
1a).
Alternately,
the
similar
isobenzopyrylium intermediate derived from 2-alkynylarylketones
reacts with alkene or alkyne to achieve [4+2] cycloaddition via 6-
endo-dig oxocyclization (Scheme 1a).
Besides the two major reaction pathways, the intramolecular
ketone-alkyne cyclization shows a promising approach to access
Scheme 1. Previous work and this approach.
The investigation commenced by using 2-alkynylarylketone
1a as a model substrate to optimize the reaction conditions. As
revealed by the results in Table 1, treatment of 1a with
[RhCp*Cl2]2 (5 mol%) and CsOAc (2 equiv) in DCE at 120 °C
enabled the exclusive 5-exo-dig carbocyclization of 1a, giving
indanone 2a in 91% yield, as a single chemo-, regio- and
stereoisomer with E-geometry of the double bond (Table 1, entry
1). Screening of various solvents, such as t-AmOH, 1,4-dioxane
and toluene, assured that DCE was the most efficient (Table 1,
[a]
[b]
L. Song, G. Tian, Prof. Dr. E. V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001,
Leuven, Belgium.
E-mail: erik.vandereycken@kuleuven.be
Prof. Dr. E. V. Van der Eycken
Peoples' Friendship University of Russia (RUDN University), 6
Miklukho-Maklaya street, Moscow, 117198, Russia.
Supporting information for this article is given via a link at the end
of the document.
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10.1002/chem.201901860
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entries 2-4). Without CsOAc, the reaction did not work (Table 1,
entry 5). We also evaluated the performance of Pd(OAc)2,
resulting in complete decomposition of 1a (Table 1, entry 6).
However, switching to AgOTf as catalyst and 1,4-dioxane as
solvent enabled the exclusive 6-endo-dig carbocyclization of 1a,
giving naphthol 3a in 30% yield, as a single compound (Table 1,
entry 7). IPrAuNTf2 and CuI support the cyclization in a higher
yield (Table 1, entries 8-9). CuCl delivered 3a in 51% yield (Table
1, entry 10). When increasing the loading of CuCl to 20 mol%, 3a
was obtained in 85% yield (Table 1, entry 11). Without CsOAc,
the reaction did not work (Table 1, entry 12).
starting material. Moreover, the phenyl group could be replaced
by thiophene, pyridine or cyclohexene, leading to the
corresponding naphthols 3i-k in 31-87% yield. Additionally,
substrates with various acetophenone moiety were well tolerated,
resulting in the corresponding naphthols 3l-o in 42-79% yield. The
propiophenone substrate reacted smoothly under AgOTf catalyst,
giving the corresponding indanone 3p (45%).
Table 2. Rhodium(III)-catalyzed 5-exo-dig carbocyclization[a][b]
With the optimal conditions in hand, various substrates were
studied to evaluate the scope of the rhodium(III)-catalyzed 5-exo-
dig carbocyclization to synthesize 1-indanones (Table 2). The
reaction was applicable to 2-alkynylarylketones with various
electron-donating or electron-withdrawing groups at the para
position of the phenylethynyl moiety. The corresponding
indanones 2b-f were obtained in 82-93% yield. Reaction with
meta-Me- or ortho-OMe-substituted 2-alkynylarylketone also
smoothly proceeded to give the corresponding indanones with
87% (2g) and 76% (2h) yields respectively. Additionally, the
phenyl group could be replaced by thiophenyl, pyridyl or
cyclohexenyl, resulting in the corresponding indanones 2i-k in 34-
84% yield. Furthermore, substrates with a modified acetophenone
moiety were well tolerated, leading to the corresponding
indanones 2l-p in 47-90% yield. Notably, the propiophenone
substrate turned out to be compatible, offering the corresponding
indanone 2q (53%).
Table 1. Optimization of the carbocyclization conditions[a]
[a] 1 (0.3 mmol), [RhCp*Cl2]2 (0.015 mmol), CsOAc (0.6 mmol), DCE (1.0 mL).
[b] Isolated yield.
Table 3. Cu-catalyzed 6-endo-dig carbocyclization[a][b]
[a] Conditions: 1a (0.3 mmol), catalyst, CsOAc (0.6 mmol), solvent (1.0 mL).
[b] Isolated yield. [c] Without CsOAc.
We next focused on the scope of copper(I)-catalyzed 6-endo-
dig carbocyclization to produce 1-naphthols (Table 3). Substrates
with diverse electron-donating or electron-withdrawing groups at
the para position of the phenylethynyl moiety gave the
corresponding naphthols 3b-f in 65-92% yield. Reaction with
[a] 1 (0.3 mmol), CuCl (0.06 mmol), CsOAc (0.6 mmol), 1,4-dioxane (1.0 mL).
[b] Isolated yield. [c] AgOTf (20 mol%) instead of CuCl.
To explore the mechanism of this chemo- and regioselective
carbocyclization process, a series of experiments were performed
(Scheme 2). When silyl enol ether 4a was conducted under the
standard conditions for the rhodium(III)-catalyzed 5-exo-dig
meta-Me
2-alkynylarylketone
smoothly
afforded
the
corresponding naphthol in a yield of 82% (3g). However, the
ortho-OMe 2-alkynylarylketone led to recovery of most of the
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carbocyclization, 4a was recovered in 65% yield, while 2-
alkynylarylketone 1a and indanone 2a were obtained in yields of
10% and 12% respectively. Without CsOAc, 4a was recovered in
82% yield, and 1a was obtained in 7% yield, while there was no
2a formed, it is because there is no CsOAc to form reactive
Cp*Rh(OAc)2 from [Cp*RhCl2]2. These results suggest that two
pathways are involved in the construction of 2a from 1a and
enolate formation of 1a is only an intermediate of the minor
pathway. Then 4a was treated under standard conditions for the
copper(I)-catalyzed 6-endo-dig carbocyclization. After 2h, 4a was
recovered in 80% yield, 9% 1a was isolated. When the reaction
was performed under 12h, the starting material partially
decomposed, as only 17% of 4a was recovered, leading to the
formation of 25% 1a. Without CsOAc, 4a was recovered in 9%
yield, while 1a and TBS-protected naphthol 6a were obtained in
the yields of 11% and 72% respectively. These results indicate
that enolate formation of 1a is the key intermediate in the
construction of 3a from 1a.
produce alkenylrhodium(III) intermediate B (from path A), gives
product
2a.
For
the
copper(I)-catalyzed
6-endo-dig
carbocyclization, the coordination of CuI to the triple bond in
intermediate D gives intermediate F (path D). Subsequent
intramolecular 6-endo-dig carbocyclization produces intermediate
G, which undergoes protonation by acetic acid to produce 3a.
In summary, we have developed a catalyst-controlled
intramolecular carbocyclization of 2-alkynylarylketones. Under
rhodium(III)-catalyzed 5-exo-dig carbocyclization, 1-indanones
are obtained in an exclusive chemo-, regio- and stereoselective
manner. When employing copper(I)-catalyzed 6-endo-dig
carbocyclization, 1-naphthols are chemo- and regioselectively
produced.
Acknowledgements
Liangliang Song and Guilong Tian appreciate the China
Scholarship Council (CSC) for providing a doctoral scholarship.
We acknowledge the FWO [Fund for Scientific Research-
Flanders (Belgium)] for financial support. We acknowledge the
support of RUDN University Program 5-100.
Keywords: carbocyclization • C-H activation • rhodium • copper
• enolate
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Liangliang Song, Guilong Tian and Erik
V. Van der Eycken*
Page No. – Page No.
Chemo- and Regioselective Catalyst-
Controlled Carbocyclization of
Alkynyl Ketones: Rapid Synthesis of
1-Indanones and 1-Naphthols
A catalyst-controlled 5-exo-dig and 6-endo-dig carbocyclization of 2-alkynylarylketones for
rapid synthesis of 1-indanones and 1-naphthols is developed in exclusive chemo-,
regioselectivity.
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