Interrupted Carbonyl-Alkyne Metathesis

Article abstract of DOI:10.1002/adsc.201901358

Carbonyl-olefin metathesis and carbonyl-alkyne metathesis represent established reactivity modes between carbonyls, alkenes, and alkynes under Lewis and Br?nsted acid catalysis. Recently, an interrupted carbonyl-olefin metathesis reaction has been reporte

Full text of DOI:10.1002/adsc.201901358

Title: Interrupted Carbonyl-Alkyne Metathesis
Authors: Corinna Schindler, Austin McFarlin, Rebecca Watson, and
Troy Zehnder
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10.1002/adsc.201901358
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Interrupted Carbonyl-Alkyne Metathesis
Austin T. McFarlin, Rebecca B. Watson, Troy E. Zehnder, and Corinna S. Schindler*
Willard Henry Dow Laboratory, Department of Chemistry, University of Michigan, 930 North University Avenue,
Ann Arbor, Michigan 48109, United States
Dedicated to Professor Eric N. Jacobsen on the occasion of his 60th birthday.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Carbonyl-olefin metathesis and carbonyl-alkyne
metathesis represent established reactivity modes between
carbonyls, alkenes, and alkynes under Lewis and Brønsted
acid catalysis. Recently, an interrupted carbonyl-olefin
metathesis reaction has been reported that results in
tetrahydrofluorenes via a distinct fragmentation of the
reactive intermediate. We herein report the development of
an analogous transformation interrupting the carbonyl-
alkyne metathesis reaction path resulting in dihydrofluorene
products relying on Lewis acidic superelectrophiles as active
catalytic species.
Keywords: carbonyl-alkyne metathesis; interrupted
carbonyl-alkyne metathesis; superelectrophile; Lewis acid
catalysis; Nazarov cyclization
Figure 1. Selected reactivity modes between carbonyls,
alkenes, and alkynes under Lewis and Brønsted acid
catalysis.
Ring-closing carbonyl-olefin metathesis between
ring-opening transitioning through a strained oxetene
carbonyl and olefin functional groups has emerged as
intermediate. We herein report that aryl ketones 4
a powerful strategy for carbon-carbon bond formation
bearing a pendant alkyne can also result in the forma-
(Fig. 1A).[1-5] Several Lewis acids have been identified
tion of dihydrofluorenes 6 when converted under
for their ability to catalyze this transformation,
catalytic amounts of Lewis acidic superelectrophile[14]
including FeCl3,[6] GaCl3,[7] I2,[8] trityl[9] and
(Fig. 1D). Based on our studies, we propose a reaction
tropylium[10] tetrafluoroborate salts, resulting in a
path that interrupts carbonyl-alkyne metathesis via a
variety of cyclopentenes, cyclohexenes, polyaromatic
distinct fragmentation of intermediate oxetenes to
hydrocarbons, and functionalized pyrrolines. Lewis
enable a subsequent Nazarov cyclization resulting in
acid-catalyzed carbonyl-olefin metathesis reactions
the dihydrofluorene products.
proceed via an initial [2+2]-cycloaddition to form
intermediate oxetanes and a subsequent retro [2+2]-
In initial efforts we investigated the conversion of
cycloaddition to result in the desired metathesis
alkyne 7 with catalytic amounts of FeCl3 and observed
products.[11] In comparison, under Brønsted acid
the formation of dihydrofluorene 8 as a new product in
catalysis this reaction path was shown to be interrupted
40% yield, albeit with near complete conversion of the
to result in the formation of tetrahydrofluorenes 3 (Fig.
starting material (entry 1, Table 1). Subsequent
1B).[12] Specifically, a distinct fragmentation of the
attempts focused on the evaluation of additional,
oxetane via intermediate benzylic carbocations
simple Lewis acids, however the results obtained
enabled an oxygen-atom-transfer step to ultimately
proved inferior and did not produce significant
yield the tricyclic products. Additionally, alkyne-
amounts of dihydrofluorene 8. We have recently
carbonyl metathesis relying on Lewis or Brønsted
shown that Lewis acidic superelectrophiles can
acids has been recognized as an efficient strategy to
function as potent catalysts for the activation of less
access substituted enones 5 from carbonyl and alkyne
reactive substrates in carbonyl-olefin metathesis
precursors 4 (Fig. 1C).[13] The reaction similarly relies
reactions.[15] Specifically, suitable silver salts can
on an initial [2+2]-cycloaddition and a subsequent
abstract halides X from neutral metal complexes MXn
1
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10.1002/adsc.201901358
Advanced Synthesis & Catalysis
Table 1. Reaction optimization relying on Lewis acid
superelectrophiles.
AgSbF6 provided dihydrofluorene 8 in an increased
yield of 61% (entry 2, Table 1). Subsequent
investigations focused on evaluating Lewis acids
varying in strength, including FeCl3, InCl3, GaCl3, and
ZnCl2, in combination with AgSbF6 as the silver salt
(entries 3-6, Table 1). The corresponding he-
terobimetallic ion pairs provided the desired
dihydrofluorene 8 in up to 62% yield. Importantly,
[GaCl2]+[SbF6]- resulting upon chloride abstraction
from GaCl3 was identified as the most promising
catalyst (entry 5, Table 1). Subsequent efforts focused
on varying the ratio of neutral metal salt, AgSbF6
(entries 7-9, Table 1). When heterobimetallic ion pair
[AlCl2]+ 2[SbF6]- was generated upon chloride
abstraction from AlCl3 with two equivalents of
AgSbF6, diminished yields of 8 were observed in 25%
(entry 7, Table 1). Nevertheless, [GaCl2]+ 2[SbF6]-
generated in situ proved superior and resulted in the
desired product in 70% yield (entry 8, Table 1).
Conversely, increased loadings of AgSbF6 (30 mol%)
together with 10 mol% GaCl3 were shown to be
inferior resulting in diminished yields of 42%.
Subsequently, we focused on the evaluation of
additional solvents and identified that electron-
deficient aromatic solvents resulted in increased yields
of dihydrofluorene 8 (entries 10-14, Table 1).
Ultimately, 10 mol% GaCl3 and 20 mol% AgSbF6 in
0.05 M trifluorotoluene at room temperature were
established as optimal, resulting in the formation of
dihydrofluorene 8 in 98% yield (entry 14, Table 1).
Importantly, converting aryl ketone 7 with either 20
mol% AgSbF6 or 10 mol% GaCl3 resulted in
diminished yields of 8 in 7% and 64%, respectively,
suggesting that both metal salts are required to form
the optimal catalyst (entries 15 and 16, Table 1). We
also considered the possibility that this
heterobimetallic ion pair could fragment in situ to
resulting in the formation of superelectrophilic
heterobimetallic ion pairs.[16] Based on these results,
we next evaluated various Lewis acid superelectro-
philes, obtained via chloride abstraction from neutral
Lewis acids, for their ability to catalyze the formation
of 8. Specifically, the ion pair [AlCl2]+[SbF6]-
generated from equimolar amounts of AlCl3 and
Table 2. Substrate Scope.
2
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10.1002/adsc.201901358
Advanced Synthesis & Catalysis
result in the formation of SbF5 as a strong Lewis acid
catalyst. However, when aryl ketone 7 was converted
with catalytic amounts of SbF5 under otherwise
optimal reaction conditions, the desired product was
generated in diminished yields of 62% (entry 17, Table
1).
The optimal reaction conditions identified proved
general for a variety of electronically and sterically
differentiated dihydrofluorenes (Table 2). Specifically,
the unsubstituted dihydrofluorene 9 was generated in
58% yield while bisester 8 was formed in 92% yield,
respectively, demonstrating that a Thorpe-Ingold
effect is beneficial for the transformation. Both
electron-rich and -poor aryl ketones were tolerated
under the optimized reaction conditions, providing
chloro-substituted product 10 in 62% overall yield and
methyl-substituted product 12 in 85% yield. Electron-
deficient substituents on the alkyne moiety were
tolerated and para-chlorinated dihydrofluorenes 11
and 14 were obtained in 59% and 91% yield,
respectively. Additionally, substitution on the carbon
backbone incorporating large aromatic moieties or
smaller aliphatic substituents was well tolerated
resulting in the formation of the desired dihydro-
fluorene products in up to 86% yield (13, 15, 16, Table
2).
The formation of dihydrofluorene 21 has been reported
by Miura and coworkers upon treatment of aryl ketone
18 with catalytic amounts of In(OTf)3 in trifluoro-
Figure 3. A. Conversion of aryl ketone 23 to
dihydrofluorene 9 in 58% yield. B. Revised mechanistic
hypothesis for the formation of dihydrofluorenes 31 via
interrupted carbonyl-alkyne metathesis.
toluene at elevated temperatures (Fig. 2A).[17] The
authors suggest a reaction path that relies on initial
metal enolate formation and subsequent addition into
the activated alkyne to result in the formation of an
intermediate vinylic carbocation. This carbocation is
trapped by the metal enolate to form cyclohexene 20
that upon final Friedel-Crafts arylation gives rise to
dihydrofluoroene 21. We hypothesized that an
alternate mechanistic scenario could rely on an initial
carbonyl-alkyne metathesis via oxetene 19 that upon
cycloreversion either results in the tetrasubstituted
alkene or its isomerized cyclohexene analog 20 (Fig.
2A). To investigate these mechanistic hypotheses, we
synthesized mechanistic probe molecule 22 as an
analog of the proposed intermediate 20 (Fig. 2B).
However, when 22 was converted under our optimal
reaction conditions relying on catalytic GaCl3 and
AgSbF6 or the conditions reported by Miura utilizing
catalytic amounts of In(OTf)3, the desired product 9
was not observed. Nevertheless, aryl ketone 23 was
shown to be a viable substrate under our optimal
reaction conditions resulting in the formation of
dihydrofluorene 9 in 58% yield (Fig. 3A). Based on
Figure 2. A. Proposed initial mechanistic hypothesis relying
on carbonyl-alkyne metathesis and Friedel-Crafts arylation.
B. Mechanistic probe 22 converted under optimal
conditions.
3
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10.1002/adsc.201901358
Advanced Synthesis & Catalysis
these results, we considered an alternate reaction path
that relies on distinct oxetene fragmentation and is
inspired by our previous insights obtained in
interrupted carbonyl-olefin metathesis reactions (Fig.
3B). Specifically, we propose an initial activation of
aryl ketone 25 with the Lewis acid superelectrophile to
result in Lewis acid-base complex 26. This complex
subsequently undergoes carbonyl-alkyne metathesis to
form oxetene 27 as a reactive intermediate. Rather than
undergoing a cycloreversion following established
carbonyl-alkyne metathesis, we hypothesize that
oxetene 27 can fragment to result in the formation of a
benzylic carbocation 28. This divergent fragmentation
interrupts the carbonyl-alkyne metathesis reaction
path to result in 28 as a distinct intermediate that can
undergo a subsequent Nazarov cyclization to yield the
tricyclic carbon core. Rearomatization of 29 results in
cyclohexene 30 which upon elimination of water
results in dihydrofluorene 31 and the regeneration of
the Lewis acid catalyst.
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functional groups to result in the formation of
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relies on Lewis acidic superelectrophiles as active
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substituted aryl ketones bearing pendant alkyne
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Experimental Section
A flame-dried flask was charged with 7 (0.17 mmol),
GaCl3 (0.017 mmol), AgSbF6 (0.034 mmol), and
trifluorotoluene (0.05 M) under a nitrogen atmosphere.
The resulting mixture was allowed to react at room
temperature for 24 hours. The reaction was
subsequently filtered through a plug of silica eluting
with DCM. The filtrate was concentrated under
reduced pressure to remove all volatile components.
The crude material was purified using column
chromatography to afford 61 mg (92% yield) of 8.
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Acknowledgements
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We thank the NIH/National Institute of General Medical Sciences
(R01-GM118644), the Alfred P. Sloan Foundation, the David and
Lucile Packard Foundation and the Camille and Henry Dreyfus
Foundation for financial support. R.B.W. thanks the National
Science Foundation for a predoctoral fellowship.
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10.1002/adsc.201901358
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201901358
Advanced Synthesis & Catalysis
COMMUNICATION
Interrupted Carbonyl-Alkyne Metathesis
Adv. Synth. Catal. Year, Volume, Page – Page
Austin T. McFarlin, Rebecca B. Watson, Troy E.
Zehnder, and Corinna S. Schindler*
6
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