GaCl3-Catalyzed Ring-Opening Carbonyl-Olefin Metathesis

Article abstract of DOI:10.1021/acs.orglett.8b02086

The development of a Lewis acid-catalyzed ring-opening cross-metathesis reaction which enables selective access to acyclic, unsaturated ketones as the carbonyl-olefin metathesis products is described. While catalytic amounts of FeCl₃ were previously identified as optimal to catalyze ring-closing metathesis reactions, the complementary ring-opening metathesis between cyclic alkenes and carbonyl functionalities relies on GaCl₃ as the superior Lewis acid catalyst.

Full text of DOI:10.1021/acs.orglett.8b02086

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
GaCl3‑Catalyzed Ring-Opening Carbonyl−Olefin Metathesis
Haley Albright, Hannah L. Vonesh, Marc R. Becker, Brandon W. Alexander, Jacob R. Ludwig,
Ren A. Wiscons, and Corinna S. Schindler*
Department of Chemistry, Willard Henry Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor,
Michigan 48109, United States
S
* Supporting Information
ABSTRACT: The development of a Lewis acid-catalyzed
ring-opening cross-metathesis reaction which enables selective
access to acyclic, unsaturated ketones as the carbonyl−olefin
metathesis products is described. While catalytic amounts of
FeCl3 were previously identified as optimal to catalyze ring-
closing metathesis reactions, the complementary ring-opening
metathesis between cyclic alkenes and carbonyl functionalities relies on GaCl3 as the superior Lewis acid catalyst.
Table 1. Reaction Optimization for Catalytic Carbonyl−
he metathesis reaction between two alkenes is among the
most powerful catalytic strategies for carbon−carbon bond
a
Olefin Ring-Opening Metathesis
T
formation to enable synthetic access to functionalized olefins.1
One important variation of the olefin metathesis reaction is ring-
opening cross-metathesis (ROCM) during which a cyclic alkene
undergoes ring-opening and subsequent cross-metathesis with
another alkene to form more structurally complex olefins,
including symmetrically capped (3) and end-differentiated (4)
products (Figure 1A).2,3 Carbonyl−olefin metathesis reactions
between olefin and carbonyl functionalities similarly enable the
construction of carbon−carbon bonds to access functionalized
olefins.4,5 However, despite important progress, the currently
available procedures for carbonyl−olefin metathesis remain
significantly less advanced.6,7 Lewis acid-catalyzed approaches
have been recently developed as viable synthetic alternatives to
entry Lewis acid cat. loading (mol %) solvent conc (M) yield (%)
1
2
3
4
5
6
7
8
AlCl3
BF3·OEt2
TiCl4
FeBr3
InCl3
FeCl3
FeCl3
FeCl3
FeCl3
GaCl3
GaCl3
GaCl3
GaCl3
GaCl3
Fe(OTf)3
Sc(OTf)3
HCl
10
10
10
10
10
10
5
20
10
10
5
20
10
10
10
10
10
10
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.01
0.1
0.1
0.1
0.01
0.5
0.1
0.1
0.1
0.1
0
2
0
0
25
33
11
27
11
47
34
20
8
34
4
13
0
9
10
11
12
13
14
15
16
17
18
TfOH
2
a
Conditions: all reactions were performed with 0.4 mmol of
benzaldehyde and 0.1 mmol of 1-methylcyclopentene in 1,2-
dichloroethane (DCE; 0.1 M, 1 mL) at 25 °C for 24 h. Yields were
determined by GC analysis.
existing strategies for carbonyl−olefin metathesis.8,9 For
example, upon reaction with catalytic amounts of FeCl3, aryl
ketone substrates can undergo an intramolecular [2 + 2]-
cycloaddition to form intermediate oxetanes which subse-
quently fragment in a retro [2 + 2]-cycloaddition to form the
Figure 1. Ring-opening olefin−olefin metathesis and carbonyl−olefin
metathesis reactions.
Received: July 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02086
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Table 2. Ring Strain of Cyclic Alkenes
a
b
Ring-strain energy (kcal/mol).11 Conditions: all reactions were
performed with 4.0 equiv of 11 and 1.0 equiv of olefin substrates with
10 mol % of GaCl3 in DCE (0.1 M) at 25 °C for 24 h.
desired carbonyl−olefin ring-closing metathesis products.
Additionally, examples of intermolecular carbonyl−olefin
cross-metathesis and ring-opening metathesis reactions have
recently been reported to rely on carbocations as catalysts, albeit
resulting in lower overall yields of the isolated products.10 Our
studies toward a Lewis acid-catalyzed carbonyl−olefin ring-
opening metathesis show similar observations of the desired
products forming in ∼50% yield, as initially attributed to the
formation of regioisomeric oxetane intermediates 7 and 8 and
subsequent decomposition of the aldehyde metathesis product
10 (Figure 1B). We herein report insight into the controlling
features of this transformation with a specific emphasis on
substrate scope and competing reaction pathways.
To develop a catalytic carbonyl−olefin ring-opening meta-
thesis reaction, we focused on aryl aldehydes 5 and substituted
cyclopentenes 6 as the substrates. We envisioned cyclopentenes
6 as ideal substrates for reaction optimization as the inherent
ring strain of the proposed [3.2.0] intermediate oxetane bicycle
was expected to facilitate the fragmentation to metathesis
products. Additionally, the electronic characteristics of 1-
substituted cyclopentenes were expected to favor the formation
of oxetane 7 and, therefore, ketone 9 as the major metathesis
product. Initial efforts centered on the evaluation of distinct
Lewis acids varying in strength in the carbonyl−olefin
metathesis reaction of benzaldehyde 11 with 1-methylcyclo-
pentene 12 (Table 1). Strong Lewis acids such as AlCl3 or BF3·
Figure 3. NMR fragmentation studies of oxetanes 40 and 41.
OEt2 did not prove efficient in promoting the desired carbonyl−
olefin ring-opening metathesis (entries 1 and 2, Table 1).
Similarly, TiCl4 and FeBr3 were inefficient catalysts in this
transformation (entries 3 and 4, Table 1). However, promising
results were obtained with catalytic amounts of InCl3 as the
Lewis acid resulting in the formation of ketone 13 as the
exclusive metathesis product in 25% yield (entry 5). Increased
yields of alkyl ketone 13 in 33% were observed with 10 mol % of
FeCl3 (entry 6, Table 1), while alternate FeCl3 loadings as well as
running the reaction at lower concentrations did not result in
increased yields of 13 (entries 7−9, Table 1). Subsequent efforts
identified GaCl3 as the superior Lewis acid catalyst for
carbonyl−olefin ring-opening metathesis resulting in the
formation of the alkyl ketone 13 in 47% yield (entry 10, Table
1). Varied catalyst loadings of 5% or 20% resulted in diminished
Figure 2. Evaluation of the substrate scope of GaCl3-catalyzed carbonyl−olefin ring-opening metathesis.
B
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Figure 4. Fragmentation studies of oxetane exo-41.
Figure 6. Carbonyl−ene reaction pathway is competing in catalytic
carbonyl−olefin ring-opening metathesis reactions.
a variety of substituted, cyclic alkenes with benzaldehyde and
GaCl3 as the Lewis acid catalyst (Table 2). Interestingly, yields
obtained in the carbonyl−olefin ring-opening metathesis do not
correlate to the inherent ring strain of the cyclic alkenes as
cycloheptane 17 and cyclooctene 18 with a ring strain of 6.3 and
7.4 kcal/mol, respectively, result in no formation of the desired
product, while cyclohexene 16 with a lower ring strain of 1.7
kcal/mol forms the corresponding metathesis product, albeit in
a low yield of 18% (Table 2). Next, we evaluated additional
aldehydes and cyclic alkenes upon their ability to undergo the
desired carbonyl−olefin ring-opening metathesis (Figure 2). A
variety of electronically and sterically differentiated aromatic
aldehydes proved viable under the reaction conditions and
resulted in up to 47% of the metathesis product (19−36, Figure
2). Aliphatic aldehydes were not effective for the promotion of
metathesis. Importantly, the corresponding aliphatic ketones
were formed as the exclusive products, while no formation of
metathesis products 10 resulting upon fragmentation of
proposed regioisomeric oxetane 8 were observed. Distinct
substitution on the cyclopentene was tolerated (37 and 38,
Figure 2), while the corresponding 1-methylcyclohexene formed
39 in 18% yield.
Our subsequent efforts aimed at the elucidation of whether
the formation of a regiosiomeric mixture of oxetane
intermediates (7 and 8) and subsequent selective decom-
position of aldehyde 10 was responsible for a maximum of 50%
yield of the carbonyl−olefin metathesis product. As part of these
studies, we independently prepared a mixture of regioisomeric
Figure 5. NMR experiments of the GaCl3-catalyzed carbonyl−olefin
ring-opening metathesis reaction.
yields of 34% and 20%, respectively (entries 11 and 12, Table 1).
Similarly, other concentrations resulted in lower yields of the
desired metathesis product 13 (entries 13 and 14, Table 1).
Metal triflates such as Fe(OTf)3 or Sc(OTf)3 and Brønsted acids
were not effective in promoting the desired ring-opening
metathesis reaction, which is consistent with our previous
observations in Lewis acid-catalyzed carbonyl−olefin metathesis
(entries 15−18, Table 1). Importantly, alkyl ketone 13 was the
only metathesis product isolated for all of the catalysts evaluated,
while the corresponding aldehyde 10 was not observed.
oxetanes 40 and 41 via a Paterno−Bu
̈
chi reaction12 (Figure 3A).
We were able to enrich this mixture chromatographically to
contain predominantly oxetane 40 as the expected major
intermediate in carbonyl−olefin metathesis reactions of 11 and
12 (>5:1 ratio 40:41; Figure 3B).
The conversion of this enriched mixture of oxetane 40 under
the optimal conditions for carbonyl−olefin ring-opening
metathesis was subsequently monitored by NMR analysis
(Figure 3B). After 10 min, clean conversion to 13 as the single
olefinic product was isolated in 61% yield along with 7% yield of
benzaldehyde 11. Notably, no significant aldehyde signals were
We next investigated the effect of ring strain11 in the
carbonyl−olefin ring-opening metathesis reaction by converting
C
DOI: 10.1021/acs.orglett.8b02086
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observed in the NMR spectra from the aldehyde metathesis
product. In the ensuing experiments, we were able to obtain exo-
41 as a single regio- and stereoisomer and subject it to 10 mol %
of GaCl3 (Figure 4A) in NMR studies. Importantly, exo-41
corresponds to the minor oxetane regioisomer that could be
formed under carbonyl−olefin metathesis conditions of 11 and
12. However, no formation of aldehyde 42 was observed, and
the reaction resulted in complete decomposition of substrate.
To determine the stability of the anticipated carbonyl−olefin
metathesis products 13 and 42, we prepared both compounds
independently and subjected them to the optimized reaction
conditions (Figure 4B). While methyl ketone 13 proved stable
under the reaction conditions, aldehyde 42 underwent rapid
decomposition. Based on these results, we turned our attention
to in situ NMR experiments of GaCl3-catalyzed carbonyl−olefin
metathesis between 11 and 12 (Figure 5). Within 20 min, the
exclusive formation of one set of alkene signals is observed which
corresponds to methyl ketone 13 (blue, Figure 5B). However, a
new set of signals at 3.4 ppm also appeared which did not
correspond to ketone 13 (orange, Figure 5B). After 24 h, signals
corresponding to a second, unknown compound formed (gray,
Figure 5B). Importantly, no signals corresponding to oxetanes
40 or 41 were observed in the course of these NMR studies. Our
subsequent efforts were aimed at the isolation and identification
of both byproducts. Upon conducting the reaction on larger
scale, pure samples of both compounds were isolated. Byproduct
A formed immediately within 20 min as a competing compound
to the desired metathesis product 13 and was identified as
bicyclopentane 44, formed in 20% yield (Figure 6). The second
byproduct B, formed in 10% yield, was characterized as pyran
45. Importantly, both compounds are not formed in a carbonyl−
olefin metathesis reaction path and do not represent products
resulting from fragmentation of intermediate oxetanes 40 and 41
or decomposition of aldehyde 42. These results are consistent
with the regioselective formation of oxetane 40 as the exclusive
intermediate in catalytic carbonyl−olefin ring-opening meta-
thesis reactions. Furthermore, the formation of both bicyclo-
pentane 44 and pyran 45 is consistent with a competing
carbonyl−ene reaction path to result in diene 43 as a reactive
intermediate which subsequently undergoes addition with a
second equivalent of 1-methylcyclopentene 12 to form
bicyclopentane 44 or a second equivalent of benzaldehyde 11
to form pyran 45 (Figure 6).
Experimental procedures, crystal structure data and NMR
studies (PDF)
Accession Codes
CCDC 1849848 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: corinnas@umich.edu.
ORCID
Corinna S. Schindler: 0000-0003-4968-8013
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH/National Institute of General Medical
Sciences (R01-GM118644), the Alfred P. Sloan Foundation,
and the David and Lucile Packard Foundation for financial
support. H.A. and J.R.L. thank the National Science Foundation
for predoctoral fellowships. M.R.B. thanks the Rackham
Graduate School for an international student fellowship.
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02086.
D
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