Modular Cyclopentenone Synthesis through the Catalytic Molecular Shuffling of Unsaturated Acid Chlorides and Alkynes

Article abstract of DOI:10.1021/jacs.0c10832

We describe a general strategy for the intermolecular synthesis of polysubstituted cyclopentenones using palladium catalysis. Overall, this reaction is achieved via a molecular shuffling process involving an alkyne, an α,β-unsaturated acid chloride, which serves as both the alkene and carbon monoxide source, and a hydrosilane to create three new C-C bonds. This new carbon monoxide-free pathway delivers the products with excellent yields. Furthermore, the regioselectivity is complementary to conventional methods for cyclopentenone synthesis. In addition, a set of regio- and chemodivergent reactions are presented to emphasize the synthetic potential of this novel strategy.

Full text of DOI:10.1021/jacs.0c10832

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Modular Cyclopentenone Synthesis through the Catalytic Molecular
Shuffling of Unsaturated Acid Chlorides and Alkynes
Yong Ho Lee, Elliott H. Denton, and Bill Morandi*
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ABSTRACT: We describe a general strategy for the intermolecular synthesis of polysubstituted cyclopentenones using palladium
catalysis. Overall, this reaction is achieved via a molecular shuffling process involving an alkyne, an α,β-unsaturated acid chloride,
which serves as both the alkene and carbon monoxide source, and a hydrosilane to create three new C−C bonds. This new carbon
monoxide-free pathway delivers the products with excellent yields. Furthermore, the regioselectivity is complementary to
conventional methods for cyclopentenone synthesis. In addition, a set of regio- and chemodivergent reactions are presented to
emphasize the synthetic potential of this novel strategy.
Scheme 1. Context of the Work
he construction of multiple C−C bonds in a single
T
reaction allows for a dramatic increase in molecular
complexity.1,2 These reactions, when modular, allow for rapidly
generating libraries of complex molecules.3 As part of our
investigation into palladium-catalyzed carbofunctionalizations,
we recently reported such a modular process best described as
an intermolecular carboformylation of alkynes.4 A molecular
shuffling strategy was key to orchestrate a sequential bond
formation in a programmed order: (1) an aromatic acid
chloride was first deconstructed to its aryl, CO, and Cl
fragments by a Pd catalyst; (2) the individual fragments on the
Pd center were then merged via consecutive carbometalation
of an alkyne, CO reinsertion, and C−H reductive elimination,
to provide the carboformylated compounds with excellent
stereoselectivity.
We thus questioned whether this unique reactivity pattern
could be further utilized in the construction of cyclo-
pentenones.5,6 These highly functionalized motifs, commonly
found in natural products, bioactive compounds, and key
synthetic building blocks, are often accessed intramolecularly
via the Pauson−Khand reaction (PKR)7,8 or Nazarov
cyclization.9,10 This strategy can be useful but often results in
an inherent lack of flexibility given the need for the synthesis of
the intermediate over several steps, undermining its potential.
By contrast, the intermolecular PKR enables chemists to
envision a simple one-step synthesis of the cyclopentenones,
yet the feasibility is traditionally limited (Scheme 1a, left).11,12
Specific challenges are (1) alkenes show low reactivity; (2)
unreliable control of regioselectivity with respect to the alkene
component, and (3) the requirement of excess hazardous
chemicals (e.g., pressurized CO gas or stoichiometric cobalt−
carbonyl complexes). While several creative solutions have
been demonstrated to overcome specific challenges, such as
the alkene scope being improved by the preinstallation of a
cleavable directing group13,14 and the use of CO surrogates15
and less toxic metal catalysts/reagents,16,17 these developments
have not yet provided a general solution. Instead, approaches
that are mechanistically distinct from the PKR introduce
Received: October 13, 2020
https://dx.doi.org/10.1021/jacs.0c10832
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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paradigms that are often complementary in nature. One such
example is the development of cyclization reactions of
unsaturated carbonyl compounds and alkynes to generate
cyclopentenones using Co/Rh and Ni catalysts, respectively
(Scheme 1a, right).18,19
reaction. Presumably, this decreased reactivity is due to
hampered alkenyl coordination to the Pd species, which is
required for the intramolecular cyclization.23
The yield of the desired product increased proportionally to
the steric bulk of the trialkylsilane (Table 1, entry 5, and see
SI). An inexpensive bulky silane, triisopropylsilane (iPr3SiH),
proved optimal. Alternative hydride sources, such as formate
salts, failed to deliver the product (Table 1, entry 6). We
performed an experiment using 1a as a limiting reagent, as well
as a separate experiment using equimolar amounts of all
reagents, to demonstrate the reaction’s efficiency. Both
reactions afforded 3a in good yields of 84% and 78%,
respectively (Table 1, entries 7 and 8). This result highlights
the high efficiency with respect to the CO surrogate.24 The
catalyst system was found to be highly active, with lower
catalyst loadings of 1.0, 0.5, and 0.2 mol % giving the desired
product in 95%, 82%, and 53% yield, respectively (see SI). In
the absence of either the ligand or Pd precatalyst, the
formation of 3a was not observed (Table 1, entry 9). Other
transition metal catalysts such as Ni(cod)2, Co2(CO)8,
[Rh(cod)Cl]2, or [Ir(cod)Cl]2 did not afford 3a (Table 1,
entry 11, and see SI for details).
We hypothesized that we could utilize the previously
described carboformylation process as a distinct manifold for
the intermolecular creation of carbocycles with a unique
substitution pattern (Scheme 1b).20,21 Specifically, we
questioned if a proposed key intermediate of the carboformy-
lation reaction, I, could be diverted to undergo an intra-
molecular cyclization. Such a framework for cyclopentenone
synthesis could, in principle, offer several complementary
features when compared to the state-of-the-art: (1) an
alternative de novo reaction design where a wide range of
alkene substrates can be tolerated; (2) safe and practical
application due to the absence of pressurized CO as a reagent;
(3) facile creation of a quaternary carbon center at the 5-
position, a rare substitution pattern. Herein, we report the
successful realization of an intermolecular PK-type reaction of
internal alkynes using an α,β-unsaturated acid chloride as an
alkenyl and CO source (Scheme 1c).
We next explored the substrate scope of this transformation
(Table 2). β-Dialkyl, β-diarylsubstituted and β-monosubsti-
tuted enoyl chlorides are well tolerated, giving a single
regioisomer in each instance. We were able to confirm the
structure of compound 3e by X-ray crystallography. Notably,
we could construct a variety of challenging quaternary carbon
centers demonstrated by several novel examples (3b−3f),
including spirocycles. Previously, this rare substitution pattern
has only ever been formed in Pauson−Khand cycloaddition
reactions as a minor regioisomer with highly strained
alkenes.25,26 Sterically hindered β-aryl enoyl chlorides (3k−
3o) provided excellent yields, while other aryl-substituted acid
chlorides resulted in moderate to good yields, regardless of
electronic properties. A large variety of functional groups
including ethers (3b, 3l, 3q, 3r, 3ac), alkenes (3d), carbamates
(3f), nitriles (3z, 3an), esters (3m, 3w), aldehydes (3x),
sulfones (3y), halogens (F: 3u, 3ad, 3af, Cl: 3o, 3s, Br: 3t, and
even I: 3ab), and nitro groups (3aa) were compatible under
the reaction conditions. It is noteworthy that the reductively
labile groups (e.g., esters, halides) survived the reductive
reaction conditions. Acid chlorides bearing heterocycles such
as thiophenes (3ah, 3aj) and furans (3ag, 3ai) are also effective
reaction partners.
As a model reaction for our initial investigations, an α,β-
unsaturated acid chloride (1a) and an alkyne (2a) were
combined with a Pd precatalyst and a range of phosphine
ligands that have been shown to mediate the reversible
decarbonylation of acid chlorides.4,22 Gratifyingly, we identi-
fied several suitable phosphine ligands for this reaction.
Importantly, the carboformylation product was not observed
to any detectable extent, effectively validating our hypothesis
that the carboformylation process can indeed be interrupted to
deliver cyclopentenones (see SI). A systematic investigation
led to the best yields of 3a being obtained with an electron-
deficient monophosphine ligand, MP1 (Table 1 and see SI).
While triarylphosphines other than MP1 resulted in moderated
yields of 3a, the results show a dependence on both the ratio of
P to Pd and the electronics of the phosphine ligands (Table 1
and see SI). An increased P to Pd ratio, particularly with more
basic or sterically less hindered phosphines, impeded the
Table 1. Reaction Optimization
Conveniently, the reaction can be performed directly from
the α,β-unsaturated carboxylic acid, when combined with
Ghosez’s reagent, for in situ formation of the acid chloride (3d,
3f, 3x).27 In this manner, geranic acid was smoothly converted
to the corresponding cyclopentenone (3d).
a
entry
variations from above conditions
3a (%)
1
2
3
4
5
6
7
8
none
99
79
37
68
30
<3
84
78
n.d.
8
Remarkably, acryloyl chloride could be used as both an
ethene and a CO surrogate (3ak), addressing a classical
limitation of the conventional PKRs.28 Further, the reaction
also works with both α-substituted and α,β-disubstituted enoyl
chlorides bearing methyl (3al), fluoro (3am),29 cyano (3an),
and phenyl (3ao) groups, to furnish a single diastereomer in
these cases bearing an additional β-substituent in moderate to
low yield. In the reaction of 2,3-diphenylacryloyl chloride, an
additional product (3ao-2) arising from isomerization of the
desired product was also observed. Likewise, the reaction with
sorbic acid chloride bearing a conjugated diene functionality
also resulted in isomerization of the distant alkene to give 3ar
(E/Z = 82:18, separable E/Z isomers).17d To further test
MP2 (5.0 mol %) instead of MP1
MP2 (10.0 mol %) instead of MP1
MP3 (5.0 mol %) instead of MP1
Et3SiH instead of iPr3SiH
HCO2M (M = K or Na) instead of iPr3SiH
1a/2a/iPr3SiH equivalent ratio = 1.0/1.5/1.0
1a/2a/iPr3SiH equivalent ratio = 1.0/1.0/1.0
no MP1 or no [Pd(allyl)Cl]2
Pd(PPh3)4 (5.0 mol %) instead of [Pd(allyl)Cl]2/MP1
Ni, Co, Rh, or Ir instead of [Pd(allyl)Cl]2
9
10
11
n.d.
a
The GC yields are based on the moles of a limiting reagent versus n-
dodecane, an internal standard.
B
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a
Table 2. Scope with Respect to α,β-Unsaturated Acid Chlorides
a
b
c
d
All yields are isolated as a single regioisomer unless stated otherwise. Open system, 50 mmol scale. iPr3SiD (1.5 equiv). The corresponding
e
carboxylic acid (1.5 equiv) and Ghosez’s reagent (1.5 equiv) instead of 1. 3-Hexyne (1.5 equiv) instead of 2a. For details, see SI.
C
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a
variation in the substitution pattern of the α,β-unsaturated acid
chloride, fully substituted systems were examined. 3-Methyl-
1H-indene-2-carbonyl chloride, a ring-fused tetrasubstituted
enoyl chloride, affords the desired tricyclic compound (3ap) as
a single diastereomer. When an acyclic tetrasubstituted enoyl
chloride was subjected to the reaction conditions, two isomers
(3aq-1 and 3aq-2) were produced, which may result from an
acyl Mizoroki−Heck-type coupling followed by β-H elimi-
nation.2,20 It is possible that the steric bulk installed into the
substrate prevents the desired product formation. From these
studies, it appears that the reaction is sensitive to steric
encumbrance at the α-position of the acid chloride,
presumably resulting from a less favorable carbometalation
step of the alkenyl-Pd species into an alkyne due to increased
steric bulk. Gratifyingly, the developed conditions were easily
translated to multigram scale (50 mmol) experiments,
affording compound 3a in 73% yield (7.1 g).
Table 3. Scope with Respect to Internal Alkynes
A set of functionalized dialkyl alkynes reacted efficiently
(Table 3). Additionally, a cyclic alkyne (3bc), diarylalkyne
(3bf), and even a bis-trimethylsilyl alkyne (3bg) all undergo
the reaction in moderate to excellent yields. The reaction is
compatible with alkyl-silyl (3bk−3bp) and aryl-silyl (3bh)
alkynes, furnishing the corresponding products with excellent
regioselectivity, offering a versatile functional handle for further
decoration.30 It is worth noting that the extremely bulky
triisopropylsilyl group (3bp) is also tolerated, without any
erosion of regioselectivity. Additionally, several functionalities
appended to the alkyne, such as alkyl chlorides (3bb),
phthalimides (3bu), esters (3bv−3bx, 3cb), carbamates
(3cc), silyl ethers (3bo), and S- and N-heteroaryl groups
(3bz and 3ca), were well tolerated. While negligible
regioselectivity was observed for unsymmetrical aryl-alkyl
(3bi, 3bj) and alkyl-alkyl (3bq−3bv) alkynes, a modest
improvement resulted from using a sterically differentiated
unsymmetrical alkyne (3bt), with a preference for alkenyl
insertion at the more sterically encumbered position,
presumably to minimize steric repulsion during carbopallada-
tion. However, a polar functionality installed at the β-position
relative to the alkyne (3bw−3cc) leads to a slight preference
for the opposite regioisomer, resulting in the directing group
tether being situated at the 2-position of the corresponding
cyclopentenone. Terminal alkynes did not provide the
corresponding cyclopentenones, while conversion of the alkyne
was observed, suggesting other processes such as polyaddition
are operative.
a
All yields are isolated as a single regioisomer unless otherwise stated.
Isolated as an inseparable mixture of regioisomers. For details, see SI.
b
Four interesting products can in theory be obtained from the
combination of our three starting materials and reagents. While
3a was the only observed product under the standard reaction
conditions (see SI), it was found that, in the absence of a
phosphine ligand, its regioisomer (4a), from a formal reductive
[3 + 2] cyclization, is formed,19,20c demonstrating ligand-
controlled regioselectivity (Scheme 2a).31 The modulated
reactivity of the system in the presence of a phosphine ligand is
thus crucial to allow the proposed fundamental steps of the
reaction to occur in the right sequence. Further, Rh(I), a
popular catalyst for carbonylation chemistry, showed a distinct
reactivity with α,β-unsaturated acid chlorides, forming the
hydroacylated product (5a) stereoselectively with an unopti-
mized yield of 59%.32 Thus, this metal-based chemodivergence
can also lead to useful substrates for subsequent Nazarov-type
reactions (Scheme 2a).9,10
decarbonylation of the acid chloride, resulting in the formation
of toluene (see SI).4,33 We thus hypothesized that this
compound could serve as a novel CO surrogate in carbon-
ylation reactions.15,22g,24 Intriguingly, a four-component
coupling was achieved when phenylacetyl chloride, acting as
a CO equivalent, was coupled with a vinyl iodide, acting as an
alkene partner, to deliver the cyclopentenone product (3as) in
moderate yield with excellent regioselectivity (Scheme 2b).20,34
Other vinyl (pseudo)halides required harsher reaction
conditions and/or an exogenous chloride source to increase
their conversion (3at and 3au). This unique reactivity
demonstrates that a variety of vinyl (pseudo)halides can also
be used in a four-component coupling to deliver the desired
cyclopentenone products.
Interestingly, the use of an aryl stannane as a carbon
nucleophile, in place of the hydride nucleophile, led to the
pentasubstituted product (3av) in 58% yield.35 This is another
During our studies, we found that subjecting phenylacetyl
chloride to the reaction conditions resulted in reductive
D
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a
Scheme 2. Synthetic Applications
Crystallographic data (CCDC 2045252, compound 3v)
(CIF)
Crystallographic data (CCDC 2035179, compound 3bu-
1, major) (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Bill Morandi − ETH Zürich, 8093 Zürich, Switzerland;
orcid.org/0000-0003-3968-1424; Email: bill.morandi@
org.chem.ethz.ch
Authors
Yong Ho Lee − ETH Zürich, 8093 Zürich, Switzerland;
orcid.org/0000-0002-9768-7560
Elliott H. Denton − ETH Zürich, 8093 Zürich, Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10832
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The financial support by the European Research Council
under the European Union’s Horizon 2020 research and
innovation program (Shuttle Cat, Project ID: 757608), the
ETH Zu
acknowledged. We thank the NMR, MS (MoBiAS), and X-ray
(SMoCC) service departments at ETH Zurich for technical
̈
rich, and LG Chem (fellowship to Y.H.L.) is gratefully
̈
assistance. We are also grateful to Prof. E. M. Carreira for
sharing chiral GC and M. Isomura and V. Gerken for technical
help.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10832.
■
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Experimental details for all reactions and analytic details
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Crystallographic data (CCDC 2035178, compound 3e)
(CIF)
Crystallographic data (CCDC 2045251, compound 3l)
(CIF)
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