Palladium-Catalyzed Cascade Carbonylation to α,β-Unsaturated Piperidones via Selective Cleavage of Carbon–Carbon Triple Bonds

Article abstract of DOI:10.1002/anie.202108120

A direct and selective synthesis of α,β-unsaturated piperidones by a new palladium-catalyzed cascade carbonylation is described. In the presented protocol, easily available propargylic alcohols react with aliphatic amines to provide a broad variety of interesting heterocycles. Key to the success of this transformation is a remarkable catalytic cleavage of the present carbon–carbon triple bond by using a specific catalyst with 2-diphenylphosphinopyridine as ligand and appropriate reaction conditions. Mechanistic studies and control experiments revealed branched unsaturated acid 11 as crucial intermediate.

Full text of DOI:10.1002/anie.202108120

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Accepted Article
Title: Palladium-catalyzed cascade carbonylation to α,β-unsaturated
piperidones via selective cleavage of carbon-carbon triple bonds
Authors: Yao Ge, Fei Ye, Ji Yang, Anke Spannenberg, Haijun Jiao,
Ralf Jackstell, and Matthias Beller
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10.1002/anie.202108120
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RESEARCH ARTICLE
Palladium-catalyzed cascade carbonylation to α,β-unsaturated
piperidones via selective cleavage of carbon-carbon triple bonds
Yao Ge, Fei Ye, Ji Yang, Anke Spannenberg, Haijun Jiao, Ralf Jackstell,* and Matthias Beller*
Dr. Y. Ge, Dr. F. Ye, Dr. J. Yang, Dr. H. Jiao, Dr. R. Jackstell, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e. V.
Albert-Einstein-Straße 29a,18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Dr. F. Ye
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Key Laboratory of Organosilicon Material Technology of
Zhejiang Province, Hangzhou Normal University. No. 2318, Yuhangtang Road, 311121, Hangzhou (P. R. China)
Supporting information for this article is given via a link at the end of the document.
Abstract: A direct and selective synthesis of α,β-unsaturated
piperidones by a new palladium-catalyzed cascade carbonylation is
described. In the presented protocol, easily available propargylic
alcohols react with aliphatic amines to provide a broad variety of
interesting heterocycles. Key to the success of this transformation is
a remarkable catalytic cleavage of the present carbon-carbon triple
bond by using a specific catalyst with 2-diphenylphosphinopyridine as
ligand and appropriate reaction conditions. Mechanistic studies and
control experiments revealed branched unsaturated acid 11 as crucial
intermediate.
extensively investigated and applied in academia and industry for
several decades.[10] In this respect, aminocarbonylation allows for
atom-economic and convenient way to construct α,β-unsaturated
piperidones. However, only few intramolecular amino-
carbonylation reactions were reported, which exclusively worked
for specific substrates and suffered from poor yields.[11]
Introduction
Compared with carbon-carbon bond forming processes, the
corresponding selective cleavage reactions are much less
developed. Hence, this area is still considered as one of the holy
grails in modern organic synthesis.[1] While significant progress
has been made in the past decades, specifically with C-C and
C=C bonds,[2,3] the cleavage of carbon-carbon triple bonds is rare
and remains a highly challenging subject[4] owing to the
extraordinarily large bond dissociation energy (>200 kcal/mol).[1m]
Apart from alkyne metathesis (Scheme 1a),[5] such
transformations need stoichiometric amounts of special
organometallic reagents, oxidants, etc.[6] Indeed, only few
catalytic methods are known which involve C≡C triple bond
scissions.[7] Remarkably, unlike these reported alkyne cleavage
reactions, here we present
a novel breaking/rearranging
annulation reaction of alkynols which offers a step- and atom-
economical route for the synthesis of α,β-unsaturated piperidones.
α,β-Unsaturated piperidones are part of many biologically
important compounds. Thus, they are commonly used as building
blocks of the preparation of natural compounds and to access
new bio-active molecules.[8] For example, Piperlongumine is a
natural product reported to selectively kill cancer cells over non-
malignant cells in vitro and in vivo.[8a] In addition, Oleraciamide D
showed cytotoxicity against SH-SY5Y cells,[8b] while aza-
Goniothalamin inhibited Ehrlich tumor growth (Scheme 1d).[8c]
Thus, several methodologies have been established towards their
synthesis in recent years.[9] Main approaches to this class of
compounds include C-H oxidation reactions[9a-c] and
intramolecular cyclization reactions (Scheme 1b).[9d-h] Despite
these significant advances, still limitations exist with respect to
substrate scope and the use stoichiometric amounts of oxidants
or additives.
Scheme 1. (a) Summary of the main catalytic methods for C≡C cleavage. (b)
Summary of the main currently available synthetic methods for α,β-unsaturated
piperidones. (c) This work. (d) Selected examples of biologically active
molecules.
Recently, we started to investigate the alkoxy- and
aminocarbonylation of propargylic alcohols.[12] During the course
of this work, we discovered that α,β-unsaturated piperidones can
be synthesized in a straightforward and general manner by a new
palladium-catalyzed cascade carbonylation of alkynols and
aliphatic amines through highly selective C≡C cleavage reaction
(Scheme 1c).
As one of the most important methods for producing value-
added carboxylic acid derivatives from unsaturated compounds,
transition-metal-catalyzed carbonylation reactions have been
1
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Results and Discussion
unsaturated amide 4 as main product. In the presence of
monophosphine ligands L5-L8 with different backbones and
chelating units, no conversion was observed. Surprisingly, using
the imidazole-based ligand L9, product 3aa was afforded in 40%
yield, together with lactone 5 as side product (11% yield). Clearly,
3aa cannot be formed by a traditional alkyne carbonylation-
cyclization sequence. Next, other monophosphine ligands L10-
L12 were tested and 3aa was obtained in similar yields (36-42%),
together with lactone 5 as major side product (5-15% yield).
Gratifyingly, diphenyl(2-pyridyl)-phosphine L13, which was
introduced by Drent et al [16], gave an improved yield of 3aa (60%).
By variation of critical reaction parameters (catalyst precursor,
acidic co-catalyst, temperature, pressure, etc.) in the presence of
L13, the yield of 3aa reached 78% at a low catalyst loading (0.2
mol% Pd) (see Supporting information, Tables S1-S5).
Model reaction and catalyst optimization. We started our
investigations using the carbonylation of 1-ethynyl-1-
cyclohexanol 1a with benzylamine 2a. Notably, this
transformation is intrinsically challenging: First of all, benzyl
amine and related aliphatic ones are generally not suitable for
these carbonylations due to the stronger basicity, which retards
the generation of the catalytically active palladium hydrides.[13]
Obviously, alkynol such as 1a is prone to produce many products
such as the corresponding branched or linear α,β-unsaturated
amides, lactones and acids. In Figure 1 and Scheme 2, selected
carbonylated products, which might originate from this benchmark
reaction are shown. To control the desired palladium-catalyzed
aminocarbonylation reaction, a highly selective catalyst system is
needed to balance the compatibility of reactant partners and the
speed of individual elementary steps.[14] In general, the choice of
ligand is crucial for controlling both selectivity and activity.[15] Thus,
we tested different mono- and bidentate phosphine ligands (4 or
2 mol%, respectively) in the carbonylation of 1a in the presence
of 1 mol% PdBr2, HFIP (solvent), 40 bar CO, and 120°C. For
comparison, no reaction occurred without ligand or palladium
present. Initially, some commonly used bisphosphine ligands L1-
L4 were evaluated. While DPEphos L1, bis(2-dicyclohexyl-
phosphinophenyl) ether L2, 1,2-bis((di-tert-butylphosphan-
yl)methyl)benzene L3 did not exhibit any catalytic activity, L4 with
2-pyridyl-tert-butylphosphino groups gave the linear ɑ,β,γ,δ-
Mechanistic investigations & catalytic cycle. To gain insights
into the reaction mechanism and the formation of the unexpected
product 3aa, several control experiments were conducted
(Scheme 2a-d). First, the carbonylation of 1-ethynylcyclohexene
9 (with or without 1 equiv. water) was examined under the
standard conditions. However, formation of 3aa was not observed,
showing the reaction did not proceed through the equilibrium of
alkynol 1a with 1-ethynylcyclohexene 9. Instead, 7 was obtained
in 33-60% yield (see Supporting information, Scheme S1).
Figure 1. Pd-catalyzed carbonylation of 1-ethynyl-1-cyclohexanol 1a with benzylamine 2a: Influence of phosphine ligands. Reaction conditions: 1a (0.5 mmol), 2a
(1.0 mmol), PdBr2 (1.0 mol%), bisphosphine ligand (2.0 mol%) or monophosphine ligand (4.0 mol%), CO (40 atm), HFIP (2.0 mL), 20 h at 120 oC. The yields of
products were determined by GC analysis with mesitylene as internal standard. [a] Pd(dba)2 (0.2 mol%), L13 (0.8 mol%), TfOH (10 mol%).
Using cyclohexylacetylene 10 under identical conditions failed to
the hydroxyl group in 1a. Next, all the possible compounds (4-8)
give any carbonylation product, demonstrating the crucial role of
generated in the novel carbonylation sequence were prepared
2
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10.1002/anie.202108120
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independently, isolated and examined to ascertain the
intermediates leading to the formation of 3aa. Astonishingly,
reaction of amides 4, 6, 7, 8 and lactone 5 with CO under standard
conditions provided in no case 3aa, thus excluding the possibility
that these compounds function as intermediates towards 3aa
(Scheme 2a).
As another attempt to identify key intermediates, the kinetic
progress of the reaction between alkynol 1a and benzylamine 2a
was examined under the optimal conditions. As shown in Scheme
2b, 1a was initially converted into 2-(cyclohex-1-en-1-yl)acrylic
acid 11. Then, 3aa was generated along with the consumption of
the reaction intermediate 11. Starting material 1a was fully
converted after 30 min and formation of the branched ɑ,β,γ,δ-
unsaturated acid 11 achieved a maximum yield of 70% after 20
min. In the following three hours, the yield of desired product 3aa
increased steadily, and reached 78% yield after 180 min. Notably,
the side-product lactone 5 started to be generated after 30 min
and kept in a small amount (8% yield).
occurs regioselectively at the less hindered position leading to
amino acid H. We hypothesize that H is highly reactive, which
gives the unsaturated β-lactam I upon cyclization. It should be
noted that the developed catalyst system could be crucial as the
ligand might facilitate this key step by acting as a proton shuttle.
Due to the ring-strain in the resulting 4-membered ring compound,
I is prone to relief the energy by isomerization to J. We assume
through a p-allyl-palladium intermediate K,[17] the more stable
ring expanded product 3aa is formed.
Substrate Scope. With optimized conditions established for the
model reaction, we examined the generality of the cascade
carbonylation process. Actually, this novel transformation is
observed with a variety of propargylic alcohols. As shown in Table
1a, diverse α,β-unsaturated piperidones can be conveniently
prepared in the presence of the optimal catalytic system. Simple
aliphatic and aromatic substituents (tert-butyl, phenyl) at the 4-
position of cyclohexyl group were well tolerated to furnish 3ba (dr
= 3/1) and 3ca (dr = 2.4/1) in good yields (51% and 53%,
respectively). An array of carbocyclic ring systems (five-, eight-,
and twelve-membered) reacted smoothly, providing the
corresponding α,β-unsaturated piperidones 3da-3fa in 58-82%
yields. Similarly, substrates 1g-1i containing heteroatoms
(oxygen, sulfur, nitrogen) were amenable to this approach, giving
rise to 3ga-3ia in 46-63% yields with an increased catalyst loading
(1 mol%). In addition, non-cyclic alkynols 1j-1m bearing different
alkyl and benzyl groups afforded the corresponding desired
products 3ja-3ma in 58-90% yields. When 3-methylhept-1-yn-3-
ol 1n was subjected to the optimized conditions, the
corresponding carbonylation product was obtained in 75% yield
with 1.5/1 regioselectivity (3n’a/3na). On the other hand, starting
from -alkyl-aryl-substituted alkynols 1o-1r, carbonylation
Next, control experiments were performed by using acid 11 as
starting material (Scheme 2c). At this point it should be noted that
acid 11 has not been isolated before and proved to be a highly
reactive
compound,
which
easily
underwent
oligo-
merization/polymerization; thus, only traces of 11 were detected
in the control reaction without benzylamine 2a. However, the
desired intermediate could be prepared in situ in 56% GC yield in
the presence of NH4BF4 at 60 °C. Finally, the target compound
α,β-unsaturated piperidone 3aa was produced in 35% yield after
addition of benzylamine 2a into the system and heating at 120 °C
at N2 atmosphere. This reaction sequence confirmed that acid 11
is indeed a reaction intermediate in the overall process.
To clarify the origin of the acyl group in piperidone 3aa, the
reaction was carried out under 4 atm 13CO atmosphere (Scheme
2d). Thus, 13C-labeled 3aa was synthesized smoothly in 68% yield, proceeded successfully and delivered 3oa-3ra in 25-74% yields.
which revealed that carbon monoxide forms the CO moiety of 3aa.
When deuterated alkynol 1a was tested under optimized
conditions, the D atom ended up on the carbon in a-position to the
nitrogen atom (Scheme 2e).
Next, we evaluated the general scope of this new three
component process with respect to the reactivity of alkylamines.
As shown in Table 1b, various benzylamines with electron-neutral,
electron-deficient, and electron-rich substituents proved to be
useful. Besides, substituents in para-, meta-, and ortho-position
of the phenyl ring had no significant influence on the catalysis.
Thus, 3ab-3ai were produced in 44-80% yields. In addition, other
primary alkylamines (2j-2m) including sterically crowded ones (2n,
2o) reacted smoothly and gave the corresponding piperidones
3aj-3ao in 30-67% yields. Notably, thienyl- and pyridyl-
substituted amines 2p, 2q were well tolerated, affording 3ap and
3aq in 51% and 38% yield, respectively. It is worth mentioning
that functionalized amine with nonprotected hydroxy group can be
transformed into the desired piperidone 3ar in 65% yield with
excellent selectivity.
Finally, selected alkylamines 2s-2u containing methoxy, allyl, and
homoallyl substituents reacted well to give the desired products
3s-3u in 34-77% yields, which provides easy access to diverse
α,β-unsaturated piperidone derivatives. To be noted,
Geranylamine 2v and (-)-cis-Myrtanylamine 2w led to the desired
products 3av and 3aw (dr = 1/1) in 81% and 51% yield
respectively, highlighting the substrate scope of this protocol.
Based on all these results and previous mechanistic studies of
Pd-catalyzed carbonylations,[15] we suggest the following
mechanism of this novel palladium-catalyzed cascade
carbonylation of alkynols (Scheme 3). Initially, the catalytic cycle
starts from the cationic palladium hydride species B, which is
generated from Pd0 phosphine complexes A after protonation in
the presence of acid. Subsequently, the carbon-carbon triple
bond of alkynol 1a coordinates to the metal center to form
complex C, followed by Pd-H insertion into the alkyne, which
affords the branched alkenyl-Pd intermediate D regioselectively.
The regioselectivity of this process is controlled by the 2-
pyridyldiphenylphosphine ligand. Then, Pd complex D transforms
into the corresponding acyl Pd species E through a facile CO
insertion process. After dehydration of hydroxy group and
hydrolysis with water as nucleophile, intermediate E leads to 2-
(cyclohex-1-en-1-yl)acrylic acid 11 and regenerates the palladium
hydride species B. After cycle I, the π-allyl-palladium intermediate
F is formed selectively by Pd-H insertion into the cyclic olefinic
bond of 11. This intermediate undergoes a fast equilibrium with
the corresponding σ-palladium complexes G. Next, amination
3
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10.1002/anie.202108120
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Scheme 2. Standard conditions: Pd(dba)2 (0.2 mol%), L13 (0.8 mol%), TfOH (10 mol%), HFIP (2.0 mL), CO (40 atm), 120 oC, 20 h. 1a or 4-10 (0.5 mmol),
benzylamine 2a (1.0 mmol). The yields of products were determined by crude 1H NMR analysis using dibromomethane as the internal standard. a) Control
experiments with 4-10. b) Kinetic monitoring of intermediates over time: The X-axis represents reaction time, and the Y-axis represents intermediate distribution. c)
Control experiments with 11. d) Reaction with labeled 13CO. e) Reaction with deuterated 1a [a] Pd(dba)2 (0.2 mol%), L13 (0.8 mol%), TfOH (10 mol%),1a (0.5
mmol), benzylamine 2a (1.0 mmol), H2O (0.5 mmol), HFIP (2.0 mL), CO (40 atm), 120 oC, 20 h.
Scheme 3. Proposed catalytic cycle
4
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Table 1. Pd-catalyzed carbonylation of alkynols 1a-r with amines 2a-w [a]
[a] Standard reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Pd(dba)2 (0.2 mol%), L13 (0.8 mol%), TfOH (10.0 mol%), CO (40 atm), HFIP (2.0 mL), 20 h at 120 oC.
Isolated yields were given within the parentheses. The NMR yields (values before the parentheses) were determined by crude 1H NMR analysis using
dibromomethane as the internal standard. [b] 1n (0.1 mmol), 2a (0.2 mmol), Pd(dba)2 (1.0 mol%), L13 (4.0 mol%), TfOH (20.0 mol%). [c] 1a (0.25 mmol), 2a (0.5
mmol), Pd(dba)2 (0.4 mol%), L13 (1.6 mol%), TfOH (20.0 mol%). [d] Displacement ellipsoids correspond to 30% probability. Only one of the two molecules of the
asymmetric unit is depicted; see Figure S1 in Supporting Information 1.4.
cleavage reaction, which provides the basis for a unique redox-
neutral cascade carbonylation process. Based on control
Conclusion
experiments and mechanistic studies, here the unfavorable C≡C
In summary, while studying the palladium-catalyzed
bond cleavage step takes place under relatively mild conditions.
functionalization of alkynols, we observed a novel catalytic C≡C
5
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Key for this effective step is the formation of a high energy
intermediate (unsaturated β-lactam), which releases the ring
strain by C-C migration to make the overall reaction
thermodynamically feasible. From a synthetic standpoint, this new
transformation presents a practical strategy for the synthesis of
α,β-unsaturated piperidones utilizing easily available propargylic
alcohols and aliphatic amines directly as robust surrogates. Under
optimal conditions, diverse α,β-unsaturated piperidones were
achieved in a fast and step-economic way, without need for
isolation of intermediates. In fact, 40 out of 41 here prepared
molecules have not been described before to the best of our
knowledge. We believe this methodology also provides inspiration
for conceptually new synthetic approaches complementing
conventional organic synthesis.
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Acknowledgements
This work is supported by the state of Mecklenburg-Western
Pommerania and the BMBF (Bundesministerium für Bildung und
Forschung) in Germany. We thank the analytical team of LIKAT,
and Dr. Christoph Kubis for the support of 13CO. Fei Ye thanks
the National Natural Science Foundation of China (No. 21801056)
for financial support. Dedicated to Professor Dr. Christian
Bruneau on the occasion of his birthday and excellent work in
organometallic catalysis.
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Keywords: α,β-unsaturated piperidones • palladium • C≡C
cleavage • cascade carbonylation • alkynol • catalysis
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Entry for the Table of Contents
RESEARCH ARTICLE
Yao Ge, Fei Ye, Ji Yang, Anke Spannenberg, Haijun
Jiao, Ralf Jackstell,* and Matthias Beller*
Page No. – Page No.
Palladium-catalyzed cascade carbonylation to α,β-
unsaturated piperidones via selective cleavage of
carbon-carbon triple bonds
Magical Mystery Tour: A catalytic carbonylative cleavage of carbon-carbon triple bonds is achieved. This allows for a general anddirect
synthesis of α,β-unsaturated piperidones by palladium-catalyzed cascade carbonylation of alkynols.
8
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