Ligand-Controlled Palladium-Catalyzed Carbonylation of Alkynols: Highly Selective Synthesis of α-Methylene-β-Lactones

Article abstract of DOI:10.1002/anie.202006550

The first general and regioselective Pd-catalyzed cyclocarbonylation to give α-methylene-β-lactones is reported. Key to the success for this process is the use of a specific sterically demanding phosphine ligand based on N-arylated imidazole (L11) in the presence of Pd(MeCN)₂Cl₂ as pre-catalyst. A variety of easily available alkynols provide under additive-free conditions the corresponding α-methylene-β-lactones in moderate to good yields with excellent regio- and diastereoselectivity. The applicability of this novel methodology is showcased by the direct carbonylation of biologically active molecules including natural products.

Full text of DOI:10.1002/anie.202006550

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Accepted Article
Title: Ligand-controlled Palladium-catalyzed Carbonylation of Alkynols:
Highly Selective Synthesis of α-Methylene-β-lactones
Authors: Yao Ge, Fei Ye, Jiawang Liu, Ji Yang, Anke Spannenberg,
Haijun Jiao, Ralf Jackstell, and Matthias Beller
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10.1002/anie.202006550
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COMMUNICATION
Ligand-controlled Palladium-catalyzed Carbonylation of Alkynols:
Highly Selective Synthesis of α-Methylene-β-lactones
Yao Ge, Fei Ye, Jiawang Liu, Ji Yang, Anke Spannenberg, Haijun Jiao, Ralf Jackstell, and Matthias
Beller*
[a]
[b]
Dr. Y. Ge, Dr. F. Ye, Dr. J. Liu, J. Yang, Dr. A. Spannenberg, Dr. H. Jiao,Dr. R. Jackstell, Prof. Dr. M. Beller
Leibniz-Institute for Catalysis, 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 Chemistry and Material
Technology of Zhejiang Province, Hangzhou Normal University, No. 2318, Yuhangtang Road, 311121, Hangzhou, PR China
 These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: The first general and regioselective Pd-catalyzed
cyclocarbonylation to give α-methylene-β-lactones is reported. Key to
the success for this process is the use of a specific sterically
demanding phosphine ligand based on N-arylated imidazole (L11) in
the presence of Pd(MeCN)2Cl2 as pre-catalyst. A variety of easily
available alkynols provide under additive-free conditions the
corresponding α-methylene-β-lactones in moderate to good yields
with excellent regio- and diastereoselectivity. The applicability of this
novel methodology is showcased by the direct carbonylation of
biologically active molecules including natural products.
demonstrated in the decarboxylation to allenes on
thermolysis.[3b,3e]
α-Alkylidene-β-lactones have emerged as important
synthetic targets due to their occurrence in a variety of natural
compounds and biologically active molecules (Scheme 1).[1] For
example, lactones A[1a-c] and B[1d] were separated from Grazielia
species and Disynaphia multicrenulata. Moreover, C exhibits
promising inhibitory activities against certain fungal pathogens.[1e]
In addition, α-alkylidene-β-lactones D and E were studied as
potent and selective inhibitors for serine hydrolase ABHD16A.[1f-g]
Following this work, F also served as a sensitive probe for
detecting ABHD16A activity in mouse brain membrane lysates.[1g]
Apart from these medicinal applications, specifically α-methylene-
β-lactones attracted interest in material sciences; e.g. well-
defined copolymers with controllable molecular weight and
narrow polydispersity were prepared by ring-opening
polymerization. Here, the vinylidene groups of the lactones could
be further functionalized, producing well-defined blocks with
designable segments.[2] In organic chemistry, the high degree of
functional groups in a compact manner allows diverse synthetic
utilizations and makes this class of compounds interesting
building blocks.[3] More specifically, owing to their inherent strain
in the four-membered ring, they readily undergo ring opening
reactions with a wide range of nucleophiles by either acyl C–O or
alkyl C–O bond cleavage.[3f,3g] Besides the usual electrophilic
sites of the carbonyl and oxetane carbon atoms contained in β-
lactones, Michael-type additions of nucleophiles and radicals at
the methylene carbon atom are feasible[3h] and offer attractive
possibilities for preparative purposes. Notably, the carboxy-
activated exo-methylene group serves as reactive dienophile,
while the α,β-unsaturated carbonyl moiety promises potential as
heterodiene for [4+2]-cycloadditions.[3e] Moreover, α-methylene-
β-lactones constitute convenient allene equivalents as
Scheme 1. Natural compounds and biologically active molecules with α-
methylene-β-lactone skeleton
Considering the value of α-alkylidene-β-lactones in organic
synthesis, significant interest in their preparation exists.[4]
Because of the dense functionalization, mainly special synthetic
methods have been developed for this class of compounds
including [2+2]-cycloaddition of ketenes,[3n,4a-c] lactonization of β-
hydroxycarboxylic acids or derivatives,[3d,4d-g] elimination of
selenoxide
from
α-methyl-substituted
lactones,[3b]
and
deoxygenation of β-peroxylactones.[3f,4g-h]
More recently, also rhodium- or palladium-catalyzed
carbonylation of alkynols have been disclosed.[5] Thus, α-
(triorganosilyl)-methylene-β-lactones (Scheme 2a),[5a-b] α-
(alkoxycarbonyl)-methylene-β-lactones (Scheme 2b),[5c-d] and (Z)-
α-chloro/bromo-alkylidene-β-lactones (Scheme 2b)[5e-f] were
obtained. Notably, the synthesis of parent α-methylene-β-
lactones gained less success due to the highly reactive exo-
methylene double bond. In fact, to the best of our knowledge,
there is only one reported example for the carbonylation of 1-
methyl-2-butyn-1-ol described, leading to 4,4-dimethyl-3-
methyleneoxetan-2-one in 5% yield with probably polymeric
esters as other products through a palladium-catalyzed process
(Scheme 2c).[5g]
Despite these problems, we thought the cyclocarbonylation
of propargylic alcohols in the presence of an improved catalyst
would offer a most straightforward and atom-efficient access to
these products. Thus, we became attracted by this challenge.
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10.1002/anie.202006550
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Based on our interest in the development of carbonylation
reactions,[6] herein, we report the first general and highly selective
Pd-catalyzed carbonylation of propargylic alcohols to provide a
family of new α-methylene-β-lactones (Scheme 2d).
42%
42/58
71%
71/29
56%
60/40
41%
67%
77/23
100
80
60
40
20
0
2a 3a
46/54
35%
45/55
36%
47/53
yield of 2a
2a/3a
57%
80/20
3%
5/95
56%
98/2
30%
97/3
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
Scheme 2. Rhodium- or palladium-catalyzed cyclocarbonylation of alkynols
Figure 1. Pd-catalyzed cyclocarbonylation of 1-ethynyl-1-cyclohexanol 1a:
Influence of phosphine ligands. Reaction conditions: 1a (0.5 mmol), [Pd(π-
cinnamyl)Cl2] (1.0 mol%), bidentate ligand (2.0 mol%) or monodentate ligand
(4.0 mol%), and CO (40 bar) in THF (2.0 mL) at 100 °C for 20 h. The ratio of
2a/3a and the yield were determined by GC using mesitylene as the internal
standard.
At the beginning of our studies, 1-ethynyl-1-cyclohexanol 1a
was chosen as model substrate. To identify a suitable catalyst
system, a variety of ligands (in the case of diphosphine ligands 2
mol%, in the case of monophosphine ligands 4 mol%) were tested
in the presence of [Pd(π-cinnamyl)Cl]2 (Figure 1). Initially, the
reactivity of bidentate phosphines L1-L5 with different backbones
and chelating units was evaluated. When L1 (Xantphos), L2
(BINAP), L4 (dtbpx) and L5 were applied, almost equal amounts
of the desired β-lactone 2a and butenolide 3a were obtained. L3
(DPPF) proved to be not suitable at all, leading to 3a in 55% with
3% yield for 2a. No progress was achieved when monodentate
ligand L6 (BuPAd2) was used in this reaction. However, in the
presence of L7 (PtBu3) a slightly improved regioselectivity (71/29)
was obtained. Based on this result, we assumed that tert-butyl
groups may have a positive influence on the desired branched
selectivity. Thus, other monodentate ligands L8-L11 were tried
with different backbones bearing tert-butyl substituents on the
phosphorus atom. Indeed, more-sterically hindered L8 (JohnPhos)
gave 80/20 selectivity and 57% yield of 2a. When the N-phenyl-
pyrrole-based ligand L9 was applied, a similar selectivity (77/23)
and a higher yield (67%) were observed. To further increase the
steric bulk of the ligand, we introduced substituents on the ortho
position of the phenyl group resulting in the new ligand L10, which
was prepared in good yield in two reaction steps (see SI Scheme
S1 for detail). With this ligand in hand, the regioselectivity could
be improved to 97/3, albeit the reactivity was affected negatively
(30% yield of 2a). Finally, to our delight, the 1-(2,6-
diisopropylphenyl)-1H-imidazole-based phosphine L11,[7] gave
an acceptable yield (56%) and excellent 98/2 regioselectivity.
Next, we tried to improve the reactivity further in the presence
of L11 as the ligand of choice (see SI; Table S2-S6). Variation of
critical parameters (solvent, pre-catalyst, temperature, pressure)
revealed the following optimal conditions: 1 mol% Pd(MeCN)2Cl2
as catalyst precursor, metal/ligand ratio of 1: 6, methyl tert-butyl
ether (MTBE) as solvent, 100 °C, 40 bar CO. Hence, the desired
β-lactone 2a was obtained in excellent yield (98%) and
regioselectivity (98/2).
With optimized reaction conditions established, a range of
easily available and structurally diverse propargylic alcohols were
examined. It is worthy to note that all of the desired α-methylene-
β-lactones were obtained in isolated yield with excellent
regioselectivity and diastereoselectivity. Notably, the latter is likely
to be controlled by the substrates. The alkynols with different
substituents (dimethyl, phenyl, ketal) on the 3- or 4-position of
cyclohexyl group were transformed into the corresponding
products 2a-2e in yields of 60–97% and excellent selectivity. This
protocol can be readily scaled-up to carbonylation of 1.0 gram of
1a. This reaction proceeded smoothly, providing 2a in 92% yield.
Substrates 1f-1i containing heteroatoms (oxygen, sulfur,
nitrogen) proved to be viable too and gave the corresponding β-
lactones 2f-2i in 81–98% yields with >20/1 selectivity. Five-
membered ring substrates such as 1j can be also applied
successfully in this carbonylation reaction (83% yield of 2j). In
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10.1002/anie.202006550
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case of the carbonylation of the 1-ethynylcyclododecan-1-ol 1k,
the use of L10 instead of L11 led to a higher yield of 2k (88%).
Noncyclic alkynols 1l-1r bearing different alkyl and benzyl groups
underwent lactonization smoothly and gave the desired products
2l-2r in 38-90% yields. By increasing the catalyst loading (5 mol%
Pd(MeCN)2Cl2, 30 mol% L11), the corresponding products 2m
and 2q were isolated in 90% and 49% yield, respectively, with
>20/1 regioselectivity. When α-monoalkyl-substituted propynyl
alcohol 1s was subjected to the optimized conditions, 2s was
obtained, albeit in a lower isolated yield. On the other hand,
starting from α-monoaryl-substituted alkynol 1t, carbonylation
proceeded at increased catalyst loading to give 2t in 58% yield.
Interestingly, dicarbonylated product 2u was obtained directly in
56% isolated yield by carbonylation of dialkynol 1u. It should be
noted that the synthesis of such multiply β-lactone is not an easy
task. In fact, to our knowledge no such transformation has been
described yet.
of some of the complex substrates, typically 5 mol% of palladium
catalyst was applied. Under otherwise similar conditions, in all
cases the reactions proceeded well with excellent regio- and
diastereoselectivities. More specifically, tropinone-derived
propargylic alcohol 1v delivered the desired product 2v, with good
efficiency (81% yield). Pentoxifyllin, a drug with anti-inflammatory
properties, was transformed to the corresponding product 2w
smoothly (85% yield). Recently, much attention has been paid to
steroidal containing spiro-heterocycles for their characteristic
physiological activities.[9] Thus, we investigated reactions of
pharmaceutically relevant steroidal alkynols: ethynyl estradiol,
ethisterone, levonorgestrel, and lynestrenol, which are used for
contraception and gynecological disorders. All these compounds
participated efficiently in this transformation to provide the
carbonylative products 2x-2z, 2aa in high yields (85-93%).
Notably, the molecular structure of ethynyl estradiol derivative 2x
was unambiguously confirmed by X-ray structure analysis.[10]
Similarly, α-methylene-β-lactones 2ab-2af derived from other
steroid hormones such as dihydrocholesterol, stanolone and
epiandrosterone, were obtained in 41-87% yields with excellent
selectivity. Moreover, homopropargylic alcohols also proved to be
suitable substrates and afforded the corresponding 5-membered
products with excellent regioselectivity (see SI, Scheme S2).
Table 1. Pd-catalyzed cyclocarbonylation of alkynols: Substrate scope.[a]
Table 2. Pd-catalyzed cyclocarbonylation of alkynols derived from biologically
active and natural products.[a]
[a] Unless otherwise noted, all reactions were performed in MTBE (2.0 mL) at
100 °C for 20 h in the presence of 1 (0.5 mmol), Pd(MeCN)2Cl2 (1.3 mg, 0.005
mmol), L11 (11.2 mg, 0.03 mmol), and CO (40 bar). Isolated yields were given
before the parentheses. The NMR yields (values within the parentheses),
regioselectivity of 2/3 and diastereoselectivity of 2 were determined by crude 1H
NMR analyses using dibromomethane as the internal standard. [b] 1a (1 g, 8
mmol), Pd(MeCN)2Cl2 (21 mg, 0.08 mmol), L11 (178 mg, 0.48 mmol), MTBE
(30 mL). [c] 0.1 mmol of 1 was used.
[a] Unless otherwise noted, all reactions were performed in MTBE (2.0 mL) at
100 °C for 20 h in the presence of 1 (0.1 mmol), Pd(MeCN)2Cl2 (1.3 mg, 0.005
mmol), L11 (11.2 mg, 0.03 mmol), and CO (40 bar). Isolated yields were given
before the parentheses. The NMR yields (values within the parentheses),
regioselectivity of 2/3 and diastereoselectivity of 2 were determined by crude 1H
NMR analyses using dibromomethane as the internal standard. [b] 0.5 mmol of
1 was used.
The importance of this novel methodology is showcased by
the late-stage modification of biologically active and natural
products,[8] which provides easy access to diverse α-methylene-
β-lactones, highlighting the substrate scope of this protocol and
its potential utility in organic synthesis. Due to the poor solubility
It should be noted that more than 80% of the here described
α-methylene-β-lactones are prepared for the first time. This
clearly demonstrates the synthetic value of this novel
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methodology. We assumed that our new products can be
conveniently used as interesting basic building blocks.[3] Thus, to
showcase their utility, selected follow-up transformations were
conducted by using 2b as the starting material (Scheme 3). To
illustrate the possibility to prepare functionalized acrylic acid
derivatives, α-methylene-β-lactone 2b readily underwent ring
opening with benzylamine in the presence of Pd(OAc)2, affording
β-hydroxy amide 4 in 61% yield. Furthermore, α-methylene-β-
lactones provide an easy and efficient entry into α-alkylidene-β-
lactones applying cross metathesis in the presence of Grubbs II
catalyst. Indeed, a good yield of 5 was obtained with high Z-
selectivity (stereochemistry determined by NOESY study, see SI
for detail). Particularly, this route allows for the efficient
preparation of focused libraries of β-lactones, which have found
use as biological research probes and therapeutic agents.[11]
Addition of carbon- or hetero-nucleophiles gives access to α-
alkylated β-lactones. Exemplarily, the Rh-catalyzed conjugate
addition of phenylboronic acid to 2b provided 6 in 40% yield and
the treatment of 2b with thiophenol and triethylamine provided α-
(thiomethyl)-β-lactone 7 via a nucleophilic conjugate addition.
Finally, four-membered thiolactones can be made in a facile
manner by employing Lawesson’s reagent. The synthesis of -
methylene-β-S-thiolactone 8 illustrated the diverse possibilities for
the construction of novel sulfur heterocycles.
(see SI, Scheme S4). In order to differentiate between these two
possibilities, control experiments were performed. As shown in
Scheme 4b (entry 1), the carbonylation of propargylic alcohol 1a
was also carried out with a Pd(0) pre-catalyst. However, in the
presence of Pd(dba)2 under the standard reaction conditions, no
conversion was observed. In contrast, using Pd(dba)2 in the
presence of 2 mol% of hydrochloric acid gave the desired product
2a in 98% yield (Scheme 4b, entry 2). These experiments
provided clear evidence for a mechanism involving catalytically
active palladium hydride species. Although the detailed reaction
mechanism of the cyclocarbonylation of propargylic alcohols
remains to be further elucidated, based on our previous studies
on alkoxycarbonylations[6b,13] as well as mechanistic studies by
Cole-Hamilton, Drent and Sparkes[14], it is most likely that this
reaction goes through the Pd hydride mechanism shown in
Scheme 4 (a).[15]
Scheme 3. Further synthetic transformations of 2b. Reagents and conditions:
(i) Pd(OAc)2, PPh3, BnNH2,CH2Cl2, rt for 16 h. (ii) Grubbs' 2nd generation, 1-
octene, CH2Cl2, reflux for 10 h. (iii) [Rh(cod)Cl]2, KOH/ H2O, PhB(OH)2, dioxane,
60 °C for 1h. (iv) PhSH, Et3N, MeOH, rt, 24 h. (v) Lawesson's Reagent, PhCH3,
reflux for 6 h.
Regarding the mechanism of this novel carbonylation
reaction, in principle two main pathways are possible (Scheme 4,
a): 1) Initially, the active palladium hydride species I could be
generated in situ by the combination of palladium precursor with
phosphine ligands,[12] in which an excess of phosphine ligand
(L11) is needed to reduce the initial Pd(II) precursor. After
coordination of the alkyne to this complex followed by migratory
insertion into the Pd-H bond, the corresponding alkenyl-Pd
complex II should be obtained, which is transformed into the
corresponding acyl complex III via CO coordination and insertion.
Finally, intramolecular nucleophilic attack of hydroxyl on the acyl
carbonyl leads to the formation of the desired lactone and
regeneration of the [Pd-H]+ species. Alternatively, the Pd(II)
precursor is reduced in situ to a Pd(0) species (probably by an
excess amount of phosphine ligands). The Pd(0) species
undergoes insertion into the oxygen-hydrogen bond of alkynol
affording the corresponding alkoxypalladium complex. Then,
insertion of CO into palladium-oxygen bond would give the Pd
acyl species. Intramolecular addition of the palladium hydride to
the triple bond would form metallacycle complex, which leads to
the formation of the desired lactone and regenerates the catalyst
Scheme 4. (a) Proposed mechanism. (b) Control experiments.
In summary, we developed the first catalyst system for a
general and selective cyclocarbonylation of alkynols to produce
synthetically useful α-methylene-β-lactones. By applying
a
distinctive ligand, a wide range of propargylic alcohols was
efficiently transformed into the corresponding α-methylene-β-
lactones in good yields (up to 98%) with high regio- and
diastereoselectivity (>20/1). The applicability of this methodology
is specifically highlighted by the functionalization of biologically
active and natural molecules. Combining this novel procedure
with established functionalizations allows for an efficient
preparation of privileged β-lactone scaffolds. This efficient
procedure features the following advantages: high atom economy,
additive free reaction conditions, availability of substrates and
obtained excellent selectivities. It complements the current
methodologies for carbonylations in organic synthesis as shown
by the synthesis of 30 products; the vast majority of them are new.
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Acknowledgements
This work is supported by the State of Mecklenburg-Vorpommern
and the BMBF, Germany. We thank the analytical team of LIKAT.
Keywords: alkynol • palladium • phosphine • carbonylation •
catalysis • α-methylene-β-lactone
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Yao Ge, Fei Ye, Jiawang Liu, Ji Yang,
Anke Spannenberg, Haijun Jiao, Ralf
Jackstell, and Matthias Beller*
Page No. – Page No.
Ligand-controlled
Palladium-
catalyzed Carbonylation of Alkynols:
Highly Selective Synthesis of α-
Methylene-β-lactones
A special catalyst for tensed problems: The advanced Pd/L11 system enables
highly regioselective carbonylation of alkynols for synthesis of a wide range of 4-
membered α-methylene-β-lactones.
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