Palladium-Catalyzed Hydroalkylation of Alkynes with Cyclopropanols: Access to γ,δ-Unsaturated Ketones

Article abstract of DOI:10.1002/adsc.201800200

A palladium-catalyzed hydroalkylation of alkynes with cyclopropanols has been developed. This reaction provided a straightforward way to the synthesis of γ,δ-unsaturated ketones in moderate to good yields, exhibiting high atom economy and Z/E selectivity. Deuterated tri-substituted alkenes could also be expediently produced by using deuterium oxide as a co-solvent. (Figure presented.).

Full text of DOI:10.1002/adsc.201800200

Title: Palladium-Catalyzed Hydroalkylation of Alkynes with
Cyclopropanols: Access to γ,δ-Unsaturated Ketones
Authors: Hao Liu, Zhiyuan Fu, Shang Gao, Yue Huang, Aijun Lin, and
Hequan Yao
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800200
Link to VoR: http://dx.doi.org/10.1002/adsc.201800200

10.1002/adsc.201800200
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201
Palladium-Catalyzed Hydroalkylation of Alkynes with
Cyclopropanols: Access to γ,δ-Unsaturated Ketones
Hao Liu,a‡ Zhiyuan Fu,a‡ Shang Gao,a Yue Huang,b Aijun Lina* and Hequan Yaoa*
a. State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy,
China Pharmaceutical University, Nanjing, 210009, P. R. China
Fax: (+86)-25-8327-1042; e-mail: hyao@cpu.edu.cn; cpuhyao@126.com and ajlin@cpu.edu.cn
b. Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, 210009, P. R. China
‡These authors contributed equally to this work.
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract: A palladium-catalyzed hydroalkylation of
alkynes with cyclopropanols has been developed. This
reaction provided a straightforward way to the synthesis
of γ,δ-unsaturated ketones in moderate to good yields,
exhibiting high atom economy and Z/E selectivity.
Deuterated tri-substituted alkenes could also be
expediently produced by using deuterium oxide as a co-
solvent.
Keywords:
palladium-catalyzed;
hydroalkylation;
alkynes; cyclopropanols; γ,δ-unsaturated ketones
The ongoing development of transition-metal-
mediated selective C-C bonds activation/cleavage
methods can offer plenty of opportunities to
implement novel synthetic strategies, because C-C
bonds are ubiquitous in organic molecules.[1]
However, the activation of C-C bonds remains
challenging due to the highly inert nature of C-C
bonds, resulting in an energetically unfavorable
reaction compared to the activation of C-H bonds.[2]
Over the past decades, considerable attention has been
focused on searching for new means of activating C-C
bonds.[3] By taking advantage of the inherent ring-
strain in small rings, researchers acquired an efficient
method of achieving this goal.[4]
Scheme 1. Ring-opening transformation of cyclopropanols
by Orellana, Walsh and Cha, respectively (Scheme
1b).[7] Li and coworkers described a rhodium-
catalyzed C-H activation of arenes with
cyclopropanols (Scheme 1c).[8] Copper-catalyzed
carbene-transfer coupling reaction of cyclopropanols
with diazoesters has been realized by Wang and co-
workers (Scheme 1d).[9] These pioneering works will
encourage chemists to exploit more transformations
of cyclopropanols, broadening their synthetic scope
and functionality. To the best of our knowledge, no
related work on the transition-metal-catalyzed
hydroalkylation of alkynes with cyclopropanols has
been realized. Functionalization of alkynes is a
familiar and fundamental objective in organic
synthesis, because of the availability of alkynes, as
well as the widespread application of functionalized
alkenes.[10] As a part of our continuous efforts to
explore various transformations of alkynes,[11] herein,
we will describe our latest work on the palladium-
Cyclopropanols[5] are readily available three-
membered-ring structure which can be considered as
the equivalents of homoenolates. They have been
used in many cross-coupling reactions to construct -
functionalized ketones through C-C bonds cleavage.
In this context, the radical meditated ring-opening
reaction of cyclopropanols was widely explored to
construct C-C, C-N and C-X (X = S, halogen) bonds
(Scheme 1a).[6] Transition-metal-catalyzed cross-
coupling reactions of cyclopropanols with aryl halides,
benzyl halides, and acyl halides have been achieved
catalyzed
hydroalkylation of alkynes
with
1
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10.1002/adsc.201800200
Advanced Synthesis & Catalysis
cyclopropanols to access γ,δ-unsaturated ketones Screening of additional ligands revealed that
(Scheme 1e).
PtBu3·HBF4 performed best and further improved the
yield to 96% (Table 1, entries 9-14). When the
reaction was carried out with other Pd sources and
PtBu3·HBF4, the yield of 3aa decreased obviously
(Table1, entries 15-17).[12] Decreasing the catalyst
loading negatively impacted the reaction efficiency
(Table 1, entries 18 and 19). The reaction did not
occur under catalyst free conditions (Table 1, entries
20 and 21). Other solvents such as DMF, MeCN,
THF and DMSO were inferior to toluene (see the
Supporting Information (SI) for more details on the
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
T
Ligand
Yield
(%)[b]
26[d]
trace
trace
trace
trace
66
1[c]
2[c]
3[c]
4[c]
5[c]
6[c]
7[c]
8
Pd(PPh3)4
Pd2(dba)3
PdCl2
80
/
optimization
of
reaction
conditions).
The
80
/
configuration of 3aa was assigned as (Z) by NOE
analysis and the (E)-isomer was not observed in the
1H NMR (see SI for details).
80
/
Pd(OAc)2
[Pd(allyl)Cl]2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd(TFA)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
/
80
/
/
80
Table 2. Substrate scope of cyclopropanols.[a, b, c]
100
120
100
100
100
100
100
100
100
100
100
100
100
100
100
100
/
/
65
/
79
9
PPh3
55
10
Cy-JohnPhos
dppm
93
11
N.D.
<10
89
12
dppb
13
PCy3
14
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
HBF4
96(92)[d]
14
15
16
21
17
<10
92
18[e]
19[f]
20
85
N.D.
N.D.
21
/
[a]
Reaction conditions: 1a (0.5 mmol), 2a (0.25 mmol),
[Pd] (10.0 mol%), ligand (20.0 mol%) in 1.0 mL
toluene under argon for 24 h. N. D. = no detected.
The yield was determined by 1H NMR analysis.
1a (0.25 mmol) and 2a (0.25 mmol) were used.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
7.5 mol% catalyst and 15.0 mol% ligand were used.
5.0 mol% catalyst and 10.0 mol% ligand were used.
[a]
Reaction conditions: 1 (0.5 mmol), 2a (0.25 mmol),
We initiated our study with 1-benzylcyclopropanol
Pd(PPh3)4 (10.0 mol%), PtBu3·HBF4 (20.0 mol%) in
1a and diphenylacetylene 2a as the model substrates.
The desired coupling product 3aa was isolated in
26% yield with Pd(PPh3)4 as the catalyst at 80 °C in
toluene under an argon atmosphere (Table 1, entry 1).
Other catalysts such as Pd2(dba)3, PdCl2, Pd(OAc)2
and [Pd(allyl)Cl]2 were ineffective (Table 1, entries 2-
5). Increasing the temperature resulted in higher
yields (Table 1, entries 6 and 7). The product 3aa
could be achieved in 79% yield when the ratio of 1a
and 2a was improved to 2:1 (Table 1, entry 8).
1.0 mL toluene under argon at 100 oC for 24 h.
[b]
Isolated yields.
[c]
Z/E ratios were determined by 1H NMR analysis, Z/E >
50:1.
[d]
10.0 mmol scale.
[e]
The ratio of isomers was determined by 1H NMR
analysis.
2
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10.1002/adsc.201800200
Advanced Synthesis & Catalysis
With the optimized conditions in hand, we then yield. When multisubstituted cyclopropanols 1s and1t
investigated the substrate scope and generality of this were tested, a mixture of 3as/3as’ was achieved in
reaction with a series of cyclopropanols. Results of 36% yield (5.2:1), and 3at/3at’ could be furnished in
the tests were summarized in Table 2. 85% yield (14.4:1). To gain insight into the utility and
Benzylcyclopropanols with electron-donating or efficiency of the reaction, a gram-scale experiment
electron-withdrawing groups at the para-position of was carried out, and the product 3aa (1.51 g) could be
the benzene ring produced 3aa-3af in moderate to achieved in 93% yield on 10.0 mmol scale.
good yields. The steric hindrance did not affect the
After checking the scope and generality of the
reactivity, and the products 3ag and 3ah with a cyclopropanols, we then shifted our attention to
methyl group at the meta- or ortho-positon of the investigating the substrate scope of alkynes (Table 3).
benzene ring were obtained in 84% and 97% yields. Alkynes bearing both electron-donating and electron-
Product 3ai with 2-naphthyl group was achieved in withdrawing groups produced 3ba-3ga in moderate to
91% yield. Phenyl-, 2-thienyl-, cyclohexyl- and good yields. Products 3ha-3ja with meta-methyl,
phenethyl-substituted cyclopropanols all coupled with ortho-methoxy and dimethoxy groups were achieved
2a in good efficiency (3aj-3am). The cyclopropanols in 59%-73% yields. Replacing the benzene ring with
1n-1p containing phenyl and TBS ether groups thiophene ring, 3ka was achieved with 81% yield.
reacted smoothly to deliver 3an, 3ao and 3ap in 71%, Moreover, asymmetric internal alkynes 2l and 2m
65% and 59% yield, respectively. Notably, lithocholic were used to figure out the regioselectivity of this
acid-derived cyclopropanol was also viable, affording reaction, leading to a mixture of 3la/3la’ in 46% yield
3aq in 84% yield, which provided an efficient (1.2:1), and 3ma/3ma’ in 86% yield (5.9:1).
platform for the further functionalization of complex Asymmetric alkyne 2n with a methoxy group at the
molecules. The bicyclic substrate 1r underwent para-position of the benzene ring afforded 3na/3na’
selective C-C bond cleavage to provide 3ar in 65% in 88% yield (8.1:1). Terminal alkyne 2o was also
compatible in this reaction and offered 3oa/3oa’ in
54% yield (1.7:1). Aliphatic internal alkynes were
inactive substrates and could not realize the
Table 3. Substrate scope of alkynes. [a, b, c]
transformation under the standard reaction conditions.
Scheme 2. Further studies of the reaction.
To gain some mechanistic insight into this reaction,
a deuterium-labeling experiment with cyclopropanol
1a was performed and the deuterium ratio at the
hydroxyl of cyclopropanol 1a-d was 30% after stirred
with deuterium oxide (D2O) for 24 h (Scheme 2a).
The reaction of 1a-d (30% D) and 2a led to the
formation of 3aa’-d in 89% yield with 29% deuterium
[a]
Reaction conditions: 1a (0.5 mmol), 2 (0.25 mmol),
Pd(PPh3)4 (10.0 mol%), PtBu3·HBF4 (20.0 mol%), in
ratio (Scheme 2b). When D2O was used as a co-
solvent, the deuterated product 3aa-d was obtained in
80% yield with 95% deuterium ratio (Scheme 2c). We
speculated that the coordination of oxygen to
palladium catalyst could improve the efficiency of the
H/D exchange.
toluene (1.0 mL) at 100 oC for 24 h under argon.
[b]
[c]
Isolated yields.
Z/E ratios were determined by 1H NMR analysis, Z/E >
50:1.
[d]
The ratio of isomers was determined by 1H NMR
analysis.
3
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10.1002/adsc.201800200
Advanced Synthesis & Catalysis
chromatography on silica gel with PE/EA (v/v = 100:1) to
afford the desired products 3.
On the basis of the above results of the deuterium-
labeling experiments and previous works,[5d, 5e, 13]
a
plausible catalytic cycle of this reaction was proposed
as shown in Scheme 3. Initially, the oxidative ligation
of alkyne 2a to the Pd(0) catalyst forms the complex
I.[13e] Ligand exchange of cyclopropanol 1a with
complex I affords the intermediate II, which
subsequently undergoes hydrogen transfer to afford
vinylpalladium species III.[14] β-Carbon elimination
of cyclopropanol generates homoenolate IV.[7a, 7c, 8]
Finally, reductive elimination produces the product
γ,δ-unsaturated ketone 3aa and regenerates Pd(0)
catalyst to the next catalytic cycle. Further studies to
determine the mechanism are in progress in our
laboratory.
Acknowledgements
Generous financial support from the National Natural Science
Foundation of China (NSFC21502232 and NSFC 21572272) and
the Fundamental Research Funds for the Central Universities
(2632018ZD02) is gratefully acknowledged. We also thank Dr.
Brandon McCullough at University of Utah for the help of
preparing the manuscript.
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In summary, we have developed a palladium-
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Ketones: A sealed tube was charged with cyclopropanols 1
(0.5 mmol, 2.0 equiv.), alkynes 2 (0.25 mmol, 1.0 equiv.),
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4
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10.1002/adsc.201800200
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800200
Advanced Synthesis & Catalysis
UPDATE
Palladium-Catalyzed Hydroalkylation of Alkynes
with Cyclopropanols: Access to γ,δ-Unsaturated
Ketones
Adv. Synth. Catal. Year, Volume, Page – Page
Hao Liu,a‡ Zhiyuan Fu,a‡ Shang Gao,a Yue Huang,b
Aijun Lina* and Hequan Yao a*
6
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