Rhodium-Catalyzed Ring-Opening Hydroacylation of Alkylidenecyclopropanes with Chelating Aldehydes for the Synthesis of γ,δ-Unsaturated Ketones

Article abstract of DOI:10.1021/acs.orglett.0c01751

The first intermolecular ring-opening hydroacylation of alkylidenecyclopropanes with chelating aldehydes through a rhodium-catalyzed acrylamide-promoted protocol is reported. This highly efficient catalytic system enables the direct synthesis of a diverse

Full text of DOI:10.1021/acs.orglett.0c01751

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Letter
Rhodium-Catalyzed Ring-Opening Hydroacylation of
Alkylidenecyclopropanes with Chelating Aldehydes for the
Synthesis of γ,δ-Unsaturated Ketones
Hong-Shuang Li,*,# Shi-Chao Lu,# Zhi-Xin Chang, Liqiang Hao, Fu-Rong Li, and Chengcai Xia
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ABSTRACT: The first intermolecular ring-opening hydroacyla-
tion of alkylidenecyclopropanes with chelating aldehydes through a
rhodium-catalyzed acrylamide-promoted protocol is reported. This
highly efficient catalytic system enables the direct synthesis of a
diverse range of linear γ,δ-unsaturated ketones. Good functional
group compatibility is demonstrated for the completely atom-
economical and remarkably selective proximal C−C bond cleavage
process. Mechanistic studies reveal that the bidentate coordination
of N,N-dimethylmethacrylamide (L1) to the acylrhodium inter-
mediates might facilitate the cyclopropane ring fragmentation and
isomerization.
he past two decades have witnessed a portfolio of
chemical transformations of alkylidenecyclopropanes
transition-metal-catalyzed hydroacylation6 of alkene-containing
components. Shair and co-workers were among the first to
develop a rhodium(I)-catalyzed ring-opening hydroacylation of
vinylcyclopropanes for the synthesis of cyclooctenones in an
intramolecular fashion (Scheme 1a).7 A similar hydroacylation
of ACPs with the intramolecular aldehyde moieties was
T
(ACPs) in the presence of transition-metal catalysts for the
rapid elaboration of structural complexity.1 With respect to the
ring opening, the reaction pathways affected by the
substitution patterns on the cyclopropyl ring or the terminal
of the double bond of ACPs would be complicated and
versatile,1c since the unleashing of cyclopropyl ring strain
facilitates the distal C−C bond or proximal C−C bond
cleavage. Consequently, the evolution of transition-metal-
catalyzed selective cleavage of the C−C bond of readily
accessible ACPs2 is highly challenging and desirable for
accessing diversified functionalized molecules.
γ,δ-Unsaturated ketone (homoallylic ketone), a moiety
ubiquitously found in marketed drugs (Figure 1),3 can serve
as an intriguing building block for the preparation of naturally
occurring products and therapeutically useful heterocyclic or
polycyclic compounds.4 Traditional methods for the synthesis
of γ,δ-unsaturated ketones usually required a multistep reaction
sequence.5 Accordingly, chemists turn their attention to the
subsequently accomplished by Furstner et al. using a rhodium
̈
catalyst (Scheme 1b).8 Surprisingly, there are few intermo-
lecular hydroacylation methods that effectively target the
homoallylic ketones. In 2009, Ohmura, Suginome, and co-
workers reported a selective synthesis of γ,δ-unsaturated
ketones through a nickel(0)-catalyzed ring-expanding hydro-
acylation reaction of methylenecyclopropanes (MCPs) with
simple aldehydes (Scheme 1c).9 However, this method was not
suitable for the hydroacylation of ACPs.
Intrigued by these impressive precedents, we wondered
about the feasibility of the hydroacylation reactions between
ACPs and chelating aldehydes to deliver linear γ,δ-unsaturated
ketones (Scheme 1d). Such a transformation faces the
following fundamental challenges: (1) a stable acylrhodium
intermediate is indispensable for establishing the hydro-
acylation of ACPs; (2) the ring-opening hydroacylation
process must outcompete the conventional direct hydro-
acylation of the alkene moiety of ACPs, which means that the
Received: May 24, 2020
Figure 1. Selected marketed drugs containing γ,δ-unsaturated ketone
scaffold.
https://dx.doi.org/10.1021/acs.orglett.0c01751
© XXXX American Chemical Society
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A

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Letter
Scheme 1. Transition-Metal-Catalyzed Ring-Opening
Hydroacylation for the Synthesis of γ,δ-Unsaturated
Ketones
Table 1. Optimization Studies for the Rhodium-Catalyzed
Synthesis of γ,δ-Unsaturated Ketone 3aa
a
b
entry
variation from the standard conditions
none
without L1
L2 instead of L1
L3 instead of L1
yield (%)
1
2
3
4
5
6
7
8
73
33
25
64
62
45
53
48
59
64
55
70
60
58
L4 instead of L1
100 mol % of L1 instead of 25 mol % of L1
50 mol % of L1 instead of 25 mol % of L1
10 mol % of L1 instead of 25 mol % of L1
1.5 equiv of 2a instead of 2.5 equiv of 2a
PPh3 instead of (p-Me-C6H4)3P
without K2CO3
p-xylene instead of toluene
0.1 M instead of 0.2 M
120 °C instead of 140 °C
9
10
11
12
13
14
cyclopropane ring fragmentation and isomerization is predom-
inant over reductive elimination;7 and (3) control of the
selectivity would be a difficult task in order to obtain high
yields of the desired linear γ,δ-unsaturated ketones. In
continuation of our research on rhodium(I)-catalyzed
regioselective C−C bond formation reactions,10 herein we
describe the development of a new strategy that highlights the
chelation assistance of a catalytic amount of N,N-dimethylme-
thacrylamide (L1), enabling the first example of the
intermolecular hydroacylation of ACPs by the proximal C−C
bond cleavage.
a
Unless otherwise noted, each reaction was run with 1a (0.2 mmol, 1
equiv) and 2a (2.5 equiv) in 1 mL of toluene at 140 °C for 24 h.
b
Isolated yield. COD = 1,5-cyclooctadiene.
Finally, the ring-opening hydroacylation proved to be less
efficient when it was performed at a lower temperature (entry
14).
The generality of the rhodium-catalyzed intermolecular ring-
expanding hydroacylation with regard to the alkylidenecyclo-
propane partner was subsequently investigated utilizing the
optimized conditions (Scheme 2). The methyl-, tert-butyl-, and
methoxy-substituted benzylidenecyclopropanes all reacted
smoothly with salicylaldehyde 1a under rhodium(I) catalysis
to provide isolated 61−78% yields of γ,δ-unsaturated ketones
(3ab−3ae). Significantly, a variety of alkylidenecyclopropane
derivatives bearing electron-neutral or electron-deficient
groups expressed moderate to good reactivity to produce the
desired ketones (3af−3ak). Of note, 2-furyl-, 3-benzofuryl-,
and 2-pyridinyl-substituted components (3al−3an) were also
compatible with the reaction conditions for the hydroacylation,
highlighting the robustness of the protocol. It was found that
the symmetrical diphenylmethylenecyclopropane underwent
the coupling reaction smoothly to afford the anticipated
compound 3ao in 54% yield. Unfortunately, the substrate
bearing a long-chain alkyl group (2p) was not allowed for this
transformation. Moreover, the substrate substituted with
methyl and phenyl groups on the double bond was also
evaluated in the coupling reaction, but the product was isolated
in low yield (3aq).
Our attention was then turned to the coupling reactions of
chelating aldehydes with ACPs, and the results are illustrated
in Scheme 3. Good functional group compatibility for the
synthesis of linear γ,δ-unsaturated ketones was again observed,
with methyl (3ba), benzyloxy (3ca), chloro (3da), trifluor-
omethyl (3ea), nitro (3fa), and ester (3ga) groups all being
well-tolerated. Electron-donating salicylaldehydes reacted with
halo-substituted partners smoothly to furnish the correspond-
ing products 3hh and 3ii in 69% and 67% yield, respectively.
Initially, we investigated the possibility of such a conversion
by examining the model reaction between salicylaldehyde 1a
and freshly prepared benzylidenecyclopropane 2a under
rhodium(I) catalysis (Table 1). In light of the bidentate
coordination of α,β-unsaturated compounds to the rhodium(I)
intermediates,10b,11 we added a commercially available material
to the mixture to promote the reaction. To our delight, the
[Rh(COD)Cl]2/(p-Me-C6H4)3P/K2CO3 catalytic system in
combination with 25 mol % of N,N-dimethylmethacrylamide
(L1) delivered 73% yield of the linear trans-γ,δ-unsaturated
ketone 3aa (entry 1). The absence of L1 proved very
detrimental to the yield of the desired ring-opening hydro-
acylation product (entry 2). It is noteworthy that 2-
ethylacrolein (L2) that could promote the hydroacylation of
1,3-dienes with salicylaldehydes10b was much less efficient
(entry 3), demonstrating the importance of acrylamides in
promoting the transformation. Switching L1 to other
homologues such as N,N-dimethylacrylamide (L3) and
methacrylamide (L4) gave slightly lower yields of the product
(entries 4 and 5). The influences of the loading of L1 on the
ring-opening hydroacylation were also examined, and all led to
low conversions (entries 6−8). In addition, decreasing the
loading of benzylidenecyclopropane 2a to 1.5 equiv lowered
the yield to 59% (entry 9). Replacing (p-Me-C6H4)3P with
PPh3 still afforded the homoallylic ketone in 64% yield (entry
10). An experiment carried out without the base showed a
poorer yield for 3aa (entry 11). The hydroacylation performed
in p-xylene produced a yield comparable to that achieved in
toluene (entry 12). However, running the reaction at a lower
concentration resulted in inferior yield of 3aa (entry 13).
B
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Scheme 2. Substrate Scope with Respect to
Alkylidenecyclopropanes
Scheme 3. Substrate Scope with Respect to Chelating
a,b
a,b
Aldehydes and Alkylidenecyclopropanes
a
Unless otherwise noted, all reactions were carried out with
salicylaldehyde 1a (0.2 mmol), alkylidenecyclopropane 2 (0.5
mmol), [Rh(COD)Cl]2 (5 mol %), (p-Me-C6H4)3P (20 mol %),
K2CO3 (10 mol %), and L1 (25 mol %) in 1 mL of toluene at 140 °C
a
Unless otherwise noted, all reactions were carried out with chelating
aldehyde 1 (0.2 mmol), alkylidenecyclopropane 2 (0.5 mmol),
[Rh(COD)Cl]2 (5 mol %), (p-Me-C6H4)3P (20 mol %), K2CO3 (10
mol %), and L1 (25 mol %) in 1 mL of toluene at 140 °C for 24 h.
b
c
for 24 h. Isolated yield. Reaction was carried out on a 1 mmol scale.
b
c
Isolated yield. 1.5 mL of toluene was used.
d
e
1
2 mL of toluene was used. Only the E-isomer was observed by H
NMR analysis of the crude mixture.
Furthermore, introducing a methoxy group at the ortho
position of the hydroxyl group on the substrate did not
influence the ring-opening hydroacylation, since a good yield
of 3jb was provided. Remarkably, exposure of the aldehyde
possessing a free phenolic hydroxyl group to the catalytic
system afforded the anticipated compound 3kb in moderate
yield. The substrates containing various medicinally relevant
and chemical biologically useful groups, including fluoro (3
lb), chloro (3mb), bromo (3nb), iodo (3ob), and trifluor-
omethoxy (3pb), were well-tolerated. However, the aliphatic
aldehyde possessing a hydroxyl group located at the proper
position such as 3-hydroxy-2,2-dimethylpropanal (3q) was not
suitable for the coupling reaction. To our delight, this protocol
can be extended to quinoline-8-carbaldehyde,6e,12 from which
a 42% yield of 3rb was obtained.
Figure 2. Substrates which failed to afford the desired products.
such as carbonyl and alkoxy groups, might account for the
unfruitful coupling reactions of the substrates (1w and 1x).
Further evidence for the role of α,β-unsaturated amide and
the catalytic mechanism was demonstrated by control
experiments (Scheme 4). Initially, benzaldehyde 4 was not
observed to deliver the linear γ,δ-unsaturated ketone 5 upon
Scheme 4. Key Mechanistic Experiments
The formation of chelation-stabilized intermediates is
essential to the success of this rhodium(I)-catalyzed ring-
opening hydroacylation process, which could be deduced from
the substrate scope studies. As shown in Figure 2, the
substituent at the ortho position of the aldehyde group has a
profound influence on the reactivity of the substrate. The
incapability of conversion of the substrates (1s−1v)6e might be
attributed to the steric hindrance that impedes the
coordination of L1 to the rhodium intermediates (vide infra,
proposed catalytic mechanism). Additionally, the weak
coordination performance of the fixed chelating moieties,
C
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Letter
reaction of the alkylidenecyclopropane 2b instead of 2a under
the standard conditions (Scheme 4a), suggesting that the ring-
expanding hydroacylation did not occur in the absence of a
chelating group. Although the intermolecular hydroacylation of
N,N-dialkylacrylamides11 or enamides13 with simple aldehydes
has been investigated, the coupling of L1 with salicylaldehyde
1a without the alkylidenecyclopropane in this [Rh(COD)Cl]2/
(p-Me-C6H4)3P/K2CO3 catalytic system only delivered 18%
yield of the product 6 with 70% NMR yield of the material
observed (Scheme 4b). Meanwhile, only a trace amount of 6
was detected with a negligible loss of L1 by NMR analysis
while performing the coupling of 1a with 2b (Scheme 4c). The
results unambiguously indicate that L1 participated in the
hydroacylation reactions sluggishly and that strong bidentate
chelation of the acrylamide to the cationic rhodium played a
pivotal role in promoting the reaction. Furthermore, a
deuterium-labeling experiment using d-1a as the substrate
under the standard reaction conditions afforded deuterium
incorporation at the γ-C (32% D) position of the carbonyl
group of the product 7 (Scheme 4d).
This method provides a complementary alternative to the
nickel-catalyzed transformation of MCPs within the hydro-
acylation arena.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01751.
Experimental details, characterization data, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Hong-Shuang Li − Institute of Pharmacology, School of
Pharmaceutical Sciences, Shandong First Medical University &
Shandong Academy of Medical Sciences, Taian 271016, P.R.
China; orcid.org/0000-0002-1740-8876;
Email: lihongshuang8625@163.com
On the basis of preliminary mechanistic investigations in
combination with previous reports on the hydroacylation of
ACPs and their analogues,7−9 a tentative mechanism for the
synthesis of γ,δ-unsaturated was proposed (Scheme 5). The
Authors
Shi-Chao Lu − State Key Laboratory of Bioactive Substance and
Function of Natural Medicines, and Beijing Key Laboratory of
Active Substance Discovery and Druggability Evaluation,
Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100050,
P.R. China; orcid.org/0000-0002-5182-7273
Zhi-Xin Chang − Institute of Pharmacology, School of
Pharmaceutical Sciences, Shandong First Medical University &
Shandong Academy of Medical Sciences, Taian 271016, P.R.
China
Scheme 5. Proposed Catalytic Mechanism
Liqiang Hao − Institute of Pharmacology, School of
Pharmaceutical Sciences, Shandong First Medical University &
Shandong Academy of Medical Sciences, Taian 271016, P.R.
China
Fu-Rong Li − Institute of Pharmacology, School of
Pharmaceutical Sciences, Shandong First Medical University &
Shandong Academy of Medical Sciences, Taian 271016, P.R.
China
Chengcai Xia − Institute of Pharmacology, School of
Pharmaceutical Sciences, Shandong First Medical University &
Shandong Academy of Medical Sciences, Taian 271016, P.R.
China; orcid.org/0000-0002-1943-5720
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01751
oxidative insertion of the rhodium(I) catalyst into the aldehyde
C−H bond of 1a in the presence of potassium carbonate
readily delivers a Rh(III) chelate I,14 which couples with 2a
through intermolecular hydrorhodation to give the stabilized
intermediate II by the bidentate chelation assistance of N,N-
dimethylmethacrylamide (L1).11 Note that selective cleavage
of the proximal C−C bond and isomerization initiated by
Rh(III), consistent with the reported literature,7,8 is more
favorable than the direct reductive elimination, thus leading to
the intermediate III. Subsequent reductive elimination and
protonation liberates the linear hydroacylation product and
reproduces the rhodium(I) catalyst.
In summary, a rhodium-catalyzed chelation-assisted inter-
molecular ring-expanding hydroacylation of ACPs with O- and
N-chelating aldehydes is reported. The reactions delivered the
linear trans-γ,δ-unsaturated ketones through selective proximal
C−C bond cleavage when monosubstituted ACPs were used as
the substrates. N,N-Dimethylmethacrylamide (L1) might
stabilize acylrhodium intermediates by bidentate coordination.
Author Contributions
#H.-S.L. and S.-C.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of Shandong Province (ZR2019MB003), the Key Research
and Development Program of Shandong Province
(2018GGX109010), Academic Promotion Programme of
Shandong First Medical University (2019LJ003), the National
Natural Science Foundation of China (21602256), the CAMS
Innovation Fund for Medical Sciences (CIFMS, 2017-I2M-2-
004), and the High-Level Project Cultivation Program of
TSMC (2018GCC16).
D
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