Palladium-Catalyzed Tandem Carbonylative Diels-Alder Reaction for Construction of Bridged Polycyclic Skeletons

Article abstract of DOI:10.1021/acs.orglett.1c00274

A palladium-catalyzed tandem carbonylative lactonization and Diels-Alder cycloaddition reaction between aldehyde-tethered benzylhalides and alkenes has been developed. A range of alkenes and aldehyde-tethered benzylhalides bearing different substituents can be successfully transformed into the corresponding bridged polycyclic compounds in good yields. This strategy provides a unique approach to complex lactone-containing bridged polycyclic compounds.

Full text of DOI:10.1021/acs.orglett.1c00274

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Letter
Palladium-Catalyzed Tandem Carbonylative Diels−Alder Reaction
for Construction of Bridged Polycyclic Skeletons
Siyuan Wang, Yangkun Zhou, and Hanmin Huang*
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ABSTRACT: A palladium-catalyzed tandem carbonylative lacto-
nization and Diels−Alder cycloaddition reaction between
aldehyde-tethered benzylhalides and alkenes has been developed.
A range of alkenes and aldehyde-tethered benzylhalides bearing
different substituents can be successfully transformed into the
corresponding bridged polycyclic compounds in good yields. This
strategy provides a unique approach to complex lactone-containing bridged polycyclic compounds.
Scheme 1. Palladium-Catalyzed Carbonylative
Lactonization and Cycloaddition
he carbonyl-containing bridged polycyclic architectures
are common structural motifs in natural products.1 Such
T
cycloadducts are also able to serve as valuable intermediates in
the synthesis of functionalized carbocycles and have therefore
attracted much attention from synthetic chemists.2 One
reliable and rapid method for the assembly of such complex
architectures is the Diels−Alder reaction with carbonyl-
containing conjugated cyclic dienes.3 Despite the tremendous
progress, most of the so far known methods have focused on a
stepwise protocol requiring tedious procedures for the
preparation of the key carbonyl-containing cyclic conjugate
dienes, thus restricting the overall scope and practicality of
these transformations. Therefore, the development of a cascade
annulation reaction with readily available acyclic substrates as
starting materials is highly desirable but challenging.
Transition-metal-catalyzed carbonylation is one of the most
intensively used methods for the synthesis of carbonyl
compounds in both academic and industrial settings.4,5
Whereas efficient carbonylation reactions have been well
developed for the synthesis of saturated lactones, direct
carbonylation access to unsaturated lactones that could be
employed in the Diels−Alder reaction has rarely been
developed. Inspired by the fact that the carbonyl oxygen
could attack the acyl-metal species to form a lactone under the
appropriate reaction conditions,6 we have successfully
established a palladium-catalyzed hydrocarbonylative cyclo-
addition reaction with two alkenes in the presence of CO
(Scheme 1).7 The HPdX-catalyzed carbonylative lactonization
of the aldehyde-tethered alkenes was involved in the reaction,
which paved a way to the synthesis of various lactone-
containing bridged polycyclic compounds in good to excellent
yields with high regioselectivities. However, the alkene-
coupling partner of the reaction was significantly limited to
aromatic alkenes. From a mechanistic perspective, the
underlying reason for the limitation can probably be assigned
to the competitive hydropalladation reaction between the two
alkenes. In this context, we envisaged that once the
carbonylation is initiated via a Pd(0) other than HPdX, the
corresponding competitive hydropalladation reaction would be
inhibited. Herein we report a cascade annulation reaction
initiated via the Pd(0)-catalyzed carbonylative lactonization of
2-bromomethyl arylaldehydes. The reaction is applicable in
synthesizing complex lactone-containing bridged polycyclic
Received: January 24, 2021
Published: March 2, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00274
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2125−2129
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Letter
compounds from simple 2-bromomethyl arylaldehydes, a
broad range of alkenes, as well as carbon monoxide.
this catalytic reaction was not only suitable for 2-
(bromomethyl)benzaldehyde but also suitable for 2-
(chloromethyl)benzaldehyde (Table 2, entry 1). Subsequently,
Guided by this hypothesis and on the basis of our previous
studies,7,8 we started our studies by investigating the model
reaction among 2-(bromomethyl)benzaldehyde (1a), styrene
(2a), and CO. The initial experiments were conducted in
anisole at 120 °C with [Pd(allyl)Cl]2 as a catalyst precursor
and RuPhos as the ligand. The extensive screening of the base
(Table 1, entries 1−6) showed NaOAc to be the best base,
a
Table 2. Substrate Scope of Aromatic Aldehyde
a
b
c
Table 1. Optimization of the Reaction Conditions
entry
R
X
3
yield (%)
endo/exo
1
2
H
H
4-MeO
3-MeO
5-MeO
4-F
4-Cl
4-Br
5-Br
3-Br
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
3aa
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
78
82
77
78
72
55
60
70
53
35
61
93:7
93:7
96:4
95:5
93:7
96:4
96:4
96:4
93:7
96:4
97:3
d
3
d
4
d
5
yield,
3aa + 3aa′(%)
b
entry
[Pd]
base
endo/exo
6
7
8
9
10
11
1
2
3
4
5
6
7
8
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd2(dba)3
PdCl2
Na2CO3
NaHCO3
NaOAc
KOAc
t-BuONa
DBU
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
15
14
35
15
trace
trace
49
29
51
38
37
33
0
64
69
93 (82)
93:7
93:7
93:7
93:7
4-Ph
3ja
a
Reaction conditions: 1 (0.50 mmol), 2a (0.75 mmol), PdBr2 (5 mol
93:7
93:7
93:7
93:7
93:7
93:7
%), RuPhos (6 mol %), NaOAc (0.75 mmol), anisole (1.0 mL), CO
b
(60 atm), 120 °C, 12 h. Isolated yield (endo + exo) based on the
c
aldehyde. Ratio (endo/exo) of the crude reaction mixture was
9
PdBr2
d
determined by GC and GC−MS. Pd2(dba)3 (2.5 mol %), 80 °C.
10
11
12
13
14
15
16
Pd(OAc)2
Pd(COD)Br2
Pd(CH3CN)2Cl2
Pd(TFA)2
PdBr2
we evaluated a series of aldehyde-tethered benzyl bromides. It
was found that 2-(bromomethyl)benzaldehydes carrying both
electron-rich and -deficient groups tethered with the phenyl
ring reacted smoothly with styrene (2a) in the presence of CO,
affording the corresponding tandem cycloadducts in 35−82%
yields with good to excellent diastereoselectivities. There was
no necessary connection between the position of the
substituent and the reaction efficiency for methoxy-substituted
2-(bromomethyl)benzaldehydes (Table 2, entries 3−5). Be-
sides, the halogen substituents, such as fluoro, chloro and
bromo atoms, were also compatible with this protocol, leading
to the corresponding products in 53−70% yields (Table 2,
entries 6−10). Notably, the desired product was obtained in
only 35% yield with 3-bromo-2-(bromomethyl)benzaldehyde
as the substrate, as most of the starting material underwent
nucleophilic substitution reaction with NaOAc (Table 2, entry
10). Furthermore, 2-bromomethyl aromatic aldehyde derived
from biphenyl could also run the reaction in 61% yield (Table
2, entries 11).
In addition to styrene 2a, a series of aryl alkenes bearing a
variety of substituents were subsequently examined. Methyl,
methoxyl, chloro, and fluoro substituents on the phenyl ring of
the styrenes were well tolerated, and the desired products
3ab−3al were successfully obtained in 61−76% yields. The
reaction efficiency was more sensitive to the position of the
substituent, and para-substituted styrenes exhibited higher
reactivities (Table 3, entries 2−4). No obvious electronic effect
was observed. Both electron-rich and -poor aryl alkenes could
react smoothly (Table 3, entries 2−10). Prop-1-en-2-ylbenzene
and (E)-prop-1-en-1-ylbenzene were also compatible with this
process but gave the corresponding products in moderate
yields, presumably due to the steric hindrance (Table 3, entries
11 and 12). It is noteworthy that the structure of the product
endo-3ae was confirmed by X-ray single-crystal diffraction
analysis.
c
93:7
93:7
93:7
c d
,
PdBr2
PdBr2
c e
,
a
Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), [Pd] (5 mol
%), RuPhos (11 mol %), base (0.75 mmol), anisole (1.0 mL), CO (20
b
atm), 120 °C, 12 h. Combined yield (3aa + 3aa′) based on the
aldehyde and the ratio (3aa/3aa′) of the crude reaction mixture was
determined by GC and GC−MS analysis using n-tetradecane as the
internal standard. The yield in parentheses is the isolated yield (3aa +
c
d
e
3aa′). RuPhos (6 mol %). CO (40 atm). CO (60 atm).
delivering the desired product 3aa in 35% yield. This result
encouraged us to optimize the reaction conditions by screening
the catalyst precursor. To our delight, when PdBr2, Pd2(dba)3,
and Pd(PPh3)4 were introduced into the catalytic system, the
desired product 3aa could be obtained with high selectivity,
albeit in moderate yield. The simple PdBr2 was proved to be
the best catalyst precursor (Table 1, entries 7−12), but almost
no reaction took place when Pd(TFA)2 was used (Table 1,
entry 13). Further investigation of the ligands disclosed that
the RuPhos exhibited the highest efficiency. (See the
Supporting Information.) By decreasing the ratio of RuPhos/
Pd from 2.2:1 to 1.2:1, the desired product was obtained in
64% yield (Table 1, entry 14). The yield rose to 82% when the
reaction was conducted under 60 atm of CO (Table 1, entry
16). Moreover, the temperature and solvent were assessed, yet
the variation of these parameters delivered no better results. As
expected, no desired product was observed in the absence of a
palladium catalyst or ligands.
Having the effective reaction conditions identified for this
transformation, the substrate scope and generality were next
explored. First, 2-(chloromethyl)benzaldehyde was tested
under the standard reaction conditions, which disclosed that
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Letter
a
a
Table 3. Scope of Aryl Alkenes
Scheme 2. Substrate Scope of Alkenes
b
c
entry
Ar, R1, R2
C6H5, H, H
3
yield (%)
endo/exo
1
2
3
4
5
6
7
8
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
82
61
70
72
68
71
71
73
76
70
54
34
93:7
91:9
95:5
95:5
91:9
92:8
92:8
91:9
91:9
95:5
82:18
85:15
2-MeC6H4, H, H
3-MeC6H4, H, H
4-MeC6H4, H, H
4-MeOC6H4, H, H
4-t-BuC6H4, H, H
4-CF3C6H4, H, H
2-ClC6H4, H, H
4-ClC6H4, H, H
4-FC6H4, H, H
C6H5, Me, H
9
10
11
12
3aj
3ak
3al
C6H5, H, Me
a
Reaction conditions: 1a (0.50 mmol), 2 (0.75 mmol), PdBr2 (5 mol
%), RuPhos (6 mol %), NaOAc (0.75 mmol), anisole (1.0 mL), CO
b
(60 atm), 120 °C, 12 h. Isolated yield (endo + exo) based on the
c
aldehyde. Ratio (endo/exo) of the crude reaction mixture was
determined by GC and GC−MS.
After the exploration with aryl alkenes, we turned our
attention to the electron-rich functionalized alkenes. As shown
in Scheme 2, such substrates containing aliphatic vinyl ethers
and an N-vinyl amide moiety were investigated under the
optimized reaction conditions, preferentially affording the
corresponding products in moderate to good yields (57−73%)
with slightly lower regioselectivity (Scheme 2, 3am−3at).
However, attempts to investigate the methyl acrylate, dimethyl
maleate, and cyclohexene were unsuccessful. These results
indicated that they were not effective coupling partners for this
transformation.9 Nevertheless, because of the high ring strain,
the cis-cyclooctene 2u and cyclopentene 2v were subjected to
the reaction to afford the desired products in moderate yields
with excellent diastereoselectivities (Scheme 2, 3au and 3av).
Moreover, the simple ethylene was employed for this reaction
under the standard conditions, providing the desired product
3aw in 54% yield. Meanwhile, the structures of products of
endo-3aq and endo-3au were confirmed by X-ray single-crystal
diffraction analysis.
a
Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), PdBr2 (5.0 mol
%), RuPhos (6.0 mol %), NaOAc (0.75 mmol), anisole (1.0 mL), CO
(20 atm), 80 °C, 12 h. The isolated yield (endo + exo) is based on
aldehyde. The ratio (endo/exo) of the crude reaction mixture was
b
determined by GC and GC−MS. Ethylene (10 atm).
Scheme 3. Synthetic Utility of the Present Reaction
Several transformations of the obtained compounds 3aq
were conducted to expand the synthetic potential of the
present reaction. As shown in Scheme 3, the reaction of 1a
with 2q on a 5 mmol scale was completed under the standard
conditions, yielding 778 mg of the corresponding product 3aq
in 72% yield with a good diameter. Alcoholysis of the ester
group afforded 4 in 78% yield under acidic conditions at room
temperature.9 Meanwhile, compound 5 was obtained in 49%
yield at 100 °C under otherwise identical conditions. The solid
structure of 5 was further confirmed by X-ray single-crystal
diffraction analysis. Subsequently, the ester group could be
reduced with triethylsilane to give the bridged cyclic ether 6 in
82% yield.10
undergoes oxidative addition to 1a, producing the benzylpalla-
dium species II. The insertion of CO into the C−Pd bond of II
affords the acylpalladium species III, followed by reductive
elimination to give the intermediate IV and regenerate the
active Pd(0) catalyst. With the assistance of the base, the
deprotonation of IV leads to the transient benzopyran-2-one V,
On the basis of the results the above and previous reports,7,8
a plausible mechanism of this carbonylative cycloaddition
reaction is proposed as the following catalytic cycle (Figure 1).
The Pd(II) catalyst precursor is reduced by CO or a phosphine
ligand to the (RuPhos)Pd(0) I species, which subsequently
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University of Science and Technology of China, Hefei
230026, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00274
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural
Science Foundation of China (21790333 and 21925111).
■
REFERENCES
Figure 1. Plausible reaction mechanism.
■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00274.
■
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Experimental procedures and characterization data
(PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Hanmin Huang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei
230026, P. R. China; Center for Excellence in Molecular
Synthesis of CAS, Hefei 230026, P. R. China; orcid.org/
0000-0002-0108-6542; Email: hanmin@ustc.edu.cn
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Transition-metal-catalyzed carbonylation reactions of olefins and
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Authors
Siyuan Wang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei
230026, P. R. China
Yangkun Zhou − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
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