Chelating Group Enabled Palladium-Catalyzed Regiodivergent Carbonylative Synthesis of 2,3-Dihydroquinolin-4(1H)-ones

Article abstract of DOI:10.1002/chem.202003003

A new procedure on palladium-catalyzed carbonylative cyclization of N-(2-pyridyl)sulfonyl (N-SO₂Py)-2-iodoanilines with terminal alkenes has been developed for the rapid construction of dihydroquinolin-4(1H)-one scaffolds. Enabled by the chelat

Full text of DOI:10.1002/chem.202003003

Accepted Article
Accepted Article
Title: Chelating Group Enabled Palladium-Catalyzed Regiodivergent
Carbonylative Synthesis of 2,3-Dihydroquinolin-4(1H)-ones
Authors: Xiao-Feng Wu, Jun Ying, Jian-Shu Wang, Lingyun Yao, and
Wangyang Lu
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0
1/2020

Chemistry - A European Journal
10.1002/chem.202003003
COMMUNICATION
Chelating Group Enabled Palladium-Catalyzed Regiodivergent
Carbonylative Synthesis of 2,3-Dihydroquinolin-4(1H)-ones
Jun Ying,[a]+ Jian-Shu Wang,[a]+ Lingyun Yao, Wangyang Lu, Xiao-Feng Wu*
[a]
[b]
[a,c]
[
a]
Dr. J. Ying, J.-S. Wang, L. Yao, Prof. Dr. X.-F. Wu
Department ofChemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’sRepublicof China
E-mail: xiao-feng.wu@catalysis.de
[
[
+
b]
c]
Dr. W. Lu, School ofMaterialsScience and Engineering, ZhejiangSci-Tech University, Hangzhou, China
Leibniz-Institutfür Katalyse e. V. an der UniversitätRostock, Albert-Einstein-Straβe 29a, 18059Rostock, Germany
These authors contribute equallyto thismanuscript.
Abstract: A new procedure on palladium-catalyzed carbonylative
cyclization of N-(2-pyridyl)sulfonyl (N-SO Py)-2-iodoanilines with
iodoanilines and diethyl ethoxycarbonylbutendienote under 34
[
8]
2
bar of CO. Ennis and Nieman reported their achievement on
producing 3-carbomethoxymethyl-2,3-dihydro-4-quinolone from
N-allyl-N-benzyloxycarbonyl-2-iodoaniline under CO pressure
terminal alkenes has been developedfor the expedite construct io n of
dihydroquinolin-4(1H)-one scaffolds. Enabled by the chelating group
and using benzene-1,3,5-triyl triformate (TFBen) as the CO source,
both aromatic and aliphatic alkenes were smoothly transformed in to
the corresponding 2,3-dihydroquinolin-4(1H)-ones in good yields w it h
excellent regioselectivities. Notably, the reaction of aromatic alkenes
produces 2-aryl-2,3-dihydroquinolin-4(1H)-ones, while 3-alkyl-2,3-
dihydroquinolin-4(1H)-ones were obtained when aliphatic alkenes
were used. This protocol has been applied in the synthesis of
antitumor agent A as well.
[
9]
with palladium as the catalyst. However, these procedures are
limited to activated alkenes or analogues. The reaction with
unactivated alkenes still remains a challenge. Recently, Beller
and co-workers demonstrated
a
palladium-catalyzed
carbonylative Heck reaction of aryl halides with unactivated
[
10]
alkenes (6 equiv.) to afford α,β-unsaturated ketones. The
reaction involves the coordination and insertion of the alkene to
the acylpalladium complex and subsequent β-hydride elimination
as the key steps. To oursurprise, no cyclization product could be
obtained when 2-iodoaniline was tested as the substate. Notably,
the cyclization of such 2-amino-enone compound usuallyrequires
2,3-Dihydroquinolin-4(1H)-ones are recognized as a class of
momentous skeletons frequently found in biologically active
compounds (Scheme 1). For example, compound A, and B are
known to exhibit significant cytotoxicity against a panelof human
[11]
additionalcatalystsor promoters. Inspired by these studies,we
assume that under the assistance of an appropriate chelating
group on 2-iodoanilines, the keyintermediate D can be stabilized,
which simultaneouslyinhibitsβ-hydrideelimination and facilitates
the formation of the desired 2,3-dihydroquinolin-4(1H)-ones
[
1,2]
tumor cell lines. Compounds C can serve asa type of valuable
[
3]
moleculeswith potent analgesic activities. Due to theirintriguing
scaffolds, a large number of synthetic approaches for the
construction of 2,3-dihydroquinolin-4(1H)-ones have been
(
Scheme 2).
[4]
reported. However,most of these methodologies rely on the use
of specifictype of substrates.
Scheme 1. Selected Biologically Active Molecules Containing 2,3-
Dihydroquinolin-4(1H)-ones.
Transition-metal-catalyzed carbonylative reactions have
emerged as one of the most efficient and straightforward methods
[
5,6]
to access carbonyl-containing compounds.
However, there
have been very few exampleson carbonylative synthesisof 2,3-
[7-9]
dihydroquinolin-4(1H)-onesbeen reported. In 2007, Alper and
Ye developed a palladium-catalyzed cyclocarbonylation of 2-
iodoanilines and allenes to produce 3-methylene-2,3-
6
dihydroquinolin-4(1H)-onesunder5 bar of CO with BMIM·PF as
[
7]
the solvent. Lateron, the same group disclosed a facile protocol
for the synthesis of 2,3,3-triethoxycarbonyl-2,3-dihydroquinolin-
4(1H)-ones via a palladium-catalyzed cyclocarbonylation of 2-
Scheme 2. Carbonylation ofAryl Ha li des and Unactivated Alkenes.
1
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Under all these backgrounds, herein, we report our new
results on chelating ligand enabled palladium-catalyzed
achieved the best yield of 89% (Table 1, entries2-7). Also, it was
found that other phosphine ligands significantly hampered the
carbonylative cyclization of (N-SO
2
Py)-2-iodoanilines and
reaction (Table 1, entries 8-11). Next, we studied the effect of
unactivated alkenes. TFBen has been used the CO source
various solvents in this reaction, and moderate to good yields of
[
12]
here,
and diverse of substituted-2,3-dihydroquinolin-4(1H)- 3aa were obtained (Table 1, entries 12-15). Furthermore,
ones can be produced in good yields with excellent
regioselectivities. Notably, the reaction of aromatic alkenes
reducing or raising the reaction temperature gave trace or no
product (Table 1, entries 16-17). It was noteworthy that the yield
produces 2-aryl-2,3-dihydroquinolin-4(1H)-ones, while 3-alkyl- of 3aa (88%) could be maintained when the amount of 2a was
2
,3-dihydroquinolin-4(1H)-ones were obtained when aliphatic
decreased (Table 1, entry 18). Additionally, it was shown that
either reducing the amount of the Pd catalyst or shortening the
reaction time gave much loweryield of the finalproduct (Table 1,
entries 19-20).
alkenes were used.
[a]
Table 1. Screeningof the Reaction Conditions.
[
a]
Table 2. Scope of Aromatic Alkenes.
(
o
Entry
[Pd]
Ligand
dppp
Solvent Temp C) Yield (%)
1
2
3
4
5
6
7
8
9
PdCl
2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
THF
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
90
37
83
Pd(OAc)
Pd(TFA)
[PdCl(cinnamy)]
Pd(acac)
Pd(PPh
Pd (dba)
2
dppp
2
dppp
18
2
dppp
16
2
dppp
89
3
)
4
dppp
70
2
3
dppp
59
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
2
2
xantphos
dppe
trace
n.r.
n.r.
n.r.
53
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
2
2
PPh
PCy
3
3
2
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
2
2
72
CH
3
CN
70
2
2
DMSO
dioxane
dioxane
dioxane
dioxane
dioxane
89
trace
n.r.
88
2
130
110
110
110
[
b]
1
8
9
0
Pd(acac)
2
[
c]
d]
1
2
Pd(acac)
Pd(acac)
2
6
[
2
8
[
a] Reaction condition: 1a (0.5 mmol, 1.0 equiv.), 2a (3.0 mmol, 6.0 equiv.), Pd
catalyst (20 mol %), ligand (20 mol %), TFBen (2.0 mmol), Et N (1.0 mmo l) ,
solvent (1.0 mL), 48 h, isolated yield. [b] 2a (2.0 mmol, 4.0equiv.).[c]Pd cata ly st
3
(10 mol %). [d] 24 h.
At the outset, the (N-SO
were treated with TFBen (4.0 equiv) in the presence of PdCl
mol %) and dppp (20 mol %) at 110 C for 48 h. To our delight,
the reaction gave the target 2-phenyl-2,3-dihydroquinolin-4(1H)-
one 3aa in 37% isolated yield (Table 1, entry 1). Then, a seriesof
2
Py)-2-iodoaniline 1a and styrene 2a
(20
2
o
[a] Reaction condition: 1a (0.5 mmol, 1.0 equiv.), 2 (2.0 mmol, 4.0 equ iv .),
Pd(acac) (20 mol %), dppp (20 mol %), TFBen (2.0 mmol), Et N (1.0 mmo l) ,
dioxane (1.0 mL), 48 h, isolated yield. [b] 2 (3.0mmol, 6.0 equiv.)
2
3
Pd catalysts were investigated and the reaction with Pd(acac)
2
2
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COMMUNICATION
[
a]
With the optimal reaction conditions (Table 1, entry 18) in
hand, the scope of aromaticalkeneswas then investigated (Table
Table 4. Scope of Aliphatic Alkenes.
2). For styrenes with eitherpara-electron-donating or withdrawing
substituents, the reaction afforded the desired products 3aa-aj in
good to excellent yields. The structure of product 3ah was
unambiguously confirmed by X-ray crystallography (CCDC
[
13]
1
999576, see the Supporting Information). Moreover, it was
found that meta-substituted styrenes were successfully
transformed to the expected products 3ak-an in high yields as
well (77-87%). The reaction of o-methylstyrenegave product 3ao
in 65% yield. It was shown that 59% yield of product 3ap was
obtained when 2,4-dimethylstyrene was treated. Additionally, the
reaction of 2-vinylnaphthaleneproceeded wellto give product 3aq
in 81% yield. It was noted that when 1,1-disubtiuted or 1,2-
disubtiuted aromaticalkeneswere tested, trace or no product 3ar-
as could be observed, which could be attributed to the steric
hindrance ofthe alkenes.
Then, a series of (N-SO
and examined in the reaction with styrene 2a as shown in Table
. For compounds having substituentssuch as methyl, methoxyl
2
Py)-2-iodoanilines1 were prepared
3
and fluorine at the C4 position, the reaction gave the
corresponding products 3ba-da in excellent yields. Additionally,
good yields of products 3ea-fa were achieved when 5-Cl and 5-
Br substituted compoundswere subjected to the reactionsystem.
[
a] Reaction condition: 1a (0.5 mmol, 1.0 equiv.), 2 (3.0 mmol, 6.0 equ iv .),
Pd(acac) (20 mol %), dppp (20 mol %), TFBen (2.0 mmol), Et N (1.0 mmo l) ,
dioxane (1.0 mL), 48 h, isolated yield. [b] 2 (2.0 mmol, 4.0equiv.)
2
3
[
a]
2
Table 3. Scope of (N-SO Py)-2-Iodoanilines.
Gratifyingly, the N-SO
easily under mild conditions, which makes the dihydroquinolin-
(1H)-one scaffold more accessible forfurther modifications. The
treatment of 3aa with excess zinc powder in mixed solvent
THF/NH Cl(aq) = 1:1) afforded the corresponding free amino
product 5 in 90% yield (Scheme 3).
2
Py directing group can be removed
4
(
4
2
Scheme 3. Removal of the N-SO PyDirecting Group.
[
a] Reaction condition: 1a (0.5 mmol, 1.0 equiv.), 2 (2.0 mmol, 4.0 equ iv .),
Pd(acac) (20 mol %), dppp (20 mol %), TFBen (2.0 mmol), Et N (1.0 mmo l) ,
dioxane (1.0 mL), 48 h, isolated yield.
2
3
To our surprise, when aliphatic alkenes were employed in the
reaction of 1a, 3-alkyl-2,3-dihydroquinolin-4(1H)-ones 4 were
obtained as shown in Table 4. It was much likely that the
regioselectivity of the reaction was affected by the electronic
effect of substituents on alkenes. For linear and branched
aliphaticalkenes, the reaction gave the desired products 4aa-ad
in high yields. The reactionof a substrate containing a carbocyclic
unit furnished product 4ae in 60% yield. Furthermore, compounds
bearing a benzene ring were converted to the expected products
Scheme 4. Synthesis of the Ant it umor Agent A.
4af-ah in good yields. Notably, 59% yield of product 4ai was
achieved when a substrate with a silyl group was treated. It was
also found that thereaction with cyclohexene didn’t occur.
To further demonstrate the utility of this protocol, the
synthesis of the antitumor agent A has been efficiently
accomplished in four steps (Scheme 4). The iodonation of
benzo[d][1,3]dioxol-5-amine 6 led to the iodide 7 in 87% yield,
3
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COMMUNICATION
which was then reacted with 2-pyridylsulfonylchloride to give the
sulfonamide 8 with a high yield of 90%. When 8 and 3-
fluorostyrene were subjected to the standard conditions, the (N-
SO
93%). Furthermore, a gram-scale experiment wasconducted for
this step, and 70% yield of 9 was obtained. Subsequently, the
removal of the N-SO Py group on 9 with zinc powder and
THF/NH Cl resulted in the antitumor agent A in 85% yield.
2
Py)-protected compound 9 was achieved in an excellent yield
(
2
4
In order to gain a better understanding of the reaction
mechanism and proven the concept of chelating effect, a few
preliminary studies were performed (Scheme 5). Firstly, no
reaction occurred when the N-benzenesulfonyl-2-iodoaniline 10
and styrene 2a were subjected to the standard conditions
(
Scheme 5, eq 1). It indicates that the coordination of the
palladium catalyst with the N atom on N-SO Py of 1 plays an
2
important role in this reaction. The reaction of the N-picolinyl-2-
iodoaniline 11 led to 25% yield of thecarbonylated compound 12
but failed to give product 13, suggesting that the lessnucleophilic
sulfuryl unit on the directing group is important in both inhibiting
the direct cyclocarbonylation of 11 and allowing coupling with
styrene (Scheme 5, eq 2). Finally, the α, β-unsaturated ketone 14
was prepared and treated with 2a under the standard conditions.
The target product 3aa was not observed, which showed that
another reaction pathwayinvolving β-hydride eliminationcould be
ruled out (Scheme 5, eq 3).
Scheme 6. Plausible Mechanism.
In conclusion, we have developed a facile and
straightforward access to structurally diverse substituted-2,3-
dihydroquinolin-4(1H)-ones in good yields and with excellent
regioselectivities via
a
palladium-catalyzed carbonylative
cyclization of (N-SO Py)-2-iodoanilines and unactivated alkenes
2
by using TFBen as the CO source. Thismethod also providesan
efficient approach forthe synthesisof the antitumor agent A. The
presence of the chelating group in thesubstratesis crucialforthe
successof the transformation.
Acknowledgements
We acknowledge financial supports from the National Natural
Science Foundation of China (21772177), Zhejiang Natural
Science Fund for Young Scholars (LQ18B020008) and Zhejiang
Sci-Tech University (17062078-Y).
Scheme 5. PreliminaryMechanistic Stud ie s.
Keywords: alkene • carbonylation • 2,3-dihydroquinolin-4(1H)-
ones • regioselectivity• palladiumcatalyst
1
0
On the basis of the previous reports and the experimental
findings, a plausible mechanismis proposed (Scheme 6). Initially,
[
[
[
1]
2]
3]
Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Tachibana, S.-C. Kuo, E.
Hamel, T. Hackl, K.-H. Lee, J. Med. Chem. 1998, 41, 1155-1162.
S.-X. Zhang, J. Feng, S.-C. Kuo, A. Brossi, E. Hamel, A. Tropsha, K.-H.
Lee, J. Med. Chem. 2000, 43, 167-176.
treatment of Pd(acac)
which reacts with the (N-SO
2
with dppp forms the active Pd(0) species,
Py)-2-iodoaniline 1a to afford the
2
Pd(II) complexA’ via oxidative addition. Then, CO, released from
TFBen, is coordinated and inserted to A’ to give the acyl Pd(II)
intermediateB’. Subsequently, coordination of styrene 2a with B’
generates the Pd(II) species C’, which can undergo alkene
M. S. Atwa l, L. Bauer, S. N. Dixit, J. E. Gearien, R. W. Morris, J. Med.
Chem. 1965, 8, 566-571.
[4]
a) C. Shen, A. Wang, J. Xu, Z. An, K. Y. Loh, P. Zhang, X. Liu, Chem.
2019, 5, 1059-1011; b) N. G. Kundu, J. S. Mahanty, P. Das, B. Das,
2
insertion with the aid of the N-SO Py directing group to give the
Tetrahedron Lett. 1993, 34, 1625-1628;c) Y. Gong, K. Kato, J. Fluor in e
Chem. 2004, 125, 767-773; d) K. W. Anderson, J. J. Tepe, Tetrahedron
key Pd(II) intermediate D’. Finally, reductive elimination of D’
leads to the desired product 3aa and regenerates the active Pd(0)
catalyst. Notably the reverse regioselectivity of aryl and alkyl
alkenes insertion in this system might due to the electron effect
from the alkenes. As the intermediate acylpalladium(II)may prefer
to bind to themore electron rich carbon of the double bond.
2002, 58, 8475-8481;e) T. Nemoto, T. Kukuda, Y. Hamada, Tetrahedron
Lett. 2006, 47, 4365-4368.
[
[
5]
6]
a) J.-B. Peng, F.-P. Wu, X.-F. Wu, Chem. Rev., 2019, 119, 2090-2127;
b) S. Sumino, A. Fusano, T. Fukuyama, I. Ryu, Acc. Chem. Res., 2014,
47, 1563-1574; c) R. Mancuso, N. Della Ca’, L. Veltri, I. Ziccarel li, B.
Gabriele, Catalysts, 2019, 9, 610-642;d) S. Zhao, N. P. Mankad, Catal.
Sci. Technol., 2019, 9, 3603-3613.
a) P. Gautam, B. M. Bhanage, Catal. Sci. Technol., 2015, 5, 4663-4702;
b) J. Cao, Z.-J. Zheng, Z. Xu, L.-W. Xu, Coord. Chem. Rev., 2017, 336,
4
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Chemistry - A European Journal
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COMMUNICATION
43-53; c) S. D. Friis, A. T. Lindhardt, T. Skrydstrup, Acc. Chem. Res.,
2016, 49, 594–605; d) H. Konishi, K. Manabe, Synlett, 2014, 25, 1971-
1986.
[
[
[
[
7]
8]
9]
F. Ye, H. Alper, J. Org. Chem. 2007, 72, 3218-3222.
K. Okuro, H. Alper, J. Org. Chem. 2012, 77, 4420-4424.
J. A. Nieman, M. D. Ennis, J. Org. Chem. 2001, 66, 2175-2177.
10] a) X.-F. Wu, H. Neumann, A. Spannenberg, T. Schulz, H. Jiao, M. Bel le r,
J. Am. Chem. Soc. 2010, 132, 14596-14602; b) X.-F. Wu, H. Neumann,
M. Beller, Angew. Chem. Int. Ed. 2010, 49, 5284-5288.
[
[
11] M. Castaing, S. L. Wason, B. Estepa, J. F. Hooper, M. C. Willis, Angew.
Chem. Int. Ed. 2013, 52, 13280-13283.
12] a) L.-B. Jiang, X. Qi, X.-F. Wu, TetrahedronLett., 2016, 57, 3368-3370;
b) J. Ying, Z. Le, Z.-P. Bao, X.-F. Wu, Org. Chem. Front., 2020, 7, 1006-
1010; c) J. Ying, Z. Le, X.-F. Wu, Org. Lett., 2020, 22, 194-198.
[
13] CCDC 1999576 contains the supplementarycrystallographic datafor this
paper. These data can be obtained free of charge from The Cambr id ge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/c if .
5
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Entry for the Table of Contents
A chelating group enabled straightforward access to structurallydiverse substituted-2,3-dihydroquinolin-4(1H)-onesin good yields
and with excellentregioselectivitiesvia palladium-catalyzed carbonylative cyclization of (N-SO Py)-2-iodoanilinesand unactivated
2
alkenes has been developed. Thismethod also providesan efficient approach forthe synthesisof the antitumor agent A.
6
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