Pd-Catalyzed sequential β-C(sp3)-H arylation and intramolecular amination of δ-C(sp2)-H bonds for synthesis of quinolinones: Via an N,O-bidentate directing group

Article abstract of DOI:10.1039/c6cc02865a

The pharmacological importance of 2-quinolinone derivatives is well known. Herein, we developed an effective protocol for the synthesis of 2-quinolinone derivatives by palladium-catalyzed sequential β-C(sp³)-H arylation and selective intramolecular C(sp²)-H/N-H amination starting with aryl iodides and carboxylic acids. A novel directing group, glycine dimethylamide, was used in the synthesis. We synthesized various quinolinone derivatives, including 5-substituted quinolinones, which are difficult to obtain using the traditional pathway. The directing group could be easily removed and could be readily transformed into other useful functional groups.

Full text of DOI:10.1039/c6cc02865a

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ARTICLE
Pd-Catalyzed Sequential β-C(sp3)–H Arylation and Intramolecular
Amination of δ-C(sp2)–H Bonds to Synthesis of Quinolinones via a
N,O-Bidentate Directing Group
Received 00th January 20xx,
Accepted 00th January 20xx
Mingyu Guan,b Yubo Pang,b Jingyu Zhang*a and Yingsheng Zhao*b
DOI: 10.1039/x0xx00000x
The pharmacological importance of 2-quinolinone derivatives is well known. Herein, we developed an effective protocol
for the synthesis of 2-quinlinolinone derivatives by palladium-catalyzed sequential β-C(sp3)–H arylation and selective
intramolecular C(sp2)–H/N–H amination starting with aryl iodides and carboxylic acids. Synthesis used a novel directing
group, glycine dimethylamide. We synthesized various quinlinolinone derivatives, including 5-substituted quinlinolinones,
which are difficult to obtain using the traditional pathway. The directing group could be easily removed and could be
readily transformed into other useful functional groups.
www.rsc.org/
applicability of the procedure for 2-quinolinone synthesis. (1)
Despite the development of numerous possible directing
groups for carboxylic acid, such as 8-aminoquinoline,6 o-
methyl hydroxyamine,7 2-methylthioaniline,8 fluorinated
aniline,9 amino ester,10 amino acid,11 isoleucine-NH2,12 and
carboxylic acids themselves,13 there are few protocols for six-
membered N-heterocycles using directing-group-assisted
Introduction
The 2-quinolinone unit is a heterocycle present in numerous
natural alkaloids, biologically active compounds, and
commercial drugs.1 Over the past decades, various synthetic
methods for 2-quinolinone have been developed. These
include Friedel–Crafts cyclization,2 transition-metal-catalyzed
cascade reaction,3 and radical reactions.4 However, further
studies showed that these methods usually suffered from
harsh reaction conditions, limited substrates scope or the use
of prefunctionalized substrates.
Cy
HO
N
N
N
Cl
H
N
N
N
N
Cl
O
In the last decades, transition-metal-catalyzed direct C–H
activation has resulted in great achievements in cross-coupling
reactions, which provide an alternative approach for
O
N
O
N
O
O
N
O
H
H
H
Cilostazol
Carteolol
constructing
versatile
synthons
without
requiring
Abilify
prefunctionalization.5 Thus,
a
convergent procedure to
H
Cl
N
O
synthesize various functional substituted 2-quinolinone
derivatives through C–H functionalization would be very
attractive in synthetic chemistry. Retrosynthesis of 2-
quinolinone revealed that it could be performed with simple
carboxylic acids and aryl iodides via palladium-catalyzed β-
C(sp3)–H arylation and subsequent intramolecular δ-C(sp2)–H
amination (Scheme 1A). However, we anticipated several
potential problems that should be addressed to ensure the
S
O
NH
O
N
N
OH
H
N
HN
H
O
N
HO
O
N
N
O
NH2
H
OH
Procaterol
Figure 1 Drugs that contain the quinlinolinone unit.
O
Experimental drug
(-)-Chaetominine
intramolecular amination.14 The groups of Shi15 and Wu16
demonstrated that a versatile intramolecular amination using
an N,N-bidentate directing group and phenylalanine
derivatives tends to generate four-membered N-heterocycles
via five-membered palladacycles. Thus, a new directing group
that can easily form seven-membered palladacycles, which are
rare, need to be explored. (2) Although β-C(sp3)–H arylation of
a.College of Physics, Optoelectronics and Energy & Collaborative Innovation Center
of Suzhou Nano Science and Technology, Soochow University, Suzhou 215006,
China. E-mail: jyzhang@suda.edu.cn
b.Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science Soochow University, Suzhou 215123,
China. E-mail: yszhao@suda.edu.cn
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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carboxylic acid derivatives with aryl iodides using directing dichloridethane. The groups of Yu, Chatani, and Hong
groups has been reported,6-12, 17 ortho-substituted aryl iodides respectively found that the directing groups including α-amino
have seldom been used as coupling partners.11 Ortho- acid, α-amino ester, and α-amino amide exhibit high activity in
substituted aryl iodides are the main substrates for the
synthesis of important drugs such as carteolol and procaterol.
Table 1 Synthesis of quinolinones from alanine with aryl idodies by palladium
catalyzed cascade C-H functionalization
A: Retrosynthesis of 2-quionlione
NPhth
O
H
H
O
R
O
R
selective amidation
of -C(sp2)-H bonds
PhthN
H
NMe2
DG
1. condition A
2. condition B
N
N
N
O
O
FG
H
ArI
FG
H
O
R
N
3
DG
2
1
NMe2
3
-arylation of
C(sp3)-H bonds
R
R = F
3a, 74%[ae,j]
R = Cl
R = Br
R = I
NPhth
3b, 81%[af,i] 3c, 80%[ae,i] 3d, 51%[af,i]
O
R = iPr
R = H
N
O
O
DG
R = OMe
R = Me
+
H
N
directing group
precursor
FG
3h, 85%[de,h]
3g, 54%[cf,i]
3f, 84%[af,j]]
3e, 81%[af,i]
H
I
R
1
NMe2
R = tBu
B: Directing group precursors
R = Br
R = Me
NPhth
3k, 56%[ae,j]
3j, 84%[de,h]
3i, 82%[de,h]
O
O
N
R
N
O
O
R1
N
new directing group
for carboxylic acid
R = CO2Me
R = Ac
R =CF3
3n, 58%[ag,j]
3m, 62%[af,i]
3l, 42%[bg,j]
O
N(iPr)2
L
O
L
R2
iPr
NMe2
Br
Oxyl amide
H2N
MeOOC
NPhth
NPhth
Me
NPhth
H2N
H2N
R
H2N
O
N
O
N
O
O
Me
N
O
O
OH
NH2
O
OMe
O
NMe2
O
O
R = H or iPr
this work
Hong
Chatani
Yu
NMe2
NMe2
NMe2
3o, 79%[de,h]
3p, 56%[ae,i]
3q, 70%[ae,i]
Scheme 1 Use of GDMA as an auxiliary for carboxylic acid.
Condition A: a
1 (0.2 mmol), Pd(OAc)2 (5 mol%), AgOAc (2 equiv), HFIP (1
mL), 80 oC, air, 12 h. b 100 oC. c 120 oC. d t-AmylOH (1 mL). e ArI (1.2 equiv). f
ArI (1.5 equiv). g ArI (1.05 equiv).
h
Condition B: PhI(OAc)2 (2.5 equiv), PivOH (0.3 equiv), HFIP (4 mL), 70
oC, Ar, 18 h. i 100 oC. j 120 oC.
Thus, there is a need for protocols that use various ortho-
substituted aryl iodides as coupling partners, which give the
key intermediate for the synthesis of various 2-quinolinones.
(3) The directing group should be easily removable or should
allow further transformation to other desired functional
groups. Herein, we report a convenient, effective, and readily
applicable protocol for the synthesis of 2-quinolinone
derivatives from carboxylic acids and aryl iodides via
Table 2 Synthesis of quinolinones from propionic acid with aryl idodies by
palladium catalyzed cascade C-H functionalization
Me2N
O
condition
C
O
O
O
condition
A
palladium-catalyzed
sequential
C–H
arylation
and
N
O
HN
R
R
NH
intramolecular amination using
a
novel N,O-bidentate
ArI
O
H
NMe2
NMe2
4
directing group. The newly developed protocol provides a
convergent path for the synthesis of key intermediates of
bioactive compounds. More importantly, various 5-substituted
2-tetrahydroquinolinones, which are difficult to synthesize
through traditional paths, were obtained in good yield
(Scheme 1).
2
1
Cl
Br
O
O
O
O
O
O
N
N
N
NMe2
NMe2
4a, 86%[c]
4c, 83%[d]
4b, 76%[c]
NMe2
[a]
[b]
[a]
2a,
2c,
79%
2b,
77%
71%
MeO
O
O
O
F3C
NMe2
N
O
N
O
O
N
Results and discussion
NMe2 Br
NMe2
[d]
[d]
4f, 84%[d]
4d,
4e,
78%
82%
2e, 86%[b]
2d, 80%[b]
2f,
[b]
Our group demonstrated that the N,O-bidentate directing
group has high activity in forming C–H bonds at the ε
position,18 which leads to a rare seven-membered palladacycle.
On the basis of these observations, we propose that glycine
dimethylamide (GDMA) might be a suitable directing group for
promoting remote C–H functionalization via the palladacycle
(Scheme 1B). At the start of our study, we explored 2-
81%
a
Condition A: 1 (0.2 mmol), ArI (1.5 equiv), Pd(OAc)2 (5 mol%), AgOAc (2
equiv), HFIP (1 mL), 80 oC, air, 36 h. b 100 oC.
c
Condition C: 2 (0.2 mmol), Pd(OAc)2 (5 mol%), PhI(OAc)2 (2 equiv), HFIP (5
mL), 70 oC, Ar, 18 h. d 100 oC.
palladium-catalyzed β-arylation of carboxyl acid derivatives.
However, none of them obtained the intramolecular amination
products, recovering the starting material only (see SI, Table
S1). As expected, phenylpropionic acid protected by GDMA
quinolinone synthesis at 120 °C through a general method
using various directing groups, namely, protected
phenylpropionic acid, PhI(OAc)2, and Pd(OAc)2 in
2 | J. Name., 2012, 00, 1-3
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could give the six-membered N-heterocycle in good yield. could be used in the transformation. Notably, ortho-
Further scanning quickly revealed that the best reaction substituted aryl iodides afforded the corresponding products
conditions, which gave 4a in 91% isolated yield (see SI, Table in good to excellent yield (3a
S2, entry 6), consisted of substrate 2a (1 equiv), Pd(OAc)2 (5 aryl iodides also worked well in this transformation, resulting
mol%), PhI(OAc)2 (2.5 equiv) in HFIP (0.04 M), temperature of in good to excellent yield of products (3i ).
70 C, and reaction time of 18 h. When the TEMPO was used
–h). Meta-and para-substituted
–
q
°
A, Synthesis of key intermediate for Carteolol from propanoic amide
as additive, 4a was obtained at 90% yield. Further controlled
experiments revealed that palladium acetate was
indispensable in this intramolecular amination.
OMe
Me2N
OMe
ArI (1.2 equiv)
Pd(OAc)2 (5 mol%)
AgOAc (2 equiv)
HFIP, 100 oC, 36 h
O
Pd(OAc)2 (5 mol%)
PhI(OAc)2 (2 equiv)
NH
HFIP, 100 o
C
HN
O
O
N
O
O
O
H
36 h
Table 3 Synthesis quinolinones from general carboxylic acid with aryl idodies by
1.982 g
2d, 75%
1.582 g
1b, 10 mmol
4d
NMe2
NMe2
palladium catalyzed cascade C-H functionalization
HN
O
N
H
O
HO
Carteolol
B, Synthesis of tryptophane derivatives from simple GDMA protected alanine
I
NP
hth
O
Pd(OAc)2 (5 mol%)
AgOAc (2 equiv)
HFIP (1 mL)
NPhth
+
HN
O
O
100 oC, 18 h
N
NMe2
H
HN
Ts
89% yield
N
O
1, 0.2 mmol
1.2 equiv
Ts
2r
NMe2
NPhth
O
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2 equiv)
HFIP (5 mL)
100 oC, Ar, 18 h
52%
N
O
N
Ts
3r
NMe2
C, The removal and transformation of directing group
HCl (37%)
NaOH (3 equiv)
MeOH/THF/H2O
80 oC, 24 h
100 oC, 18 h
N
O
O
N
O
O
N
O
84%
H
86%
4a
7a
6a
NMe2
OH
Scheme 2 The removal and transformation of directing group.
Condition A: a 1 (0.2 mmol), Pd(OAc)2 (10 mol%), AgOAc (2 equiv), HFIP (1 mL),
80 oC, air, 24 h. b 100 oC. c ArI (3 equiv). d ArI (1.5 equiv).
3,4-Dihydro-2(1H)-quinolinone derivatives were also
prepared by using GDMA-protected propionic acid and various
aryl iodides through palladium-catalyzed sequential C–H
arylation and intramolecular amination (Table 2). Gratifyingly,
the newly developed N,O-bidentate directing group displayed
strong ability to promote β-C(sp3)–H arylation. Even the ortho-
substituted aryl iodides, which have never been used as
coupling partners with propionic amide in previous reports,
e
Condition B: PhI(OAc)2 (2.5 equiv), PivOH (0.3 equiv), HFIP (4 mL), 80 oC, Ar,
18 h. f 100 oC.
g
Condition C: 2 (0.2 mmol), Pd(OAc)2 (5 mol%), PhI(OAc)2 (2 equiv), HFIP (5
mL), 70 oC, Ar, 18 h. h 100 oC.
Having identified the directing group and optimized the
catalytic system, we examined the importance of our directing
group in the construction of bioactive units by sequential C–H
functionalization (Table 1). For example, the skeleton of the
provided
5-substituted
3,4-dihydro-2(1H)-quinolinone
derivatives in good yield in two steps; such derivatives are
difficult to prepare through the traditional route.20 The halide-
substituted arene thus can give access to different functional
product
3 is the key structure in a series of bioactive
compounds.19 More importantly, the directing group can be
part of the functional group of these bioactive compounds. On
the basis of these results, GDMA-protected 2-
phthalimidopropionic acid was first treated with iodobenzene
(1.2 equiv), AgOAc (2 equiv), and Pd(OAc)2 (5 mol%) in HFIP at
groups by cross-coupling reaction (4b, 4c, and 4f).
We then explored the GDMA-directed intramolecular
amination of simple carboxylic acid derivatives under standard
conditions (Table 3). Generally, β-arylation of the Me group
using the one-pot two–step method affords the cyclized
80
°C for 12 h. NMR spectroscopy showed a nearly
quantitative yield of the crude β-arylated product. Thus, we
directly used the oxidant PhI(OAc)2 (2.5 equiv), the additive
PivOH (0.3 equiv), and the solvent HFIP (4 mL) in the arylation.
products (5a–d) in good yield. Interestingly, 5a and 5b
underwent selective diarylation at the β-C(sp3)–H position
rather than at the β-C(sp2)–H position, indicating spatial effects
on C–H activation. The β-methylene C–H bond could also be
sequentially arylated and aminated, affording 5e in synthetic
Further reaction at 70 °C for another 18 h led to the desired
cyclized product 3a at 85% yield. We then synthesized various
2-quinolinones by using different aryl iodides using the two-
step one–pot method. Gratifyingly, a broad range of electron-
withdrawing (F, Cl, Br, I, CF3 and COOMe) or electron-donating
groups (Me, MeO, iPr, and tBu) substituted with aryl iodides
acceptable yield. However, products 5g
–i obtained by one-pot
synthesis had low yield. Herein, we first isolated the β-arylated
products 2g
–
i
and then treated them under standard
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5
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Res., 2011, 45, 788; (b) L. Ackermann, Chem. Rev., 2011, 111
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Soc. Rev., 2011, 40, 1885; (e) J. Wencel-Delord and F. Glorius,
conditions for intramolecular amination. The cyclized products
,
(
5g
–i
) were obtained in good yield.
To determine the synthetic utility of sequential arylation
and intramolecular amination, we conducted a gram reaction
to form product 4d (52% total yield) from GDMA-protected
propanoic acid in two steps (Scheme 2A). Importantly, the
product of 4d is a key intermediate for the synthesis of drug
Carteolol.21 The product 3r could be observed in good yield by
employing the 1a as starting material in two steps. The
directing group, GDMA, could be easily removed with
concentrated hydrochloric acid to afford 6a in 84% yield.22 The
GDMA could be transformed into carboxylic acid 7a in 86%
yield under basic conditions23 (Scheme 2C).
Nat. Chem., 2013, 5, 369; (f) L. Ackermann, Acc. Chem. Res.,
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H. Li, C. Mapelli, M. M. Miller, and J.-Q. Yu, J. Am. Chem. Soc.,
2015, 137, 3338; (b) D.-H. Wang, M. Wasa, R. Giri and J.-Q.
Yu, J. Am. Chem. Soc., 2008, 130, 7190.
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3965.
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131, 9886.
6
7
8
9
Conclusions
10 L. C. M. Castro and N. Chatani, Chem. - Eur. J., 2014, 20, 4548.
11 W. Gong, G.-F. Zhang, T. Liu, R. Giri and J.-Q. Yu, J. Am. Chem.
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In conclusion, we developed an effective procedure for the
synthesis of 2-quinlinolinone derivatives by palladium-
catalyzed sequential β-C(sp3)–H arylation and selective 12 J. Kim, M. Sim, N. Kim and S. Hong, Chem. Sci., 2015,
6, 3611.
13 D.-H. Wang, T.-S. Mei and J.-Q. Yu, J. Am. Chem. Soc., 2008,
130, 17676.
intramolecular C(sp2)–H/N–H amination starting with aryl
iodide and carboxylic acid. Synthesis uses a novel auxiliary
directing group, GDMA. The GDMA exhibits strong ability in
promoting β-C(sp3)–H arylation and intramolecular amination,
which lead to key intermediates for bioactive compounds. Our
method provides a convenient route for the synthesis of 5-
hydroxy-3,4-dihydro-1H-quinolin-2-one, which is the key
intermediate for carteolol. GDMA can be easily removed and
can be readily transformed into useful functional groups.
14 (a) C. Wang, C.-P. Chen, J.-Y. Zhang, J. Han, Q. Wang, K. Guo,
P. Liu, M.-Y. Guan, Y.-M. Yao and Y.-S. Zhao, Angew. Chem.,
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Chem. Soc., 2008, 130, 14058; (c) Y.-Q. Deng, W. Gong, J. He
and J.-Q. Yu, Angew. Chem., Int. Ed., 2014, 53, 6692.
15 Q. Zhang, K. Chen, W.-H. Rao, Y.-J. Zhang, F.-J. Chen and B.-F.
Shi, Angew. Chem., Int. Ed., 2013, 52, 13588.
16 W.-W. Sun, P. Cao, R.-Q. Mei, Y. Li, Y.-L. Ma and B. Wu, Org.
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Pan, P.-X. Shen, L.-S. Zhang, X. Wang and Z.-J. Shi, Org. Lett.,
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18 (a) Q. Wang, J. Han, C. Wang, J.-Y. Zhang, Z.-B. Huang, D.-Q.
Shi and Y.-S. Zhao, Chem. Sci., 2014, 5, 4962; (b) M.-Y. Guan,
Acknowledgements
C.-P. Chen, J.-Y. Zhang, R.-S. Zeng and Y.-S. Zhao, Chem.
Commun., 2015, 51, 12103.
We gratefully acknowledge financial support from the Natural
Science Foundation of China (NO. 21572149) and Young
National Natural Science Foundation of China (NO. 21402133,
21403148). The PAPD Project are also gratefully
acknowledged.
19 (a) Makoto. S.. Preparation of 3-acylaminocarbostyrils as
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