Nickel-Catalyzed Remote C4-H Arylation of 8-Aminoquinolines

Article abstract of DOI:10.1021/acs.orglett.9b02403

A useful and convenient method for C-H bond arylation of 8-aminoquinoline motifs on the remote C4 position was developed. This method shows good functional group tolerance toward various Grignard reagents and aminoquinoline via a nickel catalysis, giving

Full text of DOI:10.1021/acs.orglett.9b02403

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Nickel-Catalyzed Remote C4−H Arylation of 8‑Aminoquinolines
,†,‡
†
†
†
†
,†
Longzhi Zhu, Xinghao Sheng, You Li, Dong Lu, Renhua Qiu,* and Nobuaki Kambe*
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha 410082, PR China
‡
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
*
S Supporting Information
ABSTRACT: A useful and convenient method for C−H bond arylation of 8-aminoquinoline motifs on the remote C4 position
was developed. This method shows good functional group tolerance toward various Grignard reagents and aminoquinoline via a
nickel catalysis, giving the desired arylated products in good yields. The present method affords an efficient access to construct
multisubstituted aminoquinolines.
iven the importance and versatility of quinoline
provide some idea for the functionalization of 8-aminoquino-
G
derivatives as bioactive natural products, medicines,
line. However, as for the remote C4−H functionalization of
1
functional materials (Figure 1), and directing groups for C−
aminoquinolines, only three examples have been disclosed
9
(
Scheme 1). In 2014, Zeng et al. reported the first two
substrates of Fe-catalyzed remote C4−H allylation of 8-
9
a
aminoquinolines (Scheme 1a). Wu et al. developed
phosphonation of 8-aminoquinoline at C4 position via the
combination of photocatalysis and transition metal catalysis
Scheme 1. C4−H Functionalization of 8-Aminoquinolines
Figure 1. Representative biologically active compounds.
2
H functionalization in transition-metal-catalyzed reactions,
developing highly efficient and environmentally benign
protocols for the synthesis of various functionalized quinolines
is highly desired. In the past several decades, tremendous
progress has been made for the construction of quinoline
3
motifs via cyclization of anilines derivatives or cyclization of
4
substituted alkynes intermolecularly or intramolecularly.
However, the above-mentioned methods suffer from draw-
backs such as high prefunctionalized starting materials and low
4d
selectivity in some cases. An alternative synthetic method for
functionalized quinolines is the site-selective modification of
readily accessible quinoline frameworks via C−H functional-
ization. This method provides a quick access to functionalized
quinolines. However, the regioselectivity has to be controlled.
Many reactions for the C−H bond functionalization of the
5
6
7
quinoline core are mainly on the position of C2, C3, C5,
8
and C8, which are easily accessible. However, as for the
1d,e
functionalization of the important C4 position,
which is
relatively less electrophilic (more nucleophilic) among the 8-
9
aminoquinioline core, progress is very slow. In recent years,
there are several reports concerning the functionalization on
Received: July 11, 2019
10
11
the C4 position of pyridine or quinoline motif, which
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02403
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
9
b
a
(
Scheme 1b). Ranu et al. reported high efficient cobalt-
Scheme 2. Substrate Scope for Aryl Grignard Reagents
catalyzed remote C4−H alkylation of 8-aminoquinoline with
9c
photocatalyst (Scheme 1c). As is known, the C−H bond
arylation attracts immense attention among the various kinds
of C−H functionalizations, which can greatly improve the
complexity of the obtained substrates due to the obtained
valuable biaryl structural motifs. However, the research of a
method to build up C4-arylated aminoquinolines has never
been disclosed.
Our group is very interested in the functionalization of
7
d,12
aminoquinoline core
and the cross-coupling reaction using
13
Grignard reagents as important partner. Herein, we reported
the first nickel-catalyzed C4−H arylation of 8-aminoquinolines
with aryl Grignard reagents (Scheme 1d). This method affords
a useful and convenient access to construct multisubstituted
aminoquinolines.
The cross-coupling between N-(quinolin-8-yl)pivalamide
1a) and phenylmagnesium bromide (2a) was examined as a
(
model reaction (see Supporting Information). After optimiza-
tion of reaction conditions, the C4 arylated product N-(4-
phenylquinolin-8-yl)pivalamide (3a) was generated in 78%
yield when Ni(OTf) was used as catalyst in the presence of 2
2
t
equiv of BuOK at 60 °C (Table 1, entry 1). If no nickle
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: 1 (0.2 mmol), 2 (4.0 equiv), N , isolated yield.
Reaction conditions: 24 h.
2
b
groups attached to the phenyl Grignard reagents at different
positions show no obvious steric hindrance, giving 3b−d in
middle to good yields (61−70%). When electron-donating
b
entry
variation from standard conditions
yield of 3a (%)
t
group 4-Me, 4- Bu, or 4-OMe was attached to the para
1
2
3
4
5
6
none
no Ni(OTf)2
80 (78)
c
position, the corresponding 3d−f were yielded in 57%−73%
yield. Aryl Grignard reagents possessing electron-withdrawing
substituents (4-F, 4-Cl) gave 3g,h in modest yields. Biphenyl
Grignard reagent gave 3i in a slightly lower yield. The
substituents on the quinoline core motifs were also
investigated. When an aminoquinoline having a methoxy
group on C6 position was employed, 3j was generated in 79%
yield. However, if a Br or Cl atom is attached to the C5
position, the desired products (3l,m) were not yielded, but C5
arylated product 1f was obtained in 55%, 70%, respectively,
indicating that the Kumada coupling is predominated. C5
arylated aminoquinoline can also tolerated to give 3n in 58%
yield, which shows no obvious steric hindrance to the C4
functionalization. Alkyl Grignard reagent such as butylmagne-
sium bromide and heteroaromatic Grignard reagent such as
thiophen-2-ylmagnesium bromide failed to give the corre-
sponding products (see Supporting Information).
As shown in Scheme 3, the reactions of phenylmagnesium
bromide (2a) with various kinds of aminoquinolines were
investigated. When replacing 1a with 2,2-dimethyl-N-(quino-
lin-8-yl)butanamide, the corresponding product 4a was yielded
in 61% yield. For long-chain alkyl groups and cyclohexyl group,
the arylation proceeded smoothly to give desired products 4b−
d in 65%−68% yield. It is noted that benzoyl aminoquinolines
can also be tolerated in this system without the generation of
ortho C−H bond arylated byproducts directed by 8-amino-
quinoline group (4e−j).
<1
Ni(COD) instead of Ni(OTf)
75
66
45
50
2
2
NiCl instead of Ni(OTf)
no BuOK
2
2
t
PhMgBr (3 equiv)
a
Reaction conditions: N-(quinolin-8-yl)pivalamide (1a, 0.2 mmol),
phenylmagnesium bromide (2a,1.0 M in THF, 4.0 equiv), solvent
b
(
1.0 mL), N atmosphere. GC Yield using n-dodecane as internal
2
c
standard; the isolated yield was given in parentheses. C2 arylated
product (3a′) was obtained in 10%. The crude mixture contains a
small amount of 1,2-dihydroquinoline derivative. After quenched by
NH Cl (aq), it was oxidized to quinoline by adding 1 equiv of DDQ
and stirring for 10 min at ambient temperature (procedures are
4
similar hereinafter).
catalyst was used, 3a was formed in less than 1% yield with C2
arylated product (3a′) generated in 10% yield (entry 2). When
Ni(COD) was used as catalyst under the standard condition
2
instead of Ni(OTf) , the desired product 3a was generated in
5% yield, indicating that the reactive species may be Ni(0).
NiCl can also catalyze this reaction, giving 3a in 66% yield
entry 4). Without BuOK, the reaction can be proceeded but
in lower yield (entry 5). Lower the amount of Grignard
reagent used in the reaction decreased the yield of 3a (entry
). The structure of 3a was confirmed by single crystal X-ray
2
7
2
t
(
6
analysis (figure in Scheme 2).
After having the optimized reaction conditions, we
investigated the substrate scopes of Grignard reagents (Scheme
). For various kinds of aryl Grignard reagents, the reaction
proceeded smoothly to be arylated on C4 position selectively,
yielding the desired products 3a−i in good yields. Methyl
In order to demonstrate the synthetic utility, the model
reaction was enlarged to a gram scale, and 1.3 g 3a was
generated in 61% yield (Scheme 4). The amide group could be
hydrolyzed under basic conditions to give C4-arylated
2
B
DOI: 10.1021/acs.orglett.9b02403
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope for Aminoquinolines
Scheme 5. Control Experiments
of the amide group at C8 position. N-(Naphthalen-1-
yl)pivalamide (9d) was also not arylated. When unsubstituted
quinoline (9e) was reacted with 2f, only C2-arylted product 10
14
was obtained in 65% yield, as previous reported by Da et al.
In addition, by careful analysis of the atmosphere after
reaction, a small amount of hydrogen was detected.
a
Reaction condition: 1 (0.2 mmol), 2a (4.0 equiv), N , isolated yield.
2
10a
On the basis of the above results and literature,
we
Scheme 4. Synthetic Applications
propose here a possible pathway for the C4 arylation of 8-
aminoquinoline derivatives (Scheme 6). Initially, deprotona-
Scheme 6. Possible Mechanism
a
t
Reaction conditions: Ni(OTf) (10 mol %), 2a (4 equiv), BuOK (2
2
b
equiv), THF, 60 °C/12 h. Reaction conditions: NaOH (10 equiv),
c
EtOH, 100 °C/24 h. Reaction conditions: NCS (1.1 equiv), DMF (2
d
mL), 50 °C/2 h, N . Reaction conditions: NBS (1.1 equiv), DMF (2
2
e
mL), 50 °C/2 h, N . Reaction conditions: 3-thiopheneboronic acid
2
(
1
2 equiv), Na CO (2 equiv), Pd(PPh ) (10 mol %), DMSO, N ,
2 3 3 4 2
f
40 °C/10 h. Reaction conditions: m-CPBA (2 equiv), CH Cl , 25
2 2
g
°
C/12 h, air. Reaction conditions: R-Li (5 equiv), THF (2 mL), 0
t
tion of amide 1 by BuOK followed by isomerization forms the
°C/12 h, N . See Supporting Information for details.
2
intermediate B. Coordination of the Ni(0) species which was
reduced by Grignard reagent from Ni(II) with aminoquinoline
forms intermediate C. Then, nucleophilic addition of Grignard
reagent generates intermediate D. The intermediate D then
undergoes elimination and protonation to deliver the desired
product 3 and generate Ni(0) species for the next catalytic
cycle. A nickel insertion mechanism may also be possible (see
quinoline-8-amine 5 in 90% yield. Furthermore, C5-position
could selectively brominated and chlorinated to give 3l,m in
12b
high yields according our previous report.
It should be
noted that these bromo- and cholor- products 3l,m cannot be
obtained by arylation of C5 bromo- or chloroquinolines
(
Scheme 2). With application of a Suzuki coupling reaction to
10b,c,11b
12b
Supporting Information).
this brominated compound,
the thienyl group can be
In summary, we demonstrated a useful and convenient
nickel catalyzed protocol for C4-arylation of 8-aminoquinoline
motifs. The reaction shows good tolerance toward various aryl
Grignard reagents and aminoquinoline, giving the desired
products in good yields. This method affords an efficient access
to construct multisubstituted aminoquinolines.
introduced at the C5 position to give 6a in 81% yield. The C2
position was arylated and alkylated to give 3k, 7a,b in good
yields by the reaction with organolithium reagents. N-oxide 8
was obtained by oxidation with m-CPBA.
To shed some light on the possible mechanism of the C4
arylation on 8-aminoquinlines, we performed several prelimi-
nary experiments as depicted in Scheme 5. When tert-butyl
quinolin-8-ylcarbamate (9a), quinolin-8-yl pivalate (9b), or
free amine quinolin-8-amine (9c) instead of 1a was treated
with phenylmagnesium bromide (2a) under the standard
condition, no corresponding product was detected (Scheme
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02403.
4
a). The above-mentioned results indicate the important role
C
DOI: 10.1021/acs.orglett.9b02403
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Detailed experimental procedures, characterization data,
Letter
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1
13
spectra copies of the H, C NMR for obtained
products, and X-ray data of 3a (PDF)
Accession Codes
CCDC 1842336 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*
E-mail: renhuaqiu@hnu.edu.cn (R.Q.).
*E-mail: kambe@chem.eng.osaka-u.ac.jp (N.K.).
ORCID
2
015, 71, 4450−4459.
Longzhi Zhu: 0000-0001-5161-9944
Renhua Qiu: 0000-0002-8423-9988
Notes
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progress in the synthesis of quinolines. Curr. Org. Chem. 2005, 9,
1
41−161. (b) Prajapati, S. M.; Patel, K. D.; Vekariya, R. H.; Panchal,
The authors declare no competing financial interest.
S. N.; Patel, H. D. Recent advances in the synthesis of quinolines: a
review. RSC Adv. 2014, 4, 24463−24476. (c) Ramann, G. A.; Cowen,
B. J. Recent Advances in Metal-Free Quinoline Synthesis. Molecules
ACKNOWLEDGMENTS
The authors thank the Natural Science Foundation of China
Nos. 21676076, 21878071), the Hu-Xiang High Talent
■
(
2
016, 21, 986−1008. (d) Shao, Y. D.; Dong, M. M.; Wang, Y. A.;
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Friedlander Quinoline Heteroannulation. Org. Lett. 2019, 21, 4831−
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S.-J. Palladium-Catalyzed Cascade Reactions of Isocyanides with
Enaminones: Synthesis of 4-Aminoquinoline Derivatives. ACS Catal.
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2
014, 4, 49−52. (f) Chen, P.; Nan, J.; Hu, Y.; Ma, Q.; Ma, Y. Ru(II)-
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DOI: 10.1021/acs.orglett.9b02403
Org. Lett. XXXX, XXX, XXX−XXX