Pd-Catalyzed Alkylation of (Iso)quinolines and Arenes: 2-Acylpyridine Compounds as Alkylation Reagents

Article abstract of DOI:10.1021/acs.orglett.8b02498

The first Pd-catalyzed alkylation of (iso)quinolines and arenes is reported. The readily available and bench-stable 2-acylpyridine compounds were used as an alkylation reagent to form the structurally versatile alkylated (iso)quinolines and arenes. The method affords a convenient pathway for the introduction of alkyl groups into organic molecules.

Full text of DOI:10.1021/acs.orglett.8b02498

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Alkylation of (Iso)quinolines and Arenes:
2‑Acylpyridine Compounds as Alkylation Reagents
Qingsong Wu,† Shuaijun Han,† Xiaoxiao Ren,† Hongtao Lu,† Jingya Li,‡ Dapeng Zou,*,†
Yangjie Wu,*,† and Yusheng Wu*,†,‡,§
†The College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry,
Zhengzhou University, Zhengzhou 450052, People’s Republic of China
‡Tetranov Biopharm, LLC, and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052,
People’s Republic of China
§Tetranov International, Inc.. 100 Jersey Avenue, Suite A340, New Brunswick, New Jersey 08901, United States
S
* Supporting Information
ABSTRACT: The first Pd-catalyzed alkylation of (iso)-
quinolines and arenes is reported. The readily available and
bench-stable 2-acylpyridine compounds were used as an
alkylation reagent to form the structurally versatile alkylated
(iso)quinolines and arenes. The method affords a convenient
pathway for the introduction of alkyl groups into organic molecules.
ransition-metal-catalyzed cross-coupling reactions, in
particular, palladium-mediated couplings, have been
Scheme 1. Pd-Catalyzed Cross-Coupling Reactions
Involving C(sp3) Nucleophiles and Electrophiles
T
extensively used for C(sp2)−C(sp2) bond formation in
synthetic organic chemistry and materials science during the
past several decades.1 In recent years, C(sp3) nucleophiles and
electrophiles have been investigated in Pd-catalyzed cross-
coupling reactions to build the C(sp2)−C(sp3) bond.2
However, the newly developed catalytic methods for forging
the C(sp2)−C(sp3) bond still remain a challenge in organic
synthesis. The core challenge in Pd-catalyzed alkylation is to
choose the suitable alkylation cross-coupling partners: the alkyl
organometallic species are substantially less stable than an aryl
organometallic species;3 the oxidative addition of alkyl halides
is considerably more difficult than that of aryl halides.4
Furthermore, the [Pd(II)]-alkyl intermediates are prone to β-
H elimination and isomerization, which can compete with the
formation of the desired product (Scheme 1).3,4
To overcome these pitfalls, great progress has been made in
reducing the undesired byproduct5 as well as in addressing the
problems in the handling and preparation of the cross-coupling
partner.6 However, the alkylation of (iso)quinolines and arenes
without using organometallic species have been rather limited
until now.7
Recently, reductive cross-coupling of two electrophiles has
attracted considerable attention for synthetic alkylated (iso)-
quinolines and arenes.8−11 Although the strategy avoids
employing stoichiometric organometallic partner, most nick-
el-catalyzed reductive cross-coupling reactions extensively
require stoichiometric metal powder reductants (Scheme 2,
eq 1). Coupling via C−H functionalization has also emerged as
a powerful tool for formation of alkylated (iso)quinolines and
arenes,12 but the strategy often relies on the use of directing
groups and is limited to specific C−H bonds. Fortunately,
using aryl ketones as an alkylation reagent has been reported in
several studies. In 2009, a novel route to the synthesis of
diarylmethanes via a Pd-catalyzed α-arylation of benzyl ketones
was reported (Scheme 2, eq 2).13 In 2013, Zhang14 also
reported the synthesis of diarylmethanes by using aryl methyl
ketones with aryl bromides (Scheme 2, eq 3). Unfortunately,
their methods for the introduction of the primary and
secondary alkyl chains onto (iso)quinolines and arenes are
limited. As part of our onging efforts in the development novel
methods for Pd-catalyzed cross-coupling reactions,15 we herein
report a Pd-catalyzed alkylation of (iso)quinolines and arenes
with 2-acylpyridine compounds (Scheme 2, eq 4).
Received: August 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02498
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
solvent from toluene to another one, such as H2O, THF,
CH3CN, DMF, DMA, and DMSO, the reaction yield
diminished drastically (see Table S1 for details). Subsequent
ligand screening revealed that 2,9-dimethyl-1,10-phenanthro-
line L4 was the most effective for the current reaction, giving
the product in 88% yield. Other ligands gave inferior results
(entries 12−17). Moreover, a lower yield was obtained at a
lower reaction temperature (entry 18).
Scheme 2. Transition-Metal-Catalyzed Cross-Coupling
Reactions for C(sp2)−C(sp3) Bond Formation
With the optimal reaction conditions in hand, the substrate
scope of the methylation of various quinoline halides was
studied (Scheme 3, part A). The results indicate that the
Scheme 3. Pd-Catalyzed Alkylation Reactions of Quinoline
a,b
Halides and 2-Acylpyridine Compounds
Herein, we began our investigations on the cross-coupling of
4-chloroquinoline 1a and 2-acetylpyridine 2a (Table 1). To
a
Table 1. Optimization of Reaction Conditions
b
entry
[Pd]
ligand
base
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(dba)2
Pd(acac)2
PdCl2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
t-Bu3P
L1
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
KOH
t-BuONa
NaOH
Cs2CO3
K2CO3
K3PO4
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
43
65
65
d
nr
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
72
32
43
40
nr
a
9
Reaction conditions: 1 (0.5 mmol), 2 (2.0 equiv), Pd(TFA)2 (5 mol
%), L4 (10 mol %), t-BuOK (2.5 equiv), toluene (2 mL), 120 °C, 20
10
11
12
13
14
15
16
17
nr
nr
b
c
d
h, Ar. Isolated yields. 4-Chloroquinoline was used. 4-Chloro-7-
e
72
80
73
76
88
83
78
methoxyquinoline was used. 2d (2.0 equiv), Pd(TFA)2 (10 mol %),
L4 (20 mol %), and 2.5 equiv of t-BuOK were used. nr = no reaction.
f
L2
L3
L4
L5
methylation reaction at any position of quinoline proceed
smoothly to give the desired products in 63−93% yields (3aa−
ga). Substrates possessing an electron-donating group at the C-
7 and C-2 positions afforded the target products 3ha and 3ia in
82% and 75% yields, respectively. 6-Bromoisoquinoline was
also compatible with the cross-coupling reaction to give the
desired 3ja in 90% yield.
To establish the scope of this protocol, various quinoline
halides 1a−i were reacted with 2-acylpyridines 2b−e under the
optimized conditions to give the desired products in good to
excellent yields (Scheme 3, Part B). It was found that variously
substituted substrates 2, such as ethyl, n-propyl, and benzyl,
could be used as an effective substituent group for the
alkylation reaction. The effect of various groups on the
quinoline ring was also investigated, and a strong dependence
on the position of the substituents was observed. Substrates 2
with ethyl, n-propyl groups at the C-3, C-4, C-5, C-6, C-7, and
C-8 positions worked well to give the desired products in
excellent yields (3ab, 3cb−gb, 3ac, and 3cc−gc), whereas
substrates with an ethyl or n-propyl group at the C-2 position
only gave the target molecule in moderate yield (3bb, 3bc).
Benzyl substituent substrates gave the desired benzylated
c
18
L4
a
Reaction conditions: 1a (0.5 mmol), 2a (2.0 equiv), [Pd] (5 mol %),
ligand (10 mol %), base (2.5 equiv), solvent (2 mL), 120 °C, 20 h, Ar.
b
c
d
Yield of isolated product. Reaction performed in 100 °C. nr = no
reaction.
our delight, in the presence of 5 mol % of Pd(OAc)2, 10 mol %
of PPh3, and 2.5 equiv of t-BuOK under argon at 120 °C, the
4-methylquinoline 3aa was obtained, albeit in a moderate yield
of 43% (entry 1). Then various palladium sources were
screened (entries 2−5); Pd(TFA)2 was found to be the most
effective catalyst, giving 3aa in 72% yield (entry 5). Next, the
base screening indicates that strong base is critical for the
enolization of 2-acetylpyridine and t-BuOK was the most
effective base (entries 5−11). Following this, changing the
B
DOI: 10.1021/acs.orglett.8b02498
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
products in 55−75% yields (3ad, 3cd−gd). However, the
cross-coupling reaction of 2-bromoquinoline 1b with 2-phenyl-
1-(pyridin-2-yl)ethan-1-one 2d resulted in a trace amount of
the desired product. To confirm whether the rearrangement of
the carbon skeleton will take place or not, isobutyl group
substituents 2e were used, and 1H NMR analysis of the
reaction mixture showed that no rearrangement byproducts
3ae, 3ee were observed. 4-Chloro-7-methoxyquinoline 1h and
6-bromoisoquinoline 1j worked well under the optimal
reaction conditions. When 2,2-dimethyl-1-(pyridin-2-yl)-
propan-1-one was used as an alkylation reagent, no desired
product 3af was detected.
and so on) as the cross-coupling partners to obtain the
corresponding alkylated products (see Table S2 for details).
Unfortunately, only m-methoxypropiophenone provided the
desired product in good yield. We next extended Pd-catalyzed
ethylation of quinoline halides 1a, 1e, and 1f with m-
methoxypropiophenone 6a. Reaction at the C4, C6, or C7
position of quinoline halides and the C6 position of
isoquinoline bromine 1j could obtain good yields (3ab, 3eb,
3fb, and 3jb) (Scheme 5).
Scheme 5. Pd-Catalyzed Alkylation Reactions of Quinoline
a,b
Halides and m-Methoxypropiophenone
We then examined this alkylation process using aryl
bromides as the cross-coupling partners (Scheme 4). As
Scheme 4. Pd-Catalyzed Alkylation Reactions of Aryl
a,b
Bromides and 2-Acylpyridine Compounds
a
Reaction conditions: 1 (0.5 mmol), 6a (2 equiv), Pd(TFA)2 (5 mol
%), L4 (10 mol %), t-BuOK (2.5 equiv), toluene (2 mL), 120 °C, 20
b
c
h, Ar. Isolated yields. 4-Chloroquinoline was used.
To obtain insight into the reaction mechanism, an array of
control experiments were carried out. To our surprise, α-
arylation product 3a was not obtained by quenching the
reaction after 2 h (Scheme 6, eq 1). Then a further experiment
Scheme 6. Control Reactions for Exploring the Mechanism
a
Reaction conditions: 4 (0.5 mmol), 2 (2.0 equiv), Pd(TFA)2 (5 mol
%), L4 (10 mol %), t-BuOK (2.5 equiv),toluene (2 mL), 120 °C, 20
b
c
h, Ar. Isolated yields. 2a (4.0 equiv) and t-BuOK (5.0 equiv) were
used.
expected, a variety of aryl bromides 4 reacted with 2-
acylpyridine compounds 2 to furnish the desired products in
moderate to good yield (5aa−ch). In principle, electron-
withdrawing and electron-donating substituents (such as
amide, methoxy, and ketone) were all well-tolerated under
the standard reaction conditions (5cb−fb), albeit with a
diminished yield when using electron-withdrawing substituent
substrates. When a nitrile-containing substrate was used, the
desired product 5gb was obtained in a trace amount. The
alkylation of 4-bromo-1,1′-biphenyl proceeded smoothly to
give 5ha and 5hb in good yield. The alkylation method is also
applicable to the dimethylation of 1,4-dibromonaphthalene to
obtain the desired 1,4-dimethynapthalene 5ia in 45% yield.
When 1-bromo-2-chloro-4-methoxybenzene 4j was used, the
coupling occurred exclusively at the bromine-substituted
carbon to get the desired product 5jd. No chloride
displacement product was detected in the reaction. When 2-
bromovinylbenzene was used as substrate, 5kd was obtained in
57% yield. Importantly, 1H NMR analysis of isopropyl
products 5ag, 5cg showed that no isomerization took place.
Cyclohexyl could also be introduced into arene, and the
desired 5ch was obtained in 56% yield.
was studied where α-arylation product 3a as the raw material
was added to reaction mixture, and 4-methyquinoline 3aa was
not observed (Scheme 6, eq 2), which indicated that 3a was
not the intermediate in this transformation. Next, the picolinic
acid was isolated from the reaction mixture of 4-chloroquino-
line and 1-(pyridin-2-yl)butan-1-one. When H218O was added
in the reaction, the 18O-labeled picolinic acid was detected by
HRMS spectrum, which suggested that H2O might be involved
in the C−C bond cleavage process. On the basis of the above
results and related reports,14,16 a reaction pathway for the
alkylation of (iso)quinolines and arenes was proposed (see
Scheme S3 for details).
In summary, we have developed a novel and highly efficient
approach for the preparation of alkylated (iso)quinolines and
arenes using Pd-catalyzed cross coupling of (iso)quinoline
halides and arene halides with abundant and readily available
2-acylpyridine compounds. The alkylation of (iso)quinolines
and arenes proceeds smoothly to give the corresponding
products in moderate to excellent yields with no rearrangement
byproducts. The current method, which displays a broad
Next, in order to expand the utility of this reaction, we
investigated a variety of ketone derivatives (such as 1-(pyridin-
3-yl)ethan-1-one, 1-(pyridin-4-yl)ethan-1-one, acetophenone,
C
DOI: 10.1021/acs.orglett.8b02498
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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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.8b02498.
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1
Experimental procedures and H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zdp@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
*E-mail: yusheng.wu@tetranovglobal.com.
ORCID
Yangjie Wu: 0000-0002-0134-0870
Yusheng Wu: 0000-0001-7023-9541
(13) Schmink, J. R.; Leadbeater, N. E. Org. Lett. 2009, 11, 2575.
(14) Wang, X.; Liu, L. H.; Shi, J. H.; Peng, J.; Tu, H. Y.; Zhang, A. D.
Eur. J. Org. Chem. 2013, 2013, 6870.
Notes
(15) (a) Liang, A. P.; Li, X. J.; Liu, D. F.; Li, J. Y.; Zou, D. P.; Wu, Y.
J.; Wu, Y. S. Chem. Commun. 2012, 48, 8273. (b) Li, X. J.; Zou, D. P.;
Leng, F. Q.; Sun, C. X.; Li, J. Y.; Wu, Y. J.; Wu, Y. S. Chem. Commun.
2013, 49, 312. (c) Leng, F. Q.; Wang, Y. P.; Li, H.; Li, J. Y.; Zou, D.
P.; Wu, Y. J.; Wu, Y. S. Chem. Commun. 2013, 49, 10697. (d) Liang,
A. P.; Han, S. J.; Wang, L.; Li, J. Y.; Zou, D. P.; Wu, Y. J.; Wu, Y. S.
Adv. Synth. Catal. 2015, 357, 3104. (e) Mu, B.; Li, J. Y.; Zou, D. P.;
Wu, Y. S.; Chang, J. B.; Wu, Y. J. Org. Lett. 2016, 18, 5260. (f) Zhang,
Y. D.; Geng, Z. Y.; Li, J. Y.; Zou, D. P.; Wu, Y. J.; Wu, Y. S. Adv. Synth.
Catal. 2017, 359, 390. (g) Han, S. J.; Ren, X. X.; Wu, Q. S.; Liang, A.
P.; Li, Y. J.; Zou, D. P.; Wu, Y. J.; Wu, Y. S. Adv. Synth. Catal. 2018,
360, 2308.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (21172200, 21702191) for financial support.
■
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DOI: 10.1021/acs.orglett.8b02498
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