Palladium-Catalyzed Intermolecular Aerobic Annulation of o-Alkenylanilines and Alkynes for Quinoline Synthesis

Article abstract of DOI:10.1021/acs.orglett.6b01008

A new approach to construct 2,3-disubstituted quinolines is described via Pd-catalyzed oxidative cyclization of o-vinylanilines and alkynes with molecular oxygen. This transformation is supposed to undergo intermolecular amination of alkyne, insertion of the olefin, and oxidative cleavage of C-C bond sequence.

Full text of DOI:10.1021/acs.orglett.6b01008

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Intermolecular Aerobic Annulation of
o‑Alkenylanilines and Alkynes for Quinoline Synthesis
Jia Zheng,† Zun Li,† Liangbin Huang,† Wanqing Wu,*,† Jianxiao Li,† and Huanfeng Jiang*,†,‡
†Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P. R. China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: A new approach to construct 2,3-disubstituted
quinolines is described via Pd-catalyzed oxidative cyclization of
o-vinylanilines and alkynes with molecular oxygen. This
transformation is supposed to undergo intermolecular
amination of alkyne, insertion of the olefin, and oxidative cleavage of C−C bond sequence.
uinolines represent an interesting class of N-containing
Scheme 1. Transformations of Aminoalkenes
1
Q heterocycles that frequently occur in natural products
and are key structures of several pharmaceutical compounds2
(Figure 1). These moieties have been reported to possess a
Figure 1. Selected Bioactive Molecules Containing the Quinoline
Moiety.
diverse range of biological properties that are anticancer,3
antimicrobial,4 anti-inflammatory,2b and antipsychotics.5 In
view of the tremendous biological importance of quinolines,
numerous synthetic protocols to elaborate this molecular
scaffold have been developed over the years.6−10 Among
them, o-substituted anilines, a type of useful building blocks,
have proven potential in the synthesis of quinolines.8−10 For
example, Korivi’s group demonstrated a Ni-catalyzed cycliza-
tion of 2-iodoanilines with aroylalkynes to produce 2,4-
disubstituted quinolines.8 2-Carbonyl and ethynyl-anilines
have also been employed to construct polysubstituted quinoline
derivatives which were catalyzed by Au, Pd, Cu, etc.9,10
However, the development of efficient protocols for the
assembly of this molecular scaffold still remains a demanding
goal due to their significance.
Alternately, transition metal-catalyzed amination of C−C
multiple bonds has emerged as a powerful tool for versatile
synthesis of N-containing molecules.11 Generally, fast intra-
molecular aminometalation occurs to achieve annulations,
which affords the corresponding heterocyclic compounds
(e.g., indoles, Scheme 1, a).12 By contrast, achieving
intermolecular cyclizations of amino-alkenes/alkynes is chal-
lenging and relatively rare.13,14 Typically, two strategies are
employed. The first is choosing a more favored process of
nucleometalation to activate the C−C multiple bonds, such as
halopalladation.13 In the second scenario, there are two key
features: (a) removing the N-substituents to increase the
nucleophilic ability, which leads to coordination instead of
aminometalation; (b) employing another substrate with enough
activity, such as CO, isonitrile.14 In our previous report about
Pd-catalyzed [3 + 2] oxidative cyclization of allylamines and
alkynes, the active alkynes with electron-withdrawing group are
required for the insertion of the N−Pd bond (Scheme 1,b).15
On the basis of the strategy above, a Pd-catalyzed aerobic [4 +
2] annulation of o-vinylanilines and alkynes with the aid of Cu
salt and O2 is developed (Scheme 1, c). This protocol enables
rapid assembly of quinolines via C−N, C−C bond formations
and aerobic C−C bond cleavage.
After our initial investigation, we found that palladium
catalyst, ligand, and O2 are all crucial features and no reaction
occurred without any of them (see the Supporting Information
for details). Thus, we chose PdCl2, PPh3, and O2 for further
optimization. Employing 20 mol % of Cu(OAc)2 could increase
the yield from 5% to 25% (Table 1, entries 1 and 2). A certain
Received: April 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Screening for the Alkenes
b
entry
additive
Cu(OAc)2
solvent
yield (%)
1
2
3
4
5
6
7
8
MeCN
MeCN
DMSO
5
25
trace
44
53
59
53
50
n.r.
16
65
26
57
n.r.
Cu(OAc)2
Cu(OAc)2
MeCN/DMSO = 5/1
MeCN/DMSO = 10/1
MeCN/DMSO = 20/1
MeCN/EtOH = 20/1
MeCN/MeOH = 20/1
MeCN/DMSO = 20/1
MeCN/DMSO = 20/1
MeCN/DMSO = 20/1
MeCN/DMSO = 20/1
MeCN/DMSO = 20/1
MeCN/DMSO = 20/1
MeCN/DMSO = 20/1
MeCN/DMSO = 20/1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
a
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), PdCl2 (10 mol
%), PPh3 (20 mol %), Cu(TFA)2·xH2O (20 mol %) and PivOH (1
equiv) in 2 mL of MeCN/DMSO (20/1), with an O2 balloon, 80 °C
for 24 h.
c
9
Cu(OAc)2
10
11
12
Cu(OTf)2
Cu(TFA)2·xH2O
CuCl
d
a
13
Cu(TFA)2·xH2O
Cu(TFA)2 xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Scheme 3. Substrate Scope for Alkynyl Esters
e
14
f
g
15
86 (82)
n.r.
h
16
a
Reaction conditions: All reactions were performed with 1a (0.2
mmol), 2a (0.2 mmol), PdCl2 (10 mol %), PPh3 (20 mol %), additive
(20 mol %) and solvent (1.0 mL) with an O2 balloon at 80 °C for 24
b
h. Determined by GC analysis using dodecane as an internal
c
d
standard, n.r. = no reaction. Under N2. Addition of Et3N (0.1
e
f
mmol). Addition of K2CO3 (0.1 mmol). Addition of PivOH (0.1
mmol). Isolated yield. Reaction temperature was 60 °C.
g
h
amount of DMSO could promote this reaction efficiently while
increasing the amount leads to gradual inhibition (Table 1,
entries 3−6). Other reductive solvents, including EtOH and
MeOH, promoted this process as well (Table 1, entries 7−8).
However, no reaction occurred under N2 atmosphere (Table 1,
entry 9). The screening of different additives revealed that
Cu(TFA)2·xH2O is better than others (Table 1, entries 10−
12). The addition of Et3N provided a slightly lower yield while
K2CO3 led to no reaction (Table 1, entries 13−14).
Gratifyingly, the yield of 3aa increased to 86% when 1 equiv
of PivOH was employed (Table 1, entry 15). Further
investigation indicated lower temperature was negative to this
reaction (Table 1, entry 16). Therefore, the optimal reaction
condition was obtained: PdCl2 (10 mol %), PPh3 (20 mol %),
Cu(TFA)2·xH2O (20 mol %), PivOH (1 equiv) in MeCN/
DMSO (20/1) with an O2 balloon at 80 °C.
a
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), PdCl2 (10 mol
As the optimized conditions were established, we next turned
to examine the scope of 2-alkenylanilines under the optimized
reaction conditions, and the results are summarized in Scheme
2. This transformation proceeds smoothly when R is phenyl,
though phenyl-substituents such as Me and NO2 have negative
effects on this transformation (1aa, 1ab), with the correspond-
ing aldehydes obtained. No desired product was detected when
terminal and alkyl-substituted alkenes were used (1ac−1af).
Subsequently, the scope of alkynes was investigated under
the optimal conditions (Scheme 3). Alkynyl esters bearing 4-
substitued electron-donating groups, such as alkyl and alkoxy
groups, gave the desired quinolines in excellent yields (3ab−
3ad). Substrates with electron-withdrawing groups (halogen
and trifluoromethyl) were relatively sluggish and afforded
moderate yields (3ae−3ah). Similarly, ortho-, meta- and
disubstitued alkynyl esters underwent the annulation success-
%), PPh3 (20 mol %), Cu(TFA)2·xH2O (20 mol %) and PivOH (1
equiv) in 2 mL of MeCN/DMSO (20/1), with an O2 balloon, 80 °C
for 24 h.
fully to afford the corresponding products in considerable yields
(3ai−3al). Naphthyl substrate participated efficiently as well to
give the corresponding product 3am in 84% yield. In addition,
the alkynyl ester bearing benzo[d][1,3]dioxole moiety reacted
smoothly to deliver 3an in 74% yield. Gratifyingly, thiophene-
containing substrate was tolerated, though the expected
product 3ao was provided in relatively lower yield. Notably,
the alkenyl group was fully compatible as well (3ap). Switching
ethyl phenylpropiolate to methyl phenylpropiolate showed no
obvious influence to the yield (3aq). Unfortunately, 3-
phenylpropiolamide and ethyl but-2-ynoate failed to afford
the desired products 3ar and 3as.
B
DOI: 10.1021/acs.orglett.6b01008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Then our attention was turned to explore the effect of
Scheme 5. Control Experiments
substituents on the anilines (Scheme 4). As shown in Scheme
a
Scheme 4. Substrate Scope for o-Alkenyl Anilines
Scheme 6. Possible Mechanism
a
Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), PdCl2 (10 mol
%), PPh3 (20 mol %), Cu(TFA)2·xH2O (20 mol %) and PivOH (1
equiv) in 2 mL of MeCN/DMSO (20/1), with an O2 balloon, 80 °C
for 24 h.
4, functional groups such as methyl, halogen (F, Cl, Br),
trifluoromethyl, cyano, and ester groups all exhibited good
compatibility in this reaction. para-Substituted anilines with
both electron-donating group and electron-withdrawing group
proceeded smoothly to afford corresponding products 3ba−
3ha in moderate to good yields. Similarly, 5-Me- and 5-Cl-
substituted substrates gave 3ia and 3ja in 75% and 71% yields,
respectively. 4-Methyl-quinoline (3la) was obtained in 70%
yield, while only 52% yield of 8-methyl-quinoline (3ka) was
provided. To our delight, disubstituted compounds also worked
well to offer 6,8-dichloro-quinoline (3ma) and 6-chloro-8-ester-
quinoline (3na) in good yields. As expected, this protocol is
also applicable to naphthylamine, which transferred to
benzo[h]quinoline 3oa in 78% yield. However, pyridine was
not tolerant in this transformation (3pa, 3qa).
To better understand this transformation, some control
experiments were conducted (Scheme 5). Only a trace amount
of desired product was detected when 2 equiv of TEMPO or
BHT was employed (Scheme 5, eq 1), which indicates that this
transformation might undergo a radical process. When o-
aminobenzaldehyde 4 was employed instead of 1a, only a trace
amount of 3aa was observed. Thus, this reaction is supposed
not to undergo an oxidative cleavage of alkene first to give
aldehyde as the intermediate (Scheme 5, eq 2). N-Benzyl-
protecting aniline 1n decomposed under the standard
conditions, which afforded no corresponding product (Scheme
5, eq 3). In this transformation, no β-H elimination product 5
was observed. We also synthesized 5 and found it could not
convert into 3aa under the standard conditions (Scheme 5, eq
4). Thus, this reaction did not undergo the oxidative cleavage of
β-H elimination product.
A,14,15 followed by the intermolecular cis-insertion of 2a. Alkyl-
Pd species C is obtained via the intramolecular migratory
insertion of alkene. In path A, with the aid of CuII, a subsequent
reaction between C and O2 affords peroxopalladuim(III) D,
which would be converted to intermediate E by rearrange-
ment.16 Then, product 3aa and aldehyde are obtained by the
elimination of PdII−OH and cleavage of C−C bonds in
intermediate E. Finally, the active PdII species would be
regenerated by the reaction between Pd(OH)Cl with HCl.
In summary, a Pd-catalyzed intermolecular oxidative
annulation of o-alkenylanilines and alkynes has been developed.
Assisted by Cu and O2, this transformation undergoes a
sequential intermolecular alkyne amination, alkenyl migration
insertion, and aerobic C−C bond cleavage. Molecular oxygen is
used as the terminal oxidant which is also the key feature to the
cleavage of the C−C bond. This protocol provides an efficient
route to access polysubstituted quinolines, which shows good
functional group compatibility and high regioselectivity.
On the basis of the above results and literature precedents, a
plausible mechanism is proposed in Scheme 6. The reaction is
initiated by interaction of PdII and 1a to form the intermediate
C
DOI: 10.1021/acs.orglett.6b01008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01008.
■
S
Typical experimental procedure and characterization for
all products (DOC)
AUTHOR INFORMATION
Corresponding Authors
■
(10) (a) Xia, X.; Zhang, L.; Song, X.; Liu, X.; Liang, Y. Org. Lett.
2012, 14, 2480−2483. (b) Han, J.; Shen, Y.; Sun, X.; Yao, Q.; Chen, J.;
Deng, H.; Shao, M.; Fan, B.; Zhang, H.; Cao, W. Eur. J. Org. Chem.
2015, 2015, 2061−2065.
*E-mail: cewuwq@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
Notes
(11) (a) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L.
Chem. Rev. 2015, 115, 2596−2697. (b) Gulevich, A. V.; Dudnik, A. S.;
Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084−3213.
(c) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079−
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21490572 and 21420102003), Pearl River S&T Nova
Program of Guangzhou (201610010160), and the Fundamental
Research Funds for the Central Universities (2015ZY001) for
financial support.
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