Palladium-catalyzed synthesis of polysubstituted quinolines from 2-amino aromatic ketones and alkynes

Article abstract of DOI:10.1039/c4cc00939h

A palladium-catalyzed one-pot method for the synthesis of quinolines from commercial or readily available 2-amino aromatic ketones and alkynes is reported for the first time. This transformation offers an alternative method for the synthesis of polysubstituted quinoline. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00939h

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Palladium-catalyzed synthesis of polysubstituted
quinolines from 2-amino aromatic ketones
and alkynes†
Cite this: Chem. Commun., 2014,
50, 5583
Received 5th February 2014,
Accepted 25th March 2014
Wang Zhou* and Jianhua Lei
DOI: 10.1039/c4cc00939h
www.rsc.org/chemcomm
A palladium-catalyzed one-pot method for the synthesis of quino-
lines from commercial or readily available 2-amino aromatic ketones
and alkynes is reported for the first time. This transformation offers
an alternative method for the synthesis of polysubstituted quinoline.
Quinolines are ubiquitous motifs in the frameworks of natural
products1 and bioactive compounds.2 Also, they are valuable
synthons for the preparation of materials with uniquely electronic
and optical properties.3 Therefore, a variety of methods have
been developed to assemble this kind of skeleton.4 Previously, we
reported an intramolecular direct amination of sp2 C–H bonds,
finding that an ortho carbonyl group could facilitate the metalation
of an amino N–H bond.5 Based on this result and our recent study
on hydroarylation of alkyne,6 a new strategy for the synthesis of
quinoline was envisioned, which involves five transformations,
namely, (i) a carbonyl group directed metalation of N–H bond to
form intermediate A, (ii) intermolecular addition of N-metal bond
Scheme 1 An envisioned strategy for the synthesis of quinoline.
across alkyne giving metal–vinyl complex B, (iii) intramolecular the noticeable effect of temperature, the kind of acid affected
insertion into carbonyl group to form intermediate C, (iv) protolysis the yield slightly (Table 1, entries 21–25). Finally, carrying out
of the resulting metal alkoxide to liberate alcohol D and regenerate the reaction in a mixed solvent resulted in an acceptable yield
catalyst, (v) dehydration–aromatization of compound D delivering of the desired product (Table 1, entry 27).
the desired quinoline (Scheme 1).
Subsequently, the substrate scope was explored under the
To test our hypothesis, Pd(CH3CN)2Cl2 was initially chosen as a optimized conditions. The reaction of various 2-amino aromatic
catalyst for the intermolecular reaction of 2-aminobenzophenone ketone 1 with diphenylacetylene 2a is summarized in Table 2. First
1a and diphenyl acetylene 2a. Gratifyingly, in the presence of of all, a variety of 2-aminobenzophenones, which could be readily
acetic acid, 2,3,4-triphenyl quinoline 3aa was obtained in 48% available via one-step synthesis from 2-cyano aniline and aromatic
yield (Table 1, entry 1), but in the absence of acid or palladium, boronic acid,7 with functional groups, such as methyl, methoxy,
almost no product was observed (Table 1, entries 2 and 3). Further trifluoromethoxy, chloro and fluoro, were tolerated, giving the
investigation showed that DCE and PdBr2 were the best choices corresponding products in moderate to good yields (3aa–3ga). It
as the solvent and the catalyst, respectively (Table 1, entries 4–20). is worth mentioning that, in many cases, the N-pivalation product
It is worth noting that copper could not catalyze the reaction of 1 was detected when PivOH was used, which could not be
efficiently (Table 1, entries 18 and 19). Moreover, compared to isolated from the desired quinoline and lead to the product as a
mixture. Using AcOH instead of PivOH could solve this problem
easily. This reaction proceeded successfully and afforded products
with naphthalenyl and styryl substituent (3ha and 3ia). Moreover,
this approach could be also used for the assembling of 4-alkyl
College of Chemical Engineering, Xiangtan University, Xiangtan 411105, China.
E-mail: wzhou@xtu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 993171. For ESI
substituted quinolines effectively (3ja and 3ka). The structure of
product 3ka was further identified by the single-crystal study
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc00939h
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Table 1 Optimization of reaction conditionsa
Table 2 The reaction of diphenylacetylene (2a) with various 2-acyl
anilines (1)a,b
Catalyst
Entry (5 mol%)
Additive
(8 equiv.) Solvent
Yieldb
(%)
1
2
3
4
5
6
7
8
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
—
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
PdCl2
PdBr2
Pd(COD)Cl2
Pd(acac)2
Pd(CF3COO)2
Pd(OH)2
Pd(PPh3)2Cl2
Pd(OAc)2
AcOH
—
DCE
DCE
DCE
1,4-Dioxane
DCM
Toluene
DMF
THF
DMSO
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
48
Trace
0
39
42
44
Trace
11
0
31
59
34
20
13
8
17
31
10
Trace
0
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
25e
26
27
28
Cul
a
CuBr2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), PdBr2 (5.0 mol%),
[Rh(Z5-C5Me5)Cl2]2 AcOH
b
c
AcOH (1.6 mmol) at 130 1C for 18 h. Isolated yield. PivOH was used
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PivOH
TFA
63
63
54
60
38
instead of AcOH.
PivOH
PivOH
PivOH
PivOH
PivOH
AcOH
Table 3 The reaction of various acetylenes (2) with 2-aminobenzo
phenone (1a)a,b
DCE/acetonitrile (1 : 1) 74
DCE/benzonitrile (1 : 1) 83
DCE/benzonitrile (1 : 1) 74
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst, additive
(1.6 mmol) and solvent (1.6 mL) at 130 1C in seal tube for 18 h.
b
c
d
e
Isolated yield. Additive (1.2 mmol). 150 1C. 100 1C.
(see ESI† for details). Secondly, substrates with functional groups,
such as methyl, or halo substituents, such as bromo, chloro and
fluoro, on amino substituted aromatic ring could be readily trans-
formed into the desired products 3la–3pa, but quinoline with a nitro
group (3qa) was only obtained in trace of yield. Moreover, this
method furnished the polycyclic product 3ra in 63% yield.
Encouraged by the preliminary scope of the reaction, we
began to explore the scope of acetylenes (Table 3). Diphenyl
acetylenes with substituents, such as methyl, methoxy, chloro,
fluoro, nitro, could be smoothly converted into the desired
products in moderate yields (3ab–3af). 2,3-Dimethoxycarbonyl
quinoline 3ag could be obtained from the corresponding methyl
acetylenedicarboxylate. Moreover, a single isomer (3ai and 3aj)
was detected when phenylacetylene and ethyl 3-phenylpropiolate
were employed.8 Unfortunately, dialkyl acetylene could not be
the reaction partner in this transformation (3ah).
a
Reaction conditions: substrate: 1a (0.2 mmol), 2 (0.4 mmol), PdBr2
b
(5.0 mol%), AcOH (1.6 mmol) at 130 1C for 18 h. Isolated yield.
c
PivOH was used instead of AcOH.
In addition to the mechanism that metal–vinyl intermediate B
inserts into the carbonyl group, there is another possible pathway
that intermediate B undergoes protolysis to form enamine E,
which leads to the formation of quinoline by the intermolecular
annulation process (Scheme 2).9 If the formation of an enamine E
occurred, we should observe the existence of the corresponding
enamine or its hydrolysis-product 2-phenylacetophenone when
Scheme 2 Another mechanistic pathway.
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2-aminobenzophenone 1a and diphenyl acetylene 2a were
employed. However, we did not detect their existence.
Moreover, 2-aminobenzophenone 1a could not be converted
into quinoline 3aa in the presence of 2-phenylacetophenone
(Scheme 3). These results indicated that protolysis of inter-
mediate B is less likely.
In conclusion, we demonstrate for the first time a palladium-
catalyzed one-pot method for the synthesis of quinolines from
2-amino aromatic ketones and alkynes. This transformation offers
an alternative method for the synthesis of polysubstituted
quinoline.
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Financial support from the National Science Foundation of
China (No. 21102123 and 21372188) is greatly appreciated.
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Chem. Commun., 2014, 50, 5583--5585 | 5585