Copper-catalyzed oxidative cyclization of enynes for the synthesis of 4-carbonyl-quinolines with O2

Article abstract of DOI:10.1021/ol300896h

A novel copper-catalyzed oxidative cyclization of enynes and in situ formed enynes leading to 4-carbonyl-quinolines by using dioxygen as an oxygen source has been developed.

Full text of DOI:10.1021/ol300896h

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2480–2483
Copper-Catalyzed Oxidative Cyclization of
Enynes for the Synthesis of 4-Carbonyl-
quinolines with O2
Xiao-Feng Xia,† Lu-Lu Zhang,† Xian-Rong Song,† Xue-Yuan Liu,† and
Yong-Min Liang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China, and State Key Laboratory of Solid Lubrication, Lanzhou Institute
of Chemical Physics, Chinese Academy of Science, Lanzhou 730000, P. R. China
liangym@lzu.edu.cn
Received March 23, 2012
ABSTRACT
A novel copper-catalyzed oxidative cyclization of enynes and in situ formed enynes leading to 4-carbonyl-quinolines by using dioxygen as an
oxygen source has been developed.
The synthesis of diverse oxygen-containing organic
frameworks is one of the most fundamental and significant
subjects in organic chemistry. From the viewpoint of green
and sustainable chemistry, the direct utilization of mole-
cular oxygen (O2) for the construction of valuable oxygen-
containing organic compounds has been of long-standing
interest to organic chemists due to its tremendous importance
in synthetic chemistry.1 As is known, the transition-metal-
catalyzed cyclization of 1,n-enynes has emerged as a useful
tool for the synthesis of heterocyclic compounds due to the
intriguing selectivity, atom economy, and exceptional
ability to activate π-systems.2 Despite considerable pro-
gress in this field, studies focusing on the development of
mild 1,n-enyne cyclization routes using inexpensive cata-
lysts to construct new and complex compounds need to be
pursued. In recent years, copper-catalyzed reactions have
received considerable attention because of their efficiencies
† Lanzhou University.
‡ Chinese Academy of Science.
(1) (a) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005,
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Int. Ed. 2011, 50, 11062. (c) Du, F.-T.; Ji, J.-X. Chem. Sci. 2012, 3, 460.
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ꢀꢁ
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r
10.1021/ol300896h
Published on Web 05/02/2012
2012 American Chemical Society

and low costs.1b,3 However, examples of copper-catalyzed
1,n-enyne cyclization are rare,4 especially in the synthesis
of oxygen-containing quinolines.
Consequently, a series of other copper salts (e.g., CuBr2,
Cu(OAc)2, Cu(OTf)2, CuCl, CuBr, and CuI) were evalu-
ated, wherein CuCl displayed high catalytic activity (see
Table S1 in the Supporting Information (SI)). It is note-
worthy that the yield can be improved to 57% using O2
instead of air (entry 3). Lower yields were obtained when
1,10-phenanthroline (Phen) or 2,20-bipyridine were added as
ligands (entries 4 and 5). The cylization reaction did not take
place when DABCO was added as a base (entries 6 and 7). In
addition, we found that the increasing amount of CuCl has a
positive effect on the reaction yield (entries 8 and 9), in which
the yield of 2a was increased to 61% using 15 mol % CuCl.
Then the amount of dimethyl but-2-ynedioate was also
examined, and 2 equiv of dimethyl but-2-ynedioate were
found to give a better result (entry 10). When the solvent was
changed from DMF to DMAc, the yield of 83% was
obtained (entry 12). Notably, performing the reaction in
the absence of CuCl led to the complete recovery of 1a.
Using these optimized conditions, the oxidative cycli-
zation scope of the transformation was investigated.
The oxygen-containing quinoline unit represents an
important structural motif found in a variety of biologi-
cally active compounds.5 For instance, the 4-carbonyl-
quinoline moiety is contained in the design of pharmaceu-
ticals and related compounds, which has been synthesized
via many steps in traditional synthetic routes.6 Since the
substituents on the quinoline rings have a great influence
on the properties of these compounds, effective methods
for the preparation of a diverse range of substituted
4-carbonyl-quinolines are highly desirable. The classical
route to these compounds proceeded from the condensa-
tion of substituted anilines with R,β-unsaturated carbonyl
compounds under strongly acidic conditions.7 Although
the improvement of these harsh conditions has recently
been addressed by metal-catalyzed approaches, these new
methodologies are confined for the lack of generality and
limited functional-group tolerance.8 Therefore, there re-
mains a demand for versatile and effective methodologies
toconstructsubstitutedquinoline derivatives with selective
control of substitution patterns from readily accessible
building blocks. The present report is the first on a novel
and efficient copper-catalyzed oxidative cyclization of
enynes or in situ formed enynes, in which the atmospheric
molecular oxygen as the most sustainable oxidant avail-
able was incorporated into various functionalized quino-
line derivatives (Scheme 1).
Table 1. Screening Optimal Conditionsa
[Cu]
t
yield
entry (mol %) oxidant
additive
(°C) solvent (%)b
1
2
3
4
5
6
CuCl2
(10)
air
air
O2
O2
O2
O2
ꢀ
ꢀ
ꢀ
80
80
DMF
DMF
40
Scheme 1. Designed Route to Substituted 4-Carbonyl-quino-
lines
CuCl
(10)
50
CuCl
(10)
100 DMF
100 DMF
100 DMF
100 DMF
57
CuCl
(10)
Phen (20%)
30
CuCl
(10)
2,20-
25
bipyridine (20%)
Phen (20%),
DABCO
(2 equiv)
DABCO
(2 equiv)
ꢀ
CuCl
(10)
trace
7
CuCl
(10)
O2
O2
O2
O2
O2
O2
air
100 DMF
100 DMF
100 DMF
100 DMF
100 DMF
trace
61
8
CuCl
(15)
9
CuCl
(5)
ꢀ
ꢀ
50
Our investigation began with the reaction of 2-
(phenylethynyl)aniline 1a with dimethyl but-2-ynedio-
ate catalyzed by CuCl2 in air at 80 °C. To our delight, the
target cyclization product 2a was obtained (Table 1, entry 1).
10c
11d
12
13
CuCl
(15)
75
CuCl
(15)
ꢀ
53
ꢀ
CuCl
(15)
100 DMAc 83
(5) (a) Barluenga, J.; Rodriguez, F.; Fananas, F. J. Chem.;Asian J.
2009, 4, 1036. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166. (c)
Banwell, M. G. Pure Appl. Chem. 2008, 80, 669. (d) Abele, E.; Abele, R.;
Lukevics, E. Chem. Heterocycl. Compd. 2008, 44, 769.
(6) Nicolaou, K. C.; Chen, J. S.; Edmonds, D. J.; Estrada, A. A.
Angew. Chem., Int. Ed. 2009, 48, 660.
(7) For example: (a) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem.
2008, 12, 1116. (b) Horn, J.; Marsden, S. P.; Nelson, A.; House, D.;
Weingarten, G. G. Org. Lett. 2008, 10, 4117. (c) Marco-Contelles, J.;
Perez-Mayoral, E.; Samadi, A.; Carreiras, M.; do, C.; Soriano, E. Chem.
Rev. 2009, 109, 2652.
CuCl
(15)
ꢀ
100 DMAc 46
a Reaction conditions: 1a (0.2 mmol), dimethyl but-2-ynedioate (1.5
equiv), [Cu], oxidant (1 atm), additive, and solvent (2 mL) for 8 h. b Yield
of isolated product. c 2 equiv of dimethyl but-2-ynedioate was used. d 1.2
equiv of dimethyl but-2-ynedioate was used.
Org. Lett., Vol. 14, No. 10, 2012
2481

As shown in Table 2, a great variety of aminoalkynes were
converted to the corresponding 4-carbonyl-quinolines.
Several useful functional groups were tolerated, including
chloride, nitro, acetyl, and ether substituents. The presence
of electron-withdrawing or -donating groups in R2 was
well tolerated. An electron-donating substituent in R2
favored product formation (Table 2, entries 2ꢀ5), whereas
an electron-withdrawing group slightly hindered the reac-
tion (entries 6ꢀ9). When a sterically demanding ortho
substituent was used in R2, a lower yield was obtained
(entry 10). When there were substituents para to the
nitrogen atom regardless if they were electron-donating
or -withdrawing, the oxidative cyclization products were
achieved (entries 11 and 13). However, the presence of the
substituent at the ortho position of the aniline fragment
substituent, the desired oxidative cyclization product was
obtained in acceptable yield. To confirm further the struc-
tural assignment of products in the present oxidative
cyclization, the structure of the product 2b was unambigu-
ously assigned by X-ray crystallography (see the SI).
In view of these results, we turned our attention to
investigate the intramolecular oxidative cyclization. As
described in Table 3, a variety of 4-carbonyl-quinolines
were produced in the presence of catalytic amounts of
CuCl2 (10 mol %), 1,10-phenanthroline (phen; 20 mol %),
and DABCO (2 equiv) at 100 °C under 1 atm of O2 (see
Table S2 in the SI). Table 3 reveals that the electronic
property of alkyne substitutions did not show obvious
influences on the reaction efficiency. However, when
strong electron-withdrawing groups such as acetyl, nitro,
and cyano were embedded in the arylic R3, lower yields
were observed (entries 8, 9, and 11). Notably, several
functional groups such as methoxy, chloro, and bromo
were compatible with this reaction. In addition, hetero-
cycle-derived substrates also appearedtobe excellent in the
reaction, and the product 4l was isolated in 93% yield
(entry 12). Enaminones could also participate in this
reaction, giving moderate to good yields (entries 15 and
16). Surprisingly, unlike in the intermolecular oxidative
cyclization, the substrate with an alkyl group in R3 cannot
participate in the reaction (entry 17).
Table 2. CuCl-Catalyzed Synthesis of 4-Carbonyl-quinolinesa
yield
(%)b
entry
R1
R2
R3
product
Some control experiments were carried out to elucidate
the mechanism (see the SI). The reaction of substrate 3a
withH218O under the optimal reactionconditionsafforded
the 4-carbonyl-quinoline product without any 18O atoms,
as determined by MS. When the reaction was conducted
under a 18O2 atmosphere, the 4-carbonyl-quinoline prod-
uct [18O]-4m containing an 18O atom in ketone was
afforded. These results indicated that the oxygen atom in
ketone was originated from molecular oxygen (O2). When
the reaction was carried out under an Ar atmosphere, only
a trace amount of product was detected. The use of a
stoichiometric amount of copper catalyst did not give any
product under an Ar atmosphere. These results indicated
that the molecular oxygen was essential to the reaction.
Based on the above results, EPR studies,9 and ESI/MS
analysis (see the SI), a plausible mechanism for the copper-
catalyzed aerobic oxidative cyclization4a is illustrated in
Scheme 2. First, Cu(III)10 and a superoxide radical (O2•ꢀ)
are formed through the reaction of CuCl2 and O2 in the
presence of an organic base (DABCO) and Phen, which
could be detected by EPR (see the SI).1c,d,f Then, Cu(III)
can combine with 3a to form Cu(III) complex A. Succes-
sive carbocupration to the alkyne moiety gives vinyl
copperperoxyintermediateB (ESI/MSanalysis, SI). Then,
intermediate B underwent deprotonative OꢀO bond clea-
vage to give 4-carbonyl-quinoline along with the genera-
tion of Cu(II).
1
H
H
H
H
H
H
H
H
H
H
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2a
2b
2c
2d
2e
2f
83
74
73
68
80
60
57
45
42
40
75
40
2
4-Me-C6H4-
4-MeO-C6H4-
4-PhCH2O-C6H4-
3,4-di-Me-C6H3-
4-Cl-C6H4-
3-Cl-C6H4-
4-MeCO-C6H4-
4-NO2-C6H4-
2-MeO-C6H4-
Ph
3
4
5
6
7
2g
2h
2i
8
9
10
11
12
2j
4-Me
4,6-di-
Me
4-Cl
H
2k
2l
Ph
13
14
15
16
Ph
Me
Et
2m
2n
2o
2p
52
65
60
32
Ph
H
4-HO-C6H4-
n-propyl
Me
Me
H
a Reaction conditions: 1 (0.2 mmol), but-2-ynedioate (0.4 mmol),
CuCl (15%), O2 (1 atm), and DMAc (2.0 mL) at 100 °C for 10 h. b Yield
of isolated product.
hampered the reaction (entry 12). Importantly, the aryl
group R2 with an unprotected hydroxyl group was also
compatible, and the desired product was isolated in 60%
yield (entry 15). To our delight, when R2 was an alkyl
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2011, 50, 11088.
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2482
Org. Lett., Vol. 14, No. 10, 2012

Table 3. CuCl2-Catalyzed Synthesis of 4-Carbonyl-quinolinesa
Scheme 2. Proposed Mechanism for the Direct Transformation
yield
(%)b
entry
R1
R2
R3
R4
product
1
2
3
H
Ph
Ph
Ph
Ph
EtO
EtO
EtO
4ac
4b
4c
89
88
88
H
H
4-Me-C6H4-
4-MeO-
C6H4-
4
H
Ph
3,4-di-Me-
C6H3-
EtO
4d
89
5
6
7
8
H
H
H
H
Ph
Ph
Ph
Ph
3-Me-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
4-MeCO-
C6H4-
EtO
EtO
EtO
EtO
4e
4f
93
94
90
56
The proposed method proceeded using inexpensive copper
as the catalyst and molecular oxygen as the oxygen source,
making this transformation sustainable and practical. The
mechanism was also discussed according to the labeling
experiments, EPR studies, and ESI/MS analysis. Studies on
the applications of this copper-catalyzed oxidative cyclization
in organic syntheses are currently underway in our laboratory.
4g
4h
9
H
Ph
4-NO2-
C6H4-
EtO
4i
63
10
11
12
13
14
15
16
17
H
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
2-Cl-C6H4-
2-CN-C6H4-
thienyl
Ph
EtO
EtO
EtO
EtO
EtO
Ph
4j
82
50
93
95
93
79
53
H
4k
4l
H
Acknowledgment. We thank the National Science Foun-
dation NSF 21072080 and the Fundamental Research
Funds for the Central Universities (lzujbky-2011-151 and
lzujbky-2010-k09) for financial support. We acknowledge
National Basic Research Program of China (973 Program)
2010CB833203 and “111” program of MOE.
4-Me
4-Cl
H
4m
4n
4o
4p
ꢀ
Ph
Ph
H
Ph
Ph
d
H
n-propyl
EtO
ꢀ
a Reaction conditions: 3 (0.2 mmol), CuCl2 (10%), Phen (20%),
DABCO (2.0 equiv), O2 (1 atm), and DMF (2.0 mL) at 100 °C for 5 h.
b Yield of isolated product. c The structure was determined by X-ray
crystallographic analysis. d Decomposed.
Supporting Information Available. Representative ex-
perimental procedures, X-ray crystallographic data of 2b
and 4a, and 1H NMR and 13C NMR spectra of all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we demonstrated a novel copper-
catalyzed aerobic oxidative cyclization of enynes and in
situ formed enynes leading to 4-carbonyl-quinolines.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2483