Copper(II)-catalyzed three-component cascade annulation of diaryliodoniums, nitriles, and alkynes: A regioselective synthesis of multiply substituted quinolines

Article abstract of DOI:10.1002/anie.201300586

Three become one: Multiply substituted quinolines were synthesized from diaryliodoniums, alkynes, and nitriles by a Cu^II-catalyzed method. This cascade annulation is highly regioselective, step-economic, flexible with regard to the functional groups, and could potentially be applied to the synthesis of complex molecules. Copyright

Full text of DOI:10.1002/anie.201300586

Angewandte
Chemie
DOI: 10.1002/anie.201300586
Quinoline Synthesis
Copper(II)-Catalyzed Three-Component Cascade Annulation of
Diaryliodoniums, Nitriles, and Alkynes: A Regioselective Synthesis of
Multiply Substituted Quinolines**
Yong Wang, Chao Chen,* Jing Peng, and Ming Li
Quinolines are privileged scaffolds in various bioactive
natural products and many synthetic therapeutic agents.[1]
Also, they are crucial ligands for the preparation of OLED
materials[2] and asymmetric catalysts.[3] The demand of
synthetic chemists, medicinal chemists, and materials chemists
for a wide variety of substituted quinolines has increased
exponentially. Numerous named reactions (e.g. Combes
synthesis, Conrad–Limpach–Knorr synthesis, and Friedlꢀnder
synthesis) are known for the synthesis of quinolines, and most
of them use anilines or 2-acyl anilines as a starting material.[4]
From the point of sustainability and green chemistry, the
development of new approaches to quinolines from common
building blocks other than anilines is attractive. It is more
challenging to synthesize quinolines with diverse substituents,
often a requirement by medicinal and material chemists.
Although a lot of progress has been made with regard to the
modification of quinolines,[5] a more general and elegant way
to synthesize multiply substituted quinolines would be to
construct the ring from small molecules having functional
groups.[6] Herein, we would like to report an efficient method
to synthesize multiply substituted quinolines from three
components, that is, diaryliodoniums 1, alkynes 2, and nitriles
3. This regioselective [2+2+2] cyclization is catalyzed by
Cu(OTf)2 and the aryl group of the diaryliodoniums serves as
a C2 building block (Scheme 1). This cascade annulation
method is regioselective, step economic, flexible with regard
to functional groups, and is potentially applicable to complex
molecules.
Scheme 1. Three-component approach to multiply substituted quino-
lines. Tf=trifluoromethanesulfonyl.
of diphenyliodonium 1a (0.5 mmol), phenyl acetylene 2a
(1.0 mmol), and benzonitrile 3a (1.0 mmol) with Cu(OTf)2
(0.05 mmol) as catalyst was heated at 1208C in 1,2-dichlo-
ethane (DCE) for 12 h, 2,4-diphenylquinoline 4a was
obtained in 88% yield (determined by GC with n-dodecane
as internal standard; 73% yield upon isolation). The temper-
ature, solvent, and stoichiometry of the reagents were
screened to optimize the reaction conditions (Table 1; see
Supporting Information for more details). When the ratio of
the three components was adjusted to 1:1.2:1.2, product 4a
was obtained in nearly the same yield (86%, 72% upon
isolation). The use of diphenyliodonium salts with non-
coordinating anions (PF6 and OTf) gave good results but
a low was obtained when Ph2ICl was used (entry 15). A
Table 1: Optimization of the reaction conditions for the formation of 2,4-
diphenylquinoline (4a).
entry 1a/2a/3a[a] Solvent Cu(OTf)2 Base
T
Yield
(equiv)
(1 equiv) [8C] [%][b]
Diaryliodonium salts, as environmentally benign regeants
with low toxicity, are often used in the synthesis of arylated
compounds or macrocyclic supramolecular compounds.[7–9]
Our goal is to efficiently synthesize nitrogen-containing
heteroarenes from diaryl iodonium salts.[10] When a mixture
1
2
3
4
5
6
7
8
1:2:2
1:2:2
1:2:2
1:2:2
1:1.2:1.2
1:1.2:1.2
1:1:1
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
PhCF3
CH3CN
DCE
DCE
DCE
0
–
–
–
–
–
–
–
120
75
75
120 88
120 86[c]
130 86
120 67
120
120
120 58
120
120 13
120
120 83
120
120 48[c]
0
6
55
0.1
1.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
[*] Y. Wang, Prof. Dr. C. Chen, J. Peng
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical
Biology (Ministry of Education)
K2CO3
DIPEA
DMAC
–
–
–
–
–
–
0
0
9
10
11
12
13
14[d]
15[e]
16[f]
Department of Chemistry, Tsinghua University
Beijing, 100084 (China)
E-mail: Chenchao01@mails.tsinghua.edu.cn
1
0
Y. Wang, Prof. Dr. M. Li
5
College of Chemistry and Molecular Engineering
Qingdao University of Science and Technology
Qingdao, 266042 (China)
[a] The reaction was performed with 0.5 mmol of Ph2IPF6. [b] Determined
by GC with n-dodecane as internal standard. [c] 4a was isolated in 73%
yield. [d] 0.5 mmol of Ph2IOTf was used instead of Ph2IPF6. [e] 0.5 mmol
of Ph2ICl was used instead of Ph2IPF6. [f] 0.1 equiv of CuCl2 was used
instead of Cu(OTf)2. DIPEA=diisopropylethylamine, DMAC=dimeth-
ylacetamide.
[**] This work was supported by National Natural Science Foundation of
China (21102080) and Tsinghua University Initiative Scientific
Research Program (2011Z02150).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300586.
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similar anion effect was observed for the copper salts; the use
of Cu(OTf)2 gave better results than CuCl2 or Cu(OAc)2 (see
the Supporting Information). Based on the material economy
and ease of purification, the reaction conditions shown in
entry 5 were chosen as the optimal conditions. The reaction
was monitored by GC–MS and none of the isomer 2,3-
diphenylquinoline was observed. The structure of 4a was
further confirmed by single-crystal X-ray diffraction (see the
Supporting Information).[11]
With optimized conditions established, the scope of our
method was examined. Initially, a range of alkynes were
treated with diphenyliodonium salt 1a and benzonitrile (2a)
to synthesize quinolines with a variety of substituents at the 3-
and 4-positions. As shown in Scheme 2, reactions of terminal
Figure 1. Single-crystal X-ray diffraction structure of 4j. The thermal
ellipsoids are set at 35% probability.
unsymmetric alkynes may be attributed to the highly electro-
philic process of this annulation (see below).
Next, a variety of nitriles were evaluated in the reaction
with diphenyliodonium and asymmetric alkynes, phenyl
acetylene (3a) or 1-phenyl-1-butyne (3b), to synthesize
quinolines with various substituents at the 2-positon. Aryl
nitriles bearing functional groups, such as 4-methoxy, 4-
bromo, 4-trifluromethyl and 2-iodo groups, were compatible
under the reaction conditions (Scheme 3). The reactions of 2-
cyano thiophene and 1-cyano naphthalene successfully pro-
duced 2-thienyl quinoline 5e and 1-naphthyl quinoline 5 f in
excellent yields. Alkyl nitriles, such as acetonitrile, valeroni-
Scheme 2. Synthesis of 3- and 4-substituted quinolines from various
alkynes. The yields are of the isolated products.
or internal alkynes with alkyl, aryl, or ester groups all
proceeded smoothly under standard conditions and gave the
expected quinolines in moderate to excellent yields upon
isolation. This synthetic method gives quinolines with high
regioselectivity when asymmetric alkynes are used: for
terminal alkynes with either alkyl or aryl groups, these
substituents are located in the 4-position in the products (4a–
4c, 4 f); for the internal alkyne 1-phenyl-1-butyne, the phenyl
group is located in the 4-position and ethyl group to 3-position
in the product (4g); for internal alkynes, such as 1-phenyl-1-
propiolate and 2-butynoate, with electron-withdrawing
groups, the ester group is located in the 3-position in the
product (4h and 4i). Interestingly, 1,3-hexadiyne was also
applicable to this reaction and the corresponding 4-propynyl
quinoline (4j) was isolated exclusively. The structure of 4j
was unequivocally confirmed by single-crystal X-ray diffrac-
tion analysis (Figure 1).[12] The high regioselectivity for
Scheme 3. Synthesis of 2-substituted quinolines from various nitriles.
The yields are of the isolated products.
2
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trile and phenylacetonitrile, underwent the cascade annula-
tion to afford desired products, albeit in relatively lower
yields. When 3-methoxy propionitrile was used, 2-vinyl
quinoline 5h was isolated instead of 2-(2-methoxyethyl)qui-
noline. However, ethyl cyanoformate (NCCO2Et) and diethyl
cyanphosphate (NCPO(OEt)2) didnꢁt undergo the quinoline
annulation presumably because of their electron deficiency.
Gratifyingly, all the reactions gave the same regioselectivity at
3- and 4-positions.
the crystal structure it is clearly shown that the ipso position
of iodonium salt is substituted by nitrogen atom. This method
provides a convenient access to quinolines with diverse
subsituents on the phenyl ring.
The results above have shown the facile construction of
quinolines that are highly functionalized on the pyridine ring.
Finally, we attempted to prepare quinolines with functional
groups on the phenyl ring from various diaryliodoniums.
Functionalized diaryliodonium triflates were used as they are
easily prepared according to known methods.[13] Reactions of
diaryliodoniums having a range of substituents, including 2-
methyl, 4-methyl, 2-fluoro, 4-fluoro, 4-chloro, and 4-trifluoro-
methyl groups, all gave the desired products (Scheme 4). The
Figure 2. Single-crystal X-ray diffraction structure of 6a. The thermal
ellipsoids are set at 35% probability.
In the preparation of quinoline 5g, N-phenyl pentanamide
(7; presumably formed by hydrolysis of the N-phenyl
nitrilium salt[15]) was determined to be in the reaction mixture
by GC–MS (around 10% yield). N-phenyl pentanamide (7)
was formed in 85% yield when Ph2IPF6 and valeronitrile
(1 equiv) were heated with Cu(OTf)2 (0.1 equiv) in the
absence of alkyne [Eq. (1)]. This result suggests that valer-
onitrile can be readily phenylated by Ph2IPF6 (in the presence
of Cu(OTf)2) to give the N-phenyl nitrilium salt, which upon
hydrolysis forms N-phenyl pentanamide. Additionally, in the
competition reaction of benzonitrile 2a, 1-phenyl-1-butyne
3b with [(4-CH3C6H4)(4-CF3C6H4)I]+[OTf]À under standard
conditions, product 6c was formed exclusively; 6i was not
Scheme 4. Synthesis of phenyl-substituted quinolines from various
diaryliodoniums. The yields are of the isolated products.
reaction of di(m-tolyl)iodonium produced two regioisomers
in a ratio of 1:1 (6e and 6e’). As well as characterization by
NMR spectroscopy, the structure of 6a was unambiguously
confirmed by single-crystal X-ray diffraction (Figure 2).[14] In
formed [Eq. (2)]. This result may be attributed to the
dominant formation of [4-CH3C6H4]+ (leading to compound
6c) rather than [4-CF3C6H4]+ from [(4-CH3C6H4)(4-
CF3C6H4)I]+[OTf]À.
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The anion effects of iodonium salts and copper catalysts
(non-coordinating, weakly nucleophilic anions are superior)
imply that this reaction is an electrophilic process. It has been
reported that diaryliodonium salts could undergo reactions
with nucleophiles catalyzed by copper salts and proceeding
via Ar–CuIII species, which act as carbocation equivalents.[8,16]
Based on the above findings, we propose a reaction mecha-
nism involving a Ar–CuIII species (Scheme 5). Initially, Cu-
tion is believed to involve a series of cationic intermediates,
thus ensuring an efficient process and high regioselectivity.
We believe that this study reveals a new way to prepare
nitrogen-containing heterocycles from diaryliodoniums. Fur-
ther studies are being undertaken in our laboratory and will
be reported in due course.
(OTf)2 is converted into CuI by either a reduction or Experimental Section
A sealed tube was charged with diaryliodonium salt 1 (1.0 mmol) and
Cu(OTf)2 (0.1 mmol, 36.2 mg). The tube was evacuated and
recharged with N2 three times. Acetylene 2 (1.2 mmol), nitrile 3
(1.2 mmol), and 1,2-dichloroethane (2.0 mL) were added, the tube
was sealed and the mixture was stirred at 1208C for 12 h. After
completion, the mixture was cooled to room temperature, then aq.
NaHCO3 (5 mL) was added and the mixture was extracted with
dichloromethane (5 mL ꢂ 3). The organic phase was dried over
anhydrous Na2SO4. Evaporation of the solvent followed by purifica-
tion by column chromatography on silica gel (petroleum ether/diethyl
ether/triethylamine, 50:5:1 to 500:5:1) provided the corresponding
product as a yellow solid.
Received: January 23, 2013
Revised: February 27, 2013
Published online: && &&, &&&&
Keywords: alkynes · annulation · diaryliodonium · nitriles ·
.
nitrogen heterocycles
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Scheme 5. Proposed mechanism.
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Communications
Quinoline Synthesis
Y. Wang, C. Chen,* J. Peng,
M. Li
&&&& — &&&&
Copper(II)-Catalyzed Three-Component
Cascade Annulation of Diaryliodoniums,
Nitriles, and Alkynes: A Regioselective
Synthesis of Multiply Substituted
Quinolines
Three become one: Multiply substituted
quinolines were synthesized from diaryl-
iodoniums, alkynes, and nitriles by a CuII-
catalyzed method. This cascade annula-
tion is highly regioselective, step-eco-
nomic, flexible with regard to the func-
tional groups, and could potentially be
applied to the synthesis of complex
molecules.
6
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!