Synthesis of Functionalized Quinolines through a Reaction of Amides and Alkynes Promoted by Triflic Anhydride/Pyridine

Article abstract of DOI:10.1002/chem.201703832

A concise, novel and flexible metal-free single step to synthesize functionalized quinolines is reported. Triflic anhydride-mediated (Tf₂O) activation of amides is discussed in the presence of pyridine to offer strong electrophiles, thereby showcasing excellent productivity, high regio- and chemoselectivity, and widely tolerable substrates. This approach provides a straightforward and efficient way to construct azaheterocycle structures.

Full text of DOI:10.1002/chem.201703832

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Accepted Article
Title: Synthesis of Functionalized Quinolines through a Reaction of
Amides and Alkynes Promoted by Triflic Anhydride/Pyridine
Authors: Yong-Min Liang, Lian-Hua Li, and Zhi-Jie Niu
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10.1002/chem.201703832
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Synthesis of Functionalized Quinolines through a Reaction of
Amides and Alkynes Promoted by Triflic Anhydride/Pyridine
Lian-Hua Li, Zhi-Jie Niu and Yong-Min Liang*
Dedication ((optional))
A concise, novel and flexible metal-free single-step to synthesize
functionalized quinolines is reported. Triflic anhydride-mediated
(Tf2O) activation of amides is discussed in the presence of pyridine to
offer strong electrophiles, thereby showcasing excellent productivity,
high regio- and chemoselectivity, and widely tolerable substrates. This
approach provides a straightforward and efficient way to construct
azaheterocycle structures.
of amides in the presence of pyridine to enhance the intrinsic
electrophilicity of amides has been deemed as a noteworthy tool
in azaheterocycle synthesis fields. Charette and Movassaghi’s
pioneering works have been reported on
a
range of
chemoselective transformations of related reactions.[7,8]
a) Doebner – Miller reaction
As a prominent azaheterocycle, the quinoline scaffold plays a
crucial role in natural products, pharmaceuticals, and functional
materials.[1] For example, cabozantinib has been approved for the
treatment of medullary thyroid cancer (MTC); 2-oxo-quinoline
derivatives display potent proliferation inhibitory activity on tumor
cells; and quinoline containing 1,2,3-triazole has great potential to
inhibit Candida spp., and the structure is also found in drug
molecules and fluorescence materials (Figure 1).[2] In this context,
a series of significant strategies for synthesizing quinolines has
been developed over the last decade.[3,4] Typical examples are
the Doebner−Von Miller, Friedlander and Combes methods
(Scheme 1a, 1b, and 1c).[5] Despite the increase in significant
advances, certain drawbacks are still present, such as harsh
conditions, limited scope of substrates, low yields, and difficult
operations. Therefore, the development of a more effective, low-
cost, and easy-to-operate synthesis process for quinoline is still
of great value.
b) Friedländer reaction
c) Combes reaction
d) This work
N-aryl amides can readily be used as valuable precursors for
the preparation of azaheterocycles.[6] Meanwhile, the
development of triflic anhydride-mediated (Tf2O) activation
Scheme 1. Traditional synthesis of quinoline (a-c) and new anticipation (d).
In terms of potential applications in medicinal chemistry, our
team has been working on the synthesis of heterocycles for
several years.[9] As a continuation of our work, herein, we report
a new metal-free one-pot method for the synthesis of quinoline
and its derivatives with N-aryl amides as starting materials
(Scheme 1d). In this reaction, triflic anhydride proved to be a key
component to form active electrophiles. This versatile method has
been used in numerous successful examples.
The investigations were initiated using acetanilide and
diphenylacetylene as the model substrates. As shown in Table 1,
the quinoline product generated
a 65% yield using 2,6-
dichloropyridine as the base, which was more effective than the
others (Table 1, entries 1-5). According to previous studies,[7a] the
non-nucleophilic base is crucial to the reaction, 2,6-
Figure 1. Representative examples of quinoline derivatives.
dichloropyridine serve as
a
sterically hindered, weakly
nucleophilic base, thereby generating a conjunction with Tf2O and
amide to provide a unique electrophile to trap the nucleophile.
Under certain screening conditions, the gratifying productivity of
the target molecule was reached when the reaction temperature
was increased to 90°C (Table 1, entry 6). The reaction mixture
was simply purified by fast column chromatography with silica gel
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000, P.R. China
Email: liangym@lzu.edu.cn
Supporting information for this article is given via a link at the end of the
document.
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following the evaporation of the solvent, thereby delivering
quinoline with an excellent yield of 94%. The exact structure of
4aa was unambiguously determined by X-ray crystal structure
analysis.
also showed reasonable reactivity and the products presented
good yields (Table 3, 4ai and 4aj). The employment of
unsymmetrical alkynes in the reaction system resulted in isolated
products
exhibiting
excellent
yields
and
significant
regioselectivities (Table 3, 4ak-4ao). In the case of di-α-
naphtylacetylene, the desired products generated a high total
Table 1. Screening of the reaction conditionsa.
Table 2. Scope of the amide substratesa.b
.
Entry
Base additive
2,6-lutidine
dipyridine
Temp (°C)
Time (h)
14
Yield (%)c
1
2
60
60
8
14
19
3
4
2-methypyridine
2-chloropyridine
60
60
14
14
14
＜5
5
2,6-dichloropyridine
60
14
65
6b
7b
8b
2,6-dichloropyridine
2,6-dichloropyridine
2,6-dichloropyridine
90
90
90
14
6
94
65
86
12
aTf2O (2.0 equiv.) was added to a mixture of 1a (2.0 equiv.) and base
additive (2.0 equiv.) at -78 °C under Ar. After 5 min, the reaction mixture
was warmed to 0°C and maintained for 20 min. 2a (0.3 mmol, 1.0 equiv.)
was added and the reaction was stirred at the reported temperature.
bAmide (1.6 equiv.), Tf2O (2.2 equiv.). cIsolated yields.
Inspired by the optimized conditions (Table 1, entry 6), we set
out to explore the scope of the substrates. The results are
summarized in Table 2. As anticipated, acetanilide with
substituents like para and ortho-position methyl, methoxy,
dimethyl, tertiary butyl and so on produced appealing yields
ranging from 54% to 96% (Table 2, 4aa-4fa). Halogen groups,
including fluorine, also generated high yields (Table 2, 4ga-4ja).
However, poor regioselectivity was observed in the presence of a
chloro or a methyl substituent in the meta-position. In addition, the
regioisomeric products 4ka, 4ka' and 4la, 4la', which exhibited
similar size ratios, were obtained. Both α- and β-naphtyl type and
para-phenyl amides coupled smoothly with diphenylacetylene
and offered the desired products with excellent yields, specifically
98%, 85%, and 81%, respectively, given their strong conjugated
skeletons (Table 2, 4ma-4oa). Next, we evaluated the scope of
amides bearing other acyl groups. The reaction proceeded
smoothly and produced the desired products with moderate-to-
excellent yields (Table 2, 4qa-4Ba). In particular, pivaloyl and
naphthyl amides and para-nitro benzoic amide generated
unexpectedly high yields from 64% to 89% (Table 2, 4ta and 4wa-
4ya), which indecated the irrelevance of the electronic and steric
effects of the acyl groups.
We further examined the possibility of varying alkyne partners
(Table 3). Symmetrically substituted diarylacetylenes generated
the desired products with yields varying from 55% to 93% (Table
3, 4ab-4ag). The electron-donating and electron-withdrawing
groups doubtlessly participated in the reactions. The alkynes
exhibited extended heterocyclic moieties, such as thiophene,
affording the corresponding product a 33% yield (Table 3, 4ah).
Furthermore, symmetrically substituted di-aliphatic acetylenes
aReaction conditions: 1 (0.48 mmol), 2a (0.30 mmol), Tf2O (0.66 mmol), 2,6-
dichloropyridine (0.60 mmol), DCE (4.0 mL), 90 °C, 14 h. bIsolated yields. cThe
ratio was determined by 1HNMR analysis.
yield of 88% with stereoisomers with a ratio of 1:1 (Table 3, 4ap
and 4ap'). We subsequently surveyed the scope of the terminal
alkynes to assess the capability and compatibility of this quinoline
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synthesis method (Table 4). To our delight, the terminal
arylacetylenes coupled with acetanilide under the optimized
reaction conditions and transferred into the diverse quinoline
motifs to produce moderate-to-high yields (Table 4, 5aa-5aj).
More remarkably, the reaction exhibited excellent regioselectivity
and did not form other isomers.
A gram-scale model reaction was performed to shed light on
the synthetic utility of this method. The desired product 4aa was
isolated and produced
a
94% yield via fast column
chromatography with silica gel, as presented in Scheme 2. The
large-scale reaction did not affect the productivity of which we are
optimistic of the success in furthering the application of this
reaction in industrial-sized production processes.
Table 3. Scope of the alkyne substratesa,b
.
Table 4. Scope of the terminal alkyne substratesa,b
.
aReaction conditions: 1a (0.48 mmol), 3 (0.30 mmol), Tf2O (0.66mmol), 2,6-
dichloropyridine (0.60 mmol), DCE (4.0 mL), 90 °C , 14 h. bIsolated yields.
a)
aReaction conditions: 1a (0.48 mmol), 2 (0.30 mmol), Tf2O (0.66 mmol), 2,6-
dichloropyridine (0.60 mmol), DCE (4.0 mL), 90 °C, 14 h. bIsolated yields.
cThe ratio was determined by 1HNMR analysis.
b)
The exclusive structure of product 5af was confirmed by single-
crystal X-ray analysis. The terminal aliphaticacetylenes also
reacted well with acetanilide and produced persuasive yields
(Table 4, 5ak-5ao). These examples prosperously illustrate the
practicability of this reaction method and highlight the superiority
of this methodology.
Scheme 3. Mechanistic studies.
In addition, a competitive experiment between 3c and 3h was
conducted (Scheme 3).[10] Coupling was favored for the more
electron-rich substrate 3c, and produced a 5ac and 5ah quinoline
product ratio of 1.55:1. Moreover, the intermolecular competition
experiment exhibited a kinetic isotope effect (KIE) value of 1.3 and
a kH/kD=1.2 was observed from the parallel reactions. These
Scheme 2. Gram-scale exhibition of the model reaction.
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The proposed mechanism is depicted in Scheme 4. The
activation of acetanilide was expected to generate highly
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annulation and the subsequent expulsion of TfOH to offer
quinoline product 4aa. The whole process occurred with the
complete control of the substitution pattern by a one-pot method
using a wide range of readily available amides and alkyne
substrates.
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Scheme 4. Proposed mechanism.
In conclusion, we exploited a concise, novel, and flexible single-
step method for the synthesis of functionalized quinolines. The
attractive features of this chemistry include high regio- and
chemoselectivity, a wide range of substrate tolerances, and easy
handling and delivering procedures. The approach is expected to
provide a new perspective for the synthesis of biologically active
and naturally occurring quinoline derivatives.
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Acknowledgements
Financial support was received from the National Natural Science
Foundation of China (NSF21472073, NSF21532001) and the
“111” project. We thank LetPub (www.letpub.com) for its linguistic
assistance during the preparation of this manuscript.
Keywords: synthesis • quinoline • Tf2O • free-metal •
regioselectivity
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Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Lian-Hua Li, Zhi-Jie Niu and Yong-Min
Liang*
Page No. – Page No.
Synthesis of Functionalized
Quinolines through a Reaction of
Amides and Alkynes Promoted by
Triflic Anhydride/Pyridine
Text for Table of Contents
A concise, novel and flexible metal-free single-step to synthesize functionalized quinolines is reported. Triflic anhydride-mediated
(Tf2O) activation of amides is discussed in the presence of pyridine to offer strong electrophiles, thereby showcasing excellent
productivity, high regio- and chemoselectivity, and widely tolerable substrates. This approach provides a straightforward and efficient
way to construct azaheterocycle structures.
This article is protected by copyright. All rights reserved.