On-Water Synthesis of 2-Substituted Quinolines from 2-Aminochalcones Using Benzylamine as the Nucleophilic Catalyst

Article abstract of DOI:10.1021/acs.joc.8b01675

On-water synthesis of 2-substituted quinolines from 2-aminochalcone derivatives was developed using benzylamine as the nucleophilic catalyst. Various 2-aminochalcones could be applied to this protocol, and the desired 2-substituted quinoline products were isolated in excellent yields by simple filtration. Furthermore, we elucidated the role of benzylamine in this transformation and provided the detailed reaction mechanism. This protocol has several additional advantages, such as simple operation, broad substrate scope, good functional group tolerance, easy product isolation, recycling of the catalyst, and gram-scale synthesis.

Full text of DOI:10.1021/acs.joc.8b01675

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Article
On-water Synthesis of 2-Substituted Quinolines from 2-
Aminochalcones Using Benzylamine as the Nucleophilic Catalyst
So Young Lee, and Cheol-Hong Cheon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01675 • Publication Date (Web): 08 Oct 2018
Downloaded from http://pubs.acs.org on October 9, 2018
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On-water Synthesis of 2-Substituted Quinolines from 2-
Aminochalcones Using Benzylamine as the Nucleophilic
Catalyst
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So Young Lee and Cheol-Hong Cheon*
Department of Chemistry, Korea University, 145 Anamꢀro, Seongbukꢀgu, Seoul 02841,
Republic of Korea, Phone: +82ꢀ2ꢀ3290ꢀ3147; Fax: +82ꢀ2ꢀ3290ꢀ3121; Eꢀmail:
cheon@korea.ac.kr
O
R2
benzylamine
R1
R3
R3
H2O, 80 oC
R2
N
R1
NH2
30 examples
up to 99% yields
isolated by filtration
- simple operation
- broad substrate scope
- easy product isolation
- recycling of catalyst
- good functional group tolerance
- scale-up synthesis
Abstract
Onꢀwater synthesis of 2ꢀsubstituted quinolines from 2ꢀaminochalcone derivatives was
developed using benzylamine as the nucleophilic catalyst. Various 2ꢀaminochalcones could be
applied to this protocol, and the desired 2ꢀsubstituted quinoline products were isolated in
excellent yields by simple filtration. Furthermore, we elucidated the role of benzylamine in
this transformation and provided the detailed reaction mechanism. This protocol has several
additional advantages, such as simple operation, broad substrate scope, good functional group
tolerance, easy product isolation, recycling of the catalyst, and gramꢀscale synthesis.
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Introduction
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Water is an inexpensive, naturally abundant, safe, nonꢀtoxic, and environmentally
benign solvent; hence, the development of novel organic reactions in aqueous media has
attracted tremendous attention from the chemical community.1,2 In addition, since many
organic compounds are not soluble in water, the resulting products can be precipitated out
from the aqueous reaction medium after the reaction. Consequently, the products can be easily
isolated by simple filtration without tedious workꢀup and purification procedures. Ironically,
solubility is considered a prerequisite for the reactivity of organic transformations. Therefore,
the low solubility of organic compounds in water has triggered the development of several
alternative approaches to increase the effectiveness of “aqueous reactions”, such as the use of
organic coꢀsolvents, introduction of polar functional groups, and use of solubilizing materials
for the starting materials. However, these methods often tend to diminish or even negate the
advantages of water as the reaction medium over traditional solvents.2a Thus, it is highly
desired to develop organic transformations in aqueous media with either no additives or
readily available additives without specific treatments unless absolutely necessary.
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Quinolines are important building blocks found in biologically active natural products,
pharmaceuticals and materials science;3 hence, considerable effort has been made to develop
environmentally benign synthetic protocols for quinoline derivatives.4 Along this line, several
protocols have been developed for the synthesis of quinolines using water as the reaction
medium.5,6 However, most of the previous protocols are based on the Friedländer reaction, a
condensation reaction between orthoꢀaminoaryl ketones or aldehydes 1 and ketones 2 having
an active αꢀmethylene unit, mostly, 1,3ꢀdicarbonyl compounds (Scheme 1a).5,6 In addition,
these protocols generally require strong Brønsted acids or toxic transition metalꢀbased Lewis
acids to facilitate the formation of quinolines, which often leads to the poor functional group
tolerance.5 Furthermore, surfactants or ionic liquids would be employed as additives to
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increase the solubility of the starting materials and/or catalysts in aqueous systems. However,
in these approaches, either the additives and/or catalysts cannot be recycled, or additional
steps are required to recover and recycle these additives.6
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Scheme 1. Comparison of Previous Methods with Our Method for Onꢀwater Synthesis of
Quinolines
Considering the limitations of the previous protocols for the synthesis of quinolines in
aqueous media, it is highly desirable to develop organic transformations for the synthesis of
quinolines in aqueous media using readily available catalysts/promotors without particular
treatments. In this Article, we disclose the development of a novel protocol for the onꢀwater
synthesis of quinolines 3 from 2ꢀaminochalcones 4 using benzylamine as the nucleophilic
catalyst (Scheme 1b). Various 2ꢀaminochalcone derivatives 4 could be applicable to this
protocol, and the desired quinoline products 3 were obtained in excellent yields by simple
filtration of the resulting quinolines from the reaction mixture. Mechanistic studies strongly
suggested that this reaction would proceed though conjugate addition of benzylamine to 2ꢀ
aminochalcones 4, followed by condensation reaction between the amino and carbonyl group,
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and subsequently elimination of benzylamine generating quinolines 3. Furthermore,
benzylamine could be recycled several times without any loss of its catalytic activity.
Extremely simple operation, broad substrate scope, good functional group tolerance, and
gramꢀscale synthesis are the additional advantages of this protocol.
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Results and Discussion
Among the various quinoline derivatives, 2ꢀsubstituted quinolines 3 have attracted
considerable attention from the chemical community, since they not only exhibit interesting
biological activities7 but also serve as key building blocks in material sciences, for example,
in organic lightꢀemitting diodes (OLEDs)8. Thus, a great deal of effort has been made to
develop new protocols toward the synthesis of 2ꢀsubstituted quinolines 3.9 Among the various
protocols developed, the dehydrative cyclization of 2ꢀaminochalcones 4 is considered one of
the most straightforward protocols for the synthesis of 2ꢀsubstituted quinolines.10ꢀ12 However,
2ꢀaminochalcones 4 cannot be converted into the corresponding quinolines 3 because they
exist in a stable (E)ꢀconfiguration, where the amino group is positioned far away from the
carbonyl group, preventing them from undergoing the condensation reaction.13 Thus, most of
the previous methods have been aimed to bring these two functional groups in a close position
to react with each other by changing the stable (E)ꢀconfiguration of the double bond to the
unstable but reactive (Z)ꢀconfiguration via the following approaches: either
photoisomerization under UV and/or visible light,10 chemical isomerization with a
stoichiometric amount of iodine or selenium chloride in the presence of a base,11 or chemical
isomerization with a strong Brønsted acid12.
Very recently, we developed a highly efficient protocol for the synthesis of 2ꢀ
substituted quinolines 3 from 2ꢀaminochalcones 4 in organic solvents using a nucleophile
(Nuꢀ) as the catalyst (Scheme 2).14 The nucleophile underwent conjugate addition to the α,βꢀ
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unsaturated carbonyl group in 4, generating the corresponding saturated ketones 5, in which
the two amino and carbonyl groups could be positioned close enough to undergo
condensation between these two functional groups through conformational change about the
CαꢀCβ single bond. Subsequent elimination of the nucleophile afforded 3 and the catalyst was
regenerated. During the investigation of the reaction parameters in our previous studies,14
water was found to promote this transformation, although it was not as efficient as other
nucleophilic catalysts.15 Furthermore, intermediate 5 (where Nu = OH), generated by the
conjugate addition of water to ketone 4, would be the same intermediate in the proposed
mechanism of the Friedländer reaction; 5 could be formed by the addition of ketones 2 to 2ꢀ
aminobenzaldehyde derivative 1.13 Thus, we investigated the conversion of 4 into 3 in water,
where water would function as a nucleophilic catalyst.
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O
Nu
O
H
H
or OH
O
Nu
Nu = I , Br , RS , etc
R
R
O
X
X
X
+
H
R
NH2
NH2
NH2
Nu = OH
4
5 (s-trans)
1
2
conformational
change
Nu
- H2O
X
X
-
Nu
H
N
R
NH2O
R
3
5 (s-cis)
Scheme 2. Working Hypothesis for OnꢀWater Synthesis of Quinolines 3 from 2ꢀ
Aminochalcones 4.
Based on the aforementioned idea, we investigated the possibility of synthesizing 3
from 4 in water (Table 1). Contrary to our expectation, when 4a was subjected to dehydrative
cyclization in water, quinoline 3a was not formed and the starting material remained
unreacted in the reaction mixture even after a long time (entry 1). We speculated that the
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inefficiency of this transformation in water might be ascribed to the intrinsic low reactivity of
water used as the nucleophilic catalyst under these conditions.16 Thus, we decided to
investigate a more nucleophilic reagent as the potential catalyst for this transformation in
aqueous media. Since iodide was previously identified as the optimal nucleophilic catalyst in
organic solvents,14 we first explored the feasibility of using iodide as the potential catalyst for
this transformation in water. However, the reaction did not proceed at all with iodide as a
potential nucleophilic catalyst (entry 2). Since iodide is completely waterꢀsoluble, the
effective concentration of iodide around 4a in an aqueous system would be very low, which
might be responsible for its poor efficiency as a nucleophilic catalyst in water. Thus, we
explored several nonꢀionic nucleophiles as potential catalysts for this transformation.
Fortunately, when using thiol, the desired quinoline 3a was formed, albeit in low yield (entry
3). Encouraged by this result, we screened several different nucleophiles for this
transformation (entries 4ꢀ6). Among the nucleophiles tested, benzylamine was the most
efficient catalyst: with 10 mol% of benzylamine, 3a was obtained in 67% yield (entry 5).
Next, we investigated the effect of an additional alkyl group on the nitrogen atom in
benzylamine on this quinoline synthesis. Introduction of an alkyl group onto the nitrogen
atom considerably decreased the catalytic efficiency of benzylamine; secondary benzylamine
provided 3a in low yield, while tertiary benzylamine did not furnish the product at all (entries
7 and 8). To further improve the yield of 3a, the effect of the amount of benzylamine on this
formation was examined and was found to have a beneficial influence on this transformation
(entries 5, 9ꢀ11). Although the reaction did not complete with 10 mol% of benzylamine
providing quinoline 3a in 67% even after 24 h (entry 5), the reaction proceeded to completion
with more than 50 mol% of benzylamine and the rate of this reaction considerable increased
with the amount of benzylamine (entries 9ꢀ11). Among the amount of benzylamine tested, we
decided to use a stoichiometric amount of benzylamine as the optimal amount for this
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transformation. Furthermore, we could easily isolate 3a in quantitative yield by simple
4
5
filtration from the reaction mixture (entry 10).
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Table 1. Screening of Nucleophiles
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Entry
(mol%)
ꢀ
time (h)
yielda (%)
N.R.b
N.R.b
12
Nu
ꢀ
1
2
24
6
NaI
10
3
benzyl mercaptan
benzyl alcohol
benzylamine
PPh3
10
6
4
10
6
N.R.b
67 (67)c
N.R.b
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10
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7
Nꢀmethylbenzylamine
N,Nꢀdimethylbenzylamine
benzylamine
benzylamine
benzylamine
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6
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10
6
N.R.b
99
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50
2.5
1
10
11
100
200
99 (99)d
99
0.5
a Yield was determined by 1H NMR analysis of the crude mixture.
b No Reaction
c The number in parenthesis indicated yield of 3a.
d The number in parenthesis indicated isolated yield of 3a by filtration.
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o
With the optimized conditions (100 mol% benzylamine, H2O, open flask, 80 C) in
hand, we investigated the substrate scope of 2ꢀaminochalcones 4 in this transformation (Table
2). A variety of 2ꢀaminochalcone derivatives 4 could be applied to this protocol, and the
desired quinolines 3 were obtained in excellent yields (entries 1ꢀ15). The electronic effect of
the aryl group (R1) did not play a notable role in this transformation; the desired quinolines 3
were obtained in excellent yields, regardless of the electronic nature of the aryl group (R1).
Notably, that various functional groups were wellꢀtolerated in this transformation. In
particular, substrates bearing acidꢀsensitive functional groups such as acetals, silyl ethers,
ethers and esters could be used in this protocol to furnish the desired quinolines 3 in excellent
yields (entries 2, 7 and 9ꢀ11). In addition, this protocol could be applicable to 2ꢀ
aminochalcones bearing fused aromatic and heteroaromatic moieties affording 3 in excellent
yields (entries 16ꢀ19).
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Next, the substituents (R3) on the 2ꢀaminophenyl ring were explored on the efficiency
of this transformation (entries 20ꢀ26). The electronic effect and position of the substituent on
the ring had little influence on the efficiency of this transformation. Thus, 3 could be obtained
in excellent yields, regardless of the electronic nature and the relative position of the R3 group.
Furthermore, the protocol could be extended to the synthesis of quinolines bearing an alkyl
group at the 2ꢀposition. When alkyl 2ꢀaminostyryl ketones were subjected to the standard
conditions, the desired products were obtained in high to excellent yields (entries 27ꢀ29).17
Finally, this protocol was applied to the synthesis of 2,3ꢀdisubstituted quinolines; the reaction
of αꢀsubstituted 2ꢀaminochalcone 4ad provided 2,3ꢀdisubstituted quinoline 3ad in 97% yield
(entry 30). Note that the resulting quinolines 3 could be easily isolated in pure form by either
simple filtration for solid quinolines or simple extraction with ethyl acetate to remove
benzylamine from the reaction mixture.18
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Table 2. Substrate Scope
4
5
6
7
8
9
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22
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entry
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6ꢀF
time (h) yield (%)
3
1
2a
Ph
1
1
1
2
1
1
1
5
1
2
3
2
2
1
1
2
4
3
4
3
99
99
3a
3b
3c
3d
3e
3f
4ꢀMeOC6H4
4ꢀMeC6H4
4ꢀFC6H4
3a
99
4
94
5
4ꢀClC6H4
4ꢀBrC6H4
4ꢀMeO2CC6H4
4ꢀHOC6H4
4ꢀTHPOC6H4
4ꢀTBSOC6H4
4ꢀTIPSOC6H4
2ꢀMeC6H4
3ꢀMeC6H4
2ꢀBrC6H4
3ꢀBrC6H4
1ꢀnaphthyl
2ꢀnaphthyl
2ꢀfuryl
99
6
99
7a
99
3g
3h
3i
8a
99
9
87
10
11
12a
13a
14a
15a
16a
17c
18
19a
20a
76 (23)d
99
3j
3k
3l
99
94
3m
3n
3o
3p
3q
3r
3s
99
99
99
97
98
2ꢀthienyl
97
Ph
99
3t
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21a
22a
23
Ph
Ph
H
H
6ꢀCl
6ꢀBr
6ꢀMeO
7ꢀBr
6ꢀMeO
6,8ꢀBr2
H
3
3
91
99
91
99
99
97
67
83
97
97
3u
3v
Ph
H
3
3w
3x
24a
25a
26b
27
Ph
H
3
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11
12
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4ꢀMeOC6H4
Ph
H
5
3y
H
6
3z
Methyl
Isopropyl
tertꢀButyl
Ph
H
3
3aa
3ab
3ac
3ad
28a
29b
30
H
H
4
H
H
4
Me
H
24
a 3 Equivalents of benzylamine was used.
b 5 Equivalents of benzylamine was used.
c 5 Equivalents of Nꢀmethylbenzylamine was used.
d The TBS group was partly hydrolyzed during the reaction to afford 3h in 23% yield.
With these excellent results in hand, we further attempted to demonstrate the
advantage of this protocol. Since this transformation proceeded in a clean manner (without the
formation of side products) and benzylamine should not be consumed after each
transformation, we expected that the benzylamine solution would be effectively recycled
(Table 3). To our delight, the benzylamine solution could be recycled more than 5 times, and
3a was obtained in excellent yield even after 5 runs, although a slightly longer reaction time
was required with each run.
Table 3. Recycle Studies a
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entry
recycle run
time (h)
yield (%)b
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1
2
3
4
5
6
0
1
2
3
4
5
1
3
99
99
99
99
99
57
4
4.5
5
5
a A 3.0 mL solution of aqueous benzylamine solution (0.10 M, i.e., 0.30 mmol of benzylamine
in 3.0 mL of H2O) was prepared. A suspension of 4a (0.10 mmol) in the abovementioned
benzylamine solution (1.0 mL) was heated to 80 oC in an open flask. After completion of the
reaction, the reaction mixture was filtered and the solid collected was washed with the
remaining solution of benzylamine (1.0 mL x 2) to provide 3a in pure form without further
purification. Then, the filtrate (the aqueous benzylamine solution) was reꢀused as the medium
for the next reaction to test its catalytic efficiency.
b Isolated yield of 3a by filtration.
Next, we attempted to demonstrate the practicality of this protocol for a largeꢀscale
reaction (Scheme 3). To our delight, this transformation could be performed on a 20ꢀmmol
scale, and 3a was obtained in 99% yield by simple filtration.
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Scheme 3. Largeꢀscale Synthesis of Quinoline 3a
Finally, to get detailed insights into the reaction mechanism (see Scheme 2),
particularly the role of benzylamine as a nucleophilic catalyst, for this transformation, several
control experiments were carried out. We first carried out this transformation in D2O as the
reaction medium. When this transformation was performed in D2O, the incorporation of the
deuterium at the Cꢀ3 position of the quinoline ring was observed leading to a mixture of
quinoline 3a and its deuterated product 3a-[D] in 62% yield with a ratio of 0.6 : 1.0 (Scheme
4a). This result indicated that benzylamine would undergo conjugate addition to 3 leading to
enolate 6, which abstracts proton from solvent. In addition, the more solid evidence for the
1
reaction mechanism was found by monitoring this reaction with H NMR analysis. When the
mixture of 4a and benzylamine was submitted to the standard conditions, we observed the
formation of both benzylamine adduct 6a (where Nu = NHCH2Ph) and dihydroquinoline 7a
after 10 min. After 20 min, however, all peaks of the benzylamine adduct 6a completely
1
disappeared in H NMR spectrum and only those from dihydroquinoline 7a increased in the
reaction mixture. As the reaction further proceeded, dihydroquinoline 7a was gradually
converted into the corresponding quinoline 3a.19 After 1 h, only quinoline 3a was observed as
the sole product in the reaction mixture (Scheme 4b).
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Scheme 4. Controlled Experiments for Mechanistic Studies. Blue arrows indicate the peaks
from benzylamine adduct 5a and red arrows point out the peaks from dihydroquinoline 7a.
Based on these experimental results, we proposed the reaction mechanism for this
transformation (Scheme 5). Benzylamine undergoes conjugate addition to 2ꢀaminochalcones
4 to form enolates 6, which abstract proton from water to generate βꢀaminoketones 5.
Compounds 5 could undergo free rotation about the CαꢀCβ bond leading to sꢀcis conformation.
Under such a conformation, the two functional groups undergo condensation to generate
dihydroquinoline 7, which subsequently undergo the elimination of benzylamine to afford the
desired quinoline 3.
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PhH2C
PhH2C
O
NH
O
NH
O
4
5
6
7
PhCH2NH2
H2O
R
R
R
X
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proton
abstraction
H
conjugate
addition
NH2
NH2
NH2
5 (s-trans)
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conformational
change
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PhH2C
PhH2C
NH
NH
H
H
H
- PhCH2NH2
- H2O
X
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elimination
N
R
condensation
NH2O
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R
R
3
7
5 (s-cis)
Scheme 5. Proposed Reaction Mechanism for Conversion of 2ꢀAminochalcones 4 to
Quinolines 3 from using Benzylamine as the Nucleophilic Catalyst in Aqueous Medium
Conclusions
We have developed an onꢀwater protocol for the synthesis of 2ꢀsubstituted quinolines
from 2ꢀaminochalcones using benzylamine as the nucleophilic catalyst. This protocol was
applicable to a variety of 2ꢀaminochalcone derivatives, and the desired quinoline products
were obtained in excellent yields by simple filtration. In addition, we provided a detailed
reaction mechanism for this transformation by elucidating the role of benzylamine as the
nucleophilic catalyst. Furthermore, the catalytic system could be recycled several times
without significant loss of its activity. Extremely simple operation, broad substrate scope,
largeꢀscale synthesis and mild reaction conditions are additional advantages of this protocol.
Further development of other organic transformations in the presence of a nucleophilic
catalyst is underway in our laboratory, and the results will be reported in due course.
Experimental Section
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General. Commercial grade reagents and solvents were used without further purification,
unless otherwise noted. 2ꢀAminochalcone derivatives 4 were prepared by a literature protocol;
aldol condensation of acetophenone derivatives with 2ꢀnitrobenzaldehydes provided 2ꢀ
nitrochalcones, and subsequent reduction of the nitro group into an amino group afforded the
expected 2ꢀaminochalcone derivatives 4.14 1H NMR and 13C NMR spectra were recorded
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using 500 MHz and 125 MHz spectrometers, respectively. H spectra were recorded using
CDCl3 or DMSOꢀd6 as the solvent with chloroform (CHCl3; δ = 7.26 ppm) or DMSOꢀd6
(DMSOꢀd6; δ 2.50 ppm) as the internal standard. 13C spectra were obtained using CDCl3 or
DMSOꢀd6 as the solvent with chloroform (CDCl3; δ = 77.2 ppm) or DMSOꢀd6 (DMSOꢀd6; δ =
39.5 ppm) as the internal standard. The proton spectra are reported as follows: δ (position of
proton, multiplicity, coupling constant J, number of protons). Multiplicities are indicated by s
(singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (septet), m (multiplet) and br
(broad). Highꢀresolution mass spectra (HRMS) were recorded on a quadrupole timeꢀofꢀflight
mass spectrometer (QTOFꢀMS) with an electrospray ionization (ESI) source.
Synthesis of 2-Aminochalcone Derivatives 4. All previously unknown 2ꢀaminochalcone
derivatives (4h, 4i, 4j, and 4k) were prepared from a suitable acetophenone derivative and 2ꢀ
nitrobenzaldehyde by aldol condensation, followed by the reduction of a nitro group into an
amino group.14
General Procedure for the Synthesis of 2-Aminochalcone Derivatives 4. To a mixture of a
2ꢀnitrobenzaldehyde derivative (4.0 mmol, 1.0 equiv.), sodium hydroxide (16 mg, 0.40 mmol,
0.10 equiv.), and potassium carbonate (55 mg, 0.40 mmol, 0.10 equiv.) was added a relevant
acetophenone derivative (4.0 mmol, 1.0 equiv.) at room temperature. The reaction mixture
was stirred at room temperature and monitored by thin layer chromatography (TLC). After
complete consumption of the 2ꢀnitrobenzaldehyde, the reaction mixture was quenched with
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H2O and extracted with ethyl acetate. The organic layers were combined, dried over MgSO4,
and concentrated in vacuo. Recrystallization of the crude mixture in ethanol provided the
corresponding (E)ꢀ2ꢀnitrochalcone, which was directly subjected to the next reduction
conditions.
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To a solution of the resulting (E)ꢀ2ꢀnitrochalcone derivative (2.5 mmol, 1.0 equiv.) in ethanol
(25 mL) was added iron powder (70 mg, 13 mmol, 5.0 equiv.), followed by HCl (1.0 N, 1.3
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mL, 1.3 mmol, 0.5 equiv.). The resulting mixture was vigorously stirred at 80 C. After
complete consumption of the (E)ꢀ2ꢀnitrochalcone derivative, the reaction mixture was cooled
to room temperature, diluted with ethyl acetate, and filtered through a Celite pad. The filtrate
was neutralized with saturated aqueous Na2CO3 solution, and the aqueous phase was extracted
with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4,
and concentrated. The crude material was purified by recrystallization from a mixture of
methylene chloride and hexanes to provide the desired (E)ꢀ2ꢀaminochalcone derivative 4.
(E)ꢀ2ꢀAminoꢀ4’ꢀhydroxychalcone (4h)
Orange solid (0.24 g, 40% yield). Rf = 0.3 (ethyl acetate/hexanes = 1:1). 1H NMR (500 MHz,
DMSOꢀd6, ppm): δ 8.03 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 15.3 Hz, 1H), 7.67 (d, J = 7.0 Hz,
1H), 7.63 (d, J = 15.3 Hz, 1H), 7.09 (m, 1H), 6.88 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 7.8 Hz,
1H), 6.57 (t, J = 7.5 Hz, 1H), 5.65 (s, 2H). 13C{1H} NMR (125 MHz, DMSOꢀd6, ppm): δ
159.1, 156.1, 147.6, 136.9, 129.7, 129.6, 128.8, 128.7, 127.7, 126.5, 125.8, 118.1, 115.6.
HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C15H14NO2 240.1019; found 240.1017.
(E)ꢀ2ꢀAminoꢀ4’ꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀyloxychalcone (4i)
Yellow solid (0.52 g, 65% yield). Rf = 0.3 (ethyl acetate/hexanes = 1:5). 1H NMR (500 MHz,
CDCl3, ppm): δ 8.03 (m, 2H), 7.96 (d, J = 15.3 Hz, 1H), 7.52 (dd, J = 7.8, 1.4 Hz, 1H), 7.49
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(d, J = 15.3 Hz, 1H), 7.20 (m, 1H), 7.13 (m, 2H), 6.80 (t, J = 7.5 Hz, 1H), 6.72 (dd, J = 8.1,
0.9 Hz, 1H), 5.54 (t, J = 3.1 Hz, 1H), 4.04 (br. s., 2H), 3.87 (dt, J = 10.7, 3.1 Hz, 1H), 3.64 (m,
1H), 2.02 (m, 1H), 1.90 (td, J = 7.5, 3.9 Hz, 2H), 1.71 (m, 2H), 1.62 (td, J = 8.6, 4.2 Hz, 1H).
13C{1H} NMR (125 MHz, CDCl3, ppm): δ 188.9, 161.1, 146.2, 139.5, 131.9, 131.6, 130.8,
128.3, 122.0, 120.7, 119.0, 116.9, 116.2, 96.2, 62.2, 30.3, 25.2, 18.7. HRMS (ESIꢀTOF) m/z:
[M + H]+ calcd for C20H22NO3 324.1594; found 324.1593.
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(E)ꢀ2ꢀAminoꢀ4’ꢀtertꢀbutyldimethylsilyloxychalcone (4j)
Yellow solid (0.35 g, 40% yield). Rf = 0.3 (ethyl acetate/hexanes = 1:5). 1H NMR (500 MHz,
CDCl3, ppm): δ 7.98 (m, 3H), 7.52 (dd, J = 7.9, 1.0 Hz, 1H), 7.49 (d, J = 15.4 Hz, 1H), 7.19
(m, 1H), 6.92 (m, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.07 (br. s., 2H),
1.00 (s, 9H), 0.25 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 188.8, 160.3, 146.2,
139.4, 131.9, 131.6, 130.8, 128.2, 121.9, 120.6, 120.2, 119.0, 116.9, 25.7, 18.4. HRMS (ESIꢀ
TOF) m/z: [M + H]+ calcd for C21H28NO2Si 354.1884; found 354.1886.
(E)ꢀ2ꢀAminoꢀ4’ꢀtriisopropylsilyloxychalcone (4k)
Yellow solid (0.27 g, 27% yield). Rf = 0.3 (ethyl acetate/hexanes = 1:5). 1H NMR (500 MHz,
CDCl3, ppm): δ 7.97 (m, 3H), 7.51 (m, 2H), 7.19 (m, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.79 (t, J
= 7.5 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.09 (br. s., 2H), 1.29 (m, 3H), 1.13 (m, 18H).
13C{1H} NMR (125 MHz, CDCl3, ppm): δ 188.7, 160.7, 146.3, 139.3, 131.6, 131.5, 130.8,
128.2, 121.9, 120.6, 120.0, 118.9, 116.8, 18.0, 12.8. HRMS (ESIꢀTOF) m/z: [M + H]+ calcd
for C24H34NO2Si 396.2353; found 396.2351.
General Procedure for the Synthesis of 2-Substituted Quinolines 3 (Table 2). To a
suspension of (E)ꢀ2ꢀaminochalcone derivative 4 (0.20 mmol) in water (2.0 mL) was added
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benzylamine (21.8 ꢁL, 0.20 mmol; 0.60 or 1.0 mmol was used for some substrates) at room
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5
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temperature in an open flask. After complete consumption of 4, the reaction mixture was
cooled to room temperature for precipitation. Then, the precipitate was collected by filtration
and washed with water to remove benzylamine. After this simple filtration, the desired
quinoline 3 was obtained in pure form without further purification. In the case of some liquid
quinolines, the desired quinoline products were obtained by either simple extraction with
ethyl acetate (3k, 3ac and 3ad) or purification by column chromatography on silica gel (3aa
and 3ab).
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2ꢀPhenylquinoline (3a)14
Purified by filtration from the reaction mixture. White solid (41 mg, 99% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.23 (d, J = 8.5 Hz, 1H),
8.18 (m, 3H), 7.89 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.74 (m, 1H), 7.54 (m, 3H),
7.47 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.5, 148.5, 139.9, 136.9, 129.9,
129.8, 129.5, 129.0, 127.7, 127.6, 127.3, 126.4, 119.2.
2ꢀ(4ꢀMethoxyphenyl)quinoline (3b)14
Purified by filtration from the reaction mixture. Pale yellow solid (47 mg, 99% yield). Rf = 0.4
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(ethyl acetate/hexanes = 1:7). H NMR (500 MHz, CDCl3, ppm): δ 8.19 (d, J = 8.5 Hz, 1H),
8.14 (m, 3H), 7.84 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.71 (ddd, J = 8.5, 6.9, 1.4
13
Hz, 1H), 7.50 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.06 (m, 2H), 3.89 (s, 3H). C{1H} NMR (125
MHz, CDCl3, ppm): δ 161.0, 157.0, 148.4, 138.8, 132.4, 129.7 (2C), 129.0, 127.6, 127.0,
126.0, 118.7, 114.4, 55.5.
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2ꢀ(4ꢀMethylphenyl)quinoline (3c)14
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Purified by filtration from the reaction mixture. Pale yellow solid (44 mg, 99% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.20 (d, J = 8.5 Hz, 1H),
8.17 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.1 Hz,
1H), 7.72 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.51 (m, 1H), 7.34 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.5, 148.4, 139.9, 139.6, 137.0, 136.8, 129.8,
129.7 (2C), 127.6, 127.2, 126.2, 119.0, 21.5.
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2ꢀ(4ꢀFluorophenyl)quinoline (3d)14
Purified by filtration from the reaction mixture. Light green solid (42 mg, 94% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.23 (d, J = 8.4 Hz, 1H),
8.16 (m, 3H), 7.83 (m, 2H), 7.73 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.53 (ddd, J = 8.1, 6.9, 1.1
Hz, 1H), 7.21 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 164.9, 163.0, 156.4, 148.4,
137.1, 136.0, 130.0, 129.8, 129.6, 129.5, 127.6, 127.2, 126.5, 118.8, 116.0, 115.8.
2ꢀ(4ꢀChlorophenyl)quinoline (3e)14
Purified by filtration from the reaction mixture. Pale yellow solid (48 mg, 99% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.23 (d, J = 8.7 Hz, 1H),
8.16 (d, J = 8.5 Hz, 1H), 8.13 (m, 2H), 7.84 (m, 2H), 7.74 (dt, J = 7.7, 1.3 Hz, 1H), 7.55 (m,
1H), 7.50 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 156.1, 148.4, 138.2, 137.1,
135.7, 130.0, 129.8, 129.1, 128.9, 127.6, 127.3, 126.6, 118.7.
2ꢀ(4ꢀBromophenyl)quinoline (3f)14
Purified by filtration from the reaction mixture. Pale yellow solid (57 mg, 99% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.24 (d, J = 8.5 Hz, 1H),
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(m, 2H), 7.55 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 156.2,
148.4, 138.7, 137.1, 132.1, 130.0, 129.9, 129.2, 127.6, 127.4, 126.7, 124.1, 118.6.
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2ꢀ(4ꢀMethoxycarbonylphenyl)quinoline (3g)14
Purified by filtration from the reaction mixture. White solid (53 mg, 99% yield). Rf = 0.3
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(ethyl acetate/hexanes = 1:7). H NMR (500 MHz, CDCl3, ppm): δ 8.26 (m, 3H), 8.19 (m,
3H), 7.92 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.76 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H),
7.57 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 3.97 (s, 3H). C{1H} NMR (125 MHz, CDCl3, ppm): δ
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2ꢀ(4ꢀHydroxyphenyl)quinoline (3h)20
Purified by filtration from the reaction mixture. Brown solid (44 mg, 99% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:1). 1H NMR (500 MHz, DMSO, ppm): δ 9.87 (s, 1H), 8.36 (d, J =
8.5 Hz, 1H), 8.14 (m, 2H), 8.05 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.94 (dd, J = 8.2,
1.0 Hz, 1H), 7.74 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.54 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.92 (m,
2H). 13C{1H} NMR (125 MHz, DMSO, ppm): δ 159.1, 156.1, 147.5, 136.9, 129.7, 129.6,
128.8, 128.7, 127.7, 126.5, 125.8, 118.1, 115.6.
2ꢀ(4ꢀ(Tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)oxyphenyl)quinoline (3i)
Purified by filtration from the reaction mixture. Brown solid (53 mg, 87% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.18 (d, J = 8.5 Hz, 1H),
8.13 (m, 3H), 7.84 (d, J = 8.5 Hz, 1H), 7.81 (dd, J = 8.1, 0.9 Hz, 1H), 7.71 (ddd, J = 8.4, 6.9,
1.4 Hz, 1H), 7.50 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.20 (m, 2 H), 5.53 (t, J = 3.2 Hz, 1H), 3.93
(ddd, J = 11.3, 9.9, 3.0 Hz, 1H), 3.64 (m, 1H), 2.04 (m, 1H), 1.91 (m, 2H), 1.71 (m, 2H), 1.63
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(m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 158.4, 157.1, 148.4, 136.8, 133.2,
129.7(2C), 128.9, 127.6, 127.1, 126.1, 118.8, 116.8, 96.3, 62.2, 30.4, 25.3, 18.8. HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C20H20NO2 306.1489; Found 306.1492.
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2ꢀ(4ꢀtertꢀButyldimethylsilyloxyphenyl)quinoline (3j)21
Purified by filtration from the reaction mixture. Brown solid (51 mg, 76% yield). Rf = 0.3
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(ethyl acetate/hexanes = 1:10). 3j: H NMR (500 MHz, CDCl3, ppm): δ 8.18 (d, J = 8.7 Hz,
1H), 8.14 (d, J = 8.5 Hz, 1H), 8.07 (m, 2H), 7.83 (d, J = 8.5 Hz, 1H), 7.81 (m, 1H), 7.71 (ddd,
J = 8.5, 6.9, 1.4 Hz, 1H), 7.50 (m, 1H), 6.99 (m, 2H), 1.01 (s, 9H), 0.24 (s, 6H). 13C{1H}
NMR (125 MHz, CDCl3, ppm): δ 157.3, 157.2, 148.4, 136.8, 133.0, 129.7, 129.6, 129.0,
127.6, 127.0, 126.0, 120.7, 118.8, 25.8, 18.4. Compound 3h (10 mg, 23%) was isolated by the
extraction of the filtrate with ethyl acetate. Spectroscopic data were matched with the reported
values.20
2ꢀ(4ꢀTriisopropylsilyloxyphenyl)quinoline (3k)
Purified by extraction with ethyl acetate. Brown oil (76 mg, 99% yield). Rf = 0.3 (ethyl
1
acetate/hexanes = 1:10). H NMR (500 MHz, CDCl3, ppm): δ 8.18 (d, J = 8.5 Hz, 1H), 8.13
(d, J = 8.5 Hz, 1H), 8.07 (m, 2H), 7.83 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.70 (ddd,
J = 8.4, 6.9, 1.4 Hz, 1H), 7.50 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.02 (m, 2H), 1.30 (m, 3H),
13
1.14 (m, 18H). C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.7, 157.1, 148.4, 136.7, 132.6,
129.6, 128.9, 127.5, 127.0, 125.9, 120.4, 118.7, 18.0, 12.8. HRMS (ESIꢀTOF) m/z: [M + H]+
Calcd for C24H32NOSi 378.2248; Found 378.2247.
2ꢀ(2ꢀMethylphenyl)quinoline (3l)14
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Purified by filtration from the reaction mixture. Brown solid (44 mg, 99% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.22 (d, J = 8.4 Hz, 1H),
8.17 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 8.2, 1.1 Hz, 1H), 7.75 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H),
7.56 (m, 2H), 7.51 (m, 1H), 7.33 (m, 3H), 2.42 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3,
ppm): δ 160.4, 147.9, 140.8, 136.2, 136.1, 131.0, 129.8 (2C), 129.6, 128.6, 127.6, 126.8,
126.5, 126.1, 122.5, 20.5.
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2ꢀ(3ꢀMethylphenyl)quinoline (3m)14
Purified by filtration from the reaction mixture. Brown solid (41 mg, 94% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.22 (d, J = 8.5 Hz, 1H),
8.18 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.92 (m, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 8.1,
1.4 Hz, 1H), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz 1H), 7.53 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.42 (t, J
= 7.6 Hz, 1H), 7.29 (td, J = 7.6, 0.6 Hz, 1H), 2.49 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3,
ppm): δ 157.6, 148.3, 139.7, 138.6, 136.8, 130.2, 129.8, 129.7, 128.8, 128.3, 127.5, 127.3,
126.3, 124.8, 119.2, 21.7.
2ꢀ(2ꢀBromophenyl)quinoline (3n)14
Purified by filtration from the reaction mixture. Yellow solid (57 mg, 99% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.23 (d, J = 8.4 Hz, 1H),
8.18 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.76 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.71
(m, 2H), 7.64 (dd, J = 7.6, 1.8 Hz, 1H), 7.59 (td, J = 7.6, 1.1 Hz, 1H), 7.46 (td, J = 7.6, 1.1 Hz,
1H), 7.31 (td, J = 7.7, 1.7 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 158.9, 148.1,
141.8, 135.8, 133.4, 131.7, 130.1, 130.0, 129.8, 127.8, 127.7, 127.3, 127.0, 122.9, 122.0.
2ꢀ(3ꢀBromophenyl)quinoline (3o)14
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Purified by filtration from the reaction mixture. Yellow solid (57 mg, 99% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.36 (t, J = 1.8 Hz, 1H),
8.25 (d, J = 8.5 Hz, 1H), 8.17 (dd, J = 8.5, 0.8 Hz, 1H), 8.08 (dq, J = 7.8, 0.9 Hz, 1H), 7.85
(m, 2H), 7.75 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.59 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 7.55 (ddd, J
= 8.1, 6.9, 1.2 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ
155.7, 148.3, 141.7, 137.1, 132.3, 130.7, 130.4, 130.0, 129.9, 127.6, 127.4, 126.8, 126.1,
123.3, 118.7.
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2ꢀ(1ꢀNaphthyl)quinoline (3p)14
Purified by filtration from the reaction mixture. Brown solid (51 mg, 99% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.30 (d, J = 8.4 Hz, 1H),
8.23 (m, 1H), 8.13 (m, 1H), 7.94 (m, 3H), 7.78 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.72 (m, 2H),
7.61 (m, 2H), 7.50 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 159.5, 148.2, 138.8,
136.4, 134.1, 131.4, 129.9, 129.8, 129.3, 128.5, 127.9, 127.7, 127.1, 126.7 (2C), 126.1, 125.8,
125.5, 123.4.
2ꢀ(2ꢀNaphthyl)quinoline (3q)14
Purified by filtration from the reaction mixture. Brown solid (50 mg, 97% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.63 (d, J = 0.9 Hz, 1H),
8.38 (dd, J = 8.5, 1.8 Hz, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.05 (d, J =
8.5 Hz, 1H), 8.01 (m, 2H), 7.90 (m, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.76 (ddd, J = 8.4, 6.9, 1.4
Hz, 1H), 7.54 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.3, 148.5, 137.1, 137.0,
134.0, 133.7, 129.9 (2C), 129.0, 128.7, 127.9, 127.6, 127.4, 127.3, 126.9, 126.5, 125.2, 119.3.
2ꢀ(2ꢀFuryl)quinoline (3r)14
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Purified by filtration from the reaction mixture. Brown solid (38 mg, 98% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.17 (d, J = 8.5 Hz, 1H),
8.13 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.1, 1.2 Hz, 1H), 7.71 (ddd, J
= 1.4, 6.9, 8.4 Hz, 1H), 7.63 (dd, J = 1.7, 0.8 Hz, 1H), 7.50 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H),
7.22 (dd, J = 3.4, 0.7 Hz, 1H), 6.59 (dd, J = 3.4, 1.8 Hz, 1H). 13C{1H} NMR (125 MHz,
CDCl3, ppm): δ 153.8, 149.1, 148.2, 144.2, 136.8, 130.0, 129.5, 127.7, 127.3, 126.3, 117.6,
112.3, 110.2.
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2ꢀ(2ꢀThienyl)quinoline (3s)14
Purified by filtration from the reaction mixture. Yellow solid (41 mg, 97% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.14 (d, J = 8.4 Hz, 1H),
8.09 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.1, 1.2 Hz, 1H), 7.74 (dd, J =
3.7, 1.1 Hz, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.48 (m, 2H), 7.16 ppm (dd, J = 5.0, 3.7
Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 152.4, 148.2, 145.5, 136.7, 129.9, 129.4,
128.7, 128.2, 127.6, 127.3, 126.2, 126.0, 117.7.
6ꢀFluoroꢀ2ꢀphenylquinoline (3t)14
Purified by filtration from the reaction mixture. Pale yellow solid (45 mg, 99%). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.16 (m, 4H), 7.91 (d, J =
8.5 Hz, 1H), 7.54 (m, 2H), 7.48 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 161.4,
159.5, 156.9 (2C), 145.5, 139.5, 136.3, 136.2, 132.3 (2C), 129.5, 129.0, 127.8 (2C), 127.6,
120.1, 119.9, 119.8, 110.7, 110.5.
6ꢀChloroꢀ2ꢀphenylquinoline (3u)14
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Purified by filtration from the reaction mixture. Pale yellow solid (44 mg, 91% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.15 (m, 3H), 8.11 (d, J =
9.0 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.9, 2.4 Hz, 1H),
7.54 (m, 2H), 7.48 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.6, 146.7, 139.3,
135.9, 132.0, 131.4, 130.6, 129.7, 129.0, 127.8, 127.6, 126.2, 119.8.
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6ꢀBromoꢀ2ꢀphenylquinoline (3v)14
Purified by filtration from the reaction mixture. Orange solid (57 mg, 99% yield). Rf = 0.4
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.16 (d, J = 7.0 Hz, 2H),
8.13 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.5 Hz,
1H), 7.79 (dd, J = 9.0, 2.1 Hz, 1H), 7.54 (m, 2H), 7.48 (m, 1H). 13C{1H} NMR (125 MHz,
CDCl3, ppm): δ 157.8, 146.9, 139.3, 135.9, 133.2, 131.6, 129.7, 129.6, 129.0, 128.3, 127.6,
120.2, 119.9.
6ꢀMethyoxyꢀ2ꢀphenylquinoline (3w)14
Purified by filtration from the reaction mixture. Pale yellow solid (43 mg, 91% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.13 (m, 3H), 8.07 (d, J =
9.2 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.52 (m, 2H), 7.44 (m, 1H), 7.39 (dd, J = 9.2, 2.7 Hz,
1H), 7.10 (d, J = 2.7 Hz, 1H), 3.95 (s, 3H). C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.8,
13
155.2, 144.5, 139.9, 135.7, 131.3, 129.1, 129.0, 128.3, 127.4, 122.5, 119.4, 105.1, 55.7.
7ꢀBromoꢀ2ꢀphenylquinoline (3x)14
Purified by filtration from the reaction mixture. Pale yellow solid (57 mg, 99% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.37 (s, 1H), 8.19 (d, J =
8.5 Hz, 1H), 8.16 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.61
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(d, J = 8.7 Hz, 1H), 7.54 (m, 2H), 7.48 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ
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158.3, 149.0, 139.3, 136.8, 132.2, 129.9, 129.8, 129.1, 128.9, 127.7, 125.9, 123.9, 119.4.
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6ꢀMethoxyꢀ2ꢀ(4ꢀmethoxyphenyl)quinoline (3y)14
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Purified by filtration from the reaction mixture. Brown solid (53 mg, 99% yield). Rf = 0.3
(ethyl acetate/hexanes = 1:8). 1H NMR (500 MHz, CDCl3, ppm): δ 8.09 (m, 3 H), 8.03 (d, J =
9.2 Hz, 1H), 7.79 (dd, J = 8.5, 1.4 Hz, 1H), 7.36 (dd, J = 9.2, 2.7 Hz, 1H), 7.08 (d, J = 2.6 Hz,
1H), 7.04 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H) 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 160.6,
157.5, 154.8 144.5, 135.6, 132.5, 131.1, 128.7, 127.9, 122.3, 119.0, 114.3, 105.2, 55.7, 55.5.
6,8ꢀDibromoꢀ2ꢀphenylquinoline (3z)14
Purified by column chromatography on silica using a mixture of ethyl acetate and hexanes
(1:10) as an eluent. Yellow solid (70 mg, 97% yield). Rf = 0.3 (ethyl acetate/hexanes = 1:10).
1H NMR (500 MHz, CDCl3, ppm): δ 8.30 (m, 2H), 8.16 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 8.5
Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.55 (m, 2H), 7.50 (m, 1H).
13C{1H} NMR (125 MHz, CDCl3, ppm): δ 157.9, 144.0, 138.6, 136.4, 136.1, 130.2, 129.4,
129.1, 129.0, 127.8, 126.7, 120.1, 119.4.
2ꢀMethylquinoline (3aa)14
Purified by column chromatography on silica using a mixture of ethyl acetate and hexanes
(1:10) as the eluent. White solid (19 mg, 67% yield). Rf = 0.3 (ethyl acetate/hexanes = 1:5). 1H
NMR (500 MHz, CDCl3, ppm): δ 8.03 (t, J = 9.7 Hz, 2H), 7.78 (m, 1H), 7.68 (m, 1H), 7.48 (t,
J = 7.5 Hz, 1H), 7.29 (dd, J = 8.4, 1.2 Hz, 1H), 2.75 (d, J = 1.2 Hz, 3H). 13C{1H} NMR (125
MHz, CDCl3, ppm): δ 159.2, 148.0, 136.3, 129.6, 128.8, 127.6, 126.6, 125.8, 122.2, 25.5.
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2ꢀIsopropylquinoline (3ab)14
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Purified by column chromatography on silica using a mixture of ethyl acetate and hexanes
(1:10) as the eluent. Yellow oil (28 mg, 83% yield). Rf = 0.3 (ethyl acetate/hexanes = 1:10).
1H NMR (500 MHz, CDCl3, ppm): δ 8.09 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.77
(d, J = 8.1 Hz, 1H), 7.68 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.48 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H),
7.35 (d, J = 8.5 Hz, 1H), 3.27 (td, J = 13.9, 6.9 Hz, 1H), 1.40 (d, J = 7.0 Hz, 6H). 13C{1H}
NMR (125 MHz, CDCl3, ppm): δ 167.8, 147.9, 136.5, 129.4, 129.1, 127.6, 127.1, 125.8,
119.3, 37.5, 22.7.
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2ꢀ(tertꢀButyl)quinoline (3ac)10a
Purified by extraction with ethyl acetate. Yellow oil (36 mg, 97% yield). Rf = 0.3 (ethyl
1
acetate/hexanes = 1:10). H NMR (500 MHz, CDCl3, ppm): δ 8.08 (d, J = 8.2 Hz, 2H), 7.77
(d, J = 8.1 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H),
1.48 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 169.4, 147.5, 136.0, 129.5, 129.2,
127.4, 126.6, 125.8, 118.4, 38.3, 30.3.
3ꢀMethylꢀ2ꢀphenylquinoline (3ad)14
Purified by extraction with ethyl acetate. Orange oil (43 mg, 97% yield). Rf = 0.3 (ethyl
acetate/hexanes = 1:10). 1H NMR (500 MHz, CDCl3, ppm): δ 8.13 (d, J = 8.5 Hz, 1H), 8.03 (s,
1H), 7.79 (d, J = 8.1 Hz, 1H), 7.66 (m, 1H), 7.59 (m, 2H), 7.51 (m, 3H), 7.44 (m, 1H), 2.47 (s,
3H). 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 160.6, 146.6, 140.8, 137.0, 129.4, 129.2,
129.0 (2C), 128.4, 128.3, 127.7, 126.9, 126.6, 20.7.
Recycle Studies of Benzylamine (Table 3)
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A 3.0 mL solution of aqueous benzylamine solution (0.10 M, i.e., 0.30 mmol of
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benzylamine in 3.0 mL of H2O) was prepared. A suspension of 4a (0.10 mmol) in the
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o
abovementioned benzylamine solution (1.0 mL) was heated to 80 C in an open flask.
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After completion of the reaction, the precipitate was collected by filtration and washed
with the remaining benzylamine solution (1.0 mL × 2) to afford quinoline 3a in pure form
without further purification. The filtrate was tested for its catalytic activity by reusing it as
the reaction media for the next reaction.
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ORCID
CheolꢀHong Cheon: 0000ꢀ0002ꢀ6738ꢀ6193
Notes
The authors declare no competing financial interests.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:
Copies of NMR spectra for the products (PDF)
Acknowledgements
This work was supported by National Research Foundation of Korea (NRF) grants funded by
the Korean Government (NRFꢀ2015R1D1A1A01057200, NRFꢀ2017M2A8A4018045 and
NRFꢀ20100020209). C.ꢀH.C. thanks the financial support from an NRF grant funded by the
Korean Government (NRFꢀ2014ꢀ011165, Center for New Directions in Organic Synthesis).
References
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1. For a seminal report on onꢀwater synthesis, see: (a) Narayan, S.; Muldoon, J.; Finn, M.
G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. “Onꢀwater”: Unique Reactivity of
Organic Compounds in Aqueous Suspension. Angew. Chem. Int. Ed. 2005, 44, 3275ꢀ
3279. (b) A commentary on “Onꢀwater Synthesis”: Klijin, J. E.; Engberts, B. F. N.
Fast Reactions “Onꢀwater”. Nature 2005, 435, 746ꢀ747.
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2. For reviews on onꢀwater synthesis, see: (a) Kitanosono, T.; Masuda, K.; Xu, P.;
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583ꢀ597. (b) Afzal, O.; Kumar, S.; Haider, M. R.; Ali, M. R.; Kumar, R.; Jaggi, M.;
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