One-step catalytic synthesis of alkyl-substituted quinolines

Article abstract of DOI:10.1021/jo5015883

Difficult-to-access alkyl-substituted quinolines are formed directly from commercially available anilines, aldehydes, and alkynes bearing a variety of substituents. Copper(II) triflate catalyzes this three-component coupling without ligand, cocatalyst, solvent, or inert atmosphere. In addition, a two-component Povarov reaction forms 2,3-dialkyl quinolines under the same green conditions that enable the selective three-component synthesis of 2-alkyl quinolines as well as more common aryl quinolines. (Chemical Equation Presented).

Full text of DOI:10.1021/jo5015883

Note
pubs.acs.org/joc
One-Step Catalytic Synthesis of Alkyl-Substituted Quinolines
Courtney E. Meyet and Catharine H. Larsen*
Department of Chemistry, University of California, Riverside, California 92521, United States
*
S Supporting Information
ABSTRACT: Difficult-to-access alkyl-substituted quinolines
are formed directly from commercially available anilines,
aldehydes, and alkynes bearing a variety of substituents.
Copper(II) triflate catalyzes this three-component coupling
without ligand, cocatalyst, solvent, or inert atmosphere. In
addition, a two-component Povarov reaction forms 2,3-dialkyl
quinolines under the same green conditions that enable the
selective three-component synthesis of 2-alkyl quinolines as
well as more common aryl quinolines.
uinolines are valued as luminescent materials, tunable
Multicomponent coupling reactions are a powerful tool for
the synthesis of a variety of heterocycles. This mode of
1
−8
10
Q
ligands, natural products, and medicines. As in classic
2
3
Skraup, Friedlander, Doebner-Von Miller, Pfitzinger, Con-
rad−Limpach, and Combes reactions, a multitude of quinoline
syntheses developed over the past 130 years utilize a starting
heterocycle construction allows for variation in each
component while eliminating waste generated in multistep
syntheses. So-called A3 (Aldehyde-Amine-Alkyne) three-
component coupling reactions allow for maximum variability
in product structures as hundreds of aldehyde, aniline, and
4
material with two or three functional groups. For example, an
aryl amine bearing a carbonyl condenses and cyclizes with a
1
1,12
3
separate carbonyl substrate in the Friedlan
̈
der quinoline
alkyne starting materials are commercially available.
A
3
−5
2
synthesis.
Quinolines bearing aryl and other sp groups
couplings begin with the condensation of an aldehyde and an
amine to produce an imine electrophile, and attack by the
acetylide nucleophile formed from a terminal alkyne produces a
propargylamine. N-Aryl propargylamines can be converted to
are readily accessed by these methods. Additional groups must
be incorporated during the synthesis of the bifunctional starting
material as only the simplest variants tend to be commercially
4
−6
1
2
available.
heteroaromatic compounds.
Figure 1 shows a small sampling of the alkyl-substituted
quinolines that display activity against malaria, inflammation,
In 2002, a copper-catalyzed A3 coupling of aniline 1,
13
benzaldehyde 2, and alkyne 3 was reported. Condensation
to imine 4 is followed by alkynylation to propargylamine 5 as
well as in situ cyclization and oxidation to quinoline 6. A
loading of 30 mol % CuCl provides 9−48% yield of
propargylamine 5 and 31−48% yield of quinoline 6. These
product mixtures are attributed to the reduction of imine 4
during oxidation of 5 to 6, which also produces N-benzylaniline
7 (Scheme 1).
Figure 1. Alkyl quinolines with therapeutic indicators.
In 2008, Xiao et al. showed that 5 mol % AuCl could be
3
applied to convert propargylamines into 2,4-diaryl quinolines in
1
4
7
,8
65−87% yield. However, no alkyl aldehydes were incorpo-
rated, and propargylamines similar to 5, lacking an aryl group
on the alkyne, did not convert into the desired quinoline in 3
cancer, and tuberculosis. The greater activity imparted by
alkyl groups, particularly by those at C-2 adjacent to the
quinoline nitrogen, is credited to an overall increase in
8
days. In contrast, if 5 mol % AuCl is combined with 30 mol %
CuBr, this dual catalyst A forms 2,4-diaryl quinolines directly
from aryl aldehydes, anilines, and phenylacetylene derivatives.
A number of groups have applied Lewis acid, acidic resin, and
microwave methods for better conversion of aryl aldehydes to
3
lipophilicity, which increases cell permeability. However,
Friedlander annulation of 2-amino benzaldehydes with alkyl
̈
ketones can result in mixtures of 2-alkyl versus 2,3-dialkyl
3
15
5
quinolines due to nonregioselective enolate formation. Thus,
access to alkyl-substituted quinolines is a challenge medicinal
chemists continue to approach by alkylation of an advanced
quinoline starting material or by multistep procedures involving
Received: July 16, 2014
7
−9
nitroarene reduction.
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5015883 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3
Scheme 1. A Forms Propargylamine and 2-Aryl Quinoline
The bottom equation in Scheme 2 highlights the obstacle
presented when incorporation of an alkyl aldehyde is
attempted. If cyclohexanecarboxaldehyde 2′ is substituted for
benzaldehyde 2 under identical conditions, propargylamine 5′
forms rather than the corresponding quinoline. Therefore, the
barrier to cyclize and oxidize to a 2-alkyl quinoline appears
significantly higher than to a 4-alkyl quinoline: uncyclized
propargylamine 5′ remains, whereas conversion to 2-aryl-4-
alkyl quinoline 6 is complete in 3 h. Heating the reaction
mixture containing 5′ to 100 °C results in incomplete
cyclization and oxidation to the desired quinoline. As quinoline
along with Reduced Imine
6
and propargylamine 5′ are produced cleanly without
16
concurrent imine reduction, these conditions presented an
improved platform from which to optimize the efficient one-
step synthesis of 4-alkyl and 2-alkyl quinolines.
aryl-substituted quinolines. In contrast, alkyl aldehydes are
3
rarely reported in A syntheses of quinolines: as they are more
acidic than terminal alkynes, alkyl aldehydes enolize and
1
7,18
To ascertain whether copper(II) triflate is the optimal
catalyst for the A synthesis of quinolines, both Cu(I) and
Cu(II) sources were reexamined in the formation of 8a (Table
) from p-anisidine, p-fluorobenzaldehyde, and 1-octyne. A
produce side-products via Povarov reactions.
3
Herein, we present a solvent-free copper-catalyzed A3
reaction capable of producing a wide variety of quinolines
substituted with alkyl as well as aryl, fluorine, ether, thioether,
and amide groups in excellent yields under an ambient
atmosphere.
1
range of copper(I) and copper(II) acetate and halide salts did
3
not catalyze this A reaction beyond the formation of imine
(
entries 1−5). Trace product formed with 10 mol % CuBr or
Copper(II) trifluoromethanesulfonate, Cu(OTf) , is suffi-
2
CuBr·Me S (Table 1, entries 6 and 7). Superior activity was
ciently active to catalyze the formation of propargylamines from
2
observed with Cu(OTf) , CuOTf, and Cu(ClO ) as catalysts
either electron-poor p-toluenesulfonamide or electron-rich alkyl
2
4 2
1
9
(
Table 1, entries 8−10). Thus, the highest yields are obtained
amines. When p-anisidine (1), benzaldehyde (2), and 1-
with catalysts bearing less coordinating, nonhalide counterions.
At 80 °C, conversion drops when the catalyst loading is
reduced to 5 mol %, but switching from toluene to chloroform
as the solvent improves conversion and provides 78% yield of
quinoline 8a in 12 h. Note that the byproduct of this reaction is
octyne (3) are treated with 10 mol % Cu(OTf) in toluene at
2
8
0 °C, conversion to 4-alkyl quinoline 6 is complete in 3 h
(
Scheme 2). In contrast with the results from Scheme 1 in the
presence of 30 mol % CuCl, intermediate propargylamine 5 is
13
not observed in the presence of 10 mol % Cu(OTf)2.
1
equiv of water. Under an ambient atmosphere, nitrogen, or
3
argon and with up to 10 equiv of water added, this A coupling
of aldehydes, anilines, and alkynes proceeds with nearly
identical GC yields. It has been shown that the air-oxidation
Scheme 2. Aryl Aldehyde Forms Quinoline while Alkyl
Aldehyde Halts at Propargylamine under the Same
Conditions
1
4
of dihydroquinoline to quinoline is extremely rapid; thus, it is
likely that oxidation occurs as soon as the reaction is sampled.
This lower 5 mol % catalyst loading with CHCl as the
3
solvent also serves when 1-octyne is replaced with phenyl-
3
acetylene for A reactions with anilines and aryl aldehydes
(
Scheme 3). Under Procedure A, aniline and p-anisidine react
in CHCl at 80 °C to form quinolines 8b and 8c in 87% and
3
7
8% yield, respectively. 5-Aminobenzodioxole and 4-amino-
biphenyl provide good yields of 8d and 8e under Procedure A
in 12−20 h.
20,21
Because of an interest in solvent-free green chemistry,
the reaction of p-toluidine to form 6-methyl-2,4-diphenyl-
3
a
Table 1. Copper Triflate and Perchlorate Are the Most Active Catalysts for A Synthesis of 4-Alkyl Quinoline 8a
entry
Cu source
GC yield (%)
entry
Cu source
GC yield (%)
1
2
3
4
5
Cu(OAc)2
CuOAc
CuCl2
0
0
0
0
0
6
7
CuBr
5
7
CuBr·Me2S
Cu(OTf)2
CuOTf
8
72
69
72
CuI
9
CuBr2
10
Cu(ClO4)2
a
Corrected GC yield (%) of reactions carried out in toluene under an ambient atmosphere with 1.0 equiv of aniline, 1.2 equiv of aldehyde, 1.2 equiv
of alkyne, and dodecane as the internal standard.
B
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The Journal of Organic Chemistry
Note
3
Scheme 3. Efficient A Reaction of Various Anilines with
Scheme 4. Solvent-Free Conditions Required for Complete
Conversion of α-Branched Alkyl Aldehydes to Quinolines
a
a
Benzaldehydes and Alkynes under Conditions A or B
a
Isolated yield (%) of reactions carried out neat under an ambient
atmosphere with 1.0 equiv of aniline, 1.2 equiv of aldehyde, and 1.2
equiv of alkyne.
a
Isolated yield (%) of reactions carried out under an ambient
atmosphere with 1.0 equiv of aniline, 1.2 equiv of aldehyde, and 1.2
equiv of alkyne under conditions indicated by Procedure A or B.
quinoline 8f was tested without CHCl . The combination of
3
solvent-free conditions and raising the temperature to 100 °C
was required for complete conversion in only 4 h, and
quinoline 8f is isolated in 86% yield under Procedure B. 3-
is kinetically favored for less-hindered aldehydes like isovaler-
aldehyde (2b) and valeraldehyde (2c) in eqs 2 and 3 below.
(Methylthio)aniline and 2-aminobiphenyl convert to sulfide-
containing 8g and hindered 2,4,8-triphenyl quinoline 8h under
solvent-free conditions. 2-Fluorobenzaldehyde and aniline
rapidly react with 1-hexyne to give an 89% yield of 4-alkyl
quinoline 8k (Scheme 3). Thus, a variety of aldehydes and
alkynes can be incorporated simply by heating the starting
materials with 5 mol % Cu(OTf) in a capped vial or tube.
2
The true test of this method is in the incorporation of
problematic alkyl aldehydes like cyclohexanecarboxaldehyde for
the formation of 2-alkyl quinolines. Fluoro- and methoxy-
substituted anilines produce 2-cyclohexyl quinolines in nearly
identical yield (Scheme 4, 8l and 8m). 2-Ethylbutyraldehyde
combines with phenylacetylene and anilines bearing 4-methyl,
Without branching adjacent to the carbonyl, a competing
17
4
8
8
-methoxy, 4-methylthio, and 4-acetamide groups to produce
n, 8o, 8p, and 8q in up to 82% yield. Note that 6-acetamide
q provides a handle to tether quinolines to other functional
Povarov reaction forms 2,3-dialkyl quinolines. By replacing
the terminal alkyne with an additional equivalent of
isovaleraldehyde or valeraldehyde, 2,3-dialkyl quinolines 10a
and 10b are isolated in 67% and 70% yield, respectively.
This method for the multicomponent synthesis of quinolines
maximizes diversity by the direct use of commercially available
starting materials. Simply mixing and heating inexpensive
groups. Hindered 2-tert-butyl quinoline 8r is formed in 4 h in
8
5% yield under an ambient atmosphere and without solvent.
Thus, these greener solvent-free conditions are the key to the
3
A synthesis of alkyl-substituted quinolines. This operationally
simple method applies to the previously recalcitrant combina-
tion of p-anisidine 1, cyclohexanecarboxaldehyde, and 1-octyne
from Scheme 2: 2-cyclohexyl-4-n-hexyl quinoline 9a is isolated
in 69% yield after 24 h (eq 1). Note that groups synthesizing
anilines, aldehydes, and alkynes with 5 mol % Cu(OTf)
provides the first efficient A route to a range of substituted
2
3
quinolines that includes 2-alkyl quinolines. Heating the same
catalyst with p-anisidine and a valeraldehyde produces 2,3-
dialkyl quinolines via a two-component Povarov reaction.
These robust solvent-free processes complement the many
methods for making aryl-substituted quinolines, operate under
an ambient atmosphere, and tolerate water.
2
,4-dialkyl quinolines will need to heat their desired substrates
with 5 mol % Cu(OTf) for at least 24 h and monitor
2
conversion to product.
If aldehydes without branching at the α-carbon are utilized, a
mixture of quinoline products is observed in the competition
By choosing the appropriate starting aldehyde, aniline, and
alkyne, this mode of construction allows maximum variation in
14
between acetylide and enolate nucleophiles. α-Deprotonation
C
dx.doi.org/10.1021/jo5015883 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
the substituents on the quinoline while eliminating the waste
generated in multistep syntheses. In fact, the byproduct of this
reaction is 1 equiv of water. In addition to the incorporation of
alkyl or aryl aldehydes, both electron-rich and electron-poor
anilines react efficiently in these three-component couplings.
One-step variation of the substituents available on the quinoline
scaffold should allow other groups to rapidly tune their
properties, including solubility, luminescence, and biological
activity.
mol %), and CHCl
the title compound as a pale yellow solid in 87% yield (0.245 g, 0.87
3
(1.0 mL) were stirred at 80 °C for 12 h to afford
mmol) after column chromatography on silica gel (0−2−4% Et O in
2
−1
hexanes). IR (film) 3055, 3028, 2920, 1589, 1546, 1488, 1444 cm .
1
H NMR (400 MHz, CDCl , 25 °C) δ 8.24 (d, J = 8.5 Hz, 1H), 8.19
3
(
(
dd, J = 12.5, 4.1 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.69
t, J = 7.6 Hz, 1H), 7.56−7.46 (m, 7H), 7.43 (t, J = 7.4 Hz, 2H).
13
C
NMR (100 MHz, CDCl , 25 °C) δ 156.9, 149.2, 148.9, 139.7, 138.5,
1
3
30.3, 129.6, 129.6, 129.4, 128.9, 128.7, 128.5, 127.7, 126.4, 125.8,
125.7, 119.4. HRMS (ESI) m/z calcd for C H N requires 282.1283,
21
16
found 282.1287.
-methoxy-2,4-diphenylquinoline (8c). Prepared according to
general procedure A: p-Anisidine (124 mg, 1.0 mmol), benzaldehyde
(122 μL, 1.2 mmol), phenylacetylene (132 μL, 1.2 mmol), Cu(OTf)2
6
EXPERIMENTAL SECTION
■
General Methods. All reactions were set up on the benchtop in
test tubes equipped with magnetic stir bars and closed with screw caps.
Column chromatography was performed using silica gel. Copper(II)
trifluoromethanesulfonate was purchased from Alfa Aesar and used as
supplied.
(18 mg, 5 mol %), and CHCl (1.0 mL) were stirred at 80 °C for 12 h
3
to afford the title compound as a yellow oil in 78% yield (0.290 g, 0.93
mmol) after column chromatography on silica gel (0−1% Et O in
2
hexanes). IR (film) 3059, 2927, 1621, 1590, 1548, 1490, 1471, 1450
General Analytical Information. H and 13C NMR spectra were
1
−1 1
cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.22−8.20 (m, 1H), 8.18
3
measured on a 400 MHz spectrometer using CDCl as a solvent at
(d, J = 3.7 Hz, 1H), 7.80 (s, 1H), 7.63−7.40 (m, 10H), 7.23 (d, J = 2.8
3
Hz, 1H), 3.80 (s, 3H). 13C NMR (100 MHz, CDCl , 25 °C) δ 157.9,
room temperature. Some spectra include tetramethylsilane as an
internal standard. The following abbreviations are used singularly or in
combination to indicate the multiplicity of signals: s - singlet, d -
doublet, t - triplet, q - quartet, m - multiplet, and br - broad. Gas
chromatography spectra were obtained using dodecane as an internal
standard. For IR spectra, attenuated total reflection infrared (ATR-IR)
was used for analysis with selected absorption maxima reported in
3
154.7, 147.9, 145.0, 139.8, 138.8, 131.7, 129.4, 129.0, 128.9, 128.8,
128.4, 127.4, 126.7, 121.9, 119.7, 103.7, 55.5. HRMS (ESI) m/z calcd
for C H NO requires 312.1388, found 312.1393.
22
18
6,8-Diphenyl-[1,3]dioxolo[4,5-g]quinoline (8d). Prepared accord-
ing to general procedure A: 5-Aminobenzodioxole (138 mg, 1.0
mmol), benzaldehyde (122 μL, 1.2 mmol), phenylacetylene (132 μL,
1.2 mmol), Cu(OTf) (18 mg, 5 mol %), and CHCl (1.0 mL) were
−1
wavenumbers (cm ). No sample preparation was necessary for ATR
analysis. ATR-IR is based on the propagation of the infrared radiation
through an internal reflection element (crystal) with a high refractive
index, and its reflection at the interface between the crystal and the
solid material. Mass spectrometric data were recorded on a ToF
instrument using direct injection of samples in acetonitrile into the
electrospray source (ESI) and either positive or negative ionization.
General Procedure A. To a test tube equipped with a magnetic
stir bar was added 5 mol % Cu(OTf) , CHCl (1 mL), aniline (1.0
2
3
stirred at 80 °C for 12 h to afford the title compound as a pale yellow
solid in 67% yield (0.220 g, 0.67 mmol) after column chromatography
on silica gel (0−2−4% Et O in hexanes). IR (film) 2893, 1616, 1558,
2
−1 1
1487, 1457 cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.18−8.13
3
(m, 2H), 7.67 (s, 1H), 7.61−7.38 (m, 9H), 7.16 (s, 1H), 6.10 (s, 2H).
13
C NMR (100 MHz, CDCl , 25 °C) δ 155.1, 150.7, 148.2, 148.1,
3
147.3, 139.9, 139.0, 129.5, 129.1, 128.9, 128.8, 128.4, 127.4, 122.8,
2
3
118.0, 106.6, 101.8, 101.2. HRMS (ESI) m/z calcd for C H NO
22 15
2
equiv), aldehyde (1.2 equiv), and alkyne (1.2 equiv), and the reaction
was stirred at 80 °C for the indicated time. Upon completion (as
judged by GC), the mixture was cooled to room temperature and
loaded directly atop a wet-packed silica gel column. Chromatography
requires 325.1103, found 325.1102.
2,4,6-Triphenylquinoline (8e). Prepared according to general
procedure A: 4-Aminobiphenyl (170 mg, 1.0 mmol), benzaldehyde
(122 μL, 1.2 mmol), phenylacetylene (132 μL, 1.2 mmol), Cu(OTf)2
with diethyl ether (Et O) or ethyl acetate (EtOAc) in hexanes as
eluent afforded the product, identified by its bright blue UV activity on
(18 mg, 5 mol %), and CHCl (1.0 mL) were stirred at 80 °C for 20 h
2
3
to afford the title compound as a pale yellow solid in 70% yield (0.250
TLC.
g, 0.70 mmol) after column chromatography on silica gel (0−2% Et O
2
−1
General Procedure B. To a test tube equipped with a magnetic
stir bar was added 5 mol % Cu(OTf) , aniline (1.0 equiv), aldehyde
in hexanes). IR (film) 3029, 1738, 1716, 1589, 1543, 1484, 1444 cm .
1
2
H NMR (400 MHz, CDCl , 25 °C) δ 8.38 (d, J = 8.7 Hz, 1H), 8.29−
3
(
1.2 equiv), and alkyne (1.2 equiv), and the reaction was stirred at 100
8.22 (m, 2H), 8.14 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 8.7, 2.1 Hz, 1H),
7.88 (s, 1H), 7.70−7.42 (m, 12H), 7.42−7.34 (m, 1H). C NMR
(100 MHz, CDCl , 25 °C) δ 156.8, 149.6, 148.2, 140.7, 139.5, 139.2,
1
3
°C for the indicated time. Upon completion (as judged by GC), the
mixture was cooled to room temperature and loaded directly atop a
wet-packed silica gel column. Chromatography with diethyl ether
3
138.5, 130.6, 129.7, 129.6, 129.4, 129.0, 128.8, 128.6, 127.7, 127.5,
126.0, 123.5, 119.9 [2 peaks overlapped]. HRMS (ESI) m/z calcd for
C H N requires 356.1434, found 356.1433.
(
Et O) or ethyl acetate (EtOAc) in hexanes as eluent afforded the
2
product, identified by its bright blue UV activity on TLC.
-(4-Fluorophenyl)-4-hexyl-6-methoxyquinoline (8a). Prepared
according to general procedure A: p-Anisidine (124 mg, 1.0 mmol),
-fluorobenzaldehyde (127 μL, 1.2 mmol), n-octyne (177 μL, 1.2
mmol), Cu(OTf) (18 mg, 5 mol %), and CHCl (1.0 mL) were
27
18
2
6-Methyl-2,4-diphenylquinoline (8f). Prepared according to
general procedure B: p-Toluidine (108 mg, 1.0 mmol), benzaldehyde
(122 μL, 1.2 mmol), phenylacetylene (132 μL, 1.2 mmol), and
4
2
3
Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C for 4 h to afford
2
stirred at 80 °C for 12 h to afford the title compound as a yellow oil in
8% yield (0.232 g, 0.78 mmol) after column chromatography on silica
gel (0−2−4% Et O in hexanes). IR (film) 3075, 2959, 2928, 1599,
the title compound as a yellow solid in 86% yield (0.254 g, 0.86 mmol)
7
after column chromatography on silica gel (0−2−4% Et O in
2
−
1 1
2
hexanes). IR (film) 3054, 2915, 1588, 1544, 1488, 1449 cm . H
−
1 1
1
495, 1453 cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.16−8.04
NMR (400 MHz, CDCl , 25 °C) δ 8.27−8.15 (m, 3H), 7.79 (s, 1H),
3
3
13
(
m, 3H), 7.61 (s, 1H), 7.41−7.34 (dd, J = 8.0, 4.0 Hz, 1H), 7.24 (d, J =
7.66 (s, 1H), 7.61−7.44 (m, 9H), 2.49 (s, 3H). C NMR (100 MHz,
2
1
4
.7 Hz, 1H), 7.23−7.15 (m, 2H), 3.95 (s, 3H), 3.09−2.97 (m, 2H),
CDCl , 25 °C) δ 156.0, 149.1, 147.0, 139.3, 138.6, 136.7, 132.2, 129.7,
3
.81 (dt, J = 15.4, 7.6 Hz, 2H), 1.54−1.42 (m, 2H), 1.43−1.29 (m,
H), 0.98−0.85 (t, J = 4.0 Hz, 3H). C NMR (100 MHz, CDCl , 25
129.5, 129.0, 128.8, 128.6, 127.8, 127.7 125.9, 124.6, 119.7, 22.0.
13
3
HRMS (ESI) m/z calcd for C H N requires 296.1439, found
22 18
°C) δ 163.6 (d, J = 248.4 Hz), 157.6, 153.7, 148.1, 144.4, 136.2, 131.9,
296.1429.
1
29.2 (d, J = 8.3 Hz), 127.4, 121.5, 118.6, 115.7 (d, J = 21.4 Hz),
7-(Methylthio)-2,4-diphenylquinoline (8g). Prepared according to
general procedure B: 3-(Methylthio)aniline (124 μL, 1.0 mmol),
benzaldehyde (122 μL, 1.2 mmol), phenylacetylene (132 μL, 1.2
1
02.0, 55.6, 32.8, 31.8, 29.7, 29.5, 22.7, 14.2. HRMS (ESI) m/z calcd
for C H FNO requires 336.1764, found 336.1756.
22
23
2
,4,-Diphenylquinoline (8b). Prepared according to general
mmol), and Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C for 4
h to afford the title compound as a yellow solid in 64% yield (0.209 g,
0.64 mmol) after column chromatography on silica gel (0−2−4−6%
2
procedure A: Aniline (92 μL, 1.0 mmol), benzaldehyde (122 μL, 1.2
mmol), phenylacetylene (132 μL, 1.2 mmol), Cu(OTf) (18 mg, 5
2
D
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The Journal of Organic Chemistry
Note
Et O in hexanes). IR (film) 3056, 3030, 2918, 1733, 1603, 1584, 1571,
2-Cyclohexyl-6-fluoro-4-phenylquinoline (8l). Prepared according
to general procedure B: 4-Fluoroaniline (95 μL, 1.0 mmol),
cyclohexanecarboxaldehyde (146 μL, 1.2 mmol), phenylacetylene
2
−1 1
1
5
7
484, 1420 cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.18 (dd, J =
3
.3, 3.3 Hz, 2H), 8.00 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H),
13
.59−7.44 (m, 8H), 7.33 (dd, J = 8.8, 2.0 Hz, 1H), 2.66 (s, 3H).
C
(132 μL, 1.2 mmol), and Cu(OTf) (18 mg, 5 mol %) were stirred at
2
NMR (100 MHz, CDCl , 25 °C) δ 157.4, 149.5, 149.3, 141.8, 139.5,
100 °C for 4 h to afford the title compound as a pale yellow solid in
81% yield (0.247 g, 0.81 mmol) after column chromatography on silica
3
1
1
3
38.3, 129.6, 129.0, 128.8, 128.6, 127.8, 127.7, 125.9, 125.7, 123.6,
23.4, 118.7, 15.2. HRMS (ESI) m/z calcd for C H NS requires
gel (0−2% Et O in hexanes). IR (film) 3066, 3027, 2923, 1623, 1596,
22
17
2
−
1 1
27.1082, found 327.1084.
,4,8-Triphenylquinoline (8h). Prepared according to general
procedure B: 2-Aminobiphenyl (170 mg, 1.0 mmol), benzaldehyde
122 μL, 1.2 mmol), phenylacetylene (132 μL, 1.2 mmol), and
1557, 1513, 1489, 1467 cm . H NMR (400 MHz, CDCl , 25 °C) δ
3
2
8.12 (dd, J = 9.1, 5.5 Hz, 1H), 7.59−7.37 (m, 7H), 7.29 (s, 1H), 2.95
(tt, J = 12.0, 3.3 Hz, 1H), 2.07 (d, J = 11.8 Hz, 2H), 1.95−1.84 (m,
2H), 1.79 (d, J = 12.6 Hz, 1H), 1.66 (ddd, J = 24.9, 12.5, 3.0 Hz, 2H),
(
13
Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C for 48 h to afford
1.56−1.40 (m, 2H), 1.40−1.24 (m, 1H). C NMR (100 MHz, CDCl3,
25 °C) δ 165.7, 160.3 (d, J = 246.0 Hz), 148.3, 145.4, 138.1, 131.7 (d,
J = 8.8 Hz), 129.4, 128.8, 128.6, 126.3 (d, J = 9.6 Hz), 120.6, 119.2 (d,
J = 25.7 Hz), 109.0 (d, J = 22.8 Hz), 47.5, 32.9, 26.6, 26.2. HRMS
2
the title compound as a pale yellow solid in 65% yield (0.232 g, 0.65
mmol) after column chromatography on silica gel (0−1% Et O in
2
−1 1
hexanes). IR (film) 3059, 3024, 1554, 1485, 1443 cm . H NMR (400
MHz, CDCl , 25 °C) δ 8.18 (dd, J = 9.5, 2.6 Hz, 2H), 7.94−7.84 (m,
(ESI) m/z calcd for C H FN requires 306.1658, found 306.1659.
3
22 22
4
H), 7.80 (dd, J = 7.1, 1.4 Hz, 1H), 7.63−7.50 (m, 8H), 7.50−7.38
2-Cyclohexyl-6-methoxy-4-phenylquinoline (8m). Prepared ac-
cording to general procedure B: p-Anisidine (124 mg, 1.0 mmol),
cyclohexanecarboxaldehyde (146 μL, 1.2 mmol), phenylacetylene (132
(
1
1
m, 4H). 13C NMR (100 MHz, CDCl , 25 °C) δ 155.5, 149.8, 146.0,
3
41.2, 140.0, 139.3, 139.0, 131.3, 130.6, 129.8, 129.6, 128.9, 128.8,
28.5, 127.8, 127.6, 127.3, 126.5, 126.3, 125.5, 118.7. HRMS (ESI) m/
μL, 1.2 mmol), and Cu(OTf) (18 mg, 5 mol %) were stirred at 100
2
z calcd for C H N requires 358.1596, found 358.1605.
°C for 4 h to afford the title compound as a yellow oil in 79% yield
27
20
2
,4-Bis(2-fluorophenyl)quinoline (8i). Prepared according to
general procedure B: Aniline (92 μL, 1.0 mmol), 2-fluorobenzaldehyde
127 μL, 1.2 mmol), 2-fluorophenylacetylene (136 μL, 1.2 mmol), and
(0.250 g, 0.79 mmol) after column chromatography on silica gel (0−
2−4−6−8−10% Et O in hexanes). IR (film) 2924, 2851, 1620, 1593,
2
−1 1
(
1491, 1473, 1445 cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.04
3
Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C for 4 h to afford
(d, J = 9.2 Hz, 1H), 7.59−7.42 (m, 5H), 7.35 (dd, J = 9.2, 2.7 Hz, 1H),
7.23 (s, 1H), 7.16 (d, J = 2.7 Hz, 1H), 3.76 (s, 3H), 2.93 (tt, J = 11.9,
3.1 Hz, 1H), 2.07 (d, J = 11.9 Hz, 2H), 1.89 (d, J = 12.9 Hz, 2H), 1.78
(d, J = 12.7 Hz, 1H), 1.65 (ddd, J = 24.8, 12.5, 2.8 Hz, 2H), 1.48 (ddd,
2
the title compound as a greenish crystalline solid in 71% yield (0.225 g,
0
1
1
1
.71 mmol) after column chromatography on silica gel (2−4−6−8−
0% Et O in hexanes). IR (film) 3056, 2926, 1615, 1594, 1582, 1486,
2
−1
1
13
453 cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.29 (d, J = 8.4 Hz,
J = 15.8, 11.3, 3.1 Hz, 2H), 1.39−1.24 (m, 1H). C NMR (100 MHz,
3
H), 8.17 (td, J = 7.8, 1.7 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.82−7.69
CDCl , 25 °C) δ 164.0, 157.4, 147.5, 144.3, 138.9, 130.8, 129.4, 128.7,
3
13
(
m, 2H), 7.59−7.38 (m, 4H), 7.39−7.15 (m, 4H). C NMR (100
128.3, 126.3, 121.3, 120.2, 103.9, 55.5, 47.4, 33.1, 26.7, 26.2. HRMS
(ESI) m/z calcd for C22 22NO requires 316.1701, found 316.1708.
MHz, CDCl , 25 °C) δ 160.9 (d, J = 251.5 Hz), 159.8 (d, J = 248.5
H
3
Hz), 153.6, 148.6, 143.0, 131.9, 131.7, 131.1 (d, J = 8.4 Hz), 130.7 (d, J
6-Methyl-2-(pentan-3-yl)-4-phenylquinoline (8n). Prepared ac-
cording to general procedure B: p-Toluidine (108 mg, 1.0 mmol),
2-ethylbutyraldehyde (148 μL, 1.2 mmol), phenylacetylene (132 μL,
=
7.8 Hz), 130.2, 129.8, 127.8 (d, J = 11.9 Hz), 127.0, 126.0, 125.8,
1
2
25.7, 124.8, 124.5 (d, J = 2.5 Hz), 123.6 (d, J = 8.0 Hz), 116.4 (d, J =
3.1 Hz), 116.1 (d, J = 22.2 Hz). HRMS (ESI) m/z calcd for
1.2 mmol), and Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C
2
C H F N requires 317.1016, found 317.1017.
for 4 h to afford the title compound as a yellow solid in 67% yield
(0.194 g, 0.67 mmol) after column chromatography on silica gel (0−
2
1
13 2
4-Benzyl-2-(naphthalen-2-yl)quinoline (8j). Prepared according to
general procedure B: Aniline (92 μL, 1.0 mmol), 2-naphthaldehyde
188 μL, 1.2 mmol), 3-phenyl-1-propyne (150 μL, 1.2 mmol), and
1.5% Et O in hexanes). IR (film) 3055, 2959, 2928, 1592, 1557, 1489,
2
−
1 1
(
1449 cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.08 (d, J = 8.6 Hz,
3
Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C for 24 h to afford
1H), 7.64 (s, 1H), 7.58−7.46 (m, 6H), 7.18 (s, 1H), 2.90−2.77 (m,
2
the title compound as a pale yellow solid in 61% yield (0.21 g, 0.61
1H), 2.46 (s, 3H), 1.83 (p, J = 7.4 Hz, 4H), 0.88 (t, J = 7.4 Hz, 6H).
13
mmol) after column chromatography on silica gel (0−2% Et O in
C NMR (100 MHz, CDCl , 25 °C) δ 164.5, 148.0, 146.8, 138.8,
3
2
hexanes) and correction for benzyl impurity. IR (film) 3055, 3022,
135.7, 131.4, 129.7, 129.2, 128.6, 128.3, 125.6, 124.5, 120.5, 52.2, 28.4,
−
1 1
1
1
595, 1553, 1492 cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.61 (s,
21.8, 12.4. HRMS (ESI) m/z calcd for C H N requires 288.1752,
3
21 22
H), 8.42 (d, J = 6.7 Hz, 1H), 8.29 (dd, J = 8.6, 1.6 Hz, 1H), 8.04 (d, J
found 288.1760.
=
8.3 Hz, 1H), 7.98 (t, J = 7.5 Hz, 2H), 7.90−7.84 (m, 1H), 7.81 (s,
6-Methoxy-2-(3-pentanyl)-4-phenylquinoline (8o). Prepared ac-
cording to general procedure B: p-Anisidine (124 mg, 1.0 mmol), 2-
diethylbutyraldehyde (148 μL, 1.2 mmol), phenylacetylene (132 μL,
1
H), 7.75 (t, J = 7.3 Hz, 1H), 7.58−7.47 (m, 3H), 7.36−7.29 (m, 2H),
13
7
.29−7.20 (m, 3H), 4.54 (s, 2H). C NMR (100 MHz, CDCl , 25
3
°C) δ 156.7, 148.5, 147.7, 143.6, 138.6, 135.9, 134.1, 133.5, 130.2,
1.2 mmol), and Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C
2
1
29.8, 129.1, 129.0, 128.8, 127.8, 127.1, 126.9, 126.8, 126.6, 125.4,
for 4 h to afford the title compound as a yellow oil in 77% yield (0.235
g, 0.77 mmol) after column chromatography on silica gel (0−2−4−6%
1
25.2, 124.0, 123.7, 120.4, 38.8. HRMS (ESI) m/z calcd for C H N
26
19
−1 1
requires 345.1517, found 345.1501.
Et O in hexanes). IR (film) 2960, 2930, 1621, 1491 cm . H NMR
2
4
-n-Butyl-2-(2-fluorophenyl)quinoline (8k). Prepared according to
general procedure B: Aniline (92 μL, 1.0 mmol), 2-fluorobenzaldehyde
127 μL, 1.2 mmol), n-hexyne (173 μL, 1.2 mmol), and Cu(OTf) (18
(400 MHz, CDCl , 25 °C) δ 8.08 (d, J = 9.2 Hz, 1H), 7.60−7.42 (m,
3
5H), 7.37 (dd, J = 9.2, 2.8 Hz, 1H), 7.20 (d, J = 2.6 Hz, 1H), 7.18 (s,
1H), 3.77 (s, 3H), 2.81 (p, J = 7.2 Hz, 1H), 1.83 (p, J = 7.4 Hz, 4H),
(
2
0.88 (t, J = 7.4 Hz, 6H). 13C NMR (101 MHz, CDCl , 25 °C) δ 163.0,
mg, 5 mol %) were stirred at 100 °C for 4 h to afford the title
compound as a yellowish-green solid in 89% yield (0.248 g, 0.89
mmol) after column chromatography on silica gel (0−2−4% Et O in
hexanes). IR (film) 3075, 2959, 2928, 1599, 1495, 1453 cm . H
3
157.4, 147.2, 144.4, 138.9, 131.0, 129.5, 128.7, 128.3, 126.3, 121.2,
120.8, 103.9, 55.5, 52.0, 28.3, 12.3 (d, J = 5.2 Hz). HRMS (ESI) m/z
calcd for C H NO requires 306.1858, found 306.1853.
2
−1
1
21
24
NMR (400 MHz, CDCl , 25 °C) δ 8.22 (d, J = 8.3 Hz, 1H), 8.14−
6-Methylthio-2-(3-pentanyl)-4-phenylquinoline (8p). Prepared
according to general procedure B: 4-(Methylthio)aniline (125 μL,
1.0 mmol), 2-diethylbutyraldehyde (148 μL, 1.2 mmol), phenyl-
3
8
7
8
1
.01 (m, 2H), 7.77−7.67 (m, 2H), 7.56 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H),
.46−7.38 (m, 1H), 7.32 (td, J = 7.5, 1.1 Hz, 1H), 7.20 (ddd, J = 11.1,
.2, 1.0 Hz, 1H), 3.18−3.07 (m, 2H), 1.80 (tt, J = 7.8, 6.7 Hz, 2H),
.50 (dq, J = 14.7, 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13C NMR
acetylene (132 μL, 1.2 mmol), and Cu(OTf) (18 mg, 5 mol %) were
2
stirred at 100 °C for 4 h to afford the title compound as a yellow solid
in 63% yield (0.201 g, 0.63 mmol) after column chromatography on
(
1
100 MHz, CDCl , 25 °C) δ 160.8 (d, J = 249.7 Hz), 153.8, 149.0,
3
48.5, 131.7, 130.8 (d, J = 8.3 Hz), 130.5, 129.3, 128.2 (d, J = 12.3
Hz), 126.7, 126.4, 124.8 (d, J = 2.2 Hz), 123.6, 122.2 (d, J = 7.4 Hz),
16.3 (d, J = 22.9 Hz), 32.3, 32.2, 22.9, 14.0. HRMS (ESI) m/z calcd
for C H FN requires 278.1345, found 278.1343.
silica gel (0−2% Et O in hexanes). IR (film) 3057, 2959, 2922, 1737,
2
−
1 1
1587, 1552, 1481, 1455 cm . H NMR (400 MHz, CDCl , 25 °C) δ
3
1
8.08 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.9, 2.1
Hz, 1H), 7.57−7.44 (m, 5H), 7.19 (s, 1H), 2.88−2.77 (m, 1H), 2.45
19
17
E
dx.doi.org/10.1021/jo5015883 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
s, 3H), 1.82 (p, J = 7.4 Hz, 4H), 0.87 (t, J = 7.4 Hz, 6H). 13C NMR
(film) 2956, 2930, 1625, 1492, 1465 cm . H NMR (400 MHz,
−1
1
(
(
1
100 MHz, CDCl , 25 °C) δ 164.8, 147.5, 146.5, 138.3, 136.3, 129.7,
CDCl , 25 °C) δ 7.93 (d, J = 9.2 Hz, 1H), 7.75 (s, 1H), 7.31−7.23 (m,
3
3
29.6, 128.8, 128.7, 128.5, 126.0, 121.6, 121.1, 52.1, 28.3, 16.1, 12.3.
1H), 7.00 (d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 2.95 (dd, J = 9.5, 6.6 Hz,
2H), 2.81−2.70 (m, 2H), 1.81−1.66 (m, 4H), 1.49 (dq, J = 14.8, 7.4
HRMS (ESI) m/z calcd for C H NS requires 320.1473, found
3
21
22
13
20.1465.
N-[2-(3-Pentanyl)-4-phenyl-6-quinolinyl]acetamide (8q). Pre-
Hz, 2H), 1.08−1.01 (m, 3H), 1.01−0.93 (m, 3H). C NMR (100
MHz, CDCl , 25 °C) δ 159.7, 157.3, 142.4, 137.8, 134.3, 129.8, 128.2,
3
pared according to general procedure B: 4-Aminoacetanilide (151
121.1, 104.7, 55.6, 35.4, 34.5, 32.1, 23.8, 23.2, 14.2, 14.2. HRMS (ESI)
mg, 1.0 mmol), diethylbutyraldehyde (148 μL, 1.2 mmol), phenyl-
m/z calcd for C H NO requires 257.1780, found 257.1784.
17
23
acetylene (132 μL, 1.2 mmol), and Cu(OTf) (18 mg, 5 mol %) were
2
stirred at 100 °C for 4 h to afford the title compound as a white solid
ASSOCIATED CONTENT
■
in 82% yield (0.271 g, 0.82 mmol) after column chromatography on
*
S
Supporting Information
silica gel (10−20−30−40−50% Et OAc in hexanes). IR (film) 3062,
2
Copies of H and 13C NMR spectra. This material is available
1
2
960, 2929, 1737, 1695, 1655, 1621, 1604, 1552, 1516, 1501, 1459
−1 1
cm . H NMR (400 MHz, CDCl , 25 °C) δ 8.19−8.09 (m, 2H), 8.00
3
free of charge via the Internet at http://pubs.acs.org.
(
s, 1H), 7.88 (dd, J = 9.1, 1.8 Hz, 1H), 7.55−7.39 (m, 5H), 7.19 (s,
1
0
1
1
H), 2.84 (dt, J = 14.3, 7.2 Hz, 1H), 2.16 (s, 3H), 1.88−1.72 (m, 4H),
.85 (t, J = 7.4 Hz, 6H). 13C NMR (100 MHz, CDCl , 25 °C) δ 168.8,
64.5, 148.7, 145.0, 138.3, 136.0, 129.6, 128.8, 128.7, 126.0, 123.6,
20.9, 114.6, 114.5, 52.0, 28.3, 24.7, 12.4. HRMS (ESI) m/z calcd for
AUTHOR INFORMATION
■
*
3
Corresponding Author
E-mail: catharine.larsen@ucr.edu (C.H.L.).
C H N O requires 331.1810, found 331.1809.
2
2
23
2
Notes
2-tert-Butyl-6-methoxy-4-phenylquinoline (8r). Prepared accord-
ing to general procedure B: p-Anisidine (124 mg, 1.0 mmol),
pivaldehyde (131 μL, 1.2 mmol), phenylacetylene (132 μL, 1.2 mmol),
The authors declare no competing financial interest.
and Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C for 4 h to
2
ACKNOWLEDGMENTS
■
afford the title compound as a yellow oil in 85% yield (0.246 g, 0.85
Financial support was provided by the University of California
and Cancer Research Coordinating Committee Funds. We
thank UCR undergraduates Jin Park and Tomas Lagunas for
́
their contributions.
mmol) after column chromatography on silica gel (0−2% Et O in
2
−
1
1
hexanes). IR (film) 3059, 2957, 2903, 1621, 1491, 1470 cm . H
NMR (400 MHz, CDCl , 25 °C) δ 8.05 (d, J = 9.0 Hz, 1H), 7.61−
3
7.45 (m, 5H), 7.42 (s, 1H), 7.36 (dd, J = 9.2, 2.8 Hz, 1H), 7.17 (d, J =
2
.8 Hz, 1H), 3.79 (s, 3H), 1.50 (s, 9H). 13C NMR (100 MHz, CDCl3,
25 °C) δ 166.5, 157.4, 147.1, 144.1, 139.3, 131.4, 129.5, 128.7, 128.2,
125.8, 121.1, 118.9, 103.7, 55.6, 38.0, 30.4. HRMS (ESI) m/z calcd for
REFERENCES
■
(
1) (a) Jenekhe, S. A.; Lu, L.; Alam, M. M. Macromolecules 2001, 34,
315. (b) Grimsdale, A. C.; Chan, K. L.; Martin, R. E.; Pawel, G. J.;
Holmes, A. B. Chem. Rev. 2009, 109, 897.
2) Skraup, Z. H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086.
3) Friedlander, F. Ber. Dtsch. Chem. Ges. 1882, 15, 2572.
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Chem. 2005, 9, 141. (b) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org.
Chem. 2008, 12, 1116. (c) Prajapati, S. M.; Patel, K. D.; Vekariya, R.
H.; Panchal, S. N.; Patel, H. D. RSC Adv. 2014, 4, 24463.
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́
C.; Soriano, E. Chem. Rev. 2009, 109, 2652.
(6) Khong, S.; Kwon, O. J. Org. Chem. 2012, 77, 8257 and references
therein for an extensive list of recent quinoline syntheses.
(7) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488.
(8) (a) Jain, R.; Vaitilingam, B.; Nayyar, A.; Palde, P. B. Bioorg. Med.
Chem. Lett. 2003, 13, 1051. (b) Jain, M.; Vangapanda, S.; Sachdeva, S.;
Singh, S.; Singh, P. P.; Jena, G. B.; Tikoo, K.; Ramarao, P.; Kaul, C. L.;
Jain, R. J. Med. Chem. 2004, 47, 285. (c) Vangapandu, S.; Jain, M.; Jain,
R.; Kaur, S.; Singh, P. P. Bioorg. Med. Chem. 2004, 12, 2501.
(d) Monga, V.; Nayyar, A.; Vaitilingam, B.; Palde, P. B.; Jhamb, S. S.;
Kaur, S.; Singh, P. P.; Jain, R. Bioorg. Med. Chem. 2004, 12, 6465.
(e) Mai, A.; Rotili, D.; Tarantino, D.; Ornaghi, P.; Tosi, F.; Vicidomini,
C.; Sbardella, G.; Nebbioso, A.; Miceli, M.; Altucci, L.; Filetici, P. J.
Med. Chem. 2006, 49, 6897. (f) Shi, A.; Nguyen, T. A.; Battina, S. K.;
Rana, S.; Takemoto, D. J.; Chiang, P. K.; Hua, D. H. Bioorg. Med.
Chem. Lett. 2008, 18, 3364. (g) Mai, A.; Rotili, D.; Tarantino, D.;
Nebbioso, A.; Castellano, S.; Sbardella, G.; Tini, M.; Altucci, L. Bioorg.
Med. Chem. Lett. 2009, 19, 1132. (h) Kaur, K.; Jain, M.; Reddy, R. P.;
Jain, R. Eur. J. Med. Chem. 2010, 45, 3245. (i) Ding, Y.; Nguyen, T. D.
T.; Hua, D. H.; Nguyen, T. A. Anticancer Drugs 2012, 23, 897.
(j) Yamaguchi, T.; Watanabe, S.; Matsumura, Y.; Tokuoka, Y.;
Yokoyama, A. Bioorg. Med. Chem. 2012, 20, 3058. (k) Ding, Y.;
Nguyen, T. A. Apoptosis 2013, 18, 1071.
C H NO requires 292.1701, found 292.1709.
2
0
22
7
2-Cyclohexyl-6-methoxy-4-n-hexylquinoline (9a). Prepared ac-
cording to general procedure B: p-Anisidine (124 mg, 1.0 mmol),
cyclohexanecarboxaldehyde (146 μL, 1.2 mmol), n-octyne (178 μL,
(
(
(
1
.2 mmol), and Cu(OTf) (18 mg, 5 mol %) were stirred at 100 °C
2
for 24 h to afford the title compound as a clear oil in 69% yield (0.225
g, 0.69 mmol) after column chromatography on silica gel (0−2−4%
−1 1
Et O in hexanes). IR (film) 2924, 1620, 1593, 1491, 1450 cm . H
2
NMR (400 MHz, CDCl , 25 °C) δ 8.03 (d, J = 9.1 Hz, 1H), 7.33 (dd,
3
(
J = 9.2, 2.7 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.13 (s, 1H), 3.93 (s,
3
1
4
H), 3.04−2.94 (m, 2H), 2.90 (dd, J = 15.4, 8.3 Hz, 1H), 2.01 (d, J =
1.5 Hz, 2H), 1.88 (d, J = 12.8 Hz, 2H), 1.76 (dt, J = 15.4, 7.6 Hz,
H), 1.61 (ddd, J = 24.6, 12.4, 2.8 Hz, 2H), 1.54−1.40 (m, 4H), 1.33
(
dd, J = 9.7, 6.1 Hz, 4H), 0.90 (t, J = 7.0 Hz, 3H). 13C NMR (100
MHz, CDCl , 25 °C) δ 164.0, 157.2, 148.1, 143.4, 130.8, 127.2, 121.0,
3
1
1
3
19.4, 102.2, 55.7, 47.2, 33.1, 32.7, 31.8, 29.7, 29.5, 26.7, 26.2, 22.7,
4.2. HRMS (ESI) m/z calcd for C H NO requires 324.2327, found
22
30
24.2322.
-Isobutyl-6-methoxy-3-isopropylquinoline (10a). Prepared ac-
2
cording to general procedure B: p-Anisidine (124 mg, 1.0 mmol),
isovaleraldehyde (236 μL, 2.2 mmol), and Cu(OTf) (18 mg, 5 mol
2
%
) were stirred at 100 °C for 12 h to afford the title compound as a
yellow oil in 70% yield (0.180 g, 0.70 mmol) after column
chromatography on silica gel (0−2−5% Et O in hexanes). IR (film)
2
−
1
1
2
957, 1624, 1599, 1512, 1491, 1464 cm . H NMR (400 MHz,
CDCl , 25 °C) δ 7.96 (d, J = 9.2 Hz, 1H), 7.88 (s, 1H), 7.27 (dd, J =
3
9
2
0
1
2
2
.1, 2.7 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H), 3.30 (m, 1H),
.90 (d, J = 7.3 Hz, 2H), 2.33−2.14 (m, 1H), 1.32 (d, J = 6.8 Hz, 6H),
.99 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, CDCl , 25 °C) δ
3
58.1, 157.4, 141.9, 141.2, 131.1, 129.7, 128.3, 121.3, 104.8, 55.6, 43.8,
9.6, 28.9, 24.0, 22.7. HRMS (ESI) m/z calcd for C H NO requires
17
23
57.1780, found 257.1782.
-Methoxy-2-(2-methylpropyl)-3-(2-propanyl)quinoline (10b).
Prepared according to general procedure B: p-Anisidine (124 mg,
6
(9) (a) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 4, 4257.
1
.0 mmol), valeraldehyde (234 μL, 2.2 mmol), and Cu(OTf) (18 mg,
(b) O’Byrne, A.; Evans, P. Tetrahedron 2008, 64, 8067.
2
5
mol %) were stirred at 100 °C for 12 h to afford the title compound
(10) D’Souza, D. M.; Mu
(11) Blay, G.; Monleon
1498.
̈
ller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095.
as a yellow oil in 67% yield (0.173 g, 0.67 mmol) after column
chromatography on silica gel (0−4−6−10% Et O in hexanes). IR
́
, A.; Pedro, J. R. Curr. Org. Chem. 2009, 13,
2
F
dx.doi.org/10.1021/jo5015883 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
12) (a) Yoo, W. J.; Zhao, L.; Li, C.-J. Aldrichimica Acta 2011, 44, 43.
b) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem.
Soc. Rev. 2012, 41, 3790.
13) Huma, H. Z. S.; Halder, R.; Kalra, S. S.; Das, J.; Iqbal, J.
Tetrahedron Lett. 2002, 43, 6485.
(
(
(
14) Xiao, F.; Chen, Y.; Liu, Y.; Wang, J. Tetrahedron 2008, 64, 2755.
(
15) For a dual Cu(I)/Cu(II) catalyst system for the related 2-
3
aminopyridine A : Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed.
2
(
010, 49, 2743.
16) For recent A quinoline syntheses, see: (a) Zhang, Y.; Li, P.;
3
Wang, L. J. Heterocyclic Chem. 2011, 48, 153. (b) Kumar, A.; Rao, V. K.
Synlett 2011, 2157. (c) Patil, S. S.; Patil, S. V.; Bobade, V. D. Synlett
2
011, 2379. (d) Li, X.; Mao, Z.; Wang, Y.; Chen, W.; Lin, X.
Tetrahedron 2011, 67, 3858. (e) Tang, J.; Wang, L.; Mao, D.; Wang,
W.; Zhang, L.; Wu, S.; Xie, Y. Tetrahedron 2011, 67, 8465. (f) Karthik
Kumar, K.; Mohan Das, T. Carbohydr. Res. 2011, 346, 728. (g) Yao,
C.; Qin, B.; Zhang, H.; Lu, J.; Wang, D.; Tu, S. RSC Adv. 2012, 2,
3
(
759. (h) Chen, S.; Li, L.; Zhao, H.; Li, B. Tetrahedron 2013, 69, 6223.
i) McNulty, J.; Vemula, R.; Bordon, C.; Yolken, R.; Jones-Brando, L.
Org. Biomol. Chem. 2014, 12, 255.
17) (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656. (b) Bello, D.;
Ramon, R.; Lavilla, R. Curr. Org. Chem. 2010, 14, 332.
(
́
3
(
18) A quinoline syntheses incorporating alkyl aldehydes and alkyl
alkynes were not found. Replacing the alkyne with acetone can
produce a range of 4-methyl quinolines from a Povarov-type reaction
with anilines and benzaldehydes: Xiao, F.; Chen, W.; Liao, Y.; Deng,
G.-J. Org. Biomol. Chem. 2012, 10, 8593.
(19) Meyet, C. E.; Pierce, C. J.; Larsen, C. H. Org. Lett. 2012, 14, 964.
(20) Pierce, C. J.; Larsen, C. H. Green Chem. 2012, 14, 2672.
(21) (a) Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2008, 105,
1
3197. (b) Sheldon, R. A. Chem. Commun. 2008, 3352. (c) Noyori, R.
Chem. Commun. 2005, 1807. (d) Noyori, R. Green Chem. 2003, 5,
G37.
G
dx.doi.org/10.1021/jo5015883 | J. Org. Chem. XXXX, XXX, XXX−XXX