Iron-catalyzed oxidative tandem reactions with TEMPO oxoammonium salts: Synthesis of dihydroquinazolines and quinolines

Article abstract of DOI:10.1021/jo4007199

A straightforward iron-catalyzed divergent oxidative tandem synthesis of dihydroquinazolines and quinolines from N-alkylanilines using a TEMPO oxoammonium salt as a mild and nontoxic oxidant has been developed. Fe(OTf) ₂ was the Lewis acid cata

Full text of DOI:10.1021/jo4007199

Article
pubs.acs.org/joc
Iron-Catalyzed Oxidative Tandem Reactions with TEMPO
Oxoammonium Salts: Synthesis of Dihydroquinazolines and
Quinolines
́
Renate Rohlmann, Tobias Stopka, Heinrich Richter, and Olga Garcıa Mancheno*
̃
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstrasse 40, 48149 Munster, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: A straightforward iron-catalyzed divergent
oxidative tandem synthesis of dihydroquinazolines and quino-
lines from N-alkylanilines using a TEMPO oxoammonium salt
as a mild and nontoxic oxidant has been developed. Fe(OTf)2
was the Lewis acid catalyst of choice for the formation of
dihydroquinazolines, whereas FeCl3 led to better results for the
synthesis of quinolines. This divergent approach implies that, for both syntheses, direct oxidative functionalization of a α-
C(sp3)−H bond of the N-alkylanilines occurs, leading to C−N bond formation or C−C bond formation upon
homocondensation or reaction with simple olefins, respectively. Cyclization followed by a final oxidation generates these
classes of interesting bioactive heterocycles in one synthetic transformation. Additionally, the one-pot multicomponent synthesis
of quinolines from anilines, aldehydes, and olefins has also been successfully developed under these mild oxidative conditions.
reported.6 This chemistry was recently extended to the metal-
INTRODUCTION
■
catalyzed synthesis of quinolines using T+BF4 as oxidant and
−
The development of efficient and sustainable synthetic methods
is of great importance for modern organic chemistry in both
academia and industry.1 The scientific efforts already being
made in this direction are having a significant impact in the way
organic molecules are built up. One of the most appealing
current approaches involves the direct functionalization of
C−H bonds of simple starting materials.2 In these processes,
prefunctionalizations and multiple tedious purification steps can
be avoided while enhancing the step economy of the
transformation. In this regard, the dehydrogenative or oxidative
coupling of C−H bonds has recently been established as a
powerful and elegant synthetic approach for the direct
generation of C−C and C−heteroatom bonds.3 However, the
selective and effective functionalization of unreactive C(sp3)−H
bonds remains a challenge in organic synthesis. Organic
peroxides, quinones (e.g., DDQ, 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone), and more recently dioxygen are typically used
as oxidants for achieving such transformations.3 Alternatively,
our group has introduced a TEMPO oxoammonium salt
glycine derivatives as substrates.7
Herein we describe the divergent oxidative synthesis of
dihydroquinazolines and quinolines from preformed or in situ
generated N-alkylaniline derivatives upon homocondensation
or reaction with olefins, respectively. These tandem trans-
formations involve oxidative C−C or C−N coupling followed
by cyclization and oxidation and employ inexpensive iron Lewis
acid catalysts in combination with T+BF4− as an efficient, mild,
and nontoxic oxidant.
RESULTS AND DISCUSSION
■
Dihydroquinazolines by Oxidative C−N Coupling/
Cyclization/Oxidation. The quinazoline core is an important
structural moiety present in a large number of synthetic and
natural products with an extensive spectrum of bioactivities.8
For example, several quinazoline derivatives exhibit potent
anticancer, anti-inflammatory, antibiotic, or antiviral activity,
among others. Although well-established multistep processes to
synthesize these heterocyclic compounds have been described,9
it would still be highly desirable to develop more simple and
step-economical methods for their preparation. Along this line,
we decided to explore the simple homocondensation of N-
alkylanilines under oxidative conditions using TEMPO
oxoammonium salts for the synthesis of dihydroquinazolines.
An ethyl acetate group was selected as the substitution pattern
at the aniline for these studies. As the standard test reaction, we
chose the C−N coupling/cyclization/oxidation tandem reac-
(T+BF4 , 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetra-
−
fluoroborate)4 as a mild, nontoxic hydrogen acceptor for
oxidative C−H coupling reactions. This oxidant has been used
efficiently in Fe- and Cu-catalyzed oxidative C−C couplings of
benzylic C(sp3)−H bonds adjacent to a heteroatom with
enolizable pronucleophiles.5 We are devoted to broadening the
substrate scope and synthetic applicability of C−H bond
coupling reactions as part of our ongoing research program on
oxidative C−H functionalizations with TEMPO salts. Along
this line, we have recently focused our attention on the
oxidative synthesis of N-heterocycles. In our initial studies, the
use of simple olefins as weak nucleophiles for the metal-free
synthesis of oxazinones from benzylic carbamates was
Received: April 9, 2013
© XXXX American Chemical Society
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tion of N-substituted p-toluidine 1a in the presence of different
Lewis acid catalysts and oxidants (Table 1).
% of inexpensive FeCl3 as the Lewis acid catalyst (entry 2).
Surprisingly, widely employed Lewis acids such as AlCl3 and
InCl3 led to no conversion or decomposition of 1a. On the
other hand, metal triflate catalysts led to a cleaner reaction.
Cu(OTf)2 provided the same yield as FeCl3 (entries 5 and 2),
whereas Fe(OTf)2 gave the best results (entry 6). Using this
Lewis acid, 2a was formed in an excellent 95% GC and 70%
isolated yield. Decreasing the temperature to 40 °C or the
amount of oxidant to 1.5 equiv resulted in lower yields (entries
7 and 8). Interestingly, the reaction proceeded using oxygen as
the sole oxidant; however, an overoxidized cyclic byproduct,
which was difficult to separate from 2a, was also formed under
these conditions (entry 9).10 Remarkably, the TEMPO salt
used showed excellent reactivity and selectivity, in contrast to
the other oxidants tested. The well-known hydrogen abstractor
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
FeCl3
oxidant (equiv)
T (°C)
yield of 2a (%)
−
1
T+BF4 (2)
60
60
60
60
60
60
40
60
60
60
60
60
−
2
T+BF4 (2)
60
−
3
AlCl3
T+BF4 (2)
−
4
InCl3
T+BF4 (2)
trityl cation (Ph3C+BF4 , entry 10) produced 2a in only 10%
−
−
5
Cu(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
T+BF4 (2)
60
c
‑
6
T+BF4 (2)
95 (70)
yield, while other typical oxidants for oxidative radical C−H
coupling reactions such as DDQ and t-BuOOH did not provide
the desired product (entries 11 and 12).
−
7
T+BF4 (2)
72
67
−
8
T+BF4 (1.5)
d
9
O2 (1 atm)
60
Having identified the optimal reaction conditions, 10 mol %
of Fe(OTf)2 and 2 equiv of T+BF4− in DCE at 60 °C for 24 h,
the scope of the reaction was explored with different substituted
anilines 1 (Table 2). In addition to the standard p-methyl
substitution (2a, 70%), halogens such as Cl, Br, and F were also
tolerated, leading to the desired dihydroquinazolines 2b−d in
50−56% isolated yield. On the other hand, the more electron-
withdrawing CF3 group provided the quinazoline derivative 2e
in an enhanced 64% yield. Moreover, redox-sensitive
substituents, such an acetyl group, were suitable in this
reaction, with the corresponding quinazoline 2g being delivered
in 58% yield. It is worth mentioning that acid labile groups such
as nitrile (2f, 50%) and ethyl ester (2h, 31%) in the para
−
10
11
12
Ph3C+BF4 (2)
10
DDQ (2)
t-BuOOH (2)
a
Reaction conditions: 1 (0.1 mmol), catalyst (10 mol %), and oxidant
b
c
in DCE (0.2 M), 24 h. GC yield. Isolated yield by column
d
chromatography in parentheses. Concomitant formation of an
overoxidized byproduct.10
In the first attempts, 2 equiv of T+BF4− as oxidant in DCE at
60 °C was used. The reaction did not proceed in the absence of
catalyst (entry 1), whereas the dihydroquinazoline 2a was
formed in a good yield of 60% (GC) in the presence of 10 mol
a b
,
Table 2. Scope of the Reaction
a
b
Reaction conditions: 1 (0.1 mmol), Fe(OTf)2 (10 mol %), and oxidant in DCE (0.2 M), 24 h. Isolated yields by column chromatography. n.o. =
not observed.
B
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position also worked well; however, slightly lower yields of the
product were obtained. Electron-donating substituents at the
aniline, such as p-methoxy, p-phenyl, and 3,5-dimethyl groups,
also provided quinazolines 2 in moderate yields (41−55%). On
the other hand, the monosubstituted o-methyl and o- and m-
methoxy substrates (1l−m) led to a complex reaction mixture,
in which the desired product could not be identified. This can
be explained by the higher reactivity of these electron-rich
anilines toward both oxidation and aromatic nucleophilic
substitution.
Quinolines by Oxidative C−C Coupling/Cyclization/
Oxidation. Quinolines are important heterocycles present in a
large number of synthetic and natural biologically active
compounds.11 Therefore, several synthetic strategies for their
synthesis have been developed,12 such as the well-established
Povarov reaction13 between imines and olefins (hetero Diels−
Alder) followed by oxidation. It is important to mention that
the final oxidation step, the dehydrogenation of the
tetrahydroquinoline intermediate (Povarov product), is still
rather challenging, since it requires the formal removal of four
hydrogen atoms. After the initial success in the oxidative
synthesis of dihydroquinazolines, we studied the formation of
two C−C bonds by reacting anilines 1 with simple olefins 3 in
the presence of a TEMPO oxoammonium salt as a mild
oxidant.7a,14 A dehydrogenative cyclization−oxidation sequence
would then lead to the quinoline scaffold.
resulted in complete conversion, delivering 4a in a outstanding
yield of 93% (entry 4). The suitability of a range of alternative
oxidants was tested. Another oxoammonium salt derivative
possessing an acetylamido group, 4-AcNHT+BF4 ,15 was not as
−
−
effective as T+BF4 , producing 4a in significantly lower yield of
69% (entry 5). The reaction was found to be sensitive to the
TEMPO oxoammonium counterion, with −OTf, −ClO4, or
TFA− leading to reduced yields (entries 6−8). Once again, test
reactions with standard oxidants such as DDQ, DTBP, O2, and
air were carried out (entries 9−12); however, none of them led
to satisfactory conversions. Interestingly, this transformation
does not seem to be moisture and air sensitive, since the
reactions with hydrated FeCl3 or under an air atmosphere
provided similarly good results (entries 13 and 3, respectively).
Next, the substitution of the N-alkyl group at the aniline was
investigated (Figure 1). Under the optimized reaction
The reaction between aniline 1a and styrene (3a) was
initially studied in the presence of iron Lewis acid catalysts,
such as Fe(OTf)2 and FeCl3 species, at 60 °C in dichloro-
methane in a pressure Schlenk tube (Table 3). Although
quinoline 4a was formed even without a Lewis acid catalyst
using 2 equiv of T+BF4 as oxidant (entry 1), the reaction
−
stalled after 16 h, leading to the product in a moderate yield of
51%. On the other hand, performing the reaction in the
presence of 10 mol % of the inexpensive Lewis acid FeCl3
Figure 1. Effect of the substitution at the N-alkyl group.
a
Table 3. Optimization of the Reaction of 1a with Styrene
conditions (10 mol % of FeCl3, 2 equiv of 3a, and 2 equiv of
T+BF4− at 60 °C), the ester unit was replaced by other electron-
withdrawing groups such as phenyl ketone and ethyl
phosphonate, providing the corresponding substituted quino-
lines in good to moderate yields (72% of 4aa and 42% of 4ba,
respectively). On the other hand, labile subtituents such as an
electron-withdrawing nitrile or an oxazolidinone led to a low
yield of the desired product (4ca, −CN, 17%) or to no reaction
at all. Alternatively, a simple N-alkyl substituent such as benzyl
provided quinoline 4ea in a moderate 41% yield, whereas an
ethyl residue led to decomposition of the starting material.
With these results, aniline substrates bearing an ethyl ester
substituent at the nitrogen were selected for further scope and
limitation studies (Table 4). The reaction of styrene with a
number of ethyl glycines 1 was first explored (first row).
Halogens such as Br and Cl and acetyl and methoxy groups in
the para position were well tolerated, providing the
corresponding quinolines 4 in good yields (73−84%).
Substitution in the meta postion, however, proved to be less
efficient in terms of reactivity and selectivity, leading to slightly
inferior yields (4f,g, 52−68%) and lower regioselectivities
(1.6:1 ratio of 4g to 4g′).
b
entry
catalyst
oxidant (equiv)
t (h)
yield of 4a (%)
c
T+BF4 (2)
16/24
24
51
−
1
T+BF4 (2)
55
91
−
2
Fe(OTf)2
FeCl3·6H2O
FeCl3
T+BF4 (2)
24
−
3
d
T+BF4 (2)
16 (20)
24
93 (93)
−
4
AcNHT+BF4 (2)
69
40
58
<5
7
−
5
FeCl3
6
FeCl3
AcNHT+OTf− (2)
24
AcNHT+ClO4 (2)
24
−
7
FeCl3
8
FeCl3
AcNHT+TFA− (2)
24
9
FeCl3
DDQ (2)
24
10
11
12
13
14
FeCl3
(t-BuO)2 (2)
O2 (1 atm)
24
30
c
FeCl3
16/24
24
41
e
FeCl3
air
3
e
T+BF4 (2)/air
18
86
−
FeCl3
f
T+BF4 (2)
18
80
−
FeCl3
a
Conditions: 1a (0.10 mmol), 3a (0.20 mmol), Fe catalyst (10 mol
%), and oxidant in DCM (1 mL). Isolated yield. The reaction
stopped after 16 h. 0.50 mmol scale reaction in parentheses.
b
c
d
Afterward, a variety of styrenes 3 were reacted with 1a
(second row). The electronic and steric nature of the
e
f
Reaction in an air atmosphere. Reaction in DCE.
C
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a
Table 4. Scope of the Reaction of 1 with Olefins 3
a
b
c
Conditions: 1 (1 equiv), 3 (2 equiv), FeCl3 (10 mol %), and T+BF4− (2 equiv) in DCM (0.1 M) at 60 °C. 4 equiv of olefin was used. No trace of
d
the regioisomer of 4n was detected by NMR. Reaction with ethyl vinyl ether.
Scheme 1. One-Pot Reaction between Aniline 5a and Glyoxalate 6
substituents at the styrene ring did not have a great influence
on the reaction outcome, although the electron-rich styrenes
react more easily than the electron-deficient ones. Con-
sequently, the corresponding quinolines 4h−l were isolated in
comparably good yields (76−86%).
Highly challenging 1,2-disubstituted olefins and olefins with
linear aliphatic chains were also suitable reactants (third row).
Although stilbene showed a low reactivity (4m, 29%), β-alkenyl
and β-ethyl styrenes reacted more readily, leading to 2,3,4-
trisubstituted quinolines 4n,o in remarkable yields of 44% and
58%, respectively. 1-Octene also reacted well, providing
quinoline 4p in a good 66% yield. Finally, the reaction with
ethyl vinyl ether was also explored. This substrate led
exclusively to the C-3 and C-4 unsubstituted quinoline 4q
resulting from elimination of ethanol, in 64% yield.
Multicomponent One-Pot Synthesis. The in situ
formation of an imine-type intermediate duning the course of
the reaction led us to investigate the possibility of synthesizing
dihydoquinazolines directly from aniline 5a and ethyl glyoxalate
(6) in a one-pot process (Scheme 1).16,17 Unfortunately, this
one-pot transformation was not efficient, leading to the
overoxidation of the starting material as major reaction pathway
(9, 45%). The formation of this product can be explained by a
facile oxidation of the hemiaminal intermediate 7, formed prior
to the formation of imine 8.
D
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The three-component18 oxidative synthesis of quinolines
from anilines, aldehydes, and various olefins was investigated
next.19 Initially, the selected model reaction between p-
toluidine (5a), ethyl glyoxalate (6), and styrene (2a) in the
presence of FeCl3 as a Lewis acid catalyst at 60 °C in
dichloromethane was used in a brief optimization study (Table
proved again to be a more efficient oxidant than O2 (entry 4).
Consequently, the use of catalytic amounts of T+BF4− (10 mol
%) in combination with O2 as terminal oxidant only provided
4a in low yield (38%, entry 5). Moreover, the use of a slight
excess of ethyl glyoxalate (6; 1.2 equiv) was beneficial for the
reaction (entry 1 vs 2). Importantly, 2 equiv of the oxidant was
also required to attain full conversion (entry 1 vs 2), leading to
a similarly high yield of the quinoline 4a in comparison to the
previous method starting from the N-alkylaniline (90% vs 93%
yield).
−
5). The TEMPO oxoammonium salt T+BF4 (entries 1−3)
Table 5. Optimization of the Multicomponent Reaction To
a
Form Quinoline 4a
With the optimized conditions for the multicomponent
synthesis in hand, the scope of the reaction was next explored
(Table 6). The effect of the substitution of the aniline on the
reaction with styrene was first investigated (first row). The
introduction of an electron-withdrawing group such as fluoro in
the para position led to a lower yield (60%, 4r), while a chloro,
acetyl, or methoxy group provided the desired quinolines
4b,d,e in excellent yields of 90−95%. As expected, methyl
substitution at the meta position significantly hindered the
reaction (50%). Moreover, a 1.5/1 mixture of the possible
regioisomers 4g and 4g′ was formed. On the other hand,
reactions with different styrenes generally provided the
corresponding quinolines in high yields (second row;
4h,i,k,s), except for the electron-poor 4-CF3-substituted
styrene, which led to 4j in only 55% yield. Finally, the reaction
with the more challenging 1,2-disubstituted alkenes and olefins
b
entry
oxidant (equiv)
6 (equiv)
yield of 4a (%)
T+BF4 (2)
1.0
1.2
1.2
1.2
1.2
71
90
72
15
38
−
1
2
3
4
5
T+BF4 (2)
−
T+BF4 (1.2)
−
O2 (1 atm)
O2 (1 atm)/ T+BF4 (0.1)
−
a
Conditions: 5a (0.2 mmol), 6 (1.0−1.2 equiv), 3a (2 equiv), FeCl3
b
(10 mol %) and oxidant in DCM (2 mL). Isolated yield.
ab
,
Table 6. Scope of the One-Pot Multicomponent Reaction
a
b
−
Conditions: 5 (0.20 mmol), 6 (0.24 mmol), 2a (0.40 mmol), FeCl3 (10 mol %), and T+BF4 (0.40 mmol) in DCM (2 mL) for 18 h. Isolated
c
d
yields. 5 equiv of olefin was used. 4 equiv of olefin was used.
E
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Scheme 2. Synthesis of Quinolines Using Alkynes
Scheme 3. Homocondensation of 1l: Formation of the Side Product 11
Scheme 4. Isolation of the Povarov-Type Intermediate and C−H Arylation vs Cyclization Reaction
bearing solely alkyl groups such as 1-octene and norbornene
were explored (third row). Fortunately, in these cases the
corresponding quinolines 4 could still be obtained in moderate
yields (36−50%) upon reaction with a larger excess of the
olefin (4−5 equiv). The reaction with benzaldehyde was also
possible; however, a lower yield of 4ea (20%) was obtained
using the one-pot protocol in comparison to the method using
N-alkylaniline 1a 41% (see Figure 1).
with the aniline 5a and ethyl glyoxalate (6) (method B) was
explored (Scheme 2).20 The reactions with alkynes were not as
clean as those using alkenes, and several unidentified
byproducts were formed, including various amounts of the
oxidized starting material (9) under method B conditions. As a
result, the same quinolines 4 were obtained in significantly
lower yields. Moreover, the one-pot approach (method B)
proved to be only suitable when using phenylacetylene (10a),
providing 4a in a moderate 60% yield. On the other hand,
method A seemed to be more general, allowing for the
formation of quinolines 4t and 4p with the less reactive 1-
Reaction with Alkynes. Finally, the reaction between
terminal and internal alkynes 10 with the preformed N-
alkylaniline 2a (method A) and under the one-pot conditions
F
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Scheme 5. Proposed Mechanism for the Synthesis of Dihydroquinazolines, Quinolines, and Diarylmethane Derivatives
phenyl-1-propyne (10t) and 1-octyne (10p) in 36−40% yield.
Interestingly, when using 10p, we could observe for the first
time the formation of the C3 regioisomer along with the
expected C4-n-hexyl-substituted quinoline 4p (12:1 ratio of 4p
to 4p′).
14 was also observed. This demonstrates the dehydrogenative
nature of this coupling reaction. Moreover, since the quinoline
4v could not be converted into 13 upon treatment under the
standard coupling conditions, 13 and 14 have to be formed by
an initial double dehydrogenative arylation in the para position
with the loss of a molecule of o-toluidine followed by
dehydrogenative Povarov-type reactions to form the quinoline
rings (Scheme 4, eq 2).
The exact role of the iron catalyst in both transformations is
not completely clear. However, considering that the formation
of the corresponding iminium ion 8-H+ is achieved with
T+BF4− in the absence of the iron catalyst, it is more likely that
it actively participates as a Lewis acid in the cyclization and/or
C−N bond formation rather than as a co-oxidant in the
oxidative step. Interestingly, the use of the metal catalyst is
crucial in the formation of dihydroquinazolines 2 (Table 1),
whereas in the case of quinolines 4 the iron catalyst is required
for improved performance and to achieve full conversions
(Table 3).
Mechanistic Considerations. During the development of
the oxidative synthesis of dihydroquinazolines 2, the occasional
formation of a hydroxydihydroquinazoline side product of type
11 was observed (Scheme 3). This compound might be formed
by a further oxidation at the α position of the second N-
alkylaniline unit after the initial C−N bond formation step.
Then, this carbonyl intermediate might undergo a subsequent
Friedel−Crafts-type cyclization and oxidation, leading to the
final dihydroquinazoline skeleton possessing the additional
hydroxyl group. This finding sheds some light on the
mechanism of the reaction. Thus, instead of a concerted
cycloaddition between two in situ formed imine derivatives, a
stepwise nucleophilic addition of the amine 1 to an imine
followed by an intramolecular Friedel−Crafts-type reaction is
most likely involved.
It is also important to note that, in the synthesis of quinolines
4, the conversion of the oxoammonium salt T+BF4 to N-
−
On the other hand, a different scenario can be imagined in
the reaction of N-alkylanilines 1 with olefins 3. Since no
intermediate derived from a stepwise nucleophilic addition of
the olefin to form the first C−C bond was detected, only the
Povarov product tetrahydroquinoline 12a being observed, a
concerted cycloaddition is proposed to take place. When the
reaction with 1a was performed at room temperature, the
Povarov product 12a could be isolated in 33% yield along with
the corresponding quinoline 4a (Scheme 4, eq 1). As expected,
12a is an intermediate in the synthesis, and it could be
quantitatively converted into the corresponding quinoline 4a
hydroxy TEMPO (T-OH) and then the corresponding 2,2,6,6-
tetramethylpiperidine (T-H) could be followed by GC-MS.
Due to the redox-instability of the T-OH, it was oxidized to
TEMPO radical by exposure to air.4 Therefore, both the
TEMPO radical and the amine T-H (mainly as the T-H·HBF4
salt) had to be removed by chromatography after the reaction.
In the case of the synthesis of dihydroquinazolines T-H was not
formed in large amounts and the main recovered compound
was the TEMPO radical.
On the basis of the above observations, a multistep reaction
mechanism is proposed for the divergent synthesis of
dihydroquinazolines and quinolines (Scheme 5). After the
first TEMPO salt mediated in situ formation of an iminium ion
−
upon treatment with an extra 1 equiv of the T+BF4 oxidant.
Moreover, in the reaction with the 2-methyl-substituted aniline
derivative 1l, the formation of diarylmethane derivatives 13 and
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8-H+, a nucleophilic attack of the nitrogen of another molecule
of aniline 1 (blue pathway) or cycloaddition with an olefin 3
(red pathway) takes place. In the case of the dihydroquinazo-
line synthesis, the addition product 16 can again be oxidized to
the iminium derivative 17 (or carbonyl compound 19) and be
further activated by the Lewis acid, promoting the cyclization
reaction to generate corresponding tetrahydroquinazoline
intermediates of type 18. These species are not redox stable
and will be readily oxidized to the final product dihydroqui-
nazoline 2 (or the side product 11). On the other hand,
quinolines 4 are formed via final aromatization by dehydrogen-
ation of the Povarov intermediate 12. Finally, the formation of
diarylmethanes 15 (including structures 13 and 14) can be
explained by a prompt arylation reaction of an iminium
intermediate 8-H+ with two further molecules of aniline 1 when
the para position of the N-alkylaniline 1, an electron-rich arene,
is available. Subsequently, after activating the aniline as a
leaving group by protonation of the resulting intermediate, the
corresponding diarylmethanes 15 are formed. Compound 15
can then undergo a Povarov reaction with an olefin present in
the reaction mixture to form stepwise the mono- and bis-
quinoline-containing compounds 13 and 14 (see Scheme 4).
The reaction mixture was then stirred at 60 °C for 24 h. The crude
reaction mixture was directly purified by column chromatography on
silica gel.
Diethyl 6-Methyl-3-(p-tolyl)-3,4-dihydroquinazoline-2,4-dicar-
boxylate (2a).16 According to the general procedure using 1a (38.6
mg, 0.20 mmol, 1.0 equiv), the title compound 2a was obtained after
FC (pentane/EtOAc 8/1 → 6/1) as a yellow solid (26.6 mg, 0.07
mmol, 70%). 1H NMR (300 MHz, CDCl3): δ 7.32 (d, J = 8.0 Hz, 1H),
7.14 (d, J = 8.2 Hz, 3H), 7.05−6.94 (m, 3H), 5.31 (s, 1H), 4.28−4.08
(m, 4H), 2.33 (s, 3H), 2.33 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.05 (t, J
= 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 170.1, 162.6, 146.6,
141.2, 137.6, 137.4, 136.3, 130.4, 130.0 (2C), 127.0, 125.9, 122.9 (2C),
120.4, 63.5, 62.1, 62.1, 21.3, 21.0, 14.1, 13.8. HRMS (ESI+): calcd for
C22H24N2O4 + Na+ [M + Na]+ m/z 403.1628, found 403.1621. IR:
νmax 2982, 2928, 2868, 1734, 1619, 1584, 1573, 1512, 1493, 1381,
1333, 1289, 1256, 1234, 1184, 1080, 1021, 922, 855, 825, 737, 646,
616.
Ethyl 2-Oxo-2-(p-tolylamino)acetate (9). 1H NMR (300 MHz,
CDCl3): δ 8.84 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz,
2H), 4.41 (q, J = 7.1 Hz, 2H), 2.33 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 161.2, 153.8, 135.4, 133.9, 129.8,
119.9, 63.8, 21.1, 14.1. HRMS (ESI+): calcd for C11H13NO3 + Na+ [M
+ Na]+ m/z 230.0788, found 230.0802. IR: νmax 3337, 2915, 1732,
1700, 1597, 1543, 1515, 1288, 1175, 816, 698.
Diethyl 6-Chloro-3-(4-chlorophenyl)-3,4-dihydroquinazoline-2,4-
dicarboxylate (2b).16 According to the general procedure using 1b
(42.7 mg, 0.20 mmol, 1 equiv), the title compound 2b was obtained
after FC (pentane/EtOAc 8/1 → 6/1) as a yellow solid (20.9 mg, 0.05
CONCLUSIONS
■
In conclusion, a straightforward divergent oxidative synthesis of
dihydroquinazolines and quinolines using a TEMPO oxoam-
monium salt as a nontoxic, highly efficient, and mild oxidant
has been developed. The combination of inexpensive FeCl3 or
1
mmol, 50%). H NMR (300 MHz, CDCl3): δ 7.41−7.29 (m, 4H),
7.23 (d, J = 2.1 Hz, 1H), 7.12−6.98 (m, 2H), 5.29 (s, 1H), 4.34−4.08
(m, 4H), 1.25 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 169.0, 161.9, 146.7, 141.8, 138.4, 132.7, 132.4,
129.9, 129.7 (2C), 127.4, 126.5, 124.4 (2C), 121.8, 62.9, 62.5, 62.5,
14.1, 13.7. HRMS (ESI+): calcd for C20H18Cl2N2O4 + Na+ [M + Na]+
m/z 443.0536, found 443.0528. IR: νmax 2982, 2938, 2906, 2360, 2342,
1736, 1607, 1580, 1564, 1491, 1476, 1422, 1380, 1332, 1282, 1253,
1188, 1093, 1074, 1015, 915, 852, 832, 788, 752, 729, 651, 552.
Diethyl 6-Bromo-3-(4-bromophenyl)-3,4-dihydroquinazoline-2,4-
dicarboxylate (2c).16 According to the general procedure using 1c
(51.6 mg, 0.20 mmol, 1 equiv), the title compound 2c was obtained
after FC (pentane/EtOAc 8/1 → 6/1) as a yellow solid (28.8 mg, 0.06
readily available Fe(OTf)2 catalysts with T+BF4 as a formal
−
hydrogen acceptor was successfully employed. This approach
allows for the direct homocondensation of simple N-alkylani-
lines or their reaction with a variety of monosubstituted and
1,2-disubstituted olefins to generate valuable N-containing
heterocycles in one synthetic step. A mechanism involving a
multistep sequence is proposed, in which an iminium species,
obtained by initial α-oxidation of N-alkylanilines with the
TEMPO salt, is the key intermediate in both synthetic
processes. Moreover, this kind of key intermediate could be
formed in situ from the corresponding anilines and aldehydes,
allowing the development of a one-pot multicomponent
synthesis of quinolines under mild oxidative conditions.
1
mmol, 56%). H NMR (300 MHz, CDCl3): δ 7.52−7.43 (m, 3H),
7.38 (d, J = 2.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.07−6.87 (m, 2H),
5.28 (s, 1H), 4.54−3.69 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H), 1.10 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.0, 161.9, 146.7,
142.3, 138.8, 132.9, 132.6 (2C), 129.5, 127.7, 124.7 (2C), 122.1, 120.6,
120.2, 62.7, 62.6 (2C), 14.1, 13.7. HRMS (ESI+): calcd for
C20H18Br2N2O4 + Na+ [M + Na]+ m/z 532.9506, found 532.9512.
IR: νmax 2981, 2936, 2906, 2361, 2339, 1735, 1603, 1577, 1561, 1489,
1473, 1420, 1378, 1331, 1281, 1252, 1188, 1069, 1013, 909, 851, 825,
785, 729, 646, 632, 545.
EXPERIMENTAL SECTION
General Methods. NMR spectra were acquired on a 300 or 400
MHz spectrometer. Chemical shifts (δ) are reported in ppm relative to
■
1
residual solvent signals (CHCl3; 7.26 ppm for H NMR and 77.16
ppm for 13C NMR), and spin−spin coupling constants (J) are given in
Hz. 13C NMR spectra were acquired on a broad-band-decoupled
mode. Mass spectra were recorded using electrospray ionization
(ESI+) techniques and a MicroTOF mass analyzer. Analytical thin-
layer chromatography (TLC) was performed using precoated
aluminum-backed plates and visualized by ultraviolet irradiation or
KMnO4 dip. The wavenumbers (ν) of recorded IR signals are quoted
in cm−1. Dichloromethane was distilled over CaH2. Commercially
Diethyl 6-Fluoro-3-(4-fluorophenyl)-3,4-dihydroquinazoline-2,4-
dicarboxylate (2d). According to the general procedure using 1d
(39.4 mg, 0.20 mmol, 1 equiv), the title compound 2d was obtained
after FC (pentane/EtOAc 8/1 → 6/1) as a white solid (20.9 mg, 0.06
mmol, 55%). 1H NMR (300 MHz, CDCl3): δ 7.40 (dd, J = 8.7, 5.3 Hz,
1H), 7.18−7.00 (m, 5H), 6.95 (dd, J = 8.3, 2.8 Hz, 1H), 5.31 (s, 1H),
4.50−3.76 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 169.3, 162.2, 161.6 (d, 1J = 247.7 Hz),
161.2 (d, 1J = 247.6 Hz); 139.6 (d, 4J = 3.0 Hz), 136.3 (d, 4J = 2.9 Hz),
4b,5a
−
available reagents were used without further purification. T+BF4
3
3
3
and N-alkylanilines 1aa21 (−CH2COPh), 1ba22 (−CH2PO(OEt)2),
1ca23 (−CH2CN), 1da24 (−CH2-oxazolidinone), 1ea25,26 (−CH2Ph),
and 1fa26 (−CH2Et) were prepared following literature procedures.
Except for the reactions carried out under an air or O2 atmosphere, the
catalytic reactions were performed in sealed tubes under an argon
atmosphere.
General Procedure for the Synthesis of Dihydroquinazo-
lines 2. A sealed tube equipped with a magnetic stirring bar, Fe(OTf)2
(10 mol %), aniline 1 (0.2 mmol, 1.0 equiv), T+BF4− (0.40 mmol, 2.0
equiv), and DCE (0.5 mL) were added under an argon atmosphere.
127.9 (d, J = 8.4 Hz), 125.7 (d, J = 8.5 Hz, 2C), 121.7 (d, J = 8.5
Hz), 116.8 (d, 2J = 22.5 Hz), 116.5 (d, 2J = 22.9 Hz, 2C), 116.4, 113.5
3
4
(d, J = 24.2 Hz), 63.5 (d, J = 1.3 Hz), 62.6, 62.5, 14.2, 13.8. HRMS
(ESI+): calcd for C20H18F2N2O4 + Na+ [M + Na]+ m/z 411.1127,
found 411.1131. IR: νmax 3072, 2984, 2939, 2907, 2876, 2360, 2343,
1736, 1618, 1596, 1578, 1508, 1488, 1433, 1395, 1382, 1369, 1334,
1290, 1222, 1186, 1159, 1138, 1096, 1079, 1016, 959, 924, 840, 809,
741, 704, 639, 619, 564.
Diethyl 6-(Trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)-3,4-di-
hydroquinazoline-2,4-dicarboxylate (2e). According to the general
H
dx.doi.org/10.1021/jo4007199 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
procedure using 1e (9.4 mg, 0.20 mmol, 1.0 equiv), the title
compound 2e was obtained after FC (pentane/EtOAc 8/1) as a
yellow solid (31.4 mg, 0.06 mmol, 64%). 1H NMR (400 MHz,
CDCl3): δ 7.72−7.60 (m, 3H), 7.59−7.50 (m, 2H), 7.21 (d, J = 8.1
Hz, 2H), 5.43 (s, 1H), 4.36−4.07 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H),
1.08 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 168.8, 161.7,
147.8, 146.1 (q, 5J = 1.3 Hz), 142.5 (q, 5J = 1.3 Hz), 129.6 (q, 2J = 32.9
Hz), 128.8 (q, 2J = 33.2 Hz), 126.94 (q, 3J = 3.6 Hz, 2C), 126.6, 124.5
(q, J = 272.0 Hz), 124.2 (q, J = 3.8 Hz), 123.9 (q, J = 272.0 Hz),
122.9 (3C), 121.3, 62.9, 62.9, 62.8, 14.1, 13.7. 19F NMR (282 MHz,
CDCl3): δ −62.37, −62.42. HRMS (ESI+): calcd for C22H18F6N2O4 +
H+ [M + H]+ m/z 489.1244, found 489.1244. IR: νmax 2986, 1739,
1619, 1587, 1571, 1520, 1428, 1322, 1258, 1193, 1163, 1116, 1068,
1017, 910, 844, 735, 649, 612, 589.
Diethyl 4-Hydroxy-6-methoxy-3-(4-methoxyphenyl)-3,4-dihydro-
quinazoline-2,4-dicarboxylate (10). White solid (17.5 mg, 0.04
mmol, 41%). 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J = 8.7 Hz, 1H),
7.41 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 6.98 (dd, J = 8.6, 2.8
Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.61 (d, J
= 2.7 Hz, 1H), 5.12 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 4.02 (q, J = 7.1
Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H), 0.99 (t, J
= 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 170.7, 162.6, 159.8,
158.6, 145.5, 133.2, 131.9, 131.5, 129.7, 128.1, 123.6, 116.9, 114.1
(2C), 109.2, 85.6, 63.9, 62.1, 55.7, 55.6, 13.9, 13.8. HRMS (ESI+):
calcd for C22H24N2O7 + H+ [M + H]+ m/z 429.1656, found 429.1659.
IR: νmax 3475, 2981, 2840, 1737, 1620, 1494, 1377, 1228, 1193, 1165,
1031, 837.
Diethyl 3-([1,1′-Biphenyl]-4-yl)-6-phenyl-3,4-dihydroquinazoline-
2,4-dicarboxylate (2j). According to the general procedure using 1j
(51.1 mg, 0.20 mmol, 1 equiv), the title compound 2j was obtained
after FC (pentane/EtOAc 7/1) as a yellow solid (21.2 mg, 0.04 mmol,
41%). 1H NMR (300 MHz, CDCl3): δ 7.64−7.52 (m, 8H), 7.46 (ddt,
J = 13.1, 6.2, 1.9 Hz, 5H), 7.40−7.32 (m, 2H), 7.23−7.17 (m, 2H),
5.50 (s, 1H), 4.37−4.09 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 1.07 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.9, 162.6, 146.9,
142.8, 140.5, 140.2, 140.0, 139.4, 139.3, 129.0 (2C), 129.0 (2C), 128.5
(2C), 128.2, 127.7 (2C), 127.7 (2C), 127.1, 127.0, 126.6, 125.3, 123.2,
121.2, 110.1, 63.5, 62.4, 62.4, 14.2, 13.8. HRMS (ESI+): calcd for
C32H28N2O4 + H+ [M + H]+ m/z 505.2122, found 505.2124. IR: νmax
3060, 3032, 2981, 2935, 2905, 1734, 1617, 1575, 1562, 1520, 1479,
1418, 1393, 1381, 1368, 1333, 1269, 1253, 1187, 1165, 1078, 1021,
1009, 910, 840, 764, 727, 696, 645, 601, 560.
1
3
1
Diethyl 6-Acetyl-3-(4-acetylphenyl)-3,4-dihydroquinazoline-2,4-
dicarboxylate (2f). According to the general procedure using 1f
(44.3 mg, 0.20 mmol, 1 equiv), the title compound 2f was obtained
after FC (pentane/EtOAc 4/1 → 1/1) as a yellow solid (25.2 mg, 0.06
1
mmol, 58%). H NMR (300 MHz, CDCl3): δ 8.01−7.87 (m, 4H),
7.53 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 5.45 (s, 1H), 4.34−
4.05 (m, 4H), 2.60 (s, 6H), 1.23 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 196.6 (2C), 169.0, 161.9,
147.8, 147.0, 143.6, 136.2, 134.8, 130.3, 130.0 (2C), 127.1, 126.3,
122.0 (2C), 121.3, 62.9, 62.8, 62.8, 26.74, 26.7, 14.2, 13.8. HRMS (ESI
+): calcd for C24H24N2O6 + Na+ [M + Na]+ m/z 459.1527, found
459.1500. IR: νmax 3062, 2983, 2937, 2361, 2341, 1737, 1679, 1602,
1576, 1555, 1510, 1421, 1394, 1381, 1360, 1335, 1290, 1254, 1186,
1086, 1017, 958, 916, 840, 791, 729, 617, 593, 577.
Diethyl 3-(3,5-Dimethylphenyl)-5,7-dimethyl-3,4-dihydroquina-
zoline-2,4-dicarboxylate (2k). According to the general procedure
using 1k (41.5 mg, 0.20 mmol, 1 equiv), the title compound 2k was
obtained after FC (pentane/EtOAc 8/1 → 6/1) as a yellow solid (15.3
Diethyl 6-Cyano-3-(4-cyanophenyl)-3,4-dihydroquinazoline-2,4-
dicarboxylate (2g). According to the general procedure using 1g (40.8
mg, 0.20 mmol, 1 equiv), the title compound 2g was obtained after FC
(pentane/EtOAc 4/1 → 3/1) as a white solid (19.9 mg, 0.05 mmol,
50%). 1H NMR (300 MHz, CDCl3): δ 7.72−7.51 (m, 5H), 7.22−7.14
(m, 2H), 5.38 (s, 1H), 4.35−4.15 (m, 4H), 1.26 (t, J = 7.0 Hz 3H),
1.14 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 168.2, 161.3,
147.8, 146.5, 143.2, 133.8, 133.8, 130.9, 127.1, 123.0, 121.9, 118.3,
118.0, 111.2, 110.4, 63.3, 62.2, 29.9, 14.2, 13.9. HRMS (ESI+): calcd
for C22H18N4O4 + Na+ [M + Na]+ m/z 425.1220, found 425.1225. IR:
νmax 2995, 2924, 2853, 2227, 1737, 1606, 1576, 1557, 1508, 1486,
1426, 1394, 1382, 1369, 1334, 1289, 1258, 1191, 1126, 1094, 1079,
1016, 912, 844, 729, 665, 648, 594, 577.
1
mg, 0.04 mmol, 37%). H NMR (300 MHz, CDCl3): δ 7.13 (s, 1H),
6.93 (s, 1H), 6.85 (s, 1H), 6.69 (s, 2H), 5.43 (s, 1H), 4.30−4.10 (m,
4H), 2.38 (s, 3H), 2.31 (s, 3H), 2.29 (s, 6H), 1.23 (t, J = 7.1 Hz, 3H),
1.08 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 170.1, 162.6,
146.9, 143.8, 140.3, 139.3 (2C), 138.8, 134.6, 130.5, 127.7, 124.3,
120.0 (2C), 117.3, 62.1, 62.0, 60.5, 21.4 (2C), 21.1, 18.7, 14.1, 13.7.
HRMS (ESI+): calcd for C24H28N2O4 + Na+ [M + Na]+ m/z
431.1941, found 431.1942. IR: νmax 2983, 2921, 2857, 1740, 1730,
1593, 1564, 1468, 1446, 1398, 1377, 1365, 1339, 1306, 1249, 1229,
1204, 1191, 1099, 1037, 1020, 857, 842, 793, 702, 681, 662, 593.
General Procedure A for the Synthesis of Quinolines from
N-Alkylanilines. A mixture of 1 (0.5 mmol), olefin 3 (1.0 mmol, 2.0
equiv) or alkyne 10 (4.0 equiv), FeCl3 (8.0 mg, 0.05 mmol, 10 mol %),
and T+BF4− (243.0 mg, 1.0 mmol, 2 equiv) in dry DCM (5.0 mL) in a
Schlenk tube under an argon atmosphere was stirred at 60 °C. Once
the starting material was consumed (monitored by GC-MS or TLC),
the solvent was concentrated under reduced pressure and the residue
was purified by column chromatography on silica gel.
General Procedure B for the Synthesis of Quinolines via a
Three-Component Reaction. In a pressure Schlenk tube equipped
with a magnetic stirring bar, aniline 5 (0.2 mmol, 1.0 equiv) and FeCl3
(3.2 mg, 0.02 mmol, 10 mol %) were dissolved in dry DCM (2 mL)
under an argon atmosphere. After the addition of ethyl glyoxalate 6
(48 μL, 0.24 mmol, 1.2 equiv; 50% in toluene), olefin 3 or alkyne 10
(0.4 mmol, 2.0 equiv), and T+BF4− (97.2 mg, 0.4 mmol, 2.0 equiv) the
solution was stirred at 60 °C for 18 h. The crude reaction mixture was
directly purified by column chromatography to obtain the correspond-
ing quinoline derivative 4.
Triethyl 3-(4-(Ethoxycarbonyl)phenyl)-3,4-dihydroquinazoline-
2,4,6-tricarboxylate (2h). According to the general procedure using
1h (50.3 mg, 0.20 mmol, 1 equiv), the title compound 2h was
obtained after FC (pentane/EtOAc 6/1) as a yellow solid (14.7 mg,
1
0.03 mmol, 31%). H NMR (400 MHz, CDCl3): δ 8.08−8.03 (m,
3H), 7.99−7.95 (m, 1H), 7.51 (br d, J = 7.8 Hz, 1H), 7.13 (br d, J =
8.2 Hz, 2H), 5.45 (s, 1H), 4.42−4.32 (m, 4H), 4.28−4.12 (m, 4H),
1.40 (t, J = 7.1 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz,
3H), 1.10 (t, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 169.1,
165.8, 165.7, 162.0, 147.8, 146.9, 143.4, 131.2, 131.2, 129.6, 128.4,
128.3, 126.2, 122.0, 121.0, 62.9, 62.8, 62.7, 61.4, 61.3, 29.8, 14.5, 14.4,
14.2, 13.9. HRMS (ESI+): calcd for C26H28N2O8 + Na+ [M + Na]+ m/
z 519.1738, found 519.1726. IR: νmax 2982, 2937, 2907, 2875, 1738,
1712, 1608, 1580, 1561, 1511, 1425, 1392, 1383, 1367, 1334, 1256,
1178, 1100, 1077, 1018, 910, 855, 823, 711, 732, 701, 649, 611.
Diethyl 6-Methoxy-3-(4-methoxyphenyl)-3,4-dihydroquinazo-
line-2,4-dicarboxylate (2i). According to the general procedure
using 1i (42.7 mg, 0.20 mmol, 1 equiv), the title compound 2i was
obtained after FC (pentane/EtOAc 8/1 → 6/1 → 4/1) as a white
Ethyl 6-Methyl-4-phenylquinoline-2-carboxylate (4a)..7a,14 Ac-
cording to the general procedure A using 1a (96.6 mg, 0.50 mmol, 1.0
equiv) and styrene (3a; 115 μL, 1.00 mmol, 2.0 equiv), the title
compound 4a was obtained after FC (pentane/EtOAc 5/1) as a white
solid (135.9 mg, 0.47 mmol, 93%). According to the general procedure
B using 4-methylaniline (5a; 21.4 mg, 0.2 mmol, 1.0 equiv) and
styrene (3a; 46 μL, 0.4 mmol, 2.0 equiv), the title compound 4a was
obtained after FC (pentane/EtOAc 8/1) as a white solid (51.3 mg,
0.18 mmol, 90%). 1H NMR (300 MHz, CDCl3): δ 8.28 (d, J = 8.6 Hz,
1H), 8.10 (s, 1H), 7.71 (s, 1H), 7.62 (dd, J = 8.7, 1.7 Hz, 1H), 7.60−
1
solid (22.6 mg, 0.06 mmol, 55%). H NMR (300 MHz, CDCl3): δ
7.36 (d, J = 8.7 Hz, 1H), 7.13−7.00 (m, 2H), 6.94−6.83 (m, 3H), 6.74
(d, J = 2.8 Hz, 1H), 5.31 (s, 1H), 4.32−4.04 (m, 5H), 3.80 (s, 4H),
3.79 (s, 4H), 1.24 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 170.0, 162.7, 158.9, 158.3, 145.9, 136.9,
136.9, 127.5, 125.3 (2C), 121.4, 115.2, 114.7 (2C), 111.6, 64.1, 62.2,
62.1, 55.7, 55.7, 14.2, 13.9. HRMS (ESI+): calcd for C22H24N2O6 +
Na+ [M + Na]+ m/z 435.1527, found 435.1524. IR: νmax 2981, 2937,
2838, 2360, 2343, 1734, 1691, 1615, 1580, 1510, 1493, 1464, 1382,
1286, 1237, 1182, 1151, 1111, 1079, 1020, 854, 835, 798, 736, 574.
I
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The Journal of Organic Chemistry
Article
7.46 (m, 5H), 4.56 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 1.49 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 165.6, 149.0, 146.9, 146.8,
139.0, 137.8, 132.4, 130.9, 129.6, 128.7, 128.6, 127.8, 124.4, 121.5,
62.2, 22.1, 14.4. HRMS (ESI): calcd for C19H17NO2 + Na+ [M + Na]+
m/z 314.1151, found 314.1146. IR: νmax 3060, 2979, 2912, 1708, 1496,
1445, 1246, 1231, 1107, 1026, 825, 755, 700.
1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.62−7.34 (m, 3H), 2.49 (s, 1H). 13
C
NMR (75 MHz, CDCl3): δ 156.1, 148.7, 147.5, 139.8, 138.8, 136.4,
131.9, 129.9, 129.7, 129.3, 128.9, 128.7, 128.4, 127.6, 125.8, 124.5,
119.6, 22.0. HRMS (ESI): calcd for C22H17N + H+ [M + H]+ m/z
296.1434, found 296.1434. IR: νmax 3053, 1587, 1544, 1488, 1449,
1357, 1079, 1027, 878, 826, 756, 700.
Ethyl 6-Methyl-4-phenyl-1,2,3,4-tetrahydroquinoline-2-carboxy-
late (11a).7a According to the general procedure A in the reaction
at room temperature for 13 h using 1a (19.0 mg, 0.10 mmol, 1.0
equiv) and styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the title
compound 11a was isolated after FC (pentane/EtOAc 10/1) as a
white solid and as a 5/1 mixture of two diastereomers (10.0 mg, 0.03
Ethyl 6-Chloro-4-phenylquinoline-2-carboxylate (4b)..7a,14 Ac-
cording to the general procedure A using 1b (21.0 mg, 0.10 mmol,
1.0 equiv) and styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the title
compound 4b was obtained after FC (pentane/EtOAc 4/1) as a white
solid (23.0 mg, 0.07 mmol, 73%). According to the general procedure
B using 4-chloroaniline (3b; 25.5 mg, 0.2 mmol, 1.0 equiv) and styrene
(3a; 46 μL, 0.4 mmol, 2.0 equiv), the title compound 4b was obtained
after FC (pentane/EtOAc 10/1) as a white solid (56.1 mg, 0.18 mmol,
1
mmol, 33%). H NMR (400 MHz, CDCl3): δ 7.35−7.17 (m, 4H,
major and 4H, minor), 7.15−7.04 (m, 1H, major and 1H, minor), 6.89
(dd, J = 8.1, 2.0 Hz, 1H, major), 6.84 (d, J = 8.1 Hz, 1H, minor), 6.67
(d, J = 1.5 Hz, 1H, major), 6.62 (d, J = 8.1 Hz, 1H, major), 6.58 (d, J =
8.1 Hz, 1H, minor), 6.43 (s, 1H, minor), 4.41 (s, 1H, major and 1H,
minor), 4.27−4.08 (m, 3H, major and 3H, minor), 3.85 (dd, J = 10.3,
3.7 Hz, 1H, major), 2.55 (ddd, J = 12.9, 5.4, 3.2 Hz, 1H, minor), 2.33
(ddd, J = 12.8, 4.4, 3.8 Hz, 1H, major), 2.20 (ddd, J = 12.9, 10.3, 5.2
Hz, 1H, major and 1H, minor), 2.15 (s, 3H, major), 2.08 (s, 3H,
minor), 1.25 (t, J = 7.1 Hz, 3H, major), 1.26−1.21 (t, J = 7.1 Hz, 3H,
minor); 13C NMR (100 MHz, CDCl3) (only peaks of the major
diastereomer): δ 172.9, 145.0, 141.3, 129.97, 128.9, 128.7, 128.2,
127.2, 126.8, 124.3, 115.0, 61.5, 54.4, 44.0, 35.3, 20.6, 14.3. HRMS
(ESI): calcd for C19H21NO2 + H+ [M + H]+ m/z 296.1645, found
296.1642. IR: νmax 3400, 3055, 2972, 2898, 1711, 1376, 1253, 1135,
1115, 770, 703.
1
90%). H NMR (300 MHz, CDCl3): δ 8.31 (d, J = 9.0 Hz, 1H), 8.14
(s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 9.0, 2.3 Hz, 1H), 7.61−
7.39 (m, 5H), 4.56 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 165.3, 149.1, 148.2, 146.9, 136.9, 133.8,
132.9, 129.6, 129.2, 129.0, 129.0, 128.0, 123.4, 122.2, 62.5, 14.5.
HRMS (ESI): calcd for C18H14ClNO2 + Na+ [M + Na]+ m/z
334.0605, found 334.0607. IR: νmax 3062, 2981, 1717, 1453, 1374,
1240, 1139, 1107, 831, 700.
Ethyl 6-Bromo-4-phenylquinoline-2-carboxylate (4c)..7a,14 Ac-
cording to the general procedure A using 1c (26.0 mg, 0.10 mmol,
1.0 equiv) and styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the title
compound 4c was obtained after FC (pentane/EtOAc 4/1) as a white
1
solid (26.0 mg, 0.07 mmol, 73%). H NMR (300 MHz, CDCl3): δ
8.23 (d, J = 9.0 Hz, 1H), 8.14 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.85
(dd, J = 9.0, 2.1 Hz, 1H), 7.66−7.42 (m, 5H), 4.56 (q, J = 7.1 Hz, 2H),
1.48 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 165.3, 149.2,
148.1, 146.6, 137.0, 135.0, 132.8, 131.2, 129.6, 129.2, 129.0, 128.6,
124.7, 122.2, 62.5, 14.5. HRMS (ESI): calcd for C18H14BrNO2 + Na+
[M + Na]+ m/z 380.0085, found 380.0083. IR: νmax 3056, 1721, 1484,
1445, 1371, 1249, 1140, 1110, 1024, 829, 707.
(6-Methyl-4-phenylquinolin-2-yl)(phenyl)methanone (4aa).7a Ac-
cording to the general procedure A using 1aa (23.0 mg, 0.10 mmol, 1.0
equiv) and styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the title
compound 4aa was obtained after FC (pentane/EtOAc 5/1) as a
white solid (23.0 mg, 0.07 mmol, 72%). 1H NMR (300 MHz, CDCl3):
δ 8.27 (dd, J = 8.4, 1.3 Hz, 2H), 8.17 (d, J = 8.6 Hz, 1H), 8.03 (s, 1H),
7.76 (s, 1H), 7.69−7.60 (m, 2H), 7.59−7.46 (m, 7H), 2.52 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 194.1, 153.5, 149.0, 146.0, 139.0,
138.0, 136.4, 133.1, 132.4, 131.6, 130.8, 129.7, 128.8, 128.7, 128.3,
127.6, 124.7, 121.2, 22.2. HRMS (ESI): calcd for C23H17NO + Na+ [M
+ Na]+ m/z 346.1202, found 346.1208. IR: νmax 3054, 1655, 1597,
1575, 1492, 1443, 1359, 1249, 1149, 1003, 951, 825, 728.
Ethyl 6-Acetyl-4-phenylquinoline-2-carboxylate (4d).7a According
to the general procedure A using 1f (23.0 mg, 0.10 mmol, 1.0 equiv)
and styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the title compound 4d
was obtained after FC (pentane/EtOAc 2/1) as a white solid (24.0
mg, 0.08 mmol, 75%). According to the general procedure B using 4′-
aminoacetophenone (5d) (27.0 mg, 0.2 mmol, 1.0 equiv) and styrene
(3a; 46 μL, 0.4 mmol, 2.0 equiv), the title compound 4d was obtained
after FC (pentane/EtOAc 10/1) as a white solid (58.4 mg, 0.18 mmol,
Diethyl (6-Methyl-4-phenylquinolin-2-yl)phosphonate (4ba).7a
According to the general procedure A using 1ba (26.0 mg, 0.10
mmol, 1.0 equiv) and styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the
title compound 4ba was obtained after FC (pentane/EtOAc 2/1) as a
white solid (15.0 mg, 0.04 mmol, 42%). 1H NMR (400 MHz, CDCl3):
δ 8.22 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.70 (s, 1H), 7.61
(dd, J = 8.7, 1.9 Hz, 1H), 7.58−7.44 (m, 5H), 4.46−4.00 (m, 4H),
2.49 (s, 3H), 1.61−1.03 (td, J = 7.1, 0.4 Hz, 6H). 13C NMR (100
MHz, CDCl3): δ 152.2, 150.0, 148.0, 147.9, 147.6, 147.4, 138.8, 137.7,
132.3, 130.6, 129.7, 128.7, 128.7, 127.2, 127.1, 124.5, 123.9, 123.6,
63.2, 63.2, 22.1, 16.5, 16.5. 31P NMR (162 MHz, CDCl3): δ 11.15.
HRMS (ESI): calcd for C20H22NO3P + Na+ [M + Na]+ m/z 378.1230,
found 378.1230. IR: νmax 2982, 1489, 1392, 1248, 1049, 1020, 967,
793, 702.
1
90%). H NMR (400 MHz, CDCl3): δ 8.59 (d, J = 1.7 Hz, 1H), 8.44
(d, J = 8.9 Hz, 1H), 8.31 (dd, J = 8.9, 1.9 Hz, 1H), 8.19 (s, 1H), 7.83−
7.38 (m, 5H), 4.58 (q, J = 7.1 Hz, 2H), 2.62 (s, 3H), 1.50 (t, J = 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 197.5, 165.2, 151.8, 150.1,
149.8, 136.9, 136.5, 131.8, 129.7, 129.4, 129.1, 128.3, 127.7, 127.2,
122.1, 62.7, 26.9, 14.5. HRMS (ESI): calcd for C20H17NO3 + Na+ [M
+ Na]+ m/z 342.1101, found 342.1096. IR: νmax 2985, 1733, 1680,
1402, 1244, 1229, 1141, 1024, 843, 772.
Ethyl 6-Methoxy-4-phenylquinoline-2-carboxylate (4e)..7a,14 Ac-
cording to the general procedure A using 1i (21.0 mg, 0.10 mmol, 1.0
equiv) and styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the title
compound 4e was obtained after FC (pentane/EtOAc 5/1) as a white
solid (26.0 mg, 0.08 mmol, 84%). According to the general procedure
B using 4-anisidine (5e;24.6 mg, 0.2 mmol, 1.0 equiv) and styrene (3a;
46 μL, 0.4 mmol, 2.0 equiv), the title compound 4e was obtained after
FC (pentane/EtOAc 10/1) as a white solid (57.6 mg, 0.18 mmol,
6-Methyl-4-phenylquinoline-2-carbonitrile (4ca). According to
the general procedure A using 1ca (29.0 mg, 0.20 mmol) and styrene
(3a; 46 μL, 0.40 mmol, 2 equiv), the title compound 4ca was obtained
after FC (pentane/EtOAc 5/1) as a white solid (8.0 mg, 0.03 mmol,
17%). 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J = 8.6 Hz, 1H), 7.72−
7.70 (m, 1H), 7.67 (dd, J = 8.6, 1.9 Hz, 1H), 7.59−7.53 (m, 3H),
7.52−7.45 (m, 2H), 2.51 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
149.6, 147.6, 140.2, 136.6, 133.5, 132.4, 130.2, 129.5, 129.3, 129.0,
127.5, 124.7, 123.7, 117.9, 22.3. HRMS (ESI): calcd for C17H12N2 +
Na+[M + Na]+ m/z 267.0893, found 267.0902. IR: νmax 3061, 2995,
2227, 1720, 1605, 1373, 1252, 1151, 1024, 841, 705.
1
95%). H NMR (300 MHz, CDCl3): δ 8.27 (d, J = 9.3 Hz, 1H), 8.09
(s, 1H), 7.61−7.46 (m, 5H), 7.43 (dd, J = 9.3, 2.8 Hz, 1H), 7.21 (d, J =
2.8 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.47 (t, J = 7.1 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 165.7, 159.6, 148.2, 145.5, 144.4,
138.0, 132.8, 129.4, 129.3, 128.9, 128.8, 122.9, 121.9, 103.4, 62.2, 55.6,
14.5. HRMS (ESI): calcd for C19H17NO3 + H+ [M + H]+ m/z
308.1281, found 308.1282. IR: νmax 2976, 1729, 1616, 1472, 1220,
1103, 1025, 839, 707.
6-Methyl-2,4-diphenylquinoline (4ea).7a According to the general
procedure A using 1ea (20.0 mg, 0.10 mmol, 1.0 equiv) and styrene
(3a; 23 μL, 0.20 mmol, 2.0 equiv), the title compound 4ea was
obtained after FC (pentane/EtOAc 10/1) as a white solid (12.0 mg,
Ethyl 5,7-Dimethyl-4-phenylquinoline-2-carboxylate (4f).7a Ac-
cording to the general procedure A using 1k (21.0 mg, 0.10 mmol, 1.0
equiv) and styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the title
compound 4f was obtained after FC (pentane/EtOAc 5/1) as a white
1
0.04 mmol, 41%). H NMR (300 MHz, CDCl3): δ 8.23−8.11 (m,
J
dx.doi.org/10.1021/jo4007199 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
solid (21.0 mg, 0.07 mmol, 69%). H NMR (300 MHz, CDCl3): δ
mg, 0.2 mmol, 1.0 equiv) and p-(trifluormethyl)styrene (3d; 68.9 μL,
0.4 mmol, 2.0 equiv), the title compound 4j was obtained after FC
(pentane/EtOAc 10/1) as a pale yellow solid (41.1 mg, 0.11 mmol,
8.06 (s, 1H), 7.92 (s, 1H), 7.50−7.39 (m, 3H), 7.39−7.28 (m, 2H),
7.22 (s, 1H), 4.53 (q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 2.00 (s, 3H), 1.46
(t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 165.6, 150.2,
149.7, 146.4, 142.1, 140.0, 135.2, 134.3, 129.0, 128.9, 128.1, 125.6,
122.8, 62.3, 24.4, 21.5, 14.5. HRMS (ESI): calcd for C20H19NO2 + H+
[M + H]+ m/z 306.1484, found 306.1484. IR: νmax 2976, 1708, 1470,
1372, 1338, 1244, 1135, 1026, 867, 708.
1
55%). H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.7 Hz, 1H), 8.08
(s, 1H), 7.86−7.49 (m, 7H), 4.56 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H),
1.48 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 165.5, 147.3
147.0, 146.9, 139.7, 138.7, 133.0, 132.7, 131.4 (q, 2J = 32.6 Hz), 131.2,
129.3, 127.5, 126.4 (q, 3J = 3.8 Hz), 125.5 (q, 3J = 3.8 Hz), 124.0 (q, 1J
= 272.5 Hz), 123.0, 121.5, 62.4, 22.2, 14.5. 19F NMR (282 MHz,
CDCl3): δ −62.59. HRMS (ESI): calcd for C19H17NO3 + Na+ [M +
Na]+ m/z 330.1101, found 330.1088. IR: νmax 2977, 2926, 1721, 1379,
1315, 1286, 1244, 1188, 1167, 1108, 1078, 1025, 895, 826, 811, 705.
Ethyl 4-(4-(tert-Butyl)phenyl)-6-methylquinoline-2-carboxylate
(4k).7a According to the general procedure A using 1a (19.0 mg,
0.10 mmol, 1.0 equiv) and 4-(tert-butyl)styrene (3e; 37 μL, 0.20
mmol, 2.0 equiv), the title compound 4k was obtained after FC
(pentane/EtOAc 5/1) as a white solid (30.0 mg, 0.09 mmol, 86%).
According to the general procedure B using 4-methylaniline (5a; 21.4
mg, 0.2 mmol, 1.0 equiv) and 4-(tert-butyl)styrene (3e; 77.1 μL, 0.4
mmol, 2.0 equiv), the title compound 4k was obtained after FC
(pentane/EtOAc 10/1) as a white solid (60.6 mg, 0.17 mmol, 85%).
1H NMR (300 MHz, CDCl3): δ 8.28 (d, J = 8.7 Hz, 1H), 8.10 (s, 1H),
Ethyl 7-Methyl-4-phenylquinoline-2-carboxylate (4g) and Ethyl
5-Methyl-4-phenylquinoline-2-carboxylate (4g′).7a According to the
general procedure A using 1o (19.0 mg, 0.10 mmol, 1.0 equiv) and
styrene (3a; 23 μL, 0.20 mmol, 2.0 equiv), the title regioisomers 4g
and 4g′ were obtained after FC (pentane/EtOAc 10:1) as a 1.6/1
mixture and a white solid (12.0 mg, 0.04 mmol, 42%). According to
the general procedure B using 3-methylaniline (5g; 21.9 μL, 0.2 mmol,
1.0 equiv) and styrene (3a; 46 μL, 0.4 mmol, 2.0 equiv), the title
regioisomers 4g and 4g′ were obtained after FC (pentane/EtOAc 8/1)
as a 1/1.5 mixture and a white solid (30.2 mg, 0.10 mmol, 50%) (1.6/1
dr mixture). 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 8.5 Hz, 1H,
minor), 8.16 (s, 1H, major), 8.08 (s, 1H, major), 7.99 (s, 1H, minor),
7.86 (d, J = 8.6 Hz, 1H, major), 7.66 (dd, J = 8.4, 7.1 Hz, 1H), 7.59−
7.50 (m, 3H, major and 3H, minor), 7.49−7.32 (m, 3H, major and 3H,
minor), 4.56 (q, J = 7.1 Hz, 2H, major), 4.55 (q, J = 7.1 Hz, 1H,
minor), 2.58 (s, 3H, major), 2.04 (s, 3H, minor), 1.49 (t, J = 7.1 Hz,
3H, major), 1.47 (t, J = 7.1 Hz, 3H, minor). 13C NMR (75 MHz,
CDCl3): δ 165.7, 165.4, 150.3, 149.5, 149.4, 148.5, 147.8, 146.4, 141.9,
140.4, 137.7, 135.6, 131.8, 131.0, 130.1, 129.6, 129.6, 128.8, 128.7,
128.1, 128.1, 127.4, 125.9, 125.4, 123.4, 120.6, 62.2, 24.5, 21.7, 14.4.
HRMS (ESI): calcd for C19H17NO2 + Na+ [M + Na]+ m/z 314.1151,
found 314.1147. IR: νmax 2975, 2919, 1712, 1443, 1377, 1377, 1250,
1133, 1111, 1038, 777, 767, 709.
Ethyl 4-(4-Chlorophenyl)-6-methylquinoline-2-carboxylate
(4h)..7a,14 According to the general procedure A using 1a (19.0 mg,
0.10 mmol, 1.0 equiv) and 4-chlorostyrene (3b; 24 μL, 0.20 mmol, 2.0
equiv), the title compound 4h was obtained after FC (pentane/EtOAc
5/1) as a white solid (27.0 mg, 0.08 mmol, 83%). According to the
general procedure B using 4-methylaniline (5a; 21.4 mg, 0.2 mmol, 1.0
equiv) and 4-chlorostyrene (3b; 50.4 μL, 0.4 mmol, 2.0 equiv), the
title compound 4h was obtained after FC (pentane/EtOAc 10/1) as a
white solid (56.6 mg, 0.17 mmol, 85%). 1H NMR (300 MHz, CDCl3):
δ 8.28 (d, J = 9.2 Hz, 1H), 8.06 (s, 1H), 7.67−7.59 (m, 2H), 7.57−
7.50 (m, 2H), 7.50−7.42 (m, 2H), 4.56 (q, J = 7.1 Hz, 2H), 2.50 (s,
3H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 165.6,
147.7, 147.0, 146.8, 139.3, 136.2, 134.9, 132.6, 131.1, 130.9, 129.0,
127.6, 124.1, 121.4, 62.3, 22.1, 14.5. HRMS (ESI): calcd for
C19H16ClNO2 + Na+ [M + Na]+ m/z 348.0762, found 348.0747. IR:
νmax 2987, 1710, 1595, 1491, 1381, 1252, 1149, 1111, 1087, 1016, 822.
Ethyl 4-(2-Chlorophenyl)-6-methylquinoline-2-carboxylate (4i).7a
According to the general procedure A using 1a (19.0 mg, 0.10 mmol,
1.0 equiv) and 2-chlorostyrene (3c; 24 μL, 0.20 mmol, 2.0 equiv), the
title compound 4i was obtained after FC (pentane/EtOAc 5/1) as a
white solid (25.0 mg, 0.08 mmol, 77%). According to the general
procedure B using 4-methylaniline (5a; 21.4 mg, 0.2 mmol, 1.0 equiv)
and 2-chlorostyrene (3c; 51.3 μL, 0.4 mmol, 2.0 equiv), the title
compound 4i was obtained after FC (pentane/EtOAc 10/1) as a pale
red solid (57.6 mg, 0.18 mmol, 95%). 1H NMR (300 MHz, CDCl3): δ
8.28 (d, J = 8.7 Hz, 1H), 8.06 (s, 1H), 7.65−7.56 (m, 2H), 7.51−7.39
(m, 2H), 7.37−7.31 (m, 1H), 7.28 (br s, 1H), 4.56 (qd, J = 7.1, 1.0 Hz,
2H), 2.47 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 165.4, 146.8, 146.4, 146.3, 139.2, 136.4, 133.2, 132.6, 131.2,
130.8, 130.0, 129.9, 127.9, 126.9, 124.3, 121.9, 62.2, 22.0, 14.4. HRMS
(ESI): calcd for C19H16ClNO2 + Na+ [M + Na]+ m/z 348.0762, found
348.0744. IR: νmax 2985, 1711, 1556, 1475, 1435, 1370, 1248, 1228,
1151, 1128, 1107, 1057, 1025, 900, 825, 763, 734, 685, 622, 591, 521.
Ethyl 4-(4-(Trifluoromethyl)phenyl)-6-methylquinoline-2-carbox-
ylate (4j). According to the general procedure A using 1a (19.0 mg,
0.10 mmol, 1.0 equiv) and 4-(trifluoromethyl)styrene (3d; 34.4 mg,
0.20 mmol, 2.0 equiv), the title compound 4j was obtained after FC
(pentane/EtOAc 6/1) as a white solid (28.0 mg, 0.08 mmol, 78%).
According to the general procedure B using 4-methylaniline (5a; 21.4
7.78 (s, 1H), 7.64−7.59 (m, 1H), 7.59−7.54 (m, 2H), 7.51−7.44 (m,
2H), 4.55 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H),
1.42 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 165.5, 151.7, 149.0,
146.8, 146.7, 138.8, 134.7, 132.3, 130.8, 129.3, 127.9, 125.6, 124.5,
121.4, 62.1, 34.8, 31.3, 22.0, 14.4. HRMS (ESI): calcd for C23H25NO2
+ Na+ [M + Na]+ m/z 370.1778, found 370.1764. IR: νmax 2965, 1738,
1581, 1495, 1365, 1225, 1108, 840.
Ethyl 4-(4-Methoxyphenyl)-6-methylquinoline-2-carboxylate
(4l).7a According to the general procedure A using 1a (19.0 mg,
0.10 mmol, 1.0 equiv) and 4-methoxystyrene (3f; 27 μL, 0.20 mmol,
2.0 equiv), the title compound 4l was obtained after FC (pentane/
EtOAc 5/1) as a white solid (27.0 mg, 0.08 mmol, 83%).
Chromatography: pentane/ethyl acetate 5/1.ield: 76%, pale yellow
1
solid. H NMR (300 MHz, CDCl3): δ 8.28 (d, J = 8.7 Hz, 1H), 8.08
(s, 1H), 7.75 (s, 1H), 7.61 (dd, J = 8.7, 1.9 Hz, 1H), 7.52−7.43 (m,
2H), 7.26 (s, 1H), 7.12−7.04 (m, 2H), 4.56 (q, J = 7.1 Hz, 2H), 3.92
(s, 3H), 2.50 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 165.6, 160.0, 148.8, 146.8, 138.8, 132.3, 130.8, 130.8, 130.0,
128.0, 124.4, 121.3, 114.1, 110.0, 62.2, 55.4, 22.0, 14.4. HRMS (ESI):
calcd for C20H19NO3 + Na+ [M + Na]+ m/z 344.1257, found
344.1247. IR: νmax 2969, 1714, 1610, 1514, 1376, 1247, 1174, 1128,
1110, 1026, 828.
Ethyl 6-Methyl-3,4-diphenylquinoline-2-carboxylate (4m).7a Ac-
cording to the general procedure A using 1a (19.0 mg, 0.10 mmol, 1.0
equiv) and trans-stylbene (3g; 150 μL, 0.80 mmol, 4.0 equiv), the title
compound 4m was obtained after FC (pentane/EtOAc 4/1) as a white
1
solid (11.0 mg, 0.03 mmol, 29%). H NMR (300 MHz, CDCl3): δ
8.18 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 8.6, 1.8 Hz, 1H), 7.34 (s, 1H),
7.33−7.27 (m, 3H), 7.20−7.14 (m, 3H), 7.14−7.05 (m, 3H), 4.12 (q, J
= 7.1 Hz, 2H), 2.44 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 167.5, 150.8, 147.6, 145.2, 138.4, 137.2, 136.1, 132.4,
131.7, 130.3, 130.3, 129.8, 128.0, 127.8, 127.7, 127.7, 127.2, 125.4,
61.8, 22.1, 13.8. HRMS (ESI): calcd for C25H21NO2 + Na+ [M + Na]+
m/z 390.1465, found 390.1465. IR: νmax 3059, 2979, 1735, 1489, 1375,
1303, 1243, 1174, 1109, 1034, 824.
(E)-Ethyl 6-Methyl-4-phenyl-3-styrylquinoline-2-carboxylate
(4n).7a According to the general procedure A using 1a (19.0 mg,
0.10 mmol, 1.0 equiv) and (1E,3E)-1,4-diphenylbuta-1,3-diene (3h;
165 mg, 0.80 mmol, 4.0 equiv), the title compound 4n was obtained
after FC (pentane/EtOAc 10/1) as a yellow oil (17.0 mg, 0.04 mmol,
1
44%). H NMR (300 MHz, CDCl3): δ 8.14 (d, J = 8.6 Hz, 1H), 8.06
(s, 1H), 7.61 (dd, J = 8.6, 1.7 Hz, 1H), 7.46−7.27 (m, 10H), 7.07 (d, J
= 16.7 Hz, 1H), 6.77 (d, J = 16.7 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H),
2.56 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
167.5, 150.7, 145.7, 143.0, 138.5, 138.3, 137.4, 136.7, 132.2, 130.9,
130.3, 130.3, 128.9, 128.6, 128.3, 127.8, 126.8, 126.7, 124.5, 123.4,
61.7, 22.3, 13.8. HRMS (ESI): calcd for C27H23NO2 + H+ [M + Na]+
K
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m/z 394.1802, found 394.1798. IR: νmax 2980, 1732, 1558, 1493, 1372,
1303, 1240, 1155, 1118, 1020, 826, 749, 734, 698.
131.1, 129.0, 128.4, 128.4, 128.1, 128.0, 127.4, 127.0, 126.9, 124.6,
121.8, 62.4, 22.2, 14.6. HRMS (ESI): calcd for C23H19NO2 + H+ [M +
H]+ m/z 342.1489, found 342.1494. IR: νmax 3053, 2981, 1716, 1586,
1503, 1373, 1258, 1222, 1148, 1110, 1027, 821, 748.
Ethyl 3-Ethyl-6-methyl-4-phenylquinoline-2-carboxylate (4o).7a
According to the general procedure A using 1a (19.0 mg, 0.10 mmol,
1.0 equiv) and β-ethylstyrene (3i; 106 mg, 0.80 mmol, 4.0 equiv), the
title compound 4o was obtained after FC (pentane/EtOAc 4/1) as a
white solid (19.0 mg, 0.06 mmol, 58%). 1H NMR (300 MHz, CDCl3):
δ 8.01 (d, J = 8.6 Hz, 1H), 7.56−7.37 (m, 4H), 7.28−7.13 (m, 2H),
6.96 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.31
(s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 167.5, 150.4, 147.8, 144.0, 137.8, 136.5, 132.3,
131.5, 129.3, 129.2, 128.5, 128.4, 128.0, 124.9, 62.0, 23.0, 21.9, 15.8,
14.2. HRMS (ESI): calcd for C21H21NO2 + H+ [M + H]+ m/z
320.1645, found 320.1647. IR: νmax 2989, 1707, 1625, 1570, 1479,
1355, 1300, 1244, 1186, 1152, 1070, 1043, 878, 820, 750, 706.
Ethyl 4-Hexyl-6-methylquinoline-2-carboxylate (4p).7a According
to the general procedure A using 1a (19.0 mg, 0.10 mmol, 1.0 equiv)
and 1-octene (3j; 32 μL, 0.20 mmol, 2.0 equiv), the title compound 4p
was obtained after FC (pentane/EtOAc 5/1) as a white solid (20.0
mg, 0.07 mmol, 66%). According to the general procedure B using 5a
(21.4 mg, 0.2 mmol, 1.0 equiv) and 1-octene (3j; 157.0 μL, 1.0 mmol,
5.0 equiv), the title compound 4p was obtained after FC (pentane/
Ethyl 3,6-Dimethyl-4-phenylquinoline-2-carboxylate (4t).14 Ac-
cording to the general procedure B using 4-methylaniline (5a; 21.4
mg, 0.2 mmol, 1.0 equiv) and cis-β-methylstyrene (3m; 129.9 μL, 1.0
mmol, 5.0 equiv), the title compound 4t was obtained after FC
(pentane/EtOAc 10/1) as a pale red solid (29.1 mg, 0.10 mmol, 50%).
1H NMR (300 MHz, CDCl3): δ 8.07 (d, J = 8.6 Hz, 1H), 7.57−7.45
(m, 4H), 7.25−7.20 (m, 2H), 7.10 (s, 1H), 4.53 (q, J = 7.1 Hz, 2H),
2.38 (s, 3H), 2.29 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 167.6, 150.6, 148.0, 144.4, 138.0, 137.0, 131.4, 129.7,
129.3, 128.8, 128.30, 128.1, 126.4, 124.8, 62.1, 22.0, 17.0, 14.4. HRMS
(ESI): calcd for C20H19NO2 + H+ [M + H]+ m/z 306.1489, found
306.1499. IR: νmax 2987, 1713, 1626, 1568, 1489, 1367, 1299, 1246,
1191, 1154, 1073, 1044, 876, 822, 746, 704.
Ethyl 2-Methyl-7,8,9,10-tetrahydro-7,10-methanophenanthri-
dine-6-carboxylate (4u). According to the general procedure B
using 4-methylaniline (5a; 21.4 mg, 0.20 mmol, 1.0 equiv) and
norbornene (3n; 75 mg, 0.8 mmol, 4.0 equiv), the title compound 4v
was obtained after FC (pentane/EtOAc 4/1) as a white solid (27.7
mg, 0.05 mmol, 49%). 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.8
Hz, 1H), 7.73−7.64 (m, 1H), 7.50 (dd, J = 8.8, 2.0 Hz, 1H), 4.53 (td, J
= 7.1, 2.1 Hz, 2H), 2.56 (s, 4H), 2.15−2.04 (m, 2H), 1.85 (dt, J = 9.0,
2.0 Hz, 1H), 1.68 (dt, J = 9.0, 1.4 Hz, 1H), 1.49 (t, J = 7.1 Hz, 3H),
1.33−1.26 (m, 1H), 1.17−1.09 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 166.3, 155.8, 145.4, 141.4, 141.0, 138.1, 131.6, 131.0, 124.4,
122.3, 61.9, 49.6, 43.6, 41.3, 26.9, 25.8, 22.1, 14.6. HRMS (ESI): calcd
for C18H19NO2 + H+ [M + H]+ m/z 282.1489, found 282.1494. IR:
νmax 2956, 2873, 1712, 1447, 1304, 1240, 1195, 1075, 1037, 820.
Ethyl 8-Methyl-4-phenylquinoline-2-carboxylate (4v).7a Accord-
ing to the general procedure A using 1l (19.0 mg, 0.10 mmol, 1.0
equiv) and styrene (3a; 23 μL, 0.2 mmol, 2.0 equiv), the title
compound 4w was obtained after FC (pentane/EtOAc 10/1 → 4/1)
1
EtOAc 10/1) as a pale yellow oil (21.6 mg, 0.07 mmol, 36%). H
NMR (300 MHz, CDCl3): δ 8.19 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H),
7.80 (s, 1H), 7.58 (dd, J = 8.7, 1.8 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H),
3.09 (dd, J = 8.0, 7.7 Hz, 2H), 2.58 (s, 3H), 1.86−1.63 (m, 2H), 1.49
(t, J = 7.1 Hz, 3H), 1.55−1.40 (m, 2H), 1.39−1.27 (m, 4H), 0.96−
0.84 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 165.9, 149.4, 147.0,
146.3, 138.4, 131.93, 131.2, 128.6, 122.3, 120.6, 62.1, 32.3, 31.6, 29.9,
29.3, 22.6, 22.1, 14.4, 14.1. HRMS (ESI): calcd for C19H25NO2 + H+
[M + H]+ m/z 300.1958, found 300.1959. IR: νmax 2929, 2859, 1718,
1591, 1446, 1372, 1318, 1283, 1246, 1215, 1168, 1110, 1078, 1023,
936, 896, 825, 793, 705.
Ethyl 6-Methylquinoline-2-carboxylate (4q).7a According to the
general procedure A using 1a (19.0 mg, 0.10 mmol, 1.0 equiv) and
ethyl vinyl ether (3k; 20 μL, 0.20 mmol, 2.0 equiv), the title
compound 4q was obtained after FC (pentane/EtOAc 5/1) as a white
1
as a white solid (11 mg, 0.04 mmol, 38%). H NMR (400 MHz,
CDCl3): δ 8.10 (s, 1H), 7.79 (dd, J = 8.5, 0.6 Hz, 1H), 7.69−7.60 (dt,
J = 6.9, 1.1 Hz, 1H), 7.56−7.44 (m, 6H), 4.53 (q, J = 7.1 Hz, 2H), 2.95
(s, 3H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
165.9, 150.0, 147.5, 146.7, 139.3, 138.2, 130.2, 129.8, 128.7, 128.7,
128.4, 127.9, 123.8, 121.2, 62.1, 18.4, 14.5. HRMS (ESI): calcd for
C19H17NO2 + Na+ [M + Na]+ m/z 314.1151, found 314.1152. IR: νmax
2925, 1706, 1444, 1373, 1252, 1129, 1115, 1035, 768, 706.
Diethyl 6,6′-(2-Ethoxy-2-oxoethane-1,1-diyl)bis(8-methyl-4-phe-
nylquinoline-2-carboxylate) (12).7a Brown oil (15 mg, 0.02 mmol,
23%). 1H NMR (300 MHz, CDCl3): δ 8.08 (s, 2H), 7.66 (s, 2H), 7.55
(s, 2H), 7.47−7.37 (m, 10H), 5.15 (s, 1H), 4.52 (q, J = 7.1 Hz, 4H),
4.14 (q, J = 7.1 Hz, 2H), 2.88 (s, 6H), 1.48 (t, J = 7.1 Hz, 6H), 1.13 (t,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.5, 165.7, 149.7,
146.8, 139.7, 138.0, 137.8, 130.8, 129.6, 128.6, 128.6, 127.6, 123.2,
121.4, 62.0, 61.6, 57.5, 18.4, 14.4, 14.0. HRMS (ESI): calcd for
C42H38N2O6 + Na+ [M + Na]+ m/z 689.2622, found 689.2628. IR:
νmax 2980, 1734, 1713, 1488, 1464, 1443, 1377, 1246, 1151, 1117,
1026, 765, 701.
1
solid (13.8 mg, 0.07 mmol, 64%). H NMR (300 MHz, CDCl3): δ
8.20 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.66−7.58 (m, 1H),
4.55 (q, J = 7.1 Hz, 1H), 2.56 (s, 2H), 1.49 (t, J = 7.1 Hz, 2H). 13C
NMR (75 MHz, CDCl3): δ 165.5, 147.3, 146.2, 138.9, 136.5, 132.6,
130.4, 129.4, 126.3, 121.1, 62.2, 21.8, 14.4. HRMS (ESI): calcd for
C13H13NO2 + Na+ [M + Na]+ m/z 238.0838, found 238.0833. IR: νmax
2973, 2929, 2871, 1717, 1444, 1371, 1318, 1295, 1249, 1214, 1133,
1104, 826.
Ethyl 6-Fluoro-4-phenylquinoline-2-carboxylate (4r). According
to the general procedure B using 4-fluoroaniline (5h; 19 μL, 0.2 mmol,
1.0 equiv) and styrene (3a; 46 μL, 0.4 mmol, 2.0 equiv), the title
compound 4r was obtained after FC (pentane/EtOAc 5/1) as an
orange solid (34.3 mg, 0.12 mmol, 60%). 1H NMR (300 MHz,
CDCl3): δ 8.40−8.35 (m, 1H), 8.15 (s, 1H), 7.58−7.49 (m, 7H), 4.56
(q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 165.4, 162.0 (d, J = 251.1 Hz), 149.4 (d, J = 6.0 Hz), 147.4
(d, J = 2.9 Hz), 145.4, 137.2, 133.9 (d, J = 9.5 Hz), 129.5, 129.1, 129.0,
129.0 (d, J = 3.6 Hz), 121.9, 120.6 (d, J = 26.1 Hz), 109.3 (d, J = 23.3
Hz), 62.5, 14.5. 19F NMR (282 MHz, CDCl3): δ −109.0. HRMS
(ESI): calcd for C18H14FNO2 + Na+ [M + Na]+ m/z 318.0901, found
318.0887. IR: νmax 3053, 2986, 2920, 1714, 1624, 1494, 1464, 1377,
1353, 1249, 1230, 1194, 1137, 1102, 1029, 906, 872, 835, 789, 756,
702.
Ethyl 4-(2-Naphthyl)-6-methylquinoline-2-carboxylate (4s). Ac-
cording to the general procedure B using 4-methylaniline (5a; 21.4
mg, 0.20 mmol, 1.0 equiv) and 2-vinylnaphthalene (3l; 61.7 mg, 0.4
mmol, 2.0 equiv), the title compound 4s was obtained after FC
(pentane/EtOAc 4/1) as a white solid (40.5 mg, 0.12 mmol, 60%). 1H
NMR (400 MHz, CDCl3): δ 8.30 (d, J = 8.7 Hz, 1H), 8.20 (s, 1H),
8.06−7.99 (m, 2H), 7.96 (dddd, J = 8.8, 7.3, 4.1, 1.9 Hz, 2H), 7.75−
7.72 (m, 1H), 7.66−7.62 (m, 2H), 7.62−7.56 (m, 2H), 4.58 (q, J = 7.1
Hz, 2H), 2.48 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 165.8, 149.1, 147.1, 147.0, 139.2, 135.4, 133.4, 133.2, 132.5,
Ethyl 6-(2-Ethoxy-1-(4-((2-ethoxy-2-oxoethyl)amino)-3-methyl-
phenyl)-2-oxoethyl)-8-methyl-4-phenylquinoline-2-carboxylate
6
a
1
(13). . Brown solid (2.7 mg, 0.005 mmol, 5%). H NMR (400 MHz,
CDCl3): δ 8.07 (s, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.59 (s, 1H), 7.53−
7.47 (m, 5H), 7.01 (m, 2H), 6.40 (d, J = 8.2 Hz, 1H), 4.95 (s, 1H),
4.51 (q, J = 7.1 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.16 (dd, J = 7.1, 0.9
Hz, 2H), 3.91 (s, 2H), 2.88 (s, 3H), 2.16 (s, 3H), 1.48 (t, J = 7.1 Hz,
3H), 1.30 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). HRMS (ESI):
calcd for C34H36N2O6 + Na+ [M + Na]+ m/z 591.2466, found
591.2464.
General Procedure for the Synthesis of N-Ethyl Acetate
Substituted Anilines 1.27 In an ordinary vial equipped with a
magnetic stirring bar, aniline 5 (1.0 equiv), ethyl bromoacetate (1.0
equiv), sodium acetate (1.0 equiv), and ethanol (6.6 M) were added.
After the reaction mixture was stirred at 85−90 °C overnight, the
solvent was removed in vacuo. The residue was dissolved in DCM and
L
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washed with saturated NaCl (aqueous), the aqueous layer was washed
two times with DCM, and the combined organic layers were dried
over MgSO4. Finally, the residue was purified by column
chromatography.
νmax 3391, 2990, 1727, 1616, 1538, 1320, 1222, 1191, 1146, 1095,
1064, 831, 812.
Ethyl 2-((4-Acetylphenyl)amino)acetate (1f). Following the
general procedure, 1-(4-aminophenyl)ethanone (338 mg, 2.50 mmol,
1.0 equiv) was treated with ethyl bromoacetate (276 μL, 2.50 mmol,
1.0 equiv) and sodium acetate (205 mg, 2.50 mmol, 1.0 equiv) in
ethanol (0.4 mL). 1f was isolated by column chromatography
(pentane/EtOAc: gradient 20/1 to 2/1) as a white solid (273 mg,
Ethyl 2-((4-Methylphenyl)amino)acetate (1a). Following the
general procedure, p-toluidine (5a; 1.07 g, 10.0 mmol, 1.0 equiv)
was treated with ethyl bromoacetate (1.1 mL, 10.0 mmol, 1.0 equiv)
and sodium acetate (900 mg, 10.0 mmol, 1.0 equiv) in ethanol (1.5
mL). 1a was isolated by column chromatography (pentane/EtOAc:
1
1.23 mmol, 49%). H NMR (400 MHz, CDCl3): δ 7.87−7.80 (m,
1
gradient 30/1 to 6/1) as a white solid (1.70 g, 8.8 mmol, 88%). H
2H), 6.60−6.53 (m, 2H), 4.27 (br s, 1H), 4.27 (q, J = 7.1 Hz, 2H),
3.95 (s, 2H), 2.50 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 196.6, 170.4, 150.9, 130.9 (2C), 127.7, 111.9 (2C),
61.8, 45.2, 26.2, 14.3. HRMS (ESI+): calcd for C12H15NO3 + Na+ [M
+ Na]+ m/z 244.0944, found 244.0947. IR: νmax 3370, 2977, 1718,
1668, 1528, 1528, 1350, 1272, 1251, 1174, 1018, 952, 836, 805.
Ethyl 2-((4-Cyanophenyl)amino)acetate (1g). Following the
general procedure, 4-aminobenzonitrile (590 mg, 5.0 mmol, 1.0
equiv) was treated with ethyl bromoacetate (553 μL, 5.0 mmol, 1.0
equiv) and sodium acetate (410 mg, 5.0 mmol, 1.0 equiv) in ethanol
(0.75 mL). 1g was isolated by column chromatography (pentane/
EtOAc: gradient 20/1 to 2/1) as a white solid (347 mg, 1.7 mmol,
34%). 1H NMR (400 MHz, CDCl3): δ 7.47−7.42 (m, 2H), 6.63−6.48
(m, 2H), 4.82 (br s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 1.31
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 170.1, 150.1,
133.9 (2C), 120.3, 112.6 (2C), 100.1, 62.0, 45.0, 14.3. HRMS (ESI+):
calcd for C11H12N2O2 + Na+ [M + Na]+ m/z 227.0791, found
227.0790. IR: νmax 3375, 2997, 2213, 1723, 1603, 1523, 1378, 1227,
1175, 1021, 832, 816.
NMR (300 MHz, CDCl3): δ 6.83−6.74 (m, 2H), 6.62−6.55 (m, 2H),
4.23 (q, J = 7.1 Hz, 2H), 3.86 (s, 2H), 3.74 (s, 3H), 1.29 (t, J = 7.1 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 171.5, 152.8, 141.4, 115.0 (2C),
114.5 (2C), 61.4, 55.9, 47.0, 14.3. HRMS (ESI+): calcd for
C11H15NO2 + Na+ [M + Na]+ m/z 216.0995 found 216.0997. IR:
νmax 3379, 2980, 2897, 2861, 1725, 1619, 1524, 1450, 1366, 1325,
1216, 1182, 1031, 807.
Ethyl 2-((4-Chlorophenyl)amino)acetate (1b). Following the
general procedure, 4-chloroaniline (1.27 g, 10.00 mmol, 1.0 equiv)
was treated with ethyl bromoacetate (1.1 mL, 10.00 mmol, 1.0 equiv)
and sodium acetate (900 mg, 10.00 mmol, 1.0 equiv) in ethanol (1.5
mL). 1b was isolated by column chromatography (pentane/EtOAc:
gradient 20/1 to 6/1) as a white solid (780 mg, 3.65 mmol, 37%). 1H
NMR (300 MHz, CDCl3): δ 7.20−7.09 (m, 2H), 6.59−6.45 (m, 2H),
4.26 (br s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 1.30 (t, J = 7.2
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 170.9, 145.7, 129.3 (2C),
123.1, 114.3 (2C), 61.6, 46.1, 14.3. HRMS (ESI+): calcd for
C10H12ClNO2 + Na+ [M + Na]+ m/z 236.0449, found 236.0429. IR:
νmax 3377, 3001, 2989, 1730, 1606, 1506, 1450, 1347, 1220, 1179,
1094, 1024, 823, 803.
Ethyl 2-((4-Bromophenyl)amino)acetate (1c). Following the
general procedure, 4-bromoaniline (1.72 g, 10.00 mmol, 1.0 equiv)
was treated with ethyl bromoacetate (1.1 mL, 10.00 mmol, 1.0 equiv)
and sodium acetate (900 mg, 10.00 mmol, 1.0 equiv) in ethanol (1.5
mL). 1c was isolated by column chromatography (pentane/EtOAc:
gradient 20/1 to 5/1) as a white solid (850 mg, 3.29 mmol, 33%). 1H
NMR (300 MHz, CDCl3): δ 7.24 (dd, J = 8.9, 1.0 Hz, 2H), 6.46 (d, J
= 8.7 Hz, 2H), 4.25 (br s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H),
1.26 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 170.9, 146.1,
132.2 (2C), 114.8 (2C), 110.2, 61.6, 46.0, 14.3. HRMS (ESI+): calcd
for C10H12BrNO2 + Na+ [M + Na]+ m/z 279.9944, found 279.9942.
IR: νmax 3375, 3050, 3000, 2984, 1718, 1600, 1502, 1449, 1371, 1346,
1225, 1180, 1071, 1022, 815, 802.
Ethyl 4-((2-Ethoxy-2-oxoethyl)amino)benzoate (1h). Following
the general procedure, ethyl 4-aminobenzoate (413 mg, 2.50 mmol,
1.0 equiv) was treated with ethyl bromoacetate (280 μL, 2.50 mmol,
1.0 equiv) and sodium acetate (205 mg, 2.50 mmol, 1.0 equiv) in
ethanol (10 mL). 1h was isolated by column chromatography
(pentane/EtOAc: gradient 20/1 to 4/1) as a white solid (184 mg,
1
0.73 mmol, 29%). H NMR (300 MHz, CDCl3): δ 7.94−7.82 (m,
2H), 6.61−6.49 (m, 2H), 4.77 (s, 1H), 4.28 (dq, J = 16.7, 7.1 Hz, 4H),
3.93 (s, 2H), 1.35 (t, J = 7. Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 170.5, 166.8, 150.7, 131.6 (2C), 119.7,
111.8 (2C), 61.7, 60.4, 45.2, 14.5, 14.3. HRMS (ESI+): calcd for
C13H17NO4 + Na+ [M + Na]+ m/z 274.1050, found 274.1055. IR: νmax
3376, 2985, 1737, 1682, 1602, 1527, 1449, 1277, 1228, 1175, 1107,
1021, 845, 771.
Ethyl 2-((4-Methoxyphenyl)amino)acetate (1i). Following the
general procedure, 4-methoxyaniline (616 mg, 5.00 mmol, 1.0
equiv) was treated with ethyl bromoacetate (554 μL, 5.00 mmol, 1.0
equiv) and sodium acetate (410 mg, 5.00 mmol, 1.0 equiv) in ethanol
(10 mL). 1i was isolated by column chromatography (pentane/
EtOAc: gradient 20/1 to 2/1) as a white solid (888 mg, 4.25 mmol,
85%). 1H NMR (300 MHz, CDCl3): δ 7.10−6.92 (m, 2H), 6.63−6.48
(m, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.16 (br s, 1H), 3.89 (s, 2H), 2.26
(s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
171.4, 144.9, 129.9 (2C), 127.5, 113.3 (2C), 61.3, 46.3, 20.5, 14.3.
HRMS (ESI+): calcd for C11H15NO3 + Na+ [M + Na]+ m/z 232.0944,
found 232.0947. IR: νmax 3382, 2989, 2941, 1727, 1514, 1439, 1371,
1266, 1210, 1144, 1023, 821.
Ethyl 2-((4-Fluorophenyl)amino)acetate (1d). Following the
general procedure, 4-fluoroaniline (480 μL, 5.00 mmol, 1.0 equiv)
was treated with ethyl bromoacetate (554 μL, 5.00 mmol, 1.0 equiv)
and sodium acetate (410 mg, 5.00 mmol, 1.0 equiv) in ethanol (10
mL). 1d was isolated by column chromatography (pentane/EtOAc:
gradient 10/1 to 4/1) as a pale orange solid (619.5 mg, 3.14 mmol,
63%). 1H NMR (300 MHz, CDCl3): δ 6.99−6.81 (m, 2H), 6.62−6.47
(m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.18 (br s, 1H), 3.86 (s, 2H), 1.29
(t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.2, 156.3 (d, 1J
= 235.7 Hz), 143.52 (d, J = 1.8 Hz), 115.9 (d, J = 22.4 Hz, 2C),
114.0 (d, 3J = 7.5 Hz), 61.5, 46.6, 14.3. 19F NMR (282 MHz, CDCl3):
δ −127.22. HRMS (ESI+): calcd for C10H12FNO2 + Na+ [M + Na]+
m/z 220.0744, found 220.0738. IR: νmax 3382, 2993, 1724, 1511, 1450,
1369, 1349, 1255, 1206, 1144, 1025, 815, 783.
4
2
Ethyl 2-([1,1′-Biphenyl]-4-ylamino)acetate (1j). Following the
general procedure, [1,1′-biphenyl]-4-amine (425 mg, 2.50 mmol, 1.0
equiv) was treated with ethyl bromoacetate (280 μL, 2.50 mmol, 1.0
equiv) and sodium acetate (205 mg, 2.50 mmol, 1.0 equiv) in ethanol
(10 mL). 1j was isolated by column chromatography (pentane/
EtOAc: gradient 10/1 to 4/1) as an orange solid (469.3 mg, 1.83
Ethyl 2-((4-(Trifluoromethyl)phenyl)amino)acetate (1e). Follow-
ing the general procedure, 4-(trifluoromethyl)aniline (403 mg, 2.50
mmol, 1.0 equiv) was treated with ethyl bromoacetate (276 μL, 2.50
mmol, 1.0 equiv) and sodium acetate (205 mg, 2.50 mmol, 1.0 equiv)
in ethanol (0.4 mL). 1e was isolated by column chromatography
(pentane/EtOAc: gradient 10/1 to 3/1) as a white solid (375.5 mg,
1
mmol, 73%). H NMR (300 MHz, CDCl3): δ 7.58−7.51 (m, 2H),
1
7.50−7.44 (m, 2H), 7.44−7.36 (m, 2H), 7.33−7.21 (m, 1H), 6.77−
6.63 (m, 2H), 4.38 (br s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H),
1.32 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.2, 146.5,
141.2, 131.3, 129.0, 128.9, 128.8, 128.2, 127.2, 126.5, 126.3, 122.2,
113.4, 61.6, 46.0, 14.4. HRMS (ESI+): calcd for C16H17NO2 + Na+ [M
+ Na]+ m/z 278.1151, found 278.1148. IR: νmax 3389, 3058, 2985,
2906, 1727, 1611, 1531, 1492, 1438, 1375, 1254, 1202, 1026, 824, 754.
1.52 mmol, 61%). H NMR (300 MHz, CDCl3): δ 7.35 (dd, J = 8.6,
1.0 Hz, 2H), 6.53 (dd, J = 8.6, 1.0 Hz, 2H), 4.56 (br s, 1H), 4.19 (q, J
= 7.1 Hz, 2H), 3.85 (s, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 170.6, 149.5, 126.8 (q, 3J = 3.8 Hz, 2C), 121,4 (q, 1J
= 271.0 Hz), 119.8 (q, 2J = 32.6 Hz), 112.2 (2C), 61.8, 45.3, 14.3. 19
F
NMR (282 MHz, CDCl3): δ −61.18. HRMS (ESI+): calcd for
C11H12F3NO2 + Na+ [M + Na]+ m/z 270.0712, found 270.0710. IR:
M
dx.doi.org/10.1021/jo4007199 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Ethyl 2-((3,5-Dimethylphenyl)amino)acetate (1k). Following the
general procedure, 3,5-dimethylaniline (0.31 mL, 2.5 mmol, 1.0 equiv)
was treated with ethyl bromoacetate (276 μL, 2.5 mmol, 1.0 equiv)
and sodium acetate (205 mg, 2.5 mmol, 1.0 equiv) in ethanol (0.4
mL). 1k was isolated by column chromatography (pentane/EtOAc:
gradient 20/1 to 4/1) as a white solid (400 mg, 1.93 mmol, 77%). 1H
NMR (400 MHz, CDCl3): δ 6.43 (dt, J = 1.5, 0.8 Hz, 1H), 6.27 (dd, J
= 1.3, 0.7 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H + br s, 1H), 3.89 (s, 2H),
2.25 (d, J = 0.7 Hz, 6H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 171.3, 147.1, 139.1 (2C), 120.5, 111.3 (2C), 61.4,
46.2, 21.6 (2C), 14.3. HRMS (ESI+): calcd for C12H17NO2 + Na+ [M
+ Na]+ m/z 230.1151, found 230.1151. IR: νmax 3377, 2987, 2917,
1732, 1601, 1520, 1474, 1442, 1382, 1367, 1354, 1212, 1195, 1027,
812.
ASSOCIATED CONTENT
* Supporting Information
Figures giving NMR spectra of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*O.G.M.: tel, +49 251 83 33239; fax, +49 251 83 33202; e-mail,
olga.garcia@uni-muenster.de.
■
Notes
The authors declare no competing financial interest.
Ethyl 2-(o-Tolylamino)acetate (1l). Following the general
procedure, o-toluidine (536 μL, 5.0 mmol, 1.0 equiv) was treated
with ethyl bromoacetate (553 μL, 5.0 mmol, 1.0 equiv) and sodium
acetate (410 mg, 5.0 mmol, 1.0 equiv) in ethanol (0.75 mL). 1l was
isolated by column chromatography (pentane/EtOAc: gradient 30/1
ACKNOWLEDGMENTS
■
The Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie, and Prof. Frank Glorius are gratefully
acknowledged for generous support. R.R. thanks the WWU
1
Munster within a Bonus-Program for a predoctoral contract.
̈
to 10/1) as a white solid (970 mg, 5.0 mmol, 99%). H NMR (300
MHz, CDCl3): δ 7.12 (dd, J = 16.8, 8.8 Hz, 2H), 6.71 (t, J = 7.3 Hz,
1H), 6.49 (d, J = 8.4 Hz, 1H), 4.27 (br s. 1H), 4.27 (q, J = 7.1 Hz,
2H), 3.95 (s, 2H), 2.22 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 171.4, 145.2, 130.4, 127.3, 122.7, 117.9, 110.0, 61.5,
46.1, 17.5, 14.3. HRMS (ESI+): calcd for C11H15NO2 + Na+ [M +
Na]+ m/z 216.0995, found 216.0998. IR: νmax 3423, 2981, 1737, 1607,
1587, 1515, 1453, 1372, 1348, 1207, 1152, 1024, 746.
REFERENCES
■
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Ethyl 2-((2-Methoxyphenyl)amino)acetate (1m). Following the
general procedure, 2-methoxyaniline (0.28 mL, 2.5 mmol, 1.0 equiv)
was treated with ethyl bromoacetate (276 μL, 2.5 mmol, 1.0 equiv)
and sodium acetate (205 mg, 2.5 mmol, 1.0 equiv) in ethanol (0.4
mL). 1m was isolated by column chromatography (pentane/EtOAc:
1
gradient 20/1 to 2/1) as a white solid (418 mg, 2.0 mmol, 80%). H
NMR (300 MHz, CDCl3): δ 6.86 (td, J = 7.5, 1.6 Hz, 1H), 6.79 (dd, J
= 8.0, 1.6 Hz, 1H), 6.71 (ddd, J = 8.0, 7.3, 1.6 Hz, 1H), 4.93 (br s,
1H), 4.24 (q, J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.86 (s, 3H), 1.30 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.3, 147.3, 137.2,
121.3, 117.6, 110.1, 109.8, 61.4, 55.6, 45.9, 14.4. HRMS (ESI+): calcd
for C11H15NO3 + Na+ [M + Na]+ m/z 232.0944, found 232.0945. IR:
νmax 3370, 2981, 2842, 1727, 1607, 1569, 1500, 1448, 1325, 1255,
1199, 1054, 1032, 761.
Ethyl 2-((3-Methoxyphenyl)amino)acetate (1n). Following the
general procedure, 3-methoxyaniline (0.28 mL, 2.5 mmol, 1.0 equiv)
was treated with ethyl bromoacetate (276 μL, 2.5 mmol, 1.0 equiv)
and sodium acetate (205 mg, 2.5 mmol, 1.0 equiv) in ethanol (0.4
mL). 1n was isolated by column chromatography (pentane/EtOAc:
gradient 20/1 to 2/1) as a white solid (428 mg, 2.05 mmol, 82%). 1H
NMR (300 MHz, CDCl3): δ 7.10 (t, J = 8.1 Hz, 1H), 6.28 (ddd, J =
26.2, 8.1, 2.1 Hz, 2H), 6.16 (t, J = 2.3 Hz, 1H), 4.25 (q, J = 7.1 Hz,
2H), 3.89 (s, 2H), 3.77 (s, 3H + br s, 1H), 1.30 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 171.2, 160.9, 148.5, 130.2, 106.1,
103.5, 99.2, 61.5, 55.2, 45.9, 14.3. HRMS (ESI+): calcd for C11H15NO3
+ Na+ [M + Na]+ m/z 232.0944, found 232.0941. IR: νmax 3372, 2977,
2936, 2837, 1728, 1609, 1579, 1497, 1452, 1369, 1323, 1276, 1258,
1201, 1168, 1050, 1030, 845, 758.
R.; García Mancheno, O. Synlett 2013, 24, 6 and references cited
̃
therein.
(4) Reviews on N-oxoammonium chemistry: (a) Bobbitt, J. M.;
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Bruckner, C.; Merbouh, N. Oxoammonium- and nitroxide-catalyzed
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̈
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(5) (a) Richter, H.; Garcıa Mancheno, O. Eur. J. Org. Chem. 2010,
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̃
Ethyl 2-(m-Tolylamino)acetate (1o). Following the general
procedure, m-toluidine (536 μL, 5.0 mmol, 1.0 equiv) was treated
with ethyl bromoacetate (553 μL, 5.0 mmol, 1.0 equiv) and sodium
acetate (410 mg, 5.0 mmol, 1.0 equiv) in ethanol (0.75 mL). 1o was
isolated by column chromatography (pentane/EtOAc: gradient 20/1
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(6) Richter, H.; Frohlich, R.; Daniluic, C.-G.; García Mancheno, O.
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̈
̃
́
̃
For other uses of glycines and N-alkylanilines in CDC, see for
example: (b) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075.
(c) Li, H.; He, Z.; Guo, X.; Li, W.; Zhao, X.; Li, Z. Org. Lett. 2009, 11,
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(e) Han, W.; Mayer, P.; Ofial, A. R. Adv. Synth. Catal. 2010, 352, 1667.
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(a) Foster, B. A.; Coffrey, H. A.; Morin, M. J.; Rastinejad, F. Science
1
to 2/1) as a white solid (690 mg, 3.6 mmol, 71%). H NMR (300
MHz, CDCl3): δ 7.18−7.00 (m, 1H), 6.65−6.55 (m, 1H), 6.44 (dd, J
= 9.2, 1.9 Hz, 2H), 4.26 (q, J = 7.2 Hz, 3H + br s, 1H), 3.90 (s, 2H),
2.30 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
171.3, 147.2, 139.2, 129.3, 119.2, 113.9, 110.2, 61.4, 46.0, 21.7, 14.3.
HRMS (ESI+): calcd for C11H15NO2 + Na+ [M + Na]+ m/z 216.0995
found 216.0993. IR: νmax 3383, 2982, 1729, 1617, 1600, 1587, 1519,
1496, 1448, 1364, 1349, 1333, 1260, 1218, 1030, 866, 766.
N
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Article
1999, 286, 2507. (b) Lewerenz, A.; Hentschel, S.; Vissiennon, Z.;
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́
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̈
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byproduct in the reaction under an O2 atmosphere (1 atm) in 10−20%
yield. Its structure and analytical data are shown below. Ethyl 2-(5-
1
methyl-2,3-dioxoindolin-1-yl)acetate: H NMR (300 MHz, CDCl3): δ
7.50−7.42 (m, 1H), 7.39 (ddd, J = 8.1, 1.9, 0.9 Hz, 1H), 6.68 (d, J =
8.0 Hz, 1H), 4.46 (s, 2H), 4.24 (q, J = 7. Hz, 2H), 2.34 (s, 3H), 1.28
(t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 182.9, 167.0,
158.4, 148.3, 139.0, 134.2, 126.1, 117.8, 110.0, 62.3, 41.5, 20.9, 14.3;
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found 270.0739.
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́ ́ ́
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́
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heterocoupling products were obtained (e.g., in the reaction with 1a
and 1d a 2/1/2 mixture of homo-2a, homo-2d, and hetero-2ad was
formed).
́
(18) Multicomponent reactions (MCR): (a) Zhu, J.; Bienayme, H.
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See also: (b) Tietze, L. F. Chem. Rev. 1996, 96, 115. (c) Nicolaou, K.
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O
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