Palladium-catalyzed intermolecular aerobic oxidative cyclization of 2-ethynylanilines with isocyanides: Regioselective synthesis of 4-halo-2-aminoquinolines

Article abstract of DOI:10.1021/jo401707j

A robust and regioselective palladium-catalyzed intermolecular aerobic oxidative cyclization of 2-ethynylanilines with isocyanides to the synthesis of 4-halo-2-aminoquinolines is reported herein. The procedure constructs various 4-halo-2-aminoquinolines w

Full text of DOI:10.1021/jo401707j

Article
pubs.acs.org/joc
Palladium-Catalyzed Intermolecular Aerobic Oxidative Cyclization of
2‑Ethynylanilines with Isocyanides: Regioselective Synthesis of
4‑Halo-2-aminoquinolines
Bifu Liu, Hanling Gao, Yue Yu, Wanqing Wu, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong 510640, PR China
S
* Supporting Information
ABSTRACT: A robust and regioselective palladium-catalyzed
intermolecular aerobic oxidative cyclization of 2-ethynylani-
lines with isocyanides to the synthesis of 4-halo-2-amino-
quinolines is reported herein. The procedure constructs
various 4-halo-2-aminoquinolines with moderate to excellent
yields (47−94%) and broad substrates scope. Furthermore,
this process can be easily extended to synthesis of various 6H-
indolo[2,3-b]quinolines via an intramolecular Buchwald−Hartwig cross-coupling reaction in two-step one-pot manner.
tion.9g,h 2-Ethynylanilines are known to be used widely in the
INTRODUCTION
■
synthesis of substituted indoles,11 so it is straightforward that 3-
The quinoline nucleus is arguably one of the most important
amidylindoles (II) can be prepared via an intramolecular
aminopalladation of 2-ethynylanilines to form the indolylpalla-
substructures present in many natural products and synthetic
drugs with different biological activities.1 Because of their
dium complexes (I), followed by insertion of isocyanides
widespread biological activities, many different strategies for the
preparation of quinolines have been developed. Although
(Scheme 1).9i,j Considering the importance of quinoline
classical methods are widely recognized for the preparation of
Scheme 1. Aminopalladation vs Halopalladation of 2-
Ethynylanilines for the Synthesis of 3-Amidylindoles and 4-
Halo-2-aminoquinolines
quinolines, these syntheses generally involve multiple steps
and/or complex substrates.2 On the other hand, significant
efforts have been made with regard to the modification of
quinolines.3 Despite numerous approaches that have been
developed, the preparation of quinolines bearing different
substituents at specific positions employing readily available
starting materials is still an attractive research area4 since 2-
aminoquinolines are often required by medicinal and material
chemists.5 Nevertheless, the efficient synthesis of 2-amino-
quinoline architectures from easily available raw materials
remains elusive. And only a few examples were developed for
the procedure of 2-aminoquinolines.6 Meanwhile, aromatic
halides are an important class of compounds not only widely
utilized in drug and natural product synthesis,7 but also
providing good opportunities for further formation of C−C
and/or C−heteroatom bonds by transition-metal-catalyzed
compounds and our previous work on the construction of N-
coupling reactions. Thus, the development of simple and
heterocycles involving isocyanides,12 we envisioned that 2-
efficient methods for halo-2-aminoquinolines is highly desirable
because of their great significance.
ethynylanilines could undergo a halopalladation process to give
the vinylpalladium complexes (III), and the subsequent
Isocyanides have been recognized as powerful C1 synthons
in the construction of structurally appealing heteroarenes.8
isocyanides insertion would provide access to highly function-
alized quinolines (IV) in a single step (Scheme 1). As well, 2-
Therefore, it is not surprising that special attention has been
ethynylanilines have also been explored for the preparation of
paid to the insertion of isocyanides into the C−Pd bond in
substituted quinolines.13 Herein, for the first time, we present a
simple and efficient method to the construction of various of 4-
halo-2-aminoquinolines via palladium-catalyzed oxidative inter-
recent years.9 In addition, palladium-catalyzed aerobic oxidation
has drawn wide attention because of its inexpensive and
environmentally benign characteristics, particularly when
molecular oxygen is used as the sole oxidant.10 However,
only few processes utilizing molecular oxygen have been
reported concerning palladium-catalyzed isocyanides inser-
Received: August 4, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
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molecular cyclization of 2-ethynylanilines with isocyanides
using molecular oxygen as the sole oxidant.
the desired 4-chloro-2-aminoquinolines (Table 2, entries 1−
13). As shown in Table 2, aryl substituted (R1) 2-ethynylani-
lines with either an electron-donating or electron-withdrawing
group on the benzene ring were able to undergo cyclization
with tert-butylisocyanide (2a) to afford an array of 4-chloro-2-
aminoquinolines in good to excellent yields (3aa−3ma). The
molecular structure of 3ka was further characterized by X-ray
crystal diffraction measurement.15 It is noted that the ortho-
substituted substrates (1g and 1j) showed slightly lower yields
than the para-substituted ones (Table 2, entries 7−9, 10−11),
which was probably caused by the steric effects. Gratifyingly,
the standard conditions were compatible with the 2-thienyl
group (1n), providing the corresponding product in 87% yield
(entry 14). While either alkyl (entries 15−18) or propargyl
alcohol (entries 19−22) substituted (R1) 2-ethynylanilines were
treated under the same conditions, the corresponding products
were obtained in lower yields to some extent. However, silyl-
and diphenylmethanol-substituted 2-ethynylanilines failed to
give the desired products (entries 17−18 and 22). Furthermore,
we found that the addition of TFA to the reaction mixture
(after the formation of 3aa was completed) and subsequent
heating at 80 °C for further 5 h gave 4-chloro-3-phenyl-
quinolin-2-amine (3wa) in 82% yield (Table 2, entry 23).6b
Encouraged by these initial results, the substrate versatility of
2-ethynylanilines was next examined using different substituents
(R2) on the anilines (Table 3, 4a−4j). The electron-donating 4-
methyl- (4a) and 5-methoxy-substituted (4b) 2-ethynylanilines
were both reacted with 2a under the optimal conditions to
provide 5aa and 5ba in 85 and 92% yields, respectively.
However, the 2-ethynylanilines (4c−4j) with electron-with-
drawing groups (R2) reacted sluggishly with 2a and a higher
reaction temperature was needed. Especially, when 2,6-
dichloro- (4f), -CN (4i) and -COOMe (4j) substituted 2-
ethynylanilines were applied to this transformation, no desired
products were formed even with extended reaction time at 140
°C. Pleasingly, heterocyclic substituted 2-ethynylaniline 4k
efficiently annulated with 2a and afforded 5ka in 83% yield.
Unfortunately, 3-(phenylethynyl)pyridin-2-amine (4l) failed to
afford the desired product 5la. We suspected that the
coordination of the two adjacent nitrogens of 4l with Pd
catalyst might be too strong to catalyze this reaction.12d,e
Moreover, various isocyanides were also applied to probe the
scope and limitations of this approach (Table 3, 2b−2i).
Fortunately, almost all the isocyanides were found compatible
with this transformation, affording the corresponding 4-chloro-
2-aminoquinolines in good to excellent yields (Table 3, 5mb−
5mi). Notably, ethyl isocyanoacetate (2d) was also compatible
for these reaction conditions and gave 5md in 86% yield. In
addition, bromo-substituted 2-ethynylaniline (4n) was also
reacted with various isocyanides (2d−2i) effectively at 140 °C
and afforded the corresponding products (5nd−5ni) in good to
excellent yields. However, when we extended our method to
the synthesis of 4-bromo-2-aminoquinolines under the similar
conditions (Table 1, entry 15), only moderate yields of
corresponding products (6aa−6ea) could be obtained (Scheme
2).16
RESULTS AND DISCUSSION
■
To verify our hypothesis, we began our investigation with 2-
(phenylethynyl)aniline (1a) and tert-butylisocyanide (2a) in
toluene as model substrates catalyzed by PdCl2 (5 mol %) in
the presence of CuCl2 (2.0 equiv). To our delight, N-(tert-
butyl)-4-chloro-3-phenylquinolin-2-amine (3aa) could be
obtained in 35% yield (Table 1, entry 1). Screening various
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
PdCl2
additive (equiv)
oxidant
solvent yield (%)
1
−
−
−
−
−
−
CuCl2
toluene
DMF
35
2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(PPh3)4
Pd(OAc)2
PdI2
CuCl2
13
3
CuCl2
THF
10
4
CuCl2
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
trace
80
5
CuCl2
6
1 atm O2
1 atm O2
1 atm O2
1 atm O2
1 atm N2
1 atm O2
1 atm O2
1 atm O2
1 atm O2
1 atm O2
trace
63
7
LiCl (1)
LiCl (2)
LiCl (2)
LiCl (2)
KI (2)
LiCl (2)
LiCl (2)
LiCl (2)
LiBr (2)
8
83
9
90 (86)
d
10
11
12
13
14
n.d.
d
n.d.
d
n.d.
trace
trace
c
15
PdBr2
57(52)
a
Reaction conditions: Unless otherwise noted, all reactions were
performed with 1a (0.5 mmol), 2a (0.6 mmol), catalyst (5 mol %),
additive, and oxidant (2.0 equiv to 1a) in 2.0 mL of solvent (100 °C
b
for entries 1−8 and 120 °C for entries 9−15) for 12 h. Analyzed by
GC−MS using dodecane as the internal standard. Data in parentheses
c
is isolated yield. 140 °C for 12 h, and 4-bromo-N-(tert-butyl)-3-
d
phenylquinolin-2-amine was obtained. n.d = not detected.
solvents revealed that the solvent played an important role in
this reaction (entries 1−5). Notably, DMSO was identified as
the optimal solvent for the formation of 3aa (entry 5).
Considering our previous work on palladium-catalyzed
oxidation reactions with molecular oxygen as the sole
oxidant,10c CuCl2 was replaced by 1 atm of O2 in this system;
however, only trace amount of 3aa was observed (entry 6). The
yields of 3aa could be increased sharply when LiCl was added
(entries 7−8).14 Importantly, the reaction conducted at 120 °C
for 12 h gave the desired product in 86% isolated yield (entry
9). Further investigation revealed that PdCl2 was superior to
any other palladium catalysts so far tested (entries 11−14).
Additionally, 52% yield of 4-bromo-N-(tert-butyl)-3-phenyl-
quinolin-2-amine was formed when the reaction was performed
with PdBr2 (5 mol %) and 2 equiv of LiBr at 140 °C (entry 15).
With efficient reaction conditions in hand (Table 1, entry 9),
we next surveyed the substrate scope of the reaction by
employing a variety of 2-ethynylanilines (1) (Table 2).
Substituent at the terminal alkynyl (R1) of 2-ethynylanilines
was first evaluated under the standard conditions. The results
demonstrated that the electronic effects on substituted (R1) 2-
ethynylanilines had only a slight influence on the formation of
It is well-known that the tetracyclic indolo[3,2-b]quinoline
ring system exhibits numerous biological activities and found in
many important natural products.17 Procedures for the
synthesis of these scaffolds from readily available starting
materials remained scarcely described in the literature; hence,
the development of simple and general methods for their
preparation still remains a great challenge.18 Having successfully
B
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a
Table 2. Scope of 2-Ethynylanilines (R1) for the Synthesis of 4-Chloro-2-aminoquinolines
a
Reaction conditions: Unless otherwise noted, 1 (0.5 mmol), 2a (0.6 mmol), PdCl2 (5 mol %), LiCl (1.0 mmol), and O2 (1 atm) in 2.0 mL of
b
c
d
DMSO at 120 °C for 12 h. Isolated yield. 140 °C for 12 h. TFA (5 equiv) was added for further 5 h at 80 °C. n.r. = no reaction. n.d. = not
detected.
C
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a
Table 3. Versatility of 2-Ethynylanilines (R2) and Isocyanides for the Synthesis of 4-Chloro-2-aminoquinolines
a
Reaction conditions: Unless otherwise noted, 4 (0.5 mmol), 2 (0.6 mmol), PdCl2 (5 mol %), LiCl (1.0 mmol), and O2 (1 atm) in 2.0 mL of DMSO
b
c
at 120 °C for 12 h. Isolated yield. 140 °C for 12 h. n.r. = no reaction.
D
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Scheme 2. Synthesis of 4-Bromo-2-aminoquinolines
a
Scheme 3. Two-Step One-Pot Synthesis of 11-Chloro-6H-indolo[2,3-b]quinolines
a
Reaction conditions: step (1) 1j (0.5 mmol), 2 (0.6 mmol), PdCl2 (5 mol %), LiCl (2 equiv) in 2 mL of DMSO at 140 °C for 12 h under 1 atm O2;
step (2) Pd2(dba)3 (5 mol %), P(o-tol)3 (10 mol %), and t-BuONa (2 equiv) in 2.0 mL of toluene at 85 °C for 12 h.
Scheme 4. Proposed Mechanism
established the general method for the synthesis of various 4-
halo-2-aminoquinolins, we envisioned that 3-(2-bromophenyl)-
4-chloro-2- aminoquinolins (Table 3, 5nd−5ni) could easily
undergo an intramolecular Buchwald−Hartwig19 cross-coupling
reaction to afford various indolo[3,2-b]quinolines. As expected,
we found that 11-chloro-6H-indolo[2,3-b]quinolines (7a−7e)
could be conveniently prepared in good yields through a one-
pot two-step process (Scheme 3).
On the basis of our previous work on isocyanides and the
influence of the chloride ion concentration in Table 1, we
proposed a plausible mechanism in Scheme 4. Coordination of
PdX2 with the carbon−carbon triple bond affords intermediate
A, followed by trans-halopalladation14 to give intermediate B.
Subsequently, the migratory insertion of isocyanides 2 into the
σ-vinylpalladium intermediate would result in the formation of
intermediate C. Then, the seven-membered azapalladacyclic
intermediate D is formed by the intramolecular annulations of
intermediate C. Finally, reductive elimination affords E, HX,
and Pd(0) species. The Pd(0) species is oxidized to the active
PdX2 species by O2. And the unstable product E would easily
aromatize to give the final product 3.
tantly, this process can be extended to the synthesis of various
6H-indolo[2,3-b]quinolines via an intramolecular Buchwald−
Hartwig cross-coupling reaction in a two-step one-pot manner.
EXPERIMENTAL SECTION
■
General Information. Melting points were measured by a melting
point instrument and were uncorrected. H and 13C NMR spectra
1
were recorded by using a 400 MHz NMR spectrometer. The chemical
shifts are referenced to signals at 7.24 and 77.0 ppm, respectively, and
chloroform is used as a solvent with TMS as the internal standard. IR
spectra were obtained either as potassium bromide pellets or as liquid
films between two potassium bromide pellets with an infrared
spectrometer. GC−MS was obtained using electron ionization. The
data of HRMS was carried out on a high-resolution mass spectrometer
(LCMS-IT-TOF). TLC was performed by using commercially
available 100−400 mesh silica gel plates (GF254). Unless otherwise
noted, all purchased chemicals were used without further purification.
All the 2-ethynylanilines were known compounds and readily prepared
from the reactions of the corresponding 2-iodobenzenamines with
terminal alkynes directly by reported procedures.20
Typical Experimental Procedure for Synthesis of 4-Halo-2-
aminoquinolines. To the mixture of 2-ethynylanilines (1, 0.5
mmol), PdX2 (5 mol %) and LiX (2.0 equiv) in DMSO were added
successively in a test tube. After stirring for 5 min at room
temperature, isocyanide (2, 0.6 mmol) was added, and then the
mixture was stirred at 120−140 °C for 12 h under 1 atm of O2. Upon
completion, the reaction mixture was extracted with ethyl acetate (3 ×
10 mL), and the organic layers were combined, dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The residue
was separated by flash column chromatography (the eluents phases
were Vhexane/VEtOAc = 100:1, and the stationary phases were 300−400
mesh silica gel) to give the pure products 3 (X = Cl) and 5 (X = Br).
CONCLUSION
■
In summary, we have developed a novel and efficient strategy
for the construction of 4-halo-2-aminoquinolines involving Pd-
catalyzed aerobic oxidative annulations of commercially
available isocyanides with readily accessible 2-ethynylanilines.
The reaction exhibits a broad substrate scope and gives various
4-halo-2-aminoquinolines in good to excellent yields. Impor-
E
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N-(tert-Butyl)-4-chloro-3-phenylquinolin-2-amine (3aa). Light
124.5, 122.8, 122.6, 121.0, 52.1, 29.0; HRMS (ESI) m/z calcd for
C19H19Cl2N2 , 345.0920, found 345.0911.
N-(tert-Butyl)-4-chloro-3-(4-chlorophenyl)quinolin-2-amine (3ia).
+
yellow oil (133 mg, 86%): IR (KBr) 3432, 2962, 1605, 1517, 1415,
1
1223, 758, 700; H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz,
1H), 7.77 (d, J = 8.4 Hz, 1H), 7.60−7.47 (m, 4H), 7.35−7.27 (m,
3H), 4.31 (br. s, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
154.4, 147.8, 139.6, 135.2, 129.8, 129.8, 129.3, 128.5, 126.8, 124.4,
124.2, 122.4, 121.1, 51.9, 29.0; HRMS (ESI) m/z calcd for
Light yellow solid (158 mg, 92%): mp 122−124 °C; IR (KBr) 3850,
1
3435, 2922, 2355, 1744, 1605, 1515, 1239, 1050, 758; H NMR (400
MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H),
7.54−7.50 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 3H),
4.14 (br. s, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.1,
147.8, 140.0, 134.7, 133.6, 131.4, 130.0, 129.7, 126.9, 124.4, 123.0,
+
C19H20ClN2 , 311.1310, found 311.1306.
N-(tert-Butyl)-4-chloro-3-(4-methoxyphenyl)quinolin-2-amine
+
(3ba). White solid (155 mg, 91%): mp 132−134 °C; IR (KBr) 3429,
122.6, 121.0, 52.1, 29.0; HRMS (ESI) m/z calcd for C19H19Cl2N2 ,
1
2960, 1598, 1515, 1415, 1245, 757; H NMR (400 MHz, CDCl3) δ
345.0920, found 345.0914.
7.98 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.53−7.50 (m, 1H),
7.20 (d, J = 7.2 Hz, 3H), 7.02 (d, J = 7.2 Hz, 2H), 4.34 (br. s, 1H),
3.84 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 159.6,
154.8, 147.7, 139.9, 131.1, 129.7, 127.1, 126.7, 124.4, 124.0, 122.3,
121.2, 114.8, 55.2, 51.8, 29.0; HRMS (ESI) m/z calcd for
C20H22ClN2O+, 341.1415, found 341.1424.
3-(2-Bromophenyl)-N-(tert-butyl)-4-chloroquinolin-2-amine
(3ja). White solid (163 mg, 84%): mp 138−140 °C IR (KBr) 3438,
1
2960, 2918, 1763, 1609, 1517, 1414, 1242, 1048, 761; H NMR (400
MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H),
7.59−7.55 (m, 1H), 7.50−7.46 (m, 1H), 7.36−7.32 (m, 1H), 7.29−
7.25 (m, 2H), 4.00 (br. s, 1H), 1.44 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 153.7, 148.0, 140.3, 136.1, 133.5, 131.9, 130.4, 130.1, 128.4,
126.9, 124.4, 124.3, 123.5, 122.5, 120.9, 52.0, 29.0; HRMS (ESI) m/z
N-(tert-Butyl)-4-chloro-3-(p-tolyl)quinolin-2-amine (3ca). White
solid (141 mg, 87%): mp 116−118 °C; IR (KBr) 3431, 2962, 1602,
1517, 1415, 1222, 811, 756; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J
= 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.55−7.51 (m, 1H), 7.32 (d, J
= 7.6 Hz, 2H), 7.26−7.22 (m, 1H),7.18 (d, J = 7.2 Hz, 2H), 4.34 (br. s,
1H), 2.43 (s, 3H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
154.7, 147.8, 139.7, 138.4, 132.4, 132.2, 130.1, 129.7, 126.8, 124.5,
124.4, 122.4, 121.3, 51.9, 29.1, 21.5; HRMS (ESI) m/z calcd for
+
calcd for C19H19BrClN2 , 389.0415, found 389.0403.
3-(4-Bromophenyl)-N-(tert-butyl)-4-chloroquinolin-2-amine
(3ka). White solid (182 mg, 94%): mp 141−143 °C IR (KBr) 3435,
1
2962, 2920, 1758, 1606, 1516, 1414, 1241, 1052, 758; H NMR (400
MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.55 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz,
1H), 7.08 (d, J = 8.0 Hz, 2H), 4.08 (br. s, 1H), 1.33 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 154.0, 147.8, 139.9, 134.1, 132.6, 131.7, 130.0,
126.9, 124.4, 122.9, 122.9, 122.6, 121.0, 52.1, 29.0; HRMS (ESI) m/z
+
C20H22ClN2 , 325.1466, found 325.1459.
N-(tert-Butyl)-4-chloro-3-(4-ethylphenyl)quinolin-2-amine (3da).
White solid (144 mg, 85%): mp 122−124 °C; IR (KBr) 3430, 2964,
+
1
calcd for C19H19BrClN2 , 389.0415, found 389.0413.
2360, 1763, 1600, 1517, 1415, 1239, 1053, 756; H NMR (400 MHz,
N-(tert-Butyl)-4-chloro-3-(4-(trifluoromethyl)phenyl)quinolin-2-
CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51 (t, J
= 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H), 7.22−7.18 (m, 3H), 4.32 (br.
s, 1H), 2.71 (q, J1 = J2 = 7.6 Hz, 2H), 1.41 (s, 9H), 1.28 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 154.7, 147.7, 144.5, 139.6,
132.3, 129.7, 129.7, 128.8, 126.8, 124.4, 124.3, 122.3, 121.2, 51.9, 29.0,
amine (3la). Brown solid (166 mg, 88%): mp 104−106 °C IR (KBr)
1
3439, 2965, 2361, 1764, 1322, 1242, 1065, 757; H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.74 (d, J
= 8.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.28
(t, J = 7.4 Hz, 1H), 4.08 (br. s, 1H), 1.44 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 153.8, 148.0, 140.0, 139.1, 130.8 (q, J = 32.5 Hz),
130.6, 130.2, 127.0, 126.4 (q, J = 3.6 Hz), 124.5, 124.0 (q, J = 270.6
Hz), 122.8, 122.7, 121.0, 52.2, 29.1; HRMS (ESI) m/z calcd for
+
28.7, 15.2; HRMS (ESI) m/z calcd for C21H24ClN2 , 339.1623, found
339.1619.
N-(tert-Butyl)-4-chloro-3-(2,4-dimethylphenyl)quinolin-2-amine
(3ea). Light gray solid (139 mg, 82%): mp 105−107 °C; IR (KBr)
3422, 2961, 1602, 1516, 1415, 1222, 756; 1H NMR (400 MHz,
CDCl3) δ 8.04 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.58 (t, J
= 7.6 Hz, 1H), 7.29 (m, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J = 7.6
Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 4.22 (br. s, 1H), 2.43 (s, 3H), 2.10
(s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.5, 147.9,
139.8, 138.7, 136.8, 131.6, 131.3, 129.7, 129.6, 127.6, 126.8, 124.3,
123.8, 122.2, 121.2, 51.7, 29.0, 21.3, 19.1; HRMS (ESI) m/z calcd for
+
C20H19ClF3N2 , 379.1183, found 379.1175.
N-(tert-Butyl)-4-chloro-3-(4-nitrophenyl)quinolin-2-amine (3ma).
Yellow solid (151 mg, 85%): mp 142−144 °C IR (KBr) 3436, 2965,
1
2362, 1605, 1518, 1346, 1238, 758; H NMR (400 MHz, CDCl3) δ
8.38 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz,
1H), 7.61−7.57 (m, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 7.2 Hz,
1H), 4.00 (br. s, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
153.2, 148.0, 147.9, 142.2, 140.0, 131.4, 130.5, 127.0, 124.6, 124.4,
122.9, 121.9, 120.7, 52.3, 29.0; HRMS (ESI) m/z calcd for
+
C21H24ClN2 , 339.1623, found 339.1628.
N-(tert-Butyl)-4-chloro-3-(4-fluorophenyl)quinolin-2-amine (3fa).
+
C19H19ClN3O2 , 356.1160, found 356.1153.
White solid (136 mg, 83%): mp 115−117 °C; IR (KBr) 3435, 2962,
1
N-(tert-Butyl)-4-chloro-3-(thiophen-2-yl)quinolin-2-amine (3na).
2361, 1597, 1514, 1414, 1229, 757; H NMR (400 MHz, CDCl3) δ
Yellow oil (137 mg, 87%): IR (KBr) 3425, 2990, 2362, 1764, 1243,
8.00 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58−7.54 (m, 1H),
7.30−7.20 (m, 5H), 4.20 (br. s, 1H), 1.44 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 162.7 (J = 246.9 Hz), 154.4, 147.8, 140.0, 131.8 (J =
8.1 Hz), 131.0 (J = 3.3 Hz), 130.0, 126.8, 124.4, 123.2, 122.5, 121.1,
116.6 (J = 21.5 Hz), 52.0, 29.0; HRMS (ESI) m/z calcd for
1
1055, 756; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H),
7.68 (d, J = 8.0 Hz, 1H), 7.55−7.50 (m, 2H), 7.22−7.15 (m, 2H), 7.05
(d, J = 3.6 Hz, 1H), 4.61 (br. s, 1H), 1.43 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 154.9, 148.2, 142.2, 135.2, 130.3, 129.0, 127.8, 127.7,
126.9, 124.7, 122.5, 121.0, 117.1, 52.0, 29.0; HRMS (ESI) m/z calcd
for C17H18ClN2S+, 317.0874, found 317.0867.
+
C19H19ClFN2 , 329.1215, found 329.1213.
N-(tert-Butyl)-4-chloro-3-(2-chlorophenyl)quinolin-2-amine
(3ga). Yellow oil (139 mg, 81%): IR (KBr) 3433, 2961, 1764, 1608,
1516, 1413, 1240, 1054, 756; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J
= 8.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.61−7.58 (m, 2H), 7.44−
7.43 (m, 2H), 7.31−7.27 (m, 2H), 4.05 (br. s, 1H), 1.46 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 153.8, 148.0, 140.5, 134.3, 133.9, 131.8,
130.3, 130.3, 130.1, 127.8, 126.9, 124.4, 122.5, 121.9, 120.9, 52.0, 29.0;
N-(tert-Butyl)-4-chloro-3-hexylquinolin-2-amine (3oa). Yellow oil
(124 mg, 78%): IR (KBr) 3468, 2957, 2925, 1599, 1517, 1412, 1222,
755; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 1H), 7.66 (d,
J = 8.4 Hz, 1H), 7.49−7.46 (m, 1H), 7.21 (d, J = 6.8 Hz, 1H), 4.57 (br.
s, 1H), 2.74 (t, J = 8.0 Hz, 2H), 1.61−1.49 (m, 11H), 1.45−1.33 (m,
6H), 0.89 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 154.4,
146.7, 139.6, 128.9, 126.7, 124.1, 122.3, 122.3, 121.5, 51.9, 31.6, 29.4,
+
HRMS (ESI) m/z calcd for C19H19Cl2N2 , 345.0920, found 345.0917.
+
N-(tert-Butyl)-4-chloro-3-(3-chlorophenyl)quinolin-2-amine
(3ha). White solid (146 mg, 85%): mp 109−111 °C; IR (KBr) 3436,
2962, 1763, 1606, 1517, 1241, 1052, 756; 1H NMR (400 MHz,
CDCl3) δ 7.99 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.56 (t, J
= 7.6 Hz, 1H), 7.48−7.42 (m, 2H), 7.32 (s, 1H), 7.28−7.18 (m, 2H),
4.17 (br. s, 1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.9,
147.8, 139.9, 137.0, 135.2, 130.7, 130.1, 130.1, 128.8, 128.1, 126.9,
29.2, 28.6, 27.2, 22.6, 14.0; HRMS (ESI) m/z calcd for C19H28ClN2 ,
319.1936, found 319.1932.
N-(tert-Butyl)-4-chloro-3-dimethylaminomethyl-quinolin-2-
amine (3pa). Yellow solid (119 mg, 82%): mp 106−108 °C; IR (KBr)
1
3433, 2924, 2858, 1745, 1602, 1365, 1047, 757; H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.71 (br. s, 1H), 7.65 (d, J = 8.4
Hz, 2H), 7.51−7.47 (m, 1H), 7.22−7.19 (m, 1H), 3.73 (s, 2H), 2.26
F
dx.doi.org/10.1021/jo401707j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(s, 6H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.3, 147.7,
129.7, 129.4, 128.8, 128.3, 127.7, 125.0, 123.5, 121.9, 52.0, 28.9;
HRMS (ESI) m/z calcd for C19H19Cl2N2 , 345.0920, found 345.0913.
+
140.2, 129.3, 126.6, 124.5, 121.8, 120.9, 118.1, 58.1, 51.1, 44.2, 29.1;
+
HRMS (ESI) m/z calcd for C16H23ClN3 , 292.1575, found 292.1585.
N-(tert-Butyl)-4,7-dichloro-3-phenylquinolin-2-amine (5ea). Light
yellow solid (144 mg, 84%): mp 82−84 °C; IR (KBr) 2991, 1764,
1604, 1516, 1378, 1243, 1055; 1H NMR (400 MHz, CDCl3) δ 7.91 (d,
J = 8.8 Hz, 1H), 7.73 (s, 1H), 7.55−7.44 (m, 3H), 7.29 (d, J = 7.6 Hz,
2H), 7.19 (d, J = 8.8 Hz, 1H), 4.34 (br. s, 1H), 1.41 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 155.1, 148.3, 139.4, 135.7, 134.8, 129.8, 129.4,
128.7, 125.8, 125.7, 124.4, 123.0, 119.7, 52.1, 28.9; HRMS (ESI) m/z
N-(tert-Butyl)-4-chloro-3-(prop-1-en-2-yl)quinolin-2-amine (3sa).
Yellow solid (119 mg, 87%): mp 87−89 °C; IR (KBr) 3426, 2962,
1
1745, 1598, 1517, 1417, 1232, 756; H NMR (400 MHz, CDCl3) δ
7.96 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.52−7.48 (m, 1H),
7.23−7.20 (m, 1H), 5.49 (s, 1H), 5.07 (s, 1H), 4.96 (br. s, 1H), 2.04
(s, 3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.2, 147.3,
140.6, 137.7, 129.5, 126.7, 125.7, 124.0, 122.3, 121.0, 118.9, 51.7, 29.1,
+
calcd for C19H19Cl2N2 , 345.0920, found 345.0915.
+
21.8; HRMS (ESI) m/z calcd for C16H20ClN2 , 275.1310, found
6-Bromo-N-(tert-butyl)-4-chloro-3-phenylquinolin-2-amine
(5ga). Light yellow solid (159 mg, 82%): mp 119.4−121 °C; IR (KBr)
2986, 2360, 1743, 1514, 1373, 1241, 1047; 1H NMR (400 MHz,
CDCl3) δ 8.14 (s, 1H), 7.62−7.45 (m, 5H), 7.28 (d, J = 6.8 Hz, 2H),
4.32 (br. s, 1H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.6,
146.5, 138.5, 134.7, 133.0, 129.7, 129.4, 128.8, 128.5, 126.7, 125.0,
275.1302.
N-(tert-Butyl)-4-chloro-3-(1-phenylvinyl)quinolin-2-amine (3ta).
Yellow oil (136 mg, 81%): IR (KBr) 3430, 2960, 2357, 1743, 1595,
1
1518, 1221, 758; H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz,
1H), 7.75 (d, J = 8.4 Hz, 1H), 7.59−7.55 (m, 1H), 7.38−7.26 (m,
6H), 6.16 (s, 1H), 5.45 (s, 1H), 4.83 (br. s, 1H), 1.43 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 154.2, 147.8, 142.7, 139.8, 137.5, 129.8,
128.7, 128.5, 126.8, 125.9, 124.4, 124.0, 122.4, 121.0, 118.7, 51.9, 28.9;
+
122.5, 115.4, 52.1, 28.9; HRMS (ESI) m/z calcd for C19H19BrClN2 ,
389.0415, found 389.0403.
N-(tert-Butyl)-4-chloro-3-phenyl-6-(trifluoromethyl)quinolin-2-
+
amine (5ha). Light yellow solid (149 mg, 79%): mp 103−105 °C; IR
HRMS (ESI) m/z calcd for C21H22ClN2 , 337.1466, found 337.1471.
1
(KBr) 3739, 3431, 2925, 2356, 1519, 1299, 1242, 1123, 837, 700; H
(2-(tert-Butylamino)-4-chloroquinolin-3-yl)(phenyl)methanol
(3ua). Red oil (139 mg, 82%): IR (KBr) 3740, 3057, 2359, 1742,
1452, 1243, 830, 767, 691; 1H NMR (400 MHz, DMSO-d) δ 8.00 (d, J
= 8.0 Hz, 1H), 7.58−7.53 (m, 2H), 7.36−7.24 (m, 6H), 7.05 (d, J =
3.6 Hz, 1H), 6.70 (br. s, 1H), 6.63 (d, J = 3.2 Hz, 1H), 1.29 (s, 9H);
13C NMR (100 MHz, DMSO-d) δ 154.2, 146.9, 141.2, 138.1, 129.9,
128.0, 127.1, 126.0, 125.0, 124.2, 123.4, 122.4, 119.9, 69.6, 50.9, 28.6;
HRMS (ESI) m/z calcd for C20H20ClN2O−, 339.1270, found
339.1289.
NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H),
7.72−7.70 (m, 1H), 7.56−7.46 (m, 3H), 7.29 (d, J = 6.8 Hz, 2H), 4.46
(br. s, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.7, 149.3,
140.0, 134.4, 129.6, 129.5, 128.9, 127.5, 125.7 (q, J = 9.3 Hz), 125.4,
124.6 (q, J = 270 Hz), 124.1(q, J = 32.5 Hz), 122.6 (q, J = 4.3 Hz),
+
120.4, 52.3, 28.9; HRMS (ESI) m/z calcd for C20H19ClF3N2 ,
379.1183, found 379.1194.
N-(tert-Butyl)-4-chloro-3-phenyl-1,5-naphthyridin-2-amine
(5ka). Yellow solid (129 mg, 83%): mp 134−136 °C; IR (KBr) 3430,
4-Chloro-3-phenylquinolin-2-amine (3wa). Brown solid (104 mg,
1
2962, 2924, 2362, 1593, 1517, 1411, 1217, 701; H NMR (400 MHz,
82%): mp 120−122 °C; IR (KBr) 3478, 3397, 2979, 2362, 1610, 1429,
1
CDCl3) δ 8.66 (dd, J1 = 1.2 Hz, J2 = 4.0 Hz,1H), 7.99 (dd, J1 = 1.2 Hz,
J2 = 8.4 Hz, 1H), 7.55−7.44 (m, 4H), 7.32−7.30 (m, 2H), 4.41 (br. s,
1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.7, 149.3,
140.0, 134.4, 129.6, 129.5, 128.9, 127.5, 125.7 (q, J = 9.3 Hz), 125.4,
124.6 (q, J = 270 Hz), 124.1(q, J = 32.5 Hz), 122.6 (q, J = 4.3 Hz),
1245, 1048, 756; H NMR (400 MHz, acetone-d) δ 7.65−7.57 (m,
4H), 7.53−7.49 (m, 1H), 7.44−7.42 (m, 2H), 7.37−7.33 (m, 1H),
5.60 (br. s, 2H); 13C NMR (100 MHz, acetone-d) δ 157.4, 149.0,
140.9, 136.1, 131.0, 130.6, 130.1, 129.4, 127.1, 125.1, 124.4, 123.7,
+
122.5; HRMS (ESI) m/z calcd for C15H12ClN2 , 255.0684, found
+
120.4, 52.3, 28.9; HRMS (ESI) m/z calcd for C18H19ClN3 , 312.1262,
255.0678.
found 312.1252.
N-(tert-Butyl)-4-chloro-6-methyl-3-phenylquinolin-2-amine
4-Chloro-3-phenyl-N-(2,4,4-trimethylpentan-2-yl)quinolin-2-
(5aa). Yellow oil (138 mg, 85%): IR (KBr) 3433, 2962, 1600, 1515,
1
amine (5mb). White solid (145 mg, 79%): mp 102−104 °C; IR (KBr)
1417, 1323, 1221, 823, 701; H NMR (400 MHz, CDCl3) δ 7.82 (s,
1
3439, 2954, 2360, 1607, 1517, 1417, 1224, 757; H NMR (400 MHz,
1H), 7.66 (d, J = 8.4 Hz, 1H), 7.56−7.52 (m, 2H), 7.49−7.45 (m,
1H), 7.42−7.40 (m, 1H), 7.34−7.31 (m, 2H), 4.21 (br. s, 1H), 2.50 (s,
3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.0, 146.1,
139.1, 135.4, 131.9, 131.7, 129.9, 129.3, 128.5, 126.7, 124.1, 123.5,
CDCl3) δ 8.01 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.58−7.51
(m, 3H), 7.48−7.44 (m, 1H), 7.29−7.25 (m, 3H), 4.35 (br. s, 1H),
1.84 (s, 2H), 1.50 (s, 6H), 0.83 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 154.3, 147.8, 139.6, 135.2, 129.9, 129.8, 129.4, 128.6, 126.8, 124.4,
124.4, 122.3, 121.0, 55.8, 52.1, 31.6, 314, 29.2; HRMS (ESI) m/z calcd
+
121.0, 51.8, 29.1, 21.4; HRMS (ESI) m/z calcd for C20H22ClN2 ,
325.1466, found 325.1464.
+
for C23H28ClN2 , 367.1936, found 367.1925.
N-(tert-Butyl)-4-chloro-7-methoxy-3-phenylquinolin-2-amine
4-Chloro-N-isopropyl-3-phenylquinolin-2-amine (5mc). Red oil
(130 mg, 88%): IR (KBr) 3431, 2967, 1604, 1512, 1412, 1166, 758,
703; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 1H), 7.73 (d,
J = 8.4 Hz, 1H), 7.58−7.44 (m, 4H), 7.32−7.22 (m, 3H), 4.47−4.37
(m, 1H), 4.16 (d, J = 6.8 Hz, 1H), 1.15 (s, 3H), 1.13 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 154.3, 148.1, 140.1, 134.8, 130.0, 129.9,
129.4, 128.6, 126.5, 124.5, 123.6, 122.5, 121.4, 42.6, 22.8; HRMS
(5ba). Light yellow solid (156 mg, 92%): mp 130−132 °C; IR (KBr)
1
3740, 2961, 2359, 1764, 1609, 1516, 1242, 1037, 701; H NMR (400
MHz, CDCl3) δ 7.89 (d, J = 9.2 Hz, 1H), 7.53−7.42 (m, 3H), 7.30 (d,
J = 7.2 Hz, 2H), 7.10 (s, 1H), 6.91 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H),
4.26 (br. s, 1H), 3.94 (s, 3H), 1.43 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 161.3, 155.0, 149.4, 139.4, 135.3, 130.1, 129.3, 128.4, 125.7,
121.8, 115.8, 114.2, 106.1, 55.4, 51.9, 29.1; HRMS (ESI) m/z calcd for
C20H22ClN2O+, 341.1415, found 341.1408.
+
(ESI) m/z calcd for C18H18ClN2 , 297.1153, found 297.1164.
Ethyl 2-((4-chloro-3-phenylquinolin-2-yl)amino)acetate (5md).
Dark green oil (146 mg, 86%): IR (KBr) 3424, 2927, 2357, 1742,
1515, 1410, 1200, 759; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0
Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.60−7.46 (m, 4H), 7.40−7.30 (m,
3H), 4.97 (br. s, 1H), 4.27 (d, J = 5.6 Hz, 2H), 4.17 (q, J1 = J2 = 7.0
Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
171.0, 154.1, 147.4, 140.5, 134.3, 130.1, 129.9, 129.4, 128.8, 126.7,
124.5, 123.6, 123.1, 121.9, 61.1, 43.5, 14.1; HRMS (ESI) m/z calcd for
N-(tert-Butyl)-4-chloro-6-fluoro-3-phenylquinolin-2-amine (5ca).
White solid (131 mg, 80%): mp 104−106 °C; IR (KBr) 3433, 2961,
1
2355, 1601, 1516, 1416, 1236, 701; H NMR (400 MHz, CDCl3) δ
7.73−7.66 (m, 2H), 7.56−7.53 (m, 2H), 7.49−7.46 (m, 1H), 7.34−
7.30 (m, 3H), 4.27 (br. s, 1H), 1.43 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 158.3 (d, J = 239.9 Hz), 154.0, 144.6, 138.9, 134.9, 129.7,
129.4, 128.8, 128.7, 125.0, 121.5 (d, J = 9.6 Hz), 119.1 (d, J = 24.7
Hz), 108.6 (d, J = 24.4 Hz), 51.9, 29.0; HRMS (ESI) m/z calcd for
+
+
C19H19ClFN2 , 329.1215, found 329.1214.
C19H18ClN2O2 , 341.1051, found 341.1044.
N-(tert-Butyl)-4,6-dichloro-3-phenylquinolin-2-amine (5da).
N-Butyl-4-chloro-3-phenylquinolin-2-amine (5me). Yellow solid
(146 mg, 94%): mp 50−52 °C; IR (KBr) 3441, 2926, 2356, 1742,
1606, 1517, 1243, 758; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.0
Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.60−7.46 (m, 4H), 7.35−7.27 (m,
3H), 4.35 (br. s, 1H), 3.52 (q, J = 6.8 Hz, 2H), 1.56−1.48 (m, 2H),
1.37−1.28 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
White solid (151 mg, 88%): mp 106−108 °C; IR (KBr) 3431, 2960,
1
1764, 1598, 1514, 1415, 1239, 704; H NMR (400 MHz, CDCl3) δ
7.98 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.55−7.51 (m, 2H),
7.48−7.45 (m, 2H), 7.30−7.28 (m, 2H), 4.31 (br. s, 1H), 1.41 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 154.6, 146.2, 138.6, 134.8, 130.4,
G
dx.doi.org/10.1021/jo401707j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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CDCl3) δ 154.9, 148.0, 140.0, 134.8, 130.0, 129.8, 129.4, 128.6, 126.5,
124.5, 123.6, 122.5, 121.5, 41.2, 31.5, 20.1, 13.8; HRMS (ESI) m/z
calcd for C19H20ClN2 , 311.1310, found 311.1315.
N-Benzyl-3-(2-bromophenyl)-4-chloroquinolin-2-amine (5 ng).
Yellow solid (184 mg, 87%): mp 128−130 °C; IR (KBr) 3436,
2928, 2361, 1739, 1601, 1511, 1246, 751; 1H NMR (400 MHz,
CDCl3) δ 8.05 (d, J = 8.0 Hz, 1H), 7.77−7.72 (m, 2H), 7.60−7.56 (m,
1H), 7.44 (t, J = 7.6 Hz, 1H), 7.31−7.18 (m, 8H), 4.84 (dd, J1 = 6.0
Hz, J2 = 15.2 Hz, 1H), 4.71 (dd, J = 6.0 Hz, J2 = 15.2 Hz, 1H), 4.48
(br.s, 1H); 13C NMR (100 MHz, CDCl3) δ 153.9, 148.1, 141.2, 139.5,
135.5, 133.6, 131.7, 130.5, 130.4, 128.4, 128.4, 127.5, 127.0, 126.8,
124.5, 124.5, 122.9, 122.8, 121.5, 45.3; HRMS (ESI) m/z calcd for
+
4-Chloro-N-cyclohexyl-3-phenylquinolin-2-amine (5mf). Yellow
oil (141 mg, 84%): IR (KBr) 3430, 2928, 2359, 1606, 1512, 1412,
1
1341, 757, 702; H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz,
1H), 7.74 (d, J = 8.0 Hz, 1H), 7.58−7.46 (m, 4H), 7.34−7.32 (m,
2H), 7.28−7.25 (m, 1H), 4.25 (br.s, 1H), 4.20−4.10 (m, 1H), 2.04−
1.98 (m, 2H), 1.64−1.58 (m, 3H), 1.48−1.37 (m, 2H), 1.19−1.02 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 154.2, 148.1, 140.0, 134.8,
130.0, 129.8, 129.4, 128.6, 126.4, 124.8, 123.7, 122.4, 121.4, 49.2, 32.9,
+
C22H17BrClN2 , 423.0258, found 423.0263.
3-(2-Bromophenyl)-4-chloro-N-(4-methoxyphenyl)quinolin-2-
amine (5nh). White solid (175 mg, 80%): mp 132−134 °C; mp 134−
136 °C; IR (KBr) 2970, 2361, 1731, 1665, 1475, 1369, 1135, 701; 1H
NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.71−7.64 (m,
2H), 7.50−7.34 (m, 4H), 7.23−7.19 (m, 3H), 6.72 (d, J = 9.2 Hz,
2H), 5.83 (br. s, 1H), 3.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
155.6, 151.5, 147.5, 141.3, 135.2, 133.17, 132.9, 131.9, 130.7, 130.4,
128.5, 127.1, 124.5, 124.4, 123.6, 123.2, 122.1, 121.9, 113.9, 55.4;
HRMS (ESI) m/z calcd for C22H17BrClN2O+, 439.0207, found
439.0213.
+
25.8, 24.7; HRMS (ESI) m/z calcd for C21H22ClN2 , 337.1466, found
337.1460.
N-Benzyl-4-chloro-3-phenylquinolin-2-amine (5 mg). Light yel-
low solid (157 mg, 91%): mp 108−110 °C; IR (KBr) 3438, 2925,
1
2360, 1743, 1604, 1514, 1243, 757; H NMR (400 MHz, CDCl3) δ
8.04 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59−7.55 (m, 1H),
7.52−7.48 (m, 2H), 7.44−7.41 (m, 1H), 7.34−7.18 (m, 8H), 4.76 (br.
s, 1H), 4.75 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 154.6, 147.8,
140.4, 139.5, 134.5, 130.1, 129.8, 129.4, 128.7, 128.4, 127.4, 127.0,
126.6, 124.5, 123.6, 122.8, 121.8, 45.3; HRMS (ESI) m/z calcd for
3-(2-Bromophenyl)-4-chloro-N-(2,6-dimethylphenyl)quinolin-2-
amine (5ni). White solid (185 mg, 85%): mp 219−221 °C; IR (KBr)
3396, 2924, 2360, 1608, 1503, 1223, 754; 1H NMR (400 MHz,
CDCl3) δ 8.13 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.71 (d, J
= 8.4 Hz, 1H), 7.60−7.56 (m, 2H), 7.48−7.34 (m, 3H), 7.13 (s, 3H),
5.52 (br. s, 1H), 2.25 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 152.2,
148.0, 141.4, 136.0, 135.9, 135.8, 133.7, 131.3, 130.7, 130.3, 128.6,
128.0, 127.2, 126.4, 124.7, 124.4, 123.2, 122.9, 121.7, 18.8; HRMS
+
C22H18ClN2 , 345.1153, found 345.1158.
4-Chloro-N-(4-methoxyphenyl)-3-phenylquinolin-2-amine
(5mh). Yellow oil (149 mg, 83%): IR (KBr) 3419, 2355, 1739, 1600,
1510, 1415, 1239, 759; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4
Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62−7.51 (m, 6H), 7.42−7.34 (m,
3H), 6.87 (d, J = 8.8 Hz, 2H), 6.24 (br. s, 1H), 3.79 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.4, 152.0, 147.2, 140.7, 134.3, 133.1, 130.2,
130.0, 129.6, 129.0, 127.1, 124.4, 124.1, 123.6, 122.2, 121.5, 114.0,
55.5; HRMS (ESI) m/z calcd for C22H18ClN2O+, 361.1102, found
361.1098.
+
(ESI) m/z calcd for C23H19BrClN2 , 437.0415, found 437.0404.
4-Bromo-N-(tert-butyl)-3-phenylquinolin-2-amine (6aa). Light
yellow oil (92 mg, 52%): IR (KBr) 3431, 2961, 1594, 1515, 1411,
1219, 756; 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J1 = 1.2 Hz, J1 =
8.4 Hz, 1H), 7.72 (d, J = 6.4 Hz, 1H), 7.57−7.51 (m, 3H), 7.48−7.46
(m, 1H), 7.29−7.26 (m, 3H), 4.22 (br. s, 1H), 1.42 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 154.3, 147.7, 137.3, 133.5, 129.8, 129.7, 129.4,
128.6, 127.3, 127.1, 126.8, 122.6, 122.5, 52.0, 29.0; HRMS (ESI) m/z
4-Chloro-N-(2,6-dimethylphenyl)-3-phenylquinolin-2-amine
(5mi). Red brown solid (156 mg, 87%): mp 156−159 °C; IR (KBr)
1
3401, 2921, 2358, 1740, 1607, 1501, 1230, 760; H NMR (400 MHz,
CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.69−7.61 (m, 3H), 7.57−7.50 (m,
4H), 7.36−7.32 (m, 1H), 7.17−7.05 (m, 3H), 5.72 (br. s, 1H), 2.21 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 153.0, 147.8, 140.6, 136.4,
135.7, 134.9, 130.0, 129.8, 129.6, 128.9, 128.0, 127.1, 126.3, 124.4,
+
calcd for C19H20BrN2 , 355.0804, found 355.0797.
4-Bromo-N-(tert-butyl)-3-(4-methoxyphenyl)quinolin-2-amine
(6ba). Yellow solid (136 mg, 71%): mp 91−93 °C; IR (KBr) 3428,
2961, 1593, 1514, 1109, 616; 1H NMR (400 MHz, CDCl3) δ 7.96 (dd,
J1 = 1.2 Hz, J1 = 8.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.53−7.48 (m,
1H), 7.24−7.16 (m, 3H), 7.02 (d, J = 8.8 Hz, 2H), 4.30 (br. s, 1H),
3.84 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 159.6,
154.7, 147.7, 133.9, 131.0, 129.7, 129.3, 127.3, 126.8, 126.7, 122.6,
122.5, 114.7,55.2, 51.9, 29.0; HRMS (ESI) m/z calcd for
C20H22BrN2O+, 385.0910, found 385.0906.
+
123.6, 123.1, 122.0, 18.8; HRMS (ESI) m/z calcd for C23H20ClN2 ,
359.1310, found 359.1305.
Ethyl 2-((3-(2-bromophenyl)-4-chloroquinolin-2-yl)amino)-
acetate (5nd). White solid (169 mg, 81%): mp 132−134 °C; mp
134−136 °C; IR (KBr) 2970, 2361, 1731, 1665, 1475, 1369, 1135,
1
701; H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 1H), 7.79−
7.75 (m, 2H), 7.62−7.58 (m, 1H), 7.51−7.47 (m, 1H), 7.38−7.31 (m,
3H), 4.74 (br. s, 1H), 4.38 (dd, J1 = 5.6 Hz, J2 = 18.4 Hz, 1H), 4.24−
4.10 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.9, 153.4, 147.7, 141.3, 135.2, 133.5, 131.6, 130.6, 130.4, 128.4,
126.8, 124.5, 124.5, 123.2, 122.9, 121.7, 61.1, 43.5, 14.1; HRMS (ESI)
4-Bromo-N-(tert-butyl)-3-(4-chlorophenyl)quinolin-2-amine
(6ca). Light yellow solid (126 mg, 65%): mp 109−111 °C; IR (KBr)
3435, 2962, 1586, 1514, 1411, 1218, 755; 1H NMR (400 MHz,
CDCl3) δ 7.98 (dd, J1 = 1.0 Hz, J1 = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz,
1H), 7.57−7.50 (m, 3H), 7.28−7.22 (m, 3H), 4.15 (br. s, 1H), 1.43 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 153.9, 147.8, 135.7, 134.7,
133.8, 131.3, 130.0,129.7, 127.3, 126.8, 125.8, 122.8, 122.4, 52.1, 29.0;
+
m/z calcd for C19H17BrClN2O2 , 419.0156, found 419.0159.
3-(2-Bromophenyl)-N-butyl-4-chloroquinolin-2-amine (5ne). Yel-
low solid (178 mg, 92%): mp 70−72 °C; IR (KBr) 3445, 2927, 2353,
1747, 1603, 1519, 1240, 751; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J
= 8.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.61−7.57 (m, 1H), 7.50−
7.46 (m, 1H), 7.34−7.27 (m, 3H), 4.12 (br. s, 1H), 3.60−3.44 (m,
2H), 1.57−1.50 (m, 2H), 1.38−1.31 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 154.2, 148.3, 140.8, 135.7, 133.5,
131.7, 130.4, 130.3, 128.4, 126.6, 124.5, 124.5, 122.9, 122.5, 121.2,
+
HRMS (ESI) m/z calcd for C19H19BrClN2 , 389.0415, found
389.0409.
4-Bromo-N-(tert-butyl)-3-(3-chlorophenyl)quinolin-2-amine
(6da). Light yellow solid (107 mg, 55%): mp 100−102 °C; IR (KBr)
3435, 2979, 2362, 1764, 1243, 1054, 755; 1H NMR (400 MHz,
CDCl3) δ 7.93 (dd, J1 = 1.2 Hz, J1 = 8.4 Hz, 1H), 7.69 (d, J = 7.6 Hz,
1H), 7.53−7.49 (m, 1H), 7.45−7.39 (m, 2H), 7.27−7.20 (m, 2H),
7.13−7.11 (m, 1H), 4.09 (br. s, 1H), 1.39 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 153.8, 139.0, 135.1, 133.8, 130.7, 130.1, 130.0, 128.9,
128.0, 127.3, 126.8, 125.6, 122.9, 122.3, 108.8, 52.2, 29.0; HRMS
+
41.2, 31.5, 20.1, 13.8; HRMS (ESI) m/z calcd for C19H19BrClN2 ,
389.0415, found 389.0421.
3-(2-Bromophenyl)-4-chloro-N-cyclohexylquinolin-2-amine
(5nf). Yellow oil (172 mg, 83%): IR (KBr) 3433, 2924, 2362, 1609,
1507, 1410, 1339, 759, 701; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J
= 8.0 Hz, 1H), 7.78−7.74 (m, 2H), 7.60−7.46 (m, 2H), 7.37−7.25 (m,
3H), 4.21−4.09 (m, 1H), 4.00 (br. s, 1H), 2.07−1.96 (m, 2H), 1.61−
1.01 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 153.5, 148.3, 140.8,
135.8, 133.6, 131.8, 130.4, 130.2, 128.4, 126.6, 124.5, 124.4, 123.0,
122.4, 121.2, 49.2, 33.1, 25.8, 24.8; HRMS (ESI) m/z calcd for
+
(ESI) m/z calcd for C19H19BrClN2 , 389.0415, found 389.0411.
4-Bromo-N-(tert-butyl)-3-(4-fluorophenyl)quinolin-2-amine
(6ea). White solid (87 mg, 47%): mp 92−94 °C; IR (KBr) 3434,
2980, 2362, 1764, 1379, 1242, 1057, 755; 1H NMR (400 MHz,
CDCl3) δ 7.94 (dd, J1 = 1.2 Hz, J1 = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz,
1H), 7.53−7.49 (m, 1H), 7.24−7.16 (m, 5H), 4.12 (br. s, 1H), 1.39 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 162.7 (d, J = 247.0 Hz), 154.3,
+
C21H21BrClN2 , 415.0571, found 415.0575.
H
dx.doi.org/10.1021/jo401707j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
147.8, 133.9, 133.2 (d, J = 3.5 Hz), 131.7 (d, J = 8.1 Hz), 129.9, 127.3,
126.8, 126.0, 122.7, 122.4, 116.5 (d, J = 21.5 Hz), 52.0, 29.0; HRMS
(ESI) m/z calcd for C19H19BrFN2 , 373.0710, found 373.0706.
ASSOCIATED CONTENT
■
S
+
* Supporting Information
1
Copies of H and 13C NMR spectra for all products and the
crystallographic data of 3ka (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Typical Experimental Procedure for Synthesis of 11-Chloro-
6H-indolo[2,3-b]quinolines. To the mixture of 2-((2-
bromophenyl)ethynyl)aniline (1j, 0.5 mmol), PdCl2 (5 mol %) and
LiCl (2.0 equiv) in DMSO were added successively in a test tube. After
stirring for 5 min at room temperature, isocyanide (2, 0.6 mmol) was
added, and then the mixture was stirred at 140 °C for 12 h under 1
atm of O2. Upon completion, the reaction mixture was extracted with
ethyl acetate (3 × 10 mL), and the organic layers were combined,
dried over anhydrous MgSO4, filtered and concentrated under reduced
pressure. Then Pd2(dba)3 (5 mol %), P(o-tol)3 (10 mol %) and
toluene (2.0 mL) were added to the residue and heated at 85 °C for
further 12 h. Upon completion, the reaction mixture was extracted
with ethyl acetate (3 × 10 mL), and the organic layers were combined,
dried over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The residue was separated by flash column chromatography
(the eluents phases were pure hexane, and the stationary phases were
300−400 mesh silica gel) to give the pure products 7.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jianghf@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Natural Science
Foundation of China (20932002), National Basic Research
Program of China (973 Program) (2011CB808600), the
Changjiang Scholars and Innovation Team Project of Ministry
of Education, Guangdong Natural Science Foundation
(10351064101000000) and the Fundamental Research Funds
for the Central Universities (2012ZP0003) for financial
support.
6-Butyl-11-chloro-6H-indolo[2,3-b]quinoline (7a). White solid
(131 mg, 85%): mp 132−134 °C; IR (KBr) 2970, 2361, 1731,
1665, 1475, 1369, 1135, 701; 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J
= 7.6 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.58
(t, J = 7.2 Hz, 1H), 7.44−7.34 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H),
7.18−7.14 (m, 1H), 4.33 (t, J = 7.6 Hz, 2H), 1.81−1.73 (m, 2H),
1.34−1.25 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 152.0, 146.9, 142.1, 135.3, 129.1, 128.3, 127.8, 124.2, 123.9,
123.4, 122.2, 120.0, 119.8, 115.3, 108.7, 41.2, 30.5, 20.3, 13.8; HRMS
REFERENCES
■
(1) (a) Andries, K.; Verhasselt, P.; Guillemont, J.; Gohlmann, H. W.
̈
+
H.; Neefs, J.; Winkler, H.; Gestel, J. V.; Timmerman, P.; Zhu, M.; Lee,
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Huang, J.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.; May, E. W.;
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Theobald, A. J.; Wohlkonig, A.; Pearson, N. D.; Gwynn, M. N. Nature
2010, 466, 935.
(ESI) m/z calcd for C19H18ClN2 , 309.1153, found 309.1149.
6-(tert-Butyl)-11-chloro-6H-indolo[2,3-b]quinoline (7b). Yellow
solid (128 mg, 83%): mp 99−101 °C; IR (KBr) 2991, 2362, 1765,
1391, 1243, 1054, 748; 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 7.6
Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.94 (d, J
= 8.4 Hz, 1H), 7.73−7.70 (m, 1H), 7.54−7.49 (m, 2H), 7.30 (t, J = 7.6
Hz, 1H), 2.14 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.4, 146.0,
142.8, 134.5, 128.9, 128.4, 127.8, 124.3, 123.7, 123.6, 121.8, 121.1,
119.5, 115.7, 113.2, 60.3, 30.6; HRMS (ESI) m/z calcd for
+
(2) For classical methods on quinoline synthesis, see: (a) Marco-
Contelles, J.; Perez-Mayoral, E.; Samadi, A.; Carreiras, M.; do, C.;
́
C19H18ClN2 , 309.1153, found 309.1161.
11-Chloro-6-cyclohexyl-6H-indolo[2,3-b]quinoline (7c). Light yel-
low solid (134 mg, 80%): mp 203−205 °C; IR (KBr) 3847, 3737,
Soriano, E. Chem. Rev. 2009, 109, 2652. (b) Cheng, C.; Yan, S. Org.
React. 1982, 28, 37. (c) Wu, Y.; Liu, L.; Li, H.; Wang, D.; Chen, Y. J.
Org. Chem. 2006, 71, 6592. (d) Akbari, J.; Heydari, A.; Kalhor, H. R.;
Kohan, S. A. J. Comb. Chem. 2010, 12, 137. (e) Manske, R. H. F.;
Kukla, M. Org. React. 1953, 7, 59. (f) Reitsema, R. H. Chem. Rev. 1948,
43, 43. (g) Bergstrom, F. W. Chem. Rev. 1944, 35, 77.
1
2924, 2357, 1553, 1463, 1249, 742; H NMR (400 MHz, CDCl3) δ
8.68 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz,
1H), 7.75−7.71 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.59−7.50 (m,
2H), 7.33−7.29 (m, 1H), 5.14 (br. s, 1H), 2.63−2.54 (m, 2H), 1.98−
1.37 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 152.0, 146.7, 141.6,
135.3, 129.2, 128.0, 128.0, 124.4, 123.9, 123.6, 122.1, 120.3, 119.7,
115.5, 110.7, 53.7, 30.1, 26.3, 25.7; HRMS (ESI) m/z calcd for
(3) For selected recent examples, see: (a) Xia, X.; Zhang, L.; Song,
X.; Liu, X.; Liang, Y. Org. Lett. 2012, 14, 2480. (b) Ali, S.; Zhu, H.; Xia,
X.; Ji, K.; Yang, Y.; Song, X.; Liang, Y. Org. Lett. 2011, 13, 2598.
(c) Gao, G.; Niu, Y.; Yan, Z.; Wang, H.; Wang, G.; Shaukat, A.; Liang,
Y. J. Org. Chem. 2010, 75, 1305. (d) Matsubara, Y.; Hirakawa, S.;
Yamaguchi, Y.; Yoshida, Z. Angew. Chem., Int. Ed. 2011, 50, 7670.
(e) Cao, K.; Zhang, F.; Tu, Y.; Zhuo, X.; Fan, C. Chem.Eur. J. 2009,
15, 6332.
(4) Selected recent examples: (a) Ji, X.; Huang, H.; Li, Y.; Chen, H.;
Jiang, H. Angew. Chem., Int. Ed. 2012, 51, 7292. (b) Wang, Y.; Chen,
C.; Peng, J.; Li, M. Angew. Chem., Int. Ed. 2013, 52, 5323. (c) Zhang,
X.; Song, X.; Li, H.; Zhang, S.; Chen, X.; Yu, X.; Wang, W. Angew.
+
C22H20ClN2 , 335.1285, found 335.1310.
6-Benzyl-11-chloro-6H-indolo[2,3-b]quinoline (7d). Light yellow
solid (140 mg, 82%): mp 178−180 °C; IR (KBr) 3745, 2362, 1743,
1555, 1465, 1403, 1244, 744, 692; 1H NMR (400 MHz, CDCl3) δ 8.52
(d, J = 8.0 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H),
7.67−7.63 (m, 1H), 7.47−7.38 (m, 2H), 7.22−7.11 (m, 7H), 5.63 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 152.3, 147.0, 142.0, 137.0,
135.6, 129.3, 128.6, 128.5, 128.0, 127.4, 127.2, 124.2, 124.0, 123.7,
122.5, 120.5, 120.0, 115.5, 109.4, 45.0; HRMS (ESI) m/z calcd for
+
C22H16ClN2 , 343.0997, found 343.0981.
Chem., Int. Ed. 2012, 51, 7282. (d) Kulkarni, A.; Torok, B. Green Chem.
2010, 12, 875.
̈
̈
11-Chloro-6-(4-methoxyphenyl)-6H-indolo[2,3-b]quinoline (7e).
Yellow solid (141 mg, 79%): mp 227−229 °C; IR (KBr) 3849,
3734, 2355, 2324, 1745, 1515, 1244, 611; 1H NMR (400 MHz,
CDCl3) δ 8.69 (d, J = 8.0 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.05 (d, J
= 8.4 Hz, 1H), 7.71−7.67 (m, 1H), 7.59−7.51 (m, 4H), 7.39−7.36 (m,
2H), 7.14 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.1, 152.6, 147.00, 143.1, 135.8, 130.9, 129.3, 129.0,
128.6, 128.4, 124.2, 124.0, 123.9, 122.8, 121.0, 120.0, 115.7, 115.0,
109.9, 55.6; HRMS (ESI) m/z calcd for C22H16ClN2O+, 359.0946,
found 359.0941.
(5) (a) Cheng, Y.; Judd, T. C.; Bartberger, M. D.; Brown, J.; Chen,
K.; Fremeau, R. T.; Hickman, D., Jr.; Hitchcock, S. A.; Jordan, B.; Li,
V.; Lopez, P.; Louie, S. W.; Luo, Y.; Michelsen, K.; Nixey, T.; Powers,
T. S.; Rattan, C.; Sickmier, E. A.; Jean, D. J. S.; Wahl, R. C., Jr.; Wen, P.
H.; Wood, S. J. Med. Chem. 2011, 54, 5836. (b) Takenaka, N.; Chen,
J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, A. J. Am. Chem. Soc.
2010, 132, 4536. (c) He, C.; Hao, J.; Xu, H.; Mo, Y.; Liu, H.; Han, J.;
Lei, A. Chem. Commun. 2012, 48, 11073. (d) Inglis, S. R.; Jones, R. K.;
Booker, G. W.; Pyke, S. M. Bioorg. Med. Chem. Lett. 2006, 16, 387.
I
dx.doi.org/10.1021/jo401707j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(6) (a) Tomioka, T.; Takahashi, Y.; Maejima, T. Org. Biomol. Chem.
2012, 10, 5113. (b) Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.;
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