Site-Selective Deoxygenative Amination of Azine N-Oxides with Carbodiimides under Catalyst-, Activator-, Base-, and Solvent-Free Conditions

Article abstract of DOI:10.1021/acs.joc.1c00741

An operationally simple method for synthesizing 2-amino azines via [3+2] dipolar cycloaddition of azine N-oxide with carbodiimide has been demonstrated. The reaction can proceed smoothly under simple heating conditions without any transition metal catalyst, activator, base, and solvent. This transformation demonstrates a broad substrate scope and produces CO2 as the only co-product. The applicability of this method is highlighted by the late-stage modification of bioactive molecules, including quinine, (±)-α-tocopherol, and tryptamine modified quinoline.

Full text of DOI:10.1021/acs.joc.1c00741

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Site-Selective Deoxygenative Amination of Azine N‑Oxides with
Carbodiimides under Catalyst‑, Activator‑, Base‑, and Solvent-Free
Conditions
Bikash Kumar Sarmah,† Monuranjan Konwar,† and Animesh Das*
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ABSTRACT: An operationally simple method for synthesizing 2-
amino azines via [3+2] dipolar cycloaddition of azine N-oxide with
carbodiimide has been demonstrated. The reaction can proceed
smoothly under simple heating conditions without any transition
metal catalyst, activator, base, and solvent. This transformation
demonstrates a broad substrate scope and produces CO2 as the only
co-product. The applicability of this method is highlighted by the
late-stage modification of bioactive molecules, including quinine,
( )-α-tocopherol, and tryptamine modified quinoline.
Scheme 1. Metal-Free Deoxygenative C2-Amination of
Azine N-Oxide
zines, the nitrogen atom containing six-membered
heteroaromatic compounds, represent an important
A
class of compounds, which possess a variety of pharmacological
applications, including antimalarial, antimicrobial, antitumor,
and antiviral properties.1 In addition, azines are ubiquitous as a
core structure in many natural alkaloids. Therefore, the
functionalization of azines at different positions is of
considerable interest from the perspective of furthering our
understanding of their biological properties. Among them, C2
aminated azines are of utmost interest in drug discovery due to
their significance as therapeutics.2
Earlier methods to synthesize 2-aminoazines and their
derivatives revolved around the Chichibabin amination
reaction3 or via the nucleophilic aromatic substitution
(SNAr) reaction on ortho-halogenated azines. However, the
reactivity is extremely sluggish in the first case, and the latter
requires the prefunctionalization of azines.4 To address the
inherent low reactivity of azines, azine N-oxides were used as a
promising precursor in a recent study.5 Using this strategy,
metal-catalyzed amination of azine N-oxides has been
described.5e,6a−h However, these methods require a separate
step for the deoxygenation6a−e and the trace metal impurities
in the final product can cause additional difficulties for late-
stage modification of drugs. Therefore, significant research
efforts have been made to develop efficient synthetic
methodologies for constructing aminated azines without the
aid of any transition metals.
DMF,7e etc., and the method involves the formation of
unwanted byproducts originating from activating agents, base,
catalysts, etc. (see Table S1 in the Supporting Information
(SI)). Therefore, the development of an operationally simple,
easy, and straightforward method with minimal chemical waste
Received: March 30, 2021
Published: July 14, 2021
A few encouraging reports appeared in the recent
literature;7,8 one each by the groups of Londregan,7c Zhao,7e
Kim,7g and others describing the transition-metal-free direct
deoxygenative C2-amination of azine N-oxides with a
phosphorus based activating agent and/or base (Scheme
1a,b). The reaction requires halogenated solvents,6h,7b−e
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Note
and good green metrics is highly desired.9 Herein, we report
the first example of a one-step heteroaromatic C-H amination
process without the aid of any additional metal catalyst, base,
additives, or solvents. The reaction exhibited an excellent
selectivity at the C2 position and impressively low E-factor.
Owing to the 1,2-dipolar nature of the N−O bond and the
presence of an electrophilic C2 site in the azine N-oxide,5e,10
we anticipate that N-oxide may be involved in the [3+2]-
cycloaddition reaction with carbodiimide11 to give the
cycloadduct (A). The aromatization of the cycloadduct (A)
may then lead to the desired aminated azine along with
isocyanate. The corresponding isocyanate can further react
with another molecule of N-oxide to form the [3+2]-type
cycloadduct (B), which can undergo decarboxylation to give
the product and eliminate CO2 as the only co-product in the
overall reaction (Scheme 1c). The use of two amino groups in
the carbodiimide is likely to be beneficial compared to the
previously reported amino precursors such as acyl azides,7g
diazonium salts,7h and aryl thiocyanates.6h
The substrates bearing methyl (1c, 1e,f, 1j), methoxy (1b, 1g,
1i), chloro (1d), and bromo (1h) substituents led to the
aminated products 3aa−ja in 78−96% yields. Interestingly,
halogen groups were retained during these transformations,
which can be beneficial for further functionalization. Multi-
substituted quinoline N-oxides also proceeded smoothly to
deliver 3ka−ma efficiently. Furthermore, the protocol was
checked with other alkyl carbodiimides such as di-tert-butyl, di-
cyclohexyl, and di-benzyl carbodiimide derivatives (2b−d),
which also afforded the corresponding aminated products in
good to excellent yields. Interestingly, the chiral carbodiimide
2e gave the desired product 3be in 85% yield. However, the
method has failed to achieve cyclopropane ring bearing
aminated compound 3bf.
Besides, we examined various aryl carbodiimides to assess
the diversity of our protocol (Scheme 3). The substrates
a
Scheme 3. Substrate Scope with Aryl Carbodiimides
To put the plan into practice, optimization studies were
commenced by reacting 6-methoxyquinoline N-oxide 1b with
diisopropyl carbodiimide 2a (0.5 equiv) as a model substrate
in neat condition. However, the desired aminated product 3ba
was not obtained at room temperature (see Table S2 in the SI,
entry 1). Interestingly, when the reaction was carried out at 90
°C, the compound 3ba was isolated in 41% yield after 12 h
(Table S2, entry 3). Upon further increasing the temperature,
we were pleased to observe a 96% yield at 130 °C (Table S2,
entry 5). The study of the reaction at various temperatures led
us to understand the influence of the temperature on the
outcome of the reaction (see Figure S1 in the SI). As a part of
further optimization, the reaction was performed in various
solvents. A dramatic drop in yield has been observed in polar
protic solvents, whereas, in the polar aprotic solvents, the
reaction proceeds equally well as in solvent-free conditions
(Table S2, entries 10−15). Interestingly, cyclopentyl methyl
ether (CPME) was also found to be a suitable eco-friendly
ethereal solvent12 for this transformation (Table S2, entry 12).
With the optimized conditions in hand, the scope of the
reaction was investigated with a variety of substituted quinoline
N-oxides 1a−m using 2a as the standard substrate (Scheme 2).
a
Reaction conditions: azine N-oxide (1 mmol, 1 equiv), aryl
carbodiimide (0.5 mmol, 0.5 equiv), neat, 130 °C, 12 h. Isolated
yield. CPME (1 mL) was used.
b
containing both electron-donating (e.g., −CH3, −OCH3) and
electron-withdrawing (e.g., −F) groups on the aryl ring of the
carbodiimide were efficiently reacted to obtain the desired
aminated products 5aa−ad in 72−85% yields. Fortunately, the
use of CPME solvent dramatically improved the current
reaction, affording the compounds 5aa−ae, 5ba in good yields.
Notably, the aminated compounds 5ae−be, 5bf could be
obtained easily in 83−85% yields from the reaction of sterically
demanding carbodiimides 4e and 4f, indicating that a bulky
functionality is well tolerated in our reaction conditions.
Additionally, the reaction was found to be effective to other
heteroaromatic N-oxides 1n−r, proving the generality of the
present protocol. The successful amination of the bipyridine
scaffolds is encouraging as they are useful building blocks in
bifunctional metal catalysis.13
a
Scheme 2. Substrate Scope with Alkyl Carbodiimides
This method allows late-stage C-H amination of biologically
important N-heteroaromatic compounds (Scheme 4). For
example, the antimalarial drug quinine, ( )-α-tocopherol, and
tryptamine modified quinoline 6a, 6b, and 6c, respectively,
were functionalized with good to excellent yields.
The synthetic utility of the C2-aminated quinolines is
illustrated through the preparation of 2-aminoquinoline 7 by
simple acid-mediated hydrolysis of N-isopropylquinolin-2-
amine (3aa) or N-benzylquinolin-2-amine (3ad), affording
the product in very good yield (>82%). Additionally, readily
a
Reaction conditions: azine N-oxide (1 mmol, 1 equiv), alkyl
carbodiimide (0.5 mmol, 0.5 equiv), neat, 130 °C, 12 h. Isolated
yield. Cyclopropyl isothiocyanate was used.
b
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pure 5bb and 3ba were isolated in 37% and 26% yields,
respectively (Scheme 5b). The reaction between carbodiimide
10 (0.5 equiv) and 1,3-di-p-tolylcarbodiimide 4b (0.5 equiv)
led to the arylaminated product 5bb, and alkylaminated
product 3ba in 58% and 10% yields, respectively (Scheme 5c).
On the other hand, when 1,3-diisopropylcarbodiimide 2a (0.5
equiv) was used in place of arylcarbodiimide 4b (0.5 equiv),
the yields of 5bb and 3ba were reduced to 17% and 34%,
respectively (Scheme 5d). The higher yield of 5bb (58%) with
respect to 3ba (34%) suggests that the reactivity of the
carbodiimide containing aromatic backbone is likely to be
higher than that with an aliphatic substituent under the current
reaction conditions. To understand the rate of amination of
aliphatic vs aromatic carbodiimide, the investigation has been
illustrated by reacting N-oxide 1b with 2a or 4b under the
standard conditions for 5 h. A higher yield of 5bb (64%) was
obtained with respect to 3ba (41%), which revealed that the
amination of aromatic carbodiimide was faster than alkyl
carbodiimide under the reaction conditions (Scheme 5e).
Surprisingly, the oxazolo derivative 11 was isolated in 74%
yield when the reaction was carried out with N-oxide 1s and
carbodiimide 2a under the standard conditions (Scheme 5f).
This observation suggests that initially formed 1,2-dihydro-
cycloadduct 11-I1 possibly rearranged to the 2,3-dihydro-
cycloadduct 11-I2, followed by hydrogen bromide elimination,
to give the oxazolo derivative 11.
For further understanding of the mechanistic pathway, DFT
calculations have been performed using the B3LYP level of
theory (Scheme 6; please see SI for details). The calculated
free energy result and some key optimized structures are
depicted in Table S4. Initially, N-oxide 1a was reacted with 2a
(or 4b) to form 1,2 dihydroquinoline intermediate I-1A (or I-
1B) via [3+2]-dipolar cycloaddition reaction. The process is
uphill. The energy barrier for the formation of I-1B (ΔG⧧ =
34.3 kcal/mol) is slightly lowered compared to I-1A (ΔG⧧ =
40.8 kcal/mol). Subsequent aromatization afforded the desired
product 3aa (or 5ab) in a downhill process and released the
corresponding isocyanates 2a′ (or 4b′). Meanwhile, the
intermediate I-1A (or I-1B) can also easily rearrange to the
2,3-dihydroquinoline cycloadduct I-2A (or I-2B) with a low
energy barrier (TS-2A, ΔG⧧ = 23.7 kcal/mol; TS-2B, ΔG⧧ =
11.4 kcal/mol) and proceeds in a downhill process. Then, I-2A
(or I-2B) undergoes aromatization to form the product 3aa
(or 5ab) with the liberation of isocyanate 2a′ (or 4b′). The
produced isocyanate 2a′ (or 4b′) can further take part in
dipolar cycloaddition with N-oxide 1a to form cycloadduct I-
3A (or I-3B) which is an uphill process and has a barrier (TS-
3A, ΔG⧧ = 36.7 kcal/mol; TS-3B, ΔG⧧ = 33.8 kcal/mol). The
subsequent aromatization gives the aminated product 3aa (or
5ab) derived either from direct I-3A (or I-3B) or via
intermediate I-4A (or I-4B).
Scheme 4. Late-Stage Drug Modification
obtained C2-aminated quinoline 5bb can be easily transformed
into the 2-(1H-indol-1-yl)quinoline derivative 8 via a Pd-
catalyzed oxidative coupling reaction (Scheme S1; see SI).14
For practical utility, the reaction was also run on a gram
scale, and analytically pure compound 3aa was obtained in
85% yield using this method. In order to assess the efficiency of
the chemical process, we have calculated the green metrics
parameters9,15 by using our protocol and compared them with
reported methods,6h,7g which are summarized in Table S3 in
the SI. The present protocol showed a very promising atom
economy and atom efficiency values with a very low E-factor
compared to the previous protocols. There were no
byproducts, and only volatile CO2 was formed as a co-product,
which can be separated easily. Furthermore, the evolved CO2
was trapped efficiently as a bench-stable ammonium carbamate
salt 9 (Scheme S2, see SI), and this can be utilized as a reagent
and catalyst for different organic transformations.16 Taken
together, the present method is superior to all known methods
in the context of reduction of undesired chemical waste and
increase of atom economy.
To gain insight into the reaction pathway, we have
performed a series of control experiments (Scheme 5). For
Scheme 5. Controlled Experiments for Reaction Mechanism
On the basis of the previous reports,6h,7g,17 our observations,
and with the help of calculations, the plausible pathway has
been presented and is depicted in Scheme 6. At first, quinoline
N-oxide and carbodiimide take part in [3+2]-dipolar cyclo-
addition to give the 1,2-dihydroquinoline intermediate,
followed by aromatization (or via rearrangement to 2,3-
dihydroquinoline intermediate and then aromatization), to
form C2-aminated quinoline and generating isocyanate. The
produced isocyanate is further reacted with another molecule
of N-oxide to provide the [3+2]-type cycloadduct intermediate
and subsequently decarboxylate to give the desired product.
example, the reaction has not proceeded by reacting quinoline
1a′ with carbodiimide 2a (or 4a) under the optimal reaction
conditions. This suggests the role of the N-O group in this
transformation. When N-oxide 1b was treated with p-tolyl
isocyanate 4b′, the desired aminated product 5bb was isolated
in 91% yield, suggesting the isocyanate as the potential
intermediate in this transformation (Scheme 5a). To under-
stand the reactivity of aryl vs alkyl carbodiimide in the present
reaction conditions, we have performed the experiment using
N-oxide 1b (2 equiv) and isopropyl(4-methylphenyl)-
carbodiimide 10 (1 equiv) in CPME. Gratifyingly, analytically
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Scheme 6. Mechanistic Pathway
In summary, we have developed the C-H amination of azine
N-oxides with carbodiimides in the absence of metals, external
activators, base, and solvent with excellent site selectivity at the
C2 position. The origin of selectivity is derived from the
[3+2]-diploar cycloaddition reaction of polar N-oxide with
carbodiimide. Contrary to previously reported procedures, this
method not only enables the synthesis of bulky aryl bearing
aminated azines but also showcases varieties of bioactive
molecules efficiently. This reaction is highly atom economical
with CO2 gas as the only co-product.
EXPERIMENTAL PROCEDURE
■
General Procedure for C2-Amination of Azine N-Oxides
with Carbodiimides (GP-I). A mixture of azine N-oxide (1 mmol, 2
equiv) and carbodiimide (0.5 mmol, 1 equiv) was loaded in an oven-
dried 25 mL reaction tube equipped with a stirring bar. The tube was
flushed with argon and properly closed with a screw cap. Then the
reaction tube was placed in a preheated oil bath at 130 °C with
continuous stirring for 12 h. After completion of the reaction, the
crude reaction mixture was purified by column chromatography over
silica gel to obtain the analytically pure compound.
General Procedure for C2-Amination of Azine N-Oxides
with Carbodiimides (GP-II). A mixture of azine N-oxide (1 mmol, 2
equiv), carbodiimide (0.5 mmol, 1 equiv), and CPME (1 mL) was
loaded in an oven-dried 25 mL reaction tube equipped with a stirring
bar. The tube was flushed with argon and properly closed with a screw
cap. Then the reaction tube was placed in a preheated oil bath at 130
°C with continuous stirring for 12 h. After completion of the reaction,
all the volatiles were removed. The crude reaction mixture was
purified by column chromatography over silica gel to obtain the
analytically pure compound.
EXPERIMENTAL SECTION
■
General Information. All the reagents and chemicals were
purchased from common commercial suppliers like Sigma-Aldrich,
Alfa Aesar, Merck, Spectrochem, and Avra Synthesis Pvt. Ltd. and
directly used as received without any further purification unless
otherwise mentioned. Azine N-oxides,10,18 N,N′-(R)-(+)-α-methyl-
benzylcarbodiimide,19a dibenzylcarbodiimide,19b diphenylcarbodiimi-
de,19b di(p-tolyl)carbodiimide,19b di(4-methoxyphenyl)-
carbodiimide,19b di(4-fluorophenyl)carbodiimide,19b dimesitylcarbo-
diimide,19 c di(2,6-diisopropylphenyl)carbodiimide,19 c
dinaphthylcarbodiimide,19c tryptamine isothiocyanate,20 and p-tolyl
isocyanate21 were prepared according to the literature reported
procedures. CPME was freshly distilled over CaH2 and stored in 4 Å
N-Isopropylquinolin-2-amine (3aa).6h Using quinoline N-oxide
with 1,3-diisopropylcarbodiimide in accordance with GP-I, the title
compound was obtained through SiO2-gel column chromatography
(EtOAc:petroleum ether 3:17) as a light yellow solid (168 mg, 90%).
1
Mp 66−68 °C. H NMR (600 MHz, CDCl3): δ 7.81 (d, J = 9.0 Hz,
1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8
Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 9.0 Hz, 1H), 4.65 (s,
1H), 4.22−4.17 (m, 1H), 1.29 (d, J = 6.6 Hz, 6H). 13C{1H} NMR
(151 MHz, CDCl3): δ 156.5, 148.3, 137.5, 129.7, 127.5, 126.1, 123.4,
122.0, 111.3, 43.1, 23.3. HRMS (ESI) m/z: [M + H]+ calculated for
C12H15N2: 187.1235; found: 187.1235.
1
molecular sieves before use. H, 13C, and 19F NMR spectra of the
compounds were measured in CDCl3 as a solvent by using TMS as an
internal standard. Chemical shifts, δ (in ppm), are reported relative to
TMS δ (1H) 0.0 ppm, δ (13C) 0.0 ppm, which was used as the internal
reference. Otherwise, the solvents residual proton resonance and
carbon resonance CHCl3, δ (1H) 7.26 ppm, δ (13C) 77.16 ppm, was
used for calibration. Bruker Avance III 600 and 400 spectrometers
were used to record the NMR spectra. Chemical shifts (δ) values were
reported in ppm, spin-spin coupling constants (J) were expressed in
Hz, and other data were reported as follows: s = singlet, d = doublet,
dd = doublet of doublet, dt = doublet of triplet, t = triplet, m =
multiplet, q = quartet, sext = sextet, br = broad, and brs = broad
singlet. IR spectra were recorded on a PerkinElmer Instrument at
normal temperature making KBr pellet grinding the sample with KBr
(IR grade). MS (ESI-HRMS): Mass spectra were recorded on an
Agilent Accurate-Mass Q-TOF LC/MS 6520. Merck silica gel 60−
120 and Merck neutral aluminum oxide were used for column
chromatography. Melting points were recorded using a Buchi Melting
Point B-540 Instrument and are uncorrected. All starting azine N-
oxides and their amination products were characterized by
spectroscopic methods and compared to the literature wherever
applicable, otherwise stated. All the amination reactions were carried
out in oven-dried glassware under an argon atmosphere. Completion
of reactions was examined by thin layer chromatography carried out
on precoated Merck silica gel 60 F254 aluminum plates with ultraviolet
light (UV) or iodine as visualizing agents.
N-Isopropyl-6-methoxyquinolin-2-amine (3ba). Using 6-methox-
yquinoline N-oxide with 1,3-diisopropylcarbodiimide in accordance
with GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 4:21) as a light yellow oil
(207 mg, 96%). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.8 Hz,
1H), 7.58 (d, J = 9.2 Hz, 1H), 7.20 (dd, J = 8.8, 2.8 Hz, 1H), 6.93 (d,
J = 2.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 4.53 (d, J = 6.4 Hz, 1H),
4.17−4.09 (m, 1H), 3.86 (s, 3H), 1.26 (d, J = 6.4 Hz, 6H). 13C{1H}
NMR (101 MHz, CDCl3): δ 155.5, 154.7, 143.7, 136.6, 127.5, 123.6,
121.0, 111.5, 106.6, 55.6, 43.1, 23.3. HRMS (ESI) m/z: [M + H]+
calculated for C13H16N2O: 217.1336; found 217.1337.
N-Isopropyl-6-methylquinolin-2-amine (3ca). Using 6-methylqui-
noline N-oxide with 1,3-diisopropylcarbodiimide in accordance with
GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 4:21) as a yellow oil (192
mg, 96%). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.8 Hz, 1H),
7.56 (d, J = 9.2 Hz, 1H), 7.38−7.32 (m, 2H), 6.59 (d, J = 8.8 Hz,
1H), 4.60 (br, 1H), 4.20−4.12 (m, 1H), 2.43 (s, 3H), 1.28 (d, J = 6.4
Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 156.2, 146.5, 137.0,
131.6, 131.4, 126.7, 125.8, 123.3, 111.1, 43.1, 23.3, 21.2. HRMS (ESI)
m/z: [M + H]+ calculated for C13H17N2: 201.1392; found: 201.1392.
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6-Chloro-N-isopropyl Quinolin-2-amine (3da). Using 6-chlor-
oquinoline N-oxide with 1,3-diisopropylcarbodiimide in accordance
with GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 1:4) as a yellow oil (187
mg, 85%). 1H NMR (600 MHz, CDCl3): δ 7.72 (d, J = 9.0 Hz, 1H),
7.57 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.4,
2.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 4.94 (br, 1H), 4.20−4.14 (m,
1H), 1.28 (d, J = 6.4 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ
156.5, 146.5, 136.6, 130.2, 127.3, 127.0, 126.3, 123.8, 112.2, 43.1,
23.2. HRMS (ESI) m/z: [M + H]+ calculated for C12H14ClN2:
221.0846; found: 221.0844.
(184 mg, 92%). 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz,
1H), 7.43 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 6.8 Hz, 1H), 7.12−7.08
(m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.54 (d, J = 6 Hz, 1H), 4.33−4.24
(m, 1H), 2.66 (s, 3H), 1.32 (d, J = 6.4 Hz, 6H). 13C{1H} NMR (151
MHz, CDCl3): δ 155.6, 147.1, 137.5, 134.1, 129.7, 125.4, 123.0,
121.5, 111.2, 43.0, 23.0, 18.0. HRMS (ESI) m/z: [M + H]+ calculated
for C13H17N2: 201.1392; found: 201.1396.
N-Isopropyl-6-methyl-4-phenylquinolin-2-amine (3ka).23 Using
4-phenyl-6-methylquinoline N-oxide with 1,3-diisopropylcarbodii-
mide in accordance with GP-I, the title compound was obtained
through SiO2-gel column chromatography (EtOAc:petroleum ether,
N-Isopropyl-4-methylquinolin-2-amine (3ea).22 Using 4-methyl-
quinoline N-oxide with 1,3-diisopropylcarbodiimide in accordance
with GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 3:17) as an off-white solid
3:17) as an off-white solid (259 mg, 94%). Mp 109−111 °C. H
1
NMR (400 MHz, CDCl3): δ 7.64 (d, J = 9.2 Hz, 1H), 7.53−7.46 (m,
5H), 7.38−7.36 (m, 2H), 6.54 (s, 1H), 4.61 (d, J = 7.6 Hz, 1H),
4.23−4.15 (m, 1H), 2.36 (s, 3H), 1.30 (d, J = 6.4 Hz, 6H). 13C{1H}
NMR (101 MHz, CDCl3): δ 155.8, 149.3, 147.1, 139.0, 131.5, 131.4,
129.4, 128.5, 128.2, 126.3, 124.9, 122.3, 111.1, 43.1, 23.4, 21.5.
HRMS (ESI) m/z: [M + H]+ calculated for C19H21N2: 277.1705;
found: 277.1706.
1
(188 mg, 94%). Mp 107−108 °C. H NMR (600 MHz, CDCl3): δ
7.75 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.52−7.50 (m,
1H), 7.23−7.20 (m, 1H), 6.48 (s, 1H), 4.56 (br, 1H), 4.21−4.15 (m,
1H), 2.56 (s, 3H), 1.28 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 156.4, 150.3, 148.2, 145.2, 129.4, 126.4, 123.7,
121.7, 111.2, 42.9, 23.4, 19.1. HRMS (ESI) m/z: [M + H]+ calculated
for C13H17N2: 201.1392; found: 201.1413.
4,7-Dichloro-N-isopropylquinolin-2-amine (3la). Using 4,7-di-
chloroquinoline N-oxide with 1,3-diisopropylcarbodiimide in accord-
ance with GP-I, the title compound was obtained through SiO2-gel
column chromatography (EtOAc:petroleum ether, 3:17) as a yellow
N-Isopropyl-3-methylquinolin-2-amine (3fa). Using 3-methylqui-
noline N-oxide with 1,3-diisopropylcarbodiimide in accordance with
GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 3:17) as a yellow oil (170
mg, 85%). 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.4 Hz, 1H),
7.59 (s, 1H), 7.53 (dd, J = 8, 1.2 Hz, 1H), 7.50−7.46 (m, 1H), 7.22−
7.16 (m, 1H), 4.60−4.52 (m, 1H), 4.31 (d, J = 6.6 Hz, 1H), 2.22 (s,
3H), 1.33 (d, J = 6.4 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ
155.3, 147.3, 135.5, 128.4, 126.7, 126.2, 123.6, 121.8, 119.6, 42.4,
23.3, 17.5. HRMS (ESI) m/z: [M + H]+ calculated for C13H17N2:
201.1392; found: 201.1400.
N-Isopropyl-3-methoxyquinolin-2-amine (3ga). Using 3-methox-
yquinoline N-oxide with 1,3-diisopropylcarbodiimide in accordance
with GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 4:21) as a yellow oil (179
mg, 83%). 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.0 Hz, 1H),
7.51 (dd, J = 7.8, 1.2 Hz, 1H), 7.42−7.38 (m, 1H), 7.22−7.15 (m,
1H), 7.01 (s, 1H), 5.20 (d, J = 7.6 Hz, 1H), 4.54−4.45 (m, 1H), 3.93
(s, 3H), 1.31 (d, J = 6.4 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3):
δ 149.4, 143.2, 126.6, 126.1, 125.8, 123.9, 122.0, 109.3, 55.4, 42.0,
23.2. HRMS (ESI) m/z: [M + H]+ calculated for C13H17N2O:
217.1341; found: 217.1341.
1
oil (212 mg, 83%). H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.8
Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.8, 2.0 Hz, 1H), 6.67
(s, 1H), 4.66 (d, J = 7.2 Hz, 1H), 4.22−4.14 (m, 1H), 1.27 (d, J = 6.4
Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 156.6, 149.7, 142.6,
136.5, 125.6, 125.4, 123.3, 120.1, 111.2, 43.1, 23.1. HRMS (ESI) m/z:
[M + H]+ calculated for C12H13Cl2N2: 255.0456; found: 255.0456.
7-Chloro-N-isopropyl-4-methoxyquinolin-2-amine (3ma). Using
7-chloro-4-methoxyquinoline N-oxide with 1,3-diisopropylcarbodii-
mide in accordance with GP-I, the title compound was obtained
through SiO2-gel column chromatography (EtOAc:petroleum ether,
1:4) as a white solid (231 mg, 92%). Mp 119−121 °C. 1H NMR (400
MHz, CDCl3): δ 7.83 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H),
7.08 (dd, J = 8.8, 2.0 Hz, 1H), 5.87 (s, 1H), 4.63 (d, J = 6.8 Hz, 1H),
4.22−4.13 (m, 1H), 3.93 (s, 3H), 1.27 (d, J = 6.4 Hz, 6H). 13C{1H}
NMR (101 MHz, CDCl3): δ 162.8, 158.5, 149.9, 135.8, 124.8, 123.2,
121.8, 116.1, 89.0, 55.5, 43.1, 23.3. HRMS (ESI) m/z: [M + H]+
calculated for C13H16ClN2O: 251.0951; found: 251.0968.
N-(tert-Butyl)-6-methoxyquinolin-2-amine (3bb). Using 6-me-
thoxyquinoline N-oxide with di-tert-butylcarbodiimide in accordance
with GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 1:4) as a yellow solid (150
mg, 65%). Mp 82−84 °C. 1H NMR (600 MHz, CDCl3): δ 7.70 (d, J
= 9.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.19 (dd, J = 9.0, 3.0 Hz,
1H), 6.93 (d, J = 3.0 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H),
1.51 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3): δ 154.9, 131.3,
130.0, 127.2, 125.0, 123.2, 120.9, 113.1, 106.6, 55.7, 51.5, 29.7.
HRMS (ESI) m/z: [M + H]+ calculated for C14H19N2O: 231.1497;
found: 231.1498.
3-Bromo-N-isopropylquinolin-2-amine (3ha). Using 3-bromoqui-
noline N-oxide with 1,3-diisopropylcarbodiimide in accordance with
GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 1:4) as a light yellow oil
1
(206 mg, 78%). H NMR (600 MHz, CDCl3): δ 8.06 (s, 1H), 7.68
(d, J = 8.4 Hz, 1H), 7.54−7.52 (m, 1H), 7.50 (d, J = 7.8 Hz, 1H),
7.20 (t, J = 7.2 Hz, 1H), 5.18 (d, J = 6.6 Hz, 1H), 4.48−4.43 (m, 1H),
1.32 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 151.7,
147.1, 138.7, 129.8, 126.6, 126.5, 124.1, 122.5, 108.6, 43.1, 23.0.
HRMS (ESI) m/z: [M + H]+ calculated for C12H13BrN2: 265.0340;
found: 265.0371.
N-Isopropyl-8-methoxyquinolin-2-amine (3ia). Using 8-methox-
yquinoline N-oxide with 1,3-diisopropylcarbodiimide in accordance
with GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 3:17) as a light yellow
solid (201 mg, 93%). Mp 79−81 °C. 1H NMR (600 MHz, CDCl3): δ
7.83 (d, J = 9 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 7.8 Hz,
1H), 6.91 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 5.00 (d, J =
7.2 Hz, 1H), 3.99 (s, 3H), 3.97−3.92 (m, 1H), 1.25 (d, J = 6.4 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3): δ 156.3, 153.1, 139.7, 137.9,
124.1, 121.5, 119.7, 109.6, 108.4, 56.0, 43.4, 23.2. HRMS (ESI) m/z:
[M + H]+ calculated for C13H17N2O: 217.1341; found: 217.1347.
N-Isopropyl-8-methylquinolin-2-amine (3ja). Using 8-methylqui-
noline N-oxide with 1,3-diisopropylcarbodiimide in accordance with
GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 3:17) as a light yellow oil
N-Cyclohexylquinolin-2-amine (3ac).24 Using quinoline N-oxide
with 1,3-dicyclohexylcarbodiimide in accordance with GP-I, the title
compound was obtained through SiO2-gel column chromatography
(EtOAc:petroleum ether, 1:4) as a yellowish solid (200 mg, 88%). Mp
1
125−127 °C. H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.8 Hz,
1H), 7.64 (d, J = 8.4 Hz, 1H), 7.58−7.54 (m, 1H), 7.50 (m, 1H),
7.21−7.15 (m, 1H), 6.62 (d, J = 8.8 Hz, 1H), 4.72 (d, J = 5.6 Hz,
1H), 3.88−3.77 (m, 1H), 2.16−2.03 (m, 2H), 1.84−1.70 (m, 2H),
1.70−1.61 (m, 1H), 1.47−1.40 (m, 2H), 1.28−1.19 (m, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 156.5, 148.3, 137.5, 129.6,
127.5, 126.0, 123.4, 121.9, 111.1, 50.0, 33.6, 25.9, 25.6, 25.0, 24.9.
HRMS (ESI) m/z: [M + H]+ calculated for C15H19N2: 227.1543;
found: 227.1543.
N-Cyclohexyl-8-methoxyquinolin-2-amine (3ic). Using 8-methox-
yquinoline N-oxide with 1,3-dicyclohexylcarbodiimide in accordance
with GP-I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 1:4) as a white solid (235
mg, 92%). Mp 169−171 °C. 1H NMR (400 MHz, CDCl3): δ 7.84 (d,
J = 9.2 Hz, 1H), 7.19 (dd, J = 8.0, 0.8 Hz, 1H), 7.10 (t, J = 7.6 Hz,
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1H), 6.93 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.14 (brs,
1H), 4.01 (s, 3H), 3.58−3.54 (m, 1H), 2.08−2.04 (m, 1H), 1.93−
1.91 (m, 1H), 1.83−1.76 (m, 2H), 1.42−1.30 (m, 3H), 1.29−1.20
(m, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 156.9, 156.3, 153.1,
138.0, 124.1, 121.5, 119.8, 109.6, 108.4, 56.0, 50.7, 34.1, 33.7, 25.8,
25.1, 25.0. HRMS (ESI) m/z: [M + H]+ calculated for C16H21N2O:
257.1654; found: 257.1655.
8.4 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.59−7.56 (m, 1H), 7.41 (d, J
= 8.4 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.96
(d, J = 9.0 Hz, 1H), 6.80 (br, 1H), 2.35 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 154.9, 147.9, 137.9, 137.5, 133.3, 130.0, 129.9,
127.6, 126.7, 124.2, 123.1, 121.5, 111.4, 21.0. HRMS (ESI) m/z:
+
calculated for C16H15N2 [ M + H]+: 235.1235; found: 235.1246.
6-Methoxy-N-(p-tolyl)quinolin-2-amine (5bb).7g Using 6-methox-
yquinoline N-oxide, di-p-tolylcarbodiimide, and CPME (1 mL) in
accordance with GP-II, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
white solid (240 mg, 91% yield from GP-II; 237 mg, 90% yield from
GP-I). Mp 113−114 °C. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J =
9.2 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 8 Hz, 2H), 7.27−
7.24 (m, 1H), 7.16 (d, J = 8 Hz, 2H), 6.99−6.96 (m, 2H), 6.72 (brs,
1H), 3.89 (s, 3H), 2.35 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3):
δ 155.6, 153.5, 143.1, 137.8, 137.0, 132.9, 129.95, 127.9, 124.6, 121.6,
121.1, 111.7, 106.4, 55.7, 21.0.
4,7-Dichloro-N-cyclohexylquinolin-2-amine (3lc). Using 4,7-di-
chloroquinoline N-oxide with 1,3-dicyclohexylcarbodiimide in ac-
cordance with GP-I, the title compound was obtained through SiO2-
gel column chromatography (EtOAc:petroleum ether, 1:4) as a yellow
1
oil (239 mg, 81%). H NMR (600 MHz, CDCl3): δ 7.85 (d, J = 8.4
Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.18 (dd, J = 9.0, 1.8 Hz, 1H), 6.68
(s, 1H), 4.77 (brs, 1H), 3.81 (brs, 1H), 2.08−2.06 (m, 2H), 1.79−
1.75 (m, 2H), 1.68−1.65 (m, 1H), 1.45−1.40 (m, 2H), 1.28−1.18
(m, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 156.5, 149.7, 142.7,
136.5, 125.5, 125.4, 123.2, 120.0, 111.0, 50.1, 33.4, 25.8, 25.0. HRMS
(ESI) m/z: [M + H]+ calculated for C15H17Cl2N2: 295.0769; found:
295.0769.
6-Chloro-N-(p-tolyl)quinolin-2-amine (5db).7g Using 6-chloroqui-
noline N-oxide with di(p-tolyl)carbodiimide in accordance with GP-I,
the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 3:17) as a white solid
N-Benzylquinolin-2-amine (3ad).6h Using quinoline N-oxide with
dibenzylcarbodiimide in accordance with GP-I, the title compound
was obtained through SiO2-gel column chromatography (EtOAc:pe-
troleum ether, 1:4) as a white solid (211 mg, 90%). Mp 100−102 °C.
1H NMR (600 MHz, CDCl3): δ 7.82 (d, J = 9.0 Hz, 1H), 7.71 (d, J =
8.4 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.56−7.53 (m, 1H), 7.42−7.41
(m, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.32−7.27 (m, 1H), 7.24−7.22 (m,
1H), 6.63 (d, J = 9.0 Hz, 1H), 5.21 (s, 1H), 4.73 (d, J = 5.4 Hz, 2H).
13C{1H} NMR (151 MHz, CDCl3): δ 156.8, 147.8, 139.3, 137.8,
129.8, 128.8, 127.9, 127.6, 127.5, 126.1, 123.6, 122.4, 111.4, 46.0.
6-Methoxy-N-[(S)-1-phenylethyl]quinolin-2-amine (3be). Using
6-methoxyquinoline N-oxide with bis[(S)-1-phenylethyl]carbodiimide
in accordance with GP-I, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
yellow oil (236 mg, 85%). 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J
= 9.0 Hz, 1H), 7.60 (d, J = 8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 2H), 7.32
(t, J = 7.2 Hz, 2H), 7.25−7.18 (m, 2H), 6.91 (d, J = 2.8 Hz, 1H), 6.53
(d, J = 9.2 Hz, 1H), 5.56 (s, 1H), 5.07−4.91 (m, 1H), 3.85 (s, 3H),
1.61 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 155.1,
155.1, 144.9, 137.3, 137.2, 128.8, 127.2, 126.9, 126.1, 123.7, 121.5,
110.9, 106.6, 55.7, 51.9, 24.2. HRMS (ESI) m/z: [M + H]+ calculated
1
(225 mg, 84%). Mp 109−111 °C. H NMR (600 MHz, CDCl3): δ
7.81 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 2.4 Hz,
1H), 7.50 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.18 (d,
J = 7.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.75 (brs, 1H), 2.35 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 155.0, 146.3, 137.2, 136.9,
133.6, 130.5, 130.0, 128.2, 128.2, 126.3, 124.7, 121.5, 112.4, 21.0.
HRMS (ESI) m/z: [M + H]+ calculated for C16H14ClN2: 269.0846;
found: 269.0856.
N-(4-Methoxyphenyl)quinolin-2-amine (5ac).7e Using quinoline
N-oxide, di(4-methoxyphenyl)carbodiimide, and CPME (1 mL) in
accordance with GP-II, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
light yellow solid (212 mg, 85% yield from GP-II; 187 mg, 75% yield
1
from GP-I). Mp 125−127 °C. H NMR (600 MHz, CDCl3) δ 7.87
(d, J = 9.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H),
7.58−7.56 (m, 1H), 7.42−7.40 (m, 2H), 7.28−7.26 (m, 1H), 6.94−
6.92 (m, 2H), 6.87 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3): δ 156.6, 155.5, 147.7, 138.0, 132.9, 130.0, 127.6,
126.3, 124.2, 124.0, 122.9, 114.7, 111.0, 55.7.
N-(4-Fluorophenyl)quinolin-2-amine (5ad).6h Using quinoline N-
oxide, di(4-fluorophenyl)carbodiimide, and CPME (1 mL) in
accordance with GP-II, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
24.3
for C18H19N2O: 279.1492; found: 279.1493. [α]D = −65.00 (c =
0.02 M, CHCl3).
N-Phenylquinolin-2-amine (5aa).6h Using quinoline N-oxide,
diphenylcarbodiimide, and CPME (1 mL) in accordance with GP-
II, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 3:17) as an off-white solid
(187 mg, 85%). Mp 98−99 °C. 1H NMR (600 MHz, CDCl3): δ 7.92
(d, J = 9.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H),
7.61−7.58 (m, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H),
7.32−7.28 (m, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3): δ 154.5, 147.2, 140.1, 138.2,
130.1, 129.4, 127.6, 126.2, 124.1, 123.5, 123.3, 120.9, 111.7.
6-Methoxy-N-phenylquinolin-2-amine (5ba).7g Using 6-methox-
yquinoline N-oxide, diphenylcarbodiimide, and CPME (1 mL) in
accordance with GP-II, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as
1
light yellow solid (202 mg, 85%). Mp 101−103 °C. H NMR (600
MHz, CDCl3): δ 7.90 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H),
7.64 (d, J = 7.8 Hz, 1H), 7.60−7.57 (m, 1H), 7.53 (dd, J = 8.8, 4.8
Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 9.0 Hz, 2H), 6.97 (brs,
1H), 6.87 (d, J = 9.0 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ
159.1 (d, J = 242.3 Hz), 154.7, 147.6, 138.0, 136.3 (d, J = 2.6 Hz),
130.0, 127.6, 126.7, 124.2, 123.3, 122.8 (d, J = 7.8 Hz), 115.9 (d, J =
22.5 Hz), 111.6. 19F NMR (565 MHz, CDCl3): δ −119.5.
N-Mesitylquinolin-2-amine (5ae). Using quinoline N-oxide,
dimesitylcarbodiimide, and CPME (1 mL) in accordance with GP-
II, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 3:17) as a white solid (210
mg, 80%). Mp 127−129 °C. 1H NMR (600 MHz, CDCl3): δ 7.80 (d,
J = 9.0 Hz, 1H), 7.69−7.65 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.57−
7.54 (m, 1H), 7.24 (t, J = 7.2 Hz, 1H), 6.80 (br, 1H), 6.99 (s, 2H),
6.33 (d, J = 9 Hz, 1H), 2.34 (s, 3H), 2.21 (s, 6H). 13C{1H} NMR
(151 MHz, CDCl3): δ 156.9, 147.9, 138.4, 137.1, 137.0, 133.4, 130.0,
129.4, 127.6, 125.7, 123.8, 122.4, 109.0, 21.1, 18.6. HRMS (ESI) m/z:
[M + H]+ calculated for C18H19N2: 263.1543; found: 263.1550.
N-Mesityl-6-methoxyquinolin-2-amine (5be). Using 6-methoxy-
quinoline N-oxide with dimesitylcarbodiimide in accordance with GP-
I, the title compound was obtained through SiO2-gel column
chromatography (EtOAc:petroleum ether, 3:17) as a white solid
1
an off-white solid (225 mg, 90%). Mp 144−146 °C. H NMR (400
MHz, CDCl3): δ 7.84 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H),
7.55−7.52 (m, 2H), 7.38−7.33 (m, 2H), 7.27 (dd, J = 9.2, 2.8 Hz,
1H), 7.09−7.04 (m, 1H), 7.00 (s, 1H), 6.98 (d, J = 5.6 Hz, 1H), 6.81
(br, 1H), 3.89 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 155.7,
153.0, 143.2, 140.7, 136.9, 129.3, 128.2, 124.7, 122.8, 121.6, 120.1,
112.1, 106.3, 55.6.
N-(p-Tolyl)quinolin-2-amine (5ab).6h Using quinoline N-oxide, di-
p-tolylcarbodiimide, and CPME (1 mL) in accordance with GP-II, the
title compound was obtained through SiO2-gel column chromatog-
raphy (EtOAc:petroleum ether, 3:17) as a white solid (192 mg, 82%
yield from GP-II; 169 mg, 72% yield from GP-I). Mp 103−105 °C.
1H NMR (600 MHz, CDCl3): δ 7.90 (d, J = 8.4 Hz, 1H), 7.75 (d, J =
1
(248 mg, 85%). Mp 162−164 °C. H NMR (600 MHz, CDCl3): δ
7.73 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.24 (dd, J = 9.0,
2.4 Hz, 1H), 7.02−6.91 (m, 3H), 6.43 (brs, 1H), 6.31 (d, J = 8.4 Hz,
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1H), 3.87 (s, 3H), 2.33 (s, 3H), 2.21 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 155.7, 155.0, 143.7, 137.3, 137.1, 136.8, 133.8,
129.4, 127.3, 124.1, 121.6, 109.2, 106.4, 55.7, 21.1, 18.6. HRMS (ESI)
m/z: [M + H]+ calculated for C19H21N2O: 293.1654; found:
293.1654.
8.68−8.66 (m, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.82−7.76 (m, 2H),
7.59 (t, J = 8.0 Hz, 1H), 7.34−7.26 (m, 3H), 6.94−6.90 (m, 2H),
6.71 (d, J = 8.4 Hz, 1H), 6.54 (brs, 1H), 3.83 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3): δ 156.7, 156.5, 156.2, 154.7, 149.2, 138.7, 136.9,
133.5, 123.8, 123.6, 121.1, 114.7, 112.0, 107.9, 55.7.
N-(2,6-Diisopropylphenyl)-6-methoxyquinolin-2-amine (5bf).
Using 6-methoxyquinoline N-oxide with bis(2,6-diisopropylphenyl)-
carbodiimide in accordance with GP-I, the title compound was
obtained through SiO2-gel column chromatography (EtOAc:petro-
leum ether, 3:17) as a white solid (281 mg, 84%). Mp 192−194 °C.
1H NMR (600 MHz, CDCl3): δ 7.72 (d, J = 8.9 Hz, 1H), 7.58 (d, J =
9.1 Hz, 1H), 7.37−7.35 (m, 1H), 7.29−7.21 (m, 3H), 6.96 (d, J = 2.8
Hz, 1H), 6.60 (brs, 1H), 6.29 (d, J = 8.9 Hz, 1H), 3.87 (s, 3H), 3.27
(sept, J = 6.8 Hz, 2H), 1.13 (d, J = 6.2 Hz, 12H). 13C{1H} NMR (101
MHz, CDCl3): δ 156.7, 155.0, 148.3, 143.6, 137.2, 133.4, 128.3,
127.3, 124.2, 124.1, 121.7, 109.2, 106.5, 55.7, 28.7, 28.5. HRMS (ESI)
m/z: [M + H]+ calculated for C22H27N2O: 335.2123; found:
335.2143.
N-(4-Methoxyphenyl)-1,5-naphthyridin-2-amine (5rc). Using 1,5-
naphthyridine 1-oxide with di(4-methoxyphenyl) carbodiimide in
accordance with GP-I, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
1
yellow solid (196 mg, 78%). Mp 174−176 °C. H NMR (600 MHz,
CDCl3): δ 8.66 (d, J = 4.2, 1H), 8.08 (d, J = 9.2 Hz, 1H), 8.01 (d, J =
8.4 Hz, 1H), 7.49−7.45 (m, 3H), 7.07 (d, J = 9.2 Hz, 1H), 6.94 (m, J
= 9.0 Hz, 2H), 6.81 (brs, 1H), 3.84 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3): δ 156.8, 155.5, 146.8, 143.6, 141.1, 138.9, 134.2,
132.5, 124.6, 124.2, 114.7, 55.7. HRMS (ESI) m/z: [M + H]+
calculated for C15H14N3O: 252.1132; found: 252.1133.
N-Cyclohexyl-6-methoxy-4-((1R)-methoxy((1S,4S)-5-vinylquinu-
clidin-2-yl)methyl)quinolin-2-amine (6a). Using 6-methoxy-4-
((1R)-methoxy((1S,4S)-5-vinylquinuclidin-2-yl)methyl)quinoline 1-
oxide (0.5 mmol) with dicyclohexylcarbodiimide (0.25 mmol) in
accordance with GP-I, the title compound was obtained by using
SiO2-gel column chromatography (EtOAc:petroleum ether, 1:4) as a
light yellow oil (185 mg, 85%). 1H NMR (400 MHz, CDCl3): δ 7.64
(d, J = 9.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.8, 2.4 Hz,
1H), 6.75 (s, 1H), 5.70 (brs, 1H), 5.67−5.59 (m, 1H), 5.05−5.04 (m,
1H), 5.01 (brs, 1H), 3.98 (s, 3H), 3.93−3.80 (m, 1H), 3.43 (s, 3H),
3.39−3.36 (m, 1H), 3.28−3.23 (m, 1H), 3.09−3.05 (m, 1H), 2.99−
2.96 (m, 1H), 2.59 (br, 1H), 2.07−2.05 (m, 3H), 2.0−1.98 (m, 3H),
1.81−1.77 (m, 3H), 1.67−1.64 (m, 1H), 1.53−1.49 (m, 1H), 1.46−
1.39 (m, 2H), 1.36−1.29 (m, 2H), 1.27−1.24 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3): δ 178.2, 155.9, 154.2, 142.1, 138.6, 126.6,
122.3, 120.9, 116.8, 107.7, 102.5, 59.5, 57.3, 56.9, 55.0, 50.5, 43.5,
38.0, 34.1, 33.5, 33.4, 27.4, 25.8, 25.4, 25.0, 24.9, 23.4, 19.5. HRMS
(ESI) m/z: [M + H]+ calculated for C27H38N3O2: 436.2964; found:
436.2964.
7-Chloro-N-cyclohexyl-4-((2,5,7,8-tetramethyl-2-(4,8,12-tri-
methyltridecyl)chroman-6-yl)oxy)quinolin-2-amine (6b). Using 7-
chloro-4-((2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-
yl)oxy)quinoline 1-oxide (0.5 mmol) with dicyclohexylcarbodiimide
(0.25 mmol) in accordance with GP-I, the title compound was
obtained by using SiO2-gel column chromatography (EtOAc:petro-
leum ether, 1:4) as a yellow oil (282 mg, 82%). 1H NMR (600 MHz,
CDCl3): δ 8.09 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.17
(dd, J = 8.4, 1.8 Hz, 1H), 5.35 (d, J = 9.4 Hz, 1H), 3.74 (s, 1H), 2.63
(m, 2H), 2.14 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.87−1.82 (m, 2H),
1.71−1.67 (m, 3H), 1.64−1.60 (m, 7H), 1.53−1.51 (m, 2H), 1.31
(brs, 3H), 1.25 (brs, 10H), 1.15−1.12 (m, 5H), 1.08−1.06 (m, 4H),
0.88−0.84 (m, 12H). 13C{1H} NMR (151 MHz, CDCl3): δ 161.8,
158.3, 149.4, 142.6, 136.0, 129.9, 127.8, 125.9, 123.8, 123.7, 123.2,
122.0, 118.2, 115.7, 91.8, 75.4, 49.8, 40.8, 39.5, 37.6, 37.5, 37.4, 33.4,
32.9, 32.1, 29.9, 29.5, 28.1, 25.9, 25.0, 24.9, 24.6, 23.4, 22.9, 22.8,
21.2, 20.8, 20.8, 19.9, 19.8, 19.8, 14.3, 12.9, 12.0. HRMS (ESI) m/z:
[M + H]+ calculated for C44H65ClN2O2: 689.4808; found: 689.4837.
N-(2-(1H-Indol-3-yl)ethyl)quinolin-2-amine (6c). Using quinoline
N-oxide with tryptamine isothiocyanate in accordance with GP-I, the
title compound was obtained through SiO2-gel column chromatog-
raphy (EtOAc:petroleum ether, 3:17) as a brown oil (210 mg, 73%).
1H NMR (600 MHz, CDCl3) δ 8.29 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H),
6-Methoxy-N-(naphthalen-1-yl)quinolin-2-amine (5bg). Using 6-
methoxyquinoline N-oxide (1 mmol) with dinaphthylcarbodiimide
(0.5 mmol) in accordance with GP-I, the title compound was
obtained through SiO2-gel column chromatography (EtOAc:petro-
leum ether, 3:17) as a light yellow solid (231 mg, 77%). Mp 182−184
1
°C. H NMR (400 MHz, CDCl3): δ 8.14−8.07 (m, 1H), 7.93−7.88
(m, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.72 (t, J = 9.4 Hz, 2H), 7.67 (dd, J
= 7.2, 1.2 Hz, 1H), 7.57−7.45 (m, 3H), 7.29 (dd, J = 9.2, 3.2 Hz, 1H),
7.00 (d, J = 2.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 155.7, 154.9, 143.4, 137.1,
136.1, 134.8, 129.3, 128.7, 127.8, 126.5, 126.4, 126.0, 125.5, 124.8,
122.3, 121.8, 120.4, 111.3, 106.4, 55.7. HRMS (ESI) m/z: [M + H]+
calculated for C20H17N2O: 301.1336; found 301.1349.
N-(4-Methoxyphenyl)benzo[h]quinolin-2-amine (5nc). Using
benzo[h]quinoline N-oxide with di(4-methoxyphenyl)carbodiimide
in accordance with GP-I, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
1
light yellow liquid (264 mg, 88%). H NMR (400 MHz, CDCl3): δ
9.19−9.11 (m, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.89−7.85 (m, 1H),
7.70−7.62 (m, 2H), 7.61−7.52 (m, 4H), 7.00−6.90 (m, 2H), 6.91 (d,
J = 8.8 Hz, 1H), 6.75 (brs, 1H), 3.85 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3): δ 156.0, 155.0, 145.8, 137.8, 134.3, 133.4, 130.6,
127.8, 127.7, 126.2, 125.3, 124.5, 123.5, 123.2, 120.7, 114.6, 110.1,
55.7. HRMS (ESI) m/z: [M + H]+ calculated for C20H17N2O:
301.1336; found: 301.1336.
5-Nitro-N-(p-tolyl)isoquinolin-1-amine (5ob). Using 5-nitroiso-
quinoline N-oxide with di(p-tolyl)carbodiimide and CPME (1 mL) in
accordance with GP-II, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
1
brown solid (218 mg, 78%). Mp 157−158 °C. H NMR (600 MHz,
CDCl3): δ 8.40 (d, J = 7.8 Hz, 1H), 8.26 (dd, J = 12, 8.4 Hz, 2H),
7.78 (d, J = 6.0 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 8.4 Hz,
2H), 7.20 (d, J = 8.4 Hz, 2H), 2.36 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3): δ 153.2, 145.9, 145.4, 137.0, 133.8, 130.5, 129.8,
128.2, 127.6, 124.7, 121.7, 119.8, 107.5, 21.1. HRMS (ESI) m/z: [M
+ H]+ calculated for C16H14N3O2: 280.1081; found: 280.1110.
N-(4-Methoxyphenyl)-6-phenylpyridin-2-amine (5pc).25 Using 2-
phenylpyridine N-oxide with di(4-methoxyphenyl)carbodiimide in
accordance with GP-I, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
colorless oil (230 mg, 83%). 1H NMR (600 MHz, CDCl3): δ 7.98 (d,
J = 7.2 Hz, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H),
7.40 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 7.2 Hz,
1H), 6.92 (d, J = 9.0 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.56 (brs,
1H), 3.82 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 157.0,
156.3, 156.2, 139.7, 138.5, 133.6, 128.8, 128.7, 126.9, 123.9, 114.7,
111.3, 105.9, 55.7.
7.72−7.67 (m, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.54−7.52 (m, 1H),
7.37 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 7.8 Hz, 2H), 7.16−7.13 (m, 1H),
7.05 (s, 1H), 6.56 (d, J = 8.4 Hz, 1H), 4.95 (s, 1H), 3.85 (m, 2H),
3.15 (t, J = 6.6 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3): δ 157.0,
148.1, 137.4, 136.6, 129.7, 127.6, 127.6, 126.1, 123.5, 122.3, 122.3,
122.1, 119.5, 119.0, 113.4, 111.6, 111.4, 42.0, 25.5. HRMS (ESI) m/z:
[M + H]+ calculated for C19H18N3: 288.1496; found: 288.1531.
Experimental Procedure for Synthesis of 7.7a Conc. sulfuric
acid (0.3 mL) was added to the 2-alkylamino quinoline (1 mmol, 1
equiv) containing 50 mL round-bottom flask equipped with a
magnetic bar. The reaction mixture was stirred under air at 50 °C for
24 h. After the starting material was completely consumed as
N-(4-Methoxyphenyl)-[2,2′-bipyridin]-6-amine (5qc).13c Using
2,2′-bipyridine N-oxide with di(4-methoxyphenyl) carbodiimide in
accordance with GP-I, the title compound was obtained through
SiO2-gel column chromatography (EtOAc:petroleum ether, 3:17) as a
1
light yellow liquid (216 mg, 78%). H NMR (400 MHz, CDCl3): δ
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Note
confirmed by TLC, the mixture was neutralized using aq. NaOH
solution, and the desired product had precipitated out from the
reaction mixture. The collected residue was dissolved in CH2Cl2, and
the organic layer was separated in a separating funnel and dried over
anhydrous Na2SO4. All the volatile materials were removed under
reduced pressure, and the crude compound was purified through
column chromatography (neutral alumina) using ethyl acetate:petro-
leum ether (1:1) as eluent to obtain the pure product as white solid 7
(118 mg, 82% isolated yield from 3aa; 130 mg, 90% isolated yield
isopropyl-3-(p-tolyl)thiourea (200 mg, 0.96 mmol, 1 equiv) was
dissolved in THF (5 mL) in a round-bottom flask. DMAP (236 mg,
1.9 mmol, 2 equiv) was added to it. Then at 0 °C, iodine (268 mg,
1.04 mmol, 1.1 equiv) was added portionwise to this mixture. The
mixture was stirred at room temperature for overnight. After
completion of the reaction as indicated by TLC, the reaction mixture
was filtered and washed with n-hexane. The filtrate was dried by
removing the solvent under reduced pressure. The crude mixture was
purified through silica-gel column chromatography (n-hexane) to get
the pure compound as a yellow oil (90% yield, 150 mg).
1
from 3ad). 2-Aminoquinoline (7): H NMR (600 MHz, CDCl3): δ
1H NMR (400 MHz, CDCl3): δ 7.08 (d, J = 8.0 Hz, 2H), 7.03−
6.94 (m, 2H), 3.82−3.71 (m, 1H), 2.31 (s, 3H), 1.33 (d, J = 6.4 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3): δ 138.0, 137.2, 134.5, 130.1,
123.2, 50.3, 25.0, 21.0. FT-IR (KBr, selected band): 2111 cm−1 (N
CN). HRMS (ESI) m/z: [M + H]+ calculated for C11H15N2:
175.1230; found: 175.1231, [M + H2O + H]+ calculated for
C11H17N2O: 193.1336; found: 193.1337.
7.89 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.8 Hz,
1H), 7.57 (t, J = 7.4 Hz, 1H), 7.29−7.26 (m, 1H), 6.72 (d, J = 8.8 Hz,
1H), 5.33 (br, 2H). 13C{1H} NMR (151 MHz, CDCl3): δ 157.0,
146.5, 138.8, 130.3, 127.7, 125.1, 123.4, 123.1, 112.1. HRMS (ESI)
m/z: [M + H]+ calculated for C9H9N2: 145.0761; found: 145.0761.
Experimental Procedure for Synthesis of 8.26 In an oven-
dried sealed tube, 5bb (80 mg, 0.3 mmol, 1 equiv), diphenyl acetylene
(81 mg, 0.45 mmol, 1.5 equiv), Pd(MeCN)2Cl2 (4 mg, 0.015 mmol, 4
mol %), and anhydrous CuCl2 (85 mg, 0.63 mmol, 2.1 equiv) were
added, followed by dry DMF (2 mL). The reaction mixture was
stirred at 110 °C for 12 h under a N2 environment. After completion
of the reaction as confirmed by TLC, the reaction was quenched with
ice-water and extracted with ethyl acetate (10 mL × 2). The
combined organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The reaction mixture was purified
by silica-gel column chromatography (EtOAc:petroleum ether = 1:4)
to get the pure product as a yellow solid (68% yield, 90 mg).
6-Methoxy-2-(5-methyl-2,3-diphenyl-1H-indol-1-yl)quinoline
(8).7g 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 9.2 Hz, 1H), 7.84
(d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.52 (brs, 1H), 7.43 (dd,
J = 9.2, 2.4 Hz, 1H), 7.37−7.32 (m, 4H), 7.28−7.24 (m, 1H), 7.19−
7.09 (m, 6H), 7.06 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 3.94
(s, 3H), 2.46 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 158.1,
149.4, 143.2, 136.3, 136.1, 135.8, 135.0, 132.1, 131.1, 130.5, 130.5,
128.8, 128.4, 128.2, 127.5, 126.3, 125.1, 122.7, 120.9, 119.3, 118.2,
111.8, 105.4, 55.8, 21.7. HRMS (ESI) m/z: [M + H]+ calculated for
C31H25N2O: 441.1962; found: 441.1973.
Synthesis of Compound 11. 3-Bromo-4-(4-methylbenzoyl)-
quinoline N-oxide (342 mg, 1 mmol) was taken in a 25 mL reaction
tube, and diisopropyl carbodiimide (63 mg, 0.5 mmol) was added to
it. The tube was flushed with argon and closed with a screw cap. The
reaction mixture was stirred at 130 °C for 12 h. After completion of
the reaction, the crude product was purified by silica-gel column
chromatography (EtOAc:petroleum ether 1:10) to get 11 (brown
viscous oil) with 74% yield (286 mg).
1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 7.6 Hz, 1H), 7.83 (d, J
= 8.4 Hz, 2H), 7.61−7.50 (m, 2H), 7.30 (d, J = 8.0 Hz, 3H), 4.78−
4.71 (m, 1H), 3.83−3.69 (m, 1H), 2.44 (s, 3H), 1.62 (d, J = 6.8 Hz,
6H), 1.05 (d, J = 6.4 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ
192.2, 148.4, 145.8, 144.6, 144.3, 135.6, 134.4, 130.3, 129.8, 128.0,
127.9, 125.4, 124.7, 122.5, 119.5, 47.1, 46.5, 24.5, 22.0, 19.1. FT-IR
(KBr, selected band): 1671 (CO), 1604 (CN) cm−1. HRMS
(ESI) m/z: [M + H]+ calculated for C24H26N3O2: 388.2020; found:
388.2019.
CONTROLLED EXPERIMENTS FOR REACTION
MECHANISM
■
Gram-Scale Synthesis of N-Isopropylquinolin-2-amine
(3aa). A mixture of quinoline N-oxide (1 g, 6.9 mmol, 2 equiv)
and 1,3-diisopropylcarbodiimide (0.435 g, 3.4 mmol, 1 equiv) was
loaded in an oven-dried 50 mL reaction tube equipped with stirring
bar. The tube was flushed with argon and properly closed with a screw
cap. Then the tube was placed in a preheated oil bath at 130 °C with
continuous stirring for 12 h. After completion of the reaction, the
crude reaction mixture was purified by silica-gel column chromatog-
raphy (EtOAc:petroleum ether 2:10) to obtain the analytically pure
product 3aa in 85% yield (1.1 g).
Amination Reaction of 6-Methoxyquinoline N-Oxide
(1b) with p-Tolyl Isocyanate (4b′). 6-Methoxyquinoline N-
oxide (175 mg, 1 mmol), p-tolyl isocyanate (133 mg, 1 mmol),
and CPME (1 mL) were taken in a 25 mL reaction tube. The
tube was flushed with argon and properly closed with a screw
cap. Then the reaction tube was placed in a preheated oil bath
at 130 °C with continuous stirring for 12 h. All the volatile
materials were removed, and the crude mixture was purified by
silica-gel column chromatography (EtOAc:petroleum ether
1:4) to get the pure product 5bb (91% yield, 240 mg).
Amination Reaction of 6-Methoxyquinoline N-Oxide
(1b) with Carbodiimide 10. 6-Methoxyquinoline N-oxide
(175 mg, 1 mmol), isopropyl(4-methylphenyl)carbodiimide 10
(87 mg, 0.5 mmol), and CPME (1 mL) were taken in a 25 mL
reaction tube. The tube was flushed with argon and properly
closed with a screw cap. Then the reaction tube was placed in a
preheated oil bath at 130 °C with continuous stirring for 12 h.
All the volatile materials were removed, and the crude mixture
was purified by silica-gel column chromatography to obtain the
aminated product 5bb, 98 mg, 37%, and 3ba, 56 mg, 26%
yield, respectively.
Trapping of CO2 as a Bench-Stable Amine Carbamate
Ammonium Salt (9). A mixture of quinoline N-oxide (1 g, 6.9
mmol, 2 equiv) and 1,3-diisopropylcarbodiimide (0.435 g, 3.4 mmol,
1 equiv) was loaded in an oven-dried 50 mL round-bottom flask
equipped with a stirring bar. The flask was flushed with argon and
properly closed with a septum. Then one end of the cannula was
connected through the septum, and the other end of the cannula was
dipped to the precooled benzylamine containing flask. The reaction
mixture was kept in the preheated oil bath at 130 °C with continuous
stirring for 12 h. The evolved carbon dioxide was allowed to pass
through the cannula and reacted with benzyl amine to form
benzylammonium benzylcarbamate as a white solid (0.749 g, 85%
1
yield). H NMR (600 MHz, D2O): δ 7.47−7.27 (m, 10H), 4.21 (s,
1H), 4.04 (s, 4H). 13C{1H} NMR (151 MHz, D2O): δ 164.7, 161.0,
140.7, 135.2, 129.0, 128.6, 128.4, 126.8, 126.6, 44.7, 43.5. Spectral
data are in accordance with the literature.16d
Amination Reaction of 6-Methoxyquinoline N-Oxide
(1b) with Carbodiimide 10 and 4b. 6-Methoxyquinoline
N-oxide (175 mg, 1 mmol), isopropyl(4-methylphenyl)-
carbodiimide 10 (43 mg, 0.25 mmol), 1,3-di-p-tolylcarbodii-
mide 4b (55 mg, 0.25 mmol), and CPME (1 mL) were taken
in a 25 mL reaction tube. The tube was flushed with argon and
properly closed with a screw cap. Then the reaction tube was
placed in a preheated oil bath at 130 °C with continuous
Preparation of Isopropyl(4-methylphenyl)carbodiimide
(10). In a round-bottom flask, p-tolyl isothiocyanate (200 mg, 1.2
mmol, 1 equiv) and isopropyl amine (88 mg, 1.4 mmol, 1.1 equiv)
were added and flushed with nitrogen before closing with a glass
stopper. White precipitate started to come almost instantly. The
reaction mixture was stirred at that condition for about 1 h. After
confirming the completion of the reaction by TLC, the resultant 1-
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Note
stirring for 12 h. All the volatile materials were removed, and
the crude mixture was purified by silica-gel column
chromatography to obtain the aminated product 5bb, 153
mg, 58%, and 3ba, 22 mg, 10% yield, respectively.
IITG for their research fellowship. We would like to thank the
Department of Chemistry, and the Central Instrumentation
Facility, IITG for mass (FIST) and COE FAST for the NMR
(F. No. 22-3/2016-TS-II/TC) analysis and for the start-up
grant.
Amination Reaction of 6-Methoxyquinoline N-Oxide
(1b) with Carbodiimide 10 and 2a. 6-Methoxyquinoline N-
oxide (175 mg, 1 mmol), isopropyl(4-methylphenyl)-
carbodiimide 10 (43 mg, 0.25 mmol), 1,3-diisopropylcarbo-
diimide 2a (31 mg, 0.25 mmol), and CPME (1 mL) were
taken in a 25 mL reaction tube. The tube was flushed with
argon and properly closed with a screw cap. Then the reaction
tube was placed in a preheated oil bath at 130 °C with
continuous stirring for 12 h. All the volatile solvent was
removed, and the crude mixture was purified by silica-gel
column chromatography to obtain the aminated product 5bb,
45 mg, 17%, and 3ba, 73 mg, 34% yield, respectively.
Amination Reaction of 6-Methoxyquinoline N-Oxide
(1b) with Carbodiimide 2a or 4b. 6-Methoxyquinoline N-
oxide (175 mg, 1 mmol), and 1,3-diisopropylcarbodiimide 2a
(63 mg, 0.50 mmol) or 1,3-di-p-tolylcarbodiimide 4b (111 mg,
0.50 mmol) were taken in a 25 mL reaction tube. The tube was
flushed with argon and properly closed with a screw cap. Then
the reaction tube was placed in a preheated oil bath at 130 °C
with continuous stirring for 5 h. The crude reaction mixture
was purified by silica-gel column chromatography to obtain the
aminated product. Isolated yield 3ba, 88 mg, 41%. Isolated
yield 5bb, 169 mg, 64%.
REFERENCES
■
(1) (a) Joule, J. A.; Mills, K. In Heterocyclic Chemistry, 5th ed.; Wiley-
Blackwell: New York, 2010; pp 249−288. (b) Afzal, O.; Kumar, S.;
Haider, M. R.; Ali, M. R.; Kumar, R.; Jaggi, M.; Bawa, S. A Review on
Anticancer Potential of Bioactive Heterocycle Quinoline. Eur. J. Med.
Chem. 2015, 97, 871−910. (c) Hu, Y. Q.; Gao, C.; Zhang, S.; Xu, L.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00741.
■
sı
Comparison with known methods for byproducts (Table
S1), optimization of reaction conditions (Table S2),
effect of temperature on the amination of quinoline N-
oxide, determination of green chemistry metrics (Table
S3), computational data and NMR spectra for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
Animesh Das − Department of Chemistry, Indian Institute of
Technology Guwahati, Guwahati 781039, India;
orcid.org/0000-0003-2178-7116; Email: adas@iitg.ac.in
■
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Catal. 2021, 363, 2−39.
Authors
Bikash Kumar Sarmah − Department of Chemistry, Indian
Institute of Technology Guwahati, Guwahati 781039, India
Monuranjan Konwar − Department of Chemistry, Indian
Institute of Technology Guwahati, Guwahati 781039, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00741
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
A.D. gratefully acknowledges the SERB, DST (ECR/2016/
001459), and DST-INSPIRE (IFA-14-CH-135) for the
financial support. B.K.S. and M. K. would like to thank the
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