Metal-free Deoxygenative 2-Amidation of Quinoline N-oxides with Nitriles via a Radical Activation Pathway

Article abstract of DOI:10.1002/adsc.201800918

A metal-, base- and reductant-free approach for the efficient synthesis of various N-acylated 2-aminoquinolines was reported. In this work, readily available nitriles are used as the amide source, and methyl carbazate as both the radical activating reagent and oxygen source. This is the first report on the ester-radical-activated highly regioselective addition of nitriles to quinolone N-oxides. This procedure is expected to complement the current methods for functionalization of N-oxides via an electrophilic activation mechanism. (Figure presented.).

Full text of DOI:10.1002/adsc.201800918

Title: Metal-free Deoxygenative 2-Amidation of Quinoline N-oxides with
Nitriles via a Radical Activation Pathway
Authors: Long-Yong Xie , Sha Peng, Fang Liu, Jin-Yu Yi, Ming Wang,
Zilong Tang, Xinhua Xu, and Wei-Min He
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800918
Link to VoR: http://dx.doi.org/10.1002/adsc.201800918

10.1002/adsc.201800918
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-free Deoxygenative 2-Amidation of Quinoline N-oxides
with Nitriles via a Radical Activation Pathway
Long-Yong Xiea, Sha Penga, Fang Liua, Jin-Yu Yia, Ming Wangb, Zilong Tangb, Xinhua
Xuc and Wei-Min Hea,c*
a
Hunan Provincial Engineering Research Center for Ginkgo biloba, Hunan University of Science and Engineering,
Yongzhou 425100, China
Fax: (+86)-746-6381166; phone: (+86)-018175151053; e-mail: weiminhe2016@yeah.net
Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education, Hunan
b
University of Science and Technology, Xiangtan 411201, China
State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, 410082, China
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A metal-, base- and reductant-free approach for This procedure is expected to complement the current
the efficient synthesis of various N-acylated 2- methods for functionalization of N-oxides via an
aminoquinolines was reported. In this work, readily available electrophilic activation mechanism.
nitriles are used as the amide source, and methyl carbazate as
Keywords: quinoline N-oxide; 2-amidation; radical
both the radical activating reagent and oxygen source. This is
activator; N-acylated 2-aminoquinoline; nitrile
the first report on the ester-radical-activated highly
regioselective addition of nitriles to quinolone N-oxides.
compounds
and
pharmaceuticals.[13]
The
Introduction
construction of N-acylated 2-aminoquinolines
through nucleophilic substitution of electrophilic
O-activation of N-oxides with various amide
source[14] has been successfully developed. To the
best of our knowledge, there is no example of
direct synthesis of N-acylated 2-aminoquinolines
from quinoline N-oxides via a radical activation
pathway. As part of our ongoing interest in the
green chemistry,[15] we have reported the
synthesis of 2-substituted quinoline from
Quinolines are extremely important because of
their abundance in various biologically active
natural products and synthetic pharmaceuticals.[1]
Consequently, the construction of valuable
quinoline derivatives from readily available
precursors under transition-metal-free conditions
is a prominent research objective, especially in
the pharmaceutical industry.[2] The regioisomers
of quinoline molecules usually have contrasting
indications or even opposing pharmacological
activities. Therefore, the construction of various
substituted quinolines from readily accessible
quinoline N-oxides[3] via nucleophilic (Scheme 1a)
and Minisci-type radical addition[4] (Scheme 1b)
pathway under metal-free conditions represents a
highly attractive approach because of excellent
regioselectivity and high efficiency. However,
quinoline
N-oxides
through
electrophilic
activation pathway.[16] In this paper, we report for
the first time a metal-, base- and reductant-free
deoxygenative 2-amidation of quinoline N-oxides
with nitriles via a radical activation pathway
(Scheme 1c). Our present strategy not only
provides a novel, mild and efficient protocol for
the synthesis of structurally important N-acylated
2-aminoquinolines, but also complements existing
compared
with
the
well-established
electrophilic
activation
mechanism
for
functionalization of quinoline N-oxides activated
by various electrophiles (sulfonyl chlorides,[5]
acyl chlorides,[6] anhydrides,[7] PyBroP,[8] H-
functionalization of N-oxides.
phosphonate,[9]
iodine
reagents,[10]
the regioselective
boron
reagents,[11]
etc.[12]),
nucleophilic substitution of N-oxides activated by
a free radical activator have not been reported.
N-acylated 2-aminoquinolines are found in
many natural products, biologically active
1
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10.1002/adsc.201800918
Advanced Synthesis & Catalysis
Table 1. Screening the optimized reaction conditionsa
Scheme 1. Functionalization of Quinoline N-oxides
Entry Oxidant(equiv.)
2a(equiv.)
R
Solvent Yield(%)b
K2S2O8
Na2S2O8
5
5
5
5
5
5
5
5
5
5
5
5
5
5
7
3
5
5
5
5
5
5
5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
DCE
5%
9%
19%
N.R.
N.R.
N.R.
N.R.
73
1
2
DCE
Selectfluor
DTBP
DCE
3
DCE
4
TBHP
DCE
5
m-CPBA
PhI(OAc)2
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
--
DCE
6
DCE
7
DBE
8
MeNO2
67
9
THF
N.R.
6
10
11
12
13
14
15
16
17c
18d
19
20
21
22
23
DMF
DMSO
N.R.
13
PhCF3
-
-
-
-
-
-
-
-
-
-
91
Results and Discussion
90
62
Initially, the reaction of 4-methylquinoline N-oxide
(1a) with benzonitrile (2a) was selected as a model
reaction for the reaction condition optimization.
Treatment of a mixture of 1a and 2a (5 equiv.) with
NH2NHCO2Me (2 equiv.) in 1,2-dichloroethane
(DCE) at 120 ℃ for 8 h, a 5% yield of N-(4-
methylquinolin-2-yl)benzamide (3aa) along with
unidentified complex mixture that included unreacted
substrates were observed (Table 1, entry 1). Next,
various oxidants were investigated (entries 2 - 7), and
Selectfluor was found to be the most efficient oxidant
for this transformation. Subsequently, the effect of
reaction media on the efficiency was surveyed. It was
found that 1,2-dibromoethane (DBE) was the most
suitable solvent for the present reaction, while other
solvents gave lower yields or trace amount of 3aa
(entries 8 - 13). To our delight, the desired 3aa was
formed in 91% yield without DBE but under
otherwise optimal conditions (entry 14). Increasing
the loading of PhCN did not improve the outcome of
the reaction (entry 15). However, decreasing the
amount of PhCN from 5 equiv. to 3 equiv. led to the
formation of product 3aa in a mediocre 62% yield
(entry 16). Both lowering and raising the reaction
temperature resulted in relatively lower yields (entries
17 and 18). A series of alkyl hydrazinecarboxylates
were examined under the optimal conditions (entries
19 - 21). It was found that NH2NHCO2Et,
NH2NHCO2t-Bu and NH2NHCO2Bn could also
promote the 2-amidation reaction, but resulted in
distinctly decreased yields. Control experiments
(entries 22 - 23) showed that the Selectfluor and
methyl carbazate were both necessary for the success
of this transformation
65
78
83
tBu
Bn
Me
-
15
12
N.R.
N.R.
Selectfluor
[a]
Unless otherwise specified, all reactions were carried out in a
sealed tube in the presence of 1a (0.1 mmol), 2a, NH2NHCO2Me
(0.2 mmol), oxidant (0.2 mmol) and solvent (0.3 mL) at 120℃ for
8h
1
[b] Estimated by H NMR spectroscopy using diethyl phthalate as
an internal reference.
[c] at 100℃
[d] at 140℃
The optimized reaction conditions (Table 1, entry
14) were applicable for the 2-amidation of quinoline
N-oxides with nitriles. As shown in Table 2, aryl
cyanides with various synthetically valuable
functional groups present on benzene ring such as
alkyl (Me and t-Bu), alkoxy (OMe and OCF3),
halogen atom (F, Cl and Br) and trifluoromethyl, were
well compatible (3aa - 3ak). Furthermore, the yield
was slightly lower in the case of ortho-substituted
benzonitrile (3ak) than that obtained with the para-
substituted one (3af), which possibly due to the steric
factors. Polycyclic and various heteroaromatic
substituted formonitriles could also be converted into
the corresponding N-acylated 2-aminoquinolines (3al
- 3ap) in good yields. In addition, aliphatic cyanides,
such as methyl, propyl-, cyclopropyl- and
cinnamylnitrile, were also effective in producing the
desired products (3aq - 3at) in good yields. However,
when isocyanoacetate and tert-butyl isocyanide was
used as the substrate, no corresponding products were
obtained, and some unidentified complex mixtures
2
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10.1002/adsc.201800918
Advanced Synthesis & Catalysis
Scheme 2. Gram-scale synthesis and one-pot
transformation
were observed. Quinoline N-oxides bearing electron-
rich or electron-poor substituents at the 5, 6, 7, 8-
positions of quinoline ring all underwent amidation
smoothly at the 2-position. Importantly, a wide range
of functional groups were compatible under the
current reaction system, including methyl (3bc - 3bf),
methoxy (3bg), fluoro (3bh), chloro (3bi and 3bj)
bromo (3bk) and ester group (3bl). However, when
pyridine N-oxide, 2-methylquinoline N-oxide,
isoquinoline N-oxide and quinoxaline N-oxide, were
employed as the substrate, only a trace amount of the
2-amidation product were observed.
In order to understand the reaction mechanism of
the present 2-amidation reaction, a series of control
experiments were performed. Firstly, no 2-amidation
reaction occurred between quinoline and benzonitrile
under standard conditions, suggesting that the N-O
group played a pivotal role in the reaction (Scheme
3a). The addition of a radical scavenger (TEMPO or
BHT) well suppressed the 2-amidation process
(Scheme 3b). When the reaction of quinoline N-oxide,
benzonitrile and 1,1-diphenylethylene was conducted
under standard conditions, no desired product was
observed and a diphenylethylene-trapped compound
(methyl 3,3-diphenylacrylate, 5a) was detected
(Scheme 3c). These results suggested that a free-
radical pathway was probably involved in the present
reaction. No desired product was observed when
benzamide was employed instead of benzonitrile
under standard conditions, which ruled out the
intermediacy of benzamide (Scheme 3d). To probe
the O-atom transfer course, the 2-amidation reaction
of 18O-quinoline N-oxide with benzonitrile was
conducted under the standard conditions, and no 18O
was installed in the product (Scheme 3e). Performing
the 2-amidation reaction under nitrogen atmosphere
did not affect the reaction outcome (Scheme 3f).
Together, these results indicated that the oxygen atom
of amide product originates from methyl carbazate.
Finally, a kinetic isotope effect value (kH/kD ≈1.13) of
the competitive intermolecular 2-amidation involving
a 1:1 mixture of 1b/1b-d1 was detected (Scheme 3g),
revealing that the quinoline N-oxide C(sp2)-H bond
dissociation may not be the rate-determining step.
Table 2. Reaction Scopea
a) All reactions were carried out in a seal tube in the presence of 1
(0.3 mmol),
2
(1.5 mmol), Selectflour (0.6 mmol),
NH2NHCO2Me (0.6 mmol), isolated yields are reported; b) DBE
(1.2 ml) was used as the solvent.
To show the synthetic utility of this reaction,
scalable 2-amidation reactions were conducted. 4-
Methylquinoline N-oxide (1a, 10 mmol) reacted with
nitriles 2a and 2q under standard conditions, and the
desired N-acylated 2-aminoquinoline product 3aa and
3aq were obtained in 85% and 81% yields,
respectively (Scheme 2a). Furthermore, a sequential
one-pot 2-amidation/hydrolyzation was conducted to
produce 2-quinolinamine 4a in 66% yield (Scheme
2b). We have attempted to synthesize N-acylated 2-
aminoquinoline
through
one-pot
sequential
oxidantion of quinoline and 2-amidation of quinoline
N-oxide, but all efforts failed.
3
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10.1002/adsc.201800918
Advanced Synthesis & Catalysis
aminoquinoline derivatives in good to excellent yields.
This is the first report on the highly regioselective
addition of nitriles to quinoline N-oxides activated by
ester radical. In this transformation, the methyl
carbazate plays dual roles: radical activator and
oxygen source. This procedure is expected to
complement the existed methods for quinoline N-
oxide activation by various electrophilic activators.
Scheme 3. Control Experiments
Experimental Section
General Procedure for the Synthesis of 3
In a pressure tube was consecutively placed
quinoline N-oxide (0.3 mmol), nitriles (1.5 mmol, for
solid nitriles, 1.2 mL of DBE was added as the
solvent), methyl carbazate (0.6 mmol) and Selectfluor
(0.6 mmol), then the mixtures were heated to 120 °C,
The progress of the reaction was monitored by TLC.
The reaction typically took 8 h - 12 h. Upon
completion, the reaction was cooled to room
temperature, then water (5 mL) was added to the
reaction mixture, it was extracted with CH2Cl2 (5 mL
x 3) and the organic extracts were dried over
anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by
column chromatography on silica gel to obtain 3.
Based on the above experimental results and
related literature,[10c] a possible reaction mechanism is
depicted in Scheme 4. First, the oxidation of the
methyl carbazate by Selectfluor occurred via a single
electron transfer to generate a carbon-centered ester
radical with the release of molecular nitrogen, HF and
tetrafluoroborate.[17] Subsequently, the ester radical
coupled with quinoline N-oxide 1 to produce a radical
cation intermediate A which could be further oxidized
to a quinolinium intermediate B. The nucleophilic
attack of nitrile 2 to cationic α-carbon of intermediate
B generated an intermediate C, which underwent
dehydro-aromatization to form an intermediate D with
the release of a proton. Finally, the intermediate D
was decomposed to a benzimidic acid E, which
rapidly tautomerized to produce the more stable target
product 3.
Acknowledgements
We are grateful for financial support from the
post-funded projects of Hunan University of Science
and Engineering, Scientific Research Hunan
Provincial Education Department (No. 17A081) and
the 9th Science and Technology Innovation Program
(2017) of China Hunan Provincial Science &
Technology Department.
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10.1002/adsc.201800918
Advanced Synthesis & Catalysis
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10.1002/adsc.201800918
Advanced Synthesis & Catalysis
UPDATE
Metal-free
Deoxygenative
2-Amidation
of
Quinoline N-oxides with Nitriles via a Radical
Activation Pathway
Adv. Synth. Catal. Year, Volume, Page – Page
A metal-, base- and reductant-free method for the
construction
of
various
N-acylated
2-
aminoquinolines form quinoline N-oxides by the
use of NH2NHCO2Me as the radical activator and
oxygen source was first reported.
6
This article is protected by copyright. All rights reserved.