Bronsted acid catalyzed benzylic C-H bond functionalization of azaarenes: Nucleophilic addition to nitroso compounds

Article abstract of DOI:10.1021/ol501422k

A practical Bronsted acid promoted benzylic C-H functionalization of 2-alkylazaarenes and nucleophilic addition to nitroso compounds was developed under mild conditions. Switched by Bronsted acids, this method can afford azaarene-2-aldimines, azaarene-2-carbaldehyde, or azaarene-2-oximes selectively. No metal, base, oxidant, or other additives were required.

Full text of DOI:10.1021/ol501422k

Letter
pubs.acs.org/OrgLett
Brønsted Acid Catalyzed Benzylic C−H Bond Functionalization of
Azaarenes: Nucleophilic Addition to Nitroso Compounds
Xu Gao,† Feng Zhang,‡ Guojun Deng,† and Luo Yang*,†
†Key Laboratory for Environmentally Friendly Chemistry and Application of the Ministry of Education, College of Chemistry,
Xiangtan University, Hunan 411105, China
‡College of Science, Hunan Agricultural University, Hunan 410128, China
S
* Supporting Information
ABSTRACT: A practical Brønsted acid promoted benzylic
C−H functionalization of 2-alkylazaarenes and nucleophilic
addition to nitroso compounds was developed under mild
conditions. Switched by Brønsted acids, this method can afford
azaarene-2-aldimines, azaarene-2-carbaldehyde, or azaarene-2-
oximes selectively. No metal, base, oxidant, or other additives
were required.
reactions such as aldol-type reactions,9 ene reactions,10 and
uinolines and their derivatives are important motifs in
Diels−Alder reactions11 since the first preparation12 of nitro-
Q pharmaceutical and agricultural chemistry and are used as
key building blocks in natural product synthesis.1 Various
preparative methods for the synthesis of quinolines, along with
methods for the further transformation of these azaarenes, have
therefore been developed.2 Among them, the direct benzylic C−
H bond functionalization of azaarenes has stimulated tremen-
dous research interest.3−8 While the traditional benzylic
transformation via deprotonation−nucleophilic substitution/
sobenzene in 1874. In line with our interest in the C−H
activation and nucleophilic additions,5a,b,13 our previous
studies5a,b have revealed that Brønsted acids turned out to be
effective catalysts for converting 2-alkylazaarene to its more
nucleophilic enamine counterpart, and thus promoted the
benzylic C−H addition to carbonyl groups or iminium ion
(generated in situ). To the best of our knowledge, the benzylic
C−H addition of azaarenes to nitroso compounds in the absence
of strong base has not been developed. Consequently, we
envisioned a Brønsted acid catalyzed CN bond-forming
process for the functionalization of azaarenes by the nucleophilic
addition to nitroso compounds (Scheme 1, route c).
n
addition sequence requires a strong base such as BuLi or
LDA,3 recent research revealed that this transformation can be
accelerated by shifting the alkylazaarene to its enamine
counterpart assisted by a suitable Lewis4,7,8 or Brønsted acid5
(Scheme 1, route a). This strategy has been successively applied
to various nucleophilic additions of benzylic C−H bond of
azaarenes for the C−C,4−6 CC7 (Scheme 1, route a), and C−
N8 bond-forming reactions (Scheme 1, route b).
Based on our previous work on Brønsted acid promoted
nucleophilic addition of the benzylic C−H bond of azaarenes to
aromatic aldehydes, where the Brønsted acid played a crucial role
for the activation of alkylazaarenes and the aldehydes through a
six-membered hydrogen-bonding transition state, we hypothe-
sized that the nucleophilic addition of benzylic C−H bond
should proceed similarly when the CO bond was replaced by
the reactive NO bond of nitroso compounds.
On the other hand, nitroso compounds have been widely used
as attractive electrophiles in C−N and/or C−O bond-forming
Scheme 1. Benzylic C−H Functionalization of Azaarenes
To test the feasibility of the hypothesis above, we first
examined the reaction of 2-methylquinoline (1a) and p-
chloronitroso benzene (2a) catalyzed by acetic acid (Table 1,
entry 1). Unexpectedly, when the reaction was performed in
DMSO, most of the starting materials were consumed after
stirring at room temperature overnight,14 and the product was
characterized as aldimine 3a, which was obtained from the
further dehydration of the anticipated nucleophilic addition
product.
To examine the influence of acidity to the reaction, different
Brønsted acids such as pivalic acid (PivOH), benzoic acid, p-
Received: May 18, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization of the Brønsted Acid Promoted
Benzylic Nucleophilic Addition of Azaarenes
Table 2. Effect of Substituents on the Azaarene Moiety
a
b
entry
BA (mol %)
AcOH (100)
solvent
DMSO
3a yield (%)
1
2
3
4
5
6
41
0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
PivOH (100)
55
PhCO2H (100)
62
p-NO2C6H4CO2H (100)
2,4-(NO2)2C6H3CO2H (100)
p-TSA (100)
67
59
c
7
<5 (89)
75
8
pNO2C6H4CO2H (50)
p-NO2C6H4CO2H (20)
p-NO2C6H4CO2H (100)
p-NO2C6H4CO2H (100)
p-NO2C6H4CO2H (100)
p-NO2C6H4CO2H (100)
p-NO2C6H4CO2H (100)
p-NO2C6H4CO2H (100)
p-NO2C6H4CO2H (100)
9
65
d
10
52
c
11
54
12
13
14
15
16
53
1,4-dioxane
DCE
39
<5
CH3CN
toluene
trace
trace
a
Conditions: 1a (0.4 mmol), 2a (0.8 mmol), Brønsted acid (BA),
solvent (0.6 mL), reacted for 12 h at rt under argon atmosphere unless
b
otherwise noted. Isolated yields for aldimine 3a. Yield for 4a was
c
d
given in parentheses. Reacted at 40 °C. Reacted at 0 °C.
nitrobenzoic acid, and 2,4-dinitrobenzoic acid were tested
(entries 1−7); among them, p-nitrobenzoic acid was found to
be the best choice (entry 5). When the acidity was too weak, the
reaction was sluggish, and when the acidity was too strong, part of
the product (aldimine 3a) would be further hydrolyzed to afford
quinoline-2-carbaldehyde (4a).15 The loading of p-nitrobenzoic
acid was carefully evaluated next, and the best yield was obtained
when 50 mol % of acid was used (entries 6, 8, and 9). It is worth
noting that excess p-chloronitrosobenzene (2a, 2 equiv) was
required for the complete conversion of 2-methylquinoline (1a)
because part of the p-chloronitrosobenzene would undergo
homocoupling to yield azodioxy dimmer in acidic condition.
When much stronger p-TSA was used, the yield of aldimine
product was very low (<5%) and the quinoline-2-carbaldehyde
(4a) turned out to be the main product in 89% yield. We were
pleased to find that this benzylic addition can also be realized at 0
°C with moderate yield (entry 10). Next, the effect of solvents on
this reaction was also investigated. The reaction proceeded much
faster in polar solvents such DMSO and DMF (entry 12) and
much slower in 1,4-dioxane and DCE (entries 13 and 14).
Acetonitrile was not a good choice either, which may be due to its
ability to neutralize the Brønsted acid (entry 15).
Under the optimized conditions (Table 1, entry 8, with 50 mol
% of p-nitrobenzoic acid as catalyst), the substrate scope and
limitation of this benzylic C−H addition to form CN bonds
was explored. The effect of substituents on the alkylazaarene
moiety is listed in Table 2. 2-Methylquinolines bearing electron-
donating or -withdrawing substituents were successfully trans-
formed into the desired aldimine products in moderate to high
yields, such as methyl (1b), methoxy (1c), halo (1d−1g), phenyl
(1h), and trifluoromethyl groups (1i). Besides 2-methylquino-
lines, the optimized reaction conditions can also be applied to the
benzylic C−H functionalization of 2-methylquinoxaline (1j)
with p-chloronitrosobenzene (2a), but for the 2-ethylquinoline
(1k), the reaction afforded the nucleophilic addition product 3k
a
Conditions: 1a−k (0.4 mmol), 2a (0.8 mmol), p-nitrobenzoic acid
(0.2 mmol), DMSO (0.6 mL), reacted for 12 h at rt under argon
atmosphere unless otherwise noted. Isolated yields.
(which was not dehydrated) in 55% yield. However, the reaction
of 2-methylpyridine (and also 2,6-lutidine) under the same
conditions was failed even at elevated temperature for unknown
reason.
On the other hand, for the different nitroso compound (Table
3), the reaction yields relied on the electronic effect of
substituents; for example, the 4-(methoxycarbonyl)-
nitrosobenzene (2c) afforded the aldimine 3o in 94% yield,
while the relatively electron-rich 4-methylnitrosobenzene (2e)
led to a lower yield of 45%. The reasons for above results should
be attributed to that the electron-withdrawing groups would
increase the electroaffinity of nitroso compounds.
Encouraged by the exciting results obtained between the
nucleophilic additions of alkylazaarenes to substituted nitro-
sobenzenes, the application of this reaction to tert-butyl nitrite
(tBuONO) was investigated next.16 The nucleophilic addition
product was found to be oxime, but not the anticipated
dehydration product, maybe due to their different thermody-
namics stabilities (Table 4).17 Considering that both the starting
material (the tert-butyl nitrite would not dimerize) and the
products are more stable than substituted nitrosobenzenes and
aldimines, the reaction conditions were finely adjusted. When the
nucleophilic addition of alkylazaarenes to tert-butyl nitrite was
promoted by 1 equiv of benzoic acid at slightly elevated
temperature (40 °C vs rt), good to excellent yields were obtained
for all of the alkylazaarenes tested.
B
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Letter
a
Table 3. Effect of Substituents on the Nitroso Moiety
Scheme 2. Control Experiments between 2- and 4-
Methylquinolines
was not detected by GC−MS, which was similar to our previous
results obtained from the benzylic C−H addition to carbonyl
groups. These results seem to suggest a six-membered hydrogen-
bonding transition state (Scheme 3, I), in which the Brønsted
acid not only accelerates the imine−enamine transformation but
also activates the nitrosobenzene through the hydrogen bond.
a
Conditions: 1a (0.4 mmol), 2 (0.8 mmol), p-nitrobenzoic acid (0.2
mmol), DMSO (0.6 mL), reacted for 12 h at rt under Argon
atmosphere unless otherwise noted. Isolated yields.
Table 4. Nucleophilc Addition of Alkylazaarenes to tert-Butyl
Nitrite
Scheme 3. Proposed Mechanism for the Benzylic C−H
Functionalization
a
We proposed a plausible mechanism to rationalize this
Brønsted acid catalyzed benzylic C−H nucleophilic addition to
NO (Scheme 3). First, 2-methylquinoline (1a) is converted to
its more nucleophilic enamine counterpart catalyzed the by the
aromatic acid, which can also activate the polarized NO bond
through hydrogen bond to make it more electrophilic. Then, the
subsequent nucleophilic addition of the enamine to activated
NO takes place spontaneously to generate the hydroxyami-
nation intermediate II, which can undergo dehydration to
produce aldimine 3a assisted by Brønsted acid. The hydrox-
yamination intermediate II is supported by the isolation and
characterization of product 3k (Table 2). When the Brønsted
acidity is strong enough (for example, p-TSA, Table 1, entry 7),
the aldimine 3a was further hydrolyzed to afford quinoline-2-
carbaldehyde (4a).
In conclusion, we have developed an efficient benzylic C−H
functionalization of azaarenes by its nucleophilic addition to
nitroso compounds under mild conditions. Switched by
Brønsted acids, the nucleophilic addition to nitrosoarenes can
afford azaarene-2-aldimines or azaarene-2-carbaldehyde selec-
tively, and the nucleophilic addition to tert-butylnitrite yields
azaarene-2-oximes in high yields. This reaction has provided an
efficient method for the benzylic C−H transformation of 2-
alkylazaarenes to CN and CO bonds. The cheapness and
abundance of the two starting materials, the usage of benzoic acid
a
Conditions: 1a−1k (0.4 mmol), 2a (0.8 mmol), benzoic acid (0.4
mmol), DMSO (0.6 mL), reacted for 24 h 40 °C under argon
atmosphere unless otherwise noted. Isolated yields.
To shed some light on the mechanism of this benzylic C−H
functionalization, the reaction of 4-methylquinoline (1m) with p-
chloronitrosobenzene (2a) was carried out under the same
reaction conditions (Scheme 2b). However, the corresponding
nucleophilic addition product of the C4 methyl C−H to NO
C
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as the catalyst, and the mild reaction conditions should make this
method attractive for the synthesis of bioactive quinoline and
quinoxaline derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compounds characterization data, and
copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yangluo@xtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(12) Baeyer, A. Chem. Ber. 1874, 7, 1638.
■
(13) (a) Yang, L.; Correia, C. A.; Li, C.-J. Adv. Synth. Catal. 2011, 353,
1269. (b) Yang, L.; Shuai, Q.; Li, C.-J. Org. Biomol. Chem. 2011, 9, 7176.
(c) Tang, R.-J.; Luo, C.-P.; Yang, L.; Li, C.-J. Adv. Synth. Catal. 2013,
355, 869.
(14) The excess p-chloronitrosobenzene underwent homocoupling to
yield azodioxy dimmer in acidic condition.
This work was supported by the National Natural Science
Foundation of China (21202138), Xiangtan University “Aca-
demic Leader Program” (11QDZ20), New Teachers’ Fund for
Doctor Stations, Ministry of Education (20124301120007),
University Student Innovation Program, Ministry of Education
(201210530008) and Project of Hunan Provincial Natural
Science Foundation (13JJ4047, 12JJ7002), and Excellent Young
Scientist Foundation of Hunan Provincial Education Depart-
ment (13B114).
(15) Ding, D.; Dwoskin, L. P.; Crooks, P. A. Tetrahedron Lett. 2013, 54,
5211.
(16) The n-butyl nitrite (nBuONO) was also investigated and
produced the oxime 5a in similar yield as tert-butyl nitrite. The reaction
of 2-methylpyridine and tert-butyl nitrite was first realized by Goto et al.
using alkali amide in liquid ammonia at −78 °C to give the
corresponding oxime; see: Kato, T.; Goto, Y. Chem. Pharm. Bull.
1963, 11, 461.
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