Metal-Free Chemoselective Oxidation of 4-Methylquinolines into Quinoline-4-Carbaldehydes

Article abstract of DOI:10.1002/asia.202100704

A convenient protocol for the synthesis of quinoline-4-carbaldehydes via chemoselective oxidation of 4-methylquinolines using hypervalent iodine(III) reagents as oxidant is described. This method highlights metal-free and mild reaction conditions, nice yield, good functional group tolerance, and high chemoselectivity.

Full text of DOI:10.1002/asia.202100704

doi.org/10.1002/asia.202100704
Communication
Metal-Free Chemoselective Oxidation of 4-Methylquinolines into
Quinoline-4-Carbaldehydes
Jincheng Xu,[a] Yang Li,[a] Tianling Ding,*[b] and Hao Guo*[a]
Abstract: A convenient protocol for the synthesis of
quinoline-4-carbaldehydes via chemoselective oxidation of
4-methylquinolines using hypervalent iodine(III) reagents as
oxidant is described. This method highlights metal-free and
mild reaction conditions, nice yield, good functional group
tolerance, and high chemoselectivity.
Heteroaromatic aldehydes are important skeletons of natural
products.[1] Furthermore, highly reactive formyl group can be
converted into various useful functional groups conveniently.[2]
Due to this property, heteroaromatic aldehydes are frequently
used as key precursors to synthesize various biologically active
molecules, such as quinine,[3] mefloquine[4] and camptothecin[5]
derivatives. Thus, an efficient and practical method for the
synthesis of heteroaromatic aldehydes is always utility in
synthetic chemistry.
Direct oxidation of methylheteroarenes provides a conven-
ient and straightforward route for the synthesis of heteroar-
omatic aldehydes. However, compared to the less reactive
methylheteroarenes, the corresponding heteroaromatic alde-
hyde products are more easily to be over-oxidized into acids.[6]
Therefore, it is quite challenging to avoid over-oxidation of the
aldehyde products under oxidative conditions. Oxidation of
methyl-substituted N-heteroaromatics using selenium dioxide
as oxidant is a classical protocol to synthesize the correspond-
ing aldehydes (Scheme 1a).[7] However, the reaction condition is
Scheme 1. Oxidation of methylheteroarenes into heteroaromatic aldehydes.
harsh, which limit substrate scope and chemoselectivity. In
addition, a serious drawback of this method is the toxicity of
selenium dioxide.[8] As a green, cheap and highly abundant
oxidant, molecular oxygen is widely used in catalytic oxidation
process.[9] In the last few years, several methods for transition
metal-catalyzed aerobic oxidation of methyl-substituted N-
heteroaromatics have been developed (Scheme 1b).[10] But the
metal residue severely limits their application in industrial
synthesis. Chen and Itoh groups reported I2-catalyzed aerobic
oxidation of methyl-substituted N-heteroaromatics to form the
corresponding aldehydes (Scheme 1c).[11] Despite these meth-
ods avoid the use of any transition metal catalyst, they still
require high reaction temperature. Very recently, Wu and co-
workers developed a novel protocol to access N-heteroaromatic
aldehydes by the oxidation of pre-functionalized quinolines
under room temperature (Scheme 1d).[12] However, the extra
two pre-processing steps disfavor convenience and practicality
of this method. The above previous works have shown that
new methods for the chemoselective oxidation of meth-
ylheteroarenes under metal-free conditions at room temper-
ature are highly desired. Herein, we wish to report a metal-free
chemoselective oxidation of 4-methylquinolines into the corre-
sponding aldehydes using phenyliodine(III) diacetate (PIDA) as
the oxidant (Scheme 1e).
[a] J. Xu, Dr. Y. Li, Prof. Dr. H. Guo
Department of Chemistry
Fudan University
2005 Songhu Road, Shanghai 200438 (P. R China)
E-mail: Hao_Guo@fudan.edu.cn
[b] Prof. Dr. T. Ding
Department of Hematology, Huashan Hospital
Fudan University
12 Wulumuqi Middle Road, Shanghai 200040 (P. R China)
Initially, 4-methylquinoline 1a was chosen as the model
substrate for this oxidation reaction. PIDA was applied as the
oxidant and HCF2CO2H was used as the additive. The first
attempt was carried out in DMSO in the presence of 2 equiv. of
E-mail: dtl_953105@163.com
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100704
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H2O at room temperature for 48 h, affording the desired
product quinoline-4-carbaldehyde 2a in 46% NMR yield
(Table 1, entry 1). Subsequently, a series of hypervalent iodine
reagents were investigated. Disappointingly, other oxidants
were less effective (Table 1, entries 2–5). Thus, PIDA was chosen
as the oxidant for further optimization. Next, the screening of
carboxylic acids revealed that HCCl2CO2H was more favorable
(Table 1, entries 6–11). Decreasing the amount of PIDA to
1 equiv. resulted in a diminished yield (Table 1, entry 12).
Increasing the amount of PIDA to 4 equiv. led to much higher
yield (Table 1, entry 13). Next, we reduced the amount of
HCCl2CO2H to 1 equiv.. The yield was sharply decreased
(Table 1, entry 14). Then, we improved the amount of
HCCl2CO2H (Table 1, entries 15 and 16). The best result was
observed when 3 equiv. of HCCl2CO2H was applied, affording
2a in 87% isolated yield (Table 1, entry 15). Finally, the amount
of H2O was investigated, but no further improvement was
observed (Table 1, entries 17 and 18). Thus, Condition A (1,
PIDA (4 equiv.), HCCl2CO2H (3 equiv.), H2O (2 equiv.), DMSO, and
rt) was applied as the optimized condition for further studies.
With the optimized conditions in hand, we next explored
the substrate scope of this reaction. As shown in Scheme 2, a
series of 4-methylquinoline substrates were tested under
Condition A. Substrates with a strong electron donating group
(1b) or a weak donating group (1c–1j) afforded the corre-
sponding products in moderate to good yields. Delightedly,
selective oxidation took place only at the C4 position when
another methyl (1c and 1d) or active benzyl (1e) located at
benzene ring of quinoline. The active cyclopropane ring (1f)
was intact under Condition A. Substrates with an aryl (1g) or a
heteroaryl (1h) were suitable for accessing the desired prod-
ucts. Unsaturated functional groups, such as alkenyl (1i) and
alkynyl (1j), were also tolerant. Halogen-substituted reactants
(1k–1p) could be converted into the desired products in
moderate to excellent yields. Strong electron withdrawing
group substituted 4-methylquinolines (1q–1u) showed good
reactivity, yielding the corresponding products in good to
excellent yields. Gratifyingly, a variety of potentially sensitive
functional groups, such as formyl (1q), benzoyl (1r), meth-
oxycarbonyl (1s), trifluoromethyl (1t), and methylsulfonyl (1u),
were all well tolerated in this transformation. Furthermore, the
reaction of 9-methylacridine (1v) also formed the desired
product in 83% isolated yield.
Table 1. Optimization of the reaction conditions.[a]
entry oxidant [equiv.] acid [equiv.]
H2O [equiv.] NMR yield [%][b]
1
2
3
4
5
6
7
8
PIDA (2)
PIFA (2)
PhIO (2)
DMP (2)
Togni II (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (1)
PIDA (4)
PIDA (4)
PIDA (4)
PIDA (4)
PIDA (4)
PIDA (4)
HCF2CO2H (2)
HCF2CO2H (2)
HCF2CO2H (2)
HCF2CO2H (2)
HCF2CO2H (2)
HCCl2CO2H (2)
CF3CO2H (2)
CCl3CO2H (2)
CH3CO2H (2)
HCO2H (2)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
3
46 (17)[c]
25 (62)[c]
24 (33)[c]
28 (19)[c]
1 (28)[c]
49 (25)[c]
46 (38)[c]
2 (70)[c]
2 (92)[c]
2 (91)[c]
6 (76)[c]
15 (64)[c]
86 (5)[c]
27 (40)[c]
91 (87)[d]
86 (4)[c]
75 (15)[c]
88 (2)[c]
9
10
11
12
13
14
15
16
17
18
PhCO2H (2)
HCCl2CO2H (2)
HCCl2CO2H (2)
HCCl2CO2H (1)
HCCl2CO2H (3)
HCCl2CO2H (5)
HCCl2CO2H (3)
HCCl2CO2H (3)
[a] All reactions were carried out using 1a (0.5 mmol), oxidant, acid, and
H2O in anhydrous DMSO (2.5 mL) at rt for 48 h. [b] Yield was determined
by 1H NMR analysis of the crude reaction mixture using CH2Br2 (0.5 mmol)
as internal standard. [c] Recovered yield of 1a. [d] Isolated yield of 2a.
Then, we investigated the reactivities of other 4-alkylquino-
lines under the standard conditions (Scheme 3). To our delight,
4-ethylquinoline (1w) and 4-butylquinoline (1x) could be
oxidized into the corresponding benzylic alcohol (3w and 3x),
respectively. Next, some other methylheteroarenes were tested
under Condition A. Disappointingly, only 1-methylisoquinoline
(4a) could be oxidized into the desired aldehyde (5a) in a very
low yield. 3-Methylisoquinoline (4b), 2-methyl-1H-indole (4c)
and 3-methyl-1H-indole (4d) gave no desired product at all.
The bioactivities of quinoline-4-carbaldehydes have been
well-studied. For example, 2a has been found to be a highly
bioactive molecule in many fields.[13] Thus, we felt quite
interested in exploring the potential antineoplastic activity of
such compounds. Our results[14] showed that 2a and cisplatin
Scheme 2. Substrate scope. [a] All reactions were carried out using 1
(0.5 mmol), PIDA (4 equiv.), HCCl2CO2H (3 equiv.) and H2O (2 equiv.) in
anhydrous DMSO (2.5 mL) at rt for 48 h. Isolated yield was reported. [b] The
reaction was carried out for 96 h. [c] Gram-scale reaction.
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Scheme 4. Preliminary mechanism study.
Scheme 3. Substrate scope of other alkylheteroarenes.
suppressed the growth of OCI-LY 3 with IC50 values of 1.87 μM
and 0.85 μM, respectively. Obviously, 2a effectively decreased
cell viability of OCI-LY 3, which was comparable to the classic
chemotherapeutic drug-cisplatin. Next, we wanted to explore
whether this method could be used to synthesize quinoline-4-
carbaldehydes in gram-scale, so as to provide a tool for other
researchers to carry on anti-tumor studies using these com-
pounds as potential drugs. Thus, a gram-scale reaction using 1a
(10 mmol, 1.434 g) was performed, and the desired product 2a
was obtained in 71% isolated yield (Scheme 2). This result
showed that this method highlights great synthetic value.
To get insight into the reaction mechanism, several experi-
ments were carried out (Scheme 4). Firstly, to determine oxygen
atom source of the product 2a, 2 equiv. of H218O instead of H2O
was added into the reaction mixture. The result showed that no
18O labeled 2a was formed (for details, see Supporting
Information), which suggested the oxygen atom of the newly
formed carbonyl group should not from H2O. Thus, we assumed
that the role of H2O was just for hydrolysis step (vide infra).
Then, MS analysis of the reaction mixture was carried out when
1a was reacted under Condition A for 12 h. 6a and 7a were
detected (for details, see Supporting Information). These results
suggested that 6a and 7a might be two key intermediates of
this reaction. Next, 6a and 7a were employed under Condition
A, yielding 2a in 92% and 97% NMR yield, respectively. These
results support our hypothesis.
Scheme 5. Plausible mechanism.
erate intermediate 10.[16] Subsequently, intermediate 11 is
obtained via nucleophilic attack of 10 to 8. 11 undergoes
reductive elimination to produce the dichloroacetic ester 12
and PhI.[17] The resulting 12 can be hydrolyzed into the benzylic
alcohol 13 by acid catalysis. The nucleophilic substitution
reaction between 13 and PIDA occurs to result in species 14.
Then, 14 is converted into aldehyde 15 via an anion XÀ -induced
IÀ O bond cleavage. Finally, the desired product 2 is formed by a
deprotonation process.
In summary, we have developed a simple and practical acid-
induced chemoselective oxidation of 4-methylquinolines to
afford the corresponding aldehydes using PIDA as oxidant at
room temperature under metal-free conditions. This trans-
formation is excellent tolerant for a variety of functional groups.
We believe this mild oxidation method provides an attractive
alternative for synthesis of N-heteroaromatic aldehydes. Further
investigations of this strategy are currently in progress.
On the basis of the experimental results and related
literature reports, a plausible reaction mechanism is proposed
(Scheme 5). Firstly, the exchange of one or two dichloroacetic
acid with the acetoxyl group on PIDA affords hypervalent
iodine(III) 8.[15] Meanwhile, protonation of substrate 1 gives
intermediate 9 which then undergoes deprotonation to gen-
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Acknowledgements
We greatly acknowledge the financial support from Shanghai
Science and Technology Committee (18DZ1201605).
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: oxidation · aldehyde · hypervalent iodine(III) · metal-
free · quinoline
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Manuscript received: June 27, 2021
Revised manuscript received: August 17, 2021
Version of record online: ■■■, ■■■■
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COMMUNICATION
J. Xu, Dr. Y. Li, Prof. Dr. T. Ding*,
Prof. Dr. H. Guo*
1 – 5
Metal-Free Chemoselective
Oxidation of 4-Methylquinolines
into Quinoline-4-Carbaldehydes
A metal-free chemoselective
oxidant. This mild oxidation method
provides an attractive alternative for
synthesis of N-heteroaromatic
aldehydes.
oxidation of 4-methylquinolines into
the corresponding aldehydes using
phenyliodine(III) diacetate as the