Metal- and radical-free aerobic oxidation of heteroaromatic methanes: An efficient synthesis of heteroaromatic aldehydes

Article abstract of DOI:10.1039/c9ob00490d

A metal-free and radical-free synthesis of heteroaromatic aldehydes was developed through aerobic oxidation of methyl groups in an I₂/DMSO/O₂ catalytic system. Under the reaction conditions, various functional groups such as methoxy, aldehyde, ester, nitro, amide, and halo (F, Cl, Br) groups were well tolerated. The bioactive compounds like chlorchinaldin derivative and papaverine were also oxidized to the corresponding aldehydes and ketones. This reaction provided an efficient method for preparing the valuable heteroaromatic aldehydes.

Full text of DOI:10.1039/c9ob00490d

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DOI: 10.1039/C9OB00490D
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Metal- and Radical-Free Aerobic Oxidation of Heteroaromatic
Methanes: An Efficient Synthesis of Heteroaromatic Aldehydes
Rongzi Ye,a Yuanjie Cao,a Xiaoxiang Xi,a Long Liu,b and Tieqiao Chen*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
metal-free and radical-free synthesis of heteroaromatic (Scheme 1a). Great efforts have been devoted to improving
aldehydes was developed through aerobic oxidation of methyl the aldehyde-selectivity by adding additives and carefully
groups in an I2/DMSO/O2 catalytic system. Under the reaction tuning the reaction conditions, however the selectivity often
conditions, various functional groups such as methoxy, aldehyde, comes at the expense of reaction yield. In 2017, Pappo
ester, nitro, amide, and halo (F, Cl, Br) groups were well tolerated. described a Co/NHPI (N-hydroxyphthalimide) co-catalyzed
The bioactive compounds like chlorchinaldin derivative and aerobic oxidation of methylarenes in hexafluoropropan-2-ol,
papaverine were also oxidized to the corresponding aldehydes an expensive solvent (Scheme 1b).6 Due to the strong
and ketones. This reaction provided an efficient method for hydrogen-bond effect between the resulting aldehydes and
preparing the valuable heteroaromatic aldehydes.
solvent, high aldehyde-selectivity was obtained. This is a great
advance in the preparation of aldehydes from methylarenes.
Aromatic aldehydes are important synthetic intermediates
in organic synthesis. In particular, the heteroaromatic
aldehydes are widely applied in the preparation of
pharmaceuticals and materials, because heterocycles
commonly occur as the key units in those functional molecules.
Thus, development of an efficient method for their synthesis is
very important.1 The partial reduction of carboxylic derivatives
with active reductant can produce aldehydes.2 The formylation
of electron-rich arenes is also extensively used for preparing
those compounds, despite the substrate limitation and
relatively harsh reaction conditions.3 Methylarenes are
ubiquitous and recognized to be versatile building blocks in
organic synthesis.4 There is no doubt that the direct aerobic
oxidation of methyl groups would be the most straightforward
and atom-economic method for the production of aldehydes.5
However, the controlled oxidation of methylarenes to
aldehydes avoiding generation of the corresponding acids is
very challenging, because those reactions are usually mediated
by transition metals and proceed via a radical process, while
the resulting aldehydes are more easily oxidized than the
starting methylarenes under the aerobic oxidative conditions
a. Previous works:
O
Me
cat. M/[Ox]
over-oxidation
or low conversion
H
Ar
Ar
radical process
hydrogen-bond-protecting strategy
b. Pappo's work:
O
Me
Co/HNPI/O2
Ar
H
Ar
expensive solvent
CF3CH(OH)CF3 as solvent
radical process
c. Our work:
Metal-free reaction conditions
High aldehyde-selectivity
Moderate to high yields
TsOH/I2/DMSO/O2
O
Ar Me
Ar
N
radical-free process
N
H
High functional group tolerance
Scheme 1 Aerobic Oxidation of Methyl Groups for Constructing Aldehydes Using
Dioxygen as the Terminal Oxidant.
Recently, several works on the aerobic oxidative
functionalization of heteroaromatic methanes were reported.7
Those reactions proceed through a metal-free and radical-free
process, and aldehydes were proposed as a key intermediate.
Considering that auto-oxidation of aldehydes under the
dioxygen atmosphere usually is a radical reaction, we envision
that the aerobic oxidation of heteroaromatic methanes might
halt at the aldehyde step under a similar radical-free condition,
thus overcoming the issue of low aldehyde-selectivity. Herein,
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
b Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island
Resources, College of Materials and Chemical Engineering, Hainan University,
Haikou, 570228, China.
we communicate such
a radical-free aldehydes-forming
reaction (Scheme 1c). Under the reaction conditions, a variety
of heteroaromatic methanes are oxidized, generating the
corresponding aldehydes in good to high yields. To the best of
our knowledge, this is the first example of radical-free
E-mail: chentieqiao@hnu.edu.cn
Electronic Supplementary Information (ESI) available: General information,
experimental procedures, copies of 1H and 13C NMR spectra for products. See DOI:
10.1039/b000000x/
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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aldehyde-formation through aerobic oxidation of methyl entries 15 and 16). Finally, the amount of DMSO was screened
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DOI: 10.1039/C9OB00490D
groups using dioxygen as a terminal oxidant.
with 1mL loading being the optimal choice (Table 1, entries 1,
17-21).
Table 1 Direct Aerobic Oxidative of 2-Methylquinoline.a
Table 2 Metal-Free Direct Aerobic Oxidation of N-Heteroarylmethanes.a
acid/I2/DMSO/O2
heat
acid/I2/DMSO/O2
H
CHO
CH3
R
R
N
heat
N
1a
CH3
Acid
N
N
1
2
2a
O
Me
Br
MeO
Yield [%]b
Solvent
DMSO
Catalyst
Entry
1
I2
I2
TsOH
TsOH
TsOH
TsOH
92
N
CHO
N
CHO
CHO
N
CHO
2a 92%(90%)b,130 o
C
2b 90%,120 o
C
2c 91%,120 o
C
2
3
4
5
toluene
dioxane
MeCN
N.D.
N.D.
N.D.
72
I2
Cl
F
I2
KI
NaI
DMSO
N
CHO
N
N
CHO
TsOH
TsOH
TsOH
2d 85%,120 o
C
2e 87%,120 o
C
2f 93%,120 o
C
6
DMSO
65
O
O
7
8
NIS
I2
DMSO
DMSO
30
68
O2N
Acetic acid
Ph2P(O)OH
PhC(O)OH
TsOH
MeO
H
I2
I2
I2
9
DMSO
DMSO
DMSO
50
18
32
N
CHO
N
CHO
N
CHO
10
11c
2g 65%,130 o
C
2h 80%,120 o
C
2i 81%,120 o
C
NHPiv
N
CHO
12d
DMSO
DMSO
62
92
I2
I2
TsOH
TsOH
13e
N
CHO
N
CHO
N
14f
15g
16
17h
18i
19j
20j
21j
DMSO
DMSO
DMSO
DMSO
DMSO
54
60
I2
TsOH
TsOH
TsOH
TsOH
TsOH
2j 70%,130 o
C
CHO
2k 60%,130 o
C
2l 82%,130 o
C
I2
none
N
N
CHO
N.D.
81
N
I2
I2
N
2n 87%,130 o
S
CHO
N
CHO
2m 70%c,130 o
C
C
2o 60%,130 o
C
89
S
MeO
S
I2
I2
I2
TsOH
TsOH
TsOH
toluene
dioxane
MeCN
N.D.
N.D.
N.D.
CHO
CHO
CHO
N
N
Cl
Br
N
2p 92%,130 o
C
2q 83%,130 o
C
2r 76%,130 o
C
O
O
a Reaction conditions: A mixture of 1a (0.1 mmol), I2 (0.04 mmol), acid (0.1 mmol)
S
N
in DMSO (1 mL) was heated at 120 oC for 16 h under air atmosphere (1 atm, 25
CHO
N
N
Cl
b
c
mL glass tube).
GC yield using tridecane as an internal standard.
N2
i
2s 83%,130 o
C
2t 91%,100 o
C
2u 80%,100 o
C
atmosphere. 100 oC. 140 oC. 50% acid. I2 (0.02 mmol). DMSO (0.5mL).
d
e
f
g
h
O
DMSO (2 mL). j 0.1 mmol DMSO was added. N.D. = Not Detected.
N
O
N
During the aerobic oxidative functionalization of
heteroaromatic methanes, a trace amount of aldehydes were
usually detected by GC-MS.7a It was deduced that the
aldehydes might be produced as the main products by tuning
the reaction conditions. Indeed, after an extensive screening,
the selected model reactant 2-methylquinoline was converted
successfully to the corresponding aldehydes 2a in a high yield
under an acid/I2/DMSO/air catalytic oxidative condition (Table
1, entry 1).7b,8 The choice of solvent is critical for the reaction
as evident from Table 1 (entries 2-4). In addition to I2, KI, NaI
and NIS (N-iodosuccinimide) also showed catalytic reactivity
(Table 1, entries 5-7). Several acid additives were tried and it
was found that p-toluenesulfronic acid (TsOH) was the most
effective (Table 1, entries 8-10). Under N2 atmosphere, a low
yield of product (32%) was generated under similar reaction
conditions (Table 1, entry 11). When the reaction was
performed at a lower temperature (100 oC), 2a was given in 62%
yield (Table 1, entry 12); while elevating the reaction
2v 93%,100 o
C
2w 56%c,100 o
C
a Reaction conditions: A mixture of 1 (0.1 mmol), I2 (0.04 mmol), TsOH (0.1 mmol)
in DMSO (1 mL) was heated at the indicated temperature for 16 h under air
atmosphere (1 atm, 25 mL glass tube). b The data in bracket is the yield at 1 mmol
c
scale. under dioxygen atmosphere, N-Methyl-2-naphthamide was used instead
of acid.
With the optimal reaction conditions identified, an extensive
substrate scope investigation was undertaken. As shown in
Table 2, a variety of N-heteroaromatic methanes including
those bearing functional groups were aerobic oxidized,
selectively producing the corresponding aldehydes in good to
excellent yields. Thus, 2-methylquinolines with 6-methyl and
6-methoxy groups underwent aerobic oxidation to produce
the expected aldehydes in high yields (Table 2, 2b and 2c). The
halo groups like fluoro, chloro and bromo groups were well
tolerated under the reaction conditions (Table 2, 2d-2f); Of
note, the products from these reactions are potential
substrates for a variety of cross-coupling reactions. The
substrates having electron-withdrawing groups like ester and
nitro groups showed high reactivity, furnishing the desired
products 2g and 2h in 65% and 80% yields, respectively. The 2-
methylquinoline-6-carbaldehyde has also proved to be a good
substrate for this reaction, producing the corresponding
o
temperature (140 C) also did not improve the yield (Table,
entry 13). The yield is reduced to 54 % when the amount of
acid is reduced to 50 mol% (Table 1, entry 14). The iodine was
essential to this reaction. When its loading was reduced from
40 mol% to 20 mol%, the yield of 2a decreased to 60%, while
in the absence of iodine, no 2a could be detected (Table 1,
2 | J. Name., 2012, 00, 1-3
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dialdehydes 2i in 81% yield. Worth noting is that 2- TEMPO (2,2,6,6-tetramethylpiperidinyloxy) or BHT (butylated
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methylquinolines bearing alkaline amide and tertiary amine hydroxytoluene), indicating that this reDacOtIi:o1n0.1w03o9u/Cld9OnBo0t04b9e0Da
groups also served well under the present reaction conditions, radical process (eqn 1). As reported previously,7a,7b,8,10 2-
generating the oxidative products 2j, 2k in good yields, methylquinoline could be iodinated by I2 to generate a benzyl
respectively.
iodide 3. It was deduced that this compound might be an
4-Methylquinoline and 2-methylquinoxaline were also effective intermediate in this reaction. Thus, we synthesized
oxidized readily in the current catalytic aerobic oxidative the compound and found that compound 3 was converted to
system, and the corresponding heteroaromatic aldehydes the product 2a in 93% yield under the standard reaction
were produced in high yields (Table 2, 2l and 2n). It should be conditions (eqn 2), implying that our hypothesis was
noted that the aerobic oxidation of 1-methylisoquinolines reasonable. Considering that benzyl iodide 3 might hydrolyze
proceeded sluggishly under this reaction conditions. However, to quinolin-2-ylmethanol 4, the control experiment involving 4
the use of N-methyl-2-naphthamide in place of p- was also conducted. It was found that the yield of 2a was ca.
toluenesulfonic acid gave a good yield of isoquinoline-1- 30%, despite with 100% conversion of 4 (eqn 3). The result
carbaldehyde (Table 2, 2m).9 Notably, 2,3-dimethylquinoxaline indicated that compound 4 might be unstable and would
was also oxidized smoothly, forming the expected dialdehyde decompose under the reaction conditions; hence, the
(Table 2, 2o).
In the current catalytic oxidative system, benzothiazole 2a in the reaction.11 When 1a-CD3 was used as a substrate, 2a-
derivatives were found reactive and converted to the was produced in 89% yield with 87% deuterium
formation of 4 might lead to decrease of the yield of product
D
corresponding valuable benzothiazole-2-carboxaldehydes in incorporation in the present catalytic oxidative system (eqn 4).
excellent yields (Table 2, 2p-2s). The biaryl ketones were also Kinetic isotope effect (KIE) experiments were also carried out,
synthesized efficiently through oxidation of methylene using and a kinetic isotope effect (kH/kD = 2.0) was given, suggesting
the current strategy (Table 2, 2t-2v). 4-Ethylpyridine was also that C−H cleavage might be the rate-determining step in this
oxidized to 1-(pyridin-4-yl)ethanone by slightly tuning the reaction (eqn 5).
reaction conditions. Unluckily, 3-methyl quinoline and toluene
could not be oxidized under the reaction conditions.
standard conditions
H
(1)
N
Me
N
1a
2a
O
2 equiv TEMPO, 58% yield
a. Aerobic oxidation of chlorchinaldin derivative
4 equiv TEMPO, 47% yield; 4 equiv BHT, 53% yield
Cl
Cl
standard conditions witout I2
N
H
H
standard conditions
H
N
CH2I
Cl
N
CH3
Cl
N
(2)
(3)
O
O
3
2a: 93% yield
OMe
OMe
O
1 mmol
2x, 61% yield
b. Aerobic oxidation of papaverine
standard conditions
MeO
MeO
N
CH2OH
N
4
O
4: 100% conversion
2a: ca. 30% yield
some unknown products
MeO
MeO
CH2
MeO
MeO
standard conditions
N
N
standard conditions
standard conditions
(4)
D
MeO
MeO
N
CD3
N
1 mmol
2y, 52% yield
O
1a-CD3 96%-D
2a-D, 89 yield, 87%-D
Scheme 2 Controlled Oxidation of Bioactive Molecules.
D/H
This reaction is applicable for the controlled oxidation of
bioactive molecules forming the corresponding aldehydes or
ketones, indicating that this reaction would be a potential
practical method in pharmaceutical synthesis. For example,
chloroxine, an antibacterial drug, after methylzation of its
hydroxyl group, was oxidized under the reaction conditions to
produce the corresponding aldehydes in good yield, greatly
facilitating further modification of the bioactive molecule
chloroxine through transformation of aldehyde group (Scheme
2a). Papaverine is an efficient drug for treatment of the tonus
of all smooth muscle relaxation, which was also efficiently
converted to the expected ketones by using the present
aerobic oxidative strategy (Scheme 2b).
(5)
N
N
CD(H)3
3 h
O
kH/kD = 2.0
1a/1a-CD3
2a-D/2a
Thus, on the basis of these results described above and
previous literatures,7 a probable mechanism via Kornblum
oxidation is proposed in Scheme 3. At first, N-heteroaromatic
methanes undergoes an enamine tautomerization under
suitable pH conditions,12 followed by iodination with I2
activated by DMSO13 to generate a benzylic iodide 3. The
benzylic iodide 3 was then oxidized by DMSO to form the
product aldehyde via Kornblum oxidation.7,10,14 During the
reaction, I2 would be regenerated from iodide ions through
oxidation by DMSO and O2 to complete the catalytic cycle.15
On the other hand, benzylic iodide 3 might hydrolyze to
benzylic alcohol 4 which then decomposed acting as the main
side path in this reaction.11 As for the reasons why this
oxidation stopped at the aldehyde-step, DMSO might play an
important role as a mild radical scavenger,16 and thus
To gain some mechanistic information on the aerobic
oxidation forming aldehydes, several control experiments
were performed. It was found that the aerobic oxidation of 1a
still took place in the presence of excessive radical scavenger
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Qian, Z. Yan, Z. Zhou, K. Hu, J. Wang, Z. Li, Z. Zha and Z. Wang,
Org. Lett., 2018, 20, 6359; (d) F. SerpiDerO,I:F1.0P.1a0n3,9VW/ieCw.9AOSr.tBicH0le0aO4m9nl,0inDJe.
Jacq, C. Genicot and T. Ritter, Angew. Chem. Int. Ed., 2018,
57, 10697; (e) M. Rafiee, F. Wang, D. P. Hruszkewycz and S. S.
Stahl, J. Am. Chem. Soc., 2018, 140, 22.
For selected examples, see: (a) J. Liu, X. Zhang, H. Yi, C. Liu, R.
Liu, H. Zhang, K. Zhuo and A. Lei, Angew. Chem. Int. Ed., 2015,
54, 1261; (b) Y. Nagasawa, Y. Tachikawa, E. Yamaguchi, N.
Tada, T. Miura and A. Itoh, Adv. Synth. Catal., 2016, 358, 178;
(c) G. Zheng, H. Liu and M. Wang, Chin. J. Chem., 2016, 34,
519; (d) T. Abe, S. Tanaka, A. Ogawa, M. Tamura, K. Sato and
S. Itoh, Chem. Lett., 2016, 46, 348.
suppressed the oxidation of the resulting aldehydes under the
reaction conditions.
DMSO/O2
H
I-
I-
5
I2
H
N
N
N
N
suitable pH
I
O
Het
Het
Het
Het
enamine
isomerization
DMSO
Kornblum
oxidation
3
2
H2O
+
HI
N
OH
decomposed compounds
Het
6
7
(a) E. Gaster, S. Kozuch and D. Pappo, Angew. Chem. Int. Ed.,
2017, 56, 5912; This work was highlighted by Prof. Lumb, see:
(b) J.-P. Lumb, Angew. Chem. Int. Ed., 2017, 56, 9276.
For selected examples, see: (a) M. Liu, T. Chen, Y. Zhou and S.-
F. Yin, Catal. Sci. Technol., 2016, 6, 5792; (b) F. Sultana, S. P.
Shaik, A. Alarifi, A. K. Srivastava and A. Kamal, Asian J. Org.
Chem., 2017, 6, 890; (c) X. Gao, F. Zhang, G. Deng and L. Yang,
Org. Lett. 2014, 16, 3664; (d) Y.-p. Zhu, Z. Fei, M.-c. Liu, F.-c.
Jia and A.-x. Wu, Org. Lett., 2013, 15, 378.
Under metal-free conditions, 2-methylquinolines can be
oxidized by SeO2 and PhI(OAc)2 forming the corresponding
aldehydes, see: (a) L. Achremowicz, Synth. Commun., 1996,
26, 1681; (b) L. Jiang, Y. Huang, Y. Yan and Y. Xie,
Tetrahedron Lett., 2016, 57, 4149; Metal-free oxidation of 2-
methylquinoline to aldehyde as a control experiment using
TBHP/I2, NIS/TBHP, or over stoichiometric I2/DMSO as an
oxidant has also ever been reported, for selected examples,
see: (c) Z. Yan, C. Wan, Y. Yang, Z. Zha and Z. Wang, RSC Adv.,
2018, 8, 23058; (d) X. Chu, T. Duan, X. Liu, L. Feng and J. Ma
Jia, Org. Biomol. Chem., 2017, 15, 1606.
4
Scheme 3 Control experiments.
Conclusions
In summary, an efficient aldehyde-forming reaction for
preparing heteroaromatic aldehydes was developed under a
metal-free condition. This is the first radical-free synthesis of
aldehydes through aerobic oxidation of methyl groups using
dioxygen as the terminal oxidant. A variety of heteroaromatic
aldehydes including those bearing functional groups were
produced under the reaction conditions. This reaction was
applicable to the oxidation of complex molecules like
chlorchinaldin derivative and papaverine forming the
corresponding aldehydes and ketones, well demonstrating the
potential application in organic synthesis. This transformation
provided an alternative efficient method for preparing
heteroaromatic aldehydes.
8
9
At present, the detailed effect of N-methyl-2-nathamide in
the reaction is unknown. It was deduced that it might help to
provide a suitable pH condition which is important for this
reaction.
Partial financial supports from NFSC (21871070, 21573064),
and the Fundamental Research Funds for the Central
Universities (Hunan University) are gratefully acknowledged.
10 M. Liu, X. Chen, T. Chen, Q. Xu and S.-F. Yin, Org. Biomol.
Chem., 2017, 15, 9845.
11 It should be noted that benzylic alcohol 4 might be another
active intermediate which could be converted to 2a via
species 3. The direct conversion of 4 to 2a as a minor path
could also not be excluded at present.
12 A suitable pH condition is critical to this reaction: the strong
acid might promote the enamine tautomerization, but would
lead to the difficulty in the subsequent oxidation of the
resulting benzylic halides (Kornblum oxidation usually needs
assistance of weak base), see: M. Liu, X. Chen, T. Chen and
S.-F. Yin, Org. Biomol. Chem., 2017, 15, 2507; Also see Ref.s
7a and 9.
Notes and references
1
Some aromatic aldehydes are bioactive, see: (a) H. Ferhout, J.
Bohatier, J. Guillot and J. C. Chalchat, J. Essent. Oil Res., 1999,
11, 119; (b) D. L. Boger, H. Miyauchi and M. P. Hedrick,
Bioorg. Med. Chem. Lett., 2001, 11, 1517; (c) A. Spadaro, M.
Frotscher and R. W. Hartmann, J. Med. Chem., 2012, 55,
2469; Aromatic aldehydes are also widely used in organic
synthesis, see: (d) V. A. Peshkov, O. P. Pereshivko and E. V. V.
der Eycken, Chem. Soc. Rev., 2012, 41, 3790; (e) G. Ward, C. L.
Liotta, R. Krishnamurthy and S. France, J. Org. Chem., 2018,
83, 14219; (f) B. Maji, S. Vedachalan, X. Ge, S. Cai and X.-W.
Liu, J. Org. Chem., 2011, 76, 3016.
13 It was deduced I2 might be activated by DMSO through
formation of a molecular complex DMSO·I2, see: M. C.
Giordano, J. C. Baza and A. J. Arvia, J. Inorg. Nucl. Chem.,
1966, 28, 1209.
2
3
For selected examples, see: (a) J. I. Song and D. K. An, Chem.
Lett., 2007, 36, 886; (b) J. Nakanishi, H. Tatamidani, Y.
Fukumoto and N. Chatani, Synlett, 2006, 869; (c) W. M.
Chang, M. Dakanali, C. C. Capule, C. J. Sigurdson, J. Yang and
E. A. Theodorakis, ACS Chem. Neurosci., 2011, 2, 249.
For a review, see: (a) W. Kantlehner, Eur. J. Org. Chem., 2003,
2003, 2530; For some recent examples, see: (b) L. Omann, Z.-
W. Qu, E. Irran, H. F. T. Klare, S. Grimme and M. Oestreich,
Angew. Chem. Int. Ed., 2018, 57, 8301; (c) N. M. Betterley, S.
Kongsriprapan, S. Chaturonrutsamee, P. Deelertpaiboon, P.
Surawatanawong, M. Pohmakotr, D. Soorukram, V. Reutrakul
and C. Kuhakarn, Synthesis-Stuttgart, 2018, 50, 2033.
14 As shown in Table 1 (entries 2-4), no reaction was observed
in the absence of DMSO, thus a mechanism via Kornblum
oxidation was proposed.
15 The conversion of iodide ions to I2 by DMSO was a reversible
process, which could be promoted by dioxygen, see: (a) J. T.
Doi and W. K. Musker, J. Am. Chem. Soc., 1981, 103, 1159; (b)
P. R. Young and L. S. Hsieh, J. Org. Chem., 1982, 47, 1419; (c)
P. R. Young and M. Till, J. Org. Chem., 1982, 47, 1416.
16 DMSO was recognized to be a radical scavenger, see: (a) C.
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4
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4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00490D
Metal- and Radical-Free Aerobic Oxidation of Heteroaromatic
Methanes: An Efficient Synthesis of Heteroaromatic Aldehydes
Rongzi Ye, Yuanjie Cao, Xiaoxiang Xi, Long Liu, and Tieqiao Chen
A metal-free and radical-free synthesis of heteroaromatic aldehydes was developed
through aerobic oxidation of methyl groups in an I2/DMSO/O2 catalytic system.
Under the reaction conditions, various functional groups such as methoxy, aldehyde,
ester, nitro, amide, and halo (F, Cl, Br) groups were well tolerated. The bioactive
compounds like chlorchinaldin derivative and papaverine were also oxidized to the
corresponding aldehydes and ketones. This reaction provided an efficient method for
preparing the valuable heteroaromatic aldehydes.
Metal-Free Aerobic Oxidative of Methyl groups for Preparing
Heteroaromatic Aldehydes
CH3
Het
Het
CH3
N
N
I2/DMSO
O2
CHO
Het
N
Metal-free
Radical-free
Het
N
CHO
both 2-methyl and 4-methyl groups up to 92% yield
quinolinyl, quinoxalinyl, pyridinyl, benzo[d]thiazolyl methanes