Copper-Catalyzed Aerobic Oxidation of Azinylmethanes for Access to Trifluoromethylazinylols

Article abstract of DOI:10.1002/cjoc.201500918

A copper-catalyzed oxygenation of methylazaarenes was found to occur in the absence of both ligand and additive, and has been successfully employed for the synthesis of trifluoromethylazinylketols. This synthetic strategy incorporates aerobic oxidation and a trifluoromethylation in one-pot and provides a novel method for the trifluoromethylation of aliphatic C-H bond.

Full text of DOI:10.1002/cjoc.201500918

FULL PAPER
DOI: 10.1002/cjoc.201500918
Copper-Catalyzed Aerobic Oxidation of Azinylmethanes for
Access to Trifluoromethylazinylols
Gang Zheng, Hao Liu, and Mang Wang*
Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, China
A copper-catalyzed oxygenation of methylazaarenes was found to occur in the absence of both ligand and addi-
tive, and has been successfully employed for the synthesis of trifluoromethylazinylketols. This synthetic strategy
incorporates aerobic oxidation and a trifluoromethylation in one-pot and provides a novel method for the trifluoro-
methylation of aliphatic C－H bond.
Keywords aerobic oxidation, azinylmethanes, copper catalysis, synthetic methods, trifluoromethylation
Introduction
form Cu(I)-DABCO complex for efficient oxidations
(Scheme 1C). During preparing for this work, Yin and
Deng groups[6] independently reported a kind of cop-
per-catalyzed amidation of 2-methylquinolines with
amines in the absence of ligand and additive, in which
the in situ generation of aldehyde intermediate was
proposed to be involved. By comparison, we here report
an alternative ligand-free and additive-free cop-
per-catalyzed oxygenation of azinylmethanes by using
O2 as
The direct oxidation of sp3 C－H bonds provides the
most straightforward way for the functionalization of
hydrocarbons.[1] Due to the low reactivity of the ali-
phatic C－H bonds, however, stoichiometric and haz-
ardous oxidants or severe reaction conditions have to be
usually utilized for this purpose.[2] On the other hand,
copper catalyst in combination with molecular oxygen
as the ultimate oxidant has been recognized as an ideal
oxidative system due to their environmental benign and
economy.[3] Yet few examples in the oxidations of hy-
drocarbons are fit for this simple and sustainable oxida-
tion system to date.[4-6]
Scheme 1 Cu-catalyzed aerobic oxygenation of benzylic C－H
bonds of heteroarenes
Maes and co-workers[4a] reported an aerobic oxida-
tion of arylazinylmethanes to aryazinyl ketones in the
presence of a catalytic amount of CuI (Scheme 1A) in
2012. Acidic additive, such as AcOH or TFA, was re-
quired for their oxidation protocol. The acidity of the
methylene of substrates was also proven to be crucial,
for example 2-methylpyridine was difficult to oxidize
under the identical conditions. Recently, Lei[4b] devel-
oped a chloroacetate-promoted oxidation of N-hetero-
benzylic methylenes for the synthesis of hereoaryl-
methylketones under copper catalysis in dioxygen at-
mosphere (Scheme 1B). The strong activation of the
benzylic methylene C－H bonds, which resulted from
the formation of pyridium salts in the presence of chlo-
roacetate led the oxidation process occurring smoothly.
Comparatively, the acid-assisted CuI/O2 oxidation sys-
tem developed by Maes was ineffective for those sub-
strates tested by Lei. Also in 2012, Chiba et al.[4c] found
that 2- or 3-methyl indoles/pyrroles could be oxidized
by O2 leading to the corresponding aldehydes under the
copper catalysis, while the process required DABCO to
Previous work
N
O
N
Ph
[Cu]/O2
AcOH
Ph
A
O
N
N
[Cu]/O2
CH3
CH3
B
CH3
ClCH2CO2Et
CHO
[Cu]/O2
DABCO
C
N
R
N
R
This work
Oxygenation of azinylmethanes evolved by trifluoromethylation
in one-pot
N
CH
3[Cu]/O2
N
CHO
D
ligand-free, additive-free
OH
N
TMSCF3
CF3
*
E-mail: wangm452@nenu.edu.cn; Tel.: 0086-4318-5099759
Received December 31, 2015; accepted January 31, 2016; published online March 8, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500918 or from the author.
Chin. J. Chem. 2016, 34, 519—523
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
519

Zheng, Liu & Wang
FULL PAPER
oxidant (Scheme 1D). Encouraged by the achievements
obtained in trifluoromethylations[7] and our investi-
gations on the applications of (trifluoromethyl) trimethyl-
silane (TMSCF3, Ruppert-Prakash reagent),[7a,8,9] the
oxygenation has been successfully evolved by the tri-
fluoromethylation to afford trifluoromethylazinylols in
one-pot.
quently, azinylmethanes 1 (0.5 mmol) and DMF (3.0
mL) were injected via a syringe. Finally, the sealed tube
was allowed to stir at 130 ℃ and monitored by thin
layer chromatography. After complete consumption of 1,
Me3SiCF3 (2.0 mmol) and K2CO3 (0.5 mmol) were se-
quentially added to the sealed tube. Then the reaction
mixture was stirred at atmosphere temperature and
monitored by thin layer chromatography. After com-
plete consumption of 2, the reaction was quenched by
saturated aqueous solution of ammonium chloride, the
resulting mixture was poured into water, extracted with
CH2Cl2 (15 mL×3). The combined organic extracts
were washed with saturated aqueous solution of sodium
chloride (15 mL×3), dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure to
yield the crude product, which was purified by silica gel
chromatography (eluent: petroleum ether/ethyl acetate,
V∶V＝10∶1) to give the desired trifluoromethylaz-
inylols 3.
Experimental
Materials
All commercially available compounds were used as
received unless otherwise noted. All reactions were car-
ried out under dioxygen atmosphere (1 atm). Reactions
were monitored through thin layer chromatography [TLC,
silica gel 60 F254]. Subsequent to elution, spots were
visualized using UV radiation (254 nm). Flash column
chromatography was performed on silica gel 60 (particle
size 200－400 mesh, purchased from Qingdao, China).
Hydrogen nuclear magnetic resonance spectra (1H NMR),
carbon nuclear magnetic resonance spectra (13C NMR)
and fluorine nuclear magnetic resonance spectra (19F
NMR) were recorded at 25 ℃ on a Varian 500, 125 and
470 MHz spectrometer, respectively, and CDCl3 was
purchased from J&K. Chemical shifts for 1H NMR spec-
tra are reported as δ downfield from SiMe4 (δ 0.0) and
relative to the signal of SiMe4 (δ 0.00, singlet). 13C NMR
are reported as δ downfield from SiMe4 (δ 0.0) and rela-
tive to the signal of chloroform-d (δ 77.00, triplet). 19F
spectra are recorded using fluorobezene (δ 113.5) as
external standard. High-resolution mass spectra (HRMS)
were obtained on a Bruker micro TOF II focus spec-
trometer (ESI).
Results and Discussion
A survey of reaction conditions was carried out us-
ing 2-methylquinoline (1a) as the model substrate and
the selected experimental results are listed in Table 1.
As we expected, when 1a was treated with 10 mol%
CuI in DMF at 130 ℃ under O2 atmosphere, the de-
sired product quinoline-2-carbaldehyde (2a) was formed
Table 1 Aerobic oxidative of 2-methylquinolinea
General procedure for the copper-catalyzed aerobic
oxidation of aliphatic C(sp3)－H bond of N-hetero-
cyclic compounds
Entry
1
[Cu]/mol%
CuI
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
T/℃ Yieldb/%
130
130
130
130
130
130
130
130
130
130
130
100
50
66
54
43
57
34
51
33
63
33
82
0
2
CuBr
Under an oxygen atmosphere (1 atm), CuCl2•2H2O
(0.05 mmol) was added to a 25 mL sealed tube. Subse-
quently, azinylmethanes 1 (0.5 mmol) and DMF (3.0
mL) were injected via a syringe. Finally, the sealed tube
was allowed to stir at 130 ℃ and monitored by thin
layer chromatography. After complete consumption of
substrates, the resulting mixture was poured into water,
extracted with CH2Cl2 (15 mL×3). Then the combined
organic extracts were washed with saturated aqueous
solution of ammonium chloride (15 mL×3), dried over
anhydrous MgSO4, filtered and concentrated under re-
duced pressure to yield the crude product, which was
purified by silica gel chromatography (eluent: petroleum
ether/ethyl acetate, V∶V＝19∶1) to give the desired
aldehydes 2.
3
CuCl
4
CuOAc
5
Cu2O
6
Cu(MeCN)4PF6
CuSO4•5H2O
Cu(OAc)2
Cu
7
8
9
10
11c
12
13
14
15
16
17
18
19d
CuCl2•2H2O
—
CuCl2•2H2O
CuCl2•2H2O
CuCl2•2H2O
CuCl2•2H2O
CuCl2•2H2O
CuCl2•2H2O
CuCl2•2H2O
CuCl2•2H2O
81
27
42
38
32
67
24
10
130
1,4-Dioxane 130
Toluene
NMP
130
130
130
130
General procedure for the copper-catalyzed one-pot
aerobic oxidation and trifluoromethylation of ali-
phatic C(sp3)－H bond of N-heterocyclic compounds
for access to trifluoromethylazinyl alcohols
MeCN
DMF
a Reaction conditions: 1a (0.3 mmol), solvent (3.0 mL), 1 atm O2.
b Isolated yield. c No Cu salt was added. d The reaction was con-
ducted in the air.
Under an oxygen atmosphere (1 atm), CuCl2•2H2O
(0.05 mmol) was added to a 25 mL sealed tube. Subse-
520
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 519—523

Copper-Catalyzed Aerobic Oxidation of Azinylmethanes for Access to Trifluoromethylazinylols
in 66% yield after 12 h (Table 1, Entry 1). Subsequently,
various CuI/II salts including CuBr, CuCl, CuOAc, Cu2O,
Cu[(MeCN)4PF6], CuSO4•5H2O, Cu(OAc)2, CuCl2•
2H2O and Cu were examined and CuCl2•2H2O was
proven to be more efficient (Table 1, Entries 2－10). A
control experiment revealed that copper catalyst was
essential for the reaction (Table 1, Entry 11). Lower
temperature or air condition decreased the reaction yield
(Table 1, Entry 13 and Entry 19), while 81% yield of 2a
performed at 100 ℃ could be obtained by prolonging
reaction time to 12 h (Entry 12). Further screening of
the solvents revealed that DMF was the best solvent for
this transformation (Table 1, Entries 14－18). As a re-
sult, the oxidation of 2-methylquinoline 1a could give
2a in 82% yield in 4 h by using 10 mol% CuCl2•2H2O
as catalyst and O2 as oxidant in DMF at 130 ℃.
With the optimized conditions in hand, various sub-
stituted quinolines were subjected to the copper-cata-
lyzed oxidation of aliphatic C－H bond. The results are
summarized in Table 2. Both electron-donating and
electron-withdrawing groups at the 6, 7, 8, or 4-position
of quinoline ring afforded the corresponding aldehydes
in 38%－87% yields (Table 2, 2a－2m). But the reac-
tion does not work for compound 1 containing a strong
electron-withdrawing group, such as NO2, at its 6-posi-
tion. The reaction was also successful with 4-methyl-
quinoline 1n leading to 2n in 91% yield. Other hetero-
cycles, including 9-methylacridine (1o), 2-methylqui-
noxaline (1p), 2,3-dimethylquinoxaline (1q), and
2-methylbenzo[d]-thiazole (1r) also worked well lead-
ing to the corresponding aldehydes 2o－2r in good
yields (56%－89%). Compared to Lei’s work,[4b] our
methodology is compatible with 4-methylpyridine (1s)
and 2-benzylpyridine (1t) to give corresponding car-
bonyl products in 45% and 78% yields, respectively. By
comparison, the requirement of longer reaction time for
the formation of ketone 2t indicates a lower reactivity of
“methylene” in 1t than those of other substrates.
Table 2 Copper-catalyzed aerobic oxidation of azinylmethanesa
Entry
Product 2
t/h Yieldb/%
1
2
3
4
5
6
7
8
9
2a, R＝H
2b, R＝F
4
7
6
3
5
8
3
5
6
82
64
87
73
82
84
43
62
64
2c, R＝Cl
2d, R＝Br
2e, R＝Me
2f, R＝OMe
2g, R＝F
2h, R＝Cl
2i, R＝Cl
10
2j, R＝OAc
4
71
R
N
11
12
13
2k, R＝4-NH2
4
38
76
47
2l, R＝4-NHAc 10
CHO
2m, R＝4-Cl
5
14
15
16
17
4
2n
91
81
89
71
4
6
4
2o
2p
2q
Recently, our interest focuses on developing new tri-
fluoromethylation reagent and trifluoromethylation re-
actions,[8,9] especially exploring the applications of
TMSCF3 in trifluoromethylations. Considering the im-
portance of trifluoromethylated compounds, we turned
to combine the above oxygenation of azinylmethanes
18
19
2r
2s
36
12
56
45
with further nucleophilic trifluoromethylation of these
CHO
[7a,10-12]
aldehydes with TMSCF3
for the synthesis of tri-
N
fluoromethylazinylols in one-pot. As presented in Table
3, all tested substrates 1 are suitable for the present
one-pot reaction and trifluoromethylazinylols 3 were
obtained in good to excellent yields.
20
2t
24
78
On the basis of the related work,[4,6] a reaction
mechanism was proposed as described in Scheme 2.
Initially, the isomer of 1a is oxidized by Cu(II) in the
presence of O2 to afford a peroxycupric intermediate I
along with the release of a proton. Then, peroxycuprous
intermediate II was formed by an intramolecular reac-
tion of oxygen radical with benzyl followed by an elim-
ination of CuOH to give aldehyde product 2a.
a Conditions: 1 (0.3 mmol), DMF (3.0 mL), 1 atm O2. b Isolated
yield.
Cu(II) is recovered by the oxidation of Cu(I) in the
presence of O2 and proton. In the combined transforma-
tions, the nucleophilic addition of TMSCF3 onto the in
situ generated carbonyl group of 2a affords trifluoro-
Chin. J. Chem. 2016, 34, 519—523
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
521

Zheng, Liu & Wang
FULL PAPER
methylazinylol (3a) as the final product.
mate oxidant under ligand-free and additive-free condi-
tions. The study of the substrate scope showed that var-
ious N-heterocyclic compounds were converted into the
corresponding aldehydes with good to excellent yields.
Additionally, a well combination of oxidations of het-
erobenzylic methylenes with trifluoromethylation in
one-pot was realized to synthesize a set of trifluoro-
methylazinylketols which are valuable synthon in or-
ganic chemistry.
Table 3 One-pot synthesis of trifluoromethylazinyl methanolsa
OH
Me
(a) CuCl2 2H2O, O2, 130 oC, DMF
CF3
Het
1
Het
3
(b) TMSCF3, K2CO3, r.t.
(c) sat. NH4Cl aq.
Entry
Product 3
t/h Yieldb/%
1
2
3
4
5
6
3a, R＝H
8
70
53
83
67
76
79
Acknowledgement
3b, R＝F 12
3c, R＝Cl 11
R
We gratefully acknowledge the National Natural
Science Foundation of China (Nos. 21172031 and
21372040) and the National Natural Science Foundation
of Jilin Province (No. 20140101113JC) for financial
support.
CF3
OH
N
3d, R＝Br
7
3e, R＝Me 12
3f, R＝OMe 15
HO
CF3
References
8
88
3n
[1] (a) Sheldon, R. A.; Kochi, J. K. Metal Catalyzed Oxidations of Or-
ganic Compounds, Academic Press, New York, 1981; (b) Hudlucky,
M. Oxidations in Organic Chemistry, ACS Monograph Series,
American Chemical Society, Washington, DC, 1990; (c) Allen, S. E.;
Walvoord, R. R.; Padilla, S. R.; Kozlowski, M. C. Chem. Rev. 2013,
113, 6234; (d) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012,
45, 851; (e) Liu, C.; Zhang, H,; Shi, W.; Lei, A. Chem. Rev. 2011,
111, 1780; (f) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62,
2439.
7
8
N
N
N
7
87
51
CF3
OH
3p
3r
40
9
[2] (a) Gopinath, V. S. Eur. J. Med. Chem. 2013, 69, 527; (b) Ding, D.
Tetrahedron Lett. 2013, 54, 5211; (c) Tagawa, Y. Heterocycles 2003,
60, 953; (d) Achremowicz, L. Synth. Commun. 1996, 26, 1681; (e)
Karthikeyan, I.; Sekar, G. Eur. J. Org. Chem. 2014, 36, 8055; (f)
Gao, X. Org. Lett. 2014, 16, 3664.
a Conditions: 1 (0.3 mmol), CuCl2•2H2O (10 mol%), DMF (3.0
mL), 1 atm O2. Then, TMSCF3 (1.2 mmol), K2CO3 (0.3 mmol).
b Isolated yield.
Scheme 2 Proposed reaction mechanism
[3] For reviews on transition metal catalyzed oxidation reactions that
involve O2 as the oxidant, see: (a) Shi, Z.; Zhang, C.; Tang, C.; Jiao,
N. Chem. Soc. Rev. 2012, 41, 3381; (b) Stahl, S. S. Angew. Chem.,
Int. Ed. 2004, 43, 3400; Angew. Chem. 2004, 116, 3480; (c) Punni-
yamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105, 2329.
[4] For the aerobic oxygenation of methylheteroarenes catalyzed by
copper, see: (a) Houwer, J.; Tehrani, K. A.; Maes, B. U. W. Angew.
Chem., Int. Ed. 2012, 51, 2745; Angew. Chem. 2012, 124, 2799; (b)
Liu, J.; Zhang, X.; Yi, H.; Liu, C.; Liu, R.; Zhang, H.; Zhuo, K.; Lei,
A. Angew. Chem., Int. Ed. 2015, 54, 1261; Angew. Chem. 2015, 127,
1277; (c) Wang, Y.; Zhang, F.; Chiba, S. Synthesis 2012, 44, 1526.
[5] For the aerobic oxygenation of benzylic methylenes catalyzed by
copper, see: (a) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2011, 13,
1622; (b) Mahyari, M.; Laeini, M.; Shaabani, A. Chem. Commun.
2014, 50, 7855.
N
1a
H2O
O2
Cu(II)
N
O2
CF3
H
N
H+
OH
CuOH
3a
Cu
N
O
TMSCF3
I
O
[6] (a) Xie, H.; Liao, Y.-F.; Chen, S.-Q.; Chen, Y.; Deng, G.-J. Org.
Biomol. Chem. 2015, 13, 6944; (b) Huang, Y.; Chen, T.-Q.; Li, Q.;
Zhou, Y.-B.; Yin, S.-F. Org. Biomol. Chem. 2015, 13, 7289.
[7] Selected reviews on Ruppert-Prakash reagent, see: (a) Liu, X.; Xu,
C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683; (b) Prakash, G. K.
S.; Yudin, A. K. Chem. Rev. 1997, 97, 757; (c) Xu, X.-H.; Matsuza-
ki, K.; Shibata, N. Chem. Rev. 2015, 115, 731; (d) Ni, C.-F.; Hu,
M.-Y.; Hu, J.-B. Chem. Rev. 2015, 115, 765; (e) Yang, X.; Wu, T.;
Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826; (f) Egami, H.;
Sodeoka, M. Angew. Chem., Int. Ed. 2014, 53, 8294; Angew. Chem.
2014, 126, 8434; (g) Chen, P.; Liu, G. Synthesis 2013, 45, 2919.
[8] Xu, C.; Liu, J.-X.; Ming, W.-B.; Liu, Y.-J.; Liu, J.; Wang, M.; Liu,
Q. Chem. Eur. J. 2013, 19, 9104.
H
N
H
O
O
H
2a
N
Cu
II
O
Conclusions
In conclusion, we have developed a direct oxidation
of sp3-hybridized C－H bond by using cheap copper
salts as the catalyst and molecular oxygen as the ulti-
[9] Zheng, G.; Ma, X.-L.; Li, J.-H.; Zhu, D.-S.; Wang, M. J. Org. Chem.
522
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 519—523

Copper-Catalyzed Aerobic Oxidation of Azinylmethanes for Access to Trifluoromethylazinylols
2015, 80, 8910.
[12] For applications of trifluoromethylated siloxy adducts of carbonyls,
[10] Ge, G.-C.; Huang, X.-J.; Ding, C.-H.; Li, H.; Wan, S.-L.; Hou, X.-L.
Chin. J. Chem. 2014, 32, 727.
[11] Deng, X.-Y.; Lin, J.-H.; Zheng, J.; Xiao, J.-C. Chin. J. Chem. 2014,
32, 689.
see: (a) Dong, J.; Pan, L.; Xu, X.; Liu, Q. Chem. Commun. 2014, 50,
14797; (b) Liu, X.; Pan, L.; Dong, J.; Xu, X.; Zhang, Q.; Liu, Q. Org.
Lett. 2013, 15, 6242; (c) Liu, X.; Xu, X.; Pan, L.; Zhang, Q.; Liu, Q.
Org. Biomol. Chem. 2013, 11, 6703.
(Zhao, C.)
Chin. J. Chem. 2016, 34, 519—523
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