Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
c
c
entry
reagents (equiv), atmosphere, temperature
solvent (mL)
RSM (%)
yield of 1b (%)
yield of 1b′ (%)
1
2
3
4
5
6
7
8
9
NaNO2 (3.0), HCl (5.0), air, 40 °C
NaNO2 (3.0), HCO2H (5.0), air, 40 °C
NaNO2 (3.0), TFA (5.0), air, 40 °C
NaNO2 (3.0), HCl (5.0), air, 40 °C
NaNO2 (3.0), HCl (5.0), air, 40 °C
NaNO2 (3.0), HCl (5.0), air, 40 °C
NaNO2 (3.0), HCl (5.0), air, 40 °C
NaNO2 (3.0), HCl (5.0), air, 40 °C
NaNO2 (1.0), HCl (2.0), air, 40 °C
NaNO2 (2.5), HCl (3.0), air, 40 °C
NaNO2 (2.5), HCl (3.0), air, 23 °C
HFIP (0.5)
HFIP (0.5)
HFIP (0.5)
CH3CN (0.5)
DCM (0.5)
TFE (0.5)
1:1 HFIP/H2O (0.5)
4:1 HFIP/H2O (0.5)
4:1 HFIP/H2O (0.5)
4:1 HFIP/H2O (0.5)
4:1 HFIP/H2O (0.5)
4:1 HFIP/H2O (0.5)
0
45
0
53
32
37
10
0
48
19
37
17
13
25
37
59
33
67
70
<10
15
12
23
12
31
12
35
15
21
27
0
0
10
11
12
<10
<10
64
NaNO2 (2.5), HCl (3.0), N2, 23 °C
16
a
b
c
Reaction conditions: 0.4 mmol of substrate, 3 h. RSM denotes recovered starting material. Isolated yields.
were examined to demonstrate the selectivity in the C−C bond
cleavage (20a−26a). We discovered that the cleavage of the
C−C bond always occurred to liberate a longer alkyl chain
(20a−23a), which should be due to the stability of the released
alkyl radical. 4,4′-(Ethane-1,1-diyl)bis(methoxybenzene)
(25a) generated 1-(4-methoxyphenyl)ethan-1-one (25b) and
bis(4-methoxyphenyl)methanone (25b′) in 54% and 10%
yield, respectively, indicating that the aryl radical should be
more stable than the methyl radical but less stable than the
long-chain alkyl radical (26a).
Scheme 3. Mechanistic Studies
Next, a series of aryl alkanes with a benzylic methylene
group were examined (27a−41a), and the corresponding aryl
ketones were obtained smoothly. It is worth noting that
benzaldehyde was isolated as the major product when
neopentylbenzene (32a) was used as the substrate. This result
might reveal two interesting issues. One is that the four-
membered peroxide ring should be ruled out as the critical
intermediate for the C−C bond cleavage since it could not be
formed in this case. The other is that C−C bond cleavage
should occur preferentially over methylene oxidation if the
leaving alkyl radical is stable. Both linear and cyclic aryl alkanes
were compatible with this system. Especially, complex natural
products (40a and 41a) also gave the corresponding products
under the reaction conditions. However, strongly electron-
deficient aryl alkanes were not compatible with this method.
Finally, we carried out several experiments to verify the
proposed mechanism (Scheme 3). As shown in Scheme 3a,
when 2,6-di-tert-butyl-4-methylphenol (BHT) was added to
the reaction, 42b was isolated in 31% yield, which indicated
that NO2 radical should be involved in this system. When
2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) was used as an
alternative spin trapping agent, radical adduct 43b was isolated
in 16% yield, which suggested that a benzylic-carbon-centered
radical should be generated in this process. Besides, the desired
product 2b was not observed in either reaction. These results
support the possible mechanism given in Scheme 1d.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
■
sı
Experimental procedures, mechanistic studies, and
characterization and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Zhong-Quan Liu − Jiangsu Collaborative Innovation Center
of Chinese Medicinal Resources Industrialization, College of
Pharmacy, Nanjing University of Chinese Medicine, Nanjing
Authors
Jianyou Zhao − Jiangsu Collaborative Innovation Center of
Chinese Medicinal Resources Industrialization, College of
Pharmacy, Nanjing University of Chinese Medicine, Nanjing
210023, China
Tong Shen − Jiangsu Collaborative Innovation Center of
Chinese Medicinal Resources Industrialization, College of
Pharmacy, Nanjing University of Chinese Medicine, Nanjing
210023, China
In summary, we developed a NaNO2/HCl promoted
oxidation of (sp3)C−C(sp3) and (sp3)C−H bonds in aryl
alkanes. This process is transition-metal-free and chemical-
oxidant-free and proceeds under mild conditions, which makes
it attractive to synthetic organic chemistry.
4059
Org. Lett. 2021, 23, 4057−4061