Nitric acid-catalyzed aerobic oxidation of benzylic sp3 C–H bonds of isochromans, xanthenes and 9-fluorenone under additive-free conditions

Article abstract of DOI:10.1016/j.catcom.2017.12.006

HNO₃ was demonstrated to be an effective catalyst for aerobic oxidation of benzylic sp³ C–H bonds under additive-free conditions. A series of isochromans, xanthenes and fluorenes underwent this transformation to give the targeted products in low to high yields under the catalysis of HNO₃, which provided an effective method for the synthesis of the synthetically and biologically valued isochromanones, xanthones and 9-fluorenones.

Full text of DOI:10.1016/j.catcom.2017.12.006

Accepted Manuscript
Nitric acid-catalyzed aerobic oxidation of benzylic sp3 C-H bonds
of isochromans, xanthenes and 9-fluorenone under additive-free
conditions
Xinzhe Tian, Fangping Ren, Bo Zhao, Yun-Lai Ren, Shuang
Zhao, Jianji Wang
PII:
DOI:
Reference:
S1566-7367(17)30478-8
doi:10.1016/j.catcom.2017.12.006
CATCOM 5262
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
19 September 2017
9 December 2017
11 December 2017
Please cite this article as: Xinzhe Tian, Fangping Ren, Bo Zhao, Yun-Lai Ren, Shuang
Zhao, Jianji Wang , Nitric acid-catalyzed aerobic oxidation of benzylic sp3 C-H bonds
of isochromans, xanthenes and 9-fluorenone under additive-free conditions. The address
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appropriate. Catcom(2017), doi:10.1016/j.catcom.2017.12.006
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ACCEPTED MANUSCRIPT
Nitric acid-catalyzed aerobic oxidation of benzylic sp3 C−H
bonds of isochromans, xanthenes and 9-fluorenone under
additive-free conditions
Xinzhe Tian,a,c Fangping Ren,c Bo Zhao,c Yun-Lai Ren,c,* Shuang Zhao,c Jianji
Wangb,*
a College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, Gansu, P. R. China.
b School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China
E-mail address: Jwang@htu.cn
c School of Chemical Engineering & Pharmacy, Henan University of Science and Technology, Luoyang, Henan
471003, P. R. China. renyunlai@126.com

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ABSTRACT
HNO3 was demonstrated to be an effective catalyst for aerobic oxidation of benzylic
sp3 C−H bonds under additive-free conditions. A series of isochromans, xanthenes and
fluorenes underwent this transformation to give the targeted products in low to high
yields under the catalysis of HNO3, which provided an effective method for the
synthesis of the synthetically and biologically valued isochromanones, xanthones and
9-fluorenones.
Keywords:
Nitric acid
Carbon-hydrogen bonds
Aerobic oxidation
Catalysis

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1. Introduction
Selective oxidation of C−H bonds to C=O bonds is emerging as an attractive
alternative to traditional methods for synthesizing carbonyl compounds because the
used substrates are readily available [1]. Up to now, many effective methods have
been developed for these reactions [2-5], while α-oxidation of ethers to esters remains
a considerably challenging research subject and often suffers from poor selectivity
[6,7] and poor substrate scope [8,9]. In several literatures, α-oxidation of ethers to
esters relies on the use of stoichiometric amounts of metal oxidants, e.g. RuO4 [10],
permanganate [11] and nano-MnO2 [12]. In addition, significant efforts are focused on
the transition metal-catalytic strategy where several strong oxidants including sodium
hypochlorite [6] and tert-butyl hydroperoxide [7,13] have been used. Clearly, the use
of the above-mentioned oxidants is inconsistent with the criterion of the green and
sustainable chemistry. Thus the economical and green oxygen gas is a desirable
alternative [14-17], and various catalyst systems based on the transition metal
including Rh [18], Pt [19] and Co [20] complexes have been designed to enable
aerobic α-oxidation of ethers. Recently, chemists have developed several Fe-based
catalyst systems for the reactions. For example, Fe(OTf)2/pybisulidine system has
been found to have the capacity to catalyze the aerobic oxidation of phthalans and

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isochromans to the corresponding esters [21], where low conversion and selectivity
are obtained. Another Fe-based catalyst system is Fe(NO3)3·9H2O/KPF6 [22], but the
substrates are limited to isochromans, xanthenes and thioxanthenes.
O
O2
O
Y
O
Y
Previous work:
X
X
Catalyst/HCl/NaNO2
.
N O
O
Catalyst:
NaO S
3
O
O2
Catalyst: HNO3
O
Y
O
This work:
X
X
Y
Scheme 1. Aerobic oxidation of benzylic sp3 C−H of isochroman.
Very recently, a transition metal-free catalyst system containing TEMPO
derivative, HCl and NaNO2 has been explored for the α-aerobic oxidation of ethers
like isochromans to esters (Scheme 1) [23], where TEMPO derivative serves as the
catalyst, and HCl/NaNO2 seems to play a role of the co-catalyst. Without a doubt, it
should be desirable to simplify these sophisticated multi-component catalyst systems
from practical perspectives. So we have devoted ourselves to the development of a
single component catalyst for various organic reactions [24], and the readily available
HNO3 was found to be an effective catalyst for the aerobic oxidation of isochromans
to esters under additive-free conditions (Scheme 1). Moreover, the present method
was successfully applied into the aerobic oxidation of xanthenes and 9-fluorenones.
To our knowledge, HNO3 have been used as the catalyst to enable the aerobic
oxidation of benzyl alcohols in previous literatures [25-27], while HNO3-catalyzed
aerobic oxidation of C–H bonds to C=O bonds is unknown.

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2. Experimental
2.1. Materials and instruments
For the quality and suppliers of the reagents, see Table S1 in the supporting
information. Isochroman derivatives and xanthene derivatives were synthesized by a
method described in the literatures [21,23]. Gas chromatography analyses were
performed on a Varian CP-3800 instrument with a FID detector. Melting points
1
13
measurements were carried on a Mel-Temp apparatus. H and C NMR spectra were
recorded in CDCl3 on a Bruker 500 MHz instrument, and the chemical shifts are given
as δ values (ppm) downfield from tetramethylsilane.
2.2. Typical procedure for the aerobic oxidation of isochromans, xanthenes and
fluorenes
After an about 45 mL glass tube was charged with 2 mL acetonitrile, 0.5 mmol
substrate and 0.075 mmol HNO3, the system was flushed with oxygen gas three times.
Subsequently, the reaction tube was sealed and heated with magnetic stirring at 140°C
for 3 h. When the reaction time was reached, the reaction mixture was cooled to room
temperature. Finally, evaporation of solvent followed by column chromatography
yielded the targeted product. GC yields were obtained by the GC analysis of the
mixture from another parallel experiment.
3. Results and discussion
Encouraged by our prior success in applying NO2 to catalyze aerobic oxidation
of benzyl alcohols [24], we selected NO2 as the catalyst to initiate our investigation.

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As shown in Table 1 (entry 2), the targeted product was obtained in 71% GC yield
when 5-bromoisochroman was stirred in acetonitrile in the presence of 15 mol% NO2
o
and 1atm air at 140 C. Considering that a nocuous character of NO2 severely limits
its application, other compounds including NaNO2, NaNO3 and HNO3 were used as
the substitutions to carry out the reaction. The results showed that HNO3 was the most
effective one, and the targeted product was obtained in as high as 82% GC yield in the
presence of 15 mol% HNO3 (Table 1, entry 3). The catalyst loading amount had an
important effect on the reaction (Table 1, entries 3-7). No desired product was
observed in the absence of HNO3 (Table 1, entry 1), thus proving that the present
reaction is catalyzed by HNO3. When the catalyst loading was increased from 15
mol% to either 20 mol% or 30 mol%, similar results were obtained (Table 1, entry 3
vs entries 4 and 5). We tried to reduce the catalyst loading to 5 mol% but found that
this was not possible without sacrificing product yield even if the reaction time was
prolonged to 48 h (Table 1, entry 7).
Table 1. Aerobic oxidation of 5-bromoisochroman catalyzed by HNO3.[a]
O
O2, Catalyst
Solvent, 3 h
O
O
Br
Br
.
Entry Catalyst
The catalyst
loading (mol%)
Solvent
Temperature Conversion Yield[b] (%)
(oC)
(%)[b]
1
-
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
140
140
140
140
140
140
140
30
0
no
71
82
85
83
76
35
1
2
NO2
15
15
30
20
10
5
92
3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
~100
~100
~100
87
4
5
6
7[c]
39
8
15
1

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9
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
HNO3
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
CH2Cl2
THF
60
6
5
10
90
70
61
79
78
66
75
77
trace
25
89
63
87
50
90
6
11
120
160
180
140
140
140
140
140
140
140
140
140
140
140
140
88
12
~100
~100
~100
~100
3
13
14
15
16
17
DMF
38
18[d]
19[e]
20[f]
21[g]
22[h]
23[i]
24[j]
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
99
71
~100
57
~100
8
35
32
85
25[j,k] HNO3
98
[a] Reaction conditions: 5-bromoisochroman (0.5 mmol), 2 mL solvent (no drying treatment), 3 h, 1 atm air, 45 mL
reaction vessel. [b] Determined by GC with chlorobenzene as an internal standard. [c] 48 h. [d] 1 atm O2. [e] 5 atm O2.
[j]
[k]
[f] 5 atm O2, 9 h. [g] 30 atm O2. [h] 30 atm O2, 18 h. [i] Ar atmosphere.
was proceeding, 40 mL oxygen (1atm) was continuously injected into the reaction vessel in 3 h.
6 mL reaction vessel.
When the reaction
The reaction was highly dependent on the reaction temperature. For example,
o
the reaction at 60 C provided the desired product in a very low yield of 5% (Table 1,
entry 9), while 61% carbonylation product was observed in the case of 90 oC (Table 1,
entry 10). The yield of the carbonylation product greatly increased with increasing the
o
reaction temperature to 140 C but decreased as the temperature increased further
o
(Table 1, entries 3 and 8-13), revealing that 140 C was the optimal reaction
temperature. As shown in Table 1 (Table 1, entries 3 and 14-17), acetonitrile turned to
be one of the most effective solvents. The use of toluene as the solvent allowed the
desired product to be obtained in 75% yield (Table 1, entry 14). A comparable yield
was obtained in the case of dichloromethane (Table 1, entry 15), while the reaction
using N,N-dimethylformamide gave the targeted product in only 25% yield (Table 1,

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entry 17). When the reaction was performed under argon atmosphere, the targeted
product was obtained in only 6% yield (Table 1, entry 23), suggesting that oxygen
played a crucial role in the reaction. The presence of 1atm oxygen allowed the
targeted product to be obtained in 89% yield (Table 1, entry 18), while a longer
reaction time was required in order to obtain a complete conversion in the case of 5 or
30 atm oxygen pressure (Table 1, entries 19-22). These observations indicated that the
increase of the oxygen pressure reduced the reaction rate, which was probably caused
by the decrease of the concentration of the real catalytic species (NO2) because that
the higher oxygen pressure would lead to a shift of the equilibrated decomposition of
HNO3 to NO2 towards the left-hand-side (Scheme 2) [28]. Similar phenomena were
also observed in a previous literature [25] related to HNO3-catalyzed aerobic
oxidation of benzyl alcohols. It is worth noting that we had to use as big as 45 mL
reaction vessel to provide a sufficient amount of oxygen for the aerobic reaction
(Table 1, entry 18 vs entry 24). Obviously, the use of such a big reaction vessel is
disadvantageous to the large-scale application, but this problem can be overcome by
continuously injecting oxygen into the reaction vessel (Table 1, entry 25).
4 HNO3
4 NO2 + 2 H2O + O2
Scheme 2. Decomposition of HNO3 to NO2
With the optimal conditions in hands, we next evaluated the substrate scope of
the HNO3-catalyzed aerobic oxidation of benzylic sp3 C−H bonds using the optimized
reaction conditions. As shown in Table 2, isochromans were a kind of good substrates,
and a series of substituted isochromans underwent this transformation to give the

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targeted products in moderate to high yields (Table 2, entries 1-6), which seemed to
provide an economical and effective method for the synthesis of isochromanone that
often occurs as a motif in natural products and bioactive molecules [29]. In all cases,
1,1′-oxidiisochromans were observed as the major by-products. The presence of
electron-withdrawing groups on the benzene ring could increase the yields of the
targeted products. For example, when isochroman was used as the substrate, the ester
product was obtained in 66% GC yield, while 5-bromoisochroman and
7-chloroisochroman were converted to the targeted products in 89% and 86% GC
yield respectively (Table 2, entry 1 vs entries 2 and 3). However, as reported in a
previous literature [23], the isochroman with an electron-withdrawing group was not a
good substrate in the case using TEMPO/HCl/NaNO2 as the catalyst system. In
addition, we examined the oxidation of isochromans with alkyl substituents on the
saturated ‘O’ ring, and the targeted products were obtained in moderate yields (Table 2,
entries 5 and 6).
The present catalytic method can be extended to the oxidation of xanthenes, and
the resulting xanthone product is a useful structural motif frequently found
biologically interesting and medicinal compounds [30]. As shown in Table 2 (entries
7-11), various xanthenes were smoothly converted into xanthones in more than 70%
isolated yield under our reaction conditions. Moreover, no detectable amount of
by-product was observed. For example, the reaction of xanthene gave the xanthone
product in a nearly quantitative GC yield (Table 2, entry 7). Thioxanthene was also
tested as the substrate, and the corresponding oxidation product was isolated in a high

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yield, leaving the oxidizable S atom untouched (Table 2, entry 12). When several
fluorenes were used as the substrate (Table 2, entries 13-15), lower yields of the
targeted products were obtained with a high selectivity, and hardly any by-product
was found. We tried changing various reaction conditions, e.g. the reaction
temperature, the reaction time, the solvent and the catalyst loading to increase the
yield of the targeted product, but these attempts were not successful.
Table 2. Aerobic oxidation of various substrates catalyzed by HNO3. [a]
GC yield Isolated yield
Entry
1
Substrate
Product[b]
Conversion(%)[c]
(%)[c]
(%)
O
O
O
~100
66
64
O
O
O
2
99
89
81
Br
Br
O
Cl
Cl
O
3
4
99
98
86
68
78
60
O
O
H3C
O
H3C
O
O
O
O
5
98
70
67
CH3
CH3
O
O
O
98
78
98
-
70
93
73
6
7
8
CH2CH3
CH2CH3
O
99
O
O
O
O
O
~100

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O
O
9
~100
~100
-
-
71
80
O
O
O
O
10
Br
Br
Br
Br
O
O
11
12
13
14
15
~100
97
-
71
88
55
40
45
O
O
95
65
55
60
S
S
O
66
O
O
Br
O
Br
O
66
62
[a] Reaction conditions: 0.5 mmol substrate, 15 mol% HNO3 (the HNO3 loading was 30 mol% in the case of
o
entries 13-15), 2 mL acetonitrile (no drying treatment), 140 C, 3 h, 1 atm oxygen, 45 mL reaction vessel. [b] The
product was characterized by 1H-NMR and 13C-NMR. [c] Determined by GC with an internal standard.
Two kinds of mechanistic pathways for the aerobic α-oxidation of ethers have
been proposed in the previous literatures [22,31-33]. One starts with the formation of
the radical intermediates [22,31,32], while the other starts with the cleavage of
α-carbon-hydrogen bonds of ethers to afford oxocarbenium ion intermediates [33]. To
gain insight into the reaction mechanism, we performed several control experiments
where
several
well-known
radical
scavengers
[21]
including
t
2,6-dibutyl-4-methylphenol (BHT), BrCCl3 and 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) were added into the reaction system. As shown in Scheme 3, addition of
any of these reagents inhibited the formation of isochromanone. These experimental

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results seem to be consistent with a free radical-based mechanism, which reveals that
the present reaction possibly undergoes the radical pathway.
O
Radical trap
BHT
BrCCl3
TEMPO
Isochromanone/yield
full inhibition
full inhibition
22%
O
O
1 atm O2, 15 mol% HNO3
2 mL CH3CN, 140 oC, 3 h
2 equiv. radical trap
Scheme 3. Effect of radical traps on the aerobic oxidation of isochroman.
HNO3 is prone to be thermodynamically decomposed to give NO2 radical or its
dimer, especially at high temperature (Scheme 2) [28]. Indeed, the colorless solution
changed into the brown one when HNO3 was stirred in acetonitrile at 140 oC related to
our experimental condition, indicating the formation of brown NO2 during the
reaction. Thus the resulting NO2 seems to be the real catalytic species because that it
can abstract a benzylic hydrogen atom from isochroman to give a benzylic radical
[22,31], which was confirmed by our experimental result: the reaction using NO2
instead of HNO3 proceeded efficiently with 68% GC yield (Scheme 4a). In addition, a
small amount of NO+ is possibly formed in the present reaction system [28]. The
formed NO+ seems to have the capability to react with isochroman to give the
oxocarbenium ion intermediate [33], but our experimental result indicates that it can
not catalyze the present reaction (Scheme 4b).

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O
O
O
O
O
1 atm O2, 15 mol% NO2
2 mL CH3CN (dry), 140 oC, 3 h
O
(a)
+
1
1
2
68%
3
3%
1 atm O2, 15 mol% NOBF4
+
2
3
(b)
(c)
2 mL CH3CN (dry), 140 oC, 3 h
trace trace
1 atm O2, 15 mol% HNO3
another 3 h
1
2
3
+
<1% 67% 21%
1
+
2 + 3
69% 18%
2 mL CH3CN, 140 oC, 3 h
(no drying treatment)
1 atm O2, 15 mol% HNO3
1
1
+
2
3
2 mL CH3CN (dry), 140 oC, 3 h
73% 4%
(d)
1 atm O2, 15 mol% HNO3
2 mL CH3CN (dry), 140 oC, 3 h
0.1mL H2O
+
2
3
62% 23%
Scheme 4. Control experiments for the mechanism studies.
Although the detailed reaction mechanism is not clear, a plausible NO2-catalyzed
mechanism pathway is proposed based on previous literatures [22,31,32] and our
observations (Scheme 5). The resulting benzylic radical 4 reacts with NO2 to provide
the nitrite ester intermediate 5 [22,31,34], followed by the thermal decomposition of
nitrite ester 5 to afford the targeted product [22,25,26,34]. In addition, hydrolysis of
nitrite ester 5 can give isochroman-1-ol 6 based on previous literatures [35]. The
by-product (1,1′-oxidiisochroman 3) is possibly formed by the reaction between
isochroman-1-ol 6 and the oxocarbenium ion 7 or the carbenium ion 8 [22,32]. The
results shown in Scheme 4c indicate that the conversion of 1,1′-oxidiisochroman 3 is
sluggish under our experimental condition, which seems to be one of the main reasons
why a large amount of 1,1′-oxidiisochroman byproduct was observed in some cases.
As seen from Scheme 5, the presence of H2O is very critical for the formation of
1,1′-oxidiisochroman 3. Indeed, an addition of H2O into the reaction system
remarkably increased the yield of 1,1′-oxidiisochroman byproduct (Scheme 4d). In
addition, it is possible that the formed benzylic carbocation intermediate 8 reacted

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-
-
with the nucleophilic NO2 or NO3 to give the nitrite ester or nitrate ester.
H O
O
2
2
H
.
H
ONO
O
H
O
H
NO
HNO
2
2
.
.
NO
O
2
HNO
5
1
4
O
2
+
H O
2
H O
H
2
NO + H O
OH
2
2
HNO
O
2
H
H
O
+
O
+
O
O
[O]
6
2
8
7
HNO or HNO
+
2
3
H
O
O
O
H
ONO (x = 1 or 2)
x
O
O
O
3
Scheme 5. Proposed mechanism pathways.
Another possible mechanism pathway involves the formation of the peroxy
radical from the direct reaction between the benzylic radical 4 and O2 [21,34] (see
Scheme S4 in the supporting information). The resulting peroxy radical should react
with isochroman to generate 1,1′-peroxydiisochroman based on a previous literature
[21]. However, no 1,1′-peroxydiisochroman by-product was observed under our
experimental conditions, which seems to reveal that the mechanistic pathway via the
peroxy radical is ruled out.
4. Conclusions
In summary, the readily available HNO3 was found to be effective as the
metal-free catalyst for aerobic oxidation of benzylic sp3 C−H bonds of isochromans
under additive-free conditions, which provided a new method for the synthesis of the
synthetically and biologically valuable isochromanones. No other reagent apart from
1atm O2, 15 mol% HNO3 and solvent was used in the reaction, indicating that the
presented protocol is economical and practical. The present catalytic method can be

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extended to the oxidation of xanthenes and fluorenes, and a series of xanthenes and
fluorenes were smoothly converted into xanthones and 9-fluorenones in low to high
yields under the catalysis of HNO3.
Acknowledgements
We thank the financial supports from the Program for Science＆Technology
Innovation Talents in Universities of Henan Province (Grant No.15HASTIT004), the
Open Project of State Key Laboratory for Oxo Synthesis and Selective Oxidation
(Grant No. OSSO-2015-21) and the Research Planning Project of Basic and
Advanced Technology of Henan Province (Grant No.162300410020).
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Graphical abstract
Nitric acid-catalyzed aerobic oxidation of benzylic sp3 C−H
bonds of isochromans, xanthenes and 9-fluorenone under
additive-free conditions
Xinzhe Tian,a,c Fangping Ren,c Bo Zhao,c Yun-Lai Ren,c,* Shuang Zhao,c Jianji
Wangb,*
O
O
O
Y
O2
X
X
Y
HNO3
(15 mol%)
O
O
X
Y
X
Y
O
HNO3 was demonstrated to be an effective catalyst for aerobic oxidation of benzylic
sp3 C−H bonds under additive-free conditions. A series of isochromans, xanthenes and
fluorenes underwent this transformation to give the targeted products in low to high
yields under the catalysis of HNO3, which provided an effective method for the
synthesis of the synthetically and biologically valued isochromanones, xanthones and
9-fluorenones.

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Research Highlights
 HNO3 was found to be an effective catalyst for the aerobic oxidation of C−H
bonds.


An effective method for the conversion of C–H bonds to C=O bonds was
developed.
The reactions proceeded smoothly under additive-free conditions.