Ferric nitrate-promoted oxidative esterification of toluene with N-hydroxyphthalimide: Synthesis of N-hydroxyimide esters

Article abstract of DOI:10.1016/j.tetlet.2018.05.058

A ferric nitrate-promoted cross-dehydrogenative coupling reaction of N-hydroxyphthalimide (NHPI) with toluene derivatives is reported. The reaction proceeded smoothly using molecular oxygen as an oxidant, providing an efficient method for the synthesis of

Full text of DOI:10.1016/j.tetlet.2018.05.058

Accepted Manuscript
Ferric nitrate-promoted oxidative esterification of toluene with N-hydroxyph-
thalimide: synthesis of N-hydroxyimide esters
Pingping Li, Jian Sun, Xiaohe Xu, Zhisheng Mi, Yuyan Lin, Jingya Cheng,
Renren Bai, Yuanyuan Xie
PII:
S0040-4039(18)30671-3
https://doi.org/10.1016/j.tetlet.2018.05.058
TETL 50005
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 March 2018
11 May 2018
21 May 2018
Please cite this article as: Li, P., Sun, J., Xu, X., Mi, Z., Lin, Y., Cheng, J., Bai, R., Xie, Y., Ferric nitrate-promoted
oxidative esterification of toluene with N-hydroxyphthalimide: synthesis of N-hydroxyimide esters, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.058
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Ferric nitrate-promoted oxidative esterification of toluene with
N-hydroxyphthalimide: synthesis of N-hydroxyimide esters
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Pingping Lia, Jian Suna, Xiaohe Xua, Zhisheng Mib, Yuyan Lina, Jingya Chenga, Renren Baia, Yuanyuan Xiea,b*

1
Tetrahedron Letters
Ferric nitrate-promoted oxidative esterification of toluene with N-
hydroxyphthalimide: synthesis of N-hydroxyimide esters
Pingping Lia, Jian Suna, Xiaohe Xua, Zhisheng Mib, Yuyan Lina, Jingya Chenga, Renren Baia, Yuanyuan Xiea,b*
a College of Pharmaceutical sciences, Zhejiang University of Technology, Hangzhou, P.R. China.
b Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, P.R. China
ARTICLE INFO
ABSTRACT
A ferric nitrate-promoted cross-dehydrogenative coupling reaction of N-hydroxyphthalimide
(NHPI) with toluene derivatives is reported. The reaction proceeded smoothly using molecular
oxygen as an oxidant, providing an efficient method for the synthesis of N-hydroxyimide esters.
Furthermore, a plausible mechanism was proposed.
Article history:
Received
Received in revised form
Accepted
2018 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Cross-dehydrogenative coupling
Toluene derivatives
N-Hydroxyimidates
Introduction
N-Hydroxyimide esters were active intermediates, which can
be used in the synthesis of amides, esters, O-substituted
hydroxylamines.1 Over the past years, a series of methods for the
preparation of N-hydroxyimide esters have been developed. The
reported methods are summarized as follows: (1) coupling of
carboxylic acids with N-hydroxyimide (NHPI) in the presence of
N,N'-dicyclohexylcarbodiimide;2
(2)
oxidative
cross-
dehydrogenative coupling of aldehydes with NHPI in the
presence of a metal catalyst or under metal-free conditions;3 (3)
oxidative cross-dehydrogenative coupling of alcohols with NHPI
under metal-free conditions.4 The above-mentioned methods
appear to be general and efficient. However, the cross-
dehydrogenative coupling reaction of toluene derivatives with
NHPI still remains a major challenge.
In recent years, iron(III) nitrate nonahydrate [Fe(NO3)3·9H2O]
has been used as a nitration reagent, as well as a catalyst in the
oxidation of benzyl alcohols.5 In our previous work, we have
described Fe(NO3)3·9H2O catalyzed synthesis of N-hydroxyimide
ester by a cross-dehydrogenative coupling reaction of aldehydes
or alcohols with NHPI in the air.6 NHPI has also been used to
catalyze the oxidation of toluene for the preparation of N-
hydroxyimide ester. However, the use of environmentally
unfriendly co-catalyst cobalt salts and expensive solvent
1,1,1,3,3,3-hexafluoropropan-2-ol has limited the application of
this reaction.7 Therefore, synthesis of N-hydroxyimide esters
under simple and efficient reaction conditions using environment
benign, cheap and commercially available reagents, such as
toluene, Fe(NO3)3·9H2O and O2 as a green oxidant has received a
great interest.
Scheme 1. Design synthesis of N-hydroxyamide esters
Results and discussion
Initially, p-fluorotoluene 1a and NHPI 2 were used as the
model substrates to explore the optimal reaction conditions. The
results are summarized in Table 1. When Cu(NO3)2·3H2O (20
mol%) was used as a catalyst in the presence of oxygen in
CH3CN, the desired product 3a was obtained in 52% yield (entry
1). Other catalysts such as Mg(NO3)2·6H2O and NaNO2 were
found to be less effective (entries 2-3). To our delight, when
Fe(NO3)3·9H2O was used as the catalyst, the desired product was
obtained in 63% yield (entry 4). Decreasing or increasing the
reaction temperature led to lower yields (entries 5-6).

2
Tetrahedron Letter
Furthermore, the effects of different solvents were investigated
and CH3CN was found to be the optimal solvent (entries 7-10).
When in the air, 45% yield of 3a was obtained (entry 11). A
similar yield was obtained when TBHP was used as an oxidant
(entry 12). However, under a N2 atmosphere, only 30% yield of
3a was obtained (entry 13) .The effect of amount of NHPI on the
reaction was also studied, it was found that the yield of 3a
reduced when 1.0 equiv. of 2 was used (entry 14). Additionally,
changes in the amount of Fe(NO3)3·9H2O did not obviously
affected the yield of 3a (entries 15-16).
Table 1. Optimization of the reaction conditions.a
Entry
1
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
H2O
Catalyst
T. (oC)
70
Oxidant
Yield (%)b
52
Cu(NO3)2·3H2O
Mg(NO3)2·6H2O
NaNO2
O2
2
70
O2
37
3
70
O2
Trace
63
4
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
70
O2
5
60
O2
50
6
82
O2
61
7
70
O2
N.D.
27
8
EtOAc
70
O2
9
CH3CH2OH
HFIP
70
O2
10
10
11
12c
13d
14e
15f
16g
70
O2
15
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
70
air
45
70
TBHP(6.0)
59
70
--
30
70
O2
O2
O2
35
70
52
70
56
aReactions were conducted with 1a (1.0 mmol), 2 (2.0 mmol) and catalyst (20 mol%) in solvent (4 mL) under O2 (balloon) for 12 h,
d
unless otherwise noted. bIsolated yields based on 1a. cTBHP (70% in water). Under N2 atmosphere. e2 (1.0 mmol). fFe(NO3)3·9H2O (15
mol%). gFe(NO3)3·9H2O (30 mol%).
Using the established method, a control experiment was
performed. Under the standard conditions, the esterification of 4-
methoxytoluene 1l with NHPI 2 was conducted in the presence of
TEMPO. The desired product 3l was not detected and a TEMPO-
captured product 4 was obtained in 70% yield (Scheme 2, eq. 1),
which indicated that the reaction might proceed in a radical way.
Besides, when 4-methoxybenzaldehyde was used instead of 4-
methoxytoluene under the standard conditions, luckily, 78%
yields of desired product was obtained (Scheme 2, eq. 2). This
result also demonstrated that aldehyde was the reaction
intermediate. Based on the results of this experiment and the
previous reports,6,8 a plausible reaction pathway was illustrated in
Scheme 3. In this proposed mechanism, ferric nitrate functions as
a radical initiator. Hydrolysis of ferric nitrate yields HNO3, the
latter undergoes thermal decomposition to generate NO2. Then
NO2 captures a hydrogen atom from NHPI to form PINO, the
latter absorbs a hydrogen atom from toluene to produce the
corresponding radical A, which subsequently reacts with
molecular oxygen, producing peroxide radical B. Then B
captures a hydrogen atom from NHPI to produce the intermediate
C,9 which is converted to the benzaldehyde intermediate D after
losing water.10 Next, PINO obtains a hydrogen atom from
With the optimized conditions in hand, the scope of substrates
was investigated. As shown in Table 2, a series of toluene
derivatives reacted smoothly with NHPI, and the corresponding
products were obtained in moderate to good yields. The reaction
of NHPI with toluene derivatives bearing electron-withdrawing
groups, such as F, Cl, Br and I at the para-positions of benzene
rings proceeded well under the optimized conditions and gave
coupling products 3a-3d in 43-63% yields (entries 1-4). Due to
steric effects, the reaction of the toluene derivatives with a
substituent at ortho- or meta-position of benzene ring provided
the products 3e-3j in slightly lower yields 48-56 % (entries 5-10).
The reaction of a toluene derivative with a strong electron-
withdrawing group NO2 generated the corresponding product 3k
in only 40% yield (entry 11). In the cases of electron-donating
group, such as OCH3, at the para-, or othro- or meta-position of
toluene, higher yields of products 3l, 3m, and 3n were obtained,
being 73, 68, and 58%, respectively (entries 12-14). The reaction
with p-tert-butyl toluene only gave the desired product 3o in a
lower yield (entry 15). Unfortunately, the reaction did not occur
when NHPI analogues, such as N-hydroxysuccinimide (NHSI)
and N-hydroxybenzotriazole (HOBt), were used instead of NHPI.

3
aldehyde to produce the corresponding radical E, which further
reacts with PINO to produce the N-hydroxyimide ester 3.
Table 2. Reaction of 2 with toluene derivatives.a
Entry
1
R
4-F
t (h)
12
12
12
36
16
12
16
16
16
16
40
24
24
24
24
3
3a
3b
3c
3d
3e
3f
Yield (%)b
63
60
59
43
48
50
51
53
50
56
40
73
68
58
54
2
4-Cl
3
4-Br
4
4-I
5
2-F
6
2-Cl
7
2,4-Cl
2-Br
3g
3h
3i
8
9
3-Br-4-F
3-Br
10
11
12
13
14
15
3j
4-NO2
4-OCH3
3-OCH3
2-OCH3
4-tBu
3k
3l
3m
3n
3o
Scheme 3. Proposed mechanism
Acknowledgment
aReactions were conducted with 1 (1.0 mmol), 2 (2.0 mmol) and
Fe(NO3)3·9H2O (20 mol%) in CH3CN (4 mL) at 70oC for 12–40
h under O2 (balloon) conditions. bIsolated yields based on 1.
We are grateful to the National Natural Science Foundation of
China (No. 21576239) for financial support. We thank Prof. Tao
Zhou at Zhejiang Gongshang University and Dr. Xinpeng Jiang at
Zhejiang University of Technology for helpful discussions.
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Scheme 2. Control experiment
In conclusion, we have developed a novel and efficient
method for the synthesis of N-hydroxyimide esters. This is the
first report that describes the use of toluene derivatives as the
coupling partners for NHPI to give the corresponding esters. In
addition, other advantages of this methodology include using
inexpensive Fe(NO3)3·9H2O as a radical initiator and O2 as an
oxidant. Further studies on the coupling reaction of amine with
N-hydroxyimide esters are underway.
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Tetrahedron Letter
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1. Using inexpensive Fe(NO3)3·9H2O as a radical
initiator
2. Using O2 as an green oxidant
3. Synthesis of N-hydroxyimide esters from
toluene and N-hydroxyphthalimide