TBHP/TEMPO-mediated oxidative synthesis of imides from amides

Article abstract of DOI:10.1002/cjoc.201500190

A new protocol for the synthesis of imides has been developed. In the presence of copper catalyst, N-benzylamides were oxidized to the corresponding imides by TBHP/TEMPO system in moderate to good yields. Imides were synthesized through the oxidation of N-benzylamides by TBHP/TEMPO system in moderate to good yields.

Full text of DOI:10.1002/cjoc.201500190

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DOI: 10.1002/cjoc.201500190
TBHP/TEMPO-Mediated Oxidative Synthesis of Imides from
Amides
Hui Yu,*,a Yuegang Chen,a,b and Yonghao Zhanga
a Department of Chemistry, Tongji University, 1239 Siping Road, Shanghai 200092, China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200092,
China
A new protocol for the synthesis of imides has been developed. In the presence of copper catalyst, N-benzyl-
amides were oxidized to the corresponding imides by TBHP/TEMPO system in moderate to good yields.
Keywords imides, oxidation, TBHP, CuBr, TEMPO
Introduction
tinuation of our efforts on the oxidative functionaliza-
tion of amides,[8] we report our work for the oxidative
synthesis of imides from amides.
As one of the most important classes of N-containing
compounds necessary in organic and pharmaceutical
chemistry, imides could be found widely in many natu-
ral products and bioactive compounds.[1] Therefore,
various approaches have been developed for their prep-
aration. Traditional methods for the synthesis of imides
generally started from amides and carbonyl chlorides
with stoichiometric amount of salt generated as the
waste, and sometimes the preparation of corresponding
carbonyl chlorides is required.[2] Aldehydes could also
be utilized as the acylation reagents in place of carbonyl
chlorides, but excess amounts of aldehydes or NBS had
to be used in such reactions.[3] Oxidation of N-substi-
tuted amides provides an alternative route to imides and
kinds of oxidants have been proved to be efficient.[4]
Among these developed oxidants, tert-butyl hydroper-
oxide (TBHP) has attracted considerable attention as a
mild oxidant and has been used successfully for the
formation of carbon-carbon and carbon-heteroatom
bonds in recent years.[5] In most cases, these reactions
were carried out under mild conditions and only small
molecules such as H2O and t-BuOH were released as
the main byproducts. Using TBHP as the oxidant,
Taherpour has reported limited examples for the
oxidative synthesis of imides from N-alkyl amides
catalyzed by manganese(Ⅲ) acetylacetonate in ethyl
acetate under microwave irradiation (90 W, 5 min);[6] Xi
and her co-workers reported a novel copper-catalyzed
oxidation of arene-fused cyclic amines to the corre-
sponding cyclic imides, but this method was not suitable
to acyclic amines.[7] Thus, the development of practical
TBHP-mediated oxidative synthesis of imides with
broad substrate scope is still desirable. Herein, as a con-
Experimental
General
Commercially available reagents were used as re-
ceived without further purification unless otherwise in-
dicated. Reactions were magnetically stirred and moni-
tored by thin layer chromatography (TLC) using Silica
Gel 60 F254 plates and were visualized by fluorescence
quenching at 254 nm. For chromatographic purifications,
analytically pure solvents were used and the silica gel
1
(300－400 mesh) was used as the solid support. H
NMR and 13C NMR chemical shifts (δ) were reported
relative to the chemical shift of residual solvent. Refer-
ence peaks for chloroform in H NMR and 13C NMR
1
spectra were set at δ 7.26 and 77.0, respectively.
Typical experimental procedure for the synthesis of
N-benzoylbenzamide
To a mixture of amide (0.20 mmol), CuBr (0.04
mmol, 20 mol%), and TEMPO (0.10 mmol) in acetoni-
trile (1.5 mL) was added TBHP (70 wt% in H2O, 2.0
mmol) at room temperature. The reaction vessel was
capped and allowed to stir at room temperature for 8 h.
Then the volatiles were removed under reduced pressure,
and the crude product was purified by flash chromatog-
raphy on silica gel [V(PE)∶ V(AcOEt)＝4∶1] to ob-
tain the imide product.
Results and Discussion
Initially, N-benzyl-3-methylbenzamide 1c was cho-
*
E-mail: yuhui@tongji.edu.cn; Tel.: 0086-021-65981097; Fax: 0086-021-65982287
Received March 8, 2015; accepted March 28, 2015; published online May 5, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500190 or from the author.
Chin. J. Chem. 2015, 33, 531—534
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Yu, Chen & Zhang
COMMUNICATION
sen as the model substrate to optimize the reaction con-
ditions including the catalyst, additive, solvent and tem-
perature. As shown in Table 1, the reaction of 1c with
10.0 equiv. of TBHP (70% solution in water) was ex-
amined in CH3CN at room temperature and only trace
of the product 2c could be found without catalyst (Table
1, entry 1). When copper salts (20 mol %) were added to
the reaction as catalysts, the yield of 2c could be im-
proved significantly and CuBr gave better yield than
CuCl, CuI, and CuBr2 (Table 1, entries 2－5). Further
investigation revealed that addition of TEMPO to the
reaction could increase the yield of 2c remarkably. Dif-
ferent amounts of TEMPO were screened and 0.5 equiv.
TEMPO gave the best result (Table 1, entries 6－9).
Other commercial oxidants such as DDQ and
PhI(OAc)2 were also tested to promote the reaction but
lower yields were obtained (Table 1, entries 10, 11).
Increasing the reaction temperature to 40 ℃ resulted in
a lower yield (Table 1, entry 12). The use of EtOAc or
toluene as the solvent resulted in the formation of 2c in
lower yields (Table 1, entries 13, 14). When the used
amount of TBHP was reduced to 5.0 equiv., the yield of
2c decreased to 70% (Table 1, entry 15). On the basis of
these results, entry 8 represents the optimal synthesis
conditions.
Table 2. N-Benzyl amides of various substituted benzoic
acid were investigated, and the corresponding imides
were obtained in good yields regardless of the electron-
donating or electron-withdrawing groups and the sub-
stituted positions on the benzene ring (Table 2, entries 2
－5). N-Benzyl-2-naphthamide also gave the desired
product in 86% yield under the optimized reaction con-
ditions (Table 2, entry 6). Heterocyclic substrates such
as N-benzylfuran-2-carboxamide and N-benzylthio-
phene-2-carboxamide underwent smooth reactions to
give the products in good yields (Table 2, entries 7, 8).
Aliphatic substrates such as N-benzylacetamide, N-ben-
zylisobutyramide and N-benzylpivalamide could also be
converted into the corresponding products in good
yields (Table 2, entries 9－11). N-Benzylphenylaceta-
mide and N-benzyl-2-oxo-2-phenylacetamide were also
suitable substrates in this reaction and the corresponding
imides were obtained in 70% and 73% yields, respec-
tively (Table 2, entries 12, 13). Carbamate such as ben-
Table 2 Oxidation of N-benzylamides 1 to imides 2a
10 equiv. TBHP
20 mol% CuBr
O
O
O
50 mol% TEMPO
R1
N
H
R2
R1
N
H
R2
CH3CN, r.t., 8 h
2
1
Table 1 Optimization of the reaction conditionsa
Entry R1
R2
Product Yieldb/%
O
O
O
catalyst, additive
TBHP (10.0 equiv.)
Me
Me
1
C6H5
C6H5
2a
2b
2c
2d
2e
2f
90
81
82
79
89
86
65
75
83
95
69
70
73
51
65
70
74
66
trace
71
45
0
N
H
N
H
2
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-ClC6H4
2-Naphthyl
2-Furyl
C6H5
Solvent, r.t., 8 h
2c
1c
3
C6H5
Catalyst
(20 mol%) (equiv.)
Additive
4
C6H5
Entry
Solvent Yieldb/%
CH3CN
5
C6H5
1
－
－
0
6
C6H5
2
CuCl
CuBr
CuI
－
CH3CN 54
CH3CN 60
CH3CN 32
CH3CN 52
CH3CN 68
CH3CN 72
CH3CN 82
CH3CN 74
CH3CN 46
CH3CN 65
CH3CN 68c
7
C6H5
2g
2h
2i
3
－
8
Thiophen-2-yl
Me
C6H5
4
－
9
C6H5
5
CuBr2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
－
10
11
12
13
14
15
16
17
18
19
20
21
22
i-Pr
C6H5
2j
6
TEMPO (0.2)
TEMPO (0.3)
TEMPO (0.5)
TEMPO (0.7)
DDQ (0.5)
PhI(OAc)2 (0.5)
TEMPO (0.5)
TEMPO (0.5)
TEMPO (0.5)
TEMPO (0.5)
t-Bu
C6H5
2k
2l
7
Bn
C6H5
8
C6H5CO
BnO
C6H5
2m
2n
2d
2o
2p
2q
2e
2r
2g
2s
9
C6H5
10
11
12
13
14
15
C6H5
4-MeC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-ClC6H4
4-MeOC6H4
2-Furyl
n-Bu
C6H5
C6H5
EtOAc
61
C6H5
Toluene 46
CH3CN 70d
C6H5
4-ClC6H4
C6H5
a Reaction conditions: 0.2 mmol 1c, 2 mmol TBHP (70% solution
in water), in 2.0 mL CH3CN at room temperature for 8 h. b Iso-
lated yield. c Reaction carried out at 40 ℃. d 5.0 equiv. TBHP was
used.
C6H5
a The reaction was carried out with 1 (0.2 mmol), CuBr (0.04
mmol), TEMPO (0.1 mmol), and TBHP (70 wt% in water, 2.0
mmol), in acetonitrile (2.0 mL) at room temperature for 8 h.
b Isolated yields.
Under the optimized reaction conditions, the effect
of substrates was examined with results summarized in
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Chin. J. Chem. 2015, 33, 531—534

TBHP/TEMPO-Mediated Oxidative Synthesis of Imides from Amides
zyl benzylcarbamate was also tested using the optimized
reaction and the product was isolated in 51% yield (Ta-
ble 2, entry 14). For substrates with electron-donating
group substituted at different positions on the benzyl
group of N-benzylbenzamide, the desired products were
formed in 65%－74% yields (Table 2, entries 15－18).
However, for the substrate with electron-withdrawing
group substituted on the benzyl group, only trace of the
desired product could be found (Table 2, entry 19). For
substrates with substituted group on both sides of the
benzene rings, the desired product was obtained in 71%
yield (Table 2, entry 20). The heterocyclic substrate
N-(furan-2-ylmethyl)benzamide gave 45% yield of 2g,
lower than that in the case of N-benzylfuran-2-car-
boxamide (Table 2, entry 21). N-Butylbenzamide was
also tested but no reaction occurred and all the starting
materials remained untouched (Table 2, entry 22).
Although the detailed reaction mechanism still re-
mains to be clarified, a reaction pathway is proposed as
shown in Scheme 1. The H atom adjacent to the nitro-
gen atom of the amide 1 was abstracted by TBHP to
give radical A,[8] which was oxidized by TEMPO to
form acylimine B,[9] and TEMPO was regenerated
through the oxidation of the released TEMPOH by
TBHP. With the aid of copper salt, B was attacked by
water to give the intermediate C. Finally, oxidative de-
hydrogenation of C afforded the product imide 2.[10]
More details for the mechanism still need further inves-
tigations.
was employed to the oxidative reaction, a decarboxyla-
tive oxidation reaction occurred and the product 2a was
formed in 80% yield (Scheme 2b).
Conclusions
In conclusion, we have developed an efficient and
practical method for the synthesis of imides by simple
oxidation of N-benzylamides. The reaction was carried
out under mild conditions using TBHP as the oxidant,
CuBr as the catalyst, and TEMPO as the additive.[11]
The procedure was easy to handle and various imides
have been synthesized under the optimized conditions.
Acknowledgement
Financial support from Tongji University (20123231)
is gratefully acknowledged.
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Scheme 1 Proposed mechanism
TBHP
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O
O
OH
[Cu], TBHP
-2H
+ H2O
R
N
Ar
R
N
Ar
H
H
C
2
Finally, tertiary amide N-benzyl-N-methylbenzamide
3 was also examined, and the product N-benzyl-N-me-
thylbenzamide 4 was obtained in 60% yield (Scheme
2a). Interestingly, when N-benzoyl-2-phenylglycine 5
Scheme 2 Oxidation of N-benzyl-N-methylbenzamide and
2-benzamido-2-phenylacetic acid
20 mol% CuBr
50 mol% TEMPO
10 equiv. TBHP
O
O
O
O
Ph
Ph
N
Ph
(a)
(b)
Ph
Ph
N
Ph
CH3CN, r.t., 8 h
Me
4, 60%
Me
3
20 mol% CuBr
50 mol% TEMPO
10 equiv. TBHP
O
O
COOH
Ph
N
Ph
N
H
H
CH3CN, r.t., 8 h
5
2a, 80%
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