Peroxide-mediated transition-metal-free direct amidation of alcohols with nitroarenes

Article abstract of DOI:10.1021/ol203211k

An unusual direct amidation of alcohols with nitroarenes mediated by peroxides has been discovered. The reaction tolerated a wide range of functionalities, and various aromatic amides were obtained in moderate to good yields in the absence of transition-metal catalyst. The peroxides and solvents had a significant impact on the reaction yield.

Full text of DOI:10.1021/ol203211k

ORGANIC
LETTERS
2012
Vol. 14, No. 4
984–987
Peroxide-Mediated Transition-Metal-Free
Direct Amidation of Alcohols with
Nitroarenes
Fuhong Xiao, Yong Liu, Chenglin Tang, and Guo-Jun Deng*
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China
gjdeng@xtu.edu.cn
Received December 2, 2011
ABSTRACT
An unusual direct amidation of alcohols with nitroarenes mediated by peroxides has been discovered. The reaction tolerated a wide range of
functionalities, and various aromatic amides were obtained in moderate to good yields in the absence of transition-metal catalyst. The peroxides
and solvents had a significant impact on the reaction yield.
Amide motifs are present in many natural pro-
ducts, pharmaceuticals, polymers, and biological systems.1
Amides are also of great importance as intermediates for
the preparation of various useful organic compounds.2
Amide formation reaction is one of the key cornerstone
reactions in organic chemistry.3 The amide bonds are
typically synthesized from the corresponding car-
boxylic acids and amines mediated by stoichiometric
amount of coupling reagents or by prior conversion
of carboxylic acids to activated derivatives such as
acid chlorides or anhydrides (Scheme 1, eq 1).4 In
the past few years, great efforts have been made to
develop environmentally friendly processes toward amide
synthesis.5 Recently, Li et al. reported a transition-metal-
catalyzed oxidative amidation of aldehydes with primary
amines, and various aliphaticamideshave beenachievedin
high yields.6
Very recently, an important breakthrough for amide
formation has been made by Milstein et al. The direct
coupling between amine and alcohol leading to amide was
realized using ruthenium pincer complex as catalyst by the
extrusion of dihydrogen (Scheme 1, eq 2). In this unique
transformation, alcohol was oxidized into aldehyde in situ
by the extrusion of dihydrogen (dehydrogenation),7 and
no external oxidant was used as the hydrogen acceptor.
The intermediate aldehyde reacted with amine to give a
hemiaminal that was subsequently dehydrogenated to the
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r
10.1021/ol203211k
Published on Web 01/31/2012
2012 American Chemical Society

from aromatic amines (or even nitroarenes) in the absence
of transition-metal catalyst is rare.14
Scheme 1. Different Pathways for the Amide Bond Formation
Aromatic amines are in general synthesized from the corre-
sponding nitroarenes by using reducing reagents.15 The direct
use of stable, cheap and easily handled nitroarenes with
alcohols instead of aromatic amines is an attractive approach
for CÀN bond formation. However, external reducing re-
agents such as hydrogen and transition-metals are necessary in
most cases.16 Recently, we and others developed various cata-
lytic systems for amine and imine formation between alcohols
and nitroarenes.17 The nitroarenes were reduced to amines in
situ using the borrowing hydrogen strategy (or hydrogen
transfer method),18 and no external oxidants or reducing
reagents were added to the reaction mixture. We also dis-
covered an unusual transition-metal-free direct amination of
simple cycloalkanes with nitroarenes, and secondary amines
were formed under oxidative conditions.19 As a continuing
effort to construct CÀN bonds using nitroarenes directly,
herein, we wish to report a transition-metal-free direct ami-
dation of alcohols with aromatic nitroarenes (Scheme 1, eq 3).
Our initial investigations were focused on the amidation of
benzyl alcohol (1a) with nitrobenzene (2a), and the results are
summarized in Table 1. When nitrobenzene was reacted with
benzyl alcohol in chlorobenzene in the absence of peroxide, no
N-phenylbenzamide (3a) was formed as determined by
GCÀMS and 1H NMR methods (Table 1, entry 1). Instead,
azoxybenzene (PhNdNOPh) was obtained in 48% yield
together with large amount of benzaldehyde.20 The choice
of peroxides was crucial for this reaction. Various peroxides
were investigated under an atmosphere of air.21 tert-Butyl
hydroperoxide (TBHP), cumene hydroperoxide, p-benzoqui-
none, and benzoyl peroxide were inefficient for this kind
of transformation (Table 1, entries 2À5). When dicumyl
peroxide was used, the desired product was formed in 63%
yield (Table 1, entry 6). Among the various peroxides
amide.8 This direct catalytic conversion of alcohols and
amines into amides is a particularly desirable reaction
because of its high atom efficiency and has inspired several
other research groups to further develop the reactions
using transition-metal catalysts with9 or without hydrogen
acceptors.10 However, special handling of expensive metal
complexes and ligands is required in many cases.11 Kobayashi
et al. developed a heterogeneous catalytic system for
amide synthesis. Gold or even very cheap iron, nickel, and
cobalt nanoparticles were used as catalysts, and the catalysts
could be recovered and reused several times without loss of
activity.12,13 However, in most cases, aliphatic or benzylic
amines were used as starting materials. Amide formation
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droxylamine, whereas reduction in basic media affords azoxy com-
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(21) Caution! Be careful when using TBP at these temperatures.
Org. Lett., Vol. 14, No. 4, 2012
985

examined, tert-butyl peroxide (TBP) was the most effec-
tive, and its use resulted in the formation of 3a in 87% yield
(Table 1, entry 7). Replacement of the peroxide with
oxygen did not lead to the desired product 3a (Table 1,
entry 8). Solvents also played an important role, and the
reactionsin other solventsled tomuchlower yield (Table 1,
entries 9À13).22 The choice of bases was crucial for this
reaction. Other bases were less effective (Table 1, entries
14À19). The amount of TBP is another important factor
forthe yieldofthe product. Theuseof2 equivofTBP led to
a lower yield of 3a (Table 1, entry 20). The yield did not
change when the reaction was carried out under argon
(Table 1, entry 21), whereas a slightly lower yield was
obtained when the reaction was carried out in oxygen
(Table 1, entry 22). Under the optimized reaction con-
ditions, the reaction showed good selectivity, and the
overall stoichiometry of the amide reaction was given in
Scheme 2.
Scheme 2. Overall Stoichiometry of the Amide Reaction
With the optimized reaction conditions established, the
scope of the reaction with respect to nitrobenzene and
various benzylic alcohols was investigated (Table 2). The
reactions with benzylic alcohols bearing electron-donating
groups (Table 2, entries 2 and 3) and electron-withdrawing
substituents at the aromatic ring (Table 2, entries 4 and 5)
proceeded smoothly to give the desired products in good
yields. A slightly lower yield was obtained when 4-bromo-
benzyl alcohol was used, and the desired product was
achieved in 55% yield (Table 2, entry 6). The position of
the substituents on the phenyl ring of benzyl alcohols
affected the reaction yield slightly. Moderate yields were
obtained when (2-methylphenyl)methanol (1g), (3-meth-
ylphenyl)methanol (1h), and 1-naphthalenemethanol (1i)
were used as starting materials (Table 2, entries 7À9). It
should be noted that about 20À30% imine byproducts
formed when 1h and 1i were used as the starting mate-
rials, and only trace amount of imines formed in other
cases. No significant difference was observed when
99.99% and ACS reagent purity potassium hydroxide
was used.
Table 1. Optimization of the Reaction Conditionsa
yield (%)b
conv
solvent base 2a (%) 3a
entry
oxidant
4
5
6 7
1
2
3
4
5
6
PhCl
PhCl
KOH
KOH
KOH
KOH
KOH
KOH
98
0
0 45
0 42
0 35
0 12
0
0 48
TBHP
4
0
0
0
0
0
0
0
0
0
0
8
PhC(CH3)2OOH PhCl
0
p-benzoquinone PhCl
0
Table 2. Reaction of Nitrobenzene with Benzylic Alcoholsa
(PhCOO)2
dicumyl
peroxide
TBP
PhCl
PhCl
0
0
0 78
93 63 63 11 11
7
8
9
PhCl
PhCl
DMF
KOH
KOH
KOH
98 87 66 24
5
2
O2
70
100
100
100
0 81
0
9 29
TBP
0 21 16 12
0 32 0 12
0
0
0
5
3
0
3
3
9
10 TBP
11 TBP
12 TBP
13 TBP
14 TBP
15 TBP
16 TBP
17 TBP
18 TBP
19 TBP
20c TBP
21d TBP
22e TBP
diglyme KOH
NMP KOH
0 19
0
0
anisole KOH
100 56 56 56 29
81 53 3 10
p-xylene KOH
6
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
none
85 63 51 10 14
75 52 33 52 11
100 78 30 15 11
72 39 39 39 39
KF
NaOH
K2CO3
K3PO4
Cs2CO3
KOH
KOH
KOH
70 29 30 16 15 11
66 0 23 22 59
100 58 32 13 2 17
0
100 86 86 86
100 74 23 18
0
5
5
9
a Conditions: 1a (0.6 mmol), 2a (0.2 mmol), oxidant (3.0 equiv), base
(0.1 mmol), solvent (0.5 mL), 140 °C, 24 h in air unless otherwise noted.
b GC yield based on 2a. c 2.0 equiv of TBP was used. d Under argon. e Under
oxygen.
(22) For Table 1, entry 7, the conversion of 1a and 2a was 72 and
100%, respectively. For Table 1, entries 9À11, the using of these solvents
resulted other side reactions and no desired product, and imine and
azoxybenzene were observed. For other nitroarene substrates, the
conversion of 2 was above 95%.
a Conditions: 1a (0.6 mmol), 2a (0.2 mmol), oxidant (3.0 equiv), KOH
(0.1 mmol, 99.99%), solvent (0.5 mL), 140 °C, 24 h under air. b Isolated yield.
986
Org. Lett., Vol. 14, No. 4, 2012

Table 3. Reaction of Benzyl Alcohol with Nitroarenesa
Scheme 3. Control Experiments under Various Conditionsa
a Yields are determined by 1H NMR using an internal standard.
with TBP under the standard reaction conditions (Scheme 3,
eq 3).23 Although the mechanism for the present transition-
metal-free amidation of alcohols with nitroarenes is not com-
pletely clear for now, our preliminary experiments revealed
that the amidation should start from aldehydes (in situ
oxidized from alcohols) and azoxyarenes (in situ reduced
from nitroarenes under basic media).20 The hydrogen gener-
ated from alcohols acted as the reducing reagent for nitro
group.
a Conditions: 1a (0.6 mmol), 2a (0.2 mmol), oxidant (3.0 equiv),
KOH (0.1 mmol, 99.99%), solvent (0.5 mL), 140 °C, 24 h under air. b Isolated
yield.
In summary, we have developed a novel direct ami-
dation of alcohols with nitroarenes mediated by per-
oxide. Aromatic amides were formed in moderate to
good yields in the absence of transition-metal catalyst.
The reaction showed very good selectivity, amides were
formed as the major products, and only trace amounts
of imine byproducts were observed in most cases.
Hydrogen generated from alcohol oxidation acted as
the nitro reducing reagent. The nitro reduction, alcohol
oxidation, and amide formation were realized in a
cascade. Further investigation including the scope
and mechanism of this reaction are in progress in our
laboratory.
To further explore the scope of the reaction, various
nitroarenes 2bÀj were employed to react with 1a under the
optimized conditions (Table 3). A series of functional
groups including methyl, methoxy, chloro, bromo, and
fluoro were well tolerated under the optimal reaction
conditions, and the desired products were obtained
in moderate to good yields (Table 3, entries 1À5).
The position of the substituents on the phenyl ring of
nitrobenzene slightly affected the reaction yield. Unfortu-
nately, aliphatic nitro compounds and aliphatic alcohols
are not suitable substrates for this kind of reactions under
the optimal conditions.
To gather more information, some control experiments
were set up under various reaction conditions (Scheme 3).
Under standard reaction conditions, more than 95% nitro-
benzene survived in the absence of benzyl alcohol, and only
trace amount of aniline was observed (Scheme 3, eq 1). The
reaction between benzyl alcohol and aniline mainly afforded
an imine adduct (Scheme 3, eq 2). As we previously indicated,
azoxybenzene was observed as the major adduct in the
absence of TBP. However, the desired product 3a could be
obtained in 73% yield when azoxybenzene was further treated
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (20902076),
the Hunan Provincial Natural Science Foundation
of China (11JJ1003), and the Undergraduate Investi-
gated-Study and Innovated Experiment Plan of Hunan
Province.
Supporting Information Available. General experimen-
tal procedure and characterization data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) A similar yield was obtained when pure azoxybenzene reacted
with benzaldehyde under standard reaction conditions.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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