Metal-free C-N bond-forming reaction: Straightforward synthesis of anilines, through cleavage of aryl C-O bond and amide C-N bond

Article abstract of DOI:10.1016/j.tetlet.2013.04.028

An efficient metal-free C-N bond forming reaction through cleavage of aryl C-O bond and amide C-N bond has been developed. This process represents a practical method for the facile construction of anilines with a broad substrate scope and wide functional group tolerance in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.04.028

Tetrahedron Letters 54 (2013) 3167–3170
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free C–N bond-forming reaction: straightforward synthesis
of anilines, through cleavage of aryl C–O bond and amide C–N bond
Jianzhong Yu a, Peizhi Zhang b, Jun Wu a, , Zhicai Shang a,
⇑
⇑
a Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
b School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310012, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient metal-free C–N bond forming reaction through cleavage of aryl C–O bond and amide C–N
bond has been developed. This process represents a practical method for the facile construction of ani-
lines with a broad substrate scope and wide functional group tolerance in moderate to excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 23 January 2013
Revised 21 March 2013
Accepted 8 April 2013
Available online 15 April 2013
Keywords:
C–N bond formation
Metal-free
Anilines
Aryl C–O bond
Anilines are important intermediates for the synthesis of agro-
chemicals, pharmaceuticals, dyes, and pigments. Traditionally, the
manufacturing processes for anilines are based on aromatic nitra-
tion and the continuous catalytic hydrogenation of nitroaromatic
compounds. Both of them are limited to the preparation of those
molecules containing sensitive functional groups. In addition,
these processes generate a large amount of waste liquid in the
use of sulfuric acid and nitric acid and cause environmental pollu-
tion.1,2 Recent progresses of aniline synthesis via transition-metal-
catalyzed cross-coupling reaction of aryl halides with ammonia or
ammonia surrogates have been reported.3 The palladium-cata-
lyzed synthesis of anilines has been developed through couplings
of aryl halides (X= I, Br, Cl) or phenol derivatives with ammonia.4
Similarly, the copper-catalyzed coupling reaction of ammonia with
aryl iodides or aryl bromides is available, while the coupling with
less reactive but more economically attractive aryl chlorides does
not occur.5 Also, the copper-catalyzed reaction of aromatic boronic
acids with ammonia enables direct access to anilines.6 Despite
remarkable advances, there are some notable limitations. Particu-
larly, the presence of heavy transition-metal impurities in the final
products remains a major problem. A wide variety of functional
groups, including iodo and bromo moieties are typically sensitive
in palladium- and copper-catalyzed coupling reactions. For these
reasons, the development of metal-free methods will probably pro-
vide new ways for constructing anilines.7
Phenols and their derivatives are common reagents.8 The aryl
C–O bond is generally ‘inert’ so that the cleavage of aryl C–O bond
is very difficult.9 Only very few examples have been reported for
the construction of anilines starting from phenol-derived com-
pounds under metal-free conditions.10 For example, the alkyl-
ation-Smiles rearrangement-hydrolysis sequence has been used
for the preparation of anilines, but this method requires harsh
reaction conditions and has limited substrate scope.10b Herein,
we report the example of metal-free cleavage of aryl C–O bond
and amide C–N in aryloxyamides, which leads to the formation
of new C–N bond. Use of this type reaction provides an efficient
and straightforward access to anilines. This general method has
highly appreciated qualities of a chemical transformation, includ-
ing simple operation, high selectivity, and affordable starting
materials.
Initially, we selected aryloxyamides 1–7 as our model system
for the investigation of C–N bond-forming reaction. We treated
aryloxyamides with sodium hydroxide as base (2.0 equiv) in N,N-
dimethylformamide solvent at 140 °C (Table 1). No expected C–N
bond-forming reactions were observed with 1, 2, and 3 (Table 1,
entries 1–3, yields <5%). To our delight, the desired C–N bond-
forming reaction was observed with 4 (Table 1, entry 4), albeit in
low yield. Then, we tested the variation of R1 groups (R2=H). Com-
pared with aryloxyamides 5 and 6, the use of aryloxyamide 7 per-
formed much better in the C–N bond-forming reactions, producing
the highest yield up to 55% (Table 1, entries 5–7). As a result, we
found that carbon chain length (n) and substituents (R1 and R2)
had a large effect on the C–N bond formation and aryloxyamide
7 (n = 0, R1 = CH3, R2 = H) was identified as the best substrate in
the synthesis of anilines.
⇑
Corresponding authors. Tel.: +86 571 87951352; fax: +86 571 87951895 (J.W.);
tel.: +86 571 87952379; fax: +86 571 87951895 (Z.S.).
E-mail addresses: wujunwu@zju.edu.cn (J. Wu), shangzc@zju.edu.cn (Z. Shang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.028

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J. Yu et al. / Tetrahedron Letters 54 (2013) 3167–3170
Table 1
Optimization studies for aryloxyamides 1–7 as substrates for C–N bond-forming reactionsa
R2
R1
CONH2
NaOH (2 eq.)
Cl
NH2
Cl
O
n
DMF, 140 o
C
1-7
8
Entry
Aryloxyamides
n
R1
R2
Yieldb (%)
1
2
3
4
5
6
7
1
2
3
4
5
6
7
0
0
1
0
0
0
0
CH3
COCH3
H
H
Ph
CH3
H
H
H
H
<5
nr
nr
32
50
47
55
CONH2
CH3
H
H
a
Reaction conditions: 1 (1.0 mmol), NaOH (2.0 mmol), DMF (4.0 mL), 140 °C, 3 h.
Isolated yield after column chromatography.
b
Table 2
Optimization studies for reaction conditionsa
CONH2
base
Cl
NH2
Cl
O
solvent
7
8
Entry
Base (equiv)
Solvent
Temp/Time
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3 (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
NaH (2.0)
NaOH (2.0)
NaOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (1.0)
CH3CN
DMF
DMF
DMF
DMF
Reflux/16 h
Reflux/16 h
Reflux/16 h
Reflux/16 h
120 °C/3 h
140 °C/3 h
140 °C/3 h
140 °C/3 h
140 °C/3 h
160 °C/3 h
140 °C/3 h
140 °C/3 h
140 °C/3 h
n.r.
n.r.
n.r.
13
9
55
60
55
65
63
65
64
48
DMF
DMF
DMAC
DMSO
DMSO
DMSO/DMPU (3:1)
DMPU
9
10
11
12
13
DMSO
a
Reaction conditions: 7 (1.0 mmol), base (1.0–2.0 mmol), solvent (4.0 mL).
Isolated yield after column chromatography.
b
Next, aryloxyamide 7 was chosen as the model substrate to
optimize the reaction conditions. Bases, solvents, and co-solvent
were investigated at varied temperature (Table 2). We observed
that the C–N bond-forming reaction proceeded to afford the prod-
uct 8 in the presence of a variety of bases, and KOH was the best
choice in the formation (Table 2, entry 7). Different solvents were
also investigated, and dimethyl sulfoxide (DMSO) was the optimal
solvent (Table 2, entry 9). 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyramidinone (DMPU) is often used as a co-solvent,11 and the
same activity was shown with DMSO/DMPU (3:1 ratio; Table 2, en-
try 11). We were pleased to find that the reaction also proceeded to
give 8 even in the presence of 1.0 equiv of KOH, albeit in a decrease
in isolated yield (Table 2, entry 13). After the screening, the opti-
mum conditions for C–N bond-forming reaction were as follows:
KOH as base, DMSO as solvent, DMPU as co-solvent, and the reac-
tion was carried out at 140 °C.
ortho-positions provided moderate to excellent yields. Some sub-
strates containing electron-neutral and electron-rich groups in
DMSO as reaction solvent were found with very low yields (Table 3,
10d–f). Delightedly, we found that the use of DMPU as co-solvent
could dramatically increase the reactivity for the formation (10d–
f). The method showed a wide substrate scope with good func-
tional group tolerance. The aryloxyamides containing halogen
substituted groups, such as F, Cl, Br, and I (10l–s), showed good
reactivity, which offered an opportunity for further derivatizations
through transition-metal-catalyzed techniques. Moreover, the sub-
strates containing base-sensitive groups including the nitro, ester,
aldehyde, and ketone groups were obtained successfully in the
presence of only 1.0 equiv of KOH in moderate to high yields
(10t–w). The 2-(2,3,6-trimethylphenoxy) propanamide, 2-(2,6-di-
methyl phenoxy) propanamide, and 2-(4-bromo-2,6-dimethyl
phenoxy) propanamide, which are more sterically hindered with
two methyl groups at the C2 and C6 positions, also led to moderate
yields (10x–z). Polycyclic-based substrates could be transformed
to the corresponding anilines (10aa–bb). It is noteworthy that het-
eroaryl substrates could also be successfully converted into the
corresponding anilines (10cc–dd).
We then explored the scope of this novel method. As shown in
Table 3, all the substrates 9 derived quite easily from the corre-
sponding phenols were examined under the standard reaction con-
ditions. We found that the substrates containing electron-deficient,
electron-neutral, and electron-rich groups at the para-, meta-, or

J. Yu et al. / Tetrahedron Letters 54 (2013) 3167–3170
3169
Table 3
Scope of metal-free synthesis of anilinesa
O
KOH (1-2 eq.)
ArO
ArNH2
NH2
DMSO or DMSO/DMPU(3:1)
140 oC, 3-16 h
9
10
O
O2N
NH2
Ph
NH2
NH2
NH2
Ph
10a
6h 48%b
10b
3h 76%
10c
4h 90%
10d
16h 5%a, 41%b
MeO
MeO
NH2
NH2
NH2
NH2
10e
10f
10g
6h 62%
10h
8h 87%
16h 0%,38%b
6h 5%a, 56%b
O2N
NO2
F
NH2
NH2
NH2
NH2
10j
10k
3h 95%
10l
16h 35%b
10i
16h 39%b
3h 53%
Cl
Br
Br
NH2
I
NH2
NH2
NH2
10n
3h 85%
10p
4h 65%
10m
3h 86%
10o
6h 71%
Br
Cl
Cl
NC
NH2
Cl
NH2
NH2
NH2
10r
10q
10t
10s
3h 83%c
4h 52%
4h 60%
3h 77%
O
H
O
NH2
NH2
NH2
MeO2C
NH2
Et
10u
10v
10w
10x
8h 48%c
8h 56%c
6h 81%c
16h 45%b
NH2
NH2
Br
NH2
NH2
10z
10y
16h 50%b
10bb
6h 81%
10aa
6h 56%
8h 64%b
NH2
O
O
O
NH2
10cc
8h 48%
10dd
8h 79%b
aReaction conditions: 9 (1.0 mmol), KOH (2.0 mmol), DMSO (4 mL), 140 °C.
bReaction conditions: 9 (1.0 mmol), KOH (2.0 mmol), DMSO (3 mL) and DMPU (1 mL), 140 °C.
cReaction conditions: 9 (1.0 mmol), KOH (1.0 mmol), DMSO (4 mL), 140 °C.
Our proposed mechanism for the reaction is shown in Scheme 1.
The first step of the reaction is the formation of the aryloxyamide
anion A, a nucleophile by deprotonation of 9 in the presence of
hydroxide ion.12 The nucleophile attacks the aromatic nucleus in
an ipso fashion to form a five-membered transition state.13 Break-
ing of the C–N bond in the transition state regenerates aryloxya-
mide anion A in an unproductive process. Breaking of the C–O
bond in the transition state leads to the formation of oxoanion B
in a productive process. Oxoanion B attacks carbonyl carbon via
an intramolecular nucleophilic addition to break the C–N bond,
releasing the anilinium ion C.14 This anilinium ion C captures pro-
ton from water to give the final product aniline 10.
In conclusion, an efficient and metal-free method for construct-
ing anilines from aryloxyamides through cleavage of aryl C–O bond
and amide C–N bond has been developed. This transformation is an
extremely simple way and offers anilines in moderate to excellent

3170
J. Yu et al. / Tetrahedron Letters 54 (2013) 3167–3170
O
O
H2N
O
O
R
OH
R
R
H2O
NH
O
O
NH
9
A
reactive conformation
+
+
H
N
O
O
NH2
NH
H2O
R
R
R
N
H
R
O
O
10
C
oxoanion B
transition state
Scheme 1. Plausible reaction mechanism.
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yields via more environmentally benign processes. The reaction
displays a broad scope of substrates and tolerates a number of
functional groups, including halogen and base-sensitive groups.
We believe that the method should have potential to become a
widely used transformation in many applications and further re-
searches are going on in our laboratory.
Acknowledgment
Funding from the National Natural Science Foundation of China
(No. 31071720) is greatly acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
028.
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