One-pot conversion of phenols to anilines via Smiles rearrangement

Article abstract of DOI:10.1016/j.tetlet.2013.06.022

A convenient one-pot synthesis of phenols to anilines using 2-chloroacetamide/K₂CO₃/DMF system catalyzed by KI via Smiles rearrangement has been described. The synthesis of extensive amino aromatic products from phenols containing electron withdrawing group, has been performed in moderate to excellent yields to demonstrate the potentiality of this method in bio-medicinal and pharmaceutical applications.

Full text of DOI:10.1016/j.tetlet.2013.06.022

Accepted Manuscript
One-pot Conversion of Phenols to Anilines via Smiles Rearrangement
Yong-Sheng Xie, B.V.D. Vijaykumar, Kiwan Jang, Hong-Hyun Shin, Hua Zuo,
Dong-Soo Shin
PII:
S0040-4039(13)00978-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.022
TETL 43075
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 May 2013
30 May 2013
6 June 2013
Please cite this article as: Xie, Y-S., Vijaykumar, B.V.D., Jang, K., Shin, H-H., Zuo, H., Shin, D-S., One-pot
Conversion of Phenols to Anilines via Smiles Rearrangement, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.06.022
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Tetrahedron Letters
journal homepage: www.elsevier.com
One-pot Conversion of Phenols to Anilines via Smiles Rearrangement
Yong-Sheng Xie,a,b B. V. D. Vijaykumar,a Kiwan Jang,a Hong-Hyun Shin,c Hua Zuo,d Dong-Soo Shin*,a
aDepartments of Chemistry and Physics, Changwon National University, Changwon, 641-773, S. Korea
bCollege of Chemical and Environmental Engineering, Chongqing Three Gorges University, Chongqing, 404100, P.R. China
cDaelim Chemical Co. Ltd., Haman, 718-844, S. Korea
dCollege of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient one-pot synthesis of phenols to anilines using 2-chloroacetamide/K2CO3/DMF
system catalyzed by KI via Smiles rearrangement has been described. The synthesis of
extensive amino aromatic products from phenols containing electron withdrawing group, has
been performed in moderate to excellent yields to demonstrate the potentiality of this method
in bio-medicinal and pharmaceutical applications.
Available online
Keywords:
Phenol
2013 Elsevier Ltd. All rights reserved.
Aniline
Smiles rearrangement
One-pot synthesis
Anilines are powerful tools in constructing various
heterocyclic systems useful for pharmaceutical and bio-medicinal
applications.1 Several methods have been developed for the direct
conversion of phenols to anilines, because phenols are diverse
and commercially available starting materials used in industries.
These methods include Bucherer reaction,2 activation of phenols
with 4-chloro-2-phenylquinazoline3 or diethyl chlorophosphate,4
palladium-catalyzed amination5 etc. However, all of them have
some practical difficulties. The well-known Bucherer reaction is
a simple and efficient method to prepare aromatic amines from
phenols, but the transformation is generally restricted to the
naphthalene system and related heterocycles. Activation of
phenols with 4-chloro-2-phenylquinazoline which is an
etherification/ rearrangement/ hydrolysis procedure requires
benzo[b]thiophen,6a,6e N-aryl-2-hdroxypropionamides,6c 2-bromo-
l-naphthylamine,6d 6-amino-1-tetralone,6f 4-amino-benzofuran,6g
and 2,3-dihaloanilines.6h,6i However, most of these methods
often require NaH/dimethylformamide (DMF) system, which has
a peril of uncontrollable exothermic reaction conditions.7 Even
though, alternative approaches with NaOH/DMF or NaOH/DMA
gave encouraging results to replace hazardous NaH/DMF system,
it needs harmless treatment of liquid waste which in turn
increases the cost and thus
a limitation for large-scale
preparation.6f So, there is always been a demand for apt method
to establish practical synthesis of aryl amines.
Cl
Cl
o
NH2
Cl
Cl
extremely high temperature (275-325 C) for rearrangement and
Cs2CO3
3e
4
NH2
+
Cl
strong base conditions. Amination of aryl diethyl phosphate
esters, prepared from toxic diethyl chlorophosphate, requires
potassium metal in liquid ammonia. The palladium-catalyzed
amination is an enduring ligand and palladium method and needs
to derive aryl sulfonates from phenols that has serious problems
with respect to cost, and can’t be applied to the halogenoaryl
sulfonate because of the competition of cross-coupling between
aryl halide and amine.
DMF
reflux, 4 h
OH
O
Cl
O
1e
2
N
O
H
Scheme 1. Unexpected conversion of phenols to anilines under Smiles
rearrangement conditions
A method for the direct conversion of phenols to anilines by
alkylation/Smiles rearrangement/hydrolysis sequence has already
been reported.6 This method has been exploited to synthesize a
series of important amino aromatic compounds, such as 4-amino-
The syntheses of heterocyclic compounds based on Smiles
rearrangement including N-alkyl-2H-benzo[b][1,4]oxazin-3(4H)-
one derivatives from 2-chlorophenols and N-alkyl-2-
chloroacetamides have been reported by our group.8 In
continuation of our efforts in the development of simple, eco-
friendly and cost-effective methodologies, we herein wish to
report a one-pot tandem synthesis of anilines from phenols using
2-chloroacetamide and K2CO3 in DMF catalyzed by KI.
________
*Corresponding author: E-mail: dsshin@changwon.ac.kr
Phone: +82-55-213-3437, Fax: +82-55-213-3439

2
Tetrahedron Letters
Our initial attempts to extend the research towards design
alone. This describes the importance of catalyst KI in the
activation of O-alkylation when K2CO3 used as a base with all
kinds of phenols. It was also observed that phenols having
electron-withdrawing substituent on the aromatic ring only
accelerated Smiles rearrangement reaction. The phenols that are
attached to a heterocyclic ring gave low yields when compared to
others. Even though, this method provides the scope to extend the
research in the synthesis of substituted amino pyridines (Table 2,
Entry 8), which have both chemical and biological significance9
(neurological diseases, K+ channel blockers, apoptosis,
carcinogenic activity and chronic toxicity etc.) and are starting
materials in the production of various drugs.
and synthesis of 7-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one (4)
starting from 2,4-dichlorophenol (1e) and 2-chloroacetamide (2)
were failed, instead 2,4-dichloroaniline (3e) was isolated
exclusively under Cs2CO3/DMF reaction conditions as shown in
Scheme 1. This conversion can be explained by de-acylation of
acylamide, which was formed after O-alkylation/Smiles
rearrangement sequence. This result encouraged us to explore
direct conversion of phenols to anilines as a convenient
alternative to the previous methodologies. In addition, DMF can
be easily recovered by distillation under reduced pressure and
then the residue can be directly purified using silica gel column
chromatography, thus avoiding a formal aqueous workup.
Various phenols were examined to achieve the corresponding
anilines.
Table 2. Conversion of various phenols to anilines
O
Base, Solvent
ArNH2
+
Cl
+
ArOH
KI
90 - 150 oC,
1 - 4 h
O
NH2
O
O
1
3
2
Base, Solvent
Cl
KI
+
NH2
+
90 - 150 oC,
1 - 4 h
H2N
HO
Temperature
Conditions
Producta
Yield (%)b
Base(s)
Entry
1
ArOH
1a
2
3a
90 oC, 2 h then
H2N
HO
HO
2.5 eq. K2CO3/ 0.2 eq. KI
2.5 eq. K2CO3/ 0.2 eq. KI
75
150 oC, 4 h
Scheme 2. The three-step one-pot synthesis of anilines from phenols
Table 1. Optimization of the conversion of 1a to 3a
O
O
1a
3a
90 oC, 2 h then
H2N
2
3
70
150 oC, 4 h
O
O
1b
3b
Entry
Base
Na2CO3
K2CO3
Solvent
DMF
Conditions
150 oC, 4 h
Yielda (%)
60c
69d
84
0 b
0b
2.5 eq. CsCO3 or
2.5 eq. K2CO3 or
90 oC, 2 h then
H2N
1
2
3
4
5
HO
N
N
2.5 eq. K2CO3/ 0.2 eq. KI 150 oC, 4 h
CH3CN
DMF
DMF
reflux, 4 h
1c
3c
90 oC, 1 h then 150 oC, 4 h
90 oC, 2 h then 150 oC, 4 h
90 oC, 1 h then 150 oC, 4 h
54
63
75
Cs2CO3
K2CO3
Cl
Cl
Cl
90 oC, 1-2 h
38c
65
2.5 eq. CsCO3 or
4
HO
H2N
2.5 eq. K2CO3/ 0.2 eq. KI then 150 oC, 4 h
K2CO3/KI c
DMF
1d
1e
3d
3e
Cl
aYields of isolated products
bOnly 2-(4-acetylphenoxy)acetamide formation was observed
90 oC, 2 h then
HO
Cl
H2N
Cl
c20 mol% of KI to 1a.
5
6
7
2.5 eq. K2CO3/ 0.2 eq. KI
62
150 oC, 4 h
Cl
Cl
To establish the appropriate reaction conditions, we have
chose 1-(4-hydroxyphenyl)ethanone (1a) as a phenol substrate
and examined the effects of formal bases and solvents (Scheme
2). At first, we examined the reaction of 1a (1 equiv) with 2-
chloroacetamide (1.2 equiv) in DMF in the presence of different
bases (2.5 equiv) and the results are summarized in Table 1.
Among the three bases we found that K2CO3 is the better one
when compared with both Cs2CO3 and Na2CO3. We have also
tried the reaction in acetonitrile and were able to isolate only 2-
(4-acetylphenoxy)acetamide (in 91% yield) an O-alkylated
product, may be due to lower boiling point which is not sufficient
to induce Smiles rearrangement. Optimal conditions for the
preparation of 3a in 75% yield were identified (Table 1, Entry 5),
using the catalyst KI which effectively accelerated the O-
alkylation process.
90 oC, 1-2 h
44c
78
2.5 eq. CsCO3 or
HO
NO2
1f
H2N
NO2
3f
2.5 eq. K2CO3/ 0.2 eq. KI then 150 oC, 4 h
90 oC, 1-2 h
then 150 oC, 4 h
50c
92
HO
H2N
2.5 eq. CsCO3 or
2.5 eq. K2CO3/ 0.2 eq. KI
O2N
O2N
1g
3g
NH2
OH
90 oC, 2 h then
2.5 eq. K2CO3/ 0.2 eq. KI
150 oC, 4 h
8
42
54
Cl
N
Cl
N
1h
3h
Cl
Cl
90 oC, 2 h then
150 oC, 4 h
9
2.5 eq. K2CO3/ 0.2 eq. KI
N
N
1i
3i
NH2
Cl
OH
Cl
90 oC, 2 h then
0d
56
2.5 eq. K2CO3 or
2.5 eq. K2CO3/ 0.2 eq. KI
10
150 oC, 4 h
Cl
Cl
N
1j
Cl
Cl
N
3j
NH2
OH
The typical experimental procedure involves heating a mixture
Cl
Cl
of phenol (1)/ClCH2CONH2/K2CO3/KI in the mole ratio of
o
o
90 oC, 2 h then
150 oC, 4 h
0d
63
2.5 eq. K2CO3 or
2.5 eq. K2CO3/ 0.2 eq. KI
1/1.2/2.5/0.2 for 1 h at 90 C in DMF and then 4 h at 150 C.
Then, the solvent was directly removed under reduced pressure
and residue was purified by flash column chromatography to give
the corresponding aniline (3). The one-pot syntheses of anilines
3a-3k have been performed and the yields of products have been
presented in Table 2.
11
N
N
NH2
1k
3k
OH
aConfirmed by 1H NMR and mass spectrometry
bYields of isolated products with K2CO3/cat. KI unless mentioned
cYield of product when Cs2CO3 used as a base
dYield product when K2CO3 used as a base
This method describes a facile conversion of simple phenols
(Table 2, Entry 1, 2, 3, 6 and 7), chlorophenols (Table 2, Entry 4,
5, 9, 10 and 11, which even include heterocyclic phenols) to their
corresponding anilines. It can be seen from the results described
in the table 2 (Entry 10 & 11) that the heterocyclic phenols did
not avail anilines and not even phenolic O-alkylation with K2CO3
We further like to emphasize the applicability of our method in
improving the reaction yields. For example, the synthesis of 5,7-
dichloro-2-methylquinolin-8-amine10 (3k) (Table 2, Entry 11)
which is an important key intermediate in the preparation of a
series of antiamyloidogeneic agents. Moreover, our one-pot
tandem O-alkylation/Smiles rearrangement/hydrolysis approach

Chem. Soc. 2008, 29, 1379; (c) Fang, L.; Zuo, H.; Li, Z.-B.; He, X.-Y.;
Wang, L.-Y.; Tian, X.; Zhao, B.-X.; Miao, J.-Y.; Shin, D.-S. Med.
Chem. Res. 2011, 20, 670; (d) Tian, X.; Wu, R.-M.; Liu, G.; Li, Z.-B.;
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34, 585.
is more convenient, safe, eco-friendly and cost-effective. All the
compounds were confirmed by 1H, 13C NMR and Mass
spectroscopic analysis.11,12 The analytical data of known products
1-(4-aminophenyl)ethanone (3a)11d,f, 1-(4-aminophenyl)butan-1-
one (3b)11d
, , 2,6-dichloroaniline
4-aminobenzonitrile (3c)11c
(3d)11b, 2,4-dichloroaniline (3e)11e, 4-nitroaniline (3f)11c,d, 2-
nitroaniline (3g)11b,c,d and 2-chloropyridin-3-amine (3h)11a are
identical with the literature.11 We are presently engaged with the
biological evaluation of various aniline derivatives and
corresponding heterocyclic compounds (chiral and achiral) which
have been designed and synthesized so far in our laboratory.
9. (a) Kowol, C. R.; Trondl, R.; Heffeter, P.; Arion, V. B; Jakupec, M.
A.; Roller, A.; Galanski, M.; Berger, W.; Keppler, B. K. J. Med. Chem.
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press, doi: http://dx.doi.org/10.1016/j.ygyno.2013.04.019.
In summary, we have developed a convenient and efficient
one-pot three-step route for direct conversion of phenols to
anilines using ClCH2CONH2/K2CO3/DMF system with catalytic
KI, through Smiles rearrangement as the key step. A range of
phenols with electron-withdrawing groups were examined,
providing the corresponding anilines in moderate to good yields
and demonstrating the potentiality of this transformation towards
pharmaceutical and biological aspects.
10. Gautier, E. C. L.; Barnham, K. J.; Huggins, P. J.; Parsons, J. G.
WO2008074068, June 26, 2008.
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J. E.; Goe, G. L. Tetrahedron 1995, 51, 13177; (b) Choi, H. Y.; Chi, D.
Y. J. Am. Chem. Soc. 2001, 123, 9202; (c) Lee, D.-Y.; Hartwig, J. F.
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Zhou, X. Eur. J. Org. Chem. 2010, 2010, 1854; (e) Moon, B.-S.; Choi,
H.-Y.; Koh, H.-Y.; Chi, D.-Y. Bull. Korean Chem. Soc. 2011, 32, 472;
(f) Liu, Y.; Yao, B.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G.; Li, J.-H.
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Acknowledgements
12. Analytical and Spectral data/Physical data of new compounds:
Solvents were dried and purified by conventional methods prior to use.
1H and 13C NMR Spectroscopic data were recorded on an Avance 400
MHz spectrometer in CDCl3 solution using trimethylsilane as an
internal standard. Gas chromatography-mass spectrometric (GC-MS)
analyses were carried out with a Hewlett-Packard 5890-5970 system.
Silica gel (60–120 mesh) was used for flash column chromatography.
5-Chloroquinolin-8-amine (3i): Brown solid; mp 87.5-88.5 oC; 1H
NMR (400 MHz, CDCl3): δ = 8.79 (dd, J = 4.0 ,1.6 Hz, 1H), 8.46 (dd,
J = 8.4, 1.6 Hz, 1H), 7.48 (dd, J = 8.4, 4.0 Hz, 1H), 7.38 (d, J = 8.0 Hz,
1H), 6.82 (d, J = 8.0 Hz, 1H), 5.02 (br s, 2 H, NH2); 13C NMR (100
MHz, CDCl3): δ = 109.5, 118.1, 122.1, 126.6, 127.3, 132.9, 138.9,
This work was supported by grants from the Ministry of
Environment (KME, 412-111-008), National Research
Foundation (NRF-2010-0029634) and Ministry of Knowledge
Economy (MKE, R0000495), South Korea.
Supplementary data
Supplementary data associated with this article can be found
in the online version.
143.4, 147.8; Mass (EI): m/z
=
178 (100%, [M]+). 5,7-
Dichloroquinolin-8-amine (3j): Yellowish solid; mp 122.5-123.9 oC;
1H NMR (400 MHz, CDCl3): δ = 8.80 (dd, J = 4.4, 1.6 Hz, 1 H), 8.44
(dd, J = 8.4, 1.6 Hz, 1 H), 7.47-7.50 (m, 2 H), 5.36 (br s, 2 H, NH2);
13C NMR (100 MHz, CDCl3): δ = 113.5, 117.7, 122.0, 125.3, 127.6,
133.0, 138.6, 140.2, 148.5; Mass (EI): m/z = 212 (100%, [M]+). 5,7-
Dichloro-2-methylquinolin-8-amine (3k): Yellow solid; mp 133.5-
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Graphical Abstract (for review)
Graphical abstract
One-pot Conversion of Phenols to Anilines via Smiles Rearrangement