N-arylation of amines with o-silylaryl triflate

Article abstract of DOI:10.14233/ajchem.2013.14423

An efficient, transition-metal-free procedure for the N-arylation of amines 1 has been achieved by allowing those substrates to react with o-silylaryl triflate 2 in the presence of CsF. Good to excellent yields of arylated products 3 are obtained under very mild reaction conditions. This chemistry readily tolerates a variety of functional groups.

Full text of DOI:10.14233/ajchem.2013.14423

Asian Journal of Chemistry; Vol. 25, No. 12 (2013), 6690-6692
http://dx.doi.org/10.14233/ajchem.2013.14423
N-Arylation of Amines with o-Silylaryl Triflate
1
2
Y.G. LEE , D.I. JUNG1,* and J.T. HAHN
1Department of Chemistry, Dong-A University, Busan 604714, Republic of Korea
2Department of Beautycare, Youngdong University, Youngdong 370701, Republic of Korea
*Corresponding author: Tel./Fax: +82 51 2007249; E-mail: dijung@dau.ac.kr
(Received: 8 August 2012;
Accepted: 27 May 2013)
AJC-13550
An efficient, transition-metal-free procedure for the N-arylation of amines 1 has been achieved by allowing those substrates to react with
o-silylaryl triflate 2 in the presence of CsF. Good to excellent yields of arylated products 3 are obtained under very mild reaction
conditions. This chemistry readily tolerates a variety of functional groups.
Key Words: N-Arylation, o-Silylaryl triflate, CsF, Amines.
not suitable for acid-sensitive compounds, can be corrosive
and often produces side reactions, such as carbonization11. In
this paper, we report an efficient an reliable procedure to N-
arylate amines under mild reaction conditions. Recently,
silylaryl triflate 212 has been employed to generate benzyne
under mild reaction conditions, which can easily undergo a
variety of synthetically useful nucleophilic13 and cycloaddi-
tion reactions14,15. However, the arylation of amines has not
been widely studied due to the difficulty in generating arynes
under convenient reaction conditions.
INTRODUCTION
Establishing an efficient, reliable method for the N-
arylation of amines is currently active area of research in
organic synthesis. Such aryl subunits are commonly found in
a variety of biologically active and natural compounds1, agro-
chemicals2, HIV-1 protease inhibitors and compounds3 of
interest in material science.
Traditionally4, the N-arylation of amines has been carried
out under copper-mediated Ull-mann-type conditions involving
the coupling of amines with aryl halides5. Although these
copper promoted reactions are useful, they usually require
harsh reaction conditions and stoichiometric amounts of
copper and the yields are not very reproducible6. Recently, a
number of valuable new methods have been developed for the
N-arylation of amines7. Buchwald and Hartwig8,9 have demons-
trated that the Cu- or Pd-catalyzed N-arylation of a variety of
amines by aryl halides is a powerful method for the synthesis
of arylamines. Despite these significant recent improvements,
there still are limitations in present N-arylation methods. For
example, it is still difficult to present N-arylation methodology
may not accommodate certain organic functionality. Of the
functional groups that are incompatible with the Cu- or Pd
catalyzed N-arylation methodology, the most important are
probably halides. Most reaction conditions are fairly harsh,
usually requiring high temperatures (> 110 ºC) and strong
polar and often toxic solvents. The direct coupling of aromatic
carboxylic acids and aryl halides or the carbonylation of aryl
halides with a palladium catalyst to generate the corresponding
aryl esters is difficult10. In the classical methods for esterifi-
cation, a strong acid, such as sulfuric acid, is needed, which is
Recently, we reported reactions of 2-alkenyl- and 2-
hydrazinyl-1-methylpyrroles with aryne generated from
silylaryl triflate under very mild reaction conditions provide
excellent yields of arylated products, while tolerating many
functional groups16. Here in, we wish to report the full details
of this very efficient arylation procedure and our studies on
the addition to silylaryl triflate.
EXPERIMENTAL
General procedure for the mono-N-arylation of aromatic
amines. To a solution of MeCN (5 mL), aromatic amine (0.50
mmol) and silylaryl triflate (0.50 mmol) was added CsF
(1 mmol). The reaction mixture was allowed to stir at room
temperature and monitored by TLC to establish completion
of the reaction. The resulting solution was washed with brine
(20 mL) and extracted with diethyl ether (20 mL). The com-
bined ether fractions were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford the desired product.
Diphenylamine (Table-1, entry 1). Purification by flash
chromatography (30:1, hexane/EtOAc) afforded the indicated

Vol. 25, No. 12 (2013)
N-Arylation of Amines with o-Silylaryl Triflate 6691
compound (38 mg) in a 92 % yield as a white solid: m.p. 49-
50 ºC (lit.17 mp 50-52 °C). The 1H and 13C NMR spectra match
the literature data18.
temperature for 24 h. Diphenylamine was obtained in a 90.2
% yield (Scheme-I) (Table-1, entry 1).
General procedure for the amines, 2,5-dimethoxytetra-
hydrofuran, 1,3-acetone carboxylic acid and silylaryl triflate.
To a solution of MeCN (5 mL), amines (0.50 mmol), silylaryl
triflate (0.50 mmol), 2,5-dimethoxytetra hydrofuran (0.50
mmol) and 1,3-acetone carboxylic acid (0.50 mmol) was added
CsF (1 mmol). The reaction mixture was allowed to stir at
room temperature and monitored by TLC to establish comple-
tion of the reaction. The resulting solution was washed with
brine (20 mL) and extracted with diethyl ether (20 mL).
The combined ethereal fractions were dried over Na2SO4
and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel to afford the
desired product.
H
N
R
TMS
OTf
CsF
NH2
+
MeCN, r.t
R
1
2
3
R: a = H
e = 4 - NO2
R: a = H
e = 4 - NO2
b = 3 - CH3 f = 4 - I
c = 3 - Cl g = 4 - OCH3
d = 4 - Cl h = 4 - Br
b = 3 - CH3 f = 4 - I
c = 3 - Cl
d = 4 - Cl
g = 4 - OCH3
h = 4 - Br
Scheme-I
We next studied the scope of this methodology by
allowing a wide variety of aromatic amines to react with the
silylaryltriflates 219. The results are summarized in Table-1.
Aniline itself and aniline with electron-donating and with-
drawing groups (Table-1, entries 1 and 3-8), such as nitro,
iodo, bromo and methoxy groups, all react well with silylaryl
triflate 2 and CsF to afford excellent yields of the desired
phenyl-substituted products. It is noteworthy that haloanilines
also react with silylaryl triflate 2 to generate the desired halo-
substituted products in excellent yields (Table-1). Halides,
which are unlikely to survive under the Pd-mediated amination
reaction conditions are readily accommodated by our reaction
conditions. In order to synthesize biologically active com-p-
ounds, when the reaction of amines (aniline, m-toluidine, 3-
chloroaniline, 4-chloroaniline), 2,5-dimethoxytetra-hydrofuran,
1,3-acetone dicarboxylic acid and silylaryl triflate 2 (Tables
2 and 3), good yields of the N-arylated products are still
obtained (Schemes II and III).
RESULTS AND DISCUSSION
Preparation of the aryne precursor: The aryne 2 were
selected as substrate for our experiments. Aryne precursor 2
was selected as the simplest and most readily available aryne
to study the scope of this chemistry. The synthesis of silylaryl
triflate 2 has already been reported.
N-Arylation of aromatic amines: Our initial studies
focused on achieving optimal reaction conditions for the N-
arylated product using aniline and silylaryl triflate 1 as the
model system. We first allowed 2-(trimethylsilyl)phenyl triflate
2 to react with 1 equiv of CsF and 1.2 equiv of aniline in
MeCN at room temperature for 20 h. Diphenylamine was
obtained in an 90.2 % yield and only a trace of triphenylamine
was isolated.After trying several reactions, we found that THF
was also a good solvent for the N-arylation of aniline and CsF
can be replaced by n-Bu4NF (TBAF). Although the reaction
time can be dramatically decreased to 0.5 h when nBu4NF is
allowed to react with the silylaryl triflate 2 to generate benzyne,
the yield is a little lower. The optimal reaction conditions thus
far developed employ 0.50 mmol of aniline, 1.1 equiv of
silylaryl triflate 2 and 0.15 g of CsF in MeCN (5 mL) at room
NH2
H
N
CH2COOH
TMS
OTf
CsF
O
+
OCH3
+
+
H3CO
MeCN
O
CH2COOH
R
R
1
2
4
5
3
R: a = H
R: a = H
b = 3 - CH3
c = 3 - Cl
d = 4 - Cl
b = 3 - CH3
c = 3 - Cl
d = 4 - Cl
Scheme-II
TABLE-1
FACILE N-ARYLATION OF AROMATIC AMINES
Entry
1
CsF (mmol)
Time (h)
Isolated yield (%)
90.2
Amine 1
Silylaryltriflate (mmol) 2
Product 3
H
N
a
0.5
1
24
CH3
H
N
2
3
b
c
0.5
0.5
1
1
24
24
92.1
84.3
Cl
H
N
H
N
Cl
NO2
I
4
5
6
7
8
d
e
f
0.5
0.5
0.5
0.5
0.5
1
1
1
1
1
24
24
24
24
24
86.6
85.7
92.2
89.5
91.1
H
N
H
N
H
N
OCH3
Br
g
H
N
h
aAll reactions were run under the following reaction conditions, under otherwise specified: 0.50 mmol of amine and the indicated amount of silyaryl
triflate and CsF were stirred in 5 mL of MeCN at room temperature. Only monoarylated product was obtained.

6692 Jung et al.
Asian J. Chem.
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H
N
TMS
OTf
CsF
+
+
H3CO
OCH3
MeCN
O
1a
2
4
3a
Scheme-III
TABLE-2
N-ARYLATION OF AROMATIC AMINES BY
USING 2,3-DIMETHOXYTETRAHYDROFURAN 4
AND 1,3-ACETONEDICARBOXYLIC
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ACID 5 WITH o-SILYLARYL TRIFLATE 2
Starting CsF
materials (mmol)
Isolated
yield (%)
Entry
Amine
Product
1
2
3
4
4 + 5
4 + 5
4 + 5
4 + 5
1
1
1
1
87.6
90.3
85.7
83.9
1a
1b
1c
1d
3a
3b
3c
3d
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TABLE-3
N-ARYLATION OF AROMATIC AMINES
BY USING 2,5-DIMETHOXYTETRAHYDROFURAN
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WITH o-SILYLARYL TRIFLATE 2
Starting CsF
materials (mmol)
Isolated
yield (%)
Entry
1
Amine
Product
4
1
89.8
1a
3a
Substantially we reported20,21the synthesis of N-substituted
pyrroles and nortropinones in the reaction of amines with 2,5-
dimethoxytetrahydrofuran and 1,3-acetone dicarboxylic acid.
When the reaction of aniline, 2,5-dimethoxytetrahydrofuran
and silylaryltriflate 2 with CsF in MeCN executed, good yield
of diphenylamine as a N-arylated product is still obtained. But
synthesis of N-substituted pyrrole and nortropinone did not
occur (Tables 2 and 3).
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aromatic amines react well with silylaryl triflate and CsF under
very mild reaction conditions to afford good to excellent yields
of the desired products. It should be pointed out that a variety
of other functional groups, including halide should be readily
tolerated under present reaction conditions.
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Conclusion
An efficient, mild, transition-metal-free method is devel-
oped for the N-arylation of amines. Monoarylated amines can
easily be obtained from primary amines by simply control-
ling the ratio of the reactants. A variety of functional groups
are compatible with the reaction conditions, including nitro,
iodo, bromo and methoxy groups. It is also shown that halides,
which are not compatible with Pd-mediated arylation proce-
dures, readily tolerate the reaction conditions.
14. H. Yoshida, M. Watanabe, H. Fukushima, J. Ohshita and A. Kunai,
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67, 5553 (2002).
19. 4-Aminopyridine and 2-Aminopyridine React with the Silylaryl Triflate
1a to Afford an Unknown Salt; No N-Arylated Products were Isolated
under our Usual Reaction Conditions.
ACKNOWLEDGEMENTS
20. D.I. Jung, J.H. Song, Y.H. Kim, D.H. Lee, H.A. Song, Y.G. Lee, Y.M.
Park, S.K. Choi, J.T. Hahn and S.J. Cho, Bull. Korean Chem. Soc., 25,
1932 (2004).
This work was supported by the grant from Dong-A Uni-
versity (2012).
21. D.I. Jung, J.H. Song, D.H. Lee, Y.H. Kim, Y.G. Lee and J.T. Hahn,
Bull. Korean Chem. Soc., 27, 1493 (2006).
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