An Efficient N- and O-Arylation Procedure
by aryl halides is a powerful method for the synthesis of
arylamines and diaryl ethers. Evans10 and Chan11 have inde-
pendently reported the synthesis of diaryl ethers by the copper-
(II)-promoted cross-coupling of phenols and aryl halides.
Despite these significant recent improvements, there still are
limitations in present N- and O-arylation methods. For example,
(1) it is still difficult to prepare N-arylated sulfonamides12 and
present N-arylation methodology may not accommodate certain
organic functionality. Of the functional groups that are incom-
patible with the Cu- or Pd-catalyzed N-arylation methodology,
the most important are probably halides, sulfonates,13 hydroxyl
groups,14 and probably carbon-carbon triple bonds. (2) Phenols
can smoothly be converted to diaryl ethers only if no strong
electron-withdrawing group is present.7a,b (3) Most reaction
conditions are fairly harsh, usually requiring high temperatures
(>110 °C), and strong polar and often toxic solvents.
provides excellent yields of arylated products, while tolerating
many functional groups.22 Herein, we wish to report the full
details of this very efficient arylation procedure and our studies
on the regioselectivity of addition to a number of unsymmetrical
substituted silylaryl triflates.
Results and Discussion
Preparation of the Aryne Precursors. The arynes 1a-e
were selected as substrates for our experiments. Aryne precursor
1a was selected as the simplest and most readily available aryne
to study the scope of this chemistry. Aryne precursors 1b, 1d,
and 1e were selected to study the regioselectivity of the arylation
procedure. The synthesis of silylaryl triflates 1a,18 1b,23 1c,19c
and 1d24 has already been reported, and the precursor 1e25 can
easily be prepared by a similar three-step procedure from the
corresponding 2-bromo-4,6-dimethylphenol.
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 difficult.15
The direct esterification of phenols by aliphatic or aromatic
carboxylic acids is virtually impossible due to the poor
nucleophilicity of phenols.16 In the classical methods for
esterification, a strong acid, such as sulfuric acid, is needed,
which is not suitable for acid-sensitive compounds, can be
corrosive, and often produces side reactions, such as carboniza-
tion, oxidation, etc.17 In this paper, we report an efficient and
reliable procedure to N-arylate amines and sulfonamides and
O-arylate phenols and carboxylic acids under mild reaction
conditions, which can tolerate a wide variety of functional
groups, including halide, ester, amide, hydroxyl, nitro, aldehyde,
and ketone groups.
N-Arylation of Aromatic Amines. Our initial studies focused
on achieving optimal reaction conditions for the N-arylated
product using aniline and silylaryl triflate 1a as the model
system. We first allowed 2-(trimethylsilyl)phenyl triflate (1a)
to react with 2.0 equiv of CsF and 1.2 equiv of aniline in MeCN
at room temperature for 20 h. Diphenylamine was obtained in
an 81% 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 30 min when TBAF is allowed to
react with the silylaryl triflate 1a to generate benzyne, the yield
is a little lower. The optimal reaction conditions thus far
developed employ 0.25 mmol of aniline, 1.1 equiv of silylaryl
triflate 1a, and 2.0 equiv of CsF in MeCN at room temperature
for 10 h. Diphenylamine was obtained in a 92% yield (Scheme
1) (Table 1, entry 1).
Recently, silylaryl triflate 1a18 has been employed to generate
benzyne under very mild reaction conditions, which can easily
undergo a variety of synthetically useful nucleophilic19 and
cycloaddition reactions.20 However, the arylation of amines,21
sulfonamides, phenols, and carboxylic acids by arynes has not
been widely studied due to the difficulty in generating arynes
under convenient reaction conditions. Very recently, we reported
that the reaction of a variety of amines, sulfonamides, carbam-
ates, phenols, and carboxylic acids with arynes generated from
a variety of silylaryl triflates under very mild reaction conditions
SCHEME 1
(10) (a) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998,
39, 2937-2940. (b) Decicco, C. P.; Song, S.; Evans, D. A. Org. Lett. 2001,
3, 1029-1032.
(11) Chan, D. M. T.; Monaco, K. L.; Wang, R.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936.
(12) (a) Combs, A. P.; Rafalski, M. J. Comb. Chem. 2000, 2, 29-32.
(b) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-6048.
(13) Deng, B.-L.; Lepoivre, J. A.; Lemiere, G. Eur. J. Org. Chem. 1999,
2683-2689.
(14) Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287-289.
(15) (a) Yamamoto, T. Synth. Commun. 1979, 9, 219-222. (b) Ramesh,
C.; Kubota, Y.; Miwa, M.; Sugi, Y. Synthesis 2002, 2171-2173.
(16) Beyer, H.; Walter, W. Handbook of Organic Chemistry; Prentice
Hall Europe: London, UK, 1996; p 497.
We next studied the scope of this methodology by allowing
a wide variety of aromatic amines to react with the silylaryl
triflates 1a, 1b, and 1c.26 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,
cyano, ester, ketone, amide, and methoxy groups, all react well
with silylaryl triflate 1a and CsF to afford excellent yields of
the desired phenyl-substituted products. It is noteworthy that
(17) (a) Fischer, E. Ber. 1895, 28, 3254-3257. (b) Butts, J. J. Am. Chem.
Soc. 1931, 53, 3560-3561.
(18) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211-
1214.
(22) (a) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673-4675. (b) Liu,
Z.; Larock, R. C. Org. Lett. 2004, 6, 99-102.
(19) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247-3249. (b) Yoshida, H.; Fukushima, H.;
Ohshita, J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43, 3935-3938. (c)
Yoshida, H.; Sugiura, S.; Kunai, A. Org. Lett. 2002, 4, 2767-2769.
(20) (a) Pen˜a, D.; Escudero, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Angew.
Chem., Int. Ed. 1998, 37, 2659-2661. (b) Yoshida, H.; Watanabe, M.;
Fukushima, H.; Ohshita, J.; Kunai, A. Org. Lett. 2004, 6, 4049-4051.
(21) Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem.
2001, 66, 1403-1412.
(23) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Am. Chem. Soc.
1999, 121, 5827-5828.
(24) Yoshida, H.; Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A. J. Am.
Chem. Soc. 2003, 125, 6638-6639.
(25) Silylaryl triflate 1e was prepared from 2-bromo-4,6-dimethylphenol
in a manner similar to the preparation of silylaryl triflate 1c.
(26) 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.
J. Org. Chem, Vol. 71, No. 8, 2006 3199