An efficient fluoride-mediated O-arylation of sterically hindered halophenols with silylaryl triflates under mild reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2011.03.124

The reaction between 2,6-dihalophenols and 2-(trimethylsilyl)aryl triflates in the presence of CsF using acetonitrile as solvent at room temperature led to the formation of functionalized diaryl ethers in very good yields.

Full text of DOI:10.1016/j.tetlet.2011.03.124

Tetrahedron Letters 52 (2011) 2849–2852
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient fluoride-mediated O-arylation of sterically hindered
halophenols with silylaryl triflates under mild reaction conditions
⇑
Karimi S. Gebara, Gleison A. Casagrande, Cristiano Raminelli
Faculdade de Ciências Exatas e Tecnologia, Universidade Federal da Grande Dourados, Rodovia Dourados-Itahum, Km 12, CEP 79.804-970, Dourados, MS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction between 2,6-dihalophenols and 2-(trimethylsilyl)aryl triflates in the presence of CsF using
acetonitrile as solvent at room temperature led to the formation of functionalized diaryl ethers in very
good yields.
Received 15 February 2011
Revised 15 March 2011
Accepted 23 March 2011
Available online 7 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
O-Arylation
Functionalized diaryl ethers
Benzyne chemistry
Silylaryl triflates
Mild reaction conditions
Diaryl ether subunits are commonly found in a variety of bio-
logically active substances,1 in natural products,2 in agrochemi-
cals,3 and in compounds of interest in materials science.4
Therefore, a number of methods for diaryl ethers syntheses have
been reported in the literature.5–8 Among them, those which em-
ploy transition metals are the most popular and are represented
by the following transformations: Ullmann-type reactions which
are typified by the coupling of phenols and aryl halides promoted
by copper;6 Buchwald–Hartwig cross-couplings involving phenols
and aryl halides in the presence of catalytic amounts of palladium7
Table 1
Optimization of the synthesis of 1,3-diiodo-2-phenoxybenzene (3a) (Eq. 1)a
I
I
TMS
Base
Solvent, Temperature
+
OH
O
OTf
Time
I
I
3a
1a
2a
Entry
2a (equiv)
Base (equiv)
Solvent
Time (h)
Temperature (°C)
Isolated yield (%)
1
2
3
4
5
6
7
8
1.1
1.5
2
1.5
1.5
1.5
1.5
1.5
CsF (2.2)
CsF (3.0)
CsF (4.0)
CsF (3.0)
CsF (3.0)
MeCN
MeCN
MeCN
MeCN
MeCN
THF
24
24
24
24
12
24
24
24
rt
rt
rt
50
rt
rt
0
77
90
92
91
46
58
79
0
n-Bu4NF (1.8)
KF/[18]crown-6 ether (1.5/1.5)
THF
MeCN
rt
a
Reaction conditions: 0.3 mmol of 2,6-diiodophenol (1a), the indicated amount of benzyne precursor 2a, the indicated amount of base, and 5 mL of solvent were stirred at
the temperature shown for 24 h.
⇑
Corresponding author. Tel.: +55 67 34102093; fax: +55 67 34102072.
E-mail address: raminelli@ufgd.edu.br (C. Raminelli).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.124

2850
K. S. Gebara et al. / Tetrahedron Letters 52 (2011) 2849–2852
and Chan–Evans–Lam-type reactions which may be exemplified by
the coupling between phenols and organoboron reagents in the
presence of copper.8
In order to circumvent the exposed drawbacks related to the
O-arylation processes using transition metals,6–8 Liu and Larock
reported in the literature an efficient transition-metal-free reaction
for the O-arylation of phenols and carboxylic acids employing ary-
nes generated from silylaryl triflates and a source of fluoride ions.10
In the same way, we have used silylaryl triflates to generate ary-
nes under mild reaction conditions, which can undergo syntheti-
Although the methodologies for the preparation of diaryl ethers
which were mentioned above are of great importance in prepara-
tive organic chemistry,6–8 they have generally employed harsh
reaction conditions, or are incompatible with some functionalities
present in the phenolic compound, including halide substituents
and carbon–carbon triple bonds (for this case undesired reactions
can occur mostly in palladium-catalyzed processes), or an organo-
boron reagent9 has to be prepared before the coupling reaction is
carried out. Besides, in all mentioned transformations toxic or
expensive transition metals are used as reagents or catalysts.6–8
cally useful cycloaddition11 and insertion reactions.12 On
a
related theme, we wish to present through this work the O-aryla-
tion of sterically hindered dihalophenols, in the presence of silyla-
ryl triflates and a source of fluoride ions, in order to produce
functionalized diaryl ethers, which may be considered versatile
building blocks in synthetic organic chemistry and are in most
Table 2
Synthesis of 1,3-dihalo-2-phenoxybenzenes (3a–i) by the reaction of 2,6-dihalophenols (1a–f) and aryne precursors (2a–d) in the presence of CsFa
Entry
Halophenol (1)
Aryne precursor (2)
Halophenoxybenzene (3)
Isolated yield (%)
I
TMS
I
O
OH
1
90
OTf
2a
I
I
3a
1a
I
I
I
I
Me
OH
Me
O
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
90
3b
1b
I
I
I
I
O
O
OH
O
Quantitative
Me
Me
3c
1c
I
I
I
I
O2N
OH
O2N
Cl
O
65
1d
3d
I
I
I
Cl
OH
O
Quantitative
I
3e
1e
Cl
Cl
I
OH
I
O
95
85
80
Cl
Cl
3f
I
1f
TMS
OTf
Me
Me
Me
F
O
O
Me
F
1c
1c
Me
2b
I
I
3g
TMS
F
F
O
O
OTf
Me
2c
I
I
3h
OMe
OMe
O
TMS
OTf
O
9
1c
93
Me
I
3i
2d
a
Reaction conditions: 0.3 mmol of 2,6-dihalophenol (1a–f), 0.45 mmol of the benzyne precursor 2a–d, 0.9 mmol of CsF, and 5 mL of acetonitrile were stirred at room
temperature for 24 h.

K. S. Gebara et al. / Tetrahedron Letters 52 (2011) 2849–2852
2851
cases novel thyroid hormone derivatives with possible application
in medicinal chemistry.13
the aryne produced in the reaction course, oriented the nucleo-
philic attack of the phenol, leading to the exclusive formation of
the regioisomer 3i. Accordingly, the structure proposed for 3i is
according to the pattern of regioselectivity followed by a number
of reactions between 3-methoxy-1,2-benzyne and nucleo-
philes.10,15 So far it remains unclear which factor (electronic or ste-
ric) governs the exclusive formation of compound 3i and further
experiments ought to be carried out to solve this matter.
The structures of compounds 3a–i were assigned on the basis of
a variety of spectroscopic techniques, namely, according to their IR,
LRMS, 1H, and 13C NMR spectra. All new compounds (3c–i) pro-
vided HRMS that agree with the proposed structures.
In summary, a simple and efficient O-arylation reaction be-
tween sterically hindered halophenols and silylaryl triflates in
the presence of CsF using acetonitrile as solvent at room tempera-
ture was developed and functionalized diaryl ethers were pro-
duced in excellent yields. Through this transition-metal-free
process carbon–oxygen bonds were formed presumably via arynes
produced under mild reaction conditions. The synthetic methodol-
ogy described led to functionalized diaryl ethers, which are versa-
tile building blocks in preparative organic chemistry and are in
most cases novel thyroid hormone derivatives with possible appli-
cation in medicinal chemistry.
Initially, allowing the reaction of 2,6-diiodophenol (1a) with
1.1 equiv of 2-(trimethylsilyl)phenyl triflate (2a) in the presence
of 2.2 equiv of CsF at room temperature for 24 h, we obtained
1,3-diiodo-2-phenoxybenzene (3a) in a 77% yield (Table 1, entry
1). In an attempt to improve the obtained yield (entry 1), subse-
quent work focused on the optimization of these reaction condi-
tions (Table 1, entries 2–8).
When the transformation was carried out using 1.5 equiv of the
silylaryl triflate 2a and 3 equiv of CsF at room temperature for 24 h,
we isolated the desired product 3a in a very good yield of 90%
(Table 1, entry 2). No significant improvement in the yield for
1,3-diiodo-2-phenoxybenzene (3a) was achieved when 2,6-diiodo-
phenol (1a) was subjected to the reaction with 2 equiv of the silyl-
aryl triflate 2a in the presence of 4 equiv of CsF at room
temperature for 24 h (entry 3) or when 2,6-diiodophenol (1a)
was allowed to react with 1.5 equiv of the benzyne precursor 2a
and 3 equiv of CsF at 50 °C for 24 h (entry 4). Treatment of the
diiodinated phenol 1a with 1.5 equiv of the silylaryl triflate 2a
and 3 equiv of CsF at room temperature for 12 h gave the desired
product 3a in only 46% isolated yield (entry 5). Afterward, in order
to explore the effect of the fluoride ions source on the reaction,
1.8 equiv of tetrabutylammonium fluoride (TBAF) was added to
the mixture of 2,6-diiodophenol (1a) and 1.5 equiv of 2-(trimethyl-
silyl)phenyl triflate (2a) in THF at room temperature. After 24 h,
1,3-diiodo-2-phenoxybenzene (3a) was obtained in a low yield of
58% (entry 6). Treatment of the diiodinated phenol 1a with
1.5 equiv of the benzyne precursor 2a, 1.5 equiv of KF and 1.5 equiv
of [18]crown-6 ether in THF at 0 °C led to the formation of the diio-
dinated diaryl ether 3a in 79% yield (entry 7). No further attempts
were made to optimize the reactions depicted in entries 6 and 7. As
can be seen in Table 1, entry 8, compound 3a was not obtained and
the starting materials 1a and 2a were recovered when the reaction
was carried out in the absence of CsF. This experiment shows that
the success of our reaction depends dramatically on the presence
of a source of fluoride ions.
Acknowledgments
We gratefully acknowledge the Conselho Nacional de Desen-
volvimento Científico e Tecnológico (CNPq) and the Fundação de
Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Esta-
do de Mato Grosso do Sul (FUNDECT) for financial support.
Supplementary data
Supplementary data (experimental procedures and compound
characterization data) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.03.124.
Employing the optimal conditions shown in Table 1, entry 2,14
we examine the scope of this process using various diiodinated
phenols and aryne precursors (Table 2). When the reaction was
carried out using a phenol bearing an electron-donating group
(1b) and the silylaryl triflate 2a, we obtained the diiodinated diaryl
ether 3b in an excellent yield of 90% (entry 2). Treatment of a phe-
nol bearing an electron-withdrawing group (1c) with the benzyne
precursor 2a gave the diiodinated diaryl ether 3c in a quantitative
yield (entry 3). By performing the transformation between 2,6-
diiodo-4-nitrophenol (1d) and the silylaryl triflate 2a, we obtained
compound 3d in an isolated yield of 65% (entry 4). In this case, the
powerful electron-withdrawing group present in the phenol 1d
promoted a more sluggish transformation leading to the desired
product 3d in moderate yield. In both reactions where we em-
ployed choroiodophenols (1e and 1f), the halogenated diaryl ethers
(3e and 3f) were produced in excellent yields P95% (entries 5 and
6).
Turning our attention to the effect of substituted silylaryl tri-
flates on the reaction course, we allowed the reaction of 4-acet-
yl-2,6-diiodophenol (1c) with the electron-rich silylaryl triflate
2b and obtained the diiodinated diaryl ether 3g in a good 85% yield
(entry 7). Treatment of the phenol 1c with the electron-poor aryne
precursor 2c gave the desired product 3h in an 80% isolated yield
(entry 8). To understand better the regioselectivity of the reaction
when unsymmetrical arynes are employed, we allowed 4-acetyl-
2,6-diiodophenol (1c) to react with the 3-methoxy-substituted ar-
yne precursor 2d and obtained the diiodinated diaryl ether 3i in an
excellent yield of 93% (entry 9). This result indicates that electronic
and/or steric factors, promoted by the 3-methoxy group present in
References and notes
1. For some recent exemples, see: (a) Tipparaju, S. K.; Muench, S. P.; Mui, E. J.;
Ruzheinikov, S. N.; Lu, J. Z.; Hutson, S. L.; Kirisits, M. J.; Prigge, S. T.; Roberts, C.
W.; Henriquez, F. L.; Kozikowski, A. P.; Rice, D. W.; McLeod, R. L. J. Med. Chem.
2010, 53, 6287; (b) Sun, M.; Wu, X.; Chen, J.; Cai, J.; Cao, M.; Ji, M. Eur. J. Med.
Chem. 2010, 45, 2299; (c) Su, D.-S.; Lim, J. J.; Tinney, E.; Wan, B.-L.; Young, M. B.;
Anderson, K. D.; Rudd, D.; Munshi, V.; Bahnck, C.; Felock, P. J.; Lu, M.; Lai, M.-T.;
Touch, S.; Moyer, G.; DiStefano, D. J.; Flynn, J. A.; Liang, Y.; Sanchez, R.; Perlow-
Poehnelt, R.; Miller, M.; Vacca, J. P.; Williams, T. M.; Anthony, N. J. J. Med. Chem.
2009, 52, 7163; (d) Boyer, S. H.; Jiang, H.; Jacintho, J. D.; Reddy, M. V.; Li, H.; Li,
W.; Godwin, J. L.; Schulz, W. G.; Cable, E. E.; Hou, J.; Wu, R.; Fujitaki, J. M.;
Hecker, S. J.; Erion, M. D. J. Med. Chem. 2008, 51, 7075.
2. For some recent exemples, see: (a) Plaza, A.; Keffer, J. L.; Bifulco, G.; Lloyd, J. R.;
Bewley, C. A. J. Am. Chem. Soc. 2010, 132, 9069; (b) Schuehly, W.; Voith, W.;
Teppner, H.; Kunert, O. J. Nat. Prod. 2010, 73, 1381; (c) Wang, J.-Z.; Chen, Q.-H.;
Wang, F.-P. J. Nat. Prod. 2010, 73, 1288; (d) Greve, H.; Kehraus, S.; Krick, A.;
Kelter, G.; Maier, A.; Fiebig, H.-H.; Wright, A. D.; König, G. M. J. Nat. Prod. 2008,
71, 309.
3. (a)Agrochemicals: Composition, Production, Toxicology, Applications; Müller, F.,
Ed.; Wiley-VCH: Weinheim, 2000; (b) Cremlyn, R. J. W. Agrochemicals:
Preparation and Mode of Action; John Wiley & Sons: Chichester, 1991.
4. (a) Murotani, E.; Lee, J.-K.; Chatzichristidi, M.; Zakhidov, A. A.; Taylor, P. G.;
Schwartz, E. L.; Malliaras, G. G.; Ober, C. K. A. C. S. Appl. Mater. Interfaces 2009, 1,
2363; (b) Lafitte, B.; Jannasch, P. Adv. Funct. Mater. 2007, 17, 2823; (c) Theil, F.
Angew. Chem., Int. Ed. 1999, 38, 2345.
5. For reviews, see: (a) Frlan, R.; Kikelj, D. Synthesis 2006, 2271; (b) Sawyer, J. S.
Tetrahedron 2000, 56, 5045.
6. For reviews, see: (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48,
6954; (b) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
7. (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 1995, 34,
1348; (b) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
8. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett.
1998, 39, 2933; (b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937; (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan,
D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.

2852
K. S. Gebara et al. / Tetrahedron Letters 52 (2011) 2849–2852
9. Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine;
Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005.
10. (a) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99; (b) Liu, Z.; Larock, R. C. J. Org. Chem.
2006, 71, 3198.
11. (a) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R. C. J. Org. Chem.
2008, 73, 219; (b) Raminelli, C.; Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 4689.
12. (a) Toledo, F. T.; Comasseto, J. V.; Raminelli, C. J. Braz. Chem. Soc. 2010, 21, 2155;
(b) Toledo, F. T.; Marques, H.; Comasseto, J. V.; Raminelli, C. Tetrahedron Lett.
2007, 48, 8125.
13. (a), 11th ed.Goodman s The Pharmacological Basis of Therapeutics; Brunton, L. L.,
Lazo, J. S., Parker, K. L., Eds.; McGraw-Hill: New York, 2006; (b), 6th ed.Foye’s
Principles of Medicinal Chemistry; Lemke, T. L., Williams, D. A., Roche, V. F., Zito,
S. W., Eds.; Williams & Wilkins: Baltimore, 2008.
J = 7.8 Hz, 2H), 7.34–7.27 (m, 2H), 7.05 (tt, J = 7.4, 1.2 Hz, 1H), 6.81–6.77 (m,
2H), 6.68 (t, J = 7.8 Hz, 1H); 13C NMR 75 MHz (CDCl3, ppm): 156.2, 153.9, 140.2,
129.6, 128.5, 122.4, 115.5, 91.4; IR (KBr, cmÀ1): 1588 (m), 1484 (S), 1548 (m),
1417 (S), 768 (S), 850 (F), 489 (w); LRMS (m/z,%): 139 (8.0), 168 (37.0), 422 (M+,
100.0).
5-Acetyl-1,3-diiodo-2-phenoxybenzene (3c): yield 139.0 mg (quantitative);
yellowish solid; mp 195–198 °C; 1H NMR 300 MHz (CDCl3, ppm): 8.42 (s,
2H), 7.34–7.29 (m, 2H), 7.11–7.05 (m, 1H), 6.79–6.77 (m, 2H), 2.60 (s, 3H); 13
C
NMR 75 MHz (CDCl3, ppm): 194.3, 157.7, 155.7, 140.4, 136.8, 129.8, 122.8,
115.6, 91.4, 26.6; IR (KBr, cmÀ1): 3056 (w), 3011 (w), 1687 (S), 1589 (m), 1567
(m), 1535 (m), 1488 (m), 1470 (m), 718 (S), 706 (S), 496 (m); LRMS (m/z,%): 43
(20.0), 139 (7.3), 464 (M+, 100.0); HRMS Calcd for [C14H10I2O2+Na]+: 486.8668.
Found: 486.8659.
14. General procedure for O-arylation of sterically hindered halophenols: To a vial
(10 mL) were added the appropriate 2,6-dihalophenol 1a–f (0.3 mmol), the
appropriate aryne precursor 2a–d (0.45 mmol), acetonitrile (5 mL), and CsF
(0.9 mmol, 0,1368 g). The vial was sealed using a cap, and the reaction mixture
was stirred for 24 h at room temperature. Afterward, brine (5 mL) was added to
the mixture, which was extracted with ethyl acetate (3 Â 10 mL). The organic
phase was dried over MgSO4. After filtration, the solvent was evaporated under
reduced pressure. The residue was purified by column chromatography on
silica gel, using hexane as eluent unless otherwise indicated, affording the
desired products 3a-i.
5-Acetyl-1,3-diiodo-2-(3-methoxyphenoxy)benzene (3i): yield 138.0 mg (93%);
off-white solid; mp 171–173 °C; 1H NMR 300 MHz (CDCl3, ppm): 8.41 (s, 2H),
7.19 (t, J = 8.3 Hz, 1H), 6.63 (dd, J = 8.3, 1.7 Hz, 1H), 6.40 (t, J = 2.4 Hz, 1H), 6.30
(dd, J = 8.3, 1.7 Hz, 1H), 3.79 (s, 3H), 2.59 (s, 3H); 13C NMR 75 MHz (CDCl3,
ppm): 194.2, 161.1, 157.6, 156.7, 140.4, 136.8, 130.1, 108.2, 107.7, 102.4, 91.4,
55.4, 26.5; IR (KBr, cmÀ1): 3001 (w), 1681 (S), 1265 (S), 757 (m), 709 (m), 683
(m), 637 (m), 487 (w); LRMS (m/z,%): 43 (27.8), 225 (8.0), 367 (16.2), 494 (M+,
100.0); HRMS Calcd for [C15H12I2O3+H]+: 494.8954. Found: 494.8957.
15. (a) Gallo, R. D. C.; Rezende, H. V.; Muzzi, R. M.; Raminelli, C. Quim. Nova 2009,
32, 2437; (b) Peña, D.; Pérez, D.; Guitián, E. Angew. Chem., Int. Ed. 2006, 45,
3579.
1,3-Diiodo-2-phenoxybenzene (3a): yield 113.9 mg (90%); off-white solid; mp
61–63 °C (lit.16 mp 68.5–68.9 °C); 1H NMR 300 MHz (CDCl3, ppm): 7.86 (d,
16. Jorgensen, E. C. J. Org. Chem. 1964, 29, 3396.