2-(Trimethylsilyl)ethanol as a new alcohol equivalent for copper-catalyzed coupling of aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2011.08.023

2-(Trimethylsilyl)ethanol as a new alcohol equivalent has been employed for copper-catalyzed coupling of aryl iodides. Using mild reaction conditions, it has been observed that substituted phenols and phenols with sensitive functional groups can be readily prepared.

Full text of DOI:10.1016/j.tetlet.2011.08.023

Tetrahedron Letters 52 (2011) 5338–5341
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2-(Trimethylsilyl)ethanol as a new alcohol equivalent for copper-catalyzed
coupling of aryl iodides
Mullick Dibakar a,b, Anjanappa Prakash a,b, Kumaravel Selvakumar a, , Kandasamy Ruckmani c,
,
⇑
⇑
Manickam Sivakumar d,
⇑
a Synthetic Chemistry, Syngene International Ltd, Biocon Park, Plot 2 & 3, Jigani Link Road, Bommasandra Industial Area, Bangalore 560 099, India
b Bharathidasan Institute of Technology, Bharathidasan University, Tiruchirappalli 620 024, India
c Department of Pharmaceutical Technology, Anna University, Truichirappalli 620 024, India
d Department of Chemical & Environmental Engineering, University of Nottingham (Malaysia campus), Semenyih 43500, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(Trimethylsilyl)ethanol as a new alcohol equivalent has been employed for copper-catalyzed coupling
of aryl iodides. Using mild reaction conditions, it has been observed that substituted phenols and phenols
with sensitive functional groups can be readily prepared.
Received 1 July 2011
Revised 1 August 2011
Accepted 2 August 2011
Available online 8 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalysis
Alcohol surrogates
Cross-coupling
2-(Trimethylsilyl)ethanol
Aryl ethers and phenols are very important structural motifs of
numerous biologically active natural products and important phar-
maceutical compounds and polymers in the material science
industries and consequently, much research has been focused on
their synthesis.1–3 Available methods for the synthesis of aryl
ethers and phenols via direct nucleophilic or Cu(I)-catalyzed sub-
stitution of an aryl halide with an alcohol typically require high
reaction temperatures and/or a large excess of the alcohol and
are limited in substrate scope.4–6 The need to employ HMPA,
DMSO, or DMF as solvent further diminishes the applicability of
these methods, particularly for large-scale processes.
The formation of carbon-heteroatom bonds by transition metal
catalyzed cross-coupling methodology has been the subject of sig-
nificant interest during the past few years.7 Although the majority
of efforts has focused on C–N bond forming processes, techniques
for the formation of aromatic C–O bonds have also been
reported.8–10 Buchwald and Hartwig groups as well as others, have
shown that tertiary alcohols, silanols, and phenols, all lacking
b-hydrogen groups, can be efficiently coupled with aryl chlorides
and bromides.10 The copper-mediated Ullmann ether synthesis is
a classical method for the synthesis of aryl alkyl ethers.11 The syn-
thetic scope of this reaction, however, is reduced as a result of the
harsh reaction conditions. This C–O bond forming process requires
strong bases such as alkoxides or sodium hydride. Other severe
drawbacks include the following requirements: (a) a large amount
of the alkoxide, (b) high temperatures, (c) highly polar aprotic sol-
vents, and (d) stoichiometric quantities of the copper salt.12
Aromatic carbon–oxygen bond formation under a mild condi-
tion is a difficult transformation. For reactions of inactivated aryl
halides, direct, uncatalyzed substitutions and copper-mediated
couplings typically require temperatures of 120 °C or higher.13–15
Diazotization and displacement with oxygen nucleophiles is gener-
ally limited to synthesis of phenol and uses stoichiometric
amounts of copper in its mildest form.16 One of the conventional
methods for the reactions of inactivated aryl halides to phenols
via boronic acid formation followed by peroxide treatment is well
known.17 Since the general methods for the preparation of aryl
boric acids do not lend themselves to a direct synthesis of hydroxy-
phenylboric acids, it was necessary to introduce the phenolic
hydroxyl by indirect methods. The direct hydroxylation of aryl
halides has been a major challenge in coupling chemistry. Buch-
wald and co-workers achieved this goal for the first time, by apply-
ing their bulky, monodentate ligands which facilitate C–O
reductive elimination.18 Chen and co-workers reported the palla-
dium-catalyzed hydroxylation of highly activated aryl bromides
in the presence of P(t-Bu)3.19 Recently, iron-catalyzed method for
the conversion of inactivated aryl halides to phenol has been
⇑
Corresponding authors. Tel.: +6 03 8924 8156; fax: +6 03 8924 8017 (M.S.).
E-mail addresses: selva.kumar@syngeneintl.com (K. Selvakumar), ruckmani@-
tau.edu.in (K. Ruckmani), Sivakumar.Manickam@nottingham.edu.my (M. Sivaku-
mar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.023

M. Dibakar et al. / Tetrahedron Letters 52 (2011) 5338–5341
5339
Table 1
Table 3
Screening of ligands for Cu-catalyzed C–O couplinga
2-(Trimethylsilyl)ethanol as oxygen surrogate in the copper-catalyzed coupling of
aryl and heterocyclic iodidea
Entry
1
Substrate
Product
Yieldb (%)
96 (93)
Me3Si
I
O
OH
SiMe3
I
O
CuI, Ligand
Cs2CO3, toluene, 14 h, 110 oC
Si
Si
I
O
Entry
1
Ligand
Yieldb (%)
0
2
3
86 (91)
92 (90)
CN
CN
O
H2N
NH2
I
Si
H
N
N
H
2
3
0
0
CN
CN
I
O
N
N
Si
4
5
6
7
8
9
91 (94)
95 (89)
89 (87)
94 (96)
85 (91)
94 (88)
NC
NC
NH2
I
O
4
5
0
Si
NH2
NH
F
F
I
O
F
Si
22
F
NH
I
O
Si
N
N
Br
Cl
6
96
Br
Cl
I
O
Si
a
Br
Reaction conditions: Aryl iodide (1 mmol), 2-trimethylsilyl alcohol (3 mmol),
CuI (10 mol %), ligand (20 mol %), Cs2CO3 (2.0 mmol), toluene (0.5 ml), Schlenk tube,
110 °C, 14 h.
Br
I
I
O
Si
Si
b
Isolated yield.
O
O
Table 2
Screening of base for Cu-catalyzed C–O couplinga
10
11
80 (83)
88 (87)
Cl
Cl
Cl
Cl
Cl
Cl
Me3Si
I
I
O
OH
SiMe3
Si
CuI,1,10-phenanthroline
Base, toluene, 14 h, 110 oC
Cl
Cl
I
O
Si
Si
Entry
Base
Yieldb (%)
12
13
93 (90)
90 (81)
MeO
OHC
MeO
OHC
1
2
3
4
5
6
Et3N
0
68
0
88
0
I
K2CO3
Na2CO3
K3PO4
Pyridine
Cs2CO3
O
I
O
96
Si
14
15
92 (93)
91 (95)
a
Reaction conditions: Aryl iodide (1 mmol), 2-trimethylsilyl alcohol (3 mmol),
CuI (10 mol %), 1,10-phenanthroline (20 mol %), base (2.0 mmol), toluene (0.5 ml),
Schlenk tube, 110 °C, 14 h.
N
N
N
N
I
O
Si
b
Isolated yield.
I
O
developed with water as the solvent at 180–200 °C.20 Although the
economic attractiveness of copper has led to remarkable progress
in the development of copper-catalyzed coupling reaction,21 the
copper-mediated hydroxylation of aryl halides with hydroxide
salts (e.g., KOH and NaOH) as nucleophiles to directly form phenols
under mild conditions is limited.22
Despite these developments, there are very limited reports of
selective hydroxylation methods being developed where one halo-
gen group (I or Br) can be hydroxylated exclusively in the presence
of other halo group. Phenols are often quite polar and their purifi-
cation can be challenging. Furthermore, the relative acidity and
nucleophilicity of phenols make them incompatible with many
reactions. For these reasons, we sought to synthesize protected
Si
16
17
81 (88)
88 (78)
I
O
Si
CF3
Cl
CF3
Cl
I
O
Si
18
83 (82)
F
F
(continued on next page)

5340
M. Dibakar et al. / Tetrahedron Letters 52 (2011) 5338–5341
or –Cl existed in the aromatic ring (Table 3, entries 7–11). The
Table 3 (continued)
mild reaction conditions and increased scope relative to conven-
tional ones would render this protocol attractive to synthetic
chemists. Further studies on the scope of the reactions of trimeth-
ylsilyl ethanol with different aryl bromides and chlorides are in
progress.
Entry
Substrate
Product
Yieldb (%)
92 (79)
I
O
Si
19
F
F
I
O
Si
20
21
76 (88)
78 (72)
Acknowledgments
HOH2C
F3CO
HOH2C
I
The authors, D.M., P.A., and K.S. thank Syngene international
Ltd for granting permission to carry out this work at Syngene.
M.S. and K.R. thank Bharathidasan and Anna universities for all
the support.
O
Si
F3CO
a
Reaction conditions: Aryl iodide (1 mmol), 2-trimethylsilyl alcohol (3 mmol),
CuI (10 mol %), 1,10-phenanthroline (20 mol %), Cs2CO3 (2.0 mmol), toluene
(0.5 ml), Schlenk tube, 110 °C, 14 h.
Supplementary data
b
Isolated yield is given. Yield given in bracket is for the deprotected product.
Supplementary data (experimental and analytical data for new
compounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.08.023.
phenols that would be tolerant of a variety of reaction conditions.
To meet these needs, a stable alcohol surrogate is required for the
hydroxylation and it is also important that the resulting ether com-
pound with alcohol surrogate to be stable during further transfor-
mations. Moreover, we also sought to avoid harsh conditions and
strong basic hydroxide salts (e.g., KOH and NaOH) as nucleophiles
and DMSO or DMF as solvent. So, it was a natural extension for us
to investigate the copper-catalyzed coupling of aliphatic alcohols
with aryl halides.23
During the past few years, some significant modifications have
been made. In 2002, Buchwald’s group first reported that using
10 mol % of CuI in conjunction with 20 mol % of 1,10-phenanthro-
line could make C–O bond formation between aryl iodides and
aliphatic alcohols successfully under mild reaction conditions
(Cs2CO3/120 °C/18–38 h).24 We have introduced trimethylsilyl eth-
anol as primary aliphatic alcohol for ether formation which can be
easily deprotected by using fluoride source.25
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examined in the reaction of iodobenzene and trimethylsilyl
ethanol using the following catalyst system: 10 mol % CuI/
20 mol % ligand/Cs2CO3/110 °C/14 h and toluene as solvent. The
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From the results, it was apparent that 1,10-phenanthroline
showed the best activity. Further experiments were performed
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(3 mmol), and toluene (0.5 ml). The test tube was sealed, and the reaction
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with diethyl ether. The filtrate was concentrated. Purification of the residue by
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