A very simple copper-catalyzed synthesis of phenols employing hydroxide salts

Article abstract of DOI:10.1002/anie.200903639

Cheap and cheerful: The direct coppercatalyzed hydroxylation of activated and unactivated aryl iodides or bromides has been achieved using metal hydroxide salts (MOH). Selective hydroxylation in a H20/ co-solvent system avoids formation of the related biaryl ether by-product and the low cost of the copper catalytic system makes this method very competitive.

Full text of DOI:10.1002/anie.200903639

Angewandte
Chemie
DOI: 10.1002/anie.200903639
À
C O Coupling
AVery Simple Copper-Catalyzed Synthesis of Phenols Employing
Hydroxide Salts**
Anis Tlili, Ning Xia, Florian Monnier, and Marc Taillefer*
Phenols are very important intermediates in the chemical,
We recently developed a simple copper-catalyzed syn-
thesis of aniline from the coupling reaction between aqueous
ammonia and aryl halides in the presence of diketone-type
ligands.[9] These results encouraged us to investigate related
systems for preparing phenols from aryl halides and hydrox-
ide salts. As part of our studies on the copper-catalyzed
arylation of nucleophiles,[8] we now report that the selective
hydroxylation of both activated and unactivated aryl bro-
mides and iodides can be achieved in aqueous media using a
metal hydroxide and a catalytic system in which copper is
used together with simple diketone ligands.[10]
We initially selected iodobenzene as the model substrate
and 0.5 equivalents of TMHD (2,2,6,6-tetramethyl-3,5-hepta-
nedione, L1) as ligand for optimization of the reaction
conditions. Our first test was performed in NMP (N-methyl-
2-pyrrolidone) using a catalytic amount of CuI (0.1 equiv),
with potassium hydroxide (3.0 equiv) as the nucleophile
(Table 1, entry 1).
pharmaceutical, and materials industries, with more than 7.2
[1,2]
megatons of phenol itself produced per year.
Nowadays,
about 90% of the world’s phenol demand is satisfied by the
Hock process, which involves the peroxidation of cumene,
itself obtained from benzene propylation. This industrial
process, which is not very efficient in yield (overall 5%) and
energy use, also produces large amounts of acetone and a-
methylstyrene co-products. Alternative oxidation technolo-
gies that avoid production of acetone have been proposed,[2b,c]
but none have succeeded in replacing the Hock process.
For the preparation of functionalized phenols, non-
oxidative methods are used, such as traditional nucleophilic
aromatic substitution; however, the range of substituents is
often limited by the necessarily harsh reaction conditions or
by the electronic requirements of the substrate.[3] An inter-
esting iridium-based catalytic system has been reported for
preparation of non-ortho-substituted phenols, which involves
a one-pot, aromatic borylation/oxidation sequence;[4] more
recently, the groups of Buchwald,[5a] Kwong,[5c] Diaconescu,[5d]
and Beller[5e,f] have developed very efficient systems based on
palladium/phosphine ligand catalysis, which allow selective
formation of phenols from different aryl halides.[5] However,
these systems are more expensive than copper and not as
favorable for toxicity issues.
Table 1: Hydroxylation of PhI using various solvents and copper sources
in the presence of ligand TMHD L1.[a]
Therefore, the development of a cheaper, copper-cata-
lyzed system enabling the direct hydroxylation of aryl halides
has become an important goal. There are, however, two
critical problems to be resolved; first, the direct copper-
catalyzed coupling reaction between unactivated aryl halides
and hydroxide at temperatures below 2008C has never been
reported (indeed, one study has shown that this reaction is
very difficult even at 200–3008C with microwave heating).[6]
Second, copper-catalyzed coupling between phenols and aryl
halides is well known,[7,8a,b,d,f] and this could be a prominent
concurrent reaction once phenol is formed in situ, thus
affording symmetric diaryl ethers as reaction products.
Solvent
(2 mL)
MOH
Yield[b] [%]
1
1’
1
2
3
4
5
6
7
8
NMP
H2O
DMSO
KOH
KOH
KOH
KOH
KOH
20
20
50
19
15
60
70
80
30
30
45
65
40
95
75
20
0
20
28
20
20
15
5
20
20
0
0
0
0
0
DMSO/H2O
DMF/H2O
DMSO/H2O
DMF/H2O
DMSO/H2O
MIBK/H2O
NMP/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
7:1
7:1
3:1
3:1
3:1
3:1
3:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
KOH
KOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
KOH
9
10
11[c]
12[d]
13[e]
14
15[f]
16
17
18
[*] A. Tlili, Dr. N. Xia, Dr. F. Monnier, Dr. M. Taillefer
CNRS, UMR 5253, Institut Charles Gerhardt Montpellier AM2N
ENSCM, 8, rue de l’Ecole Normale
60[g], 80[i]
0[h], 0[j]
75
0
5
0
34296 Montpellier Cedex 5 (France)
Fax: (+33)467-144-319
E-mail: marc.taillefer@enscm.fr
florian.monnier@enscm.fr
[a] Reactions performed at 1308C with 3.0 equiv of MOH and 0.1 equiv of
CuI unless otherwise noted. [b] Yield determined by GC with 1,3-
dimethoxybenzene as standard. [c] With 1.5 equiv of CsOH. [d] With
2.5 equiv of CsOH. [e] At 1208C. [f] With 0.4 equiv of L1. [g] With
0.05 equiv of CuI. [h] With 0.01 equiv of CuI. [i] With 0.05 equiv of CuI, at
1408C. [j] With 0.01 equiv of CuI, at 1408C.
[**] The authors are grateful to CNRS, the region of Languedoc
Roussillon and the ANR for a PhD grant and financial support.
Supporting information for this article, including general proce-
dures for isolation and characterization of phenols, is available on
the WWW under http://dx.doi.org/10.1002/anie.200903639.
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Communications
At 1308C, we observed the formation of only small
(Table 2, entries 1,3). Interestingly, the selectivity was always
À
amounts of phenol 1 and also some biaryl ether 1’ resulting
from the arylation of the former by PhI. The same reaction
under aqueous conditions afforded a low yield of 1, although
full selectivity was observed (Table 1, entry 2); DMSO alone
also afforded acceptable and promising, but non-selective,
formation of phenol (Table 1, entry 3). At this stage, we
systematically tested mixed-solvent systems over a range of
compositions using either KOH or CsOH as the nucleophile
(Table 1, entries 4–10). Fair to good yields of phenols were
obtained with DMSO/H2O or DMF/H2O (3:1 ratio; Table 1,
entries 6,7) but some diaryl ether by-product 1’ (15–20%)
was found in all cases. CsOH (DMSO/H2O, 3:1 mixture)
yielded 1 with improved selectivity (Table 1, entry 8); how-
ever, disappointing results were obtained with CsOH in
MIBK/H2O (methyl isobutyl ketone) or NMP/H2O mixtures
(Table 1, entries 9,10).
We were pleased to find that with a DMSO/H2O ratio of
1:1, PhI could be selectively coupled at 1308C to give 1 in
quantitative yield (Table 1, entry 14). It is worth noting that at
lower concentrations of CsOH, when the temperature is
decreased to 1208C, or when only 0.4 equivalents of ligand L1
is used, the yield of phenol is reduced (Table 1, entries 11–
13,15). Furthermore, under optimal conditions (Table 1,
entry 14), but with small quantities of CuI (0.05 and
0.01 equiv), the yield of 1 decreased to 60% and 0%,
respectively (Table 1, entries 16,17). A slightly higher tem-
perature did not improve the efficiency of the system,
whatever the amount of copper used (Table 1, entries 16,17).
The reaction also takes place selectively under the same
conditions (Table 1, entry 14) with the less expensive potas-
sium hydroxide KOH replacing CsOH as the base (Table 1,
entry 18). However, since the yield of isolated product (75%)
was slightly lower than with CsOH, we continued using the
latter to examine the influence the ligand effects upon the
reaction (Table 2; ligands L1–L8).
excellent, and no trace C C coupling product resulting from
arylation of the diketone was detected. Other classical ligands
for Ullmann coupling also worked well (selectivity 100%),
but with slightly lower yields (70 to 84%). As L3 is
approximately five-times less expensive than L1, L3 was
chosen to explore the scope of this new route for phenol
preparation.
The relationship between experimental conditions and
reactivity/selectivity is still not clear. The key factor for the
success of our system is the use of a well-defined ratio of
water/base/co-solvent (Table 1, entry 14). In contrast, the
nature of the ligand seems to be less important. The full and
exclusive conversion of PhI into PhOH could indicate that the
phenol, in equilibrium with the corresponding phenolate, is
not able to react at all with PhI under our optimal conditions
(owing to, for example, solubility reasons). A crucial point
seems to be the concentration of water (a high concentration
favors the reaction), which improves the solubility of the
hydroxide ion and thus its ability to intervene as a nucleo-
phile. The use of DMSO, which is miscible with water and
known to behave as a superbasic media in the presence of
alkali metal hydroxides, is also probably a key feature of our
catalytic system.[11] It is difficult to perform a correlation
between the structure of the copper species in the medium
(assumed to be a copper(I) complex) and our experimental
conditions.
We then explored the breadth of application of this new
method using the optimized experimental conditions
(Table 2, ligand L3). Thus, in a mixed solvent system of
DMSO/H2O (1:1), the CuI/diketone-L3 system efficiently
promotes cross-coupling reactions between CsOH and aryl
iodides with electron-withdrawing groups (EWGs), to afford
the corresponding phenols in good to excellent yields
(Table 3, entries 2–8). In some cases, with activated substrates
such as p-iodonitro-, p-iodoaceto-, or p-iodocyanobenzene,
reactions can proceed efficiently even at lower temperature
(1108C; Table 3, entries 2–4). Note that the copper/ligand
system proved necessary even in the case of a strongly
activating group (p-NO2) to afford the coupling product
(Table 3, entry 2). Subsequently, we performed the coupling
reaction with aryl iodides deactivated by electron-donating
groups (EDGs), and we obtained the desired products in
excellent yields (Table 3, entries 11–15). Note that the
reaction is also possible with electron-donating substituents
at lower temperature (1108C), as illustrated by the case of 3,5-
dimethyliodobenzene (excellent yield obtained in 36 h
instead of 24 h at 1308C; Table 3, entry 14).
Of the four b-diketones investigated, all except L2 were
effective, especially TMHD L1 and dibenzoylmethane L3
Table 2: Synthesis of phenols by copper catalyzed hydroxylation of PhI in
aqueous media using various ligands L.[a,b]
Ligands L
Yield[a] [%]
95
Ligands L
Yield[a] [%]
70
For 2-diiodobenzene and 4-iodophenol in particular, we
observed the quantitative formation of the double- or mono-
reduction products, respectively (Table 3, entries 9,10). The
starting p-iodophenolate, or o-iodophenolate formed in situ
by initial monohydroxylation of 2-diiodobenzene, could favor
a radical mechanism by stabilizing the resulting phenolate
radical anion (OC6H4CÀ); this radical then could easily lead to
the observed phenol product. Although aryl iodides are
interesting substrates, we turned our attention to arylation of
aryl bromides, which are less reactive electrophiles but of
greater interest for industrial applications. Various phenols
L1
L5
L2
L3
L4
30
97
65
L6
L7
L8
85
84
75
[a] Yield determined by GC with 1,3-dimethoxybenzene as standard.
[b] Yield of 1 without any ligand: 20% (1’, 0%).
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Table 3: Synthesis of phenols by copper-catalyzed hydroxylation of
salts (NaI), and carry out its subsequent in situ copper-
aryliodides and bromides.[a]
catalyzed trapping by the hydroxide ion (Table 4, entry 1).[12]
Although the diketone L1 was able to promote these two
successive catalytic reactions, N,N-dimethylenediamine L7
Table 4: Copper/ligand-catalyzed hydroxylation of arylbromides in the
presence of NaI.
ArI
ArOH
PhOH
Isolated yield [%]
97
1
2
PhI
1
2
22[b], 90[c]
3
4
5
6
7
8
3
4
5
6
7
8
90[c]
91[c]
95
ArBr
ArOH
Isolated yield [%]
1
2
3
1
6
5
85, 75[a]
70
70
90
75, 95[d]
84
4
16
88
5
6
9
87
9
1
95
10
80, 83[b]
10
11
12
1
9
95
90
82
7
17
85
[a] DMSO used instead of dioxane. [b] Toluene used instead of dioxane.
10
13
14
11
12
84
proved to be much more efficient. Before the addition of
CsOH/water, the halide exchange was usually performed at
1108C in 1,4-dioxane, though toluene or DMSO could also be
used. This method was successfully extended to aryl bromides
deactivated by electron-donating p-methyl-, p- or m-methoxy
substituents (Table 4, entries 5–7) or an electron-withdrawing
group, such as p-phenyl or p-fluoro (Table 4, entries 2,3).
2-Bromonaphthalene was also selectively converted into the
corresponding naphthol under these conditions (88%;
Table 4, entry 4).
96, 71,[c] 90[e]
15
16
13
14
84
78, 7[b]
17
15
83, 17[b]
82,[c] 27[b]
84, 20[b]
94, 24[b]
In conclusion, we have discovered a general, economical,
and efficient method for the direct copper-catalyzed synthesis
of phenols from all kinds of aryl iodides and bromides. This
selective procedure avoids the otherwise typical formation of
the related biaryl ether by-product. The H2O/co-solvent
system used is unusual, and work is currently in progress to
elucidate how it functions. The convenience of employing an
aqueous hydroxide ion and the low cost of the copper
catalytic system make this method very competitive.[5] It could
be easily adapted to industrial-scale production, and would be
particularly useful where safety and environmental factors are
a greater concern. The catalytic system is not that different
from that which in 2007 allowed us to perform the copper-
catalyzed synthesis of anilines using aqueous ammonia.[9]
With these tools in hand we can now propose a general
alternative, both for amination and hydroxylation of aromatic
halides, to the existing palladium-based catalytic systems.[5b]
18
19
20
2
3
4
[a] General reaction conditions: 1308C for 24 h. [b] 1308C, 24 h, without
CuI and ligand. [c] 1108C, 24 h. [d] 1308C, 36 h. [e] 1108C, 36 h.
were generated from reactive aryl bromides, including
p-bromocyanobenzene, o- and p-acetobromobenzene, and
m- and p-nitrobromobenzene (Table 3, entries 16–20). In all
of these cases, blank experiments performed in the absence of
a copper–ligand catalytic system revealed only very poor
conversion of aryl bromides into their corresponding phenols
(Table 3, entries 16–20).
We then applied these conditions to bromobenzene, but at
first the cross-coupling failed. However, we were able to
obtain 1, formed in excellent yield from the copper-catalyzed
production of iodobenzene from bromobenzene and iodide
Received: July 3, 2009
Published online: October 13, 2009
Angew. Chem. Int. Ed. 2009, 48, 8725 –8728
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8727

Communications
À
[6] C. M. Kormos, N. E. Leadbeater, Tetrahedron 2006, 62, 4728.
[7] For some examples of the copper-catalyzed arylation of phenols,
see: a) B. H. Lipshutz, J. B. Unger, B. R. Taft, Org. Lett. 2007, 9,
1089; b) H. Zhang, D. Ma, W. Cao, Synlett 2007, 243; c) R. K.
Gujadhur, C. G. Bates, D. Venkataraman, Org. Lett. 2001, 3,
4315; d) P. J. Fagan, E. Hauptman, R. Shapiro, A. Casalnuovo,
J. Am. Chem. Soc. 2000, 122, 5043; e) A. V. Kalinin, J. F. Bower,
P. Riebel, V. Snieckus, J. Org. Chem. 1999, 64, 2986.
Keywords: arylation · copper · C O coupling · hydroxylation ·
phenol
.
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8728
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