Practical imidazole-based phosphine ligands for selective palladium-catalyzed hydroxylation of aryl halides

Article abstract of DOI:10.1002/anie.200804898

(Chemical Equation Presented) The phenol countdown: Novel imidazole-based phosphine ligands are synthesized on scales up to 100 g by a convenient lithiation-phosphorylation method. The phosphines are stable towards air and moisture and are successfully applied as ligands in the palladium-catalyzed selective hydroxylation of aryl halides (see scheme, dba=dibenzylideneacetone).

Full text of DOI:10.1002/anie.200804898

Communications
DOI: 10.1002/anie.200804898
Synthetic Methods
Practical Imidazole-Based Phosphine Ligands for Selective Palladium-
Catalyzed Hydroxylation of Aryl Halides**
Thomas Schulz, Christian Torborg, Benjamin Schꢀffner, Jun Huang, Alexander Zapf,
Renat Kadyrov, Armin Bꢁrner, and Matthias Beller*
Phenols are an integral part of numerous pharmaceuticals,
polymers, and natural products.[1] In the past the non-
oxidative preparation of this class of compounds involved
nucleophilic aromatic substitution of activated aryl halides,
often under harsh reaction conditions.[2] Smith, Maleczka, and
co-workers reported the preparation of non-ortho-substituted
phenols under milder conditions.[3] However, two steps, CH-
activation/borylation and oxidation, were required for the
desired transformation. In contrast to well-established palla-
dium-catalyzed aryl ether formations,[4–6] the direct hydroxy-
lation of aryl halides has been a major challenge in coupling
chemistry. Buchwald and co-workers achieved this goal for
the first time,[7a,b] applying their bulky, monodentate ligands[8]
Scheme 1. Synthesis of dialkyl-2-(N-arylimidazolyl)phosphines.
À
which facilitate C O reductive elimination. Chen and co-
workers[7c] reported the Pd-catalyzed hydroxylation of highly
activated aryl bromides in the presence of P(tBu)3.[9]
Despite these developments, there is a need for easily
available ligands which lead to generally applicable, more
active catalyst systems for this coupling reaction. Clearly, for
selective hydroxylation it is important that the subsequent
coupling reaction of the phenol towards diaryl ethers is
controlled.
Herein, we describe the synthesis of new, sterically
demanding phosphine ligands based on N-arylated imidazoles
(Scheme 1), and their use in the synthesis of phenols from the
corresponding aryl halides. Various dialkyl-2-(N-arylimida-
zolyl)-phosphines (1–10) were synthesized in one or two
reaction steps. Notably, the most active 1-(2,6-diisopropyl-
phenyl)-1H-imidazole-based phosphine ligands (1–3) can be
readily prepared on 100 g scale. The corresponding N-aryl-
1H-imidazole unit, which is present in many natural products,
including amino acids, nucleic acids, and imidazole-based
alkaloids,[10] is easily available by various synthetic strategies
and allows high tunability.[11]
Ligands 1–10 are synthesized using either a copper-
catalyzed Ullmann reaction[12] or by a four-component con-
densation of the corresponding aniline with paraformalde-
hyde, ammonium acetate, and an a-dicarbonyl component
(glyoxal or benzil).[13] The resultant N-arylated imidazoles
were regioselectively deprotonated with n-butyl lithium in
THF at À308C, and the resulting carbanion subsequently
quenched with the corresponding dialkylchlorophosphines to
give the desired phosphines in good-to-excellent yields after
aqueous work up and single recrystallization from H2O/EtOH
(Scheme 1). Unlike the known N-aryl-2-(dialkylphosphino)-
(benz)imidazoles,[14,15] the addition of N,N,N’,N’-tetramethy-
lethylenediamine (TMEDA) was not required for selective
metalation.[6,16]
The novel phosphine ligands were treated with selenium
to give the corresponding phosphine selenides. The magni-
tude of the coupling constant between the phosphorus and
selenium atoms was strongly dependent upon the nature of
the organic substituents bound to phosphorus.[17] The values
of the coupling constants of 1–10 are in the same range as
Buchwaldꢀs biaryl phosphines 13 and 14 (Table 1), suggesting
that the electronic and steric effect of both ligand classes is
comparable.
To test the new ligands and their applicability to cross-
coupling reactions, the palladium-catalyzed hydroxylation of
aryl halides was carried out. Initially, a catalyst derived from
[Pd(dba)2] (dba = dibenzylideneacetone) and ligand 4 showed
moderate activity in the hydroxylation of mesityl bromide
with sodium hydroxide in a 1:1 mixture of water and 1,4-
dioxane at 1008C (Table 2). The use of potassium hydroxide
in place of sodium hydroxide gave slightly improved results,
as did NaOtBu and CsOH, whereas triethylamine, K3PO4, and
inorganic carbonates were ineffective in the reaction. In
combination with KOH, 1,4-dioxane was by far the most
[*] T. Schulz, C. Torborg, B. Schꢀffner, Dr. J. Huang, Dr. A. Zapf,
Prof. Dr. A. Bꢁrner, Prof. Dr. M. Beller
Leibniz-Institut fꢂr Katalyse e.V. an der Universitꢀt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
Dr. R. Kadyrov
Evonik Degussa GmbH—Business Line Catalysis
Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang (Germany)
[**] We thank Dr. W. Baumann, Dr. C. Fischer, A. Koch, S. Buchholz,
S. Schareina, A. Kammer, and S. Rossmeisl for excellent analytical
support. We gratefully acknowledge Evonik (formerly Degussa) for
financial support.
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804898.
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Chemie
31
=
P
Table 1: Chemical shifts and
77Se coupling constants for 2-(N-
Table 3: Ligands for Pd-catalyzed hydroxylation of mesityl bromide.[a]
arylimidazolyl)phosphine selenides.[a]
Entry
Ligand
R
R’
R’’
Yield [%]
Ligand
d [ppm]
1JP Se [Hz]
=
1
2
3
1
2
3
Ad
Cy
tBu
77; 72;[b] 88[c]
1
2
3
4
5
6
7
8
9
59.3
40.3
62.2
58.9
60.0
63.0
59.0
58.9
59.0
62.2
45.2
71.1
718
732
726
712
713
724
715
716
717
726
710
742
0
49
4
5
6
4
5
6
Ad
Ad Ph
tBu Ph
H
56
75
62
10
13
14
7
8
9
7
8
9
2-OMe
4-OMe
3,4-OMe
0
0
0
[a] The corresponding ligand (0.03 mmol) and selenium (2 equivalents)
were dissolved in CDCl3 (0.7 mL) in a NMR tube, heated for a short time
at 508C and submitted to 31P NMR spectroscopy.
10
10
58
Table 2: Pd-catalyzed hydroxylation of mesityl bromide.
11
12
11
12
0
0
13
14
13
14
Cy
tBu
1
Base[a]
Conversion [%]
Yield [%]
8[d]
NaOH
KOH
51
57
66
<5
5
14
7
55
90
<5
43
55
50
<5
5
8
7
46
<1
<1
CsOH·H2O
Na2CO3
K2CO3
Cs2CO3
K3PO4
NaOtBu
NEt3
15
16
PtBu3–HBF4
15
16
3
0
[a] [Pd2(dba)3] (1 mol%), ligand (4 mol%), KOH (3 equivalents), H2O/
1,4-dioxane (1:1, 1.2 mL, 0.8 M), 1008C, 20 h; [b] toluene as organic
cosolvent; [c] with CsOH·H2O (3 equivalents) as base, no addition of
water; [d] under Buchwald’s reaction conditions (mesityl bromide
(1 mmol), [Pd2(dba)3] (2 mol%), ligand 14 (8 mol%), KOH (3 equiv-
alents), 1,4-dioxane, H2O, 1008C, 6 h), a yield of 88% was verified.[7a]
–
Solvent[b]
Conversion [%]
Yield [%]
1,4-dioxane
THF
MeOH
DMSO
Toluene
DMF
57
36
95
20
9
55
36
14
20
9
gave better results. For example, adamantyl-substituted
ligands proved superior compared to the tert-butyl-substi-
tuted ligands, whereas cyclohexyl-substituted phosphines led
to no reactivity at all (Table 3, entries 1–3). Moreover, for
reaction to proceed, substitution at both ortho-positions on
the aryl ring was necessary (Table 3, entries 7–9). Ligands
with a less sterically demanding substitution pattern (mesityl,
Table 3, entry 4) were inferior to more bulky ones (2,6-
diisopropylphenyl, Table 3, entry 1). Consequently, combin-
ing these positive structural features, that is, 1-adamantyl
groups attached to phosphorus and isopropyl groups at the 2-
and 6-positions of the aryl ring, led to the highest yield in the
model reaction (Table 3, entry 1; 77%).
43
<1%
Pd source[c]
Conversion [%]
Yield [%]
[Pd(dba)2]
Pd(OAc)2
[Pd(CH3CN)2Cl2]
[Pd(PPh3)4]
57
29
12
55
29
12
<5
<5
[a] [Pd(dba)2] (1 mol%), ligand 4 (4 mol%), base (3 equivalents), H2O/
1,4-dioxane (1:1, 1.2 mL, 0.8 M), 1008C, 5 h; [b] [Pd(dba)2] (1 mol%),
ligand 4 (4 mol%), KOH (3 equivalents), H2O/organic solvent (1:1,
1.2 mL, 0.8 M), 1008C, 5 h; [c] [Pd] (1 mol%), ligand 4 (4 mol%), KOH
(3 equivalents), H2O/1,4-dioxane (1:1, 1.2 mL, 0.8 M), 1008C, 5 h.
Advantageously, substituents on the imidazole ring could
also be altered to improve reactivity (Table 3, entries 5, 6). It
is important to note that the commercially available ligands
tested led to low or no reactivity (Table 3, entries 11,12,15,
and 16). Furthermore, only trace amounts of product were
detected from the reaction with Buchwaldꢀs XPhos ligands
under these conditions (Table 3, entries 13,14).
effective organic cosolvent. The other palladium sources
investigated were inferior to [Pd(dba)2].
Next, different ligands were applied to the model
hydroxylation reaction, and compared with commercially
available ligands (Table 3). In general, the more bulky ligands
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Table 5: Palladium-catalyzed synthesis of phenols from aryl halides.[a]
To understand the behavior of the new catalysts, com-
petitive experiments were carried out in the presence of
olefins, alkynes and amines (Table 4). One equivalent (with
Table 4: Selectivity of the hydroxylation reaction in presence of compet-
ing nucleophiles.[a]
Entry
1
Substrate
Yield [%]
88[b]
2
3
93
90[c]
Nucleophile
Yield of
phenol [%]
Ratio (phenol/coupling product)
74
55
16
>15:1
2.5:1
4
5
6
83
73
>50:1
80[c]
[a] Mesityl bromide (1 mmol), competing nucleophile (1 mmol), [Pd2-
(dba)3] (1 mol%), ligand 1 (4 mol%), KOH (3 equivalents), 1,4-dioxane
(0.6 mL), H2O (0.6 mL), 1008C, 20 h.
7
8
50
91
respect to mesityl bromide) of styrene, phenylacetylene, or
morpholine was added to the reaction mixture without
optimization. Surprisingly, in the presence of styrene, the
potential Heck reaction did not occur and the hydroxylated
product was formed in 74% yield. Similarly, the coupling
reaction in the presence of morpholine is highly chemo-
selective, albeit with a reduced conversion. Conversely, the
alkyne–arene coupling competed with the hydroxylation.
Nevertheless, 55% of the desired phenol was obtained, with
22% of the diarylalkyne. These experiments demonstrate for
the first time the high specificity of a palladium catalyst
system towards hydroxylation reactions.
Finally, the scope of the catalyst system [Pd2(dba)3]/
ligand 1 was examined by treating various aryl bromides and
chlorides with KOH in water/1,4-dioxane (Table 5). Different
alkyl-substituted aryl bromides and chlorides were converted
into the corresponding phenols in good-to-excellent yields
(Table 5, entries 1–6; 73–93%). Both activated substrates,
such as 4’-bromobenzophenone (Table 5, entry 8; 91%) and
4-bromonitrobenzene (Table 5, entry 9; 99%), and deacti-
vated arenes, such as anisoles and thioanisoles (Table 5,
entries 10–12; 88–94%), were fully converted. For aryl
chloride substrates, the use of CsOH as a base led to better
results and full conversion. In comparison with 2- and 4-
chloroanisole, the hydroxylation of 2-bromo-6-methoxynaph-
thalene was less selective and afforded the corresponding
naphthalene-2-ol in moderate yield (Table 5, entry 7; 50%).
On using 1-bromo-2-chlorobenzene as the substrate, as
expected when substitution of bromide competes with the
substitution of chloride, substitution of bromide occurred
preferentially (Table 5, entry 13), and only a small amount
(< 5%) of the chloride-substituted product could be detected.
For full conversion of 4-chloroquinaldine, only 1 mol% of
9
10
11
99
94[b]
90[b]
12
13
14
15
88
78[d]
99[e]
68[f]
[a] Substrate (1 mmol), [Pd2(dba)3] (1 mol%), ligand 1 (4 mol%), KOH
(3 equivalents), 1,4-dioxane (0.6 mL), H2O (0.6 mL), 1008C, 20 h;
[b] CsOH·H2O (3 equivalents) as base with 1,4-dioxane (1.2 mL) and
no addition of water, 1208C; [c] [Pd2(dba)3] (2 mol%), ligand
(8 mol%); [d] product=2-chlorophenol; [e] [Pd2(dba)3] (0.5 mol%),
ligand 1 (2 mol%); [f] [Pd2(dba)3] (4 mol%), ligand 1 (16 mol%).
1
palladium (0.5 mol% of [Pd2(dba)3]) was required (Table 5,
entry 14; 99%). Conversely, complete hydroxylation in the
presence of a nitrile group necessitated a higher catalyst
loading (Table 5, entry 15; 68%).
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Buchwald, J. Am. Chem. Soc. 2000, 122, 1360; c) J. P. Wolfe, H.
In summary, we synthesized a series of novel imidazole-
based phosphine ligands. These phosphines were readily
generated in high yields and purities from the corresponding
imidazole precursors, by a convenient lithiation–phosphory-
lation method. Notably, the preparations could be easily
scaled up to afford the phosphines on 100 g scale for potential
applications. The ligands are remarkably stable towards air
and were successfully applied as ligands in the palladium-
catalyzed selective hydroxylation of aryl halides with low
palladium loadings in the majority of cases. The hydroxylation
procedure was uncomplicated and did not require special
reagents.[3] Further applications of these ligands are currently
under investigation in our laboratories.
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Received: October 7, 2008
Published online: December 22, 2008
Keywords: chemoselectivity · homogeneous catalysis ·
.
hydroxylation · palladium · phosphines
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