Palladium N-heterocyclic carbene catalysts for synthesis of diaryl ethers

Article abstract of DOI:10.1055/s-2008-1078548

Novel functionalized 1,3-dialkylimidazolinium (LH) salts as precursors for N-heterocyclic carbenes (NHCs) have been prepared and successfully applied in the palladium-catalyzed synthesis of diaryl ethers and arylation of benzaldehydes. An efficient cataly

Full text of DOI:10.1055/s-2008-1078548

LETTER
1781
Palladium N-Heterocyclic Carbene Catalysts for Synthesis of Diaryl Ethers
P
alladium NH
C
Cataly
i
sts for
t
Synthe
a
sis of
D
iary
t
l
E
thers Akkoç,a Nevin Gürbüz,a Engin Çetinkaya,b İsmail Özdemir*a
a
b
Received 3 March 2008
Dedicated to Prof. Dr. Bekir Çetinkaya on the occasion of his 65th birthday
or are rather expensive. Furthermore, tertiary phosphines
Abstract: Novel functionalized 1,3-dialkylimidazolinium (LH)
salts as precursors for N-heterocyclic carbenes (NHCs) have been
prepared and successfully applied in the palladium-catalyzed syn-
thesis of diaryl ethers and arylation of benzaldehydes. An efficient
require air-free handling to prevent their oxidation and are
susceptible to P–C bond cleavage at elevated tempera-
tures.10 In the past few years, N-heterocyclic carbenes
catalyst system was prepared in situ from Pd(OAc)2, 1,3-dialkylim- (NHCs) have emerged as versatile ligational building
idazolinium bromides (LHBr), and NaH.
blocks for a large variety of coordination compounds in
organometallic chemistry and homogeneous catalysis.11–15
Key words: C–O bond formation, etherification, palladium
coupling, N-heterocyclic carbene.
On the other hand, palladium complexes of NHC
ligands,16 in particular, have proved to be excellent cata-
lysts for coupling reactions.
The formation of carbon–heteroatom bonds by the transi-
tion–metal-catalyzed cross-coupling methodology has
been the subject of significant interest during the past few
years.1 Diaryl ethers represent a common feature in natu-
ral products, pharmaceuticals and agrochemicals as well
as in industrial polymers.2 The most general method for
the synthesis of diaryl ethers has been the copper-mediat-
ed Ullmann coupling of aryl halides and phenols.3 How-
ever, harsh reaction conditions such as high temperature
(125–220 °C), the usual requirement of stoichiometric
quantities of the copper catalysts, and the low to moderate
yields have greatly limited the utility of this reaction.4 Due
to these problems significant efforts have been undertaken
in the last decade to develop more efficient and environ-
mentally benign catalytic coupling processes of phenols.
The current status of the methodology has been described
in detail by different research groups.5
We have previously reported the use of in situ formed imi-
dazolidin-2-ylidene, tetrahydropyrimidin-2-ylidene,
tetrahydrodiazepin-2-ylidene,
and
benzimidazol-2-
ylidene palladium(II) systems that exhibit high activity
for various coupling reactions of aryl bromides and aryl
chlorides.17 Recently we reported that the in situ genera-
tion of catalysts, from [RuCl2(p-cymene)]2 and pyrimidin-
ium or benzimidazolium salt in the presence of Cs2CO3,
selectively promote the diarylation of 2-pyridylbenzene
with aryl bromides.18
Although the nature of the NHC ligand in complexes has
a tremendous influence on the rate of catalyzed reactions,
the use of 1,3-dialkylimidazolidin-2-ylidene ligands in
coupling reactions is a neglected area. In order to find
more efficient palladium catalysts we have prepared a se-
ries of 1,3-disubstituted imidazolinium salts 2a–c
(Scheme 1). We now report the use of the in situ generated
catalytic system composed of commercially available and
stable reagents, Pd(OAc)2 as palladium source, 1,3-di-
alkylimidazolinium bromides (LHBr) 2a–c as carbene
precursors and NaH as a base for the formation of aryl
ethers from the reactions of aryl chlorides with a variety
of phenols.
The increased attention in this field over the past years has
led to the development of several catalyst systems, which
enable aryl ether formation under much milder conditions
compared to the classical Ullmann and Goldberg reac-
tions.5a,c,6 So far, mainly copper7 and palladium8 com-
plexes have evolved as catalysts for this type of reaction.
Recently, palladium-catalyzed formation of aryl ethers
was reported by Hartwig and Buchwald.9 These efforts,
however, were mostly successful in reactions employing
electron-deficient aryl halides in the presence of a large
amount of the catalyst. They examined electron-rich
bulky phosphine ligands mainly for the preparation of di-
aryl ethers.
1,3-Dialkylimidazolinium bromides 2a–c are convention-
al NHC precursors. The preparation of 1,3-dialkylimida-
zolinium bromide was carried out according to the
reported procedures (Scheme 1).19,20 The salts are air- and
moisture-stable both in the solid state and in the solution.
The structures of 2a–c were determined by their charac-
teristic spectroscopic data and elemental analyses. 13C
NMR chemical shifts were consistent with the proposed
structure; the imino carbon appeared as a typical singlet in
the 1H-decoupled mode at d = 158.2, 157.5 and 157.6 ppm
However, the major drawback of these reactions is that the
phosphine ligands are comparatively difficult to prepare
1
for imidazolinium bromides 2a–c, respectively. The H
SYNLETT 2008, No. 12, pp 1781–1784
1
6
.0
7
.2
0
0
8
NMR spectra of the imidazolinium salts further supported
the assigned structures; the resonances for C(2)-H were
observed as sharp singlets at d = 9.20, 9.22 and 9.15 ppm
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1078548; Art ID: D06408ST
© Georg Thieme Verlag Stuttgart · New York

1782
M. Akkoç et al.
LETTER
OMe
Br–
N
)
+
Br
N
2a
OMe
N
Br
N
1
OMe
Br–
N
)
+
N
OMe
Br–
Br
2c
N
)
+
N
2b
Scheme 1 Synthesis of 1,3-dialkylimidazolinium bromides (LHBr)
for 2a–c, respectively. The IR data for imidazolinium salts sterically more hindered 2,6-di-tert-butyl-4-methylphenol
2a–c clearly indicated the presence of the C=N group with were lower yields obtained (Table 1, entries 1–6).
a n(C=N) vibration at 1645, 1649 and 1648 cm–1 for 2a–c,
The procedure is simple and does not require induction
periods. All complexes led to good conversions (74–96%)
at low catalyst concentration (2.0 mmol%). Although not
respectively. The NMR values were similar to those found
for other 1,3-dialkylimidazolinium salts.21
With Pd(OAc)2 as the catalyst, 1,3-dialkylimidazolinium dramatic, consistent differences in yields were observed
bromides 2a–c (Scheme 1) as the NHC ligand precursors, in the reactions according to the ligand precursors 2a–c.
NaH as the base and toluene as the solvent, our initial ex- Presumably, the bulkier ligands derived from 2a–c are
ploration of the reaction conditions for the palladium-cat- more effective in stabilizing the palladium complex. Con-
alyzed etherification of phenols focused on the coupling trol experiments showed that in the absence of either
of 2,6-di-tert-butyl-4-methylphenol and 4-chloroace- Pd(OAc)2 or LHBr, no reaction was observed.
tophenone (Table 1, entries 1–3). The coupling was tested
In conclusion, functional and bulky electron-rich NHC
in different bases, Na2CO3, K2CO3, Cs2CO3 and K3PO4.
ligand precursors with an imidazoline backbone, when
The best results for etherification of 2,6-di-tert-butyl-4-
combined with Pd(OAc)2, afford a highly active catalyst
for the etherification of phenol derivatives with aryl chlo-
rides. The ligand precursors 2a–c are particularly effec-
tive, and with 2.0 mmol% Pd, a variety of aryl halides and
methylphenol using 4-chloroacetophenone were obtained
at 100 °C in toluene using NaH as base, and a catalyst sys-
tem generated in situ from 2 mmol% of Pd(OAc)2 and 4%
mmol of LHBr 2a–c. Other solvents like dioxane, o-xy-
phenols react efficiently and with high selectivity. De-
lene or DMF provided lower yield of the product (up to
tailed investigations, focusing on imidazolin-2-ylidene
57%).
substituent effects, functional group tolerance and catalyt-
Table 1 summarizes representative results from screening ic activity in this and other coupling reactions are ongo-
the three imidazolinium salts (LHBr), for a variety of sub- ing.
strates that underwent etherification. Several trends are
readily apparent: The use of NHC ligand precursors 2a–c
allowed lower reaction temperatures (100 °C). Electron-
Acknowledgment
This work was financially supported by the Technological and Sci-
entific Research Council of Turkey [TÜBİTAK (106T106)], and
the İnönü University Research Fund (İ.Ü. B.A.P: 2008/10).
rich and electron-poor aryl chlorides reacted with phenols
in good to excellent yields and selectivities. Only for the
Synlett 2008, No. 12, 1781–1784 © Thieme Stuttgart · New York

LETTER
Palladium NHC Catalysts for Synthesis of Diaryl Ethers
1783
Table 1 Coupling of Aryl Chlorides with Various Phenols
Pd(OAc)2 (2 mol%)
LHBr (4 mol%)
OH
R
Cl
O
R
+
NaH, toluene
Rn
Rn
Entry
LHBr
Phenol
ArCl
Yield (%)a,b
O
C
1
2
3
2a
2b
2c
76
80
82
Me
Cl
OH
4
5
6
2a
2b
2c
70
74
75
MeO
Cl
7
8
9
2a
2b
2c
81
92
91
O
C
OH
Me
Me
Cl
Cl
Cl
Cl
Cl
10
11
12
2a
2b
2c
79
83
86
Cl
13
14
15
2a
2b
2c
82
93
95
O
C
Me
O
OH
Me
Me
16
17
18
2a
2b
2c
78
88
92
Cl
Cl
Cl
Cl
19
20
21
2a
2b
2c
88
94
96
O
C
O2N
OH
Me
Me
22
23
24
2a
2b
2c
76
82
81
25
26
27
2a
2b
2c
84
89
88
O
C
Me
Me
OH
28
29
30
2a
2b
2c
74
89
92
31
32
33
2a
2b
2c
72
79
77
O
C
Me
Me
OH
34
35
36
2a
2b
2c
78
75
77
a Reaction conditions: aryl chloride (1.0 mmol), phenol (1.1 mmol), NaH (1.4 mmol), Pd(OAc)2 (2.0 mol%), 2 (4.0 mol%), toluene (3 mL), 100
°C, 20 h.
b Yields are based on aryl chloride and all reactions were monitored by GC.
2004, 248, 2337. (c) Kunz, K.; Scholz, U.; Ganzer, D.
References and Notes
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Synlett 2008, No. 12, 1781–1784 © Thieme Stuttgart · New York

1784
M. Akkoç et al.
LETTER
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(1.1 mmol) was added and the resulting solution was stirred
for 1 h at r.t. and heated for 12 h at 80 °C. Et2O (10 mL) was
added to the reaction mixture. A white solid was precipitated
in this period. The precipitate was then crystallized from
EtOH–Et2O (1:2).
1-(2-Methoxyethyl)-3-(cyclohexylmethyl)imidazolinium
Bromide (2a): yield: 2.65 g (87%); mp 29 °C. IR: 1465
(C=N) cm–1. 1H NMR (300.13 MHz, CDCl3): d = 3.11 (s, 3
H, OMe), 3.38 (t, J = 4.8 Hz, 2 H, NCH2CH2O), 3.59 (t, J =
4.8 Hz, 2 H, NCH2CH2O), 3.79, 3.89 (m, 4 H, NCH2CH2N),
0.72–1.41 (m, 11 H, CH2C6H11), 3.15 (d, 2 H, CH2C6H11),
9.20 (s, 1 H, 2-CH). 13C NMR (75.46 MHz, DMSO): d =
47.3, 48.8 (NCH2CH2N), 68.6 (OMe), 58.5 (NCH2CH2O),
53.8 (NCH2CH2O), 49.2 (CH2C6H11), 25.0, 25.6, 34.9, 39.7
(CH2C6H11), 158.2 (2-CH). Anal. Calcd for C13H25N2OBr:
C, 51.15; H, 8.25; N, 9.18. Found: C, 51.23; H, 8.18; N, 9.24.
1-(2-Methoxyethyl)-3-(2,3,5,6-tetramethylbenzyl)im-
idazolinium Bromide (2b): yield: 3.22 g (91%); mp 156–
157 °C. IR: 1649 (C=N) cm–1. 1H NMR (300.13 MHz,
CDCl3): d = 2.20 [s, 6 H, CH2C6H(CH3)4-2,6], 2.22 [s, 6 H,
CH2C6H(CH3)4-3,5], 3.32 (s, 3 H, OMe), 3.60 (t, J = 8.0 Hz,
2 H, NCH2CH2O), 4.04 (t, J = 8.0 Hz, 2 H, NCH2CH2O),
3.76–3.81 (m, 4 H, NCH2CH2N), 4.89 [s, 2 H,
CH2C6H(CH3)4-2,3,5,6], 6.97 [s, 1 H, CH2C6H(CH3)4-
2,3,5,6], 9.22 (s, 1 H, 2-CH). 13C NMR (75.46 MHz, CDCl3):
d = 14.9 [CH2C6H(CH3)4-2,6], 19.5 [CH2C6H(CH3)4-3,5],
48.4 [CH2C6H(CH3)4-2,3,5,6], 47.0 (NCH2CH2N), 68.3
(OMe), 57.9 (NCH2CH2O), 45.9 (NCH2CH2O), 127.3,
131.8, 132.9, 133.7 [CH2C6H(CH3)4], 157.5 (2-CH). Anal.
Calcd for C17H27N2OBr: C, 57.47; H, 7.66; N, 7.88. Found:
C, 57.39; H, 7.61; N, 7.93.
1-(2-Methoxyethyl)-3-(2,3,4,5,6-pentamethylbenzyl)im-
idazolinium Bromide (2c): yield: 3.28 g (89%); mp 182–
183 °C. IR: 1648 (C=N) cm–1. 1H NMR (CDCl3): d = 2.22 [s,
6 H, CH2C6 (CH3)5-2,6], 2.25 [s, 3 H, CH2C6 (CH3)5-4], 2.30
[s, 6 H, CH2C6 (CH3)5-3,5], 3.35 (s, 3 H, OMe), 3.63 (t, J =
8.0 Hz, 2 H, NCH2CH2O), 4.09 (t, J = 8.0 Hz, 2 H,
NCH2CH2O), 3.83–3.88 (m, 4 H, NCH2CH2N), 4.91 [s, 2 H,
CH2C6(CH3)5-2,3,4,5,6], 9.15 (s, 1 H, 2-CH). 13C NMR
(75.46 MHz, CDCl3): d = 17.1 [CH2C6(CH3)5-2,3,5,6], 17.4
[CH2C6(CH3)5-4], 49.6 [CH2C6(CH3)5], 69.4 (OMe), 59.0
(NCH2CH2O), 48.3 (NCH2CH2O), 47.5, 48.2 (NCH2CH2N),
125.9, 133.6, 136.7 [CH2C6(CH3)5], 157.5 (2-CH). Anal.
Calcd for C18H29N2OBr: C, 58.53; H, 7.91; N, 7.58. Found:
C, 58.47; H, 7.81; N, 7.62.
General Procedure for the Diaryl Ether Formation: A
dried Schlenk tube was charged with NaH (1.4 mmol) and
purged with argon. The phenol (1.1 mmol) and toluene (3
mL) were added, and the mixture was stirred at 100 °C for
30 min under argon. The reaction mixture was cooled to r.t.
and the tube was charged with Pd(OAc)2 (2.0 mmol%), 1,3-
dialkyimidazolinium bromides 2 (4.0 mmol%) and aryl
chloride (1.0 mmol). The mixture was heated at 100 °C for
20 h. At the conclusion of the reaction, the mixture was
cooled, extracted with Et2O, filtered through a pad of silica
gel with copious washings, concentrated and purified by
flash chromatography on silica gel. The purity of the
compounds was checked by GC and yields are based on the
aryl chloride.
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Synlett 2008, No. 12, 1781–1784 © Thieme Stuttgart · New York