New functionalized N-heterocyclic carbene ligands for arylation of benzaldehydes

Article abstract of DOI:10.1002/jhet.48

Novel functionalized 1, 3-dialkylimidazolinium salts (LHCl) as NHC precursors have been prepared and successfully applied in palladium-catalyzed arylation of benzaldehydes. The ortho position of aromatic aldehydes was directly and selectively arylated wit

Full text of DOI:10.1002/jhet.48

186
New Functionalized N-Heterocyclic Carbene Ligands for
Arylation of Benzaldehydes
Vol 46
a
Oznur Dogan, Nevin Gu¨rbu¨z, Ismail Ozdemir, * and Bekir C¸ etinkaya
a
a
b
¨
¨
_
˘
a
¨ ¨
Department of Chemistry, Faculty Science and Art, Inonu University, 44280 Malatya, Turkey
bDepartment of Chemistry, Faculty Science, Ege University, 35100 Bornova-Izmir, Turkey
*E-mail: iozdemir@inonu.edu.tr
Received February 13, 2008
DOI 10.1002/jhet.48
Published online 23 March 2009 in Wiley InterScience (www.interscience.wiley.com).
Novel functionalized 1,3-dialkylimidazolinium salts (LHCl) as NHC precursors have been prepared
and successfully applied in palladium-catalyzed arylation of benzaldehydes. The ortho position of aro-
matic aldehydes was directly and selectively arylated with aryl chlorides in the presence of a catalytic
system prepared in situ from Pd(OAc)2, 1,3-dialkylimidazolinium chlorides (2a–c), and Cs2CO3.
J. Heterocyclic Chem., 46, 186 (2009).
INTRODUCTION
alkylated under palladium, ruthenium, or rhodium catal-
ysis [9]. However, aryl chlorides were rarely used,
despite the fact that chlorinated arenes are cheaper to
manufacture and therefore play a vital role as intermedi-
ates in the chemical industry. Presumably, this is due to
the fact that the chlorides were generally found to be
unreactive under the conditions employed to couple bro-
mides, iodides, and triflates.
The functionalization of aryl compounds is of major
importance in the field of modern arene chemistry
because of the ubiquity of aromatic and heteroaromatic
units in fine chemical intermediates, pharmaceutical,
agrochemicals, polymers, liquid crystals, new materials
[1], and ligands for homogeneous transition metal cata-
lysts [1]. Among the different aromatic functionalization
reactions, palladium-catalyzed coupling processes such
as the Heck [2], Suzuki [3], Kumada [4], Sonogashira
[5], Buchwald-Hartwig amination [6], and other CAC
and CAO bond forming reactions offer elegant possibil-
ities for the synthesis of substituted arenas. The main
advantages of the coupling processes are based on the
ready availability of starting materials, the simplicity
and generality of the methods, and the broad tolerance
of palladium catalysts toward various functional groups.
Therefore, the ability to couple an aryl halide directly at
the unreactive CAH position of an arene without the
need for a sacrificial electrophilic boron or tin fragment
would be highly desirable [7]. The selective functionali-
zation of CAH bonds has attracted substantial interest
due to potential shortening of synthetic sequences [8].
At present, development of methods for sp2 CAH bond
functionalization in directing-group containing arenas
and electron-rich heterocycles has received the most
attention. For a number directing group containing sub-
stances, the conversion of aromatic ortho-CAH bonds to
CAC bonds has been demonstrated. Compounds con-
taining amide, pyridine, oxazoline, imine, ketone, and
phenol directing groups have been ortho-arylated or
Recently, it has been shown that palladium complexes
of N-heterocyclic carbene [NHC] ligands offer distinct
advantages as possible alternatives for Pd/phosphine sys-
tems in CAC coupling reactions [10]. Thus, some highly
active palladium systems with monodentate carbene
ligands have been developed for the activation of aryl
chlorides [11].
We have previously reported the use of an in situ
formed imidazolidin-2-ylidene, tetrahydropyrimidin-2-
ylidene and tetrahydrodiazepin-2-ylidene, benzimidazol-
2-ylidene palladium(II) systems that exhibit high activity
for various coupling reactions of aryl bromides and aryl
chlorides [12]. Recently, we report that the in situ gen-
eration of catalysts, from [RuCl2(p-cymene)]2 and pyri-
midinium or benzimidazolium salt in the presence of
Cs2CO3, selectively promote the diarylation of 2-pyri-
dylbenzene with aryl bromides [13].
The nature of the NHC ligand has a tremendous influ-
ence on the rate of catalyzed reactions. To find more ef-
ficient palladium catalysts, we have prepared a series of
new bulky or functional 1,3-dialkylimidazolinium (2a–
c), containing imidazoline ring. Herein, we report a
Miaura coupling of aryl chlorides (Scheme 1) using a
C
V
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New Functionalized N-Heterocyclic Carbene Ligands for Arylation of Benzaldehydes
187
Scheme 1
as the solvent. Our initial exploration of the reaction
conditions for the palladium-catalyzed arylation of alde-
hydes focused on the coupling of benzaldehyde and 4-
chloroacetophenone [Table 1, entries 1–3]. The best
results for mono ortho-arylation of benzaldehydes using
4-chloroacetophenone were obtained at 100ꢁC in DMF
using Cs2CO3 as base, and a catalyst system generated
in situ from 1% mmol of Pd(OAc)2 and 2% mmol of
LHCl (2a–c).
mild practical in situ generated catalytic system com-
posed of commercially available and stable reagents,
Pd(OAc)2 as the palladium source, 1,3-dialkylimidazoli-
nium chloride (2a–c) as a carbene precursor, and
Cs2CO3 as a base.
Table
1 summarizes representative results from
screening the three imidazolinium salts (LHCl), for a
variety of substrates that undergo ortho-arylation. Sev-
eral trends are readily apparent: The use of NHC ligand
precursors 2a–c allowed lower reaction temperatures
(100ꢁC), and shorter reaction times. The procedure is
simple and does not require induction periods. All com-
plexes led to good conversions (79 to 95%) at low cata-
lyst concentration (1.0 mmol%). Although not dramatic,
consistent differences in yields were observed in the
reactions according to the ligand precursors 2a–c. Pre-
sumably, the bulkier ligands derived from 2a–c are
more effective in stabilizing the palladium complex.
This new method was compatible with the presence of
both electron-withdrawing and electron-donating groups
in the para position of the halobenzene. Table 1 also
shows that a diverse group of aromatic aldehydes can be
coupled. Control experiments showed that in the ab-
sence of either Pd(OAc)2 or LHCl, no reaction was
observed. It is worth noting that, in contrast to our
RESULTS AND DISCUSSION
1,3-Dialkylimidazolinium chlorides (2a–c) are con-
ventional NHC precursors. The functionalized or bulky
imidazolinium salts, 2a–c, were synthesized by consecu-
tive alkylation of 1-benzhydrylimidazoline (1) with alkyl
halides (Scheme 2).
According to Scheme 2, the salts (2a–c) were
obtained in almost quantitative yield by quarternization
of 1-benzhydrylimidazoline [1] in DMF with alkyl hal-
ides [14,15]. The salts are air- and moisture-stable both
in the solid state and in solution. The structures of 2a–c
were determined by their characteristic spectroscopic
data and elemental analyses. 13C NMR chemical shifts
are consistent with the proposed structure; the imino
carbon resonance appeared as a typical singlet in the
1H-decoupled mode at 157.8, 158.6, and 157.7 ppm,
1
respectively, for imidazolinium chlorides 2a–c. The H
Scheme 2. Synthesis of 1,3-dialkylimidazolinium chlorides (LHCl).
NMR spectra of the imidazolinium salts further sup-
ported the assigned structures; the resonances for C[2]-
H were observed as sharp singlets in the 8.75, 8.58, and
8.31 ppm, respectively, for 2a–c. The IR data for imida-
zolinium salts 2a–c clearly indicate the presence of the
AC¼¼NA group with a m(C¼¼N) vibration at 1636,
1650, and 1645 cmꢀ1, respectively, for 2a–c. The NMR
values are similar to those found for other 1,3-dialkyli-
midazolinium salts [15].
It is worth noting that in situ formation of the NHC
complex by deprotonation of the imidazolinium salt led
to significantly better results than the use of the pre-
formed complex. The success of these processes as well
as the recent reports by Miura and coworkers [16–19]
prompted us to examine whether in situ generated NHC
complexes could be used for the direct arylation of the
arene rings of aromatic aldehydes. Formyl groups are
synthetically very useful because they can be converted
to many other functional groups. Herein, we report a
mild, practical, Pd-catalyzed arylation of benzaldehydes
using air-stable Pd(OAc)2 as the catalyst, 1,3-dialkylimi-
dazolinium chlorides (LHCl, 2a–c, Scheme 2) as the
NHC ligand precursors, Cs2CO3 as the base, and DMF
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 1
Arylation of benzaldehyde derivatives by Pd-NHC complexes.
Entry
LHCl
R
Aromatic aldehyde
Product
Yielda,b (%)
1
2
3
2a
2b
2c
COCH3
COCH3
COCH3
84
87
89
4
5
6
2a
2b
2c
OCH3
OCH3
OCH3
83
88
90
7
8
9
2a
2b
2c
COCH3
COCH3
COCH3
89
95
92
10
11
12
2a
2b
2c
OCH3
OCH3
OCH3
79
82
83
13
14
15
2a
2b
2c
COCH3
COCH3
COCH3
92
94
92
16
17
18
2a
2b
2c
OCH3
OCH3
OCH3
84
91
89
19
20
21
2a
2b
2c
COCH3
COCH3
COCH3
82
87
85
22
23
24
2a
2b
2c
OCH3
OCH3
OCH3
80
79
80
a Reactions conditions: 1.0 mmol of R-C6H4Cl-p, 1.0 mmol of aldehyde, 2 mmol Cs2CO3, 1.0 mmol% Pd(OAc)2, 2 mmol% 1,3-dialkylimidazoli-
nium salt, DMF (3 mL), 100ꢁC, 15 h.
b Yield determined by NMR and GC, purity of compounds was checked by NMR and yields are based on the aldehyde.

March 2009
New Functionalized N-Heterocyclic Carbene Ligands for Arylation of Benzaldehydes
189
Preparation of 1-benzhydryl-3-(ethoxyethyl)imidazoli-
nium chloride (2c). This compound was prepared from 1-
(benzhydryl)imidazolin (2 g, 9.6 mmol) and 2-ethoxyethyl
chloride (1.15 g, 10.5 mmol) in DMF (3 mL). Yield: 2.70 g
(89%), ir: 1645 cmꢀ1 (C¼¼N). 1H NMR (d, CDCl3): 0.89 (t,
3H, J ¼ 5.7 Hz, OCH2CH3), 3.31 (q, 2H, J ¼ 5.7 Hz,
OCH2CH3), 3.46 (t, 2H, J ¼ 4.2 Hz, NCH2CH2O), 3.58 (t,
findings, arylation of benzaldehyde with 4-bromoanisole
in the presence of Ni(dppe)Br2/Zn has been reported to
give diaryl carbinols [20].
The palladium-catalyzed arylation of carbonyl com-
pounds or phenols, reported by Miura is considered to
proceed via coordination between the phenolate or eno-
late oxygen of the substrates and the arylpalladium in-
termediate [16]. Consequently, one may expect that oxy-
gen from the aldehyde may function as a phenolate
oxygen.
2H,
J
¼
3.9 Hz, CH2CH2O), 3.73 and 4.04 (m, 4H,
NCH2CH2N), 6.26 (s, 1H, CH(C6H5)2), 6.96–7.59 (m, 10H,
Ar), 8.31 (s, 1H, 2ACH). 13C NMR (d, CDCl3): 14.9
(OCH2CH3), 47.8 (OCH2CH3), 65.5 (NCH2CH2O), 66.2
(NCH2CH2O), 48.3 and 49.9 (NCH2CH2N); 66.4 (CH(C6H5)2);
128.3, 128.8, 129.2, and 135.7 (Ar), 157.8 (2ACH). Anal.
Calcd. for C20H25N2OCl: C, 69.65; H, 7.31; N, 8.12. Found:
C, 69.66; H, 7.29; N, 8.11.
EXPERIMENTAL
General procedure for arylation of benzaldehyde
derivatives. A dried Schlenk flask equipped with a magnetic
stirring bar was charged with the aldehyde (1.0 mmol), aryl
chloride (1.0 mmol), Pd(OAc)2 (0.01 mmol), imidazolinium
chloride (0.02 mmol), Cs2CO3 (2.0 mmol), and DMF (3 mL).
After stirring at 100ꢁC for 15 h, the mixture was cooled to
room temperature and then quenched by addition of aqueous
1N HCl and extracted with diethyl ether. The isolated organic
layer was dried over MgSO4, filtered, concentrated in vacuo,
and purified by column chromatography on silica gel eluting
with ethyl acetate/hexane (1:5). Analysis of the reaction prod-
uct was carried out by NMR and GC-MS.
All reactions for the preparation of 1,3-dialkylimidazolinium
salts [2a–c] were carried out under argon using standard
Schlenk-type flasks. All reagents were purchased from Aldrich
Chemical (Istanbul). The solvents, Et2O over Na, DMF over
BaO, EtOH over Mg were distilled before use. All H and 13C
1
NMR experiments were performed in CDCl3. 1H NMR and
13C NMR spectra were recorded using a Bruker AC300P FT
spectrometer operating at 300.13 MHz (1H), 75.47 MHz (13C).
Chemical shifts (d) are given in ppm relative to TMS, cou-
pling constants (J) in Hz. Melting points were measures in
open capillary tubes with an Electrothermal-9200 melting point
apparatus and are uncorrected. Elemental analyses were per-
formed by TUBITAK (Ankara, Turkey) Microlab.
Acknowledgments. This work was financially supported by the
Technological and Scientific Research Council of Turkey
Preparation of 1-benzhydryl-3-(2,4,6-trimethylbenzyl)-
imidazolinium chloride (2a). To a solution of 1-(benzhydryl)
imidazolin (2.0 g, 9.6 mmol) in DMF (3 mL), 2,4,6-tri-methyl-
benzylchloride (1.78 g, 10.5 mmol) was added; the resulting
solution was stirred for 1 h at room temperature and heated
for 12 h at 80ꢁC. Et2O (10 mL) was added to the reaction
mixture. A white solid precipitated during this period. The pre-
cipitate was then crystallized from EtOH/Et2O (1:2). Yield:
3.12 g (86%), mp 209–210ꢁC; ir: 1636 cmꢀ1 (C¼¼N). 1H
NMR (d, CDCl3): 2.19 (3H, CH2C6H2(CH3)3-4), 2.26 (s, 6H,
CH2C6H2(CH3)3-2,6), 3.88 (s, 4H, NCH2CH2N), 5.79 (s, 2H,
CH2A(C6H2)A(CH3)3-2,4,6), 6.80 (s, 2H, CH2A(C6H2)
A(CH3)3), 6.45 (s, 1H, CH(C6H5)2), 7.26–7.37 (m, 10H, Ar),
8.75 (s,1H, 2ACH). 13C NMR (d, CDCl3): 21.1 (CH2C6H2
(CH3)3-4), 20.3 (CH2C6H2(CH3)3-2,6), 47.1 (CH2A(C6H2)A
(CH3)3-2,4,6), 48.0 and 48.7 (NCH2CH2N), 65.9 (CH(C6H5)2),
125.5, 128.6, 129.1, 129.5, 139.9, 135.9, 139.0, and 139.3 (Ar),
157.8 (2ACH). Anal. Calcd. for C26H29N2Cl: C, 72.54; H, 7.23;
N, 6.59. Found: C, 72.56; H, 7.28; N, 6.55.
Preparation of 1-benzhydryl-3-(methoxyethyl)-imidazoli-
nium chloride (2b). This compound was prepared from 1-
(benzhydryl)imidazolin (2 g, 9.6 mmol) and 2-methoxyethyl
chloride (1.0 g, 10.5 mmol) in DMF (3 mL). Yield:2.65 g
(91%), mp 144–145ꢁC; ir: 1650 cmꢀ1 (C¼¼N). 1H NMR (d,
CDCl3): 3.25 (s, 3H, OCH3), 3.57 (t, 2H, J ¼ 4.4 Hz,
NCH2CH2O), 3.78 (t, 2H, J ¼ 4.4 Hz, NCH2CH2O), 3.89 and
4.13 (m, 4H, NCH2CH2N), 6.37 (s, 1H, CH(C6H5)2), 7.32 (m,
10H, Ar); 8.58 (s, 1H, 2ACH). 13C NMR (d, CDCl3): 48.3
and 48.8 (NCH2CH2N), 59.3 (OCH3), 66.1 (NCH2CH2O), 50.3
(NCH2CH2O), 69.0 (CH(C6H5)2), 128.9, 129.3, 129.7, and
136.1 (Ar), 158.6 (2ACH). Anal. Calcd. for C19H23N2OCl: C,
68.97; H, 7.01; N, 8.47. Found: C, 68.93; H, 6.98; N, 8.50.
¨
_
TUBITAK [(106T106)], TUBITAK-CNRS (France) [TBAG-U/
¨
_
_ ¨
¨ ¨
181 (106T716)], and Inonu University Research Fund (I.U.
B.A.P: 2008/39).
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