A comparative study of hydroxyl- and carboxylate-functionalized imidazolium and benzimidazolium salts as precursors for N-heterocyclic carbene ligands

Article abstract of DOI:10.1002/aoc.3343

The preparation of imidazolium and benzimidazolium salts with hydroxyl or carboxylate functions has been achieved using straightforward synthetic pathways. These salts in combination with palladium(II) acetate give active catalytic systems for Suzuki reac

Full text of DOI:10.1002/aoc.3343

Full Paper
Received: 1 April 2015
Revised: 13 May 2015
Accepted: 20 May 2015
Published online in Wiley Online Library: 15 July 2015
(wileyonlinelibrary.com) DOI 10.1002/aoc.3343
A comparative study of hydroxyl- and
carboxylate-functionalized imidazolium and
benzimidazolium salts as precursors for
N-heterocyclic carbene ligands
Andrés Allegue, María Albert-Soriano and Isidro M. Pastor*
The preparation of imidazolium and benzimidazolium salts with hydroxyl or carboxylate functions has been achieved using
straightforward synthetic pathways. These salts in combination with palladium(II) acetate give active catalytic systems for Suzuki
reaction. A comparative study has been performed, which has revealed that both the heterocycle and the functional group are
important for the catalytic activity and stability of the catalyst. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: N-heterocyclic carbenes; imidazolium; benzimidazolium; palladium; Suzuki–Miyaura
carbenes have been less considered. In the case of 1,3-
dimethylbenzimidazolium derivative, similar versatility and effi-
Introduction
The study and development of catalytic systems involving transi-
tion metals for organic transformations is a field of interest in syn-
thetic organic chemistry. In this context, the use of N-heterocyclic
carbenes (NHCs) as ligands for transition metal catalysis has experi-
enced a growing importance during the last few decades.[1] These
types of ligands are unique due to their tunable steric and elec-
tronic properties.[2] Among the various applications for metal–
NHC complexes, metal-catalysed cross-coupling reactions have
been widely explored, palladium being the most used metal.[3]
The preparation of catalysts with NHC ligands, in many cases, needs
inert atmosphere and anhydrous reaction conditions.[4] However,
Organ and co-workers have described the preparation of stable
Pd–NHC complexes by the introduction of a pyridine ligand, de-
scribed as PEPPSI (pyridine-enhanced precatalyst preparation stabi-
lization and initiation).[5] Also, as an interesting alternative, active
catalysts have been prepared in situ, by mixing a metal source
and the corresponding NHC precursor.[6] The main precursors for
NHCs are azolium salts, and particularly imidazolium derivatives.
Moreover, imidazole can be functionalized by the introduction of
functional groups on the side chains (on the nitrogens), generating
precursors for functionalized NHCs.[7] In this regard, various func-
tional groups have been included in order to modify the physical
and chemical properties of the resulting NHCs.[8]
ciency of the ligand compared with the imidazole analogue has
been reported.[10] The steric effect of N-substituents has been
considered for benzimidazolium derivatives. Thus, Yaşar and
co-workers have described the preparation of 1,3-
dialkylbenzimidazolium chlorides, bearing various benzyl and
phenethyl substituents, as precursors of palladium carbene ligands
for catalysis.[11] Additionally, this type of dialkylbenzimidazolium
salt has been employed in the preparation of well-defined
palladium(II) complexes of PEPPSI type.[12] The use of bulkier sub-
stituents, such as N,N-diadamantylbenzimidazolium salts, has been
reported by Organ and co-workers, also considered in the study be-
ing the influence of substituents (with different electronic proper-
ties) in positions C5 and C6 of benzimidazole.[13] Moreover,
benzimidazole carbene sulfonamidate from binaphthyl-2,2′-
diamine[14] and various bis-benzimidazolium derivatives[15] have
been considered as potential carbene and bis-carbene ligands,
respectively. Regarding functionalized benzimidazole-based NHC
ligands, Huynh and co-workers have described the preparation of
different thioether-functionalized benzimidazol-2-ylidene ligands.[16]
Furthermore, palladium complexes from imidazolium and
benzimidazolium salts bearing alkyl–aryl thioether functions have
been compared in the Suzuki reaction, the thioether group acting
as a hemilabile ligand.[17]
The coupling between boronic acid derivatives and organic elec-
trophiles (Suzuki–Miyaura reaction) is one of the preferred reactions
for carbon–carbon bond formation, due to the stability and non-
toxicity of the boron reagents. Moreover, there are other appealing
features of this transformation, such as substrate tolerance and mild
reaction conditions. So, Suzuki coupling can be taken as an easy
and typical cross-coupling benchmark reaction[9] in order to
compare the efficiency of catalytic systems prepared from palla-
dium together with various functionalized imidazolium and
benzimidazolium derivatives. The catalytic activity of NHCs based
on imidazole has been examined,[3] while benzimidazole-based
The chemical stability of carbenes and carbene complexes is di-
rectly related to the population of the carbon p(π) orbital,[18] so dif-
ferent activities for imidazolium and benzimidazolium derivatives
should be expected. Also, the comparison of the catalytic activity
*
Correspondence to: Isidro M. Pastor, Organic Chemistry Department, Faculty of
Sciences and Instituto de Síntesis Orgánica (ISO), University of Alicante,
Apartado 99, 03080 Alicante, Spain. E-mail: ipastor@ua.es
Organic Chemistry Department, Faculty of Sciences and Instituto de Síntesis
Orgánica (ISO), University of Alicante, Apartado 99, 03080, Alicante, Spain
Appl. Organometal. Chem. 2015, 29, 624–632
Copyright © 2015 John Wiley & Sons, Ltd.

Comparative study of functionalized imidazolium and benzimidazolium salts
of functionalized imidazolium and benzimidazolium is relevant.
Herein, we report our findings on the effectiveness of various
imidazolium and benzimidazolium salts functionalized with hy-
droxyl and carboxylate moieties as precursors of NHCs. In addition,
the catalytic systems formed in combination with palladium(II) ace-
tate are compared in the Suzuki reaction.
1494 (C¼N); δH (300 MHz, CD3OD): 3.93 (2H, qd, J = 9.8, 5.3 Hz,
NCH2), 4.24–4.35 (1H, m, CHO), 4.36–4.46, 4.53 (1H, 1H, m, dd, J =
14.4, 3.8, CH2O), 6.86–7.02 (3H, m, ArH), 7.19–7.33 (4H, m, ArH)
7.53–7.61 (1H, m, ArH), 7.62–7.70 (1H, m, ArH), 8.13 (1H, s, NCHN);
δC (75 MHz, CD3OD): 48.8 (NCH2), 69.4 (CHOH), 70.1 (CH2O), 111.6,
115.6, 120.0, 122.2, 123.4, 124.2, 130.6 (ArCH), 135.4, 143.8 (ArC),
145.6 (NCHN), 159.9 (ArC–Ph); m/z (HPLC-ESI): 269 [M]+, MS2 [269]:
159 (20%), 119 (100%).
2-(Benzo[d]imidazol-1-yl)cyclohexanol (6). Off white solid; m.p.
156–158°C (acetone–hexane); Rf 0.74 (MeOH–AcOEt, 2:1); ν 1496
(C¼N); δH (300 MHz, CDCl3): 1.32–1.63, 1.67–1.95 (3H, 3H, 2m, CH2
ring), 2.01 (1H, d, J = 12.8 Hz, CH2 ring), 2.15–2.30 (1H, m, CH2 ring),
3.87–4.06 (2H, m, NCHCHO), 5.70 (1H, s, OH), 7.09 (1H, t, J = 7.6 Hz,
ArH), 7.20 (1H, t, J = 7.6 Hz, ArH), 7.37–7.49 (3H, m, ArH and NCHN);
δC (75 MHz, CDCl3): 24.6, 25.4, 32.0, 34.6 (CH2 ring), 62.6 (CHNCHO),
72.3 (CHO), 110.8, 119.5, 122.2, 122.7 (ArCH), 133.9, 140.8 (ArC),
142.9 (NCHN); m/z (HPLC-ESI): 217 [M]+, MS2 [217]: 119 (100%).
Experimental
All commercially available reagents and solvents were purchased
(Acros, Aldrich, Fluka) and used without further purification.
Ultrasound-irradiated reactions were performed using a Selecta
Ultrasons bath (6 l, 150 W). The optimization reactions were carried
out with a Carrousel 12 Plus™ Reaction Station. Melting points were
determined with a Reichert Thermovar hot plate apparatus and are
1
uncorrected. H NMR and 13C NMR spectra were recorded at the
technical service of the University of Alicante (SSTTI – UA),
employing a Bruker AC-300 or a Bruker Advance-400. CDCl3 was
employed as solvent, unless otherwise stated, and tetrame-
thylsilane as internal reference. Chemical shifts (δ) are given in
ppm and the coupling constants (J) in Hz. Low-resolution mass
spectra (EI) were obtained at 70 eV with an Agilent 5973 Network
spectrometer, with fragment ions m/z reported with relative inten-
sities (%) in parentheses. Low-resolution HPLC with electrospray
ionization (HPLC-ESI) mass spectra were recorded at the technical
service of the University of Alicante (SSTTI – UA), employing an
Agilent 1100 series apparatus with the possibility of MS/MS.
Infrared spectra were recorded with an FT-IR 4100 LE (JASCO, Pike
Miracle ATR) spectrometer. Spectra were recorded from neat sam-
Hydroxyl-Functionalized Imidazolium and Benzimidazolium
Chlorides
In a round-bottom flask, the hydroxyl-functionalized imidazolium
(1 or 2) or benzimidazolium (5 or 6) (5 mmol), acetonitrile (10 ml)
and benzyl chloride (1.1 eq., 5.5 mmol) were added. The mixture
was refluxed with stirring for 16 h. Finally the solvent was removed
under reduced pressure and the product was purified by recrystal-
lization from acetone.
1-Benzyl-3-(2-hydroxy-2-phenylethyl)imidazolium chloride (3).
White solid; m.p. 190–192°C (acetone); Rf 0.48 (AcOEt–MeOH, 1:1);
ν 1561 (C¼N); δH (400 MHz, CD2Cl2): 4.34 (1H, dd, J = 13.7, 7.1 Hz,
NCHHCH), 4.72 (1H, dd, J = 13.7, 3.1 Hz, NCHHCH), 5.05–5.16 (1H,
m, CHOH), 5.27 (2H, s, NCH2Ph), 6.58 (1H, d, J = 5.7 Hz, OH), 6.93
(1H, t, J = 1.8 Hz, CHCH), 7.00 (1H, t, J = 1.7 Hz, CHCH), 7.16–7.38
(10H, m, ArH), 9.94 (s, 1H, NCHN); δC (100 MHz, CDCl3): 53.3, 56.9
(NCH2Ph; NCH2CHOH), 70.9 (CHOH), 120.6, 123.5, 126.0, 127.8,
128.5, 128.7, 129.4 (ArC), 132.7, 137.4 (NCHCHN, NCHCHN), 140.0
(NCHN).
ples, without further preparation, and results are given in cmꢀ1
.
Analytical TLC was performed on Merck aluminium sheets with sil-
ica gel 60 F254, 0.2 mm thick. Silica gel 60 (0.04–0.06 mm) was
employed for flash chromatography. The conversion of the reac-
tions and purity of the products were determined by GC analysis
using a Younglin 6100GC, equipped with a flame ionization detec-
tor and a Phenomenex ZB-5MS column (5% PH-ME siloxane): 30 m
(length), 0.25 mm (inner diameter) and 0.25 μm (film).
1-Benzyl-3-(2-hydroxycyclohexyl)imidazolium chloride (4). White
solid; m.p. 153–155°C (acetone); Rf 0.56 (AcOEt–MeOH, 2:1); ν 1557
(C¼N); δH (300 MHz, CDCl3): 1.20–1.60, 1.65–1.95, 2.00–2.20 (3H,
3H, 2H, 3m, 4 × CH2 ring), 2.75–3.10 (1H, br s, OH), 3.60–3.80,
4.22–4.37 (1H, 1H, 2m, NCHCO, CHOH), 5.45 (1H, d, J = 14.5 Hz,
PhCHH), 5.52 (1H, d, J = 14.5 Hz, PhCHH), 7.22–7.29, 7.31–7.39,
7.39–7.51 (1H, 3H, 3H, 3m, ArH and NCHCHN), 10.06 (1H, s, NCHN);
δC (75 MHz, CDCl3): 24.2, 24.7, 31.5, 34.5 (CH2 ring), 53.3 (CH2Ph),
66.1 (NCHCHOH), 72.1 (HOCH), 120.9, 121.4 (NCHCHN), 129.1,
129.3(5), 129.4(1) (ArCH), 133.3 (ArC), 136.6 (NCHN); m/z (HPLC-ESI):
257 [M ꢀ Cl]+, MS2 [257]: 159 (100%), 91 (60).
Hydroxyl-Functionalized Imidazoles and Benzimidazoles
Imidazole or benzimidazole (10 mmol) and the corresponding
epoxide (10 mmol) were placed into a high-pressure flask. The neat
mixture was stirred at 60°C for 16 h and the product was purified
from the crude reaction by recrystallization from acetone–hexane.
2-(Imidazol-1-yl)-1-phenylethanol (1). Off white solid; m.p.
130–134°C (acetone–hexane); Rf 0.72 (MeOH–AcOEt, 2:1); ν 3139,
3118 (CH2); δH (300 MHz, CDCl3): 4.07–4.13 (2H, m, CH2), 4.91 (1H,
dd, J = 7.0, 4.6 Hz, CHOH), 6.88, 6.92 (2H, 2s, NCHCHN), 7.28–7.40
(6H, m, NCHN, ArH); δC (75 MHz, CDCl3): 55.3 (NCH2), 74.2 (CHO),
121.5, 127.1, 128.4, 129.4, 129.7, 139.0 (ArC, ArCH, NCHCHN), 143.0
(NCHN); m/z (HPLC-ESI): 189 [M]+, MS2 [189]: 69 (100%).
2-(Imidazol-1-yl)cyclohexanol (2). White solid; m.p. 120–124°C
(acetone–hexane); Rf 0.67 (MeOH–AcOEt, 2:1); ν 1500 (C¼N); δH
(300 MHz, CDCl3): 1.26–1.51, 1.58–1.76, 1.76–1.90, 1.98–2.10, 2.11–
2.22 (3H, 1H, 2H, 1H, 1H, 2H, 5m, CH2 ring), 3.53–3.76 (2H, m,
NCHCHO), 6.86, 6.91 (1H, 1H, 2s, NCHCHN), 7.35 (1H, s, NCHN); δC
(75 MHz, CDCl3): 24.5, 25.2, 32.4, 34.3 (CH2 ring), 64.0 (CHN), 73.0
(CHO), 117.3, 128.6 (NCHCHN), 136.3 (NCHN); m/z (HPLC-ESI): 167
[M]+, MS2 [167]: 69 (100%).
1-Benzyl-3-(2-hydroxy-3-phenoxypropyl)benzimidazolium chlo-
ride (7). Off white solid; m.p. 97–100°C (acetone); ν 1551 (C¼N); δH
(300 MHz, CDCl3): 3.86 (1H, t, J = 9.1 Hz, NCHHCHOH), 4.19 (1H,
dd, J = 9.6, 4.5 Hz, NCHHCHOH), 4.59 (1H, m, CHOH), 4.87–5.01
(2H, m, OCH2), 5.78 (2H, s, NCH2Ph), 6.48 (1H, d, J = 6.7 Hz, OH),
6.87 (2H, dd, J = 8.7, 0.9 Hz, ArH), 6.96 (1H, t, J = 7.4 Hz, ArH),
7.20–7.55 (10H, m, ArH), 7.63–7.80 (1H, m, ArH), 10.94 (1H, s, NCHN);
δC (75 MHz, CDCl3): 50.1, 51.7 (NCH2), 67.0 (CHOH), 68.3 (OCH2),
113.2, 113.7, 114.6, 121.3, 126.9, 127.0, 128.2, 129.2, 129.4, 129.6
(ArCH), 131.0, 132.2, 132.7 (ArC), 143.9 (NCHN), 158.0 (ArC-O); m/z
(HPLC-ESI): 359 [M ꢀ Cl]+, MS2 [359]: 265 (18%), 249 (24), 222
(100), 221 (25), 209 (53), 207 (21), 145 (18), 133 (12), 132 (15), 131
(78), 119 (40).
1-(Benzo[d]imidazol-1-yl)-3-phenoxypropan-2-ol (5). Brown solid;
m.p. 139–141°C (acetone–hexane); Rf 0.79 (MeOH–AcOEt, 2:1); ν
Appl. Organometal. Chem. 2015, 29, 624–632
Copyright © 2015 John Wiley & Sons, Ltd.
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A. Allegue et al.
1-Benzyl-3-(2-hydroxycyclohexyl)benzimidazolium chloride (8).
Off white solid; m.p. 211–214°C (CH3CN–Et2O); Rf 0.69 (AcOEt–
MeOH, 2:1); ν 1555 (C¼N); δH (300 MHz, CDCl3): 1.36–1.72, 1.74–
1.99, 2.15–2.35 (3H, 3H, 2H, 3m, 4 × CH2 ring), 4.37–4.53 (2H, m,
CH2), 5.73 (1H, d, J = 15.2 Hz, PhCHH), 5.75 (1H, s, OH), 5.84 (1H, d,
J = 15.2 Hz, PhCHH), 7.31–7.40 (3H, m, ArH), 7.43–7.58 (5H, m,
ArH), 7.78 (1H, d, J = 8.1 Hz, ArH), 11.32 (1H, s, NCHN); δC (75 MHz,
CDCl3): 24.1, 24.9, 32.3, 34.7 (CH2 ring), 51.6 (CH2Ph), 64.7
(NCHCHOH), 69.9 (CHOH), 113.6, 113.7, 126.6, 126.7, 128.4, 129.1,
129.3 (ArCH), 131.2, 131.9, 132.9 (ArC), 142.6 (NCHN); m/z (HPLC-
ESI): 307 [M ꢀ Cl]+, MS2 [307]: 289 (12%), 209 (100), 131 (18), 91 (39).
room temperature. The resultant solid was filtered and washed with
dichloromethane (3 × 10 ml) and then dried under vacuum.
2-(3-Methylimidazol-3-ium-1-yl)acetate (13). White solid; m.p.
250–260°C (dec., CH2Cl2); Rf 0.51 (MeOH–H2O, 4:1); ν 1618 (C¼N);
δH (300 MHz, D2O): 3.89 (3H, s, CH3), 4.81 (2H, s, CH2), 7.41, 7.40
(2H, 2s, NCHCHN), 8.68 (1H, s, NCHN); δC (75 MHz, D2O): 36.6 (CH3),
52.4 (CH2), 124.0, 124.2 (NCHCHN), 137.8 (NCHN), 172.9 (COOꢀ);
m/z (HPLC-ESI): 141 [M ꢀ Cl]+, MS2 [141]: 123 (100%), 95 (69).
2-(Methylbenzimidazol-3-ium-1-yl)acetate (14). White solid; m.p.
250–260°C (dec., CH2Cl2); Rf 0.58 (MeOH–H2O, 4:1); ν 1608 (C¼N); δH
(300 MHz, D2O): 4.15 (3H, s, CH3), 5.04 (2H, s, CH2), 7.65–7.73 (2H, m,
ArH), 7.82–7.89 (1H, m, ArH), 7.90–7.96 (1H, m, ArH), 9.44 (1H, s,
NCHN); δC (75 MHz, D2O): 32.6 (CH3), 49.0 (CH2), 112.4, 112.6,
126.4, 126.6 (ArCH), 131.0, 131.4 (ArC), 141.7 (NCHN), 171.5 (COOꢀ);
m/z (HPLC-ESI): 191 [M ꢀ Cl]+, MS2 [191]: 173 (39%), 146 (67), 145
(100), 133 (22), 132 (12), 121 (20), 119 (13).
1-Methoxycarbonylmethyl-3-methylimidazolium and
1-Methoxycarbonylmethyl-3-benzimidazolium Chlorides
1-Methylimidazole or 1-methylbenzimidazole (10 mmol) and
methyl chloroacetate (10 mmol) were added to a high-pressure
flask, and the mixture was placed into an ultrasound bath during
1 h (for imidazole) or 2 h (for benzimidazole). The resultant solid
was washed with diethyl ether.
Cross-Coupling Reaction. Typical Procedure
In a vessel, aryl bromide (3 mmol) was added to a solution of
boronic acid (3.6 mmol), palladium(II) acetate (0.003 mmol), the
corresponding azolium salt (0.003 or 0.006 mmol) and the base
(12 mmol) in MeOH (6 ml). The resulting mixture was refluxed for
3 h, and after allowing the reaction mixture to cool to room temper-
ature, it was extracted with EtOAc (3 × 10 ml). The combined or-
ganic layers were dried over anhydrous MgSO4 and the organic
solvent was removed under reduced pressure. The crude products
were purified by column chromatography (silica gel, mixture of
EtOAc and hexane). For physical, spectroscopic and analytical data,
as well as literature references, see the supporting information.
1-(Methoxycarbonylmethyl)-3-methylimidazolium chloride (9).
White solid; m.p. 123–126°C (Et2O); Rf 0.5 (MeOH); ν 1755 (C¼N);
δH (300 MHz, CDCl3): 3.73 (3H, s, NCH3), 4.03 (3H, s, OCH3), 5.54
(2H, s, CH2), 7.59, 7.79 (1H, 1H, 2t, J = 1.7 Hz, CHCH), 10.27 (1H, s,
NCHN); δC (75 MHz, CDCl3): 36.8 (NCH3), 50.1 (CH2), 53.4 (OCH3),
123.1, 124.1 (CHCH), 138.7 (NCHN), 166.9 (COOMe); m/z (HPLC-
ESI): 155 [M ꢀ Cl]+, MS2 [155]: 95 (100%).
1-(Methoxycarbonylmethyl)-3-methylbenzimidazolium chloride
(10). White solid; m.p. 149–152°C (dec., Et2O); Rf 0.46 (MeOH); ν
1741 (C¼N); δH (400 MHz, D2O): 3.91 (3H, s, CH3O), 4.18 (3H, s,
CH3N), 5.54 (2H, s, CH2), 7.72–7.79, 7.83–7.89, 7.89–7.95 (2H, 1H,
1H, 3m, ArH); δC (100 MHz, D2O): 33.8 (NCH3), 48.0 (CH2), 54.3
(OCH3), 113.5, 113.8, 127.8, 128.0 (ArCH), 131.9, 132.3 (ArC), 142.9 Results and Discussion
(NCHN), 169.0 (CO2H); m/z (HPLC-ESI): 205 [M ꢀ Cl]+, MS2 [205]:
Preparation of Imidazolium and Benzimidazolium Salts
145 (100%).
The regioselective ring opening of epoxides constitutes one of the
most general methods for the synthesis of hydroxyl-functionalized
imidazoles and benzimidazoles. Based on this methodology,[19] im-
idazole was reacted with styrene oxide or cyclohexene oxide pro-
ducing the corresponding functionalized imidazoles 1 and 2 with
76 and 60% isolated yield, respectively. These imidazoles were sub-
sequently reacted with benzyl chloride, in MeCN at 80°C, yielding
the imidazolium chlorides 3 and 4 in 54 and 93% isolated yield, re-
spectively (Scheme 1). Likewise, benzimidazole produced the corre-
sponding benzimidazole derivatives 5 and 6 and the hydroxyl-
functionalized salts 7 and 8 by ring opening of 2-(phenoxymethyl)
oxirane or cyclohexene oxide and subsequent quaternization with
benzyl chloride (Scheme 1). Both benzimidazolium salts were ob-
tained with better overall isolated yields than the imidazolium ones.
1-Carboxymethyl-3-methylimidazolium and
1-Carboxymethyl-3-benzimidazolium Chlorides
In a high-pressure flask, the methyl acetate derivative 9 or 10 (10
mmol) and concentrated HCl (37%, 0.8 ml, 10 mmol) were added,
and the resulting mixture was refluxed during 1 h. The resultant
solid was washed with acetone and diethyl ether.
1-Carboxymethyl-3-methylimidazolium chloride (11). White
solid; m.p. 184–187°C (CH2Cl2); Rf 0.44 (MeOH); ν 1721 (C¼N); δH
(300 MHz, CDCl3): 3.93 (3H, s, CH3), 5.11 (2H, s, CH2), 7.48 (1H, t, J =
1.8 Hz, CHCH), 7.50 (1H, t, J = 1.8 Hz, CHCH), 8.79 (1H, s, NCHN); δC
(75 MHz, CDCl3): 35.9 (CH3), 49.9 (CH2), 123.4 (CHCH), 137.3 (NCHN),
170.0 (COOH); m/z (HPLC-ESI): 141 [M ꢀ Cl]+, MS2 [141]: 95 (100%).
1-Carboxymethyl-1-methylbenzimidazolium chloride (12). White
solid; m.p. 225°C (dec., CH2Cl2); Rf 0.36 (MeOH); ν 1720 (C¼N); δH
(300 MHz, D2O): 4.07 (3H, s, CH3), 5.36 (2H, s, CH2), 7.59–7.68 (2H,
m, ArH), 7.71–7.77 (1H, m, ArH), 7.71–7.84 (1H, m, ArH), 9.28 (1H, s,
NCHN); δC (75 MHz, D2O): 33.2 (CH3), 47.5 (CH2), 112.8, 113.1,
127.0, 127.2 (ArCH), 131.3, 131.6 (2 × ArC), 142.4 (NCHN), 169.7
(COOH); m/z (HPLC-ESI): 191 [M ꢀ Cl]+, MS2 [191]: 145 (100%).
Zwitterionic Imidazolyl and Benzimidazolyl Acetates
The imidazole or benzimidazole derivative 11 or 12 (10 mmol), di-
chloromethane (15 ml) and triethylamine (TEA; 10 mmol) were
added to a reaction tube. The mixture was stirred during 1 day at
Scheme 1. Synthesis of hydroxyl-functionalized imidazolium and
benzimidazolium derivatives.
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Appl. Organometal. Chem. 2015, 29, 624–632

Comparative study of functionalized imidazolium and benzimidazolium salts
The preparation of carboxylate-functionalized salts was per-
formed following another strategy starting from 1-methylimidazole
and 1-methylbenzimidazole. Their reaction with methyl chloroace-
tate, in an ultrasound bath, produced the expected imidazolium
and benzimidazolium chlorides 9 and 10, which were finally hydro-
lysed to the zwitterionic compounds 13 and 14 by subsequent acid
treatment (37% aqueous HCl, producing salts 11 and 12), and basic
treatment with TEA (Scheme 2).
bromide (TBAB) and cetyltrimethylammonium bromide (CTAB) be-
ing selected.
For the comparative study, we decided to conduct a design of
experiments approach,[21] which allowed us to check the maximum
range of variables in a minimum set of assays providing valuable in-
formation concerning the critical factors and best combinations to
obtain the highest yield of 1-phenylnaphthalene (15). The selection
of experiments was carried out according to a Taguchi L25 array.
Table 2 collects the results obtained for the azolium salts 3, 7 and
13. Those azolium salts were chosen, at the outset, to cover the li-
gand diversity in this work; thus salts 3 and 13 present an imidazole
ring in comparison with salt 7 with a benzimidazole ring, and salts 3
and 7 bear a hydroxyl functional group versus salt 13 having a car-
boxyl moiety.
In general, there is enough dispersion among the results so the
optimal conditions could be quite dependent on the catalytic sys-
tem employed, as well as on the other factors, or also some param-
eters could interact. However, the experiments without solvent or
base give poor results independent of the other factors (Fig. 1).
Comparative Study of Various Imidazolium and
Benzimidazolium Salts
The coupling reaction between 1-bromonaphthalene and
phenylboronic acid was chosen as a model reaction in order to
evaluate the various catalytic systems, and palladium(II) acetate
was selected as palladium source. The parameters, which are pre-
sented in Table 1, were selected to study the best reaction condi-
tions, different levels being selected for each variable. (1) Solvent:
a variety of solvents were considered, namely toluene (apolar sol-
vent), N,N-dimethylacetamide (DMA; polar aprotic solvent), water
and methanol (polar protic solvents), and also we considered the
reaction without solvent (neat conditions). (2) Amount of palla-
dium: palladium(II) acetate was considered as source of palladium
based on our previous experience,[20] and three levels were tested
(i.e. 0.1, 0.2 and 0.5 mol% of palladium). (3) Ratio of Pd to azolium
salt: the ratios 1:1, 1:2 and 1:5 were used, and the case with no
azolium salt was employed as control. (4) Base: three inorganic ba-
ses (i.e. K2CO3, KHCO3, K3PO4) and an organic base (TEA) were used
in the study, and additionally the use of no base was considered as
an additional level for this parameter. (5) Additive: the use or not of
an additive was included in the study, tetra-n-butylammonium
Table 2. Comparative study for salts 3, 7 and 13 using Suzuki–Miyaura
reactiona
Entry Solvent
Pd
Ratio
Base
Additive
Yield (%)b
(mol%) Pd:salt
3
7
13
1
Toluene
Toluene
Toluene
Toluene
Toluene
Neat
0.1
0.2
0.5
0.1
0.2
0.5
0.1
0.2
0.1
0.2
0.2
0.1
0.2
0.5
0.1
0.2
0.5
0.1
0.2
0.1
0.1
0.2
0.1
0.2
0.5
1:1
1:2
1:5
1:2
K3PO4
KHCO3
K2CO3
TEA
CTAB
TBAB
None
CTAB
TBAB
TBAB
None
CTAB
TBAB
CTAB
None
CTAB
TBAB
CTAB
TBAB
CTAB
TBAB
CTAB
TBAB
None
TBAB
CTAB
TBAB
None
CTAB
46 56 50
2
3
37 24
3
69 77 87
4
1
2
8
5
8
5
5
No salt None
1:2 K3PO4
No salt KHCO3
6
71 55 42
7
Neat
9
8
9
8
Neat
1:1
1:2
1:5
1:2
1:5
1:2
K2CO3
TEA
17 20 22
9
Neat
6
5
9
4
8
7
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Neat
None
K3PO4
KHCO3
K2CO3
H2O
16 20
H2O
2
80 43
H2O
50 46 44
38 37 38
H2O
No salt TEA
H2O
1:1
None
6
13 15
MeOH
MeOH
MeOH
MeOH
MeOH
DMA
No salt K3PO4
55 51 52
43 80 77
45 60 74
Scheme 2. Preparation of carboxylate-functionalized imidazole and
benzimidazole zwitterions.
1:1
1:2
1:5
1:2
1:5
1:2
KHCO3
K2CO3
TEA
7
7
10 14
Table 1. Parameters and levels for the design of experiments approach
None
K3PO4
KHCO3
4
6
58 57 27
41 73 57
41 42 50
Levels
Parameters
DMA
Solvent
Pd(OAc)2
(mol%)
Ratio
Pd:azolium salt
Base
Additive
DMA
No salt K2CO3
DMA
1:1
1:2
TEA
8
2
11 13
DMA
None
4
5
1
2
3
4
5
Neat
0.1
0.2
0.5
Only Pd
1:1
None
None
TBAB
aReaction conditions: 1-bromonaphthalene (1 mmol), phenylboronic
acid (1.2 mmol), additive (0.2 mmol), base (4 mmol) and 2 ml of solvent.
Toluene
Water
K3PO4
1:2
KHCO3 CTAB
K2CO3
bYield obtained using GC analysis, employing tridecane as internal
Methanol
DMA
1:5
TEA
standard.
Appl. Organometal. Chem. 2015, 29, 624–632
Copyright © 2015 John Wiley & Sons, Ltd.
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A. Allegue et al.
Table 3. Study of optimal conditions for salts 4, 8 and 14 using Suzuki–
Miyaura reactiona
Entry Solvent
Pd
Ratio
Base
Additive
Yield (%)b
(mol%) Pd:salt
4
8
14
1
Toluene
Toluene
Toluene
Toluene
Toluene
H2O
0.1
0.2
0.5
0.1
0.2
0.2
0.1
0.2
0.1
0.5
0.1
0.2
0.1
0.1
0.2
0.1
0.2
0.5
1:1
1:2
1:5
1:2
K3PO4
KHCO3
K2CO3
K3PO4
CTAB
TBAB
None.
CTAB
TBAB
None
CTAB
TBAB
TBAB
TBAB
CTAB
TBAB
None
TBAB
CTAB
TBAB
None
CTAB
51 49 48
17 15 14
61 50 49
45 49 41
25 25 20
91 72 55
46 44 51
61 44 59
39 54 55
84 89 81
67 73 78
66 21 37
79 80 88
18 21 31
52 29 40
45 41 41
68 51 54
59 38 53
2
3
4
5
No salt K2CO3
6
1:2
1:5
1:2
1:1
1:1
1:2
1:5
1:2
1:5
1:2
K3PO4
KHCO3
K2CO3
K2CO3
KHCO3
K2CO3
K3PO4
K2CO3
K3PO4
KHCO3
7
H2O
8
H2O
9
H2O
10
11
12
13
14
15
16
17
18
MeOH
MeOH
MeOH
MeOH
DMA
DMA
DMA
No salt K2CO3
DMA
1:1
1:2
K3PO4
K2CO3
DMA
aReaction conditions: 1-bromonaphthalene (1 mmol), phenylboronic
acid (1.2 mmol), additive (0.2 mmol), base (4 mmol) and 2 ml of solvent.
bYield obtained using GC analysis, employing tridecane as internal
standard.
employed (Fig. 4). Thus, the use of an additive has relevance only
when performing the reaction in water, although the yields are
lower when comparing with other solvent in the absence of addi-
tive (Fig. 4).
Figure 1. Boxplot of experimental data from Table 2 as a function of (a)
solvent and (b) base.
Finally, a general trend related to the influence of the various
azolium salts in the coupling reaction cannot be concluded from
the data,[22] so both the heterocycle and the functional group at
the substituent could play a role in the catalytic system. In order
to obtain a better picture of this feature, the coupling between 1-
bromonaphthalene and phenylboronic acid was carried out in the
presence of K2CO3 (4 equiv.) in refluxing methanol, employing 0.1
mol% of Pd(OAc)2 in combination with 0.1 or 0.2 mol% of the cor-
responding salt (4, 8, 13 and 14; Scheme 3). Comparable yields or
slightly lower, for some of the salts, are obtained when performing
these experiments in the presence of 20 mol% of TBAB (Scheme 3).
Certainly for any azolium salts, the use of TBAB has no positive ef-
fect in methanol, being even detrimental for some catalytic sys-
tems. Comparing azolium salts with the same functional group
and substituent, better results are achieved with benzimidazolium
derivatives (Scheme 3). Furthermore, the study shows that a ratio
of 1:1 works better when a carboxyl-functionalized azolium salt is
employed, and in contrast a 1:2 ratio is preferable when using
hydroxyl-functionalized derivatives. This could be related to the fact
that carboxylate functionality is less labile, as ligand, than the corre-
sponding hydroxyl. Lastly, it is worth commenting that, under the
optimal conditions described in Scheme 3, but in the absence of
any azolium salt, the yield decreases to 49%. Consequently, active
Additionally, the use of the organic base, TEA, produces low yields
in any case (Fig. 1).
Following our plan, the study was completed employing the
other azolium salts synthesized, imidazolium derivative 4 and
benzimidazolium salts 8 and 14. A new set of 18 experiments with
salts 4, 8 and 14 was carried out, excluding the assays with the con-
ditions that lead to bad results systematically (i.e. no solvent, no
base or the use of an organic base). The results are presented in
Table 3. The reaction is better performed employing 0.1 mol% of
Pd(OAc)2 in the presence of an azolium salt (0.1 or 0.2 mol%), with
an inorganic base in MeOH.
With all the results obtained after both sets of experiments, we
observe a positive effect employing an azolium salt in comparison
with the reactions performed only with palladium(II) acetate (Fig. 2).
Apparently, there are no significant differences between the inor-
ganic bases considered (Fig. 2), it being possible to obtain good re-
sults with any of them. Regarding the solvents, methanol seems to
be the best choice (Fig. 3), although employing certain conditions,
good results can be achieved with the other solvents. Moreover,
the use of an additive seems not to have a positive effect on the
outcome of the reaction (Fig. 3). Taking a look in more detail, there
is an interaction between the use of an additive and the solvent
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Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 624–632

Comparative study of functionalized imidazolium and benzimidazolium salts
Figure 3. Boxplot of experimental data from Tables 2 and 3 as a function of
(a) solvent and (b) additive.
Figure 2. Boxplot of experimental data from Tables 2 and 3 as a function of
(a) ratio of Pd to salt and (b) base.
complex, formed by palladium and any of the salts, improves the
outcome of the reaction.
In order to broaden the comparison to other aryl halides, the
coupling reactions were performed employing the best reaction
conditions for the azolium salts 4, 8, 13 and 14 (Table 4). The use
of a more sterically hindered bromide, such as 1-bromo-2-
methylnaphthalene, results in the formation of the expected prod-
uct 16 with lower yields (Table 4, entries 5–8). The yield is not im-
proved by prolonging the reaction time, as it is observed
employing imidazolium salt 8 (Table 4, entry 6, footnote ‘c’).
Additionally, the use of a more reactive aryl bromide (i.e. 4-
bromoacetophenone) results in the quantitative formation of the
biaryl 17 in all cases (Table 4, entries 9–12). On the contrary, the
electron-rich 1-bromo-4-methoxybenzene reacts more slowly and
the yields range from 55 to 80% after 3 h, albeit the yields increase
on lengthening the time to 8 h (Table 4, entries 13–16, and footnote
‘c’). Indeed, the catalytic systems seem to be sensitive to the
electronic properties, so the less deactivated 1-bromo-4-tert-
butylbenzene gives good yields after 3 h (Table 4, entries 17–20).
Additionally, the catalytic systems produce 3-phenylpyridine (20)
in moderate yields (Table 4, entries 21–24). The reaction does not
proceed further for 3-bromopyridine, with any of the catalytic
Figure 4. Interaction graph between solvent and additive: ( ) without
additive; (■) 20 mol% of TBAB; (×) 20 mol% of CTAB.
•
systems, probably due to deactivation of the active catalyst by
substrate and/or product coordination. Finally, the reaction of 1-
chloronaphthalene gives no formation of product 15 without any
of the studied azolium salts. For the coupling between 4-
chloroacetophenone and phenylboronic acid, the product 17 is
Appl. Organometal. Chem. 2015, 29, 624–632
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

A. Allegue et al.
NHCs from imidazole and benzimidazole derivatives reported in
the literature, although the reaction conditions are not the same re-
garding solvent, temperature and palladium loading. In relation to
the catalyst, the complexes bearing thioether functions are
employed with a palladium loading 10-fold higher than those pre-
sented herein (1 mol% instead of 0.1 mol%). The catalysts based on
thioether-functionalized NHCs are well-defined complexes with
two or one NHC ligands, so the complexes have to be previously
prepared and isolated, while the catalytic systems described with
hydroxyl- and carboxyl-functionalized NHCs are prepared in situ.
For activated aryl bromides, such as 4-bromoacetophenone, the
coupling product has been obtained quantitatively with thioether-,
hydroxyl- and carboxyl-functionalized NHCs, but the sulfur-based
NHC complexes work at room temperature (instead of 65°C) with
1 mol% of palladium (instead of 0.1 mol%). On the other hand, for
less activated electrophiles, such as 4-bromoanisole, higher temper-
atures (85°C), longer reaction times (21 h) and a palladium loading of
1 mol% are needed when using sulfur-functionalized NHC ligands.
The reaction using 4-chloroacetophenone produces slightly better
yields (10–30% higher) with the sulfur-containing complexes. How-
ever, better activity has been described for a thiolate-functionalized
benzimidazolin-2-ylidene palladium complex16a) when compared
with the catalytic systems described in this work. The palladium
loading for thiolate-functionalized NHC–Pd complex could be re-
duced to 0.001 and 0.0025 mol% for 4-bromoacetophenone and
4-bromoanisole, respectively.
Scheme 3. Yield of 1-phenylnaphthalene with the various azolium salts,
employing two different Pd-to-azolium salt ratios.
Table 4. Comparison of azolium salts 4, 8, 13 and 14 for different aryl
halidesa
Entry
Ar–X
Azolium Product
salt (mol%)
Yield
(%)b
1
1-Bromonaphthalene
4 (0.2)
8 (0.2)
15
16
17
18
19
20
86
89
2
3
13 (0.1)
14 (0.1)
4 (0.2)
84
Mercury Poisoning Test for Imidazolium Salts 4 and 13 and
Benzimidazolium Salts 8 and 14
4
93
5
1-Bromo-2-methylnaphthalene
4-BrC6H4COMe
23
34 (37)c
The ability of Hg(0) to form amalgam with metal particles can be
employed as an easy test to differentiate between homogeneous
and heterogeneous catalysis. The suppression of catalysis by Hg
(0) is evidence for a heterogeneous catalyst. On the contrary, if
Hg(0) does not suppress catalysis, then that is evidence for a ho-
mogeneous catalyst.[23] A large excess of Hg(0), in relation to the
amount of metal to be poisoned, should be employed in order
to avoid incomplete poisoning.[24] We considered performing this
type of experiment for catalytic systems formed by Pd(OAc)2 and
salts 4, 8, 13 and 14, since palladium is one of the metals with
which mercury easily forms amalgam. Thus, in a representative ex-
periment under standard conditions employing the catalytic mix-
tures formed by palladium(II) acetate/salt (4, 8, 13 or 14), the
reaction between 1-bromonaphthalene and phenylboronic acid
was carried out in the presence of a large excess of elemental mer-
cury (in a molar ratio of 300:1 to 330:1 Hg/Pd) which was added af-
ter 5 min. Table 5 collects the yields of product 15, from GC analysis
(using tridecane as internal standard), after 5 min of reaction, before
adding Hg(0), and after 3 h with the mercury. In contrast, parallel
mercury-free experiments give yields comparable to entries 1–4
in Table 4. For the functionalized salts with a hydroxyl group (i.e.
4 and 8), the catalytic activity is almost completely stopped after
addition of the mercury (Table 5, entries 1, 2 and 3, 4). Conse-
quently, 4 and 8 in combination with palladium seem not to form
very stable active catalysts or they only work to stabilize nanoparti-
cles formed in the reaction media. On the contrary, the salts con-
taining a carboxylate group on the substituent form more stable
homogeneous palladium catalysts which continue the reaction af-
ter the addition of mercury (Table 5, entries 5, 6 and 7, 8), as previ-
ously observed.[20] Particularly, the catalytic system formed with
salt 14 gives homogeneous catalysis after the addition of mercury,
producing 15 with a yield of 85%. However, the formation of
6
8 (0.2)
7
13 (0.1)
14 (0.1)
4 (0.2)
22
8
26
9
99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
8 (0.2)
>99
13 (0.1)
14 (0.1)
4 (0.2)
97
>99
66 (87)c
55 (89)c
57 (85)c
80 (92)c
89
4-MeOC6H4Br
8 (0.2)
13 (0.1)
14 (0.1)
4 (0.2)
4-t-BuC6H4Br
8 (0.2)
92
13 (0.1)
14 (0.1)
4 (0.2)
87
94
3-Bromopyridine
65
8 (0.2)
68
13 (0.1)
14 (0.1)
67
70
aReaction conditions: 1-bromonaphthalene (3 mmol), phenylboronic
acid (3.6 mmol), Pd(OAc)2 (0.003 mmol), imidazolium salt (4, 0.006
mmol or 13, 0.003 mmol) or benzimidazolium salt (8, 0.006 mmol or
14, 0.003 mmol), MeOH (6 ml).
bIsolated yield of pure product after recrystallization or column
chromatography (>95% GC or 1H NMR analysis).
cIsolated yield for the reaction performed during 8 h instead of 3 h.
formed with yields below 12% in all cases, and the formation of the
product cannot be improved by extending the reaction time.
The catalytic systems described have activities similar to those of
sulfonamide-functionalized[14] and thioether-functionalized[17]
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Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 624–632

Comparative study of functionalized imidazolium and benzimidazolium salts
Table 5. Mercury poisoning test for catalytic systems of Pd(OAc)2 and
azolium salts 4, 8, 13 and 14a
Furthermore, the ratio between palladium and salt can be 1:1 for
carboxylate functionalization, or 1:2 for hydroxyl functionalization.
Although investigated under different reaction conditions, the cat-
alytic systems based on hydroxyl- and carboxyl-functionalized
NHCs have activities comparable to those of other sulfur-
functionalized NHC ligands, except for thiolate derivatives.
The information derived from the study of various substrates and
the mercury poisoning tests for four different salts (4, 8, 13 and 14)
pointed out that the catalytic system of palladium and salt 14 (i.e.
carboxylate-functionalized benzimidazole derivative) is the most
robust among those studied. Consequently, both the heterocycle
ring and the functional group play a role in the formation of active
catalyst, albeit the influence of the heterocyclic system is slightly
more significant.
Entry
Azolium salt (mol%)
Conditionsb
5 min
Yield (%)c
1
2
3
4
5
6
7
8
4 (0.2)
26
32
42
46
22
40
31
85
5 min then Hg(0) + 3 h
5 min
8 (0.2)
13 (0.1)
14 (0.1)
Acknowledgements
5 min then Hg(0) + 3 h
5 min
Financial support from the University of Alicante (VIGROB-285) and
the Spanish Ministerio de Economía y Competitividad (CTQ2011-
24165) is acknowledged.
5 min then Hg(0) + 3 h
5 min
5 min then Hg(0) + 3 h
aReactions performed employing: 1-bromonaphthalene (1 mmol),
phenylboronic acid (1.2 mmol), Pd(OAc)2 (0.001 mmol), imidazolium
salt (4, 0.002 or 13, 0.001 mmol) or benzimidazolium salt (8, 0.002 or
14, 0.001 mmol), MeOH (2 ml).
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