The synthesis of some perhydrobenzimidazolinium salts and their application in Pd-Carbene catalyzed heck and suzuki reactions

Article abstract of DOI:10.3390/molecules14062032

Novel 1,3-dialkylperhydrobenzimidazolinium chloride salts were prepared as precursors of N-heterocyclic carbenes 3a-e by reacting N, N'- dialkylcyclohexandiamine, triethyl orthoformate and ammonium chloride. The salts were characterized spectroscopically

Full text of DOI:10.3390/molecules14062032

Molecules 2009, 14, 2032-2042; doi:10.3390/molecules14062032
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
The Synthesis of Some Perhydrobenzimidazolinium Salts and
Their Application in Pd-Carbene Catalyzed Heck and Suzuki
Reactions
Murat Yiğit
Department of Chemistry, Faculty of Science and Art, Adıyaman University, 02040 Adıyaman,
Turkey; E-Mail: myigit@adiyaman.edu.tr; Fax: +90 416 223 1774
Received: 13 May 2009; in revised form: 27 May 2009 / Accepted: 3 June 2009 /
Published: 5 June 2009
Abstract: Novel 1,3-dialkylperhydrobenzimidazolinium chloride salts were prepared as
precursors of N-heterocyclic carbenes 3a-e by reacting N,N’-dialkylcyclohexandiamine,
triethyl orthoformate and ammonium chloride. The salts were characterized
spectroscopically and the complexes formed in situ from Pd(OAc)2 and 3 have been tested
as catalysts in homogenous Heck and Suzuki reactions.
Keyword: Heck and Suzuki reactions; perhydrobenzimidazolinium salt; palladium;
carbene; catalyst
1. Introduction
Palladium-catalyzed C-C bond formation is one of the most fundemental and important reactions in
modern synthetic chemistry [1,2]. It represents the key the step in a wide range of preparative organic
processes, from the synthesis of natural products [3] to supramolecular chemistry and material science
[4]. Common methodologies used are the palladium mediated coupling of the organic halides or halide
equvalents with Grignard reagents, organotin or organoboron reagents where monodentate phosphine
are usually employed as ancillary ligands [5-8]. Recently, N-heterocyclic carbenes (NHCs) have been
used as alternative or better ancillary ligands than phosphine. The major advantage of NHCs in
catalysis is that an increased stability of the active catalyst is often observed, allowing for lower
operational catalyst loadings, prolonged reaction times and tolerance of increased reaction
temperatures [9-11]. The Heck and Suzuki couplings are fascinating reactions from a catalysis science
perspective. Virtually all forms of palladium can be used as precatalysts for the simpler reactions, yet

Molecules 2009, 14
2033
specifically designed catalysts are required for activation of bulky or electronically unactivated
substrates. Additionally, in many cases, extremely small amounts of palladium (ppm or ppb levels) are
sufficient to give very high turnover frequencies, whereas in others, 10% or higher precatalyst loadings
are required to obtain adequate product yields [12]. Initially, water-soluble phosphines were used as
ligands for the cross-coupling reactions in aqueous media [13], but in recent years, other hydrophilic
phosphine-free systems [14] and soluble palladium nanoparticles [15-17] have also been found to be
higly efficient catalysts for this transformation. The use of water as a solvent for chemical reactions
clearly has both economical and environmental advantages because it is inexpensive, abundant,
nontoxic, nonflammable and readily separable from organic compounds [18]. There have been a
number of reports of the palladium-mediated Heck and Suzuki reaction being performed using water
as solvent [19-27]. Due to the large number of Suzuki and other coupling reactions that are carried out
in aqueous [19] or biphasic systems, there has been an increased interest in the development of water-
soluble ligands for these reactions. Shaughnessy and co-workers utilized both sterically demanding
water-soluble alkylphosphines [28] and triarylphosphines [29] in Suzuki and Heck couplings of aryl
bromides, respectively. We have previously reported the use of the various catalytic systems, such as
palladium catalyzed cross-coupling, ruthenium catalyzed hydrogenation and rhodium catalyzed
arylation or hydrosilylation [30-34]. Although the nature of the NHC ligand on complexes has a
tremendous influence on the rate of catalyzed reactions, the use of perhydrobenzimidazolinium ligands
in Heck and Suzuki reactions is a neglected field. In order to find more efficient catalyst, we have
prepared a series of new perhydrobenzimidazolinium chlorides, 3a-e (Scheme 1), containing a
saturated benzimidazole ring and we report here an in situ palladium-carbene based catalytic system
for Heck and Suzuki cross-coupling of aryl halides.
2. Results and Discussion
The general route to the p-substituent containing ligand precursors is shown in Scheme 1. The
condensation of 1,2-diaminocyclohexane with aldehydes in ethanol gave the corresponding Schiff
bases in high yields. Reduction of these Schiff bases with NaBH4 in methanol leads to N,N’-dialkyl-
cyclohexan-1,2-diamines. The symmetrical 1,3-dialkylperhydrobenzimidazolinium salts 3 were easly
synthesized in high yields from the N,N’-dialkylcyclohexan-1,2-diamines, triethyl ortoformate and
ammonium chloride. After purification, the 1,3-dialkylperhydrobenzimidazolinium salts 3a-e were
obtained in good yields (85-90%). The salts are soluble in the common polar solvents ethanol and
dichloromethane and are stable under air and in the presence of moisture. The structures of 3 were
13
determined by their spectroscopic data and elemental analyses (see Experimental section). The C-
NMR spectra of 3a-e show only sharp high field signals [159.5 ppm (3a), 162.1 ppm (3b), 161.9 ppm
(3c), 162.5 ppm (3d), 162.0 ppm (3e)] for the imino carbon and for a benzylic carbon [58.7 ppm (3a),
1
66.7 ppm (3b), 66.6 ppm (3c), 67.0 ppm (3d), 66.8 ppm(3e)]. The H-NMR spectra of the perhydro-
benzimidazolinium salts further supported the assigned structures. The resonances of the C(2)-H were
observed as sharp singlets at δ= 10.87, 10.96, 10.74, 11.10, 10.79 ppm for 3a-e, respectively. The
benzylic protons appeared as a doublet at 4.36- 5.50 ppm. The IR data for perhydrobenzimidazolinium
3a-e salts clearly indicate the presence of the –C=N- group with a ν(C=N) vibration at 1,644, 1,592,
1,612, 1,587 and 1,600 cm-1 for 3a-e, respectively. These NMR and IR values were similar to those
reproted for other 1,3-dialkylperhydrobenzimidazolinium and 1,3-dialkylimidazolinium salts [33,35].

Molecules 2009, 14
Scheme 1. Synthesis of 1,3-dialkylperhydrobenzimidazolinium salts.
2034
Ar
NH2
N CH Ar
NH
NH
i
ii
Ar-CHO
Ar
+
NH2
N CH Ar
2
1
Ar
iii
a
CH3
Ar
N
+)
b
Cl-
CH2CH3
N
CH3
CH
Ar
3a, b, c, d, e
c
CH3
d
e
OCH2CH3
Reagents and conditions: (i) EtOH, 3h, reflux; (ii) MeOH, NaBH4, 5h, RT; (iii) HC(OEt)3, NH4CI,
12h, 110 °C.
The Pd-catalyzed Heck reaction is an efficient way to prepare styrene derivatives, which are
important chemicals for many applications. The Heck couplings of styrene with aryl bromides to form
alkenes were undertaken with Pd(OAc)2/3a-e as catalysts. The choice of bases and solvents are usually
important in achieving an efficient cross coupling reaction. The widely used solvents such as DMF,
DMSO, toluene, dioxane, THF and CH3CN had remarkable effects on the coupling reaction. For
optimal reaction conditions, the Pd(OAc)2-catalyzed cross coupling of bromobenzene with styrene was
o
employed as the model reaction using ligand 3a at 80 C; Cs2CO3, K2CO3, K3PO4 and t-BuOK were
tested as the base. The coupling reactions of aryl bromides and styrene were carried out in DMF/H2O
(3:3 mL) with 1 mol% Pd(OAc)2, 2 mol% 3 and 2 equiv. K2CO3 for 2 h at 80oC. The results are
summarized in Table 1.
Control experiments indicate that the coupling reactions did not occur in the absence of 3a. Under
these reaction conditions, a wide range of aryl bromides bearing electron-donating or electron-
withdrawing groups react with styrene affording the coupled products in excellent yields (Table 1,
entries 3, 4, 8, 15, 18 and 22). Enhancements in activity, although less significant, are also observed
employing 4-bromobenzaldehyde instead of 4-bromoacetophenone (entries 1–5 and 11-15,
respectively).

Molecules 2009, 14
Table 1. The Heck coupling reaction of aryl bromides with styrene.
2035
Pd(OAc)2 , salt
Br
R
+
R
DMF/H2O , K2CO3
Entry
1
R
SALT
3a
3b
3c
Yield (%)b,c
COCH3
COCH3
COCH3
COCH3
COCH3
CHO
CHO
CHO
CHO
CHO
H
96
95
98
98
96
95
94
96
91
97
94
93
90
92
95
92
88
93
91
87
86
89
85
81
84
2
3
4
3d
3e
5
6
3a
3b
3c
7
8
9
3d
3e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3a
3b
3c
H
H
H
3d
3e
H
OCH3
OCH3
OCH3
OCH3
OCH3
CH3
3a
3b
3c
3d
3e
3a
3b
3c
CH3
CH3
CH3
3d
3e
CH3
aReaction conditions: R-C6H4Br-p 1.0 mmol, styrene 1.5 mmol, K2CO3 2.0 mmol, Pd(OAc)2 1%
b
(molar ratio), 3a-e 2% (molar ratio), water (3 mL)/DMF (3 mL), 80°C, 2 h. Isolated yields are
c
based on aryl bromide. All reactions were monitored by GC, and the compound purity was
checked by NMR.
However, chloroarenes do not react under standard conditions, and yields are typically <5%. A
systematic study on the substituent effect in the perhydrobenzimidazolinium salts 3a-e indicated that
the introduction of a p-isopropylbenzyl substituent on the N-atoms notably increased the yield of
product (Table 1, entries 3, 8, 13, 18, 23). Comparatively the perhydrobenzimidazolinium salts
displayed better performance than benzimidazolinium salts in the Heck and Suzuki reactions [36,37].
Due to the palladium/imidazolium salt catalyst systems display high reactivity with aryl chlorides in
the Suzuki cross-coupling reaction has been applied successfully to the synthesis of fenbuten and to a
key intermediate in the synthesis of sartans [38]. The Suzuki coupling of phenylboronic acid with aryl
chlorides to form biaryls were undertaken with Pd(OAc)2 /3a-e as catalysts.

Molecules 2009, 14
Table 2. The Suzuki coupling reaction of aryl chlorides with phenylboronic acid.
2036
Pd(OAc)2 , salt
B(OH)2
R
R
Cl
+
DMF / H2O , K2CO3
Entry
1
R
SALT
3a
3b
3c
Yield (%)b,c
COCH3
COCH3
COCH3
COCH3
COCH3
CHO
CHO
CHO
CHO
CHO
H
94
95
97
98
92
93
97
98
94
91
87
89
86
94
90
84
86
88
89
82
78
75
81
77
74
2
3
4
3d
3e
5
6
3a
3b
3c
7
8
9
3d
3e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3a
3b
3c
H
H
H
3d
3e
H
OCH3
OCH3
OCH3
OCH3
OCH3
CH3
3a
3b
3c
3d
3e
3a
3b
3c
CH3
CH3
CH3
3d
3e
CH3
aReaction conditions: R-C6H4CI-p 1.0 mmol, phenylboronic acid 1.5 mmol, K2CO3 2.0 mmol,
Pd(OAc)2 1% (molar ratio), 3a-e 2% (molar ratio), water (3 mL)/DMF (3 mL), 80°C, 1h. bIsolated
c
yields are based on aryl chloride. All reactions were monitored by GC, and the compound purity
was checked by NMR.
Similar reaction conditions were employed for the Suzuki reactions. The coupling reactions of aryl
chlorides and phenylboronic acid were carried out in DMF/H2O (3:3 mL) with 1 mol% Pd(OAc)2, 2
mol% 3 and 2 equiv. K2CO3 for 1 h at 80oC. We started our investigation examining the coupling of 4-
chloroacetophenone and phenylboronic in the presence of Pd(OAc)2 /3. The results are summarized in
Table 2. It can be show these salts are an effective ligand precursor for the coupling of unactivated,
activated and deactivated chlorides. These results are in agreement with other reports [38-43].
3. Conclusions
In conclusion, we have synthesized five 1,3-dialkylperhydrobenzimidazolinium chloride salts and
have investigated their catalytic activity in the Heck and Suzuki coupling reactions. The procedure is

Molecules 2009, 14
2037
simple and efficient toward various types of aryl halides and does not require an induction period. The
advandage of the catalyst is that it has low-loading capabilities, and it is usable in air. Detailed
investigations, focusing on imidazolidin-2-ylidene and benzimidazolin-2-ylidene substituent effects,
functional group tolerance, and catalytic activity in this and other coupling reactions are ongoing.
4. Experimental
4.1.General
All reactions for the preparation of 1,3-dialkylperhydrobenzimidazolinium salts 3a-e were carried
out under argon using standard Schlenk-type flasks. Heck and Suzuki coupling reactions were carried
out in air. 1,2-Diaminocyclohexane (mixture of cis and trans), aldehydes and other reagents were
purchased from Aldrich Chemical Co. (Turkey). All 1H- and 13C-NMR were recorded in CDCI3 using
a Bruker AC300P FT spectrometer operating at 300.13 MHz (1H) or 75.47 MHz (13C). Chemical shifts
(δ) are given in ppm relative to TMS, coupling constants (J) in hertz. FT-IR spectra were recorded as
KBr pellets in the range 400-4000 cm-1 on a Mattson 1000 spectrophotometer (wavenumbers, cm-1).
GC were measured by GC-FID on a Agilent 6890N gas chromatograph equipped with an HP-5 column
of 30 m length, 0.32 mm diameter and 0.25 μm film thickness. Melting points were measured in open
capillary tubes with an Electrothermal-9200 melting point apparatus and uncorrected. Elemental
analyses were performed at TUBITAK (Ankara, Turkey) Microlab.
4.2. General procedure for preparation of the 1,3-dialkylperhydrobenzimidazolinium chlorides 3a-e
A mixture of N,N’-dialkylcyclohexan-1,2-diamine (6.80 mmol), NH4CI (6.80 mmol) and triethyl
orthoformate (5 ml) was heated for 12 h at 110oC. Upon cooling to room temperature, colorless
crystals of 3a-e were obtained. The crystals were filtered, washed with diethyl ether (3 x 15 mL) and
dried under vacuum. The crude product was recrystallized from EtOH/Et2O.
1,3-bis(4-Methylbenzyl)perhydrobenzimidazolinium chloride (3a). Yield: 2.27 g, 90%; mp: 238oC; IR
1
(cm-1) ν = 1,644 (-CH=N-); H-NMR (CDCI3) δ: 1.32-1.41 (m, 4H, NCHCH2CH2CH2CH2CHN),
1.66-1.69 (m, 4H, NCHCH2CH2CH2CH2CHN), 3.71-3.80 (m, 2H, NCHCH2CH2CH2CH2CHN), 2.29
(s, 6H, CH2C6H4CH3-p), 4.38 and 5.19 (d, 4H, J=11.1 Hz, CH2C6H4CH3-p), 7.13 and 7.24 (d, 8H,
J=6.0 Hz, CH2C6H4CH3-p), 10.87 (s, 1H, 2-CH); 13C-NMR (CDCI3) δ: 21.3
(NCHCH2CH2CH2CH2CHN), 22.8 (NCHCH2CH2CH2CH2CHN), 49.8 (NCHCH2CH2CH2CH2CHN),
18.3 (CH2C6H4CH3-p), 58.7 (CH2C6H4CH3-p), 128.7, 128.8, 130.0, 139.0 (CH2C6H4CH3-p), 159.6 (2-
CH); Anal. Calcd. for C23H29N2CI: C, 74.89; H, 7.86; N, 7.59. Found C, 74.62; H, 7.71; N, 7.67.
1,3-bis(4-Ethylbenzyl)perhydrobenzimidazolinium chloride (3b). Yield: 2.41 g; 85%, mp: 146oC; IR
1
(cm-1) ν = 1,592 (-CH=N-); H-NMR (CDCI3) δ: 1.11-1.48 (m, 4H, NCHCH2CH2CH2CH2CHN),
1.73-2.09 (m, 4H, NCHCH2CH2CH2CH2CHN), 3.10-3.22 (m, 2H, NCHCH2CH2CH2CH2CHN), 1.21
(t, 6H, J=7.8 Hz, CH2C6H4CH2CH3-p), 2.64 (q, 4H, J=7.5 Hz, CH2C6H4CH2CH3-p), 4.41, 5.05 and
4.68, 5.26 (d, 4H, J=14.7 Hz, and J=15.0 Hz, CH2C6H4CH2CH3-p), 7.19 and 7.32 (d, 8H, J=7.8 Hz,
13
CH2C6H4CH2CH3-p), 10.96 (s, 1H, 2-CH); C-NMR (CDCI3) δ: 23.5 (NCHCH2CH2CH2CH2CHN),
28.5 (NCHCH2CH2CH2CH2CHN), 50.6 (NCHCH2CH2CH2CH2CHN), 15.4 (CH2C6H4CH2CH3-p),

Molecules 2009, 14
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22.6 (CH2C6H4CH2CH3-p), 66.7 (CH2C6H4CH2CH3-p), 128.6, 130.1, 145.1, 159.4 (CH2C6H4CH2CH3-
p), 162.1 (2-CH); Anal. Calcd. for C25H33N2CI: C, 75.66; H, 8.32; N, 7.06. Found C, 75.24; H, 8.54;
N, 7.19.
1,3-bis(4-Isopropylbenzyl)perhydrobenzimidazolinium chloride (3c). Yield: 2.15 g; 87%, mp: 133-
135oC; IR (cm-1) ν = 1,612 (-CH=N-); 1H-NMR (CDCI3) δ: 1.09-1.33 (m, 4H,
NCHCH2CH2CH2CH2CHN), 1.78-2.04 (m, 4H, NCHCH2CH2CH2CH2CHN), 3.15-3.18 (m, 2H,
NCHCH2CH2CH2CH2CHN), 1.20 (d, 12H, J=9 Hz, CH2C6H4CH(CH3)2-p), 2.85 (hept, 2H, J=6.9 Hz,
CH2C6H4CH(CH3)2-p), 4.66 and 5.50 (d, 4H, J=15 Hz, CH2C6H4CH(CH3)2-p), 7.18 and 7.29 (d, 8H,
J=8.1 Hz, CH2C6H4CH(CH3)2-p), 10.74 (s, 1H, 2-CH); 13C-NMR (CDCI3) δ: 23.8
(NCHCH2CH2CH2CH2CHN), 27.3 (NCHCH2CH2CH2CH2CHN), 50.5 (NCHCH2CH2CH2CH2CHN),
18.4 (CH2C6H4CH(CH3)2-p), 33.7 (CH2C6H4CH(CH3)2-p), 66.6 (CH2C6H4CH(CH3)2-p), 127.2, 128.5,
130.3, 149.5 (CH2C6H4CH(CH3)2-p), 161.9 (2-CH); Anal. Calcd. for C27H37N2CI: C, 76.32; H, 8.71;
N, 6.59. Found C, 76.81; H, 8.93; N, 6.80.
1,3-bis(4-Biphenylbenzyl)perhydrobenzimidazolinium chloride (3d). Yield: 2.37 g; 86%, mp: 263-
265oC; IR (cm-1)
ν
=
1,587 (-CH=N-); 1H-NMR (CDCI3) δ:1.15-1.28 (m, 4H,
NCHCH2CH2CH2CH2CHN), 1.83-2.13 (m, 4H, NCHCH2CH2CH2CH2CHN), 3.26-3.29 (m, 2H,
NCHCH2CH2CH2CH2CHN), 4.56, 5.14 and 4.85, 5.37 (d, 4H, J=15 Hz and J=14.7 Hz
13
CH2C6H4C6H5), 7.33-7.62 (m, 18H, CH2C6H4C6H5), 11.10 (s, 1H, 2-CH); C-NMR (CDCI3) δ: 23.6
(NCHCH2CH2CH2CH2CHN), 27.5 (NCHCH2CH2CH2CH2CHN), 50.6 (NCHCH2CH2CH2CH2CHN),
67.0 (CH2C6H4C6H5), 127.0, 127.8, 128.8, 129.2, 132.0, 140.1, 141.6, 159.5 (CH2C6H4C6H5), 162.5
(2-CH); Anal. Calcd. for C33H33N2CI: C, 80.40; H, 6.70; N, 5.68. Found C, 80.21; H, 6.86; N, 5.54.
1,3-bis(4-Ethoxybenzyl)perhydrobenzimidazolinium chloride (3e). Yield: 1.84 g; 82%, mp: 226oC; IR
1
(cm-1) ν = 1,600 (-CH=N-); H-NMR (CDCI3) δ: 1.05-1.20 (m, 4H, NCHCH2CH2CH2CH2CHN),
1.70-2.00 (m, 4H, NCHCH2CH2CH2CH2CHN), 3.05-3.07 (m, 2H, NCHCH2CH2CH2CH2CHN), 1.23
(t, 6H, J=9 Hz, CH2C6H4OCH2CH3-p), 3.91 (q, 4H, J=6.4 Hz, CH2C6H4OCH2CH3-p), 4.56 and 4.92
(d, 4H, J=10.8 Hz, CH2C6H4OCH2CH3-p), 6.78 and 7.26 (d, 8H, J=8.7 Hz, CH2C6H4OCH2CH3-p),
10.79 (s, 1H, 2-CH); 13C-NMR (CDCI3) δ: 23.7 (NCHCH2CH2CH2CH2CHN), 27.8
(NCHCH2CH2CH2CH2CHN), 50.5 (NCHCH2CH2CH2CH2CHN), 14.9 (CH2C6H4OCH2CH3-p), 63.6
(CH2C6H4OCH2CH3-p), 66.8 (CH2C6H4OCH2CH3-p), 115.2, 124.9, 130.1, 159.4 (CH2C6H4OCH2CH3-
p), 162.0 (2-CH); Anal. Calcd. for C25H33N2O2CI: C, 70.01; H, 7.70; N, 6.53. Found C, 70.18; H, 7.54;
N, 6.71.
4.3. General procedure for the Heck coupling reactions
Pd(OAc)2 (1.0 mmol%), the appropriate 1,3-dialkylperhydrobenzimidazolinium salt 3a-e (2
mmol%), aryl bromide (1.0 mmol), styrene (1.5 mmol), K2CO3 (2 mmol), water (3 mL) and DMF (3
mL) were added to a small Schlenk tube and the mixture was heated at 80 ◦C for 2 h. At the conclusion
of the reaction, the mixture was cooled, extracted with ethyl acetate–hexane (1 : 5), filtered through a
pad of silica gel with copious washing, concentrated and purified by flash chromatography on silica

Molecules 2009, 14
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gel. All reactions were monitored by GC. The purity of the compounds was checked by NMR and
yields are based on aryl bromide.
4.4. General procedure for the Suzuki coupling reactions
Pd(OAc)2 (1.0 mmol%), the appropriate 1,3-dialkylperhydrobenzimidazolinium salt 3a-e (2
mmol%), aryl chloride (1.0 mmol), phenylboronic acid (1.5 mmol), K2CO3 (2 mmol), water (3 mL)
and DMF (3 mL) were added to a small Schlenk tube and the mixture was heated at 80 ◦C for 1 h. At
the conclusion of the reaction, the mixture was cooled, extracted with ethyl acetate–hexane (1 : 5),
filtered through a pad of silica gel with copious washing, concentrated and purified by flash
chromatography on silica gel. All reactions were monitored by GC. The purity of the compounds was
checked by NMR and yields are based on aryl chloride.
Acknowledgements
Financial support from Inonu University Research Fund (BAP 2007/29) is gratefully
acknowledged.
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Sample Availability: Samples of the compounds are available from the authors.
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