Facile formation of imidazolinium salt by reaction of corresponding diamine and trimethyl orthoformate in 1,1,1,3,3,3-hexafluoroisopropanol

Article abstract of DOI:10.3987/COM-13-S(S)80

The preparation of imidazolinium salts, which can be used as precursors of pincer-type N-heterocyclic carbene ligands, is described. The formation of imidazolinium salts under standard conditions is difficult, but they have been successfully synthesized by reaction of the corresponding diamines and trimethyl orthoformate in 1,1,1,3,3,3-hexafluoroisopropanol. The synthesis of new chiral C₂ symmetric imidazolinium salts is also described.

Full text of DOI:10.3987/COM-13-S(S)80

HETEROCYCLES, Vol. 88, No. 2, 2014
1539
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 1539 - 1551. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 2nd July, 2013, Accepted, 17th September, 2013, Published online, 26th September, 2013
DOI: 10.3987/COM-13-S(S)80
FACILE FORMATION OF IMIDAZOLINIUM SALT BY REACTION OF
CORRESPONDING DIAMINE AND TRIMETHYL ORTHOFORMATE IN
1
,1,1,3,3,3-HEXAFLUOROISOPROPANOL
Kensuke Usui and Masahisa Nakada*
Department of Chemistry and Biochemistry, School of Advanced Science and
Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555,
Japan; E-mail: mnakada@waseda.jp
Dedicated to Professor Victor Snieckus on the occasion of his 77th birthday
Abstract – The preparation of imidazolinium salts, which can be used as
precursors of pincer-type N-heterocyclic carbene ligands, is described. The
formation of imidazolinium salts under standard conditions is difficult, but they
have been successfully synthesized by reaction of the corresponding diamines and
trimethyl orthoformate in 1,1,1,3,3,3-hexafluoroisopropanol. The synthesis of new
chiral C symmetric imidazolinium salts is also described.
2
1
N-Heterocyclic carbenes (NHCs) were first reported as organometallic complexes by Öfele and
2
3
Wanzlick, and were isolated as stable crystals by Arduengo in 1968. Since their discovery, stable NHCs
have been drawing attraction from many chemists because of their unique structures and properties.
NHCs have been extensively studied, especially in oganometallic chemistry, as new ligands that can be
4
5
used as substitutes for phosphine ligand. Recently, NHCs have also been recognized as organocatalysts.
Research on NHCs is therefore expected to be further developed.
Pincer-type ligands have been studied since the early 1970s, and are known to form stable metal
6
complexes by forming carbon–metal bonds and coordination bonds with σ-donor heteroatoms such as
nitrogen and phosphorus. Metal complexes of pincer-type ligands show high and long-lasting catalytic
activities, and have therefore been used for many catalytic reactions.
Consequently, pincer-type NHC ligands are expected to be useful. However, a limited number of
7
,8
pincer-type NHC ligands have been described, and their applications in asymmetric catalysis have not
been reported. The development of new pincer-type NHC ligands could contribute to developments in
organometallic chemistry as well as asymmetric catalysis.

1540
HETEROCYCLES, Vol. 88, No. 2, 2014
We therefore decided to design and synthesize chiral C symmetric pincer-type NHC ligands 1 and 2,
2
which are shown as their complexes in Figure 1. In this paper, we report the preparation of imidazolinium
salts corresponding to 1 and 2, which are only formed in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP).
R
R
O
R
R
N
N
N
N
N
N
N
N
N
N
M
M
O
O
M
M
N
N
N
N
N
O
N
1
2
Figure 1. Designed pincer-type NHC ligands
We first prepared achiral diamine 7 (Scheme 1) to investigate the preparation and properties of the
corresponding imidazolinium salts and NHCs. The first step in the synthesis of 7 was the preparation of 4
by
a
Suzuki–Miyaura coupling reaction. The palladium-catalyzed coupling reaction of
o-nitrophenylboronic acid 3, which was prepared from 1-iodo-2-nitrobenzene according to the report by
9
Yu, with 2-bromopyridine afforded 4 under standard conditions. Reduction of 4 with NaBH gave
4
arylamine 5, which was converted to bis-amide 6 by reaction with oxallyl chloride; subsequent DIBAL-H
reduction afforded diamine 7.
NO2
NO2
N
NaBH4
THF/MeOH = 20/1
NH2 N
2-bromopyridine, Pd(OAc) (5 mol%)
2
B(OH)2
PPh (20 mol%), K CO
3
2
3
rt, 3 d, 89%
DME/EtOH/H O = 4/1/1, 70 °C, ovn
2
66%
3
4
5
O
O
NH HN
(
COCl) , Et N
2 3
NH HN
DIBAL-H, 1,4-dioxane
50 °C, 3 h, 30%
CH Cl , rt, 1 h, 88%
2
2
N
N
N
N
6
7
Scheme 1. Preparation of diamine 7

HETEROCYCLES, Vol. 88, No. 2, 2014
1541
We next examined the conversion of diamine 7 to the corresponding imidazolinium salts (Table 1).
However, none of the reactions using the reported conditions afforded imidazolinium salts 8 (entries 1–4).
The low reactivity of diamine 7 was assumed to be the result of internal hydrogen bonding of the
1
,2-diamine. The reaction was therefore carried out in 1-butanol to weaken the hydrogen bonds (entry 4).
As a result, a polar compound was formed, which appeared on the base line in thin-layer chromatography,
but was converted to the formamide of 7 during evaporation of the solvent. HFIP is a volatile solvent and
easily removed under reduced pressure. Moreover, HFIP has been reported to be slightly acidic (pKa =
9
.3) and a strong hydrogen-bond donor with high ionizing power and polarity; it therefore activates
1
0
orthoesters towards nucleophilic attack of amino groups. So, we examined the reaction of 7 with
trimethyl orthoformate in HFIP, and found that the reaction proceeded even at room temperature (entry 5)
to afford imidazolinium salts 8a and 8b in79% and 73% yields, respectively.
Table 1. Preparation of imidazolinium salts 8a (X = BF ) and 8b (X = Cl)
4
NHHN
N
N
X
N
N
N
N
7
8
a
entry
reagent (equiv)
solvent
temp (°C)
120
yield (%)
1
2
3
4
5
6
NH BF (3.0), HCO H (cat.),
HC(OEt)3
0
0
0
0
4
4
2
NH BF (3.0)
HC(OEt) /toluene = 1/10
reflux
reflux
reflux
rt
4
4
3
NH BF (3.0), HC(OEt) (2.0)
toluene
4
4
3
NH BF (3.0)
HC(OEt) /n-BuOH = 1/10
4
4
3
NH BF (1.2)
HC (OMe) /HFIP = 1/10
79 (X = BF4)
73 (X = Cl)
4
4
3
NH Cl (1.2)
HC(OMe) /HFIP = 1/10
rt
4
3
a
1
Yields determined by H-NMR using fluorene as internal standard.
Once imidazolinium salts 8a and 8b had been successfully synthesized, we proceeded to prepare chiral
diamine 13 and its imidazolinium salts. 2-Bromophenyl benzyl ether 10, prepared from 2-bromophenol 9,
was converted to compound 11 by a palladium-catalyzed coupling reaction. Benzyl ethers in 11 were
removed by hydrogenolysis to afford bisphenol 12, which was successfully converted to the chiral
diamine 13 by reaction with 2-fluoropyridine.

1542
HETEROCYCLES, Vol. 88, No. 2, 2014
(
1R, 2R)-1,2-cyclohexanediamine
Br
Br
BnCl, K CO , DMF
Pd2(dba)3 (5 mol%), (R)-BINAP (12 mol%)
2
3
OH
OBn
NH HN
7
0 °C, 1.5 h, 99%
t-BuONa, toluene, reflux, 25 h, 90%
BnO
OBn
9
10
11
H , Pd/C (cat.)
MeOH/AcOH = 1/1, 5 d
2HCl
2
NH HN
2-fluoropyridine, NaH, DMF
2 d,120 °C, 35%
NH HN
O
O
then aq. HCl, quant.
HO
OH
N
N
12
13
Scheme 2. Preparation of diamine 13
Table 2. Preparation of imidazolinium salts 14a (X = BF ) and 14b (X = Cl)
4
NH HN
N
N
X
O
N
O
N
O
N
O
N
1
3
14
a
entry
reagent (equiv)
NH BF (5.0)
solvent
temp (°C)
yield (%)
1
2
3
4
5
HC(OEt)3
HC(OEt)3
HC(OEt)3
120
120
120
rt
0
0
0
4
4
NH Cl (5.0)
4
HCl, EtOH
NH BF (1.2)
HC(OMe) /HFIP = 1/10
59 (X = BF4)
73 (X = Cl)
4
4
3
NH Cl (1.2)
HC(OMe) /HFIP = 1/10
rt
4
3
a
1
Yields determined by H-NMR using fluorene as internal standard.
Diamine 13 was not converted to the corresponding imidazolinium salts under standard conditions (Table
, entries 1-3); however, the reaction conditions used for the synthesis of 8 (Table 1, entries 5 and 6)
significantly accelerated the formation of imidazolinium salts 13, even at room temperature, and 13a
2

HETEROCYCLES, Vol. 88, No. 2, 2014
1543
(entry 5) and 13b (entry 6) were successfully obtained in 59% and 73% yields, respectively.
Imidazolinium salts 8 and 14 were unstable and easily hydrolyzed and converted to the corresponding
1
formamides. The formation of these salts was therefore confirmed by H-NMR spectroscopy and mass
spectrometry of the crude products. Selected chemical shifts [ (ppm), downfield from tetramethylsilane]
of imidazolinium salts 8 and 14 are shown in Figure 2.
Hb
NH HN
Hb
Hb
N
N
N
N
Cl
N
BF H
N
Ha
4
a
N
N
N
N
8
a
7
8b
1H-NMR(DMSO-d6)
1H-NMR(DMSO-d6)
1H-NMR(DMSO-d6)
(H ) = 4.174 ppm
(H ) = 4.175 ppm
b
b

(H ) = 3.454 ppm
(H ) = 8.917 ppm
(H ) = 8.889 ppm
b
a
a
Hb
Hb
Hb
NH HN
N
N
N
N
Cl
BF4
O
N
O
N
O
N
O
N
O
O
N
Ha
Ha
N
1
4a
1
3
14b
1H-NMR(DMSO-d6)
1H-NMR(DMSO-d6)
1H-NMR(DMSO-d6)
(H ) = 3.280 ppm
(H ) = 3.914 ppm
(H ) = 3.911 ppm
b
b

(H ) = 9.471 ppm
(H ) = 9.470 ppm
b
a
a
Figure 2. Selected chemical shifts [ (ppm), downfield from tetramethylsilane] of diamines 7 and 13, and
imidazolinium salts 8 and 14
Imidazolinium salts 8 and 14 were found to be unstable in less-polar solvents, but, interestingly, were
stable in polar solvents such as methanol and dimethyl sulfoxide (DMSO). For all the imidazolinium salts,
the H signals were found at around 4 ppm (downfield from tetramethylsilane) in DMSO-d , i.e., shifted
b
6
downfield compared with the H signals of the corresponding diamines, and the H signals appeared at
b
a
around 9 ppm, suggesting formation of the imidazolinium salts.

1544
HETEROCYCLES, Vol. 88, No. 2, 2014
Once imidazolinium salts 14a and 14b were obtained as described above, we finally examined the
synthesis of metal complexes of 14-M (Table 3). As the imidazolinium salts 14a and 14b were unstable,
they were prepared just before the reactions in Table 3, and used after removing all volatile materials
under reduced pressure.
We first examined the synthesis of silver complexes of 14a and 14b, which have been reported to be
1
1
converted to various metal complexes. The reactions of 14a and 14b with Ag O were carried out in the
2
presence of MS 4A, but complex mixtures or only formamide 15 were obtained (entries 1–3).
We then examined the synthesis of palladium complexes of 14a and 14b using a base and Pd(OAc) , but
2
only observed the formation of complex mixtures (entries 4–6). The formation of 15 suggests that it
might be derived from the NHC of 14b, which is too unstable to be isolated. Usually, imidazolinium salts
are stable and isolable in air. The low stability of the NHC of 14 could therefore be attributed to a factor
such as degradation accelerated via ylide formation by the formed carbene and pyridine nitrogen. The
unsuccessful results in Table 3 will be useful in the further design and synthesis of new NHC ligands.
Table 3. Attempted preparation of metal complexes of 14a and 14b
base (1.5 equiv)
N
N
N HN
CHO
N
N
MY (1.5 equiv)
n
X
O
N
O
N
O
O
O
N
O
N
M
N
N
14-X
14-M
15
entry
X
base
none
M Y
solvent
temp (°C)
yield (%)
x
z
a
b
b
b
1
Cl
Ag O
(CH Cl)2
rt
80
rt
complex mixture
2
2
a
c
2
Cl
none
Ag O
(CH Cl)2
0
2
2
a
3
BF4
BF4
BF4
BF4
none
Ag O
(CH Cl)2
complex mixture
complex mixture
complex mixture
complex mixture
2
2
4
5
6
NaOMe
KHMDS
t-BuOK
Pd(OAc)2
Pd(OAc)2
MeOH
THF
rt
rt
Pd(OAc)2
THF
rt
a
b
c
MS 4A was added. 1.0 equiv Ag O was used. Formamide 15 was formed.
2

HETEROCYCLES, Vol. 88, No. 2, 2014
1545
In conclusion, new chiral C symmetric imidazolinium salts were successfully synthesized. We found that
2
the formation of imidazolinium salts was significantly enhanced, even at room temperature, when the
reaction was carried out in HFIP. The use of HFIP in the synthesis of imidazolinium salts enables the
formation of new imidazolinium salts that are difficult to prepare under known conditions. Further
investigations of the use of HFIP in the preparation of imidazolinium salts are now underway, and the
results will be reported in due course.
EXPERIMENTAL
1
13
1
13
H and C NMR spectra were recorded on 400 MHz spectrometer. H and C chemical shifts are
reported in ppm downfield from tetramethylsilane (TMS, δ scale) with the solvent resonances as internal
standards. The following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; band, several overlapping signals; brs, broad. IR spectra were recorded on
a FT/IR spectrometer. Mass spectra were provided at the Materials Characterization Central Laboratory,
Waseda University. All reactions were carried out under an argon atmosphere with dry, freshly distilled
solvents under anhydrous conditions, unless otherwise noted. All reactions were monitored by thin-layer
chromatography carried out on 0.25 mm silica gel plates using UV light as visualizing agent and
phosphomolybdic acid and heat as developing agents. Silica gel (60, particle size 0.040-0.063 mm) was
used for flash chromatography. Preparative thin-layer chromatography (PTLC) separations were carried
out on self-made 0.3 mm silica gel plates. THF was distilled from sodium/benzophenone ketyl. Toluene
was distilled from sodium. MeOH was distilled with a small amount of magnesium and I . All
2
commercially available reagents were used without further purification. Optical rotations were measured
on a polarimeterat a wavelength of 589 nm. High resolution mass spectra (HRMS) were obtained by
either an electronspray ionization (ESI) or a fast atom bombardment (FAB), and theoretical monoisotopic
molecular masses were typically ≤5 ppm. Melting point was uncorrected. Melting point was uncorrected.
TLC Rfs of purified compounds were included.
1
2
2
0
2
-(2-Nitrophenyl)pyridine (4). To a suspension of K CO (4.65 g, 33.6 mmol), Pd(OAc) (0.189 g,
2 3 2
.840 mmol), and PPh (0.882 g, 3.36 mmol) in 170 mL of DME/EtOH/H O = 4/1/1 was added
3
2
-nitrophenylboronic acid (3) (3.37 g, 20.2 mmol) and 2-bromopyridine (1.60 mL, 16.8 mmol). After
stirring at 70 °C overnight, the reaction mixture was concentrated under reduced pressure. To the residue
were added water (100 mL) and Et O (100 mL), and the aqueous layer was extracted with Et O (50 mL ×
2
2
2
). The combined organic layers were washed with brine (50 mL), dried over Na SO , and evaporated.
2 4
The residue was purified by silica gel chromatography (hexane/EtOAc = 6/1) to afford
-(2-nitrophenyl)pyridine (4) (2.23 g, 66%) as white solid. Spectroscopic data were in agreement with
2
12
1
those previously reported: R = 0.28 (hexane/EtOAc = 2/1); H NMR (400 MHz, CDCl ): δ 8.66 (d, J =
f
3

1546
HETEROCYCLES, Vol. 88, No. 2, 2014
5
.0 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 7.7, 7.7 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.63 (dd, J
=
7.7, 7.7 Hz, 1H), 7.55 (dd, J = 7.7, 7.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.32 (dd, J = 7.7, 5.0 Hz, 1H).
1
3
2
-(Pyridin-2-yl)benzenamine (5). To a solution of 2-(2-nitrophenyl)pyridine (4) (2.23 g, 11.1 mmol) in
THF/ MeOH = 20/1 (230 mL) was added NaBH (2.53 g, 66.9 mmol). After stirring at room temperature
4
for 3 days, the reaction mixture was concentrated under reduced pressure. To the residue were added
water (100 mL) and Et O (100 mL), and the aqueous layer was extracted with Et O (50 mL × 2). The
2
2
combined organic layers were washed with brine (50 mL), dried over Na SO , and evaporated. The
2
4
residue was purified by silica gel chromatography (hexane/EtOAc
=
10/1) to afford
2
-(pyridin-2-yl)benzeneamine (5) (1.68 g, 89%) as a reddish liquid. Spectroscopic data were in agreement
1
3
1
with those previously reported: R = 0.43 (hexane/EtOAc = 2/1); H NMR (400 MHz, CDCl ): δ 8.61 (d,
f
3
J = 5.0 Hz, 1H), 7.77 (dd, J = 7.7, 7.7 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H),
.21–7.15 (m, 2H), 6.79 (dd, J = 7.7, 7.7 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 5.74 (br, 2H).
7
1
2
N ,N -Bis(2-(pyridin-2-yl)phenyl)oxalamide (6). To a solution of 2-(pyridin-2-yl)benzeneamine (5)
1.68 g, 9.89 mmol) and Et N (1.67 mL, 11.9 mmol) in dichloromethane (DCM) (50 mL) was added a
(
3
solution of (COCl) (ca. 0.5 mL) in DCM (2 mL) dropwise at room temperature until the starting material
2
disappeared. The resulting mixture was quenched with saturated aqueous NaHCO (20 mL), and the
3
aqueous layer was extracted with DCM (20 mL × 2). The combined organic layers were washed with
water (20 mL), dried over Na SO , and evaporated. The residue was purified by trituration
2
4
1
2
(
hexane/EtOAc = 2/1) to afford N ,N -bis(2-(pyridin-2-yl)phenyl)oxalamide (6) (1.71 g, 88%) as a
1
reddish brown solid: R = 0.41 (hexane/EtOAc = 2/1); H NMR (400 MHz, CDCl ): δ 13.68 (s, 2H), 8.88
f
3
(d, J = 4.9 Hz, 2H), 8.67 (d, J = 8.3 Hz, 2H), 7.84 (dd, J = 7.8, 7.8 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.71
(d, J = 7.8 Hz, 2H), 7.47 (dd, J = 7.8, 7.8 Hz, 2H), 7.31 (dd, J = 7.8, 4.9 Hz, 2H), 7.25 (dd, J = 8.3, 7.8 Hz,
1
3
2
1
H); C NMR (100 MHz, CDCl ): δ 158.9, 157.5, 148.3, 137.6, 136.3, 129.9, 128.9, 127.3, 124.5, 122.6,
3
22.1, 121.8; IR (ATR): 3059.2, 1678.4, 1583.6, 1512.0, 1474.1, 1439.3, 1419.7, 1312.5, 753.6, 547.9
–
1
+
cm ; mp 225 °C; HRMS (ESI) calcd. for C H O N [M+H ] 395.1503, found 395.1502.
2
4
19
2
4
1
2
1
2
N ,N -Bis(2-(pyridin-2-yl)phenyl)ethylenediamine (7). To a solution of N ,N -bis(2-(pyridin-2-
yl)phenyl)oxalamide (6) (105 mg, 0.266 mmol) in 1,4-dioxane (2.7 mL) was added DIBAL (1.02 M in
toluene, 2.22 mL, 2.26 mmol). After stirring at 50 °C for 3 h, the resulting mixture was quenched with
saturated aqueous Rochelle salt (3 mL) and diluted with Et O (5 mL), and the aqueous layer was
2
extracted with Et O (5 mL × 2). The combined organic layers were washed with brine (5 mL), dried over
2
Na SO , and evaporated. The residue was purified by silica gel chromatography (hexane/EtOAc = 15/1)
2
4
1
2
to afford N ,N -bis(2-(pyridin-2-yl)phenyl)ethylenediamine (7) (29.0 mg, 30%) as a yellow solid: R =
f
1
0
.50 (hexane/EtOAc = 2/1); H NMR (400 MHz, CDCl ): δ 8.38 (br, 2H), 8.30 (d, J = 5.0 Hz, 2H), 7.70
3
(dd, J = 7.7, 7.7 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 7.7 Hz, 2H), 7.26 (dd, J = 8.2, 7.2 Hz, 2H),

HETEROCYCLES, Vol. 88, No. 2, 2014
1547
1
7
.07 (dd, J = 7.2, 5.0 Hz, 2H), 6.83 (d, J = 7.7 Hz, 2H), 6.73 (dd, J = 7.7, 7.7 Hz, 2H), 3.55 (s, 4H); H
NMR (400 MHz, DMSO-d ): δ 8.62 (br, 2H), 8.23 (d, J = 5.0 Hz, 2H), 7.85 (dd, J = 7.7, 7.7 Hz, 2H),
6
7
2
.80 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 7.7 Hz, 2H), 7.23 (dd, J = 8.2, 7.7 Hz, 2H), 7.21 (dd, J = 7.7, 5.0 Hz,
1
3
H), 6.82 (d, J = 7.7 Hz, 2H), 6.67 (dd, J = 7.7, 7.7 Hz, 2H), 3.46 (br, 4H); C NMR (100 MHz, CDCl ):
3
δ 159.6, 147.6, 147.3, 136.7, 130.3, 129.4, 122.1, 121.6, 120.6, 115.8, 111.4, 42.6; IR (ATR): 3257.7,
–
1
3
056.6, 2849.0, 1602.7, 1580.9, 1560.6, 1510.2, 1477.0, 1439.0, 744.2, 626.3 cm ; mp 146.4 °C; HRMS
+
(
ESI) calcd. for C H N [M+H ] 367.1917, found 367.1917.
2
4
23
4
General procedure for the preparation of imidazolinium salts. To a suspension of diamine and NH X
4
(
1.2 equiv. of diamine) in HFIP (0.1 M) was added CH(OMe) (10% w/w of HFIP). After stirring at room
3
temperature for 1 h, to the mixture was added an internal standard, and then the excess CH(OMe) and
3
HFIP were removed under reduced pressure to afford a crude residue. The residue was dissolved in
1
DMSO-d , and the solution was analyzed by H-NMR. NMR yields were obtained by careful integration
6
based on the internal standard.
1
,3-Bis(2-(pyridin-2-yl)phenyl)imidazolinium tetrafluoroborate (8a). According to general procedure,
1
2
1
,3-bis(2-(pyridin-2-yl)phenyl)imidazolinium tetrafluoroborate (8a) was prepared from N ,N -bis(2-
(
pyridin-2-yl)phenyl)ethylenediamine (7) (8.0 mg, 0.022 mmol) and NH BF (2.7 mg, 0.026 mmol). The
4 4
NMR yield was obtained using fluorene (3.9 mg, 0.024 mmol) as an internal standard (79%): R = 0.25
f
1
(
DCM/MeOH = 10/1); H NMR (400 MHz, DMSO-d ): δ 8.92 (s, 1H), 8.71 (d, J = 4.6 Hz, 2H), 8.00 (dd,
6
J = 7.8, 7.8 Hz, 2H), 7.78–7.74 (m, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.66–7.60 (m, 6H), 7.50 (dd, J = 7.8,
1
3
4
.6 Hz, 2H), 4.17 (s, 4H); C NMR (100 MHz, DMSO-d ): δ 158.9, 157.2, 155.0, 149.5, 137.7, 136.0,
6
-
1
33.7, 131.2, 130.0, 127.3, 124.0, 123.2, 52.7; HRMS (ESI) calcd. for C H N [M-BF ] 377.1761,
25
21
4
4
found 377.1754.
1
,3-Bis(2-(pyridin-2-yl)phenyl)imidazolinium chloride (8b). According to general procedure,
1
2
1
,3-bis(2-(pyridin-2-yl)phenyl)imidazolinium chloride (8b) was prepared from N ,N -bis(2-(pyridin-2-
yl)phenyl)ethylenediamine (7) (9.1 mg, 0.025 mmol) and NH Cl (1.6 mg, 0.030 mmol). The NMR yield
4
was obtained using fluorene (5.2 mg, 0.031 mmol) as an internal standard (73%): R = 0.14 (DCM/MeOH
f
1
=
10/1); H NMR (400 MHz, DMSO-d ): δ 8.89 (s, 1H), 8.68 (d, J = 5.0 Hz, 2H), 7.98 (dd, J = 7.7, 7.7
6
Hz, 2H), 7.75–7.72 (m, 2H), 7.70 (d, J = 7.7 Hz, 2H), 7.65–7.59 (m, 6H), 7.48 (dd, J = 7.7, 5.0 Hz, 2H),
1
3
4
1
3
2
.18 (s, 4H) ppm; C NMR (100 MHz, DMSO-d6): δ 158.9, 157.3, 155.0, 149.5, 137.7, 136.0, 133.7,
-
31.1, 130.0, 127.3, 124.0, 123.2, 52.7 ppm; HRMS (ESI): calcd. for C H N [M-Cl ] 377.1761, found
2
5
21
4
77.1761.
-Benzyloxybromobenzene (9). To a suspension of 2-bromophenol (8) (1.79 g, 10.4 mmol) and K CO
1
3
2
3
(2.86 g, 20.7 mmol) in DMF (10 mL) was added benzyl chloride (1.31 mL, 11.4 mmol). After stirring at
7
0 °C for 1.5 h, to the resulting mixture was added MeOH (0.5 mL), Et O (20 mL), and water (20 mL),
2

1548
HETEROCYCLES, Vol. 88, No. 2, 2014
and the aqueous layer was extracted with Et O (10 mL × 2). The combined organic layers were washed
2
with water (20 mL) and brine (20 mL), dried over Na SO , and evaporated. The residue was purified by
2
4
silica gel chromatography (hexane/EtOAc = 100/1) to afford 2-benzyloxybromobenzene (9) (2.69 g,
1
3
9
9%) as a clear liquid. Spectroscopic data were in agreement with those previously reported: R = 0.71
f
1
(
hexane/EtOAc = 2/1); H NMR (400 MHz, CDCl ): δ 7.56 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H),
3
7
1
.39 (dd, J = 7.3, 7.3 Hz, 2H), 7.33 (d, J = 7.3 Hz, 1H), 7.23 (dd, J = 8.0, 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz,
H), 6.85 (d, J = 8.0 Hz, 1H) 5.17 (s, 2H).
1
2
t
(
1R,2R)-N ,N -Bis(2-benzyloxyphenyl)-1,2-cyclohexanediamine (10). To a suspension of NaO Bu (980
mg, 10.2 mmol), (R)-BINAP (254 mg, 0.407 mmol), and Pd (dba) (156 mg, 0.170 mmol) in degassed
2
3
toluene (12 mL), was added a solution of (1R,2R)-1,2-cyclohexanediamine (388 mg, 3.40 mmol) and
2
-benzyloxybromobenzene (9) (2.24 g, 8.48 mmol) in degassed toluene (5 mL). After stirring at 140 °C
®
for 25 h, the resulting mixture was diluted with Et O (30 mL), filtered through a Celite pad, and
2
evaporated. The residue was purified by silica gel chromatography (hexane/EtOAc = 50/1) to afford
1
2
(
1R,2R)-N ,N -bis(2-benzyloxyphenyl)-1,2-cyclohexanediamine (10) (1.46 g, 90%) as a clear viscous
1
liquid: R = 0.35 (hexane/EtOAc = 10/1); H NMR (400 MHz, CDCl ): δ 7.26–7.12 (m, 10H), 6.88 (dd, J
f
3
=
7.8, 7.8 Hz, 2H), 6.81 (d, J = 7.8 Hz, 2H), 6.71 (d, J = 7.8 Hz, 2H), 6.64 (dd, J = 7.8, 7.8 Hz, 2H), 4.99
(d, J = 12.0 Hz, 2H), 4.93 (d, J = 12.0 Hz, 2H), 4.57 (br, 2H), 3.30 (br, 2H), 2.31 (br, 2H), 1.75 (br, 2H),
1
3
1
1
1
.43 (br, 2H), 1.31 (br, 2H); C NMR (100 MHz, CDCl ): δ 146.4, 138.4, 137.2, 128.4, 127.7, 127.1,
3
21.8, 116.3, 111.9, 110.5, 70.5, 57.0, 32.4, 24.5; IR (ATR): 3405.7, 3062.2, 2928.7, 2856.2, 1599.8,
–
1
27
D
506.4, 1444.7, 1023.4, 732.0, 696.1 cm ; [α]
+5.4 (c 0.0054, CHCl ); HRMS (ESI) calcd. for
3
+
C H O N [M+H ] 479.2693, found 479.2695.
32
35
2
2
1
2
(
1R,2R)-N ,N -Bis(2-hydroxyphenyl)-1,2-cyclohexanediamine dihydrochloride (11). To a solution of
1
2
(
1R,2R)-N ,N -bis(2-benzyloxyphenyl)-1,2-cyclohexanediamine (10) (336 mg, 0.701 mmol) in
MeOH/AcOH = 1/1 (8 mL) was added Pd/C (743 mg, 0.0701 mmol). After vigorously stirring under H2
atmosphere at room temperature for 5 days, the resulting mixture was diluted with EtOAc (10 mL) and
®
filtered through a Celite pad. The filtrate was added conc. HCl (0.2 mL) and evaporated, and then the
1
2
residue was purified by trituration (EtOAc) to afford (1R,2R)-N ,N -bis(2-hydroxyphenyl)-1,2-
cyclohexanediamine dihydrochloride (11) (284 mg, quant.) as a gray powder: R (before hydrochloride
f
1
salt) = 0.35 (hexane/EtOAc = 2/1); H NMR (400 MHz, DMSO-d ): δ 10.27 (br, 2H), 8.36 (br, 2H), 7.14
6
(d, J = 7.3 Hz, 2H), 6.95 (d, J = 7.3 Hz, 2H), 6.92 (dd, J = 7.3, 7.3 Hz, 2H), 6.80 (dd, J = 7.3, 7.3 Hz, 2H),
1
3
3
.58 (br, 2H), 1.88 (br, 2H), 1.66 (br, 2H), 1.40 (br, 2H), 1.21 (br, 2H); C NMR (100 MHz, DMSO-d ):
6
δ 148.9, 127.3, 124.9, 120.4, 119.3, 115.7, 58.7, 28.5, 23.5; IR (ATR): 2941.7, 2680.2, 1736.7, 1600.4,
–
1
29
D
1
508.6, 1470.6, 1236.5, 1097.8, 1039.9, 751.1 cm ; [α] –16.0 (c 0.0050, MeOH); mp 111 °C
+
(
decomposition); HRMS (ESI) calcd. for C H O N Na [M–2HCl+Na ] 321.1573, found 321.1574.
1
8
22
2
2

HETEROCYCLES, Vol. 88, No. 2, 2014
1549
1
2
(
1R,2R)-N ,N -Bis(2-(pyridin-2-yloxy)phenyl)-1,2-cyclohexanediamine (12). To a suspension of NaH
1
2
(
60% in oil, 132 mg, 3.29 mmol) in DMF (3.3 mL) was added (1R,2R)-N ,N -bis(2-hydroxyphenyl)-1,2-
cyclohexanediamine dihydrochloride (11) and 2-fluoropyridine (0.283 mL, 3.29 mmol). After stirring at
20 °C for 2 days, to the resulting mixture were added water (5 mL) and Et O (5 mL), and the aqueous
1
2
layer was extracted with Et O (5 mL × 2). The combined organic layers were washed with water (10 mL)
2
and brine (5 mL), dried over Na SO , and evaporated. The residue was purified by silica gel
2
4
1
2
chromatography (hexane/EtOAc = 4/1) to afford (1R,2R)-N ,N -bis(2-(pyridin-2-yloxy)phenyl)-1,2-
1
cyclohexanediamine (12) (103 mg, 35%) as a clear viscous liquid: R = 0.35 (hexane/EtOAc = 2/1); H
f
NMR (400 MHz, CDCl ): δ 8.14 (d, J = 5.1 Hz, 2H), 7.51 (dd, J = 8.0, 7.0 Hz, 2H), 7.01 (dd, J = 8.0, 7.6
3
Hz, 2H), 6.93 (d, J = 7.6 Hz, 2H), 6.90 (dd, J = 7.0, 5.1 Hz, 2H), 6.71 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.0
1
Hz, 2H), 6.34 (dd, J = 7.6, 7.6 Hz, 2H), 4.09 (br, 2H), 3.20 (br, 2H), 2.09 (br, 2H), 1.23 (br, 6H); H
NMR (400 MHz, DMSO-d ): δ 8.06 (d, J = 4.9 Hz, 2H), 7.67 (dd, J = 8.2, 6.8 Hz, 2H), 7.01 (dd, J = 6.8,
6
4
.9 Hz, 2H), 6.94 (dd, J = 7.7, 7.7 Hz, 2H), 6.83 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 7.7 Hz, 2H), 6.75 (d, J =
.7 Hz, 2H), 6.53 (dd, J = 7.7, 7.7 Hz, 2H), 4.54 (br, 2H), 3.28 (br, 2H), 1.92 (br, 2H), 1.58 (br, 2H), 1.18
7
1
3
(
br, 4H); C NMR (100 MHz, CDCl ): δ 163.5, 147.8, 141.1, 140.4, 139.3, 125.9, 121.5, 118.4, 116.7,
3
1
1
4
12.3, 110.4, 56.4, 31.7, 24.0; IR (ATR): 3394.8, 3056.8, 2930.3, 2855.7, 1606.3, 1509.7, 1466.3, 1424.5,
-1
28
D
+
234.9, 736.5 cm ; [α]
+1.36 (c 0.012, CHCl ); HRMS (ESI) calcd. for C H O N Na [M+Na ]
3 28 28 2 4
75.2104, found 475.2110.
(3aR,7aR)-1,3-Bis(2-(pyridin-2-yloxy)phenyl)-3a,4,5,6,7,7a-hexahydrobenzoimidazolium
tetrafluoroborate (14a). According to general procedure, (3aR,7aR)-1,3-bis(2-(pyridin-2-yloxy)phenyl)-
1
2
3
a,4,5,6,7,7a-hexahydrobenzoimidazolium tetrafluoroborate (14a) was prepared from (1R,2R)-N ,N -
bis(2-(pyridin-2-yloxy)phenyl)-1,2-cyclohexanediamine (12) (13.1 mg, 0.029 mmol) and NH BF (3.6
4
4
mg, 0.034 mmol). The NMR yield was obtained using phenanthrene (4.9 mg, 0.028 mmol) as an internal
1
standard (59%): R = 0.28 (DCM/MeOH = 10/1); H-NMR (400 MHz, DMSO-d ): δ 9.47 (s, 1H), 8.11 (d,
f
6
J = 5.0 Hz, 2H), 7.84 (dd, J = 8.2, 6.9 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.55 (dd, J = 7.8, 7.8 Hz, 2H),
7
.42 (dd, J = 7.8, 7.8 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.17 (dd, J = 6.9, 5.0 Hz, 2H), 7.02 (d, J = 8.2 Hz,
13
2
H), 3.92 (br, 2H), 2.06 (br, 2H), 1.76 (br, 2H), 1.42 (br, 2H), 1.19 (br, 2H); C NMR (100 MHz,
DMSO-d6): δ 161.7, 160.6, 148.2, 147.4, 140.8, 130.8, 126.9, 126.8, 125.8, 123.2, 120.1, 111.7, 69.5,
–
2
7.0, 23.1; HRMS (ESI) calcd. for C H O N [M-BF ] 463.2129, found 463.2129.
2
9
27
2
4
4
(3aR,7aR)-1,3-Bis(2-(pyridin-2-yloxy)phenyl)-3a,4,5,6,7,7a-hexahydrobenzoimidazolium
chloride
(14b). According to general procedure, (3aR,7aR)-1,3-bis(2-(pyridin-2-yloxy)phenyl)-3a,4,5,6,7,7a-
1
2
hexahydrobenzoimidazolium chloride (14-Cl) was prepared from (1R,2R)-N ,N -bis(2-(pyridin-2-
yloxy)phenyl)-1,2-cyclohexanediamine (12) (13.4 mg, 0.030 mmol) and NH Cl (1.9 mg, 0.036 mmol).
4
The NMR yield was obtained using phenanthrene (5.3 mg, 0.030 mmol) as an internal standard (73%): Rf

1550
HETEROCYCLES, Vol. 88, No. 2, 2014
1
=
0.13 (DCM/MeOH = 10/1); H-NMR (400 MHz, DMSO-d ): δ 9.47 (s, 1H), 8.08 (d, J = 5.4 Hz, 2H),
6
7
8
2
1
.83 (dd, J = 8.6, 7.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.53 (dd, J = 8.2, 8.2 Hz, 2H), 7.41 (dd, J = 8.2,
.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.15 (dd, J = 7.2, 5.4 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 3.91 (br,
1
3
H), 2.04 (br, 2H), 1.74 (br, 2H), 1.40 (br, 2H), 1.18 (br, 2H); C NMR (100 MHz, DMSO-d ): δ 161.7,
6
60.6, 148.3, 147.4, 140.7, 130.8, 127.0, 126.9, 125.7, 123.1, 120.1, 111.7, 69.6, 27.0, 23.1; HRMS
–
(
ESI): calcd. for C H O N [M-Cl ] 463.2129, found 463.2131.
2
9
27
2
4
ACKNOWLEDGEMENTS
This work was financially supported in part by a Grant-in-Aid for Challenging Exploratory Research (No.
2
3659014) from JSPS, Japan, the Global COE program "Center for Practical Chemical Wisdom" by
MEXT, and a Waseda University Grant for Special Research Projects.
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