One-pot synthesis of imidazolines from aldehydes: detailed study about solvents and substrates

Article abstract of DOI:10.1016/j.tet.2006.11.007

Imidazolines were prepared in one-pot operation from aldehydes and diamines through oxidation of aminal intermediates by NBS. This method could be applied to various aromatic and aliphatic aldehydes and N-nonsubstituted and N-monosubstituted 1,2-diamines. Furthermore, it was found that CH₂Cl₂ could be altered to TBME, a more environmentally friendly solvent, in the reaction using N-nonsubstituted 1,2-diamines. The reaction conditions were very mild and chemoselective.

Full text of DOI:10.1016/j.tet.2006.11.007

Tetrahedron 63 (2007) 638–643
One-pot synthesis of imidazolines from aldehydes: detailed
study about solvents and substrates
y
y
*
Hiromichi Fujioka, Kenichi Murai, Ozora Kubo, Yusuke Ohba and Yasuyuki Kita
*
Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 28 August 2006; revised 1 November 2006; accepted 2 November 2006
Available online 16 November 2006
Abstract—Imidazolines were prepared in one-pot operation from aldehydes and diamines through oxidation of aminal intermediates by NBS.
This method could be applied to various aromatic and aliphatic aldehydes and N-nonsubstituted and N-monosubstituted 1,2-diamines. Fur-
thermore, it was found that CH2Cl2 could be altered to TBME, a more environmentally friendly solvent, in the reaction using N-nonsubstituted
1,2-diamines. The reaction conditions were very mild and chemoselective.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
as mild reaction conditions, low reaction temperature
(0 ꢀC–rt), and the use of an almost neutral reagent (NBS).
After our study, several methods to prepare imidazolines
from aldehydes were reported.5g,10
The importance of imidazolines in biochemistry has recently
increased, since they are found in many biologically active
compounds.1 They are also used in organic synthesis as syn-
thetic intermediates,2 chiral ligands,3 chiral auxiliaries,4 and
so on. Furthermore, many oxidizing methods of imidazo-
lines to imidazoles, which are also found in many biological
compounds, have been reported.5 Development of an effi-
cient method to synthesize imidazolines is a very important
issue in the synthetic organic field. Many methodologies
have been developed so far. Most of them are the methods
using nitriles6 and esters7 as starting materials. However,
these previous methods have several drawbacks. They need
a high reaction temperature or acidic conditions. Further-
more, in the case of nitrile compounds, the use of highly
toxic cyanide is necessary for their preparation. Although
several new methods have recently been reported8 to over-
come these drawbacks, they must use special starting mate-
rials such as azalactones,8a 2-aryl-1,1-dibromoethanes,5e
and amino amides.8b The development of simple methods
that overcome the previous drawbacks is strongly desirable.
H
N
H2N
CH2Cl2
NH2
R-CHO
NBS
R
R
N
H
Br
N
N
H
N
H
R
N
H
Scheme 1.
On the other hand, from the point of green chemistry, it is
desirable not to use the halogen containing solvents. How-
ever, our reported method used CH2Cl2. We then tried to
use other solvents, which do not contain halogen atoms, in
our method. We discovered that the tert-butyl methyl ether
(TBME) is as effective as CH2Cl2.
We recently communicated an efficient one-pot synthesis of
imidazolines.9 Thus, the first condensation of aldehydes and
diamines forms aminals without any catalyst in CH2Cl2.
Next, the addition of N-bromosuccinimide (NBS) oxidizes
them to afford imidazolines in the one-pot operation
(Scheme 1). This reaction is the first method to prepare imi-
dazolines from aldehydes and has several advantages, such
Herein, we report the improvement of our imidazoline syn-
thetic method by altering the solvent for an environmentally
friendly reaction and the generality of the reaction using
aromatic and aliphatic aldehydes and N-nonsubstituted and
N-substituted diamines.
2. Results and discussion
Keywords: Imidazoline; Aldehyde; Diamine; NBS.
First, we examined the reaction in various solvents using
benzaldehyde and ethylenediamine (Table 1). The reaction
in CH2Cl2 proceeded in excellent yield (entry 1). On the
* Corresponding authors. Tel.: +81 6 6879 8225; fax: +81 6 6879 8229
(Y.K.); e-mail addresses: fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp
JSPS research fellow.
y
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.11.007

H. Fujioka et al. / Tetrahedron 63 (2007) 638–643
639
Table 1
reactions of aliphatic aldehydes, the primary one (entry 9),
the unsaturated one (entry 10), the primary one with benzo-
ate ester (entry 11), and the secondary one (entry 12), also
proceeded well. Most of the aldehydes gave almost the
same results in CH2Cl2 and TBME, whereas in some cases,
the yields of the products in TBME tend to be decreased
probably due to the lower solubility of the aminal intermedi-
ates in the solvent (entries 3, 4, 9, and 10).
(1.05 eq)
H2N
NH2
H
N
then NBS (1.05 eq)
solvent (0.1 M), 0 °C- rt
Ph
Ph-CHO
N
Entry
Solvent
Yield (%)
1
2
3
4
5
CH2Cl2
AcOEt
THF
Toluene
TBME
99
73
76
75
99
Table 3 shows the results of the reactions of various typical
aldehydes and (dl)-trans-1,2-diphenylethylene-1,2-diamine.
Since the studies about asymmetric reactions using chiral
imidazolines as chiral ligands are increasing,3 diphenylethyl-
enediamine is a very popular chiral diamine.11 In these
cases, the reactions of both the aromatic and aliphatic alde-
hydes proceeded in high yields regardless of the solvent.
other hand, the reactions in AcOEt, THF, and toluene re-
sulted in moderate and insufficient yields (entries 2–4).
However, the reaction in TBME proceeded similar to that
in CH2Cl2 (entry 5). Here, we have improved our reaction
to an environmentally friendly one. We then examined the
generality of the reaction in CH2Cl2 and TBME.
Lastly, we studied the reactions using some N-monosub-
stituted diamines (Table 4). The reactions of N-benzyl ethyl-
enediamine 2c with both aromatic and aliphatic aldehydes
resulted in moderate yields both in CH2Cl2 and TBME
(entries 1 and 2). The N-benzyl ethylenediamine decreased
the yields more than ethylenediamine (Table 2, entries 1
and 9). This is probably because the formation of the inter-
mediates, aminals, is difficult due to the N-substituent. We
also studied the reactions of the diamines 2d and 2e prepared
from phenylalanine. Various N-monosubstituted diamines
such as 2d and 2e are easily prepared from amino acids.
The N-benzyl substituted diamine 2d resulted in good yields
in CH2Cl2, whereas the yields of the imidazolines in TBME
are not good (entries 3 and 4). The results in entries 1–4 show
The results from the reactions of ethylenediamine and
various aldehydes in both CH2Cl2 and TBME are shown in
Table 2. As shown in entries 1–8, the reactions using various
aromatic aldehydes having electron donating groups (entries
2 and 6) or electron withdrawing groups (entries 3, 4, and 7)
and pyridine aldehyde (entry 8) proceeded well to give the
corresponding imidazolines in good yields. It is noteworthy
that aldehydes having a nitrile or an ester were selectively
converted to imidazolines without affecting the functional
groups (entries 3 and 4), although such functional groups
were used as starting materials in the previous methods. The
Table 2
(1.05 eq)
2a
H2N
NH2
H
N
then NBS (1.05 eq)
R-CHO
1
R
solvent (0.1 M), 0 °C- rt
N
3
Entry
R–CHO
Product yield in
CH2Cl2, TBME (%)
Entry
R–CHO
Product yield in
CH2Cl2, TBME (%)
Cl
CHO
1a
1
3a (99, 99)
7
3g (83, 85)
CHO
1g
CHO
MeO
NC
CHO
N
2
3
4
3b (94, 96)
3c (95, 80)
3d (94, 76)
8
9
3h (100, 99)
3i (96, 77)
3j (87, 73)
1h
1b
CHO
CHO
CHO
1c
Ph
1i
MeOOC
CHO
1d
Ph
10
1j
F
BzO
CHO
8
CHO
1e
5
6
3e (96, 98)
3f (83, 84)
11
12
3k (98, 98)
3l (85, 81)
1k
Ts
N
CHO
1f
CHO
1l

640
H. Fujioka et al. / Tetrahedron 63 (2007) 638–643
Table 3
functions are used for constructing imidazoline rings in the
Ph
Ph
previous methods. We also showed that CH2Cl2 could be al-
tered to TBME, a more environmentally friendly solvent.
This reaction could be applied to a wide variety of aldehydes
and diamines. Therefore, this method must be an useful tool
to synthesize imidazolines and imidazoles in the fields of
synthetic organic chemistry and medicinal chemistry.
2b (1.05 eq)
H2N
NH2
Ph
N
then NBS (1.05 eq)
solvent (0.1 M), 0 °C-rt
R
R
CHO
N
H
Ph
4a-d
1
Entry
R–CHO
Product yield
in CH2Cl2, TBME (%)
4. Experimental
4.1. General
CHO
1
2
4a (92, 88)
1a
1
The H and 13C NMR spectra were measured at 270 and
300 MHz spectrometers with tetramethylsilane as the inter-
nal standard at 20–25 ꢀC. IR spectra were recorded by a
diffuse reflectance measurement of samples dispersed in
KBr powder. E. Merck silica gel 60 was used for column
chromatography.
1h
4b (96, 92)
N
CHO
CHO
1m
3
4
4c (87, 98)
4d (95, 90)
4.2. Preparation of aldehydes
TsN
CHO 1l
Aldehydes 1a–1j and 1m are commercially available. Com-
pounds 1k and 1l were prepared as follows.
Table 4
4.2.1. 9-Hydroxynonyl benzoate. Benzoyl chloride (1.5 mL,
12.9 mmol) was added to a solution of nonane-1,9-diol
(3.1 g, 19.3 mmol) and triethylamine (2 mL, 14.3 mmol) in
CH2Cl2 (100 mL) under N2 and the mixture was stirred for
12 h. The mixture was poured into water and the resulting
solution was extracted with CH2Cl2. Organic layer was dried
over Na2SO4, and evaporated in vacuo. The residue was
purified by SiO2 column chromatography (Hex/AcOEt¼
3/1) to give 9-hydroxynonyl benzoate (2.33 g, 68%) as a
colorless oil. IR (KBr): 3335, 2929, 2855, 1720, 1600,
R''
N
diamine 2 (1.05 eq), then NBS (1.05 eq)
solvent (0.1 M), 0 °C-rt
R-CHO
1
R
5a-c
N
R'
Entry
R–CHO
Diamine
Product yield
in CH2Cl2, TBME (%)
1
2
Ph–CHO
5a (64, 57)
5b (41, 34)
2c
2d
CHO
H2N
NHBn
Ph
Ph–CHO
CHO
Bn
3
4
5c (96, 51)
5d (94, 27)
1
1452, 1275, 1113, 711 cmꢁ1; H NMR (270 MHz, CDCl3):
H2N
NHBn
d¼1.28–1.50 (10H, m), 1.50–1.59 (2H, m), 1.76 (2H, m),
3.13 (2H, t, J¼6.6 Hz), 3.64 (2H, t, J¼6.7 Hz), 7.26–7.46
(2H, m), 7.52–7.58 (1H, m), 8.02–8.05 (2H, m); 13C NMR
(68 MHz, CDCl3): d¼25.7, 26.0, 28.6, 29.1, 29.3, 29.4, 32.7,
62.9, 65.0, 128.1, 129.2, 130.3, 132.6, 166.4; EI-HRMS m/z
calcd for C16H24O3 (M+): 264.1725; found: 264.1731.
Ph
Bn
H2N HN
5
Ph–CHO
CHO
5e (67)a
5f (66)a
2e
6
Ph
a
Reactions in TBME were not examined.
4.2.2. 9-Oxononyl benzoate (1k). A solution of 9-hydroxy-
nonyl benzoate (2.32 g, 8.78 mmol) in CH2Cl2 (10 mL) was
added to a solution of PCC (3.4 g, 15.8 mmol) in CH2Cl2
(30 mL) under N2 and the mixture was stirred overnight.
The mixture was filtered through Florisil. The filtrate was
evaporated in vacuo. The residue was purified by SiO2 col-
umn chromatography (Hex/AcOEt¼4/1) to give 1k (1.83 g,
79%) as a colorless oil. IR (KBr): 2931, 2856, 1719, 1452,
that CH2Cl2 is an effective solvent in the reactions of
N-monosubstituted diamines. The reason why 2d gave better
yields than 2c is that the formation of the aminal is more
favorable from 2d because the benzyl substituent on the
ethylene unit and N-substituent repel each other. Then,
even the diamine 2e with the bulkier cyclohexyl substituent
gave moderate yields (entries 5 and 6). These results show
that our reaction can also be applied to the N-substituted
diamines, from amino acid derivatives, which have a sub-
stituent on ethylene group.
1277, 1112, 912, 740, 713 cmꢁ1 1H NMR (270 MHz,
;
CDCl3): d¼1.30–1.50 (8H, m), 1.61–1.66 (2H, m), 1.71–
1.79 (2H, m), 2.42 (2H, dt, J¼7.3, 1.9 Hz), 4.31 (2H, t,
J¼6.6 Hz), 7.26–7.47 (2H, m), 7.52–7.58 (1H, m), 8.02–
8.06 (2H, m), 9.76 (1H, t, J¼1.9 Hz); 13C NMR (75 MHz,
CDCl3): d¼22.0, 25.9, 28.6, 29.0 (2C), 29.2, 43.9, 65.0,
128.3, 129.5, 130.4, 132.8, 166.7, 202.9; FAB-HRMS m/z
calcd for C16H23O3 (MH+): 263.1647; found: 263.1640.
3. Conclusion
In conclusion, we developed an efficient method to synthe-
size the imidazolines from aldehydes and 1,2-diamines.
The reaction conditions are very mild and the reactions
proceed from 0 ꢀC to rt. It is also chemoselective. The func-
tions such as an ester and a nitrile can tolerate, whereas such
4.2.3. N-Toluene-4-sulfonylpiperidine-4-carbaldehyde
(1l). A solution of (N-toluene-4-sulfonylpiperidin-4-yl)-
methanol12 (1.60 g, 5.94 mmol) in CH2Cl2 (10 mL) was

H. Fujioka et al. / Tetrahedron 63 (2007) 638–643
641
added to a solution of PCC (1.9 g, 8.9 mmol) in CH2Cl2
1487, 1443, 1254, 1177, 1028, 912, 837, 743 cmꢁ1
;
(35 mL) under N2. The mixture was stirred overnight.
The resulting mixture was filtered through Florisil. The
filtrate was evaporated in vacuo. The residue was purified
by SiO2 column chromatography (Hex/AcOEt¼3/2) to give
1l (863 mg, 54%) as a colorless solid. Mp 106 ꢀC; IR (KBr):
2928, 2845, 2719, 2257, 1728, 1597, 1335, 1163, 912,
1H NMR (300 MHz, CD3OD): d¼3.71 (4H, s), 3.82 (3H,
s), 6.92–6.97 (2H, m), 7.70–7.75 (2H, m); 13C NMR
(68 MHz, CD3OD): d¼50.28, 55.83, 114.63, 123.30,
129.83, 163.10, 166.94; FAB-HRMS m/z calcd for
C10H13N2O (MH+): 177.1028; found: 177.1024. Anal. Calcd
for C10H13N2O: C, 68.16; H, 6.86; N, 15.90. Found: C,
67.86; H, 6.87; N, 15.78.
743 cmꢁ1
;
1H NMR (270 MHz, CDCl3): d¼1.70–1.84
(2H, m), 1.94–2.04 (2H, m), 2.18–2.29 (1H, m), 2.44 (1H,
s), 2.56–2.65 (2H, m), 3.48–3.55 (2H, m), 7.32 (2H, d,
J¼8.1 Hz), 7.63 (2H, d, J¼8.1 Hz), 9.60 (1H, s); 13C NMR
(75 MHz, CDCl3): d¼21.4, 24.5, 45.0, 46.5, 127.4, 129.6,
132.7, 143.6, 202.3; FAB-HRMS m/z calcd for
C13H18NO3S (MH+): 268.1007; found: 268.0995.
4.4.3. 4-(4,5-Dihydro-1H-imidazol-2-yl)benzonitrile (3c).
Eluent: AcOEt to AcOEt/MeOH/TEA¼15/1/1. Mp 202 ꢀC;
IR (KBr): 3160, 2875, 2387, 2295, 2225, 1597, 1554, 1433,
1277, 1176, 849 cmꢁ1 1H NMR (300 MHz, CD3OD):
;
d¼3.67 (4H, s), 7.69 (2H, d, J¼8.1 Hz), 7.81 (2H, d,
J¼8.1 Hz); 13C NMR (75 MHz, CD3OD): d¼50.7, 115.1,
118.8, 128.8, 133.1, 135.2, 165.9. Anal. Calcd for
C10H9N3: C, 70.16; H, 5.30; N, 24.54. Found: C, 69.98; H,
5.44; N, 24.52.
4.3. Preparation of diamines
Compounds 2a, 2b, and 2c are commercially available.
Compound 2d was prepared as per the reported method.13
Compound 2e was prepared as follows.
4.4.4. Methyl 4-(4,5-dihydro-1H-imidazol-2-yl)benzoate
(3d). Eluent: AcOEt to AcOEt/MeOH/TEA¼15/1/1. Mp
176 ꢀC; IR (KBr): 3201, 2931, 1719, 1606, 1477, 1277,
4.3.1. N1-Cyclohexyl-3-phenylpropane-1,2-diamine (2e).
LiAlH4 (1.91 g, 40.2 mmol) was added dropwise in three
portions to a solution of 2-amino-N-cyclohexyl-3-phenyl-
propionamide14 (1.417 g, 5.72 mmol) in THF (58 mL) at
0 ꢀC under N2. The resulting mixture was refluxed for 2
days. The mixture was cooled to 0 ꢀC and quenched by the
addition of water (2 mL), 15% NaOH aq (2 mL), and water
(2 mL) successively. AcOEt and Celite were added to the
mixture and the solution was stirred vigorously and filtered
through Celite pad. The filtrate was evaporated in vacuo
and the residue was purified by SiO2 column chromato-
graphy (CH2Cl2/MeOH/TEA¼50/1/1 to 10/1/1) to give 2e
(950 mg, 71%) as a colorless oil. IR (KBr): 3665, 3645,
3026, 2926, 2851, 2187, 1946, 1807, 1574, 1495, 1452,
912, 743 cmꢁ1; 1H NMR (300 MHz, CDCl3): d¼1.00–1.32
(8H, m), 1.58–1.87 (5H, m), 2.34–2.53 (3H, m), 2.77 (2H,
dt, J¼18.0, 6.2 Hz), 3.02–3.10 (1H, m), 7.19–7.33 (5H,
m); 13C NMR (68 MHz, CDCl3): d¼24.9, 25.0, 26.1, 33.5,
33.8, 42.9, 52.9, 53.1, 56.8, 125.9, 128.1, 128.9, 139.0;
FAB-HRMS m/z calcd for C15H25N2 (MH+): 233.2018;
found: 233.2020.
1
1107, 864 cmꢁ1; H NMR (270 MHz, CD3OD): d¼3.66
(4H, s), 3.80 (3H, s), 7.74 (2H, d, J¼8.7 Hz), 7.93 (2H, d,
J¼8.7 Hz); 13C NMR (68 MHz, CD3OD): d¼51.4, 53.7,
129.2, 131.3, 134.0, 136.1, 167.1, 168.4. Anal. Calcd for
C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.40; H, 5.93; N, 13.55.
4.4.5. 2-(2-Fluorophenyl)-4,5-dihydro-1H-imidazole (3e).
Eluent: AcOEt to AcOEt/MeOH/Et3N¼15/1/1. Mp 85 ꢀC;
IR (KBr): 3466, 3153, 2947, 2868, 2253, 2208, 1620, 1604,
1462, 1283, 1215, 912, 743 cmꢁ1 1H NMR (300 MHz,
;
CD3OD): d¼3.71 (4H, s), 7.12–7.25 (2H, m), 7.44–7.52
(1H, m), 7.78 (1H, dt, J¼7.7, 1.8 Hz); 13C NMR (68 MHz,
CD3OD): *d¼50.22, 116.99, 117.32, 119.17, 119.35,
125.34, 125.39, 131.28, 131.33, 133.50, 133.63, 159.82,
163.32, 163.36, 163.50 (*tautomers); FAB-HRMS m/z calcd
for C9H10FN2 (MH+): 165.0828; found: 165.0835.
4.4.6. 2-o-Tolyl-4,5-dihydro-1H-imidazole (3f). Eluent:
AcOEt/MeOH/TEA¼15/1/1. Mp 88 ꢀC; IR (KBr): 3153,
2931, 2866, 1614, 1593, 1496, 1454, 1285, 1263,
1
4.4. General procedure to synthesize imidazolines
981 cmꢁ1; H NMR (270 MHz, CDCl3): d¼2.48 (3H, s),
3.74 (4H, s), 4.19–4.72 (1H, br s), 7.14–7.31 (3H, m), 7.45
(1H, d, J¼7.4 Hz); 13C NMR (68 MHz, CDCl3): d¼20.5,
50.1, 125.6, 128.1, 129.2, 130.6, 131.0, 136.7, 165.3;
FAB-HRMS m/z calcd for C10H13N2 (MH+): 161.1079;
found: 161.1090. Anal. Calcd for C10H12N2: C, 74.97; H,
7.55; N, 17.48. Found: C, 75.14; H, 7.64; N, 17.46.
The mixture of aldehyde (1 mmol) and diamine (1.05 mmol)
in dry TBME or CH2Cl2 (10 mL) was stirred at 0 ꢀC for
30 min under N2. NBS (1.05 mmol) was added to the mix-
ture and the resulting solution was stirred overnight at rt. Re-
action was quenched by the addition of satd Na2S2O5 aq,
10% NaOH aq, or satd NaHCO3 aq (for ester or nitrile con-
taining compounds). The mixture was extracted with AcOEt
or CH2Cl2. Organic layer was dried over Na2SO4, and evapo-
rated in vacuo. The residue was purified by SiO2 column
chromatography to give imidazoline (yields are shown in
tables).
4.4.7. 2-(2-Chlorophenyl)-4,5-dihydro-1H-imidazole
(3g). Eluent: AcOEt/MeOH/Et3N¼15/1/1. Mp 67 ꢀC; IR
(KBr): 3661, 3433, 3155, 2941, 2868, 2201, 1614, 1591,
1335, 1277, 912, 743 cmꢁ1
;
1H NMR (300 MHz,
CD3OD): d¼3.75 (4H, s), 7.35–7.53 (4H, m); 13C NMR
(68 MHz, CD3OD): d¼50.63, 127.87, 130.93, 131.38,
132.13, 132.16, 133.27, 166.06; FAB-HRMS m/z calcd for
C9H10ClN2 (MH+): 181.0532; found: 181.0532.
4.4.1. Compounds’ data. Imidazolines 3a,15 3i,16 3j,16 4a,17
4b,4b and 4c3d are known compounds.
4.4.2. 2-(4-Methoxyphenyl)-4,5-dihydro-1H-imidazole
(3b). Eluent: AcOEt to AcOEt/MeOH/Et3N¼15/1/1 to 15/
2/2. Mp 135 ꢀC; IR (KBr): 3196, 2936, 1614, 1574, 1520,
4.4.8. 2-(4,5-Dihydro-1H-imidazol-2-yl)pyridine (3h). El-
uent: CH2Cl2/MeOH/TEA¼10/1/1. Mp 94 ꢀC; IR (KBr):
3182, 1606, 1568, 1497, 1456, 1422, 1280, 983 cmꢁ1
;

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H. Fujioka et al. / Tetrahedron 63 (2007) 638–643
1H NMR (300 MHz, CD3OD): d¼3.74 (4H, s), 7.39–7.44
(1H, m), 7.79–7.85 (1H, m), 7.92–7.96 (1H, m), 8.54–8.57
(1H, m); 13C NMR (75 MHz, CD3OD): d¼50.8, 123.6,
127.0, 138.4, 149.4, 150.4, 166.7; FAB-HRMS m/z calcd
for C8H10N3 (MH+): 148.0875; found: 148.0870. Anal.
Calcd for C8H9N3: C, 65.29; H, 6.16; N, 28.55. Found: C,
65.22; H, 6.25; N, 28.28.
FAB-HRMS m/z calcd for C18H21N2 (MH+): 265.1705;
found: 265.1707.
4.4.14. 1,4-Dibenzyl-2-phenyl-4,5-dihydro-1H-imidazole
(5c). Eluent: AcOEt/TEA¼20/1. Mp 88 ꢀC; IR (KBr):
3062, 2930, 2250, 2189, 1595, 1569 cmꢁ1 1H NMR
;
(270 MHz, CDCl3): d¼2.79 (1H, dd, J¼13.8, 8.0 Hz),
3.06–3.15 (2H, m), 3.34 (1H, t, J¼10.0 Hz), 4.08 (1H, A
in ABq, J¼15.9 Hz), 4.17 (1H, B in ABq, J¼15.9 Hz),
4.41–4.48 (1H, m), 7.04–7.07 (2H, m), 7.17–7.39 (11H,
m), 7.53–7.57 (2H, m); 13C NMR (68 MHz, CDCl3):
d¼42.1, 52.5, 54.6, 65.4, 125.9, 126.6, 127.0, 127.9,
128.0, 128.2, 128.4, 129.4, 129.7, 131.0, 137.6, 138.2,
166.1; FAB-HRMS m/z calcd for C23H23N2 (MH+):
327.1861; found: 327.1870.
4.4.9. 8-(4,5-Dihydro-1H-imidazol-2-yl)octyl benzoate
(3k). Eluent: CH2Cl2/MeOH/TEA¼10/1/1. Mp 67 ꢀC; IR
(KBr): 3188, 2930, 2849, 1714, 1612, 1281, 1123 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d¼1.34–1.43 (8H, m), 1.59–
1.62 (2H, m), 1.71–1.78 (2H, m), 2.24 (2H, t, J¼7.78 Hz),
3.58 (4H, s), 4.31 (2H, t, J¼6.7 Hz), 4.27–4.34 (1H, br s),
7.28–7.47 (2H, m), 7.53–7.59 (1H, m), 8.04 (1H, d,
J¼3.85 Hz); 13C NMR (68 MHz, CDCl3): d¼25.9, 26.6,
28.6, 29.0, 29.1, 29.2, 29.2, 49.4, 64.9, 128.1, 129.3,
130.3, 132.6, 166.4, 167.9; FAB-HRMS m/z calcd for
C18H27N2O2 (MH+): 303.2073; found: 303.2086.
4.4.15. 1,4-Dibenzyl-2-phenethyl-4,5-dihydro-1H-imid-
azole (5d). Eluent: AcOEt/TEA¼20/1. Colorless oil; IR
(KBr): 2922, 2848, 1604, 1494, 1454 cmꢁ1 1H NMR
;
(270 MHz, CDCl3): d¼2.51–2.68 (3H, m), 2.90–3.20 (5H,
m), 4.06–4.25 (3H, m), 7.02 (2H, d, J¼6.8 Hz), 7.14–7.30
(13H, m); 13C NMR (68 MHz, CDCl3): d¼29.6, 32.9,
42.2, 50.0, 54.2, 64.5, 125.8, 125.9, 126.7, 127.0, 128.0,
128.1, 128.2, 128.4, 129.1, 137.3, 138.5, 140.9, 165.1;
FAB-HRMS m/z calcd for C25H27N2 (MH+): 355.2174;
found: 355.2178.
4.4.10. 4-(4,5-Dihydro-1H-imidazol-2-yl)-N-toluene-4-
sulfonylpiperidine (3l). Eluent: AcOEt/MeOH/Et3N¼15/
1/1 to 5/1/1. Mp 173–174 ꢀC; IR (KBr): 3402, 3153, 2930,
2868, 2253, 1794, 1620, 1333, 1163, 913, 743 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d¼1.71–1.85 (2H, m), 1.94–
1.98 (2H, m), 2.21–2.38 (3H, m), 2.44 (3H, s), 3.59 (4H,
s), 3.77–3.81 (2H, m), 7.33 (2H, d, J¼7.9 Hz), 7.64 (2H,
d, J¼8.2 Hz); 13C NMR (75 MHz, CDCl3): d¼21.4, 28.7,
35.4, 45.7, 49.0, 127.5, 129.6, 132.6, 143.6, 169.3; FAB-
HRMS m/z calcd for C15H22N3O2S (MH+): 308.1433;
found: 308.1433.
4.4.16. 4-Benzyl-1-cyclohexyl-2-phenyl-4,5-dihydro-1H-
imidazole (5e). Eluent: Hex/AcOEt¼4/1 to AcOEt to
AcOEt/Et3N¼20/1. Colorless oil; IR (KBr): 3059, 3024,
2934, 1952, 1612, 1593, 1495, 1450, 1402, 772, 748,
700 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d¼0.86–1.09
4.4.11. 4-(4,5-trans-Diphenyl-4,5-dihydro-1H-imidazol-
2-yl)-N-toluene-4-sulfonylpiperidine (4d). Eluent: Hex/
AcOEt/TEA¼10/5/1. Mp 191 ꢀC; IR (KBr): 3377, 3028,
2926, 2851, 2255, 1807, 1599, 1493, 1454, 1337, 1163,
912, 725 cmꢁ1; 1H NMR (300 MHz, CDCl3): d¼1.80–2.02
(4H, m), 2.44 (3H, s), 2.24–2.48 (3H, m), 3.68–3.75 (2H,
m), 4.61 (2H, s), 7.12–7.14 (3H, m), 7.24–7.34 (9H, m),
7.63 (2H, d, J¼8.1 Hz); 13C NMR (68 MHz, CDCl3):
d¼21.6, 29.0, 29.1, 35.6, 45.7, 126.1, 127.3, 127.5, 128.5,
129.5, 133.0, 143.4 (2C), 167.4; FAB-HRMS m/z calcd for
C27H30N3O2S (MH+): 460.2059; found: 460.2061.
(3H, m), 1.16–1.34 (3H, m), 1.47–1.61 (4H, m), 2.74 (1H,
dd, J¼13.6, 8.4 Hz), 3.16–3.22 (3H, m), 3.39 (1H, t,
J¼10.1 Hz), 4.32–4.42 (1H, m), 7.19–7.45 (10H, m); 13C
NMR (68 MHz, CDCl3): d¼24.9, 25.0, 25.1, 29.9, 30.6,
41.9, 47.9, 54.2, 64.5, 125.6, 127.6, 127.7, 127.8, 128.9,
129.1, 131.7, 138.3, 165.2; FAB-HRMS m/z calcd for
C22H27N2 (MH+): 319.2174; found: 319.2174.
4.4.17. 4-Benzyl-1-cyclohexyl-2-phenethyl-4,5-dihydro-
1H-imidazole (5f). Eluent: AcOEt/Et3N¼20/1 to 10/1. Col-
orless oil; IR (KBr): 3666, 3645, 2855, 2176, 1946, 1798,
1
1599, 1416, 912, 743 cmꢁ1; H NMR (300 MHz, CDCl3):
4.4.12. 1-Benzyl-2-phenyl-4,5-dihydro-1H-imidazole
(5a). Eluent: AcOEt/TEA¼10/1. Mp 66 ꢀC; IR (KBr):
d¼0.93–1.43 (6H, m), 1.57 (2H, t, J¼13.3 Hz), 1.73 (2H,
d, J¼11.3 Hz), 2.45 (2H, t, J¼8.2 Hz), 2.57 (1H, dd,
J¼13.5, 9.3 Hz), 2.91–3.06 (3H, m), 3.12 (2H, dd, J¼13.4,
4.2 Hz), 3.22 (1H, t, J¼9.6 Hz), 4.15 (1H, m), 7.17–7.33
(10H, m); 13C NMR (75 MHz, CDCl3): d¼25.3, 25.5,
25.6, 29.8, 30.5, 31.0, 33.0, 42.3, 48.4, 53.7, 64.0, 125.9,
126.0, 128.1, 128.2, 128.3, 129.2, 138.9, 141.4, 164.8;
HRMS m/z calcd for C24H31N2 (MH+): 347.2487; found:
347.2498.
2844, 2196, 1569, 912, 742 cmꢁ1 1H NMR (270 MHz,
;
CDCl3): d¼3.37 (2H, t, J¼9.9 Hz), 3.91 (2H, t, J¼9.9 Hz),
4.27 (2H, s), 7.23–7.39 (8H, m), 7.58–7.62 (2H, m); 13C
NMR (68 MHz, CDCl3): d¼50.9, 53.0, 53.2, 126.8, 127.0,
127.8, 128.1, 128.2, 128.4, 130.0, 131.0, 137.7; FAB-
HRMS m/z calcd for C16H17N2 (MH+): 237.1392; found:
237.1403.
4.4.13. 1-Benzyl-2-phenethyl-4,5-dihydro-1H-imidazole
(5b). Eluent: Hex/AcOEt¼4/1 to AcOEt to AcOEt/
Et3N¼40/1 to 10/1 to 5/1. Colorless oil; IR (KBr): 3026,
1H NMR (300 MHz, CDCl3): d¼2.54–2.59 (2H, m), 3.00–
3.06 (2H, m), 3.21 (2H, t, J¼9.8 Hz), 3.72 (2H, t,
J¼9.9 Hz), 4.23 (2H, s), 7.17–7.40 (5H, m); 13C NMR
(68 MHz, CDCl3): d¼29.8, 32.9, 50.2, 50.5, 51.7, 126.1,
127.1, 127.4, 128.2, 128.4, 128.6, 137.3, 141.0, 166.4;
Acknowledgements
2930, 2860, 1607, 1495, 1454, 1265, 1028, 748, 700 cmꢁ1
;
This work was supported by Grant-in-Aid for Scientific
Research (S) and Grant-in-Aid for Scientific Research for
Exploratory Research from Japan Society for the Promotion
of Science and by Grant-in-Aid for Scientific Research on
Priority Areas (17035047) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.

H. Fujioka et al. / Tetrahedron 63 (2007) 638–643
643
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