1,2-disubstituted hexahydro-1 H -benzo[d]imidazoles: Synthesis, characterization, and stability

Article abstract of DOI:10.1055/s-0030-1258256

Starting from commercially available (hetero)aromatic nitriles and (1R,2R)-cyclohexane-1,2-diamine, nine NH-imidazolines (hexahydro-1H-benzo[d] imidazoles) were synthesized in good yields. The molecular structures of three imidazolines were confirmed by X-ray analysis. N-Benzylation afforded some of the desired N-benzylimidazolines, but was incompatible with imidazolines that possessed strong electron-accepting heteroaromatic groups at C2. In the latter cases, the products decomposed during column chromatography to form N,N-disubstituted cyclohexane-1,2-diamines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258256

3934
PAPER
1,2-Disubstituted Hexahydro-1H-benzo[d]imidazoles: Synthesis,
Characterization, and Stability
H
exahydro
i
-
1
H
-b
ř
enzo[
d
]i
í
midazoles Tydlitát,a Filip Bureš,*a Jiří Kulhánek,a Aleš Růžičkab
a
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573,
Pardubice 532 10, Czech Republic
Fax +420(46)6037068; E-mail: filip.bures@upce.cz
Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573,
Pardubice 532 10, Czech Republic
b
Received 3 August 2010; revised 9 August 2010
(Figure 1).15,16 The synthesis of imidazolines 4 involved
the condensation of exo-camphordiamine dihydro-
chloride17 with picolinimidate generated in situ from pyri-
dine-2-carbonitrile and sodium methoxide. The resulting
Abstract: Starting from commercially available (hetero)aromatic
nitriles and (1R,2R)-cyclohexane-1,2-diamine, nine NH-imidazo-
lines (hexahydro-1H-benzo[d]imidazoles) were synthesized in
good yields. The molecular structures of three imidazolines were
confirmed by X-ray analysis. N-Benzylation afforded some of the camphor-imidazoline was further functionalized at the
desired N-benzylimidazolines, but was incompatible with imidazo-
imidazoline nitrogen N1 to afford 4 as a pair of two sepa-
lines that possessed strong electron-accepting heteroaromatic
rable regioisomers. In an effort to extend this study, we
groups at C2. In the latter cases, the products decomposed during
decided to modify the imidazoline ligand by replacing the
column chromatography to form N,N¢-disubstituted cyclohexane-
camphor moiety with cyclohexane. Specifically, we pro-
1,2-diamines.
posed hexahydro-1H-benzo[d]imidazoles 5–11 and 12,13
Key words: heterocycles, imidazolines, chiral pool, N-benzylation,
(Figure 1), which feature annulated cyclohexane and imi-
stability
dazoline rings and various pendants at C2. As recently re-
ported by Beller et al.,18,19 pyridine bis-imidazolines
(pybim) similar to 13 have shown promising activities in
Optically active molecules featuring imidazole or imida-
asymmetric epoxidation of alkenes while their catalytic
zoline (dihydroimidazole) cores constitute an important
activity can be further tuned by various N-substitutions.
class of organic compounds. They have been used in a va-
Hence, we report herein our attempts to synthesize imida-
riety of chemistry applications including the following:
zolines 5–11 and 12,13, their full spectral characteriza-
nitrogen ligands coordinating transition metals,1,2 biolog-
tion, and attempted N-modification and resulting stability.
ically active substances (IBS, imidazoline binding site),3
ionic liquids,4 and N-heterocyclic carbenes (NHCs).5,6
Due to the presence of stereogenic centers directly at
C4(C5) of the imidazoline ring, imidazolines7 have also
been widely used as chiral auxiliaries resembling oxazo-
H
H
lines.8,9 However, in contrast to oxazolines, imidazolines
offer the possibility for N-functionalization to fine-tune
their electronic properties.10 Optically active imidazoline
derivatives efficiently catalyze a wide range of asymmet-
ric reactions including allylation, hydrogenation, and ad-
dition of diethylzinc to aldehydes, along with Heck
reactions and many others.1,11–13 Currently, imidazolines
are perhaps the most often employed ligands and, despite
recent progress in their preparation,14 they are most com-
monly prepared by condensation of readily available
chiral 1,2-diamines with carboxylic acids and their deriv-
atives, such as imidates, amidines, esters, acyl chlorides,
and nitriles.
N
N
N
N
N
N
N
N
N
R1
R1
R1
R1
R
3
R
1
R
2
R = (hetero)aryl
R
1 = H, Me
4
R
1 = H, alkyl, acyl,
benzoyl, sulfonyl
H
H
N
N
H
H
Y
N
N
H
HN
N
H
H
H
R
5–11
12, 13
R = (hetero)aryl
Y = CH, N
As a part of our research focused on the development of
new terpene-derived imidazolines, we have recently re-
ported the synthesis and application of terpene-annulated
imidazoles 1–3 and camphor-annulated imidazolines 4
Figure 1 Previous 1–4 and newly proposed 5–13 imidazoles/imida-
zolines
The construction of the imidazoline core has been accom-
plished via a convenient condensation of (hetero)aromatic
imidates with (1R,2R)-cyclohexane-1,2-diamine in a
manner similar to that used for the construction of 4.16 The
SYNTHESIS 2010, No. 22, pp 3934–3940
Advanced online publication: 14.09.2010
DOI: 10.1055/s-0030-1258256; Art ID: Z19810SS
x
x.
x
x
.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

PAPER
Hexahydro-1H-benzo[d]imidazoles
3935
method A
H
H
H
H
N
N
CN
R
Na, MeOH
in situ
MeO
NH
H2N
NH2
H
H
N
N
H
Et3N, MeOH, 40 °C
N
HN
N
H
H
H
R
R
5–8
12
method B
CN
H
H
H
H
N
N
HCl, R2OH
2 = Me or Et
R2O
NH•HCl
H2N
NH2
H
H
R1
N
H
Et3N, CH2Cl2, 25 °C
HN
N
N
H
H
R
R1
H
R1
9–11
13
Scheme 1 Synthesis of NH-imidazolines
(hetero)aromatic imidates were synthesized from com- sult, imidazoline 8 was obtained in a low yield. However,
mercially available nitriles. Whereas the treatment of all of the prepared NH-imidazolines 5–13 were fully char-
1
electron-poor nitriles (R = pyridin-2-yl, pyridine-2,6-diyl, acterized by EI-MS, H and 13C NMR, and optical rota-
pyrimidin-2-yl, pyrazin-2-yl, and isoquionolin-1-yl) with tions (see Supporting Information). Despite the
sodium methoxide in methanol20 afforded the desired im- problematic synthesis of 8, a slow evaporation of its ethyl
idates directly within one to three hours [as monitored on acetate solution afforded crystals suitable for X-ray anal-
TLC (SiO2, EtOAc) or by GC/MS], electron-rich nitriles ysis. A similar crystallization procedure for the solution of
(R = phenyl, benzene-1,3-diyl, 1H-pyrrol-2-yl, thiophen- hydrochloride 12 in chloroform–methanol also afforded
2-yl) were treated with gaseous hydrochloric acid in measurable crystals. Moreover, a deuterated chloroform
methanol (Pinner synthesis)21–25 to furnish imidates solution of 11 with Mosher’s acid, used for the determina-
1
hydrochlorides. Subsequently, the imidates and imidates tion of optical purity by H NMR spectroscopy, crystal-
hydrochlorides were each condensed with (1R,2R)-cyclo- lized directly in an NMR tube to provide suitable crystals.
hexane-1,2-diamine in methanol–triethylamine (Method Thus, we were able to confirm the molecular structures of
A) or dichloromethane–triethylamine (Method B) to af- imidazolines 8, 11, and 12 by X-ray crystal structure anal-
ford the desired NH-imidazolines 5–13 (Scheme 1, ysis (Figures 2– 4, see also Supporting Information). The
Table 1).
ORTEP plots in Figures 2– 4 show the several key fea-
tures: the spatial arrangement and solid-state structures of
the prepared Mosher salts of 11 (Figure 3), hydrogen
bonding of HCl to 12 (Figure 4) and confirmed the abso-
lute configurations of each stereogenic centre.
Table 1 NH-Imidazolines 5–13 Prepared
20
Product R
Method Yield Mp
[a]D
(c)a
(%)
66
31
96
3b
(°C)
5
6
pyridin-2-yl
A
A
A
A
B
B
B
A
B
110–112
157–159
149–152
120–122
159–162
309–312
199–201
315–322
261–263
+141.6
+ 84.4
+159.3
+ 31.6
+148.0
+ 45.0
+158.0
+192.4
+215.0
pyrimidin-2-yl
pyrazin-2-yl
7
8
isoquinolin-1-yl
phenyl
9
94
72
74
52
37
10
11
12
13
1H-pyrrol-2-yl
thiophen-2-yl
pyridine-2,6-diyl
benzene-1,3-diyl
a Concentration c is 0.5 g/100 mL MeOH.
b Problematic synthesis of imidate (see text).
During the sodium methoxide catalyzed conversion of
isoquinoline-1-carbonitrile to imidate, facile substitution
of the cyano to methoxy group was observed, and as a re-
Figure 2 Crystal structure of 8; vibrational ellipsoids of the ORTEP
plot are shown at the 50% probability level (R = 0.06, 150 K)
Synthesis 2010, No. 22, 3934–3940 © Thieme Stuttgart · New York

3936
J. Tydlitát et al.
PAPER
Figure 3 Crystal structure of 11 (left) and crystal packing of the
Mosher’s salts of 11 (right); vibrational ellipsoids of the ORTEP plot
are shown at the 50% probability level (R = 0.07, 150 K), molecules
of solvent omitted for clarity
In the next reaction step, N-alkylation of the prepared im-
idazolines was attempted. Treatment of imidazolines 5–7
and 9–11 with 1.3 equivalents lithium bis(trimethylsi-
lyl)amide (LHMDS) and subsequent reaction with benzyl
bromide afforded N-benzylimidazolines 14–16 and 20–22
(Scheme 2, Table 2).
Figure 4 Crystal structure of 12 (up) and its hydrogen bonding to
HCl (down); vibrational ellipsoids of the ORTEP plot are shown at
the 50% probability level (R = 0.07, 150 K)
However, decomposition of the electron-poor imidazo-
lines 14–16 occurred during purification by column chro-
matography (SiO2) or within a few days upon standing to
yield N,N¢-disubstituted (1R,2R)-cyclohexane-1,2-di-
amines 17–19 (Scheme 2, Table 2). We have observed
such imidazoline ring opening previously only for N-sul-
fonyl camphor-imidazolines 4.16 However the decomposi-
tion of imidazolines 14–16 proceeded to such a degree
that N-alkylation as well as other attempted N-substitu-
tions led to pure N,N¢-disubstituted (1R,2R)-cyclohexane-
1,2-diamines 17–19. Only the imidazolines 15 and 16
with pyrimidin-2-yl and pyrazin-2-yl R substituents could
be isolated as pure compounds, although their decomposi-
tion to 18 and 19 did occur after two days. Whereas the
ring opening in imidazolines 14–16 was facilitated by the
presence of electron-accepting substituents at C2
[R = pyridin-2-yl, pyrimidin-2-yl and pyrazin-2-yl], imi-
dazolines 20–22 with substituents such as phenyl, 1H-pyr-
rol-2-yl, and thiophen-2-yl were more stable. However, a
slow decomposition occurred after few weeks. Finally, N-
alkylation of imidazolines 12 and 13 proved to be unfea-
sible due to the formation of an inseparable mixture of
three to four products. It should be noted that the above-
mentioned decomposition occurred independently on the
alkylating or acylating agent used.
In this work, we have demonstrated a facile synthesis of
optically pure imidazolines annulated with cyclohexane
(1,2-disubstituted hexahydro-1H-benzo[d]imidazoles).
Overall nine NH-imidazolines, six of which had not been
previously prepared, were synthesized from commercial-
ly available precursors. NH-Imidazolines 9, 11, and 12
were already synthesized previously by other meth-
ods.19,26,27 The molecular structures of imidazolines 8, 11,
and 12 were confirmed by X-ray analysis. In certain cases,
1. LHMDS, THF, –20 °C
column chrom. (SiO2)
H
H
H
H
O
R
H
H
HN
N
2. BnBr, THF, 25 °C
N
N
NH HN
Ph
Ph
R
R
5–7
17–19
14–16
1. LHMDS, THF, –20 °C
2. BnBr, THF, 25 °C
H
H
H
H
HN
N
N
N
Ph
R
R
9–11
20–22
Scheme 2 Attempted N-substitution of imidazolines 5–7 and 9–11
Synthesis 2010, No. 22, 3934–3940 © Thieme Stuttgart · New York

PAPER
Hexahydro-1H-benzo[d]imidazoles
3937
was used as an internal reference (CDCl3: 7.25 and 77.23 ppm;
MeOD: 3.31 and 49.15 ppm). Coupling constants (J) are given in
Hz. The apparent resonance multiplicity is described as s (singlet),
br s (broad singlet), d (doublet), t (triplet), q (quartet), and m (mul-
tiplet). Protons of the substituents at the C2-position are marked as
follows: Ph (phenyl), Py (pyridin-2-yl), Pm (pyrimidin-2-yl), Pz
(pyrazin-2-yl), Isq (isoquinolin-2-yl), Ph (phenyl), Pyr (1H-pyrrol-
2-yl), Th (thiophen-2-yl), Py2 (pyridine-2,6-diyl), and Ben (ben-
zene-1,3-diyl). The protons of the benzyl substituent at the N1-po-
sition are marked as Bn. Additional NMR techniques such as 1H–1H
Table 2 N-Benzylimidazolines 14–16 and 20–22, and 1,2-Di-
amines 17–19 Prepared
Product
14b
15
R
Yield (%)
[a]D20 (c)a
–
pyridin-2-yl
pyrimidin-2-yl
pyrazin-2-yl
pyridin-2-yl
pyrimidin-2-yl
pyrazin-2-yl
phenyl
–
31
46
37
38
35
58
65
59
+ 52.4
+ 75.4
– 30.0
– 19.6
– 31.6
+ 31.2
+136.0
+ 67.2
16
COSY, H–13C HMBC and H–13C HMQC were used for regular
signal assignment. Some of the cyclohexane carbons were not ob-
served in 13C NMR spectra as a result of imidazoline tautomerism
(averaged signals). The mass spectra were measured on a GC/MS
configuration comprised of an Agilent Technologies – 6890N gas
chromatograph (HP-5MS column, length 30 m, I.D. 0.25 mm, film
0.25 mm) equipped with a 5973 Network MS detector (EI 70 eV,
mass range 33–550 Da). Elemental analyses were performed on an
EA 1108 Fisons instrument. Optical rotation values were measured
on a Perkin-Elmer 341 instrument, concentration c is given in g/100
mL MeOH.
1
1
17
18
19
20
21
1H-pyrrol-2-yl
thiophen-2-yl
22
a Concentration c is 0.5 g/100 mL MeOH.
b Detected only by GC/MS (see Supporting Information).
For spectral characterization of methyl 1H-pyrrole-2-carbimidate
hydrochloride, methyl thiophene-2-carbimidate hydrochloride and
NH-imidazolines 9, 11, and 12, see Supporting Information. X-ray
crystal data for compounds 8, 11, and 12 are deposited at CCDC.30
N-alkylation of the prepared imidazolines proved to be
complicated by the subsequent imidazoline ring opening,
which led to N,N¢-disubstituted (1R,2R)-cyclohexane-
1,2-diamines. The ring opening occurred by column chro-
matography (SiO2) or upon standing. Based on our obser-
vations, this decomposition was facilitated by the
presence of electron-accepting substituents at C2 of the
imidazoline and, consequently, the imidazolines with py-
ridin-2-yl, pyrimidin-2-yl, and pyrazin-2-yl substituents
were isolated in small yields or were not isolated at all. On
the other hand, imidazolines bearing phenyl, 1H-pyrrol-2-
yl and thiophen-2-yl substituents were more stable and
could be isolated in 58–65% yields. However, their de-
composition was observed upon standing for few weeks.
In light of the large number of published imidazolines, it
is somewhat curious that there have been no prior reports
of their instability and facile ring-opening. However, in
2006 Braddock et al.28,29 reported on a convenient prepa-
ration of enantiomerically pure 1,2-diphenylethane-1,2-
diamine (DPEDA) that utilized the synthesis of N-acyl-
NH-Imidazolines 5–8, and 12; Method A; General Procedure
Na (15 mg, 0.65 mmol) was added to a solution of carbonitrile
(0.876 mmol) in anhyd MeOH (10 mL). The reaction mixture was
stirred at 25 °C until TLC (SiO2, EtOAc) or GC/MS showed total
conversion of the carbonitrile into the imidate (usually 1–3 h).
(1R,2R)-Cyclohexane-1,2-diamine (100 mg, 0.876 mmol), Et3N
(0.32 mL, 4.36 mmol), AcOH (3 drops) were added and the result-
ing solution was stirred at 40 °C for 12 h. The solvent was evapo-
rated in vacuo and the crude product was purified by column
chromatography (SiO2, EtOAc–MeOH–aqNH3, 1:1:0.01) to afford
pure 5–8 and 12.
(3aR,7aR)-2-(Pyridin-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-ben-
zo[d]imidazole (5)
The title compound was synthesized from pyridine-2-carbonitrile
(91 mg, 0.876 mmol); yield: 117 mg (66%); off-white solid; mp
110–112 °C; Rf = 0.37; [a]D20 +141.6 (c 0.5, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.32–1.41 (m, 2 H, CH2), 1.54–
1.58 (m, 2 H, CH2), 1.81–1.84 (m, 2 H, CH2), 2.30 (d, J = 10.9 Hz,
2 H, CH2), 3.16–3.19 (m, 2 H, 2 × CH), 6.12 (br s, 1 H, NH), 7.31–
2,4,5-triphenylimidazoline (N-acyl-iso-amarine) and its 7.34 (m, 1 H, Py), 7.73 (t, J = 7.8 Hz, 1 H, Py), 8.14 (d, J = 7.9 Hz,
1 H, Py), 8.54 (d, J = 4.8 Hz, 1 H, Py).
subsequent acid-catalyzed ring opening (aq HCl). This re-
action afforded N,N¢-disubstituted-1,2-diphenylethane-
1,2-diamines in a similar way as for 17–19.
13C NMR (90 MHz, CDCl3): d = 25.19, 31.00, 71.10 (br), 122.17,
125.38, 136.78, 148.89, 148.92, 165.47.
EI-MS (70 eV): m/z (%) = 201 ([M]+, 36), 172 (36), 159 (100), 146
(35), 105 (33), 78 (26).
Reagents and solvents were reagent-grade and were purchased from
Penta, Aldrich, and Acros, and used as received. Column chroma-
tography was carried out with silica gel 60 (particle size 0.040–
0.063 mm, 230–400 mesh; Merck) and commercially available sol-
vents. TLC was conducted on aluminum sheets coated with silica
gel 60 F254 obtained from Merck, with visualization by UV lamp
(254 or 360 nm). EtOAc–MeOH–aqNH3 (1:1:0.01) was used as the
solvent system for determining all Rf values. Melting points were
measured on a Büchi B-540 melting point apparatus in open capil-
laries and are uncorrected. 1H and 13C NMR spectra were recorded
in CDCl3 at 360/400/500 MHz and 90/100/125 MHz, respectively,
on a Bruker AMX 360 or Bruker Avance 400/500 instrument at
25 °C. Chemical shifts are reported in ppm relative to the signal of
Me4Si. The residual solvent signal in the 1H and 13C NMR spectra
Anal. Calcd for C12H15N3 (201.27): C, 71.61; H, 7.51; N, 20.88.
Found: C, 71.37; H, 7.29; N, 20.50.
(3aR,7aR)-2-(Pyrimidin-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-ben-
zo[d]imidazole (6)
The title compound was synthesized from pyrimidine-2-carbonitrile
(92 mg, 0.876 mmol); yield: 50 mg (31%); yellowish oil; mp 157–
159 °C; Rf = 0.27; [a]D20 +84.4 (c 0.5, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.27–1.33 (m, 2 H, CH2), 1.50–
1.59 (m, 2 H, CH2), 1.74–1.80 (m, 2 H, CH2), 2.28 (d, J = 11.8 Hz,
2 H, CH2), 3.14–3.20 (m, 2 H, 2 × CH), 5.05 (br s, 1 H, NH), 7.29
(t, J = 4.9 Hz, 1 H, Pm), 8.76 (d, J = 4.9 Hz, 2 H, Pm).
Synthesis 2010, No. 22, 3934–3940 © Thieme Stuttgart · New York

3938
J. Tydlitát et al.
PAPER
13C NMR (90 MHz, CDCl3): d = 25.09, 30.88, 70.48, 121.73,
157.49, 157.57, 164.01.
13C NMR (90 MHz, CDCl3): d = 23.83, 28.82, 64.55, 111.69,
115.21, 120.08, 127.51, 158.84.
EI-MS (70 eV): m/z (%) = 202 ([M]+, 19), 173 (42), 160 (100), 147
EI-MS (70 eV): m/z (%) = 189 ([M]+, 95), 160 (30), 146 (100), 134
(50), 106 (28), 79 (16).
(22), 119 (13), 93 (39).
Anal. Calcd for C11H14N4 (202.26): C, 65.32; H, 6.98; N, 27.70.
Found: C, 65.14; H, 7.05; N, 27.42.
Anal. Calcd for C11H15N3 (189.26): C, 69.81; H, 7.79; N, 21.65.
Found: C, 69.65; H, 8.15; N, 21.39.
(3aR,7aR)-2-(Pyrazin-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-ben-
zo[d]imidazole (7)
The title compound was synthesized from pyrazine-2-carbonitrile
(92 mg, 0.876 mmol); yield: 170 mg (96%); off-white solid; mp
149–152 °C; Rf = 0.56; [a]D20 +159.3 (c 0.5, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.29–1.42 (m, 2 H, CH2), 1.49–
1.62 (m, 2 H, CH2), 1.85 (t, J = 12.2 Hz, 2 H, CH2), 2.20 (d, J = 11.0
Hz, 1 H, CH2), 2.42 (d, J = 11.4 Hz, 1 H, CH2), 3.11 (t, J = 12.5 Hz,
1 H, CH), 3.27 (t, J = 12.6 Hz, 1 H, CH), 6.09 (br s, 1 H, NH), 8.49–
8.51 (m, 1 H, Pz), 8.61 (d, J = 2.4 Hz, 1 H, Pz), 9.37 (s, 1 H, Pz).
13C NMR (90 MHz, CDCl3): d = 24.25, 25.25, 30.35, 30.72, 66.33,
73.40, 142.93, 143.72, 144.01, 145.56, 163.10.
EI-MS (70 eV): m/z (%) = 202 ([M]+, 27), 173 (33), 160 (100), 147
(36), 106 (25), 79 (14).
1,3-Bis((3aR,7aR)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imida-
zol-2-yl)benzene (13)
The title compound was synthesized from diethyl benzene-1,3-di-
carbimidate dihydrochloride (257 mg, 0.876 mmol); yield: 104 mg
(37%); off-white solid; mp 261–263 °C; Rf = 0.38; [a]D20 +215.0 (c
0.5, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.29–1.38 (m, 4 H, CH2), 1.50–
1.52 (m, 4 H, CH2), 1.80–1.82 (m, 4 H, CH2), 2.24 (d, J = 11.6 Hz,
4 H, CH2), 3.08 (d, J = 6.9 Hz, 4 H, 2 × CH), 4.86 (br s, 2 H, NH),
7.35 (t, J = 7.8 Hz, Ben), 7.81 (d, J = 7.8 Hz, 2 H, Ben), 8.08 (d,
J = 12.6 Hz, 1 H, Ben).
13C NMR (90 MHz, CDCl3): d = 25.15, 30.99, 69.81, 125.00,
128.83, 129.04, 131.11, 165.20.
EI-MS (70 eV): m/z (%) = 322 ([M]+, 68), 293 (32), 279 (100), 267
(88), 226 (21), 182 (16), 129 (17).
Anal. Calcd for C11H14N4 (202.26): C, 65.32; H, 6.98; N, 27.70.
Found: C 65.13; H, 6.65; N, 27.52.
Anal. Calcd for C20H26N4 (322.45): C, 74.50; H, 8.13; N, 17.38.
Found: C, 74.35; H, 8.24; N, 17.27.
1-((3aR,7aR)-3a,4,5,6,7,7a-Hexahydro-1H-benzo[d]imidazol-2-
yl)isoquinoline (8)
The title compound was synthesized from isoquinoline-1-carboni-
trile (135 mg, 0.876 mmol); yield: 8 mg (3%); off-white solid; mp
120–122; Rf = 0.63; [a]D20 +31.6 (c 0.5, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.37–1.42 (m, 2 H, CH2), 1.58–
1.67 (m, 2 H, CH2), 1.87 (d, J = 8.5 Hz, 2 H, CH2), 2.35 (br s, 2 H,
CH2), 3.29 (br s, 2 H, 2 × CH), 7.65–7.70 (m, 3 H, Isq), 7.81 (d,
J = 7.4 Hz, 1 H, Isq), 8.48 (d, J = 5.6 Hz, 1 H, Isq), 9,62 (d, J = 8.8
Hz, 1 H, Isq).
13C NMR (90 MHz, CDCl3): d = 23.03, 25.30, 31.16, 31.85, 123.22,
126.89, 127.22, 128.55, 128.67, 130.51, 137.01, 141.21, 148.12,
165.98.
N-Alkylation of Imidazolines 5–7 and 9–11; General Procedure
LiN(SiMe3)2 (1 M solution in THF, 0.51 mL, 0.51 mmol, 1.3 equiv)
was added to a solution of imidazoline (0.392 mmol) in anhyd THF
(10 mL) under argon at –20 °C. The resulting yellow solution was
stirred for 30 min whereupon benzyl bromide (0.051 mL, 0.431
mmol, 1.1 equiv) in THF (5 mL) was added and the reaction mixture
was stirred at 25 °C for an additional 3 h. The solvent was evaporat-
ed in vacuo and the crude product was purified by column chroma-
tography (SiO2, EtOAc–MeOH–aqNH3, 1:1:0.01) to afford either
imidazolines 14–16 and 20–22 or N,N¢-disubstituted (1R,2R)-cy-
clohexane-1,2-diamines 17–19.
(3aR,7aR)-1-Benzyl-2-(pyridin-2-yl)-3a,4,5,6,7,7a-hexahydro-
1H-benzo[d]imidazole (14)
EI-MS (70 eV): m/z (%) = 251 ([M]+, 41), 222 (24), 208 (100), 155
The title compound was synthesized from imidazoline 5, however,
it could not be isolated in pure form. This product was detected only
by GC/MS and decomposed to 17 during purification by column
chromatography (see Supporting Information).
EI-MS (70 eV): m/z (%) = 291 ([M]+, 100), 106 (84), 91 (78), 79
(28).
(40), 128 (45).
NH-Imidazolines 10, 13; Method B; General Procedure
To a suspension of imidate hydrochloride (0.876 mmol) in CH2Cl2
(10 mL) were added (1R,2R)-cyclohexane-1,2-diamine (100 mg,
0.876 mmol), Et3N (0.32 mL, 4.36 mmol), and AcOH (3 drops) and
the resulting solution was stirred at 25 °C for 48 h. The reaction was
monitored on TLC (SiO2, EtOAc) or GC/MS. The solvent was
evaporated in vacuo and the crude product was purified by column
chromatography (SiO2, EtOAc–MeOH–aqNH3, 1:1:0.01) to afford
pure 9–11 and 13.
(3aR,7aR)-1-Benzyl-2-(pyrimidin-2-yl)-3a,4,5,6,7,7a-hexahy-
dro-1H-benzo[d]imidazole (15)
The title compound was synthesized from imidazoline 6 following
the general procedure; yield: 36 mg (31%); off-white solid; mp
164–166 °C; Rf = 0.40; [a]D20 +52.4 (c 0.5, MeOH).
1H NMR (400 MHz, CD3OD): d = 1.21–1.50 (m, 4 H, CH2), 1.76–
1.86 (m, 2 H, CH2), 1.98 (d, J = 11.2 Hz, 1 H, CH2), 2.30 (d,
J = 11.1 Hz, 1 H, CH2), 2.91 (t, J = 12.0 Hz, 1 H, CH), 3.18 (t,
J = 12.0 Hz, 1 H, CH), 4.54–4.60 (m, 2 H, Bn), 7.18–7.27 (m, 5 H,
Bn), 7.55 (t, J = 4.8 Hz, 1 H, Pm), 8.90 (d, J = 3.2 Hz, 2 H, Pm).
13C NMR (100 MHz, CD3OD): d = 24.22, 25.30, 29.42, 30.76,
49.78, 70.26, 70.67, 122.06, 127.20, 127.75, 128.24, 137.50,
157.62, 159.12, 165.50.
(3aR,7aR)-2-(1H-Pyrrol-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-ben-
zo[d]imidazole (10)
The title compound was synthesized from methyl 1H-pyrrole-2-car-
bimidate hydrochloride (141 mg, 0.876 mmol); yield: 120 mg
(72%); off-white solid; mp 309–312 °C; Rf = 0.24; [a]D20 +45.0 (c
0.5, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.21–1.30 (m, 2 H, CH2), 1.47–
1.49 (m, 2 H, CH2), 1.78–1.80 (m, 2 H, CH2), 2.25 (d, J = 11.6 Hz,
2 H, CH2), 3.31–3.40 (m, 2 H, 2 × CH), 6.19 (s, 1 H, Pyr), 7.04 (s,
1 H, Pyr), 7.59 (s, 1 H, Pyr), 10.21 (s, 2 H, NH).
EI-MS (70 eV): m/z (%) = 292 ([M]+, 75), 237 (34), 201 (40), 159
(17), 106 (79), 91 (100).
Synthesis 2010, No. 22, 3934–3940 © Thieme Stuttgart · New York

PAPER
Hexahydro-1H-benzo[d]imidazoles
3939
(3aR,7aR)-1-Benzyl-2-(pyrazin-2-yl)-3a,4,5,6,7,7a-hexahydro-
1H-benzo[d]imidazole (16)
The title compound was synthesized from imidazoline 7 following
the general procedure; yield: 66 mg (46%); yellowish oil; Rf = 0.64;
[a]D20 +75.4 (c 0.5, MeOH).
1H NMR (400 MHz, CD3OD): d = 1.21–1.51 (m, 4 H, CH2), 1.75–
1.86 (m, 2 H, CH2), 1.97 (d, J = 11.2 Hz, 1 H, CH2), 2.32 (d,
J = 10.8 Hz, 1 H, CH2), 2.95 (t, J = 14.4 Hz, 1 H, CH), 3.22 (t,
J = 14.4 Hz, 1 H, CH), 4.59 (d, J = 15.6 Hz, 1 H, Bn), 4.76 (d,
J = 15.6 Hz, 1 H, Bn), 7.21–7.28 (m, 5 H, Bn), 8.67–8.68 (m, 2 H,
Pz), 8.97 (s, 1 H, Pz).
13C NMR (100 MHz, CD3OD): d = 25.54, 26.58, 30.81, 32.06,
51.22, 71.92, 71.94, 128.55, 128.95, 129.61, 139.08, 145.03,
146.16, 146.96, 147.86, 165.77.
1H NMR (400 MHz, CD3OD): d = 1.28–1.46 (m, 4 H, CH2), 1.77–
1.83 (m, 2 H, CH2), 1.97–2.00 (m, 1 H, CH2), 2.21–2.22 (m, 1 H,
CH2), 2.70–2.76 (m, 1 H, CHNHBn), 3.73 (d, J = 12.8 Hz, 1 H, Bn),
3.94 (d, J = 12.8 Hz, 1 H, Bn), 3.97 (m, 1 H, CHNHCOPz), 7.24–
7.27 (m, 5 H, Bn), 8.69–8.70 (m, 1 H, Pz), 8.78 (d, J = 2.4 Hz, 1 H,
Pz), 9.23 (d, J = 1.2 Hz, 1 H, Pz).
13C NMR (100 MHz, CD3OD): d = 25.74, 26.18, 31.68, 33.26,
50.88, 54.00, 61.02, 128.59, 129.73, 129.78, 140.09, 144.87,
144.97, 146.51, 148.64, 165.71.
EI-MS (70 eV): m/z (%) = 310 ([M]+, 2), 219 (12), 187 (26), 176
(18), 146 (25), 106 (61), 91(100), 79 (28).
Anal. Calcd for C18H22N4O (310.39): C, 69.65; H, 7.14; N, 18.05.
Found: C, 69.89; H, 7.30; N, 18.16.
EI-MS (70 eV): m/z (%) = 292 ([M]+, 94), 237 (16), 201 (14), 186
(13), 159 (9), 106 (84), 91 (100), 79 (15).
(3aR,7aR)-1-Benzyl-2-phenyl-3a,4,5,6,7,7a-hexahydro-1H-ben-
zo[d]imidazole (20)
The title compound was synthesized from imidazoline 9 following
the general procedure; yield: 84 mg (58%); yellowish oil; Rf = 0.42;
[a]D20 +31.2 (c 0.5, MeOH).
1H NMR (400 MHz, CD3OD): d = 1.20–1.47 (m, 4 H, CH2), 1.72–
1.75 (m, 1 H, CH2), 1.80–1.87 (m, 2 H, CH2), 2.28–2.31 (m, 1 H,
CH2), 2.76–2.82 (m, 1 H, CHNHBn), 3.14–3.17 (m, 1 H, CHNH-
COPh), 4.13 (d, J = 16.4 Hz, 1 H, Bn), 4.50 (d, J = 16.0 Hz, 1 H,
Bn), 7.22–7.30 (m, 5 H, Bn), 7.42–7.49 (m, 5 H, Ph).
13C NMR (100 MHz, CD3OD): d = 25.74, 26.63, 31.29, 32.29,
52.58, 71.59, 72.68, 128.56, 129.00, 129.71, 129.89, 131.45,
132.93, 139.32, 171.49 (1 signal is missing).
EI-MS (70 eV): m/z (%) = 290 ([M]+, 56), 235 (38), 199 (21), 157
(35), 104 (20), 91 (100).
N-[(1R,2R)-2-(Benzylamino)cyclohexyl]pyridine-2-carbox-
amide (17)
The title compound was synthesized from imidazoline 5 following
the general procedure. This product was obtained after purification
of 14 by column chromatography; yield: 57 mg (37%); yellowish
oil; Rf = 0.62; [a]D20 –30.0 (c 0.5, MeOH).
1H NMR (400 MHz, CD3OD): d = 1.27–1.42 (m, 4 H, CH2), 1.75–
1.78 (m, 2 H, CH2), 1.97–1.99 (m, 1 H, CH2), 2.13–2.15 (m, 1 H,
CH2), 2.61 (m, 1 H, CHNHBn), 3.65 (d, J = 13.2 Hz, 1 H, Bn), 3.85
(d, J = 13.2 Hz, 1 H, Bn), 3.91–3.95 (m, 1 H, CHNHCOPy), 7.17–
7.25 (m, 5 H, Bn), 7.52 (t, J = 6.8 Hz, 1 H, Py), 7.94 (t, J = 7.6 Hz,
1 H, Py), 8.09 (d, J = 8.0 Hz, 1 H, Py), 8.63 (d, J = 4.4 Hz, 1 H, Py).
13C NMR (100 MHz, CD3OD): d = 25.78, 26.21, 32.12, 33.37,
51.21, 54.20, 61.03, 123.34, 127.86, 128.24, 129.54, 129.59,
138.93, 141.14, 149.81, 151.19, 166.87.
Anal. Calcd for C20H22N4 (290.40): C, 82.72; H, 7.64; N, 9.65.
Found: C, 82.86; H, 7.70; N, 9.76.
EI-MS (70 eV): m/z (%) = 309 ([M]+, 2), 291 (25), 218 (16), 204
(28), 187 (60), 175 (33), 146 (24), 106 (64), 91(100), 78 (45).
(3aR,7aR)-1-Benzyl-2-(1H-pyrrol-2-yl)-3a,4,5,6,7,7a-hexa-
hydro-1H-benzo[d]imidazole (21)
Anal. Calcd for C19H23N3O (309.41): C, 73.76; H, 7.49; N, 13.58.
Found: C, 73.85; H, 7.55; N, 13.69.
The title compound was synthesized from imidazoline 10 following
the general procedure; yield: 96 mg (65%); off-white solid; mp
149–151 °C; Rf = 0.13; [a]D20 +136.0 (c 0.5, MeOH).
1H NMR (400 MHz, CD3OD): d = 1.20–1.46 (m, 4 H, CH2), 1.75–
1.84 (m, 2 H, CH2), 1.91–1.94 (d, 1 H, J = 10.1 Hz, CH2), 2.27 (d,
J = 8.0 Hz, 1 H, CH2), 2.84 (t, J = 14.0 Hz, 1 H, CHNHBn), 3.15 (t,
J = 13.6 Hz, 1 H, CHNHCOPyr), 4.50 (d, J = 16.4 Hz, 1 H, Bn),
4.79 (d, J = 16.4 Hz, 1 H, Bn), 6.14 (s, 1 H, Pyr), 6.41–6.42 (m, 1
H, Pyr), 6.94 (d, J = 0.8 Hz, 1 H, Pyr), 7.25–7.32 (m, 5 H, Bn).
N-[(1R,2R)-2-(Benzylamino)cyclohexyl]pyrimidine-2-carbox-
amide (18)
The title compound was synthesized from imidazoline 6 following
the general procedure. This product was obtained after purification
of 15 by column chromatography; yield: 46 mg (38%); yellowish
oil; Rf = 0.56; [a]D20 –19.6 (c 0.5, MeOH).
1H NMR (400 MHz, CD3OD): d = 1.29–1.48 (m, 4 H, CH2), 1.77–
1.82 (m, 2 H, CH2), 2.01–2.03 (m, 1 H, CH2), 2.18–2.21 (m, 1 H,
CH2), 2.65–2.70 (m, 1 H, CHNHBn), 3.69 (d, J = 12.8 Hz, 1 H, Bn),
3.90 (d, J = 12.8 Hz, 1 H, Bn), 3.93–3.99 (m, 1 H, CHNHCOPz),
7.19–7.29 (m, 5 H, Bn), 7.63 (t, J = 4.8 Hz, 1 H, Pm), 8.94 (d,
J = 4.8 Hz, 1 H, Pm).
13C NMR (100 MHz, CD3OD): d = 25.63, 26.50, 30.63, 32.22,
51.88, 70.77, 72.23, 110.38, 112.81, 122.00, 122.94, 128.31,
128.46, 129.80, 139.43, 163.47.
EI-MS (70 eV): m/z (%) = 279 ([M]+, 100), 207 (46), 196 (78), 91
(89).
13C NMR (100 MHz, CD3OD): d = 25.81, 26.21, 31.97, 33.27,
49.78, 54.56, 61.00, 124.48, 128.37, 129.65, 129.69, 140.81,
158.97, 159.06, 165.09.
EI-MS (70 eV): m/z (%) = 310 ([M]+, 6), 205 (28), 187 (51), 176
(36), 146 (24), 124 (20), 106 (17), 91 (100).
Anal. Calcd for C18H21N3 (279.38): C, 77.38; H, 7.58; N, 15.04.
Found: C, 77.49; H, 7.50; N, 14.96.
(3aR,7aR)-1-Benzyl-2-(thiophen-2-yl)-3a,4,5,6,7,7a-hexahydro-
1H-benzo[d]imidazole (22)
The title compound was synthesized from imidazoline 11 following
the general procedure; yield: 85 mg (59%); yellowish oil; Rf = 0.49;
[a]D20 +67.2 (c 0.5, MeOH).
Anal. Calcd for C18H22N4O (310.39): C, 69.65; H, 7.14; N, 18.05.
Found: C, 69.92; H, 7.24; N, 18.10.
1H NMR (400 MHz, CD3OD): d = 1.21–1.48 (m, 4 H, CH2), 1.75–
1.84 (m, 2 H, CH2), 1.92 (d, J = 12.0 Hz, 1 H, CH2), 2.29 (d,
J = 10.0 Hz, 1 H, CH2), 2.92 (t, J = 14.8 Hz, 1 H, CHNHBn), 3.19
(t, J = 14.7 Hz, 1 H, CHNHCOTh), 4.42 (d, J = 16.4 Hz, 1 H, Bn),
4.74 (d, J = 16.4 Hz, 1 H, Bn), 7.09 (t, J = 4.0 Hz, 1 H, Th), 7.27–
7.34 (m, 6 H, Bn + Th), 7.61 (d, J = 4.0 Hz, 1 H, Th).
N-[(1R,2R)-2-(Benzylamino)cyclohexyl]pyrazine-2-carbox-
amide (19)
The title compound was synthesized from imidazoline 7 following
the general procedure. This product was obtained after purification
of 16 by column chromatography; yield: 54 mg (35%); off-white
solid; mp 91–94 °C; Rf = 0.70; [a]D20 –31.6 (c 0.5, MeOH).
Synthesis 2010, No. 22, 3934–3940 © Thieme Stuttgart · New York

3940
J. Tydlitát et al.
PAPER
Lorenz, J. C.; McKellop, K. B.; O’Brien, E. M.; Qiu, F.;
Simpson, R. D.; Smith, L.; So, R. C.; Spinelli, E. M.; Vitous,
J.; Zavattaro, C. J. Org. Chem. 2004, 69, 5187.
(14) Liu, H.; Du, D.-M. Adv. Synth. Catal. 2009, 351, 489.
(15) Kulhánek, J.; Bureš, F.; Šimon, P.; Schweizer, W. B.
Tetrahedron: Asymmetry 2008, 19, 2462.
13C NMR (100 MHz, CD3OD): d = 25.59, 26.48, 30.88, 32.05,
52.13, 71.34, 72.77, 128.34, 128.62, 128.76, 129.86, 130.19,
130.24, 132.92, 139.18, 164.83.
EI-MS (70 eV): m/z (%) = 296 (M+, 80), 241 (30), 205 (25), 163
(35), 110 (22), 91 (100).
Anal. Calcd for C18H20N2S (296.43): C, 72.93; H, 6.80; N, 9.45; S,
10.82. Found: C, 73.00; H, 6.74; N, 9.41; S, 10.71.
(16) Bureš, F.; Kulhánek, J.; Růžička, A. Tetrahedron Lett. 2009,
50, 3042.
(17) Busacca, C. A.; Campbell, S.; Dong, Y.; Grossbach, D.;
Ridges, M.; Smith, L.; Spinelli, E. J. Org. Chem. 2000, 65,
4753.
(18) Bhor, S.; Anilkumar, G.; Tse, M. K.; Klawonn, M.; Döbler,
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7, 3393.
(19) Anilkumar, G.; Bhor, S.; Tse, M. K.; Klawonn, M.;
Bitterlich, B.; Beller, M. Tetrahedron: Asymmetry 2005, 16,
3536.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
This research was supported by the Ministry of Education, Youth
and Sport of the Czech Republic (MSM 0021627501).
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Synthesis 2010, No. 22, 3934–3940 © Thieme Stuttgart · New York