Camphor-annelated imidazolines with various N1 and C2 pendants as tunable ligands for nitroaldol reactions

Article abstract of DOI:10.1016/j.tetasy.2012.06.016

Starting from (1R,2S,3R)-camphordiamine and (hetero)aromatic imidates and orthoformate, nine new camphor-annelated NH-imidazolines were synthesized. Subsequent N-modification was carried out via methylation, acylation, benzoylation, and sulfonylation. Two regioisomers were usually isolated with the ratios reflecting the structure of the starting NH-imidazoline and the electrophile used. All of the successfully prepared N1- and C2-substituted camphor-annelated imidazolines were applied to the asymmetric version of a Cu(II)-catalyzed Henry reaction. The electronic effects of both N1- and C2-pendants on the chemical and asymmetric outcomes of the nitroaldol reaction have been studied and discussed. 2012 Elsevier Ltd.

Full text of DOI:10.1016/j.tetasy.2012.06.016

Tetrahedron: Asymmetry 23 (2012) 1010–1018
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Camphor-annelated imidazolines with various N1 and C2 pendants as
tunable ligands for nitroaldol reactions
a
a,
⇑
a
b
c
ˇ
ˇ
´
ˇ ˇ
Jirí Tydlitát , Filip Bureš , Jirí Kulhánek , Grzegorz Mloston , Aleš Ru˚ zicka
a Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, Pardubice CZ-532 10, Czech Republic
b
´
Department of Organic and Applied Chemistry, University of Łódz, Tamka 12, PL-91-403, Poland
c Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, Pardubice CZ-532 10, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 June 2012
Accepted 22 June 2012
Starting from (1R,2S,3R)-camphordiamine and (hetero)aromatic imidates and orthoformate, nine new
camphor-annelated NH-imidazolines were synthesized. Subsequent N-modification was carried out via
methylation, acylation, benzoylation, and sulfonylation. Two regioisomers were usually isolated with
the ratios reflecting the structure of the starting NH-imidazoline and the electrophile used. All of the suc-
cessfully prepared N1- and C2-substituted camphor-annelated imidazolines were applied to the asym-
metric version of a Cu(II)-catalyzed Henry reaction. The electronic effects of both N1- and C2-pendants
on the chemical and asymmetric outcomes of the nitroaldol reaction have been studied and discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
We have recently synthesized (R)-(+)-camphor-, (1S)-(ꢀ)-b-
pinene-, and (1S,2S,3S,5R)-(+)-isopinocampheone-derived series
Naturally occurring monoterpenes constitute a readily available
and attractive subclass of the chiral pool. Synthetic attempts to
incorporate these chiral moieties into the backbone of a heterocy-
clic compound such as (bi)pyridines, terpyridines, phenathrolines,
and pyrazines, have steadily attracted considerable attention from
organic chemists due to the resulting unique properties of such
derivatives.1 This class of optically active compounds has found
broad application in asymmetric homogeneous catalysis.2 Whereas
the synthesis and applications of the aforementioned six-mem-
bered terpene-annelated heterocycles are numerous, reports on
five-membered analogues remain scarce.3 Conversely, oxazolines4
or imidazolines5 and their use as efficient transition metal N-coor-
dinating ligands are well known and have recently been reviewed
extensively.6 Nowadays, chiral imidazolines are very often used as
ligands that upon coordination of a suitable transition metal, cata-
lyze a wide range of asymmetric reactions such as allylation, epox-
idation, copolymerization, hydrogenation, Diels–Alder reactions,
Heck reactions, Baylis–Hillman reactions, and Friedel–Crafts alky-
lations.7 Hence, the combination of a terpene moiety as a source
of chirality and a chelating imidazoline ring could give an interest-
ing N-coordinating ligand. In contrast to very popular oxazolines,
imidazoline ligands are capable of further modification at the N1
position, which opens the possibility of further ligand design and
the tuning of electronic properties.7b
of imidazoles as well as cyclohexane- and camphor-annelated imi-
dazolines (Fig. 1).8–10 All derivatives bear a terpene moiety fused to
the imidazole/imidazoline through the C4 and C5 positions and
additional pendants at the C2 position. This arrangement assures
the generation of a bidentate N@C–C@N coordination pocket.
Whereas the imidazoles were synthesized from terpene-derived
diketones and monooximes,8 imidazolines, as dihydroanalogues
of imidazoles, were prepared from commercially available
(1R,2R)-cyclohexane-1,2-diamine or (1R,2S,3R)-camphordiamine,
reported by Busacca et al.,11 and (hetero)aromatic imidates.9,10
Herein we report an extension of the series of camphor-annelated
imidazolines by the replacement of the (hetero)aromatic moiety
attached to the imidazoline C2, their N-modification, and a subse-
quent study of such tunable ligands in the asymmetric version of a
Cu(II)-catalyzed Henry reaction.12
2. Results and discussion
2.1. Synthesis
The synthesis of target camphor-annelated imidazolines is out-
lined in Scheme 1. In the first step, the starting (hetero)aromatic
nitriles were converted into appropriate imidates via a sodium
methoxide-catalyzed reaction with methanol or the Pinner synthe-
sis. Whereas the nitriles bearing electron-deficient heteroaromates
(pyridine, pyrazine, pyrimidine, isoquinoline) underwent a direct
reaction with methanol in the presence of a catalytic amount of
sodium methoxide, benzonitrile, pyrrole-2-carbonitrile, and
⇑
Corresponding author. Tel.: +420 4660 37099; fax: +420 4660 37068.
E-mail address: filip.bures@upce.cz (F. Bureš).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.016

J. Tydlitát et al. / Tetrahedron: Asymmetry 23 (2012) 1010–1018
1011
imidazoles
transformed into tridentate PyBim ligand 8 in a similar way (88%
yield). A treatment of exo-camphordiamine with trimethyl ortho-
formate afforded C2-unsubstituted camphor-annelated imidazole
9 (82%), which proved to be very unstable and decomposed within
a week.
In order to prevent imidazoline tautomerism and to further
tune the ligand’s electronic properties and complexation ability,13
NH-imidazolines 1–8 were N-functionalized. Starting with imidaz-
oline 1 as the model substrate, we attempted its alkylation, acyla-
tion, benzoylation, and sulfonylation. Deprotonation of 1 with
LHMDS followed by the reaction with RX electrophiles possessing
either electron-donating or electron-withdrawing substituents
afforded the target ligands 10–18 in good overall yields (Scheme 1,
Table 2). Since the starting imidazoline 1 bearing an unsymmetri-
cal camphor moiety underwent tautomerism, N-substitution
yielded two regioisomers a and b. In general, the pronounced for-
mation of the less sterically demanding regioisomers 10b–15b
with an anti-arrangement of the camphor 1-methyl and R groups
was observed. More importantly, both regioisomers were separa-
ble by simple column chromatography, but the N-sulfonylated
regioisomers 16b–18b, that were detected in the crude reaction
mixture by GC/MS, decomposed during column chromatography,
to yield N,N-disubstituted camphordiamines/diamides 24–26
(Scheme 2). We have recently reported on similar ring-openings
of N-functionalized cyclohexane-annelated imidazolines.9
N
N
N
N
N
N
R
R
R
(Het)Ar
(Het)Ar
(Het)Ar
R = H, CH3
imidazolines
H
H
H
H
H
H
N
N
N
N
N
N
N
R
R
R
(Het)Ar
N
R = H, alkyl, acyl,
aroyl, sulphonyl
R = H, benzyl
Figure 1. Known terpene- and cyclohexane-annelated imidazole and imidazoline
According to the preliminary results of the ligand screening in
the asymmetric version of a Cu(II)-catalyzed Henry reaction (see
below),10 all of the remaining NH-imidazolines 2–8 were anisoylat-
ed. Whereas the anisoylation of pyrazine- and isoquinoline-substi-
tuted NH-imidazoline 2 and 4 afforded separable regioisomers for
compounds 19a/b and 21a/b, the separation of regioisomers 20a/
b derived from pyrimidine-substituted imidazoline 3 was unsuc-
cessful. In contrast to the N-functionalization of all NH-imidazo-
lines 1–4, anisoylation of the phenyl- and thienyl-substituted
imidazolines 5 and 7 mainly afforded regiosiomers 22a (77%) and
ligands.
thiophene-2-carbonitrile had to be converted into imidate hydro-
chlorides by the HCl-catalyzed Pinner reaction. Both imidates
and imidate hydrochlorides were subsequently treated with
(1R,2S,3R)-camphordiamine, prepared in a three step synthesis
from (R)-camphorquinone and rac-DPEDA,10,11 to afford NH-imi-
dazolines 1–4 and 5–7 in yields of 43–92% and 57–91%, respec-
tively (Table 1). Pyridine-2,6-dicarbonitrile was also smoothly
H
NH2
.2HCl
NH2
H
H
H
NH
Na/MeOH
HCl/R'OH
CN
MeO
NH
HetAr
N
HetAr
MeOH/TEA/AcOH
HetAr
1-4
1. LHMDS/THF/0 °C
2. RX/THF/0 to 25 °C
H
H
H
H
H
NH2
N
N
N
N
R
R
.2HCl
NH2
(Het)Ar
(Het)Ar
CN
R'O
NH.HCl
(Het)Ar
H
H
NH
H
(Het)Ar
N
10a-23a
10b-23b
MeOH/TEA/AcOH
(Het)Ar
5-7
H
NH2
NC
N
CN
N
N
CH(OCH3)3
1. Na/MeOH
H
H
.2HCl
NH2
N
HN
N
N
H
N
H
NaOAc/AcOH
2. MeOH/TEA/AcOH
H
H
9
NH2
8
.2HCl
NH2
H
Scheme 1. Synthetic approach to terpene-annelated imidazolines and their subsequent N-functionalization.

1012
J. Tydlitát et al. / Tetrahedron: Asymmetry 23 (2012) 1010–1018
Table 1
ing could be significantly suppressed by storing the ligands with a
few drops of triethylamine.
Structure, yields, and specific rotations of NH-imidazolines 1–9
½ ꢁ (c 0.5, MeOH)
a 2D0
Compd.
(Het)Ar
Yield (%)
2.2. Crystallography
1
92
ꢀ43.2
ꢀ34.5
ꢀ36.0
ꢀ74.9
ꢀ30.0
Crystals suitable for X-ray analysis were prepared by slow diffu-
sion of hexane into EtOAc, CH2Cl2, or MeOH solutions of imidazo-
lines 5, 7, 8, 19b, and 23b. The ORTEP plots in Figure 2 confirm
the proposed molecular structure and absolute configurations on
the particular stereogenic centers and show the spatial arrange-
ment in the solid state. Front and side views are provided. While
the thiophene ring in 7 is almost coplanar with the imidazoline
(torsion angle of about 2°), the phenyl ring in 5 is substantially
twisted out of the imidazoline plane by 36°. This twist is, however,
usual for 2-(hetero)aryl imidazoles and imidazolines.14 The PyBim
ligand 8 showed two camphor moieties oppositely oriented. This
compound showed very strong hydrogen bonding to water or
other protic solvents (the molecule of H2O bonded to N3 and
N3A was omitted for clarity). The two anisoylated regioisomers
19b and 23b differ considerably. While the anisoyl moiety in pyr-
azine-derived imidazoline 19b is bent coplanar to the pyrazine ring
N
2
3
4
5
82
67
43
91
N
N
N
N
N
to allow p–p stacking, the anisoyl moiety in thiophene-substituted
ligand 23b adopted the opposite arrangement with the benzene
ring almost perpendicular to the imidazoline central plane (torsion
angle of about 79°).
6
7
57
63
ꢀ13.8
ꢀ27.2
N
2.3. Asymmetric Henry reaction
The enantioselectivities of the successfully synthesized ligands
10–23 were preliminarily tested in a copper(II)-catalyzed asym-
metric nitroaldol reaction (Henry reaction).15 The reactions were
carried out on 4-nitrobenzaldehyde with CH3NO2/Cu(OAc)2/ligand
in ethanol on a 0.5 mmol scale (Table 3).8,10,16 No additional base
was used in order to study the ligand’s electronic behavior. While
the NH-imidazolines, which undergo imidazoline tautomerism,
afforded the desired nitroaldol almost as racemates (e.g., 1, Table 3,
entry 1), N-substituted imidazolines yielded nitroaldol in enantio-
meric excesses of up to 67%. The nitroaldol reaction catalyzed by
the N-methyl and N-benzyl imidazolines 10a/b and 11a/b afforded
nitroaldol products in chemical yields of 92–94% and enantioselec-
tivities of up to 51% (Table 3, entries 2 and 3). More importantly,
the use of either regioisomer a or b enabled the formation of either
the (R)- or (S)-nitroaldol. Thus, the reaction catalyzed by regioi-
somers a afforded (R)-nitroaldols and the reaction with regioisom-
S
N
8
9
88
82
ꢀ24.4
ꢀ26.6
H
23a (61%) and only trace amounts of regioisomers 22b (7%) and 23b
(6%). Functionalization of pyrrole-substituted imidazoline 6 and Py-
Bim ligand 8 yielded an inseparable mixture of products, although
compound 6 was also N-protected by methylation. All of the iso-
lated target compounds 20–23 showed a higher stability during
the purification by column chromatography than 16–18 but
regioisomers 19a and 23a decomposed slowly to diamides 27 and
28 after one month of storing (Scheme 2). However, this ring-open-
ers
b
yielded (S)-nitroaldols. N-Isobutyryl and N-benzoyl
Table 2
N-Functionalization of NH-imidazolines 1–7
HetAr (starting NH-imidazoline)
RX
Products
Yield (%)/ratioa
Pyridin-2-yl 1
Pyridin-2-yl 1
Pyridin-2-yl 1
Pyridin-2-yl 1
Pyridin-2-yl 1
Pyridin-2-yl 1
Pyridin-2-yl 1
Pyridin-2-yl 1
Pyridin-2-yl 1
Pyrazin-2-yl 2
Pyrimidin-2-yl 3
Isoquinolin-1-yl 4
Phenyl 5
MeI
BnBr
(CH3)2CHCOCl
PhCOCl
10a/10b
11a/11b
12a/12b
13a/13b
14a/14b
15a/15b
16a/16b (24)
17a/17b (25)
18a/18b (26)
19a (27)/19b
20a/20b
21a/21b
22a/22b
23a (28)/23b
95/1:1
91/1:1
89/0:1
78/0:1
90/1:3
98/1:4
53/43b
51/46b
41/39b
84/2:3
49/7:10c
96/1:1
84/11:1
67/10:1
4-(MeO)PhCOCl
4-(NO2)PhCOCl
4-(Me)PhSO2Cl
4-(MeO)PhSO2Cl
4-(NO2)PhSO2Cl
4-(MeO)PhCOCl
4-(MeO)PhCOCl
4-(MeO)PhCOCl
4-(MeO)PhCOCl
4-(MeO)PhCOCl
Thiophen-2-yl 7
a
b
c
Overall isolated yields and ratios of regioisomers a:b.
Isolated yields of regioisomer a/diamides 24–26.
Overall isolated yield of the mixture of regioisomers a and b, the ratio was estimated according to 1H NMR spectra.

J. Tydlitát et al. / Tetrahedron: Asymmetry 23 (2012) 1010–1018
1013
H
H
H
N
H
O
H
H
O
O
O
H
H
O
column chrom. (SiO2)
or HCl/H2O
NH HN
NH HN
O
N
N
N
S
or
N
N
O
S
O
or
HetAr
HetAr
24
MeO
27, HetAr = Pyrazin-2-yl
28, HetAr = Thiophen-2-yl
, R = Me
R
R
MeO
25, R = OMe
26, R = NO2
16b-18b
19a, 23a
Scheme 2. Observed ring-opening of N-functionalized imidazolines.
Figure 2. ORTEP representations and spatial arrangement of the NH-imidazolines (a) 5, (b) 7, and (c) 8 and regioisomers (d) 19b and (e) 23b measured at 150 K. The thermal
ellipsoids are shown at the 50% probability with arbitrary spheres for H atoms. Molecules of the solvents were omitted for clarity.
regioisomers 12b and 13b gave the (S)-nitroaldol in the yields of
87% and 90% and with enantiomeric excesses of 45% and 60%,
respectively (Table 3, entries 4 and 5). In addition to N-benzoyl li-
gand 13b, the reaction times and stereochemical outcomes can be
affected by attaching electron-donating (methoxy) and electron-
withdrawing (nitro) substituents to the benzoyl moiety. While
the reaction with the anisoyl-substituted regioisomer 14b gave
the (S)-nitroaldol in a yield of 89% and with ee 67% within 24 h,
the 4-nitrobenzoyl-substituted analogue 15b afforded the same
product in 76% yield and with 46% ee after 54 h (Table 3, entries
6 and 7). According to the proposed mechanism of the Cu(II)-cata-
lyzed nitroaldol reaction,15a and the fact that both ligands possess
the same N@C–C@N binding pocket and absolute configurations,
the observed variation in the yields and enantioselectivities must
be due to the electronic density on the copper(II) ion. Higher imi-
dazoline basicity and subsequent higher electron saturation of the
active Cu(II)-coordination site in the anisoyl-substituted imidazo-
lines 14a/14b resulted in higher complex stability. Hence, the

1014
J. Tydlitát et al. / Tetrahedron: Asymmetry 23 (2012) 1010–1018
Table 3
3. Conclusion
Asymmetric Henry reactiona
OH
In conclusion, starting from enantiomerically pure (1R,2S,3R)-
camphordiamine, we have synthesized nine new camphor-ann-
elated NH-imidazolines 1–9. Two general methods starting with
the in situ generated imidates or imidate hydrochlorides were em-
ployed. Molecular structures and absolute configurations of imi-
dazolines 1,10 5, 7, and 8 were confirmed by X-ray analysis. The
NH-imidazolines 1–5 and 7 were further N-functionalized by
methylation, acylation, benzoylation, and sulfonylation 10–23.
Two regioisomers a and b were generally obtained. The spatial
arrangements and absolute configurations of two regioisomers
19b and 23b were also confirmed by crystallography. The ratio of
regioisomers a/b differed according to the structure of the starting
NH-imidazoline and the electrophile used. More importantly, both
regioisomers were separable by column chromatography. Some
regioisomers proved to be unstable, yielding camphor-derived
diamides 24–28. All successfully synthesized and isolated regioi-
somers were applied as nitrogen ligands in the asymmetric version
of a Cu(II)-catalyzed nitroaldol reaction. Whereas regioisomers a
afforded (R)-nitroaldols, regioisomers b gave the (S)-product. Thus,
either (R)- or (S)-nitroaldol products could be obtained as the ma-
jor products with one set of ligands. In addition, the reaction times/
yields and stereochemical outcomes of the nitroaldol reaction can
be affected by the electronic nature of the appended auxiliaries. Li-
gands possessing electron-donating anisoyl pendants afforded the
desired nitroaldols after relatively short times, in good chemical
yields, and with generally high ees; ligands with an electron-with-
drawing nitrobenzoyl moiety required longer reaction times and
gave lower chemical yields and ees. Thus, by having the basic cam-
phor-annelated imidazoline scaffold as in 9, the ligand property-
tuning and subsequent chemical and stereochemical outcomes of
the Henry reaction can easily be tailored by modification of the
N1- and C2-pendants.
O
H
CH2NO2
CH3NO2
ligand
Cu(OAc)2/
/EtOH
O2N
O2N
Entry
Ligand
Time (h)b
Yield (%)c
ee (%) configurationd
1
2
3
4
5
6
7
8
1
24
36/36
36/36
36
90
92/94
94/92
87
9/(S)
10a/10b
11a/11b
12b
21 (R)/46 (S)
43 (R)/51 (S)
45 (S)
13b
36
90
60 (S)
14a/14b
15a/15b
16a
17a
18a
19a/19b
21a/21b
22a/22b
23a/23b
24/24
54/54
36
24
48
24/24
24/24
24/24
24/24
92/89
81/76
92
41 (R)/67 (S)
29 (R)/46 (S)
17 (R)
9
89
87
18 (R)
17 (R)
10
11
12
13
14
36/30
66/74
12/8
14/9
28 (R)/24 (S)
22 (R)/14 (S)
10 (R)/5 (R)
9 (R)/6 (R)
a
Reactions were performed on a 0.5 mmol scale with Cu(OAc)2 (10%) and ligands
(10.5%) with nitromethane (10 equiv) in ethanol (5 mL) under N2 at room
temperature.
b
Monitored by TLC (SiO2; Hexane/EtOAc 2:1).
Isolated yields after column chromatography.
c
d
Determined by HPLC analysis with a Chiralcel OD-H column and simulta-
neously deduced from [a] values.
Henry reaction may take place exclusively on the active chiral cat-
alyst with asymmetric induction of up to 41/67%. Moreover, the
electron rich (basic) imidazoline also facilitated deprotonation of
the nitromethane in the rate-limiting step12c and the nitroaldol is
generated faster (24 h, 92/89% yields). The observed ligand elec-
tronic tuning is in accordance with that observed for the nitroaldol
reaction catalyzed by electron-rich Cu(II) carboxylates (e.g.,
methoxybenzoate or 2,4-dimethoxybenzoate).15a,16 These cop-
per(II) carboxylates afforded the desired nitroaldols in short reac-
tion times and with generally higher ees. The nitro group in
ligands 15a/15b had the opposite effect; prolonged reaction time
(54 h) and lower ee (29/46%). The application of N-sulfonyl imidaz-
olines 16a–18a provided the nitroaldol products within reaction
times of 24–48 h, according to the substitution of the benzenesul-
fonyl moiety, and rather low enantioselectivities (17–18%). Com-
pared to an amide linker as in 12–15, the more electronegative
sulfonamidic one in 16–18 seemed to be less suitable for electronic
fine-tuning.
In an extension of our study on ligand design and tuning, the
remaining NH-imidazolines 2–7 were N-anisoylated to yield target
ligands 19–21 and 22–23. Whereas the application of pyrazine-
and isoquinoline-derived regioisomers 19a/b and 21a/b (Table 3,
entries 10 and 11) afforded similar chemical and stereochemical
outcomes as those for pyridine-derived ligands 14a/b, both regioi-
somers of the phenyl- and thiophene-derived imidazolines 22a/b
and 23a/b yielded only the (R)-nitroaldols with very low chemical
yields and ees (Table 3, entries 13 and 14). This observation clearly
demonstrates the crucial role of the N@C–C@N binding pocket
(similar to bipy and other related ligands)2,17 for efficient chelation
of Cu(II) ions. The aforementioned differences in the spatial
arrangement of 19b and 23b also play an important role. However,
the results obtained with ligands 19 and 21 are generally worse
than those observed for pyridine-derived imidazolines 14, which
may be explained as a result of the higher electron-withdrawing
character of the pyrazine and isoquinoline rings. Diamides 24–
28, when applied as ligands in the nitroaldol reactions, yielded
only trace amounts of the desired nitroaldol even after prolonged
reaction times of up to 72 h.
4. Experimental
4.1. General
The starting (Het)Ar-nitriles are commercially available. The
starting methyl 1H-pyrrole-2-carbimidate hydrochloride and
methyl thiophene-2-carbimidate hydrochloride were synthesized
according to the literature.9 For full spectroscopic characterization
of compounds 1, 10–18, and 24–26 see our preliminary communi-
cation.10 Preliminary enantioselectivity screening of ligands 10–23
in the Cu(II)-catalyzed Henry reaction was carried out according to
the literature.8,10,16 The enantiomeric excesses were determined by
HPLC analysis with a Chiralcel OD-H column (85/15 hexanes/i-
PrOH, 0.8 mL/min, 230 nm): (R)-enantiomer tR = 23.19 min, (S)-
enantiomer 28.59 min. THF was freshly distilled from Na/benzo-
phenone under Ar. Evaporation and concentration in vacuo were
performed at water aspirator pressure. Column chromatography
(CC) was carried out with SiO2 60 (particle size 0.040–0.063 mm,
230–400 mesh; Merck) and commercially available solvents.
Thin-layer chromatography (TLC) was conducted on aluminum
sheets coated with SiO2 60 F254 obtained from Merck, with visual-
ization by a UV lamp (254 or 360 nm). Melting points (mp) were
measured on a Büchi B-540 melting-point apparatus in open cap-
illaries and are uncorrected. 1H and 13C NMR spectra were recorded
in CDCl3 at 400 MHz or 100 MHz, respectively, with Bruker
AVANCE 400 instruments at 25 °C. Chemical shifts are reported
in ppm relative to the signal of Me4Si. Residual solvent signals in
the 1H and 13C NMR spectra were used as the internal reference
(CDCl3—7.25 and 77.23 ppm for 1H and 13C NMR, respectively).
Coupling constants (J) are given in Hz. The apparent resonance

J. Tydlitát et al. / Tetrahedron: Asymmetry 23 (2012) 1010–1018
1015
multiplicity is described as s (singlet), br s (broad singlet), d (dou-
blet), dd (doublet of doublet), t (triplet), q (quartet), and m (multi-
plet). Additional NMR techniques such as 1H–1H COSY, HMBC, and
HMQC were used for regular signal assignment. Optical rotation
values were measured on a Perkin Elmer 341 instrument, concen-
tration c is given in g/100 mL MeOH. The mass spectra were mea-
sured on GC/MS configuration comprised of an Agilent
Technologies—6890N gas chromatograph (HP-5MS column, length
1H), 3.92 (br s, 1H), 4.29 (br s, 1H), 6.52 (br s, 1H), 7.62–7.68 (m,
3H), 7.77–7.79 (m, 1H), 8.45 (d, J = 5.6 Hz, 1H), 9.63 (d, J = 9.2 Hz,
1H); 13C NMR (100 MHz, CDCl3, 25 °C): d = 12.37, 19.04, 23.88,
26.22, 34.41, 48.05, 48.62, 50.15, 122.94, 126.81, 127.15, 128.56,
128.56, 130.37, 136.91, 141.13, 148.20, 163.96; EI-MS (70 eV) m/
z (rel. int.): 305 (M+, 29), 222 (100), 196 (74), 128 (14); Elemental
analysis calcd for C20H23N3 (305.42): C 78.65, H 7.59, N 13.76;
found: C 78.37, H 7.53, N 13.61.
30 m, I.D. 0.25 mm, film 0.25 lm) equipped with a 5973 Network
MS detector (EI 70 eV, mass range 33–550 Da). Elemental analyses
were performed on a Thermo Flash 2000 CHNS experimental or-
ganic analyzer.
4.2.4. 4,40-Pyridin-2,6-diylbis[(1R,2S,6R,7S)-1,10,10-trimethyl-
3,5-diazatricyclo[5.2.1.02,6]dec-3-ene] 8
The title compound was synthesized from pyridine-2,6-dicarbo-
nitrile (80.1 mg) following the general method. Off-white solid,
4.2. General method for the synthesis of NH-imidazolines 1–4
and 8
yield 236 mg (88%), mp 104–106 °C, ½a D20
¼ ꢀ24:4 (c 0.5, MeOH).
ꢁ
1H NMR (400 MHz, CDCl3, 25 °C): d = 0.86 (s, 6H), 0.96 (s, 6H),
1.05–1.08 (m, 2H), 1.11 (s, 6H), 1.26–1.32 (m, 2H), 1.51–1.57 (m,
2H), 1.73–1.79 (m, 2H), 2.19 (d, J = 4.0 Hz, 2H), 4.01 (d,
J = 10.4 Hz, 2H), 4.22 (d, J = 10.4 Hz, 2H), 6.08 (br s, 2H), 7.65 (t,
J = 7.4 Hz, 1H), 8.34 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3,
25 °C): d = 11.96, 18.71, 23.67, 25.75, 34.0, 48.00, 48.87, 49.60,
66.33, 71.72, 125.86, 138.30, 163.47, 178.52; EI-MS (70 eV) m/z
(rel. int.): 431 (M+, 23), 348 (100), 322 (54), 238 (17), 207 (21),
95 (21); Elemental analysis calcd for C27H37N5 (431.62): C 75.13,
H 8.64, N 16.23; found: C 75.46; H 8.79; N 16.65.
Sodium (5 mg) was added to dry methanol (10 mL) followed by
the appropriate heteroaromatic nitrile (1.24/0.62 mmol) and the
resulting solution was stirred at 25 °C until TLC (SiO2; EtOAc) or
GC/MS showed total conversion of the nitrile into the correspond-
ing imidate (usually 1–4 h). (1R,2S,3R)-Camphordiamine dihydro-
chloride (299 mg, 1.24 mmol), triethylamine (0.5 mL) and acetic
acid (3 drops) were then added and the resulting solution was stir-
red at 40 °C for 12 h. The solvent was evaporated in vacuo and the
crude product was purified by column chromatography (SiO2;
EtOAc/MeOH 2:1) to afford pure product.
4.3. General method for the synthesis of NH-imidazolines 5–7
4.2.1. (1R,2S,6R,7S)-1,10,10-Trimethyl-4-(pyrazin-2-yl)-3,5-
diazatricyclo[5.2.1.02,6]dec-3-ene 2
To a suspension of imidate hydrochloride (1.24 mmol) in
dichloromethane (10 mL), (1R,2S,3R)-camphordiamine dihydro-
chloride (299 mg, 1.24 mmol), triethylamine (0.5 mL), and acetic
acid (3 drops) were added and the resulting solution was stirred
at 25 °C for 24 h. The solvent was evaporated in vacuo and the
crude product was purified by column chromatography (SiO2;
EtOAc/MeOH 2:1) to afford pure product.
The title compound was synthesized from pyrazine-2-carboni-
trile (130.3 mg) following the general method. Off-white solid,
yield 260 mg (82%), mp 120–121 °C, ½a D20
¼ ꢀ34:5 (c 0.5, MeOH).
ꢁ
1H NMR (400 MHz, CDCl3, 25 °C): d = 0.66 (s, 3H), 0.78 (s, 3H),
0.86 (s, 3H), 0.80–0.95 (m, 2H), 1.28–1.36 (m, 1H), 1.52–1.61 (m,
1H), 1.92 (d, J = 4.8 Hz, 1H), 3.73 (d, J = 10.0 Hz, 1H), 4.04 (d,
J = 10.0 Hz, 1H), 6.85 (br s, 1H), 8.32–8.33 (m, 1H), 8.43 (d,
J = 2.8 Hz, 1H), 9.22 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3,
25 °C): d = 11.77, 18.27, 23.40, 25.73, 33.86, 47.64, 48.27, 49.46,
73.36, 74.34, 143.00, 143.44, 144.35, 145.55, 161.44; EI-MS
(70 eV) m/z (rel. int.): 256 (M+, 26), 186 (40), 173 (100), 147
(76), 95 (35); Elemental analysis calcd for C15H20N4 (256.34): C
70.28, H 7.86, N 21.86; found: C, 69.99, H 7.72, N 21.83.
4.3.1. (1R,2S,6R,7S)-1,10,10-Trimethyl-4-phenyl-3,5-diazatricyclo-
[5.2.1.02,6]dec-3-ene 5
The title compound was synthesized from ethyl benzimidate
hydrochloride (230.2 mg) following the general method. Off-white
solid, yield 287 mg (91%), mp 150–152 °C, ½a D20
¼ ꢀ30:0 (c 0.5,
ꢁ
MeOH). 1H NMR (400 MHz, CDCl3, 25 °C): d = 0.81 (s, 3H), 0.95 (s,
3H), 0.99 (s, 3H), 1.00–1.06 (m, 2H), 1.42–1.49 (m, 1H), 1.66–1.74
(m, 1H), 2.02 (d, J = 4.4 Hz, 1H), 3.75 (d, J = 10.0 Hz, 1H), 4.09 (d,
J = 10.0 Hz, 1H), 5.46 (br s, 1H), 7.29–7.39 (m, 3H), 7.70 (d,
J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, 25 °C): d = 12.18,
18.59, 23.73, 26.13, 34.28, 47.61, 48.32, 49.73, 127.37, 128.48,
130.65, 131.03, 164.40; EI-MS (70 eV) m/z (rel. int.): 254 (M+,
26), 184 (38), 171 (100), 145 (67), 95 (18); Elemental analysis calcd
for C17H22N2 (254.37): C 80.27, H 8.72, N 11.01; found: C 80.01, H
8.50, N 10.60.
4.2.2. (1R,2S,6R,7S)-1,10,10-Trimethyl-4-(pyrimidin-2-yl)-3,5-
diazatricyclo[5.2.1.02,6]dec-3-ene 3
The title compound was synthesized from pyrimidine-2-carbo-
nitrile (130.3 mg) following the general method. Off-white solid,
yield 213 mg (67%), mp 138–140 °C, ½a D20
¼ ꢀ36:0 (c 0.5, MeOH).
ꢁ
1H NMR (400 MHz, CDCl3, 25 °C): d = 0.81 (s, 3H), 0.98 (s, 3H),
1.03 (s, 3H), 1.04–1.07 (m, 2H), 1.45–1.51 (m, 1H), 1.66–1.73 (m,
1H), 2.12 (d, J = 4.8 Hz, 1H), 3.94 (d, J = 10.4 Hz, 1H), 4.23 (d,
J = 10.4 Hz, 1H), 7.25 (br s, 1H), 7.30 (t, J = 4.8 Hz, 1H), 8.75 (d,
J = 4.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, 25 °C): d = 12.15,
18.73, 23.69, 26.05, 34.24, 48.12, 48.70, 49.72, 73.61, 75.05,
121.83, 156.67, 157.39, 162.43; EI-MS (70 eV) m/z (rel. int.): 256
(M+, 17), 186 (19), 173 (84), 147 (100), 95 (16); Elemental analysis
calcd for C15H20N4 (256.34): C 70.28, H 7.86, N 21.86; found: C
70.02, H 7.70, N 21.70.
4.3.2. (1R,2S,6R,7S)-1,10,10-Trimethyl-4-(1H-pyrrol-2-yl)-3,5-
diazatricyclo[5.2.1.02,6]dec-3-ene 6
The title compound was synthesized from methyl 1H-pyrrole-
2-carbimidate hydrochloride (160.7 mg) following the general
method. Off-white solid, yield 172 mg (57%), mp 203–205 °C,
½
a 2D0
ꢁ
¼ ꢀ13:8 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3, 25 °C):
d = 0.82 (s, 1H), 0.90 (s, 1H), 0.96–1.03 (m, 2H), 1.08 (s, 3H),
1.48–1.55 (m, 1H), 1.68–1.74 (m, 1H), 2.11 (d, J = 4.4 Hz, 1H),
3.96 (d, J = 10.4 Hz, 1H), 4.12 (d, J = 10.4 Hz, 1H), 6.17 (s, 1H),
7.00 (s, 1H), 7.56 (s, 1H), 10.23 (s, 1H), 12.28 (s, 1H); 13C NMR
(100 MHz, CDCl3, 25 °C): d = 11.72, 18.53, 23.51, 25.05, 33.33,
47.63, 49.05, 49.06, 65.84, 70.97, 111.53, 114.93, 119.67, 127.13,
157.48; EI-MS (70 eV) m/z (rel. int.): 243 (M+, 42), 173 (32), 160
(100), 134 (62), 95 (28); Elemental analysis calcd for C15H21N3
(243.35): C 74.03, H 8.70, N 17.27; found: C 74.33; H 8.88; N 17.54.
4.2.3. (1R,2S,6R,7S)-4-(Isoquinolin-1-yl)-1,10,10-trimethyl-3,5-
diazatricyclo[5.2.1.02,6]dec-3-ene 4
The title compound was synthesized from isoquinolin-1-carbo-
nitrile (192.2 mg) following the general method. Off-white solid,
yield 163 mg (43%), mp 105–107 °C, ½a D20
¼ ꢀ74:9 (c 0.5, MeOH).
ꢁ
1H NMR (400 MHz, CDCl3, 25 °C): d = 0.87 (s, 1H), 0.97–1.16 (m,
8H), 1.51–1.56 (m, 1H), 1.73–1.79 (m, 1H), 2.15 (d, J = 3.6 Hz,

1016
J. Tydlitát et al. / Tetrahedron: Asymmetry 23 (2012) 1010–1018
4.3.3. (1R,2S,6R,7S)-1,10,10-Trimethyl-4-(thiophen-2-yl)-3,5-
diazatricyclo[5.2.1.02,6]dec-3-ene 7
The title compound was synthesized from methyl thiophene-2-
carbimidate hydrochloride (181.9 mg) following the general meth-
od. Off-white solid, yield 203 mg (63%), mp 124–126 °C,
130.28, 143.06, 144.16, 144.59, 147.28, 157.73, 161.66, 169.59;
EI-MS (70 eV) m/z (rel. int.): 390 (M+, 7), 255 (37), 172 (12), 135
(100), 77 (10); Elemental analysis calcd for C23H26N4O2 (390.48):
C 70.75, H 6.71, N 14.35; found: C 70.47, H 6.67, N 14.11.
½
a 2D0
ꢁ
¼ ꢀ27:2 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3, 25 °C):
4.5.2. Imidazoline 19b
d = 0.83 (s, 3H), 0.96 (s, 3H), 1.05 (s, 3H), 1.22–1.27 (m, 2H),
1.45–1.53 (m, 1H), 1.68–1.75 (m, 1H) 2.12 (d, J = 4.4 Hz, 1H) 3.88
(d, J = 10.0 Hz, 1H), 4.12 (d, J = 10.0 Hz, 1H), 7.02–7.04 (m, 1H),
7.46 (m, 1H), 7.92 (d, J = 3.2 Hz, 1H); 13C NMR (100 MHz, CDCl3,
25 °C): d = 12.09, 18.61, 23.65, 25.72, 33.89, 47.75, 48.90, 49.37,
70.76, 73.16, 128.27, 129.43, 131.60, 132.13, 159.82; EI-MS
(70 eV) m/z (rel. int.): 260 (M+, 34), 190 (51), 177 (100), 151
(71), 95(29); Elemental analysis calcd for C15H20N2S (260.40): C
69.19, H 7.74, N 10.76, S 12.31; found: C 69.39; H 7.81; N 10.56;
S 12.49.
The title compound was synthesized from NH-imidazoline 2
(100 mg) following the general method. Off-white solid, yield
76 mg (50%), mp 155–157 °C, Rf = 0.18 (EtOAc/CH2Cl2/NH4OH(aq)
1:1:0.01), ½a 2D0
ꢁ
¼ ꢀ114:6 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3,
25 °C): d = 0.82 (s, 3H), 0.99–1.02 (m, 1H), 1.05 (s, 3H), 1.15 (s, 3H),
1.17–1.23 (m, 1H), 1.53–1.60 (m, 1H), 1.64–1.72 (m, 1H), 2.04 (d,
J = 4.8 Hz, 1H), 3.76 (s, 1H), 4.16 (d, J = 9.6 Hz, 1H), 4.41 (d,
J = 9.2 Hz, 1H), 6.74 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H),
8.27 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.77 (s, 1H); 13C NMR
(100 MHz, CDCl3, 25 °C): d = 12.00, 19.20, 23.50, 25.65, 34.88,
47.43, 49.25, 49.76, 55.53, 69.40, 81.96, 113.65, 127.71, 130.50,
143.27, 144.26, 144.58, 147.43, 159.00, 162.25, 169.44; EI-MS
(70 eV) m/z (rel. int.): 390 (M+, 5), 255 (21), 186 (20), 135 (100),
77 (8); Elemental analysis calcd for C23H26N4O2 (390.48): C
70.75, H 6.71, N 14.35; found: C 70.35, H 6.76, N 14.02.
4.4. (1R,2S,6R,7S)-1,10,10-Trimethyl-3,5-diazatricyclo[5.2.1.02,6]-
dec-3-ene 9
(1R,2S,3R)-Camphordiamine dihydrochloride (80 mg, 0.33
mmol), trimethyl orthoformate (0.1 mL; 0.91 mmol), and NaOAc
(4.1 mg, 0.05 mmol) were dissolved in AcOH (1 mL). The reaction
mixture was then stirred at 25 °C for 24 h, diluted with EtOAc,
and washed with aq NaOH (1 M). The layers were separated, the
water layer was extracted with EtOAc (2 ꢂ 50 mL), the combined
organic extracts were dried (Na2SO4), and the solvent was evapo-
rated. The crude product was triturated with petroleum ether to af-
ford 9 as a white solid. White solid, yield 48 mg (82%), mp 122–
4.5.3. Imidazolines 20a/b
The mixture of regioisomers was synthesized from NH-imidaz-
oline 3 (100 mg) following the general method. Both regioisomers
a and b (ratio 7:10) were not separable by column chromatogra-
phy. Viscous oil, yield 75 mg (49%), Rf = 0.41 (EtOAc/CH2Cl2/NH4O-
H(aq) 1:1:0.01). 1H NMR (400 MHz, CDCl3, 25 °C): d = 0.84 (s, 3H),
0.89 (s, 2.1H), 1.05 (s, 2.1H), 1.05–1.12 (m, 0.7H), 1.13 (s, 3H),
1.17 (s, 3H), 1.18 (s, 2.1H), 1.21–1.25 (m, 2H), 1.31–1.37 (m,
0.7H), 1.54–1.61 (m, 1.7H), 1.68–1.73 (m, 1H), 1.82–1.86 (m,
0.7H), 2.13 (d, J = 4.7 Hz, 1H), 2.33 (d, J = 4.6 Hz, 1H), 3.67 (s,
2.1H), 3.75 (s, 3H), 4.19 (d, J = 9.2 Hz, 1H), 4.37 (d, J = 9.2 Hz,
0.7H), 4.45 (d, J = 9.2 Hz, 1H), 4.69 (d, J = 9.2 Hz, 1H), 6.51 (d,
J = 8.8 Hz, 1.4H), 6.68 (d, J = 8.8 Hz, 2H), 6.92 (t, J = 4.9 Hz, 0.7H),
7.07 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1.4H), 7.43 (d,
J = 8.8 Hz, 2H), 8.40 (d, J = 4.8 Hz, 1.4H), 8.56 (d, J = 5.2 Hz, 2H).
EI-MS (70 eV) m/z (rel. int.): 390 (M+, 1), 255 (48), 186 (30), 135
(100), 77 (6).
124 °C, ½a 2D0
ꢁ
¼ ꢀ26:6 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3,
25 °C): d = 0.78 (s, 3H), 0.96 (s, 3H), 1.01 (s, 3H), 0.98–1.05 (m,
2H), 1.44–1.49 (m, 1H), 1.66–1.70 (m, 1H) 1.96 (d, J = 4.6 Hz, 1H)
3.63 (d, J = 10.2 Hz, 1H), 3.88 (d, J = 10.2 Hz, 1H), 4.68 (br s, 1H);
13C NMR (100 MHz, CDCl3, 25 °C): d = 12.11, 18.75, 23.85, 26.12,
34.46, 48.12, 48.20, 49.63, 71.52, 74.10, 155.16; EI-MS (70 eV) m/
z (rel. int.): 178 (M+, 8), 108 (29), 95 (100), 69 (46); Elemental anal-
ysis calcd for C11H18N2 (178.27): C 74.11, H 10.18, N 15.71; found:
C 73.58; H 10.01; N 15.46.
4.5. General method for the synthesis of imidazolines 19–23
4.5.4. Imidazoline 21a
Lithium bis(trimethylsilyl)amide (0.78 mL, 0.78 mmol, 1 M
solution in THF, LHMDS) was added to a solution of imidazoline
2–7 (0.39 mmol) in dry THF (10 mL) under Ar at 0 °C. The resulting
yellow solution was stirred for 30 min whereupon a solution of 4-
anisoylchloride (80.2 mg, 0.47 mmol) in THF (1 mL) was added
dropwise and the reaction was stirred at 25 °C for an additional
3 h (monitored by TLC). The reaction was quenched with aq NH4Cl
(5 drops), the solvents were evaporated in vacuo, and the crude
mixture of regioisomers was purified by column chromatography
(SiO2; indicated solvent system). Triethylamine (5 drops) was
added to the combined fractions from the column chromatography
before the solvent was evaporated.
The title compound was synthesized from NH-imidazoline 4
(119.1 mg) following the general method. Viscous oil, yield
82 mg (48%), Rf = 0.38 (EtOAc/CH2Cl2/NH4OH(aq) 1:1:0.01),
½
a 2D0
ꢁ
¼ þ102:4 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3, 25 °C):
d = 0.94 (s, 3H), 1.06 (s, 3H), 1.22–1.30 (m, 2H), 1.43 (s, 3H),
1.58–1.65 (m, 1H), 1.86–1.94 (m, 1H), 2.39 (d, J = 4.8 Hz, 1H),
3.51 (s, 3H), 4.46 (d, J = 9.2 Hz, 1H), 4.87 (d, J = 9.2 Hz, 1H), 6.12
(d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 6.0 Hz, 1H),
7.51–7.59 (m, 3H), 8.00 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 5.6 Hz, 1H);
13C NMR (100 MHz, CDCl3, 25 °C): d = 12.97, 20.22, 23.62, 26.74,
34.27, 47.97, 48.73, 51.20, 55.29, 71.27, 76.97, 112.31, 121.21,
125.35, 126.92, 126.98, 128.02, 128.09, 129.44, 130.31, 135.79,
141.79, 151.60, 157.79, 160.99, 169.94; EI-MS (70 eV) m/z (rel.
int.): 439 (M+, 5), 304 (54), 135 (100), 77 (11); Elemental analysis
calcd for C28H29N3O2 (439.55): C 76.51, H 6.65, N 9.56; found: C
76.29, H 6.70, N 9.49.
4.5.1. Imidazoline 19a
The title compound was synthesized from NH-imidazoline 2
(100 mg) following the general method. Viscous oil, yield 52 mg
(34%), Rf = 0.23 (EtOAc/CH2Cl2/NH4OH(aq) 1:1:0.01), ½a D20
¼ þ26:0
ꢁ
(c 0.5, MeOH). 1H NMR (400 MHz, CDCl3, 25 °C): d = 0.88 (s, 3H),
1.03 (s, 3H), 1.09 (s, 3H), 1.17–1.24 (m, 1H), 1.28–1.35 (m, 1H),
1.51–1.59 (m, 1H), 1.81–1.89 (m, 1H), 2.29 (d, J = 4.4 Hz, 1H),
3.66 (s, 3H), 4.36 (d, J = 9.2 Hz, 1H), 4.65 (d, J = 9.2 Hz, 1H), 6.52
(d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 8.03 (dd, J = 2.4 Hz,
J = 1.2 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 1.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3, 25 °C): d = 12.93, 19.68, 23.55, 26.45,
34.22, 47.78, 48.87, 51.26, 55.46, 73.00, 76.81, 113.31, 128.51,
4.5.5. Imidazoline 21b
The title compound was synthesized from NH-imidazoline 4
(119.1 mg) following the general method. Off-white solid, yield
82 mg (48%), Rf = 0.31 (EtOAc/CH2Cl2/NH4OH(aq) 1:1:0.01),
½
a 2D0
ꢁ
¼ ꢀ116:6 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3, 25 °C):
d = 0.90 (s, 3H), 1.14–1.21 (m, 1H), 1.24 (s, 3H), 1.26–1.29 (m,
1H), 1.35 (s, 3H), 1.60–1.67 (m, 1H), 1.75–1.83 (m, 1H), 2.25 (d,
J = 4.8 Hz, 1H), 3.60 (s, 3H), 4.26 (d, J = 9.6 Hz, 1H), 4.62 (d,

J. Tydlitát et al. / Tetrahedron: Asymmetry 23 (2012) 1010–1018
1017
J = 9.6 Hz, 1H), 6.35 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.38
(d, J = 5.6 Hz, 1H), 7.54–7.61 (m, 2H), 7.65–7.67 (m, 1H), 8.23–8.27
(m, 2H); 13C NMR (100 MHz, CDCl3, 25 °C): d = 12.20, 20.01, 23.50,
25.79, 35.12, 47.65, 48.60, 49.86, 55.37, 68.28, 81.65, 112.80,
121.34, 125.66, 126.90, 127.02, 128.06, 128.09, 129.55, 130.29,
136.23, 141.72, 151.37, 158.50, 161.28, 168.82; EI-MS (70 eV) m/
z (rel. int.): 439 (M+, 5), 304 (45), 235 (12), 207 (15), 135 (100),
77 (11); Elemental analysis calcd for C28H29N3O2 (439.55): C
76.51, H 6.65, N 9.56; found: C 76.35, H 6.72, N 9.51.
3H), 4.08 (d, J = 9.0 Hz, 1H), 4.32 (d, J = 9.0 Hz, 1H), 6.78–6.81 (m,
3H), 6.95–6.97 (m, 1H), 7.24–7.25 (m, 1H), 7.53 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3, 25 °C): d = 12.13, 19.22, 23.59,
25.80, 34.92, 47.15, 49.67, 49.74, 55.62, 70.30, 80.71, 113.65,
127.01, 128.15, 128.35, 129.66, 130.68, 133.98, 156.18, 162.42,
170.32; EI-MS (70 eV) m/z (rel. int.): 394 (M+, 5), 259 (13), 190
(26), 135 (100), 77 (4); Elemental analysis calcd for C23H26N2O2S
(394.53): C 70.02, H 6.64, N 7.10, S 8.13; found: C 69.53, H 6.76,
N 6.62, S 8.15.
4.5.6. Imidazoline 22a
4.6. Ring-opening of imidazolines 19a and 23a
The title compound was synthesized from NH-imidazoline 5
(99.2 mg) following the general method. Viscous oil, yield
Pure regioisomers 19a and 23a underwent spontaneous slow
hydrolysis to diamides 27 and 28 within 1 month. These products
were purified by column chromatography.
116 mg (77%), Rf = 0.21 (EtOAc/hexane 1:2), ½a D20
¼ þ1:4 (c 0.5,
ꢁ
MeOH). 1H NMR (400 MHz, CDCl3, 25 °C): d = 0.88 (s, 3H), 1.07 (s,
6H), 1.30–1.35 (m, 2H), 1.53–1.60 (m, 1H), 1.81–1.89 (m, 1H),
2.28 (d, J = 4.8 Hz, 1H), 3.66 (s, 3H), 4.30 (d, J = 9.2 Hz, 1H), 4.62
(d, J = 9.2 Hz, 1H), 6.48 (d, J = 8.8 Hz, 2H), 7.05–7.13 (m, 3H), 7.18
(d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, 25 °C): d = 13.01,
19.77, 23.64, 26.48, 34.40, 47.52, 48.81, 51.22, 55.46, 73.49,
75.94, 113.07, 127.88, 128.14, 128.32, 129.40, 130.65, 132.58,
160.75, 161.63, 170.37; EI-MS (70 eV) m/z (rel. int.): 388 (M+, 5),
253 (18), 170 (25), 135 (100), 77 (11); Elemental analysis calcd
for C25H28N2O2 (388.50): C 77.29, H 7.26, N 7.21; found: C 77.15,
H 7.52, N 7.18.
4.6.1. N-[(1R,2S,3R,4S)-3-(4-Methoxybenzoylamino)-4,7,7-
trimethylbicyclo[2.2.1]hept-2-yl]pyrazine-2-carboxamide 27
The title compound was obtained from regioisomer 19a. Off-
white solid, mp 249–251 °C, Rf = 0.37 (EtOAc/CH2Cl2/NH4OH(aq)
1:1:0.01), ½a 2D0
ꢁ
¼ ꢀ78:6 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3,
25 °C): d = 0.90 (s, 3H), 0.97 (s, 3H), 1.15 (s, 3H), 1.42–1.53 (m,
2H), 1.65–1.71 (m, 1H), 1.82–1.86 (m, 1H), 2.12 (d, J = 4.4 Hz,
1H), 3.83 (s, 3H), 4.27 (t, J = 8.4 Hz, 1H), 4.46 (t, J = 8.4 Hz, 1H),
6.06 (br d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.65 (d,
J = 8.8 Hz, 2H), 8.11 (br d, J = 6.4 Hz, 1H), 8.33 (dd, J = 2.4 Hz,
J = 1.6 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 9.32 (d, J = 1.6 Hz, 1H). 13C
NMR (100 MHz, CDCl3, 25 °C): d = 12.16, 2 ꢂ 21.51, 26.39, 35.71,
47.95, 48.87, 50.54, 55.65, 56.72, 60.31, 114.04, 127.10, 128.77,
142.62, 144.55, 144.66, 147.42, 162.47, 162.49, 167.29. EI-MS
(70 eV) m/z (rel. int.): 408 (M+, 1), 285 (6), 257 (42), 229 (5), 150
(4), 135 (100), 107 (4), 77 (4).
4.5.7. Imidazoline 22b
The title compound was synthesized from NH-imidazoline 5
(99.2 mg) following the general method. Off-white solid, yield
11 mg (7%), mp 151–153 °C, Rf = 0.16 (EtOAc/hexane 1:2),
½
a 2D0
ꢁ
¼ ꢀ62:8 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3, 25 °C):
d = 0.80 (s, 3H), 0.98–1.02 (m, 1H), 1.03 (s, 3H), 1.13 (s, 3H),
1.15–1.24 (m, 1H), 1.49–1.56 (m, 1H), 1.62–1.70 (m, 1H), 2.06 (d,
J = 4.8 Hz, 1H), 3.71 (s, 3H), 4.05 (d, J = 9.2 Hz, 1H), 4.37 (d,
J = 9.2 Hz, 1H), 6.65 (d, J = 8.8 Hz, 2H), 7.09–7.17 (m, 3H), 7.26 (d,
J = 8.4 Hz, 3H), 7.37 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3,
25 °C): d = 12.03, 19.23, 23.47, 25.72, 34.89, 47.13, 49.24, 49.47,
55.44, 69.55, 80.69, 113.37, 127.81, 127.87, 128.02, 129.48,
130.50, 132.53, 161.42, 161.98, 169.68; EI-MS (70 eV) m/z (rel.
int.): 388 (M+, 10), 253 (10), 184 (45), 135 (100), 77 (6); Elemental
analysis calcd for C25H28N2O2 (388.50): C 77.29; H 7.26, N 7.21;
found: C 76.92, H 7.28, N 6.96.
4.6.2. N-[(1R,2S,3R,4S)-3-(4-Methoxybenzoylamino)-4,7,7-tri-
methylbicyclo[2.2.1]hept-2-yl]thiophene-2-carboxamide 28
The title compound was obtained from regioisomer 23a. Off-
white solid, mp 161–163 °C, Rf = 0.18 (EtOAc/hexane 1:2),
½
a 2D0
ꢁ
¼ ꢀ30:0 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3, 25 °C):
d = 0.88 (s, 3H), 0.96 (s, 3H), 1.12 (s, 3H), 1.38–1.50 (m, 2H),
1.62–1.69 (m, 1H), 1.80–1.84 (m, 1H), 2.12 (d, J = 4.4 Hz, 1H),
3.83 (s, 3H), 4.18 (dd, J = 8.8 Hz, J = 5.6 Hz, 1H), 4.46 (t, J = 8.8 Hz,
1H), 6.07–6.10 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.99 (dd,
J = 4.8 Hz, J = 4.0 Hz, 1H), 7.34 (d, J = 4.0 Hz, 1H), 7.38 (d,
J = 4.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3,
25 °C): d = 12.12, 21.48, 21.49, 26.30, 35.58, 47.82, 49.03, 50.42,
55.64, 57.33, 60.27, 114.17, 126.73, 127.89, 128.37, 128.73,
129.77, 139.09, 150.79, 162.56, 167.18. EI-MS (70 eV) m/z (rel.
int.): 285 (9), 261 (50), 233 (8), 135 (100), 111 (41), 77 (5).
4.5.8. Imidazoline 23a
The title compound was synthesized from NH-imidazoline 7
(101.6 mg) following the general method. Viscous oil, yield
94 mg (61%), Rf = 0.29 (EtOAc/hexane 1:2), ½a D20
¼ þ9:4 (c 0.5,
ꢁ
MeOH). 1H NMR (400 MHz, CDCl3, 25 °C): d = 0.85 (s, 3H), 0.96 (s,
3H), 1.06 (s, 3H), 1.14–1.30 (m, 2H), 1.49–1.57 (m, 1H), 1.77–1.85
(m, 1H), 2.26 (d, J = 4.4 Hz, 1H), 3.69 (s, 3H), 4.27 (d, J = 8.8 Hz,
1H), 4.50 (d, J = 8.8 Hz, 1H), 6.57–6.60 (m, 4H), 7.10 (dd,
J = 4.8 Hz, J = 1.2 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3, 25 °C): d = 12.90, 19.53, 23.58, 26.33, 34.34,
47.27, 48.92, 51.06, 55.44, 74.53, 75.83, 113.18, 126.83, 127.95,
128.59, 129.60, 130.36, 134.00, 155.50, 161.82, 170.46; EI-MS
(70 eV) m/z (rel. int.): 394 (M+, 5), 259 (20), 176 (27), 135 (100),
77 (12); Elemental analysis calcd for C23H26N2O2S (394.53): C
70.02, H 6.64, N 7.10, S 8.13; found: C 69.91, H 6.54, N 7.03, S 8.02.
4.7. Crystallography
The X-ray data for colorless crystals of 5 (CCDC 874023), 7
(CCDC 874024), 8 (CCDC 717409), 19b (CCDC 874026), and 23b
(CCDC 874025) were obtained at 150 K using Oxford Cryostream
low-temperature device on a Nonius KappaCCD diffractometer
with MoK radiation (k = 0.71073 Å), a graphite monochromator,
a
and the
u and v scan mode. Data reductions were performed with
DENZO-SMN.18 The absorption was corrected by integration meth-
ods.19 Structures were solved by direct methods (Sir92)20 and re-
fined by full matrix least-square based on F2 (SHELXL97).21
Hydrogen atoms were mostly localized on a difference Fourier
map, however to ensure uniformity of the treatment of the crystal,
all hydrogen atoms were recalculated into idealized positions (rid-
ing model) and assigned temperature factors Hiso(H) = 1.2 Ueq (pi-
vot atom) or of 1.5 Ueq for the methyl moiety with C–H = 0.96,
0.97, 0.98, and 0.93 Å for methyl, methylene, and hydrogen atoms
4.5.9. Imidazoline 23b
The title compound was synthesized from NH-imidazoline 7
(101.6 mg) following the general method. Off-white solid, yield
9 mg (6%), Rf = 0.42 (EtOAc/hexane 1:2), ½a D20
¼ ꢀ78:1 (c 0.5,
ꢁ
MeOH). 1H NMR (400 MHz, CDCl3, 25 °C): d = 0.82 (s, 3H), 0.95–
0.99 (m, 1H), 1.01 (s, 3H), 1.14 (s, 3H), 1.17–1.20 (m, 1H), 1.50–
1.58 (m, 1H), 1.62–1.68 (m, 1H), 2.04 (d, J = 4.8 Hz, 1H), 3.81 (s,

1018
J. Tydlitát et al. / Tetrahedron: Asymmetry 23 (2012) 1010–1018
on sp2 carbon atoms, respectively. H-atoms in the N–H groups
were placed according to Fourier map, in 5, one half of the H atom
was placed to both nitrogen atoms.
Crystallographic data for structural analysis have been depos-
ited with the Cambridge Crystallographic Data Centre. Copies of
this information may be obtained free of charge from The Director,
CCDC, 12 Union Road, Cambridge CB2 1EY, UK (fax: +44-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://
www.ccdc.cam.ac.uk).
7. For selected recent applications of imidazoline ligands see: (a) Bastero, A.;
Bella, A. F.; Fernández, F.; Jansat, S.; Claver, C.; Gómez, M.; Muller, G.; Ruiz, A.;
Font-Bardía, M.; Solans, X. Eur. J. Inorg. Chem. 2007, 132–139; (b) Anilkumar, G.;
Bhor, S.; Tse, M. K.; Klawonn, M.; Bitterlich, B.; Beller, M. Tetrahedron:
Asymmetry 2005, 16, 3536–3561; (c) Bastero, A.; Claver, C.; Ruiz, A.; Castillón,
S.; Daura, E.; Bo, C.; Zangrando, E. Chem. Eur. J. 2004, 10, 3747–3760; (d) Guiu,
E.; Claver, C.; Benet-Buchholz, J.; Castillón, S. Tetrahedron: Asymmetry 2004, 15,
3365–3373; (e) Davenport, A. J.; Davies, D. L.; Fawcett, J.; Russell, D. R. J.
Organomet. Chem. 2006, 691, 3445–3450; (f) Busacca, C. A.; Grossbach, D.; So, R.
C.; O’Brien, E. M.; Spinelli, E. M. Org. Lett. 2003, 5, 595–598; (g) Xu, J.; Guan, Y.;
Yang, S.; Ng, Y.; Peh, G.; Tan, C.-H. Chem. Asian J. 2006, 1, 724–729; (h)
Nakamura, S.; Hyodo, K.; Nakamura, Y.; Shibata, N.; Toru, T. Adv. Synth. Catal.
2008, 350, 1443–1448.
8. Kulhánek, J.; Bureš, F.; Šimon, P.; Schweizer, W. B. Tetrahedron: Asymmetry
2008, 19, 2462–2469.
Acknowledgment
ˇ ˇ
9. Tydlitát, J.; Bureš, F.; Kulhánek, J.; Ru˚ zicka, A. Synthesis 2010, 3934–3940.
This research was supported by the Ministry of Education,
Youth, and Sport of the Czech Republic.
ˇ ˇ
10. Bureš, F.; Kulhánek, J.; Ru˚ zicka, A. Tetrahedron Lett. 2009, 50, 3042–3045.
11. Busacca, C. A.; Campbell, S.; Dong, Y.; Grossbach, D.; Ridges, M.; Smith, L.;
Spinelli, E. J. Org. Chem. 2000, 65, 4753–4755.
12. For recent reviews on the Henry reaction see: (a) Palomo, C.; Oiarbide, M.; Laso,
A. Eur. J. Org. Chem. 2007, 2561–2574; (b) Boruwa, J.; Gogoi, N.; Saikia, P. P.;
References
Barua, N.
C Tetrahedron: Asymmetry 2006, 17, 3351–3356; (c) Luzzio, F.
Tetrahedron 2001, 57, 915–945; (d) Shibasaki, M.; Yoshikawa, N. Chem. Rev.
2002, 102, 2187–2209.
1. (a) Tanyeli, C.; Akhmedov, I. M.; Isßik, M. Tetrahedron Lett. 2004, 45, 5799–5801;
´
(b) Malkov, A. V.; Pernezza, D.; Bell, M.; Bella, M.; Massa, A.; Teply, F.; Meghani,
13. (a) Flanagan, S. P.; Guiry, P. J. J. Organomet. Chem. 2006, 691, 2125–2154; (b)
Arai, T.; Yokoyama, N.; Yanagisawa, A. Chem. Eur. J. 2008, 14, 2052–2059.
ˇ
´
P.; Kocovsky, P. J. Org. Chem. 2003, 68, 4727–4742; (c) Chen, C.; Tagami, K.;
Kishi, Y. J. Org. Chem. 1995, 60, 5386–5387; (d) Kwong, H.-L.; Wong, W.-L.; Lee,
W.-S.; Cheng, L.-S.; Wong, W.-T. Tetrahedron: Asymmetry 2001, 12, 2683–2694;
(e) Chelucci, G.; Loriga, G.; Murineddu, G.; Pinna, G. A. Synthesis 2003, 73–78;
(f) Kulhánek, J.; Bureš, F.; Ludwig, M. Arkivoc 2010, ii, 315–322.
ˇ
14. Szotkowski, T.; Bureš, F.; Pytela, O.; Kulhánek, J.; Trávnícek, Z. J. Heterocyclic
Chem. 2006, 43, 1583–1589.
15. For recent examples on the nitroaldol reaction see: (a) Evans, D. A.; Seidel, D.;
Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125,
12692–12693; (b) Ma, K.; You, J. Chem. Eur. J. 2007, 13, 1863–1871; (c) Blay, G.;
2. Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129–3170.
3. (a) Sewald, N.; Wendisch, V. Tetrahedron: Asymmetry 1996, 7, 1269–1272; (b)
Watson, A. A.; House, D. A.; Steel, P. J. J. Org. Chem. 1991, 56, 4072–4074; (c)
Obijalska, E.; Mloston´ , G.; Linden, A.; Heimgartner, H. Tetrahedron: Asymmetry
2008, 19, 1676–1683.
Climent, E.; Fernández, I.; Hernández-Olmos, V.; Pedro, J.
Asymmetry 2007, 18, 1603–1612; (d) Panov, I.; Drabina, P.; Padelková, Z.;
Šimu˚ nek, P.; Sedlák, M. J. Org. Chem. 2011, 76, 4787–4793.
R Tetrahedron:
ˇ
ˇ
16. Bureš, F.; Szotkowski, T.; Kulhánek, J.; Pytela, O.; Ludwig, M.; Holcapek, M.
4. (a) Wiley, R. H.; Bennett, L. L. Chem. Rev. 1949, 44, 447–476; (b) Frump, J. A.
Chem. Rev. 1971, 71, 483–505.
Tetrahedron: Asymmetry 2006, 17, 900–907.
17. Marek, A.; Kulhánek, J.; Bureš, F. Synthesis 2009, 325–331.
18. Otwinowski, Z.; Minor, W. Methods in Enzymology 1997, 276, 307–326.
19. Coppens, P. In Crystallographic Computing; Ahmed, F. R., Hall, S. R., Huber, C. P.,
Eds.; Munksgaard: Copenhagen, 1970; pp 255–270.
20. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J. Appl. Crystalogr.
1993, 26, 343–350.
5. Ferm, R. J.; Riebsomer, J. L. Chem. Rev. 1954, 54, 593–613.
6. (a) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561–3651;
(b) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151–4202; (c) Gómez,
M.; Muller, G.; Rocamora, M. Coord. Chem. Rev. 1999, 193–195, 769–835; (d)
Zhou, J.; Tang, Y. Chem. Soc. Rev. 2005, 34, 664–676; (e) Jönsson, C.; Hallman, K.;
Andersson, H.; Stemme, G.; Malkoch, M.; Malmström, E.; Hult, A.; Moberg, C.
Bioorg. Med. Chem. Lett. 2002, 12, 1857–1861; (f) Fraile, J. M.; García, J. I.;
Mayoral, J. A. Coord. Chem. Rev. 2008, 252, 624–646.
21. Sheldrick, G. M. SHELXL-97; University of Göttingen: Göttingen, 1997.