Utilizing terpene derivatives in the synthesis of annulated terpene-imidazoles with application in the nitroaldol reaction

Article abstract of DOI:10.1016/j.tetasy.2008.10.026

Two classes of terpene derivatives (diketones and monoximes) were condensed into annulated terpene-imidazoles using two general methods. Method A, involving the condensation of terpene diketones and aldehydes, gave lower yields than Method B, which employed terpene monoximes and amines. The mechanism of Method B is discussed. Using both methods, overall 11 new imidazole ligands were synthesized and fully characterized. The molecular structures of the side product 16 and intermediate 4b were also characterized by X-ray analysis. Regarding 1a, N-methylation and subsequent ortho-lithiation and quenching with diphenylphosphinechloride were proven. The synthesized ligands were tested in the Henry reaction providing reaction times 24-72 h and enantioselectivities up to 32% especially for the pyridine 2-substituted ligands 1c, 2c, 3b and N,P-ligand 17.

Full text of DOI:10.1016/j.tetasy.2008.10.026

Tetrahedron: Asymmetry 19 (2008) 2462–2469
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Tetrahedron: Asymmetry
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Utilizing terpene derivatives in the synthesis of annulated
terpene-imidazoles with application in the nitroaldol reaction
a
a,
a
b
*
ˇ
Jirí Kulhánek , Filip Bureš , Petr Šimon , W. Bernd Schweizer
a
ˇ
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, nám. Cs. legií 565, Pardubice 532 10, Czech Republic
b Laboratorium für Organische Chemie, ETH Zürich, Honggerberg, HCI 8093, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 September 2008
Accepted 28 October 2008
Two classes of terpene derivatives (diketones and monoximes) were condensed into annulated terpene-
imidazoles using two general methods. Method A, involving the condensation of terpene diketones and
aldehydes, gave lower yields than Method B, which employed terpene monoximes and amines. The
mechanism of Method B is discussed. Using both methods, overall 11 new imidazole ligands were syn-
thesized and fully characterized. The molecular structures of the side product 16 and intermediate 4b
were also characterized by X-ray analysis. Regarding 1a, N-methylation and subsequent ortho-lithiation
and quenching with diphenylphosphinechloride were proven. The synthesized ligands were tested in the
Henry reaction providing reaction times 24–72 h and enantioselectivities up to 32% especially for the pyr-
idine 2-substituted ligands 1c, 2c, 3b and N,P-ligand 17.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives bearing a terpene unit fused directly with an imidazole
ring (Fig. 1). Terpenes such as (1R)-(+)-camphor, (1S)-(ꢀ)-b-pinene
Naturally occurring monoterpenes and their incorporation into
more complex heterocyclic molecules such as pyridines, bipyri-
dines, terpyridines, phenanthrolines or imines have attracted the
efforts of organic chemists over the past two decades.1–7 Annula-
tion of the monoterpene moiety renders a unique class of chiral
N,N-coordinating ligands that are, upon complexation of a suitable
transition metal, widely applied as catalysts in various asymmetric
reactions (e.g. cyclopropanation, allylic substitution/oxidation,
hydrosilylation or Henry reaction).1–4,7 The most common terpene
motives come from monocyclic menthane or bicyclic terpenes such
as carane, pinane or bornane as well as from their derivatives.
Whereas the synthesis of six-membered heterocycles annulated
with terpene moieties seems to have been proven, five-membered
analogues remain a challenge. Very few examples of terpene-annu-
lated five-membered (di)azoles are currently reported in the liter-
ature. A multistep reaction of glyoxalmonohydrazone and camphor
enolate affords camphor-annulated pyrrole derivatives.8 Camphor-
pyrazole derivatives were synthesized by the reaction of 3-
hydroxymethyl or 3-formylcamphor with semicarbazides or
hydrazines.9,10 Camphor-annulated pyrazoles were also applied
in the synthesis of chiral 2,6-di-N-pyrazolylpyridines.11 However,
no attempts to prepare terpene-imidazoles have so far been re-
ported in the literature and, therefore, we focused, herein, on the
and (1S,2S,3S,5R)-(+)-isopinocampheol were used as readily avail-
able and inexpensive starting materials. Hydroxyketones,12–14 bro-
moketones,15,16 diketones17–19 or -nitrosoketones (monoximes)20
a
as suitable 1,2-bifunctional electrophiles (in our case generated
from terpenes) and aldehydes or amines as counterparts are the
most often employed starting compounds in such condensations
leading to an imidazole ring. To the best of our knowledge, no
attention has been paid to the compounds proposed in Figure 1
and, therefore, we herein report the synthesis, properties and full
spectroscopic characterization of imidazoles 1–3 featuring three
different annulated terpene moieties and five (hetero)aromatic
substituents at the 2-position as well as their preliminary applica-
tion as optically active N-ligands in the Henry reaction.
N
N
R1
N
N
R1
N
N
R1
R2
R2
R2
1
2
3
R
1 = H, CH3
R2 = Ph, 2-(PPh2)Ph, 1-naphthalene, 2-pyridine, 2-furane, 2-thiophene
* Corresponding author. Tel.: +420 4660 37099; fax: +420 4660 37068.
E-mail address: filip.bures@upce.cz (F. Bureš).
Figure 1. Annulated terpene-imidazoles.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.026

J. Kulhánek et al. / Tetrahedron: Asymmetry 19 (2008) 2462–2469
2463
a-Nitrosoketones or
a-hydroxyiminoketones may also be
2. Result and discussion
applied in the synthesis of imidazoles and, therefore, our further
efforts were focused on the nitrosation/oximation of camphor,
nopinone or isopinocampheone. The camphorquinone monoxime
13 could be selectively generated from the camphorquinone 6 by
simple treatment with hydroxylamine in ethanol.27 Conversely,
the reaction of the camphor or nopinone with iso-amylnitrite28
afforded the desired monooximes 13 and 14 in a more straightfor-
ward manner (Scheme 2). Unfortunately, a similar transformation
on isopinocampheone 11 furnished an inseparable mixture of
products, where the desired monoxime was not found.
In order to prepare precursors suited for condensation into an
imidazole, the appropriate terpene diketones were synthesized.
The (1R)-(+)-camphor was directly oxidized by SeO2 to furnish
camphorquinone 6 in a nearly quantitative yield.21 Starting from
the available (1S)-(ꢀ)-b-pinene involving ozonolysis followed by
reduction with dimethylsulfide, (+)-nopinone 7 could be isolated
in 80% yield.22 A subsequent formylation using ethylformate23
and treatment with formaldehyde24 afforded
a,b-unsaturated
ketone 9 in 62% overall yield. The repeated ozonolysis and dimethyl-
sulfide reduction of 9 afforded the desired PinDione25 10 in 70%
yield. A similar three-step reaction sequence applied to (+)-isopi-
nocampheon 11, prepared by the oxidation26 of the commercially
available (1S,2S,3S,5R)-(+)-isopinocampheol, gave the third desired
diketone 12 (Scheme 1) in 61% overall yield with a reversed abso-
lute configuration of the methyl group at C-4.4
O
NH2OH/EtOH
6
N
OH
13
O
N
iAmONO/tBuOK
5 or 7
13 or
O
O
O
SeO2/Ac2O
OH
14
6
7
5
Scheme 2. Camphorquinone and PinDione monoximes.
O
O
MeONa/HCOOEt
toluene
1. O3/CH2Cl2
2. Me2S
The initial condensation reaction into an imidazole, using a con-
venient set of conditions (Method A: benzaldehyde or pyridine-2-
carbaldehyde and ammonium acetate in propane-2-ol or
DMSO),17,18 was verified on terpene diketones 6, 10 and 12. The de-
sired imidazoles 1a, 1c, 2a, 2c and 3a–b bearing phenyl or pyridyl
substituents at the 2-position were isolated in moderate yields
(Scheme 3, Table 1). The yields attained (7–38%) are substantially
lower due to the undesirable formation of bis(terpene)-annulated
pyrazine derivatives (e.g., the camphor representative 15). In the
case of pyridine-2-carbaldehyde as the starting aldehyde, another
side product was isolated. Its structure was assigned to the substi-
tuted imidazo[1,5-a]pyridine 16 formed from three molecules of
pyridine-2-carbaldehyde. The facile formation of such a product
was confirmed by independent treatment of the pyridine-2-carbal-
dehyde with ammonium acetate. Its formation could be slightly
OH
8
O
O
O
CH2O/K2CO3/Δ
1. O3/CH2Cl2
2. Me2S
8
9
10
O
similar to 7
PDC/CH2Cl2
OH
O
O
11
12
Scheme 1. Synthesis of terpene-derived diketones.
R
N
N
N
O
R
6, 10 or 12
R
R
Method A
N
H
N
H
N
H
3a
1a R = phenyl
1c R = pyridin-2-yl
2a R = phenyl
2c R = pyridin-2-yl
R = phenyl
3b R = pyridin-2-yl
Side products:
N
N
N
N
N
N
15
16
N
R
N
N
R
N
R
N
R
NH2
13 or 14
Method B
N
N
H
H
OH
2a R = phenyl
1a R = phenyl
4a R = n-C9H19
4b R = cyclohexyl
4c R = furan-2-yl
1b
2b R = naphthalen-1-yl
2c R = pyridin-2-yl
2d R = thiophen-2-yl
R = naphthalen-1-yl
1c R = pyridin-2-yl
1d
R = thiophen-2-yl
2e
R = furan-2-yl
Scheme 3. Synthesis of the annulated-terepene imidazoles 1–3.

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J. Kulhánek et al. / Tetrahedron: Asymmetry 19 (2008) 2462–2469
Table 1
Condensations—methods A/B
derivatives 4 in the first step were confirmed by X-ray analysis
(see below) as well as by the recent report by Pedro et al.7 The
amine used in excess in the cyclization reaction may have served
as a base, deprotonating either the hydroxy or –CH2– group. The
deprotonation of the hydroxy group (path A) seemed to be more
probable than path B. However, as the acidity of the –CH2– group
increases or as the respective C-anion is more stabilized by reso-
nance to the attached R-substituent (R = (hetero)aromate), such
deprotonation may take place and path B becomes more feasible.
As the amines with aliphatic residues (R = n-nonyl and cyclohexyl)
or the aromatic furfurylamine do not greatly stabilize such anions
(aliphatic ones even destabilize the C-anion by a positive inductive
effect), the reaction will terminate at ‘imino-oximes’ 4 or will not
take place at all. This supposition also confirms all other attempted
experiments on PinDione monoxime 14, where we were able to
synthesize only furane-2-yl derivative 2e from the above-men-
tioned amines. An intramolecular attack of the generated N-anion
to the C@N double bond, subsequent elimination of water and a fi-
nal 2H- to 1H-imidazole tautomerism most likely lead to the target
imidazoles 1a–d.
Compd
R
Yield (%) (Method)
½
a 2D0
ꢁ
(CH3OH)
A: 38
B: 55
B: 52
A: 10
B: 33
B: 41
A: 32
B: 51
B: 50
A: 8
B: 39
B: 42
B: 41
A: 28
A: 7
1a
1b
1c
1d
2a
2b
2c
Phenyl
+46.3a
Naphthalen-1-yl
Pyridin-2-yl
Thiophen-2-yl
Phenyl
+41.4b
+56.0a
+53.0b
ꢀ26.2a
Naphthalen-1-yl
Pyridin-2-yl
ꢀ21.1b
ꢀ17.0a
2d
2e
3a
3b
4a
4b
4c
Thiophen-2-yl
Furan-2-yl
Phenyl
Pyridin-2-yl
n-Decyl
ꢀ20.5b
+33.0b
+55.0a
+8.0a
B: 40
B: 52
B: 66
+59.9b
+72.4b
+87.8b
Cyclohexyl
Furan-2-yl
a
Concentration c is 1.0 g/100 mL.
Concentration c is 0.5 g/100 mL.
b
In order to further enhance the complexation ability and
explore possible functionalization of the prepared phenyl ligands
(series a), we attempted to introduce a phosphine chelating func-
tionality at the 2-position. N-Methylation of 1a using the nBuLi/
MeI system afforded exclusively only one isomer in 95% yield
(anti-arrangement of methyl groups). Its direct ortho-lithiation
and quenching with diphenylphosphinechloride provided the
functionalized imidazole 17 in 61% yield (Scheme 5).
suppressed by a slow addition of pyridine-2-carbaldehyde into the
reaction mixture, using DMSO as a solvent.
Due to the difficulties with the condensation of terpene dike-
tones, we turned our attention to the monoximes 13 and 14. It is
well known that treatment of an
a-monoxime with aliphatic
amines furnishes 2-substituted imidazoles.20,29,30 Starting from
benzylamine, 1-naphthalenemethylamine, 2-picolylamine, 2-thi-
ophenemethylamine and furfurylamine, we were able to condense
monoximes 13 and 14 into imidazoles 1a–d and 2a–e (Scheme 3,
Table 1). Upon optimization of the reaction conditions, we
achieved the best yields conducting the reaction without solvent
(neat) under a slight excess of amine (1.5 equiv) at 150 °C (Method
B). The yields attained (33–55%) were considerably higher than
those for the condensation of diketones 6, 10 or 12. Whereas the
formation of the side product similar to 16 was suppressed, the
pyrazine derivatives remained as side products. A full account on
the terpene-pyrazine derivatives formation will be given else-
where. In the case of n-decylamine, cyclohexanemethylamine
and furfurylamine as the starting amines and camphor-monoxime
13 as an electrophile, we did not observe the formation of the de-
sired imidazole derivatives at all; ‘imino-oximes’ 4a–c were iso-
lated instead. Isolation of such intermediates and the fact that no
hints on the mechanism of such a condensation have been given
in the literature so far prompted us to investigate the reaction
mechanism in more detail. Scheme 4 illustrates our proposed reac-
tion path. The facile formation and structure of ‘imino-oxime’
Ph2P
N
1. nBuLi/THF/MeI, 95%
1a
N
2. nBuLi/THF/Ph2PCl, 61%
17
Scheme 5. The functionalization of 2-phenylcamphorimidazole 1a.
Whereas we were unable to grow a suitable crystal for the X-ray
analysis of target ligands 1–3 (all attempted crystals for 1a and 1d
showed heavy disorders), the molecular structures of side products
15 and 16 and intermediate 4b were also confirmed by crystallo-
graphy. The structure of 15 has been previously reported.31,32
Figure 2 shows ORTEP plots of 16 and 4b. The almost planar
molecule 16 packed with parallel layers of molecules separated
by 3.5 Å shifted by 1.3 Å along C10–C1 shows typical p–p stacking.
The enantioselectivities of the synthesized ligands were exam-
ined in the nitroaldol reaction (Henry reaction33,34). Its asymmetric
excess of
R
R
H2N
N
R
O
N
H2N
N
N
R
N
N
R
N
N
R
path B
N
OH
13
OH
OH
4
OH
OH
-H2O
excess of
path A
N
R
2H - to 1H-imidazole
H2N
tautomerism
N
N
R
R
R
N
H
N
N
O
1a-d
Scheme 4. Proposed mechanism of the condensation between monoximes and amines (Method B).

J. Kulhánek et al. / Tetrahedron: Asymmetry 19 (2008) 2462–2469
2465
Table 2
Asymmetric Henry reaction
NO2
O
CH3NO2/ligand/Cu(OAc)2
CH3CH2OH
O2N
O2N
OH
Ligand
Yield (%)a
Reaction timeb (h)
ee/configurationc
1a
1b
1c
1d
2a
2b
2c
2d
2e
3a
3b
17
4a
4b
4c
76
62
98
86
89
73
96
81
61
72
85
89
76
65
68
48
72
24
36
48
72
24
36
48
48
24
48
48
48
48
9/(S)
7/(S)
29/(S)
11/(S)
11/(R)
12/(R)
32/(R)
8/(R)
6/(R)
13/(S)
27/(S)
29/(S)
21/(S)
16/(S)
18/(S)
a
Isolated yields.
b
c
Monitored by TLC (SiO2; hexane/EtOAc 2:1).
Determined by chiral HPLC analysis on
] values.35
a
Daicel Chiracel OB column and
simultaneously deduced from [
a
in the Henry reaction. The attained yields and ees were even higher
than those for target ligands a, b, d and e, which were most likely
caused by their higher coordination ability given by the presence of
imino as well as oxime functionalities.
3. Conclusion
Figure 2. Crystal structures of the side product 16 (a) and ‘imino-oxime’ 4b (b)
obtained at 173 and 293 K, respectively. Vibrational ellipsoids of the ORTEP plot are
shown at the 50% probability level.
In this work, we have shown the first synthesis of annulated ter-
pene-imidazole derivatives. Starting with terpene diketones and
employing two aldehydes, we synthesized six new derivatives in
moderate yields. On the other hand, Method B starting with ter-
pene monoximes and amines afforded nine terpene-imidazole
derivatives (1a–d and 2a–e) and three ‘imino-oximes’ 4a–c in a
more straightforward manner and with higher yields. The pro-
posed mechanism of the monoxime and amine condensation—
Method B, involves the formation of an ‘imino-oxime’ 4, its C-
deprotonation, intramolecular attack of the N-nucleophile to the
C@N double bond, subsequent elimination of water and finally a
2H- to 1H-imidazole tautomerism. The electronic effects and the
nature of R-substituents strongly affect the entire reaction course.
Both methods also furnished terpene-pyrazine derivatives, and in
the case of the pyridine-2-carbaldehyde, we observed formation
of the side product 16. The molecular structure of the side products
16 and 4b has also been confirmed by X-ray analysis. Imidazole 1a
bearing a phenyl ring at the 2-position is capable of N-methylation
and ortho-lithiation furnishing, after quench with (Ph)2PCl, N,P-
chelating ligand 17. The enantioselective screening of these ligands
in the Henry reaction revealed that an N@C–C@N binding pocket
similar to that in bipy ligands is crucial. Whereas for the pyridine
ligands 1c, 2c and 3b, quick reaction times and enantioselectivities
of up to 32% were achieved, the other ligands, except for 17,
showed longer reaction times and lower ees. However, the attained
version involves a reaction between an aldehyde and a nitroalkane
catalyzed by chiral ligands chelating mainly copper (II),35,7 zinc36
or rare earth metal salts.37 This reaction serves as a basic screening
of the enantioselectivity, giving a first insight into the catalytic
behaviour of the studied ligands. The reactions were carried out
at 0.5 M scale with excess of nitromethane (10 equiv) under the
conditions given in Ref. 38. The attained yields and enantiomeric
excesses (ee’s) for ligands 1–3, 17 as well as for ‘imino-oximes’ 4
are summarized in Table 2. All the optically active compounds pre-
pared were able to catalyze the Henry reaction as bases, affording
the desired nitroaldol in isolated yields of 61–98% and reaction
times of 24–72 h at 25 °C. Whereas the Henry reaction catalyzed
by ligands series 1, 3, 4 and 17 afforded the (S)-2-nitro-1-(4-nitro-
phenyl)ethanol, the reaction with ligand series
2 gave the
(R)-enantiomer. The yields and ees increase within the individual
series 1–3, varying only in the nature of the R-substituent, in a gen-
eral way—naphthalen-2-yl (b), phenyl (a), thiophen-2-yl (d) and
pyridin-2-yl (c/3b). The bulkier and uncoordinating substituents
such as naphthyl or phenyl most probably prevented access of
the copper(II) ion towards the imidazole nitrogens and, as
expected, the attained yields and ees were low. On the other hand,
from the data in Table 2, it can be clearly seen that the best chem-
ical yields (up to 98%), quick reaction times (24 h) and ees (up to
32%) were achieved by applying the ligands bearing a pyridin-2-
yl substituent 1c, 2c and 3b, respectively. These three ligands most
probably bind the copper(II) ion by means of the N@C–C@N coor-
dination pocket similar to that known from the 2,20-bipyridine
(bipy)39 and its related ligands. Hence, the chemical yields and also
enantiomeric excesses are higher. N,P-Chelating ligand 17 showed
a similar enantioselectivity (29% ee) as that observed for the pyri-
dine derivatives. In addition, ‘imino-oximes’ 4 were also examined
ees resemble those we observed for the similar
a-amino acid-de-
rived imidazole ligands.38
4. Experimental
4.1. General
Reagents and solvents (reagent grade) were purchased from
Aldrich and used as received. THF was freshly distilled from

2466
J. Kulhánek et al. / Tetrahedron: Asymmetry 19 (2008) 2462–2469
Na/benzophenone under N2. The starting diketones 6, 10 and 12 or
monoximes 13 and 14 were synthesized according to the literature
procedures (see above). Evaporation and concentration in vacuo
were performed at water aspirator pressure. The condensation
reactions (method B) were carried out in a glass pressure tube (Al-
drich). Column chromatography (CC) was carried out with SiO2 60
(particle size 0.040–0.063 mm, 230–400 mesh; Merck) and com-
mercially available solvents. Thin-layer chromatography (TLC)
was conducted on aluminium sheets coated with SiO2 60 F254 ob-
tained from Merck, with visualization by UV lamp (254 or
360 nm). Melting points (mp) were measured on a Büchi B-540
melting-point apparatus in open capillaries and are uncorrected.
1H and 13C NMR spectra were recorded in CDCl3 at 360/500 MHz
or 90/125 MHz, respectively, with Bruker AMX 360 or Bruker
AVANCE 500 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 an internal reference
(CDCl3—7.25 and 77.23, DMSO-d6—2.55 and 39.51 and CD3OD—
3.31 and 49.15 ppm for 1H and 13C NMR, respectively). Coupling
constants (J) are given in Hertz. The apparent resonance multiplic-
ity is described as s (singlet), br s (broad singlet), d (doublet), dd
(doublet of doublet), t (triplet), q (quartet) and m (multiplet). Pro-
tons of the substituents at the 2-position are marked as follows: Ph
(Phenyl), Np (naphthalen-1-yl), Py (pyridine-2-yl), Th (thiophen-2-
yl), Fur (furan-2-yl), Dec (n-decyl) and Chex (cyclohexyl). Addi-
tional NMR techniques such as 1H–1H COSY, HMBC and HMQC
were used for regular signal assignment. Some target imidazoles
showed two sets of signals or broad signals in 1H and 13C NMR
spectra as a result of hindered imidazole tautomerism or possible
association (may be partially suppressed by adding a drop of
TFA).38 Optical rotation values were measured on a Perkin Elmer
341 instrument, concentration c is given in g/100 mL CH3OH. The
mass spectra were measured on GC/MS configuration comprising
Agilent Technologies—6890N gas chromatograph (HP-5MS col-
27.06, 34.07, 49.67, 52.35, 59.93, 124.56, 127.65, 128.3, 128.69,
130.45, 145.82 (1C missing). EI-MS (70 eV) m/z (rel. int.): 252
(M+, 29), 237 (100), 223 (17), 209 (98), 195 (18), 104 (23), 77
+
(17). HR-FT-MALDI-MS (3-HPA): m/z calcd for [C17H21N2
]
253.1699; found 253.1693 [MH+]. Elemental Anal. Calcd for
C17H20N2 (252.35): C, 80.91; H, 7.99; N, 11.10. Found: C, 80.88;
H, 7.89; N, 11.01.
4.2.2. (1R,8R)-9,9-Dimethyl-4-phenyl-3,5-diazatricyclo-
[6.1.1.02.6]deca-2(6),3-diene 2a
The title compound was synthesized from diketone 10 (2.74 g,
18 mmol). Yield 1.37 g (32%), mp 227–228 °C, ½a D20
¼ ꢀ26:2 (c
ꢁ
1.0, CH3OH). 1H NMR (360 MHz, CDCl3, 25 °C): d = 0.70 (s, 3H,
CH3), 1.40 (s, 3H, CH3), 1.48 (d, 1H, J = 9.0 Hz, CH2), 2.32–2.36 (m,
1H, CH), 2.70–2.81 (m, 3H, CH + CH2), 2.87 (dd, 1H, J = 15.9 Hz,
J = 3.3 Hz, CH), 7.26 (t, 1H, J = 6.6 Hz, Ph), 7.37 (t, 2H, J = 7.2 Hz,
Ph), 7.79 (d, 2H, J = 7.2 Hz, Ph). 13C NMR (90 MHz, CDCl3, 25 °C):
d = 21.21, 26.46, 26.69, 33.82, 40.81, 41.62, 42.52, 124.26, 127.63,
128.74, 130.33, 131.16, 142.86 (1C missing). EI-MS (70 eV) m/z
(rel. int.): 238 (M+, 74), 223 (100), 209 (29), 195 (64), 183 (17),
170 (35), 104 (41), 77 (19). HR-FT-MALDI-MS (3-HPA): m/z calcd
for [C16H19N2+] 239.1543; found 239.1547 [MH+]. Elemental Anal.
Calcd for C16H18N2 (238.33): C, 80.63; H, 7.61; N, 11.75. Found:
C, 80.70; H, 7.65; N, 11.74.
4.2.3. (1S,7R,8S)-7,9,9-Trimethyl-4-phenyl-3,5- diazotricyclo-
[6.1.1.02.6]deca-2(6),3-diene 3a
The title compound was synthesized from diketone 12 (3.00 g,
18 mmol). Yield 1.27 g (28%), mp 127–130 °C, ½a D20
¼ þ55:0 (c
ꢁ
1.0, CH3OH). 1H NMR (360 MHz, CDCl3, 25 °C): d = 0.66 + 0.78 (s,
3H, CH3), 1.19 + 1.28 (d, 3H, J = 7.2 Hz, CH3), 1.36 + 1.37 (s, 3H,
CH3), 1.47 (d, 1H, J = 8.7 Hz, CH2), 1.99–2.10 + 2.14–2.19 (m, 1H,
CH), 2.51–2.55 + 2.68–2.78 (m, 2H, CH2 + CH), 2.92–2.97 + 3.11–
3.19 (m, 1H, CH), 7.20 (t, 1H, J = 7.2 Hz, Ph), 7.28 (t, 2H, J = 6.9 Hz,
Ph), 7.85 (d, 2H, J = 6.9 Hz, Ph). 13C NMR (90 MHz, CDCl3, 25 °C):
d = 17.31, 17.66, 20.80, 23.68, 26.65, 27.35, 30.37, 31.06, 35.27,
36.03, 41.21, 41.47, 42.76, 44.47, 48.57, 49.06, 124.48, 127.28,
128.61, 130.76, 131.78, 143.12 (2C missing). EI-MS (70 eV) m/z
(rel. int.): 252 (M+, 67), 237 (100), 223 (19), 209 (76), 195 (34),
184 (36), 104 (33), 77 (24). HR-FT-MALDI-MS (3-HPA): m/z calcd
for [C17H21N2+] 253.1699; found 253.1695 [MH+]. Elemental Anal.
Calcd for C17H20N2 (252.35): C, 80.91; H, 7.99; N, 11.10. Found:
C, 80.85; H, 7.96; N, 11.04.
umn, length 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). High
resolution FT-MALDI spectra were measured with an IonSpec Ulti-
ma Fourier transform (FT) instrument with [(2E)-3-(4-tert-butyl-
phenyl)-2-methylprop-2-eneylidene]malononitrile (DCTB) or 3-
hydroxypicolinic acid (3-HPA) as a matrix. The most important sig-
nals are reported in m/z units with M as the molecular ion. Com-
pounds 4a–c fragment so easily that the ions corresponding to
the neutral loss of water are the base peaks in EI and FT-MALDI
(DCTB) mass spectra ([MꢀH2O]+ and [MHꢀH2O]+). Elemental anal-
yses were performed on EA 1108 Fisons instrument.
4.3. Method A (in DMSO)
4.2. Method A (in iPrOH)
Pyridine-2-carbaldehyde (7 mL, 65 mmol) was added dropwise
to a mixture of diketone 6, 10 or 12 (18 mmol) and ammonium
acetate (23 g, 0.3 mol) in dry DMSO (150 mL) under N2 at 100 °C.
The reaction mixture was stirred for 4 h at 100 °C and poured into
cold aq ammonia (300 mL). The product was extracted with CH2Cl2
(300 mL), washed successively with water (3 ꢂ 200 mL), the organ-
ic layer dried over Na2SO4) and the solvent evaporated. The crude
product was purified by CC(SiO2; EtOAc–hexane 1:1) and repeat-
edly by CC (SiO2; CHCl3–CH3OH 100:1).
Freshly distilled benzaldehyde (9 mL, 80 mmol) was added to a
mixture of diketone 6, 10 or 12 (18 mmol) and ammonium acetate
(15 g, 0.19 mol) in propan-2-ol (300 mL). The reaction mixture was
refluxed for 48 h, after which the solvent was removed in vacuo,
the residue taken up in CH2Cl2 (200 mL), and washed successively
with satd NaHCO3 (aq 100 mL) and brine (100 mL). The organic
layer was dried, the solvent evaporated and the crude product
purified by CC (SiO2; EtOAc/hexane 1:1).
4.3.1. (1R,7S)-1,10,10-Trimethyl-4-pyridin-2-yl-3,5-diazat-
ricyclo[5.2.1.02.6]deca-2(6),3-diene 1c
4.2.1. (1R,7S)-1,10,10-Trimethyl-4-phenyl-3,5-diazatricyclo-
[5.2.1.02.6]deca-2(6),3-diene 1a
The title compound was synthesized from diketone 6 (3.0 g,
The title compound was synthesized from diketone 6 (3.0 g,
18 mmol). Yield 0.46 g (10%), mp 199–200 °C, ½a D20
¼ þ56:0 (c
ꢁ
18 mmol). Yield 1.73 g (38%), mp 278–280 °C, ½a D20
ꢁ
¼ þ46:3 (c
1.0, CH3OH). 1H NMR (500 MHz, CDCl3, 25 °C): d = 0.88 (s, 3H,
CH3), 0.92 (s, 3H, CH3), 0.96–1.12 (m, 2H, CH2), 1.20 + 1.37 (br s,
3H, CH3), 1.73–1.78 (m, 1H, CH2), 2.00–2.03 (m, 1H, CH2), 2.88
(br s, 1H, CH), 7.11 (t, 1H, J = 6.0 Hz, Py), 7.67–7.69 (m, 1H, Py),
8.04–8.07 (m, 1H, Py), 8.42 (d, 1H, J = 5.0 Hz), 10.62 (br s, 1H,
NH). 13C NMR (125 MHz, CDCl3, 25 °C): d = 11.32, 19.17, 20.15,
1.0, CH3OH). 1H NMR (360 MHz, CDCl3, 25 °C): d = 0.89 (s, 6H,
2 ꢂ CH3), 0.93–1.06 (m, 2H, CH2), 1.26 (s, 3H, CH3), 1.68–1.76 (m,
1H, CH2), 1.92–1.99 (m, 1H, CH2), 2.87 (d, 1H, J = 3.6 Hz, CH), 5.42
(br s, 1H, NH), 7.22–7.35 (m, 3H, Ph), 7.85 (d, 2H, J = 6.9 Hz,
Ph). 13C NMR (90 MHz, CDCl3, 25 °C): d = 11.43, 19.37, 20.27,

J. Kulhánek et al. / Tetrahedron: Asymmetry 19 (2008) 2462–2469
2467
26.83, 33.92, 49.09, 49.76, 60.25, 117.72, 121.77, 136.70, 136.85,
4.4.1. (1R,7S)-1,10,10-Trimethyl-4-phenyl-3,5-diazatricyclo-
148.45, 149.12 (2C missing). EI-MS (70 eV) m/z (rel. int.): 253
(M+, 30), 238 (100), 210 (84), 196 (12), 105 (11), 77 (10). HR-FT-
MALDI-MS (3-HPA): m/z calcd for [C16H20N3+] 254.1652; found
254.1647 [MH+]. Elemental Anal. Calcd for C16H19N3 (253.34): C,
75.85; H, 7.56; N, 16.59. Found: C, 75.78; H, 7.51; N, 16.61.
[5.2.1.02.6]deca-2(6),3-diene 1a
The title compound was synthesized from monoxime 13
(3.26 g, 18 mmol) and benzylamine (2.89 g, 27 mmol). Yield
2.50 g (55%). Experimental data are consistent with the derivative
1a obtained by method A.
4.3.2. (1R,8R)-9,9-Dimethyl-4-pyridin-2-yl-3,5-diazatricyclo-
[6.1.1.02.6]deca-2(6),3-diene 2c
4.4.2. (1R,7S)-1,10,10-Trimethyl-4-naphthalen-2-yl-3,5-
diazatricyclo[5.2.1.02.6]deca-2(6),3-diene 1b
The title compound was synthesized from diketone 10 (2.74 g,
The title compound was synthesized from monoxime 13
(3.26 g, 18 mmol) and 1-naphthalenemethylamine (4.24 g,
18 mmol). Yield 0.35 g (8%), mp 156–158 °C, ½a D20
¼ ꢀ17:0 (c 1.0,
ꢁ
CH3OH). 1H NMR (500 MHz, DMSO-d6, 25 °C): d = 0.59 + 0.61 (s,
3H, CH3), 1.31–1.34 (m, 1H, CH2), 1.38 (s, 3H, CH3), 2.28–2.30
(m, 1H, CH), 2.66–2.83 (m, 4H, CH + CH2), 7.22 (m, 1H, Py), 7.78
(m, 1H, Py), 7.90 (m, 1H, Py), 8.50 (m, 1H, Py), 12.49 (br s, 1H,
NH). 13C NMR (125 MHz, CDCl3, 25 °C): d = 21.42, 25.83, 26.77,
28.32, 33.75, 39.85, 41.53, 117.73, 121.83, 136.92, 137.66,
148.57, 149.64 (2C missing). EI-MS (70 eV) m/z (rel. int.): 239
27 mmol). Yield 2.83 g (52%), mp 204–207 °C, ½a D20
¼ þ41:4 (c
ꢁ
0.5, CH3OH). 1H NMR (500 MHz, CDCl3, 25 °C): d = 0.91 (s, 6H,
CH3), 0.92–0.96 (m, 1H, CH2), 0.99–1.05 (m, 1H, CH2), 1.30 (s, 3H,
CH3), 1.70–1.73 (m, 1H, CH2), 1.94–1.97 (m, 1H, CH2), 2.86 (d,
1H, J = 4.0 Hz, CH), 7.35 (t, 1H, J = 7.8 Hz, Np), 7.43–7.46 (m, 2H,
Np), 7.54 (d, 1H, J = 7.2 Hz, Np), 7.75 (d, 1H, J = 8.2 Hz, Np), 7.80–
7.83 (m, 1H, Np), 8.65–8.68 (m, 1H, Np). 13C NMR (125 MHz, CDCl3,
25 °C): d = 11.60, 19.57, 20.45, 27.24, 34.26, 50.03, 52.45, 59.97,
125.21, 126.16, 126.42, 126.46, 126.84, 128.39, 128.68, 129.18,
131.15, 134.18, 145.74 (2C missing). EI-MS (70 eV) m/z (rel. int.):
302 (M+, 43), 287 (95), 273 (15), 259 (100), 245 (10), 154 (10),
127 (11), 106 (12). HR-FT-MALDI-MS (DCTB): m/z calcd for
[C21H23N2+] 303.1856; found 303.1857 [MH+]. Elemental Anal.
Calcd for C21H22N2 (302.41): C, 83.40; H, 7.33; N, 9.26. Found: C,
83.34; H, 7.32; N, 9.28.
(M+, 51), 224 (100), 210 (41), 196 (62), 171 (18), 105 (25), 78
+
(22). HR-FT-MALDI-MS (3-HPA): m/z calcd for [C15H18N3
]
240.1495; found 240.1500 [MH+]. Elemental Anal. Calcd for
C15H17N3 (239.32): C, 75.28; H, 7.16; N, 17.56. Found: C, 75.27;
H, 7.16; N, 17.57.
4.3.3. (1S,7R,8S)-7,9,9-Trimethyl-4-pyridin-2-yl-3,5-diazatri-
cyclo[6.1.1.02.6]deca-2(6),3-diene 3b
The title compound was synthesized from diketone 12 (3.00 g,
18 mmol). Yield 0.32 g (7%), mp 100–101 °C, ½a D20
ꢁ
¼ þ8:0 (c 1.0,
4.4.3. (1R,7S)-1,10,10-Trimethyl-4-pyridin-2-yl-3,5-
diazatricyclo[5.2.1.02.6]deca-2(6),3-diene 1c
The title compound was synthesized from monoxime 13
(3.26 g, 18 mmol) and 2-picolylamine (2.92 g, 27 mmol). Yield
1.50 g (33%). Experimental data are consistent with the derivative
1c obtained by method A.
CH3OH). 1H NMR (500 MHz, DMSO-d6, 25 °C): d = 0.60 + 0.68 (s,
3H, CH3), 1.28 + 1.38 (d, 3H, J = 7.0 Hz, CH3), 1.42 + 1.44 (s, 3H,
CH3), 1.43–1.49 (m, 1H, CH2), 2.10–2.12 + 2.25–2.27 (m, 1H, CH),
2.67–2.97 (m, 2H, CH + CH2), 3.05–3.09 + 3.26–3.28 (m, 1H, CH),
7.20–7.23 (m, 1H, Py), 7.76–7.78 (m, 1H, Py), 7.90–7.92 (m, 1H,
Py), 8.50–8.52 (m, 1H, Py). 13C NMR (125 MHz, DMSO-d6, 25 °C):
d = 16.24, 16.64, 20.70, 23.45, 26.00, 26.56, 29.51, 30.11, 31.76,
35.09, 35.08, 41.98, 42.32, 44.21, 47.35, 47.76, 120.85, 124.71,
130.98, 138.54, 139.23, 143.00, 148.72 (1C missing). EI-MS
(70 eV) m/z (rel. int.): 253 (M+, 44), 238 (100), 224 (19), 210 (83),
196 (25), 185 (33), 105 (25), 78 (19). HR-FT-MALDI-MS (DCTB):
m/z calcd for [C16H20N3+] 254.1652; found 254.1652 [MH+]. Ele-
mental Anal. Calcd for C16H19N3 (253.34): C, 75.85; H, 7.56; N,
16.59. Found: C, 75.79; H, 7.51; N, 16.60.
4.4.4. (1R,7S)-1,10,10-Trimethyl-4-thiophen-2-yl-3,5-
diazatricyclo[5.2.1.02.6]deca-2(6),3-diene 1d
The title compound was synthesized from monoxime 13
(3.26 g, 18 mmol) and 2-thiophenemethylamine (3.06 g, 27 mmol).
Yield 1.91 g (41%), mp 286–289 °C, ½a D20
ꢁ
¼ þ53:0 (c 0.5, CH3OH). 1H
NMR (360 MHz, CD3OD, 25 °C): d = 0.93 (s, 3H, CH3), 0.95 (s, 3H,
CH3), 0.95–1.02 (m, 2H, CH2), 1.77–1.83 (m, 1H, CH2), 2.00–2.04
(m, 1H, CH2), 2.84 (d, 1H, J = 3.6 Hz, CH), 7.04 (t, 1H, J = 5.1 Hz,
Th), 7.31 (d, 1H, J = 5.1 Hz, Th), 7.35 (d, 1H, J = 3.6 Hz, Th). 13C
NMR (90 MHz, CD3OD, 25 °C): d = 11.65, 19.77, 20.70, 28.08,
35.26, 51.09, 53.51, 60.86, 124.04, 125.71, 128.69, 135.81, 143.32
(2C missing). EI-MS (70 eV) m/z (rel. int.): 258 (M+, 42), 243 (95),
229 (20), 215 (100), 201 (21), 121 (18), 106 (19), 91 (10), 77
(12). HR-FT-MALDI-MS (DCTB): m/z calcd for [C15H19N2S+]
259.1263; found 259.1260 [MH+]. Elemental Anal. Calcd for
C15H18N2S (258.38): C, 69.73; H, 7.02; N, 10.84; S, 12.41. Found:
C, 69.76; H, 7.05; N, 10.86; S, 12.36.
4.3.4. 3-Pyridin-2-yl-N-[(1E)-pyridin-2-ylmethylidene]-
imidazo[1,5-a]pyridin-1-amine 16
The pure title compound was prepared by a 4 h stirring of pyr-
idine-2-carbaldehyde (7 mL, 65 mmol) with ammonium acetate
(23 g, 0.3 mol) in DMSO (150 mL) at 100 °C. Yield 4.2 g (65%), mp
184–186 °C. 1H NMR (500 MHz, CDCl3, 25 °C): d = 6.75 (t, 1H,
J = 9.0 Hz), 7.02 (t, 1H, J = 9.0 Hz), 7.22–7.25 (m, 1H), 7.30–7.34
(m, 1H), 7.80–7.86 (m, 2H), 8.00 (d, 1H, J = 10 Hz), 8.30 (d, 1H,
J = 8.0 Hz), 8.44 (d, 1H, J = 8.0 Hz), 8.67 (d, 1H, J = 4.5 Hz), 8.75 (d,
1H, J = 4.5 Hz), 9.50 (s, 1H), 9.98 (d, 1H, J = 7.4 Hz). 13C NMR
(125 MHz, CDCl3, 25 °C): d = 114.62, 118.00, 121.79, 121.85,
122.11, 122.44, 124.20, 126.64, 129.30, 133.68, 136.52, 136.77,
138.57, 148.35, 149.97, 151.13, 154.55, 155.89. HR-FT-MALDI-MS
(3-HPA): m/z calcd for [C18H14N5+] 300.1249; found 300.1241
[MH+]. Elemental Anal. Calcd for C18H13N5 (299.33): C, 72.23; H,
4.38; N, 23.40. Found: C, 72.25; H, 4.39; N, 23.42.
4.4.5. (1R,8R)-9,9-Dimethyl-4-phenyl-3,5-diazatricyclo-
[6.1.1.02.6]deca-2(6),3-diene 2a
The title compound was synthesized from monoxime 14
(3.01 g, 18 mmol) and benzylamine (2.89 g, 27 mmol). Yield
2.19 g (51%). Experimental data are consistent with the derivative
2a obtained by method A.
4.4.6. (1R,8R)-9,9-Dimethyl-4-naphthalen-1-yl-3,5-
diazatricyclo[6.1.1.02.6]deca-2(6),3-diene 2b
4.4. Method B
The title compound was synthesized from monoxime 14
(3.01 g, 18 mmol) and 1-naphthalenemethylamine (4.24 g,
A mixture of monoxime 13 or 14 (18 mmol) and amine
(27 mmol) was heated in a glass pressure tube for 1 h at 150 °C.
The resulting crude product was purified by CC (SiO2, EtOAc–hex-
ane 2:1).
27 mmol). Yield 2.60 g (50%), mp 226–230 °C, ½a D20
¼ ꢀ21:1 (c
ꢁ
0.5, CH3OH). 1H NMR (500 MHz, CDCl3, 25 °C): d = 0.65 (s, 3H,
CH3), 1.37 (s, 3H, CH3), 1.45 (d, 1H, J = 8.9 Hz, CH2), 2.30–2.33 (m,

2468
J. Kulhánek et al. / Tetrahedron: Asymmetry 19 (2008) 2462–2469
1H, CH), 2.68–2.73 (m, 3H, CH + CH2), 2.83 (dd, 1H, J = 15.7 Hz,
J = 3.0 Hz, CH), 7.39 (t, 1H, J = 7.5 Hz, Np), 7.44–7.48 (m, 2H, Np),
7.56 (d, 1H, J = 7.2 Hz, Np), 7.78 (d, 1H, J = 8.2 Hz, Np), 7.82–7.84
(m, 1H, Np), 8.64–8.66 (m, 1H, Np). 13C NMR (125 MHz, CDCl3,
25 °C): d = 21.13, 26.41, 26.67, 33.77, 40.75, 41.63, 42.51, 125.29,
126.27, 126.31, 126.39, 126.91, 128.47, 128.62, 128.89, 131.09,
134.18, 142.50 (2C missing). EI-MS (70 eV) m/z (rel. int.): 288
1H, Dec –1CH2), 10.62 (br s, 1H, NH). 13C NMR (125 MHz, CDCl3,
25 °C): d = 11.75, 14.32, 18.10, 20.33, 22.89, 24.11, 27.79, 29.60,
29.83, 29.87, 29.95, 30.78, 32.14, 32.59, 45.61, 47.76, 53.83,
55.19, 160.99, 170.29. EI-MS (70 eV) m/z (rel. int.): 302 ([MꢀH2O]+,
26), 287 (100), 273 (12), 259 (100), 190 (11), 159 (12), 146 (10).
HR-FT-MALDI-MS (DCTB): m/z calcd for [C20H35N2+] 303.2795;
found 303.2794 [MHꢀH2O+]. Elemental Anal. Calcd for C20H36N2O
(320.28): C, 74.95; H, 11.32; N, 8.74. Found: C, 74.76; H, 11.29;
N, 9.16.
(M+, 89), 273 (100), 259 (48), 245 (45), 207 (40), 154 (39), 127
+
(31), 77 (22). HR-FT-MALDI-MS (DCTB): m/z calcd for [C20H21N2
]
289.1699; found 289.1700 [MH+]. Elemental Anal. Calcd for
C20H20N2 (288.39): C, 83.30; H, 6.99; N, 9.71. Found: C, 83.25; H,
7.05; N, 9.72.
4.4.11. (1S,4R)-3-(Cyclohexylmethylimino)-4,7,7-
trimethylbicyclo[2.2.1]heptan-2-one oxime 4b
The title compound was synthesized from monoxime 13
(3.26 g, 18 mmol) and cyclohexanemethylamine (3.06 g, 27 mmol).
4.4.7. (1R,8R)-9,9-Dimethyl-4-pyridin-2-yl-3,5-
diazatricyclo[6.1.1.02.6]deca-2(6),3-diene 2c
The title compound was synthesized from monoxime 14
(3.01 g, 18 mmol) and 2-picolylamine (2.92 g, 27 mmol). Yield
1.68 g (39%). Experimental data are consistent with the derivative
2c obtained by method A.
Yield 2.59 g (52%), mp 127–129 °C, ½a D20
ꢁ
¼ þ72:4 (c 0.5, CH3OH). 1H
NMR (500 MHz, CDCl3, 25 °C): d = 0.78 (s, 3H, CH3), 0.86–0.95 (m,
1H, CH2), 0.95 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.09–1.14 (m, 1H,
CH2), 1.16–1.26 (m, 2H, Chex), 1.39–1.50 (m, 2H, Chex), 1.61–
1.74 (m, 8H, CH2 + Chex), 1.89–1.95 (m, 1H, CH2), 3.22 (d, 1H,
J = 4.4 Hz, CH), 3.55 (dd, 1H, J = 13.6 Hz, J = 6.4 Hz, CH2Chex), 3.72
(dd, 1H, J = 13.6 Hz, J = 6.4 Hz, CH2Chex). 13C NMR (125 MHz,
CDCl3, 25 °C): d = 11.80, 18.12, 20.37, 24.15, 26.40, 26.95, 31.60,
32.59, 39.79, 45.57, 47.85, 55.16, 60.45, 161.74, 169.48. EI-MS
4.4.8. (1R,8R)-9,9-Dimethyl-4-thiophen-2-yl-3,5-
diazatricyclo[6.1.1.02.6]deca-2(6),3-diene 2d
The title compound was synthesized from monoxime 14
(3.01 g, 18 mmol) and 2-thiophenemethylamine (3.06 g, 27 mmol).
(70 eV) m/z (rel. int.): 258 ([MꢀH2O]+, 23), 243 (100), 229 (13),
Yield 1.85 g (42%), mp 233–236 °C, ½a D20
ꢁ
¼ ꢀ20:5 (c 0.5, CH3OH). 1H
215 (94). HR-FT-MALDI-MS (DCTB): m/z calcd for [C17H27N2
]
+
NMR (360 MHz, CDCl3, 25 °C): d = 0.68 (s, 3H, CH3), 1.37 (s, 3H,
CH3), 1.44 (d, 1H, J = 9.2 Hz, CH2), 2.28–2.31 (m, 1H, CH), 2.68–
2.75 (m, 3H, CH + CH2), 2.81 (dd, 1H, J = 9.2 Hz, 2.5 Hz, CH), 6.96
(t, 1H, J = 5.1 Hz, Th), 7.16 (d, 1H, J = 5.1 Hz, Th), 7.25–7.27 (m,
1H, Th). 13C NMR (90 MHz, CDCl3, 25 °C): d = 21.55, 26.78, 27.04,
34.12, 41.10, 41.90, 42.85, 122.29, 124.45, 127.76, 129.02, 131.12,
134.75, 138.98. EI-MS (70 eV) m/z (rel. int.): 244 (M+, 85), 229
(100), 215 (40), 201 (72), 189 (38), 176 (41), 120 (20), 110 (22),
92 (11). HR-FT-MALDI-MS (3-HPA): m/z calcd for [C14H17N2S+]
245.1107; found 245.11.06 [MH+]. Elemental Anal. Calcd for
C14H16N2S (244.36): C, 68.81; H, 6.60; N, 11.46; S, 13.12. Found:
C, 68.90; H, 6.67; N, 11.41; S, 13.08.
259.2252; found 259.2250 [MHꢀH2O]+. Elemental Anal. Calcd for
C17H28N2O (276.42): C, 73.87; H, 10.21; N, 10.13. Found: C,
73.73; H, 9.71; N, 10.24.
4.4.12. (1S,4R)-3-(Furan-2-ylmethylimino)-4,7,7-
trimethylbicyclo[2.2.1]heptan-2-one oxime 4c
The title compound was synthesized from monoxime 13
(3.26 g, 18 mmol) and furfurylamine (2.62 g, 27 mmol). Yield
3.09 g (66%), mp 142–145 °C, ½a D20
ꢁ
¼ þ87:8 (c 0.5, CH3OH). 1H
NMR (500 MHz, CDCl3, 25 °C): d = 0.80 (s, 3H, CH3), 0.93 (s, 3H,
CH3), 1.05 (s, 3H, CH3), 1.41–1.46 (m, 1H, CH2), 1.49–1.55 (m, 1H,
CH2), 1.71–1.77 (m, 1H, CH2), 1.91–1.97 (m, 1H, CH2), 3.22 (d,
1H, J = 4.5 Hz, CH), 4.89 (d, 1H, J = 16.8 Hz, CH2Fur), 5.04 (d, 1H,
J = 16.8 Hz, CH2Fur), 6.18–6.19 (m, 1H, Fur), 6.29–6.30 (m, 1H,
Fur), 7.33–7.34 (m, 1H, Fur), 8.07 (br s, 1H, NH). 13C NMR
(125 MHz, CDCl3, 25 °C): d = 11.61, 18.06, 20.42, 24.04, 32.46,
45.89, 47.79, 51.14, 55.40, 106.26, 110.35, 141.66, 154.83, 161.80,
171.46. EI-MS (70 eV) m/z (rel. int.): 242 ([MꢀH2O]+, 38), 227
(100), 213 (14), 199 (95), 185 (14), 121 (15), 106 (15). HR-FT-MAL-
DI-MS (DCTB): m/z calcd for [C15H19N2O+] 243.1492; found
243.1492 [MHꢀH2O]+. Elemental Anal. Calcd for C15H20N2O2
(260.33): C, 69.20; H, 7.74; N, 10.76. Found: C, 69.28; H, 7.81; N,
10.81.
4.4.9. (1R,8R)-4-Furan-2-yl-9,9-dimethyl-3,5-
diazatricyclo[6.1.1.02.6]deca-2(6),3-diene 2e
The title compound was synthesized from monoxime 14
(3.01 g, 18 mmol) and furfurylamine (2.62 g, 27 mmol). Yield
1.68 g (41%), mp 118–123 °C, ½a D20
ꢁ
¼ þ33:0 (c 0.5, CH3OH). 1H
NMR (500 MHz, CDCl3, 25 °C): d = 0.65 (s, 3H, CH3), 1.36 (s, 3H,
CH3), 1.42 (d, 1H, J = 9.2 Hz, CH2), 2.29–2.31 (m, 1H, CH), 2.68–
2.75 (m, 3H, CH + CH2), 2.82 (dd, 1H, J = 13.0 Hz, J = 2.9 Hz, CH),
6.38–6.39 (m, 1H, Fur), 6.70 (d, 1H, J = 3.4 Hz, Fur), 7.30–7.31 (m,
1H, Fur), 8.92 (br s, 1H, NH). 13C NMR (125 MHz, CDCl3, 25 °C):
d = 21.47, 25.74, 26.91, 34.08, 41.07, 41.84, 42.77, 105.51, 111.94,
127.24, 136.28, 141.47, 146.68 (1C missing). EI-MS (70 eV) m/z
(rel. int.): 228 (M+, 96), 213 (100), 199 (42), 185 (53), 173 (34),
160 (40), 120 (19), 94 (20). HR-FT-MALDI-MS (DCTB): m/z calcd
for [C14H17N2O+] 229.1335; found 229.1332 [MH+]. Elemental Anal.
Calcd for C14H16N2O (228.29): C, 73.66; H, 7.06; N, 12.27. Found: C,
73.70; H, 7.10; N, 12.29.
4.5. (1R,7S)-4-[2-(Diphenylphosphanyl)phenyl]-1,10,10-
trimethyl-3,5-diazatricyclo[5.2.1.02.6]deca-2(6),3-diene 17
n-BuLi (4.15 mL, 6.64 mmol, 1.6 M sol. in hexane) was added to
a solution of 1a (1.676 g, 6.64 mmol) in dry THF (20 mL) under N2,
at 0 °C and the reaction mixture stirred for 10 min. Iodomethane
(1 g, 7.2 mmol) was added, the reaction mixture stirred for 1 h at
0 °C and quenched with water. The product was extracted with
ether (3 ꢂ 50 mL), combined organic layers were dried (Na2SO4)
and concentrated in vacuo to afford pure N-methyl derivative.
Yield 1.68 g (95%), oil. 1H NMR (500 MHz, CDCl3, 25 °C): d = 0.90
(s, 6H, CH3), 0.98–1.03 (m, 2H, CH2), 1.36 (s, 3H, CH3), 1.72–1.77
(m, 1H, CH2), 1.92–1.96 (m, 1H, CH2), 2.84 (s, 1H, CH), 3.67 (s,
3H, N-CH3), 7.27–7.30 (m, 1H, Ph), 7.36–7.39 (m, 2H, Ph), 7.56–
7.59 (m, 2H, Ph). EI-MS (70 eV) m/z (rel. int.): 266 (M+, 42), 251
(100), 237 (15), 223 (56), 118 (17), 77 (15). n-BuLi (1.03 mL,
1.65 mmol, 1.6 M sol. in hexane) was added to a solution of the
4.4.10. (1S,4R)-3-(Decylimino)-4,7,7-trimethylbicyclo-
[2.2.1]heptan-2-one oxime 4a
The title compound was synthesized from monoxime 13
(3.26 g, 18 mmol) and n-decylamine (4.24 g, 27 mmol). Yield
2.31 g (40%), oil, ½a D20
ꢁ
¼ þ59:9 (c 0.5, CH3OH). 1H NMR (500 MHz,
CDCl3, 25 °C): d = 0.78 (s, 3H, CH3), 0.85 (t, 3H, J = 6.6 Hz, Dec
–
10CH3), 0.90 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.22–1.33 (m, 14H,
Dec –3CH2–9CH2), 1.39–1.49 (m, 2H, CH2), 1.57–1.62 (m, 2H, Dec
2CH2), 1.68–1.73 (m, 1H, CH2), 1.88–1.92 (m, 1H, CH2), 3.22 (d,
1H, J = 4.3 Hz, CH), 3.71–3.77 (m, 1H, Dec –1CH2), 3.86–3.92 (m,
–

J. Kulhánek et al. / Tetrahedron: Asymmetry 19 (2008) 2462–2469
2469
N-methyl derivative (399 mg, 1.5 mmol) in dry THF (40 mL) under
References
N2 and the reaction mixture stirred for 30 min at 0 °C. A solution of
Ph2PCl (350 mg, 1.58 mmol) in THF (2 mL) was added dropwise
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mixture extracted with ether (2 ꢂ 50 mL), the combined organic
layers were dried (Na2SO4) and the solvent evaporated in vacuo.
The crude product was purified by CC (SiO2; CH3OH–CHCl3
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Crystallographic data for 4b, C17H28N2O, unit cell dimension
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ˇ
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Acknowledgments
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This research was supported by the Czech Science Foundation
(203/07/P013) and by the Ministry of Education, Youth and Sport
of the Czech Republic (MSM 0021627501). We thank Professor O.
Pytela for the discussion concerning the proposed mechanism
42. Sheldrick, G. M. SHELXL97, Program for the Refinement of Crystal Structures;
University of Göttingen: Germany, 1997.
ˇ ˇ
and Dr. A. Ru˚ zicka for the X-ray measurement of 4b.