Stereoselective synthesis of (1R,3R,4R)-3-(1,2,4-triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1] heptan-2-ones

Article abstract of DOI:10.1016/S0957-4166(02)00208-2

(1R,3R,4R)-3-(1,2,4-Triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1] heptan-2-ones were prepared in 68-94% d.e. in three steps from (1R)-(+)-camphor via coupling of (1R,4R)-3-[(E)-(dimethylamino)methylidene]-1,7,7-trimethylbicyclo[2.2.1] heptan-2-one with hydrazinoazines followed by oxidative cyclisation of the intermediate hydrazones with methanolic bromine. The structures were determined by 2D NMR techniques and NOESY spectroscopy as well as by X-ray diffraction.

Full text of DOI:10.1016/S0957-4166(02)00208-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 821–833
Stereoselective synthesis of
(1R,3R,4R)-3-(1,2,4-triazolo[4,3-x]azin-3-yl)-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones
Urosˇ Grosˇelj, Simon Recˇnik, Jurij Svete,* Anton Meden and Branko Stanovnik
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, PO Box 537, 1000 Ljubljana, Slovenia
Received 1 March 2002; accepted 26 April 2002
Abstract—(1R,3R,4R)-3-(1,2,4-Triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones were prepared in 68–94% d.e.
in three steps from (1R)-(+)-camphor via coupling of (1R,4R)-3-[(E)-(dimethylamino)methylidene]-1,7,7-trimethylbicy-
clo[2.2.1]heptan-2-one with hydrazinoazines followed by oxidative cyclisation of the intermediate hydrazones with methanolic
bromine. The structures were determined by 2D NMR techniques and NOESY spectroscopy as well as by X-ray diffraction.
© 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Recently, a series of alkyl 2-substituted 3-(dimethyl-
amino)propenoates have been prepared and were
found to be versatile reagents for the preparation of
various heterocyclic systems. In connection with this,
their chiral cyclic analogs have been employed in the
synthesis of heteroaryl substituted a-amino- and a-
hydroxy acids and their analogs via ‘ring switching’
transformations, 1,3-dipolar cycloadditions, and amina-
tions.18,19 In continuation of our work in this field, we
(1R,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-one ((+)-
camphor) 1 and its derivatives certainly belong among
the most frequently used types of chiral compounds.
They have been employed as chiral building blocks,
chiral ligands for various asymmetric reagents and/or
catalysts, resolving agents, and shift reagents in NMR
spectroscopy.1,2 For example, chiral pyridine and 2,2%-
bipyridine thioethers and diols derived from (+)-cam-
phor were used as NꢀS and NꢀO ligands for
asymmetric catalysis.3,4 Similarly, reaction of 3-
hydroxymethylidenecamphor5 with amines followed by
reduction of the exocyclic CꢁC double bond leads to
3-aminomethylidenecamphor derivatives exhibiting
local anaesthetic and smooth muscle relaxant
properties.6–8
now report
a one-pot preparation of the novel
(1R,3R,4R)-3-(1,2,4-triazolo[4,3-x]azin-3-yl)-1,7,7-tri-
methylbicyclo[2.2.1]heptan-2-ones 6a–g.
2. Results and discussion
The starting material, (1R,4R)-3-[(E)-(dimethyl-
amino)methylidene]-1,7,7-trimethylbicyclo[2.2.1]-hept-
an-2-one 2,20 was prepared in 43% yield by treatment
of (1R)-(+)-camphor 1 with bis(dimethylamino)-tert-
butoxymethane (Bredereck’s reagent) in DMF under
reflux. Treatment of 2 with hydrazinoazines 3a–g, hav-
ing the hydrazine group attached at the position adja-
cent to the ring nitrogen atom, in methanol in the
presence of an equimolar amount of hydrochloric acid
at room temperature followed by oxidative cyclisation
with methanolic bromine in the presence of sodium
acetate afforded the corresponding (1R,3R,4R)-
3-(1,2,4-triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo-
[2.2.1]heptan-2-ones 6a–g in 37–79% yields and in 68–
94% d.e. Compounds 6a–g were obtained and char-
On the other hand, the 1,2,4-triazolo[4,3-x]azine moiety
is a constituent of several biologically active com-
pounds, such as trazodone and 3-phenyl-1,2,4-tri-
azolo[4,3-b]pyridazine.9,10
A
common
synthetic
approach towards 1,2,4-triazolo[4,3-x]azines consists of
treatment of a hydrazinoazine with an aldehyde to give
the corresponding hydrazone, which is then oxidatively
cyclised into the corresponding 1,2,4-triazolo[4,3-
x]azine.11–13 In this manner, 1,2,4-triazolo[4,3-x]azin-3-
yl substituted alanines14,15 and polyols16,17 have also
been prepared from suitable chiral aldehydes.
* Corresponding author. Tel.: +386 1 2419 100; fax: +386 1 2419 220;
e-mail: jurij.svete@uni-lj.si
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00208-2

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U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
acterised as mixtures of the major endo-isomers 6a–g and
the minor exo-isomers 6%a–g. Upon repeated crystallisa-
tion, compounds 6c–g were obtained in diastereomeri-
cally pure form, while compounds 6a and 6b were
obtained in 98 and 92% d.e., respectively. Treatment of
diastereomerically pure 6e with sodium methoxide in
methanol under reflux resulted in the Dimroth rearrange-
ment of the 1,2,4-triazolo[4,3-a]pyrimidine system to give
(1R,3R,4R) - 3 - (1,2,4 - triazolo[1,5 - a]pyrimidin - 2 - yl)-
1,7,7-trimethylbicyclo-[2.2.1]heptan-2-one 7 in 92% d.e.
and in 55% yield. According to previous observations for
3-(dimethylamino)propenoates and 1,2,4-triazolo[4,3-
x]azines, the reaction mechanism could be explained by
the initial substitution of the dimethylamino group of 2
with the hydrazino group of 3 to give the enehydrazine
4, which tautomerises into the hydrazone form 5. Further
oxidation of 5 with bromine leads to 1,2,4-triazolo[4,3-
x]azine derivative 6. This proposed reaction mechanism
is supported by the isolation of the hydrazone interme-
diates 5b and 5c, which were obtained in 78 and 22% d.e.,
respectively. Compounds 5b,c and 7 were obtained and
characterised as mixtures of the major endo-isomers 5b,c
and 7 and the minor exo-isomers 5%b,c and 7%. (Scheme
1, Table 1).
7
1
2
i
O
O
6
3
4
5
3'
NMe2
1
2
7
1
ii
2
O
N
NHNH2
O
6
3
N
+
4
3''
1''
5
N
R
N
2''
NMe2
NH
R
N
H
3a-g
2
4a-g
R
N
7
1
iii, iv
N
2
O
O
O
O
N
N
6
+
3
H
H
4
HN
5
N
N
3'
4'
5'
N
H
H
N 2'
N
N
6'
R
5'a-g
N
N
N
NH
N
1'
R
6'a-g
(minor isomer)
(minor isomer)
7'
8'
R
6a-g
(major isomer)
5a-g
(major isomer)
N
v
O
O
O
N
+
H
H
N
N
H
N
N
N
N
N
N
7'
(minor isomer)
N
N
6e
7
(major isomer)
Scheme 1. (i) tert-BuOCH(NMe2)2, DMF, reflux, then crystallisation; (ii) MeOH, HCl, rt; (iii) Br2, MeOH, AcONa, rt; (iv)
chromatographic purification; (v) MeONa, MeOH, reflux.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
823
Table 1. Hydrazinoazines 3a–g, enehydrazines 4a–g, hydrazones 5a–g, and camphor derivatives 6a–g
3. Structure determination
cross peaks in the HMBC spectrum. Generally, the
magnitude of the coupling constants JC-H for nuclei
3
The structures of starting compound 2, hydrazones
5b,c, and camphor derivatives 6a–g, 7 were determined
with cis-configuration about the CꢁC double bond are
smaller (2–6 Hz) than that for trans-oriented nuclei
(8–12 Hz).27,28 The magnitude of coupling constant
(3JC-H=4.8 Hz) showed the (E)-configuration around
the exocyclic CꢁC double bond in compound 2. The
(3R)-configuration (endo-configuration) of compounds
1
by spectroscopic methods (IR, H and 13C NMR, 2D
NMR, NOESY spectroscopy, MS) and by elemental
analyses for C, H, and N. Compounds 5b,c, 6a–g, and
7 were characterised as mixtures of diastereomers. Spe-
cific rotation angles for compounds 6a–g were mea-
sured with the diastereomerically pure samples 6c–g
and diastereomerically enriched samples 6a,b, obtained
upon repeated crystallisation of mixtures of
diastereomers. Total assignment of 13C signals for com-
pound 6a was achieved by means of HMQC, HMBC
and NOESY. Spectroscopic data of compounds 2, 5–7
were in agreement with the data for related 1,2,4-tria-
zolo[4,3-x]azines, 1,2,4-triazolo[1,5-a]pyrimidines, and
camphor derivatives.9,10,21–26
5–7 was determined on the basis of the magnitude of
25,26
the coupling constant, JH3-H4
.
In the major endo-
isomers 5b,c, 6a–g, and 7, coupling constant JH3-H4
=
4.3–5.3 Hz, while in the minor exo-isomers 5%b,c, 6%a–g,
and 7%, no coupling between these two protons (JH3-H4
ꢀ0 Hz) was observed. The (3R)-configuration of 6a
was also established on the basis of the NOE effect
between the C(5%) proton of the heteroaryl residue and
the C(3) and C(4) protons of the camphor residue (Fig.
1).
The structures of compounds 2, 5c, 6b,c,e and 7 were
also determined by X-ray diffraction (Figs. 2–7)
3.1. Structure of enaminone 2, hydrazones 5b,c, and
camphor derivatives 6a–g, 7
The configuration about the exocyclic CꢁC double
bond in 2 was determined by NMR on the basis of
long-range coupling constants (3JC-H) between the
methylidene proton (HꢀC(3%)) and the carbonyl carbon
(OꢁC(2)), measured from the antiphase splitting of
4. Stereoselectivity
It has been reported previously, that 3-formylcamphor
and its derivatives exist in solution as mixtures of

824
U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
O
O
O
O
H
R
H
H
NOE
H
H
H
N
H
R
NMe2
NOE
H
J ~ 0.5 Hz
J = 4.3-5.1 Hz
3JC-H = 4.8 Hz (cis)
N
5-7 (endo)
major isomers
5'-7' (exo)
minor isomers
N
2 (E)
6a
Figure 1.
5. Conclusion
(Z/E)-3-hydroxymethylidenecamphor and exo/endo-3-
formylcamphor where the ratio between the various
(1R,3R,4R)-3-(1,2,4-Triazolo[4,3-x]azin-3-yl)-1,7,7-tri-
methylbicyclo[2.2.1]heptan-2-ones can be prepared
stereoselectively from o-hydrazinoazines and (+)-cam-
phor by a three-step synthesis. The synthesis proceeds
by transformation of (+)-camphor with Bredereck’s
reagent into (1R,4R)-3-[(E)-(dimethylamino)methyl-
idene]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one followed
by dimethylamine substitution with hydrazinoazines to
give the corresponding hydrazones which are then oxi-
datively cyclised with methanolic bromine to give
(1R,3R,4R)-3-(1,2,4-triazolo[4,3-x]azin-3-yl)-1,7,7-tri-
methylbicyclo[2.2.1]heptan-2-ones in fair yields and
high d.e. The structures of products were determined by
1H NMR, 2D HMBC correlation techniques, NOESY
spectroscopy, and X-ray analysis. Although diastereo-
selective formation of (1R,3R,4R)-3-(1,2,4-triazolo[4,
3-x]azin-3-yl)-1,7,7-trimethylbicyclo-[2.2.1]heptan-2-
ones could be due to kinetic as well as thermodynamic
possible
isomers
depends
on
the
solvent
employed.21,23,24 Although the crystal structure of the
2-formylcamphor derived enaminone 2 was determined
by X-ray diffraction, compound 2 might still isomerise
1
in solution. However, the single set of signals in the H
NMR spectrum of 2, taken in CDCl3, indicates that
compound 2 exists (in CDCl3 solution) as a single
(1R,4R)-isomer with (E)-configuration about the exo-
cyclic double bond.
1
On the other hand, the H NMR spectra of isolated
hydrazones 5b,c, taken in CDCl3 solution, showed that
these exist as mixtures of the endo-isomers 5b,c and the
exo-isomers 5%b,c in a ratio of 89:11 and 61:39, respec-
tively. In DMSO-d6 solution, 5b/5%b isomerised into a
mixture of 4b, 5b, and 5%b in a ratio of 16:70:14 and
5c/5%c isomerised into a mixture of 4c, 5c, and 5%c in a
ratio of 15:48:37. Similarly, upon standing in DMSO-d6
solution at room temperature for 4 days, diastereomer-
ically pure compound 6c isomerised to a mixture of the
endo-isomer 6c and the exo-isomers 6%c in a ratio of
97.5:2.5. Furthermore, heating
a
solution of
diastereomerically pure compound 6e in methanol for
10 h afforded a mixture of 6e, 6%e, 7, and 7% in a ratio
of 71:3:25:1, respectively. Therefore, both types of com-
pounds, the intermediate hydrazones as well as 1,2,4-
triazolo[4,3-x]azines as the final products, exist in
solution predominantly in the endo-isomeric forms 5
and 6 (Scheme 2).
Stereoselective formation of compounds 5 and 6 might
be predominantly due to equilibrium between the less
strained endo-isomers 5 and 6 and the more strained
exo-isomers 5% and 6%. The products 6 could initially be
formed as mixtures of the endo-isomers 6 and the
exo-isomers 6%, which can equilibrate via the enol form
6¦ into the more thermodynamically stable endo-iso-
mers 6. Thermodynamic control in the stereoselective
formation of the less strained endo-isomers 6 is sup-
ported by the fact that the Dimroth rearrangement of
6e into 7, carried out with sodium methoxide in
methanol under reflux, took place with almost no
epimerisation at the C(3) centre. On the other hand,
kinetically controlled stereoselective formation of the
endo-isomers 6 still cannot be excluded on the basis of
these studies (Scheme 3).
Figure 2. The asymmetric unit of compound 2. Ellipsoids are
plotted at 50% probability level. H atoms are drawn as circles
of arbitrary radii.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
825
Figure 3. The asymmetric unit of compound 5c. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of
arbitrary radii.
factors, the experimental evidence indicates that thermo-
dynamic control predominates in formation of the
endo-isomers.
a Perkin–Elmer Spectrum BX FTIR spectrophotome-
ter. Microanalyses were performed on a Perkin–Elmer
CHN Analyser 2400. Column chromatography (CC)
was performed on silica gel (Fluka, silica gel 60, 0.04–
0.06 mm). Medium-pressure liquid chromatography
(MPLC) was performed with a Bu¨chi isocratic system
with detection† on silica gel (Merck, silica gel 40, 0.015–
0.035 mm); column dimensions (dry filled): 15×460 mm;
backpressure: 10–15 bar; detection: UV 254 nm; sample
amount: 100–150 mg of isomeric mixture per each run.
The d.e. of the isolated and the diastereomerically
enriched compounds 5–7 were determined by 1H NMR.
6. Experimental
6.1. General methods
Melting points were determined on a Kofler micro hot
1
stage. The H NMR spectra were obtained on a Bruker
Avance DPX 300 at 300 MHz for 1H and 75.5 MHz for
13C nucleus, using DMSO-d6 and CDCl3, with TMS as
the internal standard, as solvents. Mass spectra were
recorded on an AutoSpecQ spectrometer, IR spectra on
† Donation of Alexander von Humboldt Foundation, Germany.

826
U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
Figure 4. The asymmetric unit of compound 6b. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of
arbitrary radii.
Figure 5. The asymmetric unit of compound 6c. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of
arbitrary radii.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
827
Volatile components were evaporated in vacuo, the
residue was dissolved in CH2Cl2 (70 mL) and washed
with water (2×60 mL). The organic phase was dried over
anhydrous Na2SO4, filtered, and the filtrate was evapo-
rated in vacuo. The residue was dissolved in petroleum
ether (40 mL), cooled (−20°C), and the precipitate was
collected by filtration to give 2 (2670 mg, 43%), which
1
was characterised by spectral (IR, H NMR, and 13C
NMR) and elemental analyses.; mp 59–62°C (petroleum
ether), lit.20 mp 63–64°C (petroleum ether); [h]2D0=+484.8
1
(c 0.506, CH2Cl2). H NMR (CDCl3): l 0.84, 0.89, 0.94
(9H, 3s, 1:1:1, 3Me), 1.30–1.46 (2H, m, CH2), 1.52–1.64
(1H, m, 1H of CH2), 1.92–2.04 (1H, m, 1H of CH2), 2.90
(1H, br d, J=3.8 Hz, HꢀC(4)), 2.98 (6H, s, NMe2), 7.00
(1H, d, J=0.76 Hz, HꢀC(3%)). 13C NMR (CDCl3): l 10.0,
19.4, 21.1, 28.8, 30.7, 42.6, 48.4, 48.6, 56.8, 111.4, 141.5,
207.7. Found: C, 75.28; H, 10.43; N, 6.57. C13H21NO
requires: C, 75.32; H, 10.21; N, 6.76%; wmax (KBr) 1690
cm−1 (CꢁO).
6.3. General procedure for the preparation of mixtures
of (1R,3R,4R)-3-{[N-(6-substituted pyridazin-3-yl)-
hydrazono]methyl}-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
ones 5b,c and their (1R,3S,4R)-epimers 5%b,c
Hydrochloric acid (37%, 0.05 mL, ꢀ0.5 mmol) was
added to a stirred suspension of compound 2 (104 mg,
0.5 mmol) and hydrazine 3b,c (0.5 mmol) in methanol
(1.5 mL) and the mixture was stirred at rt for 3 h. The
precipitate was collected by filtration and washed with
cold (0°C) methanol (ꢀ10 mL) to give a white solid,
1
which was characterised by spectral (IR and H NMR)
and elemental analyses. Isomeric mixtures 5b/5%b and
5c/5%c were prepared in this manner.
Figure 6. The asymmetric unit of compound 6e. Ellipsoids are
plotted at 50% probability level. H atoms are drawn as circles
of arbitrary radii.
In DMSO-d6 solution, the mixtures 5b/5%b and 5c/5%c
isomerised into the mixtures 4b/5b/5%b and 4c/5c/5%c,
The minor isomers 5%–7% were not isolated and were
1
1
characterised only by H NMR.
respectively. The isomers 4b,c were characterised by H
NMR.
tert-Butoxy-bis(dimethylamino)methane, (+)-camphor
1, 2-hydrazinopyridine 3a and 1-hydrazinophthalazine
3d are commercially available (Fluka AG). 3-Hydrazino-
6-phenylpyridazine 3b,29 6-chloro-3-hydrazinopyri-
dazine 3c,30 2-hydrazinopyrimidine 3e,31 2-hydrazino-
pyrazine 3f,32 and 6-chloro-2-hydrazinopyrazine 6g33
were prepared according to the procedures described in
the literature. Compound 2 has previously been prepared
from 1 via formylation followed by treatment with
dimethylamine.20
6.3.1. (1R,3R,4R)-3-[(6-Phenylpyridazin-3-yl)hydrazono-
methyl]-1,7,7-trimethylbicyclo-[2.2.1]heptan-2-one 5b and
its (1R,3S,4R)-epimer 5%b. Prepared from compound 2
and 3-hydrazino-6-phenylpyridazine 3b; 89 mg (51%) of
a white solid; 5b:5%b=89:11; mp 224–228°C; [h]2D0=−39.3
(c 0.293, CH2Cl2). (Found: C, 72.51; H, 7.28; N, 16.27.
C21H24N4O requires: C, 72.39; H, 6.94; N, 16.08.); wmax
(KBr) 1740 cm−1 (CꢁO).
NMR data for the major (1R,3R,4R)-isomer 5b: 1H NMR
(CDCl3): l 0.96, 0.98, 1.03 (9H, 3s, 1:1:1, 3Me), 1.40–1.88
(4H, m, 2CH2), 2.30–2.37 (1H, m, HꢀC(4)), 3.43 (1H, t,
J=5.5 Hz, HꢀC(3)), 7.37–7.52 (3H, m, 3H of Ph), 7.59
(1H, br d, J=9.4 Hz, HꢀC(4%)), 7.73 (1H, br d, J=9.4
Hz, HꢀC(5%)), 7.74 (1H, d, J=6.0 Hz, HꢀC(3¦)), 7.92–
7.99 (2H, m, 2H of Ph), 11.72 (1H, br s, HꢀN(1¦)).
Source of chirality: (+)-camphor 1 (Fluka AG), product
number 21300, purum, natural, ]97.0% (GC, sum of
enantiomers), [h]25406=+54.5 2.5 (c 10, EtOH), [h]2D0=
+42.5 2.5 (c 10, EtOH), mp 176–180°C. The e.e. of
(+)-camphor 1 is not specified by the producer (Fluka
AG).
6.2. (1R,4R)-3-[(E)-(Dimethylamino)methylidene]-1,7,7-
NMR data for the minor (1R,3S,4R)-isomer 5%b: 1H NMR
(CDCl3): l 0.78 (3H, s, Me), 2.61 (1H, d, J=4.1 Hz,
HꢀC(4)), 2.96 (1H, d, J=3.8 Hz, HꢀC(3)), 7.78 (1H, d,
J=4.1 Hz, HꢀC(3¦)). In DMSO-d6 solution, a mixture
of 5b and 5%b isomerised into a mixture of 4b, 5b, and
5%b.
trimethylbicyclo[2.2.1]heptan-2-one 2
A mixture of compound 1 (4567 mg, 30 mmol), DMF
(50 mL), and tert-butoxy-bis(dimethylamino)methane
(10 mL, 48.4 mmol) was heated under reflux for 7 h.

828
U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
Figure 7. The asymmetric unit of compound 7. Ellipsoids are plotted at 50% probability level. H atoms are drawn as circles of
arbitrary radii.
NMR data for the (1R,4R)-isomer 4b: 1H NMR
(DMSO-d6): l 2.81 (1H, d, J=3.4 Hz, HꢀC(3)), 6.90
(1H, d, J=7.5 Hz, HꢀC(3¦), 6.98 (1H, d, J=9.4 Hz,
HꢀC(4%)), 7.58 (1H, d, J=9.4 Hz, HꢀC(5%)), 8.48 (1H,
br d, J=7.5 Hz, HꢀN(2¦), 9.23 (1H, s, HꢀN(1¦));
4b:5b:5%b=16:70:14.
NMR data for the (1R,4R)-isomer 4c: 1H NMR
(DMSO-d6): l 2.76 (1H, d, J=3.8 Hz, HꢀC(3)), 6.84
(1H, d, J=7.9 Hz, HꢀC(3¦), 6.99 (1H, d, J=9.4 Hz,
HꢀC(4%)), 7.58 (1H, d, J=9.0 Hz, HꢀC(5%)), 8.45 (1H,
br d, J=7.5 Hz, HꢀN(2¦), 9.34 (1H, s, HꢀN(1¦));
4c:5c:5%c=15:48:37.
6.4. General procedure for the preparation of mixtures
of (1R,3R,4R)-3-[1,2,4-triazolo[4,3-x]azin-3-yl]-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ones 6a–g and their
(1R,3S,4R)-epimers 6%a–g
6.3.2. (1R,3R,4R)-3-[(6-Chloropyridazin-3-yl)hydrazono-
methyl]-1,7,7-trimethylbicyclo-[2.2.1]heptan-2-one 5c and
its (1R,3S,4R)-epimer 5%c. Prepared from compound 2
and 6-chloro-3-hydrazinopyridazine 3c; 74 mg (48%) of
a white solid; ratio 5b:5%b=61:39 (in CDCl3); mp 208–
214°C; [h]2D3=−9.3 (c 0.484, CH2Cl2). Found: C, 58.94;
H, 6.49; N, 18.40. C15H19ClN4O requires: C, 58.72; H,
6.24; N, 18.26%; wmax (KBr) 1746 cm−1 (CꢁO).
Hydrochloric acid (37%, 0.10 mL, ꢀ1 mmol) was
added to a stirred mixture of compound 2 (207 mg, 1
mmol), hydrazine 3a–g (1 mmol), and methanol (5 mL)
and the resulting mixture was stirred at rt for 5–7 h.
The reaction mixture was cooled to 0–5°C (ice-bath),
sodium acetate (246 mg, 3 mmol) was added and, with
vigorous stirring, a solution of bromine (0.051 mL, ꢀ1
mmol) in methanol (3 mL) was added dropwise over a
period of 5–10 min. The mixture was stirred at 0–5°C
(ice-bath) for 2–6 h. Volatile components were evapo-
rated in vacuo, dichloromethane (40 mL) was added to
the residue and the mixture was washed with saturated
aqueous sodium bicarbonate solution (50 mL) and
brine (50 mL). The organic phase was dried over anhy-
drous sodium sulphate, filtered, and the filtrate was
evaporated in vacuo. The residue was purified by CC.
Fractions containing the product were combined and
evaporated in vacuo. Compounds 6c–f were addition-
ally purified by MPLC. Fractions containing the
product were combined and evaporated in vacuo to
give a white solid, which was characterised by spectral
NMR data for the major (1R,3R,4R)-isomer 5c: 1H
NMR (CDCl3): l 0.94, 0.98, 1.05 (9H, 3s, 1:1:1, 3Me),
1.44–1.95 (4H, m, 2CH2), 2.28–2.35 (1H, m, HꢀC(4)),
3.36 (1H, dd, J=5.1, 6.2 Hz, HꢀC(3)), 7.29 (1H, d,
J=9.4 Hz, HꢀC(4%)), 7.50 (1H, d, J=9.4 Hz, HꢀC(5%)),
7.62 (1H, d, J=6.4 Hz, HꢀC(3¦)), 11.53 (1H, br s,
HꢀN(1¦).
NMR data for the minor (1R,3S,4R)-isomer 5%c: 1H
NMR (CDCl3): l 0.90, 0.96, 1.01 (9H, 3s, 1:1:1, 3Me),
2.09 (1H, tt, J=4.0, 11.7 Hz, 1H of CH2), 2.48 (1H, d,
J=4.1 Hz, HꢀC(4)), 2.92 (1H, d, J=4.9 Hz, HꢀC(3)),
7.30 (1H, d, J=9.4 Hz, HꢀC(4%)), 7.51 (1H, d, J=9.4
Hz, HꢀC(5%)), 7.59 (1H, d, J=4.9 Hz, HꢀC(3¦)), 10.93
(1H, br s, HꢀN(1¦). In DMSO-d6 solution, a mixture of
5c and 5%c isomerised into a mixture of 4c, 5c, and 5%c.

U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
829
Scheme 2. Isomerisation of compounds 5b,c and 6c,e in solution: (i) DMSO-d6, rt, 4 days; (ii) MeOH, reflux.
(IR, 1H NMR, 13C NMR, and MS) and elemental
analyses. Isomeric mixtures 6a–g/6%a–g were prepared
in this manner.
6.4.1. (1R,3R,4R)-3-[1,2,4-Triazolo[4,3-a]pyridin-3-yl]-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 6a and its
(1R,3S,4R)-epimer 6%a. Prepared from compound 2 and
2-hydrazinopyridine (3a), 6 h, CC (EtOAc); 100 mg
(37%) of a white solid; mp 186–190°C; 6a:6%a=84:16.
Found: C, 71.60; H, 7.24; N, 15.65. C16H19N3O
requires: 71.35; H, 7.11; N, 15.60%; wmax (KBr) 1749
cm−1 (CꢁO).
Repeated crystallisation of isomeric mixtures 6a–g/6%a–
g from a mixture of chloroform and n-heptane fur-
nished diastereomerically enriched compounds 6a (98%
d.e.) and 6b (92% d.e.) and diastereomerically pure
compounds 6c–g (100% d.e.), which were characterised
by melting point and measurement of the specific rota-
tion. Diastereomerically enriched mixtures 6a/6%a, 6b/
6%b and diastereomerically pure compounds 6c–g were
prepared in this manner.
NMR data for the major (1R,3R,4R)-isomer 6a: 1H
NMR (CDCl3): l 1.06, 1.10, 1.12 (9H, 3s, 1:1:1, 3Me);
1.76–1.92 (4H, m, 2CH2), 2.59–2.61 (1H, m, HꢀC(4)),
4.05 (1H, d, J=4.5 Hz, HꢀC(3)), 6.83 (1H, dt, J=1.1,

830
U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
Scheme 3. Stereoselective formation of the endo-isomers of compounds 5 and 6.
6.8 Hz, HꢀC(6%)); 7.24 (1H, ddd, J=1.1, 6.8, 9.4 Hz,
HꢀC(7%)); 7.76 (1H, dt, J=1.1, 9.4 Hz, HꢀC(8%)), 8.11
(1H, dt, J=1.1, 7.2 Hz, HꢀC(5%)). 13C NMR (CDCl3): l
10.1 (MeꢀC(1)), 19.6 (MeꢀC(7)), 20.1 (MeꢀC(7)), 22.3
(C(5)), 30.3 (C(6)), 46.6 (C(7)), 47.1 (C(3)), 47.6 (C(4)),
59.0 (C(1)), 114.0 (C(6%)), 116.9 (C(8%)), 122.8 (C(5%)),
127.3 (C(7%)), 144.1 (C(3%)), 150.4 (C(8a)), 213.6 (C(2)).
NMR data for the minor (1R,3S,4R)-isomer 6%b: 1H NMR
(CDCl3): l 1.03, 1.08, 1.10 (9H, 3s, 1:1:1, 3Me); 2.96 (1H,
d, J=4.2 Hz, HꢀC(4)), 4.02 (1H, s, HꢀC(3)), 7.97–8.01
(2H, m, 2H of Ph), 8.13 (1H, d, J=9.4 Hz, HꢀC(8%)).
Upon repeated crystallisation of 6b/6%b from a mixture
of chloroform and n-heptane, diastereomerically
enriched mixture of isomers 6b and 6%b with the following
physical data was obtained: 6b:6%b=96:4; mp 255–261°C;
[h]2D5=+107.5 (c 0.400, CHCl3).
NMR data for the minor (1R,3S,4R)-isomer 6%a: 1H NMR
(CDCl3): l 0.87, 0.96, 1.09 (9H, 3s, 1:1:1, 3Me), 3.36 (1H,
d, J=4.1 Hz, HꢀC(4)), 3.57 (1H, s, HꢀC(3)), 7.67 (1H,
dt, J=1.1, 9.4 Hz, HꢀC(8%)), 8.59 (1H, dt, J=1.1, 7.2 Hz
HꢀC(5%)). Upon repeated crystallisation of 6a/6%a from a
mixture of chloroform and n-heptane, diastereomerically
enriched mixture of isomers 6a and 6%a with the following
physical data was obtained: 6a:6%a=99:1; mp 178–182°C;
[h]2D6=−9.5 (c=0.474, CHCl3).
6.4.3. (1R,3R,4R)-3-[6-Chloro-1,2,4-triazolo[4,3-b]pyri-
dazin-3-yl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 6c
and its (1R,3S,4R)-epimer 6%c. Prepared from compound
2 and 6-chloro-3-hydrazinopyridazine (3c), 3 h, CC and
MPLC (EtOAc); 216 mg (71%) of a white solid; mp
178–183°C; 6c:6%c=97:3. Found: C, 59.11; H, 5.83; N,
18.30. C15H17ClN4O requires: C, 59.11; H, 5.62; N,
18.38%; wmax (KBr) 1743 cm−1 (CꢁO).
6.4.2.
(1R,3R,4R)-3-[6-Phenyl-1,2,4-triazolo[4,3-b]-
pyridazin-3-yl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
6b and its (1R,3S,4R)-epimer 6%b. Prepared from com-
pound 2 and 3-hydrazino-6-phenylpyridazine (3b), 2 h,
CC (EtOAc); 274 mg (79%) of a white solid; mp
248–256°C; 6b:6%b=92:8. Found: C, 72.51; H, 6.56; N,
16.10. C21H22N4O requires: C, 72.81; H, 6.40; N, 16.17%;
wmax (KBr) 1744 cm−1 (CꢁO); m/z (EI) 346 (M+);
(m/z (HRMS): 346.180050. C21H22N4O requires:
346.179362.).
NMR data for the major (1R,3R,4R)-isomer 6c: 1H NMR
(CDCl3): l 1.07, 1.11 (9H, 2s, 1:2, 3Me); 1.49–1.58
(1H, m, 1H of CH2), 1.70–1.87 (2H, m, 2H of CH2),
1.88–2.02 (1H, m, 1H of CH2), 2.53–2.59 (1H,
m, HꢀC(4)), 4.37 (1H, dd, J=1.5, 4.5 Hz, HꢀC(3)), 7.10
(1H, d, J=9.4 Hz, HꢀC(7%)), 8.08 (1H, d, J=9.8 Hz,
HꢀC(8%)). 13C NMR (CDCl3): l 10.1, 19.7, 20.1, 22.4,
30.3, 46.5, 46.8, 48.0, 59.2, 122.5, 126.9, 143.1, 147.9,
149.7, 213.1.
NMR data for the major (1R,3R,4R)-isomer 6b: 1H NMR
(CDCl3): l 1.09, 1.12, 1.14 (9H, 3s, 1:1:1, 3Me); 1.50–1.60
(1H, m, 1H of CH2), 1.71–1.87 (2H, m, 2H of CH2),
1.91–2.06 (1H, m, 1H of CH2), 2.57–2.63 (1H, m,
HꢀC(4)), 4.52 (1H, dd, J=1.1, 4.5 Hz, HꢀC(3)), 7.52–
7.59 (4H, m, 3H of Ph and HꢀC(7%)), 7.90–7.97 (2H, m,
2H of Ph), 8.17 (1H, d, J=9.4 Hz, HꢀC(8%)). 13C NMR
(CDCl3): l 10.2, 19.7, 20.1, 22.5, 30.3, 46.78, 46.81, 48.2,
59.2, 119.8, 125.5, 127.7, 129.6, 131.3, 134.7, 143.8, 148.0,
153.9, 213.6.
NMR data for the minor (1R,3S,4R)-isomer 6%c: 1H NMR
(CDCl3): l 1.01, 1.07 (6H, 2s, 1:1, 2Me); 2.89 (1H, d,
J=3.8 Hz, HꢀC(4)), 3.90 (1H, s, HꢀC(3)), 7.10 (1H, d,
J=9.4 Hz, HꢀC(7%)), 8.04 (1H, d, J=9.8 Hz, HꢀC(8%)).
Upon repeated crystallisation of 6c/6%c from a mixture
of chloroform and n-heptane, diastereomerically pure
isomer 6c with the following physical data was obtained:
6c:6%c=100:0; mp 180–184°C; [h]2D5=+97.0 (c 0.400,
CHCl3).

U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
831
6.4.4. (1R,3R,4R)-3-[1,2,4-Triazolo[4,3-b]phthalazin-3-
yl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 6d and its
(1R,3S,4R)-epimer 6%d. Prepared from compound 2 and
3-hydrazinophthalazine (3d), 2 h, CC (EtOAc) and
MPLC (ethyl acetate/petroleum ether, 1:1); 195 mg
(61%) of a white solid; mp 223–227°C; 6d:6%d=96:4.
Found: C, 71.20; H, 6.31; N, 17.20. C19H20N4O
requires: C, 71.23; H, 6.29; N, 17.49%; wmax (KBr) 1747
cm−1 (CꢁO); m/z (EI) 320 (M+); (m/z (HRMS):
320.164950. C19H20N4O requires: 320.163711.).
and MPLC (EtOAc); 159 mg (59%) of a white solid;
mp 250–258°C; 6f:6%f=86:14. (Found: C, 66.94; H,
6.70; N, 21.03. C15H18N4O requires: C, 66.64; H, 6.71;
N, 20.73.); wmax (KBr) 1754 cm−1 (CꢁO).
NMR data for the major (1R,3E,4R)-isomer 6f: 1H
NMR (CDCl3): l 1.06, 1.11, 1.14 (9H, 3s, 1:1:1, 3Me),
1.65–2.06 (4H, m, 2CH2), 2.67 (1H, t, J=4.0 Hz,
HꢀC(4)), 4.07 (1H, dd, J=1.3, 4.3 Hz, HꢀC(3)), 7.88
(1H, d, J=4.9 Hz, HꢀC(8%)), 8.18 (1H, dd, J=1.9, 4.9
Hz, HꢀC(6%)), 9.34 (1H, d, J=1.9 Hz, HꢀC(5%)). 13C
NMR (CDCl3): l 10.1 19.5, 20.2, 22.3, 30.5, 46.8, 47.2,
47.7, 59.2, 116.1, 130.0, 144.9, 145.0, 146.0, 213.4.
NMR data for the major (1R,3R,4R)-isomer 6d: 1H
NMR (CDCl3): l 1.07, 1.11, 1.12 (9H, 3s, 1:1:1, 3Me);
1.59–1.87 (3H, m, 3H of CH2), 1.93–2.05 (1H, m, 1H of
CH2), 2.53–2.59 (1H, m, HꢀC(4)), 4.45 (1H, dd, J=1.1,
4.9 Hz, HꢀC(3)), 7.76–7.83 (1H, m, 1H of Ar), 7.89–
7.98 (2H, m, 2H of Ar), 8.59 (1H, s, HꢀC(6%)), 8.64–8.69
(1H, m, 1H of Ar). 13C NMR (CDCl3): l 10.2, 19.7,
20.11; 22.3, 30.3, 46.8, 46.8, 48.3, 59.2, 123.5, 123.6,
124.0, 128.4, 131.1, 134.3, 143.0, 147.7, 148.6, 213.7.
NMR data for the minor (1R,3S,4R)-isomer 6%f: 1H
NMR (CDCl3): l 2.23–2.35 (1H, m, 1H of CH2), 3.44
(1H, d, J=4.1 Hz, HꢀC(4)), 3.61 (1H, s, HꢀC(3)), 8.60
(1H, dd, J=1.5, 4.5 Hz, HꢀC(6%)), 9.30 (1H, d, J=1.5
Hz, HꢀC(5%)). Upon repeated crystallisation of 6f/6%f
from
a
mixture of chloroform and n-heptane,
diastereomerically pure isomer 6f with the following
physical data was obtained: 6f:6%f=100:0; mp 253–
256°C; [h]2D5=−83.0 (c 0.336, CHCl3).
NMR data for the minor (1R,3S,4R)-isomer 6%d: 1H
NMR (CDCl3): l 3.88 (1H, d, J=4.5 Hz, HꢀC(4)), 3.97
(1H, s, HꢀC(3)). Upon repeated crystallisation of 6d/6%d
from
a
mixture of chloroform and n-heptane,
6.4.7. (1R,3R,4R)-3-[5-Chloro-1,2,4-triazolo[4,3-a]pyra-
zin-3-yl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 6g and
its (1R,3S,4R)-epimer 6%g. Prepared from compound 2
and 6-chloro-2-hydrazinopyrazine (3g), 3 h, CC (ethyl
acetate/petroleum ether, 2:1); 182 mg (60%) of a white
solid; mp 243–256; 6g:6%g=97:3. Found: C, 59.31; H,
5.51; N, 18.00. C15H17ClN4O requires: C, 59.11; H,
5.62; N, 18.38%; wmax (KBr) 1748 cm−1 (CꢁO).
diastereomerically pure isomer 6d with the following
physical data was obtained: 6d:6%d=100:0; mp 227–
231°C; [h]2D5=+66.0 (c 0.444, CHCl3).
6.4.5.
(1R,3R,4R)-3-[1,2,4-Triazolo[4,3-a]pyrimidin-3-
yl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 6e and its
(1R,3S,4R)-epimer 6%e. Prepared from compound 2 and
2-hydrazinopyrimidine (3e), 3 h, CC and MPLC
(CHCl3/MeOH, 20:1); 114 mg (42%) of a white solid;
mp 253–258°C; 6e:6%e=92:8. Found: C, 66.86; H, 6.75;
N, 21.02. C15H18N4O requires: C, 66.64; H, 6.71; N,
20.73%; wmax (KBr) 1753 cm−1 (CꢁO).
NMR data for the major (1R,3R,4R)-isomer 6g: 1H
NMR (CDCl3): l 1.08, 1.12 (9H, 2s, 2:1, 3Me), 1.27–
1.42 (1H, m, 1H of CH2), 1.70–1.88 (2H, m, 2H of
CH2), 1.92–2.05 (1H, m, 1H of CH2), 2.53 (1H, t,
J=4.0 Hz, HꢀC(4)), 4.72 (1H, dd, J=1.1, 4.5 Hz,
HꢀC(3)), 7.84 (1H, s, HꢀC(6%)), 9.24 (1H, s, HꢀC(8%)).
13C NMR (CDCl3): l 10.1, 19.8, 19.8, 21.7, 30.0, 46.7,
49.1, 50.67; 59.3, 121.5, 129.8, 143.5, 146.5, 147.5,
212.2.
NMR data for the major (1R,3R,4R)-isomer 6e: 1H
NMR (CDCl3): l 1.03, 1.09, 1.14 (9H, 3s, 1:1:1, 3Me);
1.54–1.67 (1H, m, 1H of CH2), 1.75–1.87 (1H, m, 1H of
CH2), 1.89–2.04 (1H, m, 1H of CH2), 2.25–2.36 (1H, m,
1H of CH2), 2.73 (1H, t, J=4.3 Hz, HꢀC(4)), 4.06 (1H,
dd, J=1.5, 4.5 Hz, HꢀC(3)), 6.88 (1H, dd, J=3.8, 7.2
Hz, HꢀC(6%)), 8.65 (1H, dd, J=1.9, 3.8 Hz, HꢀC(7%)),
8.74 (1H, dd, J=1.9, 7.2 Hz, HꢀC(5%)). 13C NMR
(CDCl3): l 10.1, 19.5, 20.2, 22.3, 30.6, 46.7, 47.5, 47.6,
59.3, 109.8, 132.2, 143.3, 154.2, 154.4, 214.2.
NMR data for the minor (1R,3S,4R)-isomer 6%g: 1H
NMR (CDCl3): l 3.07 (1H, d, J=4.2 Hz, HꢀC(4)), 3.61
(1H, s, HꢀC(3)). Upon repeated crystallisation of 6g/6%g
from
a
mixture of chloroform and n-heptane,
diastereomerically pure isomer 6g with the following
physical data was obtained: 6g:6%g=100:0; mp 245–
251°C; [h]2D5=+237.0 (c 0.430, CH2Cl2).
NMR data for the minor (1R,3S,4R)-isomer 6%e: 1H
NMR (CDCl3): l 0.81, 0.97, 1.10 (9H, 3s, 1:1:1, 3Me);
3.44 (1H, d, J=4.2 Hz, HꢀC(4)), 3.57 (1H, s, HꢀC(3)),
8.62 (1H, dd, J=1.9, 3.8 Hz, HꢀC(7%)), 9.01 (1H, dd,
J=1.9, 7.2 Hz, HꢀC(5%)). Upon repeated crystallisation
of 6e/6%e from a mixture of chloroform and n-heptane,
diastereomerically pure isomer 6e with the following
physical data was obtained: 6e:6%e=100:0; mp 255–
258°C; [h]2D5=−147.6 (c 0.245, CHCl3).
6.5. (1R,3R,4R)-3-[1,2,4-Triazolo[1,5-a]pyrimidin-2-yl]-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 7 and its
(1R,3S,4R)-epimer 7%
A solution of sodium methoxide in methanol (0.82 M,
1 mL) was added to a solution of diastereomerically
pure 6e (200 mg, 0.74 mmol) in methanol (7 mL) and
the mixture was refluxed for 20 min. A solution of
sodium methoxide in methanol (0.82 M, 1 mL) was
added and the reaction mixture was heated under reflux
for 30 min. The reaction mixture was cooled, neu-
tralised with a solution of acetic acid (100%, 1 mL) in
6.4.6. (1R,3R,4R)-3-[1,2,4-Triazolo[4,3-a]pyrazin-3-yl]-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 6f and its
(1R,3S,4R)-epimer 6%f. Prepared from compound 2 and
2-hydrazinopyrazine (3f), 3 h, CC (CHCl3/MeOH, 20:1)

832
U. Grosˇelj et al. / Tetrahedron: Asymmetry 13 (2002) 821–833
methanol (6 mL), and evaporated in vacuo. The residue
was purified by CC (EtOAc). Fractions containing the
product were combined and evaporated in vacuo to
give a mixture of 7 and 7%, which was characterised by
(150 K). At low temperature it became obvious that the
lattice is in fact primitive and there are indeed four
molecules in the asymmetric unit. In the case of com-
pound 5c the presence of the centre of inversion was
excluded by the argument stated above as well as by a
final successful refinement in the space group P1, which
clearly showed that the chiral parts of the two
molecules are equal and can not be related by the
centre of inversion. In other cases there were no special
issues that would require comments. The plots of the
final refined contents of the asymmetric units of com-
pounds 2, 5c, 6b, 6c, 6e, and 7 are presented in Figs.
2–7.
1
spectral (IR, H NMR, and 13C NMR) and elemental
analyses. Yield: 110 mg (55%) of a white solid; 7:7%=
96:4; mp 190–200°C; [h]2D1=+103.9 (c 0.440, CH2Cl2).
Found: C, 66.88; H, 6.64; N, 21.05. C15H18N4O
requires: C, 66.64; H, 6.71; N, 20.73%; wmax (KBr) 1744
cm−1 (CꢁO).
NMR data for the major (1R,3R,4R)-isomer 7: 1H
NMR (DCCl3): l 1.04, 1.08 (9H, 2s, 2:1, 3Me), 1.40–
1.56 (1H, m, 1H of CH2), 1.64–1.84 (3H, m, 3H of
CH2), 2.60 (1H, t, J=4.0 Hz, HꢀC(4)), 4.12 (1H, dd,
J=1.1, 4.9 Hz, HꢀC(3)); 7.08 (1H, dd, J=4.1, 6.8 Hz,
HꢀC(6%)), 8.79 (1H, dd, J=1.9, 4.1 Hz, HꢀC(8%)), 8.82
(1H, dd, J=1.9, 6.8 Hz, HꢀC(5%)). 13C NMR (CDCl3):
l 10.1, 19.6, 20.0, 22.2, 30.3, 46.5, 49.2, 51.3, 59.3,
110.3, 136.1, 154.8, 156.0, 167.2, 214.9.
Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre.39
Acknowledgements
NMR data for the minor (1R,3S,4R)-isomer 7%: 1H
NMR (CDCl3): l 3.11 (1H, d, J=4.2 Hz, HꢀC(4)), 3.54
(1H, s, HꢀC(3)).
The financial support from the Ministry of Education,
Science and Sport, Slovenia, through grant PS-0502-
0103, is gratefully acknowledged. The authors wish to
express their gratitude to the Alexander von Humboldt
Foundation, Germany, for the donation of a Bu¨chi
medium-pressure liquid chromatograph. Crystallo-
graphic data were collected on the Kappa CCD Nonius
diffractometer in the Laboratory of Inorganic Chem-
istry, Faculty of Chemistry and Chemical Technology,
University of Ljubljana, Slovenia. We acknowledge
with thanks the financial contribution of the Ministry
of Education, Science and Sport, Republic of Slovenia
through grant Packet X-2000 and PS-511-102, which
thus made the purchase of the apparatus possible.
6.6. X-Ray structure analysis for compounds 2, 5c,
6b,c,e, 7
The crystal structures of compounds 2, 5c, 6b, 6c, 6e,
and 7 were determined. Single crystal X-ray diffraction
data were collected at room temperature on a Nonius
Kappa CCD diffractometer using the Nonius Collect
Software.34 Indexing and scaling of the data were per-
formed using DENZO and SCALEPACK.35 Structures
were solved by means of SIR-92,36 while the refinement
and plotting were carried out using the Xtal3.437 pro-
gram package. Refinement was carried out on F by a
full-matrix least-squares procedure. In all cases the
non-hydrogen atoms were refined anisotropically while
the hydrogen atoms were geometrically restrained (rid-
ing) and their isotropic atomic displacement parameters
(ADP) were not refined. These values were set to 1.5
times the isotropic ADP of methyl carbon atoms to
which the H atoms were bound and to 1.2 times of the
ADP of the ‘carrying’ atoms in other cases. Absorption
correction was not performed. The weighting scheme in
all cases was Regina.38
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