Asymmetric catalysis; 140:1 tris(2-pyridyl)methane derivatives with a chiral bridging atom

Article abstract of DOI:10.1055/s-2001-18716

Two different series of C₁-symmetric tris(2-pyridyl)methane tripod ligands were synthesized with pyridin-2-yl, 6-phenylpyridin-2-yl and 6-methoxy- or 6-menthyloxypyridin-2-yl substitutents. The menthoxy devivatives were resolved with respect to

Full text of DOI:10.1055/s-2001-18716

2484
PAPER
Asymmetric Catalysis; 140:1 Tris(2-pyridyl)methane Derivatives with a Chiral
Bridging Atom
140:
T
ris(2-pyridy
e
l)methane
D
n
erivatives
w
r
ith
a
C
h
i
iral Bridging
B
Atom runner,* Reinhard J. Maier, Manfred Zabel2
Institut für Anorganische Chemie, Universität Regensburg, D-93040 Regensburg, Germany
Fax +49(941)9434439; E-mail: henri.brunner@chemie.uni-regensburg.de
Received 19 July 2001; revised 7 September 2001
trogen ligands which coordinate facially to transition met-
Abstract: Two different series of C1-symmetric tris(2-py-
ridyl)methane tripod ligands were synthesized with pyridin-2-yl, 6-
phenylpyridin-2-yl and 6-methoxy- or 6-menthyloxypyridin-2-yl
substitutents. The menthoxy devivatives were resolved with respect
als. Their analogues are tris(2-pyridyl) compounds, in
which the bridging atom can be carbon, nitrogen, phos-
phorus or arsenic.6 There are major differences between
to the bridging carbon atom by chromatography. In reactions with tris(pyrazolyl)borate and tris(2-pyridyl)methane tripods.
CuCl2 and RhCl3 complexes were obtained which could be ana-
The tris(pyrazolyl)borates are monoanionic, whereas the
lyzed by X-ray crystallography. In the formation of the Rh complex
tris(2-pyridyl)methane ligands are neutral. Furthermore,
an ortho-metallation of the 6-phenyl substituent occurred giving
pyridine is more basic than pyrazole, thus it should be a
rise to a / -element of chirality. Whereas the chiral tripod ligand
better -donor and it is reported to be a better -acceptor
conferred a stable configuration to the Rh atom, a fast equilibration
of the - and -isomers was observed.
than pyrazole.7 Chiral C3-symmetric tris(pyra-
zolyl)borates8 and tris(2-pyridyl)methane derivatives9 are
Key words: chiral tripod ligands, tris(2-pyridyl)methane deriva-
tives, Cu-complex, Rh-complex, ortho-metallation, absolute con-
figuration
known, but only few C1-symmetric tripods are mentioned
in the literature10 and no C1-symmetric tris(2-pyridyl) de-
rivatives have been reported. Therefore, we synthesized
tris(2-pyridyl) derivatives, in which a carbon atom bridges
three different pyridine substituents, an unsubstituted 2-
Introduction
pyridine, a 6-methoxy- or 6-menthoxy-substituted 2-pyri-
dine and a 6-phenyl-substituted 2-pyridine.11 Some of the
compounds were resolved with respect to the configura-
tion of the bridging carbon atom.11 As in a facial coordi-
nation, a tripod ligand with a chiral bridging atom confers
chirality to the metal centre, this stereochemical aspect
was investigated in Cu and Rh complexes.11 According to
a concept recently presented in this journal,12 chiral C1-
symmetric tris(2-pyridyl) ligands should provide enanti-
There are two different types of tridentate ligands. Either
the ligand is flat and coordinates in a mer-fashion at an oc-
tahedron or the ligand is tripodal and coordinates in a fac-
fashion at an octahedron. Chiral examples are the pybox
ligand introduced by Nishiyama et al.3 (mer-type) and the
trisphosphane ligands of Burk et al.4 and Huttner et al.5
(fac-type). Tris(pyrazolyl)borates are well known trisni-
Scheme 1 (a) CH3ONa, CH3OH, reflux/ (1R,2S,5R)-(–)-menthol, NaH, 90 °C; (b) n-BuLi, THF, –60 °C/ n-BuLi, THF, –78 °C; (c) 1. CH3OH,
–78 °C r.t., 2. H2O, HCl, 3. K2CO3.
Synthesis 2001, No. 16, 30 11 2001. Article Identifier:
1437-210X,E;2001,0,16,2484,2494,ftx,en;Z08301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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Tris(2-pyridyl)methane Derivatives with a Chiral Bridging Atom
2485
oselective catalysts, in which the configuration at the met-
al atom is held constant throughout the catalysis.
Racemic Tris(2-pyridyl)methane Derivatives
For the preparation of tris(2-pyridyl)methane derivatives
with a chiral branching atom the commercially available
2-phenylpyridine was converted into 2-bromo-6-phe-
nylpyridine via 2-amino-6-phenylpyridine.13 The ketone 3
was accessible by addition of the lithiopyridine derivative
obtained from 2-bromo-6-phenylpyridine to pyridine-2-
carbonitrile. After a lithium-bromine exchange in 2-bro-
mo-6-methoxypyridine14 2 (prepared from 2,6-dibro-
mopyridine 1) the resulting organometallic compound 4
Figure 1
was added to the ketone 3 to give the racemic tris(2-py- one diastereomer. Therefore, the alcohol functionality
ridyl)methanol derivative 5 (Scheme 1).
was separated from the bridgehead atom by a methylene
group. The alcohol 5 was transformed to the bromide 8 by
deprotonation with n-BuLi and reaction with thionyl bro-
mide. Lithium-bromine exchange and reaction with
paraformaldehyde gave the 2,2,2-tris(2-pyridyl)ethanol
derivative 9 with 79% yield (Scheme 2).
For the resolution of rac-5 the formation of diastereomer-
ic salts with the chiral acids (1S)-(+)-camphorsulfonic ac-
id,
(2R,3R)-(+)-tartaric
acid,
(2R,3R)-(–)-
dibenzoyltartaric acid, (R)-(–)-mandelic acid, (S)-(–)-
malic acid and (R)-(+)-4-(2-chlorophenyl)-2-hydroxy-
5,5-dimethyl-1,3,2-dioxophosphorane-2-oxide was at- The ethanol derivative 9 could be transformed to the tosy-
tempted without success.11 Therefore, the chiral auxilia- late 10. Surprisingly, the reaction of 10 with sodium meth-
ries were covalently bound to 5 by esterification with oxide in methanol did not liberate the alcohol 9 but
(1R,2S,5R)-menthoxy- and (1S,2R,4S)-borneoxyacetic afforded the methane derivative 11 in 84% yield
acid, respectively. These acids were prepared and trans- (Scheme 3). Carboxylates including (1R,2S,5R)-men-
formed to the acid chlorides according to literature thoxyacetate and (1S,2R,4S)-borneoxyacetate gave the
methods15,16 and reacted with deprotonated 5 (n-butyllith- same product, as did alkoxides (e.g. sodium menthoxide)
ium) to give 81% and 54% of the diastereomeric esters 6 and sodium hydride in toluene at 70 °C. In the literature
and 7, respectively (Figure 1).
such a loss of formaldehyde has been reported for 2,2,2-
trisphenylethanol but not for the analogous trispyridineth-
anol.17,18 The conversion of the ethyl alcohol 9 to the cor-
responding ethyl bromide derivative could be performed
by refluxing in a solution of thionyl bromide in chloro-
form.11
The esters 6 and 7 were obtained as 1:1 mixtures of dias-
tereomers differing in the configuration of the branching
carbon atom of the tris(2-pyridyl)methane moiety. They
are crystalline substances, which could be recrystallized
from petroleum ether and diisopropyl ether. However, re-
peated recrystallizations did not result in an enrichment of
Scheme 2 (a) 1. n-BuLi, THF, r.t., 2. SOBr2, –70 °C r.t.; (b) 1. n-BuLi, Et2O, –90 °C, 2. paraformaldehyde, –90 °C r.t., 3. H2O.
Scheme 3 (a) TsCl, py, r.t., 60 h; (b) CH3ONa, CH3OH, reflux, 14 h.
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H. Brunner et al.
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For both alcohols 14 and 18 the diastereomers could be
Diastereomeric Tris(2-pyridyl)methane Derivates
enriched by chromatography, but only the butanol deriva-
Another possibility for the formation of diastereomeric tive 18 was used subsequently, because it was configura-
tris(2-pyridyl)methane derivatives is to introduce one py- tionally stable at the branching carbon atom. Repeated
ridyl group, which is substituted with a chiral substituent. chromatography of 18 on silica gel gave a 95:5 enrich-
The (1R,2S,5R)-menthyl group was chosen for this pur- ment of the faster moving diastereomer. An X-ray analy-
pose. (1R,2S,5R)-Menthol was deprotonated with sodium sis of a rhodium complex of 18 (see below) allowed the
hydride and reacted with 2,6-dibromopyridine 1 to afford assignment of (S)-configuration at the bridging atom of
the menthoxy substituted bromopyridine 12 in 83% yield. the faster moving isomer. The propyl substituent with its
After lithium-bromine exchange in 12 to give 13, reaction terminal OH group at the end in 18 has two major advan-
with the ketone 3 gave the tris(2-pyridyl)methanol deriv- tages. First, 18 can be modified to adjust the solubility
ative 14 (Scheme 1). The diastereomers of 14 are formed without changing the complexation properties of the
as a 1:1 mixture. By repeated chromatography on silica tris(2-pyridyl) moiety, and second, the ligand can be het-
gel it was possible to enrich the faster moving isomer to a erogenized by covalent binding to a solid phase.
ratio of 98:2.
The alcohol 14 is the key intermediate for the subsequent
syntheses. Deprotonation of 14 with sodium hydride fol-
Metal Complexes
lowed by addition of methyl iodide gave the methyl ether
From the racemic methane derivative 11 the CuCl2 com-
15. In this reaction no epimerization took place since the
plex 19 was prepared in methanol in 72% yield. Exclusion
diastereomeric excess of 14 was retained in 15. The con-
of air is important, because the literature reports an exam-
version of the alcohol 14 to the bromomethane 16 was
performed with thionyl bromide. As the diastereomeric
excess of the alcohol 14 was almost completely lost in the
ple in which a methane derivative was air-oxidized to the
corresponding methanol derivative.20 Diffusion of ether
into a methanolic solution of 11 and CuCl2 gave green
reaction to the bromide 16 a SNi retention mechanism
crystals of 19 suitable for X-ray analysis. In addition to
must be excluded. White and Faller proposed either a SN2
the two chloride ligands the copper(II) centre is chelated
or a SN1 mechanism for the halogenation of tris(2-py-
by ligand 11 in a bidentate way (Figure 2). Copper(II)
ridyl)methanol with SOX2 (X = Br, Cl).19 The reaction of
16 with n-BuLi led to an organometallic intermediate
which could either be hydrolyzed with water to give the
methane derivative 17 (73%) or treated with oxetane in
the presence of an equimolar amount of BF3 OEt2 to pro-
vide the 4,4,4-tris(2-pyridyl)butan-1-ol derivative 18 with
complexes in which a tris(2-pyridyl)methane derivative
coordinates as a tripod ligand are also known.20,21 The un-
coordinated methoxy-substituted pyridine ring is rotated
by 28° relative to the Cu1-C12-C13 plane. The structure
can be described as distorted square planar. In the unit cell
there are two pairs of enantiomers.
56% yield (Scheme 4).
Scheme 4 (a) 1. NaH, DMF, r.t. 2 h, 2. CH3I, r.t.; (b) 1. n-BuLi, Et2O, –78 °C; 2. SOBr2, –78 °C à r.t., 3. NaHCO3; (c) 1. n-BuLi, Et2O, –90 °C
r.t., 2. H2O; (d) 1. n-BuLi, Et2O, –90 °C, 2. oxetane, BF3 OEt2, –90 °C r.t., 3. H2O, HCl, 4. K2CO3.
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Tris(2-pyridyl)methane Derivatives with a Chiral Bridging Atom
2487
Figure 3 Schematical representation of all possible diastereomers
of 20.
Figure 2 ORTEP representation (50% probability) of 19. Selected
distances [Å] and angles [°]: Cu1-Cl1 2.24, Cu1-Cl2 2.27, Cu1-N1
2.03, Cu1-N3 2.03, Cl1-Cu1-Cl2 94, Cl1-Cu1-N1 93, Cl1-Cu1-N3
161, Cl2-Cu1-N1 155, Cl2-Cu1-N3 95, N1-Cu1-N3 87.
1
ing the crystals at –25 °C in DMF-d7 the H NMR spec-
trum indicated a 98.4:1.6 distribution. The ratio shifted to
97.8:2.2 at 0 °C and to 96.8:3.2 at 21 °C. Recooling to
–25 °C brought the ratio back to 98.4:1.6. Heating the so-
lution to 50 °C gave an increase of the less abundant dias-
tereomer to 3.6%. Further heating to about 80 °C caused a
reversible broadening of the signals. However, at this tem-
perature the H NMR spectrum started to show irrevers-
ible changes. This temperature-sensitive equilibration is
assigned to the interconversion of the / -helicity.
The rhodium complex 20 was synthesized from rhodi-
um(III) chloride trihydrate and the butanol derivative 18
in ethanol. If a 65:35 mixture of the two diastereomers of
18 (the faster moving diastereomer in excess) is used, the
1H NMR spectrum of the complex 20 exhibits four signals
with the chemical shifts in DMSO-d6 of 9.25, 9.32, 9.55
and 9.62 ppm (integration 62:32:2:4) for the downfield
proton py-H6. This means that in solution four diastere-
omers are present. The X-ray analysis of 20 (see below)
shows that in its formation an ortho-metallation has taken
place. In addition to the two asymmetric centres (bridge-
head atom of the ligand and metal atom) the ortho-metal-
lation establishes a new element of chirality. The ortho-
metallation can occur at two different coordination sites,
which define a right-handed helix ( ) and a left-handed
helix( ), respectively. In Figure 3 the four possible dias-
tereomeric complexes are drawn schematically together
with their configurational symbols starting with the asym-
metric centre in the ligand. Provided that the specification
of the metal chirality is based on the nitrogen atoms of the
pyridine ligands in their respective priority, the metal has
the opposite configuration compared to the bridgehead
carbon atom.
1
Single crystals suitable for X-ray analysis were obtained
from a concentrated solution of 20 in DMSO on standing
in an open vessel (anhydrous DMSO is hygroscopic). An
ORTEP representation of the complex 20, which has the
configuration (SC,RRh, Rh), is shown in Figure 4. Three
crystals were measured and gave the same result. As a 1H
NMR study of the single crystals at r.t. gave an isomer ra-
tio of 97:3, we assign the (SC,RRh, Rh)-configuration to
the 97% isomer (chemical shift in DMSO-d6 9.25 ppm) in
the 97:3 mixture (identical with the 62% isomer in the
62:32:2:4 mixture) and we assume its rapid equilibration
in solution with the (SC,RRh, Rh)-isomer (9.55 ppm). Then
the 32% isomer (9.32 ppm) in the 62:32:2:4 mixture
should be the (RC,SRh, Rh)-isomer and the 4% isomer
(9.62 ppm) should have (RC,SRh, Rh)-configuration.
For the separation of the main diastereomer, the 62:32:2:4
mixture of 20 was dissolved in DMSO (gentle warming).
Then the solvent was distilled off in vacuo without warm-
ing above 50 °C, because at higher temperatures the com-
plex reacts with the solvent,11 until first crystals appeared.
After standing for a few days at r.t. the crystals were fil-
tered off. 1H NMR experiments in DMF-d7 showed at r.t.
a ratio of 96.8:3.2 (only two isomers present). On dissolv-
20 has a distorted octahedral structure, in which the Rh-Cl
and Rh-C bond lengths are in agreement with comparable
rhodium complexes.22 However, the Rh-N bonds differ
considerably (1.98, 2.08 and 2.19 Å), whereas in the
tris(2-pyridyl)methanol-RhCl3 complex the lengths vary
only between 2.03 and 2.05 Å.22a This means that the
ortho-metallation has a significant influence on the Rh-N
distances. The bond Rh1-N2 is shortened because of the
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H. Brunner et al.
PAPER
five-membered chelate ring. In contrast, the bond Rh1-N3
is elongated as a result of the strong trans-effect of the
phenyl substituent. These distortions also affect the Rh1-
N1 bond. Surprisingly the bond Rh1-N2 is shorter than
Rh1-C1.22b In the unit cell there are 6 molecules of the
complex. The space group is P 61 and the crystal system
hexagonal. At the edges of the unit cells along the c axis
channels are formed, in which solvent molecules reside in
a disordered manner. In Figure 5 six molecules of
(SC,RRh, Rh)-20 are shown in their arrangement around
the channel along the c axis. On the left, the left-handed
sense of the helix is obvious from the numbers 1–6. On the
right, the side view is represented.
The preparation of air-sensitive compounds was carried out under
purified N2 using standard Schlenk techniques. Solvents were dried
and degassed according to standard procedures and stored under N2.
Commercial starting materials were used without further purifica-
tion. For the chromatographies Merck Geduran® 60 silica gel (63–
200 m) was used. Reaction mixtures and chromatography frac-
tions were analyzed with precoated silica gel 60 F254 TLC plates
(Merck). Melting points: SMP-20 (Büchi), not corrected. MS: MAT
311A (EI), MAT 95 (DCI) (both Finnigan) and TSQ 7000 (ESI)
(ThermoQuest). Optical rotations: Perkin-Elmer 241 polarimeter (1
dm cells). IR spectra: Acculab 3 (Beckman). 1H NMR: AC250 (250
MHz) and ARX400 (400 MHz) (both Bruker), internal standard
TMS. 13C NMR: ARX400 (1H decoupled, 101 MHz, Bruker).
Figure 4 ORTEP representation (50% probability) of (SC,RRh, Rh)-
20. Selected distances [Å] and angles[°]: Rh1-Cl1 2.35, Rh1-Cl2
2.36, Rh1-C1 2.00, Rh1-N1 2.08, Rh1-N2 1.98, Rh1-N3 2.19, Cl1-
Rh1-Cl2 89, Cl1-Rh1-N2 92, Cl1-Rh1-N3 88, Cl1-Rh1-N1 171, Cl1-
Rh1-C1 84, Cl2-Rh1-N2 177, Cl2-Rh1-N3 91, Cl2-Rh1-C1 97, N1-
Rh1-C1 103, N2-Rh1-N3 92, N2-Rh1-N1 84, N2-Rh1-C1 81, N3-
Rh1-N1 85, N3-Rh1-C1 168.
The following compounds were synthesized according to the litera-
ture: 2-Amino-6-phenylpyridine,13 2-bromo-6-phenylpyridine,13 2-
bromo-6-methoxypyridine (2),14 [(1R,2S,5R)-2-isopropyl-5-meth-
ylcyclohexyloxy]acetic acid,15 [(1S,2R,4S)-1,7,7-trimethyl-bicyc-
lo[2.2.1]hept-2-yloxy]acetic acid.16 n-Butyllithium was used as a
Figure 5 Complex 20: a top view (along the c axis), b side view (along the b axis)
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Tris(2-pyridyl)methane Derivatives with a Chiral Bridging Atom
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1.6 M solution in hexane (Merck). The acronym PE for petroleum
ether (bp 40–60 °C) will be used. In the 1H NMR data the abbrevi-
ation py designates the unsubstituted pyridine ring, py' the meth-
oxy- or menthoxy-substituted ring and py'' the phenyl-substituted
ring.
(6-Methoxypyridin-2-yl)(6-phenylpyidin-2-yl)pyridin-2-ylme-
thyl [(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy]acetate (6)
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxyacetic acid (5.36 g,
25.0 mmol) was cooled to 0 °C and thionyl chloride (8.7 mL, 14 g,
0.12 mol) was added. The mixture was refluxed for 5 h. After cool-
ing the solution was submitted to a Kugelrohr distillation (bp
100 °C/1 mbar) yielding the acid chloride as a colorless oil, which
was kept under N2 and directly used for the following esterification.
(6-Phenylpyridin-2-yl)(pyridin-2-yl)methanone (3)
To a suspension of 2-bromo-6-phenylpyridine (25.2 g, 107 mmol)
in anhyd Et2O (500 mL) was added n-BuLi (72 mL, 115 mmol, 1.6
M in hexane) within 1 h at –78 °C. The mixture was allowed to
warm to r.t. (clear orange solution). The solution was cooled to
–78 °C and a solution of 2-cyanopyridine (11.7 g, 112 mmol) in an-
hyd Et2O (150 mL) was added over a period of 45 min. The mixture
was allowed to warm to r.t. and poured into ice water (500 mL). HCl
(2 M, 150 mL) was added and the solution stirred vigorously. After
separation of the phases the organic phase was extracted with HCl
(2 M, 3 100 mL). The combined aq phases were refluxed for 2 h
and carefully neutralized at r.t. with solid K2CO3. The resulting sus-
pension was extracted with CH2Cl2 (5 50 mL). The combined or-
ganic extracts were dried (Na2SO4) and evaporated. The residue was
chromatographed through silica gel (6 cm 6 cm ) with CH2Cl2–
Et2O (1:1) and recrystallized from PE–acetone (10:1) to give 3 (11.3
g, 41%) as pale pink needles; mp 90–92 °C.
A cooled solution (0 °C) of the alcohol 5 (7.39 g, 20.0 mmol) in
THF (40 mL) was deprotonated by addition of n-BuLi (12.5 mL,
20.0 mmol, 1.6 M in hexane) over a period of 15 min. After stirring
for 15 min a solution of the acid chloride (see above) in THF (25
mL) was added within 20 min. The mixture was warmed to 40 °C
and stirred for 24 h. The cooled solution was quenched with H2O (2
mL) and washed with sat. aq NaCl (3 20 mL), dried (Na2SO4) and
evaporated. The residue was recrystallized from diisopropyl ether to
give 6 (9.62 g, 81%) as colorless crystals; mp 65–68 °C. All at-
tempts at enriching one diastereomer by recrystallization failed.
Analytical data for a 1:1 mixture of the two diastereomers:
[ ] (c = 0.5, n-hexane, r.t.): –40.1 (589 nm), –41.9 (578 nm), –47.7
(546 nm), –80.0 (436 nm), –125 (365 nm).
1H NMR (250 MHz, CDCl3): The signals were not assigned to the
1H NMR (250 MHz, CDCl3): = 8.80 (ddd, 1 H, 3J = 4.8 Hz,
4J = 1.8 Hz, 5J = 0.9 Hz, py-H6), 8.17 (ddd, 1 H, 3J = 7.8 Hz,
4J = 1.2 Hz, 5J = 1.0 Hz, py-H3), 8.10–7.91 (m, 5 H), 7.89 (ddd, 1 H,
3J = 7.8 Hz, 3J = 7.6 Hz, 4J = 1.8 Hz, py-H4), 7.50 (ddd, 1 H,
different diastereomers.
= 8.53 (ddd, 1
H; 3J = 4.8 Hz,
4J = 1.8 Hz, 5J = 0.9 Hz, py-H6), 8.53 (ddd, 1 H, 3J = 4.8 Hz,
4J = 1.8 Hz, 5J = 0.9 Hz, py-H6), 7.88–7.77 (m, 8 H), 7.72 (dd, 1 H,
3J = 7.8 Hz, 3J = 7.7 Hz, py''-H4), 7.72 (dd, 1 H, 3J = 7.8 Hz,
3J = 7.7 Hz, py''-H4), 7.64 (ddd, 1 H, 3J = 8.1 Hz, 3J = 7.4 Hz,
4J = 1.8 Hz, py-H4), 7.64 (ddd, 1 H, 3J = 8.1 Hz, 3J = 7.4 Hz,
4J = 1.8 Hz, py-H4), 7.60 (dd, 1 H, 3J = 7.6 Hz, 4J = 1.2 Hz, py''-H3/
5), 7.60 (dd, 1 H, 3J = 7.6 Hz, 4J = 1.2 Hz, py''-H3/5), 7.55 (dd, 2 H,
3
4
3J = 7.6 Hz, J = 4.8 Hz, J = 1.2 Hz, py-H5), 7.48–7.37 (m, 3 H,
Ph).
IR (KBr): 1660s (C=O) cm–1.
MS (PI-EI, 70 eV): m/z (%) = 260 (M, 100), 232 (M–CO, 38), 231
(M–CO–H, 85), 154 (M–pyCO, 36), 127 (M–pyCO–HCN, 34), 78
(C5H4N, 41), 51 (C4H3, 12).
3
3J = 8.1 Hz, J = 7.5 Hz, py'-H4), 7.43–7.30 (m, 8 H), 7.15 (ddd, 2
H, 3J = 7.4 Hz, 4J = 4.8 Hz, 5J = 1.2 Hz, py-H5), 6.60 (dd, 2 H,
3J = 8.1 Hz, 4J = 0.8 Hz, py'-H5), 4.51 (AB, 1 H, 2J = 16.2 Hz,
OCHAHB), 4.50 (AB, 1 H, 2J = 16.2 Hz, OCHAHB), 4.45 (AB, 1 H,
Anal calcd for C17H12N2O (260.3): C, 78.44; H, 4.65; N, 10.76.
Found: C, 78.39; H, 4.70; N, 10.76.
2
2J = 16.2 Hz, OCHAHB), 4.45 (AB, 1 H, J = 16.2 Hz, OCHAHB),
3.71 (s, 6 H, OCH3), 3.18 (dt, 1 H, 3J = 10.5 Hz, 3J = 2.1 Hz, OCH),
3.17 (dt, 1 H, 3J = 10.5 Hz, 3J = 2.2 Hz, OCH), 2.37 2.24 (m, 2 H),
2.15 2.04 (m, 2 H), 1.67 1.55 (m, 4 H), 1.34 1.15 (m, 4 H), 1.03
0.73 (m, 6 H), 0.87 (d, 3 H, 3J = 6.5 Hz, CH3), 0.86 (d, 3 H,
(6-Methoxypyridin-2-yl)(6-phenylpyridin-2-yl)pyridin-2-ylme-
thanol (5)
A solution of 2 (8.22 g, 43.0 mmol) in anhyd THF (50 mL) was
cooled to –75 °C and n-BuLi (29 mL, 46 mmol, 1.6 M in hexane)
was added within 30 min. The resulting solution of 4 was cooled to
–85 °C and a solution of 3 (10.4 g, 40.0 mmol) in THF (90 mL) was
added over a period of 2 h. After stirring for 15 min at –80 °C
MeOH (55 mL, 43 g, 1.3 mol) was added. The mixture was allowed
to warm to r.t. and acidified with HCl (2 M, 200 mL). The organic
solvents were removed and the aq residue was made alkaline with
NaOH (6 M). The resulting emulsion was extracted with Et2O (4
50 mL). After washing the combined ethereal solutions with water
(2 50 mL), the organic solution was dried (Na2SO4) and evaporat-
ed to give the crude product, which was recrystallized from Et2O.
Colorless crystals of 5 (9.32 g, 63%); mp 92–94 °C.
3
3J = 6.5 Hz, CH3), 0.85 (d, 6 H, J = 7.1 Hz, CH3), 0.70 (d, 3 H,
3J = 6.9 Hz, CH3), 0.69 (d, 3 H, 3J = 6.9 Hz, CH3).
IR (KBr): 1775s (C=O) cm–1.
MS (PI-EI 70 eV) m/z (%): 565 (M, 0.6), 368 (M–menOCH2CO,
11), 352 (M–menOCH2COO, 100), 337 (M–menOCH2CO–OCH3,
6), 245 (M–menOCH2COO–C5H3NOCH3+H, 7)
Anal calcd for C35H39N3O4 (565.7): C, 74.31; H, 6.95; N, 7.43.
Found: C, 74.03; H, 6.96; N, 7.36.
(6-Methoxypyridin-2-yl)(6-phenylpyidin-2-yl)pyridin-2-ylme-
thyl [(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yloxy]ace-
tate (7)
This compound was prepared by a method analogous to that used
for 6. Thus, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yloxy-
acetic acid (1.33 g, 6.25 mmol) and 5 (1.26 g, 3.4 mmol) gave the
product 7. Recrystallization from pentane yielded colorless crystals
of 7 (1.03 g, 54%); mp 104–109 °C. No enrichment of a diastere-
omer could be achieved by recrystallization.
1H NMR (250 MHz, CDCl3): = 8.55 (ddd, 1 H, 3J = 4.9 Hz,
4J = 1.8 Hz, 5J = 1.0 Hz, py-H6), 7.98–7.92 (m, 2 H, Ph), 7.78 (ddd,
1 H, 3J = 8.0 Hz, 4J = 1.2 Hz, 5J = 1.0 Hz, py-H3), 7.79–7.62 (m, 3
3
3
4
H, py''), 7.66 (ddd, 1 H, J = 8.0 Hz, J = 7.4 Hz, J = 1.8 Hz, py-
H4), 7.57 (dd, 1 H, 3J = 8.2 Hz, 3J = 7.4 Hz, py'-H4), 7.47–7.34 (m,
3 H, Ph), 7.33 (s br, 1 H, OH), 7.32 (dd, 1 H, 3J = 7.4 Hz,
4J = 0.8 Hz, py'-H3), 7.18 (ddd, 1 H, 3J = 7.4 Hz, 3J = 4.9 Hz,
4J = 1.3 Hz, py-H5), 6.62 (dd, 1 H, 3J = 8.2 Hz, 4J = 0.8 Hz, py'-H5),
3.74 (s, 3 H, CH3).
Analytical data for a 1:1 mixture of the two diastereomers:
[ ] (c = 0.54, CH2Cl2, r.t.): –27.0 (589 nm), –27.0 (578 nm), –32.0
MS (PI-EI, 70 eV) m/z (%): 369 (M, 71), 291 (M–C5H4N, 41), 261
(M–C5H3NOCH3, 100), 215 (M–C5H3NPh, 59), 154 (C5H3NPh,
31), 108 (C5H3NOCH3, 12), 78 (C5H4N, 35).
(546 nm), –58.1 (436 nm), –101 (365 nm).
1H NMR (250 MHz, CDCl3): The signals were not assigned to the
different diastereomers.
= 8.53 (ddd, 1
H, 3J = 4.8 Hz,
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 8.53 (ddd, 1 H, 3J = 4.8 Hz,
Anal calcd for C23H19N3O2 (369.4): C, 74.78; H, 5.18; N, 11.37.
Found: C, 74.66; H, 5.19; N, 11.31.
Synthesis 2001, No. 16, 2484–2494 ISSN 0039-7881 © Thieme Stuttgart · New York

2490
H. Brunner et al.
PAPER
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 7.88–7.79 (m, 8 H), 7.72 (dd, 2 H,
3J = 7.9 Hz, 3J = 7.6 Hz, py''-H4), 7.65 (ddd, 2 H, 3J = 8.1 Hz,
3J = 7.4 Hz, 4J = 1.9 Hz, py-H4), 7.59 (dd, 2 H, 3J = 7.7 Hz,
4J = 1.1 Hz, py''-H3/5), 7.54 (dd, 2 H; 3J = 8.1 Hz, 3J = 7.5 Hz, py'-
2-(6-Methoxypyridin-2-yl)-2-(6-phenylpyridin-2-yl)-2-pyridin-
2-ylethyl p-toluenesulfonate (10)
To a solution of 9 (2.20 g, 5.80 mmol) in anhyd pyridine (40 mL)
was added p-TsCl (2.36 g, 12.0 mmol). After stirring the solution at
r.t. for 60 h the mixture was quenched with ice water (50 mL). An
aq solution of NaHCO3 (1 M, 10 mL) was added and the resulting
emulsion extracted with CH2Cl2 (4 15 mL). The organic layer was
washed with NaHCO3 (1 M, 3 10 mL), water (2 10 mL), dried
(Na2SO4) and evaporated to dryness. The crude product was sus-
pended in Et2O, stirred and filtered to give 10 as a slightly brownish
powder (2.15 g, 69%); mp 127–129 °C.
H4), 7.43–7.31 (m, 8 H), 7.14 (ddd, 2 H, J = 7.4 Hz, J = 4.8 Hz,
4J = 1.2 Hz, py-H5), 6.59 (dd, 2 H, 3J = 8.1 Hz, 4J = 0.7 Hz, py'-H5),
4.43 (AB, 2 H, 2J = 16.4 Hz, OCHAHB), 4.41 (AB, 2 H,
2J = 16.4 Hz, OCHAHB), 3.77–3.68 (m, 2 H), 3.71 (s, 3 H, OCH3),
3.71 (s, 3 H, OCH3), 2.17 2.00 (m, 4 H), 1.74–1.58 (m, 4 H), 1.29–
1.06 (m, 6 H), 0.88 (s, 3 H, CH3), 0.88 (s, 3 H, CH3), 0.82 (s, 3 H,
CH3), 0.82 (s, 3 H, CH3), 0.76 (s, 3 H, CH3), 0.74 (s, 3 H, CH3).
3
3
IR (KBr): 1780s (C=O) cm–1.
1H NMR (250 MHz, CDCl3): = 8.41 (ddd, 1 H, 3J = 4.8 Hz,
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 7.88-7.80 (m, 2 H, Ph), 7.66-7.55
MS (PI-EI, 70 eV) m/z (%): 563 (M, 0.7), 368 (M–bornOCH2CO,
10), 352 (M–bornOCH2COO, 100), 337 (M–bornOCH2CO–OCH3,
7), 245 (M–bornOCH2COO–C5H3NOCH3+H, 7).
3
3
4
(m, 2 H), 7.56 (ddd, 1 H, J = 8.1 Hz, J = 7.5 Hz, J = 1.9 Hz,
pyH4), 7.49 (dd, 1 H, J = 8.2 Hz, J = 7.5 Hz, py'-H4), 7.44–7.34
(m, 5 H), 7.27 (ddd, 1 H, 3J = 8.1 Hz, 4J = 1.2 Hz, 5J = 0.9 Hz, py-
H3), 7.17 (dd, 1 H, 3J = 7.3 Hz, 4J = 1.4 Hz, py''-H3/5), 7.09 (ddd, 1
H, 3J = 7.5 Hz, 4J = 4.8 Hz, 5J = 1.1 Hz, py-H5), 7.09-7.04 (m, 2 H,
Ph'), 6.92 (dd, 1 H, 3J = 7.5 Hz, 4J = 0.7 Hz, py'-H3), 6.57 (dd, 1 H,
3J = 8.2 Hz, 4J = 0.7 Hz, py'-H5), 5.49 (AB, 1 H, 2J = 9.4 Hz,
CHAHB), 5.49 (AB, 1 H, 2J = 9.4 Hz, CHAHB), 3.60 (s, 3 H, OCH3),
2.29 (s, 3 H, CH3).
3
3
Anal. calcd for C35H37N3O4 (563.7): C, 74.58; H, 6.62; N, 7.45.
Found: C, 74.72 ; H, 6.77; N, 7.17.
Bromo(6-methoxypyridin-2-yl)(6-phenylpyridin-2-yl)pyridin-
2-ylmethane (8)
5 (8.05 g, 21.8 mmol) was dissolved at r.t. in THF (50 mL) and
deprotonated with n-BuLi (15 mL, 24 mmol, 1.6 M in hexane) with-
in 10 min. The resulting solution was cooled to –70 °C and a solu-
tion of thionyl bromide (2.0 mL, 5.4 g, 26 mmol) in THF (30 mL)
was added within 30 min. The resulting mixture was allowed to
warm to r.t. over a period of 3 h. After 12 h of stirring, the mixture
was quenched with sat. aq NaHCO3 solution (25 mL). The organic
solvent was removed and the aq residue extracted with Et2O–
CH2Cl2, 5:1 (3 20 mL). The combined organic extracts were
washed with brine (2 20 mL), dried and evaporated to give a
brown oil. The residue was chromatographed through silica gel (8
cm 5 cm ) with Et2O–CH2Cl2 (5:1) to give bromide 8 (7.48 g,
79%) as a yellow highly viscous oil.
IR (KBr): 1180s (SO2) cm–1.
MS (PI-EI, 70 eV) m/z (%): 537 (M, 0.2), 366 (M–TsO, 4), 351 (M–
TsO–CH3, 100), 322 (M–TsO–CH3–CH2O, 15).
Anal. calcd for C31H27N3O4S (537.6): C, 69.26; H, 5.06; N, 7.82.
Found: C, 69.16; H, 5.15; N, 7.76.
(6-Methoxypyridin-2-yl)(6-phenylpyridin-2-yl)pyridin-2-ylme-
thane (11)
A mixture of 10 (512 mg, 0.95 mmol) and a solution of NaOMe in
MeOH (10% w/w, 10 mL) was refluxed for 14 h. The solution was
allowed to cool to r.t. and acidified with HCl (10%). After dilution
with H2O (80 mL) it was extracted with CH2Cl2 (3 10 mL). The
organic phase was washed with K2CO3 (1 M, 2 10 mL), water (2
10 mL), dried (Na2SO4) and evaported. The residue was chro-
matographed through silica gel (15 cm 2.5 cm ) with Et2O
(Rf = 0.53) to give 11 (281 mg, 84%) as a yellowish, highly viscous
oil.
1H NMR (250 MHz, CDCl3): = 8.63 (ddd, 1 H, 3J = 4.8 Hz,
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 7.86–7.80 (m, 2 H, Ph), 7.77–7.62
(m, 2 H, py''), 7.62 (ddd, 1 H, 3J = 8.1 Hz, 3J = 7.5 Hz, 4J = 1.9 Hz,
py-H4), 7.55 (dd, 1 H, 3J = 8.2 Hz, 3J = 7.5 Hz, py'-H4), 7.53 (dd, 1
3
H, J = 7.7 Hz, 4J = 1.0 Hz, py''-H3/5), 7.41 (ddd, 1 H, 3J = 8.1 Hz,
4J = 1.1 Hz, 5J = 0.9 Hz, py-H3), 7.39–7.29 (m, 3 H, Ph), 7.18 (ddd,
3
3
4
1 H, J = 7.5 Hz, J = 4.8 Hz, J = 1.1 Hz, py-H5), 7.13 (dd, 1 H,
3J = 7.5 Hz, 4J = 0.7 Hz, py'-H3), 6.63 (dd, 1 H, 3J = 8.2 Hz,
4J = 0.7 Hz, py'-H5), 3.74 (s, 3 H, CH3).
1H NMR (250 MHz, CDCl3): = 8.57 (ddd, 1 H, 3J = 4.9 Hz,
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 7.99–7.93 (m, 2 H, Ph), 7.71–7.57
3
3
4
(m, 2 H), 7.62 (ddd, 1 H, J = 7.9 Hz, J = 7.4 Hz, J = 1.9 Hz,
pyH4), 7.50 (dd, 1 H, J = 8.2 Hz, J = 7.3 Hz, py'-H4), 7.49–7.30
(m, 5 H), 7.14 (ddd, 1 H, 3J = 7.4 Hz, 3J = 4.9 Hz, 4J = 1.3 Hz, py-
H5), 6.92 (dd, 1 H, 3J = 7.3 Hz, 4J = 0.7 Hz, py'-H3), 6.59 (dd, 1 H,
3J = 8.2 Hz, 4J = 0.8 Hz, py'-H5), 5.98 (s, 1 H, pypy'py''CH), 3.80 (s,
3 H, CH3).
3
3
2-(6-Methoxypyridin-2-yl)-2-(6-phenylpyridin-2-yl)-2-pyridin-
2-ylethanol (9)
To a solution of 8 (8.20 g, 19.0 mmol) in Et2O (150 mL) was added
n-BuLi (13 mL, 21 mmol, 1.6 M in hexane) within 20 min at
–90 °C. Paraformaldehyde (0.68 g, 23 mmol) was added in one por-
tion and the mixture was allowed to warm to r.t. over 4 h. After stir-
ring for 10 h the mixture was quenched with H2O (25 mL). The
phases were separated and the organic layer was washed with H2O
(4 20 mL). After drying (Na2SO4) the solvent was evaporated. The
MS (PI-EI, 70 eV) m/z (%): 353 (M, 100), 352 (M–H, 71), 338 (M–
CH3, 43), 337 (M–H–CH3, 19), 275 (M–C5H4N, 16), 245 (M–
C5H3NOCH3, 63), 199 (M–C5H3Ph, 51).
Anal calcd for C23H19N3O (353.4): C, 78.17; H, 5.42; N, 11.89.
Found: C, 77.34; H, 5.52; N, 11.75
residue was chromatographed through silica gel (8 cm 5 cm
with Et2O–CH2Cl2 (1:1, Rf = 0.56) to give compound 9 (5.79 g,
)
79%) as a brownish oil.
2-Bromo-6-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-oxy]-
pyridine (12)
1H NMR (250 MHz, CDCl3): = 8.59 (ddd, 1 H, 3J = 4.8 Hz,
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 7.92–7.86 (m, 2 H, Ph), 7.71–7.61
(m, 2 H, py''), 7.60 (ddd, 1 H, 3J = 8.0 Hz, 3J = 7.5 Hz, 4J = 1.9 Hz,
py-H4), 7.50 (dd, 1 H, 3J = 8.3 Hz, 3J = 7.4 Hz, py'-H4), 7.46 7.33
(m, 3 H, Ph), 7.18 (ddd, 1 H, 3J = 7.5 Hz, 4J = 4.8 Hz, 5J = 1.1 Hz,
A mixture of (1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-ol
(115 g, 730 mmol) and NaH powder (2.96 g, 176 mmol) was slowly
heated to 60 °C. After gas evolution ceased the temperature was
raised to 90 °C and the mixture was stirred for 2 h. A clear solution
resulted, which was allowed to cool to 50 °C. Solid 2,6-dibromopy-
ridine (33.4 g, 141 mmol) was added in portions. The suspension
was heated to 90 °C and stirred for 20 h at this temperature. After
cooling to r.t. Et2O (100 mL) was added and the mixture quenched
with H2O (30 mL). The aq layer was extracted with Et2O (2 20
mL) and the organic extracts were concentrated to yield an oil from
py-H5), 6.99 (ddd, 1 H, J = 8.0 Hz, J = 1.1 Hz, J = 0.9 Hz, py-
H3), 6.92 (dd, 1 H, 3J = 6.9 Hz, 4J = 1.9 Hz, py''-H3/5), 6.64 (dd, 1 H,
3J = 8.3 Hz, 4J = 0.7 Hz, py'-H3/5), 6.58 (dd, 1 H, 3J = 7.4 Hz,
4J = 0.7 Hz, py'-H3/5), 6.3 (s br, 1H, OH), 4.98 (AB, 1 H,
2J = 11.2 Hz, CHAHBOH), 4.96 (AB, 1 H, 2J = 11.2 Hz, CHAH-
BOH), 3.74 (s, 3 H, CH3).
3
4
5
Synthesis 2001, No. 16, 2484–2494 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Tris(2-pyridyl)methane Derivatives with a Chiral Bridging Atom
2491
which unreacted menthol was distilled off (95 °C/0.2 mbar). The
residue was subjected to a fractional distillation to give 12 as a col-
orless liquid (36.4 g, 83%); bp 86–93 °C/10–3 mbar.
[ ] (c = 1.7, CH2Cl2, r.t.): –85.0 (589 nm), –89.4 (578 nm), –103
(546 nm), –195 (436 nm), –372 (365 nm).
1H NMR (250 MHz, CDCl3): = 8.57 (ddd, 1 H, 3J = 4.9 Hz,
[ ] (c = 2.2, CHCl3, r.t.): –85.1 (589 nm), –89.0 (578 nm), –102
(546 nm), –179 (436 nm), –304 (365 nm).
4J = 1.8 Hz, 5J = 1.0 Hz, py-H6), 7.98-7.92 (m, 2 H, Ph), 7.90 (ddd,
3
4
5
1 H, J = 8.0 Hz, J = 1.2 Hz, J = 0.9 Hz, py-H3), 7.77 7.60 (m,
3 H), 7.68 (ddd, 1 H, 3J = 8.0 Hz, 3J = 7.4 Hz, 4J = 1.8 Hz, py-H4),
7.56 (dd, 1 H, 3J = 8.2 Hz, 3J = 7.4 Hz, py'-H4), 7.45–7.33 (m, 3 H,
1H NMR (250 MHz, CDCl3): = 7.36 (dd, 1 H, 3J = 8.1 Hz,
3J = 7.5 Hz, py-H4), 6.98 (dd, 1 H, 3J = 7.5 Hz, 4J = 0.7 Hz, py-H3),
6.60 (dd, 1 H, 2J = 8.1 Hz, 3J = 0.7 Hz, py-H5), 4.97 (dt, 1 H,
3J = 10.7 Hz, 3J = 4.4 Hz, OCH), 2.20–2.11 (m, 1 H), 1.97 (dsept, 1
H, 3J = 2.7 Hz, 3J = 7.0 Hz, CH(CH3)2), 1.76–1.41 (m, 4 H), 1.23
0.72 (m, 3 H), 0.92 (d, 3 H, 3J = 6.4 Hz, CH3), 0.89 (d, 3 H,
3J = 6.9 Hz, CH3), 0.78 (d, 3 H, 3J = 6.9 Hz, CH3).
3
4
Ph), 7.35 (s br, 1 H, OH), 7.33 (dd, 1 H, J = 7.4 Hz, J = 0.8 Hz,
py'-H3), 7.21 (ddd, 1 H, J = 7.4 Hz, J = 4.9 Hz, J = 1.2 Hz, py-
3
3
4
H5), 6.55 (dd, 1 H, J = 8.2 Hz, 4J = 0.8 Hz, py'-H5), 4.75 (dt, 1 H,
3
3J = 10.7 Hz, J = 4.3 Hz, OCH), 2.07 1.80 (m, 2 H), 1.67 0.72
3
(m, 7 H), 0.81 (d, 3 H, 3J = 7.1 Hz, CH3), 0.80 (d, 3 H, 3J = 6.5 Hz,
CH3), 0.54 (d, 3 H, 3J = 7.0 Hz, CH3).
MS (PI-EI, 70 eV) m/z (%): 313/311 (M, 8/9), 176/174 (M–C10H17,
97/100), 95 (M–Br–C10H17, 71).
13C NMR (62.9 MHz, CDCl3): = 162.7 (Cq), 162.1 (Cq), 161.9
(Cq), 161.5 (Cq), 154.4 (Cq), 147.2 (CH), 139.2 (CH), 139.1 (Cq),
136.8 (CH), 135.7 (CH), 128.9 (CH), 128.6 (2 CH), 126.8 (2 CH),
123.9 (CH), 122.2 (CH), 122.0 (CH), 118.7 (CH), 113.8 (CH),
109.5 (CH), 81.1 (Cq), 74.4 (CH), 47.1(CH), 40.5 (CH2), 34.5
(CH2), 31.4 (CH), 26.3 (CH), 23.8 (CH2), 22.2 (CH3), 20.6 (CH3),
16.5 (CH3).
Anal calcd for C15H22BrNO (312.3): C, 57.70; H, 7.10; N, 4.49.
Found: C, 57.73; H, 7.0; N, 4.59.
{6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]pyridin-2-
yl}(6-phenylpyridin-2-yl)pyridin-2-ylmethanol (14)
To a cooled solution (–80 °C) of 12 (8.43 g, 27.0 mmol) in THF (40
mL) was added n-BuLi (16 mL, 26 mmol, 1.6 M in hexane) over a
period of 30 min. After stirring for 30 min the mixture was cooled
to –90 °C and a solution of 3 (6.51 g, 25.0 mmol) in THF (50 mL)
was added within 60 min. Further 60 min of stirring was followed
by addition of MeOH (25 mL) over a period of 30 min. The solution
was allowed to warm to r.t. and H2O (10 mL) and HCl (2 M, 15 mL)
were added. The organic solvent was removed and the remaining aq
solution was extracted with CH2Cl2 (20 mL). After neutralizing
with K2CO3 (solid) the mixture was extracted with CH2Cl2 (2 20
mL). The organic phases were washed with K2CO3 (1 M, 2 40
mL), H2O (2 20 mL), dried (Na2SO4) and evaporated. The residue
was stirred with PE (200 mL) and the undissolved ketone was fil-
tered off. The filtrate was concentrated and heated in the Kugelrohr
apparatus to 120 °C at a pressure of 10–4 mbar to remove the vola-
{6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]pyridin-2-
yl}methoxy(6-phenylpyridin-2-yl)pyridin-2-ylmethanol (15)
To a mixture of 14 (1.48 g, 3.00 mmol) and NaH (suspension 80%
in toluene) (105 mg, 3.50 mmol) was added DMF (10 mL). After
stirring at r.t. for 2 h a solution resulted. A solution of methyl iodide
(0.47 g, 3.3 mmol) in DMF (1 mL) was added and the mixture was
stirred for 12 h. After addition of aq NH3 (2 M, 25 mL) and vigorous
stirring the mixture was acidified with HCl (2 M). The combined
CH2Cl2 extracts (5 15 mL) were washed with HCl (2 M, 2 10
mL), K2CO3 (1 M, 2 10 mL) and H2O (2 10 mL) and dried
(Na2SO4). The residue was chromatographed through silica gel (15
cm 2 cm ) with CH2Cl2–Et2O (15:1, Rf = 0.48) to give 15 (1.18
g, 77%) as a yellowish, highly viscous oil. The diastereomeric ex-
cess of the product was equal to the starting material.
tiles. The residue was passed through silica gel (11 cm 6 cm
)
Analytical data for a 1:1 mixture of the diastereomers:
with PE–Et2O (3:1, Rf = 0.27) to give 14 (6.93 g, 56%) as a 1:1 mix-
ture of the two diastereomers as a yellowish, highly viscous oil. The
faster moving diastereomer could be enriched by chromatography
(silica gel, 85 cm 2.5 cm , PE–Et2O, 2:1). The first 20% of the
product was chromatographed again and this operation was repeat-
ed once more. Then the first 20% of the resulting product showed a
diastereomeric excess of 96%.
[ ] (c = 1.1, CH2Cl2, r.t.): –57.7 (589 nm), –60.0 (578 nm), –68.1
(546 nm), –116 (436 nm), –180 (365 nm).
1H NMR (250 MHz, CDCl3): The signals were not assigned to the
different diastereomers.
= 8.62 (ddd, 1
H, 3J = 4.8 Hz,
4J = 1.8 Hz, 5J = 1.0 Hz, py-H6), 8.62 (ddd, 1 H, 3J = 4.9 Hz,
4J = 1.8 Hz, 5J = 0.9 Hz, py-H6), 7.96–7.90 (m, 4 H, Ph), 7.76–7.51
(m, 11 H), 7.46 (dd, 1 H, 3J = 7.3 Hz, 4J = 1.5 Hz, py''-H3/5), 7.43–
7.31 (m, 6 H, Ph), 7.28 (dd, 1 H, 3J = 7.5 Hz, 4J = 0.8 Hz, py'-H3),
Analytical date for a 1:1 mixture:
1H NMR (250 MHz, CDCl3): = 8.55 (ddd, 1 H, 3J = 4.9 Hz,
4J = 1.9 Hz, 5J = 1.0 Hz, py-H6), 8.54 (ddd, 1 H, 3J = 4.9 Hz,
4J = 1.9 Hz, 5J = 1.0 Hz, py-H6), 8.00–7.93 (m, 4 H, Ph), 7.86 (ddd,
3
4
7.21 (dd, 1 H, J = 7.5 Hz, J = 0.8 Hz, py'-H3), 7.16 (ddd, 1 H,
3J = 7.3 Hz, 3J = 4.8 Hz, 4J = 1.3 Hz, py-H5), 7.15 (ddd, 1 H,
3J = 7.3 Hz, 3J = 4.8 Hz, 4J = 1.3 Hz, py-H5), 6.52 (dd, 1 H,
3J = 8.2 Hz, 4J = 0.8 Hz, py'-H5), 6.51 (dd, 1 H, 3J = 8.2 Hz,
4J = 0.8 Hz, py'-H5) 4.65 (dt, 1 H, 3J = 10.7 Hz, 3J = 4.3 Hz, OCH),
4.63 (dt, 1 H, 3J = 10.7 Hz, 3J = 4.3 Hz, OCH), 3.41 (s, 3 H, OCH3),
3.41 (s, 3 H, OCH3), 2.04–1.69 (m, 4 H), 1.65–1.34 (m, 6 H), 1.27–
3
4
5
1 H, J = 8.1 Hz, J = 1.2 Hz, J = 1.0 Hz, py-H3), 7.77–7.60 (m,
9 H), 7.54 (dd, 1 H, 3J = 8.2 Hz, 3J = 7.4 Hz, py'-H4), 7.54 (dd, 1 H,
3J = 8.2 Hz, 3J = 7.4 Hz, py'-H4), 7.47–7.33 (m, 6 H, Ph), 7.35 (s br,
2 H, OH), 7.30 (dd, 1 H, 3J = 7.4 Hz, 4J = 0.8 Hz, py'-H3), 7.28 (dd,
1 H, 3J = 7.4 Hz, 4J = 0.8 Hz, py'-H3), 7.19 (ddd, 1 H, 3J = 7.4 Hz,
3J = 4.9 Hz, 4J = 1.2 Hz, py-H5), 7.18 (ddd, 1 H, 3J = 7.3 Hz,
3J = 4.9 Hz, 4J = 1.3 Hz, py-H5), 6.53 (dd, 1 H, 3J = 8.2 Hz,
3
0.69 (m, 8 H), 0.81 (d, 3 H, J = 7.1 Hz, 3 H, CH3), 0.80 (d, 3 H,
3J = 7.1 Hz, CH3), 0.76 (d, 3 H, J = 6.5 Hz, CH3), 0.75 (d, 3 H,
3
3J = 6.4 Hz, CH3), 0.53 (d, 3 H, J = 7.0 Hz, CH3), 0.51 (d, 3 H,
3
3
4
4J = 0.8 Hz, py-'H5), 6.52 (dd, 1 H, J = 8.2 Hz, J = 0.8 Hz, py'-
H5), 4.71 (dt, 2 H, 3J = 10.7 Hz, 3J = 4.3 Hz, OCH), 2.07–1.77 (m,
4 H), 1.67–0.72 (m, 14 H), 0.83 (d, 3 H, 3J = 7.0 Hz, CH3), 0.81 (d,
3J = 7.0 Hz, CH3).
MS (PI-EI, 70 eV) m/z (%): 507 (M, 14), 492 (M–CH3, 22), 477
(M–CH2O, 26), 339 (M–OCH3–C10H17, 100).
3
3 H, 3J = 7.1 Hz, CH3), 0.80 (d, 3 H, J = 6.5 Hz, CH3), 0.76 (d, 3
H, 3J = 6.5 Hz, CH3), 0.59 (d, 3 H, 3J = 7.0 Hz, CH3), 0.53 (d, 3 H,
3J = 7.0 Hz, CH3).
Bromo{6-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-oxy]py-
ridin-2-yl}(6-phenylpyridin-2-yl)pyridin-2-ylmethane (16)
To a solution of 14 (8.75 g, 17.7 mmol) in Et2O (80 mL) was added
n-BuLi (11 mL, 18 mmol, 1.6 M in hexane) within 15 min at
–78 °C. After 15 min stirring a solution of thionyl bromide (1.62
mL, 4.37 g, 21.0 mmol) in Et2O (25 mL) was added at –78 °C over
a period of 30 min. Within 4 h the mixture was allowed to come to
MS (PI-DCI) m/z (%): 494 (MH, 100).
Anal. calcd for C32H35N3O2 (493.7): C, 77.86; H, 7.15; N, 8.51.
Found: C, 77.57; H, 7.46; N, 8.13.
Analytical date for a 98:2 mixture of the diastereomers:
Synthesis 2001, No. 16, 2484–2494 ISSN 0039-7881 © Thieme Stuttgart · New York

2492
H. Brunner et al.
PAPER
r.t. and stirred for 12 h. The reaction was quenched by addition of
sat. aq NaHCO3 (50 mL). After addition of CH2Cl2 (50 mL) the or-
ganic layer was separated, washed with sat. aq NaHCO3 (3 30
mL), half sat. aq NaCl (3 30 mL) and dried (Na2SO4). The evap-
oration of the solvent yielded the crude product, which was purified
by chromatography through silica gel (8 cm 5 cm ) with Et2O
(Rf = 0.85) to give 16 (8.79 g, 89%) as a yellow, glassy substance.
MS (PI-EI, 70 eV) m/z (%): 477 (M, 34), 434 (M–C3H7, 21), 340
(M–C10H17, 58), 339 (M–C10H18, 100), 338 (M–H–C10H18, 78), 246
(M+H–C5H3NOmen, 30), 245 (M–C5H3NOC10H19, 45).
Anal. calcd for C32H35N3O (477.7): C, 80.46; H, 7.38; N, 8.80.
Found: C, 80.24; H, 7.26; N, 8.67.
4-{6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]pyridin-
2-yl}-4-(6-phenylpyridin-2-yl)-4-pyridin-2-ylbutan-1-ol (18)
To a cooled solution (–90 °C) of 16 (4.41 g, 7.90 mmol) in Et2O
(100 mL) was added n-BuLi (6.3 mL, 10 mmol, 1.6 M in hexane)
within 15 min. After stirring for 30 min oxetane (0.82 mL, 0.73 g,
13 mmol) and BF3 OEt2 (1.6 mL, 1.8 g, 13 mmol) were added at
–90 °C. The mixture was allowed to warm to r.t. over a period of 4
h and then stirred for 1 h. After addition of H2O (20 mL) and HCl
(2 M, 10 mL) small portions of CH2Cl2 were added until the dark oil
dissolved. The resulting mixture was made alkaline with sat. aq
K2CO3 (20 mL). The separated aq layer was extracted with a 2:1
mixture of Et2O and CH2Cl2 (3 15 mL). The combined organic
phases were washed with sat. aq K2CO3 (2 20 mL), sat. aq NaCl
(2 20 mL), dried (Na2SO4) and concentrated. The residue was
chromatographed through silica gel (10 cm 6 cm ) with CH2Cl2
Et2O [CH2Cl2–Et2O, 1:0, 10:1, 5:1, 1:1, 0:1; Rf (Et2O) = 0.41] to
give 18 (2.36 g, 56%) as a 1:1 mixture of the two diastereomers as
a yellowish, highly viscous oil.
Analytical data for a 1:1 mixture of the diastereomers:
[ ] (c = 1.2, CH2Cl2, r.t.): –69.6 (589 nm), –72.8 (578 nm), –83.4
(546 nm).
1H NMR (250 MHz, CDCl3): The signals were not assigned to the
different diastereomers.
= 8.66 (ddd, 1
H, 3J = 4.8 Hz,
4J = 1.8 Hz, 5J = 1.0 Hz, py-H6), 8.65 (ddd, 1 H, 3J = 4.8 Hz,
4J = 1.9 Hz, 5J = 1.0 Hz, py-H6), 7.89–7.82 (m, 4 H, Ph), 7.73–7.61
(m, 4 H), 7.60 (ddd, 2 H, 3J = 8.1 Hz, 3J = 7.5 Hz, 4J = 1.9 Hz, py-
H4), 7.56 (dd, 1 H, 3J = 8.2 Hz, 3J = 7.5 Hz, py'-H4), 7.55 (dd, 1 H,
3J = 8.2 Hz, 3J = 7.5 Hz, py'-H4), 7.46 (dd, 1 H, 3J = 7.5 Hz,
4J = 1.2 Hz, py'-H3), 7.45 (dd, 1 H, J = 7.5 Hz, J = 1.3 Hz, py'-
H3), 7.40–7.23 (m, 10 H), 7.19 (ddd, 1 H, 3J = 7.5 Hz, 3J = 4.8 Hz,
4J = 1.1 Hz, py-H5), 7.18 (ddd, 1 H, 3J = 7.5 Hz, 3J = 4.8 Hz,
4J = 1.0 Hz, py-H5), 6.55 (dd, 2 H, 3J = 8.2 Hz, 4J = 0.7 Hz, py'-H5),
4.54 (dt, 1 H, 3J = 10.8 Hz, 3J = 4.3 Hz, OCH), 4.51 (dt, 1 H,
3
4
3
3J = 10.8 Hz, J = 4.3 Hz, OCH), 2.05 1.66 (m, 4 H), 1.60–1.47
(m, 4 H), 1.43–1.20 (m, 4 H), 1.12–0.66 (m, 6 H), 0.80 (d, 3 H,
The faster moving diastereomer (S)-18 could be enriched by chro-
matography (85 cm 2.5 cm ) with CH2Cl2–Et2O, 1.4:1. The first
20% of the product were chromatographed again and this operation
was repeated three times. Then the first 20% of the resulting product
showed a diastereomeric excess of 90%.
3
3J = 7.0 Hz, CH3), 0.79 (d, 3 H, J = 7.0 Hz, CH3), 0.73 (d, 3 H,
3
3J = 6.5 Hz, CH3), 0.69 (d, 3 H, J = 6.5 Hz, CH3), 0.51 (d, 3 H,
3J = 7.0 Hz, CH3), 0.51 (d, 3 H, 3J = 7.0 Hz, CH3).
MS (PI-DCI (NH3) m/z (%): 558/556 (MH, 57/54), 478 (MH–Br,
100).
Analytical data for a 1:1 mixture of the two diastereomers:
{6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]pyridin-2-
yl}(6-phenylpyridin-2-yl)pyridin-2-ylmethane (17)
[ ] (c = 0.4, CH2Cl2, r.t.): –66.0 (589 nm), –69.6 (578 nm), –79.5
(546 nm), –143 (436 nm), –251 (365 nm).
To a solution of 16 (1.11 g, 2.00 mmol) in Et2O (40 mL) was added
n-BuLi (1.50 mL, 2.40 mmol, 1.6 M in hexane) over a period of 30
min at –90 °C. The solution was allowed to warm slowly to r.t. and
quenched with water (10 mL). After the addition of HCl (2 M, 2
mL) the phases were separated. The aq layer was extracted with
CH2Cl2 (3 5 mL). The combined organic phases were washed with
sat. aq K2CO3 (3 10 mL), dried over Na2SO4 and evaporated. The
crude product was chromatographed through silica gel, (20 cm 1.5
cm ) with CH2Cl2–Et2O, 10:1 (Rf = 0.40) to provide 17 (0.78 g,
73%) as a colorless, highly viscous oil.
1H NMR (400 MHz, CDCl3): = 8.56 (ddd, 1 H, 3J = 4.9 Hz,
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 8.55 (ddd, 1 H, 3J = 4.9 Hz,
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 7.96–7.92 (m, 4 H, Ph), 7.65–7.51
(m, 6 H), 7.47 (dd, 2 H, 3J = 8.2 Hz, 3J = 7.5 Hz, py'-H4), 7.45–7.31
(m, 8 H), 7.23 (dd, 1 H, 3J = 6.8 Hz, 4J = 2.0 Hz, py''-H3/5), 7.21 (dd,
1 H, 3J = 7.0 Hz, 4J = 1.8 Hz, py''-H3/5), 7.11 (ddd, 1 H, 3J = 7.3 Hz,
3J = 4.9 Hz, 4J = 1.1 Hz, py-H5), 7.11 (ddd, 1 H, 3J = 7.3 Hz,
3J = 4.9 Hz, 4J = 1.2 Hz, py-H5), 6.89 (dd, 1 H, 3J = 7.5 Hz,
3
4
4J = 0.7 Hz, py'-H3), 6.89 (dd, 1 H, J = 7.5 Hz, J = 0.7 Hz, py'-
3
H3), 6.49 (dd, 2 H, J = 8.2 Hz, 4J = 0.6 Hz, py'-H5), 4.70 (dt, 1 H,
Analytical data for a 1:1 mixture of the two diastereomers:
3J = 10.8 Hz, 3J = 4.3 Hz, OCH), 4.70 (dt, 1 H, 3J = 10.7 Hz,
3
3J = 4.1 Hz, OCH), 3.63 (t, 4 H, J = 6.1 Hz, CH2OH), 3.15–2.94
[ ] (c = 2.9, CH2Cl2, r.t.): –82.2 (589 nm), –85.6 (578 nm), –97.7
(546 nm), –170 (436 nm).
1H NMR (250 MHz, CDCl3): The signals were not assigned to the
(m, 4 H), 2.10–1.94 (m, 2 H), 1.90–1.80 (m, 2 H), 1.68–0.74 (m,
3
3
18 H), 0.84 (d, 6 H, J = 7.0 Hz, CH3), 0.80 (d, 6 H, J = 6.5 Hz,
CH3), 0.60 (d, 6 H, 3J = 7.0 Hz, CH3), OH protons at about 3 ppm
very broad.
different diastereomers.
= 8.56 (ddd, 1
H, 3J = 4.9 Hz,
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 8.56 (ddd, 1 H, 3J = 4.9 Hz,
4J = 1.8 Hz, 5J = 0.9 Hz, py-H6), 8.00–7.94 (m, 4 H, Ph), 7.70–7.56
(m, 4 H), 7.64 (dd, 2 H, 3J = 7.6 Hz, 3J = 7.2 Hz, py''-H4), 7.51 (ddd,
MS (PI-DCI) m/z (%): 536 (MH, 100).
Anal. calcd for C35H41N3O2 (535.7): C, 78.47; H, 7.71; N, 7.84.
Found: C, 77.68; H, 7.95; N, 7.30.
3
4
5
1 H, J = 8.0 Hz, J = 1.3 Hz, J = 0.9 Hz, py-H4), 7.47 (dd, 2 H,
3J = 8.2 Hz, 3J = 7.3 Hz, py'-H4), 7.46–7.33 (m, 7 H), 7.31 (dd, 1 H,
3J = 7.4 Hz, 4J = 1.2 Hz, py''-H3/5), 7.30 (dd, 1 H, 3J = 7.5 Hz,
4J = 1.2 Hz, py''-H3/5), 7.13 (ddd, 2 H, 3J = 7.4 Hz, 3J = 4.9 Hz,
4J = 1.3 Hz, py-H5), 6.85 (dd, 1 H, 3J = 7.2 Hz, 4J = 0.8 Hz, py''-H3/
5), 6.83 (dd, 1 H, 3J = 7.3 Hz, 4J = 0.8 Hz, py''-H3/5), 6.50 (dd, 2 H,
Analytical data for (S)-18 in a 95:5 mixture of (S)-18:(R)-18:
[ ] (c = 1.2, CH2Cl2, r.t.): –46.3 (589 nm), –48.0 (578 nm), –54.4
(546 nm), –90.6 (436 nm), –129 (365 nm).
1H NMR (400 MHz, CDCl3): = 8.55 (ddd, 1 H, 3J = 4.9 Hz,
4
3J = 8.2 Hz, J = 0.7 Hz, py'-H5), 5.94 (s, 2 H, pypy'py''CH), 4.85
4J = 1.9 Hz, 5J = 0.9 Hz, py-H6), 7.96–7.92 (m, 2 H, Ph), 7.63–7.56
(dt, 1 H, 3J = 10.8 Hz, 3J = 4.3 Hz, OCH), 4.84 (dt, 1 H,
3J = 10.8 Hz, 3J = 4.3 Hz, OCH), 2.06–1.83 (m, 4 H), 1.68–1.57 (m,
4 H), 1.52–1.14 (m, 4 H), 1.06–0.74 (m, 6 H), 0.86 (d, 3 H,
3
3
4
(m, 2 H), 7.54 (ddd, 1 H, J = 8.1 Hz, J = 7.4 Hz, J = 1.9 Hz,
pyH4), 7.47 (dd, 1 H, J = 8.2 Hz, J = 7.5 Hz, py'-H4), 7.44–7.33
3
3
(m, 4 H), 7.21 (dd, 1 H, J = 7.6 Hz, J = 1.2 Hz, py''-H3/5), 7.12
3
4
3J = 6.6 Hz, CH3), 0.84 (d, 3 H, J = 7.0 Hz, CH3), 0.80 (d, 3 H,
3
(ddd, 1 H, 3J = 7.4 Hz, 3J = 4.9 Hz, 4J = 1.1 Hz, py-H5), 6.88 (dd, 1
3J = 6.9 Hz, CH3), 0.78 (d, 3 H, J = 6.5 Hz, CH3), 0.61 (d, 3 H,
3
H, J = 7.5 Hz, J = 0.7 Hz, py'-H3), 6.48 (dd, 1 H, J = 8.2 Hz,
3
4
3
3J = 6.9 Hz, CH3), 0.57 (d, 3 H, 3J = 6.9 Hz, CH3).
4J = 0.7 Hz, py'-H5), 4.67 (dt, 1 H, 3J = 10.8 Hz, 3J = 4.2 Hz, OCH),
3
3.62 (t, 2 H, J = 6.1 Hz, CH2OH), 3.10–2.97 (m, 2 H), 2.04–1.93
Synthesis 2001, No. 16, 2484–2494 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Tris(2-pyridyl)methane Derivatives with a Chiral Bridging Atom
2493
(m, 1 H), 1.86 1.79 (m, 1 H), 1.66–0.76 (m, 9 H), 0.83 (d, 3 H,
5.05 (s, 1 H, OH), 4.44 (dt, 1 H, 3J = 10.5 Hz, 3J = 4.7 Hz, OCH),
3
3J = 7.0 Hz, CH3), 0.78 (d, 3 H, J = 6.5 Hz, CH3), 0.58 (d, 3 H,
3.92 (m, 2 H, CH2OH), 3.74–3.64 (m, 1 H, pypy'py''CCHAHB),
3.47–3.37 (m, 1 H, pypy'py''CCHAHB), 2.13–1.97 (m, 3 H, men-
3J = 7.0 Hz, CH3), OH proton at about 3 ppm very broad.
C6HH+men-C2H), 1.80–1.64 (m,
4
H, CH2CH2OH+men-
13C{1H} NMR (101 MHz, CDCl3): = 164.6 (Cq), 164.2 (Cq),
162.4 (Cq), 162.1 (Cq), 155.0 (Cq), 147.6 (CH), 139.4 (Cq), 138.6
(CH), 136.0 (CH), 135.1 (CH), 128.6 (CH), 128.5 (2 CH), 126.6 (2
CH), 126.0 (CH), 123.2 (CH), 121.0 (CH), 117.2 (CH), 115.3 (CH),
108.6 (CH), 74.1 (CH), 63.1 (Cq), 62.9 (CH2), 47.0 (CH), 40.5
(CH2), 34.4 (CH2), 33.6 (CH2), 31.2 (CH), 28.7 (CH2), 26.2 (CH),
23.7 (CH2), 22.1 (CH3), 20.5 (CH3), 16.4 (CH3).
C5HH+men-C6HH), 1.64–1.54 (m, 1 H, men-C1H), 1.25–1.15 (m, 1
H, men-C8H), 1.12-0.98 (m, 2 H, men-C5HH+men-C6HH), 0.96 (d,
3 H, 3J = 6.6 Hz, CH3), 0.60 (d, 3 H, 3J = 6.9 Hz, CH3), 0.26 (d, 3
H, 3J = 7.0 Hz, CH3).
13C{1H} NMR (101 MHz, DMF-d7): = 171.6 (d, 1J = 25.7 Hz, Cq-
Rh), 169.4 (Cq), 168.8 (Cq), 159.3 (Cq), 156.7 (Cq, J = 1.0 Hz, py''-
C6H or Ph-C2H), 155.4 (Cq, J = 1.4 Hz, py''-C6H or Ph-C2H), 155.0
(py-C6H), 147.2 (Cq), 142.0 (py'-C4H), 140.7 (Ph-C3H), 140.0 (py-
C4H), 138.8 (py''-C4H), 128.6 (Ph-C4/5H), 123.8 (Ph-C6H), 123.5
(py-C5H), 122.2 (Ph-C4/5H), 122.1 (py''-C3H), 120.8 (py-C3H),
118.5 (py'-C3H), 117.7 (py''-C5H), 107.5 (py'-C5H), 79.9 (men-
C1H), 63.6 (Cq, J = 2.1 Hz, pypy'py''C), 61.7 (CH2OH), 46.1 (men-
C2H), 39.7 (men-C6H2), 34.9 (men-C4H2), 31.8 (men-C5H), 30.4
(pypy'py''CCH2), 29.0 (CH2CH2OH), 25.2 (men-C8H), 23.0 (men-
C3H2), 22.4 (men-C5CH3), 21.1 (men-C8HCH3), 15.3 (men-
C8HCH3).
Dichloro[(6-methoxypyridin-2-yl)(6-phenylpyridin-2-yl- N)-
(pyridin-2-yl- N)methane]copper(II) (19)
Anhyd CuCl2 (28.0 mg, 0.21 mmol) was dissolved in a solution of
racemic 11 (73.0 mg, 0.21 mmol) in MeOH (2 mL). After diffusion
of Et2O into the methanolic solution 19 (72.0 mg, 72%) was ob-
tained as green, air-stable crystals; mp 185 °C (decomp.). Some of
the crystals were suitable for X-ray analysis.
MS (PI-ESI) m/z (%): 451 (M–Cl, 43), 415 (M–Cl–HCl, 100), 354
(MH–CuCl2, 25).
MS (PI-ESI): m/z (%) = 1455 (M2+K, 4), 1439 (M2+Na, 19), 746
(M+K, 31), 730 (M+Na, 100), 672 (M – Cl, 27), 536 (M – RhCl2+2
H, 16).
Anal. calcd for C23H19Cl2CuN3O (478.9): C, 56.62; H, 3.93; N,
8.61. Found: C, 56.28; H, 4.09; N, 8.37.
(RRh
,
Rh)-Dichloro[(S)-4-{6-[(1R,2S,5R)-2-isopropyl-5-methyl-
Anal. calcd for C35H40Cl2N3O2Rh (708.5): C 59.33; H, 5.69; N,
5.93. Found: C, 58.90; H, 5.79; N, 5.83.
cyclohexyloxy]pyridin-2-yl- N}-4-[6-(2-phenyl- C1)pyridin-2-
yl- N]-4-(pyridin-2-yl- N)butan-1-ol]rhodium(III) (20)
To a solution of 18 (S:R = 65:35, 1.50 g, 2.80 mmol) in EtOH (150
mL) was added rhodium(III) chloride trihydrate (645 mg, 2.45
mmol) at ambient temperature. This solution was stirred for 12 h
and the resulting yellow solid was filtered off, washed with EtOH
(4 5 mL), Et2O (4 5 mL) and dried. After addition of Et2O (30
mL) and PE (20 mL) to the mother liquid the solution was stirred
for 12 h to give a second fraction of 20. Concentration of the mother
liquid to a volume of 25 mL gave a third fraction. The yield of the
fine crystalline air-stable powder was altogether 1.35 g (78%); mp
>250 °C.
X-Ray Structure Analysis, General Remarks
The structures were solved by direct methods (SIR-97) and refined
by full-matrix anisotropic least squares (SHELXL97) on F2. The H
atoms were calculated geometrically and a riding model was ap-
plied during the refinement process. Absorption corrections were
not used. For the measurement a diffractometer of the type STOE-
IPDS with Mo-K radiation and graphite monochromator was used.
Further details of the crystal structure investigation may be ob-
tained, free of charge, from the Cambridge Crystallographic Data
Centre, where the structures have been deposited.
For separation of the major diastereomer, a 62:32:2:4 mixture of 20
(300 mg) was dissolved in DMSO (25 mL) at 45 °C. The solution
was submitted to a Kugelrohr distillation at 45 °C/10–3 mbar to re-
move the solvent until first crystals appeared. This sat. solution was
allowed to stand for several days. Then the product was filtered off
to give 20 (90 mg) as fine yellow needles, with a de of 94%. X-ray
quality yellow prisms were obtained by leaving a concentrated so-
lution of 20 in DMSO undisturbed in an open vessel for about two
weeks.
X-Ray Structure Analysis of ( )-19
C23H19Cl2CuN3O, MW = 487.86; green prisms; crystal size [mm]:
0.21 0.15 0.11; space group P 21/n; monoclinic; Z = 4; a/b/c
[Å] = 9.3622(8)/14.6885(9)/15.8021(14);
[°] = 105.084(10);
V = 2098.2(3) Å3; dcalcd = 1.544 g cm–3; F(000) = 996; = 1.32
mm–1; T = 173(1) K; -scan: 2.30 < 2 < 26.78°; 27241 reflections
collected, 4451 independent, 3067 observed (I > 2 I); Rint = 0.0550;
R (I > 2 I): R1 = 0.0342; wR2 = 0.0723; R (all data): R1 = 0.0602;
wR2 = 0.0782; gof = 0.868; CCDC 163405.
Analytical data for (SC,RRh, Rh)-20 in
(SC,RRh, Rh)-20:(SC,RRh, Rh)-20:
a 97:3 mixture of
X-Ray Structure Analysis of (SC,RRh, Rh)-20
C35H40Cl2N3O2Rh, MW = 708.51; yellow prisms; crystal size
[mm]: 0.14 0.10 0.08; space group P 61; hexagonal; Z = 6; a/c
[Å] = 24.5147(11)/9.8658(5); V = 5134.7(4) Å3; dcalcd = 1.375
g cm–3; F(000) = 2196; = 0.689 mm–1; T = 293(2) K; -scan: 2.82
< 2 < 25.90°; 69461 reflections collected, 6627 independent, 5942
observed (I > 2 I); Rint = 0.0380; R (I > 2 I): R1 = 0.0312;
wR2 = 0.0710; R (all data): R1 = 0.0352; wR2 = 0.0736; gof = 1.035;
absolute structure parameter –0.02(2); CCDC 163406. On solving
the structure a solvent accessible area containing electron density
was detected. The contribution of the disordered solvent to the cal-
culated structure factors was taken into account by back-Fourier
transformation with the program SQUEEZE.23 The void was locat-
ed at (0, 0, 0), it had a size of 533 Å3 and contained 29 electrons.
[ ] (c = 0.26, DMSO, r.t.): –58.0 (589 nm), –50.2 (578 nm), –17.0
(546 nm).
3
1H NMR (400 MHz, DMF-d7): = 9.50 (ddd, 1 H, J = 5.4 Hz,
4J = 1.8 Hz, 5J = 0.6 Hz, py-H6), 8.96 (ddd, 1 H, 3J = 7.7 Hz,
4J = 1.3 Hz, 5J = 0.4 Hz, Ph-H3), 8.20 (ddd, 1 H, 3J = 8.2 Hz,
4J = 1.3 Hz, 5J = 0.8 Hz, py-H3), 8.15 (ddd, 1 H, 3J = 8.1 Hz,
3J = 7.2 Hz, 4J = 1.8 Hz, py-H4), 8.03–7.95 (m, 3 H, py''), 7.89 (dd,
1 H, 3J = 8.4 Hz, 3J = 7.9 Hz, py'-H4), 7.79 (ddd, 1 H, 3J = 7.7 Hz,
4J = 1.3 Hz, 5J = 0.3 Hz, Ph-H6), 7.64 (dd, 1 H, 3J = 7.9 Hz,
4J = 1.0 Hz, py'-H3), 7.47 (ddd, 1 H, 3J = 7.2 Hz, 4J = 5.4 Hz,
5J = 1.4 Hz, py-H5), 7.28 (ddd, 1 H, 3J = 7.7 Hz, 3J = 7.2 Hz,
3
4
4J = 1.5 Hz, Ph-H4/5), 7.25 (dd, 1 H, J = 8.5 Hz, J = 1.0 Hz, py'-
H5), 7.03 (ddd, 1 H, 3J = 7.6 Hz, 3J = 7.3 Hz, 4J = 1.2 Hz, Ph-H4/5),
Synthesis 2001, No. 16, 2484–2494 ISSN 0039-7881 © Thieme Stuttgart · New York

2494
H. Brunner et al.
PAPER
(11) Maier, R. J. Ph. D. Thesis; Universität Regensburg:
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