Synthesis of bipyridine analogues of metomidate for conjugate formation with the 99mTc(I)-tricarbonyl complex

Article abstract of DOI:10.1007/s00706-010-0278-4

Ethyl 2,2′-bipyridine-5-carboxylate was converted to (2,2′-bipyridine-5-yl)methanol and (S)-1-(2,2′-bipyridine-5-yl) ethanol. The latter synthesis comprised five steps and resolution by HPLC on a chiral stationary phase. Both alcohols were reacted with me

Full text of DOI:10.1007/s00706-010-0278-4

Monatsh Chem (2010) 141:437–443
DOI 10.1007/s00706-010-0278-4
ORIGINAL PAPER
Synthesis of bipyridine analogues of metomidate for conjugate
formation with the 99mTc(I)-tricarbonyl complex
•
Anna Schweifer Ilse Zolle Frank Wuggenig
•
•
•
Kurt Mereiter Friedrich Hammerschmidt
Received: 18 February 2010 / Accepted: 22 February 2010 / Published online: 17 April 2010
Ó Springer-Verlag 2010
Abstract Ethyl 2,20-bipyridine-5-carboxylate was con-
verted to (2,20-bipyridine-5-yl)methanol and (S)-1-(2,20-
bipyridine-5-yl)ethanol. The latter synthesis comprised five
steps and resolution by HPLC on a chiral stationary phase.
Both alcohols were reacted with methyl 1H-imidazole-5-
carboxylate in a Mitsunobu reaction to give mixtures of the
desired methyl 1-(2,20-bipyridine-5-yl)alkyl-1H-imidazole-
5-carboxylate as main product and the methyl 1-(2,20-
bipyridine-5-yl)alkyl-1H-imidazole-4-carboxylate as side
product. The structure of (R)-(-)-methyl 1-(2,20-bipyridine-
5-yl)ethyl-1H-imidazole-4-carboxylate was determined by
X-ray structure analysis.
MTO, ETO, and structural analogues have been evalu-
ated for their potency to inhibit specific [131I]IMTO
binding to rat adrenal membranes [10]. It was found that
the (R) enantiomer of MTO is a much better ligand than the
(S) enantiomer (IC50 = 3.7 vs. 492 nM). Removal of the
methyl group from the benzylic carbon atom gave an
achiral species, which blocked [131I]IMTO binding less
efficiently (IC50 = 28.8 nM) than the parent MTO. Fur-
thermore, analogues containing a substituted phenyl or a
pyridine-3-yl ring (IC50 = 20.7 nM) in place of the phenyl
ring were evaluated. Recently, 11C-metomidate was intro-
duced as the first carbon-11 labeled radiotracer for PET
investigations of the adrenal cortex and its tumours [11–
14]. Subsequent developments include [18F]FETO for PET
[15, 16] and [123I]IMTO for SPECT investigations [17–20].
We have synthesized 4-(trimethylstannyl)MTO as a pre-
cursor for radiohalogenations with 123I, 131I, 76Br, and 18F,
primarily with radioiodine [21].
Keywords Heterocycles ꢀ Alkylations ꢀ Resolution ꢀ
Nucleophilic substitutions ꢀ X-ray structure determination
Introduction
Technetium-99m forms stable coordination complexes
with a variety of ligands of medicinal importance [22, 23].
The 99mTc(I)-tricarbonyl complex has been successfully
used for the coupling of bidentate and tridentate ligands
with the organometallic [99mTc(CO)3]? core [24–26]. To
probe the application of 99mTc(I)(CO)?3 complexes of MTO
for imaging of the adrenal cortex, its structure had to be
modified appropriately. Thus the phenyl ring was replaced
by a 2,20-bipyridine-5-yl ring, with or without conservation
of the methyl group at the stereogenic centre. The syntheses
of these two bidentate ligands 2a and 2b are reported.
Metomidate ((R)-(?)-methyl 1-(1-phenylethyl)-1H-imid-
azole-5-carboxylate, MTO, 1a Fig. 1) and the corresponding
ethyl ester etomidate (ETO, 1b) are short-acting hypnotics
[1–4] and potent inhibitors of 11b-hydroxylase in the adrenal
cortex [5–9].
Ilse Zolle: deceased April 8 2009.
A. Schweifer ꢀ F. Wuggenig ꢀ F. Hammerschmidt (&)
Institute of Organic Chemistry, University of Vienna,
Vienna, Austria
e-mail: friedrich.hammerschmidt@univie.ac.at
Results and discussion
K. Mereiter
Institute of Chemical Technologies and Analytics,
Vienna University of Technology, Getreidemarkt 9/164SC,
1060 Vienna, Austria
We decided first to prepare the achiral compound 2a,
which is more easily accessible than the homochiral
123

438
A. Schweifer et al.
CO2Et
N
N
N
1) NaOH
2) SOCl2/DMF
MeLi/
Et2O
O
N
O
R
OMe
3) (MeO)MeNH2Cl/
pyridine
96%
5-bipy
5-bipy
N
N
N
RO2C
MeO2C
7
8
92%
N
N
6
NaBH4
92%
HO
2a R = H
2b R = Me
1a R = Me (metomidate)
1b R = Et (etomidate)
5-bipy = 2,2´-bipyridine-5-yl
5-bipy
Fig. 1 Structures of metomidate, etomidate, and analogues
N
N
( )-3b
Scheme 2
compound 2b, by the Mitsunobu method used previously
[21], because the required alcohol 3a is a known compound
[27]. The secondary alcohol (S)-3b is unknown and we
expected it to be difficult to obtain. Furthermore, we
wanted to see whether the Mitsunobu reaction developed to
synthesize a variety of structural analogues of MTO
worked in this case also (Scheme 1).
Thus, (2,20-bipyridine-5-yl)methanol (3a) was coupled
with methyl 1H-imidazole-5-carboxylate (4) using Ph3P–
di-t-butyl azodicarboxylate (DtBAD) in THF at 0 °C. After
3 h, the starting alcohol had been consumed and two
overlapping spots of reaction products could be detected by
TLC. They could be isolated by flash column chromatog-
raphy in 60 and 6% yield and were assigned the structures
2a and 5a, anticipating later results. Surprisingly, in the
previous experiments only the desired products, the methyl
1-alkyl-1H-imidazole-5-carboxylates, were detected when
benzylic alcohols were used in place of (2,20-bipyridine-5-
yl)methanol [21].
methyllithium to 7 at low temperature furnished methyl
ketone 8 in 96% yield. CBS-reduction [29] could give the
desired alcohol (S)-3b directly. Although the enantiomeric
excesses are generally high with this method, but not
C99%, we decided to reduce the ketone with NaBH4 to
( )-3b and resolve it by HPLC on a chiral stationary phase
(Chiralcel OD) (Scheme 3). Both enantiomers had 99% ee
by analytical HPLC on a Chiralcel OD-H column ((-)-3b:
tR = 19.3 min; (?)-3b: tR = 23.2 min, isopropanol–
n-hexane 30:70). To determine the absolute configuration of
the enantiomers, the alcohols ( )- and (?)-3b were deri-
1
vatised with (S)-MTPACl and the H NMR spectra of the
respective (R) Mosher esters were recorded (Scheme 4).
Assuming that the two diastereomers have conforma-
tions as depicted for (?)-3bꢀMTPA-(R) and (-)-3bꢀ
MTPA-(R) [30], the resonances of the Me and OMe groups
will be shielded (lower d values) by the aromatic substit-
uents in the former diastereomer and deshielded (higher d
values) in the latter. This allowed assignment of the (R) and
(S) configurations to (?)-3b and (-)-3b.
This result encouraged us to proceed to the preparation
of 2b, with a methyl substituent at the benzylic carbon
atom, which was also essential for the high potency in
MTO. The respective alcohol (S)-3b was accessed from the
known ester 6 (Scheme 2) [27].
To obtain more of the desired enantiomer (S)-(-)-3b,
the (R) enantiomer was transformed into the p-nitro-
benzoate (S)-9 using a combination of the Mitsunobu
reaction (SN2 reaction; Ph3P/p-O2NC6H4CO2H/diisopropyl
azodicarboxylate (DIAD)) and base-catalyzed transesteri-
fication (overall yield 47%, Scheme 3). Alcohol (S)-3b
It was hydrolysed under basic conditions to give the
corresponding sodium salt, which was converted in a one-
pot reaction via the acid chloride to Weinreb amide 7 in an
overall yield of 92% [28]. Smooth addition [28] of
Scheme 1
R
OH
R
5-bipy
R
5-bipy
+
DtBAD/
Ph3P
H
N
N
N
N
MeO2C
MeO2C
+
THF
N
N
N
N
4
MeO2C
3a R = H
(S)-3b R = Me
2a R = H
2b R = Me
5a R = H
5b R = Me
5-bipy = 2,2´-bipyridine-5-yl
N
N
123

Synthesis of bipyridine analogues of metomidate
439
Scheme 3
1) p-O2NC6H4CO2H/
OH
5-bipy
OC(O)Ar
5-bipy
Ph3P/DIAD
47%
(S)-9
resolution
by HPLC
(R)-(+)-3b
( )-3b
OH
MeOH/H2O/
KOH
5-bipy
Ar = p-O2NC6H4
(S)-(-)-3b
5-bipy = 2,2´-bipyridine-5-yl
Scheme 4
MeO Ph
MeO Ph
5-bipy
O
(S)-MTPACl/
pyridine
OH
O
5-bipy
CF3
CF3
S
R
R
R
5-bipy
H
O
H
O
(+)-3b·MTPA-(R)
( )-3b
(-)-3b·MTPA-(R)
(+)-3b
(+)-3b·MTPA-(R)
δ
Me = 1.62 ppm
δ
Me = 1.68 ppm
δΟMe = 3.45 ppm
δΟMe = 3.54 ppm
(99% ee) was converted in the same way as 3a to two
isomeric imidazole derivatives, an oily major one (2b,
70%) and a crystalline minor one (5b, 11%, Scheme 1).
Careful inspection of the 1H and 13C NMR spectra
revealed significant similarities between the spectra of the
two main and two side products of the Mitsunobu coupling
and significant differences between the two pairs of spec-
tra, taking into account the changes brought about by the
methyl substituent (‘‘Experimental’’ section). To unequiv-
ocally assign the structures, that of the minor and
crystalline MTO analogue 5b derived from alcohol (S)-
(-)-3b was determined by X-ray structure analysis (Fig. 2).
The minor analogue has structure 5b and the major one 2b.
Consequently, the minor MTO analogue derived from
alcohol 3a has structure 5a and the major one 2a.
Experimental
1H NMR spectra were recorded on a Bruker DRX 400
spectrometer (400.13 MHz) in CDCl3 using the residual
solvent peak as internal reference (d = 7.24 ppm). 13C
NMR spectra (in part J modulated) were recorded on the
above spectrometer operating at 100.61 MHz (internal
reference CDCl3; d = 77.00 ppm). IR spectra were recor-
ded as films on a silicon disc using a Perkin–Elmer 1600
FT-IR spectrometer [33]. Optical rotations were measured
in a 1 dm cell at 20 °C on a Perkin–Elmer 341 polarimeter.
Elemental analyses (C, H, N) were conducted using the
Perkin–Elmer 2400 CHN elemental analyzer, and the
results were in good agreement with the calculated values.
TLC was performed on Merck plates coated with 0.25 mm
layers of silica gel 60 F254. Spots were visualized by UV
and/or with iodine or by dipping the plate into a solution of
24 g (NH4)6Mo7O24ꢀ4H2O and 1 g Ce(SO4)2ꢀ4H2O in
500 cm3 10% H2SO4 in water, followed by heating with a
heat gun. Flash chromatography was performed with
In conclusion, we have prepared analogues of metomi-
date and its demethylated version with a 2,20-bipyridine-5-
yl substituent in place of the phenyl rings. Investigation of
the ligating properties and the biological relevance of the
novel systems is under way [31, 32].
Fig. 2 Molecular structure of
5b in the solid state. Note that
the nitrogen atoms in bipyridine
are here anti-configured
123

440
A. Schweifer et al.
(d, J = 1.3 Hz, 1H, Hhet), 7.57 (d, J = 1.3 Hz, 1H, Hhet),
7.57 (dd, J = 8.4, 2.0 Hz, 1H, Har), 7.29 (ddd, J = 7.7,
4.8, 1.1 Hz, 1H, Har), 5.18 (s, 2H, NCH2), 3.83 (s, 3H,
OCH3) ppm; 13C NMR (100.61 MHz): d = 162.9 (CO),
156.8 (Car), 155.1 (Car), 149.2 (HCar), 148.2 (HCar), 137.9
(HChet), 137.0 (HCar), 136.1 (HCar), 134.5 (Chet), 130.4
(Car), 125.0 (HChet), 124.1 (HCar), 121.3 (HCar), 121.2
(HCar), 51.7 (OCH3), 48.7 (NCH2) ppm; IR (Si):
Merck silica gel 60 (230–400 mesh). THF was distilled
from potassium and Et2O from LiAlH4. Analytical HPLC
was performed with a Jasco System (PU-980 pump, UV
975, and RI 930) using a Chiralcel OD-H column, Ø
0.46 cm 9 25 cm. Preparative HPLC was performed on a
Dynamix Model SD-1 equipped with a Model UV-1
absorbance detector using a Chiralcel OD column, Ø
5 cm 9 50 cm.
ꢀ
m ¼ 2; 949, 1,723, 1,549, 1,461, 1,438, 1,381, 1,231,
1,201 cm-1
.
Methyl 1-[(2,20-bipyridine-5-yl)methyl]-1H-imidazole-5-
carboxylate and methyl 1-[(2,20-bipyridine-5-yl)methyl]-
1H-imidazole-4-carboxylate (2a and 5a, C16H14N4O2)
At 0 °C and under Ar a solution of 0.279 g (2,20-
bipyridine-5-yl)methanol (3a, 1.5 mmol) in 3 cm3 dry
THF was added to a stirred suspension of 0.465 g Ph3P
(1.77 mmol, 1.18 equiv.) and 0.189 g methyl 1H-imidaz-
ole-4-carboxylate (4, 1.5 mmol, 1.0 equiv.) in 2 cm3 dry
THF. After addition of 0.414 g DtBAD (1.8 mmol,
1.2 equiv.) dissolved in 3 cm3 dry THF the reaction
mixture was stirred for 3 h at 0 °C (TLC, MeOH–Et2O 1:5,
no starting material detectable). The solvent was removed
under reduced pressure and the resulting viscous oil was
stirred for 2 h with 5 cm3 Et2O. After filtration, the mother
liquor was concentrated in vacuo; 5 cm3 water and 5 cm3
HCl (2 M) were added and the mixture was extracted twice
with CH2Cl2 to remove impurities. After addition of
10 cm3 NaOH (2 M), the products were extracted twice
with CH2Cl2. The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The residue was
purified by flash column chromatography (MeOH–Et2O
1:100, then 1:5; TLC on silica: Et2O–MeOH 5:1, 2a and 5a
overlap, with streaking; TLC on aluminium oxide:
CH3CN–toluene–conc. NH3 50:50:1, 2a: Rf = 0.7, 5a:
Rf = 0.6) to give 0.265 g (60%) 2a, m.p. 125–126 °C
(CH2Cl2–n-hexane), and 25 mg (6%) 5a, m.p. 130–131 °C
(CH2Cl2–n-hexane).
N-Methoxy-N-methyl 2,20-bipyridine-5-carboxamide
(7, C13H13N3O2)
A mixture of 0.82 g ester 6 (3.59 mmol), 0.172 g NaOH
(4.30 mmol, 1.2 equiv.), 19 cm3 water, and 8.2 cm3 EtOH
was stirred and heated under reflux until the starting
material was consumed (30 min, TLC, AcOEt). The
solution was concentrated under reduced pressure and the
residue was dried in a vacuum desiccator over KOH for
18 h. SOCl2 (20 cm3) and 0.04 cm3 DMF were added to
the residue. The mixture was stirred and heated under
reflux for 1 h. After cooling the SOCl2 was removed under
reduced pressure (3 mm Hg); 41 cm3 dry CH2Cl2 and
0.419 g
N,O-dimethylhydroxylamine
hydrochloride
(4.30 mmol, 1.2 equiv.) were added to the residue. The
stirred mixture was cooled to 0 °C and 1.16 cm3 dry
pyridine (1.136 g, 14.36 mmol, 4 equiv.) was added drop-
wise. After stirring for 2.5 h at room temperature, the
mixture was concentrated under reduced pressure. Brine
was added and the mixture was extracted three times with
AcOEt. The combined organic layers were dried (Na2SO4)
and concentrated under reduced pressure to leave a residue
which was purified by flash chromatography (TLC: AcOEt,
Rf = 0.37) to give 0.807 g (92%) amide 7 as a yellow oil.
1H NMR (400.13 Hz): d = 8.98 (dd, J = 2.1, 0.8 Hz, 1H,
Har), 8.65 (ddd, J = 4.8, 2.0, 0.8 Hz, 1H, Har), 8.42 (dd,
J = 8.3, 0.8 Hz, 1H, Har), 8.40 (ddd & dt, J = 7.8, 1.0,
0.8 Hz, 1H, Har), 8.12 (dd, J = 8.3, 2.1 Hz, 1H, Har), 7.78
(ddd & td, J = 7.8, 7.4, 2.0 Hz, 1H, Har), 7.29 (ddd,
J = 7.4, 4.8, 1.0 Hz, 1H, Har), 3.53 (s, 3H, OCH3), 3.36 (s,
3H, NCH3) ppm; 13C NMR (100.63 MHz): d = 167.4,
157.5, 155.2, 149.3, 148.9, 137.1, 136.9, 129.4, 124.1,
1
2a: H NMR (400.13 MHz): d = 8.63 (ddd, J = 4.8,
1.7, 0.8 Hz, 1H, Har), 8.53 (d, J = 2.3 Hz, 1H, Har), 8.34 (d
with unresolved couplings, J * 8.1 Hz, 2H, Har), 7.77 (dt,
J = 7.7, 1.7 Hz, 1H, Har), 7.76 (d, J = 1.0 Hz, 1H, Hhet),
7.69 (d, J = 1.0 Hz, 1H, Hhet), 7.57 (dd, J = 8.3,
2.3 Hz,1H, Har), 7.27 (ddd, J = 7.7, 4.8, 1.2 Hz, 1H,
Har), 5.56 (s, 2H, NCH2), 3.78 (s, 3H, OCH3) ppm; 13C
NMR (100.61 MHz): d = 160.5 (CO), 156.1 (Car), 155.5
(Car), 149.2 (HCar), 148.2 (HCar), 142.1 (HChet), 138.3
(HChet), 136.9 (HCar), 135.9 (HCar), 131.8 (Car), 123.9
(HCar), 122.3 (Chet), 121.1 (HCar), 121.0 (HCar), 51.6
ꢀ
121.5, 120.1, 61.2, 33.2 ppm; IR (Si): m ¼ 2; 936, 2,971,
1,644, 1,589, 1,457, 1,435, 1,418, 1,384 cm-1
.
1-(2,20-Bipyridine-5-yl)ethanone (8, C12H10N2O)
A solution of 1.09 cm3 MeLi (1.74 mmol, 1.6 M in Et2O,
0.4% LiCl) was added dropwise to a stirred mixture of
0.384 g Weinreb amide 7 (1.58 mmol) in 18 cm3 dry THF
under argon at -55 °C. The stirred reaction mixture was
allowed to warm up slowly in the cooling bath from
-55 °C until the starting material was consumed (TLC,
when -40 °C after 50 min). Water (10 cm3) was added
and the mixture was extracted three times with AcOEt. The
ꢀ
(OCH3), 47.5 (NCH2) ppm; IR (Si): m ¼ 2; 951, 1,715,
1,462, 1,437, 1,365, 1,126, 1,112 cm-1
.
1
5a: H NMR (400.13 MHz): d = 8.63 (ddd, J = 4.8,
1.8, 0.7 Hz, 1H, Har), 8.54 (br. d, J = 2.0 Hz, 1H, Har),
8.39 (d, J = 8.4 Hz, 1H, Har), 8.35 (ddd, J = 7.7, 1.1,
0.7 Hz, 1H, Har), 7.78 (dt, J = 7.7, 1.8 Hz, 1H, Har), 7.58
123

Synthesis of bipyridine analogues of metomidate
441
combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The residue was purified
by flash chromatography (AcOEt, Rf = 0.64) to give
0.300 g (96%) ketone 8 as a crystalline solid, m.p. 112–
114 °C (n-hexane with some CH2Cl2). 1H NMR
(400.1 MHz): d = 9.18 (dd, J = 2.3, 0.8 Hz, 1H, Har),
8.68 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H, Har), 8.50 (dd,
J = 8.3, 0.8 Hz, 1H, Har), 8.45 (dt, J = 8.0, 2 9 1.0 Hz,
1H, Har), 8.31 (dd, J = 8.3, 2.3 Hz, 1H, Har), 7.82 (ddd,
J = 8.0, 7.6, 1.8 Hz, 1H, Har), 7.33 (ddd, J = 7.6, 4.7,
1.0 Hz, 1H, Har), 2.64 (s, 3H, CH3) ppm; 13C NMR
(100.6 MHz): d = 196.5, 159.5, 155.0, 149.5, 149.4,
137.0, 136.5, 131.9, 124.5, 121.9, 120.8, 26.8 ppm; IR
was allowed to warm slowly to ?10 °C within 3 h and then
concentrated after addition of 1 cm3 water. The residue
was purified by flash chromatography (AcOEt) to give a
mixture of hydrazo ester and 1.017 g p-nitrobenzoate (S)-9.
KOH (2 M, in MeOH–H2O 4:1, 10 cm3) was added and the
mixture was stirred for 18 h at room temperature. The
solution was concentrated under reduced pressure. Water
(5 cm3) was added and the mixture was extracted three
times with AcOEt. The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography to
give 0.166 g (47%) (S)-(-)-3b, [a]D20 = -46.9°cm2 g1
(c = 1.21, acetone), ee 99% by HPLC, m.p. 57–59 °C
before crystallisation from n-hexane containing a few
drops of CH2Cl2, afterwards 60–61 °C.
-1
ꢀ
(Si): m ¼ 1; 682, 1,588, 1,383, 913 cm
.
( ), (R)-(?), and (S)-(-)-1-(2,20-bipyridine-5-yl)ethanol
(( )-3b, (R)-(?)-3b, and (S)-(-)-3b, C12H12N2O)
(R)-Mosher esters of ( )-3b and (?)-3b
NaBH4 (0.054 g, 1.43 mmol) was added to a stirred
solution of 0.283 g ketone 8 (1.43 mmol) in 17 cm3 dry
EtOH at 0 °C. After stirring for 10 min at 0 °C and 15 min
at room temperature, 1 cm3 acetone and 5 cm3 water were
added. The mixture was extracted three times with Et2O.
The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. The residue was
purified by flash chromatography (AcOEt, Rf = 0.33) to
give 0.263 g (92%) alcohol ( )-3b as a crystalline solid,
A solution of 0.015 g ( )-3b (0.075 mmol) and 0.20 cm3
solution of (S)-MTPA-Cl (0.16 mmol, in dry CH2Cl2:
200 mg/cm3) in 0.5 cm3 dry CH2Cl2 and 1 cm3 dry
pyridine was left at room temperature for 18 h. Water
(5 cm3) was added and after stirring for 5 min the mixture
was extracted three times with CH2Cl2. The combined
organic layers were washed with 5 cm3 HCl (2 M), then
with a saturated aqueous solution of NaHCO3, dried,
and concentrated under reduced pressure. The residue
was flash chromatographed (AcOEt, Rf = 0.69) to give
0.031 g (quantitative) of a mixture of (?)-3bꢀMTPA-(R)
and (-)-3bꢀMTPA-(R) as an oil. The (R)-Mosher ester of
(?)-3b was prepared similarly. 1H NMR (400.13 MHz)
of (R)-Mosher ester of (?)-3b (only diagnostic signals
are given): d = 3.45 (q, J = 1.0 Hz, OCH3), 1.62 (d,
J = 6.8 Hz, CH3) ppm; of (-)-3b: 3.54 (q, J = 1.0 Hz,
OCH3), 1.68 (d, J = 6.6 Hz, CH3) ppm.
1
m.p. 62–64 °C (n-hexane with some CH2Cl2). H NMR
(400.13 Hz): d = 8.63 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H, Har),
8.57 (dt, J = 2.3, 2 9 0.7 Hz, 1H, Har), 8.31 (ddd & dt,
J = 7.8, 1.2, 1.0 Hz, 1H, Har), 8.27 (dd, J = 8.1, 0.7 Hz,
1H, Har), 7.80–7.75 (m, 2H, Har), 7.26 (ddd, J = 7.6, 4.8,
1.2 Hz, 1H, Har), 4.98 (q, J = 6.6 Hz, 1H, CHO), 2.81 (br.
s, 1H, OH), 1.51 (d, J = 6.6 Hz, 3H, CH3) ppm; 13C NMR
(100.63 MHz): d = 155.9, 155.3, 149.1, 146.9, 141.1,
137.0, 134.1, 123.6, 121.1, 120.9, 67.9, 25.1 ppm; IR
(R)-Methyl 1-[1-(2,20-bipyridine-5-yl)ethyl]-1H-imidazole-
5-carboxylate and (R)-Methyl 1-[1-(2,20-bipyridine-5-yl)-
ethyl]-1H-imidazole-4-carboxylate
ꢀ
(Si): m ¼ 3; 356, 2,973, 1,591, 1,576, 1,559, 1,462, 1,437,
1,098, 1,075 cm-1; analytical HPLC: Chiralcel OD-H
(5 °C, 0.3 cm3/min, isopropanol–n-hexane 30:70), (-)-
3b: tR = 19.3 min, (?)-3b: tR = 23.2 min.
(2b and 5b, C17H16N4O2)
Solutions of 0.115 g (S)-(-)-3b (0.57 mmol, dissolved in
2 cm3 dry THF) and 0.170 g di-t-butyl azodicarboxylate
(0.74 mmol, 1.3 equiv., dissolved in 2 cm3 dry THF) were
added to a stirred mixture of 0.193 g Ph3P (0.74 mmol,
1.3 equiv.) and 0.079 g methyl 1H-imidazole-5-carboxyl-
ate (0.63 mmol, 1.1 equiv.) in 2 cm3 dry THF at -30 °C
under Ar. The reaction mixture was allowed to warm to
room temperature in the cooling bath within 2 h (TLC,
MeOH–Et2O 1:5); three drops of water were added and the
reaction mixture was concentrated under reduced pressure;
4 cm3 water and 3 cm3 HCl (2 M) were added to the
residue and the mixture was extracted twice with CH2Cl2.
The aqueous phase was adjusted to pH 8–9 by use of
NaOH (1 M) then extracted three times with CH2Cl2. The
combined organic layers were dried (Na2SO4) and
Preparative HPLC of 0.331 g ( )-3b on a chiral
stationary phase (Chiralcel OD, water-cooled: 10 °C,
240 cm3/min, isopropanol–n-hexane 30:70) gave 0.143 g
less polar enantiomer (-)-3b (ee by HPLC 99%, [a]2D0
=
-46.7°cm2g-1 (c = 0.60, acetone); m.p. 60–61 °C (n-
hexane with some CH2Cl2)) and 0.165 g more polar (?)-3b
(ee by HPLC 99%).
Transformation of (R)-(?)-3b into (S)-(-)-3b via Mitsun-
obu reaction followed by saponification
DIAD (0.41 cm3, 0.433 g, 2.14 mmol, 1.2 equiv.) was
added, under argon, to a stirred mixture of 0.356 g (R)-(?)-
3b (1.78 mmol), 0.560 g Ph3P (2.14 mmol, 1.2 equiv.),
0.357 g p-O2NC6H4CO2H (2.14 mmol, 1.2 equiv.), and
6 cm3 dry THF cooled to -30 °C. The reaction mixture
123

442
A. Schweifer et al.
Acknowledgments The project was supported by the Austrian
¨
concentrated under reduced pressure. The residue was
purified by flash chromatography (MeOH–Et2O 1:10; TLC
in MeOH–Et2O 1:5 Rf = 0.58 for 2b, Rf = 0.06 for 5b) to
give 0.124 g (70%) 2b as a viscous oil and 0.020 g (11%)
5b as a crystalline solid, m.p. 140-141 °C (CH2Cl2–n-
hexane).
2b: [a]2D0 = ?66.7°cm2g-1 (c = 0.73, acetone); 1H
NMR (400.13 Hz): d = 8.64 (ddd, J = 4.8, 1.8, 1.0 Hz,
1H, Har), 8.52 (br. d, J = 2.4 Hz, 1H, Har), 8.37–8.34 (m,
2H, Har), 7.82 (d, J = 0.8 Hz, 1H, Hhet), 7.79 (td, J = 7.6,
1.8 Hz, 1H, Har), 7.78 (d, J = 0.8 Hz, 1H, Hhet), 7.55 (ddd,
J = 8.3, 2.4, 0.5 Hz, 1H, Har), 7.29 (ddd, J = 7.6, 4.8,
1.0 Hz, 1H, Har), 6.42 (q, J = 7.3 Hz, 1H, CHCH3), 3.77
(s, 3H, OCH3), 1.92 (d, J = 7.3 Hz, 3H, CH3) ppm; 13C
NMR (100.63 MHz): d = 160.6 (CO), 155.9 (Car), 155.5
(Car), 149.2 (HCar), 147.4 (HCar), 139.4 (HChet), 138.5
(HChet), 136.9 (HCar), 136.8 (Car), 134.5 (HCar), 123.9
(HCar), 122.3 (Chet), 121.09 (HCar), 121.0 (HCar), 53.4
National Bank (Jubilaumsfonds Project No. 8680). We thank S.
Felsinger for recording the NMR spectra and Dr M. Berger for
proofreading the manuscript.
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