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J. Ba´lint et al. / Tetrahedron: Asymmetry 12 (2001) 3435–3439
4.2. Determination of the enantiomeric excess by gas
chromatography
The phases were separated. The aqueous phase was
extracted again by dichloromethane (3×25 mL). The
combined organic phase was dried over Na2SO4 and
the solvent was removed in vacuo to afford an oil
(4.73 g). Vacuum distillation afforded an oil of (S)-6-
fluoro-2-methyl-quinoline (4.46 g, 54%,), which solid-
ified on standing or scratching [h]2D0=−69.5 (c=1,
ethanol) e.e.GC=99.2%, mp: 40–42°C.
Gas chromatographic measurements were completed
on a Hewlett-Packard HP 5890/II instrument using
FID. Separations were achieved on a 12 m×0.1 mm
fused silica open tubular column coated with Chirasil-
Dex (methyl silicone polymer substituted with perme-
thylated b-cyclodextrin) chiral stationery phase.16 H2
carrier gas was used (1 mL/min), with split injection
and 150°C analysis temperature. Acetate derivatives
were analyzed, which were synthesized by the gener-
ally used method (acetic acid anhydride with triethyl-
amine, 80°C, 2 h).17
Workup of the resolution mother liquor was similar
to that of the diastereoisomeric salt after evaporation
of the solvent, yielding an oil of (R)-6-fluoro-2-
methyl-quinoline, (10.41 g, 125%), [h]2D0=+33.8 (c=1,
ethanol) e.e.GC=48.1%.
4.3. Small scale resolution of FTHQ (general
procedure)
Similarly, workup of the recrystallization mother
liquor gave (S)-6-fluoro-2-methyl-quinoline (oil,
1.21 g, 15%), [h]D20=−43.9 (c=1, ethanol) e.e.GC
62.5%.
=
Racemic FTHQ 1 (2.0 g) and the resolving agent
(tartaric acid, dibenzoyl-tartaric acid or di-p-toluoyl
tartaric acid, 1.0 or 0.5 molar equiv.) were dissolved
in the given solvent (see Table 1) with heating. The
solution was cooled to room temperature. Crystalliza-
tion was induced by scratching. The crystals were
filtered after 5 minutes (Table 1) or given time (Table
2). In the case of the time-scale experiments stirring
was only occasional. The diastereoisomeric salt and
the mother liquor were worked up separately.
4.5. Aromatization of (R)-FTHQ by oxygenation
Propionic acid (40 mL) was stirred for 15 min with
NaBr (0.25 g, 2.43 mmol) and Co(AcO)2·4H2O 0.60
g, 2.41 mmol). To the purplish solution was added
(R)-FTHQ (7.80 g, 47.2 mmol, e.e.=94%). The mix-
ture was kept under air pressure (8 bar) at 120–140°C
for 8 h. Propionic acid was removed in vacuo (10
mmHg) then the product was purified by vacuum dis-
tillation (0.3 mmHg). Yield: 6.00 g of oily substance
(6-fluoro-2-methyl-quinoline, 37 mmol, 78%, [h]2D0=0
Workup of the diastereoisomeric salt is as follows:
The crystals were suspended in water (20 mL) and
NaOH
(1
g)
was
added.
After
adding
1
(c=1 ethanol). H NMR (CDCl3): 2.7 (s, 3H, CH3),
dichloromethane (10 mL), the mixture was stirred for
5 min. The phases were separated. The aqueous phase
was extracted again with dichloromethane (3×10 mL).
The combined organic phase was dried over Na2SO4
and the solvent was removed in vacuo. FTHQ is an
oily substance, which, depending on its enantiomeric
excess, may crystallize upon scratching. The NMR
and FT-IR spectra and the elemental composition are
identical to those of the racemate.
1.50 (m, 1H), 7.3–7.4 (m, 3H, Ar), 7.9–8.0 (m, 2H,
Ar).
The product contained 12% (mol/mol) of propionic
acid: 1.2 (t, 3H, CH3), 2.4 (d, 2H, CH2).
4.6. Aromatization of (R)-FTHQ by elemental sulfur
FTHQ (7.80 g, 47.2 mmol, [h]2D0=+66.1 (c=1, etha-
nol) and sulfur (3.30 g, 103 mmol) were kept at 202–
206°C for 40 min. Following heavy gas evolution the
mixture became dark brownish-red. After this time,
the mixture was cooled to 80°C and distilled in vacuo
(0.3 mmHg) to yield a dark yellow oil of 6-fluoro-2-
methyl-quinoline (6.84 g, ca. 42 mmol, ca. 89%)
which solidified on standing [h]2D0=+4.0 (c=1 ethanol)
4.4. Resolution of FTHQ by di-p-toluoyl tartaric acid
in the presence of HCl
A solution of (R,R)-di-p-toluoyl tartaric acid (19.50
g, 50.5 mmol) in methanol (60 mL) at about 50°C
was treated with FTHQ (16.60 g, 100.5 mmol) and
37% aqueous HCl solution (4 mL, 49 mmol). After
cooling to room temperature, crystallization was ini-
tiated by scratching. The thick suspension was stirred
for 10 min, then filtered. The filter cake was washed
with methanol (4×5 mL) and dried to afford the solid
diastereoisomeric salt (20.04 g). The salt was dis-
solved in hot methanol (100 mL) and cooled slowly
to −5°C. After stirring for 1 h at −5°C the mixture
was filtered, washed with methanol (4×5 mL) and
dried to afford white crystalline diastereoisomeric salt
(15.5 g), [h]2D0=−124.0 (c=1 methanol).
1
mp 40–46°C. The H NMR spectrum of the product
is identical to that described in Section 4.5. The
product contained ca. 7% of unreacted FTHQ.
Acknowledgements
The Hungarian OTKA Foundation (Project No.
T29251, F.E.) is gratefully acknowledged for financial
support. J.B. thanks the OTKA foundations for post-
doctoral fellowship (D32705). G.E. thanks the OTKA
foundation for a postdoctoral fellowship (D29445).
The crystals were suspended in water (150 mL) and
NaOH (4 g) was added. After adding dichloro-
methane (25 mL), the mixture was stirred for 5 min.