96
R. Csuk et al. · An Alternative and Efficient Route to Chlorophacinone
In summary, our approach allows the synthesis of
chlorophacinone in a straightforward manner from
commercially available starting materials.
Experimental Section
General methods
Fig. 2. Selected 13C NMR spectroscopic data of 1; A in
D ]DMSO (shortly after dissolving); B in CDCl solution.
Melting points are uncorrected (Leica hot stage micro-
scope). The solvents were dried according to usual proce-
dures.
[
6
3
Recently, we became interested in the synthesis [11]
of radiolabelled [12] 1 which is free of any signifi-
cant amounts of 2 and other impurities difficult [13] to
remove. Therefore, an alternative synthesis for 1 was
called for.
rac-2-(4-Chlorophenyl)phenyl acetic acid (4)
To a mixture of racemic mandelic acid (3) (19.0 g,
◦
0
.12 mol) and chlorobenzene (70 mL) at 70 C SnCl (48.8 g,
4
0
.19 mol) was slowly added and the mixture heated under re-
Retrosynthetic planning revealed mandelic acid
◦
flux for 8 h. After cooling to 25 C, the reaction mixture was
(
3) as an appealing starting material; it is commer-
poured onto crushed ice and extracted with dichloromethane
cially available and cheap. Thus, 3 was reacted with
(
2
4 × 200 mL). The extracts were washed (10 % aq. HCl,
5 mL; water 2 × 25 mL) and dried (Na SO ), and the sol-
chlorobenzene (Scheme 1) in the presence of SnCl
4
2
4
[
14] to afford 85 % of the phenylacetic acid 4. Alterna-
vent was removed. Recrystallization from ethanol yielded 4
(
1
tive routes to 4 have been devised [15 – 19] but yields
dropped significantly upon scaling up. Treatment of 4
with oxalyl chloride [20] at room temperature gave the
chloride 5 which could be used in the next step without
any purification. Friedel-Crafts reaction of 5 with 1,3-
indanedione (6) provided chlorophacinone (1). HPLC
analysis [21] of this material gave no indication for the
presence of significant amounts of diphacinone.
◦
25.2 g, 85 %) as a colorless solid. M. p. 116 – 118 C (lit.:
◦ ◦
17 – 118 C [23]; 115 – 117 C [16]).
rac-2-(Phenyl-4-chlorophenylacetyl)indane-1,3-dione
(
chlorophacinone) (1)
◦
At 0 C to a solution of 4 (3.4 g, 13.7 mmol) in dry
dichloromethane (30 mL), oxalyl chloride (3.5 g, 27.4 mmol)
◦
was added, and the mixture was stirred at 25 C for 12 h.
As previously [22] shown, 1 adopts in the solid state
The solvents were removed under reduced pressure, and the
residue was dissolved in dry dichloromethane (20 mL). This
solution was slowly added to a mixture of 1,3-indanedione
the keto form A (Fig. 2). Contrary to this finding, on
dissolving 1 in CDCl and leaving the solution stand
3
1
3
for an hour at room temperature, the C NMR spec-
trum revealed the presence of 19 signals, among them
three signals (δ = 198.01, 188.23 and 184.17 ppm)
which are typical for a C=C unit carrying an oxygen-
containing substituent. Guided by symmetry consid-
(
6) (2.0 g, 13.7 mmol) and AlCl (3.2 g, 24.0 mmol) in dry
3
dichloromethane (20 mL). Stirring was continued for 12 h.
The mixture was poured onto crushed ice (containing 10 %
aq. HCl) and extracted with ethyl acetate (4 × 200 mL).
The extracts were dried (Na SO ), washed (10 % aq. HCl,
2
4
erations, therefore in CDCl the presence of an enol
3
25 mL; then water, 2 × 25 mL) and dried again (Na SO ),
2
4
form B is most likely. A similar behavior is observed in and the solvents were removed. Flash chromatography (sil-
[
D ]DMSO although the enolization needs more time ica gel, hexane/ethyl acetate, 8 : 2) yielded 1 (3.0 g, 60 %) as
6
◦
◦
to take place.
a pale-yellowish solid. M. p. 137 – 140 C (lit.: 140 C [6]).
[
[
[
[
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10.1515/znb-2011-0116
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