Catalytic asymmetric protonation of fluoro-enolic species: Access to optically active 2-fluoro-1-tetralone

Article abstract of DOI:10.1016/S0957-4166(03)00585-8

Three racemic α-fluorinated benzyl β-ketoesters have been synthesized by electrophilic fluorination with Selectfluor. They were submitted to our well established palladium-mediated cascade reaction (deprotection, decarboxylation and protonation of the resulting enolic species) producing optically active α-fluoro ketones. With benzyl 2-fluoro-1-tetralone-2-carboxylate as substrate, (S)-(-)-2-fluoro-1-tetralone with up to 65% enantiomeric excess was obtained using quinine as the chiral base and Pd/C type 807104 from Merck as the heterogeneous catalyst.

Full text of DOI:10.1016/S0957-4166(03)00585-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2755–2761
Catalytic asymmetric protonation of fluoro-enolic species: access
to optically active 2-fluoro-1-tetralone
Markus A. Baur,a,b Abdelkhalek Riahi,a Franc¸oise He´nina,* and Jacques Muzarta
aUnite´ mixte de recherche ‘Re´actions Se´lectives et Applications’, CNRS-Universite´ de Reims Champagne-Ardenne, BP 1039,
51687, Reims Cedex 2, France
bInstitut fu¨r Anorganische Chemie, Universita¨tsstraße 31, 93053 Regensburg, Germany
Received 25 June 2003; accepted 21 July 2003
Abstract—Three racemic a-fluorinated benzyl b-ketoesters have been synthesized by electrophilic fluorination with Selectfluor™.
They were submitted to our well established palladium-mediated cascade reaction (deprotection, decarboxylation and protonation
of the resulting enolic species) producing optically active a-fluoro ketones. With benzyl 2-fluoro-1-tetralone-2-carboxylate as
substrate, (S)-(−)-2-fluoro-1-tetralone with up to 65% enantiomeric excess was obtained using quinine as the chiral base and Pd/C
type 807104 from Merck as the heterogeneous catalyst.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
to avoid racemisation of this centre bearing a hydrogen
with enhanced acidity. For this purpose, only
The synthesis of cyclic and acyclic chiral fluoro-organic
compounds is an important topic in modern pharma-
ceutical and agricultural chemistry;1 non-racemic chiral
a-fluoro ketones are also useful for asymmetric epoxy-
dation of alkenes.2 The generation of a quaternary
fluoro stereogenic centre in the a-position to a carbonyl
is now well developed using at least a stoichiometric
amount of a chiral fluorinating agent2,3 or a chiral
substrate.4 Catalytic methods have also been reported
which consist of asymmetric alkylation of racemic a-
fluoro carbonyl compounds under phase-transfer condi-
tions,5 and fluorination of b-ketoesters activated by
chiral Lewis acid–TADDOL complexes6 or under catal-
ysis by chiral palladium complexes.7 The enantioselec-
tive creation of a tertiary fluoro centre a to a carbonyl
group is more problematic since most of the above
methods work in media, which are not neutral enough
diastereoselective syntheses and
a
photochemical
approach have been reported.8 The development of
catalytic procedures is highly desirable and we report
here our studies dealing with the well established palla-
dium/chiral base-catalysed cascade reaction9 starting
from a racemic a-fluoro-b-ketoesters such as A. The
sequence could furnish optically active a-fluoroketone
D
, via oxoacid B and enolic species C, this latter being
probably an enolate associated to the protonated base
(Scheme 1).
2. Results and discussion
The first step of hydrogenolysis is a heterogeneous
Pd-catalyzed reaction and it turned out that the type of
the Pd on charcoal used not only influenced the benzyl
Scheme 1. The three steps of the cascade reaction.
* Corresponding author. Tel: +33-(0)3-2691-3310; fax: +33-(0)3-2691-3166; e-mail: francoise.henin@univ-reims.fr
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00585-8

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M. A. Baur et al. / Tetrahedron: Asymmetry 14 (2003) 2755–2761
cleavage efficiency, but also the enantioselectivity of the
protonation step.10 the hydrogenolysis delivers the reac-
tive b-ketoacid, the amount of which is probably kept
low compared to that of the chiral base during the
reaction. After the decarboxylation step, the stereose-
lectivity of the carbonyl compound is induced by the
catalytically-active base which protonates the prochiral
enolic species. Enantioselective decarboxylations start-
ing directly from the free acids and leading to precur-
sors of either the anti-inflammatory agent Naproxen or
enantioenriched a-amino acids have also been recently
reported.11
The nature of the catalyst used, palladium on charcoal,
was especially crucial. The modification of the surface
properties or the Pd and H2O contents were sufficient
to induce dramatic differences in reactivity or enan-
tioselectivity. With the usually employed 5% Pd/C type
Engelhard 5011,16 the results were not reproducible (ee
of 7 varied from 28 to 66% in presence of quinidine as
a base and the yields of 8 from 0 to 30%). Pd/C
Engelhard 506717 which initially delivered good results
(Table 1, entry 1), later led also to reproductibility
problems. Pd/C Fluka 7599218 and 7599019 gave infe-
rior results (entries 2 and 3) to Pd/C Merck 80710420
(entry 4). This latter catalyst led mainly to constant and
reproducible results. With Pd(0) (prepared by PdCl2
reduction), the reaction was slow (entry 5). The cleav-
age of the benzyl ester has been reported using the
Wilkinson catalyst and a silane as hydrogen source,21
but under hydrogen atmosphere this homogeneous cat-
alyst resulted in both low reaction rate and ee (entry 6).
Therefore, further experiments were carried out with
Pd/C type 807104 from Merck.
The substrates, b-oxoesters 2, 4 and 6 were synthesized
from the corresponding unsubstituted oxoesters 1, 3
and 5, by electrophilic fluorination with Selectfluor™
(Scheme 2). The transformation of the linear compound
1 requires a base such as NaH,12 no conversion being
observed under neutral conditions.13 However, an unex-
pected competitive fluorination at the benzylic position
occurred (THF, acetonitrile). In contrast, fluorination
worked smoothly and selectively without base for the
cyclic compounds 3 and 5.
The simple aminoalcohols 10–12 (Fig. 1) have previ-
ously led to good results in asymmetric protonation of
tetralone enolic species9a,10,22 and were tested in our
experiments (Table 2). However, 10–12 as well as
aminoalcohols 13 and 14,23 are not effective (Table 2,
entries 7–11): poor ee’s of 7 were observed and fair
amounts of 8 were isolated in most cases. In contrast,
the natural cinchona alkaloids 15–18 provided ee’s up
to 65% (entries 12–15) and produced low amounts of
the defluorination product.
Employing the catalytic cascade reaction in order to
obtain optically active fluoro ketones, the substrate
(0.17 mmol) and the chiral base (0.3 equiv.) (Fig. 1)
were dissolved in MeCN (10 mL). The Pd catalyst
(0.025 equiv.) was added then and the hydrogen atmo-
sphere provided by a gasbag. Starting from the linear
compound 2 in the first experiment, we observed com-
plete defluorination leading to deoxybenzoin as
product. This was unexpected as the CꢀF bond is
usually stable towards hydrogenolysis under Pd cataly-
sis, but the presence of a base and the benzylic position
of the fluorine atom facilitate dehalogenation.14 A dif-
ferent problem occurred with 4, since the reaction
product, 2-fluorocyclohexanone, was too volatile for an
effective work-up.15 Fortunately, benzyl 2-fluoro-1-tet-
ralone-2-carboxylate 6 was a suitable starting material
for our studies. When submitted to the above condi-
tions, the expected 2-fluoro-1-tetralone 7 was isolated
besides small amounts of the defluorinated product 8
and the compound issued from the over-reduction of 7:
2-fluoro-1-tetralol 9 (Scheme 3). The relative quantities
of each product and the ee’s of 7 were strongly depen-
dent on the reaction conditions.
Cinchona alkaloids 15–18 delivered promising results
and some of their derivatives 19–2824 showed good
catalytic performances during other asymmetric proto-
nations.11 With these modified alkaloids, defluorination
and over-reduction were minor reactions (entries 16–
25), but none of them was found to be superior to
quinine and quinidine for the asymmetric process. The
presence of a hydroxyl group is not crucial to observe
enantioselectivity, since 9-amino(9-deoxy)epicinchonine
19 induced 19% ee (entries 12 and 16). However, the
enantioselectivity never reached more than 25%, what-
ever the substitution at this amino group (entries 18–
23). The transformation of the C-9-hydroxyl function
Scheme 2. Electrophilic fluorination of b-oxoesters 1, 3 and 5.

M. A. Baur et al. / Tetrahedron: Asymmetry 14 (2003) 2755–2761
2757
Figure 1. Chiral bases used as inductors.
Scheme 3. Reaction of benzyl 2-fluoro-1-tetralone-2-carboxylate 6.
Table 1. Influence of the supported catalyst on the transformation of 6a
Entry
Catalyst (equiv.)
Time (h)
Productsb
8 (%)c
7 (%)c
ee of 7 (%)d
1
2
3
4
5
6
5% Pd/C Engelhard 5067 (0.025)
5% Pd/C Fluka 75992 (0.025)
10% Pd/C Fluka 75990 (0.025)
10% Pd/C Merck 807104 (0.025)
Pd(0) (0.25)
1
1
1
1
2
2
96; 94
98; 99
98; 92
95; 74
14; 17
2; 2
4; 6
2; 1
2; 8
62.6; 56.9
63.1; 59.9
50.7; 65.6
66.0; 67.9f
59.8; 51.2
20.5; 18.3
Tracese
Tracese
Tracese
Rh(PPh3)3Cl (0.025)
a Conditions: 6, MeCN, rt, 18 (0.3 equiv.), H2 delivered by a gasbag except entry 6 (40 bar).
b The expressed results correspond to two experiments (entries 5 and 6) or to the extreme values of several experiments (entries 1–4).
c Yields are determined by HPLC, using 2-methoxynaphthalene as standard.
d 2-Fluorotetralone of (S) configuration, ee determined by HPLC analysis.
e Yields <0.4%.
f Overall, nine experiments were carried out with this Pd/C, in seven cases the ee was 59–68%, in two cases only 48% and 50% ee were found.

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M. A. Baur et al. / Tetrahedron: Asymmetry 14 (2003) 2755–2761
Table 2. Reaction of 6 in the presence of chiral bases 10–28a
Entry
Base
Time (h)
Productsb
7c (%)
8c (%)
ee of 7d (%) (config.)
7
8
9
10
11
12
13
14
15g
16g
17
18
19
20
21
22
23
24
25
26
27
28
0.5
0.5
0.5
0.5
0.5
2
2
2
2
2
2
2
2
2
2
2
2
2
60; 74
71; 71
69; 73
52; 71
40; 53
97; 98
95; 97
99; 87
94; 93
96; 95
95; 94
86; 85
97; 93
96; 97
98; 96
97; 95
95; 89
97; 97
97; 96
40; 26
29; 29
31; 27
1; 5
60; 46
3; 3
1.5; 1.7 (R)
0.6; 1.1 (R)
0e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3.4; 0.8 (S)
0.6; 1.3 (S)
51.4; 51.5 (R)
50.0; 50.1 (S)
64.7; 64.8 (R)
62.5; 64.4 (S)
20.4; 17.9 (S)
24.1; 14.7 (S)
6.7; 1.5 (S)
20.0; 25.1 (S)
2.7; 2.4 (S)
17.4; 19.4 (S)
24.9; 20.7 (S)
8.1; 8.0 (S)
5.9; 1.7 (S)
20.9, 21.1 (S)
5; 3
Tracesf; 13
6; 7
2; 2
1; 1
3; 2
3; 7
2; 3
2; 1
1; 1
1; Tracesf
1; 1
2; 2
2
a Conditions: 6, Pd/C Merck 807104 (0.025 equiv.), base (0.3 equiv.), MeCN, rt, H2 delivered by a gasbag.
b The expressed results correspond to two experiments.
c Yields are determined by HPLC, using 2-methoxynaphthalene as standard; the yield of 9 was low (0–4%), therefore it is not listed in Table 2.
d Ee determined by HPLC analysis.
e Not detected by HPLC (l=254 nm).
f Yields <0.4%.
g Not fully soluble in MeCN.
into carbamate 27 or ether 28 also gave disappointing
more defluorination was observed (entry 28). Ee’s of 7
were almost unchanged for a reaction time between
0.25 h (entry 29) and 16 h (entry 30); the amount of 9
remained low, while that of 8 increased and it became
the main product after 52 h (91%), ee of 7 decreasing to
8% (entry 31). A reaction carried out under 40 bar led
to an ee similar to the standard conditions (entry 32). A
tenfold amount of Pd/C induced a high degree of
defluorination and the ee dropped to 25% (entry 33).
With a threefold quantity of quinine, results were simi-
results25 (entries 24 and 25).
As quinine 18 delivered the best results, variations of
the experimental conditions were carried out with this
base (Table 3). Switching to THF as solvent decreased
the ee from 65 to 60% (entry 26). With EtOAc, ee may
increase, but the result was not reproducible (entry 27).
Furthermore, defluorination increased in both solvents.
At 45°C, ee’s are identical to standard conditions, but
Table 3. Variation of the catalysis parameters with 6 as substrate and 18 as a base
Entry
Change/standard conditionsa
Productsb
7c (%)
8c (%)
9c (%)
ee of 7d (%)
26
27
28
29
30
31
32
33
34
Solvent: THF
Solvent: EtOAc
T=45°C
Time=0.25 h
Time=16 h
81; 77
86; 97
60; 86
4; 5
53; 64
9
12; 16
5; 3
98
11; 23
14; 2
32; 14
Tracesf
35; 36
91
8; n.d.e
n.d.e; 1
8; n.d.e
0; 0
59; 61.8
70.3; 59.2
65.9; 68.0.
64.4; 66.6
69.8; 51.8
8.2
64; 60
24.6; 26
55.0
12; n.d.e
n.d.e
Time=52 h
H2 pressure=40 bar, time=0.25 h
Pd/C, 0.25 equiv.
0.9 equiv. of 18
Tracesf
57; 62
2
0; 0
38; 35
n.d.e
a Standard conditions: 6, Pd/C Merck 807104 (0.025 equiv.); 18 (0.3 equiv.); MeCN, rt, H2 delivered by a gasbag, reaction time, 2 h.
b The expressed results correspond to two experiments.
c Yields are determined by HPLC, using 2-methoxynaphthalene as standard.
d (S) Configuration.
e Not detected by HPLC (l=254 nm).
f Yields <0.4%.

M. A. Baur et al. / Tetrahedron: Asymmetry 14 (2003) 2755–2761
2759
4. Experimental
lar to standard catalysis (entry 34). It could be logical
to correlate the decrease of the ee with the liberation of
racemizing HF issued from the defluorination (entries
31 and 33), but this was not observed in all cases
(entries 26, 27, 28, 30).
4.1. General
IR spectra were measured on a Beckman Acculab 3.
1H, 13C and 19F spectra were recorded on Bruker AC
250, Avance 300 or Avance 600. Mass spectra were
obtained by electronic impact (EI-MS; Finnigan MAT
311A) or by chemical ionization (GC-CI; JEOL D-300).
Flash chromatography: silica gel Merck 9385 (230–400
mesh); (ordinary) chromatography: silica gel 60 Merck
(70–230 mesh). The melting point is uncorrected (Bu¨chi
SMP 20). Elemental analysis was done with Perkin–
Elmer CHN 2400. HPLC were recorded on a Hewlett–
Packard HP1090M, column thermostat Agilent 1100
Series, column Daicel OD-H (length 250 mm, 5 mm
inner diameter), using 2-methoxynaphtalene as internal
standard for quantitative analysis. The solvents used
for synthesis and catalysis were dried by standard pro-
cedures. Preparation of starting material was performed
under argon or nitrogen atmosphere.
Further reactions have been carried out in order to
approach the mechanism of the different reactions
(Table 4). Stirring enantioenriched 7 under standard
conditions (Pd/C, quinine, MeCN, H2, rt), the ee of 7
stayed constant, but 8 and 9 were formed (entry 35).
Without hydrogen, no by-product was detected and a
longer reaction time led to a drop of the ee (entry 36).
Analogous experiments performed from racemic 7
under a hydrogen atmosphere did not lead to enan-
tioenrichment of 7 but by-products 8 and 9 were
formed (entry 37). No transformation was observed in
the absence of hydrogen (entry 38). Thus, deracemisa-
tion of 7 was excluded during its reduction to 8 or 9. As
expected, racemic 6 was stable under standard condi-
tions in the absence of hydrogen (entry 39). From these
experiments, it appears that defluorination is probably
a hydrogenolysis (compare runs 35 and 36) and that
liberated HF did not racemise 7 (see above). On the
contrary, the supported palladium catalyst racemizes
even without hydrogen (entry 36).
The precursors for fluorination were prepared as
described for 19c and by transesterification26 with benzyl
alcohol of the corresponding ethyl oxo-ester, commer-
cially available for 3 or synthezised following reported
procedures.27
4.2. Fluorination of oxoesters
4.2.1. Fluoro-3-oxo-2,3-diphenylpropionic acid benzyl
ester 2. To a suspension of NaH (60% in mineral oil;
120 mg; 3.00 mmol) in THF (10 mL), 3-oxo-2,3-
diphenylpropionic acid benzyl ester9c (990 mg, 3.00
mmol) in THF (20 mL) was added slowly at 0°C. The
mixture was stirred for 0.5 h at 0°C and then 1 h at rt.
After dilution with DMF (30 mL), Selectfluor® (1.06 g,
3.00 mmol) was added in one portion. The mixture was
stirred overnight. After addition of water, it was
extracted with Et2O (3×50 mL); the organic extracts
were dried over MgSO4 and evaporated. The crude
product was successively purified by flash chromatogra-
phy (petroleum ether:EtOAc 95:5) and chromatography
(CH2Cl2). This procedure did not allow to remove a
low amount of by-product fluorinated at the benzylic
3. Conclusions
In conclusion, the use of the catalytic cascade reaction
with benzyl 2-fluoro-1-tetralone-2-carboxylate as sub-
strate showed that switching from a-alkylated b-
ketoesters to comparable fluoro substituted compounds
is not a simple analogous application. The reaction is
much more sensitive to the nature of the Pd catalyst
generating reproducibility problems. The aminoalco-
hols we previously used proved to be inappropriate
catalysts in regard to the ee’s, furthermore they may
promote fast defluorination. Not only is the chiral
inductor important, but the adapted conditions are
essential for success and to avoid defluorination or
racemisation. Associated to Pd/C catalyst type 807104
from Merck and the commercial quinine and quinidine
turned out to be the most successful catalytically active
bases for this reaction, leading to enantiomeric excesses
up to 65%.
1
position (about 3%). Colorless oil (570 mg, 55%). H
NMR (CDCl3, 250 MHz): l 5.33 (d, 1H, J=10.0 Hz,
CHHPh), 5.38 (d, 1H, J=10.0 Hz, CHHPh), 7.28–7.67
(m, 13H, aromatics), 7.92–7.99 (m, 2H, aromatics)
ppm; 13C DEPT135 NMR (CDCl3, 62.9 MHz): l 68.7
Table 4. Further experimentsa
Entry
Substrate
H2
Time (h)
Products
7 (%)
8 (%)
9 (%)
ee of 7 (%)
35
36
37
38
39
7 (50/55% ee)
7 (62.6/65.9% ee)
7 (racemic)
7 (racemic)
6 (racemic)
Yes
No
Yes
No
No
16
48
16
16
48
10/68
100/100
71/94
100/100
–
74/25
0/0
27/4
0/0
–
16/6
0/0
2/2
0/0
–
50.6/53.6
23.0/34.5
Racemic
Racemic
–
a Reaction conditions: 6, Pd/C Merck 807104 (0.025 equiv.); 18 (0.3 equiv.); MeCN, rt, H2 delivered by a gasbag.

2760
M. A. Baur et al. / Tetrahedron: Asymmetry 14 (2003) 2755–2761
(s, CH2Ph), 126.1 (d, J=8.8 Hz), 128.6 (s), 129.0 (s),
129.8 (s), 130.6 (d, J=5.0 Hz), 134.3 (s) ppm: CH
aromatic; 19F NMR (235 MHz, CDCl3): l −157.2 (s)
ppm; GC–MS (CI): 6.8 min, m/z (%)=91 (22)
[PhꢀCH2], 108 (42) [PhCH2OH], 244 (36) [M+−PhCO],
262 (100) [M+−PhCO+NH4].
67.7 (s), 93.3 (d, J=193.9 Hz, CF), 127.3 (s), 128.0 (s),
128.5 (d, J=2.9 Hz), 128.6 (s), 128.8 (s), 134.6 (s), 132.7
(d, J=193.9 Hz, C), 143.1 (s), 167.2 (d, J=26.5 Hz,
CꢁO ester), 188.5 (d, J=19.2 Hz, CꢁO oxo) ppm; 19F
NMR (235 MHz, CDCl3): l −164.94 (dd, J=22.4, 10.3
Hz) ppm; MS (PI–EI) m/z (%)=91 (100) [PhCH2], 118
(26), 164 (43) [C10H9FO], 298.1 (27) [M]; C18H15FO3
(298.3); HPLC: [Chiralcel OD-H, hexane:isopropanol
97:3, 0.6 mL/min, 25°C, 210 nm, 35.8 min and 42.9
min]. Anal. calcd: C, 72.47; H, 5.07. Found: C, 72.21;
H, 4.84%.
By-product
(3-oxo-2,3-diphenylpropionic
acid
1
fluorobenzyl ester): H NMR (CDCl3, 250 MHz): 5.85
(d, 0.03H, 2JH,F=47.8 Hz, CFHPh); 19F NMR (235
2
MHz, CDCl3): l −179.87 (d, JH,F=47.8 Hz, CFHPh);
GC–MS (CI): 7.1 min, m/z (%)=91 (27) [PhꢀCH2], 106
(97), 108 (86) [PhCH2OH], 116 (28), 134 (22)
[PhCH2COO], 220 (11) [PhCOCHPhCOO], 268 (100);
C22H17FO3 (348.4).
4.3. Hydrogenolysis–decarboxylation–protonation
Benzyl-2-fluoro-1-tetralone-2-carboxylate 6 (50.4 mg,
0.17 mmol) and the chiral base (0.3 equiv., 0.051 mmol)
were dissolved in acetonitrile (10 mL). Then the Pd
catalyst (0.025 equiv., 4.25 mmol) was added and the
hydrogen atmosphere was provided by a gasbag.
4.2.2. Benzyl 2-fluorocyclohexanone-2-carboxylate 4. To
benzyl cyclohexanone-2-carboxylate 3 (1.50 g, 6.46
mmol) in acetonitrile (65 mL), Selectfluor® (2.29 g, 6.46
mmol) was added in one portion and the reaction
mixture was stirred for 20 h at rt. After removal of the
solvent, the residue was taken up in CH2Cl2/H2O and
extracted with CH2Cl2 (3×50 mL). The organic layer
was washed with water and dried over MgSO4, filtered
and evaporated. The crude product was purified by
flash chromatography (petroleum ether:EtOAc 90:10).
Colorless liquid (1.30 g, 80%). IR (neat): w 2980, 2890,
1760, 1730 cm−1; 1H NMR (300 MHz, CDCl3): l
1.74–1.98 (m, 4H), 2.08–2.24 (m, 1H), 2.36–2.63 (m,
2H), 2.65–2.79 (m, 1H), 5.24 (d, 1H, J=12.1 Hz,
CHHPh), 5.29 (d, 1H, J=12.1 Hz, CHHPh), 7.30–7.42
(m, 5H, aromatics) ppm; 13C NMR (75.5 MHz,
CDCl3): l 20.8 (d, J=5.2 Hz), 26.6 (s), 36.0 (d, J=21.4
Hz), 39.6 (s), 67.8 (s), 96.4 (d, J=196.8 Hz, CF), 128.3
(s), 128.6 (s), 128.7 (s), 134.8 (s), 166.8 (d, J=25.1 Hz,
CꢁO ester), 201.8 (d, J=19.9 Hz, CꢁO oxo) ppm; 19F
NMR (235 MHz, CDCl3): l 160.97 (ddd, J=21.9, 13.7,
5.1 Hz) ppm; GC–MS (CI): 7.1 min, m/z (%)=91 (10)
[PhꢀCH2], 108 (29) [PhCH2OH], 134 (5) [C6H9FO+
NH4], 250 (4) [M], 268 (100) [M++NH4]; C14H15FO3
(250.3).
After the time indicated in Tables 1–4, the reaction
mixture was filtered through a pad of Celite 545 (10 cm,
CH2Cl2 as solvent) to remove the palladium catalyst
and through a short SiO2 column (CH2Cl2) to remove
the base. The solvents were eliminated at rt.
4.3.1. 2-Fluoro-1-tetralone 728. 1H NMR (300 MHz,
CDCl3): l 2.20–2.38 (m, 1H), 2.53 (dddd, 1H, J=16.8,
9.8, 5.3, 4.2 Hz), 3.08 (dd, 2H, J=9.8, 4.2 Hz), 5.10
(ddd, 1H, J=47.9, 12.8, 5.3 Hz, FCH), 7.22 (d, 1H,
J=7.7 Hz), 7.30 (t, 1H, J=7.5 Hz), 7.48 (td, 1H,
J=7.5, 1.4 Hz), 8.01 (dd, 1H, J=8.0, 1.1 Hz) ppm; 19F
NMR (235 MHz, CDCl3): l −191.36–190.25 (m) ppm;
C10H9FO (164.2); [h]2D0=−35.5 (c 0.42, dioxane) (S)
configuration, ee[HPLC] 59%; lit.29 +64.9 (c 0.43, diox-
ane) (R) configuration, ee >95%). HPLC: [Chiralcel
OD-H, hexane: isopropanol 97:3, 0.6 mL/min, 25°C,
210 nm, (R)-(+): 22.2 min, (S)-(−): 23.5 min].
4.3.2. 1-Tetralone 8. HPLC: [Chiralcel OD-H, hex-
ane:isopropanol 97:3, 0.6 mL/min, 25°C, 210 nm, 13.4
min].
4.2.3. Benzyl 2-fluoro-1-tetralone-2-carboxylate 6. To
benzyl 1-tetralone-2-carboxylate 4 (2.34 g, 8.35 mmol)
in acetonitrile (100 mL), Selectfluor® (2.96 g, 8.35
mmol) was added in one portion. The reaction mixture
was stirred for 19 h at rt. After evaporation of the
solvent, the remaining residue was taken up (H2O/
CH2Cl2) and extracted three times with CH2Cl2 (3×100
mL). The combined organic layers were dried over
MgSO4 and evaporated. Flash-chromatography
(petroleum ether:EtOAc 90:10) afforded an orange oil.
Recrystallisation from Et2O gave a colorless solid (1.72
g, 69%). Mp=64–65°C; IR (KBr): w 1760, 1600, 1460
4.3.3. 2-Fluoro-1-tetralol 9. This compound is identical
to a sample issued from the NaBH4 reduction of 2-
fluorotetralone leading to
a
70/30 mixture of
diastereomers, where a OH, F-cis-relative configuration
has been attributed to the major diastereomer by com-
1
parison of H NMR spectra with those described in the
literature.30 MS (EI) m/z (%)=91 (36), 119 (100), 148
(70) [M−H2O], 166 (42) [M]; C10H11FO (166.2); HPLC:
[Chiralcel OD-H, hexane:isopropanol 97:3, 0.6 mL/min,
25°C, 210 nm, 25.8 min and 28.4 min (cis-isomers); 27.6
min and 30.0 min (trans-isomers)].31
1
cm−1; H NMR (300 MHz, CDCl3): l 2.55 (dddd, 1H,
J=13.8, 11.3, 8.0, 5.2 Hz), 2.72 (dddd, 1H, J=13.8,
11.3, 7.4, 5.0 Hz), 3.00 (ddd, 1H, J=17.3, 7.8, 5.2 Hz),
3.17 (dt, 1H, J=17.3, 6.2 Hz), 5.22 (d, 1H, J=12.3 Hz,
CHHPh), 5.30 (d, 1H, J=12.3 Hz, CHHPh), 7.22–7.33
(m, 6H, aromatics), 7.37 (t, 1H, J=8.1 Hz, aromatic),
7.55 (td, 1H, J=7.5, 1.4 Hz, aromatic), 8.08 (dd, 1H,
J=7.8, 1.2 Hz, aromatic) ppm; 13C NMR (75.5 MHz,
CDCl3): l 24.8 (d, J=7.3 Hz); 31.9 (d, J=22.1 Hz),
Acknowledgements
Professor Henri Brunner is greatly acknowledged for
giving M.B. the opportunity to carry out the largest
part of the experimental work described herein in
Regensburg. We thank the European Community for a

M. A. Baur et al. / Tetrahedron: Asymmetry 14 (2003) 2755–2761
2761
Marie Curie fellowship to M.B. (contract HPTMT-CT-
2000-00112) and Professor C. Portella for making it
possible.
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forsch. B 2000, 55, 369; (c) Brunner, H.; Baur, M. A.
Eur. J. Org. Chem. 2003, 2854–2862.
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