(Salen)chromium Complex Mediated Asymmetric Ring Opening of meso- And Racemic Epoxides with Different Fluoride Sources

Article abstract of DOI:10.1002/1615-4169(200202)344:2<165::AID-ADSC165>3.0.CO;2-1

The asymmetric ring opening of five meso-and three racemic epoxides with different fluorinating reagents in the presence of stoichiometric or slightly sub-stoichiometric amounts of Jacobsen's enantiopure (salen)chromium chloride complex A gave the corresponding optically active vicinal fluorohydrins. Silver fluoride was used as one of the fluoride sources either in the presence of Bu₄N⁺H₂F₃^- in diethyl ether or in acetonitrile. The latter reactions starting from cyclohexene oxide (1) showed maximum 72% ee in the formed fluorohydrin 2 isolated in 90% yield. From other meso-epoxides such as cyclopentene oxide and cycloheptene oxide the corresponding fluorohydrins were isolated in 80% and 82% yield with 65% and 62% ee, respectively. In case of ring opening under similar conditions of the racemic styrene oxide or phenyl glycidyl ether 83% and 75% of the fluorohydrins with fluorine in the primary position were isolated with 74% ee and 65% ee, respectively. Tetrahydronaphthalene oxide yielded a 2:1 mixture of trans- (23% ee) and cis-2-fluoro-3,4-benzocyclohexenol (2% ee) suggesting competing S_N2 and S_N1 type ring openings. Other epoxides such as cyclooctene oxide, cis-stilbene oxide and α-methylstyrene oxide did not react or gave the fluorohydrins with very small enantiomeric excess.

Full text of DOI:10.1002/1615-4169(200202)344:2<165::AID-ADSC165>3.0.CO;2-1

FULL PAPERS
(
Salen)chromium Complex Mediated Asymmetric Ring Opening
of meso- and Racemic Epoxides with Different Fluoride Sources
G¸nter Haufe,* Stefan Bruns
Organisch-Chemisches Institut, Westf‰lische Wilhelms-Universit‰t, Corrensstra˚e 40, 48149 M¸nster, Germany
Fax: ( ‡ 49)-251-83-39772, e-mail: haufe@uni-muenster.de
Received December 27, 2000; Revised received November 26, 2001; Accepted December 13, 2001
Abstract: The asymmetric ring opening of five meso- opening under similar conditions of the racemic
and three racemic epoxides with different fluorinating styrene oxide or phenyl glycidyl ether 83% and
reagents in the presence of stoichiometric or slightly 75% of the fluorohydrins with fluorine in the primary
sub-stoichiometric amounts of Jacobsen×s enantio- position were isolated with 74% ee and 65% ee,
pure (salen)chromium chloride complex A gave the respectively. Tetrahydronaphthalene oxide yielded a
corresponding optically active vicinal fluorohydrins. 2:1 mixture of trans- (23% ee) and cis-2-fluoro-3,4-
Silver fluoride was used as one of the fluoride sources benzocyclohexenol (2% ee) suggesting competing SN2
‡
À
either in the presence of Bu N H F in diethyl ether and S 1 type ring openings. Other epoxides such as
4
2
3
N
or in acetonitrile. The latter reactions starting from cyclooctene oxide, cis-stilbene oxide and a-methyl-
cyclohexene oxide (1) showed maximum 72% ee in styrene oxide did not react or gave the fluorohydrins
the formed fluorohydrin 2 isolated in 90% yield. with very small enantiomeric excess.
From other meso-epoxides such as cyclopentene
oxide and cycloheptene oxide the corresponding
fluorohydrins were isolated in 80% and 82% yield Keywords: catalysis; enantioselectivity; epoxide ring
with 65% and 62% ee, respectively. In case of ring opening; fluorohydrins; transition metals.
Introduction
tive electrophilic fluorination of b-ketoesters containing
a tertiary carbon center using Seebach-type enantiopure
¾
During the past years both the academic and the titanium TADDOLate complexes and selectfluor as
[
6]
economic interest in fluorinated compounds hassteadily the source of positive fluorine.
grown because of their unique properties.[ Most
1]
In contrast, there was only one example of an
importantly, a single fluorine substituent does not enantioselective nucleophilic fluorination, namely a
change the steric demand of a molecule but, on the kinetic resolution (maximum 16% ee) during fluorode-
other hand, it can modify the electronic properties such hydroxylation of silyl ethers using an (S)-proline-based
[
7]
as acidity of neighboring groups or the dipole moment analogue of DAST, when we recently described the
fairly dramatically. This is particularly important for enantioselective introduction of fluoride into symmetric
tuning of the biological activity of pharmaceuticals or or racemic epoxides with potassium hydrogen difluoride
agrochemicals.[
2]
in the presence of equimolar amount of Jacobsen×s
In this respect enantioselective syntheses are of enantiopure (salen)chromium chloride complex A. This
particular interest. Recently, asymmetric syntheses of complex has successfully been applied as a pre-catalyst
[
3]
fluorinated compounds have been reviewed. There are in asymmetric epoxide ring opening with azide previ-
[
8]
many different methods to construct optically active ously. For the synthesis of optically active fluorohy-
fluorinated molecules from fluorinated building blocks drins, however, stoichiometric or slightly sub-stoichio-
by asymmetric carbon-carbon bond formations, dera- metric amounts of the enantiopure Lewis acid A have
cemizations of fluorinated compounds or substitution of been necessary to effect moderate enantioselectivity. In
halogens, oxygen or nitrogen functions with fluoride in all cases the formation of the corresponding chlorohy-
compoundswhich are already optically active. Moreover, drins was observed as a side reaction. For example, an
there are two methods for the electrophilic asymmetric 89:11 mixture of (R,R)-(À)-2-fluorocyclohexanol (2)
introduction of fluorine into a molecule. The electro- (55% ee) and (R,R)-(À)-2-chlorocyclohexanol (3) (20%
philic fluorination of the a-position in carbonyl com- ee) was formed from cyclohexene oxide (1) and KHF2
pounds using (i) Differding×s N-fluorocamphorsultam using 100 mol % of (S,S)-(‡)-(salen)chromium chlor-
and analogues,[ or N-fluoro compounds derived from ide. With 10 mol % of this Lewis acid only 11% ee was
4]
[
5]
[9]
Cinchona alkaloids, and (ii) a catalytic enantioselec- found in the fluorohydrin 2.
Adv. Synth. Catal. 2002, 344, No. 2
¹ VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 2002 1615-4150/02/34402-165 ± 171 $ 17.50+.50/0
165

FULL PAPERS
G¸nter Haufe, Stefan Bruns
Now we present further attempts to improve the
selectivity and the chemical yield of epoxide ring
opening with fluorinating reagents mediated by the
enantiopure Lewis acid A. Furthermore, we tried to
lower the necessary quantity of A well below stoichio-
metric amount.
Scheme 1.
Now we have combined the enantiopure Lewis acid A
with different sources of fluoride equivalents for the
asymmetric ring opening of cyclohexene oxide (1)
Results and Discussion
(
Tables 1 and 2) and other meso- and racemic epoxides
[
9]
Ring opening of epoxides with different fluoride sources (Table 3) in order to overcome the drawbacks of KHF
2
proceeds diastereoselectively in an anti-fashion. The as the source of fluoride ion.
regiochemistry of ring opening can be directed by the
Ring opening of 1 with Olah×s reagent (Table 1,
used fluorinating reagent. With the comparably acidic entry 1) or triethylamine tris(hydrogen fluoride)
[
14]
HF itself or Olah×s reagent (Py  9 HF), fluorohydrins (Et N  3 HF) (entry 2) in diethyl ether in the pres-
3
with the fluorine substituent in the position which is ence of 20 mol % of (R,R)-(À)-(salen)chromium chlor-
better stabilized in the carbocationic intermediate are ide A, however, gave mixtures of (S,S)-(‡)-2-fluorocy-
formed following an S 1 like pathway, while with more clohexanol (2) and (S,S)-2-chlorocyclohexanol (3) with
N
nucleophilic reagents such as trialkylamine hydrogen no or very low enantiomeric excesses. Also tetrabutyl-
‡
À
fluorides or potassium hydrogen difluoride the re- ammonium dihydrogen trifluoride (Bu N H F ) in
4
2 3
gioisomers bearing the fluorine substituent in the less dichloroethane, which already has been used for ring
[
15]
hindered position are formed preferably according to an opening of epoxides without catalysts earlier, gave 2
[
9,10]
S 2 like mechanism.
Until recently, besides our with low ee in a mixture with 3 (entry 3). The enantio-
N
[
9]
mentioned method, syntheses of optically active selectivity was higher (60% ee) with 20 mol % of A in
fluorohydrins have been restricted to the ring opening diethyl ether as the solvent at low conversion (entry 4).
of enantiopure epoxides with different achiral fluori- However, this reaction is quite slow and the Lewis acid A
nating reagents,[ or deracemization using classical or is not stable under these reaction conditions giving rise
11]
[
12]
enzymatic processes,
or asymmetric reductions of for the formation of significant quantity of3. Atextended
[
13]
fluorinated carbonyl compounds.
reaction time, more 2 is formed, but, at least partially,
non-catalytically. Consequently the ee dropped to 41%
after 50 hours of reaction time (entry 5). Obviously,
chloride is split off from A and opens epoxide 1 giving 3
first under catalytic effect of remaining A, but later in a
non-catalytic way. This could explain the low enantiose-
lectivity observed in 3 (9% ee). Using 100 mol % of A
(
entry 6) only 10% of 2 (57% ee), but 65% of 3 were
formed. In a similar stoichiometric reaction of 1 with A in
Table 1. Ring opening of cyclohexene oxide (1) with different fluorinating reagents in the presence of (R,R)-(À)-
salen)chromium chloride (A).
(
Entry
A
Solvent
Temperature
[8C]
Time
[h]
Fluoride
Source
Ratio (GC)[a]
[%] 3 [%]
ee 2/3[b]
[%]
[
mol %]
2
[
c]
1
2
3
20
20
20
Et
20
100
100
20
Et O
À 78 !‡ 20
0 !‡ 20
0 !‡ 20
À 20 !‡ 20
0 !‡ 20
35
75
85
90
20
50
35
20
115
Py  9 HF
4 0
5
26
30
0/7
10/20
6/n.d.
2
c]
Et O
Et N Â 3 HF
20[
5
2
3
‡
À
À
À
À
C H Cl
Bu N H F
2
4
2
4
2
3
3
3
3
‡
4
5
6
7
8
20
2O
Bu N H F
421
60/9
11
65
4
2
‡
Et O
Bu N H F
16
10
0
41/n.d.
57/n.d.
±/0
2
4
2
‡
Et O
Bu N H F
2
4
2
Et O
35
20
AgF
AgF (20 mol %)
Et N Â 3 HF
3
100
2
c]
Et O
2
19
23[
43/3
[d]
[
[
[
[
a]
Portion of the product mixture (GC) besides starting material 1.
b]
c]
d]
Determined by GC using a chiral b-cyclodextrin phase.
Formation of higher molecular weight products (cf. Ref. ) was observed.
[9]
1
30 mol %.
1
66
Adv. Synth. Catal. 2002, 344, 165 ± 171

(
Salen)chromium Complex Mediated Asymmetric Ring Opening
FULL PAPERS
‡
À
3
Table 2. Ring opening of cyclohexene oxide (1) with Bu N H F in the presence of (R,R)-(À)-(salen)chromium chloride (A)
4
2
and AgF.
Entry
‡
À
Ratio (GC)[a]
ee [%][b]
of 2
A
AgF
[mol %]
Bu N H F
Solvent
Temp.
[8C]
Time
[h]
4
2
3
[
mol %]
[mol %]
2
[%]
3 [%]
1
2
3
10
10
20
10
10
20
100
100
50
100
100
20
100
100
100
Et O
20
20
20
35
35
35
90
70
80[
35
35
4
140
140
20
20
20
20
20
20
35
4
0
18
0
68
2
Et O
18
0
2
0
68
67
66
65
65
18
58
4
2
Et O
42
36
88[
52
55
18
2
4
5
6
7
8
9
0
1
20
20
Et
2O
c]
100
100
100
100
20
100
100
100
100
100
about 2
about 2
Et O
2
2
Et O
35
19
70
0
2
DMF
TBME
CH Cl
d]
100
20
0
2
2
1
1
10
100
100
100
Et O
0
60
2
[e]
Et O
2
88 465
[
[
[
[
[
a]
The difference to 100% is the remaining epoxide 1.
Determined by GC using a chiral b-cyclodextrin phase.
b]
c]
d]
e]
5
9% isolated yield (based on converted 1).
Sealed tube.
1 % isolated yield.
6
the presence of TMSN , Jacobsen et al. observed liberated only during the work-up process. The chloride
3
exclusive formation of the chlorohydrin 3 with <50% forming 3 is perhaps cleaved from the mentioned
ee. Also with other halide sources and different metal intermediate compound and subsequently opens the
[
8d]
salen complexes low enantioselectivity was observed.
epoxide. When catalyst A was refluxed in diethyl ether
It might be that, in the presence of the used amine HF with an equimolar amount of AgF, no AgCl was isolated
reagents, chloride is split off from the complex A and but some amount of a solid was formed, which could not
transferred to the epoxide with low enantioselectivity. A be isolated. This solid dissolved when equimolar
[
17]
‡
À
comparative mechanism described for the catalytic amounts of both 1 and Bu N H F were added to the
4
2
3
asymmetric ring opening of epoxides with azide seems mixture and the fluorohydrin 2 was isolated after usual
not to operate in this case. Also, a halogen exchange at work-up. In a next set of experiments we examined this
the metal center seems not to occur. Accordingly, we reaction in more detail (Table 2).
‡
À
tried to use AgF for the first time both as the fluoride
Ring opening of epoxides with Bu N H F without
4 2 3
source in epoxide ring opening and to trap chloride. Lewis acids needed heating to 100 8C or even more for
[
15]
However, the reaction of 1 in diethyl ether in the several hours. In the presence of A, ring opening
presence of 100 mol % of A and 100 mol % of AgF gave occurred at room temperature. However, the amount of
no fluorohydrin 2 at all. The chlorohydrin 3 was formed formed 2 depends on the quantity of the applied
exclusively as a racemate (entry 7).
complex A. In entries 1 ± 4a two-fold amount of 2 with
As a consequence of these results, we used next respect to the used A and AgF was formed in the
‡
À
2 3
Et N Â 3 HFas the hydrofluorinating reagent, 20 mol % presence of 100 mol % of Bu N H F . Elongation of
3
4
of A as the mediator and added 20 mol % of AgF in the reaction time did not increase the yield of 2 and the
order to remove liberated chloride from the reaction enantiomeric excess was almost independent from the
mixture by formation of AgCl. However, after 115 hours amount of the Lewis acidic complex A and AgF, when
at 20 8C, a mixture of 55% of 1, 19% of 2 (43% ee) and used in an 1:1 ratio (entries 1 ± 5, Scheme 1). In contrast,
23% of 3 (3% ee) was found (entry 8). Thus, no free when 100 mol % of A and only 50 mol % of AgF were
chloride seems to be generated under these conditions. used, 35% of the chlorohydrin 3 was formed again
For the formation of 2, the chromium complex A (entry 6). Also when other solvents than diethyl ether
probably acts exclusively as a conventional Lewis acid such as DMF or TBME were used, a significant amount
activating the epoxide for ring opening by the respective of 3 was found, even in the presence of 100 mol % of
fluoride equivalent. However, in non of the reactions AgFrelated to A (entries 7 and 8). Thus, a direct transfer
(
except Table 1, entries 1 and 3, but these results are of chloride from A to the epoxide seems to occur. In CH2
falsified by non-catalytic formation of 2 and succeeding Cl in a sealed tube at 80 8C in the presence of 20 mol %
2
higher molecular weight products), the formed amount of both A and AgF the fluorohydrin 2 was formed
of 2 exceeds the amount of used A. Obviously, the exclusively, but with as low as 4% ee. Thus, the non-
mediator is not regenerated from an intermediate catalytic ring opening leading to the racemic product
compound under the reaction conditions and 2 is seems to be the major reaction.
Adv. Synth. Catal. 2002, 344, 165 ± 171
167

FULL PAPERS
G¸nter Haufe, Stefan Bruns
Table 3. Results of ring opening of meso- and racemic epoxides with silver fluoride (1.5 equivalents) in acetonitrile mediated
by (R,R)-(À)-(salen)chromium chloride (A).
Epoxide
Lewis acid
mol %]
Temperature
[8C]
Reaction
Time [h]
Fluorohydrin
[%, GC]
Yield[a]
[%]
Enantiomeric
excess [%][
b]
[
c]
1
00
50
70
50
70
70
50
72
50
50
20
20
50
80[
85[
100
80
75
90
85
±
62
44
72
66
n.d.
n.d.
c]
50
[d]
[c]
1
00
[c]
80
50
10
100
100[
c]
traces
50[e]
±
50
60
20
190
240
82
±
65
1
1
00
00
70
no reaction
11
±
90[f]
n.d.
n.d.
5
5
5
0
0
0
50
70
40
5
30
10
43[g]
28[h]
50[i]
83
74
<1
65
n.d.
75
[
[
[
[
[
[
[
[
[
a]
b]
c]
d]
e]
f]
Isolated yield, calculated on the basis of consumed epoxide.
Determined by GC using a b-cyclodextrin phase.
1
H and F NMR data agree with those published for the racemic compound.[18,19]
19
(
S,S)-(‡)-A was used.
1
H, C and 19F NMR data agree with those published for the racemic compound.[20]
13
Pressure vessel.
g]
h]
i]
[15b]
(
2
1
S)-(‡)-2-Fluoro-1-phenylethanol.
-Fluoro-2-phenylpropanol.
-Fluoro-3-phenoxypropan-2-ol (absolute configuration not determined), 1H and 19F NMR spectra agree with those
[
10e,21]
published for the racemic compound.
The results presented in Tables 1 and 2 suggest that
Accordingly, we decided to apply acetonitrile as a
‡
À
neither AgF itself nor Bu N H F seems to be directly more polar solvent in order to (i) increase the solubility
4
2
3
the fluoride sources. In order to investigate whether of AgFand (ii) to supply the possibility for coordination
‡
À
Bu N H F only increases the solubility of AgF in of a solvent molecule to the complex in order to perhaps
4
2 3
diethyl ether because of its phase transfer properties, we facilitate the disjunction of the metal complex from the
‡
À
employed about 2 mol % of Bu N H F (entries 10 intermediate.
4
2
3
and 11). Again, double the molar amount of 2 related to
The reaction of cyclohexene oxide (1) and other meso-
A was formed in case of application of 10 mol % of A, and racemic epoxides with AgF in acetonitrile in the
‡
À
1
00 mol % of AgFand 2 ± 5 mol % of Bu N H F . This presence of stoichiometric or slightly sub-stoichiometric
4 2 3
means that also under these conditions the regeneration amount of the (R,R)-(À)-(salen)chromium complex A
of the mediator from a probably covalently bound provided 2 and other vicinal fluorohydrins with good
intermediate seems not to occur. Thus, an intermediate enantiomeric excess avoiding the formation of chloro-
formed from one molecule of the complex A and two hydrins as side products, which were found under the
[
9]
molecules of a compound derived from the epoxide 1 is previous conditions or applying KHF . The results are
2
not excluded. However, even with 100 mol % of each A summarized in Table 3.
and AgF the reaction was not complete after 40 hours at
In the most selective experiment, treatment of cyclo-
3
5 8C and also a small quantity of 3 was formed under hexene oxide (1) with silver fluoride in acetonitrile with
these conditions.
100 mol % of (S,S)-(‡)-(salen)chromium chloride at
1
68
Adv. Synth. Catal. 2002, 344, 165 ± 171

(
Salen)chromium Complex Mediated Asymmetric Ring Opening
FULL PAPERS
3
5 8C for 40 hours gave (R,R)-(À)-2-fluorocyclohexanol
in 90% isolated yield with 72% ee. The ring opening of
cyclopentene oxide in the presence of 100 mol % of A
yielded 80% of the corresponding fluorohydrin with
6
2% ee. The enantiomeric excess dropped to 44% when
only 50 mol % of A was used. Under these conditions
from cycloheptene oxide 82% of the fluorohydrin was
isolated showing 65% ee. Cyclooctene oxide did not
react, even after 190 hours at 70 8C and from cis-stilbene
oxide only 11% (GC) of a fluorohydrin was formed after
Scheme 3.
2
40 hours at 90 8C in a sealed tube.
A surprising result was found for the reaction of the conditions for a catalytic ring opening with fluoride
racemic tetrahydronaphthalene oxide with AgF in the equivalents.
presence of 50 mol % of the (S,S)-(‡)-(salen)complex.
Two cis/trans isomeric fluorohydrins with benzylic
fluorine were isolated in a 2:1 ratio. While the trans- Experimental Section
compound showed 23% ee, the corresponding cis-
isomer was formed with only 2% ee (Scheme 2, relative
stereochemistry is shown, absolute configuration has
not been determined).
This result can be explained in terms of the probable
mechanism of the ring opening (Scheme 3). In general,
asymmetric ring opening of epoxides mediated by
enantiopure Lewis acids is most enantioselective in
such cases when the nucleophile is delivered directly
General Remarks
1H NMR (300.13 MHz), 13C NMR (75.5 MHz), and 19F NMR
(
282.4MHz) spectra were recorded in CDCl on a Bruker WM
3
1
13
3
00 apparatus with TMS for H NMR, CDCl for C NMR,
3
1
9
and CFCl for F NMR as internal standards. Mass spectra
3
(
(
70 eV) were obtained by GC/MS using a Varian GC 3400
quartz capillary column HP1 (0.33 mm) dimensions: 25 m, È
0
.2 mm). GC was performed on a Hewlett-Packard 5890 II gas
chromatograph with HP1 (0.52 mm, 25 m, È 0.33 mm, 40 ±
80 8C, heating rate 10 8C/min, N2 as carrier gas). The
from the metal center with opening of the epoxide (S 2)
N
or by activation of the epoxide by a Lewis acid and
2
concerted attack of an external nucleophile (S 2- enantiomeric excesses were determined by chiral GC (b-
N
like),[
8,16]
¾
likewise by a comparative mechanism with cyclodextrin column, Supelco, Beta-Dex 120 (0.25 mm, 30 m,
participation of a second molecule of the metal com-
Æ 0.25 mm, isothermic, temperature between 80 8C and 110 8C
depending on the products, N as carrier gas). (Salen)chromi-
um chloride has been prepared according to Ref. All starting
materials and reagents were obtained from Acros (Janssen) or
Fluka. The used solvents were purified by distillation.
plex.[8d,17]
2
[23]
In contrast, in an S 1-like ring opening due to the long
N
distance of the cationic center from of the chiral metal
complex covalently bound to the former epoxideoxygen
atom, the steering effect will be less efficient leading to
poor enantioselectivity. Thus, the cis-isomer should be
formed in an S 1-like process while the trans-isomer
seems to be formed both by an S 2-type mechanism and
the competing S 1 reaction. Consequently, the enantio-
meric excess is relatively low compared to the related
reactions of styrene oxide and phenyl glycidyl ether (see Under an argon atmosphere the appropriate amount of the
Table 3). In the latter epoxides the terminal position is
better accessible to the nucleophile in an S 2-type
process. The corresponding fluorohydrins were isolated
in 83% and 75% yield with 74% and 65% ee, respec-
tively (Table 3).
We are continuing our investigations with alternative
reaction conditions and other enantiopure Lewis acids,
Ring Opening of Cyclohexene Oxide (1) with
Different Hydrofluorinating Reagents in the Presence
of the (Salen)chromium Complex A; General
Procedure
N
N
N
chromium complex A (cf. Table 1) and cyclohexene oxide (1)
147 mg, 1.5 mmol) were dissolved in diethyl ether (5 mL) and
stirred for 15 min at room temperature or below this temper-
ature (cf. Table 1). Using a syringe, the respective hydro-
fluorinating reagent (2 mmol), dissolved in diethyl ether
5 mL) or, in case of Bu N H F , as a commercially available
solution (50 ± 55%) in 1,2-dichloroethane, was added. The
mixture was stirred at the given temperature for the time given
(
N
‡
À
(
4 2 3
[
22]
particularly fluorinated ones (cf. Ref. ), in order to in Table 1. In order to monitor the progress of the reaction
avoid competition with other nucleophiles and to find samples of the reaction mixture were taken, diluted with
Scheme 2.
Adv. Synth. Catal. 2002, 344, 165 ± 171
169

FULL PAPERS
G¸nter Haufe, Stefan Bruns
diethyl ether (1 mL), neutralized with aqueous ammonia,
washed with water, dried with magnesium sulfate, filtered
(column with 3 cm of silica gel, cyclohexane/ethyl acetate, 5:1)
in order to remove traces of the metal complex, silver salts, and
oligomeric material. After removing the solvent the residue
was analyzed by GC and chiral GC. Pure fluorohydrins were
isolated by column chromatography (silica gel 70 ± 260 mesh,
cyclohexane/ethyl acetate, 5:1). Yields and enantiomeric
excesses are given in Table 3. Spectroscopic data of the
optically active fluorohydrins agree with those published for
the racemic compounds (see Table 3).
(
short column with 2 cm of silica gel, 2 mL of diethyl ether),
and analyzed by gas chromatography. After the reaction time
given in Table 1, the mixture was poured into a 2 M aqueous
ammonia solution (10 mL), the phases were separated and the
aqueous phase was extracted with diethyl ether (5 Â 10 mL).
The combined organic layer was washed with water (2 Â
10 mL) and dried with magnesium sulfate. The solvent was
evaporated and the crude product was filtered (column with
cm of silica gel, diethyl ether) in order to remove traces of the
3
metal complex, and oligomeric material. After removing the
solvent the residue was analyzed by GC and chiral GC. The
product mixtures were separated by column chromatography
Ring Opening of Tetrahydronaphthalene Oxide with
AgFin the Presence of A in Acetonitrile
(
silica gel 70 ± 260 mesh, cyclohexane/ethyl acetate, 5:1). The
According to the protocol given above, tetrahydronaphthalene
oxide (146 mg, 1.0 mmol) was reacted with AgF (89 mg,
0.7 mmol) in the presence of (S,S)-(‡)-A (316 mg, 0.5 mmol)
in acetonitrile (5 mL). After work-up, the epoxide was
separated by column chromatography to release a 2:1 mixture
of the cis/trans-isomeric fluorohydrins. Yield: 54mg (72%,
based on 46% conversion). The isomers were partially
separated by column chromatography under the conditions
mentioned above.
reaction conditions and enantiomeric excesses are given in
Table 1.
Ring Opening of Cyclohexene Oxide (1) with AgFand
Tetrabutylammonium Dihydrogen Trifluoride in the
Presence of the (Salen)chromium Complex A
trans-2-Fluoro-3,4-benzocyclohexenol: 1H NMR: d ˆ 1.88
According to the general procedure, cyclohexene oxide (1; 0.5
‡
À
(m, 1H, H5a), 2.15 (m, 1H, H6a), 2.50 (br s, 1H, OH), 2.90 (m, 2H,
or 1 mmol) was treated with AgF and Bu N H F in the
4
2 3
2
H
and H ), 4.13 (m, 1H, H ), 5.40 (dd, 1H, J ˆ 53.2 Hz,
5
e
6e
1
HF
presence of the (salen)chromium complex A under the
conditions listed in Table 2.
3
JHH ˆ 7.1 Hz, H ), 7.12 (m, 1H, arom), 7.26 (m, 2H, arom), 7.46
2
1
3
3
(
m, 1H, arom); C NMR: d ˆ 26.9 (s, C5), 27.7 (d, J
ˆ
ˆ
CF
(
S,S)-(‡)-2-Fluorocyclohexanol (2): In a typical experi-
ment, the complex (R,R)-(À)-A (632 mg, 1.0 mmol) and AgF
128 mg, 1.0 mmol) was stirred in dry diethyl ether (10 mL) at
5 8C for 3 hours. Then cyclohexene oxide (1; 98 mg, 1.0 mmol)
was added, and after further 15 min of stirring at this temper-
2
1
7
1
1
1
.1 Hz, C6), 70.6 (d,
J
ˆ 19.1 Hz, C1), 94.4 (d,
J
CF
CF
3
73.1 Hz, C2), 126.3 (s, C7×), 127.8 (d, J ˆ 7.5 Hz, C8×),
CF
(
3
4
2
28.3 (s, C6×), 128.5 (d, J ˆ 3.1 Hz, C5×), 133.0 (d, J
ˆ
CF
CF
3
19
8.4Hz, C3), 136.1 (d,
J
ˆ 4.8 Hz, C4); F NMR: d ˆ
CF
3
2
1 19
‡
À
À178.6 (dd, JFH ˆ 53.2 Hz, JFH ˆ 13.3 Hz). H and F NMR
ature, Bu N H F (0.7 mL of a 50 ± 55% solution in 1,2-
4
2
3
data agree with published results.[
18]
dichloroethane, 1.0 mmol) was added. After 20 hours of
refluxing, the reaction was stopped at 88% conversion of 1
and worked up as described above to give (S,S)-(‡)-2. Yield:
1
cis-2-Fluoro-3,4-benzocyclohexenol: H NMR: d ˆ 2.03 (m,
2
1
H, H and H ), 2.85 (m, 1H, H ), 3.05 (m, 1H, H ), 4.05 (m,
5a 6a 5e 6e
2
3
H, H ), 5.45 (dd, 1H, J ˆ 53.2 Hz, J ˆ 2.9 Hz), 7.15 (m,
1
HF
HH
6
1 mg (59%, based on 88% conversion); mp 21 ± 22 8C
1
3
[18]
20
1H, arom), 7.30 (m, 2H, arom), 7.41 (m, 1H, arom); C NMR:
(
(
solidified in the refrigerator, Ref. : mp 22 8C); [a] : ‡ 12.0
D
3
2
[24]
20
d ˆ 26.2 (d, JCF ˆ 2.4Hz, C6), 27.3 (s, C5), 68.9 (d,
J
CF
ˆ
c 1.0, CHCl , 65% ee, GC) (Lit. : [a] : ‡ 16.4( c 1.0, CHCl ,
3
D
3
1
1
1
8.7 Hz, C1), 90.5 (d,
J
ˆ 171.8 Hz, C2), 126.3 (s, C6'),
CF
>
95% ee, GC).
4
4
28.6 (d, J ˆ 2.9 Hz, C5'), 129.5 (d, J ˆ 2.2 Hz, C7×), 130.6
CF
CF
Additionally 2% of the chlorohydrin 3 was detected by GC.
3
2
(
d, J ˆ 4.5 Hz, C8×), 132.0 (d, J ˆ 17.8 Hz, C3), 137.1 (d,
CF
CF
The spectroscopic data of 2 agree with those published for the
3
1
9
2
racemic compound.[
9a,18,19]
J
CF ˆ 4.3 Hz, C4); F NMR: d ˆÀ 176.5 (dd, JFH ˆ 53.0 Hz,
3
JFH ˆ 19.1 Hz).
Ring Opening of Epoxides with AgFin the Presence
of the (Salen)chromium Complex A in Acetonitrile;
General Procedure
Acknowledgements
This research project was generously supported by the Deutsche
Forschungsgemeinschaft (Grant No. Ha 2145/1-3) and the
Fonds der Chemischen Industrie.
Under an argon atmosphere a mixture of the epoxide
(
1.0 mmol) and the chromium complex (632 mg, 1.0 mmol, or
3
1
1
16 mg, 0.5 mmol) in dry acetonitrile (5 mL) was stirred for
5 min at room temperature, treated with AgF (191 mg,
.5 mmol, or 96 mg, 0.75 mmol) and heated with stirring at
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with water (2 Â 10 mL) and dried with magnesium sulfate. The
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