Substrate range of the titanium TADDOLate catalyzed asymmetric fluorination of activated carbonyl compounds

Article abstract of DOI:10.1002/hlca.201100375

The substrate range of the [TiCl₂(TADDOLate)] (TADDOL=α,α,α′,α′-tetraaryl-1,3-dioxolane-4, 5-dimethanol)-catalyzed asymmetric α-fluorination of activated β-carbonyl compounds has been investigated. Optimal conditions for catalysis are characterized by using 5 mol-% of TiCl₂(naphthalen-1- yl)-TADDOLate) as catalyst in a saturated (0.14 mol/l) MeCN solution of F-TEDA (1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis- [tetrafluoroborate]) at room temperature. A series of α-methylated β-keto esters (3-oxobutanoates, 3-oxopentanoates) with bulky benzyl ester groups (60-90% ee) or phenyl ester (67-88% ee) have been fluorinated readily, whereas α-acyl lactones were also readily fluorinated, but gave lower inductions (13-46% ee). Double stereochemical differentiation in β-keto esters with chiral ester groups raised the stereoselectivity to a diastereomeric ratio (dr) of up to 96.5:3.5. For the first time, β-keto S-thioesters were asymmetrically fluorinated (62-91.5% ee) and chlorinated (83% ee). Lower inductions were observed in fluorinations of 1,3-diketones (up to 40% ee) and β-keto amides (up to 59% ee). General strategies for preparing activated β-carbonyl compounds as important model substrates for asymmetric catalytic α-functionalizations are presented (>60 examples). Copyright

Full text of DOI:10.1002/hlca.201100375

Helvetica Chimica Acta – Vol. 95 (2012)
353
Substrate Range of the Titanium TADDOLate Catalyzed Asymmetric
Fluorination of Activated Carbonyl Compounds
a
a
b
a
a
by Andreas Bertogg ), Lukas Hintermann ) ), Dominique P. Huber ), Mauro Perseghini ),
a
a
1
Maria Sanna ), and Antonio Togni* ) )
a) Laboratorium fꢀr Anorganische Chemie, ETH Zꢀrich, Wolfgang-Pauli-Strasse 10, CH-8093 Zꢀrich
(
e-mail: togni@inorg.chem.ethz.ch)
b) Department Chemie, Technische Universitꢁt Mꢀnchen, Lichtenbergstr. 4,
D-85748 Garching bei Mꢀnchen
The substrate range of the [TiCl (TADDOLate)] (TADDOL ¼ a,a,a’,a’-tetraaryl-1,3-dioxolane-
2
4
,5-dimethanol)-catalyzed asymmetric a-fluorination of activated b-carbonyl compounds has been
investigated. Optimal conditions for catalysis are characterized by using 5 mol-% of TiCl (naphthalen-1-
2
yl)-TADDOLate) as catalyst in a saturated (0.14 mol/l) MeCN solution of F-TEDA (1-(chloromethyl)-4-
fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-[tetrafluoroborate]) at room temperature. A series of a-
methylated b-keto esters (3-oxobutanoates, 3-oxopentanoates) with bulky benzyl ester groups (60 – 90%
ee) or phenyl ester (67 – 88% ee) have been fluorinated readily, whereas a-acyl lactones were also readily
fluorinated, but gave lower inductions (13 – 46% ee). Double stereochemical differentiation in b-keto
esters with chiral ester groups raised the stereoselectivity to a diastereomeric ratio (dr) of up to 96.5 :3.5.
For the first time, b-keto S-thioesters were asymmetrically fluorinated (62 – 91.5% ee) and chlorinated
(
83% ee). Lower inductions were observed in fluorinations of 1,3-diketones (up to 40% ee) and b-keto
amides (up to 59% ee). General strategies for preparing activated b-carbonyl compounds as important
model substrates for asymmetric catalytic a-functionalizations are presented (>60 examples).
1. Introduction. – The chiral Lewis acid-catalyzed asymmetric halogenation of b-
keto esters has been introduced as a model reaction of significance for fundamental
research in catalysis and for synthetic applications in 2000 (Scheme 1) [1 – 4].
Asymmetric halogenations of b-keto esters, particularly fluorinations, have since then
been studied with a range of other chiral metal catalysts, including palladium(II),
nickel(II), copper(II), and zinc(II) (for reviews, see [5 – 7]). In parallel, the substrate
range of asymmetric fluorination has been extended to cyclic b-keto esters [8 – 10], a-
chloro-b-keto esters [11 – 13], b-keto phosphonates [5][9][10][14][15], a-acyl-g-
lactames [16]. Besides the examples presented in our communication [1a] (cf.
[
2][3][17]) and its use in specific applications [4][11][16][18], no detailed study of
the substrate range of the original titanium TADDOLate-catalyzed fluorination has
been reported. Here, we describe a systematic study of the scope of the original Ti-
TADDOLate
(TADDOL ¼ a,a,a’,a’-tetraaryl-1,3-dioxolane-4,5-dimethanol)-cata-
lyzed fluorination of b-keto esters, and extensions of the substrate range to additional
functional groups and substitution patterns. Important advances include the introduc-
1)
Authors are listed in alphabetical order.
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Helvetica Chimica Acta – Vol. 95 (2012)
tion of phenyl b-keto esters as substrates (up to 90% ee), and the extension of the
reaction to a-acyl lactones, b-keto amides, and b-diketones, and, notably, b-keto
thioesters (up to 91% ee) as substrates for asymmetric catalytic fluorination reactions.
The substrates 1 – 56 are investigated. In Chapt. 3, the syntheses of more than 60
activated carbonyl compounds, which are of general interest as substrates for
asymmetric electrophilic functionalizations, are discussed.
Scheme 1. Asymmetric Ti-Catalyzed Fluorination of Activated Carbonyl Compounds with Catalyst
Complexes K1 and K2
2
. Results and Discussion. – In a preceding article, we have detailed the
development of conditions for the asymmetric Ti-TADDOLate-catalyzed fluorination
and, in part; chlorination) of b-keto esters [3]. As a result of the initial optimization, it
(
was determined that catalytic fluorinations are best performed at a 5-mol-% level of
the crystalline catalyst complexes K1 or K2 with a small excess of a saturated F-TEDA
(
¼1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate))
solution in MeCN as the halogenating reagent (Scheme 1). Some examples of the
fluorination of b-keto esters had already been presented in our initial communication
[
1a]; they are included here for completeness, together with full experimental data. The
results of the substrate screening will be presented in tabular form according to
substrate type. Overall, more than 50 new halogenated products are described. The
catalytic halogenations were usually characterized by complete and clean conversion to
products, with reaction times ranging from a few minutes to several hours at ambient
temperature. The fluorinated and some chlorinated products were isolated in analyti-
cally pure state after column chromatography in good yields.
2
.1. Catalytic Fluorination of b-Keto Esters. a) Catalytic Fluorination of Benzoyl-
propanoates. The 2-benzoylpropanoates including the model substrate 1 for reaction
development [3] have been investigated thoroughly. Results for the catalytic
fluorination are collected in Table 1. In line with the preliminary observations [1a],
the aromatic substituents of the TADDOLato ligand [1b][1c] play a key role in
determining stereoselectivity. The induction obtained with catalyst K2, bearing
naphthalen-1-yl (Nap-1) groups in the TADDOL ligand, was higher than with the
Ph-bearing K1. All of the substrates with the open-chain 2-benzoylpropanoate
substructure were fluorinated within a relatively narrow selectivity range of 60 – 80%
ee by K2 (Table 1, Entries 1 – 13). Substitutions at the benzoyl group of the substrate
exert a secondary influence on the stereoselectivity, and such effects are more pronounced

Helvetica Chimica Acta – Vol. 95 (2012)
355
in reactions with catalyst K2. Electronic variations of the substrates (Entries 1 and 8, vs.
0; Entry 11 vs. 12) had smaller effects on enantioselectivity than steric factors (e.g.,
1
Entry 1 vs. 3 – 5). The bulky diphenylmethyl ester group induced high enantioselec-
tivity in the fluorination (Entry 5). The crude fluorination products were often
accompanied by a little chlorinated by-product [4]. A radical mechanism has been
suggested to cause this side reaction, the benzoyl group favoring such a pathway [18].
b) Catalytic Fluorination of 3-Oxobutanoates. In Tables 2 and 3, the results obtained
with 2-alkyl-3-oxobutanoates and 2-alkyl-3-oxopentanoates as substrates, respectively,
are compiled. As a consequence of the greater tendency towards enolization of those
substrates, due to reduced steric repulsion of the substituents at C(2) and C(3),
catalytic fluorinations were faster than with the 2-benzoylpropanoates. Substrates with
aliphatic chains in the ester group, i.e., 15 and 16, were fluorinated with lower
enantioselectivity (Table 2, Entries 1 and 2) than benzyl esters, 17 and 18. A fairly high
ee value was observed in the fluorination of the simple phenyl ester 21 with catalyst K2.
Additional substitutions of the phenyl group did not increase enantioselectivity (cf.
22 – 24). Substrates with a 2-Me group were most successfully fluorinated, whereas
other a-substituents induced lower enantioselectivity (of 25 – 27).
c) Catalytic Fluorination of 3-Oxopentanoates. The 3-oxopentanoates (Table 3)
were fluorinated with higher enantioselectivities than 2-benzoylpropanoates (Table 1)
and 3-oxobutanoates (Table 2). With catalyst K2, inductions of over 60% ee were
obtained even with the simple ethyl ester 28, whereas the bulkier benzyl esters gave
inductions of 70 – 90% ee (Entries 2 – 4). While steric bulk increased enantioselectivity
in the benzyl ester series, it is remarkable that the simple phenyl ester 32 likewise gave
fluorinated product with ee values close to 90% with catalyst K2 (Entry 5). Replacing
phenyl by bulkier aryl groups had no beneficial effects on reaction selectivity (Entries 6
and 7).
The absolute configuration of excess (þ)-1F, (þ)-28F, 29F, 30F, and 32F (optical
rotations measured in MeOH soln.) was assigned as (2S) by correlation experiments
and comparison of the sign of optical rotation with literature data [19], as detailed in
[
3]. A sample of (þ)-15F obtained by fluorination with catalyst K2 (Table 2, Entry 1)
displayed a specific rotation of [a] ¼ þ20.55. By comparison with the reported optical
D
rotation value of (þ)-(S)-15F, [a] ¼ þ45.8 (c ¼ 2.10, MeOH) [19], the absolute
D
configuration of the excess enantiomer in our sample could be assigned as (S), and the
optical purity was calculated as 45%, which closely matches our GC-derived value of
45% ee. In terms of the absolute configuration, fluorinated products emerging from
catalysis with (R,R)-TADDOL ligands were usually dexrotatory (positive sign of
optical rotation) and had an excess-enantiomer configuration of (2S). This relationship
was established for 1F, 15F, 28F, 29F, 30F, and 32F. By analogy, the reaction products in
Tables 1 – 3 probably all possess the (2S) excess-enantiomer configuration.
d) Catalytic Fluorination of a-Acyl Lactones. a-Acyl lactones were fluorinated with
lower enantioselectivity than open-chain b-keto esters (Table 4). This may, in part, be a
consequence of the high degree of enolization of the substrates, which favors a non-
catalyzed background reaction. With the less reactive fluorinating reagents N-
fluorobenzenesulfonimide (NFSI) or N-fluoropyridinium tetrafluoroborate (NFPy)
rather than F-TEDA (Fig. 1), the enantioselectivity in the fluorination of the strongly
enolized substrates 35 and 36 was increased (Table 4, Entries 2, 3, and 5), whereas no

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 1. Enantioselective Fluorination of Substituted 2-Benzoylpropanoatesa)
Entry Structure
X ¼ H X ¼ F ee (K1) [%] ee (K2) [%] Yield [%]b)
1
1
2
3
4
5
1F
2F
3F
4F
5F
28
35
42
38
59
61.5
71
76
69
85
59
2
3
4
5
67
73
70
82
6
7
6
7
6F
7F
57.5
55
62
44
68.5
n.d.
8
9
8
9
8F
28
26
21
56
61
55
73
94
76
9F
1
0
10
10F

Helvetica Chimica Acta – Vol. 95 (2012)
357
Table 1 (cont.)
Entry Structure
X ¼ H X ¼ F ee (K1) [%] ee (K2) [%] Yield [%]b)
1
1
11
11F
n.d.
67
53
1
2
12
12F
17
65
34
1
1
3
4
13
14
13F
14F
34
61
20
89
93
2 – 6
a) For the general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of catalyst
and 1.15 equiv. of F-TEDA in MeCN solution at ambient temperature. Reaction times range from 20 min
b
to 5 h. ) Yield of analytically pure product from a representative catalytic run.
Fig. 1. Electrophilic NꢀF reagents used for catalytic fluorinations
corresponding change of ee value in dependence of the fluorinating reagent had earlier
been observed for substrate 1, for which enolization was negligible [3].
e) Double Stereochemical Differentiation in the Catalytic Fluorination of Enantio-
merically pure b-Keto Esters. The catalytic fluorination of b-keto esters incorporating a
stereogenic center in the ester alkyl group should be diastereoselective with either
achiral or chiral catalysts. With enantiomerically pure catalysts of opposite absolute
configurations, characteristic effects of double stereochemical differentiation can be
expected, and this strategy might be used to further increase the stereoselectivity of the
reaction [20]. The diastereoisomer ratio (dr) of the reaction products is conveniently
measured by integration of the 1 F-NMR signals for the diastereoisomer fluorination
products. The cholesteryl and nopyl (¼2(6,6-dimethylbicyclo[3.3.1]hept-2-enyl)ethyl)
9

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 2. Enantioselective Fluorination of Substituted 3-Oxobutanoatesa)
b
Entry Structure
X ¼ H X ¼ F ee (K1) [%] ee (K2) [%] Yield ) [%]
1
15
15F
21
45
44c)
2
16
16F
35 – 44
37
90
3
4
17
18
17F
18F
30 – 37d)
65
96
80
51
69e)
5
6
19
20
19F
20F
55
46
57
61
88
n.d.
7
8
21
22
21F
22F
24
24
81
74
55
57
9
23
24
23F
24F
37
73
67
83
92
1
0
48.5

Helvetica Chimica Acta – Vol. 95 (2012)
359
Table 2 (cont.)
Entry Structure
b
X ¼ H
25
X ¼ F
25F
ee (K1) [%]
ee (K2) [%]
Yield ) [%]
83
1
1
1
6
1
1
2
3
26
27
26F
27F
1
24
57
40
74
31
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of catalyst and
1
5
.15 equiv. of F-TEDA in MeCN solution at ambient temperature. Reaction times range from 20 min to
b
c
h. ) Yield of analytically pure product from a representative catalytic run involving K2. ) Losses
d
during isolation of the volatile product. ) The ee range represents variability over several experiments;
an ee value of 38.4% was observed at 08. ) Result obtained with 3 mol-% of K2.
e
esters 40 and 41, respectively, were fluorinated with little or no diastereoselectivity in
the presence of the achiral catalyst CpTiCl (Table 5, Entries 1 and 2), whereas the
3
chiral catalysts K1 and K2 (each incorporating (R,R)-configured TADDOL ligand)
induced dr values of similar magnitude than the enantiomeric ratios (er) observed in
catalytic fluorinations of 2-methyl-3-oxopropanoates (cf. Table 2). The substrates
shown in Table 5 are enantiomerically pure only with respect to the stereogenic center
of the ester group, but epimeric mixtures of keto forms by virtue of the stereogenic
tertiary center at C(2). However, since the fluorination of both epimers proceeds via
the same enolate, in which C(2) is no longer a stereogenic center, this is no
complication. Menthyl esters 42 and 43 were fluorinated with moderate diastereose-
lectivity under CpTiCl catalysis. There was a marked stereochemical differentiation
3
with catalysts K1 and K2. The combination of the (R,R)-TADDOL-derived catalysts
with (1S)-menthyl ester 43 is the ꢃmatchedꢄ combination, in which K2 further enhances
the effect of the substrate chirality. In the mismatched combination with 42, the
intrinsic diastereoisomeric induction of the substrate is neutralized by K1, and
completely overturned by catalyst K2. Methyl mandelate ester 44 displayed significant
double stereochemical differentiation: the ꢃmatchedꢄ case represents the highest
stereoselectivity yet observed in a Ti-TADDOLate-catalyzed fluorination (dr 96.5 :3.5,
de 93%).
f) Steric Model of Induction in Catalytic Fluorinations of b-Keto Esters. The absolute
configurations of the diastereoisomers in the experiments of Table 5 have been
assigned, where possible, based on the known sense of induction of the catalyst K2,
which has been shown to induce the (S)-configuration at the stereogenic F-carrying

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 3. Enantioselective Fluorination of Substituted 3-Oxopentanoatesa)
b
Entry Structure
X ¼ H X ¼ F ee (K1) [%] ee (K2) [%] Yield ) [%]
1
28
28F
29.5
62
n.d.
2
3
29
29F
48
71
82
30
31
30F
31F
53 – 55
88 – 90
89
87
4
58
81
5
6
32
33
32F
33F
45
28
87 – 88
86
50
35
7
34
34F
15
30
55
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of catalyst and
.15 equiv. of F-TEDA in MeCN solution at ambient temperature. Reaction times range from 20 min to
1
5
b
h. The ee values show variations over several experiments. ) Yield of analytically pure product from a
representative catalytic run.
centers [3]. A steric model of a substrate/catalyst complex has been developed in the
preceding study [3], based on calculated structures of Ti-enolate intermediates [18] and
the molecular structure of a dienolate complex determined by X-ray analysis [16].
According to this model, the stereoselectivity of fluorination is rationalized by
assuming a trajectory of attack of the NꢀF reagent on the diastereotopic face of the

Helvetica Chimica Acta – Vol. 95 (2012)
361
Table 4. Enantioselective Fluorination of a-Acyl Lactones with Catalyst K2a)
b
c
Entry
1
Structure
X ¼ H
35
Enol ) [%]
76
X ¼ F
35F
ee (K2) [%]
Yield ) [%]
70
16
d
f
2
3
4
35
35
36
76
76
45
35F
35F
36F
24 )
(99) )
e
f
39 )
(75) )
13
85
5
6
36
37
45
5
36F
37F
46e)
29
(70)f)
86
7
8
38
39
5
2
38F
39F
51
63
89
ca. 5g)
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of K2 and
1
5
.15 equiv. of F-TEDA in MeCN solution at ambient temperature. Reaction times range from 20 min to
b
c
h. ) Degree of enolization of the substrate (R ¼ H) in CDCl soln. ) Yield of analytically pure product
3
d
from a representative catalytic run. ) Reaction performed with NFSI as fluorinating agent, reaction time
2
analysis. ) Value less accurate due to incomplete baseline separation in HPLC.
e
f
4 h. ) NFPy-BF used as fluorinating reagent, reaction time 5 d. ) Conversions according to NMR
4
g
substrate in the energetically most favorable Ti-enolate complex that is opposite to the
shielding ligand aryl group (Fig. 2).
This steric model is in agreement with structural information from the X-ray
structure of the complex [Ti((Nap-1)-TADDOLato) (b-ketonato) ] [16], incorporat-
2
2
ing the deprotonated substrate 29 twice as chelating O,O-ligand at Ti-atom. The CꢀH
to p edge-to-face interaction in that structure (cf. Fig. 8 in [3]) is an important element
that should be present not only in benzyl, but also phenyl and thiophenyl esters, and
may be responsible for the high inductions (up to 90% ee) observed with simple phenyl
ester (i.e., 21, 32, and 33) and phenyl thioester substrates (i.e., 48), in spite of their small
size. The substrate/ligand arrangement shown in Fig. 2 can also explain the favorable
result observed in the double stereochemical differentiation experiment with substrate

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 5. Diastereoselective Fluorination of b-Keto Esters with Chiral Ester Groupsa)
Entry Structure
X ¼ H/F dr
CpTiCl3 K1
55 : 45 60 : 40
Yieldb)
%]
[
K2
1
40/40F
80 : 20
56
2
3
41/41F
42/42F
50 : 50
59 : 41
75 : 25
n.d.
59
37: 63c) 51 : 49c) 75 : 25c)
4
5
43/43F
44/44F
63 : 37d) 74 : 26d) 82 : 18d)
n.d.
66 : 34e,f) 88 : 12f) 96.5 : 3.5f) 59
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of catalyst and
1
5
.15 equiv. of F-TEDA in MeCN solution at ambient temperature. Reaction times range from 20 min to
b
c
h. ) Yield of analytically pure product from a representative catalytic run. ) dr (1’R,2S)/(1’R,2R) ¼
d
e
ul/lk. ) dr (1’S,2S)/(1’S,2R) ¼ lk/ul. ) Ratio observed in a stoichiometric fluorination of the Na-enolate.
f
)
dr (1’R,2S)/(1’R,2R) ¼ ul/lk.
4
4: the latter only differs from 29 by the presence of a CO Me group in the benzylic
2
position (E; representing H of coordinated 29 in Fig. 2), which points away from the
Si
reaction center and tolerates more steric bulk than the constrained HRe position.
2
.2. Catalytic Fluorination of b-Keto Thioesters. Thioesters, which are more reactive
than esters, are useful building blocks in synthesis. Asymmetric electrophilic a-
fluorinations of thioesters have not been reported, to our knowledge. A potential side
reaction, the sulfide oxidation with fluoride addition (fluoro-Pummerer rearrange-

Helvetica Chimica Acta – Vol. 95 (2012)
363
Fig. 2. Steric model showing blockage of the Re-face of the deprotonated and metal-ligated substrate by
the aryl group of the catalyst, directing the attack of the electrophilic NF reagent to the Si-face
ment) of alkyl thioethers, has been realized with F-TEDA as reagent, however [21].
Nevertheless, the asymmetric Ti-catalyzed fluorination of b-keto thioesters proceeded
readily and gave a-fluorinated products in up to 91.5% ee (Table 6; yields not
optimized). Relative to their parent esters, thioesters are fluorinated with higher
enantioselectivities.
Table 6. Enantioselective Fluorination of b-Keto Thioestersa)
Entry Structure
X ¼ H X ¼ F ee (K1) [%] ee (K2) [%] Yield b) [%]
1
45
46
47
48
45F
46F
47F
48F
47
50
45
34
62
13
2
3
4
78
39
69
n.d.
78
90 – 91.5
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of catalyst and
.15 equiv. of F-TEDA in MeCN solution at ambient temperature. Reaction times range from 20 min to
1
5
b
h. Ranges of ee values represent variations over several experiments. ) Yield of analytically pure
product from a representative catalytic run.
Catalytic fluorination reactions of b-keto dithioesters 57 and 58, and mixed S,O-
thioester 59 (Fig. 3) were not successful. These substrates, bearing thiocarbonyl groups,
decomposed under reaction conditions.

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 3. Thioester substrates, which could not be successfully fluorinated
2
.3. Catalytic Fluorination of b-Keto Amides. b-Keto amides were catalytically
fluorinated to afford the corresponding products with moderate enantioselectivities
Table 7). The reaction proceeded sluggishly compared to similar esters. The
(
1,3
enolization of secondary b-keto amides was strongly reduced by occurrence of A -
strain in the enol form. In fact, none of the enols was detected by H-NMR
1
spectroscopy in CDCl solutions of 49 or 50.
3
Table 7. Fluorination of b-Keto Amidesa)
b
Entry
1
Structure
X ¼ H
49
X ¼ F
49F
ee (K1) [%]
ee (K2) [%]
Yield ) [%]
n.d.c)
21 – 27
45 – 59
2
50
50F
35.9
55.0
75
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of catalyst and
1
.15 equiv. of F-TEDA in MeCN solution at ambient temperature. Reaction time < 15 h. Ranges of ee
b
values represent variations over several experiments. ) Yield of analytically pure product from a
representative catalytic run. ) Product contained inseparable chlorinated side product as impurity.
c
The asymmetric catalytic fluorination of a series of a-acyl g-lactams has been
realized with NFSI as fluorinating agent in toluene solution, however (Scheme 2); the
results have already been reported [16].
Scheme 2. Asymmetric Catalytic Fluorination of a-Acyl Lactames Reported in [16]

Helvetica Chimica Acta – Vol. 95 (2012)
365
2
.4. Catalytic Fluorination of 1,3-Diketones. 1,3-Diketones should be less suitable
substrates for catalytic fluorination, because they are highly enolized (danger of a
background reaction), and because the electronic differentiation of the two C¼O
groups is less pronounced than in b-keto esters, implying that the differentiation of the
enantiotopic faces of the enolized substrate is more difficult. Indeed, 1,3-diketones gave
low inductions in the catalytic fluorination reaction (Table 8).
Table 8. Enantioselective Fluorination of 1,3-Diketones Catalyzed by K2a)
b
c
Entry
1
Structure
X ¼ H
51
Enol ) [%]
X ¼ F
51F
ee (K2) [%]
Yield ) [%]
90
0
90
2
3
4
5
6
52
53
54
55
56
< 1
52F
53F
54F
55F
56F
17
27
0
67
70
67
94
82
4
95
97
2
d
0 )
18
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of K2 and
1
5
.15 equiv. of F-TEDA in MeCN solution at ambient temperature. Reaction times range from 20 min to
b
1
h. ) Percentage of enolization in the starting material, determined by H-NMR in CDCl soln. of
3
c
freshly dissolved samples. ) Yield of analytically pure product from a representative catalytic run.
d
)
Value is based on a determined [a]D value of 0 (c ¼ 0.595, MeOH); however, the optical rotation of an
enantiomerically pure sample is not known.
To clarify the influence of the non-catalyzed background fluorination of the
substrate enol form, selected reactions were carried out with F-TEDA, NFSI, and
NFPy (Fig. 1). The latter two reagents have lower fluorinating power than F-TEDA
[
22] and display slower background fluorinations. For the highly enolized cyclo-

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66
Helvetica Chimica Acta – Vol. 95 (2012)
pentanone 51, enantioselectivity of fluorination was indeed higher with the less reactive
reagents (Table 9, Entry 1), whereas no change of enantioselectivity was observed for
fluorination of the less enolized 52 and 53 (Table 9, Entries 2 and 3). The highly
enolized tetralone 54 failed to show induction with all reagents. It appears that the non-
catalyzed background fluorination of highly enolized substrates is important with F-
TEDA, but can sometimes be suppressed by using less reactive fluorinating reagents
(compare also the results in Table 4). However, even in the absence of a background
reaction, the levels of enantioselectivity remained low in the fluorination of 1,3-
diketones, as a consequence of insufficient electronic and steric differentiation of the
substrate C¼O groups.
Table 9. Variation of the Fluorinating Agent for the Diketonesa)
b
ee (K2) [%]c)
Entry
1
Structure
Enol ) [%]
X ¼ F
F-TEDA
0
NFSI
NFPy-BF4
40 (2 w)
90
51F
15 (1 d)
2
3
4
< 1
52F
53F
54F
17
27
0
18 (1 d)
26 (1 d)
0
15 (5 d)d)
23 (5 d)d)
n.d.
4
95
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of catalyst and
b
1
(
.15 equiv. of F-TEDA in MeCN solution at ambient temperature. ) Enol content of a dissolved sample
1
c
d
H-NMR, CDCl ) of substrate (X ¼ H). ) Reaction time in parentheses. ) 50% Conversion.
3
2
.5. Selected Asymmetric Catalytic Chlorinations. In connection with our work on
asymmetric catalytic fluorination, we had also shown that TiCl (TADDOLato)
2
complexes are catalysts for asymmetric chlorinations with N-chlorosuccinimide
(
NCS) [4]. Some of the new substrate types have also been submitted to the conditions
of the asymmetric catalytic chlorination reaction with catalyst K2 (Table 10).
3
. Synthesis of Catalysis Substrates. – Over the past ten years, a-substituted b-keto
esters have become popular model substrates for metal-catalyzed asymmetric electro-
philic substitutions. We present here an overview of the most-efficient synthetic
methods which have been used to prepare the substrates in this work. For a general
review of the synthesis and reactivity of b-keto esters, see [23].

Helvetica Chimica Acta – Vol. 95 (2012)
367
Table 10. Asymmetric Titanium-TADDOLate Catalyzed Chlorinationsa)
Entry Structure
X ¼ H X ¼ Cl Time [min] ee (K2) [%] Yield [%]
1
15
15Cl
15
40
n.d.
2
3
4
32
32Cl
20
82b)
83
48
30
48Cl
30Cl
20
30
83
71
82
c
82 ꢁ 3 )
a) For a general reaction scheme, see Scheme 1. Reactions were performed with 5 mol-% of K2 and
b
1
.15 equiv. of NCS in MeCN solution at ambient temperature. ) ee 90% at 08 in CH Cl ; see also
2
2
preceding report [3]. c) Value is less accurate due to incomplete baseline separation of HPLC peaks.
3
.1. Transesterification of b-Keto Esters. Observations of the simplified (as opposed
to regular esters) thermal exchange of alkoxy groups in b-keto esters go back to 1887
24]. Transesterification of lower alkyl b-keto esters was studied by Cohn (1900) [25],
[
Lapworth and Hann (1902) [26], and Bader et al. (1951) [27]. Heating an alcohol with
neat ethyl acetoacetate to 140 – 1508 is often sufficient to bring about the reaction.
According to Witzeman and Nottingham [28][29], transesterifications starting from
bulky alkyl acetoacetates are faster and require none of the proposed catalysts like 4-
i
(
dimethylamino)pyridine (DMAP) [30] or Ti(O Pr) [31], since they exchange alcohol
4
groups via an elimination/addition mechanism. The ease of thermal transesterification
of b-keto esters has sometimes been ignored by authors of more or less efficient
catalytic protocols for that reaction (cf. [32] for a comment on the ꢃyet-another-one-
catalystꢄ idea). We have prepared numerous substituted acetoacetates starting from
ethyl 2-methylacetoacetate (15) or other lower alkyl b-keto esters in fair-to-good yield
(
Scheme 3). The reactants were sometimes refluxed in toluene with addition of
catalytic DMAP [30], though the latter may not always be necessary. Since the reaction
is reversible, either one reactant should be used in excess, or the lower alcohol
component should be removed, which is most easily achieved by evaporation (for
MeOH and EtOH), if the reaction is performed in a vessel open to air.
3
.2. Esterification via Acyl Activation of b-Keto Carboxylic Acids. Even though b-
keto carboxylic acids are not thermally stable at elevated temperatures, they can be
esterified via acyl-activation protocols, or O-alkylation by dialkyl sulfates or Meerwein
salt [23]. Acyl activation of 2-methyl-3-oxobutanoic acid (66), in particular, with the

3
68
Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 3. Transesterifications
Appel reagent (PPh /CCl ) [33] has been reported [34]. We have successfully used
3
4
cyanuric chloride (¼2,4,6-trichloro-1,3,5-triazine; 67) as an acyl activating reagent [35]
for the coupling of carboxylic acids 66 and 68 with several benzylic alcohols, phenols, or
thiols in the presence of N,N-dimethylaniline as mild base (Scheme 4). The moderately
stable acid 66 [36] was either freshly synthesized prior to use, or stored at ꢀ 788,
whereas the crystalline acid 68 was stable under ambient conditions.
An alternative acyl activation protocol for the free b-keto carboxylic acids via an
azolide is described further below.
3
.3. Alcoholysis of Diketenes. In an attempt to prepare 1,1-dimethylpropyl
propanoate (74) from propanoyl chloride and 2-methylbutan-2-ol in the presence of
Et N, oxetanone 75 was obtained instead (Scheme 5). This b-lactone is more directly
3
formed from Et N and propanoyl chloride via elimination to a ketene and dimerization
3
[
37][38]. This side reaction does not take place in the presence of the weaker base N,N-
dimethylaniline, and the desired ester 74 is obtained (Scheme 5). Still, the generation of
the ketene dimer was welcome, since the nucleophilic ring opening of 75 with alcohols
provided a straightforward route to 2-methyl-3-oxopropanoates as suitable model
substrates for our studies. We have already reported a simplified synthesis of 75 (56%
yield, 97% purity; remainder: propionic anhydride) that profits from an aqueous
workup [4]. The reaction, which had originally been performed on large scale, gave
lower yields when repeated on smaller scale. On large-scale, the heat of reaction was
sufficient to bring the mixture to the boiling point, but, on small scale, at ambient
temperature, the reaction was slow and gave lower yield, unless external heating was
applied. b-Lactone 75 is a lachrymatory liquid with limited shelf-life, which polymerizes
slowly at ambient temperature. It reacts with Ph CHOH to ester 31 in a pyrrolidino-
2
pyridine (PPy)-catalyzed [39] reaction (Scheme 5,b). For more-hindered alcohols as
nucleophiles, the polymerization of 75, which is presumably also catalyzed by the
pyridine, accompanies esterification. Such problems were circumvented by an initial

Helvetica Chimica Acta – Vol. 95 (2012)
369
Scheme 4. Esterification via Acyl Activation of b-Keto Carboxylic Acids
ring opening of 75 with 1H-imidazole to the 1-acyl-1H-imidazolide 76 [40]. Reaction of
the latter with alcohols proceeded readily in the presence of CF COOH (TFA) [4],
3
rather than the more common base catalysis used in esterifications with azolides [41].
Several alcohols, phenols, and thiophenol were transformed to 2-methyl-3-oxopenta-
noates by this method (Scheme 5,c); the reaction was not successful with 4-nitrophenol.
The activated 1-acyl-1H-imidazole can also be prepared directly from b-keto
carboxylic acids and carbonyldiimidazole (CDI). For example, ester 16 was prepared
from acid 66 by one-pot 1-acyl-1H-imidazole generation and esterification under acidic
conditions (Scheme 5,d). Lactone 75 undergoes non-catalyzed ring opening also with
other azoles, such as 3-(tert-butyl)-1H-pyrazole (77) to give pyrazolide 78, or with
Bn NH to give amide 49 (Scheme 6,a and b). For the weak nucleophile Ph NH, the 1H-
2
2
imidazole/TFA activation strategy was used with success (Scheme 6,c).

3
70
Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 5. Synthesis of b-Keto Esters via Diketenes and Acylimidazolides: a) Expected and Unexpected
Product from the Reaction of tert-Amyl Alcohol, Propanoyl Chloride, and Different Amine Bases;
b) Nucleophilic Ring Opening of a Diketene; c) Diketene Ring Opening with Azoles to Acyl Azolides,
Followed by Esterification under Acid Activation; d) Esterification via Imidazolides Generated from a b-
Keto Acid
Scheme 6. Ring-Opening Reactions of Diketene 75 with N-Containing Nucleophiles
3
.4. Synthesis of b-Keto Esters by Claisen Condensation. Claisen condensation of
ketones with Et CO in the presence of 2 equiv. of NaH gave 1 and 14 (Scheme 7,a and
2
3
b) [42]. The procedure was straightforward, but the products required additional

Helvetica Chimica Acta – Vol. 95 (2012)
371
Scheme 7. Synthesis of b-Keto Esters by Claisen Condensation
purification by chromatography for use as catalysis substrates. In case a solid Na-
enolate was obtained from the Claisen-reaction mixture, the latter could be purified by
filtration and washing with inert solvent, before the ester was released by acidification.
Aroyl propanoates were alternatively obtained via Claisen condensation of propa-
noates with alkyl benzoates (Scheme 7,c and d).
Claisen condensations with alkyl trithiocarbonates 79 gave b-keto dithioesters 57
and 58 (Scheme 8,a), or, using the mixed O-ethyl-S-(a-xylyl) dithiocarbonate 80 as
electrophile (Scheme 8,b), the O-ethyl 2-benzoylthiopropanoate (59; Scheme 8,c).
Reagent 80 was used, because an initial Claisen condensation of the propanoylphenone
enolate with O,S-diethyl dithiocarbonate had produced inseparable mixtures of
dithioester 58 and thioester 59. The analogous product mixture generated from 80
was readily separated by chromatography.
3
.5. a-Alkylation of Enolates. Classical acetoacetate alkylation was applied in some
cases, but the selectivity of mono- vs. dialkylation was low. Examples are shown in
Scheme 9. The low yields of 25 and 63 reflect losses during the separation of mono- and
dialkylation products by chromatography. However, benzoylacetone was methylated in
high yield to diketone 53 (Scheme 9,c).
3
.6. Synthesis of b-Keto Esters via Aldol Addition and Oxidation. A general access
to a-methylated b-keto esters involves the addition of a propanoate to an aldehyde,
followed by oxidation of the hydroxy ester. Scheme 10,a, shows applications of this
strategy for the synthesis of 3 – 5 and 69. Oxidation of the aldol adducts was carried out
with pyridinium chlorochromate (PCC) or Jones reagent.

3
72
Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 8. Synthesis of Thioester Derivatives
Scheme 9. Synthesis of a-Substituted b-Dicarbonyl Compounds by Alkylation
3
.7. Synthesis of 1,3-Diketones and a-Acyl Lactones. a-Acyl lactones 35 – 39 and 1,3-
diketones 51 – 55 were prepared by Claisen condensation [43]. A Mukaiyama-type
Claisen reaction [44] was used in the preparation of 2-benzoylcyclododecanone (56)
(
Scheme 10, b).
4
. Conclusions. – The substrate range of the Ti-TADDOLate Lewis acid-catalyzed
electrophilic fluorination of activated dicarbonyl compounds has been studied. The
original b-keto ester substrates have been structurally varied in the ester moiety, at
C(2) and C(3). Variations at C(3) were readily tolerated, but variations at C(2) were
not. Increasing the size of the benzyl ester group in b-keto esters led to higher
enantioselectivities (up to 90% ee) in the catalytic fluorination. However, an equally

Helvetica Chimica Acta – Vol. 95 (2012)
373
Scheme 10. a) Synthesis of b-Keto Esters by Oxidation of Hydroxy Esters Obtained from Aldol
Additions. b) Synthesis of a 1,3-Diketone by Mukaiyama Acylation.
high enantioselectivity was obtained with simple phenyl ester substrates. The reaction
has also been extended to other activated carbonyl derivatives, including b-keto
thioesters, b-keto amides, and b-diketones. b-Keto thioesters have been fluorinated
with up to 90% ee and showed no sign of oxidative degradation. On the other hand,
thioesters and dithioesters were no suitable substrates. For highly enolized b-diketones,
it was established that a non-catalyzed background fluorination takes place; this
background reaction is partially suppressed by using less reactive fluorinating reagents
such as NFSI or N-fluoropyridinium tetrafluoroborate. The steric course of the
fluorination has been interpreted in terms of a model which correctly predicts the
absolute sense of induction.
Experimental Part
General. Reactions were carried out under Ar. Substrate 15 was purchased from Acros or Avocado.
F-TEDA (ꢃSelectfluorꢀ; the BF
4
salt was used on all occasions) and NCS were obtained from Aldrich.
Column chromatography (CC): silica gel 60 (SiO ; 40 – 63 mm; Fluka). NMR Spectra: in CDCl at
2
3
ambient temp. (20 – 258), chemical shifts (d [ppm]) relative to internal Me Si, unless otherwise noted;
4
13
19
C-NMR shifts relative to solvent peaks; F-NMR spectra referenced against internal CFCl3.
. Abbreviations. CDI, 1,1’-Carbonyldiimidazole; Cy, cyclohexyl; DMAP, 4-(dimethylamino)pyri-
2
dine; F-TEDA, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate);
i
LDA, lithium diisopropylamide, Pr NLi; NCS, N-chlorocuccinimide; NFPy, 1-fluoropyridinium tetra-
2
fluoroborate; NFSI, N-fluorobenzenesulfonimide; Nopyl, 2-(6,6-dimethylbicyclo[3.1.1]hept-2-enyl)eth-
yl; PCC, pyridinium chlorochromate; TFA, CF COOH; y, pseudo.
3
3. Enantiomer Excesses (ee) Determinations. The ee-values were determined by HPLC or GC
analyses; HPLC analyses were conducted on normal phase Daicel Chiralcel anal. columns (4.6 ꢂ
i
2
50 mm) of the OJ, OD, or OB type with hexane/ PrOH as mobile phase. GC analyses were performed
ꢀ1
on Supelco b- or g-DEX 120 (30 m) columns; carrier gas, He flow rate, 1.4 ml min ; split injector, 42 ml
min , 2008; FID detector, air/H 350/35 ml min , 2508.
ꢀ
1
ꢀ1
2
4. General Procedures for Catalytic Halogenations. a) Preparation of a Sat. Soln. of F-TEDA. In a
1
00-ml brown glass bottle, MeCN (anal. reagent grade) was added to finely powdered F-TEDA (BF4

3
74
Helvetica Chimica Acta – Vol. 95 (2012)
salt; ꢃSelectfluorꢄ; 6.0 g) and granular molecular sieves (3 ꢅ, 10 g) up to the 100-ml mark. The contents
were stirred magnetically for 1 h. The bottle was set aside for sedimentation of suspended particles. The
supernatant, a sat. soln. of the F-TEDA, had a concentration of ca. 0.145m (iodometric titration) [45],
and was used for catalytic reactions. Note: The soln. had a shelf-life of at least two weeks. Occasionally,
the soln. became turbid (opalescent), and this was accompanied by unsatisfactory performances in
catalysis.
b) General Procedure for Catalytic Fluorinations (GP 1). To the substrate (0.25 mmol) in MeCN
(
1 ml), the catalyst was added (0.0125 mmol, 5 mol-%), and the mixture was stirred until a clear soln. had
formed. Optionally, molecular sieves or other additives were added at this point. The reaction was started
by addition of a sat. F-TEDA soln. (0.145m in MeCN; 2.0 ml, 0.29 mmol). The mixture was stirred at r.t.
to complete conversion (TLC check) or until no further change could be observed. Workup: 1) Aqueous
t
Workup: The mixture was flushed into a separatory funnel using BuOMe (30 – 50 ml) and H O (50 –
2
1
00 ml). The aq. phase was discarded, and the org. phase was filtered over a small plug of neutral/
deactivated Al O on cotton. The filtrate was evaporated, and the residue was analyzed by chiral HPLC
2
3
or GC. Yields and additional analytical data were obtained after further purification by CC on SiO .
2
t
2
) Nonaqueous Workup: Alternatively, the mixture was diluted with BuOMe (30 – 50 ml) and
directly filtered over Al O as described above.
2
3
c) General Procedure for Catalytic Halogenations (Fluorination and Chlorination) with Non-Ionic
Reagents (GP 2). Given the good solubility of the respective reagents, catalytic fluorination with NFSI or
chlorination with NCS was readily carried out in a range of solvents: to a soln. of the substrate
(
0.25 mmol) in the solvent (1 ml; MeCN unless otherwise mentioned) was added catalyst, and the
mixture was stirred until all was dissolved. The solid halogenation reagent (0.275 – 0.325 mmol; 1.1 –
.3 equiv.) was added, and the mixture was stirred at r.t.; see GP 1 for workup and purification.
1
5
. Catalysis Products. The halogenated compounds were prepared according to GP 1 (chlorinations:
t
GP 2) and purified by CC with an appropriate solvent mixture ( BuOMe/hexane). Optical rotations refer
to product samples obtained by catalysis with (R,R)-configured TADDOL-ligands, unless otherwise
mentioned.
6. Catalytic Fluorination of b-Keto Esters. a) Catalytic Fluorination of 2-Benzoylpropanoates.
Products were prepared according to GP 1; typical reaction times: 4 – 16 h. Yields and ee values are
compiled in Table 1.
Ethyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (1F). The product was dried in a rotary
i
ꢀ1
evaporator to prevent evaporation losses. HPLC (Chiralcel OB-H; hexane/ PrOH 96 :4; 0.5 ml min ):
t
t (minor) 13.5, t (major) 16.0 min. R ( BuOMe/hexane 1:5) 0.45. [a] ¼ þ16.5 (c ¼ 0.595, MeOH; 21%
R
R
f
D
1
ee by HPLC); [a] ¼ þ53.8 (c ¼ 0.545, MeOH; 61.7% ee). H-NMR (300 MHz): 1.20 (t, J ¼ 7.1, 3 H ) ;
D
1
1
.87 (d, J(F,H) ¼ 22.5, 3 H); 4.25 (CD of A CD; y-qd, J ¼ 7.1, 2.3, 2 H); 7.42 – 7.51 (m, 2 H); 7.56 – 7.63 (m,
3
13
H); 8.00 – 8.10 (m, 2 H). C-NMR (75.5 MHz): 13.8 (Me); 20.9 (d, J(F,C) ¼ 23, Me); 62.5 (CH ); 97.0
2
(
d, J(F,C) ¼ 195, C); 128.6 (CH); 129.7 (d, J(F,C) ¼ 5, CH); 133.4 (d, J(F,C) ¼ 3, C); 133.9 (CH); 168.4
19
(
d, J(F,C) ¼ 25, CO); 191.7 (d, J(F,C) ¼ 25, CO). F-NMR (282 MHz): ꢀ 152.3 (qt, J(F,H) ¼ 22.5, 1.5).
þ
EI-MS: 225 (0.4, [M þ H] ), 105 (100). Anal. calc. for C H FO (224.23): C 64.28, H 5.84; found: C
12
13
3
6
4.14, H 5.68. Known compound [19][46]: the literature value for an enantiomerically pure sample with
S)-configuration: [a]
¼ þ85.4 (c ¼ 1.97, MeOH) [19].
Methyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (2F). GC: (b-DEX, 1008): t (minor) 101.4,
(
D
R
t
1
t (major) 103.8 min. R ( BuOMe/hexane 1:10) 0.19. H-NMR (250 MHz): 1.88 (d, J(F,H) ¼ 22.5, 3 H);
R
f
3
.80 (s, MeO); 7.42 – 7.51 (m, 2 H); 7.56 – 7.64 (m, 1 H); 8.02 – .07 (m, 2 H). 13C-NMR (62.9 MHz): 21.3 (d,
J(F,C) ¼ 24.7, Me); 53.5 (Me); 97.3 (d, J(F,C) ¼ 195.0, C); 128.8 (d, J(F,C) ¼ 0.8, CH); 129.9 (d, J(F,C) ¼
5
.5, CH); 133.4 (d, J(F,C) ¼ 3.7, C); 134.1 (CH); 169.0 (d, J(F,C) ¼ 25.6, CO); 191.9 (d, J(F,C) ¼ 25.0,
19
þ
CO). F-NMR (282 MHz): ꢀ 152.2 (q, J(F,H) ¼ 22.6). EI-MS: 210 (<1, M ), 105 (100). Known
compound, CAS No. 144462-33-9 (R).
1
,1-Dimethylpropyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (3F). HPLC (Chiralcel OB-H;
i
ꢀ1
t
hexane/ PrOH 99.7:0.3; 0.5 ml min ): t (minor) 14.7, t (major) 18.9 min. R ( BuOMe/hexane 1:10)
R
R
f
1
0
3
7
.51. [a] ¼ þ25.2 ꢁ 0.7 (c ¼ 1.825, MeOH; 32.9% ee). H-NMR (300 MHz): 0.72 (t, J ¼ 7.5, 3 H); 1.31 (s,
D
H); 1.38 (s, 3 H); 1.60 – 1.76 (AB of ABC , 2 H); 1.83 (d, J(F,C) ¼ 22.4, 3 H); 7.42 – 7.50 (m, 2 H); 7.55 –
3
13
.62 (m, 1 H); 8.02 – 8.08 (m, 2 H). C-NMR (62.9 MHz): 7.8, 20.7 (d, J(F,C) ¼ 24); 24.9; 25.1; 33.5; 86.5;

Helvetica Chimica Acta – Vol. 95 (2012)
375
9
1.6 (d, J(F,C) ¼ 193); 128.5 (d, J(F,C) ¼ 1); 129.6 (d, J(F,C) ¼ 5); 133.6 (d, J(F,C) ¼ 3); 133.7; 167.4 (d,
19
J(F,C) ¼ 26, CO); 191.6 (d, J(F,C) ¼ 25, CO). F-NMR (282 MHz): ꢀ 151.2 (qq, J(F,H) ¼ 22.4, 1.6).
þ
þ
FAB-MS: 289 (8, [M þ Na] ), 267 (20, [M þ H] ), 197 (100). Anal. calc. for C H FO (266.31): C 67.65,
15
19
3
H 7.19; found: C 67.63, H 7.15.
Benzyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (4F). HPLC (Chiralcel OJ; hexane/ PrOH
i
ꢀ1
t
9
5 :5; 1.0 ml min ): t (minor) 17.1, t (major) 20.6 min. R ( BuOMe/hexane 1:5) 0.51. [a] ¼ þ37.2 (c ¼
R
R
f
D
1
1
.0, MeOH; 70.0% ee). H-NMR (200 MHz): 1.87 (d, J(F,H) ¼ 22.5, 3 H); 5.17 (d, J ¼ 12.1, 1 H); 5.24 (d,
13
J ¼ 12.1, 1 H); 7.14 – 7.31 (m, 5 H); 7.32 – 7.45 (m, 2 H); 7.49 – 7.61 (m, 1 H); 7.93 – 8.04 (m, 2 H). C-NMR
(
1
75.5 MHz): 20.9 (d, J(F,C) ¼ 23, Me); 67.9 (CH ); 96.9 (d, J(F,C) ¼ 196, CF); 128.2 (CH); 128.5 (CH);
2
28.6 (CH); 128.6 (CH); 129.7 (d, J(F,C) ¼ 5, CH); 133.3 (d, J(F,C) ¼ 4, C); 133.8 (CH); 134.4 (C); 168.3
19
(
d, J(F,C) ¼ 26, CO); 191.4 (d, J(F,C) ¼ 25, CO). F-NMR (188.3 MHz): ꢀ 152.1 (qt, J(F,H) ¼ 22.5, 1.5).
þ
ESI-MS: 304.3 (100, [M þ NH ] ). Anal. calc. for C H FO (286.30): C 71.32, H 5.28; found: C 71.42, H
4
17 15
3
5
.21.
Diphenylmethyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (5F). HPLC (Chiralcel OJ; hexane/
i
ꢀ1
t
PrOH 95 :5; 1.0 ml min ): t (major) 14.1, t (minor) 18.9 min. R ( BuOMe/hexane 1:5) 0.50. [a] ¼
R
R
f
D
1
þ19.0 ꢁ 0.2 (c ¼ 1.83, MeOH; 56% ee). H-NMR (300 MHz): 1.89 (d, J(F,H) ¼ 22.5, 3 H); 6.91 (s, 1 H);
7
.01 – 7.07 (m, 2 H); 7.10 – 7.21 (m, 3 H); 7.22 – 7.37 (m, 7 H); 7.48 – 7.55 (m, 1 H); 7.90 – 7.97 (m, 2 H).
1
3
C-NMR (75.5 MHz): 20.8 (d, J(F,C) ¼ 23.5, Me); 78.9 (CH); 81.7 (d, J(F,C) ¼ 195.5, C); 126.7 (CH);
27.1 (CH); 128.0 (CH); 128.3 (CH); 128.4 (CH); 128.5 (CH); 128.6 (CH); 129.6 (CH); 129.7 (CH);
33.3 (d, J(F,C) ¼ 3, C); 133.8 (CH); 138.5 (C); 138.7 (C); 167.5 (d, J(F,C) ¼ 26, CO); 191.2 (d, J(F,C) ¼
1
1
2
19
þ
5, CO). F-NMR (282 MHz): ꢀ 152.5 (qt, J(F,H) ¼ 22.4, 1.5). HR-MALDI-MS: 385.121 ([M þ Na] ;
calc. 385.121). Anal. calc. for C H FO (362.40): C 76.23, H 5.28; found: C 76.28, H 5.49.
23
19
3
2
,3,4,5,6-Pentafluorobenzyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (6F). HPLC (Chiralcel
i
ꢀ1
t
OJ; hexane/ PrOH 95 :5; 0.5 ml min ): t (major) 17.1, t (minor) 19.3 min. R ( BuOMe/hexane 1:10)
R
R
f
1
0
1
(
(
2
.22. H-NMR (300 MHz): 1.88 (d, J(F,H) ¼ 22.6, 3 H); 5.23 (dt, J ¼ 12.2, J(F,H) ¼ 1.4, 1 H); 5.34 (dt, J ¼
13
2.2, J(F,H) ¼ 1.4, 1 H); 7.38 – 7.47 (m, 2 H); 7.54 – 7.63 (m, 1 H); 7.94 – 8.01 (m, 2 H). C-NMR
75.5 MHz): 20.9 (d, J(F,C) ¼ 23.2, Me); 55.0 (CH ); 96.9 (d, J(F,C) ¼ 196.5, CF); 108.0 (m, C); 128.8
2
2
CH); 129.7 (d, J(F,C) ¼ 5.5, CH); 133.2 (C); 134.2 (CH); 135.6 – 147.8 (m, 5 CF )); 168.0 (d, J(F,C) ¼
19
6.2, CO); 190.8 (d, J(F,C) ¼ 24.4, CO). F-NMR (282 MHz): ꢀ 161.5 (m, 2 FꢀC ); ꢀ 152.5 (q,
Ar
J(F,H) ¼ 22.6, 1 FꢀC(2)); ꢀ 151.9 (tt, J(F,F) ¼ 20.9, 2.7, 1 FꢀC ); ꢀ 141.8 (m, 2 FꢀC ). EI-MS: 376
Ar
Ar
þ
(
M ), 105 (100). Anal. calc. for C H O F (376.25): C 54.27, H 2.68; found: C 54.56, H 2.99.
17 10 3 6
4
-(Trifluoromethyl)benzyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (7F). HPLC (Chiralcel OJ;
i
ꢀ1
1
hexane/ PrOH 98 :2; 0.5 ml min ): t (major) 34.4, t (minor) 41.3 min. H-NMR (250 MHz): 1.89 (d,
R
R
J(F,H) ¼ 22.5, 3 H); 5.21 (d, J ¼ 12.5, 1 H); 5.29 (d, J ¼ 12.5, 1 H); 7.28 (d, J ¼ 8.0, 2 H); 7.35 – 7.43 (m,
1
3
2
H); 7.50 (d, J ¼ 8.0, 2 H); 7.53 – 7.61 (m, 1 H); 7.93 – 8.00 (m, 2 H). C-NMR (75.5 MHz): 21.1 (d,
J(F,C) ¼ 23.2, Me); 67.0 (CH ); 97.1 (d, J(F,C) ¼ 194.9, CF); 124.0 (q, J(F,C) ¼ 272.3, C); 125.7 (q,
2
J(F,C) ¼ 3.7, CH); 128.4 (CH); 128.8 (CH); 129.8 (d, J(F,C) ¼ 5.5, CH); 130.9 (q, J(F,C) ¼ 32.4, C); 133.3
(
d, J(F,C) ¼ 3.7, C); 134.2 (CH); 138.4 (d, J(F,C) ¼ 1, C); 168.3 (d, J(F,C) ¼ 25.9, CO); 191.4 (d, J(F,C) ¼
19
2
1
4.7, CO). F-NMR (282 MHz): ꢀ 152.3 (qt, J(F,H) ¼ 22.5, 1.5, 1 F); ꢀ 63.2 (3 F). EI-MS: 354 (2.4 ·
ꢀ5 þ
0
14 4 3
, M ), 105 (100). Anal. calc. for C18H F O (354.30): C 61.02, H 3.98; found: C 60.87, H 4.14.
Ethyl 2-Fluoro-3-(4-methoxyphenyl)-2-methyl-3-oxopropanoate (8F). GC (b-DEX, 1388): t (minor)
R
t
1
16.5, t (major) 119.0 min. R ( BuOMe/hexane 1:5) 0.27. [a] ¼ þ18.7 (c ¼ 0.58, MeOH; 56.3% ee).
R
f
D
1
H-NMR (300 MHz): 1.20 (t, J ¼ 7.1, 3 H); 1.86 (d, J(F,H) ¼ 22.6, 3 H); 3.88 (s, 3 H); 4.25 (m, 2 H); 6.90 –
13
6
.96 (m, 2 H); 8.02 – 8.09 (m, 2 H). C-NMR (75.5 MHz): 14.1 (Me); 21.2 (d, J(F,C) ¼ 23.5, Me); 55.7
(
(
(
(
Me); 62.6 (CH ); 97.3 (d, J(F,C) ¼ 194.9, CF); 114.0 (d, J(F,C) ¼ 1, CH); 126.4 (d, J(F,C) ¼ 3.7, C); 132.4
2
19
d, J(F,C) ¼ 5.8, CH); 164.3 (C); 168.9 (d, J(F,C) ¼ 25.6, CO); 190.1 (d, J(F,C) ¼ 24.7, CO). F-NMR
þ
282 MHz): ꢀ 151.5 (qt, J(F,H) ¼ 22.6, 1.5). EI-MS: 254 (1.2, M ), 135 (100). Anal. calc. for C H O F
13
15
4
254.26): C 61.41, H 5.95; found: C 61.44, H 5.95.
Methyl 2-Fluoro-3-(4-methoxyphenyl)-2-methyl-3-oxopropanoate (9F). GC (b-DEX, 1348): t (mi-
R
t
nor) 118.6, t (major) 121.2 min. R ( BuOMe/hexane 1:10) 0.16. [a] ¼ þ26.7 ꢁ 0.1 (c ¼ 1.025, MeOH;
R
f
D
2)
Quaternary C(ꢀF)-nuclei (higher-order spin system) gave rise to 5 m signals centered at 135.8,
39.2, 140.5, 144.0, and 147.4.
1

3
76
Helvetica Chimica Acta – Vol. 95 (2012)
1
6
2
(
1.7% ee). H-NMR (300 MHz): 1.87 (d, J(F,H) ¼ 22.6, 3 H); 3.78 (s, 3 H); 3.88 (s, 3 H); 6.88 – 6.97 (m,
13
H); 8.02 – 8.09 (m, 2 H). C-NMR (75.5 MHz): 21.3 (d, J(F,C) ¼ 23.5, Me); 53.4 (Me); 55.7 (Me); 97.4
d, J(F,C) ¼ 194.9, CF); 114.1 (d, J(F,C) ¼ 1, CH); 126.4 (d, J(F,C) ¼ 3.5, C); 132.5 (d, J(F,C) ¼ 5.8, CH);
19
1
64.4 (C); 169.3 (d, J(F,C) ¼ 25.8, CO); 190.2 (d, J(F,C) ¼ 24.7, CO). F-NMR (282 MHz): ꢀ 151.5 (qt,
þ
J(F,H) ¼ 22.6, 1.5). EI-MS: 240 (1.5, M ), 135 (100). Anal. calc. for C H FO (240.23): C 60.00, H 5.45;
12
13
4
found: C 59.96, H 5.52.
Ethyl 2-Fluoro-2-methyl-3-(4-nitrophenyl)-3-oxopropanoate (10F). GC (b-dex, 1508): t (minor)
R
t
1
8
(
1
4.1, t (major) 86.1 min. R ( BuOMe/hexane 1:5) 0.44. H-NMR (300 MHz): 1.23 (t, J ¼ 7.1, 3 H); 1.90
R
f
13
d, J(F,H) ¼ 22.6, 3 H); 4.28 (m, 2 H); 8.19 – 8.24 (m, 2 H); 8.28 – 8.33 (m, 2 H). C-NMR (75.5 MHz):
4.0 (Me); 20.9 (d, J(F,C) ¼ 23.2, Me); 63.1 (CH ); 97.3 (d, J(F,C) ¼ 194.3, CF); 123.9 (d, J(F,C) ¼ 1,
2
CH); 130.9 (d, J(F,C) ¼ 5.8, CH); 138.1 (d, J(F,C) ¼ 3.4, C); 150.7 (C); 167.8 (d, J(F,C) ¼ 25.6, CO); 190.9
19
þ
(
(
d, J(F,C) ¼ 26.2, CO). F-NMR (282 MHz): ꢀ 152.9 (qt, J(F,H) ¼ 22.6, 1.3). EI-MS: 269 (0.3, M ), 150
100). Anal. calc. for C H FNO (269.23): C 53.54, H 4.49, N 5.20; found: C 53.51, H 4.60, N 5.21.
12
12
5
i
Phenyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (11F). HPLC (Chiralcel OD-H; hexane/ PrOH
9.5 :0.5; 0.5 ml min ): t (major) 21.6, t (minor) 23.3 min. R ( BuOMe/hexane 1:10) 0.33. H-NMR
ꢀ
1
t
1
9
R
R
f
(
300 MHz): 2.04 (d, J(F,H) ¼ 22.5, 3 H); 6.95 – 6.99 (m, 2 H); 7.21 – 7.26 (m, 1 H); 7.31 – 7.39 (m, 2 H);
13
7
2
.47 – 7.55 (m, 2 H); 7.61 – 7.68 (m, 1 H); 8.12 – 8.17 (m, 2 H). C-NMR (75.5 MHz): 21.1 (d, J(F,C) ¼
3.1, Me); 97.1 (d, J(F,C) ¼ 196.1, CF); 121.0 (CH); 126.7 (CH); 129.0 (CH); 129.7 (CH); 129.9 (d,
J(F,C) ¼ 5.2, CH); 133.5 (d, J(F,C) ¼ 3.4, C); 134.3 (CH); 150.0 (C); 167.3 (d, J(F,C) ¼ 26.3, CO); 191.4
19
þ
(
(
d, J(F,C) ¼ 25.7, CO). F-NMR (282 MHz): ꢀ 152.3 (qt, J(F,H) ¼ 22.5, 1.5). EI-MS: 272 (0.7, M ), 105
100). Anal. calc. for C H FO (272.28): C 70.58, H 4.81; found: C 70.74, H 4.98.
16
13
3
4
-Methoxyphenyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanoate (12F). HPLC (Chiralcel OD-H;
i
ꢀ1
t
hexane/ PrOH 99.5 :0.5; 0.5 ml min ): t (minor) 40.1, t (major) 44.3 min. R ( BuOMe/hexane 1:5) 0.37.
R
R
f
1
H-NMR (250 MHz): 2.03 (d, J(F,H) ¼ 22.6, 3 H); 3.77 (s, 3 H); 6.81 – 6.91 (m, 4 H); 7.47 – 7.56 (m, 2 H);
13
7
9
1
.60 – 7.68 (m, 1 H); 8.12 – 8.16 (m, 2 H). C-NMR (62.9 MHz): 21.1 (d, J(F,C) ¼ 23.3, Me); 55.7 (Me);
7.1 (d, J(F,C) ¼ 196.3, CF); 114.7 (CH); 121.8 (CH); 129.0 (CH); 129.9 (CH); 133.5 (C); 134.3 (CH);
19
43.5 (C); 157.9 (C); 167.6 (d, J(F,C) ¼ 26.2, CO); 191.4 (d, J(F,C) ¼ 24.7, CO). F-NMR (282 MHz):
þ
ꢀ
152.2 (q, J(F,H) ¼ 22.6). EI-MS: 302 (19, M ), 105 (100). Anal. calc. for C H FO (302.30): C 67.54, H
17
15
4
5
.00; found: C 67.60, H 5.15.
Ethyl 2-Fluoro-2-methyl-3-(naphthalen-2-yl)-3-oxopropanoate (13F). HPLC (Chiralcel OJ; hexane/
i
ꢀ1
t
PrOH 90 :10; 0.6 ml min ): t (minor) 14.5, t (major) 17.1 min. R ( BuOMe/hexane 1:5) 0.60. [a] ¼
R
R
f
D
1
ꢀ
13.0 (c ¼ 1.065, MeOH; 60.6% ee). H-NMR (300 MHz): 1.19 (t, J ¼ 7.1, 3 H); 1.93 (d, J(F,H) ¼ 22.6,
H); 4.17 – 4.35 (m, 2 H); 7.52 – 7.65 (m, 2 H); 7.84 – 7.91 (m, 2 H); 7.95 – 8.00 (m, 1 H); 8.04 – 8.08 (m,
3
13
1
H); 8.66 (s, 1 H). C-NMR (75.5 MHz): 13.9 (Me); 21.0 (d, J(F,C) ¼ 23, Me); 62.6 (CH ); 97.2 (d,
2
J(F,C) ¼ 195, CF); 124.7 (d, J(F,C) ¼ 3, CH); 126.8 (CH); 127.7 (CH); 128.4 (CH); 129.0 (CH); 130.0
(
CH); 130.6 (d, J(F,C) ¼ 4, C); 132.1 (d, J(F,C) ¼ 8, CH); 132.3 (d, J(F,C) ¼ 1, C); 135.8 (C); 168.6 (d,
19
J(F,C) ¼ 26, CO); 191.5 (d, J(F,C) ¼ 25, CO). F-NMR (188.3 MHz): ꢀ 151.3 (qdd, J(F,H) ¼ 22.6, 1.7,
þ
1
.3). EI-MS: 274 (8, M ), 155 (100). Anal. calc. for C H FO (274.29): C 70.06, H 5.51; found: C 70.21,
16
15
3
H 5.59.
Ethyl 2-Fluoro-1,2,3,4-tetrahydro-1-oxonaphthalene-2-carboxylate (14F). HPLC (Chiralcel OB-H;
i
ꢀ1
t
hexane/ PrOH 85 :15; 0.5 ml min ): t (minor) 27.6, t (major) 33.7 min. R ( BuOMe/hexane 1:5) 0.23.
R
R
f
1
[
a] ¼ þ0.2 (c ¼ 1.25, MeOH; 19.8% ee). H-NMR (250 MHz): 1.28 (t, J ¼ 7.2, 3 H); 2.55 (dddd,
D
J(F,H) ¼ 22.5, J ¼ 14.0, 7.3, 5.2, 1 HꢀC(3)); 2.73 (dddd, J(F,H) ¼ 11.4, J ¼ 14.0, 7.5, 5.4, 1 HꢀC(3)); 3.08
(
ddd, J ¼ 17.2, 7.5, 5.1, 1 H of CH (4)); 3.20 (ddd, J ꢃ 17, 7, 6, 1 H of CH (4)); 4.30 (q, J ¼ 7.1, 2 H); 7.26 –
2
2
13
7
2
1
(
(
.41 (m, 2 H); 7.56 (td, J ¼ 7.5, 1.5, 1 H); 8.08 (dd, J ¼ 7.9, 1.4, HꢀC(8)). C-NMR (62.9 MHz): 14.0 (Me);
4.8 (d, J(F,C) ¼ 7, CH ); 31.8 (d, J(F,C) ¼ 22, CH ); 62.4 (CH ); 93.1 (d, J(F,C) ¼ 194, CF); 127.2 (CH);
2
2
2
28.4 (d, J(F,C) ¼ 1, CH); 128.7 (CH); 130.5 (C); 134.5 (CH); 143.1 (C); 167.3 (d, J(F,C) ¼ 26, CO); 188.6
1
9
d, J(F,C) ¼ 19, CO). F-NMR (188.3 MHz): ꢀ 164.7 (ddd, J(F,H) ¼ 22.4, 11.4, 1.1). ESI-MS: 254.16
þ
100, [M þ NH ] ). Anal. calc. for C H FO (236.24): C 66.09, H 5.55; found: C 65.82, H 5.55.
4
13 13
3
b) Catalytic Fluorination of 3-Oxobutanoates. Products were obtained according to GP 1; yields and
ee values are compiled in Table 2. The reaction times for this set of substrates were usually <1 h.
Ethyl 2-Fluoro-2-methyl-3-oxobutanoate (15F). GC (b-DEX, 708): t (minor) 15.7, t (major)
R
R
1
1
6.5 min. R (Et O/hexane 1:5) 0.64. [a] ¼ þ20.55 ꢁ 0.08 (c ¼ 1.00, MeOH; 45.3% ee). H-NMR
f
2
D

Helvetica Chimica Acta – Vol. 95 (2012)
377
(
2
250 MHz): 1.31 (t, J ¼ 7.1, 3 H); 1.69 (d, J(F,H) ¼ 22.1, 3 H); 2.33 (d, J(F,H) ¼ 4.6, 3 H); 4.27 (q, J ¼ 7.1,
13
H). C-NMR (62.9 MHz): 14.1 (Me); 19.9 (d, J(F,C) ¼ 22.8, Me); 25.1 (Me); 62.7 (CH ); 97.8 (d,
2
19
J(F,C) ¼ 193.7, CF); 167.0 (d, J(F,C) ¼ 25.3, CO); 202.5 (d, J(F,C) ¼ 28.6, CO). F-NMR (282 MHz):
ꢀ
157.6 (qq, J(F,H) ¼ 22.1, 4.6). Known compound, CAS No. 122795-13-5.
,2-Diphenylethyl 2-Fluoro-2-methyl-3-oxobutanoate (16F). HPLC (Chiralcel OD-H; hexane/ PrOH
i
2
ꢀ1
t
9
8 :2; 0.4 ml min ): t (minor) 26.6, t (major) 28.5 min. R ( BuOMe/hexane 1:10) 0.37. [a] ¼ þ12.8
R
R
f
D
1
(
3
c ¼ 0.39, MeOH; 35.2% ee). H-NMR (300 MHz): 1.50 (d, J(F,H) ¼ 22.1, 3 H); 2.00 (d, J(F,H) ¼ 4.5,
13
H); 4.41 (t, J ¼ 7.7, 1 H); 4.69 – 4.82 (m, 2 H); 7.18 – 7.36 (m, 10 H). C-NMR (75.5 MHz): 19.5 (d,
J(F,C) ¼ 23, Me); 24.6 (Me); 49.6 (CH); 68.2 (CH ); 97.4 (d, J(F,C) ¼ 194, CF); 127.0 (CH); 128.1 (CH);
2
19
1
28.1 (CH); 128.7 (CH); 140.1 (C); 140.1 (C); 166.6 (d, J(F,C) ¼ 26, CO); 201.6 (d, J(F,C) ¼ 28, CO). F-
þ
NMR (188.3 MHz): ꢀ 157.5 (qq, J(F,H) ¼ 22.1, 4.5). ESI-MS: 332.3 (100, [M þ NH ] ). Anal. calc. for
4
C H FO (314.36): C 72.60, H 6.09; found: C 72.44, H 6.18.
19
19
3
i
Benzyl 2-Fluoro-2-methyl-3-oxobutanoate (17F). HPLC (Chiralcel OJ; hexane/ PrOH 96 :4; 0.5 ml
ꢀ
1
t
min ): t (minor) 34.5, t (major) 42.1 min. R ( BuOMe/ hexane 1:5) 0.45. [a] ¼ þ17.8 (c ¼ 1.13,
R
R
f
D
1
MeOH; 50.4% ee). H-NMR (300 MHz): 1.69 (d, J(F,H) ¼ 22.1, 3 H); 2.28 (d, J(F,H) ¼ 4.6, 3 H); 5.24 (s,
13
2
1
ꢀ
H); 7.30 – 7.41 (m, 5 H). C-NMR (75.5 MHz): 19.7 (d, J(F,C) ¼ 23); 24.9; 68.0; 97.6 (d, J(F,C) ¼ 194);
19
28.1; 128.6; 128.7; 134.6; 166.7 (d, J(F,C) ¼ 26, CO); 202.1 (d, J(F,C) ¼ 29, CO). F-NMR (282 MHz):
þ
157.5 (qqq, J(F,H) ¼ 22.1, 4.5, 0.4). EI-MS: 224 (0.1, M ), 91 (100). Anal. calc. for C H FO (224.23):
12
13
3
C 64.28, H 5.84; found: C 64.25, H 5.78.
(
Naphthalen-1-yl)methyl 2-Fluoro-2-methyl-3-oxobutanoate (18F). HPLC (Chiralcel OJ; hexane/
i
ꢀ1
t
PrOH 96 :4; 1.0 ml min ): t (minor) 24.0, t (major) 27.7 min. R ( BuOMe/hexane 1:5) 0.49. [a] ¼
R
R
f
D
1
þ19.6 (c ¼ 1.14, MeOH; 68.8% ee). H-NMR (300 MHz): 1.67 (d, J(F,H) ¼ 22.1, 3 H); 2.22 (d,
13
J(F,H) ¼ 4.5, 3 H); 5.63 – 5.73 (m, AB-system, 2 H); 7.40 – 7.60 (m, 4 H); 7.79 – 7.96 (m, 3 H). C-NMR
(
1
75.5 MHz): 19.7 (d, J(F,C) ¼ 23, Me); 24.9 (Me); 66.5 (CH ); 97.6 (d, J(F,C) ¼ 194, C); 123.2 (CH);
2
25.2 (CH); 126.1 (CH); 126.8 (CH); 127.8 (CH); 129.8 (CH); 130.0 (C); 131.4 (C); 133.7 (C); 166.7 (d,
19
J(F,C) ¼ 26, CO); 202.1 (d, J(F,C) ¼ 28, CO). F-NMR (282 MHz): ꢀ 157.4 (qq, J(F,H) ¼ 22.1, 4.5). EI-
þ
MS: 274 (11, M ), 141 (100). Anal. calc. for C H FO (274.29): C 70.06, H 5.51; found: C 70.04, H 5.66.
16
15
3
2
,3,4,5,6-Pentafluorobenzyl 2-Fluoro-2-methyl-3-oxobutanoate (19F). GC (b-DEX, 958): t (minor)
R
t
1
9
3
(
2
2
2.1, t (major) 93.8 min. R ( BuOMe/hexane 1:10) 0.22. H-NMR (300 MHz): 1.69 (d, J(F,H) ¼ 22.2,
R
f
13
H); 2.31 (d, J(F,H) ¼ 4.5, 3 H); 5.32 (s, 2 H). C-NMR (75.5 MHz): 20.0 (d, J(F,C) ¼ 22.8, Me); 25.0
3
Me); 55.2 (CH ); 96.7 (d, J(F,C) ¼ 195.2, CF); 108.4 (m, CF); 136.1 – 147.4 (m, CF )); 166.4 (d, J(F,C) ¼
2
19
5.9, CO); 201.9 (d, J(F,C) ¼ 28.6, CO). F-NMR (282 MHz): ꢀ 161.4 (m, 2 F); ꢀ 157.8 (qq, J(F,H) ¼
þ
2.2, 4.5, 1 F); ꢀ 151.7 (tt, J(F,F) ¼ 20.8, 2.5, F); ꢀ 142.1 (m, 2 F). EI-MS: 314 (0.5, M ), 181 (100). Anal.
calc. for C H F O (314.18): C 45.88, H 2.57; found: C 45.84, H 2.77.
12
8
6
3
i
4-Nitrobenzyl 2-Fluoro-2-methyl-3-oxobutanoate (20F). HPLC (Chiralcel OB-H; hexane/ PrOH
ꢀ
1
t
1
7
5 :25; 0.4 ml min ): t (major) 20.9, t (minor) 22.2 min. R ( BuOMe/hexane 1:2) 0.31. H-NMR
R
R
f
(
8
300 MHz): 1.73 (d, J(F,H) ¼ 22.2, 3 H); 2.33 (d, J(F,H) ¼ 4.7, 3 H); 5.33 (s, 2 H); 7.51 (d, J ¼ 8.5, 2 H);
13
.24 (d, J ¼ 8.5, 2 H). C-NMR (75.5 MHz): 20.1 (d, J(F,C) ¼ 22.8, Me); 25.1 (Me); 66.4 (CH ); 97.8 (d,
2
J(F,C) ¼ 194.9, CF); 124.1 (CH); 128.5 (CH); 141.9 (C); 148.1 (C); 166.6 (d, J(F,C) ¼ 25.6, CO); 202.6 (d,
19
J(F,C) ¼ 28.6, CO). F-NMR (282 MHz, CDCl ): ꢀ 157.6 (qq, J(F,H) ¼ 22.2, 4.7). Anal. calc. for
3
C H FNO (269.23): C 53.54, H 4.49, N 5.20; found: C 54.02, H 5.04, N 5.16.
12
12
5
Phenyl 2-Fluoro-2-methyl-3-oxobutanoate (21F). GC (b-DEX, 1058): t (minor) 57.9, t (major)
R
R
t
1
5
9.1 min. R ( BuOMe/hexane 1:10) 0.28. H-NMR (300 MHz): 1.83 (d, J(F,H) ¼ 22.1, 3 H); 2.44 (d,
f
13
J(F,H) ¼ 4.6, 3 H); 7.09 – 7.13 (m, 2 H); 7.24 – 7.31 (m, 1 H); 7.37 – 7.43 (m, 2 H). C-NMR (75.5 MHz):
2
1
0.0 (d, J(F,C) ¼ 22.5, Me); 25.2 (Me); 97.8 (d, J(F,C) ¼ 195.2, C); 121.1 (CH); 126.7 (CH); 129.8 (CH);
19
50.2 (C); 165.6 (d, J(F,C) ¼ 25.6, CO); 202.3 (d, J(F,C) ¼ 28.5, CO). F-NMR (282 MHz): ꢀ 157.4 (qq,
þ
J(F,H) ¼ 22.1, 4.6). EI-MS: 210 (4, M ), 121 (100). Anal. calc. for C H FO (210.20): C 62.85, H 5.27;
11
11
3
found: C 62.13, H 5.44.
3
,5-Dimethylphenyl 2-Fluoro-2-methyl-3-oxobutanoate (22F). GC (b-DEX, 848): t (minor) 621,
R
t
t (major) 632 min. R ( BuOMe/hexane 1:10) 0.38. [a] ¼ þ7.3 ꢁ 0.4 (c ¼ 1.09, MeOH; 73.7% ee).
R
f
D
3)
Quaternary C(ꢀF)-nuclei (higher order spin system) gave rise to 5 m signals centered at: 136.1,
39.4, 140.6, 144.1, and 147.4.
1

3
78
Helvetica Chimica Acta – Vol. 95 (2012)
1
H-NMR (300 MHz): 1.81 (d, J(F,H) ¼ 22.1, 3 H); 2.31 (s, 6 H); 2.43 (d, J(F,H) ¼ 4.5, 3 H); 6.71 (s, 2 H);
13
6
1
.90 (s, 1 H). C-NMR (75.5 MHz): 20.0 (d, J(F,C) ¼ 22.5, Me); 21.3 (Me); 25.2 (Me); 97.8 (d, J(F,C) ¼
95.5, C); 118.6 (C); 128.4 (C); 139.7 (C); 150.0 (C); 165.7 (d, J(F,C) ¼ 25.6, CO); 202.3 (d, J(F,C) ¼ 28.3,
19
þ
CO). F-NMR (282 MHz): ꢀ 157.3 (qq, J(F,H) ¼ 22.2, 4.6). EI-MS: 238.1 (32, M ), 122 (100). Anal.
calc. for C H FO (238.26): C 65.54, H 6.35; found: C 65.48, H 6.19.
13
15
3
2
,6-Dimethylphenyl 2-Fluoro-2-methyl-3-oxobutanoate (23F). GC (b-DEX, 1028): t (minor) 139,
R
t
t (major) 142 min. R ( BuOMe/hexane 1:10) 0.39. [a] ¼ þ12.30 ꢁ 0.06 (c ¼ 1.11, MeOH; 72.7% ee).
R
1
f
D
H-NMR (300 MHz): 1.86 (d, J(F,H) ¼ 22.2, 3 H); 2.12 (s, 6 H); 2.46 (d, J(F,H) ¼ 4.9, 3 H); 7.07 (s, 3 H).
13
C-NMR (75.5 MHz): 16.2 (Me); 20.2 (d, J(F,C) ¼ 12.8, Me); 25.3 (Me); 98.1 (d, J(F,C) ¼ 195.0, CF);
1
26.7 (CH); 129.0 (CH); 130.0 (C); 147.5 (C); 164.7 (d, J(F,C) ¼ 25.8, CO); 202.8 (d, J(F,C) ¼ 28.8, CO).
19
þ
F-NMR (282 MHz): ꢀ 156.5 (qq, J(F,H) ¼ 22.2, 4.9). EI-MS: 238 (30, M ), 122 (100). Anal. calc. for
C H FO (238.26): C 65.54, H 6.35; found: C 65.34, H 6.25.
1
3
15
3
2
,4,6-Trimethylphenyl 2-Fluoro-2-methyl-3-oxobutanoate (24F). GC (b-DEX, 1138): t (minor) 137,
R
t
1
t (major) 140 min. R ( BuOMe/hexane 1:10) 0.40. H-NMR (300 MHz): 1.85 (d, J(F,H) ¼ 22.1, 3 H);
R
f
13
2
2
1
.07 (s, 6 H); 2.26 (s, 3 H); 2.46 (d, J(F,H) ¼ 4.8, 3 H); 6.87 (s, 2 H). C-NMR (75.5 MHz): 16.1 (Me);
0.2 (d, J(F,C) ¼ 22.5, Me); 20.9 (Me); 25.3 (Me); 98.0 (d, J(F,C) ¼ 194.3, CF); 129.6 (C); 129.6 (CH);
19
36.2 (C); 145.2 (C); 164.9 (d, J(F,C) ¼ 25.6, C); 202.8 (d, J(F,C) ¼ 28.9, C). F-NMR (282 MHz):
þ
ꢀ
156.5 (qq, J(F,H) ¼ 22.1, 4.8). EI-MS: 252 (37, M ), 136 (100). Anal. calc. for C H FO (252.28): C
14
17
3
6
6.65, H 6.79; found: C 66.75, H 6.93.
i
Ethyl 2-Benzyl-2-fluoro-3-oxobutanoate (25F). HPLC (Chiralcel OJ; hexane/ PrOH 95 :5; 1.0 ml
ꢀ
1
t
min ): t (major) 16.4, t (minor) 25.7 min. R ( BuOMe/hexane 1: 5) 0.39. [a] ¼ þ1.6 (c ¼ 1.535, MeOH;
R
R
f
D
1
6
.2% ee). H-NMR (300 MHz): 1.24 (t, J ¼ 7.1, 3 H); 2.13 (d, J(F,H) ¼ 5.1, 3 H); 3.37 (dd, J(F,H) ¼ 26.5,
13
J ¼ 14.7, 1 H) 3.43 (dd, J(F,H) ¼ 25.1, J ¼ 14.7, 1 H); 4.22 (q, J ¼ 7.1, 2 H); 7.18 – 7.32 (m, 5 H). C-NMR
(
(
75.5 MHz): 13.9 (Me); 26.2 (Me); 39.7 (d, J(F,C) ¼ 20, CH ); 62.6 (CH ); 99.9 (d, J(F,C) ¼ 200, C); 127.4
2
2
CH); 128.4 (CH); 130.3 (d, J(F,C) ¼ 1, CH); 133.0 (C); 165.6 (d, J(F,C) ¼ 25, CO); 202.3 (d, J(F,C) ¼ 30,
19
þ
þ
CO). F-NMR (282 MHz): ꢀ 165.1 (tq, J(F,H) ¼ 25.5, 5.2). EI-MS: 238 (8, M ), 218 (98, [M ꢀ HF] ),
1
96 (100). Anal. calc. for C H FO (238.26): C 65.54, H 6.35; found: C 65.25, H 6.14.
13
15
3
i
Benzyl 2-Acetyl-2-fluoro-3-methylbutanoate (26F). HPLC (Chiralcel OJ; hexane/ PrOH 98.5 :1.5;
ꢀ
1
t
1
.0 ml min ): t (major) 20.6, t (minor) 26.0 min. R ( BuOMe/hexane 1:5) 0.44. [a] ¼ þ8.4 (c ¼ 0.835,
R
R
f
D
1
MeOH; 23.8% ee). H-NMR (250 MHz): 0.91 (d, J ¼ 6.9, 3 H); 0.91 (d, J ¼ 6.9, 3 H); 2.27 (d, J(F,H) ¼
5
.3, 3 H); 2.73 (dsept., J(F,H) ¼ 30.4, J ¼ 6.9, 1 H); 5.20, 5.26 (AB, J ¼ 12.2, 2 H); 7.28 – 7.42 (m, 5 H).
C-NMR (62.9 MHz): 15.8 (d, J(F,C) ¼ 3, Me); 16.1 (d, J(F,C) ¼ 3, Me); 26.8 (d, J(F,C) ¼ 1, Me); 33.4 (d,
13
J(F,C) ¼ 21, CH); 67.9 (CH ); 128.3 (CH); 128.6 (CH); 128.6 (CH); 134.7 (C); 165.9 (d, J(F,C) ¼ 27,
2
19
CO); 202.4 (d, J(F,C) ¼ 29, CO). F-NMR (188.3 MHz): ꢀ 182.2 (dq, J(F,H) ¼ 30.4, 5.3). ESI-MS: 270.3
þ
(
100, [M þ NH ] ). Anal. calc. for C H FO (252.28): C 66.65, H 6.79; found: C 66.59, H 6.85.
4
14 17
3
i
Benzyl 1-Fluoro-2-oxocyclopentanecarboxylate (27F). HPLC (Chiralcel OJ; hexane/ PrOH 85 :15;
ꢀ1
t
0
.8 ml min ): t (major) 27.1, t (minor) 34.9 min. R ( BuOMe/hexane 1:5) 0.19. [a] ¼ ꢀ33.2 (c ¼ 1.285,
R
R
f
D
1
MeOH; 56.8% ee). H-NMR (250 MHz): 2.03 – 2.16 (m, 2 H); 2.21 – 2.42 (m, 1 H); 2.42 – 2.51 (m, 3 H);
13
2
(
.4 (ddd, J(F,H) ¼ 19.9, J ¼ 14.4, 7.3, 1 H); 5.21, 5.27 (AB, J ¼ 12.2, 2 H); 7.28 – 7.41 (m, 5 H). C-NMR
62.9 MHz): 18.0 (d, J(F,C) ¼ 3, CH ); 33.8 (d, J(F,C) ¼ 21, CH ); 35.6 (CH ); 67.7 (CH ); 94.7 (d,
2
2
2
2
J(F,C) ¼ 200, CF); 128.1 (CH); 128.6 (CH); 128.6 (CH); 134.6 (C); 167.2 (d, J(F,C) ¼ 28, CO); 207.3 (d,
19
J(F,C) ¼ 17, CO). F-NMR (188.3 MHz): ꢀ 164.4 (dd, J(F,H) ¼ 21.2, 20.2). ESI-MS: 254.3 (100, [M þ
þ
NH ] ). Anal. calc. for C H FO (236.24): C 66.09, H 5.55; found: C 65.93, H 5.53.
4
13 13
3
c) Catalytic Fluorination of 3-Oxopentanoates. Products were obtained according to GP 1; yields and
ee values are compiled in Table 3. Reaction times for this type of substrates were typically < 1 h.
Ethyl 2-Fluoro-2-methyl-3-oxopentanoate (28F). GC (b-DEX, 828): t (minor) 15.1, t (major)
R
R
1
1
2
6.3 min. H-NMR (300 MHz): 1.08 (t, J ¼ 7.2, 3 H); 1.29 (t, J ¼ 7.2, 3 H); 1.68 (d, J(F,H) ¼ 22.3, 3 H);
19
.59 – 2.76 (m, 2 H); 4.25 (q, J ¼ 7.2, 2 H). F-NMR (282 MHz): ꢀ 159.7 (qt, J(F,H) ¼ 22.3, 3.0). Known
compound, CAS No. 106815-14-9 (S), 106815-09-2 (R).
Benzyl 2-Fluoro-2-methyl-3-oxopentanoate (29F). HPLC (Chiralcel OJ; hexane/ PrOH 96 :4; 1.0 ml
i
ꢀ
1
t
min ): t (minor) 11.7, t (major) 15.3 min. R ( BuOMe/hexane 1:10) 0.30. [a] ¼ þ32.5 (c ¼ 0.905,
R
R
f
D
1
MeOH; 70.8% ee). H-NMR (300 MHz): 1.04 (t, J ¼ 7.2, 3 H); 1.70 (d, J(F,H) ¼ 22.2, 3 H); 2.53 – 2.79
13
(
CD of A CDX, 2 H); 5.23 (s, 2 H); 7.27 – 7.45 (m, 5 H). C-NMR (75.5 MHz): 7.0 (d, J(F,C) ¼ 2, Me);
3

Helvetica Chimica Acta – Vol. 95 (2012)
379
2
1
0.1 (d, J(F,C) ¼ 23, Me); 30.6 (CH ); 67.8 (CH ); 97.8 (d, J(F,C) ¼ 194, CF); 128.1 (CH); 128.6 (CH);
19
2
2
28.6 (CH); 134.7 (C); 166.8 (d, J(F,C) ¼ 26, CO); 204.9 (d, J(F,C) ¼ 27, CO). F-NMR (188.3 MHz):
þ
ꢀ
159.5 (qt, J(F,H) ¼ 22.2, 3.1). EI-MS: 238 (0.02, M ), 91 (100). Anal. calc. for C H FO (238.26): C
13
15
3
6
5.54, H 6.35; found: C 65.28, H 6.30.
,4,6-Tris(1-methylethyl)benzyl 2-Fluoro-2-methyl-3-oxopentanoate (30F). HPLC (Chiralcel OD-H;
2
i
ꢀ1
t
hexane/ PrOH 99.8 :0.2; 0.3 ml min ): t (major) 27.8, t (minor) 29.8 min. R ( BuOMe/hexane 1:10)
0
R
R
f
1
.48. [a] ¼ þ14.8 (c ¼ 0.77, MeOH; 52.5% ee); þ 24.1 (c ¼ 1.11, MeOH; 85.6% ee). H-NMR
D
(
300 MHz): 1.03 (t, J ¼ 7.2, 3 H); 1.22 (d, J ¼ 6.9, 6 H); 1.23 (d, J ¼ 6.9, 6 H); 1.26 (d, J ¼ 6.9, 6 H); 1.67 (d,
J(F,H) ¼ 22.2, 3 H); 2.61 (ddq, J ¼ 19.1, 7.1, J(F,H) ¼ 2.6, 1 H); 2.72 (ddq, J ¼ 19.2, 7.1, J(F,H) ¼ 3.5, 1 H);
13
2
.89 (sept., J ¼ 7.0, 1 H); 3.13 (sept., J ¼ 6.9, 2 H); 5.33 (s, 2 H); 7.04 (s, 2 H). C-NMR (75.5 MHz): 6.9 (d,
J(F,C) ¼ 2); 20.1 (d, J(F,C) ¼ 23); 23.9; 24.3; 29.5; 30.5; 34.3; 61.4; 97.8 (d, J(F,C) ¼ 194); 121.2; 125.1;
19
1
49.0; 150.1; 167.2 (d, J(F,C) ¼ 25, CO); 204.9 (d, J(F,C) ¼ 27, CO). F-NMR (188.3 MHz): ꢀ 159.2 (qt,
þ
J(F,H) ¼ 22.3, 2.9). EI-MS: 365 (0.3, M ), 217 (100). Anal. calc. for C H FO (364.50): C 72.49, H 9.13;
22
33
3
found: C 72.36, H 9.07.
Diphenylmethyl 2-Fluoro-2-methyl-3-oxopentanoate (31F). HPLC (Chiralcel OJ; hexane/ PrOH
i
ꢀ1
t
7
0 :30; 0.25 ml min ): t (major) 36.1, t (minor) 39.4 min. R ( BuOMe/hexane 1:10) 0.37. [a] ¼ þ38.2
R
R
f
D
1
(
(
(
c ¼ 1.02, MeOH; 81.2% ee). H-NMR (300 MHz): 1.00 (t, J ¼ 7.2, 3 H); 1.71 (d, J(F,C) ¼ 22.1, 3 H); 2.53
ddq, J ¼ 19.0, 7.1, J(F,H) ¼ 2.5, 1 H); 2.68 (ddq, J ¼ 19.0, 7.2, J(F,H) ¼ 3.7, 1 H); 6.91 (s, 1 H); 7.24 – 7.38
13
m, 10 H). C-NMR (75.5 MHz): 6.9 (d, J(F,C) ¼ 2); 20.0 (d, J(F,C) ¼ 23); 30.7; 78.8; 97.8 (d, J(F,C) ¼
1
94); 126.8; 126.9; 128.2; 128.3; 128.6; 128.6; 139.0; 166.0 (d, J(F,C) ¼ 26, CO); 204.6 (d, J(F,C) ¼ 27,
19
þ
CO). F-NMR (188.3 MHz): ꢀ 159.5 (qdd, J(F,H) ¼ 22.1, 3.4, 2.6). ESI-MS: 332.3 (100, [M þ NH ] ).
4
þ
HR-MALDI-MS: 337.121 ([M þ Na] ; calc. 337.121). Anal. calc. for C H FO (314.35): C 72.60, H 6.09;
19
19
3
found: C 72.58, H 6.28.
3
After standing for 1 d in CDCl soln., the hydro-dealkyloxycarbonylation product, 2-fluoropentan-3-
one (probably formed by reaction with traces of HCl from the solvent), could be detected in an NMR
19
sample: F-NMR: ꢀ 184.6 (dq, J(F,H) ¼ 46.9, 23.5).
Phenyl 2-Fluoro-2-methyl-3-oxopentanoate (32F). GC (b-DEX, 1328): t (minor) 23.8, t (major)
R
R
1
t
2
(
4.4 min. R ( BuOMe /hexane 1:10) 0.35. [a] ¼ þ17.8 ꢁ 0.1 (c ¼ 0.64, MeOH; 88.2% ee). H-NMR
f
D
300 MHz): 1.16 (A of A CD, y-t, J ¼ 7.2, 3 H); 1.84 (d, J(F,H) ¼ 22.3, 3 H); 2.83 (CD of A CD, y-qd,
3
3
3
13
J ¼ 7.2, 2.5, 2 H); 7.07 – 7.13 (m, 2 H); 7.23 – 7.30 (m, 1 H); 7.36 – 7.43 (m, 2 H). C-NMR (75.5 MHz): 7.2
(
(
Me); 20.3 (d, J(F,C) ¼ 22.8, Me); 30.8 (CH ); 97.8 (d, J(F,C) ¼ 195.4, C); 121.1 (CH); 126.7 (CH); 129.8
2
19
CH); 150.2 (C); 165.7 (d, J(F,C) ¼ 25.9, CO); 205.2 (d, J(F,C) ¼ 27.2, CO). F-NMR (282 MHz):
þ
ꢀ
159.6 (qt, J(F,H) ¼ 22.3, 3.0). EI-MS: 224 (11, M ), 57 (100). Anal. calc. for C H FO (224.23): C
12
13
3
6
4.28, H 5.84; found: C 64.37, H 5.82.
-Methoxyphenyl 2-Fluoro-2-methyl-3-oxopentanoate (33F). GC (b-DEX, 1408): t (minor) 58.2,
4
R
t
1
t (major) 59.2 min. R ( BuOMe/hexane 1:5) 0.28. H-NMR (250 MHz): 1.16 (A of A CD, y-t, J ¼ 7.1,
R
f
3
3
3
2
(
H); 1.82 (d, J(F,H) ¼ 22.3, 3 H); 2.82 (CD of A CD, y-qd, J ¼ 7.1, 2.5, 2 H); 3.80 (s, 3 H); 6.87 – 6.91 (m,
3
13
H); 7.01 – 7.04 (m, 2 H). C-NMR (62.9 MHz): 7.2 (Me); 20.3 (d, J(F,C) ¼ 22.2, Me); 30.8 (CH ); 55.7
2
Me); 97.9 (d, J(F,C) ¼ 194.8, CF); 114.7 (CH); 121.9 (CH); 143.7 (C); 157.9 (C); 166.0 (d, J(F,C) ¼ 25.7,
19
CO); 205.2 (d, J(F,C) ¼ 27.2, CO). F-NMR (282 MHz): ꢀ 159.5 (q, J(F,H) ¼ 22.6). EI-MS: 254 (50,
þ
M ), 57 (100). Anal. calc. for C H FO (254.26): C 61.41, H 5.95; found: C 61.36, H 5.89.
13
15
3
2,6-Di-(tert-butyl)-4-methylphenyl 2-Fluoro-2-methyl-3-oxopentanoate (34F). The product used for
analysis was exceptionally obtained using a catalyst derived from (S,S)-configured (nap-1)-TADDOL.
i
ꢀ1
HPLC (Chiralcel OD-H; hexane/ PrOH 99.5 :0.5; 0.8 ml min ): t (minor) 20.6, t (major) 35.2 min. R
f
R
R
t
1
(
BuOMe/hexane 1:10) 0.55. [a] ¼ þ3.9 (c ¼ 0.79, MeOH; 45.4% ee). H-NMR (300 MHz): 1.11 (t, J ¼
D
7
2
.1, 3 H); 1.24 (s, 9 H); 1.31 (s, 9 H); 1.85 (d, J(F,H) ¼ 22.2, 3 H); 2.30 (t, J ¼ 0.6, 3 H); 2.77 – 3.05 (m,
13
H); 7.11 (q, J ¼ 0.6, 2 H). C-NMR (75.5 MHz): 6.8 (d, J(F,C) ¼ 2, Me); 21.6 (d, J(F,C) ¼ 23, Me); 31.2
); 35.2 (C); 35.2 (C); 98.9 (d, J(F,C) ¼ 198, CF); 127.2 (CH); 127.2
(
(
Me); 31.2 (Me); 31.2 (Me); 31.6 (CH
2
CH); 135.2 (C); 141.9 (C); 141.9 (C); 146.0 (C); 166.5 (d, J(F,C) ¼ 24, CO); 205.5 (d, J(F,C) ¼ 28, CO).
1
9
þ
F-NMR (188.3 MHz): ꢀ 158.5 (qdd, J(F,H) ¼ 22.2, 3.1, 3.0). ESI-MS: 368.35 ([M þ NH ] ). Anal. calc.
4
for C H FO (350.47): C 71.97, H 8.92; found: C 72.14, H 8.79.
21
31
3
d) Catalytic Fluorination of a-Acyl Lactones. Products were obtained according to GP 1; yields and
ee values are collected in Table 4.

3
80
Helvetica Chimica Acta – Vol. 95 (2012)
3
-Benzoyl-3-fluoro-3,4,5,6-tetrahydro-2H-pyran-2-one (35F). HPLC (Chiralcel OD-H; hexane/
i
ꢀ1
1
PrOH 90 :10; 0.5 ml min ): t (major) 20.7, t (minor) 23.3 min. H-NMR (300 MHz): 2.10 – 2.19 (m,
R
R
2
2
H); 2.33 – 2.45 (m, 1 H); 2.76 – 2.92 (m, 1 H); 4.52 (t, J ¼ 6, 2 H); 7.61 – 7.66 (m, 1 H); 7.47 – 7.52 (m,
13
H); 8.11 – 8.14 (m, 2 H). C-NMR (75.5 MHz): 19.8 (d, J(F,C) ¼ 5.3, CH ); 30.3 (d, J(F,C) ¼ 23.4,
2
CH ); 69.5 (CH ); 95.7 (d, J(F,C) ¼ 196.2, CF); 128.0 (CH); 130.0 (d, J(F,C) ¼ 7.5, CH) 133.0 (d,
2
2
19
J(F,C) ¼ 7.5, C); 133.9 (CH); 165.3 (d, J(F,C) ¼ 23.1, CO); 194.5 (d, J(F,C) ¼ 26.5, CO). F-NMR
þ
(
282 MHz): ꢀ 146.18 (dd, J(F,H) ¼ 22.5, 16.9). EI-MS: 222 (0.3, M ), 105 (100). Anal. calc. for
C H FO (222.21): C 64.86, H 4.99; found: C 64.98, H 5.08.
12
11
3
3
-Fluoro-3,4,5,6-tetrahydro-3-(2-phenylacetyl)-2H-pyran-2-one (36F). HPLC (Chiralcel OD-H;
i
ꢀ1
1
hexane/ PrOH 95 :5; 0.5 ml min ): t (major) 37.5, t (minor) 46.3 min. H-NMR (300 MHz): 1.93 – 2.01
R
R
(
(
m, 1 H); 2.54 – 2.64 (m, 3 H); 2.75 – 2.82 (m, 2 H); 3.02 – 3.08 (m, 2 H); 7.21 – 7.26 (m, 3 H); 7.92 – 7.98
13
m, 1 H); 7.99 – 8.03 (m, 1 H). C-NMR (62.9 MHz): 19.8 (d, J(F,C) ¼ 3.3, CH ) 29.8 (d, J(F,C) ¼ 22.5,
2
CH ); 44.5 (CH ); 70.3 (CH ); 95.6 (d, J(F,C) ¼ 195.2, CF); 127.3 (CH); 128.6 (CH); 131.4 (CH); 133.1
2
2
2
19
(
ꢀ
d, J(F,C) ¼ 1.8, C); 164.6 (d, J(F,C) ¼ 23.4, CO); 203.7 (d, J(F,C) ¼ 29.2, CO). F-NMR (282 MHz):
151.68 to ꢀ 151.52 (m). Anal. calc. for C13
H
13FO
3
(236.24): C 66.09, H 5.55; found: C 66.34, H 5.80.
i
3
-Benzoyl-3-fluoro-4,5-dihydrofuran-2(3H)-one (37F). HPLC (Chiralcel OD-H; hexane/ PrOH
ꢀ1
1
9
3
9.5 :0.5; 0.5 ml min ): t (minor) 57.5, t (major) 60.5 min. H-NMR (300 MHz): 2.68 – 2.83 (m, 1 H);
R R
.06 – 3.16 (m, 1 H); 4.49 – 4.60 (m, 2 H) 7.50 – 7.56 (m, 2 H); 7.63 – 7.69 (m, 1 H); 8.17 – 8.22 (m, 2 H).
C-NMR (75.5 MHz): 33.5 (d, J(F,C) ¼ 22, CH ); 65.5 (d, J(F,C) ¼ 5.4, CH ); 96.7 (d, J(F,C) ¼ 208.4,
13
2
2
CF); 128.3 (CH); 130.0 (d, J(F,C) ¼ 7.5, CH); 134.2 (C); 136.3 (CH); 169.4 (d, J(F,C) ¼ 19.3, CO); 193.5
19
þ
(
1
d, J(F,C) ¼ 30.1, CO). F-NMR (282 MHz): ꢀ 157.38 (dd, J(F,H) ¼ 22.6, 8.5). EI-MS: 208 (1.5, M ),
05 (100). Anal. calc. for C H FO (208.19): C 63.46, H 4.36; found: C 63.39, H 4.46.
11 9 3
3
-Fluoro-4,5-dihydro-3-(2-phenylacetyl)furan-2(3H)-one (38F). HPLC (Chiralcel OD-H; hexane/
i
ꢀ1
1
PrOH 90 :10; 0.5 ml min ): t
H) 2.75 – 2.82 (m, 1 H); 4.09 – 4.14 (m, 2 H); 4.37 – 4.51 (m, 2 H); 7.19 – 7.38 (m, 5 H). C-NMR
75.5 MHz): 32.6 (d, J(F,C) ¼ 20.9, CH ); 44.8 (CH ); 65.7 (d, J(F,C) ¼ 4.5, CH ); 96.5 (d, J(F,C) ¼ 205.4,
R R
(minor) 23.9, t (major) 28.0 min. H-NMR (300 MHz): 2.57 – 2.63 (m,
13
1
(
2
2
2
CF); 127.5 (CH); 128.7 (CH); 129.8 (CH); 131.6 (d, J(F,C) ¼ 1.5, C); 169.0 (d, J(F,C) ¼ 25.3, CO); 202.7
19
þ
(
d, J(F,C) ¼ 30, CO). F-NMR (282 MHz): ꢀ 164.43 to ꢀ 164.58 (m). EI-MS: 222 (25, M ), 91 (100).
Anal. calc. for C H FO (222.21): C 64.86; H 4.99; found: C 64.67, H 5.20.
12
11
3
3
-(2,2-Diphenylacetyl)-3-fluoro-4,5-dihydrofuran-2(3H)-one (39F). HPLC (Chiralcel OJ; hexane/
i
ꢀ1
1
PrOH 95 :5; 0.5 ml min ): t 45.5/46.9 min; incomplete separation. H-NMR (300 MHz): 2.47 – 2.63 (m,
R
13
1
(
H); 2.75 – 2.82 (m, 1 H); 4.14 (d, J ¼ 3.8, 1 H); 4.37 – 4.51 (m, 2 H); 7.19 – 7.48 (m, 10 H). C-NMR
62.9 MHz): 33.4 (d, J(F,C) ¼ 20.7, CH ); 58.9 (CH); 65.6 (d, J(F,C) ¼ 4.4, CH ); 96.6 (d, J(F,C) ¼ 207.5,
2
2
CF); 127.5 (CH); 127.9 (CH); 128.5 (CH); 128.9 (CH); 129.1 (CH); 129.2 (CH); 135.6 (C); 136.9 (C);
19
1
(
64.6 (CO); 203.5 (d, J(F,C) ¼ 29.5, CO). F-NMR (282 MHz): ꢀ 164.43 to ꢀ 164.58 (m). EI-MS: 298
þ
3, M ), 167 (100). Anal. calc. for C H FO (298.10): C 72.47, H 5.07; found: C 71.97, H 5.06.
18
15
3
7
. Double Stereochemical Differentiation Studies with Enantiomerically Pure b-Keto Esters. Products
19
were obtained according to GP 1; yields and de values (determined by F-NMR) are given in Table 5.
3b)-Cholest-5-en-3-yl 2-Fluoro-2-methyl-3-oxobutanoate (40F). Prepared according to GP1. Color-
less crystalline solid. The reactions were performed with added CH Cl (2 ml) to enhance the solubility of
(
2
2
t
the substrate. The F-TEDA is only partially dissolved under these conditions (suspension). R ( BuOMe/
f
1
hexane 1:10) 0.45. M.p. 151.5 – 152.58. H-NMR (300 MHz): 0.67 (s, 3 H); 0.86 (d, J ¼ 6.6, 3 H); 0.87 (d,
J ¼ 6.7, 3 H); 0.91 (d, J ¼ 6.6, 3 H); 0.95 – 1.67 (m, 21 H); 1.02 (s, 3 H); 1.67 (d, J(F,H) ¼ 22.2, 3 H); 1.76 –
2
.07 (m, 5 H); 2.32 (d, J(F,H) ¼ 4.5, 3 H); 2.29 – 2.39 (m, 2 H); 4.64 – 4.78 (m, 1 H); 5.38 (d, J ca. 5, 1 H).
1
3
C-NMR (75.5 MHz): 11.8 (Me); 18.7 (Me); 19.3 (Me); 19.7 (d, J(F,C) ¼ 23, MeCF); 21.0 (CH ); 22.5
2
(
(
(
Me); 22.8 (Me); 23.8 (CH ); 24.3 (CH ); 24.9 (CH); 27.4 (CH ); 28.0 (Me); 28.2 (CH ); 31.8 (CH); 31.9
2
2
2
2
CH ); 35.8 (CH); 36.2 (CH ); 36.5 (C); 36.8 (CH ); 37.6 (CH ); 39.5 (CH ); 39.7 (CH ); 42.3 (C); 49.9
2
2
2
2
2
2
CH); 56.1 (CH); 56.6 (CH); 76.5 (CH); 97.6 (d, J(F,C) ¼ 193, CF); 123.2 (CH); 138.9 (C); 166.3 (d,
19
J(F,C) ¼ 25, CO); 202.2 (d, J(F,C) ¼ 28, CO). F-NMR (188.3 MHz): ꢀ 157.3 (qq, J(F,H) ¼ 22.1, 4.4);
19
1
F{ H}-NMR (188.3 MHz): ꢀ 157.202 (s, 80%); ꢀ 157.211 (s, 20%). HR-MALDI-MS: 525.372 ([M þ
þ
Na] ; calc. 525.371). Anal. calc. for C H FO (502.74): C 76.45, H 10.22; found: C 76.41, H 10.21.
32
51
3
Nopyl 2-Fluoro-2-methyl-3-oxo-butanoate (¼2-[(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-
19
yl]ethyl 2-fluoro-3-oxobutanoate; 41F). The product was not isolated. Spectral data ( F-NMR) was

Helvetica Chimica Acta – Vol. 95 (2012)
381
obtained from crude mixtures after aqueous workup. 19F{ H}-NMR (188.3 MHz): ꢀ 157.08 (s, 75%),
1
ꢀ
157.10 (s, 25%).
(
1R,2S,5R)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-Fluoro-2-methyl-3-oxobutanoate (42F). R
f
(tBuOMe/hexane 1:5) 0.65. H-NMR (300 MHz): (major diastereoisomer): 0.75 (d, J ¼ 7.0, 3 H);
1
0
.80 – 0.96 (m, 1 H); 0.89 (d, J ¼ 6.9, 3 H); 0.91 (d, J ca. 6, 3 H); 0.96 – 1.14 (m, 2 H); 1.39 – 1.59 (m, 2 H);
1
3
.67 (d, J(F,H) ¼ 22.0, 3 H); 1.61 – 1.74 (m, 2 H); 1.73 – 1.86 (m, 1 H); 1.92 – 2.02 (m, 1 H); 2.31 (d, J ¼ 4.4,
H); 4.71 – 4.62 (m, 1 H); (minor diastereoisomer; selected signals): 0.74 (d, J ¼ 7.0, 3 H); 1.67 (d,
13
J(F,H) ¼ 22.0, 3 H). C-NMR (75.5 MHz): (major diastereoisomer): 15.9 (Me); 19.6 (d, J(F,C) ¼ 23,
Me); 20.7 (Me); 21.9 (Me); 23.2 (CH ); 24.9 (CH); 26.2 (CH); 31.3 (Me); 34.0 (CH ); 40.2 (CH ); 46.7
2
2
2
(
(
2
CH); 76.9 (CH); 97.5 (d, J(F,C) ¼ 193, CF); 166.5 (d, J(F,C) ¼ 26, CO); 202.0 (d, J(F,C) ¼ 28, CO);
minor diastereoisomer; selected signals): 16.0 (Me); 19.6 (d, J(F,C) ¼ 23, Me); 20.6 (Me); 23.2 (CH );
2
19
1
4.9 (CH); 26.1 (Me); 34.0 (CH ); 40.3 (CH ); 77.0 (CH); 97.7 (d, J(F,C) ¼ 193, CF). F{ H}-NMR
2
2
þ
(
188.3 MHz): ꢀ 156.94 (s, major); ꢀ 157.08 (s, minor). ESI-MS: 290.3 ([M þ NH ] ). Anal. calc. for
4
C H FO (272.356): C 66.15, H 9.25; found: C 66.02, H 9.20.
15
25
3
(
1S,2R,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-Fluoro-2-methyl-3-oxobutanoate (43F). Enan-
tiomeric to 42F, product not isolated; spectra recorded after aqueous workup of the crude mixture.
19
1
F{ H}-NMR (188.3 MHz): ꢀ 156.94 (s, minor); ꢀ 157.08 (s, major).
(
1R)-2-Methoxy-2-oxo-1-phenylethyl 2-Fluoro-2-methyl-3-oxopentanoate (44F). a) According to
GP 1 from 44 with K1. After CC, a colorless oil (53 mg, 59%) with a dr of 13 :87 was obtained.
b) By Fluorination of the Na-Enolate. To compound 44 (278.3 mg, 1 mmol) in sat. F-TEDA (7.5 ml in
MeCN, 1.1 mmol) were added NaH (27 mg, 1.1 mmol) and tert-amyl alcohol (0.2 ml). Bubbles
developed, and the suspension went slowly into soln. After 1 h, the reaction was not yet finished, thus
two additional portions of NaH (total 20 mg) and finally some additional F-TEDA soln. (2.5 ml) were
added. TLC indicated almost complete conversion and the generation of a side product. After workup
t
t
with H O/ BuOMe, the org. phase was filtered over little Al O and evaporated. CC ( BuOMe/hexane
1
2
2
3
1
:10) gave 178 mg (ca. 60%) of a colorless oil, which consisted, according to H-NMR, of a mixture of the
diastereoisomers of 44F, and, in addition, cleavage products ((1R)-2-methoxy-2-oxo-1-phenylethyl 2-
1
9
19
fluoropropanoate) in a ratio of 6.2 :1 ( F-NMR). According to HPLC and F-NMR, the product
t
diastereoisomers were present in a dr of 66 :34, and the cleavage products in a dr of 56 :44. R ( BuOMe/
f
1
hexane 1:5) 0.27. H-NMR (200 MHz): (major diastereoisomer): 1.09 (t, J ¼ 7.2, 3 H); 1.79 (d, J(F,H) ¼
2
2.1, 3 H); 2.59 – 2.93 (m, 2 H); 3.72 (s, 3 H); 6.00 (s, 1 H); 7.34 – 7.51 (m, 5 H); (minor diastereoisomer):
1
.12 (t, J ¼ 7.2, 3 H); 1.74 (d, J(F,H) ¼ 22.1, 3 H); 2.59 – 2.93 (m, 2 H); 3.72 (s, 3 H); 5.96 (s, 1 H); 7.34 –
13
7
3
.51 (m, 5 H). C-NMR (75.5 MHz): (major diastereoisomer) 7.0 (d, J(F,C) ¼ 2); 20.1 (d, J(F,C) ¼ 22);
0.6; 52.8; 75.4; 97.7 (d, J(F,C) ¼ 196); 127.4; 128.9; 129.5; 132.6; 166.4 (d, J(F,C) ¼ 26); 168.1; 203.9 (d,
19
J(F,C) ¼ 27). F-NMR (188.3 MHz): ꢀ 160.1 (qt, J(F,H) ¼ 22.1, 3.2, minor); ꢀ 160.4 (qt, J(F,H) ¼22.1,
19
1
2
.9, major). F{ H}-NMR (188.3 MHz): ꢀ 160.1 (s, minor); ꢀ 160.4 (s, major). ESI-MS: 314.3 (100,
þ
þ
[
M þ NH ] ), 297.2 (8, [M þ H] ). Anal. calc. for C H FO (296.29): C 60.81, H 5.78; found: C 60.95, H
4
15 17
5
5
.70.
Data of (1R)-2-Methoxy-2-oxo-1-phenylethyl 2-Fluoropropanoate: H-NMR (200 MHz): (2 diaster-
eoisomers): 1.61 (dd, J ¼ 15.3, 6.9, MeCF); 1.73 (dd, J ¼ 15.4, 6.9, MeCF); 3.74 (s, MeO); 5.13 (dq, J ¼
1
19
1
4
(
8.4, 6.9, CHF); 5.17 (dq, J ¼ 48.4, 6.9, CHF); 6.03 (s, CHPh); 7.34 – 7.51 (m, 5 arom. H). F{ H}-NMR
188.3 MHz): ꢀ 185.5 (s, 56%); ꢀ 185.6 (s, 44%).
. Catalytic Fluorination of b-Keto Thioesters. Products were obtained according to GP 1; yields and
8
ee values are compiled in Table 6.
S-Ethyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanethioate (45F). GC (g-DEX, 1008): t (minor) 404,
R
t
1
t (major) 411 min. R ( BuOMe/hexane 1:10) 0.37. H-NMR (300 MHz): 1.28 (t, J ¼ 7.4, 3 H); 1.86 (d,
R
f
J(F,H) ¼ 22.8, 3 H); 2.96 (q, J ¼ 7.4, 2 H); 7.42 – 7.49 (m, 2 H); 7.56 – 7.60 (m, 1 H); 8.03 – 8.08 (d, J ¼ 8.3,
13
2
H). C-NMR (75.5 MHz): 14.4 (Me); 22.4 (d, J(F,C) ¼ 23.1, Me); 29.8 (CH ); 103.6 (d, J(F,C) ¼ 199.5,
2
C); 128.7 (CH); 130.1 (d, J(F,C) ¼ 5.9, CH); 133.7 (d, J(F,C) ¼ 3.6, C); 134.0 (CH); 192.0 (d, J(F,C) ¼
19
2
2
5.3, CO); 197.3 (d, J(F,C) ¼ 29.5, CO). F-NMR (282 MHz): ꢀ 150.1 (qt, J(F,H) ¼ 22.6, 1.6). EI-MS:
þ
40 (1.8, M ), 105 (100). Anal. calc. for C H FO S (240.30): C 59.98, H 5.45; found: C 61.31, H 5.34.
12
13
2
An unidentified impurity could not be removed by CC.

3
82
Helvetica Chimica Acta – Vol. 95 (2012)
S-Benzyl 2-Fluoro-2-methyl-3-oxo-3-phenylpropanethioate (46F). HPLC (Chiralcel OJ; hexane/
i
ꢀ1
t
PrOH 84 :16; 0.4 ml min ): t (major) 40.1, t (minor) 43.4 min. R ( BuOMe/hexane 1:10) 0.41.
R
R
f
1
H-NMR (300 MHz): 1.87 (d, J(F,H) ¼ 22.8, 3 H); 4.15 (d, J ¼ 13.9, 1 H); 4.22 (d, J ¼ 13.9, 1 H); 7.26 (m,
13
5
H); 7.39 – 7.46 (m, 2 H); 7.54 – 7.61 (m, 1 H); 7.99 – 8.04 (m, 2 H). C-NMR (75.5 MHz): 22.3 (d,
J(F,C) ¼ 23.2, Me); 33.1 (d, J(F,C) ¼ 3.8, CH ); 103.5 (d, J(F,C) ¼ 199.5, CF); 127.8 (CH); 128.7 (d,
2
J(F,C) ¼ 0.8, CH); 128.9 (CH); 129.0 (CH); 130.0 (d, J(F,C) ¼ 5.3, CH); 133.6 (d, J(F,C) ¼ 3.7, C); 134.0
1
9
(
CH); 136.5 (C, 10); 191.8 (d, J(F,C) ¼ 25.0, CO); 196.8 (d, J(F,C) ¼ 29.9, CO). F-NMR (282 MHz):
þ
ꢀ
150.1 (qt, J(F,H) ¼ 22.8, 1.7). EI-MS: 302 (7, M ), 105 (100). Anal. calc. for C H FO S (302.37): C
17
15
2
6
8
7.53, H 5.00; found: C 67.59, H 5.15.
S-Benzyl 2-Fluoro-2-methyl-3-oxobutanethioate (47F). HPLC (Chiralcel OJ; hexane/ PrOH ¼
i
ꢀ
1
t
1
5 :15; 0.5 ml min ): t (minor) 27.6, t (major) 29.9 min. R ( BuOMe/hexane 1:10) 0.31. H-NMR
R
R
f
(
300 MHz): 1.69 (d, J(F,H) ¼ 22.1, 3 H); 2.29 (d, J(F,H) ¼ 4.4, 3 H); 4.15 (s, 2 H); 7.26 – 7.32 (m, 5 H).
13
C-NMR (75.5 MHz): 20.9 (d, J(F,C) ¼ 22.2, Me); 25.3 (Me); 33.3 (d, J(F,C) ¼ 4.4, CH ); 103.9 (d,
2
J(F,C) ¼ 198.0, C); 127.8 (CH); 128.9 (CH); 129.0 (CH); 136.4 (C); 195.5 (d, J(F,C) ¼ 31.3, CO); 200.5
19
þ
(
(
d, J(F,C) ¼ 27.7, CO). F-NMR (282 MHz): ꢀ 156.1 (qq, J(F,H) ¼ 22.1, 4.4). EI-MS: 240 (4, M ), 91
100). Anal. calc. for C H FO S (240.30): C 59.98, H 5.45; found: C 59.85, H 5.32.
12
13
2
S-Phenyl 2-Fluoro-2-methyl-3-oxopentanethioate (48F). GC (b-DEX, 1408): t (minor) 49.2,
R
t
1
t
R
(major) 50.3 min. R
f
( BuOMe/hexane 1:10) 0.39. H-NMR (300 MHz): 1.11 (t, J ¼ 7.3, 3 H); 1.74 (d,
13
J(F,H) ¼ 22.4, 3 H); 2.63 – 2.90 (m, 2 H); 7.38 – 7.46 (m, 5 H). C-NMR (75.5 MHz): 7.3 (Me); 21.2 (d,
J(F,C) ¼ 22.2, Me); 31.1 (CH ); 104.3 (d, J(F,C) ¼ 198.4, C); 125.7 (d, J(F,C) ¼ 6.4, C); 129.6 (CH); 130.1
2
19
(
CH); 134.9 (CH); 194.5 (d, J(F,C) ¼ 31.4, CO); 202.9 (d, J(F,C) ¼ 25.8, CO). F-NMR (282 MHz):
þ
ꢀ
157.9 (qt, J(F,H) ¼ 22.4, 3.1). EI-MS: 240 (17, M ), 184 (100). Anal. calc. for C H FO S (240.30): C
12
13
2
5
9.98, H 5.45; found: C 59.91, H 5.47.
. Catalytic Fluorination of b-Keto Amides. Products obtained according to GP 1; for yields and ee
9
values, see Table 7.
N,N-Dibenzyl-2-fluoro-2-methyl-3-oxopentanamide (49F). Prepared according to GP 1 from 49 with
K2, reaction time < 4 h. The product contained a minor impurity, presumably 2-Cl product. HPLC
i
ꢀ1
t
(
Chiralcel OJ; hexane/ PrOH 80 :20; 0.7 ml min ): t (major) 12.0, t (minor) 18.7 min. R ( BuOMe/
R
R
f
1
hexane 1:2) 0.55. H-NMR (200 MHz): 1.07 (t, J ¼ 7.2, 3 H); 1.82 (d, J(F,H) ¼ 23.0, 3 H); 2.66 (y-qd, J ¼
7
.2, 2.0, 2 H); 4.27 (d, J ¼ 14.7, 1 H); 4.32 (d, J ¼ 16.2, 1 H); 4.51 (d, J ¼ 16.2, 1 H); 4.69 (d, J ¼ 14.7, 1 H);
13
7
4
1
.09 – 7.46 (m, 10 H). C-NMR (75.5 MHz): 7.3 (Me); 21.4 (d, J(F,C) ¼ 24, Me); 29.9 (CH ); 48.1 (CH );
2
2
9.6 (d, J(F,C) ¼ 10, CH ); 100.0 (d, J(F,C) ¼ 197, C); 127.2 – 128.8 (several CH); 135.6 (C); 136.2 (C);
2
19
67.2 (d, J(F,C) ¼ 21, CO); 204.8 (d, J(F,C) ¼ 23, CO). F-NMR (188 MHz): ꢀ 152.1 (q, J(F,H) ¼ 23.0).
2
-Fluoro-2-methyl-3-oxo-N,N-diphenylpentanamide (50F). Prepared according to GP 1 from 50
t
with K2; reaction time < 4 h. CC ( BuOMe/hexane 1:10) gave 56 mg (75%) of colorless oil. HPLC
i
ꢀ1
t
(
Chiralcel OJ; hexane/ PrOH 70 :30; 1.0 ml min ): t (major) 14.6, t (minor) 26.4 min. R ( BuOMe/
R
R
f
1
hexane 1:2) 0.44. H-NMR (200 MHz): 0.83 (t, J ¼ 7.1, 3 H); 1.68 (d, J(F,H) ¼ 23.0, 3 H); 2.24 (dqd, J ¼
13
1
(
1
(
9.7, 7.1, J(F,H) ¼ 2.0, 1 H); 2.38 (dqd, J ¼ 19.7, 7.2, J(F,H) ¼ 3.8, 1 H); 7.20 – 7.44 (br. m, 10 H). C-NMR
75.5 MHz): 6.7 (d, J(F,C) ¼ 2, Me); 22.4 (d, J(F,C) ¼ 24, Me); 29.3 (CH ); 99.7 (d, J(F,C) ¼ 198, CF);
2
1
9
25.8 – 132.6 (br. m, CH); 129.1 (CH); 166.4 (d, J(F,C) ¼ 21, CO); 208.3 (d, J(F,C) ¼ 26, CO). F-NMR
þ
188.3 MHz): ꢀ 149.1 (br. q, J(F,H) ¼ 23.1). FAB-MS: 300 (100, [M þ H] ), 196 (21). Anal. calc. for
C H FNO (299.34): C 72.22, H 6.06, N 4.68; found: C 72.13, H 5.91, N 4.68.
18
18
2
1
0. Catalytic Fluorination of 1,3-Diketones. Products were obtained according to GP 1; for yields and
ee values, see Tables 8 and 9.
-Benzoyl-2-fluorocyclopentanone (51F). HPLC (Chiralcel OD-H; hexane/ PrOH 99.2 :0.8; 0.5 ml
i
2
ꢀ
1
1
min ): t 20.5, 22.2 min. H-NMR (300 MHz): 2.12 – 2.21 (m, 2 H); 2.25 – 2.42 (m, 1 H); 2.48 – 2.56 (m,
H); 2.74 – 2.87 (m, 1 H); 7.44 – 7.50 (m, 2 H); 7.56 – 7.62 (m, 1 H); 8.05 – 8.10 (m, 2 H). 1 C-NMR
R
3
2
(
62.9 MHz): 17.4 (CH ); 34.3 (d, J(F,C) ¼ 4.6, CH ); 37.5 (CH ); 102.0 (d, J(F,C) ¼ 186.4, CF); 128.3
2
2
2
(
2
1
CH); 129.1 (d, J(F,C) ¼ 6.5, CH); 130.0 (CH); 134.3 (d, J(F,C) ¼ 4.7, C); 168.2 (d, J(F,C) ¼ 18.7, CO);
1
9
þ
10.4 (d, J(F,C) ¼ 29.1). F-NMR (282 MHz): ꢀ 157.03 (dd, J(F,H) ¼ 22.6, 14.1). EI-MS: 206 (2, M ),
05 (100).
i
2
-Benzoyl-2-fluorocyclohexanone (52F). HPLC (Chiralcel OD-H; hexane/ PrOH 99.2 :0.8; 0.5 ml
ꢀ
1
1
min ): t (major) 17.6, t (minor) 20.1 min. H-NMR (250 MHz): 1.94 – 2.21 (m, 5 H); 3.79 – 3.88 (m,
R
R