Asymmetric oxidative α-fluorination of 2-alkylphenylacetaldehydes with AgHF2 and ruthenium/PNNP catalysts

Article abstract of DOI:10.1016/j.jfluchem.2009.05.008

During attempts directed at epoxide ring opening with different HF sources, we discovered that the Lewis acidic [RuCl(PNNP)]⁺ (1) or [Ru(OEt₂)₂(PNNP)]²⁺ (2) catalysts promote the [1,2]-phenyl shift (Meinwald rea

Full text of DOI:10.1016/j.jfluchem.2009.05.008

Journal of Fluorine Chemistry 130 (2009) 702–707
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Asymmetric oxidative
a-fluorination of 2-alkylphenylacetaldehydes
with AgHF2 and ruthenium/PNNP catalysts
1
*
Martin Althaus , Antonio Togni, Antonio Mezzetti
Department of Chemistry and Applied Biosciences, ETH Zu¨rich, CH-8093 Zu¨rich, Switzerland
A R T I C L E I N F O
A B S T R A C T
Article history:
During attempts directed at epoxide ring opening with different HF sources, we discovered that the
Lewis acidic [RuCl(PNNP)]+ (1) or [Ru(OEt2)2(PNNP)]2+ (2) catalysts promote the [1,2]-phenyl shift
(Meinwald rearrangement) in phenyl-substituted epoxides to give the corresponding 2-alkylphenyl-
Received 6 April 2009
Received in revised form 7 May 2009
Accepted 10 May 2009
Available online 18 May 2009
acetaldehydes, which are fluorinated at the a-position in the presence of silver bifluoride (AgHF2) (PNNP
is (1S,2S)-N,N0-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine). The optimization of
aldehyde fluorination with PhCH(R)CHO (R = Me, Et, iPr, tBu) as substrates showed that catalyst [1]SbF6
gives a moderate degree of enantioselectivity (up to 27% ee) and 35% yield. The substrate scope is limited
to benzylic aldehydes. The reaction is unprecedented for transition metal catalysts. Circumstantial
evidence suggests that the mechanism involves chemical oxidation followed by enantioselective
fluorination with Fꢀ.
Keywords:
Asymmetric fluorination
Fluoroaldehydes
Silver bifluoride
Ruthenium
ß 2009 Elsevier B.V. All rights reserved.
PNNP ligands
1. Introduction
the generated cation with a source of nucleophilic fluoride.
Using this strategy, a variety of
a-(arylthio)carbonyl compounds
In the wake of the recent interest in the catalytic generation of C–
F stereocenters, a number of efficient methods for the asymmetric
catalytic fluorination of dicarbonyl compounds have been devel-
oped by our [1,2] and other groups [3]. In contrast, catalytic methods
for the fluorination of monocarbonyl compounds, and in particular
of aldehydes, have been developing at a slower pace. In 2005, Enders
and Hu¨ttl [4], Jørgensen and co-workers [5], Barbas and co-workers
[6], and MacMillan and co-workers [7] independently published
were successfully fluorinated under oxidative electrolytic
conditions [10], including chiral substrates in a diastereoselec-
tive fashion [11]. Also non-sulfur containing
a-aryl ketones,
esters, and nitriles [12] can be fluorinated electrolytically (and
display diastereoselectivity when chiral) [13]. The reaction is
initiated by the anodic one-electron oxidation of the aryl group.
Deprotonation in the
a-position generates a benzylic radical
that is further oxidized to the benzylic cation. The reaction with
efficient methods forthe organocatalyticasymmetric
of aliphatic aldehydes and ketones with electrophilic N–F reagents.
With the standard proline- and imidazolidinone-based catalysts,
aryl substituted, andinparticular -disubstitutedaldehydes, gave
a-fluorination
Fꢀ from Et3Nꢁ3HF then leads to the desired
a-fluoroester [12b].
However, the oxidation of the carbonyl compounds was
invariably carried out by electrolysis and not by chemical
oxidation.
a-
a,a
lowenantioselectivity,though, and differentstructuralmotifshad to
be introduced as catalysts [8]. The perusal of the literature shows
that chiralcatalystsbased ontransition metals havenever beenused
Despite the fact that intensive research in the field of catalytic
enantioselective fluorination has been conducted for several years
now, a strategy that includes oxidation followed by reaction with
fluoride has never been employed. Herein, we describe the
for the
been used as co-catalysts in asymmetric organocatalysis [9].
An alternative method for the -fluorination of monocarbo-
a-fluorination of aldehydes. At most, achiral complexes have
asymmetric, oxidative
a-fluorination of 2-alkylphenylacetalde-
a
hydes with AgHF2 catalyzed by Ru/PNNP complexes, which is
apparently related to oxidative fluorination. We serendipitously
discovered this reaction during attempts of developing a truly
catalytic version of the enantioselective hydrofluorinations of
epoxides achieved by Haufe, who used stoichiometric or sub-
stoichiometric amounts of chromium(III) complexes [15]. This
study is part of our interest in the application of ruthenium/PNNP
complexes in a number of atom-transfer reactions (epoxidation,
cyclopropanation, hydroxylation, and Michael addition) [16], as
nyl compounds involves the electrochemical [10–13] or
chemical [14] oxidation of the substrate, followed by trapping
* Corresponding author. Tel.: +41 44 632 61 21; fax: +41 44 632 13 10.
E-mail address: mezzetti@inorg.chem.ethz.ch (A. Mezzetti).
1
Present address: University of Bristol, School of Chemistry, Cantock’s Close,
Bristol BS8 1TS, UK.
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.05.008

M. Althaus et al. / Journal of Fluorine Chemistry 130 (2009) 702–707
703
Chart 1.
well as asymmetric nucleophilic [17] and electrophilic fluorination
[2].
Scheme 1.
2. Results
2.1. Hydrofluorination of epoxides
In a preliminary study, we tested the five-coordinate, mono-
cationic catalyst [RuCl(PNNP)](PF6) ([1]PF6) [16a], prepared from
[RuCl2(PNNP)] and TlPF6 (1 equiv) for the hydrofluorination of the
model substrate meso-cyclopentene oxide with different HF
sources (Chart 1, Table 1). The reactions with Et3Nꢁ3HF,
(Bu4N)H2F3, KHF2, and PhCOF led to epoxide polymerization or
gave no conversion at all. However, with the insoluble HF source
silver(I) bifluoride (AgHF2), cyclopentene oxide (3a) was hydro-
fluorinated to the corresponding racemic fluorohydrin trans-2-
fluorocyclopentan-1-ol (4a) (run 5). Polymers with incorporated
fluorine (abbreviated as F-polymers) were observed as by-
products in varying quantities, depending on the amount of AgHF2
used (runs 6, 7).
Scheme 2.
CH2Cl2 solution of 2 (20 mol%) and AgHF2 (2.0 equiv). Under these
conditions, cyclopentene oxide 3a underwent ring opening (95%
conversion within 24 h) to 4a, which was obtained in 11% yield and
with an enantioselectivity of 25% ee (run 1). The low yield suggests
that polymerization is the main reaction pathway under these
conditions, though.
As no enantioselectivity was obtained with [RuCl(PNNP)]+ (1) as
catalyst, we turned our attention to the dicationic complex
[Ru(OEt2)2(PNNP)]2+ (2), prepared by double chloride abstraction
from [RuCl2(PNNP)] with (Et3O)PF6 (2 equiv) [16c]. Complex 2 is
strong enough as Lewis acid to effect rapid epoxide polymerization
when added to an excess of 3a (10 equiv). The optimization of the
reaction conditions showed that the polymerization of the epoxide
can be disfavored by adding the epoxide (dissolved in CH2Cl2)
slowly by syringe pump to the heterogeneous mixture of catalyst 2
(20 mol%) and AgHF2 in CH2Cl2 (Table 2). PTFE tubes, protected
from light with aluminium foil, were used as reaction vessels. The
best results were obtained by adding the epoxide over 2 h to a
Surprisingly, with cis-stilbene oxide (3b) as substrate, fluor-
odiphenylacetaldehyde (6b) was the major product in the reaction
mixture after 24 h, together with the side-products threo-4b,
erythro-4b, and diphenylacetaldehyde (5b) (Scheme 1). The ratio of
fluorodiphenylacetaldehyde 6b to the fluorohydrins 4b is 5:1:1 by
integration of the 19F NMR signals. The occurrence of both
diastereoisomers in the above experiment suggests the hydro-
fluorination of 3b might imply Lewis acid-catalyzed ring-opening
of 3b to give a benzylic carbocation, whose lifetime is long enough
to undergo isomerization before being trapped by fluoride. It has
been previously shown that diphenylacetaldehyde is the product
of a Lewis acid-catalyzed Meinwald rearrangement involving a
[1,2]-phenyl shift [18]. As the most intriguing feature of the above
reaction was the formation of the fluorinated aldehyde, we devised
an independent reaction starting from diphenylacetaldehyde.
Table 1
Screening of HF sources for the hydrofluorination of meso-epoxide 3a.
Table 2
Asymmetric hydrofluorination of meso-epoxide 3a by [Ru(OEt2)2(PNNP)](PF6)2 (2).
run
HF source (equiv)
Time (h)
Conversion (%)
(rac)-4a:F-polymersa
b
1
Et3Nꢁ3 HF (1.5)
(Bu4N)H2F3 (1.0)
KHF2 (1.5)
96
96
24
96
96
24
24
Quantitative
Run
Addition
time (h)
AgHF2
Reaction
time (h)a
Conversionb
(%)
Yieldb
(%)
ee (%)
2
0
–
b
3c
4d
5
94
(equiv)
PhCOF (1.1)
AgHF2 (1.0)
AgHF2 (2.0)
AgHF2 (4.0)
0
–
1
2
3c
4
2
2.5
2.5
24
2.0
1.0
1.2
1.0
24
21
96
10
95
93
54
70
11
9
25
25
15
12
92
1.5:1
2.7:1
2.3:1
6
Quantitative
Quantitative
4
7
2
a
Ratios were determined by integration of the 19F NMR signals of the crude
a
After completion of epoxide addition.
reaction mixture.
b
b
Determined by quantitative GC analysis of the reaction mixtures after
Only unfluorinated polymers were formed.
c
precipitation of the catalyst with hexane.
c
[Ru(OEt2)2(PNNP)](PF6)2 (2) (20 mol%) was used as catalyst.
d
A catalyst loading of 5 mol% was used.
The expected product was O-benzoyl-protected 4a.

704
M. Althaus et al. / Journal of Fluorine Chemistry 130 (2009) 702–707
Table 4
2.2.
a-Fluorination of diphenylacetaldehyde
a-Fluorination of differently substituted 2-alkylphenylacetaldehydes with [1]SbF6
as catalyst.
Diphenylacetaldehyde (5b) was treated with AgHF2 (1.4 equiv)
in the presence of 2 (20 mol%) as catalyst in CH2Cl2 (Scheme 2).
Within 6 h, 80% of 5b was converted to a mixture of fluorodiphe-
nylacetaldehyde (6b) and benzophenone [19] in 31% and 49%
yields, respectively (as determined by integration of the 1H NMR
spectra). Neither stilbene oxide nor fluorohydrins were observed in
the reaction mixture. That excludes the possibility of a retro
Meinwald rearrangement (aldehyde ! epoxide), and proves that
Run
Substrate
R
Yield (%)a
ee (%)
diphenylacetaldehyde is directly fluorinated in
a-position by
1
2
3
4
5a
5c
5d
5e
Me
Et
iPr
tBu
24
35
31
13
27
AgHF2 with complex 2 as catalyst. We were fascinated by this
finding, because oxidative fluorination with a nucleophilic fluoride
23
18
n.d.b
source might be used as a complementary approach for the
a-
a
Determined by integration of the 19F NMR signals with internal standard
fluorination of carbonyl compounds, reactions that are usually
accomplished by expensive and non-atom-economic electrophilic
octafluoronaphthalene.
b
No separation of the enantiomers was achieved by chiral GC analysis.
N–F fluorinating agents [20]. Aldehydes with two different
substituents, from which chiral -fluoroaldehydes might be
obtained, were the substrates of choice.
a-
a
dichloroethane at 60 8C, 5a is fluorinated to 6a in 12% yield and
18% ee (run 3). In all these reactions, acetophenone, the product of
oxidative decarbonylation of 5a is observed as by-product in
variable amounts [19]. Using the non-silver fluoride sources KHF2
2.3. Asymmetric
a-fluorination of aldehydes
As a prostereogenic substrate for the asymmetric
of aldehydes with AgHF2, we chose the commercially available 2-
phenylpropionaldehyde (5a). The phenyl and methyl substituents
a
-fluorination
or Et3Nꢁ3HF did not effect
a-fluorination. With AgF, the reaction
was found to be even slower, whereas the strong oxidants AgF2 or
XeF2 lead to extensive decomposition.
in
formation of a fluorinated quaternary stereogenic center. The
absence of a further -proton prevents racemization after the
fluorination step. We initiated our investigations by exposing 5a to
reaction conditions similar to those that effected the Meinwald
a
-position to the aldehyde carbonyl group allow for the
As a further optimization step, we tested the five-coordinate
complex [RuCl(PNNP)]SbF6 ([1]SbF6) in the fluorination of 2-
phenylpropionaldehyde (5a), which gave 24% yield and 27% ee
after a reaction time of 24 h (Table 4, run 1) [22]. Experiments in
toluene, THF, and 1,4-dioxane gave lower conversion of 5a and did
not improve the enantioselectivity. To assess the effect of increased
a
rearrangement and
direct -fluorination of diphenylacetaldehyde. The reactions were
carried out by adding a solution containing the catalyst and 5a to
AgHF2 in a PTFE tube that was protected from light. As
a-fluorination of cis-stilbene oxide or the
a
steric bulk of the a-alkyl groups, we tested aldehydes PhCH(R)CHO
i
t
(R = Et, 5c; Pr, 5d; Bu, 5e) (runs 2–4). The higher homologues 5c
and 5d give better yields, with 35% and 31%, respectively (runs 2
and 3) and only trace amounts of the corresponding phenyl alkyl
ketones (products of oxidative decarbonylation). The enantiomeric
excesses are lower though, reaching 23% ee for 6c, and 18% ee for
6d. The tert-butyl-substituted aldehyde 5e is poorly reactive, and
was fluorinated in 13% yield only (entry 4). The enantioselectivity
was not determined, as the enantiomers were not separable by
chiral GC analysis. The results in Table 4 show that an increase of
steric bulk of the alkyl group influences enantioselectivity to a
hardly significant extent.
a
-
fluorinated aldehydes are generally not stable, and tend to
decompose upon chromatography [5,6,21], the reaction mixtures
were worked up either by rapid filtration through a short plug of
Al2O3 or by precipitation of the catalyst with hexane. Yields were
determined by integration of 19F NMR signals with internal
standards hexafluorobenzene or octafluoronaphthalene, and the
enantioselectivity by GC analysis on chiral column (Table 3).
First fluorination attempts of 5a were carried out in the
presence of AgHF2 (2.4 equiv) and of [Ru(OEt2)2(PNNP)]2+ (2)
(20 mol%) as catalyst, which was freshly prepared from
[RuCl2(PNNP)] and (Et3O)PF6 (2 equiv) in dichloromethane at
room temperature. Under these conditions, no conversion was
observed (run 1). Upon raising the temperature, racemic 2-fluoro-
2-phenylpropionaldehyde (6a) was obtained (run 2). In 1,2-
To assess whether aldehydes other than 2-alkylphenylacetal-
dehydes would undergo Ru/PNNP-catalyzed
a-fluorination, we
tested some primary aldehydes (5f–h) and a 2,2-dialkylacetalde-
hyde (5i), as well as the methyl ketone 5j and the ethyl ester 5k as
analogues of aldehyde 5a possessing different carbonyl functional
groups (Chart 2). However, all of them were unreactive under the
catalysis conditions of Table 4. This observation is in line with the
lower reactivity of 2-phenylpropionaldehyde (5a) as compared to
diphenylacetaldehyde 5b, which reacts in CH2Cl2 at room
Table 3
Catalyst [Ru(OEt2)2(PNNP)](PF6)2 (2) for the
a-fluorination of 5a.
Run
Catalyst 2 (mol%)
Solvent
Time (h)
Yielda (%)
ee (%)
1b
2c
3
20
5
CH2Cl2
24
24
20
0
20
12
–
0
CH2Cl2
5
1,2-C2H4Cl2
18
a
Determined by integration of the 19F NMR signals with internal standard
hexafluorobenzene or octafluoronaphthalene.
b
1.3 equiv of AgHF2 were used at room temperature.
c
The mixture was heated to 60 8C in a sealed PTFE tube.
Chart 2.

M. Althaus et al. / Journal of Fluorine Chemistry 130 (2009) 702–707
705
groups in a-position. On the other hand, it would explain why the
reactivity decreases according to 5b > 5a > 2,2-dialkylacetalde-
hyde ꢂprimary aldehydes, which corresponds to the number of
cation-stabilizing
a-aromatic groups.
Also, despite the destabilization of carbocations by electron-
withdrawing groups, there are many examples in the literature
showing that such cations can indeed be generated, studied, and
used as intermediates in synthetic methods [25,26]. Examples
thereof are the solvolysis of carbonyl compounds with a good
leaving group in
a-position (e.g., OMs or OTf), loss of N2 from a-
diazo carbonyl compounds after reaction with an electrophile, or
Scheme 3.
reactions of silver(I) salts with
Alternatively, the enolates of
a
a,a
-bromo carbonyl compounds [25].
-diaryl substituted ketones or
-carbonyl radicals and a-
aldehydes can be transformed to
a
carbonyl cations [27] via subsequent one-electron oxidation steps
with the one-electron oxidant tris(1,10-phenanthroline)iron (III)
hexafluorophosphate [Fe(phen)3](PF6)3 (2 equiv), which is strong
enough to effect both one-electron transfers ([Fe(phe-
n)3]3+ + eꢀ ! [Fe(phen)3]2+: E0 = +1.15 V) [24].
Interestingly, an example of
reported, which was found to proceed via
(Scheme 3). Rearrangement of in situ generated oxirenium catꢀions
to the corresponding -keto cations and reaction with BF4 as
fluoride source gave -fluoroketones in good yields [28]. In view of
the widespread reports about the occurrence of -carbonyl cations
a-fluorination of ketones has been
a
-carbonyl cations
a
a
a
and the order of reactivity that we observe for differently
substituted aldehydes, we consider the oxidation of the aldehyde
to an
a-carbonyl cation as a possible mechanism for the a-
fluorination of aldehydes with AgHF2, as sketched in Scheme 4.
Deprotonation of the enolizable aldehyde by fluoride may form an
oxallyl complex of ruthenium(II), which is oxidized by two
equivalents of Ag(I) to give a species that can be regarded either
as an oxallyl complex of ruthenium(IV) or, equivalently, as a
ruthenium(II) complex of an
a-carbonyl cation. Finally, nucleo-
Scheme 4.
philic attack by fluoride gives the fluorinated aldehyde and
regenerates the catalyst [29]. We stress that the mechanism in
Scheme 4 is meant to be a mere working hypothesis. In particular,
as we did not attempt to detect the HF or other by-products, the
very stoichiometry of the reaction is yet uncertain.
temperature (Scheme 2). The fact that 5a requires higher
temperatures for the
a-fluorination indicates that the lack of
the aromatic group decreases the reactivity of the substrate
considerably. Thus, the presence of at least one aromatic
substituent in
a
-position of an aldehyde seems to be mandatory
4. Conclusion and outlook
to achieve a useful reactivity. In sum, the substrate scope for the
a
-
fluorination with AgHF2 is narrow at the moment, as reactive
substrates are restricted to secondary aldehydes bearing both an
This is the first transition metal catalyzed enantioselective a-
fluorination of aldehydes. Although we were not able to assess the
role of the ruthenium catalyst yet, the asymmetric induction
clearly shows that the chiral Ru/PNNP complex is involved in the
enantiodiscriminating step. Circumstantial evidence suggests that
the mechanism involves chemical oxidation followed by enantio-
selective fluorination with Fꢀ. In fact, the presence of AgHF2, which
combines a Fꢀ source with an oxidant (Ag+), is pivotal. The
underlying concept might be developed into a cheap and atom-
aryl and an alkyl group in
a-position.
3. Discussion
As only silver(I) salts are active in the fluorination of aldehydes,
we conclude that the reaction requires the presence of an oxidant.
As an enolizable aldehyde is nucleophilic in the
a-position, and
AgHF2 is a source of nucleophilic Fꢀ ions, we speculate that, during
the course of the reaction, the aldehyde is oxidized, which results
in the observed umpolung. The overall process is therefore similar
economic alternative to the a-fluorination of carbonyl compounds
with electrophilic N–F reagents. Further goals encompass a better
reproducibility of the enantioselectivity and a broader substrate
scope, that is, not limited to aldehydes with both a phenyl and an
to the known electrochemical
a-fluorination of thiols or carbonyl
compounds mentioned above [10–13]. The oxidation of the
aldehyde seems to be the only viable pathway because the
oxidation of Fꢀ is obviously impossible owing to its high standard
potential (1/2 F2 + eꢀ ! Fꢀ: E0 = +2.87 V) [23]. The reduction of
silver(I) is supported by the observation of grey solids after
completion of the reactions, which we interpret as elemental silver
(Ag+ + eꢀ ! Ag0: E0 = +0.80 V) [24]. The requirement for two
equivalents of Ag+ suggests that the aldehyde undergoes a two-
alkyl group in a-position.
5. Experimental
5.1. General experimental procedures
Reactions with air- or moisture-sensitive materials were
carried out under an argon atmosphere using Schlenk techniques.
Complexes [1]PF6 [16a], [1]SbF6 [16d], and 2 [16c] were prepared
by published procedures. 1H, 13C, 19F, and 31P NMR spectra were
recorded on Bruker AVANCE spectrometers AC 200, DPX 250, and
electron oxidation to an
a-carbonyl cation, or to a synthetic
equivalent thereof. At a first glance, this seems rather unlikely
because carbocations are destabilized by electron-withdrawing

706
M. Althaus et al. / Journal of Fluorine Chemistry 130 (2009) 702–707
DPX 300. 1H and 13C positive chemical shifts in ppm are downfield
from tetramethylsilane. 19F NMR spectra were referenced to
external CFCl3 and 31P NMR spectra were referenced to external
85% H3PO4. GC–MS was performed on a Thermo Finnigan Trace
instrument. Substrate 5c was prepared by a reduction–oxidation
sequence from (rac)-2-phenylbutyric acid, whereas 5d and 5e
were synthesized by epoxidation of the corresponding phenyl alkyl
ketones with dimethylsulfonium methylide and subsequent
Meinwald rearrangement catalyzed by BF3ꢁOEt2 [30].
(CDCl3, 200.1 MHz): d 9.77 (d, 1H, JF,H = 6.7 Hz, CHO), 7.60–7.15 (m,
5 H, arom. H), 2.63–2.40 (m, 1H, CH(CH3)2), 1.12 (d, 3 H, J = 6.8 Hz,
CH(CH3)(CH03)), 0.82 (d, 3 H, J = 7.0 Hz, CH(CH3)(CH03)). 19F NMR
(CDCl3, 188.3 MHz):
d
ꢀ189.8 (dd, 1 F, JF,H = 31.9, 6.7 Hz). GC–MS:
6d: tR = 12.0 min; m/z 180 (M+, 5), 151 ([MꢀCHO]+, 100), 131
([MꢀCHO–HF]+, 74). Chiral GC: oven 75 8C isotherm; tR = 49.9
(major) and 51.1 min; 18% ee.
5.6. 2-Fluoro-3,3-dimethyl-2-phenylbutyraldehyde (6e)
5.2. General procedure for ruthenium catalyzed
aldehydes
a
-fluorination of
Prepared according to the general procedure from aldehyde 5e
(85 mg, 0.48 mmol). Yield: 12.1 mg (0.063 mmol, 13%). 2,2-
dimethylpropiophenone was identified as a side-product by 1H
AgSbF6 (8.2 mg, 24.0
of [RuCl2(PNNP)] (20.0 mg, 24.0
dichloroethane (2 mL). The mixture was stirred for 15 h in the dark,
giving brown suspension. The appropriate aldehyde
m
mol, 0.05 equiv) was added to a solution
NMR spectroscopy and GC–MS. 1H NMR (CDCl3, 200.1 MHz):
d
9.96
(d, 1H, JF,H = 8.2 Hz, CHO), 7.55–7.23 (m, 5 H, arom. H), 1.08 (s, 9 H,
C(CH3)3). 19F NMR (CDCl3, 188.3 MHz):
F,
m
mol, 0.05 equiv) in dry 1,2-
d
ꢀ170.6 (d,
1
a
5
JF,H = 8.2 Hz). GC–MS: 6e: tR = 13.2 min; m/z 194 (M+, 1), 165
([MꢀCHO]+, 36), 138 ([MꢀC4H8]+, 100). 2,2-Dimethylpropiophe-
none: tR = 12.9 min; m/z 162 (M+, 4), 105 ([MꢀC4H9]+, 100), 77
(C6H5+, 23).
(0.48 mmol, 1 equiv) was added, then the suspension was filtered
into a PTFE tube containing AgHF2 (168 mg, 1.14 mmol, 2.4 equiv),
diluted with 1,2-dichloroethane (1 mL), and stirred at 60 8C in the
dark for 24 h. After cooling to r.t., the reaction mixture was filtered
through a short plug of Al2O3 with CH2Cl2 as eluent, and
concentrated under reduced pressure. A CH2Cl2 solution of the
residue was used for GC–MS and chiral GC analysis. Yields were
determined by integration of the 19F NMR signals, using a known
amount of octafluoronaphthalene as an internal standard (19F NMR
References
[1] Titanium(IV) TADDOLate catalysts:
(a) L. Hintermann, A. Togni, Angew. Chem. Int. Ed. 39 (2000) 4359–4362;
(b) M. Perseghini, M. Massaccesi, Y. Liu, A. Togni, Tetrahedron 62 (2006) 7180–
7190;
(c) J. Ramirez, D.P. Huber, A. Togni, Synlett (2007) 1143–1147.
[2] Ruthenium(II) PNNP catalysts: M. Althaus, C. Becker, A. Togni, A. Mezzetti,
Organometallics, 26 (2007) 5902–5911.
signals at
d
ꢀ145.1 and ꢀ153.6). A delay time of d1 > 30 s was
applied between pulses to ensure the complete relaxation of the
fluorine nuclei in different chemical environments. Enantiomeric
[3] Pd(II) catalysts:
(a) Y. Hamashima, K. Yagi, H. Takano, L. Tama´s, M. Sodeoka, J. Am. Chem. Soc. 124
(2002) 14530–14531;
excesses were determined by chiral GC on a Supelco
column (30 m ꢃ 0.25 mm, film 0.25 m), split injector (42 mL/
min, 200 8C), He carrier (1.4 mL/min).
a-DEX 120
(b) Y. Hamashima, M. Sodeoka, Synlett (2006) 1467–1478;
(c) Y. Hamashima, T. Suzuki, Y. Shimura, T. Shimizu, N. Umebayashi, T. Tamura, N.
Sasamoto, M. Sodeoka, Tetrahedron Lett 46 (2005) 1447–1450;
(d) T. Suzuki, T. Goto, Y. Hamashima, M. Sodeoka, J. Org. Chem. 72 (2007) 246–
250;
m
5.3. 2-Fluoro-2-phenylpropionaldehyde (6a)
(e) K. Moriya, Y. Hamashima, M. Sodeoka, Synlett (2007) 1139–1142;
(f) Fluorination of oxindoles: Y. Hamashima, T. Suzuki, H. Takano, Y. Shimura, M.
Sodeoka, J. Am. Chem. Soc. 127 (2005) 10164–10165;
(g) Cu(II) catalyst J.-A. Ma, D. Cahard, Tetrahedron: Asymmetry, 15 (2004) 1007–
1011;
(h) Ni(II) catalysts N. Shibata, T. Ishimaru, T. Nagai, J. Kohno, T. Toru, Synlett,
(2004) 1703–1706;
(i) Zn(II) catalysts D.S. Reddy, N. Shibata, J. Nagai, S. Nakamura, T. Toru, S.
Kanemasa, Angew. Chem. Int. Ed. 47 (2008) 164–168;
(j) Sc(III) catalysts S. Suzuki, H. Furuno, Y. Yokoyama, J. Inanaga, Tetrahedron:
Asymmetry, 17 (2006) 504–507.
Prepared according to the general procedure from aldehyde 5a
(64 mg, 0.48 mmol). Yield: 17.8 mg (0.117 mmol, 24%). Acetophe-
none was identified as side-product by 1H NMR spectroscopy and
GC–MS. The NMR spectral data of the product are consistent with
reported values [21a,31]. 1H NMR (CDCl3, 200.1 MHz):
1H, JF,H = 4.9 Hz, CHO), 7.62–7.15 (m, 5 H, arom. H), 1.82 (d, 3H,
d 9.74 (d,
JF,H = 22.7 Hz, CH3). 19F NMR (CDCl3, 188.3 MHz):
d
ꢀ160.9 (dq, 1 F,
JF,H = 22.7, 4.9 Hz). GC–MS: 6a: tR = 8.8 min; m/z 152 (M+, 9), 123
[4] D. Enders, M.R.M. Huttl, Synlett (2005) 991–993.
[5] M. Marigo, D. Fielenbach, A. Braunton, A. Kjœrsgaard, K.A. Jørgensen, Angew.
Chem. Int. Ed. 44 (2005) 3703–3706.
¨
([MꢀCHO]+, 100), 103 ([MꢀCHO–HF]+, 81). Acetophenone:
tR = 9.6 min; m/z 120 (M+, 27), 105 ([MꢀCH3]+, 100), 77 (C6H5
,
+
[6] D.D. Steiner, N. Mase, C.F. Barbas, Angew. Chem. Int. Ed. 44 (2005) 3706–3710.
[7] (a) T.D. Beeson, D.W.C. MacMillan, J. Am. Chem. Soc 127 (2005) 8826–8828;
(b) For further applications, see: O.O. Fadeyi, C.W. Lindsley, Org. Lett, 11 (2009)
943–946.
73). Chiral GC: oven 56 8C isotherm; tR = 48.9 (major) and
50.3 min; 27% ee.
[8] S. Brandes, B. Niess, M. Bella, A. Prieto, J. Overgaard, K.A. Jørgensen, Chem. Eur. J. 12
(2006) 6039–6052.
5.4. 2-Fluoro-2-phenylbutyraldehyde (6c)
[9] D.H. Pauli, M.T. Scerba, E. Alden-Danforth, L.R. Widger, T. Lectka, J. Am. Chem. Soc.
130 (2008) 17260–17261.
[10] (a) T. Fuchigami, M. Shimojo, A. Konno, K. Nakagawa, J. Org. Chem. 55 (1990)
6074–6075;
Prepared according to the general procedure from aldehyde 5c
(71 mg, 0.48 mmol). Yield: 28.0 mg (0.168 mmol, 35%). Propio-
phenone was identified as a side-product by 1H NMR spectroscopy
d 9.77 (d, 1H,
JF,H = 5.6 Hz, CHO), 7.65–7.20 (m, 5 H, arom. H), 2.40–2.00 (m,
2H, CH2), 0.99 (dd, 3 H, J = 7.4, 7.4 Hz, CH3). 19F NMR (CDCl3,
(b) A.W. Erian, A. Konno, T. Fuchigami, J. Org. Chem. 60 (1995) 7654–7659;
(c) K.M. Dawood, S. Higashiya, Y. Hou, T. Fuchigami, J. Org. Chem. 64 (1999)
7935–7939;
and GC–MS. 1H NMR (CDCl3, 200.1 MHz):
(d) M. R: Shaaban, H. Ishii, T. Fuchigami, J. Org. Chem. 66 (2001) 5633–5636;
(e) B. Zagipa, H. Nagura, T. Fuchigami, J. Fluorine Chem. 128 (2007) 1168–1173;
(f) Y. Cao, A. Hidaka, T. Tajima, T. Fuchigami, J. Org. Chem. 70 (2005) 9614–9617.
[11] D. Baba, Y.-J. Yang, B.-J. Uang, T. Fuchigami, J. Fluorine Chem. 121 (2003) 93–96.
[12] (a) E. Laurent, B. Marquet, R. Tardivel, H. Thiebault, Tetrahedron Lett. 28 (1987)
2359–2362;
188.3 MHz):
d
ꢀ175.6 (ddd, 1 F, JF,H = 26.1, 23.2, 5.6 Hz). GC–MS:
6c: tR = 10.7 min; m/z 166 (M+, 3), 137 ([MꢀCHO]+, 100), 117
([MꢀCHO–HF]+, 78). Propiophenone: tR = 11.7 min; m/z 134 (M+,
14), 105 ([MꢀC2H5]+, 100), 77 (C6H5+, 57). Chiral GC: oven 66 8C
isotherm; tR = 54.3 (major) and 55.9 min; 23% ee.
(b) E. Laurent, B. Marquet, R. Tardivel, Tetrahedron 45 (1989) 4431–4444;
(c) V. Suryanarayanan, M. Noel, J. Fluorine Chem. 92 (1998) 177–180;
(d) B. Zagipa, A. Hidaka, Y. Cao, T. Fuchigami, J. Fluorine Chem. 127 (2006) 552–
557;
(e) E. Laurent, B. Marquet, C. Roze, F. Ventalon, J. Fluorine Chem. 87 (1998) 215–
220.
5.5. 2-Fluoro-3-methyl-2-phenylbutyraldehyde (6d)
[13] L. Kabore, S. Chebli, R. Faure, E. Laurent, B. Marquet, Tetrahedron Lett. 31 (1990)
3137–3140.
[14] T. Brigaud, E. Laurent, Tetrahedron Lett. 31 (1990) 2287–2290.
Prepared according to the general procedure from aldehyde 5d
(79 mg, 0.49 mmol). Yield: 27.6 mg (0.153 mmol, 31%). 1H NMR

M. Althaus et al. / Journal of Fluorine Chemistry 130 (2009) 702–707
707
[15] (a) S. Bruns, G. Haufe, J. Fluorine Chem. 104 (2000) 247–254;
(b) G. Haufe, S. Bruns, M. Runge, J. Fluorine Chem. 112 (2001) 55–61;
(c) G. Haufe, S. Bruns, Adv. Synth. Catal. 344 (2002) 165–171.
[16] Selected papers:
[20] H. Ibrahim, A. Togni, Chem. Commun. (2004) 1147–1155.
[21] (a) S.T. Purrington, N.V. Lazaridis, C.L. Bumgardner, Tetrahedron Lett. 27 (1986)
2715–2716;
(b) F.A. Davis, P.V.N. Kasu, G. Sundarababu, H. Qi, J. Org. Chem. 62 (1997) 7546–
7547.
[22] Enantioselectivities of up to 44% ee were obtained in some preliminary experi-
ments, however, these higher values were not reproducible.
[23] J.E. Huheey, E.A. Keiter, R.L. Keiter, Inorganic Chemistry: Principles of Structure
and Reactivity, 4th ed., HarperCollins, New York, 1993.
(a) R.M. Stoop, S. Bachmann, M. Valentini, A. Mezzetti, Organometallics 19 (2000)
4117–4126;
(b) S. Bachmann, M. Furler, A. Mezzetti, Organometallics 20 (2001) 2102–2108;
(c) C. Bonaccorsi, S. Bachmann, A. Mezzetti, Tetrahedron: Asymmetry 14 (2003)
845–854;
(d) C. Bonaccorsi, A. Mezzetti, Organometallics 24 (2005) 4953–4960;
(e) P.Y. Toullec, C. Bonaccorsi, A. Mezzetti, A. Togni, Proc. Natl. Acad. Sci. U.S.A.
101 (2004) 5810–5814;
(f) F. Santoro, M. Althaus, C. Bonaccorsi, S. Gischig, A. Mezzetti, Organometallics
27 (2008) 3866–3878.
[24] P. Vany´sek, in: D.R. Lide (Ed.), 88th Ed., CRC Handbook of Chemistry and Physics
(2007–2008), vol. 8, Taylor & Francis, Boca Raton, 2007, pp. 20–29.
[25] For a review on carbocations substituted with electron-withdrawing groups, see:
X. Creary, Chem. Rev. 91 (1991) 1625–1678.
[26] For a review on a-carbonyl cations, see: X. Creary, A.C. Hopkinson, E. Lee-Ruff, in:
X. Creary (Ed.), Advances in Carbocation Chemistry, vol. 1, Jai Press Ltd., 1989, pp.
45–92.
[27] M. Ro¨ck, M. Schmittel, J. Chem. Soc., Chem. Commun. (1993) 1739–1741.
[28] K. Griesbaum, H. Keul, R. Kibar, B. Pfeffer, M. Spraul, Chem. Ber. 114 (1981) 1858–
1870.
[29] (a) Alternatively, an oxidation mechanism by hydride abstraction might be
considered. During our investigations of a Ru/PNNP complex containing a coor-
dinated b-keto ester enolate, we found that Ag+ is able to formally abstract a
hydride from the ligand producing an a-alkenyl-b-keto ester [29b]. The removal
of a hydride from the aldehyde by silver(I) would directly lead to an a-carbonyl
cation. However, we do not have conclusive evidence for such a mechanism.;
(b) M. Althaus, A. Mezzetti, unpublished results.
[17] P. Barthazy, A. Togni, A. Mezzetti, Organometallics 20 (2001) 3472–3477.
[18] Epoxide to carbonyl rearrangements are well-documented in the literature.
(a) The first example involving Brønsted acid catalysis see: J. Meinwald, S.S.
Labana, M.S. Chadha, J. Am. Chem. Soc, 85 (1963) 582–585;
(b) Al(III)-catalyzed: K. Maruoka, S. Nagahara, T. Ooi, H. Yamamoto, Tetrahedron
Lett. 30 (1989) 5607–5610;
(c) Bi(III)-catalyzed: A.M. Anderson, J.M. Blasek, P. Garg, B.J. Payne, R.S. Mohan,
Tetrahedron Lett. 41 (2000) 1527–1530;
(d) Ir(III)-catalyzed: I. Karame´, M.L. Tommasino, M. Lemaire, Tetrahedron Lett. 44
(2003) 7687–7689 ;
(e) Cr(III)-catalyzed: K. Suda, T. Kikkawa, S. Nakajima, T. Takanami, J. Am. Chem.
Soc. 126 (2004) 9554–9555.
[19] The oxidative cleavage of 2-phenylpropionaldehyde to acetophenone under
aerobic conditions and in the presence of H+ or of Lewis acidic metal ions (Cu(II),
Ce(III), V(IV)) has been reported: M. Tokunaga, H. Aoyama, Y. Shirogane, Y. Obora,
Y. Tsuji, Catal. Today, 117 (2006) 138–140.
[30] (a) F. Toda, K. Kanemoto, Heterocycles 46 (1997) 185–188;
(b) C.A. Ibarra, S. Arias, M.J. Ferna´ndez, J.V. Sinisterra, J. Chem. Soc., Perkin Trans. 2
(1989) 503–508.
[31] J. Oldendorf, G. Haufe, J. Prakt. Chem. 342 (2000) 52–57.