Development of the titanium-TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

Article abstract of DOI:10.3762/bjoc.7.166

Titanium-based Lewis acids catalyze the α-fluorination of β-ketoesters by electrophilic N-F-fluorinating reagents. Asymmetric catalysis with TADDOLato-titanium(IV) dichloride (TADDOL = α,α, α',α'-tetraaryl-(1,3-dioxolane-4,5-diyl)-dimethanol) Lewis acids

Full text of DOI:10.3762/bjoc.7.166

Development of the titanium–TADDOLate-catalyzed
asymmetric fluorination of β-ketoesters
Lukas Hintermann1,2, Mauro Perseghini1 and Antonio Togni*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1421–1435.
1Laboratorium für Anorganische Chemie, ETH Zürich,
Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland and 2Department
Chemie, Technische Universität München, Lichtenbergstr. 4, 85748
Garching bei München, Germany
doi:10.3762/bjoc.7.166
Received: 04 June 2011
Accepted: 19 September 2011
Published: 17 October 2011
Email:
Antonio Togni* - togni@inorg.chem.ethz.ch
Associate Editor: D. O'Hagan
* Corresponding author
© 2011 Hintermann et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Asymmetric catalysis; fluorination; fluoroorganic compounds;
TADDOL; titanium
Abstract
Titanium-based Lewis acids catalyze the α-fluorination of β-ketoesters by electrophilic N–F-fluorinating reagents. Asymmetric
catalysis with TADDOLato–titanium(IV) dichloride (TADDOL = α,α,α',α'-tetraaryl-(1,3-dioxolane-4,5-diyl)-dimethanol) Lewis
acids produces enantiomerically enriched α-fluorinated β-ketoesters in up to 91% enantiomeric excess, with either F–TEDA
(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) in acetonitrile solution or NFSI (N-fluoroben-
zenesulfonimide) in dichloromethane solution as fluorinating reagents. The effects of various reaction parameters and of the
TADDOL ligand structure on the catalytic activity and enantioselectivity were investigated. The absolute configuration of several
fluorination products was assigned through correlation. Evidence for ionization of the catalyst complex by chloride dissociation,
followed by generation of titanium β-ketoenolates as key reaction intermediates, was obtained. Based on the experimental findings,
a general mechanistic sketch and a steric model of induction are proposed.
Introduction
Fluoroorganic compounds have peculiar properties, rendering inclusion of fluorine, described already in 1954 for steroids
them interesting for a variety of specific applications [1-13]. (Figure 1b) [15], is now regularly explored in medicinal chem-
Single substitutions of hydrogen by fluorine can change the bio- istry. An example of interest for the present work is the modifi-
logical effects of low-molecular-weight organic compounds cation of the antibiotic erythromycine by α-fluorination of a
tremendously, for example, unlike acetic acid, fluoroacetic acid β-ketoester substructure (Figure 1c) [16]. Fluorinated agro-
(Figure 1a) is highly toxic [14]. Modulation of drug action by chemicals and drugs are now produced industrially on a large
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scale by a range of methods, including reactions with research efforts of our group towards realizing metal-catalyzed
notoriously reactive fluorine gas in the production of the anti- fluorinations [36-38] and asymmetric catalytic fluorination
cancer drug fluorouracil (Figure 1d) [17].
reactions [39], successfully channeled into the discovery of a
catalytic asymmetric α-fluorination of β-ketoesters (Scheme 1)
by means of the reagent F–TEDA and chiral titanium Lewis
acid catalysts of the TiCl2(TADDOLate) type [40-42]. The
same catalytic reaction principle has also allowed the perfor-
mance of asymmetric chlorinations and brominations of
β-ketoesters [43-45].
Figure 1: Fluorinated substances of biomedical relevance.
However, many specifically fluorinated compounds remain
difficult to access because of limitations of the synthetic
methodology or unpredictable reaction outcomes in the case of
fluorinated starting materials. Seebach coined the term “flus-
trates” for “fluorinated substrates”; a term that also hints at the
frustrations experienced by synthetic chemists in their
struggle to prepare a desired fluoroorganic target [18]. A
major synthetic challenge of fluoroorganic chemistry
is the enantioselective generation of fluorinated stereogenic
Scheme 1: Enantioselective electrophilic fluorination catalyzed by
TADDOLates K1, K2. TADDOL = α,α,α',α'-tetraaryl-(2,2-dimethyl-1,3-
dioxolane-4,5-diyl)dimethanol. Phenyl-TADDOL (T1) = tetraphenyl-
(2,2-dimethyl-1,3-dioxolane) derivative; 1-naphthyl-TADDOL (T2) =
tetra-1-naphthyl-(2,2-dimethyl-1,3-dioxolane) derivative.
carbon centers [2,19,20]. Initially, chiral auxiliary approaches After the initial report [40], many metal-catalyzed asymmetric
and diastereoselective reactions were developed, before Differ- fluorinations were discovered by others and ourselves, based on
ding and Lang found the first stoichiometric asymmetric fluo- complexes of Pd(II) [46], Cu(II) [47-49], Ni(II) [48,50] and
rination of β-ketoester enolates with a chiral N–F (N-fluo- Ru(II) [51] as catalysts [4,51]. In parallel, organocatalytic
roamine) reagent in 1988 [21]. Later work by Davis [22,23], asymmetric electrophilic fluorination of carbonyl compounds
Takeuchi [24] and their respective coworkers extended this by means of phase-transfer catalysts [52] and small-molecule
chemistry, while Haufe and coworkers were able to open meso- chiral amine catalysts were introduced and explored with great
epoxides asymmetrically with HF equivalents and chiral success [53-56]. Here we present the full range of observations
chromium–salen complexes [25,26]. In the year 2000, two on titanium-catalyzed fluorinations of β-ketoesters. The focus is
conceptually different applications of Banks’ electrophilic fluo- on the development of the reaction and the study of factors
rinating reagent F–TEDA (1-chloromethyl-4-fluoro-1,4-diazo- influencing its stereoselectivity depending on reaction parame-
niabicyclo[2.2.2]octane bis(tetrafluoroborate); TEDA = triethyl- ters and catalyst-ligand effects. We also present stereochemical
enediamine) [27-29] marked some important discoveries: First, correlations, to assign the absolute configuration of the fluorin-
a new generation of highly enantioselective chiral fluorinating ation products, and observations relevant to the mechanism of
reagents, derived by fluorine transfer [30] from F–TEDA to the the catalytic reaction. A subsequent paper will cover the sub-
quinuclidine portion of cinchona-alkaloids, was introduced by strate range of the catalytic fluorination and its extension to
the groups of Cahard [31-33] and Shibata [34,35]. Second, the other activated carbonyl compounds [57].
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Results and Discussion
Lewis acid catalyzed halogenation of acti-
vated carbonyl compounds
Overview
Nonfunctionalized ketones are halogenated in the α-position by
halogens and other electrophilic halogenating agents [58-62].
These reactions can be slow due to rate-limiting enolization of
the substrate, thus enolates or enolate equivalents are often
preferred as substrates [58]. If activated methylene derivatives
are mixed with a strong halogenating agent, the enol portion of
the tautomeric equilibirum mixture is halogenated quickly,
leaving behind the keto tautomer [63]. Further halogenation is
then limited by the rate of enolization. This effect forms the
basis of Meyer’s famous enol-titration experiments for deter-
mining the degree of enolization in activated carbonyl com-
pounds (Scheme 2a) [63-65]. Preparative halogenations of 1,3-
dicarbonyl substrates at ambient temperatures are relatively
slow and it is more common to halogenate their alkali enolates
instead [58]. From studies on the electrophilic fluorination with
N–F reagents, it is known that some β-carbonyl compounds are
α-fluorinated by simple combination of the reactants in solution
at room temperature (Scheme 2b) [66-71]. The ease of this
“neutral fluorination” protocol is directly connected to the
ability of a substrate to spontaneously enolize. We hypothe-
sized that catalytic acceleration of the enolization should also
result in catalysis of the overall electrophilic halogenation. As a
working hypothesis, it was assumed that coordination of β-keto-
carbonyl compounds to Lewis acidic metal centers should facil-
itate their transformation to a covalently coordinated enolate,
which may be fluorinated at carbon with asymmetric induction
exerted by chiral steering ligands X* at the metal (Scheme 2c).
Scheme 2: Halogenation of β-ketocarbonyl compounds: Importance of
enolization and the potential role of a metal catalyst.
F–TEDA under either “neutral” conditions [66-71] or in the
presence of Lewis acids (Figure 2).
Freshly dissolved ethyl benzoylpropionate 1 contained some
enol tautomer in CDCl3. In CD3CN, the value decreased to
Incidentally, Meyer had already observed acceleration of the below 0.5% on standing (Figure 2). Fluorination of 1 in a
keto-enol equilibration of acetoacetic ester in the presence of saturated solution of F–TEDA in acetonitrile was negligible
iron(III) chloride in ethanol solution [64]. Scattered reports on
polyhalogenations of ketones in the presence of antimony chlo-
ride have appeared [59], while Umemoto used Lewis acids in
substoichiometric amounts (0.4 equiv of ZnCl2 or AlCl3) to
accelerate fluorinations of 1,3-dicarbonyl compounds with
N-fluoropyridinium salts [72]. In 1998, Chambers and
Hutchinson reported the reaction of malonic esters with
elemental fluorine in the presence of hydrated copper(II) nitrate
at the 10 mol % level [73]. Still, the generality and synthetic
potential of Lewis acid catalyzed α-halogenations of carbonyl
compounds were not established.
Reactivity screening: Fluorination of β-ketoesters in
the presence of Lewis acids
As a starting point for our investigation, we chose to study the
Figure 2: Model substrates for catalytic fluorinations, with the degree
of enolization determined by 1H NMR measurements.
fluorinations of the readily enolizable β-ketoesters 1 and 2 and
of α-cyanoester 3 as model compounds with the reagent
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(<1%) after two weeks at ambient temperature, assuring us that The titanium complex Cp2Ti(OTf)2 (Cp = η5-cyclopentadienyl)
a background reaction would not interfere when searching for catalyzed the fluorination of both 1 and 2 (Table 1, entry 2),
catalytic reactions. After the addition of 5 to 10 mol % of Lewis whereas the corresponding zirconium complex was inactive
acids to solutions of 1 and F–TEDA in acetonitrile, the reaction (Table 1, entry 3). Both the Brønsted acid HBF4 and the Lewis
course (1→1-F) was monitored by 1H NMR analysis. Figure 3 acid BF3 accelerated the reaction. Substrate 2 with a higher ten-
shows representative 1H NMR spectra of reaction samples dency towards enolization (Figure 2) gave higher conversions,
removed after 28 h reaction time at ambient temperature. The but a similar trend. Interestingly, the conversions were different
catalysts and the corresponding conversions induced by them when substrate 2 was added to the reaction mixture in neat form
for the fluorination of substrates 1 and 2 are listed in Table 1. compared to when it was added as a stock solution in MeCN
(Table 1). This appears to reflect the enol content of 2
(Figure 2), which is much higher in a freshly dissolved sample
than in an aged solution of a polar solvent. Presumably, the enol
tautomer reacts uncatalyzed with F–TEDA, followed by a slow,
Lewis acid catalyzed fluorination of the remaining ketone. The
catalytic effects of other Lewis acids in the fluorination of 1
were semiquantitatively studied by TLC experiments and found
as presented in Scheme 3.
Strong catalytic activity was observed for complexes of
titanium and aluminum. Activity increases with the number of
strongly σ-acidic ligands (TiCl4 > CpTiCl3 > Cp2Ti(OTf)2) and
with the σ-acidity of the ligands themselves (Cp2Ti(OTf)2 >
Cp2TiCl2). Fluorides as strong π-donors are not suitable ligands
for Lewis acidic centers in the present reaction, as implied by
Figure 3: 1H NMR (250 MHz) spectra of fluorination reaction mixtures
the inactivity of TiF4. Organometallic Cp-complexes (Cp =
diluted with CDCl3 and filtered. a) Full range spectrum with signals
η5-cyclopentadienyl) are suitable halogenation catalysts, even
though halogenolysis of the metal–carbon bonds might have
been expected [27]. For metals other than Ti and Al, no signifi-
cant catalytic activity was observed in this specific model reac-
tion (Scheme 3). The fluorination of cyanoester 3 with F–TEDA
from substrate 1 and product 1-F. The catalyst was Cp2Ti(OTf)2.
Signals resulting from F–TEDA or H–TEDA are missing because of the
insolubility of those species in CDCl3. The signals for MeCN and its
13C-satellites have been cut for clarity. b) Reaction progress moni-
toring after 28 h (region 3.9–4.3 ppm) in catalytic reactions with the
Lewis acids indicated, along with the results from a blank experiment.
Table 1: Fluorination of 1 and 2 in the presence of different Lewis acids.
Entry
Catalyst (mol %)
Conversion after 28 h (%)
1→1-F
2→2-F
neata
equilibratedb
1
2
3
4
5
6
none (“blank”)
Cp2Ti(OTf)2 (5)
Cp2Zr(OTf)2(thf) (5)
HBF4·H2O (10)
BF3·Et2O (10)
ZnF2 (5)
0
38
≤2
24
11
n.d.
20
>95
n.d.c
47
5
95
8
47
22
n.d.
31
25
aneat = substrate added in substance. bequilibrated = substrate added as stock solution in MeCN. cn.d. = not determined.
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Beilstein J. Org. Chem. 2011, 7, 1421–1435.
Scheme 4: Catalysis of the “neutral” fluorination of β-ketoesters with
F–TEDA by Lewis acidic titanium complexes.
Scheme 3: Qualitative ordering of catalytic activity of several Lewis
acids in the fluorination 1→1-F.
N-chlorosuccinimide or N-chlorosulfonamides as halogenating
agents [43]. The Lewis acid catalyzed halogenations of
was not accelerated by any of the potential catalysts investi- β-ketoesters present an interesting alternative to either radical or
gated (TiCl4, BF3·Et2O, SnCl4, Sn(OTf)2, AlCl3, Mg(OTf)2, neutral noncatalyzed reaction modes.
ZnF2 or SbF3). The conversion 3→3-F in a blank reaction
amounted to 20% (3 d, MeCN, rt) or 40% (4.5 h, MeCN, Catalytic asymmetric fluorination
40 °C), but the addition of any of the aforementioned Having shown the viability of Lewis acid catalyzed fluorin-
substances rather suppressed the reaction. This may be ation, we focused on the development of an asymmetric
explained by the inability of 3 to bind in a chelating mode to catalytic fluorination reaction using enantiopure Lewis acid
metal complexes. In fact, when ketoesters 1 or 2 were mixed catalysts. Based on the screening results (Scheme 3), titanium
with TiCl4 in MeCN, they produced yellow to red colors char- or aluminum catalysts were logical choices. An enantiopure
acteristic for β-dicarbonylate complexes, whereas solutions of 3 sample of the ansa-titanocene [(EBTHI)Ti(OTf)2] (Figure 4)
remained colorless.
[79-81] indeed catalyzed the slow fluorination of 1 (14%
conversion after 18 h, 25% after 36 h, 30 d to completion) or 2
(85% conversion after 18 h), but gave racemic products
Catalytic halogenation under “neutral” conditions
While the remainder of this paper is concerned with the 1-F and 2-F.
development of asymmetric catalytic halogenations, the Lewis
acid catalyzed fluorination under neutral conditions (i.e.,
without stoichiometric base) is an attractive method also for
carrying out nonstereoselective halogenations, which can profit
from catalyst optimization for controlling reaction selectivity.
Reactions were readily performed on preparative scale as shown
for α-methyl-β-ketoester 4, which was fluorinated in high yield
with the aid of TiCl4 as a catalyst (Scheme 4a). With the same
Figure 4: Structure of the chiral ansa-metallocene [(EBTHI)Ti(OTf)2].
catalyst, β-ketoester 5 suffered partial cleavage of the ester
group, but the milder Lewis acid CpTiCl3 induced a clean fluo-
rination with high selectivity towards monofluorination Dialkoxyaluminium chlorides, which were prepared in situ from
(Scheme 4b) [74,75]. We have further explored aspects of Me2AlCl and several chiral diols, were not catalytically
selective monofluorination and sequential mixed dihalogena- active. However, the well-established Lewis acid [(R,R-
tion elsewhere [74]. This example illustrates the potential of TADDOLato)TiCl2] [82] (Scheme 1) displayed good catalytic
catalyst tuning for specific substrates in catalytic fluorination activity (5 mol %, 1→1-F in 4 h) and gave (S)-1-F with an
reactions. TiCl4 as well as CpTiCl3 (and other Lewis acids) enantiomeric excess of 28% (for a complex incorporating the
[76-78] also catalyzed the chlorination of β-ketoesters with ligand (R,R)-phenyl-TADDOL (L1)) (Table 2). Consistent
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Table 2: Effect of catalyst loading, temperature, and water content on the fluorination of 1 with catalyst K1.a
Entry
K1 (mol %)
T (°C)
Additives (mol %)
t (h)
ee (%)
1
1.2
5
rt
45b
6
25.2
26.6
26.5
25.5
23.4
22.4
27
2
rt
3
10
20
50
100
5
rt
2
4
rt
<2
<0.3
<0.3
6
5
rt
6
rt
7
rt
MS 3 Å
8
5
rt
6
28.5c
28.5
28
9
5
rt
H2O (5)
10
>12d
–
10
11
12
13
14
15
5
rt
H2O (50)
H2O (1000)
5
rt
–e
5
0
16
<8
<2
0.1f
32
5
rt
28
5
40
60
23
5
18
aAll reactions were performed in reagent grade acetonitrile stored over 3 Å molecular sieves and run to complete conversion (TLC), unless otherwise
mentioned. bReaction stopped before complete conversion. cEntries 1–6 vs 7–11 vs 12–15 were run with different batches of F–TEDA, solvent and
catalyst, leading to small selectivity deviations under seemingly identical conditions. d50% conversion. eNo reaction. fConversion stopped at 80%.
catalysis results were obtained when the crystalline Lewis acid TiCl4 (Scheme 3), and by the finding that an in situ catalyst
complexes K1 and K2 were applied instead of the complexes prepared from Ti(OiPr)4, TiF4 and TADDOL (1:1:2) (in situ
generated in situ. The synthesis, characterization and X-ray [TiF2(TADDOLate)], but not characterized) was inactive. The
structures of these complexes, which are now commercially controlled addition of water to catalytic runs did not affect the
available, have been described elsewhere [83].
selectivity, but the activity decreased at high moisture levels
(Table 2, entries 7–11). Use of reagent-grade acetonitrile, stored
over molecular sieves (3 Å) in air, was satisfactory for most
purposes. Performing the reaction in the presence of powdered
Effects of catalyst loading, moisture, and tempera-
ture
The reaction rate of catalytic fluorination increased with the molecular sieves had no beneficial effects (Table 2, entry 7). All
catalyst loading, but there was little change in the catalytic runs were conveniently carried out in closed vessels in
enantioselectivity (Table 2, entries 1–6). A minor decrease of air.
selectivity at higher catalyst loadings is attributed to the
temperature effect of the fast exothermic reactions. At low cata- Temperature effect
lyst loadings (<2 mol %) catalyst poisoning occurs, presumably, The catalysis proceeded faster at higher temperature, with a
by moisture and/or fluoride impurities from the reagent concomitant decrease of enantioselectivity (Table 3, entries
F–TEDA. The negative effect of fluoride anions on the catalytic 12–15). At 60 °C, catalyst decomposition became notable by
activity is suggested by the inactivity of TiF4 as opposed to incomplete conversions (Table 3, entry 15). At temperatures
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Beilstein J. Org. Chem. 2011, 7, 1421–1435.
below 0 °C, the catalytic reaction was slow not only because of with better solubility. Reaction with NFSI in dichloroethane
the thermal effect, but because of the limited solubility of gave 1-F with 24% ee (5 mol % K1, 40 °C, 3 d, 66% conver-
F–TEDA. Additional temperature variation experiments were sion), which is close to the enantiomeric excess observed with
carried out with the more selective catalyst K2 and phenyl ester F–TEDA in acetonitrile at the same temperature (Table 2, entry
6 as substrate (Table 3). Results for either fluorination (→6-F) 14). The fluorination of 6 with NFSI in several solvents led to
with F–TEDA or the more soluble reagent NFSI (N-fluoroben- similar results in all solvents that supported the reaction
zenesulfonimide) and NCS (N-chlorosuccinimide) for chlorina- (Table 4). In conclusion, MeCN is the preferred solvent for
tion [43] (→6-Cl) are displayed in Table 3.
catalytic fluorinations with F–TEDA, whereas CH2Cl2 is the
preferred solvent for fluorinations with NFSI [46].
Above ambient temperature, increasing temperatures give lower
selectivity (Table 3, entries 1–3). Cooling to 0 °C in some cases
increased enantioselectivity at the cost of longer reaction times
(Table 3, entries 1–3, 4–6, compare also Table 2, entry 12). The
optimum temperature depends on substrate, halogenation agent
and solvent, but satisfactory results were often achieved at
ambient temperature.
Table 4: Solvent effects on selectivity of fluorination of 6 with NFSI and
K2.
Solvent effects
Entry
Solvent
t (h)
ee (%)
The choice of solvent for the catalytic fluorinations with
F–TEDA is limited by the solubility of this reagent. Solvents
must dissolve the ionic reagent, but not deactivate the Lewis
acidic catalyst. Suspensions of F–TEDA in MeCN gave results
inferior to saturated F–TEDA solutions in MeCN (c =
0.15 mol·L−1). Nitromethane dissolved less of the reagent, and
the reaction was slower. Aside from water, one of the best
solvents for F–TEDA was N,N-dimethylformamide, however, it
1
2
3
4
MeCN
CH2Cl2
THF
40
10
18a
24
84.5
87.5
77.5
85.6
toluene
a28% conversion.
deactivated the titanium catalyst. It was possible to study a Variation of the electrophilic fluorinating agent
wider range of solvents in the asymmetric catalytic fluorination A selection of commercially available electrophilic fluorinating
by choosing NFSI (N-fluorobenzenesulfonimide) as the reagent reagents (Figure 5) was tested in the catalytic reaction in MeCN
Table 3: Effect of the temperature on the halogenation of 6 with catalyst K2.a
Entry
Reagent
Solvent
T (°C)
t (h)
Product
ee (%)
1
2
3
4
5
6
7
8
F–TEDA
F–TEDA
F–TEDA
NFSI
MeCN
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
0
rt
0.3
0.15
<0.3
–b
6-F
6-F
6-F
6-F
6-F
6-F
6-Cl
6-Cl
86
88
50
−25
0
79
89b
91
NFSI
19
NFSI
rt
10
87.5
82
NCS
rt
0.5
7
NCS
0
90
aReactions were run to complete conversion (TLC), unless otherwise mentioned. bAnalysis at 15% conversion. Complete conversion occurred after
warming to rt.
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(Table 5). The dicationic reagents F–TEDA and NFTh [84] (Ta-
ble 5, entries 1 and 2) were the most reactive. Neutral N-fluoro-
sulfonamides supported the reaction, but electron-withdrawing
groups on nitrogen were needed to induce a fast reaction
(Table 5, entries 3, 7 and 8). N-fluoropyridinium salts (Table 5,
entries 4–6) gave rise to slow catalyses. With the exception of
the dicationic N,N'-difluorobipyridinium salt (Table 5, entry 6),
the reagents induced similar enantioselectivity.
Table 5: Effect of the fluorinating agent on the catalytic fluorination of
F1 with 10 mol % K1.
Entry Reagent
Time Conversion (%) ee (%)
1
2
3
4
5
6
7
8
F–TEDAa
NFTh
<5 h
<30 h
5 d
>90
>90
90
30
<5
80
0
28
32.5
28.0
28.8
–
NFSI
NFPy
5 d
NFColl
5 d
F2-bipy
p-TsN(F)Me
SaSu–NF
7 weeks
>1 week
>1 week
≤3
–
0
–
a5 mol % of catalyst.
o-trifluoromethylphenyl Grignard reagent with 7 gave hydroxy-
ester 8 (Scheme 5b); the latter, with an excess of phenylmagne-
sium chloride, gave a mixed aryl TADDOL T5. For another ap-
proach to mixed aryl TADDOLs [93]. The more reactive
o-trifluoromethylphenyllithium failed to give a TADDOL as
well, but instead furnished the hydroxyketone 9 in low yield
(Scheme 5b).
Figure 5: Electrophilic fluorinating reagents of the N–F-type. F–TEDA
[27]; NFTh = 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) [84]; NFSI = N-fluorobenzosulfonimide [85];
SaSu–NF = saccharine-sultam derived NF reagent (3,3-dimethyl-2,3-
dihydro-1,2-benzothiazole-1,1-dioxide) [86,87]; p-TsN(F)Me [88];
NFColl = N-fluorocollidinium tetrafluoroborate and NFPy = N-fluoropyri-
dinium tetrafluoroborate [72,89]; F2-bipy = 1,1'-difluoro-bipyridinium
bis(tetrafluoroborate) [90].
Ligand variations in the asymmetric titanium-
catalyzed fluorination reaction
We tested several chiral diols in the titanium-catalyzed asym-
metric fluorination, but notable success was only achieved with
TADDOL ligands [91]. We obtained several TADDOLs
from commercial sources (T1–T3) or courtesy of A. K. Beck
from the Seebach group (T4, T8–T10). In addition, we
prepared trifluoromethylated TADDOLs (Scheme 5), because
introduction of fluorine into the ligands was expected to
increase the Lewis acidity of the catalyst complex. The
syntheses started from dioxolane-diester 7 by reaction with
3-trifluoromethylphenyl or 3,5-bis(trifluormethylphenyl) Grig-
nard reagents in the usual way to give TADDOLs T6 and T7
[92] in high yield (Scheme 5a). Interestingly, the reaction of
Scheme 5: Synthesis of trifluoromethyl-substituted TADDOL ligands.
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Beilstein J. Org. Chem. 2011, 7, 1421–1435.
The performance of several TADDOLs as ligands in the catalysis. On the contrary, T3 with a 2-naphthyl group behaved
titanium-catalyzed asymmetric fluorination of the very much like T1 towards substrate 1 and was not studied
substrates 1, 10 and 11 to the respective products 1-F, 10-F and further (entry 4). A further increase in steric requirement and
11-F is shown in Table 6. The catalysts of the type aromatic stacking area was realized with 9-phenanthrenyl-
[TiCl2(TADDOLato)] [94] were all prepared in situ from the TADDOL T4; this gave a maximal enantioselectivity with
ligands and TiCl2(OiPr)2 in MeCN. To start with, the (R)- benzyl ester 10, rather than with the bulky ester 11.
BINOL-derived complex displayed low activity and selectivity Presumably, the combined steric effects of substrate and
(Table 6, entry 1). The phenyl-TADDOL ligand T1 induced ligand cannot exceed certain optimal limits. In the series of tri-
enantiomeric excesses that increased with the steric require- fluoromethylated TADDOLs T5, T6, T7 there was a notable
ments of the substrate ester group (Table 6, entry 2). The effect decrease of enantioselectivity and finally an inversion (with
was more pronounced for 1-naphthyl-TADDOL T2 (Table 6, substrate 1) of the sense of induction that roughly correlates
entry 3), which was the ligand with the best overall perfor- with the number of CF3 groups in the ligand (Table 6, entries
mance, displaying both high selectivity and fast kinetics in the 6–8). Variations of the TADDOLs in the dioxolane backbone
Table 6: Effects of the variation of the ligand structure and substrate stereochemistry.a,b
Entry
Diol ligand
ee (%)
1-F
10-F
11-F
1
2
(R)-BINOL
−1.7c,d
n.d.
n.d.
T1
T2
T3
T4
T5
T6
T7
T8
T9
T10
R,R' = Me; Ar,Ar' =
Ph
28.2
30–37
53–55
3
R,R' = Me; Ar,Ar' =
1-Nap
57.5
26
55
n. d.
74
19
28
11
32
56
0
85e
n. d.
35f
12
4
R,R' = Me; Ar,Ar' =
2-Nap
5
R,R' = Me; Ar,Ar' =
9-Phen
36f
11.5
−5d
−32d
25
6
R,R' = Me; Ar = Ph;
Ar' = 2-CF3C6H4
7
R,R' = Me; Ar,Ar' =
3-CF3C6H4
13
8
R,R' = Me; Ar,Ar' =
3,5-(CF3)2C6H3
−12d
45
9
R = Me; R' = Ph;
Ar,Ar' = Ph
10
11
R = Me; R' = t-Bu;
Ar,Ar' = 1-Nap
56
84
R,R' = Me; Ar,Ar' =
2-MeOC6H4
0f
0
aTADDOLs in this table all have (R,R)-configuration. bAbbreviations: 1-Nap = 1-naphthyl; 2-Nap = 2-naphthyl; 9-Phen = 9-phenanthrenyl; n.d. = not
determined. cReaction for 10 h at 0 °C, conversion not complete. dA negative sign denotes inversion of the excess configuration for the fluorination
product (R), relative to the excess configuration obtained with T1 (which is (S)). eWith pure K2 instead of the in situ catalyst from T2, selectivity is
90% ee. fConversion stops before completion of the reaction.
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Beilstein J. Org. Chem. 2011, 7, 1421–1435.
had little influence on stereoselectivity (Table 6, entry 2 and 3
versus entry 9 and 10). The presence of an ortho-methoxy group
in the TADDOL aryl group was not tolerated (Table 6,
entry 11).
Assignment of absolute configurations of selected
reaction products
The excess configuration of (+)-1-F was directly assigned as
(2S) by comparison with literature data. Kitazume et al.
reported [α]D = +85.4 (c 1.97, MeOH) for (S)-1-F with an enan-
tiomeric excess of >98% [95]. Our sample ([α]D = +53.8,
(c 0.545, MeOH)) had an optical purity of 63%, which is in
good agreement with the 62% ee from the HPLC measurement.
A sample of the benzyl ester (+)-10-F (68% ee by HPLC) was
transesterified (EtOH, cat. Na, <5 min at rt) to give the known
[95] ethyl ester (+)-(S)-12-F (67.9% ee by GC). By comparison
with the literature optical rotation value, the material had an
optical purity of 73%, which is sufficiently close to the
enantioselectivity determined by GC, considering the difficul-
ties of purifying this volatile compound on a small scale
(Scheme 6). A sample of (+)-11-F of 85.6% ee (by HPLC) was
Scheme 6: Correlation experiments for the assignment of absolute
configuration to fluorination products 11-F, 10-F and 6-F. The absolute
configuration of 1-F, 13-F and 12-F in relation to the sign of their
optical rotation was established by Kitazume et al. [95] a) 1. BCl3,
CH2Cl2, −20 °C, 15 min; 2. cyanuric chloride, PhNMe2, BnOH. b)
EtOH, cat. Na, rt, 15 min. c) p-TsOH, EtOH, rt, 1 d.
treated with BCl3 and the resulting carboxylic acid esterified in Mechanistic considerations
situ with cyanuric chloride, N,N-dimethylaniline and benzyl The addition of TiCl4 to acetyl acetone (2,4-pentanedione)
alcohol yielding (+)-10-F in 77% yield (84.9% ee by HPLC), gives rise to the red-colored chelate complex TiCl2(acac)2
whose configuration has already been established by correla- (acac = acetylacetonate, κO, κO'-2,4-pentanedionate) [96,97].
tion with 12-F. Comparison of the elution order on a chiral T h e c o m p l e x [ T i C l ( κ O , κ O ' - 1 , 3 - d i p h e n y l - 1 , 3 -
HPLC column with the (+)-sign of the optical rotation implied propanedionate)(TADDOLate)(THF)], derived from dibenzoyl-
an (S)-configuration of this sample, and therefore likewise for methane, was described as being yellow [98]. When the com-
(+)-11-F. In addition, a sample of (+)-6-F was transesterified in plex K1 was mixed with β-ketoester substrates (S) in acetoni-
acidic ethanol to 12-F. Assignment of the retention time of the trile solution, yellow- or red-colored solutions were formed
major enantiomer in GC allowed the assignment of the (S)-con- within few minutes, which implies that a β-diketonate complex
figuration to (+)-(S)-6-F (Scheme 6). So far, samples emerging was formed. We therefore assume that the catalytic accelera-
from our catalytic fluorination with a catalyst incorporating tion of the electrophilic fluorination reaction with F–TEDA by
(R,R)-TADDOL ligands have displayed positive optical rota- Lewis acidic titanium complexes is due to the intermediacy of
tion and a (2S)-configuration in the excess enantiomer.
chelating titanium–enolate complexes B (Scheme 7).
Scheme 7: Mechanistic scheme proposed, based on visual and spectroscopic observations. L = solvent, counterions.
1430

Beilstein J. Org. Chem. 2011, 7, 1421–1435.
The intermediacy of cationic species A is postulated based on equilibrium between [TiCl(TADDOLato)(DME)(MeCN)]BF4
NMR experiments: A solution of K1 in CDCl3 did not show and [TiCl(BF4)(TADDOLato)(DME)], or through the effects of
any signs of ionization and kept the spectral properties expected ion pairing and variable concentrations.
for a C2 symmetric species down to 230 K. The limited solu-
bility of K1 in CD3CN prevented low temperature NMR experi- These experiments show that ionization of K1 to generate A,
ments in that solvent. However, the reaction of K1 with an under the conditions of the catalytic reaction, readily takes
equivalent of AgBF4 in CD3CN produced the signals of place. In a second step, we assume that A undergoes ligand-
species A (Scheme 7) corresponding to the formula exchange reactions with coordination of a substrate S for DME,
[TiCl(TADDOLato)(DME)(MeCN)]BF4, which is character- followed by loss of the α-carbonyl hydrogen as H+ to give a
ized by two signals for diastereotopic geminal methyl groups mono-ketonate complex B. The proton may combine with chlo-
(δ = 0.48 and 0.93 ppm), and two doublets for the diastereotopic ride counterion to give HCl, which is only weakly dissociated in
methyne hydrogens (δ = 5.08 and 5.20 ppm, J = 7.2 Hz) of the acetonitrile (the pKa of HCl in MeCN has recently been
TADDOLate backbone (Figure 6a). This monocationic species measured as 10.6) [99]. Complex B would then be attacked by
could not be isolated; after evaporation and redissolution in external F–TEDA reagent at the central carbon of the enolate,
CDCl3, the sample had lost DME (1,2-dimethoxyethane) and diastereoselectively, from the face opposite to a shielding
displayed signals corresponding to the free TADDOL ligand, TADDOLate aryl group (Scheme 7, B→C). In order to arrive at
implying decomposition of the complex. Still we were able to a simple structural model of B, we used the coordinates from
show that a silver cation is not needed for ionizing the catalyst the X-ray crystal structure of the 1-naphthyl-TADDOL com-
under these reaction conditions: When a suspension of K1 was plex K2 [83] for the [TiCl(TADDOLate)(MeCN)] fragment and
stirred with excess solid F–TEDA in CD3CN, and the suspen- coordinates for the enol of benzyl ester substrate 10, generated
sion filtered, the 1H NMR spectrum of the filtrate displayed with the simple model-building software ALCOGEN [100], for
signals for a similar cationic species corresponding to A, in add- the ketoenolate fragment. The two substructures were joined
ition to signals from the F–TEDA cation (Figure 6b). The spec- manually, such that the enolate oxygen occupies the axial pos-
trum of this C1-symmetric species displayed signals for the ition trans to chlorine at titanium, and the carbonyl oxygen
diastereotopic methyl groups (δ = 0.64 and 1.01 ppm), and two occupies the position of a dissociated acetonitrile ligand. The
broadened signals for the diastereotopic methine hydrogens (δ = resulting model is shown in Figure 7. The model nicely illus-
5.25 and 5.65 ppm) of the TADDOLate backbone. The signals trates the shielding function of a face-on 1-naphthyl group,
for ligated DME showed considerable broadening. The chem- which may direct the attack of the incoming fluorinating
ical shift difference observed may either be explained by a fast reagent.
Figure 6: 1H NMR spectra of a species of the type A, generated in CD3CN solution from K1 by ionization in the presence of: a) AgBF4, or: b) excess
F–TEDA reagent. Assignments: α-CH = dioxolane H-C(4) and H-C(5). F = signals due to F–TEDA (and some H–TEDA). DME = coordinated 1,2-
dimethoxyethane. Me = dioxolane methyl-C(2) groups.
1431

Beilstein J. Org. Chem. 2011, 7, 1421–1435.
Figure 8: Excerpt from the X-ray structure of a catalyst/substrate com-
plex [Ti(1-naphthyl-TADDOLato)(β-ketoenolate)2] [102]. Two impor-
tant attractive interactions between substrate and TADDOL ligand frag-
ments can be identified: 1. Face-to-face arrangement of the ligand
1-naphthyl group and the substrate ketoenolate plane; 2. edge-to-face
stacking interaction between the ligand naphthyl and the substrate
benzyl ester groups.
Figure 7: Steric model explaining the face selectivity observed in the
titanium–TADDOLate complex catalyzed fluorination. The structural
model of this complex [TiCl(TADDOLate)(β-ketoenolate)(MeCN)] of the
type B (Scheme 7) was obtained by combining X-ray data of K2 with a
modeled structure of the enol of substrate 10. The arrow symbolizes
the external attack of the fluorinating reagent N–F.
This hypothesis was used as a starting point for more detailed A subsequent paper will concentrate on the substrate scope of
studies; QM/MM calculations on the postulated intermediary the titanium–TADDOLate-catalyzed asymmetric fluorination of
isomeric β-ketoenolate complexes and their attack by the N–F β-ketoesters and its extension to other activated carbonyl com-
reagent were carried out, as described elsewhere [101]. Among pounds as substrates [57].
the eight diastereomeric forms of B, the most stable complex is
indeed the one predicted by the simple steric model (Figure 7),
Supporting Information
which is expected to produce the fluorination product F with
(S)-configuration, as experimentally observed [101]. More
Supporting Information File 1
recent experimental studies led to the isolation of complexes
[Ti(1-naphthyl-TADDOLato)(β-ketoenolate)2], which were
characterized by X-ray crystallography in the solid state and by
NMR spectroscopy in solution [102]. In either mono- or
bis(ketonato) complex, the shielding of one diastereomorphic
face of the coordinated enolate by a 1-naphthyl group of the
ligand was found. Either a C1-symmetric mono-ketonato or a
C2-symmetric bis(ketonato) complex will react with F–TEDA
to give the fluorinated β-ketoester product with the same sense
of induction as experimentally found in the catalytic reaction
[102]. In the X-ray structure of the bis(enolate) of benzyl
2-methyl-3-oxopentanoate [102] (Figure 8), the face-to-face
alignment of the substrate enolate, which directs the attack of
the incoming electrophile to the other face, is clearly an impor-
tant element. However, closer inspection also reveals an attrac-
tive edge-to-face CH-to-arene-π interaction between the sub-
strate benzyl ester and the ligand naphthyl group, which was not
predicted by the simplistic steric models in Figure 6. This
attractive interaction may be responsible for the generally
higher level of enantioselectivity observed in the fluorination of
benzyl and aryl esters [57] when compared to substrates
containing aliphatic alkyl ester groups [40].
Experimental procedures and characterization data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-166-S1.pdf]
Acknowledgements
We acknowledge Solvias AG for a PhD research grant to L. H.
We thank Albert K. Beck and Dieter Seebach, Laboratorium für
Organische Chemie, ETH Zürich, for samples of TADDOL
ligands.
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