Asymmetric Desymmetrization via Metal-Free C?F Bond Activation: Synthesis of 3,5-Diaryl-5-fluoromethyloxazolidin-2-ones with Quaternary Carbon Centers

Article abstract of DOI:10.1002/anie.201603210

We disclose the first asymmetric activation of a non-activated aliphatic C?F bond in which a conceptually new desymmetrization of 1,3-difluorides by silicon-induced selective C?F bond scission is a key step. The combination of a cinchona alkaloid based ch

Full text of DOI:10.1002/anie.201603210

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Communications
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International Edition: DOI: 10.1002/anie.201603210
German Edition: DOI: 10.1002/ange.201603210
Carbon–Fluorine Bond Activation
À
Asymmetric Desymmetrization via Metal-Free C F Bond Activation:
Synthesis of 3,5-Diaryl-5-fluoromethyloxazolidin-2-ones with
Quaternary Carbon Centers
Junki Tanaka, Satoru Suzuki, Etsuko Tokunaga, Gꢀnter Haufe, and Norio Shibata*
Dedicated to Professor Dieter Hoppe on the occasion of his 75th birthday
Abstract: We disclose the first asymmetric activation of a non-
most challenging topics in fluorine chemistry as it has the
highest dissociation energy (105 kcalmolÀ1) of all covalent
carbon single bonds. Additionally, fluorine is neither a good
Lewis base nor a good leaving group.[8] The activation of
À
activated aliphatic C F bond in which a conceptually new
desymmetrization of 1,3-difluorides by silicon-induced selec-
À
tive C F bond scission is a key step. The combination of
À
a cinchona alkaloid based chiral ammonium bifluoride
catalyst and N,O-bis(trimethylsilyl)acetoamide (BSA) as the
silicon reagent enabled the efficient catalytic cycle of asym-
aliphatic C F bonds has been less frequently reported than
that of aryl fluorides.[6] In most cases the fluorine atom is
bound to an activated position such as a benzylic or allylic
position, or in a-position to a carbonyl group. Harsh reaction
À
metric Csp3 F bond cleavage under mild conditions with high
À
enantioselectivities. The ortho effect of the aryl group at the
prostereogenic center is remarkable. This concept was applied
for the asymmetric synthesis of promising agrochemical
compounds, 3,5-diaryl-5-fluoromethyloxazolidin-2-ones bear-
ing a quaternary carbon center.
conditions are generally required for C F bond cleavage and
À
À
À
À
À
very stable new bonds such as H F, Si F, B F, Al F, P F and
À
À
transition-metal F bonds have to be formed to make the C F
scission reaction feasible.[6d] Besides high reaction temper-
atures, lithium reagents, strong Lewis acids, and transition
metal reagents are generally needed.[7,9] In addition, activa-
ne of the major goals in organofluorine chemistry[1] is the
tion of benzylic C F bonds by hydrogen-bonding interactions
À
O
selective formation of new carbon–fluorine bonds to either
gain access to fluorinated building blocks[2] or to introduce
fluorine into existing complex carbon skeletons at a late stage
of synthesis in order to specifically modify the physicochem-
ical properties[3] or the biological activity of compounds
intended for the exploration of novel pharmaceuticals and
agrochemicals.[4] There are many different methods described
in the literature and only very recent developments are
mentioned here such as electrophilic monofluorination,
electrophilic, nucleophilic, and radical perfluoroalkylation,
trifluoromethylthiolation, perfluoroalkylsulfonylation, and
difluorocarbene addition.[5]
with isopropanol/water or hexafluoroisopropanol have also
been described.[10]
Recently, we reported the cleavage of non-activated
À
aliphatic C F bonds by utilizing the fluorophilicity of silicon
and the formation of strong (ca. 140 kcalmolÀ1) silicon–
fluorine bonds.[11] Using this reaction, 3,5-diaryl-5-
fluoromethyloxazolidin-2-ones 1 were synthesized by a con-
ceptually new desymmetrization of non-activated aliphatic
À
1,3-difluorides with silicon-induced C F bond activation as
a key step under mild reaction conditions with bis(trimethyl-
silyl)acetamide (BSA) and catalytic CsF (Scheme 1).
To extend this chemistry, we set our next goal as
À
In recent years a second general approach to access
organofluorine compounds was discovered, namely the
selective activation of carbon–fluorine bonds in polyfluo-
rinated substrates and their replacement with carbon–hydro-
“asymmetric desymmetrization” via C F bond activation.
Our approach toward the enantioselective reaction relies on
the replacement of CsF by chiral ammonium fluorides.
À
Enantioselective reactions via C F bond activation are
quite rare. To the best of our knowledge, only two reports
À
gen or carbon–carbon bonds. There are also reports on C O,
À
À
À
À
C S, C N, and C P bond formation at the expense of C F
bonds.[6,7] However, the cleavage of a C F bond is one of the
À
[*] J. Tanaka, S. Suzuki, E. Tokunaga, Prof. Dr. N. Shibata
Department of Nanopharmaceutical Sciences and
Department of Frontier Materials, Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya, 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
Prof. Dr. G. Haufe
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
48149 Mꢁnster (Germany)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603210.
Scheme 1. Background of this research and approach to asymmetric
desymmetrization.
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have been published so far, both from our group.[12] Although
toluene and CH2Cl2/toluene mixtures for asymmetric reac-
tions with organocatalysts,[14] but in this case the enantiose-
lectivity dropped (entries 7 and 8). Next the effect of the
substituents on the benzylic moiety of catalyst was studied.
Electron-donating groups like methoxy in F afforded the
product with low asymmetric induction (entry 9). On the
other hand, the catalyst G with strong electron-withdrawing
nitro groups gave the target product with acceptable 68% ee,
but in a complex mixture (12% yield, entry 10). These results
indicate that the nature of the chiral ammonium catalyst is
crucial for asymmetric induction.
À
we achieved enantioselective C F bond cleavage, only allylic
À
fluorides, compounds with activated aliphatic Csp3 F bonds,
have been accepted as substrates. Herein, we succeeded in the
asymmetric synthesis of 3,5-diaryl-5-fluoromethyloxazolidin-
2-ones 1 having a quaternary carbon center with high
enantioselectivities via cleavage of much more challenging
À
non-activated aliphatic Csp3 F bonds (Scheme 1). The use of
a chiral ammonium bifluoride catalyst and the effect of the
ortho-substituted aryl group (ortho effect) at the prostereo-
genic center are crucial to the success of the reaction.
In initial work the reaction conditions for the asymmetric
reaction were optimized (Table 1). Chiral ammonium fluo-
rides are known to be unstable salts.[13] Therefore, we chose
the method of in situ generation of the salts from silver
fluoride and chiral ammonium bromide.[13a] Four chiral
However, the chiral ammonium bromide/AgF system
presented us with three problems: 1) in situ generated chiral
ammonium fluoride from A is unstable; 2) AgF is almost
insoluble in CH2Cl2 at low temperatures; and 3) the reaction
has to be performed in the dark to avoid reduction of silver
cation. To overcome these drawbacks, we focused on a chiral
ammonium bifluoride catalyst reported by the groups of
Corey and Maruoka.[15] Bifluoride catalysts have been
reported to be more stable, so that this catalyst was expected
to be a promising alternative in our asymmetric reaction
(Table 2). Surprisingly, this catalyst accelerated the reaction
Table 1: Optimization of conditions for the asymmetric reaction .
Entry Precat. Solvent
Temp. Time [h] Yield [%] ee [%]
Table 2: Asymmetric reaction with chiral quinidinium bifluoride.
1
2
3
4
5
6
7
8
A (QD) CH2Cl2
B (QN) CH2Cl2
C (CN) CH2Cl2
D (CD) CH2Cl2
RT
RT
RT
RT
08C
RT
RT
RT
1
4
4
97
78
82
74
59
95
27
96
37
8
0
0
35
0
4
A
E
A
A
CH2Cl2
CH2Cl2
toluene
CH2Cl2/
toluene (1:2)
CH2Cl2
16
15
24
48
13
13
Entry
2
Temp. [8C]
Time [h]
1
Yield [%]
ee [%]
9
10
F
RT
RT
24
24
88
12
8
68
G
CH2Cl2
1
2
3
4
5
6
7
2a
2a
2a
2a
2b
2c
2d
RT
0
10 min
10 min
1
45
12
1a
1a
1a
1a
1b
1c
1d
99
98
88
81
95
90
94
24
30
37
48
45
48
84
À20
À40
À40
À40
À40
12
48
rate and the transformation was completed in only 10 min at
room temperature to give the product 1a in quantitative yield
with 24% ee (entry 1). The rate acceleration effect observed
is presumably due to the higher solubility and stability of
ammonium bifluoride in organic solvents. Encouraged by this
result, we lowered the reaction temperature successively. At
À408C the enantiomeric excess was 48%, although the
reaction required 45 h reach completion (entry 4). In order
to improve the enantioselectivity of this unprecedented
asymmetric desymmetrization of bis-monofluoride 2a, we
investigated the effect of substituents on the aryl ring at the
quaternary center (entries 5–7). 2-Aryl-1,3-difluoropropan-2-
(N-phenylcarbamates) 2b and 2c, which have a methoxy
group at the para and meta position of Ar, respectively,
showed higher reactivity and yield with almost unaffected
enantioselectivity (entries 5 and 6, 90–95% yields, 45–
48% ee). Fortunately, the ortho substituent of 2d caused
ammonium bromides derived from quinidine (QD), quinine
(QN), cinchonine (CN), and cinchonidine (CD) were used as
catalyst precursors (entries 1–4). The reaction at room
temperature in the presence of quinidinium fluoride formed
in situ from A afforded the target product 1a with 97% yield
and 37% ee in 1 h (entry 1), while catalysts formed from B, C,
and D gave lower yields (74–82%) and lower or no
enantioselectivity (0–8% ee, entries 2–4). Therefore, we con-
tinued our investigations with the catalyst derived from A. At
08C a reaction time of 16 h was required and both yield and
enantioselectivity decreased (59%, 35% ee, entry 5). Meth-
ylation of the OH group of A (precatalyst E) resulted in high
product yield but no chiral induction at room temperature
(entry 6). Thus, the hydroxy group in the catalyst structure is
essential for high ee values. In previous work we often used
2
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a dramatic increase of the enantioselectivity (84% ee) and
excellent yield of 94% (entry 7).
Encouraged by the remarkable ortho effect of the
methoxy group, this methodology was extended to a variety
of substrates with other ortho-substituted phenyl rings at the
prostereogenic center (Table 3). We found that substrates
with any ortho substituents gave rise to excellent yields and
Table 3: Substrate scope of the asymmetric desymmetrization reaction.
Figure 1. a) X-ray crystallographic structure of (S)-5-fluoromethyl-3-
phenyl-5-(o-bromophenyl)oxazolidin-2-one (1h) (CCDC 1471286). b) X-
ray crystallographic structure of precatalyst C from CCDC738896.[16]
c) Proposed transition-state model TS-1 for the transformation of 2 to
(S)-1.
ray crystallography (CCDC 1471286, Figure 1a). Other com-
pounds 1 are supposed to have S configuration as well.
Scheme 2 presents our mechanistic explanation for the
asymmetric desymmetrization reaction. Initially, BSA was
activated by chiral ammonium bifluoride to provide amide
À
anion I, along with the release of Me3Si F and HF. Anion I
then abstracts the carbamate proton from 2 to generate anion
[a] Reactions were carried out at À208C.
high asymmetric induction. Electron-donating ortho substitu-
ents such as EtO and iPrO groups afforded the products 1e
and 1 f with high yields (72–92%) and high enantioselectiv-
ities (85–92% ee). Electron-withdrawing halogens, that is, Cl
and Br, were also efficient ortho functional groups to provide
1g and 1h in excellent yields (96–98%) with high enantio-
selectivities (73–84% ee). The bulkier iPrO and Br led to
higher enantioselectivities independent of their electronic
nature. Next the effect of substituents on the Ar2 group of the
carbamate was studied (2i–n). Again, reactions of substrates
with electron-donating Me and MeO groups (1i and 1j), or
halogens like Cl and Br in para position (1k and 1l), or with
powerful electron-withdrawing groups like CF3 and NO2 in
meta position (1m and 1n) gave high yields (81–94%) and
high enantioselectivities (74–86% ee). We further elaborated
the scope of this reaction with substrates having sterically
more demanding Ar1 groups at the prostereogenic center. The
substrates with ortho-methoxynaphthyl and ortho-methoxy-
biphenyl groups gave the cyclized products 1o and 1p with
82% ee and 86% ee, respectively, with > 90% yield. As
expected, very low asymmetric induction was observed for
aliphatic substrate 1q (93% yield, 17% ee). Thus, the steri-
cally demanding Ar1 group is required to gain high enantio-
selectivity.
Scheme 2. Plausible reaction mechanism.
À
II, along with Me3SiNHCOMe. Next the less hindered C F
bond of II was activated by interaction with the Si atom of
BSA, depicted by transition-state model III. This conforma-
tion induces an intramolecular cyclization with C F fission
furnishing the chiral oxazolidin-2-one 1 and Me3Si F. The
À
À
amide anion I, which is regenerated from III, is the active
catalyst in this cycle.
From difluoride 2h the S-configurated product 1h was
formed selectively (84% ee). The structure was proved by X-
To explain the high enantioselectivity achieved in the
present reactions, we postulated a transition-state structure
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for the formation of (S)-1 controlled by catalyst H. The
geometry of H was generated from our X-ray crystallographic
data of catalyst C (Figure 1b)[16] showing that the cinchona
alkaloid exists in an open conformation.[17] The absolute
configuration of product 1h determined by X-ray diffraction
(Figure 1a) was used as a model for the reacting enantiotopic
fluoromethyl group of substrates 2. The free OH group at the
prostereogenic carbon center and the OMe group of the
quinoline moiety of H should play important roles based on
the results of the catalyst screening (see entries 1, 3, and 6 in
Table 1). Hence, the transition-state structure TS-I is pro-
posed. The OH captures the anions of carbamates 2, by
intermolecular hydrogen bonding to the oxygen.[18] Addition-
ally, the carbamate anion is stabilized by ion pairing with
ammonium cation. These attractions facilitate the location of
the substrate 2 in the space between the left part of the
quinuclidine ring and the bulky bis(trifluormethyl)benzyl
group on the right. Steric repulsion induced by an ortho-
substituted aryl group efficiently moves away the benzyl
moiety of catalyst H and locks TS-I. The opposite side of the
quinoline moiety of H is blocked by its methoxy group, which
further confines the substrate molecules within the restricted
space of catalyst H (Figure 1c).
Keywords: asymmetric synthesis · C–F bond activation ·
desymmetrization · fluorine · organocatalysis
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In conclusion, we have achieved the first asymmetric
desymmetrization of 1,3-difluorides using N,O-bis(trimethyl-
silyl)acetamide and catalyzed by a cinchona alkaloid derived
ammonium bifluoride salt providing chiral, non-racemic 3,5-
diaryl-5-fluoromethyloxazolidin-2-ones in high yields with
high enantioselectivities of up to 92% ee. Since the 3,5-diaryl-
5-trifluoromethyloxazolidin-2-ones are promising agrochem-
icals (insecticides, acaricides, ectoparasiticides),[19] mono-
fluorinated analogues are highly desirable. A notoriously
À
difficult non-activated aliphatic C F bond scission was
À
realized and a metal-free, silicon-mediated selective C F
bond activation was a key step. The combination of a cinchona
alkaloid based chiral ammonium bifluoride catalyst and
a silicon reagent enabled the efficient, asymmetric cleavage
À
of Csp3 F bonds under mild conditions with high enantiose-
lectivities. The remarkable steric effect of an ortho-substi-
tuted aryl group at the prostereogenic carbon for asymmetric
induction is observed not only for MeO, but also other alkoxy
groups, halogens, and bigger aryl groups. This concept of
À
asymmetric C F bond activation might be applicable for
other types of asymmetric synthesis with cyclization. This idea
is now under consideration.
Acknowledgments
This research is partially supported by the Platform for Drug
Discovery, Informatics and Structural Life Science from The
Ministry of Education, Culture, Sports, Science and Technol-
ogy-Japan (MEXT), and Japan Agency for Medical Research
and Development (AMED), the Advanced Catalytic Trans-
formation (ACT-C) from the JST Agency, and the Kobayashi
International Foundation. We also acknowledge the help of
Chisato Terada at the beginning of this research.
4
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Received: April 1, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Carbon–Fluorine Bond Activation
J. Tanaka, S. Suzuki, E. Tokunaga,
À
ortho Effect: Non-activated Csp3 F bonds
can be cleaved selectively in the novel
desymmetrization of 1,3-difluorides. The
combination of a cinchona alkaloid based
chiral ammonium bifluoride catalyst and
N,O-bis(trimethylsilyl)acetamide facili-
tated the efficient, catalyzed asymmetric
G. Haufe, N. Shibata*
&&&& — &&&&
Asymmetric Desymmetrization via Metal-
À
Free C F Bond Activation: Synthesis of
À
3,5-Diaryl-5-fluoromethyloxazolidin-2-
ones with Quaternary Carbon Centers
Csp3 F bond cleavage. The steric ortho
effect plays an important role in the
asymmetric induction.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!