Enantioselective synthesis of β,γ-unsaturated α-fluoroesters catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1002/anie.201204521

NHC meets F: NHC-bound enolates undergo a catalytic asymmetric fluorination reaction to β,γ-unsaturated α-fluoroesters, which are obtained with good efficiency and stereoselectivity (see scheme, NFSI=N- fluorobenzenesulfonimide). The strategy overcomes possible challenges, such as fluorination in the γ position and difluorination. Experimental evidence combined with DFT calculations provides insight into the reaction mechanism. Copyright

Full text of DOI:10.1002/anie.201204521

Angewandte
Chemie
DOI: 10.1002/anie.201204521
Asymmetric Fluorination
Enantioselective Synthesis of b,g-Unsaturated a-Fluoroesters
Catalyzed by N-Heterocyclic Carbenes (NHCs)**
Yu-Ming Zhao, Man Sing Cheung, Zhenyang Lin,* and Jianwei Sun*
Chiral organofluorine compounds have attracted increasing
attention because of their valuable applications in pharma-
ceutical, agrochemical, and materials industries.[1] Thus, the
ꢀ
development of catalytic enantioselective C F bond-forma-
tion processes has become an important area in organic
synthesis.[2] In particular, the stereocontrolled fluorination at
the a position of a carbonyl group has been intensively
explored.[3,4] Since the first report by Hintermann and Togni
in 2000,[3a] a range of catalytic enantioselective a fluorination
of carbonyl compounds have been developed.[3,4] Despite the
Scheme 1. Formation of NHC-bound dienolate and further fluorina-
significant progress, there remains a great need for further
development of useful enantioselective fluorination process-
es. For example, organocatalyzed asymmetric fluorination for
the synthesis of simple a-fluoroesters remains unknown.
Herein, we report the first enantioselective fluorination
reaction catalyzed by N-heterocyclic carbenes (NHCs).
NHCs are well-known for their unique capability in
reversing the polarity of aldehydes.[5] For example, in the
presence of an NHC catalyst, the carbonyl carbon atoms of
simple aldehydes (acyl anion equivalents), the a position of
aldehydes with a leaving group at this position (enolates), and
the b position of enals (homoenolates) can be rendered
nucleophilic.[5] Very recently, Chi and co-workers have also
demonstrated the generation of dienolates in which the
g position is nucleophilic.[6] Thus, a range of new NHC-
catalyzed bond-forming processes for functionalization at the
a, b, and g positions of carbonyl carbon atoms of aldehydes
have been developed with different electrophiles. However,
tion.
fluorinating reagent and a nucleophile to afford a fluorinated
product. We also expected that a chiral NHC would induce
enantioselective C F bond formation. However, during
executing the hypothesized reaction, several challenges may
be encountered: 1) There might be a regioselectivity issue,
because both the a and g positions are nucleophilic. 2) The
mono-fluorinated product is quite easily deprotonated for
a second fluorination, thereby invoking competing difluori-
ꢀ
ꢀ
nation. 3) Instead of C F bond formation, the dienolate can
undergo protonation at the a or g position to afford a non-
fluorinated product. 4) It is not trivial to control the facial
selectivity, given the extremely high reactivity of electrophilic
fluorine and the small size of the fluorine atom. 5) The typical
basic conditions for NHC catalysis would potentially cause
product racemization. Additional complications include the
possible incompatibility of the NHC catalyst with the electro-
philic fluorinating reagent, thereby affecting catalyst turn-
over.
ꢀ
NHC-catalyzed enantioselective carbon halogen bond for-
mation, a family of important processes with paramount
utility, has not been realized.[7] In this work, we targeted the
challenging fluorination.
We started the evaluation of our hypothesis with racemic
enal 1, which bears a g-methyl-carbonate leaving group
(Table 1). In view of the above-mentioned challenges, we
initially employed a weak base (NaOAc) and a mild fluorine
source (F–TEDA). Screening of chiral precatalysts (A–E)
identified B, first developed by Bode,[9] as a promising catalyst
precursor, and the desired product 2 was obtained with
reasonably good enantioselectivity, albeit in low yield
(entry 2). As expected, the difluorinated product 3 and the
simple redox product 4 account for the mass balance. We next
examined other fluorinating reagents and found that the use
of NFSI can immediately improve the enantioselectivity
(94% ee, entry 7). Further solvent screening (entries 8–11)
reveals that the reaction in chloroform gives an improved
yield (55%, entry 10). The use of other bases, such as DBU,
HCO2Na, and K3PO4, results in either no reaction or no
formation of the desired product (entries 12–14). In the
absence of a base, no reaction was observed, suggesting that
free NHC is the active catalyst (entry 15). Decreased loading
Previously, we have reported an NHC-catalyzed redox
reaction of alkynals that bear a leaving group in g position for
the synthesis of allenoates through a key cumulative alleno-
late intermediate.[8] In continuation of our effort, we hypothe-
sized that enals that bear a leaving group in g position would
provide access to an NHC-bound dienolate (Scheme 1),
which is expected to subsequently react with an electrophilic
[*] Dr. Y.-M. Zhao, M. S. Cheung, Prof. Dr. Z. Lin, Prof. Dr. J. Sun
Department of Chemistry, The Hong Kong University of Science and
Technology, Clear Water Bay, Kowloon, Hong Kong SAR (China)
E-mail: sunjw@ust.hk
chzlin@ust.hk
[**] Financial support was provided by HKUST and Hong Kong RGC
(GRF HKUST604411 and HKUST603711). We thank Prof. Liming
Zhang (UCSB) for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204521.
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Table 1: Effect of reaction parameters.[a]
enantioselectivity and slightly dif-
ferent yields, with methyl carbon-
ate being the best starting material.
The results also suggest that the
added methanol, which is used in
excess, outcompetes the alkoxide
that results from the carbonate
leaving group, and serves as the
nucleophile in the last acyl substi-
tution step.[10]
Entry
Precat.
Base
Fluorine
source
Solvent
Additive
Yield of
2 [%]
ee of
2 [%]
2:3:4
1
2
3
4
5
6
7
8
A
B
C
D
E
B
B
B
B
B
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
DBU
F–TEDA
F–TEDA
F–TEDA
F–TEDA
F–TEDA
F–Py
NFSI
NFSI
NFSI
NFSI
NFSI
NFSI
NFSI
NFSI
NFSI
NFSI
NFSI
NFSI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
CHCl3
benzene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
22
32
48
n.r.
n.r.
0[c]
5
75
12
–
–
–
94
–
–
92
91
–
–
–
–
–
92
92
92
53:36:11
66:27:7
87:10:3
–
The NHC-catalyzed asymmet-
ric a fluorination proceeds in good
–
–
yield for
a
range of enals
20
67:33:0
21:76:3
0:100:0
82:18:0
61:39:0
0:100:0
–
ꢀ
(Scheme 2). Thus, the C F bond
formation occurs exclusively in the
a position with high ee values in
the presence of a variety of func-
tional groups, including ethers, hal-
ides, cyanides, alkenes, aryl alde-
hydes, ketones, free alcohols,
esters, and silyl-protected alcohols.
Moreover, the presence of a qua-
ternary carbon atom in g position
does not significantly affect the
reaction efficiency and trisubsti-
tuted alkene 20 was obtained as
<10
9
0[d]
10
11
12
13
14
15
16
17
18[g]
19[g]
55
B
B
B
B
B
B
B
26
0[d]
HCO2Na
K3PO4
n.r.
0[d]
0:100:0
–
–
n.r.
<10[e]
82
91
82
NaOAc[b]
NaOAc
NaOAc
NaOAc
–
MeOH[f]
MeOH[f]
MeOH[f]
>98:1:1
>98:1:1
>98:1:1
B[h]
B[i]
NFSI
[a] Order of substrate/reagent addition: precatalyst, aldehyde, fluorination reagent, additive, and base.
The yield was determined by GC analysis with n-decane as an internal standard. The ee value was
determined by HPLC analysis. [b] 0.2 equiv. [c] Decomposition of starting material. [d] Product 3 was
formed exclusively. [e] Conversion was <10%. [f] 5.0 equiv. [g] The concentration was 0.05m.
[h] 10 mol%. [i] 5 mol%. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, Mes=2,4,6-trimethylphenyl,
n.r.=no reaction, TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl.
a
single E isomer. In contrast,
a substituent in the a position sig-
nificantly slows down the reaction
(< 10% conversion after 48 h),
although the desired product 21
with a chiral quaternary carbon
center in a position was obtained
with a moderate ee value. Enals
with an alkyl substituent at the
g position
also
participate
smoothly in the a fluorination.
of NaOAc gives a lower conversion (entry 16). After consid-
erable efforts, we were pleased to find that the addition of
methanol significantly improves the yield of 2 (entry 17).
Finally, the use of 10 mol% of B and a concentration of 0.05m
leads to exclusive formation of the desired product 2 in both
excellent yield and enantioselectivity (entry 18). It is note-
worthy that no product of g fluorination was observed and
product 2 was obtained as a single E alkene.
We also prepared enals with different leaving groups in
g position, such as ethyl and tert-butyl carbonates as well as
acetate [Eq. (1)]. Under our standard conditions (entry 18,
Table 1), the reactions of these substrates all proceed to form
the same methyl ester product (2) with essentially the same
For example, desired product 23 with an nBu substituent
was obtained in excellent yield and enantioselectivity, albeit
with a low E/Z ratio. With bulkier alkyl groups, such as iPr
and tBu, the desired products were obtained with excellent
enantioselectivity and good E/Z ratio.
The efficient fluorination reaction is not limited to the
synthesis of methyl esters. It can also be applied to the
synthesis of a range of alkyl esters in the presence of different
alcohol additives, such as ethanol, isopropanol, benzyl
alcohol, allylic alcohol, propargyl alcohol, as well as
CD3OD (Table 2), in good yield and excellent enantioselec-
tivity.
The b,g-unsaturated a-fluoroesters can be transformed
into other useful compounds. For example, saturated a-
fluoroesters or acids can be obtained after a simple hydro-
genation step, with the chiral center staying untouched
[Eqs. (2) and (3)]. The optical rotation of 33 is comparable
to the literature value.[11] These a-fluoroesters and acids have
practical utility as optical materials themselves[12a] or as
synthetic intermediates for bioactive compounds.[12b–d]
With the aid of DFT calculations (see the Supporting
Information), we have proposed a reaction mechanism
2
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(Scheme 3). The catalytic cycle begins with the addition of
NHC to the enal carbonyl group. The resulting Breslow
intermediate F then undergoes elimination and deprotona-
tion to afford dienolate G, in which the chiral backbone of the
NHC blocks the Si face. The results of the calculation suggest
Scheme 2. Scope of the fluorination reaction in a position. Yields of
purified products are given. [a] The starting material (>90%) was
recovered. [b] 5.0 equiv of BnOH was used instead of MeOH, because
of the low boiling point of the methyl ester product. Bn=benzyl,
TIPS=triisopropylsilyl.
Scheme 3. Possible reaction mechanism.
that its rotamer G’, in which the Re face is blocked, is about
5.3 kcalmolꢀ1 (in free energy) less favored than G because of
the unfavored interaction between the enolate oxygen atom
and the methyl group when fully conjugated. This result is
consistent with our observed stereochemical outcome as well
Table 2: Synthesis of different esters with alternative alcohols.
as other reports.[13] Thus, subsequent C F bond formation
Entry
Product
Yield [%][a]
ee [%]
ꢀ
ꢀ
Nu H
takes place selectively on the Re face. The observed excellent
a (vs. g) regioselectivity is also consistent with DFT calcu-
1
2
3
EtOH[b]
iPrOH[b]
BnOH
26
27
28
72
51
64
90
96
94
ꢀ
lations. The barrier for C F bond formation at the g position
is higher than that at the a position by 7.1 kcalmolꢀ1. This
preference is related to the relatively high electron density at
a-C (vs. g-C) of the dienolate G, likely because of the
proximate positive charge of the triazolium moiety. Further
acyl substitution by methoxide proceeds via intermediate I to
form the desired product and regenerate the NHC catalyst.
4
29
73
93
5
6
30
31
72
69
92
93
CD3OD
ꢀ
[a] Yield of purified product. [b] A mixed solvent was used (Nu H/
CHCl3 =1:1).
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ꢀ
NFSI (0.525 mmol, 171 mg), anhydrous CHCl3 (10 mL), and the
nucleophile (2.5 mmol). NaOAc (1.0 mmol, 82 mg) was then added
and the vial was capped and removed from the glovebox. The reaction
mixture was stirred at room temperature for 48 h. Next, diethyl ether
(60 mL) and H2O (10 mL) were added. The organic layer was
separated and washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by flash
column chromatography to give the desired a-fluoroester.
DFT calculations also suggest that the C F bond formation
step is both enantioselectivity- and rate-determining (DG° =
18.3 kcalmolꢀ1). The tetrahedral intermediate I was also
located in our calculations.[14]
To gain further insight into the reaction mechanism, we
also carried out a series of NMR experiments [see Eq. (4) and
the Supporting Information]. Firstly, the formation of free
Received: June 11, 2012
Revised: July 31, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · enolates · fluorine ·
.
N-heterocyclic carbenes · organocatalysis
[1] a) K. Mꢀller, C. Faeh, F. Diederich, Science 2007, 317, 1881 –
1886; b) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320 – 330; c) P. Jeschke, ChemBio-
Chem 2004, 5, 570 – 589; d) M.-H. Hung, W. B. Farnham, A. E.
Feiring, S. Rozen in Fluoropolymers 1: Synthesis (Eds.: G.
Hougham, P. E. Cassidy, K. Johns, T. Davidson), Plenum, New
York 1999, p. 51.
NHC was observed when a solution of B was treated with
NaOAc, which was evidenced by the disappearance of the
proton signal at approximately 12 ppm. Subsequent addition
of enal 1 to the NHC resulted in immediate disappearance of
the signals of 1 with concomitant formation of a new set of
signals, presumably corresponding to dienolate G [Eq. (4a)].
Next, NFSI followed by CD3OD was added and the formation
of product 31 was observed with full conversion within ten
minutes. Furthermore, we were also interested in probing the
nature of the potential interaction between the NHC and
NFSI. Thus, instead of adding enal 1 to NHC, we added NFSI
(1 or 1.5 equiv) to the free NHC, which quickly established an
equilibrium that favored the formation of the NHC–F adduct
[Eq. (4b)]. The following addition of substrate 1 and CD3OD
led to the formation of the desired product, but in a signifi-
cantly slow rate. Indeed, the decreased reaction rate was also
observed under our catalytic conditions when the order of
substrate/reagent addition was changed to B!NaOAc!
NFSI!1. These results suggest that the free NHC reacts
faster with the aldehyde substrate than with NFSI, which
explains the observed smooth catalyst turnover.
[2] For recent reviews on catalytic asymmetric fluorination reac-
tions, see: a) V. A. Brunet, D. OꢁHagan, Angew. Chem. 2008,
120, 1198 – 1201; Angew. Chem. Int. Ed. 2008, 47, 1179 – 1182;
b) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1 – PR43; c) M.
Ueda, T. Kano, K. Maruoka, Org. Biomol. Chem. 2009, 7, 2005 –
2012; d) S. Lectard, Y. Hamashima, M. Sodeoka, Adv. Synth.
Catal. 2010, 352, 2708 – 2732; e) Y. K. Kang, D. Y. Kim, Curr.
Org. Chem. 2010, 14, 917 – 927; f) T. Furuya, A. S. Kamlet, T.
Ritter, Nature 2011, 473, 470 – 477; g) G. Valero, X. Companyꢂ,
R. Rios, Chem. Eur. J. 2011, 17, 2018 – 2037; h) U. Hennecke,
Angew. Chem. 2012, 124, 4608 – 4610; Angew. Chem. Int. Ed.
2012, 51, 4532 – 4534.
[3] For selected examples of metal-catalyzed asymmetric a fluori-
nation of carbonyl compounds, see: a) L. Hintermann, A. Togni,
Angew. Chem. 2000, 112, 4530 – 4533; Angew. Chem. Int. Ed.
2000, 39, 4359 – 4362; b) Y. Hamashima, K. Yagi, H. Takano, L.
Tamꢃs, M. Sodeoka, J. Am. Chem. Soc. 2002, 124, 14530 – 14531;
c) R. Frantz, L. Hintermann, M. Perseghini, D. Broggini, A.
Togni, Org. Lett. 2003, 5, 1709 – 1712; d) S. M. Kim, H. R. Kim,
D. Y. Kim, Org. Lett. 2005, 7, 2309 – 2311; e) Y. Hamashima, T.
Suzuki, H. Takano, Y. Shimura, M. Sodeoka, J. Am. Chem. Soc.
2005, 127, 10164 – 10165; f) N. Shibata, J. Kohno, K. Takai, T.
Ishimaru, S. Nakamura, T. Toru, S. Kanemasa, Angew. Chem.
2005, 117, 4276 – 4279; Angew. Chem. Int. Ed. 2005, 44, 4204 –
4207; g) T. Suzuki, Y. Hamashima, M. Sodeoka, Angew. Chem.
2007, 119, 5531 – 5535; Angew. Chem. Int. Ed. 2007, 46, 5435 –
5439; h) D. S. Reddy, N. Shibata, J. Nagai, S. Nakamura, T. Toru,
S. Kanemasa, Angew. Chem. 2008, 120, 170 – 174; Angew. Chem.
Int. Ed. 2008, 47, 164 – 168; i) D. H. Paull, M. T. Scerba, E.
Alden-Danforth, L. R. Widger, T. Lectka, J. Am. Chem. Soc.
2008, 130, 17260 – 17261; j) S. H. Kang, D. Y. Kim, Adv. Synth.
Catal. 2010, 352, 2783 – 2786; k) J. Erb, D. H. Paull, T. Dudding,
L. Belding, T. Lectka, J. Am. Chem. Soc. 2011, 133, 7536 – 7546;
l) Q.-H. Deng, H. Wadepohl, L. H. Gade, Chem. Eur. J. 2011, 17,
14922 – 14928; m) S. Suzuki, Y. Kitamura, S. Lectard, Y. Hama-
shima, M. Sodeoka, Angew. Chem. 2012, 124, 4659 – 4663;
Angew. Chem. Int. Ed. 2012, 51, 4581 – 4585.
In conclusion, we have developed the first NHC-catalyzed
asymmetric fluorination reaction. It represents a new reaction
of NHC-bound enolates and the first general enantioselective
synthesis of b,g-unsaturated a-fluoroesters, complementary to
existing strategies for the enantioselective synthesis of a-
fluoro carbonyl compounds. In the presence of an appropriate
ꢀ
combination of a precatalyst, a base, and an additive, the C F
bond formation occurs efficiently at the a position of enals,
thus overcoming nontrivial challenges, such as competitive
g fluorination, difluorination, nonfluorination, and NHC/
NFSI interaction, and proceeds with very good enantioselec-
tivity. The enantioenriched b,g-unsaturated a-fluoroester
products and their derivatives have broad practical utility.
DFT calculations and NMR studies on the reaction progress
both provided important insights into the reaction mecha-
nism. These results are helpful for further development of
new processes.
[4] For selected examples of organocatalyzed asymmetric a fluori-
nation of carbonyl compounds, see: a) D. Y. Kim, E. J. Park,
Org. Lett. 2002, 4, 545 – 547; b) M. Marigo, D. Fielenbach, A.
Braunton, A. Kjœrsgaard, K. A. Jørgensen, Angew. Chem. 2005,
117, 3769 – 3772; Angew. Chem. Int. Ed. 2005, 44, 3703 – 3706;
c) D. D. Steiner, N. Mase, C. F. Barbas III, Angew. Chem. 2005,
Experimental Section
General procedure: In a glovebox, an oven-dried 20 mL vial was
charged with triazolium salt B (0.05 mmol), the enal (0.5 mmol),
4
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Chemie
117, 3772 – 3776; Angew. Chem. Int. Ed. 2005, 44, 3706 – 3710;
d) T. D. Beeson, D. W. C. MacMillan, J. Am. Chem. Soc. 2005,
127, 8826 – 8828; e) J. Franzꢄn, M. Marigo, D. Fielenbach, T. C.
Wabnitz, A. Kjœrsgaard, K. A. Jørgensen, J. Am. Chem. Soc.
2005, 127, 18296 – 18304; f) D. Enders, M. R. M. Hꢀttl, Synlett
2005, 991 – 993; g) T. Fukuzumi, N. Shibata, M. Suguira, S.
Nakamura, T. Toru, J. Fluorine Chem. 2006, 127, 548 – 551; h) T.
Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura, T.
Toru, M. Shiro, Angew. Chem. 2008, 120, 4225 – 4229; Angew.
Chem. Int. Ed. 2008, 47, 4157 – 4161; i) K. Shibatomi, H.
Yamamoto, Angew. Chem. 2008, 120, 5880 – 5882; Angew.
Chem. Int. Ed. 2008, 47, 5796 – 5798; j) X. Wang, Q. Lan, S.
Shirakawa, K. Maruoka, Chem. Commun. 2010, 46, 321 – 323;
k) P. Kwiatkowski, T. D. Beeson, J. C. Conrad, D. W. C. Mac-
Millan, J. Am. Chem. Soc. 2011, 133, 1738 – 1741; l) J. Xu, Y. Hu,
D. Huang, K.-H. Wang, C. Xu, T. Niu, Adv. Synth. Catal. 2012,
354, 515 – 526.
[6] J. Mo, X. Chen, Y. R. Chi, J. Am. Chem. Soc. 2012, 134, 8810 –
8813.
ꢀ
[7] Without carbon halogen bond formation, Rovis reported beau-
tiful syntheses of a-halocarboxylic acids and derivatives by
asymmetric protonation of NHC-bound enolates: a) N. T. Rey-
nolds, T. Rovis, J. Am. Chem. Soc. 2005, 127, 16406 – 16407;
b) H. U. Vora, T. Rovis, J. Am. Chem. Soc. 2007, 129, 13796 –
13797; c) H. U. Vora, T. Rovis, J. Am. Chem. Soc. 2010, 132,
2860 – 2861.
[8] Y.-M. Zhao, Y. Tam, Y.-J. Wang, Z. Li, J. Sun, Org. Lett. 2012, 14,
1398 – 1401.
[9] M. He, J. R. Struble, J. W. Bode, J. Am. Chem. Soc. 2006, 128,
8418 – 8420.
[10] In the absence of an alcohol additive, the alkoxide (ROꢀꢀ)
resulted from the decomposition of the leaving group (ROCO2
)
is believed to serve as the nucleophile (Table 1, entries 1–16).
[11] M. Saburi, L. Sbao, T. Sakurai, Y. Uchida, Tetrahedron Lett.
1992, 33, 7877 – 7880.
[5] For selected recent reviews on NHC catalysis, see: a) E. M.
Phillips, A. Chan, K. A. Scheidt, Aldrichimica Acta 2009, 42, 55 –
66; b) H. U. Vora, T. Rovis, Aldrichimica Acta 2011, 44, 3 – 11;
c) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, R. R. Paul, A.
Jose, V. Sreekumar, Chem. Soc. Rev. 2011, 40, 5336 – 5346; d) P.
Chiang, J. W. Bode, TCI Mail 2011, 149, 2 – 17; e) Z.-Q. Rong, W.
Zhang, G.-Q. Yang, S.-L. You, Curr. Org. Chem. 2011, 15, 3077 –
3090; f) C. D. Campbell, K. B. Ling, A. D. Smith in N-Hetero-
cyclic Carbenes in Transition Metal Catalysis and Organocatal-
ysis (Ed.: C. S. J. Cazin), Springer, Berlin, 2011, p. 263; g) H. U.
Vora, P. Wheeler, T. Rovis, Adv. Synth. Catal. 2012, 354, 1617 –
1639; h) X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511 –
3522.
[12] a) A. Ishii, H. Tsuruta, T. Ootsuka, Y. Kuriyama, M. Yasumoto,
K. Inomiya, K. Ueda, Patent WO 018991A1, 2006; b) G.
Kokotos, Y.-H. Hsu, J. E. Burke, C. Baskakis, C. G. Kokotos,
V. Magrioti, E. A. Dennis, J. Med. Chem. 2010, 53, 3602 – 3620;
c) G. Kokotos, B. Johansen, V. Magrioti, M. Tsakos, Patent WO
039365A1, 2011; d) K. Graham, G. Kettschau, R. Lesche, A.
Gromov, N. Bçhnke, J. Habfeld, Patent WO 073286A1, 2011.
[13] a) Ref. [9]; b) D. T. Cohen, B. Cardinal-David, K. A. Scheidt,
Angew. Chem. 2011, 123, 1716 – 1720; Angew. Chem. Int. Ed.
2011, 50, 1678 – 1682.
[14] J. Mahatthananchai, P. Zheng, J. W. Bode, Angew. Chem. 2011,
123, 1711 – 1715; Angew. Chem. Int. Ed. 2011, 50, 1673 – 1677.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Asymmetric Fluorination
Y.-M. Zhao, M. S. Cheung, Z. Lin,*
J. Sun*
&&&& — &&&&
Enantioselective Synthesis of b,g-
Unsaturated a-Fluoroesters Catalyzed by
N-Heterocyclic Carbenes (NHCs)
NHC meets F: NHC-bound enolates
undergo a catalytic asymmetric fluorina-
tion reaction to b,g-unsaturated a-fluo-
roesters, which are obtained with good
efficiency and stereoselectivity (see
scheme, N-fluorobenzenesulfonimide).
The strategy overcomes possible chal-
lenges, such as fluorination in g position
and difluorination. Experimental evidence
combined with DFT calculations provides
insight into the reaction mechanism.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!