Enantioselective fluorination of β-ketoamides catalyzed by Ar-BINMOL-derived salan-copper complex

Article abstract of DOI:10.1002/adsc.201400603

A facile and powerful enantioselective construction of C-F containing molecules was successfully developed through asymmetric fluorination of β-ketoamides catalyzed by Ar-BINMOL-derived salan-Cu^II system (Ar-BINMOL=1,1'-Binaphthalene-2-α-arylmethanol-2'-ol, Cu = copper). The present catalytic system exhibited excellent enantioselectivity and a broad substrate scope for indanone-derived β-ketoamides under mild conditions (up to 99% ee and 99% yields). Notably, the biomimetic salan-copper complex was demonstrated for the first time to be a highly efficient catalyst in the fluorination of β-ketoamides. Experimental results and mechanistic studies indicated that both excess amount of copper salt and electrophilic attack of cationic fluorine to activated methylene assisted by amide group on the β-ketoamides were key factors for high yield and excellent enantioselectivity, respectively, in this enantioselective fluorination, which was controlled by the two-point binding between the salan-copper complex with cyclic β-ketoamides and hydrogen-bonding activation of the electrophilic fluorinating reagent.

Full text of DOI:10.1002/adsc.201400603

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DOI: 10.1002/adsc.201400603
Enantioselective Fluorination of b-Ketoamides Catalyzed by Ar-
À
BINMOL-derived Salan Copper Complex
Long-Sheng Zheng,a Yun-Long Wei,a Ke-Zhi Jiang,a Yuan Deng,a
Zhan-Jiang Zheng,a and Li-Wen Xua,b,*
a
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal
University
Fax : (+86)-571-28868915; e-mail: liwenxu@hznu.edu.cn
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education (MOE), and School of Chemistry and
b
Chemical Engineering, Shaanxi Normal University, Xi’an 710062, P. R. China
E-mail: licpxulw@yahoo.com
Received: June 21, 2014; Revised: September 6, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400603.
Abstract: A facile and powerful enantioselective
construction of C F containing molecules was suc-
and medicinal chemistry as well as modern material
science.[2,3] Especially, the unique electronic proper-
ties, size, hydrophobic/lipophilicity, and promising hy-
drogen-bonding activity of a fluorine atom can dra-
matically influence chemical reactivity and make or-
À
cessfully developed through asymmetric fluorina-
tion of b-ketoamides catalyzed by Ar-BINMOL-de-
rived salan–CuII system (Ar-BINMOL=1,1’-Bi-
naphthalene-2-a-arylmethanol-2’-ol, Cu = copper).
The present catalytic system exhibited excellent
enantioselectivity and a broad substrate scope for
indanone-derived b-ketoamides under mild condi-
tions (up to 99% ee and 99% yields). Notably, the
biomimetic salan-copper complex was demonstrat-
ed for the first time to be a highly efficient catalyst
in the fluorination of b-ketoamides. Experimental
results and mechanistic studies indicated that both
excess amount of copper salt and electrophilic
attack of cationic fluorine to activated methylene
assisted by amide group on the b-ketoamides were
key factors for high yield and excellent enantiose-
lectivity, respectively, in this enantioselective fluori-
nation, which was controlled by the two-point bind-
ing between the salan–copper complex with cyclic
b-ketoamides and hydrogen-bonding activation of
the electrophilic fluorinating reagent.
À
ganic molecules with C F bonds useful candidates for
drug development.[3] On this basis, the catalytic asym-
metric fluorination of carbonyl compounds have re-
ceived much attention as one of the most efficient
strategies for the synthesis of chiral fluorine-contain-
ing compounds, in which a lot of research has focused
on the development of chiral catalysts, including cin-
chona alkaloid or secondary amine-based organocata-
lysts and metal complexes.[4–8] Notably, the first break-
through related to the enantioselective construction
of a fluorinated stereogenic center through electro-
philic fluorination was made by Togni and Hinter-
mann with chiral titanium complex in 2000.[5] Follow-
ing this pioneering work, rapid advances in the cata-
lytic fluorination of a-substituted b-ketoester sub-
strates reported by several groups have led to signifi-
cant improvement over the past decade.[6] These
improved methodologies with transition metal-based
catalysts,[7,8] including palladium, nickel, or copper,
made great contributions to both organofluorine
chemistry and asymmetric catalysis. However, the
levels of the enantioselectivity were not high enough
in most cases, especially for the copper complex de-
rived from nitrogen-containing ligands, such as bis(ox-
azoline) or its analogues.[8,9] In this context, the
Keywords: Asymmetric catalysis; Fluorination; Ho-
mogeneous catalysis; Ketoamides; Salan
The catalytic and enantioselective incorporation of copper-catalyzed fluorination of a-substituted b-ke-
fluorine into organic molecules is one of the most toester substrates has been reported by Ma and
powerful and widely established strategies for the ste- Cahard early in 2004, however, the copper(II) triflate-
À
reoselective construction of chiral C F bonds in or- bis(oxazoline)-catalyzed fluorination only resulted in
ganic synthesis.[1] The resulting chiral organofluorine moderate enantioselectivity.[8a] And interestingly,
compounds are very fascinating in the field of organic there is no report on the enantioselective fluorination
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Long-Sheng Zheng et al.
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of a-substituted b-ketoesters catalyzed by salen
copper or salan copper complex. Thus the develop- enantioselective construction of fluorinated carbon
ment of new catalytic copper system for this fluorina- stereogenic centers by copper catalyst.
a highly efficient fluorination of b-ketoamides for the
À
tion reaction as well as the highly enantioselective
construction of a quaternary carbon-stereocenter[10] lytic fluorination, we designed and synthesized, as far
linked with amides is required. as possible, substituted salan ligands from enantiomer-
To achieve excellent enantioselectivity in the cata-
As part of a program focused upon the develop- ically pure diamines (commercial available cyclohex-
ment of a copper catalyst for broadly useful reactions, ane-1,2-diamine and 1,2-diphenylethane-1,2-diamine
we recently found that the Ar-BINMOL-derived with different absolute configuration) with BINOL-
salan ligand (Ar-BINMOL = 1,1’-Binaphthalene-2-a- derivatives, including 1,1’-binaphthalene-2-a-arylme-
arylmethanol-2’-ols) exhibited unusual molecular rec- thanol-2’-ols (Ar-BINMOLs),[12] 1,1’-spirobiindane-7-
ognition for the copper salt, and the corresponding a-phenylmethanol-7’-ol (SPINMOL),[13] and 1,1’-Bi-
salan copper(II) complex gave a high level of catalyt- naphthalene-2-phenyl-2’-ol,[14] where axial and sp3
À
ic efficiency in the asymmetric Henry reaction of al- central chirality as well as Schiff base and secondary
dehydes in terms of enantioselectivities and conver- amine moieties on salan, salalen, or salen ligands
sions.[11] Based on the experimental results in the were systematically modulated (L1 to L10, Scheme 1
Henry reaction, we hypothesized that the Ar- and Scheme 2). The syntheses of these ligands were
BINMOL-derived salan ligands bearing a crowded ar- accomplished by the coupling of an Ar-BINMOL-de-
omatic p-wall would exhibit remarkable and privi- rived aldehyde and a chiral diamine in analogy to the
leged enantioselectivity in various catalytic asymmet- reported procedures (see Supporting Information).[11]
ric reactions. The modulation of multifunctional Ar-
BINMOL-derived salen or salan ligands can take full
advantage of electronic and steric properties of the ar-
omatic substituents and chiral moieties (Figure 1),
which could lead to the development of highly effi-
cient ligands with excellent enantioselectivity for cata-
lytic asymmetric transformation according to the need
of improvement and modification of Ar-BINMOL-de-
rived salan or salen ligands (Figure 1 shows four pos-
sible approaches for the modular modification of Ar-
BINMOL-derived salan ligands for catalytic asym-
metric catalysis). Herein, we further advance this type
of Ar-BINMOL-derived salan ligands and report
Figure 1. Ar-BINMOL-derived salens or salans as a family
of chiral ligands for transition metal (M)-catalyzed organic
transformation. Easy modification of Ar-BINMOL-derived
salan ligands as following: (a) Chiral diamine; (b) Secondary
amine moieties; (c) C2-axial chirality and substituted group
on binaphthyl moieties; (d) Aromatic or benzylic substitu-
ents (-CH2-Ar).
Scheme 1. Various salan ligands (L1L9) derived from chiral
diamines and Ar-BINMOLs, SPINMOL, or BINOL for
copper-catalyzed fluorination.
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Enantioselective Fluorination of b-Ketoamides
Table 1. Catalytic evaluation of various salan ligands and
their analogues in the copper-catalyzed fluorination of b-ke-
toester 11 or b-ketoamide 13a[a]
Entry
X
[Cu]
Ligand
yield/%[b] ee/%[c]
/mol%
1
2
3
4
5
6
7
8
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
NHBn
5
3
3
3
3
5
3
3
3
3
3
3
3
3
5
3
5
5
U
99
99
96
99
-81(R)
-73(R)
-81(R)
-44(R)
-48(R)
-19(R)
56(R)
-29(R)
-54(R)
-12(R)
-11(R)
-45(R)
-22(R)
-24(R)
82(S)
Scheme 2. Different salan/salen ligands prepared from Ph-
BINMOL-derived aldehyde with different diamines.
99
99
99
97
99
99
94
75
68
In addition, to support the privileged structure of Ar-
BINMOL-derived salan L1, we also evaluated the
simple salan ligands L8 and L9 derived from (S,S)-cy-
clohexane-1,2-diamine with 2-hydroxybenzaldehyde
or 2,6-dichlorobenzaldehyde respectively. Notably, the
information of chirality mismatching or matching of
chiral diamine and BINOL-derivatives was also pro-
vided in Scheme 2, where various salan ligands L1 f
and L1g with different configuration was modulated
to determine the contributions from the chiral secon-
dary amine and the BINOL-derived back bone with
C2-axial chirality.
9
10
11
12
13
14
15
16
17
18
19
20
21
99
47(S)
-5(R)
99 (S)
97(S)
55(S)
NHBn 5[d]
At the outset, we chose methyl 1-oxo-2,3-dihydro-
1H-indene-2-carboxylate 11 as the model nucleophilic
partner for copper-catalyzed fluorination reaction.
Thus on the basis of this synthetic work, we tested the
copper-catalyzed fluorination of b-ketoester 11 with
(R,R,R,R)- L1 f (Scheme 2) as salan ligand for the ini-
tial establishment of optimal reaction conditions (see
the Supporting Information, Table S1-S3). Further ex-
periments conducted with a series of salan ligands
and it analogues showed in Scheme 1 and Scheme 2,
in which the catalytic results were provided in
Table 1. It was revealed that (S,S,S,S)- L1a resulted in
the desired product in same level of enantioselectivity
and yield in comparison to that of (R,R,R,R)- L1 f in
NHBn 5[e]
NHBn
5
70
11(S)
[a]
Reaction conditions: [Cu]: Cu
(OCOCF3)2·xH2O (3-
5 mol%), ligand (2.5 mol%), b-ketoester 11 or b-ketoa-
mide 13 (0.25 mmol), NFSI (1.2 eq), in xylene (1.5 mL),
all the reactions were carried out at 08C for 12 h;
Isolated yields
Determined by chiral HPLC analysis.
The copper salt is CuACHTUNTRGNEUNG(OAc)2, and the mixture solvent of
DCM/xylene (1:1) did not enhanced enantioselectivity in
this reaction.
The copper salt is CuACTHNUTRGNEUNG(OTf)2.
[b]
[c]
[d]
[e]
this reaction (Table 1, entry 1 and entry 15). After sur- poorer enantioselective activity (Entries 4 and 5, 44-
veying an array of reaction parameters including vari- 48% ee). It should be noted that there are no obvious
ous copper salts, solvent, temperature, and the ratio improvement in enantioselectivity when the aromatic
of copper to salan ligand (L1 f), we determined that group is 2-naphthyl or 4-tert-butylphenyl in this salan
Cu
ACHTUNGTRENNUNG
toester 11 in good enantioselectivity and yield (82%
ee in xylene, Entry 15 of Table 1). Notably, the ratio (SPINOL)-derived salan ligand L2 exhibited quite
of copper to salan ligand would be crucial to the reac- low enantioselectivity (19% ee, entry 6), which indi-
tion rate in xylene, for example, the order of yield cates that the rotatable binaphthyl moiety is very im-
after 12 h is 5/2.5 (99%)> 3/2.5 (90%)> 2.5/2.5 portant in the achievement of high level of enantiose-
(88%), and the enantioselectivity was also decreased lectivity in this reaction. Also interestingly, when the
in sequence as 81%>78%>77% ee. Under similar benzyl group was replaced by benzylic ether on this
reaction conditions, the structures of salan ligands salan ligand, the resulted ligand L3 was not good
L1a-e were proved to be important since the intro- enough to induce the enantioselective fluorination of
duction of larger and sterically bulky groups, such as b-ketoester 11 (Entry 7, only 56% ee). Although Kat-
methyl or tert-butyl substituent on 3,5-position of sukiꢁs salen ligands have been applied widely in vari-
phenyl ring of Ar-BINMOL-based back bone, led to ous organic transformations with high enantioselectiv-
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Long-Sheng Zheng et al.
ity,[15] its salan derivative (L4) has not achieved excel-
On the basis of this hypothesis, we sought an effec-
lent catalytic performance in any transformations. tive directing group on carbonyl compounds that
The poor result in enantioselectivity (29% ee) sug- could provide the desired control of stereochemistry
gested that the phenyl substituent on the 2-position of during fluorination of the a-position of functional
BINOL-derived the salan ligand (L4) was unfavora- molecules. Thus this new fluorination reaction is
ble because of its low enantioselective induction in based on the use of b-ketoamide 13a as a model sub-
this catalytic asymmetric reaction (Entry 8).
strate, an activated methylene compound with N-H
To confirm the special role of chiral cyclohexane- moiety on amide featuring multi-point binding. Nota-
1,2-diamine moiety on the Ar-BINMOL-derived bly, although advances in enantioselective fluorination
salan, (S,S)-1,2-diphenylethane-1,2-diamine (DPEN)- of b-ketoesters have been achieved, there is almost
derived salan L5 was employed as ligand in this reac- no successful study on enantioselective fluorination of
tion. As expected, L5 was not suitable ligand because b-ketoamides. The only example reported by Du and
of only moderate enantioseleectivity (Entry 9, 54% coworkers[9] suggested that the amide motif could not
ee). We also evaluated the effect of altering the salan serve as an advantageous group in copper-catalyzed
ligand by changing the secondary amine to imine or fluorination because of decreased enantioselectivity
tertiary amine on the diamine moiety. Although these in comparison to b-ketoester analogues.
ligands, L6 (Scheme 1) and L10 (Scheme 2), look pos-
With the promising results achieved by salanACHTUNGTRENNUNG(1 f)-
sibly effective in the achievement of highly enantiose- Cu catalyst in hand (Entry 15 of table 1), we contin-
lective fluorination, the reaction proceeded at a quite ued to investigate the effects of solvent, temperature,
low level of enantioselectivity (5-12% ee, entries 10, and various metal salts on enantioselective fluorina-
11, and 17). Thus it was reasonable to conclude that tion of b-ketoamide 13a (see Table S4 of Supporting
the salan ligand bearing secondary amine would be Information). Fortunately, we were pleased to observe
responsible for the well-organized transition state pro- that under the optimal reaction conditions described
moted by hydrogen bonding. Additionally, further op- above, the b-ketoamide 13a containing benzylic
timization of the salan ligand focused on the construc- amide was found to be an ideal structure in the enan-
tion of unsymmetrical salan ligand (L7), and the tioselective fluorination, which could be a model reac-
study of chirality matching (L1 f and L1g of tion to support the powerful potential of salanACHTUNGTRENNUNG(L1 f)-
Scheme 2). However, no improvement or even dimin- Cu complex with noncovalent interaction in this reac-
ished enantioselectivity was obtained when these tion. The desired fluorinated product was formed in
salan ligands were employed (Entries 12 and 16). As almost perfect yield and enantioselectivity (99% yield
a supplement, we also evaluated the catalytic activity and 99% ee, Entry 18 of Table 1). Notably, the abso-
of simple salan ligand L8 and diamine L9 (Entries 13 lute configuration of product 14a was determined by
and 14), and the reaction results supported the neces- X-ray diffraction analysis.[17]
sary modulation of Ar-BINMOL-derived salan ligand
The efficiency of this protocol is also illustrated in
with crowded aromatics. In the development of con- the fluorination of b-ketoamide 13a with NFSI on
cept of macromolecular catalysis, List and coworkers a preparative scale using 2.5 mol% of salan ligand
very recently have described that a macromolecular (Scheme 3, equation 1). The product 14a of this reac-
SPINOL-derived chiral phosphoric acid with potential tion was obtained in excellent yield and enantioselec-
p-p stacking interaction enables long-range control to tivity. Prompted by the excellent activity of salan-
induce enantioselectivity on the nanoscale.[16]
ACHTUNGTREN(NGNU L1 f)-Cu catalyst system in this reaction, we then in-
To summarize the above results, the key initial ob- vestigated the fluorination of 13a with low catalyst
servations were: (1) The hydrogen bonding would be loading. Surprisingly, when b-ketoamide 13a was used
a positive factor in the enantioselective copper-cata- a model substrate in the copper-catalyzed fluorina-
lyzed fluorination, as the secondary amine moiety of tion, even with 0.4 mol% of salan ligand L1 f, the re-
salan ligand played a crucial role in term of enantio- action could also proceed smoothly in the presence of
selectivity; (2) The rotatable aromatic p-wall/substi- 0.8 mol% of copper salt (calculated for salan-copper
tuent[11a] on the Ar-BINMOL-derived partner exhibit- complex, S/C=250). As shown in Scheme 3 (equation
ed unexpected potential in this model reaction, which 2), the catalytic fluorination reaction were completed
would be explained by the existence of aromatic inter- within 12 h to afford product 14a in good isolated
actions between catalyst and substrate; (3) These ex- yields and excellent enantioselectivities (TON=248
periments also underscore the importance of chirality and TOF=20.7, 99% isolated yields, 92%ee).
matching within the ligand and chiral cyclohexane-
In light of the above experimental results and
1,2-diamine moiety. Therefore, we reasoned that the having optimized conditions to control the stereo-
noncovalent interaction including aromatic interac- chemistry of fluorination, we next examined the gen-
tion and hydrogen bonding between salan-Cu catalyst erality of the asymmetric fluorination of various b-ke-
and functional substrate could be exploited for the toamides. As highlighted in Scheme 4, the introduc-
development of highly enantioselective fluorination.
tion of electron-donating and electron-withdrawing
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Enantioselective Fluorination of b-Ketoamides
Scheme 3. Copper-catalyzed fluorination of b-ketoamide
13a to the preparative-scale synthesis of (S)-14a under the
optimized reaction conditions; and the X-ray crystal struc-
ture of 14a is provided (CCDC 1002368).
substituents on both indanone core and the amide
group uniformly gave excellent enantioselectivity by
using NFSI as the fluorination reagent (up to 99%
ee). Thus the salan-Cu derived from (R,R,R,R)- L1 f
proved to be a highly active catalyst in this fluorina-
tion and gave full conversion to the desired products.
Moreover, this protocol was highly efficient with inda-
none-derived b-ketoamides bearing N-H group and
a wide range of groups on the aryl rings, giving excel-
lent yields and enantioselectivities. In most case, the
Scheme 4. Enantioselective salan-Cu -catalyzed fluorination:
Substrate scope
fluorinated products were obtained with ee values of ble substrate in this reaction. Unfortunately, the use
ꢀ 98% (13 examples, b-ketoamides 13a-n and 13p). of acyclic b-ketoamides 13t and 13u in this reaction
The reaction is also well suited for alkyl amine-de- led to poor conversion, and only trace products were
rived b-ketoamide 13q, which led to the correspond- detected by TLC. The enantiomeric excess (ee) of the
ing product 14q in excellent yield and enantiomeric desired product 14t or 14u could not be determined
excess (99% yield, 99%ee).
because of the failure in purification of corresponding
Although there is no report on the asymmetric flu- product. The preliminary study could be an indication
orination of 13r and it is well-known that the fluori- that it is quite challenging to prepare mono-substitut-
nation of tetralone-derived b-ketoesters is a very chal- ed fluorine-containing b-ketoamides.
lenging transformation for the achievement of highly
On the basis of the above results and on spectral
enantioselective induction,[18] the fluorinated product analysis from UV-vis, fluorescence emission spectra
14r can be readily obtained with excellent yield and (FL), electrospray ionization mass spectrometry (ESI-
good enantiomeric excess (89%ee). We then tested MS), we propose a plausible mechanistic pathway to
the fluorination reaction of the tertiary amine-substi- explain the observed reactivity. As illustrated in
tuted b-ketoamide (13s) under the above-described Figure 2, the salan-Cu catalyst may be initially gener-
reaction conditions (Scheme 5). To our delight, the ated in a first step as confirmed by ESI-MS (m/z=
fluorination of 13s also resulted in high yield and ex- 942.26: [Cu(salan L1 f)Na]+). The formation of cata-
cellent enantioselectivity in the presence of Ar- lyst-substrate complex (intermediate I) derived from
BINMOL-derived salan L1 f and copper catalyst the salan-Cu catalyst and b-ketoamide would occur
system (99% yield, 98%ee). Therefore, the aliphatic quickly. Then it binds the cationic fluorine from NFSI
tertiary amide-containing b-ketoamide is also a suita- (intermediate II), which would be trapped by b-excess
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showed that the nonconvalent interaction between
salan-Cu and b-ketoester 11 is weak in comparison to
that of the formation of catalyst-ketoamide 13a com-
plex. According to the calculated results (Figure S12
of Supporting Information), the lower-energy bands
of b-ketoamide 13a showed a preferential interaction
with salan-copper complex, which would be crucial to
the achievement of a high level of enantioselectivity
in this fluorination reaction. Notably in the last,
excess amount of copper salt guaranteed the rapid
formation of salan-Cu complex and avoided the de-
composition of this catalyst in the presence of NSFI
or under the reaction conditions (see Figure S7 of
Supporting Information).
In summary, we have developed a facile enantiose-
À
lective construction of C F containing molecules
Scheme 5. Enantioselective salan-Cu -catalyzed fluorination:
aromatic b-ketoamide with tertiary amide and acylic b-ke-
toamides
through catalytic asymmetric fluorination, in which
the chiral fluorine-containing b-ketoamides would be
a type of important fluorine/amides-based candidates
for drug development. The Ar-BINMOL-derived
salan-copper complex was firstly to be demonstrated
as a highly efficient macromolecular catalyst in the
fluorination of b-ketoamides (up to 99% ee and 99%
yields). And this approach featured experimental sim-
plicity and low catalyst loadings, in which the amount
of salan ligand could reduced to the level of
0.4 mol% (TON=248). To our knowledge, the Ar-
BINMOL-derived salan ligand-based copper catalyst
system exhibits the highest level of catalytic per-
formance in term of stereoselectivity and conversion
reported to date in the fluorination of carbonyl com-
pounds. In addition, the consequence of the enzyme-
like behavior of Ar-BINMOL-derived salan-Cu com-
plex allowed us to get indirect evidence by spectra
analysis for the great potential of non-covalent inter-
actions arise from the macromolecular salan-Cu cata-
lyst and substrates, which would be useful for the ex-
ploration of the multiple non-covalent interaction-ac-
tivated transformations in the near future.
Figure 2. Proposed mechanism of the salan-Cu catalyzed flu-
orination reaction.
amount of copper salt to set up an intramolecular nu-
cleophilic attack step. The key catalytic model with
intermediate II, as supported by SI-MS studies (Fig-
ure S1-S7 of Supporting Information), involves the
two-point binding and nonconvalent interaction of
salan-Cu catalyst with both b-ketoamide and NFSI,
including the hydrogen bonding of secondary amine,
Experimental Section
General Remarks
All reagents were used as purchased unless noted otherwise.
aromatic interaction induced from benzyl moiety.[19] b-Ketoamides 13a-r were prepared according to literature
methods.[20] Ar-BINMOL-derived Salan Ligand L1a/L1 f,
On the basis of experimental results, UV-vis absorp-
tion, fluorescent spectra (FL), and HOMO–LUMO
L3, L4, L5, L6a-b, L7, L8, L9, L10 were prepared according
to literature methods,[11] and the detailed experimental pro-
calculation of b-ketoamide (see Figure S8-S12 of Sup-
cedures were provided in the Supporting Information (SI).
porting Information), the role of the amide-group on
Toluene was dried and distilled over CaH2; and THF were
b-ketoamide is suggested to be the enhancement of
distilled from sodium and benzophenone. Flash column
catalyst-substrate interaction. For FL spectra of salan
chromatography was performed over silica (200–300 mesh).
ligand L1 f (1.0ꢂ10À5 mol/L) in the presence of b-ke-
toester 11 at various concentrations in DCM, as
shown in Figure S11, the change of fluorescence emis-
1H NMR, 13C NMR, 19F NMR were respectively recorded at
400 or 500 MHz, 101 or 126 MHz and 376 or 471 MHz re-
spectively on Advance (Brucker) 400 or 500 MHz Nuclear
sion upon addition of substrate (b-ketoester 11) Magnetic Resonance Spectrometer, and were referenced to
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the internal solvent signals. Thin layer chromatography was References
performed using silica gel; F254 TLC plates and visualized
with ultraviolet light. HPLC was carried out with a Agilent
Technologies 1260 Infinity system equipped with a photo-
diode array detector. ESI mass spectra were performed on
a Trace DSQ GC/MS spectrometer. Data are reported in
the form of (m/z). High Resolution Mass Spectra (ESI-
HRMS) were operated on a micro TOF-Q II (Bruker). IR
spectra were recorded using a FTIR apparatus (Nicolot
5700). Melting point was recorded by X-4 Optimelt (Shang-
hai optical instrument factory). Optical rotation was deter-
mined by SGW-3 Digital Automatic Polarimeter (Shanghai
INESA Physico Optical instrument Co., Ltd). The absolute
configuration was determined by single-crystal X- ray. X-ray
diffraction: Data sets were collected with Bruker APEX
DUO and Bruker APEX-II CCD diffractometers. Programs
used: data collection Bruker APEX2,[21a] data reduction
Bruker SAINT, absorption correction for multi-scan, struc-
ture solution SHELX-97,[21b] structure refinement SHELXL-
97,[21b] graphics Bruker SHELXTL.[21b]
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of b-Ketoamides 13
To a flask charged with CuACHTUNGRTNEUNG(OOCCF3)2·H2O (0.01 mmol,
2.9 mg) and (R,R,R,R)- L1 f (0.005 mmol, 4.3 mg) in solution
(DCM/xylene=2:1, 0.6 mL) was stirred at room tempera-
ture until the mixture turn from blue to brown. Then the b-
ketoamide 13 (0.20 mmol in 0.4 mL DCM) was added, then
0.4 mL xylene was added and stirred 5 min at room temper-
ature. After the reaction was cooled to À408C, NFSI
(0.22 mmol, 69.3 mg) was added in a portion. Then the reac-
tion was stirred for 12 h until completion (monitored by
TLC, PE/AcOEt=4:1). The solvent was removed under
vacuum and the product 14 was isolated by flash chromatog-
raphy (PE/AcOEt 5:1 to 4:1). The absolute configuration of
compounds 14 was assigned to be (S) by analogy to the
structure determined by single-crystal X-ray analysis per-
formed on compound 14a (see the X- ray analysis section).
All the products are confirmed by GC-MS, NMR, and IR,
and representative characterization data for 14 are listed in
the Supporting Information (SI).
Acknowledgements
Support for this Project was by the National Natural Science
Founder of China (No. 21173064, 51303043, and 21472031),
and Zhejiang Provincial Natural Science Foundation of
China (LR14B030001) is appreciated. XLW thank Dr. Zheng
Xu for her help in the calculation of the HOMO–LUMO of
the substrate. XLW also thank Prof. M. Kanai (The Universi-
ty of Tokyo), Prof. Y. Lu (The National University of Singa-
pore), Prof. M. Shibasaki (The University of Tokyo and In-
stitute of Microbial Chemistry, Tokyo), and Prof. C. G. Xia
(Lanzhou Institute of Chemical Physics, CAS) for their help
in the past years.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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COMMUNICATIONS
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8
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
Enantioselective Fluorination of b-Ketoamides Catalyzed by
9
À
Ar-BINMOL-derived Salan Copper Complex
Adv. Synth. Catal. 2014, 356, 1 – 9
Long-Sheng Zheng, Yun-Long Wei, Ke-Zhi Jiang,
Yuan Deng, Zhan-Jiang Zheng, Li-Wen Xu*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!