Dual Catalytic Switchable Divergent Synthesis: An Asymmetric Visible-Light Photocatalytic Approach to Fluorine-Containing ?γ-Keto Acid Frameworks

Article abstract of DOI:10.1021/acs.joc.8b02316

Herein, we describe a novel and efficient method for constructing a series of fluorine-containing ?γ-keto acid derivatives through combining visible-light photoredox catalysis and chiral Lewis acid catalysis. With this dual catalytic strategy, a variety of chiral ?γ-keto amides containing a gem-difluoroalkyl group and a series of fluorine-containing α,β-unsaturated-?γ-keto esters were successfully constructed with high stereoselectivities, respectively. A series of experiments showed that the chemoselectivity of this process was highly dependent on the fluorine reagents besides the Lewis acid catalysts. This approach facilitates rapid access to ?γ-keto acid derivatives, an important class of precursors for pharmaceuticals, plasticizers, and various other additives.

Full text of DOI:10.1021/acs.joc.8b02316

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Article
Dual Catalytic Switchable Divergent Synthesis: An Asymmetric Visible-light
Photocatalytic Approach to Fluorine-containing #-Keto Acid Frameworks
Hui Liang, Guo-Qiang Xu, Zhi-Tao Feng, Zhu-Yin Wang, and Peng-Fei Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02316 • Publication Date (Web): 03 Dec 2018
Downloaded from http://pubs.acs.org on December 3, 2018
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Dual Catalytic Switchable Divergent Synthesis: An Asymmetric
Visible-light Photocatalytic Approach to Fluorine-containing γ-Keto
Acid Frameworks
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Hui Liang, Guo-Qiang Xu, Zhi-Tao Feng, Zhu-Yin Wang, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China
O
OEt
F
O
O
O
F F
O
PC Rh
R=OEt
PC Rh
R=NR'2
N
Ar Br
+
N
NR'2
N
R
N
Ar
N
F
F
N
Ar
O
Me
Me
Me
up to 79% yield
up to >19:1 E/Z
up to 97% yield
up to >99% ee
ABSTRACT
Herein, we describe a novel and efficient method for constructing a series of fluorine-containing
γ-keto acid derivatives through combining visible-light photoredox catalysis and chiral Lewis acid
catalysis. With this dual catalytic strategy, a variety of chiral γ-keto amides containing a
gem-difluoroalkyl group and a series of fluorine-containing α,β-unsaturated-γ-keto esters were
successfully constructed with high stereoselectivities, respectively. A series of experiments showed that
the chemoselectivity of this process was highly dependent on the fluorine reagents besides the Lewis
acid catalysts. This approach facilitates rapid access to γ-keto acid derivatives, an important class of
precursors for pharmaceuticals, plasticizers, and various other additives.
KEYWORDS
visible-light photocatalysis, chiral Lewis acid catalysis, asymmetric difluoroalkylation, γ-keto acid
derivatives
INTRODUCTION
1
2
Fluorine-containing organic substances have been widely used as pharmaceuticals, agrochemicals,
3
4
materials and tracers for positron emission tomography due to their unique physical, chemical and
5
1-4
biological properties . The great demand of fluoro-organic compounds
continues to attract
researchers’ interests to develop new catalytic transformations for the incorporation of various fluorine
6
7
bearing groups. Recently, a number of methodologies, including the asymmetric ones, have been
2
,8
established and successfully applied into building a variety of bioactive molecules . Nevertheless, the
9
methods for enantioselective incorporation of a difluoroalkyl group into organic molecules and the
stereoselective construction of fluorine-bearing olefin skeletons,10 which also play important roles in
medicinal and pesticide chemistry (Figure 1), still remain quite limited.
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H
O
S
N
O
S
N
N
CF2H
CO Me
CF2H
H
2
N
N
N
Pantoprazol
Me
MeO
OMe
Sedaxane
(Syngenta)
F3C
CF2H
F
F
NH2
Thiazopir herbicide
N
F
HO
O
N
F
O
Ar
R1
S
R2
0
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0
Me
N
O
Me
N
HN
O
F
N
H
F
O
N
N
O
N
HO
CN
N
CF2H
iPr
Protein synthesis
inhibitor
Dow, 2010, Insecticide
Gemcitabine
NHAc
HIV-1 therapeutic agent
Figure 1.Some fluorine-containing bioactive molecules.
Over the past decade, visible-light-induced photoredox catalysis has become a powerful method to
generate reactive open-shell species from abundant native functional groups under mild conditions.11
When coupled with another catalytic cycle in a dual catalytic system, this catalytic protocol could
provide a novel and efficient access to asymmetric transformations associated with highly reactive
radical intermediates,12 which would bring new opportunity for the catalytic asymmetric incorporation
of fluorine-containing groups. In 2009, MacMillan and co-workers first elegantly established the mild
catalytic asymmetric α-trifluoromethylation of aldehydes via combining visible-light photoredox
catalysis and chiral enamine catalysis.13a Very recently, Xiao and co-workers reported the
enantioselective di-/perfluoroalkylation of β-ketoesters enabled by cooperative photoredox/nickel
catalysis.13d Different from this dual catalysis strategy, Melchiorre’s group utilized
visible-light-induced phase transfer catalysis to realize the enantioselective perfluoroalkylation of
β-ketoesters,13b and Meggers’ group realized the catalytic asymmetric perfluoroalkylation of ketones
with a chiral iridium photoredox catalyst13c. Several key advances have recently been made in this
area,13-15 however, reports on the catalytic asymmetric difluoroalkylation reaction under mild
visible-light irradiation conditions remain rare.7
Scheme 1.The stereoselective construction of fluorine-containing γ-keto acid derivatives by dual
catalytic strategy.
O
F
F
R'
N
R = NR'2
N
R'
(a)
Difluoroalkylation
N
Ph
O
O
O
Me
N
Ph
PC Rh
-keto amides
Br
+
R
N
F
F
Me
O
OEt
O
R = OEt
N
(b)
F
Difluoroalkylation/
Elimination
N
Ph
Me

-unsaturated--keto esters
Our earlier work on the catalytic enantioselective α-fluorination via the chiral iridium complex
catalysis prompted us to explore novel and efficient catalytic methods for the asymmetric
difluoroalkylation reaction.16 Based on our continuous interest in visible-light photoredox catalysis,17
we successfully developed a visible-light photoredox catalytic enantioselective difluoroalkylation of
ketones with commercially available bromodifluoroacetamides to construct a series of γ-keto amides
bearing a gem-difluoromethylene group via coupling with chiral Lewis acid catalysis. (Scheme 1a)
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This mild dual catalytic strategy provides a novel and straightforward method for the synthesis of
fluorine-containing gamma-keto acid derivatives that are widely used as precursors for pharmaceuticals
and plasticizers,18 and building blocks or starting materials for a wide number of compounds.
Furthermore, another kind of valuable fluorine-containing α,β-unsaturated-γ-keto ester was obtained
under the similar dual catalytic conditions by only replacing bromodifluoroacetamide with ethyl
bromodifluoroacetate as the fluorine resource (Scheme 1b). A series of experiments demonstrated that
the chemoselectivity of this reaction was highly dependent on the reactivity of fluorinated reagent.
1
1
1
1
1
1
1
1
1
1
2
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RESULTS AND DISCUSSION
Initially, we tested the feasibility of the reaction of 2-acyl imidazole 1a and bromodifluoroacetamide 2a
in the presence of stoichiometric amounts of diisopropylethylamine (DIPEA) in acetone at room
temperature under visible-light irradiation with a 23 W compact fluorescent lamp (CFL).
Disappointingly, no desired difluoroalkylation product 3a was observed when the chiral-at-metal
catalyst Λ-IrS was employed as both the photoredox and Lewis acid catalyst (Table 1, entry 1). An
extra photocatalyst added to the reaction mixture did not change the result，either (Table 1, entry 2).
Fortunately, when the chiral Lewis acid catalyst Λ-IrS was replaced by a rhodium complex Λ-RhS, the
expected product 3a was obtained in 42% yield with excellent enantioselectivity (Table 1, entry 3),
which can be mainly attributed to the increased ligand exchange kinetics of the rhodium complexes
involved in the catalytic cycle.19 Encouraged by the results, a series of photocatalysts were tested and
Ir(ppy)
entries 4-6). Further screening of bases and solvents showed that DIPEA was the optimal base while
the inorganic bases did not catalyze this transformation, and CH Cl was the optimal solvent for this
2 6
(dtbbpy)(PF ) gave satisfactory yield and enantioselectivity (88% yield and 97% ee) (Table 1,
2
2
reaction to give the product 3a in 94% yield with 98% ee (Table 1, entries 7-13). Control experiments
showed that photocatalyst, Λ-RhS, an organic amine base and visible-light were all essential to this
reaction (Table 1, entries 14-17).
Table 1. Optimization of the reaction conditionsa
PF6
S
t-Bu
N
M
N
Me
C
C
N
N
O
O
O
F
F
Ph
Br
PC (1 mol %), LA (4 mol %)
N
N
N
+
N
base (2 equiv), solvent (0.05 M)
N
F
F
N
Ph
O
23 W CFL, rt, N2
Me
Me
a
Me
1
2a
3a
S
t-Bu


-IrS (M = Ir)
-RhS (M = Rh)
b
c
Entry
LA
PC
base
solvent
acetone
acetone
acetone
acetone
yield (%)
ee (%)
1
2
3
4
Λ-IrS
Λ-IrS
DIPEA
DIPEA
DIPEA
DIPEA
0
0
n.a.
n.a.
97
Ru(bpy)
3
3
(PF
6
6
3
)
2
2
Λ-RhS
Λ-RhS
Ru(bpy)
(PF
)
42
78
fac-Ir(ppy)
97
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Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
/
Ir(ppy)
2
(dtbbpy)PF
6
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
acetone
acetone
88
87
94
78
36
42
92
trace
trace
0
97
97
Ir(dF(CF )ppy)
3
2
(dtbbpy)PF
6
Ir(ppy)
Ir(ppy)
Ir(ppy)
Ir(ppy)
Ir(ppy)
Ir(ppy)
Ir(ppy)
2
2
2
2
2
2
2
(dtbbpy)PF
(dtbbpy)PF
(dtbbpy)PF
(dtbbpy)PF
(dtbbpy)PF
(dtbbpy)PF
(dtbbpy)PF
/
6
6
6
6
6
6
6
CH
2
Cl
2
98
DCE
THF
DMF
98
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
97
1
0
96
11
Et
HPO
PO
3
N
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
98
1
1
1
1
1
2
3
4
5
6
K
2
4
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
K
3
4
DIPEA
DIPEA
/
Ir(ppy)
Ir(ppy)
Ir(ppy)
2
2
2
(dtbbpy)PF
(dtbbpy)PF
(dtbbpy)PF
6
6
6
0
Λ-RhS
Λ-RhS
0
1
7d
DIPEA
0
aReaction conditions: 1a(0.1 mmol), 2a (0.2 mmol), a chiral Lewis acid (4 mol %), a photocatalyst (1
b
mol %) and a base (2.0 equiv) in a solvent (2.0 mL) at rt under irradiation with a 23 W CFL. Isolated
c
d
yield after chromatography. Determined by HPLC on a chiral stationary phase. Under dark. DIPEA =
diisopropylethylamine; bpy 2,2′-bipyridine; ppy 2-phenylpyridine; dtbbpy
,4′-di-tert-butyl-2,2′-bipyridine; n.a. = not applicable.
We then evaluated the generality of this visible-light photocatalytic difluoroalkylation process under
=
=
=
4
the optimized reaction conditions described in Table 1, entry 7. We first studied the substrate scope of a
variety of 2-acyl imidazole 1. As shown in Scheme 2a, various substrates with either
electron-withdrawing groups or electron-donating groups at the para-position of the benzene ring were
smoothly converted to the corresponding difluoroalkylation products in good to excellent yields
(
71-97%) with excellent enantioselectivities (97-99%) (3b-3k). In addition, different substituents at the
meta-position of the benzene ring such as a methyl group and a chloride atom were also well tolerated
under the standard conditions to furnish the desirable products with 86-93% yields and 98-99% ee (3l,
3m). However, when a substrate with a methyl group at the ortho-position of the benzene ring was
applied to this α-difluoroalkylation process, only a trace amount of the difluoroalkylation product (3na)
was detected. Multifunctional substrates were also suitable for this reaction to furnish the
corresponding products in good yields with excellent enantioselectivities (3o-3r). A product bearing a
heteroaryl framework was also successfully synthesized, as shown for the thiophenyl-substituted
adduct 3s. Finally, this reaction could be scaled up to 1.0 mmol, and the large scale reaction proceeded
well to furnish 3a in 90% yield with excellent enantioselectivity (98% ee).The absolute configuration
was unequivocally confirmed by single crystal X-ray crystallographic analysis of the compound 3l.
(
see the Supporting Information, CCDC: 1574697).
Scheme 2. Substrate scope of difluoroalkylation reactiona,b,c
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O
O
Ir(ppy)2(dtbbpy)(PF6) (1 mol %)
O
F
F
R1
N
R1
-RhS (4 mol %)
N
Ar
Br
N
R1
+
N
DIPEA (2 equiv.)
DCM(0.05 M)
F
F
R1
N
Ar
O
N
Me
1
R1
23 W CFL, rt, N2
2
3a-z
a) substrate scope of 2-acyl imidazoles
Me
O
F
F
R = H (3a), 94% yield, 98% ee
(1a, 1 mmol) 90% yield, 98% ee
R = Cl (3b), 71% yield, 97% ee
R = Br (3c), 86% yield, 98% ee
R = F (3d), 89% yield, 98% ee
R = CF3 (3e), 89% yield, 98% ee
R = Me (3f), 94% yield, 98% ee
R = tBu (3g), 97% yield, 99% ee
R = OMe (3h), 90% yield, >99% ee
R = OEt (3i), 85% yield, 99% ee
R = Ph (3j), 96% yield, 98% ee
R = SMe (3k), 95% yield, 98% ee
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
O
R
Me
O
F
F
Me
O
F
F
Me
O
F
F
N
N
F
Me
N
N
F
N
N
N
N
N
O
N
O
N
O
N
O
Me
O
OMe
Cl
Me
3m, 93% yield, 98% ee
OMe
3
l, 86% yield, 98% ee
3n, trace
3o, 95% yield, 97% ee
Me
O
F
F
Me
O
F
F
Me
O
F
F
N
N
N
N
N
Me
O
F F
N
N
N
N
O
N
O
N
O
N
O
MeO
OMe
OEt
OCOEt
3q, 73% yield, 93% ee
S
OMe
O
3
p, 95% yield, 97% ee
3r, 87% yield, 97% ee
3s, 80% yield, 98% ee
b) substrate scope of bromodifluoroacetamides
O
F
F
O
O
O
S
O
F
F
F
F
F
F
N
N
N
N
N
N
N
N
N
Ph
O
N
Ph
O
N
Ph
O
N
Ph
O
Me
Me
Me
Me
3
t, 84% yield, 97% ee
3u, 80% yield, 98% ee
3v, 94% yield, 98% ee
3w, 92% yield, 98% ee
Ph
Boc
O
F
F
N
O
F
F
N
O
F
F
N
N
N
N
N
N
N
Ph
O
N
Ph
O
N
Ph
O
3la
Me
Me
Me
3
x, 72% yield, 98% ee
3y, 90% yield, 98% ee
3z, 87% yield, 97% ee
aReaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Ir(ppy)
(dtbbpy)(PF
) (1 mol %), Λ-RhS (4 mol %),
2
6
b
and DIPEA (2.0 equiv) in CH
2
Cl
2
(2.0 mL) at r.t. under irradiation with a 23 W CFL. Isolated yield
c
after chromatography. Enatioselectivity was determined by HPLC on a chiral stationary phase.
We then probed the substrate scope of bromodifluoroacetamides 2, which could introduce different
gem-difluoroalkyl groups into the final products. As shown in Scheme 2b, it was found that
bromodifluoroacetamides 2 bearing a five-membered or seven-membered ring worked well with 1,
affording 3t and 3u in good yields (80-84%) with excellent enantioselectivities (97-98% ee),
respectively. Some other cyclic amides containing multiple heteroatoms were also suitable substrates
for this reaction, furnishing the corresponding difluoroalkylation products in good yields with high
enantioselectivities (3v-3y). Furthermore, N,N-diethylaectamide provided the product 3z in 87% yield
and 97% ee.
Very interestingly, besides constructing a series of γ-keto amides bearing gem-difluoroalkyl groups,
this mild protocol could also be applied to synthesize monofluorinated adducts. As shown in scheme 3,
when bromofluoroacetamide 5 was used as the fluorinated reagent, a fluorine-containing γ-keto amide
derivative 6 was successfully obtained in 80% yield and excellent enantioselectivity (>99% ee) with
good diastereoselectivity (dr = 14:1) through this dual catalytic system.
Scheme 3. Monofluoroalkeylation of 2-acyl imidazole
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O
F
O
O
O
Ir(ppy)2(dtbbpy)(PF6) (1 mol %)
N
N
N
Ph Br
+
-RhS (4 mol %)
N
DIPEA (2 equiv.)
CH2Cl2 (0.05 M)
N
Ph
O
N
F
O
Ph
Ph
23 W CFL, rt, N2
6, 80% yield, >99% ee
4
5
dr = 14:1
Having synthesized a variety of valuable fluorine-containing γ-keto amide derivatives, we then
questioned whether or not this protocol could be used to prepare more useful fluorine-containing γ-keto
esters. To our surprising, when commercially available ethyl bromodifluoroacetate 7 was used as the
fluorine resource under the optimized conditions, a fluorine-containing α,β-unsaturated keto ester
derivative 8 was smoothly obtained while the expected γ-keto esters bearing a gem-difluoromethene
group was not detected. Although the monofluoroalkene skeleton is widely found in various bioactive
molecules, which can also be applied to various organic transformations, reports for the stereoselective
synthesis of this valuable skeleton are very rare.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Therefore, we decided to optimize this method for the efficient synthesis of these versatile
monofluoroalkene synthons using this dual catalytic strategy(see Table S1 in Supporting Information
for details).Under the optimized reaction conditions, we examined the scope of 2-acyl imidazoles 1
(
Scheme 4). It was found that substrates with various halo-substituents (F, Cl, Br) or electron-donating
groups such as alkyls, alkoxys, phenyl and methylthio at the para- or meta-positions of the benzene
ring were smoothly converted to the desired monofluoroalkenes in good yields (60-79%) with good to
excellent E/Z ratios (10:1->19:1) (8a-8l). However, ortho-substituents had a significant effect on this
reaction, for instance, product 8m was not formed and 8n was generated in 53% yield with low E/Z
ratio (7:1). Bifunctional and thiophenyl-substituted substrates were also suitable for this reaction to
give the corresponding products (8o-8q). Furthermore, this reaction also worked for the substrate
containing an aliphatic substituent to afford product 8r with a reduced yield (35%) as mixtures of E and
Z isomers (E/Z=1.5:1). Finally, this reaction could be scaled up from 0.1 mmol to 1.0 mmol, and the
large scale reaction proceeded well to furnish 8a in 78% yield (E/Z >19:1).
Scheme 4. Substrate scope of monofluoroalkenylation reactiona,b,c
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Ru(bpy)3(PF6)2 (2 mol %)
O
CO2Et
F
O
rac-RhS (8 mol %)
R
N
N
+
BrCF2CO2Et
DIPEA (2 equiv.)
acetone (0.05 M)
23 W CFL, rt, N2
N
R
N
Me
8
Me
O
1
7
Me
CO2Et R = H (8a), 79% yield, E/Z >19:1
R = tBu (8f), 74% yield, E/Z = 12:1
g), 74% yield, E/Z >19:1
N
(1 mmol) 78% yield, E/Z >19:1
8
F
R = OMe (
R = Cl (8b), 69% yield, E/Z >19:1
R = Br (8c), 65% yield, E/Z >19:1
R = F (8d), 79% yield, E/Z = 15:1
R = Me (8e), 65% yield, E/Z = 13:1
R = OEt ( ), 68% yield, E/Z = 10:1
8h
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R = Ph ( ), 76% yield, E/Z >19:1
8j
R = SMe ( ), 74% yield, E/Z = 12:1
8i
R
O
CO2Et
F
Me
O
CO2Et
F
Me
O
CO2Et
Me
O
CO2Et
Me
N
N
N
N
F
F
N
N
N
Cl
N
Me
Cl
Me
8
k, 62% yield, E/Z = 14:1 8l, 75% yield, E/Z = 15:1
8m, n.r.
8n, 53% yield, E/Z = 7:1
Me
O
CO2Et
O
CO Et
Me
2
N
Me
O
CO Et
N
2
F
F
O
CO Et
Me
2
N
N
F
N
N
F
N
N
Me
OEt
S
CO2Et
o, 48% yield, E/Z = 8:1 8p, 56% yield, E/Z >19:1 8q, 73% yield, E/Z >19:1 8r, 35% yield, E/Z = 1.5:1
O
8
aReaction conditions: 1 (0.1 mmol), 7 (0.2 mmol), Ru(bpy)
(PF
)
2
(2 mol %), rac-RhS (8 mol %), and
3
6
b
DIPEA (2.0 equiv) in acetone (2.0 mL) at r.t. under irradiation with a 23 W CFL. Ratio of E/Z was
1
c
determined by H NMR. Isolated yield after chromatography.
To understand the reaction mechanism, several control experiments were performed (Scheme 5).
When 2, 2, 6, 6-tetramethyl-1-piperidinyloxy (TEMPO) was added to the reaction mixture of 1a and
2
aor7, no product was generated. However, TEMPO-trapped product 9 was obtained in 90% yield and
2% yield, which indicated that the reaction involved a radical process and α-carbonyl carbon radical
7
was
formed
from
the
imidazole
substrate
(Scheme
5a,
eq
1).
When
l-(phenylsulfonyl)-2-phenyl-2-propene 10 was added into the reaction mixture under the standard
conditions, the difluoroalkylation reaction was also completely inhibited, and product 11 was isolated
in 29% yield, indicating that the difluoroacetyl radical was generated in this dual catalytic process
(
Scheme 5a, eq 2). The similar result was found when radical trapping reagent 10 was added into the
mixture of 1a and 7 (Scheme 5a, eq 3). In addition, a competition reaction using electronically different
substrates 1 with 2a afforded 3e/3h in a ratio of 3.6:1, which suggested that the difluoroalkyl radical
species attacked the more stable electron-rich enolate intermediate more favorably in the catalytic
system (Scheme 5b, eq 4). This competition reaction was also applied to the monofluoroalkenylation
reaction and gave us the same result (Scheme 5b, eq 5). Furthermore, the light-dark interval
experiments were performed according the general catalysis procedure, which showed that this dual
catalytic process was highly dependent on the visible-light (see the Supporting Information). To
understand the rate-determining step for the photoreaction, the reaction of a 1:1 mixture of 1a and
2
d -1a with 2a was carried out under the conditions described for Scheme 5c. The intermolecular KIE
was found to be 5.7, indicating that the deprotonation of 1 was a turnover limiting step of the
difluoroalkylation reaction (Scheme 5c). The quantum yield of the difuoroalkylation reaction was
determined as 2.00 which indicated that the reaction might be involved in a chain process. (see the
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Supporting Information)
Scheme 5.Mechanistic investigations.
a) Evidence for the formation of radical intermediates
O
N
9
O
TEMPO (3 equiv.)
standard conditions
N
(
1)
1a
+
2a or 6
3a or 8a
+
N
Ph
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
(
No detected)
0% for 2; 72% for 7
SO2Ph
Ph
F
F
(10, 2 equiv.)
N
(2)
(3)
1
a
+
+
2a
7
3a
+
Ph
standard conditions
O
F
(
No detected)
11, 29%
SO2Ph
Ph
F
(10, 2 equiv.)
OEt
1
a
8a
+
Ph
standard conditions
O
2
6% yield
1
2, 10% yield
b) Competitive experiment
O
O
O
F
F
N
Ar
Br
standard conditions
N
N
(
4)
N
+
N
F F
N
Ar
O
Me
2a
Me
Ar = 4-CF3C6H4 (0.1 mmol)
Ar = 4-OMeC6H4 (0.1 mmol)
3e:3h = 3.6:1
O
CO2Et
F
X
N
O
7
standard conditions
(5)
N
N
+
(0.2 mmol)
N
X = Cl, 0.1 mmol
X = Me, 0.1 mmol
X
8b:8e = 2.1:1
c) KIE experiment
O
O
F F
O
N
Ph
Br
standard conditions
N
N
(6)
+
N
N
R
R
F
F
N Ph H(D)O
Me
Me
a R=H (0.1 mmol)
d2-1a R=D (0.1 mmol)
1
2a (0.2 mmol)
64% yield
KH:KD = 5.7:1
In addition, we performed a series of Stern-Volmer quenching experiments to verify the initial
electron transfer (SET) step of the photoredox process (Figure 2 and Supporting Information). These
results showed that only the intermediate Rh-enolate but no other component is capable of quenching
the excited state of the photosensitizer Ir(ppy)
2 6
(dtbbpy)PF , and this is most likely through a reductive
quenching cycle. Also we tested the redox potentials of the substrates and the Rh-enolate intermediate,
ox
and confirmed that Rh-enolate (E
p
= 0.49 V vs SCE in CH
2 2
Cl ) has a significantly lower oxidation
ox
peak potential than 1a (E
p
= 2.25 V vs SCE in CH
2
Cl ) (see the Supporting Information).
2
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9
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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4
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5
5
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5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 6
Figure 2. Stern−Volmer quenching experiments of RhS-1a with photoexcited Ir(ppy) (dtbbpy)PF (0.1
0
mM, λex = 345 nm, λem = 552 nm). I and I are respective luminescence intensities in the absence and
presence of the indicated concentrations of the corresponding quencher.
2
1
The elimination step of the reaction is the E1cB process. According to the literature reports , when
the carbanion is more stable which means the acidity of the α-position of the leaving group is
stronger, making deprotonation irreversible, elimination process in the reaction is easier to
undergo.To explore the chemoselectivity of this transformation, we calculated the pKa of the substrate
1
a and two kinds of difluoroalkylated products by utilizing Gaussian 09W. The calculation showed that
the amide containing the gem-difluoromethene group (pKa = 30.4) was less acidic than the
corresponding ester (pKa = 28.2), which was in accord with experiment results that γ-keto amides
bearing a gem-difluoromethylene group could be smoothly obtained, but the corresponding γ-keto
esters were not detected (Figure 3). And we also found that the pKa reduced siginificantly and the
ΔpKa was increased from 2.2 to 3.1 when catalyst RhS was coordinated with these two kinds of
difluoroalkylated compounds, which means γ-keto ester bearing a gem-difluoromethylene group was
much easier to deprotonation and enolization.
O
O
F
F
[Rh]
N
O
F
F
N
Ph
N
R
R
N
H
Me
H
N Ph
Me
H
O
N Ph
Me
H
O
R = amine, 30.4
R = OEt, 28.2
R = amine, 20.0
R = OEt, 16.9
Calculated pKa
1, 31.5
Figure 3.DFT calculations.
Based on the obtained results, a reaction mechanism for this dual catalytic process was proposed, as
descripted in Figure 4. Substrate 1 first binds with rhodium complex RhS in a bidentate fashion to
provide intermediate I, which is deprotonated to generate a rhodium enolate complex II. A single
n+
electron transfer (SET) process between the excited photocatalyst ([PC*] ) and the electron-rich
intermediate II which serves as the reducing agent20 generates the highly reducing [PC](n-1)+, which in
turn transfers a single electron to the fluorine reagent 2 or 7. Generated difluoroacetyl radical III is
subsequently added to the electron-rich double bond of the rhodium enolate complex II to give the
2
2
radical intermediate IV accompanied by the stereoselective control. The radical intermediate IV is a
strong oxidizing agent and eitherdirectly reduces the fluorine reagentsvia chain propagation or
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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5
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5
5
6
quenches photoexcited catalyst to produce the reduced photoredox sensitizer, which is simultaneously
converted to an Rh-coordinated difluoroalkylated product V. For the difluoroalkylation reaction, the
desired product 3 is directly released through the ligand exchange of coordinated product V by another
substrate 1 molecule (Path A). For the other pathway, a deprotonation step occurs to generate the
2 2
second rhodium enolate complex VI when BrCF CO Et is used as the reaction partner, and an E1CB
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
elimination process occurs to intermediate VI to give VII. Finally, the monofluoroalkene product 8 is
released through the ligand exchange of coordinated product VII by another substrate 1 molecule (Path
B).
O
F
R
F
III
PC]n+
[
[
Rh]
[
Rh]
O
O
F
F
R1
N
R
[PC*]n+
II
N
photoredox
catalysis cycle
R1
N
O
2 or 4
N
II
IV
Br
H
O
e
O
R
PC](n-1)+
[
F
II
F
[
Rh]
[Rh]
N
III
O
F
F
1
R1
N
asymmetric
catalysis cycle
R
RhS
-2 x MeCN
N
I
R1
N
O
V
3
1
Path A
8
base
1
baseH
[
Rh]
[
Rh]
O
O
CO2Et
F
F F
Path B
baseH
N
OEt
N
R1
N
R1
O
N
VI
VII
base+HF
Figure 4. Proposed Reaction Mechanism
CONCLUSION
In summary, we have developed a novel and mild method for the chemo, stereo-selective synthesis
of fluorine-containing γ-keto acid derivatives via merging visible-light photocatalysis and Lewis acid
catalysis. Corresponding difluoroalkylated products were prepared in high yields with excellent
enantioselectivites, and the monofluoroalkenes were obtained in good yields with good to excellent E/Z
ratios. The calculations demonstrated the reason for the high chemoselectivity of the reaction between
2
-acyl imidazoles and fluorine reagents.
EXPERIMENTAL SECTION
General information. All glassware was thoroughly oven-dried. Chemicals and solvents were either
purchased from commercial suppliers or purified by standard techniques. Thin-layer chromatography
(TLC) plates were visualized by exposure to ultraviolet light and/or staining with phosphomolybdic
acid followed by heating on a hot plate. Flash chromatography was carried out using silica gel
(200-300 mesh). H NMR, 19F NMR and 13C NMR spectra were recorded on a Bruker AM-400 (400
1
MHz). The spectra were recorded in CDCl3 as solvent at room temperature, H, Fand 13C NMR
1
1
chemical shifts are reported in ppm relative to the residual solvent peak. The residual solvent signals
were used as references and the chemical shifts were converted to the TMS scale (CDCl3: δH = 7.26
1
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19
ppm, δC = 77.00 ppm). Data for H NMR and F NMR are reported as follows: chemical shift (δ ppm),
mul-tiplicity (s = singlet, d = doublet, t = triplet, q=quartet, m = mul-tiplet, dd = doublet), integration,
coupling constant (Hz) and assignment. Data for 13C NMR are reported as chemical shift and
mul-tiplicity (d = doublet, t = triplet, dd = doublet). HRMS were performed on a Bruker Apex II mass
instrument (ESI).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
16
23
2
-acyl imidazoles and bromodifluoroacetamides were prepared according to reported procedures.
Synthesis of 2-phenylacetic-2,2-d acid: A mixture of phenylacetic acid (3.0 g; 20.0 mmol),
2
anhydrous potassium carbonate (11.06 g; 80.0 mmol) and deuterium oxide (15 mL) was refluxed
overnight. After cooling to room temperature, the reaction mixture was acidified to pH 2 with 6 N
hydrochloric acid. The solution was extracted with diethyl ether (3 x 50 mL) and the combined organic
layers were washed with brine, dried over Na
2
SO
4
and evaporated under reduced pressure. This
acid as a white solid in 90% yield. All
procedure was repeated to give 2-phenylacetic-2,2-d
2
spectroscopic data were in agreement with the literature report.24
General catalysis procedure for the synthesis of product 3: A dried 10 mL reaction tube was
charged with the catalyst Λ-RhS (4 mol %, 3.5 mg), Ir(ppy)
corresponding 2-acyl imidazole 1 (0.1 mmol, 1.0 equiv.). The tube was purged with nitrogen and then
CH Cl (2.0 mL), bromodifluoroacetamides 2 (0.2 mmol, 2.0 equiv.) and DIPEA (0.2 mmol, 25.9 mg,
.0 equiv.) were added via a syringe. The reaction mixture was degassed by three cycles of
freeze-pump-thaw. After the mixture was thoroughly degassed, the reaction was then irradiated under a
3W CFL. After completion of the reaction, the crude mixture was purified by flash chromatography
2 6 2
(dtbbpy)(PF ) (1 mol %, 0.9 mg) and the
2
2
2
2
(
silica gel, mixtures of petroleum ether/ethyl acetate) to afford the pure product 3.
General catalysis procedure for the synthesis of product 3a at a 1 mmol scale: A dried reaction
tube was charged with the catalyst Λ-RhS (4 mol %, 35 mg), Ir(ppy)
and the corresponding 2-acyl imidazole 1 (1 mmol, 200 mg). The tube was purged with nitrogen and
then CH Cl (20 mL), bromodifluoroacetamides 2 (2 mmol, 2.0 equiv.) and DIPEA (2 mmol, 259 mg,
.0 equiv.) were added via a syringe. The reaction mixture was degassed by three cycles of
freeze-pump-thaw. After the mixture was thoroughly degassed, the reaction was then irradiated under a
3W CFL. After completion of the reaction, the crude mixture was purified by flash chromatography
silica gel, petroleum ether:ethyl acetate = 1.5:1) to afford the pure product 3a (324 mg, 90% yield, 98%
ee).
R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-3-phenyl-1-(piperidin-1-yl)butane-1,4-dione (3a) white
2 6 2
(dtbbpy)(PF ) (1 mol %, 9 mg)
2
2
2
2
(
(
solid, 94% yield, 34.1 mg (PE:EA = 1.5:1), mp = 160-162 C; Enantiomeric excess established by
HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm, hexane/isopropanol =
2
0
60:40, flow rate 1.0 mL/min, 20 C, tr (major) = 17.0 min, tr (minor) = 8.5 min.) [α]
D
= -150.00 (c 1.0,
1
CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 7.60-7.58 (m, 2H), 7.36-7.30 (m, 3H), 7.10 (s, 1H), 6.92 (s,
1H), 6.16 (dd, J = 27.6 Hz, 7.6 Hz, 1H), 3.93 (s, 3H), 3.74-3.54 (m, 3H), 3.40-3.37 (m, 1H), 1.63-1.58
1
9
(
m, 6H); F NMR (376 MHz, CDCl
3
): δ -94.0 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.3 (dd, J = 289.52
1
3
1
Hz, 26.32 Hz, 1F); C{ H}NMR (100 MHz, CDCl ): δ 185.7 (d, J = 9 Hz), 161.0 (t, J = 28 Hz), 142.3
3
1
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2
2
2
2
2
2
2
3
3
3
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5
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5
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5
5
6
(
d, J = 6 Hz), 130.8, 129.3, 128.4, 128.2, 127.2, 118.1 (dd, J = 268 Hz, 254 Hz), 55.3 (dd, J = 25 Hz,
+
17 Hz), 46.5 (t, J = 6 Hz), 44.5, 36.0, 26.3, 25.5, 24.2; HRMS (ESI) for C19
62.1675, found 362.1674.
H
22
F
2
N
3
O
2
[M+H] calcd.
3
(R)-3-(4-chlorophenyl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-dione
(3b)white solid, 71% yield, 28.0 mg (PE:EA = 1.5:1), mp = 122-124 C; Enantiomeric excess
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
established by HPLC analysis using a Chiralpak IC-3 column, ee = 97% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t (major) = 11.8 min, t (minor) = 7.7 min.)
): δ 7.53 (d, J = 8.0 Hz, 2H), 7.32 (d, J =
.4 Hz, 2H), 7.12 (s, 1H), 6.96 (s, 1H), 6.14 (dd, J = 26.8 Hz, 7.6 Hz, 1H), 3.95 (s, 3H), 3.78-3.54 (m,
H), 3.42-3.37 (m, 1H), 1.66-1.58 (m, 6H); 19F NMR (376 MHz, CDCl
): δ -94.0 (dd, J = 289.52 Hz,
.52 Hz, 1F), -103.4 (dd, J = 289.52 Hz, 26.32 Hz, 1F); C{ H}NMR (100 MHz, CDCl ): δ 185.3 (d, J
9 Hz), 160.8 (t, J = 28 Hz), 142.1 (d, J = 6 Hz), 134.4, 132.2, 129.5, 129.4, 128.6, 127.4, 118.0 (dd, J
268 Hz, 254 Hz), 54.6 (dd, J = 25 Hz, 17 Hz), 46.6 (t, J = 6 Hz), 44.6, 36.1, 26.3, 25.5, 24.2; HRMS
r
r
20
1
[α]
D
2 2 3
= -150.00 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl
8
3
7
3
1
3
1
3
=
=
+
2 3 2
(ESI) for C19H21ClF N O [M+H] calcd. 396.1285, found 396.1277；
(R)-3-(4-bromophenyl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-dione
3c) white solid, 80% yield, 35.0 mg (PE:EA = 1.5:1), mp = 120-122C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t (major) = 10.6 min, t (minor) = 7.0 min.)
): δ7.47-7.45 (m, 4H), 7.12 (s, 1H), 6.96 (s,
H), 6.13 (dd, J = 26.8 Hz, 8.0 Hz, 1H), 3.96 (s, 3H), 3.74-3.54 (m, 3H), 3.42-3.37 (m, 1H), 1.66-1.58
(
r
r
2
0
1
[α]
D
2 2 3
= -120.90 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl
1
1
9
(m, 6H); F NMR (376 MHz, CDCl
3
): δ -94.0 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.4 (dd, J = 289.52
Hz, 26.32 Hz, 1F); C{ H}NMR (100 MHz, CDCl ): δ 185.2 (d, J = 10 Hz), 160.8 (t, J =28 Hz), 142.1
d, J = 6 Hz), 132.5, 131.6, 129.9, 129.5, 127.4, 122.7, 118.0 (dd, J = 269 Hz, 255 Hz), 54.7 (dd, J = 24
1
3
1
3
(
[M+H]+
2 3 2
Hz, 17 Hz), 46.6 (t, J = 6 Hz), 44.6, 36.1, 26.3, 25.5, 24.2; HRMS (ESI) for C19H21BrF N O
calcd. 440.0780, found 440.0776.
(
R)-2,2-difluoro-3-(4-fluorophenyl)-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-dione(
d)white solid, 89% yield (PE:EA = 1.5:1), 33.8 mg, mp = 74-76 C; Enantiomeric excess established
by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t (major) = 10.9 min, t (minor) = 6.7 min.)
): δ 7.56 (dd, J = 5.6 Hz, 8.4 Hz, 2H), 7.12
(s, 1H), 7.03 (t, J = 8.4 Hz, 2H), 6.96 (s, 1H), 6.15 (dd, J = 26.8 Hz, 7.6 Hz, 1H), 3.96 (s, 3H),
.76-3.54 (m, 3H), 3.42-3.37 (m, 1H), 1.66-1.56 (m, 6H); 19F NMR (376 MHz, CDCl
): δ -94.2 (dd, J
= 289.52 Hz, 7.52 Hz, 1F), -103.5 (dd, J = 289.52 Hz, 26.32 Hz, 1F), -114.0--114.1 (m, 1F);
3
r
r
2
0
1
[α]
D
2 2 3
= -155.00 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl
3
3
1
3
1
C{ H}NMR (100 MHz, CDCl
3
): δ 185.6 (d, J = 9 Hz), 162.8 (d, J = 246 Hz), 160.9 (t, J = 28 Hz),
142.2 (d, J = 5 Hz), 132.5 (d, J = 8 Hz), 129.4, 127.3, 126.6, 118.0 (dd, J = 269 Hz, 255 Hz), 115.2,
5
4.4 (dd, J = 24 Hz, 17 Hz), 46.6 (t, J = 6 Hz), 44.6, 36.1, 26.3, 25.5, 24.3; HRMS (ESI) for
+
C
19
H
21
F
3
N
3
O
2
[M+H] calcd. 380.1580, found 380.1588.
(R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)-3-(4-(trifluoromethyl)phenyl)butane-
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1
,4-dione(3e)white solid, 89% yield (PE:EA = 1.5:1), 38.3 mg, mp = 135-137 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 90:10, flow rate 1.0 mL/min, 20C, t (major) = 6.4 min, t (minor) = 4.9 min.)
): δ 7.73 (d, J = 8.0 Hz, 2H), 7.61 (d, J =
.0 Hz, 2H), 7.13 (s, 1H), 6.98 (s, 1H), 6.25 (dd, J = 26.8 Hz, 7.6 Hz, 1H), 3.97 (s, 3H), 3.74-3.54 (m,
r
r
2
0
1
[α]
D
2 2 3
= -123.00 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl
8
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
3H), 3.41-3.38 (m, 1H), 1.65-1.60 (m, 6H); F NMR (376 MHz, CDCl
3
): δ -62.7 (s, 3F), -93.8 (dd, J =
89.52 Hz, 7.52 Hz, 1F), -103.0 (dd, J = 289.52 Hz, 30.08 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
1
):
2
3
δ 184.9 (d, J = 9 Hz), 160.7 (t, J = 28 Hz), 142.1 (d, J = 6 Hz), 135.1, 131.2, 130.3 (q, J = 32 Hz),
1
29.6, 128.0, 127.5, 125.2 (t, J = 4 Hz), 122.6, 118.1 (dd, J = 269 Hz, 255 Hz), 55.0 (dd, J = 24 Hz, 17
+
Hz), 46.6 (t, J = 6 Hz), 44.6, 36.1, 26.3, 25.5, 24.2; HRMS (ESI) for C20
30.1548, found 430.1539.
R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)-3-(p-tolyl)butane-1,4-dione
H
21
F
5
N
3
O
2
[M+H] calcd.
4
(
(3f)
white solid, 94% yield, 35.1 mg (PE:EA = 1.5:1), mp = 139-141 C; Enantiomeric excess established
by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 290 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 21.8 min, t
). H NMR (400 MHz, CDCl ): δ 7.47 (d, J = 7.6 Hz, 2H), 7.16 (d, J =
.0 Hz, 2H), 7.09 (s, 1H), 6.90 (s, 1H), 6.11 (dd, J = 27.2 Hz, 8.0 Hz, 1H), 3.92 (s, 3H), 3.74-3.53 (m,
r
(minor) = 11.0 min.)
20
1
[
α]
D
= -151.46 (c 1.0, CH
2
Cl
2
3
8
3
2
19
H), 3.41-3.36 (m, 1H), 2.30 (s, 3H), 1.64-1.58 (m, 6H); F NMR (376 MHz, CDCl
3
): δ -94.2 (dd, J =
):
89.52 Hz, 7.52 Hz, 1F), -103.4 (dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
1
3
δ 185.7 (d, J = 9 Hz), 161.0 (t, J = 28 Hz), 142.2 (d, J = 6 Hz), 138.0, 130.6, 129.3, 129.1, 127.6, 127.1,
1
2
18.1 (dd, J = 268 Hz, 254 Hz), 54.9 (dd, J = 24 Hz, 17 Hz), 46.5 (t, J = 6 Hz), 44.5, 35.9, 26.3, 25.5,
+
24 2 3 2
4.2, 21.0; HRMS (ESI) for C20H F N O [M+H] calcd. 376.1831, found 376.1823.
(R)-3-(4-(tert-butyl)phenyl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-di
one (3g) white solid, 97% yield (PE:EA = 1.5:1), 40.3 mg, mp = 196-198 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 99% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 13.7 min, t
): δ 7.51 (d, J = 8.0 Hz, 2H), 7.36 (d, J =
.0 Hz, 2H), 7.11 (s, 1H), 6.91 (s, 1H), 6.13 (dd, J = 27.6 Hz, 8.0 Hz, 1H), 3.94 (s, 3H), 3.75-3.54 (m,
r
(minor) = 7.7 min.)
2
0
1
[
α]
D
2 2 3
= -120.34 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl
8
3
2
1
9
H), 3.40-3.36 (m, 1H), 1.64-1.58 (m, 6H), 1.28 (s, 9H); F NMR (376 MHz, CDCl
3
): δ -93.9 (dd, J =
89.52 Hz, 7.52 Hz, 1F), -103.2 (dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
1
):
3
δ 185.8 (d, J = 10 Hz), 161.1 (t, J = 28 Hz), 150.9, 142.3 (d, J = 5 Hz), 130.4, 129.3, 127.6, 127.1,
1
25.4, 118.2 (dd, J = 268 Hz, 254 Hz), 54.8 (dd, J = 24 Hz, 17 Hz), 46.6 (t, J = 6 Hz), 44.5, 36.1, 34.4,
+
3
1.2, 26.3, 25.5, 24.3; HRMS (ESI) for C23
H
30
F
2
N
3
O
2
[M+H] calcd. 418.2301, found 418.2305.
(R)-2,2-difluoro-3-(4-methoxyphenyl)-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-dion
e (3h) white solid, 90% yield (PE:EA = 1.5:1), 35.3 mg, mp = 126-128 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = >99% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
r
(major) = 18.2 min, t (minor) = 11.5 min.)
2
0
1
[α]
D
= -168.55 (c 1.0, CH
2
Cl
2
). H NMR (400 MHz, CDCl ): δ 7.50 (d, J = 8.4 Hz, 2H), 7.10 (s, 1H),
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
6
.92 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.09 (dd, J = 27.2, 8.0 Hz, 1H), 3.94 (s, 3H), 3.76-3.71 (m, 4H),
3.67-3.54 (m, 2H), 3.42-3.36 (m, 1H), 1.65-1.58 (m, 6H); 19F NMR (376 MHz, CDCl
): δ -94.3 (dd, J
3
1
3
1
=
289.52 Hz, 7.52 Hz, 1F), -103.5 (dd, J = 289.52 Hz, 26.32 Hz, 1F); C{ H}NMR (100 MHz, CDCl ):
3
δ 185.8 (d, J = 9 Hz), 161.1 (t, J = 28 Hz), 159.5, 142.2 (d, J = 6 Hz), 131.9, 129.3, 127.1, 122.6, 118.1
(dd, J = 268 Hz, 253 Hz), 113.8, 55.0, 54.4 (dd, J = 24, 17 Hz), 46.5 (t, J = 6 Hz), 44.5, 36.0, 26.3, 25.5,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
24.2; HRMS (ESI) for C20
H
23
F
2
N
3
O
3
Na [M+Na] calcd. 414.1600, found 414.1599.
(R)-3-(4-ethoxyphenyl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-dione(
3
i) white solid, 85% yield, 34.3 mg (PE:EA = 1.5:1), mp = 150-152 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 99% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t (major) = 19.1 min, t (minor) = 12.4 min.)
). H NMR (400 MHz, CDCl ): δ 7.49 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H),
.93 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.08 (dd, J = 27.2, 8.0 Hz, 1H), 3.98 (q, J = 7.6 Hz, 2H), 3.94 (s,
r
r
2
0
1
[α]
D
= -146.60 (c 1.0, CH
2
Cl
2
3
6
3
1
9
H), 3.76-3.54 (m, 3H), 3.42-3.36 (m, 1H), 1.65-1.58 (m, 6H), 1.38 (t, J = 7.6 Hz, 3H); F NMR (376
): δ -94.4 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.6 (dd, J = 289.52 Hz, 26.32 Hz, 1F);
C{ H}NMR (100 MHz, CDCl ): δ 185.9 (d, J = 9 Hz), 161.1 (t, J = 29 Hz), 158.9, 142.2 (d, J = 5 Hz),
MHz, CDCl
3
1
3
1
3
1
31.9, 129.3, 127.1, 122.4, 118.1 (dd, J = 268 Hz, 253 Hz), 114.3, 63.2, 54.4 (dd, J = 24, 17 Hz), 46.6
+
(t, J = 6 Hz), 44.5, 36.1, 26.3, 25.5, 24.3, 14.7; HRMS (ESI) for C21
H
26
F
2
N
3
O
3
[M+H] calcd.
4
06.1937, found 406.1930.
(R)-3-([1,1'-biphenyl]-4-yl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-di
one (3j) white solid, 96% yield, 41.8 mg (PE:EA = 1.5:1), mp = 164-166 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 260 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
r
(major) = 16.2 min, t (minor) = 11.1 min.)
2
0
1
[α]
D
= -130.79 (c 1.0, CH
2
Cl
2
). H NMR (400 MHz, CDCl ): δ 7.67 (d, J = 8.0 Hz, 2H), 7.56 (t, J =
3
8
.8 Hz, 4H), 7.40 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H), 6.92 (s, 1H), 6.21 (dd, J =
2
7.2, 7.6 Hz, 1H), 3.95 (s, 3H), 3.77-3.55 (m, 3H), 3.42-3.37 (m, 1H), 1.63-1.58 (m, 6H); 19F NMR
(376 MHz, CDCl
3
): δ -93.9 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.1 (dd, J = 289.52 Hz, 26.32 Hz, 1F);
C{ H}NMR (100 MHz, CDCl ): δ 185.6 (d, J = 10 Hz), 161.0 (t, J = 28 Hz), 142.3 (d, J = 5 Hz),
41.0, 140.4, 131.2, 129.8, 128.6, 127.3, 127.2, 127.1, 127.0, 118.2 (dd, J = 268 Hz, 254 Hz), 54.9 (dd,
1
3
1
3
1
26 2 3 2
J = 24, 17 Hz), 46.6 (t, J = 6 Hz), 44.5, 36.1, 26.3, 25.5, 24.2; HRMS (ESI) for C25H F N O
[M+H]+
calcd. 438.1988, found 438.1982.
(R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-3-(4-(methylthio)phenyl)-1-(piperidin-1-yl)butane-1,4-
dione (3k) white solid, 95% yield, 39.8 mg (PE:EA = 1.5:1), mp = 147-149 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 19.3 min, t
). H NMR (400 MHz, CDCl ): δ 7.50 (d, J = 8.4 Hz, 2H), 7.21 (d, J =
.0 Hz, 4H), 7.10 (s, 1H), 6.93 (s, 1H), 6.11 (dd, J = 27.2, 7.6 Hz, 1H), 3.94 (s, 3H), 3.74-3.54 (m, 3H),
r
(minor) = 11.6 min.)
2
0
1
[α]
D
= -121.38 (c 1.0, CH
2
Cl
2
3
8
3.42-3.37 (m, 1H), 2.43 (s, 3H), 1.65-1.58 (m, 6H); 19F NMR (376 MHz, CDCl
): δ -94.2 (dd, J =
):
3
89.52 Hz, 7.52 Hz, 1F), -103.4 (dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
1
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δ 185.5 (d, J = 10 Hz), 160.9 (t, J = 28 Hz), 142.1 (d, J = 5 Hz), 138.8, 131.2, 129.4, 127.3, 127.2,
126.1, 118.1 (dd, J = 268 Hz, 254 Hz), 54.7 (dd, J = 24, 17 Hz), 46.5 (t, J = 6 Hz), 44.5, 36.0, 26.3,
+
2
5.4, 24.2, 15.3; HRMS (ESI) for C20
H
24
F
2
N
3
O
2
S [M+H] calcd. 408.1552, found 408.1545.
(R)-3-(3-chlorophenyl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-dione
(3l) white solid, 86% yield, 34.2 mg (PE:EA = 1.5:1), mp = 160-162 C; Enantiomeric excess
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
established by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t (major) = 11.2 min, t (minor) = 8.2 min.)
). H NMR (400 MHz, CDCl ): δ 7.59 (s, 1H), 7.48-7.47 (m, 1H),
.30-7.25 (m, 2H), 7.12 (s, 1H), 6.96 (s, 1H), 6.14 (dd, J = 26.8 Hz, 7.6 Hz, 1H), 3.95 (s, 3H),
r
r
20
1
[α]
D
= -142.30 (c 1.0, CH
2
Cl
2
3
7
3
=
.74-3.54 (m, 3H), 3.42-3.37 (m, 1H), 1.66-1.58 (m, 6H); 19F NMR (376 MHz, CDCl
): δ -93.8 (dd, J
3
1
3
1
289.52 Hz, 7.52 Hz, 1F), -103.1 (dd, J = 289.52 Hz, 26.32 Hz, 1F); C{ H}NMR (100 MHz, CDCl ):
3
δ 185.0 (d, J = 10 Hz), 160.8 (t, J = 28 Hz), 142.1 (d, J = 6 Hz), 134.1, 132.8, 130.6, 129.5(3), 129.4(6),
1
4
3
29.2, 128.4, 127.4, 118.0 (dd, J = 269 Hz, 255 Hz), 54.6 (dd, J = 24 Hz, 17 Hz), 46.5 (t, J = 6 Hz),
2 3 2
H21ClF N O
[M+H]+ calcd. 396.1285, found
4.6, 36.0, 26.3, 25.4, 24.2; HRMS (ESI) for C19
96.1277.
(R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)-3-(m-tolyl)butane-1,4-dione
(3m)
white solid, 94% yield, 35.1 mg (PE:EA = 1.5:1), mp = 158-160 C; Enantiomeric excess established
by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 17.9 min, t
). H NMR (400 MHz, CDCl ): δ 7.39-7.38 (m, 2H), 7.25-7.21 (m, 1H),
7.13-7.10 (m, 2H), 6.91 (s, 1H), 6.11 (dd, J = 27.2 Hz, 7.6 Hz, 1H), 3.93 (s, 3H), 3.75-3.53 (m, 3H),
r
(minor) = 10.9 min.)
2
0
1
[α]
D
= -174.25 (c 1.0, CH
2
Cl
2
3
3
.42-3.36 (m, 1H), 2.34 (s, 3H), 1.64-1.58 (m, 6H); 19F NMR (376 MHz, CDCl
3
): δ -94.0 (dd, J =
):
1
2
89.52 Hz, 7.52 Hz, 1F), -103.2 (dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
3
δ 185.7 (d, J = 10 Hz), 161.0 (t, J = 28 Hz), 142.2 (d, J = 5 Hz), 138.0, 131.3, 130.5, 129.3, 129.0,
1
4
3
28.2, 127.9, 127.1, 118.1 (dd, J = 268 Hz, 254 Hz), 55.1 (dd, J = 24 Hz, 17 Hz), 46.5 (t, J = 6 Hz),
+
4.5, 36.0, 26.3, 25.5, 24.2, 21.3; HRMS (ESI) for C20
76.1828.
H
24
F
2
N
3
O
2
[M+H] calcd. 376.1831, found
(R)-3-(3,4-dimethoxyphenyl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)butane-1,4-
dione (3o) white solid, 95% yield, 39.8 mg (PE:EA = 1:1), mp = 69-71 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 97% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 50:50, flow rate 1.0 mL/min, 20C, t
r
(major) = 24.3 min, t
). H NMR (400 MHz, CDCl ): δ 7.15-7.11 (m, 3H), 6.95 (s, 1H), 6.84
(d, J = 8.0 Hz,1H), 6.08 (dd, J = 27.2, 7.6 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H), 3.74-3.56
m, 3H), 3.42-3.39 (m, 1H), 1.64-1.58 (m, 6H); 19F NMR (376 MHz, CDCl
): δ -94.4 (dd, J = 289.52
Hz, 7.52 Hz, 1F), -103.4 (dd, J = 289.52 Hz, 26.32 Hz, 1F); C{ H}NMR (100 MHz, CDCl ): δ 185.6
d, J = 10 Hz), 160.9 (t, J = 29 Hz), 148.8, 148.4, 142.1 (d, J = 5 Hz), 129.2, 127.1, 123.3, 122.7, 118.0
r
(minor) = 17.6 min.)
2
0
1
[α]
D
= -161.91 (c 1.0, CH
2
Cl
2
3
(
3
1
3
1
3
(
(dd, J = 268 Hz, 254 Hz), 113.3, 110.6, 55.6, 55.5, 54.5 (dd, J = 24, 17 Hz), 46.4 (t, J = 6 Hz), 44.4,
+
3
5.9, 26.2, 25.4, 24.1; HRMS (ESI) for C21
H
26
F
2
N
3
O
4
[M+H] calcd. 422.1886, found 422.1880.
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(
R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)butane-1,
4-dione (3p) white solid, 95% yield (PE:EA = 1:2), 42.7 mg, mp = 160-162 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 97% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 0.7 mL/min, 20C, t
r
(major) = 51.8 min, t
): δ 7.14 (s, 1H), 6.99 (s, 1H), 6.81 (s, 2H),
6.07 (dd, J = 27.2, 7.6 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 6H), 3.82 (s, 3H), 3.75-3.61 (m, 3H), 3.44-3.41
r
(minor) = 60.8 min.)
2
0
1
[α]
D
2 2 3
= -125.77 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
m, 1H), 1.65-1.59 (m, 6H); 19F NMR (376 MHz, CDCl
3
): δ -94.1 (dd, J = 289.52 Hz, 7.52 Hz, 1F),
): δ 185.5 (d, J = 9 Hz),
-103.3 (dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
1
3
1
60.9 (t, J = 28 Hz), 152.8, 142.2 (d, J = 5 Hz), 137.7, 129.3, 127.2, 126.0, 118.1 (dd, J = 269 Hz, 254
Hz), 107.7, 60.6, 56.0, 54.5 (dd, J = 24, 17 Hz), 46.5 (t, J = 6 Hz), 44.5, 36.0, 26.3, 25.5, 24.2; HRMS
+
(ESI) for C22
H
28
F
2
N
3
O
5
[M+H] calcd. 452.1992, found 452.1978.
Ethyl
R)-4-(3,3-difluoro-1-(1-methyl-1H-imidazol-2-yl)-1,4-dioxo-4-(piperidin-1-yl)butan-2-yl)-2-ethoxyben
(
zoate (3q) white solid, 73% yield, 34.6 mg (PE:EA = 2:1), mp = 115-117 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 93% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
r
(major) = 17.2 min, t (minor) = 13.8 min.)
2
0
1
[α]
D
= -84.000 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl ): δ 7.72 (d, J = 8.0 Hz, 1H), 7.21-7.18 (m,
2
2
3
2
2
1
H), 7.10 (s, 1H), 6.97 (s, 2H), 6.16 (dd, J = 27.2, 7.6 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.18-4.11 (m,
H), 3.94 (s, 3H), 3.72-3.56 (m, 3H), 3.45-3.40 (m, 1H), 1.64-1.58 (m, 6H), 1.44 (t, J = 7.2 Hz, 3H),
19
.34 (t, J = 7.2 Hz, 3H); F NMR (376 MHz, CDCl
3
): δ -94.1 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.1
): δ 184.9 (d, J = 9 Hz), 166.1,
dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
1
(
3
1
2
60.7 (t, J = 28 Hz), 157.9, 142.0 (d, J = 6 Hz), 136.1, 131.0, 129.4, 127.4, 122.5, 120.4, 118.0 (dd, J =
69 Hz, 254 Hz), 115.6, 64.4, 60.6, 55.2 (dd, J = 24, 17 Hz), 46.5 (t, J = 6 Hz), 44.5, 35.9, 26.2, 25.4,
+
24.1, 14.4, 14.1; HRMS (ESI) for C24
H
30
F
2
N
3
O
5
[M+H] calcd. 478.2148, found 478.2139.
(R)-3-(2,3-dihydrobenzofuran-5-yl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)buta
ne-1,4-dione (3r) white solid, 87% yield, 35.1 mg (PE:EA = 1.5:1), mp = 70-72 C; Enantiomeric
excess established by HPLC analysis using a Chiralpak IC-3 column, ee = 97% (HPLC: IC-3, 260 nm,
hexane/isopropanol = 50:50, flow rate 1.0 mL/min, 20C, t
r
r
(major) = 19.6 min, t (minor) = 11.7 min.)
2
0
1
[α]
D
= -98.607 (c 1.0, CH
2
Cl
2
). H NMR (400 MHz, CDCl ): δ 7.41 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H),
3
7
2
.12 (s, 1H), 6.94 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.07 (dd, J = 27.2, 7.6 Hz, 1H), 4.53 (t, J = 8.8 Hz,
H), 3.95 (s, 3H), 3.77-3.54 (m, 3H), 3.41-3.36 (m, 1H), 3.25-3.12 (m, 2H), 1.66-1.58 (m, 6H); 19F
NMR (376 MHz, CDCl
3
): δ -94.3 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.6 (dd, J = 289.52 Hz, 26.32
Hz, 1F); C{ H}NMR (100 MHz, CDCl ): δ 186.0 (d, J = 9 Hz), 161.1 (t, J = 28 Hz), 160.2, 142.2 (d,
J = 6 Hz), 130.8, 129.3, 127.3, 127.2, 127.1, 122.2, 118.1 (dd, J = 268 Hz, 254 Hz), 109.2, 71.3, 54.5
1
3
1
3
(dd, J = 25, 17 Hz), 46.6 (t, J = 6 Hz), 44.5, 36.1, 29.5, 26.3, 25.5, 24.3; HRMS (ESI) for
+
C
21
H
24
F
2
N
3
O
3
[M+H] calcd. 404.1780, found 404.1772.
(R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-(piperidin-1-yl)-3-(thiophen-3-yl)butane-1,4-dione
3s) white solid, 80% yield, 29.6 mg (PE:EA = 1.5:1), mp = 149-151 C; Enantiomeric excess
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established by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 17.7 min, t
). H NMR (400 MHz, CDCl ): δ 7.47 (s, 1H), 7.30-7.28 (m, 2H), 7.14
(d, J = 0.4 Hz, 1H), 6.96 (s, 1H), 6.30 (dd, J = 26.8, 8.0 Hz, 1H), 3.95 (s, 3H), 3.77-3.56 (m, 3H),
r
(minor) = 9.0 min.)
2
0
1
[α]
D
= -94.898 (c 1.0, CH
2
Cl
2
3
3
.42-3.36 (m, 1H), 1.67-1.57 (m, 6H); 19F NMR (376 MHz, CDCl
3
): δ -94.1 (dd, J = 289.52 Hz, 7.52
): δ 185.3 (d, J =
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 1F), -102.8 (dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
1
3
1
0 Hz), 160.9 (t, J = 28 Hz), 142.2 (d, J = 5 Hz), 130.5, 129.4, 129.2, 127.3, 126.1, 125.3, 118.0 (dd, J
= 268 Hz, 255 Hz), 50.9 (dd, J = 24, 17 Hz), 46.6 (t, J = 6 Hz), 44.5, 36.1, 26.3, 25.5, 24.3; HRMS
+
(ESI) for C17
H
20
F
2
N
3
O
2
S [M+H] calcd. 368.1239, found 368.1233.
(R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-3-phenyl-1-(pyrrolidin-1-yl)butane-1,4-dione
(3t)
white solid, 84% yield (PE:EA = 1.5:1), 29.2 mg, mp = 146-148 C; Enantiomeric excess established
by HPLC analysis using a Chiralpak IC-3 column, ee = 97% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 48.9 min, t
): δ 7.58 (d, J = 7.6 Hz, 2H), 7.37-7.29 (m,
H), 7.09 (s, 1H), 6.92 (s, 1H), 6.17 (dd, J = 26.8, 8.8 Hz, 1H), 3.93 (s, 3H), 3.78-3.64 (m, 2H), 3.48 (t,
r
(minor) = 16.6 min.)
20
1
[α]
D
2 2 3
= -149.00 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl
3
J = 6.8 Hz, 2H), 1.99-1.88 (m, 2H), 1.86-1.77 (m, 2H); 19F NMR (376 MHz, CDCl
): δ -99.1 (dd, J =
):
3
1
2
89.52 Hz, 7.52 Hz, 1F), -107.0 (dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
3
δ 185.9 (d, J = 10 Hz), 161.4 (t, J = 29 Hz), 142.2 (d, J = 5 Hz), 130.7, 129.4, 128.4, 128.2, 127.3,
1
17.3 (dd, J = 266 Hz, 252 Hz), 55.0 (dd, J = 24, 18 Hz), 47.2, 46.1 (t, J = 6 Hz), 36.1, 26.2, 23.2;
+
20 2 3 2
HRMS (ESI) for C18H F N O [M+H] calcd. 348.1518, found 348.1513.
(R)-1-(azepan-1-yl)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-3-phenylbutane-1,4-dione (3u) white
solid, 80% yield, 30.0 mg (PE:EA = 1.5:1), mp = 146-148 C; Enantiomeric excess established by
HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm, hexane/isopropanol =
2
0
6
0:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 17.1 min, t
r
(minor) = 8.2 min.) [α]
D
= -169.09 (c 1.0,
1
CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 7.58 (d, J = 7.6 Hz, 2H), 7.36-7.28 (m, 3H), 7.10 (s, 1H), 6.91
(
s, 1H), 6.17 (dd, J = 27.2, 7.6 Hz, 1H), 3.93 (s, 3H), 3.78-3.72 (m, 1H), 3.64-3.53 (m, 2H), 3.43-3.36
m, 1H), 1.75-1.69(m, 4H), 1.57-1.56 (m, 4H); 19F NMR (376 MHz, CDCl
): δ -94.5 (dd, J = 289.52
): δ 185.7
d, J = 10 Hz), 162.5 (t, J = 28 Hz), 142.2 (d, J = 6 Hz), 130.8, 129.3 128.4, 128.2, 127.2, 118.1 (dd, J
(
3
13
1
Hz, 7.52 Hz, 1F), -103.1 (dd, J = 289.52 Hz, 26.32 Hz, 1F); C{ H}NMR (100 MHz, CDCl
3
(
=
268 Hz, 254 Hz), 55.4 (dd, J = 25, 17 Hz), 48.2, 47.4 (t, J = 6 Hz), 36.0, 29.4, 27.3, 26.2, 25.8;
+
HRMS (ESI) for C20
H
24
F
2
N
3
O
2
[M+H] calcd. 376.1831, found 376.1824.
(R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-1-morpholino-3-phenylbutane-1,4-dione (3v) white
solid, 94% yield, 34.0 mg (PE:EA = 1.5:1), mp = 132-134 C; Enantiomeric excess established by
HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm, hexane/isopropanol =
2
0
60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 30.7 min, t
r
(minor) = 13.3 min.) [α]
D
= -95.082 (c 1.0,
1
CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 7.58 (d, J = 7.2 Hz, 2H), 7.37-7.27 (m, 3H), 7.12 (s, 1H), 6.94
(s, 1H), 6.17 (dd, J = 26.8, 8.0 Hz, 1H), 3.94 (s, 3H), 3.76-3.60 (m, 7H), 3.55-3.49 (m, 1H); 19F NMR
376 MHz, CDCl ): δ -94.2 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.3 (dd, J = 289.52 Hz, 26.32 Hz, 1F);
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1
C{ H}NMR (100 MHz, CDCl
3
): δ 185.5 (d, J = 10 Hz), 161.4 (t, J = 29 Hz), 142.1 (d, J = 5 Hz),
130.8, 130.4, 129.5, 128.4, 127.4, 117.8 (dd, J = 267 Hz, 253 Hz), 66.6, 66.5, 55.1 (dd, J = 24, 17 Hz),
+
4
6.2 (t, J = 6 Hz), 43.4, 36.1; HRMS (ESI) for C18
364.1463.
R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-3-phenyl-1-thiomorpholinobutane-1,4-dione(3w) white
H
20
F
2
N
3
O
3
[M+H] calcd. 364.1467, found
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solid, 92% yield, 35.0 mg (PE:EA = 1.5:1), mp = 190-192 C; Enantiomeric excess established by
HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm, hexane/isopropanol =
20
6
0:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 20.5 min, t
r
(minor) = 9.0 min.) [α]
D
= -162.29 (c 1.0,
1
CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 7.57 (d, J = 6.8 Hz, 2H), 7.36-7.32 (m, 3H), 7.12 (s, 1H), 6.95
(
s, 1H), 6.16 (dd, J = 27.2, 7.6 Hz, 1H), 4.06-4.02 (m, 1H), 3.95-3.88 (m, 5H), 3.77-3.73 (m, 1H),
2
.68-2.64 (m, 4H); 19F NMR (376 MHz, CDCl
3
): δ -94.2 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.4 (dd,
): δ 185.5 (d, J = 10 Hz), 161.5 (t, J =
9 Hz), 142.1 (d, J = 5 Hz), 130.8, 130.4, 129.5, 128.5, 128.3, 127.4, 117.9 (dd, J = 268 Hz, 253 Hz),
J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}NMR (100 MHz, CDCl
1
3
2
5
20 2 3 2
5.2 (dd, J = 24, 17 Hz), 48.4 (t, J = 6 Hz), 46.1, 36.1, 28.0, 27.2; HRMS (ESI) for C18H F N O S
+
[
M+H] calcd. 380.1239, found 380.1232.
(
R)-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-3-phenyl-1-(4-phenylpiperazin-1-yl)butane-1,4-dione
(3x) white solid, 72% yield, 31.7 mg (PE:EA = 1.5:1), mp = 152-154 C; Enantiomeric excess
established by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: IC-3, 280 nm,
hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 47.5 min, t
): δ 7.59 (d, J = 7.2 Hz, 2H), 7.38-7.31 (m,
3H), 7.29-7.24 (m, 2H), 7.11 (s, 1H), 6.92-6.88 (m, 2H), 6.19 (dd, J = 27.2, 8.0 Hz, 1H), 3.96-3.91 (m,
r
(minor) = 16.7 min.)
2
0
1
[
α]
D
2 2 3
= -169.09 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl
1
9
4
H), 3.88-3.80 (m, 1H), 3.67-3.61 (m, 2H), 3.28-3.22 (m, 2H), 3.13-3.07 (m, 2H); F NMR (376 MHz,
CDCl ): δ -93.8 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -102.9 (dd, J = 289.52 Hz, 26.32 Hz, 1F);
3
13
1
3
C{ H}NMR (100 MHz, CDCl ): δ 185.5 (d, J = 9 Hz), 161.3 (t, J = 29 Hz), 150.6, 142.1 (d, J = 5 Hz),
1
1
4
30.8, 130.5, 129.4, 129.1, 128.4, 128.3, 127.3, 120.6, 117.9 (dd, J = 268 Hz, 253 Hz), 55.1 (dd, J = 24,
+
7 Hz), 49.6, 49.1, 45.4 (t, J = 6 Hz), 43.1, 36.1; HRMS (ESI) for C24
H
25
F
2
N
4
O
2
[M+H] calcd.
39.1940, found 439.1932.
tert-butyl (R)-4-(2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenylbuta-noyl)piperazine-1-ca
rboxylate (3y) white solid, 90% yield, 41.5 mg (PE:EA = 1.5:1), mp = 146-148 C; Enantiom
eric excess established by HPLC analysis using a Chiralpak IC-3 column, ee = 98% (HPLC: I
C-3, 280 nm, hexane/isopropanol = 60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 29.5 min,
2
0
1
t
r
(minor) = 18.6 min.) [α]
D
= -94.00 (c 1.0, CH
2
Cl
2
). H NMR (400 MHz, CDCl ): δ 7.58
3
(d, J = 7.6 Hz, 2H), 7.38-7.32 (m, 3H), 7.12 (s, 1H), 6.94 (s, 1H), 6.17 (dd, J = 27.2, 8.0 H
z, 1H), 3.94 (s, 3H), 3.76-3.44 (m, 6H), 3.38-3.32 (m, 2H), 1.46 (s, 9H); 19F NMR (376 MHz,
): δ -94.0 (d, J = 289.52 Hz, 1F), -103.1 (dd, J = 289.52 Hz, 26.32 Hz, 1F); 13C{ H}N
1
CDCl
3
MR (100 MHz, CDCl
3
): δ 185.5 (d, J = 9 Hz), 161.5 (t, J = 29 Hz), 154.3, 142.1 (d, J = 5
Hz), 130.8, 130.4, 129.4, 128.4, 128.3, 127.4, 117.8 (dd, J = 268 Hz, 253 Hz), 55.1 (dd, J =
+
2
4, 17 Hz), 45.4, 43.6, 36.5, 28.2; HRMS (ESI) for C23
H
29
F
2
N
4
O
4
[M+H] calcd. 463.2151, fo
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und 463.2159.
R)-N,N-diethyl-2,2-difluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenylbutanamide (3z) white
(
solid, 87% yield, 30.5 mg (PE:EA = 1.5:1), mp = 114-116 C; Enantiomeric excess established by
HPLC analysis using a Chiralpak IC-3 column, ee = 97% (HPLC: IC-3, 260 nm, hexane/isopropanol =
2
0
6
0:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 9.5 min, t
r
(minor) = 6.5 min.) [α]
D
= -170.53 (c 1.0,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 7.58 (d, J = 7.6 Hz, 2H), 7.36-7.28 (m, 3H), 7.08 (s, 1H), 6.89
(
s, 1H), 6.16 (dd, J = 26.8, 8.0 Hz, 1H), 3.91 (s, 3H), 3.62-3.53 (m, 1H), 3.51-3.44 (m, 1H), 3.43-3.36
m, 1H), 3.32-3.23 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H), 1.11 (d, J = 7.2 Hz, 3H); 19F NMR (376 MHz,
(
3
CDCl ): δ -94.9 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.7 (dd, J = 289.52 Hz, 26.32 Hz, 1F);
13
1
C{ H}NMR (100 MHz, CDCl
3
): δ 185.6 (d, J = 10 Hz), 162.1 (t, J = 29 Hz), 142.1 (d, J = 6 Hz),
1
6
30.8, 129.3, 128.3, 128.1, 127.2, 118.0 (dd, J = 268 Hz, 253 Hz), 55.3 (dd, J = 24, 18 Hz), 41.4 (t, J =
+
22 2 3 2
Hz), 36.0, 14.0, 12.1; HRMS (ESI) for C18H F N O [M+H] calcd. 350.1675, found 350.1668.
(2S,3S)-2-fluoro-1-morpholino-3-phenyl-4-(1-phenyl-1H-imidazol-2-yl)butane-1,4-dione(6) white solid,
0% yield, 30.8 mg (PE:EA = 1.5:1), dr = 14:1, mp = 184-186 C; Enantiomeric excess established by
HPLC analysis using a Chiralpak IC-3 column, ee = >99% (HPLC: IC-3, 280 nm, hexane/isopropanol
8
2
0
=
60:40, flow rate 1.0 mL/min, 20C, t
r
(major) = 35.5 min, t
r
(minor) = 24.7 min.) [α]
D
= 118.75 (c
1
1.0, CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 7.58 (d, J = 7.6 Hz, 2H), 7.36-7.28 (m, 3H), 7.08 (s, 1H),
6
.89 (s, 1H), 6.16 (dd, J = 26.8, 8.0 Hz, 1H), 3.91 (s, 3H), 3.62-3.53 (m, 1H), 3.51-3.44 (m, 1H),
1
9
3.43-3.36 (m, 1H), 3.32-3.23 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H), 1.11 (d, J = 7.2 Hz, 3H); F NMR (376
MHz, CDCl ): δ -94.9 (dd, J = 289.52 Hz, 7.52 Hz, 1F), -103.7 (dd, J = 289.52 Hz, 26.32 Hz, 1F);
C{ H}NMR (100 MHz, CDCl ): δ 185.6 (d, J = 10 Hz), 162.1 (t, J = 29 Hz), 142.1 (d, J = 6 Hz),
3
1
3
1
3
1
30.8, 129.3, 128.3, 128.1, 127.2, 118.0 (dd, J = 268 Hz, 253 Hz), 55.3 (dd, J = 24, 18 Hz), 41.4 (t, J =
+
6
Hz), 36.0, 14.0, 12.1; HRMS (ESI) for C18
H
22
F
2
N
3
O
2
[M+H] calcd. 350.1675, found 350.1668.
General catalysis procedurefor the synthesis of product 8: A dried 10 mL reaction tube was
charged with the catalyst rac-RhS (8 mol%, 7.0 mg), Ru(bpy) (PF (2 mol %, 1.7 mg) and the
3
6 2
)
corresponding 2-acyl imidazole 1(0.1 mmol, 1.0 equiv.).The tube was purged with nitrogen and then
acetone (2.0 mL), ethyl bromodifluoroacetate 7 (0.2 mmol, 40.6 mg, 2.0 equiv.) and DIPEA (0.2 mmol,
2
5.9 mg, 2.0 equiv.)were added via a syringe. The reactionmixture was degassed by three cycles of
freeze-pump-thaw. After the mixture was thoroughly degassed, the reaction was then irradiated under a
3W CFL. After completion of the reaction, the crude mixture was purified by flash chromatography
2
(silica gel, mixtures of petroleum ether/ethyl acetate) to afford the pure product 8.
General catalysis procedurefor the synthesis of product 8a at a 1 mmol scale: A dried reaction
3 6 2
tube was charged with the catalyst rac-RhS (8 mol%, 70 mg), Ru(bpy) (PF ) (2 mol %, 17 mg) and
the corresponding 2-acyl imidazole 1(1 mmol, 200 mg).The tube was purged with nitrogen and then
acetone (20 mL), ethyl bromodifluoroacetate 7 (2 mmol, 406 mg, 2.0 equiv.) and DIPEA (2 mmol, 259
mg, 2.0 equiv.)were added via a syringe. The reactionmixture was degassed by three cycles of
freeze-pump-thaw. After the mixture was thoroughly degassed, the reaction was then irradiated under a
2
3W CFL. After completion of the reaction, the crude mixture was purified by flash chromatography
1
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2
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2
2
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2
2
2
3
3
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5
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5
6
(
silica gel, petroleum ether:ethyl acetate = 2:1) to afford the pure product 8a (236 mg, 78% yield).
ethyl (E)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenylbut-2-enoate (8a) white solid, 79%
1
yield, 24.0 mg, E/Z = >19:1, R
f
= 0.22 (PE:EA = 2:1); mp=86-88C; H NMR (400 MHz, CDCl
3
): δ
7
3
.60 (d, J=6.8 Hz, 2H), 7.41-7.33 (m, 3H), 7.14 (s, 1H), 7.05 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 4.10 (s,
H); 1.21 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
): δ -127.65 (s, 1F); 13C{ H}NMR (100 MHz,
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl
3
): δ 182.4 (d, J=7 Hz), 160.8 (d, J=34 Hz), 144.8 (d, J=275 Hz), 143.2 (d, J=5 Hz), 131.5 (d, J=9
Hz), 130.7, 130.1, 129.4, 128.9 (d, J=5 Hz), 128.6, 126.9, 62.0, 35.9, 13.8; HRMS (ESI) for
+
16 2 3
C H16FN O [M+H] calcd. 303.1139, found 303.1136.
ethyl (E)-3-(4-chlorophenyl)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8b) colorless
1
oil, 69% yield, 23.2 mg, E/Z = >19:1, R
f
= 0.23 (PE:EA = 2:1); H NMR (400 MHz, CDCl
3
): δ 7.54 (d,
J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 7.07 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.10 (s, 1H),
.21 (d, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
CDCl
): δ -126.67 (s, 1F); 13C{ H}NMR (100 MHz,
1
1
3
3
):δ 182.0 (d, J=6 Hz), 160.5 (d, J=33 Hz), 145.0 (d, J=276 Hz), 143.0 (d, J=5 Hz), 135.6, 130.4
2 3
(d, J=8 Hz), 130.3, 130.2, 129.1, 128.9, 127.1, 62.1, 35.8, 13.8; HRMS (ESI) for C16H15ClFN O
+
[M+H] calcd. 337.0750, found 337.0746;
ethyl (E)-3-(4-bromophenyl)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8c) yellow oil,
1
6
5% yield, 24.7 mg, E/Z = >19:1, R
f 3
= 0.24 (PE:EA = 2:1); H NMR (400 MHz, CDCl ): δ 7.53-7.51
(m, 2H), 7.48-7.45 (m, 2H), 7.13 (s, 1H), 7.06 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 4.09 (s, 3H), 1.21 (t,
J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
): δ -126.54 (s, 1F); 13C{ H}NMR (100 MHz, CDCl
1
): δ
3
3
1
81.9 (d, J=6 Hz), 160.5 (d, J=33 Hz), 145.0 (d, J=276 Hz), 143.0 (d, J=5 Hz), 131.9, 130.5, 130.4 (d,
+
J=5 Hz), 129.6, 127.1, 124.0, 62.2, 35.9, 13.8; HRMS (ESI) for C16
81.0245, found 381.0239.
2 3
H15BrFN O [M+H] calcd.
3
ethyl (E)-2-fluoro-3-(4-fluorophenyl)-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8d) pale
1
yellow oil, 79% yield, 25.3 mg, E/Z = 15:1, R
f
= 0.24 (PE:EA = 2:1); H NMR (400 MHz, CDCl
3
): δ
7
1
.61-7.58 (m, 2H), 7.14 (d, J=0.8 Hz, 1H), 7.10-7.06 (m, 3H), 4.20 (q, J= 7.2 Hz, 3H), 4.10 (s, 3H),
.21 (t, J= 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
): δ -110.57 - -110.64 (m, 1F), -127.73 (s, 1F);
): δ 182.2 (d, J=7 Hz), 163.1 (d, J=248 Hz), 160.6 (d, J=33 Hz), 144.8
3
13
1
C{ H}NMR (100 MHz, CDCl
3
(d, J=274 Hz), 143.1 (d, J=5 Hz), 131.0 (dd, J=8 Hz, J=5 Hz), 130.5 (d, J=8 Hz), 130.2, 127.1, 126.7
+
(d, J=3 Hz), 115.8 (d, J=22 Hz), 62.1, 35.9, 13.8; HRMS (ESI) for C16
H
15
F
2
N
2
O
3
[M+H] calcd.
3
21.1045, found 321.1039.
ethyl (E)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-(p-tolyl)but-2-enoate (8e) white solid, 65%
1
yield, 20.5 mg, E/Z = 13:1, R
f
= 0.23 (PE:EA = 2:1); mp=111-113 C; H NMR (400 MHz, CDCl
3
): δ
7
.49 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 4H), 7.13 (d, J=0.8 Hz, 3H), 7.04 (s, 1H), 4.19 (q, J=7.2 Hz,
2H), 4.10 (s,3H), 2.34 (s, 3H), 1.20 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
): δ -128.37 (s, 1F);
): δ 182.6 (d, J=7 Hz), 160.8 (d, J=33 Hz), 144.4 (d, J=274 Hz), 143.2
3
1
3
1
C{ H}NMR (100 MHz, CDCl
3
(d, J=5 Hz), 139.7, 131.6 (d, J=9 Hz), 130.1, 129.4, 128.8 (d, J=6 Hz), 127.8, 126.8, 61.9, 35.9, 21.3,
+
1
3.8; HRMS (ESI) for C17
H
18FN
2
O
3
[M+H] calcd. 317.1296, found 317.1291.
ethyl (E)-3-(4-(tert-butyl)phenyl)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8f) white
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solid, 74% yield, 26.5 mg, E/Z = 12:1; R
CDCl ): δ 7.55-7.52(m, 2H), 7.42-7.39 (m, 2H), 7.13 (d, J=0.4 Hz, 1H), 7.04 (m, 1H), 4.19 (q, J=7.2
Hz, 2H), 4.10 (s, 3H), 1.29 (s, 9H), 1.21 (t, J=7.2 Hz, 3H); 19F NMR (376MHz, CDCl
): δ -128.35 (s
): δ 182.7 (d, J=7 Hz), 160.9 (d, J=33 Hz), 152.7, 144.4 (d, J=274
f
= 0.24 (PE:EA = 2:1); mp= 96-98 C; H NMR (400 MHz,
3
3
1
3
1
1F); C{ H}NMR (100 MHz, CDCl
3
Hz), 143.2 (d, J=5 Hz), 131.5 (d, J=8 Hz), 130.1, 128.7 (d, J=5 Hz), 127.7, 126.8, 125.7, 61.9, 35.9,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
34.7, 31.1, 13.8; HRMS (ESI) for C20
H
24FN
2
O
3
[M+H] calcd. 359.1765, found 359.1758.
ethyl (E)-2-fluoro-3-(4-methoxyphenyl)-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8g) white
1
solid, 74% yield, 24.5 mg, E/Z = >19:1, R
MHz, CDCl ): δ 7.55 (d, J=8.8 Hz, 2H), 7.12 (d, J=0.4 Hz, 1H), 7.04 (s, 1H), 6.90 (d, J=8.8 Hz, 2H),
.18 (q, J=7.2 Hz, 2H), 4.11 (s, 3H), 3.80 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); F NMR (376 MHz, CDCl
f
= 0.18 (PE:EA = 2:1); mp = 141-143 C; H NMR (400
3
19
4
3
):
1
-
129.53 (s, 1F); 13C{ H}NMR (100 MHz, CDCl
3
): δ 182.8 (d, J=7 Hz), 160.9 (d, J=33 Hz), 160.4,
1
1
43.9 (d, J=273 Hz), 143.2 (d, J=5 Hz), 131.3 (d, J=7 Hz), 130.6 (d, J=6 Hz), 130.0, 126.8, 123.1,
+
14.2, 61.9, 55.2, 35.9, 13.8; HRMS (ESI) for C17
H
18FN
2
O
4
[M+H] calcd. 333.1245, found 333.1240.
ethyl (E)-3-(4-ethoxyphenyl)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8h) white
1
solid, 68% yield, 20.5 mg, E/Z = 10:1, R
CDCl
f
= 0.20 (PE:EA = 2:1); mp = 122-124 C; H NMR (400 MHz,
3
): δ 7.53 (d, J=8.8 Hz, 2H), 7.12 (s, 1H), 7.04 (s, 1H), 6.88 (d, J=9.2 Hz, 2H), 4.18 (q, J=7.2 Hz,
1
9
2H), 4.10 (s, 3H), 4.03 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.20 (t, J=7.2 Hz, 3H); F NMR (376
1
MHz, CDCl
3
): -129.64 (s, 1F); 13C{ H}NMR (100 MHz, CDCl
3
): δ 182.9 (d, J=7 Hz), 161.0 (d, J=33
Hz), 159.8, 143.8 (d, J=273 Hz), 143.3 (d, J=5 Hz), 131.3 (d, J=8 Hz), 130.6 (d, J=6 Hz), 130.0, 126.8,
+
1
22.9 (d, J=2 Hz), 114.7, 63.4, 61.8, 35.9, 14.6, 13.8; HRMS (ESI) for C18
347.1402, found 347.1395.
ethyl (E)-3-([1,1'-biphenyl]-4-yl)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8i) white
H
20FN
2
O
4
[M+H] calcd.
1
solid, 76% yield, 28.9 mg, E/Z = >19:1, R
f
= 0.24 (PE:EA = 2:1); mp= 123-125C; H NMR (400 MHz,
CDCl ): δ 7.69-7.67 (m, 2H), 7.62-7.57 (m, 4H), 7.45-7.41 (m, 2H), 7.37-7.33 (m, 1H), 7.15 (d, J=0.4
3
1
9
Hz, 1H), 7.06 (s, 1H), 4.21 (q, J=7.2 Hz, 2H), 4.12 (s, 3H), 1.22 (t, J=7.2 Hz, 3H); F NMR (376 MHz,
1
CDCl
3
): δ -127.37(s, 1F); 13C{ H}NMR (100 MHz, CDCl
3
): δ 182.4 (d, J=6 Hz), 160.7 (d, J=33 Hz),
144.8 (d, J=275 Hz), 143.2 (d, J=5 Hz), 142.2, 131.0, 140.1, 131.2 (d, J=8 Hz), 130.1, 129.6, 129.4 (d,
2 3
J=6 Hz), 128.8, 127.7, 127.3, 127.0 (d, J=6 Hz), 62.0, 35.9, 13.8; HRMS (ESI) for C22H20FN O
+
[M+H] calcd. 379.1452, found 379.1448.
ethyl (E)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-3-(4-(methylthio)phenyl)-4-oxo-but-2-enoate (8j)
1
yellow solid, 74% yield, 24.5 mg, E/Z = 12:1, R
400 MHz, CDCl
f
= 0.16 (PE:EA = 2:1); mp= 116-118 C; H NMR
(
3
): δ 7.50(d, J=8.8 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.12 (s, 1H), 7.05 (s, 1H), 4.19 (q,
J=7.2 Hz, 2H), 4.10 (s, 3H), 2.46 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); 19F NMR (376MHz, CDCl
): δ
3
1
-
128.35 (s 1F); 13C{ H}NMR (100 MHz, CDCl
3
): δ 182.7 (d, J=7 Hz), 160.9 (d, J=33 Hz), 152.7,
1
1
3
44.4 (d, J=274 Hz), 143.2 (d, J=5 Hz), 131.5 (d, J=8 Hz), 130.1, 128.7 (d, J=5 Hz), 127.7, 126.8,
+
25.7, 61.9, 35.9, 34.7, 31.1, 13.8; HRMS (ESI) for C17
49.1010.
H
18FN
2
O
3
S [M+H] calcd. 349.1017, found
ethyl (E)-3-(3-chlorophenyl)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8k) colorless
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oil, 62% yield, 20.8 mg, E/Z = 14:1, R
f
= 0.22 (PE:EA = 2:1); H NMR (400 MHz, CDCl
3
): δ 7.59 (s,
1H), 7.50-7.48 (m, 1H), 7.34-7.32 (m, 2H), 7.15 (s, 1H), 7.07 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.10 (s,
H), 1.22 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
CDCl
): δ -125.84 (s, 1F); 13C{ H}NMR (100 MHz,
1
3
3
3
): δ 181.7 (d, J=6 Hz), 160.4 (d, J=34 Hz), 145.3 (d, J=277 Hz), 143.0 (d, J=4 Hz), 134.6, 132.3,
1
30.2, 130.1 (d, J=9 Hz), 129.9, 129.5, 128.8 (d, J=5 Hz), 127.2, 127.1 (d, J=5 Hz), 62.2, 35.9, 13.8;
0
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2
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4
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8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ESI) for C16
H
15ClFN
2
O
3
[M+H] calcd. 337.0750, found 337.0753.
ethyl (E)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-(m-tolyl)but-2-enoate (8l) white solid, 75%
1
yield, 23.8 mg, E/Z = 15:1; Rf = 0.23 (PE:EA = 2:1); mp=160-162 C; H NMR (400 MHz, CDCl
3
): δ
7
2
.41-7.39 (m, 2H), 7.29-7.25 (m, 1H), 7.17-7.15 (m, 1H); 7.14 (s, 1H), 7.04 (s, 1H), 4.19 (q, J=7.2 Hz,
19
H), 4.10 (s, 3H), 2.34 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); F NMR (376 MHz, CDCl
3
): δ -127.74 (s, 1F);
1
3
1
C{ H}NMR (100 MHz, CDCl
3
): δ 182.4 (d, J=7 Hz), 160.8 (d, J=33 Hz), 144.7 (d, J=274 Hz), 143.1
(
d, J=5 Hz), 138.3, 131.7 (d, J=9 Hz), 130.5, 130.3, 130.1, 129.3 (d, J=5 Hz), 128.5, 126.9, 126.0 (d,
+
J=5 Hz), 62.0, 35.8, 21.4, 13.8; HRMS (ESI) for C17
17.1291.
H
18FN
2
O
3
[M+H] calcd. 317.1296, found
3
ethyl (E)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-(o-tolyl)but-2-enoate (8n) colorless oil, 53%
1
yield, 16.7 mg, E/Z = 7:1, Rf = 0.36 (PE:EA = 2:1); H NMR (400 MHz, CDCl
3
): δ 7.53 (d, J=7.6 Hz,
2H), 7.28-7.22 (m, 2H), 7.19-7.15 (m, 2H), 7.04 (s, 1H), 4.18 (q, J=7.2 Hz, 2H), 4.02 (s, 3H), 2.55 (s,
H), 1.18 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
CDCl
): δ -122.04 (s, 1F); 13C{ H}NMR (100 MHz,
1
3
3
3
): δ 182.2 (d, J=7 Hz), 160.3 (d, J=35 Hz), 145.3 (d, J=270 Hz), 142.7 (d, J=5 Hz), 137.5, 131.0
(
d, J=13 Hz), 130.6, 130.0, 129.0, 128.2(7), 128.2(6), 127.1, 125.4, 62.0, 35.8, 19.9 (d, J=3 Hz), 13.7;
+
HRMS (ESI) for C17
H
18FN
2
O
3
[M+H] calcd. 317.1296, found 317.1289.
ethyl
(E)-3-(3-ethoxy-4-(propionyloxy)phenyl)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate
1
(8o) yellow oil, 48% yield, 20.0 mg, E/Z = 8:1, R
f
= 0.10 (PE:EA=2:1); H NMR (400 MHz, CDCl
3
): δ
7.76-7.74(m, 2H), 7.26 (d, J=0.8 Hz, 1H), 7.14-7.12 (m, 2H), 7.06 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.21
q, J=7.2 Hz, 2H), 4.14-4.08 (m, 5H), 1.43 (t, J=7.2 Hz, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.22 (t, J=7.2 Hz,
(
1
9
13
1
3H); F NMR (376MHz, CDCl
3 3
): δ -125.39 (s, 1F); C{ H}NMR (100 MHz, CDCl ): δ 181.6, 165.95,
1
60.4 (d, J=33 Hz), 158.2, 142.3 (d, J=277 Hz), 142.9 (d, J=4 Hz), 135.1, 131.5, 130.8 (d, J=8 Hz),
130.2, 127.2, 121.7, 120.4 (d, J=4 Hz), 113.9 (d, J=6 Hz), 64.7, 62.2, 60.8, 35.8, 14.6, 14.2, 13.8;
+
HRMS (ESI) for C21
H
24FN
2
O
6
[M+H] calcd.419.1613, found 419.1605.
ethyl
(E)-3-(2,3-dihydrobenzofuran-5-yl)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate
1
(
8p) white solid, 60% yield, 21.0 mg, E/Z = >19:1; R
NMR (400 MHz, CDCl
Hz, 1H), 4.58 (t, J=8.8 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 4.11 (s, 3H), 3.20 (t, J=8.8 Hz, 2H), 1.21 (t,
f
= 0.14 (PE:EA = 2:1); mp= 108-110 C; H
3
): δ 7.48 (s, 1H), 7.37-7.35 (m, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 6.78 (d, J=8.4
J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
): -129.94 (s, 1F); 13C{ H}NMR (100 MHz, CDCl
1
3
3
): δ
1
1
7
82.9 (d, J=7 Hz), 161.3 (d, J=1 Hz), 161.0 (d, J=33 Hz), 143.7 (d, J=273 Hz), 143.3 (d, J=5 Hz),
31.7 (d, J=8 Hz), 130.0, 129.6 (d, J=5 Hz), 127.8, 126.8, 125.9 (d, J=7 Hz), 122.8 (d, J=2 Hz), 109.6,
+
1.7, 61.8, 35.9, 29.4, 13.8; HRMS (ESI) for C18
H
18FN
2
O
4
[M+H] calcd. 345.1245, found 345.1238.
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ethyl (E)-2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-(thiophen-3-yl)but-2-enoate (8q) white solid,
1
60% yield, 22.6 mg, E/Z = >19:1; R
CDCl
Hz, 2H), 4.14 (s, 3H), 1.22 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl
f
= 0.15 (PE:EA = 2:1); mp= 104-106 C; H NMR (400 MHz,
3
): δ7.62-7.61 (m, 1H), 7.35-7.34 (m, 2H), 7.13 (d, J=4.0 Hz , 1H), 7.08 (s, 1H), 4.19 (q, J=7.2
): -125.33 (s, 1F);
): δ182.3 (d, J=7 Hz), 161.8 (d, J=33 Hz), 143.8 (d, J=275 Hz), 143.1
3
1
3
1
C{ H}NMR (100 MHz, CDCl
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
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7
8
9
0
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2
3
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7
8
9
0
(d, J=4 Hz), 131.1 (d, J=3 Hz), 130.1, 128.4 (d, J=8 Hz), 127.7 (d, J=7 Hz), 127.0, 126.8 (d, J=8 Hz),
+
1
26.0, 62.0, 35.9, 13.8; HRMS (ESI) for C14
H
14FN
2
O
3
S [M+H] calcd. 309.0704, found 309.0698.
ethyl (E)-2-fluoro-3-methyl-4-(1-methyl-1H-imidazol-2-yl)-4-oxobut-2-enoate (8r) colorless oil, total
1
3
5% yield, 8.4 mg, E/Z = 1.7:1, R
f
= 0.15 (PE:EA = 2:1); H NMR (400 MHz, CDCl
3
): δ 7.14 (s, 1H),
.08 (s, 1H), 4.13 (q, J=7.2 Hz, 2H), 4.06 (s, 3H), 2.16 (d, J=3.6 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H); 19
7
F
1
3
1
NMR (376 MHz, CDCl
3
): -127.84 (q,J=3.4 Hz, 1F); C{ H}NMR (100 MHz, CDCl
3
): δ 184.7 (d, J=7
Hz), 160.1 (d, J=34 Hz), 145.6 (d, J=266 Hz), 143.1 (d, J=4 Hz), 129.9, 129.5 (d, J=13 Hz), 127.0,
+
6
2
1.7, 35.8, 14.4 (d, J=5 Hz), 13.8; HRMS (ESI) for C11
H
14FN
2
O
3
[M+H] calcd. 241.0983, found
41.0977.
Trapping Experiments with TEMPO.The reactions were conducted as follows: 2-acyl imidazole
a (20.0 mg, 0.10 mmol) reacted with bromodifluoroacetamide 2a (48.4 mg, 0.2 mmol) or ethyl
1
bromodifluoroacetate 7 (40.6 mg, 0.2 mmol) and TEMPO (46.9 mg, 0.3 mmol), affording 9 in 90%
yield and 72% yield. All spectroscopic data of 9were in agreement with the literaturereport.11e
Trapping Experiments with 9.The reactions were conducted as follows: 2-acyl imidazole 1a (20.0
mg, 0.10 mmol) reacted with bromodifluoroacetamide 2a (48.4 mg, 0.2 mmol) or ethyl
bromodifluoroacetate 7 (40.6 mg, 0.2 mmol) and 9 (51.6 mg, 0.2 mmol), affording 11 in 29% yieldor12
in 10% yield. All spectroscopic data of 12were in agreement with the literaturereport.25
1
2
,2-difluoro-4-phenyl-1-(piperidin-1-yl)pent-4-en-1-one(11)colorless oil, 29% yield, 16 mg, H NMR
3
(400 MHz, CDCl ): δ 7.43 (d, J = 7.2 Hz, 2H), 7.35-7.31 (m, 2H), 7.29-7.26 (m, 1H), 5.56 (s, 1H), 5.32
(s, 1H), 3.57 (t, J = 5.2 Hz, 2H), 3.52 (t, J = 5.2 Hz, 2H), 3.40 (t, J = 19.2 Hz, 2H), 1.68-1.52 (m, 6H);
19F NMR (376 MHz, CDCl
13
1
3
3
): δ -98.3 (t, J = 18.8 Hz, 1F); C{ H}NMR (100 MHz, CDCl ): δ 161.6 (t,
J = 28 Hz), 141.2, 139.5 (t, J = 3 Hz), 128.2, 127.5, 126.2, 119.1, 118.2 (t, J = 255 Hz), 46.8 (t, J = 7
+
Hz), 44.4, 39.7 (t, J = 23 Hz), 26.4, 25.5, 24.4; HRMS (ESI) for C16
H
20
F
2
NO [M+H] calcd. 280.1513,
found 280.1508.
Competitive Experiment: Following the general procedure for the synthesis of product 3, substrates
with different substituent groups were both poured into the reaction mixture. After 14 h, the solvent
was rapidly removed under reduced pressure to afford the crude products. The yield ratio (3e:3h =
1
9
3
.6:1) was determined by F NMR analysis.
Following the general procedure for the synthesis of product 8, substrates with different substituent
groups were both poured into the reaction mixture. After 30 h, the solvent was rapidly removed under
reduced pressure and the residue was purified by silica gel chromatography to afford the mixed
1
9
products. The yield ratio (8b:8e = 2.1:1) was determined by F NMR analysis.
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Light-Dark Interval Experiment: The light-dark interval experiments were performed according
the general catalysis procedure. The conversion was determined by isolate yield of an aliquot from the
reaction mixture. An aliquot was taken out of the reaction system via syringe for every 2 h. The whole
process was performed under argon.
Kinetic Isotope Effect of the Difluoroalkylation of 2-acyl imidazole: A dried 10 mL reaction tube
0
1
2
3
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9
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9
0
was charged with the catalyst rac-RhS (4 mol%, 3.5 mg), Ir(ppy)
2
(dtbbpy)(PF
6
)
2
(1 mol%, 0.9 mg) and
-1a (0.1 mmol, 20.2 mg,
(2.0 mL), Bromodifluoroacetamides
a (0.2 mmol, 48.4 mg, 2.0 equiv.) and DIPEA (0.2 mmol, 33µl, 2.0 equiv.) were added via a syringe.
the corresponding 2-acyl imidazole 1a (0.1 mmol, 20.0 mg, 1.0 equiv.) and d
2
1
2 2
.0 equiv.). The tube was purged with nitrogen and then CH Cl
2
The reaction mixture was degassed by three cycles of freeze-pump-thaw. After the mixture was
thoroughly degassed, the reaction was then irradiated under a 23W CFL. After 6 hours the mixture was
removed to a round-bottom flask, and the solvent was removed under reduced pressure. Then the
residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate. The
1
isolated product was investigated by H NMR spectrum. The KIE value was determined by the ratios of
the proton integral averaged over two experiments.
Stern-Volmer Quenching Experiments: Stern-Volmer fluorescence quenching experiments were
2 6 2 2
run with freshly prepared solutions of 0.1 mM Ir(ppy) (dtbbpy)PF in CH Cl at room temperature. The
solutions were irradiated at 345 nm and fluorescence was measured from 400 nm to 750 nm.
ASSOCIATED CONTENT
Supporting Information
The X-ray crystallographic data (CIF) for product 3l, 6, 8i (CIF), copies of H, C and 19F spectra for
1
13
all products are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xupf@lzu.edu.cn
ORCID
Peng-Fei Xu: 0000-0002-5746-758X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to the NSFC (21632003, and 21572087), the key program of Gansu province
(17ZD2GC011) and the “111” program from the MOE of P. R. China, and Syngenta Com-pany for
financial support.
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