Enantioselective Pd-catalyzed allylation of acyclic α-fluorinated ketones

Article abstract of DOI:10.1021/jo500923u

Significant synthetic challenges remain for the asymmetric synthesis of tertiary α-fluoro ketones, which are potentially useful molecules for the development of drugs, agrochemicals, and functional materials. Herein, we describe the development of a method for the catalytic enantioselective synthesis of tertiary α-fluoro ketones via the Tsuji-Trost reaction of racemic acyclic α-fluorinated ketones. Enantioenriched acyclic α-cabonyl tertiary fluorides can be produced with the aid of a palladium/phosphinooxazoline catalyst.

Full text of DOI:10.1021/jo500923u

Subscriber access provided by UNIV LAVAL
Note
Enantioselective Pd-catalyzed Allylation
of Acyclic alpha-Fluorinated Ketones
Wengui Wang, Haiming Shen, Xiao-Long Wan, Qing-Yun Chen, and Yong Guo
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 10 Jun 2014
Downloaded from http://pubs.acs.org on June 16, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Enantioselective Pd-catalyzed Allylation of Acyclic α-Fluorinated Ketones
Wengui Wang,† Haiming Shen,† Xiao-Long Wan,† Qing-Yun Chen*,† and Yong
Guo*,†
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R.
of China
chenqy@sioc.ac.cn;
yguo@sioc.ac.cn
Table of Content
Abstract
Significant synthetic challenges remain for the asymmetric synthesis of tertiary
α-fluoroketones, which are potentially useful molecules for the development of drugs,
agrochemicals and functional materials. Herein, we describe the development of a
method for the catalytic enantioselective synthesis of tertiary α-fluoroketones via the
Tsuji–Trost reaction of racemic acyclic α-fluorinated ketones. Enantioenriched
acyclic α-cabonyl tertiary fluorides can be produced with the aid of a
palladium/phosphinooxazoline catalyst.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
1
2
3
4
5
6
7
8
9
The incorporation of fluorine into organic molecules has been studied
extensively during the past few decades as part of the increasing demand for the
development of new medicines, agrochemicals and functional materials.1
Stereodefined tertiary alkyl fluorides possess a range of interesting properties and
could potentially be applied across a number of different areas in biomedical science.
For example, flurithromycin has been reported to show better bioavailability and
metabolic stability properties than the corresponding nonfluorinated analogues.1a
Although several methods have been developed for the construction of asymmetric
tertiary alkyl fluorides, with a large number of these methods involving the
installation of a tertiary alkyl fluoride moiety α to a carbonyl group, most of these
examples have been carried out using either cyclic or doubly activated ketones.2-6 In
contrast, reports pertaining to enantioselective synthesis of simple α-carbonyl acyclic
tertiary fluorides are scarce, with only one example recently appearing in the literature
involving the stereoconvergent Negishi arylation of racemic α-bromo-α-fluoroketones,
which was reported by Fu et al.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Asymmetric allylic alkylation represents a powerful tool for the construction of
asymmetric carbon centers, and has consequently attracted considerable attention
from synthetic chemists.7 In recent years, the groups of Nakamura,5a Tunge5b,h and
Stoltz5c have all reported the development of methods for the Pd-catalyzed
enantioselective decarboxylative allylation of β-ketoesters to give cyclic tertiary
α-fluoroketones. Paquin et al.5d-g reported the Pd-catalyzed enantioselective allylation
of fluorinated silyl enol ethers or with cyclic fluorinated enol carbonates. These
ACS Paragon Plus Environment

Page 3 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
studies show that the highly enantioselective construction of tertiary α-fluoroketones
can be efficiently realized with cyclic substrates. However, in all of the acyclic
examples, the products were formed with low enantioselectivity (less than 60% ee
obtained) (Scheme 1). Although there are a few successful examples for acyclic
non-fluorinated subtrates,8 the challenge still remains for the construction of
asymmetric acyclic tertiary α-fluoroketones, especially those bearing two alkyl
substituents. Following on from our recent study involving the development of a
method capable of providing access to tertiary alkyl fluorides,9 it was envisaged that
an asymmetric allylic alkylation reaction would allow for the enantioselective
formation of acyclic tertiary α-fluoroketones (Scheme 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SCHEME 1. Enantioselective allylation of acyclic fluorinated substrates
The racemic α-fluoroketone 1a was converted to the corresponding optically
active α-fluoroketone 3a via an enolate intermediate, which was generated in situ by
the treatment of 1a with lithium bis(trimethylsilyl)amide (LiHMDS) in THF.
Subsequent treatment of the enolate with 2a in the presence of a [Pd(C3H5)Cl]2
catalyst gave the desired α-fluoroketone product 3a. This reaction was screened
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
1
2
3
4
5
6
7
against a variety of different chiral ligands in THF at temperatures in the range of
0 °C to room temperature over a period of 12 h (Table 1, entries 1–7).
8
9
Ligands L1 and L2, which are known as SiocPhos,10 gave a low ee for the
desired product. A series of PHOX ligands were studied. The ee with L3 was up to 78%
(Table 1, entry 3). The best enantioselectivity (84% ee) was given by L4 with a
moderate yield (Table 1, entry 4). When CF3 was introduced onto the rings of ligands,
the ee decreased (Table 1, entries 5 to 7). The reaction was also conducted using
sodium bis(trimethylsilyl)amide (NaHMDS) and potassium bis(trimethylsilyl)amide
(KHMDS) as the base instead of LiHMDS to investigate the effect of different
counter ions on the outcome of the reaction. It was believed that the use of different
counter ions would enhance the nucleophilicity of the fluorinated ketone enolate and
therefore improve the yield. In practice, although the use of different counter ions did
lead to improved yields of 77 and 80% for sodium and potassium, respectively, the
enantiomeric excess values of these reactions were much lower at 75 and 69% (Table
1, entries 8 and 9). We then investigated the addition of several additives to the
reaction in an attempt to increase the yield without losing selectivity. Molecular sieve
were also added to the reaction to remove any moisture from the solvent.
Unfortunately, however, this change did not lead to an improvement in the yield
(Table 1, entry 10). The addition of ammonium salts to similar reactions has been
reported to improve enantioselectivity.8a The application of this strategy to the current
reaction, however, had no discernible impact on the outcome of the reaction (Table 1,
entry 11). Lewis acids have also been reported to have a significant effect on the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
outcome of similar reactions.8a Unfortunately, however, the addition of silver bromide
or lithium chloride to the current reaction led to a reduction in the yield and the
selectivity (Table 1, entries 12 and 13). We also investigated the use of several weaker
bases including silver carbonate, silver acetate, potassium acetate and sodium acetate
(Table 1, entries 14 to 17) in an effort to improve the yield of the reaction. Although
the use of these bases led to an increase in the yield of the reaction, they also led to a
decrease in the enantiomeric excess values. The weak base, sodium acetate, provided
the best selectivity (Table 1, entry 17). A wide variety of other conditions were also
screened, including different solvents as well as the ratio of Pd to the ligand, and this
information can be found in the Supporting Information.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
1
2
3
4
5
6
7
TABLE 1. Selected conditions for the enantioselective
allylation of acyclic fluorinated ketones 1a
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entrya
1
L*
L1
L2
L3
L4
L5
L6
L7
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
Additive Yield (%)b Ee (%)
-
10c
68c
69
60
60
74
68
77
80
66
50
53
44
70
89
77
86
9
2
-
21
78
84
75
78
52
75
69
78
82
56
67
71
12
76
78
3
-
4
-
5
-
6
-
7
-
-
8d
9e
10
11
12
13
14
15
16
17
-
4Å MS f,g
nBu4NBr f
AgBrf
LiCl f
f
Ag2CO3
AgOAc f
KOAc f
NaOAc f
aReaction conditions: 0.2 mmol 1a, 0.22 mmol 2a, 1.2
equivalents of LiHMDS, 1.25 mol% [Pd(C3H5)Cl]2, 3.1
mol% L*, 2 mL anhydrous THF, 0 oC to rt, 12 h.
bIsolated yield. cYield determined by 19F NMR.
ACS Paragon Plus Environment

Page 7 of 26
The Journal of Organic Chemistry
1
2
3
4
5
dNaHMDS instead of LiHMDS. eKHMDS instead of
LiHMDS. f10 mol% additive was added. gMS
=
6
molecular sieve.
7
8
9
The conditions outlined in entry 17 of Table 1 were identified as the optimum
conditions and used to evaluate the substrate scope of the reaction (Table 2).
Substrates bearing a para substituent on the phenyl group of the starting ketone
afforded the corresponding products (3c–h) in 57–91% yield with enantiomeric
excess values range of 73–82% (Table 2, entries 3–8). Surprisingly, substrates bearing
a meta substituent on the phenyl group of the ketone gave higher enantiomeric excess
values (3j, 86% ee and 3k, 85% ee) than those bearing a para substituent (Table 2,
entries 10 and 11). A wide variety of functional groups, including methyl, methoxy,
aryl fluoride/chloride/bromide and trifluoromethyl groups were well tolerated under
the optimized reaction conditions. However, the yield and the ee value were 30 and 60%
in the case with a naphthyl substituent (Table 2, entry 12). The reaction of 1a with
methyl 2-methylprop-2-enyl carbonate (2b) gave product 3b in 84% yield with 88%
ee (Table 2, entry 2). It is noteworthy that 3i was synthesized with an ee value of 90%,
which is, to the best of our knowledge, the best ee ever reported for an acyclic tertiary
α-fluoroketones from an enantioselective allylic alkylation reaction (Table 2, entry 9).
TABLE 2. Enantioselective construction of acyclic tertiary
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
α-fluoroketones by a Pd-catalyzed allylic alkylation
Entry
Product
Yield Ee (%)b
1
2
86
84
78
88
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
1
2
3
4
5
6
7
8
9
3
4
88
74
83
88
91
57
44
74
93
30
73c
77c
77c
82c
84
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
7
8
82
9
90
10
11
12
86c
85c
60
aIsolated yield. Determined by chiral HPLC. Ee was
b
c
determined by chiral HPLC after Wacker oxidation.
It is known that cyclic ketones always give a good level of selectivity, whereas
acyclic ketones give much lower levels of enantioselectivity (Scheme 1).5a,d,e
Nakamura attributed the low selectivity of acyclic ketones to the formation of an E/Z
mixture of the palladium enolate in situ.5a Paquin also made a similar suggestion that
the poor selectivity of acyclic ketones may be related to the fact that the initially
formed Z palladium enolate rapidly equilibrates to an E/Z mixture prior to the actually
allylation reaction.5e In this current study, the allylation of acyclic fluorinated ketones
with 2a gave an average selectivity of 80% (Table 1). Interestingly, the reaction of the
cyclic fluoroketone 4 under the same conditions gave product 5 82% ee (eq 1), which
was a very similar value to that observed for the acyclic examples.5d This observation
implied that our conditions provided a very high level
ACS Paragon Plus Environment

Page 9 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
of Z/E selectivity for the generation of the acyclic enolate, as well as high selectivity
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
for the cyclic example. To confirm the stereochemistry of this step, we observed the
19
Z/E ratio of the in situ generated enolate of 1a by F NMR spectroscopy, and found
that the use of LiHMDS as a base led to a higher Z/E ratio of the enolate isomers (>
20:1) than NaHMDS or KHMDS. The Z/E ratio can be used to explain the changes in
the selectivity caused by these three strong bases (Table 1, entries 4, 8 and 9). These
results therefore confirm that changes in the Z/E ratio of the in situ generated enolate
have a significant impact on the selectivity. Finally, we used 4-methylbenzenesulfonic
anhydride (Ts2O) to trap the enolate, and the main product was isolated as a solid. The
isolated product was determined to be in the Z configuration by single crystal X-ray
analysis (Scheme 2).
SCHEME 2. Trapping the in situ generated enolate with 4-methylbenzenesulfonic
anhydride
The current reaction can also be applied to non-fluorinated ketones 7, but the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
1
2
3
4
5
6
7
8
9
selectivity was moderate (eq 2). Trost et al.8b reported the use of a Z/E enol carbonate
to give allylic α-alkylated ketone, and found that the starting Z/E value had a
significant influence on the enantioselectivity and rate of the reaction. The results of
this study would therefore suggest that our current conditions would be unsuitable for
non-fluorinated compounds, because the Z/E values of the in situ generated
non-fluorinated enolates by LiHMDS would not be as high as those observed for the
fluorinated compounds. This also implied that the highly electron withdrawing
fluorine was having a positive influence on the selectivity of the reaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The absolute configuration was assigned as R based on a comparison of the
optical rotation value of an existing product 3a.5a
Although the selectivity of our study was slightly lower than that encountered for
the cyclic ketone substrates, the best enantiomeric excess was 90%, representing the
best selectivity reported to date for the asymmetric Pd-catalyzed allylation of acyclic
α-fluoroketones. Furthermore, the current reaction has several notable characteristics,
including (1) the reaction directly used ketones through a formal C-H
functionalization without the need for the pre-formation of the corresponding allylic
enol carbonates, allylic β-ketoesters or silyl enol ethers; and (2) it can be used to
introduce an allylic alkyl group, which can be used as a handle for further
modification.
In summary, we have developed a method for asymmetric synthesis of acyclic
ACS Paragon Plus Environment

Page 11 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
α-carbonyl tertiary alkyl fluorides. The enantioselectivity of this palladium-catalyzed
allylation of acyclic α-fluoroketones reached 90% ee. The configuration of in situ
generated enolate intermediate was determined to be Z, which was helpful for
understanding the good selectivity observed in the reaction, and the presence of a
fluorine atom in the starting material had a positive effect on the selectivity.
Experimental Section
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General experiment details All reagents were comercially available and used
without further purification. All reactions were carried out under nitrogen atmosphere.
All solvents were purified according to standard methods prior to use. Melting points
were determined by differential scanning calorimetry (DSC) measurements.NMR
spectra were obtained on 400 MHz spectrometers and recorded at 25 °C. Chemical
1
shifts for H NMR spectra are reported in ppm downfield from TMS, chemical shifts
for 13C NMR spectra are recorded in ppm relative to internal chloroform (δ 77.0 ppm
for 13C), and chemical shifts for 19F NMR are reported in ppm downfield from
fluorotrichloromethane (CFCl3). Coupling constants (J) are reported in hertz. 13C
NMR was broad-band decoupled from hydrogen nuclei. Infrared spectra (IR) were
recorded with an infrared spectrometer; absorbance frequencies are given at
maximum intensity in cm−1. The mass analyzer type uesd for the HRMS is time of
flight mass spectrometry (TOF-MS) or Fourier transform ion cyclotron resonance
mass spectrometry (FTICR-MS). Column chromatography was performed using silica
gel (mesh 300–400). Optical rotation was measured using a 2 mL cell with a 1.0 dm
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
1
2
3
4
5
6
7
path length. The following abbreviations are used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, sext = sextet.
8
9
General procedure of for the enantioselective allylic alkylation reaction. To a
Schlenck tube was added α-fluorinated ketone (0.2 mmol), 1 mL freshly distilled THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
under nitrogen atmosphere and cooled down to 0 C. LiHMDS (0.24 mL, 1.0 M in
o
THF) was added dropwise. Then the tube was kept at 0 C for 1.5 h. [Pd(C3H5)Cl]2
(0.0025 mmol) and (S)-t-Bu-PHOX (0.0062 mmol) was dissolved in 1 mL freshly
distilled anhydrous THF in another Schlenck tube and stirred at room temperature for
1 h. This solution was added to the lithium enolate solution mentioned before. Allyl
methyl carbonate (0.22 mmol) and NaOAc (0.02 mmol) was added successively. The
reaction was allowed to warm to ambient temperature and reacted overnight.
Deionized water was added to the mixture and the organic layer was separated. The
aqueous layer was extracted with ether, and the combined organic layer was washed
with aqueous saturated NaCl. After drying over Na2SO4, the product was purified by
column chromatography on silica gel (hexane/Et2O).
2-Fluoro-2-methyl-1-phenylpent-4-en-1-one (3a). Yield 86% (33 mg). Colorless oil.
All spectroscopic data were in agreement with the literature.5a Enantiomeric excess
was determined by HPLC with a CHIRALCEL PC-3 column [λ = 214 nm; eluent:
hexane/isopropanol = 95/5; flow rate: 0.70 mL/min; tminor = 6.64 min, tmajor = 7.17 min;
ee% = 78%].
2-Fluoro-2,4-dimethyl-1-phenylpent-4-en-1-one (3b). Yield 84% (35 mg).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.4
ACS Paragon Plus Environment

Page 13 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Hz, 1H), 7.44 (dd, J = 8.0, 7.4 Hz, 2H), 4.91 (s, 1H), 4.79 (s, 1H) 2.87 (dd, J = 24.8,
14.4 Hz, 1H), 2.60 (dd, J = 22.8, 14.4 Hz, 1H), 1.77 (s, 3H), 1.66 (d, J = 22.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) 201.7 (d, JCF = 26.3 Hz), 139.9, 135.1 (d, JCF = 3.9 Hz),
132.9, 129.8 (d, JCF = 7.8 Hz), 128.2, 116.1, 102.2 (d, JCF = 198.3 Hz), 46.2 (d, JCF =
21.7 Hz), 24.3 (d, JCF = 24.1 Hz), 24.0 (d, JCF = 2.4 Hz); 19F NMR (376 MHz, CDCl3)
δ -150.6 (sext, J = 22.6 Hz); IR (neat) ν 1686, 1598, 1448, 1267 cm-1; MS (EI) m/z
206 [M]+; HRMS (EI-TOF-MS) calcd for C13H15OF [M] 206.1107, found 206.1111.
Enantiomeric excess was determined by HPLC with a Lux 5u Cellulose-3 Column [λ
= 254 nm; eluent: hexane/isopropanol = 90/10; flow rate: 0.70 mL/min; tminor = 6.11
min, tmajor = 6.78 min; ee% = 88%; [α]D25 -42.8 (c 0.90, CH2Cl2)].
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Fluoro-2-methyl-1-(p-tolyl)pent-4-en-1-one (3c). Yield 88% (36 mg). Colorless
oil; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.5 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H),
5.85-5.73 (m, 1H), 5.15 (d, J = 4.7 Hz, 1H), 5.12 (s, 1H), 2.91-2.79 (m, 1H),
2.68-2.56 (m, 1H), 2.39 (s, 3H), 1.63 (d, J = 21.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 200.5 (d, JCF = 25.7 Hz), 144.0, 132.2 (d, JCF = 3.9 Hz), 131.2 (d, JCF = 4.7
Hz), 130.0 (d, JCF = 7.8 Hz), 129.0, 119.7, 101.5 (d, JCF = 183.0 Hz), 43.0 (d, JCF =
22.6 Hz), 23.9 (d, JCF = 24.2 Hz), 21.6; 19F NMR (376 MHz, CDCl3) δ -151.4 (sext, J
= 21.6 Hz); IR (neat) ν 1681, 1607, 1176, 924 cm-1; MS (EI) m/z 206 [M]+; HRMS
(EI-TOF-MS) calcd for C13H15OF [M] 206.1107, found 206.1103. [α]D26 -10.4 (c 1.30,
CH2Cl2).
2-Fluoro-1-(4-methoxyphenyl)-2-methylpent-4-en-1-one (3d). Yield 74% (33 mg).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
1
2
3
4
5
6
7
8
9
Hz, 2H), 5.80-5.77 (m, 1H), 5.16 (d, J = 5.6 Hz, 1H), 5.13 (s, 1H), 3.87 (s, 3H),
2.90-2.78 (m, 1H), 2.67-2.56 (m, 1H), 1.64 (d, J = 21.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 199.0 (d, JCF = 25.5 Hz), 163.5, 132.4 (d, JCF = 9.3 Hz), 131.3 (d, JCF = 4.6
Hz), 127.5 (d, JCF = 4.5 Hz), 119.5, 113.5 (d, JCF = 1.5 Hz), 101.6 (d, JCF = 184.4 Hz),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
55.4, 43.1 (d, JCF = 21.7 Hz), 23.8 (d, JCF = 23.3 Hz); F NMR (376 MHz, CDCl3) δ
-150.9 (sext, J = 21.7 Hz); IR (neat) ν 1674, 1600, 1509, 1261, 1170 cm-1; MS (EI)
m/z 222 [M]+; HRMS (EI-TOF-MS) calcd for C13H15O2F [M] 222.1056, found
222.1055. [α]D26 -16.8 (c 0.97 CH2Cl2).
2-Fluoro-1-(4-fluorophenyl)-2-methylpentan-1-one (3e). Yield 83% (35 mg).
Colorless oil. 1H NMR(400 MHz, CDCl3) δ 8.10 (dd, J = 8.4, 5.6 Hz, 2H), 7.10 (dd, J
= 9.2, 8.4 Hz, 2H), 5.83-5.72 (m, 1H), 5.17 (s, 1H), 5.14 (s, 1H), 2.90-2.78 (m, 1H),
2.67-2.56 (m, 1H), 1.64 (d, J = 22.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.4 (d,
JCF = 25.2 Hz), 165.7 (d, JCF = 248.7 Hz), 132.8(d, JCF = 9.3 Hz), 132.7 (d, JCF = 8.6
Hz), 130.9 (d, JCF = 4.7 Hz), 119.9, 115.4 (dd, JCF = 21.7, 1.6 Hz), 101.7 (d, JCF =
185.1 Hz), 43.0 (d, JCF = 22.5 Hz), 23.8 (d, JCF = 24.0 Hz); 19F NMR (376 MHz,
CDCl3) δ -104.8 (m, 1F), -151.4 (sext, J = 21.7 Hz, 1F); IR (neat) ν 1685, 1599, 1505
1238, 1159 cm-1; MS (EI) m/z 210 [M]+; HRMS (EI-TOF-MS) calcd for C12H12OF2
[M] 210.0856, found 210.0857. [α]D27 -20.1 (c 0.83, CH2Cl2).
1-(4-Chlorophenyl)-2-fluoro-2-methylpent-4-en-1-one (3f). Yield 88% (40 mg).
Colorless oil. 1H NMR(400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0
Hz, 2H), 5.82-5.71 (m, 1H), 5.17 (s, 1H), 5.14 (s, 1H), 2.89-2.77 (m, 1H), 2.67-2.55
13
(m, 1H), 1.64 (d, J = 21.6 Hz, 3H); C NMR (100 MHz, CDCl3) δ 199.9 (d, JCF
=
ACS Paragon Plus Environment

Page 15 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
26.3 Hz), 139.6, 133.1 (d, JCF = 3.9 Hz), 131.4 (d, JCF = 8.6 Hz), 130.9 (d, JCF = 4.7
Hz), 128.6 (d, JCF = 1.5 Hz), 120.0, 101.7 (d, JCF = 185.2 Hz), 43.0 (d, JCF = 22.4 Hz),
23.8 (d, JCF = 24.1 Hz); 19F NMR (376 MHz, CDCl3) δ -151.8 (sext, J = 21.7 Hz); IR
(neat) ν 1687, 1588, 1092, 988 cm-1; MS (EI) m/z 226 [M]+; HRMS (EI-TOF-MS)
calcd for C12H12OFCl [M] 226.0561, found 226.0559. [α]D26 -14.2 (c 1.30, CH2Cl2).
1-(4-Bromophenyl)-2-fluoro-2-methylpent-4-en-1-one (3g). Yield 91% (49 mg).
Colorless oil. 1H NMR(400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 9.2
Hz, 2H), 5.82-5.71 (m, 1H), 5.17 (s, 1H), 5.14 (d, J = 3.2 Hz, 1H), 2.89-2.77 (m, 1H),
2.67-2.55 (m, 1H), 1.64 (d, J = 21.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.1 (d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
JCF = 25.5 Hz), 133.5 (d, JCF = 3.9 Hz), 131.7, 131.4 (d, JCF = 8.5 Hz), 130.9 (d, JCF
=
4.6 Hz), 128.4, 120.0, 101.7 (d, JCF = 184.4 Hz), 43.0 (d, JCF = 22.5 Hz), 23.8 (d, JCF
19
= 24.0 Hz); F NMR (376 MHz, CDCl3) δ -151.8 (sext, J = 21.7 Hz); IR (neat) ν
1687, 1583, 1073, 986 cm-1; MS (EI) m/z 270 [M]+; HRMS (EI-TOF-MS) calcd for
C12H12OFBr [M] 270.0056, found 270.0055. Enantiomeric excess was determined by
HPLC with a CHIRALCEL ID3 Column [λ = 214 nm; eluent: hexane/isopropanol =
26
99/1; flow rate: 0.50 mL/min; tminor = 5.14 min, tmajor = 4.92 min; ee% = 84%; [α]D
-10.1 (c 0.42, CH2Cl2)].
1-([1,1'-Biphenyl]-4-yl)-2-fluoro-2-methylpent-4-en-1-one (3h). Yield 57% (31 mg).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4
Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H),
5.91-5.79 (m, 1H), 5.20 (d, J = 6.0 Hz, 1H), 5.17 (s, 1H), 2.98-2.86 (m, 1H),
2.74-2.63 (m, 1H), 1.69 (d, J = 22.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5 (d,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
1
2
3
4
5
6
7
JCF = 25.5 Hz), 145.7, 139.9, 133.5 (d, JCF = 4.4 Hz), 131.2, 131.1, 130.6, 130.5, 128.9,
128.2, 127.3, 126.9, 119.8, 101.7 (d, JCF = 184.5 Hz), 43.1 (d, JCF = 21.9 Hz), 23.9 (d,
8
9
19
JCF = 22.1 Hz); F NMR (376 MHz, CDCl3) δ -151.6 (m); IR (neat) ν 2984, 1681,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1604, 1246, 1177, 1075, 924 cm-1; MS (EI) m/z 268 [M]+; HRMS (EI-TOF-MS) calcd
for C18H17OF [M] 268.1263, found 268.1261. Enantiomeric excess was determined by
HPLC with a CHIRALCEL ID3 Column [λ = 214 nm; eluent: hexane/isopropanol =
26
98/2; flow rate: 0.70 mL/min; tminor = 4.34 min, tmajor = 4.08 min; ee% = 82%; [α]D
-5.5 (c 1.51, CH2Cl2)].
1-([1,1'-Biphenyl]-4-yl)-2-fluoro-2,4-dimethylpent-4-en-1-one (3i). Yield 44% (25
mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 2H), 7.68 (d, J
= 8.0 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz,
1H), 4.94 (s, 1H), 4.83 (s, 1H), 2.91 (dd, J = 24.8, 14.4 Hz, 1H), 2.64 (dd, J = 22.4,
14.4 Hz, 1H), 1.81 (s, 3H), 1.69 (d, J = 21.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
201.1 (d, JCF = 26.3 Hz), 145.6, 139.9 (2C), 133.7 (2C), 130.5, 130.4, 128.9, 128.2,
127.3, 126.9, 116.2, 101.7 (d, JCF = 184.5 Hz), 43.1 (d, JCF = 21.9 Hz), 23.9 (d, JCF =
19
22.1 Hz); F NMR (376 MHz, CDCl3) δ -150.5 (m); IR (neat) ν 1686, 1642, 1508,
1409, 1242, 1264, 1228, 1175, 1060, 925 cm-1; MS (EI) m/z 282 [M]+; HRMS
(EI-TOF-MS) calcd for C19H19OF [M] 282.1423, found 282.1420. Enantiomeric
excess was determined by HPLC with a CHIRALCEL AD-RH Column [λ = 220 nm;
eluent: acetone/water = 70/30; flow rate: 0.70 mL/min; tminor = 17.06 min, tmajor
14.63 min; ee% = 90%; [α]D26 -29.6 (c 1.23, CH2Cl2)].
=
1-(3-Bromophenyl)-2-fluoro-2,4-dimethylpent-4-en-1-one (3j). Yield 74% (42 mg).
ACS Paragon Plus Environment

Page 17 of 26
The Journal of Organic Chemistry
1
2
3
4
1
Colorless oil. H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H),
7.69 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 5.83-5.71 (m, 1H), 5.18 (s, 1H),
5.15 (d, J = 4.8 Hz, 1H), 2.89-2.77 (m, 1H), 2.67-2.57 (m, 1H), 1.64 (d, J = 22.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 199.9 (d, JCF = 26.4 Hz), 136.6 (d, JCF = 3.8 Hz),
135.9, 132.7 (d, JCF = 8.5 Hz), 130.8 (d, JCF = 4.7 Hz), 129.9 (d, JCF = 1.5 Hz), 128.4
(d, JCF = 8.5 Hz), 122.5, 120.1, 101.6 (d, JCF = 185.2 Hz), 42.9 (d, JCF = 21.7 Hz), 23.8
(d, JCF = 24.0 Hz); 19F NMR (376 MHz, CDCl3) δ -152.1 (sext, J = 21.7 Hz); IR (neat)
ν 2929, 2844, 1726, 1694, 1254, 1116, 1025 cm-1; MS (EI) m/z 270 [M]+; HRMS
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25
(EI-TOF-MS) calcd for C12H12OBrF [M] 270.0056, found 270.0060. [α]D -15.1 (c
0.86, CH2Cl2).
2-Fluoro-2-methyl-1-(3-(trifluoromethyl)phenyl)pent-4-en-1-one (3k). Yield 93%
(48 mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.21 (d, J = 8.0 Hz,
1H), 7.81 (d, J = 7.6 Hz, 1H), 7.59 (dd, J = 8.0, 7.6 Hz, 1H), 5.83-5.72 (m, 1H), 5.19
(s, 1H), 5.15 (d, J = 4.0 Hz, 1H), 2.91-2.79 (m, 1H), 2.69-2.58 (m, 1H), 1.67 (d, J =
22.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.4 (d, JCF = 27.1 Hz), 135.4 (d, JCF =
3.9 Hz), 133.0 (d, JCF = 7.8 Hz), 131.0 (q, JCF = 31.3 Hz), 130.7 (d, JCF = 4.7 Hz),
129.4 (q, JCF = 3.6 Hz), 128.9 (d, JCF = 1.6 Hz), 126.7 (m), 123.6 (q, JCF = 272.5 Hz),
19
120.2, 101.7 (d, JCF = 192.9 Hz), 43.0 (d, JCF = 21.7 Hz), 23.8 (d, JCF = 23.2 Hz); F
NMR (376 MHz, CDCl3) δ -62.9 (m, 3F), -152.3 (sext, J = 21.6 Hz, 1F); IR (neat) ν
1694, 1334, 1169, 1132, 1076 cm-1; MS (EI) m/z 260 [M]+; HRMS (EI-TOF-MS)
calcd for C13H12OF4 [M] 260.0824, found 260. 0822. [α]D25 -15.3 (c 0.76, CH2Cl2).
2-Fluoro-2,4-dimethyl-1-(naphthalen-1-yl)pent-4-en-1-one (3l). Yield 30% (16
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
1
2
3
4
5
6
7
8
9
mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 1H), 7.97 (d, J
= 8.0 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.82 (dd, J = 7.2, 3.2 Hz, 1H), 7.56-7.47 (m,
3H), 4.94 (d, J = 34.4 Hz, 2H), 2.97 (dd, J = 25.6, 14.4 Hz, 1H), 2.67 (dd, J = 22.8,
14.4 Hz, 1H), 1.81 (s, 3H), 1.74 (d, J = 21.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
206.1 (d, JCF = 22.0 Hz), 140.1, 133.8, 133.7 (d, JCF = 2.2 Hz), 131.7, 130.5, 128.5,
127.5, 127.0 (d, JCF = 10.2 Hz), 126.2, 125.3, 124.0, 116.5, 101.7 (d, JCF = 188.8 Hz),
46.1 (d, JCF = 20.4 Hz), 24.4 (d, JCF = 24.1 Hz), 24.1 (d, JCF = 2.9 Hz); 19F NMR (376
MHz, CDCl3) δ -150.4 (m); IR (neat) ν 1683, 1645, 1507, 1446, 1372, 1235, 1084
cm-1; MS (EI) m/z 256 [M]+; HRMS (EI-TOF-MS) calcd for C17H17OF [M] 256.1263,
found 256.1260. Enantiomeric excess was determined by HPLC with a CHIRALCEL
PC-3 Column [λ = 214 nm; eluent: hexane/isopropanol = 95/5; flow rate: 0.70
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
26
mL/min; tminor = 9.72 min, tmajor = 9.16 min; ee% = 60%; [α]D -10.5 (c 0.82,
CH2Cl2)].
2-allyl-2-fluoro-3,4-dihydronaphthalen-1(2H)-one (5). Yield 50% (21 mg).
Colorless oil. All spectroscopic data were in agreement with the literature.5a
Enantiomeric excess was determined by HPLC with a CHIRALCEL IC column [λ =
214 nm; eluent: hexane/isopropanol = 90/10; flow rate: 0.50 mL/min; tminor =12.21
min, tmajor = 13.13 min; ee% = 82%].
2-methyl-1-phenylpent-4-en-1-one (8). Yield 50% (21 mg). Colorless oil. All
spectroscopic data were in agreement with the literature.8b Enantiomeric excess was
determined by HPLC with a CHIRALCEL PC-3 column [λ = 214 nm; eluent:
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
hexane/isopropanol = 90/10; flow rate: 0.50 mL/min; tminor = 6.99 min, tmajor = 7.45
min; ee% = 52%].
8
9
General procedure of for the Wacker oxidation. Product of the enantioselective
allylic alkylation (0.2 mmol) was added to a mixture of PdCl2 (0.02 mmol) and
Cu(OAc)2 (0.04 mmol) in DMA:H2O (7:1) (4 mL). The resulting mixture was stirred
for 48 h at room temperature under O2 atmosphere. After that time the reaction
mixture was diluted with Et2O, washed with brine, dried with anhydrous Na2SO4.
After removal of the solvent, the residue was submitted to column chromatography on
silica gel (EtOAc:Hexane, 1:4) giving the corresponding diketone.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Fluoro-2-methyl-1-(p-tolyl)pentane-1,4-dione (9c, Table 1, entry 3). Yield 71%
(32 mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.4 Hz, 2H), 7.24 (d,
J = 7.4 Hz, 2H), 3.48 (dd, J = 32.5, 17.3 Hz, 1H), 3.03 (dd, J = 17.3, 12.2 Hz, 1H),
13
2.39 (s, 3H), 2.14 (s, 3H), 1.65 (d, J = 21.5 Hz, 3H); C NMR (100 MHz, CDCl3) δ
203.4, 200.8 (d, JCF = 24.9 Hz), 143.7, 132.2 (d, JCF = 3.9 Hz), 129.9 (d, JCF = 7.8 Hz),
129.0, 99.1 (d, JCF = 188.4 Hz), 52.6 (d, JCF = 22.6 Hz), 30.2, 24.9 (d, JCF = 24.1 Hz),
21.6; 19F NMR (376 MHz, CDCl3) δ -151.4 (m); IR (neat) ν 1718, 1682, 1601, 1364,
1176 cm-1; MS (EI) m/z 222 [M]+; HRMS (EI-TOF-MS) calcd for C13H15O2F [M]
222.1056, found 222.1052. Enantiomeric excess was determined by HPLC with a
CHIRALCEL AD-H Column [λ = 214 nm; eluent: hexane/isopropanol = 95/5; flow
rate: 0.70 mL/min; tminor = 7.23 min, tmajor = 8.08 min; ee% = 73%; [α]D27 27.7 (c 1.02,
CH2Cl2)].
2-Fluoro-1-(4-methoxyphenyl)-2-methylpentane-1,4-dione (9d, Table 1, entry 4).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
1
2
3
4
5
6
7
8
9
Yield 64% (30 mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz,
2H), 6.93 (d, J = 9.2 Hz, 2H), 3.86 (s, 3H), 3.48 (dd, J = 32.2, 17.4 Hz, 1H), 3.02 (dd,
J = 17.2, 12.0 Hz, 1H), 2.15 (s, 3H), 1.66 (d, J = 21.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 203.5, 199.0 (d, JCF = 24.0 Hz), 163.3, 132.3 (d, JCF = 8.5 Hz), 127.4 (d, JCF
= 4.0 Hz), 113.5 (d, JCF = 1.5 Hz), 99.3 (d, JCF = 186.5 Hz), 55.4, 52.4 (d, JCF = 22.5
Hz), 30.3, 24.9 (d, JCF = 23.2 Hz); 19F NMR (376 MHz, CDCl3) δ -150.7 (m); IR (neat)
ν 2976, 1723, 1676, 1600, 1572, 1509 cm-1; MS (EI) m/z 238 [M]+; HRMS
(EI-TOF-MS) calcd for C13H15O3F [M] 238.1005, found 238.1008. Enantiomeric
excess was determined by HPLC with a CHIRALCEL IC Column [λ = 214 nm; eluent:
hexane/isopropanol = 80/20; flow rate: 0.70 mL/min; tminor = 25.28 min, tmajor = 20.98
min; ee% = 77%; [α]D26 46.5 (c 1.08, CH2Cl2)].
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Fluoro-1-(4-fluorophenyl)-2-methylpentane-1,4-dione (9e, Table 1, entry 5).
Yield 72% (34 mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 7.8, 5.4
Hz, 2H), 7.13 (dd, J = 8.8, 7.8 Hz, 2H), 3.53 (dd, J = 34.4, 17.6 Hz, 1H), 3.09 (dd, J =
17.6, 10.8 Hz, 1H), 2.16 (s, 3H), 1.65 (d, J = 21.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 203.3, 199.9 (d, JCF = 24.8 Hz), 165.5 (d, JCF = 253.3 Hz), 132.7(d, JCF
=
8.6 Hz), 132.5 (d, JCF = 9.3 Hz), 115.3(dd, JCF = 21.7, 1.5 Hz), 99.0 (d, JCF = 187.5
Hz), 52.9 (JCF = 22.5 Hz), 30.0, 24.8(d, JCF = 23.3 Hz); 19F NMR (376 MHz, CDCl3)
δ -105.5 (m, 1F), -151.6 (m, 1F); IR (neat) ν 1721, 1682, 1599, 1505, 1233, 1159 cm-1;
MS (EI) m/z 226 [M]+; HRMS (EI-TOF-MS) calcd for C12H12O2F2 [M] 226.0805,
found 226.0800. Enantiomeric excess was determined by HPLC with a CHIRALCEL
PC-3 Column [λ = 214 nm; eluent: hexane/isopropanol = 90/10; flow rate: 0.70
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
1
2
3
4
5
26
mL/min; tminor = 19.63 min, tmajor = 17.09 min; ee% = 77%; [α]D 42.0 (c 0.98,
6
7
8
CH2Cl2)].
9
1-(4-Chlorophenyl)-2-fluoro-2-methylpentane-1,4-dione (9f, Table 1, entry 6).
Yield 67% (32 mg). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz,
2H), 7.43 (d, J = 8.4 Hz, 2H), 3.53 (dd, J = 34.6, 17.8 Hz, 1H), 3.10 (dd, J = 17.8,
11.0 Hz, 1H), 2.15 (s, 3H), 1.64 (d, J = 21.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
203.3, 200.5(d, JCF = 24.8 Hz), 139.2, 133.3 (d, JCF = 4.7 Hz), 131.3 (d, JCF = 8.5 Hz),
128.5 (d, JCF = 1.5 Hz), 99.0 (d, JCF = 187.5 Hz), 53.0 (d, JCF = 22.5 Hz), 30.0, 24.8(d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
JCF = 24.1 Hz); F NMR (376 MHz, CDCl3) δ -152.0 (m); IR (neat) ν 1721, 1686,
1617, 1588, 1488, 1444, 1400, 1366, 1090 cm-1; MS (EI) m/z 242 [M]+; HRMS
(EI-TOF-MS) calcd for C12H12O2FCl [M] 242.0510, found 242. 0507. Enantiomeric
excess was determined by HPLC with a CHIRALCEL PC-3 Column [λ = 214 nm;
eluent: hexane/isopropanol = 90/10; flow rate: 0.70 mL/min; tminor = 18.13 min, tmajor
= 14.28 min; ee% = 84%; [α]D26 29.2 (c 1.15, CH2Cl2)].
1-(3-Bromophenyl)-2-fluoro-2-methylpentane-1,4-dione (9j, Table 1, entry 10).
Yield 76% (44 mg). Colorless oil. 1H NMR(400 MHz, CDCl3) δ 8.13 (s, 1H), 7.95 (d,
J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 3.54 (dd, J = 35.0,
18.0 Hz, 1H), 3.10(dd, J = 18.0, 10.4 Hz, 1H), 2.16 (s, 3H), 1.64 (d, J = 20.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 203.2, 200.2 (d, JCF = 25.6 Hz), 136.8, 135.6, 132.6 (d,
JCF = 8.6 Hz), 129.8, 128.3 (d, JCF = 8.6 Hz), 122.4, 98.8 (d, JCF = 185.2 Hz), 53.1 (d,
19
JCF = 22.5 Hz), 29.9, 24.7 (d, JCF = 23.2 Hz); F NMR (376 MHz, CDCl3) δ -152.4
(m); IR (neat) ν 1728, 1688, 1562, 1366, 1176, 1100 cm-1; MS (EI) m/z 286 [M]+;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
1
2
3
4
5
6
7
8
9
HRMS (EI-TOF-MS) calcd for C12H12O2FBr [M] 286.0005, found 286.0006.
Enantiomeric excess was determined by HPLC with a CHIRALCEL AD-H Column
[λ = 214 nm; eluent: hexane/isopropanol = 95/5; flow rate: 0.70 mL/min; tminor = 6.68
min, tmajor = 7.48 min; ee% = 86%; [α]D26 39.1 (c 1.03, CH2Cl2)].
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Fluoro-2-methyl-1-(3-(trifluoromethyl)phenyl)pentane-1,4-dione (9k, Table 1,
1
entry 11). Yield 61% (34 mg). Colorless oil. H NMR (400 MHz, CDCl3) δ 8.27 (s,
1H), 8.22 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 3.55
(dd, J = 35.2, 18.0 Hz, 1H), 3.13 (dd, J = 17.8, 10.6 Hz, 1H), 2.17 (s, 3H), 1.66 (d, J =
21.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 203.3, 200.7 (d, JCF = 25.5 Hz), 135.7 (d,
JCF = 4.7 Hz), 133.0 (d, JCF = 8.6 Hz), 130.7 (q, JCF = 32.0 Hz),129.1 (q, JCF = 3.6 Hz),
128.8 (d, JCF = 1.5 Hz), 126.6 (m), 98.9 (d, JCF = 187.4 Hz), 53.3 (d, JCF = 22.5 Hz),
29.8, 24.7 (d, JCF = 24.1 Hz); 19F NMR (376 MHz, CDCl3) δ -62.8 (s, 3F), -152.6 (m,
1F); IR (neat) ν 1722, 1692, 1612, 1335, 1290, 1230, 1169, 1182, 1075 cm-1; MS (EI)
m/z 276 [M]+; HRMS (EI-TOF-MS) calcd for C13H12O2F4 [M] 276.0773, found 276.
0769. Enantiomeric excess was determined by HPLC with a CHIRALCEL ID3
Column [λ = 214 nm; eluent: hexane/isopropanol = 95/5; flow rate: 0.70 mL/min;
tminor = 5.59 min, tmajor = 4.84 min; ee% = 86%; [α]D26 43.4 (c 0.62, CH2Cl2)].
The trapping of the enolate ion. To a Schlenck tube was added
α-fluoropropiophenone 1a (0.2 mmol), 1 mL freshly distilled THF under nitrogen
o
atmosphere. The reaction mixture was cooled down to 0 C. LiHMDS (0.24 mL, 1.0
M in THF) was added dropwise. After 1.5 h, 4-methylbenzenesulfonic anhydride (0.3
mmol, 1.5 eq) and freshly distlled THF (1 mL) were added. The reaction was allowed
ACS Paragon Plus Environment

Page 23 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
to warm to ambient temperature overnight. Deionized water was added to the mixture
and the organic layer was separated. The aqueous layer was extracted with ether, and
the combined organic layer was washed with saturated NaCl (aq). After drying over
Na2SO4, the product was purified by column chromatography on silica gel
(hexane/Et2O).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Z)-2-Fluoro-1-phenylprop-1-en-1-yl 4-methylbenzenesulfonate (6). Yield 55%
o
1
(34 mg). White solid, m.p. 88.25 C. H NMR (400 MHz, CDCl3) δ 7.63(d, J = 8.0
Hz, 2H), 7.26 (s, 5H), 7.17 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H), 2.04 (d, J = 18.5 Hz,
13
3H); C NMR (100 MHz, CDCl3) δ 153.3, 150.7, 144.7, 133.7, 131.2 (d, JCF = 2.3
Hz), 130.5, 130.4, 129.3, 128.8, 128.7, 128.2, 128.1, 21.6, 15.1 (d, JCF = 25.8 Hz); 19F
NMR (376 MHz, CDCl3) δ -105.7 (q, J = 17.7 Hz); IR (KBr) ν 1368, 1230, 1188,
1180, 1084, 1064 790, cm-1; MS (EI) m/z 306 [M]+; HRMS (EI-TOF-MS) calcd for
C16H15O3SF [M] 306.0726, found 306.0729.
Acknowledgments. This work was financially supported by National Basic
Research Program of China (973 Program) (No. 2012CB821600), National Natural
Science Foundation of China (No. 21032006, 21172241) and Shanghai Science and
Technology Commission (11ZR1445700). We also thank Prof. Xue-Long Hou and Dr.
Chang-Hua Ding for providing SiocPhos.
Supporting Information Available: Experimental detail and copies of 1H NMR,
13C NMR and 19F NMR spectroscopies for all new compounds and Chiral HPLC
analysis This material is available free of charge via Internet at http://pubs.acs.org/.
References and Footnotes
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
1
2
3
4
5
6
7
8
9
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320-330. (b) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071-1081. (c) Zhang,
C.-P.; Chen, Q.-Y.; Guo, Y.; Xiao, J.-C.; Gu, Y.-C. Chem. Soc. Rev., 2012, 41,
4536-4559. (d) Zhang, C.-P.; Chen, Q.-Y.; Guo, Y.; Xiao, J.-C. Tetrahedron 2013, 69,
10955-10989. (e) Zhang, C.-P.; Chen, Q.-Y.; Guo, Y.; Xiao, J.-C.; Gu, Y.-C. Coord.
Chem. Rev. 2014, 261, 28-72. (f) Uneyama, K. Organofluorine Chemistry; Blackwell:
Oxford, U.K., 2006.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) For reviews, see: (a) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed.
2013, 52, 8214-8264. (b) Valero, G.; Companyó, X.; Rios, R. Chem. Eur. J. 2011, 17,
2018−2037. (c) Cahard, D.; Xu, X., Couve-Bonnaire, S.; Pannecoucke X. Chem. Soc.
Rev. 2010, 39, 558-568. (d) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth.
Catal. 2010, 352, 2708-2732. (e) Smith, A. M. R.; Hii, K. K. (M.) Chem. Rev. 2011,
111, 1637-1656. (f) Shibatomi, K. Synthesis 2010, 2679-2702. (g) Ma, J.-A.; Cahard,
D. Chem. Rev. 2008, 108, PR1-PR43 and 2004, 104, 6119-6146.
(3) Selected recent examples of asymmetric electrophilic fluorination to construct a
tertiary fluoride: (a) Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136,
5225-5228 and references cited therein. (b) Li, J.; Cai, Y.; Chen, W.; Liu, X.; Lin, L.;
Feng, X. J. Org. Chem. 2012, 77, 9148-9155. (c) Deng, Q.-H.; Wadepohl, H.; Gade, L.
H. Chem. Eur. J. 2011, 17, 14922-14928. (d) Wang, L.; Meng, W.; Zhu, C.-L.; Zheng,
Y.; Nie, J.; Ma, J.-A. Angew. Chem., Int. Ed. 2011, 50, 9442-9446. (e) Kang, S. H.;
Kim, D. Y. Adv. Synth. Catal. 2010, 352, 2783-2786. (f) Reddy, D. S.; Shibata, N.;
Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem., Int. Ed. 2008, 47,
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
164-168. (g) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.;
Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 4157-4161.
8
9
(4) Selected recent examples of building block methods to construct a chiral tertiary
fluoride: (a) Wu, L.; Falivene, L.; Drinkel, E.; Grant, S.; Linden, A.; Cavallo, L.;
Dorta, R. Angew. Chem., Int. Ed. 2012, 51, 2870-2873. (b) Shibatomi, K.; Futatsugi,
K.; Kobayashi, F.; Iwasa, S.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 5625-5627.
(5) Preparation of tertiary alkyl fluorides by Pd-catalyzed allylic alkylation: (a)
Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem., Int. Ed. 2005, 44,
7248-7251. (b) Burger, E. C.; Barron, B. R.; Tunge, J. A. Synlett 2006, 2824-2826. (c)
Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed.
2005, 44, 6924-6927. (d) Bélanger, É.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin,
J.-F. J. Am. Chem. Soc. 2007, 129, 1034-1035. (e) Bélanger, É.; Houzé, C.; Guimond,
N.; Cantin, K.; Paquin, J.-F. Chem. Commun. 2008, 3251-3253. (f) Bélanger, É.;
Pouliot, M.-F.; Paquin, J.-F. Org. Lett. 2009, 11, 2201-2204. (g) Bélanger, É.; Pouliot,
M.-F.; Courtemanche, M.-A.; Paquin, J.-F. J. Org. Chem. 2012, 77, 317-331. (h)
Chattopadhyay, K.; Jana, R.; Day, V. W.; Douglas, J. T.; Tunge, J. A. Org. Lett. 2010,
12, 3042-3045.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) During the preparation of our manuscript, a stereoconvergent Negishi arylation of
racemic α-bromo-α-fluoroketones was reported, where an aryl group was
enantioselectively introduced to form the tertiary fluoride product. See: Liang, Y.; Fu,
G. C. J. Am. Chem. Soc. 2014, 136, 5520-5524.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
1
2
3
4
5
6
7
8
9
(7) Some reviews of asymmetic Pd-catalyzed allylation: (a) Ding, C.-H.; Hou,
X.-L. Top. Organomet. Chem. 2011, 36, 247-286. (b) Lu, Z.; Ma, S. Angew. Chem.,
Int. Ed. 2008, 47, 258-297. (c) Mohrand, J. T.; Stoltz, B. M. Chem. Asian J. 2007, 2,
1476-1491; (d) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395-422.
(8) Asymmetric allylic alkylation of nonfluorinated acyclic carbonyl compounds: (a)
Yan, X.-X.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao, B.-X.; Dai, L.-X.; Hou, X.-L.
Angew. Chem., Int. Ed. 2005, 44, 6544-6546. (b) Trost, B. M.; Xu, J. J. Am. Chem.
Soc. 2005, 127, 17180-17181. (c) Trost, B. M.; Xu, J.; Reichle, M. J. Am. Chem. Soc.
2007, 129, 282-283. (d) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2008, 130,
11852-11853. (e) Evans, P. A.; Clizbe, E. A.; Lawler, M. J.; Oliver, S. Chem. Sci.
2012, 3, 1835-1838.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a) Guo, Y.; Tao, G.- H.; Blumenfeld, A.; Shreeve, J. M. Organometallics 2010,
29, 1818-1823. (b) Guo, Y.; Twamley, B.; Shreeve, J. M. Org. Biomol. Chem. 2009,
7, 1716-1722. (c) Guo, C.; Wang, R.-W.; Guo, Y.; Qing, F.-L. J. Fluorine Chem.
2012, 133, 86-89. (d) Wang, W.; Chen, Q.-Y.; Guo, Y. Synlett 2011, 2705-2708. (e)
Hu, H.; Huang, Y.; Guo, Y. J. Fluorine Chem. 2012, 133, 108-114. (f) Huan, F.; Hu,
H.; Huang, Y.; Chen, Q.-Y.; Guo, Y. Chin. J. Chem. 2012, 30, 798-802. (g) Wang, Q.;
Chen, Q.-Y.; Yang, X.; Guo, Y. Synthesis 2012, 3815-3821.
(10) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am. Chem. Soc.
2001, 123, 7471-7472.
ACS Paragon Plus Environment