Thiourea-catalyzed enantioselective fluorination of β-keto esters

Article abstract of DOI:10.1002/adsc.201100660

Bifunctional chiral thioureas have been successfully used as organocatalysts in enantioselective fluorinations of β-keto esters. The corresponding products could be obtained with good to excellent enantioselectivity in high yields by using N-fluorobisbenzenesulphonimide (NFSI) as fluorination reagent. Copyright

Full text of DOI:10.1002/adsc.201100660

FULL PAPERS
DOI: 10.1002/adsc.201100660
Thiourea-Catalyzed Enantioselective Fluorination of b-Keto
Esters
Junxing Xu,a Yulai Hu,a,b,* Danfeng Huang,a Ke-Hu Wang,a Changming Xu,a
and Teng Niua
a
College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning Road (E.), Lanzhou 730070,
People’s Republic of China
Fax : (+86)-931-7971-989; e-mail: huyulai@126.com
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
b
Received: August 20, 2011; Revised: October 19, 2011; Published online: February 9, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100660.
Abstract: Bifunctional chiral thioureas have been benzenesulphonimide (NFSI) as fluorination re-
successfully used as organocatalysts in enantioselec- agent.
tive fluorinations of b-keto esters. The corresponding
products could be obtained with good to excellent Keywords: asymmetric catalysis; enantioselective flu-
enantioselectivity in high yields by using N-fluorobis- orination; b-keto esters; organocatalysis
Introduction
enantioselective fluorination of ketones and alde-
hydes via enamines,[10] and Cinchona alkaloids-in-
The chemistry of organofluorine compounds has at- duced enantioselective fluorination reactions have
tracted more and more attention in recent years be- been reported.[11] However, there is no report on
cause of their increasingly important role in medicinal enantioselective fluorination reactions using bifunc-
chemistry and material science.[1] One of the most fas- tional chiral thioureas as organocatalysts although
cinating aspects of organofluorine chemistry is the such thiourea-based organocatalysts have proved to
asymmetric synthesis of fluorinated molecules be- be remarkably useful organic catalysts in various
cause many fluorinated bioactive molecules have a asymmetric reactions.[12] Herein we demonstrate first-
stereogenic carbon-fluorine center.[2] Thus, various ly that chiral thioureas are very effective catalysts in
methods for asymmetric incorporation of a fluorine enantioselective fluorination reactions using NFSI as
atom into organic molecules have been develop- fluorination reagent.
ACHTUNGTRENNUNG
ed.[1h,i,2a,b,3] Among these procedures to produce enan-
tiopure organofluorine compounds, catalytic enantio-
selective fluorinations provide one of the most power- Results and Discussion
ful synthetic methods. Since the first report of catalyt-
ic enantioselective fluorination by Togni in 2000,[4] As a beginning of our investigation on bifunctional
these reactions have been attracting more and more thiourea-catalyzed asymmetric fluorination reactions,
attention.[5] Both chiral metal complex-catalyzed reac- we used a b-keto ester as substrate in order to com-
tions[6] and organocatalysis[7] have been investigated pare the result with those of other catalytic systems
for catalytic enantioselective fluorinations. As is well reported in the literature.[1k,6e,k,7,13] We firstly carried
known, organocatalysis using small organic molecules out the fluorination of 2a using NFSI as fluorinating
has been established as a highly selective and efficient agent in the presence of 50 mol% of 1a using THF as
method in a wide range of reactions in the last decade solvent. To our delight we found that 3a was obtained
and developed into an essential third branch of asym- in 31% ee (Scheme 1). Different solvents such as tolu-
metric catalysis that complements the fields of metal ene, dichloromethane and methanol, were tested in
and enzyme catalysis.[8] It has also been used in enan- the reaction in order to improve the ee value, but the
tioselective fluorination reactions. For example, enan- enantioselectivity was even lower. Finally methanol
tioselective fluorination of b-keto esters,[9] catalytic was found to be the best solvent. As shown in
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Table 1. Thiourea-catalyzed enantioselective fluorination of
2a.[a]
Entry Cat. Yield
[%]
ee
Entry Cat. Yield
[%]
ee
[%][b]
[%][b]
1
2
3
4
5
6
1a
1b 86
1c 85
1d 85
80
9.0
7
8
9
10
11
12
1g
1h 58
1i
1j
1k 76
1l 65
60
0.6
0.5
-8.6
-11.0
0.5
15.0
11.0
5.0
20.0
13.0
85
76
Scheme 1. Enantioselective fluorination of 2a catalyzed by
1a.
1e
1f
80
84
0.0
[a]
The reactions were carried out by adding NFSI
(0.12 mmol) to a mixture of 2a (0.1 mmol) and catalyst
(20 mol%) in methanol at room temperature for 7 days.
Enantiopurity of 3a was determined by HPLC analysis
with a Chiralcel OD-H column, 2-propanol-hexane (1:9),
1.0 mL/min, l=254 nm.
Figure 1, the configurations of catalysts 1a and 1i are
reversed. When they were used in the reaction, the
configurations of the products were also reversed
(Table 1, entries 1 and 9). The same results were ob-
tained for catalysts 1b and 1j (Table 1, entries 2 and
[b]
Figure 1. The catalysts used in this work.
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Thiourea-Catalyzed Enantioselective Fluorination of b-Keto Esters
Table 2. Optimization of reaction conditions using 1b, 1e and 1f as catalysts from 2a to 3a.[a]
Entry
Cat. (mol%)
T [8C]
Solvent
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
1b (10)
1b (30)
1b (40)
1b (50)
1b (60)
1b (80)
1e (30)
1e (50)
1f (30)
1f (50)
1b (50)
1b (50)
1b (50)
1b (50)
1b (50)
1b (50)
1b (50)
1b (50)
1b (50)
1b (50)
1b (50)
1b (50)
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
À10
À20
À60
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
EtOH
CH2Cl2
toluene
THF
76
86
92
92
96
95
91
95
80
86
90
95
78
80
80
90
90
89
90
90
90
90
10
35
52
83
79
77
25
85
15
31
30
67
27
49
35
51
37
34
25
80
85
84
9
10
11
12
13
14
15
16
17
18
19
20
21
22
MeOH/H2O 2/1
MeOH/toluene 1/1
MeOH/toluene 1/2
MeOH/toluene 1/3
MeOH
MeOH
MeOH
[a]
The reactions were carried out by adding NFSI (0.12 mmol) to a mixture of 2a (0.1 mmol) and catalyst in methanol for
7 days.
[b]
Enantiopurity of 3a was determined by HPLC analysis with a Chiralcel OD-H column, 2-propanol-hexane (1:9), 1.0 mL/
min, l=254 nm.
10). These results let us make sure that the thioureas
have an enantioselective induction effect in the fluori- tained, the catalyst loading was too high. This led us
nation of 2a. to consider how to reduce the loading of catalyst. In
Although high yield and high ee value were ob-
We next screened more thiourea catalysts such as order to solve this question, the functions of the cata-
1a–1l in the fluorination of 2a using methanol as sol- lyst must be known in the reactions. So thioureas 1m,
vent under same conditions (Table 1). Each catalyst 1n and 1o without a tertiary amine group were pre-
gave the product in good yield, but the ee values were pared and used in the fluorination of 2a. It was found
still low as shown in Table 1. We noticed that elec- that there no reactions occurred at all (Scheme 2). So
tron-rich thiourea catalysts 1b, 1e and 1f gave better it seemed that a tertiary amine group was crucial to
ee values than the electron-poor one 1d. This result make the reaction occur. Next the tertiary amines 1p
was different from that in the literature. As reported and 1q without a thiourea group were tested as cata-
in the literature, the thiourea 1d usually gave good lysts in the reactions, and the reactions gave the race-
enantioselectivity in other reactions.[14] The more hin- mic products in excellent yields although the structure
dered catalysts 1g and 1h produced almost racemic of catalyst 1q was very similar to that of catalyst 1j.
products (Table 1, entries 7 and 8). Thus, the catalysts The difference is that there is no thiourea group in 1q
1b, 1e and 1f were used for further optimization of (Scheme 2). These results made it clear that the thio-
the reaction conditions as showed in Table 2. Firstly, urea catalysts played two roles in the reaction. One
the loadings of the catalysts were checked and the re- was the control of enantioselectivity by the thiourea
sults showed that both of the yield and ee value were group, and another as a base to deprotonate 2a.
increased with the increasing catalyst loading, espe-
Based on the above evidence, we tried the reaction
cially, the ee value increased to above 83% when using triethylamine (TEA) as base and 30% thiourea
50 mol% catalyst load were used (Table 2, entries 4 1b as catalyst. To our delight, we found that the reac-
and 8). These results encouraged us for further tion gave the product in 99% ee and 95% yield at
screening of solvents, and methanol was still found to -608C (Table 3, entry 2). When the catalyst loading
be the best solvent (Table 2, entries 4 and 11-19). was reduced to 20 mol%, the ee value decreased to
Changes in temperature had little effect on yields and 95% (Table 3, entry 4). The amount of the TEA was
ee values under these conditions (Table 2, entries 4 also found to have an effect on the reaction (Table 3,
and 20-22).
entries 1–3). The best result was obtained when the
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Scheme 2. Fluorination of 2a catalyzed by thioureas without tertiary amine or by tertiary amine without thioureas.
Table 3. Effects of additives and temperature on the fluorination of 2a.[a]
Entry
Cat. (mol%)
Additive (equiv.)
t [h]
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1b (30)
1b (30)
1b (30)
1b (20)
1b (20)
1b (20)
1b (20)
1b (10)
1b (5)
1b (10)
1b (10)
1b (10)
1b (10)
1e (10)
1d (10)
1m(10)
1g (10)
TEA (2.5)
TEA (1.0)
TEA (0.5)
TEA (1.0)
DMAP (1.0)
30
36
36
36
32
32
36
42
48
30
24
36
32
42
42
42
42
À60
À60
À60
À60
À60
À60
À60
À60
À60
À40
À20
À60
À60
À60
À60
À60
À60
96
95
95
98
97
95
85
92
89
94
94
91
89
96
88
71
86
81
99
87
95
>99
95
88.0
>99
95
73
48
33
23
96
11
0
À11
NHACTHNGUTREN(UNG Pr-i)2 (1.0)
Pyridine (1.0)
DMAP (1.0)
DMAP (1.0)
DMAP (1.0)
DMAP (1.0)
K2CO3 (1.0)
NaOH (1.0)
DMAP (1.0)
DMAP (1.0)
DMAP (1.0)
DMAP (1.0)
9
10
11
12
13
14
15
16
17
[a]
NFSI (1.1 equiv.) was added to a solution of 2a (1.0 equiv), catalyst 1b (10 mol%) and additive (1.0 equiv) in MeOH
(3 mL).
Isolated yields.
[b]
[c]
Enantiopurity of 3a was determined by HPLC analysis with a Chiralcel Od-H column, 2-propanol-hexane (1:9), 1.0 mL/
min, l=254 nm.
amount of TEA was 1 equivalent. Further investiga- finally (Table 3, entries 5-7, 12 and 13). The reaction
tion showed that the ee value could still reach above temperature was also found to have a great effect on
99% when 1 equivalent of 4-dimethylaminopyridine the reaction under these conditions (Table 3, entries 8,
(DMAP) was used as base instead of triethylamine 10 and 11). It was found that the ee values increased
(Table 3, entry 5). The catalyst loading was further re- with the decrease of the reaction temperature. For ex-
duced to 10 mol% using DMAP as base and the ee ample, the ee value of the product was only 48%
value of the product was maintained above 99% when the reaction was conducted at À208C. However,
(Table 3, entry 8). When the catalyst load was reached when the reaction temperature was lowed to À608C,
to 5 mol%, the ee value was decreased to 95% the enantioselectivity of the product increased to
(Table 3, entry 9). So the best catalyst loading was above 99%.
10 mol%. Other basic additives have also been tested
With the optimized reaction conditions in hand, the
in the fluorination reaction of 2a under the same con- scope of this bifunctional thiourea-catalyzed asym-
ditions, and DMAP was found to be the best additive metric fluorination reaction was exploited to check
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Thiourea-Catalyzed Enantioselective Fluorination of b-Keto Esters
Scheme 3. Substrates scope of asymmetric fluorination catalyzed by thiourea catalyst 1b. The reaction was carried out in
MeOH at À608C for about 30 hours using 1b (10 mol%) as catalyst. Yields are of isolated product following purification by
column chromatography. Enantiomeric excesses (ee) were determined by HPLC.
the substrate generality of this strategy. It was found NaOMe was used as base instead of DMAP
that excellent yields and ee values could be obtained (Scheme 3, 3q), but the ee value of 3r was low under
for most indanonecarboxylate derivatives (Scheme 3). the same conditions (Scheme 3, 3r). The racemic
The alkoxy group in the b-keto ester has a great influ- product 3s was produced under the same conditions.
ence on ee value of the product. For example, when The reason for this is that the product 3s can be enol-
the alkoxy group was a small methyl group such as in ized during the reaction to give the racemic product.
2a, the enantioselectivity of the reaction was above
We also tried to use Selectfluor as fluorination re-
99% (Scheme 3, 3a). However, the racemic product agent instead of NFSI in the presence of 50 mol% of
3d was obtained when the alkoxy group was changed 1b as catalyst. However, the reaction gave the com-
to the bulky tertiary butyl group (Scheme 3, 3d). Flu- pletely racemic product in 86% yield. This result was
orination of tetralone deritives such as 2o and 2p totally different from the result obtained using NFSI
under these conditions gave the corresponding prod- (Table 2, entry 4). So we envisioned that the thiourea
ucts in low ee value although the yields were good group was attached to NFSI via a hydrogen bond and
(Scheme 3, 3o and 3p). When an acyclic b-keto ester the 1,3-dicarbonyl group interacted with the tertiary
such as 2q–2s was used as substrate, no fluorination amine group as showed in Figure 2. A similar interac-
reaction occurred under these conditions. However, tion was also reported by Lu.[14c] The plausible reac-
the product 3q was also obtained in 81% ee if tion mechanism is shown in Figure 2.
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Figure 2. Plausible reaction mechanism.
and19F NMR spectra were recorded on a Varian Mercury
400 plus instrument. Chemical shifts are reported in ppm
relative to tetramethylsilane (TMS), the coupling constants
J are given in Hz. The spectra were recorded in CDCl3
(unless otherwise stated) as solvent at room temperature,
Conclusion
In summary, thiourea-based bifunctional organocata-
lysts have been successfully applied in the enantiose-
lective fluorination reactions of b-keto esters. The cor-
responding products could be obtained with good to
excellent enantioselectivity in high yields when NFSI
was used as fluorination reagent. However, the reac-
tion gave only racemic products when Selectfluor was
used as fluorination reagent. The interaction between
NFSI and thiourea catalysts will be further investigat-
ed in other reactions.
1
TMS served as internal standard (d=0 ppm) for H NMR,
and CDCl3 was used as internal standard (d=77.0) for
13C NMR. CFCl3 served as an internal standard for
19F NMR. High-resolution mass spectra were obtained on a
Bruker ESQ6K spectrometer. Melting points were deter-
mined on a Beijing Taike X-4 melting point apparatus. Opti-
cal rotations were recorded on a Shanghai Jingmi WZZ-2B
polarimeter. The enantiomeric excesses of products were de-
termined by chiral-phase HPLC analysis. The catalysts 1a–
1j,[15a,b] 1k,[15c] and 1q[15d] were synthesized according to liter-
ature procedures. Compound 1p was purchased from Alfa
Aesar. The substrates 2a–2k, 2m, 2o, 2p, and 2s[16a,b] were
prepared according to literature procedures. Substrates 2l,
2n, 2q, and 2r were purchased from Alfa Aesar.
Experimental Section
General Information
All reactions that required anhydrous conditions were per-
formed by standard procedures under a nitrogen atmos-
phere. Chemicals and solvents were either purchased from
commercial suppliers or purified by standard techniques.
Flash chromatography (FC) was carried out using Qingdao
silica Gel 60 (230–400 mesh). The 1H NMR 13C NMR
General Procedure for Preparing Catalysts 1a–1j
Under a nitrogen atmosphere, to a solution of substituted
isothiocyanate (2.0 mmol) in dry THF (5.0 ml) was added 9-
aminoACTHNURTGNEU(GN 9-deoxy)epihydroquinine (685 mg, 2.1 mmol). After
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Thiourea-Catalyzed Enantioselective Fluorination of b-Keto Esters
stirring for 12 h, the reaction mixture was concentrated
under vacuum. The residue was purified by column chroma-
tography on silica gel (EtOAc/MeOH/concentrated aqueous
NH4OH as eluant) to give the desired thiourea catalyst.
Catalyst 1a was prepared according to the general proce-
Catalyst 1e was prepared according to the general proce-
dure as a white solid; overall yield; 75%. [a]2D0: À149.8 (c
1
0.34, CHCl3); H NMR (400 MHz, CDCl3): d=8.99 (s, 1H),
8.31 (s, 1H), 8.01 (s, 1H), 7.91–7.85 (m, 3H), 7.69–7.63 (m,
1H), 7.55–7.42 (m, 4H), 7.29 (d, J=9.2 Hz, 1H), 7.07 (s,
3H), 5.84 (s, 1H), 5.56 (ddd, J=17.4, 10.1, 7.5 Hz, 1H), 4.86
dure as a white solid; overall yield: 65%. [a]2D0: À167.1 (c
1
0.37, CHCl3); H NMR (400 MHz, CDCl3): d=9.11 (s, 1H),
8.49 (d, J=1.8 Hz, 1H), 8.22 (s, 1H), 7.99 (d, J=9.2 Hz,
1H), 7.80 (s, 1H), 7.38–7.34 (m, 3H), 7.27 (d, J=6.8 Hz,
1H), 7.20 (d, J=7.2 Hz, 3H), 5.91 (s, 1H), 5.69 (ddd, J=
17.2, 10.0, 7.6 Hz, 1H), 4.96–4.89 (m, 2H), 3.94 (s, 3H), 3.34
(br m, 1H), 3.12–3.06 (m, 2H), 2.69–2.66 (m, 2H), 2.25 (br
m, 1H) 1.64–1.58 (m, 3H), 1.34–1.29 (m, 1H), 0.87–0.85 (m,
1H); 13C NMR (100 MHz, CDCl3): d=180.30, 157.64,
147.46, 144.59, 140.85, 137.51, 131.46, 129.35, 126.50, 125.50,
121.79, 114.61, 102.24, 55.59, 55.09, 41.37, 39.20, 27.62, 27.16,
25.63; HR-MS (ES+): m/z=459.2207, calcd. for C27H30N4OS
(M+H): 459.2213.
(dt, J=9.3, 9.0 Hz, 2H), 3.85 (s, 3H), 3.17–3.11ACTHNGUTERNNU(G m, 1H),
2.88–2.82 (m, 2H), 2.45–2.36 (m, 2H), 2.15–2.12 (m, 1H)
1.57–1.47 (m, 3H), 1.25–1.19 (m, 1H), 0.87–0.81 (m, 1H);
13C NMR (100 MHz, CDCl3): d=181.90, 157.46, 147.27,
144.52, 140.92, 134.41, 133.02, 132.05, 131.65, 131.87, 131.46,
130.01, 128.49, 128.35, 128.24, 127.03, 126.71, 125.38, 125.21,
122.79, 121.79, 114.48, 102.15, 60.56, 55.47, 55.07, 41.09,
39.23, 27.67, 27.12, 25.68; HR-MS (ES+): m/z=509.2360,
calcd. for C31H32N4OS (M+H): 509.2370.
Catalyst 1f was prepared according to the general proce-
dure as a white solid; overall yield: 75%. [a]2D0: À185.83 (c
1
0.34, CHCl3); H NMR (400 MHz, CDCl3): d=9.26 (s, 1H),
Catalyst 1b was prepared according to the general proce-
8.43 (s, 1H), 7.96 (d, J=9.2 Hz), 7.85–7.71 (m, 4H), 7.51–
7.48 (m, 2H), 7.34–7.25 (m, 2H), 7.13 (s, 1H), 5.99 (s, 1H),
5.63 (ddd, J=17.4, 10.1, 7.5 Hz, 1H), 4.90 (dt, J=9.3,
9.0 Hz, 2H), 3.92 (s, 3H), 3.44–3.41 (m, 1H), 3.13–3.08 (m,
2H), 2.75–2.65 (m, 2H), 2.26–2.23 (m, 1H) 1.67–1.59 (m,
3H), 1.26–1.25 (m, 1H), 0.86–0.83 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=180.34, 157.71, 147.47, 144.65, 140.90,
134.95, 133.57, 131.63, 131.52, 129.45, 128.15, 127.74, 127.58,
126.78, 126.07, 123.89, 122.54, 121.80, 114.64, 102.33, 60.33,
55.61, 55.25, 41.53, 39.29, 27.75, 27.25, 25.72; HR-MS (ES+):
m/z=509.2379, calcd. for C31H32N4OS (M+H): 509.2370.
Catalyst 1g was prepared according to the general proce-
dure as a white solid; overall yield: 45%. [a]2D0: À31.8 (c
dure as a white solid; overall yield: 71%. [a]2D0: À152.3 (c
1
0.33, CHCl3); H NMR (400 MHz, CDCl3): d=8.88 (s, 1H),
8.47 (d, J=1.6 Hz, 1H), 8.22 (s, 1H), 7.98 (d, J=9.2 Hz,
2H), 7.77 (s, 1H), 7.36 (dd, J=9.2, 2.8 Hz, 1H), 7.15 (s,
1H), 7.12 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 5.87
(s, 1H), 5.69 (ddd, J=17.2, 10.0, 7.6 Hz, 1H), 4.95–4.89 (m,
2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.31 (br m, 1H), 3.12–3.06
(m, 2H), 2.68–2.64 (m, 2H), 2.25 (br m, 1H) 1.64–1.58 (m,
3H), 1.34–1.27 (m, 1H), 0.96–0.91 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=180.90, 158.33, 157.66, 147.50, 144.68,
140.97, 131.54, 130.11, 128.16, 127.43, 121.77, 114.60, 102.36,
60.71, 55.64, 55.44, 55.25, 41.38, 39.32, 27.73, 27.24, 25.74;
HR-MS (ES+): m/z=489.2308, calcd. for C28H32N4O2S (M+
H): 489.2319.
1
0.11, CHCl3); H NMR (400 MHz, CDCl3): d=8.46 (d, J=
4.3 Hz, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.66 (s, 1H), 7.32 (m,
16H), 6.67 (s, 1H), 6.02 (d, J=4.3 Hz, 1H), 5.56 (ddd, J=
17.0, 10.6, 6.3 Hz, 1H),5.48 (d, J=8.0 Hz, 1H ) 4.87 (dt, J=
11.1, 5.3 Hz, 2H), 3.89 (s, 3H), 3.08–3.00 (m, 1H), 2.85–2.78
(m, 1H), 2.39–2.14 (m, 4H), 1.81 (s, 1H) 1.54–1.49 (m, 1H),
1.31–1.23 (m, 1H), 1.15–1.11 (m, 1H) 0.83–0.81 (m, 1H);
13C NMR (100 MHz, CDCl3): d=180.05, 157.58, 147.24,
145.62, 144.23, 143.00, 141.36, 131.30, 128.79, 128.63, 128.40,
128.03, 127.67, 121.58, 118.35, 114.29, 102.21, 72.41, 61.49,
55.90, 55.81, 55.55, 41.02, 39.58, 27.69, 27.19, 25.46; HR-MS
(ES+): m/z=625.2981, calcd. for C40H40N4OS (M+H):
625.2996.
Catalyst 1c was prepared according to the general proce-
dure as a white solid; overall yield: 62%. [a]2D0: À149.6 (c
1
0.32, CHCl3); H NMR (400 MHz, CDCl3): d=9.34 (s, 1H),
8.51 (d, J=1.2 Hz, 1H), 8.19 (s, 1H), 7.97 (d, J=9.2 Hz,
1H), 7.78 (s, 1H), 7.36 (dd, J=9.2 2.4 Hz, 1H), 7.30 (d, J=
8.9 Hz, 2H), 7.13 (m, 3H), 5.96 (s, 1H), 5.68 (ddd, J=17.4,
10.0, 7.3 Hz, 1H), 4.98–4.92 (m, 2H), 3.95 (s, 3H), 3.38 (br
m, 1H), 3.22–3.19 (m, 1H), 2.75–2.61 (m, 2H), 2.27 (br m,
1H) 1.66–1.59 (m, 3H), 1.36–1.30 (m, 1H), 0.94–0.89 (m,
1H); 13C NMR (100 MHz, CDCl3): d=180.33, 157.76,
147.10, 144.62, 140.66, 136.23, 131.84, 131.52, 129.41, 128.07,
126.39, 121.88, 114.82, 102.21, 60.04, 55.63, 55.04, 41.52,
39.08, 27.52, 27.09, 25.58; HR-MS (ES+): m/z=493.1827,
calcd. for C27H29N4OClS (M+H): 493.1823
Catalyst 1h was prepared according to the general proce-
dure as a white solid; overall yield: 70%. [a]2D0: À151.0 (c
1
0.34, CHCl3); H NMR (400 MHz, CDCl3): d=8.73 (d, J=
Catalyst 1d was prepared according to the general proce-
dure as a white solid; overall yield: 58%. [a]2D0: À88.91 (c
0.31, CHCl3); 1H NMR (400 MHz, CDCl3): d=10.20 (s,
1H), 8.19 (s, 1H), 7.85 (s, 3H), 7.68 (s, 2H), 7.50 (dd, J=7.6
2.8 Hz, 1H), 7.30 (s, 1H), 6.88 (s, 1H), 5.94 (s, 1H), 5.72
(ddd, J=17.2, 9.8, 7.5 Hz, 1H), 5.03 (dt, J=10.6, 6.2 Hz,
2H), 3.98 (s, 3H), 3.49 (s, 1H), 3.25 (s, 1H), 3.07–3.04 (m,
1H), 2.75–2.73 (m, 2H), 2.32–2.31 (m, 1H) 1.71–1.66 (m,
3H), 1.43–1.38 (m, 1H), 0.91–0.87 (m, 1H); 13C NMR (100
MHz, CDCl3): d=180.44, 158.01, 147.09, 144.30, 140.66,
140.13, 132.96, 132.62, 132.29, 131.97, 131.87, 131.07, 128.90,
128.78, 128.09, 126.96, 124.25, 123.49, 122.13, 121.53, 118.82,
118.54, 114.98, 102.11, 60.61, 55.83, 54.74, 41.55, 39.01, 27.53,
27.09, 25.85; HR-MS (ES+): m/z=595.1964, calcd. for
C29H28F6N4OS (M+H): 595.1961.
4.4 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 7.69 (s, 1H), 7.47 (s, 1
H), 7.39–7.35 (m, 2H), 6.32 (s, 1H), 5.68 (ddd, J=17.4, 9.8,
7.6 Hz, 1H),5.44 (s, 1H) 4.95 (m, 2H), 3.98 (s, 3H), 3.28–
3.22 (m, 1H), 3.07 (s, 2H), 2.73–2.70 (m, 2H) 2.35–2.29 (m,
2H), 1.68–1.63 (m, 3H) 1.39 (s, 10H), 1.07–1.04 (m, 1H),
0.87–0.85 (m, 1H); 13C NMR (100 MHz, CDCl3): d=181.20,
157.55, 147.50, 144.48, 140.96, 131.23, 128.09, 121.49, 114.14,
102.14, 55.57, 55.52, 52.86, 40.61, 39.42, 38.61, 29.16, 27.73,
27.16, 25.70, 25.55; HR-MS (ES+); m/z=439.2520, calcd. for
C25H34N4OS (M+H): 439.2526.
Catalyst 1i was prepared according to the general proce-
dure as a white solid; overall yield: 70%. [a]2D0: +243.5 (c
1
0.21, CHCl3); H NMR (400 MHz, CDCl3): d=8.67 (d, J=
4.2 Hz, 1H), 8.42 (d, J=7.4 Hz, 1H) 8.10 (d, J=8.4 Hz,
2H), 7.72–7.68 (m, 1H), 7.62–7.58 (m, 1H), 7.40–7.36 (m,
Adv. Synth. Catal. 2012, 354, 515 – 526
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521

Junxing Xu et al.
FULL PAPERS
2H) , 7.27–7.23 (m, 4H) ,5.94–5.86 (m, 2H), 5.19–5.13 (m,
2H), 3.03–2.78 (m, 4H) 2.30–2.24 (m, 1H), 1.60 (s, 1H),
1.51–1.26 (m, 3H), 0.87–0.82 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=180.64, 149.98, 148.34, 139.71, 137.54, 130.17,
129.40, 129.11, 127.11, 126.52, 126.42, 124.93, 123.81, 115.15,
61.24, 48.50, 47.17, 39.08, 27.21, 26.16, 24.96; HR-MS (ES+):
m/z=429.2113, calcd. for C26H28N4S (M+H): 429.2107.
Catalyst 1j was prepared according to the general proce-
dure as a white solid; overall yield: 70%. [a]2D0: +258.6 (c
the traces of HCl to give methyl phenylglycinate hydrochlor-
ide[16c] as a white powder; yield: 14.5 g.
Methyl phenylglycinate hydrochloride (4 mmol) was sus-
pended in THF (100 mL) and the mixture was cooled to
08C. TEA (2.3 mL, 16 mmol) was added dropwise, during
which time the solution became clear. The solution was then
allowed to warm to room temperature and a solution of 4-
methoxybenzene isothiocyanate (4.4 mmol) in dry THF
(10.0 mL) was then added dropwise. After stirring for 48 h,
the reaction mixture was concentrated under vacuum. The
residue was purified by column chromatography on silica
gel (hexane/EtOAc=4:1) to give the catalyst 1m as a white
solid; yield: 0.55 g (42%).[11c] [a]D20: +11.0 (c 0.20, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.82 (s, 1H), 7.42 (s, 1H),
7.32 (d, J=1.8 Hz, 4H), 7.20 (d, J=8.8 Hz, 2H), 6.96 (d, J=
8.8 Hz, 2H), 6.84 (d, J=7.3 Hz, 1H), 6.16 (d, J=7.4 Hz,
1H), 3.82 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=180.51, 171.40, 158.99, 136.02, 129.40, 128.93,
128.59, 128.15, 127.35, 127.28, 126.59, 115.35, 114.44, 61.23,
55.47, 52.90; HR-MS (ES+): m/z=331.1114, calcd. for
C17H18N2O3S (M+H): 331.1111.
1
0.28, CHCl3); H NMR (400 MHz, CDCl3): d=8.68 (d, J=
3.9 Hz, 1H), 8.39 (d, J=8.3 Hz, 1H), 8.09 (d, J=7.7 Hz,
1H), 7.91 (s, 1H), 7.72–7.68 (m, 1H), 7.59 (t, J=15.39 Hz,
1H), 7.23 (d, J=4.1 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.93
(d, J=8.8 Hz, 2H), 5.93 (ddd, J=17.2, 10.6, 6.4 Hz, 1H),
5.82 (s, 1H ), 5.19–5.12 (m, 2H), 3.84 (s, 3H), 2.96–2.76 (m,
4H) 2.30–2.24 (m, 1H), 1.61 (s, 1H) 1.51–1.29 (m, 4H),
0.87–0.82 (m, 1H); 13C NMR (100 MHz, CDCl3): d=181.17,
158.32, 150.03, 148.42, 139.83, 130.26, 129.09, 127.24, 126.48,
123.83, 115.14, 114.64, 61.27, 55.49, 48.57, 47.19, 39.22, 27.27,
26.28, 25.07; HR-MS (ES+): m/z=459.2205, calcd. for
C27H30N4OS (M+H): 459.2213.
Catalyst 1n was prepared using the same procedure with
1m from methyl phenylglycinate hydrochloride (4 mmol)
and 1-isothiocyanatonaphthalene (4.4 mmol); yield: 0.62 g
(44%). [a]2D0: +2.3 (c 0.22, CHCl3); 1H NMR (400 MHz,
CDCl3): d=8.03–7.99 (m, 2H), 7.99–7.90 (m, 2H), 7.59–7.53
(m, 4H), 7.27–7.26 (m, 3H), 7.20–7.18 (m, 2H), 6.74 (d, J=
6.9 Hz, 1H), 6.13 (d, J=7.2 Hz, 1H), 3.65 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=181.07, 171.07, 135.84, 134.67, 131.40,
129.63, 129.14, 128.83, 128.54, 128.51, 127.45, 127.34, 127.13,
125.74, 124.81, 122.45, 61.33, 52.84; HR-MS (ES+): m/z=
351.1160, calcd. for C20H18N2O2S (M+H): 351.1162.
Catalyst 1o was prepared using the same procedure as for
1m; yield: 0.32 g (52%). [a]2D0: +7.1 (c 0.14, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.94 (s, 1H), 7.4 (d, J=
8.7 Hz, 2H), 7.34–7.33 (m, 4H), 7.22 (d, J=8.6 Hz, 2H),
7.09 (d, J=7.3 Hz, 1H), 6.09 (d, J=7.2 Hz, 1H), 5.02 (m,
1H), 1.27(d, J=6.2 Hz, 3H), 1.08 (d, J=6.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=179.85, 170.39, 136.04,
134.63, 132.79, 130.27, 128.87, 128.54, 127.27, 126.03, 70.20,
61.40, 21.67, 21.26; HR-MS (ES+): m/z=363.0921, calcd. for
C18H19ClN2O2S (M+H): 363.0929.
Preparation of Catalyst 1k
Dithioureas were prepared following the same experimental
procedure as that for monothiouras, except that two equiva-
lents of isothiocyanate are needed per amine molecule.
1
[a]2D0: +13.9 (c 0.18, CHCl3); H NMR (400 MHz, CDCl3):
d=7.67 (s, 2H), 7.44–7.40 (m, 4H), 7.31–7.23 (m, 6H), 6.53
(d, J=6.8 Hz, 2H), 4.40 (q, J=16.8 Hz, 2H), 2.15 (d, J=
12.0 Hz, 2H), 1.73 (s, 2H), 1.35–1.22 (m, 4H); 13C NMR
(100 MHz, CDCl3): d=179.89, 135.81, 130.06, 127.11, 125.18,
58.86, 32.10, 24.52; HR-MS (ES+): m/z=385.1520, calcd. for
C20H24N4S2ACHTUNGTRENNUNG(M+H): 385.1515.
Preparation of Catalyst 1l
Under an nitrogen atmosphere, to a solution of substituted
1-chloro-4-isothiocyanatobenzene (2.0 mmol) in dry THF
(5.0 mL) was added (S)-diphenyl(pyrrolidin-2-yl)methanol
(2.1 mmol). After stirring for 48 h, the reaction mixture was
concentrated under vacuum. The residue was purified by
column chromatography on silica gel (hexane/EtOAc=3:2
as eluent) to give the catalyst 1l. [a]2D0: À257.4 (c 0.2,
1
CHCl3); H NMR (400 MHz, CDCl3): d=9.02 (s, 1H), 7.45–
Preparation of Catalyst 1q
7.14 (m, 12H), 5.50 (d, J=7.8 Hz, 1H), 4.07–4.02 (m, 2H),
2.98 (t, J=17.5 Hz, 1H), 2.38–2.28 (m, 1H) 2.07–2.02 (m,
1H), 1.60–1.49 (m, 1H); 13C NMR (100 MHz, CDCl3): d=
182.83, 145.07, 142.24, 138.50, 130.37, 128.63, 128.48, 128.31,
128.21, 128.16, 127.91, 127.48, 126.26, 82.99, 67.80, 52.61,
29.43, 21.79; HR-MS (ES+): m/z=423.1295, calcd. for
C24H23ClN2OS (M+H): 423.1292.
To a solution of quinine (1p) (324 mg, 1.0 mmol) and 1-me-
thoxyphenyl isothiocyanate (164 mg, 1.0 mmol) in THF
(5 mL) was added sodium hydride (80 mg, 2.0 mmol, 60% in
mineral oil). The reaction mixture was stirred at 258C for
12 h. After completion, the reaction mixture was quenched
with water (10 mL) and extracted with dichloromethane (3ꢁ
20 mL). The combined organic extracts were washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated
under vacuum. The residue was purified by flash column
chromatography (MeOH:CH2Cl2 =1:30) to afford 1q as a
white solid; yield: 317 mg (65%). [a]2D0: +121.1 (c 0.28,
General Procedure for Preparing Catalysts 1m–1o
l-Phenylglycine (13.7 g, 90.8 mmol) was dissolved in MeOH
(250 mL) and the mixture was cooled to 08C. SOCl2
(13.2 mL, 181.6 mmol) was added dropwise over a period of
45 min, during which time the solution became clear and
began to reflux gently. The reaction mixture was refluxed
for 4 h, and then the solvent was removed using a rotary
evaporator. The residue was re-dissolved in MeOH and then
the MeOH was evaporated again under vacum to remove
1
CHCl3); H NMR (400 MHz, CDCl3): d=8.72 (d, J=4.4 Hz,
1H), 8.60 (s, 1H), 7.99 (d, J=9.2 Hz, 1H), 7.69 (s, 1H),
7.44–7.22 (m, 3H), 7.10 (d, J=8.6 Hz, 1H), 6.87 (d, J=
8.6 Hz, 2H), 5.89–5.72 (m, 1H), 5.06–4.94 (m, 2H), 3.95–
3.78 (m, 6H), 3.50–3.37 (m, 1H), 3.17–2.96 (m, 2H), 2.66–
2.52 (m, 2H), 2.22 (s, 1H) 1.86–1.74 (m, 3H), 1.61–1.46 (m,
522
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Adv. Synth. Catal. 2012, 354, 515 – 526

Thiourea-Catalyzed Enantioselective Fluorination of b-Keto Esters
3H); 13C NMR (100 MHz, CDCl3): d=186.55, 168.91,
157.97, 147.29, 144.84, 141.50, 131.66, 129.26, 125.50, 122.02,
119.43, 114.33, 114.05, 101.92, 59.61, 56.43, 55.51, 47.46,
42.55, 39.52, 27.41, 24.11; HR-MS (ES+): m/z=490.2161,
calcd. for C28H31N3O3S (M+H) 490.2159.
J=199.3 Hz), 84.13, 38.30 (d, J=24.1 Hz), 27.81; 19F NMR
(CDCl3, 376.5 MHz): d=À162.68 (q, J=33.6 Hz); HPLC
(Chiralcel Ad-H, i-PrOH/hexane=02/98, 1.0 mL/min,
254 nm): t1 =12.0 min, t2 =13.8 min.
Compound 3e: White solid; yield: 96%; ee: 95%; mp 73–
768C; Rf =0.4, hexane/EtOAc=8:1; [a]2D0: À5.0 (c 0.10,
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.83 (d, J=7.7 Hz,
General Procedure for Fluorination of b-Keto Esters
2
1H), 7.71–7.66 (m, 1H), 7.48–7.43 (m, 2H), 7.32–7.23 (m,
5H), 5.27 (d, J=12.3 Hz, 1H), 5.20 (d, J=12.3 Hz, 1H),
3.78 (dd, J=16.9, 11.4 Hz, 1H), 3.44 (dd, J=23.2, 17.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=194.96 (d, J=
18.4 Hz), 167.04 (d, J=28.1 Hz), 150.71 (d, J=3.6 Hz),
136.67, 134.58, 133.17, 128.58, 128.54, 128.47, 127.91, 126.53,
125.56, 94.52 (d, J=201.9 Hz), 67.73, 38.13 (d, J=23.8 Hz);
19F NMR (CDCl3, 376.5 MHz): d=À163.14 (q, J=34.6 Hz);
HPLC (Chiralcel OD-H, i-PrOH/hexane=10/90, 1.0 mL/
min, 254 nm): t1 =15.9 min (major), t2 =18.6 min (minor).
Compound 3f: White solid; yield: 95%; ee: 90%; mp 89–
918C; Rf =0.4, hexane/EtOAc=5:1; [a]2D0: À43.3 (c 0.12,
To a solution of b-keto ester 2 (0.1 mmol, 1.0 equiv.) and
DMAP (12.2 mg, 0.1 mmol, 1.0 equiv.) in MeOH (3 mL) was
added catalyst 1b (4.9 mg, 0.01 mmol, 0.1 equiv.) at À608C.
The mixture was stirred for 30 min and then NFSI (34.6 mg,
0.11 mmol, 1.1 equiv.) was added. The resulting mixture was
stirred at À608C for 42 hours or the time shown in Table 3.
The reaction was monitored by TLC. After completion of
the reaction, the reaction mixture was concentrated under
vacuum. The residue was purified by flash column chroma-
tography to give product 3.
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.77 (d, J=8.0 Hz,
Compound 3a: White solid; yield: 92%; ee: >99%; mp
1H), 7.52 (d, J=0.8 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 3.83–
3.76 (m, 4H), 3.47 (dd, J=23.3, 17.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=193.62 (d, J=16.7 Hz), 167.25 (d, J=
27.4 Hz), 152.11 (d, J=4.3 Hz), 143.41, 131.52, 129.49,
126.82, 126.62, 94.41 (d, J=201.2 Hz), 53.23, 37.82 (d, J=
23.6 Hz); 19F NMR (CDCl3, 376.5 MHz): d=À166.92 (q, J=
33.8 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane=02/98,
1.0 mL/min, 254 nm): t1 =18.4 min (minor), t2 =20.4 min
(major).
79–818C; Rf =0.3, hexane/EtOAc=5:1; [a]2D0: À27.5 (c 0.13,
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.84 (d, J=7.7 Hz,
1H), 7.71 (m, 1H), 7.52–7.46 (m, 2H), 3.85–3.77 (m, 4H),
3.47 (dd, J=23.3, 17.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=195.10 (d, J=18.0 Hz), 167.76 (d, J=28.0 Hz),
150.80 (d, J=4.0 Hz), 136.76, 133.13, 128.63, 126.57, 125.63,
94.56 (d, J=200.0 Hz), 53.23, 38.18 (d, J=24.0 Hz);
19F NMR (CDCl3, 376.5 MHz): d=À165.77 (q, J=34.5 Hz);
HPLC (Chiralcel Od-H, i-PrOH/hexane=10/90, 1.0 mL/
min, 254 nm): t1 =12.4 min (major), t2 =14.8 min (minor).
Compound 3b: Colourless oil; yield: 95%; ee: 90%; Rf =
0.4, hexane/EtOAc=5:1; [a]2D0: À18.4 (c 0.14, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.85 (d, J=7.7 Hz, 1H),
7.73–7.69 (m, 1H), 7.52-.7.45 (m, 2H), 4.28 (q, J=21.4 Hz,
2H), 3.81 (dd, J=17.6, 11.5 Hz, 1H), 3.46 (dd, J=23.3,
17.6 Hz, 1H), 1.26 (t, J=14.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=195.24 (d, J=18.1 Hz), 167.26 (d, J=27.7 Hz),
150.86 (d, J=3.6 Hz), 136.67, 133.25, 128.60, 126.56, 125.62,
94.46 (d, J=201.6 Hz), 62.58, 38.22 (d, J=23.9 Hz), 13.99;
19F NMR (CDCl3, 376.5 MHz): d=À163.11 (q, J=34.8 Hz);
HPLC (Chiralcel Od-H, i-PrOH/hexane=10/90, 1.0 mL/
min, 254 nm): t1 =9.8 min (major), t2 =11.2 min (minor).
Compound 3c: White solid; yield: 93%; ee: 81%; mp 48–
518C , Rf =0.5, hexane/EtOAc=5:1; [a]2D0: À12.51 (c 0.12,
Compound 3g: White solid; yield: 96%; ee: 86%; mp 87–
888C; Rf =0.4, hexane/EtOAc=5:1; [a]2D0: À14.7 (c 0.12,
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.77 (d, J=8.2 Hz,
1H), 7.48–7.43 (m, 2H), 7.36–7.31 (m, 3H), 7.27–7.25 (m,
2H), 5.28 (d, J=12.3 Hz, 1H), 5.21 (d, J=12.3 Hz, 1H),
3.75 (dd, J=17.9, 11.3 Hz, 1H), 3.43 (dd, J=22.8, 17.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=193.56 (d, J=
18.5 Hz), 167.73 (d, J=28.1 Hz), 152.09 (d, J=3.7 Hz),
143.45, 134.46, 131.67, 129.55, 128.64, 128.09, 126.84, 126.71,
94.40 (d, J=203.1 Hz), 68.00, 37.85 (d, J=24.1 Hz);
19F NMR (CDCl3, 376.5 MHz): d=À162.59 (q, J=34.2 Hz);
HPLC (Chiralcel AD-H, i-PrOH/hexane=02/98, 1.0 mL/
min, 254 nm): t1 =28.0 min (minor), t2 =29.7 min (major).
Compound 3h: White solid; yield: 94%; ee: 89%; mp 87–
898C; Rf =0.4, hexane/EtOAc=5:1; [a]2D0: À26.25 (c 0.16,
1
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.71–7.69 (m, 2H),
CHCl3); H NMR (400 MHz, CDCl3): d=7.84 (d, J=7.7 Hz,
7.63–7.61 (m, 2H), 3.82–3.76 (m, 4H), 3.47 (dd, J=22.7,
18.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=193.89 (d,
J=18.2 Hz), 167.22 (d, J=27.8 Hz), 152.13 (d, J=3.8 Hz),
135.84, 132.42, 132.38, 131.92, 129.91, 129.76, 129.43, 126.66,
1H), 7.73–7.69 (m, 1H), 7.52–7.45 (m, 2H), 5.14 (m, 1H),
3.78 (dd, J=17.6, 11.7 Hz, 1H), 3.45 (dd, J=23.3, 17.6 Hz,
1H), 1.25 (dd, J=9.8, 6.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d=195.32 (d, J=18.0 Hz), 166.8 (d, J=27.4 Hz),
150.90 (d, J=3.6 Hz), 136.58, 133.27, 128.52, 126.52, 125.63,
94.36 (d, J=201.5 Hz), 70.65, 38.19 (d, J=24.0 Hz), 21.52,
21.40; 19F NMR (CDCl3, 376.5 MHz): d=À163.00 (q, J=
35.0 Hz); HPLC (Chiralcel Ad-H, i-PrOH/hexane=02/98,
1.0 mL/min, 254 nm): t1 =14.9 min (minor), t2 =15.9 min
(major).
Compound 3d: Colourless oil; yield: 95%; racemic; Rf =
0.4, hexane/EtOAc=8:1; 1H NMR (400 MHz, CDCl3): d=
7.84 (d, J=7.7 Hz, 1H), 7.70–7.67 (m, 1H), 7.51–7.44 (m,
2H), 3.74 (dd, J=17.5, 10.7 Hz, 1H), 3.42 (dd, J=22.8,
17.5 Hz, 1H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3):
d=195.30 (d, J=18.0 Hz), 166.2 (d, J=27.6 Hz), 150.94 (d,
J=3.7 Hz), 136.42, 133.56, 128.44, 126.43, 125.45, 94.32 (d,
19
94.33 (d, J=202.6 Hz), 53.36, 37.76 (d, J=24.2 Hz);
F NMR (CDCl3, 376.5 MHz): d=À164.35 (q, J=33.8 Hz);
HPLC (Chiralcel AD-H, i-PrOH/hexane=02/98, 1.0 mL/
min, 254 nm): t1 =20.1 min (minor), t2 =22.2 min (major).
Compound 3i: White solid; yield: 95%; ee: 85%; mp 91–
958C; Rf =0.4, hexane/EtOAc=5:1; [a]2D0: À9.1 (c 0.12,
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.69–7.66 (m, 2H),
7.61–7.58 (m, 1H), 7.34–7.32 (m, 3H), 7.27–7.24 (m, 2H),
5.27 (d, J=12.3 Hz, 1H), 5.21 (d, J=12.3 Hz, 1H), 3.75 (dd,
J=17.8, 11.2 Hz, 1H), 3.42 (dd, J=22.8, 17.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=193.79 (d, J=18.2 Hz),
167.67 (d, J=28.1 Hz), 152.11 (d, J=3.7 Hz), 134.45, 132.38,
132.02, 129.90, 128.63, 128.07, 126.67, 94.31 (d, J=203.2 Hz),
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Junxing Xu et al.
FULL PAPERS
67.99, 37.7 5 (d, J=24.3 Hz); 19F NMR (CDCl3, 376.5 MHz):
d=À166.14 (q, J=34.0 Hz); HPLC (Chiralcel AD-H, i-
PrOH/hexane=02/98, 1.0 mL/min, 254 nm): t1 =31.4 min
(minor), t2 =33.5 min (major).
Compound 3o: Colourless oil; yield: 86%; ee: 11%; Rf =
0.4, hexane/EtOAc=8:1; 1H NMR (400 MHz, CDCl3): d=
8.08–8.06 (m, 1H), 7.58–7.54 (m, 1H), 7.39–7.35 (m, 1H),
7.29 (d, J=7.7 Hz, 1H), 3.83 (s, 3H), 3.23–3.05 (m, 2H),
2.79–2.67 (m, 1H), 2.60–2.50 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=188.44 (d, J=19.0 Hz), 167.80 (d, J=26.0 Hz),
143.11, 134.60, 130.40, 128.75, 128.47, 127.26, 93.26 (d, J=
192.8 Hz), 53.04, 31.82 (d, J=22.1 Hz), 24.80 (d, J=7.7 Hz);
19F NMR (CDCl3, 376.5 MHz): d=À166.63 (q, J=34.0 Hz);
HPLC (Chiralcel OD-H, i-PrOH/hexane=10/90, 1.0 mL/
min, 254 nm): t1 =10.5 min, t2 =11.5 min.
Compound 3j: White solid; yield: 93%; ee: 92%; mp 101–
1048C; Rf =0.4, hexane/EtOAc=8:1; [a]2D0: À25.0 (c 0.12,
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.63 (s, 1H), 7.53
(d, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 3.80–3.72 (m,
4H), 3.41 (dd, J=23.3, 17.5 Hz, 1H), 2.43 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=195.11 (d, J=18.2 Hz), 167.72 (d, J=
28.2 Hz), 148.21 (d, J=3.8 Hz), 138.79, 138.04, 133.24,
126.20, 125.38, 94.89 (d, J=201.3 Hz), 53.14, 37.83 (d, J=
23.7 Hz), 21.02; 19F NMR (CDCl3, 376.5 MHz): d=À163.10
(q, J=34.3 Hz); HPLC (Chiralcel AD-H, i-PrOH/hexane=
02/98, 1.0 mL/min, 254 nm): t1 =14.8 min (major), t2 =
16.3 min (minor).
Compound 3p: Colourless oil; yield: 89%; ee: 20%; Rf =
1
0.4, hexane/EtOAc=10:1; H NMR (400 MHz, CDCl3): d=
8.08–8.06 (m, 1H), 7.56–7.51 (m, 11 H), 7.37–7.29 (m, 4H),
7.26–7.22 (m, 3H), 5.29 (d, J=12.3 Hz, 1H), 5.21 (d, J=
12.3 Hz, 1H), 3.18–3.10 (m, 1H), 3.02–2.95 (m, 1H),2.77–
2.65 (m, 1H), 2.58–2.48 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=188.40 (d, J=18.7 Hz), 167.12 (d, J=26.3 Hz),
142.98, 134.62, 134.50, 128.70, 128.51, 128.43, 128.35, 127.93,
127.19, 93.20 (d, J=194.2 Hz), 67.63, 31.75 (d, J=22.1 Hz),
24.73 (d, J=7.3 Hz); 19F NMR (CDCl3, 376.5 MHz): d=
À166.99 (q, J=33.6 Hz); HPLC (Chiralcel OD-H, i-PrOH/
hexane=10/90, 1.0 mL/min, 254 nm): t1 =12.6 min (major),
t2 =14.7 min (minor).
Compound 3q: Colourless oil; yield: 76%; ee: 81%; Rf =
0.5, hexane/EtOAc=15:1; [a]2D0: +17.0 (c 0.21, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.27–7.21 (m, 5H), 4.22 (q,
J=21.4 Hz, 2H), 3.42 (d, J=14.1 Hz, 1H), 3.18 (d, J=
14.1 Hz, 1H), 2.28 (s, 3H), 1.28 (t, J=14.3 Hz 3H);
13C NMR (100 MHz, CDCl3): d=204.59 (d, J=19.7 Hz),
170.50 (d, J=21.3 Hz), 137.38, 134.58, 130.15, 128.22, 127.16,
86.10 (d, J=189.7 Hz), 62.90, 40.72 (d, J=21.0 Hz), 25.45,
14.02; 19F NMR (CDCl3, 375 MHz): d=À166.49 (q, J=
33.9 Hz); HPLC (Chiralcel OJ-H, i-PrOH/hexane=10/90,
0.8 mL/min, 210 nm): t1 =19.8 min (major), t2 =22.3 min
(minor).
Compound 3r: Colourless oil; yield: 41%; ee: 48%; Rf =
0.5, hexane/EtOAc=20:1; [a]2D0: À37.0 (c 0.12, MeOH);
1H NMR (400 MHz, CDCl3): d=7.68–7.27 (m, 5H), 4.29–
4.22 (m, 2H), 1.90 (d, J=1.6 Hz, 1.5H), 1.85 (d, J=1.6 Hz,
1.5H), 1.20–1.17 (m, 3H); 13C NMR (100 MHz, CDCl3): d=
191.75 (d, J=24.3 Hz), 168.55 (d, J=24.1 Hz), 133.88,
133.29, 130.94, 129.87, 129.69, 129.63, 128.93, 97.90 (d, J=
193.5 Hz), 62.55, 21.03 (d, J=22.9 Hz), 13.83 (d, J=6.8 Hz);
19F NMR (CDCl3, 376.5 MHz): d=-148.29; HPLC (Chiralcel
OB-H, i-PrOH/hexane=10/90, 0.5 mL/min, 254 nm): t1 =
14.38 min (major), t2 =16.41 min (minor).
Compound 3k: White solid; yield: 95%; ee: 89%; mp 94–
978C; Rf =0.4, hexane/EtOAc=8:1; [a]2D0: À11.5 (c 0.13,
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.61 (s, 1H) 7.49
(d, J=7.8 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.32–7.23 (m,
5H), 5.26 (d, J=12.3 Hz, 1H), 5.19 (d, J=12.4 Hz, 1H),
3.72 (dd, J=17.5, 11.4 Hz, 1H), 3.38 (dd, J=23.1, 17.5 Hz,
1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): d=195.04
(d, J=18.1 Hz), 167.16 (d, J=28.2 Hz), 148.17 (d, J=
3.7 Hz), 138.76, 137.99, 134.62, 133.31, 128.54, 128.44, 128.31,
128.09, 127.93, 126.19, 125.40, 94.88 (d, J=201.7 Hz), 67.68,
37.82 (d, J=23.8 Hz), 24.80; 19F NMR (CDCl3, 376.5 MHz):
d=-162.95 (q, J=34.4 Hz); HPLC (Chiralcel AD-H, i-
PrOH/hexane=02/98, 1.0 mL/min, 254 nm): t1 =24.8 min
(major), t2 =27.8 min.
Compound 3l: Colourless oil; yield: 95%; ee: 87%; Rf =
0.3, hexane/EtOAc=4:1; [a]2D0: +60.0 (c 0.10, CHCl3);
1H NMR (400 MHz, CDCl3): d=3.83 (s, 3H), 2.62–2.53 (m,
1H), 2.52–2.48 (m, 2H), 2.39–2.27 (m, 1H), 2.18–2.12 (m,
2H); 13C NMR (100 MHz, CDCl3): d=207.38 (d, J=
16.8 Hz), 167.81 (d, J=27.7 Hz), 94.71 (d, J=200.1 Hz),
52.98, 35.64, 33.84 (d, J=20.8 Hz), 18.00 (d, J=3.2 Hz);
19F NMR (CDCl3, 376.5 MHz): d=À165.95 (t, J=42.3 Hz);
HPLC (Chiralcel OB-H, i-PrOH/hexane=10/90, 1.0 mL/
min, 220 nm): t1 =26.2 min (minor), t2 =29.2 min (major).
Compound 3m: Colourless oil; yield: 96%; ee: 95%; Rf =
0.4, hexane/EtOAc=5:1; [a]2D0: +50.0 (c 0.11, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.40–7.32 (m, 4H), 5.26
(dd, J=18.1, 12.2 Hz, 2H), 2.59–2.51 (m, 1H), 2.50–2.45 (m,
2H), 2.39–2.26 (m, 1H), 2.15–2.07 (m, 2H); 13C NMR
(100 MHz, CDCl3): d=207.32 (d, J=16.8 Hz), 167.24 (d, J=
27.7 Hz), 134.58, 128.66, 128.62, 128.14, 94.65 (d, J=
200.3 Hz), 67.73, 35.68, 33.84 (d, J=20.9 Hz), 18.02 (d, J=
Compound 3s: Colourless oil; yield: 49%; racemic; Rf =
1
0.4, hexane/EtOAc=20:1; H NMR (400 MHz, CDCl3): d=
19
8.06–8.03 (m, 2H), 7.67–7.62 (m, 1H), 7.53–7.49 (m, 2H),
5.88 (d, J=48.8 Hz, 1H), 4.34–4.27 (m, 2H), 1.26 (t, J=
14.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=189.48 (d,
J=20.3 Hz), 167.85 (d, J=24.1 Hz), 134.51, 133.28, 133.27,
129.50, 129.47, 128.79, 90.00 (d, J=197.5 Hz), 62.69, 13.91;
19F NMR (CDCl3, 376.5 MHz): d=À189.05 (d, J=48.6 Hz);
HPLC (Chiralcel AD-H, i-PrOH/hexane=06/94, 1.0 mL/
min, 254 nm): t1 =7.7 min (major), t2 =8.1 min (minor).
3.3 Hz); F NMR (CDCl3, 376.5 MHz): d=À162.61 (d, J=
41.8 Hz); HPLC (Chiralcel OD-H, i-PrOH/hexane=10/90,
1.0 mL/min, 254 nm): t1 =13.8 min (major), t2 =15.4 min
(minor).
Compound 3n: Colourless liquid; yield: 94%; ee: 43%;
1
Rf =0.3, hexane/EtOAc=4:1; H NMR (400 MHz, CDCl3):
d=4.45–4.40 (m, 2H), 2.91–2.81 (m, 1H), 2.64–2.50 (m,
1H), 2.46 (d, J=4.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=203.16 (d, J=31.2 Hz), 169.06 (d, J=24.4 Hz), 96.20 (d,
J=204.3 Hz), 65.70 (d, J=4.5 Hz), 31.96 (d, J=21.1 Hz),
19
25.85;
F NMR (CDCl3, 376.5 MHz): d=À164.3; HPLC
(Chiralcel AD-H, i-PrOH/hexane=05/95, 0.5 mL/min,
210 nm): t1 =20.7 min (major), t2 =22.6 min (minor).
524
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 515 – 526

Thiourea-Catalyzed Enantioselective Fluorination of b-Keto Esters
Chem. 2008, 120, 170; Angew. Chem. Int. Ed. 2008, 47,
164; i) Y. Hamashima, K. Yagi, H. Takano, L. Tamꢃs,
M. Sodeoka, J. Am. Chem. Soc. 2002, 124, 14530; j) T.
Suzuki, T. Goto, Y. Hamashima, M. Sodeoka, J. Org.
Chem. 2007, 72, 246; k) N. Shibata, J. Kohno, K. Takai,
T. Ishimaru, S. Nakamura, T. Toru, S. Kanemasa,
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Acknowledgements
This work was supported by Key Laboratory Polymer Mate-
rials of Gansu Province (Northwest Normal University), Bio-
active Product Engineering Research Center for Gansu Dis-
tinctive Plants, State Key Laboratory of Applied Organic
Chemistry, Lanzhou University.
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