Organocatalytic asymmetric one-pot sequential conjugate addition/dearomative fluorination: Synthesis of chiral fluorinated isoxazol-5(4 H)-ones

Article abstract of DOI:10.1021/jo302419e

A facile one-pot sequential conjugate addition/dearomative fluorination transformation of isoxazol-5(4H)-ones with nitroolefins and N- fluorobenzenesulfonimide (NFSI) has been developed. By using a bifunctional chiral tertiary amino-thiourea catalyst, a series of chiral fluorinated isoxazol-5(4H)-ones containing one fluorine-substituted quarternary stereocenter were obtained in high yields with high enantio- and diastereoselectivities. Further transformation of adducts could afford isoxazolidin-5-one derivatives with three contiguous stereocenters.

Full text of DOI:10.1021/jo302419e

Article
pubs.acs.org/joc
Organocatalytic Asymmetric One-Pot Sequential Conjugate
Addition/Dearomative Fluorination: Synthesis of Chiral Fluorinated
Isoxazol-5(4H)‑ones
Wen-Ting Meng, Yan Zheng, Jing Nie, Heng-Ying Xiong, and Jun-An Ma*
Department of Chemistry, Tianjin University, Tianjin, 300072, P. R. of China
S
* Supporting Information
ABSTRACT: A facile one-pot sequential conjugate addition/
dearomative fluorination transformation of isoxazol-5(4H)-
ones with nitroolefins and N-fluorobenzenesulfonimide
(NFSI) has been developed. By using a bifunctional chiral
tertiary amino-thiourea catalyst, a series of chiral fluorinated
isoxazol-5(4H)-ones containing one fluorine-substituted quar-
ternary stereocenter were obtained in high yields with high
enantio- and diastereoselectivities. Further transformation of
adducts could afford isoxazolidin-5-one derivatives with three contiguous stereocenters.
lones.6 Encouraged by these results and as a part of our continued
INTRODUCTION
■
interest in the stereoselective synthesis of organofluorine
Fluorinated heteroalicyclic scaffolds are important structural
compounds,7,8 we envisioned that fluorinated isoxazolinones
units because of their frequent appearance in many pharmaceut-
icals and biologically active compounds.1 The development of
could be constructed using isoxazol-5(4H)-ones as the aromatic
relay partners. Herein, we report our efforts in developing this
one-pot sequential process. Our studies show that this addition
reaction of isoxazol-5(4H)-ones to nitroolefins in the presence of
chiral amino-thiourea catalysts proceeds to produce aromatic
isoxazol-5-ol intermediates (Int-A), which could be further
fluorinated with concurrent dearomatization to afford the
fluorinated chiral isoxazol-5(4H)-ones (Scheme 1).
efficient methods for the construction of these useful building
blocks is of significant interest in organic chemistry. To this end,
many reports have provided efficient approaches to the
construction of various fluorinated heteroalicyclic compounds,
such as fluorinated tetrahydropyrans, tetrahydrofurans, flava-
nones, cyclohexenones, thiacyclohexanes, piperidines, tetrahy-
dropyrroloindoles, and tetrahydrofuroindoles.2 Despite this
promising progress, it is still highly desirable to broaden the
diversity of fluorinated hereroalicycles and to develop new
catalytic asymmetric methods to access chiral fluorinated
hereroalicyclic species. Isoxazol-5(4H)-ones, an important class
of five-membered heteroalicyclic rings, have exhibited a range of
applications in organic synthesis and medicinal chemistry.3
However, a survey of the literature reveals that the asymmetric
version for the synthesis of optically active isoxazolinone
derivatives is still elusive.
The asymmetric dearomatization of aromatic compounds
offers straightforward access to chiral molecules with cyclic
skeletons and has received much attention over the past
decades.4 Although a wide variety of catalytic asymmetric
dearomatization transformations have been discovered, relatively
few dearomative fluorination reactions have been reported.5
Recently, Gaunt and co-workers provided a single elegant
example of the phenol dearomatization using an asymmetric
sequential transformation strategy that affords the fluorinated
decalin in excellent enantioselectivity,5a and Gouverneur’s group
described an organocatalytic asymmetric fluorocyclization
reaction of indoles involving an intramolecular cyclization/
dearomative fluorination process.5b Our group reported a
catalytic asymmetric one-pot sequential 1,4-addition/dearoma-
tive fluorination to afford optically active fluorinated pyrazo-
RESULTS AND DISCUSSION
■
We initially investigated the reaction of 3-phenylisoxazol-5(4H)-
one 1a (1.3 equiv) with trans-β-nitrostyrene 2a (1.0 equiv) and
N-fluorobenzenesulfonimide (NFSI, 1.5 equiv) in toluene at
room temperature by using saccharide-derived chiral tertiary
amino-thiourea catalyst A (Figure 1), developed previously in
our laboratory.9 After substrate 2a completely disappeared
(monitored by TLC), the electrophilic fluorinating reagent NFSI
was then added to the reaction system. In the presence of catalyst
A, the fluorinated product 3a was obtained in good yield (Table
1, entry 1); accordingly, the heteroaromatic isoxazol-5-ole (Int-
a) was isolated in 27% yield. The use of 4-dimethylaminopyr-
idine (DMAP) and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)
gave similar results (entries 2 and 3). Subsequently, several
inorganic bases were employed as additives (entries 4−7). It was
found that the use of Na2CO3 provided the best results (entry 5,
88%, 99:1 dr, 52% ee). After a series of amino-thioureas B−G
were screened by using Na2CO3 as additive (entries 8−13), we
were pleased to find that the catalyst D, which incorporates chiral
Received: November 1, 2012
Published: December 4, 2012
© 2012 American Chemical Society
559
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567

The Journal of Organic Chemistry
Article
Scheme 1. One-Pot Sequential Strategy for the Synthesis of Chiral Fluorinated Isoxazol-5(4H)-ones
Figure 1. Bifunctional tertiary amino-thiourea catalysts tested in the one-pot sequential transformation.
1,2-diphenylethane-1,2-diamine at the thiourea backbone,
affords the sequential product 3a in 93% yield and with 54% ee
(entry 10). It is very interesting that the use of catalysts F and G,
which do not contain a saccharide motif, resulted in a slight
decrease in enantioselectivity (entries 12 and 13). Further
modifications of modular organocatalyst D have been made by
using different cyclic tertiary amine substituents to give a series of
new catalysts H−L (Figure 1). Chiral catalyst H promoted this
one-pot sequential transformation with a good enantioselectivity
of 80% ee, whereas catalyst I exhibited a moderate level of
stereoselectivity with an opposite sense of asymmetric induction
(entries 14 and 15). These results indicate that the (S,S)-
configuration of 1,2-diphenylethane-1,2-diamine matched the β-
D-glucopyranose to enhance the stereochemical control. Bifunc-
tional catalysts J, K, and L with an (S,S)-configuration of the 1,2-
diphenylethane-1,2-diamine moiety can also induce good
enantioselectivities (entries 16−18). Subsequent optimization
of other reaction parameters, such as solvent, catalyst loading,
and temperature (entries 19−27) led to the discovery that the
best results were obtained as the reaction was performed in Et2O
at room temperature employing 5 mol % tertiary amino-thiourea
J as catalyst (93% yield, 99:1 dr, 86% ee; entry 24).
naphthalenyl-substituted nitroolefins to afford the products 3j
and 3k in good yields and enantioselectivities with uniformly
high diastereoselectivities (entries 10 and 11). Notably, the
heteroaromatic substrate was also tolerated, affording the desired
product 3l in high yield and diastereoselectivity, albeit with
decreased enantioselectivity (90% yield, 99:1 dr, 64% ee, entry
12). In addition, we investigated the addition reaction with alkyl-
substituted nitroolefins, such as (E)-1-nitropent-1-ene and (E)-
4-methyl-1-nitropent-1-ene. These substrates were found to be
unsuitable for this asymmetric sequential transformation, and no
product was observed. The basis for this intriguing difference in
nitroolefin reactivity is not well understood at this stage. Further
exploration of the substrate scope focused on the nucleophilic
isoxazol-5(4H)-ones. It appeared that electron-donating and
electron-withdrawing substituents on the aromatic ring can be
tolerated, and good to high stereocontrol was observed for the
products 3m−s (entries 13−19). Finally, the single stereoisomer
of 3i proved to be crystalline, thus allowing the determination of
the absolute configuration of two adjacent stereogenic centers to
be (4S, 1′S) by means of X-ray crystallographic analysis (see the
Supporting Information).10
These sequential products 3 are useful synthetic intermediates
and can be readily transformed into isoxazolidin-5-ones, known
to be important structural elements of varied pharmacologically
active compounds.11 For instance, reduction of 3b using NaBH4,
followed by condensation with Boc2O gave rise to fluorinated
isoxazolidin-5-one 4 in 55% yield with moderate diastereose-
lectivity. Notably, three contiguous stereocenters were con-
structed without erosion of enantiopurity during these trans-
formations (Scheme 2).
Under the optimized experimental conditions, the scope of the
one-pot sequential transformation was investigated with a variety
of isoxazol-5(4H)-ones 1 and nitroolefins 2, and the results are
summarized in Table 2. This asymmetric one-pot multistep
reaction is compatible with a series of nitroolefin substrates,
delivering the fluorinated isoxazolinones 3a−i in 87−94% yields
with 80−92% enantioselectivities and excellent diastereoselecti-
vites (entries 1−9). The reaction worked well with 1- and 2-
560
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567

The Journal of Organic Chemistry
Article
a
Table 1. Effect of Catalyst, Solvent, Temperature, and Other Reaction Conditions for the Sequential Reaction
b
c
entry
catalyst (mol %)
solvent
temp (°C)
additive
yield (%)
dr
ee (%)
1
2
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)
B (10)
C (10)
D (10)
E (10)
F (10)
G (10)
H (10)
I (10)
J (10)
K (10)
L (10)
J (10)
J (10)
J (10)
J (10)
J (10)
J (5)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
62
68
70
80
88
84
76
89
89
93
81
85
82
94
91
93
91
93
94
58
93
78
57
93
88
70
81
98:2
98:2
52 (−)
50 (−)
48 (−)
47 (−)
52 (−)
50 (−)
49 (−)
40 (−)
23 (−)
54 (−)
41 (−)
19 (−)
39 (−)
80 (−)
51 (+)
84 (−)
84 (−)
79 (−)
64 (−)
48 (−)
86 (−)
46 (−)
54 (−)
86 (−)
80 (−)
86 (−)
48 (−)
DMAP
3
DBU
98:2
4
NaHCO3
Na2CO3
K2CO3
99:1
5
99:1
6
>99:1
99:1
7
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
8
98:2
9
99:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
>99:1
97:3
95:5
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
99:1
Et2O
CH3CN
CH3OH
Et2O
J (1)
Et2O
d
26
J (5)
Et2O
27
J (5)
Et2O
40
a
Unless otherwise noted, all reactions were carried out with isoxazolin-5-one (1a) (21.0 mg, 0.13 mmol), nitrostyrene (2a) (14.9 mg, 0.10 mmol),
tertiary amino-thiourea catalyst in solvent (1 mL) for 48 h. Then NFSI (47.3 mg, 0.15 mmol) and additive (0.12 mmol) were added at the same
b
c
d
temperature, and stirring was maintained for 24 h. Determined by 19F NMR analysis of the crude product; Determined by HPLC analysis; After
the addition of NFSI and Na2CO3, the reaction was performed for 72 h.
To obtain more information about this sequential trans-
formation, we performed step-by-step control experiments. In
the presence of the tertiary amino-thiourea catalyst J, compound
1a was transformed into the C-substituted intermediate Int-a
(Scheme 3), which was isolated in almost quantitative yield with
88% ee. Subsequent treatment of this intermediate Int-a with
Na2CO3 and N-fluorobenzenesulfonimide in the absence of
catalyst J afforded dearomatization−fluorination product 3a in
90% yield with 95:5 dr and 84% ee. These results indicated that
the chiral catalyst not only controls the stereochemistry in the
first step but also is essential for the diastereoselective formation
of the C−F bond in the subsequent transformation. On the basis
of the above experimental results and other work,6,12 a possible
mechanism for the one-pot sequential 1,4-addition/dearomative
fluorination transformation is proposed in Figure 2. First, the
nitroolefin forms a hydrogen-binding complex with the thiourea
group of the chiral catalyst, and the isoxazol-5(4H)-one
substrate, in its enol form, is coordinated via hydrogen-binding
to the amino moiety. Hydrogen-bond-assisted enol-type addition
to the nitroolefin proceeds through a highly organized open
transition state. In the subsequent electrophilic fluorination step,
isoxazol-5-olate is reassociated with the catalyst system to form a
highly organized structure followed by a hydrogen bond-assisted
reaction with the fluorinating reagent.
CONCLUSION
■
In summary, we have developed a new one-pot sequential
conjugate addition/dearomative fluorination reaction of iso-
xazol-5(4H)-ones with nitroolefins and NFSI. This trans-
formation was cooperatively promoted by saccharide-based
bifunctional organocatalysts that contain tertiary amine and
thiourea moieties to activate substrates simultaneously. A series
of fluorinated isoxazolin-5-ones were obtained in high yields and
diastereoselectivities with good to high enantioselectivites.
Further mechanistic investigation and extension of this protocol
to the synthesis of bioactive products are ongoing in our
laboratory.
EXPERIMENTAL SECTION
■
General Information. Solvents were distilled following standard
procedures before use. Analytical thin-layer chromatography was
performed on 0.20 mm silica gel plates. Silica gel (200−300 mesh)
was used for flash chromatography. 1H, 13C, and 19F NMR were
recorded at 400 or 600 MHz (1H NMR), 100 or 150 MHz (13C NMR),
as well as 376 MHz (19F NMR). Chemical shifts were reported in ppm
561
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567

The Journal of Organic Chemistry
Article
a
Table 2. Catalytic Asymmetric One-Pot Sequential Conjugate Addition/Dearomative Fluorination Transformation
a
Unless otherwise noted, all reactions were carried out with isoxazolin-5-one (1) (0.13 mmol), nitroolefins 2 (0.10 mmol), and 5 mol % of tertiary
amino-thiourea catalyst J in Et2O (1 mL) at 25 °C for 48 h. Then NFSI (47.3 mg, 0.15 mmol) and anhydrous Na2CO3 (12.7 mg, 0.12 mmol) were
b
c
added at the same temperature, and stirring was maintained for 24 h. Determined by 19F NMR analysis of the crude product. The ee value was
determined by HPLC analysis, and the absolute configurations of other fluorinated products were assigned on the basis of analogy with study of 3i.
downfield from internal Me4Si and external CCl3F, respectively. HRMS
were recorded on a miorOTOF-QII (APCI ion source), APEXIII 7.0
TESLA FTMS (ESI ion source), or IonSpec 4.7 T FTMS (MALDI ion
source).
562
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567

The Journal of Organic Chemistry
Article
1H), 5.27 (d, J = 12.9 Hz, 1H), 5.75−5.92 (m, 1H), 6.50 (d, J = 7.0 Hz,
1H), 7.03−7.05 (m, 4H), 7.11 (s, 3H), 7.23 (d, J = 3.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 183.6, 170.7, 169.8, 169.6, 132.7, 129.7,
128.6, 127.8, 127.4, 82.9, 75.6, 73.5, 73.2, 70.4, 68.2, 61.6, 58.0, 26.4,
24.2, 20.8, 20.6, 20.5, 20.4; IR (KBr) ν 3352, 2935, 1760, 1537, 1370,
1212, 1035, 912, 702 cm−1; HRMS (ESI) found m/z 670.2802 [M +
H]+, calcd for C34H43N3O9S + H 670.2798.
Scheme 2. Further Synthetic Transformation of Product 3b
into Fluorinated Isoxazolidin-5-one 4
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1S,2S)-2-(azepan-1-
yl)-1,2-diphenylethyl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl tri-
acetate (K): light yellow solid; 1.54 g; 45% yield; mp 102−104 °C;
[α]20D −46.2 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 1.63 (s,
5H), 1.77 (s, 2H), 1.95 (s, 2H), 2.00−2.14 (m, 12H), 2.58−2.77 (m,
4H), 3.81 (d, J = 8.9 Hz, 1H), 4.05 (d, J = 12.1 Hz, 1H), 4.38−4.40 (m,
1H), 4.75 (s, 1H), 5.04−5.11 (m, 2H), 5.23−5.29 (m, 1H), 5.83 (s, 1H),
7.06 (s, 3H), 7.12 (m, 3H), 7.24−7.26 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 183.6, 170.7, 169.9, 169.5, 129.5, 129.0, 128.6, 128.2, 127.6,
82.7, 73.4, 70.2, 68.2, 61.6, 58.8, 51.9, 26.3, 20.7, 20.5, 20.4, 20.3; IR
(KBr) ν 3344, 2932, 1753, 1537, 1371, 1228, 1037, 911, 701 cm−1;
HRMS (MALDI) found m/z 684.2949 [M + H]+, calcd for
C35H45N3O9S + H 684.2955.
Materials. Unless otherwise noted, all commercially available
compounds and solvents were used as provided without further
purification. Organocatalysts A−G6,9 and isoxazol-5-ones13,14 were
prepared according or in analogy to the reported procedures.
General Procedure for the Synthesis of Catalysts. To a stirred
solution of (1S,2S)-1,2-diphenyl-2-(piperidin-1-yl)ethanamine15 (5.0
mmol) in dichloromethane (20 mL) was added a solution of saccharide-
derived isothiocyanate (5.0 mmol) in dry dichloromethane (20 mL) at 0
°C. The mixture was stirred at room temperature for 24 h (TLC) and
concentrated. The resulting residue was purified by column
chromatography on silica gel with the eluent (CH2Cl2/Et3N 100/1)
to give the white solid, which was dissolved in a minimal amount of
dichloromethane and slowly precipitated from solution by the addition
of petroleum ether at 0 °C. Filtration afforded the desired cyclic tertiary
amino-thiourea H. The catalysts of I−L were prepared by this similar
procedure.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1S,2S)-1,2-diphenyl-2-
(pyrrolidin-1-yl)ethyl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl tri-
acetate (H): light yellow solid; 1.77 g; 54% yield; mp 104−106 °C;
[α]20D −1.8 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 1.70−1.76
(m, 4H), 1.93 (s, 2H), 2.01−2.09 (m, 12H), 2.46−2.57 (m, 4H), 3.85−
3.88 (m, 1H), 3.93 (d, J = 8.4 Hz, 1H), 4.11−4.16 (m, 1H), 4.38−4.41
(m, 1H), 4.92 (d, J = 7.4 Hz), 5.10 (t, J = 9.7 Hz), 5.31−5.34 (m, 1H),
5.73−5.85 (m, 1H), 7.10 (s, 4H), 7.15−7.19 (m, 3H), 7.22−7.25 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 184.3, 170.6, 169.9, 169.6, 130.0,
129.5, 128.0, 127.7, 127.3, 83.2, 73.5, 73.0, 70.8, 68.2, 61.6, 52.1, 50.3,
47.6, 23.1, 22.9, 20.7, 20.6, 20.5; IR (KBr) ν 3356, 2963, 1753, 1538,
1371, 1228, 1038, 911, 704 cm−1; HRMS (ESI) found m/z 656.2637 [M
+ H]+, calcd for C33H41N3O9S + H 656.2642.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1S,2S)-2-(azocan-1-yl)-
1,2-diphenylethyl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl triace-
tate (L): light yellow solid; 1.43 g; 41% yield; mp 120−122 °C; [α]20
D
1
−3.0 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.23 (s, 3H),
1.36−1.49 (m, 3H), 1.69−1.76 (m, 2H), 1.97−2.04 (m, 12H), 2.06−
2.15 (m, 8H), 3.88 (d, J = 9.1 Hz, 1H), 4.10 (d, J = 12.3 Hz, 1H), 4.16−
4.22 (m, 1H), 4.30−4.33 (m, 1H), 4.99 (t, J = 8.9 Hz, 1H), 5.09 (t, J = 9.5
Hz, 2H), 5.32 (t, J = 8.4 Hz, 1H), 5.97−6.06 (m, 1H), 7.21 (d, J = 13.6
Hz, 7H), 7.32−7.44 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 183.6,
170.7, 169.9, 169.6, 130.9, 128.9, 128.6, 127.8, 127.1, 82.5, 73.3, 73.2,
73.1, 72.8, 70.6, 70.5, 68.3, 65.6, 61.8, 61.7, 45.0, 32.4, 30.6, 26.7, 20.8,
20.6, 19.2, 14.2, 13.7; IR (KBr) ν 3333, 2939, 1750, 1539, 1371, 1228,
1039, 912, 702 cm−1; HRMS (MALDI) found m/z 698.3106 [M + H]+,
calcd for C36H47N3O9S + H 698.3111.
General Procedure of Asymmetric Conjugate Addition/
Dearomative Fluorination Transformation. Isoxazol-5-one (0.13
mmol), nitroolefin (0.10 mmol), and the amino-thiourea catalyst (0.005
mmol) were added to a 10 mL Schlenk equipped with a magneton. The
vial was refilled with Ar three times. Et2O (1 mL) was added, and the
resulting mixture was stirred at room temperature under Ar atmosphere
for 48 h (monitored by TLC). Then NFSI (0.15 mmol) and anhydrous
Na2CO3 (0.12 mmol) were added, and the mixture was stirred at the
same temperature for 24 h (monitored by TLC). The system was
purified by flash chromatography with ethyl ether/petroleum ether (1/
25, v/v) to afford the fluorinated product.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1R,2R)-1,2-diphenyl-2-
(pyrrolidin-1-yl)ethyl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl tri-
acetate (I): light yellow solid; 1.74 g; 53% yield; mp 95−98 °C; [α]20
D
+21.2 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 1.69−1.73 (m,
4H), 1.98 (s, 2H), 2.01−2.09 (m, 12H), 2.38−2.51 (m, 4H), 3.78 (d, J =
9.5 Hz, 1H), 3.87 (d, J = 5.1 Hz, 1H), 4.08 (d, J = 11.4 Hz, 1H), 4.21−
4.25 (m, 1H), 4.78−4.82 (m, 1H), 4.96−4.50 (m, 1H), 5.30−5.33 (m,
1H), 5.69 (t, J = 8.7 Hz, 1H), 6.27 (d, J = 5.3 Hz, 1H), 7.14 (d, J = 7.2 Hz,
2H), 7.22−7.24 (m, 4H), 7.26 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 6.7 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 183.2, 170.5, 169.7, 169.6, 129.4,
128.5, 128.0, 127.8, 127.3, 82.9, 73.3, 72.7, 71.6, 71.0, 68.4, 61.7, 59.8,
49.5, 22.9, 20.6, 20.5; IR (KBr) ν 3362, 2962, 1752, 1538, 1371, 1228,
1038, 911, 704 cm−1; HRMS (ESI) found m/z 656.2637 [M + H]+, calcd
for C33H41N3O9S + H 656.2642.
4-Fluoro-(2-nitro-1-phenylethyl)-3-phenyl-4H-isoxazol-5-one
(3a): light brown solid; mp 78−80 °C; 30.5 mg; 93% yield; 86% ee
[determined by HPLC analysis Daicel Chirapak IC, hexane/i-PrOH =
90/10, 220 nm UV detector, 1.0 mL/min, tR = 9.6 min (minor) and tR =
10.8 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D −17.4 (c
1
1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 4.58−4.63 (m, 1H),
5.17−5.23 (m, 1H), 5.42−5.47 (m, 1H), 6.85 (d, J = 7.6 Hz, 2H),7.27 (t,
J = 7.4 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.5 Hz, 2H), 7.69 (t, J
= 7.3 Hz, 1H), 7.75 (d, J = 7.40, 2H); 13C NMR (100 MHz, CDCl3) δ
2
2
170.7 (d, JC−F = 22.3 Hz), 161.1 (d, JC−F = 14.5 Hz), 133.0, 130.1,
129.7, 129.6, 128.4, 127.1 (d, 3JC−F = 1.0 Hz), 125.4 (d, 3JC−F = 0.8 Hz),
92.5 (d, 1JC−F = 205.6 Hz), 72.1 (d, 3JC−F = 2.7 Hz), 47.0 (d, 2JC−F = 23.2
Hz); 19F NMR (376 MHz, CDCl3) δ −162.20 (d, J = 6.0 Hz); IR (KBr)
ν 2962, 2925, 1811, 1561, 1378, 1261, 1137, 1091, 868, 799, 695 cm−1;
HRMS (APCI) found m/z 329.0934 [M + H]+, calcd for C17H13FN2O4
+ H 329.0937.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(3-((1S,2S)-1,2-diphenyl-2-
(piperidin-1-yl)ethyl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl tria-
cetate (J): light yellow solid; 1.81 g; 54% yield; mp 105−107 °C; [α]20
D
−71.2 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.25−1.45 (m,
4H), 1.59 (s, 2H), 1.67 (s, 2H), 1.85−2.08 (m, 12H), 2.27−2.51 (m,
4H), 3.60 (d, J = 9.1 Hz, 1H), 3.83 (d, J = 9.7 Hz, 1H), 4.08 (d, J = 12.1
Hz, 1H), 4.37−4.42 (m, 1H), 4.68−4.89 (m, 1H), 5.06 (t, J = 9.6 Hz,
Scheme 3. Step-by-Step Control Experiments
563
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567

The Journal of Organic Chemistry
Article
Figure 2. Proposed mechanism for the one-pot sequential transformation.
4-Fluoro-4-(1-(4-methoxyphenyl)-2-nitroethyl)-3-phenylisoxazol-
5(4H)-one (3b): yellow solid; mp 148−150 °C; 33.7 mg; 94% yield; 92%
ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH
= 90/10, 220 nm UV detector, 1.0 mL/min, tR = 8.4 min (minor) and tR
= 9.7 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D −7.6 (c
1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 4.51−4.56
(m, 1H), 5.13−5.19 (m, 1H), 5.37−5.42 (m, 1H), 6.77 (s, 4H), 7.60 (t, J
= 7.5 Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H); 13C
130.4, 130.3, 129.8, 127.0 (d, 3JC−F = 1.2 Hz), 125.2 (d, 3JC−F = 1.4 Hz),
116.8 (d, 2JC−F = 22.0 Hz), 92.3 (d, 1JC−F = 206.3 Hz), 72.1 (d, 3JC−F
=
2
2.8 Hz), 46.4 (d, JC−F = 23.6 Hz); 19F NMR (376 MHz, CDCl3) δ
−106.38−−112.44 (m), −162.24 (d, J = 5.7 Hz); IR (KBr) ν 2962,
2932, 1811, 1605, 1562, 1513, 1378, 1236, 1137, 869, 693 cm−1; HRMS
(ESI) found m/z 369.0665 [M + Na]+, calcd for C17H12F2N2O4 + Na
369.0663.
4-(1-(4-Chlorophenyl)-2-nitroethyl)-4-fluoro-3-phenylisoxazol-
5(4H)-one (3e): light yellow solid; mp 126−128 °C; 32.6 mg; 90% yield;
81% ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-
PrOH = 95/5, 220 nm UV detector, 1.0 mL/min, tR = 11.2 min (minor)
NMR (100 MHz, CDCl3) δ 170.9 (d, 2JC−F = 22.5 Hz), 161.2 (d, 2JC−F
=
3
14.5 Hz), 133.0, 129.7, 129.6, 129.2, 127.8, 127.1 (d, JC−F = 0.9 Hz),
125.4, 92.5 (d, 1JC−F = 206.5 Hz), 72.3 (d, 3JC−F = 2.3 Hz), 55.3, 46.2 (d,
2JC−F = 23.0 Hz); 19F NMR (376 MHz, CDCl3) δ −161.64 (d, J = 5.4
and tR = 13.9 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20
+1.0 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 4.55−4.60 (m,
D
1
Hz); IR (KBr) ν 2963, 2920, 1810, 1557, 1376, 1257, 869, 799, 544
cm−1; HRMS (ESI) found m/z 359.1039 [M + H]+, calcd for
C18H15FN2O5 + H 359.1043.
1H), 5.15−5.21 (m, 1H), 5.38−5.43 (m, 1H), 6.79 (d, J = 8.4 Hz, 2H),
7.26 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 7.6 Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H),
7.75 (d, J = 7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.5 (d, 2JC−F
= 22.4 Hz), 161.0 (d, 2JC−F = 14.5 Hz), 136.4, 135.8, 133.2, 129.9, 129.8,
4-Fluoro-4-(2-nitro-1-p-tolylethyl)-3-phenylisoxazol-5(4H)-one
(3c): light yellow solid; mp 104−106 °C; 31.5 mg, 92% yield; 90% ee
[determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH =
95/5, 220 nm UV detector, 0.8 mL/min, tR = 9.4 min (minor) and tR =
15.7 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D −3.2 (c
1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 4.53−4.58
(m, 1H), 5.15−5.20 (m, 1H), 5.39−5.44 (m, 1H), 6.73 (d, J = 8.1 Hz,
2H), 7.06 (d, J = 7.9 Hz, 2H), 7.60 (t, J = 7.6 Hz, 2H), 7.68 (t, J = 7.4 Hz,
1H), 7.75 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.8 (d,
2JC−F = 22.6 Hz), 161.2 (d, 2JC−F = 14.6 Hz), 140.2, 133.0, 130.3, 129.7,
3
3
129.5, 127.0 (d, JC−F = 1.1 Hz), 125.2 (d, JC−F = 1.1 Hz), 116.8 (d,
2JC−F = 22.0 Hz), 92.3 (d, 1JC−F = 206.4 Hz), 72.9 (d, 3JC−F = 3.0 Hz),
46.5 (d, 2JC−F = 23.6 Hz); 19F NMR (376 MHz, CDCl3) δ −162.31 (d, J
= 5.6 Hz); IR (KBr) ν 2964, 2925, 1812, 1559, 1494, 1379, 1379, 1192,
1090, 869, 798, 688 cm−1; HRMS (ESI) found m/z 358.0362 [M +
Na]+, calcd for C17H12ClFN2O4 + Na 385.0367.
4-(1-(4-Bromophenyl)-2-nitroethyl)-4-fluoro-3-phenylisoxazol-
5(4H)-one (3f): light yellow solid; mp 132−134 °C; 35.4 mg, 87% yield;
80% ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-
PrOH = 95/5, 220 nm UV detector, 0.8 mL/min, tR = 11.8 min (minor)
128.2, 127.1 (d, 3JC−F = 1.2 Hz), 125.5 (d, 3JC−F = 1.2 Hz), 92.6 (d, 1JC−F
= 205.7 Hz), 72.2 (d, 3JC−F = 2.6 Hz), 46.6 (d, 2JC−F = 23.2 Hz), 21.1; 19
F
and tR = 11.7 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20
NMR (376 MHz, CDCl3) δ −162.01 (d, J = 5.6 Hz); IR (KBr) ν 2922,
1810, 1561, 1379, 1264, 1093, 870, 744, 692 cm−1; HRMS (ESI) found
m/z 365.0908 [M + Na]+, calcd for C18H15FN2O4 + Na 365.0914.
4-Fluoro-4-(1-(4-fluorophenyl)-2-nitroethyl)-3-phenylisoxazol-
5(4H)-one (3d): light brown solid; mp 85−88 °C; 30.1 mg, 87% yield;
86% ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-
PrOH = 95/5, 220 nm UV detector, 0.8 mL/min, tR = 11.0 min (minor)
D
+17.2 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 4.53−4.58 (m,
1H), 5.15−5.21 (m, 1H), 5.38−5.43 (m, 1H), 6.73 (d, J = 8.4 Hz, 2H),
7.41 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 7.6 Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H),
7.75 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.5 (d, 2JC−F
= 22.2 Hz), 160.9 (d, 2JC−F = 14.3 Hz), 133.2, 132.9, 129.9, 129.8, 127.0
3
3
1
(d, JC−F = 1.2 Hz), 125.2 (d, JC−F = 1.2 Hz),124.6, 92.2 (d, JC−F
=
and tR = 13.2 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20
206.4 Hz), 71.9 (d, 3JC−F = 2.8 Hz), 46.6 (d, 2JC−F = 23.7 Hz); 19F NMR
(376 MHz, CDCl3) δ −162.31 (d, J = 5.4 Hz); IR (KBr) ν 2963, 1811,
1724, 1559, 1261, 1074, 869, 797, 689 cm−1; HRMS (APCI) found m/z
407.0037 [M + H]+, calcd for C17H12BrFN2O4 + H 407.0042.
D
−20.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ4.56−4.61 (m,
1H), 5.15−5.21 (m, 1H), 5.38−5.43 (m, 1H), 6.83−6.86 (m, 2H), 6.97
(t, J = 8.4 Hz, 2H), 7.61 (t, J = 7.5 Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H), 7.75
(d, J = 7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.6 (d, 2JC−F
=
4-Fluoro-4-(2-nitro-1-(3-phenoxyphenyl)ethyl)-3-phenylisoxazol-
5(4H)-one (3g): yellow solid; mp 80−82 °C; 39.1 mg, 93% yield; 80% ee
22.5 Hz), 163.4 (d, 1JC−F = 251.0 Hz), 161.0 (d, 2JC−F = 14.5 Hz), 133.1,
564
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567

The Journal of Organic Chemistry
Article
[determined by HPLC analysis Daicel Chirapak IC, hexane/i-PrOH =
90/10, 220 nm UV detector, 1.0 mL/min, tR = 9.7 min (minor) and tR =
14.2 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D +27.6 (c
7.57 (m, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 170.8 (d, 2JC−F = 22.5 Hz), 161.2 (d, 2JC−F
=
14.5 Hz), 133.6, 133.0, 129.7, 129.6, 128.7, 128.0, 127.8, 127.4, 127.2 (d,
1
1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 4.54−4.58 (m, 1H),
3JC−F = 1.1 Hz), 127.1, 126.5, 125.5 (d, 3JC−F = 1.0 Hz), 124.8, 92.6 (d,
1JC−F = 205.9 Hz), 72.2 (d, 3JC−F = 2.5 Hz), 47.1 (d, 2JC−F = 23.3 Hz); 19
F
5.12−5.17 (m, 1H), 5.38−5.43 (m, 1H), 6.45 (s, 1H), 6.60 (d, J = 7.7
Hz, 1H), 6.90 (d, J = 7.8 Hz, 2H), 6.97−7.00 (m, 1H), 7.17 (t, J = 7.4 Hz,
1H), 7.24 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.55 (t, J = 7.6 Hz,
2H), 7.65 (t, J = 7.4 Hz, 1H), 7.73 (d, J = 7.9 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 170.5 (d, 2JC−F = 22.6 Hz), 161.1 (d, 2JC−F = 14.6 Hz),
158.2, 156.0, 133.0, 131.0, 130.0, 129.8, 127.0 (d, 3JC−F = 1.1 Hz), 124.1,
122.5, 120.2, 119.3, 118.5, 92.4 (d, 1JC−F = 205.7 Hz), 71.9 (d, 3JC−F = 2.9
Hz), 46.8 (d, 2JC−F = 23.4 Hz); 19F NMR (376 MHz, CDCl3) δ −162.46
(d, J = 5.6 Hz); IR (KBr) ν 3261, 2961, 2921, 2238, 1811, 1723, 1594,
1561, 1489, 1330, 1277, 1251, 1158, 750, 691 cm−1; HRMS (ESI) found
m/z 420.1124 [M]+, calcd for C23H17FN2O5 420.1121.
NMR (376 MHz, CDCl3) δ −159.22 (d, J = 7.6 Hz); IR (KBr) ν 2962,
2928, 1810, 1724, 1560, 1378, 1284, 1137, 1065, 866, 748, 693 cm−1;
HRMS (ESI) found m/z 378.1014 [M]+, calcd for C21H15FN2O4
378.1016.
4-Fluoro-4-(1-(furan-2-yl)-2-nitroethyl)-3-phenylisoxazol-5(4H)-
one (3l): brown oil liquid; 20.4 mg, 90% yield; 64% ee [determined by
HPLC analysis Daicel Chirapak IC, hexane/i-PrOH = 90/10, 220 nm
UV detector, 1.0 mL/min, tR = 9.8 min (major) and tR = 10.8 min
(minor)]; >99:1 dr [determined by 19F NMR]; [α]20 −47.4 (c 1.0,
D
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 4.69−4.74 (m, 1H), 5.15−
4-(1-(2-Chlorophenyl)-2-nitroethyl)-4-fluoro-3-phenylisoxazol-
5(4H)-one (3h): white solid; mp 130−132 °C; 33.7 mg, 93% yield; 90%
ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH
= 95/5, 220 nm UV detector, 0.8 mL/min, tR = 11.9 min (minor) and tR
= 12.7 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D −10.0
5.21 (m, 1H2), 5.30−5.34 (m, 1H), 6.01 (d, J = 3.3 Hz, 1H), 6.28−6.30
(m, 1H), 7.38 (d, J = 1.1 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.67 (t, J = 7.4
Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 171.0
(d, 2JC−F = 22.1 Hz), 161.2 (d, 2JC−F = 14.2 Hz), 144.7, 142.4 (d, 3JC−F
=
3
10.4 Hz), 132.9, 129.7, 127.0 (d, JC−F = 1.1 Hz), 125.1, 111.5, 111.1,
90.7 (d, 1JC−F = 207.0 Hz), 70.8 (d, 2JC−F = 1.5 Hz), 41.5 (d, 2JC−F = 26.3
Hz); 19F NMR (376 MHz, CDCl3) δ −163.50 (d, J = 5.4 Hz); IR (KBr)
ν 2963, 2930, 1814, 1724, 1563, 1501, 1377, 1327, 1137, 1018, 869, 748,
694 cm−1; HRMS (APCI) found m/z 319.0724 [M + H]+, calcd for
C15H11FN2O5 + H 319.0730.
1
(c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 5.04−5.10 (m, 1H),
5.36 (d, J = 3.8 Hz, 1H), 5.43−5.48 (m, 1H), 7.26 (d, J = 8.9 Hz, 2H),
7.30 (d, J = 7.0 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H),
7.72 (d, J = 7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 171.0 (d, 2JC−F
= 22.6 Hz), 161.3 (d, 2JC−F = 14.0 Hz), 135.9, 135.1, 133.0, 131.1, 130.8,
3
1
129.8, 129.4, 128.2, 127.2 (d, JC−F = 1.0 Hz), 125.3, 92.6 (d, JC−F
=
3-(4-Chlorophenyl)-4-fluoro-4-(2-nitro-1-phenylethyl)isoxazol-
5(4H)-one (3m): light yellow solid; mp 122−125 °C; 33.4 mg, 92%
yield; 87% ee [determined by HPLC analysis Daicel Chirapak IC,
hexane/i-PrOH = 90/10, 220 nm UV detector, 1.0 mL/min, tR = 10.3
205.2 Hz), 72.9 (d, 3JC−F = 1.5 Hz), 42.5 (d, 2JC−F = 27.6 Hz); 19F NMR
(376 MHz, CDCl3) δ −161.42 (s); IR (KBr) ν 2962, 2925, 18077, 1557,
1447, 1381, 1193, 1138, 1081, 863, 760, 692 cm−1; HRMS (ESI) found
m/z 362.0465 [M]+, calcd for C17H12ClFN2O4 362.0470.
min (minor) and tR = 12.0 min (major)]; >99:1 dr [determined by 19
F
NMR]; [α]20D +16.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
4.53−4.58 (m, 1H), 5.14−5.20 (m, 1H), 5.42−5.47 (m, 1H), 6.86 (d, J =
7.5 Hz, 2H), 7.27−7.31 (m, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.59 (d, J = 8.5
Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.4
4-(1-(2-Bromophenyl)-2-nitroethyl)-4-fluoro-3-phenylisoxazol-
5(4H)-one (3i): white solid; mp 130−132 °C; 35.4 mg, 87% yield; 90%
ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH
= 95/5, 220 nm UV detector, 0.8 mL/min, tR = 12.2 min (minor) and tR
= 13.6 min (major)]; dr =97:3 dr [determined by 19F NMR]; [α]20
2
2
(d, JC−F = 22.2 Hz), 160.4 (d, JC−F = 14.6 Hz), 139.5, 130.2, 130.2,
D
−26.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 5.00−5.05 (m,
1H), 5.34−5.39 (m, 1H), 5.42−5.47 (m, 1H), 7.19−7.25 (m, 2H),
7.40−7.35 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H),
7.63 (t, J = 7.3 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 171.0 (d, 2JC−F = 22.6 Hz), 161.3 (d, 2JC−F = 13.9 Hz), 134.4,
133.0, 131.3, 129.5, 128.8, 127.1 (d, 3JC−F = 1.4 Hz), 125.4 (d, 3JC−F = 1.4
3
1
129.7, 129.4, 129.2, 128.3, 123.8 (d, JC−F = 1.0 Hz), 92.3 (d, JC−F
=
205.8 Hz), 72.0 (d, 2JC−F = 2.6 Hz), 47.0 (d, 2JC−F = 23.1 Hz); 19F NMR
(376 MHz, CDCl3) δ −162.53 (d, J = 6.0 Hz); IR (KBr) ν 2963, 2921,
1813, 1560, 1378, 1342, 1261, 1092, 870, 800, 702 cm−1; HRMS (ESI)
found: m/z 362.0469 [M]+, calcd for C17H12ClFN2O4 362.0470.
3-(4-Bromophenyl)-4-fluoro-4-(2-nitro-1-phenylethyl)isoxazol-
5(4H)-one (3n): light yellow solid; mp 143−145 °C; 34.2 mg, 84% yield;
81% ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-
PrOH = 95/5, 220 nm UV detector, 0.8 mL/min, tR = 12.3 min (minor)
1
2
Hz), 92.6 (d, JC−F = 204.6 Hz), 73.1, 45.3 (d, JC−F = 26.2 Hz); 19F
NMR (376 MHz, CDCl3) δ −161.29 (d, J = 7.2 Hz), −162.34 (d, J = 5.6
Hz); IR (KBr) ν 2963, 2925, 1797, 1553, 1261, 1067, 863, 798, 690
cm−1; HRMS (ESI) found m/z 405.9968 [M]+, calcd for
C17H12BrFN2O4 405.9964.
and tR = 14.1 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20
D
+17.4 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 4.53−4.58 (m,
1H), 5.14−5.20 (m, 1H), 5.42−5.46 (m, 1H), 6.86 (d, J = 7.4 Hz, 2H),
7.29 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H),
7.75 (d, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.4 (d, 2JC−F
= 22.3 Hz), 160.5 (d, 2JC−F = 14.7 Hz), 139.1, 133.1, 132.1, 130.2, 129.7,
129.4, 129.2, 128.4 (d, 3JC−F = 1.2 Hz), 128.3, 128.1, 124.3 (d, 3JC−F = 1.1
4-Fluoro-4-(1-(naphthalen-1-yl)-2-nitroethyl)-3-phenylisoxazol-
5(4H)-one (3j): yellow solid; mp 122−124 °C; 31.4 mg, 83% yield; 82%
ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH
= 95/5, 220 nm UV detector, 0.8 mL/min, tR = 12.4 min (major) and tR
= 15.4 min (minor)]; >99:1 dr [determined by 19F NMR]; [α]20D −76.4
1
Hz), 92.3 (d, 1JC−F = 205.6 Hz), 72.0 (d, 2JC−F = 2.6 Hz), 47.0 (d, 2JC−F
=
(c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 4.73−4.78 (m, 1H),
23.2 Hz); 19F NMR (376 MHz, CDCl3) δ −162.55 (d, J = 5.8 Hz); IR
(KBr) ν 2962, 2923, 1812, 1592, 1560, 1432, 1332, 1158, 1089, 870, 750,
699 cm−1; HRMS (ESI) found m/z 405.9966 [M]+, calcd for
C17H12BrFN2O4 405.9964.
5.31−5.37 (m, 1H), 5.50−5.55 (m, 1H), 6.90−6.92 (m, 1H), 7.31 (s,
1H), 7.30−7.56 (m, 2H), 7.60−7.66 (m, 3H), 7.70−7.77 (m, 4H), 7.82
(d, J = 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.2 (d, 2JC−F
=
22.7 Hz), 161.2 (d, 2JC−F = 14.0 Hz), 133.9, 132.7, 130.9, 130.7, 129.4,
128.8, 127.0 (d, 3JC−F = 1.7 Hz), 126.3, 136.0, 125.7, 125.3, 125.0, 92.9
(d, 1JC−F = 205.0 Hz), 73.5 (d, 3JC−F = 1.0 Hz), 40.5 (d, 2JC−F = 24.1 Hz);
19F NMR (376 MHz, CDCl3) δ −159.22 (d, J = 7.6 Hz); IR (KBr) ν
4-Fluoro-4-(2-nitro-1-phenylethyl)-3-m-tolylisoxazol-5(4H)-one
(3o): light yellow solid; mp 99−101 °C; 31.5 mg, 92% yield; 80% ee
[determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH =
95/5, 220 nm UV detector, 1.0 mL/min, tR = 11.7 min (minor) and tR =
12.9 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D −6.8 (c
1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 2.48 (s, 3H), 4.59−4.63
(m, 1H), 5.14−5.20 (m, 1H), 5.43−5.48 (m, 1H), 6.87 (d, J = 7.4 Hz,
2H), 7.26−7.30 (m, 2H), 7.34−7.36 (m, 1H), 7.55 (d, J = 2.4 Hz, 2H),
2964, 2925, 1809, 1560, 1377, 1138, 1078, 1053, 867, 770, 692 cm−1;
HRMS (ESI) found m/z 378.1013 [M]+, calcd for C21H15FN2O4
378.1016.
4-Fluoro-4-(1-(naphthalen-2-yl)-2-nitroethyl)-3-phenylisoxazol-
5(4H)-one (3k): yellow solid; mp 122−124 °C; 31.8 mg, 84% yield; 77%
ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH
= 95/5, 220 nm UV detector, 0.8 mL/min, tR = 12.9 min (minor) and tR
= 17.3 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D +30.0
7.73−7.75 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.8 (d, 2JC−F
=
22.4 Hz), 161.2 (d, 2JC−F = 14.3 Hz), 139.7, 133.9, 130.1, 129.6, 129.5,
128.4, 127.4 (d, 3JC−F = 1.0 Hz), 125.3 (d, 3JC−F = 1.3 Hz), 124.3, 124.2,
92.6 (d, 1JC−F = 205.5 Hz), 72.1 (d, 2JC−F = 3.0 Hz), 47.0 (d, 2JC−F = 23.2
Hz), 21.5; 19F NMR (376 MHz, CDCl3) δ −162.19 (d, J = 5.6 Hz); IR
(KBr) ν 2963, 2927, 1804, 1559, 1438, 1379, 1342, 1261, 1092, 882, 797,
1
(c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 5.24−5.32 (m, 1H),
5.53−5.65 (m, 2H), 6.92 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H),
7.33 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 4.5 Hz, 4H), 7.42−7.50 (m, 2H),
565
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567

The Journal of Organic Chemistry
Article
701 cm−1; HRMS (APCI) found m/z 343.1089 [M + H]+, calcd for
C18H15FN2O4 + H 343.1094.
one 1a (42 mg, 0.26 mmol), trans-β-nitrostyrene 2a (30 mg, 0.20
mmol), and the amino-thiourea catalyst J (6.7 mg, 0.01 mmol) were
added to a 10 mL Schlenk equipped with a magneton. The vial was
refilled with Ar three times. Et2O (2 mL) was added, and the resulting
mixture was stirred at room temperature under Ar atmosphere for 48 h
(monitored by TLC). The reaction was concentrated and purified by
flash chromatography with ethyl ether/petroleum ether (1/15, v/v) to
afford the addition intermediate (Int-a): light brown solid; mp 44−46
°C; 60.8 mg, 98% yield; 88% ee [determined by HPLC analysis Daicel
Chirapak IA, hexane/i-PrOH = 80/20, 254 nm UV detector, 0.8 mL/
min, tR = 4.4 min (minor) and tR = 6.1 min (major)]; [α]20D −2.4 (c 1.0,
CH2Cl2); 1H NMR (400 MHz, DMSO) δ 4.53−4.57 (m, 1H), 5.12−
5.17 (m, 1H), 5.35−5.42 (m, 1H), 7.27−7.30 (m, 1H), 7.34 −7.40 (m,
4H), 7.50 (s, 2H), 7.60−7.62 (d, J = 6.7 Hz, 3H), 12.96 (s, 1H); 13C
NMR (100 MHz, DMSO) δ 171.5, 162.9, 139.5, 131.8, 129.8, 129.4,
129.1, 128.2, 128.0, 127.9, 127.3, 76.8, 38.4; IR (KBr) ν 3431, 2932,
1669, 1612, 1554, 1487, 1378, 1159, 1032, 760, 698 cm−1; HRMS (ESI)
found m/z 310.0957 [M]+, calcd for C17H14N2O4 310.0954.
To a solution of Int-a (46.5 mg, 0.15 mmol) in Et2O (2 mL) were
added NFSI (63 mg, 0.2 mmol) and anhydrous Na2CO3 (22 mg, 0.2
mmol). The mixture was stirred at room temperature for 24 h
(monitored by TLC). The reaction was quenched with water (5 mL)
and extracted with EtOAc (5 mL × 3), and the organic layer was washed
with brine (5 mL × 3) and dried over Na2SO4. The organics were
filtered, concentrated, and purified by flash chromatography with ethyl
ether/petroleum ether to afford the fluorinated product 3a. 44.3 mg;
90% yield; 84% ee [determined by HPLC analysis Daicel Chirapak IC,
hexane/i-PrOH = 90/10, 220 nm UV detector, 1.0 mL/min, tR = 9.6 min
(minor) and tR = 10.8 min (major)]; 95:5 dr [determined by 19F NMR].
Procedure for Further Synthetic Transformation. To a solution
of 3b (71.7 mg, 0.2 mmol) in anhydrous CH3OH (3 mL) was slowly
added NaBH4 (75.7 mg, 20.0 mmol) in batches at 0 °C under argon
atmosphere. After 8 h (monitored by TLC) at room temperature, 1 N
HCl was added, the reaction was quenched with EtOAc (5 mL × 3), and
the organic layer was washed with brine (5 mL × 3) and dried over
Na2SO4. The organics were filtered and concentrated. The solid
obtained was directly for next reaction.
4-Fluoro-3-(3-methoxyphenyl)-4-(2-nitro-1-phenylethyl)isoxazol-
5(4H)-one (3p): white solid; mp 147−149 °C; 32.6 mg, 91% yield; 78%
ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH
= 95/5, 220 nm UV detector, 1.0 mL/min, tR = 11.9 min (minor) and tR
= 12.8 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D −6.8
(c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 4.61−4.66
(m, 1H), 5.17−5.23 (m, 1H), 5.42−5.47 (m, 1H), 6.87 (d, J = 7.5 Hz,
2H), 7.27 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.49 (d, J = 4.9 Hz,
2H), 7.54 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 170.7 (d, 2JC−F = 22.4
Hz), 161.1 (d, 2JC−F = 14.3 Hz), 160.3, 130.8, 130.1, 129.8, 129.6, 128.5,
126.5, 119.5 (d, 3JC−F = 1.8 Hz), 119.4, 111.5, 92.5 (d, 1JC−F = 205.6 Hz),
72.1 (d, 2JC−F = 2.8 Hz), 55.5, 47.0 (d, 2JC−F = 23.3 Hz); 19F NMR (376
MHz, CDCl3) δ −162.19 (d, J = 5.5 Hz); IR (KBr) ν 2963, 2944, 1800,
1550, 1454, 1380, 1295, 1245, 1037, 873, 791, 703 cm−1; HRMS (ESI)
found m/z 358.0961 [M]+, calcd for C18H15FN2O5 358.0965.
3-(2-Chlorophenyl)-4-fluoro-4-(2-nitro-1-phenylethyl)isoxazol-
5(4H)-one (3q): white solid; mp 126−128 °C; 31.9 mg, 88% yield; 85%
ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH
= 90/10, 220 nm UV detector, 1.0 mL/min, tR = 12.6 min (minor) and tR
= 13.3 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20
D
−283.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 4.29−4.34 (m,
1H), 5.15−5.21 (m, 1H), 5.33−5.38 (m, 1H), 6.87 (d, J = 7.3 Hz, 2H),
7.32 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.49−7.53 (m, 1H),
7.55−7.60 (m, 2H), 7.70 (d, J = 7.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 170.0 (d, 2JC−F = 22.6 Hz), 159.4 (d, 2JC−F = 13.0 Hz), 134.1,
133.1, 132.0, 130.1, 130.0, 129.8, 129.7, 128.3, 127.5, 124.1 (d, 3JC−F
=
1.2 Hz), 92.5 (d, 1JC−F = 202.9 Hz), 72.7 (d, 2JC−F = 2.2 Hz), 46.8 (d,
2JC−F = 23.6 Hz); 19F NMR (376 MHz, CDCl3) δ −154.80 (d, J = 7.6
Hz); IR (KBr) ν 2969, 2927, 1803, 1556, 1430, 1379, 1143, 1095, 860,
766, 700 cm−1; HRMS (ESI) found m/z 362.0467 [M]+, calcd for
C17H12ClFN2O4 362.0470.
4-Fluoro-3-(naphthalen-1-yl)-4-(2-nitro-1-phenylethyl)isoxazol-
5(4H)-one (3r): light yellow solid; mp 103−106 °C; 33.3 mg, 88% yield;
79% ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-
PrOH = 98/2, 220 nm UV detector, 0.6 mL/min, tR = 20.2 min (minor)
and tR = 22.3 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20
D
−132.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 4.47−4.50 (m,
1H), 5.20−5.26 (m, 1H), 5.41−5.46 (m, 1H), 6.74 (d, J = 7.5 Hz, 2H),
7.10 (t, J = 7.7 Hz, 2H), 7.28−7.32 (m, 1H), 7.42−7.46 (m, 1H), 7.59 (t,
J = 7.4 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.96 (d,
J = 8.2 Hz, 1H), 8.05 (d, J = 7.3 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H); 13C
To a solution of the above intermediate and DMAP (24.4 mg, 0.2
mmol) in THF (5 mL) was added Boc2O (65.6 mg, 0.3 mmol) at 0 °C
under argon atmosphere. After 12 h (monitored by TLC) at room
temperature, the mixture was concentrated and purified by flash
chromatography (petroleum ether/ethyl acetate = 20:1) to obtain the
product 4: yellow solid; mp 48−51 °C; 50.6 mg, 55% yield; 76:24 dr
[determined by HPLC analysis Daicel Chirapak IC, hexane/i-PrOH =
90/10, 220 nm UV detector, 1.0 mL/min, major diastereomer: tR =
11.773 min and tR = 14.543 min, 94% ee; minor diastereomer: tR = 13.1
min and tR = 16.7 min, 94% ee]; [α]20D −9.8 (c 1.0, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 1.54 (s, 9H, O(CH3)3), 3.78 (s, 3H, OCH3),
5.03−5.09 (m, 1H, CH2NO2), 5.14−5.19 (m, 1H, CH2NO2), 6.49 (s,
1H, CH), 6.81 (d, J = 8.3 Hz, 2H, Ar−H), 6.97 (d, J = 8.3 Hz, 2H, Ar−
NMR (100 MHz, CDCl3) δ 170.4 (d, 2JC−F = 22.8 Hz), 161.0 (d, 2JC−F
=
12.6 Hz), 139.1, 134.1, 133.6, 129.9, 129.7, 129.4, 129.2, 128.8, 128.5,
128.2, 128.0, 127.9, 127.1, 125.8, 125.0, 122.2 (d, 3JC−F = 1.3 Hz), 93.4
(d, 1JC−F = 205.0 Hz), 72.5 (d, 2JC−F = 2.4 Hz), 47.2 (d, 2JC−F = 23.4 Hz);
19F NMR (376 MHz, CDCl3) δ −156.84 (d, J = 6.7 Hz); IR (KBr) ν
2963, 2924, 1808, 1724, 1560, 1513, 1377, 1260, 1092, 869, 802, 776,
703 cm−1; HRMS (ESI) found m/z 378.1021 [M]+, calcd for
C21H15FN2O4 378.1016.
4-Fluoro-3-(naphthalen-2-yl)-4-(2-nitro-1-phenylethyl)isoxazol-
5(4H)-one (3s): white solid; mp 150−152 °C; 32.2 mg, 85% yield; 83%
ee [determined by HPLC analysis Daicel Chirapak AD, hexane/i-PrOH
= 98/2, 220 nm UV detector, 0.5 mL/min, tR = 38.7 min (minor) and tR
= 42.4 min (major)]; >99:1 dr [determined by 19F NMR]; [α]20D +59.0
H), 7.54 (d, J = 4.8 Hz, 3H, Ar−H), 7.86 (d, J = 7.2 Hz, 2H, Ar−H); 13
C
2
NMR (100 MHz, CDCl3) δ 160.2, 155.3 (d, JC−F = 17.9 Hz), 151.3,
131.6, 130.6, 129.7, 129.4, 128.1, 127.3 (d, 3JC−F = 2.9 Hz), 114.6, 105.9
(d, 1JC−F = 214.0 Hz), 96.1 (d, 2JC−F = 14.8 Hz), 84.5, 74.6 (d, 3JC−F = 3.6
Hz), 55.2, 46.2 (d, 2JC−F = 23.2 Hz), 27.6; 19F NMR (376 MHz, CDCl3)
δ −170.47 (d, J = 8.2 Hz); IR (KBr) ν 2964, 2935, 1745, 1560, 1515,
1374, 1278, 1256, 1158, 1031, 991, 848, 769, 694 cm−1; HRMS (ESI)
found m/z 461.1641 [M]+, calcd for C23H25FN2O7 461.1646.
1
(c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 4.72−4.77 (m, 1H),
5.18−5.24 (m, 1H), 5.50−5.55 (m, 1H), 6.85 (d, J = 7.6 Hz, 2H), 7.25
(t, J = 7.6 Hz, 2H), 7.54−7.56 (m, 1H), 7.68−7.70 (m, 1H), 7.72−7.74
(m, 2H), 7.96−8.00 (m, 2H), 8.05 (d, J = 7.7 Hz, 1H), 8.33 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 170.8 (d, 2JC−F = 22.6 Hz), 161.1 (d, 2JC−F
=
3
14.7 Hz), 139.1, 135.1, 132.8, 130.9 (d, JC−F = 2.5 Hz), 130.1, 129.9,
129.6, 129.4, 129.3, 129.1, 129.0, 128.4, 128.1, 127.6, 122.8 (d, 3JC−F
=
ASSOCIATED CONTENT
1.1 Hz), 122.4, 92.8 (d, 1JC−F = 206.2 Hz), 72.1 (d, 2JC−F = 3.0 Hz), 47.2
(d, 2JC−F = 23.2 Hz); 19F NMR (376 MHz, CDCl3) δ −162.43 (d, J = 5.4
Hz); IR (KBr) ν 2959, 2931, 1797, 1726, 1560, 1456, 1382, 1344, 1276,
1122, 1069, 880, 818, 753, 705 cm−1; HRMS (ESI) found m/z 378.1019
[M]+, calcd for C21H15FN2O4 378.1016.
■
S
* Supporting Information
1H and 13C NMR spectra and HPLC analytic results for the
products 3a−s, Int-a, and 4, as well as crystallographic data for
compound 3i (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Step-by-Step Procedure for Asymmetric Conjugate Addi-
tion, then Dearomative Fluorination Transformation. Isoxazol-5-
566
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567

The Journal of Organic Chemistry
Article
Rev. 2004, 104, 1. (b) Chambers, R. D. Fluorine in Organic Chemistry;
Blackwell: Oxford, 2004. (c) Thayer, A. M. Chem. Eng. News 2006, 84,
15. (d) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (e) Kirk, K. L.
Org. Process Res. Dev. 2008, 12, 305. (f) Hu, J.; Zhang, W.; Wang, F.
Chem. Commun. 2009, 7465. (g) Cahard, D.; Xu, X.; Couve-Bonnaire,
S.; Pannecoucke, X. Chem. Soc. Rev. 2010, 39, 558. (h) Lectard, S.;
Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010, 352, 2708. (i) Nie,
J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455.
(9) (a) Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org.
Lett. 2007, 9, 923. (b) Li, X.-J.; Liu, K.; Ma, H.; Nie, J.; Ma, J.-A. Synlett
2008, 3242. (c) Ma, H.; Liu, K.; Zhang, F.-G.; Zhu, C.-L.; Nie, J.; Ma, J.-
A. J. Org. Chem. 2010, 75, 1402. (d) Nie, J.; Li, X.-J.; Zheng, D.-H.;
Zhang, F.-G.; Cui, S.; Ma, J.-A. J. Fluorine Chem. 2011, 132, 468.
(10) The relative and absolute configuration of compound 3i was
confirmed by X-ray crystal structure analysis. CCDC 879309 (3i)
contains the supplementary crystallographic data for this paper (see the
Supporting Information). These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
AUTHOR INFORMATION
Corresponding Author
*E-mail: majun_an68@tju.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully appreciate the National Natural Science
Foundation of China (NSFC Nos. 20972110, 20902067, and
21002068) for financial support.
REFERENCES
■
(1) For the recent reviews, see: (a) Wilkinson, S. C.; Salmon, R.;
Gouverneur, V. Future Med. Chem. 2009, 1, 847. (b) Purser, S.; Moore,
P. R.; PSwallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(c) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
(2) (a) Vardelle, D.; Gamba-Sanchez, D.; Martin-Mingot, A.;
Jouannetaud, M.-P.; Thibaudeau, S.; Marrot, J. Chem. Commun. 2008,
1473. (b) Kishi, Y.; Nagura, H.; Inagi, S.; Fuchigami, T. Chem. Commun.
2008, 3876. (c) Rudler, H.; Parlier, A.; Hamon, L.; Herson, P.; Daran, J.-
C. Chem. Commun. 2008, 4150. (d) Lin, R.; Ding, S.; Shi, Z.; Jiao, N. Org.
Lett. 2011, 13, 4498. (e) Wilkinson, S. C.; Lozano, O.; Schuler, M.;
Pacheco, M. C.; Salmon, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2009,
48, 7083. (f) Cui, H.; Li, P.; Chai, Z.; Zheng, C.; Zhao, G.; Zhu, S. J. Org.
Chem. 2009, 74, 1400. (g) Zhou, C.; Ma, Z.; Gu, Z.; Fu, C.; Ma, S. J. Org.
Chem. 2008, 73, 772. (h) Kishi, Y.; Inagi, S.; Fuchigami, T. Eur. J. Org.
Chem. 2009, 103. (i) Xu, T.; Mu, X.; Peng, H.; Liu, G. Angew. Chem., Int.
Ed. 2011, 50, 8176. (j) Wang, H.-F.; Cui, H.-F.; Chai, Z.; Li, P.; Zheng,
C.-W.; Yang, Y.-Q.; Zhao, G. Chem.Eur. J. 2009, 15, 13299. (k) Li, F.;
Nie, J.; Wu, J.-W.; Zheng, Y.; Ma, J.-A. J. Org. Chem. 2012, 77, 2398.
(3) (a) Laughlin, S. K.; Clark, M. P.; Djung, J. F.; Golebiowski, A.;
Brugel, T. A.; Sabat, M.; Bookland, R. G.; Laufersweiler, M. J.; VanRes,
T. A.; Sabat, M.; Bookland, R. G.; Laufersweiler, M. J.; VanRens, J. C.;
Townes, J. A.; Lily, C.; Hsieh, B. D.; Xu, S. C.; Walter, R. L.; Mekel, M. J.;
Janusz, M. J. Bioorg. Med. Chem. Lett. 2005, 15, 2399. (b) Cordaliza, M.;
(11) (a) Conti, P.; Dallanoce, C.; Amici, M. D.; Micheli, C. D.; Klotz,
K. N. Bioorg. Med. Chem. 1998, 6, 401. (b) Kang, Y. Y.; Shin, K. J.; Yo, K.
H.; Seo, K. J.; Hong, C. Y.; Lee, C. S.; Park, S. Y.; Kim, D. J.; Park, S. W.
Bioorg. Med. Chem. Lett. 2000, 10, 95. (c) Abbiati, G.; Beccalli, E. M.;
Broggini, G.; Zoni, C. Tetrahedron 2003, 59, 9887.
(12) (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J.
Am. Chem. Soc. 2005, 127, 119. (b) Hamza, A.; Schubert, G.; Soos
́
, T.;
Papai, I. J. Am. Chem. Soc. 2006, 128, 13151. (c) Zhu, J.-L.; Zhang, Y.;
́
Liu, C.; Zheng, A.-M.; Wang, W. J. Org. Chem. 2012, 77, 9813.
(13) Khrowov, N. V. J. Gen. Chem. 1947, 17, 1816.
(14) Jiang, Y.; Chen, X.; Zheng, Y.-S.; Xue, Z.-Y.; Shu, C.; Yuan, W.-C.;
Zhang, X.-M. Angew. Chem., Int. Ed. 2011, 50, 7304.
(15) Kim, K. H.; Lee, S.; Lee, D.-W.; Ko, D.-H.; Ha, D.-C. Tetrahedron
Lett. 2005, 46, 5991.
Faircloth, G. T.; Castro, M. A.; del Corral, J. M. M.; Lop
Feliciano, A. S. J. Med. Chem. 1996, 39, 2865. (c) Gonzalez, M.; Segura, J.
L.; Seoane, C.; Martín, N. J. Org. Chem. 2001, 66, 8872.
́ ́
ez-Vazquez, L.;
́
(4) For recent reviews, see: (a) Pape, A. R.; Kaliappan, K. P.; Kundig, P.
̈
Chem. Rev. 2000, 100, 2917. (b) Subba Rao, G. S. R. Pure Appl. Chem.
2003, 75, 1443. (c) Harman, W. D. Top. Organomet. Chem. 2004, 7, 95.
(d) Ortiz, F. L.; Iglesias, M. J.; Fernan
G. R. Chem. Rev. 2007, 107, 1580. (e) Zhou, Y.-G. Acc. Chem. Res. 2007,
40, 1357. (f) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 467.
́
dez, I.; Sanchez, C. M. A.; Gomez,
́
̈
́
(g) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068.
For selected recent examples on catalytic asymmetric dearomatization,
see: (h) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.;
Minamistsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew.
Chem., Int. Ed. 2008, 47, 3787. (i) Quideau, S.; Lyvinec, G.; Marguerit,
M.; Bathany, K.; Ozanne-Beaudenon, A.; Buffeteau, T.; Cavagnat, D.;
́ ́
Chenede, A. Angew. Chem., Int. Ed. 2009, 48, 4605. (j) Garcia-Fortanet,
J.; Kessler, F.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 6676. (k) Qi,
J.; Beeler, A. B.; Zhang, Q.; Porco, J. A., Jr. J. Am. Chem. Soc. 2010, 132,
13642.
(5) (a) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 404. (b) Lozano, O.; Blessley, G.; del Campo, T. M.;
Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman, R.;
Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 8105.
(6) Li, F.; Sun, L.; Teng, Y.; Yu, P.; Zhao, J. C.-G.; Ma, J.-A. Chem.
Eur. J. 2012, 18, 14255.
(7) (a) Cui, H.-F.; Dong, K.-Y.; Zhang, G.-W.; Wang, L.; Ma, J.-A.
Chem. Commun. 2007, 2284. (b) Nie, J.; Zhu, H.-W.; Cui, H.-F.; Hua,
M.-Q.; Ma, J.-A. Org. Lett. 2007, 9, 3053. (c) Wang, L.; Meng, W.; Zhu,
C.-L.; Zheng, Y.; Nie, J.; Ma, J.-A. Angew. Chem., Int. Ed. 2011, 50, 9442.
(d) Wu, J.-W.; Li, F.; Zheng, Y.; Nie, J. Tetrahedron Lett. 2012, 53, 4828.
(8) For selected reviews on asymmetric synthesis of chiral organo-
fluorine compounds, see: (a) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem.
567
dx.doi.org/10.1021/jo302419e | J. Org. Chem. 2013, 78, 559−567