Regioselective nucleophilic addition of 3-aryl-5-difluoromethyl-isoxazoles to aldehydes

Article abstract of DOI:10.1016/j.jfluchem.2012.11.003

A series of 5-difluoromethyl-isoxazoles 2 were prepared, and their regioselective nucleophilic addition to aldehydes was investigated. It was found that the nucleophilic difluoromethylation of aldehydes with 5-difluoromethyl-isoxazoles could be efficiently and uniquely achieved in the presence of LDA as a base that provides a large steric hindrance. In contrast, 3,4,5-trisubstituted 5-difluoromethyl isoxazoles were alternatively afforded as the sole product in moderate yields when n-BuLi was used as the base.

Full text of DOI:10.1016/j.jfluchem.2012.11.003

Journal of Fluorine Chemistry 145 (2013) 1–7
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Regioselective nucleophilic addition of 3-aryl-5-difluoromethyl-isoxazoles
to aldehydes
a
a
a
Xueyan Yang a, Xiang Fang a, , Dong Zhang , Yanlin Yu , Zhengdong Zhang , Fanhong Wu
*
a,b,**
a Key Laboratory for Advanced Material and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, China
b School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 120 Caobao Road, Shanghai 200235, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of 5-difluoromethyl-isoxazoles 2 were prepared, and their regioselective nucleophilic addition
to aldehydes was investigated. It was found that the nucleophilic difluoromethylation of aldehydes with
5-difluoromethyl-isoxazoles could be efficiently and uniquely achieved in the presence of LDA as a base
that provides a large steric hindrance. In contrast, 3,4,5-trisubstituted 5-difluoromethyl isoxazoles were
alternatively afforded as the sole product in moderate yields when n-BuLi was used as the base.
ß 2012 Elsevier B.V. All rights reserved.
Received 29 August 2012
Received in revised form 11 November 2012
Accepted 15 November 2012
Available online 28 November 2012
Keywords:
Difluoromethylation
Regioselectivity
Nucleophilic addition reaction
Isoxazole
1. Introduction
is rarely described in the literature [22,23]. The difluoromethyl
isoxazoles exert two nucleophilic positions, which, under the
Selective introduction of fluorine atoms or fluorine-containing
moieties to organic molecules has become a common and powerful
strategy in different research fields, such as pharmaceuticals,
biochemistry, and material science [1–4]. Among the various
fluorination methods, nucleophilic fluoroalkylation of the substrate
with fluorinated carbanions represents the most widely used for
the synthesis of fluorinated derivatives [5–9]. Currently, (fluoroalk-
yl)silanes RfSiR3 (such as TMSCF3) [10,11,8,12] and hydrofluor-
ocarbons (such as CF3H, PhSO2CF2H, PhSCF2H, HCF2PO(OEt)2) are
the most frequently used nucleophilic fluoroalkylation agents [13–
19]. The advantage of using RfH as a fluoroalkylation agent lies on
the fact that functionalization of a C–H bond is the most atom-
economical way in organic synthesis [20].
treatment of a proper base, may generate a difluoromethyl anion or
a 4-position isoxazole anion (Scheme 1). In continuation of our
ongoing research on the difluoromethylation reaction [24], we
report here a specific and efficient strategy toward the regiose-
lective nucleophilic addition reaction of 5-difluoromethyl iso-
xazoles to aldehyde. The selection of bases as well as addition order
of starting materials has proven crucial for the reactivity.
2. Results and discussion
General methods known for the preparation of fluoroalkyl
isoxazoles involve the 1,3-dipolarcycloaddition and addition of
hydroxylamine to conjugated ynone or
b-diketone derivatives
Recently, synthesis of fluorinated heterocyclic compounds,
especially isoxazoles, is of particular interest to chemists because
they exhibit various bioactivities [21]. Many examples have been
reported with respect to the synthesis of trifluoromethylated
isoxazoles. However, to the best of our knowledge, preparation of
difluoromethyl isoxazoles in using nucleophilic addition reactions
[25–29]. Using the latter reaction, we prepared the starting
materials, 5-difluoromethyl-isoxazoles 2a–2d, in 75–85% yields by
condensation of 1-difluoromethylated with
a range of 1,3-
dicarbonyl derivatives in the presence of excess hydroxylamine
hydrochloride at reflux in ethanol (Scheme 2).
Subsequently, we carried out a model nucleophilic addition
reaction in which benzaldehyde 3a was used as a model substrate to
react with isoxazole 2a. As shown in Table 1, no reaction took place
when NaOH and DBU were applied as the base at room temperature
(Table 1, entry 1–2). However, when n-BuLi was employed,
the reaction proceeded, and a further optimization revealed that
the addition order of the materials was critical for the regioselec-
tivity. In our first procedure (A), the 5-difluoromethyl-isoxazoles 2a,
* Corresponding author. Tel.: +86 21 64253530; fax: +86 21 64253074.
** Corresponding author at: Key Laboratory for Advanced Material and Institute of
Fine Chemicals, School of Chemistry and Molecular Engineering, East China
University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Tel.: +86 21 64253530; fax: +86 21 64253074.
E-mail addresses: fangxiang@ecust.edu.cn (X. Fang), wfh@sit.edu.cn (F. Wu).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.11.003

2
X. Yang et al. / Journal of Fluorine Chemistry 145 (2013) 1–7
E+
O
N
E+
O
O
N
N
CF2H
R1
CF2H
CF2 E
R1
R1
base
base
E
Scheme 1. Possible nucleophilic reactions of difluoromethyl isoxazoles.
O
O
O
O
NH2OH.HCl
N
N
H2SO4
CF2H
CF2H
R
CF2H
R
R
EtOH / reflux
OH
1a-1d
a R = Ph
2a-2d
b R = 4-FPh
c R = 4-OCH3Ph
d R = 2-Thienyl
Scheme 2. Preparation of the 5-difluoromethyl-isoxazoles 2.
benzaldehyde 3a and n-BuLi were mixed at À78 8C in one-pot, and
the mixture was allowed gradually to room temperature. After
stirring overnight, the difluoromethylated product 4aa as well as the
3,4,5-trisubstituted isoxazole 5aa was obtained in low yields
(Entries 3–5) with a significant amount of unreacted starting
materials.
In the second procedure (B), to a solution of 2a in THF at À78 8C,
n-BuLi was added dropwise. After first stirring for 1 h, 3a was
added dropwise at À78 8C, and the mixture was allowed gradually
to room temperature, stirring over night. To our delight, the sole
nucleophilic addition product, 3,4,5-trisubstituted isoxazole 5aa,
was afforded in 56%, 69% and 75% yields in terms of the different
final reaction temperatures (Entries 8–10). Notably, addition of an
excess amount of n-BuLi only led to a slightly increased yield in
procedure A (Entries 6–7), while a mixture of 4aa and 5aa was
provided with 3 equiv. n-BuLi in procedure B (Entry 12). In
contrast, when LDA (1.2 equiv.) with a relatively large steric
hindrance was used as a base under the same condition, the
difluoromethylated product 4aa was solely afforded in both
procedures. Procedure A seems to be superior in this case over
B since the former gave the desired unique product in a higher
yield of 75% (Entry 13) than the latter (51% Yield, entry 14). So, the
optimal reaction conditions for the regioselective nucleophilic
addition of 3-aryl-5-difluoromethyl-isoxazoles to aldehydes as
follows: 3,4,5-trisubstituted isoxazole 5aa was produced in 75%
yield when benzaldehyde 3a was added dropwise to a mixture of
2a and 1.2 equiv. of n-BuLi at À78 8C (Entry 10) and the
difluoromethylated product 4aa was afforded in 75% yield by
treatment of 2a, 3a and 1.2 equiv. of LDA in one-pot (Entry 13).
Having established the optimized reaction condition, a variety
of aldehydes were used to probe the substrate scope of the
reaction and the results are summarized in Table 2. Use of LDA
(according to procedure A) and BuLi (according to procedure B) as
the base led to the formation of the desired product 4 and 5 in
Table 1
Survey of reaction conditions.
O
N
OH
Ph
O
N
O
O
N
base, THF
Temp
H
CF2H
+
Ph
+
CF2H
Ph
Ph
Ph
F
F
Ph
OH
5aa
4aa
3a
2a
Entry
Base
2a:3a:base
Temperature
Procedurea,b
Product
Yield %c
1
2
NaOH
DBU
1:1.2:2
rt
0
0
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.5
1:1.2:3
rt
3
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
LDA
À78 8C to À30 8C
À78 8C to 0 8C
À78 8C to rt
À78 8C to rt
À78 8C to rt
À78 8C to À30 8C
À78 8C to 0 8C
À78 8C to rt
À78 8C to rt
À78 8C to rt
À78 8C to rt
À78 8C to rt
A
A
A
A
A
B
B
B
B
B
A
B
4aa+5aa
4aa+5aa
4aa+5aa
4aa+5aa
4aa
26d
20d
21d
37d
47
4
5
6
7
8
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.5
1:1.2:3
5aa
56
9
5aa
69
10
11
12
13
14
5aa
75
5aa
69
4aa+5aa
4aa
80
1:1.2:1.2
1:1.2:1.2
75
LDA
4aa
51
a
Procedure A: A mixture of 2a, 3a and base was stirred at À78 8C in one-pot.
b
c
Procedure B: A mixture of 2a and base was stirred at À78 8C for 1 h, and then 3a was added dropwise.
Isolated yield.
d
A large amount of unreacted starting materials.

X. Yang et al. / Journal of Fluorine Chemistry 145 (2013) 1–7
3
Table 2
Regioselective nucleophilic addition of different aldehydes with 5-difluoromethyl-isoxazoles 2a–d.
OH
R2
O
N
LDA, THF
-78 oC to rt
R1
F
F
O
O
N
4
+
R2
H
CF2H
R1
O
N
n-BuLi, THF
-78 oC to rt
CF2H
OH
R1
3
2a-d
R2
5
Entry
1
R1
R2
Ph (3a)
Base
Product
Yield %a
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
LDAb
BuLic
LDAb
BuLic
LDAb
BuLic
LDAb
BuLic
LDAb
BuLic
LDAb
BuLic
LDAb
BuLic
LDAb
BuLic
LDAb
BuLic
LDAb
BuLic
BuLic
BuLic
BuLic
BuLic
LDAb
BuLic
LDAb
BuLic
4aa
75
5aa
5ab
5ac
5ad
5ba
5bb
5bc
5bd
5ca
75
2
2-Furyl (3b)
4ab
4ac
4ad
4ba
4bb
4bc
4bd
4ca
4cc
63
64
3
4-MeOC6H4 (3c)
4-CF3C6H4 (3d)
Ph (3a)
56
55
4
77
76
5
4-FC6H4 (2b)
4-FC6H4 (2b)
4-FC6H4 (2b)
4-FC6H4 (2b)
4-MeOC6H4 (2c)
4-MeOC6H4 (2c)
53
59
6
2-Furyl (3b)
4-MeOC6H4 (3c)
4-CF3C6H4 (3d)
Ph (3a)
48
55
7
47
54
8
66
68
9
62
57
10
4-MeOC6H4 (3c)
58
5cc
5ce
56
11
12
13
14
15
4-MeOC6H4 (2c)
4-MeOC6H4 (2c)
2-Thienyl (2d)
2-Thienyl (2d)
2-Thienyl (2d)
4-NO2C6H4 (3e)
n-C3H7 (3g)
Ph (3a)
70
Complicated
55
5da
5db
2-Furyl (3b)
4-MeOC6H4 (3c)
51
4dc
4dd
54
5dc
5dd
44
16
2-Thienyl (2d)
4-CF3C6H4 (3d)
66
60
a
Isolated yield.
b
c
Procedure A: A mixture of 2, 3 and LDA was stirred at À78 8C in one-pot.
Procedure B: A mixture of 2 and n-BuLi was stirred at À78 8C for 1 h, then 3 was added dropwise.
moderate-to-reasonable yields, respectively. For the aldehydes
with electron-withdrawing substituents on the aromatic ring
(such as 3d and 3e), the yields are generally higher than those with
electron-donating substituents (such as 3c), which can be ascribed
to the intrinsic reactivity of the aldehyde derivatives.
moderate yields using n-BuLi as a base. Compared to the previously
developed difluoromethylation reagents, 5-difluoromethyl isoxa-
zoles merit their relatively easy availability and superior atom-
economical feature in fluoroalkylation reactions.
As for the different 5-difluoromethyl-isoxazole substrates, the
electronic nature of the substituents on the aromatic ring (such as
2b vs 2c) does not impact evidently the reactivity, giving the
corresponding adducts in similarly moderate yields. Although 5-
difluoromethyl-isoxazole could react with non-enolizable alde-
hydes [18], we note that, in the present case, 2c did not react
efficiently with an enolizable aldehyde (3g) (Table 2, entry 12).
4. Experimental
All melting points were uncorrected. IR spectra were measured
on a Nicolet Magna IR-550 spectrometer. High-resolution mass
spectra were carried out on a Finnigan GC-MS-4021 spectrometer.
1H and 13C NMR spectra were recorded on a Bruker AC-500
spectrometer with Me4Si as an internal standard. 19F NMR spectra
were obtained on a Bruker AC-500 spectrometer in CDCl3 with
CFCl3 as an external standard, in which downfield shifts were
3. Conclusions
designated as negative. All chemical shifts (d) are expressed in
In conclusion, we have developed a versatile regioselective
nucleophilic reaction of aldehydes with 5-difluoromethyl iso-
xazoles. The reaction depended on the base employed and different
procedures of adding the aldehydes to give the different products.
A variety of aldehydes could be difluoromethylated with different
5-difluoromethyl-isoxazoles by treatment of LDA as a base with
a large steric hindrance. In contrast, the 3,4,5-trisubstituted
5-difluoromethyl isoxazoles were alternatively produced in
parts per million and coupling constants (J) are given in Hertz.
4.1. General procedure for the preparation of 5-difluoromethyl
isoxazoles 2
A mixture of 1-difluoromethyl
b-diketone 1 (5 mmol) and
hydroxylamine hydrochloride (6 mmol in 20 mL ethanol) and
concentrated sulfuric acid (5 mmol) was stirred for 2–10 h at

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X. Yang et al. / Journal of Fluorine Chemistry 145 (2013) 1–7
reflux. Then the reaction mixture was poured slowly to a 10 mL
10% sodium carbonate solution and extracted with ethyl acetate
(3Â 10 mL). After dried with sodium sulfate and removal of the
solvent, the residue was purified by flash chromatography
(petroleum ether/ethyl acetate = 10:1) to give 2 in 75–85% yields.
(0.6 mmol) (dissolved in 1 mL THF) was added dropwise at À78 8C,
The mixture was stirred at this temperature for 1 h, and then
benzaldehyde (3a) (0.6 mmol) was added dropwise at À78 8C.
Then the mixture was raised to room temperature, stirring
overnight. The reaction was then quenched with saturated
aqueous ammonium chloride or brine. The aqueous layer was
extracted with ethyl acetate (3Â 5 mL) and the combined organic
layer was washed with brine (10 mL), dried over Na2SO4 and
concentrated under vacuum. The resulting residue was purified by
flash chromatography (petroleum ether/ethyl acetate = 10:1) to
give 5aa (113 mg, 75% yield) as a white solid.
4.1.1. 5-(Difluoromethyl)-3-phenylisoxazole (2a)
White solid, m.p. 49.1–49.5 8C; IR (cmÀ1, KBr): 3426, 3117,
1619, 1370, 1106, 1060, 770, 695. 1H NMR (CDCl3, 500 MHz)
d:
7.84–7.80 (m, 2H), 7.52–7.48 (m, 3H), 6.89 (s, 1H), 6.80 (t, 1H,
J = 53.8 Hz). 19F NMR (CDCl3, 470 MHz)
H = 53.8 Hz). 13C NMR (CDCl3, 125 MHz)
d
: À118.6 (d, 2F, JF-
d: 164.7, 163.2, 131.3,
129.8, 128.6, 127.6, 107.9 (t, J = 239.4 Hz), 102.6. EI-MS (m/z) 195
4.2.1. 2,2-Difluoro-1-phenyl-2-(3-phenyl-isoxazol-5-yl)-ethanol
(4aa)
White solid, m.p. 105.6–106.6 8C; IR (cmÀ1, KBr): 3359, 2937,
1612, 1443, 1404, 1280, 1184, 772, 692. 1H NMR (CDCl3, 400 MHz)
(M+, 87), 144 (100), 116 (19), 77 (21). HRMS (EI) calcd for
C
10H7F2NO: 195.0496, found: 195.0497.
4.1.2. 5-Difluoromethyl-3-(4-fluoro-phenyl)-isoxazole (2b)
d
: 7.78–7.76 (m, 2H), 7.47 (d, 2H, J = 2.4 Hz), 7.45 (d, 1H, J = 1.2 Hz),
White solid, m.p. 68.5–69.5 8C; IR (cmÀ1, KBr): 3379, 3223,
7.41 (d, 1H, J = 4 Hz), 7.37–7.35 (m, 4H), 6.71 (s, 1H), 5.34 (s, 1H).
2720, 2471, 1685, 1597, 1254, 774. 1H NMR (CDCl3, 500 MHz)
d
: 7.8
(d, 2H, J = 8.4 Hz), 7.4 (d, 2H, J = 8.4 Hz), 6.83 (s, 1H), 6.77 (t, 1H,
J = 53.8 Hz). 19F NMR (CDCl3, 470 MHz)
: À109.4 (s, 1F), À117.8 (d,
2F, JF-H = 53.8 Hz). 13C NMR (CDCl3, 125 MHz)
164.2 (t,
19F NMR (CDCl3, 367.5 MHz)
d
: À105.9 (dd, 1F, JF-F = 268 Hz, JF-
H = 9 Hz), À109.9 (dd, 1F, JF-F = 268 Hz, JF-H = 13 Hz). 13C NMR
d
(CDCl3, 100.6 MHz) d: 164.1 (t, J = 33.9 Hz), 162.3, 134.6, 130.5,
d
:
129.0, 128.7, 128.6, 128.4, 127.6, 126.9, 115.8 (t, J = 247.1 Hz),
103.3, 74.8 (t, J = 28.6 Hz). EI-MS (m/z) 301 (M+, 6), 195 (100), 145
(9), 77 (22). HRMS (EI) calcd for C17H13F2NO2: 301.0914, found:
301.0913.
J = 30.7 Hz), 164.1 (d, J = 251.5 Hz), 161.6, 128.9, 124.1, 116.3 (d,
J = 22 Hz), 107.2 (t, J = 239.4 Hz), 101.9. EI-MS (m/z) 213 (M+, 100),
162 (78), 134 (43). HRMS (EI): C10H6F3NO, calcd: 213.0401, found:
213.0402.
4.2.2. (5-Difluoromethyl-3-phenyl-isoxazol-4-yl)-phenyl-methanol
(5aa)
Light yellow solid, m.p. 166–167 8C; IR (cmÀ1, KBr): 3335, 2924,
1446, 1352, 1283, 1181, 1067, 1042, 751, 693. 1H NMR (CDCl3,
4.1.3. 5-(Difluoromethyl)-3-(4-methoxyphenyl)isoxazole (2c)
White solid, m.p. 71.9–72.1 8C; IR (cmÀ1, KBr): 3433, 3118,
2940, 2842, 2041, 1614, 1437, 1256, 1067, 830. 1H NMR (CDCl3,
500 MHz)
d
: 7.76 (d, 2H, J = 8.65 Hz), 7.0 (d, 2H, J = 8.63 Hz), 6.83 (s,
400 MHz)
d: 7.43–7.40 (m, 1H), 7.36–7.35 (m, 4H), 7.32–7.30 (m,
1H), 6.78 (t, 1H, J = 53.8 Hz), 3.86 (s, 3H). 19F NMR (CDCl3,
3H), 7.22–7.20 (m, 2H), 7.04 (t, 1H, J = 53.4 Hz), 5.97 (s, 1H). 19F
470 MHz)
125 MHz)
d
d
: À118.6 (d, 2F, JF-H = 53.8 Hz). 13C NMR (CDCl3,
NMR (CDCl3, 367.5 MHz)
d
: À115.0 (dd, 1F, JF-F = 307 Hz, JF-
: 164.8 (t, J = 30.9 Hz), 162.8, 162.2, 129.1, 121.0,
H = 50 Hz), À118.4 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz). 13C NMR
115.2, 108.0 (t, J = 239.3 Hz), 102.4, 56.1. EI-MS (m/z) 225 (M+, 100),
174 (72), 146 (53). HRMS (EI): calcd for C11H9F2NO2: 225.0601,
found: 225.0602.
(CDCl3, 100.6 MHz) d: 162.2, 159.9 (t, J = 25.5 Hz), 140.7, 130.0,
128.9, 128.7, 128.6, 127.8, 127.0, 126.7, 121.1, 107.3 (t,
J = 238.6 Hz), 68.2. EI-MS (m/z) 301 (M+, 100), 77 (43). HRMS
(EI) calcd for C17H13F2NO2: 301.0914, found: 301.0911.
4.1.4. 5-(Difluoromethyl)-3-(thiophen-2-yl)isoxazole (2d)
Yellow oil; IR (cmÀ1, KBr): 3135, 2964, 2927, 1737, 1617, 1553,
4.2.3. 2,2-Difluoro-1-furan-2-yl-2-(3-phenyl-isoxazol-5-yl)-ethanol
(4ab)
1467, 1104, 1059. 1H NMR (CDCl3, 500 MHz)
d: 7.50 (dd, 1H,
J1 = 3.65 Hz, J2 = 1.16 Hz), 7.47 (dd, 1H, J1 = 5.06 Hz, J2 = 1.16 Hz),
7.14 (dd, 1H, J1 = 5.06 Hz, J2 = 3.65 Hz), 6.82 (s, 1H), 6.77 (t, 1H,
Yellow solid, m.p. 112–113 8C; IR (cmÀ1, KBr): 3376, 2927,
1755, 1663, 1612, 1443, 1404, 1280, 1184, 769, 693. 1H NMR
J = 53.70 Hz). 19F NMR (CDCl3, 470 MHz)
d
: À118.8 (d, 2F, JF-
(CDCl3, 400 MHz) d: 7.81–7.78 (m, 2H), 7.47 (t, 3H, J = 6.4 Hz), 7.44
(s, 1H), 6.85 (s, 1H), 6.48 (d, 1H, J = 3.6 Hz), 6.39 (dd, 1H, J = 3.2 Hz,
J = 2.0 Hz), 5.35 (t, 1H, J = 10.6 Hz), 2.97 (s, 1H). 19F NMR (CDCl3,
H = 53.70 Hz). 13C NMR (CDCl3, 125 MHz)
d
: 165.6 (t, J = 31.1 Hz),
159.4, 131.0, 130.1, 129.9, 129.5, 108.8 (t, J = 239.7 Hz), 103.7. EI-
MS (m/z) 201 (M+, 100), 150 (77), 122 (66). HRMS (EI) calcd for
C8H5F2NOS: 201.0060, found: 201.0058.
367.5 MHz)
d
: À105.3 (dd, 1F, JF-F = 268 Hz, JF-H = 9 Hz), À110.1
(dd, 1F, JF-F = 268 Hz, JF-H = 11 Hz). 13C NMR (CDCl3, 100.6 MHz)
d
:
163.8 (t, J = 34.6 Hz), 162.4, 147.7, 143.5, 130.6, 129.0, 127.8, 126.9,
114.9 (t, J = 247.8 Hz), 110.8, 110.2, 103.2, 69.4 (t, J = 29.2 Hz). EI-
MS (m/z) 291 (M+, 1), 195 (100), 97 (42.6), 77 (7). HRMS (EI) calcd
for C15H11F2NO3: 291.0707, found: 291.0708.
4.2. General procedures for reaction of 2 with different aldehydes 3
Procedure A: Under nitrogen atmosphere, to a stirred solution
of isoxazole (2a) (0.5 mmol) and benzaldehyde (3a) (0.6 mmol)
with 1 mL THF in a Schlenk tube, LDA (0.6 mmol) (dissolved in
1 mL THF) was added dropwise at À78 8C. The mixture was
stirred at this temperature for 1 h, and then was raised to room
temperature, stirring overnight. The reaction was quenched with
saturated aqueous ammonium chloride or brine. The aqueous
layer was extracted with ethyl acetate (3Â 5 mL) and the
combined organic layer was washed with brine (10 mL), dried
over Na2SO4 and concentrated under vacuum. The resulting
residue was purified by flash chromatography (petroleum ether/
ethyl acetate = 10:1) to give 4aa (113 mg, 75% yield) as a white
solid.
4.2.4. 2,2-Difluoro-1-furan-2-yl-2-(3-phenyl-isoxazol-5-yl)-ethanol
(5ab)
Light gray solid, m.p. 103.9–104.5 8C; IR (cmÀ1, KBr): 3327,
2917, 1639, 1500, 1468, 1449, 1361, 1279, 1067, 946, 738, 698. 1H
NMR (CDCl3, 400 MHz)
d: 7.49–7.40 (m, 6H), 7.13 (t, 1H,
J = 52.4 Hz), 6.35 (dd, 1H, J = 3.4 Hz, J = 1.8 Hz), 6.20 (d, 1H,
J = 3.2 Hz), 5.92 (s, 1H), 2.66 (s, 1H). 19F NMR (CDCl3,
367.5 MHz)
d
: À116.7 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz), À118.3
(dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz). 13C NMR (CDCl3, 100.6 MHz)
d
:
161.7, 160.9 (t, J = 25.3 Hz), 152.9, 143.5, 130.2, 128.9, 128.6, 127.5,
118.7, 110.8, 108.9, 106.9 (t, J = 238.5 Hz), 61.6. EI-MS (m/z) 291
(M+, 100), 222 (61.5), 144 (54.5), 77 (56.4). HRMS (EI) calcd for
C15H11F2NO3: 291.0707, found: 291.0701.
Procedure B: Under nitrogen atmosphere, to a stirred solution
of isoxazole (2a) (0.5 mmol) and 1 mL THF in a Schlenk tube, n-BuLi

X. Yang et al. / Journal of Fluorine Chemistry 145 (2013) 1–7
5
4.2.5. 2,2-Difluoro-1-(4-methoxy-phenyl)-2-(3-phenyl-isoxazol-5-
yl)-ethanol (4ac)
White solid, m.p. 150.2–151.2 8C; IR (cmÀ1, KBr): 3423, 2922,
1610, 1514, 1442, 1252, 1172, 1082, 1034, 765, 689. 1H NMR
(t, J = 243.7 Hz), 104.7, 86.8. EI-MS (m/z) 319 (M+, 1), 214 (7.2),
213 (100), 107 (29.2), 105 (6.6), 79 (14.4). HRMS (EI) calcd for
C17H12F3NO2: 319.0820, found: 319.0821.
(CDCl3, 400 MHz)
2H, J = 8.8 Hz), 6.89–6.86 (m, 2H), 6.72 (s, 1H), 5.28 (t, 1H,
J = 11.0 Hz), 3.80 (s, 3H), 2.69 (s, 1H). 19F NMR (CDCl3, 367.5 MHz)
d
: 7.79–7.75 (m, 2H), 7.48–7.44 (m, 3H), 7.32 (d,
4.2.10. [5-Difluoromethyl-3-(4-fluoro-phenyl)-isoxazol-4-yl]-
phenyl-methanol (5ba)
White solid, m.p. 105.5–106.5 8C; IR (cmÀ1, KBr): 3352, 1608,
1527, 1467, 1228, 1064, 945, 829, 739, 697. 1H NMR (CDCl3,
d
: À106.3 (dd, 1F, JF-F = 265 Hz, JF-H = 8 Hz), À109.7 (dd, 1F, JF-
F = 268 Hz, JF-H = 11 Hz). 13C NMR (CDCl3, 100.6 MHz)
d
: 160.9 (t,
400 MHz)
d: 7.37–7.30 (m, 5H), 7.21–7.18 (m, 2H), 7.06–7.01 (m,
J = 34.6 Hz), 158.9, 133.2, 129.8, 129.7, 128.5, 127.0, 116.3 (t,
J = 247.3 Hz), 114.3, 103.2, 74.8 (t, J = 28.2 Hz), 56.0. EI-MS (m/z)
331 (M+, 1), 195, 137 (100), 109 (9.7), 94 (4.4), 77 (6.5). HRMS (EI)
calcd for C18H15F2NO3: 331.1020, found: 331.1017.
2H), 6.92 (t, 1H, J = 8.4 Hz), 5.97 (s, 1H). 19F NMR (CDCl3,
367.5 MHz)
d
: À110.2 (s, 1F), À114.9 (dd, 1F, JF-F = 312 Hz, JF-
H = 51 Hz), À118.4 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz). 13C NMR
(CDCl3, 100.6 MHz) d: 163.7 (d, J = 250.5 Hz), 161.4 (t, J = 21.7 Hz),
140.4, 130.8, 130.7, 128.9, 128.8, 128.4, 127.6, 126.6, 123.8, 120.9,
115.8 (d, J = 21.7 Hz), 107.3 (t, J = 238.7 Hz), 68.1. EI-MS (m/z) 319
(M+, 100), 240 (25.1), 213 (21.9), 162 (47.5), 105 (48.6), 95 (12.5),
77 (21.4). HRMS (EI) calcd for C17H12F3NO2: 319.0820, found:
319.0818.
4.2.6. (5-Difluoromethyl-3-phenyl-isoxazol-4-yl)-(4-methoxy-
phenyl)-methanol (5ac)
White solid, m.p. 132–133 8C; IR (cmÀ1, KBr): 3380, 2922, 1610,
1512, 1465, 1359, 1258, 1174, 1042, 943, 805. 1H NMR (CDCl3,
400 MHz)
2H), 7.12 (t, 1H, J = 52.8 Hz), 6.85–6.82 (m, 2H), 5.90 (s, 1H), 3.79 (s,
3H), 2.29 (s, 1H). 19F NMR (CDCl3, 367.5 MHz)
: À114.6 (dd, 1F, JF-
F = 310 Hz, JF-H = 53 Hz), À118.9 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz).
13C NMR (CDCl3, 100.6 MHz)
: 160.9 (t, J = 34.6 Hz), 158.8, 136.5,
d: 7.45–7.40 (m, 1H), 7.37–7.34 (m, 4H), 7.15–7.12 (m,
4.2.11. 2,2-Difluoro-2-[3-(4-fluoro-phenyl)-isoxazol-5-yl]-1-furan-
2-yl-ethanol (4bb)
d
Brown solid, m.p. 103.7–104.9 8C; IR (cmÀ1, KBr): 3384, 2924,
d
1605, 1432, 1238, 1106, 823, 746. 1H NMR (CDCl3, 400 MHz)
d:
133.2, 129.0, 128.5, 127.0, 114.3, 106.9 (t, J = 237.8 Hz), 100.5, 65.4,
56.0. EI-MS (m/z) 331 (M+, 1), 222 (71.9), 135 (75.8), 109 (51.8), 94
(9), 77 (27.4). HRMS (EI) calcd for C18H15F2NO3: 331.1020, found:
331.1004.
7.81–7.77 (m, 2H), 7.44 (s, 1H), 7.16 (t, 2H, J = 8.6 Hz), 6.81 (s, 1H),
6.49 (d, 1H, J = 3.2 Hz), 6.40 (dd, 1H, J = 3.2 Hz, J = 1.6 Hz), 5.34 (dd,
1H, J = 12.4 Hz, J = 8.8 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
: À105.1
(dd, 1F, JF-F = 268 Hz, JF-H = 10 Hz), À109.5 (s, 1F), À110.3 (dd, 1F, JF-
F = 268 Hz, JF-H = 11 Hz). 13C NMR (CDCl3, 100.6 MHz)
: 164.1 (d,
d
4.2.7. 2,2-Difluoro-2-(3-phenyl-isoxazol-5-yl)-1-(4-trifluoromethyl-
phenyl)-ethanol (4ad)
J = 250.7 Hz), 161.3 (t, J = 23 Hz), 143.5, 128.9, 128.4, 116.3, 110.8,
110.2, 105.3 (t, J = 236.7 Hz), 103.2, 73.6 (t, J = 32.4 Hz). EI-MS (m/z)
309 (M+, 1), 213 (100), 97 (50.9). HRMS (EI) calcd for C15H10F3NO3:
309.0613, found: 309.0616.
Yellow oil; IR (cmÀ1, KBr): 3302, 2927, 1701, 1619, 1411, 1327,
1166, 1117, 1066, 772, 692. 1H NMR (CDCl3, 400 MHz)
d: 7.79–7.75
(m, 2H), 7.63 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.4 Hz), 7.48–7.45
(m, 3H), 6.76 (s, 1H), 5.43 (dd, 1H, J = 11.4 Hz, J = 9.6 Hz). 19F NMR
4.2.12. [5-Difluoromethyl-3-(4-fluoro-phenyl)-isoxazol-4-yl]-furan-
2-yl-methanol (5bb)
(CDCl3, 367.5 MHz)
d
: À62.7 (s, 3F), À105.2 (dd, 1F, JF-F = 268 Hz, JF-
H = 9 Hz), À110.1 (dd, 1F, JF-F = 268 Hz, JF-H = 11 Hz). 13C NMR
White solid, m.p. 100.5–102.8 8C; IR (cmÀ1, KBr): 3381, 1607,
(CDCl3, 100.6 MHz)
d
: 163.8 (t, J = 34.6 Hz), 150.0, 144.2, 136.5,
1465, 1367, 1277, 1044, 930, 811, 749. 1H NMR (CDCl3, 400 MHz)
d:
129.7, 129.0, 127.0, 125.5, 114.9 (t, J = 243.6 Hz), 106.7, 100.5, 73.6
(t, J = 29.2 Hz). EI-MS (m/z) 369 (M+, 1), 190, 173 (100), 145 (54.9),
95 (5.2), 75 (4). HRMS (EI) calcd for C18H12F5NO2: 369.0788, found:
369.0796.
7.46–7.42 (m, 3H), 7.12 (t, 1H, J = 52.4 Hz), 7.13–7.09 (m, 2H), 6.34
(dd, 1H, J = 3.2 Hz, J = 1.6 Hz), 6.19 (d, 1H, J = 3.2 Hz), 5.89 (s, 1H).
19F NMR (CDCl3, 367.5 MHz)
d
: À109.8 (s, 1F), À116.7 (dd, 1F, JF-
F = 312 Hz, JF-H = 51 Hz), À118.3 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz).
13C NMR (CDCl3, 100.6 MHz)
: 163.9 (d, J = 250.8 Hz), 161.0 (t,
d
4.2.8. (5-Difluoromethyl-3-phenyl-isoxazol-4-yl)-(4-
trifluoromethyl-phenyl)-methanol (5ad)
Light yellow solid, m.p. 157–158 8C; IR (cmÀ1, KBr): 3379, 2922,
1701, 1462, 1331, 1114, 1044, 836, 771, 701. 1H NMR (CDCl3,
J = 25.6 Hz), 152.7, 143.5, 130.6, 123.6, 118.6, 116.2, 115.9, 110.8,
108.8, 106.9 (t, J = 238.7 Hz), 61.5. EI-MS (m/z) 309 (M+, 100), 240
(39.1), 230 (26.2), 162 (57.5), 95 (29.6). HRMS (EI) calcd for
C15H10F3NO3: 309.0613, found: 309.0611.
400 MHz)
J = 4.0 Hz), 7.30 (d, 2H, J = 8.4 Hz), 7.06 (t, 1H, J = 52.6 Hz), 6.07 (s,
1H). 19F NMR (CDCl3, 367.5 MHz)
: À62.6 (s, 3F), À114.8 (dd, 1F, JF-
F = 312 Hz, JF-H = 51 Hz), À118.4 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz).
13C NMR (CDCl3, 100.6 MHz)
: 160.2 (t, J = 34.6 Hz), 159.1, 148.9,
144.4, 138.1, 130.6, 130.2, 128.8, 126.8, 126.7, 125.7, 106.7 (t,
J = 243.5 Hz), 100.5, 67.0. EI-MS (m/z) 369 (M+, 1), 242 (4.6), 190
(64.5), 173 (100), 145 (57.7), 125 (4.5), 95 (5.9), 75 (4.6). HRMS (EI)
calcd for C18H12F5NO2: 369.0788, found: 369.0786.
d: 7.97 (s, 1H), 7.52 (d, 2H, J = 8.0 Hz), 7.37 (d, 4H,
4.2.13. 2,2-Difluoro-2-[3-(4-fluoro-phenyl)-isoxazol-5-yl]-1-(4-
methoxy-phenyl)-ethanol (4bc)
d
White solid, m.p. 115.6–116.6 8C; IR (cmÀ1, KBr): 3405, 2922,
d
1603, 1512, 1239, 1032, 840. 1H NMR (CDCl3, 400 MHz)
d
: 7.78–
7.75 (m., 2H), 7.33 (d, 2H, J = 8.8 Hz), 7.15 (t, 2H, J = 8.6 Hz), 6.88 (d,
2H, J = 8.8 Hz), 6.69 (s, 1H), 5.27 (t, 1H, J = 10.8 Hz), 3.80 (s, 3H). 19
NMR (CDCl3, 367.5 MHz)
: À105.8 (dd, 1F, JF-F = 266 Hz, JF-
H = 8 Hz), À109.58 (s, 1F), À110.1 (dd, 1F, JF-F = 266 Hz, JF-
H = 10 Hz). 13C NMR (CDCl3, 100.6 MHz)
162.1 (d,
F
d
d
:
4.2.9. 2,2-Difluoro-2-[3-(4-fluoro-phenyl)-isoxazol-5-yl]-1-phenyl-
ethanol (4ba)
Colorless solid, m.p. 60.9–61.9 8C; IR (cmÀ1, KBr): 3413, 2923,
1604, 1527, 1431, 1238, 1163, 1078, 829, 731. 1H NMR (CDCl3,
J = 250.7 Hz), 160.9, 158.9, 150.3, 133.2, 132.1, 128.3, 116.0,
114.7 (t, J = 243.7 Hz), 100.5, 83.4, 54.7. EI-MS (m/z) 349 (M+, 1),
213 (8.1), 137 (100), 109 (9.3), 94 (4.4), 77 (3.2). HRMS (EI) calcd for
C18H14F3NO3: 349.0926, found: 349.0930.
400 MHz)
3H), 7.15 (t, 2H, J = 8.6 Hz), 6.68 (s, 1H), 5.34 (t, 1H, J = 10.8 Hz),
2.69 (s, 1H). 19F NMR (CDCl3, 367.5 MHz)
: À105.7 (dd, 1F, JF-
F = 266 Hz, JF-H = 8 Hz), À109.5 (s, 1F), À110.0 (dd, 1F, JF-F = 266 Hz,
JF-H = 10 Hz). 13C NMR (CDCl3, 100.6 MHz)
: 162.1 (d, J = 250.4 Hz),
158.9, 150.6, 140.9, 132.1, 128.7, 127.6, 116.2, 114.7
d: 7.78–7.74 (m, 2H), 7.42–7.40 (m, 2H), 7.38–7.35 (m,
4.2.14. [5-Difluoromethyl-3-(4-fluoro-phenyl)-isoxazol-4-yl]-(4-
methoxy-phenyl)-methanol (5bc)
d
Light yellow solid, m.p. 116.1–117.1 8C; IR (cmÀ1, KBr): 3401,
2919, 1609, 1513, 1259, 1174, 1069, 1037, 944, 806. 1H NMR
d
(CDCl3, 400 MHz) d: 7.35–7.30 (m, 2H), 7.12 (d, 2H, J = 8.8 Hz), 7.11

6
X. Yang et al. / Journal of Fluorine Chemistry 145 (2013) 1–7
(t, 1H, J = 52.8 Hz), 7.07–7.01 (m, 2H), 6.86–6.82 (m, 2H), 5.88
(s, 1H), 3.79 (s, 3H). 19F NMR (CDCl3, 367.5 MHz)
: À110.3 (s,
1F), À114.42 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz), À118.90 (dd, 1F,
JF-F = 308 Hz, JF-H = 50 Hz). 13C NMR (CDCl3, 100.6 MHz)
: 162.1
4.2.19. 2,2-Difluoro-1-(4-methoxy-phenyl)-2-[3-(4-methoxy-
phenyl)-isoxazol-5-yl]-ethanol (4cc)
White solid; m.p. 109.1–110.3 8C; IR (cmÀ1, KBr): 3426, 3136,
2937, 1612, 1462, 1430, 1255, 1101, 1078, 1036, 831, 812. 1H NMR
d
d
(d, J = 250.5 Hz), 159.9, 132.8, 130.8, 130.7, 128.2, 121.2, 115.9,
115.7, 106.4 (t, J = 238.5 Hz), 68.9, 55.8. EI-MS (m/z) 349
(M+, 100), 162 (13.5), 135 (61.7), 109 (72.9), 94 (9.8), 77
(12.4). HRMS (EI) calcd for C18H14F3NO3: 349.0926, found:
349.0925.
(CDCl3, 400 MHz) d: 7.71 (d, 2H, J = 8.8 Hz), 7.32 (d, 2H, J = 8.8 Hz),
6.97 (d, 2H, J = 8.6 Hz), 6.87 (d, 2H, J = 8.8 Hz), 6.67 (s, 1H), 5.27 (t,
1H, J = 10.6 Hz), 3.85 (s, 3H), 3.79 (s, 3H). 19F NMR (CDCl3,
367.5 MHz)
d
: À106.8 (dd, 1F, JF-F = 268 Hz, JF-H = 9 Hz), À110.8
(dd, 1F, JF-F = 268 Hz, JF-H = 11 Hz). 13C NMR (CDCl3, 100.6 MHz)
d
:
165.3, 161.5, 158.6, 134.6, 130.1, 129.4, 129.0, 128.4, 128.1, 127.7,
126.5, 115.8, 114.7 (t, J = 245.8 Hz), 103.0, 74.8, 60.1, 55.2. EI-MS
(m/z) 361 (M+, 37), 225 (100), 137 (67). HRMS (EI) calcd for
4.2.15. 2,2-Difluoro-2-[3-(4-fluoro-phenyl)-isoxazol-5-yl]-1-(4-
trifluoromethyl-phenyl)-ethanol (4bd)
Yellow solid, m.p. 92.4–93.4 8C; IR (cmÀ1, KBr): 3447, 2923,
1609, 1465, 1431, 1327, 1167, 1129, 1068, 839. 1H NMR (CDCl3,
C19H17F2NO4: 361.1126, found: 361.1113.
400 MHz)
7.16 (t, 2H, J = 8.6 Hz), 6.72 (s, 1H), 5.42 (dd, 1H, J = 12.0 Hz,
J = 9.2 Hz). 19F NMR (CDCl3, 367.5 MHz)
: À62.3 (s, 3F), À105.0
(dd, 1F, JF-F = 266 Hz, JF-H = 9 Hz), À109.58 (s, 1F), À110.11 (dd, 1F,
JF-F = 266 Hz, JF-H = 11 Hz). 13C NMR (CDCl3, 100.6 MHz)
: 161.2 (d,
J = 250.7 Hz), 158.3, 150.7, 144.2, 132.7, 130.0, 128.3, 127.6, 119.3,
114.6 (t, J = 243.7 Hz), 100.3, 83.5. EI-MS (m/z) 387 (M+, 1), 213
(100), 175 (31), 127 (20.5). HRMS (EI) calcd for C18H11F6NO2:
387.0694, found: 387.0691.
d
: 7.77 (dd, 2H, J = 8.8 Hz, J = 5.2 Hz), 7.59–7.54 (m, 4H),
4.2.20. (5-(Difluoromethyl)-3-(4-methoxyphenyl)isoxazol-4-yl)(4-
methoxyphenyl)methanol (5cc)
d
White solid, m.p. 85.3–87.1 8C; IR (cmÀ1, KBr) 3359, 2840, 1611,
1512, 1463, 1253, 1034, 808. 1H NMR (CDCl3, 400 MHz)
d: 7.54 (d,
2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0 Hz), 6.88 (d, 2H, J = 8.0 Hz), 6.83
(d, 2H, J = 8.0 Hz), 6.75 (t, 1H, J = 56.0 Hz), 6.08 (s, 1H), 3.80 (s, 3H),
d
3.76 (s, 3H). 19F NMR (CDCl3, 367.5 MHz)
d
: À114.8 (dd, 1F, JF-
F = 308 Hz, JF-H = 50 Hz), À117.1 (dd, 1F, JF-F = 307 Hz, JF-H = 50 Hz).
13C NMR (CDCl3, 100.6 MHz)
: 168.4, 161.4, 159.3, 133.3, 129.5,
d
128.1, 127.6, 119.2, 114.7, 114.3, 113.9, 109.7 (t, J = 238.4 Hz), 66.4,
60.5, 55.4. EI-MS (m/z) 361 (M+, 85), 252 (46.3), 135 (100), 109
(40.6), 77 (10.3). HRMS (EI) calcd for C19H17F2NO4: 361.1126,
found: 361.1118.
4.2.16. [5-Difluoromethyl-3-(4-fluoro-phenyl)-isoxazol-4-yl]-(4-
trifluoromethyl-phenyl)-methanol (5bd)
White solid, m.p. 95.5–96.5 8C; IR (cmÀ1, KBr): 3334, 2924,
1695, 1327, 1126, 1066, 860. 1H NMR (CDCl3, 400 MHz)
d: 8.22 (d,
2H, J = 8.0 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.0 Hz), 7.07–
7.03 (m, 2H), 7.03 (t, 1H, J = 52.8 Hz), 6.10 (s, 1H). 19F NMR (CDCl3,
4.2.21. (5-(Difluoromethyl)-3-(4-methoxyphenyl)isoxazol-4-yl)(4-
nitrophenyl)methanol (5ce)
367.5 MHz)
F = 314 Hz, JF-H = 51 Hz), À118.20 (dd, 1F, JF-F = 314 Hz, JF-
H = 52 Hz). 13C NMR (CDCl3, 100.6 MHz)
162.3 (d,
d
: À62.5 (s, 3F), À109.8 (s, 1F), À114.5 (dd, 1F, JF-
Yellow oil; IR (cmÀ1, KBr) 3359, 1614, 1532, 1353, 1256, 1043,
803. 1H NMR (CDCl3, 400 MHz)
d
: 8.08 (d, 2H, J = 8.8 Hz), 7.49 (d,
1H, J = 7.6 Hz), 7.43 (t, 1H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.8 Hz), 7.02 (t,
1H, J = 52.8 Hz), 6.86 (d, 2H, J = 8.8 Hz), 6.18 (s, 1H), 3.81 (s, 3H). 19
d
:
J = 250.8 Hz), 158.4, 158.3, 144.2, 130.9, 130.6, 126.8, 125.6,
115.9, 107.6 (t, J = 138.7 Hz), 100.8, 64.5. EI-MS (m/z) 387 (M+,
1), 190 (62.5), 173 (100), 145 (56.7), 127 (13.2), 107 (10.6), 95 (6),
75 (3.3). HRMS (EI) calcd for C18H11F6NO2: 387.0694, found:
387.0691.
F
NMR (CDCl3, 367.5 MHz)
d
: À115.0 (dd, 1F, JF-F = 320 Hz, JF-
H = 55 Hz), À117.3 (dd, 1F, JF-F = 320 Hz, JF-H = 55 Hz). 13C NMR
(CDCl3, 100.6 MHz)
d: 162.2, 161.1, 160.3, 148.2, 142.6, 132.2,
130.2, 129.6, 123.1, 121.4, 120.0, 119.4, 114.2, 107.5 (t,
J = 237.5 Hz), 66.0, 55.4. HRMS (EI) calcd for C18H14F2N2O5:
376.0871, found: 376.0873.
4.2.17. 2,2-Difluoro-2-[3-(4-methoxy-phenyl)-isoxazol-5-yl]-1-
phenyl-ethanol (4ca)
White solid; m.p. 99.3–100.1 8C; IR (cmÀ1, KBr): 3426, 3136,
2937, 1612, 1462, 1430, 1255, 1101, 1078, 1036, 831, 812. 1H NMR
4.2.22. (5-Difluoromethyl-3-thiophen-3-yl-isoxazol-4-yl)-phenyl-
methanol (5da)
(CDCl3, 400 MHz)
7.37–7.34 (m, 3H), 6.95 (d, 2H, J = 8.8 Hz), 6.66 (s, 1H), 5.32 (dd, 1H,
J = 12.0 Hz, J = 9.6 Hz), 3.84 (s, 3H). 19F NMR (CDCl3, 367.5 MHz)
À106.9 (dd, 1F, JF-F = 268 Hz, JF-H = 9 Hz), À110.9 (dd, 1F, JF-
F = 268 Hz, JF-H = 12 Hz). 13C NMR (CDCl3, 100.6 MHz)
: 167.2,
d
: 7.68 (d, 2H, J = 8.8 Hz), 7.42–7.39 (m, 2H),
Light yellow solid, m.p. 66.2–67.2 8C; IR (cmÀ1, KBr): 3410,
3107, 1558, 1463, 1353, 1280, 1177, 1116, 1041, 922, 845, 817,
d
:
763, 699. 1H NMR (CDCl3, 400 MHz)
d: 7.41 (dd, 1H, J = 5.2 Hz,
J = 1.2 Hz), 7.38–7.35 (m, 3H), 7.34–7.31 (m, 2H), 7.18 (dd, 1H,
J = 3.6 Hz, J = 0.8 Hz), 7.03 (t, 1H, J = 52.8 Hz), 7.02 (t, 1H, J = 4.4 Hz),
d
161.4, 155.8, 134.6, 130.1, 129.2, 129.0, 128.4, 128.3, 127.7, 126.7,
115.8, 114.4 (t, J = 247.8 Hz), 103.0, 74.8 (t, J = 28.2 Hz), 55.4. EI-MS
(m/z) 331 (M+, 34), 225 (100), 107 (17). HRMS (EI) calcd for
6.13 (s, 1H). 19F NMR (CDCl3, 367.5 MHz)
d
: À114.9 (dd, 1F, JF-
F = 312 Hz, JF-H = 51 Hz), À118.8 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz).
13C NMR (CDCl3, 100.6 MHz)
: 160.5, 156.5, 140.2, 129.2, 129.1,
d
C
18H15F2NO3: 331.1020, found: 331.1021.
1298.96, 128.6, 128.5, 127.7, 126.9, 120.3, 110.1 (t, J = 234.1 Hz),
107.2, 68.1. EI-MS (m/z) 307 (M+, 62), 256 (31.2), 228 (24.7), 201
(25.5), 150 (51.2), 105 (100), 84 (60.4), 77 (49). HRMS (EI) calcd for
4.2.18. (5-(Difluoromethyl)-3-(4-methoxyphenyl)isoxazol-4-
yl)(phenyl)methanol (5ca)
White solid, m.p. 125.6–126.6 8C; IR (cmÀ1, KBr) 3501, 2979,
1610, 1515, 1456, 1387, 1249, 1054, 855, 702. 1H NMR (CDCl3,
C15H11F2NO2S: 307.0479, found: 307.0475.
4.2.23. (5-Difluoromethyl-3-thiophen-3-yl-isoxazol-4-yl)-furan-3-
yl-methanol (5db)
Yellow solid, m.p. 73.6–74.6 8C; IR (cmÀ1, KBr): 3340, 1551,
1466, 1363, 1279, 1149, 1042, 921, 822, 723. 1H NMR (CDCl3,
400 MHz) d: 7.66 (d, 1H, J = 0.8 Hz), 7.45 (d, 1H, J = 4.8 Hz), 7.39 (d,
1H, J = 4.0 Hz), 7.27 (s, 1H), 7.05 (dd, 1H, J = 5.0 Hz, J = 3.8 Hz), 6.79
(t, 1H, J = 52.6 Hz), 6.61 (dd, 1H, J = 3.8 Hz, J = 1.6 Hz). 19F NMR
400 MHz)
d: 7.59–7.55 (m, 2H), 7.33–7.30 (m, 5H), 6.90 (d, 2H,
J = 12 Hz), 6.70 (t, 1H, J = 52.0 Hz), 6.15 (s, 1H), 3.81 (s, 3H). 19F
NMR (CDCl3, 367.5 MHz)
d
: À115.0 (dd, 1F, JF-F = 308 Hz, JF-
H = 50 Hz), À116.5 (dd, 1F, JF-F = 308 Hz, JF-H = 50 Hz). 13C NMR
(CDCl3, 100.6 MHz)
d
: 168.9, 161.5, 158.0, 141.0, 129.6, 128.6,
127.9, 127.0, 126.1, 119.2, 114.3, 109.7 (t, J = 237.9 Hz), 66.4, 55.4.
EI-MS (m/z) 331 (M+, 100), 252 (17.5), 135 (74.3), 105 (15.6), 77
(13.1). HRMS (EI) calcd for C18H15F2NO3: 331.1020, found:
331.1017.
(CDCl3, 367.5 MHz)
d
: À116.7 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz),
À118.3 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz). 13C NMR (CDCl3,
100.6 MHz)
d: 162.5 (t, J = 27.8 Hz), 156.1, 152.1, 148.7, 129.9,

X. Yang et al. / Journal of Fluorine Chemistry 145 (2013) 1–7
7
129.1, 127.9, 127.3, 121.8, 113.4, 106.4 (t, J = 241.7 Hz), 58.3. EI-MS
(m/z) 297 (M+, 1), 295 (68.4), 150 (17.2), 95 (100). HRMS (EI) calcd
for C13H9F2NO3S: 297.0271, found: 297.0130.
J = 8.0 Hz), 7.44 (d, 2H, J = 8.4 Hz), 7.42 (d, 1H, J = 1.2 Hz), 7.24 (dd, 1H,
J = 3.6 Hz, J = 1.2 Hz), 7.04 (dd, 1H, J = 5.2 Hz, J = 3.6 Hz), 7.01 (t, 1H,
J = 52.6 Hz), 6.25 (s, 1H). 19F NMR (CDCl3, 367.5 MHz)
d
: À62.69,
À114.5 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz), À118.6 (dd, 1F, JF-
F = 312 Hz, JF-H = 51 Hz). 13C NMR (CDCl3, 100.6 MHz)
: 155.2,
4.2.24. 2,2-Difluoro-1-(4-methoxy-phenyl)-2-(3-thiophen-3-yl-
isoxazol-5-yl)-ethanol (4dc)
Yellow solid, m.p. 96.8–97.8 8C; IR (cmÀ1, KBr): 3435, 2925,
1609, 1512, 1464, 1249, 1174, 1030, 839, 712. 1H NMR (CDCl3,
d
152.4, 143.9, 129.6, 128.8, 127.8, 127.0, 121.8, 119.6, 117.7, 116.5,
114.8 (t, J = 234.8 Hz), 107.0, 66.9. EI-MS (m/z) 375 (M+, 84.5), 324
(29.5), 201 (45.2), 173 (57.3), 150 (100), 127 (40.4), 84 (80.4). HRMS
(EI) calcd for C16H13F2NO3S: 375.0352, found: 375.0349.
400 MHz)
J = 4.8 Hz, J = 4.0 Hz), 6.90 (d, 2H, J = 6.0 Hz), 6.56 (s, 1H), 5.27 (t,
1H, J = 11.0 Hz), 3.81 (s, 3H). 19F NMR (CDCl3, 367.5 MHz)
: À106.3
(dd, 1F, JF-F = 266 Hz, JF-H = 8 Hz), À109.7 (dd, 1F, JF-F = 266 Hz, JF-
H = 10 Hz). 13C NMR (CDCl3, 100.6 MHz)
: 159.8, 159.2, 133.1,
d: 7.46–7.44 (m, 2H), 7.32 (d, 2H, J = 8.4 Hz), 7.12 (dd, 1H,
d
Acknowledgements
d
129.1, 128.7, 128.4, 128.2, 127.8, 114.7 (t, J = 243.9 Hz), 113.8, 73.8
(t, J = 28 Hz), 55.3. EI-MS (m/z) 337 (M+, 3.6), 201 (21.9), 137 (100),
135 (5.4), 94 (3.7). HRMS (EI) calcd for C16H13F2NO3S: 337.0584,
found: 337.0590.
The authors thank the National Natural Science Foundation of
China (No. 20972050, No. 21172148 and No. 21202044) and the
Science and Technology Commission of Shanghai Municipality (No.
10540501300) for financial support.
4.2.25. (5-Difluoromethyl-3-thiophen-3-yl-isoxazol-4-yl)-(4-
methoxy-phenyl)-methanol (5dc)
References
Yellow oil; IR (cmÀ1, KBr): 3379, 2923, 1610, 1512, 1461, 1255,
1028, 820, 719. 1H NMR (CDCl3, 400 MHz)
d
: 7.40 (d, 1H, J = 4.8 Hz),
7.23 (s, 2H), 7.15 (d, 1H, J = 3.6 Hz), 7.09 (t, 1H, J = 52.8 Hz), 7.02 (t,
1H, J = 4.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 6.07 (s, 1H), 3.80 (s, 3H). 19
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F
NMR (CDCl3, 367.5 MHz)
d
: À114.4 (dd, 1F, JF-F = 310 Hz, JF-
H = 52 Hz), À119.4 (dd, 1F, JF-F = 312 Hz, JF-H = 51 Hz). 13C NMR
(CDCl3, 100.6 MHz)
d: 160.5, 160.0, 139.2, 133.0, 129.2, 128.5,
127.7, 122.6, 114.5, 107.8 (t, J = 241.7 Hz), 68.1, 55.4. EI-MS (m/z)
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4.2.26. 2,2-Difluoro-2-(3-thiophen-3-yl-isoxazol-5-yl)-1-(4-
trifluoromethyl-phenyl)-ethanol (4dd)
White solid, m.p. 119–120 8C; IR (cmÀ1, KBr): 3356, 2924, 1699,
1330, 1114, 1064, 716. 1H NMR (CDCl3, 400 MHz)
d
: 8.22 (d, 2H,
J = 8.0 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.55 (d, 2H, J = 8.0 Hz), 7.13 (t,
1H, J = 4.2 Hz), 6.69 (s, 1H), 5.42 (dd, 1H, J = 11.6 Hz, J = 9.6 Hz). 19
NMR (CDCl3, 367.5 MHz)
: À63.2 (s, 3F), À105.2 (dd, 1F, JF-
F = 268 Hz, JF-H = 9 Hz), À110.2 (dd, 1F, JF-F = 268 Hz, JF-H = 11 Hz).
13C NMR (CDCl3, 100.6 MHz)
: 162.5, 156.1, 128.9, 128.7, 128.4,
F
d
d
128.3, 127.8, 114.7 (t, J = 243.6 Hz), 113.9, 73.8. EI-MS (m/z) 375
(M+, 13.8), 201 (100), 175 (26.2), 127 (23.1). HRMS (EI) calcd for
C16H10F5NO2S: 375.0352, found: 375.0356.
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