General 5-Halomethyl Isoxazoline Synthesis Enabled by Copper-Catalyzed Oxyhalogenation of Alkenes

Article abstract of DOI:10.1021/acs.joc.9b02031

A general and efficient oxyhalogenation of unsaturated ketoximes has been achieved through copper catalysis with diethyl bromomalonate, N-chlorosuccinimide, and N-iodosuccinimide, yielding 5-chloromethyl, 5-bromomethyl, and 5-iodomethyl isoxazolines in go

Full text of DOI:10.1021/acs.joc.9b02031

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Note
General 5-Halomethyl Isoxazolines Synthesis Enabled
by Copper-Catalyzed Oxyhalogenation of Alkenes
Xiaoqing Li, Yu Ding, Lijie Qian, Yang Gao, Xinqiang Wang, Xinhuan Yan, and Xiangsheng Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02031 • Publication Date (Web): 10 Sep 2019
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The Journal of Organic Chemistry
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General5-Halomethyl Isoxazolines Synthesis Enabled by
Copper-Catalyzed Oxyhalogenationof Alkenes
Xiaoqing Li,* Yu Ding‡, Lijie Qian‡, Yang Gao, Xinqiang Wang, Xinhuan Yan and Xiangsheng Xu*
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College of chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. China
Supporting Information Placeholder
Cu(OTf)2 (5 mol%)
1,10-Phen (5 mol%)
Na2CO3 (1 equiv)
MeCN, Ar, 80 oC
R3
R2
OH
R1
O
N
X
N
X
-Y
+
R2 R3
R
R
R1
X = Cl, Br, I
X-Y: diethyl bromomalonate, NCS and NIS
[
]
ABSTRACT: A general and efficient oxyhalogenation of unsaturated ketoximes has been achieved through copper catalysis with
diethyl bromomalonate, NCS and NIS, yielding 5-chloromethyl, 5-bromomethyl as well as 5-iodomethyl isoxazolines in good to excellent
yields.
5-Halomethyl isoxazolines represent a versatile building block for
the rapid construction of valuable heterocycles and bioactive
molecules. For instance, they can be transformed into isoxazole1
and pyrrolidin-3-ol2 via dehydrohalogenation and reduction,
respectively. Furthermore, fused cyclopropyl-3-amino-2,4-oxazine
BACE inhibitor can be synthesized with chloromethyl 3-(5-bromo-
2-fluorophenyl) isoxazoline through multistep ring opening and
cyclization sequences (Figure 1).3 Conventional methods to
synthesize 5-halomethyl isoxazolines use the 1,3-dipolar
cycloaddition of nitrile oxides with allyl halide (Scheme 1a).
However, the protocol suffers from moderate yields of the
products.3,4 Alternatively, oxyhalogenation of allylic oximes
allows for efficient access to this valuable functionality (Scheme
1b).2,5 Despite robust investigation, these methods are generally
limited by the utilization of stoichiometric oxidants and a large
excess of halides and the low halide atom economy. Thus, a general
and cheap catalytic platform for oxyhalogenation of allylic oximes
remains highly desired.
Oximes6 has employed copper catalysis as a versatile tool for
radical rocesses. Han7 and Wang8, who through copper catalyzed
single-electron-transfer (SET) processes have generated iminoxyl
radical from allylic oximes and developed oxyalkynylation,
oxyamination
and
oxytrifluoromethylthiolation
with
ethynylbenziodoxolone (EBX), amines and AgSCF3, respectively.
Liang9, Liu10 and Hu11 have identified an array of Cu catalyzed
protocols for oxytrifluoromethylation of allylic oximes. In these
reactions, the role of copper catalysts was the generation of active
CF3-containing intermediates. Wang and co-workers have applied
copper catalyzed atom transfer process to generate azido radicals
from TMSN3 and developed oxyazidation based on radical cross
coupling.12 Recently, we questioned whether 5-halomethyl
isoxazolines synthesis might be accomplished in a general sense
via copper catalysis with readily available halide source. Herein,
we describe our work towards this goal, which has led to the
development of a powerful platform for catalytic construction of
chloromethyl, bromomethyl as well as iodomethyl isoxazolines
(Schem 1c).
Recent progress toward the oxyfunctionalization of allylic
previous works
OH
N
N
O
X
N
OH
(a)
(b)
OMe
N
X
O
+
N
R
R
Cl
R
N
R
R
OH
N
O
X
N
Me
R
O
O
N
NH
CuX2/Pd(OAc)2, AlCl3 or CBr4or CHI3 /tBuONO, CuX or I2/TBHP
BACE inhibitor
R
NH2
O
X
This work
OH
N
O
X
N
N
X-Y
(c)
F
[Cu], base
R
R
OH
O
O
H2N
HN
N
diethyl bromomalonate, NCS and NIS
X-Y:
R
R
R
Scheme 1. Synthesis of 5-halomethyl isoxazolines.
Figure 1. Transformation of 5-halomethyl isoxazolines.
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We began our investigations into the proposed copper-catalyzed
oxyhalogenation of allylic oximes by evaluating different Br source
(Scheme 2). Upon stiring allylic oxime 1a with N-
Bromosuccinimide (NBS) in the presence of Cu(OTf)2, 1,10-
phenanthroline (1,10-phen), and Na2CO3, we observed 60% HPLC
yield of the desired isoxazoline 3a. Inspired by Leonori’s work on
iminobromogenation of olefins,13 diethyl bromomalonate 2b was
then employed as bromo source. To our delight, 91% HPLC yield
of the desired isoxazoline 3a was obtained. Other commercially
available α-bromoesters, such as ethyl bromoacetate 2c and ethyl
2-bromoisobutyrate 2d were less effective. We next explored the
sensitivity of these reactions to various changes in the standard
conditions. Other Cu salts were moderately successful (Table 1,
entries 2−4), while other ligands uniformly less effective than 1,10-
phen (Table 1, entries 5−7). Similarly, a number of bases were also
effective in these reactions, but the reaction yields diminished with
Cs2CO3 (Table 1, entries 8−11). Also, the reaction is moderately
successful in THF and EtOH (Table 1,entry 12 and 14), but
considerably less so in other solvents (Table 1, entries 14- 17).
Control reactions of 1a lacking Cu(OTf)2 and 1, 10-phen were
uniformly less effective (Table 1, entries 18−19), while lacking
Na2CO3 was unsuccessful (Table 1, entry 20). Notably, 20 mol%
of Na2CO3 could provide the desired isoxazoline 3a in 86% HPLC
yield (Table 1, entry 21).
16
17
Cu(OTf)2
Cu(OTf)2
-
1,10-phen
1,10-phen
1,10-phen
-
Na2CO3
Na2CO3
Na2CO3
Na2CO3
-
DCE
17
53
31
20
0
1
2
3
4
5
6
7
8
PhMe
MeCN
MeCN
MeCN
MeCN
18
19
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
20
21 d
1,10-phen
1,10-phen
Na2CO3
86
a
Reaction conditions: 1a (0.2 mmol), 2b (0.24 mmol), copper
catalyst (0.01 mmol), base (0.2 mmol), solvent (1 mL), 80 oC, 0.5
h, under argon. b HPLC yields using toluene as an internal standard.
c isolated yield. d 20 mol% of Na2CO3 used.
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With optimal oxybromination conditions in hand, we probed the
generality of this process with respect to the allylic oximes. As
shown in Scheme 2, a diverse array of aromatic oximes with a
variety of functional groups (methyl, methoxyl, fluoro, chloro,
bromo, nitro, triflurormethyl and ester groups) performed well
using this protocol (compounds 3a–3l, 60–97% yield). Notably, we
found that phenolic oxime could be bromooxygenated, though with
modest reaction efficiency (3m, 41%). Moreover, naphthyl oxime
was found to be a competent substrate in this transformation (3n,
73% yield). Furthermore, thiophenyl oxime could be employed
without loss in efficiency (3o, 85% yield). With respect to
substituted allylic group, we have found that a range of oximes with
substitution at the R1, R2 and R3 positions were effective
substrates in this protocol (3p–3r, 71–93% yield). Perhaps most
importantly, this transformation is not limited to aromatic oximes.
For example, phenethyl can be readily incorporated in this copper
cyclization (3s, 80% yield). Scalability of this reaction was
demonstrated through the preparation of 3a on 6.5 mmol scale.
2
(1.2 equiv)
Cu(OTf)2 (5 mol%)
1,10-phen (5 mol%)
Na2CO3 (1 equiv)
MeCN, Ar, 80 oC, 0.5 h
OH
O
3a
Br
Br
N
N
Ph
O
Ph
1a
2b
(1.2 equiv)
EtO2C
CO2Et
N Br
Br
COOEt
R3
R2
COOEt
OH
Cu(OTf)2 (5 mol%)
1,10-phen (5 mol%)
Na2CO3 (1 equiv)
O
N
Br
N
Br
O
R2 R3
R
R
R1
3
MeCN, Ar, 80 oC
2a
, 60%
2b
, 91%
2c
, 21%
2d
, 47%
R1
1
Scheme 2. oxybromination of 1a with various Br source. a HPLC
yields using toluene as an internal standard are reported for
reactions at 0.2 mmol scale.
O
O
N
N
O
N
Br
Br
Br
MeO
R
Table 1. Optimization of the reaction conditions a
b
OMe
3a
, R = H, 85% (82%)
NO2
3j
3k
, 78%
, 71%
OH
O
3b
, R = Me, 64%
Br
N
2b
, [Cu]/L
N
O
N
O
3c
, R = OMe, 75%
N
base, solvent
Ph
Ph
3d
, R = F, 81%
, R = Cl, 77%
, R = Br, 73%
3a
Br
1
Br
3e
3f
Entr
y
Yield/%
R
3n
, 73%
Cu
Ligand
base
Sol.
b
3g
, R = NO2, 90%
, R = CF3, 97%
3l
, R = Me, 60%
c
3h
3m
, R =OH, 41%
1
Cu(OTf)2
Cu(OAc)2
CuCl2
1,10-phen
1,10-phen
1,10-phen
1,10-phen
bpy
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K3PO4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
91(85)c
89
3i
, R = CO2Me, 93%
O
N
2
O
N
N
O
S
3
76
Br
Ph
Br
4
CuI
88
Br
O
Br
Br
3o
, 73%
5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
55
3q
, 75%
3p
, 93%
6
TMEDA
68
N
O
N
7
PPh3
26
Ph
Ph
Br
8
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
78
3s
, 80%
3r
, 71%
9
Cs2CO3
K2CO3
28
10
11
12
13
14
15
82
Scheme 3. Scope of the oxybromination strategy. aIsolated yields
are reported for reactions at 0.2 mmol scale for 0.5~2 h. b6.5 mmol
scale, and product 3a was obtained in 1.283 g. c2 equiv. of Na2CO3
used
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
76
80
H2O
54
EtOH
DMA
72
40
Inspired by the excellent results above, we next evaluated the
ability of this copper catalysis to accommodate chlorooxygenation
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The Journal of Organic Chemistry
of allylic oximes using N-chlorosuccinimide (NCS) as Cl source.
NCS (1.2 equiv)
Cu(OTf)2 (5 mol%)
Phen (5 mol%)
Na2CO3 (1 equiv)
O
1
2
As described in Scheme 4, with various oximes examined in the
oxybromination reaction (scheme 3), the desired chloromethyl
isoxazolines were successfully achieved in good to excellent yields
under the optimal reaction conditions (4a-4s, 61-97%).
OH
N
Cl
N
3
4
Ph
Ph
MeCN, Ar, 80 oC, 5 h
7
, 74%
6
5
6
7
8
NCS (1.2 equiv)
Scheme 6. Control experiment
R3
R2
OH
Cu(OTf)2 (5 mol%)
1,10-phen (5 mol%)
Na2CO3 (1 equiv)
O
N
Cl
N
Based on these experiments and previous results, a plausible
mechanism is proposed in Scheme 7. Cu(II) is SET reduced by the
iminoxyl anion A, formed by deprotonation of substrates 1 or 6, to
generate the iminoxyl radical (resonance structures B and B’),
along with Cu(I).7,8 Then, iminoxyl radical B (or B’) undergoes O-
or N-atom 5-exo-trig radical cyclization relying on the length of
carbon chain, delivering the radical intermediate C or C’.
Subsequently, homolytic halide atom transfer with the polarized
SOMOphile (X-Y) would furnish the targeted 5-halomethyl
isoxazolines 3-5 or nitrone 7 as well as the electron-poor Y
radicals.13 Finally, single electron reduction of Y radicals by Cu(I)
forms Y anion with the concomitant regeneration of Cu(II). Y anion
can also act as a base to deprotonate the substrates 1 or 6.
R2 R3
R
R
R1
MeCN, Ar, 80 oC
R1
1
4
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O
O
N
N
O
N
Cl
Cl
MeO
Cl
R
OMe
4j
NO2 , 78%
4a
, R = H, 90%
, R = Me, 97%
, R = OMe, 83%
, R = F, 87%
, R = Cl, 97%
, R = Br, 95%
, R = NO2, 80%
, R = CF3, 95%
4k
, 78%
4b
4c
4d
4e
4f
4g
4h
4i
O
N
O
N
Cl
Cl
R
4n
, 71%
4l
, R = Me, 61%
OH
N
c
4m
, R = OH, 73%
, R = CO2Me, 84%
base
O
N
O
R
n
N
N
O
O-
S
1
6
or
Cl
N
Ph
Cl
Cl
O
Y-
Cu(II)
Br
R
4o
, 85%
4p
, 76%
n
4q
, 72%
A
N
O
Cl
N
Ph
X
Ph
Cl
, 72%
O
N
Cu(I)
O
O
4r
, 68%
4s
Y
N
3-5
7
R
a
Scheme 4. Scope of the oxychrologenation strategy. Isolated
yields are reported for reactions at 0.2 mmol scale for 0.5~5 h. c2
equiv of Na2CO3 used
or
R
n
B
O
N
n =1
X
N
R
Although we recently developed the TBHP-induced
iodocyclization of allylic oximes with I2, the protocol is less
effective for electron-rich aryl and aliphatic oximes.5d Therefore,
we turned our attention to defining the capacity for copper
catalyzed oxyiodo genation of allylic oximes in the presence of N-
iodosuccinimide (NIS) (Scheme 5). To our delight, both methyl
substituted aromatic (5a, 97%) and aliphatic (5b, 96%)
isoxazolines were successfully achieved in excellent yields under
the optimal reaction.
X-Y
R
C
O
N
O
N
R
n = 2
R
n
B'
C'
Scheme 7.Proposed mechanism
In conclusion, we have developed a highly efficient copper
catalyzed oxyhalogenation of alkenes using readily available halide
source, such as diethyl bromomalonate, NCS and NIS. This
protocol serves as general and convenient approach for the rapid
access of 5-halomethyl isoxazolines, which exhibited good
substrate scope and function group compatibility. This
transformation is predicated on a significant modification of the
reported oxyhalogenation of allylic oximes as both stoichiometric
amounts of oxidants and a large excess of halides are avoided.
NIS (1.2 equiv)
Cu(OTf)2 (5 mol%)
1,10-phen (5 mol%)
Na2CO3 (1 equiv)
OH
O
N
N
R
I
R
MeCN, Ar, 80 oC, 0.5 h
1
5a
, R= 4-MeC6H4, 97%
, R= PhCH2CH2, 96%
5b
Scheme 5. oxyiodonalization of allylic oximes
EXPERIMENTAL SECTION
As iminoxyl radical possesses an electronic structure with the
single-electron spin density delocalized on both the O- and N-atom,
iminoxyl radical-promoted cyclization of γ,δ-unsaturated
General method. Unless stated otherwise, all reactions were
carried out under an argon atmosphere. All solvents were purified
and dried according to standard methods prior to use. All
commercial reagents were used without additional purification.
Flash chromatography was carried out with silica gel (200-300
mesh). Melting points were determined without correction on a
5c,7,14
ketoximes often affords nitrone products.
To verify that this
reaction experienced an iminoxyl radical involved process, γ,δ-
unsaturated ketoxime 6 was subjected to the standard conditions
with NCS. As expected, nitrones 7 was obtained in 74% yield
(Scheme 6) .
digital melting-point apparatus. H NMR and 13C NMR spectra
were recorded at 500 MHz (or 600MHz) and 125 MHz (or 150
1
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MHz) spectrometers in CDCl3 using tetramethylsilane (TMS) as
atmosphere. The resulting suspension was stirred for 0.5 h at 80℃
(block heaters). The mixture was extracted with ethyl acetate (3 x
15 mL). The combined organic layers were washed with brine (10
mL), dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography on silica gel to
give the products 5.
1
2
3
4
5
6
7
8
internal standard, respectively.19F NMR spectra were recorded at
400 MHz spectrometers. High-resolution mass spectra (HRMS)
were recorded using ion trap (compounds 3-5 and 7) and ICR
+
(compound 1i) with an positive-ion electrospray ionization (ESI )
source, and ICR (compounds 1k and 1m) with an negative-ion
-
electrospray ionization (ESI) source.
Gram scale reaction. A flame dry 25 mL schlenk flask was
charged with 1a (1.05g, 6.5 mmol), diethyl bromomalonate (1.86
g, 7.8 mmol), Na2CO3 (689.0 mg, 6.5 mmol), Cu(OTf)2 (117.6 mg,
0.33mmol), 1,10-Phen (64.4 mg, 0.33 mmol) in anhydrous MeCN
(15 mL) under argon atmosphere. The resulting suspension was
stirred for 2 h at 80℃(block heaters). The mixture was extracted
with ethyl acetate (3 x 25 mL). The combined organic layers were
washed with brine (20 mL), dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel to give the products 3a (1.283 g, 5.34
mmol).
Synthesis of starting oximes 1. Oximes 1 were synthesized
according to the reported procedures.15 The starting substrates 1a-
d, 1g-h, 1n-o, 1q,15a 1e, 1j,15b 1f,15c 1l, 1r,15d 1p,15e 1s15f are
known compounds, and their NMR data were identical with those
in the literature.
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methyl 4-(1-(hydroxyimino)but-3-en-1-yl)benzoate (1i). The
reaction of methyl 4-formylbenzoate (1.64 g, 10 mmol) give 1i as
white soild (1.50 g, 68%), mp 72-73 ℃ , Rf = 0.22, (petroleum
1
ether/ethyl acetate 10:1); H NMR (600 MHz, CDCl3) δ 9.12 (s,
1H), 8.06 – 8.03 (m, 2H), 7.70 (d, J = 8.3 Hz, 2H), 5.98 – 5.85 (m,
1H), 5.22 – 5.09 (m, 2H), 3.93 (s, 3H), 3.60 (d, J = 6.2 Hz, 2H).
13C{1H} NMR (150 MHz, CDCl3) δ 166.8, 156.2, 139.9, 131.7,
130.6, 129.8, 126.3, 117.4, 52.3, 30.8. HRMS (ESI) m/z calcd for
C12H15NO3 [M+H]+ : 222.1125, found 222.1128.
1-(3,4-dimethoxyphenyl)but-3-en-1-one oxime (1k). The reaction
of 3,4-dimethoxybenzaldehyde (1.66 g, 10mmol) give 1k as
colorless oil (1.22 g, 55%), Rf =0.17 (petroleum ether/ethyl acetate
5:1); 1H NMR (600 MHz, CDCl3) δ 9.01 (s, 1H), 7.26 (d, J = 4.1
Hz, 1H), 7.19 – 7.12 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.99 – 5.86
(m, 1H), 5.20 – 5.07 (m, 2H), 3.89 (d, J = 1.2 Hz, 7H), 3.57 (d, J =
6.2 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3) δ 156.5, 150.2,
148.9, 132.5, 128.3, 119.5, 117.0, 110.7, 108.9, 55.9, 55.8, 30.9.
HRMS (ESI) m/z calcd for C12H13NO3 [M-H]- : 218.0812, found
218.0835.
1-(o-hydroxybenzene)but-3-en-1-one oxime (1m). The reaction of
2-hydroxybenzaldehyde (1.22 g，20 mmol) give 1m as white soild
(0.90 g，51%), mp 75-76℃, Rf = 0.36, (petroleum ether/ethyl
acetate 10:1); 1H NMR (600 MHz, CDCl3) δ 11.95 – 11.42 (m, 1H),
8.56 – 8.08 (m, 1H), 7.48 – 7.40 (m, 1H), 7.30 – 7.22 (m, 1H), 6.99
(d, J = 8.2 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.00 – 5.88 (m, 1H),
5.24 – 5.10 (m, 2H), 3.70 – 3.63 (m, 2H). 13C{1H} NMR (150 MHz,
CDCl3) δ 160.3, 157.6, 131.5, 130.9, 127.9, 119.5, 117.7, 117.6,
117.4, 29.1. HRMS (ESI) m/z calcd for C10H11NO2 [M-H]-
:176.0706, found 176.0720.
5-(Bromomethyl)-3-phenyl-4,5-dihydroisoxazole
(3a).5b
Compound 3a was prepared following the general procedure A.
The reaction of 1a (32.2 mg, 0.2 mmol) give 3a as white soild (41
mg, 85%); mp 59-61℃, Rf = 0.65 (petroleum ether/ethyl acetate
1
5:1); H NMR (500 MHz, CDCl3) δ 7.71 – 7.64 (m, 2H), 7.45 –
7.37 (m, 3H), 5.05 – 4.95 (m, 1H), 3.58 (dd, J =10.4, 4.3 Hz, 1H),
3.51 (dd, J = 17.0, 10.5 Hz, 1H), 3.41 (dd, J = 10.4, 8.3 Hz, 1H),
3.33 (dd, J = 17.0, 6.4 Hz, 1H).
5-(Bromomethyl)-3-(p-tolyl)-4,5-dihydroisoxazole
(3b).1
Compound 3b was prepared following the general procedure A.
The reaction of 1b (35.0 mg, 0.2 mmol) give 3b as white soild (32.4
mg, 64%); mp 88-89℃, Rf = 0.67 (petroleum ether/ethyl acetate
5:1); 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.22
(d, J = 8.0 Hz, 2H), 5.04 – 4.93 (m, 1H), 3.57 (dd, J = 10.3, 4.3 Hz,
1H), 3.50 (dd, J = 17.0, 10.4 Hz, 1H), 3.40 (dd, J = 10.3, 8.4 Hz,
1H), 3.31 (dd, J = 17.0, 6.3 Hz, 1H), 2.38 (s, 3H).
5-(Bromomethyl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazole
(3c).5b Compound 3c was prepared following the general procedure
A. The reaction of 1c (38.3 mg, 0.2 mmol) give 3c as white soild
(40.6 mg, 75%); mp 77-78℃, Rf = 0.42 (petroleum ether/ethyl
acetate 5:1); 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.9, 2H),
6.92 (d, J = 8.9, 2H), 5.01 – 4.91 (m, 1H), 3.83 (s, 3H), 3.57 (dd, J
= 10.3, 4.2 Hz, 1H), 3.49 (dd, J = 16.9, 10.4 Hz, 1H), 3.39 (dd, J =
10.3, 8.4 Hz, 1H), 3.29 (dd, J = 16.9, 6.3 Hz, 1H).
General procedure for the synthesis of isoxazolines.
5-(Bromomethyl)-3-(4-fluorophenyl)-4,5-dihydroisoxazole (3d).
Compound 3d was prepared following the general procedure A.
The reaction of 1d (35.8 mg, 0.2 mmol) give 3d as white soild (42
mg, 81%); mp 49-50℃, Rf = 0.65 (petroleum ether/ethyl acetate
The general procedure A. A flame dry 8 mL tube was charged
with oximes 1 (0.2 mmol), diethyl bromomalonate (2b) (57.4 mg,
0.24 mmol), Na2CO3 (21.2 mg, 0.2 mmol), Cu(OTf)2 (3.6 mg,
0.01mmol), 1,10-Phen (1.0mg, 0.01 mmol) in anhydrous MeCN (1
mL) under argon atmosphere. The resulting suspension was stirred
for 0.5-2 h at 80℃(block heaters). The mixture was extracted with
ethyl acetate (3 x 15 mL). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel to give the products 3.
The general procedure B. A flame dry 8 mL tube was charged
with oximes 1or 6 (0.2 mmol), NCS (32.0 mg, 0.24 mmol), Na2CO3
(21.2 mg, 0.2 mmol), Cu(OTf)2 (3.6 mg, 0.01mmol), 1,10-Phen
(1.0mg, 0.01 mmol) in anhydrous MeCN (1 mL) under argon
atmosphere. The resulting suspension was stirred for 0.5-5 h at 80
℃(block heaters). The mixture was extracted with ethyl acetate (3
x 15 mL). The combined organic layers were washed with brine
(10 mL), dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
to give the products 4 or 7.
1
5:1); H NMR (500 MHz, CDCl3) δ 7.69 – 7.63 (m, 2H), 7.15 –
7.06 (m, 2H), 5.05 – 4.95 (m, 1H), 3.58 (dd, J = 10.4, 4.2 Hz, 1H),
3.50 (dd, J = 17.0, 10.5 Hz, 1H), 3.41 (dd, J = 10.4, 8.2 Hz, 1H),
3.31 (dd, J = 17.0, 6.4 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3)
δ 163.9 (d, J = 250.0 Hz), 155.1, 128.8 (d, J = 8.5 Hz), 125.4 (d, J
= 3.4 Hz), 116.0 (d, J = 22.5Hz), 79.84, 39.7, 33.1. 19F NMR (400
MHz, CDCl3) δ -109.4. HRMS (ESI) m/z calcd for C10H10BrFNO
[M+H]+ : 257.9924, found 257.9927.
5-(Bromomethyl)-3-(4-chlorophenyl)-4,5-dihydroisoxazole (3e).1
Compound 3e was prepared following the general procedure A.
The reaction of 1e (39.1 mg, 0.2 mmol) give 3e as white soild (42.3
mg, 77%); mp 104-105℃, Rf = 0.58 (petroleum ether/ethyl acetate
5:1); 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.6, 2H), 7.37 (d,
J = 8.6, 2H), 5.05 – 4.97 (m, 1H), 3.57 (dd, J = 10.4, 4.2 Hz, 1H),
3.48 (dd, J = 17.0, 10.5 Hz, 1H), 3.41 (dd, J = 10.4, 8.1 Hz, 1H),
3.29 (dd, J = 17.0, 6.5 Hz, 1H).
5-(Bromomethyl)-3-(4-bromophenyl)-4,5-dihydroisoxazole (3f).5b
Compound 3f was prepared following the general procedure A. The
reaction of 1f (48.0 mg, 0.2 mmol) give 3f as white soild (48.1 mg,
73%); mp 109-110℃, Rf = 0.54 (petroleum ether/ethyl acetate 5:1);
1H NMR (500 MHz, CDCl3) δ 7.53 (s, 4H), 5.06 – 4.96 (m, 1H),
The general procedure C. A flame dry 8 mL tube was charged
with oximes 1 (0.2 mmol), NIS (53.9 mg, 0.24 mmol), Na2CO3
(21.2 mg, 0.2 mmol), Cu(OTf)2 (3.6 mg, 0.01mmol), 1,10-Phen
(1.0mg, 0.01 mmol) in anhydrous MeCN (1 mL) under argon
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The Journal of Organic Chemistry
3.58 (dd, J = 10.4, 4.2 Hz, 1H), 3.53 -3.37 (m, 2H), 3.29 (dd, J =
17.0, 6.5 Hz, 1H).
0.48 (petroleum ether/ethyl acetate 5:1); 1H NMR (500 MHz,
CDCl3) δ 9.63 (s, 1H), 7.39 – 7.30 (m, 1H), 7.21 (dd, J = 7.8, 1.6
Hz, 1H), 7.05 (dd, J = 8.3, 0.9 Hz, 1H), 6.99 – 6.88 (m, 1H), 5.03 –
4.94 (m, 1H), 3.66 – 3.54 (m, 2H), 3.48 – 3.38 (m, 2H). 13C{1H}
NMR (125 MHz, CDCl3) δ 158.1, 157.4, 132.1, 128.5, 119.7,
117.2, 113.5, 78.6, 39.8, 32.7. HRMS (ESI) m/z calcd for
C10H11BrNO2 [M+H]+ : 255.9977, found 255.9968.
1
2
3
4
5-(Bromomethyl)-3-(4-nitrophenyl)-4,5-dihydroisoxazole
(3g).5bCompound 3g was prepared following the general procedure
A. The reaction of 1g (41.2 mg, 0.2 mmol) give 3g as yellow soild
(51.5 mg, 90%); mp 159-160℃, Rf = 0.41 (petroleum ether/ethyl
5
6
7
8
1
acetate 3:1); H NMR (500 MHz, CDCl3) δ 8.32 – 8.21 (m, 2H),
5-(Bromomethyl)-3-(naphthalen-2-yl)-4,5-dihydroisoxazole (3n).2
Compound 3n was prepared following the general procedure A.
The reaction of 1n (42.2 mg, 0.2 mmol) give 3n as white soild (42.8
mg, 73%); mp 87-88℃, Rf = 0.61 (petroleum ether/ethyl acetate
5:1); 1H NMR (500 MHz, CDCl3) δ 7.97 (dd, J = 8.7, 1.7 Hz, 1H),
7.91 (s, 1H), 7.86 (dd, J = 8.3, 4.7 Hz, 3H), 7.57 – 7.50 (m, 2H),
5.10 – 5.02 (m, 1H), 3.68 – 3.58 (m, 2H), 3.50 – 3.41 (m, 2H).
7.90 – 7.77 (m, 2H), 5.16 – 5.06 (m, 1H), 3.61 (dd, J = 10.6, 4.1
Hz, 1H), 3.55 (dd, J = 17.0, 10.7 Hz, 1H), 3.47 (dd, J = 10.6, 7.9
Hz, 1H), 3.36 (dd, J = 17.0, 6.7 Hz, 1H).
5-(Bromomethyl)-3-(4-(trifluoromethyl)phenyl)-4,5-
9
dihydroisoxazole (3h). Compound 3h was prepared following the
general procedure A. The reaction of 1h (45.8 mg, 0.2 mmol) give
3h as white soild (59.8 mg, 97%); mp 68-69 ℃ , Rf = 0.48
(petroleum ether/ethyl acetate 5:1); 1H NMR (500 MHz, CDCl3) δ
7.78 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 5.11 – 5.01 (m,
1H), 3.60 (dd, J = 10.5, 4.1 Hz, 1H), 3.53 (dd, J = 17.0, 10.6 Hz,
1H), 3.45 (dd, J = 10.5, 7.9 Hz, 1H), 3.34 (dd, J = 17.0, 6.6 Hz,
1H). 13C{1H} NMR (125 MHz, CDCl3) δ 155.1, 132.5, 132.0(q, J
= 32.4 Hz), 127.0, 125.7 (q, J = 3.8 Hz), 124.8, 122.7, 80.2, 39.3,
33.1. 19F NMR (400 MHz, CDCl3) δ -62.9. HRMS (ESI) m/z calcd
for C11H10F3BrNO [M+H]+: 307.9898, found 307.9894.
Methyl4-(5-(Bromomethyl)-4,5-dihydroisoxazol-3-yl)benzoate (3i).
16 Compound 3i was prepared following the general procedure A.
The reaction of 1i (43.8 mg, 0.2 mmol) give 3i as white soild (55.6
mg, 93%); mp 135-137℃, Rf = 0.40 (petroleum ether/ethyl acetate
5:1); 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 8.4, 2H), 7.72 (d,
J = 8.5, 2H), 5.10 – 4.96 (m, 1H), 3.92 (s, 3H), 3.58 (dd, J = 10.4,
4.2 Hz, 1H), 3.52 (dd, J = 17.0, 10.6 Hz, 1H), 3.43 (dd, J = 10.4,
8.1 Hz, 1H), 3.33 (dd, J = 17.0, 6.6 Hz, 1H).
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13
14
15
16
17
18
19
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(Bromomethyl)-3-(thiophen-2-yl)-4,5-dihydroisoxazole
(3o).1
Compound 3o was prepared following the general procedure A.
The reaction of 1o (33.4 mg, 0.2 mmol) give 3o as yellow oil (36.2
mg, 73%); Rf = 0.41 (petroleum ether/ethyl acetate 5:1); 1H NMR
(500 MHz, CDCl3) δ 7.41 (dd, J = 5.1, 1.1 Hz, 1H), 7.23 (dd, J =
3.6, 1.1 Hz, 1H), 7.07 (dd, J = 5.1, 3.7 Hz, 1H), 5.04 – 4.95 (m,
1H), 3.61 – 3.48 (m, 2H), 3.40 (dd, J = 10.4, 8.4 Hz, 1H), 3.34 (dd,
J = 16.8, 6.4 Hz, 1H).
5-(Bromomethyl)-3-(4-bromophenyl)-4,4-dimethyl-4,5-
dihydroisoxazole (3p) . Compound 3p was prepared following the
general procedure A. The reaction of 1p (53.6 mg, 0.2 mmol) give
3p as white soild (64.8 mg, 93%); mp 71-72 ℃ , Rf = 0.62
(petroleum ether/ethyl acetate 5:1); 1H NMR (500 MHz, CDCl3) δ
7.56 – 7.51 (m, 2H), 7.50 – 7.46 (m, 2H), 4.48 (t, J = 6.7 Hz, 1H),
3.60 (dd, J = 10.8, 6.6 Hz, 1H), 3.52 (dd, J = 10.8, 6.8 Hz, 1H),
1.48 (s, 3H), 1.32 (s, 3H). 13C{1H}C NMR (125 MHz, CDCl3) δ
164.1, 132.0, 129.0, 127.8, 124.4, 89.5, 51.6, 27.5, 25.6, 18.9.
HRMS (ESI) m/z calcd for C12H14Br2NO [M+H]+ : 345.9437,
found 345.9442.
5-(Bromomethyl)-3-(3-nitrophenyl)-4,5-dihydroisoxazole
(3j).
Compound 3j was prepared following the general procedure A. The
reaction of 1j (41.2 mg, 0.2 mmol) give 3j as white soild (40.6 mg,
71%); mp 72-73℃, Rf = 0.48 (petroleum ether/ethyl acetate 5:1);
1H NMR (500 MHz, CDCl3) δ 8.43 (t, J = 1.9 Hz, 1H), 8.29 – 8.24
(m, 1H), 8.12 – 8.02 (m, 1H), 7.61 (t, J = 8.0 Hz, 1H), 5.15 – 5.05
(m, 1H), 3.64 – 3.52 (m, 2H), 3.47 (dd, J = 10.6, 7.7 Hz, 1H), 3.38
(dd, J = 17.0, 6.7 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ
154.5, 148.5, 132.3, 130.9, 129.9, 124.8, 121.6, 80.4, 39.2, 33.0.
HRMS (ESI) m/z calcd for C10H10BrN2O3 [M+H]+ : 284.9869,
found 284.9868.
5-(Bromomethyl)-5-methyl-3-phenyl-4,5-dihydroisoxazole (3q).1
Compound 3q was prepared following the general procedure A.
The reaction of 1q (35.0 mg, 0.2 mmol) give 3q as colorless oil (38
mg, 75%); Rf = 0.58 (petroleum ether/ethyl acetate 5:1); 1H NMR
(500 MHz, CDCl3) δ 7.72 – 7.57 (m, 2H), 7.49 – 7.31 (m, 3H), 3.58
– 3.45 (m, 3H), 3.13 (d, J = 17.0 Hz, 1H), 1.66 (s, 3H).
7-Bromo-3-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazole (3r).
Compound 3r was prepared following the general procedure A.
The reaction of 1r (40.2 mg, 0.2 mmol) give 3r as white soild (39.9
mg, 71%); mp 109-111℃, Rf = 0.63 (petroleum ether/ethyl acetate
5-(Bromomethyl)-3-(3,4-dimethoxyphenyl)-4,5-dihydroisoxazole
(3k). Compound 3k was prepared following the general procedure
A. The reaction of 1k (44.2 mg, 0.2 mmol) give 3k as white soild
(47.1 mg, 78%); mp 92-93℃, Rf = 0.32 (petroleum ether/ethyl
1
5:1); H NMR (500 MHz, CDCl3) δ 7.73 – 7.65 (m, 2H), 7.46 –
7.38 (m, 3H), 4.73 – 4.65 (m, 2H), 3.65 – 3.57 (m, 1H), 2.17 – 2.01
(m, 3H), 1.88 – 1.75 (m, 1H), 1.60 – 1.50 (m, 1H), 1.42 – 1.31 (m,
1H). 13C{1H} NMR (125 MHz, CDCl3) δ 163.9, 130.4, 128.9,
128.6, 127.1, 84.11, 47.1, 42.6, 29.7, 25.8, 18.0. HRMS (ESI) m/z
calcd for C13H15BrNO [M+H]+ : 280.0332, found 280.0331.
1
acetate 5:1); H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 1.9 Hz,
1H), 7.04 (dd, J = 8.3, 2.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 5.02
– 4.93 (m, 1H), 3.90 (s, 6H), 3.57 (dd, J = 10.3, 4.2 Hz, 1H), 3.49
(dd, J = 16.9, 10.4 Hz, 1H), 3.39 (dd, J = 10.3, 8.4 Hz, 1H), 3.30
(dd, J = 16.9, 6.3 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ
155.8, 151.1, 149.3, 121.9, 120.5, 110.6, 108.8, 79.6, 56.0 (d, J =
3.8 Hz), 39.8, 33.2, 29.7. HRMS (ESI) m/z calcd for C12H15BrNO3
[M+H]+ : 300.0229, found 300.0223.
5-(Bromomethyl)-3-phenethyl-4,5-dihydroisoxazole
(3s).17
Compound 3s was prepared following the general procedure A.
The reaction of 1s (37.8 mg, 0.2 mmol) give 3s as colorless oil (42.9
mg, 80%); Rf = 0.57 (petroleum ether/ethyl acetate 3:1); 1H NMR
(500 MHz, CDCl3) δ 7.35 – 7.27 (m, 2H), 7.25 – 7.18 (m, 3H), 4.84
– 4.70 (m, 1H), 3.43 (dd, J = 10.3, 4.2 Hz, 1H), 3.22 (dd, J = 10.3,
8.3 Hz, 1H), 3.04 (dd, J = 17.4, 10.3 Hz, 1H), 2.97 – 2.87 (m, J =
8.0, 2.8 Hz, 2H), 2.84 (dd, J = 17.4, 6.1 Hz, 1H), 2.68 (dd, J = 14.8,
7.1 Hz, 2H).
5-(Bromomethyl)-3-(o-tolyl)-4,5-dihydroisoxazole (3l). Compound
3l was prepared following the general procedure A. The reaction of
1l (35.0 mg, 0.2 mmol) give 3l as pale brown oil (30.4 mg, 60%);
Rf = 0.57 (petroleum ether/ethyl acetate 5:1); 1H NMR (500 MHz,
CDCl3) δ 7.37 – 7.22 (m, 4H), 5.00 – 4.91 (m, 1H), 3.63 – 3.52 (m,
2H), 3.47 – 3.33 (m, 2H), 2.56 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3) δ 156.9, 138.2, 131.7, 129.6, 128.9, 128.2, 1259, 78.6, 42.2,
5-(Chloromethyl)-3-phenyl-4,5-dihydroisoxazole
(4a).5c
Compound 4a was prepared following the general procedure B.
The reaction of 1a (32.2 mg, 0.2 mmol) give 4a as white soild (39.3
mg. 81%); mp 51-52℃, Rf = 0.37 (petroleum ether/ethyl acetate
33.3, 23.0. HRMS (ESI) m/z calcd for C11H13BrNO [M+H]+
254.0175, found 254.0178.
:
1
10:1). H NMR (500 MHz, CDCl3) δ7.68 – 7.66 (m, 2H), 7.43 –
5-(Bromomethyl)-3-(o-hydroxybenzene)-4,5-dihydroisoxazole
7.40 (m, 3H), 5.02 – 4.69 (m, 1H), 3.71 (dd, J = 11.3, 4.5 Hz, 1H),
3.58 (dd, J = 11.2, 7.4 Hz, 1H), 3.42 (dd, J = 17.0, 10.5 Hz,
1H),3.35 (dd, J = 17.0, 6.3 Hz, 1H).
(3m). Compound 3m was prepared following the general procedure
A with 0.4 mmol of Na2CO3 (42.4 mg). The reaction of 1m (35.4
mg, 0.2 mmol) give 3m as pale brown oil (21.0 mg, 41%); Rf =
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5-(Chloromethyl)-3-(p-tolyl)-4,5-dihydroisoxazole
(4b).1
129.9 , 126.6, 80.2 , 52.2 , 44.7 , 38.1 .HRMS (ESI) m/z calcd for
1
2
3
4
5
6
7
8
Compound 4b was prepared following the general procedure B.
The reaction of 1b (35.0 mg, 0.2 mmol) give 4b as white soild (45.0
mg. 97%); mp 76-77℃, Rf = 0.33 (petroleum ether/ethyl acetate
10:1). 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.21
(d, J = 7.9 Hz, 2H), 4.92 – 4.86 (m, 1H), 3.49 (dd, J = 17.0, 10.3
Hz, 1H), 3.40 (dd, J = 10.5, 4.1 Hz, 1H), 3.18 – 3.24 (m, 2H),2.38
(s, 3H).
C12H13ClNO3 [M+H]+ : 254.0578, found 254.0577.
5-(Chloromethyl)-3-(3-nitrophenyl)-4,5-dihydroisoxazole
(4j).
Compound 4j was prepared following the general procedure B. The
reaction of 1j (41.2 mg, 0.2 mmol) give 4j as white soild (37.2 mg,
78%); mp 84-85℃, Rf = 0.29 (petroleum ether/ethyl acetate 5:1);
1H NMR (500 MHz, CDCl3) δ 8.43 (t, J = 1.9 Hz, 1H), 8.26 (m,
1H), 8.11 – 8.00 (m, 1H), 7.61 (t, J = 8.0 Hz, 1H), 5.13 – 5.08 (m,
1H), 3.74 (dd, J = 11.5, 4.2 Hz, 1H), 3.65 (dd, J = 11.5, 6.8 Hz,
1H), 3.55 (dd, J = 17.0, 10.7 Hz, 1H), 3.40 (dd, J = 17.0, 6.7 Hz,
1H). 13C{1H} NMR (125 MHz, CDCl3) δ 154.5, 148.4, 132.2,
130.8, 129.8, 124.7, 121.5, 80.5, 44.8, 37.9. HRMS (ESI) m/z calcd
for C10H10ClN2O3 [M+H]+ : 241.0375, found 241.0373.
5-(Chloromethyl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazole
(4c).1 Compound 4c was prepared following the general procedure
B. The reaction of 1c (38.2 mg, 0.2 mmol) give 4c as white soild
(36.9 mg. 83%); mp 72-74℃, Rf = 0.36 (petroleum ether/ethyl
acetate 5:1). 1H NMR (500 MHz, CDCl3) δ 7.61 – 7.59 (d, J = 8.8
Hz, 2H), 6.92 – 6.90 (d, J = 8.8 Hz, 2H), 4,96 – 4.91 (m, 1H), 3.83
(s, 1H), 3.69 (dd, J = 11.2, 4.4 Hz, 1H), 3.55 (dd, J = 11.2, 7.5 Hz,
1H), 3.36 (dd, J = 16.9, 10.5 Hz, 1H), 3.30 (dd, J = 16.9, 6.3 Hz,
1H).
9
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12
13
14
15
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(3,4-dimethoxyphenyl)-5-(Chloromethyl)-4,5-dihydroisoxazole
(4k). Compound 4k was prepared following the general procedure
B. The reaction of 1k (44.2 mg, 0.2 mmol) give 4k as white soild
(39.8 mg, 78%); mp 74-76 ℃ , Rf = 0.21 (petroleum ether/ethyl
3-(4-fluorophenyl)-5-(Chloromethyl)-4,5-dihydroisoxazole (4d).1
Compound 4d was prepared following the general procedure B.
The reaction of 1d (35.8 mg, 0.2 mmol) give 4d as white soild (37.0
mg. 87%); mp 58-59℃, Rf = 0.30 (petroleum ether/ethyl acetate
acetate 5:1); H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 1.9 Hz,
1
1H), 7.04 (dd, J = 8.3, 2.0 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.99
– 4.91 (m, 1H), 3.90 (s, 6H), 3.69 (dd, J = 11.2, 4.3 Hz, 1H), 3.55
(dd, J = 11.2, 7.5 Hz, 1H), 3.47 (dd, J = 16.8, 10.4 Hz, 1H), 3.30
(dd, J = 16.8, 6.3 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ
155.8, 151.0, 149.1, 121.7, 120.4, 110.5, 108.7, 79.6, 55.8 (d, J =
3.2 Hz), 44.8, 38.6, 29.6. HRMS (ESI) m/z calcd for C12H15ClNO3
[M+H]+ : 256.0735, found 256.0739.
1
10:1). H NMR (500 MHz, CDCl3) δ 7.69 – 7.66 (m, 1H), 7.07 –
7.14 (m, 1H), 4.96 – 5.01 (m, 1H), 3.71 (dd, J = 11.3, 4.2 Hz, 1H),
3.57 (dd, J = 11.3, 7.3 Hz, 1H), 3.47 (dd, J = 16.9, 10.5 Hz, 1H),
3.32 (dd, J = 16.9, 6.5 Hz, 1H).
3-(4-chlorophenyl)-5-(Chloromethyl)-4,5-dihydroisoxazole (4e).1
Compound 4e was prepared following the general procedure B.
The reaction of 1e (39.1 mg, 0.2 mmol) give 4e as white soild (45.0
mg. 97%); mp 85-86℃, Rf = 0.32 (petroleum ether/ethyl acetate
10:1). 1H NMR (500 MHz, CDCl3) δ 7.59 (d. J =7.1 Hz, 2H), 7.37
(d, J = 7.1 Hz, 2H), 4.97 – 5.02 (m, 1H), 3.70 (dd, J = 9.5, 3.6 Hz,
1H), 3.58 (dd, J = 9.5, 6.0 Hz, 1H), 3.46 (dd, J = 14.0, 8.8 Hz, 1H),
3.30 (dd, J = 14.0, 5.4 Hz, 1H).
5-(chloromethyl)-3-(o-tolyl)-4,5-dihydroisoxazole (4l). Compound
4l was prepared following the general procedure B. The reaction of
1l (35.0 mg, 0.2 mmol) give 4l as light yellow oil (25.4 mg, 61%);
Rf = 0.28 (petroleum ether/ethyl acetate 10:1); 1H NMR (500 MHz,
CDCl3) δ 7.35 (dd, J = 7.6, 1.1 Hz, 1H), 7.33 – 7.23 (m, 3H), 4.96
– 4.91 (m, 1H), 3.61 – 3.53 (m, 2H), 3.72 (dd, J = 11.3, 4.3 Hz,
1H), 3.39 (dd, J = 16.9, 6.2 Hz, 1H), 2.56 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3) δ 156.9, 138.1, 131.6, 129.6, 128.9, 128.1,
125.9, 78.7, 44.9, 41.1, 22.8. HRMS (ESI) m/z calcd for
C11H13ClNO [M+H]+ : 210.0680, found 210.0680.
3-(4-bromophenyl)-5-(Chloromethyl)-4,5-dihydroisoxazole (4f).1
Compound 4f was prepared following the general procedure B. The
reaction of 1f (48.0 mg, 0.2 mmol) give 4f as white soild (51.7 mg,
95%); mp 105-106 ℃ , Rf = 0.30 (petroleum ether/ethyl acetate
2-(5-(Chloromethyl)-4,5-dihydroisoxazol-3-yl)phenol
(4m).
Compound 4m was prepared following the general procedure B
with 0.4 mmol of Na2CO3 (42.4 mg). The reaction of 1m (35.4 mg,
0.2 mmol) give 4m as white soild (30.6 mg, 73%); mp 67-68℃, Rf
= 0.37 (petroleum ether/ethyl acetate 10:1);1H NMR (500 MHz,
CDCl3) δ 9.64 (s, 1H), 7.38 – 7.30 (m, 1H), 7.21 (dd, J = 7.8, 1.6
Hz, 1H), 7.04 (dd, J = 8.3, 1.0 Hz, 1H), 6.94 (m, 1H), 5.01 – 4.96
(m, 1H), 3.73 (dd, J = 11.4, 4.4 Hz, 1H), 3.65 – 3.53 (m, 2H), 3.45
(dd, J = 16.9, 6.5 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ
158.1, 157.3, 132.0, 128.4, 119.6, 117.1, 113.5, 78.6, 44.5, 38.7.
HRMS (ESI) m/z calcd for C10H11ClNO2 [M+H]+ : 212.0472,
found 212.0474.
1
10:1); H NMR (500 MHz, CDCl3) δ 7.52 (s, 4H), 3.30 (dd, J =
16.9, 6.5 Hz, 1H), 5.02 – 4.96 (m, 1H), 3.70 (dd, J = 11.4, 4.3 Hz,
1H), 3.58 (dd, J = 11.3, 7.2 Hz, 1H), 3.46 (dd, J = 16.9, 10.5 Hz,
1H).
5-(Chloromethyl)-3-(4-nitrophenyl)-4,5-dihydroisoxazole (4g).18
Compound 4g was prepared following the general procedure B.
The reaction of 1g (41.2 mg, 0.2 mmol) give 4g as white soild (38.0
mg, 80%); mp 154-155℃, Rf = 0.38 (petroleum ether/ethyl acetate
1
3:1); H NMR (500 MHz, CDCl3) δ 8.32 – 8.20 (m, 2H), 7.89 –
7.79 (m, 2H), 5.12 – 5.07 (m, J = 10.9, 6.8, 4.1 Hz, 1H), 3.75 (dd,
J = 11.5, 4.1 Hz, 1H), 3.65 (dd, J = 11.5, 7.0 Hz, 1H), 3.53 (dd, J =
17.0, 10.7 Hz, 1H), 3.39 (dd, J = 17.0, 6.7 Hz, 1H).
5-(chloromethyl)-3-(naphthalen-2-yl)-4,5-dihydroisoxazole (4n).1
Compound 4n was prepared following the general procedure B.
The reaction of 1n (42.2 mg, 0.2 mmol) give 4n as white soild (34.9
mg, 71%); mp 78-79℃, Rf = 0.30 (petroleum ether/ethyl acetate
10:1); 1H NMR (500 MHz, CDCl3) δ 7.96 (dd, J = 8.7, 1.7 Hz, 1H),
7.91 (s, 1H), 7.88 – 7.81 (m, 3H), 7.57 – 7.48 (m, 2H), 5.07 – 5.00
(m, 1H), 3.75 (dd, J = 11.3, 4.4 Hz, 1H), 3.65 – 3.58 (m, 2H), 3.46
(dd, J = 16.8, 6.5 Hz, 1H).
5-(Chloromethyl)-3-(4-(trifluoromethyl)phenyl)-4,5-
dihydroisoxazole (4h).18 Compound 4h was prepared following the
general procedure B. The reaction of 1h (45.8 mg, 0.2 mmol) give
4h as white soild (50.3 mg, 95%); mp 79-80 ℃ , Rf = 0.36
(petroleum ether/ethyl acetate 10:1); 1H NMR (500 MHz, CDCl3)
δ 7.79 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 5.06 (m, 1H),
3.74 (dd, J = 11.4, 4.2 Hz, 1H), 3.62 (dd, J = 11.4, 7.2 Hz, 1H),
3.52 (dd, J = 17.0, 10.7 Hz, 1H), 3.37 (dd, J = 17.0, 6.6 Hz, 1H).
5-(chloromethyl)-3-(thiophen-2-yl)-4,5-dihydroisoxazole
(4o).1
Compound 4o was prepared following the general procedure B.
The reaction of 1o (33.4 mg, 0.2 mmol) give 4o as light yellow oil
(34.2 mg, 85%); Rf = 0.26 (petroleum ether/ethyl acetate 10:1);1H
NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 5.1, 1.1 Hz, 1H), 7.23 (dd,
J = 3.6, 1.1 Hz, 1H), 7.07 (dd, J = 5.1, 3.7 Hz, 1H), 5.01 – 4.96 (m,
1H), 3.71 (dd, J = 11.3, 4.3 Hz, 1H), 3.60 – 3.49 (m, 2H), 3.35 (dd,
J = 16.8, 6.4 Hz, 1H).
3-(4-bromophenyl)-5-(chloromethyl)-4,4-dimethyl-4,5-
dihydroisoxazole (4p). Compound 4p was prepared following the
general procedure B. The reaction of 1p (53.6 mg, 0.2 mmol) give
methyl
4-(5-(Chloromethyl)-4,5-dihydroisoxazol-3-yl)benzoate
(4i). Compound 4i was prepared following the general procedure
B. The reaction of 1i (43.8 mg, 0.2 mmol) give 4i as white soild
(42.5 mg, 84%); mp 124-126℃, Rf = 0.26 (petroleum ether/ethyl
1
acetate 5:1); H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 6.7 Hz,
2H), 7.71 (d, J = 8.6 Hz, 2H), 4.99 – 5.04 (m, 1H), 3.91 (s, 3H),
3.71 (dd, J = 11.3, 4.3 Hz, 1H), 3.60 (dd, J = 11.3, 7.1 Hz, 1H),
3.50 (dd, J = 16.9, 10.6 Hz, 1H), 3.34 (dd, J = 16.9, 6.6 Hz, 1H).
13C{1H} NMR (125 MHz, CDCl3) δ 166.3, 155.5 , 133.1 , 131.4 ,
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4p as white soild (45.5 mg, 76%); mp 61-62 ℃ , Rf = 0.30
(petroleum ether/ethyl acetate 10:1); 1H NMR (500 MHz, CDCl3)
δ 7.55 – 7.52 (m, 2H), 7.51 – 7.47 (m, 2H), 4.42 (t, J = 6.5 Hz, 1H),
3.78 (dd, J = 11.6, 6.2 Hz, 1H), 3.71 (dd, J = 11.6, 6.8 Hz, 1H),
1.48 (s, 3H), 1.33 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ
163.9, 131.9, 128.9, 127.6, 89.5, 51.3, 40.6, 25.5, 18.9. HRMS
(ESI) m/z calcd for C12H14BrClNO :[M+H]+ : 301.9941, found
301.9943.
1
2
3
4
5
6
7
8
NMR spectra (PDF).
AUTHOR INFORMATION
Corresponding Author
5-(chloromethyl)-5-methyl-3-phenyl-4,5-dihydroisoxazole (4q).1
Compound 4q was prepared following the general procedure B.
The reaction of 1q (35.04 mg, 0.2 mmol) give 4q as colorless oil
*X. Li. E-mail: xqli@zjut.edu.cn.
*X. Xu. E-mail: future@zjut.edu.cn.
9
1
(30.0 mg, 72%); H NMR (500 MHz, CDCl3) δ 7.70 – 7.62 (m,
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Author Contributions
2H), 7.43 – 7.27 (m, 3H), 3.61 (q, J = 11.2 Hz, 2H), 3.53 (d, J =
16.9 Hz, 1H), 3.16 – 3.05 (m, 1H), 1.62 (s, 3H).
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
7-iodo-3-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazole (4r).18
Compound 4r was prepared following the general procedure B.
The reaction of 1r (40.2 mg, 0.2 mmol) give 4r as white soild (31.9
mg, 68%); mp 89-90℃, Rf = 0.50 (petroleum ether/ethyl acetate
10:1);1H NMR (500 MHz, CDCl3) δ 7.69 – 7.68 (m, 2H), 7.42 (dd,
J = 5.1, 1.9 Hz, 3H), 4.59 – 4.53 (m, 2H), 3.61 – 3.56 (m, 1H), 2.13
– 1.93 (m, 3H), 1.86 – 1.72 (m, 1H), 1.56 – 1.46 (m, 1H), 1.42 –
1.31 (m, 1H).
ACKNOWLEDGMENT
This work was supported by National Key Research and
Development Program of China (2017YFC0210900).
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Compound 4s was prepared following the general procedure B. The
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1
mg,72%); Rf = 0.50 (petroleum ether/ethyl acetate 5:1); H NMR
(500 MHz, CDCl3) δ 7.34 – 7.28 (m, 2H), 7.23 (dd, J = 10.5, 4.5
Hz, 3H), 4.76 (m, 1H), 3.57 (dd, J = 11.2, 4.4 Hz, 1H), 3.39 (dd, J
= 11.2, 7.4 Hz, 1H), 3.03 (dd, J = 17.3, 10.4 Hz, 1H), 2.93 (td, J =
8.0, 2.9 Hz, 2H), 2.85 (dd, J = 17.3, 6.1 Hz, 1H), 2.69 (m, 2H).
13C{1H} NMR (125 MHz, CDCl3) δ 157.8, 140.2, 128.5, 128.2,
126.4, 78.6, 44.7, 40.8, 32.5, 29.1. HRMS (ESI) m/z calcd for
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1
mp 87-89℃, Rf = 0.43 (petroleum ether/ethyl acetate 10:1); H
NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.22 (d, J =
8.0 Hz, 2H), 4.94 – 4.88 (m, 1H), 3.50 (dd, J = 17.0, 10.3 Hz, 1H),
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5-(iodomethyl)-3-phenethyl-4,5-dihydroisoxazole (5b). Compound
5b was prepared following the general procedure C. The reaction
of 1s (37.8 mg, 0.2 mmol) give 5b as white soild (60.4 mg, 96%);
mp 54-55℃, Rf = 0.54 (petroleum ether/ethyl acetate 5:1); 1H NMR
(500 MHz, CDCl3) δ 7.34 – 7.28 (m, 2H), 7.23 (dd, J = 10.6, 4.6
Hz, 3H), 4.69 (m, 1H), 3.27 (dd, J = 10.0, 4.1 Hz, 1H), 3.07 – 2.99
(m, 2H), 2.93 (td, J = 8.0, 2.3 Hz, 2H), 2.74 (dd, J = 17.4, 6.2 Hz,
1H), 2.70 – 2.62 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ
157.5, 140.2, 128.6, 128.2, 126.4, 79.2, 43.2, 32.5, 29.2, 7.8.
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316.0193.
3-(chloromethyl)-5-phenyl-3,4-dihydro-2H-pyrrole 1-oxide (7).
Compound 7 was prepared following the general procedure B. The
reaction of 6 (35.0 mg, 0.2 mmol) give 7 as brown soild (30.9 mg,
74%); mp 90 – 91℃, Rf = 0.51 (ethyl acetate); 1H NMR (500 MHz,
CDCl3) δ 8.40 – 8.30 (m, 2H), 7.45 (dd, J = 5.3, 2.0 Hz, 3H), 4.54
(s, 1H), 4.38 (dd, J = 11.6, 4.3 Hz, 1H), 3.84 (dd, J = 11.6, 2.8 Hz,
1H), 3.27 – 3.03 (m, 2H), 2.45 – 2.33 (m, 1H), 2.28 (ddd, J = 15.7,
11.7, 5.7 Hz, 1H). 13C{1H} NMR (125 MHz, (CD3)2SO) δ 139.4,
130.1, 128.3, 126.89, 74.1, 45.6, 28.4, 18.9. HRMS (ESI) m/z calcd
for C11H13ClNO [M+H]+ : 210.0683, found 210.0680.
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