Halonium ion mediated synthesis of 2-halomethylene-3-oxoketoxime derivatives from isoxazoline N -oxides

Article abstract of DOI:10.1021/jo401283x

A protocol for the N-bromosuccinimide (NBS)- and trichloroisocyanuric acid (TCCA)-mediated synthesis of novel 2-halomethylene-3-oxoketoximes via one-pot halogenation/oxidation of isoxazoline N-oxide derivatives is described here. The keto functionality of 3-ketoximes was selectively reduced by lithiumaluminum hydride to synthesize an unprecedented type of Baylis-Hillman oxime, which underwent N-O coupling to produce new isoxazoline N-oxide derivative.

Full text of DOI:10.1021/jo401283x

Note
pubs.acs.org/joc
Halonium Ion Mediated Synthesis of 2‑Halomethylene-3-
oxoketoxime Derivatives from Isoxazoline N‑Oxides
Mustafa J. Raihan, R. R. Rajawinslin, Veerababurao Kavala, Chun-Wei Kuo, Ting-Shen Kuo, Chiu-Hui He,
Hsiu-Ni Huang, and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei116, Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: A protocol for the N-bromosuccinimide
(NBS)- and trichloroisocyanuric acid (TCCA)-mediated
synthesis of novel 2-halomethylene-3-oxoketoximes via one-
pot halogenation/oxidation of isoxazoline N-oxide derivatives
is described here. The keto functionality of 3-ketoximes was
selectively reduced by lithiumaluminum hydride to synthesize
an unprecedented type of Baylis−Hillman oxime, which
underwent N−O coupling to produce new isoxazoline N-oxide derivative.
espite the rising importance of 3-oxoketoximes as an
substituted 3-oxoketoxime (D, R = 4-NO2, X = Br). The
Dintermediate, the synthesis of the ketoxime derivatives is product was formed via the removal of the Ha of the
an existing challenge.1 The reported methodologies are plagued
intermediate B (pathway b, Scheme 1). This result is quite
exciting as it demonstrates an unprecedented methodology for
the synthesis of 2-halomethylene-substituted 3-oxoketoximes,
which are unknown in the literature. In the literature, protocols
for the preparation of similar analogues from the corresponding
diketones are plagued by the lack of selectivity.4 It is
noteworthy to mention here that the 2-methylene-substituted
diketones are well-known precursors for several pharmaceuti-
cally active target molecules and natural products.5 Moreover,
our 2-halomethylene-substituted 3-ketoximes have the potential
to act as an α,β-unsaturated ketone, α,β-unsaturated oxime and
vinyl bromide. This result demonstrates an unprecedented
utility of isoxazoline N-oxide.
Encouraged by this preliminary observation, we conducted a
search for the most favorable conditions for this conversion
(Table 1). To pursue this goal, we replaced NBS with TCCA to
observe the effect of the halogen atom on this transformation
(entry 2). We isolated the intermediate and passed through a
silica gel column. In this case, our desired oxoketoxime was
obtained as the major product. The increment of the yield from
bromo to chloro derivative is probably due to the higher
electronegativity of the chlorine atom compared to the bromine
atom, and this fact facilitates the removal of the proton (Ha,
Scheme 1) in the case of the chloro derivative (B, X = Cl).
Because of the faster removal of the proton, the ketoxime (D)
derivative was formed at a faster rate than the diketohalocyano
(C) derivative. Hence, to enhance the rate of removal of the
proton, we treated the intermediate (B, X = Cl) with the
inorganic base, sodium bicarbonate (entry 3). However, the
desired product was obtained in moderate yield along with a
significant amount of the long-chain diketohalocyano com-
by the use of strong bases, complex combination of reagents,
multistep reactions, and low productivity.1 For these reasons,
the variation in the 3-oxoketoxime family is limited. Hence, to
introduce further diversity and expand this area, a new source
of starting material and a more convenient protocol are needed.
On the other hand, although significant progress has been
made on the development of new and novel protocols for the
synthesis of isoxazoline N-oxide derivatives, the utilities of the
N-oxides are less explored.2,3 Most of the reports describe the
reduction of the N-oxides into β-hydroxyamines, synthesis of
isoxazoline derivatives, 1, 2-addition at the C−N bond, and
cycloaddition at the CNO moiety.2 We also utilized isoxazoline
N-oxide derivatives to achieve substituted cinnamaldehyde
derivative and highly functionalized long-chain diketohalocyano
skeletons (C, Scheme 1).3 However, more efforts are necessary
to diversify the application of these N-oxides. Keeping these
points in mind, we report herein the NBS- and TCCA-
mediated synthesis of 2-halomethylene-3-oxo-ketoxime deriva-
tives from cyclohexene fused isoxazoline N-oxides.
In our recent publication on the halonium ion mediated C−
C bond cleavage of isoxazoline N-oxide (A), we envisaged that
the long-chain diketohalocyano skeleton (C, Scheme 1) was
formed via a nitric oxide intermediate (B).3a In an attempt to
collect further evidence for the formation of the intermediate,
we isolated the intermediate B (Scheme 1, when R = 4-NO2, X
= Br) and passed it through a silica gel column. However, on
eluting with a mixture of hexane and ethyl acetate, we did not
achieve our desired intermediate. The intermediate was
converted into, mainly, diketohalocyano compound (C, when
R = 4-NO2, X = Br), and in addition to that a minor amount of
white solid was obtained as a byproduct (entry 1, Table 1). 1H
and 13C NMR, mass, and single-crystal X-ray structures (Figure
1) showed that the white solid is a 2-bromomethylene-
Received: June 14, 2013
Published: August 14, 2013
© 2013 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 1. Base-Mediated Formation of the 3-Oxo-ketoxime
Table 1. Effect of Different Reagents
a,b
yield (%)
entry
[X]+
reagent
solvent
time
D
C
c
c
d
1
2
3
4
5
6
7
NBS
silica gel
silica gel
nd
27
71
55
63
38
62
61
83
89
59
16
9
d
TCCA
TCCA
TCCA
TCCA
TCCA
TCCA
TCCA
NBS
nd
NaHCO3 (0.25 equiv)
NaHCO3(1.10 equiv)
aq. NaHCO3 (0.25 equiv)
NaHCO3 (0.25 equiv)
NaHCO3 (1.0 equiv)
Et3N (0.30 equiv)
CH3CN
CH3CN
CH3CN
MeOH
MeOH
CH3CN
CH3CN
CH3CN
CHCl3
3.5 h
3.5 h
12 h
7 h
15
27
7
e
d
5 h
nd
f
8
5 min
5 min
40 h
12 h
40 h
f
9
Et3N (0.30 equiv)
g
10
NBS
74
88
49
g
11
NBS
g
12
TCCA
CH3CN
a
b
Yields refer to isolated and purified compounds. Unless otherwise stated, standard reaction conditions: 1 (0.5 mmol), NBS (1.1 equiv) or TCCA
c
(0.37 equiv), solvent (3 mL), rt, 3 min then base was added. The reaction was quenched with water and extracted with ethyl acetate. The
intermediate was passed through a silica gel column. nd = not determined. 1 M aq solution of NaHCO3 was used. Compound B was not found in
the crude H NMR. Reference 3a.
d
e
f
g
1
With the optimized conditions in hand, we explored the
scope of the methodology with NBS and TCCA. To pursue
this goal, we examined the effect of substitution on the phenyl
ring (Table 2). In the case of NBS treatment, the products were
obtained in good to excellent yields in the presence of an
electron-withdrawing group at the para- and meta-positions of
the phenyl ring (entries 1, 3, and 5). However, when the phenyl
ring contains o-NO2 functionality, the desired 3-oxoketoximes
were acquired in fewer yields (entries 11 and 13). The products
were obtained in moderate yields in the casess of halo-
substituted derivatives (entries 7, 13, 15, and 17). The
isoxazoline N-oxide with unsubstituted phenyl ring also
produced the expected ketoxime in moderate yield (entry 9).
In contrast to NBS treatment of isoxazoline N-oxides, a slight
different trend was observed with TCCA. The o- (entry 2) and
p-NO2 derivatives (entry 12) afforded the desired products in
good yields. However, the reaction offered the products in
lower yields in the cases of m-NO2 and p-CN derivatives
(entries 4 and 6). In the presence of halo substitution, the
Figure 1. Single-crystal X-RD structure of 1a.
pound (C). The result was not improved on varying the
amount of base (entries 4 and 5) or by changing the solvent
from acetonitrile to methanol (entries 6 and 7). Then, we used
the organic base triethylamine and observed a dramatic
increment of the product yield (entry 8). Similar results were
attained in the case of bromo derivative as well (entry 9).
Hence, the scope of the methodology was evaluated by using
triethylamine as base and acetonitrile as solvent.
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Note
Table 2. NBS and TCCA Treatment of Different Cyclohexene-Fused Isoxazoline N-Oxide Derivatives
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The Journal of Organic Chemistry
Note
Table 2. continued
a
b
Yields refer to isolated and purified compounds. Unless otherwise stated, standard reaction conditions: N-oxide (0.5 mmol), NBS (1.1 equiv) or
c
d
TCCA (0.37 equiv), solvent (3 mL), rt for 1 or 3 min then base was added. Base was added after 3 min of NBS/TCCA treatment. Base was added
after 1 min of NBS/TCCA treatment.
products were achieved in moderate yields (entries 8, 14, 16,
and 18), and the results are comparable with the outcome of
NBS treatment (entries 7, 13, 15, and 17). For the
unsubstituted phenyl ring, the yield of the desired 3-
oxoketoxime was similar to the results attained from the NBS
treatment of the same isoxazoline N-oxide derivative.
Scheme 2. NBS and TCCA Treatment of 4,4-
Dimethylcyclohexene-Fused Isoxazoline N-Oxide Derivative
In order to extend the scope of our protocol, we treated 4,4-
dimethyl-substituted cyclohexene fused isoxazoline N-oxide
derivative with NBS and TCCA (Scheme 2). In both cases, the
product was obtained in good yields; however, NBS was found
to be more productive than TCCA.
After studying various cyclohexene fused isoxazoline N-oxide
derivatives, we treated 4-methyleneisoxazoline N-oxide deriva-
tive with NBS and TCCA (Scheme 3), and the corresponding
halomethylene derivatives were obtained in good yields.
After evaluating the scope of our protocol, we focused our
attention toward exploring the synthetic application of our 3-
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The Journal of Organic Chemistry
Note
Scheme 3. NBS and TCCA Treatment of 3-Methyl-4-
methyleneisoxazoline N-Oxide Derivative
Figure 2. Crystal structure of compound 1c.
constants (Hz), and integration. IR spectra were recorded on an FT-IR
spectrometer and are reported in cm−1. Melting points were recorded
using an electrothermal capillary melting point apparatus and are
uncorrected. HRMS spectra were recorded using ESI-TOF or EI+
mode. Isoxazoline N-oxides were synthesized by following the
procedure depicted in our previous publication.3b
Representative Procedure for Preparation of 3-Oxoketox-
ime Derivatives. To a stirred solution of isoxazoline N-oxide
derivative (0.5 mmol) in CH3CN (4 mL) in a 50 mL round-bottom
flask was added NBS (1.1 equiv) or TCCA (0.37 equiv) at ambient
temperature. The reaction was monitored by TLC. After complete
conversion of the starting material into the intermediate (3 min for
1a/b to 5a/b and 1 min for 6a/b to 9a/b), triethylamine (30 mol %)
was added to the reaction mixture and the reaction was monitored by
TLC. After completion of the reaction, the reaction mixture was added
to 15 mL of brine solution and the organic layer was extracted with
ethyl acetate (15 mL × 3). The combined organic layer was dried over
magnesium sulfate, and the solvent was evaporated at reduced
pressure. The resulting residue was further purified by column
chromatography.
Procedure for the Reduction of 1a. To a stirred solution of
compound 1a (0.5 mmol) in dry THF (3 mL) under N2 at 0 to −5 °C
in a two-necked round-bottom flask was added LAH (0.75 mmol) in
small pinches. The reaction mixture was stirred for 10 min, and then it
was quenched with water. Ten milliliters of brine water was added to
the reaction mixture, and then the reaction mixture was extracted with
ethyl acetate. The solvent was evaporated, and the crude reaction
mixture was purified with column chromatography.
oxoketoxime. In the literature, we found that both keto and
oxime functionalities are prone to undergo reduction with
suitable reducing agent.6 In our case, to reduce the keto group
selectively, we treated the compound 1a with lithium aluminum
hydride, and we were pleased to find that 3-hydroxyketoxime
(1c) was formed (Scheme 4 and Figure 2). This result is very
important and interesting as it produces a special type of
Baylis−Hillman oxime, which contains a 3-bromo functionality.
There is no reported method in the literature that describes the
synthesis of such compound.7 On treating compound 1c with
HTIB in MeOH, the corresponding isoxazoline N-oxide was
formed. This isoxazoline N-oxide is new in the literature as it
contains halo functionality at cyclohexene ring.2,3
Next, we protected the OH functionality of compound 1a
with acetate to obtain the Baylis−Hillman oxime acetate
(Scheme 5). However, on treatment with LAH, compound 1e
underwent acetate deprotection and reduction to produce
compound 1c in poor yield.
In conclusion, here we have demonstrated an unprecedented
halonium ion and base-mediated transformation of isoxazoline
N-oxide derivatives into 3-oxoketoximes. The reaction occurs
via the nitric oxide intermediate. The base-mediated removal of
a proton from the nitric oxide intermediate produces the
ketoxime derivatives. Selective reduction of the keto function-
ality of the 3-oxoketoxime produces a novel type of Baylis−
Hillman oxime derivative.
Compound 1e was prepared by the acetylation of compound 1a,
following our previous report.3b
(E)-(2-Bromo-6-(hydroxyimino)cyclohex-1-enyl)(4-nitrophenyl)-
methanone (1a): light yellow solid (151.1 mg, 89%); mp 144−146
1
°C; IR (KBr, cm−1) 1685, 1606, 1527, 1344; H NMR (400 MHz,
EXPERIMENTAL SECTION
■
CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.32 (s,
1H), 2.85 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.03 (pentet, J =
6.4 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ 192.9, 155.9, 150.9,
139.9, 135.8, 130.5, 130.3, 124.3, 36.1, 21.9, 21.1; MS (FAB) m/z
(relative intensity): 339 (M++1, 87), 337 (78), 257 (11), 241 (5);
HRMS (ESI) calcd for C13H12N2O479Br ([M + H]+): 338.9980, found
338.9986.
General Information. Reagents and solvents were purchased from
various commercial sources and were used directly without any further
purification unless otherwise stated. Column chromatography was
performed with 63−200 mesh silica gel. H and 13C NMR spectra
1
were recorded at 400 and 100 MHz, respectively. Chemical shifts are
reported in parts per million (δ) using TMS and chloroform as
internal standards, and coupling constants are expressed in hertz. Data
are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, m = multiplet, br = broad singlet), coupling
(E)-(2-Bromo-6-(hydroxyimino)cyclohex-1-enyl)(3-nitrophenyl)-
methanone (2a): colorless solid (149.0 mg, 88%); mp 156−158 °C;
1
IR (KBr, cm−1) 1637, 1535, 1344; H NMR (400 MHz, CDCl3) δ
Scheme 4. Preparation of 4-Bromomethyleneisoxazoline N-Oxide
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The Journal of Organic Chemistry
Note
Scheme 5. Reduction of OH-Protected 3-Oxoketoxime
8.67 (t, J = 1.7 Hz, 1H), 8.42 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 8.23−8.21
(m, 1H), 7.71−7.67 (m, 1H), 7.35 (s, 1H), 2.85 (t, J = 6.1 Hz, 2H),
2.75 (t, J = 6.6 Hz, 2H), 2.03 (pentet, J = 6.4 Hz, 2H); 13C NMR (400
MHz, CDCl3) δ 192.5, 155.7, 148.9, 136.9, 135.4, 134.9, 130.5, 130.3,
128.1, 124.3, 36.1, 21.8, 21.1; MS (EI) m/z (relative intensity) 338
(M+, 24), 321 (100), 293 (43), 249 (51), 231 (76), 215 (56); HRMS
(ESI) calcd for C13H11N2O479Br (M+) 337.9902, found 337.9907.
(E)-4-(2-Bromo-6-(hydroxyimino)cyclohex-1-enecarbonyl)-
benzonitrile (3a): colorless solid (145.5 mg, 91%); mp 149−151 °C;
372.9587, calcd for C13H11N2O435Cl81Br ([M + H]+): 374.9570, found
374.9550.
(E)-(2-Bromo-6-(hydroxyimino)cyclohex-1-enyl)(2,4-
dichlorophenyl)methanone (8a): colorless solid (127.7 mg, 70%);
1
mp 138−140 °C; IR (KBr, cm−1) 1638, 1462, 1343; H NMR (400
MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.46 (d, J = 2.0
Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 2.77 (t, J = 6.2 Hz, 2H), 2.71−
2.67 (m, 2H), 1.94 (pentet, J = 6.4 Hz, 2H); 13C NMR (400 MHz,
CDCl3) δ 191.4, 155.6, 139.4, 137.3, 135.1, 133.5, 133.2, 131.6, 129.9,
127.6, 36.4, 21.6, 21.2; HRMS (ESI) calcd for C13H11NO279Br35Cl2
([M + H]+) 361.9350, found 361.9359, calcd for C13H11NO281Br35Cl2
1
IR (KBr, cm−1) 1638, 1404, 1299; H NMR (400 MHz, CDCl3) δ
7.96 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 2.82 (t,
J = 6.1 Hz, 2H), 2.71 (t, J = 6.7 Hz, 2H), 2.03−1.97 (m, 2H); 13C
NMR (400 MHz, CDCl3) δ 193.2, 155.7, 138.5, 135.7, 132.9, 130.2,
129.8, 118.1, 117.0, 36.1, 21.8, 21.1; MS (ESI) m/z (relative intensity)
319 (M+ + 1, 100), 280 (20), 262 (13); HRMS (ESI) calcd for
C14H12N2O279Br ([M + H]+) 319.0082, found 319.0089.
(E)-(2-Bromo-6-(hydroxyimino)cyclohex-1-enyl)(3-bromophenyl)-
methanone (4a): colorless solid (121.1 mg, 65%); mp 144−146 °C;
IR (KBr, cm−1) 1670, 1636, 1421, 1343; 1H NMR (400 MHz, CDCl3)
δ 8.02 (t, J = 1.8 Hz, 1H), 7.78 (dt, J = 7.8, 1.3 Hz, 1H), 7.76 (s, 1H),
7.69 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 2.81 (t, J
= 6.2 Hz, 2H), 2.70 (t, J = 6.7 Hz, 2H) 1.98 (pentet, J = 6.4 Hz, 2H);
13C NMR (400 MHz, CDCl3) δ 193.2, 155.6, 137.3, 136.8, 135.9,
([M
+
H]+ ) 363.9329, found 363.9337, calcd for
C13H11NO281Br37Cl35Cl ([M + H]+) 365.9299, found 365.9310,
calcd for C13H11NO281Br37Cl2 ([M + H]+) 367.9269, found 367.9288.
(E)-(2-Bromo-6-(hydroxyimino)cyclohex-1-enyl)(2-bromophenyl)-
methanone (9a): colorless solid (124.3 mg, 67%); mp 119−121 °C;
IR (KBr, cm−1) 1639, 1428, 1226; H NMR (400 MHz, CDCl3) δ
1
7.79 (dd, J = 7.6, 2.0 Hz, 1H), 7.67 (dd, J = 7.8, 1.4 Hz, 1H), 7.49 (s,
1H), 7.38 (dt, J = 7.6, 1.6 Hz, 1H), 7.33 (dt, J = 7.6, 1.9 Hz, 1H), 2.77
(t, J = 6.2 Hz, 2H), 2.71 (t, J = 7.0 Hz, 2H), 1.96 (pentet, J = 6.5 Hz,
2H); 13C NMR (400 MHz, CDCl3) δ 192.7, 155.5, 136.9, 136.1,
135.1, 133.2, 132.6, 129.9, 127.3, 122.1, 36.3, 21.5, 21.1; HRMS (ESI)
calcd for C13H12NO279Br2 ([M + H]+) 371.9235, found 371.9241,
calcd for C13H12NO279Br81Br ([M + H]+) 373.9214, found 373.9218,
calcd for C13H12NO281Br2 ([M + H]+) 375.9193, found 375.9204.
(E)-(2-Bromo-6-(hydroxyimino)-3,3-dimethylcyclohex-1-enyl)(4-
nitrophenyl)methanone (10a): colorless solid (157.5 mg (inseparable
mixture of E and Z (6:1), 86%); mp 181−183 °C; IR (KBr, cm−1)
3431, 1639; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.6 Hz, 2H),
8.02 (d, J = 8.6 Hz, 2H), 2.81−2.78 (m, 2H), 1.95 (t, J = 6.8 Hz, 2H),
1.31 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 192.5, 154.3, 150.3,
139.2, 139.1, 135.3, 130.2, 124.3, 38.3, 34.7, 18.6; HRMS (EI) calcd
for C15H15N2O479Br ([M]+) 366.0215, found 366.0213, calcd for
C15H15N2O481Br ([M]+) 368.0195, found 368.0189.
132.2, 130.6, 129.8, 128.3, 123.3, 36.1, 21.9, 21.1; HRMS (ESI) calcd
for C13H12NO279Br2 ([M + H]+) 371.9235, found 371.9245, calcd for
C13H12NO279Br81Br ([M + H]+) 373.9214, found 373.9212, calcd for
C13H12NO281Br2 ([M + H]+) 375.9193, found 375.9193.
(E)-(2-Bromo-6-(hydroxyimino)cyclohex-1-enyl)(phenyl)-
methanone (5a): colorless solid (107.0 mg, 73%); mp 132−134 °C;
1
IR (KBr, cm−1) 1672, 1638, 1448, 1346, 1309, 1241; H NMR (400
MHz, CDCl3) δ 7.88 (d, J = 7.4 Hz, 2H), 7.79 (s, 1H), 7.57 (t, J = 7.4
Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 6.1 Hz, 2H), 2.69 (t, J =
6.6 Hz, 2H), 1.97 (pentet, J = 6.4 Hz, 2H); 13C NMR (400 MHz,
CDCl3) δ 194.6, 155.5, 136.4, 135.4, 133.9, 129.6, 129.3, 128.9, 36.1,
21.9, 21.1; HRMS (ESI) calcd for C13H13NO279Br ([M + H]+)
294.0129, found 294.0134, calcd for C13H13NO281Br ([M + H]+)
296.0108, found 296.0121.
(E)-(2-Bromo-6-(hydroxyimino)cyclohex-1-enyl)(2-nitrophenyl)-
methanone (6a): light brown solid (128.6 mg, 76%); mp 110−112
°C; IR (KBr, cm−1) 1640, 1533, 1348; 1H NMR (400 MHz, CDCl3) δ
7.78−7.76 (m, 1H), 7.67−7.59 (m, 3H), 7.33 (br, 1H), 2.81 (t, J = 6.1
Hz, 2H), 2.71 (t, J = 6.7 Hz, 2H), 1.96 (pentet, J = 6.4 Hz, 2H); 13C
NMR (400 MHz, DMSO) δ 190.7, 154.3, 149.0, 135.3, 134.9, 132.6,
131.9, 128.9, 126.3, 123.6, 35.4, 21.2, 20.5; MS (ESI) m/z (relative
intensity) 341 [(M+ + 2) + 1, 100], 339 (M++1, 97), 305 (40), 300
(27), 259 (83), 231 (37); HRMS (ESI) calcd for C13H12N2O479Br
([M + H]+) 338.9980, found 338.9988, calcd for C13H12N2O481Br ([M
+ H]+) 340.9959, found 340.9975.
(E)-(2-Bromo-6-(hydroxyimino)cyclohex-1-enyl)(5-chloro-2-
nitrophenyl)methanone (7a): colorless solid (106.5 mg, 57%); mp
128−130 °C; IR (KBr, cm−1) 1637, 1539, 1377; 1H NMR (400 MHz,
DMSO) δ 11.43 (s, 1H), 7.98 (m, 2H), 7.96 (m 1H), 2.81 (t, J = 5.9
Hz, 2H), 2.63 (t, J = 6.5 Hz, 2H), 1.89 (pentet, J = 6.1 Hz, 2H); 13C
NMR (400 MHz, DMSO) δ 189.7, 154.5, 147.5, 136.4, 134.8, 134.6,
131.3, 130.2, 128.6, 125.7, 35.5, 21.1, 20.5; MS (ESI) m/z (relative
intensity) 375 [(M+ + 2) + 1, 23], 373 (M+ + 1, 17), 322 (3); HRMS
(ESI) calcd for C13H11N2O435Cl79Br ([M + H]+) 372.9591, found
2-(Bromomethylene)-3-(hydroxyimino)-1-(4-nitrophenyl)butan-
1
1-one (11a): colorless solid (127.7 mg, 82%); mp 149−151 °C; H
NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.38−8.35 (m, 2H),
8.11−8.08 (m, 2H), 7.49 (s, 1H), 2.09 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 193.1, 154.1, 150.3, 143.4, 139.1, 130.1, 124.3, 111.3, 9.7;
HRMS (EI) calcd for C11H9N2O479Br ([M]+) 311.9746, found
311.9743, calcd for C11H9N2O481Br ([M]+) 313.9725, found 313.9769.
(E)-(2-Chloro-6-(hydroxyimino)cyclohex-1-enyl)(4-nitrophenyl)-
methanone (1b): colorless solid (122.0 mg, 83%); mp 172−174 °C;
IR (KBr, cm−1) 1683, 1626, 1527, 1346; 1H NMR (400 MHz, CDCl3)
δ 8.28 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.87 (s, 1H), 2.69
(t, J = 6.4 Hz, 4H), 2.01 (pentet, J = 6.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 192.5, 155.5, 150.9, 140.2, 139.6, 132.7, 130.4, 124.2,
33.7, 21.1, 21.0; MS (FAB) m/z (relative intensity) 295 (M++1, 100),
262 (7), 227 (15), 184 (13); HRMS (FAB) calcd for C13H12N2O435Cl
([M + H]+) 295.0486, found 295.0489.
(E)-(2-Chloro-6-(hydroxyimino)cyclohex-1-enyl)(3-nitrophenyl)-
methanone (2b): colorless solid (109.6 mg, 74%); mp 165−167 °C;
1
IR (KBr, cm−1) 1634, 1534, 1344; H NMR (400 MHz, CDCl3) δ
8.65 (t, J = 1.8 Hz, 1H), 8.42 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 8.20 (dd,
J = 6.7, 1.1 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.52 (s, 1H), 2.71 (m,
4H), 2.03 (pentet, J = 6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
191.9, 155.5, 148.9, 139.7, 137.2, 134.8, 132.5, 130.3, 128.1, 124.2,
33.7, 21.1, 21.0; MS (FAB) m/z (relative intensity) 294 (M+, 13), 277
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Note
(61), 231 (51), 203 (48); HRMS (FAB) calcd for C13H11N2O435Cl
(M+) 294.0407, found 294.0414.
(relative intensity) 332 [(M+ + 4) + 1, 32], 330 [(M+ + 2) + 1, 92],
328 [(M+ + 1, 76], 314 (100), 312 (85); HRMS (FAB) calcd for
C13H11NO235Cl79Br ([M + H]+) 327.9740, found 327.9748, calcd for
C13H11NO235Cl81Br ([M + H]+) 329.9719, found 329.9734, calcd for
C13H11NO237Cl81Br ([M + H]+) 331.9689, found 331.9707.
(E)-(2-Chloro-6-(hydroxyimino)-3,3-dimethylcyclohex-1-enyl)(4-
nitrophenyl)methanone (10b): colorless solid (115.8 mg, 72%); mp
146−148 °C; IR (KBr, cm−1) 3345, 2963, 1686, 1527, 1347; 1H NMR
(400 MHz, CDCl3) δ 8.30−8.27 (m, 2H), 7.99−7.97 (m, 2H), 7.74
(br, 1H), 2.75 (t, J = 6.8 Hz, 2H), 1.89 (t, J = 6.8 Hz, 2H), 1.30 (s,
6H); 13C NMR (100 MHz, DMSO-d6) δ 192.2, 154.1, 150.4, 144.8,
139.6, 132.4, 130.2, 124.4, 37.6, 34.9, 26.2, 18.6; HRMS (EI) calcd for
C15H15N2O435Cl (M+) 322.0720, found 322.0711.
(E)-4-((2-Chloro-6-(hydroxyimino)cyclohex-1-enyl)(hydroxy)-
methyl)benzonitrile (3b): light yellow solid (102.5 mg, 75%); mp
172−174 °C; IR (KBr, cm−1) 1635, 1406, 1350; 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.54 (s,
1H), 2.71−2.66 (m, 4H), 2.01 (pentet, J = 6.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 192.5, 155.4, 139.2, 138.7, 132.7, 132.6, 129.6,
117.9, 116.9, 33.5, 20.9, 20.8; MS (FAB) m/z (relative intensity): 275
(M+ + 1, 63), 185 (50), 154 (100), 136 (81); HRMS (FAB) calcd for
C14H12N2O235Cl ([M + H]+) 275.0587, found 275.0585.
(E)-(3-Bromophenyl)(2-chloro-6-(hydroxyimino)cyclohex-1-enyl)-
methanone (4b): colorless solid (110.1 mg, 67%); mp 162−164 °C;
1
IR (KBr, cm−1) 1636, 1421, 1350; H NMR (400 MHz, CDCl3) δ
2-(Chloromethylene)-3-(hydroxyimino)-1-(4-nitrophenyl)butan-
1-one (11b): colorless solid (103.0 mg, 77%); mp 131−133 °C; IR
8.01 (t, J = 1.7 Hz, 1H), 7.77 (dt, J = 7.8, 1.3 Hz, 1H), 7.71 (s, 1H),
7.70−7.68 (m, 1H), 7.34 (t, J = 7.8 Hz, 1H), 2.71−2.65 (m, 4H),
2.02−1.96 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 192.7, 155.5,
138.9, 137.7, 136.8, 132.9, 132.2, 130.6, 128.2, 123.3, 33.7, 21.2, 21.0;
MS (FAB) m/z (relative intensity): 332 [(M+ + 4) + 1, 24], 330 [(M+
+ 2) + 1, 75], 328 [(M+ + 1, 62], 314 (100), 312 (89); HRMS (FAB)
calcd for C13H11NO235Cl79Br ([M + H]+) 327.9740, found 327.9748,
calcd for C13H11NO235Cl81Br ([M + H]+) 329.9719, found 329.9734,
calcd for C13H11NO237Cl81Br ([M + H]+) 331.9689, found 331.9698.
(E)-(2-Chloro-6-(hydroxyimino)cyclohex-1-enyl)(phenyl)-
methanone (5b): colorless solid (92.4 mg, 74%); mp 147−149 °C; IR
(KBr, cm−1) 1668, 1637, 1352, 1240; 1H NMR (400 MHz, CDCl3) δ
7.89 (s, 1H), 7.87 (s, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz,
2H), 2.68−2.66 (m, 2H), 2.65−2.63 (m, 2H), 1.98 (pentet, J = 6.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 194.0, 155.4, 138.4, 135.8,
134.0, 133.5, 129.5, 128.9, 33.7, 21.2, 21.1; MS (FAB) m/z (relative
intensity) 250 (M+ + 1, 100), 154 (88), 136 (58); HRMS (FAB) calcd
for C13H13NO235Cl ([M + H]+) 250.0635, found 250.0639.
(E)-(2-Chloro-6-(hydroxyimino)cyclohex-1-enyl)(2-nitrophenyl)-
methanone (6b): brown solid (121.8 mg, 83%); mp 112−114 °C; IR
(KBr, cm−1) 1724, 1683, 1637, 1535; 1H NMR (400 MHz, DMSO-d6)
δ 11.4 (s, 1H), 7.97−7.95 (m, 1H), 7.87−7.86 (m, 2H), 7.81−7.76 (m,
1H), 2.66 (t, J = 6.1 Hz, 2H), 2.60 (t, J = 6.6 Hz, 2H), 1.91 (pentet, J =
6.3 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 190.1, 154.1, 148.9,
137.9, 134.9, 132.6, 132.5, 131.9, 127.1, 123.6, 33.0, 20.5, 20.4; HRMS
(ESI) calcd for C13H10N2O435Cl ([M − H]−) 293.0329, found
293.0324.
1
(KBr, cm−1) 3695, 1687, 1525; H NMR (400 MHz, DMSO-d6):
11.66 (s, 1H), 8.38−8.35 (m, 2H), 8.11−8.08 (m, 2H), 7.35 (s, 1H),
2.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.4, 153.3, 150.4,
140.9, 139.4, 130.1, 124.4, 121.6, 9.8; HRMS (EI) calcd for
C11H8N2O435Cl ([M − H]−) 267.0173, found 267.0178, calcd for
C11H8N2O437Cl ([M − H]−) 269.0142, found 269.0172.
(E)-3-Bromo-2-(hydroxy(4-nitrophenyl)methyl)cyclohex-2-enone
oxime (1c): colorless solid (116.0 mg, 68%); mp 165−167 °C; IR
1
(KBr, cm−1) 3402, 1632, 1522, 1344; H NMR (400 MHz, CDCl3):
8.14 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.42 (s, 1H), 6.08
(d, J = 11.7 Hz, 1H), 5.09 (d, J = 11.6 Hz, 1H), 2.87 (t, J = 6.2 Hz,
2H), 2.81 − 2.57 (m, 1H), 2.57 − 2.49 (m, 1H), 1.95 − 1.81 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 155.7, 150.7, 147.2, 134.7, 133.3,
126.3, 123.6, 75.4, 37.6, 22.3, 21.7; MS (ESI) m/z (relative intensity)
343 [(M+ + 2) + 1, 100], 343 (M+ + 1, 91), 325 (12), 321 (25), 298
(37); HRMS (ESI) calcd for C13H14N2O479Br ([M + H]+) 341.0137,
found 341.0135, calcd for C13H14N2O481Br ([M + H]+) 343.0116,
found 343.0118.
4-Bromo-3-(4-nitrophenyl)-3,5,6,7-tetrahydrobenzo[c]isoxazole
1-oxide (1d): yellow solid (103.4 mg, 61%); mp 156−158 °C; IR
(KBr, cm−1) 2949, 1630, 1523; 1H NMR (400 MHz, CDCl3): 8.24 (d,
J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 6.06 (t, J = 2.6 Hz, 1H),
2.73−2.64 (m, 4H), 2.03−1.97 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 148.6, 142.4, 134.9, 129.3, 124.2, 116.5, 115.8,80.0, 35.4,
22.4, 20.5; MS (ESI) m/z (relative intensity) 337 (M− − 1, 100), 309
(8); HRMS (ESI) calcd for C13H1079BrN2O4 ([M − H]−) 336.9824,
found 336.9817.
( E ) - 1 - ( 3 - B r o m o - 2 - ( 4 - n i t r o b e n z o y l ) c y c l o h e x - 2 -
enylideneaminooxy)ethanone (1e): white solid (156.0 mg, 82%); mp
136−138 °C; IR (KBr, cm−1) 2942, 1772, 1689, 1527; 1H NMR (400
MHz, DMSO-d6): 8.35−8.33 (m, 2H), 8.16−8.14 (m, 2H), 2.89 (t, J =
6.0 Hz, 2H), 2.80 (t, J = 6.6 Hz, 2H), 1.97 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 191.9, 167.6, 161.7, 150.5, 139.0, 136.1, 134.0,
130.4, 124.3, 35.4, 22.3, 21.0, 19.2; HRMS (ESI) calcd for
C15H1279BrN2O5 ([M − H]−) 378.9930, found 378.9936, calcd for
C15H1281BrN2O5 ([M − H]−) 380.9909, found 380.9896.
(E)-(5-Chloro-2-nitrophenyl)(2-chloro-6-(hydroxyimino)cyclohex-
1-enyl)methanone (7b): colorless solid (104.2 mg, 63%); mp 139−
1
141 °C; IR (KBr, cm−1) 1636, 1540, 1377; H NMR (400 MHz,
DMSO-d6) δ 11.42 (s, 1H), 7.98−7.97 (m, 2H), 7.95−7.94 (m, 1H),
2.68 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 6.5 Hz, 2H), 1.89 (pentet, J = 6.3
Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 189.0, 154.1, 147.3,
139.1, 136.5, 134.5, 131.9, 131.0, 129.6, 125.7, 33.1, 20.4, 20.3; MS
(FAB) m/z (relative intensity) 329 (M+ + 1, 20), 210 (3), 174 (13);
HRMS (FAB) calcd for C13H11N2O435Cl2 ([M + H]+) 329.0096,
found 329.0092.
(E)-(2-Chloro-6-(hydroxyimino)cyclohex-1-enyl)(2,4-
dichlorophenyl)methanone (8b): colorless solid (97.2 mg, 61%); mp
152−154 °C; IR (KBr, cm−1) 1638, 1465, 1351, 1225; 1H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H),
7.39 (s, 1H), 7.32 (dd, J = 8.4, 21.9 Hz, 1H), 2.68 (t, J = 6.7 Hz, 2H),
2.62 (t, J = 6.2 Hz, 2H), 1.96 (pentet, J = 6.5 Hz, 2H); 13C NMR (100
MHz, DMSO-d6) δ 190.9, 155.4, 139.3, 139.2, 134.9, 134.5, 133.9,
133.3, 131.5, 127.6, 34.0, 21.2, 20.9; MS (FAB) m/z (relative
intensity) 320 [(M+ + 2) + 1, 100], 318 (M+ + 1, 95), 282 (13), 173
(23); HRMS (FAB) calcd for C13H11NO235Cl3 ([M + H]+) 317.9855,
found 317.9861.
ASSOCIATED CONTENT
* Supporting Information
Crystallographic data and spectroscopic data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: cheyaocf@ntnu.edu.tw.
■
(E)-(2-Bromophenyl)(2-chloro-6-(hydroxyimino)cyclohex-1-enyl)-
Notes
methanone (9b): colorless solid (114.4 mg, 70%); mp 127−129 °C;
The authors declare no competing financial interest.
1
IR (KBr, cm−1) 1687, 1640, 1583, 1427, 1354; H NMR (400 MHz,
CDCl3) δ 7.77 (dd, J = 7.6, 1.9 Hz, 1H), 7.67 (dd, J = 7.7, 1.3 Hz, 1H),
7.39 (dt, J = 7.5, 1.0 Hz, 1H), 7.33 (dt, J = 7.5, 1.9 Hz, 1H), 2.69 (t, J =
6.7 Hz, 2H), 2.63 (t, J = 6.2 Hz, 2H), 1.97 (pentet, J = 6.5 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 192.6, 155.4, 139.4, 136.9, 135.2,
134.2, 133.4, 132.6, 127.6, 121.9, 34.0, 21.2, 10.9; MS (FAB) m/z
ACKNOWLEDGMENTS
■
This work was supported by the National Science Council of
the Republic of China (NSC-100-2113-M-003-008-MY3) and
National Taiwan Normal University (99T3030-2, 99-D and
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Note
100-D-006). Collection of spectral data at the Instrumentation
Center of National Taiwan Normal University is gratefully
acknowledged.
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