Metal-free oxysulfonylation and aminosulfonylation of alkenyl oximes: Synthesis of sulfonylated isoxazolines and cyclic nitrones

Article abstract of DOI:10.1039/c8ob02879f

Intramolecular oxysulfonylation of alkenyl oximes was reported. Using iodine as the catalyst, TBHP as the oxidant, and sulfonyl hydrazides as the sulfonyl radical source, a variety of sulfonylated isoxazolines were obtained in moderate to excellent yields

Full text of DOI:10.1039/c8ob02879f

Organic &
Biomolecular Chemistry
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Metal-free oxysulfonylation and
aminosulfonylation of alkenyl oximes: synthesis
of sulfonylated isoxazolines and cyclic nitrones†
Cite this: Org. Biomol. Chem., 2019,
7, 898
1
a
a
a
a
a,b
Zhong-Qi Xu, Lin-Chuang Zheng, Lin Li, Lili Duan* and Yue-Ming Li
*
Received 18th November 2018,
Accepted 21st December 2018
Intramolecular oxysulfonylation of alkenyl oximes was reported. Using iodine as the catalyst, TBHP as the
oxidant, and sulfonyl hydrazides as the sulfonyl radical source, a variety of sulfonylated isoxazolines were
obtained in moderate to excellent yields. Cyclic nitrones could also be readily obtained under the same
conditions.
DOI: 10.1039/c8ob02879f
rsc.li/obc
β,γ-unsaturated oximes. For example, Han et al. reported the
cyclization of β,γ-unsaturated oximes to build isoxazolines
As an important class of nitrogen- and oxygen-containing het- (Scheme 1a). In this protocol, oxime radicals were generated
Introduction
1
3
erocycles, isoxazolines have been frequently found in natural using commercially available TEMPO or DEAD as the radical
1
2
3
products, fine chemicals or pharmaceuticals. Such struc- initiator, and 4,5-dihydroisoxazoles were obtained in good
tures can also be utilized as useful building blocks in organic yields via radical cyclization and subsequent capture of the
4
5
synthesis or coordination groups in chiral ligands. For these thus formed radical intermediates.
reasons, construction of isoxazoline skeletons from readily
available starting materials has attracted considerable atten- potential in medicinal chemistry,
The sulfone functionality has shown important application
1
4
and cyclization of
tion, and 1,2-difunctionalization of unactivated alkenes was β,γ-unsaturated oxime radicals and capture of the resulting
proved to be one of the most efficient methods for the prepa- radicals with sulfonyl radicals would be an ideal route to sulfo-
6
ration of isoxazolines.
nyl-containing isoxazolines. Li et al. showed that introduction
Among these studies, generation and subsequent addition of the sulfonyl group into isoxazolines could be realized via
of oxime radicals (iminoxyl radical) to CvC double bonds has radical cyclization of β,γ-unsaturated oximes and subsequent
shown application potential for the construction of isoxazo- coupling of the thus generated radical intermediates with
15
lines due to the easy availability and structural diversity of the sulfonyl radicals. In this report, the key sulfonyl radicals were
starting materials. By changing the substituents in the ketox- generated using sodium sulfonate as the sulfonyl source in the
imes, a variety of functional groups could be introduced into presence of an excess amount of copper acetate and potassium
the target molecules. Oxime radicals and their analogous ami-
noxyl radicals such as TEMPO have been extensively studied
7
since the 1960s, and cyclization of β,γ-unsaturated oximes
provided a straightforward approach to a variety of isoxazo-
lines. So far, heterocycles bearing different functional groups
8
9
10
11
such as trifluoromethyl, halogen, cyano, amino group,
and azide
1
2
have been prepared via cyclization of
a
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and
Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin,
People’s Republic of China
b
CAS Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, People’s Republic of China
†
Electronic supplementary information (ESI) available: Optimization of reaction
conditions and characterization of products. CCDC 1879645. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c8ob02879f
Scheme 1 Strategies for the construction of isoxazolines.
898 | Org. Biomol. Chem., 2019, 17, 898–907
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a
fluoride, and the desired sulfonyl isoxazolines were obtained Table 1 Optimization of reaction conditions
in up to 88% yields. Two possible reaction pathways were pro-
posed, and the sulfonyl radical pathway seemed to be more
likely.
In a previous report, 2 equiv. of Cu(OAc) was used to gene-
2
rate sulfonyl radicals. It is always desirable to develop a tran-
sition metal-free protocol from medicinal chemistry point of
b
Entry
Base
Solvent
Catalyst
Yield (%)
view. Herein we wish to present a new method for the prepa-
ration of sulfonylated isoxazolines using sulfonyl hydrazides
as the sulfonyl radical source under transition metal-free and
mild conditions.
1
2
3
4
5
6
7
8
9
NaOAc
NaOMe
KF
DCE
DCE
DCE
DCE
MeCN
THF
Diox
Diox
Diox
Diox
Diox
Diox
Diox
Diox
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
NaI
24
21
24
30
20
28
36
74
87
91
47
83
Trace
44
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
3
3
3
3
3
3
3
3
3
Sulfonyl hydrazides are easily available and shelf-stable
reagents and have been widely applied in organic synthesis
1
6
17
such as the sulfenylation reaction and arylation reaction.
NIS
I
2
Furthermore, sulfonyl radicals could be readily generated from
1
1
0
1
sulfonyl hydrazides and utilized for in situ radical sulfonyla-
FeI
MnI
ZnI2
2
1
8
tion of a variety of unsaturated substrates. For example, 12
2
1
8a
13
NaHCO3
None
Taniguchi et al.
reported that sulfonyl radicals were gener-
14
I
2
ated from sulfonyl hydrazides using oxygen as the oxidant,
1
8b
a
and an iron salt as the catalyst. Li et al. showed that sulfonyl
radicals could be generated from sulfonyl hydrazides with
iodine as the catalyst and TBHP as the oxidant.
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol, 2.0 equiv.), TBHP
(
(
70% aqueous solution, 0.75 mmol, 3.0 equiv.), solvent (2.0 mL), base
1.5 equiv.), catalyst (0.3 equiv.), under argon and stirring at room
b
temperature for 24 h. Isolated yield based on 1a.
a
Results and discussion
Table 2 Reaction scope of β,γ-unsaturated ketoximes
Inspired by these literature results, we initiated the metal-free
oxysulfonylation of alkenyl oximes using sulfonyl hydrazide as
the sulfonyl source, and a variety of iodine sources as the cata-
lysts in the presence of an appropriate amount of oxidant. It
was assumed that ketoxime substrates and sulfonyl hydrazides
would generate the corresponding free radicals in the presence
of suitable oxidants provided that CvC double bonds in the
substrates remained intact under the oxidation conditions.
Intramolecular cyclization produced an isoxazolinomethyl free
radical, and subsequent radical coupling yielded the desired
sulfonylated isoxazolines.
1
b
Entry
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
(1a) Ph
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
91
87
84
85
80
96
73
94
94
85
61
82
88
90
79
64
(1b) 4-FPh
(1c) 4-ClPh
(1d) 4-BrPh
(1e) 4-CF Ph
3
(1f) 4-MePh
(1g) 4-OMePh
(1h) 3,4-DiMePh
(1i) 3-MePh
(1j) 2-OMePh
(1k) 4-Biphenyl
(1l) 2-Naphthyl
(1m) 2-Thiophene
(1n) t-Butyl
To test this assumption, oxysulfonylation of β,γ-unsaturated
ketoxime 1a with p-toluenesulfonyl hydrazide 2a was selected
as the model reaction (Table 1). Initially, various oxidants such
10
as TBHP, DTBP, and K S O were tested. TBHP was found to 11
2
2 8
12
13
14
2 2 8
be suitable for this protocol, and reactions with DTBP, K S O
1
9
and other oxidants were not successful. The effect of bases
was examined (entries 1–4) and the yield of 3aa was increased 15
to 30% when NaHCO was used (entry 4). A slightly higher
3
(1o) n-Hexane
(1p) Cy
1
1
6
7
yield of the desired 3aa was obtained when reaction media
were changed to 1,4-dioxane (entry 7). Various catalysts con-
taining iodine were screened (entries 8–13), and a pretty good
a
Reaction conditions: 1 (0.25 mmol), 2a (0.5 mmol, 2.0 equiv.), TBHP
(0.3 equiv.), NaHCO (1.5 equiv.), 1,4-
catalyst (entry 10). Transition-metal catalyst MnI2 could also dioxane (2.0 mL), under argon and stirring at room temperature for
2
isolated yield (91%) was observed when I was utilized as the
(
0.75 mmol, 3.0 equiv.), I
2
3
b
2
4 h. Isolated yield based on 1a.
2 2
promote this reaction in a satisfactory yield, but FeI and ZnI
seemed to be not suitable for this reaction. The product 3aa
was obtained in merely medium yield in the absence of base
(entry 14).
β,γ-unsaturated ketoximes 1 as the substrates and benzene-
Encouraged by these preliminary results, the synthetic via- sulfonyl hydrazide 2a as the sulfonylating agent. The results
bility of the reactions was studied using
a
series of are summarized in Table 2. As shown in Table 2, this reaction
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tolerated a wide range of ketoximes. First, various aromatic if it could also undergo aminosulfonylation through N atom 5-
1
0b,11,13d
oximes with a para-substituent on the phenyl ring, substrates exo-trig cyclization.
with both electron-withdrawing groups such as 4-F (1b), 4-Cl aryl sulfonyl hydrazides could participate smoothly in the reac-
1c), 4-Br (1d) or 4-CF (1e) and electron-donating groups such tions. The electronic properties of sulfonyl hydrazides showed
As shown in Table 4, a series of
(
3
as 4-Me (1f) and 4-MeO (1g) underwent the oxysulfonylation a drastic effect on the course of the reactions when substrate
reactions smoothly, and the desired products (3aa–3ga) were 1r was subjected to the reaction, probably due to the lower
obtained in good to excellent yields (entries 1–7). Reactions of reactivity compared with that of β,γ-unsaturated ketoximes. In
ketoxime substrates bearing disubstituted (1h) or m-/o-substi- these cases, higher yield would be observed when an electron-
tuted (3ia, 3ja) benzene rings could also proceed pretty well donating substituent was present in sulfonyl hydrazides
(
(
entries 8–10). To our delight, thiophene-containing oxime (2a, 2c, 2d). Low yield was observed when sulfonyl hydrazide
1m) was found adaptable for the reaction and afforded the bearing an electron-withdrawing substituent (2g) was sub-
desired product in 88% yield. In addition, the reaction of ali- jected to the reaction. The structure of 4ra was further con-
1
9
phatic ketoximes (1n–1p) could proceed smoothly, and the firmed by X-ray diffraction analysis.
target products 3na–3pa were obtained in high yields. To demonstrate the application potential of this reaction,
Moreover, product 3qa containing a quaternary carbon center oxysulfonylation of substrate 1a with 2a was carried out on the
was obtained in 51% yield. gram scale under the optimized conditions, and the desired
Then, the scope of sulfonyl hydrazides (2b–2l) was studied product 3aa was obtained in 70% isolated yield (Scheme 2a).
under the same conditions. The results are summarized in In addition, the [3 + 2] cycloaddition of nitrones with dipolaro-
Table 3. The reaction of sulfonyl hydrazides with substituents philes was performed using 4ra and methyl propiolate as start-
2
0
at the para-position, either electron-donating or electron-with- ing materials.
As expected, the desired product 5 was
drawing, gave the corresponding products (3ad–3ah) in high obtained in 75% yield as a cis-diastereomer with a high dia-
1
3d,20
yields. The reaction of meta-substituted substrate 2c gave stereoselectivity.
The relative configuration of the com-
1
product 3ac in lower yield, and ortho-substituted substrate 2j pound was further confirmed by H-NMR and NOE experi-
provided product 3aj in poor yield, suggesting that the steric ments (Scheme 2b).
effect showed a significant effect on the course of the reaction.
1
9
Furthermore, para-halogen substituted sulfonyl hydrazides
(
2f–2h) were smoothly involved in reactions and provided the
a,b
Table 4 Scope of γ,δ-unsaturated ketoximes
target products (3af–3ah) in excellent yields. The reaction of
alkyl sulfonyl hydrazide 2l gave the desired product 3al in low
yield, possibly due to the low stability of the aliphatic sulfonyl
radical.
To further investigate the applicability of this protocol, the
reaction of γ,δ-unsaturated ketoxime 1r was carried out to see
a
Table 3 Reaction scope of sulfonyl hydrazides
a
Reaction conditions: 1r (0.25 mmol), 2 (0.5 mmol, 2.0 equiv.), TBHP
(0.3 equiv.), NaHCO (1.5 equiv.), 1,4-
dioxane (2.0 mL), under argon and stirring at room temperature for
(
0.75 mmol, 3.0 equiv.), I
2
3
b
2
4 h. Isolated yield based on 1r.
2
b
Entry
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
(2b) Ph
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
98
82
86
91
91
96
95
79
35
94
38
(2c) 3-MePh
(2d) 4-tBuPh
(2e) 4-OMePh
(2f) 4-FPh
(2g) 4-ClPh
(2h) 4-BrPh
(2i) 4-CF3Ph
(2j) 2-FPh
3aj
3ak
3al
10
1
(2k) 2-naphthyl
(2l) n-Bu
1
a
Reaction conditions: 1a (0.25 mmol), 2 (0.5 mmol, 2.0 equiv.), TBHP
(0.3 equiv.), NaHCO (1.5 equiv.), 1,4-
dioxane (2.0 mL), under argon and stirring at room temperature for
(0.75 mmol, 3.0 equiv.), I
2
3
b
2
4 h. Isolated yield based on 1a.
Scheme 2 Extension of the scopes of the reactions.
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Control reactions were performed to understand the mecha- strates, providing the C-centered radical intermediates D and
nism of the reactions. First, 2.0 equiv. of 1,1-diphenylethylene E, respectively. Finally, the C-centered radical D or E reacts
was added to the reaction mixture of the model reaction, with sulfonyl radical A to provide the sulfonylated isoxazoline
merely less than 10% yield of 3aa was obtained, but (2-tosyl- 3 or nitrone 4, respectively.
ethene-1,1-diyl)dibenzene 6 was isolated in 55% yield, indicat-
ing the participation of sulfonyl radicals in the reaction.
(
Scheme 3a) Then, the radical scavenger TEMPO was added to
Conclusions
the reaction system. The oxysulfonylation reaction was almost
completely inhibited and the TEMPO-trapped isoxazoline 7
was obtained in 15% yield. In addition, when TEMPO was
used as a substrate instead of p-tosylhydrazine 2a, the desired
product 7 was obtained up to 66% yield, suggesting the invol-
vement of an iminoxyl radical intermediate in the reaction
In summary, we have reported an efficient oxysulfonylation
reaction of ketoximes with sulfonyl hydrazides. In the presence
of an iodine catalyst and a suitable oxidant, a range of desired
sulfonylated isoxazolines were obtained with moderate to
excellent yields under mild conditions. Sulfonylated nitrones
could be obtained in good yields under the same conditions.
Application of this transformation in organic synthesis is
underway.
(Scheme 3b and c).
Based on these observations and the previously reported
results, a plausible reaction pathway is proposed in Scheme 4.
Initially, TBHP is decomposed to give tert-butoxyl and tert-
butylperoxy radicals with the assistance of iodine. The reaction
of sulfonyl hydrazide 2 with these radicals generates sulfonyl Experimental
radical A and releases molecular nitrogen.
Experimental details
The anionic intermediate 1′ was first afforded through the
Reactions were carried out with commercially available
3
deprotonation of the β,γ-unsaturated oxime 1 with NaHCO .
1
13
•
•
reagents in oven-dried apparatus. H and C NMR spectra
3d were recorded on a Bruker DRX 400 spectrometer at 298 K
using deuterated chloroform as the solvent and TMS as the
internal reference. Column chromatography was performed
employing 200–300 mesh silica gel unless otherwise noted.
Thin layer chromatography (TLC) was performed on silica gel
GF254. Melting points were measured on a digital melting-
point apparatus without correction of the thermometer. HRMS
analyses were carried out with a Varian FTICR-MS 7.0T. IR
spectra were recorded on a BRUKER TENSOR 37. Unless other-
wise indicated, starting materials and reagents used in the
study were purchased and were used as received without
further purification.
Single-electron oxidation of 1′ by t-BuO or t-BuOO gave the
1
O-centered radical B or N-centered radical C. As reported,
the iminoxyl radical can undergo both O- and N-atom 5-exo-
trig radical cyclization depending on the structure of the sub-
General procedure for the synthesis of compounds 3
A 35 mL Schlenk-type tube equipped with a magnetic stir bar
was charged with β,γ-unsaturated ketoxime 1a (0.25 mmol,
4
0 mg) and p-toluenesulfonyl hydrazide 2a (0.5 mmol, 95 mg).
Then, I (9.5 mg), NaHCO (0.375 mmol, 32 mg), TBHP
0.75 mmol, 97 mg, 70% solution in water), and 1,4-dioxane
2 mL) were added to this system. Hereafter, the reaction tube
Scheme 3 Control reactions.
2
3
(
(
was purged with argon and the reaction mixture was stirred at
room temperature for 24 h. Then, the reaction mixture
was filtered and evaporated to give the crude product. The
residue was purified by column chromatography (ethyl
acetate : petroleum ether = 1 : 10, v/v) to afford the desired
product 3aa.
General procedure for the synthesis of compounds 4
A 35 mL Schlenk-type tube equipped with a magnetic stir bar
was charged with γ,δ-unsaturated ketoxime 1r (0.25 mmol,
51 mg) and p-toluenesulfonyl hydrazide 2a (0.5 mmol, 95 mg).
Then, I (9.5 mg), NaHCO (0.375 mmol, 32 mg), TBHP
2
3
Scheme 4 Plausible pathway of the reaction.
(0.75 mmol, 97 mg, 70% solution in water), and 1,4-dioxane
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(2 mL) were added to this system. The reaction tube was (dd, J = 22.8, 8.0 Hz, 4H), 7.60 (d, J = 8.1 Hz, 2H), 7.33 (d, J =
purged with argon. After stirring at room temperature for 24 h, 7.9 Hz, 2H), 5.14–5.01 (m, 1H), 3.62–3.51 (m, 2H), 3.43 (dd, J =
the reaction mixture was filtered and evaporated to obtain the 17.2, 7.4 Hz, 1H), 3.30 (dd, J = 14.0, 8.8 Hz, 1H), 2.40 (s,
1
3
crude product. The residue was purified by column chromato- 3H). C NMR (101 MHz, CDCl
3
) δ 155.9, 145.5, 136.3, 132.2,
graphy (ethyl acetate : petroleum ether = 1 : 2, v/v) to afford the 132.16 (q, J = 32.9 Hz), 130.2, 128.0, 127.1, 125.80 (q, J =
1
9
desired product 4ra.
-Phenyl-5-tosylmethyl-4,5-dihydroisoxazole (3aa). Compound (376 MHz, CDCl
aa was prepared according to the general procedure and 909.4, 847.1, 568.3 cm . HRMS-ESI (m/z): [M + Na] calcd for:
3.8 Hz), 123.71 (q, J = 272.2 Hz), 75.4, 59.7, 40.0, 21.7. F NMR
3
3
) δ −63.0. IR (KBr): ν = 2928.6, 1329.6, 1116.6,
−1
+
3
+
was isolated as a white solid (71.7 mg, 91% yield) after
C
18
H
16
F
3
NNaO
3
S , 406.0695; found: 406.0698.
flash chromatography (EtOAc/petroleum ether 10% v/v).
3-(p-Tolyl)-5-tosylmethyl-4,5-dihydroisoxazole (3fa). Compound
1
M.p. 95–98 °C. H NMR (400 MHz, CDCl ) δ 7.74 (d, J = 8.0 Hz, 3fa was prepared according to the general procedure and
3
2
3
H), 7.59–7.53 (m, 2H), 7.36–7.27 (m, 5H), 5.08–4.93 (m, 1H), was isolated as a light-yellow solid (79.1 mg, 96% yield) after
13
.58–3.45 (m, 2H), 3.32 (m, 2H), 2.38 (s, 3H). C NMR flash chromatography (EtOAc/petroleum ether 10% v/v).
1
(101 MHz, CDCl ) δ 156.8, 145.3, 136.5, 130.5, 130.1, 128.8, M.p. 125–127 °C. H NMR (400 MHz, CDCl ) δ 7.75 (d, J =
3 3
1
28.1, 126.8, 74.8, 59.9, 40.4, 21.7. The NMR data were in 7.4 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.32 (d, J = 7.7 Hz, 2H),
1
5
agreement with reported results.
7.14 (d, J = 7.6 Hz, 2H), 5.07–4.94 (m, 1H), 3.59–3.46 (m, 2H),
3
-(4-Fluorophenyl)-5-tosylmethyl-4,5-dihydroisoxazole (3ba). 3.36 (dd, J = 17.1, 6.9 Hz, 1H), 3.27 (dd, J = 13.7, 8.8 Hz, 1H),
1
3
3
Compound 3ba was prepared according to the general pro- 2.39 (s, 3H), 2.31 (s, 3H). C NMR (101 MHz, CDCl ) δ 156.8,
cedure and was isolated as a light-yellow solid (72.5 mg, 87% 145.3, 140.9, 136.4, 130.1, 129.5, 128.1, 126.8, 125.9, 74.6, 59.9,
yield) after flash chromatography (EtOAc/petroleum ether 10% 40.5, 21.7, 21.5. The NMR data were in agreement with
1
15
v/v). M.p. 144–147 °C. H NMR (400 MHz, CDCl
7
3
) δ 7.75 (d, J = reported results.
3-(4-Methoxyphenyl)-5-tosylmethyl-4,5-dihydroisoxazole (3ga).
.8 Hz, 2H), 7.61–7.52 (m, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.02 (t,
J = 8.3 Hz, 2H), 5.09–4.94 (m, 1H), 3.57–3.47 (m, 2H), 3.38 (dd, Compound 3ga was prepared according to the general pro-
J = 17.1, 7.2 Hz, 1H), 3.28 (dd, J = 14.0, 8.8 Hz, 1H), 2.39 (s, cedure and was isolated as a white solid (63.0 mg, 73% yield)
1
3
3
1
(
H). C NMR (101 MHz, CDCl
3
) δ 163.9 (d, J = 251.4 Hz), after flash chromatography (EtOAc/petroleum ether 15% v/v).
1
55.9, 145.4, 136.3, 130.2, 128.83 (d, J = 8.5 Hz), 128.0, 125.1 M.p. 149–152 °C. H NMR (400 MHz, CDCl ) δ 7.75 (d, J = 8.0
d, J = 3.3 Hz), 116.0 (d, J = 22.0 Hz), 74.9, 59.8, 40.4, 21.7.
3
1
9
F
Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.84
NMR (376 MHz, CDCl ) δ −109.1. IR (KBr): ν = 2980.3, 2919.1, (d, J = 8.5 Hz, 2H), 5.05–4.93 (m, 1H), 3.76 (s, 3H), 3.56–3.45
3
−
1
13
1
(
3
602.0, 1511.9, 1287.8, 1138.6, 907.4, 836.6 cm . HRMS-ESI (m, 2H), 3.40–3.23 (m, 2H), 2.39 (s, 3H). C NMR (101 MHz,
+
+
m/z): [M + H] calcd for: C17
34.0913.
-(4-Chlorophenyl)-5-tosylmethyl-4,5-dihydroisoxazole (3ca). ment with reported results.
Compound 3ca was prepared according to the general pro- 3-(3,4-Dimethylphenyl)-5-tosylmethyl-4,5-dihydroisoxazole (3ha).
H
17FNO
3
S , 334.0908; found: CDCl
3
) δ 161.4, 156.4, 145.3, 136.4, 130.1, 128.4, 128.1, 121.3,
114.2, 74.5, 59.9, 55.4, 40.6, 21.7. The NMR data were in agree-
1
5
3
cedure and was isolated as a light-yellow solid (73.4 mg, 84% Compound 3ha was prepared according to the general pro-
yield) after flash chromatography (EtOAc/petroleum ether 10% cedure and was isolated as a light-yellow solid (80.7 mg, 94%
1
v/v). M.p. 148–151 °C. H NMR (400 MHz, CDCl
3
) δ 7.74 (d, J = yield,) after flash chromatography (EtOAc/petroleum ether
1
7
5
(
.6 Hz, 2H), 7.50 (d, J = 7.7 Hz, 2H), 7.36–7.27 (m, 4H), 10% v/v). M.p. 110–113 °C. H NMR (400 MHz, CDCl
.10–4.96 (m, 1H), 3.59–3.45 (m, 2H), 3.42–3.23 (m, 2H), 2.39 (d, J = 7.7 Hz, 2H), 7.39–7.25 (m, 4H), 7.08 (d, J = 7.7 Hz, 1H),
s, 3H). C NMR (101 MHz, CDCl
3
) δ 7.75
1
3
3
) δ 156.0, 145.4, 136.5, 5.05–4.92 (m, 1H), 3.57–3.45 (m, 2H), 3.36 (dd, J = 17.1, 7.0 Hz,
1
36.3, 130.2, 129.1, 128.0, 127.3, 75.1, 59.8, 40.2, 21.7. The 1H), 3.27 (dd, J = 13.9, 8.7 Hz, 1H), 2.39 (s, 3H), 2.20 (s, 6H).
1
5
13
NMR data were in agreement with reported results.
-(4-Bromophenyl)-5-tosylmethyl-4,5-dihydroisoxazole (3da). 130.1, 130.0, 128.1, 127.9, 126.2, 124.4, 74.6, 59.9, 40.5, 21.7,
Compound 3da was prepared according to the general pro- 19.8, 19.7. IR (KBr): ν = 2920.4, 1596.9, 1296.7, 1139.9, 913.5,
cedure and was isolated as a light-yellow solid (83.8 mg, 85% 814.3, 564.4 cm . HRMS-ESI (m/z): [M + Na] calcd for:
yield) after flash chromatography (EtOAc/petroleum ether 10%
C NMR (101 MHz, CDCl ) δ 157.0, 145.3, 139.6, 137.2, 136.4,
3
3
−
1
+
+
C
19
H
21NNaO
3
S , 366.1134; found: 366.1139.
1
3
v/v). M.p. 160–162 °C. H NMR (400 MHz, CDCl ) δ 7.74 (d, J =
3-(m-Tolyl)-5-tosylmethyl-4,5-dihydroisoxazole (3ia). Compound
7
5
.5 Hz, 2H), 7.50–7.41 (m, 4H), 7.32 (d, J = 7.8 Hz, 2H), 3ia was prepared according to the general procedure and
.11–4.95 (m, 1H), 3.58–3.46 (m, 2H), 3.42–3.23 (m, 2H), 2.40 was isolated as a light-yellow solid (77.4 mg, 94% yield) after
1
3
3
(s, 3H). C NMR (101 MHz, CDCl ) δ 156.1, 145.4, 136.3, 132.1, flash chromatography (EtOAc/petroleum ether 10% v/v).
1
1
30.2, 128.2, 128.0, 127.7, 124.9, 75.1, 59.7, 40.1, 21.7. The M.p. 113–116 °C. H NMR (400 MHz, CDCl ) δ 7.75 (d,
3
1
5
NMR data were in agreement with reported results.
J = 7.6 Hz, 2H), 7.47–7.30 (m, 4H), 7.28–7.13 (m, 2H), 5.17–4.86
5
-Tosylmethyl-3-[4-(trifluoromethyl)phenyl]-4,5-dihydroisox- (m, 1H), 3.59–3.49 (m, 2H), 3.38 (dd, J = 17.1, 7.1 Hz, 1H), 3.27
1
3
azole (3ea). Compound 3ea was prepared according to the (dd, J = 13.9, 8.8 Hz, 1H), 2.39 (s, 3H), 2.30 (s, 3H). C NMR
general procedure and was isolated as a white solid (76.7 mg, (101 MHz, CDCl ) δ 157.0, 145.3, 138.6, 136.4, 131.3, 130.1,
0% yield) after flash chromatography (EtOAc/petroleum ether 128.7, 128.6, 128.1, 127.4, 124.0, 74.7, 59.9, 40.4, 21.7, 21.3.
3
8
1
1
15
0% v/v). M.p. 204–207 °C. H NMR (400 MHz, CDCl ) δ 7.73 The NMR data were in agreement with reported results.
3
902 | Org. Biomol. Chem., 2019, 17, 898–907
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3
-(2-Mthoxyphenyl)-5-tosylmethyl-4,5-dihydroisoxazole (3ja). δ 166.5, 145.2, 136.4, 130.1, 128.0, 74.0, 59.7, 39.8, 33.1, 28.0,
1
5
Compound 3ja was prepared according to the general pro- 21.7. The NMR data were in agreement with reported results.
cedure and was isolated as a light-yellow solid (73.4 mg, 85%
3-Pentyl-5-tosylmethyl-4,5-dihydroisoxazole (3oa). Compound
yield) after flash chromatography (EtOAc/petroleum ether 10% 3oa was prepared according to the general procedure and
1
v/v). M.p. 95–98 °C. H NMR (400 MHz, CDCl ) δ 7.75 (d, J = was isolated as a white solid (61.1 mg, 79% yield) after
3
7
6
.4 Hz, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 7.2 Hz, 3H), flash chromatography (EtOAc/petroleum ether 10% v/v).
1
.94–6.82 (m, 2H), 5.05–4.87 (m, 1H), 3.77 (s, 3H), 3.59 (dd, J = M.p. 72–75 °C. H NMR (400 MHz, CDCl
3
) δ 7.72 (d, J = 8.3 Hz,
1
7.6, 10.3 Hz, 1H), 3.54–3.36 (m, 2H), 3.29 (dd, J = 13.9, 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.88–4.73 (m, 1H), 3.44 (dd, J =
1
3
1
H), 2.39 (s, 3H). C NMR (101 MHz, CDCl
3
) δ 157.6, 156.5, 14.0, 4.5 Hz, 1H), 3.23–3.06 (m, 2H), 2.93 (dd, J = 17.4, 7.0 Hz,
1
7
45.2, 136.5, 131.7, 130.1, 129.4, 128.1, 120.8, 117.9, 111.4, 1H), 2.39 (s, 3H), 2.26 (t, J = 7.7 Hz, 2H), 1.48 (p, J = 7.5 Hz,
1
3
4.7, 60.0, 55.5, 43.0, 21.7. The NMR data were in agreement 2H), 1.32–1.21 (m, 4H), 0.82 (t, J = 6.9 Hz, 3H). C NMR
1
5
with reported results.
3
(101 MHz, CDCl ) δ 159.5, 145.2, 136.4, 130.1, 128.0, 73.5,
3-[(1,1′-Biphenyl)-4-yl]-5-tosylmethyl-4,5-dihydroisoxazole (3ka). 59.8, 42.4, 31.3, 27.5, 25.9, 22.3, 21.7, 13.9. IR (KBr): ν =
Compound 3ka was prepared according to the general pro- 2924.9, 2861.2, 1597.9, 1318.8, 1147.8, 1087.8, 814.8, 563.3,
cedure and was isolated as a white solid (59.7 mg, 61% yield) 521.6 cm−1
.
HRMS-ESI (m/z): [M
S , 332.1291; found: 332.1295.
+
Na] calcd for:
+
+
after flash chromatography (EtOAc/petroleum ether 10% v/v).
C
16
H
23NNaO
3
1
M.p. 176–179 °C. H NMR (400 MHz, CDCl ) δ 7.76 (d, J =
3-Cyclohexyl-5-tosylmethyl-4,5-dihydroisoxazole
(3pa).
3
8
.3 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.59–7.50 (m, 4H), 7.38 (t, Compound 3pa was prepared according to the general pro-
J = 7.5 Hz, 2H), 7.35–7.29 (m, 3H), 5.13–4.95 (m, 1H), 3.63–3.49 cedure and was isolated as a white solid (51.4 mg, 64% yield)
(
m, 2H), 3.42 (dd, J = 17.1, 7.2 Hz, 1H), 3.30 (dd, J = 14.0, after flash chromatography (EtOAc/petroleum ether 20% v/v).
.7 Hz, 1H), 2.39 (s, 3H). C NMR (101 MHz, CDCl ) δ 156.6, M.p. 64–67 °C. H NMR (400 MHz, CDCl ) δ 7.71 (d, J = 8.3 Hz,
3 3
1
3
1
8
1
1
1
(
4
45.4, 143.2, 140.0, 136.4, 130.2, 128.9, 128.1, 127.9, 127.6, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.85–4.69 (m, 1H), 3.42 (dd, J =
27.4, 127.3, 127.1, 74.9, 59.9, 40.4, 21.7. IR (KBr): ν = 2919.7, 14.1, 4.6 Hz, 1H), 3.21–3.02 (m, 2H), 2.92 (dd, J = 17.3, 7.0 Hz,
−
1
595.3, 1316.5, 1150.6, 1085.7, 764.4, 567.5 cm . HRMS-ESI 1H), 2.38 (s, 3H), 2.35–2.25 (m, 1H), 1.85–1.65 (m, 4H), 1.61 (d,
+
+
13
m/z): [M + Na] calcd for: C23
14.1138.
H
21NNaO
3
S , 414.1134; found: J = 11.8 Hz, 1H), 1.30–1.17 (m, 4H), 1.15–1.06 (m, 1H).
C
NMR (101 MHz, CDCl ) δ 163.1, 145.2, 136.4, 130.1, 128.0,
3
3
-(Naphthalen-2-yl)-5-tosylmethyl-4,5-dihydroisoxazole (3la). 73.4, 59.8, 40.8, 37.1, 30.3, 30.2, 25.8, 25.7, 21.7. IR (KBr): ν =
−
1
Compound 3la was prepared according to the general pro- 2928.5, 2853.3, 1448.6, 1302.5, 1150.7, 819.1, 566.6 cm
cedure and was isolated as a light-yellow solid (74.9 mg, 82% HRMS-ESI (m/z): [M
.
+
+
+
Na] calcd for: C H NNaO S ,
1
7
23
3
yield) after flash chromatography (EtOAc/petroleum ether 10% 344.1291; found: 344.1295.
1
v/v). M.p. 147–150 °C. H NMR (400 MHz, CDCl
3
) δ 7.90–7.81
5-Mehyl-3-phenyl-5-tosylmethyl-4,5-dihydroisoxazole (3qa).
(m, 2H), 7.81–7.72 (m, 5H), 7.54–7.43 (m, 2H), 7.32 (d, J = Compound 3qa was prepared according to the general pro-
7
1
.6 Hz, 2H), 5.13–4.99 (m, 1H), 3.71–3.46 (m, 3H), 3.32 (dd, J = cedure and was isolated as a white solid (42.0 mg, 51% yield)
1
3
3.4, 9.2 Hz, 1H), 2.39 (s, 3H). C NMR (101 MHz, CDCl
3
)
after flash chromatography (EtOAc/petroleum ether 10% v/v).
1
δ 157.0, 145.4, 136.4, 134.2, 132.9, 130.2, 128.7, 128.5, 128.1, M.p. 110–113 °C. H NMR (400 MHz, CDCl ) δ 7.77–7.69 (m,
3
1
27.9, 127.4, 126.9, 126.3, 123.4, 75.0, 59.9, 40.3, 21.7. The 2H), 7.61–7.55 (m, 2H), 7.40–7.26 (m, 5H), 3.91 (d, J = 18.9 Hz,
1
5
NMR data were in agreement with reported results.
1H), 3.43 (s, 2H), 3.16 (d, J = 17.2 Hz, 1H), 2.38 (s, 3H), 1.65 (s,
1
3
3
-(Thiophen-2-yl)-5-tosylmethyl-4,5-dihydroisoxazole (3ma). 3H). C NMR (101 MHz, CDCl ) δ 157.3, 145.1, 137.6, 130.3,
3
Compound 3ma was prepared according to the general pro- 130.0, 129.3, 128.8, 127.8, 126.7, 84.1, 63.0, 44.8, 26.2, 21.7.
1
5
cedure and was isolated as a yellow solid (70.7 mg, 88% yield) The NMR data were in agreement with reported results.
after flash chromatography (EtOAc/petroleum ether 10% v/v). 3-Phenyl-5-[(phenylsulfonyl)methyl]-4,5-dihydroisoxazole (3ab).
) δ 7.74 (d, J = Compound 3ab was prepared according to the general pro-
.3 Hz, 2H), 7.37–7.28 (m, 3H), 7.17–7.13 (m, 1H), 7.05–6.96 cedure and was isolated as a light-yellow solid (73.8 mg, 98%
m, 1H), 5.11–4.91 (m, 1H), 3.63–3.48 (m, 2H), 3.40 (dd, J = yield) after flash chromatography (EtOAc/petroleum ether 10%
1
M.p. 120–122 °C. H NMR (400 MHz, CDCl
3
8
(
1
1
6.9, 7.2 Hz, 1H), 3.29 (dd, J = 14.0, 8.7 Hz, 1H), 2.39 (s, 3H). v/v). M.p. 140–142 °C. H NMR (400 MHz, CDCl
3
) δ 7.88 (d, J =
1
3
C NMR (101 MHz, CDCl ) δ 152.6, 145.4, 136.3, 131.1, 130.1, 7.8 Hz, 2H), 7.69–7.49 (m, 5H), 7.44–7.27 (m, 3H), 5.12–4.98
29.1, 128.9, 128.1, 127.5, 75.0, 59.7, 41.1, 21.7. The NMR data (m, 1H), 3.62–3.47 (m, 2H), 3.43–3.25 (m, 2H). C NMR
3
1
3
1
1
5
were in agreement with reported results.
(101 MHz, CDCl
3
) δ 156.9, 139.3, 134.3, 130.6, 129.5, 128.8,
3
-(tert-Butyl)-5-tosylmethyl-4,5-dihydroisoxazole
Compound 3na was prepared according to the general pro- agreement with reported results.
cedure and was isolated as a white solid (66.5 mg, 90% yield) 3-Phenyl-5-[(m-tolylsulfonyl)methyl]-4,5-dihydroisoxazole (3ac).
(3na). 128.7, 128.1, 126.8, 74.7, 59.8, 40.4. The NMR data were in
1
5
after flash chromatography (EtOAc/petroleum ether 10% v/v). Compound 3ac was prepared according to the general pro-
1
M.p. 93–95 °C. H NMR (400 MHz, CDCl ) δ 7.73 (d, J = 8.3 Hz, cedure and was isolated as a light-yellow solid (64.6 mg, 82%
3
2
1
1
H), 7.31 (d, J = 8.1 Hz, 2H), 4.88–4.70 (m, 1H), 3.44 (dd, J = yield) after flash chromatography (EtOAc/petroleum ether 10%
1
4.0, 4.4 Hz, 1H), 3.22–3.08 (m, 2H), 2.98 (dd, J = 17.2, 7.2 Hz, v/v). M.p. 133–136 °C. H NMR (400 MHz, CDCl
3
) δ 7.71–7.65
1
3
H), 2.39 (s, 3H), 1.12 (s, 9H). C NMR (101 MHz, CDCl3) (m, 2H), 7.63–7.53 (m, 2H), 7.47–7.42 (m, 2H), 7.38–7.30 (m,
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1
3
7
H), 5.14–4.87 (m, 1H), 3.67–3.48 (m, 2H), 3.41 (dd, J = 17.1, 10% v/v). M.p. 147–150 °C. H NMR (400 MHz, CDCl
3
)
1
3
.1 Hz, 1H), 3.29 (dd, J = 14.0, 8.9 Hz, 1H), 2.39 (s, 3H).
C
δ 7.78–7.71 (m, 2H), 7.70–7.65 (m, 2H), 7.57 (dd, J = 7.7,
NMR (101 MHz, CDCl
3
29.4, 128.8, 128.7, 128.3, 126.8, 125.2, 74.7, 59.7, 40.4, 21.4. (m, 2H), 3.40–3.26 (m, 2H). C NMR (101 MHz, CDCl )
3
) δ 156.9, 139.9, 139.1, 135.1, 130.6, 1.8 Hz, 2H), 7.40–7.30 (m, 3H), 5.15–5.01 (m, 1H), 3.60–3.49
1
3
1
1
5
The NMR data were in agreement with reported results.
δ 156.8, 138.4, 132.8, 130.6, 129.7, 129.7, 128.9, 128.6, 126.8,
5
-{[4-(tert-Butylphenyl)sulfonyl]methyl}-3-phenyl-4,5-dihy- 74.6, 60.0, 40.4. IR (KBr): ν = 3082.0, 2932.9, 1571.5, 1302.0,
−
1
+
droisoxazole (3ad). Compound 3ad was prepared according to 1141.8, 757.1, 611.4 cm . HRMS-ESI (m/z): [M + H] calcd for:
the general procedure and was isolated as a light-yellow solid C H BrNO S , 379.9951; found: 379.9955.
+
1
6
15
3
(
76.8 mg, 86% yield) after flash chromatography (EtOAc/pet-
3-Phenyl-5-{[(4-trifluoromethylphenyl)sulfonyl]methyl}-4,5-
1
roleum ether 10% v/v). M.p. 123–125 °C. H NMR (400 MHz, dihydroisoxazole (3ai). Compound 3ai was prepared according
CDCl ) δ 7.79 (d, J = 8.3 Hz, 2H), 7.64–7.48 (m, 4H), 7.44–7.28 to the general procedure and was isolated as a white solid
3
(
m, 3H), 5.16–4.94 (m, 1H), 3.62–3.48 (m, 2H), 3.40 (dd, J = (72.9 mg, 79% yield) after flash chromatography (EtOAc/pet-
1
1
7.1, 7.1 Hz, 1H), 3.29 (dd, J = 13.9, 9.2 Hz, 1H), 1.29 (s, 9H). roleum ether 10% v/v). M.p. 153–155 °C. H NMR (400 MHz,
C NMR (101 MHz, CDCl ) δ 158.3, 156.9, 136.3, 130.5, 128.8, CDCl ) δ 8.04 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H),
1
3
3
3
1
28.8, 127.9, 126.8, 126.6, 74.8, 59.7, 40.3, 35.4, 31.1. IR (KBr): 7.63–7.52 (m, 2H), 7.42–7.27 (m, 3H), 5.22–4.98 (m, 1H),
−
1
13
ν = 2966.3, 1595.6, 1311.5, 1159.0, 889.9, 763.7, 572.4 cm
HRMS-ESI (m/z): [M
.
3.64–3.50 (m, 2H), 3.42–3.28 (m, 2H). C NMR (101 MHz,
+
+
+
Na] calcd for: C H NNaO S , CDCl ) δ 156.8, 142.9, 135.87 (q, J = 33.0 Hz), 130.7, 128.9,
2
0
23
3
3
3
80.1291; found: 380.1295.
128.9, 128.5, 126.8, 126.62 (q, J = 3.4 Hz), 123.04 (q, J = 273.1
1
9
5
-{[(4-Methoxyphenyl)sulfonyl]methyl}-3-phenyl-4,5-dihy- Hz), 74.5, 59.9, 40.4. F NMR (376 MHz, CDCl
3
) δ −63.2. IR
droisoxazole (3ae). Compound 3ae was prepared according to (KBr): ν = 2931.5, 1403.1, 1326.0, 1129.6, 842.8, 759.6,
the general procedure and was isolated as a light-yellow solid 607.3 cm−
75.5 mg, 91% yield) after flash chromatography (EtOAc/pet- NNaO
5-{[(2-Fluorophenyl)sulfonyl]methyl}-3-phenyl-4,5-dihydro-
) δ 7.80 (d, J = 8.0 Hz, 2H), 7.65–7.52 (m, 2H), 7.44–7.28 isoxazole (3aj). Compound 3aj was prepared according to the
m, 3H), 7.06–6.88 (m, 2H), 5.12–4.92 (m, 1H), 3.82 (s, 3H), general procedure and was isolated as a yellow solid (27.9 mg,
1
.
HRMS-ESI (m/z): [M
+
Na] calcd for:
3
S , 392.0539; found: 392.0543.
+
+
(
C
17
H
14
F
3
1
roleum ether 10% v/v). M.p. 114–117 °C. H NMR (400 MHz,
CDCl
(
3
1
3
3
.62–3.46 (m, 2H), 3.44–3.21 (m, 2H). C NMR (101 MHz, 35% yield) after flash chromatography (EtOAc/petroleum ether
1
CDCl
3 3
) δ 164.1, 156.9, 130.8, 130.5, 130.3, 128.8, 128.8, 126.8, 10% v/v). M.p. 109–111 °C. H NMR (400 MHz, CDCl ) δ
1
14.7, 74.9, 60.1, 55.8, 40.4. The NMR data were in agreement 7.99–7.82 (m, 1H), 7.69–7.53 (m, 3H), 7.40–7.28 (m, 4H),
1
5
with reported results.
7.26–7.14 (m, 1H), 5.28–4.93 (m, 1H), 3.79 (dd, J = 14.0, 4.5 Hz,
1
3
5
-{[(4-Fluorophenyl)sulfonyl]methyl}-3-phenyl-4,5-dihydro- 1H), 3.65–3.29 (m, 3H). C NMR (101 MHz, CDCl ) δ 159.7 (d,
3
isoxazole (3af). Compound 3af was prepared according to the J = 256.1 Hz), 156.8, 136.7 (d, J = 8.6 Hz), 130.6, 130.4, 128.8,
general procedure and was isolated as a light-yellow solid 128.7, 127.4, 127.2, 126.8, 124.9 (d, J = 3.7 Hz), 117.4 (d, J =
1
9
(
72.7 mg, 91% yield) after flash chromatography (EtOAc/pet- 21.1 Hz), 74.5, 59.4, 40.5. F NMR (376 MHz, CDCl
3
) δ −108.7.
1
roleum ether 10% v/v). M.p. 128–130 °C. H NMR (400 MHz, IR (KBr): ν = 2925.5, 1597.8, 1475.3, 1312.4, 1140.6, 906.1,
CDCl ) δ 7.96–7.85 (m, 2H), 7.63–7.52 (m, 2H), 7.41–7.29 (m, 761.0, 689.5 cm . HRMS-ESI (m/z): [M + Na] calcd for:
−
1
+
3
+
3
3
2
1
4
H), 7.26–7.15 (m, 2H), 5.16–5.01 (m, 1H), 3.63–3.48 (m, 2H),
.41–3.25 (m, 2H). C NMR (101 MHz, CDCl ) δ 166.1 (d, J =
3
C
16
H
14FNNaO
3
S , 342.0571; found: 342.0575.
5-[(Naphthalen-2-ylsulfonyl)methyl]-3-phenyl-4,5-dihydro-
57.2 Hz), 156.8, 135.4 (d, J = 3.0 Hz), 131.1 (d, J = 9.7 Hz), isoxazole (3ak). Compound 3ak was prepared according to the
30.6, 128.9, 128.6, 126.8, 116.8 (d, J = 22.7 Hz), 74.7, 60.1, general procedure and was isolated as a yellow solid (82.6 mg,
0.4. F NMR (376 MHz, CDCl ) δ −102.4. The NMR data were 94% yield) after flash chromatography (EtOAc/petroleum ether
1
3
1
9
3
1
5
1
in agreement with reported results.
-{[(4-Chlorophenyl)sulfonyl]methyl}-3-phenyl-4,5-dihydro- (s, 1H), 8.03–7.79 (m, 4H), 7.70–7.50 (m, 4H), 7.41–7.27 (m,
isoxazole (3ag). Compound 3ag was prepared according to the 3H), 5.18–4.97 (m, 1H), 3.69–3.52 (m, 2H), 3.51–3.32 (m, 2H).
10% v/v). M.p. 169–171 °C. H NMR (400 MHz, CDCl ) δ 8.46
3
5
1
3
general procedure and was isolated as a light-yellow solid
C NMR (101 MHz, CDCl ) δ 156.9, 136.1, 135.5, 132.2, 130.6,
3
(
80.6 mg, 96% yield) after flash chromatography (EtOAc/pet- 130.0, 129.9, 129.6, 129.5, 128.8, 128.7, 128.1, 127.9, 126.8,
1
roleum ether 10% v/v). M.p. 142–145 °C. H NMR (400 MHz, 122.4, 74.8, 59.8, 40.4. IR (KBr): ν = 3057.3, 1300.8, 1143.4,
CDCl ) δ 7.88–7.77 (m, 2H), 7.57 (dd, J = 7.7, 1.8 Hz, 2H), 1125.2, 910.0, 819.7, 780.5 cm . HRMS-ESI (m/z): [M + Na]
7
3
−
1
+
3
+
.54–7.49 (m, 2H), 7.38–7.30 (m, 3H), 5.14–5.01 (m, 1H), calcd for: C20
H
17NNaO
3
S , 374.0821; found: 374.0825.
1
3
.61–3.48 (m, 2H), 3.42–3.24 (m, 2H). C NMR (101 MHz,
5-[(Butylsulfonyl)methyl]-3-phenyl-4,5-dihydroisoxazole (3al).
CDCl ) δ 156.8, 141.1, 137.8, 130.6, 129.8, 129.6, 128.9, 128.6, Compound 3al was prepared according to the general pro-
3
1
26.8, 74.7, 60.0, 40.4. The NMR data were in agreement with cedure and was isolated as a yellow solid (26.7 mg, 38% yield)
1
5
reported results.
after flash chromatography (EtOAc/petroleum ether 10% v/v).
1
5
-{[(4-Bromophenyl)sulfonyl]methyl}-3-phenyl-4,5-dihydro- M.p. 89–92 °C. H NMR (400 MHz, CDCl ) δ 7.66–7.51 (m, 2H),
3
isoxazole (3ah). Compound 3ah was prepared according to the 7.43–7.26 (m, 3H), 5.32–5.06 (m, 1H), 3.57 (dd, J = 17.0, 10.5
general procedure and was isolated as a yellow solid (90.3 mg, Hz, 1H), 3.42 (dd, J = 14.5, 7.5 Hz, 1H), 3.24 (dd, J = 17.0, 7.0
9
5% yield) after flash chromatography (EtOAc/petroleum ether Hz, 1H), 3.14–3.01 (m, 3H), 1.88–1.67 (m, 2H), 1.53–1.33 (m,
904 | Org. Biomol. Chem., 2019, 17, 898–907
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1
3
+
+
2
H), 0.91 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl
3
)
3
(m/z): [M + Na] calcd for: C20H23NNaO S , 380.1291; found:
δ 157.0, 130.7, 128.9, 128.6, 126.9, 75.0, 56.9, 54.5, 40.5, 23.8, 380.1294.
2
1.7, 13.6. IR (KBr): ν = 2955.3, 2869.9, 1267.7, 1132.1, 912.2,
2-{[(4-tert-Butylphenyl)sulfonyl]methyl}-4,4-dimethyl-5-phenyl-
−
1
+
7
56.8, 691.5 cm . HRMS-ESI (m/z): [M + Na] calcd for: 3,4-dihydro-2H-pyrrole 1-oxide (4rd). Compound 4rd was pre-
+
C H NNaO S , 304.0978; found: 304.0982.
pared according to the general procedure and was isolated as a
1
4
19
3
4
,4-Dimethyl-5-phenyl-2-tosylmethyl-3,4-dihydro-2H-pyrrole light-yellow solid (69.9 mg, 70% yield) after flash chromato-
1
1
-oxide (4ra). Compound 4ra was prepared according to the graphy (EtOAc/petroleum ether 50% v/v). M.p. 104–107 °C. H
general procedure and was isolated as a white solid (63.4 mg, NMR (400 MHz, CDCl ) δ 7.86–7.75 (m, 4H), 7.57–7.48 (m, 2H),
3
7
5
1% yield) after flash chromatography (EtOAc/petroleum ether 7.40–7.27 (m, 3H), 4.59–4.43 (m, 1H), 4.42–4.28 (m, 1H),
1
0% v/v). M.p. 169–172 °C. H NMR (400 MHz, CDCl
3
)
3.30–3.09 (m, 1H), 2.63–2.39 (m, 1H), 2.18–1.96 (m, 1H), 1.36
1
3
δ 7.81–7.72 (m, 4H), 7.38–7.26 (m, 5H), 4.55–4.43 (m, 1H), 4.36 (s, 3H), 1.34–1.23 (m, 12H). C NMR (101 MHz, CDCl3)
(dd, J = 13.7, 2.6 Hz, 1H), 3.20 (dd, J = 13.7, 11.0 Hz, 1H), 2.47 δ 158.2, 148.6, 136.4, 129.9, 128.4, 128.1, 127.8, 126.5, 65.5,
(
9
dd, J = 13.2, 7.3 Hz, 1H), 2.37 (s, 3H), 2.02 (dd, J = 13.1, 58.8, 43.7, 42.6, 35.3, 31.1, 28.0, 26.4. IR (KBr): ν = 2969.3,
1
3
−1
.8 Hz, 1H), 1.34 (s, 3H), 1.29 (s, 3H). C NMR (101 MHz, 1541.7, 1308.3, 1155.9, 767.3, 694.3, 570.1 cm . HRMS-ESI
+
+
CDCl
3
) δ 148.6, 145.3, 136.3, 130.1, 129.9, 128.4, 128.4, 128.2, (m/z): [M + Na] calcd for: C23
H
29NNaO
3
S , 422.1760; found:
1
3
27.9, 65.5, 58.7, 43.7, 42.5, 28.0, 26.4, 21.7. IR (KBr): ν = 422.1765.
−
1
026.4, 2966.6, 1578.8, 1303.7, 1142.1, 766.5, 544.4 cm
.
2-{[(4-Chlorophenyl)sulfonyl]methyl}-4,4-dimethyl-5-phenyl-
+
+
HRMS-ESI (m/z): [M
+
Na] calcd for:
C
20
H
23NNaO
3
S , 3,4-dihydro-2H-pyrrole 1-oxide (4rg). Compound 4rg was pre-
3
80.1291; found: 380.1295.
pared according to the general procedure and was isolated as a
Crystal data for 4ra. C H NO S, M = 357.45, a = 10.1298(3) yellow solid (29.3 mg, 31% yield) after flash chromatography
2
0
23
3
1
Å b = 18.7025(5) Å c = 19.0521(5) Å α = 90°, β = 90°, γ = 90°, V = (EtOAc/petroleum ether 50% v/v). M.p. 151–154 °C. H NMR
3
3
0
609.47(17) Å , T = 113.15 K, space group Pbca, Z = 8, μ(MoKα) = (400 MHz, CDCl
3
) δ 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 7.5 Hz,
.198 mm− , 41 041 reflections measured, 4310 independent 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.40–7.30 (m, 3H), 4.52 (q, J = 9.7,
values were 0.0400 (I > 8.8 Hz, 1H), 4.37 (d, J = 13.8 Hz, 1H), 3.24 (dd, J = 13.5,
σ(I)). The final wR(F ) values were 0.0977 (I > 2σ(I)). The final 11.0 Hz, 1H), 2.50 (dd, J = 13.1, 7.4 Hz, 1H), 2.05 (dd, J = 12.9,
1
reflections (Rint = 0.0558). The final R
1
2
2
2
13
R values were 0.0483 (all data). The final wR(F ) values were 10.0 Hz, 1H), 1.37 (s, 3H), 1.31 (s, 3H). C NMR (101 MHz,
1
2
0
1
.1037 (all data). The goodness of fit on F was 1.039. CCDC CDCl
879645.† 128.2, 65.4, 58.6, 43.8, 42.5, 28.0, 26.4. IR (KBr): ν = 2974.3,
,4-Dimethyl-5-phenyl-2-[(phenylsulfonyl)methyl]-3,4-dihydro- 1539.0, 1306.4, 1157.3, 1086.1, 865.9, 760.1 cm . HRMS-ESI
3
) δ 149.0, 141.0, 137.8, 130.0, 129.9, 129.4, 128.5, 128.2,
−
1
4
+
+
2
3
H-pyrrole 1-oxide (4rb). Compound 4rb was prepared accord- (m/z): [M + Na] calcd for: C19H20ClNNaO S , 400.0745; found:
ing to the general procedure and was isolated as a light-yellow 400.0748.
solid (53.2 mg, 62% yield) after flash chromatography (EtOAc/ 4,4-Dimethyl-2-[(naphthalen-2-ylsulfonyl)methyl]-5-phenyl-
NMR 3,4-dihydro-2H-pyrrole-1-oxide (4rk). Compound 4rk was pre-
) δ 7.91 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 7.8 Hz, pared according to the general procedure and was isolated as a
H), 7.62 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.39–7.29 yellow solid (39.4 mg, 40% yield) after flash chromatography
1
petroleum ether 50% v/v). M.p. 160–163 °C.
400 MHz, CDCl
H
(
3
2
1
(m, 3H), 4.52 (q, J = 10.1 Hz, 1H), 4.39 (dd, J = 13.7, 2.4 Hz, (EtOAc/petroleum ether 50% v/v). M.p. 139–142 °C. H NMR
1
H), 3.21 (dd, J = 13.5, 11.2 Hz, 1H), 2.50 (dd, J = 13.2, 7.4 Hz, (400 MHz, CDCl
3
) δ 8.47 (s, 1H), 8.03–7.91 (m, 1H), 7.90–7.82
1
H), 2.05 (dd, J = 13.1, 9.8 Hz, 1H), 1.37 (s, 3H), 1.31 (s, 3H). (m, 2H), 7.82–7.70 (m, 2H), 7.67–7.51 (m, 2H), 7.40–7.25 (m,
C NMR (101 MHz, CDCl ) δ 148.5, 139.5, 134.2, 129.9, 129.5, 3H), 4.65–4.40 (m, 2H), 3.29 (t, J = 12.3 Hz, 1H), 2.53 (dd, J =
3
1
3
1
28.4, 128.1, 127.9, 65.5, 58.7, 43.7, 42.6, 28.0, 26.4. IR (KBr): 12.8, 7.4 Hz, 1H), 2.15–1.99 (m, 1H), 1.35 (s, 3H), 1.31 (s, 3H).
−
1
13
ν = 2929.9, 1553.9, 1449.6, 1306.0, 1151.9, 732.4, 569.3 cm
HRMS-ESI (m/z): [M
.
C NMR (101 MHz, CDCl ) δ 148.6, 136.2, 135.5, 132.2, 129.9,
3
+
+
+
Na] calcd for:
C
19
H
21NNaO
3
S , 129.9, 129.8, 129.5, 129.5, 128.4, 128.4, 128.1, 128.1, 127.9,
3
66.1134; found: 366.1136.
122.4, 65.6, 58.7, 43.7, 42.6, 28.0, 26.4. IR (KBr): ν = 2970.4,
−
1
4
,4-Dimethyl-5-phenyl-2-[(m-tolylsulfonyl)methyl]-3,4-dihydro- 2933.8, 1551.4, 1303.3, 1146.2, 1128.2, 768.3, 541.8 cm
.
+
+
2
H-pyrrole 1-oxide (4rc). Compound 4rc was prepared accord- HRMS-ESI (m/z): [M
+
Na] calcd for:
C
23
H
23NNaO
3
S ,
ing to the general procedure and was isolated as a light-yellow 416.1291; found: 416.1295.
solid (58.1 mg, 65% yield) after flash chromatography (EtOAc/ Methyl 4,4-dimethyl-3a-phenyl-6-tosylmethyl-3a,4,5,6-tetra-
NMR hydropyrrolo[1,2-b]isoxazole-3-carboxylate (5). The compound
) δ 7.83–7.76 (m, 2H), 7.73–7.65 (m, 2H), 3ra (89.4 mg, 0.25 mmol) was mixed with methyl propiolate
.47–7.39 (m, 2H), 7.39–7.30 (m, 3H), 4.52 (m, 1H), 4.37 (dd, (105 mg, 1.25 mmol) using benzene as a solvent in a 50 mL
1
petroleum ether 50% v/v). M.p. 155–158 °C.
400 MHz, CDCl
H
(
3
7
J = 13.7, 2.6 Hz, 1H), 3.19 (dd, J = 13.6, 11.1 Hz, 1H), 2.51 (dd, flask. The mixture was heated for 24 h at 80 °C. After removal
J = 13.2, 7.4 Hz, 1H), 2.39 (s, 3H), 2.06 (dd, J = 13.1, 9.7 Hz, of the solvent, the residue was purified by silica gel chromato-
1
3
1
H), 1.37 (s, 3H), 1.31 (s, 3H). C NMR (101 MHz, CDCl3) graphy (ethyl acetate : petroleum ether = 1 : 15, v/v) to give
1
δ 148.6, 139.9, 139.3, 134.9, 129.9, 129.3, 128.4, 128.1, 125.0, 83 mg of product 5 (75%) as a colorless oil. H NMR
6
1
5.5, 58.7, 43.7, 42.6, 28.0, 26.4, 21.3. IR (KBr): ν = 2959.5, (400 MHz, CDCl
3
) δ 7.76 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.7 Hz,
553.8, 1297.9, 1142.4, 868.6, 769.1, 719.3 cm− . HRMS-ESI 2H), 7.36–7.27 (m, 3H), 7.23–7.15 (m, 2H), 7.15–7.09 (m, 1H),
1
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3
1
0
1
6
.83–3.63 (m, 5H), 3.31 (dd, J = 13.4, 9.9 Hz, 1H), 2.39 (s, 3H),
J. Am. Chem. Soc., 2001, 123, 2907–2908; (c) K. Wakita,
G. B. Bajracharya, M. A. Arai, S. Takizawa, T. Suzuki and
H. Sasai, Tetrahedron: Asymmetry, 2007, 18, 372–376.
6 (a) T. Courant and G. Masson, J. Org. Chem., 2016, 81,
6945–6952; (b) G. Yin, X. Mu and G. Liu, Acc. Chem. Res.,
2016, 49, 2413–2423; (c) X.-W. Lan, N.-X. Wang and Y. Xing,
Eur. J. Med. Chem., 2017, 2017, 5821–5851.
.95 (dd, J = 12.9, 5.0 Hz, 1H), 1.64–1.49 (m, 1H), 1.25 (s, 3H),
1
3
3
.71 (s, 3H). C NMR (101 MHz, CDCl ) δ 165.8, 155.5, 145.0,
43.9, 136.9, 130.0, 127.9, 127.8, 126.9, 126.8, 111.9, 83.0, 61.4,
0.0, 51.6, 45.4, 44.1, 27.7, 27.2, 21.7. HRMS-ESI (m/z):
+
+
[M + H] calcd for: C24
H
28NO
5
S , 442.1683; found: 442.1688. IR
(KBr): ν = 2962.9, 1711.2, 1613.5, 1439.9, 1315.5, 1149.9, 768.1,
71.7, 510.9 cm−
1
.
7 (a) M. Lucarini, G. F. Pedulli and A. Alberti, J. Org. Chem.,
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1994, 59, 1980–1983; (b) G. Carlo, G. Patrizia and
L. Osvaldo, Angew. Chem., Int. Ed., 2008, 47, 4790–4796;
(c) T. Vogler and A. Studer, Synthesis, 2008, 1979–1993;
Conflicts of interest
(
d) T. Ludger and S. Armido, Angew. Chem., Int. Ed., 2011,
0, 5034–5068.
There are no conflicts to declare.
5
8
9
(a) Y.-T. He, L.-H. Li, Y.-F. Yang, Y.-Q. Wang, J.-Y. Luo,
X.-Y. Liu and Y.-M. Liang, Chem. Commun., 2013, 49, 5687–
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We acknowledge financial support from the National Natural
Science Foundation of China (NSFC 21672106 and NSFC
2
1272121) and Tianjin Municipal Commission of Science and
Technology (15JCZDJC33300).
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