Trifluoromethyl Vinyl Sulfide: A Building Block for the Synthesis of CF3S-Containing Isoxazolidines

Article abstract of DOI:10.1021/acs.joc.7b02639

Trifluoromethyl vinyl sulfide, a potential building block for pharmaceutically and agrochemically relevant products, is prepared and used for the first time in high-pressure-mediated 1,3-dipolar cycloaddition reactions with nitrones to synthesize (trifluoromethyl)sulfanyl isoxazolidines.

Full text of DOI:10.1021/acs.joc.7b02639

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Article
(Trifluoromethyl) Vinyl Sulfide: a Building Block for
the Synthesis of CF3S-Containing Isoxazolidines
Alejandra Riesco-Domínguez, Jeroen van de Wiel, Trevor A. Hamlin, Bas van Beek,
Stephen D. Lindell, Daniel Blanco-Ania, F. Matthias Bickelhaupt, and Floris P.J.T. Rutjes
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02639 • Publication Date (Web): 10 Jan 2018
Downloaded from http://pubs.acs.org on January 10, 2018
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The Journal of Organic Chemistry
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(Trifluoromethyl) Vinyl Sulfide: a Building Block for the Syn-
thesis of CF3S-Containing Isoxazolidines
Alejandra Riesco-Domínguez,† Jeroen van de Wiel,† Trevor A. Hamlin,§ Bas van Beek,§ Stephen
D. Lindell,‡ Daniel Blanco-Ania,† F. Matthias Bickelhaupt,*,†,§ Floris P. J. T. Rutjes*,†
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†Radboud University, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, the Nether-
lands
§Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM), Vrije Universiteit
Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, the Netherlands
‡Bayer CropScience AG, Industriepark Höchst, G836, 65926 Frankfurt am Main, Germany
Supporting Information Placeholder
ABSTRACT: (Trifluoromethyl) vinyl sulfide, a potential building block for pharmaceutically and agrochemically relevant
products, is prepared and used for the first time in high-pressure-mediated 1,3-dipolar cycloaddition reactions with
nitrones to synthesize (trifluoromethyl)sulfanyl isoxazolidines.
containing compounds.6 However, incorporation via sim-
INTRODUCTION
ple CF3S-containing building blocks is still unprecedented
The (trifluoromethyl)sulfanyl group (SCF3) represents a
privileged substituent in agrochemicals and pharmaceuti-
cals because of the strong electron withdrawing effect and
the large Hansch lipophilicity parameter (π = 1.44).1
Cefazaflur,2 a first-generation cephalosporin antibiotic,
toltrazuril,3 an antiprotozoal agent, and a losartan ana-
logue,4 developed as potential hypotensive agent, are
prominent examples of biologically active compounds
bearing the SCF3 group (Figure 1).
so that the use of a CF3S-containing reagent could be an
alternative strategy to construct CF3S-substituted hetero-
cycles. More specifically, (trifluoromethyl) vinyl sulfide
(2) could be an attractive building block to provide
straightforward access to a wide variety of hetero- and
carbocycles via cycloaddition reactions. Previously re-
ported examples of cycloaddition reactions of alkene 2 are
rather scarce: there is a single example of a Diels–Alder
reaction with 2,3-dimethylbutadiene to yield the corre-
sponding CF3S-cyclohexene,7 and two cyclopropanation
examples with organomercury reagents to yield CF3S-
substituted cyclopropanes.8
The potential of this unexplored chemistry and the inher-
ent biological attractiveness of these molecules motivated
us to further study the reactivity of alkene 2 in cycloaddi-
tion reactions. Thus, we herewith present the study of the
first 1,3-dipolar cycloaddition reactions of 2 with several
nitrones9 to synthesize a novel group of isoxazolidines
(Scheme 1).
Figure 1. Bioactive heterocycles containing the SCF3
group.
Hence, CF3S-containing compounds are considered ap-
pealing targets in the agrochemical and pharmaceutical
fields and, consequently, modern research has focused on
efficient (trifluoromethyl)sulfanylation methods. The
main strategies that have been developed to synthesize
CF3S-containing compounds have focused on direct C–S
bond formation5 and trifluoromethylation of sulfur-
RESULTS AND DICSUSSION
Scheme 1. Synthesis of CF3S-containing isoxazoli-
dines.
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catalytic amount of In(OTf)3 and alkene 2 at 21 °C in THF,
1
but no conversion into the product was observed. When
applying the same conditions at 80 °C with nitrone 6c (R
= Me), less than 7% conversion into the final product was
observed by 1H NMR, presumably because of the low reac-
tivity of this alkene and perhaps due to its volatility.
Therefore, we decided to perform these reactions under
high-pressure conditions (Table 2), which is an estab-
lished and powerful tool to increase the rate of cycloaddi-
tion reactions.10 Thus, when using 1.3 equiv of 2 at 21 °C
under a 15 kbar pressure (entry 1) we gratifyingly observed
an 83% conversion into isoxazolidines 4c and 7c (regioi-
someric ratio 4c/7c 13:1, diastereomeric ratio [dr] cis-
4c/trans-4c 7:2). Nitrone 6b gave only 56% conversion
under the same reaction conditions (entry 4), with similar
regio- and diastereoisomeric ratios. When increasing the
concentration of alkene 2, 93 and 75% conversions into
compounds 4c and 4b were obtained, respectively (en-
tries 2 and 5). Finally, an increase of the temperature to 50
°C gave nearly full conversion into the desired cis- and
trans-products 4c and 4b (entries 3 and 6).
Azoxybenzene11 8 was formed in all reactions as a side
product (Scheme 2) and could not be separated in any
case from trans-4 by column chromatography. Thus, we
used galvinoxyl to prevent the formation of compound 8.12
We were pleased to see that when using three equiv of
alkene 2 at 50 °C, in the presence of 1–3 mol % of gal-
vinoxyl as radical scavenger (entries 7 and 8), not only full
conversion into the desired product 4b was obtained, but
also the formation of the azoxy compound 8 was fully
suppressed.
2
3
4
5
6
7
8
9
We commenced our investigations by forming alkene 2 in
situ. Because of its high volatility,7 we first performed the
elimination reactions in deuterated solvents in order to
instantly measure conversions from commercially availa-
ble chloro alkane 1 into alkene 2, with no need for further
treatment or isolation of the alkene. We tested several
bases (Et3N, DBU, KOtBu, KOH and KOTMS) in the pres-
ence of various deuterated solvents (CD2Cl2, THF-d8,
CD3OD and DMF-d7; see Supporting Information [SI] for
experimental details) to eventually choose a solution of
KOtBu in THF-d8 at 21 °C for 90 min as the final method
for the in situ synthesis of alkene 2 with full conversion.
Initially, we focused on the synthesis of 2,5-disubstituted
isoxazolidines 3 using N-substituted hydroxylamines 5
and paraformaldehyde as precursors for the in-situ syn-
thesis of the dipoles (Table 1). The nitrone intermediates
were used without isolation in a one-pot process with a
preformed solution of alkene 2 (3 equiv) and In(OTf)3
(0.06 equiv). In this manner, we obtained isoxazolidine 3a
in 22% yield after column chromatography. Increasing the
concentration of 2 (6 equiv) resulted in a yield of 38%
(entry 1). Isoxazolidines 3b–e were synthesized in yields
between 20–30% applying the same reaction conditions
with different substrates (entries 2–5). However, yields
were rather low after column chromatography in all cases
(see SI for experimental details).
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Table 1. Synthesis of isoxazolidines 3a−e.
Furthermore, our reactions gave the exo-products as the
major diastereoisomers (the cis-isomers), showing a 3:1
diastereomeric ratio (entries 7 and 8). Having these re-
sults in hand, the scope of nitrones in this 1,3-dipolar cy-
cloaddition was examined by employing the conditions
shown in entry 7. We first synthesized a total of eighteen
nitrones (6a–r) with phenyl (containing both electron-
donating and electron-withdrawing groups in the 2-, 3-
and 4- positions), heterocyclic and carbamoyl substitu-
ents in excellent yields (see SI). Then, we studied the
scope of the 1,3-dipolar cycloaddition reactions between
alkene 2 and nitrones 6a–r (Table 3).
Entry
Compound
R
Yield (%)
1
3a
3b
3c
3d
3e
C6H5
38
20
22
30
23
2
3-CF3C6H4
3,5-Cl2C6H3
C6H5CH2
Cy
3
4a
5a
aEt3N (1.0 equiv) was used.
As shown in Table 3, high and excellent yields (total
yields) were observed for compounds 4a–c, 4f–i, 4l and
4n. In addition, in most of the cases the major product
(cis-4) was separated from the other isomers by column
chromatography in good yields (cis-4a–c, cis-4f–j, cis-4m
and cis-4q). Unfortunately, in a few cases the isomers 4
were obtained as a mixture that could not be separated
(4d,e, 4k,l and 4n). For compounds 4o and 4p, the trans-
4 isomer and the corresponding regioisomers 7 were pre-
sent as a mixture.13 The assignment of the cis- and trans-
isomers was performed by 2D NMR studies (NOESY).
With these results in hand and because of the low yields
in the synthesis of 3a−e, we changed our strategy to the
synthesis of 2,3,5-trisubstituted isoxazolidines 4, exhibit-
ing a second (hetero)aromatic group on the 3-position
and introducing consequently a second chiral center in
the molecule (Scheme 2, Table 2).
Scheme 2. Formation of compounds 4, 7 and 8.
We first performed the reaction with nitrone 6a (R = H), a
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Table 2. Optimization process for the 1,3-dipolar cycloaddition reaction of nitrones 6 with alkene 2.
1
2
En-
try
Nitrone
2
R
t (°C)
Scavenger
cis-4/trans-4 8a
Conversiona (yield)b
(equiv)
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
6c
6c
6c
6b
6b
6b
6b
6b
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
1.3
3
21
21
–
76:22
79:21
76:24
79:21
79:21
77:23
76:24
76:24
5%
83% (41%)c
93% (–)
–
22%
6%
7%
3
50
21
–
96% (85%)c
56% (35%)c
75% (–)
1.3
3
–
21
–
38%
17%
0%
1%
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3
50
50
50
–
91% (79%)c
100% (78%)
100% (–)
3
Galvinoxyl (3%)
3
Galvinoxyl (1%)
aCalculated by integration of the 1H NMR signals of the crude mixtures. bIsolated after column chromatography. ctransꢀIsomer contaminated with
7.
Table 3. Scope of the high-pressure-promoted 1,3-dipolar cycloaddition reaction.
aCombined yield. Calculated by H NMR of the crude. Galvinoxyl was not used in the reaction. cis-4o,p/trans-4o,p/(mixture of iso-
mers 7).
b
1
c
d
To evaluate the apparent regioselectivity of the cycloaddi-
tion, high-level DFT calculations were carried out at the
BP86/TZ2P14 level, using the ADF program.15 Tetrahydro-
furan was simulated using the COSMO solvation model.16
Thermochemical corrections were computed using the
temperature and pressure under which the experiments
were performed (see SI for computational details).
The diastereoselectivity was lower for compounds 4o and
4p, which contained an indole and a pyrrole substituent,
respectively. In these cases, a mixture of cis- and trans-
diastereoisomers was obtained approximately in a 3:2
ratio. In addition, for compounds 4o and 4p, a 7:3 ratio of
a mixture cis-7 and trans-7 from the regioisomer 7 was
observed. For these two compounds (4o and 4p), the total
yields were significantly lower because of incomplete
conversion into the products and purification problems.
Finally, when using a non-aromatic nitrone, the final
benzyl amide isoxazolidine 4r was synthesized in 60%
yield.
Scheme 3. Formation of compounds 10 and 11.
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phile 2 up to their respective TS (indicated by the dot) computed
at the BP86/TZ2P level.
We focused on understanding the regioselectivity of
the cycloaddition between a simple model nitrone 9 with
2 (Scheme 3). This reaction proceeds in a concerted and
asynchronous manner with a Gibbs free energy barrier of
21.3 and 24.0 kcal mol−1 for 10 and 11, respectively (Table
4). The ∆∆G‡ of 2.7 kcal mol−1 facilitates a high degree of
regioselectivity, resulting in a calculated product ratio of
98:2 for 10/11. Furthermore, the experimentally observed
regioisomer 10 is more stable than 11 (∆∆Grxn = 3.9 kcal
mol−1). The calculated product ratio for the model nitrone
cycloaddition is in line with experimentally observed re-
gioselectivity of reactions involving the majority of the
nitrones 6.
1
2
3
4
5
6
7
8
Applying the ASM along the reaction coordinate defined
by the bending of the 1,3-dipole, it is revealed that reactiv-
ity differences in the reaction between 9 and 2 leading to
10 (blue curve) and 11 (red curve) are a result of ΔEint
(Figure 2a). ΔEstrain remains nearly constant for both reac-
tions along the reaction coordinate. Next, the EDA terms
were analyzed and the ΔEPauli dominates and is chiefly
responsible for the difference in the interaction energies
(Figure 2b). The more favorable ΔVelstat and ΔEoi curves
associated with the reaction leading to 11 are unable to
overcome for increased steric repulsion associated with
this approach. These results highlight the fact that the
reaction results from the least hindered approach, leaving
the SCF3 group far away from the CH2 group. See SI for an
ASA and EDA analysis on 6m and 6p.
9
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Table 4. Computed activation barriers, reaction en-
ergies (kcal mol−1), and product distribution com-
puted at the COSMO(THF)-BP86/TZ2P level of theo-
ry.
Compound ∆E‡ (∆G‡)
∆Erxn (∆Grxn
−17.6 (−6.1)
−14.3 (−2.2)
)
Product ratioa
In summary, we have developed the synthesis of a new
class of 5-[(trifluoromethyl)sulfanyl]isoxazolidines. The
reactions utilized for their synthesis were high-pressure-
promoted 1,3-dipolar cycloaddition reactions between
(trifluoromethyl) vinyl sulfide 2 and various easily synthe-
sized nitrones. The results of our DFT computations are
in harmony with experimental results and were leveraged
to show that the high regioselectivity of these cycloaddi-
tion reactions originates from minimizing steric repul-
sion.
10
11
12.8 (21.3)
15.0 (24.0)
98
2
aCalculated at 50 °C and 15 kbar based on the ∆∆G‡ between
10 and 11 (see SI for details).
Insight into why regioisomer 10 is favored over the other,
11, is provided by the activation strain model (ASM)17 (also
known as the distortion-interaction model).18 In this
framework, the potential energy surface ΔE(ζ) is decom-
posed along the reaction coordinate ζ into the strain ΔE-
strain(ζ) associated with deforming the individual reactants
plus the actual interaction ΔEint(ζ) between the deformed
reactants.
EXPERIMENTAL SECTION
General information. Reagents were obtained from commercial suppli-
ers and were used without purification. Standard syringe techniques were
applied for the transfer of dry solvents and air- or moisture-sensitive
reagents. Tetrahydrofuran was used as a solvent after distillation. Potas-
sium tert-butoxide was used as a 1.0 M solution in tetrahydrofuran. The
ꢁE‡(ζ) = ꢁEstrain(ζ) + ꢁEint(ζ)
(1)
The ΔEint(ζ) between the reactants is further analyzed by
an energy decomposition analysis (EDA) in the conceptu-
al framework provided by the Kohn–Sham molecular or-
bital (KS-MO) model19 and is decomposed into three
physically meaningful terms:
high-pressure experiments were run in
a high-pressure apparatus
equipped with a one-wall-piston cylinder for pressures up to 15 kbar (1.5
GPa).Reactions were performed in 1–1.5-mL PTFE ampules closed by
screwed stainless steel stoppers. These ampules were inserted into the
high-pressure vessel filled with 80-100 petroleum ether and transmission
medium. Reactions were followed, and RF values were obtained, using
thin layer chromatography (TLC) on silica gel-coated plates (Merck 60
F254) with the indicated solvent mixture. Detection was performed with
UV light, and/or by charring at ca. 150 °C after dipping into a solution of
KMnO4. Infrared spectra were recorded on an IR-ATR Bruker TENSOR 27
spectrometer. High-resolution mass spectra were recorded on a JEOL
AccuTOF (ESI) or a MAT900 (EI, CI, and ESI) GC-TOF. NMR spectra
were recorded at 298 K on a Varian Inova 400 (400 MHz), Bruker Avance
III 400 MHz or Bruker Avance III 500 MHz spectrometer in the solvent
indicated. Chemical shifts are given in parts per million (ppm) with re-
ꢁEint(ζ) = ꢁVelstat(ζ) + ꢁEPauli(ζ) + ꢁEoi(ζ)
(2)
The ΔVelstat(ζ) term corresponds to the classical electro-
static interaction between unperturbed charge distribu-
tions, ΔEPauli(ζ) is responsible for any steric repulsion, and
the ΔEoi(ζ) accounts for charge transfer (HOMO–LUMO
interactions) and polarization.
1
spect to tetramethylsilane (0.00 ppm) as internal standard for H NMR;
and CDCl3 (77.16 ppm) as internal standard for 13C NMR. Coupling con-
stants are reported as J values in hertz (Hz). 1H NMR data are reported as
follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, dd =
doublet of doublets, dt = doublet of triplets, dtdq = doublet of triplet of
doublet of quartets, dq = doublet of quartets, ddd = doublet of doublet of
doublets, ddt = doublet of doublets of triplets, dddd= doublet of doublets
of doublets of doublets, ddquint = doublet of doublet of quintets,
dddquint = doublet of doublet of doublet of quintets, quint = quintet, t =
triplet, td = triplet of doublets, tt = triplet of triplets m = multiplet, b =
broad), coupling constants (Hz), integration and assignment. Com-
pounds were fully characterized by 1H, 13C, 2D gDQCOSY, gHSQC,
gHMBC, NOESY and HOESY spectra. The characterization and assign-
ment of isoxazolidines 4a–r were done either from isolated compounds
or mixtures of isomers. Column or flash chromatography was carried out
using ACROS silica gel (0.035–0.070 mm, and 60 Å pore diameter).
Figure 2. (a) Activation strain and (b) energy decomposition
analyses of the cycloaddition reactions of nitrone 9 with dieno-
General Procedure for the Synthesis of (Trifluoromethyl) Vinyl
Sulfide 2. (2-Chloroethyl) (trifluoromethyl) sulfide (1.0 equiv) was dis-
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solved in distilled THF (0.40 M) under inert atmosphere and cooled
2-(3,5-Dichlorophenyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(3c).
down to 0 °C. Then, KOtBu (1.0 equiv, 1.0 M solution in THF) was added
slowly and the mixture was warmed up to 21 °C for 90 minutes. This
According to the general procedure, the reaction of hydroxylamine 5c
(29.3 mg, 0.166 mmol) afforded isoxazolidine 3c (10.33 mg, 0.033 mmol)
as a green oil, after column chromatography (heptane/AcOEt/Et3N,
1
2
3
4
5
6
7
8
1
solution was used for the cycloaddition reactions of alkene 2. H NMR
1
[400 MHz, δ (ppm), THF-d8]: 6.54 (dd, J = 16.5, 9.4 Hz, 1 H), 5.75–5.66 (m,
2 H). 13C NMR [101 MHz, δ (ppm), THF-d8]: 129.8 (q, J = 306.5 Hz), 124.4
(q, J = 1.0 Hz), 121.3 (q, J = 3.2 Hz). 19F NMR [377 MHz, δ (ppm), THF-d8]:
−43.6.7
12.2:1:0.13). H NMR [500 MHz, δ (ppm), CDCl3]: 6.99 (t, J = 1.8 Hz, 1 H),
6.91 (d, J = 1.8 Hz, 2 H), 5.98 (dd, J = 8.0, 4.1 Hz, 1 H), 3.75 (ddd, J = 8.9,
8.1, 4.4 Hz, 1 H), 3.27 (ddd, J = 9.2, 8.6, 7.1 Hz, 1 H), 3.01–2.87 (m, 1 H),
2.47–2.36 (m, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 151.6, 135.4, 129.7
(q, J = 307.9 Hz), 122.5, 114.2, 81.2 (q, J = 2.6 Hz), 51.6, 35.8 (q, J = 1.1 Hz).
FTIR [ꢀ̅
(cm−1)]: 2924, 2850, 1587, 1260, 1115, 1051, 796. HRMS (EI) m/z:
General Procedure for the Synthesis of Hydroxylamines 5b and 5c.
The corresponding nitrobenzene (12b or 12c; 1 equiv) was added to a
flame-dried Schlenk tube containing a suspension of Pd/C (0.25 equiv) in
[M+•] calcd for C10H8Cl2F3NOS 316.9656; found 316.9657. RF: 0.45 (hep-
tane/AcOEt, 4:1). Yield: 20%.
.
9
dry THF (10 mL). The mixture was cooled to 0 °C and N2H4 H2O (2.0
10
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equiv) was added dropwise. The reaction was carefully monitored by TLC
until the starting material disappeared. The crude mixture was diluted
with THF (10 mL) and filtered over a pad of diatomaceous earth. The
solvent was evaporated in vacuo and the crude mixture was purified by
column chromatography using CH2Cl2 under a nitrogen atmosphere.
General Procedure for the Synthesis of Isoxazolidines 3d and 3e. A
solution of hydroxylamine hydrochloride 5d or 5e (1 equiv) in THF (0.22
M) and Et3N (1equiv) was added to a solution of paraformaldehyde (3
equiv) in THF (0.22 M) at 0 °C. Then, a cooled solution (0 °C) of alkene 2
(6.0 equiv) was subsequently added to the solution containing paraform-
aldehyde and the hydroxylamine. Finally, a solution of In(OTf)3 (0.06
equiv) in dry THF (22 mM) was added to the reaction mixture. The reac-
tion mixture was warmed up to 21 °C and stirred for 16 hours. Then, the
reaction mixture was quenched with a saturated aqueous solution of
NaHCO3 (10 mL) and the aqueous layer was extracted with AcOEt (2 × 10
mL). The combined organic layers were dried over MgSO4, filtered off
and concentrated in vacuo. The crude mixture was purified by column
chromatography using the indicated eluent to afford isoxazolines 3d and
3e.
N-[3-(Trifluoromethyl)phenyl]hydroxylamine (5b). According to the gen-
eral procedure, the reaction of 1-nitro-3-(trifluoromethyl)benzene 12b (1.0
g, 5.23 mmol) afforded hydroxylamine 5b (885 mg, 5.00 mmol) as a pale
1
yellow oil. H NMR [400 MHz, δ (ppm), CDCl3]: 7.41–7.34 (m, 1 H), 7.28–
7.26 (m, 1 H), 7.23–7.19 (m, 1 H), 7.15–7.10 (m, 1 H), 6.74–4.98 (bs, 2 H). RF:
0.31 (CH2Cl2). Yield: 95%. NMR spectral data are in accordance with pre-
viously reported data.20
N-(3,5-Dichlorophenyl)hydroxylamine (5c). According to the general
procedure, the reaction of 1,3-dichloro-5-nitrobenzene 12c (1.0 g, 5.22
mmol) afforded hydroxylamine 5c (827 mg, 4.65 mmol) as a yellow solid.
1H NMR [400 MHz, δ (ppm), CDCl3]: 6.93 (t, J = 1.8 Hz, 1 H), 6.88 (d, J =
1.8 Hz, 2 H), 6.79 (bs, 1 H), 5.31 (bs, 1 H). RF: 0.33 (CH2Cl2). Yield: 89%.
NMR spectral data are in accordance with previously reported data.20
2-Benzyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine (3d). According to the
general procedure, the reaction of hydroxylamine hydrochloride 5d (26.8
mg, 0.169 mmol) afforded isoxazolidine 3d (13.2 mg, 0.050 mmol) as a
colorless oil, after column chromatography (heptane/AcOEt/Et3N,
9:1:0.1). 1H NMR [500 MHz, δ (ppm), CDCl3]: 7.40–7.36 (m, 2 H), 7.35–7.30
(m, 2 H), 7.30–7.27 (m, 1 H), 5.86 (dd, J = 8.3, 4.4 Hz, 1 H), 4.35–3.82 (m, 2
H), 3.34–3.11 (m, 1 H), 3.11–2.40 (m, 1 H), 2.83 (dtd, J = 11.9, 8.0, 3.3 Hz, 1
H), 2.40–2.18 (m, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 136.2, 130.3 (q,
J = 307.9 Hz), 128.9, 128.4, 127.5, 81.3 (q, J = 2.4 Hz), 61.7, 53.3, 36.5. 19F
General Procedure for the Synthesis of Isoxazolidines 3a–c. A solu-
tion of the corresponding hydroxylamine 5 (1 equiv) in THF (0.22 M) was
added to a solution of paraformaldehyde (3 equiv) in THF (0.22 M) at 0
°C. Then, a cooled solution (0 °C) of alkene 2 (6.0 equiv) was subsequent-
ly added to the solution containing paraformaldehyde and the hydroxyl-
amine. Finally, a solution of In(OTf)3 (0.06 equiv) in dry THF (44 mM)
was added to the reaction mixture. The reaction mixture was warmed up
to 21 °C and stirred for 16 hours. Then, the reaction mixture was
quenched with a saturated aqueous solution of NaHCO3 (10 mL) and the
aqueous layer was extracted with AcOEt (2 × 10 mL). The combined or-
ganic layers were dried over MgSO4, filtered off and concentrated in
vacuo. The crude mixture was purified by column chromatography using
the indicated eluent to afford isoxazolines 3a–c.
NMR [471 MHz, δ (ppm), CDCl3]: −39.9. FTIR [ꢀ̅
(cm−1)]: 2849, 1606, 1497,
1455, 1117, 755, 698. HRMS (EI) m/z: [M+•] calcd for C11H12F3NOS 263.0592;
found 263.0604. RF: 0.41 (heptane/AcOEt, 4:1). Yield: 30%.
2-Cyclohexyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine (3e). According to
the general procedure, the reaction of hydroxylamine hydrochloride 5e
(23.1 mg, 0.152 mmol) afforded isoxazolidine 3e (20.4 mg, 0.080 mmol) as
a colorless oil, after column chromatography (heptane/AcOEt, 19:1 →5:1).
1H NMR [400 MHz, δ (ppm), CDCl3]: 5.82 (dd, J = 8.1, 4.2 Hz, 1 H), 3.43–
3.13 (m, 1 H), 2.85–2.73 (m, 1 H), 2.68–2.50 (m, 1 H), 2.68–2.18 (m, 1 H),
2.31–2.18 (m, 1 H), 1.83–1.69 (m, 2 H), 1.66–1.52 (m, 2 H), 1.39–1.13 (m, 6 H).
13C NMR [101 MHz, δ (ppm), CDCl3]: 130.4 (q, J = 308.1 Hz), 80.8 (q, J = 2.2
Hz), 65.8, 51.5, 36.6, 26.0, 24.8, 24.4. 19F NMR [377 MHz, δ (ppm), CDCl3]:
2-Phenyl-5-[(trifluoromethyl)sufanyl]isoxazolidine (3a). According to the
general procedure, the reaction of N-phenylhydroxylamine 5a (17.8 mg,
0.163 mmol) afforded isoxazolidine 3a (15.3 mg, 0.163 mmol) as a brown
solid, after column chromatography (heptane/AcOEt, 19:1 →4:1). 1H NMR
[500 MHz, δ (ppm), CDCl3]: 7.34–7.27 (m, 2 H), 7.08–7.05 (m, 2 H), 7.03
(tt, J = 7.3, 1.1 Hz, 1 H), 5.98 (dd, J = 8.1, 4.3 Hz, 1 H), 3.85–3.71 (m, 1 H),
3.24 (ddd, J = 9.3, 8.2, 7.6 Hz, 1 H), 2.91 (dtdq, J = 13.2, 8.2, 4.0, 0.8 Hz, 1
H), 2.48–2.28 (m, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 149.8, 130.1
(q, J = 307.7 Hz), 129.0, 123.0, 116.1, 81.1 (q, J = 2.2 Hz), 52.0, 36.0 (q, J = 1.1
−40.0. FTIR [ꢀ̅
(cm−1)]: 2924, 2854, 1728, 1455, 1258, 1082, 1009, 788. RF:
0.44 (heptane/AcOEt, 9:1). Yield: 53%.
General Procedure A for the Syntheses of Nitrones 6d–g, 6i, 6j, 6l–r.
The corresponding aldehyde (1.0 equiv, dissolved in 1.5 mL of dry EtOH
for solid compounds) was added to a solution of N-phenylhydroxylamine
(1.05 equiv) in dry EtOH (1.0 mL) at 21 °C under a nitrogen atmosphere.
The reaction mixture was stirred for 16–21 h and then the solvent was
removed under vacuo. The crude mixture was purified by column chro-
matography using the indicated eluent to afford nitrones 6d–g, 6i, 6j, 6l–
r.
Hz). 19F NMR [471 MHz, δ (ppm), CDCl3]: −39.8. FTIR [ꢀ (cm−1)]: 2860,
̅
1599, 1491, 1295, 1109, 752, 692. HRMS (EI) m/z: [M+•] calcd for
C10H10F3NOS 249.0435; found 249.0458. RF: 0.56 (heptane/AcOEt, 4:1).
Yield: 38%.
General Procedure B for the Syntheses of Nitrones 6a–c, 6h and 6k.
The corresponding aldehyde (1.0 equiv) was added to a solution of N-
phenylhydroxylamine (1.0 equiv) in dry EtOH (1.0 mL) and the flask was
wrapped with aluminum foil. The reaction mixture was stirred at 21 °C for
16–21 h and then the solvent was removed under vacuo. The crude mix-
ture was purified by column chromatography using the indicated eluent
to afford nitrones 6a–c, 6h and 6k.
2-[3-(Trifluoromethyl)phenyl]-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(3b). According to the general procedure, the reaction of hydroxylamine
5b (56.2 mg, 0.318 mmol) afforded isoxazolidine 3b (23.5 mg, 0.071 mmol)
as a colorless oil, after column chromatography (heptane/AcOEt/Et3N,
12.2:1:0.13). 1H NMR [500 MHz, δ (ppm), CDCl3]: 7.41 (ddquint, J = 8.2, 7.2,
0.8 Hz, 1 H), 7.29–7.25 (m, 2 H), 7.23–7.19 (m, 1 H), 6.01 (dd, J = 8.0, 4.2
Hz, 1 H), 3.83 (ddd, J = 9.1, 8.2, 4.3 Hz, 1 H), 3.30 (ddd, J = 9.1, 8.5, 7.4 Hz, 1
H), 3.02–2.90 (m, 1 H), 2.48–2.38 (m, 1 H). 13C NMR [126 MHz, δ (ppm),
CDCl3]: 150.1, 131.3 (q, J = 32.3 Hz), 129.8 (q, J = 307.9 Hz), 129.4, 124.0 (q, J
= 272.4 Hz), 119.2 (q, J = 3.8 Hz), 118.9, 112.3 (q, J = 4.0 Hz), 81.1 (q, J = 2.4
Hz), 51.7, 35.8 (q, J = 1.2 Hz). 19F NMR [471 MHz, δ (ppm), CDCl3]: −39.9,
(Z)-N,1-Diphenylmethanimine oxide (6a).21 According to the general pro-
cedure B, the reaction of benzaldehyde (47.0 µL, 0.458 mmol) with N-
phenylhydroxylamine (50 mg, 0.458 mmol) afforded nitrone 6a (71 mg,
0.360 mmol) as a white solid, after column chromatography (hep-
tane/AcOEt, 5:1 →1:1). 1H NMR [400 MHz, δ (ppm), CDCl3]: 8.44–8.36 (m,
2 H), 7.92 (s, 1 H), 7.81–7.74 (m, 2 H), 7.53–7.43 (m, 6 H). Yield: 79%.
−62.8. FTIR [ꢀ̅
(cm−1)]: 2956, 2925, 2855, 1593, 1328, 1120, 795, 698. HRMS
(EI) m/z: [M+•] calcd for C11H9F6NOS 317.0309; found 317.0325. RF: 0.44
(heptane/AcOEt, 4:1). Yield: 22%.
5
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The Journal of Organic Chemistry
Page 6 of 11
Hz, 1 H), 7.83–7.75 (m, 2 H), 7.59 (tt, J = 7.9, 0.5 Hz, 1 H), 7.54–7.46 (m, 3
H), 3.95 (s, 3 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 166.5, 149.0, 133.6,
132.6, 131.6, 131.0, 130.6, 130.4, 130.2, 129.3, 129.0, 121.7, 52.4. FTIR [ꢀ
(cm−1)]:
3064, 2952, 1718, 1434, 1278, 1187, 1072, 912, 729, 684. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C15H14NO3 256.0968; found 256.0984. RF: 0.07
(CH2Cl2). Yield: 80%.
(Z)-1-(4-Fluorophenyl)-N-phenylmethanimine oxide (6b).22 According to
the general procedure B, the reaction of 4-fluorobenzaldehyde (98.0 µL,
0.916 mmol) with N-phenylhydroxylamine (100 mg, 0.916 mmol) afforded
nitrone 6b (178.5 mg, 0.829 mmol) as a white solid. 1H NMR [400 MHz, δ
(ppm), CDCl3]: 8.49–8.42 (m, 2 H), 7.91 (s, 1 H), 7.80–7.75 (m, 2 H), 7.55–
7.44 (m, 3 H), 7.23–7.14 (m, 2 H). Yield: 91%.
1
2
3
4
5
6
7
8
̅
(Z)-1-(3-Methoxyphenyl)-N-phenylmethanimine oxide (6j). According to
the general procedure A, the reaction of 3-methoxybenzaldehyde (0.063
mL, 0.514 mmol) with N-phenylhydroxylamine (59 mg, 0.540 mmol)
afforded nitrone 6j (115 mg, 0.506 mmol) as a yellow oil, after column
(Z)-N-Phenyl-1-(4-tolyl)methanimine oxide (6c).22 According to the gen-
eral procedure B, the reaction of 4-methylbenzaldehyde (163.0 µL, 1.375
mmol) with N-phenylhydroxylamine (127 mg, 1.375 mmol) afforded
nitrone 6c (267.2 mg, 1.26 mmol) as yellow crystals, after column chro-
matography (heptane/AcOEt, 5:1 →1:1). 1H NMR [400 MHz, δ (ppm),
CDCl3]: 8.34–8.27 (m, 2 H), 7.89 (s, 1 H), 7.81–7.75 (m, 2 H), 7.51–7.43 (m, 3
H), 7.33–7.28 (m, 2 H), 2.42 (s, 3 H). Yield: 92%.
1
chromatography (CH2Cl2 →CH2Cl2/MeOH, 10:0.2). H NMR [400 MHz, δ
9
(ppm), CDCl3]: 8.38 (dd, J = 2.7, 1.5 Hz, 1 H), 7.92 (s, 1 H), 7.81–7.75 (m, 2
H), 7.66 (dddd, J = 7.7, 1.5, 1.0, 0.5 Hz, 1 H), 7.52–7.44 (m, 3 H), 7.38 (dd, J
= 8.3, 7.7 Hz, 1 H), 7.05 (ddd, J = 8.3, 2.7, 1.0 Hz, 1 H), 3.89 (s, 3 H). 13C
NMR [101 MHz, δ (ppm), CDCl3]: 159.7, 149.1, 134.7, 131.9, 130.0, 129.5,
10
11
12
13
14
15
16
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
129.2, 122.3, 121.8, 118.1, 112.7, 55.4. FTIR [ꢀ̅
(cm−1)]: 3060, 2834, 1553, 1270,
(Z)-N-Phenyl-1-[4-(trifluoromethyl)phenyl]methanimine oxide (6d).23 Ac-
cording to the general procedure A, the reaction of 4-
(trifluoromethyl)benzaldehyde (91 mg, 0.523 mmol) with N-
phenylhydroxylamine (60 mg, 0.549 mmol) afforded nitrone 6d (139 mg,
0.523 mmol) as a yellow solid. 1H NMR [400 MHz, δ (ppm), CDCl3]: 8.54–
8.48 (m, 2 H), 8.00 (s, 1 H), 7.83–7.76 (m, 2 H), 7.76–7.70 (m, 2 H), 7.55–
7.47 (m, 3 H). Yield: 99%.
1025, 769, 684. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H13NO2Na
250.0839; found 250.0857. RF: 0.06 (CH2Cl2). Yield: 98%.
(Z)-N-Phenyl-1-[3-(trifluoromethyl)phenyl]methanimine oxide (6k).25 Ac-
cording to the general procedure B, the reaction of 3-
(trifluoromethyl)benzaldehyde (61 µL, 0.458 mmol) with N-
phenylhydroxylamine (50 mg, 0.458 mmol) afforded nitrone 6k (116 mg,
0.437 mmol) as a white solid, after column chromatography (hep-
(Z)-1-[4-(Pentafluoro-λ6-sulfanyl)phenyl]-N-phenylmethanimine
oxide
1
tane/AcOEt, 5:1 →1:1). H NMR [400 MHz, δ (ppm), CDCl3]: 8.70 (dq, J =
(6e). According to the general procedure A, the reaction of 4-
(pentafluoro-λ6-sulfanyl)benzaldehyde (120 mg, 0.517 mmol) with N-
phenylhydroxylamine (59 mg, 0.543 mmol) afforded nitrone 6e (163.3 mg,
0.505 mmol) as a white-yellow solid. 1H NMR [400 MHz, δ (ppm), CDCl3]:
8.52–8.45 (m, 2 H), 8.00 (s, 1 H), 7.89–7.81 (m, 2 H), 7.81– 7.74 (m, 2 H),
7.58–7.46 (m, 3 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 154.5, 149.1, 133.6,
2.3, 1.0 Hz, 1 H), 8.59 (dddd, J = 7.9, 1.7, 1.2, 0.6 Hz, 1 H), 8.01 (s, 1 H), 7.84–
7.75 (m, 2 H), 7.72 (dq, J = 8.5, 1.1 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.55–
7.48 (m, 3 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 149.1, 133.1, 131.8 (q, J =
1.0 Hz), 131.5, 131.5, 130.5, 129.5, 129.3, 127.3 (q, J = 3.7 Hz), 125.7 (q, J = 3.9
Hz), 122.6, 121.9. FTIR [ꢀ̅
(cm−1)]: 3124, 1604, 1330, 1120, 1068, 770, 692.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H11F3NO 266.0787; found
266.0799. RF: 0.35 (CH2Cl2). Yield: 95%.
132.5, 130.7, 129.5, 128.9, 126.5 (quint, J = 4.4 Hz), 121.9. FTIR [ꢀ̅
(cm−1)]:
3057, 1594, 1573, 1074, 821, 810, 765. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C13H11F5NOS 324.0476; found 324.0482. RF: 0.45 (CH2Cl2). Yield: 98%.
(Z)-N-Phenyl-1-(2-tolyl)methanimine oxide (6l).26 According to the general
procedure A, the reaction of 2-methylbenzaldehyde (0.061 mL, 0.524
mmol) with N-phenylhydroxylamine (60 mg, 0.551 mmol) afforded
nitrone 6l (107 mg, 0.508 mmol) as a yellow-brown solid, after column
(Z)-1-(4-Methoxyphenyl)-N-phenylmethanimine oxide (6f).24 According to
the general procedure A, the reaction of 4-methoxybenzaldehyde (0.063
mL, 0.514 mmol) with N-phenylhydroxylamine (59 mg, 0.540 mmol)
afforded nitrone 6f (110 mg, 0.484 mmol) as a yellow-brown solid, after
1
chromatography (CH2Cl2 →CH2Cl2/MeOH, 10:0.2). H NMR [400 MHz, δ
(ppm), CDCl3]: 9.42–9.32 (m, 1 H), 8.07 (s, 1 H), 7.81–7.73 (m, 2 H), 7.53–
7.44 (m, 3 H), 7.39–7.33 (m, 2 H), 7.28–7.23 (m, 1 H), 2.46 (s, 3 H). Yield:
97%.
1
column chromatography (CH2Cl2 →CH2Cl2/MeOH, 10:0.2). H NMR [400
MHz, δ (ppm), CDCl3]: 8.44–8.36 (m, 2 H), 7.84 (s, 1 H), 7.79–7.72 (m, 2
H), 7.50–7.37 (m, 3 H), 7.01–6.93 (m, 2 H), 3.86 (s, 3 H). Yield: 94%.
(Z)-1-(2-Methoxyphenyl)-N-phenylmethanimine oxide (6m).25 According
to the general procedure A, the reaction of 2-methoxybenzaldehyde (70
mg, 0.514 mmol) with N-phenylhydroxylamine (59 mg, 0.540 mmol)
afforded nitrone 6m (106 mg, 0.464 mmol) as an orange-brown solid,
(Z)-1-(3-Fluorophenyl)-N-phenylmethanimine oxide (6g).25 According to
the general procedure A, the reaction of 3-fluorobenzaldehyde (0.060
mL, 0.564 mmol) with N-phenylhydroxylamine (62 mg, 0.564 mmol)
afforded nitrone 6g (118 mg, 0.548 mmol) as a light brown solid, after
1
after column chromatography (CH2Cl2 →CH2Cl2/MeOH, 10:0.2). H NMR
1
[400 MHz, δ (ppm), CDCl3]: 9.48 (dd, J = 7.9, 1.7 Hz, 1 H), 8.40 (s, 1 H),
7.85–7.73 (m, 2 H), 7.53–7.39 (m, 4 H), 7.13–7.06 (m, 1 H), 6.93 (dd, J = 8.4,
1.1 Hz, 1 H), 3.89 (s, 3 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 157.6, 149.8,
column chromatography (heptane/CH2Cl2, 1:4 →CH2Cl2/MeOH, 10:1). H
NMR [400 MHz, δ (ppm), CDCl3]: 8.44 (ddd, J = 10.6, 2.6, 1.6 Hz, 1 H),
7.94 (s, 1 H), 7.90 (ddt, J = 8.1, 1.6, 0.7 Hz, 1 H), 7.80–7.73 (m, 2 H), 7.54–
7.47 (m, 3 H), 7.44 (td, J = 8.1, 5.9 Hz, 1 H), 7.17 (tdd, J = 8.1, 2.6, 1.0 Hz, 1
H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 162.8 (d, J = 245.5 Hz), 149.1,
133.5, 132.6 (d, J = 9.1 Hz), 130.4, 130.1 (d, J = 8.4 Hz), 129.4, 125.1 (d, J = 3.0
Hz), 121.8, 118.0 (d, J = 21.7 Hz), 115.3 (d, J = 24.7 Hz). Yield: 97%.
132.3, 129.8, 129.4, 129.2, 128.9, 122.0, 121.0, 120.1, 110.0, 55.8. FTIR [ꢀ
3058, 1577, 1288, 1046, 746, 691, 611. RF: 0.07 (CH2Cl2). Yield: 90%.
̅
(cm−1)]:
(Z)-N-Phenyl-1-(thiophen-3-yl)methanimine oxide (6n).27 According to the
general procedure A, the reaction of thiophene-3-carbaldehyde (0.047
mL, 0.535 mmol) with N-phenylhydroxylamine (61 mg, 0.562 mmol)
afforded nitrone 6n (109 mg, 0.535 mmol) as a white-yellow solid, after
(Z)-N-Phenyl-1-(3-tolyl)methanimine oxide (6h).25 According to the gen-
eral procedure B, the reaction of 3-methylbenzaldehyde (42 µL, 0.458
mmol) with N-phenylhydroxylamine (50 mg, 0.458 mmol) afforded
nitrone 6h (95.3 mg, 0.451 mmol) as a yellow oil, after column chroma-
tography (heptane/AcOEt, 5:1 →1:1). 1H NMR [400 MHz, δ (ppm), CDCl3]:
8.32 (tq, J = 1.8, 0.7 Hz, 1 H), 8.12 (dddquint, J = 7.8, 1.8, 1.2, 0.7 Hz, 1 H),
7.89 (s, 1 H), 7.81–7.75 (m, 2 H), 7.53–7.44 (m, 3 H), 7.38 (t, J = 7.8 Hz, 1
H), 7.32–7.27 (m, 1 H), 2.43 (s, 3 H). 13C NMR [101 MHz, δ (ppm), CDCl3]:
149.3, 138.5, 134.9, 132.0, 130.8, 130.0, 129.4, 129.3, 128.7, 126.6, 121.9, 21.6.
1
column chromatography (heptane/CH2Cl2, 1:1 →heptane/CH2Cl2, 0:1). H
NMR [400 MHz, δ (ppm), CDCl3]: 9.16 (ddd, J = 3.1, 1.2, 0.7 Hz, 1 H), 8.06
(d, J = 0.6 Hz, 1 H), 7.82–7.76 (m, 2 H), 7.52–7.46 (m, 3 H), 7.45 (dd, J =
5.2, 1.2 Hz, 1 H), 7.39 (dd, J = 5.1, 3.0 Hz, 1 H). Yield: 99%.
(Z)-1-(1H-Indol-2-yl)-N-phenylmethanimine oxide (6o). According to the
general procedure A, the reaction of 1H-indole-2-carbaldehyde (80 mg,
0.551 mmol) with N-phenylhydroxylamine (63 mg, 0.579 mmol) afforded
FTIR [ꢀ̅
(cm−1)]: 3092, 2963, 2920, 1652, 1590, 1459, 1088, 781, 692. HRMS
1
(ESI-TOF) m/z: [M + H]+ calcd for C14H14NO 212.1070; found 212.1085.
nitrone 6o (130 mg, 0.551 mmol) as a yellow-brown solid. H NMR [500
MHz, δ (ppm), CDCl3]: 11.69 (s, 1 H), 8.14 (s, 1 H), 7.87–7.80 (m, 2 H), 7.67
(dd, J = 8.1, 1.0 Hz, 1 H), 7.55–7.45 (m, 4 H), 7.32 (ddd, J = 8.2, 6.9, 1.1 Hz, 1
H), 7.16 (ddd, J = 8.0, 6.9, 1.0 Hz, 1 H), 6.94 (s, 1 H). 13C NMR [126 MHz, δ
(ppm), CDCl3]: 147.4, 136.0, 130.2, 129.9, 129.4, 127.6, 126.8, 125.2, 121.3,
Yield: 98%.
(Z)-1-[3-(Methoxycarbonyl)phenyl]-N-phenylmethanimine oxide (6i). Ac-
cording to the general procedure A, the reaction of methyl 3-
formylbenzoate (90 mg, 0.548 mmol) with N-phenylhydroxylamine (63
mg, 0.576 mmol) afforded nitrone 6i (112 mg, 0.439 mmol) as a yellow oil,
120.8, 112.3, 108.6. FTIR [ꢀ̅
(cm−1)]: 3315, 3067, 1593, 1502, 1345, 1234, 818,
733. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H12N2ONa 259.0842;
found 259.0858. RF: 0.13 (CH2Cl2). Yield: 99%.
1
after column chromatography (CH2Cl2 →CH2Cl2/MeOH, 10:1). H NMR
[400 MHz, δ (ppm), CDCl3]: 8.88 (dddd, J = 7.9, 1.7, 1.2, 0.5 Hz, 1 H), 8.80
(tt, J = 1.7, 0.5 Hz, 1 H), 8.13 (ddd, J = 7.9, 1.7, 1.2 Hz, 1 H), 8.01 (d, J = 0.5
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The Journal of Organic Chemistry
(Z)-N-Phenyl-1-(1H-pyrrol-2-yl)methanimine oxide (6p). According to the
and trans-4b (3.5 mg, 0.010 mmol, 8%) as a pale yellow oil, after column
general procedure A, the reaction of 1H-pyrrole-2-carbaldehyde (52 mg,
0.547 mmol) with N-phenylhydroxylamine (60 mg, 0.550 mmol) afforded
nitrone 6p (62 mg, 0.333 mmol) as a dark brown solid, after column
chromatography (heptane/CH2Cl2, 9:1). Total yield: 99%.
1
2
3
4
5
6
7
8
rac-(3R,5R)-3-(4-Fluorophenyl)-2-phenyl-5-
1
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4b). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 7.49–7.43 (m, 2 H), 7.25–7.19 (m, 2 H), 7.11–7.05 (m, 2 H),
7.05–7.01 (m, 1 H), 6.99–6.93 (m, 2 H), 6.01 (dd, J = 8.1, 4.3 Hz, 1 H), 4.40
(dd, J = 9.0, 7.0 Hz, 1 H), 3.39 (dddq, J = 13.7, 9.0, 8.1, 0.9 Hz, 1 H), 2.39–
2.28 (m, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 162.6 (d, J = 247.0 Hz),
148.6, 135.4 (d, J = 3.1 Hz), 130.1 (q, J = 307.8 Hz), 128.92, 128.91 (d, J = 7.2
Hz), 124.0, 117.7, 116.2 (d, J = 21.6 Hz), 80.5 (q, J = 2.3 Hz), 67.7, 47.1. 19F
chromatography (CH2Cl2 →CH2Cl2/MeOH, 10:0.1). H NMR [500 MHz, δ
(ppm), CDCl3]: 12.21 (s, 1 H), 7.95 (s, 1 H), 7.81–7.73 (m, 2 H), 7.52–7.38 (m,
3 H), 7.07 (td, J = 2.7, 1.3 Hz, 1 H), 6.70 (dt, J = 3.6, 1.6 Hz, 1 H), 6.40 (dt, J
= 3.9, 2.5 Hz, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 147.1, 129.5, 129.3,
126.1, 125.3, 121.3, 121.0, 115.9, 111.3. FTIR [ꢀ̅
(cm−1)]: 3317, 3062, 1580, 1403,
1294, 1074, 1045, 740, 686. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H11N2O 187.0866; found 187.0885. RF: 0.45 (heptane/AcOEt, 1:1). Yield:
61%.
NMR [471 MHz, δ (ppm), CDCl3]: −39.9. FTIR [ꢀ̅
(cm−1)]: 3071, 1597, 1455,
1256, 1226, 1110, 1029, 905, 804, 754. HRMS (EI) m/z: [M+•] calcd for
C16H13F4NOS 343.0654; found 343.0650. RF: 0.26 (heptane/CH2Cl2, 17:3).
9
(Z)-1-(Furan-2-yl)-N-phenylmethanimine oxide (6q).28 According to the
general procedure A, the reaction of furan-2-carbaldehyde (0.043 mL,
0.520 mmol) with N-phenylhydroxylamine (60 mg, 0.546 mmol) afforded
nitrone 6q (97 mg, 0.520 mmol) as a light brown solid, after column
10
11
12
13
14
15
16
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
rac-(3R,5S)-3-(4-Fluorophenyl)-2-phenyl-5-
[(trifluoromethyl]sulfanyl]isoxazolidine (trans-4b). H NMR [500 MHz, δ
1
1
chromatography (CH2Cl2 →CH2Cl2/MeOH, 10:0.2). H NMR [400 MHz, δ
(ppm), CDCl3]: 7.44–7.40 (m, 2 H), 7.25–7.20 (m, 2 H), 7.10–7.04 (m, 2 H),
6.99–6.92 (m, 3 H), 6.05 (dd, J = 6.8, 3.9 Hz, 1 H), 4.88 (t, J = 7.2 Hz, 1 H),
2.98–2.90 (m, 1 H), 2.87 (ddd, J = 13.3, 7.3, 3.9 Hz, 1 H). 13C NMR [126 MHz,
δ (ppm), CDCl3]: 162.3 (d, J = 242.3 Hz), 150.7, 135.6, 128.9, 128.4 (d, J = 8.3
Hz), 122.6, 116.2 (d, J = 21.7 Hz), 115.3, 81.2, 67.4, 46.2. The carbon signal of
SCF3 was not observed. 19F NMR [471 MHz, δ (ppm), CDCl3]: −39.4. FTIR
(ppm), CDCl3]: 8.16 (s, 1 H), 8.01 (dt, J = 3.5, 0.7 Hz, 1 H), 7.83–7.77 (m, 2
H), 7.58 (dd, J = 1.8, 0.7 Hz, 1 H), 7.52–7.44 (m, 3 H), 6.65 (dd, J = 3.6, 1.8
Hz, 1 H). Yield: 99%.
(Z)-2-(Benzylamino)-2-oxo-N-phenylethan-1-imine oxide (6r). According
to the general procedure A, the reaction of N-benzyl-2-oxoacetamide (56
mg, 0.343 mmol) with N-phenylhydroxylamine (26 mg, 0.240 mmol)
[ꢀ̅
(cm−1)]: 3071, 1686, 1598, 1154, 1052, 937, 693. HRMS (EI) m/z: [M+•]
calcd for C16H13F4NOS 343.0654; found 343.0676. RF: 0.21 (hep-
1
afforded nitrone 6r (34.5 mg, 0.135 mmol) as a white solid. H NMR [400
tane/CH2Cl2, 17:3).
MHz, δ (ppm), CDCl3]: 10.39 (s, 1 H), 7.72–7.67 (m, 2 H), 7.66 (s, 1 H),
7.58–7.46 (m, 3 H), 7.40–7.27 (m, 5 H), 4.64 (d, J = 5.9 Hz, 2 H). 13C NMR
[101 MHz, δ (ppm), CDCl3]: 160.8, 147.5, 137.8, 131.7, 130.3, 129.7, 128.9,
2-Phenyl-3-(4-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine (4c). The
solution containing alkene 2 (3.0 equiv) in distilled THF (500 μL) at 0 °C
was added to a PTFE tube containing nitrone 6c (1.0 equiv). The tube was
filled up with distilled THF, closed and brought to 15 kbar at 50 °C for 16
hours. Then, the reaction mixture was filtered off and the solvent was
removed under vacuo. The crude mixture was purified by column chro-
matography (heptane/CH2Cl2, 4:1) to afford isoxazolidine cis-4c (17.1 mg,
0.050 mmol, 50%) as white solid and trans-4c (12.1 mg, 0.36 mmol, 35%)
as a brown oil, contaminated with regioisomers 7c and azoxybenzene 8.
Total yield: 85%.
128.0, 127.7, 121.6, 43.3. FTIR [ꢀ̅
(cm−1)]: 3255, 3121, 2945, 1634, 1516, 1059,
768, 751, 683. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H14N2O2Na
277.0948; found 277.0956. RF: 0.68 (CH2Cl2/MeOH, 10:0.2). Yield: 39%.
General Procedure for the Synthesis of Isoxazolidines 4a, 4b, 4d–r.
The solution containing alkene 2 in distilled THF (3 equiv, 1.48 M) at 0 °C
was added to a PTFE tube containing the corresponding nitrone 6 (1
equiv) and galvinoxyl (0.03 equiv). The tube was filled up with distilled
THF, closed and brought to 15 kbar at 50 °C for 16 hours. Then, the reac-
tion mixture was filtered off and the solvent was removed under vacuo.
The crude mixture was purified by column chromatography using the
indicated eluent to afford isoxazolidines 4a, 4b, 4d–r.
rac-(3R,5R)-2-Phenyl-3-(4-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine
1
(cis-4c). H NMR [500 MHz, δ (ppm), CDCl3]: 7.40–7.34 (m, 2 H), 7.23–
7.16 (m, 4 H), 7.03–6.95 (m, 3 H), 6.00 (dd, J = 8.1, 4.3 Hz, 1 H), 4.36 (dd, J
= 9.0, 7.2 Hz, 1 H), 3.38 (dddq, J = 13.7, 9.0, 8.1, 0.9 Hz, 1 H), 2.39–2.32 (m, 1
H), 2.36 (s, 3 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 148.9, 138.1, 136.6,
130.2 (q, J = 307.7 Hz), 130.0, 128.8, 127.1, 123.7, 117.6, 80.5 (q, J = 2.2 Hz),
2,3-Diphenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine (4a). According to
the general procedure, the reaction of nitrone 6a (26 mg, 0.119 mmol)
and alkene 2 in a 1 mL PTFE high-pressure tube afforded cis-4a (24.9 mg,
0.77 mmol, 65%) as a white solid and a mixture of cis- and trans-4a and
regioisomers 7a (12.6 mg, 0.039 mmol, 33%) as a yellow oil, after column
chromatography (heptane/CH2Cl2, 9:1). Total yield: 98%.
68.1, 47.3, 21.3. 19F NMR [471 MHz, δ (ppm), CDCl3]: −39.9. FTIR [ꢀ
̅
(cm−1)]: 3056, 2962, 1597, 1489, 1257, 1107, 752, 691. HRMS (EI) m/z: [M+•]
calcd for C17H16F3NOS 339.0905; found 339.0890. RF: 0.21 (hep-
tane/CH2Cl2, 4:1).
rac-(3R,5R)-2,3-Diphenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine (cis-
4a).
rac-(3R,5S)-2-Phenyl-3-(4-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(trans-4c). 1H NMR [500 MHz, δ (ppm), CDCl3]: 7.36–7.33 (m, 2 H), 7.25–
7.16 (m, 4 H), 7.02–6.98 (m, 2 H), 6.97–6.92 (m, 1 H), 6.06 (dd, J = 6.8, 3.8
Hz, 1 H), 4.85 (t, J = 7.2 Hz, 1 H), 2.95 (dddq, J = 13.2, 7.6, 6.8, 0.9 Hz, 1 H),
2.85 (ddd, J = 13.2, 7.2, 3.8 Hz, 1 H), 2.36 (s, 3 H). 13C NMR [126 MHz, δ
(ppm), CDCl3]: 151.0, 137.9, 136.9, 130.1 (q, J = 307.7 Hz), 129.8, 128.8, 126.6,
122.2, 115.2, 82.3 (q, J = 2.2 Hz), 67.9, 46.4, 21.3. 19F NMR [471 MHz, δ
1H NMR [500 MHz, δ (ppm), CDCl3]: 7.52–7.47 (m, 2 H), 7.43–7.37 (m, 2
H), 7.35–7.30 (m, 1 H), 7.24–7.18 (m, 2 H), 7.04–6.99, (m, 1 H), 6.99–6.95
(m, 2 H), 6.01 (dd, J = 8.1, 4.4 Hz, 1 H), 4.41 (dd, J = 9.0, 7.1 Hz, 1 H), 3.41
(dddq, J = 13.6, 9.0, 8.1, 0.9 Hz, 1 H), 2.44–2.31 (m, 1 H). 13C NMR [126
MHz, δ (ppm), CDCl3]: 148.8, 139.8, 130.2 (q, J = 307.7 Hz), 129.3, 128.8,
128.3, 127.2, 123.8, 117.6, 80.5 (q, J = 2.5 Hz), 68.3, 47.2. FTIR [ν ̅
(cm−1)]:
3070, 2963, 1598, 1489, 1258, 1114, 1031, 966, 928, 752, 700. HRMS (EI) m/z:
[M+•] calcd for C16H14F3NOS 325.0748; found 325.0765. RF: 0.20 (hep-
tane/CH2Cl2, 9:1).
(ppm), CDCl3]: −39.3. FTIR [ꢀ̅
(cm−1)]: 3063, 2925, 1599, 1487, 1152, 1053,
756, 686. HRMS (EI) m/z: [M+•] calcd for C17H16F3NOS 339.0905; found
339.0924. RF: 0.13 (heptane/CH2Cl2, 4:1).
2-Phenyl-3-[4-(trifluoromethyl)phenyl]-5-
rac-(3R,5S)-2,3-Diphenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine (trans-
[(trifluoromethyl)sulfanyl]isoxazolidine (4d). According to the general
procedure, the reaction of nitrone 6d (50 mg, 0.190 mmol) and alkene 2
in a 1.5 mL PTFE high-pressure tube, containing approximately 300 μL of
glass beads, afforded a mixture of isoxazolidines cis- and trans-4d and
regioisomers 7d (53.1 mg, 0.137 mmol, 73%) as a pale yellow solid oil, after
1
4a). H NMR [500 MHz, δ (ppm), CDCl3]: 7.50–7.45 (m, 2 H), 7.41–7.36
(m, 2 H), 7.35–7.30 (1 H), 7.25–7.18 (m, 2 H), 7.04–6.98 (m, 2 H), 6.98–6.93
(m, 1 H), 6.07 (dd, J = 6.8, 3.8 Hz, 1 H), 4.90 (t, J = 7.3 Hz, 1 H), 3.02–2.92
(m, 1 H), 2.88 (ddd, J = 13.3, 7.3, 3.8 Hz, 1 H). 13C NMR [126 MHz, δ (ppm),
CDCl3]: 151.0, 139.9, 129.9 (q, J = 307.8 Hz), 129.2, 128.8, 128.2, 126.7, 122.4,
column chromatography (heptane/CH2Cl2, 17:3). FTIR [ꢀ̅
(cm−1)]: 1597,
115.2, 82.3 (q, J = 2.0 Hz), 68.1, 46.3. FTIR [ꢀ̅
(cm−1)]: 3065, 1598, 1489, 1206,
1490, 1325, 1104, 1051, 850, 754, 692. HRMS (EI) m/z: [M+•] calcd for
C17H13F6NOS 393.0622; found 393.0624. RF: 0.20 (heptane/CH2Cl2, 17:3).
Total yield: 73%.
1108, 1049, 842, 796, 665. HRMS (EI) m/z: [M+•] calcd for C16H14F3NOS
325.0748; found 325.0750 . RF: 0.11 (heptane/CH2Cl2, 9:1).
3-(4-Fluorophenyl)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(4b). According to the general procedure, the reaction of nitrone 6b (27
mg, 0.125 mmol) and alkene 2 in a 1 mL PTFE high-pressure tube afforded
cis-4b (27.6 mg, 0.080 mmol, 64%) as a white solid, a mixture of cis- and
trans-4b and regioisomers 7b (13.1 mg, 0.038 mmol, 27%) as a yellow oil
rac-(3R,5R)-2-Phenyl-3-[4-(trifluoromethyl)phenyl]-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4d). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 7.72–7.55 (m, 4 H), 7.25–7.18 (m, 2 H), 7.05–7.00 (m, 1 H),
6.97–6.93 (m, 2 H), 6.00 (dd, J = 8.0, 4.3 Hz, 1 H), 4.50 (dd, J = 9.1, 6.7, 1
H), 3.43 (dddq, J = 13.7, 9.1, 8.0, 0.9, 1 H), 2.33 (ddd, J = 13.7, 6.7, 4.3 Hz, 1
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 148.4, 144.1, 130.6 (q, J = 32.6 Hz),
0.025 mmol, 10%) as a yellow solid, after column chromatography (hep-
130.0 (q, J = 307.8 Hz), 129.0, 127.4, 126.3 (q, J = 3.8 Hz), 124.09 (q, J = 272.1
Hz), 124.05, 117.4, 80.4 (q, J = 2.2 Hz), 67.5, 46.9.
tane/CH2Cl2, 9:1). Total yield: 99%.
1
2
rac-(3R,5R)-3-(3-Fluorophenyl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4g). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 7.34 (td, J = 8.1, 5.9 Hz, 1 H), 7.28–7.18 (m, 4 H), 7.06–6.98
(m, 2 H), 6.98–6.93 (m, 2 H), 5.98 (dd, J = 8.1, 4.3 Hz, 1 H), 4.41 (dd, J = 9.1,
6.8 Hz, 1 H), 3.39 (dddq, J = 13.7, 9.1, 8.1, 0.9 Hz, 1 H), 2.33 (ddd, J = 13.7,
6.8, 4.3 Hz, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 163.4 (d, J = 247.0
Hz), 148.6, 142.5 (d, J = 7.2 Hz), 130.9 (d, J = 8.3 Hz), 130.1 (q, J = 307.9 Hz),
128.9, 123.9, 122.7 (d, J = 2.9 Hz), 117.4, 115.3 (d, J = 21.3 Hz), 114.1 (d, J = 22.6
Hz), 80.4 (q, J = 2.4 Hz), 67.5 (d, J = 1.9 Hz), 46.9. 19F NMR [471 MHz, δ
3
4
5
6
7
8
9
rac-(3R,5S)-2-Phenyl-3-[4-(trifluoromethyl)phenyl]-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4d). H NMR [500 MHz, δ
1
(ppm), CDCl3]: 7.70–7.56 (m, 4 H), 7.27–7.18 (m, 2 H), 7.00–6.96 (m, 3 H),
6.04 (dd, J = 6.3, 4.6 Hz, 1 H), 4.97 (t, J = 7.1 Hz, 1 H), 3.01–2.83 (m, 2 H).
13C NMR [126 MHz, δ (ppm), CDCl3]: 150.5, 144.1, 130.5 (q, J = 32.5 Hz),
130.0 (q, J = 307.8 Hz), 129.0, 127.0, 126.2 (q, J = 3.9 Hz), 122.7, 115.1, 82.2 (q,
J = 2.1 Hz), 67.5, 45.9.
3-[4-(Pentafluoro-λ6-sulfanyl)phenyl]-2-phenyl-5-
(ppm), CDCl3]: −39.9. FTIR [ꢀ̅
(cm−1)]: 3062, 1594, 1489, 1448, 1258, 1111,
1044, 915, 833, 752, 690. HRMS (EI) m/z: [M+•] calcd for C16H13F4NOS
343.0654; found 343.0675. RF: 0.22 (heptane/CH2Cl2, 17:3).
[(trifluoromethyl)sulfanyl]isoxazolidine (4e). According to the general
procedure, the reaction of nitrone 6e (37.8 mg, 0.143 mmol) and alkene 2
in a 1 mL PTFE high-pressure tube afforded a mixture of isoxazolidines
cis- and trans-4e and regioisomers 7e (41 mg, 0.091 mmol, 72%) as a
white solid, after column chromatography (heptane/CH2Cl2, 17:3). FTIR
10
11
12
13
14
15
16
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
rac-(3R,5S)-3-(3-Fluorophenyl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4g). H NMR [500 MHz, δ
1
[ꢀ̅
(cm−1)]: 2963, 1670, 1585, 1261, 1120, 1104, 817, 753, 584. HRMS (EI) m/z:
(ppm), CDCl3]: 7.35 (td, J = 8.1, 5.9 Hz, 1 H), 7.25–7.20 (m, 4 H), 7.04–6.94
(m, 4 H), 6.05 (dd, J = 6.8, 4.0 Hz, 1 H), 4.90 (t, J = 7.4 Hz, 1 H), 2.99–2.91
(m, 1 H), 2.33 (ddd, J =13.2, 7.4, 4.0 Hz, 1 H). 13C NMR [126 MHz, δ (ppm),
CDCl3]: 163.4 (d, J = 247.1 Hz), 150.6, 142.6 (d, J = 7.2 Hz), 130.7 (d, J = 8.3
Hz), 128.9, 122.6, 122.2 (d, J = 2.8 Hz), 115.2 (d, J = 21.6 Hz), 115.1, 113.7 (d, J =
22.7 Hz), 80.2 (q, J = 2.5 Hz), 67.4 (d, J =2.1 Hz), 46.0. 19F NMR [471 MHz,
[M+•] calcd for C16H13F8NOS2 451.0311; found 451.0318. RF: 0.21 (hep-
tane/CH2Cl2, 17:3). Total yield: 72%.
rac-(3R,5R)-3-[4-(Pentafluoro-λ6-sulfanyl)phenyl]-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4e). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 7.85–7.72 (m, 2 H), 7.64–7.55 (m, 2 H), 7.30–7.21 (m, 2 H),
7.09–7.02 (m, 1 H), 7.02–6.92 (m, 2 H), 6.00 (dd, J = 8.0, 4.3 Hz, 1 H), 4.52
(dd, J = 9.2, 6.6, 1 H), 3.43 (dt, J = 13.7, 8.6, 1 H), 2.32 (ddd, J = 13.7, 6.6, 4.3
Hz, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 153.7–153.4 (m), 148.3, 144.0,
130.0 (q, J = 307.9 Hz), 129.1, 127.3, 127.0, 124.2, 117.3, 80.4 (q, J = 2.3 Hz),
67.1, 46.7.
δ (ppm), CDCl3]: −39.4. FTIR [ꢀ̅
(cm−1)]: 3070, 1593, 1488, 1451, 1256, 1109,
947, 787, 691. HRMS (EI) m/z: [M+•] calcd for C16H13F4NOS 343.0654;
found 343.0667. RF: 0.15 (heptane/CH2Cl2, 17:3).
2-Phenyl-3-(3-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine (4h). Ac-
cording to the general procedure, the reaction of nitrone 6h (49 mg,
0.234 mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube afforded
isoxazolidine cis-4h (46 mg, 0.136 mmol, 57%) as an off white solid and
isoxazolidine trans-4h and regioisomers 7h (26 mg, 0.077 mmol, 31%) as
a yellow solid, after column chromatography (heptane/CH2Cl2, 17:3 →7:3).
Total yield: 88%.
rac-(3R,5S)-3-[4-(Pentafluoro-λ6-sulfanyl)phenyl]-2-phenyl-5-
1
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4e). H NMR [500 MHz, δ
(ppm), CDCl3]: 7.80–7.74 (m, 2 H), 7.60–7.56 (m, 2 H), 7.28–7.21 (m, 2 H),
7.01–6.97 (m, 3 H), 6.03 (dd, J = 5.9, 5.0, 1 H), 4.97 (t, J = 7.1 Hz, 1 H), 3.01–
2.80 (m, 2 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 153.7–153.4 (m), 150.4,
143.9, 130.0 (q, J = 307.9 Hz), 129.0, 127.1, 127.0, 122.8, 115.1, 82.2 (q, J = 2.2
Hz), 67.1, 45.8.
rac-(3R,5R)-2-Phenyl-3-(3-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(cis-4h). 1H NMR [500 MHz, δ (ppm), CDCl3]: 7.31–7.28 (m, 1 H), 7.27–7.24
(m, 2 H), 7.22–7.17 (m, 2 H), 7.14–7.10 (m, 1 H), 7.02–6.94 (m, 3 H), 5.98
(dd, J = 8.1, 4.4 Hz, 1 H), 4.35 (dd, J = 9.0, 7.2 Hz, 1 H), 3.37 (dddq, J = 13.6,
9.0, 8.1, 0.9 Hz, 1 H), 2.38–2.32 (m, 1 H), 2.36 (s, 3 H). 13C NMR [126 MHz,
δ (ppm), CDCl3]: 148.9, 139.7, 139.1, 130.2 (q, J = 307.7 Hz), 129.1, 129.1,
3-(4-Methoxyphenyl)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(4f). According to the general procedure, the reaction of nitrone 6f (54
mg, 0.238 mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube af-
forded isoxazolidine cis-4f (44.3 mg, 0.125 mmol, 53%), a mixture of isox-
azolidines cis- and trans-4f (27.3 mg, 0.077 mmol, 32%) and isoxazolidine
trans-4f mixed with cis-4f and regioisomers 7f (12.4 mg, 0.035 mmol, 15%)
as yellow oils, after column chromatography (heptane/CH2Cl2, 7:3). Total
yield: 99%.
128.8, 127.6, 124.2, 123.6, 117.5, 80.5 (q, J = 2.2 Hz), 68.3, 47.2, 21.6. FTIR [ꢀ
̅
(cm−1)]: 3028, 1599, 1489, 1040, 1001, 839, 737, 724, 692. HRMS (EI) m/z:
[M+•] calcd for C17H16F3NOS 339.0905; found 339.0925. RF: 0.41 (hep-
tane/CH2Cl2, 4:1).
rac-(3R,5S)-2-Phenyl-3-(3-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine
1
rac-(3R,5R)-3-(4-Methoxyphenyl)-2-phenyl-5-
(trans-4h). H NMR [500 MHz, δ (ppm), CDCl3]: 7.31–7.18 (m, 5 H), 7.14–
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4f). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 7.43–7.35 (m, 2 H), 7.23–7.18 (m, 2 H), 7.04–6.99 (m, 1 H),
6.99–6.95 (m, 2 H), 6.94–6.90 (m, 2 H), 6.01 (dd, J = 8.1, 4.3 Hz, 1 H), 4.34
(dd, J = 8.9, 7.3 Hz, 1 H), 3.82 (s, 3 H), 3.37 (dddq, J = 13.8, 8.9, 8.2, 0.9 Hz,
1 H), 2.46–2.25 (m, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 159.6, 148.8,
131.4, 130.2 (q, J = 307.8 Hz), 128.8, 128.4, 123.8, 117.8, 114.6, 80.5 (q, J = 2.2
7.10 (m, 1 H), 7.03–6.98 (m, 2 H), 6.98–6.91 (m, 1 H), 6.06 (dd, J = 6.8, 3.7
Hz, 1 H), 4.85 (t, J = 7.3 Hz, 1 H), 2.95 (dddq, J = 13.2, 7.6, 6.8, 0.9 Hz, 1 H),
2.86 (ddd, J = 13.2, 7.3, 3.7 Hz, 1 H), 2.36 (s, 3 H). 13C NMR [126 MHz, δ
(ppm), CDCl3]: 151.2, 139.9, 139.0, 130.0 (q, J = 307.8 Hz), 129.0, 128.9, 128.8,
127.1, 123.7, 122.3, 115.1, 82.4 (q, J = 2.1 Hz), 68.1, 46.4, 21.6. 19F NMR [471
MHz, δ (ppm), CDCl3]: −39.3. FTIR [ꢀ̅
(cm−1)]: 3029, 1598, 1489, 1150, 1111,
Hz), 68.0, 55.4, 47.2. 19F NMR [471 MHz, δ (ppm), CDCl3]: −39.9. FTIR [ꢀ
̅
1045, 785, 692. HRMS (EI) m/z: [M+•] calcd for C17H16F3NOS 339.0905;
found 339.0931. RF: 0.34 (heptane/CH2Cl2, 4:1).
(cm−1)]: 3003, 1614, 1515, 1298, 1103, 1031, 816, 773. HRMS (EI) m/z: [M+•]
calcd for C17H16F3NO2S 355.0854; found 355.0861. RF: 0.15 (hep-
tane/CH2Cl2, 4:1).
Methyl 3-{2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidin-3-yl}benzoate
(4i). According to the general procedure, the reaction of nitrone 6i (26
mg, 0.102 mmol) and alkene 2 in a 1 mL PTFE high-pressure tube, con-
taining approximately 150 μL of glass beads, afforded isoxazolidine cis-4i
(17.3 mg, 0.045 mmol, 44%) as an off white solid and a mixture of isoxa-
zolidines cis- and trans-4i and regioisomers 7i (18.2 mg, 0.047 mmol,
47%) as a brown-yellow solid, after column chromatography (hep-
tane/CH2Cl2, 3:2). Total yield: 91%.
rac-(3R,5S)-3-(4-Methoxyphenyl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4f). H NMR [500 MHz, δ
1
(ppm), CDCl3]: 7.38–7.35 (m, 2 H), 7.22–7.18 (m, 2 H), 7.01–6.98 (m, 2 H),
6.97–6.93 (m, 1 H), 6.92–6.89 (m, 2 H), 6.06 (dd, J = 6.8, 3.7 Hz, 1 H),
4.87–4.77 (m, 1 H), 3.81 (s, 3 H), 3.00–2.90 (m, 1 H), 2.84 (ddd, J = 13.2, 7.2,
3.7 Hz, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 159.5, 151.0, 131.8, 130.0
(q, J = 307.8 Hz), 128.8, 127.9, 122.4, 115.4, 114.5, 82.3 (q, J = 2.3 Hz), 67.7,
55.5, 46.3. FTIR [ꢀ̅
(cm−1)]: 3002, 1512, 1489, 1248, 1109, 1030, 794, 693.
Methyl-3-{rac-(3R,5R)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidin-
HRMS (EI) m/z: [M+•] calcd for C17H16F3NO2S 355.0854; found 355.0855.
RF: 0.10 (heptane/CH2Cl2, 4:1).
1
3-yl}benzoate (cis-4i). H NMR [500 MHz, δ (ppm), CDCl3]: 8.11 (t, J = 1.8
Hz, 1 H), 8.01 (dt, J = 7.7, 1.4 Hz, 1 H), 7.76 (dddd, J = 7.7, 1.8, 1.2, 0.5 Hz, 1
H), 7.48 (t, J = 7.7 Hz, 1 H), 7.24–7.19 (m, 2 H), 7.07–7.00 (m, 1 H), 6.98–
6.94 (m, 2 H), 6.01 (dd, J = 8.0, 4.5 Hz, 1 H), 4.50 (dd, J = 8.9, 7.0 Hz, 1 H),
3.93 (s, 3 H), 3.43 (dddq, J = 13.6, 8.9, 8.0, 0.9 Hz, 1 H), 2.42–2.30 (m, 1 H).
13C NMR [126 MHz, δ (ppm), CDCl3]: 166.8, 148. 6, 140.4, 131.6, 131.1, 130.0
(q, J = 307.7 Hz), 129.6, 129.0, 128.3, 124.0, 117.6, 80.4 (q, J = 2.5 Hz), 67.9,
3-(3-Fluorophenyl)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(4g). According to the general procedure, the reaction of nitrone 6g (52
mg, 0.242 mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube af-
forded isoxazolidine cis-4g (46.6 mg, 0.136 mmol, 56%) as a white solid, a
mixture of cis- and trans-6g (27.8 mg, 0.081, 34%) as a yellow oil, and
isoxazolidine trans-6g mixed with cis-6g and regioisomers 7g (8.5 mg,
52.4, 46.9. 19F NMR [471 MHz, δ (ppm), CDCl3]: −39.9. FTIR [ꢀ (cm−1)]:
̅
3015, 1729, 1598, 1489, 1301, 1247, 1114, 1025, 786, 692, 674. HRMS (EI) m/z:
8
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The Journal of Organic Chemistry
[M+•] calcd for C18H16F3NO3S 383.0803; found 383.0824. RF: 0.27 (hep-
tane/CH2Cl2, 3:2).
2-Phenyl-3-(2-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine (4l). Ac-
cording to the general procedure, the reaction of nitrone 6l (49 mg, 0.234
mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube afforded isoxa-
zolidine cis-4l (1.9 mg, 0.0056 mmol; used for characterization) as a col-
orless oil and a mixture of isoxazolidines cis- and trans-4l (79.5 mg, 0.234
mmol, 99%) as a yellow solid, after column chromatography (hep-
1
2
3
4
5
6
7
8
Methyl-3-{rac-(3R,5S)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidin-3-
yl}benzoate (trans-4i). 1H NMR [500 MHz, δ (ppm), CDCl3]: 8.12 (t, J = 1.8
Hz, 1 H), 8.02–7.98 (m, 1 H), 7.69 (dt, J = 7.8, 1.6 Hz, 1 H), 7.47 (t, J = 7.7, 1
H), 7.26–7.18 (m, 2 H), 7.00–6.98 (m, 2 H), 6.97–6.94 (m, 1 H), 6.06 (dd, J
= 6.7, 4.0 Hz, 1 H), 4.96 (t, J = 7.3 Hz, 1 H), 3.93 (s, 3 H), 3.01–2.94 (m, 1 H),
2.91 (ddd, J = 13.3, 7.4, 4.0 Hz, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]:
166.8, 150.7, 140.5, 131.19, 131.14, 130.0 (q, J = 307.9 Hz), 129.57, 129.55, 128.9,
127.8, 122.6, 115.2, 82.3 (q, J = 2.2 Hz), 67.6, 52.4, 46.1. 19F NMR [471 MHz, δ
tane/CH2Cl2, 4:1). FTIR [ꢀ̅
(cm−1)]: 3025, 1596, 1489, 1258, 1109, 1041, 972,
754, 695. HRMS (EI) m/z: [M+•] calcd for C17H16F3NOS 339.0905; found
339.0923. RF: 0.23 (heptane/CH2Cl2, 4:1). Total yield: 99%.
rac-(3R,5R)-2-Phenyl-3-(2-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(cis-4l). 1H NMR [500 MHz, δ (ppm), CDCl3]: 7.72 (dd, J = 7.2, 1.7 Hz, 1 H),
7.26–7.17 (m, 5 H), 7.00 (tt, J = 7.4, 1.2 Hz, 1 H), 6.96–6.88 (m, 2 H), 6.01
(dd, J = 8.1, 4.2 Hz, 1 H), 4.61 (dd, J = 9.1, 7.1 Hz, 1 H), 3.44 (dddq, J = 13.5,
(ppm), CDCl3]: −39.4. FTIR [ꢀ̅
(cm−1)]: 3064, 1720, 1598, 1489, 1285, 1107,
1020, 799, 751, 692. HRMS (EI) m/z: [M+•] calcd for C18H16F3NO3S
383.0803; found 383.0810. RF: 0.22 (heptane/CH2Cl2, 3:2).
9
10
11
12
13
14
15
16
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
9.1, 8.1, 0.9 Hz, 1 H), 2.35 (s, 3 H), 2.25 (ddd, J = 13.5, 7.1, 4.2 Hz, 1 H). 13
C
3-(3-Methoxyphenyl)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(4j). According to the general procedure, the reaction of nitrone 6j (50
mg, 0.190 mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube, con-
taining approximately 300 μL of glass beads, afforded isoxazolidine cis-4j
(33.8 mg, 0.095 mmol, 53%) as a white solid, a mixture of isoxazolidines
cis- and trans-4j (3 mg, 0.0084 mmol, 5%) as a yellow oil and isoxazoli-
dines trans-4j and 7j (18.2 mg, 0.051 mmol, 22%) as a yellow oil, after
column chromatography (heptane/CH2Cl2, 7:3). Total yield: 80%.
NMR [126 MHz, δ (ppm), CDCl3]: 148.9, 138.0, 134.6, 130.8, 130.1 (q, J =
307.4 Hz), 128.9, 127.8, 127.3, 126.6, 123.5, 117.2, 80.5 (q, J = 2.2 Hz), 64.5,
45.6, 19.7. 19F NMR [471 MHz, δ (ppm), CDCl3]: −40.0.
rac-(3R,5S)-2-Phenyl-3-(2-tolyl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine
1
(trans-4l). H NMR [500 MHz, δ (ppm), CDCl3]: 7.65–7.62 (m, 1 H), 7.27–
7.15 (m, 5 H), 6.97–6.93 (m, 3 H), 6.06 (dd, J = 6.7, 3.9 Hz, 1 H), 5.04 (t, J =
7.5 Hz, 1 H), 2.89 (ddd, J = 13.1, 7.5, 3.9 Hz, 1 H), 2.80 (dddq, J = 13.1, 7.5,
6.7, 0.9 Hz, 1 H), 2.39 (s, 3 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 151.1,
137.8, 134.3, 130.8, 128.7, 127.8, 127.0, 126.2, 122.1, 114.7, 82.2 (q, J = 2.3 Hz),
65.3, 44.6, 19.4.
rac-(3R,5R)-3-(3-Methoxyphenyl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4j). 1H NMR [400 MHz, δ
(ppm), CDCl3]: 7.29 (t, J = 7.9 Hz, 1 H), 7.24–7.17 (m, 2 H), 7.09–6.95 (m, 5
H), 6.85 (ddd, J = 8.3, 2.7, 1.1 Hz, 1 H), 5.99 (dd, J = 8.1, 4.3 Hz, 1 H), 4.37
(dd, J = 9.1, 7.0 Hz, 1 H), 3.81 (s, 3 H), 3.43–3.32 (m, 1 H), 2.36 (ddd, J = 13.7,
7.0, 4.3 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 160.4, 148.9, 141.6,
130.3, 130.2 (q, J = 307.7 Hz), 128.8, 123.6, 119.3, 117.3, 113.8, 112.4, 80.5 (q, J =
2.5 Hz), 68.0, 55.4, 47.2 (q, J = 1.2 Hz). 19F NMR [377 MHz, δ (ppm),
3-(2-Methoxyphenyl)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(4m). According to the general procedure, the reaction of nitrone 6m (53
mg, 0.234 mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube af-
forded isoxazolidine cis-4m (35.6 mg, 0.100 mmol, 43%) as an off white
solid and a mixture of isoxazolidines cis- and trans-4m (29.6 mg, 0.083
mmol, 28%) as a yellow solid, after column chromatography (hep-
tane/CH2Cl2, 7:3). Total yield: 71%.
CDCl3]: −39.9. FTIR [ꢀ̅
(cm−1)]: 3006, 2838, 1599, 1490, 1117, 757, 694.
HRMS (EI) m/z: [M+•] calcd for C17H16F3NO2S 355.0854; found 355.0868.
RF: 0.16 (heptane/CH2Cl2, 7:3).
rac-(3R,5R)-3-(2-Methoxyphenyl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4m). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 7.65 (dd, J = 7.6, 1.7 Hz, 1 H), 7.28 (ddd, J = 8.2, 7.5, 1.8 Hz,
1 H), 7.25–7.19 (m, 2 H), 7.01–6.94 (m, 4 H), 6.91 (dd, J = 8.3, 1.0 Hz, 1 H),
5.94 (dd, J = 8.0, 4.5 Hz, 1 H), 4.87 (dd, J = 9.1, 6.1 Hz, 1 H), 3.86 (s, 3 H),
3.40 (dddq, J = 13.6, 9.1, 8.0, 0.9 Hz, 1 H), 2.30–2.20 (m, 1 H). 13C NMR [126
MHz, δ (ppm), CDCl3]: 156.3, 149.4, 130.3 (q, J = 307.7 Hz), 128.9, 128.4,
rac-(3R,5S)-3-(3-Methoxyphenyl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4j). H NMR [400 MHz, δ
1
(ppm), CDCl3]: 7.29 (t, J = 8.1 Hz, 1 H), 7.25–7.19 (m, 2 H), 7.07–6.92 (m, 5
H), 6.89–6.81 (m, 1 H), 6.06 (dd, J = 6.8, 3.8, 1 H), 4.86 (t, J = 7.4 Hz, 1 H),
3.81 (s, 3 H), 2.96 (dddq, J = 13.3, 7.6, 6.8, 0.9 Hz, 1 H), 2.87 (ddd, J = 13.3,
7.3, 3.8 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 160.3, 151.0, 141.6,
130.2, 130.0 (q, J = 307.8 Hz), 128.8, 122.3, 118.8, 115.1, 113.7, 112.0, 82.3 (q, J =
2.3 Hz), 68.0, 55.5, 46.3. 19F NMR [377 MHz, δ (ppm), CDCl3]: −39.3. FTIR
127.5, 123.1, 121.3, 116.7, 110.5, 80.6 (q, J = 2.4 Hz), 62.1, 55.5, 45.0. FTIR [ꢀ
̅
(cm−1)]: 3075, 1599, 1490, 1243, 1106, 1027, 897, 751, 664. HRMS (EI) m/z:
[M+•] calcd for C17H16F3NO2S 355.0854; found 355.0875. RF: 0.19 (hep-
tane/CH2Cl2, 7:3).
[ꢀ
̅
(cm−1)]: 3064, 1720, 1598, 1489, 1347, 1107, 1020, 799, 750, 692. HRMS
H]+ calcd for C17H17F3NO2S 356.0932; found
(ESI-TOF) m/z: [M
+
356.0939. RF: 0.13 (heptane/CH2Cl2, 7:3).
rac-(3R,5S)-3-(2-Methoxyphenyl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4m). H NMR [500 MHz, δ
1
2-Phenyl-3-[3-(trifluoromethyl)phenyl]-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (4k). According to the general
procedure, the reaction of nitrone 6k (49 mg, 0.234 mmol) and alkene 2
in a 1.5 mL PTFE high-pressure tube afforded a mixture of isoxazolidines
cis- and trans-4k and 7k (87.4 mg, 0.222 mmol, 95%) as a white-yellow
(ppm), CDCl3]: 7.59 (dd, J = 7.6, 1.5 Hz, 1 H), 7.31–7.26 (m, 2 H), 7.06–7.02
(m, 2 H), 7.00–6.88 (m, 4 H), 5.99–5.96 (m, 1 H), 5.26 (dd, J = 7.5, 5.8 Hz, 1
H), 3.88 (s, 3 H), 2.90 (ddd, J = 12.7, 7.5, 5.0 Hz, 1 H), 2.84–2.76 (m, 1 H).
13C NMR [126 MHz, δ (ppm), CDCl3]: 156.3, 151.2, 128.9, 128.8, 128.1, 127.2,
122.0, 121.1, 114.9, 110.4, 82.4 (q, J = 2.2 Hz), 62.9, 55.5, 43.7. The carbon
solid, after column chromatography (heptane/CH2Cl2, 17:3 →7:3). FTIR [ꢀ
̅
(cm−1)]: 2927, 1598, 1490, 1263, 1144, 1045. HRMS (EI) m/z: [M+•] calcd for
C17H13F6NOS 393.0622; found 393.0639. RF: 0.38 (heptane/CH2Cl2, 4:1).
Total yield: 95%.
signal of SCF3 was not observed. FTIR [ꢀ̅
(cm−1)]: 2839, 1599, 1490, 1256,
1106, 1026, 751, 692. HRMS (EI) m/z: [M+•] calcd for C17H16F3NO2S
355.0854; found 355.0862. RF: 0.15 (heptane/CH2Cl2, 7:3).
rac-(3R,5R)-2-Phenyl-3-[3-(trifluoromethyl)phenyl]-5-
2-Phenyl-3-(thiophen-3-yl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine (4n).
According to the general procedure, the reaction of nitrone 6n (48 mg,
0.234 mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube afforded a
mixture of isoxazolidines cis- and trans-4n (68.4 mg, 0.206 mmol, 88%)
as a yellow solid, after column chromatography (heptane/CH2Cl2, 3:2).
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4k). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 7.73–7.69 (m, 2 H), 7.60–7.56 (m, 1 H), 7.54–7.48 (m, 1 H),
7.26–7.20 (m, 2 H), 7.05–7.00 (m, 1 H), 6.98–6.93 (m, 2 H), 5.99 (dd, J =
8.0, 4.5 Hz, 1 H), 4.51 (dd, J = 9.0, 6.7 Hz, 1 H), 3.41 (dddq, J = 13.6, 9.0, 8.0,
0.8 Hz, 1 H), 2.37–2.28 (m, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]:
148.6, 141.1, 131.6 (q, J = 32.4 Hz), 130.4 (q, J = 1.2 Hz), 129.9 (q, J = 308.0
Hz), 129.9, 129.0, 125.2 (q, J = 3.8 Hz), 124.0 (q, J = 272.4 Hz), 124.1, 123.9 (q,
J = 3.8 Hz), 117.4, 80.4 (q, J = 2.5 Hz), 67.8, 46.8.
FTIR [ꢀ̅
(cm−1)]: 3095, 1598, 1489, 1257, 1163, 1110, 1031, 837, 792, 754, 692.
HRMS (EI) m/z: [M+•] calcd for C14H12F3NOS2 331.0312; found 331.0330. RF:
0.19 (heptane/CH2Cl2, 17:3). Total yield: 88%.
rac-(3R,5R)-2-Phenyl-3-(thiophen-3-yl)-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4n). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 7.36 (dd, J = 5.0, 3.0 Hz, 1 H), 7.30–7.27 (m, 1 H), 7.25–7.20
(m, 2 H), 7.19 (dd, J = 5.0, 1.3 Hz, 1 H), 7.02 (tt, J = 7.4, 1.2 Hz, 1 H), 7.00–
6.96 (m, 2 H), 6.00 (dd, J = 8.2, 4.2 Hz, 1 H), 4.51 (dd, J = 8.8, 6.7 Hz, 1 H),
3.36–3.28 (m, 1 H), 2.38 (ddd, J = 13.6, 6.7, 4.2 Hz, 1 H). 13C NMR [126 MHz,
δ (ppm), CDCl3]: 148.9, 140.4, 130.2 (q, J = 307.7 Hz), 128.8, 127.3, 126.1,
123.9, 122.7, 117.5, 80.5 (q, J = 2.5 Hz), 64.6, 45.9.
rac-(3R,5S)-2-Phenyl-3-[3-(trifluoromethyl)phenyl]-5-
1
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4k). H NMR [500 MHz, δ
(ppm), CDCl3]: 7.73–7.70 (m, 1 H), 7.68–7.64 (m, 1 H), 7.60–7.56 (m, 1 H),
7.53–7.48 (m, 1 H), 7.26–7.20 (m, 2 H), 6.92–6.88 (m, 3 H), 6.06–6.02 (m, 1
H), 4.96 (t, J = 7.2 Hz, 1 H), 2.98–2.86 (m, 2 H). 13C NMR [126 MHz, δ
(ppm), CDCl3]: 150.6, 141.1, 131.6 (q, J = 32.4 Hz), 130.4 (q, J = 1.2 Hz), 129.7,
128.9, 125.1 (q, J = 4.0 Hz), 123.5 (q, J = 3.8 Hz), 122.7, 115.2, 82.3 (q, J = 2.4
Hz), 67.5, 46.0.
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rac-(3R,5S)-2-Phenyl-3-(thiophen-3-yl)-5-
2-Phenyl-3-(1H-pyrrol-2-yl)-4-[(trifluoromethyl)sulfanyl]isoxazolidine (7p).
1
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4n). H NMR [500 MHz, δ
(ppm), CDCl3]: 7.32 (dd, J = 5.0, 3.0 Hz, 1 H), 7.30–7.27 (m, 1 H), 7.26–7.20
(m, 2 H), 7.09 (dd, J = 5.0, 1.4 Hz, 1 H), 7.06–6.95 (m, 3 H), 6.03 (dd, J =
7.2, 4.9 Hz, 1 H), 5.01 (t, J = 6.5 Hz, 1 H), 2.96 (dt, J = 13.0, 6.4 Hz, 1 H),
2.78 (ddd, J = 12.7, 7.3, 4.7 Hz, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]:
150.2, 140.6, 130.2 (q, J = 307.7 Hz), 128.8, 127.0, 125.8, 122.7, 122.4, 115.7, 81.9
(q, J = 2.2 Hz), 64.2, 44.6.
1H NMR [400 MHz, δ (ppm), CDCl3]: 8.65 (bs, 1 H), 7.30–7.23 (m, 2 H),
7.06–6.99 (m, 3 H), 6.81–6.77 (m, 1 H), 6.27–6.19 (m, 1 H), 6.19 (m, 1 H),
5.11 (d, J = 7.8 Hz, 1 H), 4.66–4.55 (m, 1 H), 4.22 (q, J = 7.5 Hz, 1 H), 4.15
(dd, J = 8.6, 6.8 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 149.2, 129.3,
126.0, 123.4, 118.8, 115.2, 109.0, 108.8, 73.5, 65.3, 48.7 (q, J = 1.3 Hz). The
carbon signal of SCF3 was not observed.
1
2
3
4
5
6
7
8
9
2-Phenyl-3-(1H-pyrrol-2-yl)-4-[(trifluoromethyl)sulfanyl]isoxazolidine (7p).
1H NMR [500 MHz, δ (ppm), CDCl3]: 8.57 (bs, 1 H), 7.31–6.66 (m, 7 H),
6.27–6.15 (m, 1 H), 4.82 (d, J = 4.2 Hz, 1 H), 4.65–4.50 (m, 2 H), 4.26–4.10
(m, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 149.6, 129.4, 126.0, 124.1,
118.1, 115.2, 109.1, 108.7, 70.3, 65.3, 48.7. The carbon signal of SCF3 was not
observed.
3-(1H-Indol-2-yl)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine (4o).
According to the general procedure, the reaction of nitrone 6o (56 mg,
0.237 mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube afforded
isoxazolidines cis- and trans-4o (20.3 mg, 0.056 mmol, 24%; contaminat-
ed with 8) as an brown-yellow oil and a mixture of isoxazolidine trans-4o
and regioisomers 7o (35.6 mg, 0.098 mmol, 41%) as a brown oil, after
10
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13
14
15
16
17
18
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20
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23
24
25
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column chromatography (heptane/CH2Cl2, 11:9). FTIR [ꢀ
zolidines cis- and trans-4o: 3413, 3060, 2962, 1599, 1436, 1258, 1110, 1022,
788, 756, 684, 660. FTIR [ꢀ
(cm−1)] of isoxazolidine trans-4o and regioi-
̅
(cm−1)] of isoxa-
3-(Furan-2-yl)-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine
(4q).
According to the general procedure, the reaction of nitrone 6q (44 mg,
0.234 mmol) in a 1.5 mL PTFE high-pressure tube afforded isoxazolidine
cis-4q (33.2 mg, 0.105 mmol, 45%) as an off white solid and isoxazolidines
trans-4q and 7q (24.7 mg, 0.078 mmol, 34%) as a yellow oil, after column
chromatography (heptane/CH2Cl2, 23:2 →heptane/CH2Cl2, 0:1). Total
yield: 79%.
̅
somers 7o: 3406, 3059, 2963, 1597, 1455, 1231, 1107, 1014, 793, 693. Total
yield: 65%.
rac-(3R,5R)-3-(1H-Indol-2-yl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4o). 1H NMR [500 MHz, δ
(ppm), CDCl3]: 8.67 (bs, 1 H), 7.61–7.58 (m, 1 H), 7.40–7.37 (m, 1 H), 7.25–
7.18 (m, 3 H), 7.15–7.12 (m, 1 H), 7.05–7.02 (m, 3 H), 6.50 (d, J = 2.0 Hz, 1
H), 6.07 (dd, J = 8.3, 3.5 Hz, 1 H), 4.77 (dd, J = 9.4, 5.6 Hz, 1 H), 3.44–3.32
(m, 1 H), 2.50 (ddd, J = 13.8, 5.6, 3.5 Hz, 1 H). 13C NMR [126 MHz, δ (ppm),
CDCl3]: 148.6, 136.2, 135.6, 130.0 (q, J = 306.8 Hz), 129.1, 128.6, 123.9, 122.6,
120.6, 120.4, 116.7, 111.5, 100.9, 80.7 (q, J = 2.4 Hz), 62.2, 44.9. RF: 0.51 (hep-
tane/CH2Cl2, 1:1).
rac-(3R,5R)-3-(Furan-2-yl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4q). 1H NMR [400 MHz, δ
(ppm), CDCl3]: 7.45 (dd, J = 1.8, 0.9 Hz, 1 H), 7.31–7.22 (m, 2 H), 7.10–6.98
(m, 3 H), 6.37 (dd, J = 3.2, 1.8 Hz, 1 H), 6.35 (d, J = 3.2 Hz, 1 H), 6.00 (dd, J
= 8.1, 4.5 Hz, 1 H), 4.50 (dd, J = 8.8, 6.5 Hz, 1 H), 3.23 (dddq, J = 13.5, 8.8,
8.1, 0.9 Hz, 1 H), 2.63 (ddd, J = 13.5, 6.5, 4.5 Hz, 1 H). 13C NMR [101 MHz, δ
(ppm), CDCl3]: 151.0, 148.7, 143.0, 130.2 (q, J = 307.7 Hz), 128.9, 124.2, 117.5,
110.8, 109.0, 80.5 (q, J = 2.6 Hz), 63.0, 42.4 (q, J = 1.2 Hz). FTIR [ꢀ̅
(cm−1)]:
rac-(3R,5S)-3-(1H-Indol-2-yl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4o). H NMR [500 MHz, δ
2922, 1489, 1453, 1254, 1106, 1037, 936, 743, 680. HRMS (EI) m/z: [M+•]
calcd for C14H12F3NO2S 315.0541; found 315.0538. RF: 0.48 (heptane/CH2Cl2,
7:3).
1
(ppm), CDCl3]: 8.50 (bs, 1 H), 7.57–7.47 (m, 3 H), 7.32 (dt, J = 8.2, 0.9 Hz, 1
H), 7.06–7.03 (m, 1 H), 6.98–6.90 (m, 2 H), 6.86–6.82 (m, 2 H), 6.40 (d, J =
2.1 Hz, 1 H), 5.84 (dd, J = 8.3, 4.0 Hz, 1 H), 4.28 (dd, J = 9.4, 5.7 Hz, 1 H),
2.82 (dt, J = 13.7, 8.9 Hz, 1 H), 2.16–2.09 (m, 1 H). 13C NMR [126 MHz, δ
(ppm), CDCl3]: 148.5, 134.4, 132.7, 129.0, 128.6, 122.6, 122.5, 120.6, 119.5,
116.2, 111.3, 100.5, 82.1 (q, J = 2.4 Hz), 59.8, 44.6. RF: 0.42 (heptane/CH2Cl2,
1:1).
rac-(3R,5S)-3-(Furan-2-yl)-2-phenyl-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4q). H NMR [400 MHz, δ
1
(ppm), CDCl3]: 7.37 (dd, J = 1.8, 0.9 Hz, 1 H), 7.27–7.22 (m, 2 H), 7.09–7.05
(m, 2 H), 6.98 (tt, J = 7.3, 1.2 Hz, 1 H), 6.30 (dd, J = 3.3, 1.8 Hz, 1 H), 6.26
(dt, J = 3.3, 0.8, 1 H), 6.11 (dd, J = 7.4, 5.2 Hz, 1 H), 5.00 (dd, J = 7.7, 4.3, 1
H), 3.17 (dddq, J = 13.7, 7.4, 4.3, 0.8, 1 H), 2.77–2.67 (m, 1 H). 13C NMR [101
MHz, δ (ppm), CDCl3]: 151.6, 149.2, 142.8, 130.0 (q, J = 307.7 Hz), 128.8,
123.0, 116.2, 110.6, 108.4, 81.8 (q, J = 2.5 Hz), 61.6, 41.6 (q, J = 1.2 Hz). FTIR
3-(1H-Indol-2-yl)-2-phenyl-4-[(trifluoromethyl)sulfanyl]isoxazolidine (7o).
1H NMR [500 MHz, δ (ppm), CDCl3]: 7.64–7.59 (m, 2 H), 7.38–6.97 (m, 16
H), 6.59–6.55 (m, 2 H), 5.25 (d, J = 8.2 Hz, 1 H), 4.94 (d, J = 4.4 Hz, 1 H),
4.67–4.61 (m, 1 H), 4.61–4.56 (m, 1 H), 4.31 (q, J = 7.6 Hz, 1 H), 4.25–4.18
(m, 2 H), 4.11 (dd, J = 9.3, 6.2 Hz, 1 H). 13C NMR [126 MHz, δ (ppm),
CDCl3]: 149.3, 148.9, 135.9, 135.7, 135.5, 132.8, 129.2, 129.2, 128.5, 127.9, 123.4,
123.2, 122.7, 122.5, 120.8, 120.6, 120.3, 115.1, 115.0, 111.3, 111.2, 103.1, 100.6, 73.2,
72.7, 70.1, 65.6, 52.4, 48.1.
[ꢀ̅
(cm−1)]: 2872, 1599, 1490, 1262, 1118, 1046, 757, 694. HRMS (EI) m/z:
[M+•] calcd for C14H12F3NO2S 315.0541; found 315.0545. RF: 0.39 (hep-
tane/CH2Cl2, 7:3).
N-Benzyl-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine-3-
carboxamide (4r). According to the general procedure, the reaction of
nitrone 6r (25 mg, 0.098 mmol) and alkene 2 in a 1 mL PTFE high-
pressure tube afforded isoxazolidine cis-4r (3.2 mg, 0.0084 mmol, 9%;
used for NMR characterization) as a white solid and a mixture of isoxa-
zolidines cis- and trans-4r (16.1 mg, 0.042 mmol, 51%) as a yellow-white
2-Phenyl-3-(1H-pyrrol-2-yl)-5-[(trifluoromethyl)sulfanyl]isoxazolidine (4p).
According to the general procedure, the reaction of nitrone 6p (44 mg,
0.234 mmol) and alkene 2 in a 1.5 mL PTFE high-pressure tube afforded a
mixture of isoxazolidines cis- and trans-4p and 7p (33 mg, 0.105 mmol,
45%) as a brown oil, after column chromatography (heptane/CH2Cl2, 4:1 →
solid, after column chromatography (heptane/CH2Cl2, 17:3
→
CH2Cl2/MeOH, 24:1). FTIR [ꢀ̅
(cm−1)]: 3385, 3309 2930, 1668, 1597, 1454,
CH2Cl2/MeOH, 10:1). FTIR [ꢀ̅
(cm−1)]: 3421, 2960, 1597, 1489, 1154, 1109,
1161, 1029, 697. HRMS (EI) m/z: [M+•] calcd for C18H17F3N2O2S 382.0963;
1082, 1029, 756, 722. HRMS (EI) m/z: [M+•] calcd for C14H13F3N2OS
314.0701; found 314.0706. RF (unassigned mixture): 0.46, 0.30, 0.24, 0.20
(heptane/CH2Cl2, 1:1). Total yield: 45%.
found 382.0964. Total yield: 60%.
rac-(3R,5R)-N-Benzyl-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine-
1
3-carboxamide (cis-4r). H NMR [400 MHz, δ (ppm), CDCl3]: 7.59–7.52
rac-(3R,5R)-2-Phenyl-3-(1H-pyrrol-2-yl)-5-
(m, 1 H), 7.37–7.27 (m, 7 H), 7.11–7.03 (m, 1 H), 7.02–6.97 (m, 2 H), 5.88
(dd, J = 8.1, 4.7 Hz, 1 H), 4.56 (dd, J = 14.8, 6.1 Hz, 1 H), 4.49 (dd, J = 14.8,
5.9 Hz, 1 H), 4.31 (dd, J = 9.6, 3.5 Hz, 1 H), 3.19–3.07 (m, 1 H), 2.75–2.65 (m,
1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 169.7, 148.8, 137.6, 129.6 (q, J =
308.1 Hz), 129.5, 128.9, 127.9, 127.8, 123.9, 115.1, 80.3 (q, J = 2.5 Hz), 67.6,
43.7, 39.4.
[(trifluoromethyl)sulfanyl]isoxazolidine (cis-4p). 1H NMR [400 MHz, δ
(ppm), CDCl3]: 8.65 (bs, 1 H), 7.28–7.22 (m, 2 H), 7.08–6.98 (m, 3 H), 6.81–
6.77 (m, 1 H), 6.21–6.18 (m, 1 H), 6.15–6.12 (m, 1 H), 6.03 (dd, J = 8.3, 3.6
Hz, 1 H), 4.62 (dd, J = 8.9, 5.6 Hz, 1 H), 3.34–3.17 (m, 1 H), 2.48–2.36 (m, 1
H). 13C NMR [101 MHz, δ (ppm), CDCl3]: δ 148.9, 130.0 (q, J = 307.9 Hz),
129.0, 128.8, 123.8, 116.8, 115.2, 109.1, 106.7, 80.7 (q, J = 2.3 Hz), 62.5, 44.6.
rac-(3R,5S)-N-Benzyl-2-phenyl-5-[(trifluoromethyl)sulfanyl]isoxazolidine-
1
rac-(3R,5S)-2-Phenyl-3-(1H-pyrrol-2-yl)-5-
[(trifluoromethyl)sulfanyl]isoxazolidine (trans-4p). H NMR [500 MHz, δ
3-carboxamide (trans-4r). H NMR [500 MHz, δ (ppm), CDCl3]: 7.52–7.43
1
(m, 1 H), 7.36–7.23 (m, 7 H), 7.11–7.02 (m, 3 H), 5.91 (t, J = 6.8 Hz, 1 H),
4.54–4.49 (m, 2 H), 4.46 (dd, J = 15.0, 5.6 Hz, 1 H), 3.29 (ddd, J = 13.5, 7.3,
3.9 Hz, 1 H), 2.62 (ddd, J = 13.9, 8.1, 6.2 Hz, 1 H). 13C NMR [126 MHz, δ
(ppm), CDCl3]: 169.1, 149.4, 137.6, 129.6 (q, J = 308.1 Hz), 129.0, 128.8, 127.7,
127.6, 123.6, 115.1, 82.3 (q, J = 2.5 Hz), 67.1, 43.5, 39.0.
(ppm), CDCl3]: 8.57 (bs, 1 H), 7.31–6.66 (m, 7 H), 6.27–6.15 (m, 1 H), 5.97
(t, J = 6.4 Hz, 1 H), 5.07 (dd, J = 7.0, 4.4 Hz, 1 H), 3.00 (ddd, J = 12.2, 7.1, 4.4
Hz, 1 H), 2.68 (dt, J = 13.1, 6.4 Hz, 1 H). 13C NMR [101 MHz, δ (ppm),
CDCl3]: 150.0, 129.9, 128.9, 123.8, 118.0, 115.8, 107.2, 106.3, 82.1, 62.7, 43.2.
The carbon signal of SCF3 was not observed.
ASSOCIATED CONTENT
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Page 11 of 11
The Journal of Organic Chemistry
Scheeren. H. W.; Rutjes. F. P. J. T. Eur. J. Org. Chem. 2014, 1438–
Supporting Information
1444. (c) Matsumoto, K.; Hamana H.; Iida, H. Helv. Chim. Acta
2005, 88, 2033–2234. (d) Jenner, G. Tetrahedron 2002, 58, 5185–
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699–701.
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2
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The Supporting Information is available free of charge on the
ACS Publications website. Detailed optimization reaction
1
conditions, H NMR, 13C NMR spectra (PDF), computational
details, ASA and EDA of 6m and 6p and Cartesian coordi-
nates.
5
6
7
8
9
(13) It is important to note that the assignment of the cis- and
trans-diastereoisomers of 7 could not be clarified by NMR stud-
ies.
(14) (a) Becke, A. D. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38,
3098–3100. (b) Perdew, J. P. Phys. Rev. B: Condens. Matter Mater.
Phys. 1986, 33, 8822–8824. (c) Lenthe, E. V.; Baerends, E. J. J.
Comput. Chem. 2003, 24, 1142–1156.
AUTHOR INFORMATION
Corresponding Author
*E-mail: f.m.bickelhaupt@vu.nl
*E-mail: floris.rutjes@ru.nl
Notes
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The authors declare no competing financial interest.
(15) (a) te Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca
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ACKNOWLEDGMENT
This work has been supported by the FP7 Marie Curie Ac-
tions of the European Commission via the ITN ECHONET
Network (MCITN-2012-316379) and NWO via the Planetary
and Exo- Planetary Science program (PEPSci) and the Dutch
Astrochemistry Network (DAN). We thank Dr. Paul B. White
for his help in the assignment of the diastereo- and regioi-
somers.
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