Synthesis of 4-Isoxazolines through Gold(I)-Catalyzed Cyclization of Propargylic N-Hydroxylamines

Article abstract of DOI:10.1021/acs.joc.6b01499

New catalytic methods for the synthesis of 4-isoxazolines have been developed via catalytic intramolecular cyclizations of propargylic N-hydroxylamines. The reactions proceed rapidly in less than 1 h at room temperature in the presence of 5 mol % (PPh₃)AuCl/5 mol % AgOTf or 5 mol % (PPh₃)AuNTf₂. This process features an efficient route to 4-isoxazolines with high yields, short reaction times, and mild reaction conditions.

Full text of DOI:10.1021/acs.joc.6b01499

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Article
Synthesis of 4-Isoxazolines through Gold(I)-
Catalyzed Cyclization of Propargylic N-Hydroxylamines
Bandari Chandrasekhar, Sewon Ahn, and Jae-Sang Ryu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01499 • Publication Date (Web): 15 Jul 2016
Downloaded from http://pubs.acs.org on July 17, 2016
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The Journal of Organic Chemistry
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Synthesis of 4ꢀIsoxazolines through Gold(I)ꢀCatalyzed
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Cyclization of Propargylic NꢀHydroxylamines
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B. Chandrasekhar, Sewon Ahn and JaeꢀSang Ryu*
College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52
Ewhayeodaeꢀgil, SeodaemunꢀGu, Seoul 03760, Republic of Korea.
AUTHOR EMAIL ADDRESS: ryuj@ewha.ac.kr
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CORRESPONDING AUTHOR FOOTNOTE: Fax+82 2 3277 2851; Tel: +82 2 3277 3008
ABSTRACT: New catalytic methods for the synthesis of 4ꢀisoxazolines have been developed via
catalytic intramolecular cyclizations of propargylic Nꢀhydroxylamines. The reactions proceed rapidly in
less than one hour at room temperature in the presence of 5 mol% (PPh3)AuCl/5 mol% AgOTf or 5
mol% (PPh3)AuNTf2. This process features an efficient route to 4ꢀisoxazolines with high yields, short
reaction times, and mild reaction conditions.
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Introduction
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4ꢀIsoxazolines1 (2,3ꢀdihydroisoxazoles) are not only important scaffolds for various biologically
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active compounds, but are also versatile synthetic intermediates for the preparation of interesting
natural products.3 The reductive opening of 4ꢀisoxazolines provides access to building blocks such as β–
amino ketones,4 β–amino alcohols,4 and βꢀlactams.5 In addition, due to the thermal instability of the Nꢀ
O bond associated with the πꢀsystem, 4ꢀisoxazolines can be thermally or catalytically isomerized to
various structures such as 2ꢀacylaziridine,6 4ꢀoxazoline,7 and pyrrole8 (Figure 1). Although their value in
both chemistry and biology has been widely recognized, only a few methods to obtain such scaffolds
have been described so far: the [3+2] cycloadditions between nitrones and alkynes,9 cycloadditions
between oxaziridines and alkynes,10 and the cyclization of propargylic Nꢀhydroxylamines. Among these,
the 1,3ꢀdipolar cycloaddition of nitrones to acetylenes is one of the most attractive approaches to the
synthesis of 4ꢀisoxazolines. However, this method often suffers from poor regioselectivity and limited
substrate scope for alkynes (e.g., acetylene carboxylates and related electronꢀdeficient acetylenes).
Recently, the cyclization of propargylic Nꢀhydroxylamines has emerged as an alternative pathway for
the synthesis of 4ꢀisoxazolines, and not surprisingly, only a few catalytic methods have been reported to
date. Such a transformation can be accelerated by Pd(OAc)2,11 ZnI2ꢀDMAP,12 NaAuCl4•2H2OꢀDMAP,13
AgBF4,14 or ZnMe2.15 Although these methods provide synthetic routes to 4ꢀisoxazaolines with the
desired regioselectivity, some of these methods require additional bases (Et3N or DMAP), rather long
reaction times (12‒48 h for Pd(OAc)2), high temperatures, or high loading of catalysts (10‒300 mol%).
Therefore, the development of mild and efficient catalytic conditions to facilitate access to synthetically
useful 4ꢀisoxazolines is still needed. In the course of our studies on goldꢀcatalyzed reactions to construct
complex heterocycles, we developed a highly efficient synthetic method, which can produce 4ꢀ
isoxazolines in very short times. Herein, we report a mild gold(I)ꢀcatalyzed cyclization of propargylic
Nꢀhydroxylamines to yield 4ꢀisoxazolines at room temperature in 5‒60 minutes.
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Figure 1. 4ꢀIsoxazoline as a versatile synthetic intermediate.
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Results and Discussion
Although gold(III) catalyzes the cyclization of propargylic Nꢀhydroxylamines in the presence of 20
mol% of DMAP under refluxing CH2Cl2 conditions, gold(I)ꢀcatalyzed cyclization has long been
elusive.13 To assess the feasibility of gold(I)ꢀcatalyzed cyclization of propargylic Nꢀhydroxylamine, we
began to investigate the cycloisomerization of NꢀbenzylꢀNꢀ(1,3ꢀdiphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine
(1a) in the presence of various gold(I) and gold(III) catalysts in CH2Cl2 at room temperature (Table 1).
First, we carried out cyclization reactions using cationic phosphine Au(I) chloride catalysts. (PPh3)AuCl
produced the cyclization product 2a in 33% yield after 48 h but 66% starting material was recovered
(Table 1, entry 1). Unfortunately, this reaction was sluggish and other phosphine ligands such as PCy3
and PMe3 could not improve the result (entries 2 and 3). An NHC ligand such as IPr was not effective,
either (entry 4). As expected, gold(III) catalysts such as AuCl3 or NaAuCl4•2H2O facilitated the reaction
and afforded the cyclized product 2a in 56% and 51% yields, respectively (entries 5 and 6). However,
these catalysts also produced the undesired byproduct chalcone (3a), which was presumably generated
from the addition of gold(III) catalyst to the already formed 4ꢀisoxazoline 2a during the reaction and the
subsequent hydrolysis of Iꢀ3 during workup (Scheme 1). Molecular sieve removal of H2O and flash
chromatography could not prevent the formation of 3a. This might originate from the intrinsic
properties of gold(III) catalysts to easily form a complex with 4ꢀisoxazolines.13 Indeed, the reaction of
2a and AuCl3 afforded 3a in 30% yield with complicated unidentified byproducts after 48 h (eq 1). To
our surprise, the gold(I) catalyst, AuCl afforded 2a as a sole product in 15 min (entry 7). The reaction
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was very rapid and no byproduct formation was observed. After a series of optimization studies,
(PPh3)AuNTf2 (5 mol%) was identified as the best catalyst for the cyclization reaction (entry 8). In the
presence of (PPh3)AuNTf2 (5 mol%), 4ꢀisoxazoline 2a was isolated in 91% yield after 15 min at room
temperature without the formation of 3a.
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Table 1. Catalyst Screening and Optimization of Reaction Conditions.a
yield (%)b
time
entry
Auꢀcatalyst
(h)
Rec 1ac
2a
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(PPh3)AuCl
(PCy3)AuCl
(PMe3)AuCl
(IPr)AuCl
AuCl3
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NaAuCl4·2H2O
AuCl
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(PPh3)AuNTf2
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0
a Reaction conditions: 1a (62.6 mg, 200 ꢁmol), Auꢀcatalyst (10.0 ꢁmol, 5 mol%), CH2Cl2 (2 mL).
Isolated yields after flash column chromatography. c Recovered 1a.
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Scheme 1. Plausible Mechanism for the Formation of 3a.
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The significant difference in the reactivity of (PPh3)AuCl and (PPh3)AuNTf2 prompted us to further
investigate the effect of anion and silver coꢀcatalysts on the cyclization reaction as shown in Table 2.
Interestingly, the addition of 5 mol% of silver salts to the (PPh3)AuCl reaction remarkably accelerated
the cyclization process. The reactions were completed in 0.5‒1 hours and afforded 2a as the sole
product in 79‒90% yield (Table 2, entries 1‒6). Particularly, the reaction using (PPh3)AuCl/AgNTf2
gave 2a with a comparable yield to the reaction using (PPh3)AuNTf2 (1 h, 87%, Table 2, entry 4, vs 0.25
h, 91%, Table 1, entry 8). The best result was obtained with (PPh3)AuCl/AgOTf, which afforded the 4ꢀ
isoxazoline 2a in 90% in 0.5 h. Meanwhile, the AuCl/AgOTf reaction was slower than the
(PPh3)AuCl/AgOTf reaction and 3% of byproduct chalcone (3a) was isolated (Table 2, entry 7).
According to the previous literature,14 AgBF4 is known to catalyze the cyclization. However, AgOTf
was not an effective catalyst. When it was employed alone, only 24% of 2a was obtained after 48 h
along with 54% of byproduct 3a (Table 2, entry 8). Obviously, the (PPh3)AuCl/AgOTf system exhibited
better activity than (PPh3)AuCl or AgOTf alone, which might be because of the silver salt effect16 or
anion effect. Therefore, in order to compare the silver salt effect and the anion effect, we carried out the
cyclization reaction in the presence of (PPh3)AuOTf prepared by premixing (PPh3)AuCH3 and TfOH in
the absence of silver salts, which provided 4ꢀisoxazoline 2a in 76% yield and 3a in 5% yield
respectively after 5 min (Table 2, entry 9). The reaction was rapid and comparably efficient. Therefore,
the anion effect was evidently significant. Although AgOTf alone can catalyze the cyclization, the
remarkable reactivity of the (PPh3)AuCl/AgOTf system must originate from the intrinsic activity of
Au(I)ꢀcatalyst and its anion. As another evidence of this, (PPh3)AuNTf2 alone without any silver salt
catalyzed the cyclization of propargylic Nꢀhydroxylamines with comparable reactivity (vide supra).
Interestingly, TfOH alone could not catalyze the cyclization and was unable to generate 2a and 3a
(Table 2, entry 10).
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Table 2. The Silver Salt and Solvent Effect on the Cyclization.a
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yield (%)b
entry
catalyst
solvent
time (h)
2a
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NRd
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(PPh3)AuCl/AgOTs
(PPh3)AuCl/AgSbF6
(PPh3)AuCl/AgBF4
(PPh3)AuCl/AgNTf2
(PPh3)AuCl/AgNO3
(PPh3)AuCl/AgOTf
AuCl/AgOTf
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
0.5
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0.75
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9 c
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(PPh3)AuCH3/TfOH
TfOH
ꢀ
(PPh3)AuCl/AgOTf
(PPh3)AuCl/AgOTf
(PPh3)AuCl/AgOTf
(PPh3)AuNTf2
0
CH3CN
0
Toluene 0.25
Toluene 0.5
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0
a Reaction conditions: 1a (62.6 mg, 200 ꢁmol), Auꢀcatalyst (10.0 ꢁmol, 5 mol%), Agꢀsalt (10.0 ꢁmol,
5 mol%), CH2Cl2 (2 mL). Isolated yields after flash column chromatography. TfOH (10.0 ꢁmol, 5
mol%) was used instead of Agꢀsalt. d No reaction.
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Au(I)ꢀcatalyzed cyclization reactions of propargylic Nꢀhydroxylamines showed a negligible solvent
effect on the yield and the reaction time. The reactions were effective in various solvents such as
CH2Cl2, THF, CH3CN, and toluene (Table 2, entry 6 and entries 11‒14). Based on table 2, we chosen
the relatively nonꢀpolar solvent, toluene for further study (Table 2, entries 13 and 14).
After we identified (PPh3)AuCl/AgOTf and (PPh3)AuNTf2 as the best catalysts, we investigated the
scope of Au(I)ꢀcatalyzed cyclization reactions of propargylic Nꢀhydroxylamines using
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(PPh3)AuCl/AgOTf or (PPh3)AuNTf2 independently under optimized conditions (Scheme 2). Both the
(PPh3)AuCl/AgOTf catalyst system and the (PPh3)AuNTf2 catalyst worked well with a wide variety of
substrates and showed broad functional group compatibility. The cyclization yields are fully comparable
and independent of the electronic nature. Substrates 1b–d bearing electronꢀdonating substituents as R3
group underwent the cyclization reactions very smoothly and provided the corresponding 4ꢀisoxazolines
2b–d at room temperature in good to excellent yields (76–99%). Substrates 1e–i bearing electronꢀ
withdrawing substituents as R3 groups also provided the desired 4ꢀisoxazolines 2e–i in good yields (68–
98%) under the same reaction conditions. Evidently, no reactivity difference between the
(PPh3)AuCl/AgOTf catalyst system and the (PPh3)AuNTf2 was observed. The Au(I)ꢀcatalyzed
cyclization reaction was also applicable to the substrates carrying aliphatic, naphthyl, thiophenyl
substitutents as R3 to deliver the corresponding 4ꢀisoxazolines (2j–l and 2r). Modifications to the R1 and
R2 groups were carried out as well. The substrates bearing electronꢀdonating pꢀmethoxyphenyl,
electronꢀwithdrawing pꢀnitrophenyl and aliphatic groups in the R2 underwent clean conversion to 4ꢀ
isoxazolines (2m–o, 2r, and 2s). The benzyl group in R1 could be replaced with a pꢀmethoxybenzyl
(PMB) group and a tꢀbutyl group without loss of reactivity. Although bulky tꢀbutyl substituted 4ꢀ
isoxazoline 2q was very unstable and decomposed to 3a during column chromatography, 2q was
successfully isolated in over 90% yield by rapid flash chromatography.
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Scheme 2. Synthesis of 4ꢀIsoxazolines under Optimized Conditions.
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Moreover, the potential of this reaction was further proved by preliminary experiments using
optically active propargylic Nꢀhydroxylamine (eq 2). The enantioenriched propargylic Nꢀ
hydroxylamine, (R)ꢀ1a can be cyclized without loss in enantiopurity, which suggests that this reaction is
mild enough to allow 4ꢀisoxazolines from enantiopure propargylic Nꢀhydroxylamines under
preservation of the stereochemical integrity. Therefore, it is applicable to the stereoselective synthesis of
4ꢀisoxazolines when it is coupled to diastereoselective or enantioselective synthesis of propargylic Nꢀ
hydroxylamine.
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Mechanistically, we speculate that Au(I) catalyst A coordinates with the alkyne of 1a and
subsequent cyclization leads to the Au(I) complex C. Subsequent deprotonation generates the Au(I)
complex D, which readily decomposes to yield protodeaurated 4ꢀisoxazoline 2a and regenerates the
cationic gold(I) catalyst A (Scheme 3).
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Scheme 3. Plausible Mechanism.
Conclusions
In conclusion, we have successfully developed an efficient goldꢀcatalyzed cyclization of propargylic
Nꢀhydroxylamines to furnish synthetically valuable 4ꢀisoxazolines under mild conditions (room
temperature, 5 mol% catalyst loading) in short reaction times (5‒60 minutes). This is the first report on
the construction of 4ꢀisoxazolines using gold(I)ꢀcatalyzed intramolecular cyclization. We believe that
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this methodology will be very useful in synthetic organic chemistry and medicinal chemistry. Its
application to the synthesis of bioactive natural products is currently underway in our laboratory.
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Experimental Section
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General Methods All reactions were performed in ovenꢀdried glassware fitted with a glass stopper
under positive pressure of Ar with magnetic stirring, unless otherwise noted. Airꢀ and moistureꢀsensitive
liquids and solutions were transferred via syringe or stainlessꢀsteel cannula. TLC was performed on 0.25
mm E. Merck silica gel 60 F254 plates and visualized under UV light (254 nm) or by staining with
cerium ammonium molybdenate (CAM), potassium permanganate (KMnO4) or pꢀanisaldehyde. Flash
chromatography was performed on E. Merck 230−400 mesh silica gel 60. Reagents were purchased
from commercial suppliers, and used without further purification unless otherwise noted. Solvents were
distilled from proper drying agents (CaH2 or Na wire) under Ar atmosphere at 760 mm Hg. All
moistureꢀ and/or oxygenꢀsensitive solids were handled and stored in a glove box under N2. NMR spectra
were recorded at 24 °C. Chemical shifts are expressed in ppm relative to TMS (1H, 0 ppm), CDCl3 (1H,
7.26 ppm; 13C, 77.2 ppm), C6D6 (1H, 7.16 ppm; 13C, 128.1 ppm), acetoneꢀd6 (1H, 2.05 ppm; 13C, 206.2,
29.9 ppm), and C6H5F (19F, −113.15 ppm); coupling constants are expressed in Hz. High resolution
mass spectra (HRMS) were obtained by electrospray ionization (ESI) or electron ionization (EI).
Infrared spectra were recorded with peaks reported in cm–1.
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Procedure for the synthesis of nitrone S1a‒f.
(Z)-N-Benzylidene-benzylamine-N-oxide (S1a).17 NꢀBenzylhydroxylamine (2.00 g, 16.2 mmol, 1.00
equiv), benzaldehyde (1.65 mL, 16.2 mmol, 1.00 equiv) and anhydrous MgSO4 (1.95 g, 16.2 mmol, 1.00
equiv) were suspended in anhydrous CH2Cl2 (80 mL). After stirring at room temperature for 15 h, the
resulting suspension was filtered and washed with CH2Cl2 (100 mL). The filtrate was concentrated by
rotary evaporation. The residue was purified by column chromatography (1:1 hexane/EtOAc) to afford
(Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide (S1a) (3.40 g, 99%) as a white solid. TLC: Rf 0.45 (1:1
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hexane/EtOAc). H NMR (400 MHz, CDCl3): δ 8.22‒8.19 (m, 2H), 7.49‒7.39 (m, 9H), 5.06 (s, 2H).
13C NMR (100 MHz, CDCl3): 134.6, 133.3, 130.6, 130.5, 130.0, 129.3, 129.0, 128.8, 128.5, 71.3.
HRMS (ESI) m/z calcd for C14H13NNaO [M+ Na]+ 234.0889, found 234.0896.
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(Z)-N-(4-Methoxybenzylidene)-1-phenylmethanamine oxide (S1b).18 NꢀBenzylhydroxylamine (493
mg, 4.00 mmol, 1.00 equiv), pꢀmethoxybenzaldehyde (535 ꢁL, 4.40 mmol, 1.10 equiv) and 4 Ǻ
molecular sieves (500 mg) were suspended in anhydrous toluene (12 mL). After stirring at room
temperature for 12 h, the resulting suspension was filtered and washed with CH2Cl2 (20 mL). The
filtrate was concentrated by rotary evaporation. Recrystallization from hexanes/EtOAc (4:1) afforded
S1b (960 mg, 99%) as a white solid. TLC: Rf 0.35 (1:1 hexane/EtOAc). 1H NMR (400 MHz, CDCl3): δ
8.20 (d, J = 8.8 Hz, 2H), 7.46 (dd, J = 8.0 Hz, 2.0 Hz, 2H), 7.42‒7.36 (m, 3H), 7.32 (s, 1H), 6.90 (d, J =
8.8 Hz, 2H), 5.01 (s, 2H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3): 161.3, 134.2, 133.6, 130.8, 129.3,
129.1, 129.0, 123.5, 113.9, 70.8, 55.5. HRMS (ESI) m/z calcd for C15H15NNaO2 [M+ Na]+ 264.0995,
found 264.1001.
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(Z)-N-(4-Nitrobenzylidene)-1-phenylmethanamine oxide (S1c).18 NꢀBenzylhydroxylamine (493 mg,
4.00 mmol, 1.00 equiv), pꢀnitrobenzaldehyde (664 mg, 4.40 mmol, 1.10 equiv) and 4 Ǻ molecular
sieves (500 mg) were suspended in anhydrous toluene (12 mL). After stirring at room temperature for
12 h, the resulting suspension was filtered and washed with CH2Cl2 (20 mL). The filtrate was
concentrated by rotary evaporation. The residue was purified by column chromatography (1:1
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hexane/EtOAc) to afford S1c (830 mg, 81 %) as a yellow solid. TLC: Rf 0.55 (1:1 hexane/EtOAc). H
NMR (400 MHz, CDCl3): δ 8.36 (d, J = 9.2 Hz, 2H), 8.23 (d, J = 9.2 Hz, 2H), 7.52 (s, 1H), 7.50‒7.48
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(m, 2H), 7.45‒7.43 (m, 3H), 5.11 (s, 2H). C NMR (100 MHz, CDCl3): 148.0, 136.2, 132.7, 132.3,
129.6, 129.5, 129.3, 129.0, 123.9, 72.2. HRMS (ESI) m/z calcd for C14H13N2O3 [M+ H]+ 257.0921,
found 257.0925.
(Z)-N-(2-Methylpropylidene)benzylamine-N-oxide (S1d).17 NꢀBenzylhydroxylamine (247 mg, 2.00
mmol, 1.00 equiv), 2ꢀmethylpropionaldehyde (183 ꢁL, 2.00 mmol, 1.00 equiv) and anhydrous MgSO4
(240 mg, 2.00 mmol, 1.00 equiv) were suspended in anhydrous Et2O (10 mL). After Stirring at room
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temperature for 15 h, the resulting suspension was filtered and washed with CH2Cl2 (20 mL). The
filtrate was concentrated by rotary evaporation. Recrystallization from hexanes/EtOAc (4:1) afforded
S1b (230 mg, 65%) as a white solid. TLC: Rf 0.15 (3:1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ
7.4‒7.35 (m, 5H), 6.47 (d, J = 7.2 Hz, 1H), 4.86 (s, 2H), 3.16 (sept, J = 6.4 Hz, 1H), 1.08 (d, J = 6.4 Hz,
6H). 13C NMR (100 MHz, CDCl3): 144.7, 133.2, 129.2, 129.0, 128.9, 69.4, 26.1, 18.9. HRMS (ESI) m/z
calcd for C11H15NNaO [M+ Na]+ 200.1046, found 200.1055.
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(Z)-N-Benzylidene-1-(4-methoxyphenyl)methanamine
oxide
(S1e).19
Nꢀ(4ꢀ
Methoxybenzyl)hydroxylamine (766 mg, 5.00 mmol, 1.00 equiv), benzaldehyde (508 ꢁL, 5.00 mmol,
1.00 equiv) and anhydrous MgSO4 (600 mg, 5.00 mmol, 1.00 equiv) were suspended in anhydrous
CH2Cl2 (25 mL). After stirring for 12 h at room temperature, the resulting suspension was filtered and
washed with CH2Cl2 (20 mL). The filtrate was concentrated by rotary evaporation. The residue was
purified by column chromatography (1:1 hexane/EtOAc) to afford S1e (1.16 g, 96%) as a white solid.
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TLC: Rf 0.48 (1:2 hexane/EtOAc). H NMR (400 MHz, CDCl3): δ 8.21‒8.18 (m, 2H), 7.41‒7.38 (m,
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5H), 7.33 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 4.99 (s, 2H), 3.82 (s, 3H). C NMR (100 MHz, CDCl3): δ
160.3, 134.1, 131.1, 130.6, 128.8, 128.6, 125.3, 114.5, 70.8, 55.5. HRMS (ESI) m/z calcd for
C15H16NO2 [M+ H]+ 242.1176, found 242.1177.
(Z)-N-(Cyclohexylmethylene)-1-phenylmethanamine
oxide
(S1f).4
Nꢀ(4ꢀ
Methoxybenzyl)hydroxylamine (493 mg, 4.00 mmol, 1.00 equiv), cyclohexylaldehyde (550 ꢁL, 4.40
mmol, 1.10 equiv) and anhydrous MgSO4 (530 mg, 4.40 mmol, 1.10 equiv) were suspended in
anhydrous toluene (12 mL). After stirring for 16.5 h at room temperature, the resulting suspension was
filtered and washed with CH2Cl2 (20 mL). The filtrate was concentrated by rotary evaporation. The
residue was recrystallized from hexane/EtOAc, and the mother liquor was further purified by column
chromatography (1:1 hexane/EtOAc) to afford S1f (858 mg, 99%) as a white solid. TLC: Rf 0.22 (1:2
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hexane/EtOAc). H NMR (400 MHz, CDCl3): δ 7.36 (m, 5H), 6.45 (d, J = 7.2 Hz, 1H), 4.84 (s, 2H),
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2.97 (m, 1H), 1.85‒1.82 (m, 2H), 1.68‒1.64 (m, 3H), 1.40‒1.29 (m, 2H), 1.25‒1.06 (m, 3H). C NMR
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(100 MHz, CDCl3): δ 143.2, 133.4, 129.2, 129.0, 128.9, 69.5, 35.2, 28.9, 26.1, 25.4.
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General procedure for the synthesis of propargylic Nꢀhydroxylamines 1a‒s.20
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To an ovenꢀdried, 25ꢀmL oneꢀarm roundbottom flask, anhydrous Et2O (12.0 mL), nitrone (1.20 mmol,
1.20 equiv), ZnBr2 (45.0 mg, 0.20 mmol, 0.20 equiv), alkyne (1.00 mmol, 1.00 equiv), iꢀPr2NEt (226 ꢁL,
1.30 mmol, 1.30 equiv) and TMSOTf (217 ꢁL, 1.20 mmol, 1.20 equiv) were added sequentially at room
temperature. The heterogeneous mixture was stirred at room temperature for indicated time. The
resulting suspension was filtered through a plug of silica gel (1 cm × 5 cm), washed with Et2O (50 mL),
and concentrated by rotary evaporation. The crude product of the reaction was dissolved in MeOH (10
mL) with magnetic stirring, and treated with a p-toluenesulfonic acid (19.0 mg, 0.1 mmol). After
completion of the TMS deprotection, the resulting mixture was concentrated by rotary evaporation. The
residue was purified by column chromatography (hexanes/EtOAc) to afford propargylic Nꢀ
hydroxylamines 1a‒s.
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N-Benzyl-N-(1,3-diphenylprop-2-yn-1-yl)hydroxylamine (1a).4
1a was prepared from
phenylacetylene (110 µL, 1.00 mmol) and the (Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide (S1a) (253 mg,
1.20 mmol). Reaction time: 16 h. Then, the reaction mixture was stirred for an additional 2 h after the
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addition of pꢀtoluenesulfonic acid. White solid (260 mg, 84%). TLC: Rf 0.25 (9:1 hexanes/EtOAc). H
NMR (400 MHz, CDCl3): δ 7.64 (d, J = 7.2 Hz, 2H), 7.59‒7.56 (m, 2H), 7.42‒7.27 (m, 11H), 5.00 (s,
1H), 4.96 (brs, 1H), 4.07 (d, J = 13.2 Hz, 1H), 4.00 (d, J = 13.2 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 137.5, 137.1, 132.2, 129.9, 129.2, 128.7, 128.6, 128.5, 128.4, 128.3, 127.8, 122.9, 88.9, 84.6, 63.2,
60.6. HRMS (ESI) m/z calcd for C22H20NO [M+ H]+ 314.1539, found 314.1542. IR (KBr film): 3229,
3062, 3030, 2905, 1489, 1453 cm–1.
N-benzyl-N-(1-phenyl-3-(p-tolyl)prop-2-yn-1-yl)hydroxylamine (1b).21 1b was prepared from 4ꢀ
ethynyltoluene (127 µL, 1.00 mmol) and the (Z)ꢀNꢀbenzylideneꢀbenzylamineꢀN-oxide (S1a) (253 mg,
1.20 mmol). Reaction time: 16 h. Then, the reaction mixture was stirred for an additional 1 h after the
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addition of pꢀtoluenesulfonic acid. White solid (220 mg, 67%). TLC: Rf 0.37 (9:1 hexanes/EtOAc). H
NMR (400 MHz, CDCl3): δ 7.64 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.42‒7.27 (m, 8H), 7.16
(d, J = 8.0 Hz, 2H), 5.00 (s, 1H), 4.88 (brs, 1H), 4.08 (d, J = 13.2 Hz, 1H), 4.00 (d, J = 13.2 Hz, 1H),
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2.37 (s, 3H). C NMR (100 MHz, CDCl3): δ 138.8, 137.7, 137.4, 132.1, 129.9, 129.3, 129.1, 128.6,
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128.5, 128.3, 127.7, 119.9, 89.2, 83.9, 63.4, 60.7, 21.7. HRMS (ESI) m/z calculated for C23H22NO
[M+H]+ 328.1696, found 328.1702. IR (KBr film): 3229, 3062, 3029, 2918, 1509, 1452 cm–1.
N-Benzyl-N-(3-(3,5-dimethoxyphenyl)-1-phenylprop-2-yn-1-yl)hydroxylamine (1c). 1c was prepared
from 1ꢀethynylꢀ3,5ꢀdimethoxybenzene (162 mg, 1.00 mmol) and the (Z)ꢀNꢀbenzylideneꢀbenzylamineꢀN-
oxide (S1a) (253 mg, 1.20 mmol). Reaction time: 2 h. Then, the reaction mixture was stirred for an
additional 2 h after the addition of pꢀtoluenesulfonic acid. White solid (373 mg, quantitative yield).
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TLC: Rf 0.37 (5:1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.62 (dd, J = 8.8 Hz, 1.2 Hz, 2H),
7.38‒7.26 (m, 8H), 6.72 (d, J = 2.4 Hz, 2H), 6.48 (t, J = 2.4, 1H), 5.16 (brs, 1H), 4.96 (s, 1H), 4.03 (d, J
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= 12.8 Hz, 1H), 3.98 (d, J = 12.8, 1H), 3.80 (s, 6H). C NMR (100 MHz, CDCl3): δ 160.7, 137.4,
137.1, 129.9, 129.2, 128.6, 128.5, 128.4, 127.8, 124.2, 110.0, 102.1, 88.9, 84.3, 63.3, 61.4, 55.7. HRMS
(ESI) m/z calculated for C24H23NNaO3 [M+Na]+ : 396.1570, found 396.1563. IR (KBr film): 3228,
3029, 2360, 1588, 1453, 1205 cm–1. mp: 134‒135 oC.
N-Benzyl-N-(3-(4-pentylphenyl)-1-phenylprop-2-yn-1-yl)hydroxylamine (1d).22 1d was prepared from
1ꢀethynylꢀ4ꢀpentylbenzene (195 µL, 1.00 mmol) and the (Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide (S1a)
(253 mg, 1.20 mmol). Reaction time: 4 h. Then, the reaction mixture was stirred for an additional 1 h
after the addition of pꢀtoluenesulfonic acid. White solid (360 mg, 94%). TLC: Rf 0.43 (9:1
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hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H),
7.42‒7.27 (m, 8H), 7.17 (d, J = 8.0 Hz, 2H), 5.03 (s, 1H), 4.75 (brs, 1H), 4.11 (d, J = 13.2 Hz, 1H), 4.00
(d, J = 13.2 Hz, 1H), 2.62 (t, J = 7.6 Hz, 2H), 1.62 (quintet, J = 7.6 Hz, 2H), 1.37‒1.29 (m, 4H), 0.90 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 143.9, 137.7, 137.3, 132.1, 129.9, 129.1, 128.7, 128.6,
128.5, 128.3, 127.7, 120.1, 89.3, 83.8, 63.4, 60.8, 36.1, 31.6, 31.2, 22.7, 14.2. HRMS (ESI) m/z
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calculated for C27H29NNaO [M+Na]+ 406.2141, found 406.2136. IR (KBr film): 2954, 2927, 2856,
1509, 1453 cm–1.
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N-Benzyl-N-(3-(4-fluorophenyl)-1-phenylprop-2-yn-1-yl)hydroxylamine (1e). 1e was prepared from pꢀ
fluorophenylacetylene (115 µL, 1.00 mmol) and the (Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide (S1a) (253
mg, 1.20 mmol). Reaction time: 2 h. Then, the reaction mixture was stirred for an additional 1 h after
the addition of pꢀtoluenesulfonic acid. White solid (330 mg, quantitative yield). TLC: Rf 0.49 (5:1
hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.8 Hz, 2H), 7.55 (dd, J = 8.8 Hz, 5.6 Hz,
2H), 7.41‒7.28 (m, 8H), 7.05 (t, J = 8.8 Hz, 2H), 4.98 (s, 1H), 4.05 (d, J = 12.8 Hz, 1H), 4.00 (d, J =
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12.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 162.8 (d, JC−F = 248.4 Hz), 137.5, 137.2, 134.1 (d, JC−F
=
8.5 Hz), 129.9, 129.1, 128.6 128.5, 128.4, 127.8, 119.1 (d, JC−F = 3.1 Hz), 115.8 (d, JC−F = 21.6 Hz),
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87.8, 84.4, 63.2, 60.6. F NMR (376 MHz, CDCl3): δ ‒110.8. HRMS (EI TOF) m/z calculated for
C22H19FNO [M+H]+ 332.1445, found 332.1443. IR (KBr film): 3240, 2903, 1600, 1505, 1229, 835, 697
cm–1. mp: 134‒136 oC.
N-Benzyl-N-(3-(3,4-dichlorophenyl)-1-phenylprop-2-yn-1-yl)hydroxylamine (1f). 1f was prepared
from 3,4ꢀdichlorophenylacetylene (171 mg, 1.00 mmol) and the (Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide
(S1a) (253 mg, 1.20 mmol). Reaction time: 2 h. Then, the reaction mixture was stirred for an additional
1 h after the addition of pꢀtoluenesulfonic acid. White solid (330 mg, 86%). TLC: Rf 0.43 (9:1
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hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 1.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H),
7.44‒7.26 (m, 10H), 5.05 (brs, 1H), 4.97 (brs, 1H), 4.03 (d, J = 13.2 Hz, 1H), 3.97 (d, J = 13.2 Hz, 1H).
13C NMR (100 MHz, Acetoneꢀd6): δ 139.6, 139.2, 134.2, 133.0, 132.9, 132.5, 131.7, 130.1, 129.8, 129.1,
129.0, 128.7, 127.9, 124.7, 89.9, 85.9, 64.4, 61.7. HRMS (ESI) m/z calculated for C22H18Cl2NO [M+H]+
382.0760, found 382.0759. IR (KBr film): 3233, 3029, 1738, 1473, 1217, 736, 697 cm–1. mp: 133–136
oC.
N-benzyl-N-(1-phenyl-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)hydroxylamine (1g). 1g was
prepared from pꢀ(trifluoromethyl)phenyl acetylene (163 µL, 1.00 mmol) and the (Z)ꢀNꢀ
benzylidenebenzylamineꢀN-oxide (S1a) (253 mg, 1.20 mmol). Reaction time: 6 h. Then, the reaction
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mixture was stirred for an additional 1 h after the addition of pꢀtoluenesulfonic acid. White solid (267
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mg, 70%). TLC: Rf 0.37 (9:1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz,
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2H), 7.64‒7.60 (m, 4H), 7.42‒7.28 (m, 8H), 5.03 (s, 1H), 4.95 (brs, 1H), 4.09 (d, J = 13.2 Hz, 1H), 4.00
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(d, J = 13.2 Hz, 1H). C NMR (100 MHz, CDCl3): δ 137.1, 137.0, 132.4, 130.5 (q, JC−F = 32.5 Hz),
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129.8, 129.1, 128.7, 128.6, 128.5, 127.9, 126.8, 125.5 (q, JC−F = 3.9 Hz), 124.1 (q, JC−F = 270.1 Hz),
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87.5, 87.4, 63.3, 60.9. F NMR (376 MHz, CDCl3): δ ‒63.2. HRMS (ESI) m/z calcd for C23H19F3NO
[M+H]+ 382.1413, found 382.1411. IR (KBr film): 3031, 2905, 1613, 1452, 758, 698 cm–1. mp: 146‒
148 oC.
4-(3-(Benzyl(hydroxy)amino)-3-phenylprop-1-yn-1-yl)benzonitrile (1h). 1k was prepared from 4ꢀ
ethynylbenzonitrile (127 mg, 1.00 mmol) and the (Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide (S1a) (253
mg, 1.20 mmol). Reaction time: 2 h. Then, the reaction mixture was stirred for an additional 1 h after
the addition of pꢀtoluenesulfonic acid. Yellow solid (180 mg, 53%). TLC: Rf 0.36 (4:1 hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ 7.65 (s, 4H), 7.61 (d, J = 7.2 Hz, 2H), 7.42‒7.28 (m, 8H), 5.02 (s, 1H),
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4.05 (d, J = 13.2 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H). C NMR (100 MHz, CDCl3): δ 136.9, 132.7,
132.3, 129.8, 129.1, 128.8, 128.7, 128.6, 128.5, 127.9, 127.8, 118.6, 112.1, 89.7, 87.2, 63.4, 60.9.
HRMS (ESI) m/z calculated for C23H19N2O [M+H]+ 339.1492, found 339.1498. IR (KBr film): 3220,
2227, 1599, 1452, 846, 736 cm–1. mp: 170–172 oC.
Methyl 4-(3-(benzyl(hydroxy)amino)-3-phenylprop-1-yn-1-yl)benzoate (1i). 1i was prepared from
Methyl 4ꢀethynylbenzoate (160 mg, 1.00 mmol) and the (Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide (S1a)
(253 mg, 1.20 mmol). Reaction time: 16 h. Then, the reaction mixture was stirred for an additional 1 h
after the addition of pꢀtoluenesulfonic acid. White solid (278 mg, 75%). TLC: Rf 0.31 (9:1
hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.4 Hz, 2H), 7.64‒7.62 (m, 4H), 7.41‒7.28
(m, 8H), 5.02 (s, 1H), 4.99 (brs, 1H), 4.06 (d, J = 13.2 Hz, 1H), 4.00 (d, J = 13.2 Hz, 1H), 3.93 (s, 3H).
13C NMR (100 MHz, Acetoneꢀd6): δ 166.8, 139.6, 139.3, 132.8, 130.8, 130.4, 130.1, 129.8, 129.1,
129.0, 128.9, 128.7, 127.9, 90.7, 87.6, 64.5, 61.7, 52.6. HRMS (ESI) m/z calculated for C24H21NNaO3
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[M+Na]+ 394.1414, found 394.1415. IR (KBr film): 3452, 2951, 1722, 1276, 769, 697 cm–1. mp: 145–
147 oC.
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N-benzyl-N-(1-phenylnon-2-yn-1-yl)hydroxylamine (1j).6a 1j was prepared from 1ꢀoctyne (148 uL,
1.00 mmol) and the (Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide (S1a) (253 mg, 1.20 mmol). Reaction time:
2 h. Then, the reaction mixture was stirred for an additional 1 h after the addition of pꢀtoluenesulfonic
acid. Colorless oil (260 mg, 81%). TLC: Rf 0.51 (5:1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ
7.54 (d, J = 8.8 Hz, 2H), 7.36‒7.25 (m, 8H), 4.69 (s, 1H), 3.88 (s, 2H), 2.38 (td, J = 7.2 Hz, 2.0 Hz, 2H),
1.63 (quintet, J = 7.2 Hz, 2H), 1.48 (m, 2H), 1.36‒1.30 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 138.0, 137.3, 129.9, 129.1, 128.5, 128.4, 128.0, 127.6, 89.7, 74.9, 62.7, 60.5, 31.5,
29.1, 28.9, 22.8, 19.2, 14.3. HRMS (ESI) m/z calcd for C22H28NO [M+H]+ 322.2165, found 322.2168.
IR (KBr film): 3200, 2954, 2929, 2857, 1453 cm–1.
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N-Benzyl-N-(3-(6-methoxynaphthalen-2-yl)-1-phenylprop-2-yn-1-yl)hydroxylamine (1k). 1k was
prepared from 2ꢀethynylꢀ6ꢀmethoxynaphthalene (182 mg, 1.00 mmol) and the (Z)ꢀNꢀ
benzylidenebenzylamineꢀN-oxide (S1a) (253 mg, 1.20 mmol). Reaction time: 1 h. Then, the reaction
mixture was stirred for an additional 1 h after the addition of pꢀtoluenesulfonic acid. White solid (225
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mg, 57%). TLC: Rf 0.37 (9:1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.73‒7.68
(m, 4H), 7.58 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.45‒7.25 (m, 8H), 7.16 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.13
(d, J = 2.8 Hz, 1H), 5.07 (s, 1H), 4.84 (s, 1H), 4.16 (d, J = 13.2 Hz, 1H), 4.07 (d, J = 13.2 Hz, 1H), 3.93
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(s, 3H). C NMR (100 MHz, C6D6): δ 159.3, 139.3, 138.9, 135.2, 132.6, 130.4, 130.2, 130.1, 129.9,
129.5, 129.0, 128.6, 128.3, 128.0, 127.6, 120.3, 118.9, 106.6, 89.8, 64.4, 61.8, 55.2. HRMS (ESI) m/z
calculated for C27H24NO2 [M+H]+ 394.1802, found 394.1797. IR (KBr film): 3234, 3060, 3029, 1628,
1601, 759, 737 cm–1. mp: 148–150 oC.
N-Benzyl-N-(1-phenyl-3-(thiophen-3-yl)prop-2-yn-1-yl)hydroxylamine (1l). 1l was prepared from 3ꢀ
ethynylthiophene (99 µL, 1.00 mmol) and the (Z)ꢀNꢀbenzylidenebenzylamineꢀN-oxide (S1a) (253 mg,
1.20 mmol). Reaction time: 16 h. Then, the reaction mixture was stirred for an additional 1 h after the
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addition of pꢀtoluenesulfonic acid. White solid (278 mg, 87%). TLC: Rf 0.29 (9:1 hexanes/EtOAc). H
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NMR (400 MHz, CDCl3): δ 7.63‒7.61 (m, 2H), 7.55 (dd, J = 2.8 Hz, 1.2 Hz, 1H), 7.40‒7.37 (m, 3H),
7.36‒7.27 (m, 6H), 7.21 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 4.96 (s, 1H), 4.04 (d, J = 13.2 Hz, 1H), 3.99 (d, J
= 13.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 137.5, 137.2, 130.4, 129.9, 129.4, 129.2, 128.6, 128.5,
128.3, 127.8, 125.5, 121.9, 84.3, 83.9, 63.3, 60.3. HRMS (ESI) m/z calculated for C20H18NOS [M+H]+
320.1104, found 320.1100. IR (KBr film): 3231, 3106, 3029, 2904, 1453, 1357 cm–1. mp: 139–141 oC.
N-Benzyl-N-(1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-yl)hydroxylamine (1m).23 1m was prepared
from phenylacetylene (110 µL, 1.00 mmol) and the (Z)ꢀNꢀ(4ꢀmethoxybenzylidene)ꢀ1ꢀ
phenylmethanamine oxide (S1b) (290 mg, 1.20 mmol). Reaction time: 16 h. Then, the reaction mixture
was stirred for an additional 1 h after the addition of pꢀtoluenesulfonic acid. White solid (210 mg, 61%).
TLC: Rf 0.45 (9:1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.59‒7.57 (m, 2H), 7.55 (d, J = 8.8
Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.37‒7.32 (m, 5H), 7.29 (d, J = 7.2 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H),
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4.95 (brs, 1H), 4.02 (s, 2H), 3.81 (s, 3H). C NMR (100 MHz, CDCl3): δ 159.7, 137.2, 132.1, 130.4,
130.0, 129.5, 128.6, 128.5, 128.4, 127.7, 123.0, 113.9, 88.7, 85.0, 62.7, 60.4, 55.5. HRMS (ESI) m/z
calcd for C23H22NO2 [M+H]+ 344.1651, found 344.1649. IR (KBr film): 3231, 3062, 3030, 1511, 1251
cm–1.
N-Benzyl-N-(1-(4-nitrophenyl)-3-phenylprop-2-yn-1-yl)hydroxylamine (1n).21 1n was prepared from
phenylacetylene (110 µL, 1.00 mmol) and the (Z)ꢀNꢀ(4ꢀnitrobenzylidene)ꢀ1ꢀphenylmethanamine oxide
(S1c) (308 mg, 1.20 mmol). Reaction time: 4 h. Then, the reaction mixture was stirred for an additional
1 h after the addition of pꢀtoluenesulfonic acid. White solid (295 mg, 82%). TLC: Rf 0.40 (9:1
hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.23 (dt, J = 8.8 Hz, 2.0 Hz, 2H), 7.83 (dt, J = 8.8 Hz,
2.0 Hz, 2H), 7.60‒7.58 (m, 2H), 7.45‒7.30 (m, 8H), 5.06, (s, 1H), 4.19 (d, J = 12.8 Hz, 1H), 4.13 (d, J =
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12.8 Hz, 1H). C NMR (100 MHz, CDCl3): δ 147.2, 145.0, 136.5, 132.2, 129.9, 129.8, 129.2, 128.8,
128.7, 128.1, 123.7, 122.3, 90.3, 82.9, 62.6, 61.8. HRMS (ESI) m/z calcd for C22H19N2O3 [M+H]+
359.1390, found 359.1386. IR (KBr film): 3238, 3030, 1597, 1489 cm–1.
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N-Benzyl-N-(4-methyl-1-phenylpent-1-yn-3-yl)hydroxylamine (1o).21 1o was prepared from
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phenylacetylene (55.0 µL, 500 ꢁmol), (Z)ꢀNꢀ(2ꢀmethylpropylidene)ꢀ1ꢀphenylmethanamine oxide (S1d)
(106 mg, 600 ꢁmol). Reaction time: 16 h. Then, the reaction mixture was stirred for an additional 4 h
after the addition of pꢀtoluenesulfonic acid. White solid (115 mg, 82%). TLC: Rf 0.40 (9:1
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hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.52‒7.49 (m, 2H ), 7.42 (d, J = 8.4 Hz, 2H ), 7.34‒
7.25 (m, 6H ), 4.42 (s, 1H ), 4.23 (d, J = 12.8 Hz, 1H), 3.89 (d, J = 12.8 Hz, 1H), 3.39 (d, J = 8.8 Hz,
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1H), 2.14 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl3): δ
137.7, 132.1, 129.6, 128.6, 128.5, 128.4, 127.6, 123.2, 88.0, 85.4, 66.5, 62.5, 31.1, 20.2, 20.0. HRMS
(ESI) m/z calcd for C19H22NO [M+ H]+ 280.1696, found 280.1697. IR (KBr film): 3453, 2960, 1489,
1384 cm–1.
N-(1,3-Diphenylprop-2-yn-1-yl)-N-(4-methoxybenzyl)hydroxylamine (1p).21 1p was prepared from
phenylacetylene (110 µL, 1.00 mmol) and the (Z)ꢀNꢀbenzylideneꢀ1ꢀ(4ꢀmethoxyphenyl)methanamine
oxide (S1e) (290 mg, 1.20 mmol). Reaction time: 16 h. Then, the reaction mixture was stirred for an
additional 12 h after the addition of pꢀtoluenesulfonic acid. White solid (355 mg, quantitative yield).
TLC: Rf 0.30 (5:1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 6.8 Hz, 2H), 7.59‒7.57
(m, 2H), 7.41‒7.31 (m, 8H), 6.82 (dt, J = 8.8 Hz, 2.8 Hz, 2H), 5.02 (s, 1H), 4.06 (d, J = 13.2 Hz, 1H),
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4.00 (d, J = 13.2 Hz, 1H), 3.80 (s, 3H). C NMR (100 MHz, CDCl3): δ 159.3, 137.7, 132.2, 131.0,
129.2, 129.1, 128.7, 128.6, 128.5, 128.3, 122.9, 114.0, 89.0, 84.6, 63.1, 60.5, 55.5. HRMS (ESI) m/z
calcd for C23H22NO2 [M+H]+ 344.1645, found 344.1650. IR (KBr film): 3231, 3061, 2906, 1489, 1301
cm–1.
N-(tert-Butyl)-N-(1,3-diphenylprop-2-yn-1-yl)hydroxylamine (1q). 1q was prepared from
phenylacetylene (550 µL, 5.00 mmol) and Nꢀtertꢀbutylphenylnitrone (1.06 g, 6.00 mmol). Reaction
time: 16 h. Then, the reaction mixture was stirred for an additional 12 h after the addition of pꢀ
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toluenesulfonic acid. Light yellow solid (1.10 g, 79%). TLC: Rf 0.47 (9:1 hexanes/EtOAc). H NMR
(400 MHz, CDCl3): δ 7.66 (d, J = 8.8 Hz, 2H), 7.51‒7.48 (m, 2H), 7.39‒7.29 (m, 6H), 5.20 (s, 1H), 4.34
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(brs, 1H), 1.36 (s, 9H). C NMR (100 MHz, CDCl3): δ 140.4, 131.7, 128.5, 128.4, 128.3 (2C), 127.6,
123.3, 88.7, 87.2, 60.2, 56.8, 26.8. HRMS (ESI) m/z calcd for C19H22NO [M+H]+ 280.1696, found
280.1698. IR (KBr film): 3532, 3457, 2971, 1597, 1490, 720, 650 cm–1. mp: 76–79 oC.
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N-Benzyl-N-(1,3-dicyclohexylprop-2-yn-1-yl)hydroxylamine (1r).
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cyclohexylacetylene 95% (230 µL, 1.00 mmol) and (Z)ꢀNꢀ(cyclohexylmethylene)ꢀ1ꢀ
phenylmethanamine oxide (S1f) (261 mg, 1.20 mmol). Reaction time: 24 h. Then, the reaction mixture
was stirred for an additional 2 h after the addition of pꢀtoluenesulfonic acid. White solid (323 mg, 99%).
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TLC: Rf 0.25 (6:1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 7.40‒7.25 (m, 5H), 4.39 (s, 1H),
4.11 (d, J = 12.8 Hz, 1H), 3.79 (d, J = 12.8 Hz, 1H), 3.22 (d, J = 4.0 Hz, 1H), 2.55‒2.51 (m, 1H), 2.09‒
0.86 (m, 21H). 13C NMR (100 MHz, CDCl3): δ 137.8, 129.5, 128.5, 127.4, 93.3, 74.8, 64.9, 62.5, 40.3,
33.3, 33.2, 30.6 (2C), 29.3, 26.8, 26.3, 26.1, 25.0. HRMS (ESI) m/z calcd for C22H32NO [M+H]+
326.2478, found 326.2483.
IR (KBr film): 3534, 3462, 2927, 1604, 1495, 743, 699 cm–1. mp: 76‒78 oC.
N-benzyl-N-(1-cyclohexyl-3-phenylprop-2-yn-1-yl)hydroxylamine (1s).4 1s was prepared from
phenylacetylene (110 µL, 1.00 mmol) and (Z)ꢀNꢀ(cyclohexylmethylene)ꢀ1ꢀphenylmethanamine oxide
(S1f) (261 mg, 1.20 mmol). Reaction time: 16.5 h. Then, the reaction mixture was stirred for an
additional 2.5 h after the addition of pꢀtoluenesulfonic acid. White solid (272 mg, 85%). TLC: Rf 0.5
(7:1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.53 (dd, J = 6.8 Hz, 2.8 Hz, 2H), 7.42 (d, J = 6.8
Hz, 2H), 7.35‒7.29 (m, 6H), 4.60 (brs, 1H), 4.20 (d, J = 13.2 Hz, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.47
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(d, J = 8.8 Hz, 1H), 2.14‒2.12 (m, 2H), 1.88‒1.67 (m, 4H), 1.36‒0.97 (m, 5H). C NMR (100 MHz,
CDCl3): δ 137.8, 132.1, 129.5, 128.6, 128.5, 128.4, 127.5, 123.2, 88.3, 85.3, 65.3, 62.5, 40.3, 30.8, 30.7,
26.8, 26.3, 26.1. HRMS (ESI) m/z calcd for C22H26NO [M+H]+ 320.2009, found 320.2015. IR (KBr
film): 3535, 3457, 2925, 1598, 1489, 756, 691 cm–1. mp: 126‒128oC. (Lit.4 126‒128oC.)
General procedure for the synthesis of 4ꢀisoxazoline 2a‒s.
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(PPh3)AuCl/AgOTf: In a 25 mL oneꢀarm roundbottom flask, propargylic Nꢀhydroxylamine (200
ꢁmol), (PPh3)AuCl (5.0 mg, 10.0 ꢁmol, 5 mol%), and AgOTf (2.6 mg, 10.0 ꢁmol, 5 mol%) were
dissolved in anhydrous toluene (4 mL) under Ar atmosphere. The resulting suspension was stirred at
room temperature (as shown in table 2). Upon completion of the reaction, the reaction mixture was
filtered through a plug of Celite, and rinsed with ether (20 mL). The filtrate was concentrated by rotary
evaporation. The residue was purified by column chromatography (19:1 hexanes/EtOAc).
(PPh3)AuNTf2: In a 25 mL oneꢀarm roundbottom flask, propargylic Nꢀhydroxylamine (200 ꢁmol) and
(PPh3)AuNTf2 (7.4 mg, 10.0 ꢁmol, 5 mol%) were dissolved in anhydrous toluene (4 mL) under Ar
atmosphere. The resulting suspension was stirred at room temperature (as shown in table 2). Upon
completion of the reaction, the reaction mixture was filtered through a plug of Celite, and rinsed with
ether (20 mL). The filtrate was concentrated by rotary evaporation. The residue was purified by column
chromatography (hexanes/EtOAc).
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2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazole (2a).4,21 2a was prepared from NꢀbenzylꢀNꢀ(1,3ꢀ
diphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1a) (62.6 mg, 200 ꢁmol). Purification by column
chromatography (98:2 hexanes/EtOAc) afforded 2a as a yellow solid. Reaction time: 15 min, yield: 59.0
mg (94%) for (PPh3)AuCl/AgOTf. Reaction time: 30 min, yield: 56.3 mg (90 %) for (PPh3)AuNTf2.
TLC: Rf 0.65 (9:1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.58‒7.56 (m, 2H), 7.43 (d, J = 8.4
Hz, 2H), 7.37‒7.23 (m, 11H), 5.42 (d, J = 2.4 Hz, 1H), 5.05 (d, J = 2.4 Hz, 1H), 4.43 (d, J = 12.8 Hz,
1H), 4.11 (d, J = 12.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 153.1, 142.3, 136.6, 129.8, 129.3, 128.9,
128.7, 128.6, 128.5, 127.8 (2C), 127.3, 125.9, 95.9, 73.8, 63.6. HRMS (ESI) m/z calcd for C22H20NO
[M+ H]+ 314.1539, found 314.1526. IR (KBr film): 3061, 1600, 1493, 771, 697 cm–1. mp: 105–108 oC.
(Lit.4 102‒104 oC).
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(E)-Chalcone (3a). TLC: Rf 0.62 (9:1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 8.03 (dt, J =
1.2 Hz, 6.8 Hz, 2H), 7.81 (d, J = 16.0 Hz, 1H), 7.66‒7.64 (m, 2H), 7.61‒7.56 (m, 2H), 7.53‒7.49 (m,
2H), 7.44–7.42 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 190.7, 145.0, 138.4, 135.1, 133.0, 130.7,
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129.2, 128.8, 128.7, 128.6, 122.3. HRMS (ESI) m/z calcd for C15H13O [M+H]+ 209.0961, found
209.0964. IR (KBr film): 3059, 1664, 1606, 1215, 746, 688 cm–1.
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2-Benzyl-3-phenyl-5-(p-tolyl)-2,3-dihydroisoxazole (2b). 2b was prepared from NꢀbenzylꢀNꢀ(1ꢀphenylꢀ
3ꢀ(pꢀtolyl)propꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1b) (65.4 mg, 200 ꢁmol). Purification by column
chromatography (98:2 hexanes/EtOAc) afforded 2b as a yellow solid. Reaction time: 15 min, yield: 53.0
mg (81%) for (PPh3)AuCl/AgOTf. Reaction time: 15 min, yield: 52.7 mg (79 %) for (PPh3)AuNTf2.
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TLC: Rf 0.74 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.47 (dt, J = 8.0 Hz, 2.0 Hz, 2H),
7.40 (dm, J = 8.0 Hz, 2H), 7.36 (dm, J = 8.0 Hz, 2H), 7.17‒7.12 (m, 4H), 7.09‒7.05 (m, 2H), 6.88 (d, J
= 8.0 Hz, 2H), 5.11 (d, J = 2.8 Hz, 1H), 4.87 (d, J = 2.8 Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H), 3.92 (d, J =
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13.2 Hz, 1H), 2.01 (s, 3H). C NMR (100 MHz, CDCl3): δ 153.7, 143.6, 139.5, 138.0, 130.1, 129.8,
129.2, 129.0, 128.2, 128.1, 128.0, 127.2, 126.6, 96.1, 75.0, 64.2, 21.7. HRMS (EI) m/z calcd for
C23H21NO [M]+ 327.1623, found 327.1625. IR (KBr film): 3028, 1653, 1510, 759, 731 cm–1.
2-Benzyl-5-(3,5-dimethoxyphenyl)-3-phenyl-2,3-dihydroisoxazole (2c). 2c was prepared from Nꢀ
benzylꢀNꢀ(3ꢀ(3,5ꢀdimethoxyphenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1c) (74.6 mg, 200 ꢁmol).
Purification by column chromatography (95:5 hexanes/EtOAc) afforded 2c as a pale yellow solid.
Reaction time: 10 min, yield: 74.6 mg (99%) for (PPh3)AuCl/AgOTf. Reaction time: 15 min, yield: 67.1
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mg (90%) for (PPh3)AuNTf2. TLC: Rf 0.54 (5:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.39‒
7.36 (m, 4H), 7.17‒7.01 (m, 6H), 6.92 (d, J = 2.4 Hz, 2H), 6.54 (t, J = 2.4 Hz, 1H), 5.13 (d, J = 3.2 Hz,
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1H), 4.86 (d, J = 3.2 Hz, 1H), 4.34 (d, J = 13.2 Hz, 1H), 3.93 (d, J = 13.2 Hz, 1H), 3.25 (s, 3H). C
NMR (100 MHz, CDCl3): δ 161.9, 153.7, 143.4, 137.8, 131.8, 130.2, 129.2, 128.9, 128.2, 128.1, 127.9,
104.8, 102.6, 97.6, 74.8, 64.1, 55.3. HRMS (ESI) m/z calculated for C24H24NO3 [M+H]+ 374.1751,
found 374.1758. IR (KBr film): 3017, 2360, 1592, 1215, 698, 668 cmꢀ1.
2-Benzyl-5-(4-pentylphenyl)-3-phenyl-2,3-dihydroisoxazole (2d).15 2d was prepared from NꢀbenzylꢀNꢀ
(3ꢀ(4ꢀpentylphenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1d) (76.6 mg, 200 ꢁmol). Purification by
column chromatography (98:2 hexanes/EtOAc) afforded 2d as a yellow syrup. Reaction time: 5 min,
yield: 58.0 mg (76%) for (PPh3)AuCl/AgOTf. Reaction time: 15 min, yield: 62.0 mg (81 %) for
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(PPh3)AuNTf2. TLC: Rf 0.60 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.50 (dt, J = 8.4 Hz,
1.6 Hz, 2H), 7.41‒7.35 (m, 4H), 7.17‒7.02 (m, 6H), 6.95 (d, J = 8.4 Hz, 2H), 5.13 (d, J = 3.2 Hz, 1H),
4.87 (d, J = 3.2 Hz, 1H), 4.34 (d, J = 13.2 Hz, 1H), 3.92 (d, J = 13.2 Hz, 1H), 2.38 (t, J = 7.6 Hz, 2H),
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1.45 (quintet, J = 7.6 Hz, 2H), 1.25‒1.13 (m, 4H), 0.83 (t, J = 7.6 Hz, 3H). C NMR (100 MHz,
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CDCl3): δ 153.7, 144.6, 143.6, 138.0, 130.1, 129.2, 129.1, 129.0, 128.2, 128.1, 128.0, 127.5, 126.7,
96.2, 74.9, 64.2, 36.4, 32.1, 31.8, 23.3, 14.7. HRMS (ESI) m/z calcd for C27H30NO [M+H]+ 384.2322,
found 384.2329. IR (KBr film): 3061, 2928, 1652, 770, 733 cmꢀ1.
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2-Benzyl-5-(4-fluorophenyl)-3-phenyl-2,3-dihydroisoxazole (2e). 2e was prepared from NꢀbenzylꢀNꢀ
(3ꢀ(4ꢀfluorophenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1e) (66.2 mg, 200 ꢁmol). Purification by
column chromatography (98:2 hexanes/EtOAc) afforded 2e as a yellow oil. Reaction time: 10 min, yield:
65.0 mg (98%) for (PPh3)AuCl/AgOTf. Reaction time: 15 min, yield: 52.3 mg (79 %) for (PPh3)AuNTf2.
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TLC: Rf 0.65 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.38 (dd, J = 8.8 Hz, 1.2 Hz, 2H),
7.34 (dd, J = 8.8 Hz, 1.2 Hz, 2H), 7.24 (dd, J = 8.8 Hz, 5.2 Hz, 2H), 7.18‒7.13 (m, 4H), 7.10‒7.05 (m,
2H), 6.65 (tt, J = 8.8 Hz, 2.0 Hz, 2H), 4.96 (d, J = 2.8 Hz, 1H), 4.83 (d, J = 2.8 Hz, 1H), 4.27 (d, J =
13.2 Hz, 1H), 3.89 (d, J = 13.2 Hz, 1H). 13C NMR (100 MHz, C6D6): δ 163.8 (d, JCF = 247.6 Hz), 152.6,
143.3, 137.8, 130.0, 129.2, 129.1, 128.5, 128.5, 128.5, 128.2, 127.9, 126.0 (d, JCF = 3.9 Hz), 116.0 (d,
JCF = 21.6 Hz), 96.7 (d, JCF = 1.6 Hz), 96.7, 75.0, 64.1. 19F NMR (376 MHz, CDCl3): δ ‒111.9. HRMS
(EI) m/z calcd for C22H18FNO [M]+ 331.1372, found 331.1367. IR (KBr film): 3029, 1602, 1510, 733,
697 cmꢀ1.
2-Benzyl-5-(3,4-dichlorophenyl)-3-phenyl-2,3-dihydroisoxazole (2f). 2f was prepared from Nꢀbenzylꢀ
Nꢀ(3ꢀ(3,4ꢀdichlorophenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1f) (76.4 mg, 200 ꢁmol).
Purification by column chromatography (98:2 hexanes/EtOAc) afforded 2f as a pale yellow solid.
Reaction time: 40 min, yield: 74.0 mg (97%) for (PPh3)AuCl/AgOTf. Reaction time: 60 min, yield: 62.6
1
mg (82%) for (PPh3)AuNTf2. TLC: Rf 0.61 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.46
(d, J = 2.0 Hz, 1H), 7.33 (dt, J = 8.0 Hz, 1.6 Hz, 2H), 7.29 (dt, J = 8.0 Hz, 1.6 Hz, 2H), 7.18‒7.06 (m,
6H), 6.93 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.83 (d, J = 2.8 Hz, 1H), 4.77 (d, J =
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2.8 Hz, 1H), 4.20 (d, J =13.2 Hz, 1H), 3.84 (d, J =13.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 151.0,
141.7, 136.3, 133.1, 132.9, 130.6, 129.7, 128.9, 128.8, 128.6, 128.0, 127.9, 127.8, 127.2, 125.1, 97.8,
73.9, 63.6. HRMS (EI) m/z calcd for C22H17Cl2NO [M]+ 381.0687, found 381.0683. IR (KBr film):
3062, 1651, 1468, 1046, 732, 676 cmꢀ1. mp: 88–89 oC.
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2-Benzyl-3-phenyl-5-(4-(trifluoromethyl)phenyl)-2,3-dihydroisoxazole (2g). 2g was prepared from Nꢀ
benzylꢀNꢀ(1ꢀphenylꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)propꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1g) (76.2 mg, 200
ꢁmol). Purification by column chromatography (98:2 hexanes/EtOAc) afforded 2g as a white solid.
Reaction time: 30 min, yield: 62.2 mg (82%) for (PPh3)AuCl/AgOTf. Reaction time: 60 min, yield: 72.4
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mg (95 %) for (PPh3)AuNTf2. TLC: Rf 0.68 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.36
(dt, J = 8.0 Hz, 1.6 Hz, 2H), 7.33 (dt, J = 8.0 Hz, 1.6 Hz, 2H), 7.24‒7.14 (m, 8H), 7.11‒7.06 (m, 2H),
5.03 (d, J = 2.8 Hz, 1H), 4.82 (d, J = 2.8 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 3.86 (d, J = 13.2 Hz, 1H).
13C NMR (100 MHz, C6D6): δ 152.1, 142.9, 137.6, 132.9 (q. JCF = 1.6 Hz), 131.3, 130.9, 130.0, 129.3,
129.1, 128.3 (q. JCF = 20.9 Hz), 127.9, 126.7, 126.0 (q. JCF = 3.9 Hz), 125.2 (q. JCF = 270.9 Hz), 99.3,
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74.9, 64.1. F NMR (376 MHz, CDCl3): δ ‒62.8 HRMS (ESI) m/z calcd for C23H19F3NO [M+H]+
382.1413, found 382.1414. IR (KBr film): 3063, 1494, 1125, 731, 697 cmꢀ1. mp: 124–127 oC.
4-(2-Benzyl-3-phenyl-2,3-dihydroisoxazol-5-yl)benzonitrile (2h). 2h was prepared from 4ꢀ(3ꢀ
(benzyl(hydroxy)amino)ꢀ3ꢀphenylpropꢀ1ꢀynꢀ1ꢀyl)benzonitrile (1h) (67.6 mg, 200 ꢁmol). Purification by
column chromatography (95:5 hexanes/EtOAc) afforded 2h as a white solid. Reaction time: 30 min,
yield: 46.0 mg (68%) for (PPh3)AuCl/AgOTf. Reaction time: 60 min, yield: 47.3 mg (70 %) for
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(PPh3)AuNTf2. TLC: Rf 0.65 (4:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.33 (dt, J = 8.0 Hz,
1.6 Hz, 2H), 7.29 (dt, J = 8.0 Hz, 1.6 Hz, 2H), 7.18‒7.13 (m, 4H), 7.10‒7.03 (m, 2H), 7.02 (dt, J = 8.8
Hz, 2.0 Hz, 2H), 6.87 (dt, J = 8.8 Hz, 2.0 Hz, 2H), 4.97 (d, J = 2.8 Hz, 1H), 4.78 (d, J = 2.8 Hz, 1H),
13
4.18 (d, J = 13.2 Hz, 1H), 3.82 (d, J = 13.2 Hz, 1H). C NMR (100 MHz, CDCl3): δ 151.4, 141.4,
136.2, 133.1, 132.4, 129.7, 128.8, 128.6, 128.0, 127.9, 127.2, 126.4, 118.7, 112.5, 99.7, 74.0, 63.6.
HRMS (ESI) m/z calcd for C23H19N2O [M+H]+ 339.1492, found 339.1497. IR (KBr film): 3061, 3029,
2226, 1607, 738, 697 cmꢀ1. mp: 118–120 oC.
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Methyl 4-(2-benzyl-3-phenyl-2,3-dihydroisoxazol-5-yl)benzoate (2i). 2i was prepared from methyl 4ꢀ
(3ꢀ(benzyl(hydroxy)amino)ꢀ3ꢀphenylpropꢀ1ꢀynꢀ1ꢀyl)benzoate (1i) (74.2 mg, 200 ꢁmol). Purification by
column chromatography (95:5 hexanes/EtOAc) afforded 2i as a white solid. Reaction time: 45 min,
yield: 59.0 mg (80%) for (PPh3)AuCl/AgOTf. Reaction time: 60 min, yield: 57.9 mg (78 %) for
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(PPh3)AuNTf2. TLC: Rf 0.50 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 8.02 (dt, J = 8.8 Hz,
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1.6 Hz, 2H), 7.41 (dt, J = 8.8 Hz, 1.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.17‒
7.12 (m, 4H), 7.10‒7.05 (m, 2H), 5.08 (d, J = 2.8 Hz, 1H), 4.82 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 13.2
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Hz, 1H), 3.85 (d, J = 13.2 Hz, 1H), 3.44 (s, 3H). C NMR (100 MHz, C6D6): δ 166.6, 152.6, 142.9,
137.7, 133.8, 131.4, 130.5, 130.0, 129.2, 129.1, 128.3, 128.2, 127.9, 126.4, 99.5, 74.9, 64.1, 52.1.
HRMS (EI) m/z calcd for C24H21NO3 [M]+ 371.1521, found 371.1516. IR (KBr film): 3061, 3028, 2950,
1720, 1242, 772, 697 cmꢀ1. mp: 146–147 oC.
2-Benzyl-5-hexyl-3-phenyl-2,3-dihydroisoxazole (2j).14 2j was prepared from NꢀbenzylꢀNꢀ(1ꢀ
phenylnonꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1j) (64.2 mg, 200 ꢁmol). Purification by column chromatography
(98:2 hexanes/EtOAc) afforded 2j as a yellow oil. Reaction time: 10 min, yield: 56.0 mg (87%) for
(PPh3)AuCl/AgOTf. Reaction time: 10 min, yield: 53.3 mg (83 %) for (PPh3)AuNTf2. TLC: Rf 0.57
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(9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.38 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
7.21‒7.17 (m, 2H), 7.13‒7.04 (m, 4H), 4.76 (s, 1H), 4.49 (m, 1H), 4.28 (d, J = 13.2 Hz, 1H), 3.89 (d, J
= 13.2 Hz, 1H), 2.03 (t, J = 7.6 Hz, 2H), 1.40 (quintet, J = 7.6 Hz, 2H), 1.23‒1.09 (m, 6H), 0.85 (t, J =
13
7.2 Hz, 3H). C NMR (100 MHz, C6D6): δ 156.2, 144.3, 138.2, 129.9, 129.1, 128.9, 128.0, 127.9,
127.8, 96.0, 74.4, 64.3, 32.3, 29.6, 27.7, 26.8, 23.4, 14.7. HRMS (ESI) m/z calcd for C22H28NO [M+H]+
322.2165, found 322.2169. IR (KBr film): 3062, 2954, 2927, 1453, 771, 669 cmꢀ1.
2-Benzyl-5-(6-methoxynaphthalen-2-yl)-3-phenyl-2,3-dihydroisoxazole (2k). 2k was prepared from Nꢀ
benzylꢀNꢀ(3ꢀ(6ꢀmethoxynaphthalenꢀ2ꢀyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1k) (78.6 mg, 200
ꢁmol). Purification by column chromatography (95:5 hexanes/EtOAc) afforded 2k as a yellow solid.
Reaction time: 10 min, yield: 55.0 mg (70%) for (PPh3)AuCl/AgOTf. Reaction time: 30 min, yield: 61.0
mg (78%) for (PPh3)AuNTf2. TLC: Rf 0.54 (9:1 hexanes/EtOAc). 1H NMR (400 MHz, C6D6): δ 8.05 (s,
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1H), 7.59 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 4H), 7.33 (d, J = 8.8
Hz, 1H), 7.20‒7.16 (m, 3H), 7.11‒7.01 (m, 4H), 6.85 (d, J = 1.2 Hz, 1H), 5.25 (d, J = 2.4 Hz, 1H), 4.94
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(d, J = 2.4 Hz, 1H), 4.41 (d, J = 13.2 Hz, 1H), 3.98 (d, J = 13.2 Hz, 1H), 3.34 (s, 3H). C NMR (100
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MHz, C6D6): δ 159.3, 153.9, 143.6, 138.0, 135.8, 130.8, 130.1, 129.5, 129.2, 129.1, 129.0, 128.1, 128.0,
127.6, 125.9, 125.1, 125.0, 120.1, 106.7, 96.9, 75.1, 64.2, 55.2. HRMS (ESI) m/z calcd for C27H24NO2
[M+H]+ 394.1802, found 394.1806. IR (KBr film): 3060, 3028, 2360, 1625, 751, 697 cmꢀ1. mp: 121–
123 oC.
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2-Benzyl-3-phenyl-5-(thiophen-3-yl)-2,3-dihydroisoxazole (2l). 2l was prepared from NꢀbenzylꢀNꢀ(1ꢀ
phenylꢀ3ꢀ(thiophenꢀ3ꢀyl)propꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1l) (63.8 mg, 200 ꢁmol). Purification by
column chromatography (98:2 hexanes/EtOAc) afforded 2l as a white solid. Reaction time: 5 min, yield:
48.0 mg (75%) for (PPh3)AuCl/AgOTf. Reaction time: 15 min, yield: 50.0 mg (78%) for (PPh3)AuNTf2.
TLC: Rf 0.72 (9:1 hexanes/EtOAc). 1H NMR (400 MHz, C6D6): δ 7.37 (d, J = 7.2 Hz, 2H), 7.33 (d, J =
7.2 Hz, 2H), 7.17‒7.12 (m, 5H), 7.10‒7.04 (m, 2H), 6.93 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 6.72 (dd, J = 5.2
Hz, 3.2 Hz, 1H), 4.92 (d, J = 2.8 Hz, 1H), 4.81 (d, J = 2.8 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H), 3.87 (d, J
13
= 13.2 Hz, 1H). C NMR (100 MHz, C6D6): δ 150.0, 143.4, 137.9, 131.0, 130.1, 129.2, 129.0, 128.2,
128.1, 127.9, 126.6, 126.4, 123.7, 96.7, 74.8, 64.2. HRMS (ESI) m/z calcd for C20H18NOS [M+H]+
320.1104, found 320.1108. IR (KBr film): 3107, 3028, 1659, 1453, 787, 657 cmꢀ1. mp: 85–88 oC.
2-Benzyl-3-(4-methoxyphenyl)-5-phenyl-2,3-dihydroisoxazole (2m). 2m was prepared from Nꢀbenzylꢀ
Nꢀ(1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1m) (68.6 mg, 200 ꢁmol).
Purification by column chromatography (95:5 hexanes/EtOAc) afforded 2m as a yellow solid. Reaction
time: 15 min, yield: 68.0 mg (99%)for (PPh3)AuCl/AgOTf. Reaction time: 20 min, yield: 63.0 mg (92%)
1
for (PPh3)AuNTf2. TLC: Rf 0.52 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.53‒7.51 (m,
2H), 7.41 (d, J = 6.8 Hz, 2H), 7.26 (dt, J = 8.8 Hz, 2.4 Hz, 2H), 7.18‒7.14 (m, 2H), 7.10 (dt, J = 7.6 Hz,
1.2 Hz, 1H), 7.04‒7.00 (m, 3H), 6.78 (dt, J = 8.8 Hz, 2.4 Hz), 5.14 (d, J = 2.8 Hz, 1H), 4.87 (d, J = 2.8
Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H), 3.94 (d, J = 13.2 Hz, 1H), 3.27 (s, 3H). 13C NMR (100 MHz, C6D6):
δ 160.2, 153.5, 138.0, 135.4, 130.1, 130.0, 129.5, 129.3, 129.1, 129.0, 128.1, 126.6, 114.7, 97.2, 74.6,
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64.0, 55.3. HRMS (EI) m/z calcd for C23H21NO2 [M]+ 343.1572, found 343.1564. IR (KBr film): 3062,
3029, 2836, 1653, 1608, 763, 698 cmꢀ1. mp: 68–70 oC.
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2-Benzyl-3-(4-nitrophenyl)-5-phenyl-2,3-dihydroisoxazole (2n). 2n was prepared from NꢀbenzylꢀNꢀ(1ꢀ
(4ꢀnitrophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1n) (71.6 mg, 200 ꢁmol). Purification by
column chromatography (97:3 hexanes/EtOAc) afforded 2n as a brown solid. Reaction time: 10 min,
yield: 71.0 mg (99%) for (PPh3)AuCl/AgOTf. Reaction time: 15 min, yield: 61.0 mg (85%) for
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(PPh3)AuNTf2. TLC: Rf 0.60 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.81 (dt, J = 8.8 Hz,
2.0 Hz, 2H), 7.49–7.47 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.14‒7.03 (m, 6H), 6.99 (dt, J = 8.0 Hz, 2.0
Hz, 2H), 4.91 (d, J = 2.8 Hz, 1H), 4.63 (d, J = 2.8 Hz, 1H), 4.28 (d, J = 12.8 Hz, 1H), 3.77 (d, J = 12.8
13
Hz, 1H). C NMR (100 MHz, C6D6): δ 154.3, 149.9, 148.1, 137.1, 130.8, 130.1, 130.0, 129.3, 129.2,
129.1, 128.1, 126.6, 124.2, 95.3, 73.5, 63.9. HRMS (EI) m/z calcd for C22H18N2O3 [M]+ 358.1317,
found 358.1318. IR (KBr film): 3062, 3030, 1519, 734, 696 cmꢀ1. mp: 120–122 oC.
2-Benzyl-3-isopropyl-5-phenyl-2,3-dihydroisoxazole (2o).4, 12 2o was prepared from NꢀbenzylꢀNꢀ(4ꢀ
methylꢀ1ꢀphenylpentꢀ1ꢀynꢀ3ꢀyl)hydroxylamine (1o) (55.8 mg, 200 ꢁmol). Purification by column
chromatography (98:2 hexanes/EtOAc) afforded 2o as a colorless oil. Reaction time: 30 min, yield: 50.7
mg (91%) for (PPh3)AuCl/AgOTf. Reaction time: 15 min, yield: 49.0 mg (88%) for (PPh3)AuNTf2.
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TLC: Rf 0.62 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.50 (dt, J = 7.6 Hz, 1.6 Hz, 2H),
7.41 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.10 (tt, J = 7.6 Hz, 1.6 Hz, 1H), 7.06‒6.95 (m, 3H),
5.02 (d, J = 2.8 Hz, 1H), 4.20 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 13.2 Hz, 1H), 3.51 (dd, J = 6.4 Hz, 2.8
Hz, 1H), 1.66 (octet, J = 6.4 Hz, 1H), 0.91 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 153.8, 138.2, 130.3, 130.2, 129.3, 129.0, 128.9, 128.0, 126.5, 93.9, 77.2, 64.7, 34.6,
19.0, 18.9. HRMS (ESI) m/z calcd for C19H22NO [M+H]+ 280.1696, found 280.1699. IR (KBr film):
3062, 3029, 2957, 2360, 1653, 1494, 1295, 1070, 696 cmꢀ1.
2-(4-Methoxybenzyl)-3,5-diphenyl-2,3-dihydroisoxazole (2p). 2p was prepared from Nꢀ(1,3ꢀ
diphenylpropꢀ2ꢀynꢀ1ꢀyl)ꢀNꢀ(4ꢀmethoxybenzyl)hydroxylamine (1p) (68.6 mg, 200 ꢁmol). Purification by
column chromatography (95:5 hexanes/EtOAc) afforded 2o as a yellow solid. Reaction time: 30 min,
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yield: 57.3 mg (84%) for (PPh3)AuCl/AgOTf. Reaction time: 60 min, yield: 56.0 mg (82%) for
(PPh3)AuNTf2. TLC: Rf 0.57 (5:1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.59–7.56 (m, 2H),
7.39‒7.22 (m, 10H), 6.88 (dt, J = 8.8 Hz, 2.8 Hz, 2H), 5.42 (d, J = 2.8 Hz, 1H), 5.05 (d, J = 2.8 Hz, 1H),
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4.38 (d, J = 12.8 Hz, 1H), 4.06 (d, J = 12.8 Hz, 1H), 3.82 (s, 3H). C NMR (100 MHz, CDCl3): δ
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159.3, 153.0, 142.3, 131.1, 129.2, 129.0, 128.7, 128.6, 128.5 127.7, 127.3, 125.9, 113.9, 95.8, 73.4,
62.9, 55.4. HRMS (ESI) m/z calcd for C23H22NO2 [M+H]+ 344.1645, found 344.1647. IR (KBr film):
2360, 1611, 1512, 1248, 697 cmꢀ1. mp: 77–79 oC.
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2-(tert-Butyl)-3,5-diphenyl-2,3-dihydroisoxazole (2q).10 2q was prepared from Nꢀ(tertꢀbutyl)ꢀNꢀ(1,3ꢀ
diphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1q) (56.0 mg, 200 ꢁmol). Purification by column
chromatography (98:2 hexanes/EtOAc) afforded 2q as a colorless oil. Reaction time: 15 min, yield: 51.0
mg (91%) for (PPh3)AuCl/AgOTf. Reaction time: 10 min, yield: 55.4 mg (99%) for (PPh3)AuNTf2.
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TLC: Rf 0.75 (9:1 hexanes/EtOAc). H NMR (400 MHz, C6D6): δ 7.52 (dd, J = 8.0 Hz, 1.6 Hz, 2H),
7.47 (dd, J = 8.0 Hz, 1.6 Hz, 2H), 7.20 (t, J = 7.6 Hz, 2H), 7.11‒7.01 (m, 4H), 5.14 (d, J = 2.8 Hz, 1H),
5.01 (d, J = 2.8 Hz, 1H), 1.15 (s, 9H). 13C NMR (100 MHz, C6D6): δ 153.4, 145.9, 129.8, 129.4, 129.2,
129.1, 128.1, 127.8, 126.4, 98.3, 69.6, 61.1, 25.7. HRMS (ESI) m/z calcd for C19H22NO [M+H]+
280.1696, found 280.1697. IR (KBr film): 3027, 2973, 1656, 1493, 1449 cmꢀ1.
2-Benzyl-3,5-dicyclohexyl-2,3-dihydroisoxazole (2r). 2r was prepared from NꢀbenzylꢀNꢀ(1,3ꢀ
dicyclohexylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1r) (65.1 mg, 200 ꢁmol). Purification by column
chromatography (15:1 hexanes/EtOAc) afforded 2r as a yellow solid. Reaction time: 10 min, yield: 37.3
mg (58%) for (PPh3)AuCl/AgOTf. Reaction time: 20 min, yield: 53.0 mg (82%) for (PPh3)AuNTf2.
TLC: Rf 0.57 (15:1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.39‒7.26 (m, 5H), 4.46 (d, J = 1.6
Hz, 1H), 4.08 (d, J = 12.8 Hz, 1H), 3.71 (d, J = 12.8 Hz, 1H), 3.44 (dd, J = 6.8 Hz, 1.6 Hz, 1H), 2.11‒
13
1.54 (m, 11H), 1.26‒0.69 (m, 11H). C NMR (100 MHz, CDCl3): δ 159.5, 137.4, 129.9, 128.4, 127.5,
90.5, 75.1, 64.1, 43.8, 35.6, 31.2, 31.0, 29.3, 29.1, 26.8, 26.4, 26.2, 26.1. HRMS (ESI) m/z calcd for
C22H32NO [M+H]+ 326.2478, found 326.2483. IR (KBr film): 3030, 2925, 1668, 1496, 1450 cmꢀ1. mp:
60‒62 oC.
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The Journal of Organic Chemistry
2-Benzyl-3-cyclohexyl-5-phenyl-2,3-dihydroisoxazole (2s).4 2s was prepared from Nꢀ(benzyl)ꢀNꢀ(1ꢀ
cyclohexylꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine (1s) (63.9 mg, 200 ꢁmol). Purification by column
chromatography (60:1 hexanes/EtOAc) afforded 2s as a yellow solid. Reaction time: 60 min, yield: 62.8
1
2
3
4
5
6
7
8
1
mg (98%) for (PPh3)AuCl/AgOTf. Reaction time: 20 min, yield: 55.5 mg (87%) for (PPh3)AuNTf2. H
9
NMR (400 MHz, CDCl3): δ .53 (d, J = 7.2 Hz, 2H), 7.43(d, J = 7.2 Hz, 2H), 7.38‒7.28 (m, 6H), 5.32 (d,
J = 2.8 Hz, 1H), 4.25 (d, J = 12.8 Hz, 1H), 3.84 (d, J = 12.8 Hz, 1H), 3.68 (dd, J = 6.8 Hz, 2.8 Hz, 2H),
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1.90‒1.87 (m, 1H), 1.76‒1.62 (m, 4H), 1.46‒1.37 (m, 1H), 1.30‒0.94 (m, 4H) 0.87‒0.76 (m,1H). C
NMR (100 MHz, CDCl3): δ 152.4, 137.0, 130.1, 129.4, 128.9, 128.5, 128.4, 127.6, 125.8, 94.1, 75.8,
64.1, 43.7, 29.5, 29.2, 26.7, 26.3, 26.2. HRMS (ESI) m/z calcd for C22H26NO [M+H]+ 320.2009, found
320.2014. IR (KBr film): 3062, 2923, 1652, 1494, 1448 cmꢀ1. mp: 90‒92oC. (Lit.4 88‒91 oC).
Synthesis of chiral 4ꢀisoxazoline (S)ꢀ2a.
(R)-N-Benzyl-N-(1,3-diphenylprop-2-yn-1-yl)hydroxylamine (R-1a). 23,24 (R)-1a was prepared according
to the previously reported procedure.23,24 A solution of dimethylzinc (1.2 M) in toluene (1.3 mL, 1.6
mmol) was added dropwise to a solution of diꢀ(tꢀbutyl) (R,R)ꢀtartrate [(R,R)ꢀDTBT] (52.5 mg, 0.2
o
mmol) in toluene (6 mL) at 0 C under an Ar atmosphere. After the reaction mixture was stirred for 10
min, a solution of racemic NꢀbenzylꢀNꢀ(1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)hydroxylamine
(1m) (68.7 mg, 0.1 mmol) in toluene (6 mL) was added dropwise. The mixture was stirred for 10 min,
and a solution of nitrone S1a (121 mg, 1.0 mmol) in toluene (8 mL) and phenylacetylene (112 uL, 1.0
mmol) were added dropwise. After stirred for 18 h at 0 oC, the mixture was quenched with NH4Cl (pH =
o
4ꢀ5) at 0 C. The organic layer was separated and extracted with EtOAc (4 × 50 mL), dried over
anhydrous Na2SO4, and filtered. The filtrate was concentrated by rotary evaporation. The residue was
purified by column chromatography (9:1 hexanes/EtOAc) to afford (R)-1a as a white solid (213 mg,
68%). The spectral data matched to those of 1a. Chiral HPLC Method: Phenomenex Lux 5 ꢁ Celluloseꢀ
1 column 250 × 4.6 mm; Injection volume, 5 ꢁL; Flow rate, 1.0 mL/min; Elution method, iꢀ
PrOH/hexane 2.4/97.6 isocratic (0‒45 min); UV detection at 254 nm; t1 = 11.2 min (major isomer), t2 =
12.4 min (minor isomer): [α]ꢁꢀꢂ.ꢂ +41.2 (c 0.6, MeOH), 84% ee.
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