Sc(OTf)3-catalyzed [3 + 2]-cycloaddition of nitrones with ynones

Article abstract of DOI:10.1039/d0ob02158j

An efficient approach to access functionalized (2,3-dihydroisoxazol-4-yl) ketones has been developed by reacting nitrones 4 with ynones 7 or terminal ynones 10 in a one-pot fashion. The reaction went through a formal Sc(OTf)3-catalyzed [3 + 2]-cycloaddition process to generate a number of functionalized (2,3-dihydroisoxazol-4-yl) ketones 11aa-11aw, 11ba-11la and 12aa-12ae in moderate to good yields. This journal is

Full text of DOI:10.1039/d0ob02158j

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DOI: 10.1039/D0OB02158J
Journal Name
ARTICLE
Sc(OTf)3-Catalyzed [3+2]-Cycloaddition of Nitrones with Ynones
Chun-Ting He,a,b Xiao-Li Han,a Yan-Xue Zhang,a Zhen-Ting Du,b Chang-Mei Sia,* and Bang-Guo Weia
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient approach to access functionalized (2,3-dihydroisoxazol-4-yl) ketones has been developed by reacting nitrones
4 with ynones 7 or terminal ynones 10 in a one-pot fashion. The reaction went through a formal Sc(OTf)3-catalyzed [3+2]-
cycloaddition process to generate a number of functionalized (2,3-dihydroisoxazol-4-yl) ketones 11aa-11aw, 11ba-11la
and 12aa-12ae in moderate to good yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
ketoester and ketoamide. To our best knowledge, there are
only a few successful examples to react nitrones with ynones
because of the poor electron-withdrawing property of keto
Introduction
One important aspect in current organic chemistry is to
develop efficient and practical synthetic methodologies,1
which allow for access to various scaffolds existing in a large
number of auxiliaries,2 building blocks,3 biological compounds
and clinical drugs.4 Particularly, the synthesis of N-heterocycles
has attracted considerable attention in past few decades, due
to their biological significance and wide synthetic
transformations.5-9 Among the enormous methods, the most
straightforward and divergent approaches include [4+2] Diels–
Alder cycloadditions,6,7 [2+2] cycloadditions8 and 1,3-dipolar
cycloadditions.9
In the past decade, nitrones have been widely used in organic
synthesis, providing access to various skeletons of bioactive
products.10 Nitrones are mainly involved in two kinds of
transformations. One type is metal-catalyzed 1,2-addition with
different nucleophiles,11-13 including organozinc reagents,12
terminal alkynes and ynamides,13 to give secondary amines.
The other type is 1,3-dipolar [3+2] cycloadditions with
different dipolarophiles,14-18 including alkynyl esters,15 α,β-
unsaturated carbonyl compounds,16 4-acetoxyallenoates17
and the Kinugasa reaction.18 In 1990s, Chan and coworkers
achieved [3+2] cycloaddition of alkyl nitrones with alkynyl
Fischer carbene complexes under thermal conditions (Figure 1,
1).15a,b De Armas and García-Tellado reported PPh3-catalyzed
1,3-dipolar cycloaddition of nitrones with alkyne carboxylates
(Figure 1, 2).15c Mikami group published the asymmetric
“Acetylenic” [3+2] cycloaddition of nitrones through the
catalysis with chiral cationic PdII Lewis acid (Figure 1, 3).15d It is
worth mentioning that all of these powerful approaches used
the electron deficient acetylenes containing the ester groups,
carbonyl. In 2009, Frontier group pioneeredly established a
mild and convenient reaction sequence for the synthesis of
Nazarov cyclization substrates, in which [3+2] dipolar
cycloaddition of a nitrone and an electron-deficient alkyne
could give an isolable isoxazoline intermediate. Alkyl
substituted alkynes were applized in this case (Figure 1, 4).19
Subsequently, regio- and enantioselective cycloaddition of
nitrone to alkynones was successfully accomplished for the
synthesis of optically pure Δ4-isoxazolines by Sibi group in 2014
(Figure 1, 5).20 In 2015, the formal 1,3-dipolar cycloaddition
process of nitrones with diketone activated alkynes was
reported by Prathapan and Rappai.21a In 2020, Jiang and Tu
group reported the synthesis of polycyclic indoles via
organocatalytic bicyclization of α-alkynylnaphthalen-2-ols with
nitrones.21b On the basis of our efforts in the 1,3-dipolar
cycloaddition,22 we envisioned that some metal salts could
catalyze such cyclization reactions and expand the scope of
alkynones. Herein we present an efficient approach to
multisubstituted (2,3-dihydroisoxazol-4-yl) ketones 11aa-11ae
through Sc(OTf)3-catalyzed [3+2] cycloaddition of nitrones 4
with both ynones 7 and terminal ynones 10 (Figure 1, 6).
Results and discussion
As shown in Scheme 1, a variety of nitrones 4 and ynones 7
were prepared to investigate our [3+2] cycloaddition reaction.
The synthesis of nitrones 4 started from corresponding
aldehyde 1 and underwent the following three known steps:
oxime formation, reduction with NaBH3CN and subsequent
condensation with other aldehyde in presence of anhydrous
Na2SO4 (See Supporting Information)(Scheme 1).23 Meantime,
ynones 7 were obtained through the coupling reaction of
terminal alkynes 5 with acyl chlorides 6 (Scheme 2),24 and the
terminal ynones 10 were prepared from corresponding
aldehyde 8 using the known procedure (See Supporting
Information)( Scheme 3).25
a
Department of Natural Medicine, School of Pharmacy, Fudan University, 826
Zhangheng Road, Shanghai 201203, China
b
College of Science, Northwest A&F University, 22 Xinong Road, Shaanxi,
Yangling, 712100, China
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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[3+2] cycloaddition Process15a,b
O
OH
O
View Article Online
b, c
a
DOI: 10.1039/D0OB02158J
R4
R4
H
R4
MeO
MeO
M(CO)5
R1
+
O-
H
TMS
R
M(CO)5
reflux
N
8
10
9
+
(1)
Scheme 3. The synthesis of terminal ynones 10. Reagents and conditions: a.
solvent
R2
O
R2
Ethynyltrimethylsilane, n-BuLi, THF, 0oC-rt; b. K2CO3, MeOH; c. MnO2, DCM,
rt.
N
R1
R
Addition-[3,3]-Shift Process15c
Our investigation started with the reaction of nitrone 4a with
ynone 7a. When the mixture of 4a and 7a was heated without
Bn
HO
Bn
R
CO2Me -O
Bn
H
+
N
R
N
PPh3
N
any additive20 at 65 C and 80 C for 24 h, 11aa was produced
in 21% and 45% yield respectively (Table 1, entries 1-2). The
treatment with homologous PPh3 under ligand-free
conditions15c did not generate any desired cyclization product
11aa (Table 1, entry 3). The known catalyst (PdCl2/AgPF6) also
failed to produce the desired 11aa under ligand-free
conditions15d (Table 1, entry 4). To obtain the desired product
11aa, various metal catalytic systems such as Au and Ir were
screened, unfortunately the results were disappointing (Table
1, entries 5-9). Delightfully, AuCl3 could lead to the desired
product 11aa in 55% yield (Table 1, entry 10). To improve the
reaction yield, various Lewis acids were screened, and the
results indicated that several rare earth Lewis acids could
catalyze this [3+2] cycloaddition, but the yield of 11aa was low
o
o
O
(2)
R
CO2Me
CO2Me
15d
Pd(II)-Ag(I)-Catalyzed [3+2] cycloaddition
Me
-O
R
Me
H
N
R
O
PdCl2/Ag salt
Chiral Ligand
N
*
(3)
+
CO2Et
O
COOEt
O
[3+2]/[O] sequence for synthesis of Nazarov substrates19
Me
R2
O
-O
CH3
H
+
N
N
R3
R2
R3
O
O
R1
+
(4)
R3
R1
R2
R1
Table 1. Optimization of reaction conditions.
Ph
Bn
Bn
O
O
Synthesis of Optically Pure 4-Isoxazolines 20
N
N
△
DCE
Ph
R2
N
Ph
conditions
R1
O
O
Ph
-O
R2
H
+
N
O
Ph
Zn(OTf)2
O
H
N
(5)
+
R3
O
4a
11aa
7a
Chiral Ligand
R3
N
R1
Entriesa
1c
Catalyst
Equiv.
-
-
ToC
65
80
rt
rt
80
rt
80
120
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
Time/h
24
24
24
24
24
24
24
24
24
6
Y% b
21
45
NR
trace
trace
NR
NR
NR
NR
55
23
40
35
38
51
53
-
88
N
N
-
-
This Work: Sc(III)-Catalyzed [3+2]-Cycloaddition
2c
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17d
18
19
20
PPh3
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.05
R1
Bn
PdCl2/AgPF6
N
R3
R2
[IrCl(COD)]2/PPh3
(Ph3P)AuCl/AgNTf2
(Ph3P)AuCl/AgNTf2
(Ph3P)AuCl/AgNTf2
Ph3PAuN(OTf)2/AgNTf2
AuCl3
Sc(OTf)3
DCE, rt
Bn
O
O
(6)
N
R1
R3
O
R2
O
7 R1=Ar, cyclopropyl,
thiophenyl, pyridinyl
10 R1=H
11 R1=Ar, cyclopropyl,
thiophenyl, pyridinyl
12 R1 =H
4
Zn(OTf)2
Y(OTf)3
Pr(OTf)3
Eu(OTf)3
Dy(OTf)3
Lu(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
6
6
6
6
6
6
6
6
Figure 1. Our strategy to access functionalized (2,3-dihydroisoxazol-4-yl)
ketones.
O
Bn
O
a
c
b
OH
N
OH
Ph
N
Ph
N
Ph
H
H
R3
6
6
73
45
2
1
3
4
rt
a
Scheme 1. The synthesis of nitrones 4. Reagents and conditions: a.
The reactions were performed with 5a (0.5 mmol), 7a (2.0 mmol) and LA
b
c
NH2OH.HCl, NaOH, 50% EtOH, rt, 1 h; b. NaBH3CN, 2N HCl, MeOH, rt, 4 h; c. in dry THF (3 mL) at assigned reaction temperature. Isolated yield.
substituted aldehyde, Na2SO4, DCM, rt, 18 h.
Toluene as solvent. d H2O as solvent. NR = No reaction.
O
O
(Table 1, entries 11-16). Exhilaratingly, Sc(OTf)3 with DCE as
the solvent significantly increased the yield of 11aa up to 88%
yield (Table 1, entry 18). When the reaction was conducted in
water,26 the desired product 11aa was not observed (Table 1,
entry 17). Different stoichiometry of Sc(OTf)3 was also
investigated, showing the yield of 11aa significantly dropped
a
R1
R1
R2
Cl
R2
5
7
6
Scheme 2. The synthesis of ynones 7. Reagents and conditions: a. CuI,
PdCl2(PPh3)2, Et3N, THF, rt, overnight.
2 | J. Name., 2012, 00, 1-3
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when the loading of catalyst was reduced (Table 1, entries 19- naphthalenone 7t could generate the desired 11ao-11at in
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20).
moderate yields. Alkyl ynones 7u and heDteOrIo: 1c0y.1c0li3c9k/De0tOonB0e2s1758vJ-
7w could also afford the desired products 11au-11aw, albeit in
low yields. The chemical structures of 11aa-11aw were
unambiguously confirmed based on the X-ray crystallographic
analysis of compound 11ac (see the Supporting Information).27
R1
Bn
Ph
Bn
O
O
N
N
R1
R2
Sc(OTf)3
DCE, rt
O
R2
O
Bn
Ph
4a
O
11
7
N
Bn
O
R
Ph
Sc(OTf)3
DCE, rt
N
Bn
Bn
Ph
Bn
O
O
O
R
N
N
N
R1
S
Ph
O
Ph
Bn
O
Ph
Ph
4
7a
11
Ph
Ph
Ph
O
O
O
Bn
O
Bn
11ai 62%
11aj 83%
11aa R1 = C6H5, 88%
O
N
O
Cl
N
N
Ph
Cl
Ph
Br
Ph
11ab R1 =4-ClC6H4, 50%
11ac R1 =4-OEtC6H4, 48%
11ad R1 =4-MeC6H4, 60%
11ae R1 =4-CNC6H4, 93%
Bn
O
Bn
Ph
N
Ph
O
Ph
N
Ph
O
O
O
S
Ph
N
11ba 75%
11da 63%
11ca 86%
Ph
Ph
11af R1 =4-CF3C6H4, 98%
O
O
Bn
O
Bn
N
11ag R1 =4-CO2MeC6H4, 86%
N
Bn
O
O
11ak 67%
11al 77%
N
Ph
Ph
11ah R1=4-NO2C6H4, 82%
Ph
Bn
O
Bn
N
O
O
Ph
MeO
N
Ph
Bn
O
Ph
O
Cl
O
O
N
O
Ph
N
Ph
11fa 84%
11ea 97%
11ga 96%
Ph
Ph
Ph
O
O
R2
Bn
11an 87%
O
11am 52%
Bn
N
O
N
O
Bn
O
Ph
Bn
Ph
N
Bn
O
Ph
11ao R2 =4-ClC6H4, 73%
O
Ph
N
11ap R2 =4-OMeC6H4, 64%
Ph
Ph
Ph
O
MeS
11aq R2 =4-MeC6H4, 70%
Ph
O
NC
O
O2N
O
O
O
11ar R2 =4-NO2C6H4, 74%
11as R2 =4-CNC6H4, 82%
O
11ia 76%
11ha 91%
11ja 67%
Bn
11at 83%
11au 28%
O
Bn
S
N
N
Ph
Ph
Bn
Ph
O
Bn
Ph
N
O
N
Ph
Ph
O
F3C
O
S
O
11ka 77%
11la 71%
O
a
Scheme 5. The reactions of different nitrones 4 with 7aa,b
.
The reactions
N
O
11ac
were performed with nitrones 4 (0.5 mmol), 1,3-diphenylprop-2-yn-1-one
7a (0.5 mmol), and Sc(OTf)3 (0.1 mmol) in DCE (2 mL) at rt for 6 h. b Isolated
yield.
11aw 31%
11av 34%
Scheme 4. The reactions of nitrone 4a with ynones 7a,b
.
The reactions
a
were performed with nitrone 4a (0.5 mmol), ynones 7a-7w (0.5 mmol), and
Next, we focused our examination on the scope and limitation
of different nitrones 4b-4l with 1,3-diphenylprop-2-yn-1-one
7a. In general, all aryl substituted nitrones 4 could react with
7a to give desired cycloaddition products 11ba-11la in
moderate to excellent yields (Scheme 5). Although the
reactions of 7a with ortho and meta electron-donating
substituted nitrones 4b-4d gave moderate yields (75% for
11ba, 86% for 11ca and 63% for 11da), almost all para
electron-donating substituted nitrones 4e-4h could produce
the desired 8ea-8ha in excellent yields. On the contrary, para
electron-withdrawing substituted nitrones 4i-4k led to
relatively low yields (11ia-11ka). It is worth noting thiophene
substituted nitrone 4l could afford the desired cycloaddition
product 11la in 71% yield.
Sc(OTf)3 (0.1 mmol) in DCE (2 mL) at rt for 6 h. b Isolated yield.
Then, we turned to investigate the scope and limitation of
substituted ynones 7a-7w for this Sc(OTf)3-catalyzed [3+2]-
cycloaddition reaction with nitrone 4a. As shown in Scheme 4,
various R1 groups were first evaluated. para electron-donating
substituted ynones 7a-7d afforded the desired products 11aa-
11ad in relatively low yields, compared with para electron-
withdrawing substituted ynones (CN, COOEt, CF3 and NO2),
which led to the corresponding products 11ae-11ah in
excellent yields. Alkyl, thiophenyl and pyridinyl substituted
ynones 7i-7n were also examined, the desired 11ai-11an were
produced in moderate yields. A variety of R2 groups were next
examined.
Substituted
phenylketones
7o-7s
and
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Furthermore, we extended our method to react terminal [3+2]-cycloaddition to afford the products 11/12 and release
View Article Online
DOI: 10.1039/D0OB02158J
ynones 10a-10e with nitrone 4a (Scheme 6). When para Sc(OTf)3, which went back to participate in the reaction cycle.
substituted electron-donating substituted terminal ynones 10a
N-O cleavage of 11at was straightforward and with 77%
and 10b were examined, the desired products 12aa, 12ab
yield of divinyl ketone 14 under m-CPBA oxidation,19 which
were obtained in 49% and 47% yields, respectively.
was a Nazarov precursor (Scheme 7).
Disappointingly, 1-(3-chlorophenyl)prop-2-yn-1-one 10c
Bn
O
O
O
afforded the corresponding 12ac in only 18% yield. Notably,
alphatic alkyl ynones were also suitable substrates for the
cycloaddition. 5-Phenylpent-1-yn-3-one 10d and 1-
cyclohexylprop-2-yn-1-one 10e, could generate the desired
N
a
Ph
Ph
O
12ad and 12ae in 35% and 33% yields, respectively.
14
11at
Bn
Bn
O
O
N
N
Sc(OTf)3
DCE, rt
Scheme 7. The synthesis of ynones 7. Reagents and conditions: a. m-CPBA,
DCM, rt, overnight, 77%.
Ph
R4
O
R4
O
Conclusions
4a
10
Bn
12
In summary, we established an efficient approach for the
synthesis of 2,3-dihydroisoxazol-4-yl ketones 11. Both ynones
7 and terminal ynones 10 proved to be suitable dipolarophiles
for such a Sc(OTf)3-catalyzed cycloaddition with nitrones 4. As
a result, a number of functionalized 2,3-dihydroisoxazol-4-yl
ketones 11aa-11aw, 11ba-11la and 12aa-12ae were achieved
in moderate to good yields under mild reaction conditions.
Bn
Bn
Ph
O
O
O
N
N
N
Ph
Ph
O
Br
O
O
Cl
12aa 49%
12ac 18%
12ab 47%
Bn
Bn
Ph
O
O
N
N
Experimental
General
Ph
O
General: Reactions were monitored by TLC-FID. Flash
chromatography was performed on silica gel (300-400 mesh)
with petroleum/EtOAc as the eluent. HRMS was conducted on
Thermo Scientific LTQ Orbitrap XL apparatus. IR spectra were
measured using a film on a Fourier transform infrared
spectrometer. NMR spectra were recorded at 400 MHz or 500
MHz, and chemical shifts are reported in δ (ppm) referenced
to an internal TMS standard for 1H NMR and CDCl3 (77.16 ppm)
for 13C{1H} NMR. The heat source was oil bath.The Benzyl zinc
bromide reagents were synthesized according to the known
method.22b
O
12ad 35%
12ae 33%
Scheme 6. The reactions of terminal ynones 10 with 4aa,b
.
The reactions
a
were performed with nitrone 4a (0.5 mmol), terminal ynones 10 (0.5
mmol), and Sc(OTf)3 (0.1 mmol) in DCE (2 mL) at rt for 6 h. b Isolated yield.
O
R1
Sc(OTf)3
R2
7/10
OTf
TfO
Sc
R1
General Procedure for synthesis of 11 or 12. To a solution of
compound 4 (0.47 mmol, 1.0 equiv), Sc(OTf)3 (0.09 mmol, 0.2
equiv) and 7 or 10 (0.47 mmol, 1.0 equiv) in 2 mL DCE were
stirred at rt for 6 h. The residue was purified by flash
chromatography on silica gel (PE/EA) to give 11 or 12.
(2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-
yl)(phenyl)methanone 11aa.13e Yellow solid (161 mg, 88%,
PE/EA = 10:1); mp 94–96 oC; 1H NMR (400 MHz, CDCl3) δ 7.46–
7.41 (m, 4H), 7.39–7.29 (m, 7H), 7.25–7.18 (m, 5H), 7.09–7.00
(m, 4H), 5.62 (s, 1H), 4.47 (d, J = 13.2 Hz, 1H), 4.32 (d, J = 13.6
Hz, 1H) ppm.
Sc(OTf)3
O
OTf
O
R1
R2
R2
O
N
R3
O
Sc(OTf)2
OTf
Bn
R1
Bn
O
11/12
N
R2
Bn
O
R3
N
4
R3
13
Figure 2. Proposed mechanism of the [3+2]-Cycloaddition.
On the basis of our experimental results and the
precedent ynones chemistry,28 a possible mechanism for this
Sc(OTf)3-catalyzed [3+2]-cycloaddition of nitrones with ynones
was illustrated in Figure 2. First, the carbonyl group in ynones
7/10 was activated by Sc(OTf)3. The activated ynones
intermediate 13 subsequently reacted with nitrones through
(2-Benzyl-5-(4-chlorophenyl)-3-phenyl-2,3-dihydroisoxazol-
4-yl)(phenyl)methanone 11ab. Yellow oil (104 mg, 50%, PE/EA
= 15:1); IR (film) vmax: 3061, 3030, 2924, 2852, 1619, 1489,
1
1354, 1091, 836, 698 cm-1; H NMR (500 MHz, CDCl3) δ 7.44–
7.39 (m, 4H), 7.39–7.28 (m, 8H), 7.25–7.22 (m, 1H), 7.18–7.14
(m, 2H), 7.11–7.04 (m, 4H), 5.61 (s, 1H), 4.45 (d, J = 13.0 Hz,
4 | J. Name., 2012, 00, 1-3
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1H), 4.29 (d, J = 13.5 Hz, 1H) ppm; 13C{1H} NMR (126 MHz, PE/EA = 10:1); IR (film) vmax: 3062, 3030, 2951,Vi2ew84Ar0ti,cle1O7n2lin3e,
-1
1
DOI: 10.1039/D0OB02158J
CDCl3) δ 191.5, 160.5, 140.3, 138.5, 136.8, 135.4, 131.8, 130.8, 1625, 1280, 1111, 733, 698 cm ; H NMR (400 MHz, CDCl3) δ
129.6, 128.9, 128.6, 128.3, 128.0 (3C), 127.7, 126.0, 113.8, 7.77–7.73 (m, 2H), 7.46–7.40 (m, 4H), 7.39–7.27 (m, 9H), 7.25–
76.1, 63.1 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for 7.19 (m, 2H), 7.07–7.02 (m, 2H), 5.65 (s, 1H), 4.46 (d, J = 13.6
+
C29H23ClNO2 : 452.1411, found: 452.1414.
Hz, 1H), 4.31 (d, J = 13.2 Hz, 1H), 3.86 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 191.4, 166.1, 160.0, 140.2, 138.4, 135.3,
(2-Benzyl-5-(4-ethoxyphenyl)-3-phenyl-2,3-
dihydroisoxazol-4-yl)(phenyl)methanone 11ac. Yellow solid 132.0, 131.8, 131.6, 129.5, 129.4, 129.0, 128.9, 128.6, 128.0
o
(105 mg, 48%, PE/EA = 10:1); mp 123–125 C; IR (film) vmax
:
(2C), 127.9, 127.7, 114.6, 76.2, 63.2, 52.3 ppm; HRMS (ESI-
3059, 3029, 2980, 2928, 1604, 1506, 1356, 1251, 735, 697 cm-1; Orbitrap) m/z: [M+H]+ calcd for C31H26NO4 : 476.1856, found:
1H NMR (500 MHz, CDCl3) δ 7.46–7.38 (m, 6H), 7.37–7.27 (m, 476.1858.
+
5H), 7.25–7.21 (s, 2H), 7.20–7.15 (m, 2H), 7.12–7.05 (s, 2H),
(2-Benzyl-5-(4-nitrophenyl)-3-phenyl-2,3-dihydroisoxazol-
6.60–6.55 (m, 2H), 5.56 (s, 1H), 4.46 (d, J = 13.5 Hz, 1H), 4.29 (d, 4-yl)(phenyl)methanone 11ah. Yellow solid (180 mg, 82%,
J = 13.5 Hz, 1H), 3.97–3.88 (m, 2H), 1.39–1.32 (m, 3H) ppm; PE/EA = 10:1); mp 103–105 oC; IR (film) vmax: 3062, 3030, 2925,
1
13C{1H} NMR (100 MHz, CDCl3) δ 191.8, 162.6, 161.0, 140.9, 2851, 1627, 1522, 1349, 1105, 733, 696 cm-1; H NMR (400
139.0, 135.8, 131.6, 131.5, 129.7, 129.1, 128.6, 128.0, 127.9 MHz, CDCl3) δ 7.96–7.91 (m, 2H), 7.45–7.37 (m, 6H), 7.37–7.28
(3C), 119.6, 114.0, 112.2, 76.0, 63.7, 29.9, 14.7 ppm; HRMS (m, 7H), 7.27–7.23 (m, 2H), 7.12–7.05 (m, 2H), 5.69 (s, 1H),
+
(ESI-Orbitrap) m/z: [M+H]+ calcd for C31H28NO3 : 462.2063, 4.46 (d, J = 13.6 Hz, 1H), 4.31 (d, J = 13.2 Hz, 1H) ppm; 13C{1H}
found: 462.2066.
NMR (100 MHz, CDCl3) δ 191.1, 158.1, 148.5, 139.8, 138.2,
(2-Benzyl-3-phenyl-5-p-tolyl-2,3-dihydroisoxazol-4-
135.1, 133.7, 132.3, 130.2, 129.5, 128.8, 128.6 (2C), 128.1 (2C),
yl)(phenyl)methanone 11ad. Yellow oil (123 mg, 60%, PE/EA = 127.6, 123.0, 115.8, 76.4, 63.2 ppm; HRMS (ESI-Orbitrap) m/z:
+
10:1); IR (film) vmax: 3083, 3060, 3029, 2921, 2851, 1615, 1494, [M+H]+ calcd for C29H23N2O4 : 463.1652, found: 463.1651.
1354, 730, 697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.47–7.41 (m,
(2-Benzyl-5-cyclopropyl-3-phenyl-2,3-dihydroisoxazol-4-
4H), 7.41–7.37 (m, 2H), 7.37–7.25 (m, 6H), 7.24–7.20 (m, 1H), yl)(phenyl)methanone 11ai. Yellow oil (112 mg, 62%, PE/EA =
7.15–7.11 (m, 2H), 7.09–7.03 (m, 2H), 6.91–6.87 (m, 2H), 5.59 10:1); IR (film) vmax: 3061, 3029, 1605, 1574, 1494, 1380, 1336,
(s, 1H), 4.48(d, J = 13.2 Hz, 1H), 4.30(d, J = 13.6 Hz, 1H), 2.24 (s, 1051, 909, 697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66–7.62 (m,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 191.8, 162.4, 141.2, 2H), 7.49–7.45 (m, 1H), 7.43–7.33 (m, 7H), 7.32–7.27 (m, 4H),
140.8, 138.9, 135.7, 131.5, 129.7, 129.1, 128.7, 128.6 (2C), 7.26–7.21 (m, 1H), 5.47 (s, 1H), 4.31 (d, J = 13.2 Hz, 1H), 4.13 (d,
128.0, 127.9, 127.8, 124.7, 112.9, 76.1, 63.2, 21.6 ppm; HRMS J = 13.2 Hz, 1H), 1.66–1.59 (m, 1H), 1.15–1.11 (m, 1H), 1.05–
(ESI-Orbitrap) m/z: [M+H]+ calcd for C30H25NO2 : 432.1958, 1.00 (m, 1H), 0.84–0.78 (m, 2H) ppm; 13C{1H} NMR (100 MHz,
+
found: 432.1958.
CDCl3) δ 191.8, 167.5, 141.2, 140.7, 135.5, 131.5, 129.6, 128.6,
4-(4-Benzoyl-2-benzyl-3-phenyl-2,3-dihydroisoxazol-5-
128.5, 128.4, 128.3, 128.0, 127.7, 127.4, 114.4, 74.4, 63.4, 9.7,
yl)benzonitrile 11ae. Yellow oil (194 mg, 93%, PE/EA = 10:1); IR 9.1, 8.5 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
+
(film) vmax: 3060, 3028, 1590, 1492, 1455, 1354, 1191, 761, 693 C26H24NO2 : 382.1801, found: 382.1801.
cm-1; 1H NMR (500 MHz, CDCl3) δ 8.46–8.40 (m, 2H), 7.53–7.50
(2-Benzyl-3-phenyl-5-(thiophen-3-yl)-2,3-dihydroisoxazol-4-
(m, 1H), 7.46–7.41 (m, 4H), 7.37–7.34 (m, 3H), 7.34–7.29 (m, yl)(phenyl)methanone 11aj. Yellow oil (166 mg, 83%, PE/EA =
4H), 7.26–7.23 (m, 2H), 7.11–7.07 (m, 2H), 7.04–7.01 (m, 1H), 10:1); IR (film) vmax: 3107, 3061, 3029, 1599, 1575, 1452, 1343,
5.66 (s, 1H), 4.46 (d, J = 13.5 Hz, 1H), 4.32 (d, J = 13.5 Hz, 1H) 1156, 791, 697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53–7.49 (m,
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 191.2, 186.5, 183.4, 1H), 7.47–7.40 (m, 4H), 7.39–7.28 (m, 7H), 7.26–7.14 (m, 4H),
158.6, 152.7, 151.0, 149.8, 148.4, 146.3, 140.1, 138.2, 136.5, 7.06–7.02 (m, 1H), 6.90–6.86 (m, 1H), 5.56 (s, 1H), 4.45 (d, J =
135.2, 134.7, 133.0, 132.9, 132.0, 129.5, 128.9, 128.6, 128.1, 13.6 Hz, 1H), 4.28 (d, J = 13.6 Hz, 1H) ppm; 13C{1H} NMR (100
127.7, 127.3, 124.1, 122.6, 115.1, 93.5, 76.0, 63.2, 29.7, 29.2, MHz, CDCl3) δ 191.5, 156.7, 140.5, 139.1, 135.5, 131.7, 129.9,
26.0ppm;
HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for 129.6, 128.7, 128.5 (2C), 128.1, 127.9 (2C), 127.8, 127.7, 125.3,
+
C30H23N2O2 : 443.1754, found: 443.1756.
(2-Benzyl-3-phenyl-5-(4-(trifluoromethyl)phenyl)-2,3-
dihydroisoxazol-4-yl)(phenyl)methanone 11af. Yellow oil (225
112.6, 75.9, 63.1 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd
for C27H22NO2S+: 424.1365, found: 424.1367.
(2-Benzyl-3-phenyl-5-(thiophen-2-yl)-2,3-dihydroisoxazol-4-
mg, 98%, PE/EA = 20:1); IR (film) vmax: 3062, 2924, 2853, 1599, yl)(phenyl)methanone 11ak. Yellow oil (134 mg, 67%, PE/EA =
1
1558, 1450, 1323, 1128, 1066, 697 cm-1; H NMR (500 MHz, 15:1); IR (film) vmax: 3083, 3061, 3029, 1599, 1575, 1494, 1363,
1
CDCl3) δ 7.45–7.40 (m, 4H), 7.36–7.29 (m, 12H), 7.24–7.22 (m, 728, 696 cm-1; H NMR (500 MHz, CDCl3) δ 7.54–7.49 (m, 4H),
1H), 7.08–7.04 (m, 2H), 5.66 (s, 1H), 4.46 (d, J = 13.5 Hz, 1H), 7.47–7.45 (m, 1H), 7.44–7.37 (m, 4H), 7.35–7.27 (m, 8H), 6.94–
4.31 (d, J = 13.0 Hz, 1H) ppm; 13C{1H} NMR (126 MHz, CDCl3) δ 6.91 (m, 1H), 5.59 (s, 1H), 4.53 (d, J = 13.0 Hz, 1H), 4.35 (d, J =
191.5, 159.8, 140.2, 138.4, 135.3, 132.1, 131.2, 129.9, 129.7, 13.0 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 191.3,
128.9, 128.7 (2C), 128.2 (d, J = 6.6 Hz), 128.1, 127.8, 124.9 (d, J 155.9, 140.5, 139.5, 135.4, 132.8, 131.8, 130.8, 129.9, 129.8,
= 3.8 Hz), 115.0, 76.2, 63.4 ppm; 19F NMR (376 MHz, CDCl3) δ - 128.7, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.6, 127.3,
63.23 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for 112.2, 75.7, 63.1 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd
+
C30H23F3NO2 : 486.1675, found: 486.1678.
for C27H22NO2S+: 424.1365, found: 424.1364.
Methyl-4-(4-benzoyl-2-benzyl-3-phenyl-2,3-
(2-Benzyl-3-phenyl-5-(pyridin-3-yl)-2,3-dihydroisoxazol-4-
dihydroisoxazol-5-yl)benzoate 11ag. Yellow oil (194 mg, 86%, yl)(phenyl)methanone 11al. Yellow solid (153 mg, 77%, PE/EA
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 11
ARTICLE
Journal Name
= 10:1); mp 141–143 oC; IR (film) vmax: 3087, 3030, 2848, 2229, 7.27 (m, 7H), 7.26–7.19 (m, 4H), 7.12–7.06 (m, 2H), 6.87–6.82
View Article Online
1
1625, 1599, 1353, 1133, 757, 698 cm-1; H NMR (400 MHz, (m, 2H), 5.61 (s, 1H), 4.47 (d, J = 13.2 HzD, O1HI: )1,0.410.2389/(Dd0,OJB=0211538.2J
CDCl3) δ 7.45–7.38 (m, 5H), 7.38–7.27 (m, 8H), 7.26–7.23 (m, Hz, 1H), 2.20 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
4H), 7.12–7.06 (m, 2H), 5.67 (s, 1H), 4.45 (d, J = 13.6 Hz, 1H), 191.4, 161.0, 142.2, 140.6, 135.9, 135.6, 130.4, 129.6, 129.5,
4.31 (d, J = 13.6 Hz, 1H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 129.1, 128.5 (2C), 128.4, 127.9, 127.8 (2C), 127.7, 127.6, 113.2,
191.1, 158.6, 138.2, 135.2, 132.2, 131.9, 131.6, 129.9, 129.5, 76.2, 63.1, 21.4 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd
+
128.8, 128.6 (2C), 128.1 (3C), 127.6, 117.9, 115.4, 113.9, 76.3, for C30H26NO2 : 432.1958, found: 432.1957.
63.2 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
C28H23N2O2 : 419.1754, found: 419.1757.
(2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)(4-
+
nitrophenyl)methanone 11ar. Yellow oil (162 mg, 74%, PE/EA
= 10:1); IR (film) vmax: 3062, 3030, 2923, 2852, 1617, 1592,
1
(4-Benzoyl-2-benzyl-3-phenyl-2,3-dihydroisoxazol-5-
1522, 1346, 848, 697 cm-1; H NMR (500 MHz, CDCl3) δ 7.88–
yl)methyl acetate 11am. (102 mg, 52%, PE/EA = 10:1); IR (film) 7.82 (m, 2H), 7.49–7.41 (m, 4H), 7.40–7.31 (m, 7H), 7.30–7.26
vmax: 3062, 3030, 1748, 1628, 1577, 1494, 1452, 1352, 906, 728, (m, 2H), 7.21–7.15 (m, 2H), 7.12–7.06 (m, 2H), 5.63 (s, 1H),
698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53–7.45 (m, 3H), 7.42– 4.46 (d, J = 13.5 Hz, 1H), 4.34 (d, J = 13.5 Hz, 1H) ppm; 13C{1H}
7.31 (m, 7H), 7.30–7.23 (m, 5H), 5.52 (s, 1H), 4.68–4.56 (m, 2H), NMR (126 MHz, CDCl3) δ 189.4, 164.5, 149.0, 144.2, 140.4,
4.36 (d, J = 13.2 Hz, 1H), 4.18 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} 135.2, 131.5, 129.8, 129.7, 128.8, 128.7, 128.3 (2C), 128.2,
NMR (100 MHz, CDCl3) δ 190.9, 169.9, 158.3, 140.3, 139.7, 127.8, 127.0, 123.0, 114.17, 75.5, 63.3, 29.9 ppm; HRMS (ESI-
+
135.2, 132.3, 129.5, 128.6, 128.5, 128.0, 127.9, 127.3, 116.3, Orbitrap) m/z: [M+H]+ calcd for C29H23N2O4 : 463.1652, found:
74.3, 63.5, 56.9, 20.4 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ 463.1655.
+
calcd for C26H23NO4 : 413.4651, found: 413.4653.
(2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazole-4-
(4-Benzoyl-2-benzyl-3-phenyl-2,3-dihydroisoxazol-5-
carbonyl)benzonitrile 11as. Yellow oil (172 mg, 82%, PE/EA =
yl)methyl acetate 11an. (164 mg, 87%, PE/EA = 15:1); IR (film) 20:1); IR (film) vmax: 3064, 3032, 2918, 2851, 2252, 1617, 1359,
1
vmax: 3062, 3029, 2966, 2871, 1650, 1598, 1579, 1479, 892, 758, 909, 734, 698 cm-1; H NMR (400 MHz, CDCl3) δ 7.46–7.41 (m,
697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.49–7.38 (m, 5H), 7.37– 4H), 7.38–7.26 (m, 11H), 7.20–7.15 (m, 2H), 7.13–7.07 (m, 2H),
7.28 (m, 5H), 7.20–7.13 (m, 3H), 7.04–6.99 (m, 2H), 5.21 (s, 1H), 5.62 (s, 1H), 4.46 (d, J = 13.2 Hz, 1H), 4.33 (d, J = 13.6 Hz, 1H)
4.35 (d, J = 13.2 Hz, 1H), 4.20 (d, J = 13.2 Hz, 1H), 1.25 (s, 9H), ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 189.7, 164.1, 142.4,
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 193.3, 167.0, 140.8, 140.2, 135.1, 131.5, 131.3, 129.7, 129.2, 129.0, 128.6, 128.5,
139.9, 135.6, 132.2, 129.7, 128.5, 128.4, 128.3, 127.9, 127.7, 128.2, 128.1, 128.0, 127.6, 126.9, 118.0, 114.4, 113.7, 75.4,
127.3, 109.3, 76.3, 63.0, 33.7, 28.3 ppm; HRMS (ESI-Orbitrap) 63.1 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
+
+
m/z: [M+H]+ calcd for C27H27NO2 : 397.5088, found: 397.5089.
C30H23N2O2 : 443.1754, found: 443.1755.
(2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)(4-
Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)(naphthalen-
chlorophenyl)methanone 11ao. Yellow oil (157 mg, 73%, 2-yl)methanone 11at. Yellow solid (184 mg, 83%, PE/EA =
o
PE/EA = 15:1); IR (film) vmax: 3087, 3062, 3030, 2847, 1618, 15:1); mp 110–112 C; IR (film) vmax: 3059, 3030, 2846, 1614,
1592, 1491, 1353, 750, 697 cm-1; H NMR (400 MHz, CDCl3) δ 1573, 1492, 1358, 755, 696 cm-1; H NMR (400 MHz, CDCl3) δ
7.45–7.39 (m, 4H), 7.37–7.26 (m, 8H), 7.25–7.20 (m, 3H), 7.13– 7.87–7.82 (m, 1H), 7.69–7.63 (m, 1H), 7.57–7.39 (m, 9H), 7.38–
7.08 (m, 2H), 7.02–6.96 (m, 2H), 5.61 (s, 1H), 4.45 (d, J = 13.2 7.28 (m, 6H), 7.26–7.21 (m, 2H), 7.05–6.98 (m, 1H), 6.98–6.91
Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, (m, 2H), 5.68 (s, 1H), 4.51 (d, J = 13.6 Hz, 1H), 4.35 (d, J = 9.6 Hz,
CDCl3) δ 190.2, 162.4, 140.4, 137.7, 136.9, 135.4, 130.9, 130.3, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 191.4, 162.0, 140.6,
129.6 (2C), 128.5, 128.1, 128.0, 127.7, 127.3, 127.2, 113.4, 135.6, 135.5, 134.7, 130.6, 130.5, 129.6, 129.5, 129.0, 128.6,
1
1
75.9, 63.1 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for 127.9 (2C), 127.8, 127.7 (2C), 127.5, 126.2, 125.0, 113.6, 76.2,
C29H23ClNO2 : 452.1411, found: 452.1414.
+
63.1 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
C33H26NO2 : 468.1958, found: 468.1959.
Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)(tetrahydro-
+
(2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)(4-
methoxyphenyl)methanone 11ap. Yellow solid (136 mg, 64%,
PE/EA = 10:1); mp 126–128 oC; IR (film) vmax: 3061, 3029, 2933, 2H-pyran-4-yl)methanone 11au. Yellow solid (56 mg, 28%,
1
2838, 1597, 1572, 1351, 1255, 754, 696 cm-1; H NMR (400 PE/EA = 10:1); mp 121–123 oC; IR (film) vmax: 3061, 3030, 2953,
1
MHz, CDCl3) δ 7.46–7.40 (m, 6H), 7.36–7.30 (m, 3H), 7.29–7.27 2841, 1636, 1591, 1491, 1383, 1028, 737 cm-1; H NMR (500
(m, 2H), 7.27–7.20 (m, 4H), 7.15–7.08 (m, 2H), 6.58–6.51 (m, MHz, CDCl3) δ 7.60–7.51 (m, 3H), 7.50–7.44 (m, 2H), 7.43–7.38
2H), 5.61 (s, 1H), 4.46 (d, J = 13.6 Hz, 1H), 4.28 (d, J = 13.2 Hz, (m, 2H), 7.37–7.28 (m, 7H), 7.27–7.24 (m, 1H), 5.41 (s, 1H),
1H), 3.69 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 190.4, 4.41 (d, J = 13.5 Hz, 1H), 4.19 (d, J = 13.0 Hz, 1H), 3.80–3.71 (m,
162.5, 160.1, 140.6, 135.6, 131.3, 131.2, 130.4, 129.6, 129.5, 2H), 2.97–2.89 (m, 1H), 2.88–2.79 (m, 1H), 2.53–2.44 (m, 1H),
128.5 (2C), 128.0, 127.8 (2C), 127.7, 113.1, 113.0, 76.5, 63.1, 1.60–1.45 (m, 2H), 1.39–1.31 (m, 1H), 1.22–1.15 (m, 1H) ppm;
55.3 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for 13C{1H} NMR (126 MHz, CDCl3) δ 197.7, 162.2, 141.0, 135.2,
+
C30H26NO3 : 448.1907, found: 448.1909.
131.3, 129.5, 129.3, 128.6, 128.5, 128.1, 127.9 (2C), 127.3,
(2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)(p-
114.4, 73.9, 67.1, 67.0, 63.2, 44.3, 28.8, 28.7 ppm; HRMS (ESI-
+
tolyl)methanone 11aq. Yellow oil (143 mg, 70%, PE/EA = 20:1); Orbitrap) m/z: [M+H]+ calcd for C28H28NO3 : 426.2063, found:
IR (film) vmax: 3087, 3061, 3030, 2921, 1605, 1492, 1352, 734, 426.2065.
696 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.46–7.40 (m, 4H), 7.37–
6 | J. Name., 2012, 00, 1-3
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Page 7 of 11
Organic & Biomolecular Chemistry
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Journal Name
Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)(3-
ARTICLE
Benzyl-3-(4-chlorophenyl)-5-phenyl-2,3-dihydroisoxazol-4-
View Article Online
methylthiophen-2-yl)methanone 11av. Yellow oil (70 mg, 34%, yl)(phenyl)methanone 11ea. Yellow oil (D2O11I: 1m0.g10, 3997/D%0,OPBE0/2E1A58=J
PE/EA = 20:1); IR (film) vmax: 3062, 3029, 2923, 2852, 1607, 10:1); IR (film) vmax: 3061, 3030, 1615, 1595, 1574, 1490, 1355,
1492, 1403, 1371, 695 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.46– 1089, 732, 694 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.44–7.37 (m,
7.39 (m, 4H), 7.38–7.35 (m, 2H), 7.35–7.27 (m, 6H), 7.25–7.21 4H), 7.37–7.30 (m, 5H), 7.28–7.26 (m, 1H), 7.26–7.24 (m, 1H),
(m, 1H), 7.20–7.16 (m, 2H), 7.10–7.07 (m, 1H), 6.62–6.59 (m, 7.23–7.18 (m, 4H), 7.10–7.00 (m, 4H), 5.58 (s, 1H), 4.49 (d, J =
1H), 5.59 (s, 1H), 4.47 (d, J = 13.0 Hz, 1H), 4.26 (d, J = 13.5 Hz, 13.5 Hz, 1H), 4.28 (d, J = 13.0 Hz, 1H) ppm; 13C{1H} NMR (126
1H), 2.28 (s, 3H) ppm; 13C{1H} NMR (126 MHz, CDCl3) δ 184.3, MHz, CDCl3) δ 191.6, 162.4, 139.3, 138.4, 135.2, 133.6, 131.6,
160.3, 142.9, 140.3, 137.0, 135.8, 131.3, 130.7, 130.6, 129.7, 130.7, 129.6, 129.5, 129.0, 128.9, 128.6 (2C), 128.0, 127.9,
129.1, 128.6, 128.1, 128.0, 114.8, 63.2, 29.9, 15.8 ppm; HRMS 127.7, 127.2, 113.0, 75.2, 63.1 ppm; HRMS (ESI-Orbitrap) m/z:
+
(ESI-Orbitrap) m/z: [M+H]+ calcd for C28H24NO2S+: 438.1522, [M+H]+ calcd for C29H23ClNO2 : 452.1411, found: 452.1414.
found: 438.1524.
Benzyl-3-(4-methoxyphenyl)-5-phenyl-2,3-dihydroisoxazol-
Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)(3,5-
4-yl)(phenyl)methanone 11fa. White solid (181 mg, 84%,
dimethylisoxazol-4-yl)methanone 11aw. Yellow oil (65 mg, PE/EA = 10:1); mp 108–110 oC; IR (film) vmax: 3060, 3030, 2932,
31%, PE/EA = 10:1); IR (film) vmax: 3061, 3030, 2927, 1621, 2835, 1613, 1510, 1354, 1247, 1174, 696 cm-1; H NMR (400
1
1593, 1491, 1422, 872, 758, 697 cm-1; 1H NMR (400 MHz, MHz, CDCl3) δ 7.45–7.39 (m, 3H), 7.38–7.30 (m, 6H), 7.24–7.18
CDCl3) δ 7.47–7.43 (m, 2H), 7.40–7.35 (m, 3H), 7.35–7.31 (m, (m, 4H), 7.09–7.00 (m, 4H), 6.86–6.81 (m, 2H), 5.58 (s, 1H),
3H), 7.31–7.27 (m, 5H), 7.26–7.22 (m, 2H), 5.59 (s, 1H), 4.42 (d, 4.45 (d, J = 13.2 Hz, 1H), 4.28 (d, J = 13.2 Hz, 1H), 3.75 (s, 3H)
J = 13.6 Hz, 1H), 4.25 (d, J = 13.6 Hz, 1H), 2.16 (s, 3H), 2.04– ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 191.7, 162.0, 159.3,
1.99 (m, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 183.7, 138.6, 135.6, 132.7, 131.5, 130.5, 129.6, 129.5, 128.9 (2C),
169.6, 162.1, 158.5, 140.1, 135.2, 131.6, 129.4, 129.0, 128.6, 128.5, 127.9, 127.8, 127.7, 127.5, 113.9, 113.5, 75.6, 62.9, 55.2
+
128.5, 128.2, 128.0, 127.9, 127.7, 126.7, 117.8, 115.7, 75.7, ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C30H26NO3 :
63.2, 12.1, 10.7 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd 448.1907, found: 448.1908.
+
for C28H25N2O3 : 437.1859, found: 437.1864.
(2-Benzyl-5-phenyl-3-p-tolyl-2,3-dihydroisoxazol-4-
Benzyl-3-(2-chlorophenyl)-5-phenyl-2,3-dihydroisoxazol-4-
yl)(phenyl)methanone 11ga. Yellow solid (206 mg, 96%, PE/EA
o
yl)(phenyl)methanone 11ba. Colorless oil (132 mg, 75%, PE/EA = 10:1); mp 83–85 C; IR (film) vmax: 3059, 3028, 2922, 2854,
= 10:1); IR (film) vmax: 1619, 1574, 1471, 1445, 1356, 1072, 889, 1621, 1574, 1492, 1354, 888, 696 cm-1; H NMR (500 MHz,
1
1
731, 695 cm-1; H NMR (500 MHz, CDCl3) δ 7.53–7.46 (m, 3H), CDCl3) δ 7.45–7.41 (m, 2H), 7.40–7.36 (m, 2H), 7.36–7.30 (m,
7.40–7.30 (m, 6H), 7.26–7.19 (m, 6H), 7.14–7.03 (m, 4H), 6.17 5H), 7.24–7.17 (m, 4H), 7.12–7.01 (m, 6H), 5.58 (s, 1H), 4.45 (d,
(s, 1H), 4.54–4.41 (m, 2H) ppm; 13C{1H} NMR (126 MHz, CDCl3) J = 13.5 Hz, 1H), 4.29 (d, J = 13.0 Hz, 1H), 2.29 (s, 3H) ppm;
δ 191.1, 163.4, 138.4, 137.7, 135.5, 134.1, 131.5, 130.8, 129.8, 13C{1H} NMR (126 MHz, CDCl3) δ 191.7, 161.9, 138.6, 137.5,
129.7, 129.6, 129.1, 129.0, 128.9, 128.5, 128.0, 127.9, 127.7, 135.6, 131.4, 130.5, 129.6, 129.5, 129.2, 128.9, 128.5, 127.8,
127.2, 127.1, 111.7, 72.4, 63.6 ppm; HRMS (ESI-Orbitrap) m/z: 127.8, 127.7, 127.6, 127.5, 113.4, 75.8, 63.0, 26.9, 21.2 ppm;
+
+
[M+H]+ calcd for C29H23ClNO2 : 452.1411, found: 452.1414.
HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C30H26NO2 :
Benzyl-3-(3-chlorophenyl)-5-phenyl-2,3-dihydroisoxazol-4-
432.1958, found: 432.1957.
yl)(phenyl)methanone 11ca. Yellow solid (186 mg, 86%, PE/EA
(2-Benzyl-3-(4-(methylthio)phenyl)-5-phenyl-2,3-
= 20:1); mp 125–127 oC; IR (film) vmax: 3061, 3029, 2849, 1617, dihydroisoxazol-4-yl)(phenyl)methanone 11ha. Yellow solid
1
1595, 1574, 1491, 1355, 761, 694 cm-1; H NMR (400 MHz, (204 mg, 91%, PE/EA = 10:1); IR (film) vmax: 3060, 3029, 2921,
CDCl3) δ 7.47–7.40 (m, 3H), 7.38–7.29 (m, 6H), 7.24–7.18 (m, 2852, 1621, 1574, 1491, 1355, 1127, 695 cm-1; H NMR (500
1
6H), 7.11–7.01 (m, 4H), 5.58 (s, 1H), 4.50 (d, J = 13.2 Hz, 1H), MHz, CDCl3) δ 7.44–7.39 (m, 2H), 7.38–7.29 (m, 7H), 7.23–7.17
4.29 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ (m, 6H), 7.09–7.01 (m, 4H), 5.57 (s, 1H), 4.46 (d, J = 13.5 Hz,
191.5, 162.4, 142.8, 138.4, 135.1, 134.3, 131.6, 130.7, 129.7, 1H), 4.27 (d, J = 13.0 Hz, 1H), 2.43 (s, 3H) ppm; 13C{1H} NMR
129.6, 129.5, 128.8, 128.6, 128.0 (2C), 127.9, 127.8, 127.7, (126 MHz, CDCl3) δ 191.7, 162.2, 138.5, 137.9, 137.5, 135.4,
127.2, 125.9, 112.9, 75.2, 63.2 ppm; HRMS (ESI-Orbitrap) m/z: 131.5, 130.6, 129.6, 129.5, 128.9, 128.5, 128.2, 127.9, 127.7,
+
[M+H]+ calcd for C29H23ClNO2 : 452.1411, found: 452.1415.
Benzyl-3-(3-bromophenyl)-5-phenyl-2,3-dihydroisoxazol-4-
yl)(phenyl)methanone 11da. Yellow oil (151 mg, 63%, PE/EA =
127.4, 126.7, 113.2, 75.5, 63.0, 15.8 ppm; HRMS (ESI-Orbitrap)
m/z: [M+H]+ calcd for C30H26NO2S+: 464.1678, found: 464.1681.
4-(4-Benzoyl-2-benzyl-5-phenyl-2,3-dihydroisoxazol-3-
10:1); IR (film) vmax: 3060, 3028, 1615, 1594, 1573, 1490, 1472, yl)benzonitrile 11ia. Yellow solid (163 mg, 76%, PE/EA = 15:1);
o
1354, 891, 693 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.61–7.58 (m, mp 132–134 C; IR (film) vmax: 3061, 3028, 2227, 1616, 1574,
1
1H), 7.44–7.40 (m, 2H), 7.39–7.30 (m, 8H), 7.24–7.19 (m, 4H), 1492, 1356, 1127, 890, 696 cm-1; H NMR (400 MHz, CDCl3) δ
7.17–7.13 (m, 1H), 7.09–7.00 (m, 4H), 5.57 (s, 1H), 4.50 (d, J = 7.59–7.54 (m, 4H), 7.43–7.38 (m, 2H), 7.37–7.28 (m, 5H), 7.25–
13.2 Hz, 1H), 4.28 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} NMR (100 7.17 (m, 4H), 7.11–7.00 (m, 4H), 5.62 (s, 1H), 4.55 (d, J = 13.2
MHz, CDCl3) δ 191.6, 162.5, 143.1, 138.4, 135.1, 131.6, 131.0, Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} NMR (100 MHz,
130.8, 130.7, 130.0, 129.6 (2C), 128.9, 128.6, 128.1, 127.9, CDCl3) δ 191.5, 162.9, 146.2, 138.2, 134.7, 132.3, 131.7, 131.0,
127.8, 127.2, 126.4, 122.6, 112.9, 75.2, 63.2 ppm; HRMS (ESI- 129.6, 129.5, 128.8, 128.7, 128.4, 128.2, 128.0, 127.8, 118.9,
+
Orbitrap) m/z: [M+H]+ calcd for C29H23BrNO2 : 496.0906, found: 112.5, 111.5, 75.0, 63.3 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+
+
496.0909.
calcd for C30H23N2O2 : 443.1754, found: 443.1757.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 11
ARTICLE
4-(4-Benzoyl-2-benzyl-5-phenyl-2,3-dihydroisoxazol-3-
Journal Name
Benzyl-3-phenyl-2,3-dihydroisoxazol-4-yl)(3-
View Article Online
DOI: 10.1039/D0OB02158J
yl)benzonitrile 11ja. Yellow solid (150 mg, 67%, PE/EA = 10:1); chlorophenyl)methanone 12ac. Yellow oil (31 mg, 18%, PE/EA
mp 166–168 oC; IR (film) vmax: 3062, 1611, 1574, 1519, 1348, = 10:1); IR (film) vmax: 3063, 3030, 1630, 1602, 1565, 1494,
1
1
1127, 911, 732, 695 cm-1; H NMR (400 MHz, CDCl3) δ 8.19– 1352, 1134, 741, 697 cm-1; H NMR (400 MHz, CDCl3) δ 7.61–
8.12 (m, 2H), 7.67–7.61 (m, 2H), 7.45–7.39 (m, 2H), 7.38–7.29 7.59 (m, 1H), 7.53–7.45 (m, 2H), 7.41–7.36 (m, 3H), 7.36–7.26
(m, 5H), 7.27–7.19 (m, 4H), 7.13–7.01 (m, 4H), 5.69 (s, 1H), (m, 8H), 7.25–7.24 (m, 1H), 5.43 (s, 1H), 4.37 (d, J = 13.6 Hz,
4.58 (d, J = 12.8 Hz, 1H), 4.32 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} 1H), 4.18 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} NMR (100 MHz,
NMR (100 MHz, CDCl3) δ 191.5, 162.9, 148.2, 147.4, 138.2, CDCl3) δ 187.7, 155.0, 141.0, 140.2, 135.1, 134.7, 131.9, 129.9,
134.7, 131.7, 131.0, 129.7, 129.5, 128.8, 128.7, 128.5, 128.2, 129.4, 128.6, 128.5, 128.1 (2C), 127.9, 127.3, 126.1, 119.8,
128.0, 127.8, 123.7, 112.5, 74.8, 63.3 ppm; HRMS (ESI-Orbitrap) 71.6, 63.9 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
+
+
m/z: [M+H]+ calcd for C29H23N2O4 : 463.1652, found: 463.1653. C23H19ClNO2 : 376.1098, found: 376.1101.
(2-Benzyl-5-phenyl-3-(4-(trifluoromethyl)phenyl)-2,3- (2-Benzyl-3-phenyl-2,3-dihydroisoxazol-4-yl)-3-
dihydroisoxazol-4-yl)(phenyl)methanone 11ka. Yellow oil (179 phenylpropan-1-one 12ad. Yellow oil (82 mg, 35%, PE/EA =
mg, 77%, PE/EA = 10:1); IR (film) vmax: 3063, 1619, 1575, 1491, 15:1); IR (film) vmax: 3062, 3028, 2925, 2857, 1652, 1535, 1494,
1356, 1325, 1124, 1067, 695 cm-1; 1H NMR (400 MHz, CDCl3) δ 1128, 748, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40–7.36 (m,
7.60–7.53 (m, 4H), 7.45–7.40 (m, 2H), 7.38–7.29 (m, 5H), 7.25– 1H), 7.36–7.27 (m, 6H), 7.27–7.16 (m, 7H), 7.14–7.09 (m, 2H),
7.19 (m, 4H), 7.12–7.00(m, 4H), 5.65 (s, 1H), 4.52 (d, J = 13.2 5.19 (s, 1H), 4.27 (d, J = 13.2 Hz, 1H), 4.03 (d, J = 13.2 Hz, 1H),
Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, 2.92–2.84 (m, 2H), 2.82–2.72 (m, 2H) ppm; 13C{1H} NMR (100
CDCl3) δ 191.6, 162.7, 144.8, 138.4, 135.0, 131.6, 130.9, 129.6, MHz, CDCl3) δ 193.6, 152.8, 141.0, 140.4, 135.2, 129.3, 128.5
129.5, 128.9, 128.6, 128.1, 128.0 (d, J = 3.3 Hz), 127.8, 125.4 (d, (2C), 128.4 (2C), 127.9, 127.7, 127.2, 126.2, 120.7, 70.7, 63.7,
J = 3.8 Hz), 122.8, 112.8, 75.2, 63.2 ppm; 19F NMR (376 MHz, 41.7, 30.6 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
+
CDCl3) δ -62.50 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd C25H24NO2 : 370.1801, found: 370.1802.
+
for C30H23F3NO2 : 486.1675, found: 486.1679.
Benzyl-3-phenyl-2,3-dihydroisoxazol-4-
(3-Benzyl-5-phenyl-3-(thiophen-2-yl)-2,3-dihydroisoxazol-4- yl)(cyclohexyl)methanone 12ae. Yellow oil (84 mg, 33%, PE/EA
yl)(phenyl)methanone 11la. Yellow solid (145 mg, 71%, PE/EA = 20:1); IR (film) vmax: 3063, 3030, 2929, 2853, 1648, 1608,
1
= 20:1); mp 124–126 oC; IR (film) vmax: 3062, 3029, 2849, 1621, 1451, 1128, 733, 697 cm-1; H NMR (500 MHz, CDCl3) δ 7.51–
1
1574, 1492, 1354, 1133, 888, 696 cm-1; H NMR (400 MHz, 7.48 (m, 1H), 7.38–7.34 (m, 2H), 7.34–7.25 (m, 4H), 7.25–7.20
CDCl3) δ 7.49–7.40 (m, 4H), 7.39–7.29 (m, 3H), 7.24–7.18 (m, (m, 4H), 5.20 (s, 1H), 4.31 (d, J = 13 Hz, 1H), 4.08 (d, J = 13 Hz,
5H), 7.10–7.02 (m, 5H), 6.94–6.90 (m, 1H), 5.94 (s, 1H), 4.46 (d, 1H), 2.63–2.53 (m, 1H), 1.81–1.64 (m, 5H), 1.50–1.39 (m, 1H),
J = 13.2 Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} NMR 1.29–1.14 (m, 4H) ppm; 13C{1H} NMR (126 MHz, CDCl3) δ 198.5,
(100 MHz, CDCl3) δ 191.5, 162.3, 144.4, 138.5, 135.2, 131.6, 151.9, 140.6, 135.3, 129.3, 128.5, 128.4, 127.9, 127.6, 127.1,
130.7, 129.6, 129.5, 129.0, 128.6, 128.0, 127.9, 127.7, 127.3, 119.4, 70.8, 63.7, 48.4, 29.8, 29.2, 25.8, 25.7, 25.6 ppm; HRMS
+
126.9, 125.7, 125.3, 113.2, 71.2, 62.5 ppm; HRMS (ESI-Orbitrap) (ESI-Orbitrap) m/z: [M+H]+ calcd for C23H26NO2 : 348.195,
m/z: [M+H]+ calcd for C27H22NO2S+: 424.1365, found: 424.1366. found: 348.1958.
(2-Benzyl-3-phenyl-2,3-dihydroisoxazol-4-yl)(4-
2-Benzylidene-1-(naphthalen-2-yl)-3-phenylpropane-1,3-
bromophenyl)methanone 12aa. Yellow oil (96 mg, 49%, PE/EA dione 14 m-CPBA (148 mg, 0.86 mmol, 2.0 equiv) was added to
= 10:1); IR (film) vmax: 3087, 3062, 3030, 1602, 1453, 1354, a solution of 11at (200 mg, 0.43 mmol, 1.0 equiv) in DCM
1133, 1068, 749, 697 cm-1; H NMR (400 MHz, CDCl3) δ 7.59– (2.2 mL) at 0oC. The reaction was stirred at 0oC~rt overnight.
1
7.51 (m, 4H), 7.41–7.36 (m, 4H), 7.36–7.30 (m, 5H), 7.29–7.27 The mixture was quenched with saturated Na2S2O3 and
(m, 1H), 7.26–7.23 (m, 1H), 5.44 (d, J = 1.2 Hz, 1H), 4.39 (d, J = NaHCO3 solution and extracted with EtOAc (3×20mL). The
13.2 Hz, 1H), 4.18 (d, J = 13.2 Hz, 1H) ppm; 13C{1H} NMR (100 organic layers were combined, washed with brine, dried over
MHz, CDCl3) δ 188.1, 154.6, 140.2, 138.2, 135.1, 131.8, 129.6, MgSO4 and the solvent was concentrated in vacuo and purified
129.3, 128.5 (2C), 128.0, 127.9, 127.3, 126.8, 119.8, 71.7, 63.9 by flash chromatography on silica gel to give 14. Yellow oil
+
ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C23H19BrNO2 : (119 mg, 77%, PE/EA = 50:1); IR (film) vmax: 3360, 3058, 2922,
1
420.0593, found: 420.0596.
2851, 1667, 1596, 1574, 1447, 1260, 1229 cm-1; H NMR (400
(2-Benzyl-3-phenyl-2,3-dihydroisoxazol-4-yl)(p-
MHz, CDCl3) δ 8.48–8.43 (m, 1H), 8.09–8.02 (m, 1H), 7.95–7.82
tolyl)methanone 12ab. Yellow oil (117 mg, 47%, PE/EA = 10:1); (m, 5H), 7.63–7.59 (m, 6H), 7.41–7.33 (m, 3H), 7.24–7.22 (m,
IR (film) vmax: 3061, 3029, 2919, 2851, 1604, 1494, 1351, 1129, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 196.9, 194.9, 144.0,
748, 697 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.61–7.55 (m, 2H), 139.6, 137.5, 136.1, 133.8, 133.1, 132.6, 132.6, 132.1, 130.5,
7.42–7.36 (m, 4H), 7.36–7.26 (m, 6H), 7.26–7.19 (m, 3H), 130.2, 129.9, 129.6, 129.5, 128.9, 128.8, 128.6, 128.6, 127.8,
5.45(s, 1H), 4.37 (d, J = 13.2 Hz, 1H), 4.16 (d, J = 13.2 Hz, 1H), 126.8, 124.3 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for
+
2.39 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 189.1, 154.0, C26H18O2 : 362.4199, found: 362.4198.
142.7, 140.5, 136.8, 135.3, 129.3, 129.2, 128.5 (2C), 128.2,
128.0, 127.8, 127.4, 119.8, 71.8, 63.9, 21.5 ppm; HRMS (ESI-
+
Orbitrap) m/z: [M+H]+ calcd for C24H22NO2 : 356.1645, found:
Acknowledgements
356.1647.
We thank the National Natural Science Foundation of China
(21702032 to C.-M. Si and 21772027 to B.-G. Wei) and the
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 9 of 11
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
9
(a) F. Li, G. Cao, Y. Gao and D. Teng, RSC Adv. 2017, 7, 10816;
Open Research Fund Program of Beijing Key Lab of Plant
Resource Research and Development, BTBU (No. PRRD-2019-
YB2) for financial support. The authors also thank Dr. Han-Qing
Dong (Arvinas, Inc.) for helpful suggestions.
View Article Online
(b) C. Shen, Y. Yang, L. Wei, W. W. Dong, L. W. Chung and C. J.
DOI: 10.1039/D0OB02158J
Wang, iScience. 2019, 11, 146; (c) S. Roscales and J. Plumet,
Org. Biomol. Chem. 2018, 16, 8446.
10 (a) S. I. Murahashi and Y. Imada, Chem. Rev. 2019, 119, 4684;
(b) A. Angyal, A. Demjen, J. Wolfling, L. G. Puskas and I.
Kanizsai, J. Org. Chem. 2020, 85, 3587; (c) M. Liu, T. Zhou, M.
Zhang, J. Zhao and Q. Zhang, Asian J. Org. Chem. 2019, 8,
1363.
11 For recent selected examples: (a) Y. A. Khomutova, V. O.
Smirnov, H. Mayr and S. L. Ioffe, J. Org. Chem. 2007, 72, 9134;
(b) J. T. Reeves, C. Lorenc, K. Camara, Z. Li, H. Lee, C. A.
Busacca and C. H. Senanayake, J. Org. Chem. 2014, 79, 5895;
(c) F. M. Cordero, C. Vurchio and A. Brandi, J. Org. Chem.
2016, 81, 1661; (d) S. Yang, D. Liao, X. Tian and X. Lei, Org.
Lett. 2016, 18, 376. (e) M. Hasegawa, T. Suga, T. Soeta, Y.
Ukaji, J. Org. Chem. 2020, 85, 11258.
12 For reviews on nucleophilic addition of organometallics to
nitrones, see: (a) R. Bloch, Chem. Rev. 1998, 98, 1407; (b) P.
Merino, S. Franco, F. L. Merchan and T. Tejero, Synlett.
2000, 4, 442; (c) M. Lombardo and C. Trombini, Curr. Org.
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(e) M. Lombardo and C. Trombini, Synthesis. 2000, 6, 759; (f)
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB02158J
Sc(OTf)3-Catalyzed [3+2]-Cycloaddition of Nitrones with
Ynones
R1
Bn
N
R3
R2
Bn
O
Sc(OTf)3
O
N
R3
R1=Ar, cyclopropyl,
R1
O
R2
thiophenyl, pyridinyl, H
O
39 examples, 18-98%