KOAc-Catalyzed one-pot three-component 1,3-dipolar cycloaddition of α-diazo compounds, nitrosoarenes, and alkenes: An approach to functionalized isoxazolidines

Article abstract of DOI:10.1021/acs.joc.9b00299

A direct, highly efficient KOAc-catalyzed one-pot three-component approach for the preparation of various functionalized isoxazolidines via the 1,3-dipolar cycloaddition reactions of readily accessible diazo compounds, nitrosoarenes, and alkenes has been reported. The cheap and readily available catalyst and starting materials, excellent functional group compatibility, wide substrate scope, high yields, and excellent chemo-, regio-, and diastereoselectivities make this protocol an attractive alternative.

Full text of DOI:10.1021/acs.joc.9b00299

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Article
KOAc-Catalyzed one-pot three-component 1,3-dipolar
cycloaddition of #-diazo compounds, nitrosoarenes, and
alkenes: an approach to functionalized isoxazolidines
Xing Li, Tao Feng, Dongjun Li, Hong-Hong Chang, Wen-Chao Gao, and Wen-Long Wei
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00299 • Publication Date (Web): 08 Mar 2019
Downloaded from http://pubs.acs.org on March 8, 2019
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KOAc-Catalyzed one-pot three-component 1,3-dipolar cycloaddition
of α-diazo compounds, nitrosoarenes, and alkenes: an approach to
functionalized isoxazolidines
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Xing Li,* Tao Feng, Dongjun Li, Honghong Chang, Wenchao Gao and Wenlong Wei
College of Biomedical Engineering, Taiyuan University of Technology, 79 West Yingze Street,
Taiyuan 030024, People’s Republic of China.
ABSTRACT: A direct, highly efficient KOAc-catalyzed one-pot three-component approach for
the preparation of various functionalized isoxazolidines via the 1,3-dipolar cycloaddition reactions
of readily accessible diazo compounds, nitrosoarenes and alkenes has been reported. The cheap
and readily available catalyst and starting materials, excellent functional group compatibility, wide
substrate scope, high yields, and excellent chemo-, region- and diastereo-selectivities make this
protocol an attractive alternative.
R1
R3
N2
R4
O
O
R4
R3
KOAc
5 mol%
N
Ar
+
, 50 oC
O
R2
DCE
R2
N
R1OC
Ar
46 examples
up to 99% yield
transition-metal free
atom- and step-economic reaciton
cheap, readily available catalyst and starting materials
good to excellent results
broader substrate scope
high functional group compatibility
■ INTRODUCTION
Environmentally benign transformations and cost-effective strategies have become the target in modern
synthetic organic chemistry. Catalysis plays a crucial role for this purpose, and the development of one-pot
multicomponent routes becomes of great interest and importance. Therefore, the developing an efficient
transition-metal-free one-pot multicomponent approach that allows for using a cheap and readily available
catalyst for the synthesis of target products is highly desirable.
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Isoxazolidines represent a class of important and powerful heterocyclic skeletons frequently found in
many biologically active natural products and medicinal molecules.1 In addition, a number of molecules
containing isoxazolidine ring have attracted much attention as nucleoside analogues.2 Isoxazolidines are also
vital and versatile intermediates3 due to the ease of N−O bond cleavage, which could be further converted to
β-amino acids,4 β-lactams1a and 3-amino alcohols5 via the reductive cleavage of N−O bonds. Therefore, it is
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not surprising that great effort has been devoted to the development of novel, efficient and practical methods
1a
for the construction of isoxazolidines,6,
including cycloadditions of hydroxylamines with alkenes,7
cycloadditions of oxaziridines with olefins or arynes,8 cycloadditions of O-silyloxime with alkenes,9
cycloaddition of cyclopropanes with nitrosoarenes,10 annulation of 2-nitrosopyridine with allylstannanes,11
cascade reaction of N-alkoxyazomethine ylides,12 reaction of oxime ethers and cyclopropane diesters,13
nitrone cycloadditions of 1,2-cyclohexadiene,14 and others.15 Although these approaches have proven to be of
importance, the most popular and conventional methods are the [3+2] cycloadditions of nitrones with
alkenes (Scheme 1A).16-18 However, these methods generally involve the use of transition-metals and
complex nitrones which require a separate preparation step. In the past decades, more atom-economical
one-pot multi-component reactions have been observed for the synthesis of various compounds, which play
an increasingly important role in organic synthesis. Bhattacharya, Liu, Zhong and Córdova developed
asymmetric three-component methods of aldehydes, aryl hydroxylamine (complex substrates) and olefins to
access diverse chiral isoxazolidines, respectively.19 Additionally, one-pot strategies of diazo compounds,
nitrosoarenes and olefins were also well documented to construct this scaffold by Tan and Molander,
respectively, and the former is an example of asymmetric catalysis.20 Liu and Huang independently
demonstrated three-component processes of arylenes, functionalized olefins (complicated substrates) and
nitrosoarenes for the construction of isoxazolidines, too.21 Despite the success of these important and
valuable multi-component methods, more efficient methods with better results making use of easily
accessible and cheap starting materials is still highly appealing. In this context, Che,22 Liu23 and their
co-workers reported the 1,3-dipolar cycloaddition to synthesize various functionalized isoxazolidines via the
ruthenium porphyrin and [IPrAuCl]/AgNTf2 catalyzed three-component reactions of diazo compounds,
nitrosoarenes and alkenes, respectively (Scheme 1B). Typically, these two strategies also require the
utilization of transition-metal catalysts which still suffer from high cost and complicated purifying
procedures. It is notable that developing transition-metal-free multicomponent approaches have attracted
intense interest and increasing attention. Recently, trifluoromethanesulfonic acid catalyzed three-component
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cycloaddition of diazo compounds, nitrosoarenes and alkenes for access to isoxazolidines has been described
by Zhong24 and co-workers (Scheme 1C). Nevertheless, the use of a strong acid greatly lowered the
functional group tolerance, reduced the substrate scope and significantly limited its application, and the
reaction yields were not high enough for some substrates. On the other hand, to the best of our knowledge,
the examples that sterically hindered 1,1-disubstituted olefins are used as substrates in three-component
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routes are not observed. Therefore, the development of
a more efficient transition-metal-free
three-component strategy to isoxazolidines which allows for employing readily available, inexpensive and
environmentally benign catalysts with broader substrate scope and high functional group compatibility is
highly desirable. Potassium acetate (KOAc) is an abundant, cheap and nontoxic reagent. To the best of our
knowledge, however, the utilization of KOAc as a catalyst in organic synthesis has received less attention.
Herein, we will report a KOAc-catalyzed, atom- and step-economic one-pot three-component cycloaddition
of diazo compounds, nitrosoarenes and alkenes for the synthesis of functionalized isoxazolidines without the
need of any transition metal as a catalyst, in which broader substrate scope and better results were observed.
Previous works:
[16-18]
A
: Transition-metal catalyzed cycloaddition of nitrones with olefins
R2
R2
O
O
A
N
[Metal]
N
A
+
solvent
R1
R1
B
B
B
: Ru and Au catalyzed one-pot three-component cycloaddition
N2
O
[Ru(TTP)(CO)(MeOH)][22]
or
Ar
N
O
O
N
R1
A
Ar
+
R1
[23]
[IPrAuCl]/AgNTf2
B
B
A
[24]
C
: TfOH catalyzed one-pot three-component cycloaddition
N2
O
Ar
N
O
O
O
N
TfOH
, DCM, rt
R1
A
Ar
+
R1
B
B
A
This work:
N2
O
N
Ar
O
B
A
C
transition-metal-free
KOAc
N
R1
Ar
+
R1
C
(5 mol%)
DCE, 50 oC
B
A
wide substrate scope
excellent functional group compatibility
cheap and readily available catalyst
good to excellent results
Scheme 1. Different Strategies to Construct Functionalized Isoxazolidines
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■ RESULTS AND DISCUSSION
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Initially, the cycloaddition of ethyl diazoacetate (EDA, 1a), nitrosobenzene 2a and styrene 3a was selected
as the model reaction to evaluate catalysts. Gratifyingly, 75% yield could be obtained when 10 mol% KOAc
was employed as a catalyst (Table 1, entry 1). Encouraged by this preliminary result, we screened the effect
of different bases such as t-BuOK, KOH, K2CO3, K3PO4 and DBU. However, no better results were
observed. Strong bases (t-BuOK, KOH) indicated inferior catalytic activities with trace amount of product
4a (Table 1, entries 2−3), and K2CO3, K3PO4 and DBU catalyzed the reaction to give slightly lower yields
compared to KOAc (Table 1, entries 4−6). Notably, only 8% yield was attained in the absence of a base,
which suggested that the existence of a suitable base was crucial for this transformation (Table 1, entry 7). A
series of solvents were then examined and DCE proved to be the best choice (Table 1, entry 1). The use of
CH3CN, toluene and 1,4-dioxane provided the product 4a in somewhat lower yields (Table 1, entries 8−10).
Other solvents such as CH3OH, THF and CH3NO2 were less effective and gave obviously lower yields
(Table 1, entries 11−13). To our delight, reducing the amount of KOAc to 5 mol% did not affect the yield
(Table 1, entry 14). However, the adjustment of reaction temperature resulted in no further improvement in
yields (Table 1, entries 15 and 16 vs. 14). Moreover, the reaction proceeded more smoothly and gave the best
yield when the 1a/2a/3a molar ratios were 1.2:1.2:1 (99%, Table 1, entry 17).
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Table 1. Optimization of Reaction Conditionsa
NO
O
catalyst
solvent
O
N
N2
+
+
O
EtOOC
3a
1a
2a
4a
entry
1
catalyst
KOAc
t-BuOK
KOH
solvent
DCE
T (oC)
50
yield of 4a (%)
75
2
DCE
50
trace
trace
61
3
DCE
50
4
K2CO3
K3PO4
DBU
DCE
50
5
DCE
50
68
6
DCE
50
62
7
---
DCE
50
8
8
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
CH3CN
MePh
50
74
9
50
73
10
11
12
13
14b
1,4-dioxane 50
70
CH3OH
THF
50
50
50
50
53
30
CH3NO2
DCE
28
75
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15b
16b
17c
KOAc
KOAc
KOAc
DCE
DCE
DCE
30
60
50
65
76
99
7
8
9
a
Unless noted, all reactions were performed with 1a (0.1
mmol), 2a (0.1 mmol), 3a (0.1 mmol) and 10 mol% of catalyst in
1.0 mL of solvent for 24 h. b 5 mol% of KOAc was used and 48%
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c
yield was obtained when 2.5 mol% KOAc was utilized.
1a:2a:3a:KOAc = 1.2:1.2:1:0.05.
With the established optimal reaction conditions using KOAc as a catalyst in hand, we next evaluated the
substrate scope of this transformation using a variety of different olefins 3, and the results are summarized in
Scheme 2. Various styrenes bearing electron-donating groups such as methyl or electron-withdrawing
groups such as fluoro, chloro, and bromo at any position, reacted well with 1a and 2a to afford the desired
products 4a−4j in 83−99% yields with a single isomer or high diastereoselectivities, which demonstrated
that the electronic and steric properties of substituents had little influence on the transformation. It should be
noted that dimethyl substituted product 4e was obtained in 98% yield. Moreover, ethylenes substituted with
a heteroaryl group such as 2-vinylpyridine and 4-vinylpyridine also worked well, giving the desired products
4k and 4l in 90% yields with excellent diastereoselectivities, respectively. It was found that the sterically
hindered 1-vinylnaphthalene and 2-vinylnaphthalene reacted smoothly to furnish the products 4m and 4n in
82% and 83% yields with high diastereoselectivities, respectively. Gratifyingly, 1,2-disubstituted aryl
alkenes such as (E)-chalcone and ethyl cinnamate could be converted successfully into the desired products
4o and 4p with good yields and diastereoselectivities. Then, this process was extended to alkyl alkenes.
When a variety of aliphatic terminal alkenes containing various functional groups were subjected to the
transformation, high yields and diastereoselectivities were provided (4q−4v). Notably, the greater the
distance between the functional group and C=C double bond of olefin is, the slightly lower the yield (4q vs.
4r, and 4s vs. 4t). For 1,2-disubstituted aliphatic alkenes, not only (Z)-isomer but also (E)-isomer substrates
were suitable for the reaction, affording the corresponding single isomer products 4w−4y in excellent yields.
This catalytic method was well applicable to cyclic olefinic bond, too (4z).
Scheme 2. Scope of Various Dipolarophilesa,b
R1
O
O
O
5 mol% KOAc
DCE, 50 o
N
Ph
N2
N
+
+
R1
R2
R2
C
O
Ph
EtOOC
3
1a
2a
4
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N
N
R6
O
O
O
O
N
N
Ph
O
Ph
N
Ph
N
Ph
N
Ph
EtOOC
EtOOC
4m, 82%, 90:10d
EtOOC
EtOOC
4n
EtOOC
d
d
4k
, 83%, 87:13
, 90%, 95:5
4l
, 90%
OH
Ph
Ph
, R6 = H,
4a
99%
O
O
OH
O
O
N
Ph
N
N
Ph
N
Ph
Ph
4b,
R
6 = 2-Me, 98%
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O
, R6 = 3-Me, 98%
4c
COOEt
EtOOC
, R6 = 4-Me, 99%c
EtOOC
4p
EtOOC
4r
EtOOC
4d
4e
Ph
d
d
, R6 = 2,5-diMe, 98%
, R6 = 2-F, 89%, 91:9d
4o
, 88%, 89:11
, 84%, 93:7
4q
, 99%
, 95%
O
4f
O
Br
O
O
O
O
N
Br
S
, R6 = 3-F, 88%, 89:11d
, R6 = 4-F, 84%, 86:14d
, R6 = 4-Cl, 84%, 87:13d
, R6 = 4-Br, 83%, 87:13d
4g
4h
4i
N
N
Ph
Ph
N
Ph
Ph
EtOOC
EtOOC
EtOOC
EtOOC
4j
d
4u, 94%, 95:5d
, 96%, 97:3
d
4v
4s
4t, 87%
, 81%, 82:18
O
COOMe
COOEt
COOMe
O
O
O
O
N
Ph
N
Ph
N
Ph
N
Ph
N
Ph
COOMe
COOEt
COOMe
EtOOC
4x
EtOOC
O
EtOOC
4w
EtOOC
4z
e
e
f
4y
, 99%
, 99%
, 96%
, 81%
a
1a
2a
3
Unless noted, all reactions were carried out with
(0.12 mmol),
b
(0.12 mmol), (0.1 mmol) and 5 mol% of KOAc
as a catalyst in 1.0 mL of DCE at 50 oC for 24 h. Isolated yield. 60 oC was adopted. The dr values were
c
d
determined by molar mass of isolated diastereomers. e cis-alkene was used. f trans-alkene was used.
Subsequently, the scope of various nitrosoarenes 2 was investigated. As shown in Scheme 3, the electronic
and steric effects of the substituents on the nitrosobenzene had little influence on the reaction yields. Both
electron-rich (4aa−4ac) and electron-deficient (4ad−4af) groups on the phenyl ring of the nitrosobenzene
were equally well tolerated, giving the corresponding products in good to high yields. With respect to
diastereoselectivity, better results were observed for both meta- and para-substituted substrates compared to
ortho-substituted substrates, which might be due to the steric hindrance. It was noteworthy that the
heteroaryl nitroso compounds, such as 2-nitrosopyridine and 2-methyl-6-nitrosopyridine, were found to be
compatible with these conditions, offering the corresponding single isomer products 4ag and 4ah in high
yields, respectively. To our delight, single isomer products 4ai and 4aj could be obtained with good yields
when dimethyl and dichloro substituted nitrosobenzenes were employed as substrates. Next, the examination
of alkyl diazoacetate 1 revealed that the steric hindrance of ester groups did not obviously affect the
transformation. The methyl diazoacetate and bulky t-butyl diazoacetate could provide the products 4ak and
4al in excellent yields with high diastereoselectivities, respectively. Additionally, the diazoketone was
suitable for this reaction with 67% yield and good diastereoselectivity, too (4am).
Scheme 3. Scope of Various Nitrosoarenes and α-Diazo Compoundsa,b
Ph
R3
O
O
5 mol% KOAc
DCE, 50 o
N
N2
N
Ar
+
+
Ph
O
C
Ar
R3OC
3a
1
2
4
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H3C
H3C
H3C
Ph
R7
Ph
Ph
N
O
N
O
O
Ph
O
N
N
N
N
EtOOC
4ag
EtOOC
EtOOC
EtOOC
4ai
, 82%
4ah
, 86%
, 90%
, R7 = 2-Me, 67%, 71:29c
, R7 = 3-Me, 79%, 81:19c
, R7 = 4-Me, 84%, 87:13c
, R7 = 2-Cl, 74%, 75:25c
, R7 = 3-Cl, 91%
4aa
4ab
4ac
4ad
4ae
4af
Cl
Cl
Ph
Ph
Ph
Ph
O
N
O
O
O
N
Ph
Ph
N
Ph
N
10
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50
51
52
53
54
55
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58
59
60
PhOC
MeOOC
t-BuOOC
EtOOC
c
c
, R7 = 4-Cl, 99%
4al
, 94%
4aj
4am
, 67%, 89:11
, 87%, 30 h
4ak
, 95%, 97:3
a
1
2
3a
Unless noted, all reactions were performed with (0.12 mmol), (0.12 mmol), (0.1 mmol) and 5 mol%
of KOAc as a catalyst in 1.0 mL of DCE at 50 oC for 24 h. Isolated yield. The d.r. was determined by
b
c
molar mass of isolated diastereomers.
To further demonstrate the utility of this method, more challenging 1,1-disubstituted olefins were
examined as substrates which have never been explored in three-component system. As listed in Scheme 4,
all examined substrates afforded the desired products 4an−4ar in 84−90% yields. 87%, 90% and 88% yields
were obtained when methacrylaldehyde, methyl methacrylate and ethyl methacrylate were employed as
substrates, respectively (4an−4ap). Interestingly, the presence of a or even two large phenyl groups did not
impede this reaction affording the corresponding products 4aq and 4ar in 86% and 84% yields, respectively.
These results demonstrated that electronic effect of functional groups played a more important role than
steric effect for 1,1-disubstituted olefins and the stronger the electron-withdrawing ability of substituents
was, the higher the yield.
Scheme 4. Investigation of Various 1,1-Disubstituted Olefinsa,b
R4
R4
O
R5
O
O
5 mol% KOAc
N
Ph
N2
N
+
+
DCE, 50 o
C
R5
O
Ph
EtOOC
3
1a
2a
4
Ph
Ph
Ph
O
O
O
O
O
COOMe
COOEt
CHO
N
COOEt
Ph
Ph
N
N
N
Ph
Ph
N
Ph
EtOOC
4ao
EtOOC
EtOOC
4aq
EtOOC
EtOOC
c
4ap
, 88%
, 86%, 95:5
4an
4ar
, 84%
, 87%, 30 h
, 90%
a
1a
2a 3
(0.12 mmol), (0.1 mmol) and 5 mol% of
all reactions were performed with
(0.12 mmol),
KOAc as a catalyst in 1.0 mL of DCE at 50 oC for 24 h. Isolated yield. The d.r. value was
b
c
determined by molar mass of isolated diastereomers.
Lactones, lactams and their derivatives have received considerable attention because of their presence in
numerous compounds of biological interest and their importance as drugs and biological agents. Bicyclic
isoxazolidines containing lactone or lactam belong to this type of useful molecular scaffolds. Subsequently,
this newly developed method was investigated and applied in the synthesis of these two kinds of
isoxazolo-bicycles. The reaction of allyl α-diazoacetate 6 with 2a proceeded smoothly under the standard
conditions, giving the targeted bicyclic isoxazolidine 7 in 83% yield (Scheme 5, eq 1). Compared with 6,
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allylamine α-diazoacetate 8 was more reactive as a substrate and offered the desired product 9 in 81% yield
5
6
(Scheme 5, eq 2).
7
8
9
N2
O
O
O
O
KOAc (5 mol%)
DCE, 50 oC, 48 h
yield: 83%
O
O
6
N
(1)
(2)
+
+
N
Ph
2a
O
Ph
7
10
11
12
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60
N2
N
KOAc (5 mol%)
DCE, 50 oC, 8 h
N
O
N
N
Ph
2a
O
O
Ph
8
yield: 81%
9
Scheme 5. Synthetic Applications of This Approach
To demonstrate the synthetic potential of this present approach, two selected reactions were performed on
a 1.0 mmol scale of starting materials. As shown in Scheme 6, in the presence of 5 mol% KOAc, 4a was
obtained in 97% yield via the reaction of 1.0 mmol of styrene 3a with 1.2 equiv. of 1a and 2a (Scheme 6, eq
1). Additionally, the reaction of 1.0 mmol of styrene 3a with 1.2 equiv. of 1a and 2c could provide 4ab as
the major isomer product with 76% yield and 4:1 dr (Scheme 6, eq 2).
O
O
O
5 mol% KOAc
DCE (5 mL)
N
N2
+
+
N
Ph
(1)
(2)
Ph
O
50 o
C
EtOOC
4a
1a
2a
3a
, 97% yield
O
N
H3C
Ph
O
N
O
5 mol% KOAc
DCE (5 mL)
N2
+
+
Ph
O
H3C
50 o
C
EtOOC
4ab
, 76% yield, dr = 4:1
1a
2c
3a
Scheme 6. 1.0 mmol-Scale Version
To probe the importance of the hydrogen on the α-carbon atom of α-diazocarbonyl compounds 1 in this
reaction, the three-component cycloaddition of 2-diazo-1-phenyl-1,3-butanedione 1f which lacks the
hydrogen on the α-carbon atom, nitrosobenzene 2a and styrene 3a was carried out under the standard
reaction conditions. The fact that no corresponding isoxazolidine was detected strongly suggested the
existence of the hydrogen on the α-carbon atom was crucial for this process (Scheme 7, eq 1). In addition, as
shown in Table 1, weak bases as catalysts proved to be more efficient, and out of those weak bases examined,
KOAc showed better catalytic activity. To gain an insight into the role of KOAc, several control experiments
were next carried out. The nitrone intermediate 10a was successfully obtained when the reaction of EDA 1a
with nitrosobenzene 2a was performed using KOAc or KOH as a catalyst (Scheme 7, eq 2, entries 1 and 2).25
However, only 18% yield of 10a was attained in the absence of any catalyst (Scheme 7, eq 2, entry 3). So the
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first role of the base such as KOAc or KOH might promote the deprotonation of EDA 1a and facilitate the
followed generation of intermediate 10a. Subsequently, when the styrene 3a was added to these three
reaction systems and stirred for another 3 h, the desired product 4a was obtained in 74% yield for KOAc
system (Scheme 7, eq 2, entry 1). However, KOH catalytic system gave trace amount of 4a and only 5%
yield was offered in the absence of any catalyst (Scheme 7, eq 2, entries 2 and 3). These three results
indicated the high importance of KOAc during the course of the cyclization. Additionally, only 14% yield of
4a was obtained if KOAc was removed before styrene 3a was added (Scheme 7, eq 2, entry 4), and the
reaction of the prepared intermediate 10a with styrene 3a also offered only 11% yield in the absence of
KOAc (Scheme 7, eq 4), which further demonstrated the essential role of KOAc in this step. For justifying
the exact role of K+ and AcO−, NaOAc, CsOAc and Ca(OAc)2 were utilized as catalysts to realize the
reaction, and 72%, 77% and 68% yields were provided (Scheme 7, eq 2, entries 5−7), respectively, which
demonstrated that AcO− really play an important role in this reaction. In contrast, it was observed that the
reaction of 1f and 2a failed to result in the desired nitrone intermediate in the presence of 5 mol% KOAc
(Scheme 7, eq 3), which may be the reason why no final cycloaddition product was detected after the styrene
was added. At the same time, the reaction of the intermediate 10a with styrene 3a could proceed very
smoothly in the presence of KOAc and up to 98% yield of the desired product 4a was obtained (Scheme 7,
eq 5), suggesting that intermediate 10a is key active intermediate of this multicomponent reaction. All these
experiments clearly revealed that AcO− was indispensable, and the in situ formation of the active nitrone
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intermediate is crucial.
N2
O
KOAc (5 mol%)
Ph
N
(1)
(2)
no desired product
+
+
DCE, 50 o
C
Ph
Ph
O
O
1f
2a
3a
3a
O
(
)
H
Ph
Ph
Catalyst (5 mol%)
DCE, 50 oC, 12 h
O
N
Ph
O
N
+
N2
EtOOC
N
3 h
COOEt
1a
Ph
Ph
EtOOC
2a
intermiderate 10a
4a
10a
4a
entry
catalyst
yield of
yield of
1
2
3
4
5
6
7
KOAc
KOH
---
KOAc
NaOAc
CsOAc
Ca(OAc)2
72%
69%
18%
72%
69%
74%
63%
74%
trace
5%
14%
72%
77%
68%
N2
3a
(
)
O
KOAc (5 mol%)
Ph
Ph
N
no product
(3)
no nitrone intermediate
+
DCE, 50 o
C
3 h
Ph
O
O
1f
2a
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O
Ph
DCE, 50 oC, 20 h
Ph
O
N
EtOOC
N
+
(4)
KOAc
Ph
Ph
EtOOC
10a
3a
4a
, 11% yield
(1.1 equiv)
(0.1 mol)
7
8
9
O
Ph
Ph
O
KOAc (5 mol%)
DCE, 50 oC, 20 h
N
10
11
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EtOOC
N
+
(5)
Ph
Ph
EtOOC
4a
, 98% yield
10a
3a
(0.1 mol)
(1.1 equiv)
Scheme 7. Control Experiments
On the basis of the aforementioned experimental results and corresponding literatures26, a plausible
mechanism is proposed in Scheme 8. Initially, the intermediate A is provided from the starting material 1 via
a deprotonation reaction process in the presence of 5 mol% of KOAc. Then, the intermediate A reacts with
nitrosobenzen 2a to form the intermediate B which further was protonated with H+ to generate the
intermediate C that might be transformed to D. Subsequently, active nitrone intermediate E is smoothly
formed through D with the releasion of N2.25 At last, this in situ generated nitrone E undergoes 1,3- dipolar
cycloaddition reaction with the alkene 3 to afford the final product isoxazolidine 4. So KOAc first might
activate diazo ester to react with nitrosobenzene and promote subsequent cleavage of diazo group to generate
the nitrone intermediate. At the same time, it also facilitated the 1,3-dipolar cycloaddition to afford the
corresponding isoxazolidines.
N
N
N
N
PhNO
2a
H
+ H+
KOAc
- H+
N2
O
R
O
O
O
R
R
N
O
O
O
Ph
1
A
B
B
N
NH
N
3
Ph
H
N
N
O
- N2
A
O
O
R
N
O
O
O
O
ROOC
B
R
N
R
N
O
Ph
H
Ph
O
Ph
O
A
C
D
E
4
Scheme 8. Proposed Mechanism
■ CONCLUSION
In summary, we have developed
a low-cost, highly atom-economical KOAc-catalyzed one-pot
three-component strategy to synthesize functionalized isoxazolidine derivatives via the cycloaddition of
readily accessible diazo compounds, nitrosoarenes and alkenes as starting materials. The transformation
showed broad substrate scope and good functional group tolerance, and was very suitable for
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sterically-hindered 1,1-disubstituted olefines. More importantly, with only 5 mol% KOAc, most products
were provided in high yields and excellent diastereoselectivities under mild reaction conditions.
7
8
■ EXPERIMENTAL SECTION
9
General Information. 1H NMR spectra were taken on a Bruker AVANCE III 600 MHz NMR
spectrometers. The chemical shifts are reported in ppm downfield to the CDCl3 resonance (δ =
7.27). Spectra are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration, and assignment. 13C
NMR data were collected at 150 MHz with complete proton decoupling. The chemical shifts are
reported in ppm downfield to the central CDCl3 resonance (δ = 77.0). High-resolution mass
spectra were performed on a micrOTOF-Q II instrument with an ESI source. Melting points were
measured with a RD-II melting point apparatus and are uncorrected. Unless otherwise noted, all
reagents and solvents obtained from commercial sources were used without further purification.
Deuterated solvents were purchased from Sigma–Aldrich. Column chromatography was
performed on silica gel (200-300 mesh). All yields were referred to isolated yields (average of two
runs) of compounds.
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General procedure for KOAc-catalyzed three-component cycloaddition of α-diazo
compounds, nitrosoarenes and alkenes. To a reaction system of nitrosoarene 2 (0.12 mmol),
α-diazo compound 1 (0.12 mmol) and KOAc (0.5 mg, 0.005 mmol, 5 mol%) in DCE (1.0 mL)
was added alkene 3 (0.1 mmol). Subsequently, the resultant solution was stirred at 50 oC (oil bath)
and monitored by TLC. Upon completion of consumption of alkene, the reaction mixture was
purified by silica gel column chromatography to give the corresponding cycloaddition product.
1.0 mmol-Scale preparation of 4a. To a reaction system of nitrosobenzene 2a (129.0 mg, 1.2
mmol), EDA 1a (136.8 mg, 1.2 mmol) and KOAc (5.0 mg, 0.05 mmol, 5 mol%) in DCE (3.0 mL)
o
was added styrene 3a (115.8 μL, 1.0 mmol). The resultant solution was then stirred at 50 C (oil
bath) for 24 h. At last, the reaction mixture was purified by silica gel column chromatography to
give the product 4a (288.3 mg, 97% isolated yield).
1.0 mmol-Scale preparation of 4ab. To a reaction system of 1-methyl-3-nitrosobenzene (145.3
mg, 1.2 mmol), EDA 1a (136.8 mg, 1.2 mmol) and KOAc (5.0 mg, 0.05 mmol, 5 mol%) in DCE
(3.0 mL) was added styrene 3a (115.8 μL, 1.0 mmol). The resultant solution was then stirred at 50
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oC (oil bath) for 24 h. At last, the reaction mixture was purified by silica gel column
chromatography to give the product 4ab (236.5 mg, 76% isolated yield, dr = 4:1).
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The KOAc-catalyzed reaction of EDA 1a with nitrosobenzene 2a. To the mixture system of
nitrosobenzene 2a (21.5 mg, 0.2 mmol) and 5 mol% KOAc (1.0 mg, 0.01 mmol) in DCE (1.0 mL)
was added EDA 1a (22.8 mg, 0.2 mmol). Subsequently, the resultant solution was stirred at 50 oC
(oil bath) for 24 h and the reaction mixture was purified by silica gel column chromatography to
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1
give the corresponding nitrone intermediate 10a. H NMR of the intermediate indicated that the
nitrone 10a had been formed (See Supporting Information).
Characterization Data of All Products.
Ethyl 2,5-diphenylisoxazolidine-3-carboxylate (4a). Yellow oil (99% yield, 29.5 mg), 1H NMR
(CDCl3, 400 MHz), δ 1.34 (t, J = 7.1 Hz, 3H), 2.72-2.79 (m, 1H), 2.88-2.95 (m, 1H), 4.28 (q, J =
7.1 Hz, 2H), 4.50 (dd, J = 8.9, 5.8 Hz, 1H), 5.04 (dd, J = 9.4, 6.8 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H),
7.14 (d, J = 7.8 Hz, 2H), 7.29-7.35 (m, 2H), 7.36-7.41 (m, 3H), 7.48-7.51 (m, 2H) ppm; 13C{1H}
NMR (CDCl3, 100 MHz), δ 13.2, 40.2, 60.8, 67.6, 79.1, 113.1, 121.1, 126.1, 127.6, 127.6, 128.1,
136.3, 150.2, 170.5 ppm; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H19NNaO3 320.1257; found
320.1261.
Ethyl 2-phenyl-5-(o-tolyl)isoxazolidine-3-carboxylate (4b). Yellow oil (98% yield, 30.5 mg),
1H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz, 3H), 2.32 (s, 3H), 2.62-2.69 (m, 1H), 2.91-2.98
(m, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.52 (dd, J = 9.0, 5.8 Hz, 1H), 5.24 (dd, J = 9.4, 6.8 Hz, 1H),
7.00 (t, J = 7.3 Hz, 1H), 7.14-7.18 (m, 3H), 7.21-7.27 (m, 2H), 7.30-7.34 (m, 2H), 7.68-7.70 (m,
1H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 19.5, 40.7, 61.9, 68.6, 80.3, 114.1, 122.1,
125.9, 126.5, 128.1, 129.2, 130.4, 135.8, 151.2, 171.5 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for
C19H22NO3 312.1594; found 312.1599.
Ethyl 2-phenyl-5-(m-tolyl)isoxazolidine-3-carboxylate (4c). Yellow oil (98% yield, 30.6 mg),
1H NMR (CDCl3, 400 MHz), δ 1.35 (t, J = 6.8 Hz, 3H), 2.38 (s, 3H), 2.71-2.79 (m, 1H), 2.84-2.94
(m, 1H), 4.29 (q, J = 7.0 Hz, 2H), 4.51 (t, J = 7.5 Hz, 1H), 5.03 (t, J = 8.3 Hz, 1H), 7.00 (t, J = 7.3
Hz, 1H), 7.14 (d, J = 8.0 Hz, 3H), 7.25-7.34 (m, 5H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ
14.2, 21.5, 41.3, 61.9, 68.7, 80.3, 114.2, 122.1, 124.2, 127.7, 128.6, 129.2, 137.2, 138.4, 151.3,
171.6 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C19H22NO3 312.1594; found 312.1599.
Ethyl 2-phenyl-5-(p-tolyl)isoxazolidine-3-carboxylate (4d). Yellow oil (99% yield, 30.9 mg),
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1H NMR (CDCl3, 400 MHz), δ 1.34 (t, J = 7.2 Hz, 3H), 2.36 (s, 3H), 2.70-2.77 (m, 1H), 2.85-2.92
(m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.49 (dd, J = 8.9, 6.0 Hz, 1H), 5.00 (dd, J = 9.6, 6.7 Hz, 1H),
7.00 (t, J = 7.3 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 8.7, 7.4
Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 21.3, 41.2, 61.9,
68.7, 80.2, 114.2, 122.0, 127.2, 129.2, 129.3, 134.2, 138.5, 151.3, 171.6 ppm; HRMS (ESI) m/z:
[M + H]+ Calcd for C19H22NO3 312.1594; found 312.1598.
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Ethyl 5-(2,5-dimethylphenyl)-2-phenylisoxazolidine-3-carboxylate (4e). Yellow oil (98% yield,
1
32.0 mg), H NMR (CDCl3, 400 MHz), δ 1.34 (t, J = 7.1 Hz, 3H), 2.27 (s, 3H), 2.35 (s, 3H),
2.60-2.68 (m, 1H), 2.89-2.97 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.51 (dd, J = 8.9, 6.0 Hz, 1H),
5.20 (dd, J = 9.6, 6.6 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.02-7.09 (m, 2H), 7.14 (dd, J = 8.7, 1.0
Hz, 2H), 7.29-7.35 (m, 2H), 7.51 (s, 1H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 19.0,
21.2, 40.3, 61.9, 68.7, 76.9, 114.1, 122.0, 126.4, 128.8, 129.2, 130.3, 132.3, 135.4, 136.0, 151.4,
171.6 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C20H24NO3 326.1751; found 326.1753.
Ethyl 5-(2-fluorophenyl)-2-phenylisoxazolidine-3-carboxylate (4f). Yellow oil (89% isolated
yield, 28.2 mg, dr = 91:9), 1H NMR (CDCl3, 400 MHz), δ 1.32 (t, J = 7.2 Hz, 3H), 2.67-2.75 (m,
1H), 2.93-3.01 (m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.52 (dd, J = 9.9, 5.4 Hz, 1H), 5.37 (dd, J = 8.8,
7.4 Hz, 1H), 6.99-7.02 (m, 1H), 7.03-7.09 (m, 1H), 7.14 (dd, J = 8.6, 0.9 Hz, 2H), 7.18 (td, J = 7.7,
1.1 Hz, 1H), 7.28-7.35 (m, 3H) , 7.68 (td, J = 7.5, 1.7 Hz, 1H) ppm; 13C{1H} NMR (CDCl3, 100
MHz), δ 14.2, 39.8, 61.9, 68.6, 73.3, 73.4, 114.2, 115.2 (d, J = 21.2 Hz), 122.3, 124.4 (d, J = 3.5
Hz), 127.7 (d, J = 3.7 Hz), 129.2, 129.8 (d, J = 8.1 Hz), 150.9, 159.1 (d, J = 245.1 Hz), 171.3 ppm;
HRMS (ESI) m/z: [M + H]+ Calcd for C18H19FNO3 316.1343; found 316.1348.
Ethyl 5-(3-fluorophenyl)-2-phenylisoxazolidine-3-carboxylate (4g). Yellow oil (88% isolated
yield, 27.7 mg, dr = 89:11), 1H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz, 3H), 2.67-2.75 (m,
1H), 2.88-2.96 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.50 (dd, J = 8.9, 5.5 Hz, 1H), 5.06 (dd, J = 9.0,
7.1 Hz, 1H), 6.99-7.06 (m, 2H), 7.13 (dd, J = 8.6, 0.9 Hz, 2H), 7.22-7.26 (m, 2H), 7.29-7.38 (m,
3H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 41.0, 61.9, 68.5, 79.3, 79.4, 113.8 (d, J =
22.1 Hz), 114.2, 115.3 (d, J = 21.0 Hz), 122.3, 122.6 (d, J = 2.9 Hz), 129.2, 130.1 (d, J = 8.1 Hz),
140.1 (d, J = 7.3 Hz), 150.9, 161.7 (d, J = 244.8 Hz), 171.3 ppm; HRMS (ESI) m/z: [M + H]+
Calcd for C18H19FNO3 316.1343; found 316.1348.
Ethyl 5-(4-fluorophenyl)-2-phenylisoxazolidine-3-carboxylate (4h). Yellow oil (84% isolated
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yield, 26.5 mg, dr = 86:14), 1H NMR (CDCl3, 400 MHz), δ 1.34 (t, J = 7.1 Hz, 3H), 2.68-2.76 (m,
1H), 2.85-2.93 (m, 1H), 4.28 (qd, J = 7.1, 0.7 Hz, 2H), 4.50 (dd, J = 8.9, 5.6 Hz, 1H), 5.03 (dd, J =
9.2, 7.0 Hz, 1H), 7.0 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 8.7 Hz, 2H), 7.12-7.16 (m, 2H), 7.29-7.35 (m,
2H), 7.45-7.51 (m, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 41.1, 61.9, 79.6, 114.2,
115.4 (d, J = 21.6 Hz), 122.2, 128.9 (d, J = 8.4 Hz), 129.2, 133.1 (d, J = 3.2 Hz), 151.0, 161.6 (d, J
= 245.7 Hz), 171.5 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C18H19FNO3 316.1343; found
316.1356.
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Ethyl 5-(4-chlorophenyl)-2-phenylisoxazolidine-3-carboxylate (4i). Yellow oil (84% isolated
1
yield, 27.9 mg, dr = 87:13), {lit.22c: Oil, 77% yield, dr = 80:20}, H NMR (CDCl3, 600 MHz), δ
1.34 (t, J = 7.1 Hz, 3H), 2.68-2.73 (m, 1H), 2.87-2.93 (m, 1H), 4.29 (qd, J = 7.1, 1.5 Hz, 2H), 4.51
(dd, J = 9.0, 5.5 Hz, 1H), 5.04 (dd, J = 9.2, 7.0 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 7.13-7.15 (m,
2H), 7.31 (dd, J = 8.7, 7.4 Hz, 2H), 7.35-7.38 (m, 2H), 7.43 (dt, J = 8.9, 2.3 Hz, 2H) ppm.
Ethyl 5-(4-bromophenyl)-2-phenylisoxazolidine-3-carboxylate (4j). Yellow oil (83% isolated
1
yield, 31.2 mg, dr = 87:13), {lit.22c: Oil, 63% yield, dr = 82:18}, H NMR (CDCl3, 400 MHz), δ
1.33 (t, J = 7.2 Hz, 3H), 2.66-2.73 (m, 1H), 2.86-2.94 (m, 1H), 4.28 (q, J = 7.2 Hz, 2H), 4.50 (dd,
J = 8.9, 5.5 Hz, 1H), 5.02 (dd, J = 9.0, 7.2 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 7.8, 2H),
7.30 (dd, J = 8.5, 7.5 Hz, 2H), 7.36 (d, J = 8.4, 2H), 7.51 (d, J = 8.4 Hz, 2H) ppm.
Ethyl 2-phenyl-5-(pyridin-2-yl)isoxazolidine-3-carboxylate (4k). Yellow oil (90% isolated
yield, 26.9 mg, dr = 95:5), 1H NMR (CDCl3, 400 MHz), δ 1.27 (t, J = 7.0 Hz, 3H), 2.84-2.92 (m,
1H), 2.93-3.06 (m, 1H), 4.22 (q, J = 7.0 Hz, 2H), 4.49 (dd, J = 8.8, 4.8 Hz, 1H), 5.31 (t, J = 7.1 Hz,
1H), 7.02 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.22-7.28 (m, 1H), 7.32 (t, J = 7.6 Hz, 2H),
7.66-7.77 (m, 2H), 8.55 (d, J = 4.7, 1H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.1, 39.5,
61.7, 80.4, 114.5, 121.0, 122.4, 123.1, 129.1, 136.9, 149.0, 150.8, 158.3, 171.3 ppm; HRMS (ESI)
m/z: [M + H]+ Calcd for C17H19N2O3 299.1390; found 299.1395.
Ethyl 2-phenyl-5-(pyridin-4-yl)isoxazolidine-3-carboxylate (4l). Yellow oil (90% yield, 26.9
1
mg), H NMR (CDCl3, 400 MHz), δ 1.31 (t, J = 7.1 Hz, 3H), 2.66-2.73 (m, 1H), 2.91-2.99 (m,
1H), 4.25 (q, J = 7.1 Hz, 2H), 4.52 (dd, J = 8.7, 5.0 Hz, 1H), 5.11 (t, J = 8.0 Hz, 1H), 7.03 (t, J =
7.3 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.40 (d, J = 4.9 Hz, 2H), 8.62 (d, J
= 4.8 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.1, 40.5, 62.0, 68.2, 78.2, 114.3, 121.5,
122.6, 129.3, 147.1, 150.2, 150.6, 171.0 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C17H19N2O3
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299.1390; found 299.1399.
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Ethyl 5-(naphthalen-1-yl)-2-phenylisoxazolidine-3-carboxylate (4m). Yellow oil (82% isolated
yield, 28.5 mg, dr = 90:10), 1H NMR (CDCl3, 400 MHz), δ 1.30 (t, J = 7.2 Hz, 3H), 2.77-2.84 (m,
1H), 3.10-3.18 (m, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.61 (dd, J = 8.9, 5.4 Hz, 1H), 5.79 (dd, J = 8.0,
7.4 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.32 (dd, J = 8.6, 7.4 Hz, 2H),
7.48-7.54 (m, 3H), 7.82 (d, J = 8.2 Hz, 1H), 7.87-7.91 (m, 2H), 7.95-7.98 (m, 1H) ppm; 13C{1H}
NMR (CDCl3, 100 MHz), δ 14.2, 29.7, 40.6, 61.8, 68.6, 77.0, 114.3, 122.2, 123.0, 123.4, 125.6,
125.7, 126.3, 128.6, 128.8, 129.0, 129.3, 130.6, 133.6, 133.7, 151.2, 171.4 ppm; HRMS (ESI) m/z:
[M + H]+ Calcd for C22H22NO3 348.1594; found 348.1592.
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Ethyl 5-(naphthalen-2-yl)-2-phenylisoxazolidine-3-carboxylate (4n). White solid (83% isolated
yield, 29.0 mg, dr = 87:13); mp 96-98 oC; 1H NMR (CDCl3, 400 MHz), δ 1.35 (t, J = 7.1 Hz, 3H),
2.80-2.88 (m, 1H), 2.94-3.02 (m, 1H), 4.30 (q, J = 6.9 Hz, 2H), 4.57 (t, J = 7.2 Hz, 1H), 5.24 (t, J
= 8.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.50 (t, J
= 3.3 Hz, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 3.3 Hz, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.92 (s,
1H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 41.2, 61.9, 68.7, 80.4, 114.2, 122.2, 124.5,
126.5, 127.8, 128.0, 128.6, 129.2, 133.1, 133.4, 151.2, 171.6 ppm; HRMS (ESI) m/z: [M + H]+
Calcd for C22H22NO3 348.1594; found 348.1583.
Ethyl 4-benzoyl-2,5-diphenylisoxazolidine-3-carboxylate (4o). Yellow oil (88% isolated yield,
35.3 mg, dr = 89:11), {lit.24: 82% yield, dr = 8:1}, 1H NMR (CDCl3, 600 MHz), δ 1.33 (t, J = 7.1
Hz, 3H), 4.31-4.39 (m, 2H), 5.00 (d, J = 5.2 Hz, 1H), 5.04 (dd, J = 8.7, 5.2 Hz, 1H), 5.31 (d, J =
8.8 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 7.18 (dd, J = 8.6, 1.0 Hz, 2H), 7.30-7.35 (m, 4H), 7.35-7.37
(m, 3H), 7.45-7.49 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.65 (dd, J = 8.5, 1.3 Hz, 2H) ppm.
Diethyl 2,5-diphenylisoxazolidine-3,4-dicarboxylate (4p). Yellow oil (84% isolated yield, 31.0
mg, dr = 93:7), {lit.24: 75% yield, dr = 30:1}, 1H NMR (CDCl3, 400 MHz), δ 1.12 (t, J = 7.1 Hz,
3H), 1.35 (t, J = 7.1 Hz, 3H), 4.04-4.09 (m, 3H), 4.33 (t, J = 6.8 Hz, 2H), 4.96 (d, J = 4.8 Hz, 1H),
5.23 (d, J = 8.6 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.9 Hz, 2H),
7.37-7.43 (m, 3H), 7.52 (d, J = 6.8 Hz, 2H) ppm.
Ethyl-5-(hydroxymethyl)-2-phenylisoxazolidine-3-carboxylat (4q). Yellow oil (99% yield,
24.9 mg), {lit.22c: 94% yield, dr = 95:5}, 1H NMR (CDCl3, 400 MHz), δ 1.32 (t, J = 7.0 Hz, 3H),
2.43 (dd, J = 7.4, 5.3 Hz, 1H), 2.48-2.55 (m, 1H), 2.56-2.63 (m, 1H), 3.70-3.77 (m, 1H), 3.95 (d, J
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= 12.4 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.38-4.43 (m, 1H), 4.43 (dd, J = 9.3, 4.1 Hz, 1H), 7.00 (t,
J = 7.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H) ppm.
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Ethyl 5-(2-hydroxyethyl)-2-phenylisoxazolidine-3-carboxylate (4r). Yellow oil (95% yield,
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25.2 mg), {lit.22c: Oil, 88% yield, dr = 95:5}, H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz,
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3H), 2.00 (d, J = 6.0 Hz, 2H), 2.07 (s, 1H), 2.38-2.46 (m, 1H), 2.60-2.68 (m, 1H), 3.85 (s, 2H),
4.25-4.31 (m, 3H), 4.35 (dd, J = 8.7, 7.2 Hz, 1H), 6.97 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H),
7.29 (t, J = 7.7 Hz, 2H) ppm.
Ethyl 5-(bromomethyl)-2-phenylisoxazolidine-3-carboxylate (4s). Yellow oil (81% isolated
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yield, 25.4 mg, dr = 82:18), {lit.22c: Oil, 82% yield, dr = 95:5}, H NMR (CDCl3, 400 MHz), δ
1.33 (t, J = 7.1 Hz, 3H), 2.53-2.69 (m, 2H), 3.53-3.65 (m, 2H), 4.26 (qd, J = 7.1, 2.2 Hz, 2H), 4.39
(dd, J = 8.8, 4.4 Hz, 1H), 4.45-4.52 (m, 1H), 7.01 (t, J = 7.3 Hz, 1H), 7.07 (dd, J = 8.6, 0.9 Hz,
2H), 7.27-7.33 (m, 2H) ppm.
Ethyl 5-(3-bromopropyl)-2-phenylisoxazolidine-3-carboxylate (4t). Brown oil (87% yield, 29.8
1
mg), H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz, 3H), 1.87-1.95 (m, 2H), 1.96-2.05 (m,
1H), 2.10-2.22 (m, 1H), 2.33-2.41 (m, 1H), 2.57-2.65 (m, 1H), 3.43-3.55 (m, 2H), 4.07-4.15 (m,
1H), 4.26 (q, J = 7.1 Hz, 2H), 4.35 (dd, J = 8.9, 5.7 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 7.03 (d, J =
8.3 Hz, 2H), 7.29 (t, J = 7.8 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 29.7, 31.3,
33.4, 38.5, 61.8, 68.0, 77.6, 114.1, 121.9, 129.1, 151.1, 171.5 ppm; HRMS (ESI) m/z: [M + H]+
Calcd for C15H21BrNO3 342.0699; found 342.0698.
Ethyl 5-((methylthio)methyl)-2-phenylisoxazolidine-3-carboxylate (4u). Yellow oil (94%
isolated yield, 26.4 mg, dr = 95:5), 1H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz, 3H), 2.24 (s,
3H), 2.48-2.53 (m, 1H), 2.26-2.68 (m, 1H), 2.78 (dd, J = 13.9, 5.9 Hz, 1H), 2.88 (dd, J = 13.9, 6.4
Hz, 1H), 4.25-4.32 (m, 2H), 4.34-4.37 (m, 1H), 4.37 (dd, J = 9.0, 5.2 Hz, 1H), 6.97 (td, J = 8.2,
0.9 Hz, 1H), 7.07 (dd, J = 8.6, 1.0 Hz, 2H), 7.27-7.32 (m, 2H) ppm; 13C{1H} NMR (CDCl3, 150
MHz), δ 17.1, 19.6, 39.2, 40.8, 64.7, 70.9, 81.6, 117.2, 125.1, 131.9, 153.8, 174.2 ppm; HRMS
(ESI) m/z: [M + H]+ Calcd for C14H20NO3S 282.1158; found 282.1160.
Ethyl 2-phenyl-5-(propionyloxy)isoxazolidine-3-carboxylate (4v). Yellow oil (96% isolated
yield, 28.2 mg, dr = 97:3), 1H NMR (CDCl3, 400 MHz), δ 1.14 (t, J = 7.5 Hz, 3H), 1.35 (t, J = 7.2
Hz, 3H), 2.33-2.41 (m, 2H), 2.73-2.85 (m, 2H), 4.20 (dd, J = 8.9, 3.7 Hz, 1H), 4. 27-4.38 (m, 2H),
6.63 (d, J = 5.0 Hz, 1H), 7.04 (t, J = 7.0 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 7.27-7.32 (m, 2H) ppm;
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13C{1H} NMR (CDCl3, 100 MHz), δ 8.7, 14.2, 27.6, 38.4, 62.0, 66.7, 94.4, 116.0, 123.4, 128.8,
150.1, 170.3, 173.5 ppm; HRMS (ESI) m/z: [M + Na]+ Calcd for C15H19NNaO5 316.1155; found
316.1168.
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3-ethyl 4,5-dimethyl 2-phenylisoxazolidine-3,4,5-tricarboxylate (4w). Yellow oil (99% isolated
yield, 33.4 mg), {lit.24: 98% yield}, 1H NMR (CDCl3, 400 MHz), δ 1.31 (t, J = 7.1 Hz, 3H), 3.52
(s, 3H), 3.68 (s, 3H), 4.26-4.33 (m, 2H), 4.33 (d, J = 7.1 Hz, 1H), 4.79 (d, J = 6.9 Hz, 1H), 5.01 (d,
J = 7.4 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.27 (t, J = 7.6 Hz, 2H) ppm.
3-ethyl 4,5-dimethyl 2-phenylisoxazolidine-3,4,5-tricarboxylate (4x). Yellow oil (96% isolated
yield, 32.5 mg), {lit.24: 90% yield, dr = 20:1}, 1H NMR (CDCl3, 400 MHz), δ 1.32 (t, J = 7.1 Hz,
3H), 3.61 (s, 3H), 3.86 (s, 3H), 4.28 (td, J = 7.2, 2.7 Hz, 2H), 4.34 (dd, J = 5.0, 3.9 Hz, 1H), 4.82
(d, J = 3.4 Hz, 1H), 5.13 (d, J = 5.4 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H),
7.30 (t, J = 7.8 Hz, 2H) ppm.
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Triethyl 2-phenylisoxazolidine-3,4,5-tricarboxylate (4y). Yellow oil (99% isolated yield, 36.2
mg), {lit.24: 77% yield, dr = 20:1}, 1H NMR (CDCl3, 400 MHz), δ 1.03 (t, J = 7.1 Hz, 3H), 1.18 (t,
J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 3.80-3.99 (m, 2H), 4.10 (dd, J = 7.1, 2.5 Hz, 2H),
4.26-4.37 (m, 3H), 4.78 (d, J = 7.2 Hz, 1H), 4.97 (d, J = 7.4 Hz, 1H), 6.97 (t, J = 7.3 Hz, 1H), 7.14
(d, J = 7.8 Hz, 2H), 7.24-7.29 (m, 2H) ppm.
Ethyl
4,6-dioxo-2,5-diphenylhexahydro-2H-pyrrolo[3,4-d]isoxazole-3-carboxylate
(4z).
Colourless oil (81% isolated yield, 29.7 mg), {lit.22c: 91% yield, dr = 95:5}, 1H NMR (CDCl3, 400
MHz), δ 1.30 (t, J = 7.1 Hz, 3H), 4.23-4.35 (m, 2H), 4.40 (dd, J = 7.6, 0.6 Hz, 1H), 5.16 (d, J =
7.7 Hz, 1H), 5.25 (s, 1H), 6.52-6.54 (m, 1H), 6.54 (d, J = 2.2 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H),
7.13 (dd, J = 8.6, 0.8 Hz, 2H), 7.25 (d, J = 2.6 Hz, 1H), 7.27 (d, J =1.3 Hz, 1H), 7.29-7.30 (m, 1H),
7.31 (d, J = 2.2 Hz, 2H) ppm.
Ethyl 5-phenyl-2-(o-tolyl)isoxazolidine-3-carboxylate (4aa). Yellow oil (67% yield, 20.1 mg, dr
= 71:29), 1H NMR (CDCl3, 400 MHz), δ 1.18 (t, J = 7.1 Hz, 3H), 2.35 (s, 3H), 2.64-2.71 (m, 1H),
3.01-3.09 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.38 (dd, J = 9.0, 4.3 Hz, 1H), 5.35 (t, J = 7.8 Hz, 1H),
7.00-7.05 (m, 1H), 7.14-7.19 (m, 2H), 7.30-7.40 (m, 4H), 7.52 (d, J = 7.2 Hz, 2H) ppm; 13C{1H}
NMR (CDCl3, 100 MHz), δ 14.0, 18.4, 40.3, 61.4, 67.3, 79.3, 119.2, 125.2, 126.3, 126.7, 126.97,
128.2, 128.5, 128.6, 130.8, 131.2, 138.9, 148.1, 170.8 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for
C19H22NO3 312.1594; found 312.1607.
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Ethyl 5-phenyl-2-(m-tolyl)isoxazolidine-3-carboxylate (4ab). Yellow oil (79% yield, 24.6 mg,
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dr = 81:19), H NMR (CDCl3, 600 MHz), δ 1.34 (t, J = 7.1 Hz, 3H), 2.35 (s, 3H), 2.71-2.76 (m,
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1H), 2.88-2.94 (m, 1H), 4.29-4.34 (m, 2H), 4.51 (dd, J = 8.9, 5.8 Hz, 1H), 5.05 (dd, J = 9.5, 6.8
Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.94-6.98 (m, 2H), 7.20 (t, J = 7.7 Hz, 1H), 7.33-7.37 (m, 1H),
7.38-7.41 (m, 2H), 7.49 (d, J = 7.1 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 150 MHz), δ 17.1, 24.6,
44.2, 64.7, 71.4, 83.0, 114.2, 117.7, 125.8, 129.9, 131.4, 131.5, 131.9, 140.4, 141.9, 154.1, 174.5
ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C19H22NO3 312.1594; found 312.1596.
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Ethyl 5-phenyl-2-(p-tolyl)isoxazolidine-3-carboxylate (4ac). Yellow oil (84% yield, 26.2 mg, dr
= 87:13), 1H NMR (CDCl3, 600 MHz), δ 1.34 (t, J = 7.1 Hz, 3H), 2.31 (s, 3H), 2.70-2.76 (m, 1H),
2.87-2.93 (m, 1H), 4.29 (qd, J = 7.1, 0.5 Hz, 2H), 4.48 (dd, J = 8.9, 5.7 Hz, 1H), 5.05 (dd, J = 9.4,
6.9 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.37-7.41
(m, 2H), 7.48 (d, J = 7.1 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 150 MHz), δ 17.1, 23.5, 44.1, 64.7,
71.7, 82.9, 117.2, 130.0, 131.4, 131.5, 132.6, 134.5, 140.4, 151.8, 174.5 ppm; HRMS (ESI) m/z:
[M + H]+ Calcd for C19H22NO3 312.1594; found 312.1600.
Ethyl 2-(2-chlorophenyl)-5-phenylisoxazolidine-3-carboxylate (4ad). Yellow oil (74% yield,
24.6 mg, dr = 75:25), 1H NMR (CDCl3, 600 MHz), δ 1.21 (t, J = 7.1 Hz, 3H), 2.62-2.68 (m, 1H),
2.85 (qd, J = 6.0, 1.4 Hz, 1H), 4.16-4.24 (m, 2H), 4.63 (dd, J = 8.6, 1.3 Hz, 1H), 5.44 (dd, J = 10.0,
5.9 Hz, 1H), 7.01 (td, J = 7.7, 1.6 Hz, 2H), 7.33-7.37 (m, 2H), 7.39-7.42 (m, 2H), 7.47-7.50 (m,
2H), 7.54 (dd, J = 8.2, 1.6 Hz, 1H) ppm; 13C{1H} NMR (CDCl3, 150 MHz), δ 16.9, 43.1, 64.3,
70.3, 82.3, 122.8, 127.0, 127.9, 129.7, 130.1, 131.4, 132.9, 141.4, 149.9, 173.7 ppm; HRMS (ESI)
m/z: [M + H]+ Calcd for C18H19ClNO3 332.1048; found 332.1053.
Ethyl 2-(3-chlorophenyl)-5-phenylisoxazolidine-3-carboxylate (4ae). Yellow oil (91% yield,
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30.1 mg), H NMR (CDCl3, 400 MHz), δ 1.34 (t, J = 7.1 Hz, 3H), 2.72-2.80 (m, 1H), 2.87-2.97
(m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.45 (dd, J = 8.7, 6.1 Hz, 1H), 5.02 (dd, J = 9.5, 6.7 Hz, 1H),
6.95-7.01 (m, 2H), 7.14-7.19 (m, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.34-7.42 (m, 3H), 7.48 (d, J = 7.2
Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 41.2, 62.0, 68.4, 80.5, 112.3, 114.2,
122.0, 127.1, 128.7, 130.3, 135.0, 136.9, 152.5, 171.1 ppm; HRMS (ESI) m/z: [M + Na]+ Calcd
for C18H18ClNNaO3 354.0867; found 354.0865.
Ethyl 2-(4-chlorophenyl)-5-phenylisoxazolidine-3-carboxylate (4af). Yellow oil (99% yield,
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32.8 mg), H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz, 3H), 2.71-2.79 (m, 1H), 2.87-2.97
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(m, 1H), 4.28 (q, J = 7.0 Hz, 2H), 4.43 (dd, J = 8.7, 6.1 Hz, 1H), 5.01 (dd, J = 9.4, 6.8 Hz, 1H),
7.07 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.35-7.42 (m, 3H), 7.47 (d, J = 7.4 Hz, 2H) ppm;
13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 41.3, 62.0, 68.6, 80.3, 115.5, 127.1, 128.7, 128.7, 128.7,
129.1, 137.0, 149.8, 171.1 ppm; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H18ClNNaO3
354.0867; found 354.0868.
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Ethyl 5-phenyl-2-(pyridin-2-yl)isoxazolidine-3-carboxylate (4ag). Yellow oil (86% yield, 25.7
1
mg), H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz, 3H), 2.64-2.72 (m, 1H), 2.88-2.96 (m,
1H), 4.28 (q, J = 7.1 Hz, 2H), 4.86 (dd, J = 9.0, 7.4 Hz, 1H), 5.57 (d, J = 5.2 Hz, 1H), 6.89 (ddd, J
= 7.2, 4.9, 0.9 Hz, 1H), 7.31-7.36 (m, 2H), 7.36-7.41 (m, 2H), 7.44-7.48 (m, 2H), 7.60-7.64 (m,
1H), 8.27 ( dq, J = 4.9, 0.8 Hz, 1H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 40.6, 61.7,
63.0, 81.8, 109.9, 117.7, 127.1, 128.6, 128.7, 137.4, 138.2, 147.6, 161.4, 172.0 ppm; HRMS (ESI)
m/z: [M + H]+ Calcd for C17H19N2O3 299.1390; found 299.1390.
Ethyl 2-(6-methylpyridin-2-yl)-5-phenylisoxazolidine-3-carboxylate (4ah). Yellow oil (90%
1
yield, 28.1 mg), H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz, 3H), 2.45 (s, 3H), 2.60-2.67
(m, 1H), 2.85-2.94 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.88 (t, J = 8.1 Hz, 1H), 5.65 (d, J = 5.0 Hz,
1H), 6.74 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.30-7.40 (m, 3H), 7.42-7.48 (m, 2H), 7.50
(t, J = 7.7 Hz, 1H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.2, 24.3, 40.7, 61.5, 62.9, 80.8,
106.7, 117.1, 127.0, 128.5, 128.6, 137.7, 138.3, 156.6, 160.8, 172.3 ppm; HRMS (ESI) m/z: [M +
H]+ Calcd for C18H21N2O3 313.1547; found 313.1547.
Ethyl 2-(3,4-dimethylphenyl)-5-phenylisoxazolidine-3-carboxylate (4ai). Yellow oil (82%
yield, 26.7 mg), 1H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.2 Hz, 3H), 2.21 (s, 3H), 2.25 (s, 3H),
2.68-2.76 (m, 1H), 2.85-2.93 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.48 (dd, J = 8.9, 5.7 Hz, 1H),
5.05 (dd, J = 9.2, 7.0 Hz, 1H), 6.88 (dd, J = 8.2, 2.4 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 7.05 (d, J =
8.2 Hz, 1H), 7.33-7.41 (m, 3H), 7.48 (d, J = 6.9 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz),
δ 14.2, 18.9, 20.1, 41.2, 61.7, 80.0, 111.7, 115.7, 127.1, 128.5, 128.6, 130.2, 130.3, 137.4, 137.6,
149.2, 171.6 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C20H24NO3 326.1751; found 326.1753.
Ethyl 2-(3,5-dichlorophenyl)-5-phenylisoxazolidine-3-carboxylate (4aj). Yellow oil (87% yield,
1
31.8 mg), H NMR (CDCl3, 400 MHz), δ 1.33 (t, J = 7.1 Hz, 3H), 2.73-2.81 (m, 1H), 2.91-2.99
(m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.40 (dd, J = 8.8, 6.2 Hz, 1H), 4.99 (dd, J = 9.7, 6.5 Hz, 1H),
6.95-6.98 (m, 1H), 7.02 (d, J = 1.8 Hz, 2H), 7.36-7.43 (m, 3H), 7.46-7.50 (m, 2H) ppm; 13C{1H}
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NMR (CDCl3, 100 MHz), δ 14.1, 41.2, 62.1, 68.0, 80.7, 112.5, 113.4, 121.7, 127.0, 128.7, 135.6,
136.4, 153.0, 170.5 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C18H18Cl2NO3 366.0658; found
366.0669.
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Methyl 2,5-diphenylisoxazolidine-3-carboxylate (4ak). Yellow oil (95% yield, 27.0 mg, dr =
97:3), 1H NMR (CDCl3, 400 MHz), δ 2.73-2.81 (m, 1H), 2.88-2.96 (m, 1H), 3.86 (s, 3H), 4.53 (dd,
J = 8.9, 5.9 Hz, 1H), 5.04 (dd, J = 9.5, 6.8 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 7.1 (d, J = 7.8 Hz,
2H), 7.29-7.36 (m, 3H), 7.36-7.42 (m, 2H), 7.48 (d, J = 6.9 Hz, 2H) ppm; 13C{1H} NMR (CDCl3,
100 MHz), δ 41.1, 52.9, 68.5, 80.2, 114.1, 122.2, 127.1, 128.7, 129.2, 137.1, 151.1, 172.1 ppm;
HRMS (ESI) m/z: [M + H]+ Calcd for C17H18NO3 284.1281; found 284.1288.
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Tert-butyl 2,5-diphenylisoxazolidine-3-carboxylate (4al). Yellow solid (94% yield, 30.6 mg);
o
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mp 77-78 C; HNMR (CDCl3, 400 MHz), δ 1.51 (s, 9H), 2.66-2.74 (m, 1H), 2.83-2.91 (m, 1H),
4.40 (t, J = 7.6 Hz, 1H), 5.04 (t, J = 8.2 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H),
7.24-7.33 (m, 2H), 7.34-7.45 (m, 3H), 7.50 (d, J = 7.4 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100
MHz), δ 28.0, 41.3, 69.3, 80.1, 82.1, 114.1, 121.8, 127.1, 128.6, 129.1, 137.6, 151.4, 170.5 ppm;
HRMS (ESI) m/z: [M + H]+ Calcd for C20H24NO3 326.1751; found 326.1744.
(2,5-diphenylisoxazolidin-3-yl)(phenyl)methanone (4am). White solid (67% yield, 22.1 mg, dr
o
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= 89:11); mp 178-180 C; H NMR (CDCl3, 400 MHz), δ 2.84-3.99 (m, 2H), 5.11 (t, J = 7.5 Hz,
1H), 5.20 (dd, J = 8.5, 6.0 Hz, 1H), 7.01-7.05 (m, 1H), 7.16 (d, J = 8.6 Hz, 2H), 7.31-7.40 (m, 5H),
7.45-7.50 (m, 4H), 7.55-7.60 (m, 1H), 8.17 (d, J = 8.4 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100
MHz), δ 40.6, 71.8, 80.3, 114.2, 122.2, 127.1, 128.6, 128.6, 129.2, 129.3, 133.4, 134.9, 137.2,
150.8, 196.9 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C22H20NO2 330.1489; found 330.1478.
Ethyl 5-formyl-5-methyl-2-phenylisoxazolidine-3-carboxylate (4an). Yellow oil (87% yield,
22.9 mg), 1H NMR (CDCl3, 400 MHz), δ 1.14 (t, J = 7.1 Hz, 3H), 1.51 (s, 3H), 2.39 (dd, J = 12.8,
4.1 Hz, 1H), 3.05 (dd, J = 12.8, 9.0 Hz, 1H), 4.09 (qd, J = 7.1, 2.9 Hz, 2H), 4.47 (dd, J = 9.0, 4.2
Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 8.1 Hz, 2H), 7.25-7.30 (m, 2H), 9.56 (s, 1H) ppm;
13C{1H} NMR (CDCl3, 100 MHz), δ 13.9, 18.2, 38.9, 61.4, 64.9, 86.6, 115.0, 122.4, 128.8, 148.1,
170.4, 201.4 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C14H18NO4 264.1230; found 264.1233.
3-ethyl 5-methyl 5-methyl-2-phenylisoxazolidine-3,5-dicarboxylate (4ao). Yellow oil (90%
yield, 26.4 mg), 1H NMR (CDCl3, 400 MHz), δ 1.24 (t, J = 7.1 Hz, 3H), 1.67 (s, 3H), 2.52 (dd, J =
12.6, 6.2 Hz, 1H), 3.25 (dd, J = 12.7, 8.6 Hz, 1H), 3.52 (s, 3H), 4.18-4.24 (m, 2H), 4.49 (dd, J =
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8.6, 6.2 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 7.8 Hz, 2H), 7.22 (dd, J = 8.6, 7.4 Hz, 2H)
ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 14.1, 22.0, 42.0, 52.4, 61.7, 66.4, 83.4, 114.3, 122.0,
128.6, 149.8, 171.0, 173.1 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C15H20NO5 294.1336;
found 294.1334.
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Diethyl 5-methyl-2-phenylisoxazolidine-3,5-dicarboxylate (4ap). Yellow oil (88% yield, 27.0
mg), 1H NMR (CDCl3, 400 MHz), δ 1.07 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.66 (s, 3H),
2.52 (dd, J = 12.6, 6.6 Hz, 1H), 3.23 (dd, J = 12.7, 8.5 Hz, 1H), 3.91 (q, J = 7.2 Hz, 2H), 4.20 (q, J
= 7.2 Hz, 2H), 4.47 (dd, J = 8.3, 6.7 Hz, 1H), 6.92 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 7.8 Hz, 2H),
7.21 (dd, J = 8.4, 7.4 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 13.6, 14.1, 21.9, 42.1,
61.5, 61.7, 66.5, 83.5, 114.2, 121.7, 128.5, 150.1, 171.0, 172.5 ppm; HRMS (ESI) m/z: [M + H]+
Calcd for C16H22NO5 308.1492; found 308.1497.
Diethyl 2,5-diphenylisoxazolidine-3,5-dicarboxylate (4aq). Yellow oil (86% yield, 31.8 mg, dr
= 95:5), 1H NMR (CDCl3, 400 MHz), δ 1.00 (t, J = 7.2 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H), 2.75 (dd,
J = 12.5, 6.3 Hz, 1H), 3.61 (dd, J = 12.5, 8.4 Hz, 1H), 3.88 (q, J = 7.1 Hz, 2H), 4.01 (q, J = 7.1 Hz,
2H), 4.45 (dd, J = 8.4, 6.3 Hz, 1H), 6.89 (t, J = 7.3 Hz, 1H), 7.06 (d, J = 7.7 Hz, 2H), 7.18-7.22 (m,
2H), 7.25-7.32 (m, 3H), 7.45-7.49 (m, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 13.7, 13.9,
43.4, 61.6, 61.9, 66.2, 87.2, 114.7, 122.1, 125.3, 128.3, 128.4, 128.6, 137.8, 149.6, 170.5, 171.6
ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C21H24NO5 370.1649; found 370.1645.
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Ethyl 2,5,5-triphenylisoxazolidine-3-carboxylate (4ar). Yellow oil (84% yield, 31.4 mg), H
NMR (CDCl3, 400 MHz):δ 1.07 (t, J = 7.2 Hz, 3H), 3.30-3.43 (m, 2H), 3.98 (q, J = 7.2 Hz, 2H),
4.35 (dd, J = 8.8, 4.8 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 7.19-7.32 (m, 8H),
7.43 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz): δ 13.9,
45.1, 61.5, 67.1, 87.4, 114.9, 121.7, 126.2, 126.4, 127.4, 127.6, 128.2, 128.3, 128.6, 143.0, 143.2,
150.2, 170.9 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C24H24NO3 374.1751; found 374.1742.
1-phenyltetrahydro-3H,6H-furo[3,4-c]isoxazol-6-one (7). White solid (83% yield, 17.1 mg); mp
162-164 oC; 1H NMR (C2D6OS(D-DMSO), 400 MHz), δ 3.46-3.54 (m, 1H), 3.91 (dd, J = 8.8, 7.5
Hz, 1H), 4.08 (dd, J = 8.9, 2.2 Hz, 1H), 4.33 (dd, J = 9.4, 2.9 Hz, 1H), 4.47 (dd, J = 9.2, 7.7 Hz,
1H), 5.00 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 7.06 (dd, J = 8.6, 0.9 Hz, 2H), 7.30 (dd, J =
8.7, 7.2 Hz, 1H) ppm; 13C{1H} NMR (C2D6OS(D-DMSO), 100 MHz), δ 42.2, 67.1, 71.6, 72.5,
114.4, 122.4, 129.1, 149.3, 174.6 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C11H12NO3
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206.0812; found 206.0809.
5-methyl-1-phenylhexahydro-6H-pyrrolo[3,4-c]isoxazol-6-one (9). White solid (81% yield,
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9
o
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17.7 mg); mp 114-116 C; H NMR (CDCl3, 400 MHz), δ 2.91 (s, 3H), 3.25-3.31 (m, 1H), 3.31
(dd, J = 10.2, 2.4 Hz, 1H), 3.62 (dd, J = 10.1, 8.3 Hz, 1H), 3.90 (dd, J = 8.6, 1.8 Hz, 1H), 4.05 (dd,
J = 8.8, 6.6 Hz, 1H), 4.42 (d, J = 8.5 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.16 (dd, J = 8.5, 0.8 Hz,
2H), 7.28-7.30 (m, 2H) ppm; 13C{1H} NMR (CDCl3, 100 MHz), δ 30.0, 39.4, 53.3, 70.7, 73.0,
114.6, 122.3, 129.0, 150.3, 170.3 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C12H15N2O2
219.1128; found 219.1132.
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■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1039/x0xx00000x
1H NMR spectra of the nitrone intermediate 10a, and copies of NMR spectra for all compounds
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: lixing@tyut.edu.cn
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We appreciate gratefully the Natural Science Foundation of Shanxi Province (No. 201601D011028) for
financial support.
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Cycloadditions of 1,2-Cyclohexadiene. J. Am. Chem. Soc. 2016, 138, 2512.
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Isoxazolidines via Nitroso Aldol Reaction of Distal Dialdehydes. Org. Lett. 2018, 20, 1023. b) Xie, J.; Xue, Q.; Jin,
H.; Li, H.; Cheng, Y.; Zhu, C. A Visible-light-promoted Aerobic C–H/C–N Cleavage Cascade to Isoxazolidine
Skeletons. Chem. Sci. 2013, 4, 1281. c) Kang, J. Y.; Bugarin, A.; Connell, B. T. Conversion of Nitrosobenzenes to
Isoxazolidines: an Efficient Cascade Process Utilizing Reactive Nitrone Intermediates. Chem. Commun. 2008,
3522. d) Yin, Z.; Zhang, J.; Wu, J.; Liu, C.; Sioson, K.; Devany, M.; Hu, C.; Zheng, S. Double Hetero-Michael
Addition of N-Substituted Hydroxylamines to Quinone Monoketals: Synthesis of Bridged Isoxazolidines. Org. Lett.
2013, 15, 3534. e) Yao, T.; Ren, B.; Wang, B.; Zhao, Y. Highly Selective Synthesis of Dihydrobenzo[d]isoxazoles
and Dihydrobenzo[d]oxazoles from Oximes and Arynes via in Situ Generation of Nitrones. Org. Lett. 2017, 19,
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(16) Reviews on 1,3-dipolar cycloadditions: a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Heterocycles
from Alkylidenecyclopropanes. Chem. Rev. 2003, 103, 1213. b) Stanley, L. M.; Sibi, M. P. Enantioselective
Copper-Catalyzed 1,3-Dipolar Cycloadditions. Chem. Rev. 2008, 108, 2887. c) Gothelf, K. V; Jørgensen, K. A.
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Asymmetric 1,3-Dipolar Cycloaddition Reactions. Chem. Rev. 1998, 98, 863. d) Appukkuttan, P.; Mehtaa, V. P.;
der Eycken, E. V. V. Microwave-Assisted Cycloaddition Reactions. Chem. Soc. Rev. 2010, 39, 1467.
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(17) Selected examples: a) Kano, T.; Hashimoto, T.; Maruoka, K. Asymmetric 1,3-Dipolar Cycloaddition
Reaction of Nitrones and Acrolein with a Bis-Titanium Catalyst as Chiral Lewis Acid. J. Am. Chem. Soc. 2005,
127, 11926. b) Carmona, D.; Lamata, M. P.; Viguri, F.; RodrÍguez, R.; Oro, L. A.; Lahoz, F. J.; Balana, A. I.;
Tejero, T.; Merino, P. Enantioselective 1,3-Dipolar Cycloaddition of Nitrones to Methacrolein Catalyzed by
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(η5-C5Me5)M{(R)-Prophos}
Containing
Complexes
(M
=
Rh,
Ir;
(R)-Prophos
=
1,2-bis(Diphenylphosphino)propane): On the Origin of the Enantioselectivity. J. Am. Chem. Soc. 2005, 127, 13386.
c) Wang, X.; Weigl, C.; Doyle, M. P. Solvent Enhancement of Reaction Selectivity: a Unique Property of Cationic
Chiral Dirhodium Carboxamidates. J. Am. Chem. Soc. 2011, 133, 9572. d) Palomo, C.; Oiarbide, M.; Arceo, E.;
García, J. M.; López, R.; González. A.; Linden, A. Lewis Acid Catalyzed Asymmetric Cycloadditions of Nitrones:
α′-Hydroxy Enones as Efficient Reaction Partners. Angew. Chem., Int. Ed. 2005, 44, 6187. e) Yang, X.; Cheng, F.;
Kou, Y.-D.; Pang, S.; Shen, Y.-C.; Huang, Y.-Y.; Shibata, N. Catalytic Asymmetric 1,3-Dipolar Cycloaddition of
β-Fluoroalkylated α,β-Unsaturated 2-Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and
γ-Amino Alcohols. Angew. Chem., Int. Ed. 2017, 56, 1510.
(18) Selected examples: a) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. New Strategies for Organic
Catalysis: The First Enantioselective Organocatalytic 1,3-Dipolar Cycloaddition. J. Am. Chem. Soc. 2000, 122,
9874. b) Shen, Z.-L.; Goh, K. K. K.; Wong, C. H. A.; Loo, W.-Y.; Yang, Y.-S.; Lu, J.; Loh, T.-P. Synthesis and
Application of a Recyclable Ionic Liquid-Supported Imidazolidinone Catalyst in Enantioselective 1,3-Dipolar
Cycloaddition. Chem. Commun. 2012, 48, 5856. c) Atienza, R. L.; Roth, H. S.; Scheidt, K. A. N-Heterocyclic
Carbene-Catalyzed Rearrangements of Vinyl Sulfones. Chem. Sci. 2011, 2, 1772. d) Zheng, L.; Gao, F.; Yang, C.;
Gao, G.-L.; Zhao, Y.; Gao, Y.; Xia, W. Visible-Light-Mediated Anti-Regioselective Nitrone 1,3-Dipolar
Cycloaddition Reaction and Synthesis of Bisindolylmethanes. Org. Lett. 2017, 19, 5086. e) Hoogenboom, J.;
Zuilhof, H.; Wennekes, T. Versatile Scope of a Masked Aldehyde Nitrone in 1,3-Dipolar Cycloadditions. Org. Lett.
2015, 17, 5550.
(19) Selected examples: a) Chatterjee, A.; Maiti, D. K.; Bhattacharya, P. K. Water Exclusion Reaction in
Aqueous Media: Nitrone Formation and Cycloaddition in a Single Pot. Org. Lett. 2003, 5, 3967. b) Rios, R.;
Ibrahem, I.; Vesely, J.; Zhao, G.-L.; Córdova, A. A Simple One-Pot, Three-Component, Catalytic, Highly
Enantioselective Isoxazolidine Synthesis. Tetrahedron Lett. 2007, 48, 5701. c) Vesely, J.; Rios, R.; Ibrahem, I.;
Zhao, G.-L.; Eriksson, L.; Córdova, A. One-Pot Catalytic Asymmetric Cascade Synthesis of Cycloheptane
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Derivatives. Chem. - Eur. J. 2008, 14, 2693. d) Chua, P. J.; Tan, B.; Yang, L.; Zeng, X.; Zhu, D.; Zhong, G.
Highly Stereoselective Synthesis of Indanes with Four Stereogenic Centers via Sequential Michael Reaction and
[3+2] Cycloaddition. Chem. Commun. 2010, 46, 7611. e) Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.;
Zhong, G. Water—More Than Just a Green Solvent: A Stereoselective One-Pot Access to All-Chiral
Tetrahydronaphthalenes in Aqueous Media. Chem. - Eur. J. 2010, 16, 3842. f) Zhu, D.; Lu, M.; Dai, L.; Zhong, G.
Highly Stereoselective One-Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an
Organocatalytic Process. Angew. Chem., Int. Ed. 2009, 48, 6089.
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(20) a) Wu, M.-Y.; He, W.-W.; Liu, X.-Y.; Tan, B. Asymmetric Construction of Spirooxindoles by
Organocatalytic Multicomponent Reactions Using Diazooxindoles. Angew. Chem., Int. Ed. 2015, 54, 9409. b)
Molander, G. A.; Cavalcanti, L. N. Synthesis of Trifluoromethylated Isoxazolidines: 1,3-Dipolar Cycloaddition of
Nitrosoarenes, (Trifluoromethyl)diazomethane, and Alkenes. Org. Lett. 2013, 15, 3166.
(21) a) Chen, H.; Wang, Z.; Zhang, Y.; Huang, Y.; Highly trans-Stereoselective Synthesis of Bicyclic
Isoxazolidines via Copper-Catalyzed Triple Cascade Catalysis. J. Org. Chem. 2013, 78, 3503. b) Kawade, R. K.;
Liu, R.-S. Copper-Catalyzed Three-Component Annulations of Alkenes, Nitrosoarenes, and
N-Hydroxyallylamines To Form Fused Oxazinane/Isoxazolidine Heterocycles. Angew. Chem., Int. Ed. 2017, 56,
2035. c) Sharma, P.; Jadhav, P. D.; Skaria, M.; Liu, R.-S. Stereoselective Annulation between An Allene, An
Alkene, and Two Nitrosoarenes to Access Bis(isoxazoliodine) Derivatives. Org. Biomol. Chem. 2017, 15, 9389.
(22) a) Xu, H.-W.; Li, G.-Y.; Wong, M.-K.; Che, C.-M. Asymmetric Synthesis of Multifunctionalized Pyrrolines
by a Ruthenium Porphyrin-Catalyzed Three-Component Coupling Reaction. Org. Lett. 2005, 7, 5349. b) Li, G.-Y.;
Chen, J.; Yu, W.-Y.; Hong, W.; Che, C.-M. Stereoselective Synthesis of Functionalized Pyrrolidines by
Ruthenium Porphyrin-Catalyzed Decomposition of α-Diazo Esters and Cascade Azomethine Ylide
Formation/1,3-Dipolar Cycloaddition Reactions. Org. Lett. 2003, 5, 2153. c) Reddy, A. R.; Guo, Z.; Siu, F.-M.;
Lok, C.-N.; Liu, F.; Yeung, K.-C.; Zhou, C.-Y.; Che, C.-M. Diastereoselective Ruthenium Porphyrin-catalyzed
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in Vitro Biological Activities. Org. Biomol. Chem. 2012, 10, 9165.
(23) Pagar, V. V.; Liu, R.-S. Gold-Catalyzed Cycloaddition Reactions of Ethyl Diazoacetate, Nitrosoarenes, and
Vinyldiazo Carbonyl Compounds: Synthesis of Isoxazolidine and Benzo[b]azepine Derivatives. Angew. Chem., Int.
Ed. 2015, 54, 4923.
(24) Xu, Z.-J.; Zhu, D.; Zeng, X.; Wang, F.; Tan, B.; Hou, Y.; Lv, Y.; Zhong, G. Diastereoselective
HOTf-Catalyzed Three-component One-pot 1,3-Dipolar Cycloaddition of α-Diazo Ester, Nitrosobenzene and
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(25) The corresponding active nitrone intermediate 10a was determined by 1H-NMR and HRMS (See
Supporting Information).
9
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Diazomethane. A New Group of Nitrones. J. Chem. Soc. (C) 1969, 7, 1073.
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