Acyclic nitronate olefin cycloaddition (ANOC): regio- And stereospecific synthesis of isoxazolines

Article abstract of DOI:10.1039/d0sc05607c

We report the first demonstrations of intra- and intermolecular acyclic nitronate olefin cycloaddition (ANOC) reactions that enable the highly efficient syntheses of isoxazolines bearing various functional groups. This general approach to accessing γ-lactone fused isoxazolines was hitherto unprecedented. The room temperature transformations reported herein exhibit wide substrate scopes, as evidenced by more than 70 examples, including the generation of five tricyclic isoxazolines. The robustness of this methodology was confirmed by a series of trials that afforded highly functionalized isoxazolines. Both experimental results and density functional theory calculations indicate that these transformations proceed via the in situ formation of acyclic nitronates together with concerted [3+2] cycloaddition and tert-butyloxy group elimination processes to give regio- and stereospecificity. This journal is

Full text of DOI:10.1039/d0sc05607c

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Acyclic Nitronates Olefins Cycloaddition (ANOC): Regio- and
Stereo-specific Synthesis of Isoxazolines
Liang Ma, Luyao Kou, Feng Jin, Xionglve Cheng, Suyan Tao, Gangzhong Jiang, Xiaoguang Bao,*
Xiaobing Wan*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We report the first demonstrations of intra- and intermolecular acyclic nitronate olefin cycloaddition (ANOC) reactions that
enable the highly efficient syntheses of isoxazolines bearing various functional groups. This general approach to accessing
γ-lactone fused isoxazolines was hitherto unprecedented. The room temperature transformations reported herein exhibit
wide substrate scopes, as evidenced by more than 70 examples, including the generation of five tricyclic isoxazolines. The
robustness of this methodology was confirmed by a series of trials that afforded highly functionalized isoxazolines. Both
experimental results and density functional theory calculations indicate that these transformations proceed via the in situ
formation of acyclic nitronates together with concerted [3+2] cycloaddition and tert-butyloxy group elimination processes
to give regio- and stereo-specificity.
mechanisms suffer from various drawbacks, including the need
for stoichiometric quantities of toxic reagents, harsh reaction
conditions, labor-intensive procedures and undesired side
Introduction
Fused bicyclic isoxazolines are present in many natural products
and biologically relevant molecules,1 and can also serve as
versatile intermediates in synthetic chemistry.2 Intramolecular
nitrile oxide olefin cycloaddition (INOC) provides a classical
route to the synthesis of these bicyclic moieties,3 especially
those found in biologically important molecules.4 Silyl
nitronates can serve as synthetic equivalents of nitrile oxides in
1,3-dipolar cycloadditions with olefins. Thus, intramolecular
silyl nitronate olefin cycloaddition (ISOC) has emerged as a
powerful alternative to INOC for the syntheses of isoxazoline-
fused bicycles.5 A representative process is shown in Scheme
1a. Here, a Michael addition provides nitro compound A, having
a tethered alkene moiety. The in situ conversion of A to nitrile
oxide B with a stoichiometric amount of a dehydrating reagent
(PhNCO/Et3N or (Boc)2O/4-dimethylaminopyridine) is followed
by 1,3-dipolar cycloaddition to give the desired fused bicyclic
isoxazoline compound (representing the INOC process).
Alternatively, the reaction of A with TMSCl and Et3N affords silyl
nitronate C, which undergoes [3+2] cycloaddition and the
subsequent elimination of a silyloxy group in the presence of
TBAF or acid to form a fused bicyclic isoxazoline (the ISOC
process). The ISOC process typically provides better regio- and
stereo-selectivities than the INOC process as a result of the
near-linear geometry of nitrile oxides. However, both
reactions.6
(a) classical route
+
NO2
XH
N
O
X
Michael addition
nt
reage
INOC
B, nitrile oxide
rating
N
Dehyd
NO2
X
O
X
O
X
OTMS
TMSCl,
N
ISOC
A
Et
TMSOH
3
N
C, silyl nitronate
(b) this work: intramolecular acyclic nitronates olefins cycloaddition
[3+2]
cycloaddition
O
OtBu
O
O
TBN
O
O
N
N
N
N2
OtBu
X
O
X
O
X
X
tBuOH
F, nitroso acetal
D
E, acyclic nitronate
Scheme 1 Synthesis of isoxazoline fused bicyclic compounds.
Fused bicyclic isoxazolines are highly important, especially
because of their unique functionalities, and so it would be
beneficial to devise creative yet practical strategies for the
construction of a new library of such compounds. In the present
work, we developed a novel methodology for this purpose, as
shown in Scheme 1b. This new approach consists of a coupling
reaction between diazo compound D bearing a tethered alkene
and tert-butyl nitrite to give an acyclic nitronate, E. The
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
China. E-mail: xgbao@suda.edu.cn, wanxb@suda.edu.cn.
† Electronic Supplementary Information (ESI) available: [Experimental procedures,
spectroscopic data, and NMR spectra. CCDC 2011278, 2011280, 2011281 and
2021609]. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000
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subsequent intramolecular [3+2] cycloaddition of E provides
nitroso acetal F, after which the elimination of a tert-butyloxy Table 1 Optimization for Intramolecular Reaction
group generates the desired fused bicyclic isoxazoline.
Journal Name
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a
DOI: 10.1039/D0SC05607C
O
O
O
Denmark and coworkers developed an elegant strategy for
H
N2
catalyst
N
the rapid construction of polycyclic nitroso acetal systems
through the tandem [4+2]/[3+2] cycloaddition of nitroalkenes,
employing cyclic nitronates as key intermediates.7 In sharp
contrast, the synthetic utility of the analogous reactions of
acyclic nitronates has been seriously limited8 by a lack of
general methods for the preparation of these compounds and
by their low thermal stability. This thermal instability presented
several potentially severe challenges with regard to the goal of
the present research. Specifically, it was not certain that acyclic
nitronates could be readily obtained from the coupling of diazo
compounds and tert-butyl nitrite. In addition, it was uncertain
if these acyclic nitronates, after being generated in situ, would
be successfully intercepted by the olefins rather than
undergoing undesired side reactions.9 In addition, it was vital to
identify suitable conditions to promote elimination of the tert-
butyloxy group of the nitroso acetals so as to obtain the desired
fused bicyclic isoxazolines.
tBuONO
O
+
O
solvent, T
1
2
3
Entry
1
2
3
4
5
6
7
8
Catalyst
Cu(OAc)2·H2O
T (oC)
Solvent
Yield(%)b
80
80
80
80
80
80
25
25
25
25
25
25
25
25
25
25
25
25
25
toluene
toluene
toluene
MeCN
MeNO2
DMF
< 5c
< 5d
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
< 5
53
37
33
85
64
58
< 5
63
< 5
< 5
< 5
< 5
< 5
< 5
< 5
< 5
DMF
MeNO2
MeCN
toluene
DMSO
acetone
dioxane
DCE
9
10
11
12
13
14
15
16
17
18
19
Results and discussion
THF
NMP
Recently,
we
reported
the
Cu(OAc)2·H2O-catalyzed
EA
multicomponent reaction of diazo compounds, alkenes and
tert-butyl nitrite in the presence of DABCO to construct diverse
isoxazoline derivatives.10 However, using this approach, the γ-
lactone fused isoxazoline 3 (entry 1, Table 1) was not obtained
in any significant amount when diazo compound 1 (derived
from cinnamyl alcohol) was used as the substrate. Interestingly,
a moderate yield was achieved in MeCN in the absence of
Cu(OAc)2·H2O and DABCO (entry 4), indicating that different
mechanisms were involved in these two systems. In addition,
the data showed that lowering the temperature did not affect
the reaction. After extensive screenings, the optimized
conditions were determined to comprise the use of DMF as the
solvent under catalyst free conditions at room temperature,
which gave the trans-cycloadduct 3 in a high 85% yield (entry 7).
The use of solvents other than DMF inhibited the formation of
the desired product 3 (entries 8-19). Notably, no other
diastereomer was observed in this cycloaddition reaction,
indicating this intramolecular acyclic nitronate olefin
cycloaddition (ANOC) proceeded through a concerted process.
Both γ-lactones11 and isoxazolines1,2 are key
pharmacophores in many biologically active compounds, both
synthetic and naturally occurring, and can serve as versatile
synthons for organic chemistry. However, γ-lactone fused
isoxazolines remain an elusive subclass of heterobicycles
primarily as a result of the difficulty inherent in constructing this
framework.12 This has hindered the detailed study of the
potential biological activity and synthetic utility of such
compounds. Fortunately, the ANOC process reported herein
provide a general approach to accessing new γ-lactone fused
isoxazolines.
CHCl3
H2O
a Reaction conditions: : diazo compound 1 (0.2 mmol, 1.0 equiv),
tert-butyl nitrite 2 (0.6 mmol, 3.0 equiv) and solvent (2.0 mL) at
b
c
25 °C for 12 h unless otherwise noted. Isolated yields.
.
Cu(OAc)2 H2O (0.02 mmol, 10 mol%), DABCO (0.2 mmol, 1.0
equiv) were used. d DABCO (0.2 mmol, 1.0 equiv) was used.
With this goal in mind, we explored the substrate scope of
this new process, with the results summarized in Table 2. Diazo
compounds obtained from a variety of substituted cinnamyl
alcohol derivatives were employed in this transformation and
the desired fused bicyclic isoxazolines 4-15 were achieved in
moderate to excellent yields. The presence of both electron-
withdrawing (CN, CF3, F, Cl, Br, I) and electron-donating (MeS,
alkyl, ether) groups on the phenyl ring were well tolerated in
this intramolecular cycloaddition reaction. Notably, the
cycloadduct 16 was generated as the exclusive product among
four possible stereoisomers in a high 80% yield when the diazo
compound obtained from 4-phenyl-3-buten-2-ol was used as
the substrate. The relative stereo configuration of 16 was
confirmed by single crystal X-ray diffraction. Diazo compounds
derived from alkyl-substituted allyl alcohols were also
determined to be suitable substrates for this intramolecular
ANOC reaction, and gave the corresponding fused bicyclic
isoxazolines 17-25 in satisfactory yields. Notably, when we
attempted to use a diazo ketone in the reaction, the fused
bicyclic isoxazoline cyclopentanone 26 was obtained with
complete regio- and stereoselectivity. The phenyl group could
also be replaced with a furan ring in this ANOC process to
generate the corresponding cycloadduct 27 in a moderate yield.
2 | J. Name., 2012, 00, 1-3
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b
c
To further demonstrate the utility of this annular chemistry unless otherwise noted. For 24 h. Molecular structure of 6,
View Article Online
DOI: 10.1039/D0SC05607C
as a means of allowing the one-pot construction of a wide range 16, 29, 31 with ellipsoids at the 50% probability level.
of isoxazolines, we applied the optimized conditions to
The scalability of this novel methodology was demonstrated
generate diazo compounds bearing cyclic olefins. As by performing a gram-scale experiment (using 10 mmol of the
anticipated, a variety of tricyclic compounds (28-32) were substrate), in which the cycloadduct 12 was obtained in a high
obtained, each as a single stereoisomer, with regio- and stereo- 79% yield (Scheme 2). This product was subsequently
specificity and in good yields. The present methodology was derivatized to illustrate potential synthetic applications. These
found to allow the rapid construction of tricyclic heterocycles derivatizations including hydrolysis (33), esterification (34),
bearing three contiguous stereogenic centers starting from ammonolysis (35) and ring expansion (36) reactions, all of which
simple substrates. The exact structures of the fused tricyclic readily proceeded to give highly functionalized isoxazolines in
products 29 and 31 were further verified by X-ray high yields.
crystallography, which confirmed the stereochemistry at the
bridgehead carbon atoms in each.
O
O
N2
F
OH
10 mmol
O
Table 2 Scope of diazo compoundsa
OH
HO
F
OEt
N
O
O
F
TBN
N
O
O
X
34, yield: 91%
R2 R4
O
R4
R3
R2
R1
N
DMF
Et3
LiOH
2 O/THF,
33, yield: 94%
,
tBuONO
LiCl
N2
+
H
rt
R1
X
N
EtOH,
room temperature
R3
O
rt
O
O
N
O
OH
N
O
O
Ph
H
LiCl, Et3
N
1) NH2NH2
2) NaNO2
NH
bicyclic products
H
F
F
N
O
O
O
N
O
H
Br
H
N
F
O
Ph
NH2
O
O
O
O
H
H
12, 1.75g, yield: 79%
35, yield: 84%
NC
36, yield: 68%
N
O
N
O
O
4, 90%
6, 83%
5, 87%
Scheme 2 Synthetic utility.
O
N
O
O
N
O
O
O
H
O
O
H
H
H
O
Cl
Br
S
N
O
O
N
O
O
7, 97%
9, 78%
10, 89%
8, 67%
O
O
O
F
O
O
1.0 equiv. BHT
O
O
N
O
F3
C
H
N2
F
tBuONO
O
+
H
O
H
O
O
(a)
H
25 oC, DMF
F
N
N
Br
O
O
N
N
O
12, 84%
O
O
O
Br
1
2
3, 72% yield
11, 86%
14, 92%
13, 70%
O
O
O
O
O-
N+
H
O
O
O
H
O
H
O
tBuONO
N
N2
O
+
Ph
O
OtBu
N
(b)
O
N
Ph
Ph
Et
O
O
25 oC, DMF
Ph
Br
N
Br
O
17, 76%b
15, 71%
37
38, 13% yield
39, 5% yield
16, 80%
O
N
O
O
N
O
O
O
O
O
O
O
H
O
O
O
O-
H
25 oC, DMF
N
O
N+
N
N
O
O
OtBu
O
O
O
(c)
Ph
N
O
Br
18, 71%b
19, 61%
20, 66%
21, 67%
22, 51%
39
38, 15% yield
O
O
O
O
O
O
H
O
H
O
H
O
H
H
N
N
O
N
O
O
26, 50%
N
N
O
O
O
O
O
O
N2
25, 78%b
23, 65%
Ph
24, 73%
27, 38%
tBuONO
O
(d)
Et
25 oC, DMF
Ph
N
O
tricyclic products
cycloadduct
starting material
cycloadduct
starting material
40
41, 28% yield
O
O
O
O
O
H
O
H
H
N2
N2
H
O
O
N
O
N
Scheme 3 Probe for the possible mechanism.
O
H
H
28, 74%
29, 82%
Furoxan, a dimer of a highly reactive nitrile oxide, could not
be detected in the products of these reactions, indicating that
nitrile oxide did not serve as the reaction intermediate in the
formation of these γ-lactone fused isoxazolines.12b Further
control experiments were carried out to elucidate the reaction
pathway involved in these transformations (Scheme 3). In these
trials, butylated hydroxytoluene was added to the reaction as a
radical trapping reagent and the desired product 3 was still
O
O
O
O
N2
O
H
O
O
H
N2
H
H
O
N
N
O
O
H
31, 79%
30, 83%
O
O
O
H
H
O
H
N2
N
O
32, 77%
a
Reaction conditions: diazo compounds (0.2 mmol), tert-butyl obtained in a high 72% yield. This result indicated that radical
nitrite (0.6 mmol, 3.0 equiv) and DMF (2.0 mL) at 25 °C for 12 h intermediates were not involved in the formation of the fused
bicyclic isoxazolines. We next prepared diazo compound 37
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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from (Z)-2-bromo-3-phenylprop-2-en-1-ol and subjected it to between the bigger atoms/groups presented aVtiewthAerticblerOidnlginee
DOI: 10.1039/D0SC05607C
this transformation. As shown in Scheme 3b, a small amount of carbons is mainly responsible for the less effective reactions in
acyclic nitronate 39 was detected along with the formation of Scheme 3b-3d. Finally, the elimination of tBuOH from INT2 leads
the fused bicycle isoxazole 38 in 13% yield. As expected, the to the desired product 3. This process can be assisted by a water
cycloaddition of 39 evidently generated 38, indicating that molecule that serves as a shuttle to transfer a proton via TS3
acyclic nitronates serve as key reaction intermediates in this (Figure S1 in the ESI†).
ANOC process. The most common approach to the synthesis of
acyclic nitronates involves the reaction between aliphatic nitro theory (DFT) calculations,
Based upon our experimental data and density functional
plausible mechanism was
a
compounds and electrophilic reagents, which typically developed, as shown in Scheme 4. In this process, a nucleophilic
produces a mixture of stereoisomers. In contrast, the present substitution reaction between the diazo compound and the
work successfully demonstrated the stereospecific synthesis of tert-butyl nitrite triggers the formation of acyclic nitronate
trans-acyclic nitronates based on the room temperature intermediate G, having a trans configuration. This compound
coupling of diazo compounds and tert-butyl nitrite under subsequently undergoes a concerted [3+2] cycloaddition to
neutral conditions.
produce the nitroso acetal H. Finally, elimination of a tert-
Computational studies were performed to gain mechanistic butyloxy group delivers the desired fused bicyclic isoxazoline
insights into the ANOC reaction. First, a transition state (TS) of with regio- and stereo-specificity.
nucleophilic substitution between the diazo compound (1) and
the tert-butyl nitrite (2) is located as TS1, in which the N1...C1
distance is shortened to 1.86 Å, while the distance of C1...N2 is
lengthened to 1.38 Å (Figure S1 in the ESI†). Subsequently, the
acyclic nitronate intermediate with a trans configuration (INT1)
is afforded along with the dissociation of N2. In addition, the
possible cis configuration of acyclic nitronate (INT1ʹ) was also
considered. The calculated activation barrier leading to the cis
structure is 1.4 kcal/mol higher than that of trans one and the
formed INT1ʹ is 3.7 kcal/mol higher in energy than INT1. Thus,
the trans configuration of acyclic nitronate is more feasible to
generate. Moreover, computational study suggests that the
process leading to the acyclic nitronate intermediate could be
promoted by trace amount of water, which was further verified
by experimental results (for details, see Table S1 in the ESI†).
R
H
N2
O
O
N
O
O
O
O
+
N
O
R
H
O
N2
G
[3+2]
O
O
O
cycloaddition
N
N
O
O
O
O
H
H
R
R
OH
H
The TS of nucleophilic substitution can be stabilized by water Scheme 4 Proposed catalytic cycle.
molecule(s) via H-bonding interaction (Figure S2 in the ESI†).
Next, the formed INT1 could undergo intramolecular [3+2]
We next proceeded to evaluate the intermolecular version
cycloaddition between the nitronate and the alkenyl moieties. of this ANOC process (Table 3). A small amount of the
The corresponding transition state is located as TS2, in which cycloadduct 42 was detected following the multicomponent
the C1...C2 and O1...C3 distances are shortened to 2.13 and 2.56 reaction between 4-tert-butylstyrene, ethyl diazoacetate and
Å, respectively. Thus, a bicyclic intermediate INT2 is given via a tBuONO. After examining a variety of reaction parameters, we
concerted step. It should be noted that the two hydrogen atom found that the desired product (42) could be obtained in an 80%
attached to the two bridge carbons, respectively, are in a cis yield using BF3·Et2O as a Lewis acid catalyst in MeCN at room
configuration in INT2. The corresponding TS leading to the trans temperature (for details, see Table S2 in the ESI†). As expected,
configuration, INT2ʹ, is shown as TS2ʹ, which is 2.3 kcal/mol computations suggested that the presence of BF3·Et2O
higher than TS2. The formation of INT2 via TS2 is favorable promoted the nucleophilic substitution process to provide the
because the C2=C3 and the N=O moieties are in the same acyclic nitronate intermediate (Figure S5 in the ESI†).
orientation, which is ready to undergo cyclization. For TS2′, Subsequently, the substrate scope for this intermolecular
however, the aformentioned two moieties are far away due to acyclic nitronate olefin cycloaddition was assessed. A set of
the trans orientation, which is not good for cyclization. substituted styrenes bearing electron-donating and
-
Consequently, the formation of the cis configuration INT2 via withdrawing groups, such as halide atoms and alkyl, alkoxyl,
TS2 is more favorable to occur, which is consistent with ester, nitro, cyano and trifluoromethyl groups, were found to be
experimental observation. The favored cis configuration of INT2 well tolerated, affording the corresponding isoxazolines in
implies that this [3+2] reaction might be sensitive to the steric moderate to high yields (43-56, 38%-75% yields). In addition, 2-
hindrance caused by the groups attached to the two bridge vinylnaphthalene could be used to obtain the desired product
carbons. When Br or Ph group is attached to C2 (37/40), the (57) in a satisfactory yield of 74%. Moreover, regioselectivity
calculated activation barriers for the intramolecular [3+2] could be achieved by employing appropriate substrates. As an
cycloaddition are 24.6 and 24.5 kcal/mol (Figures S3 and S4 in example, methyl (E)-3-(4-vinylphenyl)acrylate gave complete
the ESI†), respectively, which are considerably higher than that regioselectivity based on cycloaddition at the terminal double
of the unsubstituted substrate. The repulsive interaction bond even in the presence of the internal unsaturation (58, 64%
4 | J. Name., 2012, 00, 1-3
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yield). A styrene substrate modified with a borate ester moiety
ARTICLE
To further demonstrate the utility of this transformation, we
View Article Online
DOI: 10.1039/D0SC05607C
was also found to provide product 59, demonstrating that this examined the applicability of diazo compounds derived from
methodology could be suitable for the late-stage derivatization various alcohols and acids (Table 4). The diazo ester derivatives
of complicated molecules. Acrylates and an acrylamide also of phenol and phenylmethanol provided good yields of the
took part in the reaction to furnish the corresponding products corresponding adducts 75 (67% yield) and 76 (92% yield),
in good yields (61-67). Notably, several vulnerable functional respectively. Substrates containing potentially bioactive
groups, including thioether, hydroxyl and amide moieties, were skeletons, such as furan, trifluoromethyl and thiophene
compatible with this cycloaddition protocol, albeit providing moieties, were also well tolerated (77-79, 45%-86% yields).
moderate yields (60, 40% yield; 62, 51% yield; 67, 55% yield). With respect to diazo ketones, phenyl and alkyl analogues
Interestingly, vinyl silanes and a vinyl sulfone were also viable reacted smoothly, although the latter showed a lower efficiency
substrates and gave the corresponding cycloadducts in (80, 69% yield; 81, 31% yield). In addition, an α-diazo ketone
synthetically useful yields (68, 61% yield; 69, 55% yield; 70, 28% bearing a phenylsulfonyl group reacted with a good yield (82,
yield). Pentafluoro styrene also functioned well to give the 72% yield).
cycloadduct 71 in a 56% yield. The unsaturated heterocycle
thiophene was also observed to deliver the corresponding Table 4 Scope of diazo compoundsa
product 72 in a 64% yield. In addition, aliphatic 1-octene and 1-
O
R
10 mol% BF3.Et2
O
hexene were found to participate in the transformation to
generate the anticipated products in moderate yields (73, 33%
yield; 74, 48% yield).
O
tBuONO
+
+
N2
tBu
N
R
CH3CN, rt, 12 h
O
tBu
O
O
Ph
O
CF3
O
Table 3 Scope of alkenesa
O
Ph
O
O
O
O
O
N
N
N
O
10 mol% BF3.Et2O
OEt
N
O
O
O
O
tBuONO
tBu
S
+
+
tBu
R
tBu
N2
tBu
OEt
N
CH3CN, rt, 12 h
O
R
76, 92%
75, 67%
77, 45%
78, 66%
O
O
42, R = 4-tBu, 80%
43, R = H, 74%
Ph
49, R = 4-CN, 69%
50, R = 4-Acetoxy, 75%
51, R = 3-F, 68%
52, R = 3-Cl, 75%
53, R = 3-Br, 62%
54, R = 3-CF3, 66%
55, R = 2-Cl, 63%
56, R = 4-NO2, 61%
O
O
O
O
S
Ph
OEt
O
O
OEt
O
O
N
44, R = 4-F, 67%
45, R = 4-Cl, 75%
46, R = 4-Br, 50%
47, R = 4-CH3, 75%
48, R = 4-OCH3, 38%
N
O
N
O
N
O
N
N
O
tBu
O
tBu
tBu
tBu
R
57, 74%
80, 69%
79, 86%
81, 31%
82, 72%
O
a
Reaction conditions: 4-tert-butylstyrene (0.5 mmol), diazo
OEt
O
O
OEt
OEt
compounds (1.0 mmol, 2.0 equiv), tert-butyl nitrite (1.0 mmol,
2.0 eqiuv), BF3·Et2O (0.05 mmol, 10 mol %) and MeCN (2.0 mL)
at 25 °C under air for 12 h.
N
O
N
O
N
S
O
O
B
MeOOC
O
58, 64%
60, 40%
59, 55%
O
Conclusions
O
OEt
OEt
O
63, R = CH3, 70%
64, R = Et, 75%
65, R = nBu, 75%
66, R = tBu, 76%
OEt
In conclusion, this work demonstrated an entirely novel series
of intra- and intermolecular ANOC reactions. This methodology
provides both regio- and stereo-specificity via a distinct
mechanism and offers a powerful means of obtaining a wide
range of isoxazolines with excellent functional group tolerance
at room temperature. Notably, a new library of γ-lactone fused
isoxazolines with important biological and synthetic potential
was synthesized, including five tricyclic fused isoxazolines.
These compounds are readily transformed into potentially
useful, highly functionalized isoxazolines, thus confirming the
synthetic utility of this approach. Both mechanistic experiments
and DFT calculations indicated that the smooth generation of
acyclic nitronates and subsequent interception by carbon-
carbon double bond were responsible for the rapid construction
of isoxazolines. The application of this methodology to the total
synthesis of complex natural products is currently underway in
our laboratory.
N
O
H
N
O
O
HO
O
N
RO
O
O
O
O
61, 76%
62, 51%
O
O
OEt
O
OEt
O
OEt
OEt
N
O
N
O
Si
H2N
N
O
S
N
O
O
Si
O
O
67, 55%
68, 61%
69, 55%
70, 28%
O
O
OEt
OEt
O
O
F
O
OEt
N
OEt
F
F
N
O
O
N
N
S
F
O
F
71, 56%
72, 64%
73, 33%
74, 48%
a
Reaction conditions: alkenes (0.5 mmol), ethyl diazoacetate
(1.0 mmol, 2.0 equiv), tert-butyl nitrite (1.0 mmol, 2.0 eqiuv),
BF3·Et2O (0.05 mmol, 10 mol %) and MeCN (2.0 mL) at 25 °C
under air for 12 h.
Conflicts of interest
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Chemical Science
Page 6 of 7
ARTICLE
Journal Name
Tartakovskii, O. A. Luk'yanov, N. I. Shlykova andVSie.wS.ArNticolevOiknolinve,
Zh. Org. Khim., 1967, 3, 980.
There are no conflicts to declare.
9
For common decomposition reactionDs OoIf: 1a0c.1y0c3li9c/Dn0iStrCo0n5a6t0e7sC,
see ref 6a.
Acknowledgements
10 R. Chen, Y. Zhao, S. Fang, W. Long, H. Sun and X. Wan, Org.
Lett., 2017, 19, 5896.
This work was funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD),
NSFC (grant numbers 21973068, 21971175, 21572148). We
thank Michael Judge, MSc, from Liwen Bianji, Edanz Editing
China (www.liwenbianji.cn/ac), for editing the English text of a
draft of this manuscript.
11 For selected examples on this topic, see: (a) M. Cianfanelli, G.
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6 | J. Name., 2012, 00, 1-3
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Page 7 of 7
Chemical Science
View Article Online
DOI: 10.1039/D0SC05607C
Acyclic Nitronates Olefins Cycloaddition (ANOC): Regio- and Stereo-specific Synthesis of Isoxazolines
Liang Ma, Luyao Kou, Feng Jin, Xionglve Cheng, Suyan Tao, Gangzhong Jiang, Xiaoguang Bao,
Xiaobing Wan
Chem. Sci., 2020, Volume, Page – Page
DOI: 10.1039/x0xx00000x
O
O
R2
R4
O
R4
R3
R2
R1
catalyst free
N2
tBuONO
+
R1
O
N
room temperature
R3
O
O
O
O
N
O
O
O
H
O
H
O
H
O
H
H
H
O
H
H
H
H
N
N
N
N
O
O
O
O
O
H
H
H
Regio- and Stereo-specificity
Mild conditions
Simple operation
Wide substrates scope
A novel acyclic nitronate olefin cycloaddition (ANOC) reaction was successfully established, which enabled
facile construction of various isoxazolines.