Dehydrogenative TEMPO-Mediated Formation of Unstable Nitrones: Easy Access to N-Carbamoyl Isoxazolines

Article abstract of DOI:10.1002/chem.201501314

N-carbamoyl nitrones represent an important class of reagents for the synthesis of a variety of natural and biologically active compounds. These compounds are generally converted into valuable 4-isoxazolines upon cyclization reaction with dipolarophiles. However, these types of N-protected nitrones are highly unstable, which limits their synthesis, storage and practical use, enforcing alternative lengthy or elaborated synthetic routes. In this work, a 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)-mediated formal "dehydrogenation" of N-protected benzyl-, allyl- and alkyl-substituted hydroxylamines followed by in situ trapping of the generated unstable nitrones into N-carbamoyl 4-isoxazolines is presented. A plausible mechanism is also proposed, in which the dipolarophile shows an important assistant role in the generation of the active nitrone intermediate. This simple protocol avoids the problematic isolation of N-carbamoyl protected nitrones, providing new synthetic possibilities in isoxazoline chemistry.

Full text of DOI:10.1002/chem.201501314

DOI: 10.1002/chem.201501314
Full Paper
&
Organic Synthesis |Hot Paper|
Dehydrogenative TEMPO-Mediated Formation of Unstable
Nitrones: Easy Access to N-Carbamoyl Isoxazolines
Andrea Gini,[a, b] Marwin Segler,[c] Dominik Kellner,[a, b] and Olga García MancheÇo*[a, b]
Abstract: N-carbamoyl nitrones represent an important class
of reagents for the synthesis of a variety of natural and bio-
logically active compounds. These compounds are generally
converted into valuable 4-isoxazolines upon cyclization reac-
tion with dipolarophiles. However, these types of N-protect-
ed nitrones are highly unstable, which limits their synthesis,
storage and practical use, enforcing alternative lengthy or
elaborated synthetic routes. In this work, a 2,2,6,6-tetra-
methylpiperidin-1-oxyl (TEMPO)-mediated formal “dehydro-
genation” of N-protected benzyl-, allyl- and alkyl-substituted
hydroxylamines followed by in situ trapping of the generat-
ed unstable nitrones into N-carbamoyl 4-isoxazolines is pre-
sented. A plausible mechanism is also proposed, in which
the dipolarophile shows an important assistant role in the
generation of the active nitrone intermediate. This simple
protocol avoids the problematic isolation of N-carbamoyl
protected nitrones, providing new synthetic possibilities in
isoxazoline chemistry.
Introduction
4-Isoxazolines are valuable five-membered heterocycles[1] with
interesting biological activities, including anti-inflammatory or
miotic kinesin inhibition properties among others.[2] In addi-
tion, they are also used as versatile building blocks for the
preparation of numerous biological active compounds, such as
1,3-amino-alcohols and -carbonyls,[3] b-lactams,[4] a variety of
N-heterocycles[5] or natural products such as alkaloids
(Figure 1).[6]
Several methods for the preparation of isoxazolines and
isoxazolidines have been described, which are mainly based
on the 1,3-dipolar cycloaddition reaction (1,3-DC) between
isolated stable nitrones[7] with alkynes and olefins as
dipolarophiles, including both metal-catalyzed and metal-free
approaches.[8] Despite the various powerful available methods,
they are basically restricted to the use of N-alkyl and N-aryl-
substituted nitrones. This leads to isoxazolines with groups at
the nitrogen that are difficult to cleave or are even unremova-
ble, which significantly limits the scope of this methodology
for further synthetic applications.[9] Therefore, the use of nit-
Figure 1. Versatility of isoxazolines as building blocks and biactive units.
rones bearing removable electron-withdrawing groups, such as
acyl or carbamoyl units is highly desirable. These dipole spe-
cies are, however, difficult to isolate and manipulate due to
their intrinsic instability. Thus, only a few examples have been
reported in the literature,[10–11] in which such nitrones have
been generated in situ from N-acyl-protected precursors. A
prominent example is the base-mediated elimination of the
sulfonyl group of N-carbamoyl N-hydroxy-a-amido sulfones
(Scheme 1a).[10]
[a] A. Gini,+ D. Kellner, Prof. Dr. O. G. MancheÇo
Institute for Organic Chemistry, University of Regensburg
Universitätsstrasse 31, 93053 Regensburg (Germany)
E-mail: olga.garcia-mancheno@ur.de
[b] A. Gini,+ D. Kellner, Prof. Dr. O. G. MancheÇo
Straubing Center of Science for Renewable Resources (WZS)
Schulgasse 16, 94315 Straubing (Germany)
Another interesting but challenging approach implies the
direct dehydrogenative oxidation of simple starting materials
such as N-acyl hydroxylamines into nitrones, avoiding numer-
ous synthetic steps and extra functionalities in the precursor.[12]
Based on our experience on oxidative coupling reactions of
C(sp3)ÀH bonds using 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO) derivatives as mild oxidants,[13] we aimed at a more
direct and general metal-free method for the synthesis of N-
protected isoxazolines (Scheme 1b). Consequently, we present
herein an efficient TEMPO-mediated in situ formation and
[c] M. Segler+
Institute of Organic Chemistry, University of Münster
Corrensstrasse 40, 248149 Münster (Germany)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501314.
Chem. Eur. J. 2015, 21, 12053 – 12060
12053
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
genative cross-coupling (CDC) reactions[14] such as organic
peroxides, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),
or TEMPO oxoammonium salts did not lead to the desired
product (Table 1, entries 1–3), the use of a TEMPO radical[15–16]
provided isoxazoline 3a in a promising 25% yield (entry 4). A
complete conversion of the hydroxylamine 1a was observed
with all the oxidants explored. However, except for the reac-
tion with TEMPO, a complex reaction mixture was obtained in
which only traces of the desired product were present. This in-
dicates that the in situ formed N-carbamoyl nitrone and/or the
product decompose readily in the presence of a strong oxi-
dant. Conversely, when using a TEMPO radical the low conver-
sion into 3a and observation of certain decomposition byprod-
ucts at room temperature could be attributed to a not effec-
tive next cycloaddition step. The increase of the temperature
to 508C favored the overall transformation, most probably by
increasing the efficiency of the second 1,3-cycloaddition trap-
ping reaction. Thus, 3a was obtained in a good 75% yield
(entry 5). Other TEMPO radical derivatives were also suitable
oxidants (entries 6–7), leading to slightly lower yields (60–
64%). Taking TEMPO as the oxidant of choice, the temperature,
solvent, and amount of oxidant was finally optimized. Conse-
quently, the use of two equivalents of TEMPO at 708C in
CH2Cl2 in a pressure schlenk tube[17] led to an improved yield
of 87% (entry 8).
Scheme 1. Approaches for the in situ generation and trapping of N-
carbamoyl-protected nitrones.
trapping of unstable nitrones for the synthesis of N-carbamoyl
isoxazolines.
With these excellent results in hand, the scope of the reac-
tion was explored. Various N-acyl and N-carbamoyl-protected
benzylhydroxylamines were evaluated in the reaction with 2a
(Table 2). The carbamoyl group Boc proved to be superior to
its corresponding acyl group pivaloyl (Piv) (87% vs. 17%).
Other carbamate substitution (R=EtO and BnO) was well toler-
ated, leading to isoxazolines 3 in moderate to good yields.
However, a low yield (21%) and a significant decomposition of
the starting material 1 were observed when using sterically
hindered protecting groups such as Troc (2,2,2-trichloroethyl
carbonate) In addition, it was observed that in the reaction
Results and Discussion
Initially, N-Boc-protected benzylhydroxylamine (1a) (Boc=tert-
butoxycarbonyl) was chosen as a model substrate for the
one-pot in situ oxidative nitrone formation and cycloaddition
trapping reaction with dimethyl acetylenedicarboxylate (2a,
DMAD) (Table 1).
A number of oxidants were tested under neat conditions or
in dichloromethane as the solvent at room temperature to
minimize the possible decomposition of the generated N-
carbamoyl nitrone. Whereas the typical reagents for dehydro-
Table 1. Optimization of the model reaction.[a]
Table 2. Scope of the reaction: N-carbamoyl/acyl group variation.[a,b]
Entry
Oxidant (equiv)
Solvent
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
tBuOOH (2)
DDQ (2)
TEMPO+BF4 (2)
neat
RT
RT
RT
RT
50
50
50
70
70
70
70
50
–
<5
<5
25
75
64
60
87
63
80
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
BTF[c]
À
TEMPO (2)
TEMPO (2)
4-NHAc-TEMPO (2)
4-OH-TEMPO (2)
TEMPO (2)
TEMPO (2)
TEMPO (2.5)
–
9
10
11
12
CH2Cl2
CH2Cl2
CH2Cl2
[c]
TEMPO (0.1)/O2
25
[a] 1a (0.25 mmol, 1 equiv), 2a (4 equiv), and oxidant in CH2Cl2 (0.125m)
at the corresponding temperature for 24 h. [b] Isolated yields. [c] 1 atm of
O2 was used. BTF=Benzotrifluoride (or trifluorotoluene).
[a] 1 (0.25 mmol, 1 equiv), 2 (4 equiv) and TEMPO (2 equiv) in CH2Cl2
(0.125m) at 708C for 24 h. [b] Isolated yields.
Chem. Eur. J. 2015, 21, 12053 – 12060
www.chemeurj.org
12054
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
a byproduct 4a, derived from the addition of TEMPO to the
dipolarophile 2a, was also formed in high yields. This
explains the need of employing an excess of 2a to achieve
high conversions into 3.
The reaction of hydroxylamine 1a with different dipolaro-
philes 2 was then investigated (Table 3). The diethylester
Table 3. Scope of the reaction: Dipolarophile variation.[a,b]
Scheme 2. DMAD as a cheap sacrificial reagent: Enrollment of less reactive
dipolarophiles.
Table 4. Scope of the reaction: Substitution of the N-Boc hydroxylamine
1.[a,b]
[a] 1 (0.25 mmol, 1 equiv), 2 (4 equiv) and TEMPO (2 equiv) in CH2Cl2
(0.125m) at 708C for 24 h. [b] Isolated yields. [c] n.d.=not detected.
[d] 96 h reaction.
derivative 2b reacted in a similar way to 2a (84% vs. 87%).
Furthermore, the bulkier tert-butyl acetylenedicarboxylate (2c)
provided 3 f in a good 52% yield, whereas the use of the
monoethylester 2d led to no desired reaction. In these last
cases, a substantial decomposition of the in situ formed ni-
trone was observed. Unexpectedly, other typical cyclic dipolar-
ophiles such as N-methyl (2e) and N-phenyl maleimide (2 f)
showed a low reactivity, providing the corresponding isoxazoli-
dines 3i and 3j in only 22 and 5% yield. Finally, unactivated di-
polarophiles such as styrene and butyl vinyl ether did not par-
ticipate in the reaction under our standard conditions. In order
to enroll more effectively the less reactive dipolarophiles such
as maleimides in the cycloaddition step, the reaction was car-
ried out in the presence of 2a as a cheap sacrificial reagent
(Scheme 2). Considering the higher performance of DMAD as
a dipolarophile and the formation of 4a, we envisioned that
2a might be involved in an important mechanistic step of the
process and therefore it may facilitate the reaction of other di-
polarophiles (see below for further discussion). Satisfactorily,
the desired products 3i and 3j were then obtained in 50 and
44% yields after 96 h, and only traces of the product derived
from 2a were formed (3a, <5%).[18]
[a] 1 (0.25 mmol, 1 equiv), 2a (4 equiv) and TEMPO (2 equiv) in CH2Cl2
(0.125m) at 708C for 24 h. [b] Isolated yields.
Next, a variety of different N-substituted N-Boc hydroxyl-
amines was studied (Table 4). First of all, it is worth mentioning
that the reaction could be scaled up to 5 mmol without detri-
ment on the reactivity (3a, 82% yield, 24 h). Moreover, elec-
tron-donating groups such as p-tBu, p-OMe, and m-OMe at the
aromatic unit led to similar good results (51, 84, and 71%
yield, respectively). However, the introduction of substituents
at the ortho position, such as an o-MeO group, was not well
tolerated and translated to a significant drop on the yield to
43%. Furthermore, halogen-containing (p-Br and p-ClC6H4-)
Chem. Eur. J. 2015, 21, 12053 – 12060
www.chemeurj.org
12055
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
and electron-deficient (p-CF3C6H4-) substrates 1q–s also
reacted satisfactorily, providing 3 in good yields (63–80%).
This methodology showed a remarkable broad structural
scope since not only benzylic but also the more demanding al-
lylic (1t) and alkylic (1u–w)-substituted N-Boc hydroxylamines
could be successfully enrolled in this transformation. Conse-
quently, allyl isoxazoline 3t was obtained in a good 50% yield
and alkyl derivatives 3u–w in moderate to excellent yields (up
to 74%).
ilar reaction between TEMPO and electron-poor endiynes has
been postulated by Kçnig and Schreiner as an intermediate
step (radical A) for a radical 5-exo-dig cyclization (Scheme 3,
Eq. (2)).[19]
The course of the model reaction between 1a and DMAD
(2a) was next followed by GC-FID in the first 7 h (Scheme 3,
Eq. (3)). We could observe that the hydroxylamine was rapidly
consumed (<10% left after 60 min). At the same time almost
two equivalents of DMAD have reacted and the formation of
the TEMPO addition byproduct 4a was observed. However, the
final cycloaddition product 3a was built up comparably slowly.
Furthermore, the dipolar cycloaddition reaction with the elec-
tron-deficient N-carbamoyl nitrones is generally less favored
than the classical with N-aryl or alkyl derivatives (Scheme 4).[20]
Reactivity and mechanistic studies
To better understand the formation of 4a, DMAD (2a) was
reacted with stoichiometric amounts of the oxidant TEMPO
(Scheme 3, Eq. (1)). While no reaction was observed in the ab-
Scheme 4. Reactivity comparison between in situ formed unstable N-Boc
and stable N-Bn nitrones.
The reaction with N-benzyl hydroxylamine 5, which leads to
a stable and isolable nitrone 8,[21] proceeded more readily than
the one with the N-Boc derivative 1a. Thus, milder conditions
(RT vs. 708C) were required. Additionally, the unstable N-carba-
moyl nitrone may ready decompose under the employed
temperature and long reaction times. Therefore, the nitrone
might not be present in high concentrations, which suggests
the participation of a different intermediate.
&
*
^
Scheme 3. Reactivity insights. : DMAD 2a; : product 3a; : 4a;
~
: hydroxyamine 1a.
sence of 1a, the byproduct 4a was obtained quantitatively in
the presence of the substrate hydroxylamine. These results in-
dicate, as we initially anticipated, a certain interaction or prior
reaction with the substrate, which might suggest an active
participation of the dipolarophile in the in situ generation of
the required nitrone species. Moreover, the formation of 4a by
a radical addition of TEMPO to 2a to form a more reactive
carbon-centered radical can be envisioned. In this regard, a sim-
With all this information, a plausible mechanism is depicted
in Scheme 5. First, a hydrogen atom abstraction from the hy-
droxylamine 1 occurs. This hydrogen can be abstracted directly
by TEMPO[15] or by the carbon-centered radical 9 obtained
upon reversible radical addition of TEMPO to 2a. The nitroxide
10 is then formed together with 4 or TEMPOH, which can also
react with 2a in a conjugate addition way to form the same
byproduct. Next, two molecules of nitroxide 10 disproportion-
Chem. Eur. J. 2015, 21, 12053 – 12060
www.chemeurj.org
12056
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
transition state (TS) could be found for the formation of the
radicals 9 and 10, respectively. The calculations also indicate
that the following disproportionation of 10 is an exothermic
process. Additionally, the subsequent cycloaddition has an acti-
vation barrier of just 4.4 kcalmolÀ1. Nitrone 11 should then
react fast in the 1,3-DC step and thus, as previously postulated,
only be present in low concentrations in the reaction media.
This explains why nitrone 11 could not be detected by NMR
spectroscopy, GC or MS analysis during the mechanistic stud-
ies. Furthermore, all this implies that the final cycloaddition
step is not likely to be the rate-determining, but instead one
involved in the formation of the intermediate nitroxide 10 or
nitrone 11.
Conclusion
Scheme 5. Mechanistic proposal.
In summary, we have presented an effective method for the
synthesis of N-carbamoyl/-acyl 4-isoxazolines by a TEMPO-
mediated in situ formation and trapping by 1,3-dipolar cyclo-
addition of unstable N-protected nitrones. Carbamates were
superior to simple acyl protecting groups, leading to good
yields on the corresponding aryl, vinyl, and alkyl substituted
isoxazolines (up to 87%). Moreover, the employed
dipolarophile showed an important assisting role in the slow
generation of the active, unstable N-protected nitrone.
ate by a SET process followed by deprotonation to form
nitrone 11 and hydroxylamine 1,[22] the later entering again in
the oxidation cycle. Lastly, the cycloaddition between the
generated nitrone 11 and 2a takes place to form the final
isoxazoline product 3.
Finally, to obtain more mechanistic insights into the two
proposed possible pathways a) and b) for the formation of the
nitroxide intermediate 10, byproduct 4a and nitrone 11, and
the subsequent 1,3-DC step, DFT-calculations were performed
(Scheme 6).[23]
Experimental Section
Consequently, to complete the formation of nitroxide 10,
one of the two possible endothermic intermediate steps has
to take place. However, pathways a) and b) are similar in
energy, not allowing the exclusion of one of them since no
General information and materials
1H-, 13C- and 19F NMR spectra were recorded in CDCl3, (reference
signal: 1H=7.26, 13C=77.16 ppm, CDCl3) on a Bruker Avance
300 MHz spectrometer. Chemical shifts (d) are given in ppm and
spin–spin coupling constants (J) are given in Hz. Analytical thin
layer chromatography was performed using silica gel 60 F254 and
a solution of KMnO4 or an iodine camera served as a staining
agent. Column chromatography was performed on silica gel 60
(0.040–0.063 mm). Exact masses (HRMS (ESI+)) were recorded on
an Agilent Q-TOF 6540 UHD spectrometer (samples in CH3OH as
the solvent). CH2Cl2 and Et3N were dried over molecular sieves. THF
was distilled and dried over Na. TEMPO was purified by sublima-
tion under reduced pressure. Other solvents and commercially
available reagents were used without further purification. All the
flasks were dried under vacuum using a heating gun.
Synthesis of N-protected 4-isoxazolines 3
General procedure: In a screw-cap Schlenk tube, the correspond-
ing N-protected N-benzylhydroxyamine derivative 1 (1.00 equiv)
was dissolved in dry CH2Cl2 (2.00 mL). Dimethyl acetylenedicarbox-
ylate (2a) (4.00 equiv) and TEMPO (2.00 equiv) were added and the
reaction mixture was stirred at 708C for 24 h. The solvent was re-
moved under reduced pressure and the obtained crude product
was purified by flash column chromatography on silica gel eluting
with pentane/AcOEt to give the corresponding N-protected
isoxazoline 3.
2-tert-Butyl 4,5-dimethyl 3-phenylisoxazole-2,4,5-tricarboxylate
(3a): According to the general procedure, N-Boc N-benzyl hydrox-
ylamine (1a) (0.25 mmol, 63.3 mg, 1.00 equiv), dry CH2Cl2 (2 mL),
2a (122 mL, 1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg,
Scheme 6. DFT gas phase (B2PLYP-D3/def2-TZVP//BP86-D3/def2-TZVP) calcu-
lated relative enthalpy profiles for the formation of nitroxide 10, nitrone 11,
and byproduct 4a, as well as for the 1,3-DC reaction.
Chem. Eur. J. 2015, 21, 12053 – 12060
www.chemeurj.org
12057
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
0.50 mmol, 2.00 equiv) were reacted. The crude product was puri-
fied by flash column chromatography on silica gel eluting with
pentane/AcOEt ((%AcOEt): 1 (30); 5 (50); 15 (300) 25% (200 mL)) to
give 3a as a viscous oil (0.218 mmol, 79.3 mg, 87%). 1H NMR
(300 MHz, CDCl3): d=7.34–7.20 (m, 5H), 6.06 (s, 1H), 3.87 (s, 3H),
3.57 (s, 3H), 1.39 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=161.4,
158.1, 155.2, 149.9, 138.7, 128.8, 127.4, 111.0, 84.3, 68.9 53.6, 52.2,
28.1 ppm; MS-ESI: m/z: calcd for [C18H21NO7Na]+: 386.1210; found:
386.1207.
7.42–7.36 (m, 5H), 6.27 (s, 1H), 4.88 (d, J=11.8 Hz, 1H), 4.72 (d, J=
4.6 Hz, 1H), 3.97 (s, 3H), 3.66 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=160.8, 157.5, 149.4, 137.3, 128.9, 128.2, 127.4, 111.3,
94.2, 75.7, 69.1, 53.7, 52.4 ppm; MS-ESI: m/z: calcd for [C21H19
Cl3NO7Na]+: 459.9728; found: 459.9729.
2-tert-Butyl 4,5-diethyl 3-phenylisoxazole-2,4,5-tricarboxylate
(3 f): According to the general procedure, hydroxylamine 1a
(0.25 mmol, 55.8 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2b (160 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (50), 5 (50), 10 (100), 15% (400 mL)] to give 3 f as
light-yellow oil (0.21 mmol, 82.2 mg, 84%). 1H NMR (300 MHz,
CDCl3): d=7.42–7.29 (m, 5H), 6.11 (s, 1H), 4.41 (q, J=7.2 Hz, 2H),
4.15–4.02 (m, 2H), 1.46 (s, 9H), 1.40 (t, J=7.2 Hz, 3H), 1.13 ppm (t,
J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=161.0, 157.9, 155.3,
150.1, 138.9, 128.8, 127.5, 110.7, 84.3, 69.0, 63.2, 61.2, 28.2 ppm;
MS-ESI: m/z calcd for [C20H26NO7]+ =392.1704; found: 392.1710.
Dimethyl 2-[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]maleate (4a):
1H NMR (300 MHz, CDCl3): d=5.94 (s, 1H), 6.43 (s, 1H), 3.91 (s, 3H),
3.68 (s, 3H), 1.60–1.52 (m, 6H), 1.17 (s, 6H), 1.12 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=167.4, 165.6, 95.6, 61.4, 52.9, 51.4,
39.7, 31.9, 20.5, 16.8 ppm; GCMS (T0 50–208CminÀ1; Tmax 2808C):
for [C15H25NO5]; tR =10.4 min; m/z (%): 300 [MH+] (23), 269 [M+
ÀC2H6] (100).
2-Pivaloyl 4,5-dimethyl 3-phenylisoxazole-4,5-dicarboxylate
(3b): According to the general procedure, hydroxylamine 1b
(0.50 mmol, 104.0 mg, 1.00 equiv), dry CH2Cl2 (4 mL), 2a (245 mL,
2.00 mmol, 4.00 equiv), and TEMPO (157.6 mg, 1.00 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (30); 5 (50); 20% (200 mL)] to give 3b as a viscous oil
(0.090 mmol, 31.3 mg, 17%). 1H NMR (300 MHz, CDCl3): d=7.40–
7.31 (m, 5H), 6.43 (s, 1H), 3.98 (s, 3H), 3.65 (s, 3H), 1.27 ppm (s,
9H); 13C NMR (75 MHz, CDCl3): d=178.6, 161.1, 157.8, 148.4, 138.1,
128.8, 128.7, 127.3, 111.9, 67.3, 53.6, 52.2, 39.6, 26.3 ppm; MS-ESI:
m/z: calculated for [C18H21NO6Na]+: 370.1261; found: 370.1257.
2,4,5-tri-tert-Butyl 3-phenylisoxazole-2,4,5-tricarboxylate (3g):
According to the general procedure, hydroxylamine 1a
(0.25 mmol, 55.8 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2c (226.3 mg,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (100), 5 (100), 10 (200), 15 (200), 20% (200 mL)] to
give 3g as light-yellow oil (0.13 mmol, 58.1 mg, 52%). 1H NMR
(300 MHz, CDCl3): d=7.42–7.33 (m, 5H), 6.05 (s, 1H), 1.62 (s, 9H),
1.49 (s, 9H), 1.32 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=160.1,
156.6, 155.3, 149.9, 139.3, 128.5, 128.5, 127.6, 111.5, 85.0, 83.8, 81.9,
69.2, 28.1, 28.0, 27.9 ppm; MS-ESI: calcd for [C24H33NO7Na]+:
470.2149; found: 470.2152.
2-Ethyl 4,5-dimethyl 3-phenylisoxazole-2,4,5-tricarboxylate (3c):
According to the general procedure, hydroxylamine 1c
(0.25 mmol, 63.3 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a (122 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (30); 5 (50); 15 (300) 25% (200 mL)] to give 3c as a vis-
cous solid (0.21 mmol, 69.9 mg, 84%). 1H NMR (300 MHz, CDCl3):
d=7.46–7.28 (m, 5H), 6.22 (s, 1H), 4.30 (qd, J=14.3, 7.9 Hz, 1H),
4.26 (qd, J=14.2, 7.9 Hz, 1H), 3.95 (s, 3H), 3.65 (s, 3H), 1.30 ppm (t,
J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=161.1, 157.9, 155.0,
150.0, 137.8, 131.9, 129.0, 122.8, 110.3, 84.6, 68.3, 53.6, 52.2,
28.0 ppm; MS-ESI: m/z: calcd for [C16H17NO7Na]+: 358.0897; found:
358.0903.
2-tert-Butyl-4,6-dioxo-3-phenyl-5-methylhexahydro-2H-pyrrolo-
[3,4-d] isoxazole-2 carboxylate (3i): In a screw-cap schlenk tube,
hydroxylamine 1a (0.50 mmol, 112.0 mg, 1.00 equiv), N-methylma-
leimide (2d) (1.00 mmol, 173.0 mg, 2.00 equiv), 2a (1.00 mmol,
122 mL, 2.00 equiv), and TEMPO (1.00 mmol, 142.2 mg, 2.00 equiv)
were dissolved in dry CH2Cl2 (4 mL), and the reaction mixture was
stirred at 708C for 4 days. The solvent was removed under reduced
pressure and the obtained crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 0 (200), 5 (200), 10 (200), 15 (200), 20% (200 mL)] to
give 3h as light-yellow oil (0.25 mmol, 83.0 mg, 50%). 1H NMR
(300 MHz, CDCl3): d=7.44–7.31 (m, 5H), 5.74 (s, 1H), 4.94 (d, J=
7.3 Hz, 1H), 3.76 (d, J=7.3 Hz, 1H), 3.01 (s, 3H), 1.41 ppm (s, 9H);
13C NMR (75 MHz, CDCl3): d=174.3, 172.1, 156.7, 138.1, 129.0,
128.2, 126.0, 83.7, 78.2, 65.9, 56.2, 27.8, 25.5 ppm; MS-ESI: m/z:
calcd for [C16H25NO7Na]+: 366.1523; found: 366.1527.
2-Benzyl 4,5-dimethyl 3-phenylisoxazole-2,4,5-tricarboxylate
(3d): According to the general procedure, hydroxylamine 1d
(0.25 mmol, 064.2 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a (122 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (30); 5 (50); 15 (300) 25% (200 mL)] to give 3d as
2-tert-Butyl-4,6-dioxo-3,5-diphenylhexahydro-2H-pyrrolo[3,4-d]
isoxazole-2 carboxylate (3j): In a screw-cap schlenk tube, hydrox-
ylamine 1a (0.50 mmol, 112.0 mg, 1.00 equiv), 2a (1.00 mmol,
122 mL, 2.00 equiv), N-phenylmaleimide (2e) (1.00 mmol, 173.0 mg,
2.00 equiv), and TEMPO (1.00 mmol, 142.2 mg, 2.00 equiv) were
dissolved in dry CH2Cl2 (4 mL), and the reaction mixture was stirred
at 708C for 4 days. The solvent was removed under reduced pres-
sure and the obtained crude product was purified by flash column
chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 5 (100), 5 (100), 15 (200), 20% (500 mL)] to give 3t as
a 1:7 mixture of diasteroisomers (0.22 mmol, 86.3 mg, 44%).
1
a viscous oil (0.10 mmol, 39.7 mg, 40%). H NMR (400 MHz, CDCl3):
d=7.42–7.30 (m, 10H), 6.23 (s, 1H), 5.28 (d, J=12.2 Hz, 1H), 5.21
(d, J=12.2 Hz, 1H), 3.95 (s, 3H), 3.65 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=161.1, 157.9, 156.4, 149.8, 138.1, 134.9, 129.0,
128.9, 128.72, 128.5, 127.4, 111.2, 69.1, 69.0, 53.7, 52.3 ppm; MS-ESI:
m/z calcd for [C21H19NO7Na]+: 420.1054; found: 420.1058.
2-(2,2,2-Trichloroethyl) 4,5-dimethyl 3-phenylisoxazole-4,5-tricar-
boxylate (3e): According to the general procedure, hydroxylamine
1e (0.25 mmol, 74.7 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a (122 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (50), 5 (50), 10 (200), 15% (300 mL)] to give 3e as a vis-
Major diasteroisomer: 1H NMR (300 MHz, CDCl3): d=7.53–7.26 (m,
10H), 5.90 (s, 1H), 5.09 (d, J=7.4 Hz, 1H), 3.93 (d, J=7.4 Hz, 1H),
1.34 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=173.5, 171.1, 157.0,
138.2, 134.3, 129.2, 129.2, 129.0, 126.3, 126.1, 126.1, 125.9, 84.1,
1
cous oil (0.05 mmol, 22.9 mg, 21%). H NMR (300 MHz, CDCl3): d=
Chem. Eur. J. 2015, 21, 12053 – 12060
www.chemeurj.org
12058
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
78.4, 66.34, 56.4, 27.9 ppm; MS-ESI: m/z: calcd for [C22H22N2O5Na]+:
417.1421; found: 417.1419.
CDCl3): d=7.52–7.45 (m, 2H), 7.30–7.24 (m, 2H), 6.09 (s, 1H), 3.95
(s, 3H), 3.65 (s, 3H), 1.47 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=
161.1, 157.9, 155.0, 150.0, 137.8, 131.9, 129.0, 122.8, 110.3, 84.6,
68.3, 53.6, 52.2, 28.0 ppm; MS-ESI: m/z calcd for [C18H20BrNO7Na]+:
464.0315; found: 464.0312.
2-tert-Butyl 4,5-dimethyl 3-(4-tert-butylphenyl)isoxazole-2,4,5-
tricarboxylate (3m): According to the general procedure, hydrox-
ylamine 1m (0.25 mmol, 72.8 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a
(122 mL, 1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (50), 5 (50), 10 (200), 25% (200 mL)] to give 3m as
pale-yellow viscous oil (0.16 mmol, 53.3 mg, 51%). 1H NMR
(300 MHz, CDCl3): d=7.40–7.29 (m, 4H), 6.12 (s, 1H), 3.95 (s, 3H),
3.66 (s, 3H), 1.46 (s, 9H), 1.30 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3): d=161.4, 158.1, 155.5, 151.6, 149.8, 135.5, 126.9, 125.7,
125.5, 111.0, 84.2, 68.6, 53.5, 52.2, 34.6, 31.4, 31.3, 28.0 ppm; MS-
ESI: m/z: calcd for [C22H30NO7]+: 420.2018; found: 420.2017.
2-tert-Butyl 4,5-dimethyl 3-(4-chlorophenyl)isoxazole-2,4,5-tricar-
boxylate (3r): According to the general procedure, hydroxylamine
1r (0.25 mmol, 64.4 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a (122 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (50), 5 (50), 10 (200), 15% (300 mL)] to give 3r as vis-
1
cous oil (0.16 mmol, 64.6 mg, 65%). H NMR (300 MHz, CDCl3): d=
7.33 (s, 4H), 6.10 (s, 1H), 3.95 (s, 3H), 3.65 (s, 3H), 1.47 ppm (s, 9H);
13C NMR (75 MHz, CDCl3): d=161.2, 157.9, 155.0, 150.0, 137.3,
134.6, 129.0, 128.7 110.4, 84.6, 68.3, 53.6, 52.2, 28.0 ppm; MS-ESI:
calcd for [C18H21ClNO7]+: 398.1001; found: 398.1000.
2-tert-Butyl 4,5-dimethyl 3-(4-methoxyphenyl)isoxazole-2,4,5-tri-
carboxylate (3n): According to the general procedure, hydroxyla-
mine 1n (0.25 mmol, 63.3 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a
(122 mL, 1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (50), 5 (50), 10 (200), 15 (300), 25% (200.00 mL)] to
give 3n as a viscous oil (0.21 mmol, 82.5 mg, 84%). 1H NMR
(300 MHz, CDCl3): d=7.33–7.26 (m, 2H), 6.91–6.83 (m, 2H), 6.08 (s,
1H), 3.94 (s, 3H), 3.79 (s, 3H), 3.64 (s, 3H), 1.46 ppm (s, 9H);
13C NMR (75 MHz, CDCl3): d=161.4, 159.9, 158.1, 155.2, 149.6,
130.8, 128.6, 114.1, 110.9, 84.2, 68.5, 55.3, 53.5, 52.1, 28.0 ppm; MS-
ESI: m/z calcd for [C19H23NO8Na]+: 416.1316; found: 416.1315.
2-tert-Butyl 4,5-dimethyl 3-(4-trifluoromethylphenyl)isoxazole-
2,4,5-tricarboxylate (3s): According to the general procedure, hy-
droxylamine 1s (0.25 mmol, 72.8 mg, 1.00 equiv), dry CH2Cl2 (2 mL),
2a (122 mL, 1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg,
0.50 mmol, 2.00 equiv) were reacted. The crude product was puri-
fied by flash column chromatography on silica gel eluting with
pentane/AcOEt [(%AcOEt): 1 (50), 5 (50), 10 (200), 15% (300 mL)] to
give 3s as a viscous oil (0.16 mmol, 67.9 mg, 63%). 1H NMR
(300 MHz, CDCl3): d=7.62 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.2 Hz,
2H), 6.18 (s, 1H), 3.95 (s, 3H), 3.65 (s, 3H), 1.47 ppm (s, 9H);
13C NMR (75 MHz, CDCl3): d=161.01, 157.78, 154.99, 150.28, 142.54
130.79 (q, J=32.5 Hz), 127.70 (q, J=266.8 Hz), 125.71 (q, J=
3.7 Hz), 122.10, 110.02, 84.72, 68.22, 53.56, 52.20, 27.97 ppm;
19F NMR (300 MHz, CDCl3): d=À62.67 ppm; MS-ESI: m/z calcd for
[C19H20F3NO7Na]+: 454.1084; found: 454.1073.
2-tert-Butyl 4,5-dimethyl 3-(3-methoxyphenyl)isoxazole-2,4,5-tri-
carboxylate (3o): According to the general procedure, hydroxyla-
mine 1o (0.25 mmol, 63.3 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a
(122 mL, 1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (50), 5 (50), 10 (200), 15% (300 mL)] to give 3o as
a pale-yellow viscous oil (0.18 mmol, 69.8 mg, 71%). 1H NMR
(300 MHz, CDCl3): d=7.26–7.20 (m, 1H), 7.02–6.70 (m, 3H), 6.06 (s,
1H), 3.91 (s, 3H), 3.76 (s, 3H), 3.61 (s, 3H), 1.43 ppm (s, 9H);
13C NMR (75 MHz, CDCl3): d=161.3, 159.9, 158.0, 155.2, 149.8,
140.1, 129.8, 119.5, 114.3, 112.8, 110.9, 84.3, 68.8, 55.3, 53.5, 52.2,
28.1 ppm; MS-ESI: calcd for [C19H23NO8Na]+: 416.1316; found:
416.1314.
2-tert-Butyl 4,5-dimethyl 3-vinylisoxazole-2,4,5-tricarboxylate
(3t): According to the general procedure, hydroxylamine 1t
(0.25 mmol, 43.3 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a (122 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (100), 5 (100), 10% (300 mL)] to give 3t as a light
yellow oil (0.13 mmol, 39.1 mg, 50%). 1H NMR (300 MHz, CDCl3):
d=6.00–5.84 (m, 1H), 5.63 (d, J=6.1 Hz, 1H), 5.43 (d, J=17.0 Hz,
1H), 5.27 (d, J=10.2 Hz, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 1.52 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): d=161.5, 158.0, 155.7, 150.2,
133.8, 118.2, 109.8, 84.3, 67.31, 53.5, 52.2, 28.1 ppm; MS-ESI: m/z:
calcd for [C14H20NO7]+: 314.1234; found: 314.1234.
2-tert-Butyl 4,5-dimethyl 3-(2-methoxyphenyl)isoxazole-2,4,5-tri-
carboxylate (3p): According to the general procedure, hydroxyla-
mine 1p (0.25 mmol, 63.3 g, 1.00 equiv), dry CH2Cl2 (2 mL), 2a
(122 mL, 1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica eluting with pentane/AcOEt
[(%AcOEt): 1 (50), 5 (50), 15 (200), 20% (300 mL)] to give 3p as
light-yellow viscous oil (0.11 mmol, 42.4 mg, 43%). 1H NMR
(300 MHz, CDCl3): d=7.33–7.27 (m, 2H), 6.99–6.86 (m, 2H), 6.51 (s,
1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.63 (s, 3H), 1.43 ppm (s, 9H);
13C NMR: 161.6, 158.4, 157.4, 155.4, 149.7, 130.1, 129.1, 126.5, 120.9,
111.2, 111.1, 83.9, 64.4, 55.8, 53.5, 52.1, 28.1 ppm; MS-ESI: m/z calcd
for [C19H23NO8Na]+: 416.1316; found: 416.1317.
2-tert-Butyl 4,5-dimethyl 3-cyclohexylsoxazole-2,4,5-tricarboxy-
late (3u): According to the general procedure, hydroxylamine 1u
(0.25 mmol, 50.8 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a (122 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (100), 5 (50), 10% (300 mL)] to give 3u as a light-
yellow oil (0.19 mmol, 68.6 mg, 74%). 1H NMR (400 MHz, CDCl3):
d=5.07 (d, J=2.8 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 1.68 (m, 5H),
1.50 (s, 9H), 1.20–0.84 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=
162.1, 158.3, 157.2, 150.7, 109.3, 84.0, 70.7, 53.3, 52.2, 41.2, 30.0,
29.8, 28.1, 26.3, 26.2, 26.0, 25.8 ppm; MS-ESI: m/z: calcd for
[C18H28NO7]+: 370.1860; found: 370.1855.
2-tert-Butyl 4,5-dimethyl 3-(4-bromophenyl)isoxazole-2,4,5-tri-
carboxylate (3q): According to the general procedure, hydroxyla-
mine 1q (0.25 mmol, 75.5 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a
(122 mL, 1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (50), 5 (50), 10 (200), 15% (300 mL)] to give 3q as
light-yellow oil (0.16 mmol, 70.6 mg, 80%). 1H NMR (300 MHz,
2-tert-Butyl 4,5-dimethyl 3-ethylisoxazole-2,4,5-tricarboxylate
(3v): According to the general procedure, hydroxylamine 1v
(0.25 mmol, 43.8 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a (122 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
Chem. Eur. J. 2015, 21, 12053 – 12060
www.chemeurj.org
12059
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Chem. Commun. 2000, 1449–1458; c) K. V. Gothelf, K. A. Jørgensen,
Chem. Rev. 1998, 98, 863–909. See also: d) R. Huisgen, J. Org. Chem.
1976, 41, 403–419.
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (100), 5 (100), 10% (300 mL)] to give 3v as light-
yellow oil (0.13 mmol, 39.1 mg, 50%). 1H NMR (300 MHz, CDCl3):
d=5.16 (dd, J=6.8, 3.4 Hz, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 1.86 (m,
1H), 1.70 (m, 1H), 1.52 (s, 9H), 0.96 ppm (t, J=7.4 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=161.8, 158.20, 156.5, 150.6, 118.7,
110.1, 83.9, 67.2, 53.3, 52.2, 28.1, 27.0, 8.8 ppm; MS-ESI: m/z: calcd
for [C14H21NO7]+: 316.1391; found: 316.1387.
[9] For stable N-protected nitrones, such as benzyl, allyl, or glycosyl, see:
a) P. N. Confalone, G. Pizzolato, D. L. Confalone, M. R. Uskokovic, J. Am.
Chem. Soc. 1980, 102, 1954–1960; b) K. Ben Ayed, A. Beauchard, J.-F.
Poisson, S. Py, M. Y. Laurent, A. Martel, H. Ammar, S. Abid, G. Dujardin,
Eur. J. Org. Chem. 2014, 2924–2932; c) A. Vaseila, R. Voeffray, Helv. Chim.
Acta 1982, 65, 1953–1964; d) S. Cicchi, M. Marradi, M. Corsi, C. Faggi, A.
Goti, Eur. J. Org. Chem. 2003, 4152–4161.
2-tert-Butyl 4,5-dimethyl 3-isobutylisoxazole-2,4,5-tricarboxylate
(3w): According to the general procedure, hydroxylamine 1w
(0.25 mmol, 50.8 mg, 1.00 equiv), dry CH2Cl2 (2 mL), 2a (122 mL,
1.00 mmol, 4.00 equiv), and TEMPO (78.8 mg, 0.50 mmol,
2.00 equiv) were reacted. The crude product was purified by flash
column chromatography on silica gel eluting with pentane/AcOEt
[(%AcOEt): 1 (100), 5 (50), 10% (300 mL)] to give 3w as a light-
yellow oil (0.08 mmol, 27.8 mg, 32%). 1H NMR (300 MHz, CDCl3):
d=5.24–5.03 (m, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 1.87–1.47 (m, 3H),
1.46 (s, 9H), 0.95 (d, J=6.5 Hz, 3H), 0.88 ppm (d, J=6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=160.7, 157.2, 156.0, 149.8, 110.7, 83.0,
63.8, 52.3, 51.1, 42.3, 27.0, 23.5, 22.5, 20.3 ppm; MS-ESI: m/z: calcd
for [C16H25NO7Na]+: 366.1523; found: m/z=366.1527.
[10] a) X. Guinchard, Y. VallØe, J.-N. Denis, Org. Lett. 2005, 7, 5147–5150;
b) C. Gioia, F. Fini, A. Mazzanti, L. Bernardi, A. Ricci, J. Am. Chem. Soc.
2009, 131, 9614–9615.
[11] a) K. M. Partridge, M. E. Anzovino, T. P. Yoon, J. Am. Chem. Soc. 2008,
130, 2920–2921; b) N. Morita, R. Kono, K. Fukui, A. Miyazawa, H. Masu, I.
Azumaya, S. Ban, Y. Hashimoto, I. Okamoto, O. Tamura, J. Org. Chem.
2015, 80, 4797–4802.
[12] An isolated early example using Ag2O as the oxidant: a) S. A. Hussain,
A. H. Sharma, M. J. Perkins, D. Griller, Chem. Commun. 1979, 289–291.
For a photocatalytic approach for stable N-aryl nitrones, see: b) H. Hou,
S. Zhu, F. Pan, M. Rueping, Org. Lett. 2014, 16, 2872–2875.
[13] For our previous contributions, see: a) H. Richter, O. García MancheÇo,
Org. Lett. 2011, 13, 6066–6069; b) H. Richter, R. Frçhlich, C. G. Daniliuc,
O. García MancheÇo, Angew. Chem. Int. Ed. 2012, 51, 8656–8660;
Angew. Chem. 2012, 124, 8784–8788; c) R. Rohlmann, T. Stopka, H.
Richter, O. García MancheÇo, J. Org. Chem. 2013, 78, 6050–6064, and
references therein.
Acknowledgements
[14] Selected reviews on dehydrogenative coupling reactions: a) C.-J. Li, Acc.
Chem. Res. 2009, 42, 335–344; b) C. J. Scheuermann, Chem. Asian J.
2009, 4, 436–451; c) M. Klussmann, D. Sureshkumar, Synthesis 2011,
353–369; d) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780–
1824; e) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215–1292; f) R.
Rohlmann, O. García MancheÇo, Synlett 2013, 24, 6–10.
The Deutsche Forschungsgemeinschaft and DECHEMA (Max-
Buchner-Forschungsstipendium) are gratefully acknowledged
for generous support. We also thank Dr. Peter Nesvadba (BASF
Schweiz AG) for the donation of various TEMPO derivatives.
[15] For the oxidation of hydroxylamines to nitrones with TEMPO, see: a) S.
Murarka, A. Studer, Adv. Synth. Catal. 2011, 353, 2708–2714; b) P.
Merino, I. Delso, T. Tejero, F. Cardona, A. Goti, Synlett 2007, 2651–2654.
[16] Selected reviews on TEMPO chemistry: a) T. Stopka, O. García Manche-
Ço, Synthesis 2013, 45, 1602–1611; b) L. Tebben, A. Studer, Angew.
Chem. Int. Ed. 2011, 50, 5034–5068; Angew. Chem. 2011, 123, 5138–
5174; c) T. Vogler, A. Studer, Synthesis 2008, 1979–1993; d) R. A. Shel-
don, I. W. C. E. Arends, Adv. Synth. Catal. 2004, 346, 1051–1071.
[17] The use of DCE at 708C provided similar results (80 vs. 87% yield).
[18] Unfortunately, the extension to nonactivated dipolarophiles such as sty-
rene was not possible using DMAD as a cheap sacrificial reagent.
[19] B. Kçnig, W. Pitsch, M. Kleon, R. Vasold, M. Prall, P. R. Schreiner, J. Org.
Chem. 2001, 66, 1742–1746.
[20] Electron-withdrawing groups at the nitrogen lower the energy of the
HOMO, which affects the HOMOnitrone –LUMOdipolarophile interaction. See:
Molecular Orbitals and Organic Chemical Reactions: Reference Edition,
(Ed.: I. Fleming), Wiley-VCH, 2010.
[21] For the reaction of isolated N-Bn nitrone 8 with DMAD, see: N. CoÅkun,
A. Öztürk, Tetrahedron 2006, 62, 12057–12063.
Keywords: cycloadditon · dehydrogenative · isoxazolines ·
TEMPO · unstable N-acyl nitrones
[1] Selected reviews: a) T. M. V. D. Pinho e Melo, Eur. J. Org. Chem. 2010,
3363–3376; b) P. Grünanger, P. Vita-Finzi, Isoxazolines, in The Chemistry
of Heterocyclic Compounds, Vol. 49, (Eds.: E. C. Taylor, A. Weissberger),
John Wiley & Sons, 1991, (Chapter 2) pp. 416–647.
[2] a) A. G. Habeeb, P. N. Praveen Rao, E. E. Knaus, J. Med. Chem. 2001, 44,
2921–2927; b) M. E. Frakey, R. M. Garbaccio, G. D. Hartman, PCT Int.
Appl. WO2006/023440, 43, 2006.
[3] Representative example: P. Aschwanden, L. Kværnø, R. W. Geisser, F.
Kleinbeck, E. M. Carreira, Org. Lett. 2005, 7, 5741–5742.
[4] a) A. Sakakura, M. Hori, M. Fushimi, K. Ishihara, J. Am. Chem. Soc. 2010,
132, 15550; b) M. M.-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 4572–
4573; c) F. M. Cordero, F. Pisaneschi, A. Goti, J. Ollivier, J. Salaün, A.
Brandi, J. Am. Chem. Soc. 2000, 122, 8075–8076; d) D. A. Evans, F. Keli-
beck, M. Rueping, in Asymmetric Synthesis - The Essentials, (Eds.: M.
Christmann, S. Bräse), Wiley-VCH, Weinheim, 2007, pp. 72, and referen-
ces therein.
[22] a) K. U. Ingold, K. Adamic, D. F. Bowman, T. Gillan, J. Am. Chem. Soc.
1971, 93, 902–908; b) D. F. Bowman, J. Brokenshire, T. Gillan, K. U.
Ingold, J. Am. Chem. Soc. 1971, 93, 6551–6555; c) D. F. Bowman, T.
Gillan, K. Ingold, J. Am. Chem. Soc. 1971, 93, 6555–6561.
[5] See, for example: N. Wada, K. Kaneko, Y. Ukaji, K. Inomata, Chem. Lett.
2011, 40, 440–443, and referenced cited therein.
[23] The DFT calculations were performed using Turbomole 6.5. [a) F. Furche,
R. Ahlrichs, C. Hättig, W. Klopper, M. Sierka, F. Weigend, Comp. Mol. Sci.
2014, 4, 91–100] within Gaussian basis sets [b) Gaussian 09 (Revi-
sionB.01), M. J. Frisch et al., Gaussian, Inc., Wallingford CT, 2010]. Geom-
etry optimizations were performed with the BP86 density functional
and the triple-z basis set def2-TZVP, using the resolution of identity (RI-
J) approximation. Single point energies were calculated with the
double hybrid functional B2PLYP [c) L. Goerigk, S. Grimme, Comp. Mol.
Sci. 2014, 4, 576–600] and def2-TZVP as the basis set. Grimme’s disper-
sion correction D3 was used in all calculations [d) S. Grimme, Comp.
Mol. Sci. 2011, 1, 211 –228].
[6] For example: a) A. Brandi, F. Cardona, S. Cicchi, F. M. Cordero, A. Goti,
Chem. Eur. J. 2009, 15, 7808–7821; b) H. Wei, C. Qiao, G. Liu, Z. Yang, C.
Li, Angew. Chem. Int. Ed. 2013, 52, 620–624; Angew. Chem. 2013, 125,
648–652, and references therein.
[7] a) I. A. Grigor’ev, in Nitrile Oxides, Nitrones and Nitronates in Organic Syn-
thesis: Novel Strategies in Synthesis (Ed.: H. Feuer), John Wiley & Sons
Inc., New Jersey, 2008 (2nd Ed.), (Chapter 2) pp. 129–434; b) P. Merino,
in Science of Synthesis Vol. 27, (Ed. A. Padwa), Thieme, Stuttgart, 2004,
pp. 511–580; c) R. Bloch, Chem. Rev. 1998, 98, 1407–1438. See also:
d) F. Cardona, A. Goti, Angew. Chem. Int. Ed. 2005, 44, 7832–7835;
Angew. Chem. 2005, 117, 8042–8045.
[8] Selected overviews: a) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; (Eds.: A. Padwa,
W. H. Pearson), Wiley: New York, 2002; b) K. V. Gothelf, K. A. Jørgensen,
Received: April 2, 2015
Published online on July 17, 2015
Chem. Eur. J. 2015, 21, 12053 – 12060
www.chemeurj.org
12060
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim