Functional-group-tolerant catalytic migratory oxidative coupling of nitrones

Article abstract of DOI:10.1002/asia.201200359

A copper-catalyzed migratory oxidative-coupling reaction between nitrones and various ethers/amines exhibited high functional-group tolerance. Even in aqueous media, the reaction proceeded efficiently. For practical use of this catalysis, a unique sequent

Full text of DOI:10.1002/asia.201200359

DOI: 10.1002/asia.201200359
Functional-Group-Tolerant Catalytic Migratory Oxidative Coupling of
Nitrones
Shogo Hashizume,[a, b] Kounosuke Oisaki,*[a, b] and Motomu Kanai*[a, b]
Abstract: A copper-catalyzed migrato-
ry oxidative-coupling reaction between
nitrones and various ethers/amines ex-
hibited high functional-group tolerance.
Even in aqueous media, the reaction
proceeded efficiently. For practical use
of this catalysis, a unique sequential
Huisgen cycloaddition was demonstrat-
ed. Mechanistic investigations revealed
that the reaction proceeded through
oxidative catalytic activation of ethers/
amines to afford iminium/oxonium in-
termediates by concurrent dual one-
electron abstractions by copper(II) and
oxyl radicals.
À
Keywords: C C bond formation ·
À
C H activation · copper · cycload-
dition · nitrones
Introduction
ing biologically relevant molecules, such as proteins, lipids,
and sugars.
New, efficient, and sustainable catalytic methods for the
construction of carbon skeletons of organic molecules are
essential for advancing synthetic organic chemistry. The
direct catalytic transformation of unreactive and ubiquitous
carbon–hydrogen bonds into carbon–carbon bonds is a rapid-
ly emerging, powerful synthetic tool because cumbersome
preactivation steps and functional-group manipulations can
be omitted, thereby minimizing the number of synthetic
steps and chemical waste.[1] Cross-dehydrogenative coupling
(CDC) reactions, pioneered by Li among others, involve the
Many catalytic CDC reactions have been reported to
date,[9] but there is still much room for improvement, espe-
cially in their extension to the potential applications de-
scribed above. Moreover, the use of precious-metal catalysts
and/or wasteful oxidants, harsh reaction conditions, narrow
substrate scope, and low functional-group compatibility are
typical drawbacks of the current CDC reactions.
We have previously reported the migratory oxidative-cou-
pling reaction between nitrones and various ethers/amines
that was promoted by an inexpensive and abundant copper
catalyst and tert-butylhydroperoxide (TBHP) as a terminal
oxidant (Scheme 1).[10] This reaction involves multiple steps:
À
À
direct oxidative formation of C C bonds by coupling the C
H bonds of two distinct coupling partners in the presence of
a terminal oxidant.[2] CDC reactions generate a C C bond
À
with an escalation of the molecular oxidation level, which
contributes to an environmentally benign, streamlined syn-
thesis that is endowed with all aspects of “synthetic econo-
my” (atom economy,[3] step economy,[4] and redox econo-
my[5]). Chemoselective CDC reactions can potentially real-
ize a convergent coupling between the late-stage fragments
of a synthesis that contain other functional groups without
the need for protecting groups.[6] Furthermore, “water-toler-
ant” CDC[7] reactions might be extended to future applica-
tions in bio-orthogonal reactions,[8] which are used for label-
Scheme 1. Catalytic migratory oxidative coupling of nitrones.
À
1) selective cleavage of two distinct Csp3 H bonds (benzylic
À
À
C H bonds in nitrones and Ca H bonds in ethers/amines);
2) migration of the C=N double bond in nitrones; and
[a] S. Hashizume, Dr. K. Oisaki, Prof. Dr. M. Kanai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
À
3) site-selective C C bond-formation between nitrones and
ethers/amines. Mild reaction conditions (room temperature
and near-neutral pH) allow for the rapid synthesis of
unique, unnatural a-amino-acid derivatives that contain var-
ious functional groups. The pseudoreplicated nitrone could
be used as a foothold for further chemical transformations,
such as [2+3] cycloaddition reactions and the nucleophilic
addition of organometallic reagents.[11]
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5841-5206
E-mail: oisaki@mol.f.u-tokyo.ac.jp
kanai@mol.f.u-tokyo.ac.jp
[b] S. Hashizume, Dr. K. Oisaki, Prof. Dr. M. Kanai
Kanai Life Science Catalysis Project
ERATO (Japan) Science and Technology Agency (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Herein, we report that this oxidative-coupling reaction
can be applied to multifunctional substrates without the use
of protecting groups, even in aqueous media. Mechanistic
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200359.
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Table 1. Coupling reactions between nitrone 1a and functionalized substrates 2a–2j.[a]
studies revealed that the coupling reaction proceed-
ed through the nucleophilic attack of nitrones to
form oxonium/iminium cationic intermediates that
were oxidatively generated from ethers/amines. We
propose a unique two-electron-oxidation mecha-
nism of ethers/amines through concurrent dual one-
electron abstractions by catalytic copper(II) and
oxyl radicals.
Results and Discussion
Coupling Reactions between Nitrones and
Functionalized Substrates
The catalytic migratory oxidative-coupling reaction
proceeds under mild conditions. This property moti-
vated us to investigate the functional-group toler-
ance and chemoselectivity of this reaction. Cyclic
acetals 2a–2g, which possessed various functional
groups, were tested as coupling partners in the reac-
tions with nitrone 1a (Table 1).
The reaction of compound 2a with two distinct
acetal groups proceeded exclusively at the cyclic
acetal moiety (C1), thereby affording compound
3aa as the sole coupling product. The coupling
product at the dimethylacetal center (C4) was not
observed in this case. The reaction of compound
2b, which possesses a C5=C6 double bond, mainly
proceeded at the acetal C1 moiety, thus affording
compound 3ab. However, in this case, compound
3ab’ was also produced as a minor product through
a 5-membered cyclization reaction between the C1
[a] Standard reaction conditions: compound 1a (0.3 mmol), compound 2 (1.5 mmol),
CuOBz (0.015 mmol), 1,10-phenanthroline (0.018 mmol), NaHCO3 (0.06 mmol), and
TBHP (0.6 mmol) in DMSO (1.5 mL) at room temperature. Yields are of the isolated
products unless otherwise noted. Ratios in parenthesis are the diastereomeric ratios.
[b] Yield was determined by 1H NMR spectroscopy of inseparable mixture of the
À
and C5 atoms, followed by intermolecular C C
bond formation at the C6 position with the nitrone.
The reaction of acetal 2c, which containing a neigh-
boring cyclopropane moiety, proceeded without product and the byproducts or the starting material (see the Experimental Section).
[c] Reaction was conducted on a 0.15 mmol scale.
ring-opening of the cyclopropane (3ac). These two
results (the production of a mixture of compounds
3ab and 3ab’ versus compound 3ac) provided an
important insight into the reaction mechanism (see below).
actions of acetals 2e–2g, which contained an epoxide, an un-
ꢀ
À
Acetal 2d, which possessed an Cw C triple bond, afforded
protected primary hydroxy group, and a benzylic C H
bond, respectively, proceeded in synthetically useful yields
without opening of the epoxide or oxidation of the alcohol
the expected coupling product (3ad); none of the potential
side-reactions, such as cyclization (analogous to compound
3ab’), [2+3] cycloaddition between the nitrone and the
triple bond, Glaser coupling,[12] or alkynylation of the nitro-
nes, were observed, although copper–acetylide species
À
or the benzylic C H bond. Acetal 2h, which contained an
acetylated sugar moiety, was successfully coupled with the
nitrone at the predicted position to leave the sugar moiety
intact. Acetals 3i and 3j, which were ligated with N-Boc-
tryptophan and -tyrosine (Boc=tert-butoxycarbonyl), re-
spectively, were also successful as coupling partners. Al-
though these two amino acids contained oxidatively labile
functional groups (unprotected indole and phenol groups,
respectively), the desired reactions proceeded chemoselec-
tively in moderate-to-good yield to afford their convergent
products, compounds 3ai and 3aj, respectively.
À
should be generated through Csp H bond activation. The re-
Abstract in Japanese:
Thus, this catalytic migratory oxidative-coupling reaction
is compatible with a wide range of functional groups without
the need for protecting groups. This characteristic is advan-
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Functional-Group-Tolerant Oxidative Coupling of Nitrones
ꢀ
tageous for its application in late-stage convergent coupling
reactions in the synthesis of complex molecule.
our oxidative-coupling reaction with a terminal C C triple
bond (Table 1) we expected that a sequential combination
of these two convergent steps would provide a unique
method to rapidly increase the molecular size and structural
complexity starting from a nitrone, an amine/ether, and an
azide in aqueous media. Because both reactions are promot-
ed by a copper catalyst, we investigated a sequential one-
pot reaction of nitrone 1b, amine 2m, and BnN3 (Bn=
benzyl).
Catalysis under Aqueous Conditions
The direct modification of unprotected hydrophilic drug-like
À
molecules and biomolecules in aqueous media through a C
H functionalization process will be a useful and attractive
method in medicinal chemistry and chemical biology. How-
À
ever, catalytic C H functionalization in aqueous media is
After the CuOBz-catalyzed oxidative coupling reaction
between compounds 1b and 2m had been completed, BnN3
was added into the reaction mixture to effect the Huisgen-
cycloaddition reaction. The desired product (4) was ob-
tained in moderate yield (56%) but about 20% of com-
pound 3bm remained. Considering that the Huisgen-cyclo-
addition reaction is promoted by a copper(I) catalyst (a re-
duced form), we added reductants of copper(II) prior to the
addition of the azide. However, unexpectedly, the use of
sodium ascorbate as a reductant lowered the yield (11%).
On the other hand, the addition of an aqueous solution of
Na2S2O3, followed by the addition of a catalytic amount of
CuSO4, sodium ascorbate, and BnN3, afforded triazole 4 in
77% yield (Scheme 2). This highly chemoselective sequen-
tial transformation in aqueous media is potentially useful
for labeling bioactive molecules.[15]
[13]
À
rare, especially for Csp3 H bonds. Encouraged by the ex-
cellent functional-group tolerance of our catalytic condi-
tions, especially for an unprotected hydroxy group (Table 1,
3af), we expected that the reaction would even proceed effi-
ciently in aqueous media. Indeed, the yields that were pro-
duced in aqueous solvent (H2O/CH3CN, 1:1) were very simi-
lar to those in non-aqueous solvent (DMSO, Table 2).
Therefore, this oxidative-coupling reaction of nitrones can
be potentially used as a bio-orthogonal reaction.
Table 2. Coupling reactions under aqueous conditions.[a]
Entry
Product (3)
Aqueous condi- Non-aqueous condi-
tions[b]
tions[b,c]
t [h] Yield [%] t [h]
Yield [%]
1
3ak 5.5
3al 6.5
67
3.5
63
2
3
51 (1.2:1)
66
5
65 (2.4:1)
69
3am
1
1.5
Scheme 2. Sequential “one-pot” catalytic migratory oxidative-coupling/
Huisgen-cycloaddition reactions.
[a] Standard reaction conditions: compound 1a (0.3 mmol), compound 2
(1.5 mmol), CuOBz (0.015 mmol), 1,10-phenanthroline (0.018 mmol),
NaHCO3 (0.06 mmol), and TBHP (0.6 mmol) in H2O/CH3CN (1:1,
1.5 mL) at room temperature. [b] Yield of isolated product; the ratio in
parenthesis is the diastereomeric ratio (entry 2). [c] Data taken from
Ref. [10].
Mechanistic Investigations
To elucidate the reaction mechanism, we performed various
control experiments. Initially, we considered a “radical-
type” mechanism (Scheme 3a) in which carbon radical 5,
which was catalytically generated from ether/amine 2, at-
À
Encouraged by these results, we planned a sequential
one-pot oxidative-coupling reaction of nitrone 1b, which
tacks nitrone 1 to form the C C bond; this mechanism was
plausible for two reasons: First, the combination of cop-
per(I) and hydroperoxide produces copper(II) species and
a hydroxyl or alkoxyl radical (Fenton reaction).[16] This oxyl
ꢀ
contained a terminal C C triple bond, followed by Huisgen
cycloaddition, under aqueous conditions. The copper-cata-
lyzed Huisgen reaction is a powerful method that can
À
radical has sufficient activity to cleave the Ca H bond of
ꢀ
couple a terminal C C triple bond and an azide with excel-
ether/amine 2 in a radical-type manner (hydrogen-radical
abstraction). Second, nitrones are effective acceptors of
carbon-radical species in general.[17] The resulting aminoxyl
lent chemoselectivity and functional-group tolerance, even
under aqueous conditions.[14] Based on the compatibility of
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Scheme 4. Radical clock experiments.
trast, when using acetal 2c, which contained a neighboring
cyclopropane ring, the expected product (3ac) was obtained
without any cyclopropane ring-opening side-reactions
(Scheme 4). These two results strongly suggest that the reac-
tion does not involve a carbon-radical species (5).
In addition, subsequent control experiments also contra-
dicted this “radical-type” mechanism. First, we performed
the reactions of compound 1a with acetals 2g and 2n, which
possessed hydroxy groups at the 6- and 4-positions, respec-
tively (Scheme 5a). As shown in Table 1 , acetal 2 f pro-
duced the expected product (3af). However, acetal 2n did
not produce its corresponding coupling product; instead, or-
thoester 9 was obtained as the major side-product. Orthoest-
er 9 could not be produced through the a-carbon-radical in-
termediate (5) that was hypothesized in the “radical-type”
mechanism. Thus, compound 9 must have been formed
through intramolecular nucleophilic attack of the 4-hydroxy
group onto an oxidatively generated oxonium-cation inter-
mediate. The five-membered cyclization reaction should be
faster than the intermolecular oxidative-coupling reaction.
The oxidative-coupling product (3ag) was produced in the
case of acetal 2g because the formation of the 7-membered
ring was kinetically unfavorable.
Scheme 3. a) “Radical-type” mechanism (forbidden) and b) “polar”
mechanism (plausible).
radical (6) that is generated through attack of carbon radical
5 on compound 1 would be oxidized by copper(II), thereby
producing coupling product 3.
However, the results of our
mechanistic experiments con-
tradicted this hypothesis. Ingold
and co-workers reported rate
constants of various radical-iso-
merization reactions that were
used as “radical clocks”.[18] The
estimated rate constant of the
ring-opening reaction of the cy-
clopropylmethyl radical was
much larger than that of the
ring-closing reaction of a 5-hex-
enyl radical (k=1.3ꢁ108 mÀ1 sÀ1
and 1.0ꢁ105 mÀ1 sÀ1, respective-
ly, at 258C). As shown in
Table 1, the reaction between
nitrone 1a and acetal 2b, which
contained
a
C5=C6 double
bond, afforded a mixture of the
expected product (3ab) and cy-
clized byproduct 3ab’. In con- Scheme 5. Control experiments.
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Functional-Group-Tolerant Oxidative Coupling of Nitrones
Second, the reaction between compound 1a and N-PMP-
protected amine 2o (PMP=para-methoxyphenyl), led to
the formation of homo-coupled byproducts (10). Thus, we
subjected compound 2o to the reaction conditions in the ab-
sence of nitrone 1a and an oxidative Friedel–Crafts reaction
proceeded to afford compound 10 in 25% yield
(Scheme 5b). Dimeric compound 10 was presumably pro-
duced through nucleophilic attack of the electron-rich arene
onto an iminium-cation intermediate. Together, cationic in-
termediates 8 were generated from ether/amine substrates 2
in this present catalytic cycle.
Experimental Section
General
1H NMR and 13C NMR spectra were recorded on JEOL JNM-LA500,
JNM-ECX500, and JNM-ECA500 spectrometers that were operating at
500 MHz (1H) and 125.65 MHz (13C). Chemical shifts were reported
1
downfield of TMS (d=0 ppm) in the H NMR spectra and relative to the
solvent as an internal reference in the 13C NMR spectra. IR spectra were
recorded on a JASCO FT/IR 410 Fourier-transform IR spectrophotome-
ter. MS (ESI) was performed on a Waters ZQ4000 spectrometer and
HRMS (ESI) was performed on a JEOL JMS-T100 LC AccuTOF spec-
trometer. Column chromatography was performed on silica gel
(Merck 60, 230–400 mesh ASTM). In general, the reactions were per-
formed under an argon atmosphere. Reagents were prepared as de-
scribed in the Supporting Information or purchased from Sigma–Aldrich,
TCI (Tokyo Chemical Industry Co., Ltd.), Kanto Chemical Co., Inc., and
Wako Pure Chemical Industries, Ltd. and used without purification.
Based on these experimental results, we propose
a “polar” mechanism that involves an oxonium/iminium in-
termediate (8), which is generated from the in situ oxidation
of ethers/amines
2
by the copper/TBHP system
(Scheme 3b), as an active species.[19,20] Subsequent nucleo-
philic attack of nitrone 1 onto cation 8 produces product 3.
The detailed mechanism of the oxidation step (cation-gener-
ation step) remains unclear. Considering the fact that both
copper(II) and the tert-butoxyl radical are generated by
a Fenton reaction and that these two species are generally
one-electron oxidants, we hypothesize that the oxidation of
compound 2 proceeds through the simultaneous radical-type
General Procedure for the Migratory Oxidative-Coupling Reactions
between Nitrones and Functionalized Substrates (Table 1, for Compound
3aa)
Dry DMSO (1.5 mL) was added into a flame-dried test tube that was
charged with CuOBz (2.8 mg, 0.015 mmol; bz=benzoyl), 1,10-phenan-
throline (3.2 mg, 0.018 mmol), and NaHCO3 (5.0 mg, 0.060 mmol). The
mixture was stirred at room temperature until the copper salt had com-
pletely dissolved (approximately 10 min). Next, nitrone 1a (58.0 mg,
0.30 mmol) and cyclic acetal 2a (356 mL, 348 mg, 1.50 mmol) were added
into the test tube and the inside of the test tube was flushed with argon
gas. TBHP (5.5m in n-decane, 109 mL, 0.60 mmol) was added to the mix-
ture with a syringe and the mixture was stirred at room temperature for
4.5 h before being quenched with solid Na2S2O3. The mixture was directly
purified by column chromatography on silica gel (EtOAc/n-hexane, 1:2)
to afford compound 3aa (85.3 mg, 0.201 mmol, 67% yield). For com-
pounds 3ac, 3ai, and 3aj, the product was inseparable from the starting
material (1a) or the byproduct (11; for characterization of compound 11,
À
cleavage of the Ca H bond by hydroxyl or alkoxyl radicals
and by one-electron oxidation from the lone pair of heteroa-
toms in compound 2 with a copper(II) species (Scheme 3b,
7).[20] In this mechanism, the two-electron oxidation of
ethers/amines 2 to afford oxonium/iminium intermediates
(8) proceeds through two one-electron abstractions without
generating a radical-type intermediate (a concurrent dual
one-electron abstraction mechanism). This hypothesis is
consistent with the current experimental data.
1
see our previous report, Ref. [10a]). The yield was calculated by H NMR
spectroscopy of the mixture of compound 3 with compound 1a or com-
pound 11.
General Procedure for the Coupling Reactions under Aqueous Conditions
(Table 2, entry 1)
Conclusions
Distilled water and CH3CN (0.75 mL
each) were added into a dried test
tube that was charged with CuOBz
(2.8 mg, 0.015 mmol), 1,10-phenan-
The copper-catalyzed migratory oxidative-coupling reaction
between nitrones and ethers/amines exhibits remarkable
functional-group tolerance. Furthermore, this reaction can
be performed in aqueous media under mild conditions (at
room temperature and at near-neutral pH). These two char-
acteristics of this system are favorable for its future exten-
sion to convergent- and protecting-group-free CDC reac-
tions, as well as for the chemical labeling of biologically rel-
evant molecules. As a unique application, the sequential
one-pot catalytic oxidative-coupling/Huisgen-cycloaddition
reactions of an amine, a nitrone, and an azide were demon-
strated in aqueous solvent. Mechanistic investigations
strongly suggest that the polar mechanism is more plausible.
The reactive cationic intermediate (oxonium/iminium
cation) is likely generated through a concurrent dual one-
electron-abstraction mechanism. This mechanistic founda-
tion will be useful for the future development of synthetical-
ly useful, chemoselective oxidative-coupling reactions.
throline (3.2 mg, 0.018 mmol), and
NaHCO3 (5.0 mg, 0.060 mmol). The mixture was stirred at room temper-
ature until the copper salt had completely dissolved (approximately
10 min). Next, nitrone 1a (58.0 mg, 0.30 mmol) and acetaldehyde pinaco-
lacetal 2k (207 mL, 216 mg, 1.50 mmol) were added into the test tube and
the inside of the test tube was flushed with argon gas. TBHP (5.5m in n-
decane, 109 mL, 0.60 mmol) was added into the mixture with a syringe
and the mixture was stirred at room temperature for 5.5 h before being
quenched with a saturated solution of aqueous Na2S2O3. After diluting
this mixture with water, the aqueous layer was extracted three times with
EtOAc. The combined organic phase was dried with anhydrous Na2SO4,
filtered, and evaporated to give a crude mixture. 1H NMR spectroscopy
of the crude mixture was performed to determine the diastereomeric
ratio (for Table 2, entry 2). The crude mixture was purified by column
chromatography on silica gel (acetone/n-hexane, 1:4) to afford compound
3ak (67.2 mg, 0.200 mmol, 67% yield).
General Procedure for the Sequential One-Pot Catalytic Migratory
Oxidative-Coupling/Huisgen-Cycloaddition Reactions under Aqueous
Conditions (Scheme 2)
Distilled water and CH3CN (0.75 mL each) were added into a dried test
tube that was charged with CuOBz (2.8 mg, 0.015 mmol), 1,10-phenan-
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throline (3.2 mg, 0.018 mmol), and NaHCO3 (5.0 mg, 0.060 mmol). The
mixture was stirred at room temperature until the copper salt had com-
pletely dissolved (approximately 10 min). Next, nitrone 1b (77.8 mg,
0.30 mmol) and N,N-dimethylaniline 2m (189 mL, 182 mg, 1.50 mmol)
were added into the test tube. Finally, TBHP (5.5m in n-decane, 109 mL,
0.60 mmol) was added with a syringe and the reaction mixture was stirred
at room temperature for 5 h. The oxidative-coupling reaction was
Int. Ed. 2008, 47, 7075; h) Z.-P. Li, R. Yu, H.-J. Li, Angew. Chem.
2008, 120, 7607; Angew. Chem. Int. Ed. 2008, 47, 7497; i) S. Lin, C.-
X. Song, G.-X. Cai, W.-H. Wang, Z.-J. Shi, J. Am. Chem. Soc. 2008,
130, 12901; j) A. J. Young, M. C. White, J. Am. Chem. Soc. 2008,
130, 14090; k) C. Dubs, Y. Hamashima, N. Sasamoto, T. M. Seidel, S.
Suzuki, D. Hashizume, M. Sodeoka, J. Org. Chem. 2008, 73, 5859;
l) H. Richter, O. G. MancheÇo, Eur. J. Org. Chem. 2010, 4460; m) F.
Yang, J. Li, J. Xie, Z.-Z. Huang, Org. Lett. 2010, 12, 5214; n) J. Xie,
Z.-Z. Huang, Angew. Chem. 2010, 122, 10379; Angew. Chem. Int.
Ed. 2010, 49, 10181; o) C. Guo, J. Song, S.-W. Luo, L.-Z. Gong,
Angew. Chem. 2010, 122, 5690; Angew. Chem. Int. Ed. 2010, 49,
5558; p) E. Shirakawa, T. Yoneda, K. Moriya, K. Ota, N. Uchiyama,
R. Nishikawa, T. Hayashi, Chem. Lett. 2011, 40, 1041.
quenched with
a couple of drops of saturated solution of aqueous
Na2S2O3 to quench the TBHP. After stirring for several minutes, CuSO4
(2.4 mg, 0.015 mmol) and sodium ascorbate (5.9 mg, 0.030 mmol) were
added and the inside of the test tube was again flushed with argon. Final-
ly, benzyl azide (37.3 mL, 0.30 mmol) was added with a syringe. The reac-
tion mixture was stirred at room temperature for 18 h and the Huisgen
reaction was quenched with a saturated solution of aqueous NH4Cl. The
resulting mixture was extracted three times with EtOAc. The combined
organic layer was dried with anhydrous Na2SO4, filtered, and evaporated
to give a crude mixture. The crude mixture was purified by column chro-
matography on silica gel (EtOAc/n-hexane, 1:1 to 2:1) to afford com-
pound 4 (119 mg, 0.233 mmol, 77% yield).
[10] a) S. Hashizume, K. Oisaki, M. Kanai, Org. Lett. 2011, 13, 4288;
b) S. Hashizume, K. Oisaki, M. Kanai, Chem. Rec. 2011, 11, 236.
[11] The previously reported synthetic utility of nitrones can be catego-
rized into four main transformations: For [2+3] cyclization reac-
tions, see: a) S. E. Denmark, A. Thorarensen, Chem. Rev. 1996, 96,
137; b) K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863;
c) L. M. Stanley, M. P. Sibi, Chem. Rev. 2008, 108, 2887. For cyclo-
propane-opening cyclization reactions, see: d) I. S. Young, M. A.
Kerr, Angew. Chem. 2003, 115, 3131; Angew. Chem. Int. Ed. 2003,
42, 3023; e) A. C. Stevens, C. Palmer, B. L. Pagenkopf, Org. Lett.
2011, 13, 1528. For Kinugasa reactions, see: f) M. Kinugasa, S. Ha-
shimoto, J. Chem. Soc. Chem. Commun. 1972, 466; g) M. Miura, M.
Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60, 4999;
h) M. M.-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 4572; i) J.
Marco-Contelles, Angew. Chem. 2004, 116, 2248; Angew. Chem. Int.
Ed. 2004, 43, 2198. For reactions in which the nitrones are used as
an electrophile, see: j) D. E. Frantz, R. Fassler, E. M. Carreira, J.
Am. Chem. Soc. 1999, 121, 11245; k) S. Pinet, S. U. Pandya, P. Y.
Chavant, A. Ayling, Y. Vallee, Org. Lett. 2002, 4, 1463; l) M. R. Gar-
rett, J. C. Tarr, J. S. Johnson, J. Am. Chem. Soc. 2007, 129, 12944.
Recently, a CDC reaction that uses nitrones was reported, see: m) S.
Murarka, A. Studer, Org. Lett. 2011, 13, 2746.
Acknowledgements
This work was supported by a Grant in-Aid for Young Scientist B from
the JSPS (K.O.) and by ERATO from the JST (M.K.)
[1] a) Topics in Current Chemistry, Vol. 292 (Eds.: J.-Q. Yu, Z.-J. Shi),
Springer, 2010; b) A. R. Dick, M. S. Sanford, Tetrahedron 2006, 62,
2439; c) H. M. L. Davies, J. Du Bois, J. Q. Yu, Chem. Soc. Rev. 2011,
40, 1855; d) K. Godula, D. Sames, Science 2006, 312, 67; e) H. M. L.
Davies, J. R. Manning, Nature 2008, 451, 417; f) L. McMurray, F.
OꢂHara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885; g) W. R. Gute-
kunst, P. S. Baran, Chem. Soc. Rev. 2011, 40, 1976; h) J. Wencel-
Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740.
[2] a) C.-J. Li, Acc. Chem. Res. 2009, 42, 335; b) C. J. Scheuermann,
Chem. Asian J. 2010, 5, 436; c) M. Klussmann, D. Sureshkumar, Syn-
thesis 2011, 353; d) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev.
2011, 111, 1780.
[3] B. M. Trost, Science 1991, 254, 1471.
[4] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem.
Res. 2008, 41, 40.
[5] For discussions of the benefit of constant oxidation-level escalation
in the synthesis of complex molecules, see: a) P. S. Baran, T. J. Mai-
mone, J. M. Richter, Nature 2007, 446, 404; b) N. Z. Burns, P. S.
Baran, R. W. Hoffmann, Angew. Chem. 2009, 121, 2896; Angew.
Chem. Int. Ed. 2009, 48, 2854; c) Y. Ishihara, P. S. Baran, Synlett
2010, 1733.
[12] Terminal alkynes often cause Glaser homo-coupling in the presence
of copper salts and under oxidative conditions; see: a) C. Glaser,
Ber. Dtsch. Chem. Ges. 1869, 2, 422. For a recent review, see: b) P.
Siemsen, R. C. Livingston, F. Diederich, Angew. Chem. 2000, 112,
2740; Angew. Chem. Int. Ed. 2000, 39, 2632.
[13] For a review, see: a) C. I. Herrerꢃas, X.-Q. Yao, Z.-P. Li, C.-J. Li,
À
Chem. Rev. 2007, 107, 2546. For examples of Csp3 H functionaliza-
tion in aqueous media, see: b) C.-G. Shen, E. A. Garcia-Zayas, A.
Sen, J. Am. Chem. Soc. 2000, 122, 4029; c) B. D. Dangel, J. A. John-
son, D. Sames, J. Am. Chem. Soc. 2001, 123, 8149.
[14] a) R. Huisgen in 1,3-Dipolar Cycloaddition Chemistry (Ed.: A.
Padwa), Wiley, New York, 1984, pp. 1–176; b) A. Padwa in Compre-
hensive Organic Synthesis, Vol. 4 (Ed.: B. M. Trost), Pergamon,
Oxford, 1991, pp. 1069–1109; c) V. V. Rostovtsev, L. G. Green, V. V.
Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708; Angew.
Chem. Int. Ed. 2002, 41, 2596.
[6] For an example of CDC-type late-stage coupling reaction in synthe-
sis, see: a) D.-H. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 5767.
[15] For reviews on click chemistry, see: a) H. C. Kolb, M. G. Finn, K. B.
Sharpless, Angew. Chem. 2001, 113, 2056; Angew. Chem. Int. Ed.
2001, 40, 2004; b) H. C. Kolb, K. B. Sharpless, Drug Discovery
Today 2003, 8, 1128.
À
For examples of late-stage C H functionalization (oxidation and tri-
fluoromethylation, respectively), see: b) E. M. Stang, M. C. White,
Nat. Chem. 2009, 1, 547; c) D. A. Nagib, D. W. C. MacMillan, Nature
2011, 480, 224.
[16] The detailed mechanism of the Fenton reaction is still under debate.
For a recent discussion, see: S. Rachmilovich-Calis, A. Masarwa, N.
Meyerstein, D. Meyerstein, R. van Ekdik, Chem. Eur. J. 2009, 15,
8303 and references therein.
[17] Nitrones, oximes, imines, and Michael acceptors are excellent
carbon-radical acceptors. For O2/alkylborane-initiated radical reac-
tions, see: a) G. W. Kabalka, H. C. Brown, A. Suzuki, S. Honma, A.
Arase, M. Itoh, J. Am. Chem. Soc. 1970, 92, 710; b) H. Miyabe, M.
Ueda, T. Naito, J. Org. Chem. 2000, 65, 5043; c) J.-Y. Liu, Y.-J. Jang,
W.-W. Lin, J.-T. Liu, C.-F. Yao, J. Org. Chem. 2003, 68, 4030. For dia-
lkylzinc-initiated radical reactions, see: d) T. Akindele, K.-i.
Yamada, K. Tomioka, Acc. Chem. Res. 2009, 42, 345.
[7] For reviews of organic reactions in aqueous media, see: a) S. Ko-
bayashi, K. Manabe, Acc. Chem. Res. 2002, 35, 209; b) C.-J. Li,
Chem. Rev. 2005, 105, 3095; c) C.-J. Li, L. Chen, Chem. Soc. Rev.
2006, 35, 68; d) R. N. Butler, A. G. Coyne, Chem. Rev. 2010, 110,
6302.
[8] C. R. Bertozzi, Acc. Chem. Res. 2011, 44, 651.
[9] For representative examples of metal-catalyzed CDC reactions to
À
form Csp3 Csp3 bonds, see: a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2004,
126, 11810; b) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 3672;
c) Z. Li, C.-J. Li, Eur. J. Org. Chem. 2005, 3173; d) Y. Zhang, C.-J.
Li, Angew. Chem. 2006, 118, 1983; Angew. Chem. Int. Ed. 2006, 45,
1949; e) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2006, 128, 56; f) Z. Li,
D. S. Bohle, C.-J. Li, Proc. Natl. Acad. Sci. USA 2006, 103, 8928;
g) L. Zhao, C.-J. Li, Angew. Chem. 2008, 120, 7183; Angew. Chem.
[18] a) D. Lal, D. Griller, S. Husband, K. U. Ingold, J. Am. Chem. Soc.
1974, 96, 6355; b) B. Maillard, D. Forrest, K. U. Ingold, J. Am.
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Functional-Group-Tolerant Oxidative Coupling of Nitrones
Chem. Soc. 1976, 98, 7024. For examples of mechanistic investiga-
tion that employ radical clocks, see: c) T. D. Beeson, A. Mastrac-
chio, J. Hong, K. Ashton, D. W. C. MacMillan, Science 2007, 316,
582; d) D. Noda, Y. Sunada, T. Hatakeyama, M. Nakamura, H. Na-
gashima, J. Am. Chem. Soc. 2009, 131, 6078.
C. Farꢄs, M. Klussmann, J. Am. Chem. Soc. 2011, 133, 8106; b) E.
Boess, C. Schmitz, M. Klussmann, J. Am. Chem. Soc. 2012, 134,
5317.
[20] For a review of dehydroganative transformations through single-
electron oxidation under copper catalysis, see: C. Zhang, C. Tang, N.
Jiao, Chem. Soc. Rev. 2012, 41, 3464.
[19] For mechanistic insights into the oxidative-coupling reactions of sim-
ilar systems (CuBr/O2 and CuBr/TBHP) with tetrahydroisoquinoline
as the substrate, see: a) E. Boess, D. Sureshkumar, A. Sud, C. Wirtz,
Received: April 20, 2012
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FULL PAPER
Coupling Reactions
Shogo Hashizume, Kounosuke Oisaki,*
Motomu Kanai*
&&&& — &&&&
Functional-Group-Tolerant Catalytic
Migratory Oxidative Coupling of
Nitrones
A copper-catalyzed migratory oxida-
tive-coupling reaction between nitro-
nes and various ethers/amines exhib-
ited high functional-group tolerance,
even in aqueous media. The reaction
proceeded through a concurrent dual
one-electron-abstraction mechanism.
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www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!