Skeletal rearrangement of O-propargylic formaldoximes by a gold-catalyzed cyclization/intermolecular methylene transfer sequence

Article abstract of DOI:10.1002/anie.201501856

Abstract Skeletal rearrangement of O-propargylic formaldoximes, in the presence of gold catalysts, afforded 4-methylene-2-isoxazolines in good to excellent yields by an intermolecular methylene transfer. In addition, the cascade reaction with maleimide in

Full text of DOI:10.1002/anie.201501856

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501856
German Edition: DOI: 10.1002/ange.201501856
Synthetic Methods
Skeletal Rearrangement of O-Propargylic Formaldoximes by a Gold-
Catalyzed Cyclization/Intermolecular Methylene Transfer Sequence**
Itaru Nakamura,* Shinya Gima, Yu Kudo, and Masahiro Terada
Abstract: Skeletal rearrangement of O-propargylic formal-
doximes, in the presence of gold catalysts, afforded 4-methyl-
ene-2-isoxazolines in good to excellent yields by an intermo-
lecular methylene transfer. In addition, the cascade reaction
with maleimide in the presence of a gold catalyst afforded
isoxazole derivatives by cyclization/methylene transfer and
a subsequent ene reaction, whereas that using a copper catalyst
gave oxazepines through a 2,3-rearrangement.
S
keletal rearrangement reactions featuring p-acidic metal
catalysts provide an efficient and attractive methodology in
the construction of highly functionalized organic molecules
from readily available starting materials through cleavage of
Scheme 1. p-Acidic metal-catalyzed 2,3-rearrangement of O-propargylic
oximes.
[1]
skeletal s bonds. Typically, such skeletal rearrangements
proceed through several pathways. For divergent organic
syntheses, however, it would be desirable to be able to select
[2]
the reaction pathways using specific metal catalysts.
We have recently reported on the catalytic skeletal
rearrangement reactions of O-propargylic oximes, which
serve as an intriguing platform in the presence of p-acidic
copper and rhodium catalysts, for the efficient syntheses of
multisubstituted nitrogenous cyclic and acyclic compounds
[
3]
(
Scheme 1a).
The transformations proceed primarily
through a 2,3-rearrangement step involving the nucleophilic
attack of the oxime nitrogen atom onto the p-activated alkyne
moiety and subsequent CÀO bond cleavage and elimination
of the metal catalyst from the resulting vinylmetal intermedi-
ate A, to form the N-allenylnitrone B which can undergo
further transformations. Our preliminary DFT calculations
for the 2,3-rearrangement (Scheme 2) suggested that the
activation energy of the CÀO bond cleavage process in copper
À1
Scheme 2. Energy profile for gold- and copper-mediated 2,3-rearrange-
ment of O-propargylic formaldoxime.
catalysis [DG(Cu)] is sufficiently low (10.2 kcalmol ) to
allow efficient generation of the N-allenylnitrone INT4(Cu).
[4]
In contrast, gold catalysts, which are typical p-acidic metals,
require higher activation energy for the CÀO bond cleavage
[DG(Cu)] because of the significant stabilization of the
vinylgold intermediate INT3(Au) by relativistic effect.
À1
[5,6]
[
DG(Au) = 14.3 kcalmol ] relative to copper catalysts
The energetically less favorable CÀO bond cleavage in the
gold catalysis inspired us to develop a new type of trans-
formation resulting from the long-lived vinylgold intermedi-
ate A (M = Au) bearing the electrophilic iminium and the
nucleophilic vinylgold moieties (Scheme 1b). Herein, we
report the gold-catalyzed reactions of O-propargylic formal-
doximes (1) for the synthesis of 4-methylene-2-isoxazolines
[
*] Prof. Dr. I. Nakamura, Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
6-3 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: itaru-n@m.tohoku.ac.jp
S. Gima, Y. Kudo, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science
Tohoku University, Sendai 980-8578 (Japan)
(
2) in good to excellent yields by C=N bond cleavage
[
Eq. (1)].
[
**] This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Molecular Activation Directed toward Straight-
forward Synthesis” from the Ministry of Education, Culture, Sports,
Science and Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501856.
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[
a]
Table 1: Gold-catalyzed reactions of 1.
1
2
[b]
Entry
1
R
R
t [h]
2
Yield [%]
[
c]
[d]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1a
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
Ph
Ph
Ph
24
2a
44
0.5 2a
0.5 2b
0.5 2c
0.5 2d
86
86
81
87
68
77
81
p-MeOC H4 Ph
p-MeC H4
p-ClC H4
p-F CC H
4
nPr
Cy
H
Ph
Ph
Ph
Ph
6
Ph
Ph
Ph
Ph
Ph
Ph
6
6
[
e]
24
2e
0.5 2 f
0.5 2g
3
6
[f]
48
–
<1
0
1
2
3
4
p-MeOC H4
p-F CC H
4
nPr
Cy
H
0.5 2i
0.5 2j
0.5 2k
0.5 2l
0.5 2m
74
90
82
79
53
6
1j
1k
1l
3
6
1m Ph
[
[
a] Reactions of 1 (0.4 mmol) were conducted in the presence of
(PPh )AuNTf ] (0.02 mmol) in CH Cl (0.8 mL) at 308C. [b] Yield of the
3
2
2
2
isolated product. [c] The reaction was carried out in the presence of AuCl
10 mol%) in MeCN at 508C. [d] 3a (10%) was obtained. [e] The
reaction was carried out in 1,2-dichloroethane (DCE) at 508C. [f] 60% of
(
1
h was recovered. Tf=trifluoromethanesulfonyl.
Scheme 3. Mechanistic studies.
We initially conducted the reaction of the O-propargylic
formaldoxime 1a in the presence of AuCl (10 mol%) in
MeCN at 508C, and it afforded the 4-methylenated isoxazo-
line 2a in 44% yield along with a small amount (10%) of the
isoxazoline 3a, which does not possess a methylene group
that transfer of the methylene group proceeds in an inter-
[
7–9]
molecular manner.
Secondly, the gold-catalyzed reaction
between 1k and a nonmethylenated isoxazoline (3a, 1 equiv)
did not afford the expected product 2a (derived from
incorporation of external isoxazoline 3a); the reaction
instead afforded 2k (derived from starting material 1k;
(
Table 1, entry 1). To our delight, the yields were dramatically
improved by conducting the reaction using the cationic
(PPh )AuNTf ] in CH Cl at 308C (entry 2). In contrast,
[
8]
[
Scheme 3b). Thirdly, the reaction was carried out between
[D]-1k and monomerized formaldehyde, thus resulting in the
formation of [D]-2k, in which the deuterium content at the
methylene moiety was 99% (Scheme 3c). The results of the
above experiments indicate that the present methylene
transfer process does not involve the isoxazoline 3 or
formaldehyde, which would be expected to be liberated
during the reaction.
3
2
2
2
CuCl did not exhibit any catalytic activities (see the Support-
ing Information). The reaction can tolerate various aryl and
1
alkyl substituents both at the alkyne terminus (R ) and the
2
propargylic position (R ; entries 1–8, and 10–13). As a note,
the reaction of 1e, which possesses a highly electron-deficient
1
p-(trifluoromethyl)phenyl group as R , required longer reac-
tion times, even when carried out at 508C (entry 6). In the
case of the terminal alkyne 1h, the reaction did not afford the
desired isoxazoline (entry 9), while the reaction of 1m, which
Based on the above experiments, the reaction mechanism
can be described as a cyclization/intermolecular CÀC bond
2
does not possess any R substituents, afforded the corre-
formation/disconnection sequence, as illustrated in Scheme 4.
First, the p-acidic gold catalyst coordinates to the triple bond
of 1 to form the p-complex 4, which is subjected to an
intramolecular nucleophilic attack by the oxime nitrogen
atom to give the cyclized intermediate 5. The electrophilic
iminium moiety of 5 would react with water which is present
in trace amounts in the reaction mixture to form the
enaminylgold species 6. The nucleophilic vinylgold moiety
of 6 would then attack the iminium moiety of another 5 to
form a CÀC bond. Because the CÀC bond formation takes
sponding isoxazoline 2m in a moderate yield (entry 14). It
should be noted, however, that substrates possessing a sub-
stituent, such as n-propyl or phenyl, at the oxime moiety were
not transformed into the desired products under the opti-
mized reaction conditions, thus indicating that, for the present
transformation, the migrating group is limited to a nonsub-
stituted methylene group.
Next, several experiments were carried out to gain insight
into the reaction mechanism (Scheme 3). First, crossover
experiments were carried out using a 1:1 mixture of 1l and the
equally reactive [D]-1k, in which the formyl group was
deuterium labelled (Scheme 3a). The gold-catalyzed reaction
afforded equal amounts of normal ([D]-2k and 2l) and
crossover products (2k and [D]-2l), thus clearly indicating
place at the vinylgold terminus, the sequential process will
continuously generate another intermediate 5. Concurrently,
protonation (because of trace amounts of water) at the
nucleophilic vinylgold terminus of 8 would lead to the
iminium intermediate 9. Donation of electrons from the
2
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Scheme 5. Derivatization of 2a. DCE=1,2-dichloroethane, THF=tetra-
hydrofuran.
Scheme 4. A plausible mechanism.
Scheme 6. Catalyst-controlled cascade reactions.
nitrogen atom of the adjacent isoxazoline ring would result in
the cleavage of the CÀN bond and formation of an exo C=C
bond, thus liberating the nonmethylenated isoxazoline 3.
Electron donation from an adjacent isoxazoline ring would
continue and sequentially disconnect 2. Significant deceler-
ation resulting from an electron-deficient substituent at the
alkyne terminus (Table 1, entry 6) suggests that the decreased
nucleophilicity of the olefin moiety of 6 and 7 strongly affects
the N-allenylnitrone intermediate 19 by a 2,3-rearrangement,
thus leading to the oxazepine derivative 18 (Scheme 6).
These results strongly support our initial hypothesis that the
metal catalysts can control the pathway of the skeletal
[3e]
rearrangement
(Scheme 2).
reactions
of
O-propargylic
oximes
[
12]
[
10]
the intermolecular CÀC bond-forming process. Although
the nucleophilicity of the nonmethylenated isoxazoline 3 by
itself is insufficient to attack the iminium moiety, the
enhanced nucleophilicity resulting from the corresponding
vinylgold intermediates 6 and 7 enables the intermolecular
introduction of a methylene group. This synthetic method-
ology featuring metal-catalyzed cyclization followed by
intermolecular methylene transfer may serve as an efficient
approach to introduce a methylene group (and hopefully
other alkylidene groups) to less nucleophilic heterocycles that
are inert for Knoevenagel condensation.
In conclusion, we have successfully developed a novel
approach for the formation of 4-methylenated isoxazoline
derivatives by a reaction sequence of cyclization and an
unprecedented intermolecular methylene transfer, under
mild reaction conditions. Although such compounds are
highly useful for synthesis of functionalized isoxazolines and
isoxazoles, which are commonly found in biologically active
[13]
compounds and serve as important synthetic intermediates,
there are only a limited number of reports on preparation of
[14]
the 4-methylenated isoxazoline.
Therefore, the present
cyclization/intermolecular methylene transfer sequence is
highly useful for construction of these molecular frameworks.
Accordingly, 2 can be further derivatized into various
multisubstituted isoxazole derivatives (Scheme 5). For exam-
ple, 2a was quantitatively isomerized into the isoxazole 11
using tBuOK. Alternatively, 2a underwent an ene reaction Experimental Section
with various compounds, such as maleimide 12, azodicarbox-
ylate 14, and glyoxylate 16, to afford the corresponding
functionalized isoxazoles 13, 15, and 17, respectively, in good
1a (94.1 mg, 0.4 mmol) in CH
Cl
2
2
(0.8 mL) was added to
[
(PPh )AuNTf ] (14.8 mg, 0.02 mmol) in a V-vial under an argon
3
2
atmosphere. The mixture was stirred at 308C for 0.5 h and then passed
through a short pad of silica gel with CH Cl (50 mL). The solvents
were evaporated in vacuo and the crude product was purified by flash
silica-gel column chromatography using hexane/EtOAc (10:1) as
eluent to give product 2a (81.1 mg, 86%).
[11]
2
2
to excellent yields.
In addition, the gold-catalyzed one-pot reaction of 1a in
the presence of 12 proceeded via the isoxazoline 2a by
a cyclization/methylene transfer followed by an ene reaction,
thus affording the corresponding isoxazole 13 (Scheme 6).
This result is in sharp contrast to our previously reported
copper-catalyzed cascade reaction, which proceeds through
Keywords: copper · gold · heterocycles · rearrangements ·
synthetic methods
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Received: February 26, 2015
Revised: March 19, 2015
Published online: && &&, &&&&
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3
4
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Synthetic Methods
I. Nakamura,* S. Gima, Y. Kudo,
M. Terada
&&&& — &&&&
Skeletal Rearrangement of O-Propargylic
Formaldoximes by a Gold-Catalyzed
Cyclization/Intermolecular Methylene
Transfer Sequence
Au is not like Cu: Skeletal rearrangement
of O-propargylic formaldoximes, in the
presence of gold catalysts, effectively
afforded 4-methylene-2-isoxazolines by
intermolecular methylene transfer. The
cascade reaction in the presence of gold
proceeds by cyclization/methylene trans-
fer and a subsequent ene reaction,
whereas with a copper catalyst it pro-
ceeds by a 2,3-rearrangement.
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