Cu-catalyzed skeletal rearrangement of O-propargylic electron-rich arylaldoximes into amidodienes

Article abstract of DOI:10.1021/ol5009608

O-Propargylic oximes that possess an electron-rich p-(dimethylamino)phenyl group at the oxime moiety and an alkyl group at the propargylic position were efficiently converted in the presence of Cu(I) catalysts to the corresponding 1-amidodienes in good to excellent yields. The reaction proceeded via a 2,3-rearrangement, followed by isomerization of the resulting N-allenylnitrone to the amide, presumably through the oxaziridine intermediate.

Full text of DOI:10.1021/ol5009608

Letter
pubs.acs.org/OrgLett
Cu-Catalyzed Skeletal Rearrangement of O‑Propargylic Electron-Rich
Arylaldoximes into Amidodienes
Itaru Nakamura,*,† Yasuhiro Ishida,‡ and Masahiro Terada†,‡
‡
†Research and Analytical Center for Giant Molecules and Department of Chemistry, Graduate School of Science, Tohoku
University, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: O-Propargylic oximes that possess an electron-rich p-
(dimethylamino)phenyl group at the oxime moiety and an alkyl group at the
propargylic position were efficiently converted in the presence of Cu(I) catalysts
to the corresponding 1-amidodienes in good to excellent yields. The reaction
proceeded via a 2,3-rearrangement, followed by isomerization of the resulting N-
allenylnitrone to the amide, presumably through the oxaziridine intermediate.
ecent investigations have revealed that π-acidic metal
catalysts can efficiently initiate rearrangement reactions
The intriguing dichotomy was first observed during
investigations of the substitution effects at the oxime moiety
using substrates 1a−g that possess a benzyl group at the
propargylic position, as summarized in Table 1.
R
that involve cleavage of skeletal σ-bonds. More importantly, the
use of such catalysts can transform readily accessible molecules,
under mild reaction conditions, into highly elaborate
compounds, which are often elusive using conventional
synthetic methods.1 Moreover, such skeletal rearrangement
reactions are dramatically affected by the choice of substituents
on the substrates. The diversity of such reaction schemes has
been reported for the π-acidic metal-catalyzed skeletal
rearrangement reactions of 1,n-enynes2 and propargylic esters.3
We have recently reported on the catalytic skeletal rearrange-
ment reactions of O-propargylic oximes in the construction of
various heterocyclic compounds.4 In particular, we reported
that propargylic oximes 1 were transformed into four-
membered cyclic nitrones 2 via a 2,3-rearrangement followed
by a 4π-electrocyclization cascade (Scheme 1a).4b,e In contrast,
Table 1. Substitution Effect at the Oxime Moiety
a
a
1
Ar
time (h)
3 (%)
2 (%)
1
2
3
4
5
6
7
8
1a
p-Me2NC6H4
p-Me2NC6H4
p-Et2NC6H4
2-(1-methylpyrrolyl)
p-MeOC6H4
p-MeC6H4
24
1
3a (87)
3a (67)
3b (84)
3c (53)
3d (41)
3e (32)
3f (30)
(<1)
(<1)
(<1)
(<1)
b,c
1a
1b
1c
1d
1e
1f
24
84
36
48
64
96
2d (5)
2e (25)
2f (60)
2g (68)
Scheme 1. Catalytic Skeletal Rearrangement of O-
Propargylic Arylaldoximes 1 to (a) Four-Membered Cyclic
Nitrones 2 and (b) 1-Amidodienes 3 (Present Work)
p-ClC6H4
1g
3,5-Br2C6H3
(<1)
a
1
The yields (in parentheses) were determined using H NMR with
b
c
CH2Br2 as an internal standard. (Z)-1a isomer was used. Acetic acid
(10 mol %) was used as an additive.
In the case of p-(dimethylamino)phenyl substrate (E)-1a, the
reaction in the presence of catalytic amounts of CuCl in
acetonitrile at 100 °C selectively afforded the corresponding 1-
amidodiene 3a in a good yield (entry 1). Similarly, the reaction
of its isomer (Z)-1a, which readily proceeded to completion
within 1 h, afforded the identical 3a in a good yield using
catalytic amounts of acetic acid as an additive (entry 2).5−7
Accordingly, other electron-rich aromatic substituents such as
p-(diethylamino)phenyl, 2-(1-methylpyrrolyl), and p-anisyl
groups also selectively formed the corresponding 1-amido-
our studies herein have shown that Cu-catalyzed reactions of O-
propargylic oximes that possess a strong electron-donating p-
aryl group at the oxime moiety proceed via a distinctly different
route, specifically, substrates 1 that possess an alkyl group at the
propargylic position were converted to the corresponding 1-
amidodienes 3 in good to excellent yields (Scheme 1b).
Received: April 1, 2014
Published: April 21, 2014
© 2014 American Chemical Society
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Letter
dienes (entries 3−5). In contrast, lower ratios of 1-amidodiene
3, relative to the four-membered cyclic nitrone 2, were
observed for substrates that possess electron-withdrawing aryl
groups; in the case of substrate (E)-1g, which possesses a 3,5-
dibromophenyl group, the reaction selectively afforded the
corresponding four-membered cyclic nitrone 2g (entry 8).
The reaction conditions were optimized using substrate (E)-
1a, as summarized in Table 2. In addition to CuCl, various
Table 3. Cu-Catalyzed Reactions of (E)-1h−p for Synthesis
a
of 1-Amidodienes
b
1
R1
R2
Ph
R3 time (h)
3
yield (%)
Table 2. Optimization of Reaction Conditions
1
2
3
4
5
6
7
8
9
1h
1i
Ph
H
H
H
H
H
H
H
H
Ph
18
14
12
10
36
20
14
36
20
3h
3i
90
85
95
p-ClC6H4
Ph
1j
p-F3CC6H4
Ph
3j
c
d
1k
1l
H
Ph
3k
3l
70
Ph
Ph
Ph
Ph
Ph
Et
76
64
1m
1n
1o
1p
p-anisyl
CO2Et
H
3m
3n
3o
3p
e
72
a
catalyst
CuCl
yield (%)
63
69
1
2
3
4
5
6
7
8
87 (85)
90
Ph
b
a
CuCl
The reaction of (E)-1 (0.2 mmol) in the presence of CuCl (10 mol
c
b
c
[CuCl(cod)]2
CuBr
64
%) in acetonitrile (0.4 mL) at 100 °C. Isolated yields. The reaction
d
54
was carried out using acetic acid (10 mol %) at 60 °C. A 36:64
mixture of E/Z stereoisomers at the amide-bound olefin was obtained.
A 44:56 mixture of E/Z stereoisomers was obtained.
CuOAc
72
e
CuCl2
<1
Ph3PAuNTf2
AcOH
24
propargylic position, the reactions in the presence of CuCl
afforded 2-amidodienes 4q and 4r, respectively, in good yields
as mixtures of two diastereomers at the amide-bound olefin (eq
1). Substrate 1s having a tert-butyl group at the propargylic
<5
a
The yields were determined using 1H NMR with CH2Br2 as an
b
internal standard. Isolated yield are shown in parentheses. Acetic acid
(10 mol %) was added. 5 mol % of [CuCl(cod)]2 was used.
c
Cu(I) salts such as [CuCl(cod)]2, CuBr, and CuOAc exhibited
catalytic activities, albeit with lower yields (entries 3−5). In
contrast, the use of a Cu(II) salt (CuCl2) resulted in the rapid
decomposition of the starting material (E)-1a (entry 6). The
use of Ph3PAuNTf2 afforded only a small amount of 3a,
whereas other metal salts such as PtCl2 and PdCl2 did not
exhibit any catalytic activities (entry 7, see also Supporting
Information). Only trace amounts of 3a were observed in the
reaction in the presence of catalytic amounts of acetic acid
(entry 8). Among the reaction solvents, acetonitrile provided
the best results; however, other solvents such as toluene,
CH2Cl2, and 1,4-dioxane were also acceptable (see Supporting
Information).
Next, the optimized reaction conditions (Table 2, entry 1)
were applied to various substrates based on (E)-1 (Table 3).
Substrates that possess an electron-deficient aromatic ring at
the alkyne terminus [(E)-1i and (E)-1j, Table 3, entries 2 and
3, respectively] proceeded more rapidly than that having an
electron-rich p-anisyl group [(E)-1a, Table 2, entry 1].
Substrate (E)-1k with a terminal alkyne was converted to 4-
monosubstituted amidodiene 3k in a good yield, at a lower
reaction temperature (60 °C), and with the use of catalytic
amounts of acetic acid (entry 4).8 Substrates with alkyl, aryl,
and ethoxycarbonyl groups as the substituent at the
homopropargylic position (R2) also afforded the desired
product in good yields (entries 5−7). Moreover, 1-mono-
substituted amidodiene 3o was synthesized from substrate (E)-
1o with a methyl group at the propargylic position (entry 8).
Substrate (E)-1p that possesses a benzhydryl group at the
propargylic position was converted to the corresponding 1,4,4-
triphenyl-1-amidodiene 3p in a good yield (entry 9).
position was effectively converted to the 2-amidodiene 4s.
Moreover, the reaction of substrate (E)-1t, which possesses
alkyl groups at both the alkyne terminus and the propargyl
position, gave a mixture (ca. 1:1) of 1-amidodiene 3t and 2-
amidodiene 4t (eq 2). In the case of substrate (E)-1u, which
possesses phenyl groups at both positions, the reaction in the
presence of the Cu catalyst and acetic acid afforded α,β-
In the cases of substrates (E)-1q and (E)-1r, which possess
an alkyl group at the alkyne terminus and a phenyl group at the
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Letter
unsaturated N-acylketimine 5u in a good yield. As a note, the
reaction in the absence of acetic acid resulted in unidentifiable
tar byproducts (eq 3).
Scheme 3
In order to gain insight into the oxime hydrogen atom,
deuterium labeling experiments were carried out using substrate
(E)-1a-d, which is 99%-enriched at the oxime position (eq 4).
hydrogen atom at the homopropargyl position of (E)-1a-d.
Moreover, rapid H/D exchange at the amide group of
intermediate 10 and product 3 would also explain the low
deuterium content. Presumably, acetic acid can serve as a
proton source to accelerate the protodemetalation of the
vinylcopper species 11 or 11′, thus suppressing any undesirable
polymerization processes of the unstable allenamide species 10
or 10′ (Schemes 2 and 3). In particular, the reaction of
substrate (Z)-1a required the use of acetic acid to keep low
concentration of the in situ formation of allenylamide species
10 due to rapid catalytic 2,3-rearrangement (Table 1, entry 2).
In conclusion, we have developed a novel method to
synthesize multisubstituted 1-amidodienes. Because amido-
dienes have recently gained much attention as useful synthetic
intermediates,12−14 our methodology would provide a powerful
tool in the preparation of highly functionalized amidodienes
under mild reaction conditions. Of note, the skeletal rearrange-
ment from propargyl oxime 1 to 1-amidodiene 3 involves the
cleavages of a C−O, a N−O,15 and two C−H bonds. Further
investigations to understand the details of the reaction
mechanism, specifically that of the rearrangement process
from nitrone 8 to amide 10, are currently underway in our
laboratories.
Under the optimal reaction conditions, the reaction afforded
3a-d (60% yield), in which the deuterium content at the 2-
position of the diene moiety was determined to be 31%. The
reaction of a 1:1 mixture of (E)-1b and (E)-1h afforded only 3b
and 3h without any crossover products (detected using high-
resolution mass spectroscopy), thus indicating that the skeletal
rearrangement proceeds via an intramolecular mechanism (see
Supporting Information).
A plausible mechanism for the construction of 1-amidodiene
3 is illustrated in Scheme 2. First, the propargyl oxime
undergoes a Cu-catalyzed 2,3-rearrangement to form N-
allenylnitrone intermediate 8 through alkyne-π-activation (6),
followed by the nucleophilic attack of the oxime nitrogen atom
onto the electrophilically activated carbon−carbon triple bond,
and then the elimination of the Cu catalyst from the cyclized
vinylcopper intermediate 7 involving C−O bond cleavage. As
the resulting resonance form 8′, contributions in the form of
electron-donation from the amino group would facilitate the
rotation of the nitrone CN bond, leading to oxaziridine
intermediate 9.9 Next, a 1,2-hydrogen shift driven by the
electron-donating dimethylaminophenyl group would form N-
allenylamide 10.10 Finally, isomerization through vinylcopper
intermediate 11 would give 1-amidodiene 3.11,12 The reaction
to afford α,β-unsaturated imine 5 would involve protodeme-
talation of vinylcopper intermediate 11′, as shown in Scheme 3.
In regards to the labeling reaction of (E)-1a-d (eq 4), the low
deuterium content at the 2-position of 1-amidodiene 3a-d is
reasonable because the hydrogen at the 2-position can be
attributed to either the deuterium at the aldoxime moiety or the
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization of the products
3, 4, and 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: itaru-n@m.tohoku.ac.jp.
Notes
The authors declare no competing financial interest.
Scheme 2. A Plausible Mechanism
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Letter
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ACKNOWLEDGMENTS
■
L.; Lop
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ez, F.; Ujaque, G. Chem.Eur. J. 2013, 19, 15248.
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
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