Copper-Catalyzed Aqueous N?O Bond Cleavage of 2-Oxa-3-Azabicyclo Compounds to Cyclic cis-1,4-Amino Alcohols

Article abstract of DOI:10.1002/cssc.202001739

The N?O bond cleavage of 2-oxa-3-azabicyclo substrates, which are readily prepared by the hetero Diels-Alder reaction between nitroso dienophiles and cyclic 1,3-dienes, was effectively catalyzed by heterogeneous copper-on-carbon (Cu/C) under aqueous condi

Full text of DOI:10.1002/cssc.202001739

Chemistry–Sustainability–Energy–Materials
Accepted Article
Title: Copper-Catalyzed Aqueous N–O Bond Cleavage of 2-Oxa-3-
Azabicyclo Compounds to Cyclic cis-1,4-Amino Alcohols
Authors: Naoki Yasukawa, Yuya Miki, Marina Kuwata, Hironao Sajiki,
and Yoshinari Sawama
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.202001739
Link to VoR: https://doi.org/10.1002/cssc.202001739
01/2020

10.1002/cssc.202001739
ChemSusChem
FULL PAPER
Copper-Catalyzed Aqueous N–O Bond Cleavage of 2-Oxa-3-
Azabicyclo Compounds to Cyclic cis-1,4-Amino Alcohols
Naoki Yasukawa,[a] Yuya Miki,[a] Marina Kuwata,[a] Hironao Sajiki*[a] and Yoshinari Sawama*[a]
[a]
Dr. N. Yasukawa, Y. Miki, M. Kuwata, Prof. Dr. H. Sajiki, Dr. Y. Sawama
Laboratory of Organic Chemistry
Gifu Pharmaceutical University
1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
E-mail: sajiki@gifu-pu.ac.jp, sawama@gifu-pu.ac.jp
Supporting information for this article is given via a link at the end of the document.
Abstract: The N–O bond cleavage of 2-oxa-3-azabicyclo substrates,
which are readily prepared by the hetero Diels–Alder reaction
between nitroso dienophiles and cyclic 1,3-dienes, was effectively
catalyzed by heterogeneous copper-on-carbon (Cu/C) under aqueous
conditions to give the corresponding cyclic cis-1,4-amino alcohol
derivatives. The present method was applied to the direct
incorporation of the hydroxy and amino groups derived from a nitroso
substrate into cyclic 1,3-dienes with cis-selectivity by the combination
of the in situ-formation of 2-oxa-3-azabicyclo compounds and
following Cu/C-catalyzed N–O bond cleavage. The obtained cis-4-
aminocyclohexenols, derived from cyclohexadiene as a cyclic 1,3-
diene, could be selectively oxidized by using the catalytic ruthenium-
on-carbon (Ru/C) under oxygen atmosphere to the corresponding 4-
aminocyclohexenones at 50-65 oC or para-iminoquinones at 100-110
oC as useful reactive synthetic precursors.
removed from the reaction mixture. We have recently reported the
Cu/C-catalyzed pyrrole synthesis from monocyclic 3,6-dihydro-
1,2-oxazines via the oxidative addition of the N–O bond under
solvent-free conditions.[14] Herein, we have newly demonstrated
the Cu/C-catalyzed reductive N–O bond cleavage reaction of 2-
oxa-3-azabicyclo compounds (3) to cyclic 1,4-amino alcohols (4)
without any additives under aqueous conditions (Scheme 1). The
one-pot synthesis of 4 via the hetero Diels–Alder reaction
between nitroso dienophiles (1) and cyclic 1,3-dienes (2) and
following Cu/C-catalyzed N–O cleavage was also accomplished.
Furthermore, a novel chemical modification of 4 was examined as
will be mentioned later.
n
R
OH
n
O
N
Cu/C
H2O
2
O
N
n
R
R
Ar
Hetero
Diels-Alder
reaction
Introduction
Ar
NHAr
4
1
3
Cyclic 1,4-amino alcohols are important chemical skeletons for
natural products, medicines, biologically-active compounds, and
functional materials and can be useful building blocks in various
organic syntheses.[1] The reductive N–O bond cleavage of 2-oxa-
3-azabicyclo compounds (3), which are easily prepared by the
hetero Diels–Alder reaction ([4+2]-cycloaddition) between nitroso
dienophiles (1) and cyclic 1,3-dienes (2), is widely utilized to
construct the cis-selective cyclic 1,4-amino alcohols (4). However,
the N–O bond cleavage principally required stoichiometric
reductants, such as Zn,[2] SmI2,[3] Al(Hg),[4] Mn(CO)6,[5] CuCl,[6]
Fe2(CO)9,[7] or Mn with the catalytic Cp2TiCl.[8] Meanwhile, the
hydrogenation conditions catalyzed by palladium-on-carbon
(Pd/C)[9] or Raney-Ni[10] could promote the N–O bond cleavage
together with the undesired reduction of the olefin, carbonyl, nitro
groups, etc. Although a low-valent Fe complex-catalyzed N–O
bond cleavage reaction was recently reported, the use of the
+) High atom economy
+) Heterogeneous catalyst
+) One-pot synthesis from 1 and 2
Scheme 1. Copper-on-carbon (Cu/C)-catalyzed reductive N–O bond cleavage
of 2-oxa-3-azabicyclo compounds (3).
Results and Discussion
As the result of a detailed screening to find the optimal reaction
conditions using N-tolyl-2-oxa-3-azabicyclo[2,2,2]-oct-5-ene
(3aa) prepared from 4-methylnitrosobenzene (1a) and 1,3-
cyclohexadiene (2a), cis-4-aminocyclohex-2-en-1-ol (4aa) could
be obtained in 78% isolated yield in the presence of 10% Cu/C
(10 mol%)[15] and Na2CO3 (3 equiv.) in H2O/2-PrOH at 100 oC for
6 h (Table 1, entry 1). The present reduction could proceed in H2O
without 2-PrOH to give 4aa in 50% yield (entry 2). MeOH and tert-
BuOH also acted the same as 2-PrOH as effective co-solvents of
H2O, although the efficiency was slightly lower (entries 3 and 4).
These results indicate that 2-PrOH or hydrogen (H2) gas in situ-
generated by the dehydrogenation of 2-PrOH[16] did not play the
role of a co-reductant. Therefore, the addition of alcohol probably
improved the solubility of the substrate. We assume that the
alcohol probably acts as a solubilization agent of the substrate.
While the reaction without Cu/C did not proceed at all (entry 5),
the use of Cu(0) powder instead of Cu/C could also produce 4aa
stoichiometric malononitrile was required as a reductant.[11]
A
Cu(0) nanoparticle-catalyzed reductive N–O bond cleavage of
isoxazoline has also been reported.[12] Although copper-catalytic
reactions have emerged as powerful tools to cleave N–O bond
and access various complicated structures,[13] heterogeneous
copper-catalyzed N–O bond cleavage reaction from 2-oxa-3-
azabicyclo compounds into cyclic cis-1,4-amino alcohols has not
been accomplished to the best of our knowledge. Copper is an
abundant and inexpensive metal possessing a low toxicity. Also,
copper supported on carbon (Cu/C) is easy to handle and can be
1
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10.1002/cssc.202001739
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FULL PAPER
in 67% (entry 6). Oxidized copper species, such as Cu2O and
CuO, also catalyzed the reductive N–O bond cleavage, and 4aa
was obtained in good yields (entries 7 and 8). While stoichiometric
CuCl in MeOH was applied to N–O bond cleavage of 2-oxa-3-
azabicyclo compounds in Miller’s report (The difference of
reaction mechanism is described in SI),[6] CuCl indicated lower
catalyst activity under our aqueous conditions (entry 9). However,
other zero-valent metal species, such as Cr, Mn, Fe, Co, Ni, and
Zn powders possessed low catalytic activity in this reaction (entry
10). Pd/C was also less reactive (entry 11), and the hydrogenation
using Pd/C under atmospheric hydrogen (H2) did not give 4aa
(entry 12). The use of 10 mol% of Cu/C was better in comparison
with catalyst loading amounts to 100, 20, or 5 mol% of Cu/C
(entries 1 vs. 13–15), although reasons are unclear. The addition
of Na2CO3 to the Cu/C-catalyzed reductive N–O bond cleavage
reaction improved the yield of 4aa (entries 1 vs. 16). The reduction
rate was slow at 80 °C (entries 1 vs. 17).
[a] 3aa was prepared from 4-methylnitrosobenzene (1a) and 1,3-
cyclohexadiene (2a). See SI for a further detailed optimization. [b] Determined
by 1H NMR using 1,4-dioxane as an internal standard. [c] Isolated yield.
The reusability of heterogeneous Cu/C was next investigated
using the present N–O bond cleavage of 3aa (Table 2). Cu/C
could be recovered after reaction by simple filtration, washing H2O
and MeOH, drying in vacuo, and reused for the next run.
Consequently, Cu/C could be effectively reused at least five times
without loss of its catalytic activity.
Table 2. Reuse test of 10% Cu/C in N–O bond cleavage of 3aa.[a]
OH
10% Cu/C (10 mol%)
Na2CO3 (3 equiv.)
O
N
H2O/2-PrOH (0.9/0.1 mL)
100 oC, 6 h
Ar
NHAr
4aa
3aa
(0.1 mmol)
(Ar = 4-Me-C6H4)
Table 1. Effect of each parameter on the Cu/C-catalyzed reductive N–O bond
cleavage of 3aa to 4aa.
yield (%)[b]
recovered
run
OH
10% Cu/C (%)
3aa
0
4aa
10% Cu/C (10 mol%)
Na2CO3 (3 equiv.)
O
N
1st
2nd
3rd
4th
5th
99
>99
98
78%
76%
75%
74%
76%
H2O/2-PrOH (0.9/0.1 mL)
100 oC, 6 h
Ar
NHAr
4aa
0
3aa
(0.1 mmol)
(Ar = 4-Me-C6H4)
0
99
0
entry
changes from standard conditions[a]
none
yield (%)[b]
96
0
1
2
3
4
5
6
7
8
9
80% (78%)[c]
50%
in H2O (1 mL)
[a] 10% Cu/C was reused after simple filtration, washing with H2O and MeOH,
and drying in vacuo. See SI for a detail procedure. [b] Determined by 1H NMR
using 1,4-dioxane as an internal standard.
in H2O/MeOH (0.9/0.1 mL)
67%
in H2O/tert-BuOH (0.9/0.1 mL)
without 10% Cu/C
68%
The scope of the substrates was next investigated with the
optimized reaction conditions (Table 3). Various N-aryl-2-oxa-3-
azabicyclo[2,2,2]-oct-5-ene derivatives (3ba-3ga), bearing an
electron-withdrawing group or a halogen at the para-, meta- or
ortho-position on the aromatic nucleus at the N atom, were
efficiently transformed into the desired N–O bond cleaved
compounds (4ba-4ga) in good yields with excellent tolerance
toward coexisting reducible functionalities, such as the acetyl
(3ca), nitro (3da) and aromatic bromide (3ea-3ga) groups. The
gram-scale reaction of 3ba (6 mmol; 1.1 g) was also successfully
performed to give 4ba. The N–pyridyl, benzoxazoyl, and
0%
Cu(0) powder (10 mol%) instead of 10% Cu/C
Cu2O (10 mol%) instead of 10% Cu/C
CuO (10 mol%) instead of 10% Cu/C
CuCl (10 mol%) instead of 10% Cu/C
67%
72%
75%
57%
Cr, Mn, Fe, Co, Ni, Zn powder (each 10 mol%)
instead of 10% Cu/C
10
11
12
<6%
8%
benzothiazyl-2-oxa-3-azabicyclo[2,2,2]-oct-5-ene
derivatives
10% Pd/C (10 mol%) instead of 10% Cu/C
(3ha-3ja) could also be transformed into the corresponding cis-
1,4-amino alcohols (4ha-4ja) in moderate to good yields. The
present reaction conditions allowed as to synthesize the various
cis-4-aminocyclohex-2-en-1-ol products (4bb-4bh) from the
mono- or di-substituted 1,3-cyclohexadiene pre-substrate during
the preparation of 3bb-3bh. In some cases to construct the 3-R1
group-substituted products 4bb, 4bc, and 4be, the undesired
10% Pd/C (10 mol%) instead of 10% Cu/C
under H2
0%
13
14
15
16
17
100 mol% of 10% Cu/C
20 mol% of 10% Cu/C
5 mol% of 10% Cu/C
without Na2CO3
50%
62%
56%
65%
23%
retro hetero Diels–Alder reaction of
3 to 1 and 2 and
reconstruction partially proceed to form a mixture of 3 and its
regio-isomer,[17] both of which underwent the present N–O bond
cleavage to afford the 3-R1 group-substituted products (4bb-4be)
and 2-R1 group-substituted regio-isomers (4’). Furthermore, the 7
and 8-membered cyclic cis-1,4-amino alcohols (4bi and 4bj)
at 80 oC
2
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10.1002/cssc.202001739
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could be obtained from the corresponding N-aryl-2-oxa-3-
azabicyclo derivatives (3bi and 3bj) prepared from 1,3-
cycloheptadiene (2i) or 1,3-cyclooctadiene (2j).
Table 4. One-pot synthesis.[a]
n
(1.5 equiv.)
R
Table 3. Scope of substrates.[a]
2
OH
10% Cu/C (10 mol%)
Na2CO3 (3 equiv.)
O
N
n
R
OH
H2O/2-PrOH (0.9/0.1 mL)
r.t., 3 h
then temp. (oC), time (h)
n
Ar
10% Cu/C (10 mol%)
Na2CO3 (3 equiv.)
n
O
R
NHAr
4
R
1
H2O/2-PrOH (0.9/0.1 mL)
100 oC
N
(0.1 mmol)
Ar
NHAr
4
3
: 78% (6 h; 100 oC)
: 65% (9 h; 100 oC)
: 56% (24 h; 100 oC
: 54% (24 h; 100 oC
: 54% (24 h; 100 oC
: 43% (24 h; 100 oC
(0.1 mmol)
OH
Ar =
4-Me-C6H4 (4aa)
Ph (4ba)
4-Br-C6H4 (4ea)
3-Br-C6H4 (4fa)
2-Br-C6H4 (4ga)
4-MeO-C6H4 (4ka)
OH
N
O
Ar = Ph (4ba)
: 81% (9 h)
4ha
49% (48 h)
[c,d]
NHAr
HO
[gram scale] : 74% (12 h)
: 72% (30 h)[c]
OH
OH
4-Ac-C6H4 (4ca)
NHAr
N
N
4-NO2-C6H4 (4da): 59% (48 h)[c]
4-Br-C6H4 (4ea) : 66% (48 h)
3-Br-C6H4 (4fa) : 63% (18 h)
2-Br-C6H4 (4ga) : 63% (24 h)
4ia
73% (36 h)
[c]
S
NHPh
NHPh
4bi: 68%
NHPh
4bj: 50%
(96 h; 150 oC)
4bk: 62%
4ja
52% (36 h)
(6 h; 100 oC)[b]
(72 h; 120 oC)
[c]
Me (4bb) : 54% (24 h)[e]
Et (4bc) : 53% (24 h)[e]
Ph (4bd) : 60% (24 h)
OH
1
2
OH
2
R1 =
1
R1
[a] Isolated yield. [b] 10 equiv. of 2 were used.
3
The addition of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)
or galvinoxyl as a radical scavenger hardly influenced the
reactivity of the Cu/C-catalyzed N–O bond cleavage of 3aa to give
the desired 4aa in good yield (Scheme 2). Therefore, the single-
electron transfer (radical) pathway could be ruled out.
R1
3
NHPh
: 48% (24 h)[e]
2-R1 group-subsituted
Bn (4be)
NHPh
regio isomer (4’)
OH
OH
OH
OH
OH
iPr
Ph iPr
Ph
Me
NHPh
4bh
OH
NHPh
4bf
68% (24 h)
NHPh
10% Cu/C (10 mol%)
Na2CO3 (3 equiv.)
additive (10 mol%)
O
NHPh
NHPh
4bj
4bg
4bi
additive =
41% (48 h)[f] 62% (24 h)
69% (72 h)[c] 51% (96 h)[f]
TEMPO
galvinoxyl
: 58%
: 62%
N
H2O/2-PrOH (0.9/0.1 mL)
100 oC, 6 h
[a] Isolated yield. [b] 6 mmol of 3ba was used. [c] At 120 oC. [d] In tert-BuOH
was used instead of 2-PrOH. [e] The inseparable 2-R1 group-substituted regio-
isomer was also obtained. See the SI. [f] At 150 oC.
Ar
NHAr
4aa
3aa; 0.1 mmol
(Ar = 4-Me-C6H4)
The combination of the hetero Diels–Alder reaction between
nitroso dienophiles (1) and cyclic 1,3-dienes (2) and subsequent
Cu/C-catalyzed N–O bond cleavage reaction could provide
corresponding cyclic cis-1,4-amino alcohols (4) in a two-step one-
pot manner. The methodology enabled the direct incorporation of
both amino and hydroxyl groups derived from the nitroso
dienophiles into the corresponding cyclic 1,3-dienes (2) (Table 4).
After the hetero Diels–Alder reaction between 1 and 2 in H2O/2-
PrOH at room temperature for 3 h in the presence of Cu/C and
Na2CO3 to form 3, further stirring at 100 oC could directly produce
4 in a one-pot manner (the detailed optimization process is
described in Table S4 and S5). The 2-oxa-3-azabicyclo
derivatives (3ka and 3bk) as reaction intermediates for 4ka,
possessing an electron-sufficient aryl group on the nitrogen atom,
and 4bk, bearing a 5-membered backbone, could not be isolated
due to their lower stabilities. It is noteworthy that 4ka and 4bk
could be synthesized in a one-pot manner, while 3ka and 3bk
were unavailable by a stepwise synthesis.
Scheme 2. Addition of radical scavengers.
As a possible pathway, the N–O bond cleavage of 3 can be
initiated by the oxidative addition of Cu(0) to form intermediate A
(path A),[14] which undergoes a ligand-exchange with H2O to give
the corresponding product (4) and Cu(OH)2 (Scheme 3). A part of
the generated Cu(II) species can be converted by Cu(0) to
Cu(I).[18] Although the generated Cu(I) species can also undergo
the oxidative addition[19] of 3 to form intermediate B and product
(4) (path B), the Cu(II or III) species formed by the reaction
progress must be reduced to promote the catalytic cycles. During
the reduction process of Cu(II or III) species to Cu(0 or I), H2O2
could be generated, and the further decomposition gives O2.
3
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10.1002/cssc.202001739
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OH
O
10% Cu/C (10 mol%)
Na2CO3 (3 equiv.)
N
Ar

O
N
recovered 5
1
2a
H2O/2-PrOH (0.9/0.1 mL)
120 oC, 48 h
O
N
Ph
NHPh
6: 31%
[path A]
[path B]
5
64%
Ar
(0.1 mmol)
3
Cu/C
(Cu0)
Scheme 5. Cu/C-catalyzed reductive N–O bond cleavage of reduced substrate
(5).
CuOH
OH
HO CuIII
CuII
O
N
O
N
Cu(OH)2
Ar
A
Ar
B
The scope of substrates was investigated under reaction
conditions using Cu/C and 2-PrOH as co-solvent. Although
carbon support can be a reductant, the generation of oxidized
products, such as carbon monoxide (CO) and carbon dioxide
(CO2), were not observed. Meanwhile, a slight amount of
hydrogen (H2) gas, in situ-generated via dehydrogenation of 2-
PrOH, could be detected by gas chromatography with thermal
conductivity detector (GC/TCD). When using 2-PrOH as a co-
solvent, the reaction efficiency was moderately improved (Table
1, entries 1 vs. 2). Therefore, 2-PrOH and H2 derived from 2-PrOH
can play the role of one of the reductants of Cu(II or III) species
to Cu(0 or I) to facilitate the reaction (Scheme 3). During the
present N–O bond cleavage reaction, H2O might be a significant
reductant. However, 2-PrOH and cyclohexadiene, generated by
retro HDA reaction of the substrate, also can be reductants.
Additionally, 2-PrOH and other alcohols work as solubilization
agents of substrates, as mentioned in Table 1, entries 2 vs. 1 and
3–4.
H2O
(+ base)
H2O
(+ base)
H2O2
NHAr
O2
4
Scheme 3. Proposed reaction mechanism.
When using 18O-labeled water (H218O) without Na2CO3 and 2-
PrOH in the reaction of 3ba as a substrate, 18O2 could be detected
by gas chromatography/mass spectrometry (GC/MS) (Scheme 4
and the detailed result is described in the SI. H2O2 was not
detected). Additionally, an 18O-incorporated product was not
observed. Furthermore, 1,3-cyclohexadiene (2a), generated by
retro hetero Diels–Alder (HDA) reaction of the substrate (3), and
benzene as its oxidized form were also detected. Therefore,
cyclohexadiene as a by-product also can be reductant. 2-PrOH
was used as a co-solvent in the scope of substrates. 2-PrOH also
acts as a reductant as mentioned later. Namely, these reagents
act additively as reductants to facilitate the present N–O bond
cleavage reactions.
According to Miller’s CuCl-mediated reduction in MeOH,[6]
a
reaction mechanism through Lewis acidic Cu-catalyzed activation
of the N–O bond and subsequent nucleophilic attack to the aryl
group of 3 by a hydride, derived from 2-PrOH, is proposed
(Scheme 6). If 2-PrOD-d8 works as a deuteride source, the N–O
bond can be cleaved by Lewis acidic copper-mediated activation
and nucleophilic attack of a deuteride derived from 2-PrOD-d8 to
the aromatic ring to produce the reaction intermediate (C), and
comparatively weak C–H bond in comparison with C–D bond is
cleaved to give the N–O bond cleaved product bearing deuterium
atoms on the aromatic ring (4aa’). However, the reaction of 3aa
in a mixed solvent of deuterium oxides (D2O)/2-PrOD-d8 never
gave the product, which is deuterium-incorporated at any
positions on the aromatic ring (Scheme 6). Our reaction may
proceed via different pathways from the reaction mechanism,
proposed by Miller’s group.
OH
10% Cu/C (10 mol%)
O
N
18O2
H218O (0.5 mL)
100 oC, 6 h
m/z = 36
detected by GC/MS
Ph
NHPh
4ba: 34%
3ba
(0.4 mmol)
no 18
incorporated
O
Scheme 4. Cu/C-catalyzed reductive N–O bond cleavage in 18O-labeled water
(H218O).
During the present reaction using the 2-oxa-3-azabicyclo
derivatives (3) as
a substrate, the corresponding nitroso
compound (1) and cyclic 1,3-diene (2) were generated as by-
products via the retro hetero Diels–Alder reaction. Meanwhile, a
reduced-type substrate (5) without an olefin moiety, which never
undergoes the retro hetero Diels–Alder reaction, was also
transformed into cis-4-aminocyclohexanol (6) under the Cu/C-
catalyzed conditions (Scheme 5). Hence, it is supported that the
nitroso compound (1) and cyclic 1,3-diene (2) as by-products may
not be main reductants of the Cu species.
4
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OH
Table 5. Synthetic application of the obtained cis-1,4-aminoalkenols.[a]
10% Cu/C (10 mol%)
Na2CO3 (3 equiv.)
O
N
D2O/2-PrOD-d8 (0.9/0.1 mL)
OH
O
O
100 oC, 6 h
then
Ar
10% Ru/C
O2 (balloon)
NHAr
aqueous quench
R
R
R
3aa
(0.1 mmol)
4aa: 71%
or
toluene
50~110 oC
no deuterium
incorporated
(Ar = 4-Me-C6H4)
NHAr
NHAr
NAr
4
7
8
(2-PrOD-d8)
OH
-amino-unsaturated ketone (7) synthesis[b]
Cu
Cu
D
O
N
O
N
O
O
O
59%
R1 = Me (7aa) :
(6 h, 50 oC)
iPr
D
D3C
CD3
D
60%
D
:
H (7ba)
Ac (7ca) :
HN
H
(6 h, 50 oC)
Me
NHPh
26%
[c]
HN
(6 h, 50 oC)
Me
4aa’: not obtained
Me
Me
66%
7bh: 24%
(24 h, 65 oC)[d]
3aa
C
R1
Br (7ea)
:
(6 h, 50 oC)
iminoquinone (8) synthesis[e]
Scheme 6. Deuterium-labeling study using D2O/2-PrOD-d8.
O
O
76%
R1 = Me (8aa) :
(6 h, 100 oC)
iPr
78%
:
H (8ba)
Ac (8ca) :
(12 h, 80 oC)
The obtained cis-4-aminocyclohex-2-en-1-ol derivatives (4)
could be further modified under the ruthenium-on-carbon (Ru/C)-
catalyzed-oxygen oxidation conditions to give the corresponding
4-aminocyclohexenones (7) at 50–65 oC and para-iminoquinones
(8) at 100–110 oC (Table 5 and detailed results described in Table
S6 and S7).[16,20] 4-Aminocyclohexenone and para-imonoquinone
derivatives are well-known as useful backbones to construct
valuable bioactive compounds (antineoplastic drugs[21]) and
synthetic building blocks[22]. For example, para-imonoquinones
were prepared by the oxidative dearomatization of para-
aminophenols by using stoichiometric oxidants[23], such as
Me
67%
N
NPh
(24 h, 100 oC)
73%
8bh: 41%
R1
Br (8ea)
:
(6 h, 100 oC)
(48 h, 110 oC)
[a] Isolated yield. [b] Standard reaction conditions for 4-amino ketone synthesis:
4 (0.2 mmol), 10% Ru/C (20 mol%), toluene (1 mL) under O2. [c] 31% of starting
material and 14% of iminoquinone (8ca) were obtained. [d] 64% of starting
material was recovered. [e] Standard reaction conditions for iminoquinone
synthesis: 4 (0.2 mmol), 10% Ru/C (10 mol%), toluene (1 mL) under O2
hypervalent iodine compounds[23a], MnO2[23b], and Ag2O[23c]
.
Therefore, the present novel and green Ru/C-catalyzed
transformation is useful as a preparation method for highly-
functionalized cyclohexane derivatives.
Conclusion
We have developed an aqueous Cu/C-catalyzed N–O bond
cleavage of 2-oxa-3-azabicyclo compounds with Na2CO3 and 2-
PrOH as additives to provide cyclic cis-1,4-amino alcohols.
Furthermore, the direct incorporation of both the amino and
hydroxyl groups into cyclic 1,3-dienes could also be accomplished
by the combination of the hetero Diels–Alder reaction of nitroso
dienophiles and 1,3-dienes and subsequent Cu/C-catalyzed N–O
bond cleavage in a one-pot manner. The heterogeneous Cu/C
can be easily removed from the reaction mixture by simple
filtration and reused at least five times without any loss of catalytic
activity. The present novel and environmentally benign method
effectively provided cyclic cis-1,4-amino alcohol derivatives,
which are also efficiently oxidized under Ru/C-catalyzed oxygen
oxidation conditions to 4-aminocyclohexenones and para-
iminoquinones as useful synthetic precursors.
Experimental Section
Typical procedure in Cu/C-catalyzed N–O bond cleavage. To a
suspension of substrate (3 or 5: 0.1 mmol) in H2O (0.9 mL) and 2-PrOH
(0.1 mL) in a test tube were added 10% Cu/C (6.4 mg, 0.01 mmol) and
sodium carbonate (Na2CO3; 31.8 mg, 0.3 mmol) under argon. The reaction
mixture was placed on an organic reactor, Chemi Station (EYELA, Tokyo
Rikakikai Co., Ltd., Tokyo, Japan), and the mixture was refluxed using
external aluminum heating block (100–150 oC). After an adequate reaction
time, the reaction mixture was cooled to room temperature and passed
5
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10.1002/cssc.202001739
ChemSusChem
FULL PAPER
through a membrane filter (Millipore, Millex-LH, 0.20 mm) to remove Cu/C.
The filtrate was extracted with AcOEt (10 mL × 3). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The residue was
purified by silica-gel column chromatography to give the corresponding
cis-1,4-amino alcohol derivative (4 or 6).
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temperature under argon. After 3 h, the reaction mixture was placed on an
organic reactor, Chemi Station (EYELA, Tokyo Rikakikai Co., Ltd., Tokyo,
Japan), and the mixture was refluxed using external aluminum heating
block (100–150 oC). After an adequate reaction time, the reaction mixture
was cooled to room temperature and passed through a membrane filter
(Millipore, Millex-LH, 0.20 mm) to remove Cu/C. The filtrate was extracted
with AcOEt (10 mL × 3). The combined organic layers were dried over
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column chromatography to give the corresponding cis-1,4-amino alcohol
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Typical procedure in Ru/C-catalyzed oxidation of the N–O bond
cleaved products. To a suspension of cis-1,4-aminocyclohex-2-en-1-ol
derivative (4: 0.2 mmol) in toluene (1 mL) in a test tube was added 10%
Ru/C (20.2~40.4 mg, 0.02~0.04 mmol). The inside air was replaced with
O2 (balloon) by three vacuum/O2 cycles. The reaction system was placed
on an organic reactor, Chemi Station (EYELA, Tokyo Rikakikai Co., Ltd.,
Tokyo, Japan), and the mixture was heated up using external aluminum
heating block (at an adequate temperature. After an adequate reaction
time, the reaction mixture was cooled to room temperature and passed
through a membrane filter (Millipore, Millex-LH, 0.20 mm) to remove Ru/C.
The filtrate was concentrated in vacuo. The residue was purified by silica-
gel column chromatography to give the corresponding 4-
aminocyclohexenone derivative (7) or para-iminoquinone derivative (8).
[17] 3bc (3-ethyl substrate) was converted to the mixture of 3bc (19%) and
2-ethyl-substituted regio-isomer (38%) under the conditions without Cu/C
[3bc (0.025 mmol) and Na2CO3 (3 equiv.) in H2O/2-PrOH (225/25 μL)].
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We thank the N. E. Chemcat Corporation for the kind gift of the
various metal-on-carbon catalysts. This study was supported by
a Grant-in-Aid for JSPS Research Fellows from the Japan Society
for the Promotion of Science (JSPS, Number: 18J14010 for N. Y.)
and Grant-in-Aid for Scientific Research (C) from the Japan
Society for the Promotion of Science (JSPS: 16K08169 for Y. S.)
and Takeda Science Foundation (for Y. S.).
Keywords: N–O bond cleavage • copper • one-pot synthesis •
heterogeneous catalyst • H2O
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6
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10.1002/cssc.202001739
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FULL PAPER
Entry for the Table of Contents
OH
Cu/C
O
N
n
n
Ar
H2O
HN
Ar
n
Cu/C
Na2CO3
O
N
H2O/2-PrOH
Hetero
Diels-Alder
reaction
Ar

N–O cleavage
The N–O bond cleavage of 2-oxa-3-azabicyclo compounds could proceed in the presence of catalytic Cu/C under aqueous conditions
to give the cyclic cis-1,4-amino alcohol derivatives. Furthermore, the direct incorporation of amino and hydroxyl groups to cyclic 1,3-
dienes could also be accomplished via the hetero Diels–Alder reaction with nitroso dienophiles and cyclic 1,3-dienes and the following
Cu/C-catalyzed N–O bond cleavage in a one-pot manner.
7
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