Divergent Catalytic Approach from Cyclic Oxime Esters to Nitrogen-Containing Heterocycles with Group 9 Metal Catalysts

Article abstract of DOI:10.1021/acscatal.8b01646

We report the divergent catalytic transformation of alkene-tethered isoxazol-5(4H)-ones by using rhodium and cobalt catalysts to afford 2H-pyrroles (with Rh catalyst) and azabicyclic cyclopropanes (with Co catalyst). The rhodium-catalyzed 2H-pyrrole forma

Full text of DOI:10.1021/acscatal.8b01646

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Article
Divergent Catalytic Approach from Cyclic Oxime Esters to
Nitrogen-Containing Heterocycles with Group 9 Metal Catalysts
Takuya Shimbayashi, Gaku Matsushita, Atsushi Nanya, Akira Eguchi, Kazuhiro Okamoto, and Kouichi Ohe
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01646 • Publication Date (Web): 09 Jul 2018
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Page 1 of 10
ACS Catalysis
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Divergent Catalytic Approach from Cyclic Oxime Esters to Nitro-
gen-Containing Heterocycles with Group 9 Metal Catalysts
Takuya Shimbayashi,† Gaku Matsushita, Atsushi Nanya, Akira Eguchi, Kazuhiro Okamoto,* and Kou-
ichi Ohe*
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Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-
ku, Kyoto 615-8510, Japan
Supporting Information Placeholder
respectively.9,10 We report herein the divergence of these
nitrene-transfer reactions by employing rhodium and cobalt
catalysts, affording two different nitrogen-containing het-
erocycles, 2H-pyrroles and azabicyclo[3.1.0]hex-2-enes.
ABSTRACT: We report the divergent catalytic transfor-
mation of alkene-tethered isoxazol-5(4H)-ones by using
rhodium and cobalt catalysts to afford 2H-pyrroles (with
Rh catalyst) and azabicyclic cyclopropanes (with Co
Scheme 1. Divergent synthesis of nitrogen-containing het-
erocycles by transition metal-catalyzed transformation of
alkene-tethered isoxazol-5(4H)-ones.
catalyst). The rhodium-catalyzed 2H-pyrrole formation
involving hydrogen shift is supported by deuterium-
labeling experiments. The control experiments in the
cobalt-catalyzed reaction indicate that the bicyclic aziri-
dines as the primary product undergo a skeletal rear-
rangement assisted by metal iodide salts.
N
O
N
N
Me
cat. [Pd]
cat. [Co]
Ph
Me
Ph
Ph
Ph
Me
O
Me
6a
This work
Me
Me
cat. [Ru]
1a
2a
Me
Me
N
cat. [Ir]
N
N
cat. [Rh]
Me
Ph
Me
Me
Ph
Me
5a
Keywords: divergent catalysis, rhodium, cobalt, N-
heterocycles, decarboxylation
Me
4a
3a
2. RESULTS AND DISCUSSION
2.1. Rhodium-catalyzed 2H-Pyrrole Formation
1. INTRODUCTION
At the outset of this study, we examined the reaction of
the model substrate 1a with a catalyst precursor
([RhCl(cod)]2, 10 mol% per Rh) and various phosphine
ligands in 1,4-dioxane at 100 °C for 5 h (Table 1). Trial-
kylphosphines P(alkyl)3 (alkyl = Me, Cy, t-Bu) did not
work as ligands for 2H-pyrrole formation (entries 1–3).
When we employed PPh3 as a ligand, 2H-pyrrole 5a was
obtained as the corresponding decarboxylative cyclization
product in 67% yield (entry 4). We next examined various
triarylphosphine and bisphosphine ligands under similar
conditions. Among the various bisphosphine ligands ex-
amined, dppf exhibited the highest selectivity for 2H-
pyrrole formation, 2H-pyrrole 5a being obtained in 74%
yield (entries 5–8). When the electronic effect of the tri-
arylphosphine ligands was examined, the use of tri-
arylphosphine with electron-deficient trifluoromethyl group
P(4-CF3C6H4)3 resulted in very low conversion (entry 9).
This result makes a striking contrast to the palladium-
catalyzed aziridination, in which P(4-CF3C6H4)3 is the most
effective ligand for obtaining bicyclic aziridine 2a in the
Divergent catalytic transformation of common substrates
toward various synthetic scaffolds through the common
intermediates by changing transition metals1,2 or by using
different ligands3,4 is an efficient and powerful strategy as
well as a more challenging issue than the usual synthetic
strategy aiming at an individual approach to each target.
Such kinds of divergent approaches are considered to be
effective in the synthesis of various nitrogen-containing
heterocycles, which are privileged structural motifs in bio-
logically active molecules, including synthetic drugs.1,3
Recently, the generation of nitrogen-centered active species
generated by catalytic N–O bond cleavage of oxime esters
has emerged as one of the most attractive methods for syn-
thesizing various nitrogen-containing heterocycles.5,6 We
have recently found that isoxazol-5(4H)-ones (isoxa-
zolones) could act as the alkenylnitrene equivalent (Scheme
1), which is followed by palladium-catalyzed cyclization
with the internal olefin to form a bicyclic aziridine.7,8 Dur-
ing the course of studies, we also found different cycliza-
tion reactions of the same isoxazolones, catalyzed by iridi-
um and ruthenium, providing 2H-azirines and pyridines,
highest yield.7a
Finally, we found the electron-rich
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triarylphosphine, P(4-MeOC6H4)3, was the best ligand in
Page 2 of 10
N
O
[RhCl(cod)]2 (2.5 mol%)
P(4-MeOC6H4)3 (15 mol%)
Me
R3
R1
R2
R3
N
1
2
3
4
5
6
7
the selective formation of 2H-pyrroles (entry 10). Reduc-
ing the amount of catalyst loading to 5 mol% Rh dimin-
ished the yield of 2H-pyrrole significantly in 1,4-dioxane
(entry 11). The yield was increased to 84% (73% isolated
yield) when acetonitrile was used as the solvent (entries
12–14).
R1
O
MeCN, 100 ºC, 24 h
R2
1
5
Me
Me
Me
n-Hex
Me
n-Hex
Me
N
N
N
N
Ph
Ph
n-Pr
Ph
Ph
8
9
Me
5a 73%
Me
5d 62%
Me
5b 76%
Me
Me
Table 1. Rhodium-catalyzed formation of 2H-pyrrole 5a from
isoxazolone 1a.a
5c 76%b
N
[RhCl(cod)]2 (5 mol%)
ligand (30 mol%)
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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29
30
31
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58
59
60
Me
N
Me
Ph
O
N
N
N
Ph
Me
Me
Me
MeO
Br
Br
Ph
O
Me
Me
solvent, 100 °C
Me
5e 59%
Me
5f 59%
Me
Me
5a
5g 73%b
1a
Me
Me
Me
Me
Me
N
S
N
N
Me
entry ligand
solvent
time (h) conv (%)b yield (%)b
1
2
3
4
PMe3
PCy3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
5
5
5
5
5
5
5
5
5
5
31
0
2
0
Me
5h 41%
Me
5j 85%b
5i 50%
P(t-Bu)3
0
0
a
Reaction conditions: isoxazolone 1 (0.20 mmol), [RhCl(cod)]2 (2.5
mol%), and P(4-MeOC6H4)3 (15 mol%) in acetonitrile (2.0 mL).
[RhCl(cod)]2 (5 mol%) and P(4-MeOC6H4)3 (30 mol%) were used.
PPh3
5c dppe
99
67
38
36
74
33
2
b
88
6c dppb
7c dppf
8c rac-binap
86
96
N
H
N
O
[RhCl(C2H4)2]2 (2.5 mol%)
DPEphos (5.0 mol%)
Me
100
9
Ph
Me
Ph
9
P(4-CF3C6H4)3 1,4-dioxane
P(4-MeOC6H4)3 1,4-dioxane
(1)
O
ClCH2CH2Cl, 100 ºC, 17 h
10
100
73
81
44
69
77
84 (73)e
Me
7n 64%
11d P(4-MeOC6H4)3 1,4-dioxane 24
12d P(4-MeOC6H4)3 THF
13d P(4-MeOC6H4)3 DME
1n
24
24
24
100
100
100
14d P(4-MeOC6H4)3 MeCN
2.2. Cobalt-catalyzed Azabicyclic Cyclopro-
pane Formation
a
The reaction was carried out with isoxazolone 1a (0.20 mmol),
[RhCl(cod)]2 (5 mol%), and ligand (30 mol%) in 1,4-dioxane (2.0 mL) at
b
1
c
100 °C. Determined by H NMR spectra of the crude products. 10
d
mol% of the ligand was used. [RhCl(cod)]2 (2.5 mol%) and ligand (15
Table 3. Cobalt-catalyzed decarboxylative transformation of
isoxazolone 1a.a
mol%) were used. e The yield of isolated product.
[Co] (10 mol%)
ligand (10 mol%)
Mn (1.5 equiv)
N
O
N
Ph
N
N
The rhodium-catalyzed 2H-pyrrole formation reaction
can be applied to several substrates bearing a variety of
substituents (Table 2). When methyl, n-hexyl, and phenyl
groups were employed as R3 substituents, the correspond-
ing 2H-pyrroles were obtained in good yields (5a–c).
Isoxazolone 1d having all alkyl substituents for R1, R2, and
R3 afforded 2H-pyrrole 5d in 62% yield. Isoxazolones
bearing various aromatic substituents on R1, such as p-
methoxyphenyl, p-bromophenyl, naphthyl, and thienyl
groups also afforded 2H-pyrroles 5e–i in good yields. Tri-
cyclic product 5j was also obtained from tetralin-fused
isoxazolone 1j. The reaction of isoxazolone 1n, which
possesses an allyl group (R3 = H) gave 1H-pyrrole 7n in
place of 2H-pyrrole in good yield, when the reaction was
carried out with [RhCl(C2H4)2]2 and DPEphos in
dichloroethane at 100 °C, 17 h (eq 1).
Me
+
Ph
Me
Ph
Me
Ph
O
+
Me
Me
Me
MeCN
100 °C, 14 h
Me
Me
2a
6a
3a
1a
entry [Co]
ligand
dppe
dppbz
dppp
dppf
conv (%)b 6a (%)b 2a (%)b 3a (%)b
1
2
3
4
5
6
7
8
CoI2
CoI2
CoI2
CoI2
CoI2
CoI2
100
100
57
66 (60)
66
0
0
9
5
14
0
1
100
30
0
6
DPEphos 58
24
0
4
PPh3
56
100
79
10
0
3
CoI2(dppe) none
67
0
7
CoBr2
CoI2
dppe
dppe
6
32
43
1
9c
a
100
0
11
Reaction conditions: isoxazolone 1a (0.20 mmol), CoI2 (10 mol%), Mn
b
(0.30 mmol), and ligand (10 mol%) in acetonitrile (2.0 mL) at 100 °C.
c
Determined by 1H NMR analyses of the crude products. Reaction at
60 °C.
Table 2. Rhodium-catalyzed reaction of isoxazol-5(4H)-one 1
giving 2H-pyrrole 5.a
During the exploration of catalysis with other metals, we
found that a reaction of 1a catalyzed by a low-valent co-
balt-dppe complex, which was generated via reduction of
CoI2 with metallic Mn powder in situ,11 afforded a new
product 6a with a small amount of pyridine 3a (Table 3,
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entry 1). Hence, the reaction conditions of the cobalt- C=N double bond to form pyrroline 9 selectively. Oxida-
1
2
3
4
5
6
7
8
catalyzed reaction of isoxazolone 1a including ligands,
temperature, and solvent were examined. Acetonitrile was
also found to be the most effective solvent in the cobalt
catalysis.12 Dppe and dppbz gave the best yields of product
6a as a result of the screening of various monophosphine
and bisphosphine ligands (entries 1–6). The reaction also
proceeded smoothly when a presynthesized cobalt–
phosphine complex was used (entry 7). In sharp contrast,
the employment of a cobalt dibromide complex instead of
the iodide complex afforded the product 6a only in 6%
yield. Instead, bicyclic aziridine 2a was obtained in mod-
erate yield (entry 8). The selective formation of aziridine
2a was also observed in the reaction at a lower temperature
(entry 9).
tion of 2H-pyrrole 5a with m-CPBA afforded the corre-
sponding N-oxide 10 in good yield. The 2H-pyrrole N-
oxide derived from 5g, like 5a, was further converted to the
platinum complex 11 in moderate yield. The structure of
11 was determined by X-ray crystallographic analysis (eq 2,
Figure 1).
Azabicyclic cyclopropane 6a, which was obtained in the
cobalt-catalyzed reaction, was also applied to hydride re-
duction with NaBH3CN to give the corresponding bicyclic
amine 12 as a single diastereomer in good yield (eq 3).13
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Oxidation and reduction of 2H-pyrroles into five-
membered heterocyclic compounds
H2 (1 atm)
5% Pd/C (20 wt%)
Me
N
Me
With the optimized conditions for the selective formation
of cyclopropanes established, a variety of 1 was tested (Ta-
ble 4). Bromo, chloro, thienyl, and trifluoromethyl groups
on the aromatic substituent in R1 could be tolerated under
the reaction conditions (6f–l). Isoxazolone 1n and 1o hav-
ing one and two allyl groups afforded cyclopropanes 6n
and 6o, respectively, together with 1H-pyrroles 7n and 7o.
Ph
Ph
Ph
MeOH, rt, 12 h
Me
8
58%
DIBAL-H
(4.0 equiv)
Me
H
N
Me
N
Me
Ph
Me
THF
–78 ºC to rt, 16 h
Me
Me
5a
9 65%
O–
Table 4. The cobalt-catalyzed reaction of isoxazol-5(4H)-one 1
giving azabicyclic cyclopropane 6.a
Me
N+
Me
mCPBA (1.1 equiv)
H
CoI2 (10 mol%)
dppe (10 mol%)
Mn (1.5 equiv)
N
Me
O
N
N
R1
CH2Cl2, rt, 9 h
R1
R1
R3
Me
10 60%
O
R2
R3
R2
MeCN, 100 °C, 14 h
R2
7 (R3 = H)
1
6
Cl
Pt
Cl
1) mCPBA
(1.2 equiv)
CH2Cl2, rt
N
Me
N
N
O
N
Me
Ph
Ph
Br
Ph
Ph
N
Hex
Br
Me
Me
(2)
Br
2) [PtCl2(C2H4)]2
(0.5 equiv)
CH2Cl2, rt, 7 h
Me
6b 55%
Me
6f 65%
Me
6a 60%
Me
Me
11 41% yield
(2 steps)
5g
N
S
N
N
F3C
Me
Me
Me
Me
6k 59%
Me
Me
6i 38%
6h 56%
N
Ph
N
Me
Cl
Me
Me
Me
6m 75%
6l 60%
H
N
H
N
Figure 1. An ORTEP drawing of platinum complex 11. Hydro-
gen atoms are omitted for clarity. CCDC 1839972.
Me
Me
N
N
Ph
Ph
Ph
Ph
+
H
H
+
Me
6n 41%b
H
Me
7n 21%b
N
N
NaBH3CN (3.0 equiv)
Ph
Me
Ph
Me
(3)
6o 40%b
7o 43%b
Me
EtOH / AcOH = (10:1)
rt, 3 h
Me
a Reaction conditions: isoxazolone 1 (0.20 mmol), CoI2 (10 mol%), Mn
6a
12
(0.30 mmol), and dppe (10 mol%) in acetonitrile (2.0 mL) at 100 °C.
2.4. Deuterium-labeling Experiments
2.3. Derivatization of the reaction products
Deuterium-labeling experiments were performed to gain
insight into the mechanism of the rhodium-catalyzed reac-
tion. Deuterated isoxazolone 1a-d2 was reacted under the
standard conditions to give 2H-pyrrole 5a-d, in which one
of the deuterium atoms was incorporated into the methyl
group (85% incorporation) and the other deuterium re-
mained attached to the original carbon (eq 4). The reaction
2H-Pyrroles obtained from the rhodium-catalyzed reac-
tion could be transformed into oxidized or reduced five-
membered nitrogen-containing heterocycles by simple oxi-
dation and reduction (Scheme 2). Heterogeneous palladi-
um–carbon-catalyzed hydrogenation of 2H-pyrrole 5a af-
forded pyrroline 8 selectively, while the reaction of 2H-
pyrrole 5a with DIBAL-H resulted in the reduction of the
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Page 4 of 10
of monodeuterated isoxazolone 1a-d1 showed no signifi- did not show prominent catalytic activity toward the isom-
1
2
3
4
5
6
7
8
cant intramolecular kinetic isotope effect (eq 5). A crosso-
ver reaction using 1a-d2 and 1c in 1:1 ratio resulted in the
formation of deuterated 5a-d and 5c, which indicates that
no intermolecular exchange of hydrogen atoms occurred
during the reaction (eq 6). Moreover, allyl-substituted
isoxazolone 1n-d with one deuterium at the 2-position of an
allyl group was transformed into 1H-pyrrole 7n-d, in which
the deuterium incorporation ratio at the methyl position
was less than 12% (eq 7). This result is in sharp contrast to
the palladium-catalyzed formation of 1H-pyrroles.7c The
formation of 1H-pyrroles can be explained by assuming the
prototropic shift of mechanism from that of the palladium
catalyst.14
erization (entries 6 and 7), the efficacy of metal iodide salts
in isomerization was obvious.
Table 5. Skeletal rearrangement of bicyclic aziridine 2a into
azabicyclic cyclopropane 6a.a
N
N
Me
reagent
Ph
Ph
Me
MeCN
100 °C, 14 h
Me
6a
Me
2a
9
entry reagents
6a (%)b
CoI2 (10 mol%), dppe (10 mol%), Mn (1.5 equiv) 68
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
3
4
5
6
7
CoI2 (10 mol%)
ZnI2 (10 mol%)
SmI2 (10 mol%)
LiI (10 mol%)
Bu4NI (10 mol%)
ZnBr2 (10 mol%)
49
61
72
57
13
0
(85% D)
N
O
[RhCl(cod)]2 (2.5 mol%)
P(4-MeOC6H4)3 (15 mol%)
CH2D(H)
Ph
Me
N
Me
O
a
(4)
Ph
Reaction conditions: aziridine 2a (0.20 mmol) and reagents (as de-
D
scribed above) in acetonitrile (2.0 mL) at 100 °C. b Determined by 1H
NMR analyses of the crude products.
MeCN
100 ºC, 24 h
Me
D
D
(>98% D)
Me
(>98% D)
1a-d2
5a-d: 51%
(47% D)
2.6. Mechanistic Consideration
N
Scheme 3. A proposed catalytic cycle for rhodium- and cobalt-
catalyzed decarboxylative transformation of isoxazolone 1.
O
[RhCl(cod)]2 (2.5 mol%)
P(4-MeOC6H4)3 (15 mol%)
CH2D(H)
Ph
N
Me
Me
R3
O
N
Me
Me
(5)
O
Ph
N
R1
R2
R3
H
R1
MeCN
100 ºC, 24 h
D(H)
D
(>98% D)
O
Me
(51% D)
5
R2
[M]
.
reductive
elimination
1
1a-d2
5a-d: 47%
(83% D)
N
[M]
.
[Rh]
R3
N
R1
R2
R3
N
O
O
R1
CH2D(H)
Ph
Me
Me
H
N
A
Me
O
O
Ph
E
R2
D
D
D
N
R3
R1
Me
(>98% D)
(>98% D)
[M]
[RhCl(cod)]2 (2.5 mol%)
P(4-MeOC6H4)3 (15 mol%)
1a-d2
5a-d: 50%
N
R2
2
N
R1
[M]
.
(6)
R1
R3
+
+
M = Co
MeCN
100 ºC, 24 h
R2
ß-hydride
elimination
N
O
Me
N
.
[Rh]
R3
R2
B'
Ph
Me
B
Ph
Ph
O
N
.
[M]
N
R3
R1
Ph
M = Rh
Me
R3
H
R1
H
R2
5c: 66%
(no D incorporation)
D
1c
R2
C
N
O
H
[RhCl(C2H4)2]2 (2.5 mol%)
DPEphos (5.0 mol%)
CH2D(H)
Ph
Based on the above experimental results, the proposed
mechanism for rhodium-catalyzed 2H-pyrrole formation
and cobalt-catalyzed bicyclic aziridine formation is shown
in Scheme 3. Considering the catalytic cycles proposed for
palladium-, ruthenium-, and iridium-catalyzed reactions,
the present catalytic cycle also begins from the oxidative
addition of isoxazolone 1 to the low-valent metal species to
form intermediate A via N–O bond cleavage.7–10 Interme-
diate A rapidly undergoes decarboxylation to form
azametallacyclobutene B rather than alkenylnitrene species
N
O
(<12% D)
Ph
Me
(7)
ClCH2CH2Cl, 100 ºC, 17 h
D
Me
7n-d: 66%
(82% D)
1n-d
2.5. Control Experiments in Cobalt-catalyzed
Reaction
Considering that the cobalt-catalyzed reaction at the low-
er temperature gave aziridine 2a as a major product, gener-
ation of azabicyclic cyclopropane 6a by cobalt catalysis
would involve the skeletal rearrangement of aziridine 2a.
Therefore, we investigated several conditions of the reac-
tion of isolated aziridine 2a giving 6a (Table 5). In the
presence of CoI2, dppe, and metallic Mn, aziridine 2a was
isomerized to product 6a in good yield, which indicates
that aziridine 2a was a key intermediate for the formation
of 6a (entry 1). The isomerization proceeded in the pres-
ence of a catalytic amount of metal iodides such as CoI2,
ZnI2, SmI2, and LiI (entries 2–5). While Bu4NI and ZnBr2
B ,15 which then undergoes intramolecular cycloaddition or
¢
1,2-insertion of olefinic moieties into the metal–nitrogen
double bond to form bicyclic metallacycle C. In the cobalt-
catalyzed reaction, C–N bond-forming reductive elimina-
tion from intermediate C affords bicyclic aziridine 2 as
well as the regenerated catalyst, which is very similar to the
palladium-catalyzed system.7a,16 In the rhodium-catalyzed
reaction, on the other hand, intermediate C would isomer-
ize into aza-h3-allylrhodium intermediate D. Then the b-
hydride elimination followed by reductive elimination
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would form 2H-pyrrole 5 as well as the regenerated catalyst.
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
These reaction pathways are in good agreement with deu-
terium-labeling experiments as described above. 1H-
Pyrrole 7 is considered as the prototropically isomerized
product of 2H-pyrrole 5, which has also been confirmed by
the deuterium-labeling experiment described above.
Corresponding Author
*E-mail for K. Okamoto: kokamoto@scl.kyoto-u.ac.jp
*E-mail for K. Ohe: ohe@scl.kyoto-u.ac.jp
Current Address
It is assumed that the skeletal rearrangement of bicyclic
aziridine 2 to azabicyclic cyclopropane 6 would be trig-
gered by the coordination of the nitrogen atom to the Lewis
acidic metal species,17,18 taking the control experiments as
shown in Table 3 into consideration. Then complex F un-
dergoes a C–N bond-cleaving ring expansion simultaneous-
ly with the formation of the C–I bond to form six-
membered species G,19 which readily undergoes the C–C
bond-forming recyclization to give bicyclic product 6, re-
generating the metal iodide species (Scheme 4).
†Present Address for T. S.: Graduate School of Human and
Environmental Studies, Kyoto University, Sakyo-ku, Kyoto
606-8501, Japan.
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No competing financial interests have been declared.
ORCID
Takuya Shimbayashi: 0000-0003-1520-5829
Kazuhiro Okamoto: 0000-0001-8562-3167
Kouichi Ohe: 0000-0001-8893-8893
Scheme 4. Proposed mechanism for skeletal rearrangement of
bicyclic aziriridne 2 into azabicyclic cyclopropane 6.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on
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ACKNOWLEDGMENTS
This work was financially supported by Grants-in-Aid for
Scientific Research (B) (Grant No. 18H01976) and (C)
(Grant No. 17K05861) from JSPS. We also thank Dr. Kei-
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7
8
kynes with Cyclic Enones: A Route to Bicyclic Tertiary Al-
cohols. Angew. Chem. Int. Ed. 2012, 51, 10592–10595. (b)
Gandeepan, P.; Cheng, C. H. Cobalt Catalysis Involving π
Components in Organic Synthesis. Acc. Chem. Res. 2015, 48,
1194–1206. (c) Sen, M.; Kalsi, D.; Sundararaju, B. Co-
balt(III)-Catalyzed Dehydrative [4+2] Annulation of Oxime
with Alkyne by C-H and N-OH Activation. Chem.—Eur. J,
2015, 21, 15529–15533. (d) Nogi, K.; Fujihara, T.; Terao, J.;
Tsuji, Y. Carboxyzincation Employing Carbon Dioxide and
Zinc Powder: Cobalt-Catalyzed Multicomponent Coupling
Reactions with Alkynes. J. Am. Chem. Soc. 2016, 138, 5547–
5550.
18) For examples of aza-vinylcyclopropane rearrangement of 2-
vinylaziridines, see: (a) Atkinson, R. S.; Rees, C. W. A vinyl-
aziridine to pyrroline rearrangement. Chem. Commun. 1967,
1232. (b) Atkinson, R. S.; Rees, C. W. Reactive intermediates.
Part
VIII.
Thermolysis
of
N-(vinylaziridinyl)-
benzoxazolinones. Some new heterocyclic rearrangements. J.
Chem. Soc. C 1969, 778–782. (c) Hirner, S.; Somfai, P. Mi-
crowave-Assisted Rearrangement of Vinylaziridines to 3-
Pyrrolines: Formal Synthesis of (-)-Anisomycin. Synlett 2005,
3099–3102. (d) Birchacek, M.; Lee, D.-E.; Njardarson, J. T.
Lewis Acid Catalyzed [1,3]-Sigmatropic Rearrangement of
Vinyl Aziridines. Org. Lett. 2008, 10, 5023–5026.
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12) We assume the one-electron reduction of Co(II) precursor
with metallic manganese to form Co(I) species as the primary
low-valent catalyst. See also ref. 12 for other cobalt-catalyzed
reactions.
13) Toh, K. K.; Biswas, A.; Wang, Y. -F.; Tan, Y. Y.; Chiba, S.
Copper-Mediated Oxidative Transformation of N-Allyl
Enamine Carboxylates toward Synthesis of Azaheterocycles. J.
Am. Chem. Soc. 2014, 136, 6011–6020.
14) We assume that the rhodium-catalyzed reaction of 1n-d may
first afford 2H-pyrrole 5n-d, which readily undergoes 1,5-
hydrogen shift to form 7n-d. The deuterium on the nitrogen
atom could not be detected due to the fast H–D exchange.
19) The mechanism for the formation of pyridine 3a might be
attributed to the side pathway from intermediate G. Other-
wise, there might be a similar reaction pathway to the rutheni-
um-catalyzed pyridine formation (ref. 9b).
20) (a) Zhuo, C.-X.; Zhou, Y. ; You, S.-L. Highly Regio- and En-
antioselective Synthesis of Polysubstituted 2H-Pyrroles via
Pd-Catalyzed Intermolecular Asymmetric Allylic Dearomati-
zation of Pyrroles. J. Am. Chem. Soc. 2014, 136, 6590–6593.
(b) Zhuo, C.-X.; Cheng, Q.; Liu, W.-B.; Zhao, Q.; You, S.-L.
Enantioselective Synthesis of Pyrrole-Based Spiro- and Poly-
cyclic Derivatives by Iridium-Catalyzed Asymmetric Allylic
Dearomatization and Controllable Migration Reactions. An-
gew. Chem. Int. Ed. 2015, 54, 8475–8479. (c) The Organo-
catalytic Approach to Enantiopure 2H- and 3H-Pyrroles: In-
hibitors of the Hedgehog Signaling Pathway. Kötzner, L.;
Leutzsch, M.; Sievers, S.; Patil, S.; Waldmann, H.; Zheng, Y. ;
Thiel, W.; List, B. Angew. Chem. Int. Ed. 2016, 55, 7693–
7697. (d) Polaḱ, P.; Tobrman, T. Dearomatization Strategy for
the Synthesis of Arylated 2H-Pyrroles and 2,3,5-Trisubstituted
1H-Pyrroles. Org. Lett. 2017, 19, 4608–4611.
Me
D
N
Me
N
D
Ph
1,5-H shift
Ph
Me
7n-d
Me
5n-d
15) We have prepared the enantiopure isoxazolone 1b* by chiral
HPLC resolution and examined this for rhodium-catalyzed
2H-pyrrole formation. As a result, center chirality of isoxazo-
lone 1b* was transferred into the different carbon center of
5b* almost completely. This result indicates that the reaction
should proceed through intermediates preserving chiral infor-
mation derived from starting isoxazolone 1b*.
21) (a) Wu, K.; Meng, L.; Huai, M.; Huang, Z.; Liu, C.; Qi, X.;
Lei, A. Palladium-catalyzed aerobic (1+2) annulation of Csp3–
Me
N
[RhCl(cod)]2 (5 mol%)
P(4-MeOC6H4)3 (30 mol%)
O
N
Ph
Hex
H
bonds with olefin for the synthesis of 3-
Ph
*
(8)
*
O
azabicyclo[3.1.0]hex-2-ene. Chem. Commun. 2017, 53, 2294–
2297. (b) Veeranna, K. D.; Das, K. K.; Baskaran, S. One-Pot
Synthesis of Cyclopropane-Fused Cyclic Amidines: An Oxi-
dative Carbanion Cyclization. Angew. Chem. Int. Ed. 2017, 56,
16197–16201. (c) Ershov, O. V.; Bardasov, I. N. Methods of
assembling 3-azabicyclo[3.1.0]hexane skeleton. Chem. Heter-
ocycl. Compd. 2016, 52, 447–449 (microreview).
Me
Hex
MeCN
100 °C, 24 h
Me
5b*
86% yield
>99% ee
1b*
>99% ee
16) For examples of aza-vinylcyclopropane rearrangement of N-
vinylaziridines, see: (a) Whitlock, H. W., Jr.; Smith, G. L. The
rearrangement of an N-vinylaziridine. Tetrahedron Lett. 1965,
6, 1389–1393. (b) Ito, M. M.; Nomura, Y.; Takeuchi, Y.; To-
moda, S. Formation of Unusual Pyrroles by Photolysis of 1-
Vinyl-4,5-Dihydro-1H-1,2,3-Triazoles Chem. Lett. 1981,
1519–1522. (c) More, S. S.; Mohan, T. K.; Kumar, Y. S.;
Kumar, U. K. S.; Patel, N. B. Synthesis of novel 5-
alkyl/aryl/heteroaryl substituted diethyl 3,4-dihydro-2H-
pyrrole-4,4-dicarboxylates by aziridine ring expansion of 2-
[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic ac-
id diethyl esters Beilstein J. Org. Chem. 2011, 7, 831–838.
17) Theoritical studies for palladium-catalyzed decarboxylative
aziridination using isoxazolones have been reported. See:
Xie, H.; Lin, F.; Yang, L.; Chen, X.; Ye, X.; Tian, X.; Lei, Q.;
22) For selected examples of biological studies on 2H-pyrroles
and their derivatives, see: (a) Saito, S.; Kubota, T.; Koba-
yashi, J. Calyciphylline G, a novel alkaloid with an unprece-
dented fused-hexacyclic skeleton from Daphniphyllum
calycinum. Tetrahedron Lett. 2007, 48, 5693–5695. (b)
Zhang, Y. -M.; Tan, N.-H.; Lu, Y. ; Chang, Y.; Jia, R.-R.
Chamobtusin A, a Novel Skeleton Diterpenoid Alkaloid from
Chamaecyparis obtusa cv. tetragon. Org. Lett. 2007, 9,
4579–4581. (c) Deery, E.; Schroeder, S.; Lawrence, A. D.;
Taylor, S. L.; Seyedarabi, A.; Waterman, J.; Wilson, K. S.;
Brown, D.; Geeves, M. A.; Howard, M. J.; Pickersgill, R. W.;
Warren, M. J. An enzyme-trap approach allows isolation of
intermediates in cobalamin biosynthesis. Nature Chem. Biol.
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2012, 8, 933-940. (d) Jeppsson, F.; Eketjäll, S.; Janson, J.;
M.; Goldberg, J. A. CC-1065 and the Duocarmycins:ꢀ Synthet-
ic Studies. Chem. Rev. 1997, 97, 787–828. (d) Sorbera, L.A.;
Castaner, J.; Leeson, P. A. Bicifadine. Drugs Future 2005, 30,
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Challenges in Modern Drug Discovery: A Case Study of Bo-
ceprevir, an HCV Protease Inhibitor for the Treatment of Hep-
atitis C Virus Infection. Acc. Chem. Res. 2008, 41, 50–59. (e)
Bymaster, F. P.; Golembiowska, K.; Kowalska, M.; Choi, Y.
K.; Tarazi, F. I. Pharmacological characterization of the nore-
pinephrine and dopamine reuptake inhibitor EB-1020: Impli-
cations for treatment of attention‒deficit hyperactivity disor-
der. Synapse 2012, 66, 522. (f) Warnock, K. T.; Yang, A. R. S.
T.; Yi, H. S.; June, H. L., Jr.; Kelly, T.; Basile, A. S.; Skolnick,
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Karlström, S.; Gustavsson, S.; Olsson, L.-L.; Radesäter, A.-
C.; Ploeger, B.; Cebers, G.; Kolmodin, K.; Swahn, B.-M.;
von Berg, S.; Bueters, T.; Fälting, J. Discovery of AZD3839,
a Potent and Selective BACE1 Inhibitor Clinical Candidate
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23) For selected examples of biological studies on 3-
azabicyclo[3.1.0]hexanes, see: (a) Epstein, J. W.; Brabander,
H. J.; Fanshawe, W. J.; Hofmann, C. M.; McKenzie, T. C.;
Safir, S. R.; Osterberg, A. C.; Cosulich, D. B.; Lovell, F. M.
1-Aryl-3-azabicyclo[3.1.0]hexanes, a New Series of Nonnar-
cotic Analgesic Agents. J. Med. Chem. 1981, 24, 481-490. (b)
Rowlands, M. G.; Bunnett, M. A.; Foster, A. B.; Jarman, M.;
Stanek, J.; Schweizer, E. Analogs of Aminoglutethimide
Based on 1-Phenyl-3-azabicyclo[3.1.0]hexane-2,4-dione: Se-
lective Inhibition of Aromatase Activity. J. Med. Chem. 1988,
31, 971-976. (c) Boger, D. L.; Boyce, C. W.; Garbaccio, R.
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Divergent catalysis
using cyclic nitrene precursors
Our previous work
This work
Me
N
R3
N
R3
Ir cat.
R1
R1
Rh cat.
R2
N
R2
O
R1
N
R3
Pd cat.
Ru cat.
R1
O
R2
R3
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Co cat.
R2
N
N
R1
R3
R1
R3
R2
R2
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