Palladium-catalyzed decarboxylative intramolecular aziridination from 4h-isoxazol-5-ones leading to 1-azabicyclo[3.1.0]hex-2-enes

Article abstract of DOI:10.1002/anie.201105153

A decarboxylative intramolecular aziridination reaction of alkene-tethered 4H-isoxazol-5-ones with a palladium/phosphine catalyst gave 1-azabicyclo[3.1.0] hex-2-enes in moderate to high yields (see scheme; dba=dibenzylideneacetone). The resulting N-fused bicyclic aziridines readily reacted with various reagents to afford ring-opening pyrroline derivatives.

Full text of DOI:10.1002/anie.201105153

Communications
DOI: 10.1002/anie.201105153
Synthetic Methods
Palladium-Catalyzed Decarboxylative Intramolecular Aziridination
from 4H-Isoxazol-5-ones Leading to 1-Azabicyclo[3.1.0]hex-2-enes**
Kazuhiro Okamoto, Tomohiro Oda, Sho Kohigashi, and Kouichi Ohe*
Transition-metal-catalyzed nitrene-transfer reactions are
Table 1: Palladium-catalyzed intramolecular aziridination giving
powerful methods for incorporating nitrogen atoms directly
into organic molecules.[1,2] Organic azides[2a,b] and N-sulfonyl-
iminoiodinanes[2c–e] are highly reactive nitrene precursors, and
have been widely used for such reactions as olefin aziridina-
azabicyclo[3.1.0]hexene 2a.[a]
À
tion and C H amination. However, they must be handled
carefully or prepared immediately before use because of their
high reactivity. Therefore, the development of catalytic
nitrene-transfer reactions that use stable precursors under
mild reaction conditions is an important topic. Our research
interest has been focused on 4H-isoxazol-5-ones, five-mem-
bered cyclic oxime esters, as candidates for stable vinylnitrene
equivalents (Scheme 1). They can be readily prepared from b-
Entry
Ligand
Conversion [%][b]
Yield [%][b]
1
2
3
4
5
6
7
8
PPh3
98
91
98
81
100
100
0
14
9
0
84
76
83
69
P(4-MeC6H4)3
P(4-MeOC6H4)3
P(2-furyl)3
P(4-FC6H4)3
P(4-CF3C6H4)3
P(C6F5)3
P(2-MeC6H4)3
P(2-MeOC6H4)3
PBu3
PCy3
P(tBu)3
dppb
rac-binap
92
95 (87[c])
0
11
0
0
0
6
0
0
9
10
11
12
13[d]
14[d]
3
7
11
15
Scheme 1. 4H-isoxazol-5-ones as a vinylnitrene equivalent.
[a] The reaction was carried out with isoxazolone 1a (0.20 mmol),
[Pd2(dba)3] (2.5 mol%), and ligand (10 mol%) in 1,4-dioxane (1.3 mL).
[b] The yields were determined by 1H NMR spectroscopy of the crude
products (see the Supporting Information). [c] Yield of the isolated
product. [d] 5 mol% of ligand was used. binap=2,2’-bis(diphenylphos-
phanyl)-1,1’-binaphthyl ,Cy=cyclohexyl, dba=dibenzylideneacetone,
dppb=bis(diphenylphosphanyl)butane.
ketoesters[3] and are generally thermally stable. We envi-
sioned that the reaction of a 4H-isoxazol-5-one with a
palladium catalyst would give a nitrene complex,[4] which is
À
formed by the activation of the N O bond by a low-valent
palladium species[5] followed by decarboxylation. Herein, we
report a palladium-catalyzed decarboxylative intramolecular
aziridination reaction of alkene-tethered 4H-isoxazol-5-ones
to form N-fused bicyclic aziridines.
phine ligands were examined for this decarboxylative intra-
molecular aziridination reaction (Table 1, entries 2–9). The
use of more electron-donating triarylphosphines resulted in
similar or lower yields (Table 1, entries 2–4), whereas the use
of more electron-withdrawing triarylphosphines increased the
yields (Table 1, entries 5 and 6) up to 95% yield (87% yield
upon isolation). However, the reactions with the more
electron-deficient P(C6F5)3 or ortho-substituted triarylphos-
phines did not proceed well (Table 1, entries 7–9). Trialkyl-
phosphines or bidentate phosphine ligands were not effective
for this reaction (Table 1, entries 10–14).[7]
During the course of our investigations of several nitrene-
transfer reactions using 4H-isoxazol-5-ones, we found that the
reaction of 4H-isoxazol-5-one 1a, which possesses a methallyl
group at the 4-position, in the presence of 2.5 mol% of
[Pd2(dba)3] (5 mol% Pd) and 10 mol% of PPh3 in 1,4-dioxane
at 808C for 12 h gave the expected 1-azabicyclo[3.1.0]hex-2-
ene 2a[6] in 84% yield (Table 1, entry 1). Various triarylphos-
[*] Dr. K. Okamoto, T. Oda, S. Kohigashi, Prof. Dr. K. Ohe
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: ohe@scl.kyoto-u.ac.jp
The present intramolecular aziridination reaction is
applicable to a variety of 4H-isoxazol-5-ones possessing a
range of substituents. Table 2 summarizes the substrate scope
of this reaction, using 5 mol% or 10 mol% of the palladium
catalyst [Pd2(dba)3]/P(4-CF3C6H4)3. 4H-Isoxazol-5-ones 1b
and 1c, bearing a 2-naphthyl group and a (p-trifluorome-
thyl)phenyl group instead of a phenyl group, gave 1-
azabicyclo[3.1.0]hexenes 2b and 2c in 83% and 80% yields,
respectively (Table 2, entries 2 and 3). The use of isoxazolone
1d, having two phenyl groups on the five-membered ring
[**] This work is supported by Grant-in-Aid for Scientific Research on the
Global COE Program “Integrated Materials Science” on Kyoto
University 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.201105153.
11470
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Angew. Chem. Int. Ed. 2011, 50, 11470 –11473

Table 2: Palladium-catalyzed intramolecular aziridination giving
azabicyclo[3.1.0]hexenes 2.[a]
Entry Isoxazolone R1
R2
R3
Yield [%][b]
2a 87
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
Ph
Me
Me
Me
Me
Me
2-naphthyl Me
4-CF3C6H4 Me
Ph
2b 83
2c 80[c]
2d 88[c]
Ph
Ph
Me
Me
Bn
n-hexyl 2e 80
nPr
Me
Me
n-hexyl 2 f 63[c]
1g
1h
Me
2g 64[c]
2h 40[c]
methallyl Me
[a] The reaction was carried out with isoxazolone 1a (0.20 mmol),
[Pd2(dba)3] (2.5 mol%), and P(4-CF3C6H4)3 (10 mol%) in 1,4-dioxane
(1.3 mL). [b] Yield of the isolated product. [c] [Pd2(dba)3] (5 mol%), and
P(4-CF3C6H4)3 (20 mol%) were used.
Scheme 2. A proposed catalytic cycle.
tions, pyrrole 3j was obtained in 74% yield together with the
trace amount of pyridine 4j [Eq. (2)].
(R1 = R2 = Ph), increased the yield of the corresponding
aziridines up to 88% (Table 2, entry 4). Isoxazolone 1e,
which possesses an allyl group with a long alkyl chain (R3 = n-
hexyl), gave the bicyclic aziridine in 80% yield (Table 2,
entry 5). Isoxazolones with aliphatic groups at the imine
carbon atom were also used in the present reaction, and the
yields of 1-azabicyclo[3.1.0]hexenes 2 f–2h were moderate. In
the case of isoxazolone 1h, bearing two methallyl groups, the
corresponding aziridine 2h was obtained in 40% yield, with
one of the methallyl groups remaining intact. Furthermore,
the reaction of tricyclic isoxazolone 1i also proceeded well to
give tetracyclic compound 2i in 65% yield [Eq. (1)].
The reaction of isoxazolone 1k, which possesses both an
allyl group and a methallyl group, could result in a mixture of
three products (aziridine, pyrrole, and pyridine). Interest-
ingly, the reaction proceeded selectively in the presence of a
Pd/tBuXphos catalyst to give the corresponding bicyclic
aziridine 2k in 54% yield with a small amount of pyrrole
3k as a by-product [Eq. (3); 2k/3k = 6:1].
Scheme 2 shows a proposed catalytic cycle for the
palladium-catalyzed intramolecular aziridination reaction of
methallyl-substituted 4H-isoxazol-5-one 1a. First, the oxida-
tive addition of isoxazolone 1a to a low-valent palladium
center forms the six-membered palladacycle A, which readily
undergoes decarboxylation[8,9] to give vinylnitrene/palladium
complex B[10] and/or four-membered azapalladacyclobutene
intermediate B’.[11] Then, cycloaddition of the tethered alkene
gives two possible azapalladacycles C and C’. Both inter-
mediates can undergo the reductive elimination to produce
bicyclic aziridine 2a, and regenerate the low-valent palladium
catalyst.
The palladium-catalyzed reaction of 4H-isoxazol-5-one
1j, possessing an unsubstituted allyl group, did not give a
bicyclic aziridine,[12] instead, pyrrole 3j and pyridine 4j were
obtained in low yields.[13] The selectivity towards the pyrrole
was remarkably increased using a bulky monophosphine
ligand (tBuXPhos).[14] Under the optimized reaction condi-
Azabicyclo[3.1.0]hexenes, the products of the present
reaction, are highly reactive because of their strained N-fused
bicyclic aziridine backbone.[6d,e,15] Of the various addition
reactions to the activated olefins of these azabicyclo-
[3.1.0]hexenes, protonolysis of the bicyclic aziridines was
first examined. The reaction of azabicyclic compound 2a with
an excess amount of acetic acid in dichloromethane pro-
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www.angewandte.org 11471

Communications
ceeded at room temperature to give ring-opening addition
hydrogenation to afford the pyrroline 9d in 61% yield
(Table 3, entry 7).
product 5a in 79% yield (Table 3, entry 1). In this product the
electrophile (proton) was introduced at the 3-position on the
azabicyclo[3.1.0]hexene backbone, and the nucleophile (ace-
tate anion) was incorporated at the 6-position. This type of
A carbon electrophile showed a different reactivity
toward the bicyclic aziridine. Azabicyclo[3.1.0]hexene 2a
was treated with acetyl chloride to give the N-acetylated
enamide 10a in 91% yield [Eq. (4)]. This result indicates that
the electrophiles first combine with the nitrogen atom
followed by the nucleophilic attack of the counter anion to
give the ring-opened enamines, and that the enamines readily
isomerize into the imines with the exception of acetyl
chloride.
Table 3: Addition/ring-opening reactions of azabicyclo[3.1.0]hexenes 2.[a]
Entry Aziridine Pyrroline
Conditions
AcOH
Yield
[%][b]
d.r.[c]
1:1
1
2
2a
2a
79
Me3SiN3, H2O 62
1:1
In conclusion, we have developed a palladium-catalyzed
intramolecular aziridination reaction using methallyl-substi-
tuted 4H-isoxazol-5-ones as a vinylnitrene precursor. The
resulting N-fused bicyclic aziridines are readily converted into
1-pyrrolines by the addition/ring-opening reaction with var-
ious reagents. The pyrrole formation from an allyl-substituted
4H-isoxazol-5-one also supports the intermediacy of a vinyl-
nitrene/palladium B as well as an azapalladacyclobutane C.
Enantioselective aziridination and intermolecular nitrene-
transfer reactions using the present decarboxylation protocol
are in progress.
3
4
5
6
7
2a
2i
Br2
Br2
I2
73
63
67
2:1
>20:1
3:1
2a
2a
2d
H2, 5% Pd/C 54
H2, 5% Pd/C 61
–
Experimental Section
General Procedure for Table 2: Isoxazolone 1 (0.20 mmol) was added
to a solution of [Pd2(dba)3] (4.6 mg, 5.0 mmol) and P(4-CF3C6H4)3
(9.3 mg, 20 mmol) in 1,4-dioxane (1.3 mL) and the mixture was stirred
at 808C for 12 h. The reaction mixture was filtered through a pad of
Florisil and the filtrate was concentrated under vacuum. The residue
was chromatographed on silica gel 60 NH2 (Kanto Chemical, co. ltd.)
(hexane/EtOAc = 20:1) to give 2.
–
[a] See the Supporting Information for reaction details. [b] Yield of the
isolated product as a mixture of diastereomers. [c] Determined by
1H NMR spectroscopy.
Received: July 22, 2011
Published online: October 4, 2011
Keywords: 4H-isoxazol-5-ones · cyclization · decarboxylation ·
homogeneous catalysis · palladium
reaction also proceeded with other reagents. The use of
trimethylsilyl azide and water resulted in the ring-opening
addition of hydrogen azide to give the corresponding
azidomethyl 1-pyrroline 6a (Table 3, entry 2; 62% yield).
The reaction of azabicyclo[3.1.0]hexene 2a with molecular
bromine (Br2) afforded a dibrominated 1-pyrroline (7a) in
73% yield with a 2:1 d.r. (Table 3, entry 3). Interestingly, the
reaction of tetracyclic aziridine 2i with molecular bromine
almost exclusively gave dibromide 7i in 63% yield (d.r. >
20:1; Table 3, entry 4). Diiodination of aziridine 2a also gave
ring-opened diiodopyrroline 8a in 67% yield with a 3:1 d.r.
(Table 3, entry 5). Catalytic hydrogenation using a heteroge-
neous palladium catalyst also proceeded to give dihydrogen
adduct 9a in 54% yield (Table 3, entry 6). The diphenyl-
substituted bicyclic aziridine 2d also underwent catalytic
.
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the subsequent steps.
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a
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Angew. Chem. Int. Ed. 2011, 50, 11470 –11473
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