Selective transformation of N-(propargylic)hydroxylamines into 4-isoxazolines and acylaziridines promoted by metal salts

Article abstract of DOI:10.1246/cl.2011.440

Cyclization of N-(propargylic)hydroxylamines catalyzed by AgBF4 afforded the corresponding 4-isoxazolines in good yields. Copper salts were found to promote the further transformation to acylaziridines. The combined use of AgBF₄ and CuCl realiz

Full text of DOI:10.1246/cl.2011.440

doi:10.1246/cl.2011.440
440
Published on the web April 9, 2011
Selective Transformation of N-(Propargylic)hydroxylamines into 4-Isoxazolines
and Acylaziridines Promoted by Metal Salts
Norihiro Wada, Kentaro Kaneko, Yutaka Ukaji,* and Katsuhiko Inomata*
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa 920-1192
(Received January 28, 2011; CL-110071; E-mail: ukaji@kenroku.kanazawa-u.ac.jp, inomata@se.kanazawa-u.ac.jp)
Cyclization of N-(propargylic)hydroxylamines catalyzed
Table 1. Cyclization of 1 in the presence of a metal salt
by AgBF4 afforded the corresponding 4-isoxazolines in good
yields. Copper salts were found to promote the further
transformation to acylaziridines. The combined use of AgBF4
and CuCl realized direct transformation of N-(propargylic)-
hydroxylamines into cis-acylaziridines.
Bn
OH
N
BnN
O
MX (0.1 equiv)
m
1
2
1
R
R
R
CH Cl , rt, t h
2
2
2
1
R1
2
R
Entry
R2
1
a
MXm
t/h Yield/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
Ph
ZnI2
23
17
42
39
86
®
57
84
89
61
74
73
82
53b
64
85
70
PdCl2
PtCl2
Compounds bearing a 4-isoxazoline ring have biological
activities and are versatile synthetic intermediates for nitrogen-
containing chemicals.1 1,3-Dipolar cycloaddition of nitrones
to acetylenes is one of the most attractive approaches to the
synthesis of 4-isoxazolines, however, the method often suffers
from poor regioselectivity.1 Conjugate addition of hydroxyl-
amines to ¡,¢-unsaturated carbonyl compounds followed by
dehydration is an alternative way.1 4-Isoxazolines could be also
prepared via ring-closure of N-(propargylic)hydroxylamines
catalyzed by zinc, palladium, or gold salt in the presence of an
amine.2 Furthermore, direct ring-closure of zinc salts of N-
(propargylic)hydroxylamines, generated in situ by addition of
alkynylzinc reagents to nitrones with an ester or amide group,
has been reported.3 Recently, we have reported a one-pot
reaction consisting of an enantioselective nucleophilic addition
of alkynylzinc reagents to nitrones and a subsequent cyclization
to give the corresponding (S)-4-isoxazolines with excellent
enantioselectivity.4 However, the cyclization step was quite slow
even when excess amounts of dimethylzinc were added for the
promotion. In order to prepare 4-isoxazolines more efficiently,
the cyclization of N-(propargylic)hydroxylamines to 4-isoxazo-
lines was investigated in the presence of a metal salt. Herein, we
wish to describe our finding that AgBF4 was an efficient catalyst
for the cyclization and further addition of a copper salt could
rearrange the 4-isoxazolines to the corresponding acylaziridines.
Direct stereoselective generation of cis-acylaziridines from N-
(propargylic)hydroxylamines was also achieved with a AgBF4-
CuCl combined system.
First, the cyclization of N-benzyl-N-(1,3-diphenylprop-2-
ynyl)hydroxylamine (1a) was examined in the presence of a
catalytic amount of metal salt without an amine in CH2Cl2 at rt
as shown in Table 1. It was reported that ZnI2 and PdCl2
promoted the cyclization in the presence of an amine base.2a,2b
Although ZnI2 was not a suitable catalyst for the cyclization in
the absence of the base (Entry 1), PdCl2 promoted the cycliza-
tion to give the corresponding 4-isoxazoline in 86% yield after
17 h (Entry 2). PtCl2 was not as effective as PdCl2 (Entry 3). It
was found that silver salts also promoted the cyclization (Entries
4-6). Cationic silver salts were more effective and the cycliza-
tion was completed within 4 h by using AgBF4, rather faster than
PdCl2, to give 4-isoxazoline 2a in 89% yield (Entry 6). Activity
of AuCl3 for the cyclization was high, but unknown by-products
a
AgNO3 40
AgOTf
AgBF4
AuCl3
AuCl3
AgBF4
AgBF4
AgBF4
21
4
0.3
22
8
22
8
Ph
Ph
n-Hex
t-Bu
Ph
b
c
d
n-Pr
c
AgBF4
AgBF4
AgBF4
8
6
8
c-Hex Ph
Me n-Hex
aMost of the hydroxylamine 1a was recovered. bThe hydroxyl-
amine 1d was recovered in 14% yield. cThe amount of AgBF4
was 0.2 equiv.
e
f
were produced lowering the chemical yield of 2a (Entries 7 and
8). Thus we chose readily available AgBF4 (0.1 equiv) as the
catalyst for the cyclization of several other N-(propargylic)-
hydroxylamines 1b-1f and the corresponding 4-isoxazolines
2b-2f were obtained in good to high chemical yields (Entries
9-14). In the case of 1d, the use of 0.2 equiv of AgBF4 improved
the chemical yield (Entry 12).
During the survey of metal salts for the cyclization of 1a,
it was found that not only 4-isoxazoline 2a but also a cis-
acylaziridine 3a5f,6 was produced with complete diastereoselec-
tivity when CuCl was used (Table 2, Entry 1). Although the
transformation of 4-isoxazolines to acylaziridines had been
reported,1,5 the conditions were drastic and the diastereoselec-
tivity was not always good.
Next, direct transformation of 1a to acylaziridine 3a was
intensively investigated (Table 2). By the use of cationic copper
salts, the cis-acylaziridine 3a was obtained as a major product
(Entries 4-7). However, the reaction was messy and chemical
yield was not satisfactory. In order to accelerate the cyclization
step, a catalytic amount of AgBF4 was added. Among copper
salts examined, CuCl was most effective in the presence of
AgBF4 as a co-catalyst (Entries 9 and 13-16). By the use of 0.2
equiv of AgBF4 and 1.0 equiv of CuCl, 3a was finally obtained
in 88% yield (Entry 10). When the amount of CuCl was
Chem. Lett. 2011, 40, 440-442
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

441
Table 2. Direct transformation of 1 to 3
Table 3. Transformation of 2a to 3a promoted by a copper salt
AgBF4 (n1 equiv)
CuXm (n2 equiv)
Bn
Bn
R1
OH
Bn
N
BnN
Ph
O
N
BnN O
N
CuXm (1.0 equiv)
R2
R1
Ph
R2
CH2Cl2, rt, t h
CH2Cl2, rt, t h
Ph
3a
Ph
R1
R2
O
O
3
2a
1
2
n1
/equiv
n2
t
2
3
Entry
CuXm
t/h
Yield/%
Entry R1
R2
Ph
1
CuXm
1
2
3
4
5
CuCl
CuOTf(C6H6)0.5
Cu(OTf)2
CuBF4(CH3CN)4
Cu(BF4)2
41
4
41
22
41
23a
81
3
71
45
/equiv /h /% /%
1.0 41 16 2a
1.0 44
1.0 44
1.0 17 23 58
1
2
Ph
a 0
0
CuCl
CuCl2
CuI
CuOTfc
®
®
®
®
b
3
4
0
0
aThe 4-isoxazoline 2a was recovered in 68% yield.
5
6
7
8
0
0
0
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Cu(OTf)2 1.0 48
®
®
®
32 61
13 84
45
45
48
d
CuBF4
1.0
7
Cu(BF4)2 1.0 25
[ 2 + 2 ]
Cu
σ
π
s
a
CuCl
CuCl
CuCl
CuCl
CuCl
CuOTfc
1.0
1.0
1.0 20
0.2
0.2 23
8
8
NBn
9
Bn
N
2
1
R
R
1
10
11
12
13
14
15
16
4
88
O
R
2
R
4
8
10 58
H
H
®
®
®
®
82
35
13
42
1.0
7
8
8
8
Figure 1.
Cu(OTf)2 1.0
d
CuBF4
1.0
Although the precise reaction mechanism is not yet clear,
a radical mechanism might be ruled out, since addition of
galvinoxyl free radical in the reaction of 1a to 2a (according to
Entry 6 in Table 1) or 2a to 3a (according to Entry 2 in Table 3)
as a radical inhibitor did not affect the reaction.7-9
In the transformation of 4-isoxazoline to acylaziridine,
[1,3]-sigmatropic rearrangement is a possible pathway to afford
the cis-aziridine (Figure 1).5c-5e Copper salt might activate the
reaction via coordination by nitrogen resulting in lowering the
LUMO energy of the N-O bond.
As described above, a convenient one-pot transformation
of N-(propargylic)hydroxylamines into the corresponding 4-
isoxazolines and aziridines, which are useful synthons for the
synthesis of nitrogen-containing biologically active compounds,
has been developed.1,10 Further studies on this reaction are in
progress in our laboratory.
Cu(BF4)2 1.0
10 42
17 Ph
18 Ph
19 n-Pr Ph
20 c-Hex Ph
21
n-Hex b 0.2
t-Bu c 0.2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
1.0 27
1.0 24
1.0 41
1.0 25 14 64
1.0 24
1.0 23
®
®
®
63
72e
d 0.2
e 0.2
0.3
49e,f
7
®
76
58
22 Me
n-Hex f 0.2
aThe hydroxylamine 1a was recovered in 69% yield. bMost
of the hydroxylamine 1a was recovered. cCuOTf(C6H6)0.5
dCuBF4(CH3CN)4. The corresponding trans-isomer of 3 was
obtained in 6% (Entry 18) and in 10% (Entry 19) yields,
respectively. fAn imine, N-(1-phenylhex-1-yn-3-ylidene)-
benzylamine (4d), was obtained in 28% yield.
.
e
decreased to 0.2 equiv, the transformation proceeded a little
sluggishly to afford 3a still in high yield (Entries 11 and 12).
The one-pot cyclization-isomerization was applied to several
other N-(propargylic)hydroxylamines 1b-1f in the presence
of AgBF4 (0.2 equiv) and CuCl (1.0 equiv) to afford the
corresponding cis-acylaziridines 3b-3f (Entries 17-22).6 In the
case of cis-pivaloylaziridine 3c, a small amount of trans-isomer
was formed (Entry 18). Transformation from 1d was not so
clean and formation of the corresponding trans-isomer and a
dehydrated imine 4d was also observed (Entry 19). In the case
of 1e, increase of the amount of AgBF4 could improve the
chemical yields (Entries 20 and 21).
To confirm that copper salt promotes transformation of the
4-isoxazoline into the acylaziridine, 4-isoxazoline 2a was treated
with copper salts (Table 3). Although the reaction was rather
sluggish when CuCl was used (Entry 1), CuOTf(C6H6)0.5
realized high chemical yield (Entry 2).
The present work was financially supported in part by a
Grant-in-Aid for Scientific Research (C) from Japan Society for
the Promotion of Science (JSPS).
References and Notes
1
J. P. Freeman, Chem. Rev. 1983, 83, 241; T. M. V. D.
Pinho e Melo, Eur. J. Org. Chem. 2010, 3363.
2
a) E. J. Stoner, B. A. Roden, S. Chemburkar, Tetrahedron
Lett. 1997, 38, 4981. b) P. Aschwanden, D. E. Frantz, E. M.
Carreira, Org. Lett. 2000, 2, 2331. c) O. Debleds, C. D.
Zotto, E. Vrancken, J.-M. Campagne, P. Retailleau, Adv.
Synth. Catal. 2009, 351, 1991.
S. Pinet, S. U. Pandya, P. Y. Chavant, A. Ayling, Y. Vallee,
Org. Lett. 2002, 4, 1463; F. Cantagrel, S. Pinet, Y. Gimbert,
P. Y. Chavant, Eur. J. Org. Chem. 2005, 2694.
W. Wei, M. Kobayashi, Y. Ukaji, K. Inomata, Heterocycles
2009, 78, 717; Y. Ukaji, K. Inomata, Chem. Rec. 2010, 10,
173.
a) J. E. Baldwin, R. G. Pudussery, A. K. Qureshi, B. Sklarz,
J. Am. Chem. Soc. 1968, 90, 5325. b) I. Adachi, R.
3
4
5
Finally, when the optically active 1a (99% ee) was
subjected to the present reactions under the same conditions
as those of Entry 6 in Table 1 and Entry 10 in Table 2, the
optically active 2a (92%, 98% ee) and 3a (87%, 98% ee) were
obtained without loss of optical purities, respectively.
Chem. Lett. 2011, 40, 440-442
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

442
Miyazaki, H. Kano, Chem. Pharm. Bull. 1974, 22, 70. c) R.
8
When 2a was treated with 1.0 equiv of CuOTf(C6H6)0.5 in
ClCH2CH2Cl at 80 °C for 0.5 h, 3a was obtained in 80%
yield and diastereoselectivity was still high (3a/trans-
isomer = 20/1, determined by 1H NMR spectrum of the
crude products) different from the result of the similar
reaction promoted by Co2(CO)8 (0.5 equiv), in which cis/
trans isomers’ ratio was 2.8/1.5f This fact might suggest that
the present reaction does not proceed through a radical
pathway via the metal enolate-aza radical intermediate as
proposed in ref. 5f.
When the direct transformation of 1a to 3a according to
Entry 10 in Table 2 was performed in the presence of
galvinoxyl free radical (1.2 equiv), the reaction proceeded
sluggishly to give 3a in 10% yield accompanied by the
production of an imine, N-(1,3-diphenylprop-2-ylidene)-
benzylamine (4a) (34%). Galvinoxyl free radical might
oxidize CuCl to give more Lewis acidic Cu(II) species,
which promoted the dehydration of 1a.
Grée, R. Carrié, J. Am. Chem. Soc. 1977, 99, 6667. d) G.
Chidichimo, G. Cum, F. Lelj, G. Sindona, N. Uccella, J. Am.
Chem. Soc. 1980, 102, 1372. e) K. Tanaka, M. Ohsuga, Y.
Sugimoto, Y. Okafuji, K. Mitsuhashi, J. Fluorine Chem.
1988, 39, 39. f) T. Ishikawa, T. Kudoh, J. Yoshida, A.
Yasuhara, S. Manabe, S. Saito, Org. Lett. 2002, 4, 1907. g)
B. Alcaide, P. Almendros, J. M. Alonso, M. F. Aly, C. Pardo,
E. Sáez, M. R. Torres, J. Org. Chem. 2002, 67, 7004. h)
E. M. Budynina, E. B. Averina, O. A. Ivanova, T. S.
Kuznetsova, N. S. Zefirov, Tetrahedron Lett. 2005, 46, 657.
i) E. Gayon, O. Debleds, M. Nicouleau, F. Lamaty, A. Lee,
E. Vrancken, J.-M. Campagne, J. Org. Chem. 2010, 75,
6050.
9
6
7
The cis-stereochemistry of 3a-3f was confirmed by the
coupling constant J2-3 (6.4-7.4 Hz) between the methine
protons in aziridine rings.5
A previous report which excluded the possibility of a radical
pathway based on a controlled experiment using galvinoxyl
free radical: Y. Kuninobu, H. Ueda, A. Kawata, K. Takai,
J. Org. Chem. 2007, 72, 6749.
10 Aziridines; for example: G. Cardillo, L. Gentilucci, A.
Tolomelli, Aldrichimica Acta 2003, 36, 39, and references
cited therein.
Chem. Lett. 2011, 40, 440-442
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/