Scandium(III) triflate-TMSCl promoted cyclization of aziridin-1-yl oximes to 5,6-dihydro-4H-[1,2,4]oxadiazines

Article abstract of DOI:10.1016/j.tetlet.2006.10.096

A convenient and facile one-pot synthesis of 5,6-dihydro-4H-[1,2,4]oxadiazine is described. Treatment of aziridin-1-yl-oximes with Scandium(III) triflate readily afforded 5,6-dihydro-4H-[1,2,4]oxadiazine in the presence of chlorotrimethylsilane.

Full text of DOI:10.1016/j.tetlet.2006.10.096

Tetrahedron Letters 47 (2006) 9029–9033
Scandium(III) triflate–TMSCl promoted cyclization of
aziridin-1-yl oximes to 5,6-dihydro-4H-[1,2,4]oxadiazines
Sung Yun Cho,* Seung Kyu Kang, Jin Hee Ahn, Jae Du Ha and Joong-Kwon Choi
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong-gu,
Daejeon 305-600, Republic of Korea
Received 6 September 2006; revised 12 October 2006; accepted 19 October 2006
Available online 7 November 2006
Abstract—A convenient and facile one-pot synthesis of 5,6-dihydro-4H-[1,2,4]oxadiazine is described. Treatment of aziridin-1-yl-
oximes with Scandium(III) triflate readily afforded 5,6-dihydro-4H-[1,2,4]oxadiazine in the presence of chlorotrimethylsilane.
Ó 2006 Elsevier Ltd. All rights reserved.
1,2,4-Oxadiazines are of pharmacological relevance and
represent useful synthetic building blocks.1 There have
been few reports on the synthesis of 5,6-dihydro-4H-
[1,2,4]oxadiazines.2 The literature search revealed that
the conventional synthetic methods for [1,2,4]oxadi-
azines mainly rely on the ring opening of aziridinyl-1-yl
oximes mediated by hydrogen chloride and subsequent
cyclization of chlorides by NaOH in two steps and low
yield.
of acetyl chloride through one-step synthesis.4 Tabei
et al. synthesized the oxadiazine derivatives by the
reaction of bromoacetoacetyl bromide with benzamide
oximes in low yields.5 Treatment of aziridinylbenzaldox-
imes with hydrochloric acid and subsequent treatment
with NaOH afforded the oxadiazine derivatives in low
yields.6 Aziridines can be used as important substrates
to afford cycloaddition products or ring opened prod-
ucts mediated by Lewis acids.7 Singh and co-workers8
performed a successful application of aziridines with
alcohols to afford a ring opened product mediated by
Lewis acid.
Rajagopalan and Talaty first reported that 5,6-dihydro-
4H-[1,2,4]oxadiazine derivatives were synthesized from
1-aroylaziridine oximes.3 Zen and Harada also reported
that oxadiazines were prepared by the reaction of di-
ketones with aliphatic nitro compounds in the presence
In the course of our research for the preparation of novel
protein tyrosine phosphatase 1B (PTP1B) inhibitors,9
OH
R1
R2
R3
O
N
OH
TMSCl
N
R2
N
N
H
N
N
H
R1
Sc(OTf)3
Cl
R1
R3
1
R2
R3
2
3
OH
N
Me
O
O
N
N
i) HCl
Me
N
+
:
N
H
Me
N
H
ii) NaOH
35 %
2d
2
1
Scheme 1.
Keywords: Aziridinyl oxime; Oxadiazine; Scandium triflate.
*
Corresponding author. Tel.: +82 42 860 7077; fax: +82 42 860 7160; e-mail: sycho@krict.re.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.096

9030
S. Y. Cho et al. / Tetrahedron Letters 47 (2006) 9029–9033
Table 1. Cyclization of aziridinylbenzaldoximes catalyzed by Lewis acid
OH
O
Me
N
N
Lewis acid
Me
N
H
N
TMSCl
CH2Cl2, rt
OEt
OEt
O
O
O
O
Entry
Lewis acid
Yield (%)
1
2
3
4
5
6
7
Yb(OTf)3
AgOTf
24
0
Cu(OTf)2
BF3ÆOEt2
Et3OÆBF4
Sc(OTf)3
Sc(OTf)3
0a
0a
0
45b
77
a No substrate was recovered.
b The reaction was performed in the absence of chlorotrimethylsilane.
we sought to synthesize bioisosteric 5,6-dihydro-4H-
[1,2,4]oxadiazines to replace the cyclopenta[d][1,2]-
oxazine skeleton which has limited stability in either
acidic or basic medium. Herein, we wish to report a con-
venient and facile one-pot synthesis of 5,6-dihydro-4H-
[1,2,4]oxadiazines from aziridin-1-yl oximes mediated
by Scandium(III) triflate in the presence of TMSCl. As
shown in Scheme 1, the cyclization of aziridinyl oximes
3d mediated by hydrochloric acid and subsequent treat-
ment of NaOH afforded regioisomeric mixture of
[1,2,4]oxadiazines (35%) as inseparable mixture (2:1
1
ratio) that could be characterized by H and 13C NMR
spectra by analogy. For initial assessment, we examined
the cyclization of 2 in the presence of various Lewis acids
as given in Table 1.
The requisite substrates, aziridinylaldoximes, were
prepared by reaction of suitable aziridines with chloro-
oximes 1.10 We observed that suitable aziridinylaldoxox-
imes were easily derived from their chlorooximes (1a–f)
Table 2. Synthesis of 1,2,4-oxadiazines
OH
N
R2
OH
O
NEt
3
Sc(OTf)3
N
N
R2
N
R1
N
H
R1
TMSCl
CH2Cl2
Cl
R1
ether
R2
1
2
3
Entry
1
Chlorooxime
Aziridinyl oxime
[1,2,4]Oxadiazine
H
O
N
OH
N
OH
N
OEt
N
OEt
Cl
OEt
N
(45%)
(56%)
(62%)
(71%)
H
H
O
O
O
1a
2a
3a (>10:1)
OH
N
Ph(Me)
O
N
Me
OEt
OEt
N
2
1a
1a
Me(Ph)
N
H
O
O
Ph
3b (1.6:1:0.2)
2b
OH
Me
O
N
N
N
N
N
(81%)
(66%)
(61%)
(69%)
Me
Me
OEt
OEt
3
4
5
N
N
N
H
3c
O
O
2c
OH
OH
N
Me
Me
O
Cl
N
H
3d
1b
2d
OH
OH
O
N
Cl
N
Cl
Cl
Me
(65%)
N
Cl
(65%)
N
H
3e
Cl
Cl
Cl
1c
2e

S. Y. Cho et al. / Tetrahedron Letters 47 (2006) 9029–9033
9031
Table 2 (continued)
Entry
Chlorooxime
Aziridinyl oxime
[1,2,4]Oxadiazine
OH
N
OH
N
Me
O
N
Me
Me
Cl
(71%)
OMe
(72%)
(81%)
Cl
N
Cl
6
7
N
H
Br
OMe
3f
1d
2f
OH
OH
N
Me
O
N
N
Cl
N
(56%)
OMe
N
H
OMe
OMe
3g
2g
OH
1e
H
O
N
N
8
1e
1e
N
(42%)
(69%)
OMe
N
H
H
OMe
2h
OH
3h (3:1)
Ph(Me)
Me(Ph)
O
N
N
Me
Me
N
(56%)
9
(67%)
OMe
N
H
OMe
Ph
3i (1.3:1)
2i
OH
OH
N
Me
O
N
N
(77%)
N
Cl
10
11
(71%)
OCH2CO2Et
N
H
OCH2CO2Et
OCH2CO2Et
3j
1f
2j
OH
MeO2C
O
N
N
MeO2C
(25%)
N
(35%)
OCH2CO2Et
N
H
1f
OCH2CO2Et
3k
2k
as given in Table 2. Chlorooximes 1 were easily derived
from their aldehydes.11 To evaluate the possibility of
effecting Lewis acid-promoted cyclization of 2, a repre-
sentative selection of Lewis acids including Yb(OTf)3,
AgOTf, Cu(OTf)2, BF3ÆOEt2, and Sc(OTf)3 were tested
in their ability to form [1,2,4]oxadiazines 3. Treatment
of aziridinylaldoximes with optimal Lewis acid
smoothly afforded dihydro-4H-[1,2,4]oxadiazines 3 in
the presence of chlorotrimethylsilane. All experiments
were run at room temperature with Lewis acid
(1.1 equiv) in the presence of chlorotrimethylsilane
(1.1 equiv).12 In the preliminary experiments, Sc(OTf)3
and Yb(OTf)3 were found to facilitate the cyclization
of aziridinylaldoxime to oxadiazines, but the reaction
yields were unsatisfactory. The reaction gave only a ring
opened product when chlorotrimethylsilane was used in
the absence of Lewis acid within 30 min at room temper-
ature, and the reaction did not proceed below 0 °C
(Scheme 2). No substrate was recovered when boron tri-
fluoride-diethyl etherate or copper triflate was used.
(entries 4 and 5). The reaction was unsatisfactory
when other Lewis acids were tested (entries 2 and 3).
OH
N
Me
Cl
OH
N
75 %
Me
+
TMSCl
N
N
H
CH2Cl2
5 (3 : 1)
OH
Ph
N
Me
O
N
OH
i) Sc(OTf)3
N
N
CH2Cl2
42 %
Me
+
N
N
Cl
ii) BnBr
Cs2CO3
DMF
OMe
Me
Ph
OMe
OMe
4
1e
6
2g
(3 eq)
Scheme 2.

9032
S. Y. Cho et al. / Tetrahedron Letters 47 (2006) 9029–9033
2. Srivastava, R. M.; Morais, L. P. F.; Melo Souto, S. C.;
Carpenter, G. B.; Carvalho, L. T. Tetrahedron Lett. 2006,
47, 3173.
3. Rajagopalan, P.; Talaty, C. N. J. Am. Chem. Soc. 1966,
88, 5048.
Resubjection of ring opened product 5 in the presence of
TMSCl or Sc(OTf)3–TMSCl did not give rise to cyclized
product with only the recovered starting material.
Reaction yields were significantly improved by the addi-
tion of chlorotrimethylsilane (1.1 equiv) to the reaction
mixture, presumably because of preventing the forma-
tion of complex between Lewis acid and hydroxyl
group.13 The desired product 3d was produced by use
of either TMSOTf or TfOH in place of Sc(OTf)3–
TMSCl in low yield, 29% and 35% of the cyclized
product, respectively. Treatment of aziridinylaldoximes
(2a–k) with Scandium(III) triflate in the presence of
chlorotrimethylsilane readily afforded [1,2,4]oxadiazine
derivatives (3a–k) in moderate to excellent yields.
4. Zen, S.; Harada, K. Chem. Lett. 1982, 1711.
5. Tabei, K.; Kawashima, E.; Takada, T.; Kato, T. Chem.
Pharm. Bull. 1982, 30, 3987.
6. (a) Eremeev, A. V.; Piskunova, I. P.; Andrianov, V. G.;
Liepin’sh, E. E. Khimiya Geterotsiklicheskikh Soedinenii
1982, 4, 488; (b) Lynch, V. J. Heterocycl. Chem. 1996, 33,
1583.
7. (a) Munegumi, T.; Azumaya, I.; Kato, T.; Masu, H.;
Saito, S. Org. Lett. 2006, 8, 379; (b) Wu, J.; Sun, X.; Xia,
H.-G. Tetrahedron Lett. 2006, 47, 1509; (c) Ghorai, M. K.;
Ghosh, K.; Das, K. Tetrahedron Lett. 2006, 47, 5399; (d)
Bhanu Prasad, B. A.; Pandey, G.; Singh, V. K. Tetra-
hedron Lett. 2004, 45, 1137.
The functional group, such as carboethoxy (3a– c), was
well tolerated in the reaction and aziridinyl oximes were
readily cyclized into oxadiazines, regioselectively. In
addition, fused (3a,h) and disubstituted oxadiazines
(3b,i) were readily prepared from their corresponding
aziridinyl oximes. We performed the reaction with azi-
ridinylaldoximes (2a,b,h,i), and the corresponding
[1,2,4]oxadiazines (3a,b,h,i) were produced with no dia-
stereofacial selectivity presumably because of undergo-
ing via carbocation formation. For 3b and 3i, the
other possible isomers were not identified. We observed
that the yields of 3h and 3k were very low presumably
because of the steric and electronic environment of car-
boethoxy group. The regiochemical description of the
product was unequivocally determined by decoupling
experiment (1H TOCSY) and characteristic splitting
patterns of cyclized product.14
8. Bhanu Prasad, B. A.; Sanghi, R.; Singh, V. K. Tetrahedron
2002, 58, 7355.
9. (a) Cho, S. Y.; Kang, S. K.; Ahn, J. H.; Ha, J. D.; Choi,
J.-K. Tetrahedron Lett. 2006, 47, 5237; (b) Cho, S. Y.;
Baek, J. Y.; Han, S. S.; Kang, S. K.; Ha, J. D.; Ahn, J. H.;
Lee, J. D.; Kim, K. R.; Cheon, H. G.; Rhee, S. D.; Yang,
S. D.; Yon, G. H.; Pak, C. S.; Choi, J.-K. Bioorg. Med.
Chem. Lett. 2006, 16, 499.
10. Johnson, J. E.; Maia, J. A.; Tan, K.; Ghafouripour, A.;
Meester, P.; Chu, S. S. C. J. Heterocycl. Chem. 1986, 23,
1861.
11. (a) Pandey, M. K.; Bisai, A.; Pandey, A.; Singh, V. K.
Tetrahedron Lett. 2005, 46, 5039; (b) Liu, K.-C.; Shelton,
B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916; (c)
Kozikowski, A. P.; Adamczyk, M. J. Org. Chem. 1983, 48,
366.
12. Typical procedure: To a stirred solution of phenyl chloro-
oxime (1.3 g, 8.33 mmol) in diethyl ether (10 mL) was
added 2-methylaziridine (1.7 mL, 24.9 mmol) in ether
(1 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 2 h. The resulting mixture was poured
into water (15 mL) and extracted with ethyl acetate
(20 mL). The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography to afford 2d (0.97 g,
As an extended study, a novel cycloaddition of aziridine
4 and chlorooxime 1e afforded oxadiazine in low yield
(42%), along with by-products as inseparable mixture
(Scheme 2). The structure of cycloaddition product 6
was conformed by the same compound derived from
the cyclization of azridinyl oxime 2g and subsequent
treatment of benzyl bromide.
1
66%); H NMR (300 MHz, CDCl3) d 7.67 (m, 2H), 7.39
(m, 3H), 2.46 (m, 1H), 2.24 (d, J = 6.0 Hz, 1H), 2.18 (d,
J = 6.0 Hz, 1H), 1.41 (d, J = 5.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3) 158.4, 133.6, 129.4, 128.5, 126.8, 36.7,
36.3, 18.0; MS m/e (relative intensity) 176 (M+, 83), 130
(4), 104 (100), 77 (45). Compound (3d): To a stirred
solution of 2d (100 mg, 0.57 mmol), Sc(OTf)3 (307 mg,
0.62 mmol) in dichloromethane (3 mL) was added TMSCl
(0.62 mmol, 80 lL) at 0 °C. The reaction mixture was
stirred at room temperature for 2 h. The resulting mixture
was poured into water (10 mL) and neutralized with
NaHCO3 to pH = 7. The resulting mixture was extracted
with ethyl acetate (20 mL) and the organic layer was dried
over MgSO4. The organic layer was concentrated under
reduced pressure and purified by column chromatography
In summary, we performed a convenient and facile cycli-
zation of aziridinyl oxime to 5,6-dihydro-4H-[1,2,4]-
oxadiazines mediated by Scandium(III) triflate in the
presence of chlorotrimethylsilane.
Acknowledgment
The authors appreciate the financial support from the
Ministry of Commerce, Industry and Energy of Korea
and Bioneer Corporation.
1
to afford 3d (69 mg, 69%); H NMR (300 MHz, CDCl3)
d 7.63 (m, 2H), 7.42 (m, 3H), 4.74 (br s, 1H), 3.85 (ddq,
J = 8.6, 6.2, 2.8 Hz, 1H), 3.52 (ddd, J = 11.5, 8.6, 1.8 Hz,
1H), 3.27 (ddd, J = 11.5, 5.5, 2.8 Hz, 1H), 1.34 (d,
J = 6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) 152.3,
133.0, 130.0, 128.5, 125.9, 67.6, 46.4, 17.4; MS m/e
(relative intensity) 176 (M+, 100), 159 (22), 146 (7), 130
(13), 117 (28), 104 (99), 77 (97).
References and notes
1. (a) Mezei, J.; Kuttel, S.; Racz, I. Polish J. Pharmacol.
1984, 36, 397; (b) Crovetti, A. J.; VonEsch, A. M.; Thill,
R. J. J. Heterocycl. Chem. 1972, 9, 435; (c) Takacs, K.;
Harsanyi, K. Chem. Ber. 1970, 103, 2330; (d) Takacs, K.;
Harsanyi, K.; Kolonits, P.; Ajzert, K. I. Chem. Ber. 1975,
108, 1911–1923.
13. (a) Yamanaka, M.; Nishida, A.; Nakagawa, M. Org. Lett.
2000, 2, 159; (b) Nakagawa, M.; Kawahara, M. Org. Lett.
2000, 2, 953.

S. Y. Cho et al. / Tetrahedron Letters 47 (2006) 9029–9033
9033
14. NMR spectra were taken on
a
Bruker DRX-300
The connectivity of carbon was also conformed by the
1H homo-decoupling experiment of each peak by
irradiation and the coupling constant was determined
as described below in the typical procedure of this
article.
instrument fitted with a 5 mm 1H/broadband gradient
probe with inverse geometry (proton coils closest to the
sample). The 1D TOCSY increment of 3d (3.85 ppm)
appeared when it was irradiated with methyl (1.34 ppm).