Asymmetric 1,3-dipolar cycloaddition of nitrile oxides generated in situ by direct oxidation of aldoximes

Article abstract of DOI:10.1246/cl.2002.1112

The asymmetric 1,3-dipolar cycloaddition of nitrile oxides, generated in situ from aldoximes by direct oxidation with tert-butyl hypochlorite, to 2-propen-1-ol was achieved by utilizing diisopropyl (R,R)-tartrate as a chiral auxiliary to afford the corresponding (R)-2-isoxazolines with high enantioselectivity up to 96% ee.

Full text of DOI:10.1246/cl.2002.1112

1112
Chemistry Letters 2002
Asymmetric 1,3-Dipolar Cycloaddition of Nitrile Oxides
Generated in situ by Direct Oxidation of Aldoximes
Masamichi Tsuji, Yutaka Ukaji,ꢀ and Katsuhiko Inomataꢀ
Department of Chemical Science, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa, Ishikawa 920-1192
(Received August 5, 2002; CL-020653)
O
O
OiPr
The asymmetric 1,3-dipolar cycloaddition of nitrile oxides,
1) 1.0 R2Zn
2) 1.0 (R,R)-DIPT
R
Zn
O
Zn
generated in situ from aldoximes by direct oxidation with tert-
butyl hypochlorite, to 2-propen-1-ol was achieved by utilizing
diisopropyl (R; R)-tartrate as a chiral auxiliary to afford the
corresponding (R)-2-isoxazolines with high enantioselectivity up
to 96% ee.
OH
O
3) 1.1 R2Zn
OiPr
1A
2
O
O
O
OiPr
An
N
5) m additive
6) n X-X'
O
Zn
O
Zn
4) 1.1 AnC(H)=NOH
H
O
−HX'
in CHCl3, 0 °C
OiPr
Asymmetric 1,3-dipolar cycloaddition nowadays attracts a
great deal of attention in synthetic organic chemistry, because it
can provide optically active five-membered ring compounds.
Above all, the asymmetric 1,3-dipolar cycloaddition of nitrone to
olefins has been recently extensively studied and several efficient
methods were reported using chiral Lewis acids.1 To the contrary,
the enantioselective 1,3-dipolar cycloaddition of nitrile oxide had
not yet to meet with success although diastereoselective reactions
to the olefins bearing a chiral auxiliary have been reported.1a,2
One reason is that nitrile oxide is generally unstable and is
necessary to be generated in situ from hydroximoyl halide by
dehydrohalogenation or from primary nitro compound by
dehydration.3
We have developed the first and probably only, so far we
know, enantioselective 1,3-dipolar cycloaddition of nitrile oxides
to allylic alcohols utilizing diisopropyl tartrate (DIPT) as a chiral
auxiliary to give the corresponding 2-isoxazolines with excellent
enantioselectivity,4 and the reaction was successfully applied to
the synthesis of Lythraceae alkaloid, lasubine II.4d In our method,
nitrile oxide was generated in situ from hydroximoyl chloride by
treating with alkylzinc reagent as a base. It is well-known that
hydroximoyl chloride is rather labile compared with the
corresponding aldoxime, but nitrile oxide can be also generated
in situ from the aldoxime by treatment with sodium hypochlorite.
If the enantioselective 1,3-dipolar cycloaddition of nitrile oxide
could be realized using aldoxime as a source of nitrile oxide, the
reaction would become quite convenient and efficient. Herein we
would like to describe the enantioselective 1,3-dipolar cycloaddi-
tion of nitrile oxides generated in situ by direct oxidation of
aldoximes.
3
O
O
OiPr
X
An
C N O Zn
N O
O
OH
An
O
Zn
T (h)
OiPr
5a
[An = 4-(MeO)C6H4]
O
4
O
First, several oxidants were examined as shown in Table 1;
i.e., to 2-propen-1-ol (1A) was successively added dimethylzinc
(1.0 molar amount), (R; R)-DIPT (1.0 molar amount), a second
dimethylzinc (1.1 molar amounts), p-methoxybenzaldehyde
oxime (1.1 molar amounts), and finally an oxidant (n molar
amounts) in CHCl3 at 0 ꢁC. Although the corresponding 2-
isoxazoline 5a was obtained by the use of N-chlorosuccinimide
(NCS) as an oxidant,5 the enantioselectivity was low (Entry 1).
The use of N-bromosuccinimide (NBS) instead of NCS gave the
isoxazoline 5a with lower enantioselectivity (Entry 2). The
oxidation by N-iodosuccinimide (NIS) and ICl gave only a trace
Table 1. Asymmetric 1,3-dipolar cycloaddition of a nitrile oxide
generated in situ by the direct oxidation of an aldoximea
Entry
R
X–X0
n
Additive
m
T/h Yield/% ee/%b
1
2
3
4
5
6
7
8
9
Me NCS 1.1
Me NBS 1.1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
13
13
71
38
26
19
—
—
73
53
88
92
85
90
82
90
93
Me
NIS
1.1
13 trace
15 trace
Me I–Cl 1.1
Me Cl–OtBu 1.1
14
14
15
17
18
35
19
39
73
81
64
69
66
76
Et
iPr
iPr
iPr
1.1
1.1
2.0
3.0
2.0
2.0
When 2-propen-1-ol (1A) is successively treated with
dialkylzinc, (R; R)-DIPT, a second dialkylzinc, and aldoxime,
the zinc-bridging intermediate 3 is presumably formed. By the
addition of halogenating agent (X–X0) as an oxidant to the
putative intermediate 3, oxidation of the aldoxime residue might
proceed to generate HX0 and nitrile oxide, which would
coordinated to zinc metal as depicted in 4, and followed by
asymmetric 1,3-dipolar cycloaddition to give the corresponding
2-isoxazoline 5 in optically active form. According to this
hypothesis, the asymmetric 1,3-dipolar cycloaddition was
investigated in detail.
—
tBuOH
tBuOH
10c iPr
11c iPr
12c iPr
13d iPr
0.01 18
0.1 12
2.0 1,4-dioxane 1.5 11
2.0 1,4-dioxane 1.5 16
aReaction was carried out on a 0.5 mmol scale in 9 ml CHCl3.
bEnantioselectivities were determined by HPLC analysis (Daicel
Chiralcel OD-H). cReaction was carried out on a 0.5 mmol scale in
12 ml CHCl3. dReaction was carried out on a 1.4 mmol scale in 12 ml
CHCl3.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
1113
amount of cycloadduct (Entries 3, 4). The enantioselectivity was
enhanced by utilizing tert-butyl hypochlorite6 though chemical
yield was poor (Entry 5).7 Other oxidants, such as BrCCl3,
2,3,4,5,6,6-hexachloro-2,4-cyclohexadien-1-one, and benzyltri-
methylammonium tetrachloroiodate8 produced no isoxazoline. In
order to improve the chemical and optical yields, the alkyl group
of dialkylzinc and the molar amounts of tert-butyl hypochlorite
were varied. When diisopropylzinc was used instead of
dimethylzinc or diethylzinc, enantioselectivity was considerably
improved (Entries 5–7)9 and the use of 2.0 molar amounts of
oxidant realized over 90% ee (Entries 7–9). Unfortunately, the
enantioselectivity was fluctuated to a great extent depending on
the used tert-butyl hypochlorite. tert-Butyl alcohol, produced
with the progress of thereaction, was suspected to influence onthe
reproducibility. Thus, the reaction was carried out in the presence
of a small amount of tert-butyl alcohol to afford 5a with
reproducible good to high enantioselectivities (Entries 10, 11). As
tert-butyl alcohol seemed to dissociate the unfavorable aggrega-
tion of the intermediary zinc complex 4 for the ideal reaction
course, 1,4-dioxane was added as an additive4b resulting in the
similar reproducibility (Entry 12). Finally, by carrying out the
reaction at higher concentration (Entry 13), both the chemical
yield and enantioselectivity were improved to 76% and 93% ee,
respectively.10
As described above, efficient enantioselective 1,3-dipolar
cycloaddition of nitrile oxide generated in situ from aldoxime by
the direct oxidation was realized. The present procedure has the
great advantage not to involve the preparation of rather unstable
hydroximoyl chloride. Because of easy availability of (R; R)- and
(S; S)-DIPT, this method provides a useful way to prepare both
enantiomers of 2-isoxazolines which are the versatile intermedi-
ates for optically active ꢀ-hydroxy ketones or ꢁ-amino alcohols.
The present work was financially supported in part by the
Asahi Glass Foundation, Sasakawa Grants for Science Fellows
from the Japan Science Society, and Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science.
References and Notes
1
a) K. V. Gothelf and K. A. Jꢀrgensen, Chem. Rev., 98, 863 (1998). b) K.
V. Gothelf and K. A. Jꢀrgensen, J. Chem. Soc., Chem. Commun., 2000,
1449. c) K. V. Gothelf, in ‘‘Cycloaddition Reactions in Organic
Synthesis,’’ ed. by S. Kobayashi and K. A. Jꢀrgensen, Wiley-VCH,
Weinheim (2002), Chap. 6. d) S. Kanemasa, in ‘‘Cycloaddition
Reactions in Organic Synthesis,’’ ed. by S. Kobayashi and K. A.
Jꢀrgensen, Wiley-VCH, Weinheim (2002), Chap. 7. e) W. S. Jen, J. J.
M. Wiener, and D. W. C. MacMillan, J. Am. Chem. Soc., 122, 9874
(2000). f) S. Iwasa, S. Tsushima, T. Shimada, and H. Nishiyama,
Tetrahedron, 58, 227 (2002). g) F. Viton, G. Bernardinelli, and E. P.
Kundig, J. Am. Chem. Soc., 124, 4968 (2002). h) T. Mita, N. Ohtsuki, T.
¨
Ikeno, and T. Yamada, Org. Lett., 4, 2457 (2002).
Next, the asymmetric cycloaddition of several nitrile oxides
to allylic alcohols 1 was performed. After optimizing the molar
quantities of diisopropylzinc, aldoxime, and tert-butyl hypo-
chlorite, the corresponding 2-isoxazolines 5 could be obtained in
excellent optical yields (Table 2).11
2
3
4
H. Yamamoto, S. Watanabe, K. Kadotani, M. Hasegawa, M. Noguchi,
and S. Kanemasa, Tetrahedron Lett., 41, 3131 (2000).
K. B. G. Torssell, in ‘‘Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis,’’ VCH, New York (1988), Chap. 2.
a) Y. Ukaji, K. Sada, and K. Inomata, Chem. Lett., 1993, 1847. b) M.
Shimizu, Y. Ukaji, and K. Inomata, Chem. Lett., 1996, 455. c) Y.
Yoshida, Y. Ukaji, S. Fujinami, and K. Inomata, Chem. Lett., 1998,
1023. d) Y. Ukaji, M. Ima, T. Yamada, and K. Inomata, Heterocycles,
52, 563 (2000).
1) 1.0 iPr2Zn
2) 1.0 (R,R)-DIPT
3) k iPr2Zn
4) l RC(H)=NOH
N O
5) 1.5 1,4-dioxane
6) n ClO Bu
t
OH
R'
OH
R
in CHCl3, 0 °C
R'
1
5
5
K.-C. Liu, B. R. Shelton, and R. K. Howe, J. Org. Chem., 45, 3916
(1980).
6
7
C. J. Peake and J. H. Strickland, Synth. Commun., 16, 763 (1986).
The reason for low enantioselectivities in the case of N-halosuccinimide
is not clear. The coordination of N-halosuccinimide and/or produced
succinimide to zinc in 4 might change the ideal structure of the
intermediate to lower the enatioselectivities.
Table 2. Asymmetric 1,3-dipolar cycloaddition of nitrile oxides
generated in situ by the direct oxidation of aldoximes with tert-butyl
hypochloritea
Entry R0
1
R
k
l
n 5 Yield/% ee/%
8
9
S. Kanemasa, H. Matsuda, A. Kamimura, and T. Kakinami, Tetra-
hedron, 56, 1057 (2000).
1
2
3
4
5
6d
H
A 4-(MeO)C6H4 1.1 1.1 2.0 a
76
77
75
63
71
30
93b
92c
92b
90b
96c
89b
If the intermediate 3 was produced completely by the reaction of
alkylzinc moiety in 2 with aldoxime, the kind of alkyl group in
dialkylzinc would not influence the chemical yield and enantio-
selectivity. The fact that those were altered depending on the used
dialkylzinc might indicate the incompletion of the reaction of methyl-
and ethylzinc moiety in 2 with aldoxime.
Ph
4-ClC6H4
Heptyl
tBu
1.1 1.1 2.0 b
1.1 1.1 2.0 c
2.05 3.0 4.0 d
1.1 1.1 2.0 e
CO2Et B 4-(MeO)C6H4 1.1 1.1 2.0 f
aReaction was carried out on a 1.4-1.5 mmol scale in 12 ml CHCl3
for 15–19 h. bEnantioselectivity was determined by HPLC analysis
(Daicel Chiralcel OD-H). cEnantioselectivity was determined by
HPLC analysis (Daicel Chiralcel OB-H). dReaction was carried out
at 25 ꢁC.
10 Recently we found a concentration effect for the 1,3-dipolar cycloaddi-
tion of a nitrone to give the corresponding isoxazolidines with higher
enantioselectivity in higher chemical yield: D. Xia, Y. Ukaji, S.
Fujinami, and K. Inomata, Chem. Lett., 2002, 302.
11 A representative procedure is as follows: To a CHCl3 (3 ml) solution of
2-propen-1-ol (1A) (84 mg, 1.4 mmol) was added diisopropylzinc
(1.4 mmol, 1.4 ml of 1.0 mol lꢂ1 solution in hexane) at 0 ꢁC under an
argon atmosphere, and the mixture was stirred for 10 min. Then a CHCl3
(3 ml) solution of (R; R)-DIPT (339 mg, 1.4 mmol) was added and the
mixture was stirred for 1 h. Diisopropylzinc (1.6 mmol), a CHCl3 (3 ml)
solution of p-methoxybenzaldehyde oxime (240 mg, 1.6 mmol), a
CHCl3 (3 ml) solution of 1,4-dioxane (192 mg, 2.2 mmol), and a CHCl3
(3 ml) solution of tert-butyl hypochlorite (314 mg, 2.9 mmol) were
successively added every 10 min and the resulting solution was stirred
for 16 h at 0 ꢁC. The reaction was quenched by addition of saturated aq
NH4Cl and NaHSO3. Purification by column chromatography on silica
gel afforded 2-isoxazoline 5a (227 mg, 76%) in 93% ee.
The present asymmetric 1,3-dipolar cycloaddition was found
to proceed well even with the catalytic amount of (R; R)-DIPT,
though the reaction conditions were not yet optimized, to afford
the corresponding 2-isoxazoline with good enantioselectivity.
1) 1.25 iPr2Zn
2) 0.2 (R,R)-DIPT
N O
4) 1.8 ClOtBu
3) 1.1 AnC(H)=NOH in CHCl3, 0 °C
1.5 1,4-dioxane
OH
OH
An
5a
1A
16 h
61% yield, 81% ee