Molecular sieve 4 ? generates nitrile oxides from hydroximoyl chlorides. Development of catalyzed enantioselective nitrile oxide cycloadditions to monosubstituted alkenes

Article abstract of DOI:10.1016/j.tetlet.2009.02.178

The effective generation of nitrile oxide 1,3-dipoles from hydroximoyl chlorides can be achieved with powdered molecular sieves 3 ? and 4 ? as mild solid bases. Rate of nitrile oxide generation depends upon the choice of reaction solvents, among which alc

Full text of DOI:10.1016/j.tetlet.2009.02.178

Tetrahedron Letters 50 (2009) 2111–2114
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Tetrahedron Letters
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Molecular sieve 4 Å generates nitrile oxides from hydroximoyl chlorides.
Development of catalyzed enantioselective nitrile oxide cycloadditions to
monosubstituted alkenes
*
Fumiyasu Ono, Yasuaki Ohta, Masayuki Hasegawa, Shuji Kanemasa
Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga 816-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The effective generation of nitrile oxide 1,3-dipoles from hydroximoyl chlorides can be achieved with
powdered molecular sieves 3 Å and 4 Å as mild solid bases. Rate of nitrile oxide generation depends upon
the choice of reaction solvents, among which alcohols are the best media. A catalytic process is achieved
by use of a catalytic amount of amine in the presence of MS 4 Å leading to the amine-catalytic generation
of nitrile oxides. This new synthetic method can be applied to the catalytic enantioselective nitrile oxide
1,3-dipolar cycloaddition reactions with monosubstituted alkenes.
Received 11 December 2008
Revised 12 February 2009
Accepted 18 February 2009
Available online 26 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
We have recently reported the new synthetic application of
molecular sieves, designated MSs hereafter, in the effective cata-
lytic generation of metalated nucleophiles. Combined use of nucle-
ophile precursors with a catalytic amount of chiral Lewis acid in
the presence of MS 4 Å as base results in the smooth generation
of metal enolates or related nucleophilic species; alcohols are by
far the most appropriate reaction solvents.1 We believe that MS
4 Å (Na) acts as strong base through ion exchange with the pro-
tonic acid produced in the catalytic enolization reaction, and that
this ion exchange reaction should be more favored in alcohol med-
ia. With such a success, we paid attention to investigate the MS-
mediated dehydrohalogenation reactions under nearly neutral
reaction conditions without amine bases. The target reaction that
we aimed to demonstrate was the MS-mediated 1,3-dipolar cyclo-
addition reaction using hydroximoyl chlorides known as nitrile
oxide 1,3-dipole precursors.2
In this Letter, we will present that powdered MSs 3 Å and 4 Å
work as mild solid bases to react with hydroximoyl chlorides gen-
erating nitrile oxides. The rate of nitrile oxide generation depends
upon the choice of reaction solvent and alcohols are the best
choice. This new synthetic method can be successfully applied to
the first successful catalytic enantioselective nitrile oxide cycload-
dition reactions with monosubstituted alkenes.
romethane-d2, and toluene-d8, in the presence of powdered molec-
ular sieve 4 Å (MS 4 Å, 500 mg/mmol of 1a) at room temperature.3
The reaction was monitored after 2 and 5 h by sampling part of it.
The MS 4 Å used was removed by filtration through membrane fil-
ter.4 The filtrate was submitted to 1H NMR spectroscopic analysis
to determine the yield of cycloadduct 3 between nitrile oxide 4
and dipolarophile 2 on the basis of relative ratio to the internal ref-
erence. The results are listed out in the table of Scheme 1.
Both for the reaction times of 2 and 5 h, methanol was the most
effective solvent and acetonitrile was the second. On the other
hand, dichloromethane and toluene were poor solvents providing
only low yields of 3. Thus, MS 4 Å worked as effective base in the
Cl
N
O
a
+
OH
COOEt
Ph
COOEt
Ph
N
1a
2
3
Yield/% of 3
Solvent
2 h
5 h
42
68
77
13
12
57
80
94
36
26
DMSO-d6
CD3CN
CD3OD
CD2Cl2
Toluene- d8
Ph
C N O
A solution of benzohydroximoyl chloride (1a, 0.22 M), ethyl
acrylate (2, 1.5 equiv) as dipolarophile and fluorene as internal ref-
erence (0.2 equiv of 1a) in several deuterated reaction solvents,
such as dimethyl sulfoxide-d6, acetonitrile-d3, methanol-d4, dichlo-
4
aMS 4Å (500 mg/mmol), solvent
(0.22 M), rt
* Corresponding author.
E-mail address: kanemasa@cm.kyushu-u.ac.jp (S. Kanemasa).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.178

2112
F. Ono et al. / Tetrahedron Letters 50 (2009) 2111–2114
generation of nitrile oxide 4 from hydroximoyl chloride 1a in
methanol. However, the MS 4 Å-mediated generation of nitrile
oxide 4 from 1a is much slower than the reaction with triethyl-
amine, and it should be even more important to notice that the rate
of generation can be easily controlled by the choice of reaction
solvents.
A variety of MSs were examined as solid base for the generation
of 4 in methanol as shown in the upper table of Scheme 2. Among
MSs 3 Å, 4 Å, and 5 Å which have the same aluminosilicate frame-
work structure and Si/Al ratio of 1, MS 4 Å was found to be most
effective, and MS 3 Å was the next. MS 13X having higher alumi-
num content (Si/Al = 1.4) worked as stronger base than MS 13Y
(Si/Al = 20).
a
+
1a
2
3
1.5 equiv
aAmine catalyst (5 mol%), MS 4Å (500 mg/mmol), solvent (0.22 M), rt
Yield/%
2 h 5 h
1
Solvent
Catalyst
cat Et3N
MS4Å(H)
Toluene- d8
none
Et3N
DBU
12
76
46
26
94
78
"
"
MS4Å(Na)
Et3N•HCl
3
PhCNO
CD3OD
none
77
94
2
4
A question arose as to how much of MS 4 Å would be enough for
the complete generation of nitrile oxide 4 from the hydroximoyl
chloride precursor 1a in methanol. If MS 4 Å works as base through
ion exchange between proton and sodium cations, MS 4 Å of ca.
182.5 mg is equivalent to 1 mmol of 1a.5 When 500 mg of MS 4 Å
was used for 1 mmol of 1a (ca. 2.74 equiv to 1a), nitrile oxide 4
was generated at least in 94% yield after 5 h in methanol at room
temperature (the lower table of Scheme 2). With a small excess
amount (1.37 equiv to 1a) of MS 4 Å, the reaction generating 4 re-
mained incomplete even after 5 h.
It is interesting to find that the generation of nitrile oxide 4 from
hydroximoyl chloride 1a becomes catalytic in terms of amine in
the presence of MS 4 Å (Scheme 3). Thus, the reaction between
1a and 2 was much more accelerated with a catalytic amount
(5 mol %) of triethylamine even in toluene in the presence of MS
4 Å (500 mg/mmol of 1a) giving cycloadduct 3 in 94% yield after
5 h at room temperature. Triethylamine is known to react with
hydroximoyl chloride 1a to undergo smooth generation to nitrile
oxide 4, and the resulting triethylammonium chloride then under-
goes ion exchange with MS 4 Å to regenerate free triethylamine
catalyst. This catalytic cycle is probably repeated in the amine-cat-
alyzed reaction. It is likely that the rate of ion exchange reaction of
triethylammonium ion with MS 4 Å is much faster in toluene than
the direct deprotonation of 1a with MS 4 Å. Even 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU), a much stronger base than triethyl-
amine, worked as amine catalyst in the presence of MS 4 Å,
indicating that MS 4 Å works as stronger base than DBU.
Thus, a generation method of nitrile oxide 4 was developed by
use of MS 4 Å and hydroximoyl chloride 1a. Alcohols were the best
choice as reaction solvent.
Scheme 3.
Nitrile oxides are 1,3-dipoles showing extremely high reactivity
to monosubstituted alkenes regardless of the electronic nature of
the substituent.6 Accordingly, catalysts working effectively in ni-
trile oxide cycloaddition reactions are not available,7 indicating
that effective chirality induction with a catalytic amount of chiral
catalyst8 is extremely difficult since a catalytic amount of the chiral
dipolarophile complex can hardly predominate over the uncata-
lyzed cycloaddition reactions producing racemic product. We chal-
lenged to apply our new generation method of 1,3-dipoles in the
aid of MS 4 Å to the catalytic enantioselective versions of nitrile
oxide 1,3-dipolar cycloaddition reactions.
Our idea includes a procedure in which an equimolar mixture of
nitrile oxide precursor 1a and dipolarophile 5 is slowly added to a
mixture of MS 4 Å and chiral catalyst (Fig. 1). With this procedure,
one can expect the quick formation of chiral dipolarophile complex
6 and the relatively slow generation of nitrile oxide 4. By adjusting
the proper rate of slow addition of the both substrates, dipolaro-
phile 5 becomes chiral as soon as it is exposed to the catalyst,
and less amount of nitrile oxide 4 is gradually generated. Thus,
the reactive 1,3-dipole 4 quickly reacts with the chiral dipolaro-
phile complex 6 providing the cycloadduct in high selectivities.
Therefore, our procedure should work well. This can be called ‘a
synthetic method for the production of highly enantioenriched product
Slow addition
1a
N
N
a
Slow generation
+
O
1a
2
3
Acceptor
5
1.5 equiv
PhC
N O
4
Yield/% of 3
highly reactive
Type
Si/Al Ratio
2 h 5 h
MS
quickly
formed
3Å
4Å
5Å
13X
13Y
50
77
39
68
16
70
94
54
81
20
3A:
4A:
5A:
13X:
13Y:
1
1
1
N
Cat* + MS
Enantiomer of
cycloadduct
N
M
Ln*
O
1.4
ca 20
chiral dipolarophile
6
aMS (500 mg/mmol), CD3OD (0.22 M), rt
Catalyst cycle
MS 4Å
Yield/% of 3
Cat*
cycloadduct
mg/mmol
equiv/Na*
2 h
5 h
5
4
250
500
750
1.37
2.74
4.11
60
77
86
66
94
98
6
MS
1a
aMS 4Å, CD3OD (0.22 M), rt
Figure 1. A possibility of enantiomer synthesis through repeated stoichiometric
Scheme 2.
enantioselective reactions.

F. Ono et al. / Tetrahedron Letters 50 (2009) 2111–2114
2113
with repeated stoichiometric reactions’ as shown in the lower cata-
lyst cycle in Figure 1.
stirring with the preactivated MS 4 Å, under dry argon at room
temperature for 30 min, was found to be effective to minimize
water content in the reaction mixture. With an expectation of
shortening the reaction time, the mixed solvent of 2-propanol/
dichloromethane was replaced with 2-propanol/1,2-dichloroeth-
ane (1/5 v/v, 0.5 mL), and the reaction temperature was raised to
either 30 or 40 °C. With this procedure, dichloromethane as a
low-boiling solvent was mostly removed by spontaneous evapora-
tion through the drying tube attached to the reaction vessel.13 As a
result, the solvent contained in the reaction vessel could be kept to
be constant in volume so the rate of catalytic reaction was mostly
steady.
We used the nickel(II) aqua complex9 of R,R-DBFOX/Ph ligand A
(X = ClO4) as chiral Lewis acid catalyst and 1-acryloyl-3,5-dimeth-
ylpyrazole (5) as dipolarophile, since the substrate 5 is known to
form a strong coordination structure with the chiral catalyst A.10
In the preliminary experiment, to a mixture of commercially avail-
able MS 4 Å (120 mg) and catalyst A (X = ClO4, 0.024 mmol) in 2-
propanol/dichloromethane (1/5 v/v, 0.5 mL)11 was added slowly
at room temperature a solution of 1a and 5 in dichloromethane
(0.24 mmol each, 0.2 mL) by use of a syringe.12 This procedure took
30 min. After the addition was complete, stirring was continued for
additional 30 min at room temperature. The MS 4 Å was filtered off
through Celite. Purification of the crude product through silica-gel
column chromatography gave 7a in 81% yield with the enantiose-
lectivity of 81% ee.
Under the optimized reaction conditions of ‘synthetic method
for the generation of highly enantioenriched product with re-
peated stoichiometric reactions’, reaction was performed as fol-
lows: An equimolar solution of 2-propanol and 1,2-
With such success of the preliminary experiment in hand, the
reaction conditions were optimized in terms of the chiral catalyst
A (X = ClO4 and BF4) under dry argon, the preactivation of MS 4 Å
by heating with a heat gun under vacuum, use of the dry mixed
solvent of 2-propanol/1,2-dichloroethane (1/5 v/v, 0.5 mL), the
reaction temperature at 30 or 40 °C, and the spontaneous removal
of low-boiling solvent such as dichloromethane. Consequently,
better yield (95%) and enantioselectivity (96% ee) were observed
for 7a under the optimized reaction conditions (conditions shown
in Scheme 4).
When the pyrazole amide dipolarophile 5 was used together
with aqua complex catalyst A in a water-soluble solvent such as
alcohol, the amide linkage of both 5 and 7a tends to be hydrolyzed
so that the yield of cycloadduct 7a was significantly lowered. How-
ever, the drying procedure of alcoholic solution of catalyst A by
dichloroethane (1/5 v/v, 2 mL/mmol) containing a catalytic
amount of chiral catalyst A (X = BF4, 10 mol %) was allowed to
stir with the preactivated MS 4 Å powder (500 mg/mmol) at
room temperature under dry argon for 30 min. Then, a dichloro-
methane solution (2 mL/mmol) of hydroximoyl chlorides 1b–i
and pyrazole dipolarophile 5 was slowly added in the period
of 30 min, at 40 °C in some cases using less reactive 1,3-dipoles.
After the addition of both substrates 1b–i and 5 was complete,
the resulting mixture was stirred at the same temperature for
30 min. Purification of the crude product through silica gel col-
umn chromatography with dichloromethane/ethyl acetate (4/1
v/v) gave isoxazoline cycloadducts 7b–i in excellent yields with
perfect regioselectivities and enantioselectivities. As shown in
the table of Scheme 4, the highest yield of 7 was 94% and the
maximized enantioselectivity was up to 97% ee.
R
N
N
+
OH
•
N
•
•
•
•
• ••••
substrates 1 + 5
•
• •
Cl
•
••••
•
•• •
• •
•
O
5
1a-i
CaCl2 tube
a-f
O
N
catalyst A + MS 4A
N
R
N
H
O
7a-i
stirrer with a heater
a: Preactivation of MS 4Å (120 mg). b: R,R-DBFOX/Ph + Ni(BF4)2•6H2O (0.024
mmol each) in i-PrOH/ClCH2CH2Cl (1/5 v/v, 0.5 mL). c: stirring at rt, 0.5 h. d: 1
+ 5 (0.24 mmol each) in CH2Cl2 (0.5 mL) is slowly added (0.5 mL/h) at 30 or 40
°C. e: stirring for 0.5 h. f: filtration through Celite, short column (CH 2Cl2/ethyl
acetate = 4/1 v/v).
1
R
temp/°C
7
yield/% % ee
1a Ph
40
30
7a
7b
7c
7d
7e
7f
7g
7h
7i
94
92
88
94
74
65
88
81
67
96
97
95
93
90
93
92
92
90
1b p-MeC6H4
1c p-MeOC6H4 30
1d p-BrC6H4
30
1e p-NO2C6H4 40
O
O
O
Ni2
N
N
1f o-ClC6H4
m-ClC6H4
40
40
40
30
2ClO4
1g
Ph
1h p-C6H4
1i t-Bu
Ph
A
R,R-DBFOX/Ph
+ NiX2•6H2O
Scheme 4.

2114
F. Ono et al. / Tetrahedron Letters 50 (2009) 2111–2114
2. Slow generation of nitrile oxides from hydroximoyl chlorides and MS 4A is
One of the cycloaddition products 7a was treated with sodium
known: Kim, J. N.; Ryu, E. K. Heterocycles 1990, 31, 1693–1697.
3. Powdered molecular sieves, which are available from Aldrich Chemicals, were
used without further preactivation unless otherwise stated.
borohydride in methanol to give a quantitative yield of (5R)-
3-phenylisoxazoline-5-methanol whose absolute structure was
assigned by comparison with the authentic sample.14 Other isoxaz-
oline derivatives 7b–i were determined to be 5R-enantiomers on the
basis of the absolute stereochemistry of 7a. The stereochemistry ob-
served in the present catalytic cycloaddition reactions producing 7
involves the selective attack of nitrile oxides at the Re-face of dipol-
arophile 5. This is consistent with the mode of enantioselectivity ob-
served in our previous reactions using chelating acceptor
molecules.9a,15
In conclusion, we have developed the effective use of molecular
sieve 4 Å for the rate-controlled slow generation of nitrile oxide
1,3-dipoles from hydroximoyl chlorides in alcohol media. Less than
3 equiv of MS 4 Å was sufficient enough for the quantitative gener-
ation of nitrile oxides in a few hours. This MS 4 Å-mediated gener-
ation method of nitrile oxide can be effectively applied to the
catalytic enantioselective nitrile oxide cycloadditions with mono-
substituted alkene dipolarophiles. Such highly enantioselective
synthesis of isoxazoline enantiomers is otherwise difficult to
attain.
4. The membrane filter with a pore size of 0.5 lm was used.
5. Molecular weight of MS 4 Å was estimated on the basis of the reported
molecular formula [Na12(AlO2)12(SiO2)12Á27H2O].
6. (a)Padwa, A., Ed.1,3-Dipolar cycloaddition chemistry; John Wiley & Sons: New
York, 1984; Vols. 1 and 2, (b)Synthetic applications of 1,3-dipolar cycloaddition
chemistry toward heterocycles and natural products; Padwa, A., Pearson, W. H.,
Eds.; Wiley-Interscience: Hoboken, 2003.
7. Kanemasa, S.; Nishiuchi, M.; Kamimura, A.; Hori, K. J. Am. Chem. Soc. 1994, 116,
2324–2339.
8. (a) Sibi, M. P.; Itoh, K.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 5366–5367; (b)
Yamamoto, H.; Hayashi, S.; Kubo, M.; Harada, M.; Hasegawa, M.; Noguchi, M.;
Sumimoto, M.; Hori, K. Eur. J. Org. Chem. 2007, 2859–2864; (c) Brinkmann, Y.;
Madhushaw, R. J.; Jazzar, R.; Bernardinelli, G.; Kündig, E. P. Tetrahedron 2007,
63, 8413–8419.
9. The aqua complex of R,R-DBFOX/Ph derived from nickel(II) perchlorate in the
preliminary run and then that from nickel(II) tetrafluoroborate in the reactions
under the optimized conditions: (a) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi,
S.; Yamamoto, H.; Tanaka, J.; Wada, E.; Curran, D. P. J. Am. Chem. Soc. 1998, 120,
3074–3088; (b) Iserloh, U.; Oderaotoshi, Y.; Kanemasa, S.; Curran, D. P. Org.
Synth. 2003, 80, 46–56.
10. (a) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394–13395; (b)
Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7, 979–
981.
11. 2-Propanol was used to inhibit the subsequent alcoholysis of 7 under the
reaction conditions.
Ongoing work in our laboratory will address the application of
our newly developed methodology using MS 4 Å to other enantio-
selective transformations. The results will be presented soon.
12. A small needle of No. 23 (ca. 7.5 mL/drop) was attached to the syringe.
13. The reaction was performed in a hood so that the dichloromethane that
evaporated in the reaction could be efficiently evacuated.
14. Serizawa, M.; Ukaji, Y.; Inomata, K. Tetrahedron: Asymmetry 2006, 17, 3075–
3083.
15. (a) Kanemasa, S.; Oderaotoshi, Y.; Yamamoto, H.; Tanaka, J.; Wada, E.; Curran,
D. P. J. Org. Chem. 1997, 62, 6454–6455; (b) Kanemasa, S.; Oderaotoshi, Y.;
Tanaka, J.; Wada, E. J. Am. Chem. Soc. 1988, 120, 12355–12356.
References and notes
1. Hasegawa, M.; Ono, F.; Kanemasa, S. Tetrahedron Lett. 2008, 49, 5220–5223.