Rapid, highly efficient, and room-temperature TiCl4-catalyzed synthesis of 4-Isoxazolines under Solvent-Free Conditions

Article abstract of DOI:10.1080/00397910903537349

Δ⁴-Isoxazoline derivatives were synthesized in excellent yields via the titanium tetrachloride-catalyzed 1,3-dipolar cycloaddition reaction of nitrones withαβ,-unsaturated compounds under neat conditions at room temperatures in very short react

Full text of DOI:10.1080/00397910903537349

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Rapid, Highly Efficient, and Room-
Temperature TiCl4-Catalyzed Synthesis
of Δ4-Isoxazolines Under Solvent-Free
Conditions
Hassan Valizadeh a & Leila Dinparast a
a Faculty of Sciences, Department of Chemistry , Azarbaijan
University of Tarbiat Moallem , Tabriz, Iran
Published online: 15 Dec 2010.
To cite this article: Hassan Valizadeh & Leila Dinparast (2010) Rapid, Highly Efficient, and Room-
Temperature TiCl4-Catalyzed Synthesis of Δ4-Isoxazolines Under Solvent-Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:2, 291-297, DOI: 10.1080/00397910903537349
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Synthetic Communications1, 41: 291–297, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903537349
RAPID, HIGHLY EFFICIENT, AND ROOM-
TEMPERATURE TiCl4-CATALYZED SYNTHESIS OF
D4-ISOXAZOLINES UNDER SOLVENT-FREE
CONDITIONS
Hassan Valizadeh and Leila Dinparast
Faculty of Sciences, Department of Chemistry, Azarbaijan University of
Tarbiat Moallem, Tabriz, Iran
D4-Isoxazoline derivatives were synthesized in excellent yields via the titanium
tetrachloride–catalyzed 1,3-dipolar cycloaddition reaction of nitrones with a,b-unsaturated
compounds under neat conditions at room temperatures in very short reaction time.
Keywords: Cycloadditions; isoxazoline; nitrone; solvent-free; titanium tetrachloride
INTRODUCTION
Isoxazoline moieties and isoxazolidines[1,2] possess a wide spectrum of activities
such as antifungal, anticancer, antiviral, insecticidal, and antibiotic activities and are
precursors for different natural products.[3] One of the most common procedures for
the synthesis of these compounds is cycloaddition reaction of 1,3-dipoles to olefins.
The 1,3-dipolar cycloaddition, also known as the Huisgen cycloaddition, is a
well-known reaction in organic chemistry consisting of the reaction of alkenes or
alkynes with 1,3-dipolar compounds to synthesize various heterocycles such as iso-
xazolines.[4] A range of different substituents can be included in the dipole and the
dipolarophile, resulting in a broad range of possible cycloadducts, which serve as
useful synthetic building blocks. These reactions are synthetically very useful because
of their high stereospecificity and stereoselectivity.[5–7] Several studies have reported
on the effect of Lewis acid catalysts in these reactions.[8–10] The coordination of a
Lewis acid to dipole or dipolarophile is of fundamental importance for asymmetric
1,3-dipolar cycloadditions, because the metal can catalyze the reaction. Regio- and
stereoselectivity of these reactions can be controlled by the metal–ligand com-
plexes.[11,12] According to many published reports, TiCl4 has been used as a Lewis
acid catalyst for the broad range of reactions such as converting the acetals to the
corresponding carbonyl compounds,[13] activating the addition of carbon nucleo-
philes to acetals,[14–18] and reducing carboxylic esters to ethers.[19] Recently, we
Received September 23, 2009.
Address correspondence to Hassan Valizadeh, Faculty of Sciences, Department of Chemistry,
Azarbaijan University of Tarbiat Moallem, Tabriz 153427564, Iran. E-mail: h-valizadeh@azaruniv.edu
291

292
H. VALIZADEH AND L. DINPARAST
Scheme 1. TiCl4-catalyzed synthesis of isoxazolines in solventless system.
reported the efficient synthesis of coumaris via the TiCl4-catalyzed Pechmann
condensation of phenols with b-ketoesters.[20]
Nitrone 1,3-dipoles have been used for the synthesis of isoxazoline derivatives
in 1,3-dipolar cycloaddition reactions.[21–29] Despite the other 1,3-dipoles, nitrones
are stable compounds and do not require in situ formation. To the best of our
knowledge, no report has been made about the use of TiCl4 catalyst for 1,3-dipolar
cycloaddition of nitrones for the synthesis of isoxazole derivatives. In this report, we
highlight our results on cycloaddition reactions of nitrones 1a–e with dimethyl acet-
hylenedicarboxylate (DMAD) 2a and diethyl acethylenedicarboxylate (DEAD) 2b in
the presence of TiCl4 to produce related isoxazoline derivatives in excellent yields
in a solventless system (Scheme 1).
RESULTS AND DISCUSSION
For the beginning of this study, benzaldonitrone and DMAD were employed
as the model reactants at room temperature in the presence of TiCl4 to compare
the catalytic performance of the TiCl4. As shown in Table 1, <15% yield of D4-iso-
xazoline 3a could be detected by gas chromatography (GC) in the absence of TiCl4
(entry 1), which indicated that the catalyst should be very effective for the reaction.
Table 1. Results of using different amounts of TiCl4 and HCl on yields of isoxazolin 3aa
Entry
Catalyst
Catalyst amount (mol%)b
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
TiCl4
TiCl4
TiCl4
TiCl4
HCl
0
1
25
5
<15
86
5
3
92
85
10
1
6
25
25
25
22
25
HCl
HCl
5
10
20
a15 mmol nitrone with 15 mmol DMAD.
bMolar ratio of catalyst to nitrone.
cIsolated yields by flash chromatography for entries 2–7 and by GC for entry 1.

RAPID SYNTHESIS OF D4-ISOXAZOLINES
293
Table 2. TiCl4-catalyzed room-temperature synthesis of D4-isoxazolinesa
Entry
Olefin
Nitrone
Product
Time (min)
Yield (%)b
1
2
DMAD
DEAD
DMAD
DEAD
DMAD
DEAD
DMAD
DEAD
DMAD
DEAD
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
3a
3b
3c
3d
3e
3f
3 min
92
88
93
87
91
92
94
94
96
93
2.5 min
2.5 min
3 min
3
4
5
3 min
2.5 min
3 min
6
7
3g
3h
3i
8
2.5 min
3 min
3 min
9
10
3j
a15 mmol nitrone with 15 mmol DMAD.
bIsolated yields after flash chromatography for entries 1–10 and by GC for entries 11 and 12.
Various amounts of catalyst (1, 5, and 10 mol%) have been used for the model
reaction. The results in Table 1 show that the optimum amount of catalyst was
5 mol%. Titanium tetrachloride is known to release hydrochloric acid (HCl). This
prompted us to investigate the possibility of HCl acting as a catalyst in this
procedure. We examined the reaction using various amounts of HCl as a catalyst
and found that the reaction did not proceed smoothly in these conditions
(entries 5–7).
Having optimized the reaction conditions, several D4-isoxazolines were success-
fully synthesized (Table 2) in good yields by following this method. The reaction
mixture was stirred at room temperature. We carried out these reactions with a series
of nitrones with alkynes to obtain the corresponding five-membered heterocycles. In
all cases, the reactions were completed within 2.5–3 min of reaction time. In the
majority of the entries, the isoxazolines were formed fast and with final yields ran-
ging from good to excellent (Table 2). We conducted these reactions on a 30-mmol
scale and found smooth transformation to the isoxazoline derivatives in good yields.
Thus, the present procedure is amenable for scaling up.
EXPERIMENTAL
General Information
All reagents were purchased from Merck Company and used without
further purification. Infrared (IR) spectra were recorded in KBr and were deter-
mined on a Perkin-Elmer Fourier transform (FT)–IR spectrometer. 1H NMR
spectra were obtained in CDCl3 solution from Bruker Avance AC 400-MHz
instrument, and 13C NMR spectra were measured at 100 MHz on the aforemen-
tioned instruments. Elemental analyses were carried out on a Perkin-Elmer 240C
elemental analyzer and are reported in percentage of atomic abundance. Analyti-
cal thin-layer chromatography (TLC) was performed using precoated silica-gel 60
F254 plates (Merck, Darmstadt), and the spots were visualized with ultraviolet
(UV) light at 254 nm. Merck silica gel 60 (230–400 mesh) was used for flash
chromatography.

294
H. VALIZADEH AND L. DINPARAST
Synthesis of D4-Isoxasolines, General Procedure
TiCl4 (0.75 mmol) was added to a mixture of nitrone (15 mmol) and dipolaro-
phile (15 mmol) in a 10-ml conical flask, and the mixture was shaken for a period of
time at room temperature (TLC) as listed in Table 2. After completion of the reac-
tion, 10 ml of an aqueous sodium bicarbonate solution was added and stirred for
2–5 min. The reaction mixture was extracted three times with 7 ml of ethyl acetate.
The combined organic layers were dried over anhydrous sodium sulfate and
evaporated under reduced pressure. Then the crude mixture was purified by flash
chromatography on silica gel to afford the corresponding cycloadduct (Table 2).
Selected Spectral Data for D4-Isoxazolines
2-Methyl-3-phenyl-4,5-dicarbomethoxy-D4-isoxazoline (3a, C14H15NO5).
1
White crystals; mp 64.9–65.6 ꢀC; IR (KBr): 1753, 1716, 1654, 1116 cmꢁ1. H NMR
(400 MHz, CDCl3): d ¼ 7.36–7.25 (m, 5H, ArH), 5.00 (s, 1H, CH), 3.89 (s, 3H,
Me), 3.61 (s, 3H, Me), 2.95 (s, 3H, Me). 13C NMR (CDCl3, 100 MHz) d ¼ 33.95,
52.40, 50.72, 87.98, 111.64, 119.72, 125.32, 127.63, 129.56, 134.33, 159.58, 162.71.
Anal. calcd. (%) for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found (%): C, 60.87;
H, 5.37; N, 4.90.
2-Methyl-3-phenyl-4,5-dicarboethoxy-D4-isoxazoline (3b, C16H19NO5).
Colorless liquid; IR (KBr): 1750, 1717, 1649, 1120 cmꢁ1 1H NMR (400 MHz,
.
CDCl3): d ¼ 7.30–7.23 (m, 5H, ArH), 5.09 (s, 1H, CH), 4.14 (q, J ¼ 7.19 Hz, 2H,
OCH2CH3), 4.10 (q, J ¼ 7.25 Hz, 2H, OCH2CH3), 3.07 (s, 3H, NMe), 1.27 (t,
J ¼ 7.19 Hz, 3H, OCH2CH3), 1.23 (t, J ¼ 7.25 Hz, 3H, OCH2CH3). 13C NMR
(CDCl3, 100 MHz) d ¼ 17.41, 17.42, 35.51, 58.40, 58.96, 90.19, 113.16, 119.62,
125.11, 126.24, 129.89, 133.13, 160.50, 162.11. Anal. calcd. (%) for C16H19NO5: C,
62.64; H, 6.27; N, 4.59. Found (%): C, 62.98; H, 6.03; N, 4.40.
2-Methyl-3-(4-methylphenyl)-4,5-dicarbomethoxy-D4-isoxazoline (ꢁ31c,
C15H17NO5). White crystals; mp 50–51 ꢀC; IR (KBr): 1750, 1711, 1648, 1110 cm
.
1H NMR (400 MHz, CDCl3): d ¼ 7.31–7.25 (m, 4H, ArH), 5.11 (s, 1H, CH), 3.88 (s,
3H, Me), 3.69 (s, 3H, Me), 3.05 (s, 3H, Me), 2.38 (s, 3H, Me). 13C NMR (CDCl3,
100 MHz) d ¼ 24.12, 33.95, 52.40, 50.72, 87.98, 111.64, 119.72, 124.44, 126.36,
129.96, 135.55, 159.58, 162.71. Anal. calcd. (%) for C15H17NO5: C, 61.85; H, 5.88;
N, 4.81. Found (%): C, 62.02; H, 5.67; N, 4.62.
2-Methyl-3-(4-methylphenyl)-4,5-dicarboethoxy-D4-isoxazoline
(3d,
C17H21NO5). Colorless liquid; IR (KBr): 1759, 1723, 1649, 1121 cmꢁ1. H NMR
(400 MHz, CDCl3): d ¼ 7.29–7.20 (m, 4H, ArH), 5.02 (s, 1H, CH), 4.20 (q,
J ¼ 7.16 Hz, 2H, OCH2CH3), 4.13 (q, J ¼ 7.23 Hz, 2H, OCH2CH3), 3.13 (s, 3H,
NMe), 2.40 (s, 3H, Me), 1.29 (t, J ¼ 7.16 Hz, 3H, OCH2CH3), 1.25 (t, J ¼ 7.23 Hz,
3H, OCH2CH3). 13C NMR (CDCl3, 100 MHz) d ¼ 18.40, 18.52, 23.10, 36.50,
58.40, 58.91, 92.07, 112.17, 119.60, 124.11, 126.64, 129.80, 133.22, 161.01, 162.14.
Anal. calcd. (%) for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found (%): C, 64.08;
H, 6.49; N, 4.19.
1
2-Methyl-3-(3-nitrophenyl)-4,5-dicarbomethoxy-D4-isoxazoline
C14H14N2O7). White crystals; mp 78–79 ꢀC; IR (KBr): 1752, 1709, 1638, 1535,
(3e,

RAPID SYNTHESIS OF D4-ISOXAZOLINES
295
1356, 1120 cmꢁ1. 1H NMR (400 MHz, CDCl3): d ¼ 7.21–7.05 (m, 4H, ArH), 4.95 (s,
1H, CH), 3.80 (s, 3H, Me), 3.61 (s, 3H, Me), 3.05 (s, 3H, Me). 13C NMR (CDCl3,
100 MHz) d ¼ 32.95, 51.43, 50.32, 86.18, 113.64, 120.12, 121.26, 123.98, 125.65,
127.87, 128.90, 133.33, 160.18, 164.11. Anal. calcd. (%) for C14H14N2O7: C, 52.18;
H, 4.38; N, 8.69. Found (%): C, 52.25; H, 4.23; N, 8.50.
2-Methyl-3-(3-nitrophenyl)-4,5-dicarboethoxy-D4-isoxazoline
C16H18N2O7). Colorless liquid; IR (KBr): 1742, 1719, 1628, 1521, 1351, 1121 cmꢁ1
(3f,
.
1H NMR (400 MHz, CDCl3): d ¼ 7.19–7.00 (m, 4H, ArH), 4.96 (s, 1H, CH), 4.12
(q, J ¼ 7.06 Hz, 2H, OCH2CH3), 4.03 (q, J ¼ 6.98 Hz, 2H, OCH2CH3), 3.10 (s, 3H,
NMe), 1.31 (t, J ¼ 7.06 Hz, 3H, OCH2CH3), 1.21 (t, J ¼ 6.98 Hz, 3H, OCH2CH3).
13C NMR (CDCl3, 100 MHz) d ¼ 19.14, 20.32, 37.59, 58.48, 59.90, 95.17, 114.09,
120.99, 123.36, 124.99, 125.68, 126.94, 130.09, 136.00, 164.09, 165.14. Anal. calcd.
(%) for C16H18N2O7: C, 54.86; H, 5.18; N, 8.00. Found (%): C, 54.90; H, 5.03; N, 7.78.
2-Methyl-3-(2-methoxyphenyl)-4,5-dicarbomethoxy-D4-isoxazoline (3g,
C15H17NO6). White crystals; mp 78.7–79.8 ꢀC; IR (KBr): 1745, 1709, 1650,
1
1119 cmꢁ1. H NMR (400 MHz, CDCl3): d ¼ 7.38–7.29 (m, 4H, ArH), 5.12 (s, 1H,
CH), 4.10 (s, 3H, OMe), 3.79 (s, 3H, Me), 3.66 (s, 3H, Me), 3.00 (s, H, Me). 13C
NMR (CDCl3, 100 MHz) d ¼ 33.95, 50.90, 51.35, 51.89, 88.18, 111.14, 117.84,
118.02, 121.70, 126.65, 128.09, 130.53, 136.09, 158.50, 165.01. Anal. calcd. (%) for
C15H17NO6: C, 58.63; H, 5.58; N, 4.56. Found (%): C, 58.72; H, 5.43; N, 4.41.
2-Methyl-3-(2-methoxyphenyl)-4,5-dicarboethoxy-D4-isoxazoline (3h,
1
C17H21NO6). Colorless liquid; IR (KBr): 1749, 1720, 1650, 1115 cmꢁ1. H NMR
(400 MHz, CDCl3): d ¼ 7.38–7.27 (m, 4H, ArH), 5.20 (s, 1H, CH), 4.21 (q,
J ¼ 7.16 Hz, 2H, OCH2CH3), 4.16 (q, J ¼ 7.03 Hz, 2H, OCH2CH3), 4.14 (s, 3H,
OMe), 3.11 (s, 3H, NMe), 1.35 (t, J ¼ 7.16 Hz, 3H, OCH2CH3), 1.31 (t, J ¼ 7.03 Hz,
Hz, 3H, OCH2CH3). 13C NMR (CDCl3, 100 MHz) d ¼ 18.40, 18.52, 33.95, 50.90,
51.35, 51.89, 88.18, 111.14, 116.61, 118.56, 121.70, 126.65, 128.09, 130.53, 136.09,
158.50, 165.01. Anal. calcd. (%) for C17H21NO6: C, 60.89; H, 6.31; N, 4.18. Found
(%): C, 61.00; H, 6.14; N, 4.07.
2-Methyl-3-(2-chlorophenyl)-4,5-dicarbomethoxy-D4-isoxazoline
(3i,
C14H14ClNO5). White crystals; mp 72.4–73.9 ꢀC; IR (KBr): 1742, 1719, 1616,
1
1119 cmꢁ1. H NMR (400 MHz, CDCl3): d ¼ 7.29–7.15 (m, 4H, ArH), 5.09 (s, 1H,
CH), 3.81 (s, 3H, Me), 3.62 (s, H, Me), 3.05 (s, 3H, Me). 13C NMR (CDCl3,
100 MHz) d ¼ 33.55, 51.22, 52.30, 87.08, 112.99, 117.74, 119.25, 121.15, 126.75,
127.80, 128.30, 133.65, 164.18, 166.09. Anal. calcd. (%) for C14H14ClNO5: C,
53.94; H, 4.53; N, 4.49. Found (%): C, 54.05; H, 4.35; N, 4.32.
2-Methyl-3-(2-chlorophenyl)-4,5-dicarboethoxy-D4-isoxazoline
(3j,
C16H18ClNO5). Colorless liquid; IR (KBr): 1742, 1719, 1628, 1121 cmꢁ1. H NMR
(400 MHz, CDCl3): d ¼ 7.19–7.00 (m, 4H, ArH), 5.08 (s, 1H, CH), 4.20 (q, J ¼ 6.98 Hz,
Hz, 2H, OCH2CH3), 4.12 (q, J ¼ 7.13 Hz, 2H, OCH2CH3), 3.09 (s, 3H, NMe), 1.33
(t, J ¼ 6.98 Hz, 3H, OCH2CH3), 1.23 (t, J ¼ 7.13 Hz, 3H, OCH2CH3). 13C NMR
(CDCl3, 100 MHz) d ¼ 19.14, 20.32, 37.59, 58.48, 59.90, 95.17, 114.09, 117.78,
120.99, 122.32, 124.99, 126.94, 130.09, 136.00, 164.09, 165.14. Anal. calcd. (%)
for C16H18ClNO5: C, 56.56; H, 5.34; N, 4.12. Found (%): C, 56.58; H, 5.20; N, 3.99.
1

296
H. VALIZADEH AND L. DINPARAST
CONCLUSION
In conclusion, we have developed a simple and efficient synthesis of substituted
D4-isoxazolines via TiCl4-catalyzed 1,3-dipolar cycloaddition under solvent-free con-
ditions. Moreover, the relatively low cost of the catalyst, solvent-free condition, fast
reaction times, simple experimental procedure, and excellent yields of the products
are the advantages. We believe our procedure will find important applications in
synthetic organic chemistry.
ACKNOWLEDGMENT
The partial financial assistance from the research vice chancellor of Azerbaijan
University of Tarbiat Moallem is gratefully acknowledged.
REFERENCES
1. Mullen, G. B.; DeCcory, T. R.; Mitchell, J. T.; Allen, S. D.; Kinsolving, C. R.; Georgiev,
V. S. Studies on antifungal agents, 23: Novel substituted 3,5-diphenyl-3-(1H-imidazol-
1-ylmethyl)-2-alkylisoxazolidine derivatives. J. Med. Chem. 1988, 31, 2008.
2. Ravikumar, K. R.; Mallesha, H.; Rangappa, K. S. Synthesis and characterization of
5-substituted novel isoxazolidines derived from 1,3-dipolar cycloaddition of nitrones with
olefins: Studies of antibacterial and antifungal activities. Synth. Commun. 2003, 33, 1545.
3. Mallesha, H.; Ravikumar, K. R.; Mantelingu, K.; Rangappa, K. S. Synthesis and charac-
terization of model ultimate carcinogens=metabolites derived from lead tetraacetate
oxidation of arylnitrones: 20-Deoxyguanosine adducts. Synthesis 2001, 1459.
4. Huisgen, R. 1,3-Dipolar cycloadditions: Past and future. Angew. Chem., Int. Ed. Engl.
1963, 2, 565.
5. Pandey, G.; Sahoo, A. K.; Gadre, S. R.; Bagul, T. D.; Phalgune, U. D. [3 þ 2]-
Cycloaddition of nonstabilized azomethine ylides, 8: An efficient synthetic strategy for
epiboxidine. J. Org.Chem. 1999, 64, 4990.
6. Werner, K. M.; de los Santos, J. M.; Weinreb, S. M.; Shang, M. An intramolecular
nitroneꢁolefin dipolar cycloaddition-based approach to total synthesis of the cylindricine
and lepadiformine marine alkaloids. J. Org. Chem. 1999, 64, 4865.
7. Young, D. G. J.; Gomez-Bengoa, E.; Hoveyda, A. H. Diastereoselective intramolecular
cycloaddition of vinylsilanes and silyl nitronates: Effective control of remote acyclic
asymmetry. J. Org. Chem. 1999, 64, 692.
8. Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Control of diastereo- and enantioselectiv-
ity in metal-catalyzed 1,3-dipolar cycloaddition reactions of nitrones with alkenes: Experi-
mental and theoretical investigations. J. Org. Chem. 1996, 61, 346.
9. Milet, A.; Gimbert, Y.; Greene, A. E. Reaction of nitrones with silyl ketene acetals: A
DFT study. J. Comput. Chem. 2006, 27, 157.
10. Tanaka, J.; Kanemasa, S. Ab initio study of Lewis acid–catalyzed nitrone cycloaddition to
electron deficient alkenes: Does a Lewis acid catalyst change the reaction mechanism?
Tetrahedron 2001, 57, 899.
11. Kanemasa, S. Metal-assisted stereocontrol of 1,3-dipolar cycloaddition reactions. Synlett
2002, 1371.
12. Broggini, G.; Molteni, G.; Terraneo, A.; Zecchi, G. Transition-metal complexation in
1,3-dipolar cycloadditions. Heterocycles 2003, 59, 823.
13. Balme, G.; Gore, J. Conversion of acetals and ketals to carbonyl compounds promoted by
titanium tetrachloride. J. Org. Chem. 1983, 48, 3336.

RAPID SYNTHESIS OF D4-ISOXAZOLINES
297
14. Elliot, J. D.; Choi, V. M. F.; Johnson, W. S. Asymmetric synthesis via acetal templates, 5:
Reactions with cyanotrimethylsilane: Enantioselective preparation of cyanohydrins and
derivatives. J. Org. Chem. 1983, 48, 2294.
15. Elliot, J. D.; Choi, V. M. F.; Johnson, W. S. Asymmetric synthesis via chiral acetal tem-
plates, 7: Further studies on the cyanation reaction: The use of acetals derived from diols
with one chiral center. Tetrahedron Lett. 1984, 25, 591.
16. Denmark, E. S.; Almstead, N. G. Studies on the mechanism and origin of stereoselective
opening of chiral dioxane acetals. J. Am. Chem. Soc. 1991, 113, 8089, and references
quoted therein.
17. Davis, A. P. Deracemization by enantiodifferentiating inversion in 1,3-diols. Angew.
Chem., Int. Ed. Engl. 1997, 36, 591.
18. Sammakia, T.; Smith, R. S. Evidence for an oxocarbenium ion intermediate in Lewis
acid–mediated reactions of acyclic acetals. J. Am. Chem. Soc. 1994, 116, 7915, and refer-
ences quoted therein.
19. Yato, M.; Homma, K.; Ishida, A. Reduction of carboxylic esters to ethers with triethyl
silane in the combined use of titanium tetrachloride and trimethylsilyl trifluoromethane-
sulfonate. Tetrahedron 2001, 57, 5353.
20. Valizadeh, H.; Shockravi, A. An efficient procedure for the synthesis of coumarin deriva-
tives using TiCl4 as catalyst under solvent-free conditions. Tetrahedron Lett. 2005, 46,
3501.
21. Conti, P.; Dallanoce, C.; Amici, M. D.; Micheli, C. D.; Klotz, K.-N. Synthesis of new
D2-isoxazoline derivatives and their pharmacological characterization as b-adrenergic
receptor antagonists. Bioorg. Med. Chem. 1998, 6, 401.
22. Kanemasa, S.; Oderatoshi, Y.; Tanaka, J.; Wada, E. Highly endo- and enantioselective
asymmetric nitrone cycloadditions catalyzed by the aqua complex of 4,6-dibenzofuran-
diyl-2,20-bis(4-phenyl-oxazoline)ꢁnickel(II) perchlorate: Transition structure based on
dramatic effect of MS 4A on selectivities. J. Am. Chem. Soc. 1998, 120, 12355.
23. Suga, H.; Nakajima, T.; Itoh, K.; Kakehi, A. Highly exo-selective and enantioselective
cycloaddition reactions of nitrones catalyzed by a chiral binaphthyldiimineꢁNi(II) com-
plex. Org. Lett. 2005, 7, 1431.
24. Viton, F.; Bernardinelli, G.; Kundig, E. P. Iron and ruthenium Lewis acid–catalyzed
¨
asymmetric 1,3-dipolar cycloaddition reactions between nitrones and enals. J. Am. Chem.
Soc. 2002, 124, 4968.
25. Kodama, H.; Ito, J.; Hori, K.; Ohta, T. Synthesis of 2,6-bis(4R-trialkylsiloxymethyloxa-
zolinyl)pyridines and their use in catalytic asymmetric 1,3-dipolar cycloaddition reactions
of nitrones and activated alkenes. Tetrahedron Lett. 2001, 42, 6715.
26. Kano, T.; Hashimoto, T.; Maruoka, K. Computational study of phosphatase activity
in soluble epoxide hydrolase: High efficiency through a water bridge–mediated proton
shuttle. J. Am. Chem. Soc. 2005, 127, 11926.
´
27. Jensen, K.; Gothelf, K. V.; Hazell, R. G.; Jrgensen, K. A. Improvement of Taddolateꢁ
TiCl2-catalyzed 1,3-dipolar nitrone cycloaddition reactions by substitution of the oxazo-
lidinone auxiliary of the alkene with succinimide. J. Org. Chem. 1997, 62, 2471.
28. Carmona, D.; Lamata, M. P.; Viguri, F.; Rodriguez, R.; Oro, L. A.; Balana, A. I.; Lahoz,
F. J.; Tejero, T.; Merino, P.; Franco, S.; Montesa, I. The complete characterization of a
rhodium Lewis acidꢁdipolarophile complex as an intermediate for the enantioselective
catalytic 1,3-dipolar cycloaddition of C,N-diphenylnitrone to methacrolein. J. Am. Chem.
Soc. 2004, 126, 2716.
29. Kobayashi, S.; Kawamura, M. Catalytic enantioselective 1,3-dipolar cycloadditions
between nitrones and alkenes using a novel heterochiral ytterbium(III) catalyst. J. Am.
Chem. Soc. 1998, 120, 5840.