One pot synthesis of optically active 4-isoxazolines by asymmetric addition of alkynylzinc reagents to nitrones followed by cyclization

Article abstract of DOI:10.3987/COM-08-11566

One pot synthesis of optically active 4-isoxazolines was achieved by asymmetric addition of alkynylzinc reagents to nitrones utilizing di(t-butyl) (R,R)-tartrate as a chiral auxiliary followed by cyclization. By addition of dimethylzinc, the cyclization s

Full text of DOI:10.3987/COM-08-11566

HETEROCYCLES, Vol. 78, No. 3, 2009
717
HETEROCYCLES, Vol. 78, No. 3, 2009, pp. 717 - 724. © The Japan Institute of Heterocyclic Chemistry
Received, 1st October, 2008, Accepted, 10th November, 2008, Published online, 12th November, 2008
DOI: 10.3987/COM-08-11566
ONE POT SYNTHESIS OF OPTICALLY ACTIVE 4-ISOXAZOLINES
BY ASYMMETRIC ADDITION OF ALKYNYLZINC REAGENTS TO
NITRONES FOLLOWED BY CYCLIZATION
Weilin Wei, Masato Kobayashi, Yutaka Ukaji,* and Katsuhiko Inomata*
Division of Material Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192,
Japan; inomata@cacheibm.s.kanazawa-u.ac.jp
Abstract – One pot synthesis of optically active 4-isoxazolines was achieved by
asymmetric addition of alkynylzinc reagents to nitrones utilizing di(t-butyl)
(R,R)-tartrate as a chiral auxiliary followed by cyclization. By addition of
dimethylzinc, the cyclization step was accelerated to afford the corresponding
4-isoxazolines with up to 93% ee. Furthermore, a cyclized zinc intermediate
could be trapped with formaldehyde to give the corresponding
2,3,4,5-tetrasubstituted 4-isoxazoline with 85% ee.
INTRODUCTION
Compounds bearing a 4-isoxazoline ring are versatile synthetic intermediates1 and the key components of
optically active nitrogen-containing substances, which have potentially high value in chemical and
medicinal fields.2 One of the most attractive approaches to the synthesis of 4-isoxazolines is
1,3-diplolar cycloaddition of nitrones to acetylenes, however, the method often suffered with poor
regioselectivity. Alternative route to 4-isoxazolines is condensation of unsaturated ketones with
hydroxylamines.1 Ring-closure reaction of N-propargyl hydroxylamines catalyzed by zinc or palladium
salt also gave 4-isoxazolines.3 Furthermore, direct ring-closure reaction of zinc salt of N-propargyl
hydroxylamines, generated in situ by addition of alkynylzinc reagents to nitrones, was reported.4
However, it was mentioned that an ester or amide group was necessary in the nitrone for the promotion of
the cyclization, and the cyclization took place for a simple nitrone only when an alkyne contained an
acetyl group.4b Recently, we developed a catalytic asymmetric addition reaction of alkynylzinc reagents,

718
HETEROCYCLES, Vol. 78, No. 3, 2009
which were prepared in situ from dimethylzinc and 1-alkynes, to nitrones by utilizing di(t-butyl)
(R,R)-tartrate [(R,R)-DTBT] as a chiral auxiliary to afford the corresponding optically active
N-(R)-(α-substituted)propargyl hydroxylamines. At the same time, we found an unprecedented
phenomenon, enantiomeric enhancement by addition of methylzinc salt of a product-like racemic
hydroxylamine as an additive.5 During the course of the investigation of the enantiomeric enhancement,
a part of the addition product was observed to cyclize giving the corresponding 4-isoxazoline at the later
stage of the reaction. Herein, we wish to describe a tandem reaction consisting of a catalytic
enantioselective nucleophilic addition of alkynylzinc reagents to nitrones followed by cyclization in the
presence of a (R,R)-tartaric acid ester as a chiral auxiliary to give the corresponding (S)-4-isoxazolines
with excellent enantioselectivity of up to 93% ee. Furthermore, an intermediary 4-isoxazolin-4-yl zinc
species could be trapped by formaldehyde to form a new carbon-carbon bond to afford the corresponding
optically active 2,3,4,5-tetrasubstituted 4-isoxazoline.
RESULTS AND DISCUSSION
First an asymmetric addition reaction of alkynylzinc to N-benzyl nitrone 2A followed by cyclization was
examined (Table 1); i.e., to a mixture of 0.2 molar amount of bis(methylzinc) salt of (R,R)-DTBT and 0.2
molar amount of methylzinc salt of racemic 4-methoxyphenyl substituted hydroxylamine 4 in toluene,
equimolar amounts of dimethylzinc, nitrone 2A and phenyl acetylene (3a) were successively added at
0 °C. After stirring for 18 h at 0 °C, the reaction mixture was warmed up to rt (25 °C) and kept for 24 h
to give the cyclized product, (S)-2-benzyl-3,5-diphenyl-2,3-dihydroisoxazole (5Aa), in 51% yield and
90% ee (Entry 1).6 In order to improve the cyclization step, 1.0 molar amount of zinc iodide dissolved
in THF was added as a promoter after the initial addition reaction. After stirring for 24 h at rt, the
corresponding 5Aa was obtained with enantioselectivity of 91% ee, but only in 32% chemical yield
(Entry 2). Dimethylzinc was next examined as a promoter instead of zinc iodide. To our delight, the
cyclization reaction proceeded smoothly by using 1.6 molar amounts of dimethylzinc to give 5Aa in
improved 67% yield with high enantioselectivity (89% ee, Entry 3). When 3.2 molar amounts of
dimethylzinc were used, the chemical yield of 5Aa was further increased to 73% with 91% ee (Entry 4).
The same reaction was also carried out in ethylbenzene, whereas the chemical yield was not satisfactory
in comparison with that in toluene (Entries 4 and 5). A control experiment was carried out in the
absence of methylzinc salt of racemic 4-methoxyphenyl substituted hydroxylamine 4. The cyclized
product was obtained with poor enantioselectivity of 64% ee (Entry 6), which again confirmed that
enantiomeric enhancement could be achieved by employing the racemic product-like additive 4.

HETEROCYCLES, Vol. 78, No. 3, 2009
719
Asymmetric addition of several alkynylzinc reagents to other nitrones 2 followed by cyclization was
performed under the optimum conditions to furnish the corresponding (S)-2-benzyl-4-isoxazolines 5 with
high enantioselectivity (Table 2). The reaction of 2-bromophenyl substituted nitrone 2B with phenyl
acetylene (3a) proceeded smoothly to give the desired product 5Ba at rt with 93% ee (Entry 2).
4-Bromophenyl substituted nitrone 2C also gave good enantioselectivity with 86% ee (Entry 3). Other
aromatic acetylenes 3b and 3c reacted with 2A to give the corresponding 4-isoxazolines 5Ab and 5Ac
with up to 93% ee (Entries 4 and 5). Aliphatic acetylenes 3d and 3e afforded the corresponding
4-isoxazolines 5Ad and 5Ae in both good yields and enantioselectivities (Entries 6 and 7).
Finally, a cyclized zinc intermediate produced by tandem asymmetric addition/cyclization reaction was
trapped with formaldehyde at rt to furnish (S)-2-benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)methanol
(6) in decent chemical yield and good chiral induction with 85% ee in the presence of a product-like
additive 4 (Scheme 1).7
As described above, a catalytic asymmetric addition of alkynylzinc reagents to nitrones followed by
cyclization has been developed to provide synthetically useful optically active 4-isoxaolines. By
addition of a product-like substrate, the excellent enantioselectivities were realized.8 Furthermore, a

720
HETEROCYCLES, Vol. 78, No. 3, 2009
new carbon-carbon bond formation was achieved by the treatment of the intermediary 4-isoxazolin-4-yl
zinc species with formaldehyde to afford the corresponding optically active 2,3,4,5-tetrasubstituted 4-
isoxazoline.

HETEROCYCLES, Vol. 78, No. 3, 2009
721
EXPERIMENTAL
All of the melting points were determined by a micro melting apparatus (Yanagimoto-Seisakusho) and
1
uncorrected. The H NMR spectra were recorded on a JEOL Lambda 400 and JEOL Lambda 300
spectrometers. The chemical shifts were determined in the ꢀ -scale relative to tetramethylsilane (ꢀ = 0)
as an internal standard. The IR spectra were measured by JASCO FT/IR-230 spectrometer. The
specific optical rotations were recorded on JASCO DIP-370 spectrometer. THF was freshly distilled
from sodium diphenylketyl. All other solvents were distilled and stored over drying agents. Flash
column chromatography and thin-layer chromatography (TLC) were performed on Cica-Merck’s silica
gel 60 (No. 9385-5B) and Merck’s silica gel 60 PF254 (Art. 107749), respectively.
Representative Procedure for Tandem Asymmetric Addition/Cyclization with Nitrone 2A (Table 1,
Entry 4): To a toluene (3 mL) solution of (R,R)-DTBT (26 mg, 0.1 mmol) was added dimethylzinc (0.8
mL of 1.0 M solution in hexane, 0.8 mmol) at 0 °C under an argon atmosphere, and the mixture was
stirred for 10 min.
To the solution,
a
toluene (3 mL) solution of racemic
N-benzyl-N-[1-(4-methoxyphenyl)-3-phenylprop-2-ynyl]hydroxylamine (34 mg, 0.1 mmol) was added,
and the mixture was stirred for 10 min. A toluene (3 mL) solution of nitrone 2A (106 mg, 0.5 mmol)
and a toluene (3 mL) solution of phenylacetylene (3a) (51 mg, 0.5 mmol) were added to the resulting
solution successively. The reaction mixture was kept for 18 h at 0 °C. Then additional dimethylzinc
(1.6 mL of 1.0 M solution in hexane, 1.6 mmol) was further added to the reaction mixture at 0 °C. The
resulting solution was warmed up to 25 °C and stirred for 1 d, followed by addition of a saturated aq.
NH4Cl solution to quench the reaction. After filtration of the precipitate, the filtrate was extracted with
AcOEt. The combined extracts were washed with brine, dried over Na2SO4, and condensed under
reduced pressure. The residue was separated by TLC on SiO2 (hexane/AcOEt = 3/1) to isolate the
corresponding 5Aa (114 mg, 73%, 91% ee).
(S)-2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazole (5Aa):3b A solid. Mp 133–134 °C (from EtOH).
[ꢁ]D25 –98 (c 1.11, EtOH; 91% ee). IR (KBr) 3061, 3026, 2886, 1652, 1600, 1494, 1455, 1319, 1291,
1
1020, 914, 787, 761, 724, 693 cm–1. H NMR (300 MHz, CDCl3) ꢀ = 4.12 (d, 1H, J = 12.8 Hz), 4.44 (d,
1H, J = 12.8 Hz), 5.05 (d, 1H, J = 2.8 Hz), 5.43 (d, 1H, J = 2.8 Hz), 7.23-7.58 (m, 15H). Anal. Calcd
for C22H19NO: C, 84.34; H, 6.07; N, 4.47%. Found: C, 84.13; H, 6.14; N, 4.48%. The
enantioselectivity was determined by HPLC (Daicel Chiralcel OD-H ꢀ 2, hexane/iPrOH = 100/1, detected
at 254 nm).
(S)-2-Benzyl-3-(2-bromophenyl)-5-phenyl-2,3-dihydroisoxazole (5Ba): An oil. [ꢁ]D25 –188 (c 1.37,
EtOH; 93% ee). IR (neat) 3061, 3030, 2924, 2851, 1649, 1600, 1494, 1464, 1022, 752, 725, 694 cm–1.
1H NMR (400 MHz, CDCl3) ꢀ = 4.18 (d, 1H, J = 13.2 Hz), 4.41 (d, 1H, J = 13.2 Hz), 5.44 (d, 1H, J = 3.0

722
HETEROCYCLES, Vol. 78, No. 3, 2009
Hz), 5.54 (d, 1H, J = 3.0 Hz), 7.01-7.54 (m, 13H), 7.73 (d, 1H, J = 9.6 Hz). HRMS (FAB+) (M + H)+,
Found: m/z 392.06568. Calcd for C22H19NO79Br: 392.06500. The enantioselectivity was determined
by HPLC (Daicel Chiralcel OD-H ꢀ 2, hexane/iPrOH = 200/1, detected at 254 nm).
(S)-2-Benzyl-3-(4-bromophenyl)-5-phenyl-2,3-dihydroisoxazole (5Ca): A solid. Mp 63–65 °C
(from EtOH). [ꢀ]D25 –148 (c 0.62, EtOH; 86% ee). IR (KBr) 3030, 2875, 1653, 1600, 1484, 1071,
1
1011, 827, 762, 722, 693 cm–1. H NMR (400 MHz, CDCl3) ꢁ = 4.08 (d, 1H, J = 12.7 Hz), 4.44 (d, 1H, J
= 12.7 Hz), 5.01 (d, 1H, J = 2.8 Hz), 5.39 (d, 1H, J = 2.8 Hz), 7.01-7.57 (m, 14H). Anal. Calcd for
C22H18NOBr: C, 67.35; H, 4.59; N, 3.57%.
Found: C, 67.65; H, 4.69; N, 3.71%.
The
enantioselectivity was determined by HPLC (Daicel Chiralcel IA ꢀ 2, hexane/iPrOH = 100/1, detected at
254 nm).
(S)-2-Benzyl-5-(4-pentylphenyl)-3-phenyl-2,3-dihydroisoxazole (5Ab): A solid. Mp 60–61 °C
(from EtOH). [ꢀ]D25 –33 (c 1.70, EtOH; 93% ee). IR (KBr) 3109, 3026, 2914, 2845, 1651, 1509, 1494,
1
1452, 1415, 1271, 1215, 1073, 1014, 932, 837, 795, 745, 731, 694 cm–1. H NMR (300 MHz, CDCl3) ꢁ
= 0.89 (t, 3H, J = 6.3 Hz), 1.23-1.37 (m, 4H), 1.54-1.66 (m, 2H), 2.60 (t, 1H, J = 6.7 Hz), 4.10 (d, 1H, J =
12.8 Hz), 4.43 (d, 1H, J = 12.8 Hz), 5.03 (d, 1H, J = 2.8 Hz), 5.36 (d, 1H, J = 2.8 Hz), 7.15-7.57 (m, 14H).
HRMS (FAB+) (M + H)+, Found: m/z 384.23322.
Calcd for C27H30NO: 384.23274.
The
enantioselectivity was determined by HPLC (Daicel Chiralcel OD-H ꢀ 2, hexane/iPrOH = 80/1, detected
at 254 nm).
(S)-2-Benzyl-5-(4-bromophenyl)-3-phenyl-2,3-dihydroisoxazole (5Ac): A solid. Mp 115–116 °C
(from EtOH). [ꢀ]D25 –148 (c 0.62, EtOH; 85% ee). IR (KBr) 3028, 2898, 1651, 1600, 1567, 1494,
1463, 1450, 1317, 1295, 1262, 1249, 1115, 1047, 1026, 970, 948, 860, 767, 747, 723, 690 cm–1. 1H NMR
(400 MHz, CDCl3) ꢁ = 4.08 (d, 1H, J = 12.7 Hz), 4.44 (d, 1H, J = 12.7 Hz), 5.01 (d, 1H, J = 12.4 Hz),
5.39 (d, 1H, J = 12.4 Hz), 7.01-7.57 (m, 14H). Anal. Calcd for C22H18NOBr: C, 67.35; H, 4.85; N,
3.57%. Found: C, 67.23; H, 4.68; N, 3.54%. The enantioselectivity was determined by HPLC (Daicel
Chiralcel OD-H ꢀ 2, hexane/iPrOH = 100/1, detected at 254 nm).
(S)-2-Benzyl-5-butyl-3-phenyl-2,3-dihydroisoxazole (5Ad): An oil. [ꢀ]D25 –125 (c 1.02, EtOH; 80%
ee). IR (neat) 3062, 3029, 2956, 2929, 2871, 1673, 1602, 1494, 1455, 1305, 1156, 1075, 1029, 955, 732,
1
697 cm–1. H NMR (400 MHz, CDCl3) ꢁ = 0.92 (t, 3H, J = 7.2 Hz), 1.35-1.44 (m, 2H), 1.51-1.58 (m,
2H), 2.22 (t, 2H, J = 8.0 Hz), 4.01 (d, 1H, J = 12.8 Hz), 4.30 (d, 1H, J = 12.8 Hz), 4.66 (d, 1H, J = 1.2
Hz), 4.85 (d, 1H, J = 1.2 Hz), 7.18-7.43 (m, 10H). HRMS (FAB+) (M + H)+, Found: m/z 294.18525.
Calcd for C20H24NO: 294.18579. The enantioselectivity was determined by HPLC (Daicel Chiralcel OD
ꢀ 2, hexane/iPrOH = 100/1, detected at 254 nm).

HETEROCYCLES, Vol. 78, No. 3, 2009
723
25
(S)-2-Benzyl-5-hexyl-3-phenyl-2,3-dihydroisoxazole (5Ae): An oil. [ꢀ]D –101 (c 0.90, EtOH;
85% ee). IR (neat) 3062, 3029, 2953, 2928, 2857, 1673, 1602, 1495, 1455, 1303, 1156, 1074, 1029, 731,
697 cm–1. 1H NMR (400 MHz, CDCl3) ꢁ = 0.89 (t, 3H, J = 6.7 Hz), 1.19-1.39 (m, 4H), 1.51-1.63 (m,
4H), 2.21 (t, 2H, J = 7.6 Hz), 4.01 (d, 1H, J = 12.8 Hz), 4.30 (d, 1H, J = 12.8 Hz), 4.66 (d, 1H, J = 1.2
Hz), 4.85 (d, 1H, J = 1.2 Hz), 7.18-7.42 (m, 10H). HRMS (FAB+) (M + H)+, Found: m/z 322.21740.
Calcd for C22H28NO: 322.21709. The enantioselectivity was determined by HPLC (Daicel Chiralcel
OD-H ꢀ 2, hexane/iPrOH = 300/1, detected at 254 nm).
Hydroxymethylation of 4-Isoxazolinyl Zinc Intermediate with Formaldehyde (Scheme 1): To a
toluene (3 mL) solution of (R,R)-DTBT (26 mg, 0.1 mmol) was added dimethylzinc (0.8 mL of 1.0 M
solution in hexane, 0.8 mmol) at 0 °C under an argon atmosphere, and the mixture was stirred for 10 min.
To the solution, a toluene (3 mL) solution of racemic N-benzyl-N-[1-(4-methoxyphenyl)-
3-phenylprop-2-ynyl]hydroxylamine (34 mg, 0.1 mmol) was added, and the mixture was stirred for 10
min. A toluene (3 mL) solution of nitrone 2A (106 mg, 0.5 mmol) and a toluene (3 mL) solution of
phenylacetylene (3a) (51 mg, 0.5 mmol) were added to the resulting solution successively. The reaction
mixture was kept for 18 h at 0 °C. Then additional dimethylzinc (1.6 mL of 1.0 M solution in hexane,
1.6 mmol) was further added to the reaction mixture at 0 °C. The resulting solution was warmed up to
25 °C and stirred for 1 d. A freshly prepared THF (5 mL) solution of formaldehyde, produced by
thermal decomposion of paraformaldehyde (300 mg), was added to the resulting solution. The reaction
mixture was kept at 25 °C for 12 h and quenched by addition of a saturated aq. NH4Cl solution. After
filtration of the precipitate, the filtrate was extracted with AcOEt. The combined extracts were washed
with brine, dried over Na2SO4, and condensed under reduced pressure. The residue was separated by
TLC on SiO2 (hexane/AcOEt = 3/1) to isolate the corresponding alcohol 6 (90 mg, 52%, 85% ee).
(S)-(2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)methanol (6): An oil. [ꢀ]D25 –1 (c 0.90, EtOH;
85% ee). IR (neat) 3350, 3062, 3030, 2923, 1685, 1600, 1542, 1492, 1454, 1328, 1272, 1047, 917, 879,
757, 698 cm–1. 1H NMR (400 MHz, CDCl3) ꢁ = 1.51 (s, 1H), 4.05 (d, 1H, J = 12.8 Hz), 4.16 (d, 1H, J =
12.8 Hz), 4.35 (d, 1H, J = 12.8 Hz), 4.41 (d, 1H, J = 12.8 Hz), 5.11 (s, 1H), 7.27-7.42 (m, 15H). HRMS
(FAB+) (M + H)+, Found: m/z 328.16992. Calcd for C23H22NO: 328.17014. The enantioselectivity was
determined by HPLC (Daicel Chiralcel OD-H ꢀ 2, hexane/EtOH = 10/1, detected at 254 nm).
ACKNOWLEDGEMENTS
The present work was financially supported in part by Grant-in-Aid for Scientific Research on Priority
Areas “Advanced Molecular Transformations of Carbon Resources” from The Ministry of Education,
Culture, Sports, Science and Technology (MEXT).

724
HETEROCYCLES, Vol. 78, No. 3, 2009
REFERENCES AND NOTE
1. J. P. Freeman, Chem. Rev., 1983, 83, 241.
2. J. M. Atienza, D. Susanto, C. Huang, A. S. McCarty, and J. Colicelli, J. Biol. Chem., 1999, 274,
4839; A. G. Habeeb, P. N. P. Rao, and E. E. Knaus, J. Med. Chem., 2001, 44, 2921; R. D. Cramer, R.
J. Jilek, S. Guessregen, S. J. Clark, B. Wendt, and R. D. Clark, J. Med. Chem., 2004, 47, 6777; A. I.
Hubich, T. A. Zheldakova, T. V. Chernikhova, E. V. Koroleva, F. A. Lakhvich, and M. V. Sholukh,
Bioch. Bioph. Res. Commun., 2006, 341, 357; M. E. Fraley, R. M. Garbaccio, and G. D. Hartman,
PCT Int. Appl., 2006, 43 (WO2006/023440).
3. a) E. J. Stoner, B. A. Roden, and S. Chemburkar, Tetrahedron Lett., 1997, 38, 4981. b) P.
Aschwanden, D. E. Frantz, and E. M. Carreira, Org. Lett., 2000, 2, 2331.
4. a) S. Pinet, S. U. Pandya, P. Y. Chavant, A. Ayling, and Y. Vallee, Org. Lett., 2002, 4, 1463. b) F.
Cantagrel, S. Pinet, Y. Gimbert, and P. Y. Chavant, Eur. J. Org. Chem., 2005, 2694.
5. W. L. Wei, M. Kobayashi, Y. Ukaji, and K. Inomata, Chem. Lett., 2006, 35, 176; A. Konishi, W. L.
Wei, M. Kobayashi, S. Fujinami, Y. Ukaji, and K. Inomata, Chem. Lett., 2007, 36, 44.
6. The absolute stereochemistry of the obtained 4-isoxazolines 5 was determined to be S, because the
inversion of the stereochemistry was in principle impossible during the cyclization,
7. Partial racemization might have slightly occurred during this step.
8. The precise mechanism of the asymmetric addition reaction to nitrones 2 is still an open question.
Especially, the role of the methylzinc salt of a product-like racemic hydroxylamine 4 in the
enantiomeric enhancement remains to be accounted for. The easier assembly of the methylzinc
salts of a racemic mixture of the product-like hydroxylamines compared with that of the optically
pure (R)- or (S)-product-like hydroxylamine seems to be noteworthy for such the phenomenon.