Anionic domino C-O-heterocyclization approach for the synthesis of 5-vinyl isoxazolines

Article abstract of DOI:10.1055/s-2007-980346

5-Vinyl isoxazolines were isolated in high yields through domino nucleophilic addition-anionic C-O-heterocyclization, when allyl organometallics derived from trans-1,4-dihalobutene were reacted with nitrile oxides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-980346

LETTER
1449
Anionic Domino C–O-Heterocyclization Approach for the Synthesis of 5-Vinyl
Isoxazolines
S
ynthesis of 5-Vin
a
yl Isoxazol
v
ines eed Ahmed Qazi, Parvinder Pal Singh, Sumira Jan, H. M. Sampath Kumar*
Synthetic Chemistry Division, Indian Institute of Integrative Medicine, Jammu (Tawi) 180001, India
Fax +91(191)2548607; E-mail: hmskumar@yahoo.com
Received 5 September 2006
studied in depth despite the fact that nitrile oxides are
Abstract: 5-Vinyl isoxazolines were isolated in high yields through
domino nucleophilic addition–anionic C–O-heterocyclization,
when allyl organometallics derived from trans-1,4-dihalobutene
were reacted with nitrile oxides.
known to add to a number of nucleophiles to generate
hydroximic acid derivatives.3b–e We present, in this com-
munication, the nucleophilic addition of allyl organo-
metallic species (generated by the reaction of 1,4-
dihalobutene with metals) to nitrile oxides resulting in the
formation of 5-vinyl isoxazolines via concomitant anionic
domino C–O-heterocylization.
Key words: 1, 4-dihalobutene, nitrile oxide, 5-vinyl isoxazoline,
organometallic addition
2-Isoxazolines are valuable heterocycles with a broad
spectrum of pharmacological activities. They are also
useful because of their potential as masked aldols, the
unmasking of which can lead to useful synthetic interme-
diates including b-amino alcohols or b-keto alcohols.1 2-
Isoxazolines are obtained mainly through the 1,3-dipolar
cycloaddition of olefins to nitrile oxides and silyl
nitronates and to a lesser extent through the nitrosation of
cyclopropane accompanied by ring cleavage and cycliza-
tion.1d Of particular interest would be the synthesis of 5-
vinyl isoxazolines which are valuable intermediates in the
generation of a variety of biologically active molecules in-
cluding D,L-deoxy sugars2 and isoxazolidinyl N-alkyleth-
anolamines.2b The sole method for the synthesis of 5-vinyl
isoxazolines employs the addition of nitrile oxide to trans-
1,3-butadiene which is used as the limiting reactant.2c The
derived product mixture generally contains both mono
and bis adducts. In order to improve the synthetic proce-
dure, silyl nitronates were employed in the generation of
5-vinyl isoxazolines in good yields. Thus to our knowl-
edge, there is not a simple and alternative route for the
generation of isoxazolines in general and 5-vinyl isoxazo-
lines in particular. Nucleophilic additions of organometal-
lic reagents to various C=N compounds such as imines,
hydrazones, and oxime ethers are well established.3a
Nitrones have been successfully employed as substrates
for such additions, although nitrile oxides have not been
O
N
Br
+
M, THF
–
N
O
+
R
Br
X = Br, Cl, etc.
R
M = Mg, Zn, In/H2O
Scheme 1 Metal-mediated nucleophilic addition of trans-1,4-dibro-
mobutene to nitrile oxides
Thus, 1,4-dibromobutene was stirred with magnesium
metal in anhyd THF at ambient temperature followed by
reaction with a variety of stable and in situ generated ni-
trile oxides (Table 1). 5-Vinyl isoxazolines were isolated
in good yields and short reaction times (2–5 h, 65–85%).4
The reaction was found to be general with regard to vari-
ous metals, including zinc, magnesium and indium, and
also with regard to the dihalo compounds (1,4-dichlo-
robutene also gave analogous results). In the case of indi-
um metal,5 the reaction proceeded well in aqueous media
(THF–H2O, 1:1) even though longer reaction times were
required to achieve comparable yields with the magne-
sium reaction (30–45 h, 62–83%). When zinc–THF was
employed, the yields were comparatively low (45–63%)
even after 48 hours. The formation of 5-vinylisoxazolines
may be visualized through a mechanism involving
nucleophilic attack by the allylic organometallic species
Br
OMX
X
N
O
N
+
N
BrM
–
O
R
THF
X = Br, Cl, etc.
M = Mg, Zn, In/H2O
R
R
Scheme 2 Plausible mechanism for the formation of 5-vinyl isoxazoline through a nucleophilic addition route
SYNLETT 2007, No. 9, pp 1449–1451
0
1.
0
6.
2
0
0
7
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980346; Art ID: D26106ST
© Georg Thieme Verlag Stuttgart · New York

1450
N. A. Qazi et al.
LETTER
on the iminium carbon of benzonitrile oxide followed by domino fashion. It is interesting to note that when a
ring closure with concomitant loss of bromine through re- stoichiometric amount of allylmagnesium bromide was
positioning of double bond (Scheme 2).
treated with nitrile oxide, a mixture of the corresponding
allyl oximes was isolated in good quantity as a result of
nucleophilic addition.
Similar anionic domino C–O heterocylization reactions
involving 1,4-dihaloolefins and acetylenes have been pio-
neered by Rodriguez et al.6 The initial reaction in their In conclusion, we have presented here a facile and high-
case largely involved base-catalyzed condensation prior yielding alternate preparative protocol for 5-vinyl isox-
to domino cyclization, whereas, our approach involves a azolines. The reaction in the presence of indium offers an
cascade of C- and O-nucleophilic reactions, occurring in eco-friendly approach for the synthesis of these com-
Table 1 Synthesis of 5-Vinylisoxazoline through Metal-Mediated Addition of 1,4-Dibromobutene
Indium-mediated addition Grignard addition
Entry
Nitrile oxide
5-Vinylisoxazolinea
Time (h) (yield, %)b
Time (h) (yield, %)b
N
O
CNO
a
30 (74)
3 (81)
N
O
MeO
Cl
CNO
b
c
45 (73)
30 (81)
45 (80)
3 (78)
2 (85)
3 (83)
MeO
O
N
O
O
CNO
N
F
CNO
d
F
N
O
O2N
e
45 (71)
4 (75)
CNO
O2N
NC
N
N
O
NC
CNO
f
45 (73)
45 (76)
45 (70)
3 (80)
2 (80)
5 (72)
O
Me
CNO
g
h
Me
MeO
MeO
N
N
O
CNO
OMe
CNO
O
MeO
Me
i
45 (62)
45 (68)
42 (71)
5 (65)
3 (73)
3 (77)
OMe
MeO
Me
N
O
j
CNO
N
O
k
CNO
a All products were characterized by IR, 1H and 13C NMR, DEPT and mass spectroscopy.
b Yields obtained after column chromatography.
Synlett 2007, No. 9, 1449–1451 © Thieme Stuttgart · New York

LETTER
Synthesis of 5-Vinyl Isoxazolines
1451
reach r.t. and stirring was continued for a further 2–3 h. The
reaction was then quenched using aq NH4Cl soln (10 mL)
and diluted with CH2Cl2 (50 mL). The organic layer was
separated and the aq layer extracted with CH2Cl2 (2 × 20
mL). The combined organic layers were dried (anhydrous
Na2SO4) and evaporated under reduced pressure to afford
the crude product, which was subjected to column
pounds in aqueous media. 1,4-Dihalobutenes offer a safe
and convenient raw material for the generation of 5-vinyl
isoxazolines as compared to butadiene in terms of conve-
nience in handling.
Acknowledgment
chromatography (silica gel, 60–120 mesh, n-hexane–EtOAc,
gradient) to afford pure 3-(4-fluorophenyl)-5-vinyl 4,5-
dihydroisoxazole (0.16g, 83%) as a colorless amorphous
solid. IR (KBr): 1383, 1430, 1602, 2851, 2919, 2959, 3444
cm–1; 1H NMR (200 MHz, CDCl3): d = 2.85–2.95 (q, J = 8.0
Hz, 1 H), 3.33–3.46 (dd, J = 10.1, 6.3 Hz, 1 H), 5.1 (m, 1 H),
5.12–5.55 (m, 2 H), 5.85–5.95 (m, J = 7.36 Hz, 1 H), 7.2 (d,
J = 9.0 Hz, 2 H), 7.59 (d, J = 9.0 Hz, 2 H); 13C NMR (50
MHz, CDCl3): d = 40.4, 82.5, 115.2, 115.7, 118.2, 128.4,
128.5, 137.3, 157.5, 161.1, 163.5; MS (EI): m/z = 191.20;
Anal. Calcd for C11H10FNO: C, 69.10; H, 5.27; N, 7.33.
Found: C, 69.19; H, 5.18; N, 7.48.
The authors thank Dr. G. N. Qazi, Director-RRL for his interest and
encouragement. P.P.S. thanks CSIR New Delhi for the award of
fellowship.
References and Notes
(1) (a) Caramella, P.; Gurnager, P. In 1,3-Dipolar
Cycloaddition Chemistry, Vol. 1; Padwa, A., Ed.; Wiley:
New York, 1984, 291. (b) Huisgen, R. Angew. Chem. 1963,
75, 604. (c) Padwa, A. Angew. Chem. 1976, 88, 123.
(d) Torssel, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic Synthesis: Novel Strategies in Synthesis; VCH:
New York, 1988.
(2) (a) Caramella, P.; Bianchessi, P. Tetrahedron 1970, 26,
5773. (b) Torsell, K. B. G.; Hazell, A. C.; Hazel, R. G.
Tetrahedron 1985, 41, 5569. (c) Das, N. B.; Torsell, K. B.
G. Tetrahedron 1983, 39, 2247.
(3) (a) Bloch, R. Chem. Rev. 1998, 98, 1407; and references
cited therein. (b) Chan, T. H.; Lu, W. Tetrahedron Lett.
1988, 39, 8605. (c) Kumar, H. M. S.; Reddy, B. V. S.;
Anjaneyulu, S.; Yadav, J. S. Tetrahedron Lett. 1999, 40,
8305. (d) Kumar, H. M. S.; Anjaneyulu, S.; Reddy, E. J.;
Yadav, J. S. Tetrahedron Lett. 2000, 41, 9311.
(5) Typical Procedure for the Indium-Mediated Synthesis:
3-(4-Fluorophenyl)-5-vinyl-4,5-dihydroisoxazole (Table
1, entry d): A suspension of In powder (1.15 g, 10 mmol)
and trans-1,4-dibromobutene (1.2 g, 10 mmol) were stirred
at ambient temperature for 5 h in THF–H2O (15 mL, 1:1)
until the metal dissolved completely forming the allylindium
reagent. The reagent was then cooled to 0–5 °C and added
dropwise to a solution of p-fluorobenzonitrile oxide,
generated in situ by treatment of Et3N with the
corresponding chlorooxime (equivalent to 1.53 g, 10 mmol)
in THF (15 mL), over a period of 5 min while maintaining
the temperature between 0–5 °C. The reaction was allowed
to reach r.t. and stirring was continued for a further 45 h. The
reaction was then quenched using aq NH4Cl soln (10 mL)
and diluted with CH2Cl2 (50 mL). The organic layer was
separated and the aq layer extracted with CH2Cl2 (2 × 20
mL). The combined organic layers were dried (anhydrous
Na2SO4) and evaporated under reduced pressure to afford
the crude product, which was subjected to column
(e) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. 2002, 114, 2708.
(4) Typical Procedure for the Grignard Addition: 3-(4-
Fluorophenyl)-5-vinyl-4,5-dihydroisoxazole (Table 1,
entry d): To a suspension of Mg turnings (0.015 g, 5 mmol,
5 equiv) in anhyd THF was added trans-1,4-dibromobutene
(0.214 g, 1 mmol, 1 equiv) in small portions while stirring
the reaction mixture at r.t. (a small grain of iodine is
generally required to promote formation of the Grignard
reagent). The mixture was stirred at r.t. for 1–2 h and was
then cooled to 0–5 °C. It was then added dropwise to a
solution of p-fluorobenzonitrile oxide (equivalent to 0.137 g,
1 mmol, generated in situ by treatment of Et3N with the
corresponding chlorooxime 0.173g, 1 mmol) in THF (15
mL), over a period of 10 min while maintaining the
temperature between 0–5 °C. The reaction was allowed to
chromatography (silica gel, finer than 200 mesh, n-hexane–
EtOAc, gradient) to afford pure 3-(4-fluorophenyl)-5-vinyl-
4,5-dihydroisoxazole (1.53 g, 80%) as a colorless
amorphous solid.
(6) (a) Lavoisier, T.; Rodriguez, J.; Rodriguez, J. Synlett 1996,
339. (b) Wang, T.; Chen, J.; Zhao, K. J. Org. Chem. 1995,
60, 2668. (c) Wang, T.; Chen, J.; Landrey, D. W.; Zhao, K.
Synlett 1995, 543. (d) Wang, T.; Hong, F.; Zhoa, K.
Tetrahedron Lett. 1995, 36, 6407.
Synlett 2007, No. 9, 1449–1451 © Thieme Stuttgart · New York