Reaction of allenylmagnesium and allenylindium bromides with nitrile oxides: synthesis of novel 5-butynyl- and 5-methylisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2006.11.140

5-Butynylisoxazoles were obtained in high yields through a domino addition, C-O heterocyclization involving allenylmagnesium bromide and benzonitrile oxide in dry THF, in which the corresponding 5-methylisoxazoles were isolated in trace amounts. However, when the reactions were attempted in aqueous media using allenylindium bromide, 5-methylisoxazoles were formed as the sole products in high yields.

Full text of DOI:10.1016/j.tetlet.2006.11.140

Tetrahedron Letters 48 (2007) 887–890
Reaction of allenylmagnesium and allenylindium bromides
with nitrile oxides: synthesis of novel 5-butynyl- and
5-methylisoxazolesI
H. M. Sampath Kumar,* Parvinder Pal Singh, Syed Shafi, Pitta Bhaskar Reddy,
Kankala Shravankumar and Doma Mahender Reddy
Synthetic Chemistry Section, Regional Research Laboratory, Jammu-Tawi 180 001, India
Received 16 May 2006; revised 16 November 2006; accepted 22 November 2006
Available online 19 December 2006
Abstract—5-Butynylisoxazoles were obtained in high yields through a domino addition, C–O heterocyclization involving allenyl-
magnesium bromide and benzonitrile oxide in dry THF, in which the corresponding 5-methylisoxazoles were isolated in trace
amounts. However, when the reactions were attempted in aqueous media using allenylindium bromide, 5-methylisoxazoles were
formed as the sole products in high yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Nucleophilic additions of organometallic reagents to
various C@N compounds such as imines, hydrazones,
and oxime-ethers are well established.1 Nitrones have
been successfully employed as substrates for such addi-
tions;1b,c however, nitrile oxides have not been studied
in depth despite the fact that they are known to add
to a number of nucleophiles to generate substituted oxi-
mes. Of particular interest would be the addition of
nitrile oxides to acetylenic compounds to give
synthetically and pharmacologically valuable isoxaz-
oles.1,2 Isoxazoles and their derivatives have found sev-
eral applications3 as antibiotics, analgesics, anesthetics,
anabolics, anthelmenthics, diuretics, GABA-agonists,
anticonvulsants, muscle relaxants, and herbicides; some
isoxazole derivatives display antileprous, antitumour,
mutagenic behavior, and plant growth regulatory activ-
ity. Furthermore, isoxazoles are masked synthetic equiv-
alents of 1,3-dicarbonyl functions via the lability
associated with the N–O bond. Isoxazoles can be func-
tionalized, readily unmasked4,5 and elaborated for fur-
ther synthetic applications. As part of our continued
interest in exploring organometallic addition reactions
to various C@N compounds,6 we herein present the
nucleophilic addition of allenylmagnesium bromide to
nitrile oxides, the resulting intermediate from which
undergoes C–O heterocyclization followed by the addi-
tion to another mol of allenylmagnesium bromide to
generate 5-butynylisoxazoles in good yields. Several
benzonitrile oxides7 generated in situ, were reacted with
excess (>2 mol equiv) propargylmagnesium bromide in
THF together with a catalytic quantity (3% w/w) of
mercuric(II) chloride8 under an inert atmosphere (mer-
curic chloride on interaction with propargylmagnesium
bromide generates allenylmagnesium bromide in situ).
In most cases, 5-butynylisoxazoles were isolated in good
yields (67–84%, Table 1) after 5–6 h reaction at an ambi-
ent temperature9 with only a trace amount of the corre-
sponding 5-methylisoxazoles (5–8%). The reaction was
found to be general with regard to various substituted
nitrile oxides bearing electron-donating or electron-
withdrawing groups on the aromatic ring. However,
hindered nitrile oxides such as 2,6-dichlorobenzonitrile
oxide gave trace amounts of 5-methylisoxazole without
any butynylated product.
When this reaction was attempted in the absence of mer-
curic chloride, no product was namely observed even
after a prolonged reaction. The formation of 5-butynyl-
isoxazoles could occur in a domino fashion, nucleo-
philic addition of allenylmagnesium bromide to the
nitrile oxide followed by C–O-heterocyclization to
Keywords: Allenyl organometallic compounds; Nitrile oxide; 5-Butynyl-
isoxazoles; 5-Methylisoxazoles.
q RRL Communication No. 2445.
*
Corresponding author. Tel.: +91 2572002x292; fax: +91 2548607;
e-mail: hmskumar@yahoo.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.140

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H. M. S. Kumar et al. / Tetrahedron Letters 48 (2007) 887–890
Table 1. Magnesium-mediated synthesis of 5-butynylisoxazoles
of free propargyl bromide if present in the medium or,
(ii) SNi type reaction via intermediate 3c generated
through Schlenk equilibrium10 (Scheme 2). Since the
propargyl bromide was treated with an excess of metal
to completely convert it into allenylmagnesium bromide,
the possibility of a Wurtz-type coupling can be ruled
out. This was further confirmed by the fact that no trace
of the cycloaddition product arising from the dipolar
addition of nitrile oxide to propargyl bromide (unre-
acted, if any) could be detected in the crude product
mixture. It is pertinent to mention here that propargyl
bromide readily undergoes dipolar cycloaddition with
nitrile oxides to generate 5-bromomethylisoxazole under
the given experimental conditions. Hence, product for-
mation can be attributed to an SNi reaction as shown
in Scheme 2 involving a Schlenk equilibrium (similar
coupling between two Grignard species has already been
explained mechanistically by Schlenk10). 5-Methylisox-
azole is likely to be formed through proton capture by
intermediate 3a during quenching. The possibility of a
1,3-dipolar cycloaddition of nitrile oxide to allenylmag-
nesium bromide to generate the isoxazole nucleus can be
ruled out since allenylmagnesium halides do not form
Diels Alder adducts with any dienes under the given
experimental conditions, which shows the poor dipolar-
ophilic nature of these resonance stabilized species.
Entry
a
Isoxazole 4a
Reaction time
(h) (yield, %)b,c
O
N
5 (78)
6 (70)
5 (82)
5 (78)
O
N
b
c
MeO
O
N
Cl
O
N
d
HO
O
N
e
f
6 (84)
6 (80)
O2N
O
N
NO2
O
N
Bearing in mind the importance of indium-mediated
reactions,11 when attempted this reaction in aqueous
medium using allenylindium bromide, when the corre-
sponding 5-methyl isoxazoles were formed as the sole
products12 without any traces of 5-butynylisoxazoles
even when using excess allenylindium bromide. This
clearly confirms the mechanism of formation of this
product through proton capture by intermediate 3a
under aqueous conditions.
H3C
g
h
i
5 (72)
6 (70)
5 (67)
5 (73)
O
N
H3C
NC
F
O
N
O
This reaction was found to be high yielding and general
with regard to various nitrile oxides. With all the nitrile
oxides studied, 5-methylisoxazoles were formed as the
sole products after reaction using allenylindium bromide
(Table 2). The preparation of 5-methylisoxazoles can be
otherwise visualized only through 1,3-dipolar nitrile
oxide cycloaddition to propyne gas under adiabatic con-
ditions, which is obviously inconvenient. Thus, allenyl-
indium bromide can be a better substitute for the
synthesis of 5-methyl isoxazoles. In conclusion, we have
presented the synthesis of 5-butynylisoxazoles and 5-
methylisoxazoles in high yields with a high product
selectivity. Thus, it may be anticipated that the method
described in this work may find utility as an alternative
to existing protocols for the synthesis of 5-butynyl- and
5-methylisoxazoles.
N
j
a All products were characterized by IR, 1H/13C NMR and mass
spectral analysis.
b Isolated yields after column chromatography.
c The corresponding 5-methylisoxazoles were isolated in 5–8% yields.
generate an organometallic isoxazole intermediate 3a
(see Scheme 2), which undergoes reaction with an addi-
tional mol of allenylmagnesium bromide 2a (Scheme 1)
to generate 4. A plausible mechanism for the generation
of 5-butynylisoxazole 4 from intermediate 3a can be
visualized either through, (i) Wurtz-type of coupling of
organometallic intermediate 3b with an additional mol
Ar
Ar
InBr
Ar
MgBr
2b
2a
N
N
+
+
N
Ar
N
O
O
O
O
THF
THF-water 1:1
1
5
76-86%
4
5
5-8%
67-84%
Scheme 1. Reaction of allenyl organometallic compounds with nitrile oxides.

H. M. S. Kumar et al. / Tetrahedron Letters 48 (2007) 887–890
889
MgBr
N
N
N
Ar
Ar
C
O
OMBr
_
Ar
2
+
N
O
MBrOH
HOH
Ar
O
+
MBr
THF
1
Nucleophilic addition
C-O heterocyclization
5
3a
MgBr
C
N
O
N
N
O
Ar
O
NH4Cl (aq.)
M
2 M(OH)Br
Ar
+
Ar
Br
Br
MBr
2
+
M
M
Schlenk complex
3b
3c
4
Scheme 2. A plausible mechanism for the formation of 5-butynyl- and 5-methylisoxazoles.
Acknowledgements
Table 2. Indium-mediated synthesis of 5-methylisoxazoles in the
aqueous medium
The authors thank Dr. G. N. Qazi, Director-RRL for
his interest and encouragement. P.P.S., K.S.K., S.S.,
D.M.R., and P.B.R. thank the CSIR, New Delhi, for
the award of fellowships.
Entry
Isoxazole 4a
Reaction time
(h) (yield, %)b
N
O
a
24 (78)
Cl
N O
References and notes
b
c
24 (83)
22 (85)
Cl
1. (a) Bloch, R. Chem. Rev. 1998, 98, 1407–1438, and
references cited therein.; (b) Fiumana, A.; Lombardo,
M.; Trombini, C. J. Org. Chem. 1997, 62, 5623–5626; (c)
Torssell, K. G. B. Organic Nitro Chemistry Series. In
Nitrile Oxides, Nitrones and Nitronates in Organic Synthe-
sis; VCH: New York, 1988; Chapter 1, pp 7, 9–14; (d)
Chan, T. H.; Lu, W. Tetrahedron Lett. 1988, 39, 8605–
8609.
N
O
MeO
Cl
N
O
d
e
20 (84)
24 (82)
N
O
2. (a) Caramella, P.; Grunanger, P. In 1,3-Dipolar Cycload-
dition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984;
Vol. 1, p 291; (b) Huisgen, R. Angew. Chem. 1963, 75,
604–615; (c) Padwa, A. Angew. Chem., Int. Ed. Engl. 1976,
15, 123–136.
3. (a) Lang, S. A.; Lin, I. Y. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press, 1984; Vol. 6, pp 1–130; (b) Takeuchi, Y.; Furusaki,
F. Adv. Heterocycl. Chem. 1977, 21, 207–252; (c)
Wakefield, B. J.; Wright, D. J. Adv. Heterocycl. Chem.
1979, 25, 147–150.
4. Kochetkov, N. K.; Khomutova, E. D.; Bazilevsky, M. V.
Zh. Obshch. Khim. 1958, 28, 2736–2745.
5. (a) McMurry, J. E. Org. Synth. 1973, 53, 59, 70; (b) Stork,
G.; McMurry, J. E. J. Am. Chem. Soc. 1967, 89, 5461–
5462.
O2N
N
O
f
20 (73)
24 (75)
N O
g
F
N
O
h
24 (80)
MeO
MeO
OMe
N O
i
j
24 (81)
24 (79)
6. (a) Kumar, H. M. S.; Reddy, B. V. S.; Anjaneyulu, S.;
Yadav, J. S. Tetrahedron Lett. 1999, 40, 8305–8306; (b)
Kumar, H. M. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav, J.
S. Tetrahedron Lett. 2000, 41, 9311–9314; (c) Kumar, H.
M. S.; Anjaneyulu, S.; Reddy, B. V. S.; Yadav, J. S.
Synlett 1999, 5, 551–552.
OMe
N O
Br
MeO
a All products were characterized by IR, 1H/13C NMR and mass
spectral analysis.
b Isolated yields after column chromatography.
7. All nitrile oxides were prepared as per the literature
procedure and unstable nitrile oxides were used immedi-

890
H. M. S. Kumar et al. / Tetrahedron Letters 48 (2007) 887–890
ately without futher purification. Ref. Grundmann, C.;
Dean, J. M. Angew. Chem. 1964, 76, 682–695.
8. Hopf, H.; Bohm, I.; Kleinschroth, J. Org. Synth. 1990,
Coll. Vol. 7, 485–490.
J = 8.7 Hz); 13C NMR (50 MHz, CDCl3): d 17.1, 26.1,
55.3, 69.7, 82.1, 99.4, 114.3, 121.7, 128.2, 160.9, 162.0,
171.4; MS (EI, 70 eV) m/z (rel. int.) 227 (75), 212 (100),
174 (43), 146 (57), 77 (21), 54 (27).
9. In a typical procedure, to a suspension of magnesium
turnings (0.12 g, 5 mmol, 5 equiv) in anhydrous tetrahy-
drofuran (20 ml) and mercury(II) chloride (5 mg, 1% w/w
of propargyl bromide) was added propargyl bromide
(0.59 ml of an 80 wt % solution in toluene, 4 mmol,
4 equiv) in small portions while stirring the reaction
mixture at room temperature. (Note: A small grain of
iodine was generally required to promote formation of the
Grignard reagent.) The mixture was stirred at room
temperature for 2 h to give a cloudy light green solution.
The allenylmagnesium bromide generated was cooled to
0–5 ꢁC and added dropwise to a solution of p-meth-
oxybenzonitrile oxide (1 mmol, equivalent to 0.149 g),
generated in situ by the treatment of triethylamine
(0.14 ml) with the corresponding chlorooxime (0.185 g,
1 mmol) in dry THF (15 ml) over a period of 10 min while
maintaining the temperature between 0 and 5 ꢁC. The
reaction mass was allowed to attain rt and stirring was
continued at an ambient temperature for 6 h followed by
quenching with aqueous ammonium chloride solution
(10 ml) and diluting with dichloromethane (50 ml). The
organic layer was separated and the aqueous layer
extracted with dichloromethane (2 · 20 ml). The combined
organic layers were dried (anhydrous Na2SO4) and evap-
orated under reduced pressure to afford a crude product
which was subjected to chromatography (silica gel, 60–120
mesh, eluent; n-hexane/EtOAc gradient) to afford pure 3-
(p-methoxyphenyl)-5-butynylisoxazole as a colorless solid
(0.16 g, 70%, mp 71.2 ꢁC). IR (KBr, cmÀ1): 3281, 2966,
2937, 1608, 1527, 1459, 1431, 1256, 1176, 1064, 840, 790,
659, and 533. 1H NMR (200 MHz, CDCl3): d 2.04 (s, 1H),
2.64 (t, 2H J = 7.2 Hz), 3.02 (t, 2H J = 7.2 Hz), 3.85 (s,
3H), 6.37 (s, 1H), 6.99 (d, 2H, J = 8.7 Hz), 7.51 (d, 2H,
10. Schlenk, W. Chem. Ber. 1929, 62B, 920–924.
11. (a) Isaac, M. B.; Chan, T.-H. J. Chem. Soc. Chem.
Commun. 1995, 1003–1004; (b) Chan, T. H.; Li, C. J.; Lee,
M. C.; Wei, Z. Y. Can. J. Chem. 1994, 72, 1181–1192.
12. In a typical procedure, a suspension of indium powder
(0.126 g, 1.1 mmol), and propargyl bromide (0.13 g,
1.1 mmol, 80% solution in toluene) in 20 ml of THF/
water (1:1) was stirred at an ambient temperature for 3 h
until the metal had dissolved completely to form allenyl-
indium bromide. The above reagent was cooled to 0–5 ꢁC
and added dropwise over a period of 5 min to a stirred
solution of p-methoxybenzonitrile oxide generated in situ
(equiv 0.15 g, 1 mmol) in THF (20 ml), while maintaining
the temperature between 0 and 5 ꢁC. The reaction was
allowed to attain room temperature and stirring was
continued at an ambient temperature for 22 h followed by
quenching with aqueous ammonium chloride solution
(10 ml). The reaction was diluted with dichloromethane
(50 ml). The organic layer was separated and the aqueous
layer was extracted with dichloromethane (2 · 20 ml). The
combined organic layers were dried (anhydrous Na2SO4)
and evaporated under reduced pressure to afford a crude
product, which was subjected to chromatography (silica
gel, 60–120 mesh, eluent; n-hexane/EtOAc gradient) to
afford pure 3-(p-methoxyphenyl)-5-methylisoxazole as a
colorless amorphous solid (0.16 g, 86%); mp 69.8 ꢁC; IR
(KBr, cmÀ1): 736, 788, 838, 902, 948, 1062, 1116, 1176,
1
1258, 1298, 1441, 1527, 1612, 2934; H NMR (200 MHz,
CDCl3): d 2.46 (s, 3H), 3.85 (s, 3H), 6.23 (s, 1H), 6.98 (d,
2H, J = 6.7 Hz), 7.70 (d, 2H, J = 6.7 Hz); 13C NMR
(50 MHz, CDCl3): d 11.7, 54.8, 98.9, 113.7, 123.8, 127.6,
151.4, 161.3, 165.6; MS (EI, 70 eV) m/z (rel. int.) 189 (92),
174 (100), 146 (70), 77 (18), 63 (18), 45 (53).