Ring opening of 3-bromo-2-isoxazolines to β-hydroxy nitriles

Article abstract of DOI:10.1081/SCC-200039452

3-Bromo-2-isoxazolines were converted to the corresponding β-hydroxy nitriles by treatment with sodium iodide in the presence of either chlorotrimethylsilane or para-toluenesulfonic acid. Both methods gave β-hydroxy nitriles under relatively mild conditio

Full text of DOI:10.1081/SCC-200039452

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Ring Opening of
3‐Bromo‐2‐Isoxazolines to
β‐Hydroxy Nitriles
Martin G. Kociolek a & Kyle P. Kalbarczyk a
a Penn State Erie , The Behrend College, School of
Science , Erie, Pennsylvania, 16563, USA
Published online: 10 Jan 2011.
To cite this article: Martin G. Kociolek & Kyle P. Kalbarczyk (2004) Ring Opening
of 3‐Bromo‐2‐Isoxazolines to β‐Hydroxy Nitriles, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:23, 4387-4394, DOI: 10.1081/SCC-200039452
To link to this article: http://dx.doi.org/10.1081/SCC-200039452
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4387–4394, 2004
Ring Opening of 3-Bromo-2-Isoxazolines
to b-Hydroxy Nitriles
*
Martin G. Kociolek and Kyle P. Kalbarczyk
Penn State Erie, The Behrend College, School of Science, Erie,
Pennsylvania, USA
ABSTRACT
3-Bromo-2-isoxazolines were converted to the corresponding b-hydroxy
nitriles by treatment with sodium iodide in the presence of either chloro-
trimethylsilane or para-toluenesulfonic acid. Both methods gave b-hydroxy
nitriles under relatively mild conditions in good to moderate yields for a
variety of substituted 3-bromo-2-isoxazolines.
Key Words: Bromoformaldoxime; Bromoisoxazolines; b-Hydroxy-
nitriles; Iodotrimethylsilane; para-Toluenesulfonic acid.
DISCUSSION
Isoxazolines have long been recognized as versatile synthetic intermedi-
ates for the construction of a variety of 1,3-difunctionalized compounds, such
*
Correspondence: Martin G. Kociolek, Penn State Erie, The Behrend College, School
of Science, Erie, PA 16563, USA; Tel: 814-898-6411; Fax: 814-898-6213; E-mail:
mgk5@psu.edu.
4387
DOI: 10.1081/SCC-200039452
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4388
Kociolek and Kalbarczyk
as b-hydroxy carbonyls[1] and g-amino alcohol.[2,3] A number of conversions
of 2-isoxazolines to b-hydroxy nitriles have been reported. These include
decarboxylations of 3-carboxylic acid-2-isoxazolines,[4,5] reductive cleavage
of 3-sulfonyl-2-isoxazolines,[6,7] desilylation of 3-(trimethylsilyl)-2-isoxazo-
lines[8] and the deprotonation of 3-unsubstituted-2-isoxazolines.[9–12] In addi-
tion, ring opening of 3-bromo-2-isoxazolines to b-hydroxy nitriles has been
reported by reaction with alkanethiolates[13] as well as catalytic hydrogen-
ation.[14] b-Hydroxy nitriles have been shown to be useful intermediates in
the synthesis of complex organic molecules, and a number of methods for
their synthesis have been reported in the literature.[15–18] In the course of our
investigations into novel, synthetically useful reactions of 3-bromoisoxazolines,
we wish to report two complementary ring-opening reactions that yield
b-hydroxy nitrile products.
3-Bromo-2-isoxazolines have shown potential as versatile, easily obtain-
able synthetic intermediates. They are prepared by the reaction of alkenes with
dibromoformaldoxime.[19] These reactions proceed in generally high yields
with a variety of olefin substrates. Subsequent reaction of these bromoisoxa-
zolines with sodium iodide in the presence of either chlorotrimethylsilane
(Method A) or p-toluenesulfonic acid (Method B) resulted in facile conversion
to the b-hydroxy nitriles (Scheme 1).
A series of bromoisoxazolines was synthesized according to the method
of DeMicheli[20] and subjected to the two ring-opening conditions. The
results are summarized in Table 1.
For most substrates, both methods provided good to excellent yields of the
desired b-hydroxy nitriles. The only exception is entry 3, in which the reaction
appeared to go to completion [as observed by thin-layer chromatography
(TLC)], but isolation of the pure hydroxy nitrile proved difficult. This may
be due to the high water solubility of the dihydroxynitrile product. In addition,
the more hindered ring-fused bromoisoxazolines, entries 8 and 9, gave only
moderate yields with Method B for reasons not immediately obvious.
Method A most likely involves in situ formation of iodotrimethyl-
silane.[21] A single example of iodotrimethylsilane-induced ring opening of
Scheme 1.

b-Hydroxy Nitriles
Table 1. Conversion of 3-bromo-2-isoxazolines to b-hydroxy nitriles.
4389
Entry
1
Bromoisoxazoline/b-hydroxy nitrile
Method
% Yield
A
B
82
75
2
A
B
85
67
3
4
5
6
7
A
B
A
B
A
B
A
B
A
B
35
25
90
93
90
90
75
68
79
79
8
9
A
B
80
44
A
B
80
48
a bromoisoxazoline has been reported.[22] It is worth nothing that virtually no
reaction takes place when the bromoisoxazoline is treated with only sodium
iodide, in the absence of chlorotrimethylsilane or p-toluenesulfonic acid. It
may be proposed that the iodotrimethylsilane, or p-toluenesulfonic acid,
is acting as a Lewis acid with oxygen serving to activate the ring, facilitating
N–O bond cleavage. A concerted mechanism for this reaction can be
proposed to involve initial attack of iodide ion on the bromine of the bromo-
isoxazoline and subsequent ring opening, as shown in Scheme 2.
The production of iodine monobromide is evidenced by immediate
formation of a dark brown solution when either the chlorotrimethylsilane or
p-toluenesulfonic acid is added. This brown color dissipates during the
workup with aqueous sodium bisulfite. In the case of Method A, it would
appear that the trimethylsilyl ether is being hydrolyzed in the workup, but
attempts to isolate the ether have been unsuccessful. An alternate step-wise
mechanism for similar ring-opening reactions of isoxazolines, involving an
isoxazolium carbanion intermediate, has been previously suggested, but no
clear evidence for it has been shown here or elsewhere.

4390
Kociolek and Kalbarczyk
Scheme 2.
In conclusion, we wish to report two related ring-opening reactions of
3-bromo-2-isoxazolines to give b-hydroxy nitriles. Both methods give good
to excellent yields for a variety of easily obtainable bromoisoxazoline sub-
strates and may provide useful alternatives for the synthesis of b-hydroxy
nitriles.
EXPERIMENTAL
1H NMR spectra were obtained on a JEOL 400 MHz spectrometer in
CDCl3 using TMS as an internal standard. Infrared (IR) spectra were obtained
neat on sodium chloride plates using a Nicolet 210 infrared spectrometer.
Elemental analysis was performed by Midwest Microlab (M/M), LLC. Sol-
vents and reagents were obtained commercially and used without further
purification.
General Procedure for Ring Opening of
3-Bromo-2-Isoxazolines
The bromoisoxazoline (one equivalent) and NaI (three equivalents)
were dissolved in acetonitrile at 08C under a nitrogen atmosphere. Chlorotri-

b-Hydroxy Nitriles
4391
methylsilane (TMSCl) (Method A) or p-toluenesulfonic acid in acetonitrile
(Method B) was then added drop-wise to the solution, and the reaction was
allowed to warm to room temperature and stirred overnight. The reaction
was then diluted with diethyl ether, and the organic layer was washed with
aqueous saturated NaHCO3, aqueous saturated NaHSO3 and dried over anhy-
drous MgSO4. The solvents were evaporated under reduced pressure, and the
crude hydroxy nitrile was further purified by column chromatography on silica
gel using hexanes/ethyl acetate as elutants.
b-Hydroxy nitriles from entries 1,[23] 2,[13] 4,[24] 5,[25] 8,[7] and 9[26] were
previously reported and were characterized by the physical and spectral
properties reported below, which were consistent with those in the literature.
The hydroxy nitriles from entries 3, 6, and 7 were characterized by nuclear
magnetic resonance (NMR), IR, and element analysis, all of which were
consistent with the proposed structure.
1
Entry 1: 3-Hydroxy-3-phenylpropanenitrile.[23] Colorless oil. H NMR
(400 MHz, CDCl3): d 7.41–7.38 (m, 5H), 5.04 (t, J ¼ 6.0 Hz, 1H),
2.76 (d, J ¼ 6.0 Hz, 2H); IR (neat): 3422 (OH), 2255 (CN) cm21
.
Entry 2: 2,3-Diphenylpropanenitrile.[13] M.p. 91–92.58C (Lit. m.p. 91–
928C). 1H NMR (400 MHz, CDCl3): d 7.35–7.21 (m, 10H), 4.96
(d, J ¼ 6.0 Hz, 1H), 4.05 (d, J ¼ 6.0 Hz, 1H); IR (neat): 3419 (OH),
2254 (CN) cm21
.
Entry 3: 3,5-Dihydroxypentanenitrile. Colorless oil. 1H NMR (400 MHz,
CDCl3): d 4.40 (m, 1H), 4.16 (m, 1H), 4.30 (m, 1H), 2.91 (brs, 1H), 2.58
(m, 2H), 1.95 (m, 1H), 1.86 (m, 1H); IR (neat): 3385 (OH), 2252 (CN)
cm21; Anal. Calcd. for C5H9NO2: C, 52.16; H, 7.88; N, 12.17.
Found: C, 51.86; H, 7.77; N, 12.06.
Entry 4: 3-Hydroxyheptanenitrile.[24] Colorless oil. 1H NMR (400 MHz,
CDCl3): d 3.95 (m, 1H), 2.53 (m, 2H), 2.25 (brs, 1H), 1.59 (m, 2H), 1.37
(m, 4H), 0.91 (t, 3H); IR (neat): 3428 (OH), 2253 (CN) cm21
.
Entry 5: 3-Hydroxy-6-heptenenitrile.[25] Colorless oil. 1H NMR
(400 MHz, CDCl3): d 5.82 (m, 1H), 5.08 (m, 2H), 3.99 (m, 1H), 2.55
(m, 2H), 2.21 (m, 2H), 2.05 (brs, 1H), 1.70 (m, 2H); IR (neat):
3439 (OH), 2252 (CN), 1641 cm21
.
1
Entry 6: Ethyl-3-cyano-2-hydroxypropionate. Colorless oil. H NMR
(400 MHz, CDCl3): d 4.40 (t, 1H), 4.33 (q, 2H), 3.40 (brs, 1H), 2.83
(m, 2H), 1.33 (t, 3H); IR (neat): 3446 (OH), 2255 (CN), 1733
(C55O) cm21; Anal. Calcd. for C6H9NO3: C, 50.35; H, 6.34; N,
9.79. Found: C, 50.12; H, 6.57; N, 9.72.

4392
Kociolek and Kalbarczyk
Entry 7: 3-Hydroxy-3-(4-methoxyphenyl)-2-methylpropanenitrile. Color-
less oil. 1H NMR (400MHz, CDCl3): d 7.31 (d, 2H), 6.92 (d, 2H), 4.66
(d, 1H), 3.81 (s, 3H), 2.87 (m, 1H), 2.43 (brs, 1H), 1.22 (d, 3H); IR (neat):
3462 (OH), 2244 (CN) cm21; Anal. Calcd. for C11H13NO2: C, 69.09; H,
6.85; N, 7.32. Found: C, 69.11; H, 6.81; N, 7.15.
Entry 8: cis-2-Hydroxycyclohexanecarbonitrile.[7] M.p. 31–32.58C (Lit.
1
m.p. 32.5–348C). H NMR (400 MHz, CDCl3): d 3.80 (m, 1H), 3.03
(m, 1H), 2.35 (m, 1H), 2.03 (m, 1H), 1.81 (m, 2H), 1.71–1.51 (m,
4H), 1.37 (m, 1H); IR (neat): 3460 (OH), 2243 (CN) cm21
.
Entry 9: exo, exo-3-Hydroxybicyclo[2.2.1]heptane-2-carbonitrile.[26]
Colorless oil. 1H NMR (400 MHz, CDCl3): d 3.92 (dd, J ¼ 6.4,
2.2 Hz, 1H), 2.69 (dd, J ¼ 6.4, 2.0 Hz, 1H), 2.62 (m, 1H), 2.31
(m, 1H), 1.94 (m, 1H) 1.62–1.50 (m, 2H), 1.32 (m, 1H), 1.18–1.14
(m, 2H); IR (neat): 3338 (OH), 2240 (CN) cm21
.
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Received in the USA August 2, 2004