Convenient and improved halogenation of 3,5-diarylisoxazoles using N-halosuccinimides

Article abstract of DOI:10.1055/s-2003-40516

The convenient C-4 halogenation of 3,5-diarylisoxazoles using N-halosuccinimides (NBS, NCS, or NIS) in acetic acid is described. A strong acid catalyst was required for efficient halogenation of some isoxazoles depending on the substituent on the 5-phenyl ring. Finally, the 4-iodoisoxazoles were found to undergo a novel proto-deiodination upon heating in the presence of H₂SO₄.

Full text of DOI:10.1055/s-2003-40516

1586
PAPER
Convenient and Improved Halogenation of 3,5-Diarylisoxazoles Using
N-Halosuccinimides
Convenient and
I
u
m
proved
H
a
t
logenat
h
ion of 3,5-Diaryliso
A
xazoles
U
sing
N
-
n
H
alosuccinim
n
ides Day, Jacqueline A. Blake, Chad E. Stephens*
Center for Biotechnology and Drug Design, Department of Chemistry, Georgia State University, Atlanta, GA 30303
Fax 404-651-1416; E-mail: checes@panther.gsu.edu
Received 4 April 2003; revised 8 May 2003
dling, as well as the improved regioselectivity that they
sometimes offer, these reagents have received much at-
tention recently for the nuclear halogenation of aroma-
tics.15–17 Regarding their use with non-activated
Abstract: The convenient C-4 halogenation of 3,5-diarylisoxazoles
using N-halosuccinimides (NBS, NCS, or NIS) in acetic acid is de-
scribed. A strong acid catalyst was required for efficient halogena-
tion of some isoxazoles depending on the substituent on the 5-
phenyl ring. Finally, the 4-iodoisoxazoles were found to undergo a isoxazoles, there is a single report in the literature18 that
novel proto-deiodination upon heating in the presence of H2SO4.
details the bromination of some alkyl- and aryl-substitut-
ed isoxazoles with NBS in DMF. However, the conditions
described therein proved to be unsatisfactory for haloge-
nation of many of our diarylisoxazoles, apparently due to
the effects of substituents on the phenyl rings. That same
report, as well as a leading heterocyclic resource,19 sug-
gests that NIS is not suitable for the iodination of such
isoxazoles, although during the course of this work Ger-
shman and co-workers2 have prepared a 4-iodo-3,5-dia-
rylisoxazole using NIS in DMF.
Key words: isoxazoles, halogenation, N-halosuccinimides, iodo
cleavage, solvent effects
3,5-Diarylisoxazoles, which are readily prepared from
chalcone derivatives, comprise a common and much stud-
ied class of substituted isoxazoles.1 Most recently, these
types of isoxazoles have been studied as potential estro-
gen receptor modulators,2 as potential anti-cancer3 and
anti-microbial agents,4 as liquid crystals,5 and as linear
dyes with application to light-harvesting systems.6
As a result of our work in this area, we now wish to report
convenient and improved procedures for the halogenation
of a series of 5-aryl substituted 3,5-diarylisoxazoles with
N-halosuccinimides, including NIS. In addition, we also
describe the novel proto-deiodination of the 4-iodoisox-
azoles, a process that was observed during some of our io-
dinations.
As halogen substitution can often lead to interesting
changes in the physio-chemical and biological properties
of aromatics,7 including isoxazoles,8 we are interested in
4-halo-3,5-diarylisoxazoles for the purpose of biological
screening. Certain 4-haloisoxazoles (i.e. 4-bromo- and 4-
iodoisoxazoles) are also of interest as they serve as inter-
mediates to higher functionalized derivatives via metalla-
tion and/or transition metal-catalyzed chemistry.2,9 Our
search of the literature revealed that standard procedures
for halogenation of aryl(or alkyl)-substituted isoxazoles at
the C-4 position involve the use of strongly acidic condi-
tions, oxidizing agents, or corrosive and reactive halogen.
For example, such isoxazoles have typically been chlori-
Results
The electron density, and thus reactivity, of C-4 of the
isoxazole ring in 3,5-diarylisoxazoles is primarily affect-
ed by the electronic properties of substituents on the 5-
phenyl ring (as opposed to the 3-phenyl ring).20 We thus
chose as substrates for halogenation a series of com-
pounds (1a–e, Scheme 1) with varying substituents (i.e.,
R = H, OMe, Me, Br, or CF3) at the para-position of the 5-
phenyl ring. As these substituents range from strongly ac-
tivating (OMe) to strongly deactivating (CF3), these sub-
strates were expected to vary somewhat in regards to their
reactivity towards halogenation.
1c
nated with either Cl2 or HCl/H2O2,10 have been bromi-
nated with Br2 in the presence of either AgSO4/H2SO411 or
12
HNO3,12 and have been iodinated with I2/HNO3 and
ICl.13 In addition to the use of potentially hazardous re-
agents (particularly on a large scale), these chlorination
and bromination conditions are occasionally limited by
the formation of addition products subsequent to substitu-
tion.10,14
X
NXS, AcOH
With the aim of developing improved procedures for the
C-4 halogenation of 3,5-diarylisoxazoles, we have thus
explored the use of N-halosuccinimides (i.e., NCS, NBS,
NIS) as more convenient and milder sources of electro-
philic halogen. As a result of their convenience in han-
N
N
O
O
(plus H2SO4 or
TFA in some
cases)
R
R
2a-e X=Br
3a-e X=Cl
4a-e X=I
1a-e
a R = H; b R = OMe; c R = Me; d R = Br; e R = CF3
Synthesis 2003, No. 10, Print: 21 07 2003.
Art Id.1437-210X,E;2003,0,10,1586,1590,ftx,en;M00903SS.pdf.
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

PAPER
Convenient and Improved Halogenation of 3,5-Diarylisoxazoles Using N-Halosuccinimides
1587
Table 1 Results for Halogenation of Diarylisoxazoles 1a–e with
NXS in Refluxing HOAc
Bromination
In preliminary reactions, we found that isoxazoles 1a–c
could indeed be regioselectively brominated at the C-4
position in 3–6 h by heating with NBS in DMF at 130–
140 °C. However, bromination of the deactivated bromo-
or trifluoromethyl-substituted isoxazoles 1d–e under
these conditions proceeded quite sluggishly, with only
minimal conversions observed after prolonged heating.
As NBS has been activated by protonation with various
acids,16 we thus turned to refluxing acetic acid as solvent
in place of DMF. With this single change, we found that
bromination of the bromo-substituted isoxazole 1d was
complete in only 1.5 h (Table 1). Bromination of the tri-
fluoromethyl-substituted isoxazole 1e, on the other hand,
remained sluggish and ultimately required excess NBS (2
equiv) and an extended reaction time (8 h) to go to com-
pletion.
Prod- X
uct
R
Equiv Added Reaction Yieldb Mp
NXS Acida
Time (h) (%)
(°C)
2a Br
H
1.1
”
1.5
1.5
2.5
1.5
8
72
52
55
86
78
80
37
59
88
70
88
97
76
59
84
132–134c
141.5–142
114–115
2b Br OMe
2c Br Me
2d Br Br
2e Br CF3
”
”
118–119.5
123.5–124
84–85d
2
3a Cl
H
1.1
”
1.5
5
3b Cl OMe
3c Cl Me
3d Cl Br
3e Cl CF3
109.5–110.5
108–109
1.5
1.1
3
H2SO4 5.5
H2SO4
2
110.5–111.5
122–122.5
176.5–177.5e
158.5–159.5
90.5–91
Based on these results, the bromination of the more acti-
vated isoxazoles 1a–c was repeated using acetic acid as
solvent. With this change, we observed a noticeable de-
crease in the time required for complete bromination com-
pared to reaction in DMF (i.e., from ca. 3–6 h to 1–2 h).
H2SO4 10
3
4a
4b
I
I
I
I
I
H
1.5
”
OMe
Me
Br
TFA
3f
3
Thus, the use of acetic acid appears to clearly accelerate 4c
the bromination of 3,5-diarylisoxazoles with NBS.
1.8
2
4d
TFA
TFA
3
151.5–152
170–170.5
4e
CF3
4
10
Chlorination
a The addition of H2SO4 (3–4 drops) or trifluoroacetic acid (30 drops/
5mL HOAc) was required for complete halogenation of certain sub-
strates.
Based on the bromination results, the attempted chlorina-
tion of isoxazoles 1a–d using N-chlorosuccinimide (NCS)
(1.1 equiv) was initially performed in refluxing acetic ac-
id. In general, chlorination under these conditions pro-
ceeded noticeably slower than did bromination with NBS,
and only parent isoxazole 1a and the activated OMe-sub-
stituted isoxazole 1b could be efficiently chlorinated. In
contrast, chlorination of the other isoxazoles (1c–e) was
generally very slow and did not proceed to completion
even with extended reaction times. While the diminished
reactivity of 1d–e towards NCS is likely due to the pres-
ence of the deactivating bromo and trifluoromethyl
groups, the reason for the diminished reactivity of the me-
thyl-substituted isoxazole 1c is not readily apparent. It
should be noted that by TLC no benzylic chlorination, or
any other competing reaction, was detected in the case of
1c.
b Yield following recrystallization from EtOH or EtOH–H2O.
e Lit. mp 171–172 °C.12
c Lit. mp 132.5–133.5 °C.12
d Lit. mp 84 °C.10
f Reaction was performed at r.t.
Iodination
There have been reports of both the success2 and failure18
of the iodination of a 3,5-diarylisoxazole with N-iodosuc-
cinimide (NIS) in DMF. In our work, we found that the
parent isoxazole 1a and the methyl-substituted isoxazole
1c were readily iodinated in just a few hours upon reaction
with NIS in refluxing acetic acid. As a notable difference
from the NBS and NCS reactions, a larger excess of NIS
was required for complete iodination of each isoxazole
due to substantial decomposition of NIS to elemental io-
dine during the reaction.
For these less reactive isoxazoles, the use of a strong-acid
catalyst was examined, and this was found to lead to a sig-
nificant improvement in reaction outcome. Thus, with the
addition of a catalytic amount of sulfuric acid (3–4 drops),
the chlorination of isoxazoles 1c–d with NCS (1.1–1.5
equiv) was complete in just a few hours (Table 1). How-
ever, the trifluoromethyl-substituted isoxazole 1e again
proved least reactive towards halogenation, still requiring
an excess of NCS (3 equiv) and an extended reaction time
(10 h) to be completely chlorinated.
In contrast to the successful iodination of 1a and 1c, the
reaction of isoxazoles 1b and 1d,e with NIS under the
same conditions led to only partial conversion to iodinated
product. Interestingly, in the case of methoxy-substituted
isoxazole 1b, we observed that prolonged heating actually
resulted in nearly complete reconversion (deiodination) of
product to starting material as judged by TLC. It thus ap-
pears that proto-deiodination is a competing process with
Synthesis 2003, No. 10, 1586–1590 © Thieme Stuttgart · New York

1588
R. A. Day et al.
PAPER
this more activated substrate. Indeed, such deiodination activated phenyl ring to give a mixture of compound 5 and
may have been the cause of the previously reported failure deiodinated parent 1b. Pure 5 was isolated in 10% yield
at iodination of a diarylisoxazole with NIS.18 On the other by recrystallization.
hand, the incomplete iodination of bromo- and trifluoro-
methyl substituted isoxazoles 1d,e appears to be simply
due to the diminished reactivity of these substrates.
After much experimentation, we ultimately found that the
methoxy-substituted isoxazole 1b could be efficiently io-
dinated with NIS without deiodination by stirring at room
temperature in a mixture of acetic and trifluoroacetic ac-
id.17 Similarly, deactivated isoxazoles 1d,e were readily
iodinated by refluxing with NIS in the same acid mixture,
although the trifluoromethyl-substituted isoxazole re-
quired an even larger excess of NIS (4 equiv). In each of
these cases, the trifluoroacetic acid apparently serves to
activate the NIS by protonation,17 but does not lead to sub-
sequent deiodination.
As summarized in Table 1, the use of N-halosuccinimides
(NCS, NBS, or NIS) gave the halogenated isoxazoles 2–4
in good to excellent yields. In all cases, halogenation was
highly regioselective for C-4 of the isoxazole ring, with
essentially clean conversion to a single, more lipophilic
product typically observed by TLC. This includes when a
strong acid was used for activation of the N-halosuccinim-
ide, as well as when an activated phenyl ring was present.
Once halogenation was complete, simple dilution of the
reaction mixture with water (or aqueous thiosulfate to re-
move iodine in the case of iodination) gave the nearly pure
product, which was collected and recrystallized from eth-
anol or ethanol–water. As 10–25% of product was often
lost upon recrystallization, reported yields may not be op-
timized.
Scheme 2
The mechanism for deiodination apparently involves C-4
protonation, followed by attack of iodide by acetic acid to
form iodine acetate22,23 and regenerate the parent isox-
azole. In the case of 4b, iodine acetate apparently served
as an iodinating agent22 to give compound 5. It is notewor-
thy that the 4-bromoisoxazoles were not debrominated
under the same conditions.
This appears to be the first report of the protodeiodination
of any iodoisoxazole, although it has been observed with
other aromatic systems.24 In some cases, as with
benzene25 and imidazole26 derivatives, an easily removed
halogen is used as a protecting group to block electro-
philic attack at a more reactive position. The current find-
ing suggests the same strategy (i.e., blocking the reactive
C-4 position) may be possible with less substituted isox-
azoles, although its application remains to be shown.
Each halogenated isoxazole prepared was characterized
1
by H NMR, 13C NMR, IR, and elemental analysis. The
location of the halogen was confirmed by the absence of
both the singlet for the C-4 proton in the 1H NMR and the
strong isoxazole C–H stretch at ca. 3100–3120 cm–1 in the
IR, as well as by a distinct shift for C-4 in the 13C NMR.
Thus, while the signal for C-4 of the parent isoxazoles is
found at ca. 96–100 ppm in the 13C NMR,20 this signal is
found at ca. 102–106 ppm for the chloroisoxazoles, at ca.
88–92 ppm for the bromoisoxazoles, and at ca. 55–61
ppm for the iodoisoxazoles. Such a large upfield shift for
the 4-iodoisoxazoles is consistent with that found with the
analogous 4-iodopyrazoles.21
In conclusion, we have developed convenient and im-
proved procedures for halogenation of 3,5-diarylisox-
azoles with N-halosuccinimides (NBS, NCS, or NIS). Key
to the success of many of these halogenations is the use of
an acid catalyst for activation of the N-halosuccinimide,
particularly for those isoxazoles containing deactivating
substituents on the phenyl rings. Finally, the 4-iodoisox-
azoles were found to undergo protodeiodination back to
the parent isoxazoles upon heating in acetic acid/sulfuric
acid.
Deiodination
Starting isoxazoles were prepared from the appropriate chalcone
derivative via standard chemistry27 and characterized by 13C NMR
as outlined in the literature.20 N-Halosuccinimides were obtained
from Aldrich Chemical Co. and used as received. All NMR spectra
were recorded on a Varian Unity+300 instrument at 30 °C. Unless
otherwise noted, DMSO-d6 was used as NMR solvent, with the sol-
vent peak serving as reference (2.49 ppm for 1H NMR and 39.5 ppm
for 13C NMR). IR spectra were obtained on a Perkin One instrument
(KBr diffuse reflectance). Elemental analyses were obtained on a
Perkin Elmer 2400 (Series II) analyzer.
With iodoisoxazoles 4a–e in hand, we further explored
the acid induced deiodination of these compounds as pre-
viously observed in the synthesis of 4b. While the iodo
compounds proved stable to refluxing acetic acid, the ad-
dition of a few drops of sulfuric acid to the refluxing solu-
tion led to a slow, yet complete, deiodination back to the
parent isoxazoles (Scheme 2). In the deiodination of 4b,
the iodide interestingly underwent partial migration to the
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Convenient and Improved Halogenation of 3,5-Diarylisoxazoles Using N-Halosuccinimides
1589
Table 2 IR and NMR Spectral Data for 4-Haloisoxazoles 2–4
Pro- IR (KBr)
ducta cm–1
1H NMR (DMSO-d6)
, J (Hz)
13C NMR (DMSO-d6)
2a
3056, 1613, 1589, 1570, 1446, 1114,
768, 707, 693, 517
7.58–7.66 (m, 6 H), 7.78–8.81 (m, 2 H), 8.01– 89.8, 125.9, 126.8, 127.2, 128.4, 129.0,
8.04 (m, 2 H) 129.3, 130.5, 131.2, 161.9, 165.5
2b
3006, 2972, 2839, 1614, 1504, 1264,
1181, 1103, 1025, 831, 697, 568, 527
3.85 (s, 3 H), 7.16 (d, J = 9.0, 2 H), 7.57–7.59 55.4, 88.2, 114.7, 118.3, 127.3, 128.3,
(m, 3 H), 7.77–7.80 (m, 2 H), 7.98 (d, J = 9.0, 128.4, 128.8, 130.4, 161.2, 161.7, 165.4
2 H)
2c
3053, 2915, 2869, 1614, 1501, 1444,
1389, 1104, 991, 820, 696, 513
2.40 (s, 3 H), 7.43 (d, J = 8.0, 2 H), 7.58–7.60 21.0, 89.1, 123.2, 126.6, 127.2, 128.3,
(m, 3 H), 7.78–7.81 (m, 2 H), 7.93 (d, J = 8.1, 128.9, 129.7, 130.4, 141.2, 161.7, 165.5
2 H)
2d
2e
3064, 1601, 1485, 1402, 1383, 1100,
1075, 833, 696, 508
7.57–7.61 (m, 3 H), 7.77–7.86 (m, 4 H), 7.97 90.4, 124.8, 125.1, 127.0, 128.4, 128.7,
(d, 2 H)
129.0, 130.6, 132.4, 162.0, 164.5
3057, 1621, 1445, 1412, 1328, 1171,
1117, 1103, 1068, 844, 771, 708
7.58–7.61 (m, 3 H), 7.79–7.82 (m, 2 H), 8.00 91.5, 121.9, 125.5, 126.1, 126.2, 126.2,
(d, J = 8.4, 2 H), 8.25 (d, J = 8.3, 2 H)
126.3, 126.9, 127.6, 128.4, 128.9, 129.6,
130.6, 130.6, 131.0, 162.0, 163.9
3a
3b
3059, 1616, 1571, 1493, 1448, 1399,
1127, 769, 707, 692
7.58–7.63 (m, 6 H), 7.82–7.85 (m, 2 H), 7.99– 104.1, 125.5, 126.3, 126.5, 128.0, 129.0,
8.03 (m, 2 H) 129.3, 130.6, 131.2, 160.4, 163.8
3057, 3009, 2972, 2840, 1614, 1505,
1444, 1393, 1305, 1259, 1108, 1026,
832, 698
3.85 (s, 3 H), 7.16 (d, J = 9.0, 2 H), 7.57–7.59 55.4, 102.5, 114.8, 117.9, 126.7, 128.0,
(m, 3 H), 7.80–7.83 (m, 2 H), 7.96 (d, J = 9.0, 128.0, 129.0, 130.5, 160.2, 161.2, 163.8
2 H).
3c
3068, 2916, 1615, 1503, 1445, 1392,
1116, 1007, 821, 770, 695
2.39 (s, 3 H), 7.42 (d, J = 7.8, 2 H), 7.57–7.60 21.0, 103.5, 122.8, 126.2, 126.6, 128.0,
(m, 3 H), 7.80–7.83 (m, 2 H), 7.90 (d, J = 8.0, 129.0, 129.8, 130.6, 141.2, 160.3, 163.9
2 H)
3d
3e
3090, 3060, 1604, 1486, 1458, 1403,
1390, 1011, 831, 771, 719, 696, 485
7.57–7.61 (m, 3 H), 7.79–7.84 (m, 4 H), 7.94 104.6, 124.6, 124.8, 126.4, 128.0, 128.2,
(d, 2 H)
129.1, 130.7, 132.4, 160.4, 162.8
3060, 1601, 1446, 1414, 1328, 1172,
1108, 845, 771, 708
7.59–7.61 (m, 3 H), 7.82–7.84 (m, 2 H), 7.99 105.8, 121.9, 125.5, 126.2, 126.2, 126.3,
(d, J = 8.3, 2 H), 8.22 (d, J = 8.2, 2 H)
126.3, 127.1, 128.0, 129.1, 130.5, 130.8,
131.0, 160.5, 162.3
4a
4b
3053, 1610, 1583, 1564, 1486, 1445,
1389, 1107, 983, 765, 693
7.57–7.62 (m, 6 H), 7.73–7.76 (m, 2 H), 8.01– 59.5, 126.8, 127.5, 128.5, 128.8, 128.8,
8.04 (m, 2 H) 129.1, 130.2, 131.0, 164.7, 168.5
3060, 3004, 2977, 2943, 2837, 1611,
3.85 (s, 3 H), 7.16 (d, J = 9.0, 2 H), 7.56–7.58 55.4, 57.6, 114.5, 119.1, 128.6, 128.7,
1500, 1258, 1181, 1094, 1023, 981, 831, (m, 3 H), 7.71–7.74 (m, 2 H), 7.98 (d, J = 9.0, 128.7, 129.1, 130.1, 161.1, 164.6, 168.4
697
2 H)
4c
3063, 2911, 1611, 1500, 1380, 1097,
982, 819, 695, 512
2.40 (s, 3 H), 7.42 (d, J = 8.1, 2 H), 7.56–7.58 21.0, 58.6, 124.0, 127.3, 128.5, 128.7,
(m, 3 H), 7.71–7.75 (m, 2 H), 7.92 (d, J = 8.1, 128.7, 129.6, 130.1, 140.9, 164.6, 168.6
2 H)
4d
4e
3082, 3054, 1603, 1483, 1456, 1397,
1094, 983, 830, 770, 720, 695, 514
7.55–7.60 (m, 3 H), 7.71–7.75 (m, 2 H), 7.82 60.0, 124.5, 125.9, 128.3, 128.7, 129.3,
(d, J = 9.0, 2 H), 7.97 (d, J = 9.0, 2 H)
130.2, 132.1, 164.8, 167.4
3063, 1571, 1408, 1330, 1167, 1127,
1098, 1068, 843, 771, 708, 697
7.57–7.60 (m, 3 H), 7.73–7.76 (m, 2 H), 7.99 61.3, 122.0, 125.6, 126.0, 126.0, 126.1,
(d, J = 8.4, 2 H), 8.25 (d, J = 8.3, 2 H)
126.1, 128.2, 128.3, 128.7, 128.8, 130.0,
130.3, 130.4, 130.6, 130.9, 164.9, 167.0
a Satisfactory microanalysis were obtained: C,±0.29; H,±0.19; N,±0.19.
4-Halo-3,5-diarylisoxazoles 2-4; General Procedure
excess NXS, and thus the reaction sequence was repeated using a
strong acid catalyst. Once halogenation was complete, the solution
was diluted with H2O (or aqueous Na2S2O3 solution in the case of
iodination), and the resulting precipitate was collected, washed with
water, and recrystallized from EtOH or EtOH–H2O. Yields and an-
alytical data are given in Table 1 and Table 2. As noted in Table 1,
iodination of 1b was performed at r.t. To minimize decomposition
of NIS, all iodination reactions were protected from light by alumi-
num foil.
A solution of the isoxazole 1a–e (0.5–1.5 mmol) and the N-halosuc-
cinimide (1.1 equiv of NBS or NCS, or 1.5 equiv of NIS) in HOAc
(5 mL/mmol of isoxazole) was heated at gentle reflux (open con-
denser) with the reaction progress followed by TLC (EtOAc–hex-
anes). If halogenation was judged to no longer be proceeding,
additional NXS was added in increments until starting material was
consumed (total NXS and reaction times given in Table 1). With
some substrates, halogenation remained sluggish with addition of
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1590
R. A. Day et al.
PAPER
Deiodination of 4-Iodoisoxazoles 4; General Procedure
To the 4-iodoisoxazole (0.33 mmol) in HOAc (2 ml) was added 5–
6 drops of concentrated H2SO4 and the mixture was heated at gentle
reflux until TLC analysis showed deiodination to be complete (24–
48 h). The solution was then diluted with H2O and the resulting sol-
id was collected, rinsed with H2O, and air dried (yield: 80–90%).
The structure of the product was confirmed by comparison of the 1H
NMR, IR, and TLC to that of authentic samples. With 4b, a mixture
of 1b and 5 was obtained after 48 h, with 5 predominating. Slow re-
crystallization from EtOH–H2O gave pure 5 as colorless needles in
10% yield.
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(9) (a) Calle, M.; Cuadrado, P.; Gonzalez-Nogal, A. M.; Valero,
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Johansen, T. N.; Krogsgaard-Larsen, P. Tetrahedron 2001,
57, 2195. (c) Labadie, S. S. Synth. Commun. 1994, 25, 709.
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1765.
5-(3-Iodo-4-methoxy)-3-phenylisoxazole (5)
Mp 143.5–144.5 °C.
IR: 3096, 3059, 2975, 2944, 1610, 1492, 1466, 1280, 1269, 757,
686 cm–1.
1H NMR (CDCl3): = 3.95 (s, 3 H), 6.73 (s, 1 H), 6.91 (d, J = 8.7
Hz, 1 H), 7.47–7.50 (m, 3 H), 7.80–7.87 (m, 3 H), 8.24 (d, J = 1.5
Hz, 1 H).
13C NMR: = 56.7, 86.9, 97.9, 111.9, 121.3, 126.5, 127.2, 128.6,
129.1, 130.3, 136.0, 159.3, 162.6, 168.2.
(12) Kochetkov, N. K.; Sokolov, S. D.; Vagurtova, N. M. Zh.
Obshch. Khim. 1961, 31, 2326.
(13) Kromann, H.; Slok, F. A.; Johansen, T. N.; Krogsgaard-
Larsen, P. Tetrahedron 2001, 57, 2195.
Anal. Calcd for C16H12INO2 (377.18): C, 50.95; H, 3.21; N, 3.71.
Found: C, 51.07; 3.18; N, 3.60.
(14) Gaudiano, G.; Ricca, A.; Merlini, L. Gazz. Chim. Ital. 1959,
89, 2466.
Acknowledgment
(15) (a) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.;
Urbano, A. Tetrahedron Lett. 1996, 37, 4081.
(b) Oberhauser, T. J. Org. Chem. 1997, 62, 4504.
(16) Brown, W. D.; Gouliaev, A. H. Synthesis 2002, 83.
(17) Castanet, A.-S.; Colobert, F.; Broutin, P.-E. Tetrahedron
Lett. 2002, 43, 5047.
We thank the Georgia State University Research Fund and the
Georgia Research Alliance for fiancial support. We also thank the
students in the CHEM 3110 lab that performed preliminary halo-
genations, including Christine Walker, Nadya Jiwani and James
Yost.
(18) Sakakibara, T.; Kume, T.; Hase, T. Chem. Express 1989, 4,
85.
(19) Comprehensive Heterocyclic Chemistry II, Vol. 3;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier Science: New York, 1996, 237.
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W. J. Heterocycl. Chem. 1981, 18, 795.
(21) Felding, J.; Kristensen, J.; Bjerregaard, T.; Sander, L.;
Vedso, P.; Begtrup, M. J. Org. Chem. 1999, 64, 4196.
(22) Chen, E. M.; Keefer, R. M.; Andrews, L. J. J. Am. Chem.
Soc. 1967, 89, 428.
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Synthesis 2003, No. 10, 1586–1590 © Thieme Stuttgart · New York