Oxidation of 1-amidoalkyl-2-naphthols using (diacetoxyiodo)benzene: Unusual- formation of 1-Arylnaphtho[1,2-d]isoxazoles

Article abstract of DOI:10.1055/s-0033-1338590

The reactions of 1-amidoalkyl-2-naphthols with (diacetoxyiodo)benzene results in the unusual formation of 1-arylnaphtho[1,2-d]isoxazoles. This procedure demonstrates a useful application of (diacetoxyiodo)benzene for the oxidative formation of an N-O bond. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338590

752▌
PAPER
pOapxeridation of 1-Amidoalkyl-2-naphthols Using (Diacetoxyiodo)benzene:
Unusual Formation of 1-Arylnaphtho[1,2-d]isoxazoles
1-Arylnaphtho[1,2-d]isoxazoles
Amol V. Shelke, Bhagyashree Y. Bhong, Nandkishor N. Karade*
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra 440 033, India
Fax +91(712)2532841; E-mail: nnkarade@gmail.com
Received: 30.09.2013; Accepted after revision: 08.01.2014
(Scheme 1).8 Some of these strategies for the synthesis of
1,2-benzisoxazole derivatives have certain limitations
such as the requirement for strong basic conditions for in-
tramolecular cyclization,9 involve competitive Beckmann
rearrangement and deoximation side reactions,10 and the
stereochemical requirement for the oxime as the Z-isomer,
exclusively.8 Therefore, the development of new methods
for the synthesis of 1,2-benzisoxazole derivatives are
highly desirable.
Abstract: The reactions of 1-amidoalkyl-2-naphthols with (diace-
toxyiodo)benzene results in the unusual formation of 1-arylnaph-
tho[1,2-d]isoxazoles. This procedure demonstrates
a useful
application of (diacetoxyiodo)benzene for the oxidative formation
of an N–O bond.
Key words: 1,2-benzisoxazole, hypervalent iodine, 1-amidoalkyl-
2-naphthols, 2-hydroxyaryl ketoximes, phenolic oxidation
The various pharmaceutical and therapeutic agents con-
taining a 1,2-benzisoxazole moiety show a wide spectrum
of biological activity including antimicrobial, antithrom-
botic, anticancer, anti-HIV and antitumor (Figure 1).1
Zonisamide, an anticonvulsant,2 and the antipsychotics,
risperidone3 and paliperidone,4 are the most popular de-
rivatives of 1,2-benzisoxazole, which have been marketed
as pharmaceutical drugs. The 1,2-benzisoxazole moiety is
structurally isosteric with the indole nucleus, which thus
allows it to bind to biologically important enzymes in a
manner similar to indole derivatives.5 Therefore, the 1,2-
benzisoxazole unit has been employed widely as a carrier
for pharmacophoric moieties in the search for potential
drugs.
R
N
OH
Br
C–O bond formation
R
R
R
N–O bond
formation
1,3-dipolar
cycloaddition
LG
N
N
O
N
OH
O
Scheme 1 Reported methods for the preparation of 1,2-benzisoxa-
zoles
Hypervalent iodine reagents have gained considerable
popularity in modern organic synthesis due to their com-
mercial availability, mild reaction conditions employed,
and their reactivity, which is similar to the heavy metal
oxidants (Pb, Hg and Tl), but with fewer toxicity effects.11
(Diacetoxyiodo)benzene [PhI(OAc)2] is a parent hyperva-
lent iodine(III) reagent, which acts as a two-electron oxi-
dant in a variety of oxidative transformations.12 The
oxidation of phenolic compounds using hypervalent io-
dine(III) reagents is a very fertile area for the synthesis of
highly substituted cyclohexadienones.13 The appropriate
substitution pattern at the ortho or para positions, with re-
spect to the phenolic group, also permits the synthesis of
spiro compounds via intramolecular trapping of the oxi-
dized phenol intermediates with nucleophilic species.14
R
N
O
S
N
N
NH2
F
O
O
N
N
O
O
zonisamide
risperidone (R = H)
paliperidone (R = OH)
(antipsychotic)
(anticonvulsant)
Figure 1 Pharmaceutical drugs containing a 1,2-benzisoxazole moi-
ety
To date, the literature has reported the following methods
for the synthesis of 1,2-benzisoxazole derivatives: (a) for-
mation of an N–O bond by intramolecular cyclization of
o-hydroxybenzyloxime sulfonates or acetates,6 (b) 1,3-di-
polar cycloaddition of in situ generated benzyne with ni-
trile oxides,7 and (c) intramolecular C–O cross-coupling
reactions of the Z-isomer of o-haloacetophenone oximes
There have been several previous reports on the synthesis
of 1-amidoalkyl-2-naphthols via the three component
condensation of β-naphthol, an aldehyde and urea under
acidic conditions.15 1-Amidoalkyl-2-naphthols are typical
phenolic compounds with a primary amide-type moiety at
the benzylic position. A literature survey revealed that the
oxidation of 2-hydroxy-1-naphthaldehyde oxime and 2-
hydroxyaryl ketoximes with (diacetoxyiodo)benzene re-
sulted in the formation of alkoxynaphtho[1,8-de][1,2]ox-
azin-4(3aH)-ones and 1,2-benzisoxazole 2-oxides,
SYNTHESIS 2014, 46, 0752–0756
Advanced online publication: 07.02.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338590; Art ID: SS-2013-T0651-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Arylnaphtho[1,2-d]isoxazoles
753
respectively. Since the structures of 2-hydroxy-1-naph- without formation of any dearomatized or Hofmann-type
thaldehyde oxime16 and 2-hydroxyaryl ketoximes17 are rearrangement products.
comparable with those of 1-amidoalkyl-2-naphthols, we
Table 1 Screening of the Conditions for the Oxidation of 1a
were interested to discover the outcome of their reactions
with (diacetoxyiodo)benzene. We envisaged that the reac-
Entry
Solvent
PhI(OAc)2
(equiv)
Time
(h)
Yield
(%)a
tion of 1-amidoalkyl-2-naphthols with a hypervalent io-
dine(III) reagent could induce either a phenolic oxidation
followed by trapping of the nucleophilic oxygen of the
amide to give a spiro compound, or a Hoffmann-type re-
arrangement.18 However, we observed that the reaction of
a 1-amidoalkyl-2-naphthol with (diacetoxyiodo)benzene
resulted in the formation of an unusual product, a naph-
tho[1,2-d]isoxazole (Scheme 2). Owing to the simplicity
of 1-amidoalkyl-2-naphthol synthesis, the present meth-
odology represents a new strategy for the synthesis of
naphtho[1,2-d]isoxazoles using (diacetoxyiodo)benzene
as an oxidant under mild conditions.
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
DCE
1.2
1.5
1.5
1.2
1.5
1.2
1.2
1.2
4
2
4
4
4
6
6
8
67
72
72
61
66
59
57
54
DCE
CHCl3
MeCN
MeOH
previous work:
a Yield of isolated product.
O
N
OH
PhI(OAc)2
ROH
N
With these results in hand, we next examined the scope
and generality of the method using different 1-amido-
alkyl-2-naphthols and dichloromethane as the solvent. As
shown in Table 2, this methodology was compatible with
a variety of substituents present on the aromatic ring lo-
cated at position 3. In all the cases, good to excellent
yields were obtained.
OR
O
OH
N
R
R
OH
PhI(OAc)2
N
O
MeOH or AcOH
O
OH
present work:
Table 2 Synthesis of 1-Arylnaphtho[1,2-d]isoxazoles from 1-Ami-
doalkyl-2-naphthols Using (Diacetoxyiodo)benzene
R
PhI(OAc)2
CH2Cl2
O
R
PhI(OAc)2
Ar
O
N
NH2
Ar
N
H
CH2Cl2
O
N
NH2
OH
1a–l
H
N
2a–l
OH
O
1a–l
2a–l
Scheme 2 Oxidation of 2-hydroxy-1-naphthaldehyde oxime, 2-hy-
droxyaryl ketoximes and 1-amidoalkyl-2-naphthols with (diacetoxy-
iodo)benzene
Entry
Substrate Ar
Product
Yield (%)a
1
2
1a
1b
1c
1d
1e
1f
C6H5
2a
2b
2c
2d
2e
2f
71
67
57
70
68
74
59
63
72
61
67
74
The desired starting materials, 1-amidoalkyl-2-naphthols
1a–l, were prepared via the three-component condensa-
tion of β-naphthol, an aldehyde and urea by employing a
well-known literature method.15a The reaction of 1-[(2-
hydroxynaphthalen-1-yl)(phenyl)methylurea (1a) (1
mmol) with (diacetoxyiodo)benzene (1.2 mmol) was
studied as a model reaction. Several solvents (CH2Cl2,
CHCl3, DCE, MeCN and MeOH) were screened and the
number of equivalents of (diacetoxyiodo)benzene were
also varied in the oxidation reactions of 1a. The reaction
proceeded in all the examined solvents. However, the best
solvent proved to be dichloromethane, while the amount
of the oxidant required for a satisfactory yield of product
was 1.5 equivalents with respect to the substrate (Table 1,
entries 1–3).17 It is important to note that the oxidation of
1a in a nucleophilic solvent such as methanol (Table 1,
entry 8) was also carried out using 1.2 equivalents of (di-
acetoxyiodo)benzene, and once again 2a was obtained
2-MeC6H4
4-MeC6H4
3-MeOC6H4
3-FC6H4
3
4
5
6
2-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
2,3-Cl2C6H3
2,4-Cl2C6H3
7
1g
1h
1i
2g
2h
2i
8
9
10
11
12
1j
2j
1k
1l
2k
2l
a Yield of isolated product after column chromatography.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 752–756

754
A. V. Shelke et al.
PAPER
Oxidation; General Procedure
A plausible mechanism is depicted in Scheme 3 for the
formation of unusual product 2. The more nucleophilic
phenolic oxygen of 1 may undergo ligand association/dis-
sociation to form intermediate 3. The dearomatization of
3 is inhibited due to the formation of 4.19 The propensity
for compound 4 to undergo reductive elimination of iodo-
benzene results in the creation of the key N–O bond to
yield 5, which finally undergoes aromatization along with
the elimination of formamide to give the isoxazole 2.
To a stirred solution of the appropriate 1-amidoalkyl-2-naphthol
1a–l (2 mmol) in CH2Cl2 (15 mL) was added PhI(OAc)2 (3 mmol),
and the mixture was stirred for 2 h at r.t. The progress of the reaction
was monitored by TLC. After completion of the reaction, the sol-
vent was evaporated under reduced pressure and the residue was pu-
rified by flash column chromatography (EtOAc–PE, 0.5:99.5) to
afford products 2a–l.
1-Phenylnaphtho[1,2-d]isoxazole (2a)
Yield: 71% (353 mg); white solid; mp 172–174 °C.
IR (neat): 3046, 1635, 1587, 1486, 1236, 816, 772 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.49–7.52 (m, 4 H), 7.62–7.68 (m,
2 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.92 (d, J = 8.2 Hz, 1 H), 8.28–8.30
(m, 2 H), 8.57 (d, J = 8.2 Hz, 1 H).
R
R
ligand
exchange
O
O
13C NMR (100 MHz, CDCl3): δ = 110.8, 122.3, 125.4, 126.0, 126.6,
126.9, 127.3, 127.5, 128.6, 128.9, 131.0, 131.2, 137.6, 148.0, 162.3.
HRMS (ESI): m/z [M + H]+ calcd for C17H12NO: 246.09134; found:
246.20585.
– AcOH
N
NH2
N
H
NH2
H
Ph
Ph
OAc
OH
O
I
I
3
1
OAc
OAc
1-(o-Tolyl)naphtho[1,2-d]isoxazole (2b)
R
O
ligand
exchange
reductive
elimination
Yield: 67% (347 mg); white solid; mp 78–80 °C.
IR (neat): 2919, 2849, 1544, 1471, 1371, 1271, 1231, 1203, 1084,
1027, 1008, 922, 873, 802, 773, 752, 725, 702, 627, 561 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.86 (s, 3 H), 7.31–7.37 (m, 3 H),
7.51 (t, J = 8.0 Hz, 1 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.75 (d, J = 8.8
Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 8.21
(d, J = 8.0 Hz, 1 H), 8.58 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.3, 110.8, 122.3, 125.3, 125.9,
126.1, 126.5, 126.7, 126.9, 128.5, 129.7, 130.5, 131.1, 131.8, 137.5,
138.6, 147.5, 162.6.
– AcOH
– PhI
N
I
NH2
O
4
Ph
H
R
aromatization
– HCONH2
R
NH2
N
N
O
O
O
HRMS (ESI): m/z [M + H]+ calcd for C18H14NO: 260.1070; found:
5
2
260.1067.
Scheme 3 A plausible mechanism
1-(p-Tolyl)naphtho[1,2-d]isoxazole (2c)
Yield: 57% (296 mg); white solid; mp 146–148 °C.
In conclusion, we have described an unusual, but direct
and useful method for the synthesis of 1-arylnaphtho[1,2-
d]isoxazoles starting from 1-amidoalkyl-2-naphthols
using (diacetoxyiodo)benzene as the oxidant. This
procedure exemplifies another application of (diacetoxy-
iodo)benzene, demonstrating direct N–O bond formation,
in contrast to the earlier reports on oxidations of 2-hy-
droxy-1-naphthaldehyde oxime and 2-hydroxyaryl
ketoximes.
IR (neat): 2919, 2849, 1544, 1488, 1455, 1371, 1271, 1231, 1203,
1163, 1084, 1027, 1008, 922, 867, 773, 752, 725, 702, 554 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 7.33 (d, J = 8.0 Hz,
2 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.70 (d,
J = 8.0 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1
H), 8.20 (d, J = 8.0 Hz, 2 H), 8.58 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.7, 110.8, 122.2, 124.7, 125.3,
125.7, 126.5, 126.9, 127.3, 128.5, 129.2, 129.6, 130.2, 131.2, 137.6,
141.5, 147.9, 162.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H14NO: 260.1070; found:
260.1068.
Unless otherwise stated, all chemicals and reagents were used as re-
ceived. Petroleum ether (PE) refers to the fraction boiling in the 60–
80 °C range. All reactions were monitored by thin-layer chromatog-
raphy using Merck silica gel 60 F254 pre-coated plates (0.25 mm),
and samples were made visual under UV light. Flash column chro-
matography was performed using Rankem silica gel (230–400
mesh, particle size 0.040–0.063 mm). Reaction samples were ana-
lyzed on a Shimadzu LC 2010 LC–MS using a C18 column. Melt-
ing points were obtained using an MIC melting point apparatus. IR
spectra were recorded on a Bruker Alpha T spectrophotometer in
1-(3-Methoxyphenyl)naphtho[1,2-d]isoxazole (2d)
Yield: 70% (385 mg); white solid; mp 126–128 °C.
IR (neat): 2919, 2851, 1557, 1489, 1373, 1271, 1236, 1175, 1088,
1052, 1016, 928, 877, 815, 761, 739, 724, 642 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 7.00 (d, J = 8.0 Hz,
1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.62 (t,
J = 8.0 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.79 (s, 1 H), 7.84–7.90
(m, 2 H), 8.56 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 55.5, 110.8, 111.7, 117.7, 119.8,
122.3, 125.3, 126.0, 126.5, 126.9, 128.6, 128.7, 130.0, 131.2, 137.6,
148.0, 159.9, 162.2.
1
ATR mode; wavenumbers are reported in cm–1. H and 13C NMR
spectra were recorded on a Bruker Avance II 400 NMR spectrome-
ter. Data for 1H NMR spectra are reported as follows: chemical shift
(ppm), multiplicity, coupling constant (Hz), integration. Multiplici-
ty qualifier abbreviations are as follows: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet. HRMS was performed using
a Thermo Fisher HRMS-Q Exactive (ORBITRAP) spectrometer.
HRMS (ESI): m/z [M + H]+ calcd for C18H14NO2: 276.1019; found:
276.1018.
1-(3-Fluorophenyl)naphtho[1,2-d]isoxazole (2e)
Yield: 68% (358 mg); white solid; mp 144–148 °C.
Synthesis 2014, 46, 752–756
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Arylnaphtho[1,2-d]isoxazoles
755
IR (neat): 3069, 3050, 2922, 1615, 1592, 1553, 1473, 1446, 1372,
1300, 1248, 1202, 1087, 1061, 1008, 947, 884, 859, 819, 791, 760,
745, 724, 662, 626, 571 cm–1.
(d, J = 8.9 Hz, 1 H), 7.84 (d, J = 8.9 Hz, 1 H), 8.01 (d, J = 8.2 Hz,
1 H), 8.27 (d, J = 7.8 Hz, 1 H), 8.50–8.51 (m, 1 H), 8.59 (d, J = 8.0
Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 7.20 (t, J = 8.9 Hz, 1 H), 7.45–
7.55 (m, 2 H), 7.64–7.69 (m, 2 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.93–
8.00 (m, 2 H), 8.07 (d, J = 8.0 Hz, 1 H), 8.55 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 110.8, 122.2, 123.0, 125.5, 125.8,
126.5, 127.1, 128.6, 129.4, 130.1, 130.4, 131.2, 133.9, 137.5, 148.1,
160.7.
13C NMR (100 MHz, CDCl3): δ = 110.7, 114.1, 114.3, 117.9, 118.1,
122.2, 123.0, 125.5, 126.4, 126.5, 127.1, 128.6, 130.5, 131.2, 137.5,
148.1, 161.7 (d, J = 70 Hz), 164.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H11FNO: 264.0819; found:
264.0817.
HRMS (ESI): m/z [M + H]+ calcd for C17H1181BrNO: 324.00185;
Found: 324.29729.
1-(4-Bromophenyl)naphtho[1,2-d]isoxazole (2j)
Yield: 61% (394 mg); white solid; mp 194–198 °C.
IR (neat): 2919, 1595, 1475, 1372, 1270, 1235, 1202, 1087, 1071,
1048, 1004, 877, 834, 806, 745, 723, 682 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.55 (t, J = 8.0 Hz, 1 H), 7.66–
7.73 (m, 4 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 1 H),
8.18 (d, J = 8.5 Hz, 2 H), 8.56 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 110.7, 122.2, 125.5, 125.7, 126.3,
126.4, 126.5, 127.1, 128.6, 128.7, 131.2, 132.2, 137.5, 148.1, 161.4.
1-(2-Chlorophenyl)naphtho[1,2-d]isoxazole (2f)
Yield: 74% (418 mg); white solid; mp 96–98 °C.
IR (neat): 2917, 2848, 1633, 1601, 1543, 1475, 1398, 1370, 1270,
1235, 1179, 1113, 1084, 1049, 1005, 924, 878, 842, 800, 753, 727,
695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.47 (m, 2 H), 7.54–7.59 (m,
2 H), 7.69 (t, J = 6.0 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.84 (d,
J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 8.22–8.25 (m, 1 H), 8.61
(d, J = 8.0 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H1181BrNO: 325.9998;
found: 325.9987.
13C NMR (100 MHz, CDCl3): δ = 110.9, 122.3, 125.5, 126.5, 126.6,
126.9, 127.1, 128.6, 131.2, 131.3, 131.6, 131.8, 133.2, 137.1, 148.1,
160.3.
1-(2,3-Dichlorophenyl)naphtho[1,2-d]isoxazole (2k)
Yield: 67% (291 mg); white solid; mp 170–172 °C.
IR (neat): 3056, 1662, 1558, 1516, 1442, 1313, 1187, 1155, 1122,
1064, 1008, 1003, 941, 882, 801, 779, 742, 726, 701, 632, 563 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C17H11ClNO: 280.0524;
1H NMR (400 MHz, DMSO-d6): δ = 7.55 (t, J = 8.0 Hz, 1 H), 7.61
(t, J = 8.0 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1
H), 7.90 (d, J = 8.9 Hz, 1 H), 7.98 (d, J = 8.9 Hz, 1 H), 8.08 (d,
J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.48 (d, J = 8.0 Hz, 1 H).
found: 280.0524.
1-(4-Chlorophenyl)naphtho[1,2-d]isoxazole (2g)
Yield: 59% (330 mg); white solid; mp 184–186 °C.
IR (neat): 2920, 2851, 1705, 1596, 1471, 1453, 1369, 1269, 1234,
1203, 1083, 1048, 1003, 878, 832, 798, 742, 725, 693, 632 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.59 (t, J = 8.0 Hz, 1 H), 7.63
(d, J = 8.0 Hz, 2 H), 7.71 (t, J = 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz,
1 H), 7.94 (d, J = 8.0 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 8.27 (d,
J = 8.0 Hz, 2 H), 8.47 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 110.9, 121.5, 125.5, 125.8,
126.9, 127.1, 128.0, 128.0, 128.3, 130.2, 130.4, 130.7, 132.5, 133.9,
136.3, 147.6, 158.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H10Cl2NO: 314.0134;
found: 314.0133.
13C NMR (100 MHz, DMSO-d6): δ = 110.9, 121.5, 125.4, 125.5,
125.7, 126.3, 127.0, 128.4, 128.6, 129.2, 130.8, 136.4, 136.7, 147.6,
160.6.
HRMS (ESI): m/z [M + H]+ calcd for C17H11ClNO: 280.0524;
found: 280.0522.
1-(2,4-Dichlorophenyl)naphtho[1,2-d]isoxazole (2l)
Yield: 74% (321 mg); white solid; mp 162–164 °C.
IR (neat): 2964, 1680, 1653, 1558, 1506, 1456, 1378, 1314, 1209,
1186, 1096, 1033, 1007, 944, 864, 826, 797, 762, 729, 693, 639
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.60 (t, J = 8.0 Hz, 2 H), 7.70
(d, J = 8.0 Hz, 1 H), 7.73 (s, 1 H), 7.88 (d, J = 8.9 Hz, 1 H), 7.96 (d,
J = 8.9 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 7.9 Hz, 1
H), 8.47 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 110.8, 121.5, 124.4, 125.4,
125.8, 126.7, 127.1, 127.6, 128.5, 130.7, 132.5, 133.0, 136.3, 136.4,
147.5, 158.6.
1-(2-Bromophenyl)naphtho[1,2-d]isoxazole (2h)
Yield: 63% (407 mg); white solid; mp 104–106 °C.
IR (neat): 2921, 2852, 1538, 1455, 1373, 1315, 1231, 1095, 1076,
1022, 1003, 931, 802, 755, 726, 687, 642 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.36 (t, J = 8.0 Hz, 1 H), 7.48 (t,
J = 8.0 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H),
7.77 (t, J = 8.0 Hz, 2 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0
Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.60 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 110.9, 121.8, 122.3, 125.5, 126.5,
126.6, 127.1, 127.4, 128.6, 128.7, 131.2, 131.7, 132.1, 134.6, 137.1,
148.1, 160.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H10Cl2NO: 314.0134;
found: 314.0128.
Acknowledgment
HRMS (ESI): m/z [M]+ calcd for C17H1181BrNO: 324.0019; found:
324.0020.
The authors are thankful to the Department of Science and Techno-
logy, New Delhi, India (No. SR/S1/OC-72/2009) for the financial
support. The authors are also grateful to SAIF, Punjab University,
Chandigarh, India, for recording the NMR spectra.
1-(3-Bromophenyl)naphtho[1,2-d]isoxazole (2i)
Yield: 72% (472 mg); white solid; mp 180–182 °C.
IR (neat): 3065, 1633, 1580, 1229, 716 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43 (t, J = 7.9 Hz, 1 H), 7.58 (t,
J = 7.0 Hz, 1 H), 7.66–7.69 (m, 1 H), 7.72 (d, J = 7.0 Hz, 1 H), 7.75
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 752–756

756
A. V. Shelke et al.
PAPER
(13) (a) Tamura, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Kita,
Y. Synthesis 1989, 126. (b) Barret, R.; Daudon, M.
Tetrahedron Lett. 1990, 31, 4871. (c) Barret, R.; Daudon, M.
Synth. Commun. 1990, 20, 2907. (d) Claudio, S. B.;
Valderrama, J. A.; Tapia, R.; Farina, F.; Paredes, M. C.
Synth. Commun. 1992, 22, 955. (e) Pelter, A.; Elgendy, S.
M. A. J. Chem. Soc., Perkin Trans. 1 1993, 1891. (f) Wu, A.;
Duan, Y.; Xu, D.; Penning, T. M.; Harvey, R. G.
Tetrahedron 2010, 66, 2111.
(14) (a) Wipf, P.; Kim, Y. J. Org. Chem. 1993, 58, 1649.
(b) Murataka, M.; Yamada, K.; Hoshimo, O. J. Chem. Soc.,
Chem. Commun. 1994, 443. (c) Pelter, A.; Satchwell, P.;
Ward, R. S.; Blake, K. J. Chem. Soc., Perkin. Trans. 1 1995,
2201. (d) Dhrutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett.
2001, 4, 493. (e) Traoré, M.; Ahmed-Ali, S.; Peuchmaur,
M.; Wong, Y. S. Tetrahedron 2010, 66, 5863.
(15) (a) Khodaei, M. M.; Khosropour, A. R.; Moghanian, H.
Synlett 2006, 916. (b) Selvam, N. P.; Perumal, P. T.
Tetrahedron Lett. 2006, 47, 7481. (c) Kantevari, S.;
Vuppalapati, S. V. N.; Nagarapu, L. Catal. Commun. 2007,
8, 1857. (d) Shaterian, H. R.; Yarahmadi, H.; Ghashang, M.
Tetrahedron 2008, 64, 1263. (e) Zare, A.; Yousofia, T.;
Moosavi-Zare, A. R. RSC Adv. 2012, 2, 7988. (f) Kumar, A.;
Gupta, M. K.; Kumar, M. RSC Adv. 2012, 2, 7371. (g) Das,
V. K.; Borah, M.; Thakur, A. J. J. Org. Chem. 2013, 78,
3361.
(16) (a) Supsana, P.; Tsoungas, P. G.; Varvounis, G. Tetrahedron
Lett. 2000, 41, 1845. (b) Supsana, P.; Tsoungas, P. G.;
Aubry, A.; Skoulika, S.; Varvounis, G. Tetrahedron 2001,
57, 3445. (c) Dolka, C.; Hecke, K. V.; Meervelt, L. V.;
Tsoungas, P. G.; Van der Eycken, E. V.; Varvounis, G. Org.
Lett. 2009, 11, 2964.
References
(1) (a) Lamani, R. S.; Shetty, N. S.; Kamble, R. R.; Khazi, I. A.
M. Eur. J. Med. Chem. 2009, 44, 2828. (b) Deng, B.-L.;
Zhao, Y.; Hartman, T. L.; Watson, K.; Buckheit, R. W. Jr.;
Pannecouque, C.; De Clercq, E.; Cushman, M. Eur. J. Med.
Chem. 2009, 44, 1210. (c) Jain, M.; Kwon, C. H. J. Med.
Chem. 2003, 46, 5428. (d) Gopalsamy, A.; Shi, M.; Golas,
J.; Vogan, E.; Jacob, J.; Johnson, M.; Lee, F.; Nilakantan, R.;
Petersen, R.; Svenson, K.; Chopra, R.; Tam, M. S.; Wen, Y.;
Ellingboe, J.; Arndt, K.; Boschelli, F. J. Med. Chem. 2008,
51, 373. (e) Nuhrich, A.; Varache-Lembege, M.; Renard, P.;
Devaux, G. Eur. J. Med. Chem. 1994, 29, 75.
(2) (a) Andreas, S.-B. Expert Opin. Pharmacother. 2010, 11,
115. (b) Wroe, S. J. Zonisamide, In The Treatment of
Epilepsy, 3rd ed.; Wiley-Blackwell: Oxford, 2009, 71.
(3) (a) Swainston, H. T.; Goa, K. L. CNS Drugs 2004, 18, 113.
(b) Deeks, E. D. Drugs 2010, 70, 1001.
(4) (a) Solanki, P. V.; Uppelli, S. B.; Pandit, B. S.; Mathad, V.
T. ACS Sustainable Chem. Eng. 2013, 1, 243. (b) Yang, L.
P. H.; Plosker, G. L. CNS Drugs 2007, 21, 417.
(5) Arava, V. R.; Siripalli, U. B. R.; Nadkarni, V.; Chinnapillai,
R. Beilstein J. Org. Chem. 2007, 3, 20.
(6) (a) Kalkote, U. R.; Goswami, D. D. Aust. J. Chem. 1977, 30,
1847. (b) Stokker, G. J. Org. Chem. 1983, 48, 2613.
(c) Roman, G.; Comanita, E.; Comanita, B. Tetrahedron
2002, 58, 1617. (d) Jain, M.; Kwon, C. J. Med. Chem. 2003,
46, 5428.
(7) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 1180.
(8) Udd, S.; Jokela, R.; Franzén, R.; Tois, J. Tetrahedron Lett.
2010, 51, 1030.
(9) Lepore, S. D.; Wiley, M. R. J. Org. Chem. 1999, 64, 4547.
(10) Gualtieri, F.; Giannella, M. The Chemistry of Heterocyclic
Compounds: Isoxazoles, Part Two; Vol. 49; Grunanger, P.;
Vita-Finzi, P., Eds.; John Wiley & Sons: New York, 1999,
1–122.
(11) (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(b) Grushin, V. V. Chem. Soc. Rev. 2000, 29, 315.
(c) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523. (d) Wirth, T. Angew. Chem. Int. Ed. 2005, 44, 3656.
(e) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893.
(f) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108,
5299. (g) Brown, M.; Farid, U.; Wirth, T. Synlett 2013, 24,
424.
(17) (a) Kociolek, M. G.; Hoermann, O. Synth. Commun. 2012,
42, 2632. (b) Raihan, M. J.; Kavala, V.; Habib, P. M.; Guan,
Q.-Z.; Kuo, C. W.; Yao, C.-F. J. Org. Chem. 2011, 76, 424.
(c) Jadhav, V. K.; Deshmukh, A. P.; Wadagaonkar, P. P.;
Salunkhe, M. M. Synth. Commun. 2000, 30, 1521.
(18) (a) Zhang, L.-h.; Chung, J. C.; Costello, T. D.; Valvis, I.;
Ma, P.; Kauffman, S.; Ward, R. J. Org. Chem. 1997, 62,
2466. (b) Zhang, L.-h.; Kauffman, G. S.; Pesti, J. A.; Yin, J.
J. Org. Chem. 1997, 62, 6918. (c) Okamoto, N.; Miwa, Y.;
Minami, H.; Takeda, K.; Yanada, R. Angew. Chem. Int. Ed.
2009, 48, 9693.
(19) Prakash, O.; Saini, R. K.; Singh, S. P.; Varma, R. S.
Tetrahedron Lett. 1997, 38, 3147.
(12) Varvoglis, A. Hypervalent Iodine in Organic Synthesis;
Academic Press: London, 1997, Chap. 3.
Synthesis 2014, 46, 752–756
© Georg Thieme Verlag Stuttgart · New York