Xanthones in heterocyclic synthesis. An efficient route for the synthesis of C-3 o-Hydroxyaryl substituted 1, 2-benzisoxazoles and their N-oxides, potential scaffolds for angiotensin(II) antagonist hybrid peptides

Article abstract of DOI:10.3987/COM-11-12162

Regioselective substitution of xanthone and its nucleophilic cleavage allow the synthesis of C-3 ohydroxyaryl substituted 1, 2-benzisoxazoles or their V-oxides by cyclodehydration or oxidative cyclization of their corresponding ketoxime precursors, respectively. Molecular modeling analysis and ¹H NMR spectra indicate an intramolecular H-bonding engaging phenol OH and the isoxazole ring N atom. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-11-12162

HETEROCYCLES, Vol. 83, No. 5, 2011
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HETEROCYCLES, Vol. 83, No. 5, 2011, pp. 1077 - 1091. © The Japan Institute of Heterocyclic Chemistry
Received, 1st February, 2011, Accepted, 3rd March, 2011, Published online, 10th March, 2011
DOI: 10.3987/COM-11-12162
XANTHONES IN HETEROCYCLIC SYNTHESIS. AN EFFICIENT
ROUTE FOR THE SYNTHESIS OF C-3 o-HYDROXYARYL
SUBSTITUTED 1,2-BENZISOXAZOLES AND THEIR N-OXIDES,
POTENTIAL SCAFFOLDS FOR ANGIOTENSIN(II) ANTAGONIST
HYBRID PEPTIDES
Yiannis Gardikis,a Petros G. Tsoungas,b* Constantinos Potamitis,c Maria
Zervou,c and Paul Cordopatisa*
a Department of Pharmacy, University of Patras, Rio-Patra 26504, Greece
b Ministry of Education/Research & Technology, Athens 14631, Greece
c Institute of Organic & Pharmaceutical Chemistry, National Hellenic Research
Foundation, Athens 11635, Greece
Fax: +30-210-7713810; +30-2610-997714
E-mail: pgt@gsrt.gr; pacord@upatras.gr
Abstract - Regioselective substitution of xanthone and its nucleophilic cleavage
allow the synthesis of C-3 o-hydroxyaryl substituted 1,2-benzisoxazoles or their
N-oxides by cyclodehydration or oxidative cyclization of their corresponding
1
ketoxime precursors, respectively. Molecular modeling analysis and H NMR
spectra indicate an intramolecular H-bonding engaging phenol OH and the
isoxazole ring N atom.
INTRODUCTION
Molecules possessing the 1,2-oxazole (isoxazole) ring exhibit a wide range of biological activities and
pharmacological properties1 making the ring an eminent target for elegant and efficient ways to its
synthesis. The ring is also a precursor to useful synthetic intermediates such as -amino alcohols,2
-hydroxy ketones,3 -hydroxy nitriles4 or ,-unsaturated ketones.5
The most common reaction to form the isoxazole structure is 1,3-dipolar cycloaddition of alkynes with
nitrile oxides, generated in situ, usually by dehydration of nitro compouds6 or by dehydrogenation of
oximes.7 The formation of nitrile oxides from either -keto esters or ,-unsaturated ketones, using
hydroxylamine, is known as a one-pot isoxazole synthesis.8,9

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HETEROCYCLES, Vol. 83, No. 5, 2011
1,2-Benzoxazoles (benzisoxazoles) have long stood prominently in this class of heterocycles. Indeed,
some recent reports on the synthesis of this structure, elegant in their simplicity and efficiency, serve as
an irrefutable testimony to the continuous interest in the field. They involve, either cyclodehydration of
o-hydroxyaryl aldo/ketoximes, triggered by PPh3/DDQ,10 TsCl/iPr2NEt,11 microwave in an ionic liquid12
or CuI/DMEDA/tBuONa13 or a [3+2] cycloaddition of in situ generated nitrile oxides with arynes,14 all
under mild conditions.
1,2-Benzisoxazoles, substituted at C-3 with pharmacophores, on the other hand, is an area of intense
research, driven by potential applications in pharmaceutics.15 Derivatives have been recently investigated
as inhibitors of LTB4 binding to human neutrophiles,16 affinity ligands for serotonergic and dopaminergic
receptors,17 selective inhibitors of acetylcholinesterase18 or for atypical antipsychotic activity.19
Bearing in mind the significance of substitution at that position, incorporation of a phenol, a medically
reputed core unit,20 has been sought. This molecular scaffold will provide a diverse array of lead
structures, amino acids included, for the synthesis of hybrid peptides as Angiotensin (II) antagonists.21
Accordingly, we have developed and report, herein, an efficient protocol for the synthesis of 3-[o-
hydroxyaryl] substituted 1,2-benzisoxazoles (10-22) and their N-oxides (23-34) (Schemes 1 and 2).
RESULTS AND DISCUSSION
The adopted methodology makes use of xanthone 1 (Scheme 1). Its reactivity profile, developed by us,
has been recently reported.22 Accordingly, converting 1 to its derivatives 2 or 5, leads to substitution
patterns with a synthetically useful degree of regioselectivity.
O
R1
R2
a. R1=2-NO2; R2=H
b. R1=2-Br ; R2=H
c. R1=2-Br; R2=7-Br
d. R1=2-Ph; R2=H
e. R1=2-Ph ; R2=7-Ph
O
(i), (ii)
(iii)
8
5
1
4
O
2
7
6
2
3
O
X
X
R1
R2
O
1
a. R1=1-Me; R2=H
b. R1=4-Me; R2=H
c. R1=4-Me; R2=5-Me
X=Cl
X=OMe
3
4
O
O
5
3
Scheme 1. Reagents and Conditions: (i) c.HNO3/c.H2SO4/rt, (ii) Br2/AlCl3/ or Br2 (10-fold excess)/
AcOH/100 oC; (iii) a) SOCl2/DMF/, b) NaOMe/MeOH-THF; c) tBuLi/THP/-13 – (-10 oC)/H+/H2O.

HETEROCYCLES, Vol. 83, No. 5, 2011
1079
Conventional electrophilic substitution was performed first. Nitration of 123 introduces the NO2 group at
C-2 (or C-7) (Scheme 1, 2a). Bromination, on the other hand, introduces bromine at C-2, predominantly,
to give 2b but C-7 is also attacked to a lesser extent to give the dibromo derivative 2c. Friedel-Crafts
conditions gave 2b and 2c in 50% and 43% yields, respectively. Using a 10-fold excess of bromine in
acetic acid at 100 ºC for 4h changed the yields of the bromo derivatives to 72% and 18%, respectively. 2c
was also obtained stepwise from 2b in 40% yield. Clearly, the entries at C-2 and C-7 are facilitated and
directed from the pyran O lone pair. These entries may serve as sites of further functionalisation, for
example, a phenyl group can be incorporated into C-2 or C-7, under Suzuki conditions, giving 2d and 2e
in 90% and 78% yields, respectively.
Complementary to the above described functionalisation of 1 is a lithiation-electrophilic quench
protocol22 to 5 (Scheme 1). By means of this protocol, 1 is converted to its ketal derivative 4 via
9,9-dichloroxanthene 3.24 It is worth noting that 4 is stable enough to the substitution operations but it is
rapidly hydrolysed to 5, upon work up.22
Having xanthones 2 and 5 regioselectively substituted, they undergo nucleophilically triggered ring
opening to ketones 6 and 8 (Scheme 2).
R1
R1
OH
OR3
O
R2
R2
N
+
a. R3=H
b. R3=Me
c. R3=Et
N
Y
OH
O
1
OH
(iii)
(iv)
(i)
10-22
Y=O
Y=NOH
R1
6
7
(ii)
R1
R1
2 a-e
5 a-c
OH
R2
OH
O
R2
R2
N
N
O
+
Y
O
O
OH
OH
Y=O
Y=NOH
23-34
8
9
(ii)
Scheme 2. Reagents and Conditions: (i) KOH (12N)/DMSO/, 9 h; (ii) NH2OH-HCl/EtOH/, 6 h; (iii)
PPh3/DDQ10 or TsCl/iPr2NEt;11 (iv) Pb(OAc)4 /THF/0-5 oC-rt,2512 h or PhI(OAc)2/THF/rt, 12 h.26

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The cleaving nucleophile, through an SNAr process, ends up ortho- to the ketone carbonyl. The cleavage
is efficiently performed with alkali in ca. 80% yield while a moderate yield of ca. 50% is obtained when
an alkoxide is used. In the latter case one of the OH groups is protected as its alkyl ether (Scheme 2, 6a or
6b).
Ketones are then converted to their ketoximes 727 and 9, cyclisation of which, ultimately leads to the
target 1,2-benzisoxazoles (10-22) (Table 1) or their N-oxides (23-34) (Table 2), providing the
o-hydroxyaryl group, regioselectively substituted or not, at their C-3 position.
If no substitution is required on the heterocycles then cyclodehydration of 7 or 9 by PPh3/DDQ10 or
TsCl/iPr2NEt11 gives 10-12 or 16-18 (Table 1) while oxidative cyclisation of 7 or 9, using lead(IV)acetate
(LTA)25 or phenyliodine(III)diacetate (PIDA)26 gives the N-oxides (23-25) or (29, 30) (Table 2), as single
isomers in each case. This is clearly the result of having identical cyclisation sites on the oximes.
However, the synthetic potential of the scheme is amply demonstrated if regioselective substitution on the
target heterocycles is desired.28
It is of interest to note that substitution patterns can be built up symmetrically (Table1, entries 17, 18 and
Table 2, entries 29, 30) or unsymmetrically (Table 1, entries 13-15, 19-21 and Table 2, entries 26-28,
31-33). In the former case, cyclisation sites in 8 or 9 are identical, again, consequently, only a single
isomer was obtained. On the contrary, an unsymmetrical substitution pattern gives rise to the two possible
isomers, emanating from the alternative cyclisation modes of 8 or 9, in varying yields (Tables 1 and 2).
An interesting outcome arises from the cyclisation of the NO2-bearing oxime to give the corresponding 22
or 34. Apparently, the strongly electron withdrawing NO2 group engages its p-disposed OH group into a
mesomeric interaction, thus, hampering its participation in the cyclization process, leading to the isolation
of only one isomer.29
A molecular modeling analysis30 was performed on 17 and 23. Clustering of the results led to the lowest
energy conformers (Figures 1 and 2).
O
OH
9
N
7
1
τ1
10
11
8
2
3
6
5
τ1
τ1
13
12
4
ttτ1=C2-C7–C8-C9
1=132.7o
1= -132.7o
Br
Br
1=C2-C7-C8-C9
B
A
Figure 1. Of the lowest energy conformers of 17, A and B show an intramolecular H bond-like
interaction (green dashed lines). Dihedral angle 1 is depicted on each conformer.

HETEROCYCLES, Vol. 83, No. 5, 2011
1081
Table 1. Regioselectively substituted 1,2-benzisoxazoles (10-22).
Entry
Structure
Yield % Entry
Structure
Yield %
OH
10
76
N
O
OMe (Et)
11 (12)
48 (51)
N
O
Br
OH
OH
13a)
40
48
44
19a)
20a)
21a)
42
40
36
Br
N
N
O
O
Ph
OH
OH
14a)
Ph
N
N
O
O
Me
Me
OH
15a)
O
N
N
O
OH
Me
OH
16
49
N
O
O
Me
Br
22
59
O2N
N
OH
OH
17
18
72
69
Br
N
O
Ph
OH
Ph
N
O
a) Not isolated. Identified by 1H NMR spectra.

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HETEROCYCLES, Vol. 83, No. 5, 2011
Table 2. Regioselectively substituted 1,2-benzisoxazole 2-oxides (23-34).
Entry
Structure
Yield % Entry
Structure
Yield %
OH
O
23
57
N
O
OMe (Et)
24 (25)
54 (49)
N
O
O
Br
Br
OH
O
26a)
49
44
47
31a)
32a)
33a)
38
41
42
O
N
N
O
O
OH
OH
OH
Ph
Ph
OH
27a)
O
N
N
O
O
O
Me
Me
OH
O
28a)
O
N
N
O
O
Br
OH
29
30
64
60
Br
N
O
O
O
Ph
34
52
O2N
N
O
OH
O
OH
Ph
N
O
a) Not isolated. Identified by 1H NMR spectra.

HETEROCYCLES, Vol. 83, No. 5, 2011
1083
O
O
OH
9
N
7
1
4
10
11
8
2
3
6
5
τ2
τ2
τ2
13
12
2=124.8o
2=-124.8o
2=C2-C7-C8-C9
A
B
Figure 2. Of the lowest energy conformers of 23 A and B show an intramolecular H bond-like
interaction (green dashed lines). Dihedral angle 2 is depicted on each conformer.
Conformers A and B in 17 reveal an intramolecular H-bonding-like contact among phenol OH and ring N
atom (Figure 1). A dihedral angle 1 of ca. 133o and a 0.002Å elongation of OH bond, point to a rather
weak O-H--N interaction. Apparently, it is this interaction and the relief of some C-3/C-13 steric
congestion that force the phenol ring out of 1,2-benzisoxazole plane, locking, in a way, the structure into
1
these particular conformations. The expected highly deshielded at ca.  = 9.5ppm H signal in the 600
MHz 2D COSY spectrum of 17 appeared to be obscured. A similar H-bonding has been observed in the
1,3-benzoxazole isomer.31
A what appears to be a very weak intramolecular H-bonding interaction (OH = 8.25 ppm and 2 of ca.
125o) is also evident in conformers A and B in 23, among phenol OH and the O atom of the N-O dipole
(Figure 2).
In conclusion, the reactivity profile of xanthone allows for a simple and efficient protocol developed for
the synthesis of C-3- regioselectively substituted 1,2-benzoxazoles and their N-oxides. Todate this is the
only available methodology to obtain these pharmacologically valuable structures. A diverse and virtually
unlimited array of derivatives can thus be accessible.
EXPERIMENTAL
Melting points were measured on an Electrothermal IA9000 Series apparatus and are uncorrected.
Infrared spectra were recorded or an FT/IR-5300 spectrometer as KBr discs. Elemental analyses were
performed on a Carlo Erba 1106 analyser. NMR spectra were measured on a Bruker Avance 400 MHz
and a Varian 600 MHz spectrometers, in CDCl3 or DMSO-d6 solutions. Mass spectra were recorded by
Micromass-Platform LC or JEOL JMS-AX505W low or high resolution instruments. Analytical TLC was
run on Fluka Silica Gel F254. Preparative Flash Chromatography was run on MERCK 9385 Silica Gel.
Reagents were used as commercially purchased while solvents such as CH2Cl2, EtOAc, hexane and

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HETEROCYCLES, Vol. 83, No. 5, 2011
MeOH were purified and dried according to standard procedures.
Bromination of xanthone. General Procedures. Method A: Xanthone (1) (8.6 g, 50 mmol) in CS2 (20
mL) is mixed with aluminium chloride (14.5 g). Bromine (2.0 mL) is added dropwise and the mixture is
stirred at room temperature for 24 h. Water is then added, followed by extraction with CH2Cl2 (3X80 mL).
The combined extracts are repeatedly washed with water, dried over sodium sulphate, concentrated and
chromatographed (EtOAc: pet. ether 4:1) to give 2-bromoxanthone (2b) (5.64 g, 45%) and
2,7-dibromoxanthone (2c) (4.95 g, 30%). Method B: Bromine (3.2 mL) in acetic acid (16 mL) is added
o
dropwise to a solution of xanthone (7.8 g, 40 mmol) in acetic acid (24 mL) at 110 C. After 4 h, the
reaction is quenched with ice water and a precipitate is formed. This is collected by filtration, washed
repeatedly with water, dried and chromatographed (EtOAc: pet. ether 4:1) to give 2b (8.5 g, 75%) and 2c
(1.5 g, 10%).
o
1
2b: Mp 176 C. IR: 1696, 1314 cm-1. H NMR (400 MHz, CDCl3): δ 8.45-8.35 (d, J = 2.4 Hz, 1H),
8.30-8.25 (dd, J = 8 Hz, 1.6 Hz, 1H), 7.75-7.65 (m, 2H), 7.45-7.40 (d, J = 8 Hz, 1H), 7.35-7.25 (m, 2H).
13C NMR (100 MHz, CDCl3):  115.9, 117.5, 118.5, 121, 123.4, 124.5, 126, 134.0, 135.7, 138.6, 154.6,
155.6, 175.2. ESMS (M+H): m/z 276. Anal. Calcd for C13H7BrO2: C, 56.72; H, 2.54. Found: C, 56.55;H,
2.40%.
2c: Mp 217 oC. IR: 1710, 1291 cm-1. 1H NMR (400 MHz, CDCl3):  8.45-8.35 (m, 2H), 7.9 (dd, J = 8.8
Hz, 3.2 Hz, 2H). 7.86-7.76 (m, 2H). 13C NMR (100 MHz, CDCl3):  116, 116.4, 118.3, 118.5, 123, 123.5,
133.6, 140, 138.6, 154.7, 175. ESMS (M+H: m/z 355. Anal. Calcd for C13H6Br2O2: C, 44.06; H, 1.69.
Found: C, 43.88; H, 1.56%.
Nitration of xanthone. This was effected according to a literature method23 to give 2d, yield 58%.
Mp 206 oC (lit.,23 207 oC). IR: 3080, 1670, 1612, 1531, 1338, 1280 cm-1. 1H NMR (400 MHz, CDCl3): 
8.85 (d, J = 2.46, 1H), 8.60 (dd, J = 2.65 Hz, 2.71 Hz, 1H), 8.20 (d, J = 7.68 Hz, 1H), 7.91 (m, 2H), 7.71
(d, J = 8.45 Hz, 1H), 7.55 (t, J = 7.40 Hz, 7.57 Hz, 1H). ESMS (M+H): m/z 242.
Arylation of 2-bromoxanthone (2b). To a stirred solution of 2-bromoxanthone (2.5 g, 2 mmol) in
toluene (45 mL), ethanol (45 mL) and aqueous 2M Na2CO3, phenylboronic acid (2.25 g, 4.16 mmol) and
Pd (PPh3)4 (210 mg) are added at room temperature, under an Argon atmosphere and the mixture is heated
to reflux for 2h. EtOH (100 mL) and H2O (10 mL) are then added, the organic layer is repeatedly washed
with brine (3X50 mL), dried over sodium sulphate and chromatographed (EtOAc/petroleum ether 9:1 v/v)
to give 2-phenylxanthone (2e) (2.3 g, 90%).
Mp 159 oC, Rf = 0,85. IR: 1687, 1325 cm-1. 1H NMR (400 MHz, CDCl3):  8.51 (d, J = 2.4 Hz, 1H), 8.29
(dd, J = 8 Hz, 1.6 Hz, 1H), 7.91 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.78-7.61 (m, 4H), 7.55-7.25 (m, 5H). 13C
NMR (100 MHz, CDCl3):  117.9, 118.3, 121.1, 121.5, 124.8, 125.9, 127.9, 128.1, 128.2, 130.1, 130.8,

HETEROCYCLES, Vol. 83, No. 5, 2011
1085
130.9, 132.9, 134.6, 135.6, 140.8, 154.8, 155.8, 175.6. ESMS (M+H): m/z 273. Anal. Calcd for C19H12O2:
C, 83.80; H, 4.41. Found: C, 83.62; H, 4.34%.
Arylation of 2c. The method described above was repeated and 2,7-diphenylxanthone 2e was obtained.
o
Yield 78%. Mp 194 C, Rf = 0.47. ESMS (M+H): m/z 349. Anal. Calcd for C25H16O2: C, 86.20; H, 4.59.
Found: C, 85.99; H, 4.42%.
Nucleophilic cleavage of xanthones (2 and 5). General procedure: In a solution of xanthone (1.96 g, 10
mmol) in DMSO (20 mL), an aqueous solution of 12N KOH (30 mL) is added and the reaction mixture is
heated under reflux for 9 h (cleavage of 2a may be accomplished by heating in 6N KOH for 8 h). The
solvent is removed in vacuo and residue is treated with ice-water, slowly acidified with 10N HCl to pH=3
and exhaustively extracted with CH2Cl2 (5X50 mL). Combined extracts are repeatedly washed with water
and brine, dried over sodium sulphate, concentrated and residue is triturated with Et2O/petroleum ether to
give 2,2-dihydroxybenzophenones 6 and 8.
Nucleophilic cleavage of xanthone 1. A solution of xanthone (1.0 g) in a sodium alkoxide RONa (R=Me,
o
Et) (20 mL) was heated at 110 C in a sealed tube for 9 h. The reaction mixture after ice cooling was
concentrated and triturated as described above to give 2-hydroxy-2-alkoxybenzophenones (6b) (48%)
and (6c) (51%) as viscous oils.
1
IR: 3420, 3190, 1640 cm-1. H NMR (400 MHz, CDCl3):  10.48 (s, 1H) 7.71 (d, J = 2.44 Hz, 1H),
7.61-7.51 (m, 3H), 7.9 (d, J = 8.35 Hz, 1H) 7.01-6.96 (m, 3H). ESMS (M+H): m/z 215.
2-Hydroxy-2-Methoxybenzophenone (6b): Yield 51%. Mp 112 oC. Rf = 0.84. IR (KBr) 3420, 1615cm-1.
13
1H NMR (400MHz, CDCl3):  10.10 (br, 1H, OH), 7.80-6.90 (m, 8H, aromatic), 3.80 (s, 3H, OMe). C
NMR (100MHz, CDCl3):  157.5, 155.0, 148.1, 135.4, 131.2, 129.1, 128.0, 126.0, 125.8, 124.6, 122.2,
119.8, 118.2, 57.4. ESMS (M+H): m/z 229.
o
2-Hydroxy-2-Ethoxybenzophenone (6c): Yield 48%. Mp 90 C. Rf = 0.49 IR. (KBr) 3420, 1615cm-1.
1H NMR (400MHz, CDCl3):  10.10 (br, 1H, OH), 7.80-6.90 (m, 8H, aromatic), 4.2 (q, 2H, CH2Me),
3.80 (s, 3H, OMe). 13C NMR (400MHz, CDCl3):  157.5, 155.0, 148.1, 135.4, 131.2, 129.1, 128.0, 126.0,
125.8, 124.6, 122.2, 119.8, 118.2, 57.4. ESMS (M+H): m/z 243.
Oximes (7 and 9). Prepared and characterized according to literature methods.25,26
3-o-Hydroxyaryl-1,2-benzisoxazoles (10-22). Prepared by analogy to literature methods.10,11
3-[2-Hydroxyphenyl]-1,2-benzisoxazole (10). Isolated as oil. Yield 76%, Rf = 0.86. IR (KBr): 3280,
1615 cm-1. 1H NMR (400 MHz, CDCl3):  6.93-8.27 (m, 8H aromatic), 9.73 (s, 1H, OH). 13C NMR (100
MHz, CDCl3):  155.7, 153.1, 136.4, 135.3, 131.4, 128.3, 123.0, 121.9, 121.2, 118.7, 116.8, 111.9. ESMS
(M+1): m/z 212. Anal. Calcd for C3H9NO2 C, 73.93; H, 4.26; N, 6.63. Found: C, 73.79; H, 4.10; N,
6.40%.

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HETEROCYCLES, Vol. 83, No. 5, 2011
3-[2-Methoxyphenyl]-1,2-benzisoxazole (11). Isolated as oil. Yield 48%, Rf = 0.78. IR (KBr): 1610
1
13
cm-1. H NMR (400 MHz, CDCl3):  6.81-8.12 (m, 8H, aromatic), 3.81 (s, 3H, OCH3). C NMR (100
MHz, CDCl3):  155.4, 153.3, 135.8, 133.1, 133.4, 128.4, 123.1, 121.6, 121.2, 119.0, 116.6, 114.4, 111.8,
57.4. ESMS (M+1): m/z 226.
1
3-[2-Ethoxyphenyl]-1,2-benzisoxazole (12). Isolated as oil. Rf = 0.72. H NMR (400 MHz, CDCl3): 
6.80-8.14 (m, 8H, aromatic), 4.12 (q, 2H, OCH2CH3), 1.30 (t, 3H, OCH2CH3). 13C NMR (100 MHZ
CDCl3):  155.3, 152.8, 135.6, 133.4, 133.1, 128.4, 123.1, 121.6, 121.2, 119.0, 116.6, 114.4, 111.8, 61.0,
42.4. ESMS (M+H): m/z 240.
3-[2-Hydroxyaryl]-1,2-benzisoxazoles (13-15, 19-21). Not isolated to their individual isomers.
1
Identified by their H NMR spectra compared with those of the other derivatives and relevant lit.
data.23,32
3-[2-Hydroxy-3-methylphenyl]-7-methyl-1,2-benzisoxazole (16). IR: 3360, 1600cm1 1H NMR:
7.40-7.65 (m, 3H), 7.25 (dd, J = 8.20, 7.50, 1.30 Hz, 1H), 7.10 (dd, J = 8.0 Hz, J = 1.35 Hz, J = 1.10 Hz,
1H), 6.85 (dd, J = 8.10 Hz, J = 7.30 Hz, J = 1.20 Hz, 1H), 6.75 (dd, J = 8.20 Hz, J = 1.30 Hz, J = 0.90 Hz,
1H), 2.35 (s, 3H, Me), 2.15 (s, 3H, Me). 13C NMR (100 MHz, CDCl3):  152.6, 148.8, 128.4, 126.0,
125.4, 124.8, 120.8, 120.0, 119.5, 116.0, 110.0, 108.1, 102.4, 43.5. 42.5. ESMS (M+H): m/z 240. Anal.
Calcd for C15H13NO2: C, 75.31; H, 5.43; N, 5.85. Found: C, 75.05; H, 5.18; N, 5.60%.
3-[2-Hydroxy-4bromophenyl]-5-bromo-1,2-benzisoxazoles (17). Viscous oil. Yield 72%. ΙR: 3275,
1637 cm-1. 1H NMR (400 MHz, CDCl3):  8.50 (s, 1H), 7.70-7.65 (m, 2H), 7.55-7.50 (m, 2H), 7.45-7.40
13
(d, J = 11 Hz, 1H), 7.35-7.25 (d, J = 11 Hz, 1H), 7.28-7.18 (d, J = 12 Hz, 1H). C NMR (100 MHz,
CDCl3):  162.5, 153.3, 147.7, 134.5, 125.5, 124.9, 122.6, 122.4, 119.6, 118.8, 116.5, 108.5, 81. ESMS
(M+H): m/z 291. Anal. Calcd for C13H7Br2NO2: C, 42.27; H, 1.89; N, 3.79. Found: C, 42.05; H, 1.72; N,
3.64%.
3-[2Hydroxy-4phenyl]-5-phenyl-1,2-benzisoxazoles (18). Isolated as an off-white powder. Yield 69%.
Mp 118-119 oC, Rf = 0.84. IR (KBr): 3270, 1610 cm-1. 1H NMR (400 MHz, CDCl 3):  7.90-8.10 (m, 3H),
7.30-7.65 (m, 10H), 6.70-6.85 (m, 3H), 9.70 (s, 1H). 13C NMR (100 MHz, CDCl3):  155.5, 155.3, 153.1,
152.4, 150.6, 149.8, 141.9, 139.8, 135.4, 131.6, 130.8, 128.3, 128.1, 127.3, 124.1, 121.8, 118.8, 118.3,
116.4, 115.8, 114.4, 114.1, 110.8, 110.2. ESMS (M+1): m/z 364. Anal. Calcd for C25H17NO2: C, 82.64; H,
4.68; N, 3.85. Found: C, 82.48; H, 4.52; N, 3.60%.
3-[2-Hydroxyphenyl]-5-nitro-1,2-benzisoxazole (22). Isolated as pale yellow flakes. Yield 59%. Mp
131-132 oC, Rf = 0.69. IR (KBr): 1620, 1505, 1470, 1330 cm-1. 1H NMR (400 MHz, CDCl3):  8.15-8.74
13
(m, 3H’s, J = 8.9 Hz, J = 3.1 Hz, J = 0.8 Hz), 6.90-7.90 (m, 4H) 9.70 (s, 1H). C NMR (100 MHz,
CDCl3):  162.6, 155.4, 153.3, 135.4, 133.2, 131.1, 130.4, 124.2, 122.4, 121.6, 118.8, 116.6, 114.4.

HETEROCYCLES, Vol. 83, No. 5, 2011
1087
ESMS (M+1): m/z 257. Anal. Calcd for C13H8N2O4: C, 60.93; H, 3.12; N, 10.93. Found: C, 60.79; H, 3.0;
N, 10.69%.
3-[2-Hydroxyaryl]-1,2benzisoxazole 2-oxides (23-34). Prepared by analogy to literature methods.25,26
3-[2-Hydroxyphenyl]-1,2-benzisoxazoles 2-oxide (23). Isolated as an off-white powder. Yield 57%.
Mp 111-112 oC, Rf = 0.71. IR (KBr): 3460, 1605, 1220 cm-1. 1H NMR (600 MHz, CDCl3):  7.82-8.05 (m,
4H), 7.30-7.70 (m, 4H, J = 8.6 Hz, J = 2.9 Hz, J = 0.7 Hz), 8.20 (s,1H). 13C NMR (100 MHz, CDCl3): 
153.3, 150.6, 136.4, 135.1, 131.3, 128.3, 124.1, 123.3, 121.0 120.3, 120.0, 117.5, 116.4. ESMS (M+1):
m/z 228. Anal. Calcd for C13H9NO3: C, 68.72; H, 3.96; N, 6.16. Found: C, 68.50; H, 3.80; N, 5.90%.
3-[2Methoxyphenyl]-1,2-benzisoxazole 2-oxide (24). Isolated as a viscous oil. Yield 54%, Rf = 0.82. IR
1
(KBr): 1600, 1215 cm-1. H NMR (600 MHz, CDCl3):  7.70-7.95 (m, 4H), 7.30-7.60 (m, 4H), 3.80 (s,
3H, OMe). 13C NMR (100 MHz, CDCl3):  152.9, 150.2, 136.6, 134.8, 131.0, 128.0, 124.4, 123.1, 121.1,
119.8, 118.1, 116.9, 116.3, 57.6. ESMS (M+1): m/z 242. Anal. Calcd for C14H11NO3: C, 69.70; H, 4.56;
N, 5.80. Found: C, 69.52; H, 4.40; N, 5.52%.
1
3-[2-Ethoxyphenyl]-1,2-benzisoxazole 2-oxide (25). Isolated as a viscous oil. H NMR (400 MHZ,
CDCl3):  7.70-7.90 (m, 4H, aromatic), 7.30-7.60 (m, 4H, aromatic), 4.0 (q, 2H, OCH2CH3), 1.30 (t, 3H,
OCH2CH3). 13C NMR (100 MHZ, CDCl3):  152.6, 150.4, 136.6, 134.8, 131.2, 128.2, 124.4, 123.4, 121.4,
119.6, 118.2, 116.8, 116.4, 59.2, 41.8. ESMS (M+H): m/z 256.
3-[2Hydroxyphenyl]-1,2-benzisoxazole 2-oxides (26-28, 31-33). Not isolated to their individual
isomers. Identified by their 1HNMR spectra compared with those of the other derivatives and relevant lit.
data.25,26,32
3-[2-Hydroxy-3-methylphenyl]-1,2-benzisoxazole 2-oxide (28). IR: 3420, 1615, 1590, 1215cm-1. 1H
NMR (400 MHZ, CDCl3):  7.25-7.60 (m, 3H, aromatic), 7.20 (dd, J = 8.29, J = 7.46 Hz, J = 1.27 Hz,
1H), 7.10 (dd, J = 8.01 Hz, J = 1.27 Hz, J = 0.99 Hz, 1H), 6.80 (dd, J = 8.01 Hz, J = 7.40 Hz, J = 1.22 Hz,
1H), 6.69 (dd, J = 8.19 Hz, J = 1.20 Hz, J = 0.90 Hz, 1H), 2.38 (s, 3H, Me), 2.14 (s, 3H, Me). 13C NMR
(100 MHz, CDCl3):  151.4, 149.6, 128.4, 127.1, 126.2, 123.6, 120.7, 119.4, 118.8, 114.1, 109.4, 108.0,
102.4, 104.4, 43.6, 42.2. ESMS (M+H): m/z 242. Anal. Calcd for C14H11NO3: C, 69.70; H, 4.56; N, 5.80.
Found: C, 69.48; H, 4.39; N, 5.52 %.
3-[2-Hydroxy-4-bromophenyl]-5-bromo-1,2-benzisoxazole 2-oxide (29). Isolated as yellowish
microcrystals. Yield 64%. Mp 193 oC, Rf = 0,75. IR: 3439, 1615, 1215 cm-1. 1H NMR (400 MHz, CDCl3):
 8.23 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.58 (dd, J = 8.8, 1.9 Hz, 1H), 7.42 (dd,
J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): 
156.7, 148.7, 134.6, 132.2, 131.2, 128.1, 125.5, 123.4, 122.4, 118.7, 116.2, 110.8, 108.5. ESMS (M+H):
m/z 386. Anal. Calcd for C13H7Br2NO3: C, 40.51; H, 1.81; N, 3.63. Found: C, 40.30; H, 1.70; N, 3.45%.

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HETEROCYCLES, Vol. 83, No. 5, 2011
3-[2-Hydroxy-4-phenyl]-5-phenyl-1,2 Benzisoxazole 2-oxide (30). Isolated as amorphous solid. Yield
o
1
60%. Mp 151 C, Rf = 0.79. IR (KBr): 3430, 1610, 1220 cm-1. H NMR (400 MHz, DMSO-d6): 
7.75-7.95 (m, 3H), 7.30-7.60 (m, 10H), 6.70-6.85 (m, 3H), 8.25 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
 155.3, 155.0, 153.1, 152.4, 150.4, 148.1, 145.5, 141.9, 138.5, 135.4, 131.5, 130.8, 128.3, 128.0, 126.6,
124.1, 121.6, 118.8, 118.3, 116.1, 114.8, 114.4, 114.0, 110.8, 110.1. ESMS (M+1): m/z 380. Anal. Calcd
for C25H17NO3: C, 79.15; H, 4.48; N, 3.69. Found: C, 78.95; H, 4.26; N, 3.44%.
3-[2-Hydroxyphenyl]-5-nitro-1,2-benzisoxazole 2-oxide (34). Isolated as pale yellow microcrystals.
Yield 52%. Mp 162-163 oC, Rf = 0.68. IR (KBr): 1615, 1220 cm-1. 1H NMR (400 MHz,
CDCl3-DMSO-d6):  7.2-8.45 (m, 3H,) 7.0-7.60 (m, 4H), 8.20 (s,1H). 13C NMR (400 MHz,
CDCl3-DMSO-d6) : 159.4, 153.4, 151.1, 144.0, 135.4, 133.2, 131.6, 125.4, 123.1, 121.4, 120.1, 119.4,
117.5. ESMS (M+1): m/z 273. Anal. Calcd for C13H8N2O5: C, 57.35; H, 2.94; N, 10.29. Found: C, 57.15;
H, 2.76; N, 10.08%.
REFERENCES (AND NOTES)
1. P. Conti, C. Dallanoce, M. De Amici, C. De Micheli, and K.-N. Klotz, Bioorg. Med. Chem., 1998, 6,
401; D.-H. Ko, M. F. Maponya, M. A. Khalili, E. T. Oriaku, Z. You, and H. J. Lee, J. Med. Chem.,
1998, 8, 313; A. R. Katritzky, S. Wang, M. Zhang, and P. J. Voronkov, J. Org. Chem., 2001, 66,
6787; M. Lautens and A. Roy, Org. Lett., 2000, 2, 555; D. Giomi, F. M. Cordero, and F. Machetti,
Comprehensive Heterocyclic Chemistry III, Vol 4, Ed, by A. R. Katritzky, C. A. Ramsden, E. F. V.
Scriven, and R. J. K. Taylor, 2008, p. 365.
2. D. P. J. Curran, J. Am. Chem. Soc., 1983, 105, 5826.
3. B. H. Kim, Y. J. Chung, and E. J. Ryu, Tetrahedron Lett., 1993, 34, 8465.
4. A. P. Kozikowski and P. D. Stein, J. Am. Chem. Soc., 1982, 104, 4023.
5. D. P. Curran and B. H. Kim, Synthesis, 1986, 312.
6. N. Maugein, A. Wagner, and C. Mioskowski, Tetrahedron Lett., 1997, 38, 1547.
7. G. A. Lee, Synth. Commun., 1982, 12, 508.
8. U. S. Sørensen, E. Falch, and P. Krogsgaard-Larsen, J. Org. Chem., 2000, 65, 1003.
9. M. A. P. Martin, A. F. C. Flores, G. P. Bastos, A. Sinhorin, H. G. Bonacorso, and N. Zanatta,
Tetrahedron Lett., 2000, 41, 293.
10. N. Iranpoor, H. Firouzabadi, and N. Nowrouzi, Tetrahedron Lett., 2006, 47, 8247.
11. T. J. Dale, A. C. Sather, and J. Rebek, Jr., Tetrahedron Lett., 2009, 50, 6173.
12. K. F. Shelka, S. B. Sapkal, N. V. Shitole, B. B. Shingata, and M. S. Shingare, Org. Commun., 2009, 2,
72.

HETEROCYCLES, Vol. 83, No. 5, 2011
1089
13. S. Udd, R. Jokela, R. Franzén, and J. Tois, Tetrahedron Lett., 2010, 51, 1030.
14. A. V. Dubrovskiy and R. C. Larock, Org. Lett., 2010, 12, 1180.
15. E. Comanita, I. Popovici, G. Roman, G. Robertson, and B. Comanita, Heterocycles, 1999, 51, 2139.
16. H. Suh, S. Jeong, Y. N. Han, H. Lee, and J. Ryu, Biorg. Med. Chem. Lett., 1997, 7, 389.
17. A. Nuhrich, M. Varache-Lembege, J. Vercauteren, R. Dokhan, P. Renard, and G. Devaux, Eur. J.
Med. Chem., 1996, 31, 957.
18. A. Villalobos, J. E. Blake, C. K. Biggers, T. W. Butler, D. S. Chapin, Y. L. Chen, J. L. Ives, S. B.
Jones, D. R. Liston, A. A. Nagel, D. M. Nason, J. A. Nielsen, I.A. Shalaby, and W. F. White, J. Med.
Chem., 1994, 37, 2721.
19. J. T. Strupczewski, K. J Bordeau, Y. Chiang, E. J. Glamkowski, P. G. Conway, R. Corbett, H. B.
Hartman, M. R. Szewczak, C. A. Wilmot, and G. C. Helsey, J. Med. Chem., 1995, 38, 1119; N. J.
Hrib, J. G. Jurcak, K. L. Burgher, P. G. Conway, H. B. Hartman, L. L. Kerman, J. E. Roehr, and A. T.
Woods, J. Med. Chem., 1994, 37, 2308.
20. A. R Katritzky, S. A. Belyakov, Y. Fang, and J. S. Kiely, Tetrahedron Lett., 1998, 39, 8051; H. V.
Meyers, G. J. Dilley, T. L. Durgin, T. S. Powers, N. A. Winssinger, H. Zhu, and M. R. Pavia, Molec.
Diversity, 1995, 1, 13.
21. Angiotensin(II) increases the activity of oxidative enzymes, mainly NAD(P)H oxidase, causing
injury to vascular endothelium, thus, various diseases (see: H. Mollnau, M. Wendt, K. Szöcs, B.
Lasségue, E. Schulz, M. Oelze, H. Li, M. Bodenschatz, M. August, A. L. Kleshy, N. Tsilimingas, V.
Walter, V. Försterman, T. Meinertz, K. Griendling, and T. Münzel, Circ. Res., 2002, 90, E58; E. M.
Mervada, Z. J. Cheng, I. TikkanEn, R. Lapatto, K. Nurminen, H. Vapaatalo, D. N. Muller, A.
Fiebeler, V. Ganten, D. Ganten, and F. C. Luft, Hypertension, 2001, 37, 414).
22. M. Odrowaz-Sypniewski, P. G. Tsoungas, G. Varvounis, and P. Cordopatis, Tetrahedron Lett., 2009,
50, 5981.
23. M. Pickert and A. W. Frahm, Arch. Pharm. Med. Chem., 1998, 331, 177; W. G. A. Ibrom and A. W.
Frahm, Arzeim Forsch./Drug. Res., 1997, 47, 662; A. A. Goldberg and H. A. Walker, J. Chem. Soc.,
1953, 1349; S. N. Dhar, Ibid., 1920, 117, 1057.
24. B. Reese, Q. Song, and H. Yan, Tetrahedron Lett., 2001, 42, 1789; C. B. Reese and H. Yan, J. Chem.
Soc., Perkin Trans. 1, 2001, 1807.
25. A. J. Boulton and P. G. Tsoungas, J. Chem. Soc., Chem. Commun., 1980, 421; A. J. Boulton, P. G.
Tsoungas, and C. Tsiamis, J. Chem. Soc., Perkin Trans. 1, 1986, 1665.
26. R. M. Moriarty, B. A. Berglund, and M. S. C. Rao, Synthesis, 1993, 318; P. Supsana, P. G. Tsoungas,
and G. Varvounis, Tetrahedron, 2001, 57, 3445; A. Kotali, I. S. Lafazanis, and P. A. Harris, Molbank,
2008, M572; A. Kotali, Ibid., 2008, M573.

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1
o
27. The 2D COSY and a 2D NOESY H NMR spectra (in DMSO-d6 at 25 C) of 7 show that the
deshielded C-13 OH (=11.6 ppm) and NOH (=11.4 ppm) protons form intramolecular H-bonding
in the Z-configuration.
Η-10 Η-9
11.45
OH
9.54
OH
11.60
N
7
OH
13
Η-1
Η-12 Η-3
6
6.91
Η-2
Η-11
Η-4
6.94
7.27
1
2
5
8
12
11
4
9
7.21
3
7.02
10
6.73
6.90
6.74
7.30
7.20
7.10
7.00
6.90
6.80
6.70
ppm (t1)
ΟΗ-13
Ν-ΟΗ
ΟΗ-6
11.0
10.0
9.0
8.0
7.0
ppm (t1)
28. Electrophilic Substitution on the rings to provide entries for further transformations, cannot be
performed selectively on any of the structures 6-34.
29. Cyclization involving the p-NO2 bearing phenol is feasible.25 In the present case, however, it is
outrun by the easier alternative cyclization mode.
30. Molecular
modeling
analysis
was
performed
with
Macromodel
(Schrödinger:
http://www.schrodinger.com) software and OPLS_2005 force field. Dielectric constant (ε) was set to
4.8 to simulate CDCl3 solvent used in NMR experiments. The first step in the conformational
analysis was to construct a preliminary 3D model which was geometry optimized and was then
subjected to Conformational Search (Random Sampling) using mixed torsional/low mode sampling
with 5000 as maximum number of steps. Each one of the 64 derived conformers was energy
minimized using Truncated Newton Conjugate Gradient (TNCG) algorithm with 5000 maximum
iterations and converge on gradient with 0.001 threshold.

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31. A. Kumar and D. Kumar, ARKIVOC, 2007, (xiv), 117; W.-H. Chen and Y. Pang, Tetrahedron Lett.,
2009, 50, 6680; W.-H. Chen and Y. Pang, Ibid., 2010, 51, 1914.
32. P. G. Tsoungas and B. De Costa, Magn. Res. Chem., 1988, 26, 8.