Synthesis of 3-Substituted 2,1-Benzisoxazoles by the Oxidative Cyclization of 2-Aminoacylbenzenes with Oxone

Article abstract of DOI:10.1055/s-0035-1561471

An efficient approach to the synthesis of 2,1-benzisoxazoles through direct construction of the N-O bond by the chemoselective oxidation of 2-aminoacylbenzenes with Oxone is described. This alternative methodology is characterized by its simple and transition-metal-free conditions and good functional group compatibility utilizing Oxone as a green oxidant instead of hypervalent iodine compounds. Moreover, this new procedure simplifies the number of steps compared to the previously reported procedure by circumventing the use of 2-azido-substituted aryl ketones.

Full text of DOI:10.1055/s-0035-1561471

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–N
feature
A
M. Chiarini et al.
Feature
Synthesis
Synthesis of 3-Substituted 2,1-Benzisoxazoles by the Oxidative
Cyclization of 2-Aminoacylbenzenes with Oxone
Marco Chiarinia
Luana Del Vecchiob
Fabio Marinellib
Leucio Rossib
Antonio Arcadi*b
a Facoltà di Bioscienze e Tecnologie Agroalimentari e Ambienta-
li, Università di Teramo, Via Carlo Lerici 1, 64023 Mosciano
Sant’Angelo (Te), Italy
b Dipartimento di Scienze Fisiche e Chimiche, Università di L’Aq-
uila, Via Vetoio, 67010 Coppito (AQ), Italy
antonio.arcadi@univaq.it
Received: 11.04.2016
Accepted after revision: 03.05.2016
Published online: 22.06.2016
of the N–O bond was previously accomplished by the reac-
tion of 2-azido-substituted aryl ketones 2 promoted by iron
salts (Scheme 1a).8 These latter derivatives are obtained in
one-step from the 2-aminoacylbenzenes 1. Moreover, the
direct hypervalent iodine oxidation of suitable 2-aminoac-
ylbenzenes 1 to give the corresponding products 3 enabled
an efficient synthesis of 3-(β-styryl)-2,1-benzisoxazoles
(Scheme 1b).9
With the aim to simplify the number of steps by cir-
cumventing the use of 2-azido-substituted aryl ketones as
the starting materials and to develop a simple, safer and
sustainable strategy for the selective oxidative cyclization
of the 2-aminoacylbenzenes, herein we report the results of
our investigation on the transformation of these latter sub-
strates into the corresponding 2,1-benzisoxazoles by using
Oxone as the oxidant (Scheme 1c). Current efforts are de-
voted to circumvent the use of stoichiometric hypervalent
iodine compounds which generate equimolar amounts of
organic waste.10
Oxone is a non-toxic, cheap, and stable white solid, is
easy-to-handle, and is soluble in water. Applications of Ox-
one in synthetic chemistry represent an attractive area of
research.11 Even though the ability of Oxone to oxidize a
broad spectrum of functional groups has been demonstrat-
ed,12 no studies have been reported to date for promoting
chemoselective oxidative cyclizations of 2-aminoacylben-
zenes. Recently, Oxone was employed as a green oxidant (in
water) of nitrogen-rich heterocyclic amines to give the cor-
responding nitroaromatics via the production of a hydrox-
ylamine intermediate.13 Oxone over silica gel or alumina
was also found to oxidize primary and secondary amines
into the corresponding hydroxylamines.14 Hence, we envis-
aged that the in situ generation of the hydroxylamine func-
tion by the oxidation of the starting 2-aminoacylbenzenes 1
would allow the selective attack on the carbonyl in a subse-
DOI: 10.1055/s-0035-1561471; Art ID: ss-2016-e0249-fa
Abstract An efficient approach to the synthesis of 2,1-benzisoxazoles
through direct construction of the N–O bond by the chemoselective
oxidation of 2-aminoacylbenzenes with Oxone is described. This alter-
native methodology is characterized by its simple and transition-metal-
free conditions and good functional group compatibility utilizing Ox-
one as a green oxidant instead of hypervalent iodine compounds. More-
over, this new procedure simplifies the number of steps compared to
the previously reported procedure by circumventing the use of 2-azido-
substituted aryl ketones.
Key words Oxone, 2,1-benzisoxazoles, 2-aminoacylbenzenes, oxida-
tive cyclization, transition-metal-free
The direct construction of the N–O bond to form the
corresponding heterocyclic derivatives is a long-standing
challenge in organic synthesis.1 Despite the relevance of N–O
bonds in biologically active heterocycles, only a few meth-
ods that form this bond have been reported. Benzisoxazole
scaffolds are among the most highly recognized pharmaco-
phores because of their extensive biological activities.2 In
particular, 2,1-benzisoxazoles (anthranils) are key interme-
diates in the synthesis of various drugs,3 in addition to their
direct application as pharmacologically active compounds.4
Classically, these compounds are prepared from starting
materials with a pre-existing N–O bond. The reactions of
1,3-diketones with hydroxylamine results in 2,1-benzisox-
azoles.4a A variety of methods for the synthesis of 2,1-ben-
zisoxazoles consist of the condensation of nitroarenes and
arylacetonitriles.5 The BF3·OEt2-catalyzed reaction of glyox-
ylate esters with nitrosoarenes provided a convergent route
to this class of compounds.6 Reductive heterocyclization of
2-nitroacylbenzenes has also been frequently used to build-
up the 2,1-benzisoxazole nucleus.7 Conversely, an approach
to the synthesis of 2,1-benzisoxazoles involving formation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

B
M. Chiarini et al.
Feature
Synthesis
Biographical Sketches
Marco Chiarini received his
are focused on supramolecular
and organometallic chemistry.
In this field, particular attention
was directed toward the synthe-
sis of conjugate polymers and
on applied colloid and surfaces
chemistry. He has worked in the
field of surfactant-catalyzed re-
actions, both from the point of
view of possible synthetic appli-
cations and of basic knowledge
of micellar structure and reac-
tivity, and has acquired skills in
magnetic resonance techniques
(multinuclear NMR and EPR) ap-
plied to organic and food chem-
‘Laurea’ degree in chemistry
from the University of Camerino
in 1994, and his Ph.D. degree in
chemistry from the University
of Roma ‘Tor Vergata’ in 2000.
Presently he is a full-time Re-
searcher in Organic Chemistry
at the Department of Food
Chemistry at the University of
Teramo. His research interests
istry.
In
the
field
of
organometallic chemistry, he
has acquired expertise on the
synthesis of organic conductive
π-conjugated polymers.
Luana Del Vecchio received
he her ‘Laurea’ degree from ‘G.
D’Annunzio’ University in Chieti
in 2014. In the same year, she
moved to L’Aquila to begin her
Ph.D. in organic chemistry in
the group of Professor Antonio
Arcadi. Her research is centered
on the synthesis of heterocy-
cles.
Fabio Marinelli obtained his
‘Laurea’ degree in chemistry at
the University of Rome ‘La Sapi-
enza’ in 1980. In 1983, he be-
University. His research inter-
ests are centered on the appli-
presence of Pd and Au salts, or
by means of in situ generated
organopalladium(II) intermedi-
ates, and hydroarylation/hy-
drovinylation of internal alkynes
with aryl halides and organobo-
ron derivatives catalyzed by Pd
and Rh complexes.
cation
of
organometallic
complexes as catalysts in organ-
ic synthesis. The main topics of
his scientific activity include the
synthesis of heterocyclic com-
pounds from alkynes bearing
proximate nucleophiles in the
came
Organic
Chemistry
Researcher at the University of
L’Aquila. Since 2001, he has
been Associate Professor of Or-
ganic Chemistry at the same
Leucio Rossi obtained his ‘Lau-
rea’ degree in chemistry in
1991, and his Ph.D. in chemistry
at the University of Rome ‘La
Sapienza’. In 1995, he became
Assistant Professor of Chemistry
at the University of L’Aquila, and
since 2002, he has been Associ-
ate Professor of Chemistry at
the same University. His re-
search activity is mainly focused
on green chemistry, organic
electrosynthesis, and carbon di-
oxide recycling and reuse.
Antonio Arcadi obtained his
‘Laurea’ degree in medicinal
chemistry and technology at
the University of Rome ‘La Sapi-
enza’ in 1978 under the guid-
ance of Professor S. Cacchi. In
1979, he joined the Institute of
Chemistry at the University of
L’Aquila to undertake a teaching
fellowship and research activi-
ties on organometallic chemis-
try directed toward organic
synthesis. He was appointed As-
sociate Professor of Organic
Chemistry in 1992 at the uni-
versity of Urbino, and as Full
Professor of Organic Chemistry
in 2002 at the University of
L’Aquila. His current research in-
terests lie in the area of devel-
oping
new
synthetic
methodologies through transi-
tion-metal catalysis. More re-
cently, he has focused on the
development of gold catalysis in
organic synthesis. His other
achievements have been ob-
tained in the field of domino re-
actions as useful tools in ‘green
chemistry’.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

C
M. Chiarini et al.
Feature
Synthesis
quent heterocyclization–dehydration reaction, overriding
further oxidation of the primary amino group into the cor-
responding nitroaromatic derivatives 5.15
perature in a longer time (Table 1, entry 3). The use of other
oxidants resulted in unsatisfactory transformations (Table
1, entries 4–12).
R3
Previous Work
R3
R2
R3
R3
N3
R2
O
Oxone
R2
R1
R2
R1
O
MeCN/H2O
(1:1)
O
O
NaNO2
NaN3
NH2
a)
NHOH
R1
NH2
R1
1
1
2
R3
4
– H2O
R3
R2
FeBr2 (5 mol%)
4 Å MS (100 wt%)
CH2Cl2, 40 °C
O
R2
NO2
R1
O
N
R3
R3
R2
R1
R2
R1
R1
5
3
O
PhI(OAc)2–KOH
MeOH
O
b)
Scheme 2 Proposed reaction pathway
N
NH2
3
1
Potassium peroxydisulfate (K2S2O8) gave a low conver-
sion of 1a with no formation of 3a (Table 1, entry 4).17 Com-
plete degradation of 1a into benzoic acid occurred in the
presence of Selectfluor (Table 1, entry 5). Similarly, the con-
version of 1a into 3a was not observed by carrying out the
reaction in MeCN at room temperature by using both a
slight excess of urea hydrogen peroxide (1.5 equiv) or a
larger quantity (10 equiv) of 50% H2O2 as the oxidant (Table
1, entries 6 and 7). The 2,1-benzisoxazole 3a was isolated in
6% yield when the reaction of 1a with 50% H2O2 was carried
out at 60 °C (Table 1, entry 8). A lack of selectivity occurred
when adding AgNO3 (0.1 equiv) as the catalyst in the hydro-
gen peroxide mediated oxidation of 1a. Under these latter
conditions, the complete conversion of 1a led to the forma-
tion of 3a (30% yield) and 1,2-bis(2-benzoylphenyl)diazene-
1-oxide (5a) (22% yield) (Table 1, entry 9). According to the
literature, the further oxidation of the hydroxylamine inter-
mediate 4a into 1,2-bis(2-benzoylphenyl)diazene-1-oxide
(5a) could be accelerated by metal catalysts.18 Although
This Work
R3
R3
R2
R2
O
Oxone
O
N
c)
MeCN/H2O
(1:1)
NH2
R1
R1
Scheme 1 The previous and our present study on the oxidative cycliza-
tion of 2-aminoacylbenzenes 1 to give 2,1-benzisoxazoles 3
As a part of our ongoing research on the development of
efficient, mild, and benign protocols for oxidative cycliza-
tions to access useful heterocycles, herein, we report that
Oxone can promote the selective oxidative cyclization of
various aminoacylbenzenes 1 to achieve an effective alter-
native entry into the target 3-substituted 2,1-benzisox-
azoles 3 (Scheme 2).
We began our investigation by using commercially
available 2-aminobenzophenone (1a) in a model reaction
and the results are summarized in Table 1. According to our
previous studies on the silver-catalyzed oxidative cycliza-
tion of unprotected 2-alkynylanilines with Oxone,16 we car-
ried out the oxidation of 1a with Oxone in MeCN/H2O in the
presence of a catalytic amount of AgNO3. The desired prod-
uct 3a was isolated in 93% yield when the reaction was car-
ried out at 60 °C for 0.5 hours with an excess of Oxone (2
equiv) in the presence of AgNO3 (0.1 equiv) (Table 1, entry
1). A comparable yield of 3a was observed by omitting the
silver catalyst (Table 1, entry 2). Gratifyingly, by lowering
the amount of Oxone to one equivalent and omitting the
catalyst, product 3a was isolated in 90% yield at room tem-
methyltrioxorhenium–hydrogen
peroxide
systems,19
iron(III)-salen–H2O220 as well as mesoporous titania micro-
spheres,21 and simple TiO2 in ionic liquid22 have been used
to promote selective aniline oxidative coupling to give the
corresponding azoxybenzenes, challenges remain to afford
high selectivities, and the study of the effects of silver catal-
ysis toward this aim deserves in-depth analysis.
The formation of a variable amount of the derivative 5a
was also detected both in the presence of AgNO3 and under
metal-free conditions when m-CPBA was used as the oxi-
dant instead of hydrogen peroxide (Table 1, entries 10–
12).23 The oxidation of 1a to give the nitro derivative 6a pre-
vailed by using excess m-CPBA (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

D
M. Chiarini et al.
Feature
Synthesis
Table 1 Optimization of the Reaction Conditions
Our results clearly highlight that the oxidation of the
amino group of 1a may result in the formation of multiple
products and that the lack of selectivity can represent a
strong shortcoming. Interestingly, in the case of Oxone, the
exclusive formation of 3a was achieved in high yield avoid-
ing harsh conditions and expensive catalysts. Thus, we fi-
nalized the reaction conditions by employing a 1:1 mixture
of MeCN/H2O as the reaction medium with Oxone (1 equiv)
at room temperature. These conditions were utilized to ex-
plore the substrate scope of the oxidative cyclization of 2-
aminoacylbenzenes 1. The 2-aminochalcones 1d–k were
easily prepared by means of aldol condensation reactions
(Scheme 4a).24
Oxidant
O
O
N
NH2
1a
3a
Time (h)
Entry Oxidant (equiv)
Temp (°C)
Yield of 3a
(%)a,b
1
2
3
4
5
6
Oxone (2)c
Oxone (2)
60
60
r.t.
r.t.
r.t.
r.t.
0.5
0.5
22
24
1
93
92
O
O
Oxone (1)
90
K2S2O8 (1)
Selectfluor (3)d
– (90)d,e
–
R4
R4-CHO, NaOH
EtOH, r.t.
a)
NH2
NH2
H2NCONH2·H2O2
(1.5)d
48
– (83)e
1c
1d–k (72–88%)
7
50% H2O2 (10)f
50% H2O2 (10)f
50% H2O2 (10)g
m-CPBA (1.5)d
m-CPBA (1.5)d
m-CPBA (1.5)d
r.t.
60
60
r.t.
60
60
24
24
24
48
24
24
– (84)e
6 (84)e
30h
8
O
Pd(OAc)2 (0.05 equiv)
HCOOK (3 equiv)
9
1d,e
R4
b)
10
11
12
2 (45)e,i
3 (40)e,j
3 (41)e,k
DMF, 60 °C, 12 h
NH2
1l,m (91–99%)
a Yield of isolated product.
Scheme 4 Synthesis of 2-aminochalcones 1d–k and the palladium-
catalyzed conjugate reduction of 2-aminochalcones 1d,e
b Unless otherwise noted, all reactions were performed with 1.0 mmol of
1a in MeCN/H2O (2.5 mL/2.5 mL).
c Reaction was carried out in the presence of 0.1 equiv of AgNO3.
d Reaction was carried out in MeCN.
e Figures in parentheses refer to the recovered yield of 1a.
f Reaction was performed with 1.8 mmol of 1a in MeCN/H2O2 50 wt% in
H2O (4.0 mL/1.0 mL).
The palladium-catalyzed selective reduction reactions
of 1d,e with potassium formate led to the isolation of the
corresponding alkyl derivatives 1l,m in 99% and 91% yield,
respectively (Scheme 4b).25
The iodination of 1a–c led selectively in high yields to
the corresponding iodo derivatives 1n–p (Scheme 5a),26
which in turn underwent palladium-catalyzed cross-cou-
plings to give 1-(4-amino-[1,1’-biphenyl]-3-yl)ethan-1-one
(1q)27 and the alkynyl derivatives 1r–t (Scheme 5b).28 The
direct access to 2-aminoacyl derivative 1u was achieved
from the corresponding 2-amino-5-chlorobenzaldehyde via
rhodium-catalyzed cross-coupling with (4-methoxyphe-
nyl)boronic acid (Scheme 5c).29
g Reaction was performed with 1.8 mmol of 1a in MeCN/H2O2 50 wt% in
H2O (4.0 mL/1.0 mL) in the presence of 0.1 equiv of AgNO3.
h Compound 5a was isolated in 22% yield.
i Compound 5a was isolated in 21% yield.
j Compound 5a was isolated in 47% yield.
k Compound 5a was isolated in 35% yield.
O
O
N
N
O
m-CPBA (5 equiv)
O
O
The results of our investigations on the substrate scope
of the Oxone-mediated oxidative cyclization of 2-amino-
acylbenzenes are summarized in Table 2.
+
MeCN, 60 °C, 2 h
NH2
NO2
6a (47% yield)
1a
5a (28% yield)
Scheme 3 m-CPBA-mediated oxidative coupling of 2-aminobenzophe-
none (1a)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

E
M. Chiarini et al.
Feature
Synthesis
O
Pd(OAc)2 (0.05 equiv)
PhB(OH)2 (1.5 equiv)
i-Pr2NH (2 equiv)
Ph
R3
O
O
R2
(Cl) I
R3
NH2
EtOH/H2O (1:1)
70 °C, 15 h
I2, Ag2SO4
R3
NH2
1q (R3 = Me, 63% yield)
a)
EtOH, r.t.
b)
NH2
1a, R1 = R2 = H, R3 = Ph
1b, R1 = H, R2 = Cl, R3 = Ph
1c, R1 = R2 = H, R3 = Me
1n–p
R1
H (I)
Pd(PPh3)4 (0.01 equiv)
CuI (0.01 equiv)
R5
O
R5
(1.2 equiv)
R3
NH2
1a–c
1n–p (81–96% yield)
piperidine, r.t., 2–5 h
1r (R3 = Ph; R5 = n-C6H13; 68% yield)
1s (R3 = Ph; R5 = Ph; 93% yield)
1t (R3 = Ph; R5 = C(CH3)2OH; 90% yield)
MeO
B(OH)2
c)
O
(2 equiv)
(0.03 equiv)
t-Bu3PHBF4 (0.06 equiv)
O
Cl
Rh(COD)2Cl
Cl
H
NH2
K2CO3 (3 equiv)
NH2
1u (40% yield)
OMe
dioxane/acetone (4:1)
80 °C, 6 h
Scheme 5 Functionalization reactions of 2-aminoacylbenzenes
Table 2 Scope of the Oxone-Promoted Oxidative Cyclization of 2-Aminoacylbenzenes into 2,1-Benzisoxazoles
O
R3
R2
R2
R3
NH2
Oxone (1 equiv)
O
MeCN/H2O (1:1)
r.t.
N
R1
R1
1a–u
3a–u
Entry
1
Substrate
Time (h)
20
Product/yield (%)a
O
NH2
O
1a
N
3a (90)
2
3
16
O
Cl
Cl
NH2
O
1b
N
3b (92)
8
O
O
N
3c (92)
NH2
1c
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F
M. Chiarini et al.
Feature
Synthesis
Table 2 (continued)
Entry
4
Substrate
Time (h)
12
Product/yield (%)a
O
NH2
1d
O
N
3d (83)
5
6
7
12
12
24
OMe
O
NH2
OMe
1e
O
N
3e (81)
O
Cl
NH2
Cl
1f
O
N
3f (88)
O
F
NH2
F
1g
O
N
3g (72)
8
12
O
F
F
NH2
1h
O
N
3h (70)
9
6
O
Br
Br
NH2
1i
O
N
3i (90)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

G
M. Chiarini et al.
Feature
Synthesis
Table 2 (continued)
Entry
10
Substrate
Time (h)
20
Product/yield (%)a
O
O
O
NH2
1j
O
N
3j (86)
11
24
O
Cl
Cl
Cl
Cl
NH2
1k
O
N
3k (90)
12
23
O
NH2
1l
O
N
3l (91)
13
21
O
OMe
NH2
OMe
1m
O
N
3m (86)
14
23
O
I
I
NH2
O
O
1n
N
N
3n (–)
15
16
24
24
I
I
O
3o (–)
NH2
O
1o
Cl
Cl
NH2
O
I
N
1p
I
3p (–)c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

H
M. Chiarini et al.
Feature
Synthesis
Table 2 (continued)
Entry
17
Substrate
Time (h)
17
Product/yield (%)a
O
O
N
NH2
3q (92)
1q
18
24
H13C6
O
H13C6
NH2
O
1r
1r
N
3r (54)b
3r (80)c
19
20
6
15
O
NH2
O
O
N
3s (95)c
1s
21
22
24
OH
OH
O
NH2
N
3t (40)d
1t
8
OMe
O
Cl
NH2
OMe
Cl
1u
O
N
3u (86)
a Yield of isolated product.
b Starting material 1r was recovered in 36% yield.
c Reaction temperature = 60 °C.
d Product 7t was isolated in 30% yield.
The effect of the R3 substituent on the reaction was sur-
veyed. 2,1-Benzisoxazoles were obtained in good to high
yields from substrates bearing aryl, vinyl or alkyl R3 groups.
Although, a variety of olefins, including chalcones, were
cleaved oxidatively to give the corresponding acids with Ox-
one in acetonitrile/water mixture (1:1, v/v) at reflux tem-
perature,30 and Oxone/acetone-mediated syn-dioxygen-
ation of benzo-fused olefins has been described,31 our mild
reaction conditions were compatible with the presence of
the C=C double bond, accomplishing an alternative and very
efficient synthesis of the corresponding 3-(β-styryl)-2,1-
benzisoxazoles9 3d–k from the readily available o-amino-
chalcones 1d–k (Table 2, entries 4–11). Interestingly, the
procedure was extended to the synthesis of (E)-3-[(2-furan-
2-yl)vinyl]benzo[c]isoxazole (3j) (Table 2, entry 10). By con-
trast with the moderate yield (50%) of the 3-methyl-2,1-
benzisoxazole reported in the oxidation of 2-aminoace-
tophenone (1c) promoted by hypervalent iodine, the Ox-
one-promoted oxidation of 2-aminoacylbenzenes bearing
alkyl R3 groups 1c,l,m resulted in the formation of the cor-
responding anthranil derivatives 3c,l,m in high yields (Table
2, entries 3, 12 and 13). A variety of R2 groups were also tol-
erated. The present reaction conditions were compatible
with the presence of Cl, phenyl, and alkynyl R2 groups. In
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

I
M. Chiarini et al.
Feature
Synthesis
OH
OH
O
H3C
H3C
H3C
H3C
O
O
O
Oxone
3t (40%) +
MeCH/H2O (1:1)
r.t., 24 h
NH2
NH2
1t
7t (30% yield)
Scheme 6 Competitive side oxidation of the C≡C triple bond
the presence of the alkynyl group, better results were ob-
served at 60 °C. Indeed, the yield of 3r increased from 54%
to 80% by carrying out the reaction at 60 °C instead of at
room temperature (Table 2, entries 18 and 19). Only in the
case of the reaction of 1t did we observed the competitive
side oxidation of the carbon–carbon triple bond32 to give 7t
in 30% yield (Scheme 6).
The ortho-disubstituted derivative 1p remained unaf-
fected even at 60 °C (Table 2, entry 16).33 Moreover, in con-
trast with the reported tolerability to Oxone of some iodo
derivatives,11c,d we failed to obtain the desired iodo-2,1-
benzisoxazole derivatives 3n,o (Table 2, entries 14 and 15).
Very likely, under our reaction conditions, the iodo-2-ami-
noacylbenzene derivatives 1n,o can be oxidized by Oxone
to give iodine(V) species, which trigger further unselective
oxidative processes.34
In summary, we have developed a novel protocol for the
synthesis of 2,1-benzisoxazoles via the oxidative cyclization
reaction of 2-aminoacylbenzenes with Oxone. Such more
environmentally friendly protocols, which utilize transi-
tion-metal-free, mild reaction conditions, and inexpensive
and readily available reagents, provide an effective alterna-
tive strategy for the chemoselective construction of these
target molecules, which occupy privileged positions in the
fields of pharmaceuticals and materials science.
2-Aminochalcones 1d–k; General Procedure
The aldehyde (5.0 mmol) was dissolved in EtOH (5 mL) and NaOH (1
pellet) and 2-aminoacetophenone (1c) (5.0 mmol) were successively
added to the solution. The mixture was stirred at r.t. for 2–24 h. The
reaction progress was monitored by TLC. When the reaction was
complete, the mixture was diluted with a solution of NH4Cl (0.5 M)
and extracted with EtOAc (× 3). The combined organic phase was
dried over Na2SO4. After filtration, the filtrate was concentrated under
reduced pressure and the residue purified by silica gel flash column
chromatography.
1-(2-Aminophenyl)-3-substituted Propan-1-ones 1l,m; Typical
Procedure
Synthesis of 1-(2-Aminophenyl)-3-(4-methoxyphenyl)propan-1-
one (1m)
Pd(OAc)2 (0.008 g, 0.036 mmol) was added to a stirred solution of 1-
(2-aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (1e) (0.192
g, 0.72 mmol) in DMF (3 mL). The mixture was purged with N2 and
HCOOK (0.160 g, 1.90 mmol) was added in one portion. The tempera-
ture was raised to 60 °C and the mixture was stirred at that tempera-
ture for 12 h under an N2 atm. Next, CH2Cl2 and sat. Na2CO3 solution
were added to the cooled mixture. The organic layer was separated,
washed with H2O, and dried (Na2SO4). The solvent was evaporated
and the residue purified by flash chromatography on silica gel (n-hex-
ane/EtOAc, 98:2) to give 1-(2-aminophenyl)-3-(4-methoxyphe-
nyl)propan-1-one (1m).
1-(2-Aminophenyl)-3-phenylpropan-1-one (1l)
White solid; yield: 0.101 g (99%); mp 69–71 °C.
Unless otherwise stated, all starting materials, catalysts, and solvents
were commercially available and were used as purchased. Reaction
products were purified by flash chromatography on silica gel eluting
with n-hexane/EtOAc mixtures. Compounds 1a–c are commercially
available; compounds 1d,35 1e,36 1f,g,35 1h,24a 1i,37 1j,k,24a 1n,38 1o,39
1p,40 1q,41 3a,42 3b,43 3c,42 3d–f,9 3q,44 3s,45 3u,45 and 6a46 are known
and were identified by comparison of their physical and spectral data
with those reported in the cited references. Melting points were ob-
tained using a Büki 500 apparatus and are uncorrected. IR spectra
(KBr pellets or neat on NaCl plates) were recorded on a Perkin-Elmer
IR (KBr): 3473, 3340, 1650, 753 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.72 (ddd, J = 8.1 Hz, J = 1.5 Hz, J = 0.4
Hz, 1 H), 7.32–7.18 (m, 6 H), 6.63 (ddd, J = 8.3 Hz, J = 1.2 Hz, J = 0.5 Hz,
1 H), 6.61 (ddd, J = 8.1 Hz, J = 7.0 Hz, J = 1.2 Hz, 1 H), 6.27 (br s, 2 H,
NH2), 3.28–3.24 (m, 2 H), 3.06–3.02 (m, 2 H).
13C NMR (100.6 MHz, CDCl3): δ = 201.5 (C=O), 150.4 (C), 141.5 (C),
134.3 (CH), 131.0 (CH), 128.5 (CH), 128.4 (CH), 126.1 (CH), 117.8 (C),
117.4 (CH), 115.8 (CH), 41.0 (CH2), 30.6 (CH2).
HRMS MALDI-TOF: m/z [M + K]+ calcd for C15H15KNO: 264.0791;
found: 264.0784.
1
Spectrum Two FT-IR spectrometer. H NMR spectra were recorded at
400 MHz on a Bruker Avance III spectrometer. Chemical shifts (in
ppm) are referenced to tetramethylsilane (δ = 0) in CDCl3 or in DMSO-
d6 as an internal standard (δ = 2.49). 13C NMR spectra were obtained
using the same instrument at 100.6 MHz and were calibrated with
CDCl3 (δ = 77.00) or DMSO-d6 (δ = 30.50). HRMS spectra were record-
ed using a MALDI-TOF spectrometer: AB SCIEX TOF/TOF 5800 System.
1-(2-Aminophenyl)-3-(4-methoxyphenyl)propan-1-one (1m)
Off-white semi-solid; yield: 0.168 g (91%).
IR (neat): 3473, 3340, 1639, 1039, 753 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.72 (ddd, J = 8.1 Hz, J = 1.5 Hz, J = 0.4
Hz, 1 H), 7.26–7.21 (m, 1 H), 7.18–7.14 (m, 2 H), 6.85–6.82 (m, 2 H),
6.65–6.59 (m, 2 H), 6.29 (br s, 2 H, NH2), 3.78 (s, 3 H, OMe), 3.24–3.20
(m, 2 H), 3.00–2.96 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

J
M. Chiarini et al.
Feature
Synthesis
13C{1H} NMR (100.6 MHz, CDCl3): δ = 201.7 (C=O), 158.0 (C), 150.4 (C),
134.2 (CH), 133.5 (C), 131.1 (CH), 129.3 (2 CH), 117.9 (C), 117.4 (CH),
115.8 (CH), 114.0 (2 CH), 55.3 (CH3), 41.2 (CH2), 29.8 (CH2).
HRMS MALDI-TOF: m/z [M + H]+ calcd for C16H18NO2: 256.1336;
found: 256.1337.
13C NMR (100.6 MHz, CDCl3): δ = 198.6 (C=O), 150.2 (C), 139.7 (C),
137.6 (CH), 137.2 (CH), 131.2 (CH), 129.1 (2 CH), 128.2 (2 CH), 117.8
(C), 117.0 (CH), 111.0 (C), 88.0 (C), 80.0 (C), 31.3 (CH2), 28.8 (CH2),
28.6 (CH2), 22.5 (CH2), 19.4 (CH2), 14.0 (CH3).
HRMS MALDI-TOF: m/z [M + K]+ calcd for C21H23KNO: 344.1417;
found: 344.1410.
Selective Iodination of 2-Aminoacylbenzenes 1a–c; Typical Proce-
dure
[2-Amino-5-(phenylethynyl)phenyl](phenyl)methanone (1s)
Pale yellow solid; yield: 0.127 g (93%); mp 140–142 °C.
IR (KBr): 3437, 3325, 2210, 1630, 1243, 758 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.67–7.65 (m, 3 H), 7.57–7.53 (m, 1 H),
7.49–7.42 (m, 5 H), 7.31–7.24 (m, 3 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.28
(br s, 2 H, NH2).
13C NMR (100.6 MHz, CDCl3): δ = 198.5 (C=O), 150.7 (C), 139.6 (C),
137.8 (CH), 137.1 (CH), 131.4 (CH), 131.3 (2 CH), 129.2 (2 CH), 128.28
(2 CH), 128.27 (2 CH), 127.9 (CH), 123.5 (C), 117.8 (C), 117.2 (CH),
110.0 (C), 89.2 (C), 87.4 (C).
Synthesis of (2-Amino-5-chloro-3-iodophenyl)(phenyl)metha-
none (1p)
(2-Amino-5-chlorophenyl)(phenyl)methanone (1b) (0.300 g, 1.29
mmol), I2 (0.327 g, 1.29 mmol) and Ag2SO4 (0.402 g, 1.29 mmol) in
EtOH (10 ml) were stirred for 12 h at r.t. After this time, the crude
mixture was filtered to eliminate the precipitate of inorganic salt and
then washed with sat. Na2S2O3 solution. The organic phase was sepa-
rated, dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
(n-hexane) to give 1p.
HRMS MALDI-TOF: m/z [M + K]+ calcd for C21H15KNO: 336.0791;
found: 336.0788.
Yield: 0.444 g (94%).
[2-Amino-5-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl](phe-
nyl)methanone (1t)
1-(4-Amino-[1,1′-biphenyl]-3-yl)ethanone (1q)
Pd(OAc)2 (0.009 g, 0.04 mmol) was added to a stirred solution of
phenylboronic acid (0.146 g, 1.20 mmol) and i-Pr2NH (0.162 g, 1.60
mmol) in EtOH/H2O (3 mL/3 mL). The mixture was purged with N2,
the temperature raised to 70 °C, and the mixture stirred at the same
temperature for 15 h under an N2 atm. The cooled mixture was dilut-
ed with a solution of NH4Cl (0.5 M) and extracted with EtOAc (× 3).
The combined organic phase was dried over Na2SO4. After filtration,
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel flash column chromatography (n-hex-
ane/EtOAc, 97:3) to give 1q.
Pale yellow solid; 0.115 g (90%); mp 151–153 °C.
IR (KBr): 3432, 3315, 2224, 1625, 840, 662 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (m, 2 H), 7.57–7.52 (m, 2 H),
7.50–7.45 (m, 2 H), 7.32 (dd, J = 8.6 Hz, J = 2.0 Hz, 1 H), 6.66 (d, J = 8.6
Hz, 1 H), 6.25 (br s, 3 H, OH, NH2), 1.55 (s, 6 H).
13C NMR (100.6 MHz, CDCl3): δ = 198.5 (C=O), 150.7 (C), 139.6 (C),
137.8 (CH), 137.2 (CH), 131.4 (CH), 129.1 (2 CH), 128.3 (2 CH), 117.7
(C), 117.1 (CH), 109.5 (C), 91.6 (C), 81.8 (C), 65.6 (C), 31.6 (2 CH3).
HRMS MALDI-TOF: m/z [M + K]+ calcd for C18H17KNO2: 318.0896;
found: 318.0890.
Yield: 0.106 g (63%).
Alkynylation of (2-Amino-5-iodophenyl)(phenyl)methanone (1n);
Typical Procedure
(2-Amino-5-chlorophenyl)(4-methoxyphenyl)methanone (1u)
To a mixture of 4-methoxyphenylboronic acid (0.252 g, 1.66 mmol),
2-amino-5-chlorobenzaldehyde (0.130 g, 0.83 mmol), K2CO3 (0.344 g,
2.49 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.0012
g, 0.025 mmol) in dioxane/acetone (2 mL/0.5 mL) was added tri-t-bu-
tylphosphonium tetrafluoroborate (0.014 g, 0.050 mmol) under an N2
atm. The temperature was raised to 80 °C and the reaction mixture
was stirred at that temperature for 6 h under an N2 atm. After concen-
tration under reduced pressure, the crude residue was purified by sil-
ica gel chromatography (n-hexane/EtOAc, 92:8) to give product 1u.
Synthesis of [2-Amino-5-(phenylethynyl)phenyl](phenyl)metha-
none (1s)
Pd[(PPh)3]4 (0.005 g, 0.005 mmol) was added to a stirred solution of
(2-amino-5-iodophenyl)(phenyl)methanone (1n) (0.147 g, 0.46
mmol), phenylacetylene (0.056 g, 0.55 mmol) and CuI (0.001 g, 0.005
mmol) in piperidine (5 mL). The mixture was purged with N2 and
stirred at r.t. for 5 h under an N2 atm. The mixture was diluted with
HCl (1.0 M and extracted with EtOAc (× 3). The combined organic
phase was dried over Na2SO4. After filtration, the filtrate was concen-
trated under reduced pressure. The residue was purified by silica gel
flash column chromatography (n-hexane/EtOAc, 90:10) to give 1s.
Brown oil; yield: 0.087 g (40%).
IR (neat): 3468, 3355, 1644, 782, 747 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.69–7.65 (m, 2 H), 7.43–7.40 (m, 1 H),
7.22 (dd, J = 8.8 Hz, J = 2.5 Hz, 1 H), 6.98–6.95 (m, 2 H), 6.68 (d, J = 8.8
Hz, 1 H), 5.82 (br s, 2 H, NH2), 3.88 (s, 3 H, OCH3).
[2-Amino-5-(oct-1-yn-1-yl)phenyl](phenyl)methanone (1r)
13C{1H} NMR (100.6 MHz, CDCl3): δ = 196.5 (C=O), 162.7 (C), 148.8 (C),
133.5 (CH), 132.7 (CH), 131.8 (2 CH), 131.5 (C), 130.9 (C), 128.8 (C),
118.4 (CH), 113.6 (2 CH), 55.5 (OCH3).
HRMS MALDI-TOF: m/z [M + K]+ calcd for C14H12ClKNO2: 300.0194;
found: 300.0196.
Brown oil; yield: 0.095 g (68%).
IR (neat): 3462, 3350, 2225, 1640, 825, 758 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (m, 2 H), 7.55–7.44 (m, 4 H),
7.31 (dd, J = 8.5 Hz, J = 2.0 Hz, 1 H), 6.64 (d, J = 8.5 Hz, 1 H), 6.18 (br s,
2 H, NH2), 2.32 (t, J = 7.1 Hz, 2 H), 1.57–1.50 (m, 2 H), 1.42–1.26 (m, 6
H), 0.87 (t, J = 7.1 Hz, 3 H).
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

K
M. Chiarini et al.
Feature
Synthesis
Oxidative Cyclization of 2-Aminoacylbenzenes 1; Typical Proce-
dure
3-[(E)-2-(2-Furyl)vinyl]-2,1-benzisoxazole (3j)
Orange solid; 0.087 g (86%); mp 96–98 °C.
IR (KBr): 1629, 1522, 1451, 957, 748 cm–1
.
Synthesis of 3-[(E)-2-(4-Fluorophenyl)vinyl]-2,1-benzisoxazole
(3g)
1H NMR (400 MHz, CDCl3): δ = 7.59 (dt, J = 8.8 Hz, J = 1.1 Hz, 1 H), 7.54
(ddd, J = 9.1 Hz, J = 1.1 Hz, J = 0.8 Hz, 1 H), 7.50 (ddd, J = 1.8 Hz, J = 1.2
Hz, J = 0.5 Hz, 1 H), 7.35 (dt, J = 16.1 Hz, J = 0.5 Hz, 1 H), 7.29 (ddd, J =
9.1 Hz, J = 6.4 Hz, J = 1.0 Hz, 1 H), 7.21 (dt, J = 16.1 Hz, J = 0.5 Hz, 1 H),
6.99 (ddd, J = 8.8 Hz, J = 6.4 Hz, J = 0.8 Hz, 1 H), 6.58 (ddd, J = 3.4 Hz, J =
1.2 Hz, J = 0.6 Hz, 1 H), 6.49 (dd, J = 3.3 Hz, J = 1.8 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): δ = 163.3 (C), 157.4 (C), 151.9 (C), 143.9
(CH), 130.9 (CH), 123.9 (CH), 121.6 (CH), 119.8 (CH), 116.0 (C), 115.2
(CH), 112.9 (CH), 112.4 (CH), 109.8 (CH).
Oxone (0.270 g, 0.44 mmol) was added to a solution of (E)-1-(2-amin-
ophenyl)-3-(4-fluorophenyl)prop-2-en-1-one (1g) (0.106 g, 0.44
mmol) in MeCN/H2O (2.5 mL/2.5 mL). The mixture was stirred at r.t.
and the progress was monitored by TLC and GC–MS. After stirring for
24 h, H2O (150 mL) and CH2Cl2 (150 mL) were added. The organic lay-
er was separated and the aq layer was extracted with CH2Cl2. The
combined organic layers were washed with H2O, dried over Na2SO4,
filtered and concentrated. The filtrate was evaporated and subjected
to column chromatography on silica gel (n-hexane/EtOAc, 98:2) to
give 2,1-benzisoxazole 3g.
HRMS MALDI-TOF: m/z [M + H]+ calcd for C13H10NO2: 212.0712;
found: 212.0706.
Pale yellow solid; 0.075 g (72%); mp 124–126 °C.
IR (KBr): 1639, 1599, 1507, 1227, 967, 820, 738 cm–1
3-[(E)-2-(3,4-Dichlorophenyl)vinyl]-2,1-benzisoxazole (3k)
.
Pale yellow solid; 0.124 g (90%); mp 180–182 °C.
1H NMR (400 MHz, CDCl3): δ = 7.62 (dt, J = 8.8 Hz, J = 1.0 Hz, 1 H),
7.59–7.53 (m, 4 H), 7.30 (ddd, J = 9.1 Hz, J = 6.4 Hz, J = 1.0 Hz, 1 H),
7.22 (dd, J = 16.5 Hz, J = 0.6 Hz, 1 H), 7.12–7.08 (m, 2 H), 7.01 (ddd, J =
8.8 Hz, J = 6.4 Hz, J = 0.8 Hz, 1 H).
13C{1H} NMR (100.6 MHz, CDCl3): δ = 163.31 (J = 250.4 Hz, C), 163.30
(C), 157.4 (C), 133.8 (J = 1.1 Hz, CH), 131.9 (J = 3.4 Hz, C), 130.9 (CH),
129.0 (J = 8.2 Hz, CH), 124.1 (CH), 119.7 (CH), 116.1 (J = 21.9 Hz, CH),
115.4 (C), 115.3 (CH), 111.8 (J = 2.6 Hz, CH).
IR (KBr): 1639, 1100, 881, 820, 743 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.12 (dd, J = 2.1 Hz, J = 0.3 Hz, 1 H),
8.01 (dt, J = 8.8 Hz, J = 1.1 Hz, 1 H), 7.90 (d, J = 16.6 Hz, 1 H), 7.79 (ddd,
J = 8.4 Hz, J = 2.1 Hz, J = 0.5 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.64 (d, J =
16.6 Hz, 1 H), 7.60 (ddd, J = 9.1 Hz, J = 1.1 Hz, J = 0.8 Hz, 1 H), 7.42
(ddd, J = 9.1 Hz, J = 6.4 Hz, J = 1.0 Hz, 1 H), 7.14 (ddd, J = 8.8 Hz, J = 6.4
Hz, J = 0.8 Hz, 1 H).
13C NMR (100.6 MHz, DMSO-d6): δ = 162.8 (C), 156.7 (C), 136.4 (C),
131.7 (CH), 131.6 (C), 131.4 (CH), 131.2 (C), 130.7 (CH), 128.8 (CH),
127.3 (CH), 124.4 (CH), 120.4 (CH), 115.8 (C), 114.40 (CH), 114.35
(CH).
HRMS MALDI-TOF: m/z [M + H]+ calcd for C15H10Cl2NO: 290.0139;
found: 290.0147.
HRMS MALDI-TOF: m/z [M + H]+ calcd for C15H11FNO: 240.0825;
found: 240.0820.
3-[(E)-2-(2-Fluorophenyl)vinyl]-2,1-benzisoxazole (3h)
Pale yellow solid; 0.072 g (70%); mp 108–110 °C.
IR (KBr): 1487, 1461, 1232, 962, 815, 743 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 16.6 Hz, 1 H), 7.65 (dt, J =
8.8 Hz, J = 1.1 Hz, 1 H), 7.62 (td, J = 7.8 Hz, J = 1.5 Hz, 1 H), 7.57 (ddd,
J = 9.1 Hz, J = 1.1 Hz, J = 0.8 Hz, 1 H), 7.43 (d, J = 16.6 Hz, 1 H), 7.33–
7.28 (m, 2 H), 7.19 (td, J = 7.6 Hz, J = 1.0 Hz, 1 H), 7.12 (ddd, J = 11.0 Hz,
J = 8.2 Hz, J = 1.2 Hz, 1 H), 7.03 (ddd, J = 8.8 Hz, J = 6.4 Hz, J = 0.8 Hz, 1
H).
3-(2-Phenylethyl)-2,1-benzisoxazole (3l)
Off-yellow semi-solid; yield: 0.081 g (91%).
IR (neat): 1645, 1522, 1461, 743 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.51–7.48 (m, 1 H), 7.29–7.15 (m, 7 H),
6.87–6.83 (m, 1 H), 3.44 (t, J = 7.8 Hz, 2 H), 3.16 (t, J = 7.8 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): δ = 163.3 (C), 161.0 (J = 252.6 Hz, C),
157.4 (C), 130.9 (CH), 130.6 (J = 8.6 Hz, CH), 128.2 (J = 3.1 Hz, CH),
127.7 (J = 2.7 Hz, CH), 124.5 (J = 3.6 Hz, CH), 124.3 (CH), 123.7 (J = 11.6
Hz, C), 119.8 (CH), 116.2 (J = 22.0 Hz, CH), 116.0 (C), 115.4 (CH), 114.5
(J = 7.4 Hz, CH).
13C NMR (100.6 MHz, CDCl3): δ = 168.2 (C), 157.0 (C), 139.9 (C), 130.7
(CH), 128.6 (2 CH), 128.3 (2 CH), 126.6 (CH), 122.9 (CH), 119.7 (CH),
115.5 (C), 114.9 (CH), 34.0 (CH2), 28.8 (CH2).
HRMS MALDI-TOF: m/z [M + K]+ calcd for C15H13KNO: 262.0634;
found: 262.0630
HRMS MALDI-TOF: m/z [M + H]+ calcd for C15H11FNO: 240.0825;
found: 240.0828.
3-[2-(4-Methoxyphenyl)ethyl]-2,1-benzisoxazole (3m)
Off-yellow semi-solid; yield: 0.099 g (86%).
IR (neat): 1645, 1609, 1517, 1034, 825, 743 cm–1
3-[(E)-2-(3-Bromophenyl)vinyl]-2,1-benzisoxazole (3i)
.
Pale yellow solid; 0.097 g (90%); mp 135–137 °C.
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 9.1 Hz, 1 H), 7.27–7.21 (m, 2
H), 7.08–7.06 (m, 2 H), 6.85 (dd, J = 8.8 Hz, J = 6.4 Hz, 1 H), 6.81–6.79
(m, 2 H), 3.76 (s, 3 H, OMe), 3.40 (d, J = 7.7 Hz, 2 H), 3.10 (d, J = 7.7 Hz,
2 H).
13C NMR (100.6 MHz, CDCl3): δ = 168.4 (C) , 158.3 (C), 157.1 (C), 130.7
(CH), 132.1 (C), 129.3 (2 CH), 122.9 (CH), 119.8 (CH), 115.5 (C), 114.9
(CH), 114.1 (2 CH), 55.3 (CH3), 33.1 (CH2), 29.1 (CH2).
IR (KBr): 1620, 1563, 1517, 967, 743 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.75 (dd, J = 1.8 Hz, J = 1.4 Hz, 1 H),
7.64 (dt, J = 8.8 Hz, J = 1.1 Hz, 1 H), 7.58 (ddd, J = 9.1 Hz, J = 1.1 Hz, J =
0.8 Hz, 1 H), 7.54–7.46 (m, 3 H), 7.32 (ddd, J = 9.1 Hz, J = 6.4 Hz, J = 1.0
Hz, 1 H), 7.31–7.30 (m, 1 H), 7.28–7.26 (m, 1 H), 7.04 (ddd, J = 8.8 Hz,
J = 6.4 Hz, J = 0.8 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): δ = 162.8 (C), 157.4 (C), 137.8 (C), 133.2
(CH), 132.1 (CH), 130.9 (CH), 130.4 (CH), 129.8 (CH), 126.0 (CH), 124.5
(CH), 123.2 (C), 119.6 (CH), 116.2 (C), 115.4 (CH), 113.2 (CH).
HRMS MALDI-TOF: m/z [M + K]+ calcd for C16H15KNO2: 292.0740;
found 292.0734.
HRMS MALDI-TOF: m/z [M + H]+ calcd for C15H11BrNO: 300.0024;
found: 300.0016.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

L
M. Chiarini et al.
Feature
Synthesis
5-Oct-1-yn-1-yl-3-phenyl-2,1-benzisoxazole (3r)
13C NMR (100.6 MHz, CDCl3): δ = 195.5 (C=O), 193.7 (C=O), 146.7 (C),
141.8 (C), 137.8 (C), 136.7 (C), 134.8 (C), 134.7 (C), 133.1 (CH), 132.8
(CH), 131.4 (CH), 130.9 (CH), 130.2 (CH), 129.8 (2 CH), 129.07 (CH),
129.05 (2 CH), 128.8 (CH), 128.48 (2 CH), 128.45 (CH), 128.3 (2 CH),
123.2 (CH), 122.6 (CH).
HRMS MALDI-TOF: m/z [M + H]+ calcd for C26H19N2O3: 407.1396;
found: 407.1393.
Brown oil; yield: 0.039 g (54%).
IR (neat): 2225, 1634, 1548, 815 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.01–7.99 (m, 2 H), 7.90 (t, J = 1.2 Hz, 1
H), 7.57–7.47 (m, 4 H), 7.28 (dd, J = 9.3 Hz, J = 1.3 Hz, 1 H), 2.43 (t, J =
7.1 Hz, 2 H), 1.67–1.59 (m, 2 H), 1.51–1.43 (m, 2 H), 1.36–1.31 (m, 4
H), 0.92 (t, J = 7.1 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): δ = 164.3 (C), 156.7 (C), 134.0 (CH),
130.4 (CH), 129.3 (2 CH), 128.2 (C), 126.6 (2 CH), 123.4 (CH), 120.4
(C), 115.4 (CH), 114.3 (C), 92.0 (C), 80.4 (C), 31.4 (CH2), 28.7 (2 CH2),
22.6 (CH2), 19.5 (CH2), 14.1 (CH3).
HRMS MALDI-TOF: m/z [M + H]+ calcd for C21H22NO: 304.1701; found:
304.1698.
1-(4-Amino-3-benzoylphenyl)-3-hydroxy-3-methylbutane-1,2-di-
one (7t)
Oxone (0.176 g, 0.29 mmol) was added to a solution of [2-amino-5-
(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl](phenyl)methanone (1t)
(0.081 g, 0.29 mmol) in MeCN/H2O (2.5 mL/2.5 mL). The mixture was
stirred at r.t. and the reaction progress was monitored by TLC. After
stirring for 24 h, H2O and CH2Cl2 (150 mL) were added to the mixture.
The organic layer was separated and the aq layer was extracted with
CH2Cl2. The combined organic layers were washed with H2O, dried
over Na2SO4, filtered and concentrated. The filtrate was evaporated
and subjected to column chromatography on silica gel (n-hex-
ane/EtOAc, 85:15) to give 2-methyl-4-(3-phenyl-2,1-benzisoxazol-5-
yl)but-3-yn-2-ol (3t) (0.032 g, 40%) and 1-(4-amino-3-benzoylphe-
nyl)-3-hydroxy-3-methylbutane-1,2-dione (7t).
2-Methyl-4-(3-phenyl-2,1-benzisoxazol-5-yl)but-3-yn-2-ol (3t)
Pale yellow solid; 0.032 g (40%); mp 99–101 °C.
IR (KBr): 3412, 2322, 1614, 1548, 1176, 810, 687 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.00–7.98 (m, 2 H), 7.93 (t, J = 1.3 Hz, 1
H), 7.58–7.46 (m, 4 H), 7.27 (dd, J = 9.3 Hz, J = 1.3 Hz, 1 H), 6.60 (br s, 1
H, OH), 1.65 (s, 6 H).
13C NMR (100.6 MHz, CDCl3): δ = 164.8 (C), 156.6 (C), 133.6 (CH),
130.6 (CH), 129.3 (2 CH), 128.0 (C), 126.7 (2 CH), 124.4 (CH), 120.6
(C), 115.6 (CH), 114.2 (C), 95.0 (C), 81.8 (C), 65.7 (C), 31.5 (2 CH3).
Brown solid; 0.027 g (30%), mp 96–98 °C.
IR (KBr): 1727, 1614, 1426, 1252, 906, 779 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 2.1 Hz, 1 H), 7.84 (dd, J = 8.8
Hz, J = 2.1 Hz, 1 H), 7.64–7.62 (m, 2 H), 7.59–7.55 (m, 1 H), 7.51–7.47
(m, 2 H), 6.92 (br s, 3 H, OH, NH2), 6.77 (d, J = 8.8 Hz, 1 H), 1.47 (s, 6 H).
HRMS MALDI-TOF: m/z [M + H]+ calcd for C18H16NO2: 278.1181;
found: 278.1186.
13C NMR (100.6 MHz, CDCl3): δ = 207.5 (C=O), 198.4 (C=O), 191.9
(C=O), 155.8 (C), 139.2 (CH), 138.8 (C), 134.6 (CH), 131.9 (CH), 129.2
(2 CH), 128.4 (2 CH), 120.5 (C), 117.3 (CH), 116.8 (C), 76.6 (C), 26.8 (2
CH3).
HRMS MALDI-TOF: m/z [M + H]+ calcd for C18H18NO4: 312.1236;
found: 312.1230.
Silver-Catalyzed Oxidation of 2-Aminobenzophenone (1a) with
50% H2O2
AgNO3 (0.020 g, 0.139 mmol) and 50% H2O2 (1 mL) were added to a
solution of 2-aminobenzophenone (1a) (0.274 g, 1.39 mmol) in MeCN
(4.0 mL). The mixture was stirred at 60 °C and the reaction progress
was monitored by TLC. After stirring for 24 h, to the cooled mixture
were added H2O (150 mL) and CH2Cl2 (150 mL). The organic layer was
separated and the aq layer extracted with CH2Cl2. The combined or-
ganic layers were washed with H2O, dried over Na2SO4, filtered and
concentrated. The filtrate was evaporated and the residue subjected
to column chromatography on silica gel (n-hexane/EtOAc, 70:30) to
give 3-phenyl-2,1-benzisoxazole (3a) (0.082 g, 30%) and 1,2-bis(2-
benzoylphenyl)diazene-1-oxide (5a) (0.063 g, 22%).
Acknowledgment
This work was supported by the University of L’Aquila (Italy).
Supporting Information
Oxidation of 2-Aminobenzophenone (1a) with m-CPBA
Supporting information for this article is available online at
m-CPBA (1.489 g, 8.63 mmol) was added to a solution of 2-aminoben-
zophenone (1a) (0.34 g, 1.72 mmol) in MeCN (5.0 mL). The mixture
was stirred at 60 °C and the reaction progress was monitored by TLC.
After stirring for 2 h, to the cooled mixture were added 2 M NaOH
(150 mL) and CH2Cl2 (150 mL). The organic layer was separated and
the aq layer was extracted with CH2Cl2. The combined organic layers
were washed with H2O, dried over Na2SO4, filtered and concentrated.
The filtrate was evaporated and the residue subjected to column chro-
matography on silica gel (n-hexane/EtOAc, 70:30) to give (2-nitro-
phenyl)(phenyl)methanone (6a) (0.183 g, 47%) and 1,2-bis(2-benzo-
ylphenyl)diazene-1-oxide (5a).
http://dx.doi.org/10.1055/s-0035-1561471.
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