Reactivity of 2,1-Benzisoxazole in Palladium-Catalyzed Direct Arylation with Aryl Bromides

Article abstract of DOI:10.1002/cctc.201600047

The Pd-catalyzed direct arylation of 2,1-benzisoxazole with aryl bromides to access 3-arylbenzoisoxazoles proceeds in moderate-to-high yields with 1 mol % Pd(OAc)₂ or 2 mol % PdCl(C₃H₅)(dppb) (dppb=1,4-bis(diphenylphosphino)butane) as the catalysts and KOAc as an inexpensive base. A wide variety of (hetero)aryl bromides have been employed successfully. Moreover, arylations followed by benzisoxazole ring opening allowed the preparation of 2-aminobenzophenones in only two steps. What a couple: The Pd-catalyzed direct arylation of 2,1-benzisoxazole with aryl bromides and 1 mol % of phosphine-free Pd(OAc)₂ catalyst in association with KOAc as an inexpensive base allows the preparation of 3-arylbenzoisoxazoles in moderate-to-high yields. Moreover, the 2,1-benzisoxazole C-3-arylations followed by benzisoxazole ring opening gives access to 2-aminobenzophenones in only two steps.

Full text of DOI:10.1002/cctc.201600047

DOI: 10.1002/cctc.201600047
Full Papers
Reactivity of 2,1-Benzisoxazole in Palladium-Catalyzed
Direct Arylation with Aryl Bromides
Mohand Aidene,[a, b] Fatma Belkessam,[a, b] Jean-FranÅois SoulØ,*[b] and Henri Doucet*[b]
The Pd-catalyzed direct arylation of 2,1-benzisoxazole with aryl
bromides to access 3-arylbenzoisoxazoles proceeds in
moderate-to-high yields with 1 mol% Pd(OAc)2 or 2 mol%
PdCl(C3H5)(dppb) (dppb=1,4-bis(diphenylphosphino)butane)
as the catalysts and KOAc as an inexpensive base. A wide vari-
ety of (hetero)aryl bromides have been employed successfully.
Moreover, arylations followed by benzisoxazole ring opening
allowed the preparation of 2-aminobenzophenones in only
two steps.
Introduction
3-Arylbenzisoxazole and 2-aminobenzophenone derivatives ex-
hibit important biological properties.[1] For example, A is an in-
hibitor of the proto-oncogene Pim-1 kinase,[2] and both Brom-
fenac and Nepafenac are nonsteroidal anti-inflammatory drugs
for the treatment of ocular inflammation (Figure 1).
duced with more classical cross-coupling procedures. Although
the 4-arylation of isoxazoles has been studied in detail, only
one example of a Pd-catalyzed direct coupling of an aryl halide
with a benzisoxazole has been reported.[6] For this reaction,
a
quite high catalyst loading was employed [5 mol%
PdCl2(MeCN)2 with 10 mol% 1,2-bis(diphenylphosphino)ben-
zene (DPPBz); Scheme 1, top]. Moreover, the expensive base
AgF (2 equiv.) was used. In most cases, 3-arylbenzisoxazoles
are still prepared through organic reactions such as the intra-
molecular cyclization of 2-azidobenzophenones or the reac-
tions of nitrobenzene derivatives with phenylacetonitrile deriv-
atives (Scheme 1, middle and bottom).[7] However, for these
two methods, the substrate scope is limited because of the dif-
Figure 1. Examples of drugs containing 3-arylbenzisoxazole and 2-amino-
benzophenone motifs.
In 1982, Nakamura et al. reported that the 4-arylation of iso-
xazoles with aryl halides proceeds in moderate yields through
a CÀH bond activation with Pd catalysts.[3] Since this initial
report, the Pd-catalyzed direct arylation[4] of isoxazole deriva-
tives with aryl halides has proved to be a very powerful
method for the synthesis of a wide variety of 4-arylated isoxa-
zoles.[3,5] The major byproducts of these reactions are a base
associated with HX, instead of the metallic salts that are pro-
[a] Dr. M. Aidene, Dr. F. Belkessam
DØpartement de chimie
Tizi Ouzou University
BP 17 RP 15000 Tizi-Ouzou (Algeria)
[b] Dr. M. Aidene, Dr. F. Belkessam, Dr. J.-F. SoulØ, Dr. H. Doucet
Institut des Sciences Chimiques de Rennes
UMR 6226 CNRS-UniversitØ de Rennes
“OrganomØtalliques: MatØriaux et Catalyse”
Campus de Beaulieu, 35042 Rennes (France)
E-mail: jean-francois.soule@univ-rennes1.fr
henri.doucet@univ-rennes1.fr
Scheme 1. Reported syntheses of 3-arylbenzoisoxazoles.
ChemCatChem 2016, 8, 1583 – 1590
1583
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
ficult access to some substrates and to the poor functional-
group tolerance. The convenient synthesis of 2-aminobenzo-
phenones is also an important challenge in organic chemistry,
as they are currently prepared through multistep syntheses.[8]
Therefore, economically viable reaction conditions that pro-
mote the direct arylation of 2,1-benzisoxazole with aryl bro-
mides in the presence of a low loading of a readily available
Pd catalyst are needed to provide access to a wide variety of
arylated benzisoxazole derivatives.
at 1508C led to 1 in 47% yield with a complete conversion of
2-bromonaphthalene (Table 1, Entry 1). In 2003, de Vries and
co-workers demonstrated that if Pd(OAc)2 is employed at ele-
vated temperature as the catalyst precursor without a phos-
phine ligand, soluble palladium(0) colloids or nanoparticles are
formed, which are very efficient catalysts in the Heck and
Suzuki reactions.[9] We have recently reported that the use of
the “de Vries conditions” promoted the coupling of aryl bro-
mides with several heteroaromatics.[10] The coupling reactions
Here, we report on the reactivity of 2,1-benzisoxazole in Pd-
catalyzed direct arylation reactions with a wide variety of aryl
bromides and either a phosphine-free Pd catalyst or Pd associ-
ated with a simple diphosphine ligand (1,4-bis(diphenylphos-
phino)butane; dppb) in the presence of an inexpensive base
(Scheme 2). The ring opening of benzisoxazole for access to 2-
aminobenzophenones is also described.
of 2,1-benzisoxazole and 2-bromonaphthalene with 1 or
0.5 mol% Pd(OAc)2 catalyst at 1508C afforded the target prod-
uct 1 in very high yields of 78 and 80%, respectively (Table 1,
Entries 2 and 3). The use of 1 mol% PdCl2 catalyst was less ef-
fective, as 1 was isolated in only 35% yield (Table 1, Entry 4).
We also examined the influence of some bases; potassium car-
bonate, cesium carbonate, and sodium acetate were complete-
ly ineffective, and 2-bromonaphthalene was recovered (Table 1,
Entries 5–7). The different results obtained with KOAc and
NaOAc as bases might come from the poor solubility of NaOAc
in dimethylacetamide (DMA). The influence of the nature of
the solvent was also examined. The reaction in DMF afforded
1 in a low yield of 33%, whereas the use of N-methyl-2-pyrroli-
done (NMP) was ineffective (Table 1, Entries 8 and 9). Xylene
and cyclopentyl methyl ether (CPME), which are suitable sol-
vents for the Pd-catalyzed direct arylation of several heteroaro-
matics,[5d] were also ineffective (Table 1, Entries 10 and 11). The
reaction performed at 1208C instead of 1508C with 1 mol% of
Pd(OAc)2 catalyst afforded 1 in only 12% yield because of the
very low conversion of 2-bromonaphthalene (Table 1, Entry 12).
Then, we studied the scope of this reaction with various aryl
bromides, 1 mol% Pd(OAc)2 as the catalyst, and KOAc as the
base in DMA at 1508C (Scheme 3). First, we examined the reac-
tivity of para-substituted aryl bromides. The coupling of 2,1-
benzisoxazole with 4-bromobenzaldehyde, 4-bromoa-
Scheme 2. Pd-catalyzed direct arylation of 2,1-benzisoxazole followed by
ring opening.
Results and Discussion
Initially, we studied the reactivity of 2,1-benzisoxazole in the
presence of 2-bromonaphthalene as the arylation partner
(Table 1). The use of 2 mol% of the PdCl(C3H5)(dppb) catalyst
cetophenone, 4-bromopropiophenone, 4-bromoben-
zophenone, and ethyl 4-bromobenzoate proceeded
Table 1. Influence of the reaction conditions on the arylation of 2,1-benzisoxazole
with 2-bromonaphthalene.[a]
well to afford 2–6 in 82–93% yields. High yields of
the desired 3-arylbenzoisoxazoles 7 and 8 were also
obtained from 4-(trifluoromethyl)bromobenzene and
4-bromobenzonitrile in the presence of 1 mol%
Pd(OAc)2, whereas 9 was only obtained in a moderate
yield from the less electron-deficient 4-bromochloro-
benzene under these conditions because of the par-
tial conversion of this aryl bromide. This poor conver-
sion is probably caused by the slow oxidative addi-
tion of 4-bromochlorobenzene to Pd. Therefore, this
phosphine-free Pd catalysis is limited to some elec-
tron-deficient aryl bromides. However, 9 could be ob-
Entry Solvent Base
Catalyst
T
Conversion[b] Yield of 1[c]
[(mol%)]
[8C] [%]
[%]
1
2
3
4
5
6
7
8
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
NMP
Xylene
CPME
DMA
KOAc
KOAc
KOAc
KOAc
K2CO3
PdCl(C3H5)(dppb) (2) 150 100
47
78
80
35
–
–
–
33
0
0
Pd(OAc)2 (1)
Pd(OAc)2 (0.5)
PdCl2 (1)
150 100
150
150
150
150
150
150
150
140
110
120
97
77
0
Pd(OAc)2 (1)
Cs2CO3 Pd(OAc)2 (1)
NaOAc Pd(OAc)2 (1)
0
0
tained in
a good yield of 86% with 2 mol%
PdCl(C3H5)(dppb) catalyst. For 4-bromofluorobenzene
and bromobenzene, 2 mol% PdCl(C3H5)(dppb) again
had to be employed as the catalyst to obtain 10 and
11 in good yields.
The electron-deficient meta-substituted aryl bro-
mides 3-bromoacetophenone, 3-bromobenzonitrile,
and 3,5-bis(trifluoromethyl)bromobenzene were also
very reactive with 1 mol% Pd(OAc)2 as the catalyst
KOAc
KOAc
KOAc
KOAc
KOAc
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
51
30
0
0
15
9
10
11
12
0
12
[a] Conditions: 2,1-benzisoxazole (1.5 equiv.), 2-bromonaphthalene (1 equiv.), KOAc
(2 equiv.), 20 h. [b] Conversions of 2-bromonaphthalene determined by using GC and
NMR spectroscopy. [c] Isolated yields.
ChemCatChem 2016, 8, 1583 – 1590
www.chemcatchem.org
1584
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
19 in good-to-high yields. 2-Fluorobromobenzene, 2-chloro-
bromobenzene, and 1-bromonaphthalene were less reactive,
and again 2 mol% PdCl(C3H5)(dppb) had to be employed as
the catalyst to produce 20–22 in good yields. Heteroaryl bro-
mides are also suitable reactants for the C-3-arylation of 2,1-
benzisoxazole. The coupling of 3-bromopyridine, 3-bromoqui-
noline, and 5-bromopyrimidine in the presence of 1 mol%
Pd(OAc)2 or 2 mol% PdCl(C3H5)(dppb) as the catalyst led to
23–25 in yields of 78–89%. The reactivity of two aryl chlorides
for such couplings was also examined with 2 mol%
PdCl(C3H5)(dppb) as the catalyst. From 4-chlorobenzonitrile,
the desired product 8 was obtained in 35% yield because of
the moderate conversion of this aryl chloride; whereas, a poor
yield of 7 (<10%) was obtained from 4-(trifluoromethyl)chloro-
benzene.
The Pd-catalyzed coupling of 9-bromoantracene with 2,1-
benzisoxazole also proceed well (Scheme 4). However, only the
(2-aminophenyl)(anthracen-9-yl)methanone (26) was isolated
Scheme 4. Direct arylation of 2,1-benzisoxazole with 9-bromoanthracene.
because of the in situ benzisoxazolyl ring opening. GC–MS
analysis of the crude mixture only showed the formation of 26.
This ring opening is probably caused by the steric hindrance
of the anthracenyl moiety.
From 1,2-dibromobenzene and 2,1-benzisoxazole, the forma-
tion of several products, such as the monocoupling product
27a or the dicoupling product 27b, was possible (Scheme 5).
However, only product 27c that arose from the coupling at
positions C-3 and C-4 of 2,1-benzisoxazole followed by the
benzisoxazolyl ring opening was isolated. This method gives
a one-step access to 1-amino-9H-fluoren-9-ones, which exhibit
important physical properties.[11]
The discovery of efficient methods for the synthesis of 2-
aminobenzophenones in a limited number of steps is also an
important research field in organic synthesis. Therefore, the
scope of the benzoisoxazole ring-opening reaction for access
to 2-aminobenzophenones under classical conditions was in-
Scheme 3. Direct arylation of 2,1-benzisoxazole with a set of aryl bromides.
and afforded 13–15 in yields of 89–93%. Next, the reactivity of
a set of ortho-substituted aryl bromides was investigated. 2-
Formyl-, 2-nitrile-, and 2-(trifluoromethyl)bromobenzene in the
presence of 1 mol% Pd(OAc)2 gave the desired products 17–
Scheme 5. Direct arylation of 2,1-benzisoxazole with 1,2-dibromobenzene.
ChemCatChem 2016, 8, 1583 – 1590
www.chemcatchem.org
1585
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
pare a variety of 2-aminobenzophenones, which are valuable
building blocks, in only two steps.
Experimental Section
DMA (99%) and 2,1-benzisoxazole (99%) were purchased from
Acros. Pd(OAc)2, [Pd(C3H5)Cl]2, 1,4-bis(diphenylphosphino)butane
(98%), KOAc (99%), and 1,2-benzisoxazole (97%) were purchased
from Alfa Aesar. These compounds were not purified before use.
Preparation of PdCl(C3H5)(dppb)[13]
An oven-dried 40 mL Schlenk tube equipped with a magnetic stir-
ring bar under Ar was charged with [Pd(C3H5)Cl]2 (182 mg,
0.5 mmol) and dppb (426 mg, 1 mmol). Anhydrous dichlorome-
thane (10 mL) was added, and the solution was stirred at RT for
20 min. The solvent was removed in vacuum. The yellow powder
was used without purification. 31P NMR (81 MHz, CDCl3): d=
19.3 ppm (s).
Scheme 6. Pd-catalyzed ring opening of 3-arylbenzisoxazoles for access to 2-
aminobenzophenones.
General procedure for the synthesis of compounds 1–27
Typically, the aryl bromide derivative (1 mmol), 2,1-benzisoxazole
(0.179 g, 1.5 mmol), KOAc (0.196 g, 2 mmol), and PdCl(C3H5)(dppb)
(12.2 mg, 0.02 mmol) or Pd(OAc)2 (2.2 mg, 0.01 mmol) were dis-
solved in DMA (4 mL) under an Ar atmosphere. The reaction mix-
ture was stirred at 1508C for 20 h. Then the solvent was evaporat-
ed and the product was purified by silica gel column chromatogra-
phy.
vestigated (Scheme 6).[12] In the presence of 10 wt% of Pd/
C(10%) and NEt3 under H2 in THF, 3-phenylbenzo[c]isoxazole
(11) gave the desired 2-aminobenzophenone (28) in an almost
quantitative yield. The 3-naphthyl-substituted benzoisoxazoles
1 and 22 also afforded the expected (2-aminophenyl)(naph-
thyl)methanones 29 and 30 in high yields. From the fluoro-
and trifluoromethyl-substituted 3-aryl benzo[c]isoxazoles 15,
19, and 20, the target products 31–33 were obtained in yields
of 55, 93, and 92%, respectively. Notably, one-pot sequential
reactions that involve the C-3-arylation of 2,1-benzisoxazole
with 1-bromonaphthalene followed by the removal of the sol-
vent and treatment of the crude mixture by Pd/C(10%) and
NEt3 under H2 in THF failed to afford 2-aminobenzophenone
30.
3-(Naphthalen-2-yl)benzo[c]isoxazole (1)[14]
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 2-bromonaphtha-
lene (0.207 g, 1 mmol), 1 was obtained in 80% (0.196 g) yield as
1
a yellow solid. M.p.: 84–868C; H NMR (400 MHz, CDCl3): d=8.48 (s,
1H), 8.10 (dd, J=8.5, 2.6 Hz, 1H), 8.00–7.84 (m, 4H), 7.64 (d, J=
8.3 Hz, 1H), 7.60–7.53 (m, 2H), 7.34 (dd, J=9.0, 6.4 Hz, 1H),
7.09 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
164.7, 157.7, 133.6, 132.9, 130.5, 128.9, 128.5, 127.7, 127.4, 126.8,
126.3, 125.5, 124.5, 123.0, 120.5, 115.3, 114.4 ppm.
4-(Benzo[c]isoxazol-3-yl)benzaldehyde (2)
Conclusions
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-bromobenzalde-
hyde (0.185 g, 1 mmol), 2 was obtained in 91% (0.203 g) yield as
a yellow solid. M.p.: 174–1778C; 1H NMR (400 MHz, CDCl3): d=
10.07 (s, 1H), 8.16 (d, J=8.3 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 7.83
(d, J=8.8 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.34 (dd, J=9.0, 6.4 Hz,
1H), 7.13 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=191.1, 162.4, 157.9, 136.7, 133.2, 130.8, 130.4, 126.7, 125.8,
120.0, 115.9, 115.5 ppm; elemental analysis calcd (%) for C14H9NO2
(223.23): C 75.33, H 4.06; found: C 75.21, H 4.22.
We have demonstrated that 2,1-benzisoxazole, which is com-
mercially available at an affordable cost, reacts well in the pres-
ence of only 1 mol% of phosphine-free Pd(OAc)2 catalyst and
KOAc as an inexpensive base to afford the 3-arylated benzisox-
azoles in good to very high yields. This procedure gave the
best results using electron-deficient aryl bromides, and several
functions such as formyl, acetyl, propionyl, benzoyl, ester, ni-
trile, and trifluoromethyl were tolerated. This procedure is at-
tractive as the major byproducts of these couplings are AcOH/
KBr, it reduces the number of steps to prepare these com-
pounds, and there is no need to eliminate phosphine deriva-
tives at the end of the reaction. For these reasons, the method-
ology developed here is very promising for the sustainable
synthesis of 3-arylbenzisoxazoles. Moreover, sequential CÀH
bond activation followed by benzisoxazole ring opening using
Pd/C as catalyst under hydrogen pressure allowed us to pre-
1-[4-(Benzo[c]isoxazol-3-yl)phenyl]ethanone (3)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-bromoacetophe-
none (0.199 g, 1 mmol), 3 was obtained in 89% (0.211 g) yield as
1
a yellow solid. M.p.: 152–1568C; H NMR (400 MHz, CDCl3): d=8.10
(s, 4H), 7.84 (d, J=8.8 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.35 (dd, J=
9.0, 6.4 Hz, 1H), 7.12 (dd, J=8.8, 6.4 Hz, 1H), 2.66 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=197.1, 162.8, 157.9, 137.6, 132.1,
ChemCatChem 2016, 8, 1583 – 1590
www.chemcatchem.org
1586
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
130.7, 129.1, 126.4, 125.5, 120.2, 115.8, 115.3, 26.7 ppm; elemental
analysis calcd (%) for C15H11NO2 (237.25): C 75.94, H 4.67; found: C
75.74, H 4.54.
J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=161.8, 158.0,
133.1, 132.1, 131.0, 126.8, 126.2, 119.8, 118.2, 116.1, 115.6,
113.4 ppm; elemental analysis calcd (%) for C14H8N2O (220.23): C
76.35, H 3.66; found: C 76.42, H 3.80.
1-[4-(Benzo[c]isoxazol-3-yl)phenyl]propan-1-one (4)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-bromopropio-
3-(4-Chlorophenyl)benzo[c]isoxazole (9)[7d]
phenone (0.213 g, 1 mmol), 4 was obtained in 87% (0.218 g) yield
as a yellow solid. M.p.: 148–1508C; H NMR (400 MHz, CDCl3): d=
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-bromochloro-
1
benzene (0.191 g, 1 mmol), 9 was obtained in 86% (0.197 g) yield
8.12 (d, J=8.3 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.8 Hz,
1H), 7.64 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 6.4 Hz, 1H), 7.12 (dd,
J=8.8, 6.4 Hz, 1H), 3.05 (q, J=7.6 Hz, 2H), 1.26 ppm (q, J=7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=199.7, 162.9, 157.9, 137.5,
131.8, 130.7, 128.8, 126.4, 125.5, 120.2, 115.8, 115.2, 31.9, 8.1 ppm;
elemental analysis calcd (%) for C16H13NO2 (251.28): C 76.48, H 5.21;
found: C 76.28, H 5.06.
1
as a yellow solid. M.p.: 154–1578C; H NMR (400 MHz, CDCl3): d=
7.89 (d, J=8.3 Hz, 2H), 7.72 (d, J=8.3 Hz, 1H), 7.58 (d, J=9.0 Hz,
1H), 7.48 (d, J=8.3 Hz, 2H), 7.29 (dd, J=9.0, 6.4 Hz, 1H), 7.03 ppm
(dd, J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=163.0, 157.5,
136.2, 130.6, 129.4, 127.5, 126.6, 124.8, 120.1, 115.5, 114.3 ppm.
3-(4-Fluorophenyl)benzo[c]isoxazole (10)
[4-(Benzo[c]isoxazol-3-yl)phenyl](phenyl)methanone (5)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-bromofluoroben-
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-bromobenzophe-
zene (0.175 g, 1 mmol), 10 was obtained in 80% (0.170 g) yield as
1
none (0.261 g, 1 mmol), 5 was obtained in 82% (0.245 g) yield as
a yellow solid. M.p.: 102–1068C; H NMR (400 MHz, CDCl3): d=8.01
1
a yellow oil. H NMR (400 MHz, CDCl3): d=8.14 (d, J=8.3 Hz, 2H),
(dd, J=8.3, 6.0 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.61 (d, J=9.0 Hz,
1H), 7.32 (dd, J=9.0, 6.4 Hz, 1H), 7.25 (t, J=8.3 Hz, 2H), 7.06 ppm
(dd, J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=163.4 (d, J=
252.1 Hz), 163.3, 157.7, 130.6, 128.5 (d, J=8.5 Hz), 124.6, 120.2,
116.4 (d, J=22.1 Hz), 115.4, 114.0 ppm; elemental analysis calcd (%)
for C13H8FNO (213.21): C 73.23, H 3.78; found: C 73.10, H 3.87.
7.99 (d, J=8.3 Hz, 2H), 7.87 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.3 Hz,
2H), 7.68–7.60 (m, 2H), 7.52 (t, J=8.0 Hz, 2H), 7.36 (dd, J=9.0,
6.4 Hz, 1H), 7.13 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=195.6, 162.9, 157.9, 138.5, 137.1, 132.8, 131.5, 130.9,
130.8, 130.0, 128.5, 126.2, 125.5, 120.2, 115.8, 115.2 ppm; elemental
analysis calcd (%) for C20H13NO2 (299.32): C 80.25, H 4.38; found: C
80.34, H 4.27.
3-Phenylbenzo[c]isoxazole (11)[15]
Ethyl 4-(benzo[c]isoxazol-3-yl)benzoate (6)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and bromobenzene
(0.157 g, 1 mmol), 11 was obtained in 78% (0.152 g) yield as
a yellow solid. M.p.: 60–648C; 1H NMR (400 MHz, CDCl3): d=8.00
(d, J=8.5 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H),
7.54 (t, J=8.0 Hz, 2H), 7.47 (t, J=8.0 Hz, 1H), 7.31 (dd, J=9.0,
6.4 Hz, 1H), 7.04 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=164.3, 157.8, 130.5, 130.2, 129.2, 128.3, 126.5, 124.5,
120.5, 115.4, 114.3 ppm.
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and ethyl 4-bromoben-
zoate (0.229 g, 1 mmol), 6 was obtained in 93% (0.248 g) yield as
1
a yellow solid. M.p.: 100–1028C; H NMR (400 MHz, CDCl3): d=8.20
(d, J=8.3 Hz, 2H), 8.07 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.8 Hz, 1H),
7.62 (d, J=9.0 Hz, 1H), 7.33 (dd, J=9.0, 6.4 Hz, 1H), 7.10 (dd, J=
8.8, 6.4 Hz, 1H), 4.41 (q, J=7.6 Hz, 2H), 1.42 ppm (t, J=7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=165.4, 162.6, 157.6, 131.6, 131.2,
130.5, 130.1, 125.9, 125.2, 120.0, 115.5, 114.9, 61.1, 14.1 ppm; ele-
mental analysis calcd (%) for C16H13NO3 (267.28): C 71.90, H 4.90;
found: C 71.69, H 4.67.
3-p-Tolylbenzo[c]isoxazole (12)[7b]
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-bromotoluene
3-[4-(Trifluoromethyl)phenyl]benzo[c]isoxazole (7)
(0.171 g, 1 mmol), 12 was obtained in 39% (0.081 g) yield as
yellow solid. M.p.: 90–928C; H NMR (400 MHz, CDCl3): d=7.91 (d,
J=8.3 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.35
(d, J=8.3 Hz, 2H), 7.31 (dd, J=9.0, 6.4 Hz, 1H), 7.03 (dd, J=8.8,
6.4 Hz, 1H), 2.44 ppm (s, 3H).
1
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-(trifluoromethyl)-
bromobenzene (0.225 g, 1 mmol), 7 was obtained in 95% (0.250 g)
1
yield as a yellow solid. M.p.: 152–1568C; H NMR (400 MHz, CDCl3):
d=8.08 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 3H), 7.62 (d, J=
9.0 Hz, 1H), 7.33 (dd, J=9.0, 6.4 Hz, 1H), 7.10 ppm (dd, J=8.8,
6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=162.3, 157.8, 131.5 (q,
J=33.0 Hz), 131.3, 130.7, 126.5, 126.2 (q, J=3.7 Hz), 125.5, 123.7 (q,
J=272.3 Hz), 119.9, 115.7, 115.1 ppm; elemental analysis: calcd (%)
for C14H8F3NO (263.21): C 63.88, H 3.06; found: C 63.74, H 3.19.
1-(3-(Benzo[c]isoxazol-3-yl)phenyl)ethanone (13)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 3-bromoacetophe-
none (0.199 g, 1 mmol), 13 was obtained in 89% (0.211 g) yield as
1
a yellow solid. M.p.: 128–1328C; H NMR (400 MHz, CDCl3): d=8.58
(s, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.84 (d, J=
8.3 Hz, 1H), 7.69–7.59 (m, 2H), 7.33 (dd, J=9.0, 6.4 Hz, 1H), 7.10
(dd, J=8.8, 6.4 Hz, 1H), 2.69 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=197.0, 162.9, 157.7, 137.8, 130.7, 130.4, 129.6, 129.5,
128.7, 125.9, 125.1, 120.1, 115.5, 114.6, 26.6 ppm; elemental analysis
calcd (%) for C15H11NO2 (237.25): C 75.94, H 4.67; found: C 75.98, H
4.78.
4-(Benzo[c]isoxazol-3-yl)benzonitrile (8)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 4-bromobenzoni-
trile (0.182 g, 1 mmol), 8 was obtained in 87% (0.191 g) yield as
1
a yellow solid. M.p.: 208–2108C; H NMR (400 MHz, CDCl3): d=8.11
(d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.3 Hz, 1H),
7.66 (d, J=9.0 Hz, 1H), 7.37 (dd, J=9.0, 6.4 Hz, 1H), 7.15 ppm (dd,
ChemCatChem 2016, 8, 1583 – 1590
www.chemcatchem.org
1587
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
3-(Benzo[c]isoxazol-3-yl)benzonitrile (14)
3-[2-(Trifluoromethyl)phenyl]benzo[c]isoxazole (19)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 3-bromobenzoni-
trile (0.182 g, 1 mmol), 14 was obtained in 92% (0.202 g) yield as
a yellow solid. M.p.: 185–1898C; H NMR (400 MHz, CDCl3): d=8.28
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 2-(trifluoromethyl)-
bromobenzene (0.225 g, 1 mmol), 19 was obtained in 91%
1
1
(0.239 g) yield as a yellow oil. H NMR (400 MHz, CDCl3): d=7.91 (d,
(s, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.77 (d, J=
8.3 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.37
(dd, J=9.0, 6.4 Hz, 1H), 7.16 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=161.4, 157.8, 133.1, 130.9, 130.3, 130.2, 129.6,
129.5, 125.9, 119.6, 117.9, 115.9, 115.0, 113.8 ppm; elemental analy-
sis calcd (%) for C14H8N2O (220.23): C 76.35, H 3.66; found: C 76.24,
H 3.78.
J=8.3 Hz, 1H), 7.78–7.61 (m, 4H), 7.46 (d, J=8.3 Hz, 1H), 7.33 (dd,
J=9.0, 6.4 Hz, 1H), 7.04 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=163.0, 157.0, 131.9, 131.5, 130.8, 130.5, 129.4
(q, J=31.7 Hz), 127.2 (q, J=5.1 Hz), 125.8, 124.8, 123.1 (q, J=
273.4 Hz), 119.7, 116.7, 115.1 ppm; elemental analysis calcd (%) for
C14H8F3NO (263.21): C 63.88, H 3.06; found: C 63.97, H 3.00.
3-(2-Fluorophenyl)benzo[c]isoxazole (20)
3-(3,5-Bis(trifluoromethyl)phenyl)benzo[c]isoxazole (15)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 2-bromofluoroben-
zene (0.175 g, 1 mmol), 20 was obtained in 70% (0.149 g) yield as
a yellow solid. M.p.: 52–548C; 1H NMR (400 MHz, CDCl3): d=7.98
(td, J=7.6, 1.5 Hz, 1H), 7.78 (dd, J=9.0, 3.0 Hz, 1H), 7.62 (d, J=
9.1 Hz, 1H), 7.54–7.45 (m, 1H), 7.39–7.25 (m, 3H), 7.05 ppm (dd, J=
8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=160.2, 158.7 (d, J=
253.2 Hz), 157.8, 132.0 (d, J=8.4 Hz), 130.7, 129.6 (d, J=2.7 Hz),
124.8 (d, J=3.4 Hz), 124.4 (d, J=2.4 Hz), 121.3 (d, J=12.5 Hz),
116.6 (d, J=21.7 Hz), 116.3, 115.8, 115.2 ppm; elemental analysis
calcd (%) for C13H8FNO (213.21): C 73.23, H 3.78; found: C 73.10, H
3.87.
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 3,5-bis(trifluorome-
thyl)bromobenzene (0.293 g, 1 mmol), 15 was obtained in 93%
1
(0.308 g) yield as a yellow solid. M.p.: 86–908C; H NMR (400 MHz,
CDCl3): d=8.41 (s, 2H), 7.97 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.65 (d,
J=8.3 Hz, 1H), 7.37 (dd, J=9.0, 6.4 Hz, 1H), 7.18 ppm (dd, J=8.8,
6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=160.3, 157.8, 132.8 (q,
J=33.9 Hz), 130.8, 130.0, 126.3, 125.9, 123.1 (m), 122.8 (q, J=
273.0 Hz), 119.2, 115.9, 115.2 ppm; elemental analysis calcd (%) for
C15H7F6NO (331.21): C 54.39, H 2.13; found: C 54.27, H 2.00.
3-(6-Methoxynaphthalen-2-yl)benzo[c]isoxazole (16)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 2-bromo-6-me-
3-(2-Chlorophenyl)benzo[c]isoxazole (21)
thoxynaphthalene (0.237 g, 1 mmol), 16 was obtained in 79%
(0.217 g) yield as
a
yellow solid. M.p.: 156–1608C; 1H NMR
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 2-bromochloro-
benzene (0.191 g, 1 mmol), 21 was obtained in 62% (0.142 g) yield
as a yellow oil. 1H NMR (400 MHz, CDCl3): d=7.70–7.56 (m, 4H),
7.50–7.40 (m, 2H), 7.32 (dd, J=9.0, 6.4 Hz, 1H), 7.03 ppm (dd, J=
8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=162.9, 157.3, 132.7,
131.4, 131.3, 130.7, 130.6, 127.2, 127.0, 124.3, 121.0, 116.2,
115.2 ppm; elemental analysis calcd (%) for C13H8ClNO (229.66): C
67.99, H 3.51; found: C 68.14, H 3.70.
(400 MHz, CDCl3): d=8.33 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.86 (d,
J=8.3 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H), 7.29
(dd, J=9.0, 6.4 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.10 (s, 1H), 7.03
(dd, J=8.8, 6.4 Hz, 1H), 3.90 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=164.6, 158.9, 157.8, 135.2, 130.5, 130.1, 128.5, 127.7,
126.2, 124.2, 123.7, 123.4, 120.7, 119.8, 115.3, 114.1, 105.7,
55.3 ppm; elemental analysis calcd (%) for C18H13NO2 (275.30): C
78.53, H 4.76; found: C 78.60, H 4.89.
3-(Naphthalen-1-yl)benzo[c]isoxazole (22)[14]
2-(Benzo[c]isoxazol-3-yl)benzaldehyde (17)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 1-bromonaphtha-
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 2-bromobenzalde-
hyde (0.185 g, 1 mmol), 17 was obtained in 78% (0.174 g) yield as
a yellow solid. M.p.: 142–1468C; 1H NMR (400 MHz, CDCl3): d=
10.20 (s, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.85–7.75 (m, 2H), 7.75–7.63
(m, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.37 (dd, J=9.0, 6.4 Hz, 1H),
7.11 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
190.6, 162.6, 157.5, 134.2, 134.0, 131.0, 130.7, 130.1, 129.8, 128.8,
125.7, 119.6, 117.2, 115.4 ppm; elemental analysis calcd (%) for
C14H9NO2 (223.23): C 75.33, H 4.06; found: C 75.45, H 4.33.
lene (0.207 g, 1 mmol), 22 was obtained in 73% (0.179 g) yield as
1
a yellow solid. M.p.: 84–868C; H NMR (400 MHz, CDCl3): d=8.27–
8.20 (m, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.99–7.93 (m, 1H), 7.85 (d, J=
8.3 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.65–7.53 (m, 4H), 7.37 (dd, J=
9.0, 6.4 Hz, 1H), 7.03 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=165.6, 157.4, 133.8, 131.0, 130.7, 130.5, 128.5,
128.3, 127.3, 126.5, 125.3, 125.2, 125.0, 124.2, 120.7, 116.4,
115.1 ppm.
2-(Benzo[c]isoxazol-3-yl)benzonitrile (18)
3-(Pyridin-3-yl)benzo[c]isoxazole (23)
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 2-bromobenzoni-
trile (0.182 g, 1 mmol), 18 was obtained in 92% (0.202 g) yield as
a yellow solid. M.p.: 140–1448C; 1H NMR (400 MHz, CDCl3): d=
8.01–7.85 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H),
7.68–7.58 (m, 2H), 7.35 (dd, J=9.0, 6.4 Hz, 1H), 7.12 ppm (dd, J=
8.8, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=161.0, 157.5, 134.5,
133.1, 130.9, 130.7, 130.3, 129.7, 125.5, 120.0, 117.4, 116.0, 115.5,
110.8 ppm; elemental analysis calcd (%) for C14H8N2O (220.23): C
76.35, H 3.66; found: C 76.17, H 3.87.
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 3-bromopyridine
(0.158 g, 1 mmol), 23 was obtained in 89% (0.174 g) yield as
1
a brown solid. M.p.: 128–1308C; H NMR (400 MHz, CDCl3): d=9.28
(bs, 1H), 8.72 (bs, 1H), 8.29 (d, J=7.6 Hz, 1H), 7.80 (d, J=8.7 Hz,
1H), 7.63 (d, J=8.0 Hz, 1H), 7.53–7.47 (m, 1H), 7.34 (dd, J=9.0,
6.4 Hz, 1H), 7.11 ppm (dd, J=8.8, 6.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=161.4, 157.7, 150.5, 146.9, 133.4, 130.8, 125.4, 125.0,
124.3, 119.8, 115.6, 114.9 ppm; elemental analysis calcd (%) for
C12H8N2O (196.20): C 73.46, H 4.11; found: C 73.60, H 4.30.
ChemCatChem 2016, 8, 1583 – 1590
www.chemcatchem.org
1588
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
3-(Quinolin-3-yl)benzo[c]isoxazole (24)
(2-Aminophenyl)(naphthalen-2-yl)methanone (29)[18]
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 3-bromoquinoline
From 3-(naphthalen-2-yl)benzo[c]isoxazole 1 (0.123 g, 0.5 mmol) 29
was obtained in 88% (0.108 g) yield as a yellow solid. M.p.: 102–
1068C; 1H NMR (400 MHz, CDCl3): d=8.10 (s, 1H), 8.00–7.85 (m,
3H), 7.78 (d, J=8.2 Hz, 1H), 7.65–7.50 (m, 3H), 7.32 (t, J=7.8 Hz,
1H), 6.77 (d, J=8.2 Hz, 1H), 6.63 (t, J=7.8 Hz, 1H), 6.10 ppm (bs,
2H); 13C NMR (100 MHz, CDCl3): d=198.9, 150.7, 137.3, 134.6,
134.5, 134.2, 132.3, 130.0, 129.0, 128.0, 127.8, 127.7, 126.6, 125.7,
118.5, 117.0, 115.6 ppm.
(0.208 g, 1 mmol), 24 was obtained in 78% (0.192 g) yield as
1
a white solid. M.p.: 182–1848C; H NMR (400 MHz, CDCl3): d=9.51
(s, 1H), 8.68 (s, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H),
7.87 (d, J=8.3 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.66–7.56 (m, 2H),
7.34 (dd, J=9.0, 6.4 Hz, 1H), 7.12 ppm (dd, J=8.8, 6.4 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=161.7, 157.8, 148.1, 147.2, 133.3,
130.9, 130.8, 129.5, 128.5, 127.7, 127.4, 125.5, 121.7, 119.9, 115.7,
115.1 ppm; elemental analysis calcd (%) for C16H10N2O (246.26): C
78.03, H 4.09; found: C 78.20, H 4.33.
(2-Aminophenyl)(naphthalen-1-yl)methanone (30)[19]
From 3-(naphthalen-1-yl)benzo[c]isoxazole 22 (0.123 g, 0.5 mmol)
30 was obtained in 95% (0.117 g) yield as a yellow solid. M.p.:
142–1448C; H NMR (400 MHz, CDCl3): d=7.98–7.85 (m, 3H), 7.58–
3-(Pyrimidin-5-yl)benzo[c]isoxazole (25)
1
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 5-bromopyrimidine
7.42 (m, 4H), 7.28 (t, J=7.8 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.75 (d,
J=8.2 Hz, 1H), 6.47 (t, J=7.8 Hz, 1H), 6.46 ppm (bs, 2H); 13C NMR
(100 MHz, CDCl3): d=200.6, 151.2, 138.4, 135.1, 134.9, 133.5, 130.5,
129.7, 128.2, 126.7, 126.2, 125.6, 125.5, 124.6, 118.8, 116.9,
115.6 ppm.
(0.159 g, 1 mmol), 25 was obtained in 80% (0.158 g) yield as
a brown solid. M.p.: 144–1478C; H NMR (400 MHz, CDCl3): d=9.37
1
(s, 2H), 9.31 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H),
7.39 (dd, J=9.0, 6.4 Hz, 1H), 7.18 ppm (dd, J=8.8, 6.4 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=158.9, 158.3, 157.6, 153.7, 131.1,
126.4, 123.3, 119.1, 116.0, 115.8 ppm; elemental analysis calcd (%)
for C11H7N3O (197.19): C 67.00, H 3.58; found: C 66.88, H 3.41.
(2-Aminophenyl)(3,5-bis(trifluoromethyl)phenyl)methanone
(31)
(2-Aminophenyl)(anthracen-9-yl)methanone (26)
From
3-[3,5-bis(trifluoromethyl)phenyl]benzo[c]isoxazole
15
(0.166 g, 0.5 mmol) 31 was obtained in 55% (0.091 g) yield as
a yellow oil. H NMR (400 MHz, CDCl3): d=8.07 (s, 2H), 8.03 (s, 1H),
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 9-bromoanthra-
1
cene (0.257 g, 1 mmol), 26 was obtained in 47% (0.139 g) yield as
1
7.37 (t, J=7.8 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz,
1H), 6.6 (t, J=7.8 Hz, 1H), 5.91 ppm (bs, 2H); 13C NMR (100 MHz,
CDCl3): d=195.3, 151.6, 142.0, 135.3, 133.8, 131.7 (q, J=33.8 Hz),
128.9 (m), 123.0 (q, J=273.0 Hz), 124.2 (q, J=3.8 Hz), 117.4, 116.5,
116.0 ppm; elemental analysis calcd (%) for C15H9F6NO (333.23): C
54.07, H 2.72; found: C 54.01, H 2.89.
a yellow oil. H NMR (400 MHz, CDCl3): d=8.54 (s, 1H), 8.05 (d, J=
8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.47 (t, J=8.0 Hz, 2H), 7.41 (t,
J=8.0 Hz, 2H), 7.26 (t, J=8.0 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.69
(d, J=8.3 Hz, 1H), 6.65 (bs, 2H), 6.32 ppm (t, J=8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=202.1, 150.9, 135.3, 135.1, 131.1,
128.5, 128.3, 127.7, 126.3, 125.5, 125.4, 119.6, 116.9, 116.0 ppm; ele-
mental analysis calcd (%) for C21H15NO (297.35): C 84.82, H 5.08;
found: C 84.98, H 5.21.
(2-Aminophenyl)(2-(trifluoromethyl)phenyl)methanone
(32)[20]
1-Amino-9H-fluoren-9-one (27c)[16]
From 3-[2-(trifluoromethyl)phenyl]benzo[c]isoxazole 19 (0.132 g,
0.5 mmol) 32 was obtained in 93% (0.123 g) yield as a yellow oil.
1H NMR (400 MHz, CDCl3): d=7.76 (d, J=8.0 Hz, 1H), 7.64–7.52 (m,
2H), 7.36 (d, J=8.0 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.08 (d, J=
8.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.51 (t, J=7.8 Hz, 1H),
6.34 ppm (bs, 2H).
From 2,1-benzisoxazole (0.179 g, 1.5 mmol) and 1,2-dibromoben-
zene (0.236 g, 1 mmol), 27c was obtained in 24% (0.047 g) yield as
an orange solid. M.p.: 113–1158C; 1H NMR (400 MHz, CDCl3): d=
7.61 (d, J=8.3 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.43 (t, J=8.0 Hz,
1H), 7.32–7.17 (m, 2H), 6.83 (d, J=8.3 Hz, 1H), 6.49 (d, J=8.3 Hz,
1H), 5.52 ppm (bs, 2H).
(2-Aminophenyl)(2-fluorophenyl)methanone (33)[8a]
General procedure for the synthesis of compounds 28–33
From 3-(2-fluorophenyl)benzo[c]isoxazole 20 (0.107 g, 0.5 mmol)
33 was obtained in 92% (0.099 g) yield as a yellow solid. M.p.:
124–1268C; H NMR (400 MHz, CDCl3): d=7.49–7.36 (m, 2H), 7.35–
7.20 (m, 3H), 7.15 (t, J=7.8 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.58 (t,
J=7.8 Hz, 1H), 6.30 ppm (bs, 2H).
Typically, the 3-arylbenzoisoxazole derivative (0.5 mmol), NEt3
(0.5 mL), Pd/C (10%) (5 mg), and THF (3 mL) were introduced in an
autoclave. The autoclave was flushed with hydrogen and pressur-
ized with 10 bars of hydrogen. Then, the reaction mixture was
stirred at 258C for 12 h. The solvent was evaporated, and the prod-
uct was purified by silica gel column chromatography.
1
Acknowledgements
(2-Aminophenyl)(phenyl)methanone (28)[17]
We thank the CNRS and “Rennes Metropole” for providing finan-
cial support.
From 3-phenylbenzo[c]isoxazole 11 (0.098 g, 0.5 mmol) 28 was ob-
tained in 95% (0.093 g) yield as a white solid. M.p.: 109–1128C;
1H NMR (400 MHz, CDCl3): d=7.57 (d, J=8.0 Hz, 2H), 7.50–7.35 (m,
4H), 7.23 (t, J=7.8 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.53 (t, J=
7.8 Hz, 1H), 6.17 ppm (bs, 2H).
Keywords: CÀC coupling · CÀH activation · homogeneous
catalysis · palladium · synthetic methods
ChemCatChem 2016, 8, 1583 – 1590
www.chemcatchem.org
1589
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
[1] F. Hu, M. Szostak, Adv. Synth. Catal. 2015, 357, 2583–2614.
[2] A. C. Pierce, M. Jacobs, C. Stuver-Moody, J. Med. Chem. 2008, 51, 1972–
1975.
O. Meth-Cohn, J. Chem. Soc. Perkin Trans. 1 1983, 2077–2087; c) N. T.
Pokhodylo, Y. O. Teslenko, V. S. Matiychuk, M. D. Obushak, Synthesis
2009, 2741–2748; d) B. J. Stokes, C. V. Vogel, L. K. Urnezis, M. Pan, T. G.
Driver, Org. Lett. 2010, 12, 2884–2887; e) N. Pokhodylo, O. Shyyka, V.
Matiychuk, Med. Chem. Res. 2014, 23, 2426–2438.
[3] N. Nakamura, Y. Tajima, K. Sakai, Heterocycles 1982, 17, 235–245.
[4] a) Y. Akita, A. Inoue, K. Yamamoto, A. Ohta, T. Kurihara, M. Shimizu, Het-
erocycles 1985, 23, 2327–2333; b) A. Ohta, Y. Akita, T. Ohkuwa, M.
Chiba, R. Fukunaga, A. Miyafuji, T. Nakata, N. Tani, Y. Aoyagi, Heterocycles
1990, 31, 1951–1958; c) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev.
2007, 107, 174–238; d) T. Satoh, M. Miura, Chem. Lett. 2007, 36, 200–
205; e) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 949–957; f) L. Acker-
mann, R. Vicente, A. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792–9826;
Angew. Chem. 2009, 121, 9976–10011; g) F. Bellina, R. Rossi, Tetrahedron
2009, 65, 10269–10310; h) G. P. McGlacken, L. M. Bateman, Chem. Soc.
Rev. 2009, 38, 2447–2464; i) J. Roger, A. L. Gottumukkala, H. Doucet,
ChemCatChem 2010, 2, 20–40; j) N. Kuhl, M. N. Hopkinson, J. Wencel-
Delord, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 10236–10254; Angew.
Chem. 2012, 124, 10382–10401; k) J. Yamaguchi, A. D. Yamaguchi, K.
Itami, Angew. Chem. Int. Ed. 2012, 51, 8960–9009; Angew. Chem. 2012,
124, 9092–9142; l) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5,
369–375; m) S. I. Kozhushkov, H. K. Potukuchi, L. Ackermann, Catal. Sci.
Technol. 2013, 3, 562–571; n) M. He, J.-F. SoulØ, H. Doucet, ChemCat-
Chem 2014, 6, 1824–1859; o) R. Rossi, F. Bellina, M. Lessi, C. Manzini,
Adv. Synth. Catal. 2014, 356, 17–117; p) K. Yuan, J.-F. SoulØ, H. Doucet,
ACS Catal. 2015, 5, 978–991; q) M. R. Yadav, R. K. Rit, M. Shankar, A. K.
Sahoo, Asian J. Org. Chem. 2015, 4, 846–864; r) C. B. Bheeter, L. Chen,
J.-F. SoulØ, H. Doucet, Cat. Sci. Technol. 2016, DOI: 10.1039/C5CY02095F.
[5] For selected examples of Pd-catalyzed direct 4-arylations of isoxazoles:
a) H. A. Chiong, O. Daugulis, Org. Lett. 2007, 9, 1449–1451; b) Y. Fall, C.
Reynaud, H. Doucet, M. Santelli, Eur. J. Org. Chem. 2009, 4041–4050;
c) J. J. Dong, J. Roger, C. Verrier, T. Martin, R. Le Goff, C. Hoarau, H.
Doucet, Green Chem. 2010, 12, 2053–2063; d) K. Beydoun, H. Doucet,
ChemSusChem 2011, 4, 526–534; e) D. Roy, S. Mom, S. Royer, D. Lucas,
J.-C. Hierso, H. Doucet, ACS Catal. 2012, 2, 1033–1041.
[8] For selected examples of synthesis of (2-aminophenyl)(aryl)methanones,
see: a) S. V. Frye, M. C. Johnson, N. L. Valvano, J. Org. Chem. 1991, 56,
3750–3752; b) S. Butini, E. Gabellieri, P. B. Huleatt, G. Campiani, S. Fran-
ceschini, M. Brindisi, S. Ros, S. Sanna Coccone, I. Fiorini, E. Novellino, G.
Giorgi, S. Gemma, J. Org. Chem. 2008, 73, 8458–8468; c) J. Zhang, D.
Zhu, C. Yu, C. Wan, Z. Wang, Org. Lett. 2010, 12, 2841–2843; d) Y. K.
Kumar, G. R. Kumar, T. J. Reddy, B. Sridhar, M. S. Reddy, Org. Lett. 2015,
17, 2226–2229.
[9] A. H. M. de Vries, J. M. C. A. Mulders, J. H. M. Mommers, H. J. W. Hender-
ickx, J. G. de Vries, Org. Lett. 2003, 5, 3285–3288.
[10] H. Y. Fu, L. Chen, H. Doucet, J. Org. Chem. 2012, 77, 4473–4478.
[11] A. Morimoto, L. Biczok, T. Yatsuhashi, T. Shimada, S. Baba, H. Tachibana,
D. A. Tryk, H. Inoue, J. Phys. Chem. A 2002, 106, 10089–10095.
[12] H. Ma, A. K.-Y. Jen, J. Wu, X. Wu, S. Liu, C.-F. Shu, L. R. Dalton, S. R.
Marder, S. Thayumanavan, Chem. Mater. 1999, 11, 2218–2225.
[13] T. Cantat, E. GØnin, C. Giroud, G. Meyer, A. Jutand, J. Organomet. Chem.
2003, 687, 365–376.
[14] I. Tanasescu, M. Ionescu, I. Goia, H. Montsch, Bull. Soc. Chim. Fr. 1960,
698–700.
[15] R. A. Howie, A. Jabbar, J. R. Lewis, S. S. Nizami, C. F. Ritchie, Acta Crystal-
logr. Sect. C 2003, 59, o516–o519.
[16] M. Okubo, Y. Uematsu, Bull. Chem. Soc. Jpn. 1982, 55, 1121–1126.
[17] M. Mizuno, M. Yamano, Org. Lett. 2005, 7, 3629–3631.
[18] J. Chen, J. Li, W. Su, Molecules 2014, 19, 6439–6449.
[19] S. Chorbadjiev, C. Ivanov, B. Moskova, Synth. Commun. 1987, 17, 1363–
1371.
[20] J. Han, T. Ono, H. Uekusa, K. D. Klika, V. A. Soloshonok, Dalton Trans.
2014, 43, 5375–5381.
[6] M. Shigenobu, K. Takenaka, H. Sasai, Angew. Chem. Int. Ed. 2015, 54,
9572–9576; Angew. Chem. 2015, 127, 9708–9712.
Received: January 14, 2016
[7] For selected examples of the synthesis of 3-arylbenzoisoxazoles: a) R. B.
Davis, L. C. Pizzini, J. Org. Chem. 1960, 25, 1884–1888; b) D. G. Hawkins,
Published online on March 23, 2016
ChemCatChem 2016, 8, 1583 – 1590
www.chemcatchem.org
1590
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim