Facile Protocols towards C2-Arylated Benzoxazoles using Fe(III)-Catalyzed C(sp 2 -H) Functionalization and Metal-Free Domino Approach

Article abstract of DOI:10.1055/s-0037-1609718

Considering their growing attention in the field of medicinal chemistry and drug-discovery research, the facile and convenient approaches towards the preparation of 2-aryl benzoxazole derivatives have been described. The transformation is accomplished by using Fe(III)-catalyzed C-H activation of benzoxazoles with boronic acids to obtain a wide range of C2-arylated benzoxazoles in high yields. The developed method excludes the formation of self-coupling compounds as side products. On the other hand, the synthesis of the products is also achieved via a metal-free domino protocol by the reaction between 1-nitroso-2-naphthol and acetophenones using catalytic amounts of CBr ₄ in the presence of Cs ₂ CO ₃ as base. The devised tandem method avoids the use of pre-activated α-haloketones as substrates. Due to their immense impact in marketed drugs and molecules under clinical trial, the described method can be a powerful tool for their synthesis which restricts the use of precious metals as catalyst.

Full text of DOI:10.1055/s-0037-1609718

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–J
letter
A
en
N. Vodnala et al.
Letter
Synlett
Facile Protocols towards C2-Arylated Benzoxazoles using Fe(III)-
Catalyzed C(sp2-H) Functionalization and Metal-Free Domino
Approach
Nagaraju Vodnalaa
Raghuram Gujjarappaa
Arup K. Kabia
Mohan Kumara
Uwe Beifussb
Chandi C. Malakar*a
Method B
CBr4
NO
Method A
Fe
N
H
Ar
OH
X
N
Ar
+
OH
R
– CO
12 examples
up to 78%
22 examples
up to 89%
O
+
B
O
HO
H
0
0
0
0
0-
0
0
2
9-
4
7
8
0-
1
7
X
X = O, S
C-H activation
no precious metal
high yields
using non-activated ketones
no pre-functionalization
metal-free
R
R = H, OMe, Me,
a Department of Chemistry, National Institute of Technology
Manipur, Langol, Imphal 795004, Manipur, India
cmalakar@nitmanipur.ac.in
b Institut für Chemie, Universität Hohenheim, Garbenstr. 30,
70599 Stuttgart, Germany
Br, Cl, F, CO2Me, CN,
NO2
R
no self coupling
high yields
Received: 14.03.2018
Accepted after revision: 22.03.2018
Published online: 16.05.2018
Selected examples of bioactive compounds containing
benzoxazole moieties are depicted in Figure 1.2,3 These core
structures have also been investigated as topoisomerase II
inhibitors, PTP-1B inhibitors, cathepsin inhibitors and lyso-
phosphatidic acid acyltransferase-β inhibitors.3
DOI: 10.1055/s-0037-1609718; Art ID: st-2018-v0047-l
Abstract Considering their growing attention in the field of medicinal
chemistry and drug-discovery research, the facile and convenient ap-
proaches towards the preparation of 2-aryl benzoxazole derivatives
have been described. The transformation is accomplished by using
Fe(III)-catalyzed C–H activation of benzoxazoles with boronic acids to
obtain a wide range of C2-arylated benzoxazoles in high yields. The de-
veloped method excludes the formation of self-coupling compounds as
side products. On the other hand, the synthesis of the products is also
achieved via a metal-free domino protocol by the reaction between 1-
nitroso-2-naphthol and acetophenones using catalytic amounts of CBr4
in the presence of Cs2CO3 as base. The devised tandem method avoids
the use of pre-activated α-haloketones as substrates. Due to their im-
mense impact in marketed drugs and molecules under clinical trial, the
described method can be a powerful tool for their synthesis which
restricts the use of precious metals as catalyst.
Additionally, a number of functionalized benzoxazoles
are recognized to act as the inhibitors of fatty acid amide
hydrolase, cysteine protease inhibitors, and channel-acti-
vating protease inhibitors.3 Apart from their immense me-
dicinal use, these core structures are extensively used as
important building blocks and intermediates in organic
synthesis, and play a crucial role in the field of material sci-
ence towards the discovery of novel fluorescent materials.4
Therefore, during the recent years a tremendous growth
has been witnessed on the improvement of the existing
synthetic protocols towards C2-arylated benzoxazole scaf-
folds.5–18 Among the traditionally used methods, the most
commonly attempted approaches namely rely on: (a) met-
al-catalyzed carbonylative coupling of aryl halides with
benzoxazoles,5 (b) metal-catalyzed acylation which can be
achieved by the deprotonation of benzoxazoles,6 (c) decar-
boxylative coupling between benzoxazoles and α-carboxyl-
ic acids using transition metal salt as catalyst,7 (d) direct
arylation of benzoxazoles using metal-catalyzed coupling
reaction with pre-activated aromatic compounds.8 Recently
the Cu-catalyzed reaction towards the preparation of C2-
arylated benzoxazoles gained noteworthy attention and has
remained one of the most attractive routes.9
Key words benzoxazoles, Fe(III)-catalysis, C-arylation, C–H Activation,
domino reaction
Within the azole family, the benzoxazole core struc-
tures have gained remarkable attention in the field of me-
dicinal chemistry and drug discovery research due to their
unique biological and pharmacological profiles.1
A broad range of natural as well as non-natural benzox-
azole scaffolds are the key moieties of valuable medicinally
active molecules including marketed drugs and compounds
under clinical trial.2,3 Among the benzoxazole containing
natural and non-natural compounds, the important mole-
cule includes AJI9561, pseudopteroxazole, salviamine B,
isosalviamine E, UK-1, antibiotic A-33853, NSC-693638,
salvianen, neosalvianen, nataxazole (antitumor agent), JTP-
426427 and flunoxaprofen (anti-inflammatory drug).2,3
Additionally, among the surrogate commonly used
methods the reaction between 2-aminophenols and alde-
hydes or a broad range of carboxylic acid derivatives have
been investigated in great details.10 Apart from the dis-
cussed methods, recent literature witnessed several useful
transformations for the synthesis of C2-arylated benzoxaz-
ole scaffolds.1,11 A summary of previously reported proce-
dures towards the preparation of 2-aryl benzoxazoles is
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

B
N. Vodnala et al.
Letter
Synlett
R1
HN
CO2Me
HO
CO2Me
HO
O
N
O
N
CO2H
R2
NH
N
N
N
O
O
N
O
Me
Me
N
N
O
O
Antibiotic
(A-33853)
NSC-693638
Me
Me
UK-1
Antitumor activity
(Nataxazole)
O
N
O
N
O
CO2H
Me
O
Me
H
Me
Me
N
O
O
OH
HO
Me
N
N
O
Me
Me Me
Me
Me
AJ19561
Salviamine B
Salvianen
Pseudopteroxazole
Figure 1 Selected natural products and drug molecules containing benzoxazole moieties
N
presented in Scheme 1. Batey and co-workers introduced a
versatile one-pot domino acylation annulation approach of
H
O
+
Ar
N
NH2
R
X
CN tBu
H
Y
Ar
2-bromoanilines with acyl chlorides in the presence of
Cu(I) as catalyst for the syntheses of 2-aryl benzoxazoles
(Scheme 1a).9d The similar transformation has been also
achieved by several research groups under Cu-catalyzed
intramolecular domino cyclization reaction using the ortho-
haloanilides as substrates to obtain the products (Scheme
1h).9b,f,g The metal-free approaches for the syntheses of 2-
aryl benzoxazoles have been achieved by the intramolecu-
lar cyclization of phenolic azomethines at ambient tem-
perature using Dess–Martin periodinane (DMP) as oxidant
(Scheme 1b)9h and by the reaction between ortho-hy-
droxynitroso aromatics and α-bromoketones using Cs2CO3
as base (Scheme 1c)11b,c Additionally, C–H functionalization
of benzoxazoles using activated arenes in the presence of
transition metals such as Cu, Ni, Pd proved to be an effective
route for the syntheses of desired scaffolds (Scheme
1d,e).8i,13,16 Suckling and co-workers reported an efficient
method towards 2-aryl benzoxazoles by the reaction be-
tween 2-aminophenols, isocyanides and aryl halides. The
reaction proceeds via isocyanide insertion in the presence
of Pd catalyst to deliver the desired products (Scheme 1f).16e
Recently, Punniyamurthy has described an alternative
approach towards the same scaffold by Cu-catalyzed con-
version of bisaryloxime ethers to 2-arylbenzoxazoles that
involves a cascade C–H functionalization and C–N/C–O
bond formation under oxygen atmosphere (Scheme 1g).16f
Nevertheless, the associated limitations with previous
methods such as the use of precious metals as catalyst,
harsh reaction conditions and sensitive, and prefunctional-
ized starting materials have not been studied extensively.
Therefore, the development of an efficient approach to-
wards C2-arylated benzoxazoles using cheap metal as cata-
lyst and from non-activated substrates is highly desired.
+
X
+
X
Ar
O
Shao 2014
OH
R1
(d)
Cu(I)
Ni(II)
R
Suckling 2011
Miura 2009, Miura 2010
Itami 2009, Itami 2012
Daugulis 2007
(e)
Pd(II)
Ar
(f)
Pd(II)
N
Br
O
(g)
Cu(II)
NO
(c)
N
O
R
Cs2CO3
Punniyamurthy 2011
+
O
Ar
H
OH
Ar
N
Ar
R
R
Beifuss 2013
(h)
(b)
DMP
N
Ar
CBr4
O
(a)
Cu(I)
Fe
Br
R
Batey 2006
Punniyamurthy 2009
Yang 2014
(i)
(j)
NH2
Br
OH
R
Idrees 2010
Ar
NO
R
+
O
or
O
OH
Ar
HO
N
Cl
Ar
OH
B
H
Batey 2008
H
O
Ar
X = C, N
Y = I, Br, OTf, BR2, CO2R
Scheme 1 Protocols for the syntheses of C2-functionalized of benzox-
azoles
On the other hand, recently the nitroso compounds
were rarely investigated as starting materials for the syn-
theses of 2-substituted naphthoxazoles under transition-
metal-free reaction conditions.11b,c In these reports, the re-
action between nitrosophenols and 2-bromoacetophe-
nones were realized using Cs2CO3 as base under reflux con-
ditions to obtain the desired products in high yields
(Scheme 1c). However, apart from the use of sensitive
nitroso compounds as substrates, the developed methods
rely on the use of pre-activated α-bromoketones that could
be prepared from the reaction between acetophenones and
suitable brominating agents.19 Albeit, the described ap-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

C
N. Vodnala et al.
Letter
Synlett
proaches are shown to be general in terms of good func-
tional groups compatibility with high isolated yield of the
products, their further application suffer from the limited
commercial access to the corresponding nitroso derivatives
and tedious protocols for the preparation of both α-
bromoketones, and nitroso derivatives. Hence, we report
two distinct protocols for the convenient preparation of 2-
aryl benzoxazoles (Scheme 1i and 1j). The developed meth-
ods are based on (i) a Fe(III)-catalyzed C2-arylation of ben-
zoxazoles using C–H functionalization approach, and (ii) us-
ing the domino reaction between 1-nitroso-2-naphthol and
non-activated ketones in the presence of catalytic CBr4 and
Cs2CO3 as base.
In order to screen the optimized conditions for the Fe-
catalyzed reactions, the model substrate naphthoxazole
(1a) was reacted with phenylboronic acid (2a) in the pres-
ence of Cu salt as catalyst using N,N-bidentate ligands and
Cs2CO3 as base (Table 1, entries 1–3). Interestingly, it was
observed that the reactions using Cu(II) salts as catalyst af-
forded slightly better yields of the desired product 3a (Table
1, entries 1 and 2). Next, a reaction between naphthoxazole
(1a) and phenylboronic acid (2a) has been examined using
Pd(OAc)2 as catalyst in the presence of Davephos as ligand
which resulted in the formation of product 3a in 73% yield
under the influence of Na2CO3 as base and 1,4-dioxane as
solvent (Table 1, entry 4). However, a lower yield of the
product 3a was obtained when the same transformation
was aimed using catalytic NiCl2 in the presence of P(o-Tol)3
as ligand (Table 1, entry 5). Further the conversion of 1a and
2a into product 3a was realized under a set of reaction con-
ditions using Fe salts as catalysts (Table 1, entries 6–11). It
was found that the product 3a was isolated in high yields
when the reactions were carried out in the presence of both
Fe(II) and Fe(III) salts as catalysts. The Fe-catalyzed reac-
tions were performed using suitable dichloroalkane as oxi-
dant in the presence of ligands and base. After having sur-
veyed the literature for the best oxidants for Fe-catalyzed
reactions,20e 1,2-dichloroisobutane (DCIB) was employed as
the efficient oxidant for the reaction between substrates 1a
and 2a in order to access the product 3a in high yields.
Table 1 Screening of the Reaction Conditions towards Catalytic C–H Functionalization of 1a with 2aa
OH
N
catalyst, ligand
conditions
H
B
N
HO
+
O
O
1a
2a
3a
Entry
Catalyst, ligand
Reagents and Conditions
Yield (%) 3ab
1
2
CuCl2 (5 mol%), TMEDA (20 mol%)
Cs2CO3 (1.5 equiv), DMF, 100 °C, 20 h
39c
42c
35
73
33
78
83
57
85
75
72
25
11d
59
81
63
27
43
Cu(OAc)2 (5 mol%), TMEDA (20 mol%)
CuI (5 mol%), 1,10-phen (15 mol%)
Cs2CO3 (1.5 equiv), DMSO, 110 °C, 20 h
3
Cs2CO3 (1.5 equiv), DMSO, 100 °C, 16 h
4
Pd(OAc)2 (5 mol%), DavePhos (10 mol%)
NiCl2 (5 mol%), P(o-Tol)3 (10 mol%)
FeBr2 (5 mol%), TMEDA (20 mol%)
FeBr2 (5 mol%), 1,10-phen (10 mol%)
FeCl3 (5 mol%)
Na2CO3 (1.5 equiv), 1,4-dioxane, 120 °C, 16 h
Cs2CO3 (1.5 equiv), 1,4-dioxane, 100 °C, 16 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), DMF, 100 °C, 20 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), DMF, 100 °C, 20 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), DMF, 100 °C, 20 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), DMF, 100 °C, 16 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), DMF, 100 °C, 16 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), DMF, 100 °C, 20 h
Cs2CO3 (1.5 equiv), DMF, 100 °C, 20 h
5
6
7
8
9
FeCl3 (5 mol%), 1,10-phen (10 mol%)
FeCl3 (5 mol%), TMEDA (20 mol%)
Fe(acac)3 (5 mol%), TMEDA (20 mol%)
FeCl3 (5 mol%), 1,10-phen (10 mol%)
FeCl3 (5 mol%), 1,10-phen (10 mol%)
FeCl3 (2.5 mol%), 1,10-phen (10 mol%)
FeCl3 (5 mol%), 1,10-phen (10 mol%)
FeCl3 (5 mol%), 1,10-phen (10 mol%)
FeCl3 (5 mol%), 1,10-phen (10 mol%)
FeCl3 (5 mol%), 1,10-phen (10 mol%)
10
11
12
13
14
15
16
17
18
DCIB (1.3 equiv), DMF, 100 °C, 20 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), DMF, 100 °C, 16 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), NMP, 100 °C, 16 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), DMSO, 100 °C, 16 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), MeCN, 100 °C, 16 h
DCIB (1.3 equiv), Cs2CO3 (1.5 equiv), THF, 100 °C, 16 h
a Unless otherwise mentioned, the reactions were performed using 1a (1.0 mmol) and 2a (1.0 mmol) in solvent (2 mL) under nitrogen atmosphere.
b Isolated yields.
c Reactions were performed under air.
d Compound 1a (45%) was recovered.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

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N. Vodnala et al.
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Synlett
Among the ligands investigated 1,10-phenanthroline
showed the highest efficacy for the formation of product 3a
in the presence of Cs2CO3 (Table 1, entries 6–11). After hav-
ing the successful screening of the preliminary conditions
(Table 1, entries 1–11) it was observed that the high yield of
the product 3a was obtained when the reactions were per-
formed in the presence of both catalytic Fe and Pd salts.
However, due to the recent awareness on developing Fe-
catalyzed synthetic transformations,20 the screened Fe(III)-
catalyzed reaction was investigated under various reaction
parameters such as influence of oxidant, base, catalyst load-
ing, ligands, solvents, reaction temperature and time (Table
1, entries 12–18 and in SI). Further optimization of the con-
ditions revealed that the formation of the product 3a was
dramatically reduced when the reaction was performed in
the absence of both oxidant and base as well as with de-
creased amounts of catalyst loading (Table 1, entries 12–
14). Additionally, among the solvents tested DMF showed
maximum efficiency for the formation of product 3a (Table
1, entries 9, 15–18). A detailed optimization study (Table 1
and in SI) showed that the highest yield of the product 3a
was obtained when the reaction between 1a and 2a was
performed in the presence of 5 mol% of FeCl3 as catalyst and
10 mol% of 1,10-phenanthroline as ligand using 1.3 equiva-
lents of DCIB as oxidant, and 1.5 equivalents of Cs2CO3 as
base in anhydrous DMF as solvent at 100 °C for 16 hours
(Table 1, entry 9). These reaction parameters are considered
as optimal conditions to investigate the further scope of the
developed reaction towards the synthesis of C2-arylated
benzoxazoles (Method A).
3u,v were obtained in 74% and 71% yield, respectively when
benzothiazole 1f was reacted with boronic acids 2e and 2k.
Therefore, it has been described that the substrate scope of
the devised Fe(III)-catalyzed protocol remains general as a
broad spectrum of arylboronic acids containing diverse
functionality can be well tolerated under the reaction con-
ditions.
Based on the literature evidence,20e a plausible mecha-
nistic proposal for the Fe-catalyzed reaction between naph-
thoxazole 1a and phenylboronic acid 2a is depicted in
Scheme 2. It is believed that a reversible coordination of the
pyridyl groups delivers the active catalytic iron species A
that may lead to the formation of the iron species B via irre-
versible metalation of the C−H bond of heteroaromatic 1a
with elimination of HCl.
Next, the transmetalation of iron species B with boro-
nate intermediate C may generate the diaryl iron species D
which upon reaction with DCIB E leads to the formation of
the desired coupling product 3a, isobutene F and regener-
ates the active catalytic species A.
N
N
H
N
N
O
II
Fe
O
Cl
CsO
O
OH
B
1a
B
O
N
N
Cl
1,10-phen
II
III
HO
Fe
Fe
Cl
C
A
Cs2CO3
Having the optimized conditions in hand, next the syn-
thesis of a broad spectrum of C2-arylated benzoxazoles 3a–
v was attempted (Table 2). It is described that the aryl-
boronic acids 2a–o can be reacted successfully with benzoxaz-
oles 1a–e and benzothiazole 1f under the optimized reac-
tion conditions. The monosubstituted arylboronic acids
containing methoxy and methyl residue as electron-donat-
ing groups, as well as bromo, chloro, fluoro, ester, cyano,
and nitro groups as electron-withdrawing substituents
were well tolerated under the developed reaction condi-
tions to furnish the products 3. It is noteworthy to mention
that the high yields (84–88%) of the C2-arylated products 3
were observed with the arylboronic acids having electron-
donating groups; however, in the case of arylboronic acids
having electron-withdrawing groups the yield of the C2-
arylated products 3 remains relatively low (from 55–79%).
Moreover, it has been shown that the disubstituted arylbo-
ronic acids containing both electron-donating and electron-
withdrawing groups can be utilized efficiently for the de-
scribed Fe(III)-catalyzed C2-arylation of benzoxazoles 1a–c
and the corresponding products 3g, 3o and 3r were isolated
in 73%, 83% and 67% yields, respectively. The scope of the C–
H functionalization has also been extended using naphthyl-
boronic acid 2l to obtain the corresponding C2-arylated
product 3l in 62% yield. Moreover, C2-aryl benzothiazoles
N
OH
B
N
O
+
3a
N
N
O
HO
II
Fe
D
Me
Me
Cl
Me
2a
Cl
Me
F
E
Scheme 2 Plausible mechanism for the Fe(III)-catalyzed C2-arylation
of benzoxazoles
After the successful development of Fe(III)-catalyzed
C–H functionalization of benzoxazoles 1 with arylboronic
acids 2 (Method A), we diverted our attention towards the
syntheses of 2-aryl benzoxazoles using nitroso derivatives
and the modification of substrate used in the previous re-
ports.11b–c In the previous reports, the 2-aryl benzoxazoles
3 were furnished by the reaction between 1-nitroso-2-
naphthol and 2-bromoacetophenones using Cs2CO3 as base
and the desired products 3 were obtained via the loss of a
carbon monoxide molecule from the α-bromoketones. To
avoid the use of preactivated α-bromoketones, here we
have attempted to revise the previous method using aceto-
phenones as easily available substrates. In this regard, the
reaction between 1-nitroso-2-naphthol (4a) and acetophe-
none (5a) has been carried out in the presence of 50 mol%
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

E
N. Vodnala et al.
Letter
Synlett
Method B
CBr4 (50 mol%)
Cs2CO3 (2.1 equiv)
MeCN, 80 °C, 6 h
O
NO
OH
H
N
+
R
12 examples
53–78%
O
R
4a, b
5a–k
3a–f, 3h–i, 3k, 3m, 3w–x
MeO
N
OMe
Me
N
N
N
N
N
O
O
O
O
3d (78%)
3a (69%)
3b (76%)
3c (71%)
CO2Me
Cl
F
N
N
N
Cl
O
O
O
3h (59%)
O
3e (73%)
3i (65%)
3f (66%)
Br
NO2
N
N
N
Br
O
O
O
O
3k (55%)
3m (57%)
3w (53%)
3x (65%)
Scheme 3 Synthesis of 2-aryl naphthoxazoles using 1-nitroso-2-naphthol 4 and acetophenones 5 as substrate
of CBr4 and 2.1 equivalents of Cs2CO3 as base in MeCN as
solvent at 80 °C for six hours to obtain the desired product
3a in 69% yield (Scheme 3). However, the same transforma-
tion failed to deliver the product 3a, when 1.1 equivalents
of NBS or 1.1 equivalents of I2 were realized as halogenating
agents under the identical conditions (in SI). After the de-
tailed optimization of the conditions (in SI) for the reaction
between 4a and 5a, it was found that the maximum yield of
3a was afforded when 1 mmol of 4a was reacted with 1
mmol of 5a using 50 mol% of CBr4 and 2.1 equivalents of
Cs2CO3 in MeCN at 80 °C for six hours. Therefore, these con-
ditions are considered as the optimal conditions (Method
B). Then, the scope of the developed reaction was explored
using a number of acetophenone derivatives 5 containing
both electron-donating and electron-withdrawing groups
(Scheme 3). It was found that the substituted acetophe-
nones with methoxy and methyl groups on aromatic ring
were well tolerated under the reaction conditions (Method
B) to deliver the products 3b–d in good yields (71–78%). On
the other hand, the bromo, chloro, fluoro, ester and nitro-
substituted acetophenones furnished the corresponding
products 3e,f,h,i,k,w,x in yields ranging from 53–73%. Addi-
tionally, the product 2-phenylbenzoxazole 3m was ob-
tained in 57% yield when the reaction between 2-nitroso-
phenol 4b and acetophenone (5a) was carried out under
the standard conditions.
Table 2 Scope of the Fe(III)-Catalyzed C–H Functionalization Approach for the Synthesis of C2-Arylated Benzoxazoles 3a–va,b
Method A
FeCl3 (5 mol%)
1,10-phen (10 mol%)
DCIB (1.3 equiv)
OH
N
H
B
Cs2CO3 (1.5 equiv)
N
Ar
HO
Ar
+
O
R
O
DMF, 100 °C, 16 h
22 examples
55–89%
R
1a–f
2a–o
3a–v
Entry
1
1
2
3, Yield (%)b
N
N
(HO)2B
O
O
2a
1a
3a (85%)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

F
N. Vodnala et al.
Letter
Synlett
Table 2 (continued)
Entry
1
2
3, Yield (%)b
OMe
N
O
N
(HO)2B
OMe
2
3
O
2b
1a
1a
3b (88%)
MeO
MeO
(HO)2B
N
O
N
O
2c
3c (84%)
3d (86%)
3e (79%)
3f (71%)
3g (73%)
3h (65%)
3i (76%)
3j (64%)
Me
N
O
N
(HO)2B
Me
4
5
O
2d
1a
1a
1a
1a
1a
1a
1a
Cl
N
O
N
(HO)2B
Cl
O
2e
N
O
(HO)2B
N
Cl
6
O
Cl
2f
Cl
Cl
N
O
(HO)2B
Cl
N
N
N
N
7
O
O
O
O
Cl
2g
F
N
O
(HO)2B
F
8
2h
CO2Me
N
O
(HO)2B
CO2Me
9
2i
CN
N
O
(HO)2B
CN
10
2j
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

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N. Vodnala et al.
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Table 2 (continued)
Entry
1
2
3, Yield (%)b
NO2
N
O
N
N
(HO)2B
NO2
11
12
13
14
O
O
2k
1a
1b
1b
1b
3k (55%)
N
O
(HO)2B
2l
3l (62%)
N
O
N
(HO)2B
O
2a
3m (89%)
OMe
N
O
N
(HO)2B
OMe
O
2b
3n (87%)
Br
O
Me
Br
N
O
N
3o (83%)
N
15
16
17
18
19
(HO)2B
Me
1b
1b
1b
2m
Br
O
Br
N
O
(HO)2B
2n
3p (66%)
Cl
N
O
N
(HO)2B
Cl
O
2e
3q (74%)
Br
O
Me
Br
N
O
N
Br
(HO)2B
Me
Br
1c
2m
3r (67%)
Br
Br
N
O
N
O2N
(HO)2B
O2N
O
1d
2n
3s (69%)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

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N. Vodnala et al.
Letter
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Table 2 (continued)
Entry
1
2
3, Yield (%)b
Br
N
O
Br
N
20
21
(HO)2B
O
2o
1e
3t (63%)
Cl
N
S
N
(HO)2B
Cl
S
2e
1f
3u (74%)
NO2
N
S
N
(HO)2B
NO2
22
S
2k
1f
3v (71%)
a Reactions were performed using 1a–f (1.0 mmol) and 2a–o (1.0 mmol) in anhyd DMF (2 mL) under a nitrogen atmosphere.
b Isolated yields.
In conclusion, two facile and convenient protocols for
the syntheses of C2-aryl benzoxazoles are described.21,22
Notably, the present methods avoid the use of precious
metal as catalyst and pre-activated halogenated com-
pounds as substrates. The reaction proceeds via Fe(III)-cata-
lyzed C–H activation approach with high yields of C2-aryl
benzoxazoles and restricts the formation of self-coupling
compounds as side products. On the other hand, an effi-
cient domino approach has been devised using nitroso aro-
matics and non-activated ketones as substrates. Using these
developed methods a broad spectrum of substrate scope
was investigated to synthesize 2-aryl benzoxazoles in high
yields.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609718.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References and Notes
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Funding Information
CCM acknowledges the Science and Engineering Research Board
(SERB), New Delhi and NIT Manipur for the financial support in the
Molecular Transformations;
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V1o.
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Acknowledgment
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tute of Technology, Guwahati for recording NMR and Mass spectra.
We sincerely thank Prof. T. Punniyamurthy, V. Satheesh and R. Bag
from the Department of Chemistry, Indian Institute of Technology,
Guwahati for sample analysis and research support. DK, NV, RG and
AKK are grateful to the Ministry of Human Resource Development
(MHRD), New Delhi for fellowship support.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

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(21) General Experimental Procedure for the Synthesis of Prod-
ucts 3a–v:
Method A: A-10 mL pressure tube was charged with a mixture
of 1a–f (1.0 mmol), 2a–o (1.0 mmol), FeCl3 (0.05 mmol, 8.1 mg),
1,10-phenanthroline (0.1 mmol, 18 mg), DCIB (1.3 mmol, 165
mg), Cs2CO3 (1.5 mmol 487 mg), and DMF (2 mL). The pressure
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J

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tube was then sealed and heated at 100 °C for 16 h. After com-
pletion of the reaction, the mixture was diluted with hot EtOAc
(50 mL) and H2O (100 mL) and extracted with EtOAc (3 × 50 mL).
The combined organic layer was washed with brine (2 × 50 mL)
and dried over anhyd Na2SO4. The solvent was removed under
reduced pressure and the remaining residue was purified by
flash chromatography over silica gel using hexane–EtOAc (10:1)
as an eluent to obtain the desired products 3a–v.
Method B: In an oven-dried 100-mL round-bottomed flask 4a–
b (1.0 mmol), 5a–k (1.0 mmol), CBr4(0.5 mmol, 165 mg), Cs2CO3
(2.1 mmol, 682 mg) and 10 mL MeCN (10 mL) were added suc-
cessively and the reaction mixture was heated for 6 h at 80 °C
under nitrogen atmosphere. The reaction mixture was allowed
to cool to r.t. and then the solvent was removed under vacuum.
The crude product was purified by using column chromatogra-
phy over silica gel using hexane–EtOAc (10:1) as an eluent to get
the products 3a–f, 3h, 3i, 3k, 3m, 3w, 3x as yellow crystalline
solids.
(22) Characterization Data for 2-Phenylnaptho[1,2-d]oxazole
(3a): yield: 85%, 208 mg (Method A) and 69%, 169 mg (Method
1
B). H NMR (400 MHz, CDCl3): δ = 7.45–7.49 (m, 5 H, 8-H, 9-H,
10-H, 11-H, 12-H), 7.69 [dd, 3J (1-H, 2-H) = 7.0 Hz, 3J (2-H, 3-H)
= 8.0 Hz, 3J (3-H, 4-H) = 8.1 Hz, 3J (2-H, 3-H), 2 H, 2-H, 3-H], 7.89
[d, 3J (3-H, 4-H) = 7.0 Hz, 1 H, 4-H], 8.23–8.29 [m, 3J (5-H, 6-H)=
8.9 Hz, 2 H, 5-H, 6-H], 8.52 [d, 3J (1-H, 2-H) = 8.0 Hz, 1 H, 1-H].
13C NMR (100 MHz, CDCl3): δ = 109.8 (C-6), 115.5 (C-14), 121.2
(C-1), 123.4 (C-15), 124.3 (C-2), 124.9 (C-3), 125.9 (C-4), 126.2
(C-8, C-12), 127.5 (C-10), 127.8 (C-9, C-11), 130.0 (C-5), 130.1
(C-19), 136.5(C-16), 147.0 (C-17), 161.2 (C-18).
HRMS (EI): m/z [M + H]+ calcd for C17H12NO: 246.0918; found:
246.0914.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–J