Synthesis of 4-Alkenyl Benzoxazoles via Pd-catalyzed ortho C?H Functionalization of 2-Amidophenols

Article abstract of DOI:10.1002/adsc.201801272

A one-pot direct transformation to remotely C?H alkene functionalized 2-aryl benzoxazoles from the reaction of amidophenol and electronically deficient olefin was reported. Control experiments confirm that the Pd-catalyzed regioselective C?H activation/alkenylation occurs at the first step by leading to ortho-alkenylated amidophenol; which subsequently underwent tandem intramolecular annulation to afford C4-alkenylated 2-arylbenzoxazole derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201801272

Title: Synthesis of 4-alkenyl benzoxazoles via Pd-catalyzed ortho C-H
functionalization of 2-amidophenols
Authors: Niranjan Panda and Kanchanbala Sahoo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801272
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UPDATE
10.1002/adsc.201801272
Advanced Synthesis & Catalysis
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of 4-Alkenyl Benzoxazoles via Pd-catalyzed ortho C-H
Functionalization of 2-Amidophenols
Niranjan Panda,a* and Kanchanbala Sahooa
aDepartment of Chemistry, National Institute of Technology Rourkela, Odisha-769008, India
Email: npanda@nitrkl.ac.in
ORCID: https://orcid.org/0000-0002-7431-8826
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A one-pot direct transformation to remotely C-H
alkene functionalized 2-aryl benzoxazoles from the reaction
of amidophenol and electronically deficient olefin was
reported. Control experiments confirm that the Pd-catalyzed
regioselective C−H activation/alkenylation occurs at the first
step by leading to ortho-alkenylated amidophenol; which
subsequently underwent tandem intramolecular annulation to
afford C4-alkenylated 2-arylbenzoxazole derivatives.
Keywords: C-H activation; Benzoxazole; Pd-catalysis; C-
H alkenylation ; 2-amidophenol.
arylation,[11]
acylation,[11]
hydroxylation,[12]
Introduction
fluorination[13] and alkenylation at the C2-aryl group
of 2-aryl benzoxazoles[14] (Scheme 1d). Contrastingly,
the synthesis of benzoxazole framework with C-H
functionalization at the fused-benzene ring is less
literature precedent. To the best of our knowledge, so
far, there are only two methods have been reported
for the synthesis of such functionalized heterocyclic-
core (functionalization at C7-position only) (Scheme
1d).[15] These methods include: (i) Pd-catalyzed
regioselective C-H arylation of the 2-aryl
benzoxazoles at the remote C7 position,[15a] and (ii)
bifunctional nitrile templet driven remote C-H
alkenylation of 2-methyl benzoxazole (one example
only).[15b] Considering the pharmacological potential
The diverse biological activities of functionalized
benzoxazoles make them an ideal pharmacophore in
drug discovery research.[1] The unique chromophoric
property of the 2-aryl benzoxazoles renders them as a
useful scaffold in broader applications such as optical
brighteners, blue LED, etc.[2] Further, benzoxazoles
also serve as potential ligands in transition metal-
catalyzed coupling reactions.[3] As such, rapid access
to a broad range of benzoxazoles with different
substituents at the benzene ring is synthetically
fascinating. Plethora of methods for the synthesis of
benzoxazole core has been reported over the past
years. The condensation of ortho-aminophenol and
carboxylic acid or its surrogates represent a classical
approach to construct the benzoxazole unit.[1b]
Traditionally, this process requires harsh reaction
conditions such as high temperature, strong acids,
strong oxidative conditions, etc. To circumvent these
pitfalls, several transition metal catalyzed methods
with enhanced substrate scope and several degrees of
flexibility have been developed.[4] These strategies are
mainly: (i) transition-metal-catalyzed C−O cross-
coupling of 2-haloanilides leading to benzoxazole
Scheme 1. Synthesis of 2-aryl benzoxazoles
Previous work
H
N
R
O
N
X
X
O
Y
)
[TM]
(c)
d
n
o
(
(
b
[TM]
i
)
t
X
H
z
i
o
a
-
=
C
l
a
Z
h
o
a
n
h
l
t
o
i
t
c
r
g
o
O
N
e
n
n
u(e)
f
O
N
R
[Pd]
H
R
H
N
[TM]
remote C7-H
arylation/alkenylation
R
n
e
g
o
l
a
h
=
O
O
X
)
a
(
motif (Scheme 1a);[5-7]
(ii) copper-catalyzed
X
Ph
N
X = OH,
EWG
intermolecular domino C−N/C-O cross-coupling of
1,2-dihalobenzene with benzamides (Scheme 1b);[8]
and (iii) aromatic C−H functionalization followed by
C−O bond formation (Scheme 1c).[9] Besides, the
coordinating ability of the nitrogen has been
exploited for the regioselective ortho C−H
Pd(OAc)2, Ag2O,
CF3COOH
remote C4-H
alkenylation
EWG
(e)
Present work
of the functionalized benzoxazoles,[16] the synthesis
of remotely functionalized benzoxazole-core deemed
to be important. In continuation to our recent interest
1
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10.1002/adsc.201801272
Advanced Synthesis & Catalysis
on transition-metal catalyzed C-C and C-heteroatom
bond formation reactions in heterocycle synthesis,[17]
we herein, report a Pd-catalyzed protocol for the
tandem synthesis 4-alkenyl benzoxazoles directly
from the reaction ortho-hydroxy N-aryl amides and
electronically deficient terminal alkenes via ortho C-
Intriguingly, when 1a was treated with methyl
acrylate under the similar reaction conditions as
reported by van Leeuwen,[20a] C-alkenylated product
(e.g., 3aa´) was obtained only in 21% yield along
with a trace amount of 3aa and 2-phenyl benzoxazole
(4a, 24% yield). Thus, we intended to develop an
efficient protocol for the regioselective synthesis of
remotely alkene functionalized benzoxazole (e.g.,
3aa) from 2-amidophenol (e.g., 1a) via the sequential
regioselective C-alkenylation and subsequent
intramolecular annulation.
H
alkenylation and subsequent intramolecular
annulation under ligand-free conditions (Scheme 1f).
Results and Discussion
To access the C4-H functionalized benzoxazole
motif, we anticipated that the N-(2-hydroxy-
phenyl)benzamide (1a) might undergo transition-
metal catalyzed Fujiwara-Moritani ortho-alkenylation
and subsequent annulation to afford C4-alkenylated
2-phenyl benzoxazole (3aa). With this in mind, when
1a was treated with methyl acrylate (2a) under a
similar Pd-catalyzed reaction conditions as reported
by us for the N-tosyl benzoxazolidine synthesis,[17i] 2-
phenyl benzoxazole (4a) was produced exclusively
(25%) along with a trace (< 10%) of a new product
(from TLC) and the remaining unreacted starting
material (Scheme 2). However, at higher temperature
(i.e., 110°C), 2-phenyl benzoxazole (70%) was
produced along with a 16% of the previously new
product with a molecular weight of 279 (as shown by
the ESI-MS). The appearance of a singlet at δ 3.84
Scheme 2. Reactions of amide with alkene
OMe
2a
OH
O
N
H
O
N
Ph
Ph
O
N
Pd(OAc)2 (10 mol%),
K2S2O8 (3 equiv),
O
Ph
+
PTSA (3 equiv),
toluene (2 mL), 60°C, 14h
1a
CO2Me
3aa
4a
1
ppm in H NMR spectrum indicates the presence of
Figure 1. ORTEP of 3aa
methyl ester substituents in the new product.
Presence of doublets at δ 8.02 and 7.37 (with J = 16
Hz) suggests for the existence of an E-double bond.
Considering the 1H and 15 signals from the 13C NMR
spectra, we presumed that the structure of the new
At the onset, we intended to optimize the reaction
condition (Table 1) for the efficient synthesis of 3aa
from the model substrate 1a and methyl acrylate (2a)
in the presence of Pd-catalyst. Treatment of 1a with
2a the presence of Pd(OAc)2, oxidant (K2S2O8) and
additive (PTSA) at room temperature did not show
any change in the starting materials (entry 1). By
increasing the reaction temperature to 110°C, a
mixture of 3aa (16%) and 4a (70%) was produced
(entry 3). In the absence of oxidant, 3aa was not
formed, rather the annulated product 4a was isolated
quantitatively (entry 4). From a similar reaction in the
absence of any additive (entry 5), almost no reaction
occurred (4a was isolated in <10% yield). Solvent
screening to get a better yield of 3aa was
unsuccessful (entries 6-11). In the presence of a basic
additive such as NaOAc and Et3N the reaction did not
proceed (entries 12, 13). Interestingly, by changing
the additive from PTSA to CF3COOH (1 equiv) in the
presence of terminal oxidant K2S2O8 (1 equiv),
benzoxazole 4a was not identified, instead the desired
benzoxazole 3aa was produced, albeit in low yield
(only 20%) with the recovery of remaining starting
material (entry 14). While employing CF3COOH,
both as an additive and the solvent in the presence of
K2S2O8, 3aa was formed in 55% yield (entry 15).
compound
would
be
(E)-methyl
3-(2-
phenylbenzo[d]oxazol-4-yl)acrylate (3aa). The exact
molecular structure of 3aa was further confirmed by
X-ray crystallography (Figure 1).[18] To a side note,
sequential C-H activation and annulation leading to
the remotely C4-alkene functionalized benzoxazole
were not reported earlier though there are limited
pioneering efforts have been made on Pd- and Rh-
catalyzed aromatic C-H olefination of anilides
(Fujiwara-Moritani reaction).[19] Notably, due to the
steric reason, the Pd-catalyzed Fujiwara–Moritani
olefination
of
ortho-substituted
substrates
traditionally unsuccessful or results in poor yield.[19,
20]
Also, the hydroxyl group ortho to the directing
group usually has the deleterious effect in transition
metal catalyzed C-H activation reaction, and the O-
alkenylation would be the potential reaction. Indeed,
the alkenylation of phenol in the presence of Pd-
catalyst was reported recently by Cai and co-
workers.[21] Thus, selective C-alkenylation of 2-
amidophenol (e.g., 1a) in the presence of transition
metal catalyst is considered to be challenging.
2
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10.1002/adsc.201801272
Advanced Synthesis & Catalysis
Among the tested oxidants (e.g., oxone, BQ,
Cu(OAc)2, AgOAc, Ag2O, AgOCOCF3 and
Table 1. Optimization of reaction conditionsa
Cu(OAc)2) Ag2O (1 equiv.) served as the best oxidant
HO
CO2Me
O
O
O
Ph
O
2a (1.5 mmol)
N
Ph
N
Ph
Ph
N
H
H
catalyst, Oxidant
solvent
OH
N
CO2Me
CO2M
e
1a (0.5 mmol)
3aa
3aa' (N.D.)
4a
Entry
catalyst oxidant
(10 mol%) (equiv)
additive
(equiv)
solvent
(2 mL)
temperature
yield (%)
3aa
4a
1
2
3
4
5
6
7
8
9
Pd(OAc)2
K2S2O8 (5)
K2S2O8(5)
K2S2O8 (5)
-
PTSA (3)
PTSA(3)
PTSA(3)
PTSA(3)
-
PTSA(3)
PTSA(3)
PTSA(3)
PTSA(3)
PTSA(3)
PTSA(3)
Et3N (3)
NaOAc (3)
toluene
toluene
toluene
toluene
toluene
toluene
methanol
DCE
rt
0
0
Pd (OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
60°C
110°C
110°C
110°C
110°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
60°C
rt
<10
16
0
25
70
100
<10
30
30
20
0
0
0
0
0
0
trace
0
0
0
0
0
0
0
K2S2O8 (5)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8(1)
K2S2O8 (1)
K2S2O8 (1)
BQ (1)
AgOAc (1)
AgOAc (3)
Ag2CO3 (1)
Ag2O (1)
AgOCOCF3 (1) -
Ag2O (1)
0
35
15
10
0
0
0
THF
10 Pd(OAc)2
11 Pd(OAc)2
12 Pd(OAc)2
13 Pd(OAc)2
14 Pd(OAc)2
15 Pd(OAc)2
16 Pd(OAc)2
17 Pd(OAc)2
18 Pd(OAc)2
19 Pd(OAc)2
20 Pd(OAc)2
21 Pd(OAc)2
22 Pd(OAc)2
23 Pd(OAc)2
24 Pd(OAc)2
CH3CN
1,4-dioxane
toluene
toluene
0
0
CF3COOH(1) toluene
20
55
46
60
65
52
90
78
20
35
0
-
-
-
-
-
-
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH(1) toluene
-
-
Cu(OAc)2 (1)
Ag2O (1)
CF3COOH
CF3COOH
0
0
aReaction conditions: A mixture of 1a, 2a and additive in solvent was stirred in a closed round bottom for 14h.
to afford 3aa in optimum yield (90%) with complete
conversion of starting material over a period of 14h at
60°C (entry 20). At room temperature, no reaction
occurred (entry 24). Besides, by lowering the catalyst
loading to 5 mol% as well as oxidant concentration to
0.5 equiv., incomplete conversion occured by
offering a lower yield of 3aa (47% and 42%
respectively) even after 24h.
During our investigation to exploit the scope and
limitations of this reaction process, we noticed that
the reaction of 2-chloro-N-(2-hydroxyphenyl)-
benzamide (1c) with 2a, under optimized reaction
conditions affords 25% of the desired product (3ca)
along with the intermediate 3ca´ (50%) (Scheme 3).
Formation of 3ca´ was evident from 1H and 13C NMR
data. On heating the intermediate 3ca´ at 90°C in
CF3COOH, 3ca was produced smoothly with a
combined yield of 65% from 1c. Additionally, when
2-phenyl benzoxazole (4a) was treated with the
methyl acrylate in the presence of Pd(OAc)2 (10
mol%) and Ag2O (1 equiv) in TFA, 3aa was not
formed with complete recovery of the starting
material. Hence, the possibility for weakly
coordinating oxazole nitrogen-directed remote C4-H
alkenylation to access 3aa was disregarded. On the
other hand, we predict that the overall transformation
occurs with the initial C-alkenylation through C-H
activation (Fujiwara-Moritani reaction) followed by
an acid catalyzed annulation. In line with the reported
22]
literature,[21,
the catalytic cycle is presented in
Scheme 4. We presumed that electronically more
deficient and more reactive Pd-catalyst
(Pd(OCOCF3)2) is forming initially from the reaction
of Pd(OAc)2 and CF3COOH.[21e] The electrophilic
3
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10.1002/adsc.201801272
Advanced Synthesis & Catalysis
attack at the palladium center by the anilide forms the
palladocycle (e.g., A) through ortho-palladation. The
carbopalladation of methyl acrylate (A → B →
C) followed by reductive elimination enables the
ortho C-H alkenated amidophenol (3aa´). In the
presence of terminal oxidant (i.e., Ag2O), the newly
generated Pd(0) oxidizes to Pd(II) for the next
catalytic cycle. Finally, the cross-coupled hydroxy
anilide 3aa´ undergoes acid-catalyzed annulation[22]
to afford the desired benzoxazole 3aa.
yield. Unfortunately, similar reaction with other
para-substituted amidophenols (entries 22-24) gave
only the benzoxazoles 4v-x with the recovery of
unreacted starting materials (1v-x). Probably, due to
Table 2. Synthesis of substituted C4-alkenylated
benzoxazoles[a]
R
R
OH
2a (1.5 mmol)
Pd(OAc)2 ), Ag2O
H
O
NH
O
N
N
R
Co2Me
HO
O
CF3COOH
60°C, 14 h
R1
R1
CO2Me
R1
(0.5 mmol)
1
3
3'
Entry
amide (1)
benzoxazole (3)
% yield
Scheme 3. Control experiment
O
OH
H
CO2Me
CO2Me
N
N
CO2Me
2a
H
90
H
N
1
H
N
O
N
O
Pd(OAc)2 (10 mol%)
Ag2O (1 equiv)
CF3CO2H
+
O
Cl
1a
CO2Me
3aa
O
Cl
OH
OH
Cl
1c
3ca' (50%)
3ca, 40%
Cl
O
N
OH
H
CF3CO2H
reflux
Cl
N
88
2
Scheme 4. Reaction pathway
O
Ph
1b
CO2Me
3ba
3ca
O
O
N
O
OH
H
H+
CO2Me
Ph
NH
N
N
OH
H
Cl
85
HO
3
4
5
6
CO2Me
N
Ph
O
Cl
3aa
Ag2O
Pd(OCOCF3)2
O
1c
CO2Me
Cl
1a
3aa'
O
N
OH
OH
Pd(0)
Cl
H
CF3CO2H
N
77
52
Cl
OH
O
Cl
OH
H
Pd(OAc)2
H
N
N
Ph
Ph
1d
CO2Me
3da
3ea
Cl
Cl
O
O
N
O
Pd
Cl
H
N
OH
OCOCF3
A
MeO2C
Pd(OCOCF3)
H
N
Ph
Cl
O
C
O
1e
CO2Me
Pd
CO2Me
OCOCF3
Me
O
N
OH
OH
Me
H
CO2Me
B
N
82
O
Next, we turned our attention to study the
compatibility of this tandem C-H functionalization
and annulation protocol to form a series of C4-
functionalized benzoxazole derivatives (3) by varying
the substituents at the aromatic rings. To our pleasure,
the coupling of differently substituted amidophenols
(1a-u) with methyl acrylate (2a) gave the desired
derivatives (3aa-3ua) in moderate to good yield.
Worthy to mention that the ortho-substituents (e.g.,
1c, 1d, 1g) to the aromatic ring cause masking for
acid catalyzed annulation (e.g., 3ca´ → 3ca) due to
steric shield. As a result, the intermediate 3ca´ was
formed via dehydrogenative C-H alkenylation along
with the annulated product 3ca. Moreover, when
3ca´was heated at 90°C in TFA, C4-alkenylated
benzoxazole was formed smoothly. The reaction of
para-fluoro amidophenol, i.e., 1u with 2a procceds
with partial conversion and the desired C4-
alkenylated benzoxazole 3ua was isolated in 44%
1f
CO2Me
3fa
O
N
H
N
7
62
Me
O
Me
1g
3ga
CO2Me
NO2
O
N
OH
NO2
H
N
8
56
O
1h
CO2Me
3ha
3ia
O
N
OH
H
N
NO2
9
47
NO2
O
O
1i
1j
CO2Me
OMe
O
N
OH
OMe
H
N
10
79
CO2Me
3ja
O
N
OH
H
4
N
OMe
11
57
OMe
O
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1k
CO2Me
3ka

10.1002/adsc.201801272
Advanced Synthesis & Catalysis
Entry
Amide (1)
benzoxazole (3)
% yield
OH
O
Entry
Amide (1)
benzoxazole (3)
% yield
H
N
N
OH
H
Cl
68
12
MeO
O
OMe
Cl
Ph
N
O
23
1l
3la
0[c]
Ph
Ph
CO2Me
O
N
Cl
OH
O
N
1w
Cl
H
N
3wa
S
S
CO2Me
13
O
OH
H
55
O
N
3ma
1m
Ph
N
CO2Me
0[d]
Me
24
25
O
O
OH
3xa
Me
H
1x
Me
N
Me
N
CO2Me
14
15
35
76
OH
O2N
O
O
N
3na
H
1n
Ph
0[e]
Ph
N
CO2Me
Cl
O
OH
O
3ya
O2N
H
Ph
1y
N
Ph
N
CO2Me
O
OH
MeOC
O
Cl
1o
H
3oa
Ph
Ph
N
trace[f]
26
CO2Me
Br
N
O
O
OH
MeOC
3za
H
Ph
1z
N
Ph
N
CO2Me
16
17
75
62
O
Br
[a]
1p
1q
3pa
Reaction conditions: Amide (0.5 mmol), alkene (1.5
mmol), Pd(OAc)2 (10 mol%), Ag2O (0.5 mmol) in
CF3CO2H (2 mL) at 60°C, 14h. [b-f] Benzoxazoles 4v-4z
were formed with recovery starting material.
CO2Me
Me
OH
O
H
N
Ph
Ph
N
O
Me
3qa
steric reason, the initial anilide directed C-H
alkenylation did not occur and so the subsequent
annulation. Amidophenol with an ester substituent
(i.e., 1t) also underwent the coupling reaction with 2a,
and 3ta was formed (entry 20). Worthy to mention
here that while amidophenols with strong electron-
withdrawing groups were treated with 2a under
optimized reaction conditions, the aromatic ring gets
deactivated substantially, and the alkenylation did not
occur (entries 25 & 26), rather the benzoxazoles such
as 5-nitro and 5-acyl -2-phenylbenzo[d]oxazole (4y
and 4z respectively) were produced from the acid-
catalyzed annulation in 40% and 31% yield
respectively, with the recovery of unreacted
amidophenol.
Coupling of 1a with different alkenes to enable
the C4-alkenated benzoxazole was also investigated
(Scheme 5). It has been observed that the acrylates
are the most suitable coupling partners to afford the
desired C4-alkenylated benzoxazoles (e.g., 3aa, 3ab,
3ac, 3ae) under our Pd-catalyzed reaction conditions.
Notably, when benzyl acrylate was employed, the
benzyl 3-(2-phenyl-benzoxazol-4-yl)-acrylate (3ae)
was formed (28% yield) along with 3ad (60%), that
resulted from the hydrolysis of 3ae. Surprisingly, the
reaction of acrylic acid with 1a gave 3ad (28%) along
CO2Me
Me
OH
O
N
H
Me
N
Ph
Ph
18
O
55
1r
3ra
CO2Me
Cl
OH
H
O
Cl
N
Ph
Ph
19
N
O
57
1s
3sa
CO2Me
OH
H
MeO2C
O
N
Ph
Ph
N
20
O
40
44
MeO2C
3ta
1t
CO2Me
OH
H
O
N
Ph
Ph
21
N
O
F
F
1u
3ua
CO2Me
OH
O
H
N
Ph
Ph
N
Cl
0[b]
22
O
3va
1v
Cl
with
(E)-3-(5-benzoyl-4-oxo-2,3,4,5-tetrahydro-
CO2Me
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801272
Advanced Synthesis & Catalysis
Unless otherwise noted, the reagents (chemicals) were
purchased from commercial sources and used without
further purification. 2-Amidophenols (1) were prepared
from the reaction of aroyl chloride and 2-amino phenol by
following the procedure reported elsewhere.[23] Reactions
were monitored by TLC, and the residue was
chromatographed on a silica gel (100 - 200 mesh), using
ethyl acetate-petroleum ether (60-80°C) mixture as an
eluent. All NMR spectra were recorded on a 400 MHz (for
1H NMR) and 100 MHz (for 13C NMR) NMR spectrometer,
and chemical shifts were expressed in δ units relative to the
TMS signal as an internal reference in CDCl3.
Multiplicities are indicated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet, when multiplicity is
complex) for 1H NMR. Coupling constants, J were
reported in Hz. IR spectra were recorded on an FTIR
spectrometer (IR Affinity 1S W/L with quest ATR). High-
resolution mass spectrometry (ESI-HRMS) (Agilent 6520
Q-TOF) was used to determine the elemental composition.
benzo[b][1,4]-oxazepin-6-yl)acrylic acid (5) (40%
yield). Acrylonitrile and acrylamide were also
underwent coupling reaction by enabling the
corresponding alkenylated benzoxazole 3af and 3ag
respectively with the concordant formation of 2-
phenyl benzoxazole (4a) in a reasonable amount
(42% and 35% yield respectively) from the acid-
catalyzed intramolecular annulation of 1a.
Unfortunately, the initial anilide directed Pd-
catalyzed C-H alkenylation by vinyl acetate, methyl
cinnamate, methyl methacrylate, styrene, N,N-
dimethyl acrylamide as well as acrylophenone did not
occur[19e] under the optimized reaction conditions.
Moreover, under forcing reaction conditions, i.e., at a
higher temperature (90°C), 4a was isolated in
reasonable yield.
Scheme 5. Coupling of 1a with alkenes (2)
General Procedure for the synthesis of benzoxazolyl
acrylate (3)
Ph
O
N
Pd(OAc)2
R1
R1
1a
+
A mixture of 2-amidophenol (1, 0.5 mmol), Pd(OAc)2 (10
mol%) and silver oxide (0.5 mmol) in trifluoroacetic acid
(2 mL) was stirred at room temperature for 1h. Then,
alkene (2, 1.5 mmol) was added and then heated at 60°C
for 14h during which colour of the solution changes from
dark brown to black. After completion of the reaction
(from TLC) the reaction mixture was triturated with
EtOAc (5 mL) and neutralized with 5% aq. NaHCO3
solution. Next, the two layers were separated and the
aqueous layer was extracted with EtOAc (3 x 10 mL). The
combined organic layer was washed with aq. NaHCO3 (5
mL) solution and dried over anhydrous Na2SO4. Then
solvent was removed under reduced pressure and the crude
reaction mixture was purified by column chromatography
using EtOAc: pet. ether (2:98) to enable the desired
benzoxazoles.
Ag2O, CF3COOH
60°C, 14 h
R
2
R
3
3aa; R1 = H, R = CO2Me (90%)
3ab; R1 = H, R = CO2n-Bu (72%)
3ac; R1 = H, R = CO2Ph (59%)
3ad; R1 = H, R = CO2H (28%)[b]
3ae; R1 = H, R = CO2Bz (28%)[c]
3af; R1 = H, R = CN (42%)
3ag; R1 = H, R = CONH2 (47%)
[a] Reaction conditions: 1a (0.5 mmol), alkene (1.5 mmol),
Pd(OAc)2 (10 mol%), Ag2O (0.5 mmol) in CF3CO2H (2
mL) at 60°C, 14h. [b](E)-3-(5-benzoyl-4-oxo-2,3,4,5-
tetrahydrobenzo[b][1,4]oxaze-pin-6-yl) acrylic acid (5)
was formed in 40% yield along with 3ad. [c]In addition to
3ae, 3ad was also formed in 60% yield.
Conclusion
Synthesis and analytical data
In conclusion, a strategically simple method for
the synthesis of C4-H alkene functionalized
benzoxazole from the reaction of 2-amidophenol and
electronically deficient olefin was developed. The
said transformation proceeds through the initial Pd-
catalyzed N-acyl assisted tandem C4-H alkenylation
and subsequent acid catalyzed annulation to afford a
series of 4-alkenylated 2-arylbenzoxazoles. This
protocol was found to be most successful with the
acrylates. Other alkenes having –COOH, CN and
CONH2 were also underwent coupling reaction under
optimized reaction condition. Study on biological
activities and photophysical properties of these
benzoxazoles are going on in our laboratory.
(E)-methyl
3-(2-phenylbenzo[d]oxazol-4-yl)acrylate
(3aa): Compound 3aa was obtained from the reaction of 2-
benzamidophenol (1a) and methyl acrylate (2a) as a white
crystalline solid (125 mg, 90% yield); mp 88 - 90ºC; IR:
2924, 2854, 2358, 1710, 1627, 1550, 1431, 1355, 790, 746,
1
686 cm-1. H NMR (400 MHz, CDCl3): δ 8.36 - 8.31(2H,
m), 8.04 (d, 1H, J = 16 Hz), 7.62 - 7.54 (m, 6H), 7.48 (m,
1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.8,
163.5, 151.1, 141.0, 140.6, 31.7, 128.8, 127.8, 126.8, 126.6,
125.7, 124.8, 121.9, 111.8, 51.7. MS (ESI, +ve) m/z
(relative intensity) 302.079 [M+Na]+, 100%
(E)-Methyl
3-(2-(4-chlorophenyl)benzo[d]oxazol-4-
yl)acrylate (3ba): Compound 3ba was obtained from the
reaction of 4-chloro-N-(2-hydroxyphenyl)benzamide (1b)
and methyl acrylate as a white crystalline solid (137 mg,
88% yield); mp 120 - 122ºC; IR: 2958, 2924, 2880, 1714,
Experimental Section
General Information
1
1635, 1558, 1473, 1431, 1321, 1024, 985, 746 cm-1. H
NMR (400 MHz, CDCl3): δ 8.28 - 8.24 (m, 2H), 8.01 (d,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801272
Advanced Synthesis & Catalysis
1H, J = 16 Hz), 7.59 (d, 1H, J = 7.6 Hz), 7.53(d, 2H, J =
8.8 Hz), 7.47 (d, 1H, J = 7.6 Hz), 7.49 - 7.34 (m, 2H), 3.86
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.7, 162.5,
151.0, 140.8, 140.5, 138.0, 129.2, 129.0, 126.7, 125.8,
125.3, 125.1, 122.0, 111.8, 51.7 HRMS (ESI-TOF) m/z
(E)-Methyl 3-(2-p-tolylbenzo[d]oxazol-4-yl)acrylate (3fa):
The desired compound was obtained from the reaction of
N-(2-hydroxy-phenyl)-4-methyl benzamide (1f) and
methyl acrylate as a white crystalline solid (120 mg, 82%
yield); mp 104 – 106 ºC; IR 2956, 2920, 1699, 1626, 1498,
1
calcd for C17H13ClNO3 [M+H]+ 314.0589; Found 314.0584. 1426, 1316, 1234, 1180, 979, 760 cm-1. H NMR (400
MHz, CDCl3): δ 8.22 (d, 2H, J = 8 Hz), 8.04 (d, 1H, J = 16
Hz), 7.58 (dd, 1H, J1 = 8.4 Hz, J2 = 0.4 Hz), 7.45 (d, 1H, J
= 6.4 Hz), 7.43 (d, 1H, J = 15.6 Hz), 7.38 - 7.32 (m, 3H),
3.88 (s, 3H), 2.47(s, 3H); 13C NMR (100MHz, CDCl3): δ
167.9, 163.9, 151.0, 142.4, 141.2, 140.7, 129.6, 127.8,
126.4, 125.7, 124.6, 124.1, 121.8, 111.8, 51.7, 21.7.
HRMS (ESI-TOF) m/z calcd for C18H16NO3 [M+H]+
294.1126; Found 294.1130.
(E)-Methyl
3-(2-(2-chlorophenyl)benzo[d]oxazol-4-
yl)acrylate (3ca): Compound 3ca was obtained from the
reaction of 2-chloro-N-(2-hydroxyphenyl)benzamide (1c)
and methyl acrylate as a white crystalline solid (42 mg,
25%) along with the intermediate (E)-methyl 3-(2-(2-
chlorobenzamido)-3-hydroxyphenyl) acrylate (3ca´) (112
mg, ) as a gummy liquid. [IR: 3600 - 3200 (b), 2940, 2395,
1714, 1646, 1556,1430, 1328, 1260, 1250, 1000, 863 cm-1.
1H NMR (400 MHz, CDCl3): δ 8.63 ( s, 1H), 8.03 (d, 1H,
J = 16 Hz), 7.90 (d, 1H, J = 7.2 Hz), 7.51 - 7.43 (m, 3H),
7.43 - 7.37 (m, 1H ), 7.38 - 7.28 (m, 1H), 7.29 - 7.25 (m,
1H), 7.25 - 7.13 (m, 1H) 6.39 (d, 1H, J = 16 Hz), 3.78 (s,
3H); 13C NMR (100MHz, CDCl3): δ 166.9, 166.3, 151.3,
139.7, 132.5, 131.2, 130.8, 130.5, 129.9, 128.3, 127.4,
123.8, 121.9, 121.1, 119.3, 51.8, 31.6. MS (ESI, +ve) m/z
(relative intensity) 332.06 [M+H]+, 100%].
(E)-methyl 3-(2-o-tolylbenzo[d]oxazol-4-yl)acrylate (3ga):
The desired compound was obtained from the reaction of
N-(2-hydroxy-phenyl)-2-methyl- benzamide (1g) and
methyl acrylate as a white crystalline solid (88 mg, 60%
yield) mp 115-118ºC; IR: 2963, 2927, 2827, 1724, 1634,
1
1532, 1419, 1317, 1169, 987, 761 cm-1. H NMR (400
MHz, CDCl3): δ 8.26 (d, 2H, J = 8 Hz), 8.04 (d, 1H, J = 16
Hz), 7.59 (d, 1H, J = 8 Hz), 7.47 - 7.40 (m, 2H), 7.38 –
7.32 (m, 3 H), 3.88 (s, 3H), 2.48 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 167.8, 163.7, 150.4, 140.8, 140.6, 139.2,
131.8, 131.0, 129.8, 126.5, 126.0, 125.7, 125.6, 124.7,
121.9, 111.6, 51.0, 22.4. HRMS (ESI-TOF) m/z calcd for
C18H16NO3 [M+H]+ 294.1124; Found 294.1130.
Treatment of 3ca´ with TFA (2 mL) at 90°C produces 3ca
(60 mg) with an overall yield of 65% from 1c; mp 115-118
ºC; IR: 2949, 2924, 2850, 1714, 1635, 1558, 1473, 1431,
1321, 1172, 1024, 985, 746 cm-1. H NMR (400 MHz,
1
CDCl3): 8.28 - 8.24 (m, 1H), 8.03 (d, 1H, J = 16 Hz), 7.67
– 7.59 (m, 2H), 7.53 – 7.39 (m, 5H), 3.87 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 167.7, 161.5, 150.9, 140.3,
140.2, 133.5, 132.0, 131.9, 131.4, 126.9, 126.8, 125. 9,
125.7, 125.3, 122.1, 111.9, 51.6. HRMS (ESI-TOF) m/z
(E)-methyl
3-(2-(4-nitrophenyl)benzo[d]oxazol-4-
yl)acrylate (3ha): The desired compound was obtained was
obtained from the reaction of N-(2-hydroxy-phenyl)-4-
calcd for C17H13ClNO3 [M+H]+ 314.0581; Found 314.0584. nitro-benzamide (1h) and methyl acrylate as a white
crystalline solid (91 mg, 56% yield); mp 158 – 160 ºC;
IR: 2958, 2953, 1718, 1521, 1340, 1259, 1012, 852, 790
(E)-Methyl 3-(2-(3,4-dichlorophenyl)benzo[d]oxazol-4-
yl)acrylate (3da): Compound 3da was obtained from the
reaction of 2,4-dichloro-N-(2-hydroxyphenyl)benzamide
(1d) and methyl acrylate as a white crystalline solid (134
mg, 77%); mp 135 - 138ºC; IR: 2962, 1716, 1635, 1558,
1257, 1012, 869, 788 cm-1. 1H NMR (400 MHz CDCl3): δ
8.24 (d, 1H, J = 8.4 Hz), 8.01 (d, 1H, J = 16 Hz), 7.66 -
1
cm-1. H NMR (400 MHz, CDCl3): δ 8.51 (d, 2H, J = 8.8
Hz), 8.42 (d, 2H, J = 8.8 Hz), 8.03 (d, 1H, J = 16.4 Hz),
7.65(d, 1H, J = 8 Hz), 7.52 (d, 1H, J = 7.2 Hz), 7.48 – 7.39
(m, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
167.6, 161.1, 151.3, 149.4, 140.6, 140.1, 132.3, 128.6,
127.3, 126.2, 126.1, 124.1, 122.4, 112.1, 51.8. HRMS
7.62 (m, 2H), 7.50 (d, 1H, J = 7.2 Hz), 7.47 – 7.40 (m, 3H), (ESI-TOF) m/z calcd for C17H13N2O5 [M+H]+ 325.0824;
3.87 (s, 3H); 13C NMR (100MHz, CDCl3): δ 167.7, 160.6,
150.8, 140.2, 140.1 137.7, 134.3, 132.6, 131.3, 127.3,
127.0, 126.0, 125.5, 124.2, 122.2, 111.9, 51.6. HRMS
(ESI-TOF) m/z calcd for C17H12Cl2NO3 [M+H]+ 348.0188;
Found 348.0194.
Found 325.0822.
(E)-methyl
3-(2-(3-nitrophenyl)benzo[d]oxazol-4-
yl)acrylate (3ia): Compound 3ia was obtained from the
reaction of N-(2-hydroxy-phenyl)-3-nitrobenzamide (1i)
and methyl acrylate as a white crystalline solid ( 76 mg,
47% yield); mp 150 – 153 ºC; IR: 2958, 2924, 1714, 1520,
(E)-Methyl 3-(2-(3,4-dichlorophenyl)benzo[d]oxazol-4-
yl)acrylate (3ea): Compound 3ea was obtained from the
reaction of 3,4-dichloro-N-(2-hydroxy-phenyl)-benzamide
1340, 1257, 1012, 852, 790 cm-1. H NMR (400 MHz,
1
CDCl3): δ 9.15 - 9.13 (m, 1H), 8.69 (d, 1H, J = 6 Hz),
(1e) and methyl acrylate as a white crystalline solid (90 mg, 8.46 - 8.41 (m, 1H), 8.04 (d, 1H J = 16 Hz), 7.81 - 7.66 (t,
52% yield); mp 148-150ºC; IR: 2926, 2848, 1701, 1558,
1H, J = 8 Hz), 7.66 (d, 1H, J = 8 Hz), 7.52 (d, 1H, J = 7.6
1458, 1288, 1265, 1028, 748 cm-1. 1H NMR (400 MHz,
Hz), 7.48 - 7.37 (m, 2H), 3.90 (s, 3H). 13C NMR (100MHz,
CDCl3): δ 8.4 (d, 1H, J = 2 Hz), 8.19-8.14 (m, 1H), 8.01 (d, CDCl3): δ 167.6, 161.0, 151.2, 148.6, 140.5, 140.1, 133.3,
1H, J = 16 Hz), 7.66 – 7.59 (m, 2H), 7.49 (d, 1H, J = 7.2 130.1, 128.6, 127.2, 126.1, 126.0, 125.9, 122.5, 122.3,
Hz), 7.43 – 7.36 (m, 2H), 3.89 (s, 3H); 13C NMR (100MHz, 112.0, 51.8. HRMS (ESI-TOF) m/z calcd for C17H13N2O5
CDCl3): δ 167.6, 161.2, 151.0, 140.6, 140.2, 136.1, 133.4,
131.0, 129.3, 126.8, 126.7, 126.6, 125.9, 125.4, 122.1,
111.8, 51.7. HRMS (ESI-TOF) m/z calcd for
C17H12Cl2NO3 [M+H]+ 348.0191; Found 348.0194.
[M+H]+ 325.0824; Found 325.0819.
(E)-Methyl
3-(2-(4-methoxyphenyl)benzo[d]oxazol-4-
yl)acrylate (3ja): Compound 3ja was obtained from the
reaction of N-(2-hydroxy-phenyl)-4-methoxy benzamide
( 1j) and methyl acrylate as a white crystalline solid (121
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801272
Advanced Synthesis & Catalysis
mg, 79% yield); mp 128 - 130ºC; IR: 2924, 2848, 1701,
1608, 1498, 1423, 1290, 1172, 1020, 839, 744 cm-1. 1H
NMR (400 MHz, CDCl3): δ 8.30 - 8.26 (m, 2H), 8.03 (d,
1H, J = 16.4 Hz), 7.57 (d, 1H, J = 8 Hz), 7.45 – 7.31 (m,
3H), 7.06 (d, 2H, J = 8.8 Hz), 3.93 (s, 3H), 3.88 (s, 3H).
13C NMR (100MHz, CDCl3): δ 167.8, 163.6, 162.4, 150.9,
141.2, 140.7, 129.6, 126.1, 125.4, 124.2, 121.6, 119.3,
114.2, 111.5, 55.3, 51.5. HRMS (ESI-TOF) m/z calcd for
C18H16NO4 [M+H]+ 310.1074; Found 310.1079.
2.69 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 167.6, 164.4,
151.7, 140.3, 140.2, 126.1, 124.9, 124.2, 121.7, 111.4, 51.5,
14.5. HRMS (ESI-TOF) m/z calcd for C12H12NO3 [M+H]+
218.0812; Found 218.0817.
(E)-Methyl
3-(6-chloro-2-phenylbenzo[d]oxazol-4-
yl)acrylate (3oa): Following the general procedure, 3oa
was obtained from the reaction of N -(4-chloro-2-hydroxy-
phenyl)benzamide (1o) and methyl acrylate as a white
crystalline solid (49 mg, 31% yield), mp 138 - 140ºC; IR
3100, 2951, 2861, 1726, 1624, 1566, 1442, 1158, 987, 840,
1
653 cm-1. H NMR (400 MHz, CDCl3): δ 8.31 - 8.27 (m,
(E)-Methyl
3-(2-(3-methoxyphenyl)benzo[d]oxazol-4-
yl)acrylate (3ka): 3ka was obtained from the reaction of N
-(2-hydroxy-phenyl)-3-methoxy benzamide (1k) and
methyl acrylate as a white crystalline solid (88 mg, 57%
2H), 7.93 (d, 1H, J = 8 Hz), 7.56 - 7.55 (m, 4H), 7.45 -
7.42 (m, 1H), 7.38 (d, 1H, J = 8 Hz), 3.88 (s,1H); 13C
NMR (100MHz, CDCl3): δ 167.2, 164.0, 151.1, 139.0,
yield); mp 118 - 120ºC; IR: 2922, 2854, 1699, 1558, 1458, 131.9, 130.4, 128.8, 127.8, 127.1, 126.3, 125.5, 123.2,
1267, 1028, 983, 748 cm-1. 1H NMR (400 MHz, CDCl3):
8.06 (d, 1H, J = 16 Hz), 7.92 (d, 1H, 7.6 Hz), 7.84 (s, 1H),
7.60 (d, 1H, J = 8 Hz), 7.49 -7.43 (m, 2H), 7.41 - 7.33 (m,
2H), 7.14- 7.10(m, 1H), 3.96 (s, 3H), 3.88(s, 3H); 13C
NMR (100MHz, CDCl3): δ 167.7, 163.3, 159.8, 151.0,
140.9, 140.4, 129.9, 127.9, 126.6, 125.4, 124.8, 121.7,
120.2, 118.1, 112.2, 111.7, 55.4, 51.6. HRMS (ESI-TOF)
m/z calcd for C18H16NO4 [M+H]+ 310.1077; Found
310.1079.
111.9, 51.7. HRMS (ESI-TOF) m/z calcd for C17H13ClNO3
[M+H]+ 314.0581; Found 314.0584.
(E)-Methyl
3-(6-bromo-2-phenylbenzo[d]oxazol-4-
yl)acrylate (3pa): Following the general procedure, 3pa
was obtained from the reaction of N -(4-Bromo-2-hydroxy-
phenyl)benzamide (1p) and methyl acrylate as a white
crystalline solid (65 mg, 37% yield); mp 148 – 150 ºC; IR
3100, 2930, 2838, 1703, 1624, 1556, 1453, 1160, 932, 718
1
cm-1. H NMR (400 MHz, CDCl3): δ 8.32 - 8.27 (m, 2H),
7.92 (d, 1H, J = 8 Hz), 7.74 (d, 1H, 1.6 Hz), 7.61 - 7.52 (m,
4H), 7.38 (d, 1H, J = 8 Hz), 3.88 (s, 1H); 13C NMR
(100MHz, CDCl3): δ 167.4, 164.0, 151.5, 140.2, 139.1,
132.1, 129.0, 128.4, 127.9, 127.7, 126.4, 123.3, 117.7,
114.9, 51.8. HRMS (ESI-TOF) m/z calcd for C17H13BrNO3
[M+H]+ 358.0082; Found 358.0079.
(E)-Methyl
3-(2-(2-methoxyphenyl)benzo[d]oxazol-4-
yl)acrylate (3la): Following the general procedure,
compound 3la was obtained from the reaction of 2-
benzamidophenol (1l) and methyl acrylate (2a) as a white
crystalline solid (62 mg, 47% yield); mp 112 - 115°C. IR :
2902, 2857, 1708, 1626, 1616, 1544, 1435, 1297, 1234,
1170, 1006, 760 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.24
(dd, 1H, J1 = 8 Hz, J2 = 2 Hz), 8.08 (d, 2H, J = 16 Hz), 7.65
(E)-methyl
3-(6-methyl-2-phenylbenzo[d]oxazol-4-
– 7.61 (m, 1H), 7.58-7.52 (m, 1H), 7.47 (d, 1H, J = 7.2 Hz), yl)acrylate (3qa): Following the general procedure, 3qa
7.42 -7.33 (m, 2H), 7.17-7.09 (m, 2H), 4.05 (s, 3H), 3.87 (s, was obtained from the reaction of N-(2-hydroxy 4-
3H); 13C NMR (100 MHz, CDCl3): δ 167.9, 162.7, 158.6,
150.9, 140.9, 140.7, 133.1, 131.7, 126.5, 125.3, 124.7,
121.7, 120.8, 115.9, 112.2, 111.9, 56.1, 51.7. HRMS (ESI-
TOF) m/z calcd for C18H16NO4 [M+H]+ 310.1074; Found
310.1078.
methylphenyl)benzamide (1q) and methyl acrylate as a
white crystalline solid (91 mg, 62% yield); mp 135 - 138
ºC; IR, 2930, 2372, 1703, 1634, 1544, 1419, 1342, 1181,
1
1012, 829, 738 cm-1. H NMR (400 MHz, CDCl3): δ 8.33
- 8.28 ( m, 2H), 7.98 (d, 1H, J = 16 Hz), 7.57 - 7.52 (m,
3H), 7.44 - 7.38(m, 2H), 7. 27 (s, 1H), 3.88 (s, 3H), 2.52 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 167.7 163.0, 151.3,
140.6, 138.8, 135.2, 131.4, 128.7, 127.6, 126.9, 126.8,
125.9, 121.7, 112.0, 51.5, 21.5. HRMS (ESI-TOF) m/z
calcd for C18H16NO3 [M+H]+ 294.1125; Found 294.1130.
(E)-methyl
3-(2-(thiophen-2-yl)benzo[d]oxazol-4-
yl)acrylate (3ma): 3ma was obtained from the reaction of
thiophene 2-carboxylic acid (2-hydroxyl-phenyl)amide
(1m) and methyl acrylate as a white crystalline solid (65
mg, 46% yield), mp 100 - 102ºC; IR: 2924, 1703, 1637,
1564, 1419, 1240, 790, 744 cm-1. 1H NMR (400 MHz,
(E)-methyl
3-(7-methyl-2-phenylbenzo[d]oxazol-4-yl)-
CDCl3): δ 8.05 - 7.96 (m, 2H), 7.62 - 7.59 (m, 1H), 7.55 (d, acrylate (3ra): Following the general procedure, 3ra was
1H, J = 8 Hz), 7.45 (d, 1H, J = 7.6 Hz), 7.37- 7.30 (m, 2H),
7.24 - 7.20 (m, 1H). 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 167.7, 159.4, 150.6, 140.9, 140.3, 130.7, 130.4,
129.2, 128.2, 126.3, 125.5, 124.7, 121.7, 111.5, 51.6.
HRMS (ESI-TOF) m/z calcd for C15H12NO3S [M+H]+
286.0538; Found 286.0539.
obtained from the reaction of N-(2-hydroxy-3-
methylphenyl)benzamide (1r) and methyl acrylate as a
white crystalline solid (80 mg, 55% yield); mp 92 - 94°C;
IR: 2372, 2304, 1720, 1634, 1531, 1514, 1445, 1326, 759
1
cm-1. H NMR (400 MHz, CDCl3): δ 8.37 - 8.32 (m, 2H),
8.0 (d, 1H, J = 16 Hz), 7.59 - 7.53 (m, 3H), 7.38 (d, 1H, J =
16 Hz), 7.37 - 7.34 (m, 1H), 7.17 - 7.13 (m, 1H), 3.88 (s,
3H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.0,
163.3, 150.2, 140.9, 140.5, 131.6, 128.8, 127.8, 127.0,
126.0, 125.9, 124.2, 123.1, 120.7, 51.6, 15.4. HRMS (ESI-
TOF) m/z calcd for C18H16NO3 [M+H]+ 294.1125; Found
294.1129.
(E)-methyl
3-(2-methylbenzo[d]oxazol-4-yl)acrylate
(3na): Following the general procedure, 3na was obtained
from the reaction of N -(2-hydroxy-phenyl)acetamide (1n)
and methyl acrylate as a white crystalline solid (38 mg,
35% yield); mp 90 - 92ºC; IR 2953, 2924, 2852, 1712,
1
1425, 1319, 989, 923, 869, 748 cm-1. H NMR (400 MHz,
CDCl3): δ 7.97 (d, 1H, J = 16 Hz), 7.49 (d, 1H, J = 8 Hz),
7.42 (d, 1H, J = 7.6 Hz), 7.33 - 7.22 (m, 2H), 3.84 (s, 3H),
8
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10.1002/adsc.201801272
Advanced Synthesis & Catalysis
(E)-methyl
3-(7-chloro-2-phenylbenzo[d]oxazol-4-
yl)acrylate (3sa):
(E)-phenyl
3-(2-phenylbenzo[d]oxazol-4-yl)acrylate
Following the general procedure, 3sa was obtained from
(3ac): Following the general procedure, compound 3ac
the reaction of N-(3-chloro-2-hydroxyphenyl)benzamide
was obtained from the reaction of 2-benzamidophenol (1a)
(1s) and methyl acrylate as a white crystalline solid (89 mg, and phenyl acrylate (2c) as a white crystalline solid (99 mg,
57% yield); mp 150-152ºC; IR: 2939, 1703, 1531, 1308,
59% yield); mp 108 – 110 °C; IR 1717, 1626, 1553, 1489,
1416, 1134, 751, 696 cm-1. 1H NMR (400 MHz, CDCl3): δ
8.39 – 8.34 (m, 2H), 8.20 (d, 1H, J = 16 Hz), 7.69 – 7.63
(m, 2H), 7.60 – 7.55 (m, 3H), 7.52 (d, 1H, J = 7.6 Hz),
7.49 – 7.40 (m, 3H), 7.32 – 7.23 (m, 3H); 13C NMR
(100MHz, CDCl3): δ 165.9, 163.8, 151.2, 150.9, 142.4,
141.2, 131.9, 129.4, 129.0, 127.9, 126.8, 126.4, 126.2,
125.7, 125.0, 121.7, 121.5, 112.3. HRMS (ESI-TOF) m/z
calcd for C22H16NO3 [M+H]+ 342.1125; Found 342.1130.
1
1205, 1188, 1068, 707 cm-1. H NMR (400 MHz, CDCl3):
δ 8.35 (dd, 2H, J1 = 8 Hz, J2 = 1.2 Hz), 7.59 (d, 1H, J = 16
Hz), 7.61-7.54 (m, 3H), 7.82 (d, 1H, J = 16 Hz), 7.37-7.32
(m, 2H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
167.7, 163.9, 147.6, 141.9, 139.7, 132.2, 129.0, 128.1,
126.4, 126.2, 125.3, 125.3, 122.1, 117.3, 51.8. HRMS
(ESI-TOF) m/z calcd for C17H13ClNO3 [M+H]+ 314.0578;
Found 314.0583.
(E)-methyl
4-(3-methoxy-3-oxoprop-1-enyl)-2-
(E)-3-(2-Phenylbenzo[d]oxazol-4-yl)acrylic acid (3ad):
The desired compound 3ad was obtained from the
reaction of 2-benzamidophenol (1a) and acylic acid (2d)
as a white crystalline solid (37 mg, 28% yield) mp 198 -
200ºC (decomposition); IR: 2924, 1703, 1637, 1564, 1419,
phenylbenzo[d]oxazole-6-carboxylate (3ta): The desired
compound 3ta was obtained from the reaction of methyl 4-
benzamido-3-hydroxybenzoate (1t) and methyl acrylate as
a white crystalline solid (67 mg, 40% yield); mp 167-
170ºC; IR: 3059, 2955, 1857, 1737, 1703, 1634, 1549,
1
1240, 790, 744 cm-1. H NMR (400 MHz, CDCl3): δ 8.38 -
1428, 1326, 1290, 1153, 1051, 759, 690 cm-1. H NMR
8.33(m, 1H), 8.18 - 8.10 (m, 1H), 7.65 - 7.48 (m, 4H), 7.47
1
(400 MHz, CDCl3): δ 8.35 (dd, 2H, J1 = 8 Hz, J2 = 1.2 Hz), – 6.95 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 171.4,
8.04 (d, 1H, 16 Hz), 8.23 (dd, 1H, J1 = 24 Hz, J2 = 0.8 Hz),
7.63-7.54 (m, 3H), 7.44 (d, 1H, J = 16 Hz), 4.00 (s, 3H),
3.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.5, 166.2,
166.0, 150.8, 144.6, 139.7, 132.5, 129.0, 128.2, 127.2,
127.0, 126.3, 126.2, 122.9, 113.0, 52.6, 51.8. HRMS (ESI-
TOF) m/z calcd for C19H16NO5 [M+H]+ 338.1023; Found
338.1029.
163.6, 151.0, 142.5, 141.1, 131.7, 128.8, 127.8, 126.7,
126.2, 125.9, 124.8, 121.2, 112.1. HRMS (ESI-TOF) m/z
calcd for C16H12NO3 [M+H]+ 266.0817; Found 266.0814.
(E)-Benzyl
3-(2-phenylbenzo[d]oxazol-4-yl)acrylate
(3ae): 3ae was obtained from the reaction of 2-
benzamidophenol (1a) and benzyl acrylate (2e) as a white
crystalline solid (50 mg, 28% yield, mp 92 - 94°C) along
with 3da (60%); IR 2975, 1708, 1635, 1544, 1462, 1407,
(E)-methyl
3-(5-fluoro-2-phenylbenzo[d]oxazol-4-
1
yl)acrylate (3ua): The desired compound 3ua was
obtained from the reaction of N-(5-fluoro-2-
hydroxyphenyl)benzamide (1u) and methyl acrylate as a
white crystalline solid (65 mg, 44% yield); mp: 97 - 99°C;
2921, 2853, 1720, 1686, 1634, 1549, 1463, 1428, 1290,
1205, 1171, 1051, 914, 793, 690 cm-1. 1H NMR (400 MHz,
CDCl3): δ 8.32 (dd, 2H, J1 = 8 Hz, J2 = 1.6 Hz), 8.14 (d,
1H, J = 16 Hz), 7.62 (d, 1H, J = 16 Hz), 7.59-7.51 (m, 4H),
7.12 (dd, 1H, J1 = 10.8 Hz, J2 = 8.8 Hz), 3.89 (s, 3H); 13C
1325, 1207, 1142, 1006, 733, 678 cm-1. H NMR (400
MHz, CDCl3): δ 8.34 – 8.31 (m, 2H), 8.07 (d, 1H, J = 16
Hz), 7.63 – 7.53 (m, 6H), 7.54 – 7.33 (m, 6H), 5.34 (s,
2H); 13C NMR (100 MHz, CDCl3): δ 167.3, 163.6, 151.1,
141.0, 136.2, 131.8, 128.9, 128.6, 128.4, 128.3, 128.2,
127.9, 126.8, 126.6, 125.9, 124.9, 122.0, 111.9, 66.4.
HRMS (ESI-TOF) m/z calcd for C23H18NO3 [M+H]+
356.1287; Found 356.1282.
NMR (100 MHz, CDCl3, F-coupled): δ 167.7, 165.1, 159.9, (E)-3-(2-Phenylbenzo[d]oxazol-4-yl)acrylonitrile (3af):
157.4, 147.1, 141.7, 133.2, 133.1, 132.0, 129.0, 127.9,
126.6, 124.1, 124.0, 114.5, 114.4, 112.7, 112.5, 112.0,
111.9, 51.8. HRMS (ESI-TOF) m/z calcd for C17H13FNO3
[M+H]+ 298.0874; Found 298.0879.
The desired compound 3af was obtained from the reaction
of 2-benzamidophenol (1a) and acrylonitrile (2f) as a
white crystalline solid (52 mg, 42% yield); mp 148 -
150ºC; IR: 2958, 2954, 2848, 2208, 1541, 1419, 1240,
1060, 744, 702 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.34 –
8.29 (m 2H), 7.67 – 7.57, (m, 5H), 7.40- 7.36 (m, 2H),
7.22 (d, 1H, J = 16 Hz); 13C NMR (100MHz, CDCl3): δ
164.2, 151.1, 146.6, 140.6, 132.0, 129.0, 127.8, 126.5,
125.9, 125.5, 124.9, 118.6, 112.6, 101.2. HRMS (ESI-
TOF) m/z calcd for C16H11N2O [M+H]+ 247.0871; Found
247.0868.
(E)-Butyl 3-(2-phenylbenzo[d]oxazol-4-yl)acrylate (3ab):
Following the general procedure, 3ab was obtained from
the reaction of 2-benzamidophenol (1a) and n-butyl
acrylate (2b) as a white crystalline solid (112 mg, 70 %
yield); mp 58 - 60ºC; IR: 2958, 2934, 2926, 2922, 1703,
1
1629, 1541, 1473, 1417, 985, 790 cm-1. H NMR (400
MHz, CDCl3): δ 8.36 – 8.32 (m, 2H), 8.02 (d, 1H, J = 16
Hz), 7.62 - 7.54 (m, 4H), 7.48 - 7.33 (m, 3H), 429 (t, 2H, J
= 6.8 Hz), 1.76 (m, 2H), 1.51 (m, 2H), 1.01 (t, 3H, J = 7.2
Hz); 13C NMR (100 MHz, CDCl3): δ 167.5, 163.5, 151.0,
140.9, 140.3, 131.7, 128.8, 127.8, 126.8, 126.7, 125.7,
124.8, 122.4, 111.7, 64.4, 30.8, 19.2, 13.7. HRMS (ESI-
TOF) m/z calcd for C20H20NO3 [M+H]+ 322.1443; Found
322.1445.
(E)-3-(2-phenylbenzo[d]oxazol-4-yl)acrylamide
(3ag):
Following the general procedure, compound 3ag was
obtained from the reaction of 2-benzamidophenol (1a) and
acryl amide (2g) as a white crystalline solid (62 mg, 47%
yield); mp 190 – 192 °C (decomposition); IR 3348, 3139,
1663, 1599, 1489, 1398, 1271, 1225, 1035, 970, 715 cm-1.
1H NMR (400 MHz, CDCl3): δ 8.35 - 8.31 (m, 2H), 7.93
(d, 1H, J = 16 Hz), 7.62 - 7.52 (m, 5H), 7.45 (d, 1H, J = 7.2
9
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10.1002/adsc.201801272
Advanced Synthesis & Catalysis
Hz), 7.38 (d, 1H, J = 8 Hz), 5.8 – 5.5 (b, 2H); 13C NMR
(100MHz, CDCl3): δ 168.2, 163.5, 151.1, 140.7, 138.5,
131.8, 128.9, 127.8, 126.9, 126.8, 126.4, 125.0, 123.9,
111.6. HRMS (ESI-TOF) m/z calcd for C16H13N2O2
[M+H]+ 265.0977; Found 265.0972.
9696; (f) R. D. Viirre, G. Evindar, R. A. Batey, J. Org.
Chem., 2008, 73, 3452; (g) N. Barbero, M. Carril, R.
SanMartin and E. Dom´ınguez, Tetrahedron, 2007, 63,
10425; (h) G. Evindar, R. A. Batey, J. Org. Chem.,
2006, 71, 1802; (i) G. Altenhoff and F. Glorius, Adv.
Synth. Catal. 2004, 346, 1661.
(E)-3-(5-benzoyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]-
oxazepin-6-yl)acrylic acid (5)
[6] For cobalt-catalysis: a) J. He, F. Lin, X. Yang, D.
Wang, X. Tan, S. Zhang, Org. Process Res. Dev. 2016,
20, 1093; b) R. Hajipour, Z. Khorsandi, M. Mortazavi,
H. Farrokhpour, RSC Adv., 2015, 5, 107822; c) P. Saha,
M. A. Ali, P. Ghosh, T. Punniyamurthy, Org. Biomol.
Chem. 2010, 8, 5692.
From the reaction of 1a and 2d, 5 was formed as a white
crystaline in 40% (68 mg) yield; mp 118 – 120 ºC; IR 2930,
2975, 2857, 1689, 1635, 1562, 1407, 1325, 1207, 1142,
1
988, 742, 705 cm-1. H NMR (400 MHz, CDCl3): δ 8.34 -
8.29 (m, 2H), 8.02 (d, 1H, J = 16 Hz), 7.60 - 753(m, 4H),
7.44 (d, 1H, J = 7.6 Hz), 7.39 (s, 1H), 7.37 - 7.31 (m, 1H),
4.56 (t, 3H, J = 6 Hz), 2.87 (t, 3H, J = 6.4 Hz); 13C NMR
(100 MHz, CDCl3): δ 175.7, 167.0, 163.5, 151.0, 141.0,
140.9, 131.7, 128.8, 127.7, 126.7, 126.4, 125.7, 124.7,
121.5, 111.8, 59.4, 33.5. HRMS (ESI-TOF) m/z calcd for
C19H16NO5 [M+H]+ 338.1028; Found 338.1025.
[7] For iron-catalysis: a) K. Gopalaiah, S. N. Chandrudu,
RSC Adv., 2015, 5, 5015; b) J. Jadhav, V. Gaikwad, R.
Kurane, R. Salunkhe, G. Rashinkar, Tetrahedron, 2013,
69, 2920; c) J. Bonnamour, C. Bolm, Org. Lett. 2008,
10, 2665.
[8] a) R. D. Viirre, G, Evindar, R. A. Batey, J. Org. Chem.
2008, 73, 3452; b) S. K. Xiang, D. X. Zhang, H. Hu, W.
Tan, C. Feng, B.-Q. Wang, K.-Q. Zhao, P. Hu, H. Yang,
Tetrahedron 2013, 69, 10022; c) S. K. Xiang, D. -X.
Zhang, H. Hu, J. L. Shi, L. G. Liao, C. Feng, B.‐Q.
Wang, K.‐Q. Zhao, P. Hu, H. Yang, W.‐H. Yu, Adv.
Synth. Catal. 2013, 355, 1495.
Acknowledgements
We are thankful to SERB, (No. SB/S1/OC-21/2014), and
CSIR (Ref. No. 02(0278)/16/EMR-II), Government of India
for financial support. Dr. C.S. Purohit, School of Chemical
Science, NISER Bhubaneswar, Odisha, India is gratefully
acknowledged for crystal structure analysis.
[9] a) S. Ueda, H. Nagasawa, J. Org. Chem. 2009, 74,
4272; b) S. Ueda, H. Nagasawa, Angew. Chem. Int. Ed.
2008, 47, 6411.
References
[10] F. Yang, Y. Wu, Z. Zhu, J. Zhang, Y. Li, Tetrahedron
2008, 64, 6782.
[1] a) L. P. Singh, V. Chawla, P. Chawla, S. K. Saraf, Der
Pharma. Chemica, 2010, 2, 206; b) N. Aggarwal, A.
Kaur, K. Anand, H. Kumar, S. R. Wakode, Int. J.
Pharmaceutical Sci. Res. 2017, 2, 1; c) K. Seth, S. K.
Garg, R. Kumar, P. Purohit, V. S. Meena, R. Goyal, U.
C. Banerjee, A. K. Chakraborti, ACS Med. Chem. Lett.
2014, 5, 512; d) R. Duroux , N. Renault, J. E. Cuelho,
L. Agouridas, D. Blum, L. V. Lopes, P. Melnyk, S.
Yous J. Enzyme Inhibition Med. Chem. 2017, 32, 850.
[11] a) A. Banerjee, S. K. Santra, S. Guin, S. K. Rout, B. K.
Patel, Eur. J. Org. Chem. 2013, 1367; b) Y. Zheng, W.-
B. Song, S.-W. Zhang, L.-J. Xuan, Tetrahedron 2015,
71, 1574.
[12] K. Seth, M. Nautiyal, P. Purohit, N. Parikh, A. K.
Chakraborti, Chem. Commun. 2015, 51, 191.
[13] S.-J. Lou, D.-Q. Xu, A.-B. Xia, Y.-F. Wang, Y.-K. Liu,
[2] a) M. A. Fourati, T. Maris, W. G. Skene, C. G. Bazuin,
R. E. Prud’homme, Journal of Physical Chemistry
B. 2011, 115, 12362; b) A. Ghodbane, S. D’Alterio, N.
Saffon, N. D. McClenaghan, L. Scarpantonio, P.
Jolinat, S. Fery-Forgues, Langmuir 2012, 28, 855; c)
Y.-F. Sun, L. Zhong, X.-M. Hou, S.-Y. Ma, W.-Z.
Duan, R.-T. Wu, Color. Technol. 2012, 128, 1.
X.-H. Du, Z.-Y. Xu, Chem. Commun. 2013, 49, 6218.
[14] Q. Zhou, J.-F. Zhang, H. Cao, R. Zhong, X.-F. Hou, J.
Org. Chem. 2016, 81, 12169.
[15] a) F. Abdellaoui, C. Youssef, H. B. Ammar, T. Roisnel,
J.-F. Soule, H. Doucet, ACS Catal. 2016, 6, 4248; b) Z.
Zhang, K. Tanaka, J.-Q. Yu, Nature 2017, 543, 538.
[3] a) J. A. Jr. Enquist, B. M. Stoltz, Nature. 2008, 453,
1228–1231; b) S. Haneda, Z. Gan, K. Eda, M. Hayashi,
Organometallics 2007, 26, 6551.
[16] a) S. Yoshizaki, M. Osaki, K. Nakagawa, Y. Tamura,
Chem. Pharma. Bull. 1980, 28, 3441; b) M. S.
Malamas, E. S. Manas, R. E. McDevitt, I. Gunawan, Z.
B. Xu, M. D. Collini, Chris P. Miller,| T. Dinh, R. A.
Henderson, J. C. Keith Jr., H. A. Harris, J. Med. Chem.
2004, 47, 5021.
[4] For reviews see: a) J. He, Curr. Org. Chem. 2017, 21,
1; b) I. Nakamura, Y. Yamamoto, Chem. Rev. 2004,
104, 2127.
[17] a) N. Panda, A. K. Jena, M. Raghavender, ACS Catal.
2012, 2, 539; b) N. Panda, R. Mothkuri, J. Org. Chem.
2012, 77, 9407; c) N. Panda, A. K. Jena, J. Org. Chem.
2012, 77, 9401; d) N. Panda, R. Mothkuri, A. Pal, A. R.
Paital, Adv. Synth. Catal. 2013, 355, 2809; e) N. Panda,
I. Mattan, D. K. Nayak, J. Org. Chem. 2015, 80, 6590;
f) N. Panda, P. Mishra, I. Mattan, J. Org. Chem. 2016,
81, 1047; g) N. Panda, S. A.Yadav, S. Giri, Adv. Synth.
[5] For copper-catalysis, a) A. Ahmed, R. Singha and J. K.
Ray, Tetrahedron Lett., 2015, 56, 2167; (b) Y. Wang, C.
Wu, S. Nie, D. Xu, M. Yu and X. Yao, Tetrahedron
Lett., 2015, 56, 6827; (c) N. Khatum, S. Guin, S. K.
Rout, B. K. Patel, RSC Adv., 2014, 4, 10770; (d) M.
Mohammadi, G. R. Bardajee, N. N. Pesyan, RSC Adv.,
2014, 4, 62888; (e) F. Wu, J. Zhang, Q. wei, P. Liu, J.
Xie, H. Jiang, B. Dai, Org. Biomol. Chem., 2014, 12,
10
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Advanced Synthesis & Catalysis
Catal. 2017, 359, 654; h) N. Panda, I. Mattan, RSC
Adv., 2018, 8, 7716; i) N. Panda, S. A. Yadav,
Tetrahedron, 2018, 74, 1497; j) N. Panda, S. Ojha, J.
Organometalic Chem. 2018, 861, 244; k) N. Panda, I.
Mattan, S. Ojha, C. S. Purohit, Org. Biomol. Chem.
2018 (in press) DOI: 10.1039/c8ob01496e.
[18]Crystal structure of 3aa was deposited at the
Cambridge Crystallographic Data Centre with the
deposition number CCDC 1850873.
[19] a) H. Horino, N. Inoue, J. Org. Chem., 1981, 46,
4416; b) M. D. K. Boele, G. P. F. van Strijdonck, A. H.
M. de Vries, P. C. J. Kamer, J. G. de Vries, P. W. N. M.
van Leeuwen, J. Am. Chem. Soc. 2002, 124, 1586; c) G.
T. Lee, X. Jiang, K. Prasad, O. Repicˇ, T. J. Blacklock,
Adv. Synth. Catal. 2005, 347, 1921; d) J.-R. Wang, C.-
T. Yang, L. Liu, Q.-X. Guo, Tetrahedron Lett. 2007, 48,
5449; e) B. S. Kim, C. Jang, D. J. Lee, S. W. Youn,
Chem. Asian J. 2010, 5, 2336; f) X. Liu, K. K. Hii, J.
Org. Chem. 2011, 76, 8022; g) F. W. Patureau, T.
Besset, F. Gloruis, Angew. Chem. Int. Ed. 2011, 50,
1064; h) B. Schmidt, N. Elizarov, Chem. Commun.
2012, 48, 4350; i) F. Ferlin, S. Santoro, L. Ackermann,
L. Vaccaro, Green Chem. 2017, 19, 2510.
[20]a) C. E. Houlden, C. D. Bailey, J. G. Ford, M. R. Gagn,
G. C. Lloyd-Jones, K. I. Booker-Milburn, J. Am. Chem.
Soc. 2008, 130, 10066; b) W. Rauf, A. L. Thompson, J.
M. Brown, Chem. Commun. 2009, 3874.
[21] Y.-B. Wu, D. Xie, Z.-L. Zang, C.-H. Zhou, G.-X. Cai,
Chem. Comm. 2018, 54, 4437.
[22] D. Rambabu, P. R. K. Murthi, B. Dulla, M. V.
Basaveswara Rao, M. Pal, Synthetic Comm. 2013, 43,
3083.
[23] V. Hernandez-Olmos, A. Abdelrahman, A. El-
Tayeb, D. Freudendahl, S. Weinhausen, C. E. Müller J.
Med. Chem. 2012, 55, 9576.
11
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10.1002/adsc.201801272
Advanced Synthesis & Catalysis
UPDATE
Synthesis of 4-alkenyl benzoxazoles via Pd-
catalyzed ortho C-H functionalization of 2-
amidophenols
Adv. Synth. Catal. Year, Volume, Page – Page
Niranjan Panda,* and Kanchanbala Sahoo
12
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