Palladium-catalyzed oxidative ortho-acylation of 2-arylbenzoxazoles and 2-arylbenzothiazoles with toluene derivatives

Article abstract of DOI:10.1016/j.tet.2015.01.025

A palladium-catalyzed oxidative ortho-acylation of 2-arylbenzoxazoles and 2-arylbenzothiazoles using TBHP as oxidant was developed, in which readily available toluene derivatives were used as the in situ generated acyl sources. This reaction afforded the desired products in moderate to good yields, and exhibited excellent regioselectivity. The plausible mechanism was also proposed.

Full text of DOI:10.1016/j.tet.2015.01.025

Accepted Manuscript
Palladium-catalyzed oxidative ortho-acylation of 2-arylbenzoxazoles and 2-
arylbenzothiazoles with toluene derivatives
Yong Zheng, Wei-Bin Song, Shu-Wei Zhang, Li-Jiang Xuan
PII:
S0040-4020(15)00056-3
10.1016/j.tet.2015.01.025
TET 26348
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 November 2014
Revised Date: 29 December 2014
Accepted Date: 12 January 2015
Please cite this article as: Zheng Y, Song W-B, Zhang S-W, Xuan L-J, Palladium-catalyzed oxidative
ortho-acylation of 2-arylbenzoxazoles and 2-arylbenzothiazoles with toluene derivatives, Tetrahedron
(2015), doi: 10.1016/j.tet.2015.01.025.
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ACCEPTED MANUSCRIPT
Graphic abstract:
Palladium-catalyzed oxidative ortho-acylation of 2-arylbenzoxazoles and
2-arylbenzothiazoles with toluene derivatives
Yong Zheng, Wei-Bin Song, Shu-Wei Zhang, Li-Jiang Xuan
*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 501 Haike Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People’s Republic of China
1

ACCEPTED MANUSCRIPT
Palladium-catalyzed oxidative ortho-acylation of 2-arylbenzoxazoles and
2-arylbenzothiazoles with toluene derivatives
Yong Zheng, Wei-Bin Song, Shu-Wei Zhang, Li-Jiang Xuan
*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 501 Haike Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People’s Republic of China
*Corresponding Author. Tel/fax: +86 21 20231968. E-mail address: ljxuan@mail.shcnc.ac.cn.
2

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Abstract
A palladium-catalyzed oxidative ortho-acylation of 2-arylbenzoxazoles and 2-arylbenzothiazoles
using TBHP as oxidant was developed, in which readily available toluene derivatives were used as
the in situ generated acyl sources. This reaction afforded the desired products in moderate to good
yields, and exhibited excellent regioselectivity. The plausible mechanism was also proposed.
Keywords
Palladium; Acylation; 2-arylbenzoxazole; 2-arylbenzothiazole
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1. Introduction
Aryl ketones are important functionalities found in several biologically active natural products and
designed pharmaceutical molecules.1 Thus, construction of such substructures has always been
synthetically attractive. Traditionally, the preparation of aryl ketones mainly relies on the
Friedel-Crafts acylation in the presence of corrosive AlCl3 or the reaction of active carboxylic acid
derivatives with organometallic reagents.2 However, Friedel-Crafts acylation has intrinsic drawbacks,
such as harsh reaction conditions, poor regioselectivity, limited functional group tolerance, and large
amounts of waste. Therefore, it is highly desirable to develop more efficient methods for
synthesizing aryl ketones with fewer synthetic steps that avoid waste formation.
During recent years, the transition metal-catalyzed C−H bond activation has regained considerable
attention because of their potential to streamline organic synthesis by avoiding the prior preparation
of activated substrates and minimizing the waste and side products.3 Among plethora of transition
metal-catalyzed processes, palladium-catalyzed reactions is increasingly explored owing to their
emerging potential for the construction of new C−C, C−O, C−N, and C−X bond.4 In particular,
palladium-catalyzed acylation provide a simple, efficient and atom economic approach for preparing
acyl ketones. A variety of functional groups, including pyridyl,5 anilide,6 oxime,7 azo,8
2-phosphorylbiphenyl,9 have successfully used as directing groups in ortho-acylation reactions.
2-arylbenzoxazoles and 2-arylbenzothiazoles are important structural motifs and resourceful
intermediates for preparing many useful natural products and pharmaceuticals.10,11 For example,
compound A and its derivatives (Fig. 1), exhibit remarkable parkinsonism, hypertension, and
depression activities.12 In consideration of their wide application in medicinal chemistry, we have
great interest in preparation of these compounds. Very recently, palladium-catalyzed acylation of
benzoxazole and benzothiazole with aldehydes and alcohols were reported.13 Compared to those of
aldehydes and alcohols, toluene derivatives are low toxic, stable, commercially available, and easy
to handle and thus may be potentially used as ideal acylation reagents to achieve aryl ketones.
Herein, we report a palladium-catalyzed ortho-acylation reaction of 2-arylbenzoxazoles and
2-arylbenzothiazoles with toluene derivatives.
Fig. 1. Compounds A.
2. Results and discussion
Our initial investigation began with acylation of 2-arylbenzoxazole (1a) (0.5 mmol) with toluene (2a)
(0.5 mL) in the presence of 10 mol % Pd(OAc)2 and 70% aq. TBHP (5.0 equiv) at 125°C for 24 h
(Table 1, entry 1). As expected, the desired product 3a was obtained in 30% yield. Other Pd catalysts,
such as PdCl2, Pd(PPh3)2Cl2, Pd2(dba)3, did not give any improvement(Table 1, entries 2-4). The use
of a decane solution TBHP (5 equiv) instead of aq. TBHP was found to be more effective giving a
45 % yield of the desired product (Table1, entry 5). When TBHP loading was enhanced to 10 equiv,
the 59 % yield was obtained (Table 1, entry 6). While increasing the amount of this oxidant to 20
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equiv did not result in an increase of the yield (Table 1ꢀentry 7). Changing the oxidant to DTBP, O2,
DDQ, BQ, H2O2, and Na2S2O8, we found these oxidants were not effective (Table 1, entries 12-17).
Solvents screening indicated that chlorobenzene was the best solvent which led to the formation of
3a in 70 % yield (Table 1, entry 8). The absence of Pd catalyst or TBHP failed to give desired
product (Table 1, entries 20-21).
Table 1
Optimization of the reaction conditionsa
Entry
1
Catalyst
Oxidant
TBHPc,e
TBHPc,e
TBHPc,e
TBHPc,e
TBHPd,e
TBHPd
TBHPd,f
TBHPd
TBHPd,f
TBHPd
TBHPd
DTBP
Solvent
Yieldb(%)
Pd(OAc)2
PdCl2
30
17
25
19
45
59
56
70
66
37
44
10
0
2
3
Pd(PPh3)2Cl2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4
5
6
7
8
PhCl
9
PhCl
10
11
12
13
14
15
16
17
18
19
20
21
DMSO
Dioxane
O2
DDQ
0
BQ
0
H2O2
trace
Na2S2O8
TBHPd
TBHPd
TBHPd
0
PhCl
PhCl
30g
56h
0
Pd(OAc)2
0
a Conditions: 1 (0.5 mmol), toluene derivatives (0.5 ml), Pd(OAc)2 (10 %
mol), TBHP (10 equiv) in solvent (1 ml), 125 °C, 24 h.
b Isolated yield.
c 70% water solution.
d 5.5 M in decane.
e 5 equiv TBHP.
f 20 equiv TBHP.
g 80 °C.
h100 °C.
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With the optimal conditions in hand, a number of toluene derivatives were employed as acylation
regents to react with 2-arylbenzoxazole (1a) to generate the desired ortho C−H bond acylation
products, and the results were shown in Table 2. In general, the reactions of 2-aryl-benzoxazole with
the toluene derivatives with ortho, para, and meta electron-donating groups (CH3, OMe) on the
aromatic ring gave moderate to good yields (3b−3f), while weakly electron-withdrawing groups (Cl,
Br) on the aromatic resulted in a decrease yields (3g−3i). Meanwhile, the ortho-substituted toluenes
gave slightly poorer yields of the corresponding products possibly due to their steric hindrance (3c
and 3g). Halo groups (Cl, Br) on the aromatic ring remained intact in the products, which provided
the possibility for the further useful transformations. The presence of strongly electron-withdrawing
groups, such as NO2 and acetyl, restrained the reaction (3j and 3k). For the toluene derivatives with
more than one methyl groups( xylene, and mesitylene), the reaction only took place on one methyl
group and the others remained (3b−3e). This result was attributable to that one of the methyl groups
on the aromatic ring was preoxidized to carbonyl group and its electron-withdrawing property slows
down the subsequent oxidation.
The scope of the procedure with regard to substitute 2-arylbenzoxazole was then explored with
toluene as an acylation agent. As shown in Table 2, both electron-rich (CH3O, CH3; 3l−3n) and
electron-deficient (F, Cl; 3o−3q) 2-arylbenzoxazole derivatives could proceed smoothly and afford
the corresponding acylated products in moderate to good yields. To those 2-arylbenzoxazole with
substituted group at the meta-position of 2-phenyl gave the ortho-acylation products exclusively at
the less sterically hindered position in 66 % yield (3n).
Using the optimized reactions conditions, we next explored substrate scope for Pd-catalyzed
ortho-acylation of 2-arylbenzothiazoles with toluene derivatives (Table 3). As expected,
2-arylbenzothiazoles underwent the reaction with toluene derivations smoothly under the standard
conditions. Toluene derivatives with electron-donating groups (5b−5e) would afford higher yields of
the desired products than those bearing an electron-withdrawing group (5f−5h). This reaction was
slightly affected by the steric hindrance. Toluene substituted at the meta and para-position gave
higher yields than those with ortho-substituted groups (5f). The strong electron-withdrawing group,
such as NO2 and acetyl, obviously restrained the reaction and could not afford the desired product
under the standard reaction conditions (5i and 5j). The acylation showed high regioselectivity for the
2-arylbenzotiazoles with a meta-substituent in the benzene ring and typically occurred at the less
sterically hindered position (5l and 5n).
Using this methodology, we successfully synthesized bioactive compound A (9) and its derivative (8)
from vanillin in four steps, which avoided the tedious protocols (Scheme 1).
On the basis of previous related studies and our experiments, a possible mechanism of this
ortho-acylation reaction is proposed, as shown in Scheme 2. When the reaction undergoes in the
presence of radical scavenger TEMPO (1 equiv), only trace of 3a or 5a is formed, suggesting a
possible radical pathway. Toluene generates the benzaldehyde intermediate in the presence of
Pd(OAc)2 and TBHP, which is detected by GC-MS, then t-BuO• abstracts an H atom from
benzaldehyde to give the acyl radical.14 The active palladium reacts with 2-arylbenzoxazole or
2-arylbenzothiazole to give the palladacycle intermediate I via ortho-C−H activation. Next, acyl
radical forms either reactive Pd (IV)15 or dimeric Pd (III)16 intermediate II. Finally, the intermediate
II undergoes reductive elimination and affords the ortho-acylated product along with the
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regeneration of the active Pd (II) species, which maintains the catalytic cycle.
3. Conclusions
In summary, we have developed a Palladium-catalyzed oxidation acylation of 2-arylbenzoxazoles
and 2-arylbenzothiazoles with toluene derivatives using TBHP as an oxidant. This protocol allows us
to use simple and readily available toluene derivatives as acyl sources. Further transformation of
these products into other bioactive molecules is currently underway in our laboratory.
Table 2
Acylation of 2-arylbenzoxazoles with toluene derivatives a
a Conditions: 1 (0.5 mmol), toluene derivatives (0.5 mL), Pd(OAc)2 (10 % mol), TBHP (10 eqiuv) in
chlorobenzene (1 ml), 125 °C, 24 h. Isolated yield.
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Table 3
Acylation of 2-arylbenzothiazoles with toluene derivativesa
OMe
O
O
O
O
O
N
S
N
N
S
N
S
N
S
S
5c
, 71 %
5d
5e
, 84 %
, 82 %
5a, 74 %
5b, 69 %
Ac
Cl
Br
NO2
Cl
O
O
N
O
N
O
O
N
N
S
N
S
S
S
S
5f, 53 %
5g, 66 %
5h, 53 %
5i, trace
5j, trace
O
N
O
N
O
N
O
O
N
N
S
OMe
F
S
S
S
S
Me
Cl
F
5k, 70 %
5l, 68 %
5m, 64 %
5n, 55 %
5o, 60 %
a Conditions: 4 (0.5 mmol), toluene derivatives (0.5 mL), Pd(OAc)2 (10% mol), TBHP (10 eqiuv) in
chlorobenzene (1 ml), 125 °C, 24 h. Isolated yield.
Scheme 1. Synthesis of Compound A (9) and its derivative (8).
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Reaction conditions: a. BnBr (1.2 equiv), K2CO3 (1.5 equiv), acetone, reflux, 10 h, 97 %; b.
benzothiazole (1.5 equiv), Na2S2O8 (1.2 equiv), DMSO-H2O (4:1), 100 ,10 h, 72 %; c. toluene,
Pd(OAc)2 (10% mol), TBHP (10 equiv), PhCl, 125 ꢁ, 24 h, 70 %; d. TiCl4 (1.5 equiv), DCM, rt, 0.5
h, 94 %.
Pd(OAc)2
TBHP
CH3
N
TEMPO
O
+
N
X
PhCl, 125 °C
X
trace
CHO
CH3
Pd(OAc)2
TBHP
detected by GC-MS
O
t-BuO
Pd(OAc)2
TBHP
Ar-CH3
Ar-CHO
Ar
t-BuOH
2
OAc
Pd
Oxidative addition
N
X
AcOH
intermediate I
Cyclopalladation
L
O
AcO
L
N
X
Pd
N
X
Pd(OAc)2
intermediate II
AcOH
Reductive elimination
O
N
X
Scheme 2. Proposed reaction mechanism.
4. Experimental Section
4.1 General
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13
1H and C NMR spectra were recorded on a Bruker NMR spectrometer with CDCl3 as the solvent
and TMS as an internal standard. HRESIMS was measured on an Agilent G6224A TOF spectrometer.
TLC was performed on precoated silica gel GF254 plates (Qingdao Marine Chemical Factory).
Column chromatography was performed on silica gel (200−300 mesh, Qingdao Marine Chemical
Factory). Toluene was purified by the standard methods. Petroleum was distilled prior to use.
2-arylbenzoxazoles and 2-arylbenzothiazoles were prepared according to the reported literature.17
4.2 General procedure for the acylation of 2-arylbenzoxazoles and 2-arylbenzothiazoles
2-arylbenzoxazole 1a or 2-arylbenzothiazole 3a (0.5 mmol), Pd(OAc)2 (10 mol %), TBHP (5.5 M in
decane, 10 equiv), toluene derivatives 2a (0.5 mL), and PhCl (1 mL) were added in a sealed tube.
The reaction mixture was allowed to stir at 125 °C for 24 h. After cooling at room temperature, the
mixture was purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to
afford the pure product.
4.2.1. 2-(2-benzoyl-phenyl)benzoxazole (3a). light yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.33
(dd, J = 7.5, 1.7 Hz, 1H), 7.84–7.81 (m, 2H), 7.72–7.65 (m, 2H), 7.65–7.61 (m, 1H), 7.58–7.54 (m,
1H), 7.49–7.44 (m, 1H), 7.39–7.36 (m, 3H), 7.29–7.26 (m, 2H); 13C(100 MHz, CDCl3): δ 197.1,
161.3, 150.6, 141.7, 140.1, 137.3, 133.0, 131.1, 130.1, 129.4, 129.44, 129.2, 128.5, 128.4,128.4,
125.4, 125.2, 124.5, 120.3, 110.5; HRMS (ESI): m/z [M+Na]+ calcd for C20H13NO2Na, 322.0838;
found: 322.0848.
1
4.2.2. 2-[2-(4-methylbenzoyl)-phenyl]benzoxazole (3b). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.34–8.29 (m, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.69–7.59 (m, 3H), 7.54–7.49 (m, 1H),
7.39–7.34 (m, 1H), 7.27–7.22 (m, 2H), 7.16 (d, J = 8.1 Hz, 2H), 2.32 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 196.8, 161.4, 150.6, 144.0, 141.7, 140.3, 134.8, 131.0, 130.0, 129.7, 129.7, 129.3, 129.1,
129.1, 128.4, 125.3, 125.2, 124.5, 120.3, 110.5, 21.7; HRMS (ESI): m/z [M+Na]+ calcd for
C21H15NO2Na, 336.0995; found: 336.1003.
1
4.2.3. 2-[2-(2-methylbenzoyl)-phenyl]benzoxazole (3c). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.23–8.19 (m, 1H), 7.70–7.63 (m, 4H), 7.43–7.38 (m, 1H), 7.28 (t, J = 3.0 Hz, 2H),
7.23–7.19 (m, 3H), 7.01 (ddd, J = 8.2, 4.8, 1.6 Hz, 1H), 2.80 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 198.7, 161.6, 150.6, 141.7, 141.5, 139.8, 137.2, 131.6, 131.6, 131.0, 130.7, 130.4, 129.4, 129.2,
125.7, 125.2, 125.1, 124.5, 120.2, 110.4, 21.3; HRMS (ESI): m/z [M+Na]+ calcd for C21H15NO2Na,
336.0995; found: 336.1003.
1
4.2.4. 2-[2-(3-methylbenzoyl)-phenyl]benzoxazole (3d). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.32 (dd, J = 7.6, 1.5 Hz, 1H), 7.71–7.62 (m, 3H), 7.66 (s,1H), 7.58 (dt, J = 7.6, 1.8 Hz,
13
1H), 7.56–7.53 (m, 1H), 7.40–7.36 (m, 1H), 7.28–7.25 (m, 4H), 2.34 (s, 3H); C NMR (100 MHz,
CDCl3): δ 197.3, 161.4, 150.6, 141.7, 140.2, 138.2, 137.3, 133.9, 131.0, 130.1, 129.8, 129.3, 128.5,
128.2, 126.9, 125.4, 125.2, 124.5, 120.3, 110.5, 21.3; HRMS (ESI): m/z [M+Na]+ calcd for
C21H15NO2Na, 336.0995; found: 336.1003.
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1
4.2.5. 2-[2-(3,5-dimethylbenzoyl)-phenyl]benzoxazole (3e). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.36 – 8.28 (m, 1H), 7.73–7.61 (m, 3H), 7.56–7.51 (m, 1H), 7.44 (s, 2H), 7.42–7.35 (m,
1H), 7.30–7.25 (m, 2H), 7.11 (s, 1H), 2.29 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 197.4, 161.5,
150.7, 141.7, 140.4, 138.0, 138.0, 137.3, 134.8, 130.9, 130.0, 129.3, 128.5, 127.4, 127.4, 125.4,
125.2, 124.4, 120.3, 110.5, 21.1, 21,1; HRMS (ESI): m/z [M+Na]+ calcd for C22H17NO2Na,
350.1151; found: 350.1156.
1
4.2.6. 2-[2-(4-methoxybenzoyl)-phenyl]benzoxazole (3f). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.35–8.29 (m, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.71–7.60 (m, 3H), 7.54–7.49 (m, 1H),
7.41–7.35 (m, 1H), 7.29–7.24 (m, 2H), 6.85 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 195.8, 163.5, 161.5, 150.6, 141.7, 140.4, 131.9, 131.9, 131.0, 130.4, 129.8, 129.3, 128.4,
125.2, 125.1, 124.5, 120.3, 113.7, 113.7, 110.5, 55.4; HRMS (ESI): m/z [M+Na]+ calcd for
C21H15NO3Na, 353.0944; found: 353.0936.
1
4.2.7. 2-[2-(2-chlorobenzoyl)-phenyl]benzoxazole (3g). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.18 (dd, J = 8.1, 1.6 Hz, 1H), 7.74–7.64 (m, 4H), 7.51–7.45 (m, 1H), 7.41 (dd, J = 7.7,
13
1.8 Hz, 1H), 7.36–7.30 (m, 3H), 7.23 (td, J = 7.7, 1.7 Hz, 1H), 7.12 (td, J = 7.6, 1.2 Hz, 1H); C
NMR (100 MHz, CDCl3): δ 195.2, 161.5, 150.7, 141.6, 140.1, 137.0, 133.4, 132.3, 131.2, 131.2,
131.1, 130.9, 129.8, 129.7, 126.3, 126.2, 125.3, 124.5, 120.2, 110.7; HRMS (ESI): m/z [M+Na]+
calcd for C20H12ClNO2Na, 356.0449; found: 356.0447.
1
4.2.8. 2-[2-(4-chlorobenzoyl)-phenyl]benzoxazole (3h). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.35–8.31 (m, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.70 (m, 2H), 7.66–7.62 (m, 1H), 7.54–7.51
(m, 1H), 7.42–7.38 (m, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.31–7.28 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 195.9, 161.0, 150.5, 141.6, 139.6, 139.5, 135.8, 131.2, 130.8, 130.8, 130.3, 129.2, 128.8,
128.8, 128.4, 125.4, 125.2, 124.6, 120.4, 110.5; HRMS (ESI): m/z [M+Na]+ calcd for
C20H12ClNO2Na, 356.0449; found: 356.0447.
1
4.2.9. 2-[2-(4-bromobenzoyl)-phenyl]benzoxazole (3i). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.32 (d, J = 7.3 Hz, 1H), 7.73–7.66 (m, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.65–7.61 (m, 1H),
7.53–7.50 (m, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.42–7.38 (m, 1H), 7.31–7.28 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 196.1, 161.0, 150.5, 141.6, 139.5, 136.2, 131.7, 131.7, 131.2, 130.9, 130.3, 130.3,
129.2, 128.4, 128.3, 125.4, 125.2, 124.6, 120.4, 110.5; HRMS (ESI): m/z [M+Na]+ calcd for
C20H12BrNO2Na, 399.9942; found: 399.9944.
1
4.2.10. 2-(2-benzoyl-4-methoxyphenyl)benzoxazole (3l). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.26 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.60–7.55 (m, 1H), 7.45 (t, J = 7.4 Hz,
13
1H), 7.41–7.29 (m, 3H), 7.23–7.15 (m, 3H), 7.02 (d, J = 2.6 Hz, 1H), 3.91 (s, 3H); C NMR (100
MHz, CDCl3): δ 196.8, 161.8, 161.4, 150.5, 141.8, 137.2, 133.1, 131.0, 129.4, 128.4, 124.7, 124.3,
119.9, 117.6, 115.9, 113.6, 110.3, 55.7; HRMS (ESI): m/z [M+Na]+ calcd for C21H15NO3Na,
353.0944; found: 353.0940.
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1
4.2.11. 2-(2-benzoyl-4-methylphenyl)benzoxazole (3m). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.21 (d, J = 8.0 Hz, 1H), 7.84–7.79 (m, 2H), 7.64–7.58 (m, 1H), 7.51–7.47 (m, 1H), 7.45
(d, J = 7.4 Hz, 1H), 7.39–7.32 (m, 4H), 7.26–7.21 (m, 2H), 2.50 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 197.4, 161.5, 150.5, 141.9, 141.7, 140.0, 137.4, 133.0, 130.8, 129.4, 129.2, 129.0, 128.3,
125.0, 124.4, 122.6, 120.1, 110.4, 21.5; HRMS (ESI): m/z [M+Na]+ calcd for C21H15NO2Na,
336.0995; found: 336.1000.
4.2.12. 2-(2-benzoyl-5-methylphenyl)benzoxazole (3n). light yellow solid. 1H NMR (400 MHz,
CDCl3): δ 8.11 (m, 1H), 7.81–7.76 (m, 2H), 7.64–7.59 (m, 1H), 7.45 (d, J = 1.1 Hz, 2H), 7.43–7.39 (m,
1H), 7.35–7.30 (m, 3H), 7.25–7.21 (m, 2H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 197.2, 161.6,
150.6, 141.6, 140.6, 137.6, 137.3, 132.8, 131.8, 129.8, 129.4, 128.8, 128.3, 125.5, 125.1, 124.5,
120.2, 110.4, 21.3; HRMS (ESI): m/z [M+Na]+ calcd for C21H15NO2Na, 336.0995; found: 336.0998.
1
4.2.13. 2-(2-benzoyl-6-chlorophenyl)benzoxazole (3o). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.76 (dd, J = 7.0, 2.3 Hz, 1H), 7.70–7.58 (m, 5H), 7.46 (dd, J = 6.9, 2.1 Hz, 1H),
7.42–7.37 (m, 1H), 7.30 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 195.1, 158.7, 150.5, 142.7, 141.1,
136.4, 135.2, 133.0, 132.5, 131.4, 129.5, 128.2, 127.7, 126.9, 125.5, 124.4, 120.4, 110.7; HRMS
(ESI): m/z [M+Na]+ calcd for C20H12ClNO2Na, 356.0449; found: 356.0448.
1
4.2.14. 2-(2-benzoyl-6-fluorophenyl)benzoxazole (3p). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.75 (dd, J = 8.3, 1.4 Hz, 1H), 7.69–7.63 (m, 2H), 7.46 (dt, J = 2.8, 1.2 Hz, 1H),
7.44–7.40 (m, 3H), 7.33 (d, J = 7.9 Hz, 2H), 7.31–7.27 (m, 3H); 13C NMR (100 MHz, CDCl3): δ
195.1, 160.7 (d, JC-F = 258.6 Hz), 156.9, 150.5, 142.4, 141.3, 136.7, 133.1, 132.5 (d, JC-F = 8.9 Hz),
129.4, 128.3, 125.5, 124.8 (d, JC-F = 3.6 Hz), 124.5, 120.4, 118.6 (d, JC-F = 21.6 Hz), 115.2 (d, JC-F
13.7 Hz), 110.6; HRMS (ESI): m/z [M+Na]+ calcd for C20H12FNO2Na, 340.0744; found: 340.0755.
=
1
4.2.15. 2-(2-benzoylphenyl)-5-chlorobenzoxazole (3q). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.31–8.27 (m, 1H), 7.81 (dt, J = 7.8, 1.0 Hz, 2H), 7.71–7.67 (m, 2H), 7.60 (d, J = 2.1 Hz,
1H), 7.58–7.54 (m, 1H), 7.52–7.47 (m, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 8.7 Hz, 1H), 7.23
(dd, J = 8.7, 2.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 196.8, 162.6, 149.1, 142.7, 140.2, 137.2,
133.2, 131.4, 130.2, 130.0, 129.4, 129.3, 128.6, 128.4, 125.6, 124.9, 120.2, 111.2; HRMS (ESI): m/z
[M+Na]+ calcd for C20H12ClNO2Na, 356.0449; found: 356.0446.
1
4.2.16. 2-(2-benzoyl-phenyl)benzothiazole (5a). light yellow solid. H NMR (400 MHz, CDCl3): δ
7.9–7.94 (m, 1H), 7.76-7.84 (m, 4H), 7.69–7.60 (m, 2H), 7.58–7.55 (m, 1H), 7.43–7.36 (m, 2H),
7.34–7.29 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 197.5, 165.3, 153.5, 139.7, 137.8, 135.3, 132.6,
132.1, 130.3, 130.2, 129.6, 129.2, 128.9, 128.2, 126.1, 125.3, 123.4, 121.4; HRMS (ESI): m/z
[M+Na]+ calcd for C20H13NOSNa, 338.0610; found: 338.0619.
1
4.2.17. 2-[2-(4-methylbenzoyl)-phenyl]benzothiazole (5b). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.97–7.93 (m, 1H), 7.83–7.76 (m, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.60 (td, J = 6.9, 1.6 Hz,
2H), 7.52–7.48 (m, 1H), 7.37 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.30 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H),
7.11 (dd, J = 8.3, 1.0 Hz, 2H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.2, 165.4, 153.5,
12

ACCEPTED MANUSCRIPT
143.6, 140.0, 135.4, 135.2, 132.0, 130.2, 130.0, 129.7, 129.5, 129.0, 128.7, 126.1, 125.2, 123.5,
121.4, 21.6; HRMS (ESI): m/z [M+Na]+ calcd for C21H15NOSNa, 352.0767; found: 352.0765.
1
4.2.18. 2-[2-(3-methylbenzoyl)-phenyl]benzothiazole (5c). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.97–7.94 (m, 1H), 7.86–7.77 (m, 2H), 7.68–7.60 (m, 3H), 7.58–7.53 (m, 2H), 7.38 (ddd,
J = 8.2, 7.2, 1.3 Hz, 1H), 7.31 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.22–7.16 (m, 2H), 2.32 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 197.7, 165.4, 153.5, 139.9, 138.0, 137.7, 135.4, 133.5, 132.2, 130.2,
130.1, 129.7, 129.7, 128.8, 128.1, 126.7, 126.1, 125.3, 123.4, 121.4, 21.2; HRMS (ESI): m/z
[M+Na]+ calcd for C21H15NOSNa, 352.0767; found: 352.0764.
1
4.2.19. 2-[2-(3,5-dimethylbenzoyl)-phenyl]benzothiazole (5d). light yellow solid. H NMR (400
MHz, CDCl3): δ 7.98–7.95 (m, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.81 (dd, J = 7.9, 1.2 Hz, 1H), 7.63 (pd,
J = 7.4, 1.5 Hz, 2H), 7.58–7.51 (m, 1H), 7.44–7.37 (m, 3H), 7.32 (td, J = 7.6, 1.3 Hz, 1H), 7.05 (s,
13
1H), 2.28 (s, 6H). C NMR (100 MHz, CDCl3): δ 197.9, 165.5, 153.5, 140.1, 137.8, 137.7, 135.5,
135.1, 134.5, 132.2, 131.9, 130.1, 130.1, 129.7, 128.8, 127.3, 126.1, 125.2, 123.4, 121.4, 21.1;
HRMS (ESI): m/z [M+Na]+ calcd for C22H17NOSNa, 366.0923; found: 366.0920.
1
4.2.20. 2-[2-(4-methoxybenzoyl)-phenyl]benzothiazole (5e). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.02–7.96 (m, 1H), 7.86 (ddd, J = 8.1, 1.3, 0.6 Hz, 1H), 7.81 (ddd, J = 8.0, 1.4, 0.7 Hz,
1H), 7.80 (d, J = 8.9 Hz), 7.68–7.54 (m, 2H), 7.53–7.49 (m, 1H), 7.39 (ddd, J = 8.3, 7.3, 1.4 Hz, 1H),
7.32 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 6.82 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 196.2, 165.4, 163.3, 153.5, 140.1, 135.5, 132.0, 131.8, 130.7, 130.2, 129.9, 129.8, 128.6,
126.1, 125.2, 123.5, 121.4, 113.6, 55.4; HRMS (ESI): m/z [M+Na]+ calcd for C21H15NO2SNa,
368.0716; found: 368.0720.
1
4.2.21. 2-[2-(2-cholrobenzoyl)-phenyl]benzothiazole (5f). light yellow solid. H NMR (400 MHz,
CDCl3): δ 8.01 (dt, J = 8.2, 0.9 Hz, 1H), 7.85–7.77 (m, 2H), 7.74 (dd, J = 7.1, 1.9 Hz, 1H), 7.66 (ddd,
J = 7.5, 5.2, 1.7 Hz, 2H), 7.43 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.40–7.31 (m, 2H), 7.22 (dd, J = 8.0,
1.2 Hz, 1H), 7.13 (td, J = 7.7, 1.8 Hz, 1H), 7.03 (td, J = 7.5, 1.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 195.5, 165.4, 153.4, 139.8, 137.3, 135.5, 133.1, 132.9, 131.7, 131.1, 130.9, 130.7, 130.4,
130.3, 129.9, 126.2, 126.0, 125.3, 123.7, 121.3; HRMS (ESI): m/z [M+Na]+ calcd for
C20H12ClNOSNa, 372.0220; found: 372.0225.
1
4.2.22. 2-[2-(4-cholrobenzoyl)-phenyl]benzothiazole (5g). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.97–7.94 (m, 1H), 7.85–7.81 (m, 1H), 7.81–7.77 (m, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.65
(m, 2H), 7.56–7.52 (m, 1H), 7.40 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.35 (dd, J = 7.7, 1.3 Hz, 1H), 7.26
(d, J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 196.3, 165.0, 153.4, 139.2, 138.9, 136.3,
135.2, 131.9, 130.5, 130.4, 130.4, 129.6, 128.7, 128.6, 126.3, 125.5, 123.4, 121.5; HRMS (ESI): m/z
[M+Na]+ calcd for C20H12ClNOSNa, 372.0220; found: 372.0222.
1
4.2.23. 2-[2-(4-bromobenzoyl)-phenyl]benzothiazole (5h). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.96 (dd, J = 7.2, 1.7 Hz, 1H), 7.86–7.81 (m, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.68–7.62 (m,
2H), 7.62 (d, J = 8.7 Hz, 2H), 7.53 (dd, J = 7.1, 1.8 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.43–7.37 (m,
1H), 7.37–7.32 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 196.5, 165.0, 153.4, 139.2, 136.7, 135.1,
13

ACCEPTED MANUSCRIPT
131.9, 131.5, 130.6, 130.4, 130.4, 129.6, 128.7, 127.7, 126.3, 125.5, 123.4, 121.5; HRMS (ESI): m/z
[M+Na]+ calcd for C20H12BrNOSNa, 415.9715; found: 415.9717.
1
4.2.24. 2-(2-benzoyl-4-methoxy-phenyl)benzothiazole (5k). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.90 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.78–7.73 (m, 2H), 7.43–7.38 (m, 1H),
13
7.38–7.24 (m, 4H), 7.15 (dd, J = 8.6, 2.7 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 3.92 (s, 3H). C NMR
(100 MHz, CDCl3): δ 197.3, 165.0, 161.2, 153.5, 141.3, 137.6, 135.0, 132.7, 131.1, 129.2, 128.2,
126.0, 124.9, 124.5, 123.1, 121.3, 115.9, 113.9, 55.7; HRMS (ESI): m/z [M+Na]+ calcd for
C21H15NO2SNa, 368.0716; found: 368.0719.
1
4.2.25. 2-(2-benzoyl-5-methyl-phenyl)benzothiazole (5l). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.85–7.81 (m, 1H), 7.81–7.75 (m, 4H), 7.48 (d, J = 7.8 Hz, 1H), 7.45–7.43 (m, 1H),
13
7.42–7.35 (m, 2H), 7.34–7.28 (m, 3H), 2.52 (s, 3H). C NMR (100 MHz, CDCl3): δ 197.6, 165.6,
153.4, 140.6, 138.0, 137.0, 135.4, 132.5, 132.3, 130.9, 130.2, 129.3, 129.1, 128.1, 126.1, 125.2,
123.4, 121.3, 21.4; HRMS (ESI): m/z [M+Na]+ calcd for C21H15NO2SNa, 368.0716; found:
368.0717.
1
4.2.26. 2-[2-benzoyl-6-chloro-phenyl]benzothiazole (5m). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.92–7.87 (m, 1H), 7.84–7.80 (m, 1H), 7.72 (dd, J = 7.8, 1.5 Hz, 1H), 7.67 (dd, J = 8.3,
1.4 Hz, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.53–7.49 (m, 1H), 7.44–7.34 (m, 3H), 7.30–7.27 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 195.7, 162.1, 152.2, 142.9, 137.0, 136.3, 134.1, 132.8, 131.9, 131.7,
130.6, 129.4, 128.1, 127.4, 126.0, 125.6, 123.6, 121.2; HRMS (ESI): m/z [M+Na]+ calcd for
C20H12ClNOSNa, 372.0220; found: 372.0224.
1
4.2.27. 2-(2-benzoyl-5-fluoro-phenyl)benzothiazole (5n). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.82 (ddd, J = 9.5, 8.2, 1.4 Hz, 2H), 7.79–7.73 (m, 2H), 7.66 (dd, J = 9.2, 2.5 Hz, 1H),
13
7.58 (m, 1H), 7.44–7.37 (m, 2H), 7.35–7.27 (m, 4H); C NMR (100 MHz, CDCl3): δ 196.5, 163.9,
163.17 (d, JC-F = 251.3 Hz), 153.3, 137.7, 135.83 (d, JC-F = 3.6 Hz), 135.4, 134.58 (d, JC-F = 8.1 Hz),
132.8, 131.19 (d, JC-F = 8.6 Hz), 129.2, 128.3, 126.3, 125.7, 123.6, 121.5, 117.19 (d, JC-F = 21.4 Hz),
116.58 (d, JC-F = 23.6 Hz); HRMS (ESI): m/z [M+Na]+ calcd for C20H12FNOSNa, 356.0516; found:
356.0512.
1
4.2.28. 2-(2-benzoyl-4-fluoro-phenyl)benzothiazole (5o). light yellow solid. H NMR (400 MHz,
CDCl3): δ 7.96 (m, 1H), 7.82–7.76 (m, 4H), 7.46–7.40 (m, 1H), 7.40–7.31 (m, 5H), 7.30–7.25 (m,
1H); 13C NMR (100 MHz, CDCl3): δ 195.9, 164.0, 163.5 (d, JC-F = 254.2 Hz), 153.4, 141.9 (d, JC-F
=
6.7 Hz), 137.2, 135.2, 133.0, 131.7 (d, JC-F = 8.9 Hz), 129.2, 128.3, 126.2, 125.4, 123.4, 121.4,
117.2(d, JC-F = 21.9 Hz), 116.2 (d, JC-F = 23.4 Hz); HRMS (ESI): m/z [M+Na]+ calcd for
C20H12FNOSNa, 356.0516; found: 356.0515.
4.3 Synthesis of 6, 7, 8, and 9.
A solution of vanillin (1equiv), BnBr (1.2 equiv), and K2CO3 (1.5 equiv) in acetone was heated at
reflux for 10h. The temperature of reaction was cooled to room temperature and concentrated. The
residue was purified by by column chromatography on silica gel (petroleum ether/ethyl acetate) to
afford 6.
14

ACCEPTED MANUSCRIPT
A solution of benzothiazole (1.5 equiv), 6 (1.0 equiv), and Na2S2O8 (1.2 equiv) in DMSO/H2O (4:1)
was heated at 100°C under N2 for 10 h. Upon completion of the reaction, the mixture was diluted
with H2O and extracted with EtOAc. The organic layers were combined, washed with brine, dried
over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate) to afford 7 (72 % yield). 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J =
8.4 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.51 (dd, J = 8.4, 2.4 Hz, 1H),
7.42–7.48 (m, 3H), 7.31–7.39 (m, 4H,), 6.93 (d, J = 8.4 Hz, 1H), 5.22 (s, 2H), 3.94 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 168.0, 154.2, 150.6, 149.8, 136.6, 134.9, 128.8, 128.0, 127.3, 126.3,
124.9, 122.9, 121.6, 121.2, 113.5, 110.3, 71.1, 56.3; HRMS (ESI): m/z [M+H]+ calcd for
C21H18NO2S, 348.1839; found: 348.1834.
7 (0.5 mmol), Pd(OAc)2 (10 mol %), TBHP (5.5 M in decane, 10 equiv), toluene derivatives 2a (0.5
mL), and PhCl (1 mL) were added in a sealed tube. The reaction mixture was allowed to stir at
125 °C for 24 h. After cooling at room temperature, the mixture was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate) to afford 8 (70 % yield). 1H NMR (400
MHz, CDCl3): δ 7.73 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.62–7.57 (m, 2H), 7.34 (m, 3H),
7.30–7.20 (m, 5H), 7.15 (m, 3H), 7.02 (s, 1H), 5.12 (s, 2H), 3.95 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 196.9, 165.4, 153.2, 150.8, 149.5, 137.9, 136.0, 135.4, 132.6, 132.4, 129.3, 128.7, 128.2,
128.2, 127.5, 126.1, 126.0, 125.1, 123.1, 121.3, 114.2, 112.6, 71.1, 56.4; HRMS (ESI): m/z [M+H]+
calcd for C28H22NO3S, 452.2373; found: 452.2371.
8 was dissolved in DCM at 0°C under N2 and TiCl4 (1.5 equiv) was added slowly. The reaction was
stirred at room temperature for 0.5 h. The mixture was diluted with H2O and extracted with EtOAc.
The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified
by column chromatography on silica gel (petroleum ether/ethyl acetate) to afford 9 (94 % yield). 1H
NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 1H), 7.81–7.74 (m, 3H), 7.44 (s, 1H), 7.43–7.36 (m,
2H), 7.33–7.28 (m, 3H), 7.13 (s, 1H), 4.07 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 196.8, 165.5,
153.1, 147.7, 147.4, 137.8, 135.4, 133.5, 132.7, 129.5, 128.2, 126.1, 125.1, 125.0, 123.1, 121.3,
115.6, 111.8, 56.4; HRMS (ESI): m/z [M+Na]+ calcd for C21H15NO3SNa, 384.1604; found:
384.1605.
Acknowledgements
We are grateful to the National Science & Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (Number: 2009ZX09301-001), and the China Postdoctoral Science
Foundation (No. Y412021031).
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://
dx.doi.org/
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Supplementary Data
Palladium-catalyzed oxidative ortho-acylation of 2-arylbenzoxazoles and
2-arylbenzothiazoles with toluene derivatives
Yong Zheng, Wei-Bin Song, Shu-Wei Zhang, Li-Jiang Xuan
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, 501 Haike Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People’s Republic of
China
Content:
1H and 13C spectra of all compounds (3a-3q, and 5a-5o)

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1H and 13C spectra of 3a：

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1H and 13C spectra of 3b：

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1H and 13C spectra of 3c:

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1H and 13C spectra of 3d:

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1H and 13C spectra of 3e
:

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1H and 13C spectra of 3g:

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1H and 13C spectra of 3g:

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1H and 13C spectra of 3h:

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1H and 13C spectra of 3i:

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1H and 13C spectra of 3l:

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1H and 13C spectra of 3m: