Palladium-Catalyzed Regioselective C-H Bond Arylations of Benzoxazoles and Benzothiazoles at the C7 Position

Article abstract of DOI:10.1021/acscatal.6b00678

We report herein, a very simple catalytic system for the direct arylation of benzoxazole and benzothiazole derivatives at C7 position, namely, phosphine-free PdCl₂ associated with PivOK in NMP at 150 °C. (Thio)phenoxy chelation-assisted Pd-catalyzed C-H bond cleavage, from an opened intermediate, was proposed to explain this unique regioselectivity. This reaction allows the synthesis of 2-amino-6-arylphenols through the ring opening of the benzoxazole.

Full text of DOI:10.1021/acscatal.6b00678

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Letter
Palladium–Catalyzed Regioselective C–H Bond Arylations
of Benzoxazoles and Benzothiazoles at the C7 Position
Fatma Abdellaoui, Chiraz Youssef, Hamed Ben Ammar,
Thierry Roisnel, Jean-François Soulé, and Henri Doucet
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00678 • Publication Date (Web): 31 May 2016
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ACS Catalysis
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Palladium–Catalyzed Regioselective C–H Bond Arylations of Benzoxa-
zoles and Benzothiazoles at the C7 Position
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Fatma Abdellaoui, a, b Chiraz Youssef,b Hamed Ben Ammar,b Thierry Roisnel,a Jean-François Soulé,a* and Henri
Douceta*
aInstitut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes "Organométalliques : Matériaux et Catalyse",
Campus de Beaulieu, 35042 Rennes, France. bLaboratoire de Synthèse Organique Asymétrique et Catalyse Homogène, (UR 11ES56)
Université de Monastir, Faculté des Sciences de Monastir, avenue de l’environnement, Monastir 5000, Tunisia
ABSTRACT: We report herein, a very simple catalytic system for the direct arylation of benzoxazole and benzothiazole derivatives at C7
position, namely, phosphine-free PdCl2 associated to PivOK in NMP at 150 ºC. (Thio)phenoxy chelation-assisted Pd-catalyzed C–H bond
cleavage, from an opened intermediate, was proposed to explain this unique regioselectivity. This reaction allows the synthesis of 2-amino-6-
arylphenols through the ring opening of the benzoxazole.
KEYWORDS . Arylation – Catalysis – C–H Activation – Palladium – Benzoxazole
Over the past decades, transition metal-catalyzed regioselective
C–C bond formation methodologies led to a radical change in the
synthesis of complex organic molecules such as pharmaceuticals or
materials.1 Among them, C–H bond arylation reactions have
emerged as one of the most powerful tools for the direct C–C bond
formation with greater atom economy.2 In addition, such method-
ology allows in some cases novel regioselectivities affording prod-
ucts which were not easily accessible using more conventional
methods. Most of the regioselective C–H bond arylations required
the presence of an ortho-directing group such as amides, carboxylic
acids, imines, pyridine, etc.3 Other methods for the control of the
regioselectivity of arylations rely on the proton acidity via a con-
certed-metalation-deprotonation (CMD) pathway.4 Usually aryla-
tions of 2-phenylbenzothiazoles or 2-phenylbenzazoles via C–H
bond activation would take place preferentially at the ortho-
position of the phenyl ring, due to a directing effect of the benzoxa-
zolyl or benzothiazolyl groups (Fig. 1a).5 To overcome this regi-
oselectivity and provide an original access to C7 arylated benzoxa-
zole the presence of an additional directing group is required. As
example, in the course of their study on the synthesis of c-Met
kinase inhibitors, Cho et al. reported a direct arylation of a 2-
arylbenzoxazole at C7 position through palladium catalysis (Fig.
1b).6 This uncommon regioselectivity could arise from the pres-
ence of the hydroxy group at the C6 position, which acts as an
ortho-directing group. Phenoxy group has been firstly introduced
as directing group by Miura for palladium-promoted C–H bond
arylation of 2-arylphenols through a aryl(aryloxy)palladium inter-
mediate.7 Moreover, when a larger excess of aryl iodide (4 eq.) was
used, diarylation was also possible. However, to the best of our
knowledge, there is no other example of transition metal-catalyzed
C7 arylation of benzoxazoles or benzothiazoles, especially without
the use of an additional directing group. On the other hand, during
their investigations on palladium-catalyzed C2 direct arylation of
benzoxazole, Zhuravlev and co-worker have demonstrated a ring
opening pathway (Fig. 1c).8 Based on this equilibrium between an
opened and a closed form of benzoxazole –which is also found at
high temperature with 2-substituted benzoxazoles–9 we postulate
that 2-phenylbenzoxazole could be transitorily opened, under
proper conditions, leading to a phenoxy group, which could act as
directing group in palladium catalysis promoting a regioselective
direct C7 arylation of benzoxazole (Fig 1d). Similar intermediate
should be operative with 2-substituted benzothiazole.
a. Pd-Catalyzed Direct Arylation of 2-Phenylbenzoxazole (Wu and Zhang).[5]
C4 or C7 no reactive position
H7
H4
Pd(OAc)2 (5 mol%)
R1
Z
N
+
I
Z
N
AgOAc (1.2 equiv.)
tfa, reflux
R1
H
(4 equiv.)
Z = O or S
most reactive position
b. Pd-Catalyzed Regioselective C7 Arylation of 2-Arylbenzoxazol-6-ol (Cho).[6]
Phenoxy directing group
OH
OH
most reactive position
H7
Pd2(dba)3
X-Phos
+
Br
(1.5 equiv.)
N
O
K3PO4
toluene,
100 ºC, 13 h
N
O
45%
Ar
1 example
Ar
c. Ring-Opening Pathway in the Pd-Catalyzed Direct Arylation of Benzoxazoles
(Zhuravlev).[8]
Pd(OAc)2
PPh3
I
+
N+
via ring opening
O-
Cs2CO3
DMF
N
O
N
O
N
O
(1.5 equiv.)
H2
Ph
d. Pd-Catalyzed Regioselective C7 Arylation of Benzoxazoles and Benzothiazoles
via a Ring-Opening Pathway (this work)
R2
[Pd]
Base
H7
Br
+
R2
N+
X-
X = O or S;
R1 = Ar or Alkyl
N
X
N
X
(1.5 equiv.)
R1
R1
R1
(Thio)phenoxy as temporary directing group
Figure 1. Pd-Catalyzed C–H Arylation of Benzoxazoles.
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It is important to note that C7-arylated benzoxazole could be proton-shuttle character in CMD mechanism, which makes the C–
1
2
3
4
5
6
7
8
further easily deprotected to give a general access to 2-amino-6-
arylphenols. This motif is very interesting because it forms the core
of a range of marketed biologically active compounds (Fig. 2). For
examples, Eltrombapag is an oral medication commercialized by
GSK for the treatment of chronic hepatic C infection.10 Totrom-
bopag, also developed by GSK, is a back-up compound for eltrom-
bopag. Garenoxacin is a quinolone antibiotic for the treatment of
some bacterial infections. However, the synthesis of the 2-amino-
6-arylphenols, which are key intermediates of these drugs remain
challenging. They are generally obtained in 5 steps, with poor
overall yields, from 2-bromophenol via nitration reaction and
Suzuki cross-coupling.11
H bond cleavage easier. No yield improvement was observed using
other bases such as K2CO3, Cs2CO3, t-BuOK, or AdOK (entries 10-
13). The change of the stoichiometry of the reaction, namely, 1 eq.
of 2-phenylbenzoxazole and 1.5 eq. of 1-bromo-4-
(trifluoromethyl)benzene allowed the formation of desired product
3 in higher 85% yield (entry 14). When dried conditions were
used, no reaction occurred; whereas the addition of 4 eq. of water
promoted the reaction (entries 14-17).17, 18
9
Table 1. Optimization of the Reaction Conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF3
[Pd] (x mol%)
+
Br
CF3
N
O
N
O
Base (2 mmol)
Solvent, 140 ºC, 16 h
(1 mmol)
Ph
(1.5 mmol)
Ph
3
NH
N
CO2H
N
OH
Entry
1
2
3
4
5
6
7
8
[Pd] (x mol%)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
PdCl2 (2)
Base
Solvent
Yield in 3 (%)
OH
NH
NH
O
N
N
NH
O
N
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
PivOK
K2CO3
Cs2CO3
tBuOK
AdOK
PivOK
PivOK
PivOK
PivOK
DMA
DMSO
DMF
xylene
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
38
14
35
0
56
68
14
18
79
8
34
21
62
85
28
N.R.
72
O
OH
O
N
N
N
N
N
HO
Eltrombopag
Garenoxacin
Totrombopag
Figure 2. Marketed Drugs Containing 2-Amino-6-arylphenols.
PdCl(C3H5)(dppb) (2)
Pd2(dba)3 (1)
PdCl2 (2)
Recently, we reported the palladium-catalyzed direct arylation of
benzoxazole or benzothiazole derivatives, in which such functional
groups had not displayed any ortho-directing effect.12 In the course
of our investigation on the reactivity of 2-arylbenzoxazole, we also
employed 2-phenylbenzoxazole as starting material using our pre-
vious optimized reaction conditions (i.e., Pd(OAc)2, 2 eq. of KOAc,
in DMA at 150 ºC) (Scheme 1). To our surprise, we obtained the
unexpected C7 arylation product 1 as unique product in 31%
yield.13 This result was quite remarkable, as the previously reported
9
10
11
12
13
14[a]
15[b]
16[b, c]
17[b, c, d]
[a]
PdCl2 (2)
PdCl2 (2)
PdCl2 (2)
PdCl2 (2)
PdCl2 (2)
PdCl2 (2)
PdCl2 (2)
PdCl2 (2)
1
mmol. of 2-phenylbenzoxazole and 1.5 mmol. of 1-bromo-4-
(trifluoromethyl)benzene. [b] Dried NMP and PivOK. [c] Molecular sieves 4 Å (200 mg).
[d] 4 mmol. of water.
conditions only afforded the arylated product 2, resulting from the
In addition other
With the optimized reaction conditions in hands, we turned our
attention to the substrate scope for these direct C7 arylations of
benzoxazole derivatives (Scheme 2). First, aryl bromides with 4-
nitrile, 4-formyl, 4-propionyl or 4-ester substituents have been
successfully reacted with 2-phenylbenzoxazole to afford the C7
arylated benzoxazoles 4-7 in 62-85% yields. The reaction also
5b
benzoxazoyl directed arylation (Fig. 1a).5a,
synthetic approaches generally involved multistep synthesis or/and
poor regioselectivities.14 Only a few heterocycles display reactive
C7–H or C4–H bonds using palladium catalysis (i.e., indazoles,15
pyrazolo[1,5-a]pyrimidines,16).
proceeded in high yield using bromobenzene.
3-
Pd(OAc)2 (2 mol%)
+
CHO
Bromobenzonitrile afforded the desired product 9 in 66% yield.
The reaction was found to be slightly steric factor dependent, as 2-
bromobenzaldehyde afforded the desired product 1 in 62% yield.
3-Bromopyridine and 5-bromopyrimidine were also successfully
employed affording the C-7 arylated benzoxazoles 10 and 11 in
72% and 65% yields, respectively. Functional groups on the C2-
aryl of the benzoxazole were tolerated. Indeed, 2-(3-chloro-5-
fluorophenyl)benzoxazole was regioselectively arylated at C7
position with aryl bromides affording the desired products 12 and
13 in 59% and 64% yields, respectively. Direct arylation of a 3-
chloro-5-fluorobenzene moiety was not operative in NMP.18 Ben-
zoxazoles substituted by an alkyl group at C2 position were also
arylated at C7 position in very high yields. For example, from 2-
methybenzoxazole and a set of aryl bromides including heteroaryl
bromides, the C7-arylated products 14-21 were obtained in 53-
89% yields. The electron-rich aryl bromide 4-bromoanisole was
not reactive under these conditions. However, from 4-iodoanisole
and in the presence of a diphosphine ligand, the desired coupling
product 18 was isolated in 53% yield.18 A benzoxazole bearing a
tert-butyl group at C2 position displayed a high reactivity, as 22 was
obtained in very high yield, albeit an isopropyl substituent also
afforded the C7-arylated product 23 but in 73% yield. It is im-
KOAc (2 mmol)
DMA, 150 ºC
CHO
31%
N
O
N
O
Br
(1 mmol)
1
Ph
N
O
(1.5 mmol)
x-ray structure of 1
OHC
2 not detected
Scheme 1. Preliminary Result
Then, we chose 1-bromo-4-(trifluoromethyl)benzene as more
reactive coupling partner to screen the influence of several parame-
ters of this reaction (Table 1). The same reaction conditions al-
lowed the synthesis of C7 arylated benzoxazole 3 in 35% yield
(entry 1). First, the influence of other solvents was evaluated (en-
tries 2-5). Lower yields were obtained when the reaction was
performed in DMSO or DMF and no reaction occurred in a non-
polar solvent such as xylene. Interestingly, when NMP was used as
solvent, a higher yield of 56% in 3 was obtained (entry 5). We also
examined other palladium sources (entries 6-8). PdCl2 affords a
higher 68% yield in 3, whereas both PdCl(C3H5)(dppb) and
Pd2(dba)3 led to lower yields. The use of PivOK improved the
yield in 3 to 79% (entry 9). As proposed by Fagnou and co-
workers, the superior activity of PivOK could come from its better
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yield. This sequence reaction was also conducted from 3, without
portant to note that this reaction was not sensitive to the electronic
1
2
3
4
5
6
7
8
properties of benzoxazole ring, as benzoxazoles substituted by
methyl or nitro groups at C5 position afforded the desired C7
arylated products 24 and 25 in 69% and 65% yields, respectively.
For reactions in which lower yields were obtained (i.e., products 9,
10, 20), aryl iodides instead of aryl bromides were also employed.
However, similar yields were obtained showing that the lower
yields obtained with these electron-deficient aryl bromides do not
arise from a slow oxidative additive addition to palladium.
the isolation of the intermediate, to give the 2-amino-6-arylphenol
33 in 97% yield.
Based on Gorelsky calculations,20 the difference between the
Gibbs free energies of activation (ΔG‡298K) for the cleavage of the
C4–H and C7–H bonds of benzoxazole or benzothiazole via a
CMD pathway does not explain the complete regioselectivity on
this reaction. Nevertheless, we cannot completely deny a potential
effect of the C2 benzoxazole substituent. Then, in order to have a
better understanding of the reaction mechanism, a set of control
experiments was carried out. As expected from the previous litera-
ture,21 unsubstituted benzoxazole in the presence of 1 equiv. of
PhBr was arylated at C2 position affording 34 in 43% yield; howev-
er, in presence of 3 equiv. of PhBr, the diarylated product 8 was
isolated in 46% yield (Scheme 5.a). No reaction occurred using
unprotected 2-aminophenol, 2-methoxyaniline and N-(2-
methoxyphenyl)benzamide. Using N-benzoyl aminophenol as
starting material, we found that the arylation occurred at the C–H
bond adjacent to the OH function; however, a cyclization reaction
also took place to give the benzoxazole 4 in 37% yield with trace
amount of the arylated product 35. No arylation product arising
from an amide directed reaction was detected. From 2-(piperidin-
1-yl)phenol, in which amine was protected (no cyclization to form
a benzoxazole was possible) the arylated product 36 was regioselec-
tively obtained in 27% yield (Scheme 5.b). All these control exper-
iments seem to support a phenoxy directed arylation mechanism
via an isomerization between opened and closed benzoxazole forms
which may occur at high temperature.22 However, we cannot com-
pletely deny a SEAr mechanism, which has been proposed by
Hartwig in the case of iridium-catalyzed C7 borylation of benzoxa-
zoles.23 Finally, an intermolecular kinetic isotopic effect (KIE,
kH/kD) of 1.8 was determined from two parallel reactions. This
result suggest that the C–H bond cleavage is the “turnover-limiting
step” of this catalytic reaction (Scheme 5.c).24
9
R2
R3
R2
R3
PdCl2 (2 mol%)
+
Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PivOK (2 eq.)
NMP, 150 ºC, 16 h
(1.5 eq.)
N
O
N
O
R1
R =
4-CN
R1
N
N
4
76%
83%
65%
4-CHO
4- COEt
4-CO2Et
H
5
6
7
8
R
N
84%
N
N
O
O
N
O
71%
66%, 72%[a]
3-CN
2-CHO
9
Ph
11 67%
Ph
Ph
10 62%, 58%[a]
10 72%
N
N
R =
R
4-CN
R
14 76%
4-CF3 15 82%
4-COEt 16 89%
17 70%
4-OMe 18 0%, 53%[b]
N
O
N
O
N
O
R =
CN
12 59%
H
Me
Me
CO2Et 13 64%
21 75%
3-CN
2-CN
19 74%
20 65%, 68%[a]
R
F
Cl
CN
R' 24 R = Me, R' = COEt 69%
25 R = NO2, R' = H 65%
N
O
N
O
[a] ArI was used insed of ArBr.
R =
t-Bu 22 91%
i-Pr 23
[b] 2 mol% of Xantphos was added and the
reaction was performed from 4-iodoanisole
instead of 4-bromoanisole.
R
73%
Me
Scheme 2. Scope of the Pd-Catalyzed Benzoxazoles C7 Aryla-
tions.
We also investigated the reactivity of benzothiazoles (Scheme
3). We were pleased to find that the reaction proceeded well with
2-alkylbenzothiazoles. 2-Tert-butyl- or 2-iso-propylbenzothiazoles
were arylated using 2 mol% of PdCl2 in the presence of KOAc as
base in NMP to afford the C7 arylated products 26-29 in 54-63%
yields. 2,5-Dimethylbenzothiazole was also arylated at the C7
position in good yield. However, 2-phenylbenzothiazole displayed
no reactivity under these conditions, probably due to the formation
of a chelate complex with the palladium species.
O
N
O
N
x eq. 34
8
i)
+
1
3
43% traces
traces 46%
+
Ph
Br Ph
(x eq.)
8
a.
34
i)
CN
b.
Br
CN
+
R1
N
R2
O
R3
R1
N
R2
O
R3
R1
=
R2
H
=
(1.5 eq.)
R2
R3
4-CN
=
R3
R2
R3
PdCl2
(2 mol%)
t-Bu
t-Bu
i-Pr
26 54%
O
H
4-COEt 27 63%
4-CO2Et 28 67%
4-COEt 29 68%
Br
+
NH
O
PivOK (2 eq.)
NMP,
150 ºC, 16 h
H
H2N
OH
H2N
O
N.R.
Ph
N.R.
Me Me
Me Me
N
S
N.R.
(1.5 eq.)
N
S
CN
2-CN
30 57%
CN
R1
R1
O
N
OH
NH OH
35 traces + 4 (37%)
Scheme 3. Scope of the Pd-Catalyzed Benzothiazoles C7 Aryla-
tions.
The potential of this methodology for the access to C6 arylated
2-aminophenols, which are useful building blocks in pharmaceuti-
cals, was then investigated (Scheme 4).19
Ph
c.
36 27%
i)
CN
+
Br
CN
H/D
N
O
(1.5 eq.)
4
N
O
KIE = 1.8
37-[D]
Ph
Ph
ii)
i)
i) PdCl2 (2 mol%), PivOK (2 eq.), NMP, 150 ºC, 16 h.
R
R
R
Scheme 5. Control Experiments and Kinetic Isotopic Effect.
N
O
NH OH
R = H 31 96%
H2N
OH
8 or 3
Ph
Finally, a plausible catalytic cycle is shown in Fig. 3. We propose
a catalytic cycle involving phenoxy chelation-assisted palladium-
catalyzed regioselective C–H bond cleavage (intermediate E),
resulting from an equilibrium between the closed (C) and the
opened (D) forms of benzoxazole.25 A similar mechanism might
also be operative from benzothiazole with a sulfur chelation-
assisted C–H bond activation. Such opened transition states have
Ph
i) NaBH4 (2 eq.), AcOH (cat.), THF, rt, 16 h;
ii) Pd/C (10 mol%), EtOH, H2 (2 atm), rt, 12 h.
R = H 32 97%
R = CF3 33 97% (over 2 steps)
Scheme 4. Deprotection of Benzoxazoles.
The 2,7-diphenylbenzoxazole 8 has been deprotected using
NaBH4 to furnish the N-benzyl-2-amino-6-phenylphenol 31 in
96% yield. Then, debenzylation using Pd/C under H2 atmosphere
allowed the formation of the aminophenol 31 in excellent 97%
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Organomet. Chem. 2012, 711, 62-67; (c) Oi, S.; Sasamoto, H.;
been previously mentioned in the direct functionalization of ben-
zoxazoles or azoles at the C2 positions.8, 26
1
2
3
4
5
6
7
8
Funayama, R.; Inoue, Y., Chem. Lett. 2008, 37, 994-995.
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Int. Ed. 1997, 36, 1740-1742; (b) Kawamura, Y.; Satoh, T.; Miura, M.;
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5825.
9.Werstiuk, N. H.; Ju, C., Can. J. Chem. 1989, 67, 812-815.
10.Corman, S. L.; Mohammad, R. A., Annals of Pharmacotherapy 2010,
44, 1072-1079.
Ar–Br
Pd0
Ar
Pd
Ar
A
OH
O
Br
KOAc
KBr
H
Ar
O
N
Pd
N
H
R
R
G
OH
O
Ar
Pd
- H2O
C
N
H
R
OAc
Ar
B
+ H2O
F
Ar
O
O
N
Pd
H
9
H
R
O
OH
O
10
11
12
13
14
15
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AcOH
H
N
H
R
N
H
R
E
D
Figure 3. Proposed Mechanism.
11.Liu, K. K. C.; Sakya, S. M.; O’Donnell, C. J.; Flick, A. C.; Li, J.,
Bioorg. Med. Chem. 2011, 19, 1136-1154.
In summary, we discovered that a simple catalytic system, name-
ly, phosphine-free of PdCl2 with PivOK as base in NMP, allowed
the regioselective arylation of both benzoxazoles and benzothia-
zoles at unexpected C7-position. Mechanistic studies suggest that
an open form of benzoazoles with a palladium coordination to the
phenoxy group is the key factor for the control of the regioselectivi-
ty. We believe that this methodology is the first one allowing a
simple access to C7-arylated benzoazoles and 2-amino-6-
arylphenols. As this procedure tolerates a wide substrate scope, it
should find further applications in drug and material designs.
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13.The regioselectivity of the reaction was determined by X-Ray
analysis after recrystallization of 1 in cyclohexane (CCDC 1435542).
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ASSOCIATED CONTENT
Supporting Information. Reaction procedure and spectra are availa-
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* jean-francois.soule@univ-rennes1.fr, henri.doucet@univ-rennes1.fr
16.Bedford, R. B.; Durrant, S. J.; Montgomery, M., Angew. Chem. Int.
Ed. 2015, 54, 8787-8790.
17.NMP containing up to 5% of water; when the use of NMP
containing >5% of water led to lower yields.
18.See the supporting information for more details.
ACKNOWLEDGMENT
F. A. is grateful to Université de Tunis El Manar.. We also thank the
CNRS, “Rennes Metropole” and French Scientific Ministry of Higher
Education for providing financial support.
19.(a) Bernaskova, M.; Kretschmer, N.; Schuehly, W.; Huefner, A.;
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25.Water seems to be necessary for that equilibrium (table 1, entries 16
and 17) and should come from the solvant.
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