Palladium-catalyzed deamidative arylation of azoles with arylamides through a tandem decarbonylation-C-H functionalization

Article abstract of DOI:10.1039/c2cc18156h

A highly chemo-, regio-selective, and efficient palladium-catalyzed deamidative arylation of azoles with arylamides, as an aryl metal equivalent, has been developed. The reaction proceeds smoothly to generate the corresponding products in good yields via a tandem decarbonylation-C-H activation.

Full text of DOI:10.1039/c2cc18156h

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COMMUNICATION
Palladium-catalyzed deamidative arylation of azoles with arylamides
through a tandem decarbonylation–C–H functionalizationw
Chengliang Li,a Pinhua Li,a Jin Yanga and Lei Wang*ab
Received 30th December 2011, Accepted 27th February 2012
DOI: 10.1039/c2cc18156h
A highly chemo-, regio-selective, and efficient palladium-catalyzed
deamidative arylation of azoles with arylamides, as an aryl metal
equivalent, has been developed. The reaction proceeds smoothly to
generate the corresponding products in good yields via a tandem
decarbonylation–C–H activation.
of azoles with N-tosylhydrazones, benzyl carbonates, and
benzyl chlorides;15 alkynylation of azoles with alkynyl bromides
and alkynes;16 and dehydrogenative cross-couplings with arenes.17
It is necessary to develop a simple, mild and economic method
for the synthesis of aryl(alkyl)-azoles through the direct C–H
functionalization.
Acid amides are extremely stable, cheap and readily derived
from the corresponding carboxylic acids, which represent one
of the most common and readily available functional groups
in organic chemistry. As one kind represent example of
amides, N-alkyloxy- and N-alkylbenzamides (ArCONHOR
and ArCONHR) were used as substrates with the utilization
of the CONHOR or CONHR as the directing group in the
arylation of sp3 C–H bonds, ortho-alkylation, and ortho-
olefination of amides, as well as intramolecular cyclization
reactions through the transition-metal-catalyzed C–H activation.18
However, transition-metal-catalyzed deamidative cross-couplings
using arylamides as aryl sources have been less investigated.19
As part of our ongoing efforts devoted to the synthesis of aryl-
azoles through C–H functionalization,20 herein, we wish to
report a highly efficient chemo-, regio-selective palladium-
catalyzed deamidative cross-coupling of arylamides, not only
as the source of the aryl electrophile, but also as the aryl metal
equivalent, with azoles by a tandem decarbonylation–C–H
activation under phosphine-free conditions. It is important to
note that the CONHOR or CONHR group of arylamides acts
as halide free leaving groups, not as the directing groups in the
reactions (Scheme 1).
Transition-metal-catalyzed decarboxylative cross-coupling reactions
using carboxylic acids as aryl sources have been of great
interest recently. Compared to the general coupling partner of
organometallic reagents, decarboxylative coupling utilizes readily
available, cheap and stable carboxylic acids as substrates,
instead of sensitive organometallic compounds. In addition,
decarboxylative coupling generates CO2 without producing
toxic metal halides. In the last decade, the coupling of a variety
of carboxylic acids with different electrophiles, such as aryl
halides and triflates, as well as with arenes via tandem C–H
activation–decarboxylation has been extensively investigated by
Goossen,1 Myers,2 Forgione,3 Larrosa,4 Su,5 Crabtree,6 Becht,7
and Liu et al.8 It is important to note that a Pd-catalyzed
decarboxylative coupling of thiazoles and oxazoles with
benzoic acids has been developed by Tan recently.9 Besides
carboxylic acids, acid chlorides, formamides and arylsulfonyl
chlorides also served as aryl sources through decarbonylative or
desulfitative cross-coupling to accomplish a range of synthetic
transformations.10
Aryl(alkyl)-heterocycle structural motifs with C–C linkages
are widely used as important intermediates and versatile
building blocks for the construction of pharmaceuticals with
important biological properties.11 Among the popular approaches
to aryl(alkyl)-heterocycles, transition-metal-catalyzed C–C bond
formation through the direct aryl(alkyl)ation of C–H bonds in
heterocycles has received considerable attention.12 The following
direct cross-coupling reactions of azoles through C–H activation
have been reported: arylation of azoles with aryl halides, mesylates,
triflates, organosilicons and arylboronic acids;13 alkylation of
azoles with unactivated alkyl halides;14 benzylation and allylation
In the initial investigation on the reaction of azoles with
arylamides, benzoxazole (1a) and N-methoxybenzamide (2a)
were chosen as model substrates. When the model reaction
was carried out in DMSO in the presence of Pd(OAc)2 (5 mol%)
and K2S2O8 (2.0 equiv.) at 120 1C for 24 h, a deamidative
arylation product (3a) was isolated in 31% yield, and no direct
dehydrogenative cross-coupling product was detected. This
preliminary finding promoted us to increase the yield of 3a
by surveying various reaction parameters (ESIw, Table S1).
When the model reaction was carried out in the presence of
a Department of Chemistry, Huaibei Normal University, Huaibei,
Anhui 235000, P. R. China. E-mail: leiwang@chnu.edu.cn;
Fax: +86-561-309-0518; Tel: +86-561-380-2069
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc18156h
Scheme 1
c
4214 Chem. Commun., 2012, 48, 4214–4216
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Pd(OAc)2 (5 mol%) and K2S2O8 (2.0 equiv.), a significant
solvent effect was observed (Table S1, ESIw). Among the
solvents tested, a mixed solvent of toluene–DMSO (4 : 1)
was found to be the best one. When toluene was used as
solvent, only 20% yield of 3a was obtained. However, when
the reaction was carried out in THF, DCE or NMP, no 3a was
isolated. By changing volume ratios of toluene to DMSO,
lower yields of 3a were obtained. However, no 3a was detected
when the reaction was carried out in THF, DMF, NMP,
MeCN, dioxane, MeNO2, EtOH, or t-BuOH with DMSO in
4 : 1 volume ratios (Table S1, entries 1–21, ESIw). Next, the
effect of an oxidant on the model reaction was examined.
When the reaction was carried out in the presence of Pd(OAc)2
in toluene–DMSO (4 : 1), 55, 40, 32 and 27% yields of 3a were
obtained when K2S2O8, DDQ, (NH4)2S2O8 and Ag2CO3 were
used as oxidant, respectively. Unfortunately, organic peroxides,
C6H5I(OAc)2 and Cu(OAc)2, did not work in the reaction
(Table S1, entries 22–30, ESIw). The palladium catalyst is
essential in the reaction. A number of palladium catalytic systems
were examined. Pd(OAc)2/1,10-phenanthroline showed the
highest reactivity, and 75% yield of 3a was obtained (Table S1,
entries 31–40, ESIw).
Under the optimized reaction conditions, the substrate
scope of azoles with arylamides was examined. As can be seen
from Table 1, the reactions of benzoxazoles with different
substituted groups attached to the benzene rings, such as electron-
donating groups (CH3 and t-C4H9), and electron-withdrawing
groups (Cl and NO2), underwent deamidative arylation smoothly
with N-methoxybenzamide or N-methoxy(p-methyl)benzamide
to generate 3a–g in 71–92% yields (Table 1, entries 1–7). On
the other hand, a deamidative arylation of benzothiazole with
N-methoxy(p-methyl)benzamide gave the inferior product yield
(3h) to that of benzoxazole (entry 8 vs. 15). More simple oxazole
and thiazole derivatives, such as ethyl oxazole-5-carboxylate,
thiazole, and 4-methylthiazole, also reacted with N-methoxy-
(p-methyl)benzamide to afford 3i–k in 63–70% yields (entries
9–11). To further extend the scope of azoles, the deamidative
arylation of 1,3,4-oxadiazole derivatives with N-methoxy-
(p-methyl)benzamide was also investigated. Various 2-aryl-1,3,4-
oxadiazoles with either electron-donating or electron-withdrawing
groups on their benzene rings displayed high reactivity under
the present reaction conditions, and the corresponding
2,5-diaryl-1,3,4-oxadiazoles 3l–n were obtained in 77–85%
yields (entries 12–14). Subsequently, a variety of N-methoxy-
arylamides with different substituents on the benzene rings used as
deamidative arylation reagents was also examined. The deamidative
arylation of benzoxazole with N-methoxyarylamides, such as
N-methoxy-, N-methoxy(p-methyl)-, N-methoxy(p-chloro)-,
N-methoxy(m-chloro)-, N-methoxy(p-fluoro)-, and N-methoxy-
(p-cyano)-benzamide, proceeded smoothly to generate 3o–s
in 73–92% yields (entries 15–19). It should be noted that the
ortho-position effect of N-methoxyarylamides was observed
(Table 1, entries 20 and 21).
Table 1 The palladium-catalyzed deamidative arylations of azoles
with arylamidesa
Yieldb
[%]
Entry Azole
R1
Product
3
1
2
3
H
3a 75
3b 81
3c 86
H
4-Me
4
4-Me
3d 83
5
6
7
8
H
3e 92
3f 90
3g 71
3h 58
H
4-Me
4-Me
9
4-Me
4-Me
4-Me
3i 63
3j 66
3k 70
10
11
12
13
14
4-Me
4-Me
4-Me
3l 85
3m 77
3n 78
15
16
4-Me
4-Cl
3o 83
3p 90
17
3-Cl
3q 92
18
19
4-F
3r 82
3s 73
4-CN
20
2-Cl
3t 41
3u 49
A variety of N-substituted benzamides used as deamidative
arylation reagents with benzoxazole (1a) were examined to
investigate the scope of N-substituted benzamides (Table 2).
When N-substituted groups, such as MeO, Me, NH2, n-C4H9
and t-C4H9, attached to N-substituted benzamides, 54–75%
yields of 3a were obtained, and the N-methoxy group displayed
21
2,4-Cl2
a
Reaction conditions: azole (1.0 mmol), arylamide (1.0 mmol),
Pd(OAc)2 (0.05 mmol), Phen (0.10 mmol) and K2S2O8 (2.0 mmol) in
b
toluene–DMSO (4 : 1, 2.0 mL) at 120 1C for 24 h. Isolated yields.
c
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Table 2 The palladium-catalyzed reaction of 1a with 2a
decarbonylation–C–H activation process to generate the
corresponding products. This method presents the advantages
of good yield, mild reaction conditions and wide substrate
scope. It is important to note that the CONHOMe group in
N-methoxybenzamide acts as a halide free leaving group, not
as the ortho-directing group in the direct arylation reactions of
azoles with arylamides.
This work was financially supported by the National
Science Foundation of China (No. 20972057).
Notes and references
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a
Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), Pd(OAc)2
(0.05 mmol), Phen (0.10 mmol), K2S2O8 (2.0 mmol) in toluene–DMSO
b
(4 : 1, 2.0 mL) at 120 1C for 24 h. Isolated yields.
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Scheme 2 Possible reaction mechanism.
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the highest reactivity in the reaction. Only a trace amount of 3a
was obtained when benzamide or N,N-diethylbenzamide reacted
with 1a under the present reaction conditions. However, no
desired 3a was isolated when benzaldehyde, benzoic acid,
benozyl chloride, or ethyl benzoate was used as an arylation
reagent (Table 2).
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Although the exact mechanism of this reaction is not clear, a
proposed pathway is shown in Scheme 2. Firstly, the PdII
catalyst reacted with N-methoxyarylamide (2) to form an
intermediate A,9,21 which subsequently underwent deamidation
to generate ArPdX species and OQCQNOMe, which is easy to
decompose into urea and CO2 when quenched with water22 via
path A, and underwent decarbonylation to generate ArPdX
species and release CO via the insertion of palladium into an
amide C–N bond23 according to path B. The ArPdX species
then inserted into a CQN double bond of benzoxazole (1a) via
a carbopalladation process to form an intermediate B. Finally,
a b-hydride elimination from intermediate B generated the
cross-coupling product 3 and Pd0 species, which was reoxidized
to PdII by K2S2O8 for its catalytic cycle. FT-IR analysis of the
products showed that the ratio of CO/CO2 is 29.3/1 (ESIw,
Fig. S1 and Table S2), indicating the path B in majority via a
decarbonylation process.
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23 L. J. Goossen and J. Paetzold, Angew. Chem., Int. Ed., 2004,
43, 1095.
In conclusion, a highly chemo- and regioselective, and
efficient palladium-catalyzed deamidative cross-coupling of
arylamide, as an aryl metal equivalent, with azole has been
developed. In the presence of Pd(OAc)2/Phen/K2S2O8, the
reactions proceed smoothly in toluene–DMSO through a tandem
c
4216 Chem. Commun., 2012, 48, 4214–4216
This journal is The Royal Society of Chemistry 2012