The palladium-catalyzed tandem decarboxylation, carbon-carbon triple bond oxidation and decarbonylative arylation of the benzoxazole C-H bond

Article abstract of DOI:10.1039/c3ra41185k

A palladium-catalyzed arylation of benzoxazole has been developed. This protocol involves the tandem decarboxylation and oxidation of a carbon-carbon triple bond followed by decarbonylative arylation of the benzoxazole C-H bond.

Full text of DOI:10.1039/c3ra41185k

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The palladium-catalyzed tandem decarboxylation,
carbon–carbon triple bond oxidation and
decarbonylative arylation of the benzoxazole C–H
bond3
Cite this: RSC Advances, 2013, 3, 9193
Received 11th March 2013,
Accepted 19th April 2013
DOI: 10.1039/c3ra41185k
Dongfang Liu,a Bin Liua and Jiang Cheng*ab
www.rsc.org/advances
A palladium-catalyzed arylation of benzoxazole has been devel-
oped. This protocol involves the tandem decarboxylation and
oxidation of a carbon–carbon triple bond followed by decarbo-
nylative arylation of the benzoxazole C–H bond.
presence of Pd(dba)2 (5 mol%), Cs2CO3 (2 equiv.) and Ag2CO3 (1
equiv.) in NMP at 140 uC under O2. To our delight, the arylation
product 3aa was isolated in 20% yield (Table 1, entry 1).
Encouraged by this interesting preliminary result, we explored
the optimum reaction conditions. Solvents such as dimethylace-
tamide (DMAC), DMF and DMSO, which are often employed in
decarboxylative cross-coupling reactions, were also efficient for
this transformation to some extent. Gratifyingly, the replacement
of NMP with DMSO and DMF provided a moderate yield (Table 1,
entries 3 and 4). Further studies revealed that the co-solvent
system of DMSO and DMF played a vital role on the yield of 3aa
(Table 1, entries 5–9). When DMSO/DMF (1 : 20) was used as a
solvent, a higher yield of 86% was obtained (Table 1, entry 7). The
reaction efficiency decreased under air and N2 (Table 1, entry 7).
PdCl2 and Pd(OAc)2 were less effective, providing 3aa in 30% and
60% yields, respectively (Table 1, entries 10 and 11). In the absence
of palladium, no reaction took place. When K2CO3 and t-BuOLi
were used instead of Cs2CO3, the product was isolated in low
yields (Table 1, entries 13 and 14). Only a trace amount of product
was detected in the absence of Cs2CO3 (Table 1, entry 9).
Additionally, other silver sources tested were proven to be inferior
to Ag2CO3. A moderate 50% yield was obtained in the absence of
Ag2CO3 (Table 1, entry 12).
The transition metal-catalyzed decarboxylative C–H bond functio-
nalization is a key transformation in organic synthesis because
carboxylic acids are one of the most common and readily available
functional groups in organic chemistry (eq. (1), Scheme 1).1
Alternatively, C–H bond functionalization via metal-catalyzed
decarbonylation of aldehydes, acid chlorides and other related
functional groups is also known (eq. (3), Scheme 1).2 Recently, the
arylation reaction via transition metal-catalyzed decarboxylative or
decarbonylative functionalized reactions have been well documen-
ted.3 Meanwhile, with the development of organometallic
chemistry, the transition metal-catalyzed oxidation of alkynes into
1,2-diketones using molecular oxygen, provides a potential path-
way for the cleavage of carbon–carbon triple bonds and represents
a handle for further transformation (eq. (2), Scheme 1).4 In light of
this, a cascade reaction involving decarboxylation followed by the
sequential oxidative cleavage of the carbon–carbon triple bond
and decarbonylation is highly attractive in metal-catalyzed organic
synthesis. However, to the best of our knowledge, no examples
have been reported or studied before. In this communication, we
wish to report a palladium-catalyzed tandem decarboxylative,
triple bond oxidative and decarbonylative arylation of benzoxazole
C–H bond. The arylation of the C–H bond is an important
transformation in organic synthesis because the bis(hetero)aryl
moiety is an important structure frequently found in natural
products, pharmaceuticals, and other functional compounds.5
We began our research by using the reaction of benzoxazole
(1a) and 3-phenylpropiolic acid (2a) as a model reaction in the
After the establishment of the optimized reaction conditions,
various benzoxazole derivatives were treated with 3-phenylpropio-
lic acid (2a) to give the corresponding substituted 2-phenylbenzox-
aCollege of Chemistry & Materials Engineering, Wenzhou University, Wenzhou
325035, P. R. China
bSchool of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology, and Jiangsu Province Key Laboratory of Fine
Petrochemical Engineering, Changzhou University, Changzhou, 213164, P. R. China.
E-mail: jiangcheng@cczu.edu.cn
Scheme 1 Design plan.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra41185k
3
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Table 1 Selected results of screening the optimal conditions
Entry Palladium Base
Additive Solvent
Yield (%)a
1
2
3
4
Pd(dba)2 Cs2CO3 Ag2CO3 NMP
Pd(dba)2 Cs2CO3 Ag2CO3 DMAC
Pd(dba)2 Cs2CO3 Ag2CO3 DMSO
Pd(dba)2 Cs2CO3 Ag2CO3 DMF
Pd(dba)2 Cs2CO3 Ag2CO3 DMSO/DMF(1 : 3)
20
39
68
70
78
5
6
7
8
Pd(dba)2 Cs2CO3 Ag2CO3 DMSO/DMF(1 : 10) 80
Pd(dba)2 Cs2CO3 Ag2CO3 DMSO/DMF(1 : 20) 86 (41)b (,5)c
Pd(dba)2 Cs2CO3 Ag2CO3 DMSO/DMAC(1 : 20) 62
9
Pd(dba)2
PdCl2
—
Ag2CO3 DMSO/DMF(1 : 20) ,5
10
11
12
13
14
15
16
Cs2CO3 Ag2CO3 DMSO/DMF(1 : 20) 30
Fig. 2 Pd-catalyzed arylation of benzoxazole by aryl ethynesa.
Pd(OAc)2 Cs2CO3 Ag2CO3 DMSO/DMF(1 : 20) 60
Pd(dba)2 Cs2CO3
—
DMSO/DMF(1 : 20) 50
Pd(dba)2 tBuOLi Ag2CO3 DMSO/DMF(1 : 20) ,5
Pd(dba)2 K2CO3 Ag2CO3 DMSO/DMF(1 : 20) 33
Pd(dba)2 Cs2CO3 AgF
Pd(dba)2 Cs2CO3 Ag2O
DMSO/DMF(1 : 20) 51
DMSO/DMF(1 : 20) 64
After the decarboxylation of 3-phenylpropiolic acid, one
equivalent of terminal alkyne or phenylethyl palladium species
may be formed. Thus, we envisioned terminal alkynes also had the
similar reactivity under this procedure. As we expected, the
2-arylation of benzoxazole proceeded smoothly in 60% yield.
Notably, 1-ethynyl-4-methoxybenzene smoothly underwent aryla-
tion leading to product 3ac in 89% yield. However, for 1-ethynyl-4-
ethylbenzene, the desired product (Fig. 2, 3ae) was obtained in
61% yield. Particularly, chloro group was tolerated in this process,
and resulted in a moderate yield of 48% (Fig. 2, 3af), which
provided a versatile synthetic handle for further functionalization.
To gain preliminary insight into the reaction mechanism, some
experiments were conducted as shown in Scheme 2. The
competition experiments revealed the aryl ethyne possessing
electron donating groups was more active than those with an
electron withdrawing group analogue (eq. (1), Scheme 2). Next,
some potential intermediates were subjected to the standard
reaction conditions. However, 2-oxo-2-phenylacetaldehyde deliv-
ered the arylation product in 24% yield; while 2-oxo-2-phenylacetic
acid and benzaldehyde resulted in no reaction (eq. 3 and 4,
Scheme 2). This result ruled out the possibility of them as the
intermediate for this reaction. Moreover, no byproducts, such as 2-
(phenylethynyl)benzoxazole, 1-(benzoxazol-2-yl)-2-phenylethane-
1,2-dione, benzoxazol-2-yl(phenyl)methanone were detected (eq.
5, Scheme 2).
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Pd source (5
mol%), base (2.0 equiv.), additive (1.0 equiv.), under O2 in indicated
solvent (2 mL), 140 uC, 11 h, isolated yield. Under air. Under N2.
DMAC = N, N9-dimethylacetamide.
b
c
azole (Fig. 1, 3aa–3ja) in generally good to excellent yields. As
summarized in Fig. 1, either electron-donating groups such as
methoxy or weak electron-withdrawing groups including chloro
group in the phenyl ring of benzoxazole were tolerated during the
reaction. However, ethyl 2-phenyl-5-carboxylatebenzoxazole (3fa)
was generated in only 33% yield. Notably, for the 5-aryl
benzoxazoles, all provided the 2-arylation products in good to
excellent yields (3ga–3ja).
Based on these experimental results, a preliminary mechanism
was outlined, as shown in Scheme 3. Firstly, with the assistance of
Ag(I), one equivalent of CO2 is lost to form phenylethynyl
palladium 4.6 In the case of phenyl ethyne, the reaction of alkynyl
silver and Pd(II) may provide the phenylethynyl palladium.7
Secondly, the oxidization of 4 by O2 provides intermediate 5.
Then, after the extraction of two equivalents of CO, phenyl
palladium 6 is formed, which undergoes electrophilic attack on
the benzoxazole to form intermediate 7. The reductive elimination
of 7 takes place to form the arylation product along with a Pd(0)
species. Finally, the Pd(0) is oxidized to Pd(II) to regenerate the
catalyst.
Fig. 1 Pd-catalyzed arylation of substituted benzoxazole with 3-phenylpropiolic
acida.
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benzoxazole C–H bond. The employment of this reaction and a
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We thank the National Natural Science Foundation of China
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Province (Nos. R4110294 and LY12B02010), Jiangsu Province
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Priority Academic Program Development of Jiangsu Higher
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