Palladium-catalyzed desulfitative arylation of azoles with arylsulfonyl hydrazides

Article abstract of DOI:10.1039/c2ob26270c

Palladium-catalyzed desulfitative and denitrogenative arylation of azoles with arylsulfonyl hydrazides has been achieved. A broad scope of azoles and arylsulfonyl hydrazides has been used to produce arylated azoles in high yields.

Full text of DOI:10.1039/c2ob26270c

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Palladium-catalyzed desulfitative arylation of azoles with arylsulfonyl
hydrazides†
Xinzhang Yu, Xingwei Li* and Boshun Wan*
Received 4th July 2012, Accepted 2nd August 2012
DOI: 10.1039/c2ob26270c
Palladium-catalyzed desulfitative and denitrogenative aryla-
tion of azoles with arylsulfonyl hydrazides has been
achieved. A broad scope of azoles and arylsulfonyl hydra-
zides has been used to produce arylated azoles in high yields.
Transition metal-catalyzed direct arylation of heteroaromatics via
C–H activation has recently emerged as an efficient and straight-
forward process to construct Caryl–Caryl bonds, which have been
widely found in pharmaceuticals and natural products.1 In the
past several years, various arylating reagents have been explored
for this type of reaction, including aryl halides,2 arylsilanes,3
Scheme 1 Palladium-catalyzed desulfitative arylation of benzoxazole.
aryl boronic acids,4 arylaryltrifluoroborates,5 diaryliodonium
salts,6 and ArC(O)OH.7 ArSO2Cl has been applied as a con-
venient source of sulfonyl group during the formation of S–C,
(typically 24–48 h). In addition, the substrate scope is somewhat
limited. For example, a lower yield was obtained for thiazole
S–N, and S–O bonds.8 Furthermore, in some cases desulfitation
could occur,9 where this substrate provides the source of an aryl
group. Despite these successes, limitations of this reagent have
been noted such as moisture sensitivity and long reaction time.
Thus it is necessary to explore alternatives. In fact, the past two
years have witnessed the applications of several closely related
ArSO2X (X = H, Na, and NHNH2) compounds as a source of
aryl group in oxidative C–C coupling reactions where substrates
such as aldehydes,10 and olefins,11 have been oxidatively ary-
lated using ArSO2X. In 2011, Deng and co-workers11a and
Wang and Miao11b independently reported the palladium-cata-
lyzed arylation of olefins such as styrenes and acrylates using
ArSO2H and ArSO2Na, respectively. In late 2011, Loh and co-
workers achieved a type of oxidative coupling chemistry using
ArNHNH2 as a new arylating reagent via a denitrogenative
process.12 While our work was conducted in 2012, Tian com-
bined the features of these two processes and achieved the
desulfitative–denitrogenative coupling of olefins with
ArSO2NHNH2.13 Owing to the high activity of azoles in palla-
dium-catalyzed C–H functionalization reactions,14 You, Deng,
Wang, and Cheng have recently reported the arylation of azoles,
and indoles16b using ArSO2Na15–17 and ArSO2Cl18 (Scheme 1).
Despite these extensive studies, the previously reported systems
have limitations. In all cases, a long reaction time is necessary
substrates or for sterically hindered arylating reagents.17 To
further address issues of substrate scope, activity, and catalytic
efficiency and to continue our interest in palladium-catalyzed
oxidative coupling reactions, we now report the efficient coup-
ling of azoles with ArSO2NHNH2, which has been rarely used
as an arylating reagent.19
We initiated our studies with the screening of the conditions
for the coupling of benzoxazole (1a) and TsNHNH2 (2a) under
palladium catalysis. Initially, when Pd(OAc)2 (10 mol%) was
selected as the catalyst and Cu(OAc)2 (5 equiv) was used as an
oxidant in 1,4-dioxane in the presence of phenanthroline hydrate
(Phen·H2O), the coupled product was obtained in 52% HPLC
yield, together with two homo-coupling byproducts (Table 1,
entry 1). Under these conditions, other protic and aprotic sol-
vents examined proved less favorable. The efficiency was further
affected by a base additive. The HPLC yield was improved to
75% when Na2CO3 was applied (Table 1, entry 2). In contrast,
other bases such as CsOAc or K2CO3 proved less effective
(Table 1, entries 3–4). Gratifyingly, by switching to
Pd(MeCN)2Cl2 as a catalyst, an HPLC yield of 75% was obtained
when both Phen·H2O (6 mol%) and Na2CO3 (1.5 equiv) were
introduced, and a slightly higher yield was obtained when a
mixed solvent of dioxane and DMSO (Table 1, entry 6) was
used. Further optimization indicated that when two equivalents
of TsNHNH2 were used, the yield of product 3a was increased to
90% even with a lower catalyst loading (5 mol%, Table 1, entry 7).
We noted that TBAB has been previously used to stabilize
active palladium species in oxidative C–C coupling
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, China. E-mail: bswan@dicp.ac.cn, xwli@dicp.ac.cn
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26270c
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Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Oxidant
Additive
Solvent
Yieldb
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Dioxane
Dioxane
Dioxane
Dioxane
52
75
66
62
75
79
90
92
81f
Na2CO3
CsOAc
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Dioxane
Dioxane : DMSO (9 : 1)
Dioxane : DMSO (9 : 1)
Dioxane : DMSO (9 : 1)
Dioxane : DMSO (9 : 1)
7c,d
8d,e
9d,e
a Conditions: 1a (0.5 mmol), 2a (0.75 mmol), Pd catalyst (10 mol%), Phen·H2O (12 mol%), Cu(OAc)2 (6 equiv.), additive (1.5 equiv.), solvent
(5 mL), 100 °C, 4.5 h, under Ar. b HPLC yields based on 1a. c 2 equiv. of 2a was introduced. d Pd catalyst (5 mol%) and Phen·H2O (6 mol%) were
used. e TBAB (20 mol%) was added. f 0.6 mmol of 2a was introduced.
Table 2 Arylation of oxazoles with p-tolysulfonyl hydrazidesa
corresponding products in high yield. In contrast, a low-yielding
coupling was obtained for 6-nitrobenzoxazole with or without
the TBAB additive, indicating the limitation of this system, and
previous reports indicated that low yields were consistently
obtained for nitro-substituted azoles.15–18 Similarly, simple
oxazole and oxazoles bearing 3-ester and 4-phenyl groups are
efficient coupling partners and comparably high isolated yields
were obtained (84–91%). In addition, benzothiazoles and thia-
zoles, including thiazoles bearing vinyl, methyl, nitro, and
AcOCH2CH2 substituents in the backbone, are viable substrates,
and the coupled products were isolated in moderate to high
yield. Here a 6-nitro substituted benzothiazole coupled with
TsNHNH2 in moderate yield (54%). A vinyl-substituted thiazole
substrate gave only moderate yield (3n), likely due to a competi-
tive oxidative olefination reaction. Indeed, under the current con-
ditions, the coupling of (E)-ethyl but-2-enoate with TsNHNH2
proceeded smoothly to afford the olefination product in nearly
quantitative yield.19 Consistent with previous reports, high reac-
tivity of caffeine was also observed (Table 2) (3r).
The scope of the sulfonyl hydrazide was explored for the
coupling with 1a (Table 3). Simple benzenesulfonyl hydrazide
and those bearing electron-donating, -withdrawing, and halogen
aConditions: 1 (0.5 mmol), 2a (0.75 mmol), Pd(CH3CN)2Cl2 (5 mol%),
Phen·H2O (6 mol%), Cu(OAc)2 (3 mmol), Na2CO3 (0.75 mmol), TBAB
(0.1 mmol), 1,4-dioxane–DMSO (9 : 1, 6 mL), 100 °C, under N2 for
4.5 h. The yields are of the isolated products. bWithout TBAB.
groups at the 3- and 4-positions all undergo smooth coupling
and the products were isolated in 47–92% yield. Wang reported
that a diminished yield (49%) was obtained when sodium ortho-
tolylsulfinate was allowed to couple with 1a as a result of steric
effects of this arylating reagent.17 In our system, o-TsNHNH2
coupled smoothly with 1a to give product 3u in 67% yield,
although the efficiency of the reaction is still affected by a steric
effect. In addition to a substituted phenyl group, 1- and
2-naphthylsulfonyl hydrazides reacted with high efficiency,
although a slightly lower yield was obtained for 2-naphthylsulfo-
nyl hydrazide, also due to steric reasons.
Several experiments have been performed to explore the
mechanism of this reaction. When radical inhibitors such as
BHT and TEMPO were introduced into the reaction system of 1a
and TsNHNH2, essentially no decrease of the yield of product
3a was detected, indicating that no organic radical species is
involved.22 In addition, when the reaction of 2a was carried out
reactions.20–21 Thus when TBAB (20 mol%) was introduced, the
product was eventually obtained in 92% HPLC and 90% isolated
yield after 4.5 h with 1.5 equivalent of 2a introduced (Table 1,
entry 8). Under these optimized conditions, the amount of
TsNHNH2 can be reduced to 1.2 equiv with 81% HPLC yield
(Table 1, entry 9).
With the optimized conditions in hand, we then explored the
scope of the azole substrate in the coupling with TsNHNH2
under our standard conditions (Table 2). Simple benzoxazole
and benzoxazoles bearing electron-donating and halogen groups
at the 5 and 6 positions all reacted smoothly to give the
7480 | Org. Biomol. Chem., 2012, 10, 7479–7482
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Table 3 Arylation of benzoxazoles with arylsulfonyl hydrazidesa
In summary, we have developed palladium-catalyzed desulfi-
tative–denitrogenative arylation of azoles with arylsulfonyl
hydrazides. Various oxazoles and arylsulfonylhydrazides can be
tolerated in this reaction to afford the desired products in good to
high yields. This method expands the utility of arylsulfonyl
hydrazides as arylating reagent in C–H activation of
heteroaromatics.
Financial support from the National Basic Research Program
of China (2010CB833300) and the National Natural Science
Foundation of China (21172218) and the Dalian Institute of
Chemical Physics, Chinese Academy of Science is acknowl-
edged. We thank Dr Jian Xiao for the initial preparation of this
manuscript.
Notes and references
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aConditions: 1a (0.5 mmol), 2 (0.75 mmol), Pd(CH3CN)2Cl2 (5 mol%),
Phen·H2O (6 mol%), Cu(OAc)2 (3 mmol), Na2CO3 (0.75 mmol), TBAB
(0.1 mmol), in 1,4-dioxane–DMSO (9 : 1, 6 mL), 100°C, under N2,
4.5 h. The yields refer to isolated products. bWithout TBAB.
2 For selected examples of direct arylation of N-heterocycles by using
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Scheme 2 Proposed mechanism.
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TsNHNH2 affords a copper(II) aryl sulfonyl species (I), which
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7482 | Org. Biomol. Chem., 2012, 10, 7479–7482
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