Palladium-catalyzed reductive homocoupling of N′-tosyl arylhydrazines

Article abstract of DOI:10.1039/c3ob41546e

A novel procedure for the preparation of biaryl compounds by Pd-catalyzed homocoupling of N′-tosyl arylhydrazine has been described. N′-Tosyl arylhydrazine, as a readily available and stable coupling partner, demonstrated its generality in the homocoupling reactions. The scope of the reaction and possible mechanism have also been investigated.

Full text of DOI:10.1039/c3ob41546e

Organic &
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Palladium-catalyzed reductive homocoupling of
N’-tosyl arylhydrazines†
Cite this: Org. Biomol. Chem., 2013, 11,
8014
Jin-Biao Liu,a Lin Nie,a Hui Yan,a Li-Hua Jiang,b Jiang Wenga and Gui Lu*a,c
Received 28th July 2013,
Accepted 10th October 2013
DOI: 10.1039/c3ob41546e
www.rsc.org/obc
A novel procedure for the preparation of biaryl compounds by arenediazonium salts for the synthesis of symmetrical biaryls;
Pd-catalyzed homocoupling of N’-tosyl arylhydrazine has been however, a significant amount of by-products complicated the
described. N’-Tosyl arylhydrazine, as a readily available and stable purification process.8 Notably, aryl diazonium salts are danger-
coupling partner, demonstrated its generality in the homo- ously explosive and prone to decomposition upon storage. To
coupling reactions. The scope of the reaction and possible expand this substrate scope, and more importantly, to make
mechanism have also been investigated.
this novel coupling reaction practically useful in organic syn-
thesis, other sources that can generate nonstabilized diazo
compounds in situ have attracted our attention. N′-Tosyl aryl-
hydrazine has been considered as another safe and effective
source of active diazo compound in a Suzuki cross-coupling
reaction (Scheme 1a).9 In this paper, as part of our ongoing
study on palladium-catalyzed cross-coupling processes, we
report the symmetrical aryl–aryl bond formation via homo-
coupling of N′-tosyl arylhydrazine under mild conditions
(Scheme 1b).
First, N′-tosyl phenylhydrazine 1a derived from phenyl-
hydrazine was selected as the model substrate for the reaction
condition screening. The results are summarized in Table 1.
When Pd(OAc)2 was used as the palladium source and K2CO3
as the base, the reaction of 1a proceeded smoothly, and 58%
yield of product 2a was achieved in DMSO at room temperature
(Table 1, entry 1). Encouraged by this result, we examined
more Pd catalysts and found that PdCl2 was the best Pd
source, affording 91% yield of the desired product 2a (Table 1,
entry 4). Various bases were then screened for this reaction.
However, none of them was more efficient than K2CO3
(Table 1, entries 4–10). Other solvents, such as MeOH, dioxane
and toluene, were also investigated; however, moderate yields
were obtained (Table 1, entries 11–13). Increasing the amount
of Pd catalyst loading to 5 mol% resulted in a comparable
The aryl–aryl bond-forming reaction is an important trans-
formation in synthetic organic chemistry because the biaryl
unit is found in a large number of natural products, pharma-
ceuticals, biologically significant agrochemicals, and conduct-
ing polymers.1 Numerous studies have been carried out, and
several efficient reactions for the synthesis of biaryls have been
developed during the last century.2 Symmetrical biaryls have
traditionally been prepared through copper-mediated Ullmann
reductive homocoupling of aryl halides,3 but its requirement
of high temperature has spawned the recent development of
milder palladium-4 and nickel-5 mediated reductive homo-
couplings. The latter reactions have already provided powerful
access to synthetic biaryls despite excess external reducing
reagents (a hydrogen donor and/or an electron source) usually
being needed to regenerate the Pd(0) active species.
In recent years, considerable attention has been focused on
the transition metal-catalyzed cross-coupling reactions that
utilize arenediazonium salts as aryl electrophilic components.6
However, metal-catalyzed routes to symmetrical biaryls from
arenediazonium salts have not received much attention,
although stoichiometric cupric7a or ferrous salt7b-promoted
methods have been introduced. Furthermore, Hanna
et al. reported palladium-catalyzed homocoupling of
aInstitute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou, 510006, P. R. China.
E-mail: lugui@mail.sysu.edu.cn; Fax: (+86)-20-39943048
bSchool of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530001,
P. R. China
cInstitute of Human Virology, Sun Yat-sen University, Guangzhou, 510080,
P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 (a) Suzuki cross-coupling reaction of N’-tosyl arylhydrazine; (b)
Homocoupling of N’-tosyl arylhydrazine.
c3ob41546e
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Table 1 Influences of the reaction conditions in the homocoupling of N’-tosyl
phenylhydrazine 1aa
Table 2 Pd-catalyzed homocoupling of N’-tosyl arylhydrazinesa
Entry
1
R =
Product
Yieldb [%]
91
Entry
[Cat.]/base
Solvent
Yieldb [%]
4-Tolyl
1
2
3
4
5
6
7
8
Pd(OAc)2/K2CO3
Pd(PPh3)4/K2CO3
PdCl2(PPh3)2/K2CO3
PdCl2/K2CO3
PdCl2/Na2CO3
PdCl2/K3PO4
PdCl2/KOH
PdCl2/Et3N
PdCl2/DABCO
PdCl2/DBU
PdCl2/K2CO3
PdCl2/K2CO3
PdCl2/K2CO3
PdCl2/K2CO3
PdCl2/K2CO3
–/K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeOH
Dioxane
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
58
52
45
91
70
58
35
75
26
33
48
40
55
78
91
Trace
84
71
2
Phenyl
88
85
20
90
3c
4c
5
Methyl
9
10
11
12
13
14c
15d
16
17e
18f
4-Nitrophenyl
4-Tolyl
PdCl2/K2CO3
PdCl2/K2CO3
6
7
4-Tolyl
4-Tolyl
85
80
a Reaction conditions: 1a (0.3 mmol), PdCl2 (2.5 mol%), base
(1.0 equiv.), solvent (1 mL), rt, 2–12 h, under air. b Isolated yields.
c PdCl2 (1.25 mol%). d PdCl2 (5 mol%). e K2CO3 (0.5 equiv.). f K2CO3
(2.0 equiv.).
yield (Table 1, entry 15 versus entry 4). However, a significant
drop in yield was observed when 1.25 mol% of PdCl2 was used
(Table 1, entry 14). A palladium catalyst was necessary for this
homocoupling, and a trace product was observed in the
absence of any Pd catalyst (Table 1, entry 16). The amount of
K2CO3 was also important for this reaction (Table 1, entries 4,
17 and 18). The optimized homocoupling reaction conditions
were as follows: 1a (0.3 mmol), PdCl2 (2.5 mol%) and K2CO3
(1.0 equiv.) in DMSO at room temperature.
8c
4-Tolyl
Trace
9
4-Tolyl
4-Tolyl
92
78
10c
The scope of the Pd-catalyzed homocoupling of N′-sulfonyl
arylhydrazine was then investigated (Table 2). N′-Sulfonyl aryl-
hydrazine with substituted groups, such as phenylsulfonyl and
methylsulfonyl, could also afford the desired products in high
yields (Table 2, entries 2 and 3). However, the strong electron-
deficient nitro group lowered the yield significantly even at
higher temperature (Table 2, entry 4). N′-Tosyl arylhydrazines
with both electron-donating and electron-withdrawing groups
attached to the aromatic ring all contributed to this transform-
ation. For example, methyl and methoxyl substituents on
phenyl rings can be successfully converted into the desired
products in high yields (Table 2, entries 5–7 and 9). In
addition, substrates with halogen, trifluoromethoxy, and nitro-
substituents at the aryl moiety participated in the desired
11c
4-Tolyl
82
12c
13c
14c
15
4-Tolyl
4-Tolyl
4-Tolyl
4-Tolyl
74
68
60
50
homocoupling process at
a higher temperature (60 °C)
16c
4-Tolyl
44
(Table 2, entries 10–15). Interestingly, the homocoupling of
4-chlorophenyl and 4-bromophenyl sulfonylhydrazide led to
the exclusive formation of 2g and 2i in 78% and 74% yield,
respectively (Table 2, entries 10 and 12), indicating excellent
a Reaction conditions:
1 (0.3 mmol), PdCl2 (2.5 mol%), K2CO3
chemoselectivity in contrast to the traditional Ullmann (1.0 equiv.), DMSO (1 mL), rt, 2–12 h, under air. b Isolated yields. c 60 °C.
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Scheme 2 Cross-coupling between 1a and 1g.
Fig. 1 Proposed mechanism.
been proposed (Fig. 1).8–11 The in situ generated reductive
Pd(0) active species from the oxidative Pd(II) species undergoes
oxidative insertion to diazene B (step ii) to form the organo-
palladium intermediate D by N2 release. Then D is converted
to diarylpalladium complex E, followed by the reductive elimin-
ation (step v), to afford biaryl F and to regenerate the Pd(0)
catalyst. N′-Tosyl arylhydrazine A may have functions on both
the initial reduction (step i) and the terminal reduction
(step vi),12 allowing the homocoupling to be carried out in an
operationally simple manner without the addition of a zero-
valent metal or other terminal reductant.
Scheme 3 Control experiments.
In summary, a novel procedure for the preparation of biaryl
compounds by Pd-catalyzed homocoupling of N′-tosyl aryl-
hydrazine without the addition of zero-valent metal or other
terminal reductants was presented. N′-Tosyl arylhydrazine, as a
readily available and stable coupling partner, demonstrated its
generality in the aforementioned homocoupling reactions.
Future studies are aimed at extending the scope and synthetic
applications.
homocoupling of aryl chlorides and aryl bromides. Unfortu-
nately, the ortho-substituent of arylhydrazine was not compati-
ble with the reaction conditions (Table 2, entry 8). The aryl-
substituted, as well as the heteroaryl-substituted tosylhydra-
zide, provided moderate yields (Table 2, entry 16).
We also performed the Pd-catalyzed cross-coupling reaction
between N′-tosyl arylhydrazines 1a and 1g, and detected both
homocoupling products 2a, 2g and cross-coupling product 2ag
in a ratio of 2 : 1 : 3 (Scheme 2). The current chemoselectivity
was only moderate, and more experiments were still needed to
understand the mechanism, to optimize the reaction con-
ditions for the desired pathway and to explore its potential
applications in organic synthesis.
To explain the mechanism of this homocoupling reaction,
three control experiments were carried out (Scheme 3).
Initially, 1-phenyl-2-tosyldiazene 1a′ can be isolated in 26%
yield from N′-tosyl phenylhydrazine 1a under basic conditions,
but the direct homocoupling reaction of 1a′ can only afford
trace biphenyl 2a under the aforementioned standard con-
ditions (PdCl2 as the catalyst, without any external reductants)
(Scheme 3a). Other Pd(II) catalysts as PdCl2(PPh3)2 also failed
to give 2a (Scheme 3b). In contrast, when Pd(PPh3)4 was
utilized as the catalyst, 27% yield of 2a could be obtained
(Scheme 3c), which indicated that the novel homocoupling
reaction of N′-tosyl arylhydrazine may proceed via a Pd(0)-
mediated redox cycle.10 Moreover, N′-tosyl arylhydrazine might
have an efficient and special role in the in situ regeneration of
the reductive Pd(0) active species from the oxidative Pd(II)
species.11
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (no. 20772161, 21262008), the
Introduction of Innovative R&D Team Program of Guangdong
Province (no. 2009010058) and The National High-tech R&D
Program of China (863 Program, no. 2013AA090203).
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