An efficient Pd-catalyzed coupling of hydrazine derivatives with aryl halides

Article abstract of DOI:10.1055/s-0030-1260337

A convenient method for the intermolecular N-arylation of hydrazides with aryl halides in the presence of a palladium catalyst, a MOP-type ligand, and Cs₂CO₃ is reported. The reaction gives coupling products in good to excellent yiel

Full text of DOI:10.1055/s-0030-1260337

LETTER
2555
An Efficient Pd-Catalyzed Coupling of Hydrazine Derivatives with Aryl
Halides
Coupling of
H
a
ydrazine
D
e
rivatives
w
i
g
th
A
ryl
H
alid
-
es Fang Ma,a Zhi-Yong Peng,a Wan-Fang Li,a Xiao-Min Xie,a Zhaoguo Zhang*a,b
a
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. of China
Fax +86(21)54748925; E-mail: zhaoguo@sjtu.edu.cn
b
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China
Received 19 July 2011
economic standpoint, it presents potential problems asso-
ciated with the formation of byproducts such as arene and
aniline, along with the desired products. In addition, the
reaction conditions remain relatively harsh because of the
required use of strong base, t-BuONa, which results in
poor functional group tolerance. We have recently synthe-
sized a series of bulky and electron-rich MOP-type
ligands and applied them in Pd-catalyzed coupling reac-
tions between unreactive aryl halides and amines.16 To
continue our interest in Pd-catalyzed C–N bond formation
reactions, we decided to focus on the preparation of N-aryl
hydrazides. Herein, we report a Pd-catalyzed coupling
reaction of aryl halides and BocNHNHBoc using 2-di-
tert-butylphosphino-2¢-isopropoxy-1,1¢-binaphthyl as the
ligand to afford monoaryl-substituted hydrazines.
Abstract: A convenient method for the intermolecular N-arylation
of hydrazides with aryl halides in the presence of a palladium cata-
lyst, a MOP-type ligand, and Cs2CO3 is reported. The reaction gives
coupling products in good to excellent yields and has a high toler-
ance towards a wide spectrum of functional groups.
Key words: palladium, MOP ligands, aryl halide, N-aryl hy-
drazides, N-arylation
N-Aryl hydrazines have many important applications in
organic synthesis and industry.1 Particularly, they are ver-
satile intermediates in the preparation of biologically ac-
tive nitrogen-containing heterocyclic compounds, such as
pyrazoles,2 indoles,3 indazoles,4 pyridazines,5 and carba-
zoles.6
The tert-butyloxycarbonyl (Boc) group is a very conve-
nient amine protecting group because it is easy to remove;
this led us to test the coupling reaction of 1-bromo-4-
methylbenzene (1b) and (NH2NHBoc) with palladium
and 2-di-tert-butylphosphino-2¢-isopropoxy-1,1¢-binaph-
thyl as the catalyst and Cs2CO3 as the base in 1,4-dioxane
at 100 °C. Although the catalyst was very effective for the
amination of aryl halides with primary amines,16 it gave
poor regioselectivity (Figure 1; A/B = 27:59). Fortunate-
ly, no diaryl-substituted hydrazides were formed in the
reaction.
N-Aryl hydrazines have traditionally been prepared either
by stoichiometric oxidation of anilines to the correspond-
ing diazonium salts and subsequent reduction,7 or by elec-
trophilic amination of highly electron-rich arenes,8
aryllithium reagents,9 aryl magnesium reagents,9a and
arylzinc halides10 with dialkyl azodicarboxylates. Howev-
er, these methods often employ expensive reagents or
starting materials and require multi-step syntheses and/or
harsh conditions, which limits their tolerance towards
functional groups. In the past few decades, novel prepara-
tions of aryl-substituted hydrazines using transition-metal
catalysts have attracted growing attention. Copper acetate
catalyzed reaction between di-tert-butyl hydrazine-1,2-
dicarboxylate (BocNHNHBoc) and arylbismuth com-
pounds was reported to afford aryl-substituted hydra-
zines.11 Organoboronic acids reacting with tert-butyl
carbazate12 or azodicarboxylate13 were also efficient
methods for the preparation of aryl-substituted hydra-
zines. Pd- or Cu-catalyzed cross-coupling reactions be-
tween aryl halides and hydrazine derivatives also led to
aryl hydrazines.14 However, this reaction was case-depen-
dent and high yields were obtained only when activated
aryl bromides (para-substituted with electron-withdraw-
ing groups), aryl iodides, or specific halogenated hetero-
cycles were employed. Recently, a Pd-catalyzed coupling
reaction of aryl chlorides and hydrazine has been report-
ed.15 Although hydrazine is an ideal substrate from an
H
N
O
N
O
H2N
N
H
O
O
A
B
Figure 1
To solve the regioselectivity and purification problems,
we investigated the Pd-catalyzed coupling reaction of
1-bromo-4-methylbenzene (1b) with BocNHNHBoc. A
set of ligands L1–L9 (Figure 2) were screened and the re-
sults are summarized in Table 1.
Most ligands failed to give the desired product (Table 1,
entries 1–8). Xantphos (L1) and DPPF (L2), which are ef-
ficient ligands for amidation reactions of iodide and bro-
mide substrates,14a,17 were ineffective for the amidation of
1-bromo-4-methylbenzene (1b) due to the fact that these
SYNLETT 2011, No. 17, pp 2555–2558
Advanced online publication: 27.09.2011
DOI: 10.1055/s-0030-1260337; Art ID: W15711ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2556
F.-F. Ma et al.
LETTER
PPh2
PPh2
Table 1 Optimized Reaction Conditions for the Coupling of 1-Bro-
mo-4-methylbenzene and Di-tert-butylhydrazine-1.2-dicarboxylatea
PPh2
PPh2
O
Fe
PCy3 HBF4
Pt-Bu3 HBF4
Boc
Br
N
Pd, base
L, solvent
NHBoc
BocHN
+
NHBoc
L1
L2
L3
L4
1b
2b
Entry
1
Ligand
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
L9
L9
L9
L9
L9
L9
L9
Base
Solvent
Conversion (%)b
P(Cy)2
P(Cy)2
P(t-Bu)2
MeO
OMe Me2N
Me2N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
t-BuOH
0.7
0.0
2
L5
L6
L7
3
0.0
4
0.6
P(t-Bu)2
Oi-Pr
P(Cy)2
OMe
5
0.0
6
0.3
L8
L9
7
26.5
1.8
Figure 2 Structures of ligands L1–L9
8
9
100.0
92.0
65.7
4.8
ligands showed lower reactivity for oxidative addition of
inactivated aryl halides. Although ligands L3–L9 were
shown to promote oxidative addition of some extremely
hindered aryl chlorides,16,18 only 2-di-tert-butylphosphi-
no-2¢-isopropoxy-1,1¢-binaphthyl (L9) was found to be
effective in the present reaction. Among the ligands test-
ed, L9 is the bulkiest and most electron-rich. It was found
that greater ligand bulk facilitated reductive elimination
and led to higher reactivity.
10
11
12
13
14
15
16
17
K2CO3
KOH
t-BuONa
Cs2CO3
Cs2CO3
K3PO4
0.6
93.1
93.1
81.3
17.5c
toluene
The effects of bases and solvents on the reaction were also
investigated. Phosphate and carbonate bases were found
to be more effective than stronger bases such as t-BuONa
and KOH (Table 1, entries 9–13). Solvents seemed to be
inconsequential for the reaction; good to excellent conver-
sion was obtained in either 1,4-dioxane, t-BuOH, or tolu-
ene as solvents (Table 1, entries 9 and 14–15). When
Pd(OAc)2 was employed as the Pd source, the yield de-
creased drastically (Table 1, entry 17). Based on these re-
sults, the optimized reaction conditions were determined
as follows: Cs2CO3 as the base, 1,4-dioxane as the solvent,
and Pd(0)/L9 as the catalyst combination (Table 1, entry
9).
toluene
Cs2CO3
1,4-dioxane
a Reagents and conditions: 1-Bromo-4-methylbenzene (1.0 mmol),
di-tert-butylhydrazine-1.2-dicarboxylate (1.2 mmol), base (1.5
mmol), solvent (4.0 mL), [Pd(dba)2] (0.02 mmol), L (0.03 mmol),
100 °C, 20 h.
b Determined by GC analysis.
c Pd(OAc)2 was used as Pd source.
mophenyl)ethanone was employed as substrate, no com-
petitive ketone arylation was observed (Table 2, entry 10).
When electron-rich phenyl bromides, such as 1e, 1i, and
1m were employed, 4 mol% catalyst loading was required
for full conversion (Table 2, entries 5, 9, and 13). More-
over, for electron-neutral and electron-rich chloroben-
zenes (Table 2, entries 16, 18, 19, and 21), higher catalyst
loadings were necessary to obtain moderate to good
yields. Meanwhile, the reaction was not limited to phenyl
halides since naphthalene and heteroaromatic halides
(Table 2, entries 12 and 15) also gave the desired products
in moderate yields.
The substrate scope was studied by employing various
aryl bromides and chlorides. Under the optimized reaction
conditions, a wide variety of substrates, including aryl,
heteroaryl, and naphthalene halides, readily coupled with
BocNHNHBoc to produce N-aryl hydrazides in moderate
to high yields. The results are shown in Table 2.
Generally, aryl bromides substituted with electron-rich,
electron-neutral, or electron-poor groups at the para or
meta position worked equally well, providing the corre-
sponding coupling products in high yields. Various func-
tional groups, such as tert-butyl, methyl, methoxy, fluoro,
chloro, trifluoromethyl, trifluoromethoxy, acetyl, and cy-
ano were tolerated under these conditions. For a bromo-
chloroarene substrate (Table 2, entry 7), the reaction
occurred selectively at the C–Br bond. When 1-(4-bro-
The reaction was significantly affected by steric factors.
For aryl halides with a substituent at the ortho position,
such as 2-methyl or 2-methoxy bromobenzenes, no de-
sired coupling products were obtained, even when the less
bulky ligand L8 was employed. To prepare ortho-substi-
tuted aryl hydrazides, the coupling of NH2NHBoc with
Synlett 2011, No. 17, 2555–2558 © Thieme Stuttgart · New York

LETTER
Coupling of Hydrazine Derivatives with Aryl Halides
2557
Table 2 General Scope of Reaction with Di-tert-butyl Hydrazine-
1,2-dicarboxylate using [Pd(dba)2] and L9a
Table 3 ortho-Substituted Aryl Halides Coupling with tert-Butyl
hydrazinecarboxylate using [Pd(dba)2] and L9a
X
NHNHBoc
Pd(dba)2, L9
Entry
Starting Ar
material
X
Product Yield
(%)b
NH2NHBoc
+
Cs2CO3,1,4-dioxane
R
R
1
2
1a
1b
1c
Ph
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2a
2b
2c
2d
2e
2f
96
1
3
4-MeC6H4
4-t-BuC6H4
3,5-MeC6H3
4-MeOC6H4
4-FC6H4
96
Entry
Substrate R
X
Product Yield (%)b
89c
91
1
2
3
4
1r
1s
CH3
OCH3
Br
3r
3s
3r
3s
94c
88
94
81
3
4
1d
1e
Br
Cl
Cl
5
87c
93
1r¢
1s¢
CH3
6
1f
OCH3
a Reagents and conditions: Aryl halide (1.0 mmol), tert-butyl hydra-
zinecarboxylate (1.2 mmol), base (1.5 mmol), solvent (4.0 mL),
[Pd(dba)2] (0.040 mmol), L9 (0.060 mmol), 100 °C, 20 h.
b Isolated yield.
7
1g
1h
1i
4-ClC6H4
2g
2h
2i
85
8
4-CF3C6H4
4-CF3OC6H4
4-MeCOC6H4
4-CNC6H4
2-C10H10
87
9
95c
75
c [Pd(dba)2] (0.020 mmol), L9 (0.030 mmol) were used.
10
11
12
13
14
15
16
17
18
19
20
21
22
1j
2j
On the basis of these observations, we proposed the fol-
lowing catalytic cycle (Scheme 1). Initially, the hy-
drazides coordinate to ArPdX (II), which arises from
oxidative addition of Pd(0) to the aryl bromide. With the
two nitrogen atoms, the five-coordinate complex C is
formed, and subsequent abstraction of HBr by the base
and intramolecular rearrangement affords complex D.
Finally, reductive elimination of the monoarylated
hydrazide forms the amidato complex D to give the prod-
uct and regenerate the Pd(0) complex. When ortho-substi-
tuted aryl halides and BocNHNHBoc were employed as
substrates, it was more difficult to form complex C due to
steric hindrance, thus no products were observed. Al-
though it seemed that the Pd-catalyzed C–N bond forming
reaction occurs upon deprotonation of the more acidic
NHBoc proton, steric factors are important and free NH2
is more nucleophilic. Therefore, ortho-substituted aryl ha-
lides coupled with NH2NHBoc under the optimized reac-
tion conditions to give desired products with excellent
regioselectivity.
1k
1l
2k
2l
77
68
1m
1n
1o
1a¢
1h¢
1b¢
1e¢
1p
1m¢
1q
3-MeOC6H4
3-CF3C6H4
3-pyridine
Ph
2m
2n
2o
2a
2h
2b
2e
2p
2m
2q
89c
95
64c
75c
88
4-CF3C6H4
4-MeC6H4
4-MeOC6H4
4-EtO2CC6H4
3-MeOC6H4
3-EtO2CC6H4
75c
58c
73
71c
87
a Reagents and conditions: Aryl halide (1.0 mmol), di-tert-butylhy-
drazine-1,2-dicarboxylate (1.2 mmol), base (1.5 mmol), solvent (4.0
mL), [Pd(dba)2] (0.020 mmol), L9 (0.030 mmol), 100 °C, 20 h.
b Isolated yield.
LPd(0)
ArNR1NHR2
ArX
c [Pd(dba)2] (0.040 mmol), L9 (0.060 mmol).
R1
ortho-substituted aryl halides was examined; the results
are detailed in Table 3.
L
N
NHR2
Pd
X
Ar
Pd
Ar
L
As shown in Table 3, we obtained the products in high
yields and excellent regioselectivity for all ortho-substit-
uent substrates. Regardless of whether the ortho-substitu-
ent was methyl or methoxy, the corresponding amination
products were isolated with good yields. The two regioi-
somers were clearly distinguished from each other in the
1H NMR spectra, since the amination products contained
two distinct exchangeable NH signals.
D
NHR1NHR2
base HX
R1
HN
L
base
NHR2
Pd
Ar
X
C
Scheme 1 Proposed reaction mechanism
The reaction was also applicable to other dicarboxylate
hydrazine derivatives, such as diethyl hydrazine-1,2-di-
carboxylate. In this case, phenylhydrazide was obtained in
quantitative yields by the reaction of 1a.
In summary, we have employed 2-di-tert-butylphosphi-
no-2¢-isopropoxy-1,1¢-binaphthyl as a ligand for the syn-
thesis of aryl hydrazines by the Pd-catalyzed coupling of
Synlett 2011, No. 17, 2555–2558 © Thieme Stuttgart · New York

2558
F.-F. Ma et al.
LETTER
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ortho substituted aryl halides, similar reactions can be re-
alized by replacing BocNHNHBoc with NH2NHBoc as
the nucleophile, in which case good to excellent yields
were also obtained. The reaction provides a useful method
for preparation of aryl-substituted hydrazides with good
functionality tolerance.
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Acknowledgment
We thank the National Natural Science Foundation of China for
financial support.
References and Notes
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(19) General Procedure: An oven-dried Schlenk tube was
evacuated and backfilled with nitrogen. The Schlenk tube
was charged with [Pd(dba)2] (11.4 mg, 2.0 mmol% ), ligand
(3.0 mmol%), mono- or di(t-butoxycarbonyl)hydrazine
(1.2 mmol), and base (1.5 mmol), and capped with a rubber
septum. The Schlenk tube was evacuated and backfilled with
nitrogen three times. To the Schlenk tube were added aryl
halide (1.0 mmol) and solvent (4.0 mL). The septum was
replaced with a Teflon screw-cap and the mixture was heated
to 100 °C with stirring for 20 h. Then reaction mixture was
allowed to cool to room temperature, diluted with ethyl
acetate, filtered through Celite, and concentrated under
reduced pressure. The crude material was purified by
column chromatography on silica gel (ethyl acetate–
hexanes, 1:1→1:20)
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