Nickel-catalyzed N-arylation of benzophenone hydrazone with bromoarenes

Article abstract of DOI:10.1039/c3ra46288a

A nickel-catalyzed method for the cross-coupling of benzophenone hydrazone with aryl bromides is described. The use of a simple Ni(ii)/NHC catalyst leads to the arylated hydrazones in good or acceptable yields. This protocol provides a simple, convenient alternative to the synthesis of arylhydrazines.

Full text of DOI:10.1039/c3ra46288a

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Nickel-catalyzed N-arylation of benzophenone
hydrazone with bromoarenes†
Cite this: RSC Adv., 2014, 4, 3364
a
a
Wei Wu,ab Xin-Heng Fan, Li-Peng Zhangab and Lian-Ming Yang
*
*
Received 4th November 2013
Accepted 2nd December 2013
DOI: 10.1039/c3ra46288a
www.rsc.org/advances
A nickel-catalyzed method for the cross-coupling of benzophenone employed in catalytic cross-couplings of hydrazine-based
hydrazone with aryl bromides is described. The use of a simple Ni(II)/ nucleophilic substrates. Herein, we wish to present our initial
NHC catalyst leads to the arylated hydrazones in good or acceptable ndings on the nickel-catalyzed arylation of benzophenone
yields. This protocol provides a simple, convenient alternative to the hydrazone for arylhydrazine synthesis.
synthesis of arylhydrazines.
Benzophenone hydrazone is one of the most commonly
employed hydrazine surrogates because it is readily available
and conveniently used, and the resulting N-arylated benzophe-
none hydrazone are easily deprotected to afford the corre-
sponding free arylhydrazines. Initially, the cross-coupling
between p-bromotoluene (1a) and benzophenone hydrazone
was selected as a model reaction to screen the optimal reaction
conditions (Table 1). Since our previous work14 has proven that
a combination of [Ni]/N-heterocyclic carbene (NHC) was oen
an catalyst system more suitable for nickel-catalyzed aromatic
aminations, the two model substrates was rst subjected to the
conditions of Ni(PPh3)2Cl2/IPr$HCl/t-BuONa at room tempera-
ture in dioxane. Encouragingly, the coupling reaction was found
to proceed with 54% yield of the product 2a (entry 1). Further-
more, one advantage of the reaction is that a simple NiII
complex rather than the hard-to-handle Ni0 source (highly
sensitive to air/moisture and toxic) was employed as precatalyst.
In contrast, this cross-coupling did not occur in the absence of
the nickel catalytic system whether at room temperature or
elevated temperatures (entry 2), where only a decomposition of
benzophenone hydrazone was observed. Our experiments
showed that benzophenone hydrazone partially decomposes
into free hydrazine and benzophenone under the basic condi-
tions, and the decomposition exacerbates with elevating
reaction temperatures (entry 2). Obviously, this decomposition
side-reaction would hamper the achievement of the desired
product in excellent yields because it competes against the
desired coupling reaction. Further experimentation determined
a balance point of reaction temperatures between maximizing
the desired coupling reaction and minimizing the decomposi-
tion side-reaction, achieving a good yield of 73% (entry 3). A
survey of other common nickel sources suggested that all the
NiII precursors have a certain degree of efficacy in this trans-
formation, affording the desired product in 50–60% yields
Arylhydrazines are a highly valuable class of “building blocks”
in the synthesis of important nitrogen-containing heterocycle
frameworks such as indazoles,1 indoles (by the Fisher indole
synthesis),1,2 arylpyrazoles,1,3 and arytriazoles.1,4 Traditionally,
arylhydrazines are prepared via the stoichiometric oxidation of
anilines to the corresponding diazonium salts and subsequent
reduction with tin(II) salts or sulte ions.5 The classical method
suffers from harsh reaction conditions, limited functional
group tolerability, generation of large amounts of wastes (tin
wastes), and so on. Modern metal-catalyzed cross-coupling
technology provides an attractive alternative to the synthesis of
arylhydrazines, which has been applied over recent years.6–11 In
this regard, successful examples mainly include: (1) palladium-
catalyzed reactions such as Pd-catalyzed arylations of benzo-
phenone hydrazone6 or protected hydrazides,7 and Pd-catalyzed
direct C–N coupling of hydrazine with aryl chloride/tosylates;8
(2) Cu-catalyzed processes such as Cu-promoted arylation of
Boc-protected hydrazine,9 acylhydrazines,10 phenylhydrazine,11
and free hydrazine.12 However, in the palladium catalysis, noble
metal palladium and special ligands (usually more expensive
than Pd reagents) are required, and for the Cu-catalyzed reac-
tions, good outcomes depend substantially on the use of costly
iodoarene electrophiles. On the other hand, cheap and practical
nickel-based catalysts, a well-established partner of palladium
systems in C–N coupling reactions,13 have not yet been
aBeijing National Laboratory for Molecular Sciences (BNLMS), Key laboratory of Green
Printing, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P.R.
China. E-mail: yanglm@iccas.ac.cn; Fax: +86-10-62559373; Tel: +86-10-62565609
bGraduate School of Chinese Academy of Sciences, Beijing 100049, P.R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra46288a
3364 | RSC Adv., 2014, 4, 3364–3367
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
(entries 4–7). The nature of the bases used is crucial for this
reaction. For example, strong base t-BuOK (entry 8) led to a
substantial decomposition of benzophenone hydrazone and a
complicated outcome; weaker bases such as Cs2CO3 (entry 9)
and K3PO4 (entry 10) as well as a special base NaH (entry 11) did
not work at all. As shown, the catalytic activity of the Ni catalyst
was highly relevant to ancillary ligands since other types of
ligands (entries 12–14) and even SIPr$HCl (entry 15) (a saturated
counterpart of IPr$HCl) proved to be ineffective. For the
solvents used, THF (entry 16) was far inferior but toluene (entry
17) comparable to dioxane. Additionally, our experiments
showed that p-chlorotouene was intact and p-iodotoluene
afforded a only slightly better yield (75%) under the optimized
reaction conditions as established in entry 3 of Table 1.
Several commonly-used hydrazine equivalents were also
tested in the N-arylation reaction (Scheme 1). Consequently, it
was found that these other hydrazine surrogates did not
undergo the cross-coupling with p-bromotoluene under our
optimal conditions. The outcomes cannot yet be clearly
explained at present and further studies are needed.
Scheme 1
very high in many cases. This may be likely because the
complicated side-reactions always, to more or less degree, exist
in the present reaction system. Taking unsubstituted, electron-
neutral bromobenzene (2d) as the standard, the electronic
nature of the substituents on aryl bromides does not seem to
produce signicant inuence on the reaction (2a, 2e, 2i, 2j, and
2m). And quite different from usual metal-catalyzed coupling
reactions, the adverse inuence of electron-donating groups on
the electrophilic partner is less than that of the electron-with-
drawing ones (2a, 2e, and 2m vs. 2i and 2j). The reason is
unclear at this time. On the other hand, the reaction is
extremely sensitive to the steric effects of aryl bromides. Even
when the substituents are at the meta position of bromoarenes,
Next, we examined N-arylation of benzophenone hydrazone
with some representative bromoarenes under the optimized
conditions (Table 2). Generally, the coupling reaction indeed
took place with various aryl bromides but the yields were not
Table 2 Nickel-catalyzed N-arylation of benzophenone hydrazine
with aryl bromidesa
Table 1 Optimization of conditions for the nickel-catalyzed cross-
coupling of p-bromotoluene with benzophenone hydrazonea
Entry [Ni]
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Ni(PPh3)2Cl2 IPr$HClc
None None
Ni(PPh3)2Cl2 IPr$HCl
t-BuONa Dioxane 54d
t-BuONa Dioxane 0e
t-BuONa Dioxane 73
t-BuONa Dioxane 57
t-BuONa Dioxane 52
t-BuONa Dioxane 59
t-BuONa Dioxane 58
t-BuOK
CsCO3
K3PO4
NaH
2a 73%
2e 70%
2b 58%
2f 59%
2c 44% (46%b)
2d 74%
Ni(acac)2
NiCl2$6H2O
C1f
IPr$HCl
IPr$HCl
IPr$HCl
IPr$HCl
C2g
Ni(PPh3)2Cl2 IPr$HCl
Ni(PPh3)2Cl2 IPr$HCl
Ni(PPh3)2Cl2 IPr$HCl
Ni(PPh3)2Cl2 IPr$HCl
Dioxane NDh
Dioxane NRi
Dioxane NR
Dioxane NR
2g 22%b
2h 20%b
9
10
11
12
13
14
15
16
17
j
Ni(PPh3)2Cl2 PCy3
t-BuONa Dioxane
t-BuONa Dioxane
t-BuONa Dioxane
0
0
0
Ni(PPh3)2Cl2 DPPFk
Ni(PPh3)2Cl2 Phenal
Ni(PPh3)2Cl2 SIPr$HClm t-BuONa Dioxane
0
Ni(PPh3)2Cl2 IPr$HCl
Ni(PPh3)2Cl2 IPr$HCl
t-BuONa THF
23
2i 65%
2j 60%
2k 43%
2o 50%
2l 50%
2p 35%
t-BuONa Toluene 70
a
Reaction conditions: p-bromotoluene (1.0 mmol), the hydrazone (1.3
mmol), [Ni] (0.05 mmol), ligand (0.1 mmol), base (1.3 mmol), solvent
b
c
(2.5 mL), 50 ꢀC,
5
h.
Isolated yield.
chloride.
IPr$HCl: 1,3-bis(2,6-
d
diisopropylphenyl)imidazolium
A
room-temperature
e
reaction. Reactions conducted at rt, 60 ꢀC, and 100 ꢀC, respectively.
f
g
h
C1: Ni(PPh3)2(1-naphthyl)Cl. C2: Ni(PPh3)2(phenyl)Br. Complicated
2m 66%
2n 41%
i
j
products not determined. No reaction. PCy3: tricyclohexylphosphine.
a
k
l
DPPF: 1,10-bis(diphenylphosphino)ferrocene (0.05 mmol). Phena:
Conditions: bromoarene (1.0 mmol), hydrazone (1.3 mmol), Ni
(0.05 mmol), IPr$HCl (0.1 mmol) t-BuONa (1.3 mmol), dioxane
(2.5 mL), 50 ꢀC, 5 h; isolated yield. b The reaction conducted at 100 ꢀC.
m
1,10-phenanthroline
(0.05
mmol).
SIPr$HCl:
1,3-bis(2,6-
diisopropylphenyl)-4,5-dihydroimidazolium chloride (0.1 mmol).
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 3364–3367 | 3365

View Article Online
RSC Advances
Communication
the yields diminished apparently (2b, 2f, 2k, and 2o); the ortho-
substituted aryl bromides (more sterically demanded) gave
much lower yields of the coupled products (2c, 2g, 2h, and 2n)
with appreciable amounts of the starting material 1 recovered,
and the elevated reaction temperature scarcely help the increase
of yields (2c, 2g, and 2h). p-Dibromobenzene was smoothly
mono-arylated in a moderate yield (2l), and heteroaryl bromide
was also coupled with benzophenone hydrazone depite that the
yield was not high (2p). It must be pointed out that the current
conditions are intolerant of some functional groups such as
cyano and ester, which were found to react with the free amino
group of benzophenone hydrazone, and thus both bromo-ben-
zonitrile and benzoate are not suitable substrates for the
reaction.
Aryl benzophenone hydrazones 2 may be regarded as a form
of protected arylhydrazines and can be readily converted into
the corresponding arylhydrazines by acidic hydrolysis. In the
cases shown in Scheme 2, the hydrazone 2 was completely
deprotected at room temperature in a mixture of concentrated
hydrochloric acid and methanol (10 : 1 v/v), affording an aryl-
hydrazine hydrochloride 3 simply by ltration and washing with
CH2Cl2. Note that achieving only modest isolated yields results
mainly from easy loss of the salt 3 in the purication process.
In the practical use, oen it is not necessary to hydrolyzed
aryl benzophenone hydrazones and isolate arylhydrazines
beforehand. For example, a useful class of intermediate
compounds 4 in the synthesis of N,N-diarylhydrazines15 can be
prepared easily from the exchanging reaction of aryl benzo-
phenone hydrazones 2 with 2-pyridinealdehyde in excellent
yields (Scheme 3); when the hydrazone 2 is treated with an
enolizable ketone,6c the indole product 5 can be provided by the
Fischer reaction in a one-pot mode (Scheme 4).
Scheme 4
This protocol provides a simple, convenient, and inexpensive
route to arylhydrazines. Studies to improve the efficiency of Ni-
based catalyst systems, expand the scope of electrophilic
coupling partners, and understand the mechanistic details of
reaction are under way, and the results will be reported in due
course.
Experimental section
General procedure for nickel-catalyzed cross-couplings of
benzophenone hydrazone with aryl bromines
An oven-dried 25 mL three-necked ask was charged with
benzophenone hydrazone (1.3 mmol), Ni(PPh3)2Cl2 (0.05
mmol), IPr$HCl (0.10 mmol), and t-BuONa (1.3 mmol). The
ask was evacuated and backlled with nitrogen, with the
operation being repeated twice. A solution of the aryl bromine 1
(1.0 mmol) in dioxane (2.5 mL) was added via syringe, and
stirred at an oil bath of 50 ꢀC for 5 h. The reaction mixture was
diluted with H2O (20 mL) and ethyl acetate (30 mL). The organic
layer was separated, washed sequentially with brine (40 mL) and
water (40 mL), and dried over anhydrous Na2SO4. Concentration
under vacuum gave the crude material which was puried by
Al2O3 column chromatography (petroleum ether/EtOAc, 10 : 1)
to give the desired product 2 with the yields as listed in Table 2.
In conclusion, we have rst demonstrated the feasibility for
nickel-catalyzed cross-couplings of hydrazine-type substrates
with haloarenes. Aryl benzophenone hydrazones can be
prepared via nickel-catalyzed N-arylation of benzophenone
hydrazone with bromoarenes under relatively mild conditions.
Acknowledgements
The authors thank National Natural Science Foundation of
China (NSFC) (Project no. 20872142 and 21102150) for nancial
support of this work.
Notes and references
Scheme 2
1 A. R. Katriazky and A. F. Pozharskij, Handbook of Heterocyclic
Chemistry, Pergamon, Oxford, 2nd edn, 2000, p. 499.
2 G. R. Humphrey and J. T. Kuethe, Chem Rev., 2006, 106, 2875.
´
´
´
3 S. Fustero, M. Sanchez-Rosello, P. Barrio and A. Simon-
Fuentes, Chem. Rev., 2011, 111, 6984.
4 K. T. Potts, Chem. Rev., 1961, 61, 87.
5 (a) R. H. Poirer and F. Benington, J. Am. Chem. Soc., 1952, 74,
3192; (b) A. S. S. Peter and W. K. Norman, J. Org. Chem., 1958,
23, 1599; (c) I. D. Entwistle, B. A. W. Johnstone and
A. H. Wilby, Tetrahedron, 1982, 38, 419.
Scheme 3
3366 | RSC Adv., 2014, 4, 3364–3367
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
6 (a) J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2090; (b)
S. Wagaw, B. H. Yang and S. L. Buchwald, J. Am. Chem.
Soc., 1998, 120, 6621; (c) S. Wagaw, B. H. Yang and
S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 10251; (d)
C. Mauger and G. Mignani, Adv. Synth. Catal., 2005, 347,
773; (e) A. Klapars, J. C. Antilla, X. Huang and
C.-G. Cho, Tetrahedron Lett., 2004, 45, 117; (d) P. Starkov,
ˇ
¨
I. Zemskov, R. Sillard, O. Tsubrik and U. Maeorg,
Tetrahedron Lett., 2007, 48, 1155; (e) M. S. Lam, H. W. Lee,
A. S. C. Chan and F. Y. Kwong, Tetrahedron Lett., 2008, 49,
6192; (f) L. Jiang, X. Lu, H. Zhang, Y. Jiang and D. Ma,
J. Org. Chem., 2009, 74, 4542.
S. L. Buchwald, J. Am. Chem. Soc., 2001, 123, 7727; (f) 10 (a) H. Suzuki and A. Yamamoto, J. Chem. Res., Synop., 1992,
A. C. Ferretti, C. Brennan and D. G. Blackmond, Inorg.
Chim. Acta, 2011, 369, 292; (g) C. Mauger and G. Mignani,
280; (b) X. D. Xiong, Y. W. Jiang and D. Ma, Org. Lett., 2012,
14, 2552.
Synth. Commun., 2006, 36, 1123; (h) C. Mauger and 11 H. Rao, Y. Jin, H. Fu, Y. Yang and Y. Zhao, Chem.–Eur. J.,
G. Mignani, US Pat. 2007243999. 2006, 12, 3636.
7 (a) Z. Wang, R.-T. Skerlj and G.-J. Bridger, Tetrahedron Lett., 12 J. Chen, Y. Zhang, W. Hao, R. Zhang and F. Yi, Tetrahedron
1999, 40, 3543; (b) J. B. Arterburn, K. V. Rao, R. Ramdas Lett., 2013, 69, 613.
and B. R. Dible, Org. Lett., 2001, 3, 1351; (c) Y.-K. Lim, 13 B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang,
K.-S. Lee and C.-G. Cho, Org. Lett., 2003, 5, 979; (d)
N. Halland, M. Nazare, J. Alonso, O. R'kyek and
A. Lindenschmidt, Chem. Commun., 2011, 47, 1042.
8 (a) R. J. Lundgren and M. Stradiotto, Angew. Chem., Int. Ed.,
2010, 49, 8686; (b) A. DeAngelis, D.-H. Wang and
S. L. Buchwald, Angew. Chem., Int. Ed., 2013, 52, 1.
A. M. Resmerita, N. K. Garg and V. Percec, Chem. Rev.,
2011, 111, 1346.
14 (a) C. Chen and L.-M. Yang, J. Org. Chem., 2007, 72, 6324; (b)
C.-Y. Gao and L.-M. Yang, J. Org. Chem., 2008, 73, 1624; (c)
J.-H. Huang and L.-M. Yang, Org. Lett., 2011, 13, 3750; (d)
X.-H. Fan, G. Li and L.-M. Yang, J. Organomet. Chem., 2011,
696, 2482.
¨
9 (a) O. Loog, U. Maeorg and U. Ragnarsson, Synthesis, 2000,
1591; (b) M. Wolter, A. Klapars and S. L. Buchwald, Org. 15 W. Wu, X.-L. Li, X.-H. Fan and L.-M. Yang, Eur. J. Org. Chem.,
Lett., 2001, 3, 3803; (c) K.-Y. Kim, J.-T. Shin, K.-S. Lee and
2013, 862.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 3364–3367 | 3367