Communications
DOI: 10.1002/anie.201003764
Amination
Palladium-Catalyzed Cross-Coupling of Aryl Chlorides and Tosylates
with Hydrazine**
Rylan J. Lundgren and Mark Stradiotto*
Aryl hydrazines are highly valuable intermediates in the
synthesis of a number of important nitrogen-containing
heterocyclic frameworks such as indoles (through the Fischer
indole synthesis),[1] indazoles, aryl pyrazoles, and aryl tri-
azoles.[2] In some cases, hydrazine reacts with haloarenes
directly in nucleophilic aromatic substitution reactions; how-
ever, such reactions typically occur at high temperatures,
and/or only with highly electron-deficient haloarenes, or at
selected positions of halogenated heterocycles.[3,4] The pre-
vailing method for the preparation of aryl hydrazines relies on
the stoichiometric oxidation of anilines to their corresponding
diazonium salts and subsequent reduction.[5] The transition-
metal-catalyzed cross-coupling of aryl halides and hydrazine
represents an attractive alternative to the traditional synthesis
of aryl hydrazines. However, despite the tremendous progress
made in the field of Buchwald–Hartwig amination reactions
over the past decade,[6] no such reaction has been reported.
Hydrazine presents a number of potential problems in
palladium-catalyzed cross-coupling reactions. First, hydrazine
is an aggressive reductant of both organic and inorganic
substrates,[7] and could reduce key PdIIAr(X) species, thereby
promoting the generation of catalytically inactive Pd0 aggre-
gates, as well as reducing aryl halide substrates by hydro-
proceed rapidly under relatively mild conditions with excel-
lent monoarylation selectivity, thus providing direct access to
aryl hydrazines.
We began by screening a variety of ligands (Scheme 1)
and reaction conditions (Table 1) in the hope of effecting the
cross-coupling of 4-phenylchlorobenzene with readily avail-
Table 1: Optimization of the palladium-catalyzed cross-coupling of
4-phenylchlorobenzene and N2H4·H2O.[a]
Entry Variation from standard conditions
Conv. [%] Yield [%]
1
2
3
4
5
6
7
8
none
9 mol% of L12
>99
>99
>99
<10
0
65
51
90
45
65
95
>99
99
>99
73
61
79
0
toluene instead of 1,4-dioxane
DMA instead of 1,4-dioxane
DCE instead of 1,4-dioxane
0.3 M of ArCl instead of 0.1M
4 equiv of hydrazine instead of 2 equiv
3 equiv of NaOtBu instead of 2 equiv
KOH instead of NaOtBu
Cs2CO3 instead of NaOtBu
ArBr instead of ArCl
0
35
24
66
24
14
45
80
76
69
9
10
11
dehalogenation. Second, aryl hydrazines can undergo metal-
[8]
À
mediated N N bond cleavage, thus resulting in the forma-
12[b] N2H4·HCl instead of N2H4·H2O
13[b] N2H4·HCl instead of N2H4·H2O, 658C
14[b,c] [PdCl2(MeCN)2] instead of [{Pd-
(cinnamyl)Cl}2]
tion of undesired aniline by-products. Finally, and most
importantly, the product aryl hydrazines still possess three
À
À
reactive N H bonds that can undergo further C N cross-
coupling, thus leading to polyarylated products. Some of these
challenges have been circumvented by the use of hydrazine
surrogates with attenuated reactivity such as benzophenone
hydrazone[9] or protected hydrazides,[10] although such strat-
egies are not ideal from efficiency or economic standpoints. In
addition, aryl- or alkyl-substituted hydrazines, which are less
prone to undergo some of the above described detrimental
side reactions, have been employed as substrates.[11] Herein,
we report on a palladium catalyst system and reaction
conditions that allow, for the first time, the cross-coupling of
aryl chlorides and tosylates with hydrazine. The reactions
15[b,c] [Pd(dba)2] instead of [{Pd(cinnamyl)Cl}2]
99
<10
60
0
16
no [Pd], no ligand
[a] Standard reaction conditions: reactions were carried out on a
0.2 mmol scale, [Pd]/L=1:1.5, N2H4·H2O (2 equiv), and NaOtBu
(2 equiv), 1108C, in 1,4-dioxane (0.1m in substrate). Conversions and
yields were determined by GC analysis. [b] Employing N2H4·HCl and
NaOtBu (3.5 equiv). [c] At 908C. dba=trans,trans-dibenzylideneacetone.
able hydrazine sources. A series of structurally diverse
phosphane and N-heterocyclic carbene ligands were tested
employing [{Pd(cinnamyl)Cl}2] (1.5 mol%) and the ligand
(3 mol%) at 1108C in 1,4-dioxane with 2 equivalents of
hydrazine hydrate and NaOtBu. Electron-rich monophos-
phanes or carbenes including P(tBu)3 (L1), IPr (L2),
tBu-JohnPhos (L3), SPhos (L4), Q-Phos (L5), as well as
bisphosphanes DuPhos (L6), binap (L7), DiPPF (L8), and
Taniaphos (L9) all gave poor results: either resulting in low
conversions of the starting aryl chloride, or providing mainly
the hydrodehalogenated product. The electron-rich bisphos-
phine ligand Josiphos (L10)[6b,10a] or DalPhos P,N ligands (L11
and L12)[6l,m] provided a breakthrough in reactivity: high
[*] R. J. Lundgren, Prof. Dr. M. Stradiotto
Department of Chemistry, Dalhousie University
Halifax, Nova Scotia B3H 4J3 (Canada)
Fax: (+1)902-494-7190
E-mail: mark.stradiotto@dal.ca
[**] We are grateful to the NSERC of Canada and Dalhousie University
for their support of this work. K. D. Hesp and V. M. Marx
(Dalhousie) are acknowledged for helpful discussions.
Supporting information for this article is available on the WWW
8686
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 8686 –8690