Synthesis of Aryl Hydrazines via CuI/BMPO Catalyzed Cross-Coupling of
Aryl Halides with Hydrazine Hydrate in Water
Siripuram Vijay Kumar,a and Dawei Ma*,a
ABSTRACT The N,N’-bis(2,6-dimethylphenyl)oxalamide was discovered as a powerful ligand for Cu-catalyzed cross-coupling of aryl halides with
hydrazine hydrate, leading to the formation of a variety of aryl hydrazines at 80 oC in water under the assistance of K3PO4 and 4 mol%
cetyltrimethylammonium bromide from aryl bromides and aryl iodides. Good to excellent yields were observed in most cases.
KEYWORDS hydrazine hydrate, coupling reaction, aryl halides, ligand, copper
method are limited reaction scope and moderate yields in some
Introduction
cases. Typically, the reaction had to be conducted at higher
o
Aryl hydrazines are valuable building blocks for synthesizing
reaction temperature (110 C), which resulted in formation of
indoles,[1,2] carbazoles,[1] indazoles,[3] arylpyrazoles,[4] and
several side products.
aryltriazoles.[5] These heterocyclic motifs have been frequently
We envisioned that a more powerful ligand could make this
found in pharmaceutically important compounds, agrochemicals,
coupling reaction complete at relatively low temperatures, and
and material molecules.[6] Besides the biological and synthetic
thereby avoiding some side reactions to provide a really practical
importance, aryl hydrazines have been used in the preparation of
method for preparing aryl hydrazines from aryl halides. With this
molecular glasses for various applications.[7]
idea in mind, we attempted Cu-catalyzed arylation of hydrazine
The most conventional method for preparing aryl hydrazines
under the promotion of some oxalic diamides that showed
involves the oxidation of anilines to the corresponding diazonium
excellent ability for facilitating Cu-catalyzed coupling of aryl
salts, followed by reduction with tin salts.[8] Another classical
method is through aromatic nucleophilic substitution reaction of
aryl halides with hydrazine,[9] which is applicable only for highly
electron-deficient substrates. Owing to great diversity and
abundance of aryl halides, transition metal catalyzed
cross-coupling reaction between aryl halides and hydrazine should
be an attractive and practical approach for assembling aryl
hydrazines.[10] The challenging problems behind this coupling
reaction are chemoselectivity between coupling partner
(hydrazine) and coupling products (aryl hydrazines), and N-N bond
cleavage of aryl hydrazines in the presence of metal complexes to
give unwanted aniline by-products.[11] Given this background, it is
not surprising that very limited studies have been disclosed for
metal-catalyzed direct arylation of hydrazine,[12-14] although
tremendous progress has been achieved in Pd- and Cu-catalyzed
N-arylation.[10] The first example of Pd-catalyzed coupling reaction
of aryl halides with hydrazine was reported by Lundgren and
Stradiotto in 2010,[12] in which Mor-Dal-Phos was identified as the
best ligand to achieve satisfactory chemoselectivity. While a
considerable number of aryl chlorides worked well under the
optimized conditions to give the coupling products in 27-95%
yields, requirement of high catalytic loadings (3-10 mol%
[Pd(cinnamyl)Cl]2 and 4.5-15 mol% Mor-Dal-Phos) makes this
coupling reaction less practical. Three years later, Chen and
coworkers revealed that using PEG-400 as both ligand and solvent,
Cu-catalyzed cross-coupling of aryl halides (Br, I) with aqueous
hydrazine took place at 120 oC to afford aryl hydrazines in good to
excellent yields.[13] However, this method required both PEG-400
and 85% aqueous hydrazine as the solvents, leading to difficulty in
isolation of the coupling products. Indeed, the resultant aryl
hydrazines had to be transformed into the corresponding N-tosyl
derivatives before purification. To solve this problem, Kurandina
and co-workers discovered N,N’-bis(2,5-dimethylpyrrol-1-yl)-
oxalamide as a more efficient ligand for Cu-catalyzed coupling
reaction of aryl bromides with hydrazine.[14] Only 2.5 mol% CuBr
and 4 mol% of this ligand were sufficient to make the coupling
halides with other nucleophiles,[10a] and identified that
combination of CuI and N,N’-bis(2,6-dimethylphenyl)-oxalamide is
a better catalytic system, leading to the formation of a wide range
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of aryl hydrazines at 80 C from aryl halides (Br, I) and hydrazine
hydrate. Herein, we wish to disclose the results.
Results and Discussion
As indicated in Table 1, we selected the coupling of
4-bromotoluene 1a with hydrazine hydrate as a model reaction to
optimize the reaction conditions. Initially, we examined some
ligands the displayed excellent reactivity in Cu-catalyzed aryl
amination.[15] It was found that under the catalysis of 2 mol% CuI
and 2 mol % N,N’-bis(2,4,6-trimethoxyphenyl)oxalamide (BTMPO,
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L1),[15a] coupling reaction took place at 80 C in water under the
assistance of K3PO4 and 4 mol% cetyltrimethylammonium
bromide (CTAB, as a phase transfer catalyst), but only about 20%
conversion was observed after 7 h (entry 1). Changing the ligand
to less electron-rich L2-L4 gave improved results (entries 2-4).
However,
using
N,N’-bis(4-hydroxyl-2,6-dimethylphenyl)-
oxalamide (BHMPO, L5),[16] a hydroxyl-substituted analogue of L4,
led to a decreased yield (entry 5), which implied that a more
electron-rich substituent at the para-position of amido moiety is
not favoured for the present transformation. Thus, we attempted
using L6 that possesses an electron-withdrawing group as a ligand,
and were pleased that 2a was isolated in 82% yield (entry 6).
Interestingly, a worse result was observed in case of an
ester-embodied oxalamide as the ligand (L7, entry 7), while the
best result was obtained when
a
simple ligand,
N,N’-bis(2,6-dimethylphenyl)oxalamide (BMPO, L8), was applied
(entry 8). Changing the dimethyl groups in L8 to diethyl and
dimethoxy groups gave decreased reaction yields (entries 9 and
10). Additionally, other ligands L11-L16 that had good
performance in C-N bond formation gave poor yields or no
conversion (entries 11-16),[17] indicating that subtle change in
structure of oxalamide ligands could alter the reaction course
greatly.
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reaction complete at 80-110 C. The apparent problems of this
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, China
E-mail: madw@sioc.ac.cn
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may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800326
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