Efficient and convenient method for the synthesis of N-arylhydrazones using a palladium-catalyzed bond-forming reaction

Article abstract of DOI:10.1080/00397910500501292

A highly effective, convenient, and reproducible industrial process for palladium-catalyzed carbon-nitrogen cross coupling has been developed and applied on a large scale. Thus various functionalized N-arylhydrazones have been easily prepared and well cha

Full text of DOI:10.1080/00397910500501292

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Efficient and Convenient Method for the
Synthesis of N‐Arylhydrazones using a
Palladium‐Catalyzed Bond‐Forming Reaction
a
a
Christelle Mauger & Gérard Mignani
a
Rhodia Recherches, Centre de Recherches de Lyon, Saint‐Fons Cedex,
France
Version of record first published: 16 Aug 2006.
To cite this article: Christelle Mauger & Gérard Mignani (2006): Efficient and Convenient Method
for the Synthesis of N‐Arylhydrazones using a Palladium‐Catalyzed Bond‐Forming Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:8,
1123-1129
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Synthetic Communications , 36: 1123–1129, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500501292
Efficient and Convenient Method for the
Synthesis of N-Arylhydrazones using a
Palladium-Catalyzed Bond-Forming
Reaction
Christelle Mauger and G e´ rard Mignani
Rhodia Recherches, Centre de Recherches de Lyon, Saint-Fons Cedex,
France
Abstract: A highly effective, convenient, and reproducible industrial process for
palladium-catalyzed carbon–nitrogen cross coupling has been developed and applied
on a large scale. Thus various functionalized N-arylhydrazones have been easily
prepared and well characterized by conventional spectroscopic methods.
Keywords: Aryl chlorides, Buchwald ligands, cross coupling, hydrazone, palladium,
phosphines
In the past decade palladium-catalyzed amination, independently discovered
[
1]
[2]
by Yang and Buchwald and Baranano et al., has established itself as a
useful tool for the synthesis of arylamines. Our research group was particu-
larly interested in applying this C-N coupling methodology on a large scale
for the synthesis of N-arylhydrazones, thus leading after hydrolysis to the cor-
responding N-arylhydrazines. Indeed arylhydrazines are extensively used as
synthetic building blocks and appear as a subunit in many natural products
[3]
and substances of relevance for industry. They constitute intermediates to
[4]
various azaheterocycles or indoles via the Fischer reaction. Thus, they are
important to a diverse array of fields, such as agrochemicals, pharmaceuticals,
[
and photography. Herein we describe a practical synthesis of N-aryl hydra-
5]
zones using a palladium-catalyzed carbon–nitrogen bond-forming reaction.
Received in the U.K. April 18, 2005
Address correspondence to Christelle Mauger, Rhodia Recherches, Centre de
Recherches de Lyon, 85 rue des Fr e` res Perret, BP62, 69192 Saint-Fons Cedex,
France. Tel.: (þ33) 4 72 89 63 76; Fax: (þ33) 4 72 89 68 94; E-mail: christelle.
mauger@eu.rhodia.com
1
123

1
124
RESULTS
The palladium-catalyzed cross coupling of benzophenone hydrazone with aryl
C. Mauger and G. Mignani
[6]
halides has been shown to proceed under a variety of conditions. To find
optimum conditions, a series of experiments was performed using 4-chloroto-
[
7]
luene as the model compound. Reactions were carried out under argon or
nitrogen and with degassing solvent prior to use. As a base, sodium
hydroxide was the best choice in tert-amyl alcohol. Palladium acetate and
[
8]
Mephos displayed the best catalytic activities. This system allowed the
arylhydrazone to crystallize directly in the solvent without other purification
procedures. After having established the optimized coupling reaction
conditions, the scope of the reaction and efficiencies of the catalyst were
evaluated by investigating the coupling of benzophenone hydrazone with
various aryl halides. The results are shown in Table 1.
4-Bromotoluene, 4-chlorotoluene, bromobenzene, 4-bromochlorobenzene,
-bromoanisole, 2-bromotoluene, 4-bromofluorobenzene, and 2-bromochloro-
4
benzene react very efficiently with benzophenone hydrazone in good yields
Table 1. Palladium-catalyzed coupling of aryl halides with benzophenone hydrazone
Temp.
(8C) Solvent
Time Yield
(%)
Entry
Substrate ArX
Ligand Base
(h)
1
2
3
4
5
6
7
8
9
4-bromotoluene
4-chlorotoluene
bromobenzene
MePhos NaOH
MePhos NaOH
MePhos NaOH
103 t-AmOH
3
92
93
95
97
87
85
91
89
85
103 t-AmOH ,3
103 t-AmOH
103 t-AmOH ,5
103 t-AmOH
103 t-AmOH ,4
103 t-AmOH
103 t-AmOH
110 Anisole
4
4-bromochlorobenzene MePhos NaOH
4-bromoanisole
2-bromotoluene
4-bromofluorobenzene
MePhos NaOH
MePhos NaOH
MePhos NaOH
4
4
4
2-bromochlorobenzene MePhos NaOH
4-chlorobenzotrifluoride XPhos K PO
,6
3
4

Synthesis of N-Arylhydrazones
1125
(
.85%). As shown in some previous reports, the C-N coupling reaction is more
[
9]
reactive on bromides than chlorides; thus, the reaction on bromochloroben-
zene was totally selective at the bromine position. In contrast, in those
standard conditions, no coupling reaction occurred with a deactivated
substrate such as para-chlorobenzotrifluoride (p-C1-TFMB). It was subjected
to other coupling conditions (solvent, base, catalyst). Thus we found that the
choice of ligand was crucial to the successful Pd-catalyzed preparation of N-
aryl benzophenone hydrazone from deactivated aromatic halides. Pd/
[
10]
XPhos
version of p-Cl-TFMB into the corresponding N-arylhydrazone.
combination is the only catalyst system that allows a complete con-
In summary, we have described a C-N palladium-catalyzed coupling
reaction to develop a simple, efficient, and general methodology for the
synthesis of a variety of structurally diverse hydrazones. Reactions can
proceed with low catalyst loadings (as low as 0.05% mol), are reproducible,
and have been applied on a large scale (up to 5 kg). The scope of the reaction
is broad, as it includes electron-rich and electron-poor aryl chlorides and is
compatible with base-sensitive functional groups. This method presents
the advantages of mild conditions, easily accessible starting materials, and
ease of separation in the treatment. It is a promising method for the industrial
development of N-arylhydrazones, intermediates to azaheterocycles.
EXPERIMENTAL
1
13
H NMR and C NMR spectra were recorded using a Bruker spectrometer
1
13
operating at MHz ( H) and MHz ( C). Chemical shifts are given in ppm
relative to TMS, with coupling constants (J ) in Hz. Melting points were
measured in open capillary tubes with a Biichi B-545 melting-point
apparatus and are uncorrected. Gas chromatography was carried out using
a Varian CP-3800 gas chromatograph equipped with a FID detector and a
fused silica capillary column DP-17 (30 m ꢀ 0.32 mm ꢀ 0.25 mm). All
samples were examined under the following temperature gradient: temp. 1,
1
00 8C (0 min); temp. 2, 300 8C (5 min); rate 30 8C/min; total run time
1
1.67 min. Conversions were determined by direct integration of the peak
areas of the gas chromatograph rather than by constructing calibration
curves using standard solutions of each component. GC-MS data were
acquired using a HP 5890 series II gas chromatograph using the same
temperature gradient as described for GC analysis (Scheme 1).
General Procedure for the Palladium-Catalyzed Coupling
Reactions
In a glass reactor equipped with a condenser and a mechanical stirrer, the aryl
halide (1 mol) and ground sodium hydroxide (1.4 mol) were charged under

1
126
C. Mauger and G. Mignani
Scheme 1. Structure of the N-aryl benzophenone hydrazones.
nitrogen atmosphere in freshly degassed solvent ([ArX] ¼ 1.5M in solvent).
The mixture was heated at reflux. Complex catalysis was performed under
argon by mixing Pd(OAc)2 (0.001 mol) and ligand (0.002) in degassed
solvent for 20 min at room temperature, which were then added into the
glass vessel. Benzophenone hydrazone (1 mol) was added in 13 portions in
10-min intervals. Reaction was followed by Raman spectroscopy or GC
analysis. When completion was reached, the reaction mixture was cooled to
room temperature, and unsoluble salts were quenched with water. Layers
were separated and the arylhydrazone crystallized at about 5 8C in the
organic layer. The solid was filtered, washed with tert-amyl alcohol, and
dried at 40 8C (10 mbar). The arylhydrazone was afforded as a solid in a
good yield (see Table 1).
[11,12]
Synthesis of N-(p-Tolyl)-benzophenone Hydrazone
(1)
In a 16-L glass reactor equipped with a condenser and a mechanical stirrer,
and linked by an optic fiber to a Raman spectrometer, 4-chlorotoluene
(1.605 kg, 12.675 mol) and ground sodium hydroxide (709.8 g, 17.745 mol)
were charged under nitrogen atmosphere in 8 L of freshly degassed tert-
amyl alcohol. The mixture was heated at reflux. Complex catalysis was
preformed under argon by mixing Pd(OAc) (1.42 g, 6.3 mmol) and MePhos
2
(
4.61 g, 12.7 mmol) in degassed tert-amyl alcohol (400 mL) for 20 min at
room temperature, which were then added into the glass vessel. Benzophenone
hydrazone (2.487 kg, 12.675 mol) was added in 13 portions at 10-min
intervals. The reaction was followed by Raman spectroscopy. When the
reaction reached completion, the reaction mixture was cooled to room
temperature, and unsoluble salts were quenched with water (2 L). Layers
were separated, and the arylhydrazone crystallized at about 5 8C in the

Synthesis of N-Arylhydrazones
1127
organic phase. The solid was filtered, washed with 2.5 L of tert-amyl alcohol,
and dried at 40 8C (10 mbar). The arylhydrazone was afforded as a pale
yellow solid.
1
Yield: 3.371 kg, 93%, mp 84 8C. H NMR (CDCl ) d: 2.21 (s, 3H, CH ), 7.01
3
3
(
s, 2H, C H and C H), 7.15 (s, 2H, C H and C H), 7.36 (s, 1H, C
0
0
H), 7.53
3
3
5
2
6
4
1
(s, 1H, NH), 7.59 (s, 2H, C3
NMR (CDCl ) d: 20.2 (CH ), 113 (C and C ), 125.8–129.4 (C –C ),
H and C5
0
H), 7.66 (s, 2H, C2
0
H and C6
0
H).
C
0
3
3
2
6
1
6
1
29.2 (C and C ), 142.2 (C 55 N), 143 (C ).
3 5 1
[13]
Synthesis of N-Phenyl-benzophenone Hydrazone
(2)
This compound was prepared from bromobenzene (31.4 g, 0.2 mol) and
benzophenone hydrazone (39.2 g, 0.2 mol) in tert-amyl alcohol (180 mL).
Yield: 95% (52.2 g), mg 137.8 8C (lit. 136.5–137.5 8C).
1
H NMR (CDCl ) d: 6.85 (s, 1H, C H), 7.09 (s, 2H, C H and C H), 7.25
3
4
2
6
1
3
(s, 2H, C H and C H), 7.30–7.57 (m, 10H, C
3
0
H). C NMR (CDCl ) d:
1–6 3
5
1
13 (C and C ), 120.1 (C ), 129.2 (C and C ), 126.5–129.7 (C
2
0
–C6
0
),
6
4
3
5
2
1
32.8 (C1
0
), 138.4 (C1 ), 144.2 (C 55 N), 144.6 (C1).
0
[12]
Synthesis of N-(4-Chloro-phenyl)-benzophenone Hydrazone
(3)
This compound was prepared from 4-bromochlorobenzene (38.3 g, 0.2 mol)
and benzophenone hydrazone (39.2 g, 0.2 mol) in tert-amyl alcohol
(180 mL). Yield: 97% (60 g), mp: 116.9 8C (lit. 121–122 8C).
1
H NMR (CDCl ) d: 6.93 (s, 2H, C H and C H), 7.11 (s, 2H, C H and C H),
5
3
2
6
3
1
3
7
and C ), 124.5 (C ), 126.5–129.6 (C
.41 (s, 1H, NH), 7.29–7.55 (m, 10H, C1
0
0
0
H). C NMR (CDCl ) d: 114 (C
–6 3
2
–C6
0
), 129.0 (C and C ), 132.5 (C
0
1
),
6
4
2
3
5
1
38.0 (C1 ), 144.6 (C ), 144.8 (C 55 N).
0
1
[11]
Synthesis of N-(4-Methoxyphenyl)-benzophenone Hydrazone
(4)
This compound was prepared from 4-bromoanisole (37.4 g, 0.2 mol) and
benzophenone hydrazone (39.2 g, 0.2 mol) in tert-amyl alcohol (180 mL).
Yield: 87% (37.4 g), mp 118.9 8C.
1
H NMR (CDCl ) d: 3.69 (s, 3H, OCH ), 6.75 (s, 2H, C H and C H), 6.96
3
3
3
5
(
s, 2H, C H and C H), 7.32 (s, 1H, NH), 7.29–7.55 (m, 10H, C
3
0
0
H).
C NMR (CDCl ) d: 55.6 (OCH ), 114.0 (C and C ), 114.6 (C and C ),
2
6
1 –6
1
3
3
2
6
3
5
1
26.5–129.6 (C2
53.7 (C4).
–C6 ), 132.9 (C1 ), 138.4 (C1 ), 138.8 (C ), 143.3 (C 55 N),
0 0 0 0
1
1

1
128
C. Mauger and G. Mignani
[13]
Synthesis of N-(o-Tolyl)-benzophenone Hydrazone
(5)
This compound was prepared from 2-bromotoluene (34.2 g, 0.2 mol) and
benzophenone hydrazone (39.2 g, 0.2 mol) in tert-amyl alcohol (180 mL).
Yield: 85% (48.8 g), mp 104.2 8C (lit. 101–102 8C).
1
H NMR (CDCl ) d: 1.81 (s, 3H, CH ), 6.74 (s, 1H, C H), 6.97 (s, 1H, C H),
3
3
4
3
7.19 (s, 1H, C H), 7.66 (s, 1H, C H), 7.42 (s, 1H, N ), 7.30–7.57 (m, 10H,
C1
5 6 H
1
3
0
0
H), C NMR (CDCl ) d: 16.4 (CH ), 112.4 (C ), 119.6 (C ),
–6 3 3 6 4
1
1
20.3 (C ), 128.0 (C ), 130.2 (C ), 126.4–129.7 (C –C6 ), 132.9 (C1 ),
0 0 0
2 5 3 2
38.2 (C1 ), 142.4 (C ), 145.1 (C 55 N).
0
1
Synthesis of N-(4-Fluorophenyl)-benzophenone Hydrazone (6)
This compound was prepared from 4-bromofluorobenzene (35.01 g, 0.2 mol)
and benzophenone hydrazone (39.2 g, 0.2 mol) in tert-amyl alcohol
(
180 mL). Yield: 91% (52.4 g), mp 95.1 8C.
1
H NMR (CDCl ) d: 6.87 (s, 2H, C H and C H), 6.93 (s, 2H, C H and C H),
3
3
5
2
6
1
H). C NMR (CDCl ) d: 113.7 (C and C ), 115.7
3
7
.24–7.49 (m, 10H, C1
0
0
–6
3
3
5
(
C and C ), 126.5–129.8 (C –C6
0
2
0
), 132.7 (C1
44.2 (C 55 N), 157.1 (C4). F NMR (CDCl ) d: 248.9. Microanalysis: calcu-
0
), 138.2 (C1
0
), 141.0 (C1),
2
6
1
9
1
lated (C: 78.6; H: 5.2; N: 9.6); measured (C: 78.4; H: 5.3; N: 9.5).
3
[13]
Synthesis of N-(2-Chlorophenyl)-benzophenone Hydrazone
(7)
This compound was prepared from 2-bromochlorobenzene (38.3 g, 0.2 mol)
and benzophenone hydrazone (39.2 g, 0.2 mol) in tert-amyl alcohol
(
180 mL). Yield .98% (62 g), mp 153.6 8C.
1
H NMR (CDCl ) d: 6.71 (s, 1H, C H), 7.15 (s, 1H, C H), 7.19 (s, 1H, C H),
5
3
4
3
1
H), 8.03 (s, 1H, NH). C NMR
3
7
.71 (s, 1H, C H), 7.30–7.57 (m, 10H, C
6
0
0
1 –6
(
CDCl ) d: 114.0 (C ), 117.4 (C ), 119.9 (C ), 127.8 (C ), 129.4 (C ), 136.7–
5
3
6
2
4
3
129.7 (C2
0
–C6
0
), 132.6 (C1
0
), 138.0 (C1 ), 140.5 (C ), 146.6 (C 55 N).
0
1
Synthesis of N-(4-Trifluoromethylphenyl)-benzophenone
[
12]
Hydrazone
(8)
This compound was prepared from 4-chlorobenzotrifluoride (36.1 g, 0.2 mol)
and benzophenone hydrazone (39.2 g, 0.2 mol) in anisole (134 mL). Yield:
8
5% (57.8 g), mp 94 8C (lit. 85–86 8C).
1
H NMR (CDCl ) d: 7.07 (s, 2H, C H and C H), 7.15 (s, 2H, C H and
3
3
5
2
C H), 7.36 (s, 1H, C
6
0
H), 7.53 (s, 1H, NH), 7.59 (s, 2H, C3
4
0
H and C5 H),
0

Synthesis of N-Arylhydrazones
1129
1
H). C NMR (CDCl ) d: 20.2 (CH ), 113 (C and
0
–C6 ), 129.2 (C and C ), 142.2 (C 55 N), 143 (C ).
3 5 1
3
7
C ), 125.8–129.4 (C
.66 (s, 2H, C2
0
H and C6
0
0
3
3
2
6
9
1
1
F NMR (CDCl ) d: 14.4.
3
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