Palladium-catalyzed N-arylation of N,N-dialkylhydrazines with aryl chlorides

Article abstract of DOI:10.1002/adsc.200600299

N,N-Dialkyl-N′-arylhydrazines have been prepared usually in high to excellent yields via the reaction of N,N-dialkylhydrazines with aryl chlorides in the presence of Pd₂(dba)₃, Xphos and NaO-t-Bu in dioxane at 120°C. With ortho-subst

Full text of DOI:10.1002/adsc.200600299

UPDATES
DOI: 10.1002/adsc.200600299
Palladium-Catalyzed N-Arylation of N,N-Dialkylhydrazines with
Aryl Chlorides
Sandro Cacchi,a,* Giancarlo Fabrizi,a,* Antonella Goggiamani,a and Simona Sgallaa
a
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi
“La Sapienza”, P. le A. Moro 5, 00185 Rome, Italy
Fax : (+39)-06-4991-2780; e-mail: sandro.cacchi@uniroma1.it
Received: June 22, 2006; Published online: January 8, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: N,N-Dialkyl-N’-arylhydrazines have been
prepared usually in high to excellent yields via the
reaction of N,N-dialkylhydrazines with aryl chlor-
the procedure to the attractive class of aryl chlorides.
Herein we report the result of this study.
ides in the presence of Pd2(dba)3, Xphos and NaO-
G
t-Bu in dioxane at 1208C. With ortho-substituted
aryl chlorides best results have been obtained by
using 2-(2’,6’-dimethoxybiphenyl)dicyclohexylphos-
phine (ligand d) as the ligand.
Results and Discussion
Initial studies were directed toward finding a general
set of reaction conditions that could be applied to a
wide range of aryl chlorides and N,N-dialkylhydra-
zines. Since reactions such as that of p-chloroanisole
2a with N,N-dimethylhydrazine 1a were likely to
prove among the most difficult, we decided to opti-
mize that particular process (Scheme 1). On the basis
of our previous work, which showed that N,N-dialkyl-
hydrazine/2 LiCl adducts give significantly higher
yields than the corresponding free hydrazines, the
N,N-dimethylhydrazine/2 LiCl adduct was used in the
Keywords: aryl chlorides; carbon-nitrogen bond
forming reaction; hydrazines; palladium
Introduction
Because of their biological activities, N,N-dialkyl-N’- first reaction examined. The reaction was carried out
arylhydrazines represent an important synthetic under the following conditions: 0.025 equivs. of Pd2
target. Most of them act as inhibitors of ileal bile acid
A
transport,[1] herbicides,[2] interleukin-8 receptor antag- phenyl)dicyclohexylphosphine] – recently developed
onists,[3] antibacterial agents,[4] inhibitors of the coagu- by Buchwald et al.[9] and shown to produce catalyst
lation cascade.[5] N,N-Dialkyl-N’-arylhydrazines are systems with a greater degree of activity in the oxida-
also useful synthetic intermediates.[6] One of the most tive addition of aryl chlorides to Pd(0) species than
obvious and straightforward approaches to their syn- other commonly used ligands – 1.4 equivs. of NaO-t-
thesis would be the palladium-catalyzed N-arylation Bu in toluene at 1208C. After 24 h, the arylated N,N-
of N,N-dialkylhydrazines. Indeed, because of the lack dimethylhydrazine 3a was isolated in 45% yield. Sur-
in the literature of an efficient procedure based on prisingly, when we repeated the same reaction using
[7]
À
such a C N bond forming reaction, we recently ex- free N,N-dimethylhydrazine as the nitrogen partner,
plored this chemistry and found that the palladium- compound 3a was isolated in 65% yield. Therefore,
catalyzed reaction of aryl bromides with N,N-dialkyl- we turned our attention to optimizing the reaction of
hydrazine/2 LiCl adducts affords the desired N,N-di-
alkyl-N’-arylhydrazines usually in good yields.[8] The
procedure, however, suffers from some limitations
such as the moderate yields obtained with electron-
rich aryl bromides and the reluctance of ortho-substi-
tuted aryl bromides to give the desired products. Our
interest in N,N-dialkyl-N’-arylhydrazines prompted us
to investigate further this synthetic approach in an at-
tempt to overcome these drawbacks and to extend Scheme 1.
Adv. Synth. Catal. 2007, 349, 453 – 458
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453

Sandro Cacchi et al.
UPDATES
Table 1. Ligands, bases, and solvents in the palladium-catalyzed reaction of N,N-dimethylhydrazine 1a with p-chloroanisole
2a.[a]
Entry
Ligand
Base
Solvent
Reaction time [h]
Yield [%] of 3a[b]
1
NaO-t-Bu
toluene
24
65
2
3
4
5
6
7
8
9
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
NaO-t-Bu
NaO-t-Bu
K3PO4
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
24
24
24
24
6
5
6
8
24
81
70[c]
72
Cs2CO3
23
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaOH
80[d]
70[e]
21
dioxane
dioxane/H2O
60
10
NaOH
30[f]
11
12
NaO-t-Bu
NaO-t-Bu
dioxane
dioxane
24
24
65
75
13
NaO-t-Bu
dioxane
24
7 g]
14
15
16
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
dioxane
dioxane
dioxane
24
24
5
74
HP
G
39 h]
62[i]
[a]
Unless otherwise stated, reactions were carried out on a 0.563 mmol scale at 1208C in 2 mL of solvent using 1 equiv. of p-
chloroanisole, 2 equivs. of N,N-dimethylhydrazine, 0.025 equivs. of Pd2(dba)3, 0.1 equiv. of the phosphine ligand, and 1.4
AHCTREUNG
equivs. of base.
Yields are given for isolated products.
In the presence of 0.0125 equivs. of Pd2(dba)3 and 0.05 equivs. of Xphos.
In the presence of 0.05 equivs. of Xphos.
With 1.5 equivs. of N,N-dimethylhydrazine.
In 1.8 mL of dioxane and 0.2 mL of H2O.
In the presence of 0.05 equivs. of Xantphos.
Anisole, derived from a reduction process, was obtained in 7% yield and the starting p-chloroanisole was recovered in
50% yield.
[b]
[c]
[d]
[e]
[f]
G
[g]
[h]
[i]
In the presence of 0.05 equivs. of the phosphine ligand.
p-chloroanisole with N,N-dimethylhydrazine. Part of
our optimization work using different ligands, bases significant increase of the yield (Table 1, entry 2)
and solvents is shown in Table 1. whereas the use of DMF afforded 3a in 21% yield
Conducting our model reaction in dioxane led to a
454
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Adv. Synth. Catal. 2007, 349, 453 – 458

Palladium-Catalyzed N-Arylation of N,N-Dialkylhydrazines
UPDATES
(Table 1, entry 8). The reaction was subsequently car- only in 7% yield (Table 1, entry 13). The best result
ried out using other bases, but the desired N-aryl de- in terms of yield and reaction time was obtained
rivative was obtained in lower yield with K3PO4 when the reaction was carried using 0.025 equivs. of
(Table 1, entry 4) and NaOH (Table 1, entries 9 and Pd2(dba)3 and 0.05 equivs. of Xphos in the presence
G
10). With Cs2CO3 3a was isolated only in 23% yield of 1.4 equivs. of NaO-t-Bu in dioxane at 1208C
(Table 1, entry 5). A variety of Buchwald dialkylmo- (Table 1, entry 6). The higher efficiency in some palla-
nophosphine ligands was also screened along with dium-catalyzed reactions of catalyst systems based on
P(t-Bu)3 (added to the reaction mixture as the tetra- bulky electron-rich monophosphine ligands and palla-
E
fluoroborate salt)[10] and bidentate Xantphos.[11] In dium in a 1:1 ratio has been already observed.[12] This
general, monophosphine ligands a, b, c, and d all gave has been attributed to the propensity of bulky ligands
satisfactory results (Table 1, entries 11, 12, 14, and 16, to form monoligated LPd(0) species,[13] with beneficial
respectively), always significantly better than P
ACHTREUNG
or Xantphos. P(tBu)3 led to a 50% conversion pro-
ACHTREUNG
ducing 39% of 3a and 7% of anisole, derived from amined the reaction using various aryl chlorides and
reduction of p-chloroanisole (Table 1, entry 15). With N,N-dialkylhydrazines in order to determine the
Xantphos, which afforded N-aryl derivatives in good scope and limitations of this process. The results are
yields with a variety of aryl bromides and N,N-di- listed in Table 2.
alkylhydrazine/2 LiCl adducts,[8] the reaction was par-
Usually, under these conditions the reaction gave
ticularly unsatisfactory, compound 3a being isolated N,N-dialkyl-N’-arylhydrazines in high to excellent
Table 2. Preparation of N,N-dialkyl-N’-arylhydrazines 3 via palladium-catalyzed reaction of N,N-dialkylhydrazines 1 with
aryl chlorides 2.[a]
Entry
N,N-Dialkylhydrazine 1
Aryl chloride 2
Reaction time [h]
Yield [%] of 3[b]
1
2
3
4
5
H2NNMe2
p-MeO-C6H4-Cl
m-MeO-C6H4-Cl
m-MeO-C6H4-Cl
o-Me-C6H4-Cl
o-Me-C6H4-Cl
6
24
5
8
4
80
3a
3b
3b
3c
3c
85[c]
81
43
78[d]
6
7
7
76
3d
3e
PhCl
7.5
78e
8
2.5
78
3f
9
m-CF3-C6H4-Cl
p-MeO-C6H4-Cl
5
5
75
85
3g
3h
10
11
12
5.5
2.5
87
90
3i
3j
13
14
15
2.7
5
85
3k
3l
PhCl
88
5.5
90[d]
3m
16
p-MeO-C6H4-Cl
3.5
81
3n
17
18
19
o-Me-C6H4-Cl
PhCl
m-CF3-C6H4-Cl
5
5
5
85[d]
85
80
3o
3p
3q
Adv. Synth. Catal. 2007, 349, 453 – 458
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
455

Sandro Cacchi et al.
UPDATES
Table 2. (Continued)
Entry
N,N-Dialkylhydrazine 1
Aryl chloride 2
p-MeO-C6H4-Cl
Reaction time [h]
Yield [%] of 3[b]
20
21
3.5
7
90[d]
3r
3s
85
22
23
m-MeO-C6H4-Cl
o-Me-C6H4-Cl
3
3
87
3t
3u
87[d]
24
25
3.5
3.5
83
87
3v
PhCl
3w
26
2.5
82
3y
27
28
m-CF3-C6H4-Cl
3
3
85
80
3z
3za
29
30
p-MeO-C6H4-Cl
o-Me-C6H4-Cl
4.5
5
67 (97)[e]
85[d]
3zb
3zc
31
6
85
3zd
32
33
PhCl
m-CF3-C6H4-Cl
5
4.5
87
86
3ze
3zf
34
p-MeO-C6H4-Cl
3
83
3zg
35
36
37
m-MeO-C6H4-Cl
m-MeO-C6H4-Cl
o-Me-C6H4-Cl
4
24
3
79
3zh
3zh
3zi
82[c]
87d
38
39
3.5
3
83
88
3zj
PhCl
3zk
40
3.5
93
3zl
41
42
m-CF3-C6H4-Cl
3
3
91
84
3zm
3zn
43
7
90[d]
3zo
[a]
Unless otherwise stated, reactions were carried out on a 0.563 mmol scale at 1208C in 2 mL of dioxane using 1 equiv. of
aryl chloride, 2 equivs. of N,N-dialkylhydrazine, 0.025 equivs. of Pd2(dba)3, 0.05 equivs. of Xphos, and 1.4 equivs. of KO-t-
AHCTREUNG
Bu.
[b]
[c]
[d]
[e]
Yields are given for isolated products.
In toluene.
In the presence of ligand d.
Yield calculated by HPLC analysis.
yields with a variety of aryl chlorides. Only with o- was isolated (Table 2, entry 5). This ligand was also
chlorotoluene was moderate yield obtained successfully used in a number of reactions of o-chloro-
a
(Table 2, entry 4). To our delight, on simply replacing toluene with other N,N-dialkylhydrazines (Table 2,
Xphos with the bulky electron-rich monodentate di- entries 17, 23, 30, 37). Even the sterically encumbered
alkylphosphinobiaryl ligand d,[14] a 78% yield of 3c 2-chloro-m-xylene gave excellent yields of the desired
456
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Adv. Synth. Catal. 2007, 349, 453 – 458

Palladium-Catalyzed N-Arylation of N,N-Dialkylhydrazines
UPDATES
133.9, 131.9, 128.9, 128.9, 127.9, 127.5, 127.1, 126.9, 124.1,
118.9, 117.3, 115.0.
product under these modified conditions (Table 2, en-
tries 15, 20, 43).
Conclusions
Acknowledgements
We have developed a straightforward route for the
preparation of N,N-dialkyl-N’-arylhydrazines from
N,N-dialkylhydrazines and aryl chlorides in the pres-
Work carried out in the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Appli-
cazioni” supported by the Ministero dell’Università e della
ence of Pd2(dba)3 as the palladium source, Xphos [or Ricerca Scientifica e Tecnologica and by the University “La
G
Sapienza.”
2-(2’,6’-dimethoxybiphenyl)dicyclohexylphosphine,
ligand d, with ortho-substituted aryl chlorides] as the
ligand, dioxane as the solvent, and NaO-t-Bu as the
base. The usually high to excellent yields and the sim-
plicity of the experimental procedure make this
method particularly convenient for the preparation of
this class of compounds.
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Experimental Section
Melting points were determined with a Büchi B-545 appara-
tus and are uncorrected. All of the reagents, catalysts, and
solvents are commercially available and were used as pur-
chased, without further purification. Reaction products were
purified on axially compressed columns, packed with SiO2
25–40 mm (Macherey–Nagel), connected to a Jasco RI-031
Plus solvent delivery system and to a Jasco PU-2087 Plus re-
fractive index detector, and eluting with n-hexane/ethyl ace-
1
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In a Carousel Tube Reactor (Radley Discovery), Pd2(dba)3
R
(0.0129 g, 0.014 mmol) and Xphos (0.0134, 0.028 mmol)
were stirred at room temperature under argon in 1.0 mL of
dioxane for ten minutes. Then 4-chloroanisole (0.080 g,
0.563 mmol),
N,N-dimethylhydrazine
(0.086 mL,
1.126 mmol), 1 mL of dioxane and NaO-t-Bu (0.0757 g,
0.788 mmol) were added. The reaction mixture was stirred
at 1208C under argon for 6 h. After cooling, the reaction
mixture was diluted with ethyl acetate, washed with
NaHCO3, dried over Na2SO4 and concentrated under re-
duced pressure. The residue was purified by chromatogra-
phy (silica gel, 35 g; n-hexane/ethyl acetate, 80/20 v/v) to
give 3a; yield: 0.083 g (71%); IR (neat): n=3218,
2978 cmÀ1 1H NMR (CDCl3): d=6.89–6.80 (m, 4H), 4.01
;
(bs, 1H), 3.78 (s, 3H), 2.53 (s, 6H); 13C NMR (CDCl3): d=
153.6, 141.7, 115.5, 114.7, 55.8, 47.9; MS: calculated for
C9H14N2O=166.22; MS (m/z) (relative intensity)=166 (M+,
35), 122 (100), 151 (14), 42 (57).155.3, 154.1, 142.6, 139.9,
Adv. Synth. Catal. 2007, 349, 453 – 458
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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457

Sandro Cacchi et al.
UPDATES
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458
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Adv. Synth. Catal. 2007, 349, 453 – 458