Nickel-catalysed synthesis of 3-chloroanilines and chloro aminopyridines via cross-coupling reactions of aryl and heteroaryl dichlorides with amines

Article abstract of DOI:10.1016/S0040-4039(00)01931-6

Selective monoamination of aryl and heteroaryl dichlorides has been carried out using a catalyst combination of Ni(0) associated to 2,2′-bipyridine. The synthesis of novel 3-chloroanilines and chloro aminopyridines in good to excellent yields is allowed u

Full text of DOI:10.1016/S0040-4039(00)01931-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 247–250
Nickel-catalysed synthesis of 3-chloroanilines and chloro
aminopyridines via cross-coupling reactions of aryl and
heteroaryl dichlorides with amines
Christophe Desmarets, Raphae¨l Schneider and Yves Fort*
Synthe`se Organique et Re´activite´, UMR 7565, Universite´ Henri Poincare´-Nancy 1, BP 239,
54506 Vandoeuvre les Nancy Cedex, France
Received 18 September 2000; accepted 30 October 2000
Abstract—Selective monoamination of aryl and heteroaryl dichlorides has been carried out using a catalyst combination of Ni(0)
associated to 2,2%-bipyridine. The synthesis of novel 3-chloroanilines and chloro aminopyridines in good to excellent yields is
allowed using an excess of amine, 10 or 20 mol% catalyst and short reaction times. © 2000 Elsevier Science Ltd. All rights
reserved.
Oligoanilines have interesting electronic and magnetic
properties.1 They generate some of the most stable
radical cations and are readily oxidised to the aminium
state. Several methods for the construction of these
arylamines are known, e.g. the high temperature cop-
per-mediated Ullmann coupling of aryl iodides with
amines2 or the palladium-catalysed multiple coupling of
amines with polybromobenzenes.3 However, to our
knowledge, both approaches have not been applied to
the synthesis of unsymmetrical systems. Recently, we
have described the preparation of di- and triaminoben-
zenes from aryl and heteroaryl di- and trichlorides by a
catalyst combination of in situ generated colloidal Ni(0)
and 2,2%-bipyridine.4,5 In our search dealing with the
construction of regiodefined oligoanilines from unsym-
metrical 1,3-diaminobenzenes, we needed a convenient
access to 3-halogenoaminobenzenes. Although palla-
dium-catalysed carbonꢀnitrogen bond-forming reac-
tions are valuable synthetic methods and have found
wide applications in organic synthesis,6 the preparation
of 3-halogenoaminobenzenes has received little atten-
tion and was restricted to a few examples affording the
desired products in modest yields. For instance, 3-bro-
mophenylsulfoximine has been isolated in 51% yield by
Bolm. However, this result is restricted to the Pd-
catalysed arylation of sulfoximines.7 We wish to de-
scribe now a novel synthesis of 3-chloroanilines and
chloro aminopyridines from (het)aryl-1,3-dichlorides
via a nickel-catalysed amination reaction.
In our precedent report dealing with polyaminations of
aryl di- and trichlorides,4 the intermediate chloroanili-
nes could be isolated as side-products, even after ex-
tended reaction time at 65°C in THF. Interestingly, the
presence of these intermediates was not observed under
palladium catalysis. Indeed, Witulsky and Watanabe
reported that during amination of aryl dibromides, only
monoaminated products could be isolated as by-prod-
ucts.8,9 Moreover, the work of Beletskaya and Guilard
indicated that, using the Pd(dba)2/P(o-tolyl)3 catalyst,
the bromoamino intermediate was more reactive to-
wards amines than the starting dibromobenzene since it
did not accumulate.10 Then we thought that a conve-
nient method for the selective monoamination of aryl
dichlorides could be developed and we first compared
the reactivity of aryl dichlorides 1 and 3-chloro-
aminoarenes 2 towards N-methylpiperazine in the pres-
ence of the Ni(0)/2,2%-bipyridine catalyst under stan-
dard reaction conditions4 (Scheme 1).
Under nickel catalysis, we evidenced a great difference
of reactivity between starting materials. Indeed, a GC
monitoring of the reaction indicated that 1 was much
more rapidly consumed than 2. Compounds 1a and 1b
Keywords: catalysis; nickel; amination; chloroanilines; chloro aminopyridines.
* Corresponding author. E-mail: yves.fort@sor.uhp-nancy.fr
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01931-6

248
C. Desmarets et al. / Tetrahedron Letters 42 (2001) 247–250
H
N
O
Ni(0) (10 mol%)
Cl
Cl
Cl
N
2,2'-bipyridine
+
+
N
NaH / t-AmONa
THF, reflux
X
X
2a
2b
Me
(4 equiv.)
X = CH, 1a
X = N, 1b
Me
Me
Me
N
N
O
N
N
N
N
N
+
X
X
3a, 82%
3b, 76%
4a, 74%
4b, 72%
Scheme 1.
were completely converted after, respectively, 15 and 20
min. It also appeared that both reactions are competi-
tive since conversions of 2a and 2b were, respectively,
57 and 53% after 30 min. Finally, chloroaminoarenes
were totally converted into diaminobenzenes 3 and 4
after 1.75 h reaction time.
of dehalogenated starting material. The reaction rate
tended to slow greatly near the reaction completion and
lowering the reaction temperature resulted in incom-
plete conversion. Finally, the rate and the yield were
improved by increasing the amount of piperidine (3
equiv.), adding a slight excess of sodium hydride (2
mmol) and decreasing the reaction time to 15 min
(entry 3). Next, the efficiency of this protocol depends
on the nature of the starting amine. Using the condi-
tions determined with piperidine, 1-(3-chlorophenyl)-
morpholine 2a was obtained in only 41% yield (entry
6). The use of 20 mol% Ni afforded product 2a in 85%
yield (entry 7). We also studied the influence of the
catalyst amount during selective monoamination of 1,3-
dichlorobenzene varying the nature of the amine (Table
2). The use of 10 mol% Ni was effective for the
synthesis of 3-chloroanilines from cyclic amines like
pyrrolidine, piperidine and N-methylpiperazine (entries
1, 3 and 4), while reactions using morpholine and
secondary acyclic amines (entries 2, 5 and 6) required
20 mol% Ni to achieve completion. In all cases, the
starting material was completely consumed and the
These results encouraged us to study the selective intro-
duction of one amine group on aryl dichlorides. The
success of this methodology was, however, hinged upon
proper selection of reaction conditions. In a preliminary
study, monoaminations were first examined using 1,3-
dichlorobenzene 1a and piperidine (Table 1). When
classical reaction conditions of polyaminations were
applied (2 equiv. of amine per C-Cl unit and 10 mol%
of Ni(0)/2,2%-bipyridine catalyst in THF at 65°C),4 the
desired 1-(3-chlorophenyl)piperidine 2c was obtained in
44% yield after 30 min and the selectivity 2c/4c was
poor (entry 1). Increasing the amount of catalyst to 20
mol% did not afford a better result (entry 2), while
decreasing the amount of sodium hydride in the reac-
tion medium gave 2c in lower yields and larger amounts
Table 1. Optimisation of amine equivalents, catalyst loading and reaction time in nickel-catalysed monoamination of 1,3-
dichlorobenzenea
R1
N
R1
N
R1
N
Ni(0)
2,2'-bipyridine
R1
R2
Cl
Cl
Cl
R2
R2
R2
+
H N
+
NaH / t-AmONa
THF, reflux
1
2
4
Entry
Amine
Amine (equiv.) Ni (mol%)
Reaction time (min.)b
Selectivity 2/4 (%)b
Product
Yield (%)c
1
2
3
4
5
6
7
Piperidine
–
–
–
2
2
3
3
4
3
3
10
20
10
20
10
10
20
30
30
15
10
10
60
15
50/50
58/42
75/25
67/23
73/27
50/50
90/10
2c
–
–
–
–
44
51
68
60
66
41
85
–
Morpholine
–
2a
–
a Reactions were performed on 20 mmol of 1,3-dichlorobenzene; see Ref. 11 for further details.
b Determined by GC analysis.
c Isolated yields are average of at least two runs.

C. Desmarets et al. / Tetrahedron Letters 42 (2001) 247–250
249
Table 2. Selective monoamination of aryl dichloridesa
desired 3-chloroanilines 2 were readily isolated in good
yields.11 The main side products observed were the
monoaminoarenes arising from partial reduction, al-
though in some cases traces of 3,3%-diaminobiphenyls
were produced by homocoupling of the intermediate
chloroaminoarene.
on a multigram scale. This catalytic process displays
broad scope and efforts to design new aminoanilines
with potent ferromagnetic or conductive properties are
currently underway in our laboratories.
References
As can be seen from Table 2, this methodology was
successfully extended to 3,5- and 2,6-dichloropyridines
and enabled us to prepare an array of products with
various nitrogen substituents on the aromatic ring (en-
tries 7–11). At the present time, we assume that the
reaction proceeds at first by coordination of the amine
towards Ni(0). The subsequent oxidative addition of
the aryl halide was probably followed by CꢀN bond
formation by reductive elimination. However, the de-
pendence of nickel loading on the nature of the amine
suggests that reaction of the catalyst with amine is the
rate limiting step of the process or that catalyst lifetime
depends strongly on the used amine.
1. (a) Inada, H.; Yonemoto, Y.; Wakimoto, T.; Imai, K.;
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In summary, we have demonstrated that chloro amino-
(het)arenes are efficiently prepared by a selective
monoamination of aryl dichlorides using a Ni(0)/2,2%-
bipyridine catalyst system. The ready accessibility of
our catalyst associated with its low cost allows the
synthesis of these materials to be efficiently carried out

250
C. Desmarets et al. / Tetrahedron Letters 42 (2001) 247–250
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11. Typical procedure. 1-(3-Chlorophenyl)piperidine 2c
(Table 2, entry 1). To a suspension of degreased NaH (26
mmol) in THF (20 mL) were added piperidine (60 mmol)
and t-AmOH (4 mmol) in THF (10 mL) followed by
2,2%-bipyridine (6 mmol) and the mixture was heated at
65°C. Dried Ni(OAc)2 (2 mmol) was then added and the
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1,3-dichlorobenzene (20 mmol) and styrene (1 mmol) in
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sequentially and the reaction mixture was filtered, dried
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silica gel using 2% ethyl acetate/hexane as eluant to
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1
afford 2c (68%) as a pale yellow oil. H NMR (CDCl3,
400 MHz): 7.10 (dd, 3J=3J%=8.0 Hz, 2H); 6.85 (dd,
4J=4J%=2.0 Hz, 1H); 6.76–6.72 (m, 1H); 3.15–3.10 (m,
4H); 1.68–1.64 (m, 4H); 1.55–1.53 (m, 2H). 13C NMR
(CDCl3, 400 MHz): 153.0; 134.7; 129.8; 118.4; 115.8;
114.13; 49.96; 25.72; 24.20. Anal. calcd for C11H14NCl:
C, 67.51; H, 7.21; N, 7.16; Cl, 18.12. Found: C, 67.47; H,
7.33; N, 7.02. MS: m/z 194 (M+), 154, 140, 112, 77.
.
.