Nickel-catalysed sequential amination of aryl- and heteroaryl di- and trichlorides

Article abstract of DOI:10.1016/S0040-4020(01)00730-X

Unsymmetrical 1,3-diaminobenzenes and diaminopyridines were efficiently prepared by reaction of 3-chloroanilines and chloroaminopyridines with amines via a nickel-catalysed amination. The Ni/2,2′-bipyridine catalyst is also effective for the sequential am

Full text of DOI:10.1016/S0040-4020(01)00730-X

TETRAHEDRON
Pergamon
Tetrahedron 57 ;2001) 7657±7664
Nickel-catalysed sequential amination of aryl- and
heteroaryl di- and trichlorides
p
È
Christophe Desmarets, Raphael Schneider and Yves Fort
Á Â Â Â Â
Faculte des Sciences, Synthese Organique et Reactivite, UMR CNRS-UHP 7565, Universite Henri PoincareÐNancy 1,
B.P. 239, 54506 Vandoeuvre les Nancy cedex, France
Received 30 April 2001; revised 15 June 2001; accepted 13 July 2001
AbstractÐUnsymmetrical 1,3-diaminobenzenes and diaminopyridines were ef®ciently prepared by reaction of 3-chloroanilines and chloro-
aminopyridines with amines via a nickel-catalysed amination. The Ni/2,20-bipyridine catalyst is also effective for the sequential amination of
aryl trichlorides. After a ®rst selective monoamination of 1,3,5-trichlorobenzene, the obtained 3,5-dichloroanilines were subsequently
transformed into novel and unsymmetrical 1,3,5-triaminobenzenes. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
to develop a general protocol for the ef®cient synthesis of
1,3-di- and 1,3,5-triaminobenzenes via nickel-catalysed
amination chemistry.
Arylamines are common structural elements found in many
biologically active substrates1 as well as in materials
possessing electronic and magnetic properties.2 They are
also used as key building blocks in the synthesis of hetero-
cyclic compounds,3 pharmaceuticals or pesticides4 and in
asymmetric catalysis.5 For these reasons, there is still a
search for methods allowing an ef®cient preparation of the
less accessible derivatives and for the synthesis of novel
arylamines.
Indeed, as part of our continuing studies on arylamination
reactions,13 we recently developed the synthesis of symme-
trical di- and triaminobenzenes 1 from aryl and heteroaryl
di- and trichlorides using a colloidal Ni;0), in situ generated
by reduction of Ni;OAc)2 with t-AmONa activated sodium
hydride, associated to 2,20-bipyridine as the ligand.14 More
recently, we established a novel method for the catalytic
monoamination of aryl 1,3-dichlorides using a slightly
modi®ed nickel catalyst ;Scheme 1).15
Recently developed palladium- or copper-catalysed amin-
ations of aryl halides and arylboronic acids have emerged as
powerful synthetic methods for the preparation of substi-
tuted arylamines.6±8 Although polyamination products
have been obtained in good yields by reacting aryl poly-
bromides with amines under palladium catalysis,9 sequen-
tial amination of aryl dihalides has received little attention
and was limited to ortho derivatives. In 1996, Buchwald et
al. reported ®rst the use of the Pd2;dba)3-BINAP catalyst to
couple 2-bromo-N,N-dimethylaniline with aniline.10 Diver
et al. described also the stepwise synthesis of unsymmetrical
substituted 1,2-diaminobenzenes from ortho dibromoben-
zene using the same catalyst or Pd2;dba)3 associated to an
electron-rich mixed P,N ligand.11 Another approach to
diaminobenzenes which invoke a nucleophilic substitution
followed by a palladium-catalysed amination reaction has
also been reported very recently by Brown et al.12 In our
effort toward the construction of new aminoanilines with
potent ferromagnetic or conductive properties, we hoped
Herein, we report on the extension of this monoamination
method ®rst, to nickel-catalysed synthesis of novel unsym-
metrical 1,3-diaminobenzenes and diaminopyridines and
second, to sequential amination of 1,3,5-trichlorobenzene.
2. Results and discussion
The nickel-catalysed cross-coupling reactions of chloro-
aminoarenes 215 with secondary amines were ®rst examined
;Scheme 2).
Keywords: nickel-catalysed amination; aryl trichlorides; diamino-
benzenes; diamino-pyridines; triamino-pyridines.
p
Corresponding author. Fax: 133-03-83-40-45-58;
e-mail: yves.fort@sor.uhp-nancy.fr
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020;01)00730-X

7658
C. Desmarets et al. / Tetrahedron 57 42001) 7657±7664
Scheme 2.
As shown in Table 1, a variety of amines are suitable coupling
partners and compounds 3 could be prepared in good to excel-
lent yields using the Ni/2,20-bipyridine catalyst. For example,
1-;3-chlorophenyl)piperidine 2b could be converted to
product 3c in 75% yield using 10 mol% Ni ;entry c). The
reaction of acyclic amines with compounds 2 was slow
using 10 mol% catalyst ;entries a, b and e). The desired
products were obtained in good yields when 20 mol% of the
Table 1. Nickel-catalysed synthesis of unsymmetrical 1,3-diaminobenzenes and diaminopyridines
Entry
Starting material 2
Amine
Reaction
time ;h)a
Product 3
Isolated
yield ;%)b
Catalyst loadings of 10 and 20 mol% Ni were used respectively with cyclic and acyclic amines. All reactions were performed using 20 mmol starting material.
Determined by GC analysis.
Isolated yield after silica gel chromatography.
a
b

C. Desmarets et al. / Tetrahedron 57 42001) 7657±7664
7659
Scheme 3.
nickelcatalystwas employed. Inall cases, the startingmaterial
2 was completely consumed and the main side-product
observed was an aminoarene arising from reduction. In addi-
tion, we have also noted that variations of the molar ratio of
amine/2 exerted a notable effect on the outcome of the trans-
formation. For example, the highest yield of 3a ;52%, entry a)
was obtained in an experiment with a 2:1 ratio and 3 hours
reaction time. Using only 1.1 equiv. methylbutylamine, a
large proportion of 3,30-bis;morpholino)biphenyl ;27%), aris-
ing from homocoupling of 1-;3-chlorophenyl)morpholine 2a
with our 2,20-bipyridine liganded Ni;0) catalyst, was formed
after 4 h. All aminations were therefore performed using an
excess amine ;2 equiv.) to minimise the formation of such
biaryls. As can be seen from Table 1, this methodology was
successfully extended to 5-;or 6) chloro-3-;or 2) aminopyri-
dines and enabled us to prepare an array of products with
various nitrogen substituents on the aromatic ring ;entries
d±i).The substrate scope of our Ni reagent was also expanded
to arylpiperazine, an important class of pharmaceutical
compounds. Coupling of 3-chloro-5-piperidinopyridine 2d
with piperazine yielded 68% of the desired compound 3f
and the formation of undesired double coupling products
was not observed.
The scope of our method was further expanded to the selec-
tive monoamination of 1,3,5-trichlorobenzene. However a
Table 2. Nickel-catalysed synthesis of 3,5-dichloroanilines 4 from 1,3,5-trichlorobenzene
Entry
Amine
Ni
;mol%)
Reaction
time ;h)a
Product 4
Isolated
yield ;%)b
Reactions were performed on 20 mmol 1,3,5-trichlorobenzene.
Determined by GC analysis.
a
b
1
Yields refer to isolated yields ;average of two runs) of compounds estimated to be .95% pure as determined by H, 13C NMR, GC and HRMS analysis.

7660
C. Desmarets et al. / Tetrahedron 57 42001) 7657±7664
Table 3. Amination of 3,5-dichloroanilines 4
Entry Starting
material
Amine
Ni
;mol%)
Reaction
time ;h)a
Product 7
Yield
;%)b
Reactions were performed using 20 mmol 4 and 60 mmol amine in THF at 658C.
Determined by GC analysis.
a
b
Yields refer to isolated yields ;average of two runs) of compounds estimated to be .95% pure as determined by 1H, 13C NMR, GC and HRMS analysis.

C. Desmarets et al. / Tetrahedron 57 42001) 7657±7664
7661
further problem in the synthesis of 3,5-dichloroaminoben-
zenes 4 was the formation of di- and triaminated products 5
and 6 ;Scheme 3).
atmosphere. THF was distilled from benzophenone-sodium
adduct and stored over sodium wire. tert-Amyl alcohol was
distilled from sodium. Crushed Ni;OAc)2. 4H2O ;Fluka)
was dried under vacuum ;20 mm Hg) at 1108C for 12 h.
Sodium hydride ;65% in mineral oil, Fluka) was used
after two washings with THF under nitrogen. 2,20-Bipyri-
dine was recrystallised in hexane before use. All reagents
were purchased from commercial sources and were used
without puri®cation. Melting points were taken on a Tottoli
apparatus and were uncorrected. GC analysis were
conducted on a Shimadzu GC-8A instrument equipped
with a ¯ame-ionisation detector and using an Alltech EC5
column ;30 m£0.32 mm£2.65 mm). Flash chromatography
was performed using Kieselgel 60 ;230±400 mesh, Merck).
NMR spectra were recorded with Brucker AM 400 ;1H at
As an exploratory study, we examined the monoamination
of 1,3,5-trichlorobenzene using piperidine as a model amine
under the conditions de®ned for aryl dichlorides,15 namely
using 3 equiv. of amine and 10 mol% Ni during a short
reaction time. The reaction was monitored by GC and
stopped promptly when the starting material was consumed.
Under these conditions, we found that, besides the desired 1-
;3,5-dichlorophenyl)piperidine 4a ;49%), substantial
amounts of diaminated 5 ;6%) and triaminated 6 ;21%)
by-products were also isolated. Because of the strong elec-
tron-withdrawing properties of the m-amino group intro-
duced, p-de®cient compounds
4
and especially
5
400 MHz, 13C at 100 MHz) or AC 250 ;1H at 250 MHz, 13
C
underwent easily a new and competitive Ni-catalysed
amination reaction. Unfortunately, no signi®cant improve-
ment of the yield of 4a was observed by decreasing the
amount of sodium hydride or amine in the catalyst. Lower-
ing the reaction temperature or using 5 mol% Ni resulted in
a decrease of the reaction rate and hydrodehalogenation
products were also observed.
at 62.5 MHz). Chemical shifts are expressed in d ;ppm)
values with tetramethylsilane ;TMS) as internal reference.
IR spectra were recorded on a Perkin±Elmer 841 spectro-
meter. Yields refer to isolated yields of compounds esti-
1
mated to be up to 95% pure as determined by H NMR
and up to 98% pure as determined by capillary GC.
HRMS and combustion analysis were performed by the
Service central d'analyses duCNRS ;Vernaison, France).
Results of the nickel-catalysed monoaminations of 1,3,5-
trichlorobenzene are summarised in Table 2. As previously
observed with our Ni catalyst,15 the structure of the amine
was found to have a profound effect on the reaction time and
yield. The use of 10 mol% Ni was effective for the synthesis
of 3,5-dichloroanilines 4 from cyclic amines like piperidine,
pyrrolidine, and N-methylpiperazine ;entries a, b and d).
Aryl aminations involving the less reactive amines, morpho-
line and N-methylaminoacetaldehyde dimethyl acetal
;entries c and e), required 20 mol% Ni for the ®rst coupling.
Finally, the 2,20-bipyridine liganded Ni catalyst provided
acceptable yields of the desired products 4 and cross-
couplings of these 3,5-dichloro aminobenzenes with diverse
selection of amines were studied. Table 3 provides the
results of the double amination of substrates 4 using the
optimised conditions for the second coupling, which
consisted of 2 equiv. amine per carbon±chlorine function
and 10 or 20 mol% of the Ni catalyst respectively for cyclic
and acyclic amines. Under these conditions, our synthetic
method allowed the preparation of a variety of novel and
elaborated triaminobenzenes 7, obtained in good yields
ranging from 55 to 80%.
4.2. Nickel-catalysed synthesis of diaminobenzenes and
diaminopyridines 3
4.2.1. N-Butyl-N-methyl-3-morpholinoaniline 3a *Table
1). Typical procedure for aminations using 20 mol% Ni
catalyst. To a suspension of degreased NaH ;30 mmol) in
THF ;20 mL) were added methylbutylamine ;40 mmol) and
t-AmOH ;8 mmol) in THF ;10 mL) followed by 2,20-bipyr-
idine ;8 mmol) and the mixture was heated at 658C. Dried
Ni;OAc)2 ;4 mmol) was then added and the mixture was
further stirred at 658C for 2 h. A solution of 1-;3-chlorophe-
nyl)morpholine 2a ;20 mmol) and styrene ;2 mmol) in THF
;10 mL) was then added dropwise. The reaction was moni-
tored by GC and after complete consumption of the starting
material ;3 hours), the mixture was cooled to room tempera-
ture. Water ;1 mL) and dichloromethane ;50 mL) were
added sequentially and the reaction mixture was ®ltered,
dried over MgSO4 and evaporated. The residue was puri®ed
by silica gel column chromatography using n-hexane±
AcOEt ;70:30) as eluant to give 3a as a pale yellow oil.
1H NMR ;400 MHz, CDCl3) d ppm: 7.81±7.77 ;m, 1H),
7.30±7.25 ;m, 2H), 6.91±6.85 ;m, 1H), 3.86±3.82 ;m,
4H), 3.28±3.23 ;m, 2H), 3.13 ;t, Jˆ5.20 Hz, 4H), 2.90 ;s,
3H), 1.53±1.51 ;m, 2H), 1.34±1.32 ;m, 2H), 0.93 ;t,
Jˆ7.60 Hz, 3H). 13C NMR ;100 MHz, CDCl3) d ppm:
156.02, 149.07, 136.80, 120.96, 115.58, 66.82, 52.54,
49.32, 38.54, 28.89, 20.27, 13.94. HREIMS Obsd.
m/zˆ248.187 ;M), C15H24N2O requires 248.1888.
3. Conclusion
In summary, we have demonstrated that the catalytic system
consisting of Ni;0) associated to 2,20-bipyridine allowed the
sequential coupling of aryl- and heteroaryl di- and trichlor-
ides with amines. The synthesis of novel aryl and heteroaryl
di- and triamines has thus been achieved in good yields by
combination of two nickel-catalysed amination reactions.
4.2.2. N-Benzyl-N-methyl-3-morpholinoaniline 3b *Table
1). According to the typical procedure, 3b was obtained as a
pale yellow oil from the reaction of 1-;3-chlorophenyl)mor-
pholine 2a with methylbenzylamine using 20 mol% Ni.
Puri®cation was performed by silica gel column chromato-
4. Experimental
4.1. General comments
1
graphy using n-hexane±AcOEt ;70:30) as eluent. H NMR
;400 MHz, CDCl3) d ppm: 7.31±7.28 ;m, 2H), 7.27±7.22
;m, 3H), 7.11 ;dd, JˆJ0ˆ8.40 Hz, 1H), 6.34±6.29 ;m, 3H),
4.50 ;s, 2H), 3.83±3.78 ;m, 4H), 3.13±3.09 ;m, 4H), 2.99 ;s,
All experiments were carried out under a nitrogen

7662
C. Desmarets et al. / Tetrahedron 57 42001) 7657±7664
3H). 13C NMR ;100 MHz, CDCl3): 152.48, 150.79, 139.10,
129.67, 128.48, 126.77, 105.16, 104.73, 100.38, 66.96,
56.75, 49.65, 38.54. HREIMS Obsd. m/zˆ282.1728 ;M),
C18H22N2O requires 282.1732.
130.72, 129.80, 110.40, 50.23, 50.05, 45.96, 25.62, 24.10.
HREIMS Obsd. m/zˆ246.1852 ;M), C14H22N4 requires
246.1844.
4.2.7. Ethyl 4-*5-morpholino-3-pyridinyl)tetrahydro-1*2H)-
pyrazine carboxylate 3g *Table 1). According to the typi-
cal procedure, 3g was obtained as a pale yellow oil from the
reaction of ethyl 4-;5-chloro-3-pyridyl)-1-piperazine carb-
oxylate 2e with morpholine using 10 mol% Ni. Puri®cation
was performed by silica gel column chromatography using
AcOEt as eluent. 1H NMR ;400 MHz, CDCl3) d ppm: 7.86
;2d, Jˆ2.00 Hz, 2H), 6.67 ;dd, Jˆ2.00 Hz, 1H), 4.19 ;q,
Jˆ7.20 Hz, 2H), 3.88±3.83 ;m, 4H), 3.65±3.61 ;m, 4H),
3.18±3.15 ;m, 8H), 1.29 ;t, Jˆ7.20 Hz, 3H). 13C NMR
;100 MHz, CDCl3): 155.18, 147.17, 146.69, 130.72,
130.28, 109.84, 66.48, 61.36, 48.81, 48.65, 48.38, 43.27,
14.49. IR ;NaCl) n cm21 1699 ;CvO). HREIMS Obsd.
m/zˆ320.1857 ;M), C16H24N4O3 requires 320.1848.
4.2.3. 1-Methyl-4-*3-piperidinophenyl)piperazine 3c *Table
1). Typical procedure for aminations using 10 mol% Ni
catalyst. N-methylpiperazine ;40 mmol), t-AmOH
;4 mmol), NaH ;26 mmol), Ni;OAc)2 ;2 mmol), 2,20-bipyr-
idine ;6 mmol) and styrene ;2 mmol) were used for the
amination of 1-;3-chlorophenyl)piperidine 2b using the
standard procedure described above. 3c was obtained as a
pale yellow oil after puri®cation by silica gel column chro-
1
matography using AcOEt as eluent. H NMR ;400 MHz,
CDCl3) d ppm: 7.14 ;brs, 1H), 6.52 ;d, Jˆ4.00 Hz, 1H),
6.48±6.46 ;m, 1H), 6.43 ;d, Jˆ4.00 Hz, 1H), 3.22±3.18
;m, 4H), 3.16±3.11 ;m, 4H), 2.60±2.55 ;m, 4H), 2.36 ;s,
3H), 1.72±1.68 ;m, 4H), 1.59±1.57 ;m, 2H). 13C NMR
;100 MHz, CDCl3): 153.39, 152.22, 129.40, 108.92,
107.88, 105.28, 55.14, 51.00, 49.10, 46.02, 25.94, 24.35.
HREIMS Obsd. m/zˆ259.2041 ;M), C16H25N3 requires
259.2048.
4.2.8. 4-[6-*4-Methylpiperazino)-2-pyridinyl]morpho-
line 3h *Table 1). According to the typical procedure, 3h
was obtained as a pale yellow oil from the reaction of 3-;3-
chloro-2-pyridyl)morpholine 2f with N-methylpiperazine
using 10 mol% Ni. Puri®cation was performed by silica
gel column chromatography using n-hexane±AcOEt ;20/
4.2.4. 4-[5-*4-Methylpiperazino)-3-pyridinyl]morpholine
3d *Table 1). According to the typical procedure, 3d was
obtained as a pale yellow oil from the reaction of 4-;5-chlo-
ro-3-pyridyl)morpholine 2c with N-methylpiperazine using
10 mol% Ni. Puri®cation was performed by silica gel
1
80) as eluent. H NMR ;400 MHz, CDCl3) d ppm: 7.35
;dd, JˆJ0ˆ8.00 Hz, 1H), 6.04 ;d, Jˆ8.00 Hz, 1H), 5.98
;d, J0ˆ8.00 Hz, 1H), 3.83±3.78 ;m, 4H), 3.55±3.49 ;m,
4H), 3.48±3.42 ;m, 4H), 2.52±2.48 ;m, 4H), 2.34 ;s, 3H).
13C NMR ;100 MHz, CDCl3): 158.43, 158.31, 139.07,
96.35, 95.62, 66.80, 54.93, 49.21, 45.59, 45.06. HREIMS
obsd. m/zˆ262.1797 ;M), C14H22N4O requires 262.1793.
1
column chromatography using AcOEt as eluent. H NMR
;400 MHz, CDCl3) d ppm: 7.86 ;d, Jˆ2.80 Hz, 1H), 7.80
;d, J0ˆ2.80 Hz, 1H), 6.67 ;dd, JˆJ0ˆ2.80 Hz, 1H), 3.84 ;t,
Jˆ6.80 Hz, 4H), 3.22 ;t, Jˆ6.40 Hz, 4H), 3.16 ;t,
Jˆ6.40 Hz, 4H), 2.57 ;t, Jˆ6.40 Hz, 4H), 2.34 ;s, 3H).
13C NMR ;100 MHz, CDCl3): 147.03, 129.97, 129.20,
108.96, 66.31, 54.47, 48.54, 48.15, 45.71. HREIMS obsd.
m/zˆ262.179 ;M), C14H22N4O requires 262.1793.
4.2.9. 4-*6-Piperidino-2-pyridinyl)morpholine 3i *Table
1). According to the typical procedure, 3i was obtained as
a pale yellow oil from the reaction of 3-;3-chloro-2-pyri-
dyl)morpholine 2f with piperidine using 10 mol% Ni. Puri-
®cation was performed by silica gel column
chromatography using n-hexane±AcOEt ;50/50) as eluent.
1H NMR ;400 MHz, CDCl3) d ppm: 7.32 ;dd, Jˆ8.40 Hz,
1H), 6.04 ;d, Jˆ8.40 Hz, 1H), 5.92 ;d, Jˆ8.00 Hz, 1H),
3.82±3.78 ;m, 4H), 3.46±3.42 ;m, 8H), 1.62±1.60 ;m,
6H). 13C NMR ;100 MHz, CDCl3): 158.58, 158.52,
138.98, 96.53, 94.75, 68.88, 46.20, 45.68, 25.52, 24.82.
HREIMS Obsd. m/zˆ247.1693 ;M), C14H21N3O requires
247.1684.
4.2.5. N-*2,2-Dimethoxyethyl)-N-methyl-5-morpholino-
3-pyridinamine 3e *Table 1). According to the typical
procedure, 3e was obtained as a pale yellow oil from the
reaction of 4-;5-chloro-3-pyridyl)morpholine 2c with N-
methylaminoacetaldehyde dimethyl acetal using 20 mol%
Ni. Puri®cation was performed by silica gel column chro-
1
matography using n-hexane±AcOEt ;30/70) as eluent. H
NMR ;400 MHz, CDCl3) d ppm: 7.73 ;d, Jˆ2.40 Hz, 1H),
7.71 ;d, J0ˆ2.70 Hz, 1H), 6.50 ;dd, Jˆ2.40 Hz, J0ˆ2.70 Hz,
1H), 4.50 ;t, Jˆ5.20 Hz, 1H), 3.88±3.82 ;m, 4H), 3.45±3.40
;m, 2H), 3.40 ;s, 6H), 3.18±3.13 ;m, 4H), 3.00 ;s, 3H). 13C
NMR ;100 MHz, CDCl3): 147.16, 145.26, 126.74, 126.62,
104.99, 102.96, 66.41, 54.74, 54.43, 48.68, 38.72. HREIMS
Obsd. m/zˆ281.173 ;M), C14H23N3O3 requires 281.1739.
4.3. Synthesis of 3,5-dichloroanilines 4 from 1,3,5-tri-
chlorobenzene
4.3.1. 1-*3,5-Dichlorophenyl)piperidine 4a *Table 2).
Typical procedure for aminations using 10 mol% Ni
catalyst. Piperidine ;60 mmol), t-AmOH ;4 mmol), NaH
;26 mmol), Ni;OAc)2 ;2 mmol), 2,20-bipyridine ;6 mmol)
and styrene ;2 mmol) were used for the amination of
1,3,5-trichlorobenzene ;20 mmol). 4a was obtained as a
pale yellow oil after puri®cation by silica gel column chro-
4.2.6. 1-*5-Piperidino-3-pyridinyl)piperazine 3f *Table
1). According to the typical procedure, 3f was obtained as
a pale yellow oil from the reaction of 3-chloro-5-piperidi-
nopyridine 2d with piperazine using 10 mol% Ni. Puri®ca-
tion was performed by silica gel column chromatography
using AcOEt±MeOH ;70/30) as eluent. 1H NMR ;400 MHz,
CDCl3) d ppm: 7.84 ;d, Jˆ2.00 Hz, 1H), 7.79 ;d,
J0ˆ2.40 Hz, 1H), 6.71 ;dd, Jˆ2.00 Hz, J0ˆ2.40 Hz, 1H),
3.48 ;s, 1H), 3.18±3.16 ;m, 4H), 3.05±3.04 ;m, 4H),
1.80±1.79 ;m, 4H), 1.71±1.69 ;m, 4H), 1.59±1.58 ;m,
2H). 13C NMR ;100 MHz, CDCl3): 147.90, 146.08,
1
matography using n-hexane±AcOEt ;98/2) as eluent. H
NMR ;400 MHz, CDCl3) d ppm: 6.72 ;s, 3H), 3.16±3.14
;m, 4H), 1.67±1.62 ;m, 4H), 1.60±1.58 ;m, 2H). 13C NMR
;100 MHz, CDCl3) d ppm: 135.26, 117.85, 113.79, 49.51,
25.36, 24.11. HREIMS obsd. m/zˆ229.042 ;M),
C11H13Cl2N requires 229.0424.

C. Desmarets et al. / Tetrahedron 57 42001) 7657±7664
7663
4.3.2. 1-*3,5-Dichlorophenyl)pyrrolidine 4b *Table 2).
According to the typical procedure, 4b was obtained as a
pale yellow oil from the reaction of 1,3,5-trichlorobenzene
with pyrrolidine using 10 mol% Ni. Puri®cation was
performed by silica gel column chromatography using n-
6.15 ;t, Jˆ1.60 Hz, 1H), 6.07 ;d, Jˆ1.60 Hz, 2H), 3.83±
3.81 ;m, 4H), 3.19±3.16 ;m, 4H), 3.13±3.16 ;m, 8H),
1.72±1.67 ;m, 8H), 1.57±1.54 ;m, 4H). 13C NMR
;100 MHz, CDCl3) d ppm: 154.02, 152.91, 98.39, 97.95,
67.02, 51.34, 49.89, 26.00, 24.36. HREIMS obsd
m/zˆ329.2457 ;M), C20H31N3O requires 329.2467.
4.4.2. N1,N3-bis*2,2-dimethoxyethyl)-N1,N3-dimethyl-5-
morpholino-1,3-benzenediamine 7b *Table 3). According
to the typical procedure, 7b was obtained as a pale yellow
oil from the reaction of 4c with N-methylaminoacetalde-
hyde dimethyl acetal using 20 mol% Ni. Puri®cation was
performed by silica gel column chromatography using n-
hexane±AcOEt ;65/35) as eluent. 1H NMR ;400 MHz,
CDCl3) d ppm: 5.76 ;d, Jˆ2.00 Hz, 2H), 5.73 ;t,
Jˆ2.00 Hz, 1H), 4.52 ;t, Jˆ4.80 Hz, 2H), 3.85±3.83 ;m,
4H), 3.43±3.38 ;m, 16H), 3.16±3.14 ;m, 4H), 2.03 ;s,
6H), 1.58±1.55 ;m, 2H). 13C NMR ;100 MHz, CDCl3) d
ppm: 153.34, 150.87, 103.49, 90.49, 89.92, 66.91, 60.12,
55.62, 54.36, 50.01, 39.28. HREIMS obsd. m/zˆ398.2647
;MH1), C20H36N3O4 requires 398.2655.
1
hexane as eluent. H NMR ;400 MHz, CDCl3) d ppm:
6.57 ;t, Jˆ1.60 Hz, 1H), 6.33 ;d, Jˆ1.60 Hz, 2H), 3.19±
3.16 ;m, 4H), 1.98±1.95 ;m, 4H). 13C NMR ;100 MHz,
CDCl3) d ppm: 148.92, 135.16, 114.74, 109.71, 47.51,
25.33. HREIMS obsd. m/zˆ215.0259 ;M), C10H11Cl2N
requires 215.0268.
4.3.3. 4-*3,5-Dichlorophenyl)morpholine 4c *Table 2).
Typical procedure for aminations using 20 mol% Ni
catalyst. Morpholine ;60 mmol), t-AmOH ;8 mmol), NaH
;40 mmol), Ni;OAc)2 ;4 mmol), 2,20-bipyridine ;8 mmol)
and styrene ;2 mmol) were used for the amination of
1,3,5-trichlorobenzene ;20 mmol). 4c was obtained as a
white solid after puri®cation by silica gel column
chromatography using n-hexane±AcOEt ;95/5) as eluent.
1
Mp 868C. H NMR ;400 MHz, CDCl3) d ppm: 6.82 ;t,
Jˆ1.60 Hz, 1H), 6.73 ;d, Jˆ1.60 Hz, 2H), 3.88±3.81 ;m,
4H), 3.15±3.13 ;m, 4H). 13C NMR ;100 MHz, CDCl3) d
ppm: 152.61, 135.45, 119.18, 113.48, 66.47, 48.32.
HREIMS Obsd. m/zˆ231.022 ;M), C10H11Cl2NO requires
231.0218.
4.4.3. Ethyl 4-{3-[4-*ethoxycarbonyl)piperazino]-5-mor-
pholinophenyl}tetrahydro-1*2H)-pyrazine carboxylate
7c *Table 3). According to the typical procedure, 7c was
obtained as a pale yellow oil from the reaction of 4c with
ethyl tetrahydro-1;2H)-pyrazine carboxylate using 10 mol%
Ni. Puri®cation was performed by silica gel column chro-
4.3.4. 1-*3,5-Dichlorophenyl)-4-methylpiperazine 4d
*Table 2). According to the typical procedure, 4d was
obtained as a pale yellow oil from the reaction of 1,3,5-
trichlorobenzene with N-methylpiperazine using 10 mol%
Ni. Puri®cation was performed by silica gel column
chromatography using AcOEt as eluent. 1H NMR
;400 MHz, CDCl3) d ppm: 6.78 ;t, Jˆ1.20 Hz, 1H), 6.73
;d, Jˆ1.20 Hz, 2H), 3.21±3.19 ;m, 4H), 2.55±2.36 ;m,
4H), 2.34 ;s, 3H). 13C NMR ;100 MHz, CDCl3) d ppm:
45.99, 48.06, 54.63, 113.66, 118.67, 135.35, 152.51.
HREIMS obsd. m/zˆ244.0521 ;M), C11H14Cl2N2 requires
244.0534.
1
matography using n-hexane±AcOEt ;20/80) as eluent. H
NMR ;400 MHz, CDCl3) d ppm: 6.08 ;s, 3H), 4.13 ;q,
Jˆ7.60 Hz, 4H), 3.85±3.83 ;m, 4H), 3.63±3.60 ;m, 8H),
3.21±3.18 ;m, 4H), 3.14±3.11 ;m, 8H), 1.26 ;t,
Jˆ7.60 Hz, 6H). 13C NMR ;100 MHz, CDCl3) d ppm:
155.32, 153.08, 152.45, 98.95, 98.29, 66.82, 61.32, 60.23,
49.86, 49.59, 43.59, 14.55. IR ;NaCl) n cm21 1699 ;CvO).
HREIMS obsd. m/zˆ475.2786 ;M), C24H37N5O5 requires
475.2794.
4.4.4. 4-*3-Morpholino-5-piperidinophenyl)morpholine
7d *Table 3). According to the typical procedure, 7d was
obtained as a pale yellow oil from the reaction of 4a with
morpholine using 10 mol% Ni. Puri®cation was performed
by silica gel column chromatography using n-hexane±
4.3.5. 3,5-Dichloro-N-*2,2-dimethoxyethyl)-N-methyl-
aniline 4e *Table 2). According to the typical procedure,
4e was obtained as a pale yellow oil from the reaction of
1,3,5-trichlorobenzene with N-methylaminoacetaldehyde
dimethyl acetal using 20 mol% Ni. Puri®cation was
performed by silica gel column chromatography using n-
hexane±AcOEt ;98/2) as eluent. 1H NMR ;400 MHz,
CDCl3) d ppm: 6.65 ;t, Jˆ1.60 Hz, 1H), 6.55 ;d,
Jˆ1.60 Hz, 2H), 4.45 ;t, Jˆ5.20 Hz, 1H), 3.41±3.37 ;m,
8H), 2.96 ;m, 3H). 13C NMR ;100 MHz, CDCl3) d ppm:
150.60, 135.42, 115.88, 110.06, 102.76, 54.91, 54.70, 39.31.
HREIMS obsd. m/zˆ263.0435 ;M), C11H15Cl2NO2 requires
263.0480.
1
AcOEt ;70/30) as eluent. H NMR ;400 MHz, CDCl3) d
ppm: 6.11 ;d, Jˆ2.00 Hz, 2H), 6.03 ;t, Jˆ2.00 Hz, 1H),
3.86±3.81 ;m, 8H), 3.19±3.16 ;m, 4H), 3.13±3.10 ;m,
8H), 1.73±1.68 ;m, 4H), 1.58±1.55 ;m, 2H). 13C NMR
;100 MHz, CDCl3) d ppm: 152.80, 152.16, 98.08, 96.62,
66.77, 51.05, 49.83, 25.79, 24.17. HREIMS obsd.
m/zˆ331.2263 ;M), C19H29N3O2 requires 331.2259.
4.4.5. 4-[3-Morpholino-5-*1-pyrrolidinyl)phenyl]mor-
pholine 7e *Table 3). According to the typical procedure,
7e was obtained as a pale yellow oil from the reaction of 4b
with morpholine using 10 mol% Ni. Puri®cation was
performed by silica gel column chromatography using n-
hexane±AcOEt ;65/35) as eluent. 1H NMR ;400 MHz,
CDCl3) d ppm: 5.89 ;t, Jˆ2.00 Hz, 1H), 5.73 ;d,
Jˆ2.00 Hz, 2H), 3.87±3.83 ;m, 8H), 3.28±3.25 ;m, 4H),
3.15±3.13 ;m, 8H), 2.00±1.96 ;m, 4H). 13C NMR
;100 MHz, CDCl3) d ppm: 153.30, 149.36, 93.41, 93.13,
67.01, 50.11, 47.64, 25.35. HREIMS obsd. m/zˆ317.211
;M), C18H27N3O2 requires 317.2103.
4.4. Synthesis of triaminobenzenes 7from 3,5-dichloro-
anilines 4
4.4.1. 4-*3,5-Diperidinophenyl)morpholine 7a *Table 3).
According to the typical procedure, 7a was obtained as a
yellow solid from the reaction of 4c with piperidine using
10 mol% Ni. Puri®cation was performed by silica gel
column chromatography using n-hexane±AcOEt ;60/40)
1
as eluent. Mp 1378C. H NMR ;400 MHz, CDCl3) d ppm:

7664
C. Desmarets et al. / Tetrahedron 57 42001) 7657±7664
5. Asami, M.; Sato, S.; Watanabe, H. Chem. Lett. 2000, 990±
991.
4.4.6. 4-[3-*4-Methylpiperazino)-5-morpholinophenyl]-
morpholine 7f *Table 3). According to the typical proce-
dure, 7f was obtained as a thick oil from the reaction of 4d
with morpholine using 10 mol% Ni. Puri®cation was
performed by silica gel column chromatography using
AcOEt±MeOH ;95/5) as eluent. 1H NMR ;400 MHz,
CDCl3) d ppm: 6.08 ;d, Jˆ2.00 Hz, 2H), 6.06 ;t,
Jˆ2.00 Hz, 1H), 3.88±3.83 ;m, 8H), 3.23±3.19 ;m, 4H),
3.15±3.12 ;m, 8H), 2.70±2.68 ;m, 4H), 2.40 ;s, 3H). 13C
NMR ;100 MHz, CDCl3) d ppm: 153.06, 152.79, 97.86,
97.32, 66.87, 54.50, 49.88, 48.87, 45.21. HREIMS obsd.
m/zˆ346.2371 ;M), C19H30N4O2 requires 346.2368.
6. For reviews on palladium-catalysed aminations, see: ;a) Hart-
wig, J. F. Synlett 1997, 329±340. ;b) Hartwig, J. F. Acc. Chem.
Res. 1998, 31, 852±860. ;c) Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805±818. ;d) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 546, 125±146. ;e) Bel®eld, A. J.; Brown, G. R.;
Foubister, A. J. Tetrahedron 1999, 55, 11399±11428.
7. ;a) For recent reports on palladium-catalysed aminations, see:
;a) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307±
1309. ;b) Harris, M. C.; Geis, O.; Buchwald, S. L. J. Org.
Chem. 1999, 64, 6019±6022. ;c) Bolm, C.; Hildebrand, J. P.
J. Org. Chem. 2000, 65, 169±175. ;d) Wolfe, J. P.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1144±1157. ;e) Wolfe, J. P.;
Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1158±1174. ;f) Yin, J.; Buchwald, S. L. Org.
Lett. 2000, 2, 1101±1104. ;g) Stauffer, S. R.; Lee, S.; Stam-
buli, J. P.; Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2,
1423±1426. ;h) Harris, M. C.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 5327±5333. ;i) Zhang, X.-X.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 8027±8031. ;j) Li, G. Y.
Angew. Chem. Int. Ed. 2001, 40, 1513±1516. ;k) Ali, M. H.;
Buchwald, S. L. J. Org. Chem. 2001, 66, 2560±2565.
8. For recent reports on copper-catalysed aminations, see:
;a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233±
1236. ;b) Elliot, G. I.; Konopelski, J. P. Org. Lett. 2000, 2,
3055±3057. ;c) Lam, P. Y. S.; Deudon, S.; Hauptman, E.;
Clark, C. G. Tetrahedron Lett. 2001, 42, 2427±2429. ;d)
Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937±
2940.
4.4.7. N-*2,2-Dimethoxyethyl)-N-methyl-3,5-dimorpholi-
noaniline 7g *Table 3). According to the typical procedure,
7g was obtained as a thick oil from the reaction of 4e with
morpholine using 10 mol% Ni. Puri®cation was performed
by silica gel column chromatography using n-hexane±
1
AcOEt ;60/40) as eluent. H NMR ;400 MHz, CDCl3) d
ppm: 5.93 ;t, Jˆ1.60 Hz, 1H), 5.91 ;d, Jˆ1.60 Hz, 2H),
4.51 ;t, Jˆ5.20 Hz, 1H), 3.86±3.84 ;m, 8H), 3.43±3.39
;m, 8H), 3.16±3.14 ;m, 8H), 2.05 ;s, 3H). 13C NMR
;100 MHz, CDCl3) d ppm: 153.32, 150.92, 103.47, 94.16,
93.66, 67.02, 60.34, 55.74, 54.57, 50.04, 39.46. HREIMS
obsd. m/zˆ365.233 ;M), C19H31N3O4 requires 365.2314.
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