Transition metal-free amination of aryl halides-A simple and reliable method for the efficient and high-yielding synthesis of N-arylated amines

Article abstract of DOI:10.1016/j.tet.2008.11.072

A simple and reliable reaction protocol for the clean, fast, and high-yielding synthesis of various N-arylated amines derived from reactions of aryl halides with various (also sterically hindered) amines under transition metal-free reaction conditions is presented. Dioxane and KN(Si(CH₃)₃)₂ were found to be the ideal solvent and base for this transformation. The conversion rates and yields observed are excellent and in the majority of the reactions performed significantly higher than that obtained in their catalyzed versions. Furthermore, the selective synthesis of 6-halopyridin-2-amines and asymmetric pyridine-2,6-diamines (derived from consecutive reactions of 2,6-dibromopyridine and 2,6-dichloropyridine, respectively, with different amines) is possible in almost quantitative yields (relative to 2,6-dihalopyridine) within very short reaction times. Purification of the 6-halopyridin-2-amine intermediates is not necessary, allowing the synthesis of pyridine-2,6-diamines in 'one-pot'. However, catalysts are in many cases not required to efficiently and selectively couple aryl halides with amines, making transition metal-free versions of the Buchwald-Hartwig reaction extremely attractive for the synthesis of N-arylated amines with substrates containing substituents on the aryl halide, which either promote regioselectivity and/or do not require regioselective aminations.

Full text of DOI:10.1016/j.tet.2008.11.072

Tetrahedron 65 (2009) 1180–1187
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Transition metal-free amination of aryl halidesdA simple and reliable method
for the efficient and high-yielding synthesis of N-arylated amines
*
Jeanne L. Bolliger, Christian M. Frech
Department of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and reliable reaction protocol for the clean, fast, and high-yielding synthesis of various
N-arylated amines derived from reactions of aryl halides with various (also sterically hindered) amines
under transition metal-free reaction conditions is presented. Dioxane and KN(Si(CH3)3)2 were found to
be the ideal solvent and base for this transformation. The conversion rates and yields observed are
excellent and in the majority of the reactions performed significantly higher than that obtained in their
catalyzed versions. Furthermore, the selective synthesis of 6-halopyridin-2-amines and asymmetric
pyridine-2,6-diamines (derived from consecutive reactions of 2,6-dibromopyridine and 2,6-di-
chloropyridine, respectively, with different amines) is possible in almost quantitative yields (relative to
2,6-dihalopyridine) within very short reaction times. Purification of the 6-halopyridin-2-amine in-
termediates is not necessary, allowing the synthesis of pyridine-2,6-diamines in ‘one-pot’. However,
catalysts are in many cases not required to efficiently and selectively couple aryl halides with amines,
making transition metal-free versions of the Buchwald–Hartwig reaction extremely attractive for the
synthesis of N-arylated amines with substrates containing substituents on the aryl halide, which either
promote regioselectivity and/or do not require regioselective aminations.
Received 26 September 2008
Received in revised form 7 November 2008
Accepted 20 November 2008
Available online 27 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
organic products, which is of particular importance for the syn-
thesis of pharmaceutical fine chemicals because of their residual
The N-aryl amination (Buchwald–Hartwig reaction) has attrac-
ted enormous interest over the last 20 years and belongs nowadays
to an indispensable set of cross-coupling reactions, which finds its
application in all areas of organic chemistry, ranging from the
laboratory bench, the synthesis of pharmaceutical fine chemicals
and the production of bulk chemicals.1–3 Despite the existence of
copper-, nickel-, and iron-catalyzed versions of the Buchwald–
Hartwig reaction, palladium still remains the metal of choice for
this transformation.4–6 As a consequence, most research groups are
focused on the development of palladium complexes with newly
designed ligand systems in order to improve their efficiency, scope,
and applicability as catalyst.3 Thus, many palladium catalysts are
known, of which some efficiently couple amines with electronically
deactivated and sterically hindered aryl chlorides, occasionally
even at room temperature and in some cases to completion within
only few minutes. However, beside all the great advances achieved,
a major drawback of the Buchwald–Hartwig reaction still includes
the large amount of catalyst required (typically w1 mol %) to pro-
mote this transformation efficiently. Thus, their separation from
toxicity in the target compounds, is a central issue to consider.
Moreover, transition metal-catalyzed reactions also generate
hazardous waste (in particular in the case of copper-catalyzed
versions), which is environmentally problematic and hence, should
to be avoided wherever possible.7 Although transition metal-free
cross-coupling reactions between primary and secondary amines
and aryl halides using microwave irradiation conditions were
recently reported,8 the development of more improved synthetic
methods for the transition metal-free synthesis of aryl substituted
amines is desirable. Therefore, if aryl halides are efficiently
aminated under transition metal-free reaction conditions with
competitive conversion rates and yields when compared with its
catalyzed versions; this would greatly increase its attractiondalso
from economic and ecologic points of view.
We present here a new, convenient, generally applicable and
reliable reaction protocol for the clean, fast, and high-yielding
synthesis of N-arylated amines derived from reactions of aryl
halides with amines under transition metal-free reaction condi-
tions. Whereas dioxane and KN(Si(CH3)3)2 were found to be the
ideal solvent and base for this transformation, K3PO4 was the base
of choice for the selective synthesis of 6-halopyridin-2-amines
derived from reactions of 2,6-dihalopyridines with equimolar
amounts of dialkylamines. However, the observed conversion rates
* Corresponding author.
E-mail address: chfrech@aci.uzh.ch (C.M. Frech).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.072

J.L. Bolliger, C.M. Frech / Tetrahedron 65 (2009) 1180–1187
1181
and yields are excellent and in the majority of the reactions
performed significantly higher when compared with their cata-
lyzed versions.9 Although reports already exist, which successfully
describe the transition metal-free amination of aryl halides with
NaNH2, KNH2, LiNH2, or NaH as base,11 many of these reports
describe reactions performed with specific substrates (e.g., fluo-
rides) and/or are part of the synthesis of more complex organic
molecules.12 Moreover, it was found that the use of these bases
often lead to significantly lower conversion rates and yields when
compared to reactions performed with KN(Si(CH3)3)2 as it is for
instance generally the case when aryl halides are coupled with
dialkylamines. In addition, whereas amination reactions performed
with KN(Si(CH3)3)2 generally are successful,13 results obtained
with, e.g., NaNH2 or NaH were found to be much more substrate
dependent.14 However, an elegant method for transition metal-free
aminations of aryl chlorides was recently reported with KtBuO as
base, generally giving the N-arylated amines in high yields.15
Unfortunately, prolonged reaction times (36 h) and high reaction
temperatures (135 ꢀC) are required, refering to the need of more
efficient methods for transition metal-free amination reactions.
observed with dibenzylamine, dibutylamine, and N-methylaniline
as coupling partners (Table 1, entries 2–4). Similarly, 3,5-dime-
thoxyanilines were almost exclusively formed and isolated in very
high yields when 1-bromo-3,5-dimethoxybenzene was reacted for
20 min (or less) at 100 ꢀC with amines, such as morpholine,
dibenzylamine, dibutylamine and N-methylamine (Table 1, entries
5–8). Slightly lower conversion rates were noticed with sterically
hindered 2-bromo-1,4-dimethylbenzene (Table 1, entries 9–12). For
instance, its coupling with morpholine yielded 88% of 4-(2,5-
dimethylphenyl)morpholine within 15 min. Reactions performed
with dibenzylamine, dibutylamine, and N-methylaniline gave the
coupling products in >95% yield within 90 and 45 min, respectively.
Amination reactions performed with 1,3-dibromobenzene or 2,6-
dibromopyridine in the presence of 2.2 equiv of amines and base
yielded the 1,3-diaminobenzenes and 2,6-diaminopyridines at
100 ꢀC, generally within only 30 min of reaction time (Table 1, en-
tries 13–20). On the other hand, when dioxane solutions of
N-methylaniline, 2,6-dimethylaniline, 2,6-di(propan-2-yl)aniline,
or 3,4,5-trimethoxyaniline and KN(Si(CH3)3)2 equimolar amounts of
2,6-dibromopyridine were added at 25 ꢀC, quantitative formations
of 6-bromopyridin-2-amines were obtained within only 20 min in
all reactions examined (Table 1, entries 21–24), offering a simple
and metal-free route for the high-yielding synthesis of 6-bromo-
pyridin-2-amines and asymmetric pyridine-2,6-diamines, re-
spectively, within very short reaction times in ‘one-pot’.16 Indeed,
when to an exemplary reaction mixture of equimolar amounts of
N-methylaniline and 2,6-dibromopyridine (stirred at 25 ꢀC for
20 min) additional base and an amine, such as morpholine, piper-
idine, cis-2,6-dimethylpiperidine, 2,6-dimethylaniline, 2,6-di(pro-
pan-2-yl)aniline, or 3,4,5-trimethoxyaniline were added, >95%
yield (relative to 2,6-dibromopyridine) of the corresponding
2. Results and discussion
Exceedingly clean and efficient C–N bond formations with aryl
bromides to yield the anilines in almost all cases quantitatively and
occasionally within only a few minutes of reaction time were found
to be possible (Table 1). For instance, when morpholine was allowed
to react at 100 ꢀC in dioxane with phenyl bromide in the presence of
1.2 equiv (relative to the aryl halide) of KN(Si(CH3)3)2, quantitative
conversion into 4-phenylmorpholine was observed within less than
10 min (Table 1, entry 1). Only slightly lower conversion rates were
Table 1
Metal-free N-aryl amination using aryl bromidesa
R1
R1
NH
R2
R
R
KN(Si(CH3)3)2
N
+
Br
dioxane, T = 100 °C
R2
Entry
Aryl bromide
Amine
Conv.b [%]
t [min]
1
2
3
4
5
6
7
8
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
1-Bromo-3,5-dimethoxybenzene
1-Bromo-3,5-dimethoxybenzene
1-Bromo-3,5-dimethoxybenzene
1-Bromo-3,5-dimethoxybenzene
2-Bromo-1,4-dimethylbenzene
2-Bromo-1,4-dimethylbenzene
2-Bromo-1,4-dimethylbenzene
2-Bromo-1,4-dimethylbenzene
2,6-Dibromopyridine
2,6-Dibromopyridine
2,6-Dibromopyridine
2,6-Dibromopyridine
1,3-Dibromobenzene
1,3-Dibromobenzene
1,3-Dibromobenzene
1,3-Dibromobenzene
2,6-Dibromopyridine
Morpholine
95
98
96
99
99
98
85
92
88
97
95
99
100
100
95
100
86
<10
15
20
10
<10
15
20
10
15
90
90
45
30
30
30
30
30
60
90
60
20
20
20
20
Dibenzylamine
Dibutylamine
N-Methylaniline
Morpholine
Dibenzylamine
Dibutylamine
N-Methylaniline
Morpholine
Dibenzylamine
Dibutylamine
N-Methylaniline
Morpholine
Dibenzylamine
Dibutylamine
N-Methylaniline
Morpholine
9
10
11
12
13c
14c
15c
16c
17c
18c
19c
20c
21d
22d
23d
24d
cis-2,6-Dimethylpiperidine
Dibenzylamine
N-Methylaniline
85
96
96
N-Methylaniline
100e
100e
99e
100e
2,6-Dibromopyridine
2,6-Dibromopyridine
2,6-Dibromopyridine
2,6-Dimethylaniline
2,6-Di(propan-2-yl)aniline
3,4,5-Trimethoxyaniline
a
Reaction conditions: 2.0 mmol aryl bromide, 1.2 equiv (relative to aryl bromide) amine, 1.2 equiv (relative to aryl bromide) KN(Si(CH3)3)2, 6 ml dioxane, reactions per-
formed at 100 ꢀC under N2 atmosphere.
b
Determined by GC/MS, based on aryl halide.
Reaction performed with 2.2 equiv (relative to aryl bromide) of amine and base.
Reaction performed at 25 ꢀC with 1.0 equiv (relative to aryl bromide) amine, 1.2 equiv (relative to aryl bromide) K3PO4.
c
d
e
Refer to 6-bromopyridin-2-amine.

1182
J.L. Bolliger, C.M. Frech / Tetrahedron 65 (2009) 1180–1187
N-methyl-N-phenylpyridin-2,6-diamines were isolated in all cases
after stirring the reaction mixtures for 30 min at 100 ꢀC (Table 2).
In contrast to coupling reactions performed with equimolar
amounts of 2,6-dibromopyridine and anilines, KN(Si(CH3)3)2 were
found to be not appropriate when dialkylamines, such as mor-
pholine, piperidine, N-methylpiperazine, or dibutylamine were
used as coupling partners. Only mixtures consisting of 2,6-dipro-
mopyridine, 6-bromopyridin-2-amines, and pyridine-2,6-diamines
were observed.18 However, when K3PO4 was used instead, 6-bro-
mopyridin-2-amines were exclusively and quantitatively formed
when dialkylamines, such as morpholine, piperidine, and N-
methylpiperazine were coupled with 2,6-dibromopyridine at
100 ꢀC within 5 or 6 h, respectively. Reactions performed with
dibutylamine exhibit significantly lower conversion rates but still
lead to the quantitative formation of 6-bromo-N,N-dibutylpyridin-
2-amine after 60 h.19,20 Filtration of the resulting reaction mixtures
(in order to remove K2HPO4) and subsequent addition of equimolar
amounts of KN(Si(CH3)3)2 and another amine, such as morpholine,
piperidine, N-methylpiperazine or N-methylaniline exclusively
yielded the corresponding 2,6-diaminopyridines within only
30 min at 100 ꢀC in almost quantitative overall yields (Table 3).
Almost identical conversion rates and yields were obtained with
2,6-dichloropyridine as coupling partner. Exemplary reactions of
2,6-dichloropyridine and morpholine or piperidine with K3PO4
as base at 100 ꢀC exclusively yielded 4-(6-chloropyridin-2-yl)mor-
pholine and 2-chloro-6-piperidin-1-ylpyridine, respectively,
within 5 h. Filtration of the reaction mixtures and subsequent ad-
dition of equimolar amounts of KN(Si(CH3)3)2 and dibenzylamine
or dibutylamine quantitatively yielded N,N-dibenzyl-6-morpholin-
4-ylpyridin-2-amine and N,N-dibutyl-6-piperidin-1-ylpyridin-2-
amine, respectively, within only 30 min at 100 ꢀC (Table 3, entries 4
and 8).19
Excellent conversion rates and yields were also obtained in the
reactions performed with various aryl chlorides as well (Table 4).
For instance, when 2-chloronicotinonitrile was reacted with mor-
pholine, piperidine, and N-methylpiperazine in the presence of
K3PO4,21 the anilines were cleanly formed in >90% yield within
only 30 min or less (Table 4, entries 1–3). Significantly lower
conversion rates were observed with dibutylamine as coupling
partner: 7 h were required to fully convert 2-chloronicotinonitrile
into 2-(dibutylamino)pyridine-3-carbonitrile. On the other hand,
complete conversion was achieved within only 10 min when
N-methylaniline was coupled with 2-chloronicotinonitrile in
presence of KN(Si(CH3)3)2 (Table 4, entries 4 and 5). Exceptional
high conversion rates were observed with chlorobenzene (Table 4,
entries 6–11) and 2-chloro-1,4-dimethoxybenzene (Table 4, entries
Table 2
Metal-free N-aryl amination of 6-bromo-N-methyl-N-phenylpyridine-2-aminea
R1
R1
Br
N
N
KN(Si(CH3)3)2
dioxane, T = 100 °C
N
N
N
NH
R2
+
R2
Entry
Aryl bromide
Amine
Conv.b [%]
t [min]
1
2
3
4
5
6
7
8
6-Bromo-N-methyl-N-phenylpyridine-2-amine
6-Bromo-N-methyl-N-phenylpyridine-2-amine
6-Bromo-N-methyl-N-phenylpyridine-2-amine
6-Bromo-N-methyl-N-phenylpyridine-2-amine
6-Bromo-N-methyl-N-phenylpyridine-2-amine
6-Bromo-N-methyl-N-phenylpyridine-2-amine
6-Bromo-N-methyl-N-phenylpyridine-2-amine
6-Bromo-N-methyl-N-phenylpyridine-2-amine
Morpholine
Piperidine
cis-2,6-Dimethylpiperidine
Dibenzylamine
99
98
95
99
96
96
96
99
30
30
30
30
30
30
30
30
Dibutylamine
2,6-Dimethylaniline
2,6-Diisopropylaniline
3,4,5-Trimethoxyaniline
a
Reaction conditions: 2.0 mmol aryl bromide, 1.2 equiv (relative to aryl bromide) amine, 1.2 equiv (relative to aryl bromide) KN(Si(CH3)3)2, 6 ml dioxane, reaction performed
at 100 ꢀC under N2 atmosphere.
b
Determined by GC/MS, based on aryl halide.
Table 3
Metal-free N-aryl amination of 6-halopyridin-2-aminesa
R1
N
R1
NH +
R2
NR2
X
N
KN(Si(CH3)3)2
NR2
N
R2
dioxane, T = 100 °C
Entry
Aryl halide
Amine
Morpholine
N-Methylaniline
Dibenzylamine
Dibenzylamine
Piperidine
N-Methylaniline
Dibutylamine
Dibutylamine
Piperidine
Conv.b [%]
t [min]
1
2
3
4
5
6
7
8
9
10
4-(6-Bromopyridin-2-yl)morpholinec
4-(6-Bromopyridin-2-yl)morpholinec
4-(6-Bromopyridin-2-yl)morpholinec
4-(6-Chloropyridin-2-yl)morpholinec
2-Bromo-6-piperidin-1-ylpyridinec
2-Bromo-6-piperidin-1-ylpyridinec
2-Bromo-6-piperidin-1-ylpyridinec
2-Chloro-6-piperidin-1-ylpyridinec
99
100
99
100
97
98
98
97
95
30
30
30
30
30
30
30
30
30
30
1-(6-Bromopyridin-2-yl)-4-methylpiperazinec
6-Bromo-N,N-dibutylpyridin-2-aminec
Dibenzylamine
98
a
Reaction conditions: 2.0 mmol aryl bromide, 1.2 equiv (relative to aryl halide) amine, 1.2 equiv (relative to aryl halide) KN(Si(CH3)3)2, 6 ml dioxane, reaction performed at
100 ꢀC under N2 atmosphere.
b
Determined by GC/MS, based on aryl halide.
6-Bromopyridin-2-amines and 6-chloropyridin-2-amines were prepared by reactions of equimolar amounts of the appropriate amine and 2,6-dibromopyridine and 2,6-
c
dichloropyridine, respectively, at 100 ꢀC with 2.0 equiv (relative to 2,6-dihalopyridine) of K3PO4.

J.L. Bolliger, C.M. Frech / Tetrahedron 65 (2009) 1180–1187
1183
Table 4
Metal-free N-aryl amination using aryl chloridesa
R1
R1
NH
R
R
KN(Si(CH3)3)2
dioxane, T = 100 °C
N
+
Cl
R2
R2
Entry
Aryl chloride
Amine
Conv.b [%]
t [min]
1c
2-Chloronicotinonitrile
2-Chloronicotinonitrile
2-Chloronicotinonitrile
2-Chloronicotinonitrile
2-Chloronicotinonitrile
Chlorobenzene
Morpholine
Piperidine
N-Methylpiperazine
Dibutylamine
N-Methylaniline
Morpholine
Piperidine
93
100
98
30
15
30
420
<10
<10
15
2c
3c
4c
88
5
6
7
100
100
97
Chlorobenzene
8
9
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
cis-2,6-Dimethylpiperidine
N-Methylpiperazine
Diphenylamine
Dibenzylamine
Morpholine
Piperidine
Dibenzylamine
Dibutylamine
N-Methylaniline
Benzylamine
2,6-Diisopropylaniline
3,4,5-Trimethoxyaniline
Morpholine
92
98
67
92
100
100
100
100
100
96e
94e
92e
97
83
97
93
100
91
99
99
93
92
30
10
30
10
<10
<10
<10
<10
<10
30
30
30
30
30
30
60
60
60
10
11
12
13
14
15
16
17d
18d
19d
20
21
22
23
24
25
26
27
28
29
30
2-Chloro-1,4-dimethoxy-benzene
2-Chloro-1,4-dimethoxy-benzene
2-Chloro-1,4-dimethoxy-benzene
2-Chloro-1,4-dimethoxy-benzene
2-Chloro-1,4-dimethoxy-benzene
2-Chloro-1,4-dimethoxy-benzene
2-Chloro-1,4-dimethoxy-benzene
2-Chloro-1,4-dimethoxy-benzene
2-Chloro-1,4-dimethyl-benzene
2-Chloro-1,4-dimethyl-benzene
2-Chloro-1,4-dimethyl-benzene
2-Chloro-1,4-dimethyl-benzene
2-Chloro-3-methoxybenzonitrile
2-Chloro-3-methoxybenzonitrile
2-Chloro-3-methoxybenzonitrile
2-Chloro-3-methoxybenzonitrile
1,3,5-Trichlorobenzene
Piperidine
N-Methylpiperazine
Dibenzylamine
Morpholine
Piperidine
N-Methylaniline
3,4,5-Trimethoxyaniline
Morpholine
N-Methylpiperazine
N-Methylaniline
20
30
90
270
90
1,3,5-Trichlorobenzene
1,3,5-Trichlorobenzene
95
a
Reaction conditions: 2.0 mmol aryl chloride, 1.2 equiv (relative to aryl chloride) amine, 1.2 equiv (relative to aryl chloride) KN(Si(CH3)3)2, 6 ml dioxane, reaction performed
at 100 ꢀC under N2 atmosphere.
b
Determined by GC/MS, based on aryl halide.
Reaction performed with 2.0 mmol K3PO4.
Reaction performed with 2 equiv (relative to amine) aryl chloride.
Refer to the formation of the tertiary anilines.
c
d
e
12–19). Impressively, in almost all the reactions performed the
anilines were formed in >90% yield in less than 20 min. For
example, when 2-chloro-1,4-dimethoxybenzene was coupled with
piperidine, dibenzylamine, dibutylamine, or N-methylamine, re-
spectively, full conversions into their tertiary anilines was achieved
in all the reactions within less than 10 min. Exemplary reactions
performed with 2 equiv (relative to amine) of 2-chloro-1,4-dime-
thoxybenzene yielded the tertiary anilines quantitatively within
only 30 min when primary amines, such as benzylamine, 2,6-di-
isopropylaniline, and 3,4,5-trimethoxyaniline were used as cou-
pling partner. High conversion rates and yields were also obtained
with 2-chloro-1,4-dimethylbenzene as coupling partner (Table 4,
entries 20–23). For instance, its coupling with N-methylpiperazine
yielded 97% of 1-(2,5-dimethylphenyl)-4-methylpiperazine within
30 min; 93% conversion within 1 h was obtained with dibenzyl-
amine. In contrast to 2,6-alkylated aryl halides, which are inert
toward transition metal-free amination,22 high conversions were
observed with 2-chloro-3-methoxybenzonitrile (Table 4, entries
24–27); >90% yield within less than 1 h was achieved with mor-
pholine, piperidine, N-methylaniline, and 3,4,5-trimethoxyaniline
as coupling partners. Smooth C-N bond formations were also ob-
served with polychlorinated substrates. Exemplary reactions were
carried out with 1,3,5-trichlorobenzene (Table 4, entries 28–30). Its
treatment with 3.4 equiv of amine, gave the products in >90% yield
within only 90 min of reaction time when morpholine and
N-methylaniline were used as coupling partners; with N-methyl-
piperazine, 4.5 h were required to get 95% of the aniline.
Overall, non-catalyzed versions of the Buchwald–Hartwig were
shown to selectively yield the desired coupling products when
reactions were performed with bromobenzene, 1,4-bissubstituted
haloaromatic compounds or substrates possessing directing
groups, such as 1,3-dibromobenzene, 1-bromo-3,5-dimethoxy-
benzene, 2-chloronicotinonitrile, 2-chloro-3-methoxybenzoni-
trile, 1-chloro-3,5-dimethylbenzene 1,3,5-trichlorobenzene, or
2,6-dichloropyridine.11 Since aryne-type mechanisms are opera-
tive in transition metal-free versions of the Buchwald–Hartwig
reaction the substitution pattern of the aryl halide is of significant
importance for regioselective product formation. Thus, non-se-
lective product formation was expected to be obtained when
substrates, such as 1-bromo-4-methoxybenzene (Table 5), 2-
chlorotoluene, 4-bromobiphenyl or 4-chlorobenzonitrile were
used as coupling partners.9,23 Indeed, when, for example, 1-
bromo-4-methoxybenzene or 1-chloro-4-methoxybenzene were
coupled with morpholine, piperidine, cis-2,6-dimethylpiperidine,
dibenzylamine, dibutylamine, N-methylpiperazine or N-methyl-
amine overall yields of >90% but mixtures containing 3-methoxy-
anilines and 4-methoxyanilines were obtained within less than
30 min. In fact the product distribution corresponds to those
expected for aryne-type mechanisms.14 Similarly, when 2-bro-
motoluene or 2-chlorotoluene was coupled with amines, reaction
mixtures containing 2-methylanilines and 3-methylanilines were
obtained,23 of which the latter ones were dominant, confirming
the involvement of cyclohexa-1,3-dien-5-ynes intermediates fur-
ther. In addition, the nature of the amine has only a minor effect

1184
J.L. Bolliger, C.M. Frech / Tetrahedron 65 (2009) 1180–1187
Table 5
Metal-free N-aryl amination using 4-bromoanisole and 4-chloroanisolea
OMe
R1
NH
R2
R1
N
R2
R1
KN(Si(CH3)3)2
X
OMe
+
OMe
+
N
dioxane, T = 100 °C
R2
A
B
Entry
Aryl halide
Amine
A
B
Conv.b [%]
t [min]
1
2
3
4
4
5
6
7
8
9
10
11
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
4-Bromoanisole
4-Chloroanisole
4-Chloroanisole
4-Chloroanisole
4-Chloroanisole
4-Chloroanisole
4-Chloroanisole
Morpholine
Piperidine
cis-2,6-Dimethylpiperidine
Dibenzylamine
Dibutylamine
N-Methylaniline
Morpholine
53
51
45
58
53
56
54
54
46
55
56
57
47
49
55
42
47
44
46
46
54
45
44
43
95
97
96
92
93
99
91
96
98
92
93
99
<10
<10
30
20
20
10
<10
<10
90
<10
<10
<10
Piperidine
cis-2,6-Dimethylpiperidine
N-Methylpiperazine
Dibutylamine
N-Methylaniline
a
Reaction conditions: 2.0 mmol aryl chloride, 1.2 equiv (relative to aryl halide) amine, 1.2 equiv (relative to aryl chloride) KN(Si(CH3)3)2, 6 ml dioxane, reaction performed at
100 ꢀC under N2 atmosphere; product distributions refer relative GC-yields.
b
Determined by GC/MS, based on aryl halide.
on the product distribution, which is also characteristic for aryne-
type mechanisms.11,14,23
expressed in parts per million (ppm) coupling constants (J) are in
hertz. The 1H and 13C NMR chemical shifts are reported relative to
tetramethylsilane; the resonance of the residual protons of the
In conclusion, although aryne-type mechanisms are operative in
transition metal-free versions of the Buchwald–Hartwig reaction,
and hence the substitution pattern of the aryl halide is of impor-
tance for selective product formations catalysts are in many cases
not required to efficiently and selectively couple aryl halides with
amines. A wide variety of amines were found to undergo exceed-
ingly clean and efficient C–N bond formation with electronically
activated, deactivated and even sterically hindered aryl halides, to
give the desired N-arylated amines in almost quantitative yields
occasionally even within only a few minutes of reaction time.
Furthermore, reactions performed with 2,6-dibromopyridine and
2,6-dichloropyridine allow the selective synthesis of 6-halopyridin-
2-amines and asymmetric pyridine-2,6-diamines, respectively, in
very high overall yields generally within short reaction times.
Purification of the 6-halopyridin-2-amine intermediates is not
required for the synthesis of asymmetric pyridine-2,6-diamines.
The conversion rates and yields obtained under transition metal-
free reaction conditions are generally excellent, making the
transition metal-free version of the Buchwald–Hartwig reaction
extremely attractive for substrates with substituents on the aryl
halide, which either promote regioselectivity and/or do not require
regioselective aminations for selective product formations.
solvent was used as internal standard for 1H (
d
7.26 chloroform,
3.58 and 1.73 THF-d8) and all-d solvent signals for 13C (
d
77.0
chloroform, 67.4 and 25.2 THF-d8). All measurements were carried
out at 298 K. Abbreviations used in the description of NMR data are
as follows: s, singlet; d, duplet; t, triplet; sept, septet; m, multiplet.
Elemental analyses were performed on a Leco CHNS-932 analysator
at the University of Zurich, Switzerland.
3.3. General procedure for the amination of aryl halides
In a Young Schlenk with dioxane (6 ml) were placed appropriate
amounts of the amine, KN(Si(CH3)3)2 (or K3PO4), followed by the
aryl halide (2.0 mmol). Then the reaction mixture was stirred vig-
orously at 25 ꢀC or placed in a preheated 100 ꢀC oil bath. Samples
taken from the reaction mixture were quenched with water. The
products were extracted with diethyl ether/THF (1:1) mixtures and
analyzed by GC/MS. At the end of the reaction the mixtures were
allowed to cool to room temperature, quenched with water and
extracted with 30–50 ml of diethyl ether/THF (1:1) mixtures. The
combined extracts were washed with 1 M Na2CO3 (3ꢁ50 ml), dried
over MgSO4, filtrated, and evaporated to dryness. Where necessary,
the product was purified by flash chromatography on silica gel or
on alumina. The identities of known products were confirmed by
comparison with data reported in the literature.
3. Experimental section
3.1. General procedures
3.3.1. N,N,N0,N0-Tetrabenzylpyridine-2,6-diamine (Table 1, entry 14)
The title compound was obtained after flash chromatography on
silica gel (toluene) as pale brown oil, which solidified upon stand-
ing. Yield: 97%.
All synthetic operations were carried out in oven-dried glass-
ware using a combination of glovebox (M. Braun 150B-G-II) and
Schlenk techniques under a dinitrogen atmosphere. Solvents were
reagent grade or better, freshly distilled under N2 atmosphere by
standard procedures, and degassed before use. Deuterated solvents
were purchased from Armar. All the chemicals were purchased
from Aldrich Chemical Co., Acros Organics, ABCR or Fluka and used
as received.
1H NMR (300 MHz, CDCl3)
d
¼7.31–7.01 (m, 21H), 5.75 (d,
J¼8.1 Hz, 2H), 4.62 (s, 8H); 13C{1H} NMR (75 MHz, CDCl3)
¼158.1,
d
139.8, 129.0, 128.6, 127.8, 127.2, 94.3, 51.5. Anal. Calcd (%) for
C33H31N3: C, 84.40; H, 6.65; N, 8.95. Found: C, 84.55; H, 6.70; N,
8.99.
3.2. Analysis
3.3.2. N,N,N0,N0-Tetrabutylpyridine-2,6-diamine (Table 1, entry 15)
The title compound was obtained after flash chromatography on
silica gel (toluene) as a pale brown oil, which solidified upon
standing. Yield: 93%.
1H and 13C{1H} NMR data were recorded at 300.0 and 75.4 MHz
on a Varian Gemini 300 spectrometer. Chemical shifts (d) are

J.L. Bolliger, C.M. Frech / Tetrahedron 65 (2009) 1180–1187
1185
1H NMR (300 MHz, CDCl3)
d
¼7.46 (t, J¼8.1 Hz, 1H), 5.95 (d,
1H NMR (300 MHz, CDCl3)
d
¼7.30–7.21 (m, 2H), 7.20–7.11 (m,
J¼8.1 Hz, 2H), 3.65 (t, J¼7.7 Hz, 8H), 1.91–1.81 (m, 8H), 1.67–1.55 (m,
2H), 7.10–7.04 (m, 2H), 5.86 (d, J¼7.9 Hz, 1H), 5.84 (d, J¼8.1 Hz, 1H),
8H), 1.22 (t, J¼7.3 Hz, 12H); 13C{1H} NMR (75 MHz, CDCl3)
d¼156.9,
3.74–3.71 (m, 4H), 3.40–3.37 (m, 4H), 3.35 (s, 3H); 13C{1H} NMR
138.1, 91.7, 48.6, 30.2, 20.5, 14.1. Anal. Calcd (%) for C21H39N3: C,
75.62; H, 11.78; N, 12.60. Found: C, 75.69; H, 11.74; N, 12.66.
(75 MHz, CDCl3)
97.5, 94.0, 65.9, 44.7, 37.0. Anal. Calcd (%) for C16H19N3O: C, 71.35; H,
7.11; N, 15.60. Found: C, 71.50; H, 7.45; N, 15.57.
d
¼157.5, 156.6, 146.0, 137.4, 128.3, 125.3, 123.9,
3.3.3. N,N0-Dimethyl-N,N0-diphenylpyridine-2,6-diamine (Table 1,
entry 16)
3.3.9. N-Methyl-N-phenyl-6-piperidin-1-ylpyridin-2-amine (Table
2, entry 2)
The title compound was obtained after flash chromatography on
silica gel (toluene) as colorless powder. Yield: 99%.
The title compound was obtained after filtration over silica gel
(toluene) as brown oil. Yield: 96%.
1H NMR (300 MHz, CDCl3)
d
¼7.64–7.48 (m, 8H), 7.40 (tt,
3J¼7.1 Hz, 4J¼1.5 Hz, 2H), 7.29 (t, J¼7.3 Hz, 1H), 6.13 (d, J¼8.0 Hz,
1H NMR (300 MHz, CDCl3)
d
¼7.71–7.60 (m, 4H), 7.53–7.45 (m,
2H), 3.73 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3)
d
¼157.5, 147.0,
2H), 6.33 (d, J¼8.0 Hz, 1H), 6.23 (dd, 3J¼8.0 Hz, 4J¼1.7 Hz, 1H), 3.84
137.7, 129.1, 126.1, 124.7, 97.3, 38.0. Anal. Calcd (%) for C19H19N3: C,
78.86; H, 6.62; N, 14.52. Found: C, 78.97; H, 6.59; N, 14.66.
(br s, 4H), 3.81 (s, 3H), 1.98 (br s, 6H); 13C{1H} NMR (75 MHz, CDCl3)
d
¼158.6, 157.5, 147.2, 138.2, 129.1, 126.2, 124.5, 97.3, 95.4, 46.2, 37.9,
25.5, 24.9. Anal. Calcd (%) for C17H21N3: C, 76.37; H, 7.92; N, 15.72.
Found: C, 76.28; H, 7.91; N, 15.69.
3.3.4. 6-Bromo-N-methyl-N-phenylpyridine-2-amine (Table 1,
entry 21)
The title compound was obtained as pale yellow oil. Yield: 98%.
3.3.10. 6-[(2R,6S)-2,6-Dimethylpiperidin-1-yl]-N-methyl-N-
phenylpyridin-2-amine (Table 2, entry 3)
The title compound was obtained as pale yellow solid. Yield:
94%.
1H NMR (300 MHz, CDCl3)
d
¼7.41–7.37 (m, 2H), 7.25–7.19 (m,
3H), 7.05 (dd, J¼8.4, 7.4 Hz, 1H), 6.70 (d, J¼7.4 Hz, 1H), 6.34 (d,
J¼8.4 Hz, 1H), 3.43 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
¼158.7,
d
145.7, 140.0, 138.5, 129.9, 126.5, 126.2, 115.8, 106.9, 38.4. Anal. Calcd
(%) for C12H11BrN2: C, 54.77; H, 4.21; N, 10.65. Found: C, 54.85; H,
4.17; N, 10.69.
1H NMR (300 MHz, CDCl3)
d
¼7.31–7.02 (m, 6H), 5.84 (d,
J¼7.9 Hz, 1H), 5.76 (d, J¼7.8 Hz, 1H), 4.46 (br s, 2H), 3.36 (s, 3H),
1.85–1.42 (m, 6H), 1.12 (d, J¼6.8 Hz, 6H); 13C{1H} NMR (75 MHz,
CDCl3)
d
¼157.6, 156.7, 147.4, 138.0, 129.0, 126.1, 124.3, 95.9, 95.2,
3.3.5. 6-Bromo-N-(2,6-dimethylphenyl)-N-methylpyridin-2-amine
(Table 1, entry 22)
45.2, 37.9, 30.8, 19.0, 14.7. Anal. Calcd (%) for C19H25N3: C, 77.25; H,
8.53; N, 14.22. Found: C, 77.17; H, 8.49; N, 14.22.
The title compound was obtained as off-white powder. Yield:
97%.
3.3.11. N,N-Dibenzyl-N0-methyl-N0-phenylpyridine-2,6-diamine
(Table 2, entry 4)
The title compound was obtained after flash chromatography on
silica gel (toluene) as brownish oil. Yield: 97%.
1H NMR (300 MHz, CDCl3)
d
¼7.26–7.14 (m, 4H), 6.78 (dd,
3J¼7.4 Hz, 4J¼0.6 Hz, 1H), 6.33 (br s, 1H), 5.05 (dd, 3J¼8.3 Hz,
4J¼0.6 Hz, 1H), 2.22 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3)
¼158.0,
d
140.3, 140.0, 136.9, 135.5, 128.7, 127.3, 116.7, 103.6, 18.3. Anal. Calcd
(%) for C13H13BrN2: C, 56.34; H, 4.73; N, 10.11. Found: C, 56.29; H,
4.76; N, 10.07.
1H NMR (300 MHz, CDCl3)
d
¼7.68–7.50 (m, 14H), 7.48–7.41 (m,
2H), 6.22 (d, J¼8.0 Hz,1H), 6.18 (d, J¼8.0 Hz,1H), 5.10 (s, 4H), 3.72 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3)
d
¼157.5, 147.2, 139.3, 138.4,
129.2, 128.4, 128.1, 127.3, 126.7, 126.3, 124.7, 96.6, 94.4, 51.0, 38.1.
Anal. Calcd (%) for C26H25N3: C, 82.29; H, 6.64; N, 11.07. Found: C,
82.22; H, 6.59; N, 11.11.
3.3.6. N-[2,6-Bis(1-methylethyl)phenyl]-6-bromo-N-methyl-
pyridin-2-amine (Table 1, entry 23)
The title compound was obtained as colorless powder. Yield:
98%.
3.3.12. N,N-Dibutyl-N0-methyl-N0-phenylpyridine-2,6-diamine
(Table 2, entry 5)
The title compound was obtained after filtration over silica gel
(toluene) as pale brownish oil. Yield: 94%.
1H NMR (300 MHz, CDCl3)
d
¼7.43–7.38 (m, 1H), 7.32–7.28 (m,
2H), 7.21 (t, J¼7.8 Hz, 1H), 6.80 (dd, 3J¼7.5 Hz, 4J¼0.5 Hz, 1H), 6.72
(br s, 1H), 5.93 (d, J¼8.2 Hz, 1H), 3.25 (sept, J¼6.9 Hz, 2H), 1.20 (d,
J¼6.9 Hz, 12H); 13C{1H} NMR (75 MHz, CDCl3)
d
¼157.4, 145.6, 138.0,
1H NMR (300 MHz, CDCl3)
d
¼7.28–7.15 (m, 4H), 7.08–7.02 (m,
137.5, 130.4, 126.2, 121.8, 114.1, 101.6, 26.1, 21.6. Anal. Calcd (%) for
C17H21BrN2: C, 61.27; H, 6.35; N, 8.41. Found: C, 61.30; H, 6.40; N,
8.47.
2H), 5.73–5.68 (m, 2H), 3.35 (s, 3H), 3.34–3.29 (m, 4H), 1.56–1.46
(m, 4H), 1.32–1.19 (m, 4H), 0.86 (t, J¼7.3 Hz, 6H); 13C{1H} NMR
(75 MHz, CDCl3)
94.9, 94.0, 48.5, 37.9, 30.0, 20.4, 14.0. Anal. Calcd (%) for C20H29N3: C,
77.12; H, 9.38; N, 13.49. Found: C, 77.23; H, 9.29; N, 13.52.
d
¼157.6, 156.8, 147.4, 137.8, 129.0, 126.2, 124.3,
3.3.7. 6-Bromo-N-methyl-N-(3,4,5-trimethoxyphenyl)pyridin-2-
amine (Table 1, entry 24)
The title compound was obtained as colorless powder after flash
chromatography on silica gel (first using methylene chloride in
order to remove 2,6-dibromopyridine and then ethyl acetate as the
eluent). Yield: 98%.
3.3.13. N0-(2,6-Dimethylphenyl)-N-methyl-N-phenylpyridine-2,6-
diamine (Table 2, entry 6)
The title compound was obtained after flash chromatography on
silica gel (toluene) as brown oil. Yield: 94%.
1H NMR (300 MHz, CDCl3)
d
¼7.31 (dd, J¼8.2, 7.6 Hz, 1H), 6.74
1H NMR (300 MHz, CDCl3)
d
¼7.48–7.04 (m, 9H), 5.98 (dd,
(dd, 3J¼7.6 Hz, 4J¼0.6 Hz, 1H), 6.69 (dd, 3J¼8.2 Hz, 4J¼0.6 Hz, 1H),
3J¼8.1 Hz, 4J¼0.6 Hz, 1H), 5.93 (br s, 1H), 5.42 (dd, 3J¼7.8 Hz,
6.61 (s, 2H), 6.54 (br s, 1H), 3.84 (s, 6H), 3.83 (s, 3H); 13C{1H} NMR
4J¼0.6 Hz, 1H), 3.54 (s, 3H), 2.34 (s, 6H); 13C{1H} NMR (75 MHz,
(75 MHz, CDCl3)
106.3, 99.0, 60.9, 56.0. Anal. Calcd (%) for C14H15BrO3N2: C, 49.58; H,
4.46; N, 8.26. Found: C, 49.63; H, 4.39; N, 8.37.
d
¼156.3, 153.6, 139.9, 139.6, 135.5, 134.4, 117.7,
CDCl3)
d
¼158.4, 156.6, 147.2, 138.5, 137.2, 136.7, 129.4, 128.4, 126.4,
126.2, 124.9, 98.9, 94.3, 38.2, 18.6. Anal. Calcd (%) for C20H21N3: C,
79.17; H, 6.98; N, 13.85. Found: C, 79.07; H, 7.06; N, 13.92.
3.3.8. N-Methyl-6-morpholin-4-yl-N-phenylpyridin-2-amine
(Table 2, entry 1)
3.3.14. N0-[2,6-Bis(1-methylethyl)phenyl]-N-methyl-N-
phenylpyridine-2,6-diamine (Table 2, entry 7)
The title compound was obtained as pale yellow solid. Yield:
97%.
The title compound was obtained after flash chromatography on
silica gel (toluene) as off-white powder. Yield: 95%.

1186
J.L. Bolliger, C.M. Frech / Tetrahedron 65 (2009) 1180–1187
1H NMR (300 MHz, CDCl3)
d
¼7.44–7.10 (m, 8H), 7.03 (t, J¼8.0 Hz,
3.3.20. 2-(Dibutylamino)pyridine-3-carbonitrile (Table 4, entry 4)
The title compound was purified by flash chromatography on
silica gel (methylene chloride). The pure product was obtained as
a colorless oil. Yield: 86%.
1H), 5.90 (dd, 3J¼8.0 Hz, 4J¼0.6 Hz, 1H), 5.78 (br s, 1H), 5.31 (dd,
3J¼7.8 Hz, 4J¼0.6 Hz, 1H), 3.50 (s, 3H), 3.30 (sept, J¼6.8 Hz, 2H), 1.39
(d, J¼6.8 Hz, 12H); 13C{1H} NMR (75 MHz, CDCl3)
¼158.3, 147.9,
d
147.2, 143.2, 138.3, 134.1, 129.3, 127.6, 126.1, 124.7, 123.8, 98.6, 94.4,
38.1, 28.2, 24.0. Anal. Calcd (%) for C24H29N3: C, 80.18; H, 8.13; N,
11.69. Found: C, 79.99; H, 8.02; N, 11.61.
1H NMR (300 MHz, CDCl3)
d
¼8.24 (dd, 3J¼4.6 Hz, 4J¼2.0 Hz, 1H),
7.65 (dd, 3J¼7.6 Hz, 4J¼2.0 Hz, 1H), 6.51 (dd, 3J¼7.6 Hz, 3J¼4.6 Hz,
1H), 3.61 (t, 3J¼7.8 Hz, 4H), 1.67–1.57 (m, 4H), 1.42–1.29 (m, 4H),
0.93 (t, 3J¼7.3 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3)
¼156.5,
d
3.3.15. N-Methyl-N-phenyl-N0-(3,4,5-trimethoxyphenyl)pyridine-
2,6-diamine (Table 2, entry 8)
151.0, 143.7, 118.4, 110.1, 88.7, 48.8, 29.1, 18.8, 12.8. Anal. Calcd (%) for
C14H21N3: C, 72.69; H, 9.15; N, 18.16. Found: C, 72.64; H, 9.11; N,
18.15.
The title compound was obtained after flash chromatography on
silica gel (toluene) as off-white powder. Yield: 96%.
1H NMR (300 MHz, CDCl3)
d¼7.29–7.22 (m, 2H), 7.19–7.14 (m,
3.3.21. N-Benzyl-N-(2,5-dimethoxyphenyl)-2,5-dimethoxyaniline
(Table 4, entry 17)
The title compound was purified by flash chromatography on
silica gel (methylene chloride). The pure product was obtained as
pale yellow oil. Yield: 95%.
2H), 7.12–7.05 (m, 2H), 6.62 (s, 2H), 6.40 (br s, 1H), 6.01 (d, J¼7.8 Hz,
1H), 5.87 (d, J¼8.1 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 6H), 3.39 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3)
d
¼158.1, 154.7, 153.3, 146.9, 138.3,
137.3,133.0,129.6,126.2, 125.1, 99.5, 97.5, 97.5, 60.9, 55.9, 38.5. Anal.
Calcd (%) for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50. Found: C,
69.07; H, 6.39; N, 11.53.
1H NMR (300 MHz, CDCl3)
d
¼7.73–7.70 (m, 2H), 7.55–7.43 (m,
3H), 7.07–7.03 (m, 2H), 6.84–6.82 (m, 2H), 6.78–6.73 (m, 4H), 5.11
(s, 2H), 3.93 (s, 12H); 13C{1H} NMR (75 MHz, CDCl3)
d
¼152.3, 145.9,
3.3.16. 6-Bromo-N,N-dibutylpyridin-2-amine
138.2, 138.0, 126.3, 125.9, 124.7, 112.3, 108.5, 105.2, 55.0, 54.4, 53.8.
Anal. Calcd (%) for C23H25NO4: C, 72.80; H, 6.64; N, 3.69. Found: C,
72.89; H, 6.63; N, 3.65.
The title compound was purified by flash chromatography on
silica gel using hexane/ethyl acetate (3:1). The pure product was
obtained as a colorless oil. Yield: 97%.
1H NMR (300 MHz, CDCl3)
d
¼7.04 (dd, 3J¼8.4 Hz, 3J¼7.4 Hz, 1H),
3.3.22. N-[2,6-Bis(1-methylethyl)phenyl]-N-(2,5-dimethoxy-
phenyl)-2,5-dimethoxyaniline (Table 4, entry 18)
The title compound was purified by flash chromatography on
silica gel (toluene). The pure product was obtained as a colorless
powder. Yield: 92%.
6.44 (d, 3J¼7.4 Hz, 1H), 6.15 (d, 3J¼8.4 Hz, 1H), 3.25 (t, 3J¼7.5 Hz,
4H), 1.46–1.36 (m, 4H), 1.26–1.13 (m, 4H), 0.81 (t, 3J¼7.3 Hz, 6H);
13C{1H} NMR (75 MHz, CDCl3)
d¼157.0, 139.3, 137.9, 112.5, 102.6,
47.4, 28.6, 19.3, 13.0. Anal. Calcd (%) for C13H21BrN2: C, 54.74; H,
7.42; N, 9.82. Found: C, 54.71; H, 7.37; N, 9.74.
1H NMR (200 MHz, CDCl3)
d
¼7.35–7.21 (m, 4H), 6.92–6.87 (m,
2H), 6.82–6.79 (m, 2H), 5.83 (s, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.74 (s,
3.3.17. N,N-Dibenzyl-6-morpholin-4-ylpyridin-2-amine (Table 3,
entry 3)
3H), 3.49 (s, 3H), 3.24 (sept, 3J¼6.9 Hz, 2H), 1.19 (d, 3J¼6.9 Hz, 12H);
13C{1H} NMR (75 MHz, CDCl3)
d¼153.3, 151.8, 151.5, 147.6, 140.2,
The title compound was purified by flash chromatography on
silica gel (methylene chloride). The pure product was obtained as
pale yellow oil, which solidified upon standing, giving a colorless
powder. Yield: 99%.
138.1, 135.1, 129.3, 127.1, 123.7, 117.7, 114.7, 113.3, 112.6, 112.4, 96.9,
56.6, 56.5, 56.3, 55.7, 28.1, 24.1. Anal. Calcd (%) for C28H35NO4: C,
74.80; H, 7.85; N, 3.12. Found: C, 74.67; H, 7.79; N, 3.15.
1H NMR (300 MHz, CDCl3)
d¼7.42–7.26 (m, 11H), 6.03 (d,
3.3.23. N,N-Bis(2,5-dimethoxyphenyl)-3,4,5-trimethoxyaniline
(Table 4, entry 19)
The title compound was purified by flash chromatography on
silica gel (diethyl ether). The pure product was obtained as pale
yellow oil, which solidified upon standing. Yield: 90%.
3J¼7.8 Hz, 1H), 6.00 (d, 3J¼8.0 Hz, 1H), 4.83 (s, 4H), 3.84 (t,
3J¼4.8 Hz, 4H), 3.51 (t, 3J¼4.8 Hz, 4H); 13C{1H} NMR (75 MHz,
CDCl3)
d
¼158.6, 157.5, 139.3, 139.2, 128.6, 127.2, 126.9, 95.6, 94.6,
66.9, 51.0, 45.8. Anal. Calcd for C23H25N3O: C, 76.85; H, 7.01; N,
11.69. Found: C, 76.84; H, 6.94; N, 11.65.
1H NMR (300 MHz, CDCl3)
d
¼7.25–6.69 (m, 6H), 6.26 (s, 2H),
4.19–3.87 (m, overlapping methoxy signals, 21H); 13C{1H} NMR
(75 MHz, CDCl3)
3.3.18. N,N-Dibutyl-6-piperidin-1-ylpyridin-2-amine (Table 3,
entry 6)
d
¼154.9, 153.0, 149.2, 144.3, 136.8, 133.8, 114.0,
113.8,110.0, 97.0, 60.9, 56.4, 55.9, 55.6. Anal. Calcd (%) for C25H29NO7:
C, 65.92; H, 6.42; N, 3.07. Found: C, 65.75; H, 6.40; N, 2.99.
The title compound was purified by flash chromatography on
silica gel (toluene). The pure product was obtained as pale yellow
oil, which solidified upon standing. Yield: 96%.
1H NMR (300 MHz, CDCl3)
d
¼7.22 (dd, 3J¼8.0 Hz, 3J¼7.9 Hz, 1H),
3.3.24. 3-Methoxy-2-[methyl(phenyl)amino]benzonitrile (Table 3,
entry 26)
The title compound was obtained after flash chromatography on
silica gel (methylene chloride) as colorless powder. Yield: 98%.
5.85 (d, 3J¼7.9 Hz, 1H), 5.75 (d, 3J¼8.0 Hz, 1H), 3.46 (br s, 4H), 3.36
(t, 3J¼7.4 Hz, 4H), 1.59 (br s, 6H) overlapped with 1.61–1.51 (m, 4H),
1.38–1.27 (m, 4H), 0.92 (t, 3J¼7.3 Hz, 6H); 13C{1H} NMR (75 MHz,
1H NMR (300 MHz, CDCl3)
d
¼7.68–7.55 (m, 2H), 7.54–7.48 (m,
CDCl3)
d
¼158.6, 156.8, 138.3, 93.7, 93.0, 48.5, 46.2, 29.9, 25.4, 24.9,
3H), 7.09 (tt, 3J¼7.3 Hz, 4J¼1.0 Hz, 1H), 6.90–6.86 (m, 2H), 4.05 (s,
20.4, 13.9. Anal. Calcd (%) for C18H31N3: C, 74.69; H, 10.79; N, 14.52.
Found: C, 74.43; H, 10.75; N, 14.49.
3H), 3.61 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
139.1, 128.9, 128.0, 125.2, 118.0, 117.0, 115.0, 112.8, 55.9, 38.5. Anal.
Calcd (%) for C15H14N2O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.80;
H, 5.98; N, 11.84.
d
¼157.4, 148.2,
3.3.19. 1-Methyl-4-(6-piperidin-1-ylpyridin-2-yl)piperazine (Table
3, entry 7)
The title compound was purified by flash chromatography on
alumina (ethyl acetate). Pure product: pale yellow oil. Yield: 97%.
3.3.25. 3-Methoxy-2-[methyl(3,4,5-trimethoxyphenyl)amino]-
benzonitrile (Table 4, entry 27)
1H NMR (300 MHz, THF-d8)
d
¼7.09 (dd, 3J¼8.1 Hz, 3J¼8.0 Hz,
1H), 5.85 (d, 3J¼8.1 Hz, 1H), 5.81 (d, 3J¼8.0 Hz, 1H), 3.44–3.31 (m,
The title compound was purified by flash chromatography on
silica gel (diethyl ether). The pure product was obtained as pale
brown oil, which solidified upon standing. Yield: 96%.
8H), 2.30–2.25 (m, 4H), 2.12 (s, 3H), 1.48 (br s, 6H); 13C{1H} NMR
(75 MHz, d8-THF)
44.9, 25.4, 24.6. Anal. Calcd (%) for C15H24N4: C, 69.19; H, 9.29; N,
21.52. Found: C, 69.08; H, 9.26; N, 21.60.
d
¼158.3, 158.2, 138.1, 95.2, 94.5, 54.9, 45.8, 45.5,
1H NMR (300 MHz, CDCl3)
d
¼7.03 (dd, 3J¼7.7 Hz, 4J¼1.4 Hz, 1H),
6.93 (dd, 3J¼8.1 Hz, 4J¼1.4 Hz, 1H), 6.85 (dd, 3J¼8.1 Hz, 3J¼7.7 Hz,

J.L. Bolliger, C.M. Frech / Tetrahedron 65 (2009) 1180–1187
1187
Thomas, A.; Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311;
(c) Chen, C.; Yang, L.-M. Org. Lett. 2005, 7, 2209; (d) Kelly, R. A., III;
Scott, N. M.; Diez-Gonzalez, S.; Stevens, E. D.; Nolan, S. P. Organometallics
2005, 24, 3442; (e) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2001,
42, 247.
1H), 6.09 (s, 2H), 6.06 (br s, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.68 (s,
6H); 13C{1H} NMR (75 MHz, CDCl3)
134.1, 125.4, 121.5, 117.1, 114.3, 102.7, 97.5, 60.9, 56.0 (two over-
lapping signals). Anal. Calcd (%) for C17H18N2O4: C, 64.96; H, 5.77; N,
8.91. Found: C, 64.99; H, 5.80; N, 8.81.
d
¼153.5, 150.6, 138.2, 136.2,
6. (a) Correa, A.; Garcia Mancheno, O.; Bolm, C. Chem. Soc. Rev. 2008, 37, 1108; (b)
Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862.
7. Leadbeater, N. E.; Marco, M. Angew. Chem., Int. Ed. 2003, 42, 1407.
8. (a) Shi, L.; Wang, M.; Zhang, F. M.; Tu, Y. Q. Org. Lett. 2003, 5, 3515; (b) Narayan,
S.; Seelhammer, T.; Gawley, R. E. Tetrahedron Lett. 2004, 45, 757.
9. Transition metal-free versions of the Buchwald–Hartwig amination are (in
contrast to catalyzed versions) not regioselective, because of the involvement
of cyclohexa-1,3-dien-5-ynes as key intermediates along the reaction path.8,10
However, when substrates, such as chlorobenzene, 2-bromo-1,4-dimethoxy-
benzene, or 2-chloro-1,4-dimethylbenzene, are used as coupling partners,
regioselectivity is not required for selective product formations. Similarly,
amination reactions performed with substrates containing directing groups,
such as 1,3-dibromobenzene, 1-bromo-3,5-dimethoxybenzene, 2-chloro-
nicotinonitrile, 2-chloro-3-methoxybenzonitrile, 1,3,5-trichlorobenzene, or 2,6-
dichloropyridine also lead in selective product formations, making transition
metal-free versions of the Buchwald–Hartwig reaction generally very attractive
for substrates, which either promote regioselectivity and/or do not require
regioselective aminations.
Acknowledgements
Financial support of this work by the University of Zurich and
the Swiss National Science Foundation (SNSF) are acknowledged.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.11.072.
References and notes
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its higher solubility, lower nucleophilicity and stronger basicity.
14. For details see Table S1 in Supplementary data.
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and often lead to reaction mixtures consistent of 2,6-dibromopyridine, 6-bro-
mopyridin-2-amines, and pyridine-2,6-diamines.17 However, selective forma-
tions of asymmetric 2,6-diaminopyridines (via nickel-catalyzed aminations of
2,6-dihalopyridines) have recently been reported.5e
17. See for example: Sun, X.; Yu, Z.; Wu, S.; Wen, J. Organometallics 2005, 24, 2959.
18. The change of reaction conditions, such as the reaction temperature, reaction
time or concentration had no effect on the product distributions.
19. See, Section 3
20. Asymmetrically substituted N,N-dibutylpyridine-2,6-diamines are preferably
prepared by introducing the other amine first, since the product formation is
significantly faster.
21. K3PO4 was used as base, because 2-chloronicotinonitrile instantly reacted with
KN(Si(CH3)3)2, leading in an insoluble black precipitate.
22. Cyclohexa-1,3-dien-5-yne intermediates cannot be formed with 2-bromo-1,3-
dimethylbenzene, explaining why 2-halo-1,3-dialkylbenzenes are, in contrast
to transition metal-catalyzed versions of the Buchwald–Hartwig reaction, inert
toward amination.
4. Copper-catalyzed aryl amination, see for example: (a) Antilla, J. C.; Buchwald, S. L.
Org. Lett. 2001, 3, 2077; (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793; (c)
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Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578; (e) Ran, C.;
Dai, Q.; Harvey, R. G. J. Org. Chem. 2005, 70, 3724; (f) Hu, T.; Li, C. Org. Lett. 2005, 7,
2035; (g) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005, 70, 8107.
5. Nickel-catalyzed aryl amination, see for example: (a) Desmarets, C.;
Schneider, R.; Fort, Y. J. Org. Chem. 2002, 67, 3029; (b) Omar-Amrani, R.;
23. See Tables S2–S4 in Supplementary data.