Highly efficient and economic synthesis of new substituted amino-bispyridyl derivatives via copper and palladium catalysis

Article abstract of DOI:10.1016/j.tetlet.2008.03.096

A convenient route for the synthesis of a variety of amino-bispyridyl compounds is introduced. Bispyridylamines were prepared in three steps from commercially available 2,6-dibromopyridine, via a copper mediated alkylation followed by two consecutive N-arylation reactions catalyzed by copper and palladium, respectively.

Full text of DOI:10.1016/j.tetlet.2008.03.096

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3471–3474
Highly efficient and economic synthesis of new substituted
amino-bispyridyl derivatives via copper and palladium catalysis
a
a
b,
*
´
Sylvain Gaillard , Mohammed Kamal Elmkaddem , Cedric Fischmeister
Christophe M. Thomas b,*, Jean-Luc Renaud a,*
,
a Sciences Chimiques de Rennes, Chimie Organique et Supramole´culaire, UMR 6226, Ecole Nationale Supe´rieure de Chimie de Rennes, 35700 Rennes, France
b Sciences Chimiques de Rennes, Catalyse et Organome´talliques, UMR 6226: CNRS-Universite´ de Rennes 1, Campus de Beaulieu-35042 Rennes,
Cedex, France
Received 22 February 2008; revised 14 March 2008; accepted 19 March 2008
Available online 23 March 2008
Abstract
A convenient route for the synthesis of a variety of amino-bispyridyl compounds is introduced. Bispyridylamines were prepared in
three steps from commercially available 2,6-dibromopyridine, via a copper mediated alkylation followed by two consecutive N-arylation
reactions catalyzed by copper and palladium, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Nitrogen ligands are able to bind strongly to transition
metal atoms and can stabilize both very low and very high
oxidation states.1–6 Even if the nitrogen donor ligands have
been less extensively developed for catalytic applications
compared to phosphorus, they perform equally well or
better in some reactions than their phosphine analogues.
On the one hand, they are often less stabilizing under cat-
alytic conditions when coordinated to transition metals. On
the other hand, neutral nitrogen donor ligands are more
readily displaced from transition metal centers than anionic
units or phosphine ligands and therefore may play an inter-
esting flexible role in organometallic transformations.7
Examples of nitrogen ligands often involve diimine ligands
(heterocycles),8–12 which have been intensively studied
in asymmetric catalysis with almost all transition
metals.2–6,13 Other examples of multidentate N-donor
ligands have found only limited use in catalysis.14 Catalytic
applications of mainly late transition metal complexes have
been reported for trispyrazolylborate,15,16 triazacyclo-
nonane17 and pyridine-2,6-diimine18 ligands. A great
achievement was notably reported by Gibson and Brook-
hart with the discovery of highly active iron and cobalt
polymerization catalysts containing bulky tridentate
pyridine diimine ligands.19
As recently pointed out by Chelucci, the chemistry of
those compounds mostly relies on the efficient formation
of five-membered chelates upon metal binding. Interest-
ingly, only a few pyridine-based ligands with the potential
to form six-membered chelates with metals have been intro-
duced.
Wright’s
bis(pyridyl)
´
silane,20 Chelucci’s
dipyridylpropane,21 Najera dihydropyridylmethane, and
Kwong’s dipyridylketone23 are examples of those com-
pounds. Recently, Kempe,24 Bolm25 and Kim26 showed
the applicability of 2,20-dipyridylamines in transition
metal-catalyzed polymerization, allylic oxidation, and
transesterification, respectively. Jordan also prepared poly-
merization catalysts containing a neutral bidentate methy-
lenedipyridyl.27 Despite these interesting examples, the
chemistry of 2,20-dipyridylamines and 2,20-methylenedipyr-
idyl has mainly been limited to the study of their coordina-
tion behavior, and, to the best of our knowledge, no
sterically hindered dipyridyl derivatives were described in
the literature.
22
*
Corresponding authors. Tel.: +33 223238136; fax: +33 223238108
(J.L.R.).
E-mail addresses: cedric.fischmeister@univ-rennes1.fr (C. Fischmeis-
ter), christophe.thomas@univ-rennes1.fr (C. M. Thomas), jean-luc.
renaud@univ-rennes1.fr (J.-L. Renaud).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.096

3472
S. Gaillard et al. / Tetrahedron Letters 49 (2008) 3471–3474
H
N
+
N
N
R2
N
Br
R1
N
NH2
Br
N
Br
R1
R2
2
3
1
Scheme 1. Synthesis of substituted dipyridylamines.
Due to the high potential of such ligands in coordina-
tion chemistry, we wish to report in this Letter first the
synthesis of 6-alkyl-2-bromopyridines and 6-alkyl-
2-aminopyridines, then the preparation of some new 2,20-
bispyridylamine derivatives from the commercially avail-
able 2,6-dibromopyridine, as outlined in Scheme 1. As we
were looking for economic and attractive procedures for
the synthesis of compounds 1, the direct amination of
pyridine halides would be a valuable transformation and
will be evaluated.
NH3, Cu2O
ethylene glycol, 100 °C
R
N
Br
R
N
NH2
2a-e
3a-e
R =t-Bu (2a, 3a), i-Pr (2b, 3b), Me (2c, 3c),
Menthoxy (2d, 3d) , Borneoxy (2e, 3e)
t
-Bu
N
NH2
N
NH2
The first step of our strategy required the addition of an
alkyl substituent onto 2,6-dibromopyridine. Nevertheless,
two objectives have to be addressed (i) this addition must
proceed without any reduction of the halopyridines and
(ii) no double addition of the nucleophile must occur. As
palladium and nickel complexes often led to the elimina-
tion of secondary and tertiary Grignard reagents,28 as lith-
ium reagents could transmetallate aryl halides, we turned
our attention to copper chemistry.29 Among the copper
source, cuprates, and specifically those arising from CuI
and CuCNꢀ2LiCl,30 provided better yields than organocop-
per reagents. Then the treatment of 2,6-dibromopyridine
with 1.5 equiv of t-Bu2CuLi or t-BuCuCNLiꢀLiCl at
ꢁ78°C in THF led to compounds 2a in 66% and 94%
yields, respectively (Scheme 2). As only one tert-butyl
group was transferred from t-Bu2CuLi and because the
yield was slightly lower with this copper reagent, we used
the mixed cuprate for the addition of the iso-propyl group.
Under these reaction conditions, bromopyridine 2b was
isolated in 66% yield. Neither reduction of the bromopyri-
dine nor bis addition of the alkyl substituent was observed.
Moreover, to the best of our knowledge, this is the shortest
procedure to prepare 2a.31
OMe
OMe
2g: X= Br
3g: X= NH2
2f: X= Br
3f: X= NH2
Scheme 3. Synthesis of 2-amino-6-substituted pyridines 3.
However, the reaction of ammonia with aryl halides in
the presence of a catalytic amount of palladium38 or
copper39 has been recently reported. Following the Merck
procedure in the presence of a catalytic amount of cop-
per(I) oxide in ethylene glycol and ammonia at 100 °C,39
aminopyridines 3 were prepared in good yields (54–82%,
Scheme 3, Table 1). It is worth mentioning that other
solvents than ethylene glycol led to no reaction or lower
yields and that, starting from 2a–c, higher amounts of
corresponding alkoxypyridines were produced. Moreover,
under these reaction conditions, neither bis aryl formation
nor reduction of bromopyridines 2 was observed.
The last step in the synthesis of the new 2,20-bispyridyl-
amine was a second N-arylation reaction between amino-
pyridine 3 and bromopyridine 2. As copper-mediated
Ammonia is among the least expensive bulk chemicals
and a common nitrogen source in the synthesis. Despite
these, ammonia is rarely used in catalysis,32 and primary
arylamines are typically prepared from ammonia surro-
gates33 such as LiHMDS,34 benzophenone imine,35 allyl-
amine,36 carbamate,37 followed by a deprotection step.
Table 1
Copper catalyzed amination of 6-alkyl-2-bromopyridine 2a
R
Compound
Yieldb
(%)
t-Bu
i-Pr
Me
Menthoxy
Borneoxy
(R)-CH(OMe)(t-Bu)
6-((1R,2S,5R)-2-iso-Propyl-1-methoxy-5-
3a
3b
3c
3d
3e
3f
75
66
62
82
69
68
54
RLi or RMgBr + CuCN.2LiCl
3g
methylcyclohexyl)
a
0.5 mmol of bromopyridine 2, 2 mol % of copper(I) oxide in a 25 mL
stainless steel autoclave containing 1 mL of a solution of ethylene glycol
saturated with ammonia, 100°C, 24 h.
THF, -78°C to r.t. o/n
66-94%
Br
N
Br
R
N
Br
2a-b
b
Isolated yields, all new compounds were characterized by 1H and 13C
NMR, mass analysis.
Scheme 2. Synthesis of 2-bromo-6-alkyl pyridines 2.

S. Gaillard et al. / Tetrahedron Letters 49 (2008) 3471–3474
3473
and a general amination reaction with ammonia, as an
economic alternative to ammonia surrogate, were devel-
oped. These ligand syntheses offer the possibility of altering
the nature of the two pyridine groups and the central
N-donor atom. Applications of these derivatives as ligands
in catalysis are under active progress in our group.
R1
N
NH2
H
N
3a-c
+
t
BuOK (1.5 eq)
N
N
Pd2(dba)3 (2.5mol%)
BINAP (4 mol%)
Toluene, 90 °C
R1
R2
1
R2
N
Br
Acknowledgement
2a-c
The authors thank ‘l’Agence Nationale pour la
Recherche’ (ANR) for a grant ‘Jeunes Chercheurs-Jeunes
Chercheuses’(ANR-06-JCJC-0013).
Scheme 4. Synthesis of 6,60-substituted-2,20-dipyridylamine 1.
Ullmann coupling is now an active field of research and as
a great number of catalytic system for the synthesis of bi-
or tri-arylamines has been reported, we have carried out
some of these procedures. However, until now, no copper
catalytic system provided the desired nitrogen compounds
1. The bispyridylamine derivatives 1 were finally prepared
via a palladium-catalyzed Buchwald–Hartwig coupling
reaction.40 In the presence of 2.5 mol % of Pd2(dba)3,
4 mol % of rac-BINAP, and 1.5 equiv of t-BuOK in toluene
at 90 °C, compounds 1 were isolated in high yields (74–
98%, Scheme 4). This procedure allowed the synthesis of
C2-symmetrical or C1-symmetrical ligands and opened
the route to a library of such nitrogen ligands (Scheme 4,
Table 2).
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