Tetrahedron Letters
A practical synthesis of N,N-dimethyl-(6-arylpyrid-2-yl)alkylamines
⇑
Catherine A. Faler
ExxonMobil Chemical Company, 5200 Bayway Drive, Baytown, TX 77520, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Described is a multigram synthesis of pyridyl amine ligands, which are being studied for their potential
use in commercial processes. A practical scale-up was hindered by benzotriazole byproducts of a Grig-
nard addition. With an improved purification to remove these byproducts and a strategic re-ordering
of synthetic steps, an array of N,N-dimethyl-(6-arylpyrid-2-yl)alkylamines was made efficiently on large
scales.
Received 22 July 2010
Revised 18 August 2010
Accepted 19 August 2010
Available online 24 August 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
Pyridyl amine
Benzotriazole activation
Ethylene oligomerization
Catalysts made of Group IV metals containing pyridyl amines
have attracted attention for their applications in olefin polymeriza-
tion.1 These single site catalysts have an advantage over heteroge-
neous catalysts in that their reactivity can be tuned by ligand
variations, and they can provide polymers with greater stereoreg-
ularity.2 Recently, pyridyl amine complexes have been employed
for selective ethylene oligomerization.3 Mechanistic studies sug-
gest that metallocyclic intermediates are responsible for the
unparalleled oligomer selectivity.4
The synthesis of pyridyl amines for oligomerization catalysts
has been of interest in our laboratory. Our original synthetic proce-
dure to make pyridyl amines, shown in Figure 1, started with Suzu-
ki coupling of an aryl boronic acid to 6-bromo-2-pyridine
carboxaldehyde (1).5 After purification by column chromatogra-
phy, the aldehyde was condensed with dimethylamine and benzo-
triazole to give a stabilized iminium salt (2). Grignard addition to
the condensation adduct installed the aliphatic or aromatic substi-
tuent.6 Chromatography was needed to purify the final product,
separating it from the benzotriazole byproduct prior to metallation
with an appropriate metal precursor.
cation steps. Although this synthesis allowed rapid diversification
of R0, attempts to purify more than 5 g of ligand at one time could
not be achieved with more than 90% purity.
During the course of the Grignard addition, a white or yellow
precipitate was observed that dissolved upon aqueous ammonium
chloride quench. It was hypothesized that this precipitate was a
benzotriazole-magnesium salt and removal before workup would
simplify purification. Filtration of the crude reaction mixture over
alumina did indeed remove most of the impurities. Analysis of
the condensed filtrate by 1H NMR indicated that benzotriazole con-
stituted only 10–15% of the product. A silica gel plug eluted with
ethyl acetate was sufficient to purify the resulting pyridyl amine.
Grignard addition yields following this protocol are moderate, as
seen in Table 1. Fortunately, use of 1.5 equiv of Grignard reagent
resulted in improved yields.
It was later found that filtering the reaction mixture through
Celite using diethyl ether to wash the filtrand was as effective as
filtration through alumina and/or silica gel. Other solvents, such
as ethyl acetate or THF, have a tendency to dissolve the benzotria-
zole-magnesium salt, allowing it to contaminate the product.
To facilitate diversification of ligand synthesis, the sequence of
steps from the original preparation was rearranged (Fig. 2). This
change provided a convenient route for introducing aromatic vari-
ations in the 6-position of the pyridine ring. Thus, after Grignard
addition to a benzotriazole-activated substrate, bromopyridinyl
compound 3 was made in about 90% yield from 2-bromo-6-pyri-
dine carboxaldehyde. After filtration through Celite, NMR analysis
indicated that amine 3 was sufficiently clean, and no further puri-
fication was required. With the Suzuki coupling now as the last
step, an advanced intermediate was created and analogues with
varying aryl groups were made efficiently. A few examples of these
ligands are shown in Figure 2. In addition to the benefit of facile
Preparation of an array of ligands in small (100 mg) quantities
was achieved employing the synthesis in Figure 1. However, gram
quantities of the most promising ligands were required for further
study. The Suzuki coupling and amine condensation steps scaled
up well with a combined yield of over 80% on a 20 g scale. Unfor-
tunately, the benzotriazole generated during the Grignard addition
proved exceedingly difficult to remove, requiring a disproportion-
ately large silica gel or alumina column, and often multiple purifi-
⇑
Tel.: +1 281 834 0174; fax: +1 281 834 2480.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
Faler, Catherine A.
