Regioselectively functionalized pyridines from sustainable resources

Article abstract of DOI:10.1002/anie.201301919

Make the most of it! An Ir-catalyzed dehydrogenative condensation of alcohols and 1,3-amino alcohol was used to construct pyridine derivatives regioselectively. This method provides access to unsymmetrically substituted pyridines and tolerates a wide variety of functional groups. Three equivalents of H₂ are generated per pyridine unit formed and the alcohol substrates become completely deoxygenated. Copyright

Full text of DOI:10.1002/anie.201301919

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Angewandte
Communications
DOI: 10.1002/anie.201301919
Homogeneous Catalysis
Regioselectively Functionalized Pyridines from Sustainable
Resources**
Stefan Michlik and Rhett Kempe*
Pyridines play an important role in the life sciences.[1] For
instance, many herbicides and fungicides as well as many
thousands of drugs contain the pyridine motif.[1c,2] Further-
more, polymers based on pyridines have diverse applications
in the chemical industry.[3,4] Considering the importance of
the pyridine moiety and the required substitution of petro-
leum/coal-based chemistry, a pyridine synthesis from renew-
able resources would be an attractive goal. Such a synthesis
would find significantly faster acceptance if it provides access
to diversely functionalized pyridines that are difficult to
prepare by existing methods. Recently, the Beller group,[5a]
the Milstein group,[6a] and our group[6b] have developed
sustainable catalytic syntheses of pyrroles based on dehydro-
genative condensation reactions (Scheme 1, top).
excess of propiophenone in the presence of a catalyst and
a base and observed the formation of two pyrrole deriva-
tives.[7a] Propiophenone serves as both the substrate and as an
H2 acceptor. Considering our pyrrole synthesis (Scheme 1,
middle) and using 1,3-amino alcohols (instead of 1,2-amino
alcohols), we propose a new [2+4] pyridine synthesis which
we present here. A primary or secondary alcohol can act as
a C2 building block that reacts in the initial step with a 1,3-
amino alcohol in an iridium-catalyzed dehydrogenative
Schiff-base reaction (Scheme 1, bottom).[8] Mechanistic stud-
ies indicate that the oxidation of the amino alcohols is
significantly slower and this enables the selective formation of
the imine (Figures 1 and 2 in the Supporting Information).
Subsequently, the remaining hydroxyalkyl group is dehydro-
genated and the olefin forms through intramolecular ring
closure and elimination of water.[9] Finally, aromatization by
liberation of H2 takes place (Figures 3 and 4 in the Supporting
Information). In the course of the reaction, two equivalents of
water and three equivalents of hydrogen gas are eliminated
(Scheme 1). The choice of the alcohol substrate determines
the substituents in positions 2 and 3 of the pyridine ring;
positions 4–6 are determined by the substitution pattern of
the amino alcohol. In this way diversely substituted pyridine
derivatives are accessible regioselectively.
These syntheses are based on observations made by the
research groups of Ishii and Crabtree.[7] Ishii and co-workers
reacted 2-aminoethanol or 2-(methylamino)ethanol with an
The reaction of 3-phenylpropanol with 3-amino-3-p-
tolylpropan-1-ol was investigated (Scheme 2, top) to find
suitable conditions for the new pyridine synthesis. In studies
toward catalyst optimization we started with iridium com-
plexes stabilized by P,N ligands that can use aliphatic amino
alcohols as alkylating agents without alkylating the N
atom.[6b,10] This type of selectivity is a prerequisite for the
catalyst in our pyridine synthesis since amino alcohols are
substrates. Precatalyst A gave the highest GC yield in the
screening reaction (Scheme 2, top). Details of the syntheses of
the ligand and complex are given in the Supporting Informa-
tion.
After optimizing the reaction conditions (solvent, base,
and temperature, for details see the Supporting Information)
we observed 95% yield of 1a (Scheme 2, top) in the reaction
with 0.5 mol% of precatalyst A. The yields obtained after
a reaction time of 24 h at 908C can be improved further by
subjecting the reaction mixture to further 24 h at 1308C.
Besides full conversion of the amino alcohol and formation of
a considerable amount of the desired pyridine, a substantial
Scheme 1. Known relevant catalytic pyrrole syntheses and the pyridine
synthesis presented here.
[*] S. Michlik, Prof. Dr. R. Kempe
Lehrstuhl Anorganische Chemie II
Universitꢀt Bayreuth
amount of
a
noncyclized imino/ketone intermediate
95440 Bayreuth (Germany)
E-mail: kempe@uni-bayreuth.de
(Scheme 1, bottom left) is present after the first 24 h. The
catalyst resting state was found to be an iridium(III)
trihydride complex (Scheme 2, bottom right). It can be
made by reacting precatalyst A with, for instance, alcohols
at temperatures above 708C or with H2 (Scheme 2, bottom).
[**] This project was supported by the Deutsche Forschungsgemein-
schaft (DFG KE 756/23-1).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301919.
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can prepared. Various substituted 1,3-amino alcohols were
reacted with 3-phenylpropanol, and aryl- as well as alkyl-
substituted pyridines (1a–f, Table 1) could be obtained in
mainly very good yields. Subsequently, we used diverse
primary alcohols. These products (1g–o, Table 1) carry
a tolyl substituent in position 2 of the pyridine ring which
was brought in by the amino alcohol. Nine different primary
alcohols were used, of which seven gave rise to new pyridine
derivatives (shown in gray in Table 1). The low yield for
products 1j,k (Table 1) can be explained by the formation of
p-tolyl-(6-p-tolylpyridin-3-yl)methanamine (1o, Table 1) as
a by-product arising from self-condensation of two molecules
of the amino alcohol. This side reaction can be “favored”
(35% yield) when no other alcohol is added, leading to 5-
(aminomethyl)pyridines (1o, Table 1).
We could show that the new pyridine synthesis works well
with primary alcohols. Thus, an efficient route to 2,5-
disubstituted pyridines was achieved. If one uses 1-substituted
ethanols, 2,6-disubstituted pyridines can be prepared, and two
examples were synthesized (1q,r Table 1). However, lower
yields of isolated product were observed since the corre-
sponding cyclic imines or tetrahydropyridines were formed in
a side reaction. Since positions 3–5 of the pyridine ring are
Scheme 2. Optimized reaction conditions (top) and formation of the
catalyst resting state (trihydride, bottom right).
ꢀ
unprotected, the C C bond formed by ring closure undergoes
The trihydride is present during the entire reaction as verified
by NMR spectroscopy and no noticeable decomposition was
observed. For the pyridine syntheses precatalyst A was used
since the trihydride is extremely air sensitive and much more
difficult to handle. The trihydride is quantitatively formed
from precatalyst A in less than 30 min under catalytic
conditions. After optimization of the reaction conditions we
explored the synthetic scope of the reaction. By using
different 1,3-amino alcohols as well as primary or the
secondary alcohols, products with diverse functional groups
facile hydrogenation and hydrogen is not liberated. Further-
more, 2,4-disubstituted pyridines (1p, Table 1) are accessible.
If the appropriately substituted 1,3-amino alcohols were used,
also 3,5-disubstituted pyridines, which are accessible usually
only under extreme reaction conditions by using electrophilic
substitution reactions, could be synthesized easily (1s,
Table 1). Since this synthesis tolerates many functional
groups such as chlorides, amines, ethers, olefins, heteroarenes,
and organometallic moieties, broad application is expected.
The methodology is especially efficient regarding the forma-
Table 1: Synthesized 2,4-, 2,5-, 2,6-, and 3,5-disubstituted pyridines.[a]
Prod. Alcohol
Amino alcohol
Product[b]
precat. A [mol%]
(yield [%])
Prod. Alcohol
Amino alcohol Product[b]
precat. A [mol%]
(yield [%])
1a
1k
0.5 (90)
0.5 (86)
0.5 (63)
0.3 (70)
1b
1c
1l
1m
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Table 1: (Continued)
Prod. Alcohol
Amino alcohol
Product[b]
precat. A [mol%]
(yield [%])
Prod. Alcohol
Amino alcohol Product[b]
precat. A [mol%]
(yield [%])
1.5 (86)
0.5 (92)
1.5 (61)
1.5 (93)
1d
1e
1n
1o
1.5 (94)
1.0 (35)
1 f
1p
1q
0.5 (92)
0.5 (48)
1g
1.0 (85)
0.5 (94)
0.5 (70)
0.05 (54[c])
0.5 (57[c])
1.5 (61)
1h
1i
1r
1s
1j
1.0 (45)
[a] Reaction conditions: 12.0 mmol alcohol, 3.0 mmol amino alcohol, 3.3 mmol NaOtBu, 10.0 mL THF, precatalyst A, 24 h/908C!24 h/1308C; the
pyridine products in gray were previously unknown. [b] Yield of isolated product. [c] 24 h/908C.
tion of unsymmetrically substituted pyridines. Furthermore,
the fact that many of these pyridines were prepared here for
the first time (compounds in gray in Table 1) indicates that
our method significantly extends the scope of existing
pyridine syntheses.
Finally, we became interested in the formation of bicyclic
pyridines starting from cyclic alcohols. The optimization of
the reaction conditions was carried out on the model system
3-aminopropan-1-ol/cycloheptanol. By using the optimized
conditions, bicyclic pyridines were synthesized, including
highly substituted examples (2g,h; Table 2).
here is sustainable. The hydrogen gas formed is not just
nontoxic but is a very useful by-product. Furthermore, the two
substrates, the alcohols and the 1,3-amino alcohols, can be
obtained from renewable resources or waste feedstock.
Lignocellulosic materials are available in huge amounts,[11]
and they are indigestible and can be (partially) processed to
alcohols or polyoles.[12] The 1,3-amino alcohols can be made
from 1,3-diols and ammonia using the borrowing-hydrogen or
hydrogen-autotransfer methodology;[13,14] alternatively, they
are also accessible from malonic acid, alcohols/aldehydes, and
ammonia.[15]
Furthermore, bicyclic pyridines that bear chiral substitu-
ents are accessible starting from inexpensive chiral natural
products (2c,d; Table 2). The pyridine synthesis introduced
In summary, we have described a new catalytic pyridine
synthesis. It provides access to a variety of regioselectively
substituted pyridines, including challenging unsymmetrically
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Angewandte
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Table 2: Synthesis of bicyclic pyridines.[a]
required starting materials can be obtained from renewable
resources with ammonia serving as the nitrogen source. This
synthesis method is part of what can be called “new (catalytic)
chemistry”, which provides access to virtually any important
organic compound from renewable resources. The broad
scope of our pyridine synthesis could lead to the rapid
advance of this reaction and thus accelerate the acceptance of
the “new chemistry”.
Prod.
Alcohol
Amino alcohol
Product[b]
precat. A [mol%]
(yield [%])
Received: March 7, 2013
Published online: April 29, 2013
2a
2b
0.5 (91)
0.5 (70)
Keywords: alcohols · dehydrogenation · iridium · pyridine ·
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sustainable resources
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[a] Reaction conditions: 12.0 mmol cyclic alcohol, 3.0 mmol amino
alcohol, 3.3 mmol NaOtBu, 10.0 mL THF, precatalyst A, 24 h/908C; the
pyridine products in gray were previously unknown. [b] Yield of isolated
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substituted pyridines. A broad spectrum of functional groups
is tolerated. In the dehydrogenative condensation steps three
equivalents of H2 are liberated per formed pyridine. The
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