Direct synthesis of pyridines and quinolines by coupling of γ-amino-alcohols with secondary alcohols liberating H2 catalyzed by ruthenium pincer complexes

Article abstract of DOI:10.1039/c3cc43227k

A novel, one-step synthesis of substituted pyridine- and quinoline-derivatives was achieved by acceptorless dehydrogenative coupling of γ-aminoalcohols with secondary alcohols. The reaction involves consecutive C-N and C-C bond formation, catalyzed by a bipyridyl-based ruthenium pincer complex with a base.

Full text of DOI:10.1039/c3cc43227k

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Direct synthesis of pyridines and quinolines by
coupling of c-amino-alcohols with secondary alcohols
liberating H2 catalyzed by ruthenium pincer
complexes†
Cite this: Chem. Commun., 2013,
49, 6632
Received 1st May 2013,
Accepted 24th May 2013
DOI: 10.1039/c3cc43227k
Dipankar Srimani, Yehoshoa Ben-David and David Milstein*
www.rsc.org/chemcomm
A novel, one-step synthesis of substituted pyridine- and quinoline- catalytic coupling of nitriles with amines to selectively form
derivatives was achieved by acceptorless dehydrogenative cou- imines under mild hydrogen pressure.6g Very recently, we have
pling of c-aminoalcohols with secondary alcohols. The reaction reported the direct synthesis of pyrroles by dehydrogenative
involves consecutive C–N and C–C bond formation, catalyzed by a coupling of b-aminoalcohols with secondary alcohols.6h Here
bipyridyl-based ruthenium pincer complex with a base.
we present an efficient, one-step synthesis of pyridines based on
dehydrogenative coupling of g-aminoalcohols with secondary
The synthesis of N-heterocycles has attracted much attention alcohols, catalyzed by 1 and 2.
because of their prevalence in natural products and drugs.1 Of the
We envisioned that alcohol dehydrogenation followed by
N-heterocycles, substituted pyridines are among the most important consecutive C–N and C–C bond formation can eventually lead to
components of biologically active molecules and they are extensively dihydropyridines, which might undergo in situ dehydrogenation
used in pharmaceuticals, agrochemicals, and functional materials.2 to the corresponding pyridines, based on the excellent catalytic
Substantial progress has been achieved in derivatizing pre-existing dehydrogenation ability of complex 1 and its precursor complex 2
pyridine frameworks using metal-catalyzed cross-coupling (Scheme 1). Bergman and Ellman et al. presented a two step synthesis
protocols.3 However, the most useful and flexible approach of pyridines via dihydropyridines;7 the procedure first involves
involves the development of de novo construction of the pyridine the synthesis of dihydropyridines from imines and alkynes by
moiety. Thus, not surprisingly, much effort has been devoted rhodium-catalyzed C–H activation and electrocyclization, and then
to the synthesis of substituted pyridines4,5 using a variety of Pd/C-catalyzed air-oxidation, in acetic acid. It would be interesting to
protocols. Still, stitching together pyridines in a one-step reaction find a single catalyst that can form a dihydropyridine intermediate
using readily available starting materials remains challenging.
Recently we have developed the Ru–bipyridine-based pincer
and dehydrogenate it to the desired pyridine in one reaction.
Initially, the reaction of g-aminopropanol with 1-phenylethanol
complexes 1 and 26 (Scheme 1) which efficiently catalyze several was chosen as a model system for dehydrogenative cross-coupling to
environmentally benign reactions, including the hydrogenation of form pyridines. Thus, refluxing an equimolar amount of g-amino-
amides,6a cyclic diesters,6b urea derivatives,6c organic carbonates, propanol (2 mmol), 1-phenylethanol (2 mmol) and KOtBu (1 mmol,
carbamates and formates;6d the dehydrogenative transformation 0.5 eq. with respect to 1-phenylethanol) in 2 mL toluene for 24 h
of alcohols to carboxylic acid salts using water;6e dehydrogenative in the presence of 0.5 mol% complex 2 gave 45% yield of 2-phenyl-
cross-esterification involving primary and secondary alcohols;6f pyridine (Table 1, entry 1). Increasing the reaction time to 40 h,
or the catalyst loading to 1 mol%, did not improve the yield
of the product (Table 1, entries 2 and 3). Increasing the ratio of
g-aminopropanol : 1-phenylethanol to 1 : 2 enhanced the yield
of the desired pyridine to 62% (Table 1, entry 4).
Varying the solvent volume had a minor effect. Thus, heating
g-aminopropanol (2 mmol) and 1-phenylethanol (4 mmol) in
0.5 mL toluene in the presence of 0.5 mol% complex 2 gave
2-phenylpyridine in 53% yield after 24 h, while under the same
Scheme 1 PNN- and PNP-type ruthenium-pincer complexes.
conditions using 4 mL solvent resulted in 58% yield of the
product (Table 1, entries 5 and 6).
Department of Organic Chemistry, The Weizmann Institute of Science,
Rehovot 76100, Israel. E-mail: david.milstein@weizmann.ac.il; Fax: +972 9346569;
The solvent effect on the reaction was also examined. Thus,
Tel: +972 9342599
the yield of 2-phenylpyridine in a mixture of toluene (2 mL) and
THF (0.5 mL) (68%) was higher than in toluene (62%) or THF
† Electronic supplementary information (ESI) available: Experimental details and
spectral data. See DOI: 10.1039/c3cc43227k
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Table 1 Optimization of reaction conditions for the synthesis of 2-phenylpyridinea
Table 2 Synthesis of pyridines and quinolines using various amino alcohols and
secondary alcohols catalyzed by the Ru pincer complex 2a
Entry A : B Solvent
Time (h) Yieldb (%)
Entry Amino alcohol Alcohol
1
Product
Isolated yieldb (%)
62
1
2
3
4
5
6
7
8
9
10
1 : 1 Toluene (2 mL)
24
40
24
24
24
24
24
24
45
47
46c
62
53
58
48
25
68
52d
1 : 1 Toluene (2 mL)
1 : 1 Toluene (2 mL)
1 : 2 Toluene (2 mL)
1 : 2 Toluene (0.5 mL)
1 : 2 Toluene (4 mL)
1 : 2 Benzene (2 mL)
1 : 2 THF (2 mL)
2
70
3
4
53
24
1 : 2 Toluene + THF (2 mL + 0.5 mL) 24
1 : 2 Toluene (4 mL) 24
a
g-Aminopropanol (2 mmol), 1-phenylethanol (2 mmol or 4 mmol),
KOtBu (0.5 eq. with respect to 1-phenylethanol) and complex 2 (0.5 mol%)
b
were heated at reflux under argon. Yields of the products were
determined by gas chromatographic analysis of the crude reaction
5
80
c
mixture using m-xylene as an internal standard. 1 mol% catalyst was
d
used. Complex 3 was used.
6
7
55
48
(25%) alone, or in benzene (48%) (Table 1, entries 7–9). Actually,
the de-aromatized complex 1 can be readily formed in situ by
deprotonation of the air-stable complex 2 under basic reaction
conditions.6 The reaction in the presence of catalyst 3 led to a
lower yield (52%) of the desired pyridine (Table 1, entry 10).
Using the favourable reaction conditions we set out to
test the reactivity of various g-aminoalcohols with secondary
alcohols. A toluene–THF solution containing g-aminopropan-1-ol
(2 mmol), cycloheptanol (4 mmol), KOtBu (2 mmol) and catalyst 2
(0.01 mmol) was heated to reflux for 24 h and then cooled to room
temperature. The reaction mixture was then extracted with
dichloromethane and filtered through Celite. Evaporation of the
solvent gave a crude mixture which was further purified by
column chromatography using silica gel to obtain 70% isolated
yield of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (Table 2,
entry 2). Expanding the scope of the reaction to other cyclic
alcohols, the reaction of g-aminopropan-1-ol with cyclohexanol
in the presence of 0.5 mol% of 2 resulting in the formation
of 5,6,7,8-tetrahydroquinoline in 53% yield after 24 h reflux
8
67
9
55
50
62
55
10
11
12
13
71
45
14
a
g-Aminoalcohol (2 mmol), secondary alcohol (4 mmol), KOtBu
(2 mmol), catalyst (0.5 mol%) were heated in 2 mL toluene + 0.5 mL
b
(Table 2, entry 3) was studied. Reaction of g-aminopropan-1-ol THF mixture at reflux for 24 h. Yield of pure isolated product after
with cyclopentanol under the same conditions gave 6,7-dihydro-
column chromatography.
5H-cyclopenta[b]pyridine in only 24% isolated yield (Table 2,
entry 4). Expanding the scope of the reaction to other 3-amino-
alcohols, we studied the reaction of g-aminobutan-1-ol and (48%), 2-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (67%),
3-amino-3-phenylpropan-1-ol with various secondary alcohols. and 2-phenyl-5,6,7,8-tetrahydroquinoline (55%) in moderate to
A toluene–THF solution containing g-aminobutan-1-ol (2 mmol), good isolated yields (Table 2, entries 7–9).
cycloheptanol (4 mmol), KOtBu (2 mmol) and catalyst 2 (0.01 mmol)
Next, the scope with regard to the acylic secondary alcohol
was heated to reflux for 24 h, resulting in the formation of 2-methyl- was studied. In the case of 2-heptanol, two regioisomers can be
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine in good isolated yield formed by the abstraction of a proton bound to the primary or
(80%) after purification (Table 2, entry 5). Under similar reaction the secondary aliphatic carbon atom. Deprotonation at the less
conditions, dehydrogenative coupling of g-aminobutan-1-ol with hindered side gave 2-pentyl-6-phenylpyridine as the major product
cyclohexanol yielded 2-methyl-5,6,7,8-tetrahydroquinoline in 55% in 50% isolated yield (Table 2, entry 10). GC-MS analysis indicated
isolated yield (Table 2, entry 6). Reaction of 3-amino-3-phenyl- that together with the product pyridine, 10–20% of the corres-
propan-1-ol with the alcohols 1-phenylethanol, cycloheptanol ponding tetrahydropyridine was also obtained. In the case of the
and cyclohexanol under the same reaction conditions resulted reaction between 3-amino-3-phenylpropan-1-ol and 2-heptanol, the
in the corresponding desired pyridines, 2,6-diphenylpyridine product 6-pentyl-2-phenyl-2,3,4,5-tetrahydropyridine was isolated in
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formation catalyzed by 0.5 mol% of the bipyridyl based ruthe-
nium PNN complex 1, which is formed in situ using the air-
stable complex 2 and a base. We believe that this one step,
efficient coupling protocol which generates hydrogen gas is
attractive for the preparation of a diverse range of pyridine and
quinoline derivatives.
This research was supported by the European Research
Council under the FP7 framework (ERC No. 246837) and by
the Kimmel Center for Molecular Design. D.M. holds the Israel
Matz Professorial Chair of Organic Chemistry.
Scheme 2 Plausible mechanism of formation of pyridine derivatives via
a
sequence of dehydrogenation and condensation reactions.
20% yield. This is not very surprising, since the bipyridyl-based
Ru catalyst 1 (formed in situ from 2) is an excellent hydrogenation
catalyst. Thus, during the dehydrogenative coupling of secondary
alcohols with aminoalcohols the H2 formed can reduce the in situ
formed dihydropyridine to tetrahydropyridine. On the other hand,
we have shown that imines are not readily hydrogenated by the
bipyridyl-based pincer catalyst.6g
Encouraged by the results of the new pyridine formation
reaction, we were interested in applying the new methodology
to the synthesis of quinolines. The quinoline moiety is present in
many bioactive natural products, and various quinoline derivatives
are known to display a broad range of pharmacological properties,
which enable them to be used as anti-cancer,8a anti-HIV,8b anti-
hypertensive,8c anti-tuberculosis,8d and anti-Alzheimer8e agents.
Exploring the potential for the synthesis of quinolines, we studied
the reaction of 2-aminobenzyl alcohol with different secondary
alcohols, including 1-phenylethanol, cyclohexanol, cycloheptanol
and cyclododecyl alcohol to obtain 2-phenylquinoline, 1,2,3,4-
tetrahydroacridine, 7,8,9,10-tetrahydro-6H-cyclohepta[b]quino-
line, 6,7,8,9,10,11,12,13,14,15-decacyclododeca[b]quinoline, in
moderate to good isolated yields (Table 1, entries 11–14). After the
Notes and references
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9
¨
condensation to quinolines can proceed via a Friedlander pathway.
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6634 Chem. Commun., 2013, 49, 6632--6634
This journal is The Royal Society of Chemistry 2013