A Ruthenium Catalyst with Unprecedented Effectiveness for the Coupling Cyclization of - Amino Alcohols and Secondary Alcohols

Article abstract of DOI:10.1021/acscatal.5b02638

The ruthenium complex (8-(2-diphenylphosphinoethyl)aminotrihydroquinolinyl)(carbonyl)(hydrido)ruthenium chloride exhibited extremely high efficiency toward the coupling cyclization of -amino alcohols with secondary alcohols. The corresponding products, pyridine or quinoline derivatives, are obtained in good to high isolated yields. On comparison with literature catalysts whose noble-metal loading with respect to -amino alcohols reached 0.5-1.0 mol % for Ru and a record lowest of 0.04 mol % for Ir, the current catalyst achieves the same efficiency with a loading of 0.025 mol % for Ru. The mechanism of acceptorless dehydrogenative condensation (ADC) was proposed on the basis of DFT calculations; in addition, the reactive intermediates were determined by GC-MS, NMR, and single-crystal X-ray diffraction. The catalytic process is potentially suitable for industrial applications.

Full text of DOI:10.1021/acscatal.5b02638

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Article
A Ruthenium Catalyst with Unprecedented Effectiveness for the
Coupling Cyclization of g-Aminoalcohols and Secondary Alcohols
Bing Pan, Bo Liu, Erlin Yue, Qingbin Liu, Xinzheng Yang, Zheng Wang, and Wen-Hua Sun
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02638 • Publication Date (Web): 12 Jan 2016
Downloaded from http://pubs.acs.org on January 14, 2016
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A Ruthenium Catalyst with Unprecedented
Effectiveness for the Coupling Cyclization of gꢀ
Aminoalcohols and Secondary Alcohols
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Bing Pan,† Bo Liu,† Erlin Yue,‡ Qingbin Liu,†,* Xinzheng Yang,‡ Zheng Wang,†,‡ and WenꢀHua
Sun‡,§*
†College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024,
China.
‡ Beijing National Laboratory for Molecular Science, Institute of Chemistry, Chinese Academy
of Sciences, Beijing 100190, China.
§State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China.
KEYWORDS: ruthenium catalyst, coupling cyclization, Nꢀheterocyclic compound, AD reaction,
high efficiency
ABSTRACT: The ruthenium complex, (8ꢀ(2ꢀdiphenylphosphinoethyl)aminotrihydroquinolinyl)
(carbonyl)(hydrido)ruthenium chloride, exhibited extremely high efficiency toward the coupling
cyclization of
γꢀaminoalcohols with secondary alcohols. The corresponding products, pyridine
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or quinoline derivatives, are obtained in good to high isolated yields. On comparison with
literature catalysts whose noble metal loading with respect to γꢀaminoalcohols reached 0.5 – 1.0
mol% for Ru and the lowest record 0.04 mol% for Ir, the current catalyst achieves the same
efficiency with a loading of 0.025 mol% Ru. The mechanism of acceptorless dehydrogenative
condensation (ADC) was proposed on the basis of the DFT calculations; meanwhile the reactive
intermediates were determined by GCꢀMS, NMR and single crystal Xꢀray diffraction. The
catalytic process is potentially suitable for industrial application.
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INTRODUCTION
Among Nꢀheterocyclic compounds, pyridine and quinoline derivatives have been extensively
used in pharmaceutical and agrochemical applications.1 The pyridine derivatives have also been
incorporated in lateꢀtransition metal complexes as highly active precatalysts toward ethylene
polymerization,2 and polyethylene processes are central to the multiꢀbillion dollar market in the
petrochemical industry. These lateꢀtransition metal complexes have been used in the amount of
several tons for ongoing pilots and industrial processes,2 and therefore new methodology of
synthesizing ringꢀfused pyridine derivatives is highly demanding. There is a rich history of
versatile methodologies to synthesize pyridine, pyrrole and quinoline derivatives;3ꢀ6 the attractive
procedures use coupling cyclization promoted by either ruthenium bipyridineꢀpincer complexes
(Milstein Cat., Scheme 1)5 or iridium complexes (Kempe Cat., Scheme 1).6 Recent efforts have
been made to reduce the loading amounts of complexes through using new ligands7 or being
immobilized by silicon carbonitride,8 however, these catalytic systems still do not meet the
required efficiency for the fine chemical industry due to the high loadings of up to 0.5–1.0 mol%
for Ru,5 with the best record of 0.04% for the (most expensive) iridium catalyst.6 Therefore it is
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necessary to maximize the efficiency of catalysts and promote the use of ruthenium – the
cheapest noble metal.
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Ar
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N
N
N
R1
tBu
tBu
N
P
HN
N
NH
Ru
N
Ru
P
P iPr
iPr
iPr P Ir
iPr
Ph3P
R2
Ph
Cl
N
Ph
CO
H
R1 = CO, R2 = H
Ar: Ph or pꢀCF3Ph
Milstein Cat.
Kempe Cat.
Ru-Cat, this work
Scheme 1. Representative Complex Catalysts.
On the basis of the acceptorless dehydrogenation (AD) reactions,9 the catalytic coupling
cyclization for pyridine, pyrrole or quinoline derivatives5ꢀ8 were developed via multiꢀstep
reactions including the formation of imines achieved by the condensation of alcohols and
amines;10 the subsequent cyclization forms Nꢀheterocyclic compounds simultaneously.5,6,11 In
designing the multiꢀdentate ligands for the lateꢀtransition metal precatalysts toward ethylene
polymerization,2 the fusedꢀring ligands provided the constrained geometrical environments
around the active metal species and significantly enhanced their catalytic activities. Targeting
ringꢀfused multiꢀdentate ruthenium complex toward the coupling cyclization of γꢀaminoalcohols
and various alcohols,5a being also inspired by the efficient dearomatized catalysts with P,N,Nꢀ
type ligands,12 the P,N,Nꢀtridentate ruthenium complex (Ru-Cat) is now newly developed. The
8ꢀ(2ꢀdiphenylphosphinoethyl)aminotrihydroquinoline was synthesized and used to react with
RuHCl(CO)(PPh3)3 to form (8ꢀ(2ꢀdiphenylphosphinoethyl)aminotrihydroquinolinyl)(carbonyl)
(hydrido)ruthenium chloride (Ru-Cat). With regard to the coupling cyclization of γꢀ
aminoalcohols and secondary alcohols, the new ruthenium catalyst showed most efficiency.
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Moreover, very low loading amounts of Ru-Cat were needed to achieve the high conversion
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yields. Herein, we report the synthesis of the ruthenium catalyst and its catalytic behavior
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towards the coupling cyclization of γꢀaminoalcohols with secondary alcohols.
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EXPERIMENTAL SECTION
General Considerations: All manipulations involving phosphine derivatives and the ruthenium
complex were carried out under a nitrogen atmosphere using standard Schlenk techniques. All
solvents were dried and distilled under nitrogen prior to use, and most of the chemicals used for
coupling cyclization were purified according to standard procedures (and vacuum distillation).
1H NMR (500 MHz) and 13C NMR (125 MHz) measurements were recorded on a Bruker AVШ–
500 NMR spectrometer. GC–MS measurements were conducted on DSQII equipped a column of
HPꢀ5MS with the injector temperature of 280 °C and detector temperature of 265 °C. GC
analyses were carried out on Agilent 6820 using a column OVꢀ1701.
Syntheses and Characterization of the Ruthenium Complex
2ꢀ(Diphenylphosphino)ethanamine: A 15.81 g (0.085 mol) amount of Ph2PH and a 20 g (0.18
mol) portion of tꢀBuOK were dissolved in 300 mL freshly distilled THF, the solution was stirred
for one hour at room temperature. Then 9.5 g (0.082 mol) of 2ꢀchloroethylamine hydrochloride
was added dropwise into the aboveꢀmentioned mixture, and resultant solution was refluxed for
12 h. Removal of the solvent left a crude mixture, which was neutralized with 10% NaOH
solution and extracted with toluene. The extract was dried over Na2SO4, and the desired
compound was obtained as a yellow viscous material in yield of 38% (7.22 g) by evaporating the
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solvent. 1HNMR (CDCl3, 500 MHz)：δ ppm: 7.47–7.35 (m , 4H), 7.30–7.21 (m, 6H), 2.83–2.80
(m , 2 H), 2.22 (t , J = 4.0 Hz, 2H), 1.56 (s , 2H).
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Nꢀ(2ꢀ(Diphenylphosphino)ethyl)ꢀ5,6,7,8ꢀtetrahydroquinolinꢀ8ꢀamine):
According
to
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literature,13 the mixture of 5,6,7ꢀtrihydroꢀquinolinꢀ8ꢀone (1.47 g, 10 mmol), 2ꢀ(diphenyl
phosphino)ethanamine (3 g, 13.1 mmol) and triacetoxy sodium borohydride (4.43 g, 21 mmol) in
100 mL CH2Cl2 was stirred for 6 h at room temperature. Being quenched with the saturated
NaHCO3 solution, the mixture was extracted with ethyl acetate (3 × 30 mL). Removal of the
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solvent left a yellow oil compound of 2.7g in yield of 75%. HNMR (CDCl3, 500 MHZ) δ ppm:
8.38–8.36 (s, 1H), 7.45–7.43 (m , 4H), 7.33–7.30 (m , 7H), 7.07–7.04 (t , J = 5.0 Hz, 1H), 3.76
(s, 1H), 2.90–2.73 (m , 4H), 2.36–1.69 (m , 6H), 0.88 (d , J = 5.0 Hz, 1H).
RuHCl(CO)(PPh3)3: Using the literature method,14 triphenylphosphine (3.15 g, 12 mmol) was
dissolved in refluxed ethylene glycol monomethyl ether (60 mL). Then the solution of
RuCl3·3H2O (0.414 g, 2 mmol) dissolved in glycol ether (40 mL) and 40% of aqueous
formaldehyde (40 mL) was added quickly. The reaction mixture was refluxed for further 10 min.
After cooling to room temperature, the product was precipitated and washed with hexane (light
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green or light gray solid, 85%). HNMR (CDCl3, 500 MHz): δ ppm:7.28–7.26(m, 6H),7.24–
7.22(m, 14H),7.11–7.07(m, 18H), 7.04–6.93(m, 7H), ꢀ7.10 – ꢀ7.31(m, 1H).
(8ꢀ(2ꢀDiphenylphosphinoethyl)aminotrihydroquinolinyl)(carbonyl)(hydrido)ruthenium
chloride (RuꢀCat): According to the literature procedure,15 a mixture of RuHCl(CO)(PPh3)3 (0.6
g, 1.68 mmol) and Nꢀ(2ꢀ(diphenylphosphino)ethyl)ꢀ5,6,7,8ꢀtetrahydroquinolinꢀ8ꢀamine (1.6 g,
1.68 mmol) in 30 mL toluene was refluxed for 10 h, then the resultant solution was cooled to 40
ºC and further stirred for 2 h. The precipitate was collected by filtration and washed with
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toluene as the offꢀwhite solid in 0.94 g (75% yield). H NMR (CDCl3, 500 MHz): δ ppm: 7.85–
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7.32 (m, 28H), 3.95–3.59 (m, 2H), 2.82–2.81(m, 2H), 2.49–2.29(m, 3H), 1.75–1.73(m, 3H),
1.03–1.01 (m, 1H), ꢀ11.58 (m, J = 10.0 Hz, 1H). Anal. Calcd. for C42H40N2ORuP2: C, 67.10; H,
5.363; N, 3.726. Found: C, 61.51; H, 5,274; N, 3.742.
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General Procedure for the Coupling Cyclization
The mixture of 2.5 × 10ꢀ4 mmol Ru-Cat, 1 mmol γꢀaminoalcohol, 2 mmol secondary alcohol and
2 mmol KOtBu in 2 mL toluene and 0.5 mL THF was refluxed under argon. After the required
reaction period, the resultant solution was cooled to room temperature and extracted with ethyl
acetate to collect the organic layer. Removal of solvent gave the crude product, which was
further purified on a silica column chromatography by using ethyl acetate/ hexane as eluent,
obtaining the product of either pyridine or quinoline derivatives.
In the coupling cyclization of cyclohexanone with 1ꢀ(2ꢀaminophenyl)ethanol, the mixture of 3.64
mmol 1ꢀ(2ꢀaminophenyl)ethanol, 7.28 mmol cyclohexanone and 50 mg toluenesulfonic acid in
16 mL toluene and 4 mL THF were refluxed for 3 h; then 7.28 mmol tꢀBuOK and 0.68 mg Ru-
cat were added. The resultant solution was continuously refluxed for 24 h. After extraction with
ethyl acetate and collecting organic layer, removal of solvent left the product, which was further
purified on a silica column, obtaining 9ꢀmethylꢀ1,2,3,4ꢀtetrahydroacridine in 47%.
Monitoring Reactive Intermediates
The 178 mg (2 mmol) 3ꢀaminoꢀ1ꢀbutanol, 400 mg (4 mmol) cyclohexanol, 5.2 mg (0.007mmol)
Ru-cat, and 224 g (2 mmol) KOtBu were mixed in 2 mL toluene and 0.5 mL THF, and the
mixture was refluxed for 24 h. The resultant solution was measured by the GCꢀMS to interpret
all intermediates (MS spectra of new compounds shown in Figure S1). Separated by a silica gel
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chromatography, the main products were isolated as a white solid 2ꢀmethylꢀ1,2,3,5,6,7,8ꢀ
heptahydroquinolinꢀ4ꢀone (55%) and a pale liquid 2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline (33%),
being confirmed by NMR, MS and elemental analysis. 2ꢀMethylꢀ1,2,3,5,6,7,8ꢀ
heptahydroquinolinꢀ4ꢀone:1HNMR (CDCl3, 500MHz) δ ppm: 4.20 (s, 1H), 2.37–2.32 (m, 1H),
2.29–2.21 (m, 1H), 2.20–2.17 (m, 3H), 1.72–1.70 (m, 2H), 1.61–1.52 (m, 2H), 1.27 (s, 3H).
13CNMR (CDCl3, 125 MHz) δ ppm: 192.16, 159.12, 106.83, 48.95, 44.24, 29.07, 22.61, 22.11,
20.90, 20.82; moreover, 2ꢀmethylꢀ1,2,3,5,6,7,8ꢀheptahydroquinolinꢀ4ꢀone was also confirmed
by the single crystal XꢀRay diffraction.
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X-Ray Structure Determination. Singleꢀcrystal Xꢀray diffraction study for the Ru-Cat
complex and 2ꢀmethylꢀ1,2,3,5,6,7,8ꢀheptahydroquinolinꢀ4ꢀone was conducted on a Rigaku
Sealed Tube CCD (Saturn 724+) diffractometer with graphiteꢀmonochromated Mo Kα radiation
(λ = 0.71073 Å) at 173(2) K, and cell parameters were obtained by global refinement of the
positions of all collected reflections. Intensities were corrected for Lorentz and polarization
effects and empirical absorption. The structures were solved by direct methods and refined by
fullꢀmatrix leastꢀsquares on F2. All nonꢀhydrogen atoms were refined anisotropically and all
hydrogen atoms were placed in calculated positions. Using the SHELXLꢀ97 package, structural
solution and refinement were performed.16
Computational Details
All DFT calculations were performed using the Gaussian 09 suite of ab initio programs17 for a
hybrid metaꢀGGA level density functional M0618 in conjunction with allꢀelectron 6ꢀ31++G(d,p)
basis set for all atoms.19 All calculated structures were fully optimized in THF (ε = 7.4257)
solvent using the integral equation formalism polarizable continuum model (IEFPCM)20 with
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radii and cavityꢀdispersionꢀsolventꢀstructure terms in Truhlar and coꢀworkers’ SMD solvation
model21 for the solvent effect corrections. An ultrafine integration grid (99,590) was used for
numerical integrations. Thermal corrections were calculated within the harmonic potential
approximation on optimized structures under T = 298.15 K and 1 atm pressure.
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RESULTS AND DISCUSSION
8ꢀ(2ꢀDiphenylphosphinoethyl)aminotrihydroquinoline was synthesized by the reaction of 5,6,7ꢀ
trihydroꢀquinolinꢀ8ꢀone and 2ꢀ(diphenylphosphino)ethanamine as in the literature procedure,13
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and then further stoichiometrically reacted with fresh RuHCl(CO)(PPh3)3 in toluene according
to the literature procedure15 to form the corresponding ruthenium complex (Ru-Cat, Scheme 2).
The ruthenium complex was examined by routine analysis and confirmed by singleꢀcrystal Xꢀray
diffraction as the distorted octahedral geometry around the Ru center (Figure 1).
N
N
RuHCl(CO)(PPh3)3
OC
N
HN
Ru
H
toluene, reflux
75%
(Ph)3P
P
(Ph)2P
Ph
Ph
Ru-Cat
Scheme 2. Synthesis of ruthenium complex (Ru-Cat).
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Figure 1. ORTEP drawing of ruthenium complex with thermal ellipsoids at 30% probability
level. All Hꢀatoms are omitted for clarity.
The catalytic behavior of the ruthenium complex was explored toward the coupling cyclization
of 3ꢀaminobutanol (A) with cyclohexanol (B). The reaction employed a mixture of toluene and
THF solvents (4:1), there was no desired product without the basic activator (entry 1, Table 1);
however, the reaction was smoothly carried out in the presence of tꢀBuOK (entries 2–4, Table 1).
The data obtained indicated a good result for 2 equivalents of tꢀBuOK with respect to the
substrate (A) (entry 3, Table 1). With this ratio of tꢀBuOK to substrate (A), the other reaction
parameters have been optimized and the results of this optimization are collected in Table 1.
Table 1. Coupling cyclization of 3ꢀaminobutanol (A) with cyclohexanol (B) a
Entry A (mmol) B (mmol) Ru ratio (%) Time (h)
tꢀBuOK (mmol)
yield (%)
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22.4
22.4
22.4
22.4
22.4
44.8
44.8
44.8
44.8
44.8
0.333
0.333
0.333
0.333
0.125
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0
ꢀ
22.4
44.8
67.2
44.8
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22.4
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22.4
22.4
22.4
11.2
11.2
11.2
11.2
11.2
44.8
44.8
44.8
44.8
44.8
11.2
33.6
22.4
22.4 c
22.4 c
0.05
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44.8
44.8
67.2
44.8
44.8
22.4
22.4
22.4 b
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22.4
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0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
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a Solvent mixture of toluene and THF (4 : 1). b tꢀBuONa used. c Cyclohexanone used.
With regard to the industrial of applicable catalytic systems for the synthesis of pyridine and
quinoline derivatives, the critical issue concerns the ruthenium loading of 0.5 mol% for Milstein
catalyst and even more for iridium complexes of Kempeꢀtype catalysts.6ꢀ8 The current catalyst
described herein can promote the coupling cyclization, forming 2ꢀmethylꢀ5,6,7,8ꢀ
tetrahydroquinoline in good isolated yields, with lower ruthenium complex loading (entries 4–8,
Table 1). Within 24 h, 2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline was isolated in 54 % yield with a
0.125mmol% Ru loading with respect to the substrate (A) (entry 5, Table 1), 49 % yield with
0.05 mmol% Ru (entry 6, Table 1), and still 35 % yield with 0.025 mmol% Ru (entry 7, Table
1). In addition, the catalytic activity is maintained because of more product obtained along with
prolonging the reaction time (entries 7–10, Table 1). For optimizing the suitable ratio of
substrates (A and B), the catalytic reactions were carried out with different molar ratios of B to A
(entries 10–12, Table 1), and the best condition was observed for two equivalents of B to A.
Additionally, the reaction was also carried out with tꢀBuONa instead of tꢀBuOK (entry 13 via
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3
4
5
6
7
8
9
9, Table 1), but tꢀBuOK turned out to be better. The product can be obtained with the isolated
yield of 73 % with a loading of 0.025 mmol% Ru-Cat (entry 10, Table 1). To the best of our
knowledge, the complex described herein is the most active ruthenium catalyst in such coupling
cyclizations.5,9,10 When RuHCl(CO)(PPh3)3 is used instead of Ru-Cat using the optimum
conditions, 2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline was not observed. Ruthenium complexes do
not characteristically perform the activation toward the acceptorless dehydrogenation and
cyclization; the finely tuned ligand significantly enhanced the catalytic activity of its ruthenium
complex herein.
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11
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13
14
15
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17
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On the basis of the DFT calculations,17ꢀ21 the relative free energies of several possible
intermediates within the formation of 2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline from 3ꢀaminoꢀ1ꢀ
butanol and cyclohexanol were proposed for a plausible reaction mechanism in Scheme 3.
Firstly, the dehydrogenation of the cyclohexanol forms a 4.7 kcal/mol less stable cyclohexanone
(1), which further condenses with a 3ꢀaminoꢀ1ꢀbutanol to produce the intermediate 2 (ꢁG = 10.5
kcal/mol) with the dissociation of a water. The dehydrogenation of 2 with a C−C coupling
cyclization forms intermediate 3-i (ꢁG = 10.6 kcal/mol), which is only 0.1 kcal/mol higher than
2 in free energy; then the dissociation of a water from 3-i gives a slightly more stable
intermediate 3 (ꢁG = 7.9 kcal/mol). The dehydrogenation of 3 for the formation of the 2ꢀmethylꢀ
5,6,7,8ꢀtetrahydroquinoline is a 13.0 kcal/mol downhill step. Besides that, the byproduct 4 was
experimentally isolated, probably being formed through the dehydrogenation of 3-i into
intermediates 4-i and a following proton transfer from carbon to nitrogen. Alternatively, 4-i
could also be formed through the dehydrogenation of 2 for the formation of an unstable
intermediate 2-i without cyclization, and the following dehydrogenation of 2-i with a C−C
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coupling cyclization.
5
6
7
NH2
8
9
OH
O
N
OH
H2
O
OH
- H2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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+ H2
N
H2O
cyclohexanol
1
2
2-i
G = 17.8
ꢀ
G = 0.0
ꢀ
G = 4.7
ꢀG = 10.5
ꢀ
H2
H2
OH
N
O
O
- H2
+ H2
N
N
N
N
H
H2O
H2
4-i
3
3-i
ꢀG = 10.6
4
ꢀ
G = 14.8
ꢀ
G = –5.1
ꢀ
G = 7.9
ꢀ
G = 6.3
Scheme 3. Plausible mechanism for the coupling cyclization of 3ꢀaminoꢀ1ꢀbutanol with
cyclohexanol on the basis of calculated relative free energies.
To find direct evidence for the intermediates, the reaction solution containing 2 mmol 3ꢀ
aminoꢀ1ꢀbutanol, 4 mmol cyclohexanol, 2 mmol KOtBu, 0.35mmol% RuꢀCat in the mixture of 2
mL toluene and 0.5 mL THF, were refluxed for 24 h. The reaction was monitored by the GC–
MS, indicating the presence of 2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline and compounds 1–4
(Scheme 3). The reaction solution was subjected to column chromatography to isolate the
expected product 2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline as a pale yellow liquid in 33%, moreover,
the byꢀproduct 4 was isolated as a white solid in 55%. Both obtained compounds were confirmed
by NMR spectroscopy and routine analysis, meanwhile the molecular structure of 4 was
confirmed by single crystal Xꢀray diffraction (see SI). Baseꢀpromoted dehydration is commonly
recognized,22 therefore the presence of KOtBu enhanced the transformation of compound 3-i
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into compound 3; the more KOtBu used, the more 2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline was
obtained (entries 2–4, Table1), meanwhile less byꢀproduct 4 was formed. Compound 2 would
result from the condensation of 3ꢀaminobutanol (A) with cyclohexanone (1), being assumed as a
reactive intermediate; to confirm that, reactions using cyclohexanone instead of cyclohexanol
were conducted, the corresponding products were isolated in similar yields (entries 14 vs. 10, and
15 vs. 7, Table 1).
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17
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Subsequently, the coupling cyclization of various γꢀaminoalcohols and secondary alcohols were
extensively conducted over both 72 and 24 h, at the ruthenium complex loading of 0.025 mmol%
with respect to γꢀaminoalcohols. In all the cases, the pyridine or quinoline derivatives were
isolated in good to high yields within 72 h and considerable yields in 24 h. The results regarding
aliphatic γꢀaminoalcohols are tabulated in Table 2.
Table 2. Coupling cyclization of various aliphatic γ−aminoalcohols and secondary alcohols a
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5
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8
9
γꢀAminoꢀ
alcohol
Isolated
yield/%b
Ru molar
ratio / %
Entry
1
Alcohol
Product
NH2
0.025
0.025
73 (35)
82 (64)
OH
OH
OH
N
NH2
NH2
NH2
2
3
4
OH
OH
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
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25
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30
31
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N
0.025
0.025
92
37
OH
N
OH
OH
N
NH2
5
0.025
44
OH
N
N
NH2
NH2
OH
OH
6
7
0.05
38 (19)
51
OH
OH
N
N
0.025
H2N
OH
8
9
0.025
0.025
62
OH
OH
H2N
H2N
H2N
H2N
OH
OH
OH
OH
83 (65)
N
10
11
12
0.025
0.05
84
OH
N
40 (23)
66
OH
OH
N
0.025
N
N
OH
H2N
H2N
OH
OH
13
14
0.025
0.025
40
16
OH
N
F
F
a
Reaction conditions: γ−aminoalcohol (22.4 mmol), alcohol (44.8 mmol), tꢀBuOK (44.8 mmol)
and 0.025 mmol% Ru, solvent mixture of toluene and THF (4:1), 72 hrs. b Yields obtained in 24
hrs shown in brackets.
To achieve the same efficiency, effective systems were reported as ruthenium loading for the
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Milstein catalyst5 in 0.5 % and the Kempe catalyst in 0.5−1.5 % (Scheme 1),6a the current
system requires the lowest loading of ruthenium 0.025 %. The corresponding products were
isolated in good to high yields, such as 2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinoline in 73 % (entry 1,
Table 2), 2ꢀmethylꢀ4,6,7,8,9ꢀpentahydrocycloheptapyridine in 82 % (entry 2, Table 2), 2ꢀmethylꢀ
5,6,7,8,9,10ꢀhexahydrocyclooctapyridine in 92 % (entry 3, Table 2), 5,6,7,8,9,10ꢀ
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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46
47
48
49
50
51
52
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hexahydrocyclooctapyridinene in 84 % (entry 10, Table 2),
6,7,8,9ꢀtetrahydroꢀ5Hꢀ
cycloheptapyridine in 83 % (entry 9, Table 2 ) and 5,6,7,8ꢀtetrahydroquinoline in 62 % (entry 8,
Table 2); the secondary alcohols are all cyclic alcohols. Using cyclopentanol as the substance,
however, the corresponding products were isolated in relatively lower yields as 2ꢀmethylꢀ5,6,7ꢀ
trihydrocyclopentapyridine in 37 % (entry 4, Table 2) and 5,6,7ꢀtrihydrocyclopentapyridine in
40 % (entry 11, Table 2). In the case of the cyclic alcohols, the larger the ring of the cyclic
alcohol used, the higher the yield of the corresponding product obtained; such phenomena were
clearly observed with the entries 1 through 5 as well as entries 8 through 12. In addition, in case
of nonꢀcyclic secondary alcohols, the coupling cyclization processed with relative lower
efficiencies; for example, the substance 3ꢀaminobutanol reacted with 4ꢀmethylꢀpentanꢀ2ꢀol to
form 2ꢀ isobutylꢀ6ꢀmethylpyridine in 38 % (entry 6, Table 2), and products such as 2ꢀmethylꢀ6ꢀ
phenylpyridine in 51 % (entry 7, Table 2), 2,6ꢀdipyridine in 63 % yield (entry 6, Table 3 ).
Likely, the alcohols having phenylꢀincorporation exhibited a negative influence to achieve lower
yields of products, such as entries 1 vs. 5 and 8 vs.12. However, the electronꢀwithdrawing fluoroꢀ
substituted substance, 1ꢀ(4ꢀfluorophenyl)ethanol, showed lower conversion affording 2ꢀ(4ꢀ
fluorophenyl)pyridine in 16 % (entry 14, Table 2).
Inspired by the negative influence observed with alcohols having phenylꢀincorporation (entries
1 vs. 5 and 8 vs. 12, Table 2), the aminoalcohols containing either fused or substituted phenyl
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groups were also investigated, and the results are collected in Table 3. Consistent with the above
observations, the higherꢀordered ring number of the cyclic alcohols enhanced the coupling
cyclization, achieving gradual higher yields of the corresponding products from entries 1 to 5,
and entries 7 to 8 as well as entries 10 to 11 in Table 3. However, by comparison using the same
alcohols, the products in Table 2 were generally isolated in higher yields than the analogous
compounds in Table 3, indicating the negative influence on the reaction when using phenylꢀ
incorporated aminoalcohols. In the case of using 1ꢀ(2ꢀaminophenyl)ethanol to react with cyclic
alcohols, there were no expected products observed when using the substances cyclohexanol,
cyclopentanol, 1ꢀphenylethanol and 4ꢀmethylpentanꢀ2ꢀol, however, the selfꢀcoupling cyclization
of 1ꢀ(2ꢀaminophenyl)ethanol took place due to itself acting as the secondary alcohol. Therefore
solely 1ꢀ(2ꢀaminophenyl)ethanol was employed in the reaction, and the expected product, 2ꢀ(4ꢀ
methylquinolinꢀ2ꢀyl)benzenamine, was isolated with the high yield of 92 % (entry 12, Table 3).
This can be interpreted in terms of the 1ꢀ(2ꢀaminophenyl)ethanol easily conducting
dehydrogenation than do common cyclic alcohols, but higherꢀordered cyclic alcohols such as
cycloheptanol (entry 10, Table 3) and cyclooctanol (entry 11, Table 3) were favored due to
better dehydrogenation in order to achieve better productivities.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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32
33
34
35
36
37
38
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40
41
42
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Table 3. Coupling cyclization of various arylꢀγ−aminoalcohols and secondary alcohols a
3
4
5
6
7
8
9
γꢀAminoꢀ
alcohol
Ru molar
ratio / %
Isolated
yield/%b
Entry
1
Alcohol
Product
NH2
0.025
0.025
35
45
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
32
33
34
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OH
OH
OH
N
N
NH2
2
3
OH
OH
NH2
0.025
52
OH
N
NH2
NH2
4
5
0.025
0.025
79 (58)
81
OH
OH
OH
N
N
OH
OH
NH2
6
0.025
63
OH
N
N
OH
NH2
OH
NH2
OH
7
8
9
0.025
0.025
0.05
83 (66)
90
OH
OH
OH
N
N
46 (34)
NH2
OH
10
11
0.025
0.025
85 (70)
91
OH
OH
N
N
NH2
OH
NH2
OH
OH
12
0.025
92 (91)
N
NH2
NH2
H2N
a
Reaction conditions: γ−aminoalcohol (22.4 mmol), alcohol (44.8 mmol), tꢀBuOK (44.8 mmol)
and 0.025 mmol% Ru, solvent mixture of toluene and THF (4:1), 72 hrs. b Yields obtained in 24
hrs shown in brackets.
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8
To have cyclic ketone considered as the potential species to react with aminoꢀgroup of the
aminoalcohols, cyclohexanone was used instead of cyclohexanol to react with 1ꢀ(2ꢀ
aminophenyl)ethanol and (2ꢀaminophenyl)methanol in the presence of catalytic amounts of pꢀ
methylbenzenesulfonic acid to form an imine. Following this procedure, adding the same amount
of ruthenium catalyst, the acceptorless dehydrogenative condensation reaction was achieved with
isolating the corresponding product in 47 % from 1ꢀ(2ꢀaminophenyl)ethanol and 42 % from 1ꢀ(2ꢀ
aminophenyl)methanol (Scheme 4). Therefore the coupling cyclization can be conducted with
various γꢀaminoalcohols and secondary alcohols as well as ketones to form the corresponding
products.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
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49
50
51
52
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60
R
OH
O
R
H+
OH
+
N
NH2
H2
R
R
N
Base
O
N
R = CH3, 47 %
R = H, 42 %
Scheme 4. Two steps for coupling cyclization of cyclohexanone with either 1ꢀ(2ꢀ
aminophenyl)ethanol or (2ꢀaminophenyl)methanol.
CONCLUSIONS
In summary, the title ruthenium complex exhibited the highest efficiency toward the coupling
cyclization of various γꢀaminoalcohols and secondary alcohols under mild conditions. In most
cases, the products were formed in good to high isolated yields, but the more important
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advantage was the very low ruthenium loading of 0.025 % with regard to γꢀaminoalcohols. Such
a catalytic procedure could be a highly efficient methodology in the direct synthesis of pyridine
and quinoline derivatives from various γꢀaminoalcohols and secondary alcohols. The fusedꢀring
of multiꢀdentate ligands probably enhances the stability and catalytic performance of the
ruthenium complex. The mechanistic study of the coupling cyclization of γꢀaminoalcohols with
secondary alcohols was studied by DFT, intermediates were monitored by NMR spectroscopy
and GCꢀMS to advance our understanding of the ADC reaction. The suitability of this catalyst to
alternative reactions as well as its industrial applications is promising and will be further
investigated.
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11
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ASSOCIATED CONTENT
Supporting Information
Characterization data of all new compounds, calculation details and crystal CIF files for Ru-Cat
and compound 4 are also available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Q.L.: tel, +86ꢀ311ꢀ80787432; eꢀmail, qbinliu@yahoo.com.
* W.ꢀH. S., tel, +86ꢀ10ꢀ62557955; fax, +86ꢀ10ꢀ62618239, eꢀmail, whsun@iccas.ac.cn.
Notes
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The authors declare no competing financial interest.
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6
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ACKNOWLEDGMENT
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This work is supported by the National Natural Science Foundation of China (Nos. 21476060,
21374123, U1362204, and 21373228) and the Nature Science Foundation of Hebei Province
(No.B2014205049), China. We are grateful to Dr. Carl Redshaw for his English proofreading.
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Unprecedentedly Effective Ruthenium Catalyst for Coupling Cyclization of γ-
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Aminoalcohols and Secondary Alcohols
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Bing Pan, Bo Liu, Erlin Yue, Qingbin Liu, Xinzheng Yang, Zheng Wang and WenꢀHua Sun
NH2
OH
Ru Cat
OH
Isolated yield
up to 92%
0.025%
N
Ru Cat.
OC
N
Ru
N
(Ph)3P
N
H
Ph
Ph
The ruthenium catalyst performed extremely high efficiency toward the coupling cyclization of
ꢀaminoalcohols with secondary alcohols. The mechanism was investigated through calculation
and experimental work.
γ
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