A Ruthenium Catalyst with Unprecedented Effectiveness for the

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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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ACS Catalysis

A Ruthenium Catalyst with Unprecedented Effectiveness for the Coupling Cyclization of gAminoalcohols and Secondary Alcohols Bing Pan,† Bo Liu,† Erlin Yue,‡ Qingbin Liu,†,* Xinzheng Yang,‡ Zheng Wang,†,‡ and Wen-Hua 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, N-heterocyclic compound, AD reaction, high efficiency

ABSTRACT: The ruthenium complex, (8-(2-diphenylphosphinoethyl)aminotrihydroquinolinyl) (carbonyl)(hydrido)ruthenium chloride, exhibited extremely high efficiency toward the coupling cyclization of γ-aminoalcohols with secondary alcohols. The corresponding products, pyridine 1

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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 γ-aminoalcohols 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 GC-MS, NMR and single crystal X-ray diffraction. The catalytic process is potentially suitable for industrial application.

INTRODUCTION Among N-heterocyclic compounds, pyridine and quinoline derivatives have been extensively used in pharmaceutical and agrochemical applications.1 The pyridine derivatives have also been incorporated in late-transition metal complexes as highly active precatalysts toward ethylene polymerization,2 and polyethylene processes are central to the multi-billion dollar market in the petrochemical industry. These late-transition metal complexes have been used in the amount of several tons for ongoing pilots and industrial processes,2 and therefore new methodology of synthesizing ring-fused pyridine derivatives is highly demanding. There is a rich history of versatile methodologies to synthesize pyridine, pyrrole and quinoline derivatives;3-6 the attractive procedures use coupling cyclization promoted by either ruthenium bipyridine-pincer 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 2


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necessary to maximize the efficiency of catalysts and promote the use of ruthenium – the cheapest noble metal. Ar N tBu N P tBu Ru Cl N H CO Milstein Cat.

N R1

N

N Ru Ph3P R2 P Ph Ph 1 R = CO, R2 = H Ar: Ph or p-CF3Ph Kempe Cat. Ru-Cat, this work HN N NH iPr P Ir P iPr iPr iPr

Scheme 1. Representative Complex Catalysts. On the basis of the acceptorless dehydrogenation (AD) reactions,9 the catalytic coupling cyclization for pyridine, pyrrole or quinoline derivatives5-8 were developed via multi-step reactions including the formation of imines achieved by the condensation of alcohols and amines;10 the subsequent cyclization forms N-heterocyclic compounds simultaneously.5,6,11 In designing the multi-dentate ligands for the late-transition metal precatalysts toward ethylene polymerization,2 the fused-ring ligands provided the constrained geometrical environments around the active metal species and significantly enhanced their catalytic activities. Targeting ring-fused multi-dentate ruthenium complex toward the coupling cyclization of γ-aminoalcohols and various alcohols,5a being also inspired by the efficient dearomatized catalysts with P,N,Ntype ligands,12 the P,N,N-tridentate ruthenium complex (Ru-Cat) is now newly developed. The 8-(2-diphenylphosphinoethyl)aminotrihydroquinoline was synthesized and used to react with RuHCl(CO)(PPh3)3 to form (8-(2-diphenylphosphinoethyl)aminotrihydroquinolinyl)(carbonyl) (hydrido)ruthenium chloride (Ru-Cat). With regard to the coupling cyclization of γaminoalcohols and secondary alcohols, the new ruthenium catalyst showed most efficiency. 3


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Moreover, very low loading amounts of Ru-Cat were needed to achieve the high conversion yields. Herein, we report the synthesis of the ruthenium catalyst and its catalytic behavior towards the coupling cyclization of γ-aminoalcohols with secondary alcohols.

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). 1

H 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 HP-5MS with the injector temperature of 280 °C and detector temperature of 265 °C. GC analyses were carried out on Agilent 6820 using a column OV-1701. Syntheses and Characterization of the Ruthenium Complex 2-(Diphenylphosphino)ethanamine: A 15.81 g (0.085 mol) amount of Ph2PH and a 20 g (0.18 mol) portion of t-BuOK 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 2-chloroethylamine hydrochloride was added dropwise into the above-mentioned 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

4


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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). N-(2-(Diphenylphosphino)ethyl)-5,6,7,8-tetrahydroquinolin-8-amine):

According

to

literature,13 the mixture of 5,6,7-trihydro-quinolin-8-one (1.47 g, 10 mmol), 2-(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 solvent left a yellow oil compound of 2.7g in yield of 75%. 1HNMR (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 green or light gray solid, 85%). 1HNMR (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). (8-(2-Diphenylphosphinoethyl)aminotrihydroquinolinyl)(carbonyl)(hydrido)ruthenium chloride (Ru-Cat): According to the literature procedure,15 a mixture of RuHCl(CO)(PPh3)3 (0.6 g, 1.68 mmol) and N-(2-(diphenylphosphino)ethyl)-5,6,7,8-tetrahydroquinolin-8-amine (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 with5


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toluene as the off-white solid in 0.94 g (75% yield). 1H NMR (CDCl3, 500 MHz): δ ppm: 7.85– 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. General Procedure for the Coupling Cyclization The mixture of 2.5 × 10-4 mmol Ru-Cat, 1 mmol γ-aminoalcohol, 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 1-(2-aminophenyl)ethanol, the mixture of 3.64 mmol 1-(2-aminophenyl)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 t-BuOK and 0.68 mg Rucat 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 9-methyl-1,2,3,4-tetrahydroacridine in 47%. Monitoring Reactive Intermediates The 178 mg (2 mmol) 3-amino-1-butanol, 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 GC-MS to interpret all intermediates (MS spectra of new compounds shown in Figure S1). Separated by a silica gel


6

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chromatography, the main products were isolated as a white solid 2-methyl-1,2,3,5,6,7,8heptahydroquinolin-4-one (55%) and a pale liquid 2-methyl-5,6,7,8-tetrahydroquinoline (33%), being

confirmed

by

NMR,

MS

and

elemental

analysis.

2-Methyl-1,2,3,5,6,7,8-

heptahydroquinolin-4-one: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). 13

CNMR (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, 2-methyl-1,2,3,5,6,7,8-heptahydroquinolin-4-one was also confirmed by the single crystal X-Ray diffraction. X-Ray Structure Determination. Single-crystal X-ray diffraction study for the Ru-Cat complex and 2-methyl-1,2,3,5,6,7,8-heptahydroquinolin-4-one was conducted on a Rigaku Sealed Tube CCD (Saturn 724+) diffractometer with graphite-monochromated 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 full-matrix least-squares on F2. All non-hydrogen atoms were refined anisotropically and all hydrogen atoms were placed in calculated positions. Using the SHELXL-97 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 meta-GGA level density functional M0618 in conjunction with all-electron 6-31++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 7


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radii and cavity-dispersion-solvent-structure terms in Truhlar and co-workers’ 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.

RESULTS AND DISCUSSION 8-(2-Diphenylphosphinoethyl)aminotrihydroquinoline was synthesized by the reaction of 5,6,7trihydro-quinolin-8-one and 2-(diphenylphosphino)ethanamine as in the literature procedure,13 and then further stoichiometrically reacted with fresh RuHCl(CO)(PPh3)314 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 single-crystal X-ray diffraction as the distorted octahedral geometry around the Ru center (Figure 1).

N

RuHCl(CO)(PPh3)3 HN

(Ph)2P

toluene, reflux 75%

N OC (Ph)3P

Ru

N

P H Ph Ph Ru-Cat

Scheme 2. Synthesis of ruthenium complex (Ru-Cat).

8


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Figure 1. ORTEP drawing of ruthenium complex with thermal ellipsoids at 30% probability level. All H-atoms are omitted for clarity. The catalytic behavior of the ruthenium complex was explored toward the coupling cyclization of 3-aminobutanol (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 t-BuOK (entries 2–4, Table 1). The data obtained indicated a good result for 2 equivalents of t-BuOK with respect to the substrate (A) (entry 3, Table 1). With this ratio of t-BuOK 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 3-aminobutanol (A) with cyclohexanol (B) a Entry

A (mmol)

B (mmol)

Ru ratio (%)

Time (h)

t-BuOK (mmol)

yield (%)

1

22.4

44.8

0.333

24

0

-

2

22.4

44.8

0.333

24

22.4

33

3

22.4

44.8

0.333

24

44.8

56

4

22.4

44.8

0.333

24

67.2

58

5

22.4

44.8

0.125

24

44.8

54 9


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a

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6

22.4

44.8

0.05

24

44.8

49

7

22.4

44.8

0.025

24

44.8

35

8

22.4

44.8

0.025

24

67.2

36

9

22.4

44.8

0.025

48

44.8

65

10

22.4

44.8

0.025

72

44.8

73

11

11.2

11.2

0.025

72

22.4

29

12

11.2

33.6

0.025

72

22.4

65

13

11.2

22.4

0.025

48

22.4 b

30

14

11.2

22.4 c

0.025

72

22.4

71

15

11.2

22.4 c

0.025

24

22.4

49

Solvent mixture of toluene and THF (4 : 1). b t-BuONa 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 Kempe-type catalysts.6-8 The current catalyst described

herein

can

promote

the

coupling

cyclization,

forming

2-methyl-5,6,7,8-

tetrahydroquinoline in good isolated yields, with lower ruthenium complex loading (entries 4–8, Table 1). Within 24 h, 2-methyl-5,6,7,8-tetrahydroquinoline 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 t-BuONa instead of t-BuOK (entry 13 via


10

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9, Table 1), but t-BuOK 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, 2-methyl-5,6,7,8-tetrahydroquinoline 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. On the basis of the DFT calculations,17-21 the relative free energies of several possible intermediates within the formation of 2-methyl-5,6,7,8-tetrahydroquinoline from 3-amino-1butanol 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 3-amino-1-butanol 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 2-methyl5,6,7,8-tetrahydroquinoline 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 11


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coupling cyclization. NH2 OH

H2

O

OH

OH

O - H2 + H2

N cyclohexanol

H2O

1

∆ G = 0.0

∆ G = 4.7

2 ∆ G = 10.5

N 2-i

∆ G = 17.8

H2

H2

OH

O

O

N

N H

- H2 N

N H2

∆ G = –5.1

+ H2

N 3

∆ G = 7.9

H2O

3-i

∆ G = 10.6

4-i ∆G = 14.8

4

∆ G = 6.3

Scheme 3. Plausible mechanism for the coupling cyclization of 3-amino-1-butanol with cyclohexanol on the basis of calculated relative free energies. To find direct evidence for the intermediates, the reaction solution containing 2 mmol 3amino-1-butanol, 4 mmol cyclohexanol, 2 mmol KOtBu, 0.35mmol% Ru-Cat 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 2-methyl-5,6,7,8-tetrahydroquinoline and compounds 1–4 (Scheme 3). The reaction solution was subjected to column chromatography to isolate the expected product 2-methyl-5,6,7,8-tetrahydroquinoline as a pale yellow liquid in 33%, moreover, the by-product 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 X-ray diffraction (see SI). Base-promoted dehydration is commonly recognized,22 therefore the presence of KOtBu enhanced the transformation of compound 3-i 12


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ACS Catalysis

into compound 3; the more KOtBu used, the more 2-methyl-5,6,7,8-tetrahydroquinoline was obtained (entries 2–4, Table1), meanwhile less by-product 4 was formed. Compound 2 would result from the condensation of 3-aminobutanol (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). Subsequently, the coupling cyclization of various γ-aminoalcohols and secondary alcohols were extensively conducted over both 72 and 24 h, at the ruthenium complex loading of 0.025 mmol% with respect to γ-aminoalcohols. 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 γ-aminoalcohols are tabulated in Table 2. Table 2. Coupling cyclization of various aliphatic γ−aminoalcohols and secondary alcohols a

13


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Entry 1

γ-Aminoalcohol NH2

Alcohol

OH 2

NH2 OH

3

NH2 OH

4

OH OH

73 (35)

0.025

82 (64)

0.025

92

0.025

37

0.025

44

0.05

38 (19)

0.025

51

0.025

62

0.025

83 (65)

0.025

84

0.05

40 (23)

0.025

66

0.025

40

0.025

16

N OH N OH

N

OH

NH2

NH2

N OH

OH 7

0.025 N

OH 6

Ru molar Isolated ratio / % yield/%b

Product

NH2 OH

5

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NH2

N OH

N

OH 8 9

H2N

OH

H2N

OH

OH N OH N

10

H2N

OH

OH N

11

12

H2N

H2N

OH

OH

OH

N

OH N

13

H2N

OH

14

H2N

OH F

OH

N

OH

N F

a

Reaction conditions: γ−aminoalcohol (22.4 mmol), alcohol (44.8 mmol), t-BuOK (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 14


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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 2-methyl-5,6,7,8-tetrahydroquinoline in 73 % (entry 1, Table 2), 2-methyl-4,6,7,8,9-pentahydrocycloheptapyridine in 82 % (entry 2, Table 2), 2-methyl5,6,7,8,9,10-hexahydrocyclooctapyridine

in

92

%

(entry

3,

hexahydrocyclooctapyridinene in 84 % (entry 10, Table 2),

Table

2),

5,6,7,8,9,10-

6,7,8,9-tetrahydro-5H-

cycloheptapyridine in 83 % (entry 9, Table 2 ) and 5,6,7,8-tetrahydroquinoline 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 2-methyl-5,6,7trihydrocyclopentapyridine in 37 % (entry 4, Table 2) and 5,6,7-trihydrocyclopentapyridine 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 non-cyclic secondary alcohols, the coupling cyclization processed with relative lower efficiencies; for example, the substance 3-aminobutanol reacted with 4-methyl-pentan-2-ol to form 2- isobutyl-6-methylpyridine in 38 % (entry 6, Table 2), and products such as 2-methyl-6phenylpyridine in 51 % (entry 7, Table 2), 2,6-dipyridine in 63 % yield (entry 6, Table 3 ). Likely, the alcohols having phenyl-incorporation exhibited a negative influence to achieve lower yields of products, such as entries 1 vs. 5 and 8 vs.12. However, the electron-withdrawing fluorosubstituted substance, 1-(4-fluorophenyl)ethanol, showed lower conversion affording 2-(4fluorophenyl)pyridine in 16 % (entry 14, Table 2). Inspired by the negative influence observed with alcohols having phenyl-incorporation (entries 1 vs. 5 and 8 vs. 12, Table 2), the aminoalcohols containing either fused or substituted phenyl15


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groups were also investigated, and the results are collected in Table 3. Consistent with the above observations, the higher-ordered 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 phenylincorporated aminoalcohols. In the case of using 1-(2-aminophenyl)ethanol to react with cyclic alcohols, there were no expected products observed when using the substances cyclohexanol, cyclopentanol, 1-phenylethanol and 4-methylpentan-2-ol, however, the self-coupling cyclization of 1-(2-aminophenyl)ethanol took place due to itself acting as the secondary alcohol. Therefore solely 1-(2-aminophenyl)ethanol was employed in the reaction, and the expected product, 2-(4methylquinolin-2-yl)benzenamine, was isolated with the high yield of 92 % (entry 12, Table 3). This can be interpreted in terms of the 1-(2-aminophenyl)ethanol easily conducting dehydrogenation than do common cyclic alcohols, but higher-ordered 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.

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Table 3. Coupling cyclization of various aryl-γ−aminoalcohols and secondary alcohols a

Entry

γ-Aminoalcohol

Alcohol

Ru molar ratio / %

Isolated yield/%b

0.025

35

0.025

45

N

0.025

52

Product

NH2 1

OH

OH

OH

OH

N

NH2 2 NH2 3

N

OH OH

NH2 4

OH

OH

N

0.025

79 (58)

OH

OH

N

0.025

81

N

0.025

63

0.025

83 (66)

0.025

90

0.05

46 (34)

0.025

85 (70)

0.025

91

0.025

92 (91)

NH2 5

NH2 6

7

OH OH

OH OH NH2

8

N

OH OH NH2

9

OH

N OH

NH2 OH 10

N

OH N

NH2 OH 11

OH N

NH2 OH

OH

12

N NH2

NH2

H2N

a

Reaction conditions: γ−aminoalcohol (22.4 mmol), alcohol (44.8 mmol), t-BuOK (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. 17


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To have cyclic ketone considered as the potential species to react with amino-group of the aminoalcohols, cyclohexanone was used instead of cyclohexanol to react with 1-(2aminophenyl)ethanol and (2-aminophenyl)methanol in the presence of catalytic amounts of pmethylbenzenesulfonic 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 1-(2-aminophenyl)ethanol and 42 % from 1-(2aminophenyl)methanol (Scheme 4). Therefore the coupling cyclization can be conducted with various γ-aminoalcohols and secondary alcohols as well as ketones to form the corresponding products. OH R

R

O +

H+

OH

NH2

N

R

R

H2 Base

N R = CH3, 47 % R = H, 42 %

O N

Scheme 4. Two steps for coupling cyclization of cyclohexanone with either 1-(2aminophenyl)ethanol or (2-aminophenyl)methanol.

CONCLUSIONS In summary, the title ruthenium complex exhibited the highest efficiency toward the coupling cyclization of various γ-aminoalcohols and secondary alcohols under mild conditions. In most cases, the products were formed in good to high isolated yields, but the more important 18


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advantage was the very low ruthenium loading of 0.025 % with regard to γ-aminoalcohols. Such a catalytic procedure could be a highly efficient methodology in the direct synthesis of pyridine and quinoline derivatives from various γ-aminoalcohols and secondary alcohols. The fused-ring of multi-dentate ligands probably enhances the stability and catalytic performance of the ruthenium complex. The mechanistic study of the coupling cyclization of γ-aminoalcohols with secondary alcohols was studied by DFT, intermediates were monitored by NMR spectroscopy and GC-MS 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.

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, +86-311-80787432; e-mail, [email protected]. * W.-H. S., tel, +86-10-62557955; fax, +86-10-62618239, e-mail, [email protected]. Notes

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The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENT 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 γAminoalcohols and Secondary Alcohols Bing Pan, Bo Liu, Erlin Yue, Qingbin Liu, Xinzheng Yang, Zheng Wang and Wen-Hua Sun NH2 OH

Ru Cat OH

0.025% Isolated yield up to 92% Ru Cat.

N OC

N

Ru

(Ph)3P

N N

H

Ph

Ph

The ruthenium catalyst performed extremely high efficiency toward the coupling cyclization of

γ-aminoalcohols with secondary alcohols. The mechanism was investigated through calculation and experimental work.

24


A Ruthenium Catalyst with Unprecedented Effectiveness for the

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