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Synthesis of Substituted 2-Pyridyl-4-phenylquinolines

Department of Physical and Chemical Methodologies for Engineering, Engineering Faculty, University of Catania, V.le Andrea Doria 6, I-95125 Catania, Italy
*
Author to whom correspondence should be addressed.
Molecules 2002, 7(8), 618-627; https://doi.org/10.3390/70800618
Received: 21 June 2002 / Revised: 2 August 2002 / Accepted: 3 August 2003 / Published: 31 August 2002

Abstract

The acid-catalyzed condensation of o-aminobenzophenones with aromatic acetyl derivatives, in a basic methanol/tetrahydrofuran medium, has been used to prepare a series of substituted 2-pyridyl-4-phenylquinolines. Derivatives having two aza binding sites can act as asymmetric bidendate ligands to complex transition metals such as ruthenium, osmium or iridium. All the compounds were characterized by elemental analysis, Ei or FAB (+) MS, 1H- and 13C-NMR spectroscopies. Complete assignments of the 1H spectra were accomplished by using a combination of one- and two-dimensional NMR techniques.
Keywords: Quinoline derivatives; asymmetric bidentate aza-ligands; 2D-NMR Quinoline derivatives; asymmetric bidentate aza-ligands; 2D-NMR

Introduction

In the past few decades luminescent transition metal complexes based on polypyridine ligands, owing to their long-lived metal-to-ligand charge-transfer (MLCT) excited states, have already been used in various fields such as solar energy conversion [1], information storage [2], photocleavage of DNA [3], and oxygen sensors [4]. Although the photophysics and photochemistry of [Ru(bpy)3]2+ (bpy = 2,2’ bipiridine) have been the subject of extensive research [1,2,3,4], few other bidentate ligands, i.e. having two aza binding sites, have been prepared and the photophysical and/or photochemical properties of their complexes with transition metals studied [5]. As a continuation of previous studies in this field [6], we now report the synthesis and characterization of the ligands shown in Scheme 1, with the aim of studing the photochemical properties of their complexes with transition metals such as ruthenium, osmium or iridium. Three of these asymmetric bidendate ligands (L2L4) are new. All the compounds were characterized by elemental analysis, EI or FAB mass, 1H and 13C NMR spectroscopies. Complete assignments of the 1H spectra of the various compounds were accomplished by using a combination of one- and two-dimensional NMR techniques.
Scheme 1.
Scheme 1.
Molecules 07 00618 g002

LigandsR1R2R3Initials
L1HHHph-pq
L2CH3HHmph-pq
L3CH3HCH3mph-mpq
L4HBrCH3brph-mpq

Results and discussion

The literature describes numerous different ways to prepare substituted quinoline rings: i.e., by exploiting quinoline carboxamides [7], acid-catalyzed condensation of o-aminobenzophenones [8] with ketones [9], sequential vinylic substitution/annelation processes [10], reactions of N-arylnitrilium salts with acetylenes [11], cyclodehydration of o-vinyl anilides [12], intramolecular Wittig reactions [13], and cyclization of oximes [14]. Using o-isocyanostyrenes only symmetric biquinoline may be prepared [15]. Following the synthetic pathway previously used for the preparation of the unsubstituted ligand 4-phenyl-2-(2’-pyridyl)quinoline (L1, ph-pq) [16], namely the acid-catalyzed condensation of o-amino-benzophenone with 2- acetylpyridine derivatives, as shown in Scheme 2, we have now synthetized the ligands 4-phenyl-7-methyl-2-(2’-pyridyl)quinoline (L2, mph-pq) and 4-phenyl-7-methyl-2-[2’-(6’-methyl)pyridyl]-quinoline (L3, mph-mpq).
Scheme 2.
Scheme 2.
Molecules 07 00618 g003
The ligand 4-phenyl-6-bromo-2-[2’-(6’-methyl)-pyridyl]quinoline (L4, brph-mpq) was obtained in a three synthetic steps (Scheme 3) starting from p-nitrobromobenzene.
Scheme 3.
Scheme 3.
Molecules 07 00618 g004
2-Amino-5-bromobenzophenone (2) was obtained by condensation of p-nitrobromobenzene with phenylacetonitrile in a basic methanol/tetrahydrofuran medium to give 3-phenyl-5-bromo-2,1-benzisoxazole (1) (66%), which upon reductive cleavage (Fe/CH3COOH) of the benzisoxazole ring was converted to the desired aminoketone 2 (70 %). A subsequent Friedlander reaction [17] of the o-aminobenzophenone 2 with 2-acetyl-6-methylpyridine, using a mixture of m-cresol and phosphorous pentoxide gave ligand L4 (71%). Table I reports the results of a complete 1H-NMR analysis of ligands L1L4. Proton chemical shifts and J(H,H) values were measured at 500 MHz.
Table I. 1H NMR parameters of ligands L1L4
Table I. 1H NMR parameters of ligands L1L4
ProtonL1L2L3L4
38.53 s8.47 s8.48 s8.57 s
57.96 d7.85 d7.22 d8.06 d
J=8.0J=9.0J=7.5J=2.0
67.56-7.507.34 bd7.34 dd-
mJ=6.0J=8.5, 1.5
77.75 dt--7.79 dd
J=7.0, 1.5J=7.0, 2.0
88.26 d8.05 bs8.04 bs7.23 d
J=8.5J=7.5
3’8.71 d8.69 d7.83 d8.45 d
J=7.5J=8.0J=8.5J=8.0
4’7.90 dt7.88 dt7.77 t7.77 t
J=8.0, 2.0J=8.0, 1.5J=7.5J=8.0
5’7.37 bt7.36 dt8.47 d8.10 d
J=6.5J=7.5, 1.5J=7.5J=8.5
6’8.74 d8.73 dd--
J=4.5J=4.5, 1.0
Ph7.62-7.507.61-7.497.61-7.507.57-7.51
mmmm
Py-CH3--2.65 s2.64 s
q-CH3-2.60 s2.59 s-
Notes: The spectra were obtained in deuterated chloroform (CDCl3), chemical shifts in ppm, and coupling constants in Hz. Numbering pattern as shown in Scheme 2 and Scheme 3. Abbreviations used: bs = broad singlet, s = singlet, d = doublet, dd = double doublet, m = multiplet, t = triplet, dt =double triplet.
Assignments were aided by the use of 2D homonuclear chemical shift correlated 1H-NMR (COSY) [18]. As an example, Figure 1 shows the COSY–45 experiment of L1 and includes as the upper and left traces the related 1H-NMR spectrum, both run in deuterated chloroform (CDCl3). The 1H singlet at 8.53 ppm was easily assigned by the integration ratio to the quinoline proton H3. A four-spin system is identified, through the COSY spectrum, as connecting the 1H signals at 8.26, 7.96, 7.75, and 7.57-7.50 ppm. The doublet (ortho coupling) at 8.26 ppm and the double triplet at 7.75 ppm have been assigned to H8 and H7, respectively, by comparison with the literature 1H data for L1 in deuterated acetone [16].
The resonances for H5 and H6 could be assigned to the signals at 7.96 and 7.57-7.50 ppm, respectively. The 1H double triplet at 7.90 ppm, diagnostic for a γ-pyridine [19], and involved in another four spin system connecting the 1H signals at 8.74, 8.71, 7.90, and 7.37 ppm, was assigned to the pyridine proton H4’. As a consequence of the meta and ortho couplings showed by H4’, the doublets at 8.74, 8.71, and the broad triplet at 7.37 ppm, that in turn are correlated themselves, were easily assigned at H6’, H3’, and H5’, respectively. It is worth noting that ortho, meta, and para cross-peaks are observable in the COSY-45 spectrum and can be distinguished from the number and/or the intensity of the spots.
Figure 1. 500 MHz 1H/H1 COSY-45 spectrum of L1 in deuterated chloroform. The upper and left traces are 1D proton spectrum of L1.
Figure 1. 500 MHz 1H/H1 COSY-45 spectrum of L1 in deuterated chloroform. The upper and left traces are 1D proton spectrum of L1.
Molecules 07 00618 g001
The highest downfield shift experienced by the H3’ protons, due to deshielding by the non-bonding electrons of the nitrogen on the pyridine ring, is indicative of an anti conformation for the ligands, in agreement with the conformation considered the most probable for bipyridine [5]. According to literature data [19], confirmed by our 1H-NMR analyses, these uncomplexed molecules show an anti conformation (as depicted in Scheme 1, Scheme 2 and Scheme 3) that changes to a syn one when they act as ligands by using the nitrogen of the pyridine and quinoline rings as binding sites. According to the inductive and/or mesomeric effects of the substituents, their introduction onto the skeleton of the N-N bidendate ligand L1 influence the upfield and/or downfield chemical shift of the nearest protons, and the reactivity of these molecules as well. The structures of ligands L1-L4 was further confirmed by their 13C-NMR spectra (see Table II), which displayed the expected patterns.
Table II. 13C NMR parameters of ligandsf L1L4
Table II. 13C NMR parameters of ligandsf L1L4
CarbonL1L2L3L4
2156.40156.54155.97156.35
3119.24118.48118.62118.85
4149.23149.02148.88148.24
5125.82125.47125.45128.55
6128.30129.03128.90120.80
7129.39139.62139.55132.79
8130.21129.20129.16131.87
9148.51148.74148.70147.08
10126.78124.78124.76123.80
2’155.64155.59155.88155.31
3’121.87121.78118.82120.11
4’136.94136.87137.05137.11
5’124.03123.92123.48123.79
6’149.17149.11157.90158.04
1”138.40138.55138.74137.88
2”/6”128.44128.41128.43128.69
3”5”129.67129.63129.64129.55
4”126.78128.21128.17127.93
Py-CH3--24.6424.61
q-CH3-21.6621.67-
Notes: [a] The spectra were obtained in deuterated chloroform (CDCl3), (chemical shifts in ppm); [b] Numbering patterns as shown in Scheme 2 and Scheme 3.

Conclusions

We report the synthesis of a series of bidentate aza chelating molecules, based on a substituted 2‑pyridyl-4-phenylquinoline skeleton, that may be useful for the complexation of metal cations such as Ru, Os, and Ir. These complexes, owing to their asymmetry, may display new and interesting photophysical properties.

Experimental

General

The starting materials 2-acetylpyridine, 2-aminobenzophenone, 2-amino-4-methylbenzophenone, p-nitrobromobenzene, and phenylacetonitrile were purchased from Aldrich. All other chemicals were reagent grade. 6-Methyl-2-acetylpyridine [20] and the ligand 4-phenyl-2-(2’-pyridyl)pyridine (L1) [16], were prepared as described in the literature. All reactions were performed under an inert atmosphere of nitrogen except when otherwise stated and the solvents were dried and stored under nitrogen and over 4Å molecular sieves. Melting points are uncorrected. Elemental analyses were determined by a commercial laboratory. 1H- and 13C-NMR spectra were performed in deuterated chloroform (CDCl3) with a Varian INOVA 500 instrument. Chemical shifts were calibrated relative to the solvent resonance considered at 7.26 ppm for residual CHCl3 and at 77.0 ppm for CDCl3. The analysis of the proton spectra was carried out according to the rules for the first-order splitting with the help of integral intensities. The 13C‑NMR spectra were measured with full decoupling from the protons, and the signals were assigned with the help of SCS. The quaternary carbon atoms and CH groups were differentiated by means of the APT pulse sequence. Positive ion FAB mass spectra were obtained on a Kratos MS 50 S double-focusing mass spectrometer equipped with a standard FAB source, using 3-nitrobenzyl alcohol as a matrix. The yields, melting points and elemental analyses of the ligands synthetized are presented in Table III. The 1H- and 13C-NMR spectra with signal assignments are given in Table I and Table II, respectively.
3-phenyl-5-bromo-2,1-benzisoxazole (1): Phenylacetonitrile (1.75 g, 15 mmol) was slowly added to a vigorously stirred solution of potassium hydroxide (17.76 g, 310 mmol) in methanol (35 mL) at room temperature. After dissolution was complete, 36 mL of a methanol/tetrahydrofuran (2 : 1 v/v) solution containing p-nitrobromobenzene (3.0 g, 15 mmol) was added dropwise at 0 °C. The resulting dark mixture was stirred at 0 °C for 3 hours, at room temperature for 4 hours, refluxed overnight, and then poured into ice-water (300 mL), filtered, washed successively with cold water and methanol and recrystallized from methanol to afford compound 1 as yellow crystals; 2.22 g (66%); m.p. 112 °C; 1H-NMR (CDCl3) d: 8.05 (bs, 1H, benzisoxazole H4); 7.99 (d, 2H, J = 7.0 Hz, phenyl H2’/H6’), 7.58 (m, 3H, phenyl H4’ and H3’/H5’); 7.53 (dd, 1H, J = 10.0, 2.5 Hz, benzisoxazole H6); 7.38 (dd, 1H, J = 10.0, 1.5 Hz, benzisoxazole H7); MS, m/z 274 (MH+). Anal. Calcd. for C13H8BrNO: C, 56.95; H, 2.92; N, 5.11. Found: C, 57.19; H, 3.03; N, 4.86.
2 Amino-5-bromo-benzophenone (2): Following the procedure of Simpson and Stephenson [21], a solution, containing 0.44 g (1.6 mmol) of 1 in acetic acid (70 mL), was heated on a water-bath, and 1.0 g (18 mmol) of iron powder was added over 2.5 hours, during which time, 12 ml of water was also added. The mixture was filtered while hot and then 100 ml of water was added. The yellow precipitate was collected by filtration, washed with cold water until the water washings were clear and dried. The product was purified by column chromatography (silica; cyclohexane / ethyl acetate 9:1) followed by recrystallization from ethanol-water to afford 2 as a yellow powder; 0.31 g (70 %); m.p. 105 °C; 1H‑NMR (CDCl3) d: 7.63 (d, 2H, J = 8.5 Hz, phenyl H2’/H6’); 7.55 (m, 2H, benzene H6 and phenyl H4); 7.49 (d, 2H, J = 8.5 Hz, phenyl H3’/H5’); 7.36 (dd, 1H, J = 9.0, 2.0 Hz, benzene H4); 6.65 (d, 1H, J = 8.5 Hz, benzene H3); 6.05 (bs, 2H, NH2), MS, m/z 276 (MH+). Anal. Calcd. for C13H10BrNO: C, 56.54; H, 3.62; N, 5.07. Found: C, 56.28; H, 3.59; N, 4.95
The synthesis of L4 is given below as a general procedure for the synthesis of ligands.
4-phenyl-6-bromo-2-(2’-(6’-methyl)-pyridyl)quinoline (L4): A mixture of m-cresol (25 mL) and phosphorus pentoxide (0.81 g, 5.7 mmol) was stirred at 145 °C for 2.5 hours to afford a homogeneous solution. After cooling, 2-amino-5-bromobenzophenone (4.08 g, 15 mmol) and 2-acetyl-6-methyl-pyridine (2.03 g, 15 mmol) were added, followed by additional m-cresol (20 mL) to rinse the powder funnel. The reaction mixture was heated at 135 °C overnight. After cooling, the dark solution was poured into ethanol (200 mL) containing triethylamine (20mL). The resulting light grey precipitate was collected by filtration, continuosly extracted with a solution of ethanol/triethylamine for 24 hours, and recrystallized from n-hexane/methylene chloride to give L4 as an off white powder; 3.96 g (71%); m.p. = 212 °C.; MS, m/z 375 (MH+).
Table III. Melting points, yield and elemental analyses of ligands L1L4
Table III. Melting points, yield and elemental analyses of ligands L1L4
LigandRecrystallizationM.p:YieldFormula /Elemental Analysis
Calculated/Found (%)
Solvent(s) (° C)(%)M. w.CHN
L1EtOH15270C20H14N285.055.009.90
296.3585.005.0510.00
L2EtOH / CHCl313862C21H16N285.105.449.45
296.3585.025.639.32
L3EtOH / H2O19460C22H18N285.135.849.02
310.3885.115.939.12
L4n-C6H12 / CH2Cl221271C21H15BrN267.214.037.46
375.2667.334.347.33

Acknowledgements

The research was financially supported by the University of Catania (PRA funds).

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