Synthesis of Substituted 2-Pyridyl-4-phenylquinolines

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.

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 (L₂ – L₄) 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.

Ligands	R1	R2	R3	Initials
L1	H	H	H	ph-pq
L2	CH3	H	H	mph-pq
L3	CH3	H	CH3	mph-mpq
L4	H	Br	CH3	brph-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.

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.

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 L₁–L₄. Proton chemical shifts and J(H,H) values were measured at 500 MHz.

Table I. ¹H NMR parameters of ligands L₁ – L₄

Proton	L1	L2	L3	L4
3	8.53 s	8.47 s	8.48 s	8.57 s
5	7.96 d	7.85 d	7.22 d	8.06 d
	J=8.0	J=9.0	J=7.5	J=2.0
6	7.56-7.50	7.34 bd	7.34 dd	-
	m	J=6.0	J=8.5, 1.5
7	7.75 dt	-	-	7.79 dd
	J=7.0, 1.5			J=7.0, 2.0
8	8.26 d	8.05 bs	8.04 bs	7.23 d
	J=8.5			J=7.5
3’	8.71 d	8.69 d	7.83 d	8.45 d
	J=7.5	J=8.0	J=8.5	J=8.0
4’	7.90 dt	7.88 dt	7.77 t	7.77 t
	J=8.0, 2.0	J=8.0, 1.5	J=7.5	J=8.0
5’	7.37 bt	7.36 dt	8.47 d	8.10 d
	J=6.5	J=7.5, 1.5	J=7.5	J=8.5
6’	8.74 d	8.73 dd	-	-
	J=4.5	J=4.5, 1.0
Ph	7.62-7.50	7.61-7.49	7.61-7.50	7.57-7.51
	m	m	m	m
Py-CH3	-	-	2.65 s	2.64 s
q-CH3	-	2.60 s	2.59 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.

Table I. ¹H NMR parameters of ligands L₁ – L₄

Proton	L1	L2	L3	L4
3	8.53 s	8.47 s	8.48 s	8.57 s
5	7.96 d	7.85 d	7.22 d	8.06 d
	J=8.0	J=9.0	J=7.5	J=2.0
6	7.56-7.50	7.34 bd	7.34 dd	-
	m	J=6.0	J=8.5, 1.5
7	7.75 dt	-	-	7.79 dd
	J=7.0, 1.5			J=7.0, 2.0
8	8.26 d	8.05 bs	8.04 bs	7.23 d
	J=8.5			J=7.5
3’	8.71 d	8.69 d	7.83 d	8.45 d
	J=7.5	J=8.0	J=8.5	J=8.0
4’	7.90 dt	7.88 dt	7.77 t	7.77 t
	J=8.0, 2.0	J=8.0, 1.5	J=7.5	J=8.0
5’	7.37 bt	7.36 dt	8.47 d	8.10 d
	J=6.5	J=7.5, 1.5	J=7.5	J=8.5
6’	8.74 d	8.73 dd	-	-
	J=4.5	J=4.5, 1.0
Ph	7.62-7.50	7.61-7.49	7.61-7.50	7.57-7.51
	m	m	m	m
Py-CH3	-	-	2.65 s	2.64 s
q-CH3	-	2.60 s	2.59 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 H^4’. As a consequence of the meta and ortho couplings showed by H^4’, 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 H^6’, H^3’, and H^5’, 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.

The highest downfield shift experienced by the H^3’ 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 L₁ – L₄

Carbon	L1	L2	L3	L4
2	156.40	156.54	155.97	156.35
3	119.24	118.48	118.62	118.85
4	149.23	149.02	148.88	148.24
5	125.82	125.47	125.45	128.55
6	128.30	129.03	128.90	120.80
7	129.39	139.62	139.55	132.79
8	130.21	129.20	129.16	131.87
9	148.51	148.74	148.70	147.08
10	126.78	124.78	124.76	123.80
2’	155.64	155.59	155.88	155.31
3’	121.87	121.78	118.82	120.11
4’	136.94	136.87	137.05	137.11
5’	124.03	123.92	123.48	123.79
6’	149.17	149.11	157.90	158.04
1”	138.40	138.55	138.74	137.88
2”/6”	128.44	128.41	128.43	128.69
3”5”	129.67	129.63	129.64	129.55
4”	126.78	128.21	128.17	127.93
Py-CH3	-	-	24.64	24.61
q-CH3	-	21.66	21.67	-

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.

Table II. ¹³C NMR parameters of ligandsf L₁ – L₄

Carbon	L1	L2	L3	L4
2	156.40	156.54	155.97	156.35
3	119.24	118.48	118.62	118.85
4	149.23	149.02	148.88	148.24
5	125.82	125.47	125.45	128.55
6	128.30	129.03	128.90	120.80
7	129.39	139.62	139.55	132.79
8	130.21	129.20	129.16	131.87
9	148.51	148.74	148.70	147.08
10	126.78	124.78	124.76	123.80
2’	155.64	155.59	155.88	155.31
3’	121.87	121.78	118.82	120.11
4’	136.94	136.87	137.05	137.11
5’	124.03	123.92	123.48	123.79
6’	149.17	149.11	157.90	158.04
1”	138.40	138.55	138.74	137.88
2”/6”	128.44	128.41	128.43	128.69
3”5”	129.67	129.63	129.64	129.55
4”	126.78	128.21	128.17	127.93
Py-CH3	-	-	24.64	24.61
q-CH3	-	21.66	21.67	-

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 H^2’/H^6’), 7.58 (m, 3H, phenyl H^4’ and H^3’/H^5’); 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 H^2’/H^6’); 7.55 (m, 2H, benzene H⁶ and phenyl H⁴); 7.49 (d, 2H, J = 8.5 Hz, phenyl H^3’/H^5’); 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 L₁ – L₄

Ligand	Recrystallization	M.p:	Yield	Formula /	Elemental Analysis Calculated/Found (%)
	Solvent(s)	(° C)	(%)	M. w.	C	H	N
L1	EtOH	152	70	C20H14N2	85.05	5.00	9.90
				296.35	85.00	5.05	10.00
L2	EtOH / CHCl3	138	62	C21H16N2	85.10	5.44	9.45
				296.35	85.02	5.63	9.32
L3	EtOH / H2O	194	60	C22H18N2	85.13	5.84	9.02
				310.38	85.11	5.93	9.12
L4	n-C6H12 / CH2Cl2	212	71	C21H15BrN2	67.21	4.03	7.46
				375.26	67.33	4.34	7.33

Table III. Melting points, yield and elemental analyses of ligands L₁ – L₄

Ligand	Recrystallization	M.p:	Yield	Formula /	Elemental Analysis Calculated/Found (%)
	Solvent(s)	(° C)	(%)	M. w.	C	H	N
L1	EtOH	152	70	C20H14N2	85.05	5.00	9.90
				296.35	85.00	5.05	10.00
L2	EtOH / CHCl3	138	62	C21H16N2	85.10	5.44	9.45
				296.35	85.02	5.63	9.32
L3	EtOH / H2O	194	60	C22H18N2	85.13	5.84	9.02
				310.38	85.11	5.93	9.12
L4	n-C6H12 / CH2Cl2	212	71	C21H15BrN2	67.21	4.03	7.46
				375.26	67.33	4.34	7.33