Cycloisomerization of 3-alkynyl-2-arylpyridines and quinolines offers a straightforward approach to benzo[h]quinolines and benzo[c]-acridines. Substituent at the triple bond governs a choice between transition metal or Brønsted acid catalysis. A direct electrophilic activation by trifluoromethanesulfonic acid induces an almost quantitative cyclization of the o-aryl(phenylethynyl) fragment. PtCl2 efficiently catalyzes cyclization of 2-aryl-3-ethynylhetarenes.
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Compounds with the benzo[h]quinoline and benzo[c]acridine cores are valuable classes of heterocycles with a wide range of applications exhibiting antibacterial,1 wound healing,2 antioxidant,2 and anticancer activity.3,4,5,6, – 7 Their complexes with transition metals and organosilicon compounds were applied in cross-coupling reactions;8 , 9 bioactivity10 and fluorescence properties11,12, – 13 of these complexes have been described as well. Considering the importance of benzoquinoline derivatives, several approaches to their synthesis have been developed. Among them, methods based on the construction of the central benzene ring are quite limited, although they allow utilizing readily available pyridine derivatives.14,15,16,17,18,19, – 20
Cycloisomerization of o-ethynylbiaryls has emerged as an important tool for the synthesis of fused aromatic systems. Electrophilic activation21,22,23,24,25,26, – 27 and catalysis with transition metals28,29,30,31,32,33, – 34 are often used for cyclization. Although substantial work has been done to investigate and improve the efficiency of this transformation, for instance, via the utilization of Au-35,36, – 37 or Pt-based38 , 39 complexes, or by evaluation of the substrate and catalysts scope and limitations,40,41,42,43, – 44 carbocyclic substrates have been involved in these cyclizations almost exclusively. Reports on cycloisomerization of heteroaromatic compounds have appeared in literature only in last years.45,46,47,48,49,50, – 51 Recently, we have developed a simple and efficient procedure for the Brønsted acid-mediated cyclization of o-aryl(ethynyl)pyrimidines producing benzo[f]quinazolines.52 Here we present our findings in the cycloisomerization of various o-aryl(ethynyl)pyridines and quinolines using either transition metal catalysis or by action of Brønsted acid toward benzo[h]quinolines and benzo[c]acridines.
Starting 2-aryl-3-ethynylpyridines were prepared from 2,3-dibromopyridine 1 by a sequence of two cross-coupling reactions (Scheme 1, Table 1). The difference in reactivity of bromine atoms allows selective arylation in position 2 of the pyridine ring via the Suzuki coupling at 50°C.53 Next, the Sonogashira cross coupling was used for the introduction of the acetylenic moiety. While the reaction with phenylacetylene proceeded smoothly in DMA at 90°C forming compounds 3a–j in high yields after 6 h, trimethylsilylacetylene was completely inert. Solvent and temperature screening revealed that i-Pr2NH and 80°C were optimal conditions for the preparation of 2-aryl3-(trimethylsilylethynyl)pyridines 4a–j.
Scheme 1.
TMS group can be easily removed from pyridines 4a–j by treatment with K2CO3 in a CH2Cl2–MeOH mixture at room temperature to afford pyridines 5a–j with a terminal triple bond. For pyridines 5c,h, we demonstrated that the Sonogashira cross coupling/TMS-deprotection sequence could be performed in a one-pot fashion without affecting the overall yield.
Cycloisomerization of ethynylpyridines 5 was first attempted under conditions reported for o-alkynylbiphenyls on pyridine 5a as a test compound (Scheme 2, Table 2).28 Pyridine 5a was heated with PtCl2 in toluene at 80°C for 20 h, however, the cyclization product 6a was isolated in low yield. Other Lewis acids, such as InCl3, GaCl3, and Yb(OTf)3 were ineffective catalysts, and their use led to slow degradation of the starting material. Treatment of compound 5a with TfOH also gave no product, but using PtCl2 (10 mol %) at higher reaction temperature (110°C) furnished targeted benzo[h]quinoline 6a in 67% yield. Increasing temperature further to 130°C did not improve the yield.
Scheme 2.
1A substrate scope for the PtCl2-catalyzed cyclization of 2-aryl-3-ethynylpyrydines is sufficiently broad and includes compounds with electron-donating and electronwithdrawing substituents along with sterically hindered ones (Scheme 3). Moderately donor alkyl group at the para position of the phenyl ring promoted the cyclization: the yield of 8-ethylbenzo[h]quinoline 6b was 80%. Only ca. 50% conversion was observed in 20 h for electron-deficient substrates, but prolonged heating (up to 48 h) allowed isolation of compounds 6c–e in 55–66% yields. This is consistent with the deactivation of electron-deficient aryl ring toward an electrophilic attack. Strong electrondonating methoxy group in 2-aryl-3-ethynylpyrydine 5f had no influence on the reaction yield. Unexpectedly, dimethylamino-substituted derivative 5g was almost inert under these conditions and its cyclization occurred only at 130°С, which might be caused by a strong coordination of PtCl2 to the Me2N group. Sterically hindered pyridines 5h,i required 130°C for the successful cyclization as well. Regioselective cyclization was observed for pyridine 5j and the single isomer 6j formed via attack of the bulky PtCl2–triple bond complex on the less hindered ortho position of the m-chloro-substituted phenyl ring.
Scheme 3.
In contrast to ethynylpyridines 5a–j, phenylethynylpyridines 3a–j are more convenient targets for the direct electrophilic activation. Initially we employed TFA–CH2Cl2 system which had been previously reported for pyridinebased substrates,54 however, phenylethynylpyridine 3a was inert under these conditions and even when heated in pure TFA. Recently, we have described the successful utilization of TfOH for the cyclization of o-alkynyl(aryl)pyrimidines,52 and this protocol quantitatively provided benzo[h]quinoline 7a within 15 min (Scheme 4).
Scheme 4.
Quinolines 7b–e,h,i were also isolated in excellent yields regardless of the nature of substituents. 2-(4-Methoxyphenyl)pyridine 3f gave the mixture of the major benzo[h]quinoline 7f and the minor spiro compound 8, although similar 5-(4-methoxyphenyl)-4-(phenylethynyl)-pyrimidine gave the single corresponding spiro product.52 At 0°C, only spiro compound 8 formed from phenylethynylpyridine 3f in 93% yield (the mechanism of this ipso cyclization is analogous to that we described for pyrimidines).52 Protonation of the Me2N group in pyridine 3g appears to cause a complete deactivation of this substrate toward the cyclization; indeed no target product was detected in the complex reaction mixture of phenylethynylpyridine 3g by 1H NMR spectroscopy. TfOHpromoted reaction is less sensitive to steric factors than PtCl2-catalyzed process as unsymmetrically substituted pyridine 3j gave a mixture of isomers 7j and 7j' (cf. compound 6j, Scheme 3).
The cyclization of halo-substituted substrates 3d,e with concentrated sulfuric acid instead of TfOH was tested, as the nature of the acid is known to effect the reaction outcome (Scheme 5).52 Indeed, pyridine 3d gave a mixture of compounds 7d and 8 in a ratio 2.5:1 (total yield 73%), whereas benzo[h]quinazoline 7e was a single product for pyridine 3e. The latter result differs from the reaction of similarly substituted 5-(4-chlorophenyl)-4-(phenylethynyl)pyrimidine in concentrated sulfuric acid giving an analog of spiro compound 8 only (see the reaction of phenylethynylpyridine 3f also, Scheme 4). The pyridine core of phenylethynylpyridines 3 disfavors ipso cyclization probably because of the close position of an aryl fragment to the nitrogen atom. Fluorine atom as a stronger +M substituent weakens this effect and facilitates formation of spiro compound 8 from phenylethynylpyridine 3d.
Scheme 5.
As a further test of the applicability of this methodology to the synthesis of more complex molecules, several quinoline-based acetylenes were also examined. Substrates 11a–d were prepared from 2-chloroquinoline-3-carbaldehydes55 9a–d by the Suzuki cross coupling followed by treatment of 2-phenylquinoline-3-carbaldehydes 10a–d with Bestmann–Ohira reagent (Scheme 6, Table 3). Quinolines 12a,b were obtained by the Sonogashira reaction of compounds 11a,b with iodobenzene.
Scheme 6.
Fused benzene ring in the heterocyclic core slightly reduced reactivity of quinolines compared to pyridines, though annulated acridines 13 and 14 were obtained in good to excellent yields (Scheme 7). For cycloisomerization of terminal acetylenes 11a–d, PtCl2 catalysis was used at a slightly higher temperature than for compounds 5a–j. TfOH-mediated reaction of phenylethynylquinolines 12a,b was a little slower and completed within 1 h. Further exploration of this reaction and physical properties of the resulting compounds will be reported later.
Scheme 7.
In summary, an efficient and simple method to access a variety of benzo[h]quinolines and benzo[c]acridines by cycloisomerization of o-alkynyl(aryl)pyridines and quinolines is described. Two general protocols have been developed depending on the substrate: PtCl2 catalytic conditions are favorable for terminal acetylenes, while TfOH excels with phenylethynyl-substituted heterocycles. Various substituents in aryl fragments are tolerated.
Experimental
1H and 13C NMR spectra were recorded on a Bruker Avance 400 spectrometer 400 and 101 MHz, respectively) in CDCl3 and were referenced to the solvent residual proton (7.26 ppm) and carbon signals (77.16 ppm). Highresolution mass spectra were recorded on a Bruker Maxis HRMS-ESI-qTOF spectrometer (electrospray ionization mode). Melting points were determined on a Stuart SMP30 instrument.
Synthesis of 2-aryl-3-bromopyridines 2a–j (General method). A mixture of MeCN and MeOH (2,1, 15 ml) was added to a mixture of 2,3-dibromopyridine (1) (474 mg, 2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg, 4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg, 5 mol %) in a screw-cap vial. Reaction mixture was flushed with argon, sealed, and stirred at 50°C for 24 h in an oil bath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentrated under reduced pressure, the residue was dissolved in CH2Cl2 (20 ml), washed with water (3×10 ml) and dried over Na2SO4. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–EtOAc, 30:1) to provide pure pyridines 2a–j.
3-Bromo-2-phenylpyridine (2a).53 Yield 387 mg (83%), colorless oil.
3-Bromo-2-(4-ethylphenyl)pyridine (2b). Yield 409 mg (78%), colorless oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.28 (3H, t, J = 7.6, CH2CH 3); 2.72 (2H, q, J = 7.6, CH 2CH3); 7.11 (1H, dd, J = 8.0, J = 4.6, H Py); 7.30 (2H, d, J = 8.0, H Ph); 7.62 (2H, d, J = 8.0, H Ph); 7.97 (1H, dd, J = 8.0, J = 1.4, H Py); 8.61 (1H, dd, J = 4.6, J = 1.4, H Py). 13C NMR spectrum, δ, ppm: 15.5; 28.9; 119.9; 123.1; 127.6; 129.4; 137.1; 141.4; 145.1; 148.2; 158.4. Found, m/z: 262.0225 [M+H]+. C13H13BrN. Calculated, m/z: 262.0226.
3-Bromo-2-[4-(trifluoromethyl)phenyl]pyridine (2c). Yield 374 mg (62%), colorless solid, mp 49–50°C (mp 50– 51°C53).
3-Bromo-2-(4-fluorophenyl)pyridine (2d). Yield 423 mg (84%), colorless solid, mp 72–74°C (mp 73–74°C53). 3-Bromo-2-(4-chlorophenyl)pyridine (2e).56 Yield 395 mg (74%), colorless oil.
3-Bromo-2-(4-methoxyphenyl)pyridine (2f). Yield 405 mg (77%), colorless solid, mp 60–61°C (mp 61– 62°C53).
4-(3-Bromopyridin-2-yl)- N , N -dimethylaniline (2g).57 Yield 360 mg (65%), yellow gum.
3-Bromo-2-(2-methylphenyl)pyridine (2h).53 Yield 402 mg (81%), colorless oil.
3-Bromo-2-(3,5-dimethylphenyl)pyridine (2i). Yield 423 mg (81%), colorless oil. 1H NMR spectrum, δ, ppm (J, Hz): 2.38 (6H, s, CH3); 7.07 (1Н, br. s, H Ph); 7.11 (1H, dd, J = 8.0, J = 4.6, H Py); 7.27 (2Н, br. s, H Ph); 7.97 (1H, dd, J = 8.0, J = 1.5, H Py); 8.61 (1H, dd, J = 4.6, J = 1.5, H Py). 13C NMR spectrum, δ, ppm: 21.5; 120.0; 123.2; 127.1; 130.5; 137.6; 139.6; 141.3; 148.1; 158.8. Found, m/z: 262.0223 [M+H]+. C13H13BrN. Calculated, m/z: 262.0226.
3-Bromo-2-(3-chlorophenyl)pyridine (2j). Yield 413 mg (77%), colorless oil. 1H NMR spectrum, δ, ppm (J, Hz):
7.16 (1H, dd, J = 8.0, J = 4.6, H Py); 7.37–7.42 (2H, m, H Ar); 7.56–7.59 (1H, m, H Ar); 7.67–7.69 (1H, m, H Ar); 8.00 (1H, dd, J = 8.0, J = 1.5, H Py); 8.63 (1H, dd, J = 4.6, J = 1.5, H Py). 13C NMR spectrum, δ, ppm: 119.9; 123.8; 127.7; 129.0; 129.4; 129.6; 134.1; 141.3; 141.6; 148.3; 156.9. Found, m/z: 267.9519 [M+H]+. C11H8BrClN. Calculated, m/z: 267.9523.
Synthesis of 2-aryl-3-(phenylethynyl)pyridines 3a–j (General method). DMA (5 ml) was added to a mixture of 2-aryl-3-bromopyridine 2 (0.5 mmol), Pd(PPh3)2Cl2 (17.6 mg, 5 mоl %), and CuI (4.8 mg, 5 mоl %) in a screwcap vial. Reaction mixture was flushed with argon, phenylacetylene (56 mg, 0.55 mmоl) and Et3N (0.2 ml, 1.4 mmol) were added, the vial was sealed. The reaction mixture was stirred at 90°C in an oil bath for 6 h. Then the reaction mixture was cooled to room temperature, poured into water (40 ml), and extracted with EtOAc (3×10 ml). The combined extracts were washed with water (2×5 ml) and dried over Na2SO4. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–EtOAc, 20:1) to provide pure pyridines 3a–j.
2-Phenyl-3-(phenylethynyl)pyridine (3a). Yield 102 mg (80%), brown solid, mp 67–68°C (mp 69°C58).
2-(4-Ethylphenyl)-3-(phenylethynyl)pyridine (3b). Yield 125 mg (88%), yellow solid, mp 75–76°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.30 (3H, t, J = 7.6, CH2CH 3); 2.74 (2H, q, J = 7.6, CH 2CH3); 7.22 (1H, dd, J = 7.8, J = 4.8, H Py); 7.31–7.35 (5H, m, H Ar); 7.41–7.45 (2H, m, H Ar); 7.92 (1H, dd, J = 7.8, J = 1.8, H Py); 7.98–8.01 (2H, m, H Ar); 8.64 (1H, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: 15.7; 28.9; 87.9; 94.8; 117.8; 121.2; 123.1; 127.6; 128.5; 128.7; 129.4; 131.5; 137.0; 140.9; 145.3; 148.7; 159.7. Found, m/z: 284.1431 [M+H]+. C21H18N. Calculated, m/z: 284.1434.
3-(Phenylethynyl)-2-[4-(trifluoromethyl)phenyl]pyridine (3c). Yield 134 mg (83%), colorless solid, mp 64–65°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.31 (1H, dd, J = 7.9, J = 4.6, H Py); 7.33–7.37 (3H, m, H Ph); 7.38–7.42 (2H, m, H Ph); 7.75 (2H, d, J = 8.2, H Ar); 7.97 (1H, dd, J = 7.9, J = 1.7, H Py); 8.16 (2H, d, J = 8.2, H Ar); 8.67 (1H, dd, J = 4.6, J = 1.7, H Py). 13C NMR spectrum, δ, ppm (J, Hz): 86.9; 95.4; 118.3; 122.3; 122.6; 124.4 (q, 1 J CF = 272.1); 125.0 (q, 3 J CF = 3.8); 128.7; 129.1; 129.9; 130.9 (q, 2 J CF = 32.4); 131.6; 141.1; 143.0; 148.9; 158.2. Found, m/z: 324.0988 [M+H]+. C20H13F3N. Calculated, m/z: 324.0995. 2-(4-Fluorophenyl)-3-(phenylethynyl)pyridine (3d). Yield 130 mg (95%), colorless solid, mp 71–72°C (mp 72°C58).
2-(4-Chlorophenyl)-3-(phenylethynyl)pyridine (3e). Yield 131 mg (91%), colorless solid, mp 119–121°C (mp 121°C58).
2-(4-Methoxyphenyl)-3-(phenylethynyl)pyridine (3f).58 Yield 133 mg (93%), yellow oil.
N,N -Dimethyl-4-[3-(phenylethynyl)pyridin-2-yl]aniline (3g). Yield 125 mg (84%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 3.04 (6H, s, N(CH3)2); 6.79–6.84 (2H, m, H Ar); 7.13 (1H, dd, J = 7.8, J = 4.8, H Py); 7.31–7.36 (3H, m, H Ph); 7.45–7.52 (2H, m, H Ph); 7.87 (1H, dd, J = 7.8, J = 1.8, H Py); 8.04–8.12 (2H, m, H Ar); 8.60 (1H, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: 40.5; 88.6; 94.2; 111.6; 116.7; 120.2; 123.4; 127.5; 128.5 (2C); 130.5; 131.6; 141.2; 148.6; 151.1; 159.5. Found, m/z: 299.1533 [M+H]+. C21H19N2. Calculated, m/z: 299.1543. 2-(2-Methylphenyl)-3-(phenylethynyl)pyridine (3h).58 Yield 105 mg (78%), pale-yellow oil.
2-(3,5-Dimethylphenyl)-3-(phenylethynyl)pyridine (3i). Yield 123 mg (87%), colorless solid, mp 100–101°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.42 (6H, s, CH3); 7.10 (1Н, br. s, H Ar); 7.22 (1H, dd, J = 7.8, J = 4.8, H Py); 7.31– 7.35 (3H, m, H Ph); 7.39–7.43 (2H, m, H Ph); 7.67 (2Н, br. s, H Ar); 7.92 (1H, dd, J = 7.8, J = 1.7, H Py); 8.64 (1H, dd, J = 4.8, J = 1.7, H Py). 13C NMR spectrum, δ, ppm: 21.6; 87.9; 94.7; 117.9; 121.3; 123.1; 127.3; 128.5; 128.7; 130.6; 131.5; 137.4; 139.4; 140.8; 148.6; 160.0. Found, m/z: 284.1435 [M+H]+. C21H18N. Calculated, m/z: 284.1434.
2-(3-Chlorophenyl)-3-(phenylethynyl)pyridine (3j). Yield 122 mg (84%), brown solid, mp 92–93°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.28 (1H, dd, J = 7.8, J = 4.8, H Py); 7.33–7.37 (3H, m, H Ph); 7.41–7.47 (4H, m, H Ar); 7.91–7.96 (2H, m, H Ar and Py); 8.10–8.11 (1H, m, H Ar); 8.65 (1H, dd, J = 4.8, J = 1.7, H Py). 13C NMR spectrum, δ, ppm: 87.1; 95.4; 118.2; 122.0; 122.7; 127.7; 128.6; 129.0 (2C); 129.3; 129.6; 131.6; 133.9; 141.0; 141.2; 148.7; 158.1. Found, m/z: 290.0735 [M+H]+. C19H13ClN. Calculated, m/z: 290.0731.
Synthesis of 2-aryl-3-(trimethylsilylethynyl)pyridines 4a–j (General method). Diisopropylamine (2.5 ml) was added to a mixture of 2-aryl-3-bromopyridine 2 (1.0 mmol), Pd(PPh3)2Cl2 (35 mg, 5 mоl %), and CuI (9.6 mg, 5 mоl %) in a screw-cap vial. Reaction mixture was flushed with argon, trimethylsilylacetylene (118 mg, 1.2 mmоl) was added, the vial was sealed. The reaction mixture was stirred at 80°C in an oil bath for 4 h. Then the reaction mixture was cooled to room temperature, solvent was evaporated, and the residue was purified by column chromatography on silica (hexane–EtOAc, 20:1) to provide pure pyridines 4a,b,d–g,i,j. Pyridines 4c,h were used for the next step without isolation and purification.
2-Phenyl-3-(trimethylsilylethynyl)pyridine (4a).59 Yield 213 mg (85%), pale-yellow oil.
2-(4-Ethylphenyl)-3-(trimethylsilylethynyl)pyridine (4b). Yield 218 mg (78%), pale-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.20 (9H, s, CH3); 1.27 (3H, t, J = 7.6, CH2CH 3); 2.71 (2H, q, J = 7.6, CH 2CH3); 7.16 (1H, dd, J = 7.8, J = 4.8, H Py); 7.25–7.28 (2H, m, H Ar); 7.84 (1H, dd, J = 7.8, J = 1.4, H Py); 7.92–7.97 (2H, m, H Ar); 8.61 (1Н, dd, J = 4.8, J = 1.4, H Py). 13C NMR spectrum, δ, ppm: –0.3; 15.7; 28.9; 100.7; 103.3; 117.6; 121.0; 127.4; 129.5; 136.7; 141.4; 145.3; 148.8; 160.0. Found, m/z: 280.1508 [M+H]+. C18H22NSi. Calculated, m/z: 280.1516.
2-(4-Fluorophenyl)-3-(trimethylsilylethynyl)pyridine (4d). Yield 234 mg (87%), pale-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.20 (9H, s, CH3); 7.08–7.15 (2H, m, H Ar); 7.19 (1H, dd, J = 7.8, J = 4.8, H Py); 7.85 (1H, dd, J = 7.8, J = 1.8, H Py); 7.98–8.03 (2H, m, H Ar); 8.60 (1Н, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm (J, Hz): –0.3; 101.1; 102.8; 114.8 (d, 2 J CF = 21.5); 117.7; 121.4; 131.5 (d, 3 J CF = 8.3); 135.4 (d, 4 J CF = 3.2); 141.5; 148.8; 158.9; 163.4 (d, 1 J CF = 248.4). Found, m/z: 270.1106 [M+H]+. C16H17FNSi. Calculated, m/z: 270.1109.
2-(4-Chlorophenyl)-3-(trimethylsilylethynyl)pyridine (4e). Yield 254 mg (89%), pale-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.21 (9H, s, CH3); 7.20 (1H, dd, J = 7.8, J = 4.8, H Py); 7.38–7.43 (2H, m, H Ar); 7.85 (1H, dd, J = 7.8, J = 1.8, H Py); 7.94–8.00 (2H, m, H Ar); 8.61 (1Н, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: –0.3; 101.4; 101.7; 117.7; 121.6; 128.1; 130.9; 135.1; 137.7; 141.6; 148.9; 158.6. Found, m/z: 286.0817 [M+H]+. C16H17ClNSi. Calculated, m/z: 286.0813.
2-(4-Methoxyphenyl)-3-(trimethylsilylethynyl)pyridine (4f). Yield 253 mg (90%), pale-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.21 (9H, s, CH3); 3.86 (3H, s, OCH3); 6.93–6.99 (2H, m, H Ar); 7.14 (1H, dd, J = 7.8, J = 4.8, H Py); 7.83 (1H, dd, J = 7.8, J = 1.8, H Py); 7.98– 8.05 (2H, m, H Ar); 8.59 (1Н, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: –0.2; 55.5; 100.6; 103.4; 113.2; 117.2; 120.8; 130.9; 131.9; 141.6; 148.8; 159.5; 160.4. Calculated, m/z: 282.1309 [M+H]+. C17H20NOSi.
Found, m/z: 282.1309.
N,N -Dimethyl-4-[3-(trimethylsilylethynyl)pyridin-2-yl]aniline (4g). Yield 253 mg (86%), orange oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.23 (9H, s, CH3); 3.02 (6H, s, N(CH3)2); 6.73–6.78 (2H, m, H Ar); 7.06 (1H, dd, 7.8, J = 4.8, H Py); 7.80 (1H, dd, J = 7.8, J =1.8, H Py); 8.01– 8.09 (2H, m, H Ar); 8.56 (1Н, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: –0.1; 40.5; 100.0; 104.1; 111.4; 116.4; 119.9; 127.2; 130.5; 141.8; 148.7; 151.1; 159.6. Found, m/z: 295.1629 [M+H]+. C18H23N2Si.
Calculated, m/z: 295.1625.
2-(3,5-Dimethylphenyl)-3-(trimethylsilylethynyl)pyridine (4i). Yield 226 mg (81%), pale-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.19 (9H, s, CH3); 2.38 (6H, s, CH3); 7.05 (1Н, br. s, H Ar); 7.17 (1H, dd, J = 7.8, J = 4.8, H Py); 7.61 (2Н, br. s, H Ar); 7.85 (1Н, dd, J = 7.8, J = 1.6, H Py); 8.61 (1Н, dd, J = 4.8, J = 1.6, H Py). 13C NMR spectrum, δ, ppm: –0.2; 21.5; 100.5; 103.1; 117.7; 121.1; 127.2; 130.6; 137.3; 139.1; 141.7; 148.7; 160.2. Found, m/z: 280.1514 [M+H]+. C18H22NSi. Calculated, m/z: 280.1516.
2-(3-Chlorophenyl)-3-(trimethylsilylethynyl)pyridine (4j). Yield 242 mg (85%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 0.21 (9H, s, CH3); 7.22 (1H, dd, J = 7.8, J = 4.8, H Py); 7.35–7.40 (2H, m, H Ar); 7.85–7.90 (2H, m, H Py and Ar); 8.04–8.06 (1H, m, H Ar); 8.62 (1H, dd, J = 4.8, J = 1.7, H Py). 13C NMR spectrum, δ, ppm: –0.3; 101.7; 102.3; 118.0; 121.8; 127.7; 129.0; 129.2; 129.6; 133.8; 140.9; 141.5; 148.9; 158.4. Found, m/z: 286.0807 [M+H]+. C16H17ClNSi. Calculated, m/z: 286.0813.
Synthesis of 2-aryl-3-ethynylpyridines 5a–j (General method). A mixture of 2-aryl-3-(trimethylsilylethynyl)pyridine 4 (0.5 mmol) and K2CO3 (70 mg, 0.5 mmol) was stirred in a mixture MeOH–CH2Cl2, 2:1 (3 ml) at room temperature for 20 min. Upon completion, the reaction mixture was filtered through Celite, the filtrate was diluted with diethyl ether (20 ml), washed with water (3×10 ml), and dried over Na2SO4. Solvent was evaporated, and the residue was purified by column chromatography on silica (hexane–EtOAc, 15:1) to provide pure pyridines 5. 3-Ethynyl-2-phenylpyridine (5a). Yield 83 mg (93%), colorless solid, mp 70–72°C (mp 72°C59).
2-(4-Ethylphenyl)-3-ethynylpyridine (5b). Yield 97 mg (94%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.28 (3H, t, J = 7.6, CH2CH 3); 2.72 (2H, q, J = 7.6, CH 2CH3); 3.25 (1H, s, ≡CH); 7.19 (1H, dd, J = 7.8, J = 4.8, H Py); 7.28–7.30 (2H, m, H Ar); 7.87–7.91 (3H, m, H Py and Ar); 8.64 (1Н, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: 15.5; 28.9; 81.8; 82.9; 116.6; 121.1; 127.6; 129.3; 136.6; 142.0; 145.3; 149.1; 160.4. Found, m/z: 208.1125 [M+H]+. C15H14N. Calculated, m/z: 208.1121.
3-Ethynyl-2-[4-(trifluoromethyl)phenyl]pyridine (5c). Two-step yield 193 mg (78%), colorless solid, mp 78–79°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.28 (1H, s, ≡CH); 7.28 (1H, dd, J = 7.8, J = 4.8, H Py); 7.72 (2H, d, J = 8.1, H Ar); 7.93 (1H, dd, J = 7.8, J = 1.7, H Py); 8.07 (2H, d, J = 8.1, H Ar); 8.68 (1H, dd, J = 4.8, J = 1.7, H Py). 13C NMR spectrum, δ, ppm (J, Hz): 80.9; 83.6; 117.1; 122.0; 124.2 (q, 1 J CF = 272.1); 124.9 (q, 3 J CF = 3.8); 129.6; 130.8 (q, 2 J CF = 32.4); 142.0; 142.4; 149.2; 158.7. Found, m/z: 248.0684 [M+H]+. C14H9F3N. Calculated, m/z: 248.0682.
3-Ethynyl-2-(4-fluorophenyl)pyridine (5d). Yield 94 mg (95%), colorless solid, mp 74–75°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.26 (1H, s, ≡CH); 7.11–7.17 (2H, m, H Ar); 7.22 (1H, dd, J = 7.8, J = 4.8, H Py); 7.90 (1H, dd, J = 7.8, J = 1.8, H Py); 7.93–7.98 (2H, m, H Ar); 8.64 (1Н, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm (J, Hz): 81.5; 83.2; 115.1 (d, 2 J CF = 21.6); 116.7; 121.5; 131.4 (d, 3 J CF = 8.4); 135.3 (d, 4 J CF = 3.2); 142.1; 149.2; 159.3; 163.4 (d, 1 J CF = 248.7). Found, m/z: 198.0710 [M+H]+. C13H9FN. Calculated, m/z: 198.0714.
2-(4-Chlorophenyl)-3-ethynylpyridine (5e). Yield 98 mg (92%), colorless solid, mp 85–86°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.27 (1H, s, ≡CH); 7.23 (1H, dd, J = 7.8, J = 4.8); 7.40–7.46 (2H, m, H Ar); 7.88–7.94 (3H, m, H Ar and Py); 8.65 (1Н, dd, J = 4.8, J = 1.7, H Py). 13C NMR spectrum, δ, ppm: 81.3; 83.4; 116.8; 121.7; 128.3; 130.8; 135.2; 137.6; 142.1; 149.3; 159.1. Found, m/z: 214.0421 [M+H]+. C13H9ClN. Calculated, m/z: 214.0418.
3-Ethynyl-2-(4-methoxyphenyl)pyridine (5f). Yield 100 mg (96%), colorless solid, mp 59–60°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.25 (1H, s, ≡CH); 3.86 (3H, s, OCH3); 6.96–7.01 (2H, m, H Ar); 7.17 (1H, dd, J = 7.8, J = 4.8, H Py); 7.87 (1H, dd, J = 7.8, J = 1.8, H Py); 7.92– 7.98 (2H, m, H Ar); 8.62 (1H, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: 55.4; 81.9; 82.8; 113.5; 116.3; 120.9; 130.8; 131.8; 142.1; 149.1; 159.9; 160.4. Found, m/z: 210.0910 [M+H]+. C14H12NO. Calculated, m/z: 210.0913.
4-(3-Ethynylpyridin-2-yl)- N,N -dimethylaniline (5g). Yield 104 mg (94%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 3.02 (6H, s, N(CH3)2); 3.27 (1H, s, ≡CH); 6.75–6.81 (2H, m, H Ar); 7.10 (1H, dd, J = 7.8, J = 4.8, H Py); 7.84 (1H, dd, J = 7.8, J = 1.8, H Py); 7.93–8.00 (2H, m, H Ar); 8.60 (1H, dd, J = 4.8, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: 40.4; 82.4; 82.5; 111.5; 115.6; 120.1; 127.0; 130.4; 142.2; 149.1; 151.0; 160.2. Found, m/z: 223.1235 [M+H]+. C15H15N2. Calculated, m/z: 223.1230.
3-Ethynyl-2-(2-methylphenyl)pyridine (5h). Two-step yield 156 mg (81%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 2.23 (3H, s, CH3); 3.07 (1H, s, ≡CH); 7.23–7.34 (5H, m, H Ar and Py); 7.89 (1H, dd, J = 7.8, J = 1.7, H Py); 8.65 (1H, dd, J = 4.8, J = 1.7, H Py). 13C NMR spectrum, δ, ppm: 19.7; 80.7; 82.7; 118.7; 121.6; 125.5; 128.6; 129.3; 130.2; 136.1; 139.4; 140.6; 148.8; 162.6. Found, m/z: 194.0965 [M+H]+. C14H12N. Calculated, m/z: 194.0964.
2-(3,5-Dimethylphenyl)-3-ethynylpyridine (5i). Yield 96 mg (93%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 2.39 (6H, s, CH3); 3.23 (1H, s, ≡CH); 7.07 (1H, br. s, H Ar); 7.20 (1H, dd, J = 7.8, J = 4.8, H Py); 7.55 (2H, br. s, H Ar); 7.89 (1H, d, J = 7.8, H Py); 8.64 (1H, d, J = 4.8, H Py). 13C NMR spectrum, δ, ppm: 21.5; 81.7; 82.8; 116.9; 121.3; 127.1; 130.7; 137.6; 139.1; 141.9; 149.1; 160.8. Found, m/z: 208.1125 [M+H]+. C15H14N. Calculated, m/z: 208.1121.
2-(3-Chlorophenyl)-3-ethynylpyridine (5j). Yield 100 mg (94%), colorless solid, mp 54–55°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.29 (1H, s, ≡CH); 7.25 (1H, dd, J = 7.8, J = 4.8, H Py); 7.36–7.42 (2H, m, H Ar); 7.83–7.86 (1H, m, H Ar); 7.91 (1H, dd, J = 7.8, J = 1.7, H Py); 7.94–7.97 (1H, m, H Ar); 8.66 (1H, dd, J = 4.8, J = 1.7, H Py). 13C NMR spectrum, δ, ppm: 81.1; 83.6; 117.0; 121.9; 127.6; 129.1; 129.3; 129.5; 134.1; 140.8; 142.1; 149.3; 158.8. Found, m/z: 214.0419 [M+H]+. C13H9ClN. Calculated, m/z: 214.0418.
Synthesis of benzo[ h ]quinolines 6a–j (General method). PtCl2 (5.3 mg, 10 mоl %) was added to a solution of pyridine 5a–j (0.2 mmol) in toluene (chlorobenzene for pyridines 5g–i) (0.5 ml) in a screw-cap vial. Reaction mixture was flushed with argon, the vial was sealed and heated with stirring in an oil bath at 110°C (130°C for pyridines 5g–i) for 20 h (48 h for pyridines 5с–e). Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane– EtOAc, 15:1) to provide pure quinolines 6.
Benzo[ h ]quinoline (6а). Yield 24 mg (67%), colorless solid, mp 50–51°C (mp 51–52°C60).
8-Ethylbenzo[ h ]quinoline (6b). Yield 33 mg (80%), yellowish oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.39 (3H, t, J = 7.6, CH2CH 3); 2.90 (2H, q, J = 7.6, CH 2CH3); 7.48 (1H, dd, J = 8.0, J = 4.3, H benzoquinoline); 7.60–7.66 (2H, m, H benzoquinoline); 7.71 (1H, br. s, H benzoquinoline); 7.77 (1H, d, J = 8.8, H benzoquinoline); 8.14 (1H, dd, J = 8.0, J = 1.3, H benzoquinoline); 8.99 (1H, dd, J = 4.3, J = 1.3, H benzoquinoline); 9.21 (1H, d, J = 8.4, H benzoquinoline). 13C NMR spectrum, δ, ppm: 15.7; 29.1; 121.5; 124.5; 125.4; 126.2; 126.3; 127.8; 128.0; 129.8; 134.0; 135.8; 144.6; 146.8; 148.9. Found, m/z: 208.1118 [M+H]+. C15H14N. Calculated, m/z: 208.1121.
8-(Trifluoromethyl)benzo[ h ]quinoline (6c). Yield 27 mg (55%), colorless solid, mp 75–76°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.58 (1H, dd, J = 8.0, J = 4.4, H benzoquinoline); 7.76 (1H, d, J = 8.9, H benzoquinoline); 7.84 (1H, d, J = 8.9, H benzoquinoline); 7.92 (1H, d, J = 8.6, H benzoquinoline); 8.17–8.22 (2H, m, H benzoquinoline); 9.04 (1H, dd, 3 J = 4.4, J = 1.5, H benzoquinoline); 9.41 (1H, d, J = 8.6, H benzoquinoline). 13C NMR spectrum, δ, ppm (J, Hz): 122.9; 123.0 (q, 3 J CF = 3.3); 124.5 (q, 1 J CF = 272.2); 125.3 (q, 3 J CF = 4.3); 125.7; 127.0; 127.3; 127.6; 130.1 (q, 2 J CF = 32.4); 133.0; 133.6; 136.1; 146.0; 149.6. Found, m/z: 248.0686 [M+H]+. C14H9F3N. Calculated, m/z: 248.0682.
8-Fluorobenzo[ h ]quinoline (6d). Yield 26 mg (66%), colorless solid, mp 63–64°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.44–7.54 (3H, m, H benzoquinoline); 7.68–7.75 (2H, m, H benzoquinoline); 8.15 (1H, dd, J = 8.0, J = 1.7, H benzoquinoline); 8.99 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.30 (1H, dd, J = 9.1, 4 J HF = 5.8, H benzoquinoline). 13C NMR spectrum, δ, ppm (J, Hz): 112.0 (d, 2 J CF = 20.9); 116.2 (d, 2 J CF = 23.6); 121.8; 125.9 (d, 5 J CF = 1.1); 126.9; 127.1 (d, 4 J CF = 3.8); 127.3 (d, 3 J CF = 9.0); 128.3 (d, 5 J CF = 1.7); 135.1 (d, 3 J CF = 9.2); 136.0; 146.7; 149.3; 162.7 (d, 1 J CF = 247.9). Found, m/z: 198.0716 [M+H]+. C13H9FN. Calculated, m/z: 198.0714.
8-Chlorobenzo[ h ]quinoline (6e). Yield 27 mg (63%), colorless solid, mp 109–110°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.52 (1H, dd, J = 8.0, J = 4.4, H benzoquinoline);
7.64–7.70 (3H, m, H benzoquinoline), 7.86 (1H, d, J = 2.1, H benzoquinoline); 8.15 (1H, dd, J = 8.0, J = 1.7, H benzoquinoline); 8.99 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.22 (1H, d, J = 8.8, H benzoquinoline). 13C NMR spectrum, δ, ppm: 122.1; 126.3; 126.4; 126.8 (2C); 126.9; 127.7; 130.0; 134.4; 134.6; 136.0; 146.3; 149.3. Found, m/z: 214.0423 [M+H]+. C13H9ClN. Calculated, m/z: 214.0418.
8-Methoxybenzo[ h ]quinoline (6f). Yield 25 mg (60%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 3.98 (3H, s, OCH3); 7.00 (1H, d, J = 2.4, H benzoquinoline); 7.27 (1H, dd, J = 9.0, J = 2.4, H benzoquinoline); 7.37 (1H, dd, J = 7.9, J = 4.4, H benzoquinoline); 7.57 (1H, d, J = 8.9, H benzoquinoline); 7.66 (1H, d, J = 8.9, H benzoquinoline); 8.07 (1H, dd, J = 7.9, J = 1.7, H benzoquinoline); 8.91 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.10 (1H, d, J = 9.0, H benzoquinoline). 13C NMR spectrum, δ, ppm: 40.7; 107.6; 115.0; 120.1; 122.4; 124.9; 125.6; 125.7; 127.8; 135.6; 136.0; 147.1; 148.6; 150.6. Found, m/z: 210.0907 [M+H]+. C14H12NO. Calculated, m/z: 210.0913.
N,N -Dimethylbenzo[ h ]quinolin-8-amine (6g). Yield 24 mg (54%), orange solid, mp 110–111°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.12 (6H, s, N(CH3)2); 7.26 (1H, d, J = 2.8, H benzoquinoline); 7.37 (1H, dd, J = 9.0, J = 2.8, H benzoquinoline); 7.45 (1H, dd, J = 8.0, J = 4.4, H benzoquinoline); 7.65 (1H, d, J = 8.8, H benzoquinoline); 7.73 (1H, d, J = 8.8, H benzoquinoline); 8.13 (1H, dd, J = 8.0, J = 1.8, H benzoquinoline); 8.96 (1H, dd, J = 4.4, J = 1.8, H benzoquinoline); 9.20 (1H, d, J = 9.0, H benzoquinoline). 13C NMR spectrum, δ, ppm: 55.6; 108.1; 117.6; 121.0; 125.4; 126.1; 126.2; 126.3; 127.4; 135.3; 135.9; 146.8; 149.1; 159.8. Found, m/z: 223.1224 [M+H]+. C15H15N2. Calculated, m/z: 223.1230.
10-Methylbenzo[ h ]quinoline (6h). Yield 22 mg (57%), colorless solid, mp 73–74°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.37 (3H, s, CH3); 7.48 (1H, dd, J = 8.0, J = 4.3, H benzoquinoline); 7.55–7.59 (2H, m, H benzoquinoline); 7.66 (1H, d, J = 8.7, H benzoquinoline); 7.78–7.81 (2H, m, H benzoquinoline); 8.16 (1H, dd, J = 8.0, J = 1.8, H benzoquinoline); 9.03 (1H, dd, J = 4.3, J = 1.8, H benzoquinoline). 13C NMR spectrum, δ, ppm: 27.3; 120.7; 125.6; 126.8; 127.4; 127.6; 128.9; 130.1; 131.3; 135.3; 135.4; 138.9; 147.3; 149.2. Found, m/z: 194.0966 [M+H]+. C14H12N. Calculated, m/z: 194.0964.
7,9-Dimethylbenzo[ h ]quinoline (6i). Yield 33 mg (80%), colorless solid, mp 77–78°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.62 (3H, s, CH3); 2.74 (3H, s, CH3); 7.39 (1H, br. s, H benzoquinoline), 7.50 (1H, dd, J = 8.0, J = 4.4, H benzoquinoline); 7.65 (1H, d, J = 9.1, H benzoquinoline); 7.98 (1H, d, J = 9.1, H benzoquinoline); 8.16 (1H, dd, J = 8.0, J = 1.7, H benzoquinoline); 8.98–9.02 (2H, m, H benzoquinoline). 13C NMR spectrum, δ, ppm: 19.7; 22.0; 121.7; 122.1; 123.9; 124.1; 126.3; 130.6; 131.3; 131.9; 134.3; 135.9; 136.8; 146.8; 148.7. Found, m/z: 208.1114 [M+H]+. C15H14N. Calculated, m/z: 208.1121.
9-Chlorobenzo[ h ]quinoline (6j). Yield 26 mg (61%), colorless solid, mp 118–119°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.52 (1H, dd, J = 8.0, J = 4.4, H benzoquinoline); 7.60–7.66 (2H, m, H benzoquinoline); 7.74 (1H, d, J = 8.8, H benzoquinoline); 7.80 (1H, d, J = 8.5, H benzoquinoline); 8.14 (1H, dd, J = 8.0, J = 1.3, H benzoquinoline); 8.98 (1H, dd, J = 4.4, J = 1.3, H benzoquinoline); 9.26 (1H, d, J = 1.9, H benzoquinoline). 13C NMR spectrum, δ, ppm: 122.4; 124.1; 125.7; 126.8; 127.1; 128.8; 129.3; 131.9; 132.7; 133.4; 135.9; 145.7; 149.2. Found, m/z: 214.0411 [M+H]+. C13H9ClN. Calculated, m/z: 214.0418.
Cyclization of 2-aryl-3-(phenylethynyl)pyridines 3a–j (General method). A solution of pyridine 3a–j (0.2 mmol) in TfOH (0.5 ml) was stirred at room temperature for 15 min. The reaction mixture was poured into cold water (20 ml) and extracted with CH2Cl2 (2×5 ml). The combined extracts were washed with water (2×5 ml) and dried over Na2SO4. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–EtOAc, 15:1) to provide pure products.
6-Phenylbenzo[ h ]quinoline (7а). Yield 49 mg (96%), colorless solid, mp 139–140°C (mp 140–141°C61).
8-Ethyl-6-phenylbenzo[ h ]quinoline (7b). Yield 54 mg (95%), colorless solid, mp 95–96°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.29 (3H, t, J = 7.6, CH2CH 3); 2.81 (2H, q, J = 7.6, CH 2CH3); 7.46–7.59 (7H, m, H Ph and benzoquinoline); 7.64 (1H, dd, J = 8.4, J = 1.6, H benzoquinoline); 7.72 (1H, br. s, H benzoquinoline); 8.14 (1H, dd, J = 8.0, J = 1.7, H benzoquinoline); 9.00 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.35 (1H, d, J = 8.4, H benzoquinoline). 13C NMR spectrum, δ, ppm: 15.8; 29.4; 121.8; 124.9 (2C); 125.7; 126.0; 127.7(2C); 128.5; 130.1 (2C); 133.0; 135.9; 139.8; 140.6; 144.6; 146.4; 148.8. Found, m/z: 284.1430 [M+H]+. C21H18N. Calculated, m/z: 284.1434.
6-Phenyl-8-(trifluoromethyl)benzo[ h ]quinoline (7c). Yield 58 mg (90%), yellowish solid, mp 120–121°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.49–7.62 (6H, m, H Ph and benzoquinoline); 7.72 (1H, s, H benzoquinoline); 7.95 (1H, dd, J = 8.6, J = 1.5, H benzoquinoline); 8.18–8.23 (2H, m, H benzoquinoline); 9.05 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.55 (1H, d, J = 8.6, H benzoquinoline). 13C NMR spectrum, δ, ppm (J, Hz): 122.9 (q, 3 J CF = 3.0); 123.2; 123.8 (q, 3 J CF = 4.3); 124.5 (q, 1 J CF = 272.4); 126.0; 126.9; 127.3; 128.3; 128.8; 130.0 (2C, q, 2 J CF = 32.2); 132.2; 134.0; 136.1; 139.4; 139.9; 145.5; 149.5. Found, m/z: 324.0986 [M+H]+. C20H13F3N. Calculated, m/z: 324.0995.
8-Fluoro-6-phenylbenzo[ h ]quinoline (7d). Yield 51 mg (93%), colorless solid, mp 115–116°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.45–7.57 (8H, m, H Ph and benzoquinoline); 7.66 (1H, s, H benzoquinoline); 8.17 (1H, dd, J = 8.0, J = 1.7, H benzoquinoline); 9.00 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.55 (1H, dd, J = 8.0, 4 J HF = 6.0, H benzoquinoline). 13C NMR spectrum, δ, ppm (J, Hz): 111.1 (d, 2 J CF = 22.6); 116.0 (d, 2 J CF = 23.7); 122.1; 125.5 (d, 5 J CF = 1.0); 127.1; 127.5 (d, 3 J CF = 9.0); 128.0; 128.6 (d, 5 J C-F = 1.6); 128.7; 129.9; 134.5 (d, 3 J CF = 8.8); 136.0; 139.3 (d, 4 J CF = 3.8); 139.8; 146.0; 149.3; 162.8 (d, 1 J CF = 247.3). Found, m/z: 274.1030 [M+H]+. C19H13FN. Calculated, m/z: 274.1027.
8-Chloro-6-phenylbenzo[ h ]quinoline (7e). Yield 55 mg (95%), colorless solid, mp 129–130°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.47–7.58 (6H, m, H Ph and benzoquinoline); 7.64 (1H, s, H benzoquinoline); 7.69 (1H, dd, J = 8.8, J = 2.1, H benzoquinoline); 7.87 (1H, d, J = 2.1, H benzoquinoline); 8.16 (1H, dd, J = 8.0, J = 1.7, H benzoquinoline); 9.00 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.36 (1H, d, J = 8.8, H benzoquinoline). 13C NMR spectrum, δ, ppm: 122.4; 125.6; 126.0; 126.6; 127.1; 127.6; 128.1; 128.7; 130.0; 130.2; 133.9; 134.7; 136.1; 139.1; 139.6; 145.8; 149.3. Found, m/z: 290.0723 [M+H]+. C19H13ClN. Calculated, m/z: 290.0731.
8-Methoxy-6-phenylbenzo[ h ]quinoline (7f). Yield 37 mg (65%), colorless solid, mp 86–87°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.83 (3H, s, OCH3); 7.30 (1H, d, J = 2.5, H benzoquinoline); 7.39 (1H, dd, J = 9.0, J = 2.5, H benzoquinoline); 7.45–7.59 (6H, m, H Ph and benzoquinoline); 7.61 (1H, s, H benzoquinoline); 8.15 (1H, dd, J = 8.0, J = 1.4, H benzoquinoline); 8.98 (1H, dd, J = 4.4, J = 1.4, H benzoquinoline); 9.34 (1H, d, J = 9.0, H benzoquinoline). 13C NMR spectrum, δ, ppm: 55.5; 107.7; 116.9; 121.3; 125.1; 126.6; 126.7; 127.8; 128.6; 129.9; 134.5; 136.1; 139.5; 140.4; 148.8; 159.9. Found, m/z: 286.1222 [M+H]+. C20H16NO. Calculated, m/z: 286.1226.
6'-Phenyl-4 H -spiro[cyclohexa-2,5-diene-1,7'-cyclopenta[ b ]pyridin]-4-one (8). Yield 14 mg (26%), 38 mg (93%, isolated as a single product when the reaction was carried out at 0°C on 0.15 mmol scale), colorless solid, mp 184– 85°C. 1H NMR spectrum, δ, ppm (J, Hz): 6.56–6.60 (2H, m, =CH); 6.68–6.72 (2H, m, =CHCO); 7.24 (1H, dd, J = 7.6, J = 5.0, H Py); 7.30–7.36 (3H, m, H Ph); 7.46 (1H, s, CH=CPh); 7.56–7.59 (2H, m, H Ph); 7.71 (1H, dd, J = 7.6, J = 1.5, H Py); 8.40 (1H, dd, J = 5.0, J = 1.5, H Py). 13C NMR spectrum, δ, ppm: 61.0; 123.5; 126.1; 127.7; 128.9; 129.0; 129.2; 132.6; 134.0; 138.3; 147.4; 147.6; 147.7; 162.6; 186.1. Found, m/z: 272.1079 [M+H]+. C19H14NO. Calculated, m/z: 272.1070.
10-Methyl-6-phenylbenzo[ h ]quinoline (7h). Yield 52 mg (97%), yellowish solid, mp 145–146°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.45 (3H, s, CH3); 7.47–7.55 (7H, m, H Ph and benzoquinoline); 7.59–7.61 (2H, m, H benzoquinoline); 7.80 (1H, d, J = 8.0, H benzoquinoline); 8.15 (1H, dd, J = 8.0, J = 1.9, H benzoquinoline); 9.06 (1H, dd, J = 4.3, J = 1.9, H benzoquinoline). 13C NMR spectrum, δ, ppm: 27.8; 120.9; 125.3; 126.4; 127.0; 127.2; 127.6; 128.4; 130.2; 130.4; 131.3; 134.4; 135.4; 139.1; 140.5; 141.3; 147.2; 148.7. Found, m/z: 270.1270 [M+H]+. C20H16N. Calculated, m/z: 270.1277.
7,9-Dimethyl-6-phenylbenzo[ h ]quinoline (7i). Yield 50 mg (88%), colorless solid, mp 172–173°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.04 (3H, s, CH3); 2.62 (3H, s, CH3); 7.30 (1H, br. s, H benzoquinoline); 7.38–7.44 (5H, m, H Ph); 7.46 (1H, s, H benzoquinoline); 7.50 (1H, dd, J = 8.0, J = 4.4, H benzoquinoline); 8.09 (1H, dd, J = 8.0, J = 1.7, H benzoquinoline); 8.99 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.22 (1H, br. s, H benzoquinoline). 13C NMR spectrum, δ, ppm: 21.7; 25.0; 122.1; 122.8; 125.3; 127.1; 127.3; 128.0; 129.4; 129.6; 133.2; 134.3; 135.5; 135.6; 136.7; 140.0; 144.9; 146.4; 148.6. Found, m/z: 284.1430 [M+H]+. C21H18N. Calculated, m/z: 284.1434.
7-Chloro-6-phenylbenzo[ h ]quinoline (7j). Yield 37 mg (64%), colorless solid, 140–141°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.38–7.45 (5H, m, H Ph); 7.55 (1H, dd, J = 8.0, J = 4.4, H benzoquinoline); 7.61 (1H, s, H benzoquinoline); 7.62–7.66 (1H, m, H benzoquinoline); 7.71 (1H, dd, J = 7.6, J = 1.5, H benzoquinoline); 8.12 (1H, dd, J = 8.0, J = 1.7, H benzoquinoline); 9.02 (1H, dd, J = 4.4, J = 1.7, H benzoquinoline); 9.50 (1H, dd, J = 8.1, J = 1.5, H benzoquinoline). 13C NMR spectrum, δ, ppm: 122.8; 124.3; 125.4; 127.1; 127.2; 127.8; 129.4; 129.5; 130.0; 131.8; 131.9; 134.6; 135.7; 138.5; 143.3; 146.0; 149.4. Found, m/z: 290.0733 [M+H]+. C19H13ClN. Calculated, m/z: 290.0731.
9-Chloro-6-phenylbenzo[ h ]quinoline (7j'). Yield 15 mg (26%), colorless solid, mp 158–159°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.48–7.58 (7H, m, H Ph and benzoquinoline); 7.62 (1H, s, H benzoquinoline); 7.84 (1H, d, J = 8.8, H benzoquinoline); 8.18 (1H, dd, J = 8.0, J = 1.5, H benzoquinoline); 8.99–9.02 (1H, m, H benzoquinoline); 9.40 (1H, d, J = 2.2, H benzoquinoline). 13C NMR spectrum, δ, ppm: 122.8; 124.3; 126.1; 126.5; 128.0; 128.1; 128.7 (2C); 130.0; 131.1; 133.1; 133.5; 136.0; 139.6; 139.9; 145.3; 149.1. Found, m/z: 290.0730 [M+H]+. C19H13ClN. Calculated, m/z: 290.0731.
Treatment of 2-aryl-3-(phenylethynyl)pyridines with sulfuric acid (General method). A solution of pyridine 3d,e (0.2 mmol) in concentrated H2SO4 (98%, 0.5 ml) was stirred at room temperature for 12 h (compound 3d) or 0.5 h (compound 3e). The reaction mixture was poured into cold water (20 ml) and extracted with CH2Cl2 (2×5 ml). The combined extracts were washed with water (2×5 ml) and dried over Na2SO4. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–EtOAc, 15:1) to provide pure products. Mixture of quinoline 7d (52%) and compound 8 (21%) was obtained from pyridine 3d; quinoline 7e (88%) formed as a single product from pyridine 3e.
Synthesis of 2-phenylquinoline-3-carbaldehydes 10a–d (General method). A mixture of DMA and water (4,1, 10 ml) was added to a mixture of 2-chloroquinoline-3-carbaldehyde 9a–d (1 mmol), phenylboronic acid (128 mg, 1.05 mmol), K2CO3 (280 mg, 2.0 mmol), and Pd(PPh3)4 (56 mg, 5 mol %) in a screw-cap vial. Reaction mixture was flushed with argon, sealed, and stirred at 120°C for 3 h in an oil bath. Then the reaction mixture was cooled to room temperature, poured into water (50 ml), and extracted with EtOAс (3×10 ml). Extracts were washed with water (2×15 ml) and dried over Na2SO4. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–CHCl3, 10:1) to provide pure carbaldehydes 10a–d.
2-Phenylquinoline-3-carbaldehyde (10а). Yield 210 mg (90%), colorless solid, mp 96–97°C (mp 98°C62).
6-Methyl-2-phenylquinoline-3-carbaldehyde (10b). Yield 227 mg (92%), yellowish solid, mp 119–121°C (mp 120–121°C62).
6-Methoxy-2-phenylquinoline-3-carbaldehyde (10c). Yield 247 mg (94%), yellowish solid, mp 129–131°C (mp 130°C62).
8-Methoxy-2-phenylquinoline-3-carbaldehyde (10d). Yield 245 mg (93%), yellowish solid, mp 159–160°C. 1H NMR spectrum, δ, ppm (J, Hz): 4.10 (3H, s, OCH3); 7.19–7.22 (1H, m, H quinoline); 7.48–7.60 (5H, m, H Ph and quinoline); 7.68–7.72 (2H, m, H Ph); 8.81 (1H, s, H quinoline); 10.19 (1H, s, CHO). 13C NMR spectrum, δ, ppm: 56.4; 110.7; 121.1; 127.7; 127.8; 128.2; 128.8; 129.4; 130.7; 138.0 (2C); 141.6; 155.6; 159.3; 191.8. Found, m/z: 264.1017 [M+H]+. C17H14NО2. Calculated, m/z: 264.1019.
Synthesis of 3-ethynyl-2-phenylquinolines 11a–d (General method). A mixture of 2-phenylquinoline-3-carbaldehyde 10a–d (1 mmol), K2CO3 (280 mg, 2 mmol) and diethyl 1-diazo-2-oxopropylphosphonate (264 mg, 1.2 mmol) in MeOH (8 ml) was stirred at room temperature overnight. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–CHCl3, 20:1) to provide pure quinolines 11a–d.
3-Ethynyl-2-phenylquinoline (11а). Yield 121 mg (53%), colorless solid, mp 99–100°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.27 (1H, s, ≡CH); 7.47–7.58 (4H, m, H Ph and quinoline); 7.72–7.76 (1H, m, H quinoline); 7.80 (1H, d, J = 8.1, H quinoline); 8.00–8.03 (2H, m, H Ph); 8.16 (1H, d, J = 8.5, H quinoline); 8.44 (1H, s, H quinoline). 13C NMR spectrum, δ, ppm: 81.9; 82.8; 115.1; 126.2; 127.2 (2C); 128.1; 129.2; 129.7 (2C); 130.8; 139.5; 142.4; 147.2; 159.6. Found, m/z: 230.0970 [M+H]+. C17H12N. Calculated, m/z: 230.0964.
3-Ethynyl-6-methyl-2-phenylquinoline (11b). Yield 138 mg (57%), colorless solid, mp 107–108°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.55 (3H, s, CH3); 3.25 (1H, s, ≡CH); 7.45–7.58 (5H, m, H Ph and quinoline); 7.98–8.01 (2H, m, H Ph); 8.04 (1H, d, J = 8.5, H quinoline); 8.34 (1H, s, H quinoline). 13C NMR spectrum, δ, ppm: 22.7; 82.1; 82.6; 115.0; 125.9; 126.2; 128.1; 129.0; 129.4; 129.6; 133.1; 137.2; 139.6; 141.7; 145.9; 158.7. Found, m/z: 244.1119 [M+H]+. C18H14N. Calculated, m/z: 244.1121.
3-Ethynyl-6-methoxy-2-phenylquinoline (11c). Yield 109 mg (42%), yellow solid, mp 109–110°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.26 (1H, s, ≡CH); 3.94 (3H, s, OCH3); 7.04 (1H, d, J = 2.7, H quinoline); 7.39 (1H, dd, J = 9.2, J = 2.7, H quinoline); 7.44–7.51 (3H, m, H Ph); 7.97–8.00 (2H, m, H Ph); 8.04 (1H, d, J = 9.2, H quinoline); 8.32 (1H, s, H quinoline). 13C NMR spectrum, δ, ppm: 55.7; 82.1; 82.7; 104.4; 115.3; 123.6; 127.2; 128.1; 128.9; 129.6; 131.2; 139.6; 141.0; 143.5; 157.2; 158.3.
Found, m/z: 260.1063 [M+H]+. C18H14NO. Calculated, m/z: 260.1070.
3-Ethynyl-8-methoxy-2-phenylquinoline (11d). Yield 101 mg (39%), yellow solid, mp 101–103°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.27 (1H, s, ≡CH); 4.06 (3H, s, OCH3); 7.07 (1H, d, J = 7.7, H quinoline); 7.36 (1H, d, J = 8.1, H quinoline); 7.43–7.49 (4H, m, H Ph and quinoline); 8.01–8.04 (2H, m, H Ph); 8.39 (1H, s, H quinoline). 13C NMR spectrum, δ, ppm: 56.2; 81.9; 83.0; 109.1; 115.7; 118.9; 127.3; 127.4; 128.0; 129.0; 129.9; 139.0; 139.6; 142.3; 155.6; 158.4. Found, m/z: 260.1065 [M+H]+. C18H14NO. Calculated, m/z: 260.1070.
Synthesis of 2-phenyl-3-(phenylethynyl)quinolines 12a,b (General method). MeCN (5 ml) was added to a mixture of 3-ethynyl-2-phenylquinoline 11a,b (0.5 mmol), Pd(PPh3)2Cl2 (17.6 mg, 5 mоl %) and CuI (4.8 mg, 5 mоl %) in a screwcap vial. Reaction mixture was flushed with argon, iodobenzene (112 mg, 0.55 mmоl) and Et3N (0.17 ml, 1.25 mmol) were added, the vial was sealed; and the reaction mixture was stirred at 80°C in an oil bath for 6 h. Then it was cooled to room temperature, poured into water (40 ml) and extracted with EtOAc (3×10 ml). The combined extracts were washed with water (2×5 ml) and dried over Na2SO4. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–CHCl3, 15:1) to provide pure quinolines 12a,b.
2-Phenyl-3-(phenylethynyl)quinoline (12а).63 Yield 130 mg (85%), dark-yellow amorphous solid.
6-Methyl-2-phenyl-3-(phenylethynyl)quinoline (12b). Yield 134 mg (84%), yellow solid, mp 131–132°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.56 (3H, s, CH3); 7.30– 7.44 (5H, m, H Ph); 7.46–7.58 (5H, m, H Ph and quinoline); 8.02–8.09 (3H, m, H Ph and quinoline); 8.35 (1H, s, H quinoline). 13C NMR spectrum, δ, ppm: 22.8; 88.3; 94.5; 116.2; 123.2; 126.0; 126.5; 128.0; 128.6; 128.7; 129.0; 129.4; 129.7; 131.5; 132.8; 137.1; 139.6; 140.1; 145.7; 158.6. Found, m/z: 320.1437 [M+H]+. C24H18N. Calculated, m/z: 320.1434.
Synthesis of benzo[ c ]acridines 13a–d (General method). A mixture of quinoline 11a–d (0.2 mmol) and PtCl2 (5.3 mg, 10 mоl %) in toluene (0.5 ml) was flushed with argon in screw-cap vial, sealed, and heated with stirring in an oil bath at 120°C for 20 h. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–CHCl3, 15:1) to provide pure acridines 13a–d.
Benzo[ c ]acridine (13а). Yield 27 mg (59%), colorless solid, mp 107–109°C (mp 108°C64).
9-Methylbenzo[ c ]acridine (13b). Yield 30 mg (62%), yellowish solid, mp 126–127°C (mp 126°C65).
9-Methoxybenzo[ c ]acridine (13c). Yield 30 mg (58%), yellow solid, mp 154–155°C (mp 155°C66).
11-Methoxybenzo[ c ]acridine (13d). Yield 31 mg (60%), colorless solid, mp 115–117°C. 1H NMR spectrum, δ, ppm (J, Hz): 4.21 (3H, s, OCH3); 7.10–7.14 (1H, m, H benzoacridine); 7.48–7.53 (1H, m, H benzoacridine); 7.60–7.63 (1H, m, H benzoacridine); 7.67–7.74 (3H, m, H benzoacridine); 7.75–7.80 (1H, m, H benzoacridine); 7.85–7.89 (1H, m, H benzoacridine); 8.63 (1H, s, H benzoacridine); 9.55–9.58 (1H, m, H benzoacridine). 13C NMR spectrum, δ, ppm: 56.5; 107.3; 119.9; 125.6(2C); 125.8; 126.2; 127.4; 127.9; 128.2; 128.3; 129.1; 131.9; 134.0; 135.1; 140.4; 146.8; 155.6. Found, m/z: 260.1063 [M+H]+. C18H14NO. Calculated, m/z: 260.1070.
Synthesis of 5-phenylbenzo[ c ]acridines 14a,b (General method). A solution of quinoline 12a,b (0.2 mmol) in TfOH (0.5 ml) was stirred at room temperature for 1 h. The reaction mixture was poured into cold water (20 ml) and extracted with CH2Cl2 (2×5 ml). The combined extracts were washed with water (2×5 ml) and dried over Na2SO4. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica (hexane–CHCl3, 15:1) to provide pure acridines 14a,b.
5-Phenylbenzo[ c ]acridine (14а). Yield 57 mg (93%), yellowish solid, mp 110–112°C (mp 111–112°C61).
9-Methyl-5-phenylbenzo[ c ]acridine (14b). Yield 61 mg (96%), yellowish solid, mp 131–132°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.60 (3H, s, CH3); 7.47–7.68 (8H, m, H Ph and benzoacridine); 7.74–7.81 (2H, m, H benzoacridine); 7.87 (1H, d, J = 8.0, H benzoacridine); 8.30 (1H, d, J = 8.7, H benzoacridine); 8.51 (1H, s, H benzoacridine); 9.63 (1H, d, J = 8.0, H benzoacridine). 13C NMR spectrum, δ, ppm: 21.9; 124.9; 125.5; 126.2; 126.3; 126.6; 127.2; 127.5; 127.7; 128.5; 128.8; 129.6; 130.0; 132.1; 132.5; 133.3; 134.1; 135.9; 139.4; 140.4; 146.7; 146.9. Found, m/z: 320.1441 [M+H]+. C24H18N. Calculated, m/z: 320.1434.
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This research was supported by the Ministry of Education and Science of the Russian Federation (grant of the President of the Russian Federation no. MK-5965.2016.3).
NMR and HRMS analyses were performed at the Saint Petersburg State University Center for Magnetic Resonance Resource and Center for Chemical Analysis and Materials Research.
The authors thank Dr. Alexey Fedorov (ETH Zurich) for his help in the preparation of this manuscript.
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The Supplementary information file containing optimization of the Sonogashira reaction between pyridine 2a and TMS-acetylene and copies of 1H and 13C{1H} NMR spectra of all compounds is available from the journal website at http://springerlink.bibliotecabuap.elogim.com/journal/10593.
Published in Khimiya Geterotsiklicheskikh Soedinenii, 2017, 53(10), 1103–1113
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Shestakov, A.N., Pankova, A.S. & Kuznetsov, M.A. Cycloisomerization – a straightforward way to benzo[h]quinolines and benzo[c]acridines. Chem Heterocycl Comp 53, 1103–1113 (2017). https://doi.org/10.1007/s10593-017-2179-5
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DOI: https://doi.org/10.1007/s10593-017-2179-5