One-Pot Phosphine-Catalyzed Syntheses of Quinolines

Abstract

In this study we developed an efficient one-pot procedure for the preparation of 3-substituted and 3,4-disubstituted quinolines from stable starting materials (activated acetylenes reacting with o-tosylamidobenzaldehydes and o-tosylamidophenones, respectively) under mild conditions. The reaction appears to operate under a general base catalysis mechanism, instigated by the β-phosphonium enoate α-vinyl anion generated in situ through nucleophilic addition of PPh₃ to the activated alkyne. Michael addition of the deprotonated tosylamides to the activated alkynes and subsequent rapid aldol cyclization led to the formation of labile N-tosyldihydroquinoline intermediates. Driven by aromatization, detosylation of the dihydroquinoline intermediates occurred readily in the presence of dilute aqueous HCl to give the final quinoline products.

Introduction

The quinoline unit is found in a wide variety of pharmacologically and biologically active compounds.¹ Not surprisingly, quinoline derivatives continue to attract the attention of medicinal chemists, and strategies for accessing new scaffolds of quinoline derivatives are of great interest to synthetic chemists. In recent years, many transition metal–catalyzed processes have been developed for mild and efficient syntheses of quinolines.² Notably, the number of conventional metal-free paths for quinoline syntheses have also been growing.³ Several classical methods for targeting the quinoline core—including the Skraup, Doebner–von Miller, Friedländer, Pfitzinger, Conrad–Limpach, and Combes syntheses^4a,b—remain relevant today for the preparation of quinoline-containing materials, ligands, and pharmaceutical agents.^4a Nevertheless, such reactions are often performed under unfavorably harsh conditions, typically with either a strong acid or base and thermal assistance.^4a,b For example, the Friedländer quinoline synthesis, a particularly powerful tool for generating quinoline core systems, is performed at high temperature in the presence of either a strong acid or base.⁴ In addition to unattractive reaction conditions, the instability of the coupling partners in the Friedländer quinoline synthesis further limits its synthetic potential.^4,5 In particular, when the synthesis of 3-substituted quinolines is attempted using Friedländer methodology (R² = R³ = H), self-condensation of both aldehyde coupling partners can lower the reaction efficiency and complicate the product’s purification (Scheme 1).¹¹ To prevent self-condensation of aminobenzaldehydes in Friedländer methodology, several classical approaches, namely the Borsche, Pfitzinger, and Niemantowski quinoline syntheses, have been developed employing alternative starting materials.⁴ In a recent report, for example, aminobenzaldehydes were generated in situ from corresponding nitrobenzaldehydes and subsequently used in the Friedländer synthesis.⁵

Scheme 1.

Friedläder Quinoline Synthesis

For the synthesis of 3-substituted quinolines in particular, in 2009 Verpoort reported a one-pot methodology to avoid self-condensation of the aminobenzaldehyde by employing an aminobenzyl alcohol as a precursor; they also prevented self-condensation of the other coupling partner through late introduction of the strong base.⁶ This approach, however, requires an elevated temperature and a stoichiometric amount of the strong base. More recently, Li reported an alternative approach to 3-substituted quinolines by coupling alkynones with aminobenzaldehyde in the presence of a catalytic amount of Lewis acid as the activator.⁷ Despite the use of a mild Lewis acid, this approach requires thermal assistance, long reaction times, and the use of unstable aminobenzaldehydes. The synthesis of 3-substituted quinolines is also generally difficult when using other methods.^4a,8 Herein, we report a simple and efficient one-pot phosphine-catalyzed procedure for the synthesis of 3-substituted quinolines under mild conditions from stable starting materials.

We developed the title quinoline synthesis during an expansion of our original double-Michael reaction.^9,10 We attempted to develop alternative modes of this tandem reaction to generate a variety of heterocyclic scaffolds (Scheme 2). The double-Michael reaction requires two pronucleophilic groups in one of the starting materials to undergo the two successive Michael additions. Replacing one pronucleophilic group with an electrophilic group would alter the nature of the reaction to a cascade of nucleophilic additions (Michael addition followed by an aldol reaction, or vice versa). The presence of an N-tosyl group in the substrates not only activated the pronucleophile but also completely inhibited the self-condensation normally observed for Friedländer substrates. In fact, N-tosylated o-aminobenzaldehydes are bench-stable at room temperature for months of storage without any deterioration. The activated acetylenes are likewise very stable under storage and during the reaction.

Scheme 2.

3-Substituted Quinoline Synthesis Versus Double-Michael Reaction

Results and Discussion

In a preliminary study of the reaction, we reacted 0.1 M of N-tosyl-2-aminobenzaldehyde (1a) with 2.0 equivalents of 3-butyn-2-one (2a) in THF in the presence of 20 mol% PPh₃ as the catalyst. We stopped the reaction prior to completion, after 17 h, for a quick evaluation of its feasibility, identifying the dihydroquinoline 3a as the product in 28% yield (Table 1, entry 1). We suspected that the long reaction time might have caused 2a to oligomerize in the presence of the nucleophilic catalyst PPh₃, thereby explaining the poor reaction yield. Therefore, we tested the slow addition (syringe pump, 2 h) of 2a to the reaction mixture, but the yield was unchanged (entry 2). We observed (¹H NMR spectra) almost no oligomerization in a mixture of 2a and 20 mol% PPh₃ after several days. Increasing the reaction time from 17 to 24 h barely increased the reaction yield (entry 3), implying that a significantly longer time might be required for the reaction to reach completion. Surprisingly, the addition of a stoichiometric amount of PPh₃ did not accelerate the reaction; indeed, it completely shut down the reaction and yielded no product (entry 4). ¹H NMR spectra revealed the complete destruction of 2a within 5 min in the presence of a stoichiometric amount of PPh₃. When the concentration of 1a was increased to 0.2 M or greater, the reaction yield improved significantly (entries 1 and 5–7). Among the solvents tested for the reaction, MeCN provided the highest yield (entry 8); reactions performed in DMSO and DCM (data not shown) provided product yields lower than those obtained in THF and MeCN. The reactions of 1a in THF at concentrations of 0.4 and 0.2 M resulted in the same yields (entries 6 and 7). Because 1a is not soluble in MeCN at a concentration of 0.4 M, we considered the optimal concentration of 1a in MeCN to be 0.2 M. Decreasing the loading of the catalyst PPh₃ to 10 mol% improved the reaction yield by 4% (entry 10). The reaction yield decreased, however, after decreasing the catalyst loading of 5 mol% (entry 11). Increasing the number of equivalents of the activated acetylene 2a did not improve the reaction performance (entry 12). Careful monitoring revealed that the reaction required only 4 h to reach completion in MeCN (entry 13). Finally, decreasing the amount of 2a to 1.5 equivalents did not change the reaction yield (entry 14), but it did drop dramatically to 14% when we used 1.2 equivalents of 2a (entry 15).

Table 1.

Optimization of Dihydroquinoline Synthesis^a

entry	2a (equiv)	PPh3 (mol%)	solvent	concentrationb (M)	time (h)	yield (%)
1	2.0	20	THF	0.1	17	28
2 c	2.0	20	THF	0.1	17	28
3	2.0	20	THF	0.1	24	32
4	2.0	100	THF	0.1	24	0
5	2.0	20	THF	0.05	17	25
6	2.0	20	THF	0.2	17	67
7	2.0	20	THF	0.4	17	68
8	2.0	20	MeCN	0.2	17	71
9	2.0	20	MeCN	0.4	N/Ad	N/Ad
10	2.0	10	MeCN	0.2	17	75
11	2.0	5	MeCN	0.2	17	49
12	2.5	5	MeCN	0.2	17	47
13	2.0	10	MeCN	0.2	4	76
14	1.5	10	MeCN	0.2	4	76
15	1.2	10	MeCN	0.2	4	14

^aButynone 2a was added in one portion to a solution of 1a and PPh₃ in the indicated solvent.

^bConcentration of the aldehyde 1a.

^cAddition of butynone 2a over 2 h via syringe pump.

^dNot available.

The isolated dihydroquinoline adduct 3a was unstable and readily decomposed at room temperature.^5a Treating the vinylogous hemiaminal with acetyl chloride and pyridine resulted in the clean production of the stable quinoline 4a in excellent yield (Scheme 3a). In this two-pot procedure, decomposition of the unstable dihydroquinoline 3a during its isolation resulted in a lower yield of the quinoline product 4a. Such loss could be avoided through a one-pot procedure to directly convert the unstable dihydroquinoline intermediate into the corresponding quinoline. The ideal reagent for such a procedure would necessarily contain a “chloride” to trap the tosyl group in the form of the byproduct TsCl; in addition, it should transform the OH group into a good leaving group. Hydrogen chloride met these requirements; simply quenching the reaction with 1 M aqueous HCl provided the quinoline 4a in 88% yield together with TsCl as a byproduct (Scheme 3b). This higher yield for the isolated quinoline relative to that of the isolated dihydroquinoline confirmed the loss of the latter product through decomposition in the two-pot procedure.

Scheme 3.

(a) Quinoline Formation from Dihydroquinoline. (b) One-Pot Phosphine-Catalyzed Synthesis of Quinoline

Having optimized the one-pot procedure for the synthesis of the 3-substituted quinoline, we further examined the scope of this reaction for the synthesis of 3-acetylquinolines (Table 2). Regardless of the electron-donating or -withdrawing ability of the substituents on the aminobenzaldehyde, the reactions were highly efficient, generating the desired quinolines in high yields. Nevertheless, the nature of the substituents had a significant impact on the rate of the reaction. The reaction of the non-substituted N-tosyl-2-aminobenzaldehyde (1a) reached completion within 4 h in 88% yield (entry 1). The electronically similar N-tosyl-3-amino-2-naphthaldehyde (1b) was converted into the quinoline 4b in a comparable yield of 89% after a similar reaction time of 5 h (entry 2). The presence of electron-withdrawing groups significantly slowed the rates of the reactions (entries 3–5), whereas electron-donating groups accelerated them (entries 6 and 7). In general, the presence of a substituent, regardless of its electronic nature, had a positive impact on the yield of the reaction (entry 1 vs. entries 2–7).

Table 2.

One-Pot Phosphine-Catalyzed Syntheses of Substituted 3-Acetylquinolines^a

entry	substrate	product	time (h)	yield (%)b
1			4	88
2			5	89
3			19	94
4			19	96
5			11	95
6			1.5	99
7			1.5	92

^a2a (1.5 equiv.) was added in one portion to a solution of 1 (0.2 M) and PPh₃ (10 mol%) in MeCN.

^bIsolated yield.

The successful syntheses of the 3-acetylquinolines in Table 2 encouraged us to expand the scope of the reaction to include other 3-substituted quinolines (Table 3). In general, the reaction was highly efficient for acetylenic ketones, but much less efficient for other activated alkynes (entries 1–10 vs. entries 12 and 13). We obtained lower yields for the reactions performed with methyl propiolate or an acetylenic sulfone, due to formation of the corresponding simple Michael adducts with the aldehyde functionality intact (entries 12 and 13). With regard to the acetylenic ketone, the reactions of aryl acetylenyl ketones were faster and provided higher yields than those of alkyl acetylenyl ketones (entry 1 vs. entries 2–9). The electronic nature of the aryl group of the acetylenic ketone greatly impacted the reaction rate and yield. With electron-deficient aryl groups, the reactions required only a few minutes to reach completion in excellent yields (entry 2 vs. entries 3–8 and 11). In contrast, electron-rich aryl groups prolonged the reaction and resulted in excellent but lower yields (entry 2 vs. entries 9 and 10). We also examined the versatility of the reaction when using a multifunctional acetylenic ketone, namely a bis(acetylenic ketone); here, the reaction proceeded smoothly to form the bisquinoline product in good yield (entry 11).

Table 3.

One-Pot Phosphine-Catalyzed Syntheses of 3-Substituted Quinolines^a

entry	substrate	product	time (min)	yield (%)b
1			240	88
2			30	95
3			20	99
4			5	98
5			5	98
6			5	97
7			5	96
8			5	98
9			90	93
10			40	86
11c			5	63
12			600	61
13			5	30

^a2 (1.5 equiv.) was added in one portion to a solution of 1a (0.2 M) and PPh₃ (10 mol%) in MeCN.

^bIsolated yield.

^cDiacetylene 2q (0.10 mmol) was added to a solution of 1a (0.21 mmol, 0.21 M) and PPh₃ (20 mol%) in MeCN.

We further expanded the scope of the reaction to include less-reactive o-aminophenones as partners for the syntheses of 3,4-disubstituted quinolines. The reactions afforded the desired products, albeit in lower yields after longer reaction times (Table 3, entry 2 vs. Table 4). Longer reaction times were expected because of the lower reactivity of ketones relative to corresponding aldehydes. Among the selected o-aminophenones, those with larger R groups required the longest reaction times (entry 3 vs. entries 1, 2 and 4), although the size of the R group had only a minor impact on the reaction yield (entries 1–4).

Table 4.

One-Pot Phosphine-Catalyzed Syntheses of 3,4-Disubstituted Quinolines^a

entry	substrate	product	time(h)	yield(%)b
1			3.5	79
2			3.5	72
3			6.5	75
4			2.5	67

^a2b (1.5 equiv.) was added in one portion to a solution of 1 (0.2 M) and PPh₃ (10 mol%) in MeCN.

^bIsolated yield.

Mechanistic Discussion

Scheme 4 outlines three possible mechanistic scenarios. Mechanism 1 involves a general base catalysis. Nucleophilic addition of the free phosphine to the activated alkyne results in the phosphonium allenolate A, which acts as a base to activate the pronucleophile through deprotonation, resulting in a subsequent general base-catalyzed Michael/aldol reaction. Mechanism 2 is based on a nucleophilic phosphine catalysis, in which the phosphine is consumed and regenerated along the catalytic cycle; the ion pair B, which is also generated in mechanism 1, is presumably associated in a sufficiently tight manner to enforce the nucleophilic addition within the ion pair.⁹ Mechanism 3 is also based on a nucleophilic phosphine catalysis, where the aldol addition occurs immediately after the formation of the phosphonium allenolate A; hence, the ion pair B is not formed.

Scheme 4.

Possible Mechanistic Schemes for Phosphine-Catalyzed Dihydroquinoline Formation

Because we isolated the Michael adduct together with the quinoline product in the reaction of methyl propiolate (Table 3, entry 12),¹¹ we speculate that mechanism 3 was most unlikely to operate. As indicated in Table 5, the reaction proceeded to form the quinoline product in the presence of a catalytic amount of a non-nucleophilic base. This result supports the operation of the general base catalysis mechanism in this reaction.

Table 5.

Non-Nucleophilic Base Catalysis for Dihydroquinoline Synthesis

entry	catalyst	yield (%)a
1b	K2CO3	69
2b	Cs2CO3	71
3	1 M aq. NaOH	58

^aIsolated yield.

^bHeterogeneous reaction mixture.

In the hopes of seeing reaction intermediates that could help to identify the true mechanistic pathway out of the three possibilities discussed above, we used NMR spectroscopy to monitor the reaction between 1a and 2a in the presence of 10 mol% PPh₃ in CD₃CN; unfortunately, no intermediates were evident at any time during the course of the reaction. The ¹H NMR spectra of the reaction mixture revealed that the signal for the NH unit of reactant 1a disappeared within 10 min (Figure 1C). Apparently, the reaction was initiated rapidly in MeCN with partial deprotonation of the NH group; fast proton exchange made the NH proton undetectable, on the time scale of ¹H NMR spectroscopy, at 10.83 ppm (the presence of N-tosylaminobenzaldehyde 1a was verified through TLC analysis during the reaction period). At the same time, two new signals, corresponding to protons H^a and H^b of the dihydroquinoline adduct, were growing (Figures 1C–F). Because of rapid proton exchange, the proton of the OH group of the dihydroquinoline product was also undetectable in the ¹H NMR spectra recorded throughout the course of the reaction. In general, only the starting materials and the final dihydroquinoline products were evident (i.e., no intermediates were observed) at any time during the reactions monitored using ¹H NMR spectroscopy.

Figure 1.

¹H NMR spectra revealing the formation of the dihydroquinoline 3a. (A, B) Control experiments performed without (A) 3-butyn-2-one (2a) or (B) N-tosyl-2-aminobenzaldehyde (1a) in the reaction mixture; spectra recorded after 4 h. (C–F) Spectra of the reaction proper after (C) 10 min, (D) 1 h, (E) 3.5 h, and (F) 4 h.

Conclusion

We have developed an efficient one-pot procedure for the syntheses of 3-substituted and 3,4-disubstituted quinolines from the reactions of activated acetylenes with N-tosyl-2-aminobenzaldehydes and N-tosyl-2-aminobenzophenones, respectively. This approach provides a convenient and direct route toward 3-substituted quinolines, which are challenging to prepare using other methods. The reaction conditions are mild and many different substituents can be introduced without compromising yields.

Experimental Section

General Information

All reactions were performed in dry solvents under an Ar atmosphere and anhydrous conditions, unless otherwise indicated. DCM, THF, and MeCN were freshly distilled over CaH₂ prior to use. Anhydrous DMSO was used as received from a commercial source. All other reagents were used as received from commercial sources. Reactions were monitored through thin layer chromatography (TLC) on 0.25-mm SiliCycle silica gel plates and visualized under UV light and with permanganate or 2,4-dinitrophenylhydrazine (DNP) staining. Flash column chromatography (FCC) was performed using SiliCycle Silica-P Flash silica gel (60-Å pore size, 40–63 µm). IR spectra were recorded using a Jasco FT-IR 4100 spectrometer. NMR spectra of the dihydroquinoline 3a were obtained using Bruker Avance-500 instruments, calibrated to residual THF-d₈ as the internal reference (1.73 and 3.58 ppm for ¹H NMR spectra; 25.4 and 67.6 ppm for ¹³C NMR spectra). NMR spectra of the quinolines 4 were recorded using Bruker Avance-500 instruments, calibrated to CD(H)Cl₃ as the internal reference (7.26 and 77.0 ppm for ¹H and ¹³C NMR spectra, respectively). ¹H NMR spectral data are reported in terms of chemical shift (δ, ppm), multiplicity, coupling constant (Hz), and integration. ¹³C NMR spectral data are reported in terms of chemical shift (δ, ppm) and multiplicity, with the coupling constant (Hz) in the case of J_CF coupling. The following abbreviations indicate the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, br, broad. GC-MS data were recorded using an Agilent 6890-5975 GC mass spectrometer equipped with an autosampler and an HP5 column; samples were dissolved in DCM.

General Procedure for the Syntheses of Substrates 1

The N-tosylbenzaldehydes 1a–g were prepared from the corresponding anthranilic acids in three steps without purification of any intermediates.¹² The N-tosyl-o-aminophenones 1t and 1u were prepared directly from the corresponding o-aminophenones through a single tosylation step.¹³ The N-tosyl-o-aminophenones 1v and 1w were prepared from the corresponding 2-aminobenzonitriles in two steps, without purification of any intermediates.¹⁴

Syntheses of Substrates 2

The activated acetylene 2 were prepared in two steps, without purification of any intermediates, according to reported procedures.¹⁵

General Procedure for the Syntheses of Quinolines

o-Aminobenzaldehyde (1, 0.2 mmol), PPh₃ (5.3 mg, 10 mol%), and MeCN (1 mL) were added sequentially to a flame-dried flask (10 mL); unless otherwise noted, the mixture was stirred until complete dissolution occurred. The activated acetylene 2 (0.3 mmol) was added in one portion and then the mixture was stirred under Ar at room temperature. Upon completion of the reaction, 1 M aqueous HCl (1 mL) was added and then the mixture was stirred for 5 min before saturated aqueous NaHCO₃ (1 mL) was added to neutralize the mixture. The mixture was poured into a separatory funnel along with DCM (10 mL) and saturated aqueous NaHCO₃ (10 mL). The aqueous phase was separated and extracted with DCM (2 mL). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo; the residue was purified through flash column chromatography [ethyl acetate (EtOAc)/hexanes (Hex), 3:7, unless specified otherwise] to afford the desired quinoline product.

1-(1-Tosyl-1,4-dihydroquinolin-3-yl)ethanone (3a)

To a flame-dried flask (10 mL) were sequentially added N-tosyl 2-aminobenzaldehyde (1a) (0.2 mmol), PPh₃ (5.3 mg, 10 mol%), and MeCN (1 mL). The mixture was stirred until complete dissolution and then 3-butyn-2-one (2) (23.5 µL, 0.3 mmol) was added in one portion. The mixture was stirred under argon at room temperature; upon completion of the reaction (4.0–4.5 h), the mixture was concentrated in vacuo and purified through flash column chromatography (gradient EtOAc/Hex, 3:7 to 1L1) to furnish a slightly yellow solid (52.1 mg, 76% yield). IR (film) ν_max 3391, 3088, 3050, 3006, 2923, 1645, 1632, 1597, 1566, 1485, 1456, 1343, 1210, 1160, 1088, 1017, 1009 cm⁻¹; ¹H NMR (500 MHz, THF-d₈) δ 7.81 (d, J = 8.1 Hz, 1H), 7.41–7.37 (m, 4H), 7.32 (s, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 6.1 Hz, 1H), 5.85 (d, J = 6.1 Hz, 1H), 2.32 (s, 3H), 2.26 (s, 3H); ¹³C NMR (125 MHz, THF-d₈) δ 194.2, 143.3, 137.0, 135.0, 134.2, 132.2, 130.0, 128.9, 128.8, 126.5, 125.6, 124.8, 124.6, 73.3, 24.1, 20.2; HRMS (ESI-TOF) m/z: [M − OH]⁺ Calcd for C₁₈H₁₆NO₃S 326.0851; Found 326.0847.

1-(Quinolin-3-yl)ethanone (4a).¹⁶

30.1 mg, 88% yield; slightly yellow solid. M.p. 98–99 °C. IR (film) ν_max 3065, 3009, 2920, 1681, 1615, 1587, 1571, 1493, 1371 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.42 (s, 1H), 8.69 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 2.73 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.5, 149.5, 149.0, 137.3, 131.9, 129.22, 129.19, 129.1, 127.5, 126.7, 26.7; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₁H₁₀NO 172.0762; Found 172.0762.

1-(Benzo[g]quinolin-3-yl)ethanone (4b)

39.5 mg, 89% yield; bright yellow solid. M.p. 150–152 °C. IR (film) ν_max 3046, 2998, 2922, 1676, 1612, 1532, 1352, 1215 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.47 (s, 1H), 8.84 (s, 1H), 8.70 (s, 1H), 8.51 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.62–7.55 (m, 2H), 2.76 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.5, 149.5, 149.0, 137.3, 131.9, 129.22, 129.19, 129.1, 127.5, 126.7, 26.7; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₂NO 222.0919; Found 222.0921.

1-[7-(Trifluoromethyl)quinolin-3-yl]ethanone (4c)

44.8 mg, 94% yield; white crystalline solid. M.p. 126–127 °C. IR (film) ν_max 3059, 3020, 2929, 1689, 1594, 1464, 1124 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.50 (s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 2.77 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.1, 150.4, 148.7, 136.8, 133.3 (q, J = 32.9 Hz), 130.5, 130.4, 128.3, 127.2 (q, J = 4.4 Hz), 123.5 (q, J = 271.0 Hz), 123.1 (q, J = 4.5 Hz), 26.8; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₉F₃NO 240.0636; Found 240.0632.

1-(7-Fluoroquinolin-3-yl)ethanone (4d)

36.4 mg, 96%; white solid. M.p. 116–118 °C. IR (film) ν_max 3051, 2923, 1670, 1619, 1602, 1579, 1274, 1193 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.42 (s, 1H), 8.70 (s, 1H), 7.95 (dd, J = 8.9, 5.1 Hz, 1H), 7.77 (dd, J = 9.8, 2.3 Hz, 1H), 7.42 (dt, J = 8.7, 2.5, 1H), 2.73 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.2, 164.5 (d, J = 254.8 Hz), 150.9 (d, J = 12.7 Hz), 150.2, 140.0, 131.5 (d, J = 10.5 Hz), 128.8, 123.8, 118.2 (d, J = 25.7 Hz), 113.3 (d, J = 20.7 Hz), 26.7; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₁H₉FNO 190.0668; Found 190.0670.

1-(6,7-Difluoroquinolin-3-yl)ethanone (4e)

39.5 mg, 95% yield; white solid. M.p. 151–153 °C. IR (film) ν_max 3061, 2923, 1682, 1595, 1505, 1475, 1347, 1253, 1234 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.39 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 7.90 (dd, J = 7.7, 7.7 Hz, 1H), 7.68 (dd, J = 8.3, 8.3 Hz, 1H), 2.74 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.0, 153.7 (dd, J = 257.0, 17.8 Hz), 150.6 (dd, J = 257.0, 17.8 Hz), 147.1 (d, J = 11.2 Hz), 136.2, 129.3, 123.8 (d, J = 7.1 Hz), 115.9 (d, J = 17.2 Hz), 114.3 (d, J = 17.2 Hz), 26.7; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₁H₈F₂NO 208.0574; Found 208.0584.

1-(6,7-Dimethoxyquinolin-3-yl)ethanone (4f).¹⁷

EtOAc/Hex, 1:1. 45.7 mg, 99% yield; white solid. M.p. 160–163 °C. IR (film) ν_max 3008, 2960, 2925, 2831, 1667, 1597, 1504, 1438, 1427, 1228, 1144, 1003 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.24 (s, 1H), 8.56 (s, 1H), 7.46 (s, 1H), 7.14 (s, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 2.71 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.6, 154.4, 150.4, 147.4, 147.3, 135.0, 127.9, 122.4, 107.8, 106.0, 56.2, 56.0, 26.6; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₁₄NO₃ 232.0974; Found 232.0964.

1-(6-Methoxyquinolin-3-yl)ethanone (4g)

37.1 mg, 92% yield; light-yellow solid. M.p. 122–124 °C. IR (film) ν_max 2956, 2923, 2852, 1682, 1619, 1595, 1503, 1368, 1227, 1023 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.25 (s, 1H), 8.57 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.45 (dd, J = 9.0, 2.5 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 3.93 (s, 3H), 2.71 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.8, 158.3, 146.7, 146.0, 135.8, 130.6, 129.4, 127.9, 127.8, 124.8, 55.5, 26.8; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₁₂NO₂ 202.0868; Found 202.0870.

Phenyl(quinolin-3-yl)methanone (4h).⁷

44.2 mg, 95% yield; crystalline yellow solid. M.p. 73–75 °C. IR (film) ν_max 3052, 1647, 1616, 1597, 1571, 1287, 1243 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.33 (s, 1H), 8.56 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.88–7.86 (m, 3H), 7.69–7.63 (m, 2H), 7.58–7.48 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 194.8, 150.3, 149.4, 138.7, 136.9, 133.0, 131.8, 129.97, 129.95, 129.4, 129.1, 128.6, 127.5, 126.5; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₆H₁₂NO 234.0919; Found 234.0915.

Naphth-1-yl(quinolin-3-yl)methanone (4i).⁷

56.3 mg, 99% yield; pale-yellow oil. IR (film) ν_max 3051, 1652, 1616, 1589, 1568, 1493, 1286, 1237, 1186 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.43 (s, 1H), 8.54 (s, 1H), 8.21–8.19 (m, 2H), 8.08 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.87–7.84 (m, 2H), 7.66 (d, J = 7.1 Hz, 1H), 7.62–7.53 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ 196.3, 150.4, 149.7, 139.5, 135.2, 133.8, 132.0, 130.8, 130.7, 129.4, 129.3, 128.5, 128.4, 127.6, 127.5, 126.7, 126.6, 125.4, 124.3; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₀H₁₄NO 284.1075; Found 284.1072.

2-Fluorophenyl(quinolin-3-yl)methanone (4j)

49.2 mg, 98% yield; light-yellow solid. M.p. 84–86 °C. IR (film) ν_max 3086, 1664, 1610, 1595, 1568, 1448, 1296, 1213 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.33 (s, 1H), 8.54 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 14.1 Hz, 1H), 7.62–7.59 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.20 (t, J = 8.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 191.7, 160.1 (d, J = 253.6 Hz), 149.7, 138.9, 133.9 (d, J = 8.4 Hz), 132.1, 130.9 (d, J = 2.7 Hz), 129.9, 129.4 (d, J = 10.1 Hz), 127.5, 126.6, 126.0 (d, J = 14.4 Hz), 124.6 (d, J = 3.8 Hz), 116.4 (d, J = 21.8 Hz); HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₆H₁₁FNO 252.0825; Found 252.0829.

4-Bromophenyl(quinolin-3-yl)methanone (4k)

61.2 mg, 98% yield; white crystalline solid. M.p. 115–117 °C. IR (film) ν_max 3090, 3056, 1645, 1618, 1584, 1566, 1491, 1366, 1231, 1168, 1069 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.30 (s, 1H), 8.53 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.65 (t, J = 8.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 193.7, 150.0, 149.5, 138.6, 135.7, 131.94, 131.92, 131.4, 129.6, 129.5, 129.1, 128.2, 127.6, 126.4; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₆H₁₁BrNO 312.0024; Found 312.0013.

3,4-Dichlorophenyl(quinolin-3-yl)methanone (4l)

58.4 mg, 97% yield; light-yellow solid. M.p. 112–113 °C. IR (film) ν_max 3076, 1637, 1617, 1577, 1385, 1293, 1238 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.28 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 1.9 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.95–7.92 (m, 2H), 7.87 (ddd, J = 8.5, 7.0, 1.3 Hz, 1H), 7.69–7.61 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 192.4, 149.8, 149.6, 138.7, 136.5, 133.4, 132.1, 131.6, 130.7, 129.5, 129.12, 129.10, 128.9, 127.8, 126.4; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₆H₁₀Cl₂NO 302.0139; Found 302.0135.

3-(Quinoline-3-carbonyl)benzonitrile (4m)

49.5 mg, 96% yield; off-white crystalline solid. M.p. 105–107 °C. IR (film) ν_max 3067, 2227, 1653, 1616, 1596, 1567, 1291, 1179 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.30 (d, J = 2.7 Hz, 1H), 8.53 (d, J = 2.7 Hz, 1H), 8.21 (d, J = 10.6 Hz, 1H), 8.14 (s, 1H), 8.09 (dt, J = 9.8, 1.9 Hz, 1H), 7.95–7.92 (m, 2H), 7.89 (t, J = 9.7 Hz, 1H), 7.69 (q, J = 10.1 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 192.6, 149.74, 149.66, 138.9, 137.9, 135.8, 133.7, 133.2, 132.4, 129.6, 129.5, 129.2, 128.7, 127.9, 126.3, 117.6, 113.2; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₇H₁₁N₂O 259.0871; Found 259.0882.

3-Nitrophenyl(quinolin-3-yl)methanone (4n)

54.6 mg, 98% yield; white solid. M.p 138–140 °C. IR (film) ν_max 3086, 1642, 1612, 1527, 1491, 1346, 1285 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.31 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.50 (d, J = 8.5 Hz, 1H), 8.20 (t, J = 7.3 Hz, 2H), 7.94 (d, J = 8.5 Hz, 1H), 7.90 (t, J = 7.3 Hz, 1H), 7.77 (t, J = 7.3 Hz, 1H), 7.67 (t, J = 7.3 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 192.4, 149.71, 149.70, 148.2, 138.9, 138.3, 135.3, 132.4, 129.9, 129.5, 129.2, 128.7, 127.9, 127.2, 126.4, 124.5; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₆H₁₁N₂O₃ 279.0770; Found 279.0776.

3,4-Dimethoxyphenyl(quinolin-3-yl)methanone (4o)

54.6 mg, 93% yield; white solid. M.p. 93–95 °C. IR (film) ν_max 3042, 2995, 2934, 1637, 1592, 1580, 1513, 1418, 1295, 1264, 1247, 1228, 1143, 1113, 1020 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.28 (d, J = 1.3 Hz, 1H), 8.54 (d, J = 1.3 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.85 (t, J = 8.2 Hz, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.1, 150.4, 148.7, 136.8, 131.9, 129.22, 129.19, 129.1, 127.5, 126.7, 26.7; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₈H₁₆NO₃ 294.1130; Found 294.1130.

Quinolin-3-yl(thien-2-yl)methanone (4p).⁷

41.1 mg, 86% yield; white solid. M.p. 89–91 °C. IR (film) ν_max 3102, 3065, 1629, 1617, 1588, 1517, 1492, 1410, 1366, 1292, 1251, 1062 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.33 (s, 1H), 8.64 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.79 (d, J = 5.0 Hz, 1H), 7.70 (d, J = 5.0 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 5.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 186.1, 149.5, 149.3, 143.1, 137.7, 135.01, 134.99, 131.7, 130.6, 129.4, 129.0, 128.3, 127.6, 126.6; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₄H₁₀NOS 240.0483; Found 240.0494.

1,4-Phenylenebis(quinolin-3-ylmethanone) (4q)

Synthesized from o-aminobenzaldehyde 1 (57.8 mg, 0.21 mmol), PPh₃ (5.3 mg, 20 mol%), and the activated bis-acetylene 2q (18.2 mg, 0.1 mmol) in MeCN (1 mL); gradient: EtOAc/Hex, from 3:7 to 1:1. 24.5 mg, 63% yield; pale-yellow powder. M.p. 237–239 °C. IR (film) ν_max 3023, 1641, 1614, 1595, 1571, 1366, 1290, 1246, 1122 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.38 (s, 2H), 8.61 (s, 2H), 8.22 (d, J = 8.2 Hz, 2H), 8.03 (s, 4H), 7.96 (d, J = 8.2 Hz, 2H), 7.89 (t, J = 8.2 Hz, 2H), 7.68 (t, J = 8.2 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 194.0, 150.0, 149.6, 140.4, 139.1, 132.2, 130.0, 129.5, 129.22, 129.18, 127.8, 126.5; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₆H₁₇N₂O₂ 389.1290; Found 389.1291.

Methyl Quinoline-3-carboxylate (4r).¹⁸

22.7 mg, 61/% yield; white crystalline solid. M.p. 69–70 °C. IR (film) ν_max 3056, 2948, 2924, 2849, 1714, 1618, 1572, 1433, 1367, 1290, 1240, 1193, 1100 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.44 (s, 1H), 8.84 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 4.01 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 165.7, 149.9, 149.7, 138.7, 131.8, 129.4, 129.0, 127.3, 126.7, 122.9, 52.4; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₁H₁₀NO₂ 188.0712; Found 188.0709.

Quinolin-3-yl(tosyl)methanone (4s).¹⁹

17.0 mg, 30% yield; yellow crystalline solid. M.p. 165–170 °C. IR (film) ν_max 3068, 3056, 2925, 2851, 1616, 1593, 1585, 1497, 1312, 1304, 1290, 1153, 1140, 1091 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.25 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.86 (t, J = 8.4 Hz, 3H), 7.67 (t, J = 8.4 Hz, 1H), 7.32 (d, J = 8.3 Hz, 2H), 2.39 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 149.2, 147.0, 144.8, 137.9, 136.5, 135.0, 132.5, 130.1, 129.5, 129.1, 128.2, 127.8, 126.3, 21.5; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₆H₁₄NO₂S 284.0745; Found 284.0753.

4-Methylquinolin-3-yl(phenyl)methanone (4t).⁷

EtOAc/Hex, 1:5. 40.3 mg, 82% yield; yellow crystalline solid. M.p. 82–86 °C. IR (film) ν_max 3059, 3030, 2918, 1658, 1645, 1581, 1494, 1449, 1248, 1161 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.82 (s, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.85–7.78 (m, 3H), 7.68–7.61 (m, 2H), 7.49 (t, J = 7.8 Hz, 2H), 2.67 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.9, 148.5, 148.0, 143.5, 137.4, 133.8, 131.8, 130.3, 130.1, 130.0, 128.7, 127.5, 127.2, 124.3, 15.8; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₇H₁₄NO 248.1075; Found 248.1064.

Phenyl(4-phenylquinolin-3-yl)methanone (4u).⁷

EtOAc/Hex, 1:5. 44.6 mg, 72% yield; yellow crystalline solid. M.p. 108–110 °C. IR (film) ν_max 3062, 1654, 1570, 1486, 1324 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.83–7.78 (m, 2H), 7.63–7.61 (m, 2H), 7.57–7.54 (m, 1H), 7.46–7.42 (m, 1H), 7.30–7.25 (m, 7H); ¹³C NMR (125 MHz, CDCl₃) δ 196.7, 148.8, 148.4, 146.9, 137.3, 134.8, 133.1, 131.7, 130.4, 130.0, 129.7, 129.6, 128.4, 128.14, 128.12, 127.4, 126.7, 126.3; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₂H₁₆NO 310.1232; Found 310.1230.

4-Cyclohexylquinolin-3-yl(phenyl)methanone (4v)

47.5 mg, 75% yield; pale-yellow oil. IR (film) ν_max 3066, 2927, 2853, 1665, 1577, 1498, 1448, 1282, 1241 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.64 (s, 1H), 8.34 (br s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 6.3 Hz, 2H), 7.75 (t, J = 7.1 Hz, 1H), 7.61 (q, J = 7.3 Hz, 2H), 7.46 (t, J = 7.3 Hz, 2H), 3.25 (br s, 1H), 1.97 (br s, 2H), 1.85–1.77 (m, 4H), 1.26 (br s, 4H); ¹³C NMR (125 MHz, CDCl₃) δ 198.2, 150.7, 148.7, 148.1, 137.6, 133.8, 132.0, 130.7, 130.1, 129.6, 128.9, 128.6, 126.7, 126.6, 32.0, 27.0, 25.7; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₂H₂₂NO 316.1701; Found 316.1699.

4-Cyclopropylquinolin-3-yl(phenyl)methanone (4w)

36.6 mg, 67% yield; pale-yellow oil. IR (film) ν_max 3064, 3005, 2922, 1654, 1596, 1567, 1499, 1447, 1322, 1279, 1241, 1226, 1170 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.83 (s, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.85–7.79 (m, 3H), 7.68–7.66 (m, 1H), 7.65–7.59 (m, 1H), 7.59–7.46 (m, 2H), 2.11–2.08 (m, 1H), 0.95–0.93 (m, 2H), 0.59–0.57 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 197.2, 148.9, 148.5, 147.4, 138.0, 133.4, 132.7, 130.3, 130.0, 129.6, 128.6, 128.3, 127.1, 125.5, 12.8, 8.2; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₉H₁₆NO 274.1232; Found 274.1230.