Synthesis of 2‑Quinolones via Thiolate-Mediated Cyclization of (E)‑2-Aminocinnamic Acid Derivatives

Abstract

A new protocol for the synthesis of 2-quinolones from (E)-2-aminocinnamic acid derivatives has been developed, employing a thiolate as a nucleophilic promoter for cyclization. The reaction begins with conjugate addition of the thiolate to the 2-aminocinnamic acid derivatives, generating β-sulfide-substituted dihydrocinnamic acid intermediates. These intermediates can adopt conformations that bring the amino and carboxyl groups into close proximity through free rotation about the C_α–C_β single bond. Subsequent intramolecular condensation between the amino and carboxyl groups, followed by elimination of hydrogen sulfide, furnishes the desired 2-quinolones. A broad range of 2-aminocinnamic acid derivatives are compatible with this transformation, delivering the corresponding 2-quinolone derivatives in excellent yields. Furthermore, this method is also applicable to the synthesis of all regioisomers of 2-aza-quinolones from 2-amino-aza-cinnamate derivatives. The simple operation, facile isolation of quinolones by recrystallization, and gram-scale scalability further highlight the practical utility of this protocol.

1. Introduction

Quinolones are recognized as privileged scaffolds present in numerous biologically active molecules and pharmaceuticals. In particular, the nature and position of substituents on the quinolone core have a profound impact on their biological activities. Consequently, extensive efforts have been devoted to the synthesis of quinolone derivatives bearing diverse substituents at specific positions. While 4-quinolones have long served as key building blocks in pharmaceuticals, particularly antibiotics, in recent years there has been growing interest in 2-quinolones within the organic and medicinal chemistry communities (Figure ). This increasing attention has spurred substantial efforts toward developing efficient synthetic strategies for 2-quinolones.

1.

Representative biologically active molecules bearing a 2-quinoline motif.

Conventionally, 2-quinolones have been synthesized through condensation reactions between aniline derivatives and suitable carbonyl precursors. , For example, the Friedländer-type reaction involves a base-assisted intermolecular condensation between 2-aminoaryl ketones A and dialkyl malonates. In this process, the Knoevenagel condensation of 2-aminoaryl ketones A with malonates generates 2-(2-aminobenzylidene)­malonates I, which subsequently undergo intramolecular amide bond formation between the amino group and the ester moiety, thereby affording quinolone derivatives B bearing an ester substituent at the C3-position (Scheme a).

1. (a) Classical Friedlander-Type Cyclization for the Synthesis of Quinolines. (b) Comparison of the Reactivity of Friedlander Intermediates I with that of 2-Aminocinnamic Acid Derivatives 1 in the Synthesis of 2-Quinolones via Condensative Cyclization. (c) Comparison of Previous Protocols and This Work for Quinolone Synthesis via Condensative Cyclization of 2-Aminocinnamic Acid Derivatives 1 .

Inspired by the classical Friedländer-type cyclization, we envisioned that 2-quinolone derivatives 2 could be synthesized from 2-aminocinnamic acid derivatives 1 through an analogous intramolecular condensation between the carboxyl and amino groups. However, despite their structural simplicity and ready accessibility, 2-aminocinnamic acid derivatives 1 have been rarely explored as direct precursors for 2-quinolone synthesis. In contrast to the conventional Friedländer intermediates I, which possess an α-ester moiety and adopt a geometry in which the carboxyl and amino groups are aligned in the Z-configuration with respect to the olefinic double bond, 2-aminocinnamic acid derivatives 1 lack this α-ester functionality and preferentially exist in the more stable E-configuration. This geometric arrangement places the two reactive groups too far apart to undergo effective condensation, thereby rendering the direct intramolecular cyclization into 2-quinolones unfeasible (Scheme b). To overcome this intrinsic structural limitation, several approaches have been developed in which the more stable E-isomer is converted into the less stable Z-isomer, thereby enabling productive condensation between the carboxyl and amino groups to furnish the desired quinolones (Scheme c). , However, these reported protocols generally require harsh thermal conditions or transition-metal catalysis to promote E/Z isomerization, which can restrict substrate scope, limit functional group tolerance, and reduce practicality for large-scale synthesis. Consequently, the development of mild, operationally simple, and transition-metal-free methods for accessing 2-quinolones directly from 2-aminocinnamic acids remains a highly significant and desirable objective.

Herein, we describe the development of a novel approach for the synthesis of 2-quinolones from 2-aminocinnamic acid derivatives, employing a thiolate as a nucleophilic promoter to facilitate condensative cyclization (Scheme c). Conjugate addition of the thiolate to the 2-aminocinnamic acid derivatives furnishes the corresponding 2-aminodihydrocinnamic acid intermediates, which can adopt an s-cis conformation through free rotation about the C_α–C_β single bond, bringing the amino and carboxyl groups into close proximity. Subsequent intramolecular condensation between these groups, followed by elimination of hydrogen sulfide, delivers the desired 2-quinolones.

This protocol accommodates a broad range of 2-aminocinnamic acid derivatives, affording the corresponding quinolones in excellent yields. Moreover, it is readily applicable to the synthesis of all regioisomers of 2-aza-quinolones from the corresponding 2-amino-aza-cinnamate derivatives. Other key features of this transformation include its operational simplicity, facile product isolation by recrystallization, and scalability to gram scale quantities.

2. Result and Discussions

Our group has been engaged in a research program aimed at the development of novel protocols for the synthesis of heteroaromatic compounds from acyclic precursors, employing a nucleophile as a cyclization catalyst. , For example, we previously developed efficient methods for the synthesis of 2-substituted quinolines from 2-aminostyryl ketones, including 2-aminochalcone derivatives, using halides and benzylamine as nucleophilic catalysts.

Given that nucleophile-catalyzed cyclization efficiently converts diverse 2-aminostyryl ketone derivatives into the 2-substituted quinolines in excellent yields, we hypothesized that a similar strategy could transform 2-aminocinnamic acid derivatives 1 into the corresponding 2-quinolone derivatives 2 (Scheme ). In this proposed mechanism, conjugate addition of a nucleophile to 2-aminocinnamic acid derivatives 1 generates 2-aminodihydrocinnamic acid intermediates I _A bearing the nucleophile at the β-position. Free rotation about the C_α–C_β single bond in I _A affords the s-cis conformer I _B , which brings the amino and carboxyl groups into close proximity. This arrangement facilitates intramolecular condensation to give dihydroquinolones, and subsequent elimination of the nucleophile furnishes the desired 2-quinolones 2. While this hypothesis is mechanistically appealing, we were concerned about the reactivity of 2-aminocinnamic acid derivatives 1 relative to 2-aminostyryl ketones (X = alkyl or aryl in Scheme ). Despite their structural similarity, 2-aminocinnamic acid derivatives 1 exhibit intrinsically lower electrophilicity at the β-position than 2-aminostyryl ketones, which can lead to reduced efficiency or require harsher reaction conditions.

2. Working Hypothesis.

With this working hypothesis and the potential concerns in mind, we investigated the reaction parameters for this transformation using ethyl 2-aminocinnamate 1a as a model substrate (Table ). As a first variable, we examined different nucleophiles as potential catalysts (entries 1–7), beginning with those previously shown to be effective in the dehydrative cyclization of 2-aminostyryl ketones. However, when these nucleophilic catalysts were applied to the condensative cyclization of the ester substrate 1a, no cyclization occurred, and 1a remained unchanged even after 24 h (entries 1–4).

1. Screening of Nucleophiles .

entry	nucleophile	solvent	temp (°C)	time (h)	conversion (%)	%tield of 2a
1	TBAI	1,4-dioxane	rt	24	0	-
2	Benzylamine	1,4-dioxane	rt	24	0	-
3	PPh3	1,4-dioxane	rt	24	0	-
4	n-PrSH	1,4-dioxane	rt	24	0	-
5	NaOEt	EtOH	rt	3	100	-
6	n-PrSH + NaOH	1,4-dioxane	rt	24	46	8
7	n-PrSH + NaOH	toluene	rt	24	30	-
8	n-PrSH + NaOH	DCE	rt	24	0	-
9	n-PrSH + NaOH	EtOH	rt	24	100	32
10	n-PrSH + NaOH	ACN	rt	24	82	36
11	n-PrSH + NaOH	DMSO	rt	24	77	77
12	n-PrSH + NaOH	DMF	rt	6	100	>99
13	n-PrSH + NaOH	DMF	40	3	100	>99
14	n-PrSH + NaOH	DMF	50	2	100	>99
15	n-PrSH + NaOH	DMF	60	1	100	>99
16	n-PrSH + NaOH	DMF	70	1	100	>99
17	n-PrSH + NaOH	DMF	80	1	100	>99
18	n-PrSNa	DMF	60	1	100	>99
19	n-PrSNa	DMF	60	24	61	61
20	n-PrSNa	DMF	60	24	22	22
21	n-PrSNa	DMF	60	24	14	14
22	n-PrSH + NaOH	DMF	60	24	56	45

^aReaction conditions: 1a (0.30 mmol), nucleophile (0.36 mmol), solvent (3.0 mL) at indicated temperature.

^bDetermined by ¹H NMR analysis of the crude mixutrure.

^c2-Aminocinnamic acid was obtained via hydrolysis of the ester moiety.

^d n-PrSH (120 mol %) and base (150 mol %) were used.

^eThe crude ¹H NMR spectrum displayed only the signals of 2a, with no detectable starting material, intermediates, or side products.

^fPregenerated n-PrSNa (120 mol %) was used instead.

^g n-PrSNa (50 mol %) were used.

^h n-PrSNa (20 mol %) were used.

ⁱ n-PrSNa (10 mol %).

^j n-PrSH (60 mol %) and NaOH (75 mol %) were used.

To promote the cyclization of 1a, we next employed the anionic forms of nucleophiles, anticipating enhanced nucleophilicity (entries 5–6). In this context, ethoxide was first examined as a potential catalyst. However, instead of inducing cyclization, ethoxide led to complete hydrolysis of 1a, affording 2-aminocinnamic acid as the sole product (entry 5). To favor the Michael addition step over direct nucleophilic attack at the carboxyl group, we then turned to a softer nucleophile. In particular, thiolate, generated in situ from a thiol and a base, was evaluated as a catalyst for the condensative cyclization of 1a. When 1a was treated with thiolate generated from n-PrSH and NaOH, quinolone 2a was obtained, ableit in low yield (entry 6).

Although quinolone 2a was obtained in low yield, this result supported the feasibility of our hypothesis that quinolones could be synthesized from 2-aminocinnamic acid derivatives using a nucleophile as the cyclization catalyst. To further enhance the efficiency of this transformation, we next investigated the effect of the reaction medium (entries 6–12). The choice of solvent had a pronounced influence on the reaction efficiency. No desired product 2a was observed in toluene or 1,2-dichloroethane (entries 7 and 8). By contrast, the reactions proceeded smoothly in polar solvents such as EtOH, acetonitrile, DMSO, and DMF, although the efficiency of the transformation varied depending on the reaction medium (entries 9–12). Among the solvents tested, the reaction in DMF afforded the desired product 2a with the highest efficiency, giving a quantitative yield within 6 h (entry 12). Consequently, DMF was selected for further investigation.

With these results in hand, we next explored the effect of reaction temperature on this transformation (entries 12–17). The reaction rate increased with temperature and plateaued above 60 °C. Notably, at all reaction temperature examined, the reactions proceeded cleanly without formation of side products. Although this transformation even proceeded at room temperature, we selected 60 °C as the optimal reaction temperature to ensure the reaction efficiency (entry 15). Next, we further explored the effect of the mode of n-PrSNa generation on the transformation. When the reaction was performed using pregenerated n-PrSNa instead of in situ–generated n-PrSNa, the reaction proceeded with comparable efficiency, affording the desired product 2a in quantitative yield (entry 18). Lastly, we investigated the use of a catalytic amount of thiolate; however, the efficiency was markedly reduced compared with that of the stoichiometric reaction. When 2-aminocinnamate 1a was treated with a catalytic amount of thiolate, the starting material was not completely consumed, and quinolone 2a was obtained in an equimolar amount relative to the thiolate used (entries 19–21). Furthermore, because the in situ–generated thiolate showed similar reactivity to the pregenerated thiolate even under catalytic conditions (entries 15 and 18), the in situ–generated thiolate was employed as the promoter for this cyclization reaction in subsequent studies.

With these optimized conditions in hand, we investigated the influence of the carboxylic acid moiety on this reaction (Table ). First, we examined the effect of the ester substituent of 2-aminocinnamate (entries 1–5). All evaluated esters of 2-aminocinnamic acid, irrespective of the O-substituent (alkyl or aryl), underwent thiolate-promoted condensative cyclization to afford quinolone 2a in quantitative yield.

2. Effect of Cinnamic Acid Moiety .

entry	X	temp (°C)	time (h)	% yield of 2a
1	OEt	60	1	>99
2	OMe	60	1	>99
3	Oi-Pr	60	1	>99
4	Ot-Bu	60	1	>99
5	OPh	60	1	>99
6	NHBn	100	24	72
7	NEt2	100	3	>99
8	N(CH2)5	100	3	>99

^aReaction conditions: 1 (0.30 mmol), n-PrSH (0.36 mmol), NaOH (0.45 mmol), DMF (3.0 mL) at indicated temperature.

^bDetermined by ¹H NMR analysis of the crude mixture.

^cTwo equivalents of thiolate were used.

^dAn unidentifiable side-product was obtained along with 2a.

Next, we examined the amides of 2-aminocinnamic acid in this transformation (entries 6–8). As expected, the lower electrophilicity of the carboxyl group in amides resulted in significantly reduced reactivity compared to the corresponding esters. To promote the condensative cyclization, the reactions were carried out at 100 °C with an increased amount of thiolate. Furthermore, the amide structure significantly influenced the efficiency of the reaction. Tertiary amides afforded quinolone 2a in quantitative yield (entries 7 and 8), whereas the secondary amide gave 2a in 72% yield even with a much longer reaction time (entry 6).

With the optimized reaction conditions in hand {n-PrSH (120 mol %), NaOH (150 mol %), DMF, 60 °C, open flask}, we next examined the substrate scope of 2-aminocinnamates 1 (Table ). We first examined the effect of substituents at the C5 position of 2-aminocinnamates 1 (entries 1–9). The electronic nature of these substituents had little impact on the reaction, as all C5-substituted 2-aminocinnamates 1 furnished the corresponding quinolones 2 in high to excellent yields, irrespective of the electronic nature of the substituent. The reaction proceeded efficiently regardless of the protecting group on the phenolic OH (entries 2–3). Furthermore, even substrates bearing a free OH group were directly applicable to this protocol without the need for protection (entry 4). Next, we investigated the effect of substituent position on the phenyl ring of 2-aminocinnamates 1. Interestingly, the substituent position had little influence on the reaction efficiency, with the desired quinolones 2 were obtained in comparable yields regardless of substitution pattern (entries 2 and 10, 6 and 11, 9 and 12). This protocol was also applicable to multisubstituted 2-aminocinnamate derivatives 1, which furnished the corresponding polysubstituted quinolones 2 (entries 13 and 14). In addition, the reaction was applicable to 2-aminocinnamate derivatives bearing α- or β-substituents, furnishing the corresponding quinolone products in high yields (entries 15 and 16). Notably, all quinolone products could be readily isolated by simple recrystallization, as they precipitated upon quenching the reaction mixture with water.

3. Substrate Scope .

^aReaction conditions: 1 (0.30 mmol), n-PrSH (0.36 mmol), NaOH (0.45 mmol), DMF (3.0 mL) at 60 °C.

^bIsolation yield of 2.

^cAt 40 °C.

The substitution of a carbon atom with nitrogen can significantly alter the biological activity of the parent ring system, and the development of regioselective methods for introducing nitrogen into (hetero)­cyclic frameworks has therefore attracted considerable attention in both synthetic and medicinal chemistry. Given the broad substrate scope of our quinolone synthesis from 2-aminocinnamates, we envisioned that aza-quinolones could be similarly accessed from aza-analogues of 2-aminocinnamic acid derivatives via thiolate-mediated condensative cyclization.

Based on this idea, we applied our protocol to the synthesis of 2-aza-quinolones 4 from 2-amino-aza-cinnamates 3 (Table ). Notably, aza-cinnamates 3 were applicable to this protocol without further optimization. Furthermore, the method proved effective for all regioisomers of aza-cinnamates 3, affording the corresponding aza-quinolones 4 in high yields regardless of the nitrogen position.

4. Synthesis of Aza-Quinolones 4 from 2-Amino-Aza-Cinnamates 3 .

^aReaction conditions: 3 (0.30 mmol), n-PrSH (0.36 mmol), NaOH (0.45 mmol), DMF (3.0 mL) at 60 °C.

^bIsolation yield of 2.

Having established the substrate scope, we next turned our attention to demonstrating the synthetic utility of this protocol (Scheme ). To evaluate its practicality, the reaction was conducted on gram scale. When 10 mmol of 2-aminocinnamate 1h was subjected to the standard conditions, quinolone 2h was obtained in 92% yield (Scheme a). Importantly, 2h could be readily isolated by removing n-PrSNa through simple aqueous extraction, followed by recrystallization.

3. Synthetic Utility.

To further showcase the synthetic versatility of this protocol, the resulting quinolone products were transformed into key intermediates of biologically active compounds (Scheme b). These transformations highlight the applicability of the present methodology to the synthesis of pharmacologically relevant molecules as illustrated in Figure .

Demethylation of quinolone 2j with BBr₃ afforded compound 5 in 72% yield, a known intermediate in the synthesis of brexpiprazole, an atypical antipsychotic agent. Bromoquinolone 2h underwent cyanation under Rosenmund reaction conditions (CuCN, DMF, 150 °C) to furnish compound 6 in 83% yield, which serves as a key intermediate in the synthesis of a newly developed antibacterial candidate. Finally, palladium-catalyzed amination of 2h with LiHMDS, acting as an ammonia surrogate, provided compound 7 in 90% yield, an important building block for transient receptor potential vanilloid type 1 (TRPV1) antagonists. Notably, these synthetic routes are not only shorter and operationally simpler than previously reported methods but also provide the desired intermediates in higher overall yields.

3. Conclusions

In conclusion, we have developed a practical and efficient protocol for the synthesis of 2-quinolones from 2-aminocinnamic acid derivatives using a thiolate as a nucleophilic promoter to induce condensative cyclization. The conjugate addition of the thiolate to 2-aminocinnamic acid derivatives generates β-thio-substituted 2-aminodihydrocinnamic acid intermediates. Free rotation about the C_α–C_β bond allows adoption of an s-cis conformation, which places the amino and carboxyl group in close proximity. Subsequent intramolecular amide formation followed by elimination of the thiol furnishes the desired 2-quinolones.

A broad range of 2-aminocinnamic acid derivatives, including 2-amino-aza-cinnamates, were compatible with this protocol, affording 2-quinolone derivatives in excellent yields. Furthermore, the quinolones could be readily isolated by simple recyrstallization, since they precipitated upon quenching the reaction mixture with water. The synthetic utility of this transformation was further demonstrated through sequential functionalization of the resulting quinolones. Ongoing efforts are focused on extending this protocol to the synthesis of other biologically important quinolone derivatives, and the results will be reported in due course.

4. Experimental Section

4.1. General

All reactions were carried out in an oven-dried glassware in an open flask, unless otherwise noted. Except as otherwise indicated, all reactions were magnetically stirred and monitored by analytical thin layer chromatography (TLC) using precoated silica gel glass plates (0.25 mm) with F254 indicator. Visualization was accomplished by UV light (254 nm), with a combination of potassium permanganate and/or phosphomolybdic acid solution as an indicator. Flash column chromatography was performed using silica gel 60 (230–400 mesh). Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise noted. Commercial grade reagents and solvents were used without further purification. 2-Aminocinnamic acid derivatives 2 were prepared by a protocol reported in the literature through the Heck coupling between 2-iodoanilines with acrylic acid derivatives. ¹H NMR and ¹³C NMR spectra were recorded at 500 and 125 MHz spectrometers, respectively. Residual NMR solvents CD₃OD (δ_H: 3.31 ppm, δ_C: 49.00 ppm)} and DMSO-d ₆ (δ_H: 2.50 ppm, δ_C: 39.52 ppm) were used as internal standards for the ¹H NMR and ¹³C NMR spectra, respectively. For ¹⁹F NMR, no external standard was used. The proton spectra are reported as follows: δ (position of proton, multiplicity, coupling constant J, number of protons). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (septet), m (multiplet) and br (broad). High resolution mass spectra (HRMS) were recorded on a quadrupole time-of-flight mass spectrometer (QTOF-MS) in electrospray ionization (ESI) mode as ionization method.

4.2. General Procedure for the Synthesis of 2-Quinolones 2 (Tables , and )

A mixture of 2-aminocinnamic acid derivative 1 (or 2-amino-aza-cinnamate 3) (0.30 mmol, 1.0 equiv) and sodium hydroxide (18 mg, 0.45 mmol, 1.5 equiv) in DMF (3.0 mL) was stirred at room temperature until the base was completely dissolved. Then, n-propylthiol (n-PrSH, 0.033 mL, 0.36 mmol, 1.2 equiv) was added dropwise, and the reaction mixture was heated to 60 °C in an oil bath and monitored by TLC. Upon complete consumption of the starting material 1 (or 3), the solvent was removed under reduced pressure to afford a crude mixture of quinolone 2 (or aza-quinolone 4). The residue was purified by recrystallization from a mixture of ethyl acetate and hexane to give the desired product. If necessary, the mother liquor was further purified by silica gel chromatography (ethyl acetate/hexane), and the obtained fractions were combined with the recrystallized solid to afford quinolone 2 (or aza-quinolone 4) in the reported yield.

4.2.1. Quinolin-2­(1H)-one (2a)

A white solid; m.p. = 191–192 °C. R _f = 0.2 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.96 (d, J = 9.5 Hz, 1H), 7.66 (dd, J = 1.2, 7.9 Hz, 1H), 7.54 (ddd, J = 1.4, 7.1, 8.3 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.29–7.22 (m, 1H), 6.61 (d, J = 9.5 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.3, 142.8, 139.7, 132.0, 129.2, 124.0, 121.8, 121.4, 116.7.

4.2.2. 6-Methoxyquinolin-2­(1H)-one (2b)

A white solid; m.p. = 218–219 °C. R _f = 0.15 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.93 (d, J = 9.4 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.22–7.15 (m, 1H), 6.61 (d, J = 9.4 Hz, 1H), 3.85 (s, 3H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.7, 156.7, 141.8, 135.7, 122.4, 121.7, 121.4, 119.2, 109.8, 56.1.

4.2.3. 6-Acetyloxyquinolin-2­(1H)-one (2c)

A white solid; m.p. = 221–222 °C. R _f = 0.15 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.85 (d, J = 9.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.09 (dd, J = 2.7, 8.9 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 6.59 (d, J = 9.5 Hz, 1H), 3.35 (s, 3H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 164.6, 154.3, 142.1, 142.0, 133.1, 122.3, 121.6, 121.4, 117.7, 112.4, 54.6.

4.2.4. 6-Hydroxyquinolin-2­(1H)-one (2d)

A white solid; m.p. = 328–332 °C. R _f = 0.3 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.85 (d, J = 9.5 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 7.09 (dd, J = 2.7, 8.9 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 6.58 (d, J = 9.5 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 164.8, 154.4, 142.3, 133.2, 122.4, 121.8, 121.6, 117.9, 112.5.

4.2.5. 6-Methyquinolin-2­(1H)-one (2e)

A white solid; m.p. = 233–234 °C. R _f = 0.3 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.89 (d, J = 9.5 Hz, 1H), 7.45 (s, 1H), 7.39 (dd, J = 1.8, 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 9.5 Hz, 1H), 2.40 (s, 3H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.2, 142.6, 137.7, 133.9, 133.3, 128.7, 121.6, 121.4, 116.6, 20.8.

4.2.6. 6-Fluoroquinolin-2­(1H)-one (2f)

A white solid; m.p. = 272–273 °C. R _f = 0.2 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.94 (d, J = 9.5 Hz, 1H), 7.42 (dd, J = 2.4, 8.7 Hz, 1H), 7.39–7.32 (m, 2H), 6.66 (d, J = 9.5 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 164.9, 159.6 (d, J = 240.7 Hz), 141.9 (d, J = 3.6 Hz), 136.4, 123.2, 122.1 (d, J = 9.1 Hz), 120.0 (d, J = 25.4 Hz), 118.5 (d, J = 8.2 Hz), 113.7 (d, J = 23.6 Hz). ¹⁹F­{¹H} NMR (471 MHz, MeOD-d ₄): δ −121.9.

4.2.7. 6-Chloroquinolin-2­(1H)-one (2g)

A white solid; m.p. = 264–265 °C. R _f = 0.2 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.92 (d, J = 9.6 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 2.3, 8.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 163.5, 140.2, 137.0, 130.6, 127.6, 126.8, 121.8, 121.0, 116.9.

4.2.8. 6-(Trifluoromethyl)­quinolin-2­(1H)-one (2h)

A white solid; m.p. = 195–196 °C. R _f = 0.4 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 8.08–7.97 (m, 2H), 7.77 (dd, J = 1.8, 8.7 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 9.6 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.1, 142.2, 142.1, 128.0 (q, J = 3.6 Hz), 126.7 (q, J = 4.5 Hz), 125.8 (q, J = 33.6 Hz), 125.5 (q, J = 270.7 Hz), 123.7, 120.8, 117.5. ¹⁹F­{¹H} NMR (471 MHz, MeOD): δ −63.4.

4.2.9. 6-Bromoquinolin-2­(1H)-one (2i)

A brown solid; mp = 268–269 °C; R _f = 0.3 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.91 (d, J = 9.5 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 2.1, 8.7 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 6.64 (d, J = 9.5 Hz, 1H); ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 171.5, 147.5, 138.2, 132.4, 130.2, 125.6, 124.9, 121.5, 113.6.

4.2.10. 7-Methoxyquinolin-2­(1H)-one (2j)

A brown solid; mp = 215–235 °C; R _f = 0.3 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.88 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 6.96–6.69 (m, 2H), 6.43 (d, J = 9.5 Hz, 1H), 3.88 (s, 3H); ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.9, 163.8, 142.8, 141.7, 130.6, 118.4, 115.8, 113.6, 99.3, 56.2.

4.2.11. 7-Fluoroquinolin-2­(1H)-one (2k)

A white solid; mp = 260–272 °C; R _f = 0.3 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.95 (d, J = 9.6 Hz, 1H), 7.71 (dd, J = 6.0, 8.7 Hz, 1H), 7.11–7.00 (m, 2H), 6.56 (d, J = 9.6 Hz, 1H); ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.5 (d, J = 248.9 Hz), 165.3, 142.3, 141.4 (d, J = 11.8 Hz), 131.6 (d, J = 10.9 Hz), 120.9 (d, J = 2.7 Hz), 118.2, 112.2 (d, J = 23.6 Hz), 102.7 (d, J = 26.3 Hz); ¹⁹F­{¹H} NMR (471 MHz, MeOD-d ₄): δ −110.05.

4.2.12. 7-Bromoroquinolin-2­(1H)-one (2l)

A white solid; mp = 270–272 °C; R _f = 0.3 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.93 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.38 (dd, J = 1.8, 8.4 Hz, 1H), 6.62 (d, J = 9.6 Hz, 1H); ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.0, 142.4, 142.2, 130.7, 127.1, 123.3, 122.4, 120.3, 119.3.

4.2.13. 6,8-Dibromoquinolin-2­(1H)-one (2m)

A white solid; mp = 226–228 °C; R _f = 0.3 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.84 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 9.3 Hz, 1H), 7.73 (s, 1H), 6.66 (d, J = 9.3 Hz, 1H); ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 171.6, 144.5, 138.7, 135.3, 130.2, 125.4, 122.4, 118.5, 112.6; HRMS (ESI-TOF) m/z: [M-H]+ calcd for C₉H₅Br₂NO 301.8816; found, 301.8811.

4.2.14. Methyl 7-Fluoro-2-oxo-1,2-dihydroquinoline-5-carboxylate (2n)

A white solid; mp = 199–208 °C; R _f = 0.3 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 8.86 (d, J = 9.5 Hz) J = 0.6, 10.1 Hz, 1H), 7.61 (dd, J = 2.6, 9.3 Hz, 1H), 7.28 (dd, J = 2.6, 9.2 Hz, 1H), 6.67 (d, J = 9.5 Hz), 3.98 (s, 3H); ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 166.0 (d, J = 249.8 Hz), 164.5, 163.0, 142.5 (d, J = 11.8 Hz), 139.5, 131.5 (d, J = 9.0), 122.6 (d, J = 2.7 Hz), 117.0, 114.9 (d, J = 25.4 Hz), 106.9 (d, J = 25.4 Hz), 53.3; ¹⁹F­{¹H} NMR (471 MHz, MeOD-d ₄): δ −110.07; HRMS (ESI-TOF) m/z: [M-H]⁺ calcd for C₁₁H₈FNO₃ 222.0566; found, 222.0561.

4.2.15. 3-Methylquinolin-2­(1H)-one (2o)

A white solid; m.p. = 233–234 °C. R _f = 0.25 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.79 (s, 1H), 7.58 (dd, J = 0.8, 7.9 Hz, 1H), 7.49–7.43 (m, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.25–7.18 (m, 1H), 2.20 (d, J = 1.1 Hz, 3H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.4, 139.1, 138.8, 130.8, 130.6, 128.3, 123.7, 121.8, 116.2, 16.8.

4.2.16. 4-Methylquinolin-2­(1H)-one (2p)

A white solid; m.p. = 220–222 °C. R _f = 0.3 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.79 (d, J = 8.1 Hz, 1H), 7.54 (ddd, J = 1.3, 7.2, 8.3 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.31–7.27 (m, 1H), 6.50 (d, J = 0.8 Hz, 1H), 2.52 (d, J = 1.1 Hz, 3H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.0, 151.6, 139.4, 131.9, 125.9, 123.9, 121.8, 120.8, 117.1, 19.1.

4.2.17. 1,5-Naphthyridin-2­(1H)-one (4a)

A white solid; mp = 253–256 °C; R _f = 0.2 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 8.52 (dd, J = 1.4, 4.6 Hz, 1H), 8.02 (dd, J = 0.6, 9.8 Hz, 1H), 7.84–7.71 (m, 1H), 7.56 (dd, J = 4.6, 8.4 Hz, 1H), 6.87 (d, J = 9.8 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 164.3, 146.4, 142.6, 138.3, 136.4, 126.6, 126.4, 125.1.

4.2.18. 1,6-Naphthyridin-2­(1H)-one (4b)

A white solid; mp = 290–291 °C; R _f = 0.2 (dichloromethane/methanol = 10:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 8.82 (s, 1H), 8.46 (d, J = 5.8 Hz, 1H), 8.05 (dd, J = 0.5, 9.6 Hz, 1H), 7.29 (d, J = 5.8 Hz, 1H), 6.69 (d, J = 9.6 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.1, 150.8, 149.7, 145.5, 140.4, 124.3, 117.7, 111.3.

4.2.19. 1,7-Naphthyridin-2­(1H)-one (4c)

A brown solid; mp = 290–291 °C; R _f = 0.3 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 8.69 (s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H); ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 169.4, 144.1, 141.6, 140.2, 138.4, 127.1, 127.0, 121.9.

4.2.20. 1,8-Naphthyridin-2­(1H)-one (4d)

A yellow solid; mp = 198–200.5 °C; R _f = 0.3 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 8.55 (dd, J = 1.8, 4.8 Hz, 1H), 8.10 (dd, J = 1.7, 7.8 Hz, 1H), 7.96 (d, J = 9.5 Hz, 1H), 7.29 (dd, J = 4.8, 7.9 Hz, 1H), 6.67 (d, J = 9.5 Hz, 1H); ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 166.2, 152.1, 150.9, 141.3, 138.0, 123.3, 120.1, 116.5.

4.3. Synthetic Utility (Scheme )

4.3.1. Gram-Scale Synthesis of 2h

The reaction was performed on a gram scale according to the general procedure, with adjustments made only to the reaction scale. A mixture of ethyl (E)-2-amino-4-bromocinnamate (1h, 2.7 g, 10. mmol) and sodium hydroxide (0.60 g, 15.0 mmol, 1.5 equiv) in DMF (100 mL) was stirred at room temperature until the base was completely dissolved. Then, n-propylthiol (n-PrSH, 1.1 mL, 12 mmol, 1.2 equiv) was added dropwise, and the reaction mixture was heated to 80 °C in an oil bath and monitored by TLC. Upon complete consumption of starting material 1h, the solvent was removed in vacuo to afford a crude mixture of quinolone 2h. The crude residue was recrystallized from a mixture of ethyl acetate and hexane to afford the desired quinolone 2h in 92% (2.1 g) yield. Spectroscopic data were in good agreement with those obtained by the above reaction reported in Table .

4.3.2. Synthesis of a Key Intermidiate 5 Used in the Synthesis of Brexpiprazole

7-Methoxyquinolin-2­(1H)-one 2j (18 mg, 0.10 mmol) was dissolved in dichloromethane (DCM, 1.0 mL) under an argon atmosphere. To this solution was added boron tribromide (1 M in DCM, 0.50 mL, 5.0 equiv) dropwise at 0 °C. The reaction progress was monitored by TLC. Upon complete consumption of starting material 2j, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (ethyl acetate/hexane) to afford the desired product 5 as a white solid in 72% yield.

Spectroscopic data were in good agreement with the reported values in the literature. ,

mp = 310–315 °C; R _f = 0.1 (dichloromethane/methanol = 10:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.84 (d, J = 9.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 6.82–6.67 (m, 2H), 6.37 (d, J = 9.3 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 165.9, 162.0, 142.8, 141.7, 130.7, 117.3, 115.1, 114.0, 101.3.

4.3.3. Synthesis of 7-Cyanoquinolin-2­(1H)-one 6 via the Rosenmund Reaction

To a solution of 7-bromoquinolin-2­(1H)-one 2h (67 mg, 0.30 mmol) in DMF (3.0 mL) was added copper­(I) cyanide (54 mg, 0.60 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 150 °C in an oil bath and monitored by TLC. Upon complete consumption of the starting material 2h, the reaction mixture was cooled at room temperature. The reaction mixture was quenched with 1.0 N NaOH (3.0 mL). The mixture was filtered through Celite to remove insoluble residue. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated in vacuo to afford a crude residue, which was purified by column chromatography on silica gel (ethyl acetate/hexane) to afford the desired product 6 as a white solid in 83% yield.

Spectroscopic data were in good agreement with the reported values in the literature.

mp = 250–253 °C; R _f = 0.3 (ethyl acetate/hexane = 1:1). ¹H NMR (500 MHz, DMSO-d ₆): δ 7.99 (d, J = 9.6 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 9.6 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, DMSO-d ₆): δ 161.5, 139.4, 138.7, 129.2, 125.1, 124.2, 122.3, 118.9, 118.4, 112.0.

4.3.4. Synthesis of 7-Aminoquinolin-2­(1H)-one 7 via Buchwald–Hartwig Amination

To a solution of 7-bromoquinolin-2­(1H)-one (2h, 45 mg, 0.20 mmol, 1.0 equiv), 2-(dicyclohexylphosphino)­biphenyl (JohnPhos, 1.7 mg, 0.0048 mmol, 2.4 mol %), and tris­(dibenzylideneacetone)­dipalladium(0) {Pd₂(dba)₃, 1.8 mg, 0.0020 mmol, 1.0 mol %} in anhydrous THF (1.6 mL) was added LiHMDS (1.0 M in THF, 0.40 mL, 2.0 equiv) dropwise at 65 °C in an oil bath with stirring after degassing. The reaction mixture was monitored by TLC, and upon complete consumption of the starting material 2h, 1 M HCl aqueous solution (2.0 mL) was added, and the mixture was stirred vigorously for 30 min. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel to afford the desired product 7 as a purple solid in 55% yield.

Spectroscopic data were in good agreement with the reported values in the literature.

mp = 290–291 °C; R _f = 0.1 (ethyl acetate/hexanes = 1:1). ¹H NMR (500 MHz, MeOD-d ₄): δ 7.74 (d, J = 9.2 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 2.1, 8.5 Hz, 1H), 6.50 (d, J = 2.1 Hz, 1H), 6.24 (d, J = 9.3 Hz, 1H). ¹³C­{¹H} NMR (125 MHz, MeOD-d ₄): δ 166.1, 153.1, 143.0, 141.9, 130.2, 114.8, 113.5, 113.4, 98.6.

The data underlying this study are available in the published article and its online Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c13222.

• Characterization data for all compounds and copies of the NMR spectra (PDF) (PDF)

†.

T. W. K. and N. M. G. equally contributed to this work.

The authors declare no competing financial interest.