Metal-Free Synthesis of Functionalized Quinolines from 2-Styrylanilines and 2-Methylbenzothiazoles/2-Methylquinolines

Abstract

A facile functionalization of C(sp³)–H bonds and tandem cyclization strategy to synthesize quinoline derivatives from 2-methylbenzothiazoles or 2-methylquinolines and 2-styrylanilines has been developed. This work avoids the requirement for transition metals, offering a mild approach to activation of C(sp³)–H bonds and formation of new C–C and C–N bonds. This strategy features excellent functional group tolerance and scaled-up synthetic capability, thus providing an efficient and environmentally friendly access to medicinally valuable quinolines.

1. Introduction

Nitrogen-functionalized heterocycles are ubiquitous in pharmaceuticals, natural alkaloids, and functional materials;¹ particularly, functionalized quinoline and benzothiazole motifs possess a wide spectrum of biological activities and are considered as a privileged class of biologically active chemicals in medicinal chemistry.²Figure 1 shows some biologically active quinoline and benzothiazole derivatives. Compound I was proved to show a positive result against SARS-CoV-2, indicating a potential antiviral activity.³ Compound II levofloxacin was synthesized at Daiichi Seiyaku Co., Ltd., Tokyo, Japan. As of now, levofloxacin has become one of the most broad-spectrum antibiotics in pharmaceuticals and is being used to treat or prevent bacterial infections.⁴ Camptothecin (compound III) is a natural plant alkaloid which shows superior anticancer efficacy.⁵ Quinine (compound IV) has been commonly prescribed for the treatment of malaria.⁶ Benzothiazole derivative V is a new potential structure for treating human African trypanosomiasis.⁷

Figure 1.

Selected quinoline- and benzothiazole-based structures.

Since their first isolation from coal tar by Friedlieb Ferdinard Runge in 1834, increasing efforts have been devoted to the synthesis of substituted quinoline derivatives. Classical methods involve the condensation of aniline derivatives with ketones or aldehydes.⁸ These classical methods are still frequently used for preparation of quinoline motifs. However, some of these useful synthesis methods suffer from several drawbacks, for instance, expensive catalysts, limited substrate scope, multiple reaction steps, poor site selectivity, and so on. Recently, some new methods using 2-styrylanilines as starting materials have been disclosed (Scheme 1a). The group of Helaja reported the formation of polysubstituted quinolines by condensation of 2-styrylanilines with aldehydes.⁹ Chen’s group reported CuCl₂·2H₂O-catalyzed oxidative cyclization to generate quinolines.¹⁰ These methods are step-efficient and atom-economic. However, transition-metal or preactivated catalysts limit the industrial applications. Lyu’s group developed lactamization of the C(sp²)–H bond to synthesize 2-quinolinones, with CO₂ as the carbonyl source.¹¹ The groups of Zhang and co-workers¹² and Ma and co-workers¹³ separately reported the condensation of 2-styrylanilines with β-keto esters using I₂ or TsOH as the catalyst. Although there have been a number of synthesis strategies using 2-styrylanilines as the starting material, the development of different methods using new substrates for construction of functionalized quinolines remains of great importance.

Scheme 1. (a and b) Synthesis of Quinoline Derivatives from 2-Styrylanilines.

On the other hand, direct C–H functionalization reactions are of great importance in construction of C–C and C–X (X = N, O, S, etc.) bonds due to the omnipresence of C–H bonds in chemical feedstocks, step economy, and atom economy.¹⁴ Compared to the C(sp²)–H bonds, C(sp³)–H bonds are relatively inert because of their poor acidity, high bond dissociation energy, and ubiquitous feature.¹⁵ The activity and site selectivity of C(sp³)–H bond functionalization remain long-standing challenges. Currently, the transition-metal-catalyzed or metal-free strategies of direct functionalization of C(sp³)–H bonds have attracted tremendous attention in organic synthesis. A transition-metal (such as rhodium, palladium, iron, cobalt, and copper)-catalyzed directing-group-assisted strategy has emerged as a robust and highly efficient way to direct functionalization of C(sp³)–H bonds over the past decades.¹⁶ Despite the great achievement of this tactic, using toxic, precious metals and complicated ligands, wasting over stoichiometric amounts of oxidants and harsh reaction temperatures partly hinder the application of this method. Distinct from the above studies, functionalization of C(sp³)–H bonds via the radical process has been reported as a novel method in recent years; the reaction site usually occurs in the neighborhood of the carbonyl group, benzyl group, allyl group, oxygen atom, nitrogen atom, etc.¹⁷ These protocols feature metal-free, efficient, and simple operation. Nevertheless, the scope of C(sp³)–H bonds is limited in certain substrate species. Therefore, the development of more general methods for improving the structural diversity is highly desirable. In continuation of our previous efforts on direct C–H bond functionalization,¹⁸ we herein report an environment-friendly and efficient functionalization of C(sp³)–H bonds and tandem cyclization strategy from 2-methylbenzothiazoles or 2-methylquinolines and 2-styrylanilines by iodide catalysis to formation of functionalized quinoline derivatives (Scheme 1b). This protocol features metal-free, direct functionalization of C(sp³)–H bonds, broad substrate scope, moderate-to-good yields, and scaled-up synthetic capability. To the best of our knowledge, rare examples about metal-free functionalization of 2-methylbenzothiazole have been documented to date.¹⁹

2. Results and Discussion

We started our investigation by studying the reaction of 2-methylbenzo[d]thiazole 1a with 2-styrylaniline 2a. Excitingly, we were delighted to find that molecular iodine (0.2 equiv) catalyst in combination with the oxidant TBHP (3 equiv, 70% aq) in DMSO (1.5 mL) at 120 °C gave the best result, where the desired product 3a was obtained in 78% isolated yield (Table 1, entry 1). The reaction was sensitive to the iodide catalysts. KI and NaI were ineffective (entries 2 and 3). I₂, TBAI, and NIS were effective for the reaction, and I₂ performed the best, giving 3a in 52% yield (entries 4–6). Catalysis-equivalent screening revealed that decreasing the dosage of catalyst led to poor results, and increasing the dosage of catalyst was less effective (entries 7 and 8). The solvent was crucial for the reaction; DMF, MeCN, and NMP were inferior to DMSO (entries 9–12), owing to DMSO acting as both the solvent and oxidant in the Kornblum-type oxidation process. Expectedly, lowering or increasing the temperature resulted in lower yields (entries 13 and 14). Lowering the oxidant dosage to 0.6 mmol diminished the yield to 52% (entry 15). With a higher oxidant loading of 1.2 mmol, only 60% of 3a was obtained (entry 16). Moreover, the catalyst and oxidant were essential for the reaction, and the target product was not obtained in the absence of either element (entries 17 and 18).

Table 1. Optimization of the Reaction Conditions^a.

entry	changes from the standard conditions	yield (%)b
1	none	78
2	KI (0.2 equiv) as the catalyst	trace
3	NaI (0.2 equiv) as the catalyst	trace
4c	I2 (0.2 equiv) as the catalyst	52
5	TBAI (0.2 equiv) as the catalyst	27
6	NIS (0.2 equiv) as the catalyst	47
7	I2 (0.1 equiv) as the catalyst	49
8	I2 (0.3 equiv) as the catalyst	53
9	DMF as the solvent	15
10	MeCN as the solvent	20
11	NMP as the solvent	43
12	toluene as the solvent	trace
13	temp = 100 °C	45
14	temp = 140 °C	50
15	TBHP (2 equiv)	52
16	TBHP (4 equiv)	60
17	no catalyst	trace
18	no oxidant	trace

^aReactions were performed on a 0.3 mmol scale, 1a (0.3 mmol) and 2a (0.54 mmol.).

^bIsolated yield.

^c2 equiv of TBHP was used.

With the optimized reaction conditions in hand, we explored the effect of substituents on 2-styrylanilines and 2-methylbenzothiazoles. As shown in Scheme 2, the reaction between 2-methylbenzothiazole (1a) and 2-styrylanilines 2a–h afforded the corresponding 2-heteroaromatic quinolines 3a–h in fair-to-good yields (47–80%), revealing quite a general compatibility with the electronic nature of substituents on the benzene group of the aniline substrates. Moreover, the 2-styrylaniline substrates with the electron-donating groups showed better reactivity than those with the electron-withdrawing groups. Notably, the substituent on the benzene of the styryl motifs afforded target compounds 3i in moderate yields (49%). In addition, the substrates (2j–l) with the substituents on the benzene of 2-methylbenzothiazole, either electron-donating groups (Me and MeO) or the electron-withdrawing group (F), also afforded the desired products in fair yields (53–67%). For further verifying the generality and flexibility of the direct functionalization of 2-methylbenzothiazole, the reaction was carried out by using 2-hydrazinylpyridines as the substrates. The electron-withdrawing and electron-donating substituents at the benzene of 2-methylbenzothiazole were compatible, affording the corresponding products (3m–p) in good yields (49–76%). It is noteworthy that a strong conjugated aromatic system such as 2-methylnaphtho[1,2-d]thiazole provided the desired product 3q in 75% yield.

Scheme 2. Cyclization of 2-Methylbenzothiazoles with 2-Styrylanilines^a.

Reaction conditions: 1 (0.3 mmol), 2 (0.54 mmol), I₂ (0.2 equiv), TBHP (3 equiv), 1.5 mL of DMSO, 120 °C.

Reaction with 2-hydrazinylpyridine.

The substrate scope of the reaction for 2-methylquinolines was further investigated by slightly modifying the reaction conditions with 1 equiv of CH₃COOH as the promoter, which can activate the methyl group and promote enamine tautomerization,²⁰ and the result is shown in Scheme 3. 2-Styrylanilines, with the aryl group either on the styryl or aniline motifs bearing electron-rich (5a–e) and electron-poor substituents (5f–g and 5i), worked well, and the desired compounds were obtained in moderate-to-good yields (60–83%). The reaction of 2 with various substituted quinoline motifs was also explored. A series of 2-methylquinolines with different electronic properties smoothly finished the reaction; the target compounds were obtained in 42–81% yield (5j–n); generally, electron-withdrawing substituents (F and Cl) on the aromatic ring gave a higher yield than the electron-donating substituents (Me and MeO). 1-Methylisoquinoline, 4-methylquinoline, and 2-methylquinoxaline were all suitable for this reaction, providing the corresponding products in moderate yields (5o–q, 50–53%). Regretfully, 2-methylpyridine, 2-methyl-1H-benzo[d]imidazole, 2-methylbenzo[d]oxazole, 2-methyl-1H-indole, 2-methylimidazo[1,2-a]pyridine, and methylated caffeine were not suitable for this reaction system. Furthermore, we found that the reaction of 4a with 2a is enabled to scale up to gram quantities with good yield and efficiency (Scheme 4).

Scheme 3. Cyclization of 2-Methylquinolines with 2-Styrylanilines^a.

Reaction Conditions: 4 (0.3 mmol), 2 (0.54 mmol), I₂ (0.2 equiv), TBHP (3 equiv), CH₃COOH (1 equiv), 1.5 mL of DMSO, 120 °C.

Scheme 4. Gram-Scale Synthesis.

To gain insights into the mechanism of this process, a series of control reactions were investigated. First, 2-methylbenzothiazole and 2-methylquinoline could afford benzothiazole-2-carbaldehyde and quinoline-2-carbaldehyde in 85 and 87% isolated yields, respectively, under the standard conditions (Scheme 5a,b). These results suggest that the reaction may proceed with the oxidation of C(sp³)–H to aldehyde motifs. Second, in the presence of TEMPO or 1,1-diphenylethylene (3 equiv), the reaction of 1a with 2a was totally hindered (Scheme 5c), and the reaction of 4a with 2a was reduced from 81 to 11 and 33%, respectively (Scheme 5d). These results suggest that the reaction might involve radical species in the reaction mechanism.

Scheme 5. (a–d) Control Experiments.

On the basis of these results and previous literatures,^{18c, 19a, 19e} a proposed pathway is described in Scheme 6. The free-radical species ^tBuO^· and ^tBuOO^· were generated by a catalytic cycle of I₂ and TBHP. At first, N-heteroaromatic methane undergoes enamine tautomerization to the corresponding enamines A. Then, the addition of iodine to the enamines forms benzylic iodides B, followed by a Kornblum-type oxidation to generate aldehyde motifs C (path I). On the other hand, the free-radical addition and oxidation of enamine with ^tBuO^· or ^tBuOO^· generate an intermediate E, which is further transformed through tautomerization and oxidation to give an intermediate G; hydrolysis of G leads to the formation of aldehyde motifs C (path II). Finally, the reaction of aldehyde motifs C with 2a, followed by thermal electrocyclization and aromatization, forms target molecules.

Scheme 6. Proposed Mechanism.

3. Conclusions

In conclusion, we have developed an environment-friendly and efficient functionalization of C(sp³)–H bonds and tandem cyclization strategy from 2-methylbenzothiazoles or 2-methylquinolines and 2-styrylanilines. Various functionalized quinolines were obtained in moderate-to-excellent yields. This protocol featured avoidance of metal catalysts, broad substrate scope, good functional group compatibility, and scaled-up synthetic capability. These advantages are expected to make this protocol a powerful tool for synthesis of medicinally valuable quinoline structures.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c07736.

• Experimental procedure, characterization data, and copies of ¹H and ¹³C NMR spectra for the obtained products (PDF)

The authors declare no competing financial interest.