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Article

TMSBr-Promoted Cascade Cyclization of ortho-Propynol Phenyl Azides for the Synthesis of 4-Bromo Quinolines and Its Applications

by
Fengyan Jin
†,
Tao Yang
†,
Xian-Rong Song
,
Jiang Bai
,
Ruchun Yang
,
Haixin Ding
and
Qiang Xiao
*
Institute of Organic Chemistry, Jiangxi Science & Technology Normal University, Key Laboratory of Organic Chemistry, Jiangxi Province, Nanchang 330013, China
*
Author to whom correspondence should be addressed.
†
Co-first author.
Molecules 2019, 24(21), 3999; https://doi.org/10.3390/molecules24213999
Submission received: 30 September 2019 / Revised: 22 October 2019 / Accepted: 31 October 2019 / Published: 5 November 2019
(This article belongs to the Special Issue Modern Strategies for Heterocycle Synthesis)
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Versions Notes

Abstract

:
Difficult-to-access 4-bromo quinolines are constructed directly from easily prepared ortho-propynol phenyl azides using TMSBr as acid-promoter. The cascade transformation performs smoothly to generate desired products in moderate to excellent yields with good functional groups compatibility. Notably, TMSBr not only acted as an acid-promoter to initiate the reaction, and also as a nucleophile. In addition, 4-bromo quinolines as key intermediates could further undergo the coupling reactions or nucleophilic reactions to provide a variety of functionalized compounds with molecular diversity at C4 position of quinolines.

Graphical Abstract

1. Introduction

Quinolines are distinctive and significant frameworks which are widely existed in numerous pharmaceuticals, pesticide molecules, bioactive molecules, and natural products [1,2,3,4,5,6,7,8]. Moreover, such compounds using as ligands play crucial role in synthetic and catalysis chemistry [9,10,11,12,13]. Consequently, developing general and flexible approach towards these heterocycles has attracted much attention among synthetic chemists. Until now, despite significant achievements having been made in the construction of functionalized quinolines [14,15,16,17,18,19,20,21,22], methods for the direct synthesis of 4-halo quinolines are still limited [23,24,25,26]. 4-halo quinolines have been widely used as key synthetic intermediates for the construction of various bioactive molecules or drugs [27,28,29]. Therefore, the development of an efficient and versatile strategy towards 4-halo quinolines is highly desirable, especially through a cascade cyclization, because of the merits of efficiency and atomic economy.
Based on its distinctive bifunctional group characteristics, the cascade reaction of propynols is an important tactic in organic synthesis, which exerts a significant role in the construction of functionalized carbo- or heterocyclic compounds [30,31,32,33,34]. In the past few years, our group had developed various efficient methods to construct functionalized heterocyclics through the cascade cyclization of propargylic alcohols in the presence of acid-promoter [35,36,37,38,39,40,41,42,43,44]. For example, we recently reported an efficient approach for the construction of 4-chrolo quinolines via the cyclization of ortho-propynol phenyl azides with TMSCl as acid-promoter [45]. Taking into consideration that the coupling reaction of chloro-substituted compounds is more difficult than bromo- or iodo-substituted compounds, the further development of universal approach for the construction of 4-bromo quinolines is still desirable and necessary. Herein, we report a general TMSBr-promoted the cascade cyclization of ortho-propynol phenyl azides for constructing 4-bromo quinolines, which can further undergo the coupling reactions or nucleophilic reactions to provide a variety of functionalized compounds with molecular diversity at C4 position of quinolines (Scheme 1). Compared to the Shvartsberg’s method [26], our developed strategy has the merits of good functional groups compatibility, easy preparation of the starting material, and simple operation.

2. Results and Discussion

Initially, the reaction conditions were optimized for cascade cyclization of ortho-propynol phenyl azides 1a in the presence of TMSBr. Various solvents, temperatures, and TMSBr loading were investigated, and all cases were shown in Table 1. To our delight, with 2.5 equiv of TMSBr in different solvents—such as MeCN, CH3NO2, DCE, 1,4-dioxane, HOAc, and DCM—all reactions proceeded smoothly and cleanly to produce expected product 4-bromo-2-(4-methoxyphenyl)quinoline 2a (Table 1, entries 1–5); CH3NO2 as solvent was most suitable for this transformation (73% yield). Encouraged by this preliminary result, further efforts were then directed toward improving the yield of desired product 2a while suppressing the classical Meyer–Schuster rearrangement side reaction. Our studies on the loading of TMSBr with CH3NO2 as solvent showed that 3.5 equiv of TMSBr was the most efficient for this cascade transformation and could improve the yield of product 2a to 81% (Table 1, entries 6–8). Subsequently, the examination of the reaction temperature indicated that the choice of reaction temperature was also an important in this transformation (entries 9, 10). Furthermore, no better yield was obtained when hydrobromic acid (HBr, 48 wt % in H2O) was used instead of TMSBr as the acid promoter (entry 11). Therefore, we establish the reaction conditions as optimum: 0.2 mmol of 2-propynol phenyl azides, 3.5 equiv of TMSBr in CH3NO2 were stirred at 60 °C.
Then, we investigated the generality of the reaction with diverse substituted propynols 1 using TMSBr as acid-promoter and nucleophile, and the results are presented in Figure 1. Various substituents R1 and R2 on the aryl ring were well-tolerated under the optimal conditions, efficiently generating the corresponding products 4-bromo quinolines in favorable yields (up to 91% yield). Firstly, we investigated the influence of substituent electronic effects on this reaction, and the results indicated that substrates containing electron-donor groups (OMe, Me) gave better transformation than those containing electron-poor groups (F, Cl, Br). This might due to the fact that the reaction involved the carbocation intermediate (Intermediate B, see Scheme 4); and the electron-rich groups were good for the stabilization of carbocation intermediate. The corresponding products 4-bromo quinolines give the better yields compared to the synthesis of 4-chrolo quinolines bearing the electron-withdrawing groups. Substrates bearing ortho-position substituent provided slightly lower yields (2j–2k), indicating that the steric effect showed clear influence on this reaction. Importantly, the functionalities of halogen atoms such as fluorine, chlorine, and bromine were also tolerated for this transformation producing the target products. Such halogenated products could be converted into a variety of functionalized quinolines through cross-coupling reactions. Substrates containing two or three substituents attached to the benzene ring smoothly, and the target compounds were generated in good to excellent yields. Notably, the substrates with naphthyl or styryl group (1m and 1o) were also compatible to generate the target products in good yields (2k–2m). Then we examined the effect of a substituent (R2) on another aromatic ring on this transformation. Both electron-rich and electron-poor substituents were performed smoothly to produce the target compounds in 76–89% yields (2m–2s). It was noteworthy that the strong electron-deficient groups (CN and CF3) in R2 also proceeded well in this reaction and provided the target products in good yields. Unfortunately, no target product 2t was generated when alkyl-substituted substrate 1t was performed under the optimal conditions. Having successfully accomplished the direct formation of 4-bromo-quinolines, this cascade reaction was further extended to the construction of 4-iodo quinolines by using 2-propynol phenyl azides as starting materials with TMSI in CH3NO2 at 60 °C for 1.0 h under these circumstances. Some selected substrates (1a, 1b, 1n) were tolerated smoothly to the corresponding 4-iodo quinolines in moderate yields.
Furthermore, the synthetic utility of this TMSBr-promoted reaction of ortho-propynol azides was demonstrated by a gram-scale synthesis (Scheme 2-1). The yield of product 2a was not obvious affected when a gram-scale (5 mmol, 1.40g) experiment of 1a was performed under similar reaction conditions. Importantly, a bromine atom at the 4-position of obtained product quinolines moiety is useful and easily substituted by various functional hydrocarbon and heteroatomic groups, which persuades us to exploit synthetic transformation of 4-bromo quinolones [46,47,48]. As representative examples, the Suzuki coupling reaction of 2a with arylboronic acids to 4-aryl quinolines 3a–3d in good yield was achieved (Scheme 2-2) [46]. Notably, the corresponding product 4-vinyl quinoline 3e was also generated when the reaction of 2a with E-phenylethenylboronic acid. Furthermore, the Sonogashira coupling of 2a with arylacetylene could smoothly proceed to produce the target products 4a–4b in good yields (Scheme 2-3) [47]. More importantly, the classical reduction reaction of 2a to the corresponding quinoline 5 was also investigated (Scheme 2-4). These results clearly demonstrate the usefulness of our obtained product 4-bromo quinolines as synthetic intermediates.
As we all known, 4-aryloxy quinolines are significant structure frameworks which are existed widely in various bioactive molecules and natural products [49,50,51,52]. In this context, the synthesis of 4-aryloxy quinolines from 4-bromo quinolines is attractive because of the clean conversion and the mild reaction conditions. Therefore, the scope of the reactions was also investigated by varying the phenols. Some representative substituted 4-aryllkoxy quinolines 6a–6d were generated in acceptable yields by choosing the appropriate nucleophilic reagents (Scheme 3).
On the basis of the above experimental results and literature reports [45,53,54], we propose a plausible reaction mechanism for this reaction (Scheme 4). Firstly, a proargylic carbocation intermediate A was formed through the TMSBr-promoted the dehydration of propargylic alcohols 1. Intermediate A could easily undergo tautomerization to generate allenic carbocation intermediate B, which could be attracted by nucleophile halide anion (Br−) to produce intermediate C. Subsequently, the 6-endo-trig cyclization of intermediate C in the presence of proton forms intermediate D. Finally, the target product 2 was generated through the aromatization of the intermediate D with the generation of a nitrogen gas and a proton.

3. Materials and Methods

3.1. General Remarks

1H-NMR spectra were recorded on 400 MHz in CDCl3 and 13C-NMR spectra were recorded on 100 MHz in CDCl3. Chemical shifts (ppm) were recorded with tetramethylsilane (TMS) as the internal reference standard. Multiplicities are given as: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), q (quartet), or m (multiplet). High-resolution mass spectrometry (HRMS) was performed on a TOF/Q–TOF mass spectrometer. Copies of the 1H-NMR and 13C-NMR spectra are provided in the Supporting Information. Commercially available reagents were used without further purification. All solvents were dried under standard method.

3.2. General Procedure for the Construction of 4-Bromo Quinolines 2

To a seal tube was added ortho-propynol phenyl azides (1) (0.2 mmol), TMSBr (0.7 mmol), in CH3NO2 at 60 °C. After 1.0 h, as monitored by TLC, the reaction mixture was concentrated in vacuum and purified by column chromatography to generate 4-bromo quinolines 2.
4-Bromo-2-(4-Methoxyphenyl)quinoline (2a)
The title compound was prepared according to the 0.5, 130.8, 134.5, 148.7, 156.7, 161.1. general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2a (81%) [45]. 1H-NMR (400 MHz, CDCl3): δ 3. 79 (s, 3 H), 6.95 (dd, J = 2.0, 6.8 Hz, 2 H), 7.47–7.51 (m, 1 H), 7.63–7.67 (m, 1 H), 8.01–8.07 (m, 5 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 122.4, 126.3, 126.5, 127.0, 128.9, 129.8, 13.
4-Bromo-2-(p-tolyl)quinoline (2b)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2b (91%). 1H-NMR (400 MHz, CDCl3): δ 2.34 (s, 3 H), 7.23 (d, J = 8.4 Hz, 2 H), 7.48–7.52 (m, 1 H), 7.64–7.68 (m, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 8.04–8.08 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 21.3, 122.7, 126.5, 127.2, 127.4, 129.6, 130.0, 130.4, 134.5, 135.5, 139.9, 148.7, 157.1. HRMS (ESI, m/z): calcd for C16H12BrN: M + H = 298.0226; found: 298.0229.
4-Bromo-2-(m-tolyl)quinoline (2c)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2c (81%). 1H-NMR (400 MHz, CDCl3): δ 2.39 (s, 3 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.68 (t, J = 7.6 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.89 (s, 1 H), 8.07–8.10 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 21.5, 123.0, 124.6, 126.5, 126.6, 127.4, 128.2, 128.8, 130.0, 130.5, 130.6, 134.5, 138.3, 138.6, 148.7, 157.4. HRMS (ESI, m/z): calcd for C16H12BrN: M + H = 298.0226; found: 298.0229.
4-Bromo-2-(o-tolyl)quinoline (2d)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2d (52%). 1H-NMR (400 MHz, CDCl3): δ 2.35 (s, 3 H), 7.20–7.29 (m, 3 H), 7.41 (d, J = 6.8 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.78 (s, 1 H), 8.06–8.16 (m, 2 H). 13C-NMR (100 MHz, CDCl3): δ 20.3, 126.1, 126.1, 126.3, 126.6, 127.6, 128.9, 129.6, 130.0, 130.5, 131.1, 133.9, 136.1, 139.4, 148.4, 160.0. HRMS (ESI, m/z): calcd for C16H12BrN: M + H = 298.0226; found: 298.0227.
4-Bromo-2-phenylquinoline (2e)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2e (46%). 1H-NMR (400 MHz, CDCl3): δ 7.40–7.48 (m, 3 H), 7.54–7.56 (m, 1 H), 7.67–7.71 (m, 1 H), 8.05–8.11 (m, 5 H). 13C-NMR (100 MHz, CDCl3): δ 122.9, 126.5, 126.7, 127.5, 127.5, 128.9, 129.8, 130.1, 130.5, 134.6, 138.4, 148.8, 157.2. HRMS (ESI, m/z): calcd for C15H10BrN: M + H = 284.0069; found: 284.0071.
4-Bromo-2-(4-fluorophenyl)quinoline (2f)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2f (75%). 1H-NMR (400 MHz, CDCl3): δ 7.11–7.18 (m, 2 H), 7.52–7.56 (m, 1 H), 7.67–7.71 (m, 1 H), 8.05–8.11 (m, 5 H). 13C-NMR (100 MHz, CDCl3): δ 115.8, 116.0, 122.5, 126.6, 127.5, 129.4, 129.5, 130.0, 130.7, 134.5, 134.8, 148.7, 156.0, 162.8, 165.3. HRMS (ESI, m/z): calcd for C15H9BrFN: M + H = 301.9975; found: 301.9973.
4-Bromo-2-(4-chlorophenyl)quinoline (2g)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2g (86%). 1H-NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.4 Hz, 2 H), 7.52–7.56 (m, 1 H), 7.67–7.71 (m, 1 H), 7.99–8.10 (m, 5 H). 13C-NMR (100 MHz, CDCl3): δ 122.5, 126.6, 126.7, 127.7, 128.7, 129.1, 130.0, 130.7, 134.8, 136.0, 136.7, 148.7, 155.8. HRMS (ESI, m/z): calcd for C15H9BrClN: M + H = 317.9680; found: 317.9682.
4-Bromo-2-(4-bromophenyl)quinoline (2h)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2h (72%). 1H-NMR (400 MHz, CDCl3): δ 7.54–7.57 (m, 3 H), 7.68 (t, J = 8.4 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 2 H), 8.04–8.10 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 122.4, 124.5, 126.6, 126.7, 127.7, 129.0, 130.1, 130.7, 132.0, 134.8, 137.2, 148.7, 155.9. HRMS (ESI, m/z): calcd for C15H9Br2N: M + H = 361.9175; found: 361.9179.
4-Bromo-2-(3,4-dichlorophenyl)quinoline (2i)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2i (61%). 1H-NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.4 Hz, 1 H), 7.54–7.58 (m, 1 H), 7.69–7.73 (m, 1 H), 7.87–7.90 (m, 1 H), 8.02–8.11 (m, 3 H), 8.21 (d, J = 2.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 122.2, 126.4, 126.6, 126.8, 128.0, 129.3, 130.1, 130.8, 130.9, 133.3, 134.1, 135.0, 138.1, 148.6, 154.4. HRMS (ESI, m/z): calcd for C15H8BrCl2N: M + H = 351.9290; found: 351.9291.
4-Bromo-2-(4-bromo-2-fluorophenyl)quinoline (2j)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2j (63%). 1H-NMR (400 MHz, CDCl3): δ 7.34 (dd, J = 1.6, 6.8 Hz, 1 H), 7.40 (dd, J = 1.6, 8.4 Hz, 1 H) 7.59 (t, J = 7.2 Hz, 1 H), 7.72 (t, J = 7.2 Hz, 1 H), 7.97 (t, J = 7.6 Hz, 1 H), 8.07–8.14 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 119.8, 120.0, 124.1, 124.2, 125.8, 125.9, 126.7, 126.9, 128.1, 128.2, 128.2, 130.0, 130.7, 132.5, 132.6, 134.4, 148.6, 152.6, 159.1, 161.8. HRMS (ESI, m/z): calcd for C15H8Br2FN: M + H = 379.9080; found: 379.9084.
4-Bromo-2-(3,4-dimethoxyphenyl)quinoline (2k)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2k (88%). 1H-NMR (400 MHz, CDCl3): δ 3.87 (s, 3 H), 3.97 (s, 3 H), 6.89 (d, J = 8.4 Hz, 1 H), 7.48–7.56 (m, 2 H), 7.64–7.68 (m, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 8.05–8.08 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 55.9, 56.0, 110.2, 111.0, 120.3, 122.5, 126.4, 126.5, 127.1, 129.8, 130.5, 131.0, 134.5, 148.6, 149.4, 150.7, 156.6. HRMS (ESI, m/z): calcd for C17H14BrNO2: M + H = 344.0281; found: 344.0283.
4-Bromo-2-(3,4,5-trimethoxyphenyl)quinoline (2l)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2l (86%). 1H-NMR (400 MHz, CDCl3): δ 3.85 (s, 3 H), 3.93 (s, 6 H), 7.29 (s, 2 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 8.04 (s, 1 H), 8.07–8.10 (m, 2 H). 13C-NMR (100 MHz, CDCl3): δ 56.3, 60.9, 104.8, 122.7, 126.5, 127.5, 129.9, 130.6, 133.8, 134.6, 139.8, 148.5, 153.6, 156.7. HRMS (ESI, m/z): calcd for C18H16BrNO3: M + H = 374.0386; found: 374.0382.
4-Bromo-2-(naphthalen-1-yl)quinoline (2m)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2m (81%). 1H-NMR (400 MHz, CDCl3): δ 7.41–7.48 (m, 2 H), 7.51–7.55 (m, 1 H), 7.61–7.66 (m, 2 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.86–7.91 (m, 2 H), 7.96 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 8.19 (dd, J = 8.8 Hz, 2 H). 13C-NMR (100 MHz, CDCl3): δ 125.3, 126.1, 126.6, 126.7, 126.9, 127.0, 127.9, 128.0, 128.5, 129.6, 129.9, 130.8, 131.0, 133.9, 134.4, 137.1, 148.4, 159.1. HRMS (ESI, m/z): calcd for C19H12BrN: M + H = 334.0226; found: 334.0227.
4-Bromo-2-(naphthalen-2-yl)quinoline (2n)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2n (84%). 1H-NMR (400 MHz, CDCl3): δ 7.42–7.46 (m, 2 H), 7.50–7.54 (m, 1 H), 7.66–7.70 (m, 1 H), 7.78–7.81 (m, 1 H), 7.88 (dd, J = 2.8, 5.6 Hz, 2 H), 8.08–8.11 (m, 2 H), 8.22–8.24 (m, 2 H), 8.47 (d, J = 0.8 Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 123.0, 124.7, 126.4, 126.6, 126.7, 126.9, 127.3, 127.5, 127.7, 128.7, 128.8, 130.1, 130.6, 133.3, 134.0, 134.6, 135.6, 148.8, 156.9. HRMS (ESI, m/z): calcd for C19H12BrN: M + H = 334.0226; found: 334.0227.
4-Bromo-2-(4-methoxyphenyl)-6-methylquinoline (2o)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2o (89%). 1H-NMR (400 MHz, CDCl3): δ 2.48 (s, 3 H), 3.79 (s, 3 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.47 (dd, J = 1.6, 8.4 Hz, 1 H), 7.80 (s, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.98–8.00 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 21.7, 55.3, 114.2, 122.4, 125.3, 126.2, 128.7, 129.6, 131.1, 132.6, 133.7, 137.2, 147.3, 155.8, 160.9. HRMS (ESI, m/z): calcd for C17H14BrNO: M + H = 328.0332; found: 328.0331.
4-Bromo-6-fluoro-2-(4-methoxyphenyl)quinoline (2p)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2p (83%). 1H-NMR (400 MHz, CDCl3): δ 3.81 (s, 3 H), 6.95 (d, J = 8.4 Hz, 2 H), 7.39–7.44 (m, 1 H), 7.70 (dd, J = 2.8, 9.6 Hz, 1 H), 7.99–8.05 (m, 4 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 110.2, 110.4, 114.3, 120.5, 120.7, 123.0, 127.2, 127.3, 128.8, 130.6, 132.4, 132.5, 133.3, 133.4, 145.8, 156.1, 156.2, 159.7, 161.2, 162.2. HRMS (ESI, m/z): calcd for C16H11BrFNO: M + H = 332.0081; found: 332.0081.
4-Bromo-6-chloro-2-(4-methoxyphenyl)quinoline (2q)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2q (76%). 1H-NMR (400 MHz, CDCl3): δ 3.80 (s, 3 H), 6.95 (d, J = 8.8 Hz, 2 H), 7.57 (dd, J = 2.4, 8.8 Hz, 1 H), 7.94–8.05 (m, 5 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 114.3, 123.1, 125.5, 127.0, 128.8, 130.4, 131.4, 131.5, 133.0, 133.1, 147.1, 156.9, 161.3. HRMS (ESI, m/z): calcd for C16H11BrClNO: M + H = 347.9785; found: 347.9787.
4-Bromo-2-(4-methoxyphenyl)-6-(trifluoromethyl)quinoline (2r)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2r (87%). 1H-NMR (400 MHz, CDCl3): δ 3.80 (s, 3 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.79 (d, J = 8.8 Hz, 1 H), 8.03 (d, J = 8.4 Hz, 2 H), 8.10 (d, J = 8.4 Hz, 2 H), 8.34 (s, 1 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 114.4, 123.4, 124.6, 124.7, 125.5, 126.1, 126.1, 129.1, 130.0, 131.0, 135.0, 149.7, 158.6, 161.7. HRMS (ESI, m/z): calcd for C17H11BrF3NO: M + H = 382.0049; found: 382.0045.
4-Bromo-2-(4-methoxyphenyl)quinoline-6-carbonitrile (2s)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2s (79%). 1H-NMR (400 MHz, CDCl3): δ 3.83 (s, 3 H), 6.98 (d, J = 8.8 Hz, 2 H), 7.79 (dd, J = 1.6, 8.4 Hz, 1 H), 8.08 (dd, J = 5.6, 8.8 Hz, 3 H), 8.16 (s, 1 H), 8.47 (d, J = 1.2 Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 55.5, 110.4, 114.5, 118.5, 123.8, 126.0, 129.3, 129.7, 131.2, 131.3, 132.9, 134.5, 149.9, 159.4, 162.0. HRMS (ESI, m/z): calcd for C17H11BrN2O: M + H = 339.0128; found: 339.0128.
4-Iodo-2-(4-methoxyphenyl)quinoline (2u)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2u (62%) [45]. 1H-NMR (400 MHz, CDCl3): δ 3.89 (s, 3 H), 7.03–7.05 (m, 2 H), 7.54–7.58 (m, 1 H), 7.70–7.74 (m, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 8.09–8.12 (m, 2 H), 8.42 (s, 1 H). 13C-NMR (100 MHz, CDCl3): δ 66.4, 112.5, 114.3, 127.4, 128.9, 128.9, 130.1, 130.1, 130.5, 130.6, 131.4, 147.8, 156.7, 161.1.
4-Iodo-2-(p-tolyl)quinoline (2v)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2v (56%). 1H-NMR (400 MHz, CDCl3): 2.44 (s, 3 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.72–7.76 (m, 1 H), 7.99–8.08 (m, 4 H), 8.45 (s, 1 H). 13C-NMR (100 MHz, CDCl3): δ 21.3, 112.5, 127.4, 127.6, 129.0, 129.7, 130.2, 130.4, 130.5, 131.4, 135.2, 139.9, 147.8, 157.0. HRMS (ESI, m/z): calcd for C16H12IN: M + H = 346.0087; found: 346.0092.
4-Iodo-2-(naphthalen-2-yl)quinoline (2w)
The title compound was prepared according to the general procedure and purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 2w (67%). 1H-NMR (400 MHz, CDCl3): δ 7.54–7.57 (m, 2 H), 7.60–7.64 (m, 1 H), 7.75–7.80 (m, 1 H), 7.90–7.92 (m, 1 H), 7.99–8.05 (m, 3 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.32–8.35 (m, 1 H), 8.59 (s, 1 H), 8.63 (s, 1 H). 13C-NMR (100 MHz, CDCl3): δ 112.6, 124.8, 126.5, 126.9, 127.3, 127.7, 127.9, 128.7, 128.8, 129.2, 130.3, 130.6, 130.7, 131.5, 133.4, 134.0, 135.3, 147.9, 156.9. HRMS (ESI, m/z): calcd for C19H12IN: M + H = 382.0087; found: 382.0089.
2-(4-Methoxyphenyl)-4-(p-tolyl)quinoline (3a)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 3a (58%) [55]. 1H-NMR (400 MHz, CDCl3): δ 2.38 (s, 3 H), 3.78 (s, 3 H), 6.95 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.32–7.37 (m, 3 H), 7.59–7.63 (m, 1 H), 7.66 (s, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 8.05–8.12 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 21.3, 55.3, 114.2, 118.8, 125.6, 125.7, 125.8, 128.9, 129.2, 129.3, 129.4, 129.8, 132.3, 135.6, 138.2, 148.8, 149.0, 156.4, 160.8.
2,4-bis(4-Methoxyphenyl)quinoline (3b)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 3b (71%) [55]. 1H-NMR (400 MHz, CDCl3): δ 3.79 (s, 3 H), 3.81 (s, 3 H), 6.97 (dd, J = 8.8, 13.2 Hz, 4 H), 7.33–7.37 (m, 1 H), 7.41 (d, J = 8.8 Hz, 2 H), 7.59–7.63 (m, 1 H), 7.66 (s, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 8.06–8.12 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 55.3, 55.4, 114.0, 114.2, 118.8, 125.6, 125.7, 125.8, 128.9, 129.3, 129.8, 130.7, 132.3, 148.6, 148.9, 156.4, 159.8, 160.8.
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)quinoline (3c)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 3c (66%) [55]. 1H-NMR (400 MHz, CDCl3): δ 3.80 (s, 3 H), 6.96 (d, J = 8.8 Hz, 2 H), 7.13–7.18 (m, 2 H), 7.35–7.39 (m, 1 H), 7.43–7.46 (m, 2 H), 7.61–7.65 (m, 2 H), 7.73 (d, J = 8.4 Hz, 1 H), 8.06–8.13 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 114.2, 115.5, 115.7, 118.9, 125.3, 125.5, 126.0, 128.9, 128.5, 130.0, 131.2, 131.3, 132.0, 134.4, 134.5, 147.9, 148.8, 156.4, 160.9, 161.6, 164.1.
4-(3,5-Dimethylphenyl)-2-(4-methoxyphenyl)quinoline (3d)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 3d (62%). 1H-NMR (400 MHz, CDCl3): δ 2.34 (s, 6 H), 3.79 (s, 3 H), 6.95 (d, J = 8.8 Hz, 2 H), 7.05–7.08 (m, 3 H), 7.33–7.37 (m, 1 H), 7.59–7.63 (m, 1 H), 7.67 (s, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 8.06–8.12 (m, 3 H). 13C-NMR (100 MHz, CDCl3): δ 21.3, 55.3, 114.2, 118.7, 125.6, 125.7, 125.8, 127.3, 128.9, 129.3, 129.8, 129.9, 132.2, 138.1, 138.4, 148.7, 149.3, 156.4, 160.8. HRMS (ESI, m/z): calcd for: C24H21NO: M + H = 340.1696; found: M + H = 340.1692.
(E)-2-(4-Methoxyphenyl)-4-styrylquinoline (3e)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 3e (72%) [56]. 1H-NMR (400 MHz, CDCl3): δ 3.83 (s, 3 H), 6.99 (d, J = 8.4 Hz, 2 H), 7.27–7.39 (m, 4 H), 7.44–7.49 (m, 1 H), 7.58 (d, J = 7.2 Hz, 2 H), 7.63–7.67 (m, 1 H), 7.77 (d, J = 16.0 Hz, 1 H), 7.95 (s, 1 H), 8.08–8.12 (m, 4 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 114.2, 114.7, 123.3, 123.6, 125.2, 125.9, 127.1, 128.7, 128.8, 128.9, 129.4, 130.2, 132.4, 134.9, 136.7, 143.5, 148.8, 156.8, 160.8.
2-(4-Methoxyphenyl)-4-((4-methoxyphenyl)ethynyl)quinoline (4a)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 4a (67%) [45]. 1H-NMR (400 MHz, CDCl3): δ 3.86 (s, 3 H), 3.89 (s, 3 H), 6.95 (d, J = 8.8 Hz, 2 H), 7.05 (d, J = 8.8 Hz, 2 H), 7.55–7.59 (m, 1 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.71–7.75 (m, 1 H), 8.00 (s, 1 H), 8.13–8.16 (m, 3 H), 8.33 (d, J = 7.6 Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 84.5, 98.2, 114.2, 114.2, 114.4, 120.9, 125.7, 126.3, 126.3, 128.8, 129.8, 129.9, 130.5, 131.8, 133.5, 148.2, 156.4, 160.4, 160.9.
4-((3,5-Dimethoxyphenyl)ethynyl)-2-(4-methoxyphenyl)quinoline (4b)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 4b (76%). 1H-NMR (400 MHz, CDCl3): δ 3.78 (s, 6 H), 3.82 (s, 3 H), 6.48 (t, J = 2.0 Hz, 1 H), 6.76 (d, J = 2.4 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.96 (s, 1 H), 8.07–8.10 (m, 3 H), 8.25 (d, J = 8.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 55.5, 85.0, 97.8, 102.6, 109.7, 114.3, 121.3, 123.6, 125.6, 126.3, 126.5, 128.8, 129.9, 130.0, 130.0, 131.7, 148.2, 156.4, 160.7, 161.0. HRMS (ESI, m/z): calcd for: C26H21NO3: M + H = 396.1594; found: 396.1596.
2-(4-Methoxyphenyl)quinoline (5)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 5 (75%) [57]. 1H-NMR (400 MHz, CDCl3): δ 3.79 (s, 3 H), 6.96 (d, J = 8.8 Hz, 2 H), 7.38–7.42 (m, 1 H), 7.59–7.64 (m, 1 H), 7.70–7.75 (m, 2 H), 8.04–8.09 (m, 4 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 114.2, 118.5, 125.8, 126.9, 127.4, 128.9, 129.5, 129.5, 132.2, 136.6, 148.3, 156.9, 160.8.
2-(4-Methoxyphenyl)-4-(p-tolyloxy)quinoline (6a)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 6a (32%). 1H-NMR (400 MHz, CDCl3): δ 2.35 (s, 3 H), 3.77 (s, 3 H), 6.88–6.90 (m, 3 H), 7.04 (d, J = 8.4 Hz, 2 H), 7.18–7.21 (m, 2 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 2 H), 8.04 (d, J = 8.8 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 20.9, 55.4, 101.7, 114.0, 120.4, 120.7, 121.7, 125.4, 128.8, 129.1, 130.2, 130.7, 132.5, 135.1, 149.8, 152.3, 158.1, 160.7, 162.5. HRMS (ESI, m/z): calcd for: C23H19NO2: M + H = 342.1489; found: 342.1495.
4-(4-Chlorophenoxy)-2-(4-methoxyphenyl)quinoline (6b)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 6b (48%). 1H-NMR (400 MHz, CDCl3): δ 3.77 (s, 3 H), 6.89–6.92 (m, 3 H), 7.09 (d, J = 8.8 Hz, 2 H), 7.36 (d, J = 9.2 Hz, 2 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.65–7.70 (m, 1 H), 7.86 (d, J = 8.8 Hz, 2 H), 8.05 (d, J = 8.4 Hz, 1 H), 8.19 (d, J = 7.6 Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 55.5, 110.4, 114.5, 118.5, 123.8, 126.0, 129.3, 129.7, 131.2, 131.3, 132.9, 134.5, 149.9, 159.4, 162.0. HRMS (ESI, m/z): calcd for: C22H16ClNO2: M + H = 362.0942; found: 362.0948.
4-(4-Bromophenoxy)-2-(4-methoxyphenyl)quinoline (6c)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 6c (45%). 1H-NMR (400 MHz, CDCl3): δ 3.77 (s, 3 H), 6.89–6.93 (m, 3 H), 7.04 (d, J = 8.8 Hz, 2 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.67 (t, J = 8.4 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 8.18 (d, J = 8.0Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 102.3, 114.1, 118.2, 120.2, 121.5, 122.5, 125.7, 128.8, 129.2, 130.4, 132.1, 133.3, 149.8, 153.9, 158.1, 160.9, 161.7. HRMS (ESI, m/z): calcd for: C22H16BrNO2: M + H = 406.0437; found: 406.0431.
4-(4-Fluorophenoxy)-2-(4-methoxyphenyl)quinoline (6d)
The title compound was purified by column chromatography (silica gel, petroleum ether/ethyl acetate) to give a product 6d (53%). 1H-NMR (400 MHz, CDCl3): δ 3.77 (s, 3 H), 6.89–6.93 (m, 3 H), 7.04 (d, J = 8.8 Hz, 2 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.67 (t, J = 8.4 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 8.18 (d, J = 8.0Hz, 1 H). 13C-NMR (100 MHz, CDCl3): δ 55.4, 102.3, 114.1, 118.2, 120.2, 121.5, 122.5, 125.7, 128.8, 129.2, 130.4, 132.1, 133.3, 149.8, 153.9, 158.1, 160.9, 161.7. HRMS (ESI, m/z): calcd for: C22H16FNO2: M + H = 346.1238; found: 346.1234.

4. Conclusions

In summary, we have developed an efficient and general approach for the synthesis of 4-bromo or 4-iodo quinolines through the TMSBr promoted the cascade cyclization of ortho-propynol phenyl azides. It is noteworthy that the obtained products 4-halo quinolines could be used as key intermediate for the construction of various bioactive molecules, natural products, and drugs. A variety of 4-halo quinolines were obtained in moderate to excellent yields under mild conditions. This process does not require the use of metal catalysts, additional oxidants; water and nitrogen gas are generated as the only side products.

Supplementary Materials

The following are available online at https://www.mdpi.com/1420-3049/24/21/3999/s1.

Author Contributions

Conceptualization, Q.X.; Data curation, J.B.; Formal analysis, F.J., T.Y., and X.-R.S.; Writing—original draft preparation, F.J.; Writing—review and editing, X.-R.S., R.Y., and H.D.

Funding

This work was funded by the National Science Foundation of China (21676131 and 21462019), the Science Foundation of Jiangxi Province (20181BAB203005 and 20143ACB20012), the Education Department of Jiangxi Province (GJJ180616), Jiangxi Science & Technology Normal University (2017QNBJRC004).

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the final products are available from the authors.
Molecules 24 03999 sch001 550
Scheme 1. Our strategy for the construction of 4-bromo quinolines and its applications.
Scheme 1. Our strategy for the construction of 4-bromo quinolines and its applications.
Molecules 24 03999 sch001
Molecules 24 03999 g001a 550Molecules 24 03999 g001b 550
Figure 1. Transformation of ortho-propynol phenyl azides 1 to 4-bromo quinolines 2 a. a Unless otherwise noted, all reactions were performed with 1 (0.2 mmol) in CH3NO2 (2.0 mL) at 60 °C for 1 h. Isolated yield.
Figure 1. Transformation of ortho-propynol phenyl azides 1 to 4-bromo quinolines 2 a. a Unless otherwise noted, all reactions were performed with 1 (0.2 mmol) in CH3NO2 (2.0 mL) at 60 °C for 1 h. Isolated yield.
Molecules 24 03999 g001aMolecules 24 03999 g001b
Molecules 24 03999 sch002 550
Scheme 2. Functionality elaboration of 4-bromo-quinolines.
Scheme 2. Functionality elaboration of 4-bromo-quinolines.
Molecules 24 03999 sch002
Molecules 24 03999 sch003 550
Scheme 3. Transformation of 4-bromo quinoline 2a to 4-aryloxy quinolines 6.
Scheme 3. Transformation of 4-bromo quinoline 2a to 4-aryloxy quinolines 6.
Molecules 24 03999 sch003
Molecules 24 03999 sch004 550
Scheme 4. Proposed reaction mechanism.
Scheme 4. Proposed reaction mechanism.
Molecules 24 03999 sch004
Table
Table 1. Optimization of the reaction for the synthesis of 2a a.
Table 1. Optimization of the reaction for the synthesis of 2a a.
Molecules 24 03999 i001
EntrySolventTMSBr (x Equiv) T [°C]Yield [%]
1DCE2.56045
2MeCN2.56039
3CH2Cl22.54015
4MeNO22.56073
5HOAc2.56036
6MeNO23.56081
7MeNO23.06078
8MeNO22.06067
9MeNO23.58082
10MeNO23.5rt69
11 bMeNO23.56075
a Unless otherwise noted, all reactions were performed with 0.2 mmol of 1a in solvent (2.0 mL) for 1.0 h. b hydrobromic acid instead of TMSBr was used.

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Jin, F.; Yang, T.; Song, X.-R.; Bai, J.; Yang, R.; Ding, H.; Xiao, Q. TMSBr-Promoted Cascade Cyclization of ortho-Propynol Phenyl Azides for the Synthesis of 4-Bromo Quinolines and Its Applications. Molecules 2019, 24, 3999. https://doi.org/10.3390/molecules24213999

AMA Style

Jin F, Yang T, Song X-R, Bai J, Yang R, Ding H, Xiao Q. TMSBr-Promoted Cascade Cyclization of ortho-Propynol Phenyl Azides for the Synthesis of 4-Bromo Quinolines and Its Applications. Molecules. 2019; 24(21):3999. https://doi.org/10.3390/molecules24213999

Chicago/Turabian Style

Jin, Fengyan, Tao Yang, Xian-Rong Song, Jiang Bai, Ruchun Yang, Haixin Ding, and Qiang Xiao. 2019. "TMSBr-Promoted Cascade Cyclization of ortho-Propynol Phenyl Azides for the Synthesis of 4-Bromo Quinolines and Its Applications" Molecules 24, no. 21: 3999. https://doi.org/10.3390/molecules24213999

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