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

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.

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

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][7][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 .

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, CH 3 NO 2 , 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); CH 3 NO 2 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 CH 3 NO 2 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][7][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 H 2 O) 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 CH 3 NO 2 were stirred at 60 • C. efficient for this cascade transformation and could improve the yield of product 2a to 81% (Table 1, entries [6][7][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 R 1 and R 2 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 (R 2 ) 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 CF 3 ) in R 2 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 CH 3 NO 2 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. 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 2propynol 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 4iodo 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 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.
Molecules 2019, 24, x FOR PEER REVIEW 5 of 15 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.

Scheme 2. Functionality elaboration of 4-bromo-quinolines.
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 Scheme 2. Functionality elaboration of 4-bromo-quinolines.
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.

General Remarks
1 H-NMR spectra were recorded on 400 MHz in CDCl3 and 13 C-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 1 H-NMR and 13 C-NMR spectra are provided in the Supporting Information. Commercially available reagents were used without further purification. All solvents were dried under standard method. 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  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.

General Remarks
1 H-NMR spectra were recorded on 400 MHz in CDCl3 and 13 C-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 1 H-NMR and 13 C-NMR spectra are provided in the Supporting Information. Commercially available reagents were used without further purification. All solvents were dried under standard method.

General Remarks
1 H-NMR spectra were recorded on 400 MHz in CDCl 3 and 13 C-NMR spectra were recorded on 100 MHz in CDCl 3 . 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 1 H-NMR and 13 C-NMR spectra are provided in the Supporting Information. Commercially available reagents were used without further purification. All solvents were dried under standard method.

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 CH 3 NO 2 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-(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%). 1  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%). 1

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.