One-Pot NBS-Promoted Synthesis of Imidazoles and Thiazoles from Ethylarenes in Water

A facile and eco-friendly method has been developed for the synthesis of imidazoles and thiazoles from ethylarenes in water. The reaction proceeds via in situ formation of α-bromoketone using NBS as a bromine source as well as an oxidant, followed by trapping with suitable nucleophiles to provide the corresponding products in good yields under metal-free conditions.

As a direct and efficient approach to the synthesis of these imidazoles and thiazoles, α-halo-ketones have reacted with suitable nitrogen nucleophiles and bases in various organic solvents (Scheme 1a) [28,29].Although this method is suitable for certain synthetic conditions, sometimes, however, these procedures have one or more disadvantages such as the use of hazardous organic solvents, long reaction times, use of stoichiometric and even excess amounts of reagents, etc.To overcome these limitations, Mahesh and co-workers recently reported a two-step approach to synthesize these heterocycles from alkenes, which involves preparing α-bromoketones by reaction of olefins with NBS in water, and these α-bromoketones were treated with suitable nucleophiles to give a diverse range of imidazoles and thiazoles (Scheme 1b) [30].This method is only applied in synthesis of some specific nitrogen-containing heterocycles, but, other heterocycles are not mentioned.α-Bromoacetophenone was also reported by Shimokawa et al. to be the important intermediate dealing with ethylarenes with NBS in a mixture of ethyl acetate and water [31].In this report, a variety of ethylarenes were converted into the corresponding primary aromatic amides.Inspired by this work, we envisaged the possibility to synthesize various imidazoles and thiazoles from ethylarenes.
Molecules 2019, 24, x 2 of 13 a diverse range of imidazoles and thiazoles (Scheme 1b) [30].This method is only applied in synthesis of some specific nitrogen-containing heterocycles, but, other heterocycles are not mentioned.α-Bromoacetophenone was also reported by Shimokawa et al. to be the important intermediate dealing with ethylarenes with NBS in a mixture of ethyl acetate and water [31].In this report, a variety of ethylarenes were converted into the corresponding primary aromatic amides.Inspired by this work, we envisaged the possibility to synthesize various imidazoles and thiazoles from ethylarenes.Here, we report an NBS-promoted, one-pot method for the construction of various imidazoles and thiazoles from ethylarenes in water as a solvent (Scheme 1c).  a diverse range of imidazoles and thiazoles (Scheme 1b) [30].This method is only applied in synthesis of some specific nitrogen-containing heterocycles, but, other heterocycles are not mentioned.α-Bromoacetophenone was also reported by Shimokawa et al. to be the important intermediate dealing with ethylarenes with NBS in a mixture of ethyl acetate and water [31].In this report, a variety of ethylarenes were converted into the corresponding primary aromatic amides.Inspired by this work, we envisaged the possibility to synthesize various imidazoles and thiazoles from ethylarenes.Here, we report an NBS-promoted, one-pot method for the construction of various imidazoles and thiazoles from ethylarenes in water as a solvent (Scheme 1c).
Scheme 1. Approach for the synthesis of imidazoles and thiazoles.Scheme 1. Approach for the synthesis of imidazoles and thiazoles.
Here, we report an NBS-promoted, one-pot method for the construction of various imidazoles and thiazoles from ethylarenes in water as a solvent (Scheme 1c).
NBS plays a dual role of both a safe bromine source and an oxidant, and the reaction was carried out with water, which also acts as the oxygen source for the in situ preparation of α-bromoketones.Water is an economical, safe, and environmentally benign solvent, and, therefore, its use as a solvent for organic reactions is a very attractive option [32,33].This protocol presents an operationally simple, rapid, and environmentally friendly strategy for enriching a complex nitrogen heterocycle library.

Optimization of Reaction Conditions for Synthesis of Imi-azo[1,2-a]pyridine 3a
Our study was initiated by treating ethylbenzene (1a, 1 mmol) as model substrate with NBS (3.5 equiv.) in the presence of AIBN (10 mol %) in a mixture of ethyl acetate:water (5:1, 6 mL) at 65 • C for 1.5 h, followed by addition of 2-aminopyridine (2a) at 80 • C to give the desired imidazo[1,2-a]pyridine (3a) in 38% yield (Table 1, entry 1).Interestingly, when NBS was replaced with N-chlorosuccinimide (NCS) or N-iodosuccinimide (NIS), formation of 3a was not observed (Table 1, entries 2 and 3), whereas with N-bromophthalimide (BrNPhth), compound 3a was obtained in 34% yield (Table 1, entry 4).NBS plays a dual role of both a safe bromine source and an oxidant, and the reaction was carried out with water, which also acts as the oxygen source for the in situ preparation of α-bromoketones.Water is an economical, safe, and environmentally benign solvent, and, therefore, its use as a solvent for organic reactions is a very attractive option [32,33].This protocol presents an operationally simple, rapid, and environmentally friendly strategy for enriching a complex nitrogen heterocycle library.

Optimization of Reaction Conditions for Synthesis of Imi-azo[1,2-a]pyridine 3a
Our study was initiated by treating ethylbenzene (1a, 1 mmol) as model substrate with NBS (3.5 equiv.) in the presence of AIBN (10 mol %) in a mixture of ethyl acetate:water (5:1, 6 mL) at 65 °C for 1.5 h, followed by addition of 2-aminopyridine (2a) at 80 °C to give the desired imidazo[1,2a]pyridine (3a) in 38% yield (Table 1, entry 1).Interestingly, when NBS was replaced with Nchlorosuccinimide (NCS) or N-iodosuccinimide (NIS), formation of 3a was not observed (Table 1, entries 2 and 3), whereas with N-bromophthalimide (BrNPhth), compound 3a was obtained in 34% yield (Table 1, entry 4).No improvement in the yield was observed by using acetonitrile, acetone, and 1,4-dioxane instead of ethyl acetate (Table 1, entries 5-7).A series of screening reactions to optimize the amount of oxidant, solvent system and reaction temperature was also performed, which had no good effect (Tables S1 and S2, see the Supplementary Information for details).After extensive experimentation, it was found that the presence of ethyl acetate in the reaction mixture was detrimental to the second reaction step.Hence, the solvent of second reaction step was replaced with water, ethanol, and acetone [34,35].Water was found to be the best solvent, furnishing imidazo[1,2-a]pyridine (3a) in 67% yield (Table 1, entries 8-10).Further optimization of the reaction conditions was made by adding sodium carbonate (Table 1, entries 11 and 12).In these cases, the yield of target product was improved to 78%.It is presumed that the sodium carbonate neutralizes the acid formed in the reaction, which No improvement in the yield was observed by using acetonitrile, acetone, and 1,4-dioxane instead of ethyl acetate (Table 1, entries 5-7).A series of screening reactions to optimize the amount of oxidant, solvent system and reaction temperature was also performed, which had no good effect (Tables S1  and S2, see the Supplementary Information for details).After extensive experimentation, it was found that the presence of ethyl acetate in the reaction mixture was detrimental to the second reaction step.Hence, the solvent of second reaction step was replaced with water, ethanol, and acetone [34,35].Water was found to be the best solvent, furnishing imidazo[1,2-a]pyridine (3a) in 67% yield (Table 1, entries 8-10).Further optimization of the reaction conditions was made by adding sodium carbonate (Table 1, entries 11 and 12).In these cases, the yield of target product was improved to 78%.It is presumed that the sodium carbonate neutralizes the acid formed in the reaction, which accelerates the intramolecular cyclization of the second step.Bringing the temperature to reflux did not have any noteworthy effect on the yield of 3a (Table 1, entry 13).

Substrate Scope for the Imidazo[1,2-a]pyridines
With optimized conditions in hand, the reactions of different 2-aminopyridines with various ethylarenes were investigated to explore the scope and generality of this method for the synthesis of different imidazo[1,2-a]pyridines (Table 2).The reaction of 2-aminopyridine (2a) with ethylarenes containing electron-withdrawing groups on the aromatic ring such as halogen, trifluoromethyl, methylsulfonyl, and cyano, provided the corresponding products 3b-3h smoothly in medium to good yields (32% and 65%).Ethylbenzenes with electron-rich groups, such as methyl and methoxy, also afforded the corresponding imidazo[1,2-a]pyridines 3i and 3j in very good yield (68% and 59%).The same treatment of 1-ethylnaphthalene gave the desired product 3k in good yield (65%).Furthermore, electron-rich and electron-withdrawing groups in the 2-aminopyridines were well tolerated.The results revealed that electron-rich groups such as methyl and methoxyl afforded the corresponding products in very good yield (yields 75-80%, 3l-3p).However, introduction of the electron-withdrawing groups such as halogen, trifluoromethyl, and cyano afforded the corresponding products in lower yields (yields 56-71%, 3q-3u).

Substrate Scope for Diverse Imidazoles and Thiazoles
Encouraged by the results above, we shifted to investigate the scope of other nucleophiles.As shown in Figure 2, a range of nucleophiles were suitable for this reaction.These substrates 4a-4g were effective to give corresponding products 5a-5g in moderate to high yields (60-91%).It is worth noting that valuable and more-complex substrates were also suitable for this reaction to afford corresponding products, which is extremely useful for enriching a complex nitrogen-containing heterocycle library.
Molecules 2019, 24, x 5 of 13 With optimized conditions in hand, the reactions of different 2-aminopyridines with various ethylarenes were investigated to explore the scope and generality of this method for the synthesis of different imidazo[1,2-a]pyridines (Table 2).The reaction of 2-aminopyridine (2a) with ethylarenes containing electron-withdrawing groups on the aromatic ring such as halogen, trifluoromethyl, methylsulfonyl, and cyano, provided the corresponding products 3b-3h smoothly in medium to good yields (32% and 65%).Ethylbenzenes with electron-rich groups, such as methyl and methoxy, also afforded the corresponding imidazo[1,2-a]pyridines 3i and 3j in very good yield (68% and 59%).The same treatment of 1-ethylnaphthalene gave the desired product 3k in good yield (65%).Furthermore, electron-rich and electron-withdrawing groups in the 2-aminopyridines were well tolerated.The results revealed that electron-rich groups such as methyl and methoxyl afforded the corresponding products in very good yield (yields 75-80%, 3l-3p).However, introduction of the electron-withdrawing groups such as halogen, trifluoromethyl, and cyano afforded the corresponding products in lower yields (yields 56-71%, 3q-3u).

Substrate Scope for Diverse Imidazoles and Thiazoles
Encouraged by the results above, we shifted to investigate the scope of other nucleophiles.As shown in Figure 2, a range of nucleophiles were suitable for this reaction.These substrates 4a-4g were effective to give corresponding products 5a-5g in moderate to high yields (60-91%).It is worth noting that valuable and more-complex substrates were also suitable for this reaction to afford corresponding products, which is extremely useful for enriching a complex nitrogen-containing heterocycle library.

Gram-Scale Preparation and Practice Application
To evaluate the efficiency and potential for practical applications of our method, a scale-up experiment was carried out under the standard conditions (Scheme 2a).As a result, preparation of 3a on a gram scale (2.95 g) was carried out, giving 76% yield.The compatibility of this reaction  accelerates the intramolecular cyclization of the second step.Bringing the temperature to reflux did not have any noteworthy effect on the yield of 3a (Table 1, entry 13).

Gram-Scale Preparation and Practice Application
To evaluate the efficiency and potential for practical applications of our method, a scale-up experiment was carried out under the standard conditions (Scheme 2a).As a result, preparation of 3a on a gram scale (2.95 g) was carried out, giving 76% yield.The compatibility of this reaction encouraged us to start the study of large-scale synthesis of zolimidine, which is a gastroprotective drug previously used for peptic ulcers and gastroesophageal reflux disease [36][37][38].Starting with 1-bromo-4-ethylbenzene (1c) the intermediate product 1h was obtained on the basis of a literature procedure [39].Then, according to the standard conditions, the target product 3h was obtained in 40% yield in total (Scheme 2b).
Scheme 2. Gram-scale preparation of 3a and synthesis of the gastroprotective drug zolimidine.

Mechanism
A series of mechanistic experiments were performed to shed more light on the reaction mechanism, as shown in Scheme 3.

Scheme 3. Mechanism experiments.
Scheme 2. Gram-scale preparation of 3a and synthesis of the gastroprotective drug zolimidine.

Mechanism
A series of mechanistic experiments were performed to shed more light on the reaction mechanism, as shown in Scheme 3.
Scheme 2. Gram-scale preparation of 3a and synthesis of the gastroprotective drug zolimidine.

Mechanism
A series of mechanistic experiments were performed to shed more light on the reaction mechanism, as shown in Scheme 3. When ethylbenzene (1a) was treated with NBS (3.5 equiv.) in the presence of AIBN (10 mol%) in a mixture of ethyl acetate and water (5:1) at 65 • C for 1.5 h, 2-bromoacetophenone (1aa) was obtained in 86% yield.At the same time, α,α-dibromoethybenzene (1ab) and acetophenone (1ac) were formed in 7% and 3% yields, respectively (Scheme 3b).2-Phenylimidazo[1,2-a]pyridine (3a) was obtained in 95% yield when 2-bromoacetophenone (1aa) was directly treated with pyridin-2-amine (2a) at 80 • C for 2 h (Scheme 3c).α,α-Dibromoethybenzene (1ab) was treated with NBS (1.5 equiv.) in the presence of AIBN (10 mol %) in a mixture of ethyl acetate and water (5:1) at 65 • C for 1.5 h, followed by the reaction with 2a at 80 • C for 2 h to give 3a in 71% yields (Scheme 3d).Besides, when acetophenone (1ac) was treated with NBS (1 equiv.) at 60 • C for 1 h, followed by the reaction with 2a at 80 • C for 2 h, 3a was obtained in 86% yield (Scheme 3e).As a result, α,α-dibromoethybenzene (1ab) and acetophenone (1ac) could also be converted into 3a using the present reaction procedure and conditions, which contributes to improve the yield of this reaction.On the basis of mechanistic experiments and a literature survey [24,40], a plausible pathway for the reaction has been proposed, as shown in Scheme 4, taking the reaction of ethylbenzene (1a) and 2-aminopyridine (2a) for the synthesis of imidazo[1,2-a]pyridine (3a) as an example.α-Bromoethybenzene is formed in the reaction of ethylbenzene (1a) with bromine atoms formed from NBS (Wohl-Ziegler reaction) [41].α,α-Dibromoethybenzene (1ab) is the main product of the second Wohl-Ziegler reaction of α-bromoethylarene.The hydrolysis of α,α-dibromoethybenzene (1ab) in a mixture of ethyl acetate and water under warming conditions proceeds to give acetophenone (1ac).Meanwhile, the hydrolysis of α-bromoethybenzene may occur to form α-hydroxyethybenzene as a minor product.Acetophenone (1ac) can also be easily obtained from α-hydroxyethybenzene oxidized by NBS.Once acetophenone (1ac) is formed, it smoothly reacts with NBS to form the important intermediate 2-bromo-acetophenone (1aa) which is isolated by column chromatography and confirmed by comparison of NMR with literature.Finally, treatment of 2-bromoacetophenone (1aa) with 2a afforded the desired product 3a by cyclization.

General Information
The reagents (chemicals) were purchased from commercial sources, and used without further purification.Analytical thin layer chromatography (TLC) was performed on HSGF 254 (0.15-0.2 mm thickness) plates.All products were characterized by their NMR and MS spectra.The 1 H-(500 MHz) and 13 C-NMR (125 MHz) spectra were recorded in deuterochloroform (CDCl3) on Bruker Avance III spectrometer (Billerica, MA, USA).Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane.Proton coupling patterns are described as singlet (s), doublet (d),

Experimental Part Method
3.2.1.General Procedure for the Synthesis of Nitrogen-Containing Heterocycles Synthesis of 3a is representative.To a solution of ethylbenzene (1a, 1 mmol, 107 mg) in ethyl acetate:water (5:1, 6 mL) were added NBS (3.5 mmol, 628 mg) and AIBN (0.1 mmol, 16.5 mg) at room temperature, and the mixture was stirred at 65 • C for 1.5 h.The mixture was concentrated to dryness and then dissolved in water (5 mL), followed by reaction with 2-aminopyridine (2a, 1.2 mmol, 114 mg) and sodium carbonate (5 mmol, 534 mg) for 2 h at 80 • C.After completion of the reaction (as indicated by TLC), the crude product was extracted with ethyl acetate (3 × 10 mL).The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo.The crude product was purified by silica gel column chromatography (PE/EA = 8/1-4/1, v/v) to give 3a (78% yield) as a white solid.

Figure 1 .
Figure 1.Biologically active compounds based on imidazoles and thiazoles.

Scheme 1 .
Scheme 1. Approach for the synthesis of imidazoles and thiazoles.

Figure 1 .
Figure 1.Biologically active compounds based on imidazoles and thiazoles.

Figure 1 .
Figure 1.Biologically active compounds based on imidazoles and thiazoles.

Table 1 .
Optimization of reaction conditions a .

Table 1 .
Optimization of reaction conditions a .