Iodine Promoted Efficient Synthesis of 2-Arylimidazo[1,2-a]pyridines in Aqueous Media: A Comparative Study between Micellar Catalysis and an "On-Water" Platform.

In a new and environmentally sustainable approach, a series of 2-arylimidazo[1,2-a]pyridine derivatives were synthesized in aqueous media in the presence of iodine as a catalyst. The reaction proceeded by condensation of various aryl methyl ketones with 2-aminopyridines to afford 2-arylimidazo[1,2-a]pyridines in good overall yields. Although several of the reactions were efficiently performed "on water", the addition of a surfactant, namely, sodium dodecyl sulphate , was found effective in terms of substrate scope and yield enhancement. Both methods were successfully used for the gram-scale synthesis of a marketed drug, zolimidine. The simple experimental setup, water as "green" media, and inexpensive catalyst are some of the merits of this protocol.

Introduction

The N-bridged heterocyclic systems, particularly the imidazopyridines, are ubiquitous among several bioactive molecules.[1] Among the imidazopyridine derivatives, the imidazo[1,2-a]pyridines, particularly with substituents at 2- and 3-positions, are of significant pharmaceutical interest as they display a wide range of pharmacological activities.[2] They are an integral part of several marketed drugs,[3] for example, 2,3-disubstituted imidazo[1,2-a]pyridine, alpidem, is an anxiolytic agent and zolpidem is used for insomnia, whereas 2-disubstituted imidazo[1,2-a]pyridine, zolimidine, is used for peptic ulcer (Figure ). Imidazo[1,2-a]pyridine derivatives have also shown their potential to act as proton pump inhibitors,[4a] aromatase inhibitor,[4b] γ-aminobutyric acid , and benzodiazepine receptor agonists,[4c] cardiotonic agents,[4d] β-amyloid formation inhibitors,[4e] orally active nonpeptide bradykinin B2 receptor antagonists,[4f] and so forth.[4] In addition, the compounds with imidazo[1,2-a]pyridine moiety in the structural framework have demonstrated potential applications in dyes, optoelectronics, sensing materials, and so on.[5]

Figure 1

Chemical structures of selected imidazo[1,2-a]pyridine-based drugs containing substituents at 2- and 3-positions.

Attributing to its vast applications, this field received tremendous research interest to develop clean and efficient synthetic methodologies for imidazo[1,2-a]pyridines.[3,6−20] The classical methods for the synthesis of imidazo[1,2-a]pyridines involve cyclocondensation of 2-aminopyridines with α-haloketones[6] or their equivalents,[7] and α,β-unsaturated carbonyl compounds in conventional reaction media.[8] Other notable two-component strategies include reactions between 2-aminopyridines with various coupling partners such as metal-catalyzed oxidative addition of alkynes,[9] nitroalkenes by tandem reactions,[10] oxidative coupling of 1,3-dicarbonyl compounds,[11] and so on.[12] Multicomponent approaches including metal-catalyzed A3-coupling reactions,[13] Groebke–Blackburn–Bienaymé reaction,[14] and others[15] provide an atom-economic platform for di- and trisubstituted imidazo[1,2-a]pyridines. Recently, we reported a greener alternative to 2,3-disubstituted imidazo[1,2-a]pyridines via A3-coupling reaction using a dynamic combination of Cu(II)/Cu(I) as the catalyst in micellar media.[16] Relooking at the current literature for the synthesis of imidazo[1,2-a]pyridines, we felt interested in dehydrogenetive heteroannulation between 2-aminopyridine and arylketo compounds to afford this heterocycle with an aryl group at C-2 (Scheme ).[3,17−19] In this direction, various methods have been developed in conventional media, which include metal-catalyzed C–H functionalization[17] (e.g., Cu(OAc)2 in dichlorobenzene,[17a] CuI in dimethylformamide (DMF),[17b] CuI in 1,4-dioxane,[17c] CuI–In(OTf)3 in N-methyl-pyrrolidone (NMP)[17d]), in situ α-iodination followed by Ortoleva–King-type reaction in the presence of catalytic or stoichiometric amount of iodine[18] (e.g., I2 in dimethyl sulfoxide (DMSO),[18a] I2–NH4OAc in CHCl3,[18b] I2–FeCl3 in chlorobenzene[18d]), and few others.[19] Apart from developing new strategies, efforts are also directed toward the development of practical and scalable methods for the synthesis of imidazo[1,2-a]pyridine-based drug candidates.[6d,9d,13a,17a,20] However, these methods have one or more shortcomings like the requirement of dry conditions, use of hazardous organic solvents, Lewis acids, high temperature, and so forth.

Scheme 1

Synthesis of 2-Arylimidazo[1,2-a]pyridines from 2-Aminopyridines and Acetophenones: Conventional Methods vs Our Work in Water

With the realization of the concept of “green chemistry”[21] and the urgent requirement for the protection of our environment in the present scenario, significant research efforts have been carried out for the replacement of hazardous organic solvents and reagents with nontoxic chemicals and environmentally benign solvents for any chemical transformation. It is noteworthy to mention that solvents account for the generation of up to 85% of waste in typical chemical transformations.[22] In this purview, water as a reaction medium is the most promising alternative to replace organic solvents.[23] After Breslow’s pioneering works in the field of water as the reaction medium in the early 1980s,[24] this field of chemistry generated immense interest among the organic chemists. Later, in 2005, Sharpless noticed the remarkable water-assisted acceleration of the reaction rate with water-immiscible substrates,[25] which he termed as “on water” reactions as the reactions presumably happen at the oil–water interface. Over a period of time, both “in-water”[23] and “on-water”[26] reactions leverage limited success mostly because of the solubility issues. A proved solution to this problem is the use of surfactants which form micelles or other assemblies, and bring the substrates in the “nanoconfined” hydrophobic cores and thereby facilitate organic transformations the field fondly called as “micellar catalysis”.[27] Particularly, the hydrophobic interior of micelles, formed by the surfactants, can successfully accomplish the most challenging task of “dehydration reactions” in water. As a part of our continued efforts in carrying out dehydration reactions in micellar nanoreactors,[16,28] we envisaged the development of a simple and “green” synthetic protocol for 2-arylimidazo[1,2-a]pyridines by dehydrogenative cyclocondensation, which involves a dehydration step, will be a worthy pursuit. While developing the method in micellar media, we observed that the protocol works well without surfactants as well. We report, herein, a comprehensive study on both micellar catalysis and “on water” platform for the synthesis of 2-arylimidazo[1,2-a]pyridines in aqueous media in the presence of iodine as the catalyst (Scheme ). In addition, the method is successfully employed for one-step economical synthesis of the gastroprotective drug, zolimidine, in gram scale, which demonstrates its potential application in the pharmaceutical industry.

Scheme 2

General Scheme for I2-Catalyzed Synthesis of 2-Arylimidazo[1,2-a]pyridines in Aqueous Media

Results and Discussion

Our initial focus was on finding out the optimum condition for micellar catalysis. Acetophenone (1a) and 2-aminopyridine (2a) were selected as model substrates for the initial investigations and the results are summarized in Table . At first, an optical microscope was used to confirm the formation of emulsion droplets by taking the optical micrograph of the reaction mixtures after 10 min of stirring at room temperature (Figure a). The dynamic light scattering (DLS) experiments revealed the formation of variable-sized emulsion droplets with an average diameter of 318 nm (Figure b). These tiny droplets act as confined nonreactors, thereby enabling the micellar catalysis in their core. Our initial trial in sodium dodecyl sulphate (SDS)-derived micellar media in the absence of any catalyst did not result in the formation of any product (Table , entry 1). Next, the screening of the catalyst, the additive, and the reaction temperature was carried out to establish the optimum condition of the reaction. In this direction, iodine was selected as a catalyst as it is known to promote similar reactions.[18] A model reaction was carried out with 1.0 mmol of acetophenone (1a) and 1.2 mmol of 2-aminopyridine (2a) in the presence of 30 mol % of I2 as the catalyst in simple aqueous media in the absence of any surfactant. To our surprise, the reaction after stirring at room temperature for 24 h produced a moderate amount of the desired product (3a) with a significant amount of starting materials left in the reaction mixture (Table , entry 2). After heating the reaction mixture at 80 °C, an improvement in the yield of 3a was observed (Table , entry 3). This encouraged us to separately study the use of the “on-water” platform for the same reaction, which will be subsequently discussed. It was found that the reaction in SDS-derived micellar media is sluggish at room temperature (Table , entry 4). However, mild heating at 40 °C boosts the reaction rate and the reaction gets completed within 8 h with significant enhancement in the final yield (Table , entry 5). Further increase in temperature does not have much impact on the reaction rate and the yield (Table , entry 6). Next, a study on the mol % of the catalyst revealed that 30 mol % of I2 is ideal to carry out the reaction in a shorter time with a better yield of the product (Table , entries 5, 7–9). However, it was observed that the addition of 1 equiv or more amount of iodine results in a large drop in the yield of the desired product (3a) (Table , entry 9). Whereas amine (2a) was fully consumed after 2 h of the reaction, a significant amount of acetophenone (1a) was recovered from the reaction mixture along with the product (3a). Presumably, iodine oxidizes a part of amine (2a) to undesired side products; both reactions occur in parallel. A portion-wise addition of amine or increase in quantity (up to 2 equiv) did not produce better results. Attempts were also made to expedite the reaction by the addition of a co-oxidant, which was considered to aid the aromatization step to achieve imidazo[1,2-a]pyridines (3) (Table , entries 10,11). However, the yield of the final product, 3a, was considerably dropped because of oxidative side reactions of amine (2a). Notably, a combination of I2 and another Lewis acid (e.g., La(OTf)3) did affect a bit on decreasing the reaction time with a marginal drop in the final yield (Table , entry 12). Even La(OTf)3 was found to catalyze the same reaction with a similar efficiency by completing the reaction in 12 h with an 83% yield of 3a (Table , entry 14). The same reaction was also attempted by using Cu(I) salt as a catalyst but the reaction was found sluggish as compared to I2 as a catalyst even at an elevated temperature, providing intermediate imine as the major product (Table , entries 15,16). Based on the study, 30 mol % I2 was selected as the ideal candidate to catalyze the formation of 2-arylimidazo[1,2-a]pyridines (3). Next, attention was paid to identifying the most suitable surfactant for the “micellar catalysis” and its quantity for smooth conversion (Table , entries 17–23). Therefore, different classes of surfactants, viz., anionic (SDS), cationic (cetyl trimethylammonium bromide (CTAB)), acidic (dodecylbenzenesulfonic acid (DBSA)), and neutral (Triton X-100, TPGS-750-M) were used. It was found that 10 mol % of SDS in 2 mL of H2O (or 48 mM, which is several folds above its critical micelle concentration of 8.2 mM) was found most suitable to provide the micellar environment for the smooth conversion of the product. Notably, the designer surfactant TPGS-750-M is also useful in carrying out this reaction but the final yield is relatively low and the time duration for the completion of the reaction is marginally higher in this case (Table , entry 21). Even one trial with a mixed surfactant (SDS Triton X-100) did not give a better result in terms of yield and time for completion of the reaction. Therefore, the optimized condition is considered as 30% of I2 as a catalyst, 10 mol % SDS as the micelle forming agent, and the temperature was set at 40 °C to obtain the product at a reasonably faster rate.

Table 1

Optimization of the Reaction Condition for 2-Arylimidazo[1,2-a]pyridine (3) in Aqueous Micellar Mediaa

entry	surfactant (mol %)	catalyst (mol %)	additive (equiv)	temp (°C)	time (h)	yield % of 3ab
1	SDS (10)			rt	24	n.d.
2		I2 (30)		rt	24	35c
3		I2 (30)		80	24	54c
4	SDS (10)	I2 (30)		rt	24	78
5	SDS (10)	I2 (30)		40	08	89
6	SDS (10)	I2 (30)		55	08	90
7	SDS (10)	I2 (20)		40	24	75
8	SDS (10)	I2 (10)		40	12	66
9	SDS (10)	I2 (100)		40	02	45d
10	SDS (10)	I2 (30)	H2O2 (2)	40	06	28d
11	SDS (10)	I2 (30)	(NH4)2S2O8 (1)	40	08	42d
12	SDS (10)	I2 (30)	La(OTf)3 (0.1)	40	06	87
13	SDS (10)	I2 (30)	NH4Cl (2)	40	08	85
14	SDS (10)	La(OTf)3 (10)		40	12	83
15	SDS (10)	CuI (10)		rt	24	trace
16	SDS (10)	CuI (10)		80	24	32e
17	SDS (05)	I2 (20)		40	24	64c
18	SDS (20)	I2 (30)		40	08	86
19	CTAB (10)	I2 (30)		40	12	39c
20	Triton X-100 (10)	I2 (30)		40	24	58c
21	TPGS-750-M (2 wt %)	I2 (30)		40	12	79
22	DBSA (10)	I2 (30)		40	24	51c
23	SDS (5)/Triton X-100 (5)	I2 (30)		40	08	88

The reactions were conducted taking 1 mmol of 1a and 1.2 mmol 2a in 2 mL of water.

Isolated yield.

Variable amount of both starting materials were recovered from the reaction mixture.

Amine (2a) was consumed but a significant amount of acetophenone (1a) was recovered.

Major product isolated was imine; n.d. not determined.

Figure 2

(a) Pptical micrograph of nanoreactors formed in an aqueous solution of SDS, acetophenone (1a) and 2-aminopyridine (2a) under an inverted microscope, IX51. (b) DLS data of the reaction mixture in the presence of SDS showing the formation of emulsion droplets; the average size is 318 nm.

With the optimized condition in hand, the substrate scope of this methodology by changing various electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) in both acetophenones (1) and 2-aminopyridines (2) was examined. The methodology was found quite capable to afford a large library of 2-arylimidazo[1,2-a]pyridines (3) in good to excellent yields (Table ). All the imidazo[1,2-a]pyridine derivatives were thoroughly characterized by 1H NMR, 13C NMR, and HRMS analysis. The 1H and 13C NMR spectra were in good agreement with the reported values of the known compounds.[6,12,17−19] The newly reported compounds were also in good agreement with their expected spectral characteristic peaks. A 1H singlet peak in the range δ 7.60–8.00 ppm is the signature peak of the imidazole moiety. The same characteristic peak appeared at around δ 107–109 ppm in 13C NMR for most of the compounds except for naphthalen-1-yl-imidazo[1,2-a]pyridine (3ab, 3ac), which appeared at around 117 ppm. In general, no general trend of a substituent effect was observed in terms of reaction time when electron-donating or electron-withdrawing substituents are present both in 2-aminopyridine (2) or the aromatic ring of acetophenone (1). However, acetophenone (1a) with no substitution in the ring reacted marginally faster than other acetophenone derivatives, affording corresponding products in a relatively quicker time (3a, 3j, 3p, 3t, 3y). Also, electron-deficient 2-aminopyridines reacted a little faster with electron-rich acetophenones (3q, 3u, 3v) in comparison to that of electron rich 2-aminopyridines with electron-deficient acetophenones (3n, 3o). Although no significant substituent effect was observed on the isolated yield of imidazo[1,2-a]pyridines, it was observed that if an EDG is present in 2-aminopyridine (2) and a strong EWG is present in the aromatic ring of acetophenone (1) the yields of the product (3) drop to a certain extent (3m, 3o). Notably, heterocyclic acetyl derivatives like 2-acetylfuran and 2-acetylthiophene participated in the reaction with equal efficiency to afford corresponding imidazo[1,2-a]pyridine derivatives in good yields (3ad–ah).

Table 2

Synthesis of 2-Arylimidazo[1,2-a]pyridine Derivatives in Micellar Mediaa

All yields refer to an isolated product.

Next, we focused our attention on developing a suitable condition to carry out the same reaction “on water” based on our observation that iodine can catalyze the same reaction in the absence of the surfactant (Table , entry 2, 3). For the improvement in yield, several additives were added and the reaction condition was also varied (Table ). As the reaction gave a better yield at an elevated temperature, the autoclave condition was first tried keeping the catalyst (I2) concentration the same at 30 mol %. However, there was hardly any improvement in the yield. Probably, I2 goes out of solution into the vapor phase and, therefore, is unable to catalyze the reaction (Table , entry 1). Noticeably, the addition of 1 equiv of NH4OAc[18b] in the aqueous medium could expedite the reaction to a significant extent (Table , entry 2). Next, a variable amount of NH4Cl was added to make the aqueous medium mildly acidic and its effect in the reaction was examined. It was found that 2 equiv of NH4Cl (or 1.0 M aqueous NH4Cl) is better to get the product, 3a, in 70% yield in 4 h (Table , entry 5). However, it was observed that some quantity of starting materials was left out in each of the above cases. A time-dependent study showed the reaction does not proceed much after 4 h (Table , entries 5–7). Rather, the quantity of starting amine gets reduced in the reaction mixture. It seems the reaction under the prevalent condition reaches dynamic equilibrium after 4 h of stirring. An attempt for complete conversion by continuous sonication of the reaction mixture showed no difference in the % of yield and the reaction time (Table , entry 8). Moreover, the addition of acid (Table , entry 9) or base (Table , entry 10) did not afford any better results. An attempt to carry out the reaction in an aqueous-organic medium by adding another “green solvent” EtOH (1 part against 4 parts of H2O), considering improved solubility of reacting organic substrates would ensure better conversion in lesser time, showed more inferior results (Table , entry 11). Also, based on a report by Cai et al.,[20c] a cocatalyst CuO was added to the reaction mixture but there was no improvement observed (Table , entry 12). Therefore, the final condition for the “on-water” reaction was set as per entry 5 of Table .

Table 3

Optimization of Reaction Condition for 2-Arylimidazo[1,2-a]pyridine (3) On-Watera

entry	additive (equiv)	temp (°C)	time (h)	% yield of 3ab,c
1		autoclave	12	58
2	NH4OAc (1)	rt	12	60
3	NH4Cl (1)	rt	12	67
4	NH4Cl (1)	55	08	65
5	NH4Cl (2)	rt	04	70
6	NH4Cl (2)	rt	12	70
7	NH4Cl (2)	rt	24	72
8	NH4Cl (2)	sonication	04	67
9	HOAc (2)	rt	12	62
10	K2CO3 (2)	rt	12	32
11	EtOH (0.5 mL)	55	12	47
12	CuO (1)	rt	06	68

The reactions were conducted taking 1 mmol of 1a and 1.2 mmol 2a in 2 mL of water with 30 mol % of I2 as the catalyst.

Isolated yields of 3a.

Variable amounts of both starting materials were recovered from the reaction mixture.

Next, the utility of this synthetic method was validated by employing the optimized condition to several substrates that were already used for the synthesis of 2-arylimidazo[1,2-a]pyridines (3) in micellar media (Table ). All the reactions were monitored by thin-layer chromatography (TLC) after an hour’s interval. It was observed that 2-aminopyridine (2a) and few other derivatives are sufficiently soluble but acetophenone derivatives (1) are only sparingly soluble in the given volume of water. Presumably, this allows the reactions to occur mainly on the oil–water interface and partly in the bulk water as well. In general, the yield of 3 is lower than what is obtained in micellar media. As mentioned earlier, in all cases reactions did not proceed to completion after a certain point. As these reactions produced only the desired product, which is well separated from the starting materials in TLC, with no traces of side products, it was easily purified from the starting materials to afford imidazo[1,2-a]pyridines (3) in good to decent yields (Table ). A similar substituent effect, as seen in micellar media, was observed “on-water”. It is interesting to note that the solubility of 2-aminopyridines (2) in water played a crucial role in controlling the rate of the reactions. For example, the series of products derived from less soluble 5-methylpyridin-2-amine (2b) took 8 h to reach equilibrium as compared to 4 h for 2-aminopyridine (Table , entries 6–8). However, no product formation was seen even after a long time of stirring at room temperature if both the starting materials are sufficiently insoluble in water [e.g., reaction between 5-cyanopyridin-2-amine (2e) and 4-cyanoacetophenone (1i)]; the reactions remain sluggish even after heating. For these cases, the reaction mixtures were heated at 80 °C for 24 h and the corresponding yields were reported (Table , entries 9–11, 13). Again, heteroaromatic acetyl derivatives responded well under the prevailing condition to afford corresponding products in good yields (Table , entries 15, 16).

Table 4

Synthesis of Imidazo[1,2-a]pyridine Derivatives “On-Water”

entry no.	product (3)	temp °C	time (h)	% yielda,b	ref
1	3a	rt	4	70	(12e)
2	3b	rt	4	64	(12e)
3	3c	rt	4	62	(12e)
4	3f	rt	4	68	(12e)
5	3i	rt	4	72	(12a)
6	3j	rt	8	65	(19b)
7	3k	rt	8	69	(17c)
8	3m	rt	8	52
9	3p	80 °C	12	50	(12a)
10	3r	80 °C	24	38
11	3s	80 °C	24	40	(12a)
12	3t	rt	8	63	(18c)
13	3x	80 °C	24	43	(18c)
14	3ab	rt	8	67	(17c)
15	3ad	rt	8	71	(12e)
16	3ah	rt	8	71	(12e)

Isolated yields.

In all cases, variable amounts of acetophenone derivatives (1) and 2-aminopyridine (2) were isolated after the reaction.

Mechanism

The reaction mechanism of this dehydrogenetive cyclocondensation reaction was thoroughly studied. The earlier reports[18a,18b] suggested Ortoleva–King reaction,[29] which requires a stoichiometric amount of I2 and excess of aminopyridines, in the way to the formation of 2-arylimidazo[1,2-a]pyridines (3). However, we observed, the reaction proceeds in the presence of a substoichiometric amount of I2 (30 mol %) and only the required amount of 2-aminopyridines (1.2 equiv), which indicates that a different pathway is predominantly operated in aqueous media. It was separately checked that no α-iodination occurs on acetophenone even in the presence of 1 equiv of I2 when both components are stirred in water in the presence or absence of 1 equiv of pyridine; whole acetophenone (1a) was recovered after 24 h of stirring. Also, another trial by using 1 equiv of N-iodosuccinimide as the iodinating agent in place of I2 in the model reaction between acetophenone (1) and 2-aminopyridine (2) failed to yield any product (3), indicating that α-iodination of acetophenone is not prevalent in the aqueous medium. Besides, no spot of intermediates was seen during the course of the reactions. Based on the abovementioned facts, an oxidative cyclocondensation[28a] has been proposed as the plausible mechanistic pathway (Scheme ). The reaction is initiated by the formation of a Schiff’s base (A), which is presumably the slowest step. The role of iodine is to act as a Lewis acid to make a partial bond with imine and facilitate tautomerism. Next, the pyridyl nitrogen attacks the enamine to form the cyclic intermediate (B). In the final step, oxidative aromatization takes place by the dissolved oxygen in water[28a] to afford the product.

Scheme 3

Plausible Mechanistic Pathway for the Formation of 2-Arylimidazo[1,2-a]pyridines (3) in Aqueous Media

Reusability of Reaction Media

Reusing the reaction media for subsequent reactions adds great value to the atom-economy and thus, the overall cost of a chemical process. The reusability studies were conducted for both micellar media and simple aqueous media with or without the addition of I2 as the catalyst. As SDS is more water-soluble, it does not come to the organic phase during the extraction process, which allows recycling of the micellar media. It was observed that the reaction does not progress much in the second cycle if another batch of 30 mol % of I2 is not added. Presumably, a large amount of I2 is taken up by the organic layer during the work-up, which causes sluggishness. However, the addition of a fresh batch of I2 makes the media effective for conversion of 1a and 2a to 3a with a marginal drop in the yield up to the third cycle (Figure ). The study showed that both the reaction media can be reused for subsequent reactions for a few cycles without much change in catalytic performance.

Figure 3

Yields of the reusability study in a bar diagram.

Gram-Scale Synthesis of Zolimidine

One of the most significant achievements of this protocol is the efficient one-pot synthesis of the marketed drug zolimidine (a gastroprotective drug) in the gram scale. Therefore, 1-[4 (methylsulfonyl)phenyl]ethan-1-one (1m, 5 mmol) and 2-aminopyridine (2a, 6 mmol) were reacted in 10 mL of water, yielding zolimidine in 81% on micellar media and in 62% yield using the “on-water” approach (Scheme ).

Scheme 4

Synthesis of Zolimidine in the Gram Scale

A comparative study of the present methods with the available methods for the synthesis of 2-2-phenylimidazo[1,2-a]pyridine (3a) was also done and corresponding E-factors were also calculated (Table ). To our pleasure, we found that the E-factors of the present methods were much less in comparison to most of the previous methods. E-factors for micellar catalysis and the on-water approach were obtained as 0.75 and 1.41, respectively. Notably, the present methods are milder than many other available methods. A quick cost calculation for the synthesis of 1 mmol of zolimidine was also done involving the available methods and our methods. To our delight, the micellar catalysis was found to be not only much greener but also ∼4 times cost-effective in terms of solvents, catalysts, and additives used for this method and the other reported gram-scale synthesis of zolimidine.[17a] This opens a new economical way for the potential application in pharmaceutical industries.

Table 5

Comparison Table of Various Methods for the Synthesis of Imidazo[1,2-a]pyridinesa

sr. no.	2a (equiv)	catalyst (mol %)	auxiliary (mol %)	solvent	condition	yield (%)	E-factorb	ref
1	1.2	[Bmim]Br3 (2 mmol)	Na2CO3 (2 mmol)	neat	40 °C, 40 min	82	3.21	(19b)
2	0.5	CuI (5 mol %)	BF3·Et2O (10 mol %)	DMF	60 °C, 24 h	82	3.62	(17b)
3	3	CuI (20 mol %)	BF3·Et2O [O2]	neat	40 °C, 24 h	41	4.71	(17e)
4	1.2	CuI (20 mol %)		1,4-dioxane	100 °C, 24 h	71	23.38	(17c)
5	2	CuI (5 mol %)/	In(CF3·SO3)3 (1 mol %)	NMP	100 °C, 24 h	82	44.89	(17d)
6	1.2	Cu(OAc)2·H2O (10 mol %)	1,10-phenanthroline (10 mol %)/ZnI2 (10 mol %)	1,2-DCB	120 °C, 24 h	80	16.80	(17a)
7	1	CuO (1.1 mmol)/I2 (1.1 mmol)		MeOH	reflux, 1–2.5 h	92	17.57	(20c)
8	1.2	I2 (1 mmol)	NH4OAc (2 mmol)	CHCl3	rt, 1 h	85	93.15	(18b)
9	1	I2 (20 mol %)		cyclohexane	60 °C, 15 min	78	42.90	(18c)
10	1.2	FeCl3·6H2O (20 mol %)/I2 (20 mol %)		chlorobenzene	110 °C, 20 h	39	63.46	(18d)
10	1.2	SDS (10 mol %)/I2 (30 mol %)		water	40 °C, 8 h	89	0.75c	present method
11	1.2	I2 (30 mol %)	NH4Cl (2 mmol)	water	rt, 4 h	70	1.41c	present method

The data presented against 1 mmol of acetophenone (2a).

E-factors were calculated based on the formation of 3a.

For aqueous media, H2O was not considered in the E-factor calculation.

Conclusions

In conclusion, we have demonstrated two different conditions for I2-promoted efficient synthesis of 2-arylimidazo[1,2-a]pyridine derivatives in aqueous media. An array of acetophenone derivatives and 2-aminopyridines were condensed either in the SDS-derived micellar media or on-water platform. Whereas mild heating (40 °C) was beneficial for rate acceleration in micellar media, most of the “on-water” reactions were carried at room temperature under mild acidic conditions in the presence of NH4Cl. In both cases, the methods were successfully employed on substrates with both electron-withdrawing and electron-donating substituents in acetophenones and 2-aminopyridines to afford 2-arylimidazo[1,2-a]pyridine in good to excellent yields. Even acetyl heteroaromatic compounds are well tolerated under the reaction condition to afford the desired products in excellent yields. In general, the yields in micellar media were found better than the “on water” approach. For the “on-water” approach, it was observed that the reactions are sluggish if both the substrates are water-insoluble. In such cases, reactions were carried out at 80 °C to get moderate yields of the products. The scope of these methods was also validated by the gram-scale synthesis of a marketed drug, zolimidine. The current methodologies are superior over existing methods because of the simple experimental set-up, use of water as “green” media, mild condition, inexpensive catalyst, and high yields.

Experimental Section

General Information

All reagents were purchased from commercial sources and were used without further purification. All solvents were obtained from local suppliers and were of research grade. The reactions were monitored by TLC carried out on 0.25 mm silica gel aluminum plates (60F-254) using UV light (254 or 365 nm) for visualization. Column chromatography was performed using 60–120 mesh silica gel. 1H NMR and 13C NMR spectra were recorded on Bruker Avance (400 MHz) with tetramethylsilane as the internal standard. Chemical shifts are reported in parts per million (δ) units. Standard abbreviations are used for representing the multiplicity of NMR peaks. HRMS spectra were recorded on Q-TOF LC–MS (6545 Q-TOF LC–MS, Agilent) using ESI as the ion source. IR spectra were recorded in KBr pellets with IR Affinity 1, Shimadzu. A Particulate Systems NanoPlus Zeta/nanoparticle analyzer was used for the DLS study. An Olympus IX51 optical microscope was used for capturing microscopic images.

General Procedure for the Synthesis of 2-Arylimidazo[1,2-a]pyridines (3)

Micellar Catalysis

In a 10 mL round-bottom flask, SDS (0.1 mmol) was added in 2 mL of water and the solution was vigorously stirred for 5 min. Then, acetophenone derivative (1, 1 mmol) and I2 (0.3 mmol) were added. The reaction mixture was sonicated for 5 min and kept for stirring. After 10 min, 2-aminopyridine (2, 1.2 mmol) was added and the reaction was then stirred for several hours as mentioned in Table . The progress of the reaction was monitored by TLC after each hour. The crude products were extracted with ethyl acetate (2 × 5 mL), washed with brine, dried over anhydrous sodium sulphate, and concentrated in vacuum to afford the crude 2-arylimidazo[1,2-a]pyridine derivative. The crude product was purified by column chromatography (silica gel, 60–120 mesh) using ethyl acetate-petroleum ether as the eluent.

“On-Water” Approach

In a 10 mL round-bottom flask, 2 mL of 1 M NH4Cl was taken. Then, an acetophenone derivative (1, 1 mmol) and I2 (0.3 mmol) were added and the reaction mixture was stirred for 5 min. Next, 2-aminopyridine (2, 1.5 mmol) was added and the reaction was further stirred vigorously for several hours as mentioned in Table . The progress of the reaction was monitored by TLC after each hour. The crude products were extracted from the aqueous phase by ethyl acetate (2 × 5 mL), washed with brine, dried over anhydrous sodium sulphate, and concentrated in vacuum to afford the crude 2-arylimidazo[1,2-a]pyridine derivatives (3). The crude product was purified by column chromatography (silica gel, 60–120 mesh) using ethyl acetate–petroleum ether as the eluent. The unreacted starting materials were also recovered.

Spectral Data of New Entries

2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridine (3m)

White solid, 170 mg (75%), mp 176–178 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 2.32 (s, 3H), 7.03 (dd, J1 = 1.2 Hz, J2 = 9.2 Hz, 1H), 7.10–7.15 (m, 2H) 7.52 (d, J = 9.2 Hz, 1H), 7.71 (s, 1H), 7.88–7.93 (m, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 18.1, 107.5, 115.6 (J = 21.5 Hz), 116.7, 122.1, 123.3, 127.5 (J = 8.0 Hz), 128.0, 130.2 (J = 3.2 Hz), 144.6, 144.8, 162.6 (J = 245 Hz); HRMS (ESI): calcd for C14H11FN2 [M + H]+, 227.0979; found, 227.0971.

4-(6-Methylimidazo[1,2-a]pyridin-2-yl)benzonitrile (3o)

Yellow solid, 142 mg (61%), mp 203–205 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 7.08 (dd, J1 = 1.6 Hz, J2 = 9.2 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.70 (dt, J1 = 0.8 Hz, J2 = 8.8 Hz, 2H), 7.85 (s, 1H), 7.92 (s, 1H), 8.03 (dt, J1 = 0.8 Hz, J2 = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 18.2, 109.3, 110.8, 117.1, 119.1, 122.8, 123.4, 126.2, 128.7, 132.5, 138.5, 143.4, 145.0; HRMS (ESI): calcd for C15H11N3 [M + H]+, 234.1026; found, 234.1017.

2-(4-Methoxyphenyl)imidazo[1,2-a]pyridine-6-carbonitrile (3q)

Light brown solid, 187 mg (75%), mp 208–210 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 3.89 (s, 3H), 6.94 (dd, J1 = 1.6 Hz, J2 = 6.8 Hz, 1H), 7.02 (dt, dd, J1 = 2.8 Hz, J2 = 8.8 Hz, 2H), 7.91 (dt, J1 = 3.2 Hz, J2 = 8.8 Hz, 2H), 7.94 (s, 1H), 8.01 (s, 1H), 8.20 (dd, J1 = 0.8 Hz, J2 = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 55.4, 106.8, 109.5, 110.4, 112.6, 114.4, 117.8, 123.2, 125.2, 125.9, 127.7, 143.4, 149.0, 149.6, 160.3; HRMS (ESI): calcd for C15H11N3O [M + H]+, 250.0975; found, 250.0966.

2-(4-Bromophenyl)imidazo[1,2-a]pyridine-6-carbonitrile (3r)

Light yellow solid, 229 mg (77%), mp 246–248 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 6.99 (dd, J1 = 1.6 Hz, J2 = 6.8 Hz, 1H), 7.62 (dt, J1 = 2.4 Hz, J2 = 8.4 Hz, 2H), 7.86 (dt, J1 = 2.4 Hz, J2 = 8.4 Hz, 2H), 8.02 (s, 1H), 8.04 (s, 1H), 8.24 (dd, J1 = 0.8 Hz, J2 = 7.2 Hz 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 107.5, 110.4, 112.9, 117.5, 123.1, 123.6, 126.2, 127.8, 131.5, 132.1, 143.5, 147.9, 156.4; HRMS (ESI): calcd for C14H8BrN3 [M + H]+, 297.9974 (for 79Br) and 299.9959 (for 81Br); found, 297.9963 (for 79Br) and 299.9945 (for 81Br).

6-Bromo-2-(3-methoxyphenyl)imidazo[1,2-a]pyridine (3v)

White solid, 200 mg (66%), mp 156–158 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 3.91 (s, 3H), 6.92 (ddd, J1 = 0.8 Hz, J2 = 4.8 Hz, J3 = 5.8 Hz, 1H), 7.24 (dd, J1 = 1.2 Hz, J2 = 9.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.53–7.56 (m, 2H), 7.82 (s, 1H), 8.26, (d, J = 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 55.4, 107.0, 108.5, 111.0, 114.5, 118.1, 118.5, 125.6, 128.1, 129.8, 134.6, 144.0, 146.5, 160.1; HRMS (ESI): calcd for C14H11BrN2O [M + H]+, 303.0128 (for 79Br) and 305.0113 (for 81Br); found, 303.0116 (for 79Br) and 305.0104 (for 81Br).

6-Methyl-2-(naphthalen-1-yl)imidazo[1,2-a]pyridine (3ac)

Light yellow thick oil, 188 mg (73%); 1H NMR (400 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 7.07 (dd, J1 = 1.6 Hz, J2 = 9.2 Hz, 1H), 7.51–7.58 (m, 3H), 7.63 (d, J = 9.2 Hz, 1H), 7.76 (s, 1H), 7.83 (dd, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 7.88–7.95 (m, 3H), 8.62–8.66 (m, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 18.2, 111.0, 117.0, 122.0, 123.3, 125.4, 125.8, 126.0, 127.6, 127.8, 128.32, 128.33, 131.5, 132.0, 134.0, 144.3, 145.0; HRMS (ESI): calcd for C18H14N2 [M + H]+, 259.1230; found, 259.1216.

6-Methyl-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (3ae)

Light yellow solid, 174 mg (81%), mp 206–208 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 2.30 (s, 3H), 7.01 (dd, J1 = 1.6 Hz, J2 = 8.8 Hz, 1H), 7.10 (dd, J1 = 3.6 Hz, J2 = 4.8 Hz, 1H), 7.30 (dd, J1 = 1.2 Hz, J2 = 5.2 Hz, 1H), 7.45 (dd, J1 = 0.8 Hz, J2 = 3.6 Hz, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.67 (s, 1H), 7.84 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 18.1, 107.2, 116.6, 122.2, 123.2, 123.4, 124.8, 127.7, 128.0, 137.8, 140.6, 144.5; HRMS (ESI): calcd for C12H10N2S [M + H]+, 215.0637; found, 215.0629.