Bromodimethylsulfonium bromide: an efficient catalyst for one-pot synthesis of 4-phenacylidene flavene derivatives

Abstract

The synthesis of 4-phenacylidene flavenes (3) was accomplished by a one-pot pseudo three-component condensation reaction between salicylaldehydes and acetophenones in the presence of 20 mol % of bromodimethylsulfonium bromide (BDMS) in acetonitrile at room temperature. The attractive features of this protocol are: use of organo-catalyst BDMS, simple reaction procedure, high bond-forming efficiency, good yields, and environmentally benign reaction conditions.

Introduction

With an increasing economic and ecological pressure, new concepts and synthetic strategies are continuously being evolved for the synthesis of valuable organic compounds in a more efficient, cheaper, and environmentally benign pathways.¹ Multicomponent reactions² (MCRs) have been used very successfully to address these issues and now occupy a central position in synthetic organic methodologies.³ MCRs are environmentally benign processes as they reduce the numbers of steps, the energy consumption, and the amounts of by-products formed. Due to the numerous advantages of MCRs, they are well-used for the easy construction of diverse heterocyclic scaffolds.⁴ Among all the heterocyclic compounds, oxygen containing heterocycles are widely distributed in nature, particularly chromene moieties are widely found in flavone, flavene, flavonoid, and isoflavonoid derivatives, which have attracted substantial researchers due to their pharmaceutical activities such as antitumor, antivascular, antimicrobial, anticancer, anti-HIV activities.⁵ Due to their immense potential, various research groups have put considerable effort into the synthesis of these compounds in recent times.

Comprehensive literature survey discloses that many efforts were made toward the synthesis of chromene moieties,⁶ but a very few methods are known for the synthesis of 4-phenacylidene flavene derivatives. The following methods are reported for the synthesis of these pharmaceutically useful scaffolds as follows (i) multi-step condensation reaction of salicylaldehyde and acetophenone using, hot HCl, or AcOH,⁷ (ii) one-pot reaction of salicylaldehydes and acetophenones using I₂⁶ as catalyst under reflux conditions.⁸ The other method available for the synthesis of 4-phenacylidene flavene was reported by Mayr and co-workers⁹ from the reaction of flavylium salt with 1-phenyl-1-(trimethylsiloxy)ethene in the presence of HBF₄·OEt₂ or TfOH. These methods are associated with certain limitations such as requirement of multi-step transformations,⁷ harsh reaction condition,7, 8 prolonged reaction time,⁸ low to moderate yield,8, 9 and use of harmful and expensive catalyst.⁹ Although all of these methods are quite useful, there is still further scope to synthesize 4-phenacylidene flavene derivatives using an easy and mild reaction condition involving a cheap and effective catalyst at room temperatures for the synthesis of 4-phenacylidene flavene derivatives. Recently, our research group¹⁰ as well as others,¹¹ have demonstrated that bromodimethylsulfonium bromide (BDMS), is a constructive catalyst for various organic transformations and multicomponent reactions. The importance and usefulness of BDMS have been recently reviewed by our group.¹² BDMS is less expensive, non-toxic, easy to handle, and environmentally acceptable pre-catalyst thus we have perceived that it can be explored further for the synthesis of 4-phenacylidene flavene derivatives. In continuation of our study of the catalytic activity of BDMS for the synthesis of various heterocycles through MCR, we report herein a straight forward, simple protocol for the synthesis of 4-phenacylidene flavene derivatives using pseudo three component condensations of one molecule of salicylaldehyde, and two molecules of acetophenone in acetonitrile at room temperature, shown in Scheme 1.

For the present study, the mixture of salicylaldehyde (1 mmol) and 4′-chloro acetophenone (2 mmol) was stirred in the presence of 10 mol % of BDMS in acetonitrile (3 mL) for 6 h at room temperature. The product 4-phenacylidene flavene 3a was isolated in 56% yield after chromatographic purification (Table 1, entry 1) and it was characterized from ¹H NMR, ¹³C NMR and mass spectra. The same set of reactions were also carried out using 15 mol % and 20 mol % of BDMS in acetonitrile under identical reaction condition and it provided the desired product 3a (Table 1, entries 2 and 3) in 69%, and 78% yields, respectively. From these observations, it is clear that the yield of the product 3a increases slowly with increasing the amount of catalyst from 10% to 20%. It was noted that the yield of the product 3a did not increase significantly by increasing the amount of catalyst from 20% to 30% (Table 1, entry 4). For scrutinizing the suitable solvent system, similar reactions (Table 1, entries 5–8) were conducted in ethanol, DCM, THF, and toluene under identical reaction conditions and the highest yields and the shortest reaction times were obtained in acetonitrile. To examine the efficacy of the catalyst, several reactions were carried out in the presence of other acidic catalysts (Table 1, entries 9–12) under identical reaction conditions. From these observations, it seems to us that BDMS is an optimal catalyst for the present reaction. The reactions were very sluggish and incomplete even after 24 h of stirring at room temperatures when the same reaction was carried out in the presence of protic acid such as acetic acid and hydrobromic acid (Table 1, entries 13 and 14). It was also observed that no desired product was obtained in the absence of catalyst even after 24 h of stirring at room temperature and only the starting substrates were recovered (Table 1, entry 15).

After optimizing the reaction condition, we performed a reaction with a mixture of salicylaldehyde (1 mmol) and acetophenone (2 mmol) under identical conditions¹³ and the desired product 3b was isolated in 76% yield (Table 2, entry 2). Next, we turned our attention to investigating the scope and applicability of this reaction by carrying out the synthesis of substituted 4-phenacylidene flavenes using different acetophenone derivatives with electron-withdrawing or electron-donating groups on the ring (Table 2). Acetophenone derivatives with electron-donating or electron-withdrawing groups produced 4-phenacylidene flavene derivatives 3c–f in moderate to good yields (Table 2, entries 3–6). It is worthwhile to mention that acetophenone with electron-donating groups on the ring (Table 2, entry 5 and 6) reacts faster as compared to acetophenone with electron-withdrawing groups (Table 2, entries 3 and 4) for the present protocol.

Likewise, heteroaryl methyl ketone, 2-acetylthiophene, also provided the desired product 3g (Table 2, entry 7) in excellent yield. To verify the generality of the present protocol, the reaction was explored with other substituted salicylaldehydes bearing OEt, OMe, and Br substituent in the ring with different acetophenone derivatives and the desired products 3h–o were obtained in good yields (Table 2, entries 8–15).

For an attempt to synthesize the unsymmetrical flavene moiety, we have performed the reaction with 3-OEt salicylaldehyde (1 mmol), acetophenone (1 mmol), and 4′-OMe acetophenone (1 mmol) under the identical reaction condition, which afforded the unsymmetrical product 3p after 4 h with 72% yield, along with the formation of trace amount of symmetrical products 3h and 3j as shown in Scheme 2.

To minimize the formation of side product in unsymmetrical reaction, we next explored the reaction with chalcone (E)-3-(2-hydroxyphenyl)-1-(p-tolyl)prop-2-en-1-one 4a which was synthesized from salicylaldehyde and 4′-Me acetophenone according to the reported method¹⁴ and consecutively treated with 4′-OMe acetophenone using 20 mol % of BDMS in acetonitrile at room temperature, the reaction results in the formation of desired product 3q exclusively with 88% yield after 1.5 h as shown in Scheme 3. Similarly reaction of chalcone derived from 3-OEt salicylaldehyde and acetophenone which is (E)-3-(3-ethoxy-2-hydroxyphenyl)-1-phenylprop-2-en-1-one 4b with 4′-OMe acetophenone gave the desired unsymmetrical product 3p exclusively in 81% yield under identical reaction conditions.

All the products from 3a–3q were characterized by IR, ¹H NMR, ¹³C NMR, and Mass spectroscopy. In FTIR spectrum, it showed characteristic absorptions peaks in between 1690 and 1743 due to one carbonyl group in product 3. Similarly, compound 3 showed a diagnostic signal at the range of δ = 8.74–9.08 ppm in the ¹H NMR spectrum assignable to the olefinic hydrogen trans to the carbonyl group. Finally, the structure of one of the representative compound 3f was confirmed unambiguously by single crystal X-ray diffraction analysis (Fig. 1).

On the basis of the reported literature,⁸ we have proposed a mechanism for the formation of product 3 as shown in Scheme 4. The first step is believed to be the formation of enolic acetophenone A in the presence of catalyst BDMS and it reacts with salicylaldehyde to give 2-hydroxy chalcone B, which undergoes intramolecular cyclization, to hemiacetal species C, which then gets converted to the more reactive flavylium ion D.¹⁵ Enolic form of acetophenone A reacts as C-nucleophiles and attacks flavylium ion D to form intermediate E. Finally intermediate E oxidizes in air to form the desired final product 3 as shown in Scheme 4.

In conclusion, we have developed a simple one pot pseudo three component reaction for the synthesis of 4-phenacylidene flavene derivatives from readily available salicylaldehydes and acetophenones, using a mild catalyst at room temperature. The reaction condition is simple and transformation is quite effective for a wide range of salicylaldehyde and acetophenone derivatives. The protocol is blessed with several advantages like one-pot, good yield, use of environment friendly catalyst, mild reaction condition, and superior atom economy.