Facile synthesis of 4H-chromene derivatives via base-mediated annulation of ortho-hydroxychalcones and 2-bromoallyl sulfones

Findings

Benzo[b]dihydropyran, commonly known as 4H-chromene (1), is a privileged heterocyclic scaffold that is found in a variety of biologically active natural and synthetic products (Figure 1) [1-3]. For example, the synthetic chromene derivative HA14-1 (Figure 1) has been shown to bind to the cellular protein Bcl-2 and to induce apoptotic cell death [4]. The natural chromene rhodomyrtone (Figure 1) is known to exhibit potent antibacterial activity [5]. As a consequence, a number of methods have been developed for the synthesis of substituted 4H-chromenes [6]. This includes, inter alia, transition metal-mediated cyclizations [7], multicomponent reactions [8], ring-closing metathesis approaches [9,10], tandem reactions of 1,3-dicarbonyl compounds [11,12] and cyclocondenzation reactions of salicylic aldehydes with α,β-unsaturated carbonyl compounds [13-15]. The utility of some of these methods are limited by drawbacks such as lengthy substrate synthesis, high cost of catalysts and tedious procedures. Therefore, general synthetic methods for accessing substituted chromene derivatives from readily available materials are still in demand.

During the course of our recent investigations on annulation reactions of unsaturated sulfones [16,17], we became interested in the possibility of exploiting allenyl sulfones as a building block for heterocyclic sulfones. The synthetic potential of allenyl sulfones remains largely unexploited. This is in sharp contrast with the widespread use of electronically similar allenyl esters (allenoates) in numerous useful reactions (see for examples [18-20]). The propensity of allenyl sulfones to oligomerise and display anomalous reactivity profiles in presence of base has, to some extent, dissuaded chemists from devising synthetic applications of allenyl sulfones [21,22]. We envisaged that such problems may be circumvented by developing a synthetic surrogate for the sensitive allenyl sulfones. Investigations along this direction led to the discovery that the easily prepared 2-bromoallyl sulfones 2a,b function as allenyl sulfone surrogates in the presence of cesium carbonate (Scheme 1, path a). Bromoallyl sulfones 2a,b partake in a cesium carbonate-mediated formal vinylic substitution reaction with heteronucleophiles to afford valuable multifunctional building blocks [23]. For example, the reaction of 2a with 4-chlorophenol afforded the enol ether 3 in 84% yield (Scheme 1, path b) [24]. Similarly, treatment of 2a with salicylaldehyde furnished the 3-sulfonyl-2H-chromene derivative 4 in 69% yield (Scheme 1, path c) [24]. The formation of allenyl sulfone 5 and propargyl sulfone 6 in the reaction of 2a with cesium carbonate indicated that 5 is an intermediate in the above-mentioned reactions (Scheme 1, path d) [24].

The facile cyclocondenzation of salicylaldehyde with 2a (Scheme 1, path c) prompted us to explore analogous annulation reactions for the synthesis of functionalized chromene derivatives. The biological activities exhibited by many 4H-chromene derivatives provided an added incentive for this investigation [1]. We envisaged that the presence of a Michael acceptor double bond at the ortho position of a phenol would offer avenues for carbon–carbon bond forming annulation in its reaction with 2a,b. In view of their well-known reactivity profiles, diversity options, stability, and ease of preparation, ortho-hydroxychalcones were considered to be a suitable choice for this purpose. A pilot reaction between the o-hydroxychalcone 7a and bromoallyl sulfone 2a in the presence of 2 equivalents of cesium carbonate in acetonitrile afforded the 4H-chromene derivative 8aa in 61% yield (Scheme 2). It may be noted that these reaction conditions were developed for the reaction of 2a with phenols (see Scheme 1, paths b and c) [24].

In the ¹H NMR spectrum of 8aa, three sets of doublet of doublets were visible at δ 4.52 (1H, J = 2.3 and 9.0 Hz), δ 3.58 (1H, J = 2.3 and 17.1 Hz) and δ 3.33 (1H, J = 9.0 and 17.1 Hz) arising from the -CH₂–CH- fragment. The methyl group protons resonated as a singlet at δ 2.51. A peak at δ 197.4 in the ¹³C NMR spectrum along with the absorption peak at 1680 cm⁻¹ in the IR spectrum confirmed the presence of the keto group. All other signals were in agreement with the assigned structure.

In order to explore the scope and generality of this facile 4H-chromene synthesis, a variety of o-hydroxychalcones were prepared as previously described (Scheme 3) [6].

The cesium carbonate-mediated reaction of 2-bromoallyl sulfones 2a,b with o-hydroxychalcones 7a–i proceeded uneventfully to afford the corresponding 2-methyl-3-arylsulfonyl-4H-chromene derivatives 8aa–8ib (Scheme 4).

The annulation reaction appears to be general as evident from the results in Scheme 4. The chalcone component can accommodate chloro, bromo and methoxy groups as aromatic substituents. Polycyclic aromatic hydrocarbon frameworks (naphthalene and anthracene rings) as well as a representative heterocyclic ring (furan) may be incorporated into the 4H-chromene skeleton product by using chalcones (7c, 7d, and 7e, respectively) functionalized with these moieties. Disappointingly, attempts to extend the annulation reaction to phenols with other Michael acceptors at the ortho-position (such as unsaturated esters, enals and nitroolefins) were not successful. Additionally, a very low yield (ca. 10%) of the product 8aa was obtained when the chalcone formation (7a) and its annulation reaction with 2a were combined into a one-pot operation (mediated by KOH in ethanol).

A plausible mechanistic rationalization of the 4H-chromene formation is presented in Scheme 5. Cesium carbonate mediates the dehydrobromination of 2a to produce the allenyl sulfone 5 (see Scheme 1, path d). Additionally, deprotonation of 7a by Cs₂CO₃ generates the phenoxide anion 9. A hetero-Michael addition of 5 and 9 results in the formation of a stabilized carbanion which may be represented as the resonance structures 10 or 11. The α-sulfonyl carbanion 11 then undergoes an intramolecular Michael addition to the β-carbon of the enone unit to afford the enolate 12. Isomerization of the exocyclic olefin moiety of 12 into the endocyclic position may be assisted by internal proton transfer. Tautomerization of the resultant enol 13 to its keto form affords the final product 8aa. It may be noted that the key carbon–carbon bond forming event (conversion of 11 to 12) here is completely regioselective as the Michael addition of the stabilized carbanion 11 occurs selectively at the α-sulfonyl position (not at the less hindered terminal of the allylic carbanion 11).

Conclusion

In conclusion, a base-mediated, facile synthesis of 3-sulfonyl-4H-chromenes from o-hydroxychalcones and 2-bromoallyl sulfones was developed. The starting materials are easily available and the reaction conditions are mild. 2-Bromoallyl sulfones 2a,b functions as stable surrogates for the sensitive allenyl sulfones in this reaction. Functionalities such as carbonyl and sulfonyl groups are easily incorporated into the privileged scaffold of 4H-chromene via this method.