An efficient multicomponent, one-pot synthesis of Betti bases catalyzed by cerium (IV) ammonium nitrate (CAN) at ambient temperature

1 Introduction

Various biologically active natural products possess 1,3-aminooxygenated functional groups [1], [2]. Among these scaffolds the aminonaphthols, so called “Betti bases” [3] represent an important class of such compounds. Owing to several interesting biological activities [4], synthesis of substituted Betti bases has become an important area of synthetic organic chemistry. Mario Betti in 1901 [5] was the first who reported the synthesis of Betti bases by acid hydrolysis of 1,3-diphenylnaphthooxazine formed via modified Mannich reaction of benzaldehyde, ammonia and 2-naphthol. This reaction has been subsequently explored utilizing different N-sources. In addition, asymmetric aminonaphthols prepared using chiral amines could be utilized as chiral catalysts in performing enantioselective reactions [6]. In the last decade, Betti bases have received considerable interest and several methodologies for their synthesis have been reported. This involves the use of acidic catalysts such as Fe(HSO₄)₃ [7], CF₃CO₂H [8], FeCl₃-SiO₂ [9], NaHSO₄ [10], ionic liquids [11], Triton X-100 non-ionic surfactant in water [12], solvent free conditions utilizing catalytic amounts of p-TSA under microwave irradiation [13], and basic nano-crystalline MgO in aqueous medium [14]. A new approach utilizing solid ammonium acetate and formate as a green ammonia source rather than methanolic ammonia solution has been recently reported [15]. Another approach is the hydrolysis of amidoalkyl naphthols [16]. Although these reactions have their advantages, there are demerits such as the use of expensive low selectivity catalysts, environmentally harmful solvents, and requirement of long reaction times and non-applicability to aromatic amines. In order to overcome these problems, a general efficient and green methodology is needed utilizing cerium (IV) ammonium nitrate (CAN) as inexpensive and benign catalyst. CAN has emerged as a potential reagent for the construction of carbon-carbon and carbon-heteroatom bonds via radical intermediates. In addition it possesses many advantages such as excellent solubility in different solvents, low cost, easy handling, high reactivity and ecofriendly nature. In addition, CAN is able to catalyze organic transformations not only as one electron oxidant, but also as a Lewis acid. As a continuation of our and others interest in the synthesis of biologically relevant heterocycles performing multicomponent reactions [17], [18], [19], [20], [21], [22], [23], herein we wish to report an efficient, simple and green modified Mannich type synthesis of Betti bases using CAN as a Lewis acid catalyst at ambient temperature. Only a few reports for the C-N bond formation utilizing CAN as a Lewis acid have been reported [24].

2 Materials and methods

3 Results and discussion

In our initial experiments, three-component reaction of benzaldehyde (1a), 2-naphthol (2), and aniline (3a) in 1:1:1.2 molar ratio in methanol (20 ml) was treated with 2% mol of CAN at room temperature. We obtained Betti base 4a in 55% yield. The same applies for 5% mol of CAN. We noted that 10% mol of the catalyst gives the highest yield (Scheme 1). Higher loads of the catalyst have no effect on the overall yield. For choosing the suitable solvent, various trials were investigated with H₂O, EtOH, and tetrahydrofuran. It was noticed that in water, only the corresponding Schiff’s bases were the only isolable products. For example the multicomponent reaction of 4-methoxy bezaldehyde (1n), 2-naphthol (2) and 4-hydroxyaniline (3n) in 1:1:1.2 molar ratio in water (20 ml) utilizing 10% mol of CAN at room temperature afforded the corresponding 7n. The spectral data of 7n was in agreement with the proposed structure (see Experimental). Similarly, the reaction of aldehydes 1a–o, 2-naphthol (2) and amines 3a–o in water under the same experimental conditions afforded Schiff bases 7. It has been observed that methanol is the best solvent for the present reaction. The reaction of substituted aromatic aldehydes with substituted anilines proceeded smoothly and afforded the corresponding Betti bases in excellent yields (Table 1).

Scheme 1:

Synthesis of Betti bases 4a–o and 6a,b.

It was previously reported that it is difficult to synthesize the corresponding N,N-dialkyl derivatives of Betti bases [25]. Only a few reports concerning that matter have been reported [14], [26]. We extended our protocol to the synthesis of the corresponding alkylamino-naphthol analogues 6a,b utilizing aldehydes 1h,o, 2-naphthol (2) and alkyl amines 5a,b under the same experimental conditions, which afforded excellent yields of the desired products.

A plausible mechanism for the synthesis of 4 and 6 is formulated in Scheme 2. It is expected that condensation of aldehydes with amines in the presence of CAN as a Lewis acid catalyst forms the corresponding iminium salt intermediate followed by dehydration to form the corresponding Schiff base 7. Subsequent nucleophilic attack of 2-naphthol to Schiff base intermediate afforded the corresponding Betti base. In support of this proposed mechanism, the reaction was conducted in water utilizing 10% mol of CAN which afforded the corresponding Schiff bases 7. This could be rationalized by low solubility of reagents in water.

Scheme 2:

Proposed mechanism for the synthesis of Betti bases.

4 Conclusion

In conclusion, we have documented a three-component, one-pot synthesis of Betti bases using CAN as a Lewis acid catalyst at room temperature. Considering the advantages such as readily available starting materials, simple operations as well as the high yields, our methodology will potentially find its application to the well-known Betti bases synthesis.