Introduction 

The multi-component reaction has been projected as one of the most classical Mannich reactions and the reaction was utilized for the synthesis of β-amino carbonyl scaffolds (Mannich bases) by a one-pot reaction of aldehyde, amine; the reaction was discovered in 1917 [1]. As per literature reports, the Mannich bases are flexible organic chemicals used for many reactions as important intermediates [2–6] and broadly applicable for the synthesis of alkaloids [6]; this scaffold is also used in medicinal/pharmaceutical chemistry [7,8].

For the preparation of the mannish product, the researcher used numerous reagents, since for the last decade, Brønsted acid-based catalysts like acidic ionic liquids 

[9], HClO₄-SiO₂ [10], polymer-supported sulfonic acid [11], camphor sulfonic acid [12], acidic surfactants [13], H₃PW₁₂O₄₀ [14], and HCl [15], have been broadly applied for the production Mannich products, which provides an easy connection to Mannich bases. However, this protocol has limitations, requiring a large quantity of catalyst to perform the reaction, yielding less and having a longer reaction time. The reagents such as Lewis acids have been used for the preparation of Mannich bases includes BiCl₃[16], NbCl₅[17] ZrOCl₂·8H₂O [18], Zn(OTf)₂ [19], Yb(OPf)₃ [20], CeCl₃·7H₂O/CAN [21,22], and Ga(OTf)₃ [23]. These reagents are applied either in a solution-phase and solvent-free conditions. The reaction was also performed in the organometallic complexes of  Sb(III) [24], Ti(IV) [25], Zr(IV) [26, 27], Bi(III) [28], along with other Lewis acids, such as sulfonium [29] iodonium salts [30], which also deserve a very effective catalyst for this transformation.

Numerous acidic solvents were used for the Mannich base synthesis.  Guoying Zhao et al. have prepared brønsted acidic ionic liquids including ([Bmim]⁺[HSO₄]⁻), ([Bmim]⁺[H₂PO₄]⁻), ([Hmim]⁺Tsa⁻) and ([Hmim]⁺Tfa⁻)for the Mannich base synthesis [31].

Kun Li et al. developed a novel method for the Mannich base synthesis; the novel lipase was used for the direct synthesis of the Mannich base in water solvent [32]. Chandra Mukhopadhyay et al. have reported that the Boric acid and glycerol catalyzed efficient synthesis of Mannich base by the one-pot, three-component reaction with aldehydes, aromatic amines, and cyclic ketones in water at room temperature to produce the desired Mannich base in moderate to good yields [33]. 

The greener synthesis of the Mannich base is a challenging task for the chemist since for the last decade there is a large number of green methods are reported for the Mannich reaction. Mahmood Kamali et al.reported the solvent-free greener method for the synthesis of Mannich Bases from 4-Hydroxy-pyridine-2-one [34]. Also, Mahboob Ghadami et al. reported the sodium dodecyl sulfate micellar mediated Mannich reaction with the ultrasound irradiation of various aldehydes, aromatic amines, and acetophenone derivatives. However, this protocol usually requires higher loading of catalyst. Therefore, the development of highly potent, less costly, and non-toxic methods for the Mannich reaction is still highly desired. These studies revealed that the compounds with a β-amino carbonyl compound core have various biomedical properties, including antidiabetic, antimicrobial, antioxidant, antidyslipidemic, and anticancer activities [35-36]. However, the majority of these reported protocols have limitations such as the use of harsh conditions, loading of catalyst, toxic reagents, longer reaction time and low yields. Therefore, there is a need to develop a novel protocol for the synthesis of β-amino carbonyl compounds under mild conditions. However, we are always interested in the development of a novel methods for the synthesis of bioactive compounds [37-40]. This work aimed to develop a novel greener methodology for the synthesis of β-amino carbonyl compounds.

Experimental

All the apparatus and chemicals were used as per standard laboratory guidelines. The M.P. of the novel compound was done with melting point apparatus thermal IA9100 (Bibby Scientific Limited, Staffordshire, UK). The FTIR of the compound was recorded over the Bruker FTIR instruments. The ¹HNMR, and ¹³CNMR were recorded over the Bruker -300MHz, Bruker-400 MHz instruments. 

General procedure for the synthesis of Mannich base

The mixture of solution contains benzaldehyde (1mmol), acetophenone (1mmol), and amine (1mmol) in a Bi(OTf)₃ (1mL) and dry DCM (5mL) and the mixture was vigorously stirred at room temperature for 12-14 h. Once the reaction was completed, the product was isolated by the evaporation of the solvent and purified by simple column chromatography to afford the desired pure Mannich base in very good yields.

1,3-diphenyl-3-(phenylamino)propan-1-one (4A)

White solid, M.P. 170-171 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.87 (m, 2H), 7.64–7.58 (m, 1H), 7.54–7.46 (m, 4H), 7.40–7.36 (m, 2H), 7.32–7.26 (m, 1H), 7.18–7.15 (m, 2H), 6.74 (ddd, J=7.6, 2.2, 1.5 Hz, 1H), 6.62 (dt, J=8.6, 1.6 Hz, 2H), 5.06 (dd, J=7.6, 5.6 Hz, 1H), 4.60 (br s, 1H), 3.60 (dd, J=16.2, 5.4 Hz, 1H), 3.48 (dd, J=16.3, 7.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 198.38, 147.10, 143.20, 136.80, 133.60, 129.15, 128.50, 128.80, 128.45, 127.40, 126.34, 17.81, 113.34, 54.70, 46.32.

3-(4-chlorophenylamino)-1,3-diphenylpropan-1-one (4B)

White solid, M.P. 170-171, °C; IR ( KBr, ν cm^-1): 3365.44, 1660.14, 14980.60, 570.20, 507.23,  ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.70 (m, 2H), 7.60 (ddd, J=6.8, 4.2, 1.4 Hz, 1H), 7.55–7.48 (m, 2H), 7.48–7.34 (m, 2H), 7.38–7.44 (m, 2H), 7.08–7.01 (m, 1H), 6.42–6.77 (m, 1H), 4.90 (dd, J=7.8, 5.0 Hz, 1H), 4.54 (s, 1H), 3.42 (dd, J=8.2, 2.6 Hz, 1H), 3.63 (dd, J=8.4, 6.7 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 197.13, 146.54, 143.63, 143.52, 134.56, 129.96, 129.94, 129.78, 129.23, 128.54, 127.36, 125.49, 116.98, 55.93, 46.45.

3-(4-bromophenyl)-1-phenyl-3-(phenylamino)propan-1-one (4D)

Colorless solid; 83% yield; mp 131-133 °C; FT-IR cm^-1,  3294, 3029, 161, 1610, 1504, 1450, 1230, 1012, ; ¹H NMR (300 MHz, CDCl₃): d 3.41 (d, J=6.4 Hz, 2H), 4.95 (t, J=6.1 Hz, 1H), 6.62 (d, J=7.4 Hz, 2H), 6.75 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.8 Hz, 2H), 7.31–7.60 (m, 7H), 7.89(d, J=7.8Hz, 2H);  ¹³C NMR (50 MHz, CDCl₃): d 41.4, 54.3, 113.8, 120.2, 121.5, 128.21, 128.4, 128.8, 130.1, 131.7, 133.4, 136.2, 141.2, 145.6, 197.2.

Results and Discussion

Presently, there is an increasing demand for the introduction of economical and environmentally benign processes based on the principles of green chemistry. Herein, we have used a catalytic amount of Bi(OTf)₃ for the preparation of the Mannich base. The initial reaction on the (Bi(OTf)₃ catalyzed (0.5 mol%) three-component Mannich reaction of benzaldehyde, acetophenone, and aniline in a dry DCM solvent. The reaction mixture was stirred in the room to afford the corresponding β-amino ketone 4A in a 55% yield. Accordingly, we investigated the effect of different mol percentages of Bi(OTf)₃ (Table 1). When the reaction proceeded with 0.5mol% of Bi(OTf)₃ at room temperature for 12 h, giving compound 4A with 60% yield,  the reaction was performed with increasing in temperature to 60 °C; the formation of the product was observed with an increase in yields by 77% (Table 1, entry 4) and decrease in reaction time. The results we have obtained above highlight the importance of the temperature for the reaction. Then, the reaction was performed in the 1.0 mol% of Bi(OTf)₃ at 60 °C, obtaining desired products with 87% yield (Table 1, entry 5). Further increase of the temperature failed to improve the yield of the reaction; compound 4A was formed in 85% yield when the reaction was performed at 60 °C, with 1.5 mol% of Bi(OTf)₃.

 Table 1. Optimization of Mannish base

Further, we performed the reaction with Sc(OTf)₃, Yb(OTf)₃ and AgOTf in DCM solvent, and the result was good for the AgOTf similar to the Bi(OTf)₃ catalyst. With the optimized reaction condition in hand, then, we examined the scope multicomponent Mannich reaction with various substrates with optimized reaction conditions.  As shown in Scheme 1, Table 2, all the substrates proceed with smooth reaction with the optimized condition to afford β-amino ketones in moderate to very good yields. However, the time reaction for the completion of the reaction in case of the acetophenone with substituted aromatic aldehydes and substituted aromatic amines was longer compared with that of normal benzaldehyde and aniline.

Scheme 1. Synthesis of Mannish base

Table 2. Synthesis of Mannich bases 4A-4F

We have studied the solvent effect on the optimized reaction condition, as shown in Table 3. The reaction proceeded in the benzene, DMF, ether, THF, PEG, DMSO and DCM solvent, The reaction proceeded slowly in the DMF, ether, THF, PEG, DMSO with good to moderate yield, while the reaction proceeding in DCM resulted in the higher yield at 60 °C ( 87%, 5h)(Table 3).

It should be noted that no additional catalyst was employed in this reaction, and equivalent amounts of the starting materials were used. The present method is better than the previously reported method because the reaction condition is mild and atom-economic, thus it may have potential applications in organic synthesis. Some of the lewis acid catalyzed methods are shown in Table 4. Most of the methods show excellent yields and selectivity.

Table 3. Solvent effect on the HFIP -catalyzed Mannich reaction

Table 4.

Mechanism

The mechanism of the reaction goes via the aldol condensation followed by the azo-Michael addition reaction to produce desired Mannish base (Scheme 2), involving Bi(OTf)₃ catalyzed three-component reaction that proceeds via sequential aldol condensation and aza-Michael addition to affording the desired Mannish base (Scheme 2). The Mechanism involves the Bi(OTf)₃ to strongly activate the carbonyl compounds, hence, the reaction goes via aldol condensation to produce intermediates A, then the compound A reacts with 3 via Azo-Michael addition type reaction and gives desire product B.

Scheme 2. Proposed mechanism for Mannish reaction

Conclusion

We have applied Bi(OTf)₃ as an efficient catalyst for the Mannich reaction. Under the DCM solvent and 0.5 to 1.0 mol% of Bi(OTf)₃ catalyst, the reaction could catalyze with high yielding and diversity in substrate scope. All the synthesized compounds were characterized by using ¹HNMR, ¹³C NMR, FTIR, and Mass spectroscopy methods.

Acknowledgments

We appreciate the Camp Education Society Dr. Arvind B. Telang College of Arts, Science & Commerce for research support. The same goes to the Principal, Dr. D. Y. Patil ACS College, Pimpri, Pune-411918 for research support.

Conflict of Interest

We have no conflicts of interest to disclose.

Orcid

Somnath  Udgire:

https://orcid.org/0000-0003-1505-0273

Milind Gaikwad:

https://orcid.org/0000-0001-5917-6455

Prakash Patil:

https://orcid.org/0000-0002-6762-5537