Ultrasonic-Promoted Selective Reduction of Aldehydes vs. ketones by NaBH₄/PhCO₂Na/H₂O

Introduction

Ultrasound irradiation is an exciting new unconventional energy in organic synthesis during the past decade. The promoted organic reaction by ultrasound irradiation has higher yield, shorter reaction time and milder conditions ¹.

The Reduction of aldehydes vs. ketones is interesting in organic synthesis ².  For this achievement several modified borohydrides ^2-3 have been reported. Also some reducing systems have been used for this purpose such as: use of low temperatures ^4-5 addition of thiols ⁶, metal salts ⁷, resins ⁸ and polyethylene glycol ⁹. In this context we have investigated the reducing properties of sodium borohydride (NaBH₄) in the presence of sodium benzoate (PhCO₂Na) as co-reagent for the reduction of aldehydes vs. ketones to their corresponding alcohols in water. This reducing system has been promoted by ultrasound irradiation.

Results and Discussion

Aldehydes are more reactive than ketones in reduction reactions. But to achieve for more selectivity, the reduction reactions can be done slower. We have examined the reduction reaction of benzaldehyde as model compound with NaBH₄ in aqueous media in the presence and absence of PhCO₂Na. Our experiments showed that the reduction reaction of 1 eq. benzaldehyde completed at room temperature in the presence of 2 eq. PhCO₂Na and 1.25 eq. NaBH₄ in H₂O (3 mL) under ultrasonic irradiation (table 1,entry 10) as shown in scheme 1.

Scheme 1   Click here to View Scheme

 

After this achievement, we have decided to investigate of chemoselective reduction of aldehydes vs. ketones under optimized reaction condition. So, a mixture of benzaldehyde (1 eq.) and acetophenone (1 eq.) was prepared. The reaction mixture was treated with 1.25 equivalents of NaBH₄ and 2 equivalents of PhCO₂Na in 3 mL water at room temperature, as shown in scheme 2. After 60 min, we have observed that the reduction of benzaldehye to benzylalcohols was completed but acetophene was intact material, i.e. the competition for reduction was favor of benzaldehyde.

Scheme 2 Click here to View Scheme

 

The efficiency of this protocol was examined by the reduction of a variety of aromatic aldehydes (Table 2, entry 1-11) and aliphatic aldehydes (Table 2, entry 14-15) in the presence of structurally different ketones (aliphatic and aromatic). All reductions were completed within 20-100 min as shown in table 2. 1.25 molar equivalents of NaBH₄ and 2 molar equivalents of PhCO₂Na per one equivalents of the aldehyde were sufficient to complete conversion of aldehydes to the corresponding alcohols in excellent yields (90-95%).

Also, We have investigated the possibility of the 1,2-reduction of α,β-unsaturated aldehydes (Table 2, entry 12-13)  in presence of α,β-unsaturated ketones with NaBH₄/PhCO₂Na/H₂O/U.S. system. The reduction of cinnamaldehyde and citral by 1.25 molar equivalents of NaBH₄ in the presence of 2 molar equivalents of PhCO₂Nacarried out exclusively in 1,2-reduction manner within 60-40 minutes at room temperature. In this reaction, the corresponding α,β-unsaturated alcohol were obtained in 90% yield as shown in scheme 3. Cinnamaldehyde and Citral have showed the best efficiency and regioselectivity under this protocol.

Scheme 3 Click here to View Scheme

 

The mechanism for the influence of PhCO₂Nais not clear, but as shown in scheme 4, we think that a possible derivative of benzoate-borane as an active reductant may form in situ under reaction conditions. The benzoate-borane specie is generated by the nucleophilic attack of benzoate ion on borane (scheme 4, II) that formed from sodium borohydride in water (scheme 4, I). The benzoate-borate is less reactive than NaBH₄ and diminishes reactivity.

Scheme 4 Click here to View Scheme

 

Experimental

General

All substrates and reagents were purchased from commercially sources with the best quality. IR and ¹H NMR spectra were recorded on PerkinElmer FT-IR RXI and 300 MHz Bruker spectrometers, respectively. The products were characterized by their ¹H NMR or IR spectra and comparison with authentic samples (melting or boiling points). Organic layers were dried over anhydrous sodium sulfate. All yields referred to isolated pure products. The purity of products was determinate by ¹H NMR. Also, reactions are monitoring over silica gel 60 F₂₅₄ aluminum sheet. Sonication was carried out using a Cole Palmer high intensity ultrasonic processor (600W, 20 KHz) via a micro-tip probe and 50% amplitude.

A typical Procedure for Reduction of aldehydes with NaBH₄/PhCO₂Na/H₂O/U.S. system

In a round-bottomed flask (10 mL) equipped with a magnetic stirrer, a solution of NaBH₄ (0.047 g, 1.25 mmol) and PhCO₂Na (0.138 g, 2 mmol) in water (3 mL) was treated with benzaldehyde (0.106 g, 1 mmol) in one portion. The mixture was stirred and irradiated with ultrasound waves at room temperature for 60 minutes. Completion of the reaction was monitored by TLC (Hexane/EtOAc: 9/1). Then, water (5 mL) was added to the reaction mixture. The mixture was extracted with ether (3×10 mL) and dried over anhydrous Na₂SO₄. Evaporation of the solvent afforded the pure benzyl alcohol (0.097 g, 90%).

A typical Procedure for Competitive Reduction of aldehydes and ketones with NaBH₄/PhCO₂Na/H₂O/U.S. system

In a round-bottomed flask (10 ml) equipped with a magnetic stirrer, a solution of benzaldehyde (0.106 g, l mmol) and acetophenone (0.120 g, 1 mmol) in H₂O (3 mL) was prepared. To this solution, NaBH₄ (0.047 g, 1.25 mmol) and PhCO₂Na  (0.138 g, 2 mmol) was added. The mixture was stirred and irradiated with ultrasound waves at room temperature for 60 minutes. TLC monitored the progress of reaction. After 60 min, the reaction mixture was quenched by addition of distilled water (5 ml) and this mixture was then stirred for an additional 1 min. The mixture was extracted with CH₂Cl₂ (5×10 ml) and dried over anhydrous sodium sulfate.

Evaporation of the solvent and short column chromatography of the resulting crude material over silicagel by eluent of Hexane/EtOAc: 9/1 affords the pure liquid benzyl alcohol (0.099 g, 92%) as a sole product of reduction and acetophenone as an intact material (table 2, entry 1).

Conclusion

In this context, we have been shown that NaBH₄/PhCO₂Na/H₂O/U.S reduces a variety of aldehydes vs. ketones to their corresponding alcohols in high to excellent yields at room temperature. Reduction reactions were carried out with 1.25 molar equivalents of NaBH₄ in the presence of 2 molar equivalents of PhCO₂Na in water as green solvent. In addition, regioselectivity of this system was also investigated with exclusive 1,2-reduction of conjugated enals to their corresponding allylic alcohols in excellent yields. All reductions were accomplished with high efficiency of the reductions, using the appropriate molar ratios of NaBH₄ andPhCO₂Na, convenient reaction times (20-100 min) under green chemistry protocol, and easy work-up procedure.

Acknowledgments

The authors gratefully appreciated the financial support of this work by the research council of Islamic Azad University branch of Mahabad.

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