NaBH₄/NaNO₃/H₂O: A Convenient System for Selective Reduction of Aldehydes VS. Ketones to their Corresponding Alcohols

Introduction

The chemoselective reduction of aldehydes without affecting ketones is a well- known strategy in organic synthesis. This subject is of great interest ¹ and numerous reducing systems and modified hydroborates have been reported for this subject ^2-4 such as by use of low temperatures ^5-6 addition of thiols ⁷,  metal salts ⁸, resins ⁹ and polyethylene glycol ¹⁰ or by several modified borohydrides ^11-13. We decided to investigate the reducing properties of NaBH₄ in the presence of NaNO₃ as the co-reagent for the reduction of aldehydes vs. ketones to their corresponding alcohols. Herein, we wish to report a convenient method for the reduction of aldehydes vs. ketones to their corresponding primary alcohols with NaBH₄/NaNO₃ as reducing system in water.

Results and Discussion

Ketones are less reactive than aldehydes in reduction reactions. But this character is not sufficient for selectively reduction of aldehydes vs. ketones (scheme 1, Path A). To achieve for more selectivity, the reduction reactions can be done slower. For this purpose we have examined the reduction reaction of benzaldehyde as model compound with NaBH₄ in aqueous media in the presence and absence of NaNO₃ as shown in scheme 1. Our observation showed that the reduction reaction of 1 eq. benzaldehyde completed at room temperature in the presence of 3 eq. NaNO₃ and 1.25 eq. NaBH₄ as shown in table 1.

 

Table1: The optimization reaction condition for the reduction of benzaldehyde (1 mmol) to benzyl alcohol in water (3 mL) at room temperature.  Click here to View table

 

For investigate of selectively reduction reaction, a mixture of benzaldehyde (1 eq.) and acetophenone (1 eq.) was prepared. The reaction mixture was treated with 1.25 equivalents of NaBH₄ and 3 equivalents of NaNO₃ in 3 mL water at room temperature. As shown in scheme 1, after 30 min, we have observed that the reduction of benzaldehye to benzyl alcohols was complete but acetophene was intact material i.e. the competition for reduction was favor of benzaldehyde (scheme 1, path B). This result can not achieve by only using NaBH₄ (scheme 1, path A).

 

Scheme 1  Click here to View scheme

 

The efficiency of this protocol was examined by the reduction of a variety of aldehydes in the presence of acetophenone. All reductions were completed within 30-180 min as shown in table 2. The molar ratio of NaBH₄ is not different according to the nature of the substrates. 1.25 molar equivalents of NaBH₄ and 3 molar equivalents of NaNO₃ per one equivalents of the substrate were sufficient to complete conversion of aldehydes to the corresponding alcohols in excellent yields (90-95%).

For more investigate, the reduction of 6-oxoheptanal and 4-acetylbenzaldehyde as ketoaldehydes to their corresponding ketoalcoholes has been done as shown in scheme 2. The reductions were completed within 50-65 min and the corresponding ketoalcoholes have been isolated in excellent yields (90-92%).

 

Scheme 2 Click here to View scheme

 

The preparation of ally alcohols from the reduction of conjugated carbonyl compounds is conventional in organic synthesis. Regioselective 1,2-reduction of α,β-unsaturated aldehydes due to competing 1,2- vs. 1,4-attack by the hydride is often difficult to achieve in organic synthesis. The tendency of sodium borohydride to reduce enals in a conjugate sense is highly dependent on solvent and often ignored.¹⁴ However, several specific reagents are available.¹⁵ In this context, we also investigated the possibility of the 1,2-reduction of α,β-unsaturated aldehydes and ketones with NaBH₄/NaNO₃/H₂O system. The reduction of cinnamaldehyde by 1.25 molar equivalents of NaBH₄ in the presence of 3 molar equivalents of NaNO₃ was thus carried out exclusively in 1,2-reduction manner within 40 minutes at room temperature. In this reaction, cinnamyl alcohol was obtained in 94% yield as shown in scheme 3 (Table 2, entry 9). Citral also showed the best efficiency and regioselectivity under this protocol (Table 2, entry 10).

 

Scheme 3 Click here to View scheme

 

Table2: The Reduction of Aldehydes (1 mmol) vs. Acetophenone (1 mmol) by NaBH4 (1.25 eq.)/NaNO3 (3 mmol) in Water (3 mL) at Room Temperature.  Click here to View table

 

The mechanism for the influence of NaNO₃ is not clear, but as shown in scheme 4 we think that a possible derivative of nitrate-borane as active reductant may form in situ under reaction condition. The possibility to form borane complex via nucleophilic attack is also well-known ^16-17. The nitrate-borane specie is generated by the nucleophilic attack of nitrate ion on borane (scheme 4, II) formed from sodium borohydride and water (scheme 4, I). The nitrate-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.

A Typical Procedure

In a round-bottomed flask (10 mL) equipped with a magnetic stirrer, a solution of NaBH₄ (0.047 g, 1.25 mmol) and NaNO₃ (0.255 g, 3 mmol) in water (3 mL) was treated with 6-oxoheptanal (0.128 g, 1 mmol) in one portion. The mixture was stirred at room temperature for 50 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 7-hydroxyheptan-2-one (0.236 g, 92%, Table 1, entry 7).

Conclusion

In conclusion, we have shown that NaBH₄/NaNO₃/H₂O reduces a variety of aldehydes vs. ketones to their corresponding primary 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 3 molar equivalents of NaNO₃ 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 andNaNO₃, convenient reaction times (30-180 min) and easy work-up procedure. Therefore this new protocol for chemoselective & regioselective reduction of aldehydes could be a useful addition to the present methodologies.

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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