NaBH₄/Na₂C₂O₄/H₂O: An efficient System for Selective Reduction of Aldehydes in the presence of Ketones

Introduction

The selective reduction of aldehydes in the present of ketones is a well-honed strategy in organic synthesis. For this subject numerous reducing reagents and reducing systems have been prepared ^1-4 such as a) perform reduction reactions in low temperatures ^5-6  b) in the presence of thiols ⁷ c) by addition of  metal salts ⁸ c) by resins ⁹ d) on  polyethylene glycol ¹⁰ e) also by some modified borohydrides ^11-13. But, in terms of unavailability of reagents, non-convenient reduction reaction conditions, unacceptable ratio of selectivity and low yields of products, challenges is still remain to investigate of new reducing systems. So, we decided to investigate reducing properties of NaBH₄ in the presence of sodium oxalate (Na₂C₂O₄) as a co-reagent for the reduction of aldehydes vs. ketones to their corresponding alcohols. Herein, we wish to report a convenient and efficient system for the reduction of aldehydes vs. ketones to their corresponding alcohols with NaBH₄/Na₂C₂O₄/H₂Oas a reducing system.

Results and Disscution

Aldehydes are more reactive than ketones in reduction reactions. But it is not sufficient for sole selective reduction of aldehydes vs. ketones as shown in scheme 1, Path A. One approach is to this achievement that the reduction reactions can be carried out slower. For this purpose we have performed the reduction reaction of benzaldehyde as model compound with NaBH₄ in the presence of Na₂C₂O₄ in different conditions as shown in table 1. The experiments showed that the reduction reaction of 1 eq. benzaldehyde completed at room temperature in the presence of 3 eq. Na₂C₂O₄ and 1.5 eq. NaBH₄ in water as shown in table 1, entry 6.

Table1: The optimization reaction condition for the reduction of benzaldehyde (1 mmol) to benzyl alcohol in water (3 mL) at room temperature with NaBH₄ and Na₂C₂O₄.

The optimized conditions for reduction of benzaldehye has been used for investigate of selectively reduction reaction. Therefore a mixture of benzaldehyde (1 eq.) and acetophenone (1 eq.) was prepared. Then, the reaction mixture was treated with NaBH₄ (1 eq.)  and Na₂C₂O₄ (3 eq.) in water (3 mL) at room temperature. After 90 min, we have observed that the reduction of benzaldehye to benzyl alcohols was completed 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 different ketones. All reductions were completed within 90-180 min as shown in table 2. The molar ratio of NaBH₄ is not different according to the nature of the substrates. 1.5 molar equivalents of NaBH₄ and 3 molar equivalents of Na₂C₂O₄ per one equivalents of the substrate were sufficient to complete conversion of aldehydes to the corresponding alcohols in excellent yields (93-95%).

The reduction of conjugated carbonyl compounds is conventional method for the preparation of ally alcohols. However, reduction of α,β-unsaturated aldehydes to their corresponding primary ally alcohols is often difficult due to competing 1,2- vs. 1,4-reduction by the hydride attack. 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 and our continues to development reducing systems, ¹⁶ we also investigated the possibility of the 1,2-reduction of α,β-unsaturated aldehydes in the presence of  α,β-unsaturated ketones with NaBH₄/Na₂C₂O₄/H₂O system. The reduction of cinnamaldehyde (scheme 2) and citral (scheme 3) in the presence of benzylideneacetone and chalcone by 1.5 molar equivalents of NaBH₄ and 3 molar equivalents of Na₂C₂O₄ were thus carried out exclusively in 1,2-reduction manner within 80-90 minutes at room temperature in water. In this reaction, cinnamyl alcohol and geraniol were obtained. (Table 2, entry 9-12). Cinnamaldehyde and citral showed the best efficiency and regioselective and chemoselective reduction under this protocol.

Table2: Competitive reduction of  Aldehydes (1 mmol) vs. Ketones (1 mmol) to their corresponding alcohols  by NaBH₄ (1.5 eq.)/ Na₂C₂O₄ (3 mmol) in Water (3 mL) at Room Temperature.

	Table 2. Competitive reduction of  Aldehydes (1 mmol) vs. Ketones (1 mmol) to their corresponding alcohols  by NaBH4 (1.5 eq.)/ Na2C2O4 (3 mmol) in Water (3 mL) at Room Temperature.
	Entry	Substrate 1	Substrate 1	Time/min.	Conv. 1/ Conv. 2/%a
	1	benzaldehyde	acetophenone	90	100:0
	2	4-bromobenzaldehyde	acetophenone	90	100:0
	3	4-methylbenzaldehyde	benzophenone	100	100:0
4		4-nitrobenzaldehyde	acetophenone	90	100:0
	5	2-methoxylbenzaldehyde	cyclohexanone	180	100:0
	6	benzaldehyde	cyclohexanone	180	100:0
	7	butanal	cyclohexanone	100	100:0
	8	2-hydroxybenzaldehyde	aceyophenone	90	100:0
	9	cinnamaldehyde	benzylideneacetone	90	100:0
	10	cinnamaldehyde	chalcone	90	100:0
	11	citral	benzylideneacetone	80	100:0
	12	citral	chalcone	80	100:0

.^a Conversions refer to TLC monitoring and isolated pure products

Scheme 2

Click here to View scheme

 

Scheme 3

 

Click here to View scheme

 

The mechanism for the influence of Na₂C₂O₄ is not clear, but as shown in scheme 4 we think that a possible derivative of oxalate-borane as active reductant may form in situ under reaction condition. The possibility to form borane complex via nucleophilic attack is also well-known ¹⁷. The oxalate-borane specie is generated by the nucleophilic attack of oxalate ion on borane (scheme 4, II) formed from sodium borohydride and water (scheme 4, I). The oxalate-borate is less reactive than NaBH₄ and diminishes reactivity.

Scheme 4

Click here to View scheme

 

All substrates and reagents were purchased from commercially sources with the best quality. IR and ¹H NMR spectra were recorded on Perkin Elmer 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 (0.057 g, 1.5 mmol) and Na₂C₂O₄ (0.402 g, 3 mmol) in water (3 mL) was treated with  benzaldehyde (0.106 g, l mmol) and acetophenone (0.12 g, 1 mmol) in one portion. The mixture was stirred at room temperature for 90 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 and short-column chromatography of the resulting crude materials over silica gel (eluent; Hexane/EtOAc: 9/1), affords the pure liquid benzyl alcohol as a sole product of reduction reaction and acetophenone as an intact material.

Conclusion

In conclusion, we have shown that NaBH₄/Na₂C₂O₄/H₂O system 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 1.5 molar equivalents of NaBH₄ in the presence of 3 molar equivalents of Na₂C₂O₄ in water as green solvent. All reactions were accomplished with high efficiency of the reductions, using the appropriate molar ratios of NaBH₄ andNa₂C₂O₄, convenient reaction times (80-180 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.

Acknowlegment

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

Refrences

1. Cha. J. S.; Kim, E. J.; Kwon, O. O.; Kim, J. M. Bull. Korean Chem. Soc., 1996, 17, 50-55.
2. Nutaitis, C. F.; Gribble, G. W., Tetrahedron Lett. 1983, 24, 4287-4290.
3. Ranu, B. C.; Chakraborty, R., Tetrahedron Lett. 1990, 31, 7663-7664.
4. Yumino, S.; Hashimoto, T.; Tahara, A.; Nagashima. H. Chemistry Letters, 2014, doi: 10.1246/cl.140731.
5. Ward, D. E.; Rhee, C. K. Synth. Commun. 1988, 18, 1927–1933.
6. Ward, D. E.; Rhee, C. K. Can. J. Chem.1989, 67, 1206–1211.
7. Maki, Y.; Kikuchi, K.; Sugiyama, H.; Seto, S. Tetrahedron Lett. 1977, 18, 263–264
8. Adams, C. Synth. Commun. 1984, 14, 1349–1353.
9. Zeynizadeh, B.; Shirini, F. J. Chem. Res., Synop. 2003, 335–339.
10. Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. Synth. Commun. 2005, 35, 867–872;
11. Kuroiwa, Y.; Matsumura, S.; Toshima, K. Synlett, 2008, 19, 2523–2525.
12. Gribble, G. W.; Ferguson, D. C. Chem. Commun. 1975, 535–536.
13. Nutaitis, C. F.; Gribble, G. W. Tetrahedron Lett. 1983, 24, 4287–4290.
14. Firouzabadi, H; Afsharifar, G. R.  Bull. Chem. Soc. Jpn. 1995, 68, 2595-2602.
15. (a) Firouzabadi, H.; Tamami, B.;. Goudarzian, N. Synth. Commun. 1991, 21, 2275-2285. (b) Yoon, N. M. ; Choi, J.  Synlett. 1993, 135-136. (c) Sim, T. B.; Ahn, J. H.; Yoon, N. M. Synthesis 1996, 324-326.. (d) Bram, G.; Incan, E. D.; Loupy, A. J. Chem. Soc. Chem. Commun. 1981, 1066-1067.
16. a) Setamdideh, D.; Rafigh, M.  E-J. Chem. 2012, 4, 2338-2345. b) Setamdideh, D.;  Rahmatollahzadeh, M. J. Mex. Chem. Soc. 2012, 56, 169-175. c) Setamdideh, D.; Ghahremani, S. S. Afr. J. Chem. 2012, 65, 91-97. d) Setamdideh, D.; Khezri, B.; Rahmatollahzadeh, M. J. Serb. Chem. Soc. 2013, 78, 1-13 e) Mohamadi, M.; Setamdideh, D.; Khezri, B. Org. Chem. Inter. 2013, 2, doi:10.1155/2013/127585. f) Setamdideh, D.; Khaledi, L. S. Afr. J. Chem. 2013, 66, 150-157.g) Setamdideh, D.; Karimi, Z.; Alipouramjad, A. J. Chin. Chem. Soc. 2013, 60, 590-596. h) Setamdideh, D.; Khezri, B.; Esmaeilzadeh, S. J. Chin. Chem. Soc. 2012, 59, 1119-1124.
17. a) House, H. O. Modern Synthetic Reactions, 2nd ed.; W. A. Benjamin.: Menlo Park, CA, 1972; pp. 45–54.b) Chandrasekhar, S.; Shrinidhi, A. Synth. Commun. 2014, 44, 2051-2056. c) Ghaderi, S.; Setamdideh, D. Orient. J. Chem. 2014, 30, 1913-1917.

---

This work is licensed under a Creative Commons Attribution 4.0 International License.