Reductive Amination of Aldehydes by NaBH₄ in the Presence of NaH₂PO₄.H₂O

Introduction

The reduction of nitro, cyano, azide, carboxamide compounds is common routes for the synthesis of amines. Also, this goal has been achieved by the alkylation of amines. These methods for the preparation of secondary amines are often problemssuch as harsh reaction conditions, overalkylation, low chemical selectivity and generally poor yields. Other approach is reductive amination reaction in a single operationi.ereductive amination. The reductive aminationhas been carried out by sodium borohydride under different reducing system such as: NaBH₄/cellulose sulfuric Acid/EtOH¹, NaBH₄-amberlyst15 ², NaBH₄-silica chloride ³, NaBH₄-silica-gel-supported sulfuric acid ⁴, NaBH₄-H₃PW₁₂O₄₀ ⁵, NaBH₄/guanidine hydrochloride /H₂O ⁶, NaBH₄/Bronsted acidic ionic liquid (1-butyl-3-methyl imidazoliumtetrafluoroborate [(BMIm)BF₄]) ⁷, NaBH₄ or LiAlH₄/LiClO₄/diethyl ether ⁸ NaBH₄-PhCO₂H ⁹, NaBH₄-NiCl₂¹⁰,  Ti(O-i-Pr)₄-NaBH₄¹¹, NaBH₄-wet-clay-microwave ¹², NaBH₄/Mg(ClO₄)₂¹³, NaBH₄/B(OH)₃ or Al(OH)₃ ¹⁴ NaBH₄/Ga(OH)₃¹⁵.In continuing our efforts for the development of new reducing systems ^16-26,in this context, we have carried outthe reductive amination reaction of aldehydes with anilinesby NaBH₄/NaH₂PO₄.H₂O system in THF.

Results and Discussions

The model reaction has been selected by reductive amination of benzaldehyde with aniline. This reaction was performedwith different molar ratio of the benzaldehyde/aniline/NaH₂PO₄.H₂O/NaBH₄in different solvents for the selection of appropriate conditions. Experiments have been shown that using 1eq. of NaH₂PO₄.H₂Oin THF (3 mL) under reflux conditionsis the best conditions to complete the reductive amination of benzaldehye (1 mmol) and aniline (1 mmol) to N-benzylaniline. The reductive amination completes within 55 min with 92% yields of product as shown in
scheme 1.

Schem 1: Click here to View Schem

 

By using the various structurally different aldehydes and anilines, the efficiency of this protocol was further examined. Experiments have been shown the correspondingsecondary amines were obtained in excellent yields (85-92%) within 55-100 min as shown in Table 1.  The influence of NaH₂PO₄.H₂O is not clear but we observed sodium borohydride slowly is liberated hydrogen gas in situ in the presence of NaH₂PO₄.H₂O. Consequently, the generated molecular hydrogen combines with more easily hydride attack, thus accelerates the rate of reduction reaction.

Table 1. Reductive Amination of Aldehydes (1 mmol) with Anlines (1 mmol) by NaBH4 (1 mmol) in the presence of NaH2PO4.H2O(1 mmol) in THF (3 mL) under reflux conditions.
Entry	Aldehydes                      Anilines                                              Products			Time/min	Yielda/%
1	benzaldehyde	aniline	N-benzylaniline	55	92
2	benzaldehyde	4-bromoaniline	N-benzyl-4-bromoaniline	65	87
3	benzaldehyde	4-methylaniline	N-benzyl-4-methylaniline	60	89
4	benzaldehyde	4-nitroaniline	N-benzyl-4-nitroaniline	65	88
5	4-bromobenzaldehyde	aniline	N-(4-bromobenzyl)aniline	60	88
6	4-bromobenzaldehyde	4-methoxyaniline	N-(4-bromobenzyl)-4-methoxyaniline	85	90
7	4-methoxybenzaldehyde	4-bromoaniline	N-(4-methoxybenzyl)-4-bromoaniline	100	85
8	4-methylbenzaldehyde	aniline	N-(4-methylbenzyl)aniline	100	87
9	2-methoxybenzaldehyde	aniline	N-(2-methoxybenzyl)aniline	100	85
10	4-methylbenzaldehyde	4-methoxyaniline	N-(4-methylbenzyl)-4-methoxyaniline	90	89
11	4-bromobenzaldehyde	4-bromoaniline	N-(4-bromobenzyl)-4-bromoaniline	60	90
12	4-methoxybenzaldehyde	aniline	N-(4-methoxybenzyl)aniline	80	92
13	4-nitrobenzaldehyde	4-bromoaniline	N-(4-nitrobenzyl)-4-bromoaniline	70	90
14	2-methoxybenzaldehyde	4-methylaniline	N-(2-methoxybenzyl)-4-methylaniline	100	91

 

Experimental

IR and ¹H NMR spectra were recorded on PerkinElmer FT-IR RXI and 400 MHz Bruker spectrometers, respectively. The products were characterized by their ¹H NMR or IR spectra and comparison with authentic samples (melting or boiling points). TLC was applied for the purity determination of substrates, products and reaction monitoring over silica gel 60 F₂₅₄ aluminum sheet.

Reductive amination of banzaldehyde and aniline with NaBH₄/NaH₂PO₄.H₂O system (typical procedure)

In a round-bottomed flask (10 mL) equipped with a magnetic stirrer, a solution of benzaldehyde (0.106 g, 1 mmol), aniline (0.093 g, 1 mmol) and NaH₂PO₄.H₂O(0.14, 1 mmol) was preparedin THF (3 mL). Then the NaBH₄ (0.036 g, 1 mmol) was added to the reaction mixture and stirred under reflux conditions. TLC monitored the progress of the reaction (eluent; CCl₄/Ether: 5/2). The reaction was filtered after completion within 55 min. Evaporation of the solvent and short column chromatography of the resulting crude material over sil­ica gel (eluent; CCl₄/Ether: 5/2) afforded the N-benzylaniline (0.l66 g, 92% yield, Table 1, entry 1).

Conclusion

In this context, we have shown that the NaBH₄/NaH₂PO₄.H₂O₃ as reducing system is efficient for the reductive amination of a variety of aldehydes and anilines to their corresponding secondary amineas. Reduction reactions were carried out with NaBH₄ (1 mmol) and NaH₂PO₄.H₂O(1 mmol) in THFunder reflux conditions.Highefficiency of the reduction reactions and easy work-up procedure makes as an attractive new protocol for reductive amination of aldehydes.

Acknowledgements

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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