# Regioselective and Chemoselective Reduction ofα,β-Unsaturated Carbonyl Compounds by NaBH4/Ba(OAc)2 as a Reducing System

Authors: Mina Mohamadi; Davood Setamdideh; Behrooz Khezri
Journal: Organic Chemistry International
 (2013)

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## Abstract

α,β-unsaturated aldehydes and ketones are regioselectively reduced to the corresponding allylic alcohols with NaBH4/Ba(OAc)2 system in CH3CN. This system is also efficient for the chemoselective reduction of enals in the presence of enones at room temperature.


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## Body

## 1. Introduction

Reduction ofα,β-unsaturated carbonyl compounds widely has been carried out by different reducing agents. This reaction is highly solvent dependent and generally does not result in a useful regioselectivity [1–3]. It can follow two pathways: addition to carbonyl group (1,2-reduction) to give allylic alcohols or addition to the conjugated double bond (1,4-addition) to give saturated carbonyl compounds. To control the reducing potential and selectivity of metal hydrides specially NaBH4 (common reducing agent) for the 1,2-reduction of conjugated carbonyl compounds, numerous hydroborate agents have been developed in the following ways: (a) by the replacement of hydride(s) with bulky substituents or electron-withdrawing/releasing groups in order to discriminate between the structural and electronic environments of carbonyl groups [4–7]; (b) combination with Lewis acids [8–10] such as Luche reduction [11, 12] and mixed solvent systems [1, 2]; (c) use of transition metal hydroborates and their new modifications [13], (d) use of phosphonium tetrahydroborates [14, 15], and finally (e) immobilization on an anion exchange resin [16]. In this context and continuation of our studies for the reduction of functional groups in organic synthesis [17–20], we decided to apply NaBH4/Ba(OAc)2 as new a reducing system for reduction of α,β-unsaturated carbonyl compounds. Now we wish to report an efficient method for the regioselective reduction of α,β-unsaturated aldehydes and ketones by NaBH4/Ba(OAc)2 as a new reducing system.


## 2. Experimental

### 2.1. General

All substrates and reagents were purchased from commercial sources with the best quality and used without further purification. IR and1H 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. TLC was applied for the purity determination of substrates, products, and reaction monitoring over silica gel 60 F254  aluminum sheet.


### 2.2. A Typical Procedure for Regioselective 1,2-Reduction of Conjugated Carbonyl Compounds with NaBH4/Ba(OAc)2 as a New Reducing System

In a round-bottomed flask (10 mL) equipped with a magnetic stirrer and a condenser, a solution of benzylideneacetone (0.146 g, 1 mmol) and Ba(OAc)2 (0.05 g, 0.2 mmol) in CH3CN (3 mL) was prepared, and NaBH4 (0.076 g, 2 mmol) was added. The resulting mixture was stirred under reflux conditions. TLC monitored the progress of the reaction (eluent; n-hexan/EtOAc: 9/1). After completion of the reaction within 15 min, distilled water (5 mL) was added to the reaction mixture and it was stirred for an additional 5 min. The mixture was extracted with CH2Cl2 (3 × 8 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the pure 4-phenyl-3-buten-2-ol (0.l41 g, 95% yield, Table 2, entry 3).


## 2.1. General

All substrates and reagents were purchased from commercial sources with the best quality and used without further purification. IR and1H 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. TLC was applied for the purity determination of substrates, products, and reaction monitoring over silica gel 60 F254  aluminum sheet.


## 2.2. A Typical Procedure for Regioselective 1,2-Reduction of Conjugated Carbonyl Compounds with NaBH4/Ba(OAc)2 as a New Reducing System

In a round-bottomed flask (10 mL) equipped with a magnetic stirrer and a condenser, a solution of benzylideneacetone (0.146 g, 1 mmol) and Ba(OAc)2 (0.05 g, 0.2 mmol) in CH3CN (3 mL) was prepared, and NaBH4 (0.076 g, 2 mmol) was added. The resulting mixture was stirred under reflux conditions. TLC monitored the progress of the reaction (eluent; n-hexan/EtOAc: 9/1). After completion of the reaction within 15 min, distilled water (5 mL) was added to the reaction mixture and it was stirred for an additional 5 min. The mixture was extracted with CH2Cl2 (3 × 8 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the pure 4-phenyl-3-buten-2-ol (0.l41 g, 95% yield, Table 2, entry 3).


## 3. Results and Discussions

Due to the importance of synthetic precursors of allylic alcohols, the regioselective reduction ofα,β-unsaturated aldehydes and ketones seems to be a convenient and easy way to obtain these compounds. So, this achievement is synthetically very important. We first examined the reduction of cinnamaldehyde as a model compound. The reduction reaction took place with 0.5 molar amounts of NaBH4 in the presence of 0.2 molar amounts of Ba(OAc)2  in CH3CN at room temperature. The reaction was completed within 5 min with a complete regioselectivity (Table 1, entry 2). The product, cinnamyl alcohol, was obtained in high yield (Table 2, entry 1) as shown in Scheme 1.Table 1
Optimization of reduction reaction of cinnamaldehyde to 3-phenyl-2-propen-1-ol and benzylideneacetone to 4-phenyl-3-buten-2-ol with NaBH4/Ba(OAc)2as a reducing system.
Entry
Substrate
Molar ratioa
Solvent
Time (min)
Conversionb (%)
1
Cinnamaldehyde
1 : 0.5 : 0.5
CH3CN
2
100
2
Cinnamaldehyde
1 : 0.5 : 0.2
CH3CN
5
100
3
Cinnamaldehyde
1 : 0.25 : 0.5
CH3CN
60
>100
4
Cinnamaldehyde
1 : 0.5 : 0.2
THF
10
100
5
Cinnamaldehyde
1 : 0.5 : 0.1
CH3CN
10
100
6
Benzylideneacetone
1 : 1 : 0.5
THF
60
>100
7
Benzylideneacetone
1 : 1 : 0.5
CH3CN
60
>100
8
Benzylideneacetone
1 : 2 : 0.5
CH3CN
60
>100
9c
Benzylideneacetone
1 : 2 : 0.5
CH3CN
15
100
10c
Benzylideneacetone
1 : 2 : 0.2
CH3CN
20
100
aMolar ratio as substrate: NaBH4 : Ba(OAc)2; bcompletion of the reactions was monitored by TLC (eluent; n-hexane/EtOAc: 9/1). cReaction was carried out under reflux conditions.Table 2
Reduction ofα,β-unsaturated carbonyl compounds with NaBH4/Ba(OAc)2 as a reducing system in CH3CN.
Entry
Substrate
Product
Molar ratioc
Time (min)
Yield (%)d
1a
Cinnamaldehyde
3-phenyl-2-propen-1-ol
1 : 0.5 : 0.2
5
94
2a
Citral
3,7-dimethyl-2,6-octadien-1-ol
1 : 0.5 : 0.2
5
93
3b
Benzylideneacetone
4-phenyl-3-buten-2-ol
1 : 2 : 0.2
15
95
4b
Chalcone
1,3-diphenyl-2-propen-1-ol
1 : 2 : 0.2
15
96
5b
β-ionone
4-(2,6,6-trimethylcyclohex-1-enyl)-3-buten-2-ol
1 : 2 : 0.2
10
97
6b
2-cyclohexenone
2-cyclohexenol
1 : 2 : 0.2
10
95
7b
3-methyl-2-cyclopentenone
3-methyl-2-cyclopentenol
1 : 2 : 0.2
10
98
aThe reduction reaction was carried out at room temperature; bthe reduction reaction was carried out under reflux conditions. cMolar ratio as substrate: NaBH4 : Ba(OAc)2; dyields refer to isolated pure products.Scheme 1This procedure was also applied for the reduction of citral to geraniol (3,7-dimethyl-2,6-octadien-1-ol) which was obtained regioselectively in 93% yield. In the next attempt, we examined the reductions of conjugated enones with the NaBH4/Ba(OAc)2  reducing system. The results showed that our procedure was also regioselective and efficient, but reduction reactions were performed by using 2 molar amounts of NaBH4 in the presence of 0.2 molar amounts of Ba(OAc)2 in CH3CN under reflux conditions (Table 1, entry 9). Regioselective 1,2-reductions of benzalacetone, benzalacetophenone, β-ionone, 2-cyclohexenone, and 3-methyl-2-cyclopentenone were achieved successfully with high to excellent yields of the corresponding allylic alcohols (Table 2, entries 3–7).The chemoselective reduction of one functional group without affecting the other one is a well-known strategy for preparing molecules with ever-increasing complexity in organic synthesis. Since the reduction of enals and enones with NaBH4 in the presence of Ba(OAc)2 is dependent on molar ratio of NaBH4 and temperature, therefore, we thought that this system has a chemoselectivity towards reduction of enals over enones. The chemo- and regioselectivity of this procedure were demonstrated by a competitive reduction of cinnamaldehyde over benzalacetone as shown in Scheme 2.Scheme 2The usefulness of this chemo- and regioselectivity of the reduction was further examined with the reduction of cinnamaldehyde in the presence of other enones (Table3).Table 3
Competitive reduction of cinnamaldehyde with enones by NaBH4/Ba(OAc)2 as a reducing system at room temperature in CH3CN.
Entry
Enone
Molar ratioa
Time (min)
1,2-reduction of cinnamaldehyde/enone (%)b
1
Benzylideneacetone
1 : 1 : 0.5 : 0.2
5
100 : 0
2
Chalcone
1 : 1 : 0.5 : 0.2
5
100 : 0
3
β-ionone
1 : 1 : 0.5 : 0.2
5
100 : 0
4
2-cyclohexenone
1 : 1 : 0.5 : 0.2
5
100 : 0
5
3-methyl-2-cyclopentenone
1 : 1 : 0.5 : 0.2
5
100 : 0
aMolar ratio as substrate: cinnamaldehyde : enone : NaBH4 : Ba(OAc)2; bcompletion of the reactions was monitored by TLC (eluent; n-hexane/EtOAc: 9/1).Since the insolubility of Ba(OAc)2 in CH3CN, the reaction takes place under heterogeneous conditions. The mechanism for the influence of Ba(OAc)2 is not clear. But, we think that with the addition of Ba(OAc)2 as Lewis acid to the reaction mixture, the carbonyl group is more susceptible to attack by the hydride ions. Therefore, the rates of reduction reactions have been accelerated.To highlight the efficiency of our system, we compared our results with other reported reducing systems in the literature such as Ph3PMeBH4 [21, 22], NaBH3(OAc) [3], NaBH3CN [23], Li-n-BuBH3 [6], (i-PrO)2TiBH4 [24], NaBH4/C [25], NaBH4/wet SiO2 [26], NaBH4/Dowex1-8x [27], and NaBH4/DOWEX(R)50WX4 [28] (Table 4). Some of the reducing systems have been used in more hydride anions versus one molar equivalent of carbonyl group. Also, it should be noted that the synthesis of some reducing agents is more costly than the NaBH4/Ba(OAc)2 system. It is clear that in most cases, the NaBH4/Ba(OAc)2 system is more efficient or comparable in the reaction times and yields of products. Therefore, the NaBH4/Ba(OAc)2 system has a greater potential for 1, 2-reduction of α,β-unsaturated carbonyl compounds.Table 4
Comparison of regioselective 1,2-reduction ofα,β-unsaturated carbonyl compounds with NaBH4/Ba(OAc)2 system and other reported systems.
Entry
Reducing systems
Molar ratio,atime (h), and yield (%)
Cinnamaldehyde
Citral
Benzylideneacetone
Chalcone
β-ionone
2-cyclohexenone
1
NaBH4/Ba(OAc)2
(0.5)(0.08)(94)
(0.5)(0.08)(93)
(2)(0.25)(95)
(2)(0.25)(96)
(2)(0.25)(97)
(2)(0.25)(95)
2
Ph3PMeBH4
(1)(Im)(95)
—
(1)(3.5)(90)
(1.2)(6)(90)
(1)(6)(71)
—
3
NaBH3(OAc)
(1.67)(20)(70)
(1.67)(20)(70)
(1.67)(20)(86)
—
—
(1.67)(20)(32)
4
NaBH3CN
(2)(90)(80)
—
(2)(90)(77)
(3)(150)(0)
(2)(120)(88)
—
5
Li-n-BuBH3
—
—
(1)(2)(98)
(2)(2)(99)
(1)(2)(98)
(1)(2)(84)
6
(i-PrO)2TiBH4
(1)(0.08)(90)
(1)(0.08)(95)
—
—
—
—
7
NaBH4/C
(0.5)(Im)(92)
(0.5)(0.16)(92)
(2)(0.67)(96)
(2)(0.4)(98)
(2)(0.5)(91)
—
8
NaBH4/wet SiO2
(1)(0.016)(96)
(1)(0.066)(95)
(2)(0.15)(97)
(2)(0.25)(98)
(2)(0.25)(97)
—
9
NaBH4/Dowex1-8x
(1)(0.7)(96)
(1)(1.3)(94)
(1)(1.4)(98)
(1)(0.7)(95)
(1)(2.2)(91)
(1)(0.8)(89)
10
NaBH4/DOWEX(R)50WX4
(1)(0.25)(97)
(1)(0.33)(94)
(2)(0.91)(95)
(2)(1.5)(95)
—
—
aReducing agent/substrate. Im: immediately.


## 4. Conclusion

In this investigation, we have shown that the combination system of NaBH4/Ba(OAc)2 in CH3CN reduces a variety of α, β-unsaturated carbonyl compounds to their corresponding allylic alcohols in high to excellent yields. Reduction reactions were carried out with 0.5–2 molar equivalents of NaBH4 in the presence of 0.2 molar amounts of Ba(OAc)2. The chemoselective reduction of enals over enones was accomplished successfully with this reducing system. High efficiency of the reductions, shorter reaction times, and easy work-up procedure make it as an attractive new protocol for reduction of α,β-unsaturated carbonyl compounds, and it could be a useful addition to the present methodologies.



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