Organic Chemistry International

Volume 2013 (2013), Article ID 127585, 5 pages

http://dx.doi.org/10.1155/2013/127585

Research Article

Regioselective and Chemoselective Reduction of ,-Unsaturated Carbonyl Compounds by /Ba as a Reducing System

Mina Mohamadi, Davood Setamdideh, and Behrooz Khezri

Department of Chemistry, Faculty of Sciences, Mahabad Branch, Islamic Azad University, Mahabad 59135-443, Iran

Received 24 February 2013; Revised 12 April 2013; Accepted 12 April 2013

Academic Editor: Robert Salomon

Copyright © 2013 Mina Mohamadi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

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

1. Introduction

Reduction of ,-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 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. TLC was applied for the purity determination of substrates, products, and reaction monitoring over silica gel 60 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; -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 of α,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)2 as 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 of α,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 1

This 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 2

The usefulness of this chemo- and regioselectivity of the reduction was further examined with the reduction of cinnamaldehyde in the presence of other enones (Table 3).

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--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 of ,-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.

Acknowledgment

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

References

R. S. Varma and G. W. Kabalka, “Selective reduction of a, β-unsaturated nitrocompounds with sodium borohydride in methanolic solutions: a facile route to nitroalkenes,” Synthetic Communications, vol. 15, no. 2, pp. 151–155, 1985.

D. C. Sarkar, A. R. Das, and B. C. Ranu, “Use of zinc borohydride as an efficient and highly selective reducing agent. Selective reduction of ketones and conjugated aldehydes over conjugated enones,” Journal of Organic Chemistry, vol. 55, no. 22, pp. 5799–5801, 1990.

C. F. Nutaitis and J. E. Bernardo, “Regioselective 1,2-reduction of conjugated enones and enals with sodium monoacetoxyborohydride: preparation of allylic alcohols,” Journal of Organic Chemistry, vol. 54, no. 23, pp. 5629–5630, 1989.

S. Krishnamurthy and H. C. Brown, “9-borabicyclo[3.3.1]nonane as a highly selective reducing agent for the facile conversion of α,β-unsaturated aldehydes and ketones to the corresponding allylic alcohols in the presence of other functional groups,” Journal of Organic Chemistry, vol. 40, no. 12, pp. 1864–1865, 1975.

S. Krishnamurthy and H. C. Brown, “Selective reductions. 22. Facile reduction of α,β-unsaturated aldehydes and ketones with 9-borabicyclo[3.3.1]nonane. A remarkably convenient procedure for the selective conversion of conjugated aldehydes and ketones to the corresponding allylic alcohols in the presence of other functional groups,” Journal of Organic Chemistry, vol. 42, no. 7, pp. 1197–1201, 1977.

S. Kim, Y. C. Moon, and K. H. Ahn, “Lithium n-butylborohydride as a selective reducing agent for the reduction of enones, cyclic ketones, and selected carbonyl compounds,” Journal of Organic Chemistry, vol. 47, no. 17, pp. 3311–3315, 1982.

E. J. Corey, K. B. Becker, and R. K. Varma, “Efficient generation of the 15S configuration in prostaglandin synthesis. Attractive interactions in stereochemical control of carbonyl reduction,” Journal of the American Chemical Society, vol. 94, no. 24, pp. 8616–8618, 1972.

J. C. Fuller, E. L. Stangeland, C. T. Goralski, and B. Singaram, “Aminoborohydrides. 2. Regiospecific reductions of α,β-unsaturated carbonyl compounds with lithium pyrrolidinoborohydride. A facile conversion of α,β-unsaturated aldehydes and ketones to the corresponding allylic alcohols in high purity,” Tetrahedron Letters, vol. 34, no. 2, pp. 257–260, 1993.

B. Ganem, “Conjugate reduction and reductive alkylation of α,β-unsaturated cyclohexenones using potassium tri-sec-butylborohydride,” Journal of Organic Chemistry, vol. 40, no. 1, pp. 146–147, 1975.

J. M. Fortunato and B. Ganem, “Lithium and potassium trialkylborohydrides. Reagents for direct reduction of α,β-unsaturated carbonyl compounds to synthetically versatile enolate anions,” Journal of Organic Chemistry, vol. 41, no. 12, pp. 2194–2200, 1976.

J. L. Luche, “Lanthanides in organic chemistry. 1. Selective 1,2 reductions of conjugated ketones,” Journal of the American Chemical Society, vol. 100, no. 7, pp. 2226–2227, 1978.

A. L. Gemal and J. L. Luche, “Lanthanoids in organic synthesis. 6. The reduction of α-enones by sodium borohydride in the presence of lanthanoid chlorides: synthetic and mechanistic aspects,” Journal of the American Chemical Society, vol. 103, no. 18, pp. 5454–5459, 1981.

H. Fujii, K. Oshima, and K. Utimoto, “A facile and selective 1,2-reduction of conjugated ketones with NaBH₄ in the presence of CaCl₂,” Chemistry Letters, vol. 20, no. 10, pp. 1847–1848, 1991.

H. Firouzabadi, M. Adibi, and M. Ghadami, “Modified borohydride agents, bis(triphenylphosphine) (tetra-hydroborato)zinc complex [Zn(BH₄)₂(PPh₃)₂] and (triphenylphosphine) (tetrahydroborato)zinc complex [Zn(BH₄)₂(PPh₃)]. New ligand metal borohydrides as stable, efficient, and versatile reducing agents,” Phosphorus, Sulfur and Silicon and Related Elements, vol. 142, pp. 191–220, 1998.

H. Firouzabadi, M. Adibi, and B. Zeynizadeh, “Modified borohydride agents; efficient reduction of azides with (1,4-diazabicyclo[2.2.2]octane) (tetrahydroborato)zinc complex [Zn(BH₄)₂(dabco)] and methyltriphenylphosphonium tetrahydroborate [],” Synthetic Communications, vol. 28, no. 7, pp. 1257–1273, 1998.

A. R. Sande, M. H. Jagadale, R. B. Mane, and M. M. Salunkhe, “Borohydride reducing agent derived from anion exchange resin: selective reduction of α, β-unsaturated carbonyl compounds,” Tetrahedron Letters, vol. 25, no. 32, pp. 3501–3504, 1984.

D. Setamdideh, B. Khezri, M. Rahmatollahzadeh, and A. Aliporamjad, “Mild and efficient reduction of organic carbonyl compounds to their corresponding alcohols with Zn(BH₄)₂ under protic condition,” Asian Journal of Chemistry, vol. 24, no. 8, pp. 3591–3596, 2012.

D. Setamdideh and M. Rafig, “Reduction of carbonyl compounds to their corresponding alcohols by (nicotine)(tetrahydroborato)zinc complex as a new stable and efficient reducing agent,” E-Journal of Chemistry, vol. 9, no. 4, pp. 2338–2345, 2012.

D. Setamdideh and M. Rahmatollahzadeh, “Efficient and convenient reduction of organic carbonyl compounds to their corresponding alcohols by Zn(BH₄)₂/charcoal in THF,” Journal of the Mexican Chemical Society, vol. 56, no. 3, 2012.

D. Setamdideh, B. Khezri, and M. Rahmatollahzadeh, “Zn(BH₄)₂/Al₂O₃: a new synthetic method for the efficient and convenient reduction of organic carbonyl compounds to their corresponding alcohols,” Journal of the Serbian Chemical Society, vol. 79, pp. 1–13, 2013.

H. Firouazabadi and M. Adibi, “Modified borohydride agents 1a-d, methyltriphenylphosphonium tetrahydroborate; as a selective and an efficient reducing agent,” Synthetic Communications, vol. 26, no. 13, pp. 2429–2441, 1996.

H. Firouzabadi and M. Adibi, “Methyltriphenylphosphonium tetrahydroborate (MePh₃PBH₄). A stable, selective and versatile reducing agent,” Phosphorus, Sulfur and Silicon and Related Elements, vol. 142, pp. 125–147, 1998.

R. O. Hutchins and D. Kandasamy, “Reductions of conjugated carbonyl compounds with cyanoborohydride in acidic media,” Journal of Organic Chemistry, vol. 40, no. 17, pp. 2530–2533, 1975.

K. S. Ravikumar, S. Baskaran, and S. Chandrasekaran, “Diisopropoxytitanium(III) tetrahydroborate: a highly useful reagent for the remarkably selective 1,2-reduction of α,β-unsaturated carbonyl compounds,” Journal of Organic Chemistry, vol. 58, no. 22, pp. 5981–5982, 1993.

D. Setamdideh and B. Zeynizadeh, “Mild and convenient method for reduction of carbonyl compounds with the NaBH₄/charcoal system in wet THF,” Zeitschrift für Naturforschung B, vol. 61, no. 10, pp. 1275–1281, 2006.

B. Zeynizadeh and T. Behyar, “Fast and efficient method for reduction of carbonyl compounds with NaBH₄/wet SiO2 under solvent free condition,” Journal of the Brazilian Chemical Society, vol. 16, no. 6A, pp. 1200–1209, 2005.

B. Zeynizadeh and F. Shirini, “Mild and efficient reduction of α,β-unsaturated carbonyl compounds, α-diketones and acyloins with sodium borohydride/Dowex1-x8 system,” Bulletin of the Korean Chemical Society, vol. 24, no. 3, pp. 295–298, 2003.

D. Setamdideh, B. Khezri, and A. Alipouramjad, “NaBH₄/DOWEX(R)50WX4: a convenient reducing system for fast and efficient reduction ofcarbonyl compounds to their corresponding alcohols,” Journal of the Chinese Chemical Society, 2013.