(Caffeine)(tetrahydroborato)zinc Complex [Zn(BH4)₂(caf)]: A New Stable and Efficient Reducing Agent

Introduction

Zn(BH₄)₂ is the modified borohydride agents which has better solubility in aprotic solvents, so it use and application is interesting in organic synthesis. Zinc borohydride is unique because of the coordination ability of Zn²⁺ which is imparting selectivity in hydride-transferring reactions.Zinc borohydride is moderately stable in ethereal solution and has many applications in organic synthesis¹. Zinc borohydride as a nonconventional hydride transferring agent has been reported as an efficient chemo-, regio- and stereoselective reducing agent in several complex substrates. It can be used in a range of aprotic solvents such as, THF, Et₂O and DME².Several Combination reducing systems of Zn(BH₄)₂ such as Zn(BH₄)₂/TMEDA^3a, Zn(BH₄)₂/Me₃SiCl^3b, Zn(BH₄)₂/TFA/DME^3c,  Zn(BH₄)₂/H₂O^3d,  Zn(BH₄)₂/Al₂O₃^3e,  Zn(BH₄)₂/C ^3f, Zn(BH₄)₂/2NaCl^3g,  Zn(BH₄)₂/U.S.^3h, and Zn(BH₄)₂/ZrCl₄³ⁱare interesting and have been used for different reduction purposes.However, zinc tetrahydroborate has been used less than regular reducing agents in laboratory for the reduction of organic compounds, probably because of non-availability as a commercial reagent, being freshly prepared solution just prior to use and limitation to handling and storage. So, Zn(BH₄)₂, has been modified as stable complexes such as [Zn(BH₄)₂(dabco)]⁴,[Zn(BH₄)₂(pyz)]_n⁵, [Zn(BH₄)₂(PPh₃)] &[Zn(BH₄)₂(PPh₃)₂]⁶, [Zn(BH₄)₂(bpy)]⁷, [Zn(BH₄)₂(py)]⁸,  [Zn(BH₄)₂XP₄]⁹, [Zn(BH₄)₂(nmi)]^10a and [Zn(BH₄)₂(nic)]^10b. In continuation of our interest for preparation of new modified tetrahydroborates, we now wish to report the preparation of new stable ligand-zinc tetrahydroborate such as (caffeine)(tetrahydroborato)zinc complex, [Zn(BH₄)₂(caf)] and its reducing ability in the reduction of carbonyl compounds such as aldehydes, ketones and acyloins, a-diketones to their corresponding alcohols.

Results and Discussions

In order to determine the most appropriate reaction conditions, we first examined the reduction of benzaldehyde as a model compound as shown in Table 1. Among the tested different solvents benzaldehyde reduction was better in CH₃CN. The optimization study showed that using 0.5 molar equivalents of [Zn(BH₄)₂(caf)] in CH₃CN (3 mL) is the best conditions (Table 1, entry 9).

Table 1: Optimization of the Reduction of Benzaldehyde and Acetophenone to their Corresponding Alcohols with [Zn(BH₄)₂(caf)] at Room Temperature and Reflux Conditions.

Table 1 Optimization of the Reduction of Benzaldehyde and Acetophenone to their Corresponding Alcohols with [Zn(BH4)2(caf)] at Room Temperature and Reflux Conditions.
Entry	Substrate	Molar Ratio Substrate[Zn(BH4)2(caf)]	Solvent	Time/min	Conversiona/%
1	PhCHO	1:1	solvent free	60	100<
2	PhCHO	1:1	n-hexane	60	100<
3	PhCHO	1:1	CHCl3	60	100<
4	PhCHO	1:1	CH2Cl2	60	100<
5	PhCHO	1:1	Et2O	60	100<
6	PhCHO	1:1	DME	60	100<
7	PhCHO	1:1	CH3CN	20	100
8	PhCHO	1:1	THF	40	100
9	PhCHO	1:0.5	CH3CN	30	100
10	PhCHO	1:0.5	THF	60	100
11	PhCHO	1:0.25	CH3CN	60	100<
12	PhCHO	1:0.5	CH3OH	60	100<
13	PhCHO	1:0.5	C2H5OH	60	100<
14	PhCOCH3	1:0.5	CH3CN	60	100<
15	PhCOCH3	1:1	CH3CN	60	100<
16	PhCOCH3	1:2	CH3CN	80	100
17	PhCOCH3	1:2	THF	160	100
18b	PhCOCH3	1:1	CH3CN	60	100
a Completion of reactions was monitored by TLC (eluent; Hexane/EtOAc: 10/1), bThe reaction has been carried out under reflux conditions.

 

This procedure was also applied for the reduction of various aliphatic and aromatic aldehydes (Table 2, entries 1-9). All reductions were completed within 20-50 min by 0.5 molar equivalents of [Zn(BH₄)₂(caf)] in excellent yields of products(90-95%).

Table 2: Reduction of a Variety of Carbonyl Compounds such as Aldehydes (entries 1-9), Ketones (entries 10-14), a-diketones (15-16), Acyloins (entriy 17) and α, β-unsaturated carbonyl Compounds (entries 18-20) to their Corresponding Alcohols with [Zn(BH₄)₂(caf)] as Reducing Agent in CH₃CN.

Table 2. Reduction of a Variety of Carbonyl Compounds such as Aldehydes (entries 1-9), Ketones (entries 10-14), a-diketones (15-16), Acyloins (entriy 17) and α, β-unsaturated carbonyl Compounds (entries 18-20) to their Corresponding Alcohols with [Zn(BH4)2(caf)] as Reducing Agent in CH3CN.
Entry	Substrate	Product	Molar Ratio Substrate/[Zn(BH4)2(caf)]	Time/min	Yieldc/%
1a	benzaldehyde	benzyl alcohol	1:0.5	30	91
2a	4-chlorobenzaldehyde	4-chlorobenzyl alcohol	1:0.5	30	92
3a	4-bromobenzaldehyde	4-bromobenzyl alcohol	1:0.5	30	95
4a	2,4-dichlorobenzaldehyde	2,4-dichlorobenzyl alcohol	1:0.5	30	94
5a	4-methylbenzaldehyde	4-methylbenzyl alcohol	1:0.5	40	93
6a	4-methoxybenzaldehyde	4-methoxybenzyl alcohol	1:0.5	40	92
7a	2-methoxybenzaldehyde	2-methoxybenzyl alcohol	1:0.5	50	94
8a	3-methylbenzaldehyde	3-methylbenzyl alcohol	1:0.5	35	92
9a	4-nitrobenzaldehyde	4-nitrobenzyl alcohol	1:0.5	20	90
10b	acetophenone	1-phenylethanol	1:1	60	96
11b	benzophenone	diphenylmethanol	1:1	90	96
12b	9H-fluoren-9-one	9H-fluoren-9-ol	1:1	90	95
13b	cyclohexanone	cyclohexanol	1:1	50	95
14b	4-phenylcyclohexanone	4-phenylcyclohexanol	1:1	50	98
15b	benzil	1,2-diphenyl ethane-1,2-diol	1:1	40	93
16b	1,2-bis(4-methoxyphenyl) ethane-1,2-dione	1,2-bis(4-methoxyphenyl) ethane-1,2-diol	1:1	60	94
17b	benzoin	1,2-diphenyl ethane-1,2-diol	1:1	40	92
18a	cinnamaldehyde	3-phenyl-2-propen-1-ol	1:1	30	95
19b	benzylideneacetone	Phenyl-3-butene-2-ol	1:1	60	95
20b	chalcone	4-phenyl-3-butene-2-ol	1:1	60	96
a The reactions have been carried out at room temperature. b The reactions have been carried out under reflux conditions.c Yields refer to isolated pure products.

 

Our next attempt was the reduction of ketones. We optimized the reaction conditions with acetophenone as model compound (Table 1, entries 14-18). Due to the lower reactivity of ketones relative to aldehydes, the reduction require a higher molar amounts of [Zn(BH₄)₂(caf)]. The reduction reactions were carried out with 1 molar equivalents of [Zn(BH₄)₂(caf)] at reflux conditions in CH₃CN. All reductions were completed within 40-90 min with high to excellent yields of products (92-98%) as shown in Table 2 (entries 10-17).

We also investigated the potential of the 1,2-reduction of α,β-unsaturated aldehydes and ketones with [Zn(BH₄)₂(caf)]. The reduction of cinnamaldehyde with 0.5 molar equivalents of the [Zn(BH₄)₂(caf)] exclusivity afforded the 1,2-reduction product after 30 min at room temperature in CH₃CN. In this reaction, cinnamyl alcohol was obtained in 95% yield (Table 2, entry 18). Under this protocol, reduction of conjugated ketones such as benzylidenacetone (Table 2, entry 19) and chalcone (Table 2, entry 20) were achieved efficiently with 1 molar equivalents of [Zn(BH₄)₂(caf)] at reflux condotions in CH₃CN in excellent yields (95-96%).

The efficiency of [Zn(BH₄)₂(caf)] has been compared with other reported reducing systems (Table 3). In all cases[Zn(BH₄)₂(caf)] has a good potential for the reduction of organic carbonyl compounds.

Table 3: Comparison of the Reduction of Aldehydes and Ketones by [Zn(BH₄)₂(caf)] in CH₃CN with other Reported Reducing Agents. 

 

The stability and shelf-life [Zn(BH₄)₂(caf)] was investigated by comparing the reduction reactions of benzaldehye as model compound under different conditions. Experiments show in adverse conditions, this reducing system is stable and reducing power remains significantly.

Experimental

All substrates and reagents were purchased from commercially 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. ¹H NMR &TLC was applied for the purity determination of substrates, products and reaction monitoring over silica gel 60 F₂₅₄ aluminum sheet.

Preparation of (Caffeine)(tetrahydroborato)zinc Complex;[Zn(BH₄)₂(caf)]:

An ethereal solution of Zn(BH₄)₂ (0.16 M, 250 mL) was prepared from ZnCl₂(5.452 g, 0.04 mol) and NaBH₄ (3.177 g, 0.084 mol)according to an available procedure in the literature [12c]. Then, caffeine (7.76 g, 0.04 mol) in ether (50 mL) was added dropwise to the ethereal solution of Zn(BH₄)₂ and stirred for 30 min. Evaporation of the solvent under vacuum at room temperature gave [Zn(BH₄)₂(caf)] as a withe powder in a quantitative yield (9.16 g, 95%). Found: Zn: 22.25 %, B: 7.2 %. Calculated for C₈H₁₈B₂N₄O₂Zn, Zn: 22.61 %, B: 7.47%. Scheme 1.

Scheme 1  Click here to View scheme

 

Reduction of Benzaldehyde to Benzyl alcohol with [Zn(BH₄)₂(caf)], A Typical Procedure:

In a round-bottomed flask (10 mL), equipped with a magnetic stirrer, a solution of banzaldehye (0.106 g, 1mmol) in CH₃CN (3 mL) was prepared. The complex reducing agent (0.144 g, 0.5mmol) was then added as a solid and the mixture was stirred at room temperature. TLC monitored the progress of the reaction (eluent; CCl₄/Et₂O : 5/2). After completion of the reaction in 30 min, a solution of 5% HCl (5 mL) was added to the reaction mixture and stirred for 10 min. The mixture was extracted with CH₂Cl₂ (3 × 10 mL) and dried over the anhydrous sodium sulfate. Evaporation of the solvent and short column chromatography of the resulting crude material over silica gel by eluent of CCl₄/Et₂O : 5/2 afforded the pure liquid benzyl alcohol (0.097 g, 91% yield, table 1).

Conclusion

In this investigation, we have shown that [Zn(BH₄)₂(caf)] reduces a variety of carbonyl compounds to their corresponding alcohols in high to excellent yields. Reduction reactions were carried out with 0.5-1 molar equivalents of [Zn(BH₄)₂(caf)] at room temperature and reflux conditions in CH₃CN without any other additive. In addition, regioselectivity of this system was also investigated with exclusive 1,2-reduction of conjugated carbonyl compounds to their corresponding allylic alcohols in high to excellent yields. Reduction of acyloins and α-diketones by this reducing system also produced the corresponding vicinal diols.

Acknowledgments

The authors gratefully acknowledge financial assistance by the research council of the Islamic Azad University branch of Mahabad.

References

1. Narasimhan, S.;  Balakumar, R.  Aldrichim.Acta.1998,31, 19-26.
2. (a)  Ranu, B. C.  Synlett 1993, 885-892. b) Ranu, B. C.; Chakraborty, R.Tetrahedron Lett. 1990, 31, 7663-7664. (c) Sarkar, D. C.;  Das, A. R.;Ranu, B. C.J. Org. Chem. 1990, 55, 5799-5801.
3. (a) Kotsuki, H.; Ushio, Y.; Yoshimura, N.; Ochi, M. Bull. Chem. Soc. Jpn. 1988,61, 2684-2686.(b) Kotsuki, H.; Ushio, Y.; Yoshimura, N.; Ochi, M. J. Org. Chem. 1987, 52, 2594-2596. (c) Ranu, B. C.; Das, A. R.  J. Chem. Soc. Perkin Trans. 1 1992, 1561-1562. (d) Setamdideh, D.;Khezri, B.;Rahmatollahzadeh, M.;Aliporamjad, A.Asian J. Chem.2012, 8, 3591-3596.(e) Setamdideh, D.; Khezri, B.; Rahmatollahzadeh, M.; J. Serb. Chem. Soc. 2013, 78, 1-13. (f) Setamdideh, D.;Rahmatollahzadeh, M. J. Mex.Chem. Soc. 2012, 56, 169-175. (g) Setamdideh. D.; Khaledi, L. S. Afr. J. Chem.2013, 66, 150–157.(h) Fanari, S.;Setamdideh. D.; Orient. J. Chem., 2014, 30, 695-697. (i) Rasol, F.;Setamdideh. D.; Orient. J. Chem., 2013, 29, 497-499.
4. Firouzabadi, H.;Adibi, M.;Zeynizadeh, B. Synth. Commun.1988, 28,1257-1273.
5. Tamami, B.;Lakouraj, M. M.Synth. Commun.1995, 25, 3089-3096.
6. Firouzabadi, H.; Adibi, M. Phosphorus Sulfur Silicon Relat. Elem. 1998, 142, 125-147.
7. Zeynizadeh, B.Bull. Chem. Soc. Jpn. 2003,76, 317-326.
8. (a) Zeynizadeh, B.;Faraji, F.Bull. Korean Chem. Soc.2003, 24, 453-459. (b) Zeynizadeh, B.;Zahmatkesh, K.J. Chin. Chem. Soc.2003, 50, 267-271. (c) Zeynizadeh, B.;Zahmatkesh, K.J. Chin. Chem. Soc.2004, 51, 801-806. (d) Zeynizadeh, B.;Zahmatkesh, K.J. Chin. Chem. Soc.2005, 52, 109-112.
9. Firouzabadi, H.; Tamami, B.; Goudarzian, N.Synth. Commun.1991,21, 2275-2285.
10. (a) Zeynizadeh, B.; Setamdideh,  D. Asian J. Chem. 2009, 21, 3603-3610. (b) Setamdideh, D.;Rafig, M.E-J. Chem.2012, 9, 2338-2345.

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