Catalyst-free chemoselective reduction of the carbon–carbon double bond in conjugated alkenes with Hantzsch esters in water

Abstract

A simple, efficient and green protocol for chemoselective reduction of carbon–carbon double bond in conjugated alkenes with Hantzsch esters is described. Without any additional catalysts, a series of conjugated alkenes with strong electron-withdrawing groups were reduced in water with excellent yield. Functional groups such as nitrile, ester, nitro, fluoro, chloro, bromo, furanyl and benzyl are all tolerated by the reaction conditions employed.

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Introduction

Chemoselective reduction of carbon–carbon double bond in conjugated alkenes is an indispensable step for a large number of natural products, complex molecules and pharmaceuticals synthesis. It is a useful and challenging transformation, especially when multifunction groups exit in one molecule. In the past decades, numerous methods have been developed for this protocol.¹ Various hydride reagents have been employed such as H₂, NaBH₄, NaBH₃CN, alcohol, diimide, PhSiH₃ and so on.² Although great progress has been made, the utility of these hydride reagents suffer from at least one of the following drawbacks such as poor chemoselectivity, harsh experimental conditions, expensive catalysts and environmental problems.

In recent years, the NADH-like Hantzsch esters and their related organic hydride reagents have been widely utilized in the reduction of carbon–carbon double bond in conjugated alkenes. Compared with the traditional hydrogen reagents, the Hantzsch esters and its analogues have the advantages of high chemoselectivity, mild experimental conditions, readily available, water tolerance and environmental benign.³ Lots of structurally diverse conjugated alkenes were selective reduced with Hantzsch esters and its analogues with high yield in the presence of catalysts such as SiO₂,⁴ thiourea,⁵ Pd/C,⁶ TiCl₄,⁷ ammonium salts,⁸ peptide,⁹ S-benzyl isothiouronium chloride,¹⁰ nornicotine¹¹ and so on.

However, in all these reports, the catalyst is necessary and the absence of catalyst leads to sluggish reaction or no products. Meanwhile, almost all the reduction processes are carried through in the toxic organic solvents. Chemoselective reduction of the carbon–carbon double bond with Hantzsch esters and their related organic hydride reagents in water or in other green solvents has rarely been explored.¹¹ So the development of an effective, economical and green protocol for the reduction of carbon–carbon double bond in conjugated alkenes is still desirable. Herein, we report a simple and effective way to chemoselective reduce the carbon–carbon double bond in water without any additional catalysts.

Results and discussion

Recently, we have reported the catalyst-free reduction of aldimines using Hantzsch ester as the hydrogen source in toluene.¹² We then wonder if this catalyst-free protocol adapt to the carbon–carbon double bond reduction. Firstly, we used 2-benzylidenemalononitrile as the model substrate to examine if it could be reduced by the Hantzsch ester in absence of catalysts in toluene at 100 °C. To our delight, the chemoselective reduction of the carbon–carbon double bond took place under this catalyst-free condition and excellent yield was obtained (Table 1, entry 1, 95% yield). We also screened different solvents for the reaction such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, ethanol, dioxane and water at reflux temperature. As shown in Table 1, except the dioxane, all the solvents are adapt to the protocol and high to excellent yields were obtained. Especially, the 2-benzylidenemalononitrile can be chemoselective reduced in water with excellent yield (Table 1, entry 9, 91% yield). It is known to all, water is the best green solvent in organic reactions and it is non-toxic, non-flammable, environmentally compatible, renewable and cheap.¹³ So we chose water as the solvent to further explore. Then we studied the influence of the temperature. The results showed that the temperature play a great role in the reaction. The yield is decreasing with the decreasing of the temperature. When the temperature decreased to 0 °C, only trace of 2-benzylmalononitrile was obtained.

Table 1 The reduction of 2-benzylidenemalononitrile in different conditions^a

Entry	Solvents	Temperature	Yield (%)^b
a Unless specified otherwise, the reaction was performed at 0.2 mmol scale with 1.2 eq. of the Hantzsch ester in 2 mL solvent at reflux for 24 h.b Isolated yield.
1	Toluene	100 °C	95
2	DCM	Reflux	84
3	CHCl3	Reflux	93
4	CCl4	Reflux	91
5	DEM	Reflux	93
6	EtOAc	Reflux	90
7	EtOH	Reflux	88
8	Dioxane	Reflux	58
9	H2O	100 °C	91
10	H2O	60 °C	85
11	H2O	r.t.	52
12	H2O	0 °C	Trace

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With these promising results, we proceeded to investigate the scope and limitations of the protocol. Firstly, many structurally diverse conjugated alkenes were investigated as the substrates with Hantzsch ester in water at 100 °C. The results are summarized in the Table 2. From the results, we known that the electron-withdrawing ability of functional groups substituted on C=C bonds had strong influence on the reactivity. The conjugated alkenes with strong electron-withdrawing group are active substrates. The 2-benzylidenemalononitrile 1′, (E)-ethyl 2-cyano-3-phenylacrylate 2′, (E)-2-(4-nitrophenyl)-3-phenylacrylonitrile 4′ and (E)-(2-nitrovinyl)benzene 13′ were easily chemoselective reduced by Hantzsch ester in water without any additional catalysts. Excellent yields were obtained (entries 1–2, 4 and 13, 91%, 94%, 98%, 96%). The conjugated alkenes with weak electron-withdrawing group such as (E)-ethyl 2-benzylidene-3-oxobutanoate 8′, (E)-ethyl 2-benzoyl-3-phenylacrylate 9′, cinnamaldehyde 10′, (E)-4-phenylbut-3-en-2-one 11′ and cinnamic acid 12′ are inert substrates. When these inert substrates were carried through with the same reaction conditions, none or trace products were obtained (entries 8–12). Particularly, the (E)-2-(4-nitrophenyl)-3-phenylacrylonitrile 4′ is the active substrate while the (E)-2,3-di-phenylacrylonitrile 3′, (E)-2-(4-fluoro- phenyl)-3-phenylacrylonitrile 5′, (E)-2-(4-chlorophenyl)-3-phenylacrylonitrile 6′ and (E)-2-(4-methoxy-phenyl)-3-phenylacrylonitrile 7′ produce no products. This maybe own to the different electron-withdrawing power of the substituent (Hammett substituent parameter σ (C₆H₅) = −0.01, σ (4-NO₂⁻ C₆H₄) = 0.26, σ (4-F–C₆H₄) = 0.06, σ (4-Cl–C₆H₄) = 0.12).¹⁴

Table 2 Reduction of chemically diverse conjugated alkenes 1–13^a

Entry	Substrates	Products		Yield (%)^b
a Unless specified otherwise, the reaction was performed at 0.2 mmol scale with 1.2 eq. of the Hantzsch ester in 2 mL solvent at reflux for 24 h.b Isolated yield.
1	R1 = CN R2 = CN		1′	91
2	R1 = CN R2 = CO2Et		2′	94
3	R1 = CN R2 = Ph		3′	None
4	R1 = CN R2 = 4-NO2Ph		4′	98
5	R1 = CN R2 = 4-FPh		5′	None
6	R1 = CN R2 = 4-ClPh		6′	None
7	R1 = CN R2 = 4-MeOPh		7′	None
8	R1 = COCH3 R2 = CO2Et		8′	Trace
9	R1 = COPh R2 = CO2Et		9′	35%
10	R1 = H R2 = CHO		10′	Trace
11	R1 = H R2 = COCH3		11′	Trace
12	R1 = H R2 = COOH		12′	Trace
13	R1 = H R2 = NO2		13′	96

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Secondly, we further investigated the influence of other substituent (R₃) on those active conjugated alkenes (1, 2, 4, 13). As shown in Table 3, the conjugated alkenes with aromatic substituent, either electron-deficient or electron-rich, all underwent chemoselective reduction of the C=C double bond with Hantzsch esters in water to afford the desired alkane products in good to high yields (78–97%, 14′–16′, 20′–22′, 26′–33′, 35′, 39′–46′ and 47′, Table 3). Functional groups such as nitrile, ester, nitro, fluoro, chloro and bromo are all tolerated by the reaction conditions employed. The location of nitro on the arene of R₃ affected the reactivity, owing to the steric hindrance (32′–34′, 44′–46′, Table 3). When R₃ is a furanyl, the conjugated alkenes are also active substrates for this protocol and high yields are obtained (70%, 86% and 94%, 17′, 23′ and 36′, Table 3). Furthermore, this protocol exhibited high chemoselectivities for the challenging substrates (E)-2-(3-phenylallylidene)malono-nitrile (18), (2E, 4E)-ethyl 2-cyano-5-phenylpenta-2,4-dienoate (24) and (2E, 4E)-2-(4-nitrophenyl)-5-phenylpenta-2,4-diene- nitrile (37). In these structures with two conjugated C=C double bond, only the one adjacent to the nitrile group was reduced selectively, while the other one remained intact even in an excess of the reducing reagent and extended reaction time (18′, 24′ and 37′, Table 3). When R₃ is aliphatic group (19′, 25′, 38′), moderate yield can be obtained in the same conditions.

Table 3 Reduction of chemically diverse conjugated alkenes 14–49^ab

a Unless specified otherwise, the reaction was performed at 0.2 mmol scale with 1.2 eq. of the Hantzsch ester in 2 mL solvent at reflux for 24 h.b Isolated yield.

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Conclusions

In summary, we have developed a green and simple protocol to chemoselective reduction of C=C double bond in conjugate alkenes. A broad spectrum of substrates can participate in the process effectively to produce the desired products in good to excellent yields. The visible advantages of this method are high chemoselectivity, mild experimental conditions, water tolerance and environmental benign over the traditional methods such as hydrogenation. Especially, functional groups such as nitrile, ester, nitro, fluoro, chloro, bromo, furanyl and benzyl are all tolerated by the reaction conditions employed. Compared with the reported double bond reduction with Hantzsch esters, the remarkable features of this protocol are absence of catalysts and water as the solvent.

Experimental

All starting materials were of the commercially available (analytical grade) and used without further purification. All the solvents are used after redistillation. Reactions were monitored by thin layer chromatography using silica gel HSGF254 plates. Flash chromatography was performed using silica gel HG/T2354-92. Melting points were measured with SGW X-4 melting point apparatus. ¹H NMR (300, 400 or 600 MHz) spectra were recorded in CDCl₃. ¹H NMR chemical shifts are reported in ppm (δ) relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl₃, δ 7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, q = quartet, m = multiplet), coupling constants (Hz) and integration.¹³C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl₃, 77.0 ppm).

General experimental procedures for the reduction of the carbon–carbon double bond in conjugated alkenes reactions: a solution of alkenes (0.2 mmol) and Hantzsch esters (0.24 mmol) in water (2.0 mL) was stirred at 100 °C for 24 h. After the reaction mixtures were cooled to room temperature, the crude solution was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After removal of solvents under reduced pressure, the residue was purified through column chromatograph on silica gel to give the pure products.

Acknowledgements

We are grateful for the financial supports from the National Natural Science Foundation of China (21102115 and 81302647), the spring plan of Ministry of Education (13233637), the Sichuan Education Department (13ZA0206), the Science and Technology Department of Chengdu (12DXYB001JH), the Key Laboratory of Xihua University (Z1013314).

References

1. For reviews on reduction of C=C double bond, see: (a) M. Hudlickey, Reductions in Organic Chemistry, American Chemical Society, Washington, DC, 2nd edn, 1996; (b) P. N. Rylander, Hydrogenation Methods, Academic, New York, 1985; (c) J. Q. Li, X. Quan and P. G. Andersson, Chem. – Eur. J., 2012, 18, 10609; (d) T. L. Church and P. G. Andersson, Coord. Chem. Rev., 2008, 252, 513; (e) T. Bolano, R. Castarlenas, M. A. Esteruelas and E. Onate, J. Am. Chem. Soc., 2007, 129, 8850.
2. For examples on reduction of C=C double bond, see: (a) M. D. Bhor, M. J. Bhanushali, N. S. Nandurkar and B. M. Bhanage, Catal. Commun., 2007, 8, 2064; (b) D. Xue, Y. C. Chen, X. Cui, Q. W. Wang, J. Zhu and J. G. Deng, J. Org. Chem., 2005, 70, 3584; (c) M. Amiel-Levy and S. Hoz, J. Am. Chem. Soc., 2009, 131, 8280; (d) B. C. Ranu and S. Samanta, Tetrahedron Lett., 2002, 43, 7405; (e) Z. G. Zhang and P. R. Schreiner, Synthesis, 2007, 16, 2559; (f) D. B. Ramachary, M. Kishor and Y. V. Reddy, Eur. J. Org. Chem., 2008, 975; (g) D. B. Ramachary and M. S. Prasad, Tetrahedron Lett., 2010, 51, 5246; (h) P. Chauhan, K. Kaur, N. Bala, V. Kumar and S. S. Chimni, Indian J. Chem., 2011, 50B, 304; (i) Q. P. B. Nguyen, J. N. Kim and T. H. Kim, Tetrahedron, 2012, 68, 6513; (j) J. Xiang, E. X. Sun, C. X. Lian, Q. W. Wang and J. G. Deng, Tetrahedron, 2012, 68, 4609; (k) K. M. Lakshmi, T. Parsharamulu and S. V. Manorama, J. Mol. Catal. A: Chem., 2012, 365, 115; (l) S. Balogh, G. Farkas, J. Madarász, Á. Szöllősy, J. Kovács, F. Darvas, L. Ürge and J. Bakos, Green Chem., 2012, 14, 1146; (m) B. Ding, Z. Zhang, Y. Liu, M. Sugiya, T. Imamoto and W. Zhang, Org. Lett., 2013, 15, 3690; (n) P. Bobal and J. Bobalova, Molecules, 2013, 18, 2212.
3. For recent reviews about Hantzsch esters, see: (a) S. L. You, Chem. – Asian J., 2007, 2, 820; (b) Z. Chao and S. L. You, Chem. Soc. Rev., 2012, 41, 2498; (c) S. G. Ouellet, A. M. Walji and D. W. C. MacMillan, Acc. Chem. Res., 2007, 40, 1327; (d) Z. Y. Wang and Z. J. Jiang, Asian J. Chem., 2010, 22, 4141; (e) J. G. de Vries and N. Mrsic, Catal. Sci. Technol., 2011, 1, 727.
4. (a) M. Fujji, K. Nakamura, S. Yasui, S. Oka and A. Ohno, Bull. Chem. Soc. Jpn., 1987, 60, 2423; (b) M. Fujii, Bull. Chem. Soc. Jpn., 1988, 61, 4029.
5. (a) Z. Zhang and P. R. Schreiner, Synthesis, 2007, 2559; (b) J. F. Schneider, M. B. Lauber, V. Muhr, D. Kratzer and J. Paradies, Org. Biomol. Chem., 2011, 9, 4323.
6. Q. Liu, J. Li, X. X. Shen, R. G. Xing, J. Yang, Z. Liu and B. Zhou, Tetrahedron Lett., 2009, 50, 1026.
7. J. Che and Y. Lam, Synlett, 2010, 16, 2415.
8. (a) J. W. Yang, M. T. H. Fonseca and B. List, Angew. Chem., Int. Ed., 2004, 43, 6660; (b) S. G. Ouellet, J. B. Tuttle and D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 127, 32; (c) S. Mayer and B. List, Angew. Chem., Int. Ed., 2006, 45, 4193; (d) N. J. A. Martin and B. List, J. Am. Chem. Soc., 2006, 128, 13368; (e) J. B. Tuttle, S. G. Ouellet and D. W. C. MacMillan, J. Am. Chem. Soc., 2006, 128, 12662; (f) T. J. Hoffman, J. Dash, J. H. Rigby, S. Arseniyadis and J. Cossy, Org. Lett., 2009, 11, 2756.
9. (a) K. Akagawa, H. Akabane, S. Sakamoto and K. Kudo, Org. Lett., 2008, 10, 2035; (b) K. Akagawa, H. Akabane, S. Sakamoto and K. Kudo, Tetrahedron: Asymmetry, 2009, 20, 461; (c) N. J. A. Martin, L. Ozores and B. List, J. Am. Chem. Soc., 2007, 129, 8976; (d) N. J. A. Martin, X. Cheng and B. List, J. Am. Chem. Soc., 2008, 130, 13862.
10. Q. P. B. Nguyen, J. N. Kim and T. H. Kim, Tetrahedron, 2012, 68, 6513.
11. For a nornicotine-catalyzed transfer hydrogenation of α, β-unsaturated aldehydes using 1,4-dihydropyridine-3,5-dicarboxylic acid in aqueous solution, see: A. P. Brogan, T. J. Dickerson and K. D. Janda, Chem. Commun., 2007, 4952.
12. J. Li, Z. Wang, Z. Jiang, S. Jiang and L. Xiong, Asian J. Chem., 2011, 23, 4101.
13. Some representative reviews on reaction in water: (a) T. Adschiri, Y. W. Lee, M. Goto and S. Takami, Green Chem., 2011, 13, 1380; (b) Y. W. Wei, D. Xue, Q. Lei, C. Wang and J. L. Xiao, Green Chem., 2013, 15, 629; (c) M. Bakherad, Appl. Organomet. Chem., 2013, 27, 125; (d) L. A. de Cienfuegos, R. Robles, D. Miguel and J. Justicia, ChemSusChem, 2011, 4, 1035; (e) K. Kumaravel and G. Vasuki, Curr. Org. Chem., 2009, 13, 1820; (f) M. Raj and V. K. Singh, Chem. Commun., 2009, 44, 6687.
14. C. Hansch, A. Leo and R. W. Taft, Chem. Rev., 1991, 91, 165.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra48072k

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