A base-controlled chemoselective transfer hydrogenation of α,β-unsaturated ketones catalyzed by [IrCp*Cl₂]₂ with 2-propanol

Abstract

A simple homogeneous catalyst system based on commercially available [IrCp*Cl₂]₂ has been developed for the conjugate reduction of α,β-unsaturated ketones. Under the optimized conditions, a wide range of α,β-unsaturated ketones were reduced to saturated ketones in 83–98% yield. While switching the base from K₂CO₃ to KOH, saturated alcohols was selectively obtained.

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The catalytic transfer hydrogenation of unsaturated organic compounds is an attractive methodology in synthetic organic chemistry.¹ Chemoselective reduction of α,β-unsaturated carbonyl compounds is one of the most important subjects in this field. Since the second half of the 20th century, a number of protocols have been developed for the transfer hydrogenation of α,β-unsaturated ketones with the aim of avoiding the use of hazardous hydrogen gas^2,3 and other costly hydrogen sources (hydrosilanes,⁴ NaBH₄,⁵ Hantzsch ester⁶ etc.). This type of transformation has been achieved by the use of transition metals derived from ruthenium,^7,8 rhodium,^9,10 palladium,¹¹ iridium,¹² and nickel.¹³ The use of alcohols, formic acid and its salts is oftentimes preferred. Among them, 2-propanol is the most attractive hydrogen donor due to its good solvent properties, being less expensive, and easy to remove from the reaction system as itself or the generated acetone.^1c

Despite all these advances, considering the constitution of these catalyst systems, most of the catalysts required tedious steps of synthesis or additive ancillary ligands. Only a few processes directly applied the commercially available catalyst, and most of them also suffered from drawbacks such as low yields, high temperature, and the use of toxic solvents.^8,9 In this respect, the search for simple and practical catalyst system especially consisting of commercially available catalyst is still in high demand.

As part of our continuing interest in homogeneous iridium catalysts for organic transformations,¹⁴ we herein reported the potential of commercial available catalyst [IrCp*Cl₂]₂ in transfer hydrogenation of α,β-unsaturated ketones with 2-propanol as hydrogen source and solvent.

We began our studies by utilizing chalcone 1a as a model substrate in the presence of [IrCp*Cl₂]₂ (ref. 15) under various conditions (Table 1). Treatment of 1a with catalytic amount of [IrCp*Cl₂]₂ and K₂CO₃ in MeOH at 85 °C for 5 h gave the conjugate reduction product 2a in 31% yield with none of the double hydrogenation product 3a (Table 1, entry 1). A screening on other straight-chain fatty alcohols, that is, EtOH, 1-PrOH, and 1-BuOH, gave 2a in 36%, 70%, and 57% yields, respectively (entries 2–4). To our delight, when 2-PrOH was used, the reaction proceeded smoothly, yielding the 2a in 92% yield with excellent chemoselectivity (entry 5). To further improve the yield, a series of bases was then screened and Na₂CO₃ gave the similar result to K₂CO₃ (entry 6). Interestingly, in the case of Cs₂CO₃, the generated 2a was further hydrogenated to the saturated alcohol 3a in 64% yield (entry 7). Other strong bases, such as KOH and NaOH, gave 3a in 86, 84% yields, respectively (entries 8 and 9). Organic base NEt₃ exhibited inhibitory effect on the reaction and resulted in a low yield (entry 10). It should be noted that decreasing the amount of K₂CO₃ to 5 mol% led to full conversion of 1a and 99% of the 2a was obtained within 5 h (Table 1, entry 11). However, in the absence of K₂CO₃, the reaction proceeded sluggishly (entry 12).

Table 1 Optimization of reaction conditions in transfer hydrogenation of chalcone^a

Entry	Solvent	Base	Yield^b (%)
			2a	3a
a Reactions conditions: 1a (0.2 mmol), [IrCp*Cl2]2 (1 mol%), base (0.5 equiv.), solvent (1 mL), 85 °C, 5 h.b GC yield.c 5 mol% K2CO3 was used. Cp*: 1,2,3,4,5-pentamethylcyclopentadiene.
1	MeOH	K2CO3	31	0
2	EtOH	K2CO3	36	0
3	1-PrOH	K2CO3	70	0
4	1-BuOH	K2CO3	57	0
5	2-PrOH	K2CO3	92	0
6	2-PrOH	Na2CO3	89	0
7	2-PrOH	Cs2CO3	16	64
8	2-PrOH	KOH	2	86
9	2-PrOH	NaOH	3	84
10	2-PrOH	NEt3	14	0
11^c	2-PrOH	K2CO3	99	0
12	2-PrOH	—	66	0

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Base on the above findings and the literature data, we inferred that the role of the base was to generate a highly active Cp*IrH₂ catalyst from the dichloride (eqn (1) and (2)).¹⁶ In addition, an excess of base resulted in low solubility of the substrate, which ultimately led to low yield. To validate our assumption, a series of controlled experiments based on the volume of 2-PrOH was carried out under the condition of entry 5, as showed in Fig. 1. As expected, the yield of 2a was merely moderate when the concentration of K₂CO₃ was high. Increasing the volume of 2-PrOH improved the yield of 2a. A full conversion of 1a and 99% yield of 2a was achieved when the amount of 2-PrOH was increasing to 2 mL. Continue increasing the volume of 2-PrOH to 5 mL did not change the yield of 2a.

Fig. 1 Effect of the volume of 2-PrOH on the catalytic transfer hydrogenation of chalcone with [IrCp*Cl₂]₂.

With the optimized conditions in hands, various α,β-unsaturated ketones were then subjected to the reaction to establish the scope and generality of this protocol (Table 2). Firstly, a series of substituted chalcones were investigated (entries 2–16). The chalcones bearing electron-donating group Me and MeO on the 4′ position respectively required a higher catalyst loading and temperature to achieve satisfactory results (entries 2 and 3); while the chalcones bearing Me and MeO groups on the 4 position respectively were easy to reduce cleanly (entries 10 and 11). The transformations of halogen- and trifluoromethyl-substituted chalcones afforded desired products in 92–98% yields, and the position of the substituted groups did not significantly affect the reactivity (entries 4–7, 12–15). A similar result was observed in the case of 4′,2-disubstituted chalcone (entry 16). We also studied the cases of heterocyclic α-enones. To our delight, it still exhibited high activity and good selectivity, provided the desired products in excellent yields (entries 17 and 18). When the R² group was occupied by H or alkyl groups, the reaction also proceeded smoothly in good to excellent yields (entries 19–21). Activated α,β-unsaturated ketones 1v and 1w, which have been proved to be good substrates in the previous reports, were also reduced in high yields (entries 22 and 23). Furthermore, the present catalytic system also displayed high catalytic efficiency for the reduction of cyclic enones (entries 24 and 25). However, α,β,γ,ε-unsaturated enone 1z was proved to be sluggish substrate and only trace amount of 2z was observed (entry 26). The transfer hydrogenations of α,β-unsaturated ketones to the corresponding alcohols were also investigated by applying KOH as the base. As expected, the desired saturated alcohols were obtained in 78–92% yields, which established our findings on the base-controlled chemoselectivity (entries 1–12, 22). Finally, an α,β-unsaturated ketone 1aa bearing a non-polarized double bond was subjected to the condition (eqn (3)). To our delight, the present catalytic system selectively reduced the enone and kept the non-polarized double bond.

Table 2 [IrCp*Cl₂]₂ catalyzed transfer hydrogenation of α,β-unsaturated ketones^a

Entry	1	R^1	R^2	Yield (%)
				2^b	3^c
a Condition A: 1 (0.4 mmol), [IrCp*Cl2]2 (1 mol%), K2CO3 (5 mol%), 2-PrOH (4 mL), 85 °C, 5 h; condition B: 1 (0.4 mmol), [IrCp*Cl2]2 (1 mol%), KOH (50 mol%), 2-PrOH (4 mL), 85 °C, 5 h.b Isolated yield.c Yields were determined by GC analysis using n-hexadecane as internal standard (yield in parentheses is the isolated yield).d [IrCp*Cl2]2 (2 mol%), K2CO3 (10 mol%), 100 °C, 10 h.e 8 h.
1	1a	Ph	Ph	97 (2a)	88 (82)
2^d	1b	p-MeC6H4	Ph	90 (2b)	83
3^d	1c	p-MeOC6H4	Ph	85 (2c)	78
4	1d	p-FC6H4	Ph	92 (2d)	85
5	1e	p-ClC6H4	Ph	98 (2e)	91
6	1f	p-BrC6H4	Ph	92 (2f)	88
7	1g	m-ClC6H4	Ph	94 (2g)	84
8	1h	o-MeC6H4	Ph	96 (2h)	90
9	1i	2-Naphthyl	Ph	95 (2i)	85
10	1j	Ph	p-MeC6H4	94 (2j)	84
11	1k	Ph	p-MeOC6H4	93 (2k)	85
12	1l	Ph	p-ClC6H4	97 (2l)	89
13	1m	Ph	p-CF3C6H4	96 (2m)
14	1n	Ph	m-CF3C6H4	95 (2n)
15	1o	Ph	o-CF3C6H4	94 (2o)
16	1p	p-ClC6H4	o-CF3C6H4	93 (2p)
17	1q	Furanyl	Ph	93 (2q)
18	1r	Thiophenyl	Ph	97 (2r)
19	1s	Ph	H	87 (2s)
20	1t	Ph	Ph(CH2)2	96 (2t)
21	1u	Ph	CH3(CH2)5	94 (2u)
22	1v	Me	Ph	95 (2v)	92^e
23	1w	Me	Furanyl	94 (2w)
24	1x	–C3H6–		91 (2x)
25	1y	–C2H4–		97^c (2y)
26	1z	Ph	PhCH=CH	Trace (2z)

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A plausible mechanism is proposed in Scheme 1 to explain the selective transfer hydrogenation of α,β-unsaturated ketones to the saturated ketones or alcohols.¹⁷ In the initial step, the active catalyst A was generated via the sequences showed in eqn (1) and (2). The α-enone 1a then coordinated to A, followed by a hydride transfer to give intermediate B, which underwent an enolization to produce C. The resulting Ir-enolate C was protonated by 2-PrOH to give product 2a and produced the catalytic species D, which sequently underwent a β-elimination to reproduce the active catalyst A. Although detailed mechanism for the secondary hydrogenation of the resulting ketones in the presence of KOH is not clear. A base promoted Meerwein–Ponndorf–Verley type reaction may be responsible for this unexpected results.¹⁸ More detailed studies are required to clarify the detailed mechanism.

Scheme 1 Proposed catalytic cycle.

Conclusions

We have demonstrated that [IrCp*Cl₂]₂ was a highly effective and versatile catalyst for the transfer hydrogenation of α,β-unsaturated ketones with 2-PrOH. The simplicity of this protocol employing commercially available catalyst makes it attractive for laboratory hydrogenations without the need for hazardous H₂ and other costly hydrogen sources. By changing the base from K₂CO₃ to KOH, the products could be switched from saturated ketones to saturated alcohols.

Experimental section

An Ar purged flame-dried Schlenk tube (25 mL) containing α,β-unsaturated ketone 1 (0.40 mmol, 1 equiv.), [IrCp*Cl₂]₂ (1 mol%), and K₂CO₃ (5 mol%) were added 2-PrOH (4 mL). The reaction mixture was stirred at 85 °C for 5 h unless stated otherwise. After the reaction was complete, the solvent was removed under reduced pressure. The crude residue was purified by flash column silica gel chromatography (petroleum ether/ethyl acetate: 95 : 5 to 90 : 10) to yield the product 2.

Notes and references

1. Selected reviews: (a) R. A. W. Johnstone, A. H. Wilby and I. D. Entwistle, Chem. Rev., 1985, 85, 129; (b) R. Noyori and S. Hashiguchi, Acc. Chem. Res., 1997, 30, 97; (c) J.-i. Ito and H. Nishiyama, Tetrahedron Lett., 2014, 55, 3133.
2. (a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley-VCH, Weinheim, 1994; (b) M. Bartók and A. Molnár, Heterogeneous Catalytical Hydrogenation, Wiley-VCH, Weinheim, 1997, ch. 16, pp. 843–908; (c) S. Nishimura, Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis, Wiley-VCH, Weinheim, 2001; (d) Fine Chenicals through Heterogeneous Catalysis, ed. R. A. Sheldon and H. van Bekkum, Wiley-VCH, Weinheim, 2001.
3. Selected reference see: (a) G. Szöllösi, B. Török, L. Baranyi and M. Bartók, J. Catal., 1998, 179, 619; (b) G. Szöllősi, Á. Mastalir, Á. Molnár and M. Bartók, React. Kinet. Catal. Lett., 1996, 57, 29; (c) A. Mori, Y. Miyakawa, E. Ohashi, T. Haga, T. Maegawa and H. Sajiki, Org. Lett., 2006, 8, 3279; (d) S. Jagtap, Y. Kaji, A. Fukuoka and K. Hara, Chem. Commun., 2014, 50, 5046.
4. (a) M. Sugiura, N. Sato, S. Kotani and M. Nakajima, Chem. Commun., 2008, 4309; (b) A. Pelss, E. T. Kumpulainen and A. M. Koskinen, J. Org. Chem., 2009, 74, 7598; (c) M. Benohoud, S. Tuokko and P. M. Pihko, Chem.–Eur. J, 2011, 17, 8404; (d) J.-Y. Shang, F. Li, X.-F. Bai, J.-X. Jiang, K.-F. Yang, G.-Q. Lai and L.-W. Xu, Eur. J. Org. Chem., 2012, 2809.
5. (a) B. C. Ranu and S. Samanta, J. Org. Chem., 2003, 68, 7130; (b) A. T. Russo, K. L. Amezcua, V. A. Huynh, Z. M. Rousslang and D. B. Cordes, Tetrahedron Lett., 2011, 52, 6823.
6. Q. Liu, J. Li, X.-X. Shen, R.-G. Xing, J. Yang, Z. Liu and B. Zhou, Tetrahedron Lett., 2009, 50, 1026.
7. (a) S. Bolaño, L. Gonsalvi, F. Zanobini, F. Vizza, V. Bertolasi, A. Romerosa and M. Peruzzini, J. Mol. Catal. A: Chem., 2004, 224, 61; (b) C. A. Mebi, R. P. Nair and B. J. Frost, Organometallics, 2007, 26, 429; (c) S. Naskar and M. Bhattacharjee, Tetrahedron Lett., 2007, 48, 465.
8. (a) Y. Sasson and J. Blum, Tetrahedron Lett., 1971, 12, 2167; (b) J. Blum, Y. Sasson and S. Iflah, Tetrahedron Lett., 1972, 13, 1015; (c) Y. Sasson and J. Blum, J. Org. Chem., 1975, 40, 1887; (d) I. Ryu, T. Doi, T. Fukuyama, J. Horiguchi and T. Okamura, Synlett, 2006, 721.
9. (a) D. Beaupere, P. Bauer and R. Uzan, Can. J. Chem., 1979, 57, 218; (b) Z. Baán, Z. Finta, G. Keglevich and I. Hermecz, Green Chem., 2009, 11, 1937.
10. X. Li, L. Li, Y. Tang, L. Zhong, L. Cun, J. Zhu, J. Liao and J. Deng, J. Org. Chem., 2010, 75, 2981.
11. (a) B. Basu, M. H. Bhuiyan, P. Das and I. Hossain, Tetrahedron Lett., 2003, 44, 8931; (b) B. Basu, S. Das, P. Das and A. K. Nanda, Tetrahedron Lett., 2005, 46, 8591; (c) K. Fujimoto, T. Yoneda, H. Yorimitsu and A. Osuka, Angew. Chem., Int. Ed., 2014, 53, 1127; (d) D. B. Bagal and B. M. Bhanage, RSC Adv., 2014, 4, 32834; (e) L.-H. Gong, Y.-Y. Cai, X.-H. Li, Y.-N. Zhang, J. Su and J.-S. Chen, Green Chem., 2014, 16, 3746; (f) N. M. Patil, T. Sasaki and B. M. Bhanage, Catal. Lett., 2014, 144, 1803.
12. (a) S. Sakaguchi, T. Yamaga and Y. Ishii, J. Org. Chem., 2001, 66, 4710; (b) Y. Himeda, N. Onozawa-Komatsuzaki, S. Miyazawa, H. Sugihara, T. Hirose and K. Kasuga, Chem.–Eur. J, 2008, 14, 11076; (c) J. Li, Y. Zhang, D. Han, G. Jia, J. Gao, L. Zhong and C. Li, Green Chem., 2008, 10, 608.
13. N. Castellanos-Blanco, M. Flores-Alamo and J. J. García, Organometallics, 2012, 31, 680.
14. S.-J. Chen, G.-P. Lu and C. Cai, Synthesis, 2014, 46, 1717.
15. [IrCp*Cl₂]₂ was an efficient catalyst for the hydrogen autotransfer (or hydrogen-borrowing) process, for reviews, see: (a) G. Guillena, D. J. Ramón and M. Yus, Chem. Rev., 2010, 110, 1611; (b) Y. Ishii and Y. Obora, Synlett, 2011, 30; (c) S. Bähn, S. Imm, L. Neubert, M. Zhang, H. Neumann and M. Beller, ChemCatChem, 2011, 3, 1853; (d) T. Suzuki, Chem. Rev., 2011, 111, 1825; (e) A. C. Marr, Catal. Sci. Technol., 2012, 2, 279.
16. A. Aranyos, G. Csjernyik, K. J. Szabó and J.-E. Bäckvall, Chem. Commun., 1999, 351.
17. (a) K. Fujita, C. Asai, T. Yamaguchi, F. Hanasaka and R. Yamaguchi, Org. Lett., 2005, 7, 4017; (b) C. Löfberg, R. Grigg, M. A. Whittaker, A. Keep and A. Derrick, J. Org. Chem., 2006, 71, 8023; (c) S. Whitney, R. Grigg, A. Derrick and A. Keep, Org. Lett., 2007, 9, 3299; (d) S. Bhat and V. Sridharan, Chem. Commun., 2012, 48, 4701.
18. For base promoted reactions of ketones or alcohols under transition-metal-free conditions, see: (a) C. Walling and L. Bollyky, J. Am. Chem. Soc., 1964, 86, 3750; (b) A. Berkessel, T. J. S. Schubert and T. N. Müller, J. Am. Chem. Soc., 2002, 124, 8693; (c) Y.-F. Liang, X.-F. Zhou, S.-Y. Tang, Y.-B. Huang, Y.-S. Feng and H.-J. Xu, RSC Adv., 2013, 3, 7739 , and references therein.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, ¹H-NMR, ¹³C-NMR, and ¹⁹F-NMR spectra of all isolated products. See DOI: 10.1039/c5ra00484e

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