Using alcohols as simple H₂-equivalents for copper-catalysed transfer semihydrogenations of alkynes

Abstract

Copper(I)/N-heterocyclic carbene complexes enable a transfer semihydrogenation of alkynes employing simple and readily available alcohols such as isopropanol. The practical overall protocol circumvents the use of commonly employed high pressure equipment when using dihydrogen (H₂) on the one hand, and avoids the generation of stoichiometric silicon-based waste on the other hand, when hydrosilanes are used as terminal reductants.

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Catalytic transfer hydrogenations (TH) are attractive for the reduction of a variety of functional groups, as they offer practical protocols circumventing the need for high pressure equipment.¹ In general, for catalytic TH there is a need for easy-to-use and safe dihydrogen (H₂) sources, as these reactants are associated with the generation of one molecule of waste per turnover. Alcohols, such as the commonly employed isopropanol, fulfil the abovementioned criteria.¹

Copper-catalysed reductive transformations (so-called copper hydride catalysis)² pose formidable challenges with regard to transfer hydrogenations: On the one hand, copper hydride catalysis almost exclusively relies on hydrosilanes as reducing agents,² bringing forward a problem of atom economy due to silicon-based waste generated. On the other hand, copper(I)-catalysed homogeneous hydrogenations (based on the atom economic H₂) as investigated by us and others^3–5 generally require elevated H₂ pressure, hampering their overall practicability. Finally, copper is a readily available metal, which renders it highly attractive for catalytic (transfer) hydrogenations.⁶ It comes to a surprise that for homogeneous copper hydride catalysis, transfer hydrogenations using alcohols as H₂ equivalents have not been reported so far, as this would manifest an atom economic and practical access to copper hydride chemistry, addressing the abovementioned limitations.^7–9 Herein, we show that simple alcohols (such as isopropanol) can be employed as H₂ equivalents for a prototypical copper hydride-based catalytic transformation, namely the semireduction of internal alkynes to alkenes.^10–12

The alkyne semihydrogenation poses challenges in stereoselectivity (E vs. Z) and chemoselectivity (overreduction of the formed alkene to the corresponding alkane, Scheme 1),¹⁰ and thus serves as an ideal model reaction for catalyst development. To probe a possible transfer of a hydrogen atom from the α-position of an alcohol by means of a copper(I) catalyst, we investigated the transfer semihydrogenation of internal alkyne 1, using α,α-dideuterated benzyl alcohol (2-d₂, Scheme 1). Employing readily available [SIMesCuCl]¹³ in catalytic amounts (10 mol%) and NaOtBu as base, full conversion either with microwave or conventional heating to the corresponding alkene 3 was found. Furthermore, significant ²H-incorporation (19–58%) in the β-position of the styrene moiety of 3 was observed, which suggested the envisaged presence of a copper(I) hydride/deuteride intermediate.^14–16

Scheme 1 Deuterated alcohol as formal HD source in a copper-catalysed transfer hydrogenation. Reaction was carried out on a 0.2 mmol scale. Conversion monitored by GC analysis. Deuterium incorporation determined by ¹H/²H NMR spectroscopy. ^a The H_α resonances could not be resolved by ²H NMR spectroscopy.

No formation of the overreduced alkane was observed in this initial experiment, which encouraged us to further develop the copper-catalysed transfer semihydrogenation of alkynes. Therefore, the viability of alcohols as H₂ sources for copper hydride catalysis in a transfer hydrogenation setting was established.

To optimise the conditions of the catalytic protocol, we opted for tolane (4) as model substrate (Table 1). We first demonstrated that 10 mol% of well-defined copper(I) complexes of standard N-heterocyclic carbene (NHC) ligands¹⁷ (SIMes, IMes and IPr, respectively)¹⁸ sufficed to achieve high or full conversion in the catalytic transfer semihydrogenation of 4 employing readily available isopropanol as H₂ equivalent (Table 1, entries 1–5). Along these lines, [SIMesCuCl] as catalyst delivered the highest conversion and stereoselectivity to give stilbene Z-5 (100%, Z/E = 92 : 8, Table 1, entry 2). Notably, none of the NHC/copper(I) complexes investigated gave any overreduction to 1,2-diphenylethane (6). Other primary and/or secondary alcohols such as benzyl alcohol (2), glycerol or ethanol also gave detectable conversion, however, these H₂ equivalents could not compete with isopropanol in terms of either conversion or Z/E selectivity (Table 1, entries 6–8). The change in stereoselectivity is an indication that the alcohol employed alters the structure and/or reactivity of the active catalyst. Indeed, when other secondary alcohols (2-pentanol and 2-hexanol) were tested, also, unselective reactions in terms of stereo- and chemoselectivity were observed (see the ESI,† Section S2). The omission of NHC ligands led to diminished or complete loss of chemoselectivity, as with CuCl itself either 6% (with NaOtBu as base) or complete conversion to undesired alkane 6 (using LiOtBu) was detected (Table 1, entries 9 and 10). These results indicate the presence of heterogeneous copper catalysts when no ligand is employed (see also Scheme 3 for more details). Finally, we established that under optimised conditions, the reaction could also be carried out with microwave heating to deliver the same results as conventional heating (Table 1, entry 11).

Table 1 Copper-catalysed transfer semihydrogenation, optimisation^a

Entry	Catalyst, loading	Base	Alcohol/solvent^b	Conv. [%]	Z/E-5	6 [%]
a Reactions were carried out on a 0.2 mmol scale. Conversion and selectivity determined by GC and ^1H NMR analysis. b If not noted otherwise, 1 mL of the corresponding alcohol was employed as solvent. c 50 mol% NaOtBu was employed. d 2.0 equiv. BnOH in 1 mL 1,4-dioxane was used. e 1 mL of a glycerol/1,4-dioxane mixture (1 : 10 v/v) was employed. f Reaction was performed with microwave heating at 120 °C for 16 h.
1	[SIMesCuCl], 5 mol%	NaOtBu	iPrOH	49	90 : 10	<1
2	[SIMesCuCl], 10 mol%	NaOtBu	iPrOH	100	92 : 8	<1
3	[IPrCuCl], 10 mol%	NaOtBu	iPrOH	90	92 : 8	<1
4	[IMesCuCl], 10 mol%	NaOtBu	iPrOH	100	90 : 10	<1
5	[SIMesCuCl], 10 mol%	NaOtBu^c	iPrOH	100	84 : 16	<1
6	[SIMesCuCl], 10 mol%	NaOtBu	BnOH/1,4-dioxane^d	100	70 : 30	<1
7	[SIMesCuCl], 10 mol%	NaOtBu	Glycerol/1,4-dioxane^e	69	93 : 7	<1
8	[SIMesCuCl], 10 mol%	NaOtBu	EtOH	29	86 : 14	<1
9	CuCl, 20 mol%	NaOtBu	iPrOH	100	80 : 20	6
10	CuCl, 20 mol%	LiOtBu	iPrOH	100	>1%	>99
11	[SIMesCuCl], 10 mol%	NaOtBu	iPrOH	100	95 : 5	<1

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As the conduction of the reaction outside the microwave leads to a simpler overall procedure, we investigated the substrate scope of the copper(I)-catalysed transfer semihydrogenation with conventional heating next (Scheme 2). A variety of tolane derivatives gave the corresponding products 8a–c in very good yields and Z-stereoselectivity (≥94%, Z/E ≥ 91 : 9). Both electron-rich as well as electron-poor stilbene derivatives 8d to 8g were obtained with similarly good results in terms of yield and Z/E-selectivity, albeit that trifluoro-substituted stilbene 8g was isolated with a somewhat lower yield of 66%. Moving on to aryl alkyl-substituted alkynes as substrates, we were able to isolate benzyl-protected hexenol-derivative 8h with Z/E = 82 : 18 and in 90% yield. This result is noteworthy, as no benzyl ether deprotection was detected, albeit the overall reducing conditions of the overall process.¹⁹ The sterically more demanding cyclohexyl derivative 8i was the only compound studied which was accompanied by a negligible amount of the corresponding alkane (4%). The clean isolation of cyclopropyl styrene 8j with very good results (84%, Z/E = 97 : 3), and no evidence for a ring-opening gives an important indication that no radical intermediates are involved in the overall process.²⁰ Finally, the fully stereoselective production of Z-6-dodecene (Z-8k) in acceptable yields shows that isopropanol can also be used as H₂ equivalent with dialkyl alkynes as substrates, which are relatively unreactive in copper-based semihydrogenations.³

Scheme 2 Copper-catalysed transfer semihydrogenation, substrate scope.

Scheme 3 Influence of the NHC ligand on chemoselectivity.

It should be noted that generally, no overreduction to the corresponding alkane was observed, underscoring the ability of the NHC ligand to control chemoselectivity in the transfer hydrogenation. This feature is in stark contrast to related transfer hydrogenations employing catalytic amounts of copper nanoparticles which cleanly deliver the corresponding alkanes from alkyne starting materials.^7a The present protocol thus achieves hitherto unreached chemoselectivity for copper-catalysed transfer semihydrogenations, which can be related back to the key influence of NHC ligands. The high Z selectivity reached for most alkynes deserves some more comments: When following the reaction with 8h, a relatively fast aforegoing alkyne semihydrogenation takes place (100% conversion reached after 4h), followed by a period in which no alkane was formed but the Z/E ratio diminished, indicating a secondary isomerisation process (see the ESI† for details). These results show that close optimization of the reaction time for an alkyne of interest can lead to even higher Z/E ratios.

To underscore the significant presence of the SIMes ligand on the selectivity of the transfer semihydrogenation, we have re-investigated chlorotolane 7f as substrate. In the presence of SIMesCuCl under standard conditions, clean and stereoselective formation of the corresponding chlorostilbene 8f was observed (91%, Z/E = 93 : 7, see Scheme 2). Under identical reaction conditions but employing only copper(I) chloride as catalyst, no alkene formation was observed, instead high conversion to the corresponding dechlorinated and chlorinated overreduced alkane 9 and 10 was detected (9/10 = 66 : 34). The amount of dechlorination also depended on the counterion of the base employed: with lithium tert-butoxide, a higher percentage of the dechlorinated alkane 9 was found. (9/10 = 66 : 34 vs.9/10 = 20 : 80 with NaOtBu) This result serves as additional evidence for the fact that the active catalyst present in the transfer semihydrogenations comprises an NHC ligand which is vital for high selectivities.²¹

To address the need for readily available and cheap H₂ equivalents for transfer hydrogenations, we have demonstrated that simple alcohols can be employed in copper-catalysed transfer hydrogenations. The results show that in the realm of copper hydride catalysis both, high pressure equipment (when using H₂) as well as waste-generating hydrosilanes can be circumvented, offering a cheap access to copper hydrides and a practical overall protocol. The use of NHCs as key ligands leads to high chemoselectivity (little or no overreduction to the corresponding alkanes) and stereoselectivity (very high Z/E ratios observed). The present first entry way to copper hydride catalysis in a transfer hydrogenation setting from alcohols thus has implications for a potential broader application in reductive copper-catalysed transformations. The extension of this methodology to other common copper hydride-based transformations is currently ongoing.

This work was supported by the German Research Council (DFG, Emmy Noether Fellowship for J. F. T., TE1101/2-1; funding for T. K. through the cluster of excellence Unifying Concepts in Catalysis).

Conflicts of interest

There are no conflicts to declare.

Notes and references

1. For reviews on catalytic transfer hydrogenations, see: (a) D. Wang and D. Astruc, Chem. Rev., 2015, 115, 6621–6686; (b) T. Ikariya and A. J. Blacker, Acc. Chem. Res., 2007, 40, 1300–1308; (c) S. Gladiali and E. Alberico, Chem. Soc. Rev., 2006, 35, 226–236.
2. For reviews on copper hydride catalysis, see: (a) A. J. Jordan, G. Lalic and J. P. Sadighi, Chem. Rev., 2016, 116, 8318–8372; (b) C. Deutsch and N. Krause, Chem. Rev., 2008, 108, 2916–2927; (c) S. Rendler and M. Oestreich, Angew. Chem., Int. Ed., 2007, 46, 498–504.
3. For copper(I)-catalysed alkyne semihydrogenations, see: (a) F. Pape, N. O. Thiel and J. F. Teichert, Chem. – Eur. J., 2015, 21, 15934–15938; (b) K. Semba, R. Kameyama and Y. Nakao, Synlett, 2015, 318–322; (c) N. O. Thiel and J. F. Teichert, Org. Biomol. Chem., 2016, 14, 10660–10666; (d) T. Wakamatsu, K. Nagao, H. Ohmiya and M. Sawamura, Organometallics, 2016, 35, 1354–1357; (e) N. O. Thiel, S. Kemper and J. F. Teichert, Tetrahedron, 2017, 73, 5023–5028; (f) F. Pape and J. F. Teichert, Synthesis, 2017, 2470–2482.
4. For the related copper(I)-catalysed alkyne semireductions employing hydrosilanes, see: (a) K. Semba, T. Fujihara, T. Xu, J. Terao and Y. Tsuji, Adv. Synth. Catal., 2012, 354, 1542–1550; (b) A. M. Whittaker and G. Lalic, Org. Lett., 2013, 15, 1112–1115.
5. For the related copper(I)-catalysed transfer semihydrogenation of alkynes with other reducing agents, see: (a) H. Cao, T. Chen, Y. Zhou, D. Han, S.-F. Yin and L.-B. Han, Adv. Synth. Catal., 2014, 356, 765–769; (b) Ref. 12.
6. For reviews on catalytic hydrogenations with abundant metals, see for example: (a) T. N. Gieshoff and A. J. von Wangelin, in Non-noble metal catalysis, Molecular approaches and reactions, ed. R. J. M. Gebbink and M.-E. Moret, Wiley-VCH, Weinheim, 2019, vol. 39, pp. 97–126; (b) F. Kallmeier and R. Kempe, Angew. Chem., Int. Ed., 2018, 57, 46–60; (c) G. A. Filonenko, R. van Putten, E. J. M. Hensen and E. A. Pidko, Chem. Soc. Rev., 2018, 47, 1459–1483; (d) P. J. Chirik, Acc. Chem. Res., 2015, 48, 1687–1695; (e) R. M. Bullock, Science, 2013, 342, 1054–1055.
7. For the related transfer hydrogenations of alkynes with heterogeneous copper catalysts employing alcohols as H₂ equivalents, see: (a) T. Subramanian and K. Pitchumani, Catal. Sci. Technol., 2012, 2, 296–300; (b) H. Bao, B. Zhou, H. Jin and Y. Liu, J. Org. Chem., 2019, 84, 3579–3589.
8. For the related transfer hydrogenations of carbonyl groups with heterogeneous copper catalysts employing alcohols as H₂ equivalents, see: (a) K. Yoshida, C. Gonzalez-Arellano, R. Luque and P. L. Gai, Appl. Catal., A, 2010, 379, 38–44; (b) M.-J. Zhang, D.-W. Tan, H.-X. Li, D. J. Young, H.-F. Wang, H.-Y. Li and J.-P. Lang, J. Org. Chem., 2018, 83, 1204–1215.
9. For a review on alkyne semihydrogenation with heterogeneous catalysts, see: J. A. Delgado, O. Benkirane, C. Claver, D. Curulla-Ferré and C. Godard, Dalton Trans., 2017, 46, 12381–12403.
10. For reviews on alkyne semihydrogenation, see: (a) J. Lei, L. Su, K. Zeng, T. Chen, R. Qiu, Y. Zhou, C.-T. Au and S.-F. Yin, Chem. Eng. Sci., 2017, 171, 404–425; (b) C. Oger, L. Balas, T. Durand and J.-M. Galano, Chem. Rev., 2013, 113, 1313–1350; (c) M. Crespo-Quesada, F. Cárdenas-Lizana, A.-L. Dessimoz and L. Kiwi-Minsker, ACS Catal., 2012, 2, 1773–1786; (d) A. M. Kluwer and C. J. Elsevier, in The handbook of homogeneous hydrogenation, ed. J. G. de Vries and C. J. Elsevier, Wiley-VCH, Weinheim, 2008, pp. 374–411; (e) Á. Molnár, A. Sárkány and M. Varga, J. Mol. Catal. A: Chem., 2001, 173, 185–221.
11. For selected examples of stereoselective alkyne semihydrogenations with other metals, see: (a) A. Bacchi, M. Carcelli, M. Costa, A. Leporati, E. Leporati, P. Pelagatti, C. Pelizzi and G. Pelizzi, J. Organomet. Chem., 1997, 535, 107–120; (b) C. Belger, N. M. Neisius and B. Plietker, Chem. – Eur. J., 2010, 16, 12214–12220; (c) M. W. van Laren and C. J. Elsevier, Angew. Chem., Int. Ed., 1999, 38, 3715–3717.
12. For a example of copper(I)-catalysed transfer hydrogenation with ammonia borane, see: E. Korytiákova, N. O. Thiel, F. Pape and J. F. Teichert, Chem. Commun., 2017, 53, 732–735.
13. (SIMes = 1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene). For reviews on copper/NHC complexes, see: (a) F. Lazreg, F. Nahra and C. S. J. Cazin, Coord. Chem. Rev., 2015, 293-294, 48–79; (b) J. D. Egbert, C. S. J. Cazin and S. P. Nolan, Catal. Sci. Technol., 2013, 3, 912–926.
14. (a) N. P. Mankad, D. S. Laitar and J. P. Sadighi, Organometallics, 2004, 23, 3369–3371; (b) A. J. Jordan, C. M. Wyss, J. Bacsa and J. P. Sadighi, Organometallics, 2016, 35, 613–616.
15. Circumstantial evidence exists for the presence of benzaldehyde-d₁ after the reaction occurred. In other reactions employing 2 as H₂ equivalent, deuterated benzaldehyde could be detected by ²H NMR spectroscopy. See the ESI† for details.
16. No significant induction period for either heating method (A or B) was observed (∼30% conversion of 1 after 30 min), indicating a homogeneous catalyst (see the ESI† for more details). Over the course of time, the ratio of Z-3/E-3 diminished, suggesting a rapid Z-selective semihydrogenation followed by a Z → E isomerisation process. Literature precedence exists for these combined mechanisms, see for example: (a) D. Srimani, Y. Diskin-Posner, Y. Ben-David and D. Milstein, Angew. Chem., Int. Ed., 2013, 52, 14131–14134; (b) K. Tokmic and A. R. Fout, J. Am. Chem. Soc., 2016, 138, 13700–13705; (c) K. Murugesan, C. B. Bheeter, P. R. Linnebank, A. Spannenberg, J. N. H. Reek, R. V. Jagadeesh and M. Beller, ChemSusChem, 2019, 12, 3363–3369.
17. For selected overviews on NHC ligands, see: (a) S. P. Nolan, N-Heterocyclic carbenes, Effective tools for organometallic synthesis, Wiley-VCH, Weinheim, 2014; (b) M. N. Hopkinson, C. Richter, M. Schedler and F. Glorius, Nature, 2014, 510, 485–496; (c) J. C. Y. Lin, R. T. W. Huang, C. S. Lee, A. Bhattacharyya, W. S. Hwang and I. J. B. Lin, Chem. Rev., 2009, 109, 3561–3598; (d) V. Cesar, S. Bellemin-Laponnaz and L. H. Gade, Chem. Soc. Rev., 2004, 33, 619–636.
18. (IMes = 1, 3-Bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene, IPr = 1,3-Bis(2,6-di-iso-propylphenyl)-imidazol-2-ylidene.
19. Generally, reductive/hydrogenative conditions are employed for the cleavage of benzyl ethers, see: (a) P. G. M. Wuts and T. W. Greene, Greene's protective groups in organic synthesis, Wiley, Hoboken, 4th edn, 2007; (b) P. J. Kocieński, Protecting groups, Thieme, Stuttgart, 3rd edn, 2004.
20. (a) M. Newcomb, Tetrahedron, 1993, 49, 1151–1176; (b) D. Griller and K. U. Ingold, Acc. Chem. Res., 1980, 13, 317–323.
21. In the related heterogeneous copper-catalysed hydrogenations, NHC ligands have also been shown to significantly improve stereo- and chemoselectivity, see: (a) A. Fedorov, H.-J. Liu, H.-K. Lo and C. Copéret, J. Am. Chem. Soc., 2016, 138, 16502–16507; (b) N. Kaeffer, H.-J. Liu, H.-K. Lo, A. Fedorov and C. Copéret, Chem. Sci., 2018, 9, 5366–5371; (c) N. Kaeffer, K. Larmier, A. Fedorov and C. Copéret, J. Catal., 2018, 364, 437–445.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterisation and NMR spectra. See DOI: 10.1039/c9cc06637c

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