The FeBr₃-Catalyzed Transfer Hydrogenation of Styrene Derivatives under Mild Reaction Conditions

Abstract

The transfer hydrogenation of alkenes was realized by using a simple transition-metal compound (FeBr₃) and 1,4-cyclohexadiene (1,4-CHD) as the hydrogen donor. The conversion of a number of di- and trisubstituted alkenes was investigated, and even a tetrasubstituted alkene was successfully converted. Compared with previously published work with the more expensive InBr₃, the reaction times were considerably reduced and significantly milder reaction conditions could be applied. Interestingly, a transformation that was catalytic in 1,4-CHD, with molecular hydrogen as a stoichiometric reducing agent at 1 bar, was also accomplished.

In transfer hydrogenation reactions, dihydroaromatic compounds, such as 1,4-cyclohexadiene (1,4-CHD) and its derivatives, are used as hydrogen donors instead of molecular hydrogen (H₂). Due to the ready accessibility and ease of handling of these compounds in comparison to molecular hydrogen (since most are used are liquids), dihydroaromatic compounds represent an interesting alternative as reducing agents or hydrogen sources in organic synthesis.[1]

The transformation of alkenes with dihydroaromatic compounds under transfer hydrogenation conditions has been realized by using several Lewis acids, such as silicon-, boron-, and indium-based catalysts.[2] Based on the pioneering work by Oestreich and co-workers, who used B(C₆F₅)₃ as a Lewis acid catalyst (Scheme [1a]), the scope of the transfer hydrogenation with 1,4-CHD and derivatives thereof has steadily been expanded by several groups.[2] Some time ago, we expanded the scope of the transfer hydrogenation by using InBr₃ as a catalyst under mild to harsh conditions (20–120 °C), depending on the structure and electronic nature of the starting material (Scheme [1b]).

A considerable advantage of dihydroaromatic compounds over molecular hydrogen can be found in H–D addition to alkenes by a transfer hydrogenation reaction. The use of site-selective deuterated 1,4-CHD derivatives as H–D surrogates was pioneered by the Oestreich group, and a regioselective transfer hydrodeuteration and a transfer deuterohydrogenation were realized by Li and Hilt shortly thereafter.[3]

Recently, the use of chiral hydride sources in the transfer hydrogenation of alkenes has been reported by Oestreich and co-workers. For this purpose, chiral 1,4-cyclohexadiene derivatives were applied for the first time under B(C₆F₅)₃ catalysis for the asymmetric transfer hydrogenation of alkenes.[4]

In our previous publications, we described BF₃- and InBr₃-catalyzed transfer hydrogenations of disubstituted alkenes and some trisubstituted alkenes. Although the use of electron-deficient alkenes failed in the BF₃-catalyzed transfer hydrogenation reactions, this limitation was partly overcome by using InBr₃ as a Lewis acid catalyst at elevated temperatures (up to 120 °C). However, tetrasubstituted alkenes were unreactive under these reaction conditions.

In search of even milder reaction conditions and more reactive catalysts, we recently applied simple and easy-to-handle Fe, Co, and Ni halides for transfer hydrogenations with 1,4-CHD as the hydrogen donor and 1,1-diphenylethene (1a) as a model substrate at 20 °C or 80 °C (Scheme [2]). In the past, chlorinated solvents have proved to be superior to other solvents such as THF (Table [1], entry 11) for the transfer hydrogenation; therefore, most of the results reported here are for CH₂Cl₂ (DCM) and (ClCH₂)₂ (DCE).[2] Also, the Hilt group has recently worked on cobalt-catalyzed carbon–carbon bond-formation reactions and, for the activation of cobalt(II) complexes, zinc powder and ZnI₂ were added.[5] Based on these findings, we also tested reaction conditions in which these additives were present. The results of the model reaction shown in Scheme [2] are summarized in Table [1].

The application of nickel complexes as Lewis acids (Table [1], entries 1–6) at room temperature or at 80 °C led only to moderate conversions at best. With simple cobalt halides, the yield increased to 65% (entry 8), but only at an elevated temperature and with a prolonged reaction time of 20 hours. In all the test reactions, the Zn/ZnI₂-additives proved to have little to no effect, and these were eliminated successively over the course of the investigation. When FeCl₂ was tested as a Lewis acid, a reasonably good yield of 76% was achieved (entry 15), but for the nonproblematic substrate 1a, the reaction conditions were still not mild enough. The situation changed when iron(III) salts were applied as Lewis acid catalysts. After the first routine check of the reaction after one hour with FeCl₃ as the catalyst, a good yield of 84% was already obtained at ambient temperature (entry 19). Even better results were obtained with the reaction with FeBr₃ as the catalyst at room temperature, which resulted in a 98% yield after a one hour reaction time at 20 °C. Accordingly, the application of FeBr₃ as the superior catalyst was investigated in more detail. The results of these reactions with 1a as starting material are given in Table [2].

A catalyst loading of 5 mol% led to incomplete conversion after one hour and to the formation of some byproducts (Table [2], entry 1). With a catalyst loading of 10 mol%, the conversion was further enhanced, but byproducts (see Scheme [4a] below) were still formed. When 20 mol% FeBr₃ was used, a complete conversion without the formation of byproducts was accomplished (entry 3) and the product could be isolated in a very good yield of 96%. When the concentration of the starting material was increased from 1.0 mol/L to 2.0 mol/L, byproducts were again formed. As mentioned above, other solvents such as THF or acetonitrile were inferior (entries 4 and 5).

With these very mild reaction conditions in hand, the FeBr₃-catalyzed transfer hydrogenation was applied to a range of starting materials that previously had been successfully converted with InBr₃ as the Lewis acid catalyst at elevated temperatures.[3c] Thereafter, we intended to extend the scope further to tri- and tetrasubstituted alkenes; to the best of our knowledge, tetrasubstituted alkenes had not previously been reported as suitable substrates in transfer hydrogenation reactions. The results of the reactions are summarized in Scheme [3].[6]

For 1,1-diaryl-substituted substrates, FeBr₃ performed reasonably well in these reactions in comparison to InBr₃ as the Lewis acid catalyst and gave the desired products 2b–g in acceptable to good yields in a comparable short reaction time at room temperature. The electron-withdrawing CF₃-group was accepted as a substituent, but with respect to the previously reported Lewis acid-catalyzed transfer hydrogenation reactions, we consider the 64% yield for 2f at room temperature to be an improvement. Interestingly, for trisubstituted alkenes, FeBr₃ seems to be even more reactive and the desired products 2h–m were isolated in good to excellent yields of up to 96%. Encouraged by this result, we also attempted a transfer hydrogenation of a tetrasubstituted alkene. For this purpose, (2Z)-2,3-diphenylbut-2-ene was chosen as the substrate and, for the first time, the transfer hydrogenation of a tetrasubstituted alkene was accomplished under very mild reaction conditions to give the meso-product 2p in an unprecedented yield of 83%.

For a short mechanistic study, we performed control experiments and some ¹H NMR spectral analyses of reaction mixtures (Scheme [4]). In the control experiment, when 1a was treated with FeBr₃ in DCM in the absence of 1,4-CHD, the only product observed by GC/GCMS analysis was the dimer 3 (Scheme [4a]). This reaction has already been reported for other Lewis acids, such as TiCl₄, and the analytical data were in accordance with the literature.[7] The ¹H NMR of the starting 1,4-CHD in CD₂Cl₂ showed the presence of a small content of benzene (1,4-CHD/C₆H₆ = 99:1). After the addition of FeBr₃ to the solution, the suspension was stirred for two minutes and then the supernatant was analyzed by ¹H NMR. The ratio of 1,4-CHD to C₆H₆ changed to 78:22, and a broad signal at δ = 0.90–2.50 ppm appeared (see the Supporting Information). A rationale for this observation is that FeBr₃ releases H₂ from 1,4-CHD within a short time to generate the observed significant amounts of benzene. Because the reaction vessel in the preparative reactions described above was sealed, the H₂ remained in the flask and later acted as a reducing agent to form the reduced products of type 2. To test this hypothesis, we performed another control experiment. When the reaction of 1a with FeBr₃ was repeated in the presence of H₂ (Scheme [4a]), again, only the formation of the dimer 3 was observed. Therefore, a preparative reaction was conducted with 1a and FeBr₃ under a H₂ atmosphere (1 bar) with 15 mol% of 1,4-CHD as an activator (Scheme [4b]). In this case, only a small amount of the dimer (6%) was formed and 2a was isolated in 87% yield.[8]

The assumption that the broad signal at δ = 0.90–2.50 ppm could arise from some sort of a 1,4-CHD–FeBr₃ complex that is needed for the transformation is speculative at best. Unfortunately, all attempts to characterize any 1,4-CHD–FeBr₃ intermediate have been unsuccessful. Nevertheless, in the absence of 1,4-CHD, the dimerization product 3 is formed, and this observation appears to support the hypothesis that some sort of interaction between 1,4-CHD and FeBr₃ must be involved and that this generates an iron complex that can accept molecular hydrogen at atmospheric pressure for the hydrogenation.

In summary, we have shown that FeBr₃ is an inexpensive and very reactive catalyst for the transfer hydrogenation of various alkenes with 1,4-CHD. These reactions give moderate to excellent yields and expand the substrate scope significantly to include tetrasubstituted alkenes. Also of interest was the observation that the reaction could be realized with a catalytic amount of 1,4-CHD under a H₂ atmosphere.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes


For reviews covering not only transfer hydrogenation, but also other transfer reactions, see:
• 1a Walker JC. L, Oestreich M. Synlett 2019; 30: 2216
  Thieme ConnectSearch in Google Scholar
• 1b Keess S, Oestreich M. Chem. Sci. 2017; 8: 4688
  CrossrefPubMedSearch in Google Scholar
• 2a Chatterjee I, Oestreich M. Angew. Chem. Int. Ed. 2015; 54: 1965
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• 2b Chatterjee I, Qu Z.-W, Grimme S, Oestreich M. Angew. Chem. Int. Ed. 2015; 54: 12158
  CrossrefPubMedSearch in Google Scholar
• 2c Yuan W, Orecchia P, Oestreich M. Chem. Commun. 2017; 53: 10390
  CrossrefPubMedSearch in Google Scholar
• 2d Djurovic A, Vayer M, Li Z, Guillot R, Baltaze J.-P, Gandon V, Bour C. Org. Lett. 2019; 21: 8132
  CrossrefPubMedSearch in Google Scholar
• 2e Simonneau A, Friebel J, Oestreich M. Eur. J. Org. Chem. 2014; 2077
  Crossref
• 2f Simonneau A, Oestreich M. Angew. Chem. Int. Ed. 2013; 52: 11905
  CrossrefPubMedSearch in Google Scholar
• 2g Webb JD, Laberge VS, Geier SJ, Stephan DW, Crudden CM. Chem. Eur. J. 2010; 16: 4895
  CrossrefPubMedSearch in Google Scholar
• 2h Michelet B, Bour C, Gandon V. Chem. Eur. J. 2014; 20: 14488
  CrossrefPubMedSearch in Google Scholar
• 2i Mohr J, Oestreich M. Angew. Chem. Int. Ed. 2014; 53: 13278
  CrossrefPubMedSearch in Google Scholar
• 2j Macdonald PA, Banerjee S, Kennedy AR, van Teijlingen A, Robertson SD, Tuttle T, Mulvey RE. Angew. Chem. Int. Ed. 2023; 62: e202304966
  CrossrefPubMedSearch in Google Scholar
• 3a Walker JC. L, Oestreich M. Org. Lett. 2018; 20: 6411
  CrossrefPubMedSearch in Google Scholar
• 3b Li L, Hilt G. Org. Lett. 2020; 22: 1628
  CrossrefPubMedSearch in Google Scholar
• 3c Li L, Hilt G. Chem. Eur. J. 2021; 27: 11221
  CrossrefPubMedSearch in Google Scholar
• 4 Wolff B, Qu Z.-W, Grimme S, Oestreich M. Angew. Chem. Int. Ed. 2023; 62: e202305295
  CrossrefPubMedSearch in Google Scholar
• 5 Hilt G. Synlett 2023; 34: 23
  Thieme ConnectSearch in Google Scholar
• 6 Transfer Hydrogenation of Alkenes: General Procedure A flask was charged FeBr₃ (59.1 mg, 0.2 mmol, 20 mol%) and flushed with N₂. DCM (1 mL), the appropriate alkene (1 mmol, 1.0 equiv), and 1,4-cyclohexadiene (104 μL, 1.1 mmol, 1.1 equiv) were added sequentially, and the mixture was stirred at 20 °C until the reaction was complete (GC/MS). The mixture was then purified directly by flash column chromatography (silica gel, pentane). 2,3-Diphenylbutane (2p) Colorless oil; yield: 173 mg (92%); R_f = 0.45 (pentane). ¹H NMR (500 MHz, CDCl₃): δ = 7.41–7.34 (m, 4 H), 7.31–7.24 (m, 6 H), 2.87 (dtd, J = 6.4, 4.6, 2.6 Hz, 2 H), 1.13–1.07 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 146.6, 128.4, 127.8, 126.2, 47.4, 21.2.
• 7a Sauvet G, Vairon JP, Sigwalt P. Bull. Soc. Chim. Fr. 1970; 11: 4031
  Search in Google Scholar
• 7b Tolbert LM. J. Am. Chem. Soc. 1980; 102: 3531
  CrossrefSearch in Google Scholar

For iron-catalyzed hydrogenations of alkenes, see:
• 8a Gieshoff TN, Villa M, Welther A, Plois M, Chakraborty U, Wolf R, Jacobi von Wangelin A. Green Chem. 2015; 17: 1408
  CrossrefSearch in Google Scholar
• 8b MacNair AJ, Tran M.-M, Nelson JE, Sloan GU, Ironmonger A, Thomas SP. Org. Biomol. Chem. 2014; 12: 5082
  CrossrefPubMedSearch in Google Scholar
• 8c Lu P, Ren X, Xu H, Lu D, Sun Y, Lu Z. J. Am. Chem. Soc. 2021; 143: 12433
  CrossrefPubMedSearch in Google Scholar
• 8d Xu R, Chakraborty S, Bellows SM, Yuan H, Cundari TR, Jones WD. ACS Catal. 2016; 6: 2127
  CrossrefSearch in Google Scholar

Corresponding Author

Publication History

Received: 08 February 2024

Accepted after revision: 19 February 2024

Article published online:
01 March 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes


For reviews covering not only transfer hydrogenation, but also other transfer reactions, see:
• 1a Walker JC. L, Oestreich M. Synlett 2019; 30: 2216
  Thieme ConnectSearch in Google Scholar
• 1b Keess S, Oestreich M. Chem. Sci. 2017; 8: 4688
  CrossrefPubMedSearch in Google Scholar
• 2a Chatterjee I, Oestreich M. Angew. Chem. Int. Ed. 2015; 54: 1965
  CrossrefPubMedSearch in Google Scholar
• 2b Chatterjee I, Qu Z.-W, Grimme S, Oestreich M. Angew. Chem. Int. Ed. 2015; 54: 12158
  CrossrefPubMedSearch in Google Scholar
• 2c Yuan W, Orecchia P, Oestreich M. Chem. Commun. 2017; 53: 10390
  CrossrefPubMedSearch in Google Scholar
• 2d Djurovic A, Vayer M, Li Z, Guillot R, Baltaze J.-P, Gandon V, Bour C. Org. Lett. 2019; 21: 8132
  CrossrefPubMedSearch in Google Scholar
• 2e Simonneau A, Friebel J, Oestreich M. Eur. J. Org. Chem. 2014; 2077
  Crossref
• 2f Simonneau A, Oestreich M. Angew. Chem. Int. Ed. 2013; 52: 11905
  CrossrefPubMedSearch in Google Scholar
• 2g Webb JD, Laberge VS, Geier SJ, Stephan DW, Crudden CM. Chem. Eur. J. 2010; 16: 4895
  CrossrefPubMedSearch in Google Scholar
• 2h Michelet B, Bour C, Gandon V. Chem. Eur. J. 2014; 20: 14488
  CrossrefPubMedSearch in Google Scholar
• 2i Mohr J, Oestreich M. Angew. Chem. Int. Ed. 2014; 53: 13278
  CrossrefPubMedSearch in Google Scholar
• 2j Macdonald PA, Banerjee S, Kennedy AR, van Teijlingen A, Robertson SD, Tuttle T, Mulvey RE. Angew. Chem. Int. Ed. 2023; 62: e202304966
  CrossrefPubMedSearch in Google Scholar
• 3a Walker JC. L, Oestreich M. Org. Lett. 2018; 20: 6411
  CrossrefPubMedSearch in Google Scholar
• 3b Li L, Hilt G. Org. Lett. 2020; 22: 1628
  CrossrefPubMedSearch in Google Scholar
• 3c Li L, Hilt G. Chem. Eur. J. 2021; 27: 11221
  CrossrefPubMedSearch in Google Scholar
• 4 Wolff B, Qu Z.-W, Grimme S, Oestreich M. Angew. Chem. Int. Ed. 2023; 62: e202305295
  CrossrefPubMedSearch in Google Scholar
• 5 Hilt G. Synlett 2023; 34: 23
  Thieme ConnectSearch in Google Scholar
• 6 Transfer Hydrogenation of Alkenes: General Procedure A flask was charged FeBr₃ (59.1 mg, 0.2 mmol, 20 mol%) and flushed with N₂. DCM (1 mL), the appropriate alkene (1 mmol, 1.0 equiv), and 1,4-cyclohexadiene (104 μL, 1.1 mmol, 1.1 equiv) were added sequentially, and the mixture was stirred at 20 °C until the reaction was complete (GC/MS). The mixture was then purified directly by flash column chromatography (silica gel, pentane). 2,3-Diphenylbutane (2p) Colorless oil; yield: 173 mg (92%); R_f = 0.45 (pentane). ¹H NMR (500 MHz, CDCl₃): δ = 7.41–7.34 (m, 4 H), 7.31–7.24 (m, 6 H), 2.87 (dtd, J = 6.4, 4.6, 2.6 Hz, 2 H), 1.13–1.07 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 146.6, 128.4, 127.8, 126.2, 47.4, 21.2.
• 7a Sauvet G, Vairon JP, Sigwalt P. Bull. Soc. Chim. Fr. 1970; 11: 4031
  Search in Google Scholar
• 7b Tolbert LM. J. Am. Chem. Soc. 1980; 102: 3531
  CrossrefSearch in Google Scholar

For iron-catalyzed hydrogenations of alkenes, see:
• 8a Gieshoff TN, Villa M, Welther A, Plois M, Chakraborty U, Wolf R, Jacobi von Wangelin A. Green Chem. 2015; 17: 1408
  CrossrefSearch in Google Scholar
• 8b MacNair AJ, Tran M.-M, Nelson JE, Sloan GU, Ironmonger A, Thomas SP. Org. Biomol. Chem. 2014; 12: 5082
  CrossrefPubMedSearch in Google Scholar
• 8c Lu P, Ren X, Xu H, Lu D, Sun Y, Lu Z. J. Am. Chem. Soc. 2021; 143: 12433
  CrossrefPubMedSearch in Google Scholar
• 8d Xu R, Chakraborty S, Bellows SM, Yuan H, Cundari TR, Jones WD. ACS Catal. 2016; 6: 2127
  CrossrefSearch in Google Scholar

• Supplementary Material