Chiral Bifunctional NHC–Guanidine Ligands for Asymmetric Hydrogenation

Abstract

We report the synthesis of chiral N-heterocyclic carbene/guanidine bifunctional ligands from readily available amino alcohols. The resulting chiral bifunctional copper(I) complexes are active catalysts in an asymmetric hydrogenation of ketones. We show that the chiral linker unit can be employed for the transfer of stereoinformation.

Key words

N-heterocyclic carbenes - guanidines - bifunctional catalysts - hydrogenation - asymmetric catalysis - copper catalysis

Publication History

Received: 29 September 2023

Accepted after revision: 13 November 2023

Article published online:
14 December 2023

• References and Notes

• 1a Afewerki S, Córdova A. Chem. Rev. 2016; 116: 13512
• 1b Chen D.-F, Han Z.-Y, Zhou X.-L, Gong L.-Z. Acc. Chem. Res. 2014; 47: 2365
• 1c Du Z, Shao Z. Chem. Soc. Rev. 2013; 42: 1337
• 1d Wasilke J.-C, Obrey SJ, Baker RT, Bazan GC. Chem. Rev. 2005; 105: 1001
• 1e Zhong C, Shi X. Eur. J. Org. Chem. 2010; 2010: 2999
• 1f Allen AE, MacMillan DW. C. Chem. Sci. 2012; 3: 633
• 1g Deng Y, Kumar S, Wang H. Chem. Commun. 2014; 50: 4272
• 1h Dong X.-Q, Zhao Q, Li P, Chen C, Zhang X. Org. Chem. Front. 2015; 2: 1425
• 1i Lohr TL, Marks TJ. Nat. Chem. 2015; 7: 477

For selected examples of bifunctional catalysts, see:
• 2a Ibrahem I, Córdova A. Angew. Chem. Int. Ed. 2006; 45: 1952
• 2b Nickerson DM, Mattson AE. Chem. Eur. J. 2012; 18: 8310
• 2c Zhao Q, Li S, Huang K, Wang R, Zhang X. Org. Lett. 2013; 15: 4014
• 2d Zhao Q, Wen J, Tan R, Huang K, Metola P, Wang R, Anslyn EV, Zhang X. Angew. Chem. Int. Ed. 2014; 53: 8467
• 2e Wen J, Fan X, Tan R, Chien H.-C, Zhou Q, Chung LW, Zhang X. Org. Lett. 2018; 20: 2143

For selected examples of regioselective transformations, see:
• 3a Davis HJ, Phipps RJ. Chem. Sci. 2017; 8: 864
• 3b Kuninobu Y, Ida H, Nishi M, Kanai M. Nat. Chem. 2015; 7: 712
• 3c Bai S.-T, Bheeter CB, Reek JN. H. Angew. Chem. Int. Ed. 2019; 58: 13039

For selected examples of stereoselective transformations, see:
• 3d Genov GR, Douthwaite JL, Lahdenperä AS. K, Gibson DC, Phipps RJ. Science 2020; 367: 1246
• 3e Fanourakis A, Docherty PJ, Chuentragool P, Phipps RJ. ACS Catal. 2020; 10: 10672
• 3f Rawat VK, Higashida K, Sawamura M. Adv. Synth. Catal. 2021; 363: 1631

For a review on related Cu-catalyzed hydrogenation processes, see
• 4a Thiel NO, Pape F, Teichert JF. In Homogeneous Hydrogenation with Non-Precious Catalysts, Chap. 4. Teichert JF. Wiley-VCH; Weinheim: 2019: 87

For an example of a 1,4-reduction, see:
• 4b Zimmermann BM, Kobosil SC. K, Teichert JF. Chem. Commun. 2019; 55: 2293

For a reviews on copper hydride chemistry, see:
• 5a Jordan AJ, Lalic G, Sadighi JP. Chem. Rev. 2016; 116: 8318
• 5b Deutsch C, Krause N, Lipshutz BH. Chem. Rev. 2008; 108: 2916
• 5c Rendler S, Oestreich M. Angew. Chem. Int. Ed. 2007; 46: 498
• 6 Zimmermann BM, Tran Ngoc T, Tzaras D.-I, Kaicharla T, Teichert JF. J. Am. Chem. Soc. 2021; 143: 16865

For selected examples of nucleophilic copper hydride chemistry, see:
• 7a Pape F, Thiel NO, Teichert JF. Chem. Eur. J. 2015; 21: 15934
• 7b Thiel NO, Teichert JF. Org. Biomol. Chem. 2016; 14: 10660
• 7c Pape F, Teichert JF. Synthesis 2017; 49: 2470
• 7d Thiel NO, Kemper S, Teichert JF. Tetrahedron 2017; 73: 5023
• 7e Brechmann LT, Kaewmee B, Teichert JF. ACS Catal. 2023; 13: 12634
• 8a Kobayashi Y, Takemoto Y. Top. Heterocycl. Chem. 2015; 50: 71
• 8b Concellón C, Del Amo V. Top. Heterocycl. Chem. 2015; 50: 1

For reviews on chiral NHCs, see:
• 9a Thongpaen J, Manguin R, Baslé O. Angew. Chem. Int. Ed. 2020; 59: 10242
• 9b Janssen-Müller D, Schlepphorst C, Glorius F. Chem. Soc. Rev. 2017; 46: 4845
• 9c Wang F, Liu L.-j, Wang W, Li S, Shi M. Coord. Chem. Rev. 2012; 256: 804

For chiral guanidines, see:
• 10a Nájera C, Yus M. Top. Heterocycl. Chem. 2015; 50: 95

For selected examples, see:
• 10b Terada M, Ube H, Yaguchi Y. J. Am. Chem. Soc. 2006; 128: 1454

For a review on a similar design of bidentate NHC ligands bearing a chiral linker unit, see:
• 11a Pape F, Teichert JF. Eur. J. Org. Chem. 2017; 4206

For selected examples, see:
• 11b Khan RK. M, Zhugralin AR, Torker S, O’Brien RV, Lombardi PJ, Hoveyda AH. J. Am. Chem. Soc. 2012; 134: 12438
• 11c Khan RK. M, O’Brien RV, Torker S, Li B, Hoveyda AH. J. Am. Chem. Soc. 2012; 134: 12774
• 12 Wei Y, Lu L.-Q, Li T.-R, Feng B, Wang Q, Xiao W.-J, Alper H. Angew. Chem. Int. Ed. 2016; 55: 2200
• 13 Guo R, Lu S, Chen X, Tsang C.-W, Jia W, Sui-Seng C, Amoroso D, Abdur-Rashid K. J. Org. Chem. 2010; 75: 937
• 14 Wan KY, Roelfes F, Lough AJ, Hahn FE, Morris RH. Organometallics 2018; 37: 491
• 15 Jiang Z, Toffano M, Vo-Thanh G, Bournaud C. ChemCatChem 2021; 13: 712

Alcohol-tethered NHC precursors have successfully been employed in transition-metal catalysis; for examples, see:
• 16a Clavier H, Coutable L, Toupet L, Guillemin J.-C, Mauduit M. J. Organomet. Chem. 2005; 690: 5237
• 16b Martin D, Kehrli S, d’Augustin M, Clavier H, Mauduit M, Alexakis A. J. Am. Chem. Soc. 2006; 128: 8416
• 16c Kehrli S, Martin D, Rix D, Mauduit M, Alexakis A. Chem. Eur. J. 2010; 16: 9890
• 16d Jahier-Diallo C, Morin MS. T, Queval P, Rouen M, Artur I, Querard P, Toupet L, Crévisy C, Baslé O, Mauduit M. Chem. Eur. J. 2015; 21: 993
• 16e Pape F, Thiel NO, Teichert JF. Chem. Eur. J. 2015; 21: 15934
• 16f Pape F, Teichert JF. Synthesis 2017; 49: 2470
• 17 Ligand Precursor 6 Brown solid; yield: 312 mg (63%). ¹H NMR (600 MHz, CDCl₃): δ = 9.15 (s, 1 H, H-14), 8.40 (s, 1 H, H-15)*, 7.39–7.34 (m, 4 H, H-6, H-11), 7.21–7.19 (m, 7 H, H-16*, H-7, H-8, H-12, H-13), 7.02 (s, 1 H, H-20), 6.98 (s, 1 H, H-20′), 6.92 (d, ³ J _N–Ha,₄ = 8.4 Hz, 1 H, N–Ha), 6.36 (d, ³ J ₉,₄ = 11.1 Hz, 1 H, H-9), 5.99 (br s, 1 H, N–Hb), 5.90 (dd, ³ J ₄,₉ = 11.1 Hz, ³ J ₄,_N–Ha= 8.2 Hz, 1 H, H-4), 3.77 (m, 2 H, H-2), 2.33 (s, 3 H, H-22), 2.05 (s, 3 H, H-19), 1.88 (s, 3 H, H-19′), 1.20 (d, ³ J ₁,₂ = 6.6 Hz, 6 H, H-1), 1.10 (d, ³ J ₁,₂ = 6.4 Hz, 6 H, H-1′). ¹³C NMR (151 MHz, CDCl₃): δ = 153.9 (C-3), 141.9 (C-21), 136.6 (C-14), 135.2 (C-10), 134.5 (C-18), 133.9 (C-18′), 133.7 (C-5), 130.5 (C-17), 130.2 (C-20′), 130.0 (C-20), 129.9 (Ar-C), 129.4 (Ar-C), 129.3 (Ar-C), 127.9 (Ar-C), 127.8 (Ar-C), 123.9 (C-16)*, 123.3 (C-15)*, 68.1 (C-9), 59.1 (C-4), 46.0 (C-2), 23.2 (C-1′), 22.1 (C-1), 21.2 (C-22), 17.1 (C-19), 17.0 (C-19′). ¹⁹F NMR (471 MHz, CDCl₃): δ = –71.7 (d, ¹ J _F,_P = 713.2 Hz). ³¹P NMR (202 MHz, CDCl₃): δ = –143.9 (sept, ¹ J _P,_F = 713.2 Hz). HRMS (ESI): m/z [M – PF₆]⁺ calcd for C₃₃H₄₂N₅: 508.3435; found: 508.3435.
• 18 Ligand Precursor 7 Yellow solid; yield: 178 mg (70%). ¹H NMR (600 MHz, CDCl₃): δ = 8.84 (s, 1 H, H-8), 8.13 (app t, ³ J = 1.6 Hz, 1 H, H-9)*, 7.24 (app t, ³ J = 1.6 Hz, 1 H, H-10)*, 7.04 (s, 2 H, H-14, H-14′), 5.71 (br s, 1 H, N–Ha), 4.91 (dd, ³ J ₅,_4b= 10.8 Hz, ³ J ₅,_4a =3.0 Hz, 1 H, H-5), 4.05 (m, 1 H, H-4a), 3.87 (d, ³ J _4b,₅ = 11.2 Hz, 1 H, H-4b), 4.03–3.58 (m, 3 H, N–Hb, H-1), 2.36 (s, 3 H, H-16), 2.03 (s, 3 H, H-13), 2.00 (s, 3 H, H-13′), 1.33 (d, ³ J ₂,₁ = 6.3 Hz, 6 H, H-2), 1.24 (d, ³ J ₂′,₁= 6.3 Hz, 6 H, H-2′), 1.09 (s, 9 H, H-7). ¹³C NMR (151 MHz, CDCl₃): δ = 153.4 (C-3), 141.9 (C-15), 137.5 (C-8), 134.2 (C-12), 133.8 (C-12′) 130.3 (C-14), 130.2 (C-14′), 130.1 (C-11), 124.1 (C-9)*, 121.4 (C-10)*, 68.7 (C-5), 45.2 (C-1), 41.5 (C-4), 34.7 (C-6), 26.4 (C-7), 22.2 (C-2), 22.0 (C-2′), 21.2 (C-16), 17.3 (C-13), 17.0 (C-13′). ¹⁹F NMR (471 MHz, CDCl₃): δ = –71.7 (d, ¹ J _F,_P = 714.2 Hz). ³¹P NMR (202 MHz, CDCl₃): δ = –144.2 (sept, ¹ J _P,_F = 714.2 Hz). HRMS (ESI): m/z [M – PF₆]⁺ calcd for C₂₅H₄₂N₅: 412.3435; found: 412.3132.
• 19 (1S)-1-Phenylethanol (16): Typical Procedure for Asymmetric Hydrogenation By following the reported procedure,⁶ in an Ar-filled glove box, a 5 mL vial equipped with a stirrer bar was charged with CuCl (1.98 mg, 2.00 μmol, 10.0 mol%), the appropriate ligand precursor 6 or 7 (2.4 μmol, 12 mol%), and t-BuONa (24.9 mg, 0.26 mmol, 1.30 equiv). The vial was capped inside the glovebox and then transferred outside. The solids were dissolved in THF (1.00 mL), and the resulting mixture was stirred for 15 min at 40 °C. 15-Crown-5 (25.0 μL, 0.260 mmol, 1.30 equiv) was added to the mixture. Acetophenone (15; 24.0 mg, 0.20 mmol, 1.00 equiv) was dissolved in THF (1.00 mL) and the solution was transferred to the reaction vial. The vial was placed in an autoclave and the septum was pierced with a needle under a N₂ counterflow. The autoclave was purged with H₂ (3 × 10 bar), and the mixture was stirred at the appropriate temperature for 72 h under a H₂ atmosphere (100 bar). After removal of the H₂ atmosphere and equilibration of the mixture to r.t., the crude mixture was filtered through a small plug of silica gel [1 × 5 cm; eluent: CH₂Cl₂ (20 mL)] and then all the volatiles were removed under reduced pressure. The conversion of the product 16 was determined by ¹H NMR and/or HPLC. The ee of the crude product 16 was determined by HPLC analysis. The crude mixture could be further purified by flash column chromatography [silica gel, EtOAc–cyclohexane (1:5)] for more precise analysis.

For other copper-catalyzed asymmetric hydrogenations of ketones, see:
• 20a Shimizu H, Igarashi D, Kuriyama W, Yusa Y, Sayo N, Saito T. Org. Lett. 2007; 9: 1655
• 20b Shimizu H, Nagano T, Sayo N, Saito T, Ohshima T, Mashima K. Synlett 2009; 3143
• 20c Junge K, Wendt B, Addis D, Zhou S, Das S, Fleischer S, Beller M. Chem. Eur. J. 2011; 17: 101
• 21 Kantam ML, Laha S, Yadav J, Likhar PR, Sreedhar B, Jha S, Bhargava S, Udayakiran M, Jagadeesh B. Org. Lett. 2008; 10: 2979