Ruthenium-Catalyzed Direct Cross-Coupling of Secondary Alcohols to β-Disubstituted Ketones

Abstract

The β-disubstituted ketone functionality is prevalent in biologically active compounds and in pharmaceuticals. A ruthenium-catalyzed direct synthesis of β-disubstituted ketones by cross-coupling of two different secondary alcohols is reported. This new protocol was applied to the synthesis of variety of β-disubstituted ketones from various cyclic, acyclic, symmetrical, and unsymmetrical secondary alcohols. An amine–amide metal–ligand cooperation in a Ru catalyst facilitates the activation and formation of covalent bonds in selective sequences to provide the products. Kinetic and deuterium-labeling experiments suggested that aliphatic alcohols oxidize faster than benzylic secondary alcohols. A plausible mechanism is proposed on the basis of mechanistic and kinetic studies. Water and H₂ are the only byproducts from this selective cross-coupling of secondary alcohols.

1 Introduction

2 Catalytic Self- or Cross-Coupling of Alcohols and Selectivity Challenges

3 Recent Developments in the Synthesis of β-Disubstituted Ketones

4 Scope of Ruthenium-Catalyzed Cross-Couplings of Secondary Alcohols

5 Mechanistic Studies and Proposed Mechanism

6 Conclusion

Key words

cross-coupling - alcohols - ketones - ruthenium catalysis - homogeneous catalysis - green synthesis

• References

• 1a Toh QY, McNally A, Vera S, Erdmann N, Gaunt MJ. J. Am. Chem. Soc. 2013; 135: 3772
• 1b Maeyama K, Yamashita K, Saito H, Aikawa S, Yoshida Y. Polym. J. (Tokyo) 2012; 44: 315
• 1c Vooturi SK, Cheung CM, Rybak MJ, Firestine SM. J. Med. Chem. 2009; 52: 5020
• 1d Walter MW. Nat. Prod. Rep. 2002; 19: 278
• 1e Smith MB, March J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed. Wiley-Interscience; Hoboken: 2007
• 2a Caine D. In Comprehensive Organic Synthesis, Vol. 3. Trost BM, Fleming I. Pergamon; Oxford: 1991. Chap. 1.1, 1-63
• 2b Reetz MT. Angew. Chem., Int. Ed. Engl. 1982; 21: 96
• 3a Parthasarathy G, Hart R, Jamro E, Miner L. Clean Technol. Environ. Policy 2005; 7: 219
• 3b Metzger JO, Eissen M. C. R. Chim. 2004; 7: 569
• 3c Jenck JF, Agterberg F, Droescher MJ. Green Chem. 2004; 6: 544
• 4a Huang F, Liu Z, Yu Z. Angew. Chem. Int. Ed. 2016; 55: 862
• 4b Obora Y. Top. Curr. Chem. 2016; 374: 1
• 4c Obora Y. ACS Catal. 2014; 4: 3972

For reviews on borrowing-hydrogen methodology, see:
• 5a Corma A, Navas J, Sabater MJ. Chem. Rev. 2018; 118: 1410
• 5b Faisca Phillips AM, Pombeiro AJ. L, Kopylovich MN. ChemCatChem 2017; 9: 217
• 5c Chelucci G. Coord. Chem. Rev. 2017; 331: 1
• 5d Yang Q, Wang Q, Yu Z. Chem. Soc. Rev. 2015; 44: 2305
• 5e Nandakumar A, Midya SP, Landge VG, Balaraman E. Angew. Chem. Int. Ed. 2015; 54: 11022
• 5f Ketcham JM, Shin I, Montgomery TP, Kriche MJ. Angew. Chem. Int. Ed. 2014; 53: 9142
• 5g Pan S, Shibata T. ACS Catal. 2013; 3: 704
• 5h Obora TD, Ishii Y. Synlett 2011; 2011: 30
• 5i Bähn S, Imm S, Neubert L, Zhang M, Neumann H, Beller M. ChemCatChem 2011; 3: 1853
• 5j Dobereiner GE, Crabtree RH. Chem. Rev. 2010; 110: 681
• 5k Guillena G, Ramón DJ, Yus M. Chem. Rev. 2010; 110: 1611
• 5l Watson AJ. A, Williams JM. J. Science 2010; 329: 635
• 5m Nixon TD, Whittlesey MK, Williams JM. J. Dalton Trans. 2009; 753
• 5n Hamid MH. S. A, Slatford PA, Williams JM. J. Adv. Synth. Catal. 2007; 349: 1555
• 5o Guillena G, Ramón DJ, Yus M. Angew. Chem. Int. Ed. 2007; 46: 2358

For reviews on acceptorless dehydrogenation of alcohols, see:
• 6a Crabtree RH. Chem. Rev. 2017; 117: 9228
• 6b Khusnutdinova JR, Milstein D. Angew. Chem. Int. Ed. 2015; 54: 12236
• 6c Gunanathan C, Milstein D. Chem. Rev. 2014; 114: 12024
• 6d Gunanathan C, Milstein D. Science 2013; 341: 1229712
• 6e Gunanathan C, Milstein D. Acc. Chem. Res. 2011; 44: 588
• 7a Das UK, Ben-David Y, Leitus G, Diskin-Posner Y, Milstein D. ACS Catal. 2019; 9: 479
• 7b Paudel K, Pandey B, Xu S, Taylor DK, Tyer DL, Torres CL, Gallagher S, Kong L, Ding K. Org. Lett. 2018; 20: 4478
• 7c Nielsen M, Junge H, Kammer A, Beller M. Angew. Chem. Int. Ed. 2012; 51: 5711
• 7d Sølvhøj A, Madsen R. Organometallics 2011; 30: 6044
• 7e Gnanaprakasam B, Ben-David Y, Milstein D. Adv. Synth. Catal. 2010; 352: 3169
• 7f Gunanathan C, Shimon LJ. W, Milstein D. J. Am. Chem. Soc. 2009; 131: 3146
• 7g Zhang J, Leitus G, Ben-David Y, Milstein D. J. Am. Chem. Soc. 2005; 127: 10840
• 8a Chakraborty S, Daw P, Ben-David Y, Milstein D. ACS Catal. 2018; 8: 10300
• 8b Tan D.-W, Li H.-X, Zhu D.-L, Li H.-Y, Young DJ, Yao J.-L, Lang J.-P. Org. Lett. 2018; 20: 608
• 8c Sahoo AR, Lalitha G, Murugesh V, Bruneau C, Sharma GV. M, Suresh S, Achard M. J. Org. Chem. 2017; 82: 10727
• 8d Jiménez MV, Fernández-Tornos J, Modrego FJ, Pérez-Torrente JJ, Oro LA. Chem. Eur. J. 2015; 21: 17877
• 9a Aitchison H, Wingad RL, Wass DF. ACS Catal. 2016; 6: 7125
• 9b Xie Y, Ben-David Y, Shimon LJ. W, Milstein D. J. Am. Chem. Soc. 2016; 138: 9077
• 9c Kozlowski JT, Davis RJ. ACS Catal. 2013; 3: 1588
• 10a Chaudhari C, Siddiki SM. A. H, Shimizu K.-i. Top. Catal. 2014; 57: 1042
• 10b Makarov IS, Madsen R. J. Org. Chem. 2013; 78: 6593
• 11a Liu T, Wang L, Wu K, Yu Z. ACS Catal. 2018; 8: 7201
• 11b Roy BC, Debnath S, Chakrabarti K, Paul B, Maji M, Kundu S. Org. Chem. Front. 2018; 5: 1008
• 11c Shee S, Paul B, Panja D, Roy BC, Chakrabarti K, Ganguli K, Das A, Das GK, Kundu S. Adv. Synth. Catal. 2017; 359: 3888
• 11d Wang Q, Wu K, Yu Z. Organometallics 2016; 35: 1251
• 12 Thiyagarajan S, Gunanathan C. J. Am. Chem. Soc. 2019; 141: 3822
• 13 Ji J, Liu P, Sun P. Chem. Commun. 2015; 51: 7546
• 14 Zhu X, Ye C, Li Y, Bao H. Chem. Eur. J. 2017; 23: 10254
• 15 Rey J, Hu H, Snyder JP, Barrett AG. M. Tetrahedron 2012; 68: 9211
• 16a Kong W, Yu C, An H, Song Q. Org. Lett. 2018; 20: 349
• 16b Xia Z.-H, Zhang C.-L, Gao Z.-H, Ye S. Org. Lett. 2018; 20: 3496
• 17 Akhtar WM, Cheong CB, Frost JR, Christensen KE, Stevenson NG, Donohoe TJ. J. Am. Chem. Soc. 2017; 139: 2577
• 18a Thiyagarajan S, Gunanathan C. ACS Catal. 2018; 8: 2473
• 18b Krishnakumar V, Gunanathan C. Chem. Commun. 2018; 54: 8705
• 18c Thiyagarajan S, Gunanathan C. ACS Catal. 2017; 7: 5483
• 18d Krishnakumar V, Chatterjee B, Gunanathan C. Inorg. Chem. 2017; 56: 7278
• 18e Chatterjee B, Gunanathan C. Chem. Commun. 2016; 52: 4509
• 18f Chatterjee B, Gunanathan C. Org. Lett. 2015; 17: 4794
• 19 Anaby A, Schelwies M, Schwaben J, Rominger F, Hashmi AS. K, Schaub T. Organometallics 2018; 37: 2193
• 20 Chakraborty S, Lagaditis PO, Förster M, Bielinski EA, Hazari N, Holthausen MC, Jones WD, Schneider S. ACS Catal. 2014; 4: 3994