A Computational Study of C–H Bond Abstraction in β-Amino Alcohols: O-side Activation over N-side via Boronate Adduct Formation

Nil Sanosa; Adrián Gómez-Suárez; Ignacio Funes-Ardoiz

doi:10.1055/a-2714-8611

Synthesis
DOI: 10.1055/a-2714-8611

Paper

Published as part of the Special Issue in Honor of Prof. Franziska Schoenebeck, the 2025 Women in Chemistry Award Winner

A Computational Study of C–H Bond Abstraction in β-Amino Alcohols: O-side Activation over N-side via Boronate Adduct Formation

Authors

Nil Sanosa

¹Departamento de Química, Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Complejo Científico Tecnológico, Universidad de La Rioja, Logroño, Spain
Adrián Gómez-Suárez

²Organic Chemistry, Bergische Universität Wuppertal, Wuppertal, Germany
Ignacio Funes-Ardoiz

¹Departamento de Química, Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Complejo Científico Tecnológico, Universidad de La Rioja, Logroño, Spain

Abstract

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Abstract

A density functional theory (DFT) study was performed to evaluate the reaction mechanism underlying the chemoselective C–H abstraction in β-amino alcohols under a photoredox-catalyzed platform. Our results support a three-step mechanism based on the formation of a highly activated tetracoordinated boronate adduct followed by a selective hydrogen atom transfer (HAT) and a Giese-type radical addition, which together generate the experimentally observed γ-oxo-δ-amino esters. We demonstrated that α-hydroxy C–H bonds are more readily activated toward the HAT step than the α-amino C–H bond. This enhanced chemoselectivity arises from the tetracoordinated boronate adduct, which increases the hydridic character of the α-hydroxy H atom and lowers the bond dissociation enthalpy (BDE) of the C–H bond.

Keywords

Density functional theory - β-Amino alcohols - Chemoselectivity - Boron activation - Reaction mechanism - HAT

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References

References

1a Rogge T, Kaplaneris N, Chatani N. et al. Nat Rev Methods Primers 2021; 1: 43
1b Hartwig JF, Larsen MA. ACS Cent Sci 2016; 2: 281-292
1c Karimov RR, Hartwig JF. Angew Chem Int Ed 2018; 57: 4234-4241

2a Wang F, Wang B, Wang Q, Wang L. Eur J Org Chem 2024; e202401206
2b Nechab M, Mondal S, Bertrand MP. Chem Eur J 2014; 20: 16034-16059
2c Yi H, Zhang G, Wang H. et al. Chem Rev 2017; 117: 9016-9110
2d Chu JCK, Rovis T. Angew Chem Int Ed 2018; 57: 62-101
2e Capaldo L, Quadri LL, Ravelli D. Green Chem 2020; 22: 3376-3396
2f Yi W, Liu J, Hu X. Chem Commun 2025; 61: 407-418

3a Wang J, Zhou F, Xu Y, Zhang L. Chem Asian J 2025; e202401114
3b Kumar V, Singh A, Sharma R. Tetrahedron 2025; 105: 123456
3c Jiang Y, Li H, Tang H. et al. Chem Sci 2025; 16: 962-969

4 Galeotti M, Salamone M, Bietti M. Chem Soc Rev 2022; 51: 2171-2223

5a Shaw MH, Shurtleff VW, Terrett JA, Cuthbertson JD, MacMillan DWC. Science 2016; 352: 1304-1308
5b Le C, Liang Y, Evans RW, Li X, MacMillan DWC. Nature 2017; 547: 79-83
5c Ye J, Kalvet I, Schoenebeck F, Rovis T. Nat Chem 2018; 10: 1037-1041
5d Ryder ASH, Cunningham WB, Ballantyne G. et al. Angew Chem Int Ed 2020; 59: 14986-14991
5e Askey HE, Grayson JD, Tibbetts JD. et al. J Am Chem Soc 2021; 143: 15936-15943
5f Jeffrey JL, Terrett JA, MacMillan DWC. Science 2015; 349: 1532-1536
5g Tian Y, Liu Z-Q. Green Chem 2017; 19: 5230
5h Twilton J, Christensen M, DiRocco DA, Ruck RT, Davies IW, MacMillan DWC. Angew Chem Int Ed 2018; 57: 5369-5373
5i Niu L, Liu J, Liang XA, Wang S, Lei A. Nat Commun 2019; 10: 467
5j Wang Y, Carder HM, Wendlandt AE. Nature 2020; 578: 403
5k Gorelik DJ, Dimakos V, Adrianov T, Taylor MS. Chem Commun 2021; 57: 12135
5l Carder HM, Suh CE, Wendlandt AE. J Am Chem Soc 2021; 143: 13798
5m Zhang YA, Gu X, Wendlandt AE. J Am Chem Soc 2022; 144: 599-605
5n Shen Y, Funez-Ardoiz I, Schoenebeck F, Rovis T. J Am Chem Soc 2021; 143: 18952-18959
5o Muñoz-Molina JM, Bafaluy D, Funes-Ardoiz I. et al. Organometallics 2022; 41: 1099-1105
5p Sanosa N, Montiel-Cervantes C, Rubio-Muñoz M, Sampedro D, Funes-Ardoiz I. Synlett 2024; 35: 1149-1152

6 Merkens K, Sanosa N, Funes-Ardoiz I, Gómez-Suárez A. ACS Catal 2022; 12: 13186-13192
7 Kepp KP. Inorg Chem 2016; 55: 9461

8a Li YM, Xu M, Lai MT. et al. Nature 2000; 405: 689-694
8b Leung D, Abbenante G, Fairlie DP. J Med Chem 2000; 43: 305
8c Ghosh AK, Bilcer G, Schiltz G. Synthesis 2001; 2001: 2203-2229
8d Concellon J, Rodriguez-Solla H. Curr Org Chem 2008; 12: 524-543

9a Marotta A, Adams CE, Molloy JJ. Angew Chem Int Ed 2022; 61: e202207067
9b Kaiser D, Noble A, Fasano V, Aggarwal VK. J Am Chem Soc 2019; 141: 14104-14109
9c Zhu C, Dong J, Liu X. et al. Angew Chem Int Ed 2020; 59: 12817-12821

10a Lunic D, Sanosa N, Funes-Ardoiz I, Teskey CJ. Angew Chem Int Ed 2022; 61: e202207647
10b Zou W, Gao L, Cao J. et al. Chem Eur J 2022; 28: e202104004

11 Sanosa N, Ambrosi D, Ruiz-Campos P, Sampedro D, Funes-Ardoiz I. Chem Eur J 2023; 29: e202301406
12 Frisch MJ, Trucks GW, Schlegel HB. et al. Gaussian 16, Revision C.01. Wallingford CT: Gaussian, Inc.; 2016
13 Zhao Y, Truhlar DG. Theor Chem Acc 2008; 120: 215-241
14 Hehre WJ, Ditchfield R, Pople JA. J Chem Phys 1972; 56: 2257-2261
15 Cossi MM, Rega N, Scalmani G, Barone V. J Comb Chem 2003; 24: 669-681
16 Álvarez-Moreno M, de Graaf C, López N, Maseras F, Poblet JM, Bo C. J Chem Inf Model 2015; 55: 95-103
17 CYLview 1.0. Legault CY. Université de Sherbrooke, 2020 http://www.cylview.org

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