A Homolytic Substitution Approach for Directing Group-Free Nickel-Catalyzed Dialkylation of Unactivated Alkenes

Fei Cong; Jun Wei Ng; Ming Joo Koh

doi:10.1055/a-2352-4902

Synlett, Table of Contents

Synlett 2025; 36(03): 199-205
DOI: 10.1055/a-2352-4902

synpacts

A Homolytic Substitution Approach for Directing Group-Free Nickel-Catalyzed Dialkylation of Unactivated Alkenes

Fei Cong

^aDepartment of Chemistry, National University of Singapore, 4 Science Drive 2, Republic of Singapore, 117544

,

Jun Wei Ng

^aDepartment of Chemistry, National University of Singapore, 4 Science Drive 2, Republic of Singapore, 117544

,

Ming Joo Koh ∗

^aDepartment of Chemistry, National University of Singapore, 4 Science Drive 2, Republic of Singapore, 117544

› Author Affiliations

Abstract

All articles of this category

Abstract

The selective construction of two C(sp³)–C(sp³) bonds through trimolecular cross-coupling of unactivated alkenes remains one of the most difficult challenges in organic synthesis. Despite previous advances in metal-catalyzed coupling for the dicarbofunctionalization of alkenes, dialkylation is still problematic due to the instability of the requisite metal–alkyl intermediate, which undergoes facile β-hydride elimination or protodemetalation. Recently, our group was successful in developing a bimolecular homolytic substitution (S_H2) strategy that circumvents metal–alkyl side reactions and accomplishes the challenging cross-coupling of metal–alkyl intermediates with alkyl radicals in the absence of a directing auxiliary, permitting a highly regioselective dialkylation of unactivated alkenes.

1 Introduction

2 Nickel-Catalyzed Dicarbofunctionalization of Unactivated Alkenes

3 Nickel-Catalyzed Dialkylation of Unactivated Alkenes

4 Conclusions and Perspectives

Key words

nickel catalysis - dialkylation - unactivated alkenes - bimolecular homolytic substitution - radicals

Full Text

References

References and Notes

1a Slayden, S. W.; Liebman, J. F. In The Chemistry of Functional Groups Supplement A3: The Chemistry of Doubly-Bonded Functional Groups, Patai, S. (ed.), Wiley, Chichester, 1997.
1b Multicomponent Reactions in Organic Synthesis. Zhu J, Wang Q, Wang M.-X. Wiley-VCH; Weinheim: 2015

2a Geist E, Kirschning A, Schmidt T. Nat. Prod. Rep. 2014; 31: 441
2b Derosa J, Tran VT, van der Puyl VA, Engle KM. Aldrichimica Acta 2018; 51: 21

3 Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752

For selected examples, see:

4a Jensen KH, Sigman MS. Org. Biomol. Chem. 2008; 6: 4083
4b McDonald RI, Liu GS, Stahl SS. Chem. Rev. 2011; 111: 2981
4c Yin G, Mu X, Liu G. Acc. Chem. Res. 2016; 49: 2413
4d Zhang J.-S, Liu L, Chen T, Han L.-B. Chem. Asian J. 2018; 13: 2277
4e Dhungana RK, Kc S, Basnet P, Giri R. Chem. Rec. 2018; 18: 1314
4f Tu H.-Y, Zhu S, Qing F.-L, Chu L. Synthesis 2020; 52: 1346
4g Badir SO, Molander GA. Chem 2020; 6: 1327

For selected examples, see:

5a Wu L, Wang F, Wan X, Wang D, Chen P, Liu G. J. Am. Chem. Soc. 2017; 139: 2904
5b Ouyang X.-H, Song R.-J, Hu M, Yang Y, Li J.-H. Angew. Chem. Int. Ed. 2016; 55: 3187
5c Qi X, Diao T. ACS Catal. 2020; 10: 8542
5d Qin T, Cornella J, Li C, Malins LR, Edwards JT, Kawamura S, Maxwell BD, Eastgate MD, Baran PS. Science 2016; 352: 801
5e Gu J.-W, Min Q.-Q, Yu L.-C, Zhang X. Angew. Chem. Int. Ed. 2016; 55: 12270
5f Guo L, Tu H, Zhu S, Chu L. Org. Lett. 2019; 21: 4771
5g García-Domínguez A, Mondal R. Angew. Chem. Int. Ed. 2019; 58: 12286
5h Campbell MW, Compton JS, Kelly CB, Molander GA. J. Am. Chem. Soc. 2019; 141: 20069
5i Sun S.-Z, Duan Y, Mega RS, Somerville RJ, Martin R. Angew. Chem. Int. Ed. 2020; 59: 4370
5j Mega RS, Duong VK, Noble A, Aggarwal VK. Angew. Chem. Int. Ed. 2020; 59: 4375

6a Jana R, Pathak TP, Sigman MS. Chem. Rev. 2011; 111: 1417
6b Hu X. Chem. Sci. 2011; 2: 1867

7a Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
7b Seechurn CC. C. J, Kitching MO, Colacot TJ, Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 5062

8 Tasker SZ, Standley EA, Jamison TF. Nature 2014; 509: 299
9 Derosa J, Tran VT, Boulous MN, Chen JS, Engle KM. J. Am. Chem. Soc. 2017; 139: 10657
10 Derosa J, van der Puyl VA, Tran VT, Liu M, Engle KM. Chem. Sci. 2018; 9: 5278
11 Derosa J, Kleinmans R, Tran VT, Karunananda MK, Wisniewski SR, Eastgate MD, Engle KM. J. Am. Chem. Soc. 2018; 140: 17878
12 Zhang J.-X, Shu W. Org. Lett. 2022; 24: 3844
13 Basnet P, Kc S, Dhungana RK, Shrestha B, Boyle TJ, Giri R. J. Am. Chem. Soc. 2018; 140: 15586
14 Li W, Boon JK, Zhao Y. Chem. Sci. 2018; 9: 600

15a Wang H, Liu C.-F, Martin RT, Zhao H, Gutierrez O, Koh MJ. Nat. Chem. 2022; 4: 188
15b Wang Z.-C, Luo X, Zhang J.-W, Liu C.-F, Koh MJ, Shi S.-L. Nat. Catal. 2023; 6: 1087

16 Yang T, Jiang Y, Luo Y, Lim JJ. H, Lan Y, Koh MJ. J. Am. Chem. Soc. 2020; 142: 21410
17 García-Domínguez A, Li Z, Nevado C. J. Am. Chem. Soc. 2017; 139: 6835
18 Shu W, García-Domínguez A, Quiros MT, Mondal R, Cardenas DJ, Nevado C. J. Am. Chem. Soc. 2019; 141: 13812

19a Liu W, Lavagnino MN, Gould CA, Alcázar J, MacMillan DW. C. Science. 2021; 374: 1258
19b Tsymbal AV, Bizzini LD, MacMillan DW. C. J. Am. Chem. Soc. 2022; 144: 21278
19c Mao E, MacMillan DW. C. J. Am. Chem. Soc. 2023; 145: 2787
19d Sakai HA, MacMillan DW. C. J. Am. Chem. Soc. 2022; 144: 6185
19e Gould CA, Pace AL, MacMillan DW. C. J. Am. Chem. Soc. 2023; 145: 16330

20 During the course of preparing our manuscript, a paper on alkene dialkylation involving S_H2 mechanism appeared on ChemRxiv: Wang J. Z., Lyon W. L., MacMillan D. W. C.; Nature; 2024, 628: 104; also published as a preprint: ChemRxiv 2023, DOI: 10.26434/chemrxiv-2023-q4whd
21 Cong F, Sun G.-Q, Ye S.-H, Hu R, Rao W, Koh MJ. J. Am. Chem. Soc. 2024; 146: 10274
22 Zhou W, Dmitriev IA, Melchiorr P. J. Am. Chem. Soc. 2023; 145: 25098

23a Barreiro EJ, Kümmerle AE, Fraga CA. M. Chem. Rev. 2011; 111: 5215
23b Gant TG. J. Med. Chem. 2014; 57: 3595
23c Steverlynck J, Sitdikov R, Rueping M. Chem. Eur. J. 2021; 27: 11751

24 Sakakibara Y, Itami K, Murakami K. J. Am. Chem. Soc. 2024; 146: 1554