Development of enantiospecific coupling of secondary and tertiary boronic esters with aromatic compounds

Odachowski, Marcin; Bonet, Amadeu; Essafi, Stephanie; Conti-Ramsden, Philip; Harvey, Jeremy N.; Leonori, Daniele; Aggarwal, Varinder K.

Abstract

The stereospecific cross-coupling of secondary boronic esters with sp² electrophiles (Suzuki-Miyaura reaction) is a long-standing problem in synthesis but progress has been achieved in specific cases using palladium catalysis. However, related couplings with tertiary boronic esters are not currently achievable. In order to address this general problem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an electron from the aromatic ring or react in a Friedel-Crafts-type manner, respectively, generating a cationic species, which would trigger 1,2-migration of the boron substituent, creating the new C-C bond. Elimination (preceded by further oxidation in the former case) would re-sult in rearomatization giving the coupled product stereospecifically. Initial work was examined with 2-furyllithium. Alt-hough the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different steric demands and functional groups (esters, azides, nitriles, alcohols, ethers). The reaction also worked well with other electron rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position. Conditions were also found in which the B(pin)- moiety could be retained in the product, ortho to the boron substituent. This protocol, which created a new C(sp²)-C(sp³) and an adjacent C-B bond, was again applicable to a range of secondary and tertiary boronic esters. In all cases the coupling reaction occurred with complete stereospecificity. Computational studies verified the competing processes involved and were in close agreement with the experimental observations.

Citation

Odachowski, M., Bonet, A., Essafi, S., Conti-Ramsden, P., Harvey, J. N., Leonori, D., & Aggarwal, V. K. (2016). Development of enantiospecific coupling of secondary and tertiary boronic esters with aromatic compounds. Journal of the American Chemical Society, 138(30), 9521-9532. https://doi.org/10.1021/jacs.6b03963

• Journal Article Type: Article
• Acceptance Date: Jul 6, 2016
• Online Publication Date: Jul 22, 2016
• Publication Date: Aug 3, 2016
• Deposit Date: Jul 12, 2016
• Publicly Available Date: Jul 22, 2016
• Journal: Journal of the American Chemical Society
• Print ISSN: 0002-7863
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 138
• Issue: 30
• Pages: 9521-9532
• DOI: https://doi.org/10.1021/jacs.6b03963
• Keywords: Stereospecific, Organoboron, Boronic ester, Synthetic methods, Transition metal-free coupling, Quaternary centres, Computational chemistry, DFT
• Public URL: https://hull-repository.worktribe.com/output/440865
• Publisher URL: http://pubs.acs.org/doi/abs/10.1021/jacs.6b03963
• Additional Information: Copy of article published in: Journal of the American Chemical Society, 2016, v.138, issue 30
• Contract Date: Jul 12, 2016