The 2‐Pyridyl Problem: Challenging Nucleophiles in Cross‐Coupling Arylations

Abstract

Xinlan Cook received her MChem degree from the University of York in 2017, completing her master's thesis during ayear-long placementa tF.Hoffmann-La Roche (Basel, Switzerland),synthesising novel molecules for the treatment of Alzheimer's disease. She is now completing her doctoral research in the group of Prof. M. C. Willis at the University of Oxford, investigating novel reagents for C(sp 2 )ÀC(sp 2 )d esulfinative cross-coupling reactions. Antoine de Gombert graduated from Chimie ParisTech and UniversitØ Pierre et Marie Curie with aDiplôme d'IngØnieur and MSci. After working on visible light catalysis at CSIRO (Australia), he completed a6 -month internship at F. Hoffmann-La Roche in Switzerland. He is currently aPhD student with Prof. M. C. Willis at the University of Oxford, where his research focuses on the mechanistica spects of palladium-catalysed desulfinative cross-coupling reactions. Janette McKnight obtained her MChem degree from the University of Bath in 2017. During this time, she undertook an industrial placementy ear in process chemistry at GSK Stevenage, before returning to complete afinal year project in the field of CÀH activation with Prof. C. Frost. She moved to the University of Oxford for postgraduate study,where she is currently working on C(sp 2 )ÀC(sp 3 )desulfinativec ross-coupling reactions under the supervision of Prof. M. C. Willis.

Recent Advances in Synthetic Transformations with Robust Yet Reactive B(dan) Moiety

“…Around the same time, Yoshida and Tsuchimoto achieved the direct SMC with diverse aryl-B(dan), demonstrating even robust C(aryl)-B(dan) bonds could be smoothly activated without acidic deprotection (Scheme 68).74 The use of KOtBu as a base under anhydrous conditions is also the key to the successful reaction, and11 B NMR experiments revealed that a transmetalation-active borate species was generated only with KOtBu. Synthetic significance of this method was demonstrated by the smooth SMC with -B(dan), which provides convenient and effective solution to "2-pyridyl problem" in the conventional SMC 49. A quite similar SMC was also reported by Mutoh and Saito.…”

“…Borylative substitution of organic halides with (pin)B-B(dan) was found to be also feasible with a copper catalyst; a variety of alkyl, alkenyl, aryl and heteroaryl halides were smoothly coupled with (pin)B-B(dan) to give the respective R-B(dan) in high yields (Scheme 28) 48. Especially, it should be noted that 2-pyridyl-B(dan) obtained by this reaction shows excellent stability toward aqueous work-up and isolation by Florisil column chromatography, being in stark contrast to the well-known instability of its B(OH) 2 -and B(pin)-counterparts 49. Formation of a ring-opened product in the reaction of cyclopropylmethyl bromide would imply that one-electron transfer process is involved in the reaction pathway (Scheme 29), and a proposed catalytic cycle is shown in Scheme 30.…”

Synform Issue 2021/10

“…This synthetic challenge has been recognised in the literature and it is frequently referred to as the '2-pyridyl problem'. 6 Professor Leonori said: "I learned about the difficulties in making and handling 2-borylated pyridines and other azines while I was working with Prof. Varinder Aggarwal in Bristol (UK). Indeed, one of the projects I contributed to was aimed at the development of novel transition-metal-free cross-couplings between C2-lithiated pyridines and alkyl boronic esters.…”

Inhibition of (dppf)nickel-catalysed Suzuki-Miyaura cross-coupling reactions by α-halo-N-heterocycles

“…10,11 Despite this, many synthetic methods that are readily deployed using aryl substrates are not easily applied to the synthesis of heterocyclic compounds; a salient example is the poor stability of 2-pyridylboronic acids, such that 'slow release' alternatives such as trifluoroborates or MIDA boronates are required. 12 Here we describe the identification of dinickel(II) species that readily form in catalytic reactions where α-halo-N-heterocycles are present; these are inert towards transmetalation with organoboron and organotin reagents, but undergo reaction with Grignard reagents. These complexes are therefore not competent for Suzuki-Miyaura cross-coupling reactions but do not impede Kumada-Tamao-Corriu crosscoupling reactions.…”