A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

Abstract

The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pKa values of functionalized N‐, S‐, and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.

Nucleophilic C–H Etherification of Heteroarenes Enabled by Base-Catalyzed Halogen Transfer

“…Thus, existing routes for N -heteroaryl C–H etherification require independent synthesis of a functionalized arene followed by an alcohol substitution reaction. A common strategy in this regard involves heteroaryl N -oxide or N -triflyl formation en route to nitro-, cyano-, or phosphonium-substituted azines. − Alternatively, a two-step metalation/halogenation sequence provides heteroaryl halides; however, this often requires irreversible metalation and a directing group for good selectivity. − Thus, a new activation strategy is likely required if N -heteroaryl C–H etherification is to be achieved in a single operation. In addition to increased synthetic efficiency, a new oxidative coupling method could complement the scope, selectivity, and practicality of existing routes to aromatic ethers.…”

Reliable Functionalization of 5,6‐Fused Bicyclic N‐Heterocycles Pyrazolopyrimidines and Imidazopyridazines via Zinc and Magnesium Organometallics

“…We have initiated our investigations by calculating the p K a ‐values of all ring protons in compounds 1 a , 1 b , 2 a and 2 b as well as the BF 3 ‐complex 2 c using previously developed computational protocol [10e] (Figure 1). These p K a ‐values clearly indicated that position 7 of the pyrazolo[1,5‐ a ]pyrimidines 1 b is the most acidic and should be selectively metalated.…”

Synthesis of Natural Products by C−H Functionalization of Heterocycless

“…The most classic type of C−H functionalization relies on the direct deprotonation of acidic C−H bonds [50] . In this respect, direct deprotonation of heterocycles is highly attractive owing to the differential acidity of heterocyclic C−H bonds [51] . This approach has been found particularly effective for the C−H functionalization of electron‐deficient heterocycles, while directing group effect can be used for their electron‐rich counterparts.…”