The directing group wins over acidity: kinetically controlled regioselective lithiation for functionalization of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives

Abstract

Regioselective lithiation followed by functionalization of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives with different electrophiles was achieved in good to excellent yields. When the title compound is treated with n-butyl lithium, lithiation occurs selectively at the aromatic carbon having less acidic proton despite the presence of thermodynamically more acidic 1,3-dithiane proton in the same molecule. Computationally calculated pKa values of the available reactive site protons and the experimental results suggest that the regioselective lithiation in 2-(2,4-dihalophenyl)-1,3-dithiane derivatives is not governed by thermodynamic acidity rather exclusively dictated by the kinetic removal of protons due to cooperative coordination (complex induced proximity effect, CIPE) and inductive effects of the 1,3-dihalo substituents present in the aromatic ring. By employing this regioselective functionalization, diverse 1,2,3,4-tetra-substituted aromatic compounds were prepared with ease.

Barbier Continuous Flow Preparation and Reactions of Carbamoyllithiums for Nucleophilic Amidation

“…The coordination of the formamide moiety to LDA is thus a kinetically determining factor which surpasses C−H acidity and thermodynamic considerations. Similar coordination effects were recently described for rationalizing the regioselectivities of the lithiation of a series of aromatic dithianes, which was mainly controlled by coordination effects and kinetics, rather by than the thermodynamics of lithiation . Thus, the successful development of this Barbier continuous flow metalation of formamides relies more on favourable kinetics of lithiation than on a thermodynamically highly acidic formamide C−H bond.…”

“…[20] According to thesec ompetition experiments, the thermodynamic acidity of formamide 1a was estimated to be pK a % 30 (between 10 a and 10 c,S cheme 4). [18] This ranking was furtherc onfirmed by ab initio calculations.…”

“…Reaction free energies forg eneration of lithiated DMF from monomeric LDA are positive (that is, unfavorable) by 7.2 kcal mol À1 ,w hich is in obvious disagreement with the synthetic and equilibration experiments. [18,20] It remains striking that the lithiation of 1a can be performed in the presence of enolizable ketones like 2a-d which are much stronger CÀHa cids (pK a % 20). [22] The lithiation of DMFi se xergonic by 2.5 kcal mol À1 under these conditions due to favorable Lewis acid/Lewis base interactions between the amide lone pair electrons and the second lithium cation.…”

“…Interestingly, [4e] under theseo ptimized flow conditions, no side-products derived from al ithiation of the electrophile (EÀ X) were found. [17] To explaint he preferential formamide lithiation, we have determined the relative free energies of lithiation of formamide 1a in comparison with other well-known CÀH acids [18] such as 2-phenyl-1,3-dithiane (10 a), 3,5-difluoroanisole (10 b), 3,5-difluorobenzene (10 c)a nd benzothiazole (10 d)b y performing competition experiments using pivaldehyde (2h) as electrophile (Scheme 4). The relative free energies DDG8 of deprotonation (with 1a taken as reference) show that formamide 1a is located between the dithiane (10 a)a nd 1,3-fluorobenzenes (10 b,c)w ith respect to its lithiation preference (Scheme 4).…”

“…Furthermore, the experimental (Scheme 4) and theoretical (Scheme5,r ight scale) DDG of metallation are following similart rends as the reported pK a values of the selected CÀHr eference acids. [18,20] It remains striking that the lithiation of 1a can be performed in the presence of enolizable ketones like 2a-d which are much stronger CÀHa cids (pK a % 20). Scheme2.Continuousf low lithiation of N,N-dimethyl thioformamide( 7a)i n the presence of norcamphor (2i).…”