Enantioselective Intramolecular α‐Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

Abstract

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N'-aryl-N-benzyl-Nisopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to > 99 % ee. Treatment with acid induces an "azatropic shift" with retention of configuration, the product of which may be hydrolysed to the target amine.

Benzo‐fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re‐contraction of Cyclic Ureas

“…CD spectra of other compounds 2 e , 6 a , 6 e , and 8 h showed similar negative bands at 220 nm (see SI). We therefore conclude that other structural analogues are homochiral with 2 i , which has a configuration consistent with the stereochemically retentive migration of the aryl ring [15] to the S configured organolithium that we expect to be formed using the R enantiomer of 3 .…”

“…N-Benzyl ureas [15] and amides [16] are deprotonated enantioselectively by chiral lithium amide bases. The most successful bases have been 3 or 4 (Table 1) combined with a hindered (for example, N-i-Pr-substituted) substrate.…”

Chemical Insights into Oxidative and Nitrative Modifications of DNA

“…The carbo- Once formed, the radical at C1 can be further oxidized to form a carbocation, while in the presence of molecular oxygen, a peroxyl radical is formed, followed by the release of a superoxide anion and the formation of a carbocation at the C1 position. The carbocation formed by either of the above two pathways is hydrolyzed by water; this process is accompanied by the release of the base and the formation of 2 -deoxyribonolactone [140], which is unstable and undergoes β-elimination of 3 -phosphate to provide a butenolide that has a half-life of 20 h in single-stranded DNA (32-54 h in duplex DNA), followed by rapid elimination and δ-elimination of 5 -phosphate on heating or at a basic pH to form 5-methylenfuran-2-one (5MF) [141][142][143] (Figure 37). The reaction of the C2′ radical of the 2′-deoxyribose in DNA with O2 generates a peroxyl radical, which is subsequently transformed into an oxyl radical.…”

Aryne‐Enabled C−N Arylation of Anilines

“…[9,10] Likewise, Smiles-Truce transformations have received renewed attention in the recent literature, as they can enable common functional groups such as aryl sulfonamides, sulfinamides, and ureas to be used as C-arylating agents under mild conditions. [11,12] Aniline addition to benzyne is a known reaction, [13] whereas the postulated rearrangement step through a strained four-membered, spirocyclic transition state has very little precedent. There are, however, many examples of analogous 4-membered transition state aryne rearrangements onto carbonyl groups (e.g.…”