C(sp³)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (S_NAr)

Abstract

Conspectus The asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums. While investigating the lithiation chemistry of ureas (a “Cinderella” sister of the more established amides and carbamates), we noted an unexpected Truce–Smiles (T-S) rearrangement involving the 1,4-N → C transposition of a urea N ′-aryl group to the α-carbanion of an adjacent N -benzyl group. Despite this reaction formally constituting an S N Ar substitution, we found it to be remarkably tolerant of the electronic properties of the migrating aryl substituent and the degree of substitution at the carbanion. Moreover, in contrast to classical S N Ar reactions, the rearrangement was sufficiently rapid that it took place under conditions compatible with configurational stability in an organolithium intermediate, enabling enantiospecific arylation at benzylic stereogenic centers. Experimental and computational studies confirmed a low kinetic barrier to the aryl migration arising from the strong preference for a trans arrangement of the urea N ′-aryl and carbonyl groups, populating a reactive conformer in which spatial proximity was enforced between the carbanion and N ′-aryl group, hugely accelerating ipso -substitution. This discovery led us to uncover a whole series of conformationally accelerated intramolecular N → C aryl transfers using different anilide-based functional groups, including a diverse range of urea, carbamate, and thiocarbamate-substituted anions. Products included enantioenriched α-tertiary amines (including α-arylated N-heterocycles) and alcohols, as well as rare α-tertiary thiols. Synthetically challenging diarylated centers with differentiated aryl groups featured heavily in all product sets. The absolute enantiospecificity (retention versus inversion) of the reaction was dependent on the heteroatom α to the lithiation site: the origin of this stereodivergence was probed both experimentally and computationally. Asymmetric variants of the rearrangement were realized by enantioselective deprotonation, and connective strategies were developed in which an intermolecular C–C bond-forming event preceded the anionic rearrangement. Substrates where the N ′-nucleofuge (at the aryl ipso position) was tethered to the migrating arene allowed us to use the rearrangement as a ring expansion method to generate 8- to 12-membered medium-ring ...

A regiodivergent Truce–Smiles rearrangement: a strategy for the synthesis of arylated indoles promoted by KN(SiMe3)2

“…15 The T-S rearrangement 11 can also produce arylated products via a 2-electron pathway and is similar to S N Ar reactions. While Truce-Smiles rearrangement reactions generally require electron-withdrawing groups, the original work by Truce 16 and recent studies by Clayden 17,18 and others 19,20 have demonstrated that electron-withdrawing groups are not always needed.…”

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

“…[8] Shibata et al demonstrated an asymmetric synthesis of CF 3 -substituted nine-membered heterocycles by Pd-catalyzed decarboxylative ring expansion strategy, [9] and the enantioselec-tive construction of medium ring bridged biaryls is noteworthy. [10] Ring expansion is a particularly appealing approach to the synthesis of medium rings, [11] and we previously reported the racemic ring expansion, by a conformationally accelerated intramolecular S N Ar reaction, [12] of benzo-fused heterocycles (ring size n) to provide cyclic ureas with ring size n + 3 (Scheme 1b). [13] In this paper, we now show that a related ring expansion can be rendered asymmetric by the employment of a chiral lithium amide base, and furthermore that the acid-promoted 'azatropic shift' [14] of the product ureas, which induces re-contraction back to a benzo-fused nitrogen heterocycle of ring size n + 1, is remarkably stereochemically retentive.…”

“…Optimal conditions for bases 3 and 4 (entry 7) and found to be comparable, with slightly higher er from 3. We assume that DMPU [18] induces the formation of a solvent-separated ion pair that engages rapidly in the unactivated S N Ar reaction [12,19] required for enantioselective ring expansion.…”

Truce‐Smiles Rearrangement of Diaryliodonium Salts in Ionic Liquids

“…Only the original work (Scheme 1b) and more recent works by Clayden have proven effective. [3,5] On the other hand, the diversity of the Truce-Smiles rearrangement can be expanded by altering the migrating aromatic rings or the leaving linker groups. [3] To date, the linking atom (A) including carbon, [6] nitrogen, [7] phosphorous, [8] oxygen, [9] or most commonly, sulphur in sulfones, [10] have been documented to be suitable for these AÀ C aryl migrations.…”