Synthesis of 1-Arylcycloalkenamines by Intramolecular Arylation of Lithiated Ureas

Abstract

The deprotonation of N′-arylurea derivatives of cyclohexenamines by alkyllithiums leads to migration of the N′-aryl substituent from N′ to the allylic position α to N via rearrangement of a urea-stabilised allyllithium intermediate. The product ureas may be solvolysed to reveal 1-arylcyclohexenamines.

Modern Aspects of the Smiles Rearrangement

“…In principle, these diarylallylamine ureas could be oxidized to provide access to amino acid derivatives. The rearrangement of N ‐allyl ureas was also reported for the multigram synthesis of 1‐arylcycloalkenamines …”

“…The rearrangement of N-allyl ureas was also reported for the multigram synthesis of 1-arylcycloalkenamines. [54] The Clayden rearrangement suggests ad irect route to a-arylated non-natural amino acids using amino acid derived ureas 125.H owever,t he direct transformation of ureas to these valuable products was complicated by hydantoin (126)f ormation followinga ryl migration of amino acid enolates (Scheme 37). [55] Use of an N-(4-methoxybenzyl) protecting group provided ar oute to the desired amino acid derivatives, through oxidative deprotection and hydrolysis of the hydantoin.…”

Pseudoephedrine‐Directed Asymmetric α‐Arylation of α‐Amino Acid Derivatives

“…[2] Ar ange of methods for the asymmetric a-alkylation of readily available amino acids makes simple quaternary amino acids bearing a-alkyl groups readily accessible. [16] Electron-deficient rings may be introduced intra- [17][18][19][20] or intermolecularly [21][22][23] by stereoselective aryne or S N Ar chemistry.Maruoka et al [24] achieved an asymmetric phase-transfer arylation with Cr complexes of electron-rich arenes.We previously reported [25] ar acemic approach to the synthesis of a-aryl amino acids that makes use of the rearrangement of N-aryl urea derivatives [26][27][28][29][30] of amino acid enolates with migration of an aromatic ring from NtoC.The reaction formally involves an intramolecular nucleophilic aromatic substitution reaction, [31,32] but is much more general with regard to ring electronics than atypical S N Ar reaction. [16] Electron-deficient rings may be introduced intra- [17][18][19][20] or intermolecularly [21][22][23] by stereoselective aryne or S N Ar chemistry.Maruoka et al [24] achieved an asymmetric phase-transfer arylation with Cr complexes of electron-rich arenes.…”

“…[3][4][5][6][7][8][9] There are far fewer options for the asymmetric introduction of aryl rings [10,11] to the a-carbon atom of a-amino acids to make quaternary a-arylated amino acids,and those that exist suffer from severe limitations in scope.R acemic a-arylations have been achieved through Pd [12][13][14] or Fe [15] catalyzed reactions of enolates to form heterocyclicamino acid derivatives,with an asymmetric version requiring ac omplex multi-step sequence. [16] Electron-deficient rings may be introduced intra- [17][18][19][20] or intermolecularly [21][22][23] by stereoselective aryne or S N Ar chemistry.Maruoka et al [24] achieved an asymmetric phase-transfer arylation with Cr complexes of electron-rich arenes.We previously reported [25] ar acemic approach to the synthesis of a-aryl amino acids that makes use of the rearrangement of N-aryl urea derivatives [26][27][28][29][30] of amino acid enolates with migration of an aromatic ring from NtoC.The reaction formally involves an intramolecular nucleophilic aromatic substitution reaction, [31,32] but is much more general with regard to ring electronics than atypical S N Ar reaction. [33] Kawabata et al [34] simultaneously reported ac hiral memory effect in ar elated reaction that allowed certain members of the class of a-aryl a-amino acid derivatives to be prepared with good enantioselectivity.Aiming to solve the problem of asymmetric arylation of amino acids,particularly with electron-rich rings,wedecided to start from Myers very general methods for asymmetric alkylation, [8,9,35,…”

“…We previously reported [25] ar acemic approach to the synthesis of a-aryl amino acids that makes use of the rearrangement of N-aryl urea derivatives [26][27][28][29][30] of amino acid enolates with migration of an aromatic ring from NtoC.The reaction formally involves an intramolecular nucleophilic aromatic substitution reaction, [31,32] but is much more general with regard to ring electronics than atypical S N Ar reaction. [33] Kawabata et al [34] simultaneously reported ac hiral memory effect in ar elated reaction that allowed certain members of the class of a-aryl a-amino acid derivatives to be prepared with good enantioselectivity.…”