The scope and mechanism of phosphonium-mediated S(N)Ar reactions in heterocyclic amides and ureas.
An efficient "one-step" synthesis of cyclic amidines and guanidines has been developed. Treatment of cyclic amides and ureas with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), base, and nitrogen nucleophiles leads to the formation of the corresponding cyclic amidines and guanidines, typically in good to excellent yields. This method has also been used to prepare heteroaryl ethers and thioethers using phenol and thiophenol nucleophiles. Time course NMR and HPLC-MS studies have facilitated explicit characterization of the proposed intermediates (the phosphonium salt and HOBt adduct); the data reveal a stepwise reaction pathway.
Wan
Zhao-Kui
ZK
Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA. zwan@wyeth.com
Wacharasindhu
Sumrit
S
Levins
Christopher G
CG
Lin
Melissa
M
Tabei
Keiko
K
Mansour
Tarek S
TS
D000577:Amides / Q000737:chemistry*; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry; D000586:Amination; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013997:Time Factors; D014508:Urea / Q000737:chemistry*
D000577:Amides; D000578:Amidines; D006146:Guanidines; D009943:Organophosphorus Compounds; D012997:Solvents; C031032:benzotriazol-1-yloxy-tris(dimethylamino)phosphonium; D014508:Urea